Solid-Supported Reagents and Catch-and

Transcription

REVIEW
2409
Solid-Supported Reagents and Catch-and-Release Techniques in Organic
Synthesis
Solid-Sup ortedReagentsandCatch-and-Rel aseTechniques Solinas, Maurizio Taddei*
Antonio
Dipartimento Farmaco Chimico Tecnologico, Università di Siena, Via A. Moro 2, 53100 Siena, Italy
Fax +39(0577)234275; E-mail: [email protected]
Received 2 April 2007; revised 10 May 2007
Abstract: The use of polymer-supported reagents, catalysts and
scavengers (and their appropriate combinations) represents a powerful approach for the synthesis of organic compounds, using both
traditional and parallel solution-phase methodologies, and it has
been of great interest in recent years, especially in the field of pharmaceutical research. Polymer-supported synthesis circumvents the
need to bind the substrate to a solid support, and thereby allows for
the reactions to be monitored with familiar analytical techniques.
The purpose of this publication is to review the recent synthetic
transformations (from 2001) carried out with solid-supported reagents, including the catch-and-release techniques, which represent
a hybrid approach in between scavenging and solid-phase synthesis.
1
2
3
4
5
5.1
5.2
6
6.1
6.2
7
8
9
Introduction
Oxidation
Reduction
Protection and Deprotection
Carbon–Carbon Bond Formation
Catch-and-Release Strategies
Reagents for Carbon–Carbon Bond Formation
Carbon–Heteroatom Bond Formation
Reagents for Carbon–Heteroatom Bond Formation
Multistep Procedures
Conclusions
Notes Added in Proof
Key words: solid-supported reagents, polymer-bound reagents,
parallel synthesis, catch and release, combinatorial chemistry
1
Introduction
Solid-phase organic synthesis (SPOS) is routinely used in
the pharmaceutical industry for the preparation of libraries of small organic molecules for screening purposes.
The advantages of this strategy have been thoroughly described in the literature: excess reagents can be employed
to help drive the reactions to completion, mere washing of
the solid phase is required to remove impurities and excess reagents, and a vast number of compounds can be
synthesised using well-established techniques for an increased molecular diversity.1
The SPOS methodology does, however, have limitations.
These include: (a) possible presence of resin vestiges in
the final molecules (functionality employed to attach the
molecule to the solid support), (b) the need for two extra
SYNTHESIS 2007, No. 16, pp 2409–2453xx. 207
Advanced online publication: 24.07.2007
DOI: 10.1055/s-2007-983806; Art ID: E18007SS
© Georg Thieme Verlag Stuttgart · New York
steps in any synthetic strategy (i.e. the attachment of the
starting material to the solid support and the removal of
the final compound from the resin), (c) severe scale limitations connected to the loading capacity of the solid support, (d) monitoring of the reaction and the reaction
products attached to the resin, and (e) the need to re-optimise the solution-phase chemistry on the solid support of
choice.
A possible alternative that maintains some of the advantages of SPOS but circumvents many of the previous limitations is the synthesis of organic compounds employing
polymer-supported reagents, scavengers and catalysts
(Scheme 1).
Although the use of polymer-supported reagents has been
reported since the 1960s,2 interest has grown rapidly in recent years especially within the field of pharmaceutical research, in which high-throughput screening requires large
amounts of products (10–100 mg) of high purity (> 90%)
in focused libraries.3
Parallel libraries prepared with solid-supported reagents
(SSRs) and scavengers address all these issues, as SSRaided reactions are often very clean and high-yielding, excess reagent can be employed to drive the reaction to completion, and the work-up involves only simple operations
of filtration and evaporation of the solvent. Moreover, the
course of the reaction and the purity of the intermediates
and products can be monitored using straightforward
techniques such as HPLC-MS, GC-MS or standard
NMR).
Solid-Phase Synthesis
substrate + reagents
recovered
excess/spent
product(s) + reagents
Product(s)
on beads
SSR-Assisted Solution-Phase Synthesis
substrate + reagents
product(s)
excess
substrate
product(s)
in solution
reagent + substrate
excess
+ product(s)
and
spent reagent
product(s)
in solution
Scheme 1 General scheme of solid-phase organic chemistry versus
solid-supported reagent-assisted solution-phase synthesis
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A. Solinas, M. Taddei
Among the different possibilities in polymer-assisted organic synthesis (supported reagents, catalysts and scavengers), this review covers solid-supported reagents. These
include compounds that are bound to the resin support either covalently or ionically, used as stoichiometric reagents, allowing for selective transformations of certain
functionalities and the formation of new bonds.
However, as another powerful concept has emerged with
the idea of SSR application to parallel library synthesis,
some space will be dedicated to catch-and-release techniques. The use of suitably functionalised polymer supports to selectively capture the required product away
from any contaminating impurities, allowing for its recovery (catch and release) in pure form, constitutes a sort of
hybrid between scavenging and solid-phase synthesis. In
the sections regarding the carbon–carbon and carbon–heteroatom bond-forming strategies, the use of catch-and-release strategies is described when it represents a synthetic
strategy and the resin-bound compounds allow transformations that result in the formation of new bonds. The
‘Multistep Procedures’ section reviews the application of
multiple solid-supported reagents for complex syntheses
and mentions scavengers as well, although the systematic
use of solid-supported agents to scavenge by-products and
excess starting materials (which allows for the purification of the reaction products generated in solution) is left
out, as it represents primarily a purification technique. For
the systematic use of scavengers4 and supported catalysts,5 the reader may benefit from several recent review
articles.
2
Oxidation
In recent years, the hypervalent iodine reagent 1-hydroxy1,2-benziodoxol-3(1H)-one 1-oxide (IBX) has attracted
substantial interest because of the mild conditions required for the oxidation of alcohols to aldehydes or ketones.6 However, IBX is insoluble in most organic
solvents with the exception of dimethyl sulfoxide, and this
is a drawback that has often limited the practical applica-
Biographical Sketches
Antonio Solinas (on the left) was
born in Sassari, Italy, in 1971. After a
degree in chemistry from the University of Sassari, he received his PhD
from the University of Southampton
(UK) in 2002. In Southampton, he
worked in the group of Professor
Tom Brown, in the research area of
modified oligonucleotides. Since
2004, he is working with Professor
Maurizio Taddei at the University of
Siena. Currently, his research inter-
ests are focused on the areas of solidsupported reagents and the synthesis
of novel ‘hedgehog signalling pathway’ inhibitors.
Maurizio Taddei (on the right) was
born in Florence in 1955 and obtained his doctoral degree in Chemistry in 1979 from the Department of
Organic Chemistry of the University
of Florence.
1984, and Associate Professor at the
Faculty of Agronomy of the University of Florence in 1992. In 1994 he
became Professor of Organic Chemistry at the Faculty of Science at the
University of Sassari, and since 2001
he is Professor of Organic Chemistry
at the faculty of Pharmacy of the University of Siena. In 1990 he was
awarded the G. Ciamician silver
medal of the Organic Chemistry Division of the Italian Chemical Soci-
ety. He is author of more than 150
papers in scientific journals in the
field of organic synthesis, bioorganic
chemistry and medicinal chemistry.
His fields of interest are in natural
product and biologically active product synthesis, high-throughput organic synthesis, and development of
microwave-assisted synthetic methodologies.
After a post-doctoral stay at the University Chemical Laboratories in
Cambridge (UK) with Prof. Ian
Fleming, he became Research Assistant at the University of Florence in
Synthesis 2007, No. 16, 2409–2453
© Thieme Stuttgart · New York
REVIEW
Solid-Supported Reagents and Catch-and-Release Techniques
tion of this reagent. Consequently, some research groups
have reported the synthesis of polymer-supported IBX reagents and their use in oxidative reactions.
The preparation of polymer-supported IBX reagents had
been independently reported by three different groups, all
of which used a similar approach – binding the IBX precursor 1 to the solid support, followed by activation of the
reagents (Scheme 2).
O
X
O
2
HO
a
b
+
I
c
d
I
1
O
7
I O
O OH
COOH
O
NH2
SiO2
O
COOt-Bu
O
N
H
SiO2
3
I
O
SiO2
O
O
N
H
6
5
I
O
I
determined via oxidation of benzyl alcohol to benzaldehyde in dichloromethane and was found to be in good
agreement with loadings obtained for other polymer-supported IBX reagents.
COOH
O
2411
8
Scheme 3 Synthesis of polymer-supported IBX reagent 8. Reagents
and conditions: (a) suspension polymerisation, AIBN, PVA (87–89%
hydrolysed), 2-ethylhexan-1-ol, heat; (b) I2, NaIO4, H2SO4, Ac2O,
AcOH, CH2Cl2, r.t., 24 h; (c) KMnO4, methyltri-n-octylammonium
chloride, H2O, CH2Cl2, heat, 24 h; (d) NBu4SO5H, MeSO3H, CH2Cl2,
r.t., 5 h.
O
I
4
HO
O
Scheme 2 A general scheme of the polymer-supported IBX reagent
4 via binding of the precursor to the solid support and subsequent activation to generate the active compound
Each of the three methods, however, involved the synthesis of the IBX precursors via elaborate synthetic steps.
The starting material was 2-amino-5-hydroxybenzoic acid, which was coupled onto appropriately functionalised
supports such as macroporous supports,6 gel-type PSbased support (PS = polystyrene),7 or silica gel.8 After a
subsequent activation step, the supported IBX reagents
were able to carry out the fast and efficient conversion of
alcohols to aldehydes or ketones.
A mild and efficient procedure for the oxidation of alcohols with a polymer-supported IBX reagent in the presence of triethylamine in dichloromethane was reported by
Lei and collaborators, who prepared 2 by anchoring 2iodo-5-hydroxy benzoic acid to an aminomethyl-polystyrene resin elongated with different spacers. Polymer-supported reagent 2 was used to oxidise substituted benzyl
alcohols and biphenyl alcohols to the corresponding compound efficiently, in good-to-excellent yields and purities:
recycling was possible at least four times without any obvious loss of activity.9
A more recent synthesis of a solid-supported IBX reagent
did not require a late-stage linkage step, and thus the incorporation of potentially labile covalent bonds into the
supported reagent was avoided.10
The synthesis of IBX reagent 8 was carried out completely on solid support (Scheme 3), although a limitation of
the method was that the preparation started from the noncommercially available polymer 5. The loading of 8 was
A reaction protocol that employs dichloromethane as the
solvent and an oxidant-to-alcohol ratio of 2:1 was established; this resulted in the transformation of alcohols to
the corresponding aldehydes in five hours (Table 1).
Polymer-supported IBX 8 oxidised both electron-rich and
electron-deficient benzyl alcohols to the corresponding
benzaldehydes in excellent yields and purity. However,
Table 1 Oxidation of a Series of Alcohols Using Polymer-Supported IBX Reagent 8
Entry
Alcohol
Conversion
(%)
Selectivity
(%)
1
HO
86
98
2
HO
100
100
3
HO
100
100
52
82
100
100
OMe
NO2
4
5
5
O
OH
OH
O
Synthesis 2007, No. 16, 2409–2453
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oxidation of a primary alkyl alcohol proved to be more
difficult, and lower yields were obtained even when the
reaction times were longer. The kinetics of the oxidation
of hydroquinone by the supported iodoxybenzoic acid in
a stirred batch reactor have been investigated.11 A first-order dependence on the concentration of the substrate hydroquinone and the supported IBX reagent was observed
and effects related to intraparticle diffusion were studied.
The performance of the supported reagent in a packed bed
was also studied by continuous flow of a solution of hydroquinone. The product quinone concentration profile at
the reactor exit showed limited dependence on the flow
rates that were studied.
Polymer-supported IBX esters 10 and amides 12 were
prepared by use of a two-step strategy.12 The first step involved the coupling of 2-iodobenzoic acid to a hydroxy or
amino polystyrene, and was followed by activation of the
intermediate products 9 and 11 (Scheme 4). These reagents were tested as oxidants for the conversion of benzyl alcohol into benzaldehyde, highlighting better
performances by IBX amide derivative 12 (one-hour reaction, with an oxidant-to-alcohol ratio of 2:1 using 12).
Table 2 Results of Alcohol Oxidation Using the Polymer-Supported IBX Amide 12
Entry
Alcohol
Conversion (%)
1
HO
>99
2
HO
>99
NO2
3
OMe
4
>99
6
5
OH
a
O
c
O
>99
HO
OH
81
OH
O
O I
10 O
I
9
O
O
NH2
b
H
N
c
O
I
11
H
N
O
O
I
O
O
12
Scheme 4 Synthesis of polymer-supported IBX esters and amides.
Reagents and conditions: (a) 2-iodobenzoic acid, DIC, DMAP, DMF,
r.t., 18 h; (b) 2-iodobenzoic acid, BOP, HOBt, DIPEA, DMF, r.t., 4 h;
(c) NBu4SO5H, MeSO3H, CH2Cl2, r.t., 18–20 h.
The explanation for the increased activity of 12 is related
to the fact that, compared to the IBX ester oxidant, the carbonyl oxygen of the IBX amide can enter into a stronger
intramolecular non-bonding interaction with iodine. Consequently, this leads to the formation of a favorable equilibrium state between 12 and a cyclic IBX derivative. The
polymer-supported IBX amides displayed excellent oxidative activity, and different alcohols were transformed
into the corresponding aldehydes or ketones (see Table 2).
The introduction of an additional spacer between the polymer support and IBX amide group (Figure 1) improved
the initial conversion rate (up to 60% conversion) of alcohols into the corresponding aldehyde or ketone.13
This was particularly evident when the oxidation of longchain alkyl alcohols, such as decan-1-ol, was carried out.
In particular, while a moderate rate enhancement was observed for the IBX amide resins with a short spacer (bAla, 14) and longer spacer (w-AUA, 16), in the case of the
IBX amide resin with the e-ACA spacer (15) the converSynthesis 2007, No. 16, 2409–2453
N
H
I
O
O
O
N
H
13
O
n
I
O
N
H
14 (n = 1)
15 (n = 4)
16 (n = 9)
Figure 1 Structure of IBX-amide resin with spacers of different
lengths: 14 (0.59 mmol/g); 15 (0.60 mmol/g); 16 (0.57 mmol/g); 17
(0.54 mmol/g).
sion was increased significantly from 17% to 63% after 12
hours of reaction. Thus, it was confirmed that the observed spacer effects were consistent with the hypothesis
that the accessibility of the IBX amide toward decan-1-ol
was an important factor in increasing the reaction rate.
Moreover, an additional rate enhancement was achieved
when various alcohols were treated with the IBX amide
resin 15 in the presence of boron trifluoride–diethyl etherate complex. The alcohols were effectively converted into
the corresponding aldehydes or ketones, within 5–30 minutes, in high purities (>94%) at room temperature.
Polymer-supported 2-iodoxybenzoic acid reagents have
been used in the development of an efficient procedure14
for the highly selective oxidation of leucomycines to the
corresponding 16-membered 9-oxo and 13-oxo macrolides. Polymer-bound IBX oxidants show clear advantages over the previously employed manganese dioxide.
Different polymer-supported hypervalent iodine reagents
were described; these bore (diacetoxy)iodo (18 in
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Scheme 5), (dihalo)iodo, (hydroxy)(tosyloxy)iodo, (hydroxy)(phosphoryloxy)iodo, aryliodonium, 1,2-benziodoxol-3-one, and hypervalent iodine groups as counter
anions.15 These reagents were used for various oxidative
functional group conversions. Polymer-supported (diacetoxyiodo)benzene16 was employed in the oxidative cyclisation of ketoximes 17 to give isoxazoline 19 in excellent
yields and purity (Scheme 5). Compound 19 is an important intermediate for the synthesis of marine sponge metabolites such as aerophobin-1, aerothionin, and
homoaerothionin.
2413
The immobilisation of arylselenyl bromides 23a and 23b
was exploited to carry out oxyselenenylation reactions on
(E)-styrylacetic acid in water, to give crotonolactone 26
(Scheme 7). The best results were obtained with amphiphilic polymer-supported 23b, which was prepared
from poly(ethylene glycol)–polystyrene graft co-polymer
resin (ArgoGel®-NH2).18
SeBr Ph
24
Se
COOH
23a
Ph
O 25
O
H2O2, r.t.
OMe
OMe
Br
Br
Br
I(OAc)2
Ph
59–62%
26
18
HO
CH2NHCO(CH2)3
O
MeCN
O
NOH
SeBr
19
Scheme 5 Use of polymer-supported (diacetoxyiodo)benzene 18 in
a spirocyclisation reaction
A polystyrene-supported diazidoiodate(I) reagent was reported to give radical azidonation reactions, providing a
useful alternative to the use of the dangerous reagent iodoazide (IN3).17 Reagent 22 was synthesised starting from
supported tetraalkylammonium iodide 20 treated with diacetoxyiodobenzene and trimethylsilyl azide. Compound
22 was also used in acetonitrile at 83 °C to convert aldehydes into acyl azides and benzyl ethers into azido ethers
(Scheme 6).
+
–
+
PhI(OAc)2
NMe3I
–
NMe3I
PhI(N3)2
+
–
NMe3I
22
HO
Ph
O
OMOM
Br
28
Se
Se
29
O(CH2)2OMe
O
O(CH2)2OMe
OMOM
SeBr
quant.
30
O
O
O
R1
R2
O
OMOM
N3
22
R1
23b
A chiral (enantiomerically pure) polymer-bound selenenylbromide reagent, 30 (Scheme 8), was prepared starting
from polystyrene, TentaGel, or mesoporous silica solid
supports.19
Br2, 0 °C
TMSN3
N3
SeBr
OAc
OAc
21
20
23a
Scheme 7 Selenolactonisation and deselenenylation reactions of
(E)-styrylacetic acid using polymer-supported arylselenenyl bromide
23a
27
O
NHCO(CH2)3
n
O
OMe
17
SeBr
=
N
COOMe
O
O
O
Br
R1
N3
N
Se
OR
H
Ph
31
Me3SnH, AIBN
N3
22
OMOM
30, MeOH
O
R2
60%
OMe
OMe
32 up to 80% ee
Scheme 6 Synthesis and applications of the new supported diazidoiodate(I) 22
Scheme 8 Synthesis of reagent 30 on solid support and its employment in stereoselective selenenylation reactions
Arylselenyl halides are useful reagents for electrophilic
addition to double bonds to give organoseleno compounds
that are versatile intermediates in organic synthesis. However, most organoselenium reagents are insoluble in water, or decompose in its presence, thus their utility in nonanhydrous solvents is limited. The problem may be solved
by employing polymer-supported arylselenenyl bromides
such as 23a and 23b.
These selenium reagents were employed in enantioselective selenylation reactions in the presence of a nucleophile
on substrates such as styrene and styrene derivatives. The
intermediate supported selenyl adduct 31 was cleaved
with tin hydrides in the presence of 2,2¢-azobis(isobutyronitrile) (AIBN; radical conditions) to give up to 80% ee
in the products 32, a result almost comparable to those obtained using soluble (and therefore more difficult to remove) counterparts of 30.
Synthesis 2007, No. 16, 2409–2453
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REVIEW
Sheng and co-workers20 reported the synthesis of polymer-supported b-bromoethyl selenide 33, which was easily transformed into phenolic ether resins 35 via a catchand-release mechanism (Scheme 9). Oxidation–elimination of 35 was very rapid and efficient under an excess of
30% hydrogen peroxide at room temperature, to afford a
number of high-purity crude aryl vinyl ethers 36 in good
yields.
tones using excess 42 and oxalyl chloride. In these
reactions, the polymer-supported thioanisole-based reagents 41 could be recovered, regenerated and reused.
JandaJel™
cross-linker
C2H4
SeCH2CH2Br
SeBr
THF, r.t.
23
OH
34
K2CO3, NBu4I, KI
DMF, r.t.
R H2O2
40
JJ
R1
R
O
Se
SO2Ar
Ar
37
R
38
O
TFA
56–87%
–
OTf
43
O
42, (COCl)2, Et3N
63–85%
R2
R1
R2
–
+
JJ
The supported benzeneselenosulfonate 37 was used to
catch terminal alkynes that were transformed into supported alkenylselenylsulfones 38. These products were released from the resin, by trifluoroacetic acid, to give the
corresponding b-ketosulfones 39 (Scheme 10).21
R
S
OCH CH2
36
S O
+
JJ
S
42
LDA
–
+
JJ
S OTf
Scheme 9 Synthesis of aryl vinyl ethers using polymer-supported
b-bromoethyl selenide 33
Se
MeOTf
O
OH
THF, r.t.
35
41
TBHP,
PTSA
33
SeCH2CH2O
S
AlBH2NH
S
R
JJ
S
44
43
O
R1
R2
69–98%
R2
O
R1
45
Scheme 11 Synthesis of polystyrene-bound reagents 42 and 43
from 41 and their use in oxidation and epoxidation reactions
An alternative system for metal-free alkene epoxidation
reactions was based on a PS-supported phthalic anhydride
and urea–hydrogen peroxide complex (UHP). Resin 46
was prepared by microwave-mediated PEGylation of
Merrifield resin followed by esterification with trimellitic
anhydride chloride (Scheme 12).23
SO2Ar
R
39
Cl
Scheme 10 Synthesis of b-ketosulfones using supported benzeneselenosulfonate 37
O
n
The reagent 44 was used with substrates such as para-substituted benzaldehyde and benzophenone derivatives, and
furnished the corresponding epoxides in good yields.
However, the reactions with ketones afforded slightly
higher yields. The thioanisole reagent 41 was also oxidised to form the insoluble sulfoxide reagent 42, which
was employed in Swern oxidations. A number of secondary alcohols were transformed into the corresponding keSynthesis 2007, No. 16, 2409–2453
O
O
O
46
O
O
O
n
OH
n
O
O
22
Choi and Toy described a new cross-linked polystyrenebound thioanisole reagent (41) that served as a building
block for the preparation of sulfur-based reagents for organic synthesis (Scheme 11). This supported thioanisole
derivative 41 was prepared directly from 40 which was incorporated into a flexible JandaJel cross-linker support.
When treated with methyl trifluoromethanesulfonate, it
formed the corresponding sulfonium salt 43, which, in
turn, was deprotonated to form polymer-supported sulfur
ylide 44. This was able to react with aldehydes and ketones to form epoxides (45 in Scheme 11).
O
O
O
COOH
O
47
COOOH
R2
47, UHP, CH2Cl2
R1
Scheme 12
R2
O
R1
Epoxidation of alkenes using 47 and UHP
Two methods for the synthesis of aldehydes and ketones
from primary and secondary alcohols, based on the use of
a co-oxidant [tetrapropylammonium perruthenate (TPAP)
and 2,2,6,6-tetramethylpiperidine-N-oxide (TEMPO), respectively], were described independently by the research
groups of Kerr and Kirschning (Scheme 13).24
Polymer-supported amine N-oxide 48 was synthesised
from commercially available supported morpholine and
REVIEW
was employed as an efficient, selective, and readily recyclable co-oxidant in the TPAP oxidation of alcohols.24a
The oxidation reactions were made more efficient by the
addition of activated 4 Å molecular sieves to the reaction
mixture prior to the introduction of the TPAP.
The oxidation of activated alcohols proceeded well: the
yields obtained for secondary alcohols, such as 1-methylbenzyl alcohol, were reasonably good, while the oxidation
of non-activated primary alcohols proceeded somewhat
less efficiently.
and aromatic aldehydes with different functional groups
(see Table 3).
Table 3 Oxidations of Aldehydes to Carboxylic Acids with SolidSupported Oxidants
Aldehyde
Conditionsa and yield (%) of
corresponding acid
1
PhCHO
A: 99, D: 89
2
4-MeC6H4CHO
A: quant, D: 90
3
4-MeC6H4CHO
A: 96, D: 92
4
4-allylOC6H4CHO
A: 68, D: 98
5
4-BnOC6H4CHO
A: 61, D: 93
6
4-O2NC6H4CHO
A: quant, C: 89
7
4-NCC6H4CHO
A: quant, C: 84
8
4-MeO2CC6H4CHO
A: quant, C: 90
9
Ph
D: 93
10
Ph
Entry
a or b
O–
N
N+
O
48
O
OAc
+
+
–
NMe3Br
PhI(OAc)2, CH2Cl2, r.t.
NMe3 Br
2415
–
OAc
49
48, TPAP (20 mol%)
4 Å MS (activated)
CH2Cl2, r.t., 24 h
OH
CHO
11
49–100% (ref. 24a)
B: 84, C: 84
CHO
B: 92, C: 88
CHO
O
OTBS
R1
R2
49 (3 equiv), CH2Cl2,
40 °C, 24 h, TEMPO (cat.)
R1
R2
81–94% (ref. 24b)
Scheme 13 Synthesis of supported reagents 48 and 49 and their use
as co-oxidants in the TPAP- and TEMPO-mediated oxidation of alcohols. Reagents and conditions: (a) N-(phenylsulfonyl)phenyloxaziridine (4 equiv), CH2Cl2, r.t., 4 h; (b) MCPBA (3 equiv), CH2Cl2, r.t., 4
h.
12
OBn
13
The bromate(I) polymer itself was found not to be broadly
applicable in the oxidation of alcohols, but when employed in conjunction with a catalytic amount of TEMPO,
the system proved well suited for the synthesis of carbonyl compounds. The transformation was carried out in very
high yields: it is noteworthy that aldehydes with a stereogenic center in the a-position were generated without racemisation of the chiral center. Although the advantages
of the technique are the high purity of the products and
easy recycling of the co-oxidant, studies on cheaper alternatives of 49 (such as polymer-bound hypochlorites) are
under way.
Ley and co-workers25 described three useful methods for
the oxidation of aldehydes to carboxylic acids which employed solid-supported reagents such as phosphate-buffered (PB) silica gel (SiO2), supported potassium
permanganate (KMnO4) and polymer-supported chlorite,
which guarantee a vast compatibility for many aliphatic
B: 90, C: 86
CHO
OTHP
14
B: 90, C: 89
CHO
NHBoc
15
Analogously, polymer-bound bisacetoxybromate(I) 49
was synthesised by oxidative ligand transfer from bisacetoxyiodobenzene onto an anion-exchange resin and was
employed in the preparation of aldehydes and ketones
from alcohols.24b
B: 58, C: 83
CHO
B: 96, C: 87
CHO
NHCbz
16
B: 77, C: 89
O
O
CHO
17
B: 99, C: 91
AcO
AcO
CHO
a
A: PB-SiO2-KMnO4 in cyclohexane at 65 °C; B: PB-SiO2-KMnO4
in cyclohexane at r.t.; C: PS-chlorite, KH2PO4, 2-methylbut-2-ene in
t-BuOH–H2O (5:1); D: PS-chlorite, AcOH, 2-methylbut-2-ene in tBuOH.
Aldehydes have been also transformed into the corresponding hydroxamic acids 51 via a polymer-assisted version of the Angeli–Rimini reaction (Scheme 14).
Supported N-hydroxybenzensulfonamide 50 was prepared by reaction of a PS-SO2Cl with hydroxylamine. After treatment with a solution of sodium methoxide in
methanol, 50 then reacted with several aliphatic, aromatic
and heteroaromatic aldehydes to give the corresponding
hydroxamic acids 51 in very good yields. Different
amounts of the unreacted aldehyde were then sequestered
Synthesis 2007, No. 16, 2409–2453
2416
REVIEW
O O
S
Cl
O O
S
NHOH
NH2OH
50
O
O
50, MeONa, MeOH
H
55–99%
R
tion was carried out with the carbonyl compound as the
limiting reagent.
Some 1-aryl-2-azidoethanols, precursors of important biologically active natural compounds, were prepared via a
new procedure that employs polymer-supported reagents
(Scheme 16).28
NHOH
R
O
51
Scheme 14 A polymer-assisted version of the Angeli–Rimini reaction using supported N-hydroxybenzensulfonamide 50
54
R1
R2
by polystyrene sulfonyl hydrazide (Ps-Ts-NHNH2),
which left behind a solution containing the desired hydroxamic acid, free of starting components (HPLC or
TLC analysis).26
3
Although supported borohydride has been known for a
long time and several kinds of polymeric borohydrides are
commercially available, new examples in this class of reagents are still being reported.
Bhattacharyya and co-workers27 described in 2003 the
synthesis of a polymer-bound triacetoxyborohydride,
which was found to be shelf-stable in the presence of residual tetrahydrofuran. Reagent 52 was synthesised in one
step from a commercially available macroporous triethylammonium methylpolystyrene borohydride (Scheme 15)
that was treated with three equivalents of glacial acetic
acid in anhydrous tetrahydrofuran to give the supported
triacetoxyborohydride in nearly quantitative yields. Reagent 52 was shown to be a powerful reducing system for
reductive amination reactions under mild reaction conditions, and led to secondary and tertiary amines in good to
excellent yields. In this reaction, PS-benzaldehyde was
employed to selectively scavenge the excess of primary
amine and a polymer-bound isocyanate was added to the
reaction mixture to selectively scavenge excess secondary
amine. In the case of secondary amines, reductive amina-
–
+
NEt3BH4
–
NEt3BH(OAc)3
+ 3 AcOH
52
THF, 0 °C
H
N
R2
R1
R3
O
+
R3
52
R4
N3
53
CH2Cl2, 30 °C
30 min
R1
68–95%
55
BH4
57
MeOH, 30 °C
30 min
78–96%
R2
OH
N3
56
R1
R2
Scheme 16 Preparation of b-azidoalcohols 56 using polymer-supported reagents
Reduction
+
O
N3
X
39–93%
R4
N
R1
2
R
R2, R3 = H, alkyl
Scheme 15 Reductive amination using primary and secondary amines. Reagents and conditions: (a) 52 (2.5 equiv), THF; (b) PS-benzaldehyde (R2 = H) or PS-NCO (R2 = alkyl) or MP-TsOH (MP =
macroporous).
Synthesis 2007, No. 16, 2409–2453
The azide resin 53 (prepared by exchange of a sodium
azide solution with a commercial macroporous ion-exchange resin, Amberlite® IRA 900) was utilised as a reagent for the conversion of a-haloketones 54 into aazidoketones 55 (at room temperature and using dichloromethane as solvent). Azidoalcohols 56 were prepared
using a polymer-supported borohydride exchange resin
(PS-BER), which reduced only the ketone, leaving both
azido and aromatic nitro functionalities intact. The reaction products were then ready for further kinetic enzymatic resolution.
Several other applications of supported borohydrides are
reported in the multistep synthetic procedures reviewed
below, in section 6 (Carbon–Heteroatom Bond Formation).
One of the major drawbacks of using triphenylphosphine
in organic synthesis is the fact that the by-product triphenylphosphine oxide often complicates purification of the
reaction mixture. This has been overcome using different
versions of supported arylphosphine, some of them commercially available (see also section 6).29 Among the more
recent applications of supported arylphosphines, Galal
and co-workers30 reported the synthesis of new deoxyartemisinin derivatives. An important synthetic step involved the reduction of artemisin derivative 57 with PSPPh2 (Scheme 17), to give the new dihydrodeoxyartemisitene (58), and the analogue 59 which is a promising
compound that shows significant cytotoxicity against a
number of human cancer cell lines.
Silphos [PCl3–n(SiO2)n] is a reagent that is easily prepared
from the reaction of silica gel and phosphorus trichloride.31 Silphos was used, for example, by Iranpoor et al.
for the formylation and acetylation of alcohols and amines
with ethyl formate and acetate,32 and for the deoxygenation of sulfoxides and reductive coupling of sulfonyl
chlorides.33 Subsequently, the same research group reported another application for Silphos as a cheap and effi-
REVIEW
PPh2
O
O
57
N
O
O
H
92%
H
HCOOH (98%)
+
H
H
O
H
2417
Cl
64
Amberlite® IRA 938, Cl– form
H
O
R
58
OH
OOH
+
N
–
–
HCOO
65
® IRA 938, HCOO– form
Amberlite
65
RhCl(PPh3)3, DMSO
66
R
67
80–95%
H
R = COOH, COOMe, COOEt, CHO, COMe, CN, CONMe2
O
Scheme 19
O
H
O
59
O
Scheme 17 Use of a polymer-supported triphenylphosphine in the
synthesis of compound dihydrodeoxyartemisitene (58), and the analogue 59
cient heterogeneous phosphine reagent for the conversion
of epoxides into their corresponding b-bromoformates or
alkenes.34
A polymer-supported [1,3,2]oxazaphospholidine reagent,
61 (Scheme 18), was used for the clean conversion of
isothiocyanates 62 to isocyanides 63.35
OH
H2N
Cl
Ph
A polymer-supported chiral NADH model was prepared
by the grafting of phenolic compound 69 onto a Merrifield
resin via reaction with a chloromethylated polystyrene derivative (Scheme 20) followed by reduction of the quinoline ring.37
O
MeO
CHO
BnO
NO2
, DMF, K2CO3
N
62
C
Scheme 18
54–96%
N
O
MeO
R*
69
N
N
70
H H O
60
R*
MeO
N
P
O
O
N
71
61, toluene, MW,
140 °C, 30 min to 2.5 h
S
HO
O
61
N
R*
N
Cl
Ph
NEt2
MeO
68
OH
N
H
DMF, K2CO3
NEt2
R
New Amberlite®-based ammonium formate reagent 65
H
R
N
O
C
63
Synthesis of the oxazaphospholidine reagent 61
The optimisation of the reaction was carried out under microwave-assisted conditions. The thus-generated structurally diverse isocyanides 63 were used in Ugi threecomponent coupling reactions, thereby allowing for the
rapid synthesis of a library of drug-like molecules based
upon the 2-isoindolinone-7-carboxamide core template.
A simple procedure for the microwave-assisted hydrogenation of olefinic substrates was based on a recyclable hydrogen donor supported on an ion-exchange resin (which
has the advantage of being relatively inexpensive) and
Wilkinson’s catalyst.36 Polymer-supported formate reagent 65 was synthesised starting from Amberlite® IRA
938 (64; Scheme 19) and used for the reduction of alkenes
in conjunction with Wilkinson’s catalyst. For this reaction, a mixture of formylated reagent, Wilkinson’s catalyst and propenoic acid derivatives in a minimum quantity
of dimethylsulfoxide (0.5 mL) was submitted to microwave irradiation, leading to the formation of the corresponding saturated compounds. The authors regenerated
the supported hydrogen donors five times before they observed an appreciable decrease in the reaction yield.
Ph
71, Mg(ClO4)2
MeCN–benzene,
r.t., 24 h
COOMe
50%, ee = 72%
HO H
Ph
COOMe
Scheme 20 Synthesis of polymer-supported reagent 71 via precursor 70, and its use in the reduction of methyl benzoylformate
Polymer-supported reagent 71 was tested in the asymmetric reduction of methyl benzoylformate in the presence of
magnesium perchlorate in a mixture of acetonitrile and
benzene (1:2), with the result of yields that were low compared to those obtained with its homogeneous version.
The authors rationalised this result by hypothesising that
the absence of a spacer between the polymeric matrix and
the reagent would increase the accessibility of the model.
However, no additional insight on this issue has been reported since.
Bertini and co-workers38 reported a simple catch-and-release methodology for the reduction of ketones to alkanes
(Scheme 21).
The method is based on the condensation of carbonyl
compounds with 1,3-propanedithiol copolymers 72 and
cleavage of the solid-supported 1,3-dithiane derivatives
73 with sodium and ammonia or tributyltin hydride and
AIBN. Polymer 72 was prepared by copolymerisation of
2-[(4-ethenylphenyl) methyl]propane-1,3-diol bisbenzenesulfonate and styrene, subsequent replacement of the
Synthesis 2007, No. 16, 2409–2453
2418
REVIEW
O
SH
R1
72
R1
O
O
NO2
BF3.OEt2
SH
CHCl3, 30 °C
R2
S
R1
R2
O
Scheme 21 A synthetic methodology for the preparation of alkanes
using supported dithiol reagent 72
benzenesulfonate groups with thioacetate moieties, and finally, reduction with lithium aluminum hydride. The
strategy circumvents typical limitations in handling thio
compounds and is amenable to selective reductions of ketones in the presence of an ester or a second ketone group.
The same research group39 carried out the synthesis of
new soluble and insoluble versions of 1,3-dithiane reagents and described an application of these compounds
in the preparation of aldehydes from alkyl halides
(Scheme 22). They prepared cross-linked supports (using
commercial Merrifield resin) with a low concentration of
easily accessed 1,3-dithiane units 74 and tested them in
the synthesis of aldehydes from alkyl halides.
O
N OH
R1
BuLi
–30 °C or
–35 °C
S
O
Li
75
S
O
OR
N O
R1NH2,
CH2Cl2
71–98%
O
O
O
R1
N
H
O
R
82
O
O
R
H
R
Scheme 22 New 1,3-dithiane polymers 74 and their use in the synthesis of aldehydes
Protection and Deprotection
Carbamates are the most popular protecting groups for
amines and several methods for their preparation are
based on the use of supported reagents. Following a report
by Chang, Schultz and co-workers40 that described the use
of a PS-supported nitrophenol ester 76 in tetrahydrofuran
to make activated esters, the Delgado research group41 reported using the same nitrophenol resin in a versatile
method for the synthesis of carbamates. The method used
bis(trichloromethyl) carbonate (BTC) for the in situ generation of a polymer-bound chloroformate resin that, by
sequential one-pot reaction with a variety of alcohols (to
generate the supported reagent 77) and then amines, afforded the corresponding carbamates 78 in high yields and
purities in a catch-and-release fashion (Scheme 23).
Synthesis 2007, No. 16, 2409–2453
ROH,
pyridine,
CH2Cl2
Scheme 24 Synthesis of carbamates using the supported N-hydroxysuccinimide 79
Hg(ClO4).xH2O
S
53–67%
4
O
R = t-Bu, Bn
+
N O
80
81
R1
O
S
Cl
S
R I
SH–
O
BTC,
pyridine,
CH2Cl2
O
S
74
78
Synthesis of carbamates using supported resin 76
S
S
O
DMF, 50 °C
OR
N
R2
A catch-and-release method for the efficient solutionphase parallel synthesis of carbamates 82 in highly pure
form, starting from alcohols and amines, was based on
N-hydroxysuccinimide
(HOSu)
derivative
79
(Scheme 24).42 Apart from the nature of the support, both
the synthetic sequence and the nature of the products obtained were similar to those of the reagent originally reported by Delgado.
79
Cl
R1
RO
O
R = t-Bu, Bn, Me, Et, etc.
Scheme 23
R1
40–99%
O
O
R1R2NH
77
R1
Cl
NO2
61–83%
R'
O
76
[H]
R
S
ROH
OH
O
73
NO2
BTC
Analogously, the PS-HOSu resin 83 (obtained by reaction
of commercially available styrene–maleic anhydride copolymer with a 50% aqueous solution of hydroxylamine)
was employed by Chinchilla et al. for the synthesis of a
polymer-bound reagent for the protection of amino acids.43 The hydroxysuccinimide resin was treated with a
solution of 9-fluorenylmethoxycarbonyl chloride in water
in the presence of potassium carbonate (Scheme 25) in order to attach the Fmoc group to the support. Reagent 84
was then used for the Fmoc-protection of amino acids under standard conditions. The reactions were clean and the
PS-HOSu could be re-used for the preparation of new 84.
The same strategy was adopted for the preparation of
polymer-supported [2,7-di(tert-butyl)-9-fluorenyl]methyl
succinimidyl carbonate (Dtb-Fmoc-P-OSu) 85, which
was used for the synthesis of Dtb-Fmoc-protected amines
and amino acids.44 Later, the same research group45 reported a modification of the method for the synthesis of
two related polymer-supported reagents, Alloc-P-OSu 86
and Proc-P-OSu 87, which were prepared from polymeric
N-hydroxysuccinimide (P-HOSu) and, respectively, allyl
chloroformate or propargyl chloroformate. Compounds
86 and 87 were used as solid-supported reagents for the al-
REVIEW
O
83
N
O
I
+
ROCOCl
O
2419
PPh2 I–
K2CO3
O
OH
84–87
88
O
N
O
O
R
HO
I–
+
I
+
O
PPh2
HO
OH
O
89
O
89
OH
O
O
NH2 84–87, Na2CO3, H2O
R
R1
COOH
O
HO
90 OH
O
OH
Ph2P
NH
R1
O
COOH
HO
O
t-Bu
I
HO
+
O
R=
84
OH
91
OH
OH
85
O
O
92
O
93
Scheme 26 Preparation of O-isopropylidene derivatives of sugars
(such as D-ribose) using supported arylphosphine–I2 complex 88
t-Bu
86
87
Scheme 25 Synthesis of the supported succinimidyl carbonates 84–
87 used in the protection of amines and amino acids
PPh2
HBr, AcOH
PPh2HBr
94
lyloxycarbonyl (Alloc) and propargyloxycarbonyl (Proc)
protection of the amino group.
Polymer-supported carbodiimide was employed for a
cost-effective synthetic strategy for the selective protection of the exocyclic amino function of purine ribo- and
deoxyribonucleosides as N-acyl derivatives.46 The supported carbodiimide allowed for the use of the less expensive and nontoxic acidic form of common protecting
groups, rather than their chloride or anhydride forms.
A number of O-isopropylidene sugar derivatives were
readily prepared using Lewis acids in conjunction with the
dehydrating agent made of polymer-bound arylphosphine–I2 complex 88 (Scheme 26).47 The yields of thermodynamically more stable isopropylidene derivatives
were found to be often higher than those obtained with
other methods. Moreover, the polymer-bound phosphine
oxide, generally obtained from the reaction, can be readily
recovered and reduced to the original phosphine with
trichlorosilane.
Polymer-bound diphenylphosphine hydrobromide 94, obtained from commercial PS-phosphine, was employed for
the introduction and the cleavage of tetrahydropyranyl
ethers 95, as well as for glycosidation of glycols
(Scheme 27). This reagent has been shown to be sufficiently mild to leave labile 2-deoxy glycosidic bonds and
acid-labile protecting groups intact, and has even been
used in interesting reactions in which two glycosidations
were promoted in one pot.48
Polymer-supported ammonium fluoride 100 was employed as an anhydrous source of fluoride ions in order to
achieve rapid removal of an amino acid Fmoc protection
and as a catch method for a solution-phase synthesis of
oligopeptides (103) that eliminates the need for chromatographic purification (Scheme 28).49
94, DHP, CH2Cl2
ROH
94, MeOH
94
MeO
THPO
O
95
OR
MeO
THPO
MeOH
NHTBS
NH2
OMe
THPO
OMe
97
96
MeO
OMe
OH
NHAlloc
95% for
2 steps
NHAlloc
94, MeOH
98 OMe
99 OMe
90%
Scheme 27 Cleavage of THP ethers using polymer-bound diphenylphosphine hydrobromide 94
The deprotected amide ions were captured onto the cationic polymer support 101 and all the by-products derived
from the Fmoc group were removed by washing. The reaction of this resin with an Fmoc amino acid activated as
O-succinimidoyl ester resulted in the formation of a new
peptidic bond (103). This procedure was repeated on the
+
O
FmocHN
N
H
R1
–
O
NR3F
+
–
NR3 N
100
R1
101
N
H
O
R2
FmocHN
102
FmocHN
R2
92–98%
O
H
N
OSu
O
R1
N
H
103
Scheme 28
synthesis
Polymer-supported ammonium fluoride in oligopeptide
Synthesis 2007, No. 16, 2409–2453
2420
REVIEW
dipeptide, and was also found to be practical for the synthesis of relatively large amounts of targeted oligopeptides without chromatographic purification. Ammonium
fluoride 100 used in the reactions was recovered as its ammonium chloride and regenerated to the ammonium fluoride without loss of reactivity.
Polymer-supported potassium thiophenolate 104 was
used for the removal of ester, amide, and thioacetate protecting groups in the presence of methanol (Scheme 29).50
The procedure was devised for the removal of pivaloate
groups that protected indoles, but was found to have a
general applicability for the removal of various protections, such as pivaloate and acetate groups from activated
anilines, selectively in the presence of primary amines and
non-activated anilines. Pivaloate, acetate, benzoate, and
carbonate groups could also be removed from hydroxyl
functionalities, sulfonyl groups from indoles, and acetate
groups from thiols. Moreover, the thiophenolate resin 104
could be used in catalytic amounts in the presence of
methanol, and recycled without loss of activity.
R1
–
S O
1) CH2Cl2, Et3N,
2) Amberlite® IRA 67
NH2 + O2N
1) filtration and evaporation of
the solvent + Et3N
2) MeI, Cs2CO3, DMF
O
HN
105 O N
2
S O
O
N
filtration and evaporation of
the solvent + MeI
S O
106 O N
2
SH
107
Cs2CO3, THF
(MW)
85–95%
NH
108
filtration and evaporation of
the solvent
+
R2NH
S K (cat.)
MeOH 104
O
R2
RO
Ph
Scheme 30 General procedure for polymer-assisted alkylation of
primary amines
O
R2N
O
Cl
ROH
R1O
X
SO3H
109
X R1O
HO
RSH
RS
Scheme 29
gy
X
or
O
The polymer-assisted thiophenolate deprotection strate-
The 4-nitrobenzenesulfonyl (nosyl) protection of a primary or a secondary amine can be removed by the use of solid-supported thiol 107 (Scheme 30).51 The method, which
employed conditions that are compatible with parallel
synthesis, was effective for the deprotection of several
primary and secondary nosyl derivatives and gave the corresponding amines 108. It was also found to be compatible with microwave-assisted conditions.
This strategy was applied to the selective alkylation of primary amines in a parallel mode as well,52 providing a useful and efficient alternative, in particular, for the
monomethylation of primary amines. The method can be
complemented with the use of supported reagents and
scavenger-aided procedures and, as the last step of the reaction is compatible with reductive amination conditions,
it is a useful approach for the conversion of primary
amines into tertiary amines.
The solid-supported strong acid 109 (Amberlyst®-15, Lewatit, Dowex 2030) was applied to the aromatic debenzylation of various functionalised phenols (Scheme 31).53
PhMe
MeOH
R2O
X = CHO or HC=CHNO2
R1 = Me; R2 = Bn, PMB
R1 = Bn; R2 = Me
Scheme 31
109
R2O
HO
110a
110b
X = CHO or HC=CHNO2
R1, R2 = H or Me
Debenzylation reactions using solid-supported acids
Polymer-supported acid 109 was used in stoichiometric
amounts in refluxing toluene, and these conditions were
found to be compatible with several functional groups, including nitrostyrene, which is susceptible to problems
when using the hydrogenation and/or reduction conditions that are otherwise frequently employed for aromatic
debenzylation reactions.
Borane complexes employed for the protection of different types of phosphorus compounds (phosphines, phosphites, and phosphinites) can be removed by treatment
with polymer-supported piperazine or N-methylpiperazine.54 Deprotection conditions have been optimised for
different types of phosphorus compounds. The phosphine
solutions resulting from this protocol can be used directly
in catalytic applications without any additional manipulation.
5
Carbon–Carbon Bond Formation
The formation of a new carbon–carbon bond is one of the
most important functional group transformations in organic chemistry. In spite of this importance, not many
Synthesis 2007, No. 16, 2409–2453
REVIEW
methods have been reported, especially when compared
with the number of examples relating to the formation of
a new carbon–heteroatom bond. This is mainly because of
some incompatibilities found in the use of carbanions and
solid supports. However, several examples show that classical carbon–carbon bond-forming reactions (such as Wittig, Mannich, Claisen or Diels–Alder reactions) can be
carried out with the assistance of polymer supports.
5.1
Resin-bound selenyl bromide 23 was employed to prepare
the new polystyrene-supported a-seleno acetate 112,
which, when treated with lithium diisopropylamide, produced a selenium-stabilised carbanion that could then react with an aldehyde. The alcohol 113, thus caught on the
resin, was oxidised with hydrogen peroxide to give a selenoxide that underwent syn-elimination to give b-keto ester 114 (Scheme 32).21
NaBH4
a-imino acetate 124, both of which were prepared from
chloromethylated resin via two- or three-step reactions
and then used in ene, Mannich and aza-Diels–Alder reactions. Resin-bound glyoxal 123 was obtained from a Merrifield-type resin carrying two different molecular sources
(121 and 122 in Scheme 34) and was transformed into activated imine 124. The reactions of 124 with silyl enolates, Danishefsky’s diene, and alkenes also proceeded
smoothly in the presence of scandium(III) triflate (20
mol%) or ytterbium(III) triflate (50 mol%) to give the corresponding a-amino acid, pyridone, and tetrahydroquinoline derivatives, respectively, in good yields.
O
O
111
CO2Et
O
OH
O
123
oxidative
cleavage
O
124
O
H2O2
COOEt
R
OH
56–87%
113
COOEt
R
126
Ph
Ph
SeBr
23
P
R1
P
Ph
115
NHPMP
NHPMP
OSiMe3
R3
Kobayashi56 reported the synthesis and applications of
polymer-supported glyoxylate monohydrate 123 and
125
HO
114
Selenyl bromide 23 was also employed to prepare a polymer-supported selenoalkylidenetriphenylphosphoranes
116 through addition to preformed alkylidenephosphoranes 115. The thus-generated resin 116 was treated with
an aldehyde to produce compound 117 on the support. For
117 with R1 ≠ H, simple cleavage with trifluoroacetic acid
gave ketone 118, whereas with R1 = H, addition of bromine followed by treatment with dimethyl sulfoxide gave
the homologated aldehyde 120 (Scheme 33).55
R1
O
TFA
Scheme 32 Synthesis of b-ketoesters 114 using the a-seleno acetate
based reagent 112
R1 a,
O
O
Se
NPMP
R1
124, Yb(OTf)3
R1
1) LDA, –78 °C
2) RCHO
OH
O
122 OH
112
OH
O
COOEt
23
R1
R2
O
124, Sc(OTf)3
COR1
O
127
HO
129
NHPMP
128
O
TFA
COR1
NHPMP
PMP = p-methoxyphenyl
Scheme 34 Synthetic strategies for the preparation of 126 and 139
using activated imine 124
Resin-bound imine 131 was used for the preparation of
quinolines 132 based on a Friedländer-type reaction between the resin-bound azomethine and ketones
(Scheme 35). The supported amine can be recycled at the
end of the reaction.57
Se
O
116
O
R1
O
b, 116
c
R2
R2
Br
117
O
121
Se
SeNa
THF, DMF
Ph
oxidation
OH
BrCH2COOEt
SeBr
Ph
Ph
2421
117
R1
d
R2
Se
119
NH2
R2CH2COR1
Se
e
R2CH2CHO
88–93%
N
131
130
118
OMe
OMe
R2
131
R2
MeO
120
Scheme 33 Solid-phase synthesis of ketones and aldehydes.
Reagents and conditions: (a) THF, r.t., 30 min; (b) R2CHO, THF, reflux, 2 h; (c) 25% TFA, CH2Cl2, r.t., 4 h; (d) HBr, CH2Cl2, r.t., 4 h; (e)
DMSO, THF, r.t., 1 h; (f) Br2, CHCl3, r.t., 30 min.
R1
O
50–79%
MeO
N
R1
132
Scheme 35
Friedländer-type strategy for the synthesis of quinolines
Synthesis 2007, No. 16, 2409–2453
2422
REVIEW
Variously substituted methyleneaziridines 133 were assembled on resins through a robust ether linkage. These
products reacted with different Grignard reagents and
electrophiles such as benzyl or allyl halides, under copper
catalysis, to give the corresponding alkylated imines
134.58 These products, cleaved in acidic medium, gave an
array of 1,3-disubstituted propanones 135 with good
yields and purity (Scheme 36).
A microwave-enhanced, rapid, and efficient solid-phase
version of the Sonogashira reaction was applied to the
coupling of 3-haloaryl-substituted resins 136 with various
acetylene derivatives, and gave excellent yields. The corresponding products 138 were obtained after trifluoroacetic acid mediated cleavage of products 137 from the resin
(Scheme 37).59
R
X
O
N
R1MgX, CuI, then
CH2=CHCH2Br
O
R
R1
N
136
NH
R
O
H
137
NH
134
R
R
O
R
Pd(PPh3)2Cl2, CuI
Et2NH, DMF
+
R
filtration,
then H+
133
TFA
138
O
NH2
O
R
Scheme 37
R
A polymer-assisted Sonogashira reaction
1
R
The yields of the reactions, comparing two different versions of the halophenyl resin 136, are presented in
Table 4.
135
Scheme 36
Table 4
Synthesis of 1,3-disubstituted propanones
Comparison of 3-Iodophenyl and 3-Bromophenyl Resins in Polymer-Assisted Sonogashira Coupling Reactions
Entry
Alkyne
1
H
SiMe3
Yielda
Yieldb
94%
97%
Product
H
O
H2N
2
89%
92%
H
O
H2N
3
92%
OH
98%
O
O
H
4
–
NH2
95%
H
NHFmoc
NH2
O
H2N
5
98%
94%
H
NHBoc
NH2
O
H2N
6
0%
H
H2N
a
b
With 3-iodophenyl resin.
With 3-bromophenyl resin.
Synthesis 2007, No. 16, 2409–2453
0%
–
REVIEW
Following up on a previous report on the complete functionalisation of small- and large-diameter bromopolystyrene beads (and their applications for solid-supported
reagents, scavengers and diversity-oriented synthesis),60
Spring and collaborators described the development of a
cost-effective method of derivatising 4-bromopolystyrene.61 The resin was chemically modified, in one-step reactions, to generate a range of functionalised resins for
different chemical purposes. The group carried out the
transformation of co-polymerised 4-bromopolystyrene
into a range of polymer-supported reagents and scavengers by bromine–magnesium exchange using a trialkylmagnesate complex, followed by quenching with a variety
of electrophiles. Wittig reactions, as well as Mitsunobu
and halogenation reactions, were explored to assess the
utility of such resins in organic synthesis.
A polymer-supported phosphorane that behaves as a supported acyl anion equivalent was prepared starting from
supported phosphine and bromoacetonitrile under microwave irradiation. Proton abstraction with triethylamine,
followed by reaction with an activated carboxylate derived from a N-Fmoc a-amino acid, gave the supported
acylphosphorane 141. This caught intermediate can be released using ozone or dimethyldioxirane in order to obtain
the intermediate diketonitrile 142. Nucleophilic displacement of the cyano group with different nucleophiles, followed by reduction with supported borohydride, gave
hydroxyesters or amides 144 (Scheme 38).62
Magnetic nanoparticles (4 nm) were employed as an orthogonal matrix to assist solid-phase reactions. A magnetic-nanoparticle-supported
homogeneous
palladium
catalyst was employed for promoting the Suzuki crosscoupling of an aryl halide, which was on the resin, with
excess arylboronic acid that was in solution. The palladium catalyst was magnetically isolated and recycled from
the reaction mixture by applying an external magnetic
field, while the Suzuki products were recovered by filtration, cleaved from the resin, and purified via recrystallisation.
Recently, the Tanner research group64 reported the development and applications of three new solid-supported reagents for the synthesis of carbonyl compounds and
olefins.
N
Ph
P
1) BrCH2CN, MW, 15 min
2) Et3N
Ph
Ph
P
Ph
CN
139
COOH
Ph
R1
EDC, DMAP
Ph
P
CN
piperidine, R2COCl
NHFmoc
O
140 R1
Ph
O
Ph
P
O
RO
145
O
N
H
O
R1
N
Cl
147
146
R2-MgX
N
R'
H
N
O
141
R1
O
O
1
R
R2
BH4
H
N
O
O
R
O
O
Mg
R1
24–36%
O
R2
144
O
R2
SH
148
Ph
N
S
O
PhMgBr
Ph
O
N
Gao and collaborators described the use of magnetic
nanoparticles as an orthogonal support for polymer-assisted reactions, and demonstrated an application of this strategy for solid-phase Suzuki cross-coupling reactions.
Cl
149
Scheme 38 Polymer-supported phosphorane 141 as a supported
acyl anion equivalent
63
146
The PS-bound Weinreb amide reagent 147 was prepared
by reduction of supported oxime 145 that had been further
acylated. Compound 147 was then treated with different
Grignard reagents for the preparation of carbonyl compounds (Scheme 39).
N
R1
R2
O
H
N
O
O
Scheme 39 Polymer-bound Weinreb amide reagent 147 and its use
in the synthesis of carbonyl compounds
NHR3
HO
R1
O
2
142
NHR3
R3NH2
143
O
O
H
N
O
R
O
Analogous supported S-(2-pyridyl) thioates 149 were synthesised starting from 148 (Scheme 40) and this reagent
was treated with phenylmagnesium bromide to generate
the corresponding carbonyl compounds. In this example,
an overaddition of aliphatic Grignard reagent generated
the tertiary alcohols, thus limiting the method to the synthesis of aryl ketones.
CN
O3 or
CN
O
O
R
FmocHN
2423
Br
Mg
S
O
70%
Ph
Ph
Ph
N
SH
Ph
Scheme 40 Supported S-(2-pyridyl) thioates 149 and their use in the
synthesis of aryl ketones
Synthesis 2007, No. 16, 2409–2453
2424
REVIEW
A solid-supported version of the Peterson methylation reagent was prepared starting from a bromoarene that was
transformed under standard conditions into the supported
bromomethylsilane 150 (Scheme 41).
Polymer-supported allylboron reagents 155 were prepared starting from supported N-sulfonylamino alcohol
153 and different allylboranes (Scheme 42).65 This reagent was able to efficiently transfer the allylic moiety
onto a nucleophile, such as imine 156, in the presence of
boron trifluoride–diethyl etherate complex. In this reaction, the recyclability of the supported reagent was also
demonstrated.
O
B
Me
O
R
S
3
154
O
N
N
SH
156
NHBoc
OH
159
N
Ph
Boc
160
Scheme 43 A stereoselective polymer-assisted synthesis of N-Boc(2S,3S)-3-hydroxy-2-phenylpiperidine (160)
reagent-mediated allylation of Boc-L-phenylglycinal as a
key step (Scheme 43).
Starting from commercial Merrifield resin, a series of new
polymer-bound organotin compounds,67 including resinbound dimethyltin reagents has been prepared.68 Distannanes 162 (Scheme 44) were found to be very effective in
iodine-mediated cyclisation reactions of unsaturated compounds.
HO
R
NaH, DMF
Cl
O
R2SnCl2, R2SnH2,
AIBN, hν, toluene
Sn X
161 R
X = Cl or H
R = Me or Bu
R
5 mol%
Pd(PPh3)4
O
O
Sn R
Sn R
R
B
162
R
N
O
R1
Ar
O
Me
155
BF3.OEt2, THF
94–98%
N
N
N
N
Ph
Me 155
H
N
I
162, C6H6, reflux
N
164
163
I
Ar
R
ArI or ArOTf, Pd(0)
SH
157
O
O
O
161
Sn
Ar
R
165
I2, hν
Ar-I
R
Scheme 44
Scheme 42
1) DIBAL-H, CH2Cl2
–78 °C
2) allyltributyltin
158
MeCN, r.t.
Ph
153
N
CO2Me
OH
H
N
+
N
R1
several steps
Ar
Reagents for Carbon–Carbon Bond Formation
Me
BocHN
23–30%
This compound, activated in the presence of tert-butyllithium, reacted with aldehydes to generate the corresponding
terminal alkene in solution. The reaction was carried out
on several aromatic aldehydes with a range of different
substituents on the aromatic ring.
S
R1
84–99%
R2
+ R2NH2
Polymer-supported Peterson methylation reagent 150
O
HN
91%
Ar
151
R1
SnBu3
OH
Si
5.2
OH
158
150
OH
Scheme 41
Br 1) t-BuLi
2) ArCHO
Si
Br
SO2NHCHCO2H
R1CHO +
New distannane reagents on solid support
Preparation and application of a new allylating agent
The allylation of aldehydes, and imines generated in situ
from aldehydes and amines, with allyltributyltin was promoted by a recoverable and reusable polymer-supported
sulfonamide of N-glycine 158, leading to good to high
yields in various cases.66 Most of the tributyltin residue
was recovered as tributyltin chloride. A highly stereoselective synthesis of N-Boc-(2S,3S)-3-hydroxy-2-phenylpiperidine (160) was carried out using the supported-
Synthesis 2007, No. 16, 2409–2453
The resin-bound tin reagents 161 (X = Cl or H) were successfully used in a catalytic Stille coupling cycle. The resin-bound distannanes were found to be more effective in
atom-transfer-cyclisation reactions than other previously
described resin-bound distannanes. Resin-bound tin reagents 161 were also investigated as potential catch-andrelease reagents for the radioisotopic labelling of aromatic
compounds.67
REVIEW
2425
6
Carbon–Heteroatom Bond Formation
6.1
found to be a suitable activating agent for difficult peptide
couplings, such as reactions involving a,a-dialkyl amino
acids.70
For the synthesis of amides or esters, the classical approach is to catch the carboxylic acid on a resin that carries an activating frame, and then treat the resin with
amines or alcohols in order to release the thus-formed
amide or ester.
O
HN
Br
O
S
N
H
H
N
S
O
166
A similar reagent, 172 [a supported version of 2-(7-aza1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), Scheme 47], was used for the
preparation of a collection of unsaturated sulfonamide hydroxamic acids 174. Compound 171 was prepared by Suzuki coupling and the crude product (mixed with Suzuki
by-products that did not contain the carboxylic group) was
caught by the resin. After washing, resin product 173 was
treated with O-tetrahydropyranylhydroxylamine to relase
the protected hydroxamic acid 174.71
O O
S
N
H
O
N
COOH
S
R1COCl
O
N
O
1
N
R
R2NH2
R2OH
R2SH
O
2
R1
167
R
N
O H
O O
S
N
H
Me2N
O
1
R2
S
R
NMe2
171
O
R
O
N
N
172
2
R1
O
N
O O
S
N
H
O
N
O O
S
N
H
173
N
N
Scheme 45 Acylation of amines, alcohols, and thiols using supported reagent 167
THPONH2
O
An acylated version of a substituted pyrimidine was anchored to a Merrifield-type resin (167 in Scheme 45). Reagent 167 was used to transfer the acylating group to
different amines, alcohols, and thiols with consequent formation of the corresponding amides and esters. At the end
of the process, the support 166 was recovered, reacylated,
and reused.69
A new polymer-supported benzotriazolyl-N-oxy-tris(dimethylamino)phosphonium (BOP) reagent, 169, was prepared starting from commercially available polystyrenebound 1-hydroxybenzotriazole 168 (Scheme 46), and
used for peptide coupling reactions. PS-BOP was also
O O
S
N
H
OH
N
N
N
168
R1 R2
O O
S
N
H
169
FmocHN
Me2N NMe2
Me2N P PF6
O O
O
S
N
N
H
N
N
169
COOH
N
N
N
170
R3NH2
R1 R2
68–82% FmocHN
O
3
CONHR
FmocHN
Scheme 46
A polymer-supported BOP analogue
O
R1
O O
S
N
H
Scheme 47
NHOTHP
174
(33% overall yield)
Polymer-supported HATU coupling agent 174
An analogous two-step procedure was reported for the
parallel synthesis of hydroxamic acids from carboxylic
acids and hydroxylamine in good to high yields.72 It involved the formation of a polymer-bound 1-hydroxybenzotriazole active ester and subsequent reaction with either
O-protected or free hydroxylamine. The hydroxamates
were isolated with high purities by simple evaporation of
the volatile solvents. The use of free hydroxylamine led to
increased yields while high purities were maintained. Recycling of the resin to produce the same or a different hydroxamic acid was achieved by a three-step protocol
which is easily amenable to automation and is also costeffective.
A useful transformation of aldehydes into the corresponding amines was carried out using supported hydrazine
17773 as the starting point for a series of polymer-supported hydrazones 178 (Scheme 48).
Polymer-bound hydrazones 178 reacted with alkyl and
aryl organolithium reagents under 1,2-addition to the carbon–nitrogen double bond to afford the corresponding hydrazines 179. These products were released from the solid
support through a reductive nitrogen–nitrogen bond
Synthesis 2007, No. 16, 2409–2453
2426
REVIEW
ON
H
N
Cl
OHC
N
175
176
F
N
NH2
183
184
O
H2N
N
R1
N
BH4
N
NH2
N
HN
R2Li
R1
21–67%
R2
179
R1
Scheme 50
F
N
H
185
78%
R1
2MgX
NH2
H 178
177
R
F
Synthesis of amines using solid-supported amine 183
R2
180
NH
Scheme 48 Synthesis of branched amines 180 using supported hydrazine 177
MeCSNH2
Br
S
186
cleavage with a borane-tetrahydrofuran complex, with Rbranched primary amines (180) as the end result.
An analogous approach was employed for the clean conversion of aldehydes to nitriles using a solid-supported
hydrazine (Scheme 49). The hydrazine was treated with
various aldehydes to give supported hydrazones 182,
which underwent reactions with 3-chloroperbenzoic acid
(MCPBA) to give the corresponding N-oxides. Upon
elimination, the nitriles were formed.74 In order to obtain
clean products, it was necessary to use an excess of
MCPBA and then scavenge any unreacted oxidant
through the addition of polyvinylpyridine.
O
NMeNH2
181
R1
N
R1
N
182
MCPBA
Scheme 49
N
+
NH
186
RNH2
R
60–70%
Scheme 51
N
H
187
Synthesis of acetimidates using supported reagent 186
Recently, catch-and-release approaches have been successfully applied to the synthesis of guanidines, with the
resultant development of different guanidinylating reagents on insoluble support (190 and 194).
A pyrazole-based reagent was bound to cellulose beads
through a triazene-type linker, as shown in Scheme 52.
Reaction of 190 with primary and secondary amines generated the guanidine 191 on the resin (from which it was
released with aqueous hydrochloric acid). The guanidine,
in the form of hydrochloride 192, was recovered, by filtration, in good yieds and purity.77
Cl–
R1 CN
NH2+
+
N
N2 H2N
189 N
N
N
Synthesis of nitriles using a supported hydrazine
The transformation of primary amines into the corresponding acetimidates was carried out using different supported alkyl halides (Scheme 51). The thioacetamide was
caught on the resin to form supported thioacetimidate 186.
This then reacted with different amines, with concomitant
cleavage from the support, to form the corresponding acetimidates 187.76
Synthesis 2007, No. 16, 2409–2453
N
N
NH
190
188
A tandem three-phase preparation of amines was developed, starting from the supported primary amine resin
183. In this process, an aldehyde was caught on the resin,
with consequent generation of the corresponding imine
184. The resin was then treated with a primary amine that
displaced the aldehyde residue from the resin to form an
imine that, after treatment with supported borohydride,
gave secondary amine 185. The process takes place in a
single reaction vessel: the resin behaved as a ‘chaperone’
(the authors used this term to indicate a resin-to-resin
transfer agent) for the reaction and the secondary amines
were obtained in good yields, free from the usual by-products of reductive aminations (Scheme 50).75
H
N
R1
N
R
H
190, EtOH, reflux
N
N
R1
H
N
2
N
R2
NH
191
R1
HCl (1 M)
H2N
N
NH
Scheme 52
190
R2
⋅HCl
192
Synthesis of guanidines using cellulose-bound reagent
Earlier on, another method for the amidination of amines
was carried out using reagent 194, which behaved as a
polymer-bound amidinating agent (Scheme 53). From a
supported diketone, the guanidyl pyrazole 194 was
formed. Further reaction with nucleophilic primary and
secondary amines allowed for direct transformation into
the corresponding guanidines in a one-step procedure.78 A
variety of amines, such as aliphatic, benzylic, and aromatic amines, as well as amino acids, amino sugars, and di-
REVIEW
amines, were used as substrates for this procedure. The
reaction can be accelerated dramatically under microwave-irradiation conditions, and polymer-bound reagent
194 can be effectively regenerated and reused.
O
N
H
O
S P
X
OR
199a
O
TMSCl
NaI, CH2Cl2, r.t.
+
NH2
1
or R
O P
NH
N
H
R2
S
200b
N
X
NH2
N
–
O
O
O P
O
N
X
–
N
O
N
O
O–
O–
+
OH
OH
1
R1
PEG
NH
–
194
X
O
N
H3N Cl
S
OR
X
OR
N
N
H
EtOH, 75 °C
N
H
+
–
O P
O
193
NH3
H2N
O
S P
O
NH
200a
–
O
199b
O
O
O
PEG
DMSO,
NaHCO3,
155 °C
Cl
2427
R
194
50–99%
1
R
NH
H2N
or
NH
2
N
H2N
R
O
X
NH
NH
Scheme 53 Preparation and use of polystyrene-bound 3,5-dimethyl-1H-pyrazole-1-carboxamidine 194
N
X
–O
P
O
O
–O P
O
–O
HO
HO
O
HO
O
OH
O–
A different strategy was developed by Pastor and coworkers79 for the synthesis of N,N-bis(tert-butoxycarbonyl)-protected guanidines 196, starting from a diverse set
of amines (Scheme 54). Polymer-supported carbodiimide
was used as the activating agent for the coupling of N,Nbis(tert-butoxycarbonyl) thiourea and various amines.
Polymer-supported trisamine 196 was employed as a
scavenger in this process, which was followed by deprotection with trifluoroacetic acid to afford terminal
guanidines 198.
S
BocHN
NHBoc
BocHN
N C N
195
NBoc
+
R1
H
N
NH2
R2
25% TFA in CH2Cl2
H2N
R1
R2
197
N
N
H
R1
NH2
196
NH
R2
198 (as TFA salt)
Scheme 54
Use of PS-carbodiimide in the amidination of amines
Polymer-bound oxathiaphospholanes 199a and 199b
were employed as solid-phase reagents for regioselective
phosphorylation and thiophosphorylation of unprotected
nucleosides and carbohydrates in the presence of 1H-tetrazole (Scheme 55).80
This strategy presented a general approach with initial immobilisation of the phosphitylating reagents on a solid
support using the appropriate linkers and subsequent reaction with alcohols. Washing of the support guaranteed the
removal of unreacted reagents. Oxidation and dealkyla-
X = O, S
OH
OH
Scheme 55 Polymer-bound oxathiaphospholanes for phosphorylation reactions
tion reactions, followed by cleavage, led to the release of
phosphorylated products. This strategy offered the advantages of high regioselectivity and facile isolation of reaction products. The supported oxathiaphospholanes 199a
and 199b were used for the prepartion of several compounds, some of which are shown in Scheme 55.
The synthesis of solid-phase reagents 205 for selective
monophosphorylation of carbohydrates and nucleosides
was reported in a subsequent paper.81 These different
classes of aminomethyl polystyrene resin-bound linkers
(201–204) of p-acetoxybenzyl alcohol were treated with
2-cyanoethyl N,N-diisopropylchlorophosphoramidite to
afford the corresponding polymer-bound phosphitylating
reagents (Scheme 56). Phosphitylating reagents 205 were
used for reactions with a number of unprotected nucleosides and carbohydrates, again in the presence of 1H-tetrazole.
Diaryl sulfides 209 were prepared by direct nickel(II)-catalysed coupling of thiols 206 with iodoaryl bound to SynPhase polystyrene lanterns 207, in the presence of
polymer-supported borohydride.82 This method resulted
in the formation of the disulfide on the surface of the polymer, thereby allowing for the washing away of the excess
thiol and the catalyst. Cleavage of the acid from resin 208
gave a collection of diaryl sulfides 209 in good yields
(Scheme 57).
New polymer-supported triorganotin halides 211 have
been used for the aromatic halogenation of variously substituted anilines 212 (see also Scheme 44 in section 5).83
Treatment of several aromatic amines with n-butyllithium
and polymer-supported organotin halides 211, followed
Synthesis 2007, No. 16, 2409–2453
2428
REVIEW
A number of catch-and-release methods for the synthesis
of carbon–heteroatom bonds have been applied to the synthesis of heterocycles. For example, variously functionalised o-aminophenols 214 were transformed into
benzoxazoles 217 by joint action of Merrifield resin and
carbon disulfide in the presence of diisopropylcarbodiimide (DIC) in acetonitrile (Scheme 59). The substrates
were caught on the resin, oxidised, and finally released
with different primary or secondary amines to give 2-aminobenzoxazole products 217.84
O
O
S
NBoc
O AcO
OH
201
202
NH
AcO
OH
203
204
OH
HO
linker
O P
Cl
N
O
NC
HO
+
R1
S
N
H2N
214
205
ROH
O
a
R1
215
b
O
linker
O P
O
OR
HO P
O–
R2
N
R3
OR
O–
Scheme 56 Synthesis of polymer-bound phosphitylating reagents
205 using various resin-bound linkers
I
SH
S
(bpy)2NiBr2
207 O
R1
O
208
206
R1
O
S
TFA
HO
70–100%
R1
209
O
Scheme 57 Preparation of aryl sulfides using polymer-supported
borohydride and iodoaryl-functionalised SynPhase polystyrene lanterns
by treatment with bromine or iodine monochloride, yielded para-halogenated aromatic amines 213, with high
yields and high selectivities (Scheme 58). Polymer-supported organotin halides reagents 211 were regenerated
and reused without loss of efficiency.
Cl
PhBu2SnLi
SnBu2Ph
210
I2
SnBu2I
211
NH2
NH2
211, ICl
R
R
67–100%
212
I
(selectivity 87:13 to 100:0
vs. dihalo product)
213
Scheme 58 Supported organotin reagent 211 used for regioselective
halogenation
Synthesis 2007, No. 16, 2409–2453
O
c
R1
N
217
O
R1
S
O
N
216
Scheme 59 Reagents and conditions: (a) CS2, DIC, Et3N, MeCN,
r.t., 24 h; (b) MCPBA, CH2Cl2, 0 °C, 3 h; (c) R2R3NH, MeCN, 80 °C,
6 h.
NMe3BH4
O
O
When R1 was a nitro group, it was also possible to introduce further diversification to the key resin 215 by reduction of the nitro moiety and subsequent reaction with acid
chlorides or isocyanates. Various 6-functionalised 2-aminobenzoxazole analogues were generated in this manner.
Supported arylphosphine was used for the transformation
of ortho-amino benzamides (derived from isatoic anhydride) into 2-amino-substituted 3H-quinazoline-4-ones
219.85 This strategy exploited the aza-Wittig reaction of
polymer-supported iminophosphoranes 218 with isocyanate, alongside concomitant cleavage of the molecule from
the resin and formation of a carbodiimide intermediate
that finally rearranged to the desired quinazolinones 219
(Scheme 60).
Supported alkyl N-methyl-N-polystyreneamino-2-isocyano acrylate 220 was prepared from supported N-methylaniline, b-ketoisonitrile, and 1-(diethoxymethyl)imidazole. Reagent 220 was used for the solution-phase synthesis of 1-substituted imidazole-4-carboxylates 221, carried out in a catch-and-release fashion starting from
amines (Scheme 61).86 The reactions proceeded under microwave irradiation to afford imidazole-4-carboxylates in
both high yields and chemical purity.
The polymer-assisted solution-phase (PASP) synthesis of
a 192-member two-dimensional array of 1,5-biaryl pyrazoles 224 {1-12,1-16} was carried out in a fully automated manner using a multiprobe top-filtration robot and
incorporated a catch-and-release step (Scheme 62). A tetrafluorophenol resin was used to catch the library of pyrazoles that carried a carboxylic function. Washing of resin
223 removed all impurities and by-products, and the final
REVIEW
2429
O
O
a, RNH2
O
b,
NHR
O
N
H
PPh2
NH2
O
O
c, R1NCO
NHR
NHR
N C NR1
N PPh2
68–89%
218
O
A catch-and-release strategy for the preparation of a combinatorial array of 2,4,5-trisubstituted pyrimidines 227
was developed through the reaction of b-ketoesters and bketoamides onto a solid-supported piperazine, under very
mild microwave-assisted conditions. Solid-supported
enaminone 225 was formed and reacted via cyclocondensation with several guanidines, under thermal or microwave heating, to afford the corresponding pyrimidines
227 in good yields and purity (Scheme 63). Recycling of
the support was also possible.88
N
219
O
NH
O
+
N
R1
N
H2N
+
–
O
NH
R2
R2
O
227
Y = O, NH
In a similar approach, a cellulose-based resin carrying an
aniline function was used to prepare a library of pyrazoles
(229) and isoxazoles (230) in solution. Polymer-bound
enaminone 228 was formed in situ and, after treatment
with hydroxylamine or phenylhydrazine, was transformed
into the corresponding isomerically pure target heterocycles in high yield, with restoration of the starting cellulose
beads (Scheme 64).89 The use of the cellulose-based support was crucial in order to obtain good yields in the last
step under microwave irradiation.
R1
NH
HN
O
R2
NH2
O
O
R2 228
F
222
OH
R2
N
R
R3
H
N
N
F
NH
NH
R1
MW
N
N
H
R2
229
or
R1
N
O
R2
230
Scheme 64 Preparation of a library of pyrazoles (229) and isoxazoles (230) in solution using cellulose-bound reagent 228
R4
O
F
O
O
NH2NH2 or NH2OH
1
F
NH2
O
N
O
O
OH
F
F
O
F
O
226
N
N
recycle
R2
HN R1
R2
R
NO3 NH2
Y-R1
O
F
O
1
NH
recycle
amide 224 was released by treatment with amine. This is
a general strategy for the prepartion of amides and concomitant purification of the intermediate carboxylic acid
to afford library compounds directly in high yield and purity.87
R2
N
Scheme 63 Polymer-assisted preparation of a combinatorial array
of 2,4,5-trisubstituted pyrimidines 227
N
Scheme 61 Polymer-assisted solution-phase synthesis of 1-substituted imidazole-4-carboxylates using supported alkyl N-methyl-Npolystyreneamino-2-isocyano acrylate 220
N
+
N
N
221
R1
O
+
H2N
R1
R2NH2
220
O
R2
R2
C
R1 80–98%
O
O
225
N
OEt
–
+
N
N
CH(OMe)2
Y-R1
N
N
C
Y R1
N
O
OEt
N
–
+
N
R2
N
R1
Y R1
+
Scheme 60 Supported aza-Wittig strategy for the synthesis of 219.
Reagents and conditions: (a) DMAP (0.1 equiv), DMF, r.t., 8 h; (b)
C2Br2Cl4, Et3N, CH2Cl2, Ar, reflux, 5 h; (c) PhMe or xylene, Ar, reflux, 8–24 h.
N
NH +
N
NHR1
N
R3
N
O
R4
224
223
Scheme 62 Catch-and-release strategy for the synthesis of 1,5-biaryl pyrazoles 224
A commercially available silica-supported toluenesulfonic acid was employed in the microwave-assisted synthesis
of pyrazoles, resulting in the development of a rapid and
efficient two-step protocol for the transformation of aryl
trifluoromethyl ketone enolate derivatives into 1,5-diaryl3-trifluoromethylpyrazoles.90
Synthesis 2007, No. 16, 2409–2453
2430
REVIEW
Oxazoline inhibitors of LpxC were synthesised via a
catch-and-release ring-forming reaction for the parallel
synthesis of libraries of oxazolines (Scheme 65). Different a-hydroxyamines and acid chlorides were used to generate molecular diversity, and the N-acylation product 231
was captured onto polymer-bound p-toluenesulfonyl
chloride, thereby eliminating the need for an extractive
purification in the first step. The resin-bound intermediate
233, after extensive washing to remove non-nucleophilic
impurities, was treated with a volatile, non-nucleophilic
base to promote ring-forming cleavage from the resin.
O
O
NHOPG
HO
NHOPG
Et3N
NH2
HO
RCOCl
NH
O
231
R
O
NHOPG
i)
TsCl
232
pyridine
O
S O
O
ii) wash
O
NH
R
233
O
NHOPG
N
O
R
234
Et3N, pyridine
O
deprotection
NHOH
N
O
R
235
Scheme 65 Synthesis of oxazoline inhibitors of LpxC via a catchand-release ring-forming reaction using a polymer-bound tosyl chloride
The sequence resulted in the formation of oxazoline targets 235 in moderate yields (40–60%) and high purity
(>90%), and proved to be amenable to parallel, semi-automated methods of synthesis.91 A library of oxazoline
LpxC inhibitors, the key feature of which was the zinc
binding group at the 4-position of the heterocycle, was
generated. All compounds were screened for antibacterial
activity against wild-type E. coli (R477), hypersensitive
LpxC1 E. coli (G17S), and P. aeruginosa (PA01).
6.2
Reagents for Carbon–Heteroatom Bond Formation
Solid-supported carbodiimide is one of the reagents of
choice for the synthesis of amides and is becoming a routine reagent.92 It follows that several systematic studies on
the optimisation of the reaction conditions for the formation of amides have been reported. For instance, the coupling of 1-methylindole-3-carboxylic acid 236 with
different amines has been investigated in order to establish the best reaction conditions under microwave irradiation (Scheme 66). A complete conversion occurred in the
presence of soluble 1-hydroxy-1H-benzotriazole (HOBt)
in five minutes at 150 °C, and amides 237 were thus generated.93
Synthesis 2007, No. 16, 2409–2453
O
COOH RNH2, HOBt
PS-carbodiimide
MW, 150 °C, 5 min
N
68–98%
NHR
N
236
237
Scheme 66
Use of solid-supported carbodiimide in amide synthesis
A supported carbodiimide was also employed for the single-vessel solution-phase transformation of esters or lactones into amides. The ester linkage was cleaved using
benzyltrimethylammonium hydroxide, then neutralisation
with supported toluenesulfonic acid (MP-TsOH) followed, and the crude product was finally treated with
HOBt, polymer-bound carbodiimide, and an excess of
amine. After the coupling, the by-products were scavenged with additional MP-TsOH and MP-carbonate.94
The PS-bound carbodiimide was employed in a key step
of the synthesis of compound UK-427,857 (maraviroc;
240), a potent antagonist of the CCR5 receptor that is currently undergoing phase III clinical trials as a treatment
for HIV.95
Once the reaction of 4,4-difluorocyclohexanoic acid and
the precursor amine 239 was complete, simple filtration
through a pad of silica furnished 240, which was recrystallised to analytical purity from toluene–hexane
(Scheme 67).
NH2
O
O
NH
N
N
O
N
N
H
238
239
PS-carbodiimide
4,4-difluorocyclohexanoic acid
O
48%
NH
F
F
N
N
N
N
240
Scheme 67 Synthesis of maraviroc (240) using a polymer-supported carbodiimide
Another interesting example of the use of polymer-supported carbodiimide was published by Lamothe and collaborators, who reported the efficient one-pot preparation
of amides using a polymer-supported strategy96 that was
improved by the use of HOBt to enhance the reactivity of
the supported reagent. Subsequently, HOBt was easily removed from the reaction medium by the use of a supported carbonate base as scavenger (Scheme 68).
A library of polyfunctionalised dihydropyrimidine-5-carboxylic amides 242 was prepared in a multistep sequence
that integrated a variety of techniques, such as automated
and parallel microwave synthesis, the use of polymer-supported reagents, fluorous synthesis and purification strat-
REVIEW
R2
R2
COOH
HN
N
X
2431
R3
PS-DCC, HOBt,
R4NH2
MW, 100–120 °C,
15 min
X
N
37–89%
R1
241
NH2
R2NCS
H
N
R1
O
O
CONHR4
HN
H
N
R1
246
247
249
250
251
NH
O
249
N
N
NH2
Scheme 68 Synthesis of a library of polyfunctionalised dihydropyrimidine-5-carboxylic amides 242 using polymer-bound DCC
250
Scheme 70
The use of supported PS-DCC also allowed for the formation of triazolobenzodiazepine in a one-pot amidation and
alkyne–azide cycloaddition (Scheme 69). The azide derived from anthranilic acid was in fact treated with propargylamine and PS-DCC; amide 244 immediately
cyclised to the tricyclic triazole 245. This reaction occurred in better yields than the corresponding reaction that
was carried out with soluble DCC.98 Using this approach,
a multi-arrayed library of the circumdatin family of natural products was prepared.99
N3
MeHN
N
COOH
N
243
N
244
O
N
N
245
NEt2
P
N
251
Polymer-supported synthesis of substituted oxadiazole
ic diamines 252 with carboxylic acids (using PScarbodiimide) yielded 253, using 1-hydroxy-7-azabenzotriazole (HOAt) as additive (Scheme 71, path a).
path a
i) PS-carbodiimide
HOAt, R5COOH
R3
ii) PS-trisamine
R2
NH
R1
R3
Y
253
NHR4
NHR4
Y
R4
R3
R2
AcOH
R5
O
Y
R1
R2
252
R1
path b
N
254
R4
R6NCS
PS-carbodiimide
N
R5
NH2
R3
Y
N
NHR6
N
2
R
R1
255
Scheme 71 Different PS-carbodiimide-assisted strategies for the
synthesis of substituted benzimidazole 254 (Y = CH) and imidazopyridine 255 (Y = N)
PS-carbodiimide
N3
N
C
X = O, S, R1 = H, Me; R2 = H, 2-Me, 4-Me, 2-Cl, 4-Br, 3-NO2;
R3 = Me, Ph; R4 = Bn, Pr
egies, and even a continuous-flow hydrogenation
system.97 The key dihydropyrimidine-5-carboxylic acid
intermediates 241 were obtained in a two-step sequence:
a Biginelli multicomponent condensation of benzyl or allyl b-ketoesters with aldehydes and (thio)ureas was followed by suitable benzyl- or allyl-deprotection strategies.
Further functionalisation of the acid cores with amines
was done using a polymer-supported version of N,N¢-dicyclohexylcarbodiimide (PS-DCC).
R2
248
R2
N
NH
O
NH 64–82%
S
R3
R1
242
N N
R1
O
Scheme 69 Synthesis of triazolobenzodiazepines 245 in a one-pot
reaction using polymer-supported DCC
The use of polymer-supported carbodiimide is also well
documented in cyclocondensation reactions. An efficient
one-pot solution-phase synthesis of 2-amino-1-oxa-3,4diazoles 248 was carried out starting from different acylhydrazines and isothiocyanates.100 A cocktail of polymersupported reagents 249, 250, and 251 was employed to
help facilitate both cyclisation and purification
(Scheme 70).
A small library of benzimidazoles 255 was prepared
through the use of polymer-bound reagents and scavengers. The polymer-assisted reaction of substituted aromat-
The excess HOAt was scavenged using a polymer-bound
trisamine. When compounds 253 were treated with acetic
acid, an acid-catalysed cyclodehydration occurred, thereby affording benzimidazoles in good yields and purity.101
Finally, the conversion of sulfanylimidazoles 256, obtained from a three-component reaction, into imidazo[5,1b][1,3]thiazin-4-ones 257 was obtained in high yields using PS-DCC (Scheme 72).102
A polymer-supported phosphoryl azide was synthesised
starting from phenol resin 258. The synthetic applications
of this polymer-supported version of diphenylphosphoryl
azide (DPPA), 260, were explored through a study of the
conversion of a variety of carboxylic acids (aromatic, aliphatic and heterocyclic carboxylic acids) into urethanes
and ureas via Curtius rearrangement reactions
(Scheme 73).103
The reaction between an arylsulfonyl azide and a substrate
that contains an active methylene group is a useful method
for the preparation of diazo carbonyl compounds. Unfortunately, sulfonyl azides are potentially hazardous owing
to their propensity for explosive decomposition under varSynthesis 2007, No. 16, 2409–2453
2432
REVIEW
R2
CHO
O
COOH
S
Ph
O O
S
Cl
S
Ph
N
HN
O O
S
N3
261
NaN3, H2O
DMF
256
NH2
R1
NH2
Br
O
PS-DCC
COOH
O
261
R2
Ph
R1
O
R2
O
O
Scheme 72 Conversion of sulfanylimidazoles 256 into imidazo[5,1-b][1,3]thiazin-4-ones 257 using PS-DCC
263
O
Ph
H
N
Ph
P
N
Boc
N
Br
94
O
O
O
265
O
OH
PhOPOCl2
P
O
Scheme 74
agent
PhO Cl
258
O
P
O
260
260
R2OH or R2NH2
OH
PS-benzenesulfonyl azide 261 as a diazo transfer re-
N3
267
DMA, 25 °C, 72 h
PhO N3
R1
N
Boc
266
259
NaN3
O
O 264
Rh(OAc)2
O
262
S
N
257
N2
Et3N, toluene, 80 °C
N
R1
N
Boc
R1
34–80%
R-Br
H
N
OR2 or
O
R1
H
N
R-N3
O
ious reaction conditions. Polymer-supported benzenesulfonyl azide provides a diazo transfer reagent with
improved process safety characteristics, and thus represents an excellent reactant for laboratory use. The polymer-supported benzenesulfonyl azide resin, represented
by 261, was prepared in one step from commercially
available polymer-supported benzenesulfonyl chloride by
treatment with sodium azide at room temperature.104
Product 261 was used in the preparation of diazo compound 263 (Scheme 74), which reacted with protected
amino acid amide 264 to give amido ketone 265. This
compound was then cyclised in the presence of PSPPh2Br 94 to give bicyclic isoxazole 266, an original cyclic non-planar platform that is ideal for combinatorial
chemistry.105
Solid-supported azide 267 was prepared from sodium
azide and Amberlite or PS-tetraalkylammonium bromide.
This reagent was employed for the preparation of alkyl
azides that were further used in ‘click’ reactions with
monosubstituted alkynes (Scheme 75).106
Classical methylation reagents are often very dangerous
because of the risk of DNA methylation if the handler is
contaminated with the substance. However, the following
reagents can be considered safe alternatives because the
polymeric support prevents both inhalation of the reagent
and its absorption through the skin.
N
N
35–100%
N
NHR2
Scheme 73 Synthesis and applications of 260, a polymer-supported
version of DPPA
Synthesis 2007, No. 16, 2409–2453
MeO2C
CO2Me
268
Scheme 75
ted azide
R
Preparation of 1,2,3-triazoles using a polymer-suppor-
The use of polymer-bound triazenes 270 as alkylating reagents for the esterification of sulfonic acids was explored, and a general procedure was developed for the
synthesis of sulfonic esters (Scheme 76). The PS-supported diazonium salt 269 reacted with methylamine and the
resulting supported methyl triazene was used to methylate
sulfonic and phosphonic acids. Different alkylating triazenes were prepared, and resulted in the production of the
corresponding alkyl sulfonates and phosphonates in good
yields and purity.107 Using the same method, enantioenriched R-substituted sodium sulfonates, synthesised via
asymmetric synthesis, were transformed into esters without loss of enantiomeric excess.
+
Me
–
N2BF4
O
O
MeNH2
Cl
269
O O
S
R
OH
or
O
Scheme 76
N
NH
Cl
270
270
P
R1 1 OH
R
N
O O
S
OMe
R
or
O
P
R1 1 OMe
R
Synthesis of different esters using triazene 270
REVIEW
Polymer-supported methyl sulfonate 271 was prepared by
the reaction of polymer-supported sulfonic acid with trimethyl orthoacetate, in the absence of solvent, at room
temperature. Then, various aromatic and aliphatic carboxylic acids were treated with this reagent, in the presence of
potassium carbonate, to provide the corresponding methyl
ester, such as 272, in high yields (Scheme 77).108 Simple
filtration of the reaction mixture and removal of the solvent gave methyl esters with high purity (>98%).
Later, the same research group reported a microwave-enhanced PASP esterification reaction.112
The dehydrating polymer-supported triphenylphosphine
ditriflate 276 was prepared starting from supported triphenylphosphine oxide 275 with triflic anhydride, and
was used as a powerful dehydrating reagent (Scheme 79).
Ph
O O
S
OH
MeC(OMe)3
COOH
NHBoc
K2CO3, MeCN
reflux
P
H2O2
CH2Cl2
Ph
Ph
O O
S
O 271
COOMe
271
NHBoc
272
Scheme 77 Polymer-supported methyl sulfonate 271 and its use in
the methylation of carboxylic acids
Polymer-supported O-methylisourea 274a, a new reagent
for the O-methylation of carboxylic acids, was prepared in
one step starting from commercially available solid-supported carbodiimide 273.109 The reagent was used for the
preparation of methyl esters from the corresponding carboxylic acids, with high purity (Scheme 78). This methodology was extended to the synthesis of polymersupported O-benzylisoureas 274b and O-allylisoureas
274c, for use in the synthesis of esters from carboxylic acids.110
N
C
O
R
OH
Scheme 78
74–94%
HN
N
O
274
R
OR1
O
275
(CF3SO2)2O
CH2Cl2
Ph
–
Ph
P
OSO2CF3
+
Ph
OSO2CF3
Scheme 79
Polymer-supported triphenylphosphine ditriflate 276
The potential of 276 as a general dehydrating reagent/activating agent was demonstrated in the synthesis of esters,
anhydrides, thioacetates, amides, tripeptides, ethers, epoxides, azides, and nitriles. Moreover, the polymer-supported triphenylphosphine oxide was easily recovered and
reused several times without loss in activity.113
An insoluble polystyrene-supported triflating reagent,
279, was prepared by Chung and Toy by suspension copolymerisation of N-(4-vinylphenyl)trifluoromethanesulfonimide 277, styrene and JandaJel cross-linker 278,
thus incorporating the triflimide functional group into the
polymer
during
the
polymerisation
process
(Scheme 80).114
JJ
+
NTf2
279
Cu(OTf)2
N
273
P
276, used as
dehydrating agent
+
R1OH,
2433
NTf2
OR1
Finally, a general approach was devised for the preparation of polymer-supported O-alkylisoureas for the Oalkylation of carboxylic acids.111 The supported O-alkylisoureas (such as 274a–d), prepared by reaction of an alcohol with a polymer-bound carbodiimide under copper(II)
catalysis, were used to transform carboxylic acids into the
corresponding methyl, benzyl, allyl, and p-nitrobenzyl esters. The reaction was highly chemoselective and afforded
high yields and very high purity after simple filtration of
the resin and evaporation of the solvent. The reactions
were carried out using both conventional or microwave
heating. In the latter case, reaction times were as short as
3–5 minutes, without a compromise in the yield, purity, or
chemoselectivity.
O
278
277
OH
274a: R1 = methyl
274b: R1 = benzyl
274c: R1 = allyl
274d: R1 = p-nitrobenzyl
O-Alkylation of carboxylic acids using 274a–d
O
OTf
279
Et3N
280
Scheme 80
New polymer-supported triflating agent 279
This reagent, in the presence of triethylamine, allowed for
the efficient synthesis of aryl triflates 280, in essentially
pure form (after filtration and concentration operations),
from a wide range of phenols. The reagent 279 can be easily recovered, regenerated, and reused. Other reagents
were evaluated as triflating reagents, but they afforded
only modest yields of the desired products in representative reactions.
In solution, the treatment of formamides 281 with p-toluenesulfonyl chloride leads to the synthesis of a number of
isonitriles 282 in reasonable yield and purity, but the
work-up and purification of this reaction are problematic,
due to the reactivity of the isonitriles. However, a polymer-assisted version of the reaction has been reported by
the Bradley research group. In it, PS-sulfonyl chloride ofSynthesis 2007, No. 16, 2409–2453
2434
REVIEW
fered a fast and efficient solution, as only a simple filtration and acidic work-up (to remove the pyridine) were
required in order to obtain the isonitriles in exceptional
purity (Scheme 81). The use of microwave irradiation and
three equivalents of sulfonyl chloride resin made the
method very reproducible and robust, as the sulfonyl chloride resin was also quantitatively regenerated.115
Cl
Cl
N
+
N
Cl
283
NH
N C N
NH
S
O
Cl
S
H
N
281
Cl
O
O
285
284
Cl
+
N
C
–
S
282 (49–100% purity)
R
BocHN
R
HN
283
NH2 +
NHBoc
NHBoc
Scheme 81 A new method for the synthesis of isonitriles 282 using
PS-sulfonyl chloride
286
Scheme 82
A few more interesting synthetic transformations have
been carried out using polymer-bound triphenylphosphine-based reagents. A general method for Mitsunobu
reactions was carried out using a combination of polymersupported azodicarboxylate and anthracene-tagged phosphine reagents.116 The use of polymer-supported azodicarboxylate was instrumental in the facilitated removal of
reaction byproducts, as well as excess alcohol, through
simple filtration, while the anthracene-tagged phosphine
allowed for the removal of the phosphine/phosphine oxide
by sequestration through a Diels–Alder reaction using a
polymer-bound maleimide dienophile.
The tagged phosphine compounds were easily prepared
and were found to behave like triphenylphosphine in initial experiments. Chemoselective removal of the anthracene-tagged phosphine through Diels–Alder
cyclisation was highly orthogonal and allowed for the tolerance of a broad range of functional groups, although a
drawback of the methodology is that it is limited by problems arising from the generation of final products that can
react with the polymer-bound dienophile. On the other
hand, the Mitsunobu reaction with supported phosphine
and diethyl azodicarboxylate (DEAD) was possible
through the exclusive use of highly loaded soluble ringopening-metathesis polymers. This method appeared to
be superior to the traditional use of soluble DEAD in conjunction with JandaJel-PPh3 or PS-PPh3, or using JandaJel-PPh3 and PS-DEAD.117
The first example of a polymer-supported Mukaiyama reagent, 283, was prepared using a design-of-experiments
approach, and proved to be effective for the formation of
carbodiimides 285 through the dehydration of thioureas
284, and for a one-pot guanylation of primary amines using Boc thiourea (Scheme 82).118
A different supported version of the Mukaiyama reagent
was prepared through the linking of a 6-chloronicotinoyl
chloride to a PS-resin that carried a free amino group, followed by alkylation of the nitrogen. Compound 289 was
used for the preparation of b-lactams in solution by the
Staudinger reaction (Scheme 83).119
Synthesis 2007, No. 16, 2409–2453
NBoc
A new polymer-supported Mukaiyama reagent
The ketene that was generated from a carboxylic acid under sonication with the resin was treated with the imine to
afford the b-lactams, while the excess imine was removed
by reduction and then acid scavenging, a protocol that can
easily be applied in parallel synthesis. The same reagent
was employed in the synthesis of esters from carboxylic
acids and alcohols.120
O
a
b, c
Cl
O
4 NHBoc
287
O
O
N
H
N
N
H
d
Cl
288
N
I–
I
289
O
R1
OH
+
R2
N
R3
289
Bu3N
60–88%
R1
R2
N
O
R3
Scheme 83 Reagents and conditions: (a) N-Boc-6-aminocaproic
acid, Cs2CO3, DMF, 80 °C, 3 d; (b) TFA, CH2Cl2; (c) 6-chloronicotinoyl chloride in CH2Cl2, DIPEA; (d) MeI, 75 °C, 2 h; (d) neat TFA,
70 °C, 2 h.
Two other polymer-supported versions of the Mukaiyama
reagent (290 and 291) were prepared starting from a
Wang- or a Merrifield-type resin that was alkylated with
chloropyridine (Scheme 84).121
Reagents 290 and 291 proved to be useful in coupling reactions for the synthesis of esters and amides from carboxylic acids and alcohols or primary or secondary
amines, in particular when poorly nucleophilic amines
were used.
An alternative synthesis of polymer-supported Mukaiyama reagents 292 and 293 using Merrifield resin and potassium iodide was reported, and proved to be effective for
the formation of carbodiimides through the dehydration of
thioureas, and for a one-pot guanylation of primary
amines (Scheme 85). Libraries of 2-oxazolidines122 294
REVIEW
N
Cl
Tf2O, CH2Cl2
OH
X
N
Chen and Huang124 synthesised new polymer-supported
alkenyl(phenyl) iodonium salts 295, which served as effective alkenyl transfer reagents in the preparation of bfunctionalised enamines 298 via nuclephilic cleavage of
the caught intermediate 297 (Scheme 86). It was possible
to regenerate the polymer support, and the regenerated
polymeric hypervalent iodonium salts showed activity
levels similar to those of the freshly prepared reagents.
–
Cl
N
KI, DMF
Cl
Ar
I(OH)OTs
R1R2NH or R1OH
base, CH2Cl2, 290
RCOOH
H
N
H
N
290: X = OTf
291: X = I
Cl
Ar
EtOOC
RCONR1R2 or RCOOR1
291, 3-acetylacetanilide,
DMF, Et3N, r.t.
295
RNH2
+ Boc
N C N
Nu
NHBn
Ar
NuH (or Nu–)
EtOOC
H
N
Boc
R
H
N
297
H
N
Boc
NBoc
Novel solid-supported Mukaiyama reagents 290 and
Scheme 86
salts
Similar polymer-bound iodate complexes (299a and
299b) were used for the PASP activation of 2-deoxythioglycosides 300, which, in the presence of alcohols,
acted as glycosyl donors to provide 2-deoxyglycosides
301 in good to excellent yields (Scheme 87).125
+
O
O
+
OH
N
X
OTf
R1
+
+
OH
OH
H2N
R1
R3
O
293
R1
R
N
H
O
R3
300
R3
R1
2
76–94%
SPh
O
RO
63–95%
301
OR'
Scheme 87 Polymer-bound iodate complexes for the PASP activation of 2-deoxythioglycosides
O
R2
N
+
299b
299a
R'OH
RO
–
NMe3I(OH)OTs
299a
O
OH
N
H
+
–
NMe3I(O2CCF3)2
R2
O
292
–
X
N
292: X = Cl
293: X = F
R2
NHBn
New polymer-supported alkenyl(phenyl) iodonium
NMe3I
–
298
Nu = SCN, Et2N, Br, CN, morpholine, etc.
were prepared through the combination of a chemoselective acylation step (using polymer-supported Mukaiyama
reagent 292 or 293) with a catch-and-release cyclisation
reaction that employed polymer-supported tosyl chloride
or polymer-supported 2-fluoropyridinium triflate 293.
O
NHBn
COOEt
291, DMF,
Et3N, r.t.
S
Scheme 84
291
296
I
Ar
S
H
N
2435
N
294
R3
Scheme 85 Use of polymer-supported 2-fluoropyridinium triflates
292 and 293 in the synthesis of oxazolidines
The amide was prepared using 292 with different carboxylic acids and b-amino alcohols. The free hydroxy group
of the intermediates was caught by 293. Further cyclisation, brought on by heating of the resin in the presence of
a base, gave 5-substituted oxazolines 294. Since the reaction proceeded almost exclusively with inversion of configuration, it was possible to obtain diastereomerically
pure compounds.
A solid-supported Vilsmeier-type salt was prepared from
the formamide of a piperazine linked to a PS-resin and this
reagent, activated with triphosgene, was used in the
formylation of aromatic compounds.123
Isolation of the target glycosides was simplified by a new
set of thiophilic reagents and a scavenging protocol that
utilised a borohydride exchange resin to quantitatively sequester the sulfur-containing impurities that were generated during the reaction, thus minimising work-up and
product isolation.
The synthetic versatility of polymer-bound hypervalent
iodate(I) reagents was demonstrated for selected examples in natural product synthesis and natural product derivatisation.126
Iodoacetoxylation of glycals was the initial step for the
preparation of deoxygenated disaccharides, part of the
carbohydrate units of the landomycins. In a second example, a one-pot multistep rearrangement of the decanolide
decarestrictine D backbone was initiated by iodotrifluoroacylation of the olefinic double bond.
Supported triphenylphosphine was employed in the azaWittig cyclisation of azidoketone 303; this constituted the
Synthesis 2007, No. 16, 2409–2453
2436
REVIEW
Me
Bu
Me
O
PO(OEt)2
O
PS-PPh3
toluene, reflux
+
NH
303
Bu
N
307
308
O
N
R1
1
306
R
8–86%
X
X = OEt, Ot-Bu, Me, H
R1 = OMe, Cl, CN, H
C16H33
304
Scheme 88
R
Me
76%
–
N
C16H33
N3
302
F
Scheme 90 Cyclisation reactions of 306 with polymer-supported
fluoride 307 at refluxing temperature
Synthesis of lanopylin B1 (304)
last step of the first synthesis of lanopylin B1 (304)
(Scheme 88).127
7
A method for a rapid and efficient synthesis of 1,3,4-oxadiazoles 305a involved the combined use of polymer-supported reagents and microwave heating, starting from a
variety of readily available carboxylic acids and acid hydrazides.128 Two methods were developed (Scheme 89),
one relying on PS-carbodiimide and HATU (not shown),
the other on supported 2-tert-butylimino-2-diethylamino1,3-dimethylperhydro-1,3,2-diazaphosphorine
(PSBEMP), for the coupling–cyclisation step.
Traditionally, solid-phase organic synthesis has been the
method of choice for the production of large libraries, but
in recent years this strategy has been superseded by SSRaided methods. Therefore, this last methodology has been
applied to the multistep synthesis of libraries and even
natural products. This task has been accomplished using
different supported reagents in some of the steps of the
synthesis, and generally involves the integration of transformations carried out with supported reagents with purification steps that employ scavengers to help removing
excess reagents.
HATU, PS-BEMP
MeCN, MW
150 °C, 20 min
R
O
R1
OH
R
O +
NOH
N
H
NH2
R2
R
O
N
R1
N
305a
O
N
N
2
305b R
NH2
MeCN, PS-PPh2
CCl3CN, MW
150 °C, 20 min
Scheme 89 Synthesis of 1,3,4- and 1,2,4-oxadiazoles (305a and
305b) using different solid-supported strategies
The same research group modifed the methodology by
employing amidoximes and then published a convenient
synthesis of 1,2,4-oxadiazoles 305b from a variety of carboxylic acids and acid hydrazides in one simple step under mild reaction conditions129 using commercially
available PS-PPh2 resin combined with microwave heating (Scheme 89). Thus 1,2,4-oxadiazoles 305b were obtained in high yields through automated procedures.
Starting from ethynylanilines and using a polymer-supported fluoride, it was possible to prepare various 1,2-disubstituted indoles.130 The cyclisation reaction of acylated
ethynylanilines 306 with different substituents at the aromatic ring (Scheme 90) was carried out through the use of
(polystyrylmethyl)trimethylammonium fluoride (307)
and gave the corresponding indoles 308 in good yields
and with a good level of purity. Polymer-supported fluoride 307 was recycled in the case of cyclisations of ethyl
2-(1-hexynyl)phenylcarbamate.
Synthesis 2007, No. 16, 2409–2453
Multistep Procedures
A library of N,N-bis(benzyloxycarbonyl)-1-L-cysteinylglycyl-3-dimethylaminopropylamide disulfides 311, an
alternative substrate for trypanothione reductase and
structural analogues, was prepared using polymer-supported reagents.131 The starting point for the synthesis was
the coupling reaction of CbzGlyOH and 3-(N,N-dimethylamino)propylamine using PS-N-ethyl-N¢-(3-dimethylaminopropyl)carbodiimide (PS-EDC) in the presence of
4-(N,N-dimethylamino)pyridine (DMAP). Removal of
the benzyloxycarbonyl (Cbz) group by catalytic hydrogenation was followed by coupling with cystine derivative
310 in the presence of HOBt. Finally, removal of HOBt
using PS-triethylammonium carbonate as a scavenger
gave 311 in good yields (Scheme 91).
A solid-supported solution-phase synthesis of 4-amino1,2,4,5-tetrahydro-2-benzazepin-3-ones 314–316 was deH2N
NMe2
HN
Cbz-GlyOH
PS-EDC
NMe2
309
CbzHN
O
O
CbzHN
H2, Pd/C
PS-EDC,
HOBt
NMe2
N
H
PS-Et3N(CO3)1/2
S
CbzHN
S
HOOC
S
NHCbz
S
COOH
CbzHN
310
311
H
N
O
NMe2
Scheme 91 Preparation of a library of N,N-bis(benzyloxycarbonyl)1-L-cysteinylglycyl-3-dimethylaminopropylamide disulfides 311
using polymer-supported reagents
REVIEW
scribed;132 it employed a variety of polymer-supported reagents and scavengers to give a library of compounds with
excellent overall yields and purities (Scheme 92). Starting
from racemic aminomethyl phenylalanine 312, reductive
amination with different aldehydes in the presence of PScyanoborohydride gave secondary amine 313. The excess
amine 313 was scavenged with a supported aldehyde and
then the resulting amino acid was cyclised with PS-EDC.
After deprotection of the Boc group, an additional functionalisation with a series of carboxylic acids was carried
out, again with PS-EDC as the coupling agent, to produce
a library based on scaffold 316.
R2 N C
O
1
R
NH2
N
H
X
i) DMF
ii)
317
NH2
SO3H
O
R1
N
H
H
N
H
N
R2
X
CBr4, r.t., 3 h
318
PPh2
N C N
N
DMF, MW, 140 °C, 1 h
HOOC
NHBoc
HOOC
R1CHO
1
H2N
NHBoc
R
TFA
EDC
N
R1
BocHN
N
H2N
O
314
R1
315
EDC
R2COOH,
82–100%
O
N
R2
N
H
O
R
319
R1
316
Scheme 92 The multistep polymer-assisted synthesis of substituted
tetrahydro-2-benzazepin-3-ones 314–316
A multistep approach to 5-substituted 2-amino-1,3,4-oxadiazoles 319a (and their 2-aminosulfonylated derivatives
319b) using polymer-supported reagents and microwave
heating was published by Ley and collaborators,133 who
developed and validated two different and convenient
synthetic routes. Initially, however, the required 1,4-disubstituted (thio)semicarbazide starting materials 318
were prepared via a condensation reaction of the appropriately substituted acylhydrazine 317 and iso(thio)cyanate,
after a scavenging sequence that used a mixture of
macroporous sulfonic acid and aminomethyl polystyrene
to sequester any unreacted hydrazine 317 and/or
iso(thio)cyanate (Scheme 93).
The first route was based on the solution-phase cyclisation
of semicarbazides, promoted by an immobilised DCC reagent (Scheme 93, route A). The cyclodehydration of
semicarbazide compounds 317 with a resin-bound DCC
equivalent led cleanly to the desired heterocyclic products, but the described protocol required the use of a significant amount of the supported DCC reagent. Therefore,
an alternative approach was developed, and cyclisation
was induced through the use of a mixture of a PS-triphenylphosphine equivalent and carbon tetrabromide
(Scheme 93, route B). When an immobilised triethylamine was used in order to regulate the pH of the system,
Route B
R2
1
X = O 319a
X = S 319b
313
O
N N
H
N
312
32–78%
(2-step yield)
Route A
CHO
BH3CN
2437
N
H
X
Scheme 93 A multistep approach to 5-substituted-2-amino-1,3,4oxadiazoles and derivatives 319a,b using polymer-supported
reagents
this proved to be a particularly effective combination, as
it gave excellent conversions into the corresponding oxadiazoles 319a. A simple filtration of the reaction mixture
through a functionalised-silica-packed cartridge (aminopropyl-NH2) significantly improved the purity of the
products (>95% as determined by LC–MS). The one-pot
preparation of the 2-aminosulfonylated analogues via a
microwave-assisted three-component coupling of an acylhydrazine, an isocyanate, and sulfonyl chloride, promoted
by a polymer-supported phosphazine base, allowed for the
preparation of over 1500 discrete compounds for screening purposes.
Dondoni and Massi134 described an efficient synthetic
strategy that led to the production of an array of 3,4-dihydropyrimidin-2-(1H)-ones 320. The synthesis was carried
out using a solid-supported ytterbium(III) catalyst, aldehydes, 1,3-dicarbonyl compounds, and urea (Biginelli reaction) under solvent-free conditions (Scheme 94). Each
member of the library was purified using a sequence of
acidic and basic polymer-supported scavengers.
Moreover, the Dondoni research group135 reported a multicomponent cyclocondensation as a method for the preparation of highly functionalised 2- and 4-dihydropyridylalanines and 2- and 4-pyridylalanines, as well as
their N-oxides. The compatibility of the strategy with a
O
O
R1
O
+
R2
R3
SO3–
R3
R2
N
H
Scheme 94
NH2
Yb3+
3
SO3H
NH
R1
320
H2N
H
a, b
O
O
+
NMe3OH
–
+
O
Polymer-assisted Biginelli reactions
Synthesis 2007, No. 16, 2409–2453
2438
REVIEW
PASP synthesis approach was established by the exploitation of an orchestrated sequence of polymer-supported reagents and sequestrants. The method employed a one-pot
thermal Hantzsch-type cyclocondensation of the aldehyde, ketoester, and enamine mixture, in which one of the
reagents (either the aldehyde or ketoester) carried the unmasked (protected) chiral glycinyl moiety.
The coupling of N-Boc-O-benzyl aspartate b-aldehyde
321, benzaldehyde and aminocrotonate esters afforded
tetrasubstituted
b-(4-dihydropyridyl)alanines
322
(Scheme 95), which were easily oxidised to the corresponding N-oxides 324. The latter may be applied as units
in different artificial peptides, as demonstrated by their insertion into tripeptides.
t-BuOOC
+
COOt-Bu
H
+
PhCHO
sugar alcohols.136 The methodology was based on the
treatment of primary sugar alcohols 325 with trichloroacetyl isocyanate (TAI), to afford sugar urethanes 326.
Quenching of the reaction with a large excess of methanol
transformed the unreacted TAI into methyl urethane,
thereby allowing for the sequestration of urethanes 326
with phosphazene base PS-BEMP as ionic pairs bound to
the resin. Subsequent filtration and treatment with potassium hydroxide in methanol, followed by neutral aqueous
work-up, released the starting sugar alcohols in high
yields and purity (Scheme 96).
O
OBnOH
BnO
326
BnOOC
Me
+
MeOC
SO3H
NHBoc
+
–
Ph
t-BuOOC
COOt-Bu
BnOOC
N
Me
BnOOC
Ph
NHBoc
322
t-BuOOC
Scheme 96 Use of the trichloroacetyl isocyanate (TAI) as a new sequestering-enabling reagent
NHBoc
323
COOt-Bu
+
NH2
BnOOC
N
Me
O–
NHBoc
324
Scheme 95 Polymer-assisted multistep synthesis of 4-pyridylalanine N-oxides 324
The same group devised a hybrid solution-phase/solidphase synthesis of oligosaccharides that used trichloroacetyl isocyanate as a sequestration-enabling reagent of
The scope of the derivatisation–sequestering strategy was
demonstrated by its successful application to the solutionphase synthesis of various trisaccharides, under the conditions reported in Scheme 97.
A convenient preparation of aryl ether derivatives was described, in which a sequence of functionalised polymers
was used.137 Two distinct uses of supported arylphosphine
were examined. Intermediate compounds 332 were sucessfully synthesised via Mitsunobu coupling of phenols
OH
O
O
O
O
OBz
O
OBnOBn
328
OBz
327
NMe3BH4
BnO
–
BnO
O
O
329
O
OMe
OLev
O
O
OH O
O
O
O
OH O
331
O
OMe
O
OH
Synthesis of trisaccharide 331 using the trichloroacetyl isocyanate methodology
Synthesis 2007, No. 16, 2409–2453
O
BnO
1) NIS, TMSOTf,
CH2Cl2, –15 °C
2) Cl3CC(O)NCO,
then MeOH
3)
BEMP
OBn
O
4) 0.5 M KOH in MeOH
Scheme 97
O
O
BzO
MeOH, Et2O, r.t.
2) Cl3CC(O)NCO,
then MeOH
3)
BEMP
OBnOBn
OH
BzO
O
O
O
BzO
1) MeOTf, CH2Cl2, r. t.
2) Cl3CC(O)NCO,
then MeOH
3)
BEMP
+
1)
(2.0 equiv)
BnO
SEt
O
OBnOBn
O
BnO
trichloroacetyl carbamates,
polymer-bound
release
Me
i) MCPBA
ii)
N
CH2Cl2, r.t.
0.5 M KOH in MeOH
60 °C
Py2Cr2O7
N
H
N-t-Bu
P
Ph
t-BuOOC
COOt-Bu
N
sequestration
NH2
OMe
Et2N
MeOH
CCl3
O
H
N CCCl3
NMe3OH
321
O
O N
H
BnO
O
H2N
O
O
OBnO
O C N CCCl3
O
BnO
4 Å MS, CH2Cl2, r.t.,
then MeOH
BnO
OMe derivatisation
325
O
O
BzO
330
O
O
O
O
OMe
LevO
(Lev = levulinoyl)
REVIEW
2439
with N-protected aminoalcohols using a supported
arylphosphine in
the presence of triethylamine
(Scheme 98, route A). An alternative approach to 332 required treatment of alkyl chlorides (synthesised starting
from the N-protected aminoalcohols) with phenolates,
generated by treating the phenol substrates with polymersupported 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) in
chloroform, in the presence of a catalytic quantity of potassium iodide (Scheme 98, route B). After removal of the
N-protecting group from compound 332, reaction with a
set of sulfonyl chlorides in the presence of supported
DIPEA followed by purification by treatment with aminomethyl polystyrene and supported mesatoic anhydride 333
furnished the desired library of target compounds 334.
H2SO4 (7%) in
dioxane, 80 °C, 1 h
R1
NHNH2
O
+
R2
R2
N
R1
N
H
335
3
R X, DMF, r.t., 3 h
N
R4 S
R2
N
1
R
N
H
R3
1) R4SH,
2)
337
R2
+
TBD
N
1
R
N
H
SO3H
X
R3
–
336
3) NH3 (2 M in MeOH)
Scheme 99 Synthesis of dialkyl[2-(3-alkylsulfanylmethyl-1H-indol-2-yl)ethyl]amines 337
OH PS-PPh2
1
R
Me
DEAD, CH2Cl2, Route A
r.t.
O
N PG
HO
R1
1,2
N PG 2)
1,2
Me I
BzO
O
1) DMF–MeCN, R2SO2Cl,
DIPEA
O
2) DMF–MeCN,
NH2
N
O
1,2
O
O
3) DMF–MeCN, O
S
N
1,2
R1
R2
334
1
R
333
Scheme 98
334
Polymer-assisted preparation of aryl ether derivatives
Another multistep procedure was described for the preparation of dialkyl[2-(3-alkylsulfanylmethyl-1H-indol-2yl)ethyl]amines 337.138 The method involved the nucleophilic ring opening of 2,2-dialkyl-1,2,3,4-tetrahydro-gcarbolinium salts 336 with thiols, and employed solidsupported reagents in key synthetic steps: the insertion reaction was mediated by a strong, polymer-supported base,
while the purification of the target compounds was facilitated by resin-bound sulfonic acid (Scheme 99).
Kirschning and co-workers139 reported the PASP synthesis of deoxyglycosides that is shown in Scheme 100. This
glycosylation protocol was used to transform glycals 338
into 2-iodoglycosyl acetates 339 using a polymer-bound
bis(acetoxy)iodate(I) complex. The anomeric center was
then activated with polymer-bound silyl triflate, and thus
2-deoxy-2-iodoglycosides 340 were generated in very
good yields in the presence of different glycosyl acceptors.
TfO
O
NMe2
339
H
O
Et
Si
TBSO
SO3H
3) NH3 (2 M in MeOH)
N
338
–
Route B
1) PS-DBU
Cl
+
NMe3I(OAc)2
332
OH
TBSO
N PG
R1
1,2
O
BzO
Scheme 100
sides 340
OAc
Et
Me I
BzO
TBSO
340
O
OR
Polymer-assisted synthesis of 2-deoxy-2-iodoglyco-
A polymer-assisted approach was employed for the solution-phase synthesis of short di- and trinucleotide building
blocks, such as 344, in order to obtain large amounts of
oligonucleotides without the need for chromatographic
purification.140 The method used polyvinyl pyridinium tosylate as the activator of a nucleoside-3¢-O-phosphoramidite 341 in the coupling step with a 5¢-OH nucleoside
(such as 342) or dinucleotide. The resulting phosphite triester 343 was either sulfurised or oxidised to 344 using
polystyrene-bound trimethylammonium tetrathionate or
periodate (Scheme 101). The strategy allowed for the synthesis of building blocks that could be converted into either phosphoramidites or H-phosphonates for further
elongation in solution or on solid support. All the polymer-supported reagents employed could be regenerated
and reused.
Baer and Masquelin141 developed a novel solid-phase synthesis of a library of 2,4-diaminothiazoles 347, starting
from the polymer-bound thiouronium salt 345
(Scheme 102). The synthetic strategy involved the formation of polymer-bound thioureido–thiourea intermediates
346, which, by treatment with different bromo-ketones,
underwent S-alkylation. This was followed by a base-catalysed intramolecular ring closure and cleavage to give
2,4-diaminothiazoles 347. The strategy tolerated a wide
range of functionalities as well as protecting groups.
A polymer-supported approach was employed for the solution-phase synthesis of a library of useful acyl ketones,
thio ketones, and amino ketones 350 from amino acids as
Synthesis 2007, No. 16, 2409–2453
2440
DMTrO
DMTrO
1
O
341
REVIEW
PV
B1
O
B
O
O
+
P OR
N
X = O, S
P X
O
–
NH TsO
RO
O
343
+
B2
LevO
HO
O
rene turned out to be the best amine for this reaction and,
in the presence of acid nucleophiles, the resin played the
role of scavenger for the unreacted acid. After the establishment of optimal reaction conditions, an 80-array library was generated through the use of diverse
nucleophiles as acids, amines, and thiols.
B2
i, ii
+
PS
NMe3
2–
S4O6
NMe
3
+
+
O
344
B2
+ R1NCS b
NH2
c,
345
N
R2COCH2Br
NH
+
S
NH
RHN
346
S
O
NH
S
H2N
S
S
N
N
RHN
O
NHR1
SH
O
NHR1
S
S
R2
N
R2
H2N
N
H
N2
O
348
R
R1H
Cbz
R1
N
H
N
H
Base
O
Br
349
O
PS
NH2Cl
R2
Cbz
Base, CH2N2
R
Cbz
HO
PASP synthesis of short di- and trinucleotide building
S
R
Cl
HBr
350
–
NH2NH O3S
Cl a
O
P X
RO O
NMe3IO4
+
O
O
–
PS
or
ii)
OH
N
H
B1
O
i)
Scheme 101
blocks
Cbz
DMTrO
342
(Lev = levulinoyl)
O
R
OLev
347
Scheme 102 Reagents and conditions: (a) thiourea, DMA, r.t. to
85 °C; (b) DIPEA, DMF; (c) DMF, r.t.
potential cysteine protease inhibitors for the rapid optimisation of P1-P1¢ pockets of different cysteine proteases,
aimed towards the synthesis of cysteine trap protease inhibitors.142
The synthesis of diazo ketones 348, described in the literature to take place with N-methylmorpholine, was improved through the use of diazomethane in the presence of
polymer-supported N-methylmorpholine, which was employed without any particular precautions (Scheme 103).
Bromination of diazo ketone 348 was carried out using a
novel piperidinoaminomethylpolystyrene hydrobromide
reagent, which gave the monobromo ketone 349 as the
unique product in good yield. Nucleophilic substitution of
the bromo ketone was achieved with different polystyrene-supported bases in order to replace the commonly
used potassium fluoride. DimethylaminomethylpolystySynthesis 2007, No. 16, 2409–2453
Scheme 103 Synthesis of acyl ketones, thio ketones, and amino ketones 350 from amino acids
Janda and collaborators143 reported the synthesis of an array of di-, tri-, and tetrasubstituted ureas 353 from polymer-bound carbamates (Scheme 104). The starting point
for this library was the preparation of polymer-bound carbamates 351 and 352. A first approach, which was based
on the treatment of hydroxymethyl JandaJel resin with
isocyanates (R1NCO) in the presence of triethylamine to
provide polymer-bound primary amine carbamates,
proved unreliable for isocyanates other than aryl. Therefore, a second approach, which employed polymer-bound
p-nitrophenyl carbonate (synthesised from hydroxymethyl resin by reaction with p-nitrophenyl chloroformate),
was devised. The p-nitrophenyl carbonate resin was treated with a series of primary or secondary amines (R1NH2
and R1R2NH), providing primary and secondary amine
polymer-bound carbamates. These compounds were treated under ‘smart’ diversity-building cleavage conditions
using a series of aluminum amide complexes to form the
corresponding urea cleavage products 353, which were
obtained in excellent yields and purity. The applicability
OH
R1
NC
O
O
a
b
O
O
351
O
c
O
R1NH2
N
R2X
R1
O
d
352
R3R4NH
e
O
R2
NO2
R2
O
NH
R1
R4
N
353 R1
R3
Scheme 104 Reagents and conditions: (a) isocyanate (5 equiv),
Et3N (5 equiv), CH2Cl2, 24 h; (b) p-nitrophenyl chloroformate (3
equiv), NMM (3.3 equiv), CH2Cl2, 0 °C to r.t., 24 h; (c) for benzyl and
alkylamines: R1NH2 (5 equiv), i-PrEt2N (5 equiv), CH2Cl2, 24 h.; for
arylamines: R1NH2 (5 equiv), NaHMDS (2.5 equiv), THF, –78 to
0 °C, 3 h; (d) LiOt-Bu (5 equiv), R2X (10 equiv), TBAI (2.5 equiv),
DMF–THF (2:1), 24 h; (e) (i) R3R4NH (5 equiv), AlMe3 (2.5 equiv),
PhMe, 0 °C to r.t., 1 h, then PS-SO3H, 50–110 °C, 2–24 h, (ii) THF–
H2O (7:3), 20 min.
REVIEW
of this robust methodology was demonstrated in the synthesis of a series of biaryl ureas, wherein sequential solidphase Suzuki coupling and urea formation reactions were
used.
PLE
0.1 M phosphate buffer
0.5 M NaOH, pH 7, r.t.
n
MeO2C
CO2Me
n
HO2C
CO2Me HO2C
144
Ley and co-workers disclosed an application of polymer-supported reagents, including supported enzymes, in
the synthesis of g-aminobutyric acid (GABA) analogues
with three-, four-, five- and six-membered rings. The research group employed polymer-supported pig liver esterase on Eupergit® for the resolution of meso-diesters
354, which were the starting point for three-memberedring GABA analogues 359 (Scheme 105).
PLE
1) BH3⋅SMe2, THF,
–10 °C to r.t.
+
–
2)
NBn OH
SO3H
3)
O
O
CO2Me
354
1) BH3⋅SMe2, THF,
–10 °C to r.t.
ii)
+
–
NBn3OH
HO
F
CO2Me
90% ee
CO2H
EtOH, reflux
SO3H
1)
Boc
CO2Me
358
CO2H
364
HO2C
365
NH2
NH2
CO2Me
355a
O
N
H
355b
NMe3N3
NMe3I
CO2H
366
Scheme 106
N
MeOH, reflux
NH2
O
367
O
Polymer-assisted synthesis of GABA analogues
MeCN, 50 °C
CO2Me
356
Kamal and collaborators described a polymer-assisted
strategy that used both supported coupling agents and supported catalysts for the synthesis of fused [2,1b]quinazolinones 373 (Scheme 107).145
NH2
SO3H CH2Cl2, r.t.
2) 1 N HCl, reflux
HN
n
+
MeOH, reflux
O
1) SOBr2, MeOH, r.t.
2)
N
CO2Me
357
NPhth
363
NH2
F
PhthN
N3
HO2C
+
1) Reduction
2)
N
H
DMF, reflux
n
H2N
Br
O
O
N
362
HO2C
O
361
360
N
4)
NK
n
+
3
PhthN
0.1 M phosphate buffer
0.5 M NaOH, ph 7, r.t.
CO2Me
O
+
MeO2C
2441
–
+
Cl H3N
CO2Me
359
Scheme 105 Polymer-assisted synthesis of three-membered-ring
GABA analogues 359
The target products 359 were synthesised via the reduction of the carboxylic acid to 355a and 355b, achieved using borane–dimethylsulfide complex in tetrahydrofuran.
It is worth noting that, in this case, any attempt to apply
polymer-supported reducing agents to the reaction failed.
The conversion of bromide 356 into azide 357 was carried
out by application of a polymer-supported azide, while the
reduction of azide 357 was possible using either
Staudinger conditions (with polymer-supported triphenylphosphine) or by Pd/C under hydrogen atmosphere
(using Boc protection to minimise lactonisation). The reaction sequence was expanded to analogues with four-,
five- and six-membered rings. The strategy to prepare
these analogues included a slightly different combination
of polymer-supported and traditional solution-phase
chemistry (Scheme 106).
The group reported an efficient method for the synthesis
of (d)- and (l)-vasicinone via asymmetric reduction of
pyrrolo[2,1-b]quinazoline-3,9-dione 372 that used sodium borohydride with trimethylsilyl chloride as the reducing agent and a polymer-supported chiral sulfonamide as
catalyst. In the first step, 2-azidobenzoic acids were coupled with different lactams through the use of N-cyclohexylcarbodiimide N¢-methyl polystyrene to give N-(2azidobenzoyl)lactams 368. Excess acid and urea by-products were conveniently filtered off from the azidolactams
368. Intramolecular azido-reductive cyclisation of the azidolactams was carried out with polymer-supported triphenylphosphine, forming the fused [2,1-b]quinazolinones
369 in good overall yields. Bromination of deoxyvasicinones by a polymer-bound brominating agent (Amberlyst
A-26, Br3– form) afforded allylic monobromo derivatives
370 in excellent yields. The bromo-substituted deoxyvasicinones gave the acetylated derivatives upon treatment
with the acetic acid form of Amberlyst A-26. Treatment of
the acetylated intermediates with a borohydride exchange
resin in the presence of palladium(II) acetate afforded racemic vasicinones 371, which, by oxidation with poly(vinylpyridinium
dichromate)
gave
diones
372.
Enantioselective reduction of the diones was carried out
using a polymer-supported chiral sulfonamide in the presence of sodium borohydride and trimethylsilyl chloride,
Synthesis 2007, No. 16, 2409–2453
2442
REVIEW
O
OH
O
N3
+ HN
R2
R1
PS-DCC
R2
O CH2Cl2, r.t.
95–98%
R1
N
96–98%
O
N3
368
+
>99%
N
O
R2
370
N
O
R2
Ph
HO Ph
R1
NH Cr2O72–
N
DMF, 70 °C
N
Br
+
–
NMe3BH4
R2
2
N
R1
93%
O
372
ii)
N
Pd(OAc)2, MeOH
reflux
O
+
O
NaBH4, TMSCl
N
–
NMe3OAc
MeOH, r.t.
O
S
R1
+
i)
N
(S)-373
OH
(l)-vasicinone
(93%)
N
369
NaBH4, TMSCl
N
R2
THF, r.t.
N
R1
O
–
NMe3Br3
O
R2
R1
O
PPh2 2
R
CH2Cl2, r.t.
N
OH
371
O
R1
(R)-373
N
OH
(d)-vasicinone
(93%)
Scheme 107
S
N
O
Ph
HO Ph
Synthesis of optically active vasicinones
affording the optically active (l)-vasicinones or (d)-vasicinones.
More recently, some research has been aimed toward
more ambitious targets, employing solid-supported reagents in key steps of the total syntheses of important natural products. For example, Ploypradith and coworkers146 exploited four different polymer-supported reagents in the total synthesis of lamellarins 377
(Scheme 108). Amberlyst A-26 Br3–, in conjunction with
polymer-bound pyridine hydrobromide perbromide
(PVPHP) allowed the selective keto a-bromination of
ortho-substituted acetophenone derivatives, and thereby
yielded the corresponding monobromination products 374
(phenacyl bromide derivatives), which were used directly
in condensation reactions with benzyldihydroisoquinoline, mediated by Amberlyst A-26 NaCO3–. The 2H-pyrrole carbonates subsequently underwent intramolecular
Friedel–Crafts transacylation followed by lactonisation to
provide the lamellarin skeleton 377. Alternatively, Amberlyst A-26 NaCO3– was used as a base in the condensation reaction of benzyldihydroisoquinoline with a-nitrocinnamate derivatives to provide the corresponding 2ethoxycarbonyl pyrroles. These smoothly underwent Odebenzylation and were then lactonised to furnish the
lamellarin skeleton. The novel Amberlyst 15 mediated
lactonisation reactions were effective in combining the
otherwise two separate steps into a single transformation.
Dondoni and co-workers147 reported a two-step biomimetic synthesis of isotetronic acid 382. The study was promoted by the observation that L-proline failed to act as an
organocatalyst in the homoaldol reaction of ethyl pyruvate. Direct catalytic homoaldol reaction of ethyl pyruvate
was carried out using a combination of (S)-(+)-1-(2-pyrrodinylmethyl)pyrrolidine and trifluoroacetic acid as organocatalyst.
Synthesis 2007, No. 16, 2409–2453
The procedure was then optimised using polymer-supported reagents (Scheme 109) which favoured the lactonisation of the aldol and the isolation of the isotetronic acid
derivative in free-hydroxy form. In particular, an acid resin (polymer-supported sulfonic acid Amberlyst 21) was
used to promote the formation of isotetronic acid 382 (in
equilibrium with its trimeric form 381), and lactone 380.
MeO
O
Br
OCOOEt
MeO
OBn
N
O
R1 a
MeO
374
2
R
R2
MeO
375
R1
MeO
b
O
N
MeO
O
OEt
MeO
R1
MeO
R2
376
c
MeO
MeO
O
N
O
MeO
R1
377
MeO
R2
Scheme 108 Reagents and conditions: (a) Amberlyst A-26 (Br3–
form), PVPHP; (b) Amberlyst A-26 (NaCO3– form); (c) Amberlyst
15.
REVIEW
2443
NH
SO3– N
H
H
1)
N
H
CO2Et
379
, TFA
N
O
Amberlite IRC-50 carboxylic acid resin furnished the addition product 383. Conversion of 383 into the corresponding bromide 384 was carried out with carbon
tetrabromide and polymer-supported triphenylphosphine.
The subsequent transformation into azide 385 was
achieved with an azide ion-exchange resin, allowing for
the synthesis of primary amine 386 via hydrogenation
with palladium-on-carbon. The polymer-supported azide
reagent used in the reaction of 384 to 385 was prepared by
an ion-exchange reaction of a commercially available
Amberlyst resin, functionalised as a quaternary ammonium chloride, with an aqueous solution of sodium azide.
Treatment of amine 386 with an aqueous solution of trifluoroacetic acid and a further portion of palladium-oncarbon under a reducing atmosphere of hydrogen furnished nornicotine 387 as its trifluoroacetate salt. Evaporation of the solution, followed by dissolution of the
residue in ethyl acetate and addition of a polymer-supported carbonate base, liberated the free amine, which in turn
was captured on an Amberlyst 15 resin.
CF3COO–
NH4OH (aq)
SO3NH2
378
solid-phase
SO3–
2)
3) filtration
solution-phase
HO CO2Et
1)
O
OH
CO2Et
EtO2C
NMe2
EtO2C
O
O
2) filtration
380
solid-phase
381
O
–O
NHMe2
O
NHMe2
O
O
O
O
CO2Et
CO2Et
1) AcOH
2) filtration
HO CO2Et
EtO2C
O
O
O
OH
CO2Et
EtO2C
Scheme 109
acid 382
This allowed for the facile purification of the bound material by simple elution of the resin with dichloromethane
and thus enabled removal of contaminants such as ethylene diol, a by-product of the previous conversion. Release
of the nornicotine 387 from the resin was achieved by suspension of the polymer in a 2 M solution of ammonia in
methanol, followed by filtration and concentration of the
filtrate under reduced pressure. The material obtained
from this reaction sequence was determined to be of greater than 90% purity as determined by LC–MS analysis.
Nornicotine 387 was then used for the rapid construction
of a small collection of nicotine derivatives, including analogues 388–391, using a range of readily available
monomers.
O
HO
O
CO2Et
OH
382
Polymer-assisted biomimetic synthesis of isotetronic
The Ley research group has been very active in the synthesis of several natural compounds of pharmaceutical interest using sequences, sometimes exceptionally complex,
of solid-supported reagents and scavengers.
In 2002, they reported the synthesis of nornicotine, nicotine, and their derivatives, through the use of resin-bound
compounds in various steps of the synthesis
(Scheme 110).148 The synthesis involved the addition of a
Grignard reagent to pyridine-3-carbaldehyde in tetrahydrofuran at –78 °C. Quenching of the reaction with an
O
O
The same year, Ley’s research group developed a concise
biomimetic
synthetic
approach
to
carpanone
(Scheme 111).149 The synthesis began with the allylation
of commercially available sesamol 392 with allyl bromide
OH
O
O
1)
N
BrMg
2)
N
COOH
O
O
N3
NMe3N3
PPh2
O
383
O
Br
O
384
CBr4
N
(90%)
385
N
(quant.)
H2, Pd-C
1) TFA, H2O
H2, Pd-C
N
N
O
O S
R
2)
388
N
N
389
N
R
387
(58%)
3)
N
O
R
O
SO3H
N
N
386
(60%)
N
390
N
Scheme 110
O
NH2
NMe3NaCO3
N
H
O
R
N 391
H
Synthesis of nornicotine, nicotine, and their derivatives using resin-bound compounds
Synthesis 2007, No. 16, 2409–2453
2444
REVIEW
N N t-Bu
P
N
N
PF6
Br
O
In addition, Baxendale and Ley150 published a total synthesis of the amaryllidaceae alkaloid (+)-plicamine which
including a model-compound study. The elegant synthesis
of the compounds was carried out using solid-supported
reagents and scavengers in multistep reaction sequences
as shown in Scheme 112.
MW
O
OH
392
N
N
O
O
using catalytic amounts of a polymer-supported version of
cobalt(salen). Side products were scavenged from the reaction mixture by a polymer-supported trisamine scavenger and polymer-bound sodium carbonate.
O
393
Ph2
P
Ir(THF)2H2 PF6
P
Ph2
O
O
O
OH
O
394
N N
Co
O O
O
H
O
O
O
i)
H
O
O
O
NEt3 NaCO3–
ii)
O
396
A more efficient strategy151 for the synthesis of new naturally occurring amaryllidaceae alkaloids was later published by the same group (Scheme 113). The synthesis
was based on a divergent approach and was facilitated by
polymer-supported reagents and scavengers; in the process, two structural analogues of 411, 408 and 410, which
possess the required functional components and stereochemistry, were alos produced. Starting from the common
intermediate 403, two parallel pathways were followed.
One involved the initial conversion of the C3 alcohol into
a mesylate, followed by stereocontrolled nucleophilic inversion with methanol to yield 404 in high yield.
OH
395
i–iii
N
H
iii)
NH2
N
NH2
Scheme 111 A biomimetic synthetic approach to carpanone 396
using polymer-supported reagents
Alternatively, the C-3 methoxy epimer 402 was obtained
via methylation using trimethylsilyl diazomethane (TMSCHN2) and an immobilised sulfonic acid catalyst; this also
occurred in excellent yield. After cleavage of trifluoroacetate groups from both compounds 404 and 402 under
microwave conditions, the corresponding amines 405 and
406 were transformed into (+)-plicane (407) and 3-epiplicane (408) using cerium ammonium nitrate absorbed
on silica. Branching in a different direction from the same
two amines 405 and 406 led to the synthesis of the prod-
and the polymer-supported phosphazene base PS-BEMP.
The allylated product 393 was then subjected to Claisen
rearrangement, which was achieved through the use of a
toluene–ionic liquid (1-ethyl-3-methyl-1H-imidazolium
hexafluorophosphate) biphasic system that was heated in
a focused microwave well system. A critical synthetic
step, the isomerisation of 394 to 395, was carried out with
a new polymer-supported Felkin iridium catalyst. Finally,
the coupling of 395 to form carpanone 396 was carried out
O
I
+
EtOAc
O
OH
1)
95%
H
O
–
OAc
NMe3BH4
397
O
N
NHMe
N
398
N
82%
O
N
O
O
CF3CH2OH, CH2Cl2
H
2) (CF3CO)2O, CH2Cl2
O
N
O
H2N
OAc
OH
OH
O
NHMe
CF3
O
(quant.)
NHMe
O
O
CF2SO3H
N
399
Me
H
N
O
O
NHMe
O
O
N
O
O
O
Me
H
O
CF3
H
N
O
(quant.) 400
CF3
CF2SO3H
MeO3CH
O
O
H
N
O
CF3
401 (quant.) O
O
MeO
N
MeOH
96%
Me
H
NMe3OH
O
O
H
N
O
402
Scheme 112
Synthesis of dinitrogenous amaryllidaceae alkaloids
Synthesis 2007, No. 16, 2409–2453
CF3
O
REVIEW
2445
Route A
MeO
N
N
N
N
O
CF3
404
CF3
403
O
NMe3OH
+
N
O
CF3
402
O
O
NMe3OH
–
99%
+
MeOH, MW
MeO
O
O
O
O
O
H
NH
N
O
405
O
H
N
O
407
N
O
94%
H
Me
H
[Ce(NH4)2(NO3)6]
N
O
96%
H
MeO
Me
H
N
[Ce(NH4)2(NO3)6]
N
MeO
Me
H
Me
H
O
N
O
95%
MeOH, MW
MeO
H
100%
–
O
O
TMS-CHN2, MeOH
H
96%
N
O
O
Me
H
SO3H
MeSO2Cl, MeOH
H
MeO
Me
H
N
O
O
Route B
HO
Me
H
NH
O
408
406
92%
90%
MeO
MeO
H
O
H
Me
O
N
O
N
H
MeO
O
N
O
N
O
O
Me
N
Me
H
H
O
H
N
O
O
409
Scheme 113
pathways
411
OH
410
OH
OH
An efficient strategy for the synthesis of new naturally occurring amaryllidaceae alkaloids 411 using two different synthetic
of unnatural analogues, was described. The synthesis of
the target molecule was envisioned to take place via SN2
inversion of diol 415. The selective isomerisation of phenol 412 to trans-alkene 413 was carried out using a polymer-supported
iridium
catalyst
(Scheme 114).
Subsequent O-methylation using the polymer-supported
base PS-BEMP with iodomethane afforded 414 in 98%
yield. The asymmetric centers were then installed using a
Sharpless asymmetric dihydroxylation.152
ucts (–)-obliquine (409) and epi-obliquine (410), the latter
of which subsequently led to plicamine (411). The reaction sequence required an N-alkylation promoted by an
immobilised carbonate base, followed by scavenging of
the reaction mixture with an aminothiol resin. The product
411 thus-obtained was found to be identical to the reported authentic material.
Subsequently, the development of a new general asymmetric route towards both enantiomers of the anti-malarial
natural product polysphorin (416), plus a small collection
OH
MeO
OH
OMe
MeO
Ph2
+
–
P
Ir(COD)PF6
P
Ph2
412
OMe
MeI
413
N P N
N
activated H2
OMe
MeO
OMe
OMe
1) AD-mix-β
methanesulfonamide
H2O, t-BuOH
MeO
OH
OMe
MeO
OMe
OH
2)
B
HO
OH
O
HO
OH
414
415
416
Dean–Stark, toluene
3) acetone, H2O
Scheme 114
MeO
other enantiomer also
made with AD-mix-α
A general asymmetric route to polysphorin (416) and analogues
Synthesis 2007, No. 16, 2409–2453
2446
REVIEW
drofuranyl ether to afford the desired hydroxamic acid
420. An extra point of diversity could be incorporated into
the synthesis by N-alkylation of the intermediate sulfonamide 417 prior to Heck olefination to afford 419; this
could be achieved in the presence of PS-BEMP to afford
418.
The first fully automated multistep PASP synthesis of an
array of histone deacetylase (HDAc) inhibitors 420, prepared by a four- or five-step sequence, was reported in
2003.72
The immobilised reagents allowed for the entire sequence
to be carried out in a single solvent (DMF), thereby avoiding the drawbacks associated with the need for solvent interchanges. The incorporation of in-line purifications with
scavenger resins was integrated with a catch-and-release
strategy (Scheme 115).
The study was later extended to the synthesis of an array
of hydroxamic acids, structurally related to trichostatin A
(TSA), using the same parallel, multistep PASP procedure.153 After biological evaluation in vitro, a number of
these compounds were found to possess micromolar inhibitory activity in a HeLa cell nuclear extract enzyme inhibition assay (HDAc-1 and 2), and anti-proliferative
activity in human umbilical vein endothelial cells
(HUVECs). In addition, the most active compounds were
shown to be potent inhibitors of tube-formation (neovascularisation) in an in vitro model of angiogenesis.
For example, the sulfonylation of aniline, which typically
generates a mixture of mono- and bis-sulfonamides in solution, was improved by the treatment of aniline with a
sulfonyl transfer reagent derived from the immobilisation
of an appropriate aryl sulfonyl chloride on polymer-supported dialkylaminopyridine in N,N-dimethylformamide.
Any unreacted aniline remaining after incubation with the
sulfonic acid ion-exchange resin Amberlyst H-15 was
thus removed to afford monosulfonamide 417 in high purity and acceptable yield. Heck olefination of 418 with
acrylic acid to afford 419 was investigated with a variety
of immobilised palladium catalysts and was profiled using
the Reactarray SK233 automated reaction sampling system; this allowed for the minimisation of competing dehalogenation pathways with microencapsulated palladium(II) acetate (Pd EnCat) as the source of palladium
and tributylamine as base. A work-up procedure to remove the palladium catalyst exploited the carboxylic acid
functionality present in the desired product 419 in an inline catch-and-release purification step, thus providing
concomitant activation of the acid functionality by incubation of the supernatant from the Heck reaction with 2(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluoroantimonate on polystyrene (PS-HBTU). The
resin-bound activated HOBt ester was treated with a solution of O-tetrahydropyranyl hydroxylamine to release the
hydroxamate into solution. Exposure of this to Amberlyst
H-15 resulted in the final O-deprotection of the tetrahy-
An impressive application of the use of supported reagents and scavenging techniques was provided by the
Ley research group in 2004154 with the multistep total synthesis of the cytotoxic antitumour natural product
epothilone C (425), a precursor of epothilone A (426).
The researchers applied a stereoselective convergent synthetic strategy, incorporating polymer-supported reagents, catalysts, scavengers and catch-and-release
techniques to avoid aqueous work-up steps and chromatographic purification (Scheme 116). The high selectivity
and overall efficiency was comparable with those
achieved using conventional synthetic methods, and the
target molecule 425 was prepared in 29 steps, with its
longest linear sequence only 17 steps long, from readily
available materials.
Since the established synthetic routes to the epothilone
16-membered macrocycle commonly involve convergent
strategies, the route that these authors chose incorporated
the enantioselective preparation of three fragments 421,
422, and 423 (Scheme 116). Subsequent diastereoselective coupling was envisioned to provide a convergent ap-
N
N
I
I
O
Ar
S
O
N
H
90%
+
O
OH
O
S
O
N
O
S
N
+
THPONH2
419
R
Scheme 115
N
SO3H
418
SbHCl3
N
O
Pd
NMe2
–
N
O
S
R
Me2N
H
N
O
Ar
R-X
417
Ar
OH
I
66%
H2N
O
N N t-Bu
P
N
N
O
Cl S Ar
O
SO3H
O
–
O
N
H
O
Ar
S
O
N
420
R
(33% overall)
A fully automated multistep PASP strategy for the synthesis of an array of HDAc inhibitors 420
Synthesis 2007, No. 16, 2409–2453
OR
REVIEW
2447
OTBS
OTBS
S
PS-supported
reagents
starting materials
S
PS-supported
reagents
N
N
421
OTBS OH
1
OTBS
OH
15
422 O
O
13
12
6
I
S
S
423
N
7
PS-supported
reagents
N
O
O
O
424
O
OH
O
OTBS
OH
O
O
OH
O
OH
425
426
Scheme 116
Strategy for the total synthesis of epothilones C (425) and A (426)
natural product epothilone C (425), which is a starting material for the epoxidation to epothilone A (426).
proach to 425. The synthesis, which included some wellestablished chemistry as well as the integration of existing
strategies with newly devised polymer-based methodologies, was carried out by the stereoselective union of fragments 422 and 423 by a lithium aldol reaction between
C6–C7 (product numbering), followed by Wittig reaction
to incorporate fragment 421 that involved bond formation
between C12 and C13 (product numbering). Ring closure
by C1–C15 macrolactonisation subsequently provided the
Three independent methods were simultaneously investigated to construct fragment 422. The first incorporated
stereochemistry available from the application of pantolactone (427) (Scheme 117), the second relied upon Oppolzer’s sultam chiral auxiliary to induce the desired
asymmetry, and the third approach involved Kiyooka’s
N
OH
a) N
OTBS
N
O DIBAL-H
O
O
TBSCl
OH
NH2
OH
431
COOH
g)
BF3.OEt2,
then MeOH
+
H2N
BzCl
TMS
–
NEt3NaCO3
432
N
BF3.OEt2
OH
f)
OBz
d)
MgCl
429
N
N
H
TMS
OTBS
O
428
e)
OH
c)
OH
O
427
OH
OTBS
b)
+
+
2–
NEt3 S2O3
2
Ph
OBz
OH
NEt3 Ph
H2O2
433
TBSOTf
N
N
i) DIBAL-H
k) EtMgCl
O
OH
Cl , then TFA
h)
N
–
NEt3NaCO3
430
OTBS
O
OTBS
j) Al2O3.HCrO3Cl
COOH
OTBS
422
l) Al2O3.HCrO3Cl
O
OBz
OTBS
OTBS
435
OTBS
434
Scheme 117 Synthesis of fragment 422 in the convergent synthesis of epothilone C. Reagents and conditions: (a) TBSCl (2.0 equiv), PSTBD
(5.0 equiv, 2.6 mmol/g), CH2Cl2, r.t., 10 h, then MeOH, 96%; (b) DIBAL-H (1.3 equiv, 1.0 M in PhMe), PhMe, –78 °C, 30 min, then
Na2SO4×10H2O, r.t., 99%; (c) TMSCH2MgCl (4.0 equiv, 1.0 M in Et2O), THF, 60 °C, 10 h, then Amberlite IRC-50 (28 equiv, 10 mmol/g), r.t.,
94%; (d) BF3×OEt2 (1.0 equiv), r.t., 15 h, then MeOH, PS-carbonate (5.0 equiv, 3.2 mmol/g), r.t., 5 h, 98%; (e) benzoyl chloride (1.2 equiv),
PS-TBD (3.0 equiv, 2.6 mmol/g), CH2Cl2, r.t., 5 h, then PS-trisamine (1.0 equiv, 4.27 mmol/g), r.t., 73%; (f) BH3×THF (3.0 equiv, 1.0 M in
THF), THF, 0 °C, 20 h, then MeOH, PS-carbonate (15.0 equiv, 3.23 mmol/g), 30% H2O2, PS-thiosulfate (4.0 equiv, 2.0 mmol/g), then silica
gel (Et2O), 68%; (g) Et3N (3.0 equiv), PS-trityl chloride (2.0 equiv, 1.23 mmol/g), CH2Cl2, r.t., 4 h, then CH2Cl2, 5% TFA, r.t., 1 h, 88%; (h)
TBS triflate (3.0 equiv), PS-NMM (10 equiv, 3.5 mmol/g), CH2Cl2, 0 °C to r.t., 20 h, then MeOH, 98%; (i) DIBAL-H (3 equiv, 1 M in hexanes),
THF, –78 °C, 1 h, then Na2SO4×10H2O, r.t., then silica gel (hexane–EtOAc, 10:1), 77%; (j) PCC on basic alumina (4.0 equiv, 1.0 mmol/g),
CH2Cl2, r.t., 20 h, then silica gel (Et2O), 100%; (k) EtMgBr (2.0 equiv, 2.0 M in Et2O), THF, –78 °C, 2 h, then Amberlite IRC-50, then silica
gel (hexane–EtOAc, 5:1), 98%; (l) PCC on basic alumina (3.0 equiv, 1.0 mmol/g), CH2Cl2, r.t., 20 h, then silica gel (Et2O), 98%.
Synthesis 2007, No. 16, 2409–2453
2448
REVIEW
chiral borane Lewis acid methodology to place the C3
chiral center via an asymmetric Mukaiyama aldol reaction.
Highly diastereoselective aldol coupling between fragments 422 and 423 (which generated two new stereocenters), was carried out. The use of freshly prepared
lithium diisopropylamide in tetrahydrofuran reliably gave
excellent selectivity (>13:1, 80%) for the desired anti-Felkin–Anh adduct 447, with excess aldehyde required to
force the reaction to completion and a diamine polymer
used to scavenge excess acid and aldehyde from the crude
reaction mixture (Scheme 120). Protection of aldol adduct
447 was followed by ozonolysis (using polymer-supported triphenylphosphane to reduce the ozonide) to furnish
aldehyde 448 in 76% yield. This was then used in a Wittig
reaction with fragment 446. The immobilised phosphonium salt 446 was treated with excess sodium bis(trimethylsilyl)amide. Subsequent washing with anhydrous
tetrahydrofuran allowed for the isolation of the corresponding salt-free ylide, which, by coupling with aldehyde 448, afforded the necessary cis olefin 449
exclusively and in almost quantitative yield. Selective primary alcohol deprotection, followed by a two-step oxidation with catalytic TPAP in the presence of Nmethylmorpholine N-oxide (NMO) and polymer-supported chlorite, gave the corresponding carboxylic acid 450 in
75% yield. Selective removal of the allylic tert-butyldimethylsilyl ether with excess tetra-n-butylammonium fluoride provided a hydroxy acid, the starting material for
macrolactonisation, which proceeded under Yamaguchi
conditions using a polymer-supported DMAP equivalent.
Polymeric sulfonic acid resin was used to remove both
tert-butyldimethylsilyl protecting groups, to protonate the
thiazole nitrogen atom, and to capture the natural product
as an ion-exchanged salt. After a series of washes, a final
flash column chromatographic step afforded pure 425.
The high selectivity and overall efficiency was comparable with those achieved using conventional synthetic
methods.
Fragment 423 was generated from a commercially available Roche ester derivative to provide the stereochemistry
at C8 (Scheme 118).
a) DHP
Br
SO3H
OH
Br
b) NaI
436
COOH
OTHP
437
c) CuI
HN
H2N
MgBr
d) MeOH
O
H2N
SO3H
OTHP
e) Al2O3.HCrO3Cl
423
N
438
Scheme 118 Synthesis of fragment 423 in the convergent synthesis
of epothilone C. Reagents and conditions: (a) 3,4-dihydro-2H-pyran
(1.02 equiv), PS-TsOH (0.05 equiv, 4.2 mmol/g), neat, 30 min, 98%;
(b) NaI (3 equiv), 2-butanone, 75 °C, 1 h, then silica gel filtration
(Et2O), 96%; (c) CuI (1.0 equiv), 3-butenylmagnesium bromide (4.0
equiv, 0.5 M in THF), THF, –10 °C to 0 °C, 135 min, then Amberlite
IRC-50 (15 equiv, 10.0 mmol/g) and PS-trisamine (3.0 equiv, 4.36
mmol/g), r.t., 24 h, 97%; (d) MP-TsOH (0.04 equiv, 4.2 mmol/g), MeOH, r.t., 450 min, 97%; (e) PCC on basic alumina (3.0 equiv, 1.0
mmol/g), CH2Cl2, r.t., 210 min, 80%.
Fragment 421 was obtained by two independent methods;
the first involved installation of the C15 stereocenter using a Brown allylation in conjunction with a catch-and-release method to isolate the resulting allyl alcohol. The
second method incorporated a commercially available
asymmetric a-hydroxylactone derivative of malic acid to
introduce the C15 stereocenter (Scheme 119).
The details of the synthesis were described in a related
publication.155
OH
a) TBSCl
OH
DMAP
DMAP
O
O
b) MeLi
439
OTBS
c) TBSCl
OH
O
COOH
S
OTBS
O
440
d)
S
+
N
441
e) P(OEt)3
O
442
S
S
N
N
–
NEt3NaCO3
Cl
f) BuLi
S
N
443
O
P(OEt)2
H
S
N
i)
OTBS
OTBS
PPh2
h) I2
OTBS
421
–
445
NEt2
I
+
N
NEt3NaCO3
PPh2
446
PPh2I
g) CSA
OH
444
TBSO
OTBS
Scheme 119 Synthesis of fragment 421 in the convergent synthesis of epothilone C. Reagents and conditions: (a) TBSCl (1.4 equiv), PSDMAP (2.0 equiv, 1.49 mmol/g), CH2Cl2, r.t., 90 min, 97%; (b) MeLi (1.05 equiv), THF, –78 °C, 40 min, then Amberlite IRC-50 (21 equiv,
~10 mmol/g), r.t., 45 min, 98%; (c) TBSCl (1.48 equiv), PS-DMAP (2.0 equiv, 1.49 mmol/g), CH2Cl2, r.t., 150 min, 98%; (d) PS-carbonate (2
equiv, 3.5 mmol/g), MeOH, r.t., 45 min, 98%; (e) triethylphosphite (1.2 equiv), neat, 160 °C, 3 h, 84%; (f) 443 (3.5 equiv), n-BuLi (3.5 equiv,
1.6 M in hexanes), THF, –78 °C, then 442 (1.0 equiv), –78 °C to r.t., 1.5 h, then PS-benzaldehyde (5.0 equiv, 1.2 mmol/g), r.t., 30 min, then
silica gel (Et2O), 100%; (g) CSA (1.5 equiv), MeOH–CH2Cl2 (1:1), 0 °C, 150 min, then PS-carbonate (2.2 equiv, 3.5 mmol/g), 2 h, 100%; (h)
iodine (4.0 equiv), PS-triphenylphosphine (5.0 equiv, 3.3 mmol/g), MeCN–Et2O (3:1), then diethylaminomethylpolystyrene (8.0 equiv, 3.2
mmol/g), r.t., 19 h, 73%; (i) PS-triphenylphosphine (1.0 equiv, 3.3 mmol/g), PhMe, 90 °C, 18 h.
Synthesis 2007, No. 16, 2409–2453
REVIEW
2449
OTBS
OTBS
TBSO
TBSO
OTBS
O
422
NH2
N
H
O
O
OH
N
NaHDMS
2) O3
O
OTBS
PPh2
447
423
S
N
OTBS OH
O TBS
OTBS
COOH
TPAP, NMO
+
–
PPh2I
–
NEt3NaCO3
446
S
S
N
N
O
O
OH
O
OH
O
trichlorobenzoyl
chloride
DMAP
NMe3ClO2
O
OTBS TBAF
450
449
+
OTBS
O
O TBS
CSA
+
448
S
N
Scheme 120
O
NEt2
LDA, THF
+
S
OTBS
1) TBSOTf
O
OTBS
O
OH
SO3H
O
OH
425
NH3, MeOH
426
The convergent synthetic strategy for the preparation of epothilone C
Pursuing an analogous goal, Kirschning and coworkers156 reported the first synthetic advances towards
the novel diterpenoid tonantzitlolone (453): the preparation of key fragments and the synthesis of the complete
carbon backbone, 452 (Scheme 121).
starting materials
PS-supported
reagents
BnO
OTBDPS
ether, and then the ester was reduced. Oxidation was then
achieved with the reagent system of diacetoxybromate(I)
resin with TEMPO, and led to enantiomerically pure aldehyde 456 in almost quantitative yield. Aldehyde 456 was
then used to obtain the crucial fragment 460 through Horner–Emmons reaction with 457 followed by asymmetric
dihydroxylation with AD-mix a to yield 459 and subsequent reduction.
O
HO
O
H
HO
448
H
O
H
OMe
OMOM
O
HO
HO
453
O
HO
O
OBn
OBn
I
454
OTES
OTBDPS
O
OTBDPS
456
455
H
O
452
Ph
O OMe
P
OMe
Ph
Scheme 121
–
O
HO
H
+
PPh2I2
OTBDPS
O
OH
NMe3Br(OAc)2
451
(Ph)2P
OMe 457
Synthesis of 452, a precursor of tonantzitlolone (453)
The commercially available isobutyrate 454 was used to
generate building blocks 455 and 456, as reported in the
literature (Scheme 122). Compound 455 was prepared by
TES silylation, reduction, and subsequent iodination using a polymer-assisted variant of the Appel protocol. The
free hydroxyl group in 454 was protected as its TBDPS
HO
458
85%
After the retrosynthetic analysis, which outlined a convergent synthesis, a synthetic strategy was developed. The
key steps included reactions rarely used in natural product
synthesis, such as the chromium Reformatsky reaction, a
protocol for the asymmetric acylation of aldehydes, and
the use of polymer-supported reagents for both iodination
(using a polymer-assisted variant of the Appel protocol)
and oxidation of an alcohol using a diacetoxybromate(I)
resin with TEMPO.
OMe
CO2Me
HO
OTBDPS
O
HO
459
OTBDPS
460
OTBDPS
Scheme 122 Synthesis of the crucial fragment 460 in the synthesis
of precursors of tonantzitlolone
8
Conclusions
The high and diverse number of examples reported in this
review demonstrates that the field of organic synthesis assisted by solid-supported reagents has reached a certain
Synthesis 2007, No. 16, 2409–2453
2450
maturity. On the other hand, there is much room for expansion, as many of the traditional organic transformations do not yet have a polymer-assisted version. In
addition, the amount of product that can be obtained with
this technique is still low, and the cost of many supported
reagents is high. However, because of the high efficacy of
many of these processes, it is certain that efforts will continue in the search for new and more efficient supports, as
well as new reagents, that will allow this technique to
move from its current discovery phase into regular use in
preparative organic chemistry laboratories.
9
Notes Added in Proof
During proof preparation, several articles dealing with SSRs have
been published: two review articles,157a,b three reports157c–e and a
review157f on the synthesis of new supported hypervalent iodine oxidising agents, some papers dealing with Stille157g,h and Suzuki157i
couplings, a catch-and-release approach to peptidyl dicarbonyl
compounds,157j a synthesis of acylsulfonamides,157k three multistep
syntheses of heterocycle-based libraries157l–n and the use of a supported version of TsOH for deprotection of aromatic ethers.157o
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Synthesis 2007, No. 16, 2409–2453

Solid-Supported Reagents and Catch-and

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