Erythronolide and Erythromycin - The Scripps Research Institute

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Erythronolide and Erythromycin - The Scripps Research Institute
Erythronolide and Erythromycin
Y. Ishihara
O
O
propionyl CoA
Me
methylmalonyl CoA
(6 equiv.), polyketide
synthase, β-ketoacyl
reductase, β-ketoacyl
dehydratase
Me
HO
OH
Et
O
mycarose
Me
glycosyl
OH transferase
6
5
Me
OH
3
enzyme-bound 6-deoxyerythronolide seco acid
(linear heptaketide)
O
10
Me
O
O
6
5
Me
1
2
cytochrome
P450 (C6
hydroxylase)
O
OH
Et
O
6
5
Me
3
OH
O
mycarose
Me
glycosyl
OH transferase
Me
desosamine
glycosyl
transferase
Et
OH
O
6-deoxyerythronolide B
Me
OH
6
5
Me
NMe2
HO
Me
O
Me
Me
Me
OH
12
Me
O
Me
OH
[O] at C12
O-methyl
transferase
NMe2
HO
O
OMe
Et
O
Me
6
5
Me
OH
O
NMe2
HO
O
O
OH
Me
O
OMe
Me
Me
OH
O
erythromycin D
(JACS 1977, 99, 1620)
O
Me
Me
Me
OH
O
erythromycin B
(JACS 1957, 79, 6070)
Me
O
Me
Me
Me
O
Me
Me
O
2
Me
Me
3
O
5
Me
HO
OH
12
Et
O
Me
OH
6
5
Me
O
NMe2
HO
O
Me
Me
HO
Et
O
3
O
6
5
Me
NMe2
HO
O
O
Me
Me
OMe
Me
OH
O
erythromycin E
(Tet. 1975, 31, 1985)
Me
O
Et
O
Me
OH
6
5
Me
OMe
O
erythromycin F
Me
(J. Antibiot. 1982, 35, 426)
Me
OH
O
O
OH
Me
NMe2
HO
O
O
3
O
OH
OH
12
3
O
O
OH
12
Me
OH
Me
O
Me
O
Me
O
3
O
erythronolide B
O
O
3
Me
Me
OH
O
erythromycin A
(JACS 1957, 79, 6062)
Absolute configuration of
erythromycin A was first
established via X-ray
analysis in Tetrahedron
Lett. 1965, 6, 679.
Me
12
OH
Me
Me
6
5
Me
Me
[O] at C12
Me
3
O
O
Me
OH
O
erythromycin C
(JACS 1957, 79, 6074)
OH
Et
OH
O
OH
Me
O
OH
12
3
O
Me
12
HO
O
Me
HO
O-methyl
transferase
NMe2
Me
3
O
Me
Me
OH
6
5
Me
Me
Me
Me
Me
O
[O] at C12
Me
8
OH
12
Et
OH
[O] at C6
and C12
OH
12
13
Et
9
desosamine
glycosyl
transferase
erythronolide A
O
Me
Me
HO
Me
Me
cyclization
upon cleavage
from polyketide
synthase
O
Me
Me
12
Baran Lab GM 2009-08-15
OMe
O
erythromycin G
Me
(J. Antibiot. 2003, 56, 280)
Me
OH
Me
OH
12
HO
O
Me
Me
6
5
O
Me
OH
Me
3
O
OH
Me
Me
6
9
O
Me
O 12
HO
13
Me
OH
Et
erythronolide H
erythronolide I
(Org. Lett. 2009, 11, 1353)
1
Erythronolide and Erythromycin
Y. Ishihara
Our modern "retrosynthetic reflex" effectuates the following disconnections:
O
Me
10
Me
HO
O
O
Me
Me
1
2
eg.
8
OH
12
13
Et
9
Baran Lab GM 2009-08-15
erythromycin A
Me
OH
6
5
O
NMe2
HO
O
Me
OH
13
Et
O
O
OMe
Me
macrolactonization
Me
HO
OH
Et
OH
Me
Me
erythronolide A
[...]
erythromycin A:
- Currently used as an antiobiotic agent; especially useful for patients with penicillin
allergies.
- Isolation first reported in U.S. Patent 2,653,899 by R. L. Bunch and J. M. McGuire (Eli
Lilly), filed in 1952 and approved in 1953; originally called "erythromycin".
- Quotes from the 1953 patent: "[...] the empirical formula of erythromycin [is]
C38-9H69-71NO13." "We claim: 1. A method of producing an antibiotic agent which
comprises cultivating under aerobic conditions an erythromycin-producing strain of
Streptomyces erythreus in a culture medium containing assimilable sources of
carbohydrate, nitrogen and inorganic salts until substantial antibiotic activity is
produced by said organism in said culture medium. [...]"
- Structure first reported in 1957 without stereochemical assignments; X-ray analysis
established the absolute configuration at each stereocenter in 1965.
- Quote from R. B. Woodward: "Erythromycin, with all our advantages, looks at present
quite hopelessly complex, particularly in view of its plethora of asymmetric centers."
(In Perspectives in Organic Chemistry, Todd, A., Ed., Interscience Publishers: New
York 1956, p.155.)
- Quote from J. Mulzer's review entitled "Erythromycin Synthesis - A Never-Ending
Story?": "The synthesis of [...] erythromycin A and B [...] is probably the most
extensive single project in the history of synthetic organic chemistry. This
phenomenon is not rational as [they] are accessible in large quantities from
fermentation [...]. It is the complexity of the molecule's structure, the plethora of
stereocenters and functional groups and the magic of the medium ring that has
fascinated about 15 large research groups worldwide for more than a decade." (Angew.
Chem. Int. Ed. 1991, 30, 1452-1454)
- Cost of erythromycin A is 2.80 $/g, so just buy it for medchem/chembio purposes...
- This molecule caught the attention of...
- "Giants": Woodward, Stork, Corey, Danishefsky;
- "Aldol Giants": Masamune, Evans, Paterson;
- "European Giants": R. W. Hoffmann, Mulzer, and recently Carreira.
Me
Me
OH
OH
13
Me
O
Me
Me
OH
1
Me
OH
O
O
Me
Me
HO
Me
3
erythromycin A
O
HO
Me
OH
OH
1
O
OH
Me
seco acid of
erythronolide A
smaller aldol
precursors
Commonly used macrolactonization methods:
1. Corey-Nicolaou macrolactonization (PyS-SPy + PPh3 on the hydroxyacid, then heat;
J. Am. Chem. Soc. 1974, 96, 5614);
2. Masamune thiol ester activation (TlStBu on the acyl chloride to generate a thioester,
then Hg(OCOCF3)2 or CuOTf to lactonize; J. Am. Chem. Soc. 1975, 97, 3515);
3. Mukaiyama onium salt method (N-methyl-2-chloropyridinium iodide and Et3N on the
hydroxyacid; Chem. Lett. 1976, 49);
4. Mitsunobu alcohol activation (DEAD + PPh3 on the hydroxyacid; Tetrahedron Lett.
1976, 17, 2455);
5. Yamaguchi mixed anhydride lactonization (2,4,6-trichlorobenzoyl chloride + DMAP on
the hydroxyacid; Bull. Chem. Soc. Jpn 1979, 52, 1989);
6. Keck-Steglich activation (DCC + DMAP + DMAP•HCl on the hydroxyacid; Angew.
Chem. Int. Ed. 1978, 17, 522 and J. Org. Chem. 1985, 50, 2394);
7. Shiina benzoic anhydride lactonization (various benzoic anhydrides + Lewis acid or
base; Nature Protocols, 2007, 2, 2312).
Examples of asymmetric control in the synthesis of stereotriads
OH
found in polyketides (for an excellent review on this topic, see: R.
W. Hoffmann, Angew. Chem. Int. Ed. 1987, 26, 489-503):
* * *
1. Propionate enolate additions onto α-methylaldehydes (i.e. aldol);
2. Propionate enolate additions onto α-methylesters, followed by
Me
Me
carbonyl reduction;
3. Acetate enolate additions onto α-methylaldehydes followed by α-methylation;
4. Propenyl or butenyl group additions onto α-methylaldehydes, followed by
hydrogenation or hydroboration;
5. Danishefsky's diene (methylated version) Diels-Alder onto α-methylaldehydes followed
by hydrolysis and ozonolysis;
6. Crotyl-metal and pentenyl-metal additions onto α-methylaldehydes followed by ozonolysis;
7. Epoxidation of an allylic alcohol bearing a methyl group at the
allylic position, followed by methylcuprate addition;
8. Hydroboration-oxidation or hydrosilylation-oxidation of the
Me
Me
alkene motif shown on the right.
2
Erythronolide and Erythromycin
Y. Ishihara
E. J. Corey (Harvard; 1978, 1979):
- First total syntheses of erythronolide B (JACS 1978,
100, 4618 and 4620) and erythronolide A (JACS 1979,
101, 7131), synthesized in (longest linear) 31 steps (ca.
0.8% overall, yields of the last epimerizationdeprotection steps are not reported).
- 11 students worked on it, including K. C. Nicolaou.
- 50% yield for the macrolactonization, effectuated with
a modified Corey-Nicolaou procedure (substituted
imidazoles instead of pyridines).
- Key features: Cyclic stereocontrol (i.e. not a single
aldol!); convergency amenable to the synthesis of both
erythronolides A and B.
- Hard to retrosynthetically disconnect!
- "Classics-worthy" synthesis!
OH
Me
O
3
4
2
5
Me
Me
NaOMe
2
5
Allyl-Br
1
6
9
4
BzO
Me
Me
3
2
5
1
6
7
O
O O
9
8
Me
6 steps
4
5
Me
HO
3
6
7
O
10
12
Me
Me
13
4
Me
Me
Br2
8
BzO
Me
Me
1
6
O O
Me
O
OTBS
11
7
8
Me
9
10
Me
12
Me
13
Et
8 steps
12
13
Me
Me
Et
Me
Et
HO
O
1
2
3
Me
O
Me
Me
9
10
12
13
Et
tBuS
O
9
(88%, 17:1 dr)
tBu
S
Me
1
2
O
3
O
Me
8
5 steps,
then
Me
Me
Me
8
Me
OTES
2
9
8
Me
1) (COCl)2
2) Et2CuLi OH 4
1
3
Me
2
O
Me
Me
Me
O
OH
OH
OH
1
O
Me
OTES
O
Me
erythronolide B
(71%, 14:1 dr)
then 2-step [O]
O
Me
10
O
O
O
Me
7 steps
Me
O
4
Me
(Coupling partner prepared
from EtCHO in 70-85%
yield and in >100:1 dr)
O
Me
Me
OH
Me
O
11
12
13
Me
OH
2
R2BO
Me
(85%, 40:1 dr)
then 4-step redox
CHO
OTBS
1
8
c-Hx
LHMDS, then
8
6
5
Me
9
aldol
3
(The erythronolide A synthesis simply uses a coupling
partner with a protected hydroxyl group at C12)
Et
OH
9
Me
6
5
(2 steps from
chiral pool)
Me
OTBS
R2BO
7
(resolution
at this stage)
Me
Me
8
c-Hx
O
4
3
KOH
OH
O
9
MeO
O
Me
O
Me
O
O
2
5
Br
Me
O
O
O
O
Me
3
OH
Me
Me
2 steps O
OBz
Me
2
erythronolide A (R=OH)
erythronolide B (R=H)
OTBS
BrMg
OH
Me
Me
2 steps O
9
Me
OH
3
O
2
1
6
5
Me
Me
11
Me
O
O
Me
SPy
8
OH
12
13
Et
OH
OH
OBz
Me
2) CrO3
7
8
Me
R
Me
Me
1) BH3; H2O2
1
6
Me
Me
10
O
3
4
S. Masamune (MIT; 1981):
O
- First total synthesis of 6-deoxyerythronolide
Me
Me
B (JACS 1981, 103, 1568), synthesized in
9
8
(longest linear) 22 steps (<7 % overall;
aldol
missing yields for the last few steps).
Me
Me
- 4 students worked on it.
OH 6
- 41 % yield for the macrolactonization,
Me
effectuated with Masamune's own
Et
O
OH
t-butylthioester method, using CuOTf.
- Key feature: Aldol, aldol, aldol... a synthetic
mimic of a polyketide synthase.
O
OH
- Textbook-style retrosynthesis!
macrolactonization
Me
- Excellent demonstration of his own
methodology.
6-deoxyerythronolide B
O
Me
Baran Lab GM 2009-08-15
10
Me
6
5
Me
NaBH4
O
3
Me
O
Me
Me
12
13
9
Me
8
OH
Me
Et
OTES
tBuS
1
3
O
2
Me
6
5
5 steps
6-deoxyeryincluding [O] thronolide B
O
O
Me
Me
Me
3
Erythronolide and Erythromycin
Y. Ishihara
R. B. Woodward (Harvard; posthumous, 1981):
O
- First and only total synthesis of erythromycin A
Me
(JACS 1981, 103, 3210, 3213 and 3215),
10
synthesized in (longest linear) 52 steps (0.0089%
Me
overall, of which the last 10 steps, required for
7
the glycosidations, yielded 1.54%).
OH
HO 12
- 48 students worked on it, including R. M.
13
Me
Williams.
Et
O
- 70% yield for the macrolactonization, effectuated
with a Corey-Nicolaou macrolactonization.
- Key features: Aldols using asymmetric induction
O
via dithiadecalins; interestingly convergent; first
Me
detailed study on the structural requirements of
the erythronolide seco acid macrolactonization.
- The end of the "Woodwardian era"...
erythromycin A
S
SH
+
MeO
OMe
MeO
BnO
(6 steps to
(5 steps to
make; racemic) make; racemic)
Me
Me
13
5 steps
MOMO
MeO
Ra-Ni,
aldol with
EtCOStBu,
etc...
12
O
11
10
O AcO
OMe
8
9
Me
O
9
S
5
4
MesLi
O
BnO
OMe
Et
tBuS
O
Me Me
OMOM
1
2
O
3
Me
OH
Me
Me
10
HO
steps
(33%
overall)
12
13
Et
PyS
O
7
3
and then 7
steps to
manipulate
C7 and C9
O
MeO
S
Me
O
6
5
Me
OH
1
2
Me
OH
O
3
Me
O
H
6
iPr
O
Me
OH
Grignard
addition
OH
9S-dihydroerythronolide A
OH
CO2H
iPr
1 step
O
O
OH
Me
OH
iPr
O
O
iPr
O
O
Me
iPr
Me
iPr
CO2H
O
O
iPr
CO2H
CO2H
3
OH
OH
OH
O
8
O
Me
10
O
Me
Me
iPr
4
5
OH
OH
4 steps
iPr
Me
S
11
Me
O
O
O
12
Me
Me
3 steps;
racemic
2 steps
O
BnO
OMe
Me
MOMO
MeO
Me
OH
O
O
BnO
OMe
(2 steps)
13
8
Me
Butenolide strategy in polypropionate synthesis
(JACS 1987, 109, 1564):
3 steps;
racemic
3 steps i
iPr
Pr
O
O
O
Me
H
butenolide
carbonyl
attack
Me
Me
OH
O
8
Me
Me
O
OMe
MOMO
MeO
NH
6
5
O
Me
O
S
OH
BnO
O
BnS
MeO
Me
Me O
HO
O
S
O
10
NMe2
S
6
7
H
O
OAc
Me
Me
OH
G. Stork (Columbia; 1987):
OH
- First total synthesis of 9S-dihydroerythronolide
Me
A (JACS 1987, 109, 1564 and 1565), synthesized
10
in (longest linear) 30 steps (1.3 % overall).
Me
- Only one student: S. D. Rychnovsky
7
- 64 % yield for the macrolactonization,
OH
HO 12
effectuated with a Keck-Steglich
13
Me
macrolactonization.
Et
O
- Key features: Aldols performed via butenolides;
1
3
convergent synthesis.
2
O
macrolactonization
Me
H
S
Me
Me
6 steps
3) D-proline
(asym. aldol,
70%, 1:1 dr,
36% ee; then
recrystallize)
OMe
H
S
CH2OMs 1) NaH
2) AcOH
(All disconnections shown
here are aldols)
Baran Lab GM 2009-08-15
9
O
OMe
(3 steps)
erythronolide A
analog, and then
10 more steps to
erythromycin A
Me
O
11
9
OH
9S-dihydroerythronolide A
Me
OBn
7 steps
O
4
5
3
1 2
13 steps
Me
O
Mes
Et
Me
Me
8
Me
O
MgBr
1
O
PivO
2
3
Me
O
O
Me
Me
O
O
+
O
H
Me
6
5
Me
11
OPiv
6 steps
O
9
OH
(4R)-ethyl 4-hydroxy-2-hexynoate
O
Me
OH
10
Me
H
Me
OH
9 steps
Me
Et
OH
73%
Me single
isomer
Me
Et
9
11
O
6
5
Me
Me
O
1
PivO
Me
8
2
Me
OH
O
3
O
Me
Me
Me
4
Erythronolide and Erythromycin
Y. Ishihara
I. Paterson (Cambridge; 1988):
OH
- Total synthesis of 9S-dihydroerythronolide A (TL
Me
1988, 29, 1461 and 1989, 30, 7463), synthesized
10
in (longest linear) 22 steps (3.4% overall).
Me
- 2 students worked on it.
7
- 91-96% yield for the macrolactonization,
OH
HO
12
effectuated with a Yamaguchi
13
Me
macrolactonization.
Et
O
- Key features: Excellent use of "modern" (Evans
herein) aldol technology; convergent;
2
macrolactonization performed on a
O
conformationally favorable system bearing two
Me
olefins, precluding the use of acetonides.
O
Me
O
Xc
N
PhS
O
1
2
PhS
Bu2BOTf, iPr2NEt
O
(70%, 10g scale, 1:1 dr;
(racemic)
both isomers needed)
Me
OH
5
OH
9S-dihydroerythronolide A
Me
10
+
OH
10
9
11
PhS
Me
Et
5
Me
OH
1
PhS
2
Me
O
10
3
9
Me
Me
10
1) [O]
2) [H]
3) [H]
OH
Me
Me
1
PG-O
2
Me
Me
4 steps
Et
O
Me
O
O
OTBS
Me
Me
Et
O
OTMS
OTBS
Me
1) OsO4-NMO, 1h
2) Zn(BH4)2
3) OsO4-NMO, 5d
Me
9S-dihydroerythronolide A
Me
"diene"(76%)
then 6 steps
Et
2
OBn
PG-O
PG-O
Me
2
5
4
O
4 steps
1
2
PG-O
PG = TBDPS
3
OBn
Me
Me
O
8
Me
4
Me
6 steps
6
5
H
Me
OBn
1
3
OBn
PG-O
2
4
6
5
7
Me
8
O
3
OBn
Me
Me
Me
Me
Me
OBn
OBn
Me
OH
Me
6-deoxyerythronolide B
Me
Me
Me
OH
OH
3
"diene"
(40%)
Me
1
3
OBn
Me
Me
7
OBn
Me
Me
O
9
OBn
Me
O
O
O
4 steps
Me
Et
Me
OH
12
13
OH
Me
Me
O
OTBS
Me
3
4
Me
Me
O
8
7
Me
O
7
Me
Me
10
3 steps
10
6 steps
Me
O
OBn
CO2Me
SPh
12
13
Et
9
5
Me
OMe
Me
8
13
OTBS
O
2
"LACDAC"
O
Me
OMe
"diene"
1) NaOMe
2) TBSOTf
3) NCS
4) ZnBr2, enolate
of 3-pentanone
Me
CHO
Et
heat
(69%)
Me
Xc
1
OH
OTBS
Me
8
7
O
OH
13
Me
OTMS HCHO,
ZnCl2
Me
Me
3 steps to generate
phosphonate; then add
aldehyde fragment C7-C13
Me
8
9
S. J. Danishefsky (Yale; 1990):
- Relay synthesis of 6-deoxyerythronolide B (JOC
1990, 55, 1636), synthesized in (longest linear) 35
steps (ca. 0.014 % overall, yields of the last two
steps are not reported). A total synthesis from the
procedures described herein would result in
racemic 6-deoxyerythronolide B.
- Only one student worked on it.
- 17 % yield for the macrolactonization, effectuated
with a Yamaguchi macrolactonization.
- Key feature: "Formal double aldol" using a Lewisacid catalyzed diene aldehyde condensation
(LACDAC) strategy.
- Great application of his own methodology.
Me
OH
OTBS
Me
aldol
OH
O
4
3
HWE olefination
Me
5
Me
iPr
aldol
Baran Lab GM 2009-08-15
4 steps
Me
Et
O
Me
Me
O
HO
Me
OH
O
5 steps
6-deoxyerythronolide B
O
O
Me
Me
Me
5
Erythronolide and Erythromycin
Y. Ishihara
J. Mulzer (Institut für Organische Chemie; 1991):
crotyl
O
- Total synthesis of erythronolide B (JACS 1991,
addition
Me
Me carbonyl
113, 910), synthesized in (longest linear) 25 steps
10
addition
(<2.4% overall, yields of first few steps unclear).
Me
- 4 students worked on it.
7
Me
- >85% yield for the macrolactonization, effectuated
OH
OH
12
with a Yamaguchi macrolactonization.
13
Me
- Key features: Great use of a simple starting
Et
O
OH
material from the chiral pool, glyceraldehyde;
convergent; macrolactonization performed on a
2
conformationally favorable system bearing an
O
OH crotyl
addition
olefin.
Me
macrolactonization
erythronolide B
CHO
OH
HO
12
13
10
11
Me
1) Crotylation
2) Tosylation
9
O
3) Acid
4) Base
5) Me2CuLi
Me
O
Me
Me
5
1
4 steps
3
2
HO
Me
4
1) Crotylation
2) Tosylation
1
HO
3) Acid
4) Base
5) Me2CuLi
2
1
OH
OH
3
2
BnO
Me
3
Me
3 steps
OTBS
1
4
5
Me
2
Me
Me
9
10
5 steps
Me
OBn
12
13
OH
Et
8
9
Me
Me
MeOC6H4
Me
Et
OH
7
10
3 steps Me
OH O
Et
O
Me
Me
4
6
5
Me
O
9
Me
7
10
6 steps
O
3
2
Me
OH
Me
12
Me
Me
OBn
Me
Me
6
5
Me
2) TPAP-NMO
PG-O
3) crotylboronate
4) LAH
Et
5) PMBCl
6) OsO4-NMO
Et
OH
BnO
2
Me
O
Me
"crotylboronate"
Me
Me
aldol
OH
9S-dihydroerythronolide A
8
7
PG-O
O
Et
Me
O-PG
6
5
9
Me
10
11
OH
Et
O-PG
1) PMBCl
2) O3; Ph3P
3) ent-crotylboronate
OH
Me
8
7
Me
4 steps
Me
Me
O-PG
OH
Et
Et
Me
8
7
OPMB
O-PG
Me
9S-dihydroerythronolide A
Me
8
7
O
HO
9
O
Me
Me
Me
OH 1) crotyl- PG-O
boronate
OPMB 2) DDQ
3) OsO4NMO-NaIO4
O
10
11
PG-O
O
Me
Me
Me
OH
OH
PG-O
MeOC6H4
O
Me
O
3
Me
Me
MeOC6H4
(82%)
5
O
1) Sharpless AE
BuLi
Me
OBn
12
13
OH
8
O-PG
Me
7
Me
OH
Me
O
O
O
HWE
Me
Me
c-Hx
PG = cyclic acetal using cyclopentanone
SPh
9S-dihydroerythronolide A
Et
6
5
BF3
10
5 steps
Me
OH
12
13
Me
9
10
11
O
Me
9
B
3 steps PG-O
Et
SPh
Me
Me
11
12
13
Me
3
BnO
OH
Me
O
aldol
c-Hx
O
4
Me
6
5
4
R. W. Hoffmann (Universität Hans-Meerwein-Strasse; 1993):
OH
- Total synthesis of 9S-dihydroerythronolide A
Me
(ACIEE 1993, 32, 101), synthesized in a total of
aldol
23 steps (6.6% overall).
- 2 students worked on it.
Me
7
- >77% yield for the macrolactonization,
OH
HO 12
effectuated with a Yamaguchi
13
Me
macrolactonization.
Et
O
- Key feature: Completely linear synthesis, but
this synthesis is one of the shortest in total
2
number of steps.
O
- Excellent application of his own crotylation
Me
methodology.
OH
Me
Me
Baran Lab GM 2009-08-15
Me
O-PG
O
6
5
O
O
Me
Me
OH
1) TNT, HCl
2) Yamaguchi
3) HCl
C6H4OMe
6
Erythronolide and Erythromycin
Y. Ishihara
Baran Lab GM 2009-08-15
D. A. Evans (Harvard; 1997):
- Total synthesis of 6-deoxyerythronolide B (TL 1997, 38, 53), synthesized in (longest linear) 18 steps from β-ketoimide, add 2 steps to make the SM (4.3% overall).
- Only one student worked on it; 86% yield for the macrolactonization, effectuated with a Yamaguchi macrolactonization.
- Key feature: Evans aldol and its majesty. Convergency is also a plus.
Me Me
O
O
O
Me
O
O
O
O
TiCl4,
iPr NEt
2
O
O
2
1
N
3
Me
OH
4
O
7
6
5
4 steps
2
1
Xc
Me
O
Me
O
4
3
Me
5
Me
MeOC6H4
O
6
Me
7
1) BF3•OEt2
(83%)
Me
Bn
N
Me
O
Me
Bn
O
Et
Sn(OTf)2,
Et3N
O
O
O
10
9
N
11
Me
OH
12
13
6 steps Me
10
9
11
12
13
8
Me
Me
Me
8
7
Me
O
12
13
Me
2) Zn(BH4)2
Et
OH
3) DDQ
HO
3
4) NaH, CS2, MeI
2
O
5) Bu3SnH, AIBN
6) LiOOH
Me
7) TBAF
OTMS OPMB OTBS
Et
O
Et
Me
Me
1) Yamaguchi
2) Pd(OH)2
O
3) PCC
4) HCl
6
5
6-deoxyerythronolide B
Me
O
Me
Bn
K. A. Woerpel (UC Irvine; 2003):
- Total synthesis of 9S-dihydroerythronolide A (JACS 2003, 125, 101), synthesized in (longest linear) 28 steps (5.6% overall).
- Only one student worked on it.
- >80% yield for the macrolactonization, effectuated with a Yamaguchi macrolactonization.
- Key feature: Great application of his own "allylsilane [3+2]" methodology. Convergency is also a plus.
Me
OAc
PhMe2Si
BnO
OAc
Me
7 steps
>78%,
>98% ee
Me
R* = S-pantolactone
Me
1
N
2
3
OH
tBuOCl;
iPrOH,
then TBSO
EtMgBr,
1
then
CO2Et
Me
O
Me
I
O
Me
OTBS OH
7 steps
Me
O
erythro- 4 steps HO2C
nolide A
N
2
O
4
3
6
5
Me
9 steps
TBSO
1
Me
O
2
3
Ph
4
O
5
Ph
O
N
O
OH
TBSO
Et
Me Me TESO Me Me
Me HO Me
6 steps
1
O
2
3
Ph
4
N
6
7
8
O
5
11
10
9
O
BnO Me Me
OH
Me BnO Me Me
OH
9
Me Me TESO Me Me
Me
Me
OH
(86%, dr >19:1)
OH
12
9 steps
4 steps
OTBS O
Ar
O
O
Xc
Me
Me
13
OPiv
E. M. Carreira (ETH Zürich; 2005):
- Total synthesis of erythronolide A (ACIEE 2005, 44, 4036), synthesized with the best total thus far of 21 steps (1.5%).
- 2 students worked on it; 78% yield for the macrolactonization, effectuated with a Yamaguchi macrolactonization.
- Key feature: Great application of his own "Mg-mediated nitrile oxide [3+2]" methodology for polyketide synthesis.
TBSO
Et
3 steps
SnCl4,
O
COOR*
Me
SiMe2Ph
OTBS OPMB
repeat
step 1
N
6
7
8
Me Me TESO Me Me
9
O
10
Me
11 12
OH
Me
Me BnO Me Me
9S-dihydroerythronolide A
Me
Macrolactonization: 1) Since 1990, all syntheses utilized the
Yamaguchi macrolactonization method; 2) A 6-membered cyclic
acetal over the hydroxyl groups at C3 and C5 are necessary to
induce (in part) the correct conformation for the lactonization, unless
there are olefins within the seco acid that rigidify the conformation;
3) Woodward has contributed greatly toward examining different
conformations of the macrolactonization step.
Asymmetric stereocontrol: Development of aldol, dithiadecalin,
butenolide, "LACDAC", crotylations and other methods such as
[3+2] strategies, many of which were developed for the sake of
conquering the erythronolide/erythromycin family.
Other notable formal or total syntheses: Deslongchamps
(CanJChem, 1985, 63, 2818), Kinoshita (TL 1986, 27, 1815),
Kochetkov (TL 1987, 28, 3835 and 3839), Nakata (BCSJ 1989, 62,
2618), Chamberlin (JACS 1989, 111, 6247), Martin (JACS 1989,
111, 7634), Yonemitsu (JOC 1990, 55, 7), Vogel (HCA 2002, 85,
417), Crimmins (OL 2006, 8, 2191), Martin (Tet 2007, 63, 5709),
and, as a note added after this presentation, White (NatChem 2009
AOP, DOI: 10.1038/NCHEM.351).
7