The Total Synthesis of Diazonamide A

The Total Synthesis of Diazonamide A:
Literature Highlights and Current Progress Toward the
Asymmetric Formation of the C10 Quaternary Center
O
O
OH
HN
N
H
O
N
N
O
O
N
H H
Cl
Cl
NH
Erick B. Iezzi
University of Pittsburgh
Wipf Research Group
Erick Iezzi @ Wipf Group
1
9/12/2004
Presentation Outline
θ Background, biochemical studies and structural assignments
θ
θ
θ
θ
Total syntheses (Harran and Nicolaou)
Partial syntheses and synthetic strategies
Strategies of former Wipf group members
Current strategy
Erick Iezzi @ Wipf Group
2
9/12/2004
Discovery and Biological Activity of Diazonamide A
θ Isolated from the marine ascidian Diazona Angulata
(originally misidentified as Diazona chinensis) in
1991 by William Fenical and co-workers at Scripps
Institute of Oceanography1,*
O
OH
θ Novel macrocyclic peptide composed of three
common amino acids: L-tyrosine, tryptophan and
L-valine
N
H
O
G
H F
O
N
H H
θ Demonstrated potent in vitro inhibition of HCT-116
human colon carcinoma and B-16 murine melanoma
cancer cell lines (IC50 values <15 ng/ml)1,*
A
E
N
O
D
N
B
C
Cl
Cl
NH
• Diazonamide B also isolated (2.5x greater conc.),
but much less active
θ Synthetic Diazonamide A exhibited potent cytotoxic
activity against ovarian carcinoma 1A9, breast
carcinoma MCS-7 and taxol-resistant 1A9/PTX10
cell lines2
θ
HN
O
Inhibitor of tubulin assembly (into microtubules), causing
cells to accumulate at the G2/M phase of the cell cycle
1. Fenical, et al. J. Am. Chem. Soc. 1991, 113, 2303.
2. Nicolaou, et al. Angew. Chem. Int. Ed. 2002, 41, 3495.
Erick Iezzi @ Wipf Group
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9/12/2004
Tubulin and the Assembly of Microtubules
α,β-tubulin dimer
8 nm
dimer
lumen
protofilament
+
proteins are tightly bound by non-covalent bonds
θ bound guanosine triphosphate (GTP) nucleotide
(yellow)
θ
_
microtubule
O
N
O
P
O
O
P
O
NH
24 nm
O
O
O
O
P
O
O
CH2
N
N
NH2
O
θ
microtubules form the mitotic spindle during mitosis
OH OH
www.uib.no/aasland/ gensidene/tubulin.html
Erick Iezzi @ Wipf Group
www.tmd.ac.jp/artsci/ biol/textbook/cellmove.html
4
9/12/2004
Microtubule Dynamics
_
+
www.hykim.chungbuk.ac.kr/ lectures/cellbio/11/11.html
θ
stabilization of microtubules occurs when concentration of GTP is
greater than GDP
θ
depolymerization of endcapped microtubules containing GDP
tubulin is ~100X faster than ones capped with GTP tubulin
θ
tubulin dimers can easily diffuse within the cytoplasm of the cell,
whereas the polymer (microtubule) cannot
Erick Iezzi @ Wipf Group
5
9/12/2004
Mitosis and the Influence of Drugs on Microtubule Dynamics
www.swbic.org/products/clipart/images/mitosis.jpg
Cell Cycle
θ Interphase
- G1 phase - cell growth
- S phase - DNA replication
- G2 phase - cell prepares to
divide
θ M-phase
- mitosis - nuclear division
- cytokinesis - cytoplasmic
division
Erick Iezzi @ Wipf Group
Mitosis
θ Prophase
θ Prometaphase
θ Metaphase
θ Anaphase
θ Telophase
6
www.cellbio.utmb.edu/.../ microtubule_structure.html
Assembly and disassembly of microtubules
are crucial for correct function of the mitotic
spindle
θ Tubulin dimers with bound drugs (red)
cannot polymerize into microtubules
θ
9/12/2004
Diazonamide A: A Novel Inhibitor of Tubulin Assembly
Examples of microtubule-specific drugs:
Taxol, Discodermolide - bind to and stabilize microtubules during assembly
θ Colchicine, Colcemid and Nocodazole - bind to tubulin dimers and prevent assembly
θ Vinblastine, Vincristine and Dolastatin 10 - aggregate tubulin dimers which leads to depolymerization
θ
Biochemical properties of Diazonamide A
Dolastatin 10 bound in subregion of vinca site
Potent inhibitor of tubulin assembly – equivalent to
Dolastatin 10
θ Does not inhibit binding of Vinblastine, Dolastatin 10
or GTP exchange with tubulin
θ Does not stabilize Colchicine binding to tubulin
θ
Diazonamide A – inhibits assembly by: 1) binding to a
unique site on the tubulin dimer or 2) binds to ‘peptide site’,
but only when at end of growing tubes
Cruz-Monserrate, et al. Mol. Pharmacol. 2003, 63, 1273–1280
Bai, et al. J. Bio. Chem. 1990, 265, 17141
* Vinca domain – binding site of vinca alkaloids
Erick Iezzi @ Wipf Group
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9/12/2004
Studies of Cells Treated with Diazonamide A
I
II
*figure shows (left) DNA and tubulin florescense,
and (right) DNA and F-actin fluorescense
Figure I. PtK2 cells treated with IC50 concentration of
Diazonamide A: A, no drug. B, 0.3 nM Diazonamide A for 16 h.
C, 1.0 nM Diazonamide A for 16 h.
Figure II. PtK2 cells treated with 10 times IC50 concentration
of Diazonamide A: A and B, no drug. C and D, 3 nM of
Diazonamide A for 16 h.
Cruz-Monserrate, et al. Mol. Pharmacol. 2003, 63, 1273–1280
*figure shows DNA and tubulin florescense
Erick Iezzi @ Wipf Group
8
9/12/2004
Structural Assignments of Diazonamide A and B
O
O
NH2
HN
HN
O
N
H
H2N
N
O
O
N
N
N
Cl
O
OH
HO
Br
Cl
O
Cl
O
OH
HO
Cl
O
NH
NH
Nominal Diazonamide B (Fenical, 1991)
Nominal Diazonamide A (Fenical, 1991)
35
O
39
38
1
36
40
OH
1
N
H
34
HN
O
37
O
33
1
2
H2N
31
3
N
O
4
6
29
30
9
5
8
13
10
6
28
N
14
O
12
15
7
2O
N2
H H
11
17
18
24
23
19
22
O
N
N
27
O
Cl
Br
26
16
20
25
Cl
O
N
H H
NH
Cl
Cl
NH
21
(−)-Diazonamide A (Harran, 2001)
Erick Iezzi @ Wipf Group
HN
32
Diazonamide B (Harran, 2001)
9
9/12/2004
Harran’s First Total Synthesis of Diazonamide A
O
BocHN
OH
BocHN
Cl
N
O
CN
BnO
Br
I
1
OBn
2
1) Cp2ZrCl2, nBuLi, THF −78 oC - rt
Cl
3
BocHN
O
2) Pd(OAc)2, P(o-tolyl)3, Ag3PO4, 2, rt
1) BBr3, CH2Cl2, −78 oC - −20 oC
N
CN
2) 1, DIPEA, TBTU, DMF, rt
BnO
89%
85%
BnO
O
BocHN
O
N
N
H
Pd2(dba)3, 2-(di-t-butylphosphanyl)biphenyl,
CN
O
Ag3PO4, THF, 75 oC
BocHN
N
H
N
CN
O
82% BRSM
I
HO
OBn
HO
OBn
Harran, et al. Angew. Chem. Int. Ed. 2001, 40, 4765−4769.
Erick Iezzi @ Wipf Group
10
9/12/2004
Harran’s First Total Synthesis of Diazonamide A
O
O
N
H
BocHN
o
1) t-BuOK, THF, 0 C,
N
OTf
Br
CN
O
N
H
BocHN
N
CN
O
2) 4, PhCH3, −78 oC - −25 oC; H2S(g),
THF, −50 oC
O
67% (2 steps)
OBn
OH
O
HO
N
Me3C
Os
O
OBn
OH
O
O N
H
H
CMe3
Br
93:7 diastereofacial
selectivity
4
1) NaI, K2CO3, DMF, O oC, 35%
2) ZOSu, DMF, rt
3) NaBH4, CeCl3
ZHN
N
H
N
O2N
CN
O
ZHN
H
N
N
O
O
O
o
7 H2O, MeOH
0
O
Br
O
1) p-TsOH, PhCH3, 95 oC
2) Cl3CCO2H, PhCH3, 68 C, 90%
o
4) Zn , 3:1 THF/EtOH, 0 C
5) t-BuNH2/Br2, PhCH3/THF/DCM,
o
o
−78 C - −20 C
OBn OH
HO
Br
35% (5 steps)
OBn
o-NO2C6H4
O
Br
Harran, et al. Angew. Chem. Int. Ed. 2001, 40, 4765−4769.
Erick Iezzi @ Wipf Group
11
9/12/2004
Harran’s First Total Synthesis of Diazonamide A
H
N
O
H
N
N
1)
O
Me2AlHN
NH
O
H
N
N
O
ZHN
O
ZHN
PhCH3/CH2Cl2, 0 oC-rt
O
2) nPr4NRuO4, NMO, 4A MS, CH2Cl2
OBn
O
o-NO2C6H4
hv (350 nm), dioxane; then
Ac2O, pyd., DMAP, CH2Cl2
O
OBn
64% (2 steps)
Br
NH
O
85%
O
Br
o-NO2C6H4
H
N
O
O
ZHN
H
N
N
NH
O
O
1) DDQ, THF/H2O
2) Ph3PCl2, (Cl3C)2, Ph3P, Et3N, THF
3) hv (300 nm)
H
N
N
ZHN
N
O
O
AcO
AcO
24% (3 steps)
OBn
OBn
O
O
NH
Br
Harran, et al. Angew. Chem. Int. Ed. 2001, 40, 4765−4769.
Erick Iezzi @ Wipf Group
12
9/12/2004
Harran’s First Total Synthesis of Diazonamide A
Fenical's X-ray strucuture of
Diazonamide B was interpreted as
this structure:
Br
O
HN
O
N
H
NH2
O
N
O
O
N
N
O
Cl
O
Br
Cl
O
HO
N
HN
Cl
O
OH
H
N
O
C11
Cl
O
NH
NH
Initially proposed structure of Diazonamide A
- Harran's NMR data did not match that of isolated sample
- C11 lactol not observed in natural product
- synthetic sample was unstable
- Derivatization of Diazonamide B with p-Bromobenzoyl chloride and
HRMS analysis were thought to eliminate water to form the acetal at C11
O
O
HN
O
C37
O6 OH
N1
N
H
HN
O
O
N7
N
NH2
N
H
O
N
N
N
O2 O
O
Cl
O
O
H
N N2
H
Cl
NH
Revised structure of Diazonamide A
(Harran, et al. Angew. Chem. Int. Ed. 2001, 40, 4770)
H
Cl
Cl
O
O3
NH
- Acid hydrolysis of a sample (natural Diazonamide A) did not
yield valine
- studies suggested that the amine at N7 should be an OH
- Mass of sample was off by 1Da, which meant that the O3
oxygen in the original crystal strucutre was an NH
- A derivative with (S)-hydroxy isovaleric acid yielded biological
activity nearly identical to authentic Diazonamide A (>50 times
more potent than amine derivative)
Erick Iezzi @ Wipf Group
13
9/12/2004
Nicolaou’s First Total Synthesis of Diazonamide A
O
OMe
CbzHN
O
O
BocHN
BocN
n-BuLi (2 equiv.)
N
O
BocHN
N
N
Br
MOM
N
O
pTsOH, ClCH2CH2Cl
OBn
HO
OBn
O
OMe
O
NH2
OBn
O
CbzHN
1) (Boc)2O; then separate
C10 isomers
2) MOMCl
N
OH
OBn
O
N
MOM
Br
OMe
O
BocHN
1) LiOH
2) TFA
N
O
CbzHN
OBn
3) HATU, collidine
4) BCl3; NaOH
OH O
Br
N
H
OH
N
MOM
Br
O
O
CbzHN
O
N
H
1) (Boc)2O
2) IBX
N
N
H
CbzHN
O
OH
O
N
3) NaClO2
4) EDC, HOBt
OH O
N
H
Br
O
Erick Iezzi @ Wipf Group
O O
NH
NH2
BocO
TFA
N
H
1) POCl3, pyd.
2) hv, LiOAc or Ph3SnH
HN
O
N
H
Br
Nicolaou, et al. Angew. Chem. Int. Ed. 2002, 41, 3495−3499.
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9/12/2004
Nicolaou’s First Total Synthesis of Diazonamide A
O
O
N
H
CbzHN
N
1) NCS
2) TFA
N
O
N
H
CbzHN
N
Cl
O
O
NH
NH
BocO
N
H
O
CbzHN
N
H
OH O
1) H2, Pd(OH)2/C
2) EDC, HOBt,
O
N
H
N
O
N
Cl
Cl
O
DIBAL-H
Cl
N
O
O
OH
HO
H
N
HO
N
H
N
O
O
O
O
NH
O
N
Cl
Cl
NH
N
H
O
N
H
21 operations
Nicolaou, et al. Angew. Chem. Int. Ed. 2002, 41, 3495−3499.
Erick Iezzi @ Wipf Group
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9/12/2004
Nicolaou’s Second Total Synthesis of Diazonamide A
CO2Me
O
CO2Me
NHCbz
O
NHCbz
TiCl4, CH2Cl2
OH
O
+
HO
58%
N
H
OTBS
O
N
H
Br
OH
N
Cbz
OBn
Br
O
OTBDPS
N
Cbz
TBSO
N
O
O
OTBDPS
O O
B
OBn
1) TBAF
2) SO3 pyd
3) MeONH2 HCl
N
OBn
NMOM
N
Bn
NMOM
FmocHN
O
I2Sm
SmI2
N
Cbz
O
N OMe
O
O
N
Cbz
N
NH
HO
N
O
OBn
Diazonamide A
O
N
Bn
OBn
NMOM
N
Bn
Nicolaou, et al. Angew. Chem. Int. Ed. 2002, 42, 1753−1758.
Erick Iezzi @ Wipf Group
O
O
N
MOM
2) FmocValOH,
EDC, HOBt
N OMe
N
Cbz
N
Bn
N
1) SmI2, DMA
(radical cyclization)
Br
Bn
O
Pd(dppf)Cl2
N
16
NMOM
(34 total synthetic operations)
9/12/2004
Harran’s Second Total Synthesis of Diazonamide A
O
O
OH
ArO2SHN
N
H2N
TFA
TBTU, DIPEA, DMF
CO2Me
O
N
N
H
ArO2SHN
CO2Me
O
PhI(OAc)2, LiOAc
91%
N
H
N
H
OH
Br
Br
OH
O
O
O
ArO2SHN
O
O
ArO2SHN
CO2Me
O
N
H
ArO2SHN
CO2Me
O
Br
Br
O
7-8%
20-25%
CO2Me
O
N
H
N
H H
Br
N
N
N
N
H
N
N
H
~15%
OH
H2N
O
HCl
N
N
H
O
TeocHN
NH
O
NH
N
N
H
CO2H
OH
NH
O
TeocHN
- 19 operations
- 9 linear steps
O
TBTU, DIPEA, DMF
O
N
H
Erick Iezzi @ Wipf Group
Diazonamide A
91%
O
Br
17
N
H
Br
Harran, et al. Angew. Chem. Int. Ed. 2003, 42, 4961–4966
9/12/2004
Imino-Dieckmann Cyclization Strategy (Vedejs, et al.)
Br
Br
CH3CO3H
PMBBr, NaH, DMF
NaSEt, DMF, reflux
OMe
Br
OH
OPMB
66%
97%
98%
O
O
O
Br
Br
MeOCOCl, Et3N
OPMB
Br
87%
OPMB
O
O
O
DIBAL-H
O
89%
OMe
O
OMe
MeOCOCl, DMAP
OPMB
97%
O
O
O
O
OMe
O
NaOH
1) MsCl, Et3N
Br
OH
O
2) MsOH
OPMB
O
89%
O
O
O
Li
O
Br
OMe
O
TMSCHN2
1) B(Oi-Pr)3
2) n-BuLi, -78 oC
O
ONa
O
1) NaH, 0 oC
94%
Br
ONa
O
OH
O
OMe
2) H3O+
O
O
B(OH)2
77% (5 steps)
O
O
B(OH)2
(Suzuki coupling partner)
Vedejs, et al. Org. Lett. 2001, 3, 2451−2454
Erick Iezzi @ Wipf Group
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9/12/2004
Imino-Dieckmann Cyclization Strategy (Vedejs, et al.)
N
O
+
NBoc
TfO
O
O
O
Pd(dppf)Cl2 (10 mol%), THF,
O
Cs2CO3, 65 oC, 15 h
B(OH)2
(Suzuki coupling partners)
N
OMe Me
O
Me
OMe
O
O
NBoc
(atropisomers)
N
O
O
3 equiv. LDA, THF, -23 oC, 5 min.
Vedejs, et al. Org. Lett. 2001, 3, 2451−2454
NBoc
57%
O
Erick Iezzi @ Wipf Group
O
19
9/12/2004
Imino-Dieckmann Strategy for Revised Structure
OBn
OBn
OBn
O
PMBBr, K2CO3, DMF
O
+
N
PMBO
97%
Br
TBSO
OMgCl
OH
CO2Me
PMBO
O
N
N
H
Br
TBSO
O
Br
OBn
OMe
O
ClCO2Allyl, DMAP
1) NaBH4, MeOH, THF
CO2Me
PMBO
THF, CH2Cl2
BnO
2) Ms2O, Et3N
O
N
99%
O
93% (2 steps)
O
Br
O
OMe
Br
O
N
N
O
N
O
O
O
BnO
+
BnO
TfO
O
N
H
1) KHMDS
2) 1
3) Ac2O
O
Me
NBoc
NBoc
SnMe3
O
N
MOM
(Stille coupling partners)
O
Me
NHAc
BuOC6H4
N
N
O
BnO
P
O
BuOC6H4
O
POCl3, pyd.
O
N
O
NH2
1
BnO
NBoc
O
NBoc
N
O
MOM
N
H
Vedejs, et al. Org. Lett. 2004, 6, 237−240
Erick Iezzi @ Wipf Group
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9/12/2004
Cyclopropanation / Ring-Opening Strategy (Wood, et al.)
N2
O
O
O
Rh2(cap)4
O
Me
Me
OMe
OMe
89%
O
O
3 equiv. LiOMe, THF
76%
O
OMe
MeO2C
Me
Me
O
O
OMe
O
OMe
LiO
Wood, et al. Org. Lett. 2000, 2, 3521−3523
Erick Iezzi @ Wipf Group
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9/12/2004
Wood’s Strategy for Revised Structure
Me
Me
TBSOTf, Et3N, CH2Cl2,
O
OTBS
0 oC, 30 min.
N
H
N
H
Me
Rh2(OAc)4, CH2Cl2,
reflux, 5h
N2
54% (2 steps)
O
Me
Me
Me
Me
OTBS
O
O
N
H
N
H
O
TBS
Wood, et al. Tetrahedron Lett. 2003, 44, 4919−4921
Erick Iezzi @ Wipf Group
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9/12/2004
Photo-Fries Rearrangement Strategy (Magnus, et al.)
H
HN
BocHN
N
N
O
N
1) TFA, CH2Cl2, 97%
O
O
NCO2Me
1) H2/Pd/C, HCO2NH4,
MeOH, 98%
N
O
CO2Bn
2) 1, EDCI/HOBt, DMF, 80%
BnO
O
NCO2Me
2) DMAP, EDCI/CHCl3,
0.004M, 66%
BnO
OH
OMe
O
CO2Bn
1
OMe
H
H
HN
N
O
O
HN
N
hv, PhH (0.001M), 23 oC, 76%
O
O
O
N
O
O
N
O
NCO2Me
NCO2Me
O
HO
OMe
OMe
Magnus, et al. Tetrahedron Lett. 2001, 42, 7193−7196
Erick Iezzi @ Wipf Group
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9/12/2004
Claisen Rearrangement Strategy (Moody, et al.)
O
Ot-Bu
CbzHN
O
O
Ot-Bu
CbzHN
n-Bu3Sn
Ot-Bu
CbzHN
1) Chloramine-T, NaI, DMSO
OH
PdCl2(PPh3)2, LiI, DMF, 70 oC
2) BnBr, K2CO3, TBAI, DMF
I
60% (2 steps)
OH
91%
OBn
OBn
O
O
CbzHN
OH
Ot-Bu
PBr3, pyd., ether
O
Ot-Bu
CbzHN
CbzHN
50%
n-Bu4NHSO4, NaOH,
H2O, PhH, 74%
OBn
Ot-Bu
DMF, reflux
Br
97%
OH
OBn
Br
H
O
OBn
HO
Br
Br
O
CbzHN
O
CF3
F3C
Ot-Bu
O
CbzHN
Ot-Bu
I
HO
OsO4, KIO4, MeOH-EtOAc-H2O
H
88%
OBn
HO
O
H
CH2Cl2
O
83%
Br
OBn
O
O
Br
Moody, et al. Tetrahedron Lett. 2000, 41, 6893−6896
Erick Iezzi @ Wipf Group
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9/12/2004
Heck and Ullmann Coupling Strategy (Pattenden, et al.)
Ph
Ph
Ph
I
O3, PPh3, 85%; then
Pd(PPh3)4, Ag2CO3, DMF
80 oC, 95%
O
CO2H
Br
O
NaClO4, KH2PO4, t-BuOH,
H2O, butene, 97%
O
Br
Br
1) (Im)2CO, THF, 100%
2) EtO2CCH2CO2H,
(CH3)2CHMgBr, THF,
heat, 60%
Asymmetric Heck unsuccessful
Ph
O
SOCl2, (S)-2-methylbenzylamine
Ph
O
Br
H
Ph
Ph
CO2Et
pTsOH; then NaOH
NH
92%
O
CO2H
O
78%
Me
O
Br
Br
resolve diastereomers
1) NaH, Br2, THF, 99%
2) NaN3, DMF, 99%
3) PPh3, THF, H2O, 100%
O
Ph
N
Ph
O
O
Br
Br
Convert to acid chloride
NH
N
H
Ph
N
CO2Et
NH2
Br
O
O
O
1) AcCl, Et3N, CH2Cl2
NH2
CO2Et
2) in situ, 44%
O
Br
Br
N
H
Pattenden, et al. Tetrahedron Lett. 1998, 39, 8167−8170
No coupling
Erick Iezzi @ Wipf Group
25
9/12/2004
Strategies of Former Wipf Group Members (Fumiaki’s)
O
NH2
NHCbz
1) Tl(TFA)3, TFA
1) CbzCl, aq. NaOH, dioxane
2) CuI, I2, DMF
2) DDQ, aq. THF
N
H
O
I
NHCbz
N
H
73% (2 steps)
N
H
65% (2 steps)
OMOM
I
SnBu3
OTDBPS
O
I
1) HBr/AcOH
2) TBDPSO
H
N
OTDBPS
O
CO2H
78% (2 steps)
82% (2 steps)
OTDBPS
I
N
HO
2) HCl, ether, MeOH,
CH2Cl2
N
O
39% (2 steps)
OEt
OTDBPS
EDCl-HCl, DMAP,
CH2Cl2
Ph
I
CO2H
96%
O
N
O
Ph
10 mol% Pd2(dba)3,
23 mol% (R)-BINAP,
O
O
O
N
1.2 eq. Ag3PO4, DMA,
O
100 oC, 22h
N
O
1) Pd2(dba)3-CHCl3,
CuI, Ph3As, NMP
N
OTDBPS
Ph
O
O
I
2) EtOCOCl, Et3N,
DMAP, CH2Cl2
N
H
DEPC, Et3N, THF
1) Ph3P, Cl3CCCl3,
Et3N, CH2Cl2
N
OEt
O
74%, 14% ee
OEt
N
O
OEt
*(R)-BINAP gave best yields
of 7 chiral ligands examined
*highest %ee was 19%
Wipf, et al. Tetrahedron Lett. 1998, 39, 2223−2226
Erick Iezzi @ Wipf Group
26
9/12/2004
Strategies of Former Wipf Group Members (Joey’s)
OTDBPS
N
NH2
O
N
N
H
O
O
Ph
Ph
O
Ph
Me
Me
N
N
O
Ph
O
Boc
CO2Et
N
LDA, THF, -78 oC, 30 min.
Boc
N
O
N
Wipf, et al. Org. Lett. 2001, 3, 1261−1264
N
CO2Et
CO2Et
Chan Rearrangement
78%
Me
CbzHN
Me
O
N
Ph
1) HCl, Et2O; NMM,
Cbz-Val, IBCF,
Ph
Me
N
O
O
NHBoc
Ph
Ph
Me
o
-20 C; 71%
N
O
2) TsOH, toluene,
4A MS, 65 oC;
N
58%
N
CO2Et
CO2Et
Erick Iezzi @ Wipf Group
27
9/12/2004
The End
Questions?
O
HN
O
OH
N
H
O
G
H F
O
N
H H
Erick Iezzi @ Wipf Group
28
A
E
N
O
D
N
B
C
Cl
Cl
NH
9/12/2004