jiawei meng supervisors: prof. dr. - pkusz.edu.cn
TRANSCRIPT
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Reporter: Yangyang Jiang、Jiawei Meng、Feipeng Han
Supervisors: Prof. Tao Ye
Dr. Yian Guo
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Contents
1.Introduction
2.Total Synthesis of Epothilone
Ⅰ. S. J. Danishefsky: J. Am. Chem. Soc. 1997, 119, 42, 10073 - 10092.
Ⅱ. M. Shibasaki: Angew. Chem. 2000, 39, 209 - 213.
Ⅲ. M. A. Avery: Org. Lett. 2001, 3, 3607 - 3609.
3.Summary
4.Acknowledgement
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Epothilones family
Introduction
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Introduction
Isolation:
Metabolites produced by the soil-
dwelling myxobacterium Sorangium
cellulosum.
Structural Features:
• 7 stereogenic centers
• A thiazole moiety, a cis-epoxide and a
geminal methyl groups at C4
• A array of three contiguous methylene
groups
• Acyl section containing four chiral
centers.
Biological activities:
• The epothilones are a class of
potential cancer drugs.
• They prevent cancer cells from
dividing by interfering with tubulin.
• Epothilones have better efficacy and
milder adverse effects than taxanes.
H.Reichenbach, et al. Angew. Chem. 1996, 108, 1671 -1673.
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4 possible approaches for Total Synthesis of Epothilone A (2) and B (3)
failure
S. J. Danishefsky: J. Am. Chem. Soc. 1997, 119, 42, 10073–10092.
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B-Alkyl Suzuki Strategy
Approach 2:C2-C3 bond construction
strategy
Approach 3:O15-C1 bond construction
strategy
Approach 2 and 3 (Suzuki coupling Strategy)
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Synthesis of Suzuki coupling partner compound 68
Approach 2 and 3 (Suzuki coupling Strategy)
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Mechanism
Danishefsky, S, J, et al. J. Org. Chem. 1996, 61, 8000.
Clardy, J, et al. J. Am. Chem. Soc. 1979,101, 7001.
Titanium-mediated cyclocondensation
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Simmons–Smith cyclopropanation
MechanismCharette asymmetric modification
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Oxidative solvolytic fragmentation with NIS
Mechanism
Y.-Y. Yeung, et al. Adv. Synth. Catal. 2020, 362, 2039 - 2044.
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Mechanism
Reductive deiodination
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Synthesis of Suzuki coupling partner compound 68
Approach 2 and 3 (Suzuki coupling Strategy)
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Mechanism
Swern oxidation
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Mechanism
Wittig reaction
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Mechanism
Y. Tu, et al. J. Org. Chem. 2001, 66, 6502 - 6504.
Deprotection of Dithiane with bis(trifluoroacetoxy)iodobenzene
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Synthesis of Suzuki coupling partner compound 75
Approach 2 and 3 (Suzuki coupling Strategy)
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Synthesis of Suzuki coupling partner compound 75
Approach 2 and 3 (Suzuki coupling Strategy)
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Synthesis of Suzuki coupling partner compound 75
Approach 2 and 3 (Suzuki coupling Strategy)
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Mechanism
Deprotection of THP with PPTS
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Mechanism
Horner–Wadsworth–Emmons
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Mechanism
Mechanism of silyl acetylene to the corresponding iodoalkyne
T. D. Sheppard, et al. Adv. Synth. Catal. 2012, 354, 3217 - 3224.
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More concise syntheses of 75
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Mechanism
Keck asymmetric allylation
Geraci, L. S, et al. J. Am. Chem. Soc. 1993,115, 8467.
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Mechanism
Brown Asymmetric Allylation
Corey, D. R, et al. J. Am.Chem. Soc. 1985, 107, 713.
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Mechanism
Lemieux-Johnson oxidation
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Mechanism
Malaprade reaction——NaIO4 cleaves 1,2-diols to aldehydes and ketones
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Synthesis of a more advanced suzuki coupling partner
Approach 2 and 3 (Suzuki coupling Strategy)
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Mechanism
Aldol reaction
Approach 2 and 3 (Suzuki coupling Strategy)
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establishing the C11-C12 bond by Suzuki coupling
Approach 2 and 3 (Suzuki coupling Strategy)
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Mechanism
Suzuki-miyaura cross-coupling
2
13
4
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Approach 2 and 3 (Suzuki coupling Strategy)
construction ofthe 16-membered ring
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Mechanism
Yamaguchi macrolactonization
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Approach 2 and 3 (Suzuki coupling Strategy)
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Synthesis of epothilone B by approach 2 (Suzuki coupling Strategy )
Synthesis of epothilone A by approach 4(RCM Strategy)
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Summary
S. J. Danishefsky(1997)
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M. Shibasaki: Angew. Chem. 2000, 39, 209 - 213.
• Enantioselective total synthesis using simple asymmetric catalysts
• Using multifunctional asymmetric catalyses for direct aldol reaction and cyanosilylation
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Synthesis of Fragment 3
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asymmetric cyanosilylation
M. Shibasaki, et al. J. Am. Chem. Soc. 1999, 121, 2641 - 2642.
Mechanism
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Reductive deoxygenation with palladium
J. Tsuji, et al. Tetrahedron Lett. 1993, 34, 2161 - 2164.
I. Minami, et al. Synthesis. 1987, 603 - 606.
Mechanism
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Hydrotitanation
Mechanism
F. Sato, et al. Tetrahedron Lett. 1995, 36, 3203 - 3206.
Gaixia Du, et al. RSC Adv. 2017, 7, 3534.
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Synthesis of Fragment 4
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Synthesis of Fragment 4
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Parikh-Doering Oxidation
Mechanism
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Juliá–Colonna epoxidation
Mechanism
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Mechanism
Gilman reagent
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Synthesis of Fragment 4
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Synthesis of Fragment 4
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Evans–Saksena reduction
Mechanism
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Mechanism
Ley-Griffith Oxidation
1
2
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Mechanism
asymmetric aldol reaction
M. Shibasaki, et al. Angew.Chem. 1997, 109, 1942 - 1944.
Direct Catalytic Asymmetric Aldol Reactions of Aldehydes with Unmodified Ketones
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Mechanism
M. Shibasaki, et al. Synlett.1997, 971 - 973.
Baeyer–Villiger oxidation of ketones with bis(trimethylsilyl) peroxide
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Synthesis of Epothilones A
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Mechanism
Suzuki-miyaura cross-coupling
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Mechanism
Yamaguchi macrolactonization
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Epoxidation with 3,3-Dimethyldioxirane
Mechanism
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Summary
M. Shibasaki(2003)
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M. A. Avery: Org. Lett. 2001, 3, 3607 - 3609.
• Closing the ring through double-diastereoselective aldol condensation and
macrolactonization
• Synthesis of trisubstituted (Z)-olefingeometry by modifiction of a classical Normant
alkynecupration and electrophile trap
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Synthesis of compound 3
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Synthesis of compound 3
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Normant coupling reaction
Mechanism
Normant, J. F, et al. Synthesis. 1972, 63-80.
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Diastereoselective hydroboration of the triene 15 using (i-PC)2BH
Mechanism
Joshi, N. N, et al. J. Am. Chem. Soc. 1988, 53, 4059 - 4061.
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Sodium perborate reagent
Mechanism
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Synthesis of compound 4
Why does 17 introduce
sulfide?
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Evans aldol reaction
Mechanism
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Synthesis of Epothilone B
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Deprotection of Troc group using zinc metal
Mechanism
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Summary
M. A. Avery(2001)
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Contents
1. Introduction
2.Total Synthesis of Epothilone and AnaloguesⅠ. Richard E. Taylor: Org. Lett. 2001, No.1, 42221-2224
Ⅱ. Samuel J. Danishefsky: Angew. Chem. 2003, 115, 4910 –4915
Ⅲ. Ulrich Klar: Angew. Chem. 2006, 118, 8110 –8116
3.Summary
4.Acknowledgement
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Introduction
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Total Systhesis of Epothilones B and D
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Mechanism
Brown Asymmetric Allylation
Corey, D. R, et al. J. Am.Chem. Soc. 1985, 107, 713.
The Systhesis of Segment C
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Mechanism
Lemieux-Johnson oxidation
The Systhesis of Segment C
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The Systhesis of Segment A and Segment AC
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The Systhesis of Segment A and Segment AC
NHK reaction
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Mechanism
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Total Systhesis of Epothilone D and Epothilone B
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Yamaguchi酯化
Total Systhesis of Epothilone D and Epothilone B
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Prilezhaev Epoxidation
Total Systhesis of Epothilone D and Epothilone B
Mechanism
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Summary
➢ The efficient generation of a C12-C13 trisubstituted olefin
which exploits a sequential Nozaki- Hiyama-Kishi coupling
➢ A stereoselective thionyl chloride rearrangement.
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Total Systhesis of Epothilone Analogues
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Introduction
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81
The Systhesis of Carboxylic Acid 11
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82
Dess-Martin
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The Systhesis of Carboxylic Acid 11
Noyori不对称氢化
Mechanism
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84
The Systhesis of Alcohol 17
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Appel reaction
Mechanism
The Systhesis of Alcohol 17
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86
Total Systhesis of Epothilone Analogues
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87
Total Systhesis of Epothilone Analogues
Mechanism
Wittig reaction
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88
Summary
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Total Systhesis of ZK-EPO
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90
The Systhesis of Segment A and B
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91
The Systhesis of Segment C
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Parikh-Doering Oxidation
Mechanism
The Systhesis of Segment C
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The Systhesis of Segment BC
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Total Systhesis of ZK-EPO
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Epoxidation with 3,3-Dimethyldioxirane
Mechanism
Total Systhesis of ZK-EPO
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Summary
ZK-EPO epothilone B
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Total Synthesis of Epothilones & Analogues
O
R
S
N
O OH O
OH
O
epotilone A: R = H ; epotilone B: R = Me
O
O OH O
OH
N
HO
R1
R2
N
1c: R = H; 2c: R =Me (ixabepilone)
HN
R
S
N
O OH O
OH
O
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98
An Efficient Total Synthesis of (-)-Epothilone B
Retrosynthesis of Epothilone B (1)
O
S
N
O OH O
OH
O
epotilone B (1)
O
S
N
O OH O
OH
epotilone D (2)
epoxidation
12
13
aldol reaction
6
7
macrolaconization
OR
S
N
O
O
COOH
OTBS
34O
S
N
6
O
tether
N
S
OH
OH
7 8
EtTBSO
5
tethered RCM
Guo-Qiang Lin, et al. Org. Lett. 2012, 14, 6354-6357
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The Synthesis of Segment 3
OO
5 steps
30% O
COOH
OTBS
9 3
E. J. Corey, et al. J. Am. Chem. Soc. 2007, 129, 10346–10347
OO
9
OHO
10
(R)-CBS catecholborane
61%, 96% ee
1. TBSCl, imidazole DCM/DMF= 10:12. KHMDS, Tf2NPh, THF OTfTBSO
11
84% over two steps
Et2Zn, Pd(PPh3)4, THF EtTBSO
5
O3, Et3N, DCM
58% over two steps O
COOH
OTBS
3
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10
0
Mechanism
Corey-Bakshi-Shibata Reduction
OO
9
OHO
10
(R)-CBS catecholborane
61%, 96% ee
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10
1
Mechanism
Negishi Cross-coupling
OTfTBSO
11
Et2Zn, Pd(PPh3)4, THF EtTBSO
5
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10
2
The Systhesis of Segment 7 and 8
N
S
O
N
S
S1
EtO
O
DIBAL-H, DCM, -78 °C
84%
N
S
H
OS2
O
N
S
OH7
EtOH, 5% NaOH (aq.)
92%, E/Z > 20:1S3
(-)-Ipc2Ballyl, Et2O
99%, 94% ee
OH
O
ONH
O
iPr
(COCl)2, DCM then nBuLi, THF
N
O
O
O
iPr
1. NaHMDS, MeI, THF
2. LiAlH4, THF
OH
8
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10
3
Mechanism
Brown Asymmetric Allylation
D. R . Corey, et al. J. Am.Chem. Soc. 1985, 107, 713
N
S
OS3
N
S
OH7
(-)-Ipc2Ballyl, Et2O
99%, 94% ee
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10
4
Roush Asymmetric Allylation
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10
5
Synthesis of 4 via Bissiloxane-Tethered RCM Reaction
Guo-Qiang Lin, et al. Org. Lett. 2012, 14, 6354-6357
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10
6
Total Synthesis of (-)-Epothilone D (2) and (-)-Epothilone B (1)
O
S
N
OSi
iPr
OSi
F
iPr
iPr
iPr
4
O
COOH
OTBS
3
TiCl4, DIPEA, DCM
51% (73% brsm)
FSOSO
S
N
HO2C
OTBSO
OH
13
1. TBSOTf, DCM2. TBAF, THF
75% over two steps
HO
S
N
HO2C
OTBSO
OTBS
Yamaguchi’s conditions
TCBC, Et3N, DMAP, THF
81%
O
S
N
O OTBSO
OTBS
15
TFA/DCM = 1:5
91%
O
S
N
O OH O
OH
epotilone D (2)
14
m-CPBA, CDCl3
83%, dr = 4:1O
S
N
O OH O
OH
O
epotilone B (1)
Guo-Qiang Lin, et al. Org. Lett. 2012, 14, 6354-6357
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10
7
Mechanism
Corey, D. R, et al. J. Am.Chem. Soc. 1985, 107, 713.
HO
S
N
HO2C
OTBSO
OTBS
Yamaguchi’s conditions
TCBC, Et3N, DMAP, THF
81% O
S
N
O OTBSO
OTBS
15
14
Yamaguchi’s Conditions
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10
8
Mechanism
Corey, D. R, et al. J. Am.Chem. Soc. 1985, 107, 713.
O
S
N
O OH O
OH
epotilone D (2)
m-CPBA, CDCl3
83%, dr = 4:1O
S
N
O OH O
OH
O
epotilone B (1)
Epoxidation
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10
9
Summary
O
S
N
O OH O
OH
O
epotilone B (1)
OO
5 steps
30% O
COOH
OTBS
N
S
OH
OH
9 3
7
8
O
S
N
4 steps
33% OSi
iPr
OSi
F
iPr
iPr
iPr
6 steps
28%
4
Guo-Qiang Lin, et al. Org. Lett. 2012, 14, 6354-6357
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11
0
Synthesis of Lactam Analogues of the Epothilones
R. M. Borzilleri, et al. J. Am. Chem. Soc. 2000, 122, 8890-8897
O
S
N
O OH O
OH
O
I: epotilone B
HN
S
N
O OH O
OH
O
II: ixabepilone
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11
1
Total Synthesis Approach
HO2C
NH2
1. Boc2O, NaHCO3. THF/H2O2. CH3O(CH3)NH-HCl, EDCI HOBt, NMM, CDCl3
70% over two steps NHBoc
N
O
O
1. MeMgBr, THF2. n-BuLi, THF
PPh2
S
N
O
S
N
NHBoc
4 M HCl, 1,4-dioxaneS
N
NH2
R. M. Borzilleri, et al. J. Am. Chem. Soc. 2000, 122, 8890-8897
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11
2
Mechanism
Horner–Wadsworth–Emmons
NHBoc
O
n-BuLi, THF
PPh2
S
N
O
S
N
NHBoc
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11
3
Total Synthesis Approach
S
N
NH2
HO
O O O
OH
TBDMS
EDCl, HOBt, DMF, 15 h
77%
HN
O O O
OH
TBDMS
S
N
RuBnCl2(PCy3)2
C6H6 (4 mM), 22 h
HN
S
N
O O O
OH
TBDMS
HN
S
N
O O
TBDMS
OH
O
E-isomer 34%Z-isomer 7%1:5
7 8 9
10 11
R. M. Borzilleri, et al. J. Am. Chem. Soc. 2000, 122, 8890-8897
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11
4
Semi-Synthesis Approach
O
R
S
N
O OH O
OH
O
1: R = H; 2: R =Me
N3
R
S
N
O
OH
O
HO
HO2C
Pd(PPh3)4, 10 mol %, NaN3, degassed THF-H2O
1a: R = H; 2a: R =Me
R
S
N
O
OH
O
HO
HO2C
PdLn
N3-
PPh3, THF, 45 °C for 14 hthen 28% NH4OH, H2O
NH2
R
S
N
O
OH
O
HO
HO2C
1b: R = H; 2b: R =Me
EDCl, HOBt, MeCN
53% - 89%
25% - 65%
1c: R = H; 2c: R =Me (ixabepilone
or PMe3, THF-H2O, 25 °C
or H2, EtOH, PtO2
HN
R
S
N
O OH O
OH
O
R. M. Borzilleri, et al. J. Am. Chem. Soc. 2000, 122, 8890-8897
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11
5
Mechanism
Staudinger Reaction
N3
R
S
N
O
OH
O
HO
HO2C
1a: R = H; 2a: R =Me
PPh3, THF, 45 °C for 14 hthen 28% NH4OH, H2O
NH2
R
S
N
O
OH
O
HO
HO2C
1b: R = H; 2b: R =Me53% - 89%
or PMe3, THF-H2O, 25 °C
or H2, EtOH, PtO2
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11
6
Summary
R. M. Borzilleri, et al. J. Am. Chem. Soc. 2000, 122, 8890-8897
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11
7
Synthesis and Biological Activity of Epothilone Aziridines
A. R. Ren, et al. Org. Lett. 2001, 3, 2693-2696
O
S
N
O OH O
OH
HN
aziridinyl epothilone A
O
S
N
O OH O
OH
O
epothilone A
O
S
N
O OH O
OH
epothilone C
8.3% over three steps
13.3 % over eghit steps
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11
8
Synthesis of Epothilone A Aziridine via Diastereomeric Epoxide
Synthesis and Biological Activity of Epothilone Aziridines
O
S
N
O OH O
OH
epothilone C
CF3COCH3, oxoneNaHCO3, EDTA, CH3CN
O
S
N
O OH O
OH
desired epoxide20%
O
O
S
N
O OH O
OH
O
epothilone A
60%
1:3
O
S
N
O OH O
OH
O
epothilone A
1. TESCl, DIPEA, DMF
2. MgBr2-Et2O, CH2Cl2
41% over two steps
O
S
N
O OH O
OTES
Br
OH
O
S
N
O OH O
OTES
N3
OH
1. NaN3, DMF
2. p-NBA, DEAD Ph3P, THF3. NH3, MeOH
36% over two steps
1. MsCl, Et3N, CH2Cl22. Me3P, THF/H2O
3. TFA/DCM = 1:9
90% over three. steps
O
S
N
O OH O
OH
HN
aziridinyl epothilone A
Synthesis of Epothilone A Aziridine 7 via Bromohydrin 8
A. R. Ren, et al. Org. Lett. 2001, 3, 2693-2696
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11
9
In Vitro Data for Aziridine Analogues of Epothilone A
O
R
S
N
O OH O
OH
X
A. R. Ren, et al. Org. Lett. 2001, 3, 2693-2696
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12
0
K. C. Nicolaou, et al. J. Am. Chem. Soc. 2017, 139, 7318−7334
12,13-Aziridinyl Epothilones
O
R
S
N
O OH O
OH
1: epothilone C (R = H)
2: epothilone D (R = Me)
O
R
S
N
O OH O
OH
HN
1a: R = H, 70%2a: R = Me, 66%
DPH, Rh2(esp)2
CF3CH2OH
[single diastereomer]
K2CO3, DMF
BrOH
1c: R = H, 97%2c: R = Me, 95%
O
R
S
N
O OH O
OH
N
HO
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12
1
O
S
N
O OH O
OH
O
1. O3, DCM then Me2S2. TESOTf, 2,6-lutidine, DCM
82% over two stepsO
O
O OTES O
OTES
O
WCl6, n-BuLi, THF
86% Z only
DPH, Rh2(esp)2
CF3CH2OH
[single diastereomer]
90%O
O
O OTES O
OTES
HN
O
O
O OTES O
OTES K2CO3, DMF
BrOTBS
O
O
O OTES O
OTES
N
TBSO
12,13-Aziridinyl Epothilones
K. C. Nicolaou, et al. J. Am. Chem. Soc. 2017, 139, 7318−7334
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12
2
O
S
N
O OH O
OH
O
1. O3, DCM then Me2S2. TESOTf, 2,6-lutidine, DCM
82% over two stepsO
O
O OTES O
OTES
O
WCl6, n-BuLi, THF
86% Z only
DPH, Rh2(esp)2
CF3CH2OH
[single diastereomer]
90%O
O
O OTES O
OTES
HN
O
O
O OTES O
OTES K2CO3, DMF
BrOTBS
O
O
O OTES O
OTES
N
TBSO
K. C. Nicolaou, et al. J. Am. Chem. Soc. 2017, 139, 7318−7334
12,13-Aziridinyl Epothilones
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12
3
Mechanism
EssKurti−Falck Aziridination
J.R.Falck, Science 2014, 343, 61
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Epothilone B Analogues
K. C. Nicolaou, et al. J. Org. Chem. 2020, 85, 2865−2917
O
O
O OTES O
OTES
N
TBSO
1. HWE conditions
2. HF•py, THF
O
O OH O
OH
N
HO
R1
R2
N
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Epothilones were evaluated in the clinical setting
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Prof. Tao Ye, Dr. Yian Guo
All professors and faculties in SCBB
All my labmates in F211
Acknowledgements
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