jiawei meng supervisors: prof. dr. - pkusz.edu.cn
TRANSCRIPT
Reporter: Yangyang Jiang、Jiawei Meng、Feipeng Han
Supervisors: Prof. Tao Ye
Dr. Yian Guo
2
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
3
Epothilones family
Introduction
4
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.
5
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.
6
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)
7
Synthesis of Suzuki coupling partner compound 68
Approach 2 and 3 （Suzuki coupling Strategy)
8
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
9
Simmons–Smith cyclopropanation
MechanismCharette asymmetric modification
10
Oxidative solvolytic fragmentation with NIS
Mechanism
Y.-Y. Yeung, et al. Adv. Synth. Catal. 2020, 362, 2039 - 2044.
11
Mechanism
Reductive deiodination
12
Synthesis of Suzuki coupling partner compound 68
Approach 2 and 3 （Suzuki coupling Strategy)
13
Mechanism
Swern oxidation
14
Mechanism
Wittig reaction
15
Mechanism
Y. Tu, et al. J. Org. Chem. 2001, 66, 6502 - 6504.
Deprotection of Dithiane with bis(trifluoroacetoxy)iodobenzene
16
Synthesis of Suzuki coupling partner compound 75
Approach 2 and 3 （Suzuki coupling Strategy)
17
Synthesis of Suzuki coupling partner compound 75
Approach 2 and 3 （Suzuki coupling Strategy)
18
Synthesis of Suzuki coupling partner compound 75
Approach 2 and 3 （Suzuki coupling Strategy)
19
Mechanism
Deprotection of THP with PPTS
20
Mechanism
Horner–Wadsworth–Emmons
21
Mechanism
Mechanism of silyl acetylene to the corresponding iodoalkyne
T. D. Sheppard, et al. Adv. Synth. Catal. 2012, 354, 3217 - 3224.
22
More concise syntheses of 75
23
Mechanism
Keck asymmetric allylation
Geraci, L. S, et al. J. Am. Chem. Soc. 1993,115, 8467.
24
Mechanism
Brown Asymmetric Allylation
Corey, D. R, et al. J. Am.Chem. Soc. 1985, 107, 713.
25
Mechanism
Lemieux-Johnson oxidation
26
Mechanism
Malaprade reaction——NaIO4 cleaves 1,2-diols to aldehydes and ketones
27
Synthesis of a more advanced suzuki coupling partner
Approach 2 and 3 （Suzuki coupling Strategy)
28
Mechanism
Aldol reaction
Approach 2 and 3 （Suzuki coupling Strategy)
29
establishing the C11-C12 bond by Suzuki coupling
Approach 2 and 3 （Suzuki coupling Strategy)
30
Mechanism
Suzuki-miyaura cross-coupling
2
13
4
31
Approach 2 and 3 （Suzuki coupling Strategy)
construction ofthe 16-membered ring
32
Mechanism
Yamaguchi macrolactonization
33
Approach 2 and 3 （Suzuki coupling Strategy)
34
Synthesis of epothilone B by approach 2 （Suzuki coupling Strategy ）
Synthesis of epothilone A by approach 4（RCM Strategy）
35
Summary
S. J. Danishefsky（1997）
36
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
37
Synthesis of Fragment 3
38
asymmetric cyanosilylation
M. Shibasaki, et al. J. Am. Chem. Soc. 1999, 121, 2641 - 2642.
Mechanism
39
Reductive deoxygenation with palladium
J. Tsuji, et al. Tetrahedron Lett. 1993, 34, 2161 - 2164.
I. Minami, et al. Synthesis. 1987, 603 - 606.
Mechanism
40
Hydrotitanation
Mechanism
F. Sato, et al. Tetrahedron Lett. 1995, 36, 3203 - 3206.
Gaixia Du, et al. RSC Adv. 2017, 7, 3534.
41
Synthesis of Fragment 4
42
Synthesis of Fragment 4
43
Parikh-Doering Oxidation
Mechanism
44
Juliá–Colonna epoxidation
Mechanism
45
Mechanism
Gilman reagent
46
Synthesis of Fragment 4
47
Synthesis of Fragment 4
48
Evans–Saksena reduction
Mechanism
49
Mechanism
Ley-Griffith Oxidation
1
2
50
Mechanism
asymmetric aldol reaction
M. Shibasaki, et al. Angew.Chem. 1997, 109, 1942 - 1944.
Direct Catalytic Asymmetric Aldol Reactions of Aldehydes with Unmodified Ketones
51
Mechanism
M. Shibasaki, et al. Synlett.1997, 971 - 973.
Baeyer–Villiger oxidation of ketones with bis(trimethylsilyl) peroxide
52
Synthesis of Epothilones A
53
Mechanism
Suzuki-miyaura cross-coupling
54
Mechanism
Yamaguchi macrolactonization
55
Epoxidation with 3,3-Dimethyldioxirane
Mechanism
56
Summary
M. Shibasaki（2003）
57
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
58
Synthesis of compound 3
59
Synthesis of compound 3
60
Normant coupling reaction
Mechanism
Normant, J. F, et al. Synthesis. 1972, 63-80.
61
Diastereoselective hydroboration of the triene 15 using (i-PC)2BH
Mechanism
Joshi, N. N, et al. J. Am. Chem. Soc. 1988, 53, 4059 - 4061.
62
Sodium perborate reagent
Mechanism
63
Synthesis of compound 4
Why does 17 introduce
sulfide？
64
Evans aldol reaction
Mechanism
65
Synthesis of Epothilone B
66
Deprotection of Troc group using zinc metal
Mechanism
67
Summary
M. A. Avery（2001）
68
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
69
Introduction
70
Total Systhesis of Epothilones B and D
71
Mechanism
Brown Asymmetric Allylation
Corey, D. R, et al. J. Am.Chem. Soc. 1985, 107, 713.
The Systhesis of Segment C
72
Mechanism
Lemieux-Johnson oxidation
The Systhesis of Segment C
73
The Systhesis of Segment A and Segment AC
The Systhesis of Segment A and Segment AC
NHK reaction
74
Mechanism
75
Total Systhesis of Epothilone D and Epothilone B
76
Yamaguchi酯化
Total Systhesis of Epothilone D and Epothilone B
77
Prilezhaev Epoxidation
Total Systhesis of Epothilone D and Epothilone B
Mechanism
78
Summary
➢ The efficient generation of a C12-C13 trisubstituted olefin
which exploits a sequential Nozaki- Hiyama-Kishi coupling
➢ A stereoselective thionyl chloride rearrangement.
79
Total Systhesis of Epothilone Analogues
80
Introduction
81
The Systhesis of Carboxylic Acid 11
82
Dess-Martin
83
The Systhesis of Carboxylic Acid 11
Noyori不对称氢化
Mechanism
84
The Systhesis of Alcohol 17
85
Appel reaction
Mechanism
The Systhesis of Alcohol 17
86
Total Systhesis of Epothilone Analogues
87
Total Systhesis of Epothilone Analogues
Mechanism
Wittig reaction
88
Summary
89
Total Systhesis of ZK-EPO
90
The Systhesis of Segment A and B
91
The Systhesis of Segment C
92
Parikh-Doering Oxidation
Mechanism
The Systhesis of Segment C
93
The Systhesis of Segment BC
94
Total Systhesis of ZK-EPO
95
Epoxidation with 3,3-Dimethyldioxirane
Mechanism
Total Systhesis of ZK-EPO
96
Summary
ZK-EPO epothilone B
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
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
99
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
10
0
Mechanism
Corey-Bakshi-Shibata Reduction
OO
9
OHO
10
(R)-CBS catecholborane
61%, 96% ee
10
1
Mechanism
Negishi Cross-coupling
OTfTBSO
11
Et2Zn, Pd(PPh3)4, THF EtTBSO
5
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
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
10
4
Roush Asymmetric Allylation
10
5
Synthesis of 4 via Bissiloxane-Tethered RCM Reaction
Guo-Qiang Lin, et al. Org. Lett. 2012, 14, 6354-6357
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
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
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
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
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
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
11
2
Mechanism
Horner–Wadsworth–Emmons
NHBoc
O
n-BuLi, THF
PPh2
S
N
O
S
N
NHBoc
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
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
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
11
6
Summary
R. M. Borzilleri, et al. J. Am. Chem. Soc. 2000, 122, 8890-8897
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
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
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
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
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
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
12
3
Mechanism
EssKurti−Falck Aziridination
J.R.Falck, Science 2014, 343, 61
12
4
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
12
5
Epothilones were evaluated in the clinical setting
126
Prof. Tao Ye, Dr. Yian Guo
All professors and faculties in SCBB
All my labmates in F211
Acknowledgements
127