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Total Synthesis of Bryostatins
(Previous Achievement and Krischeʼs Work)
Literature seminar (2018.02.14)B4 Hongyu Chen
Contents
1. Introduction2. Previous work3. Total synthesis of Bryostatin 7 by Krische4. Summary
1. Introduction
Introduction
Isolation : From the marine bryozoan Bugula neritina (フサコケムシ)
Biosynthesis : Candidatus Endobugula sertula (Symbiotic bacterium of Bugula neritina)
Biological activity : ・Potent modulator of protein kinase C (PKC) ・Anti-cancer effect ・Anti-HIV effect ・Life-prolonging effect on Alzheimer’s disease
O
OR1
MeMeHO
OHO
MeMe O
R2
O
Me
O
O
OHOMe
OH
OMe
O
16 17
Introduction
Structure features: ・A family of 20 marine natural products ・Three heavily substituted tetrahydropyran rings ・Two acid/base-sensitive exo-cyclic unsaturated esters ・One congested C16-C17 trans-alkene ・Numerous oxygen-containing functionalities on a 26-membered lactone
O
OR1
MeMeHO
OHO
MeMe O
R2
O
Me
O
O
OHOMe
OH
OMe
O
16 17
2. Previous work
Development of Bryostatinʼs Total Synthesis
Synthesis points : ① Exo-cyclic unsaturated esters ② Congested C16-C17 trans-alkene ③ Macrolactonization ④ Complex steric structure
O
OR1
MeMeHO
OHO
MeMe O
R2
O
Me
O
O
OHOMe
OH
OMe
O
16 17
1990MasamuneBryostatin 7
1998 EvansBryostatin 2
2000 YamamuraBryostatin 3
2008 TrostBryostatin 16
2011Keck
Bryostatin 1
2011Wender
Bryostatin 9
KrischeBryostatin 7
Total Synthesis of Bryostatin 7 by Masamune (1990) (1)
Masamune, S. et al. J. Am. Chem. Soc., 1990, 112, 7407.
・ First total synthesis of Bryostatin ・ Bryostatin 7 was devided into 4 fragments and chiral enolate reagent 7 controlled enantioselectivity of the product ・ 41 steps in total
Bryostatin 7
O
OAcMeMeHO
OHO
MeMe O
AcO
O
Me
O
O
OHOMe
OH
OMe
O
1
26
B A
C
11
16 17
25
10
aldol reaction
Julia-Lythgoe olefinationmacrolactonization
O O O
OSitBuPh2
Ph2tBuSiO CHO
O
OSitBuPh2
O
O
Et3SiO
OMe
Et3CS
OB
10 3
11
16
12
1720
25
O O
MeMeMeO OAcPh2tBuSiO
OSitBuPh2
OH
PhO2S
7
5
4
6
8
AB
C
11
16
10
3
Total Synthesis of Bryostatin 7 by Masamune (1990) (2)
Masamune, S. et al. J. Am. Chem. Soc., 1990, 112, 7407.
CHOBnO
MeMe
BnO
MeMeOH
OBnO
MeMe
OOH
O
(1) (EtO)2(P=O)CH2CO2Et, NaH(2) DIBAL-H
(3) (-)-DET, Ti(OiPr)4, tBuOOH CH2Cl2 (85%)
(1) (COCl)2, Me2SO Et3N(2) Ph3P=CHCHO, C6H6
(3) NaBH4, MeOH (61%, 3 steps)(4) (+)-DET, Ti(OiPr)4, tBuOOH CH2Cl2 (80%)
O
MeMeMe
O O
Me Me
OTBDPS
OH
HO
OTHP
I
OH
OTHP
OTBDPS
CHO
RedAl-H, THF
then I2 (90%)
2 steps+
8 steps
BOTf
Me
Me
iPr2NEtEt2O(86%)
OH O O
O
OTBDPS
MeMe
MeMeTBDPSO
4 stepsO O
MeMeMeO
OAcTBDPSO
OTBDPSOH
O O
MeMeMeO
OAc
OTBDPS
TBDPSO
CHO
(1) (COCl)2, Me2SO Et3N
(2) Al2O3 (3% H2O) CH2Cl2 (60%, 2 steps)
(92% ee) (>99% ds)
11
(11S:11R = 8:1)
1 2 3
56 8 9 10
11
1214
16
15
15
4 steps
Total Synthesis of Bryostatin 7 by Masamune (1990) (3)
Masamune, S. et al. J. Am. Chem. Soc., 1990, 112, 7407.
NH2
HO2CMe
OHO
O
MeMe
Me
OPMB
I
OTBDPS
14 steps
L-Threonine
nBuLi
ODMBPhS
CHOMeMe
21
20
OH
DMBO
MeMePhS
OTBDPS
OPMB OO
MeMe
Me
22
O
PhO2S
MeMe
TESO
OTBDPS
HOMe
OO
Me
MeMe
16
(1) TESOTf, 2,6-Lut(2) DDQ(3) Me2SO, Ac2O, Et3N
(4) MoO5独HMPA独H2O(5) DDQ, SiO2(6) TMSOTf, TMSOMe or BF3OEt2, MeOH
+
O O
MeMeMeO
OAc
OTBDPS
TBDPSO
CHO
15
O
OAcMeMe
MeO
OTBDPS
O
O
Me
H
TBDPSO
MeMe
TESO
OMe
OTBDPS
O
O
MeMe
16 17 3
23
(1) PhLi, THF then BzCl, DMAP
(2) Na-Hg, MeOH/EtOAc NaHPO4
6 steps
O
OAcMeMe
MeO
CHO
O
O
Me
MeO2C
H
CO2Me
MeMe
AcO
OMe
O
O
MeMe
16 17
25
BO
SCEt3
Me Me
(1)
iPr2NEt, Et2O
(2) CSA, MeOH(3) TESOTf, CH2Cl2 2,6-lutidine
26
O
OAcMeMe
MeO
O
O
Me
H
CO2Me
MeMe
AcO
OMe16 17
27
MeO2C
OTES
OTES
COSC(Et)3
OTES 2 steps
O
OAcMeMe
MeO
O
O
Me
H
CO2Me
MeMe
AcO
OMe
MeO2C
OH
OH
CO2HOH
28
O
OHMeMe
HO
O
O
Me
H
CO2Me
MeMe
HO
OH
MeO2C
O
OH
OHO
29
(1) DCC, PPTS, py ClCH2CH2Cl
(2) K2CO3, MeOH HCl
3 steps
O
OAcMeMe
HO
OHO
O
AcO
CO2Me
Me
O
O
OH
OH
MeO2C
Bryostatin 7
HMe
Me
Total Synthesis of Bryostatin 2 by Evans (1998) (1)
Evans, D. A. et al. Angew. Chem., Int. Ed. 1998, 37, 2354.
・ Rings A-C were derived from the same set of acyclic precursors, each of which contains a common anti-1,3-diol subunit ・ This stereochemical motif can be effectively synthesized by sequential aldol and reduction reactions ・ 42 steps in total
O
OHMeMe
HO
OHO
MeMe O
O
CO2Me
Me
O
O
OH
OH
MeO2C
OnPr
H
AB
C
bryostatin 2
1
79
13
16
20 26
O
OPMBMeMe
MeO
O
MeMe O
Me
O
O
OPMB
AB
C
1
79
13
16
20 26
TBSO
OTBS
H
O O
O
R3SiO
OTBS
OPMBMe
SO2Ph
MeMe
OPMBMeMe
PhO2S
TBSO
AB
C
CONHR
H
(-)9
1OH
LG
(+)
(+)13 10
16
(-)17
20 26
Julia-Lythgoe olefination
macrolactonization
sulfone alkylation
1
XMe Me
CONHRPhO2S OPMB OTBSOH
OHC
OH OTBSOHLG
PhO2S O OH OTBS
OPMB
Me
Me Me
17 27
16 10
91
fragment A
fragment B
fragment C
Total Synthesis of Bryostatin 2 by Evans (1998) (2)
Evans, D. A. et al. Angew. Chem., Int. Ed. 1998, 37, 2354.
Ph2C H
O
Me Me N O
Bn
OOOH
Me Me
Ph PhN O
Bn
OO
ClO
PhO2S OPMBMeMe
TBSO
NHPh
O
Bu2BOTf, iPr2NEt, CH2Cl2 then aldehyde(2) Zn, THF/AcOH = 2/1
32
(1)
33
34
13 steps
40
Me Me
HO OH
CHOO
PhSO2
MeMe
Me
O
OPMB
Me
43 44
458 steps
(-)-DIPCI, NEt3, CH2Cl2then 44
46
O
PhSO2
MeMe
OH
O
OPMB
MeO
Me
PhO2S
MeMe
HOTBS
OPMB48
O
TBSO
CHO
OTBS
(1) nBuLi, THF then
(2) Ac2O, DMAP, CH2Cl2(3) Mg, HgCl2
49 O
Me
MeMe
HOTBS
OPMB50
OOTBS
TBSO
O
Me
MeMe
HOTBS
OPMB41
OOTf
TBSO
2 steps
4 steps
Total Synthesis of Bryostatin 2 by Evans (1998) (3)
Evans, D. A. et al. Angew. Chem., Int. Ed. 1998, 37, 2354.
O
PhO2S OPMBMeMe
TBSO
NHPh
O40
O
Me
MeMe
HOTBS
OPMB41
OOTf
TBSO
O
Me
MeMe
OTBS
OPMB
O
TBSO
O
PhSO2 OPMB
CONHPhOTBS
9
+
42
O
Me
MeMe
OTBS
OPMB
O
TBSO
O
HOOPMB
CONHPhOTBS
9
51
Me Me Me Me
SiO2
O
Me
MeMe
OH
OPMB
O
TESO
O
OPMB
CO2HOTES
O
OMe
55
MeOMeMe
7 steps
O
Me
MeMe
O
OPMB
O
TESO
O
OPMB
OTES
O
OMe
MeOMeMe
56
HO
O
Me
MeMe
O
OPMB
O
O
O
OPMB
OTES
O
OMe
MeOMeMe
57
HO
2,4,6-Trichlorobenzoylchloride, iPr2NEt, C6H6
then DMAP
2 steps
O
OP
O
CO2Me
58
NaHMDS, THF O
Me
MeMe
O
OPMB
O O
OPMB
OTES
O
OMe
MeOMeMe
HO
MeO2C
59
O
Me
MeMe
O
OPMB
O O
OPMB
OTES
O
OMe
MeOMeMe
HO
MeO2C
CO2Me60
O
Me
MeMe
O
OPMB
O O
OPMB
OTES
O
OMe
MeOMeMe
HO
MeO2C
CO2Me62
OMeO
(1) KHMDS, THF then OHCCO2Me
(2) Et3NSO2NCO2Me C6H6
N BO
H PhPh
Me 61
BH3-Me2S, CH2Cl2then (MeOCH2CO)2OPy, DMAP
5 steps
O
OHMeMe
HO
OHO
MeMe O
O
CO2Me
Me
O
O
OH
OH
MeO2C
OnPr
H
bryostatin 2
Z:E = 5.5:1
Total Synthesis of Bryostatin 3 by Yamamura (2000) (1)
Yamamura, S. Angew. Chem., Int. Ed. 2000, 39, 2290.
O
OAcMeMe
HO
OHO
MeMe O O
OOH
MeO2C
H
O
OnPr
bryostatin 3
B A
C
O
O
OHMe
O
OHMeMe
HO
OHO
O
MeMe O O
OOMe H
O
OnPr
B A
C
O
O
OHMe
1
10
16
2026
116
10
2026
O O
CHO
OR
OR
O
MeO
MeO MeOOR O
OMePhO2S
MeMe
RO
OR
HOR
AB C
1 2
Me Me
1
710
16OR OR
17
2026
Julia-Lythgoe olefination
macrolactonization
3
Horner-Wadsworth-Emmons reaction
・ The best condition for introducting a methoxycarbonylmethylene unit to the C13 position stereocontrolledly was studied ・ 43 steps in total
Total Synthesis of Bryostatin 3 by Yamamura (2000) (2)
Yamamura, S. Angew. Chem., Int. Ed. 2000, 39, 2290.
OS S
OBn
H
H
OTBSO
OO
O OTMS
OS S
OBn
H
HMeO2C1913
16
913
16
OS S
OBn
H
H913
16
MeO2C
NaH, phosphonate
THF, -78 → 0 ℃
8 (Z)-9 (E)-9
Total Synthesis of Bryostatin 3 by Yamamura (2000) (3)
Yamamura, S. Angew. Chem., Int. Ed. 2000, 39, 2290.
OHHO
HO
HOOH
OH64
14 stepsO
MeOMeO I
BnO 71
S S
MeMeOTBS
OTBS
tBuLi, HMPA, THFthen 71
72O
MeOMeO
73OBn
MeMeOTBS
OTBS
SS O
MeOMeO
74OBn
MeMeOTBS
SS
CHO
2 steps
O
MeOMeO
OBn
MeMeOTBS
SS OH
O O
OMe
Me
Me76
O
OO
Me
Me
MeMe
LDA, then
then LiI and 74
75
(1) TMS(CH2)2OH PhMe
(2) Me4NHB(OAc)3 AcOH/MeCN(1:2)
O
MeOMeO
OBn
MeMeOTBS
SS OH
OH O
O
Me3Si77
7 stepsO O
MeOMeO
Me MeMeO
OTBS
CHO
TBSO
OAll
O80
Total Synthesis of Bryostatin 3 by Yamamura (2000) (4)
Yamamura, S. Angew. Chem., Int. Ed. 2000, 39, 2290.
O
O
MeMe
MeMeSPh
CO2Et81
O
O
MeMe
MeMeSPh
OH82
PhSMeMe
OH
OHI
OH83
PhSMeMe
PMBO
OHI
OTBDPS84
3 steps(1) RED-Al, THF then I2
(2) F3CCO2H, H2O/THF
3 steps
OO
MeOHC
BOMO
Me Me
(1) MeLi, Et2O, tBuLi then
(2) TBSOTf, 2,6-lutidine
85 OO
Me
OBOM
Me Me
OTBS
OTBDPS
TBSO
OPMBPhSMeMe
86
3 steps
OO
Me
OBOM
Me Me
OTBS
OTBDPS
TBSO
OPhO2SMeMe
87
(1) H2, Pd(OH)2-C, EtOH(2) Me2C(OMe)2, PPTS acetone
(3) TBSOTf, TMSOMe Me2C(OMe)2, CH2Cl2
OO
MeO
Me Me
HOMe
TBSO
OTBDPS
OTBS
PhO2S
MeMe
88
2 stepsO
O
MeO
Me Me
HOMe
TBSO
OTES
OTES
PhO2S
MeMe
89
O O
MeOMeO
Me MeMeO
OTBS
CHO
TBSO
OAll
O80
+
(1) PhLi, THF, then 80 then BzCl, DMAP
(2) Na/Hg, NaHPO4 MeOH/EtOAc (2:1)
O O
MeOMeO
Me MeMeO
OTBS
CO2AllOTBS
MeMe
O
TESO
OMe
OTES
OTESO
O
Me
Me Me
90
7 steps
O O
MeOMeO
Me MeMeO
OTBS
CO2HOTES
MeMe
OOMe
OH
94
OO
O
Me
O
Me
OTES
(1) 2,4,6-trichlorobenzoyl chloride Et3N, PhMe then DMAP, PhMe
(2) HF, MeCN
O
OAcMeMe
HO
OHO
MeMe O O
OOH
MeO2C
H
O
O
bryostatin 3
O
O
OHMe
Me
O
OHMeMe
HO
OHO
O
MeMe O O
OOMe H
O
O
O
O
OHMe
Me 95
O
OHMeMe
HO
OHO
MeMe O O
OOMe
MeO2C
H
O
O
O
O
OHMe
Me 96
O
OP
O
CO2Me
58
NaH, THF
4 steps
Z:E = 9:1
Total Synthesis of Bryostatin 16 by Trost (2008)
Trost, B. M. et al. Nature. 2008, 456, 485.
O
OPivMeMe
HO
OHO
O
Me
O
O
OH
MeO2C
H
CO2Mebryostatin 16
B A
C
O
OH
OTESO
HO
Me
O
O
OTBS
MeO2C
H
B A
MeO2C
O
OPMB
O
CO2H
MeO2CB A
MeOMeMe
OTESMe
Me
PMBO
MeO2COTBS
OH
3
MeMe
MeMe
O O O
O
OTBDPS
OPMBTMS
OTBS
O O
O
OTBDPS
OPMB
TMS OH
OTBS
TBSO
O
4
56
7 8
2
Pd catalysed chemoselectivealkyne-alkyne coupling &Au catalysed 6-endo-dig cyclization
Ru catalysed alkene-alkynecoupling / Michael addition
16 171
7
5
9
30
15
1719
20
34
MeOMe Me
Yamaguchi esterification
・ Pd-catalysed chemoselective alkyne-alkyne coupling followed by Au-catalysed 6-endo-dig cyclization efficiently produced both the macrocycle and the C ring of Bryostatin 16 ・ Ru-catalysed tandem alkene-alkene coupling / Michael addition generated cis-tetrahydropyran 6 ・ 28 steps in total
Total Synthesis of Bryostatin 1 by Keck (2011) (1)
Gary E. Keck. et al. J. Am. Chem. Soc., 2011, 133 (4), 744.
・ A strategy of combining an A-ring hydroxyallylsilane and a C-ring aldehyde was selected for an attempted synthesis of Bryostatin 1 ・ A spirocylic structure formed via intramolecular cyclization of the silane at the C9 position was a major byproduct ・ 31 steps in total
O
OAcMeMe
HO
OHO
MeMe O
Me
O
O
OH
OH
MeO2C
H
CO2Me
O
O
Me
O
OAcMeO
OBPSO
MeMe O
Me
COStBuOMe H
CO2Me
AcO
OPMB
OBOM
O
OAcMeO
TMSOH
COStBuOBPS
MeMe O
Me
OMe H
CO2Me
AcO
OPMB
OBOM
HO
TMSOTf, Et2O-78 ℃
61% yield
OH
O
OTBS
MeMe Me
HO
OBOM
OPMB
OMe
OMe
Me
bryostatin 1 1
2
3
A
B
C
9
A
C
TMSO O
TMS
Prins-driven macrocyclization
1
713
20 26
Prins-driven macrocyclization
Me Me
AB
C
Me Me
Total Synthesis of Bryostatin 1 by Keck (2011) (2)
O
OMeMeMe
O
OHMeMe
OTBS
3 steps
Me
MeO O
OHMe
O
OBOMMe
2 steps SnBu3
Me OBOM
OH
Me OBOM
OPMBO
Me OBOM
OPMBHO
MgBr2, Et2O
2 steps SnBu3
MgBr2, Et2O
9798
99
100 101 102
103105
Me OBOM
OPMBO
O
MeMe
OTBS
102
EDCl, DMAPDMAP/HCl
106
6 steps
Me OBOM
OPMBOMeMe
OTBS
H
O
OMe
108
Me OBOM
OPMBOMeMe
OTBS
H
O
OMe
109CO2Me
K2CO3, MeOHOHCCO2Me
(1) CeCl3独7H2O, NaBH4 MeOH
(2) Ac2O, DMAP, py Me OBOM
OPMBOMeMe
OTBS
H
AcO
OMe
CO2Me110
O
OMeMeMe
104
Br
NBS, BPO
CCl4
Me OBOM
OPMBOMeMe
H
H
AcO
OMe
CO2Me111
O
2 steps
99
Gary E. Keck. et al. J. Am. Chem. Soc., 2011, 133 (4), 744.
Total Synthesis of Bryostatin 1 by Keck (2011) (3)
Gary E. Keck. et al. J. Am. Chem. Soc., 2011, 133 (4), 744.
O
OAc
O
H
OBPSCOStBu
MeOMe Me
2 stepsO
OAc
O
OBPSCOStBu
MeOMe Me
TMS
O
OAc
OH
OBPSCOStBu
MeOMe Me
TMSMeOHCeCl3独7H2O, NaBH4
O
OAcMeMe
MeO
OBPSO
MeMe O
Me
COStBu
OBOM
OMe H
CO2Me
AcO
112 113 114
111TMSOTf, Et2O
O
OAcMeMe
HO
OHO
MeMe O
Me
O
O
OH
OH
MeO2C
H
CO2Me
O
O
Me
bryostatin 1
1
713
20 26
OPMB
O
OAcMeMe
MeO
OTESO
MeMe O
Me
CO2H
OBOM
OMe H
CO2Me
AcO
OPMB
3 steps
O
OAcMeMe
MeO
OTESO
MeMe O
Me OBOM
OMe H
CO2Me
AcO
O
(1) DDQ CH2Cl2/pH 8 buffer
(2) 2,4,6-Cl3PhCOCl Et3N, THF then DMAP tol
O
O
OAcMeMe
MeO
OTESO
O
MeMe O
Me OBOM
OMe H
CO2Me
AcO
O
O2 steps
O
OAcMeMe
MeO
OTESO
MeMe O
Me OBOM
OMe H
CO2Me
AcO
O
O
OO
PO
CO2Me
58
NaHMDS, THFthen 118
115 116 117
118
MeO2C
Z:E = 4:1
119
3 steps
Me OBOM
OPMBOMeMe
H
H
AcO
OMe
CO2Me111
O
Total Synthesis of Bryostatin 9 by Wender (2011) (1)
Wender, P. A. et al. J. Am. Chem. Soc., 2011, 133, 9228.
O
OAcMeMe
HO
OHO
MeMe O
Me
O
O
OH
OH
MeO2C
H
CO2Me
O
O
bryostatin 9
B A
C
C3H7
1
713
19
20 26
O
OAc
OTBDPSO
MeMe O
Me
O
O
OTBS
OH H
CO2Me
O
OC3H7
4
1
713
19
20 26
intermolecular Prinscyclization
PPTS (20 mol%)MeOH, rt, 22h65% yield
O
OAcTMS
OTESA
MeMe O
Me
OH H
CO2Me
O
OTBS
HO
CO
C3H7 O
OTBDPSO
3
9
1
AB
C
MeOMe Me MeO
Me Me
O
OAcTMS
OTESA
CO2HOTBDPS
MeMe O
Me
OH H
CO2Me
OH
OTBS
HO
CO
C3H7 O1
2
MeOMe Me
Yamaguchi esterification
・ An intermolecular Prins cyclization to anneal the B ring was investigated, which prevented the spirocyclic byproduct from synthesizing ・ 25 steps in total
Total Synthesis of Bryostatin 9 by Wender (2011) (2)
Wender, P. A. et al. J. Am. Chem. Soc., 2011, 133, 9228.
EtO
O OH
O OTBDPS
OBnOH OTBDPS
OBn
O
EtO
O
(+)-Ip2BCl, Et3N, Et2Othen
then H2O2, MeOHpH 7 Buffer
OH OTBDPS
OBn
OH
EtO
OMe4NBH(OAc)3
HOAc/MeCN (1:1)
O O
O 6 stepsO
O OBn
TBDPSO OBn
LDA, THFO
OBn
TBDPSO OBn
EtO
O OH
MeO(1)
(2) PPTS, MeOH(3) NaBH4, EtOH
O
OAc
TBDPSO OH
OTES
MeOMe2Si
O
HO OH5 steps
TBSO O O R-BINOL, Ti(OiPr)4B(OMe)3, allyl-SnBu3
CH2Cl2
TBSO O OH5 steps
O
O
TBSOOMe
O
OO
(1) K2CO3
THF/MeOH
(2) NaBH4, CeCl3 MeOH(3)
7H2O
O
O O
DMAP, CH2Cl2
O
O
TBSOOMe
CO2MeOC3H7
2 stepsO
O
OOMe
CO2MeOC3H7
Br O
tBuLi, Me2Zn
then H3O+
Et2O
2 steps
O
O
OMe
CO2MeOC3H7
HO
120
121
122 123
124
125
126 127
128 129 130131
132
133134 135
136
137
Total Synthesis of Bryostatin 9 by Wender (2011) (3)
Wender, P. A. et al. J. Am. Chem. Soc., 2011, 133, 9228.
O
O
OMe
CO2MeOC3H7
HO
K2OsO4 2H2ODHQD2PYR, K2CO3K3Fe(CN)6 O
O
OMe
OH
CO2MeOC3H7
HO
OH O
O
OH
OTBS
CO2MeOC3H7
HO
OH2 steps
O
OAcMeO
TMSOTES
OOH
CO2Me
O
OTBS
HO
O
C3H7 O
OTBDPSO
O
OAc
OTBDPSO
O
Me
O
O
OTBS
OH
CO2Me
O
OC3H7
MeO
PPTS, MeOH
O
OAc
OTBDPSO
O
Me
O
O
OTBS
OH
CO2Me
O
OC3H7
MeOMeO2C
OO
POMe
O O
(1) O3, CH2Cl2 then thiourea CH2Cl2/MeOH (1:1)
NaHMDS, THF
(2)
bryostatin 9
2 steps
O
OAc
OHO
O
Me
O
O
OTBS
OH
CO2Me
O
OC3H7
HOMeO2C
137 138 139
140141
142
2,4,6-trichlorobenzoyl chlorideEt3N, PhCH3
then 139, DMAP
O
OAc
TBDPSO OH
OTES
MeOMe2Si
O
127
3.Total synthesis of Bryostatin 7 by Krische
Retrosynthetic Analysis of Bryostatin 7
Michael J. Krische. et al. J. Am. Chem. Soc., 2011, 133, 13876.
O
OAcMeMe
HO
OHO
MeMe O
AcO
O
Me
O
O
OHOMe
OH
OMe
O
Bryostatin 720 Steps (LLS), 36 Total Steps5 C-C Bonds Formed viaHydrogen-Mediated C-C Coupling
SnBu3
TMS
O
O
Me
MeMe
OTBDPS
AcO
OMe
O
Me
Fragment A
OO
OAcMeMe
MeO
O
OMe
OTBS
Fragment B(10 Steps) (10 Steps)
Fragment A
1 C-C Bond Formed viaHydrogenative CouplingC20-C21
Fragment B
4 C-C Bonds Formed viaHydrogenative CouplingC2-C3, C5-C6, C7-C8,C9-C10
TBSO
O
Me Me O6
O
O
Me
MeMe
TBOPSO
9(6 Steps) (6 Steps)
OAc独
Me
Me
OHOH11
(1 Step)
OAc OAc
OH OH
13 7
17 1
20
23
26
B A
C
13
17
20
23
26
7
1
1720
109 8
23
26
7 4 1
Krischeʼs Work (Key Reaction)
Michael J. Krische. et al. Acc. Chem. Res., 2017, 50, 2371.
Conception of Krischeʼs Work
Michael J. Krische. et al. Acc. Chem. Res., 2017, 50, 2371.
Enantioselective Ir-Catalyzed Carbonyl Allylation via Transfer Hydrogenative Coupling of Allyl Acetate
Michael J. Krische. et al. J. Am. Chem. Soc., 2008, 130, 14891.
Effect of Basic and Acidic Additives and Iridium Source in the Transfer Hydrogenative Allylation
Michael J. Krische. et al. J. Am. Chem. Soc., 2008, 130, 14891.
P
P
Cl
H3COH3CO
Cl
(R)-Cl,MeO-BIPHEP
L
Effect of Substitution of m-Nitrobenzoic Acid in the Transfer Hydrogenative Allylation
Michael J. Krische. et al. J. Am. Chem. Soc., 2008, 130, 14891.
・ Substituents of m-NO2BzOH are important for enantioselectivity ・ R1 is the preferred site of cyclometalation and the enantioselectivity would be reversed if it is blocked
Catalytically Active ortho-cyclometalated iridium(Ⅲ)-π-allyl complex V
Michael J. Krische. et al. J. Am. Chem. Soc., 2008, 130, 14891.
Complex V
[Ir(cod)Cl]2
(R)-BINAP (200 mol%)m-NO2BzOH (400 mol%)Cs2CO3 (400 mol%)
allyl acetate (200 mol%)(100 mol%)
THF, 80 ℃, 3h
80 ℃ Ⱦ rt
80 ℃, 1h
complex V
Experiments Corroborating Intervention of Ortho-Cyclometalated Iridium(Ⅲ)-π-Allyl Complex(V) as a Catalytically Relevant Entity
Michael J. Krische. et al. J. Am. Chem. Soc., 2008, 130, 14891.
・ Carbonyl allylation products are also accessible from aldehydes when employing isopropanol as a hydrogen donor ・ Complex V serves as an active catalyst in the transfer hydrogenative carbonyl allylation of aldehyde 2n under standard conditions, suggesting that complex V is indeed catalytically relevant
Proposed Stereochemical Model
Michael J. Krische. et al. J. Am. Chem. Soc., 2008, 130, 14891.
Ir-Catalyzed Transfer Hydrogenative Allylation of Benzylic Alcohol Employing Isotopically Labeled Allyl Acetate
Michael J. Krische. et al. J. Am. Chem. Soc., 2008, 130, 14891.
・ Intervention of rapid interconversion of allyl haptomers through the agency of a symmetric π-allyl is supposed
Experiments Establishing Rapid Redox Equilibration in Advance of Carbonyl Addition
Michael J. Krische. et al. J. Am. Chem. Soc., 2008, 130, 14891.
・ A very similar product distribution and yield are obtained, establishing rapid redox equilibration in advance of C-C coupling
Proposed Catalytic Mechanism
Michael J. Krische. et al. Acc. Chem. Res., 2017, 50, 2371.
・ Dehydrogenation of the secondary alcohol products is prevented by internal chelation of the homoallylic olefin
1 2
3 4
6
5
7
Survey of Enantioselective Alcohol C-H Allylations via Iridium-Catalyzed Hydrogen Transfer
R
OH
R
OH Me
R
OH F
R
OO
R
OH
Me
AcO
Cl
Cl
BocO
AcO
Me
F
CO2Me
Me
R
OH
R
OH
R
OH
R
OH
R
OH
CF3
SiMe3
OBz
OH
BzO
CF3
AcO
SiMe3
BzO
OBz
AcO
O
OO
R
OH
R
OH
R
OH
R
OH
R
OH
Me OH
NHNs
CHE2
E
Me Me
Me
O
NNs
EE
EBocO
.
Me
Me
E = CO2Me > 99% eeMichael J. Krische. et al. Acc. Chem. Res., 2017, 50, 2371.
Retrosynthetic Analysis of Bryostatin 7
Michael J. Krische. et al. J. Am. Chem. Soc., 2011, 133, 13876.
O
OAcMeMe
HO
OHO
MeMe O
AcO
O
Me
O
O
OHOMe
OH
OMe
O
Bryostatin 720 Steps (LLS), 36 Total Steps5 C-C Bonds Formed viaHydrogen-Mediated C-C Coupling
SnBu3
TMS
O
O
Me
MeMe
OTBDPS
AcO
OMe
O
Me
Fragment A
OO
OAcMeMe
MeO
O
OMe
OTBS
Fragment B(10 Steps) (10 Steps)
Fragment A
1 C-C Bond Formed viaHydrogenative CouplingC20-C21
Fragment B
4 C-C Bonds Formed viaHydrogenative CouplingC2-C3, C5-C6, C7-C8,C9-C10
TBSO
O
Me Me O6
O
O
Me
MeMe
TBOPSO
9(6 Steps) (6 Steps)
OAc独
Me
Me
OHOH11
(1 Step)
OAc OAc
OH OH
13 7
17 1
20
23
26
B A
C
13
17
20
23
26
7
1
1720
109 8
23
26
7 4 1
Synthesis of Fragment A
Michael J. Krische. et al. J. Am. Chem. Soc., 2011, 133, 13876.
Me
MeO
Me
O O
MeMe Me
EtO
O O
MeMe Me
TBSO
O
Me Me
Br TBSO
O
Me Me O
1) (CH2O)n CF3CO2H (64%)
2) Moffatt-Swern oxidation (89%)
Horner-Wadworth-Emmons olefination
(97%)
Kornblum oxidation
81%
1 � 3
5 6
2 Steps
(84%)
1) Sharpless asymmetric dihydroxylation (84%)
2) (MeO)2CMe2, PPTS DCM (92%)3) DIBAL Et2O (85%)
Me
CN
O
O
Me
OMeMe
1) HCCCH2Br, Zn PhMe: THF (2:1) (84%)2) TBDPSCl, imidazole
DMAP DCM (96%)3) Sonogashira coupling (93%)
O
O
Me
MeMe
TBOPSO
O
O
Me
MeMe
OTBDPS
AcO
OMe
O
Me
1) Hydrogen-mediated reductive coupling (Rh) (77%)2) Ac2O, Et3N, DMAP DCM (84%)
3) HF-Pyr THF (90%)4) Dess-Martin oxidation (97%)
7 8 9(86% ee) (5:1 dr)
6 9+
Fragment A(7:1 dr)
Synthesis of Fragment B Employing Multiple Transfer Hydrogenative C-C Bond Formations (1)
Michael J. Krische. et al. J. Am. Chem. Soc., 2011, 133, 13876.
OHOH OHOH OO
OTBS
OTBS
OOAc
OTBS
OTBS
O
MeMe
[Ir(cod)Cl]2 (5 mol%)(S)-Cl,MeO-BIPHEP (10 mol%)
Cs2CO3 (40 mol%)4-Cl-3-NO2-BzOH (20 mol%)Dioxane, 90 ℃
OAc
Ozonolysis
TBSClImidazole (60%)
(5 mol%)
i-PrOH (200 mol%)PhMe, 60 ℃
IrO
NO2
O
HPP
O
O
O
O
Ph2
Ph2
(S)-SEGPHOS
独Me
Me(200 mol%)
10 11(>99% ee, >30:1 dr) 12
OOH
OTBS
OTBSMeMe
13(>20:1 dr)
1) Ac2O, Et3N, DMAP THF (94%)
2) Ozonolysis (96%)
14
(72%)
(90%)
Synthesis of Fragment B Employing MultipleTransfer Hydrogenative C-C Bond Formations (2)
Michael J. Krische. et al. J. Am. Chem. Soc., 2011, 133, 13876.
OOAc
OTBS
OTBS
OH
MeMe
OOAc
O
OTBS
O
MeMe
O
OAcMeMe
MeO
O
OMe
OROO
OAcMeMe
MeO
O
OMe
OTBS
IrO
NO2
O
HPPPh2
Ph2
(5 mol%)
i-PrOH (200 mol%)Cs2CO3 (20 mol%)THF, 90 ℃
BIPHEP
OAc
OOAc
OTBS
OTBS
O
MeMe
14 15(72%)
1) TBAF, AcOH THF
2) Dess-Martin oxidation (72% over 2 steps)
16
PPTSMeOH
TBSOTf 2,6-lutidineDCM
17a, R = TBS (72%)
17b, R = H
Ozonolysis (93%)
Fragment B
Union of Fragment A and Fragment B and Total Synthesis of Bryostatin 7 (1)
Michael J. Krische. et al. J. Am. Chem. Soc., 2011, 133, 13876.
O
O
Me
MeMe
OTBDPS
AcO
OMe
O
Me
Fragment A
O
OAcMeMe
MeO
CO2MeOTBS
O
MeMe O
AcO Me
OR
O
O MeMe
O
OAcMeMe
CO2MeOTBS
O
MeMe O
AcO Me
OR
O
O MeMe
18a (56%) 18b (22%)
Both compounds are used in the next step R = TBDPS
19a (20%) 19b (51%)
(60%)
O
OAcMeMe
MeO
CO2MeOH
O
MeMe O
AcO Me
OR
O
O MeMe
O
OAcMeMe
MeO
CO2MeOH
O
MeMe O
AcO Me
OR
OH
OH
Keck-Yu annulationOO
OAcMeMe
MeO
O
OMe
OTBS
Fragment B
acidic methanolysis
acidic methanolysis
macrolactonization
1) Ti(O-i-Pr)4 (R)-BINOL (CF3)2CHOH 4A-MS, PhCF3
TMS
SnBu3
2) Fragment B TMSOTf Et2O
(92%, >20:1 dr)
O
OAcMeMe
MeO
OTESO
MeMe O
AcO Me
ORO
O
OTES
20
(34% in 3 steps)
Union of Fragment A and Fragment B and Total Synthesis of Bryostatin 7 (2)
Michael J. Krische. et al. J. Am. Chem. Soc., 2011, 133, 13876.
O
OAcMeMe
MeO
OTESO
MeMe O
AcO Me
ORO
O
OTES
20
1) OsO4, NaIO4 THF:H2O (4:1) (64%)
2) N,N-dimethyl triazolium iodide DBU, MnO2 THF:MeOH (4:1) (75%)
O
OAcMeMe
MeO
OTESO
O
MeMe O
AcO
O
Me
ORO
O
OTESOMe
21
1) [(R)-BINOL]POCH2CO2Me NaHMDS
THF (93%, 6:1 dr)2) HF-Pyr THF:H2O (100:1) (60%)
O
OAcMeMe
HO
OHO
MeMe O
AcO
O
Me
O
O
OHOMe
OH
OMe
O
Bryostatin 7
・ Prepared in 20 steps (longest linear sequence) and 36 total steps, representing the most concise route to any bryostatin reported, to date ・ Carbonyl allylation products could generate in a single manipulation and form as single enantiomers by utilizing hydrogenative methods ・ Hydrogenative methods could bypass the requirement of stoichiometric metals
4. Summary
Summary
・ Bryostatins are potent modulators of protein kinase C with promising biological activity. ・ Total synthesis of Bryostatins 1, 2, 3, 7, 9, and 16 has been reported. ・ Multiple transfer hydrogenative C-C bond formations reported by Krische, which was utilized in the total synthesis of Bryostatin 7 in 2011 simplified the total synthesis of Bryostatins.
Appendix
Appendix 1. Structure of Bryostatins (1)
O
OO
O1: R1 = Ac, R2 =
2: R1 = H, R2 =
4: R1 = OCOCH2CH(CH3)2, R2 = OCO(CH2)2CH3 5: R1 = OCOCH2CH(CH3)2, R2 = OAc 6: R1 = OCO(CH2)2CH3, R2 = OAc 7: R1 = OAc, R2 = OAc 8: R1 = OCO(CH2)2CH3, R2 = OCO(CH2)2CH3
9: R1 = Ac, R2 = OCO(CH2)2CH3 10: R1 = Piv, R2 = H 11: R1 = Ac, R2 = H 12: R1 = CO(CH2)2CH3, R2 =
O
O
13: R1 = CO(CH2)2CH3, R2 = H 14: R1 = Piv, R2 = OH 15: R1 = Ac, R2 = O
O
OH
O
OR1
MeMeHO
OHO
MeMe O
R2
O
Me
O
O
OHOMe
OH
OMe
O
Appendix 1. Structure of Bryostatins (2)
3: R1 = Ac, R2 =
20: R1 = Piv, R2 = H O
O
O
OR1
MeMeHO
OHO
MeMe O
R2
O
OOH
OMe
O
O
O
OHMe
O
OMeMe
HO
OHO
MeMe O O
OOH
OMe
O
O
O
MeO
Bryostatin 18
O
OMeMe
HO
OHO
MeMe O O
OOH
OMe
O
O
O
O
O
O
Bryostatin 19
O
OMeMe
HO
OHO
MeMe O O
O
OMe
O
O
O
MeO
Bryostatin 17
Me MeOH OH OHMe
O
OMeMe
HO
OHO
MeMe O O
O
OMe
O
O
O
OMeMe
Bryostatin 16
OH
Appendix 2. Biosynthesis of Bryostatin (1)
Sebastian Sudek. et al. J. Nat. Prod., 2007, 70 (1), 67.
Appendix 2. Biosynthesis of Bryostatin (2)
Sebastian Sudek. et al. J. Nat. Prod., 2007, 70 (1), 67.
Appendix 3. Hypothetical pathway of PKC synthesis and downregulation by bryostatin 1
Karl J. Hale. et al. Nat. Prod. Rep., 2002, 19, 413.
Appendix 4. Effect of Allyl Acetate Loading, Solvent, and Ligand in the Transfer Hydrogenative Allylation
Michael J. Krische. et al. J. Am. Chem. Soc., 2008, 130, 14891.
Appendix 5. Effect of Chiral Ligand and Temperature in the Transfer Hydrogenative Allylation
P
P
Cl
H3COH3CO
Cl
(R)-Cl,MeO-BIPHEP
Michael J. Krische. et al. J. Am. Chem. Soc., 2008, 130, 14891.
P
P
Cl
H3COH3CO
Cl
(R)-Cl,MeO-BIPHEP
Appendix 6. Chiral Ligands
P
PH3COH3CO
(R)-MeO-BIPHEP
P
P
(R)-BINAP
P
P
(R)-tol-BINAP(-)-TMBTP
S
SP
P
O
O ( )n
(S)-Cn-TUNEPHOS
P
P
P
P
(R)-H8-BINAP
P
P
(S)-BIPHEMP
N
N
P
P
CTH-(S)-P-PHOS
O
O
O
O
P
P
N
OO
N
(R)-SOLPHOS
P
P
O
O
O
O
(S)-SEGPHOS
P
P
O
OO
O
(R)-SYNPHOS
Appendix 7. Total Synthesis of Bryostatin 16 by Trost (2008) (1)
Trost, B. M. et al. Nature. 2008, 456, 485.
TMS
R1HO
O
R2
TMS
O
R2
OH
R1
OO
R2
TMSR1
Ene-Yne Coupling Michael Addition
Proposed Tetrahydropyran Synthesis
+
O O
O
OTBDPS
OPMB
7
TMS OH
OTBS8
O O O
O
OTBDPS
OPMBTMS
OTBS6
CpRu(CH3CN)3PF6DCM
34% yield+
Appendix 8. Mechanistic Proposal for Ru-Catalyzed Alkene-Alkyne Addition
Trost, B. M. et al. Org. Lett., 2000, 2 (12), 1761.
Appendix 9. Total Synthesis of Bryostatin 16 by Trost (2008) (2)
・ Pd catalyst chemoselectively inserts into the carbon-hydrogen bond of the terminal alkyne
Trost, B. M. et al. Nature. 2008, 456, 485.
O
OH
OTESO
HO
Me
O
O
OTBS
MeO2C
H
MeOMeMe
MeO2C3
MeMe
O
OH
OMeO2C
MeOMeMe
MeMe
O
OTES O
HO
OTBS
CO2Me20
Pd(OAc)2 (12 mol%)TDMPP (15 mol%)
toluene56% yield
AB AB
O
OH
OMeO2C
MeOMeMe
MeMe
O
OTES O
HO
OTBS
CO2Me20
O
OH
OTESO
Me
O
O
OTBS
MeO2C
H
MeOMeMe
21
MeMe
O
CO2Me
AuCl(PPh3) (20 mol%)AgSbF6 (20 mol%)NaHCO3
DCM/CH3CN0 ℃ to room temperature
73% yieldC
AB AB
・ Au catalyst gives 6-endo-dig cyclization product selectively
Appendix 10. 5-exo-dig & Z-isomer Selectivity of Gold-Catalyzed Cyclization
YH. Liu. et al. Org. Lett., 2005, 7 (24), 5409.
R3R4
R5
HO R2
R1
O
R4 R3
R5R2
R1
[Au]rtR1 = alkyl, R2 = aryl
1a1b1c1d1e1f1g
MeMeMeMeMeMeMe
o-ClC6H4Php-FC6H4Php-FC6H42-thienylo-ClC6H4
PhPhPhPhC3H7PhPh
PhPhPhPhC3H7PhPh
PhCyc
BuPhPhp-MeC6H4Bu
A, 3hA, 1hA, 1hA, 3hB, 3hB, 3hA, 1h
1a 2a
97%92%89%91%84%87%83%
enynol R1 R2 R3 R4 R5 condition yield
Condition A: 1% AuCl3, in CH2Cl2Condition B: 1% (PPh3)AuCl, 1% AgOTf, in THF
・ In all cases, only 5-exo-dig cyclization occurred and stereoisomerically pure compounds (Z)-2 were found to be the only reaction products
Appendix 11. Evans Aldol Reaction
https://www.chem-station.com/odos/2009/06/evans-evans-aldol-reaction.html