1 ph.d. university of rochester, 1987 - robert k. boeckman jr. part i. -lithio vinyl ether anion...
TRANSCRIPT
1
Ph.D. University of Rochester, 1987 - Robert K. Boeckman Jr. Part I. -Lithio Vinyl Ether Anion Chemistry
Part II. Synthesis of X-14547A (Indanomycin) SubunitPart III. Total Synthesis of A-23187 (Calcimycin)
PDF - Harvard, David A. EvansPart IV. Synthesis of Bryostatin Subunit
André B. Charette
Group Meeting
September 26, 2005
2
Background
• Début du BSc. Septembre 1980
• Travail été 1981 - Chimie analytique - Joseph Hubert
• Travail été 1982 - Chimie “bio-organique” - Hermann Dugas
• Automne 1982 - Décision de prendre la direction du sud pour les études graduées…
• B.Sc. Université de Montréal Mai 1983
• Début à Rochester Septembre 1983 - cours, démo, choix du boss, cumes
• Début de la recherche en Janvier 1984
• Début de la rédaction en Juillet 1987
• Soutenance: 28 septembre 1987
• Début du postdoc: 15 octobre 1987
• Fin du postdoc: 30 juin 1989…pour affronter l’Université Laval et la belle vie de prof à 27 ans…
3
-Lithio Vinylether anions
O O Li
E+
O E
t-BuLi, THF, -78 to 0 °C
O
Me
PG1O
Me
HMe
OPG2
OPG3
I
Me
OPG2
OPG3
O
Me
PG1O
Me
H
1. t-BuLi, THF, -78 to 0 °C
2.
O O Li
E+
O EY
4
Synthesis of Organolithium Compounds
R I (Br)
2 t-BuLi
R Li
2 equivalents of t-BuLi
Additiion of RI to t-BuLi
THF, -78 °C
2 LiR LiLiI +
R SPhLiDBB
R Li
LiNp can also be used but is less efficient
THF, -78 °C
O I (Br) O Li
O
OP
O
OEt
OEt
1. LDA,THF, -78°C2, ClP(O)(OEt)2 Li, NH3, EtOH
Li
O
Li
O
OP(O)(OEt)2
5
O-Phosphorylation of Lactones
OO
O
O
OP
O
OEt
OEt
1. LDA,THF, -78°C2, ClP(O)(OEt)2 1. LiNp or LiDBB,THF, -78 °C
PhHOH
85% 2. PhCHO
<5%
O SPh
1. t-BuLi, THF, -78 °C2. PhSSPh
O
O
OHTMSCH(SPh)2
HO SPh
SPh HCl (gas)CH2Cl2
O SPhSPh
O SPhPhS
O SPh
-78 °C
O
MCPBA, CH2Cl2, 0 °CΔ
30%
O O
6
Synthesis of Vinyl Sulfides
O SPh
1. t-BuLi, THF, -78 °C2. PhSSPh
O
O
OHTMSCH(SPh)2
HO SPh
SPh HCl (gas)CH2Cl2
O SPhSPh
O SPh
1. LiDBB, THF, -78 °C
2. PhCHO O
PhHOH
30%
-78 °C
i-Pr2NEt, 130 °C, 24 h80%
O SPh
Me
O SPh
Br
NBS, DMF, Et3N
1. t-BuLi, THF, -78 °C2. CH3I
O SPhMe O SPhH
H
O SPhH
H
O SPh
Me
H
H
O SPh
Me
H
H
7
Reductive Lithiation of Cyclic Ketene Monothioacetals
O SPh
1. LiDBB, THF, -78 °C
2. PhCHO O
PhHOH
30%
Li
THF, 6 h, rtLi
30%: Add the LiDBB to sulfide30%: Add the sulfide to xs LiDBB30%: Add the sulfide to titratedLiDBB
- Turns dark red after the addition- the vinylether anion is yellow
R1 S R2LiDBB
R1 S R2 Li+
+ R2
+ R1R2SLi
LiDBB
LiDBB
R2Li
R1Li
R1SLi OH
40%
8
Reductive Lithiation of Cyclic Ketene Monothioacetals
O
OP
O
OEt
OEt
1. LiNp or LiDBB,THF, -78 °C
O2. PhCHO
Li
OP
O
OEt
OEt+
O
OP
O
OEt
O
+ EtLi2. PhCHO
OH
O
OH
>80%
9
Other Possible Precursors Based on Radical Stability
O S
30%
O S
37%
O S
33%
NMe2
O S
<0%
CF3
O S N
25%
O SMe
<0%
O St-Bu
<0%
O S
35%O
10
The X-14547A Problem
O
Me O
HN
HOOC
Me
H H
H
H
O
Me
OMe
H H
PGOH
Wittig
O
Me
Me
H H
PGO
CHO
O
Me
Me
H H
PGO
OHN
O
Me
Me
H H
PGO
OH
OMe
O
Me
LiMe
H H
PGO
OMe
O
+
11
The X-14547A Problem: Cohen’s Chemistry
OR1
SPhR2
OR1
SPh
R2
LiDMAN
OR1
R2
H-78 °C
LiDMAN
-78 °C
OR1
Li
R2
Kinetic product
-40 °CO
R1LiR2
Thermodynamic product
E+ E+
OR1
ER2OR1
E
R2
T. Cohen (Pittsburg)
O
Me
LiMe
H H
PGO
O
Me
SPhMe
H
TIPSOOMe
O
1. LiDBB or LiDMAN, THF
2.
O
Me
HMe
H
TIPSO
H
O
Me
Me
H
TIPSO
H
OHOMe
<5%
>85%
12
The X-14547A Problem
O
Me
SPhMe
H
TIPSO
LiDBB, THF, -78 °C
O
Me
HMe
H
TIPSO
HO
Me
Me
H
TIPSO
O
Me
LiMe
H
TIPSOH H
2. D2O
SOH
BO
+
O
Me
SPhMe
H
TIPSOOMe
O
1. LiDBB or LiDMAN, THF
2. O
Me
HMe
H
TIPSO
H
>85%
OMe
O
H H
R LiCeCl3
R CeCl2
2. D2OO
Me
SPhMe
H
TIPSO
1. LiDBB or LiDMAN, THF
O
Me
HMe
H
TIPSO
H
>85%
O
Me
HMe
H
TIPSO
H
>85%
2. PhCHO
1. LiDBB or LiDMAN, THF
13
The X-14547A Problem: Model Study
O
Me
SPhMe
H
TIPSOOMe
O
1. LiDBB or LiDMAN, THF
2. O
Me
HMe
H
TIPSO
H
>85%
O SPh
OMe
O
1. LiDBB, THF, -78 °C
2. O
OHOMe
OMe
O SPh
(2 equiv)PPTS, CH2Cl2
OO
60%, 3:1 E:Z mixture
14
The X-14574A Problem: Synthesis of the Tetrahydropyran Subunit
HOCOOMe
Me MOMCl, i-Pr2NEtCH2Cl2 MOMO
COOMe
Me 1. LAH, Ether, 84%2. Swern, 94%
MOMOCHO
Me
LiCu2
MOMO
Me
OH
Me
HO
1. CBr4, PPh3
2. Li3. CuBr•DMS
1. O3; DMS2. K2CO3,MeOH
O
Me
OHMe
H
MOMO
PhSH, BF3•OEt2, -78 °C
O
Me
SPhMe
H
MOMO
O
Me
SPhMe
H
EEO
O
Me
SPhMe
H
TIPSO
O
Me
SPhMe
H
TBDPSO
15
The X-14547A Problem: Mass Spectrometry Studies
2. D2OO
Me
SPhMe
H
TIPSO
1. LiDBB or LiDMAN, THF
O
Me
HMe
H
TIPSO
H
>85%
m/z: 272.22 (100.0%), 273.22 (21.7%), 274.21 (3.3%), 274.22 (2.5%)
m/z: 271.21 (100.0%), 272.21 (21.4%), 273.21 (4.6%), 273.22 (1.3%)
m/z: 314.26 (100.0%), 315.27 (20.0%), 315.26 (5.1%), 316.26 (3.3%), 316.27 (3.3%)
66%
33%
O
Me
HMe
H
O
H
Si
O
Me
HMe
H
O
H
SiD
O
Me
HMe
H
O
H
SiD
M+ - C3H7
16
The X-14547A Problem: Protecting Group Issue
2. D2OO
Me
SPhMe
H
TIPSO
1. LiDBB, THF, -78 °C
O
Me
HMe
H
d1-TIPSO
H
>85%
2. D2OO
Me
SPh
O
Me
H
Si
1. LiDBB or LiDMAN, THF
t-Bu t-Bu
O
Me
SPh
O
Me
H
Si
t-Bu t-Bu
D
2. D2OO
Me
SPhMe
H
(MOM)EEO
1. LiDBB, THF,-78 °C
O
Me
DMe
H
(MOM)EEO
2. PhCHO
1. LiDBB, THF,-78 °C
O
Me
Me
H
(MOM)EEOH Ph
OH
17
The X-14547A Left Subnit Assemblage
2.O
Me
SPhMe
H
MOMO
1. LiDBB, THF,-78 °C
OMe
O
O
Me
Me
H
MOMO
3. PPTS, CH2Cl2
HCHO 42%, 3:1 E:Z
CN
Ph3P
O
Me
Me
H H
MOMO
CHO
1.
2. I2, cat.3. DIBAL-H
O
Me O
HN
Me
H H
H
H
PPh3
O
HN
Sr2CO3, Cs2CO3MOMO
1. TMSI 2. CrO3
X-14547A
18
Retrosynthetic Analysis
OO
MeMe
MeO
NH
Me
H
N
O
HOOC NHCH3
O
O
Me
Me
O
Me
HN
N
O
COOH
NHCH3
Me
NMet
OO
MeMe
PG1OMe
Me
H
OPG2
HO
H2N
HOOC NHMe
+
+
O
Me
MOMO
Me
HMe
OTBDMS
OTBDPS
O
Me
MOMO
Me
HMe
OTBDMS
OTBDPS
19
Synthesis of the Aryl Subunit
COOH
NH2
COOH
NHAc
COOH
NHAc
COOCH3
OH
COOCH3
OH
COOCH3
OH
COOH
OH
NO2
NHCOCF3 NH2 NO2 NO2
Ac2O, pyr
100%
HNO3, H2SO4
89%
KOH, H2O
reflux, 97%
MeOH, HCl
79%
H2, Pd/C
100%
TFAA, pyr
CH2Cl2, 96%
COOCH3
OH
N(CH3)COCF3
NH2
20
Synthesis of the Aryl Subunit
COOCH3
OH
NHCOCF3
COOCH3
OTBDMS
NHCOCF3
COOCH3
OTBDMS
N(CH3)COCF3
COOCH3
OH
N(CH3)COCF3
COOCH3
OH
N(CH3)COCF3
COOCH3
OH
N(CH3)COCF3
NH2 NO2 NO2
TBDMSCl, DMF
imidazole, 70%
MeI, K2CO3acetone, 56 ˚C
100%
H2, Pd/C
MeOH, 100%
HNO3, HFCH3NO2, 70%
+
21
Synthesis of the Vinyl Ether Precursor
O
Me
MOMO
Me
HMe
OTBDMS
OTBDPS O
Me
MOMO
Me
H
I
Me
OTBDMS
OTBDPS
Me BiPc2H
O
OTBDPS+MOMO H
Me
O
Me Met+
HO OMe
Me
O
1. MOMCl, i-Pr2NEt, CH2Cl2, rt2. LAH, ether 89%
MOMO OH
MeClCOCOCl, DMSO, CH2Cl2, -78 °C
then Et3N
MOMO H
Me
O
Me SnBu3
MgBr2•OEt2, CH2Cl288%
MOMO
Me
OH
Me
4.3:1 ratio of diastereomers
1. TBDMSOTf, Et3N 88%2. BH3•THF; H2O2, NaOH
MOMO
Me
OTBDMS
Me
OH
22
Synthesis of the Vinyl Ether Precursor
MOMO
Me
OTBDMS
Me
OH
1. PhSO2Cl, pyr 98%2. KCN, DMSO, 55 C, 71%
MOMO
Me
OTBDMS
Me
CN
1. TBAF, 75%2. DIBAL-H, THF then H+, 88%
O
Me
MOMO
Me
HOH
MsCl,Et3N
O
Me
MOMO
Me
H
t-BuLi, THF, 0 °C
NR
1. BuLi, KOt-Bu, THF-78 °C, 1 h2. Bu3SnCl
O
Me
MOMO
Me
HSnBu3O
Me
MOMO
Me
HOH
Ph
1. BuLi, THF-78 ˚C, 15 min
2. PhCHO
23
Synthesis of the Electrophile
I
Me
OTBDMS
OTBDPS
HO
1. TBDPSCl, imidazole2. O3; DMS
99% OTBDPSO
iPc2B
Me
OTBDMS
OTBDPS
I
Me
OTBDMS
OTBDPS
1. BH3•THF; H2O2, NaOH2. MsCl, Et3N3. NaI, reflux 74%
24
Coupling of the Fragments
O
Me
MOMO
Me
HSnBu3
Br
Me
OTBDMS
OTBDPS
1. BuLi, THF, -78 °C, 15 min
2.HMPA
O
Me
MOMO
Me
HMe
OTBDMS
OTBDPS
O
Me
MOMO
Me
HMe
OTBDMS
OTBDPS
Et2Zn, CH2I2
TsOH•H2Obenzene, 3 h, 55 °C
TsOH•H2Obenzene, 3 h, 55 °C
OO
MeMe
HOMe
Me
H
OTBDPS
OO
Me
HOMe
Me
H
OTBDPS
55%
52%
25
Incorporation of the Acyl Pyrrole
OO
MeMe
MeO
NH
Me
H
HN
MeOOC NMeCOCF3
OO
MeMe
MeO
NH
Me
H
OTBDPS
OO
MeMe
HOMe
Me
H
D
Jones oxidation
80%O
O
MeMe
HOMe
Me
H
OTBDPSO
PyrS-SPyr, PPh3, CH2Cl2
OO
MeMe
PyrSMe
Me
H
OTBDPSO
NMgCl
Toluene, -78 °C, 73%
1. TBAF2. Jones oxidation
OO
MeMe
MeO
NH
Me
H
COOH
BOP reagent, DMF
HO
H2N
COOMe
NMeCOCF3
O OH
26
Final Dehydration and Deprotection
OO
MeMe
MeO
NH
Me
H
N
O
MeOOC NMeCOCF3
PrSLi, HMPA, quant.O
O
MeMe
MeO
NH
Me
H
N
O
HOOC NHCH3
TBAF
OO
MeMe
MeO
NH
Me
H
N
O
MeOOC NHMe
PrSLi, HMPA, quant.
27
Synthesis of the C-Ring of Bryostatin
O O
O
MeHO
O
MeO2C
H
H
HMeMe
O
O
Me
H
HO
OH H
CO2Me
O
OC3H7
Me
Me OH
O
OH
OH
Me
OH OHE
O
OHMe Me
OHE
OH O
MeMe
OH OH OH O
OH
OH
Me
OH OH O
OHMe Me
OH OH O
MeMe
OH OH OH OOH OH
2
3
28
Aryl-subtituted Epoxyalcohols as 1,3-Polyol Equivalents
OH
OH
Me
O OH O
OHMe Me
OH OH O
MeMe
OH OH OH OOH OH
OMeHO
O
RO
OH O O
X
Me
OH O O
OMe
OH
Me OH
O
MeMe
OH OO O
OMeMe
O
OMeHO
O
OH
29
Retrosynthetic Analysis
O O
O
MeHO
O
MeO2C
H
H
HMeMe
O
O
Me
H
HO
OH H
CO2Me
O
OC3H7
Me
Me OH
O
O O
MeO2C
H
H
HMeMe
O
O
Me
H
HO
OH
OH
O
OH
O
HO Me
OH
CO2Me
HO
OH H
PhSO2
MeMe
30
Retrosynthetic Analysis of the C-Ring
O
HO Me
OH
CO2Me
HO
OH H
PhSO2
MeMe
O
RO Me
OROMe H
PhSO2
MeMe
O
RO Me
ORH
PhSO2
MeMe
O
PhSO2
O
Me
OR
OROH
MeMe
PhSO2 Me
O
MeMe
Me
OR
OROH
H
O
MeOMe
OHO
31
Elaboration of the Synthetic Methodology
MeOMe
O
MeO
O
HMeO
O
MeMeO
Me
OH
OH
MeOMe
OOCOPh
MeOMe
OOR
a b
c
de
70% 96%
48%
R = H, 92% (2 steps)
R = TIPS, 87%
(a) NaOH, acetone-H2O, 25 ˚C; (b) NaBH4, CeCl3•7H2O, MeOH, -78 ˚C; (c) t-BuOOH, (+)-DIPT, Ti(Oi-Pr)4, 4 Å molecular sieves, CH2Cl2, -30 ˚C; (d) DEAD, PPh3, PhCOOH, THF, C6H6; (e) TIPSOTf, Et3N, CH2Cl2, -40 ˚C.
32
Optimization of the Birch Reduction/Ozonolysis Reactions
MeOMe
OOTIPS
Li, NH3, THF, ROH
MeOMe
OTIPS
OH
MeOMe
OH
OTIPS
+
t-BuOH 2.5 1
i-PrOH 3.5 1
EtOH 3.4 1
MeOH 3.4 1
H2O 4.4 1
MeOMe
OOTIPS
MeOMe
OTIPS
OHH2, Pd/BaSO4, EtOH
97%
MeOMe
OTIPS
OH
1. DIBAL-H, THF, -78 to 0 °C2. Li, NH3, THF, i-PrOH, -78 °C
1. O3, CH2Cl2, MeOH
then DMS
O OH
MeOMe
OTIPS
OH
MeOMe
OTIPS
OAlR2
2. Me4NBH(OAc)3, AcOH, MeCN
33
Key Chemoselective Protection
MeOMe
O OH OH
OTIPS
MeOMe
O OTES OH
OTIPS
MeOMe
O OTES OPMB
OTIPS
HMe
O OTES OPMB
OTIPS
(a) TESCl, DMAP, CH2Cl2, 0 ˚C; (b) Cl3C(NH)OPMB, TfOH, Ether, 25 ˚C; (c) DIBAL, CH2Cl2, -78 ˚C
a
77%
c
91%
34
Synthesis of the Dihydropyran
PhSO2 Me
O
MeMe
Me
OTIPS
OPMBOTES
H
O
PhSO2
O
MeMe
Me
OTIPS
OPMBOTESOH
2.
1. LDA, THF, -78 ˚C
(30-40%)
PhSO2 Me
O
MeMe
PhSO2
O
MeMe
Me
OTIPS
OPMBOTES
45
Ph
O
MeMe
Me
OTIPS
OPMBOTES
OH
PhSO2
MeMe
Me
OPMB
OTIPS
a
94%
c
81%
b94%
(a) TiCl4, Et3N, -78 ˚C; 44, THF, -78 ˚C; (b) catecholborane, THF; (c) TsOH•H2O, MeOH, (MeO)3CH.
35
Functionalization of the Dihydropyran
OH
PhSO2
MeMe
Me
OPMB
OTIPS
OH
PhSO2
MeMe
Me
OPMB
OTIPS
O
OH
PhSO2
MeMe
Me
OPMB
OTIPS
HO
OMe
OH
PhSO2
MeMe
Me
OPMB
OTIPS
O
OMe
OH
PhSO2
MeMe
Me
OPMB
OTIPS
O
OMe
+
57
4.8:1 (56:57)
MeOH
PDC
orDess-Marinperiodinane
95%(2 steps)
MCPBA
56
36
Attempts at Improving the Diastereomeric Ratio
OH
PhSO2
MeMe
Me
OPMB
OTIPS
49
OH
PhSO2
MeMe
Me
OPMB
OTIPS
O
OMe
56
OH
PhSO2
MeMe
Me
OPMB
OTIPS
O
OMe
57
Entry Conditionsa Ratio (56:57)b
1 MCPBA, MeOH, -20 ˚C 4.8:1
2 MCPBA, MeOH, Na2HPO4, rt 4.8:1
3 MCPBA, CH2Cl2-MeOH (1:1), 0 ˚C --c
4 MCPBA, MeOH-C6H6 (4:1), -20 ˚C 2.5:1
5 MCPBA, MeOH-DMF (1:1), -20 ˚C 5.7:1
6 MCPBA, MeOH-DMF (4:1), -20 ˚C 4.0:1
7 Me2CO2, acetone, NaHCO3, -20 ˚C --c
8 Me2CO2, MeOH, -20 ˚C --c
a The crude reaction product was directly treated with PDC to afford ketones 56 and 57. b The ratios weredetermined by 1H NMR. c Very little of the desired ketone was obtained.
+
37
Synthesis of the Other Diastereomer
OH
PhSO2
MeMe
Me
OPMB
OTIPS
49
OH
PhSO2
MeMe
Me
OPMB
OTIPS
O
OMe
56
OH
PhSO2
MeMe
Me
OPMB
OTIPS
O
OMe
57
+
OH
PhSO2
MeMe
Me
OPMB
OTIPS
58AcOHg
OMeHg(OAc)2
MeOH
MCPBA
1:3
38
Incorporation of the ,-Unsaturated Ester Unit
OH
PhSO2
MeMe
Me
OPMB
OTIPS
O
OMe
56
OH
PhSO2
MeMe OPMB
O
OMe
Me OTIPS
HO COOMe
OH
PhSO2
MeMe OPMB
O
OMe
Me OTIPS
MeOOC
OH
PhSO2
MeMe OPMB
O
OMe
Me OTIPS
COOMe
62
a
91%
+
63 64
d91%
b
c
HOMe
O
O
39
Playing with the Oxidation State
OH
PhSO2
MeMe OPMB
OMe
Me OTIPS
COOMe
63
HO
OH
PhSO2
MeMe OPMB
OMe
Me OTIPS
CH2OH
HO
68
OH
PhSO2
MeMe OPMB
OMe
Me OTIPS
CH2OTES
TESO
69
a
88%
b, 89%
(a) DIBAL-H, CH2Cl2, -78 ˚C; (b) TESOTf, 2,6-lutidine, CH2Cl2, 25 ˚C
40
Test for the Julia Olefination Reaction
OH
PhSO2
MeMe OPMB
OMe
Me OTIPS
CH2OTES
TESO
69
OH
MeMe OPMB
OMe
Me OTIPS
CH2OTES
TESO
70
a, b, c, d
ca. 60%
(a) n-BuLi, THF, -78 ˚C; Me2CHCHO, -78 ˚C; (b) Ac2O, pyr, 25 ˚C; (c) Na-Hg, THF, MeOH, Na2HPO4; -45 ˚C to -20 ˚C;(d) TESOTF, 2,6-lutidine, CH2Cl2, 25 ˚C
41
Regeneration of the Methyl Ester…
OH
PhSO2
MeMe OPMB
OMe
Me OTIPS
CH2OTES
TESO
69
OH
PhSO2
MeMe OPMB
OMe
Me OTIPS
CH2OH
TESO
71
OH
PhSO2
MeMe OPMB
OMe
Me OTIPS
COOMe
TESO
72
a
95%
b, c
(a) HF•pyr, THF, pyr, 25 ˚C; (b) MnO2, CH2Cl2; (c) MnO2, NaCN, MeOH.