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Non-Aldol Approaches to the Synthesis of Polyketide Natural
Products
Evans Group Evening SeminarFriday June 21, 2002
Travis Dunn
R
Me
OH
Me
Keywords: Polypropionate, Polyol, Total Synthesis
R
OH
Me
O
R
OH
R
OH O
01 6/20/02 11:06 PM
Outline of Seminar
Bond constructions not covered in this seminar:1) Metal enolate reactions2) Mukaiyama aldol reactions3) Allylmetal based reactions(e.g. silanes, stannanes, boranes, borinates)
Approaches covered in this seminar:1) Cyanohydrin acetonide alkylation (Rychnovsky)2) Dithiane alkylation (Mori, Smith)3) Acyl halide/aldehyde cyclocondensation (Nelson)4) Hemiacetal oxymercuration (Leighton)5) Silylformylation (Leighton)6) Methylketene dimer ring opening (Calter)7) Oxabicyclic ring opening (Lautens)8) Directed nitrile oxide cycloaddition (Carreira)
02 6/20/02 6:23 PM
Rychnovsky's Cyanohydrin Acetonide Alkylation
Rychnovsky and Sinz, Topics in Current Chem. 2001, 216, 51-92.
R CN
O
OEt
Me LDA, HMPA;
R1X R CN
O
OEt
Me
R1
Stork, 1971
O
OTBS
TBSO
TBSO
SO2PhLDA;
El+
O
OTBS
TBSO
TBSO
SO2PhEl
O
OTBS
TBSO
TBSO
ElLithiumNapthalenide;
H+
Sinay, 1985
R
O O OO
R
Me Me Me Me
R
O O OO
R
Me Me Me Me
CN CNR
O O OO
R
Me Me Me Me
CN
ICN
LiReductiveDecyanation
Nitrile Alkylation
03 6/25/02 11:22 AM
Rychnovsky's Cyanohydrin Acetonide Alkylation
Rychnovsky and Sinz, Topics in Current Chem. 2001, 216, 51-92.
R H
OOTMS
1) TMSCNKCN/18-c-6 cat.
2) acetonedimethoxypropane CSA
OO
R
Me Me
CNUsually 1:1 mix of stereoisomers
OO
Me Me
CNMe
Me
LiNEt2, THF;
O
BrOO
Me Me
Me
Me
O
CN
76%, dr >95:5
OO
Me Me
Me
Me
O
Na/NH3
94% yield
dr>95:5
OO
Me
Me
i-Pr
C NLi
El
El
OO
Me
Me
i-Pr
ElO
O
Me
Me
i-Pr
El
Equatorial alkylation due to steric shielding by methyl of
acetonide.
Axial radical more stable by ca. 3.5 kcal/mol (calc.)
OO
Me
Me
i-Pr
El
Li
Configurationally stable at low temperature
Rychnovsky et al., J. Org. Chem. 1990, 55, 5550.04 6/25/02 11:23 AM
Iterative and Convergent Syn Polyol Synthesis
OO
Me Me
CNCl
Rychnovsky et al., J. Org. Chem. 1992, 57, 1559.
OO
Me Me
CNI
OO
Me Me
CCl
N Li
KI, 18-c-6
xylenes, reflux
LiNEt2, THF
-78 ˚C
Electrophilic diol synthonNucleophilic diol synthon
OO
Me Me
CNCl LiNEt2;
A
A
OO
Me Me
ClCN
O O
Me Me
CN
KHMDS;
allylClOO
Me Me
Cl
O O
Me Me
CN CNH
OO
Me Me
I
O O
Me Me
CN CN
KI, 18-c-6
xylenes, reflux
Tetradiol synthon B
DMPU
LiNEt2;
DMPU
B
O OO OO O
CNCNCN
O O
Cl
Me Me Me Me Me Me Me Me
CN
05 6/25/02 11:24 AM
Total Syntheses Using Cyanohydrin Acetonide Methodology
O
O
Me
OH
Me
i-Pr
OH OH OHOH OH
HO
(-)-Roxaticin
Me
Me OH
HO
OH
Me
OH OH OH OH OH OH
OO
Filipin III
i-Pr O
Me
OHOHOHOH OH OH OH
OH
OO
Me
H
OH
Roflamycoin
O O OO O O O O
Me
Me Me Me Me Me Me Me Me
i-Pr
Me
OTBS
Rychnovsky and Richardson, Tetrahedron 1999, 55, 8977.Rychnovsky and Richardson, J. Am. Chem. Soc. 1997, 119, 12360.
Rychnovsky et al., J. Am. Chem. Soc. 1997, 119, 2058.
Rychnovsky and Hoye, J. Am. Chem. Soc. 1994, 116, 1753.
06 6/25/02 11:25 AM
Roxaticin Polyol Segment Retrosynthesis
O O OO O O O O
Me
Me Me Me Me Me Me Me Me
O O
Me
Me Me
H
O
i-Pr H
OTBS
Me
O
NC
OO O O O O
Me
Me Me Me Me Me Me
i-Pr
Me
OTBS
Br BrCN
O O
Me Me
i-Pr
Me
OTBS
OHOH
Cl Cl
From Noyori hydrogenation of
chlorodione
From Noyori hydrogenation then
Frater-Seebach
From Noyori hydrogenationthen Wittig
Anti-diol linchpin
Rychnovsky and Hoye, J. Am. Chem. Soc. 1994, 116, 1753.
07 6/25/02 11:26 AM
Roxaticin Polyol Segment Fragment Synthesis
O O
Me
Me Me
H
O
i-Pr H
OTBS
Me
O
NC
OO
O O O O
Me
Me Me
Me Me Me Me
Br Br
CN
O O
Me Me
i-Pr
Me
OTBS
OHOH
Cl Cl
1) Ipc2Ballyl2) TESOTf
OTES
i-Pr
Me
OTBS84% (2 steps)
1) OsO4, NMO;2) NaIO43) "HCN"
4) acetone, CSAdimethoxypropane
59% (4 steps)
KOHO O
1) Li2NiBr42) acetone, CSAdimethoxypropane
1) Ipc2Ballyl2) BSA
77% (2 steps)OTMSO O
Me
Me Me
1) OsO4, NMO;2) NaIO43) TMSCN, KCN cat.
4) acetone, CSAdimethoxypropane
83% (4 steps)
Rychnovsky and Hoye, J. Am. Chem. Soc. 1994, 116, 1753.08 6/25/02 11:26 AM
Roxaticin Polyol: Fragment Coupling
O O OO O O O O
Me
Me Me Me Me Me Me Me Me
NC
OOO O O O
Me
Me MeMe Me Me Me
i-Pr
Me
OTBS
Br Br
CN
O O
Me Me
i-Pr
Me
OTBS
LiNEt2, THF;
Electrophile OO O O O O
Me
Me Me Me Me Me Me
Br
CN
63% yield
LiNEt2, THF;
Electrophile
91% yield
+
+
O O OO O O O O
Me
Me Me Me Me Me Me Me Me
i-Pr
Me
OTBS
CNCN
LiDBB, THF;MeOH
63% yield
(-)-Roxaticin
Rychnovsky and Hoye, J. Am. Chem. Soc. 1994, 116, 1753.
09 6/25/02 11:27 AM
Smith: Dithiane Coupling
R H
SSR H
OHS SH t-BuLi
THF/HMPAR Li
SS
R
O R
OP
I
R R
SSOH
BF3•OEt2
R R
OHO
Deprotection(Hg2+, Oxid.,
MeI, H2O)
"The advantages of this method vis-a-vis the classical aldol reaction include the following:"
1) Carbonyl introduced in protected form
2) Hydroxyl can be protected or free
3) Configuration of hydroxyl defined before coupling
4) Reaction is irreversible
5) Self-condensation is avoided
Smith et al., Acc. Chem. Res. 1998, 31, 35.
R R
SSOP
R R
OPO
Disadvantages include:
1) Nucleophilicity of sulfur occasionally problematic
2) Deprotection can be diffficult
3) Metallation of dithiane sometimes difficult
10 6/25/02 11:27 AM
Mori's Diacetate Synthon
O
OH
MeMe
SS
OOTBDPS
n-BuLi O
O
MeMe
SSOH OTBDPS
NBS, AgNO3H2O
O
O
MeMe
OH OTBDPSOO OTBDPSOO
O OTBDPSOOHSS
OO
MeMe
O
OLi
MeMe
SS
98%
78% yield
93% yield
O
OLi
MeMe
SS
O
O
Me
OH
Me
i-Pr
OH OH OHOH OH
HO
Roxaticin
Tet. Lett. 1988, 29, 5419, 5423.
Tet. Lett. 1989, 30, 4383, 4387. Tetrahedron 1995, 51, 5299, 5315.
Roxaticin synthesis
THF
11 6/25/02 11:28 AM
HO
Smith Syntheses Utilizing Dithiane Coupling
O
O
Me
N O
MeMe
H
OMeOHOH
Me MeMe
MeMeH
NH
O
MeO
OHNMe2
OH
Calyculin A
OP
OHHO
O
Me
H
CN
NO
OO
O
O
Me
Me
OH
MeOOH
Me
Me
O
Me OMe
O
Me
MeHO
OMe
Rapamycin
H
H
OO
O
O
O
O
O
OH
OH
Me
OH
HOHH
H
HO
H
Me
H
AcO
Me
OAc
Me
OMe
H
HO
OO
Me OH
H
Altohyrtin C
A
B
C
D
E
F
12 6/25/02 11:29 AM
Smith: Multicomponent Dithiane Coupling via Brook Rearrangement
Smith et al., J. Am. Chem. Soc. 1997, 119, 6925.
S S
TBS
R R'
SSOH OTBS R
R'
SSOTBS
Li
O
R'
SSOLi
TBS Li
SS
TBS
R'
O
t-BuLi, THFHMPA, -78 ˚C
Li
SS
TBS
BnOO
2.5 Equiv.-78 ˚C to -45 ˚C
SSOH OTBS
BnO OBn
86% yield
S S
TBS
t-BuLi, Et2O-78 ˚C to -45 ˚C
Li
SS
TBS
BnOO
1.2 Equiv.-78 ˚C to -45 ˚C
TBS
SSOLi
OBn
H2O
TBS
SSOH
OBn
HMPA orDMPU
H
SSOTBS
OBn
then H2O
See also: Smith et al., Org. Lett. 1999, 1, 2001.13 6/25/02 11:29 AM
Smith: Altohyrtin C Fragment Retrosyntheses
OO
I
O
O
H
H
TESO
OMe
H
TBSO
Me OTBS
H
A
B
C
D
I
TESO
OO
O
O
O
O
O
OH
OH
Me
OH
HOHH
H
HO
H
Me
H
AcO
Me
OAc
Me
OMe
H
HO
OO
Me OH
H
Altohyrtin C
A
B
C
D
E
F
OTBDPS
TBDPSOOTs
OH OHOHSSMe OTBS
BnO
OR OORSS
OMeO
MeMe
R=TBS
Smith et al., Angew. Chem. Int. Ed. 2001, 40, 191.
Smith et al., Angew. Chem. Int. Ed. 2001, 40, 196.14 6/25/02 11:30 AM
Smith: Altohyrtin C CD Ring Fragment
O
OOMe
H
HO
H
OH
BnO
BnO
OH OHSS
OMe
Smith et al., Tet. Lett. 1997, 38, 8671.
BnO
OTBSO O O
OMe
Me
9 steps from glycerol acetonide 6 steps from glyceraldehyde acetonide
A B
S S
TBS
t-BuLi,Et2O;A;
B, HMPABnO
OR ORSS
OH
R=TBS
OO
MeMe
72%
OH
OH
1) NaH, MeI2) HCl, MeOH
80% (2 steps)
1) Hg(ClO4)2CaCO32) HClO4
10:1 dr87% (2 steps)
O
OOMe
H
TBSO
H
C
D
I
TESO
O
OOMe
H
TBSO
H
OPiv
TESO
1) PivCl2) TBSCl
3) H2, Pd/C4) TESCl
1) DIBAL-H2) TsCl
3) NaI4) TESOTf
57% (4 steps)66% (4 steps)
O
O OTBS
I
MeO
TESO
H
H
15 6/25/02 11:31 AM
TBSO
OO
I
H
H
TESO
Me OTBS
A
B
OTBDPS
TBDPSOOTs
OH OHOHSSMe OTBS
Smith et al., Tet. Lett. 1997, 38, 8675.
Smith: Altohyrtin C AB Ring Fragment
OTESO
A
S S
TBS
t-BuLi,Et2O;A;
B, HMPA
65%
OMe
OO
MeMe
TBDPSO B5 steps from glyceraldehyde acetonide 5 steps from (+)Ipc2Ballyl
OTES OHSSMe OTBSTBDPSO
OO
MeMe 1) TFA/H2O
2) TsCl
79% (2 steps)
Hg(ClO4)2CaCO381%, 26:1 dr
OO
OTs
H
H
HO
Me OTBS
OTBDPS
1) TESOTf2) LiI
96% (2 steps)
O
OTESO Me
H
I
OTBDPS
16 6/25/02 11:31 AM
Nelson's Acyl Halide/Aldehyde Cyclocondensation
Nelson et al.,Tet. Lett. 1999, 40, 6535.
Me Cl
O
H R
O20% Al(SbF6)3
Hunig's baseCH2Cl2, -25 ˚C
OO
R
Aldehyde Yield
Me Cl
O Hunig's base CO
H
H H R
O(F6Sb)3Al
+
OO
R
Aldehyde Yield[2+2]
Cl
O
H R
O20% Al(SbF6)3
Hunig's baseCH2Cl2, -25 ˚C
OO
R
Me
Medr>95:5
Cl
O R3NHH R
O
Cl R
O OH
Observations:1) Ketene observed in 13C NMR2) Enolate not observed in 13C NMR3) No lactone formed in absence of Al3+
Mechanism:
Nelson et al.,Tet. Lett. 1999, 40, 6539.
C6H11CHO
BnOCH2CHO
CH2=CH(CH2)8CHO
90%
83%
81%
PhCH2CH2CHO 93%
C6H11CHO
CH2=CH(CH2)8CHO
65%
80%
17 6/25/02 11:32 AM
Nelson's Enantioselective Acyl Halide/Aldehyde Cyclocondensation
Nelson et al., J. Am. Chem. Soc. 1999, 121, 9742.
Me Br
O
H R
O10% Al cat.
Hunig's baseCH2Cl2, -50 ˚C
OO
R
Aldehyde % yield
Nelson and Wan, Org. Lett. 2000, 2, 1883.
%ee
NAl
N
N
i-Pr i-Pr
X
Bn
Tf Tf
X=Me, Cl
CCHOBnOH2CC
PhCH2CH2CHO
Me2CHCH2CHO
BnOCH2CHO
CH2=CH(CH2)8CHO
TBDPSOCH2CHO
92
93
91
91
89
93
93
80
91
91
74
86
Alpha branched, unsaturated aldehydes afford low ee, yield
18 6/25/02 11:32 AM
Nelson's Enantioselective Acyl Halide/Aldehyde Cyclocondensation
Nelson et al., J. Am. Chem. Soc. 1999, 121, 9742.
Br
O
H R
O10% Al cat.
Hunig's baseCH2Cl2, -50 ˚C
OO
R
Me
Me
Nelson and Wan, Org. Lett. 2000, 2, 1883.
NAl
N
N
i-Pr i-Pr
X
Bn
Tf Tf
X=Me, Cl
CCHOBnOH2CC
CCHOC6H11C
CCHOTMSC
CCHOPhC
BnOCH2CHO
%eeAldehyde
94
94
93
93
91
dr
88:12
91:9
98:2
99:1
99:1
% yield
78
85
85
90
83
Other aliphatic aldehydes, unsaturated enals afford low yields, ee's.
19 6/25/02 11:34 AM
Leighton's Oxymercuration of Hemiacetals
R H
O O
R
O Carbonylation
RMet
O O
R
R
O OH
R
Met
Oxymetallation
R
OHR H
O
Oct
OH
Et H
OHg(OAc)2:NaCl
or HgCl(OAc)Neat Oct
HgCl
O O
Et
+
74%-77% yield
Leighton and Sarraf, Org. Lett. 2000, 2, 403.
Leighton et al., Org. Lett. 2000, 2, 3197.
Works for aliphatic aldehydes. Ketones, aromatic aldehydes (e.g. benzaldehyde) not synthetically useful.Yields typically 65-75%,dr at least 10:1.
1 Equiv. 3 Equiv.
R
OH
Me Me
O5 mol% Yb(OTf)3
HgCl(OAc)0.125M R
HgCl
O O+
1 Equiv. Solvent
Me MeAcetone, benzaldehyde now useful substrates. Yields typically 70-85%,dr at least 20:1.
20 6/25/02 11:34 AM
Leighton's Oxymercuration of Hemiacetals
Leighton and Sarraf, Org. Lett. 2000, 2, 403.
Leighton et al., Org. Lett. 2000, 2, 3197.
i-Bu
OH
Me Me
O5 mol% Yb(OTf)3
HgCl(OAc)2 minutes i-Bu
HgCl
O O+
Me Me
Is Yb(OTf)3 simply increasing the rate of kemiketal formation?
i-BuHgCl
O O
Me Me
1:1 dr85% yield
i-BuHgCl
O O
Me Me
6:1 dr
5 mol% Yb(OTf)3
10% HgCl(OAc)acetone, AcOH i-Bu
HgCl
O O
Me Me
93% yield, >20:1 dr
Yb(OTf)3 alone is enough to promote the isomerization.
RHgCl
O O
Me Me
R
O O
Me Me
RHgCl
O O
Me Me
ClHg
Yb(OTf3)
21 6/25/02 11:35 AM
Leighton's Formylation of Mercurials
Leighton et al., Org. Lett. 2000, 2, 3205.
OctHgCl
O O
Et
Also compatible with acetonides.Yields typically 60-80%
4% Rh(acac)(CO)24% P(O-o-t-BuPh)3
H2/CO (800 psi)EtOAc, 50 ˚C
Amine
Oct
O O
Et
H
O
Amine Equiv. Yield
Amyl
OH4% Rh(acac)(CO)24% P(O-o-t-BuPh)3
H2/CO (800 psi)EtOAc, 50 ˚C
Amyl
O O
Et
H
O
0.5 DABCO
EtCHO
HgCl(OAc)
51% yield
One pot procedure delivers aldehyde in comparable yield to two step procedure, without isolation of mercurial intermediate.
pyridine
quinuclidine
TMEDADABCODABCO
1
1
0.51
0.5
0
46
364670
N
N
N
NHg
HgR
R
Cl
Cl2 RHgCl N
N
Me
MsO
Ammonium salt A 1 77
A
22 6/25/02 11:36 AM
Leighton's Silylformylation
Leighton and Chapman, J. Am. Chem. Soc. 1997, 119, 12416.
R
OSi
Ph Ph
H SiO
R
PhPh
OAc
1) 1% Rh(acac)(CO)21000 psi CO, 60 ˚C, C6H6
2) LiBEt3H3) Ac2O
R
MeAllyli-Pr
TBSOEt
dr
4.5:14:16:14:1
Yield
67%64%79%60%
R
OSi
Ph Ph
RhH
SiO
R
PhPh
RhH
SiO
R
PhPh
RhH
O
LnRh
R
OSi
Ph Ph
H
CO
SiO
R
PhPh
H
O
R H
OH OH O SiO
R
PhPh
H
OMask OH via
Tamao
SiO
R
PhPh
RhHR
OSi
Ph Ph
HCarbonylation Silylmetallation
23 6/25/02 11:37 AM
Leighton's Silylformylation/Allylation
Leighton and Zacuto, J. Am. Chem. Soc. 2000, 122, 8587.
i-Pr
OSi
H1) 3% Rh(acac)(CO)21000 psi CO, 60 ˚C, C6H6
2) H2O2, NaHCO3, heat
R2
HHH
Me
dr
77:2369:3171:2992:8
yield
59%50%45%59%
i-Pr
OH OH OH
59% plus 18% stereoisomers
R1
OSi
H1) 3% Rh(acac)(CO)21000 psi CO, 60 ˚C, C6H6
2) H2O2, NaHCO3, heat R1
OH OH OH
R2
R1
i-PrAllyl
TBSOEti-PrR2
SiAllyl
OO
HH
R
HSi
AllylOO
HR
H H O Si
Allyl
H
R
O
HH
SiAllyl
OO
HR
H HPseudo-rotation
Major pathway Minor pathway
Stereochemical rationale:
SiO
R H
O
via
24 6/25/02 11:38 AM
Leighton's Alkyne Silylformylation/Allylation
Leighton and O'Malley, Angew. Chem. Int. Ed. 2001, 40, 2915.
i-Pr
OSi
H1) 1% Rh(acac)(CO)21000 psi CO, 60 ˚C, C6H6
2) TBAF3) Ac2O
R2
HHHHH
Me
dr
4:14:1
10:18:17:1
23:1
Yield
63%68%66%83%70%70%
i-Pr
OAc OAc
83% yield, 8:1 dr
R1
OSi
H
R1
OAc OAcR1
Propargyln-Prt-Bui-Pri-Pri-Pr
R2 R3
1) 0.1% Rh(acac)(CO)21000 psi CO, 60 ˚C, C6H6
2) TBAF3) Ac2O R2 R3
R3
HHHH
MeH
i-Pr
OSi
H1) 1% Rh(acac)(CO)21000 psi CO, 60 ˚C, C6H6
2) H2O2, NaHCO3, heat i-Pr
OH OH
65% yield, 23:1 dr
Me Me
O
SiO
R H
O
via
25 6/25/02 11:38 AM
Leighton's Alkyne Silylformylation/Allylation
SiAllyl
OO
HR
HSi
AllylOO
R
H H
Stereochemical rationale:
Top allyl group experiences steric repulsion with R group
i-Pr
OSi
Ph
H1) 1% Rh(acac)(CO)21000 psi CO, 60 ˚C, C6H6
2) TBAF
i-Pr
OH OH
1:1 diastereomeric mixture
1:1 diastereomeric mixture
SiAllyl
OO
R
H H
Leighton and O'Malley, Angew. Chem. Int. Ed. 2001, 40, 2915.
Alpha allyl
group transfer
Beta allyl
group transfer
Major pathway Minor pathway
SiO
i-Pr H
OPh
SiO
i-Pr H
OPh
26 6/25/02 11:39 AM
Leighton's Retrosynthesis of Mycoticin A
Leighton and Dreher, J. Am. Chem. Soc. 2001, 123, 341.
Me
O
OHO
i-Pr
OH OH OH
OHMe
OHOHOH
Mycoticin A
i-Pr
OPMB
Me
O O OO O O O O
Me
Me Me Me Me Me Me Me Me
OH
Schreiber's polyol segment
i-Pr Me
OPMB
Me
O O OO O O O O
Me
Me Me Me Me Me Me
OTIPS
H
2223
23331222
1,3 anti aldol
27 6/25/02 11:40 AM
Leighton's Synthesis of the C23-C33 Methyl Ketone
Leighton and Dreher, J. Am. Chem. Soc. 2001, 123, 341.
i-Pr H
OPMB
Me
O
i-Pr
OPMB
Me
OHIpc2Ballyl
71% yield10:1 dr
i-PrHgCl
OPMB
Me
O O
Me Me
20 mol% Yb(OTf)3HgCl(OAc)
acetone75% yield
i-Pr
OPMB
Me
O O
Me Me
6% Rh(acac)(CO)26% P(O-o-t-BuPh)3
H2/CO (800 psi)EtOAc, 50 ˚C
0.5 Equiv DABCOO
Hi-Pr
OPMB
Me
O O
Me Me
O
Me
1) MeMgBr2) Dess-Martin
58% (3 steps)
i-Pr
OH
Me
1) A, cat. B2) PMBBr
3) PPTS, H2O
H
EtO OEtA=
62% (3 steps)
RuClCl
PCy3
N N
H
Ph
MesMesB=
28 6/25/02 11:42 AM
Leighton's Synthesis of the C12-C22 Aldehyde
Leighton and Dreher, J. Am. Chem. Soc. 2001, 123, 341.
O O O O O
Me
Me Me Me Me
OTIPS
H
OH
Me
OTIPSHSiCl3, n-BuLi
AllylMgBr
O
Me
OTIPSSi
H
Allyl Allyl
1) 3% Rh(acac)(CO)21000 psi CO, 60 ˚C, C6H6
2) H2O2, NaHCO3, heat
OH OH OH
Me
OTIPS
55% (3 steps)dr>10:1
OH O O
Me
OTIPS
Me Me
acetoneCSA
75% yield7:1 selectivity
10 mol% Yb(OTf)3HgCl(OAc)
acetone71% yieldClHg
O O O O
Me
Me Me Me Me
OTIPS8% Rh(acac)(CO)28% P(O-o-t-BuPh)3H2/CO (1000 psi)
EtOAc, 50 ˚C0.5 Equiv DABCO
82% yield
29 6/25/02 11:41 AM
Leighton's Formal Synthesis of Mycoticin A
Leighton and Dreher, J. Am. Chem. Soc. 2001, 123, 341.
i-Pr
OPMB
Me
O O OO O O O O
Me
Me Me Me Me Me Me Me Me
OTIPS
i-Pr Me
OPMB
Me
O O OO O O O O
Me
Me Me Me Me Me Me
OTIPS
H
1) TMSOTf, Hunig's base2) Aldehyde, BF3•OEt2
i-Pr
OPMB
Me
O O OHO O O O O
Me
Me Me Me Me Me Me
OTIPS
6:1 dr
1) Me4NBH(OAc)32) PPTS,dimethoxypropane49% (4 steps)
TBAF92% yield
Schreiber's polyol segment
30 6/25/02 11:42 AM
Calter: Asymmetric Methylketene Dimerization
R2NMe
O
Me
O O
Me
OMe O
C
H
MeChiral
Catalyst
N
H
HN
OMe
OH
quinidine
H CCl3
OC
O
H H
2% quinidine-50 ˚C, toluene
95% yield98% ee
Ringopening
OO CCl3 Malic acid
Hydrolysis
Wynberg's precedent: 1982
Wynberg and Staring, J. Am. Chem. Soc. 1982, 104, 166.
C
O
H H
R3N
O
Mechanism: Nucleophilic Catalysis
H CCl3
O
R3N CCl3
O O
OO CCl3
31 6/25/02 11:43 AM
Calter: Asymmetric Methylketene Dimerization
O
Me
OMeO
C
H
Me
N
H
HN
OMe
OH
quinidine
Calter J. Org. Chem. 1996, 61, 8006.
C
O
H Me
R3N
O
Mechanism: Nucleophilic Catalysis
R3N
O O
BrMe
O
Br
1) Zn, THF2) Distill ketene 1 mol% catalyst
THF, -78 ˚C
Amine %ee
Me
Me
Me
O
Me
OMe
C
O
H MeN
H
N
OMe
OH
OMe
El
Model for stereoinduction
MeO
Me
O O
500 ˚CN2
Stream
quinidinepropionylquinidine
TMS-quinidine
989798
-70-54-93
quininepropionylquinine
TMS-quinine
Amine %ee
32 6/25/02 11:44 AM
Calter: Tandem Ring Opening/Aldol Reaction
O
Me
OMe
Calter et al., Org. Lett. 2001, 3, 1499.
MeON
Me NMe
O O
Me
Me
OMe
Li
NMe
O O
Me
Me
OMe
Li
HCl/H2O
65% yield
i-PrCHO
THF
THF
N
O O
Me
Me
OMe Me
OH
i-Pr
95:5 dr 50% yield
1) LiHMDS2) i-PrCHO THF
N
O O
Me
Me
OMe Me
OH
i-Pr
80:20 dr 23% yield
74% recovered sm
Yields around 50% based on ketene dimer, dr between 85:15 and 90:1.
NMe
O O
Me
Me
OMe
Li
HMe
O
Me
N
O O
Me
Me
OMe Me
OH
Me
Me
+ 95:5 dr
55% yield
Calter et al., J. Org. Chem. 2001, 66, 7500.33 6/25/02 11:44 AM
Calter: Synthesis of Siphonarienal
O
Me
OMe
Hn-Pr
O
MeN
O O
Me
Me
OMe Me
OH
Me
Me
Calter et al., J. Org. Chem. 2001, 66, 7500.
MeON
Me
Li
CH2Cl2 35% yield plus 36% epimer
N
O O
Me
Me
OMe Me
OH
Me
Me
1) Zn(BH4)22) MsCl
63% yield (2 steps)N
O OMs
Me
Me
OMe Me
OMs
Me
Me
1) LiAlH4, THF2) LiAlH4, Et2O
HO
Me Me
Me
Me
1) TEMPO, PhI(OAc)22) Wittig
3) DIBAL-H4) MnO2
Me Me
Me
MeMe
O
H
72% (2 steps)
64% yield (4 steps)Siphonarienal
propionic anhydridequinidineN,O-dimethylhydroxylaminen-BuLi(rac)-2-methylpentanal
Starting materials:All commercially available
34 6/25/02 11:45 AM
Lautens' Oxabicyclic Ring Opening
Lautens and Chiu, Topics in Current Chemistry 1997, 190, 1-85.
H H
O O
Me Me
OH
R
OP
O
Me
OP
MeMeOP
Me
OH
R
Oxidativeolefin
cleavage
Nucleophilicring
opening
SuprafacialSN2'
OMe Me
O
X
O
Me
Me
HH
O
Me Me
OBase
Oxallyl cation
O
Me
Me
OP
HH
H
ReductionProtection[4+3]
35 6/25/02 11:45 AM
R2Al
Lautens' Enantioselective Oxabicyclic Ring Opening: Hydride Reduction
Lautens and Rovis, J. Am. Chem. Soc. 1997, 119, 11090.
MeOMe
Me
OH
O
Me
Me
OMe
HH
HO
Me
Me
OMe
HH
HO
Me
Me
OMe
HH
H
H
14% Ni(COD)221% (R)-BINAP
DIBAL-Hrt
20% Yield56% ee 70% Yield
MeOP
Me
OH
O
Me
Me
OP
HH
H14% Ni(COD)224% (R)-BINAP
P=Me, 90% Yield, 97% ee
Organoalane slow to ring open under reaction conditions
60 ˚C4 hr DIBAL-H addition
P=TIPS, 87% Yield, 95% ee
Lautens et al., J. Am. Chem. Soc. 1995, 117, 532.
Benzyl ether also toleratedCatalyst lowering possible if addition time increased
R2Al
MeOBn
Me
OH
O
Me
Me
OBn
HH
HO
Me
Me
OBn
HH
H
H
14% Ni(COD)2
DIBAL-H- 78 ˚C to rt
"High yield"
DIBAL-Cl
60-80 ˚C
36 6/25/02 11:46 AM
HNiL
Lautens' Enantioselective Oxabicyclic Ring Opening: Hydride Reduction
Lautens and Rovis, J. Am. Chem. Soc., 1997, 119, 11090.
H
MeOP
Me
OH
O
Me
Me
OP
HH
H
O
Me
Me
OP
HH
H
LNi
14% Ni(COD)224% (R)-BINAP P=Me, 90% Yield, 97% ee
60 ˚C4 hr DIBAL-H addition
P=TIPS, 87% Yield, 95% ee
Lautens et al., J. Am. Chem. Soc., 1995, 117, 532.
LNi
O
Me
Me
OP
HH
H
H
O
Me
Me
OP
HH
HRapidSlow Observed
productEnantiomerof product
H
O
Me
Me
OP
HH
H
R2AlR2Al
O
Me
Me
OP
HH
H
H
Slow Slow
Initial hydrometallation rapid and reversible.Organoalanes not implicated as intermediates.Elimination is enantioselective event.
37 6/25/02 11:47 AM
Lautens' Enantioselective Oxabicyclic Ring Opening: Methyl Addition
Lautens et al., Org. Lett. 2000, 2, 1971.
MeOR
Me
OH
O
Me
Me
OR
HH
H
Me2Zn, 10% additive
Me
5% Pd(MeCN)2Cl2
Ligand, refluxClCH2CH2Cl
R Additive %ee %yield
H none 95 84
TBDPS Zn(OTf)2 87 70
TIPS Zn(OTf)2 93 73Fe
PPh2
N
O
i-Pr
Lautens et al., J. Am. Chem. Soc. 2000, 122, 1804.
OR
OH
O
OR
H
Me2Zn, 10% additive
Me
5% Pd(MeCN)2Cl2
Ligand, refluxClCH2CH2Cl
R Additive %ee %yield
H none 90 84
TBDPS Zn(OTf)2 88 92
38 6/25/02 11:47 AM
Lautens' Enantioselective Oxabicyclic Ring Opening: Mechanism
Lautens et al., J. Am. Chem. Soc. 2001, 123, 6834.
PdL
L
Cl
Cl
PdL
L
Me
XO
R
R
Pd
L
L
Me
O
R
RMe
L2Pd
Me2Zn
R
R
Me
OPdL2X
O
R
R
Zn(OTf)2
Zn(OTf)2X
Enantioselectivecarbopallidation
Rapid ring opening
R
R
Me
OZnMe
Me2Zn
Lewis acid assists ionization of X
X
39 6/25/02 11:48 AM
Lautens' Total Synthesis of Ionomycin
Lautens et al., Org. Lett. 2002, 4, 1879.
OH
MeMeMeMeMe
OOOH
MeMe
OHOH
OOMeH H
Me
OHMe
Me OH
MeMeMe
OO
MeMe
OH O
H
O
H
1011
16
172332
1
MeOH
MeH
MeMeMe
O
H
OOH OH
O
Me
Me
OH
HH
H
23 1710
1
Hydride ring opening
Methyl ring opening
* Inversion needed
MeOH
Me
Me
HO
OH
HO
*
*
40 6/25/02 11:49 AM
Ionomycin: C17 -C23 Fragment
Lautens et al., Org. Lett. 2002, 4, 1879.
MeMe
OHOH O
H
O
H
MeOTIPS
Me
HO
O
Me
Me
OTIPS
HH
H
23 17
5% Ni(COD)210% (S)-BINAPToluene, 65 ˚C
DIBAL-H (20hrs)93-95%ee95% yield
1) Swern2) DIBAL-H
3) PMBCl
82% (3 steps)
MeOTIPS
Me
PMBO
MeMe
OTIPSOPMB OTrO
H
1) O3; NaBH42) DDQ79% (2 steps)
MeMe
OTIPSO OHO
PMP
MeMe
OTIPSOPMB OTrOH 1) TrCl2) DIBAL-HSwern
90% yield 94% (2 steps)
41 6/25/02 11:49 AM
Ionomycin: C17 -C23 Fragment
Lautens et al., Org. Lett. 2002, 4, 1879.
Me OH
MeMeMe
OO
MeMeMe
O OHO OTBS
O
Me
Me
OH
HH
H10
1
5% Pd(MeCN)2Cl25% Ligand, 10% Zn(OTf)2
Me2Zn, ClCH2CH2Clreflux
94% ee, 80% yield
MeOH
Me
HO
Me
MeOTBS
Me
PMBO
Me
MeOH
Me
Me
HO
PMP
MeMeMe
O OO O
PMP S
MeMeMe
O O
PMP
1) TBSCl2) PMBBr
1) O3; NaBH42) DDQ
1) TBAF2) Thiocarbonyl- diimidazole
1) Bu3SnH, AIBN2) TPAP, NMO3) Wittig
O
OMe1) H2, Pd(OH)22) Barton 3) TPAP, NMO
MeMeMe
O
O
OMe
Me 4) MeMgBr5) Dess-Martin
87% (2 steps)
77% (4 steps)
65% (3 steps)
49% (6 steps)
42 6/25/02 11:52 AM
Carreira's Hydroxyl Directed Nitrile Oxide Cycloaddition
Kanemasa et al., J. Am. Chem. Soc. 1994, 116, 2324.
R R
O OH
Me
ON
R R
Me
R N O MeR
[3+2]Reduction
Hydrolysis
Problems:1) Nitrile oxides unstable;prone to dimerization, decomposition2) Internal alkenes sluggish3) Mixtures of regioisomers4) Mixtures of stereoisomers
R N O NO
N
R R
O
Kanemasa, 1994:
Magnesium alkoxides of allylic alcohols are substrates showing enhanced rate, regioselectivity and diastereoselectivity. Only aromatic nitrile oxides examined.
NOH
ClPh N O
Me Me
OMgBr
2 Equivalents
ON
Ph
Me
Me Me
OMgBr
OH
Me
53% yield, dr 94:6complete regiocontrol
R N C O
Carreira et al., Angew. Chem. Int. Ed. 2001, 40, 2082.
CH2Cl2
R
RR
H R
O
N OR
MgBr
Syn product
Stereochemical rationale:
43 6/25/02 11:53 AM
Carreira's Hydroxyl Directed Nitrile Oxide Cycloaddition
R H
NOH
t -BuOCl
CH2Cl2, -78 ˚C R Cl
NOH R3
OH
R2
R1
EtMgBr (3.0 Equiv.)
i-PrOH (3.3 Equiv.)CH2Cl2, rt
R3
OMgBr
R2
R1
ON
R
R2 R1OH
R3
70-80% yieldsone isomer
ON
OH
MeON
OH
Me
ON
OH
MeON
OH
Me
Me
OHMe
Me
OH
Me
H
NOH
OTBS
Me
H
NOH
OTBS
Me
Me
Me
Me
Me
OTBS
OTBS
OTBS
OTBS
Me Me
Me Me
87% yield 82% yield
73% yield68% yield
1) Protect2) W-2 RaNi, B(OH)3>90% yield
RR3
O
R2 R1
OH
OP
Carreira et al., Angew. Chem. Int. Ed. 2001, 40, 2082.44 6/25/02 11:53 AM
Carreira's Epothilone Retrosynthesis
Carreira and Bode, J. Am. Chem. Soc. 2001, 123, 3611.
Carreira and Bode, J. Org. Chem. 2001, 66, 6410.
OMe
RO
Me
O
S
NMe
OH O
OHMe MeMe
Epothilone A (R=H)Epothilone B (R=Me)
OH
Me
O
Me O
S
NMe
OH OO
Me
MeMe
H
HO
Macro-lactonization
Aldol
N
S MeMe
ON
OH Me
OP
Epothilone A
N
S MeMe
OH
O
Me
OH
OH
H
N
S MeMe
OH Me
OP
N
Cl
OH
This hydroximinoyl chloride could not be prepared from the corresponding aldehyde.
45 6/25/02 11:54 AM
Carreira's Epothilone A Fragment Synthesis
Carreira and Bode, J. Am. Chem. Soc. 2001, 123, 3611.
Carreira and Bode, J. Org. Chem. 2001, 66, 6410.
N
S MeMe
ON
OTBS Me
OTIPS
N
S MeMe
OH
OH
Me
P
Me OH Me
OTIPSN
Cl
OHO
EtOEtO
+ P
Me
ON
OH Me
OTIPS3.0 Equiv EtMgBr3.3 Equiv i-PrOH
CH2Cl2, rt54% (94% BRSM)
O
EtOEtO
1) TBSOTf2) LiCl, DBUN
S
OMe
H
70% (2 steps)6:1 E:Z
N
S MeMe
OH OH
OTBS Me
OTIPS1) SmI2; B(OH)3
2) BEt3, NaBH468% (2 steps)
9:1 E:Z
1) SOCl22) TBAF, heat
O
77% (2 steps)
N
S MeMe
OTES
O
Me
O1) TESCl2) AcOH/H2O
3) TPAP, NMP
63% (2 steps)H
via
O OS
RR
OH
O
46 6/25/02 11:55 AM
Approaches Not CoveredBernhard Breit: Hydroformylation
R
Me
OH
Me
R
Me
OH
Me O
H
Michael Jung: "Non-Aldol Aldol"
R OSiR3
MeO R H
OSiR3
Me
O
Org. Lett. 2001, 3, 333.Tet. Lett. 2000, 41, 9719.Org. Lett. 2000, 2, 1669.Org. Lett. 1999, 1, 307.
Tet. Lett. 1999, 40, 3129.J. Am. Chem. Soc. 1997, 119, 12150.J. Am. Chem. Soc. 1993, 115, 12208.
J. Org. Chem. 2001, 66, 4870.Chem. Eur. J. 1999, 5, 2819.
Eur. J. Org. Chem. 1998, 1123.Tet. Lett. 1998, 39, 1901.
Liebigs Ann. Chem. 1997, 1841.James Leighton: Hydroformylation
J. Am. Chem. Soc. 1997, 119, 11118.Tet. Lett. 1998, 39, 6423.
J. Am. Chem. Soc. 2001, 123, 11514.
O O
R
R
O O
R
R
O
H
Keith Woerpel: Silirane Ring Opening
OSi
RR
R R
Me
Si
R Me
RR O
H R
J. Am. Chem. Soc. 1995, 117, 10575.J. Org. Chem. 1997, 62, 4737.Tetrahedron 1997, 53, 16597.
J. Am. Chem. Soc. 1999, 121, 949.Angew. Chem. Int. Ed. 2000, 39, 4295.
Acc. Chem. Res. 2000, 33, 813.J. Am. Chem. Soc. 2002, 124, 6524.
Stephen Hanessian: Conjuage Addition/Enolate Oxidation
Tet. Lett. 1996, 37, 7473.J. Am. Chem. Soc. 1997, 119, 10034.
Tet. Lett. 1999, 40, 4627.J. Am. Chem. Soc. 2001, 123, 10200.
OMe
OP
PO
O
OMe
OP
PO
OMe
OH
47 6/25/02 11:56 AM
SummaryRychnovsky: Cyanohydrin acetonide Smith: Dithiane linchpin
Nelson: Cyclocondensation Leighton: Hemiacetal oxymercuration
Leighton: Silylformylation Calter: Methylketene dimerization
Lautens: Enantioselective ring opening Carreira: Directed nitrile oxide cycloaddition
OO
Me Me
CNCl
OO
Me Me
ClCN
O O
Me Me
CN H
R R'
SSOH OTBS
Li
SS
TBS
Br
O
H R
OO
O
R
Me
MeR
OH
Me Me
O
RHgCl
O O
Me Me
R1
OSi
Allyl Allyl
H
R1
OH OH OH
R2 R2
O
Me
OMe
MeO
Me
O O
MeOR
Me
OH
O
Me
Me
OR
HH
H
Me
R Cl
NOHR3
OMgBr
R2
R1
ON
R
R2 R1OH
R3
48 6/25/02 11:56 AM
