chemistry 5.512 synthetic organic chemistry iiweb.mit.edu/5.512/www/lectures07/5.512 lecture...
TRANSCRIPT
Strategies for StereocontrolledSynthesis
Lecture 20May 11, 2007
Rick L. DanheiserMassachusetts Institute of Technology
Chemistry 5.512Synthetic Organic Chemistry II
Strategies for StereocontrolledSynthesis
Case Studies Synthesis of the L-Hexoses (Sharpless, Masamune)
S. Y. Ko. A. W. M. Lee, S. Masamune, L. A. Reed, K. B. Sharpless, and F. J. WalkerScience 1983, 220, 949
HO
OH OH
CHO
OH OH
HO
OH OH
CHO
OH OH
HO
OH OH
CHO
OH OH
HO
OH OH
CHO
OH OH
HO
OH OH
CHO
OH OH
HO
OH OH
CHO
OH OH
HO
OH OH
CHO
OH OH
HO
OH OH
CHO
OH OH
L-Allose L-Altrose L-Idose L-Mannose
L-Glucose L-Gulose L-Talose L-Galactose
Strategies for StereocontrolledSynthesis
Case Studies Synthesis of the L-Hexoses (Sharpless, Masamune)
Science 1983, 220, 949
Hannah SharplessChemistry in Britain
1986, 22, 38
“Looking GlassSugars”
Strategies for StereocontrolledSynthesis
Case Studies Synthesis of the L-Hexoses (Sharpless, Masamune)
Satoru Masamune1928 - 2003
Strategies for StereocontrolledSynthesis
Case Studies Synthesis of the L-Hexoses (Sharpless, Masamune)
K. Barry Sharpless1941-
Strategies for StereocontrolledSynthesis
Case Studies Synthesis of the L-Hexoses (Sharpless, Masamune)
S. Y. Ko. A. W. M. Lee, S. Masamune, L. A. Reed, K. B. Sharpless, and F. J. WalkerTetrahedron 1990, 46, 245
Strategies for StereocontrolledSynthesis
Case Studies Synthesis of the L-Hexoses (Sharpless, Masamune)
S. Y. Ko, A. W. M. Lee, S. Masamune, L. A. Reed, K. B. Sharpless, and F. J. WalkerTetrahedron 1990, 46, 245
Liberation from the tyranny ofsubstrate control?
Strategies for StereocontrolledSynthesis
Case Studies Synthesis of the L-Hexoses (Sharpless, Masamune)
RCHOR
OH
CHO
OH
*
*
R OH
R
OH
!
or
Stereocontrolled
Olefination
Substrate
Control
R OH
O
ROH
O
or
*StereocontrolledEpoxidation
ReagentControl
!
*
* *
R OH
OH
OH
StereocontrolledEpoxide Opening
Substrate
Control
!
*
*
Regiocontrolled openingwith inversion at C-2
Strategies for StereocontrolledSynthesis
Case Studies Synthesis of the L-Hexoses (Sharpless, Masamune)
R OH
O
ROH
O
or
*StereocontrolledEpoxidation
ReagentControl
!
*
* *
R OH
OH
OH
StereocontrolledEpoxide Opening
Substrate
Control
!
*
*
R OH
O
O
*
*R OH
O
O
*
*
R OH
O
O
*
*R OH
O
O
*
*
(-)-DET (+)-DET
Regiocontrolled openingwith inversion at C-2
R OH
R
OH
or
RCHOR
OH
CHO
OH
*
*
!Stereocontrolled
Olefination
Substrate
Control
E Alkene
Z Alkene
Strategies for StereocontrolledSynthesis
Case Studies Synthesis of the L-Hexoses (Sharpless, Masamune)
RCHOR
OH
CHO
OH
*
*
RegioselectiveOxidation
!
R OH
R
OH
!
or
Stereocontrolled
Olefination
Substrate
Control
R OH
O
ROH
O
or
*StereocontrolledEpoxidation
ReagentControl
!
*
* *
R OH
OH
OH
StereocontrolledEpoxide Opening
Substrate
Control
!
*
*
Regiocontrolled openingwith inversion
Strategies for StereocontrolledSynthesis
Case Studies Synthesis of the L-Hexoses
(Sharpless, Masamune)HO
OH OH
CHO
OH OH
L-Glucose
R OH
R
OH
or
RCHOR
OH
CHO
OH
*
*
!Stereocontrolled
Olefination
Substrate
Control
Methods for both E and Z olefination are available e.g. via Ph3P=CHCHO for E alkene
Strategies for StereocontrolledSynthesis
Case Studies Synthesis of the L-Hexoses
(Sharpless, Masamune)HO
OH OH
CHO
OH OH
L-Glucose
R OH
R
OH
or
RCHOR
OH
CHO
OH
*
*
!Stereocontrolled
Olefination
Substrate
Control
Epoxidation highly selective for E allylic alcohols
R OH
O
ROH
O
or
*StereocontrolledEpoxidation
ReagentControl
!
*
* *
Strategies for StereocontrolledSynthesis
Case Studies Synthesis of the L-Hexoses
(Sharpless, Masamune)HO
OH OH
CHO
OH OH
L-Glucose
R OH
R
OH
or
RCHOR
OH
CHO
OH
*
*
!Stereocontrolled
Olefination
Substrate
Control
Epoxidation works poorly with Z allylic alcohols
R OH
O
ROH
O
or
*StereocontrolledEpoxidation
ReagentControl
!
*
* *
OHPh2CHO
Strategies for StereocontrolledSynthesis
Case Studies Synthesis of the L-Hexoses (Sharpless, Masamune)
R OH
O
ROH
O
or
*StereocontrolledEpoxidation
ReagentControl
!
*
* *
R OH
OH
OH
StereocontrolledEpoxide Opening
Substrate
Control
!
*
*
R OH
O
O
*
*R OH
O
O
*
*
R OH
O
O
*
*R OH
O
O
*
*
(-)-DET (+)-DET
Regiocontrolled openingwith inversion at C-2
R OH
R
OH
or
RCHOR
OH
CHO
OH
*
*
!Stereocontrolled
Olefination
Substrate
Control
E Alkene
Notavailable
Strategies for StereocontrolledSynthesis
R OH
O
O
*
*R OH
O
O
*
*
R OH
O
O
*
*R OH
O
O
*
*
(-)-DET (+)-DET
E Alkene
Notavailable
R
CHO
O
O
R
O
O
CHO
RO
O
CHO
Base
R
O
O
CHO
R
O
O
CHO
R
OH
OH
CHO
R
CHO
OH
OH
Case Studies Synthesis of the L-Hexoses
(Sharpless, Masamune)
HO
OH OH
CHO
OH OH
L-Glucose
Strategies for StereocontrolledSynthesis
Case Studies Synthesis of the L-Hexoses
(Sharpless, Masamune)HO
OH OH
CHO
OH OH
L-Glucose
Epoxide opening with hydroxide not always selective and would require awkward protection- deprotection steps
R OH
O
R
OH
OR OH
OH
OH
or
*StereocontrolledEpoxide Opening
Substrate
Control
!
*
**
*
*
Regiocontrolled openingwith inversion at C-2
Strategies for StereocontrolledSynthesis
Case Studies Synthesis of the L-Hexoses
(Sharpless, Masamune)HO
OH OH
CHO
OH OH
L-Glucose
Solution: use Payne Rearrangement of thiolateR OH
O
R
OH
OR OH
OH
OH
or
*StereocontrolledEpoxide Opening
Substrate
Control
!
*
**
*
*
Regiocontrolled openingwith inversion at C-2
R OH
O
R SPh
OHPhSHNaOH
OH
RO
OH
PayneRearrangement
Strategies for StereocontrolledSynthesis
Case Studies Synthesis of the L-Hexoses
(Sharpless, Masamune)HO
OH OH
CHO
OH OH
L-Glucose
Conversion of Payne product to aldehyde
R SPh
OH
OH
R SOPh
OR
OR
1) Protect2) m-CPBA
R SPh
OR
OR
OAc
NaOAc
Ac2O, !Pummerer
Rearrangement
RCHO
OR
OR
Hydrolyze(Base or hydride)
R OH
O
R
OH
OR OH
OH
OH
or
*StereocontrolledEpoxide Opening
Substrate
Control
!
*
**
*
*
Regioselective
Oxidation
"
R
OH
CHO
OH
*
*
Strategies for StereocontrolledSynthesis
Case Studies Synthesis of the L-Hexoses (Sharpless, Masamune)
RegioselectiveOxidation
!
R OH
R
OH
!
or
Stereocontrolled
Olefination
Substrate
Control
R OH
O
ROH
O
or
*StereocontrolledEpoxidation
ReagentControl
!
*
* *
R OH
OH
OH
StereocontrolledEpoxide Opening
Substrate
Control
!
*
*
Regiocontrolled openingwith inversion
Each cycle requires8 steps
RCHOR
OR
CHO
OR
*
*
Strategies for StereocontrolledSynthesis
Case Studies Synthesis of the L-Hexoses
(Sharpless, Masamune)HO
OH OH
CHO
OH OH
L-Glucose
OHHO OHPh2CHO
O
OH
Ph
Ph
0.5 eq NaHDMF 0 °C 1 h
then
0.5 eq Ph2CHBr
88%
PCC, celiteCH2Cl2, rt
37%
NaBH4, MeOH-10 °C 2-3 h
O
SPh
Ph
Ph
OH
OH
1.3 eq PhSH0.5N NaOHaq t-BuOH! 3 h
71%
[80:20 regio in crude]
O
O
SOPhOPh
Ph
O
O
OAcOPh
Ph
SPh
Me2C(OMe)2
cat POCl3CH2Cl2
m-CPBACH2Cl2-78 °C
NaOAcAc2O! 8 h
93% overall
OPh
Ph
O
2 eq t-BuOOH1.2 eq Ti(Oi-Pr)4
1.5 eq (+) DIPTCH2Cl2 -20 °C 16 h
92%>95% ee
OH
Strategies for StereocontrolledSynthesis
Case Studies Synthesis of the L-Hexoses
(Sharpless, Masamune)HO
OH OH
CHO
OH OH
L-Glucose
O
O
OPh
Ph
OH
1.2 eq Ph3P=CHCHOPhH, rt 16 h
88%
NaBH4
MeOH-40 °C 3 h
91%
"Intermediate A"
O
O
OAcOPh
Ph
SPh
O
O
CHOOPh
Ph
O
O
CHOOPh
Ph
2.15 eq DIBALCH2Cl2
-78 °C 30 min
91%
2.5 eq K2CO3
MeOHrt 16 h
100%
"erythro"
"threo"
93% overall
O
OPh
Ph
SPh
OH
OH
O
[70:30 regio in crude]
PhSH, NaOH
H2O-t-BuOH
63%
O
O
OPh
Ph
OH
O
t-BuOOHTi(Oi-Pr)4, (-)-DIT
CH2Cl2, -20 °C 16 h
84% >95% ee
Strategies for StereocontrolledSynthesis
Case Studies Synthesis of the L-Hexoses
(Sharpless, Masamune)
HO
OH OH
CHO
OH OH
L-Glucose
O
OPh
Ph
OAc
O
O SPhO
O
OPh
Ph
SPh
OH
OHO
O
OPh
Ph
SPh
O
OO
OMe
cat CSA, CH2Cl2
rt 30 min
1) m-CPBA CH2Cl22) NaOAc Ac2O, !
90%
OH
HO CHO
OH
OH OH 20%
1) 90% TFA H2O, rt 10 min2) H2, 10% Pd/C MeOH
OH
HO CHO
OH
OH OH
1) 90% TFA H2O, rt 10 min2) H2, 10% Pd/C MeOH
95%L-Mannose
L-Glucose
O
OPh
Ph
CHO
O
O O
DIBAL
CH2Cl2
95%
O
OPh
Ph
CHO
O
O O
K2CO3
MeOH
60%
19 stepsin each route
Strategies for StereocontrolledSynthesis
Case Studies Synthesis of the L-Hexoses
(Sharpless, Masamune)
HO
OH OH
CHO
OH OH
L-Glucose
O
O
OPh
Ph
OH
O
O
OPh
Ph
OH
O
O
OPh
Ph
SPh
OH
OHO
"Intermediate A"
t-BuOOHTi(Oi-Pr)4, (+)-DIT
76%
>95% ee
PhSH, NaOHH2O-t-BuOH
[94:6 regio in crude]
Strategies for StereocontrolledSynthesis
Case Studies Synthesis of the L-Hexoses
(Sharpless, Masamune)
HO
OH OH
CHO
OH OH
L-Glucose
L-Allose
L-Altrose
O
OPh
Ph
SPh
OH
OHO
OMe
cat CSA, CH2Cl2
O
OPh
Ph
OAc
O
O SPhO90%
m-CPBA
CH2Cl2
NaOAcAc2O, !
O
OPh
Ph
CHO
OOH
HO CHO
OH
O OOH OH
DIBALCH2Cl2
81%1) 90% TFA H2O, rt 10 min2) H2, 10% Pd/C MeOH
90%
O
OPh
Ph
CHO
OOH
HO CHO
OH
O OOH OH
K2CO3
MeOH
48%
1) 90% TFA H2O, rt 10 min2) H2, 10% Pd/C MeOH19 steps
in each route