Strategies for Stereocontrolled
Synthesis
Chemistry 5.511
Synthetic Organic Chemistry II
Lecture 4
October 12, 2007
Rick L. Danheiser
Massachusetts Institute of Technology
Strategies for Stereocontrolled
Synthesis
! Thermodynamic control strategies
" What determines the relative E of stereoisomers
" Tactics for establishing thermodynamic control
O
S
HO
N
O
O
OH O
epothilone A
Strategies for Stereocontrolled
Synthesis
! Thermodynamic control strategies
" What determines the relative E of stereoisomers
" Tactics for establishing thermodynamic control
! Kinetic control strategies
" Substrate control strategies
" Reagent control strategies
" Dynamic kinetic resolution
Strategies for Stereocontrolled
Synthesis
! Thermodynamic control strategies
! Kinetic control strategies
" Substrate control strategies
# Steric approach control
# Stereoelectronic control
# Internal stereodirection and chirality transfer
" Reagent control strategies
# Achiral substrate: enantiotopic face selectivity
# Achiral substrate: enantiotopic group selectivity
# Chiral substrate: double asymmetric synthesis
" Dynamic kinetic resolution
Strategies for Stereocontrolled
Synthesis
Substrate Kinetic Control Strategies
Steric Approach Control
m-CPBA
CH2Cl2
O
Strategies for Stereocontrolled
Synthesis
Substrate Kinetic Control Strategies
Cyclohexane
A Values
(kcal/mol)
F
Cl
Br
I
0.25-0.42
0.53-0.64
0.48-0.67
0.47-0.61
OMe
OAc
OSiMe3
0.55-0.75
0.68-0.87
0.74
NH2
NMe2
1.23-1.7
1.5-2.1
CH3
Et
i-Pr
t-Bu
Vinyl
Ethynyl
Ph
1.74
1.70
2.21
4.7-4.9
1.5-1.7
0.41-0.52
2.8
CN
CHO
CH2OH
COMe
CO2Me
0.2
0.56-0.8
1.76
1.0-1.5
1.2-1.3
SiMe3
2.5
Strategies for Stereocontrolled
Synthesis
! Thermodynamic control strategies
! Kinetic control strategies
" Substrate control strategies
# Steric approach control
# Stereoelectronic control
# Internal stereodirection and chirality transfer
" Reagent control strategies
# Achiral substrate: enantiotopic face selectivity
# Achiral substrate: enantiotopic group selectivity
# Chiral substrate: double asymmetric synthesis
" Dynamic kinetic resolution
Strategies for Stereocontrolled
Synthesis
Substrate Kinetic Control Strategies
Non-covalent internal stereodirection
Z
Z
m-CPBA
benzene
R'
R'
O
R'
H
H
H
H
OH
Z
H
OH
OMe
OAc
H
Rel. Rate
1.0
0.55
0.067
0.046
0.42
Major Product
syn (10:1)
anti
anti (20:80)
ca. 1 : 1
H. B. Henbest and R. A. Wilson
J. Chem. Soc. 1959, 1958
Review on “Substrate Directable Reactions”
Hoveyda, A. H.; Evans, D. A.; Fu, G. C.
Chem. Rev. 1993, 93, 1307
Strategies for Stereocontrolled
Synthesis
Substrate Kinetic Control Strategies
Chirality Transfer
CH3C(OEt)3
cat. EtCO2H
140 °C
OEt
HO
O
(via
(via
Lis-BuBH
LAH reduction)
3 reduction)
CO2Et
Johnson Orthoester Claisen Rearrangement
See Langlois, Y. In The Claisen Rearrangement, Hiersemann, M.;
Nubbemeyer, U., Eds.; Wiley-VCH, 2007, pp 301-366
Strategies for Stereocontrolled
Synthesis
! Thermodynamic control strategies
! Kinetic control strategies
" Substrate control strategies
# Steric approach control
# Stereoelectronic control
# Internal stereodirection and chirality transfer
" Reagent control strategies
# Achiral substrate: enantiotopic face selectivity
# Achiral substrate: enantiotopic group selectivity
# Chiral substrate: double asymmetric synthesis
" Dynamic kinetic resolution
Strategies for Stereocontrolled
Synthesis
Reagent Kinetic Control Strategies
Achiral Substrate: Enantiotopic Face Selectivity
Katsuki-Sharpless Asymmetric Epoxidation
Strategies for Stereocontrolled
Synthesis
Reagent Kinetic Control Strategies
Katsuki-Sharpless Asymmetric Epoxidation
Strategies for Stereocontrolled
Synthesis
Reagent Kinetic Control Strategies
Achiral Substrate: Enantiotopic Face Selectivity
Katsuki-Sharpless Asymmetric Epoxidation
OH
t-BuOOH, Ti(Oi-Pr)4
(-)-DET, CH2Cl2
OH
O
92% ee
(96 : 4)
Reviews on Asymmetric Epoxidation
"C atalytic Asymmetric Ep oxidation of Allylic Alcohols" Johnson, R. A.; Sharp less, K. B. In C atalytic
Asymmetric Synthesis; Ojima, I., Ed.; W iley-VC H, 2000, p p 231-285
"Asymmetric Ep oxidation of Unfunctionalized Olefins and Related Reactions" Katsuki, T. In C atalytic
Asymmetric Synthesis; Ojima, I., Ed.; W iley-VC H, 2000, p p 287-326.
"Asymmetric Ep oxidation of Allylic Alcohols: The Katsuki-Sharp less Ep oxidation Reaction", Katsuki, T.;
Martin, V. S. Org. Reactions 1996, 48, 1.
Strategies for Stereocontrolled
Synthesis
Reagent Kinetic Control Strategies
Katsuki-Sharpless Asymmetric Epoxidation
OH
t-BuOOH, Ti(Oi-Pr)4
(-)-DET, CH2Cl2
OH
O
! Reaction can be run as a stoichiometric (100 mol%) or catalytic (5-10 mol%) process
! For high enantioselectivities use excess of tartrate ligand (5% Ti and 6% tartrate)
! Catalytic reactions can be run up to 1.0 M in concentration; stoichiometric at 0.1 M
! TBHP should be as concentrated as possible (commercial 5.5 M preferred to 3.0 M)
! Use of activated molecular sieves greatly expanded the catalytic version
Strategies for Stereocontrolled
Synthesis
Reagent Kinetic Control Strategies
Katsuki-Sharpless Asymmetric Epoxidation
t-BuOOH, Ti(Oi-Pr)4
(-)-DET, CH2Cl2
OH
OH
O
Compatible Functional Groups
Acetals, ketals
Nitriles
Acetylenes
Nitro
Alcohols (remote)
Olefins
Aldehydes
Pyridines
Amides
Silyl ethers
Azides
Sulfones
Carboxylic Esters
Sulfoxides
Epoxides
Tetrazoles
Ethers
Ureas
Hydrazides
Urethanes
Ketones
Incompatible Groups
Amines (most)
Carboxylic acids
Mercaptans
Phenols (most)
Phosphines
Strategies for Stereocontrolled
Synthesis
Reagent Kinetic Control Strategies
Achiral Substrate: Enantiotopic Face Selectivity
Katsuki-Sharpless Asymmetric Epoxidation
Chiral Substrates
OH
t-BuOOH, Ti(Oi-Pr)4
(-)-DET, CH2Cl2
OH
O
OH
t-BuOOH, Ti(Oi-Pr)44
(-)-DET, CH22Cl22
OH
Am
Am
Am
Am
92% ee
(96 : 4)
OH
Am
t-BuOOH, Ti(Oi-Pr)4
(-)-DET, CH2Cl2
OH
Am
OH
+
O
67 : 33
Am
O
O
Strategies for Stereocontrolled
Synthesis
Reagent Kinetic Control Strategies
Achiral Substrate: Enantiotopic Group Selectivity
Review on enzymatic enantioselective group
desymmetrization:
V. Gotor Chem. Rev. 2005, 105, 313
Lipase-Based Desymmetrization Reactions
OAc
OAc
PPL
MeO2C
CO2Me
NHCO2Bn
60%
100%ee
OAc
OH
CO2Me
HO2C
CO2Me
NHCO2Bn
M. Ohno
J. Am. Chem. Soc. 1981, 103, 2405
J. Nokami
Tetrahedron Lett. 32, 2409, 1991
CO2Me
PLE
93%
96%ee
PLE
98%
96%ee
Baker's yeast
sucrose
H2O
O
CO2H
CO2Me
O
47-52%
96-98.8% ee
O
OH
K. Mori and H. Mori
Org. Synth. Coll. Vol. 8, 312, 1993
M. Ohno
Tetrahedron Lett. 1984, 25, 2557
Another example of biotransformations in asymmetric synthesis
Strategies for Stereocontrolled
Synthesis
Reagent Kinetic Control Strategies
Achiral Substrate: Enantiotopic Group Selectivity
Coupled to Kinetic Resolution
BnO
Li
1) HCO2Me
2) RedAl
OH
OH
OBn
OBn
OBn
OH
O
A
OBn
OBn
70-80%
OBn
OBn
OH
O
ent-B
OBn
1 h 93% ee
44 h >97% ee
OH
O
B
O
OBn
>97% de
( [A + ent-A]/[B + ent-B] )
S. L. Schreiber
J. Am. Chem. Soc. 1987, 109, 1525
OH
AE
(-)-DIPT
OBn
OBn
O
ent-A
OBn
Strategies for Stereocontrolled
Synthesis
! Thermodynamic control strategies
! Kinetic control strategies
" Substrate control strategies
# Steric approach control
# Stereoelectronic control
# Internal stereodirection and chirality transfer
" Reagent control strategies
# Achiral substrate: enantiotopic face selectivity
# Achiral substrate: enantiotopic group selectivity
# Chiral substrate: double asymmetric synthesis
" Dynamic kinetic resolution
Strategies for Stereocontrolled
Synthesis
Reagent Kinetic Control Strategies
Chiral Substrate: Double Asymmetric Synthesis
O
O
OH
Ti(OiPr)4
O
O
TBHP
Ph
O
OH
O
Ph
O
O
OH
O
2.3 : 1
Ti(OiPr)4
TBHP
(+)-DET
O
+
OH
OH
O
+
99 : 1
Ph
O
OH
O
Strategies for Stereocontrolled
Synthesis
Reagent Kinetic Control Strategies
Chiral Substrate: Double Asymmetric Synthesis
O
O
OH
Ti(OiPr)4
TBHP
O
O
O
“mismatched”
O
OH
Ti(OiPr)4
TBHP
OH
O
1 : 22
calcd
(1 : 43)
O
O
OH
O
(-)-DET
“matched”
Selectivity Benchmarks
O
O
(+)-DET
O
+
OH
+
O
O
90 : 1
OH
O
Useful selectivity
Double asymmetric synthesis
(227 : 1)
91:9 (10:1)
98:2 (50:1)
Strategies for Stereocontrolled
Synthesis
Reagent Kinetic Control Strategies
Chiral Substrate: Double Asymmetric Synthesis
"What changes may organic synthesis undergo? . . . . With appropriate
chiral reagents and catalysts at hand, the synthetic design of many natural
(and unnatural) products will become straightforward, and as a result
some of the aesthetic elements of traditional organic synthesis, as
exemplified by the synthesis of erythronolide A in Section 7, may well be
lost. . . . . However, the power of the new strategy has already made
possible what appeared to be almost impossible even a few years ago. In
this sense a new era which is characterized by the evolution from
substrate-controlled to reagent-controlled organic synthesis is definitely
emerging."
S. Masamune et al., "Double Asymmetric
Synthesis and a New Strategy for
Stereochemical Control in Organic Synthesis",
Angew. Chem. Int. Ed. 1985, 24, 1.
Strategies for Stereocontrolled
Synthesis
Reagent Kinetic Control Strategies
Chiral Substrate: Double Asymmetric Synthesis
Comparison of Substrate and Reagent Control Strategies
“ . . . . Less commendable is the use of this insightful new chemistry as a
platform for offering futuristic and murky pontifications about “reagent control”
vs. “substrate control” as strategic frameworks in stereospecific synthesis. In
the opinion of this reader, the substantive importance of this distinction has
been vastly overstated. Clearly in many instances so-called substrate control
works very well. In other cases, where the stereochemical connectivity
between the “in place” stereogenicity, and the stereogenicity to be created is
tenuous, recourse to so-called “reagent control” may be the only solution. To
debate, as an abstract matter, the general superiority of one method over the
other is not unlike debating whether steamship transportation or rail
transportation is the more effective. Obviously, this is a type of circumstancedependent question which does not permit a general resolution. It must be
handled on a case-to-case basis by sensible people.”
Samuel Danishefsky
C&EN August 26, 1985
Strategies for Stereocontrolled
Synthesis
Reagent Kinetic Control Strategies
Chiral Substrate: Double Asymmetric Synthesis
Comparison of Substrate and Reagent Control Strategies
Advantages
Disadvantages
Substrate
Control
! Exploits resident chirality
Reagent
Control
! Same strategy sometimes applicable
to synthesis of both epimers
! Not applicable if substrate has strong
bias
! Applicable to substrates with low bias
! Requires reagents with very strong
bias
! Requires strong bias in substrate
! Different strategy needed for each
epimer
Strategies for Stereocontrolled
Synthesis
Reagent Kinetic Control Strategies
Chiral Substrate: Double Asymmetric Synthesis
Comparison of Substrate and Reagent Control Strategies
OH
O
CH3MgBr
CH3
Strategies for Stereocontrolled
Synthesis
Reagent Kinetic Control Strategies
Chiral Substrate: Double Asymmetric Synthesis
Comparison of Substrate and Reagent Control Strategies
O
1) Ph3P=CH2
2) m-CPBA
3) LiAlH4
CH3
OH
Strategies for Stereocontrolled
Synthesis
! Thermodynamic control strategies
! Kinetic control strategies
" Substrate control strategies
# Steric approach control
# Stereoelectronic control
# Internal stereodirection and chirality transfer
" Reagent control strategies
# Achiral substrate: enantiotopic face selectivity
# Achiral substrate: enantiotopic group selectivity
# Chiral substrate: double asymmetric synthesis
" Dynamic kinetic resolution
Strategies for Stereocontrolled
Synthesis
Kinetic Control Strategies
Classical Kinetic Resolution
B*chiral
A
+
ent-A
k1 FAST
A-B*
B*chiral
k2 SLOW
ent-A-B*
Strategies for Stereocontrolled
Synthesis
Kinetic Control Strategies
Classical Kinetic Resolution
B*chiral
A
+
ent-A
k1 FAST
A-B*
B*chiral
k2 SLOW
ent-A-B*
Strategies for Stereocontrolled
Synthesis
Kinetic Control Strategies
Classical Kinetic Resolution
B*chiral
k1 FAST
A-B*
ent-A
s = k1/k2
10
B*chiral
k2 SLOW
Selectivity
Factor
ent-A-B*
50
Strategies for Stereocontrolled
Synthesis
Kinetic Control Strategies
Dynamic Kinetic Resolution
B*chiral
A
FAST
ent-A
FAST
A-B*
B*chiral
SLOW
ent-A-B*
Review: H. Pellissier Tetrahedron 2003, 59, 8291
Strategies for Stereocontrolled
Synthesis
General Strategies for the Stereocontrolled
Synthesis of Acyclic Target Molecules
" Chiron Approach
" Ring Template Approach
" Chirality Transfer
" Acyclic Asymmetric Synthesis
Strategies for Stereocontrolled
Synthesis
! Thermodynamic Control Strategies
! Kinetic Control Strategies
! Strategies for the Synthesis of Acyclic
Target Molecules: Case Studies
" Prostaglandins from Sugars (Stork)
Strategies for Stereocontrolled
Synthesis
General Strategies for the Stereocontrolled
Synthesis of Acyclic Target Molecules
" Chiron Approach
" Ring Template Approach
" Chirality Transfer
" Acyclic Asymmetric Synthesis
Strategies for Stereocontrolled
Synthesis
Case Studies
(2) Prostaglandins from Sugars (Stork)
OH
O
CO2H
CO2H
9
8
11
HO
12
13
OH
Prostaglandin A2
6
5
14
15
OH
Prostaglandin F2!
G. Stork and S. Raucher J. Am. C hem. Soc. 1976, 98, 1583
G. Stork, T. Takahashi, I. Kawamoto, and T. Suzuki J. Am. C hem. Soc. 1978, 100, 8272
For discussions of the use of chiral natural p roducts as starting materials for the synthesis of comp lex molecules, see
(1) S. Hanessian "Total Synthesis of Natural Products: The 'C hiron Ap p roach' ", Pergamon Press: Oxford, 1983.
(2) T.-L. Ho "Enantioselective Synthesis: Natural Products from C hiral Terp enes", W iley Interscience: New York, 1992.
Strategies for Stereocontrolled
Synthesis
Case Studies
(2) Prostaglandins from Sugars (Stork)
G. Stork and S. Raucher J. Am. C hem. Soc. 1976, 98, 1583
G. Stork, T. Takahashi, I. Kawamoto, and T. Suzuki J. Am. C hem. Soc. 1978, 100, 8272
Strategies for Stereocontrolled
Synthesis
Case Studies
(2) Prostaglandins
from Sugars (Stork)
OH
CO2H
9
8
11
HO
12
13
6
14
5
15
OH
Prostaglandin F2!
Strategies for Stereocontrolled
Synthesis
Case Studies
O
(2) Prostaglandins from Sugars
(Gilbert Stork)
CO2H
OH
! Install C-8 side chain by enolate alkylation
! Thermodynamic control of stereochemistry at C-8
O
CO2R
X
R1
Prostaglandin A2
Strategies for Stereocontrolled
Synthesis
Case Studies
OH
(2) Prostaglandins from Sugars
(Gilbert Stork)
CO2H
9
8
6
11
12
HO
14
13
5
15
OH
Prostaglandin F2!
! Install C-8 side chain by enolate alkylation
! Thermodynamic control of stereochemistry at C-8
! [For PGF2!] C-9 stereochemistry by steric approach substrate control
O
H
CO2R
X
RO
O
R2
R1
1
R
Strategies for Stereocontrolled
Synthesis
Case Studies
OH
(2) Prostaglandins from Sugars
(Gilbert Stork)
CO2H
9
8
6
11
HO
12
13
14
5
15
OH
Prostaglandin F2!
! Form cyclopentanone from
acyclic precursor by nucleophilic cyclization
X
O
EWG
R2
12
New
Subtargets
O
X
R2
12
RO
R1
R1
umpolung
CO2R
(R2)
RO2C
or
CO2R
(R2)
Am
12
OR
X
Am
12
OR
OR
Strategies for Stereocontrolled
Synthesis
Case Studies
OH
(2) Prostaglandins from Sugars
(Gilbert Stork)
CO2H
9
8
6
11
12
HO
13
14
5
15
OH
Prostaglandin F2!
! The “sugar connection”: requires
translation of C-OH stereogenic centers into C-C centers
CO2R
(R2)
New
Subtargets
RO2C
CO2R
(R2)
Am
12
X
OR
OR
OH
HO
Am
12
OH
Sugars as
starting materials
C
H
OR
n
Strategies for Stereocontrolled
Synthesis
Case Studies
OH
(2) Prostaglandins from Sugars
(Gilbert Stork)
CO2H
9
8
6
11
HO
12
13
14
5
15
OH
! Set C-12 stereochemistry by
Prostaglandin F2!
chirality transfer via [3,3] sigmatropic rearrangement
CO2R
(R2)
Subtargets
RO2C
Am
12
X
OR
Z
(R) !
$
#
(R)
Am
12
OR
OR
Z
O
"
CO2R
(R2)
O
OH
"
$
#
Retron for [3,3] sigmatropic shift: #,$-unsaturated carbonyl compound
Strategies for Stereocontrolled
Synthesis
Case Studies
OH
(2) Prostaglandins from Sugars
(Gilbert Stork)
CO2H
9
8
11
12
HO
13
6
14
5
15
OH
! Set C-12 stereochemistry by
Prostaglandin F2!
chirality transfer via [3,3] sigmatropic rearrangement
CO2R
(R2)
Previous
subtargets
RO2C
Am
12
X
OR
New
Subtargets
CO2R
(R2)
Am
12
OR
OR
OH
OH
12
12
Am
RO2C
Am
X
OR
OR
OR
Strategies for Stereocontrolled
Synthesis
Case Studies
(2) Prostaglandins from Sugars
(Gilbert Stork)
! Set C-12 stereochemistry by
chirality transfer via [3,3] sigmatropic rearrangement
top face
attack
H
H
COZ
H
Z
R1
O
OH
R1
H
Z
R2
R1
R2
O
R1
R2
R2
bottom face
attack
Z
R2
Z
R1
O
R2
H
H
O
H
R1
COZ
R2
H
R1
Strategies for Stereocontrolled
Synthesis
Case Studies
OH
(2) Prostaglandins from Sugars
(Gilbert Stork)
CO2H
9
8
6
11
12
HO
13
5
14
15
OH
! Set C-12 stereochemistry by
Prostaglandin F2!
chirality transfer via [3,3] sigmatropic rearrangement
CO2R
(R2)
Previous
subtargets
RO2C
CO2R
(R2)
Am
12
X
Am
12
OR
OR
OR
OH
New
Subtargets
OH
12
12
Am
RO2C
Am
X
OR
OR
OR
Strategies for Stereocontrolled
Synthesis
Case Studies
O
CO2H
(2) Prostaglandins from Sugars (Stork)
OH
For PGA2
OH
RO2C
OR2
[3,3]
12
12
Am
"
OR2
Am
#
OR
OH
L-erythrose
Am
OHC
OR1
OR1
OR2
OH
OHC
OH
OH
Prostaglandin A2
+
OHC
Bu2CuLi
OTs
1
OR
Strategies for Stereocontrolled
Synthesis
Case Studies
OH
(2) Prostaglandins from Sugars
(Gilbert Stork)
CO2H
9
8
6
11
12
HO
13
5
14
15
OH
For PGF2!
OH
OH
Am
X
OR
Prostaglandin F2!
OR
Am
RO
OR
OR
1,2-deoxygenation
OH
OR
(both ! or ")
R1O
OR2
OR1
OH
OH
OR1
OH
OH
HO
D-Glycero-D-guloheptono-1,4-lactone
One step from D-glucose
OR1
OH
OH
O
O
Strategies for Stereocontrolled
Synthesis
Case Studies
O
CO2H
(2) Prostaglandins from Sugars (Stork)
Total Synthesis of PGA2
O
HO
O
H2C=CHMgCl
THF-CH2Cl2
0° 4 h
O
O
OH
O
ClCO2Me
pyr, -30!0°
OH
96%
OH
Prostaglandin A2
OCO2Me
OH
O
O
10 eq CH3C(OMe)3
cat EtCO2H
140° 72 h
OH
O
25% aq AcOH
120° 1 h
MeO2C
OCO2Me
OH
MeO2C
OCO2Me
83%
O
Strategies for Stereocontrolled
Synthesis
Case Studies
O
CO2H
(2) Prostaglandins from Sugars (Stork)
Total Synthesis of PGA2
OH
Prostaglandin A2
OH
1 eq Et3N
CH2Cl2 rt 1 h
MeO2C
OCO2Me
OH
OH
MeO2C
O
O
O
0.1 eq K2CO3
MeOH
rt 30 min
xyl 160° 1 h
2 eq
59% overall
(MeO)3C
MeO2C 1:1
CO2Me
H
MeO2C
OH
H
OH
CO2Me
Strategies for Stereocontrolled
Synthesis
Case Studies
O
CO2H
(2) Prostaglandins from Sugars (Stork)
Total Synthesis of PGA2
MeO2C 1:1
CO2Me
H
MeO2C
OH
1) H2, Pd-BaSO4
MeOH
2) TsCl, pyr
-20° 7 d
3) EVE
OH
H
Prostaglandin A2
MeO2C
CO2Me
H
MeO2C
OH
OTs
OCH(Me)OEt
79%
5 eq Bu2CuLi
Et2O
-40° 2 h
O
CO2H
0.5 N NaOH
! 10 min
Am
77%
OCH(Me)OEt
10 eq KOt-Bu
THF
rt 45 min
MeO2C
H
MeO2C
CO2Me
Am
OCH(Me)OEt
67%
Strategies for Stereocontrolled
Synthesis
Case Studies
O
CO2H
(2) Prostaglandins from Sugars (Stork)
Total Synthesis of PGA2
OH
Prostaglandin A2
O
O
4 eq NaIO4
MeOH
rt
2.2 eq LDA
THF
3 eq PhSeCl
CO2H
Am
CO2H
H3O+
Am
OH
OCH(Me)OEt
Prostaglandin A2
16 steps in the longest
linear sequence
Strategies for Stereocontrolled
Synthesis
Case Studies
OH
(2) Prostaglandins from Sugars (Stork)
CO2H
9
8
6
11
12
HO
13
14
Total Synthesis of PGF2!
OH
O
HO
HO
HO
OH
10
HCN
HO
11
12
OH
OH
O
14
15
OH
OH
13
5
O
15
NaBH4
aq 10% H2SO4
90%
OH
acetone
H+
Prostaglandin F2!
OH
75%
O
OH
O
O
D-glucose
O
O
commercially available
NaBH4
MeOH
10 °C 1.5 h
D-Glycero-D-guloheptono-1,4-lactone
Ac2O, pyr
CH2Cl2
-7 °C 18 h
OH
HO
O
OH
1) K2CO3, MeOH
2) ClCO2Me, pyr
3) CuSO4, aq MeOH
4) PhH, !
O
O
O
OAc
O
O
O
OH
1) Me2NCH(OMe)2
2) Ac2O, !
O
OAc
O
40% overall
O
OH
O
Strategies for Stereocontrolled
Synthesis
Case Studies
OH
CO2H
9
(2) Prostaglandins from Sugars (Stork)
8
11
12
HO
13
6
5
14
15
Total Synthesis of PGF2!
OH
Prostaglandin F2!
OH
HO
O
O
OH
O
acetone
cat H2SO4
OH
O
O
O
O
CO2Me
CH3(OMe)3
cat EtCO2H
!
O
O
O
O
54% overall
OTs
O
O
O
80%
CO2Me
1) K2CO3, MeOH
2) TsCl, pyr
3) EVE
O
1) 10 eq Bu2CuLi
Et2O, -40 °C 2 h
2) aq H2SO4
THF, rt 15 h
O
Am
OR
O
LiHMDS
RBr
THF-HMPA
OSit-BuPh2
O
RO
OR
EVE
O
HO
Am
35% overall
71%
OR = OC(H)MeOEt
OH
Strategies for Stereocontrolled
Synthesis
Case Studies
OH
CO2H
9
(2) Prostaglandins from Sugars (Stork)
8
11
12
HO
13
6
5
14
Total Synthesis of PGF2!
15
OH
Prostaglandin F2!
O
OSit-BuPh2
O
DIBAL
RO
HCN
EtOH
-10 °C
NC
50% aq AcOH
THF, 35 °C
OH
OSiR3
HO
Am
HO
Am
OR
OH
OR = OC(H)MeOEt
1.5 eq TsCl
pyr, -15 °C
NC
OR
OSit-BuPh2
6 eq KHMDS
benzene
! 5h
OH
OSiR3
TsO
Am
RO
NC
HO
EVE
Am
72%
OR
OH
37% overall
Strategies for Stereocontrolled
Synthesis
Case Studies
OH
CO2H
9
(2) Prostaglandins from Sugars (Stork)
8
11
12
HO
13
Total Synthesis of PGF2!
NC
6
14
5
15
OH
Prostaglandin F2!
OR
OSit-BuPh2
Am
RO
OR = OC(H)MeOEt
OR
31 steps in the longest
linear sequence
1) TBAF, THF
2) Collins Ox
3) AgNO3, KOH
aq EtOH
NC
OR
CO2H
AcOH
H2O-THF
40 °C 5 h
OH
Lis-Bu3BH
THF, -78 °C 1.5 h
Am
RO
CO2H
73%
HO
OR
OH
Prostaglandin F2!
Strategies for Stereocontrolled
Synthesis
[1,3] O$C Chirality Transfer
CO2R
OH
3
R1
R2
*1
2
*
R1 3
1
R2
2
X Y
X Y
[1,3] O$N Chirality Transfer
OH
3
R1
*1
NR2
R2
2
X Y
*
R1 3
1
R2
2
X Y
Review of chirality transfer via sigmatropic rearrangements
Hill, R. K. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: Orlando, 1984; Vol. 3, pp 503-572
Strategies for Stereocontrolled Synthesis
[1,3] O$N
Chirality Transfer
OH
3
R1
NR2
R2
*1
*
R1 3
2
1
R2
2
X Y
X Y
Overman Rearrangement
of Allylic Trihaloacetimidates
KH, CCl3CN
Et2O
BnO
140 °C
xylene
BnO
HN
HN
O
OH
45% overall
CCl3
Bu
OSiR3
OH
BnO
1) DBU, CCl3CN
CH2Cl2
2) 1% PdCl2(PhCN)2
benzene, rt
Review: Overman, L. E.; Carpenter, N. E. Org. React. 2005, 66, 1
Bu
72%
CCl3
O
OSiR3
NHCOCCl3