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TRANSCRIPT
Strategies for Stereocontrolled
Synthesis
Lecture 4
October 12, 2007
Rick L. Danheiser
Massachusetts Institute of Technology
Chemistry 5.511
Synthetic Organic Chemistry II
Strategies for Stereocontrolled
Synthesis
! Thermodynamic control strategies
" What determines the relative E of stereoisomers
" Tactics for establishing thermodynamic control
O
O OOH
HO
O
N
S
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
O
m-CPBA
CH2Cl2
Strategies for Stereocontrolled
Synthesis
Substrate Kinetic Control Strategies
Cyclohexane
A Values
(kcal/mol)
F
Cl
Br
I
OMe
OAc
OSiMe3
NH2NMe2
CH3Et
i-Pr
t-Bu
Vinyl
Ethynyl
Ph
CN
CHO
CH2OH
COMe
CO2Me
SiMe3
0.25-0.42
0.53-0.64
0.48-0.67
0.47-0.61
0.55-0.75
0.68-0.87
0.74
1.23-1.7
1.5-2.1
1.74
1.70
2.21
4.7-4.9
1.5-1.7
0.41-0.52
2.8
0.2
0.56-0.8
1.76
1.0-1.5
1.2-1.3
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
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
Z
m-CPBAbenzene
Z
ZH
OHOMeOAc
H
Rel. Rate1.00.550.0670.0460.42
R' R'
R'HHHH
OH
Major Product-
syn (10:1)anti
anti (20:80)ca. 1 : 1
O
Strategies for Stereocontrolled
Synthesis
Substrate Kinetic Control Strategies
Chirality Transfer
HO
CO2Et
CH3C(OEt)3cat. EtCO2H
140 °C
Johnson Orthoester Claisen Rearrangement
See Langlois, Y. In The Claisen Rearrangement, Hiersemann, M.;
Nubbemeyer, U., Eds.; Wiley-VCH, 2007, pp 301-366
HO
CO2Et
CH3C(OEt)3cat. EtCO2H
140 °C
O
OEt
(via LAH reduction)(via Lis-BuBH3 reduction)
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
Reviews on Asymmetric Epoxidation
"Catalytic Asymmetric Epoxidation of Allylic Alcohols" Johnson, R. A.; Sharp less, K. B. In CatalyticAsymmetric Synthesis; Ojima, I., Ed.; W iley-VCH, 2000, pp 231-285
"Asymmetric Epoxidation of Unfunctionalized Olefins and Related Reactions" Katsuki, T. In CatalyticAsymmetric Synthesis; Ojima, I., Ed.; W iley-VCH, 2000, pp 287-326.
"Asymmetric Epoxidation of Allylic Alcohols: The Katsuki-Sharp less Epoxidation Reaction", Katsuki, T.;
Martin, V. S. Org. Reactions 1996, 48, 1.
OH t-BuOOH, Ti(Oi-Pr)4(-)-DET, CH2Cl2
OH
O
92% ee
(96 : 4)
Strategies for Stereocontrolled
SynthesisReagent 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
SynthesisReagent Kinetic Control Strategies
Katsuki-Sharpless Asymmetric Epoxidation
OH t-BuOOH, Ti(Oi-Pr)4(-)-DET, CH2Cl2
OH
O
Compatible Functional GroupsAcetals, ketalsAcetylenesAlcohols (remote)AldehydesAmidesAzidesCarboxylic EstersEpoxidesEthersHydrazidesKetones
NitrilesNitroOlefinsPyridinesSilyl ethersSulfonesSulfoxidesTetrazolesUreasUrethanes
Incompatible GroupsAmines (most)Carboxylic acidsMercaptansPhenols (most)Phosphines
Strategies for Stereocontrolled
Synthesis
Reagent Kinetic Control Strategies
Chiral Substrates
Katsuki-Sharpless Asymmetric Epoxidation
OH t-BuOOH, Ti(Oi-Pr)4(-)-DET, CH2Cl2
OH
O
92% ee
(96 : 4)
OH t-BuOOH, Ti(Oi-Pr)4(-)-DET, CH2Cl2
OH
OAmAm
OH t-BuOOH, Ti(Oi-Pr)4(-)-DET, CH2Cl2
OH
OAmAm
OH
OAm
+
67 : 33
Achiral Substrate: Enantiotopic Face Selectivity
OH t-BuOOH, Ti(Oi-Pr)4(-)-DET, CH2Cl2
OH
OAmAm
OH t-BuOOH, Ti(Oi-Pr)4(-)-DET, CH2Cl2
OH
OAmAm
OH
OAm+
67 : 33
Strategies for Stereocontrolled
Synthesis
Reagent Kinetic Control Strategies
Achiral Substrate: Enantiotopic Group Selectivity
OAc
OAc
CO2Me
CO2Me
OAc
OH
CO2H
CO2Me
MeO2C
NHCO2Bn
CO2Me
O
O
HO2C
NHCO2Bn
CO2Me
OH
O
Baker's yeastsucrose
H2O
K. Mori and H. MoriOrg. Synth. Coll. Vol. 8, 312, 1993
47-52%96-98.8% ee
Lipase-Based Desymmetrization Reactions
PPL
60%100%ee
J. NokamiTetrahedron Lett. 32, 2409, 1991
PLE
93%96%ee
M. OhnoJ. Am. Chem. Soc. 1981, 103, 2405
PLE
98%96%ee
M. OhnoTetrahedron Lett. 1984, 25, 2557
Another example of biotransformations in asymmetric synthesis
Review on enzymatic enantioselective group desymmetrization:V. Gotor Chem. Rev. 2005, 105, 313
Strategies for Stereocontrolled
Synthesis
Reagent Kinetic Control Strategies
Achiral Substrate: Enantiotopic Group Selectivity
Coupled to Kinetic Resolution
OBn OBn
OH
BnO
Li
OBn OBn
OH
O
1) HCO2Me2) RedAl
AE(-)-DIPT
1 h 93% ee44 h >97% ee
S. L. SchreiberJ. Am. Chem. Soc. 1987, 109, 1525
70-80%
>97% de
( [A + ent-A]/[B + ent-B] )
OBn OBn
OH
O
ent-BOBn OBn
OH
O
BOBn OBn
OH
O
A ent-AOBn OBn
OH
O
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
Ph OOH
O
O OHO
O OH
O
Ph OOH
O
O
O OH
O
Ph OOH
O
Ti(OiPr)4
TBHP+
2.3 : 1
Ti(OiPr)4TBHP
(+)-DET
99 : 1
+
Strategies for Stereocontrolled
Synthesis
Reagent Kinetic Control Strategies
Chiral Substrate: Double Asymmetric Synthesis
Selectivity Benchmarks Useful selectivity 91:9 (10:1)
Double asymmetric synthesis 98:2 (50:1)
O
O OH
O
O OH
O
O
O OH
O
Ti(OiPr)4TBHP
(-)-DET
+
90 : 1(227 : 1)
“mismatched”
“matched”
O
O OH
O
O OH
O
O
O OH
O
Ti(OiPr)4
TBHP
(+)-DET
+
1 : 22 calcd(1 : 43)
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 forStereochemical 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 circumstance-
dependent 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
SubstrateControl
ReagentControl
Advantages Disadvantages
! Exploits resident chirality
! Same strategy sometimes applicable to synthesis of both epimers
! Applicable to substrates with low bias
! Requires strong bias in substrate
! Different strategy needed for each epimer
! Not applicable if substrate has strong bias
! Requires reagents with very strong bias
Comparison of Substrate and Reagent Control Strategies
Strategies for Stereocontrolled
Synthesis
Reagent Kinetic Control Strategies
Chiral Substrate: Double Asymmetric Synthesis
Comparison of Substrate and Reagent Control Strategies
O
CH3MgBr
OH
CH3
Strategies for Stereocontrolled
Synthesis
Reagent Kinetic Control Strategies
Chiral Substrate: Double Asymmetric Synthesis
Comparison of Substrate and Reagent Control Strategies
OCH3
OH
1) Ph3P=CH22) m-CPBA3) LiAlH4
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
A
+
ent-A
B*chiral
k1 FAST
B*chiral
k2 SLOW
A-B*
ent-A-B*
Strategies for Stereocontrolled
Synthesis
Kinetic Control Strategies
Classical Kinetic Resolution
A
+
ent-A
B*chiral
k1 FAST
B*chiral
k2 SLOW
A-B*
ent-A-B*
Strategies for Stereocontrolled
Synthesis
Kinetic Control Strategies
Classical Kinetic Resolution
Selectivity
Factor
s = k1/k2
10
50ent-A
B*chiral
k1 FAST
B*chiral
k2 SLOW
A-B*
ent-A-B*
Strategies for Stereocontrolled
Synthesis
Kinetic Control Strategies
Dynamic Kinetic Resolution
Review: H. Pellissier Tetrahedron 2003, 59, 8291
A
ent-A
B*chiral
B*chiral
SLOW
A-B*
ent-A-B*
FAST
FAST
Strategies for Stereocontrolled
Synthesis
" Chiron Approach
" Ring Template Approach
" Chirality Transfer
" Acyclic Asymmetric Synthesis
General Strategies for the Stereocontrolled
Synthesis of Acyclic Target Molecules
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
" Chiron Approach
" Ring Template Approach
" Chirality Transfer
" Acyclic Asymmetric Synthesis
General Strategies for the Stereocontrolled
Synthesis of Acyclic Target Molecules
Strategies for Stereocontrolled
Synthesis Case Studies
(2) Prostaglandins from Sugars (Stork)
O
CO2H
OH
OH
CO2H
OH
HO
Prostaglandin A2
568
9
1112
151314
Prostaglandin F2!
G. Stork and S. Raucher J. Am. Chem. Soc. 1976, 98, 1583
G. Stork, T. Takahashi, I. Kawamoto, and T. Suzuki J. Am. Chem. Soc. 1978, 100, 8272
For discussions of the use of chiral natural products as starting materials for the synthesis of complex molecules, see
(1) S. Hanessian "Total Synthesis of Natural Products: The 'Chiron Approach' ", Pergamon Press: Oxford, 1983.
(2) T.-L. Ho "Enantioselective Synthesis: Natural Products from Chiral Terpenes", W iley Interscience: New York, 1992.
Strategies for Stereocontrolled
Synthesis Case Studies
(2) Prostaglandins from Sugars (Stork)
G. Stork and S. Raucher J. Am. Chem. Soc. 1976, 98, 1583
G. Stork, T. Takahashi, I. Kawamoto, and T. Suzuki J. Am. Chem. Soc. 1978, 100, 8272
Strategies for Stereocontrolled
Synthesis Case Studies
(2) Prostaglandins from Sugars (Stork)
OH
CO2H
OH
HO
568
9
1112
151314
Prostaglandin F2!
Strategies for Stereocontrolled
Synthesis Case Studies
(2) Prostaglandins from Sugars (Gilbert Stork)
O
CO2H
OH
Prostaglandin A2
! Install C-8 side chain by enolate alkylation
! Thermodynamic control of stereochemistry at C-8
O
R1
CO2R
X
Strategies for Stereocontrolled
Synthesis Case Studies
(2) Prostaglandins from Sugars (Gilbert Stork)
! 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
R1
CO2R
X
R2
R1
RO
O
H
OH
CO2H
OH
HO
568
9
1112
151314
Prostaglandin F2!
Strategies for Stereocontrolled
Synthesis Case Studies
(2) Prostaglandins from Sugars (Gilbert Stork)
! Form cyclopentanone from
acyclic precursor by nucleophilic cyclization
OH
CO2H
OH
HO
568
9
1112
151314
Prostaglandin F2!
umpolung
RO2CAm
OR
CO2R(R2)
12 XAm
OR
CO2R(R2)
12
OR
New
Subtargets
R1
R2EWG
X
O
R1
R2X
O
or
RO12
12
Strategies for Stereocontrolled
Synthesis Case Studies
(2) Prostaglandins from Sugars (Gilbert Stork)
! The “sugar connection”: requires
translation of C-OH stereogenic centers into C-C centers
OH
CO2H
OH
HO
568
9
1112
151314
Prostaglandin F2!
RO2CAm
OR
CO2R(R2)
12 XAm
OR
CO2R(R2)
12
OR
New
Subtargets
C
H
OHHO OH
n
Sugars as
starting materials
Strategies for Stereocontrolled
Synthesis Case Studies
(2) Prostaglandins from Sugars (Gilbert Stork)
! Set C-12 stereochemistry by
chirality transfer via [3,3] sigmatropic rearrangement
OH
CO2H
OH
HO
568
9
1112
151314
Prostaglandin F2!
RO2CAm
OR
CO2R(R2)
12 XAm
OR
CO2R(R2)
12
OR
Subtargets
O(R)
Z
O(R)
Z
OH!
"
#$ $"
#
Retron for [3,3] sigmatropic shift: #,$-unsaturated carbonyl compound
Strategies for Stereocontrolled
Synthesis Case Studies
(2) Prostaglandins from Sugars (Gilbert Stork)
! Set C-12 stereochemistry by
chirality transfer via [3,3] sigmatropic rearrangement
OH
CO2H
OH
HO
568
9
1112
151314
Prostaglandin F2!
New
Subtargets RO2CAm
OR
12
XAm
OR
12
OR
OH OH
RO2CAm
OR
CO2R(R2)
12 XAm
OR
CO2R(R2)
12
OR
Previous
subtargets
Strategies for Stereocontrolled
Synthesis Case Studies
(2) Prostaglandins from Sugars (Gilbert Stork)
! Set C-12 stereochemistry by
chirality transfer via [3,3] sigmatropic rearrangement
R1
R2
OHO
H
R1
Z
H
R2
top faceattack
O
H
R1
Z
H
R2
R1
O
Z R2
H
Hbottom face
attack
R1
O
ZR2
HH
R1 R2
COZ
R1
R2COZ
Strategies for Stereocontrolled
Synthesis Case Studies
(2) Prostaglandins from Sugars (Gilbert Stork)
! Set C-12 stereochemistry by
chirality transfer via [3,3] sigmatropic rearrangement
OH
CO2H
OH
HO
568
9
1112
151314
Prostaglandin F2!
New
Subtargets RO2CAm
OR
12
XAm
OR
12
OR
OH OH
RO2CAm
OR
CO2R(R2)
12 XAm
OR
CO2R(R2)
12
OR
Previous
subtargets
Strategies for Stereocontrolled
Synthesis
Case Studies
(2) Prostaglandins from Sugars (Stork)
O
CO2H
OH
Prostaglandin A2For PGA2
RO2CAm
OR
12
OH[3,3]
Am
OR1
12
OR2
OH
OHCAm
OR1
OR2
OHC
OR1
OR2
OTs
Bu2CuLi
+
OHC
OH
OH
OH
L-erythrose
"#
Strategies for Stereocontrolled
Synthesis Case Studies
(2) Prostaglandins from Sugars (Gilbert Stork)
OH
CO2H
OH
HO
568
9
1112
151314
Prostaglandin F2!
For PGF2!
XAm
OROR
OH
ROAm
OROR
OROH
OH
(both ! or ")
1,2-deoxygenation R1O
OR1
OR1
OR1
OH
OH
OR2
HOOH
OH
OHOH
O
O
D-Glycero-D-guloheptono-1,4-lactone
One step from D-glucose
Strategies for Stereocontrolled
Synthesis
Case Studies
(2) Prostaglandins from Sugars (Stork)
O
CO2H
OH
Prostaglandin A2
Total Synthesis of PGA2
O
O O
HO
OCO2Me
OH
OH
MeO2C
OH
OH
O
O
OCO2Me
OH
O
O
OCO2Me
O
O
MeO2C
H2C=CHMgClTHF-CH2Cl2
0° 4 h
96%
ClCO2Mepyr, -30!0°
10 eq CH3C(OMe)3cat EtCO2H140° 72 h
83%
25% aq AcOH120° 1 h
Strategies for Stereocontrolled
Synthesis
Case Studies
(2) Prostaglandins from Sugars (Stork)
O
CO2H
OH
Prostaglandin A2
Total Synthesis of PGA2
OH
MeO2C
O
O
O
(MeO)3CCO2Me
OCO2Me
OH
OH
MeO2C
MeO2C OHH
MeO2CCO2Me
H
OH
1 eq Et3NCH2Cl2 rt 1 h
1:1
xyl 160° 1 h
0.1 eq K2CO3
MeOHrt 30 min
59% overall2 eq
Strategies for Stereocontrolled
Synthesis
Case Studies
(2) Prostaglandins from Sugars (Stork)
O
CO2H
OH
Prostaglandin A2
Total Synthesis of PGA2
Am
CO2H
OCH(Me)OEt
O
MeO2C OTs
MeO2CCO2Me
H
OCH(Me)OEt
AmMeO2C
MeO2CCO2Me
H
OCH(Me)OEt
1) H2, Pd-BaSO4
MeOH2) TsCl, pyr -20° 7 d3) EVE
5 eq Bu2CuLiEt2O
-40° 2 h
79%
67%
10 eq KOt-BuTHF
rt 45 min
0.5 N NaOH! 10 min
77%
MeO2C OHH
MeO2CCO2Me
H
OH
1:1
Strategies for Stereocontrolled
Synthesis
Case Studies
(2) Prostaglandins from Sugars (Stork)
O
CO2H
OH
Prostaglandin A2
Total Synthesis of PGA2
Am
CO2H
OH
O
H3O+
Am
CO2H
OCH(Me)OEt
O2.2 eq LDA
THF3 eq PhSeCl
4 eq NaIO4
MeOHrt
Prostaglandin A2
16 steps in the longest
linear sequence
Strategies for Stereocontrolled
Synthesis
Case Studies
(2) Prostaglandins from Sugars (Stork)
Total Synthesis of PGF2!
OH
CO2H
OH
HO
568
9
1112
151314
Prostaglandin F2!
OAc
OH
O
O
OH
O
O
O
O
O
O
O
OH OH
OAc
O
O
O
O
OH
O
O
O
HO
OH
O
OH
OH
OH O
OH
HOHCN
O
OH
HOHO
HOOH
D-glucose
NaBH4
aq 10% H2SO4
acetoneH+
90% 75%
NaBH4
MeOH10 °C 1.5 h
Ac2O, pyrCH2Cl2
-7 °C 18 h
1) Me2NCH(OMe)22) Ac2O, !
1) K2CO3, MeOH2) ClCO2Me, pyr3) CuSO4, aq MeOH
4) PhH, !40% overall
commercially available
D-Glycero-D-guloheptono-1,4-lactone
1011
1213
1415
Strategies for Stereocontrolled
Synthesis
Case Studies
(2) Prostaglandins from Sugars (Stork)
Total Synthesis of PGF2!
OH
CO2H
OH
HO
568
9
1112
151314
Prostaglandin F2!
OH
O
O
O
O
OO
O
O
O
O
CO2Me
O
O
CO2Me
OTs
OR
Am
OH
O
HO
O
Am
OR
O
RO
O
OSit-BuPh2LiHMDSRBrTHF-HMPA
acetonecat H2SO4
54% overall
CH3(OMe)3cat EtCO2H
!
80%
1) K2CO3, MeOH2) TsCl, pyr3) EVE
1) 10 eq Bu2CuLi Et2O, -40 °C 2 h2) aq H2SO4
THF, rt 15 h
35% overall
EVE
71%OR = OC(H)MeOEt
OH
O
O
O
HO
OH
Strategies for Stereocontrolled
Synthesis
Case Studies
(2) Prostaglandins from Sugars (Stork)
Total Synthesis of PGF2!
OH
CO2H
OH
HO
568
9
1112
151314
Prostaglandin F2!
Am
OH
HO
HO
OH
OSiR3
NC
Am
OH
HO
TsO
OH
OSiR3
NC
Am
OR
RO
OR
OSit-BuPh2
NC
DIBAL
HCNEtOH-10 °C
50% aq AcOHTHF, 35 °C
1.5 eq TsClpyr, -15 °C
EVE
6 eq KHMDSbenzene! 5 h
37% overall
72%
Am
OR
O
RO
O
OSit-BuPh2
OR = OC(H)MeOEt
Strategies for Stereocontrolled
Synthesis
Case Studies
(2) Prostaglandins from Sugars (Stork)
Total Synthesis of PGF2!
OH
CO2H
OH
HO
568
9
1112
151314
Prostaglandin F2!
Am
OR
RO
OR
CO2H
NC
OH
HO
CO2H
OH
1) TBAF, THF2) Collins Ox3) AgNO3, KOH aq EtOH
AcOHH2O-THF40 °C 5 h
Lis-Bu3BHTHF, -78 °C 1.5 h
Prostaglandin F2!
73%
Am
OR
RO
OR
OSit-BuPh2
NC
OR = OC(H)MeOEt
31 steps in the longest
linear sequence
Strategies for Stereocontrolled
Synthesis
[1,3] O$C Chirality Transfer
[1,3] O$N Chirality Transfer
R1R2
Y
3
OH
2
1
X
R1R2
Y
3
2
1
X
CO2R
* *
R1R2
Y
3
OH
2
1
X
R1R2
Y
3
2
1
X
NR2
* *
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 R1R2
Y
3
OH
2
1
X
R1R2
Y
3
2
1
X
NR2
* *
Review: Overman, L. E.; Carpenter, N. E. Org. React. 2005, 66, 1
Overman Rearrangement
of Allylic Trihaloacetimidates
BnO
OH
KH, CCl3CN
Et2OBnO
OHN
CCl3
BnO140 °Cxylene
HN CCl3
O45% overall
BuOSiR3
OH
1) DBU, CCl3CN CH2Cl2
2) 1% PdCl2(PhCN)2 benzene, rt
BuOSiR3
NHCOCCl372%