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