Strategies for Stereocontrolled Synthesis

Strategies for Stereocontrolled Synthesis Chemistry 5.511 Synthetic Organic Chemistry II Lecture 4 October 12, 2007 Rick L. Danheiser Massachusetts I...
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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