strategies for stereocontrolled synthesisweb.mit.edu/5.511/www/10-12-07.pdf · 10/12/2007 · some...

Strategies for Stereocontrolled

Synthesis

Lecture 4

October 12, 2007

Rick L. Danheiser

Massachusetts Institute of Technology

Chemistry 5.511

Synthetic Organic Chemistry II


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


Synthesis


" What determines the relative E of stereoisomers

" Tactics for establishing thermodynamic control

! Kinetic control strategies

" Substrate control strategies

" Reagent control strategies

" Dynamic kinetic resolution


Synthesis


! Kinetic control strategies" Substrate control strategies

# Steric approach control

# Stereoelectronic control

# Internal stereodirection and chirality transfer


# Achiral substrate: enantiotopic face selectivity

# Achiral substrate: enantiotopic group selectivity

# Chiral substrate: double asymmetric synthesis



Synthesis

Substrate Kinetic Control Strategies

Steric Approach Control

O

m-CPBA

CH2Cl2


Synthesis


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


Synthesis


! Kinetic control strategies

" Substrate control strategies










Synthesis


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


Synthesis


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)


Synthesis












Synthesis

Reagent Kinetic Control Strategies

Achiral Substrate: Enantiotopic Face Selectivity

Katsuki-Sharpless Asymmetric Epoxidation


Synthesis




Synthesis




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)


SynthesisReagent Kinetic Control Strategies



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


SynthesisReagent Kinetic Control Strategies



OH

O

Compatible Functional GroupsAcetals, ketalsAcetylenesAlcohols (remote)AldehydesAmidesAzidesCarboxylic EstersEpoxidesEthersHydrazidesKetones

NitrilesNitroOlefinsPyridinesSilyl ethersSulfonesSulfoxidesTetrazolesUreasUrethanes

Incompatible GroupsAmines (most)Carboxylic acidsMercaptansPhenols (most)Phosphines


Synthesis


Chiral Substrates



OH

O

92% ee

(96 : 4)


OH

OAmAm


OH

OAmAm

OH

OAm

+

67 : 33



OH

OAmAm


OH

OAmAm

OH

OAm+

67 : 33


Synthesis


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


Synthesis


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


Synthesis












Synthesis


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

+


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)


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.


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


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



Synthesis




O

CH3MgBr

OH

CH3


Synthesis




OCH3

OH

1) Ph3P=CH22) m-CPBA3) LiAlH4


Synthesis












Synthesis

Kinetic Control Strategies

Classical Kinetic Resolution

A

+

ent-A

B*chiral

k1 FAST

B*chiral

k2 SLOW

A-B*

ent-A-B*


Synthesis



A

+

ent-A

B*chiral

k1 FAST

B*chiral

k2 SLOW

A-B*

ent-A-B*


Synthesis



Selectivity

Factor

s = k1/k2

10

50ent-A

B*chiral

k1 FAST

B*chiral

k2 SLOW

A-B*

ent-A-B*


Synthesis


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


Synthesis

" Chiron Approach

" Ring Template Approach

" Chirality Transfer

" Acyclic Asymmetric Synthesis

General Strategies for the Stereocontrolled

Synthesis of Acyclic Target Molecules


Synthesis

! Thermodynamic Control Strategies

! Kinetic Control Strategies

! Strategies for the Synthesis of Acyclic

Target Molecules: Case Studies

" Prostaglandins from Sugars (Stork)


Synthesis

" Chiron Approach

" Ring Template Approach

" Chirality Transfer

" Acyclic Asymmetric Synthesis

General Strategies for the Stereocontrolled

Synthesis of Acyclic Target Molecules


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.




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




OH

CO2H

OH

HO

568

9

1112

151314

Prostaglandin F2!



(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




! 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!




! 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




! 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




! 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






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






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






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


Synthesis

Case Studies


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

"#




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


Synthesis

Case Studies


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


Synthesis

Case Studies


O

CO2H

OH

Prostaglandin A2


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


Synthesis

Case Studies


O

CO2H

OH

Prostaglandin A2


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


Synthesis

Case Studies


O

CO2H

OH

Prostaglandin A2


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


Synthesis

Case Studies


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


Synthesis

Case Studies



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


Synthesis

Case Studies



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


Synthesis

Case Studies



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


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%

strategies for stereocontrolled synthesisweb.mit.edu/5.511/www/10-12-07.pdf · 10/12/2007 · some...

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