Powdered KOH in DMSO: An Efficient Base for Asymmetric Cyclization via Memory of Chirality at Ambient Temperature

Wipf Group Saturday Morning Meeting

Current Literature Abstracts & Reports

Rob Lettan March 29th, 2008

Takeo Kawabata,* Katsuhiko Moriyama, Shimpei Kawkami, and Kazunori Tsubaki

Journal of the American Chemical Society, 2008, 130, 4153-4157.

Institute for Chemical Research, Kyoto University Uji, Kyoto, Japan

CO2EtR

N(CH2)nBoc X

EtO

OK

R

N(CH2)nX

CO2tBu N

CO2Et

R

Boc

(CH2)n

powdered KOH

DMSO, 20 °C

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Memory of Chirality

E

EWGR1

R2

H

EWGR1

R2

EWG

R1

R2

sp3

tetrahedralsp3

tetrahedral

sp2

trigonal planar

DeprotonationElectrophile

Addition

Retentionof

Chirality

ChiralStartingMaterial

Dynamically Chiral

Intermediate

“A formal substitution at an sp3 stereogenic center that proceeds

stereospecifically, even though the reaction proceeds by trigonalization of that

center, and despite the fact that no other permanently chiral elements are present

in the system.” -T. Kawabata

Defined As:

Fuji, K.; Kawabata, T. Chem. Eur. J. 1998, 4, 373-376.

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First Reported Observation of Chiral Memory

tBuO2CCO2tBu

NHCHO

CO2tBu

N

OLi

OLi

tBuO

tBuO2C

N

OLi

OtBu

OLi

tBuO2CCO2tBu

NHCHO

tBuO2CCO2tBu

NHCHO

Me

Me

55% yield

15% yield60% ee

LiNEt2 MeI

MeI

Seebach, D.; Wasmuth, D. Angew. Chem., Int. Ed. Engl. 1981, 20, 971.

Postulated Origins of selectivity:

1) "The achiral enolate intermediate B forms mixed aggregates with the chiral dilithio derivative A."

A

B

2) "The 6-atom-8-electron !-system is axially chiral... If this interpretation should turn out to be valid, simple amino acids may also be alkylate via derivatives of type B (R instead of CH2CO2tBu) without racemization.

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The First Rationally Designed MOC Process

O

Ph

MeO

OEt

OEt

OK

Ph

MeO

OEt

OEt

O

OEt

OEt

Ph

MeOMe

93% ee "chiral" intermediate

KH MeI

66% ee

OMe

OEt

OEt

Ph

! 65% ee

MeO

O

Ph

MeO

OEt

OEt

1. KH

2. MeI

O

OEt

OEt

Ph

MeMeO

96% ee 0% ee

Kawabata, T.; Yahiro, K.; Fuji, K. J. Am. Chem. Soc. 1991, 113, 9694-9696.

O

Ph

MeO

OEt

OEt

K O

Ph

O

EtO OEt

Me

Possible Alternative Stereochemical Origination

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The First Rationally Designed MOC Process

H

BnN

OOEt

Boc

MOMR

BnN

OOEt

Boc

MOM

OKEtO

Bn

N

Boc

Mom

KHMDS

THF/Toluene (1:4)-78 °C

RX

16-17 hup to 93% ee

Experimental Support for MOC

Variation in reaction time enolate intermediate of prior to MeI quench:

Kawabata, T.; Suzuki, T.; Nagae, Y.; Fuji, K. Angew. Chem. Int. Ed. 2000, 39, 2155-2157.

Barrier of Rotation = 16.0 kcal·mol-1

OTBSEtO

Bn

N

Boc

MOM

Z:E = 2:1

Barrier of Rotation = 16.8 kcal·mol-1

(AB quartets from CH2 of MOM)

Half-Life =

VT NMR experimentation:

5 x 10-4 at 365 K7 days @ -78 °C

Comparable substrates:

PhCO2Et

NR

Boc

BocPh O

N

O

Boc

R

1: R = H3: R = Me

2: R = H4: R = Me

Alkylation of 1 or 2 led to racemic 3 or 4.

energy minimized orientation for deprotonation

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Intramolecular MOC ApproachesAlkylations:

BocN

EtO2C

Bn

Kawabata et al.J. Am. Chem. Soc. 2003, 125, 13012-13013.

cyclic amino acids 2-azetidinones

N

O R2

R1

CO2Et

González-Muñiz, R. et al.Tetrahedron 2006, 62, 130-138.

Michael Additions:

BocN

CO2EtPh

CO2tBu

n

n = 1, 2, 3

BocN

EtO2C

Me

CO2tBu

Enolate Additions to Diazoacetals:

98% ee 82% ee

up to98% ee 95% ee

N

N

HN

S

MeO2C

O

Me

O

> 99% ee

Kawabata et al.Org. Biomol. Chem. 2005, 125, 1609-1611.

Stoodley et al.J. Chem. Soc., Perkin Trans. 1, 1993, 1761-1770.

N

O

Me

O

X

CO2iPr

N

X

CO2iPr

OH

MeO

N

X

CO2iPr

Me

OHO

N

X

O O

HO Me18 19 20

3 : 1 minor

Base

X = O, CH2

> 99% ee

Aldol Cyclizations:

Stoodley et al. Tetrahedron Lett. 2002, 43, 3919-3922.

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Asymmetric MOC Cyclization at Ambient Temperature

Overcoming Racemization

EtO

OK

R

NCH2OMe

CO2tBu

!G = 16 kcal/mol

t1/2 (-78 °C) = 22 h

t1/2 (20 °C) = < 0.1 sec

Possibility of an intramolecular MOC reactionin which "the chiral enolate intermediate reacts very rapidly within the time-scale of theirracemization."

N N N

CO2R2R1

N(CH2)nBoc X

CO2R2

R1

CO2R2 CO2R2

R1R1

Boc Boc Boc

Base

Reactivity vs Racemization?

Enantioselective approaches to rigified cyclic amino acids have played an important role in drug design and development, and in the design of novel peptides.

Revied on cyclic amino acids: Park, K.-H.; Kurth, M. J. Tetrahedron, 2002, 58, 8629-8659.

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Base/Solvent Screening

entry base (mol equiv) solvent temp, time (h) yield ee

PhCo2Et

NBoc

Br

1

base, solvent

temp N

Co2EtPh

Boc

2

1

2

5

6

11

LiOH was uneffective, NaOH and CsOH had inferior results

Increased amounts of H2O led to decreased reactivity

Solvents: CH2Cl2 proved uneffective, THF was inferior, and EtOH gives saponification.

KHMDS (1.2)

KHMDS (1.2)

KOH (3.0)

KOH (3.0)

KOH (3.0)

DMF

DMF

DMF

DMSO

1% H2O DMSO

60°C, 0.5-0°C, 0.2

20°C, 0.2

20°C, 0.2

20°C, 0.2

94

97

89

91

98

98

93

98

99

99

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Substrate Scope

entry n time (h) yield ee

powdered KOH

DMSO, 20 °C

1

4

7

10

2 Br 2

2

12

2

82

91

73

97

99

99

90

97

CO2Et

N(CH2)nBoc X

N

CO2Et

Boc

(CH2)n

PhPh

3

4

4

X

Br

Br

I

footnote 17 ? 25 495 X

Similar trend also observed with valine and methionine derived substrates.

Me CO2Et

N BrBoc

Me

N

Me

MeCO2Et

BocN

Me

MeCO2H

Fmoc

powdered KOH

DMSO, 20 °C

1) 4 M HCl

2) Fmoc-Cl

3) conc. HCl94%

single diastereomer53%

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Mechanistic Investigation

powdered KOH

DMSO, 20 °C

CO2Et

N(CH2)nBoc X

N

CO2Et

Boc

(CH2)n

PhPh

EtO

OK

R

N(CH2)nX

CO2tBu

Dynamic Chirality

CO2EtPh

CO2tBu

X

K

HO

H

Concerted SEi Process

CO2Et

N

Ph

Br BrN

Ph

CO2Et

Br

racemic

Concerted SEi Process is not plausible reaction pathway

vs

powdered KOH

DMSO, 20 °C

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Barrier of Racemizationpowdered KOH

DMSO, 20 °C

CO2Et

NBoc

Ph

Br N

Ph

CO2Et

Boc

Difficult to determine barrier of rotation b/c of relative rate of intramolecular cyclization.

Analogous Substrate:

Barrier of Racemization = 15.5 kcal/mol at -78 °C ffrom the slope, 2k = 1.99 x 10-3 min-1

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Relative Rate of Cyclization

entry n time (h) yield ee

powdered KOH

DMSO, 20 °C

1 (4 5)

7 (14 15)

2 Br 2

12

82

73

99

90

CO2Et

N(CH2)nBoc X

N

CO2Et

Boc

(CH2)n

PhPh

4

X

Br

Suggested Reasoning:

Inductive effects of bromide could slightly increase the acidity of ! proton

or

chelation assisted deprotonation

Rob Lettan @ Wipf Group Page 12 of 13 6/25/2008

Summary

CO2EtR

N(CH2)nBoc X

EtO

OK

R

N(CH2)nX

CO2tBu N

CO2Et

R

Boc

(CH2)n

powdered KOH

DMSO, 20 °C

Kawabata and coworkers demonstrated a highly enantioselective memory of chirality cyclization at ambient temperature.

The obtained cyclic amino acids are important role motifs in drug design and development, and in the design of novel peptides.

Interestingly, the cyclization of 4-membered ring systems occurs 2 to 3 times faster than the corresponding 6-membered variants.

The use of KOH in DMSO in the generation of highly reactive enolates under relatively mild conditionsfor enantioselective reactions has had little to no previous precedence, and could prove useful in thefuture for C-C bond forming processes.

Rob Lettan @ Wipf Group Page 13 of 13 6/25/2008