150 Years of Strecker Reaction

Yu Zhang

Department of Chemistry Michigan State University

Different Methods of Preparation of Chiral α-amino acids

RCOOH

O

O

R

RCHO + NH3 + HCN

RCOOH

NH2

H2

RCOOH

NH2

RCOOH

NH2

R+

N

R CO2R'

R''

N

OM

OR'

(racemates)

Kinetic Resolution Asymmetric Hydrogenation Reductive Amination

Aux *

Electrophilic Amination

Chemical or

Enzymatic MLx

Nu-

Enzym

e

Alkylation

R1CHO + R2NH2 + R3COOH + R4NC

Asymmetric Ugi Reaction

Asymmetric Strecker Reaction

Ring Openingof Aziridine

Duthaler, R. Tetrahedron. 1994, 50, 1539

Introduction to Strecker Reaction

Strecker, A. Ann. Chem. Pharm. 1850, 75, 27 Miller, S. L. Science, 1953, 117, 528

♦ Classical Strecker synthesis of α-amino acids

♦ Why Strecker reaction?

* Simple starting material, three components, efficient reaction. * Catalytic asymmetric Strecker reaction still a new and hot area. * Possibly the prebiotic process which produced amino acids on the primitive earth!

“A completely different compound was formed upon the bring together of the aldehyde- ammonia adduct and hydrocyanic acid in the presence of acids.”

In addition of chemical analysis of the new compound, characterized it physically: “The larger crystals of alanine are mother-of-pearl-shiny, hard and crunch between the teeth.”

-- Strecker, 1850

R COOH

NH2

R CN

NH2

HCNNH3R CHO + +

Strecker Reaction - An Outline

I. Mechanism study of Strecker reaction.

II. Asymmetric Strecker reaction using chiral auxiliaries

III. Catalytic asymmetric Strecker reaction

IV. Future work

V. Conclusions

Mechanism Study of Strecker Reaction

Ogata, Y.; Kawasaki, A. J. Chem. Soc. B 1971, 325-329. Stadnikoff, G. Ber. 1907, 40, 1014-19; J. Russ. Phys. Chem. Soc. 1914, 46, 1201-15. Snyesarev, A. P. J. Russ. Phys. Chem. Soc. 1914, 46, 217-23.

♦ Cyanohydrin pathway

♦ Imine pathway

R CHOHCN

R H

HO CN NH3

R H

H2N CN

cyanohydrin

R CHONH3

R H

NH HCN

R H

H2N CN

imine

♦ The argument began around early 20th century. -- Snyesarev vs. Stadnikov, 1907 - 1914

Mechanism Study of Strecker Reaction

Ogata, Y.; Kawasaki, A. J. Chem. Soc. B 1971, 325-329. Taillade, J.; Commeyras, A. Tetrahedron 1974, 30, 2493-2501

♦ Control experiments - intermediate criterion

♦ Suggested pathways in Strecker reaction

♦ Kinetic study also showed that in the presence of excess CN- the rate-determining step is imine formation.

Ph NH

CN

Ph

Ph NH

CN

Ph

Ph NH

CN

Ph

Ph NH2

Ph NH2

HCN

Ph CN

OH

HCN

Ph NPh

HCN

Ph CHO

Ph NH2

Ph CHO

Ph CHO

22 hrs(to reach equilibrium)

3 hrs

1 hr 1.5 hrs

<20%

100% !

22 hrs 60%+ +

Ar1 NH

Ar2CNHCN

Ar1 NAr2

Ar1 OH

CN

Ar2 NH2

HCN

Ar1 CHO

Ar1 CHO

+k1

k2

+

k2 > k1

Asymmetric Strecker Reaction - An Overview

Chiral Amino Acid

Carbohydateauxiliary

Chiral Auxiliary Based Synthesis

Catalytic Asymmetric Sythesis

Chiral amineauxiliary

Cyclic ketimineauxiliary

Guanidinecatalysts

Chiral Schiff basecatalysts

BINOL-basedcatalysts

Asymmetric Strecker Reaction Using Carbohydrate Auxiliary

Kunz, H.; Sager, W. Angew. Chem. Int. Ed. 1987, 26, 557-559. Kunz, H.; Sager, W.; Pfrengle, W.; Schanzenbach, D. Tetrahedron Lett. 1988, 29, 4397-4400.

♦ Preparation of carbohydrate templates

♦ Asymmetric Strecker Reaction Using Carbohydrate

O

OR

RO

OR

OR

ORMe3SiN3 O

OR

RO

OR

OR

N3O

OR

RO

OR

OR

NH2

R = Piv

SnCl4/CH2Cl2

H2/Raney Ni

O

OR

RO

OR

OR

NH2

O

OR

RO

OR

OR

N R'

H

R' CHO

Me3SiCN

O

OR

RO

OR

OR

N R'

H

O

OR

RO

OR

OR

HN R'

CNH

Me3SiCN O

OR

RO

OR

OR

HN CN

R'H

R' COOH

H3N H Cl

>90% quantitativeR:S = 7-13 : 1

ZnCl2/i-propanolor SnCl4/THF

HCl/HCOOH

ZnCl2,CHCl3

S : R = 3-9 : 1R = Piv

R = Piv

♦ Reversed Asymmetric Induction of Strecker Reaction:

Kunz, H.; Sager, W. Angew. Chem. Int. Ed. 1987, 26, 557-559. Kunz, H.; Sager, W.; Schanzenbach, D.; Decker, M. Liebigs Ann. Chem. 1991, 649-654.

Rationale of stereoselectivity in asymmetric Strecker reaction

Asymmetric Strecker Reaction Using Carbohydrate Auxiliary

O

OR

RO

OR

OR

N R'

H H

O

OR

RO

OR

O

N R'

H

O

Zn

ClCl

CN-

NOE

Conformation A Complex B

Ph NH2

Et RCHO

Ph N

Et

RR

C NC

EtH

R Ph

HCN

Fe

RCHO

CH3CHO

C2H5CHO

PhCH2CHO

SR COOH

NH2CN modified hemin-copolymer

EtOH, 20oC, 20 hrs

1) HCl

2) Pd(OH)2, H2

ee % Yield

92

96

99

57

46

41Hemin

Asymmetric Strecker Reaction Using Chiral Amine Auxiliary

Harada, K. Nature 1963, 200, 1201. Harada, K.; Saito, K. Tetrahedron Lett. 1989, 30, 4535-4538.

♦ First example of asymmetric Strecker reaction

♦ Asymmetric Strecker reaction using chiral amine and cyanide-modified hemin-copolymer

CH3CHO + HCN +Ph NH2

CH3

CH3OH Ph NH

CH3

CH3

CN

H3C COOH

NH2r.t. 5 days 1) HCl

2) Pd(OH)2, H2

(S) - Alanine(S) - methylbenzylamine17% yield, 90% ee

Vincent, S. P.; Schleyer, A.; Wong, C.-H. J. Org. Chem. 2000, 65, 4440-4443.

Asymmetric Strecker Reaction Using Chiral Amine Auxiliary

O

CHO

OBnPh NH2

(OBn)3HO CN

N

R H

H

CH3

PhTHF

CN

(S)

N

R HCN

(S)CH2Cl2

CH3H

Ph

PhHN R

CH3 CN

PhHN R

CH3 CN

(OBn)3

(S)

(R)

O

OBn

ACN

HN Ph

THF

Solvent

CH2Cl2

(OBn)3

O

OBn

COOH

NHBOC

1)

2)

*

1) MeOH, HCl2) LiOH, MeOH

*4) (BOC)2O

R/S of A Yield of A

1:3.5

7:1

82

69

C-gluco-alanine analogue

Felkin-Anh type 1,3-syn-stereoselectivity

Cram type 1,3,-trans-stereoselectivity

, Solvent3) H2, Pd/C

Asymmetric Strecker Reaction Using (R)-Phenylglycinol Auxiliary

Inaba, T.; Kozono, I.; Fujita, M.; Ogura, K. Bull. Chem. Soc. Jpn. 1992, 65, 2359-2365.

Ph NH2

OH

Ph NH

COOH

ROH

R

R COOH

NH2

Ph N COOMe

R

Ph NH

CN

ROH

S

HCl

R

R COOH

NH2

Ph NH

CN

ROH

R

+ RCHO1) KCN/NaHSO3

2) 80oC, MeOH

1) HCl

2) Separation

(R, S) : (R, R) = 4-6.7 : 1

1) SOCl2 - MeOH

2) Pb(OAc)4

(R = aryl)

Pd - HCOOH

(R = alkyl)

40-100%87-100%

41-66% over 3 steps, 79-99% ee

54-86%92-100% ee

+

Chakraborty, T. K.; Hussain, K. A.; Reddy, G. V. Tetrahedron 1995, 51, 9179-9190.

Asymmetric Strecker Reaction Using (R)-Phenylglycinol Auxiliary

R

Ph

i-Bu

t-Bu

Ph NH2

OH

PhCH2CH2

CHCl3

RCHOR N Ph

OHH

TMSCN

A

RHN Ph

OHCN

RHN Ph

OTMSCN

B

RHN Ph

OHCN

RHN Ph

OTMSCN0oC, 6-8 h

+

(S, R) Major (R, R) Minor

TBAF or 3N HCl

+

Diastereoselectivity(S, R)-A : (R, R)-B

Total Yield(A+B), %

p-MeO-Ph

82:18 92

90:10 95

54:46 87

84:16 95

88:12 92Chromatographyseparation

Asymmetric Strecker Reaction Using (R)-Phenylglycinol Auxiliary

Chakraborty, T. K.; Hussain, K. A.; Reddy, G. V. Tetrahedron 1995, 51, 9179-9190. Hosangadi, B.; Dave, R. Tetrahedron Lett. 1999, 11295.

♦ Removal of chiral auxiliary

♦ Rationale of diastereoselectivity

CN-

R

H HH O H

RN

OH

PhH

CN- re-face attack

(S, R) Major Isomer

re-face attack

Pb(OAc)4

RHN Ph

OHCN

Ph N Ph

CN

HN Ph

OHCO2Me

NH2

CO2H

Ph NH2-HCl

CO2HCH2Cl2/CH3OH0oC, 5min

Methanolic HCl

rt, 5h

Conc. HCl

reflux, 3h

1) Pb(OAc)4

2) Dil. HCl

70% in 3 steps

(S, R) Major Isomer

R = i-Pr or Ph

yield not reported

i-Pr i-Pr

Ma, D.; Tian, H.; Zou, G. J. Org. Chem. 1999, 64, 120-125.

Synthesis of α,α-Disubstituted Amino Acids Using (R)-Phenylglycinol Auxiliary

Br

Ar Me

O

MeO2C

Me

O

HN

Ph

O

Ph NH2

OH

SAr Me

CbzN

Ph

MeO2C

OH

Ar Me

N

Ph

OH

RMeO2C Me

CbzN

Ph

Ar

OH

HO2C

Me

HO2C NH2

Ar Me

NHO

Ph

CbzCl

Ar Me

HN

Ph

MeO2COH

toluene, reflux+

1) TMSCN, MeOH

2) HCl/MeOH

Unseparable isomers, 73%

+

58% 23%

Pd(OAc)2/dppp/Et3NCO/EtOH/DMSO

100%

1) NaOH/MeOH2) Pb(OAc)4

3) 3N HCl, reflux4) propylene oxide 47%

(S)-αM4CPG

* Antagonist of metabotropic glutamate receptor

Ar =

Ma, D.; Ding, K. Org. Lett. 2000, 2, 2515-2517.

♦ Synthesis of α,α-disubstituted amino acid -- the idea

Synthesis of α,α-Disubstituted Amino Acids Using (R)-Phenylglycinol Auxiliary

RCHOTMSCN

Ph NH2

OH

O

N

R''

O

R Ph

RHN Ph

OHCN

O

N

R''

O

R'PhR

R NH2

CO2H

CO2H

NH2R'

R

(S, R) major isomer + minor isomer

1) Pb(OAc)4

2) HCl

1) HCl/MeOH2) Heat3) R''X

Diastereoselectivealkylation, or aldolcondensation?

Ma, D.; Ding, K. Org. Lett. 2000, 2, 2515-2517.

Synthesis of α,α-Disubstituted Amino Acids Using (R)-Phenylglycinol Auxiliary

CH3CHOPh NH2

OH

BrCH2CO2Me

BnBr

EtI

n-PrCHO

O

N

Bn

O

H3C Ph

NO

-O

RPh

Bn

S

S

S

RCO2H

NH2E

H3C

O

N

Bn

O

EPhH3C

1) , KCN

2) HCl/MeOH then PTSA toluene, reflux3) BnBr/K2CO3 (66% yield)

1) NaHMDS, -78oC

2) Electrophile

Electophile Yield dr of C5

5

Configuration of C-5

87 > 200:1

90

50

80

> 200:1

> 200:1

8:1 (E = (S)-CH(OH)Pr)

1) Hydrolysis2) Pd/C, H2

62-80%

E

E

Favored

Disfavored

Sakamuri, S.; Kozikowski, A. P. Chem. Commun. 2001, 475-476.

Application of (R)-Phenylglycinol Auxiliary in Total Synthesis

NHAc

OH

N

CHO

OMe

N

OMe

HN

OHCO2Me

PhN

OMe

NHBOC

CO2Me

N

OMe

HN

OHCN

Ph

NHNMe

O

OH

OMe

MeOH

1) (R)-phenylglycinol, CHCl3

2) Me3SiCN3) TBAF

66% for 3 steps4:1 dr

HCl in ether

81%

7-methoxybenzolactam-V8Intermediate of potent activator of protein kinase C

1) Pb(OAc)4

2) Pd(OH)2/C, H23) BOC2O, Et3N

44% for 3 steps

Vedejs, E.; Kongkittingam, C. J. Org. Chem. 2001, 66, 7355-7364. Reddy, R.; Jaquith, J.; Neelagiri, V.; Saleh-Hanna, S.; Durst, T. Org. Lett. ASAP, Feb 2, 2002

Application of (R)-Phenylglycinol Auxiliary in Total Synthesis

N

CH3

O

H

N

NN

O

O

CH3

H

OH

O

NH CH3

CH3

HN

CN

OH

Ph

NH2

NH2

O

HNOH

Ph

NH2

O

ind

1) Sc(OTf)3,(R)-phenylglycinolCH2Cl2, rt ind

81%81:11 dr

2) Bu3SnCN

1) H2O2, K2CO3

DMSO, MeOH ind

ind =

Pd(OH)2/C, H2MeOH, rt

ind

72%

95%

(-)-Hemiasterlin cytotoxin and mitosis inhibitor

2) separation

Asymmetric Strecker Reaction Using Chiral Cyclic Ketimine

Moon, S.-H.; Ohfune, Y. J. Am. Chem. Soc. 1994, 116, 7405-7406.

♦ Asymmetric Strecker reaction using chiral cyclic ketimine -- the idea

X

Y OH

O

R CO2H

NH2

O

NX R

Y O

HCN

R CO2H

NH2

O

HNX R

Y O

HNCX NH2

CO2H

OHY

X CO2HNH2

OHY

X = alkyl or aryl, Y = H or alkyl or aryl

*

*or use:

Asymmetric Strecker Reaction Using Chiral Cyclic Ketimine

Moon, S.-H.; Ohfune, Y. J. Am. Chem. Soc. 1994, 116, 7405-7406.

♦ Preparation of intermediate C and D

NH

O

Ph

HO

HO

HN

CNH

PhO

N S O

BocHN HCH2Ph

NC-

NH2

O

Ph

HO O N

Ph

HCO2MeH

NCNaCN

O O

H2N HCH2Ph

R

O

OMe OMe

CSA

O

HN H

PhO

NH

O

Ph

HO

H

NC-

CN

1) dl-acetoin, toluene (84%)2) TFA, CH2Cl2

A R = MeB R = H

i-propanol(96% in 2 steps)

C:D = 4:1

5

5

5

5

5

6

6

6

6

6

(5S, 6S) - CKinetically favored

(5S, 6R) - DThermodynamicaly favored

TFA, rt, 5hC:D = 1:9

,

E

Moon, S.-H.; Ohfune, Y. J. Am. Chem. Soc. 1994, 116, 7405-7406.

Asymmetric Strecker Reaction Using Chiral Cyclic Ketimine

O

HN

CNH

PhO

O

NMe

Me O

NCCH2Ph Me NH2

CO2H

OHHMe

5 6

(5S, 6S) - C

t-BuOCl, Et2Othen Et3N

exo/endo = 2.4:1

1) Con. HCl

2) Dowex 50W*4(1N NH3)

1c 84%

♦ Four enantiomers and diastereomers of α-methylthreonine and two enaniomers of α-methylserine were synthesized using the same methodology.

HO2C NH2

Me

OHRH

O O

NH2 CH2PhH

R

O

HO2C NH2

Me

OHHMe

Me NH2

CO2H

OHHR

O O

NH2 HCH2Ph

R

O

Me NH2

CO2H

OHMeH

1a R = Me2a R = H

1c R = Me8b R = H

1b 1d

A R = MeB R = H

ent - A R = Meent - B R = H

α-methylthreonineα-methylserine

♦ Removal of phenylalanyl moiety and preparation of amino acid.

Namba, K.; Shinada, T.; Teramoto, T.; Ohfune, Y. J. Am. Chem. Soc. 2000, 122, 10708-10709.

Asymmetric Strecker Reaction Using Chiral Cyclic Ketimine - Application in Total Synthesis

♦ Total synthesis of Manzacidin A and C -- idea and retrosynthesis

HN N

OR2R1

O

HNC

HOCO2H

NH2 NH2

H

CN

N

NH

Ph O

H

NH

Br

O

NHN

O

CO2HH

6

R1 = CH2Ph, R2 = H orR1 = H, R2 = CH2Ph

1a Manzacidin A 1b Manzacidin C (6S isomer of 1a)

* Isolated from marine sponges, only preliminary biological tests due to availability

Asymmetric Strecker Reaction Using Chiral Cyclic Ketimine - Application in Total Synthesis

Namba, K.; Shinada, T.; Teramoto, T.; Ohfune, Y. J. Am. Chem. Soc. 2000, 122, 10708-10709.

OH

NH2

H

HNN

OHPhH2C

O

HNC

NN

OPhH2C

O

HNC

HO2C

NH2 NH2

OHH

BocHNN

OHPhH2C

O

H

O

NH

Br

O

NHN

O

CO2HH

NN

OHPhH2C

O

H

1a Manzacidin A

6

1) Et3N, Boc-L-Phe-OSu

2) p-TsOH, 2,2-dimethoxypropane3) PdCl2, CuCl, O2 (66%)

TMSOTf, 2,6-lutidine

TMSCN, ZnCl2, 2-PrOH, rt, 18h

(81%, single isomer)

O3, MeOH

(94%)

Conc. HCl

* 1b Manzacidin C (6S isomer of 1a) was synthesized using same methodology.

Asymmetric Strecker Reaction - Halfway Overview

Chiral Amino Acid

Carbohydateauxiliary

Chiral Auxiliary Based Synthesis

Catalytic Asymmetric Sythesis

Chiral amineauxiliary

Cyclic ketimineauxiliary

Guanidinecatalysts

Chiral Schiff basecatalysts

BINOL-basedcatalysts

Catalytic Asymmetric Strecker Reaction Using Chiral Guanidine Catalyst

Iyer, M. S.; Gigstad, K. M.; Namdev, N. D.; Lipton, M. J. Am. Chem. Soc. 1996, 118, 4910-4911.

♦ Pros: The first successful example of catalytic asymmetric Strecker reaction Good for some aromatic imines Low catalyst loading ♦ Cons: Narrow substrate range

R

NCHPh2

MeOH SR CN

NHPh22 equiv HCN, 2 mol% ANH

HN

O

O

HN NH2

NH

Lipton's Cyclic Dipeptide catalyst A

Entry R Temp (oC) Yield (%) ee (%)1 C6H5 -25 97 >992 p-ClC6H4 -75 97 >993 p-OMeC6H4 -75 90 964 m-NO2C6H4 -75 71 <105 3-pyridyl -75 86 <106 i-Pr -75 81 <107 t-Bu -75 80 17

Corey, E. J.; Grogan, M. J. Org. Lett. 1999, 1, 157-160.

N

N NH

Corey's bicyclic guanidine catalyst A

Catalytic Asymmetric Strecker Reaction Using Chiral Guanidine Catalyst

♦ Pros: Improved results for some aliphatic imines ♦ Cons: Narrow substrate range ee not so great

R

NCHPh2

R CN

NHPh2

toluene(0.2M), 20h

2 equiv HCN, 0.1 equiv A

(R) - product when R = Aryl(S) - product when R = Alkyl

*

Entry R Temp (oC) Yield (%) ee (%)1 C6H5 -40 96 862 p-ClC6H4 -20 88 813 p-MeOC6H4 -40 99 844 o-CH3C6H4 -20 88 505 i-Pr -40 ~95% 846 n-Hex -40 ~95% 63

Mechanism of Strecker Reaction Catalyzed by Chiral Guanidine

♦ Catalytic cycle of Guanidine catalyzed Strecker reaction

♦ Pre-transition-state assemblies for the Strecker reactions of N-benzhydryl benzaldimine (above) and N-benzhydryl pivalaldimine (below).

Corey, E. J.; Grogan, M. J. Org. Lett. 1999, 1, 157-160.

NN

H NHHNH

CN

CN

NN

H NHH

H

N

N

NH

NPh Ph

Ar

NPh2HC

N

N NPh Ph

H

Ar

NPh2HC

H

C

N

Ar

HNCHPh2

CNH A

H C N

N

NH

NPh Ph

H

C

N

A-HCN complexPre-TS assembly

Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 5315-5316.

R H

N

R CN

NCF3

O1) 1.2 equiv HCN5 mol% A, 15htoluene, -70oC

2) TFAA

N N

t-Bu

t-Bu t-Bu

t-BuO O

Al

Cl

Jacobsen's chiral (salen)Al(III) complex A

Catalytic Asymmetric Strecker Reaction Using Chiral(Salen) AI(III) Complex

♦ Pros: Good results for some aromatic imines ♦ Cons: Narrow substrate range

Entry R Yield (%) ee (%)1 C6H5 91 952 p-ClC6H4 92 813 p-OMeC6H4 93 914 2-Naphthyl 93 995 cyclohexyl 77 576 t-Bu 69 37

Asymmetric Strecker Reaction Using Chiral Schiff Base Catalyst

Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901-4902.

R R'

N N

OM

R''

R R'

N N

O

M

R''

Linker 1 amino acid Linker 2

NH

HN

O

O

NH

O

NH

N

R2iPr

R2

t-But-Bu

HO

HN

NH

S

NH

N

OMet-Bu

HO

Ph

O

NH

HN

O

O

NH

O

NH

N

R2R1

R2

R4R3

HO

O

NH

S

NH

N

R2R1

R2

Xt-Bu

HO

5

12 Metal ionsLibrary Size: 12 compoundsBest result: no metal ion (19% ee)

5

4 amino acids, 2 diamines6 salicylaldehydesLibrary Size: 48 compoundsBest result: Leucine, (R, R)-diamine,3-t-butyl substituted aldehyde(55% ee)

11 amino acids, 3 diamines4 salicylaldehydesLibrary Size: 132 compoundsBest result: t-Leucine, cyclohexyldiamine, X = 5-OMe(91% ee)

Library 1 Library 2

Library 3

Jacobsen's Schiff Base catalyst A

R H

N

R CN

NCF3

O1) 2 equiv HCN 2 mol% A, 24h toluene, -70oC

2) TFAA

Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901-4902.

Asymmetric Strecker Reaction Using Chiral Schiff Base Catalyst

♦ Pros: Good results for most aromatic and aliphatic imines Low catalyst loading ♦ Cons: No mechanism proposed

Entry R Yield (%) ee (%)1 C6H5 78 912 p-BrC6H4 65 863 p-MeOC6H4 92 914 2-Naphthyl 88 885 cyclohexyl 77 836 t-Bu 70 85

HN

NH

S

NH

N

OMet-Bu

HO

Ph

O

Jacobsen's Schiff Base catalyst A

Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2000, 39, 1279-1281.

R H

NR'

R CN

NR'

CF3

O1) HCN, 2 mol% B, 20h toluene, -70oC

2) TFAA

Asymmetric Strecker Reaction Using Chiral Schiff Base Catalyst

♦ Pros: Good results for most imines Low catalyst loading ♦ Cons: No mechanism proposed

Entry R R’ Yield (%) ee (%)1 C6H5 allyl 74 952 o-BrC6H4 allyl 88 953 m-BrC6H4 allyl 87 904 p-BrC6H4 allyl 89 895 p-OCH3C6H4 allyl 98 956 o-OCH3C6H4 allyl 93 777 t-Bu allyl 75 95(91)8 t-Bu benzyl 88 96(93)9 CH3(CH2)4 benzyl 69 78

HN

NH

X

NH

N

t-Bu

R2t-Bu

HO

R1

O

A: R1 = polystyrene, X = S, R2 = OCO(tBu)B: R1 = Ph, X = O, R2 = OCO(tBu)

Asymmetric Strecker Reaction Using Chiral Schiff Base Catalyst

Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2000, 39, 1279-1281.

♦ Catalytic asymmetric Strecker reaction using polymer-supported catalyst -- Easy to remove, no loss of reactivity after recycle, but displays slightly lower enantioselectivity,

♦ Removal of protecting group and synthesis of D-tert-leucine

H

N Ph

CN

NH

O

Ph

1) HCN, 4 mol% A, 15h toluene, -78oC

2) Ac2O, formic acid

Cycle Yield (%) ee (%)

1 97 92 5 97 9210 98 93

CN

NH

O

Ph

COOH

NH

O

Ph

COOH

NH2 HCl

Recrystalized> 99% ee

65% H2SO4

45oC, 20h

1) Conc. HCl, 70oC, 12h

2) H2, Pd/C, MeOH

99% yieldD-tert-leucine, >$100/gquant. yield, >99% ee(84% yield from imine)

Vachal, P.; Jacobsen, E. N. Org. Lett. 2000, 2, 867-870.

R CH3

N Ph

R CN

NHBnH3CHCN, 2 mol% B

toluene, -75oC

Synthesis of Quaternary Amino Acids Using Chiral Schiff Base Catalyst

♦ Pros: Good results for some aromatic imines. ♦ Cons: Low ee for some substrates.

Entry R t (h) Yield (%) ee (%)1 C6H5 24 97 902 o-BrC6H4 90 45 423 m-BrC6H4 60 97 914 p-BrC6H4 80 quant 935 p-CH3OC6H4 60 98 887 t-Bu 15 98 708 C6H5CH2CH2 17 98 41

HN

NH

X

NH

N

t-Bu

R2t-Bu

HO

R1

O

A: R1 = polystyrene, X = S, R2 = OCO(tBu)B: R1 = Ph, X = O, R2 = OCO(tBu)

Krueger, C. A.; Kuntz, K. W.; Dzierba, C. D.; Wirschun, W. G.; Gleason, J. D.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 4284-4285.

R N

Ph

Ph R NH

Ph

Ph

CN10 mol% Ligand A, 10 mol% Ti(OiPr)4

2 equiv TMSCN, 1.5 equiv i-PrOHtoluene, 20h, 4oC

Asymmetric Strecker Reaction Using Chiral Schiff Base Catalyst

♦ Pros: Good results for most imines. ♦ Cons: High catalyst loading

Entry R X Yield (%) ee (%)1 C6H5 X = 5-OMe 82 972 o-ClC6H4 X = 3,5-DiCl 85 933 o-BrC6H4 X = 3,5-DiCl 93 944 p-CH3OC6H4 X = 3,5-DiCl 99 945 2-naphthyl X = 5-OMe 80 937 t-Bu X = 3,5-DiBr 97 85

X

AA1

OH

N

O

HN

O

NH

O

OMe

O

AA2

Schiff base

Snapper & Hoveyda's Schiff base Ligand A

Porter, J. R.; Wirschun, W. G.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 2657-2658.

N

Ph

PhR NH

Ph

Ph

CN

R

10 mol% Ligand A, 10 mol% Ti(OiPr)4

2 equiv TMSCN, 1.5 equiv i-PrOHtoluene, 24h

Synthesis of Unsaturated α-Amino Acids Using Chiral Schiff Base Catalyst

♦ Pros: Good results for most imines. ♦ Cons: Hydrolysis of product difficult.

NH

Ph

Ph

CN

R HCl NH

Ph

PhR

H2N O

NHBocR

HO OHOAc, MeOH 1) TFA, Et3SiH

2) HCl, MeOH3) NaOH, (Boc)2O, dioxane

♦ Conversion of aminonitriles to Boc-protected amino acids.

Entry R X Yield (%) ee (%)1 C6H5 X = 1-naphthyl 80 842 o-MeOC6H4 X = 1-naphthyl 61 783 p-NH2C6H4 X = 3,5-DiBr 93 764 Me X = 3,5-DiBr 84 855 Me-CH=CH- X = 5-OMe 95 89

Josephsohn, N. S.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 11594-11599.

Proposed Mechanism of Chiral Schiff Base Catalyzed Strecker Reaction

♦ Proposed Mechanism of Schiff base catalyzed Strecker reaction (Above)

♦ Suggested transition-state of Strecker reaction by molecular modeling and calculation (Below)

OTi

N

OOiPr)2

XPh NP

X

X

OTi

N

OOiPr)2NPTMS

NC

Ph

NC N(H)P

Ph

I II

III

OTi

N

OOiPr)2NP

Ph

TMSCN

N

O TiO

HN

H

NH

Me

Me

O

O

O O

HNC

N

H

H

Ar

Takamura, M.; Hamashima, Y.; Usuda, H.; Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed. 2000, 39, 1650-1652. Nogami, H.; Matsunaga, S.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2001, 42, 279-283.

R H

N

R CN

HN

9 mol% A, 2 equiv TMSCN

0.2 equiv PhOH, CH2Cl2, -40oC

P

P

OPhPh

Ph

OPh

O

OAlCl

Shibasaki's bifunctional catalyst A

Asymmetric Strecker Reaction Using Bifunctional Catalyst

♦ Pros: Good results for most imines. ♦ Cons: Polymer-supported bifunctional catalyst works not well.

Entry R Yield (%) ee (%)1 C6H5 92 952 p-ClC6H4 92 953 trans-CH3(CH2)3CH=CH2 66 864 n-Hexyl 80 805 t-Bu 97 78

Takamura, M.; Hamashima, Y.; Usuda, H.; Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed. 2000, 39, 1650-1652. Nogami, H.; Matsunaga, S.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2001, 42, 279-283.

Asymmetric Strecker Reaction Using Bifunctional Catalyst

♦ Conversion of aminonitriles to amino acid derivatives.

♦ Strecker reaction using polymer-supported bifunctional catalyst

P

P

OPhPh

Ph

OPh

O

OAlCl

O

Shibasaki's bifunctional catalyst A

3

= JandaJEL

Ph H

NFlu

Ph CN

HNFlu

10 mol% A 4 equiv TMSCN

1.1 equiv tBuOH CH2Cl2, -50oC

Cycle Time(h) Yield (%) ee (%)

1 60 98 87 3 44 78 83 5 204 83 77

Ph CN

HNFlu

Ph CONH2

HNFlu

Ph CONH2

NH2HCl(g), HCO2H

rt, 1h, (100%)

1) DDQ/THF, 3oC, 1h2) 1N HCl, 3oC, 5min

3) Amberlyst A-21/MeOH (91% in 3 steps) 98% ee

93% ee100% ee

95% ee recryst.(90%)

Proposed Mechanism of Strecker Reaction Catalyzed by Bifunctional Catalyst

Takamura, M.; Hamashima, Y.; Usuda, H.; Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed. 2000, 39, 1650-1652.

P

P

OPhPh

O

OAl

Cl

O

PhPh

(CH3)3Si

N

R

PNC H

N

R

PNC H

TMS

N

R

PNC H

H

II

B

C

I

RN

H P

TMSCN

P

P

OPhPh

O

OAlCl

O

PhPh(CH3)3Si

CN

NH

R

P

catalyst A

PhOHand/or HCN

+ PhOTMSand/or TMSCN

+

Ishitani, H.; Komiyama, S.; Kobayashi, S. Angew. Chem., Int. Ed. 1998, 37, 3186-3188.

Asymmetric Strecker Reaction Using Chiral Zirconium Catalyst

N

HO

R H

+ Bu3SnCN HN

HO

R CN

10 mol% A

toluene/benzene-65oC to 0oC, 12h

♦ Pros: Catalysts commercially available, good for most aromatic imines. ♦ Cons: Not so good for aliphatic imines.

Entry R Yield (%) ee (%)1 C6H5 92 912 p-ClC6H4 90 883 o-MeOC6H4 96 894 p-MeOC6H4 97 765 C6H5(CH2)2 55 836 iBu 79 837 C8H17 72 84

Br

Br

O

O

Zr

Br

Br

O

O

Zr

Br

O

O

Br

OtBu

L

L

OtBu

L = NMI Kobayashi's Chiral Zirconium Catalyst A

Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 762-766.

Catalytic Three-Component Strecker Reaction Using Chiral Zirconium Catalyst

♦ Pros: First catalytic three-component Strecker reaction; Good results for most imines; Low catalyst loading Catalysts commercially available. ♦ Cons: Still need protecting group; No mechanism discussion.

H2N

HO

X

HN

HO

R CNX

+ + HCN1-5 mol% A

CH2Cl2, -45oC, 12hRCHO

Entry R X Yield (%) ee (%)1 C6H5 H 80 862 C6H5(CH2)2 CH3 85 943 C8H17 CH3 83 904 cyclohexyl CH3 95 945 iBu CH3 94 916 tBu CH3 quant 88

Catalytic Three-Component Strecker Reaction Using Chiral Zirconium Catalyst

Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 762-766.

HN

HO

CN

HN

MeO

CONH2

CAN NH2

CONH2

1) MeI/K2CO3

2) H2O2/OH-

94% in 2 steps63%

leucinamide

♦ Conversion of aminonitriles to amino acid derivatives.

♦ Synthesis of D-pipecolic acid methyl ester.

TBSO CHO

H2N

HO

HOCN

HN

H3CO

CO2CH3

N

H3CO

TBSOCN

HN

HO

CO2CH3

NH

4+ HCN

2.5 mol% A

CH2Cl2, -45oC, 12h(80%, 91% ee)

+1) CH3I, K2CO3 acetone, rt

2) TBAF/THF (66%)

4

1) CBr4, PPh3/CH2Cl2

2) sat. HCl(g)/CH3OH, reflux (45%)

CAN, TFAA

4CH3OH-H2O, 0oC (88%)

D-pipecolic acidmethyl ester

Attempted Application of Catalytic Asymmetric Strecker Reaction

Vedejs, E.; Kongkittingam, C. J. Org. Chem. 2001, 66, 7355-7364.

N

H

CH3

N

HO

+ Bu3SnCN

N

NN

O

O

CH3

H

OH

O

H

CH3

H CH3

XCAN

N

H

CH3

HN

HO

CN

N

H

CH3

HN

H3CO

CONH2

(-)-Hemiasterlin

10 mol% A

toluene/benzene-65oC to 0oC, 12h( > 80%, 77:23 er)

1) MeI/K2CO3

2) H2O2/NaOH, Bu4NHSO4 (> 49%)

Asymmetric Strecker Reaction - Future Work

♦ Further development of chiral auxiliary methods, more applications in total synthesis.

♦ Development of more practical asymmetric catalytic systems toward commercial process. - higher yield & ee; higher turnover; easier separation… ...

♦ Better understanding of mechanism of catalytic asymmetric process.

♦ Successful application of catalytic asymmetric process in synthesis of large molecules.

Asymmetric Strecker Reaction - Conclusions

♦ 150 years after discovery of Strecker reaction, asymmetric Strecker reaction has been a real highlight in synthesis of α-amino acids.

♦ Catalytic asymmetric Strecker reaction achieved great advance in last 5 years. Although an efficient method for preparation of simple amino acids, its application in synthesis of large molecules and commercial production still needs further development.

♦ After 20 years’ development, Strecker reaction using chiral auxiliaries has been proved an efficient method for the preparation of simple amino acids and total synthesis of large molecules.