Passerini Reaction Revisited: Atom-Economical Construction of

-Hydroxy--Aminoamides, -Ketoamide Protease Inhibitors and

-Ketoamide Natural Products

J. Edward Semple, Ph.D.

Department of Medicinal Chemistry

Corvas International, Inc.3030 Science Park Road

San Diego, CA 92121

&

Structural Bioinformatics 10929 Technology Place

San Diego, CA 92127

International Conference on Multicomponent Reactions,

Combinatorial and Related Chemistry,

Genova, Italy, April 14-16, 2003

Application of the Ugi 4CC to the Total Synthesis of Furanomycin

J. E. Semple, P. C. Wang, Z. Lysenko and M. M. Joullie J. Am. Chem. Soc. 1980, 102, 7505.

M. M. Joullie, P. C. Wang and J. E. Semple J. Am. Chem. Soc. 1980, 102, 887.

OMe CHO OMe

N

O

NH

Ph

O Ph

Me

H

OMe

NH2

O

OH

H

H H

OOH

OH

OHOH

OH

O

N

O

NH

Ph

O

HMe

Ph

Me

O

NH2

O

OH

HMe

H H

2-Methyl-5-furfural Ugi adduct-1 (R, 2R, 5S)-

Furanomycin

-D-Glucose Ugi adduct-2 (S, 2R, 5S)-

Furanomycin

(Natural)

-Hydroxy--Amino Acid Natural Products

N-Benzoyl-3-phenylisoserine:

Taxol® side chain

Bestatin:

antitumor antibiotic

and immunomodulator

Amastatin:

aminopeptidase A and leucine

aminopeptidase inhibitor

NH

OH

O

OH

O

H2N NH

CO2H

OH

O

H2N NH

HN

OH

O

O

NH

O

CO2H

CO2H

Key Intermediates to -Ketoamide Protease Inhibitors and Related Targets

Conventional Synthetic Approaches to -Hydroxy--Amino Acid Derivatives

PGNH CO2H

R1

PGNH CHO

R1R1

CO2MeHCl•H2N

OH

BocNH

R1

CO2Me

OHBoc

NH

NH

CO2R

R1 O

OH

R1'

Pn....P 4P3P2NH

NH

R1O R1'

O

HN

P2'-P3'-P4'-etc

O

PGNH CHO

R1 R1

CO2MeNH

OH

PG

1. LiOH, MeOH,

H2O, H+

2. P1' Aminoacid

coupling

PGNH

NH

CO2R

R1O

2 steps

OH

P1--Ketoamide Target

1. NaHSO3, H2O

2. KCN, KHCO3,

THF, H2O

3. HCl, reflux

4. MeOH, H+

1. Deblock P1 amine2. Coupling rxns3. Optionally deblock

P1' acid 4 Optionally elaborate

P1' residue, coupling5. Deprotect side chains6. [O]

Reprotectamino group:Boc2O,NaHCO3,THF, H2O

R1'

1. (EtS)3CLi,-78°, THF

2. HgCl2, HgO,95% MeOH

1. LiOH, MeOH,

H2O, H+

2. P1' Aminoacid

coupling

-Ketoamide Targets

Modest to Poor Yields

Route A: Cyanohydrin

Route B: Orthothioformate

Compilation of stereospecific and

asymmetric approaches: H. H. Wasserman,

M. Xia, M. R. Jorgensen, E. A. Curtis

Tetrahedron Lett. 1999, 40, 6163

Peptides and Peptidyl P1--Ketoamides

I. Schechter and A. Berger Biochem. Biophys. Res. Commun. 1967, 27, 157

Peptide Peptidyl -Ketoamide

HN

NH

HN

NH

HN

R4

R3O

O

O

R2

R1

O

NH

HN

O

OR1'

R2'

P1P2P3P4 P1' P2

'

S1

S4 S2

S3 S2'

S1'

HN

NH

HN

NH

R4

R3O

O

O

R2

R1

O

P1P2P3P4 P1' P2

'

S1

S4 S2

S3 S1'

HN

NH

O

OR1'

R2'

S2'

NH

O

scissile bond ser ine trap

P1--Ketoamides: Potent Enzyme Inhibitors

Cyclotheonamides:

CtA, N-formyl

CtB, N-acetyl

Family of macrocyclic peptides incorporating

a highly reactive P1--ketoargininamide

transition state inhibitor functionality: potent

thrombin and serine protease Inhibitors.

HN

HN

N

O

NH(Ac, CHO)O

NH

ONH

O

O

O

HN

HN NH2

OH

NH

NH

NH

H2N NH

O

NNH

O

O

MeO2C

O O

CVS 3040

Potent mixed FIIa/FXa inhibitor

with good OBA in rats

:

NH

NH

O

N

O

NH

O2S

MeO

O

NH

HN NH2

O

NH

NH

O

HN

O

O

O

OBn

Eurystatin A:

Novel macrocyclic ketoamide

with prolyl endopeptidase

(PEP) inhibitory activity.

HNHN

NH

OO

O

NH

O

O

P1-Ketoargininamide:

Potent thrombin inhibitor

(Corvas)

P1-Norvalinketoamide:

Calpain inhibitor

(Alkermes)

P1--Ketoamides: CVS 2308-99Tc Novel Thrombus Imaging Agent

N

O

N

O

NH

O

NH

O

O

O

NH

O

HN

O

NH

H2NO

O

NH

NH O

5 NNH

NH

CO2H

O

O

CO2H

O

NH

NH

CO2H

O

O NH

O

NH N

H

O

HO2C

OH

O CO2H

OH

H2N NH

N

NMe2

OOH

N

O

S

Tc

NH

O

O

H

G. P. Vlasuk, T. R. Webb, D. A. Pearson

and M. M. Abelman U. S. Patent 5492895, 1996

Serine trap

The Passerini Reaction

N

OH

O

R1

R4

O O

NH

O

R1R2

R1NC + R2R3CO + R4CO 2H

acyl

H+

O O

HO

R3

R4

R2R1 N

R3R2

R4

O

R3

-Acyloxyamide ProductM. Passerini, Gazz. Chim. Ital. 1921, 51, 126.

M. Passerini and G. Ragni, Gazz. Chim. Ital. 1931, 61, 964.

I. Ugi et al. in Isonitrile Chemistry, I. Ugi, Ed.; Academic:

New York, 1971; Chapter 7.

A. Dömling and I. Ugi, Angew. Chem. Intl. Ed. 2000, 39, 3168.

shift

Passerini Reactions of -Amino Aldehydes with TFA and Pyridine-Type Bases

PG1NHN

OH

O

R1

CF3

O

PGNH

PGNH

O2CCF3

NH

O

R1

H

PGNH

OH

NH

O

R1NH

OH

NH

O

R1R3

O

NH

NH

O

R1R3

O

O

H+

PGNH

OH

OH

O

R2

O

R2

R2

R2R2

R2R2

CF3CO2H,R1NC,Pyridine,CH2Cl2

acyl

shift

Hydrolyticwork-up

-Hydroxy--amino amide derivatives:• ca. 1:1 mixture @ new hydroxy center • retention of chirality at original centers

*

Elaboration

1. Optional sidechain deprotection2. Oxidation

Hydrolysis

-Ketoamide Derivatives-Hydroxy--amino acid "norstatine" derivatives

J. E. Semple, T. D. Owens, K. Nguyen and

O. E. Levy Organic Lett. 2000, 2, 2769.

J. E. Semple and O. E. Levy. WO 0035868 A2,

June, 2000; Priority: December 1998;

U.S. Patent 6376649 B1, April 2002.

J. E. Semple et al. Abstracts of Papers, 218th

American Chemical Society National Meeting,

New Orleans, LA, August 22-26, 1999;

ORGN-419, MEDI-240.

Passerini reaction with TFA and pyridine:

W. Lumma J. Org. Chem. 1981, 46, 3668.

TiCl4-catalyzed Passerini-type reactions:

D. Seebach et al. Chem. Ber. 1988, 121, 507;

Helv. Chim. Acta 1983, 66, 1618.

Passerini Reactions of -Amino Aldehydes with TFA: Effect of Bases

Organic Base Additive pKa % Yield 3

2,6-di-t-Butyl Pyridine ~ 9 72

2,4,6-Collidine 7.4 71

2,6-Lutidine 6.6 68

Pyridine 5.2 60

N-Methylmorpholine 7.5 41

DABCO 8.2 33

4-N,N-Dimethylaminopyridine 9.7 18

N,N-Diisopropylethylamine 11 15

FmocNH

CHO CN

O

O FmocNH

O

O

OH

NH

OOrganic base, TFA, DCM, 0 °C to RT

1 2 3

Passerini Reactions of -Amino Aldehydes with TFA

Variation 1: PGNHCH(R 2)CHO + R 1 NC + CF 3CO 2H = PGNHCH(R 2)CH(OH)CONHR 1

Cmpd PG Amino Acid SC R2 R1 % Yield

a Boc Cys(Me) CH2SMe CH2CO 2Me 62

b Fmoc Val CH(CH 3)2 CH2CO 2t -Bu 68

c Fmoc Tyr(t -Bu) CH2Ph-4-(t -BuO) CH2CO 2Et 69

d Boc Arg(NO2) (CH2)3NHC(=NH)NHNO 2 CH2CO 2Et 38

e Fmoc Arg(Pmc) (CH2)3NHC(=NH)NHPmc CH2CH2Ph 75

f Boc Arg(NO2) (CH2)3NHC(=NH)NHNO 2 t -Bu 92

g Boc Phe CH2Ph CH2CO 2Allyl 67

h Boc Phe CH2Ph t -Bu 24-71

i Cbz d -Phe CH2Ph (S )-CH(i -Bu)CO 2Bn 65

j Boc ChxAla CH2Chx t -Bu 46

k Fmoc Gly H CH2CO 2Allyl 77

l Fmoc Ala CH3 CH2CO 2Allyl 83

m Fmoc Abu CH2CH3 CH2CO 2Allyl 73

n Fmoc Val CH(CH 3)2 CH2CO 2Allyl 68

o Fmoc nor-Val (CH2)2CH3 CH2CO 2Allyl 87

p Fmoc Leu CH2CH(CH 3)2 CH2CO 2Allyl 85

q Fmoc nor-Leu (CH2)3CH3 CH2CO 2Allyl 69

r Fmoc Phe CH2Ph CH2CO 2Allyl 67

s Fmoc Tyr(t -Bu) CH2Ph-4-(t -BuO) CH2CO 2Allyl 66

t Fmoc Ser(t -Bu) CH2Ot -Bu CH2CO 2Allyl 68

u Fmoc Asp(t -Bu) CH2CO 2t -Bu CH2CO 2Allyl 60

v Fmoc Arg(Pmc) (CH2)3NHC(=NH)NHPmc CH2CO 2Allyl 76

w Fmoc Lys(Boc) (CH2)4NHBoc CH2CO 2Allyl 79

x Fmoc Thr CH3(CH)O t -Bu CH2CO 2Allyl 62

y Fmoc allo -Thr CH3(CH)O t -Bu CH2CO 2Allyl 74

HCV

Inhibitor

libraries

Thrombin

and FXa

Inhibitors,

Libraries,

Bestatin

NH

NH

R2

OH

O

PG R1

J. E. Semple, T. D. Owens,

K. Nguyen and O. E. Levy

Organic Lett. 2000, 2, 2769.

J. E. Semple and O. E. Levy,

WO 0035868 A2, 2000; US

Patent 6376649 B1, 2002

Passerini TFA Protocol: Synthesis of -Hydroxy--Amino Acid Derivatives

1. BH 3•THF,

0° to RT, 91%

2. Pyr•SO3, Et3N,

CH 2Cl2, DMSO,

0° to RT, ~quant

OH

BocNH

O

BocNHH

OH

NH

BocNH

O

OH

O

BocNH

O

OH

t-BuNC, TFA,

pyridine, CH 2Cl2,

0° to RT, 46%

1. 6N HCl, reflux

2. Boc2O, K 2CO 3,

dioxane, H 2O

3. NaHSO 4, H 2O,

72%

A, 17 grams

OH

BocNH

OH

BocNH

NH 2

HN

NH 2

NNO 2

OH

O

HN NNO 2

NHO

BocNHOH

O

NH 2

HN

BocNHH

NH 2

HN NNO 2

O

NNO 21. Me(MeO)NH•HCl,

CH 3CN, HOBt,

EDC, NMM,

0° to RT, 68%

2. LiAlH 4, THF,

-78° to 0°

3. NaHSO 4, H 2O,

-20°, 71%

t-BuNC, TFA,

pyridine, CH 2Cl2,

0° to RT, 92%

1. 6N HCl, reflux

2. Boc2O, Na 2CO 3,

dioxane, H 2O

3. NaHSO 4, H 2O,

52%

B, 5 grams

BocNHH

O

t-BuNC, TFA,

pyridine, CH 2Cl2,

0° to RT, 24% or

t-BuNC, TFA,

2,4,6-collidine, CH2Cl2,

0° to RT, 72%

OH

BocNH NH

O

OH

BocNH OH

O

1. 6N HCl, reflux, ~quant.

2. Boc2O, NaHCO 3,

THF, H2O

3. NaHSO 4, H 2O,

93%

C, 23 grams

1. Me(MeO)NH•HCl,

TBTU, HOBt, CH3CN,

RT, ~quant.

2. LiAlH4, THF,

-78° to 0°

3. NaHSO4, H2O,

-20°, 99%

BocNHOH

O

J. E. Semple, T. D. Owens, K. Nguyen

and O. E. Levy Organic Lett. 2000, 2, 2769.

Concise Synthesis of Bestatin

J. E. Semple, T. D. Owens, K. Nguyen, O. E. Levy Organic Lett. 2000, 2, 2769.

J. E. Semple, T. D. Owens, K. Nguyen, O. E. Levy, 16th International Symposium for

Synthesis in Organic Chemistry, Cambridge, UK, July 19–22, 1999; P.4.

Passerini Reactions of -Amino Aldehydes with Carboxylic Acids

L. Banfi, G. Guanti, R. Riva, A. Basso, E. Calcagno

Tetrahedron Lett. 2002, 43, 4067.

L. Banfi, G. Guanti, and R. Riva Chem. Commun. 2000, 985.

J. E. Semple and O. E. Levy. WO 0035868A2, June, 2000

(Priority: 12/18/98); US Patent 6376649 B1, April 2002.

J. E. Semple et al. Abstracts of Papers, 218th American

Chemical Society National Meeting, New Orleans, LA,

August 22-26, 1999; ORGN-419, MEDI-240.

J. E. Semple, T. D. Owens, K. Nguyen and O. E. Levy

16th International Symposium for Synthesis in Organic

Chemistry, Cambridge, UK, July 19–22, 1999; P.4.

O. E. Levy, K. Nguyen, T. D. Owens and J. E. Semple

Abstracts of Papers, 16th American Peptide Symposium ,

Minneapolis, MN, June 26–July 1, 1999; P-6653.

PGNH CHO PGNH

R2

NHR

O

O

R1

O

H2N

R2

NHR

O

O

R1

O

NH

R2

NHR

O

OH

R1

O

NH

R2

NHR

O

R1

O

O

R2

acyl migration

-Acyloxy--aminoamide:• Ca. 1,1 mixture @ new acyloxy center.• Retention of chirality @ *.

N

OH

O

R

R1

O

PGNH

R2

*

RNC, R1CO2H, solvent

-PG

Cleaveacyl moiety

NH

R2

NHR

O

OH

Ketoamide target or advanced intermediate

PG

H+

Further chemistry

[O]

Further chemistry

Passerini Reactions: Examples of“Atom-Economical” Synthesis

Entry PG R2 R1 R Solvent %Yield Comments

1 Boc (S)-(CH2)3NHC(NH2)=N-NO2 Fmoc-Pro CH2CO2Et EtOH 51

2 Boc (S)-(CH2)3NHC(NH2)=N-NO2 Alloc-Pro CH2CO2Et EtOH 50

3 Boc (S)-(CH2)3NHC(NH2)=N-NO2 Ac CH2CO2Et EtOH 35-48

4 Boc (S)-(CH2)3NHC(NH2)=N-NO2 Bz CH2CO2Et EtOH 57

5 Boc (S)-(CH2)3NHC(NH2)=N-NO2 Ph(CH2)2 CH2CO2Et EtOH 60-62 Thrombin inhibitors

6 Fmoc (S)-(CH2)3NHC(NH2)=N-PMC Ac CH2CO2Et CH2Cl2 76

7 Boc (S)-(CH2)3NHC(NH2)=N-NO2 Alloc-Pro Phe-Tyr(Cl2Bn)-OMe CH2Cl2 59 Cyclotheonamide

8 Boc (S)-(CH2)3NHC(NH2)=N-NO2 BnSO 2-7Lac-Gly CH2CO2Et EtOH 39 CVS 1778 ketoamide

9 Fmoc (S)-(CH2)3NHC(NH2)=N-PMC Ph(3-OMe)SO2-Pdn-Gly PhEt MeOH 38 CVS 2044 ketoamide

10 Fmoc (S)-(CH2)3NHC(NH2)=N-NO2 BnSO 2-d-Arg(NO2)-Sar CH2CO2Et CH2Cl2 31 FXa Inhibitor

11 Boc (S)-(CH2)3NHC(NH2)=N-NO2 PrPent-Asp(OMe)-Pro CH2CO2Allyl CH2Cl2 83 CVS 1123 ketoamide

12 Fmoc (S)-i-Pr Ac CH2CO2t-Bu CH2Cl2 84

13 Fmoc (S)-i-Pr Formyl CH2CO2t-Bu CH2Cl2 50 R1CO labile in MeOH

14 Boc (S)-i-Pr Ac CH2CO2Me CH2Cl2 66

15 Fmoc (S)-Me d-Boc-Orn(Z)- Leu-OMe CH2Cl2 73

16 Fmoc (S)-Me l-Boc-Orn(Z)- Leu-OMe CH2Cl2 75-80 Eurystatin

17 Cbz (S)-Bn Bz CH2CO2Et CH2Cl2 44

18 Fmoc (S)-Bn Bz CH2CO2Et CH2Cl2 69

19 Boc (S)-Bn Ac CH2CO2Et CH2Cl2 67

20 Cbz (S)-Bn Bz CH2CO2t-Bu MeOH 44

21 Boc (S)-(CH2)2CH3 Ac CH2CO2Me CH2Cl2 Hep C Libraries

22 Fmoc (S)-4-t-BuO-Bn BnSO 2-d-Arg(NO2)-Sar CH2CO2Et CH2Cl2 31

NH

NH

R2

O

O

PG

R1

O

R

**

CO

Note: retention @ *

Thrombin inhibitors

Thrombin inhibitors

T. D. Owens and J. E. Semple Organic Lett. 2001, 3, 3301.

J. E. Semple and O. E. Levy, WO 0035868 A2, 2000;

US Patent 6376649 B1, 2002

Novel Application to the P1--Ketoamide Thrombin Inhibitor CVS 2392

N

OH

N-NO2

NH 2

BocNH

HN N-NO 2

NH 2

HCl•H2N NH

CO2Et

OH

O

NBnSO 2NH

O

O

OH+

NH

HN N-NO2

NH2

O

O

NH

OEt

1. H2, Pd/C,HOAc, EtOH, H 2O, 40 psi,~quant

2. Moffatt [O]3. RP-HPLC, 61%

CVS 2392

NBnSO 2NH

O

O

NH

HN N-NO2

NH 2

OH

O

NH

NNH

O

O

NH

HN NH•TFA

NH2O

NH

OEt

O

O2S

CO2H

Ph

O

O

Boc

EDC, HOBt,DIEA, CH3CN,RT, 68%

OEt

O

1. NaOEt (cat), EtOH,30 min, 0°

2. HOAc, 91%

O

+

CNCH 2CO 2Et,CH2Cl2, 0° to RT,4-6 days, 60-62%

3. HCl, EtOH,

0°, 10 min, ~quant.

J. E. Semple, T. D. Owens, K. Nguyen and

O. E. Levy Organic Lett. 2000, 2, 2769.

Tandem Passerini Reaction, N-Amino Deprotection, Acyl Migration Strategy for P1--Ketoamide Thrombin Inhibitor CVS 2328

N

OH

N-NO2

NH 2

BocNH

HN N-NO2

NH 2

BocNH NH

CO 2Et

O

O

O

HN N-NO 2

NH 2

NH

NH

CO2Et

OH

OO

N

O

NH BnSO2

N

O

NH

BnSO2

HN NH•TFA

NH 2

NH

NH

CO2Et

OO

N

O

NH

O 2S

O

CNCH 2CO2Et,EtOH, 0° to RT,4 days, 39-75%

OHN

O

NH

BnSO 2

1. H2, Pd/C, HOAc, EtOH, H 2O, 40 psi, ~quant2. Moffatt [O]3. RP- HPLC, 50%

1. HCl, EtOAc, 0° to RT,~quant2. Et3N, EtOH, pH ~8.5-9, 0° to RT, 65-90%

O

+

CVS 2328J. E. Semple and T .D. Owens,

unpublished

Application to CVS 2308 -Ketoamide

CVS 2308-99Tc

Thrombus

Imaging AgentJ. E. Semple and

T. D. Owens,

unpublished

N N-NO2

NH2OH

NH

BocNH

N

O

CO2Me

O CO2H

CNO

O

BocNH

NH

O

HN

N-NO2

NH2

O

O

O

NH

N

O

MeO2C O

ONH

NH

O

HN

N-NO2

NH2

OH

O

O

NH

N

OCO2Me

OO

NH

NH

O

HN

N-NO2

NH2

O

O

NH

N

OCO2Me

OO

NNH

NHCH(Ph)2O

+ +

CH2Cl 2,

0°-RT,

5 days, 83%

1. 5 N HCl, EtOAc,

0°-RT, quant.

2. 2 eq. Et 3N,

CH3CN, pH ~9,

0°-RT,

14 hrs, 82%

1. EDC, DMSO,

DCAA, toluene,

0°-RT, 1 hr, ~quant.

2. Ph 2CHNHCONHNH 2•TFA,

NaOAc, EtOH, H 2O,

reflux, 55-82%Advanced intermediate

- 5.7 gm

Efficient Construction of P3-Pyridone P1--Ketoamide CVS 3040

J. E. Semple and J. J . Cui,

unpublished

NH

Fmoc

FmocNH

NH

O

O

O

N

ONHS

MeO

NH

NH

OH

O

N

O

NH

S

MeO

O

NH

NH

O

O

N

O

NH

S

MeO

O

HN NH•TFA

NH2

N

O

NH

S

MeO

CO2H

NC

NH

H2N N-Pmc

HN N-Pmc

NH2

N N-Pmc

NH2OH

OO

O

O

O

O

O

O

CH2Cl2,

0°-RT, 38%

Et2NH (10 eq.),

CH2Cl2,0° to RT,

12 hrs, 82%

1. Moffatt [O], ~quant2. TFA, CH2Cl2, 0° to RT3. RP-HPLC, 50-56%

+ +

CVS 3040

- 2.3 gm

Studies on the Total Synthesis of -Ketoamide Natural Products

Cyclotheonamides A and B:

CtA, N-formyl derivative

CtB, N-acetyl derivative

Family of macrocyclic peptides incorporating

a reactive P1--ketoargininamide transition

state inhibitor functionality: potent thrombin and

serine protease Inhibitors.

Synthetic studies: (a) Maryanoff, B. E.; Nicolaou,

K. C. et al. J. Am. Chem. Soc. 1995, 117, 1225.

(b) Wipf, P.; Kim, H. J. Org. Chem. 1993, 58, 5592.

(c) Hagihiri, M.; Schreiber S. L. J. Am. Chem. Soc.

1992, 114, 6570.

Cyclotheonamides E2 and E3:

Wasserman, H. H. and Zhang, R.

Tetrahedron 2002, 58, 6277.

Eurystatins:

Eurystatin A: R = Me

Eurystatin B: R = Et

Novel 13-membered macrocyclic ketoamides with

prolyl endopeptidase (PEP) inhibitory activity.

Synthetic studies: (a) Wasserman, H. H.; Peterson,

A. K. J. Org. Chem. 1997, 62, 8972. (b) Schmidt, U.;

Weinbrenner, S. J. Chem. Soc. Chem. Commun.

1994, 1003.

NHO

OH

NH

NH

O

O

O

NH

NH

NHNH2

NH

(Ac, CHO)

N

OO

NH

O O

NH

NH

O

O

NH

O

R

Cyclotheonamides: Model StudiesUtilizing Key Passerini Protocol

O-Bn(Cl2)

BocNH CO2H

CNNH

FmocNHNH

CO 2Me

O

OBn(Cl 2)

CO 2Me

O

OBn(Cl 2)

O

BocNH NH

HN

NH

H2N N-NO2

O O CO2Me

OBn(Cl 2)

O

N-Alloc

1. Et2NH, CH2Cl2 ,

0° to RT

99%

2. HCO2H, Ac2O,

CH2Cl2, RT to

reflux, 79%

3. CCl 3OCOCl,

NMM, -40° to 0°,

CH2Cl2, 39-79%

1. MeOH, HCl,

0° to RT,

98%

2. Fmoc-d-Phe-OH,

EDC, HOBt,

NMM, CH3CN,

RT, quant

1. HCl, MeOH,

0° to RT, quant

2. Et 3N, pH~ 8-9,

MeOH, RT,

98%, acyl shift

Alloc-Pro-OH,

Boc-Arg(NO2)-H,

CH 2Cl2 , 0° to

RT, 2 days, 59%

Ct A/B: N(10) through C(17)

model compound

- 550 mg

HN

HN

N

O

NH(Ac, CHO)O

NH

ONH

O

O

O

HN

HN NH2

OH

O

NH

NH

HN

NH

H2N N-NO 2

OH O CO 2Me

OBn(Cl 2)

O

N

OO

T. D. Owens, J. E. Semple Organic Lett. 2001, 3, 3301.

J. E. Semple, 219th American Chemical Society National

Meeting, San Francisco, CA March 26-30, 2000; ORGN.667.CtA/B

Total Synthesis of Eurystatin A

T. D. Owens, G. L. Araldi, R. F. Nutt and J. E. Semple Tetrahedron Lett. 2001, 42, 6271

Passerini Reactions with -Aminoaldehyde Derivatives: Summary

TFA-Pyridine Conditions:

• Efficient, concise, high-yielding synthesis of -hydroxy-amino amides and

-hydroxy--amino acid derivatives.

• Scalable, up to 65-75 gms.

Protocols Utilizing Carboxylic Acids:

• Atom-economical synthesis of relatively complex -acyloxycarboxamides.

• Orthogonal amino deprotection-acyl migration reactions occur under very mild

conditions and directly deliver complex -hydroxy--acylamino amides.

• Scalable, up to 17-20 gms.

Stereochemistry:

• ca. 1:1 to 3:1 mixture at newly created -hydroxy center.

• Retention of stereochemical integrity at other chiral centers.

Applications:

• -Hydroxy-amino amides and -hydroxy--amino acid derivatives.

• Peptidyl and peptidomimetic -ketoamide serine and cysteine protease inhibitors.

• Natural products featuring -ketoamide moieties.

Acknowledgements

Timothy D. Owens, Ph.D.

Nathaniel K. Minami

Odile E. Levy, Ph.D.

Gian-Luca Araldi, Ph.D.

Jean J. Cui, Ph.D.

Daniel V. Siev

Khanh Nguyen

Ruth F. Nutt, Ph.D.

Terence K. Brunck, Ph.D.

Prof. M. M. Joullie (PENN)