Synthesis of peptide derived amino alcohols II. Synthetic methodology for the preparation of tertiary alcohols

Tetrahedron Letters,Vol.28,No.l5,pp Printed in Great Britain

SYNTHESIS SYNTHETIC

OF PEPTIDE

METHODOLOGY

Jollie D. Godfrey,

oo40-4039/87 $3.00 + .OO Pergamon Journals Ltd.

1603-1606,1987

DERIVED AMINO ALCOHOLS

FOR THE PREPARATION

Jr., Eric M. Gordon*,

II.

OF TERTIARY

ALCOHOLS

and Derek J. Von Langen

The Squibb Instilute for Medical Research P. 0. Box 4000, Princeton, New Jersey 08543-4000

Abstract: Synthetic methods are described for alcohols (i.e., 2). These novel peptidyl tertiary enzyme (ACE). The synthetic targets resemble -CHOH(CH3)-CHZ-NHmoiety, as replacement Recently typified

we described

by structure

In particular, critical

reminiscent

of pepstatin3

secondary

can be replaced peptide

of a new series of tripeptide

configuration

hydroxyl

activity

function.

two naturally

occuring

to (different)

unusual

Recently,

backbone5,

the peptide

essential

proteolytic

inhibitor/enzyme

enzyme (ACE). were shown to be inhibitors

enzyme inhibitors.

are

Pepstatin

amino acids, each of which contains

potent inhibitory

analogue

properties

hydroxyl

is incorporated against

a

group of into a

pepsin.

Iao= 28nM

=CHg

such as 1 are the first inhibitors

this novel series of protcase

aminoalcohols,

function

These designed

Rich has shown that the secondary

retained

2

derived converting

hydroxyl

activity.

by a 3’ alcohol, and that when such a statine

1 Z-H,

Aminoalcohols

of angiotensin

of the secondary

of high enzyme inhibitory

and bestatin4,

owe their biological

statine suitable

and absolute

for the manifestation

critical

and synthesis2

L which were shown to be potent inhibitors

the presence

factors

and bestatin

the design’

the preparation of a series of tripeptide derived aminoalcohols are potential inhibitors of angiotensin converting acyltripeptide substrates for the enzyme, but contain a for the scissile amide bond.

of ACE which rely on a hydroxyl

interactions.

In order to further

inhibitors,

we wished to prepare

1603

explore the constraints the related

group to forge of enzyme binding

3’ alcohol systems.

in

1604

Our initial residue.

synthetic

Treatment

route, summarized

of pyridyl

(63%). which undergoes

extremely

Epoxidation

of s produced

specifically

by L-Ala-L-Pro

of the synthesis selective

a -21

rapid Wittig olefination mixture

with a BOC protected

bromide to afford

of diastereoisomeric

gave the desired, olefin 2 in excellent

epoxides

t-butyl ester (CH3OH) to yield a mixture

of 2 required

benzoylation

in Scheme 1. proceeded

ester 2 with methylmagnesium

primary

amine.

Treatment

yield (90%).

(90%), which were opened regio-

of tertiary

the removal of the BOC and t-butyl ester protecting

of the resulting

N-terminal chiral methylketone

alcohols 2. Completion groups, followed

of 1 with TFA/CH,Cl,

by

or HCl/dioxane

SCHEME 1

a

b CH3 90%

0

4

d

C

CH3

-

CH3

h

CH2

f4 96%

c fi

R = t-butyl-0

6

R = t-butyl-0

g

R - Ph-

LQ.

R = Ph-

L

R = t-butyl-0

11

R = Ph-

J.2 (a) CH3MgBr, THF. -78’C;

(b) CHjPPh3Br,

t-b&y1 ester, CH30H. 65’C; (e) HCl/dioxane;

KN(SiMe$~

(f)

benzene; (c) MCPBA, CHrC12- (d) L-Ala-L-Pro-

TFA/CH2C12-

(g) PhCOCI, diisopropylethylamine.

1605

gave complex mixtures was necessary

of products,

to develop

indicating

a synthesis

that 2 is quite unstable

of 2 which obviates

to acidic conditions.

use of strongly

acidic conditions

Therefore,

it

in the final

stages. A second approach function

at an earlier

to amino tertiary

(PhCOCl, diisopropylethylamine) diastereomeric afford

epoxides.

the desired

alcohol 2 involved

stage of the initial to afford

Reaction

product

sequence.

9. Subsequent

of mixture

11, but lead instead

incorporation

of the required

Hence, 5 was deblocked epoxidation

of 2 afforded

1Q with L-Ala-L-Pro-t-butyl (via N-benzamido

N-benzoyl

(TFA/CH2Cl2)

and acylated

J,Q as a mixture

ester in hot methanol

participation),

to a mixture

of

did not

of oxazolines

go. A modification Treatment

of olefin

of diastereomers, produced

of the second approach

2 with osmium tetroxide7

which were separable

cu-hydroxy aldehydes

L-Ala-L-Pro

led to the desired

u

afforded

target by a path summarized

a 89% yield of diols fi as a nearly equal mixture

by chromatography.

Oxidation8

(80-90%). both of which underwent

benzyl ester to yield amino alcohols .JJ. Hydrogenolysis

with Pearlman’s

catalyst

afforded

both amino tertiary

in Scheme 2.

of the individual smooth reductive

of the individual

alcohols 16 and u

diol isomers JJ amination

with

aminoalcohols

as pure diastereomers.’

SCHEME 2

h & 69%

’ 50

R

k 80%

(h) 0~0~ (j)

N-methylmorpholine

L-Ala-L-Pro

H2 EtOH, HCI.

benzyi

N-oxide,

ester PTSA

c

THF/H20;

salt, NaHC03

Is

-CH2Ph

a

-”

52 uM

iz

-”

676 uM

(i) pyridine 3A sieves,

. SO3

DMSO, CH2Clp

THF, isopropanol:

diisopropyiethylamine:

NaBH3CN;

(k) Pd(OH)/C,

fi

1606

Introduction activity,

of the methyl groups into 1 to give fi and u

causing

nearly a 2000 fold decline

enzyme is unable to accomodate function

Acknowledgement:

compared

steric or conformational

molecule,

methodology enzyme systems. 10

We thank the Squibb Institute

Analytical

described

Department

to ACE inhibitory

angiotensin

constraints

the chemical

of other proteolytic

detrimental

to 1. Although

the additional

imposes on the inhibitor

in the design of inhibitors

in activity

was extremely

converting

the tertiary

alcohol

herein should find utility

for their assistance

in this work.

References:

1. E. M. Gordon,

J. D. Godfrey,

Jr., D. J. Von Langen, and 8. Natarajan.

Biochem. Biophys. Res.

Commun., 1985, 126, 419. 2. J. D. Godfrey,

Jr., E. M. Gordon,

D. J. Von Langen, J. Engebrecht,

and J. Pluscec, 1. Org. Chem.,

1986, 51, 3073. 3. H. Umezawa,

T. Aoyagi. H. Morishima,

M. Matsusaki,

H. Hamada.

and T. Takeuchi,

J. Antibiot.,

1970. 23, 259. 4. H. Umezawa,

T. Aoyagi. H. Suda, M Hamada,

T. Masuda, N. Kanbayashi, 1980, 33, 642 and references 5. M. Kawai.

S. Fukasawa,

had succeeded

Ala-Pro ester, cleavable

J. Antibiot., 1976, 29, 97; h4. Ishizuka,

T. Aoyagi, and H. Umezawa,

J. Antibiot.,

cited therein.

A. S. Boparai, M S. Bernatowic,

6. If this approach

and T. Takeuchi,

T. Takeuchi,

and D. H. Rich, J. Org. Chem., 1983, 48, 1876.

to yield L the synthesis

under nonacidic

7. J. R. Parikh and W. von E. Doering,

of 2 would have required

the use of an

conditions.

J. Amer. Chem. Sot., 1967. 89, 5505; A. J. Mancuso and D. Swern.

Synthesis. 1981, 165. 8. V. Van Rheenen. 10. Applying

the recommended

ment Newsletter described

R. C. Kelly, and D. Y. Cha. Tetrahedron Letfers. 1976, 1973.

DATA: 15, [alp = -71.1” (c - 1.17, CH30H);

9. SELECTED

regarding

Ala-Pro-OH,

1984, Arch. Biochem. und Eiophys., 1984, 229. 339). compounds

whereas

for bringing

(Received

lz, [a]o = -116.5’ (c = 1.02, CH30H).

amide bond replacements

as Bz-Phe-#[C(CH3)0HCH2NH]-Ala-Pro-OH,

C(CH3)OH-CH2-NH].

referee

nomenclature

Under

this system, compound

L may be expressed

in USA 21 October

1986)

Announce-

fi and 16 would be

and the general class of compounds

the general class may be described this point to our attention.

(Nomenclature

as $[(R,S)-

as Bz-Phe-$C[(R)-CHOHCH2NH]-

as #[(R,S)-CHOH-CH2-NH].

We thank a