Diastereoselective synthesis of bicyclic amino acids via ring contraction of α-chlorolactams

Tetrahedron Letters,Vo1.24,No.48,pp Printed in Great Britain

DIASTEREOSELECTIVE

SYNTHESIS

CONTRACTION

AG, Pharma

Summary:

Bicyclic

and subjected acids

+

were

of amino

acids

formal

new centers selective

inhibitors

containing

annulation

bert Comp.

dole-2-carboxylic compound,

which

We describe isomer

directed we were

a proline

there

leading

and Schering

to their

under

of alicyclic

of asymmetry:

approaches

basic

toward

a-chloro-derivatives to give bicyclic

of angiotensin

to prepare

proline

literature

precedent

a variety

have described

system

1) . Groups

derivatives

the synthesis

1 after

creates

for stereoat Warner-Lam-

of octahydroin-

of the corresponding

to synthesize

of =1, and the related fashion.

the need

to the basic

is little

the S,S,S-isomer

our efforts

the synthesis

moiety. rinqs

acid by hydrogenation

here

80

conditions

faced with

to these

Corp.

produces

VIA RING

fashion.

of our proqram

enzyme

ACIDS

and H. Urbach

converted

to rinq contraction

In the process

The

lactams

AMINO

6230 Frankfurt/Main

Synthese,

in diastereoselective

converting

OF BICYCLIC

0040-4039/83 $3.00 + .OO 01383 Pergamon Press Ltd.

OF a-CHLOROLACTAMS

R. Henning

Hoechst

5339-5342,1983

aromatic of enantiomers 2) .

separation

compound

2 which is the 2-exo derivative 2 in diastereo-

trans-isoindole

selective

COOH

HH

1 = We used

as a key reaction

of a-chlorinated

lactams

(br. s, 1H); 4.56 2

(NMR

(60 MHz,

3.2 - 3.0 lactams

4

(m,lH);

CDC13):

(m,2H);

promoted

(mp. 185OC, 3.25

6 = 7.0

2.5-1.0

(m,lH);

NMR

Favorskii (60 MHZ,

2.13

(br. s,lH);

(m,lOH)ppm),

which

CDC13):

(d,2H); 4.0

type ring

(m,9H)ppm)

(d,J = 10 Hz,

were

prepared

53 % yield,

reflux;

then H2/Raney-Ni,

respectively. 5339

ethanol,

contraction

6 = 1.8

1.8-1.1

and

IH);

from the known

5 3) and 2 4, by a dichlorination/monodechlorination

(PC15/S02CE2,CHC13, and

the base

NEt3)

sequence 5, in 38 %

5340

H

CD

.H.

m

X

N HH

0

Hi

-f:X=CI

L

COOH

2 = 6:X=H Z

t

c j:x=H x

5:

This tuted

=CI

type of reaction has been used previously for construction of substiprolines 6) and large ring analoques of proline 7) , but the stereo-

chemical fied.

outcome

Several

tne best

i

Thus,

basic

reagents

in our hands and 2 were

being

the solution

neutralized all

and 2

to give 2

(mp. 246OC,

yield.

2 was obtained of their

benzyl

been proven which

with

by comparison

1,3-cis which

equilibrium under

makes

sizable This

this

severe

in the other

with

between

admixed

for 2 hrs,

dioxide,

and the solution

with

6,7) ,

solution.

(1.05 equiv.)

115OC

an authentic

in these

which

evaporated

(dec.)) in 94 8 yield = 10 : 5 : 1 : 1) in 96 %

1

(ratio 9 :

l),

whereas

two cases

reaction

the carboxyl

less stable

isomers,

qroup

ester,

whfCh

reflects

with

we would

1. This have not

the thermo-

can be established

In A, there

is a

ahd the six-membered

is, as a consequence,

in the equilibrium

assumption

paobably

conditions.

compared

in the case of 2, where and which

sample of its benzyl 9) .

route

the respective

basic

between

isomer

isomer

extent

mp.

by an independent

the strongly

interaction

even more

solid,

the rearrangement

acid or carbon

filtered

speci-

in isomerically pure form, according to the 270 MHz NMR spectra esters 8) . The exo position of the carboxyl group in 2 has

The high diastereoselectivity

easily

in aqueous

8 H20

CH2C12/MeOH/HOAc/H20

2 was obtained

has been obtained

dynamic

hydroxide

2 N sulfuric

(amorphous

has not been

for effecting

Ba(OH)2-

material,

Rf = 0.46,

In this way

are possible,

are suitable

with

inorganic

isomers

barium

refluxed

precipitates to dryness

where

in cases,

situation

a 1,2-cis

ring, becomes

interaction

present

to any

mixture.

is underlined by the results obtained with trans-chlorolactam 115-120°C) obtained from trans-lactam 2 13) . We obtained under the $j (mp. described reaction conditions a 1 : 1 mixture of amino acids IQa _lQb --- and --(mp. 274 - 276OC).

5341

The ratio

was deduced

from the NMR

spectrum

of the benzyl

ester mixture

g: c X=CI

9: =

Since

lob

X=H

the bicyclic

absence

14) .

of strain

skeleton there

is practically

should

flat in the trans-case,

be not much

difference

in energy

due to the

between

1Qa under equili--- and IQb, which is expressed by their equal distribution of angiotensin converting enzyme inhibratinq conditions. The preparation bitors will

from

the above

be presented

amino

acids

in a future

Acknowledgement:

and their

A review A.B.

to Dr. H.-W.

We are grateful

on the synthesis

Mauger

examples

2)

and B. Witkop,

Chem. paper

M. L. Hoefle

T. Ibuka, Bull.,

E. H. Gold

N. Masei,

22,

2779

R. A. Abramovitch

5)

w. c. Francis,

G.B.R.

(1965);

in this issue:

Europ.

Pat. Appl.,

and E. M. Smith,

I. Saji,

K. Tanaka

published;

for further

R. Henning

37 231

Europ.

and H.

(1982);

Pat. Appl.,50 800 (1982).

and 4. Inubushi,

T. Miyata

and J. M. Muchowski,

J.R.

Thornton,

Soc.,8Q, 6238 -C. E. Anagnoshopoulos, ibid LI 6)

52, 47

has been

Chem.

Pharm.

and T. Imanishi,

17 (1978).

4)

J. Amer.

derivatives

Rev.,

(1975); T. Momose,

Heterocycles,s,-

for analyticalsupport.

(1983)

and G. Bobowski,

B. R. Neustadt,

3)

of proline

Lett .,

Fehlhaber

and Notes

see the followinq Tetrahedron

Urbach,

properties

paper.

References

1)

pharmacological

Chem.

de Graaf,

Can. J. Chem.,

J. C. Werner

W. Ch. Malger

6233

(1960).

and T. R. Hopkins,

(1958); R. J. Wineman, :g*

ii, 557

E.-P.

Hsu and

(1958).

and G. Van de Kolk,

Rec. Trav.

Chim.,

p!, 786 (1962); K. Kariyone, Chem. Pharm. Bull., &3, 1110 (1960); T. Takahashi and K. Kariyone, Yakuqaku Zasshi, 22, 711 (1959), Chem.

Abstr.,

22, 21940

(1959).

5342

7)

H. T. Nagasawa, J. Med.

J. A. Elberlinq,

Chem.,

I&

J . Heterocycl.

8)

The benzyl

9)

Chem.,

esters

followinq

(t,J=8Hz);

2,

were

3.08

(q,J=4.8Hz);

2 has also been 1)

3.29

P. S. Fraser

and N. S. Mizuno,

(1971); J. A. Elberlinq 411

and H. T. Nagasawa,

(1972)-

prepared

characteristic

3.95

03c:

501

by conventional

absorptdons

(q,J=4Hz);

were

12) . The

methods

observed:

i-OBzl: 6=

i--0Bzl:b=3.82(dd,J1=10Hz,

J2=4Hz);

s-OBzl:6=4.0(d,J=lOHz)ppm. obtained

by the following

pathway: H

l-l

H2(cat.)

5N HC1

0

2) Ac20/pyridine 3)

H

4)

reflux

-CN

N

-m

e-/MeOH"

COOH

I

+,F;ll) ,,CO%

(CH3)3SiCN/Et30

2 =

=

H. Urbach,

R. Henninq,

The relative qraphy:

Lett.,

10)

M. Mitzlaff,

11)

V. Asher, 141

12)

stereochemistry

H. Urbach,

Tetrahedron

M. Mitzlaff,

of ii has been

R. Henninq, (1983),

K. Warning

Tetrahedron

M. Mitzlaff

Lett.,

proven

(1983),in

by X-ray

preparation.

crystallo-

ans E. F. Paulus,

in preparation,

and H. Jensen,

C. Becu, M. J. 0. Anteunis

Liebiqs

Ann.

Chem.,

and R. Calleus,

1713

Tetrahedron

(1978).

Lett.,

(IYal).

Houben-Weyl-Miiller,

Methoden

p. 348 ff., Stuttqart

13)

D. Tourwe

14)

The mixture ppm of about free base

Bull.

esters

intensity

Sot. Chim.

shows

in DMSO-d6.

in Germany

12 August

1983)

Belq.,

two triplets

in the 270 MHz

(CDC13) and two triplets

hydrochloride (Received

equal

Chemie,

Vol.

15/l,

1974.

and G. Van Binst,

of benzyl

der Orqanischen

82,

at 6=

11

(1976).

3.90 and 3.86

'H NMR spectrum

of the

at 6= 4.49 and 4.46 ppm for the