Synthesis of unnatural amino acids: spiro[4.5]-2-aza-decan-3-carboxylic acid

Tetrahedron Letters,Vo1.25,No.40,pp

4483-4486,19f?4 0040-4039/84 $3.00 + .OO

Printed in Great Britain

01984 Pergamon Press Ltd.

SYNTHESIS

OF UNNATURAL

WIN0

RCIDS

SPIROC4.53-2-RZA-DEC6MU-3-C&RDOXVLIC

V.Teetx* Hoechst

increased

Aktiengesellschaft,

nitriles

lipophilicity.

via alkylation

corresponding

amine,

D-6230

acids They

Frankfurt/Rain

represent

are readily

bulky

SO

proline

available

with broeoacetaldehyde

cyclisation

&CID

and H.6aul

SpiroC4.n3-2-ara-alkan-carboxylic with

I

analogues

froe cyclic

acetals,

reduction

to the

and subseguen t Strecker

to the ieine

synthesis.

Introductionr Hydrophobic

or inhibitors

this general

knowledge

dseanding

aeino

peptides.

Recently

enzyme

have

acids

been

The synthesis prepare

are known to

interactions

of substrates

play

to the active

we synthesized Cl3 in order

powerful

found

SOIY

contain

systees

in a sieilar

In persuit

described

of

and sterically

of the angiotensin

and rather

in the binding

proline-residues

the spiro-proline

of the spiroC4.53-coepound

related

role

of an enzyee.

lipophilic

to substitute

inhibitors

which

an ieportant site

in

converting

substructure

hue

C2.33.

can be used to

convenient

eannw.

Chemistry: The anion

141 and llkylated

aeide high

of cyclohexanecarbonitrile

yield

sodiue

in ethanol

(90% yield, groups

leads

converted

with

L83. Subseguent

b.p.

to give 69-72

broeoacetaldehyde

reduction the aeine

*C at 8 torr

to the cyclic

ieine

to the aeinonitrile

& can be obtained

diethylacetal

of the nitrile 4_, which

J_ rrhich should

4483

lithiuediethyl2 at -7WC

S is perforeed

is purified

i1oJ Pall.

& by eeans

with

Cleavage

in with

by distillation of the acetrl

not be isolated

of the Strecker

best

but rather

synthesis

CS, 93.

4484

C=N +

Br-CH2

/

-CH

OC2H5

CH2 CH

Li-N(Et)2

1 OC2 H5

CH2 CH

Nd

CW

(OEt ) 2

V

H+v

(--Jo

CH2 -NH2

Scheme Synthesis

of

(R,S)-spiroC4.53-2-aza-decan-3-carboxylic

acid

(IJET) 2

4485

Complete graphy

tranmforeation

and

the

arinonitrile

of the

reaction

is

& is then

performed

saponified

escaping

aqueous

froe

solution

recrystallitsd diisopropyl amino

ether

to yield

IR4S

(acetate

aeino

by

fore1

Tranaforution

water

a derivative

(77% yield)

Experiments

concerning

salt have not been

References

suitable

bo taksn

far tracem

R.kiger

C23 Schering

Corporation,

tiich

can be

me

with

resin

and

an ion exchange

recrystallisation

free e.g.

from

acid z to the benryl-

chloride

procedure

Cl, 63 gives

synthemim. of @ via

resolution

a diaster-ic

yet.

and H.8au1,

thim

EPCI SO800

journal

(19843.

(19821.

C33 Hoechmt Aktiengesellschaft, DO8 3211397 (1983). I43 tl.Larchevequs and Th.Cuvigny, Tetrahedron Lettmrm I53 A.Strecker,

Liebigs

Ann.Chee.130,

217

44, -1

(1975).

(18641.

t63 J.Raeachandran and C.H.Li, J.0rg.Chee.28, 173 (1963). C7I 'Pinner' synthesis; see D.8.Reilmon, in Patai, The Cheeistry and

Iaidates,

pp.38S-489,

Wiley

Neu York

t8I 1-(Di-
of the

and Footnotem

Cl3 V.Teetr,

hidines

of

extract

like chlwoforr/butanol/

for peptide

the optical

successful

The raw

'C (decoepositfonl).

of the amino

a
or argon.

acid hydrochloride,

treatment

in

ehroeato-

acid L by heating

of the butanol

molvents

( r.p. 20s

82%

acid z can be obtained

aeberliten

should

or other

by thin-layr

nitrogen

Evaporation

the raceeic

free ethanol

ethanol/ether. ester

the lixture. leaves

under

to the aeino

Recrusicm

in 4R HCl for five hourm. HCN

im checked

imine

(0.5 sol) dry diethylaeine

15% solution

of n-butyllithiur

are added

in hexane

of

(1975).

3 I to 312.5

at -10%

ml

under

f0.S eel) of a nitrogen.

The solution is stirred for 20 min. then cooled to -70X. Within 30 ein. 54.6 g cyclohexanecarbonitrile 1 are added, the eixture is stirred for additional 30 min. and 98.5 g broeoacetaldehyde diethylacetal 3 are added dropwise within 1 hw. The reaction fm left for 24 h. at low teeperature then uareed up to rooe teeperature and poured onto 100 g ice. After twofold extraction with SO0 rl ethyl acetate the organic layer im dried over sodium sulfate, concentrated i.vac. and subritted to a vacuue distillation. Yield: 90 g (80%) I b-p. 78-79 .C at 8 twr (lo= Pa).

4486

CO3 8piroC4.S3-2-aza-d~m-3~ubonitrilm SO.2

& x

g Minorethyl-di-(ethyfoxy)mthyl-cyclohmxanm

4_ arm stirred

in a

mixture of 300 ml ethanol and 300 ml 1 N Hcl undmr nitrmgmn or argon for 1 h.. After complete clmavagm of the starting matmrial thm solution is cooled to 0 'C and quickly adjustmd to p& with 2 N NaflH. Immmdiatmly lftwwardr tha mixture is cooled to -10 lC, 300 ml glwial acmtic acid and

cyanide MaCN) arm added and thm rmactiQh vesmml is to the aninonitrilm & is chmckmd for 5 h.. Cocaplete trannforration

17.5 g sodium

closmd

by thinlayer

chromatography

on silica

gmlj

solvmnt8

ethyl

acmtatm

/

(v/v). The R+-valums diffw substantially (0.65 vmrsus 0.3 for the nitrile). The solution is then rvapcwatod to drynmss. This petrol

ether

rau material

2~1

should

dirmctly

converted

(Received

in Germany

soon be saponifimd to an mstmr

6 June

C71.

1984)

to thm frmm

amino

acid

L or