Diastereospecific synthesis of diaziridines from D-mannitol. Access to chiral α-aminoacids.

Tetrahedron Letters,Vol.27,No.35,pp Printed in Great Britain

DIASTEBEOSPECIFIC

SYNTHESIS ACCESS

A.

Universite

Rene

Abstract --------

rue

from

D-

and

also

provides

Peres

leads

amaans

Greek

and

to

of

J.C.

of

D-MANNITOL.

Paris

chiral

Chimie

et

Associee Cedex

of

D orL

Biochimie

au

06,

CNRS

11~400)

FRANCE.

diastereoisomeric

precursors

synthesizing

Depezay*

de

(Unite

75270

-

FRON

a-AMINOACIDS.

- Laboratoire

opening

mannitol

DIAZIRIDINES

Toxicologiques

Saints

: Nucleophilic

ned

C.

Descartes et

des

OF

CHIRAL

Dureault,

Pharmacologiques 45

TO

oo40-4039/86 $3.00 + .OO Pergamon Journals Ltd.

4157-4160,1986

diaziridines

a-aminoacids

polyhydroxylated

(or

obtai-

aldehydes)

piperidines.

Many non classical a-aminoacids exhibit high biological activity. Therefore new me1 could prove very useful. The preparation of suitably protected,

thods for their synthesis

a-aminoaldehydes as chiral educts for asymmetric products has also attracted a 2 agents for a great deal of interest . Since N-protected aziridines can be aminoalkylating 3 , chiral, suitably funcvariety of nucleophiles and especially for organometallic compounds optically

tionalised

pure

aziridines

The methodology

can be precursors

we propose

ning the synthesis

of enantiomerically

(scheme I) is similar

of chiral

(R)

t

published

concer-

COOH or

NHY

2

to the one we have recently 4

or aldehydes.

.

a-hydroxyaldehydes

HO

a-aminoacids

pure

NHY

2

Nu

==+

t NU

A

I- OH

eP

COOH

CHO

OH

t

OH

2 YHN -c

This note describes

the synthesis

ridines A and -B from D-mannitol, sents,in

order

to

-

of the two functionalised

with various

check the validity

of these aziridines

Nu

nitrogen

of the proposed

followed by oxidative

cleavage 4157

protecting

diastereoisomeric

oractivating

scheme, an example leading

to

diazi-

groups and pre-

of nucleophilic

cy-aminoacids.

opening

4158

l NY

H

$

(g)or (h) or (i) HN

-

YN 1.

6

II

Scheme

*

phcH2~2ph (a)5JTh +$y;;

2

&$

.g

6_b

Y =CO,CH,P

6-c

Y=Ts

h

50%

10_b346 X 1* 85% qxXH,

COOH

2

2

CzHs 12c -

Scheme III

TsNH+

* *

TsNHiIS

13c -

4159 Diaziridines hexane

prepared

from D-mannitol

: 5,6 diimino 3,4-O- methylethylidene

are 1,2

diols 2S, 3R, 4R, 5S, 1 and 2R, 3R, 4R, 5R 1. They are obtained

yield respectively

from diazido

Diaziridine configuration heating

1 results

inversion

in refluxing

diol 3, itself

formed with 50 % yield

from reductive

ring closure

at C-2 and C-5

toluene).

5

Diaziridine

with

100 % and 60 %

from D-mannitol.

of 1 by triphenylphosphine

with

(complete

ring closure occurs after twenty hours

2 results

from reduction

of the diazido

dibromo

compound 5 by lithium aluminium hydride. This reaction involves cyclisation and configuration 6 . 3 has been formed through dimesylation of 1 into &and nucleophilic substitution inversion by bromide

ions (MgBr2) with inversion

7

at C-2 and C-5 of 4

.

In order to effect the following steps (nucleophilic opening - cleavage) the Nunsubstituted

raw diaziridines

1 and 2 were transformed

dines &a, b, c, and la, b, c, respectively Regiospecific 6a promoted dihydroxy

ring-opening

by BF3-etherate

piperidine

addition

2 with four asymmetric

opening

been shown to beapowerful of the first aziridine

heterocyclisation

derivative

carbons

&and

set of inhibitors

N protected

aziri-

.

lo

to N-benzyl

to the chiral

of known configuration.

is attractive

ring leading

into the appropriate

; bY=)jOCH2Ph ; c Y=Ts)

of dimethylcopperlithium

leads to monoalkylated

logues of 2 (using other nucleophiles) recently

(aY=CH2Ph

diaziridine 3-amino-4,5-

Synthesis

of ana-

since polyhydroxylated of glycosidase

to a non stabilised

piperidines have 8 activity . Nucleophilic

metallic

amide,

is followed by

due to attack of the amide at the C-6 of the second aziridine

cycle.

When Y= 0CH2Phor Ts, nucleophilic ring opening addition of fi or SC by dimethylcops perlithium in THF (without Lewis acid catalysis), leads to diamines JJb or NC in 46 % or 85 % 10 yield respectively . In both cases attack occurs at the less hindered carbons. The Ntosyldiaziridine

&c was found as expected

Since some benzylic be due either metallic

to

and oxydative

acid. The specific

cleavage

rotation

reported

for the synthesis herein,

in the reaction,

of the intermediate

ester

substrate

thepoorestyield metallic

group of the aziridine

ti

COmpSreS

than diaziridine

6b.

in case of 6b can

amide, or to intermolecular

carbamate.

The acetonide

diol flc led to tosyl L

of the resulting

of its methyl

: -26", lit. -22" Diastereoisomeric

cursors

is recovered

decomposition

amide attack at the carbonyl

hydrolysed

sults (B

alcohol

partial

to be a more reactive

uc

was

a-aminobutyric

well with previously

reported

re-

9J. N-Tosyl

diaziridines

of enantiomerically

the use of N-benzyl

sis of chiral polyhydroxylated

prepared

pure

diaziridines

from D-mannitol

a-aminoacids. provides

are

By extension

a promising

pre-

interesting

approach

of the results to the

synthe-

amino piperidines.

000

* (a) ref.4 ; (b) NaN3, DMF, 7O"C, 3h.; (c) MsCl, Py, 2O"C, 20h.; (d) MgBr2, CH2C12-ether, 4O"C, 20h. ; (e) LiA1H4, THF, 20°C, 6h. ; (f)PPh3, toluene, 105"C, 20h. ; (g) PbCH2Br, NEt3, THF, 20°C,

15h., 70% ; (h) PhCH20COC1,

NEt3, CH2C12,

2O"C, 60% j (i) I-KH, THF, 20°C 2-TsCl,

55%. ** (a) Me CuLi, BF3.Et20 5eq. THF -78°C --,+20°C ; (b) Me2CuLi, 2eq. THF -78°C --.m -30°C 2 (c) CF3COOH, H20, O°C, 4h. ; (d) Cr03, NaI04, AcOH, H20, ZO'C, 4h. ; (e) CH2N2, ether.

2O"C,

4160

References

and notes

:

. a) Reviews:J.W.

Apsimon and R.P. Seguin, Tetrahedron, 1979, 35, 2797. D. Hoppe, Nachr. Chem. Techn. Lab., 1982, 30,783-U. SchoEkopf in "Topics in current chemistry", 1983, 109, 65,. b) P.J. Maurer, M. Takahata and H. Rapoport, J. Am. Chem. Sot., 1984, 106, 1095 -J.M. Fitzner, R.G. Shea, J.E. Fankhauser, P.B. Hopkins, J. Org. Chem., 1985, 50, 419 -J.A. Bajgrowicz, A. El Hallaoui, R. Jacquier, Ch. Pigiere, Ph. Viallefont, Tetrahedron, 1985, 41, 1833.

W. Oppolzer, . a) J.A. Ferentz

R. Pedrosa and R. Moretti, Tetrahedron and B. Castro, Synthesis, 1983. 676.

Lett.,

1986, 7,831

b) Review :D. Tourwe, Janssen Chimica Acta, 1985, 2, 3. . a) O.C. Dermer, G.E. Heem, "Ethyleneimine and other aziridines" Academic Press, N.Y. 1969. b) A.P. Kozikowski, H. Ishida and K. Isobe, J. Org. Chem., 1979, 9, 2788- M.J. Eis and B. Ganem, Tetrahedron Lett., 1985, 6, 1153- M. Aratani, L.V. Dunkerton, T. Fukuyama, Y. Kishi, H. Kakoi, S. Sugiura, S. Inoue, J. Org. Chem., 1975, 40, 2009. Y. Le Merrer, A. Dureault, C. Gravier, D. Languin and J.C. Depezay, Tetrahedron Lett., 1985, a, 319. Y. Ittah, Y. Sasson, I. Shahak, S. Isaroom and J. Blum, J. Org. Chem., 1978, g, 4271. J.N. Denis, A. Krief, Tetrahedron, 1979, 35, 2901. P.Place, M.L. Roumestant, J. Gore, Bull. Sot. Chim. France, 1976 , 169. P. Lalegerie, G. Legler and J.M. Yon, Biochimie, 1082, 3, 977- G.W. Fleet,P.W. Smith, S.V. Evans and L.E. Fellows, J. Chem. Sot. Chem. Commun.. 1984,~ 1240 and references cited therein S.V. Evans, A.R. Hayman, L.E. Fellows, T.K.M. Shing, A.E. Derome and G.W. Fleet, Tetrahedron Lett., 1985, 2, 1465 and references cited therein- R.C. Bernotas and B. Ganem, Tetrahedron Lett., 1985, a, 4981- M.J. Eis, C.J. Rule, B.A. Wurzburg and B. Ganem, Tetrahedron Lctt., 1985, 2, 5397. J.A. Bajgrowicz, A. El Hallaoui, R. Jacquier, Ch. Pigiere, Ph. Viallefont, Tetrahedron Lett., 1984, 11, 2759. . Yields given on scheme111 and III correspond to purified products (recrystallization or HNMR spectra (250 MHz, CDC13), analyses and/or mass spectra are flash chromatography). consistent with the assigned structures. Specific rotation are taken for A= 589nm, at 20". 3 a]=+ 47" (C=1,4, CHzClz) i; 3" (C=l, CHzClz)- m.p. = 91°C 5 41" (C=l, CH$lz) ;A = -45" (C=l, CHzClzl- NMR : 7,30-7,20 (m. lOH, arom.); 3,55 (m,2H, Ha) ; 3,41-3,30 = 12,5 Hz, 4H, NCHz) ; 1,90 (d, J1,2=3,5 Hz, 2H, HI trans) ; 1,57 (m, 2H, Hq) ; = 6,3 Hz, 2H, H1 cis); 1,34 (s, 6H, C(CH3j2 ). (C=l, CH2C12) - m.p. = 104°C - 24" (C=l,5, CHzCl2) -m.p.= 60°C NMR : 7,82 (d, J = 8 Hz, 4H, arom.) ; 7,35 (d, ; 3,81 (m, 2H, H3) ; 2,76 (m, 2H, Hz) ; 2,60 (d, J1.2 = 7 Hz , 2H, H1 cis) ; 2,45 (s, 6H, CHJ-Ph); 2,38 (d, J1.z = 5 Hz, 2H, H, trans) ; 1,23 (s, 6H, C(CHJ&) 54" (C=l, CH2Clz)- NMR : 7,33-7,25 (m, lOH, arom.) ; 3,50(11x,2H, Ha) ; 3,6772 3,20 CAB, J = 13,5 HZ, 4H, NCH2) ; 1,66 (d, 51.2 = 3,5 HZ, 2H, H1 transl ; 1,6 (m, 2H, H2)

bl

=+

8,5 Hz, 4E, arom.) ; 7,35 ; 2,61 (d, 51.2 = 7 Hz, 2H, H 1 cis) ; trans) ; 1,21 (s, 6H, C(CH3j2) 2,43 (s, 6H, cH$'h); 2:25 id,3J,,2 =1,5 Hz: 2;1, ;, ) NMR : 7,50-7,20 (m, lOH, arom.) ; 3,84 (m, 2H,H4, Hg) ; 3,88-3,65 CAB, J = 13 Hz, 2H,

2

~~~H~se%I;;ci:F;~~~,~~~~~~~~~.~~~l~:~~~~~':~:~8~"d~i;'_

NCH*)

; 3,60-3,33';AB,

J = 13 HZ, 2H, NCHZ)

; 2,40 (m, 1H , Hs) ; 1,85-I,20

(m, 12H) ;

-62" (C=l, CHOCK,) -m.p= 198°C = -104" (C=l, CHzClz) -map= 124°C = -26“ (C=O,7, EtOH) -m-p= 68"C- NMR : 7,75 (d, J = 8,5 Hz, 2H, arom.) ; 7,26 (d, ; 5,lO (d, J?,~H = 10 Hz, lH, NH) ; 3,87 (m, lH, Hz) ; 3,50 (s, 3H, OCH3) ; 2,40 (s, 3H,PhCH3) ; 1,76 (m, lH, H3) ; 1,68 (m, lH, H3 ) ; 0,92 (dd, 53.4 = 7 Hz, J32 = 7,5 Hz, 3H, H4). (Received

in

France

29

May

1986)