Beckmann rearrangement of N-(α-hydroxyiminoalkylphosphonyl)amino acids. A convenient synthetic approach to novel peptide-transition-state analogs.

Beckmann rearrangement of N-(α-hydroxyiminoalkylphosphonyl)amino acids. A convenient synthetic approach to novel peptide-transition-state analogs.

Tctrahcdron Lencrs. Vol.33. No. 15, pp. 2067-2068. 1992 0040-4039/92 93.W + .OO PcrganmnRcss Ltd Printedin Great Britain BECKMANN REARRANGEMENT A...

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Tctrahcdron Lencrs. Vol.33. No. 15, pp. 2067-2068. 1992

0040-4039/92 93.W + .OO PcrganmnRcss Ltd

Printedin Great Britain

BECKMANN

REARRANGEMENT

A CONVENIENT

Eli

Breuer,-

Hisham

N-(a-HYDROXYIMINOALKYLPHOSPHONYL)AMINO

OF

SYNTHETIC

APPROACH

Zaher

TO NOVEL

of Pharmaceutical

Jerusalem,

P. 0. Box 12065,

Chemistry,

The School

Jerusalem,

91120

(TS)

intermediates

enzyme,

and

several

phosphonamidate

the

they

hydrolysis

analogs"l

represent

of

are

in enzymatic an

analogs,

amide

bond,

The Hebrew

University

of

N-(a-hydroxyiminoalkylphosphonyl)amino acid (z), which represent a new type of peptide

designed

reactions

important

peptide

the

of Pharmacy,

Israel

Abstract: Thermal Beckmann rearrangment of derivatives (2) yields acylphoaphordiamidates analogs.

mimicking

ANALOGS.

and Zeev Tashma

Department

"Transition-state

ACIDS.

PEPTIDE-TRANSITION-STATE

on

bind

approach which

show

the

assumption

better to

enzyme

resemble

powerful

than

the

the

that

inhibitors.

tetrahedral

inhibitory

structures

substrates For

to

the

example,

intermediate

activity

towards

in some

peptidases.2 Recently

we

found

that

in analogy

a-hydroxyiminobenzylphosphonamidates In

acylphosphordiamidates.4 biologically

potentially

the

to

ii

of

facile

our

compounds

we

considered

continuing derived

of type

This communication

2.

Such

reports

products

the realization

NH,OH

i

1100 --_-->

----_-> ph_C-p-NH-CH-COOB'

Ph-C-P-NH-CH-COOR' II I 0 OUe

can

guest

from

that

rearrangement for

new

to

types

acids viewed

of (2),

as

Beckmann

the would

a novel

of and

acylphosphonates

application

be

and phosphinates,'

Beclanann

N-(a-hydroxyiminoalkylphosphonyl)amino

acylphosphordiamidates analogs.e

course

a

active

hydroxyiminophosphonates,5"'7 rearrangement

to a-hydroxyiminophoaphonates undergo

lead

types

of

to TS

of this plan.

ii i Ph-CO-NH-P-NH-CB-CCXR' I OMe

II I N OMe

3 HO

1 a,

Methyl ence which

to yield

was converted %.I2

reoisomere.

H,

R’

Heating

methyl

L-Ala-OMe (E)-&

or

was

reacted

with

Gly-OEt

in CH,Cl,

in the pres-

N-(ethoxycarbonylmethyl)benaoylphosphonamidate

in situ by treatment

Simiiarly

3

=Et;b,R=R'=Me

benaoylphosphonochloridatelo

of pyridine

amidate

R =

2

with NH,OH.HCl,

to a-hydroxyiminobenaylphosphon-

gave g I3 and subsequently (E)-g

in

2067

(&),*I

refluxing

3x4 toluene

as mixtures for

4

of diaste-

or

6

h,

2068

respectively,

caused

them to rearrange

compounds

may be viewed

phosphoryl

substituting

tion

equally

well,

strategy

phonates

leading

activity. with

Acknowledgement

this

the methodology

This

tered by the Israel

with

eventually Toward

we described

analogs

for the carbonyl

of acylphosphonochloridates

biological this

as tripeptide

cleanly

with a missing

of the middle

the

to more goal,

to phosphordiamidates

free

amino

complex

we shall

developed

amino

3ax5 and ,,.I6 -

a-carbon acid.

groups

We believe

of peptides

acylphosphordiamidates

combine,

in the next

for the synthesis

These

and the tetrahedral that

should with

phase

reac-

proceed

potential

of our work,

of aminohydroxyiminophos-

recently.5r6

work

was

Academy

supported

of Sciences

in part

by the

Fund

for Basic

Research

adminis-

and Humanities.

References and Notes I.* R. Wolfenden, Ann. Rev. Biophys. Bioeng. 1976, 2, 271. R. Wolfenden and L. Frick, in "Enzyme Mechanisms, M. I. Page, A. Williams, Eds. 1987, Royal Society of Chemistry, London, p. 97. A. Tramontano, A. A. Amman, R. A. Lerner J. Am. Chem. Sot. 1988, 110, 2282. J. Jacobs, P. G. Schultz, R. Sugasawara, M. Powell, J. Am. Chem. Sot. 1987, 109, 2174. 2. A. P. Kaplan, P. A. Bartlett, Biochemistry, 1991, 30, 8165. 3. E. Breuer, A. Schlossman, M. Safadi, D. Gibson, M. Chorev, H. Leader, J. Chem. Sot. Perkin 1, 1990, 3263. 4. E. Breuer, H. Zaher, Z. Tashma, in preparation. 5. E. Breuer, M. Safadi, M. Chorev, D. Gibson, J. Org. Chem. 1990, 55, 6147. 6. E. Breuer, M. Safadi, M. Chorev, A. Vincze, P. Bel, Tetrahedron 1991, 47, 1257. 7. G. Golomb, A. Schlossman, H. Saadeh, J. M. Van Gelder, M. Levi and E. Breuer, Pharm. Res., 1992, in press. 8. Statin, an unusual B-hydroxy-r-amino acid, a constituent of pepstatine,a naturally is also considered a TS analog of a occurring inhibitor of aspartic proteinases, shortened dipeptide, lacking the nitrogen of the C-terminal acid. Fed. Am. Sot. Exp. Biol. 1976, 35, 2494. M. P. 9. G. R. Marshall, Fed. Proc., Marciniszyn, J. A. Hartsuck, J. J. ti. Tang, J. Biol. Chem. -1976, 251, 7088. 10. E. Breuer, M. Mahajna, L. D. Quin, G. S. Quin, J. Org. Chem. 1991, 56, 4791. 11. 31P WMR: 6 = 7.9 ppm (septet, J = 11 Hz). 12. (E):(g) = 3:l. WMR, (CDCl,) -=P: 6 (ppm) 17.27 (septet, J = 11 Hz, E_2a), 10.85 (septet, J = 11 Hz, Z-Pa). IH: 7.76 (2H, m), 7.42 (lH, m), 7.36 (2H, m) 3.6 (3H, d, J = 12 Hz), 4.04 (2H, q), 3.95 (2H, m), 1.15 (3H, t). 13. WMR (CHzCl,) 3*P: 6 (ppm) = 7.25 and 6.84 (two sextets, J = 11 Hz each). 14. (E):(g) = 4:1, NMR (CDCl,) *=P: 6 (ppm) 15.86, 15.5 (two sextets, E-2b), 10.85, 10.46 (6H) 1.24 (two sextets, Z-2b); =H: (E-lb): 7.46 (2H), 7.26 (3H) 4.05 (2H) 3.54-3.6 (3H). 15.

NMR (CDCl,) 31P:

6.59 ppm (appears as sextet); IH, 7.95, (2H, m), 7.39 (3H, m); 4.07 (3H). IR (neat): 3300-3100, (2H, q), 3.82, (2H, m), 3.97 (3H, d, J = 12 Hz), 1.13 ppm __ 1735, 1710, 1650, 1240, 1040 cm-l. 16. N?dR(CDCl,) 31P: 5,8 and 4,8 ppm (appear as two septets); %H: 7.95 (2H, m), 7.78 (3Hr 1730, m), 4.2 (lH, m), 3.68 (3H, dd) 3.5 (3H, 8) 1.34 (3H, dd). IR (neat: 3300-3100, 1710, 1655, 1595, 1220, 1035 cm-l.

(Received in UK 6 January 1992)