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Synthetic Communications: An
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Organic Chemistry
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Synthesis of Sulfoximinopropionic Acids

a

William L. Mock & Jiu-Tsair Tsay

Department of Chemistry , University of Illinois at

Chicago , Box 4348, Chicago, IL, 60680
Published online: 05 Dec 2006.
To cite this article: William L. Mock & Jiu-Tsair Tsay (1988) Synthesis of Sulfoximinopropionic Acids, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 18:8, 769-776, DOI:
10.1080/00397918808057844
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SYNTHETIC COMMUNICATIONS, 18(8), 769-776 ( 1 9 8 8 )

SYNTHESIS OF U-SULFOXIHINOPROPIONIC ACIDS

Downloaded by [Michigan State University] at 21:04 23 January 2015

William

L. Mock* and J i u - T s a i r Tsay

Department o f Chemistry, U n i v e r s i t y o f I l l i n o i s a t Chicago,

Box 4348, Chicago, IL, 60680
Abstract:
P-Benzyl-3-(methyl s u 1 f o x i m i n o ) p r o p i o n i c a c i d has been
prepared from 2-benzyl-3-(methylthio)propionamide by c y c l i z a t i o n
t o a i s o t h i a z o l i n o n e h y d r o c h l o r i d e w i t h N-chlorosuccinimide,
f o l l o w e d by p e r a c i d o x i d a t i o n and a c i d i c h y d r o l y s i s .

I n conjunction with
inhibitors

of

a program i n v o l v i n g t h e s y n t h e s i s o f

metalloproteases,'

we

preparation o f B-sulfoxirninopropionic
regarded

as

specifically,

analogs

of

had

need

acids

1-acylamino

for

(1).

acids

general

These may be

(2)

or,

more

as s u r r o g a t e s f o r t h e t e t r a h e d r a l adduct r e s u l t i n g

from a n u c l e o p h i l i c a t t a c k upon t h e carboxamido l i n k a g e o f t h e

corresponding peptide.

Our goal was t o i n c o r p o r a t e such f u n c t i o n -

a l i t y i n t o s u b s t r a t e analogs f o r p r o t e o l y t i c enzymes.

Standard methods

of

generating t h e sulfoximine functional

group2 proved unsuccessful i n t h i s i n s t a n c e ; 6 - e l i m i n a t i o n predom-

*To whom correspondence should be addressed.

769
Copyright 0 1988 6y Marcel Dekker, Inc.

770

MOCK AND TSAY

i n a t e d upon attempted a z o t i z a t i o n o f t h e a p p r o p r i a t e s u l f o x i d e

(3

4).

Similar

detosyl a t i o n o f an

were

encountered

+ HN3
COpH

RMS

H2S04
____)

a\,,,,

...

I n o r d e r t o avoid fragmentation,

section,

recourse was made t o an

Amide 5, assembled as described i n the

i n t r a m o l e c u l a r process.
Experimental

attempted

upon

E-(toluenesul f o n y l )sulfoximine.

tJ
Downloaded by [Michigan State University] at 21:04 23 January 2015

problems

was

treated

with

N-chlorosuccinimide,

r e s u l t i n g i n t h e 5-methylbenzylisothiazolinone

h y d r o c h l o r i d e 6.

The l a t t e r c o u l d be deprotonated w i t h t r i e t h y l a m i n e t o g i v e t h e
corresponding c y c l i c a c y l s u l f i l i m i n e ( " i s o t h i a z o l inone").

Oxida-

t i o n o f 6 w i t h E c h l o r o p e r b e n z o i c a c i d gave t h e h e t e r o c y c l e 7.
Subsequent a c i d i c h y d r o l y s i s o f 7 y i e l d e d t h e d e s i r e d m a t e r i a l 8
(i.e.,

1 with R

structure

R' = CH2C6H5).

= CH3,

a l k a l i n e h y d r o l y s i s o f 7 gave 8 - e l i m i n a t i o n

instead.

Attempted
Adjustment

o f t h e a c i d i t y o f an aqueous s o l u t i o n o f 8 t o a pH o f 3 (an appar-

CH3SCH,CH(CH,C,H,)CONH2

5
'gHSCH2

'6" SCH 2&,C"S'cH3

0
HCI

H20

m-CIC,H,CO,H

H C-NH

0"

,yo

Oc\
H2C-CH 2

CH3
CI'

&Occgs

/\

II
II

CH,SCH,CH(CH2C,HS)CO,H
NH-HCI

I\

H C-N

IPo

771

SYNTHESIS OF a-SULFOXIMINOPROPIONIC ACIDS

e n t i s o l e c t r i c p o i n t ) r e s u l t e d i n spontaneous r e c y c l i z a t i o n t o 7.
However,
stable,

o f t h e carboxylate o f 8 are q u i t e

alkaline solutions
as

are

more

strongly

acidic

solutions

( i n which

N-

p r o t o n a t i o n o f t h e s u l f o x i m i n e occurs).

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The s y n t h e t i c sequence m i g h t have been expected t o y i e l d a

d i a s t e r e o m e r i c m i x t u r e o f products, s i n c e b o t h t h e s u l f u r and t h e
m e t h i n e carbon o f 8 r e p r e s e n t s t e r e o g e n i c centers.
only a single

H'

stereoisomer was obtained,

In actuality,

as evidenced by 400 MHz

and 100 MHz 13C NHR s p e c t r a o f 8 and i t s p r e c u r s o r 7 ( i n

several

solvents),

each

of

which

exhibited

an

interpretable

p a t t e r n , w i t h no d o u b l i n g o f s i g n a l s a t t r i b u t a b l e t o t h e presence
o f an epimer.

A careful

search o f t h e r e a c t i o n p r o d u c t m i x t u r e

f a i l e d t o t u r n up a diastereomer.

A t e n t a t i v e assignment o f con-

f i g u y a t i o n f o r 8 c o u l d be made based upon an NOE experiment w i t h

7.

I r r a d i a t i o n a t t h e hydrogen resonance frequency o f t h e

methyl group of

2-

7 d u r i n g d a t a a c q u i s i t i o n f o r a 400 MHz l H NMR

spectrum r e s u l t e d i n a s e l e c t i v e enhancement o f t h e s i g n a l from

t h e methylene hydrogens o f t h e benzyl group,
perturbing the signal

from

w i t h o u t comparably

any o t h e r CH i n t h e , molecule.

It

f o l l o w s t h a t t h e s e two r e s i d u e s e x i s t i n c l o s e s p a t i a l p r o x i m i t y ,
and

so

must

depicted).

have

a c-&

Therefore,

Such s t e r e o s p e c i f i c i t y
ted.3

relationship

in

t h e y-lactam

8 i s assigned t h e RR:SS

(as

configuration.

i n t h i o e t h e r o x i d a t i o n i s n o t unpreceden-

I n t h i s i n s t a n c e we cannot say whether i t i s a k i n e t i c o r

an e q u i l i b r i u m phenomenon w i t h r e s p e c t t o 6.

While the l a t t e r

substance ought t o be c o n f i g u r a t i o n a l l y s t a b l e , t h a t need n o t b e

772

MOCK AND TSAY

t h e case f o r t h e peroxysulfurane which i s t h e presumed intermedia t e y i e l d i n g 7.

Evidence p e r t a i n i n g t o t h e mechanism by which 5 y i e l d s 6 i s
also available.

A priori,

two pathways seem e q u a l l y p l a u s i b l e ,

Downloaded by [Michigan State University] at 21:04 23 January 2015

corresponding t o e i t h e r i n i t i a l

1-o r 2 - c h l o r i n a t i o n

genating agent (Scheme, paths a and b).

by t h e halo-

However, when t h e crude

halogenation product c o n t a i n i n g 6 was o x i d i z e d d i r e c t l y t o 7, a

minor

by-product

n i t r i l e - s u l f o n e 9.

occurred,

which

has

been

identified

We suggest t h a t t h i s supports path b.

as

the
Ambi-

dent n u c l e o p h i l i c i t y o f t h e carboxamide group a l l o w s concurrent

f o r m a t i o n o f i n t e r m e d i a t e 10, which upon p e r a c i d o x i d a t i o n o f t h e
sulfonium
indicated.

i o n center might

reasonably

ring-open

i n t h e manner

We have no p l a u s i b l e a l t e r n a t i v e e x p l a n a t i o n f o r such

f a c i l e o x i d a t i v e dehydration of a carboxamide.

Scheme
path a

path b

773

SYNTHESIS OF B-SULFOXIMINOPROPIONIC ACIDS

I n conclusion,

a p r a c t i c a b l e and a p p a r e n t l y s t e r e o s e l e c t i v e

synthesis

o f B-sulfoximinopropionic

acid

derivatives

has

been

devised.

Substance 8 i s a moderately e f f e c t i v e i n h i b i t o r of t h e

enzyme carboxypeptidase A, as w i l l be d e s c r i b e d elsewhere.

Downloaded by [Michigan State University] at 21:04 23 January 2015

Experimental Section

(5).

2-Benzyl-3-(1nethylthio)propionamide
o b t a i n e d f r o m 33.0

To

the

anion

mol) o f d i e t h y l benzylmalonate and 1

g (0.13

e q u i v o f sodium e t h o x i d e i n 90 mL o f h o t e t h a n o l was added p o r tionwise

12.75

(0.13

mol)

of

chloromethyl

methyl

sulfide,

whereupon t h e m i x t u r e was heated w i t h s t i r r i n g a t 80 "C f o r 30 min

(NaC1 prec).

A f t e r cooling,

followed

by p a r t i t i o n i n g

between

w a t e r and e t h e r w i t h subsequent e v a p o r a t i o n o f t h e e t h e r e x t r a c t ,
an o i l was o b t a i n e d which was d i r e c t l y h y d r o l y z e d w i t h 40 g o f
potassium h y d r o x i d e i n 50 mL o f water and 150 mL o f methanol under
r e f l u x f o r 4 h.
d i l u t e d w i t h 0.5
w i t h ether.

The r e s u l t i n g c o o l e d s o l u t i o n was concentrated,

L o f water,

a d j u s t e d t o pH 7, and t h e n e x t r a c t e d

The aqueous phase was subsequently a c i d i f i e d and

e x t r a c t e d w i t h a l a r g e volume o f methylene c h l o r i d e .

The r e s i d u e

o b t a i n e d upon e v a p o r a t i o n o f t h e o r g a n i c phase was r e c r y s t a l l i z e d

from c h l o r o f o r m and from chloroform-heptane t o y i e l d 19.4 g (76%)
o f white crystals o f

2-(methylthio)methyl-2-benzylmalonic

m.p.

165 "C

3.35

(s, 2H), and 7.37

(dec);

'H

NMR (CD30D) 6 2.17

(s, 5H) ppm.

(5,

3H), 2.93

acid,

(s, 2H),

Upon h e a t i n g i n t h e m o l t e n

s t a t e u n t i l c e s s a t i o n of carbon d i o x i d e e v o l u t i o n ,

15.3

g (0.06

mol) of t h i s m a t e r i a l y i e l d e d 12.2 g (97%) o f 2-benzyl-3-(methylthio)propionic

acid,

m.p.

104 "C,

a f t e r r e c r y s t a l l i z a t i o n from

774

MOCK AND TSAY

chloroform-heptane;

l H NMR (CDC13) 6 2.13

= 4 Hz),

(m,

2.77-3.00

(d, 2H, J

(d, 2H, J = 2 Hz), 7.33

lH), 3.02

(s, 1H) ppm; MS m/e 210 (M');

and 11.85

( s , 3H), 2.75

( s , 5H)

I R (KBr) 1705 cm-l.

This

m a t e r i a l was converted i n t e t r a h y d r o f u r a n s o l u t i o n i n t o a mixed

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anhydride by means o f e t h y l chloroformate (1.1

ethylamine (1.3

equiv,

0 "C,

30 min),

e q u i v ) and t r i -

w i t h subsequent r e a c t i o n

d i r e c t l y w i t h an excess o f anhydrous ammonia ( 3 h) t o y i e l d amide

5 (89%), m.p.

77-78.5

"C,

from e t h y l acetate and cyclohexane;

IR

(KBr) 1650 cm-l.

S-Methyl b e n z y l i s o t h i a z o l i n o n e h y d r o c h l o r i d e (6).
t i o n o f 2.09
portions
initial

To a s o l u -

g (10 n o l ) o f 5 i n 20 mL o f chloroform was added i n

1.60

( 1 2 mmol)

exotherm,

o f 3-chlorosuccinimide.

t h e m i x t u r e was

p r e c i p i t a t e o f 6 was c o l l e c t e d ,

NMR (DzO) 6 2.20

I R (KBr) 1720 cm-l.

s t i r r e d overnight.

1.65 g (68%). m.p.

(s, 3H), 3.00-3.65

After

A white

130-132

(m, 5H), and 7.33

(5,

an

"C; l H

5H) ppm;

M a t e r i a l so obtained was o x i d i z e d d i r e c t l y .

Dehydrochlorination o f 6 with triethylamine yielded the isothiazol i n o n e , I R (KBr) 1600 cm-l.

S-Methylbenzylisothiazolinone o x i d e (7).

To a s l u r r y o f 1.22

g ( 5 mnol) o f 6 i n 30 mL o f methylene c h l o r i d e was added a solut i o n o f 1.22

g ( 6 mnol) o f E c h l o r o p e r b e n z o i c a c i d i n 20 mL o f

methylene c h l o r i d e .

After

s t i r r i n g a t 25 "C

homogeneous s o l u t i o n was obtained,

25 mL of
carbonate,

overnight a c l e a r

which was washed i n t u r n w i t h

10% sodium b i s u l f i t e s o l u t i o n ,

and 2 x 25 mL o f water.

4 x 25 mL o f 5% sodium

A f t e r d r y i n g (Na2S04) t h e

s o l u t i o n was concentrated and d i l u t e d w i t h e t h e r t o p r e c i p i t a t e a

R-SULFOXIMINOPROPIONIC

SYNTHESIS OF

R e c r y s t a l l i z a t i o n ( x 2) from c h l o r o f o r m and e t h e r y i e l d e d

solid.

g (60%) o f 7,

0.66

MHz) 6 2.61
lH,

(5,

J = 4.7,

ppm;

Downloaded by [Michigan State University] at 21:04 23 January 2015

775

ACIDS

I3C

127.56,

NMR

129.11,

Hz),

(CDC13,
129.86,

(dec);

l H NMR (CDCl3,

(d, d , lH, J = 4.0,

3H), 3.03
13.2

"C

120-122

m.p.

3.57-3.60

(m,

13.7

Hz), 3.34

3H) and 7.20-7.35

100 MHz) 6 35.99,

42.53,

(m,

46.91,

400
(dd,
5H)

53.27,

136.62 and 181.50 ppm; I R ( K B r ) 1680 cm-l.

A l s o i s o l a t e d by p r e p a r a t i v e s i l i c a TLC was 35 mg of 9, m,p.

"C; I H NMR (CDC13) 3.07 ( s , 3H), 3.07-3.73

96-98

(s,

5H) ppm; MS m/e 223 (M');

(m, 5H), and 7.37

I R ( K R r ) 2250 (CN),

1298 and 1120

( s o 2 ) cm-1.

t-Benzyl-3-( methyl sul f oxi m i no) propi oni c

(8).

A s o l u t i o n o f 112 mg (0.5

hydrochl o r i de

acid

mmol) o f 7 i n 4 mL o f t e t r a h y d r o -

f u r a n and 1 mL o f conc h y d r o c h l o r i c a c i d was s t i r r e d f o r 24 h.

Removal o f s o l v e n t under reduced p r e s s u r e and r e c r y s t a l 1 iz a t i on o f
t h e r e s i d u e from methanol and c h l o r o f o r m y i e l d e d 118 mg (86%) o f

8, m.p.

153.5

= 10.0,

16.7

Hz), 3.15

(dd, lH, J = 10.0,

l H ) , 3.72

( s , 3H), 4.15

J = 12.0,

18.7 Hz), and 7.23-7.35

(dd, lH, J = 3.9,

MHz) 6 38.67,

40.15,

42.73,

and

ppm;

IR

173.62

CiiH15N03S.HCl:
47.41;

(dd, l H , J

"C ( d e c ) ; 'H NMR (CD30D, 4 0 0 MHz) 6 3.08

H, 5.74;

C , 47.57;
N, 5.03;

Acknowledgement.

H,

16.7 Hz), 4.28

(m,

(dd, l H ,

(m, 5H) ppm; 13C NMR (CD30D, 100

55.71,

128.36,
1730

(KBr)

16.7 Hz), 3.50-3.60

5.81;

129.52,

cm-l;

N, 5.04;

130.28,

Anal.

S, 11.54.

137.61,

Calcd.

for

Found: C,

S , 11.52.

T h i s work was supported by t h e U n i v e r s i t y

o f I l l i n o i s Research Board.

7 76

MOCK AND TSAY

References

1.

Mock, W. t. and Tsay, J.-T.,

2.

Kennewell, P.

Biochemistry, 1986,

0. and Taylor, J . B.,

Chem. Soc.

25,

2920.

Rev. 1975,

4,

189.

Downloaded by [Michigan State University] at 21:04 23 January 2015

3.

Glass, R. S.,
1987,

52,

3537.

Petsom, A.,

and

Wilson, G. S.,

J. Org. Chem.,