37 α-Aminophosphonous Acids: A New Class of Biologically Active Amino Acid Analogs
Downloaded by UNIV OF CALIFORNIA SAN DIEGO on April 3, 2016 | http://pubs.acs.org Publication Date: November 11, 1981 | doi: 10.1021/bk-1981-0171.ch037
Ε. K. BAYLIS, C. D. CAMPBELL, J. G. DINGWALL, and W. PICKLES Central Research Laboratories, Ciba-Geigy (UK) Limited, Tenax Road, Manchester M17 1WT, England
Phosphorus analogues of the important naturally occurring amino acids have received considerable attention in the past ten years in both academic and industrial laboratories and some have shown useful biological activity: aminomethanephosphonic acid 1 and phosphinothrycin 2, a naturally occurring glutamic acid analogue, are plant growth regulants/ herbicides while the dipeptide 3 is an antibacterial agent. The possibility of phosphorus analogues of amino-acids acting as false substrates and so interfering with biological mechanisms led us to consider the α-amino-phosphonous acids 4 as perhaps the closest analogues.
Only one α-aminophosphonous acid, the glycine analogue, was reported in the literature at the outset of this work. It was prepared . by the ammonolysis of chloromethanephosphonous acid, a method not applicable to other α-amino acid analogues. This paper describes a general synthesis of the α-amino phosphonous acids and some of their physical, chemical and biological properties. 1
0097-615 6/81/0171-018 3$05.00/0 © 1981 American Chemical Society Quin and Verkade; Phosphorus Chemistry ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
184
PHOSPHORUS
CHEMISTRY
Among the many methods available for the synthesis of α-aminophosphonic acids that of Tyka , involving the addition of dialkylphosphite to benzylimines, followed by hydrogenolysis, appeared the most adaptable to our purposes, since the addition of hypophosphorous acid to imines to give N-substituted α-aminophosphonous acids was well documented . Thus addition of hypophosphorous acid to the benzylamine imines 5 readily gave the N-benzylaminophosphonous acids 6. However, a l l attempts to hydrogenolyse 6 failed because of P-H catalyst poisoning, and under more severe conditions with higher catalyst loadings carbon-phosphorus bond cleavage occurred. 2
Downloaded by UNIV OF CALIFORNIA SAN DIEGO on April 3, 2016 | http://pubs.acs.org Publication Date: November 11, 1981 | doi: 10.1021/bk-1981-0171.ch037
3
H P0 3
2
R = Ph, Pr
RCHP—H I OH NHCHPh
RCH=NCHPh 2
EtOH
1
2
Needing instead an acid labile protecting group we turned to diphenylmethylimines. Hypophosphorous acid added to imines derived from diphenylmethylamine in ethanol (Method A) to give the diphenylmethylaminophosphonous acids 7. Alternatively, reaction of the diphenylmethylamine salt of hypophosphorous acid with aldehydes and ketones in refluxing ethanol (Method B) or preferably dioxan (Method C) gave the same product. R
R
,0 C-P-H R "| 0H NHCH(Ph).
i>h C=N-CH
f
R
H P0 3
N
2
f
Ph
N
Method A (Ethanol) R
N
R f
-
C=0
+
Ph
CHNH H P0 / 3 2 2 Q
p
h
i) Η i i ) propylene oxide
x
Method Β (Ethanol) Method C (Dioxan)
o
o
κ
*° .C-PrH R" I OH NH f
0
Acid cleavage of the diphenylmethyl group could be achieved under a variety of conditions e.g. i) 49% HBr, 100°, 45 min., i i ) TFA/Anisole, reflux, 30 min. and the free aminophosphonous acid 8 then obtained by treatment of the hydrobromide salt with propylene oxide in ethanol, or simply by heating the trifluoroacetates in ethanol.
Quin and Verkade; Phosphorus Chemistry ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
37.
BAYLis E T A L .
a-Aminophosphonous
Acids
185
Downloaded by UNIV OF CALIFORNIA SAN DIEGO on April 3, 2016 | http://pubs.acs.org Publication Date: November 11, 1981 | doi: 10.1021/bk-1981-0171.ch037
The f o l l o w i n g amino a c i d a n a l o g u e s were Amino a c i d [ M . P t . , Method ( y i e l d %)]
prepared:
Alanine [223-4°C, 0(45)] V a l i n e [201-5 C , A ( 6 9 ) , Β ( 4 9 ) ] Leucine [222-3°C, A ( 4 7 ) , B(78)] Phenylalanine [227-8°C, C (36)] M e t h i o n i n e [231 C , C ( 2 5 ) ] Glutamic a c i d [154°C, C (38)] The a n a l o g u e s o f s e r i n e a n d t y r o s i n e were p r e p a r e d from s u i t a b l y p r o t e c t e d hydroxy aldehydes and the tryptophan a n a l o g u e from i n d o l e p y r u v i c a c i d . A w i d e s e l e c t i o n o f o t h e r o - a m i n o p h o s p h o n o u s a c i d s was a l s o p r e p a r e d from a l i p h a t i c , a r o m a t i c and h e t e r o c y c l i c a l d e h y d e s and a l i p h a t i c k e t o n e s . The cr-aminophosphonous a c i d s c a n be r e s o l v e d by c l a s s i c a l procedures using the α-methylbenzylamine s a l t s o f N-benzyloxycarbonyl derivatives. We h a v e r e s o l v e d t h r e e c r - a m i n o p h o s phonous a c i d s ( a l a n i n e , v a l i n e a n d m e t h i o n i n e a n a l o g u e s ) a n d o b t a i n e d b o t h d - and _ l - e n a n t i o m e r s w i t h >99% o p t i c a l p u r i t y . A c r y s t a l structure determination o f a protected dipeptide d e r i v a t i v e o f (-)1-aminoethanephosphonous a c i d showed t h e (-)aminophosphonous a c i d t o have R s t e r e o c h e m i s t r y . D i - and o l i g o - p e p t i d e s w i t h a terminala-aminophosphonous a c i d r e s i d u e h a v e been p r e p a r e d b y c o u p l i n g w i t h N - h y d r o x y succinimide esters o f N-benzyloxycarbonylamino acids or peptides. R I ZNH-CH-COONSu
i)
a q . NaHCO^
f
+
f
R R R I ^0 i ) i i ) i i i ) I I ^0 H NCHP-H » H NCHC0NHCHP—H ^DH ^ 0 H p
i i ) HBr/HOAc
p
i i i ) propylene oxide
As w e l l a s p e p t i d e f o r m a t i o n t h e α - a m i n o p h o s p h o n o u s a c i d s u n d e r g o t h e t y p i c a l amine r e a c t i o n s o f a m i n o a c i d s . Further, t h e y c a n be o x i d i s e d t o t h e c o r r e s p o n d i n g a m i n o p h o s p h o n i c a c i d s without racemisation. F o r e x a m p l e , o x i d a t i o n o f t h e ( S , R) d i p e p t i d e 9 w i t h m e r c u r i c c h l o r i d e gave a phosphonic d i p e p t i d e i d e n t i c a l to Alaphosphin i n q u a n t i t a t i v e y i e l d , and s e r v e d to confirm the stereochemical assignments.
Quin and Verkade; Phosphorus Chemistry ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
186
PHOSPHORUS
CH
CHEMISTRY
CH.
0
HgCl
2
H NCHCONHCHP—H (S) (R) ^ O H 9
d
Downloaded by UNIV OF CALIFORNIA SAN DIEGO on April 3, 2016 | http://pubs.acs.org Publication Date: November 11, 1981 | doi: 10.1021/bk-1981-0171.ch037
(9)
ALAPHOSPHIN
R
When o u r work o n s y n t h e s i s o f α - a m i n o p h o s p h o n o u s a c i d s was e s s e n t i a l l y c o m p l e t e a n d a p a t e n t f i l e d f, a b r i e f r e p o r t appeared^ d e s c r i b i n g t h e s y n t h e s i s o f t h r e e o-aminophosphonous a c i d s by a d d i t i o n o f hypophosphorous a c i d t o oximes. I n b i o l o g i c a l s t u d i e s w i t h i n CIBA-GEIGY t h e a l a n i n e , v a l i n e a n d m e t h i o n i n e a n a l o g u e s a n d d e r i v e d p e p t i d e s show s i g n i f i c a n t a n t i b a c t e r i a l a c t i v i t y when t e s t e d i n a m i n i m a l a g a r medium. T h e v a l i n e a n d m e t h i o n i n e a n a l o g u e s a n d t h e d i p e p t i d e 9 possess i n v i v o a c t i v i t y and a l l t h r e e a r e e f f e c t i v e a g a i n s t e x p e r i m e n t a l i n f e c t i o n s i n t h e mouse. T h e a n t i b a c t e r i a l a c t i v i t y o f the v a l i n e analogue i s antagonised by v a l i n e , a n d t h i s a n d o t h e r p r e l i m i n a r y s t u d i e s i n d i c a t e t h a t t h e mode o f a c t i o n o f b o t h t h e v a l i n e a n a l o g u e a n d t h e d i p e p t i d e 9 i s by t r a n s p o r t i n t o t h e b a c t e r i a l c e l l f o l l o w e d by i n h i b i t i o n o f p r o t e i n s y n t h e s i s . This i s i n contrast to the phosphonic d i p e p t i d e Alaphosphin which a c t s by t r a n s p o r t i n t o the b a c t e r i a l c e l l and i n t r a - c e l l u l a r r e l e a s e o f t h e a l a n i n e mimectic which i n t e r f e r e s w i t h b a c t e r i a l c e l l w a l l synthesis. The parent aminophosphonic a c i d i s i t s e l f i n a c t i v e and c l e a r l y not transported i n t o the b a c t e r i a l celle. The phosphonous a n a l o g u e o f a l a n i n e a n d p e p t i d e s d e r i v e d from i t a l s o a f f e c t t h e g r o w t h o f p l a n t s a t l o w c o n c e n t r a t i o n s
REFERENCES 1. 2. 3. 4. 5.
U.S. Patent 3,160,632, 1964; Chem. Abstr. 62, 4053F Tyka, R., Tetrahedron Lett. 1970, 677 Schmidt, Η., Chem. Ber. 1948, 81, 477 Ger. Offen. 2,722,162, 1977; Chem. Abstr. 88, 105559 Khomutov, R.M., Osipova, T.I , Izv. Akad. Nauk SSSR, Ser. Khim. 1978, 1951 6. Atherton, F.R., Hall, M.J., Hassall, C.H., Lambert, R.W., Ringrose, P.S., Antimicrobial Agents and Chemotherapy, 1979, 696. RECEIVED
July 7, 1981.
Quin and Verkade; Phosphorus Chemistry ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
