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Pergamon

0040-4039(95)01010-6

Tetrahedron Letters

Vol. 36, No. 29, pp. 5187-5190, 1995

Elsevier Science Ltd

Printed in Great Britain

0040-4039/95 9.50+0.00

S i m p l e T o t a l S y n t h e s e s o f N - S u b s t i t u t e d P o l y a m i n e D e r i v a t i v e s

U s i n g N - T r i t y l a m i n o A c i d s ~

P e t r o s M a m o s , a G e o r g i o s K a r i g ia n n i s , b C o s t as A t h a n a s s o p o u l o s , b

S o f i a B i c h t a , b D i m i t r i o s K a l p a x i s a a n d D i o n i s s i o s P a p a i o a n n o u b *

Departments of Medicine and Chemistry,b Universityof Patr0.s, 265 00 l'atras. Greece

G i o v a n n i S i n d o n a

Department of Chemistry. Llnivcrsityof Calabria. 1-87030 Arcavacata di Rende (('s). Italy

bs t r ac t : A general methodology for the total synthesis of N- alkyl- and acylpolyamine derivatives

is described which is based on the coupling of suitable N -trit ylami no acids with amines followed by

lithium aluminium hydride reduction of the thus obtained amides.

Polyam ines, such as sperm ine (1) and s permidin e (2), are intere sting natural products which are

involved in a variety of very import ant biological functions.2 Moreover, polyamine surrogates with

amin o acids such as tyros ine3 or arginine,4 isolated from spiders, exhibit potent inhibitionof mammalian

neu rot rans mitt er receptors . Various synthetic protocols have been devised which allow the preparation

of polyamine analogs selectivily modified at their amino functions. These protocols involve either the

selective protection of the amino functions of polyamines with groups such as me thylene, tosyl (Ts), tert-

butoxy carbon yl (Boc), benzyloxycarbonyl (Cbz) and phthalyl (Phth),5 and most recently metal cations6

and the 4-azidobenzyloxcarbonylgroup, 7 or the assembly of th e polyamine sceleton from suitably

protected amino comp onents using reactions such as the reductive alkylation,8 the Michael addition on

acrylonitrile,2,9 acylation followed by lithium aluminium hydride (I.AH) reduction, l and the alkylation of

sulfonylamides 1 or mor e recently triflyl amides using the Mitsunobu reaction. 12 We now wish to repo rt

our preliminary results o n the developme nt of a general me thodology which allows easy access to

mon o- and di-N- alkyl- and acylated sper mine derivatives using readily available N-tritylamino acids as

building blocks.

Key-featu res in our approach are (a) the use of the bulky triphenym ethyl (trityl, Trt) group and the

readily remove d by hydrogenolysis benzyl group for blocking the desired am ino functions and (b) the

l.AH-mediated reduct ion of amides, derived from the con densa tion of suitable N-tritylamino acids with a

series of amines . The Trt gro up was chosen for N-protection because it is compatible with complex metal

5187

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5 1 8 8

R 0

" N ~ v , K - ( ) H

t'

3 ; R = T r t

2 5 ; R = F m o c

R . , ~ 0 H

T r t ~ N ~ N ~ N ~ I ~ . _

, ~lrI

H O - .R

6 ; R = M e

7 ; R = t B u

8 ; R = P h

. A I

R t-I

T n ,

T r t

H R

9 ;

R = E t

l O ; R = C I I x B u t

1 1 ; R = B n

I t 2 N % N t t E

1 ) C C / B t O H

R C ( X 3 I I ' E A

D M A P

O t i H

T r t " N , , " x ~ N % N . ~ " , , . , ~ 1 ~1 . T r

H I t 0

4

~ [L A H

t t t i

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H H

;

R = H

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R = B n

1 .

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3 . t t J P d - C

H R , , O

H " N ~ N ~ N - ~ N . . H

O ~ R I ' I

1 2 ; R = ( C H 2 ) I 4 M e

1 3 ; R = t B u

t t

l I

R . .N . . ~ N ~ . ~ N ... R 3

H ~ 2

2 ; R J = R 2 = R 3 = H

7 ,g ; R l = R 3 = T r t , R 2 = H x

2 9 ; R ~ = H , R 2 = B n , R ~ = T r t

" F r t ~ ~ . O t

N - v .

H O

1 4

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D C C / B t O H

R t t

Tr t , .

~ N ~ N ~ N ~ N . _

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L A t l o r

1 . P i p

2 . L A I I

H

i

T r N . . .~ N . R

H 0

1 5 ; R = E t

1 6 ; R = H x

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I . A H

O H

R l

U ~ 2

2 6 ; R ~ = R 3 = T r t , R 2 = H x

: 1 7 ; R L = F m o c , R 2 = B n , R 3 = T r t

3 o r 2 5 1 B O P / D I E A

H

L A H w-- T r t X N ~ . ~ / ~ - R

i

1 8 ; R = E t

1 9 ; R = H x

2 0 ; R = B n

1. TsOH.H20

2 . M B O P / D I E A

O R H

T ~ , N . , , . , ~ N ~ / ~ ~ . ~ , . , , . . ~ ,

4 I Y r t

H H O

2 1 ; R = H x

2 2 ; R = B n

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5 1 8 9

h y d r i d e s 1 3 a n d c o n f e r s h i g h l i p o p h i l i c it y t o i n t e r m e d i a t e s , t h u s f a c il i ta t i n g w o r k - u p a n d p u r i fi c a ti o n

p r o c e d u r e s i n v o l v i n g fl as h c o l u m n c h r o m a t o g r a p h y (F C C ) .

T h u s , N - tr i t y l a t i o n 1 4 o f t h e c o m m e r c i a l l y a v a i l a b l e [5 - al an i n e p r o d u c e d c r y s t a l l i n e T r t- l~ - A l a ( 3 ) i n

8 8 % y i el d . C o u p l i n g o f 3 w i t h p u t r e s c i n e ( 1 , 4 - d i a m i n o b u t a n e ) i n D M F f o r 2 4 h a t R T , i n th e p r e s e n c e o f

N , N ' -d i c y c io h e x y l c a r bo d i i m i d e ( D C C ) a n d l - h y d r o x y b e n z o t r i a z o l e ( B t O H ) p r o d u c e d a 8 2 % y i e ld o f

c r y s ta l li n e b i sa m i d e 4 , w h i c h u p o n L A H r e d u c t i o n f o r 1 0 h i n r e fl u x in g T H F , p r o d u c e d a 5 7 % y i e ld o f

N I N 1 2 - d i tr i ty l s p e r m i n e

( 5 ). T h i s c o m p o u n d w a s s h o w n t o b e a v e r s a ti l e in t e r m e d i a t e f o r t h e p r o d u c t i o n

o f a v a r i e t y o f d i a lk y l- a n d a c y l s p e r m i n e d e r i v a t i v e s . T h u s , r e a c t i o n o f 5 w i t h a v a r i e t y o f ac y l c h lo r i d e s ,

e . g . a c e t yl , p i v a lo y l a n d b e n z o y l c h l o ri d e , i n t h e p r e s e n c e o f t r i e th y l a m i n e ( T E A ) a n d 4 - d i m e t h y l a m i n o -

p y r id i n e ( D M A P ) i n C H C I 3 f o r 3 0 m i n a t 0 C a n d 2 h a t R T , p r o d u c e d t h e d i a c yl a te d s p e r m i n e

d e r i v a t i v e s 6 - 8 i n 7 5 - 8 5 % y i e l d s , w h i c h c o u ld b e u n e x c e p t i o n a l ly r e d u c e d w i t h [ . A H i n r e fl u x i n g T H F f o r

1 - 2 d t o t h e c o r r e s p o n d i n g d i a lk y l at e d s p e r m i n e d e r i v a t i v e s 9 - 1 1 i n 6 2 - 7 0 % y i el d s . I n p ar ti c u la r,

d e r i v a t i v e 1 1 i s v a l u a b le f o r t h e s y n t h e s i s o f t e r m i n a l l y d i s u b s ti t u te d s p e r m i n e d e r i v a t iv e s . T h u s ,

d e t r i t y l a t i o n o f I 1 w i t h T s O H . H 2 0 i n r e f lu x i n g i s o p r o p a n o l , fo l l o w e d b y ac y l a t i o n w i th e . g . p a l m i t o y l

a n d p i v a lo y l c h l o ri d e s , i n t h e p r e s e n c e o f T E A a n d D M A P , a n d f in a ll y c at a ly t ic h y d r o g e n o l y s i s o f t h e

d e r i v e d a m i d e s u s i n g 1 0 % P d - C i n g l ac i al A c O H f o r 6 h a t R T , r e a d i ly p r o d u c e d t h e t e r m i n a l l y d i a c y l a t e d

s p e r m i n e a n a l o g s 1 2 a n d 1 3 , r e s p e c t i v e l y i n 6 4 -7 5 % y i el ds .

T h i s m e t h o d o l o g y c o u l d be a l s o a p p l i e d i n t h e s y n t h e s i s o f m o n o - N - f u n c t i o n a l iz e d s p e r m i n e

d e r i v a t i v e s . T h u s , N - t r i ty l a ti o n o f t h e a l s o c o m m e r c i a l l y av a i la b le , / -a m i n o b u t y r i c a c id ( G A B A ) p r o d u c e d

a 8 5 % y i e l d o f c r y s ta l l in e T r t - G A B A ( 1 4 ) , w h i c h u p o n c o n d e n s a t i o n w i t h a v a r i e t y o f a m i n e s , e . g . e t h y l,

h e x y l ( H x ) a n d b e n z y la m i n e , i n t h e p r e s e n c e o f D C C a n d B t O H i n D M F , f o r 3 h a t 0 C a n d 2 4 h a t R T ,

p r o d u c e d t h e c o r r e s p o n d i n g c r y st al li n e a m i d e s 1 5 - 1 7 i n 7 2 - 90 % y i e ld s . L A H r e d u c t io n o f th e s e a m i d e s

f o r 1 -2 d at r e fl u x i n g T H F , p r o d u c e d t h e N - t r i ty l a t e d p u t r e s c i n e d e r i v a t i v e s 1 8 - 2 0 r e s p e c t i v e l y , i n 6 5 -

8 0 % y i e ld s . D e t r i t y l at i o n o f e .g . 1 9 a n d 2 0 w i th T s O H . H 2 0 i n r e fl u x in g i s o p r o p a n o l f o r 4 h p r o d u c e d

t h e c o r r e s p o n d i n g t o s y l a t e s w h i c h u p o n c o u p l i n g w i t h T r t- l~ - A la , i n th e p r e s e n c e o f e i t h e r t h e c o u p l i n g

a g e n t b e n z o t r ia z o l - 1 - y i o x y tr i s (d i m e t h y l a m i n o ) p h o s p h o n i u m h e x a f l u o r o p h o s p h a t e ( B O p ) IS a n d d i is o -

p r o p y l e t h y l a m i n e ( D I E A ) o r c h e a p e r , b u t i t t a k e s l o n g e r re a c t i o n t im e s , w i t h D C C / B t O H , g a v e t h e

b i s am i d e s 2 1 a n d 2 2 , r e s p e c t i v e l y i n 6 8 - 7 4 % y i el d s . F i n al ly , I . A H r e d u c t i o n o f t h e s e c o m p o u n d s

p r o d u c e d t h e c o r r e s p o n d i n g s p e r m i n e d e r i v a t iv e s 2 3 a n d 2 4 , i n 6 5 -7 0 % y i el ds .

F u r t h e r m o r e , p u t r e s c in e d e r i v a t iv e s 1 8 - 2 0 a r e i n t e re s t in g i n t e rm e d i a te s i n th e a s s e m b l y a l s o o f

t h e s p e r m i d i n e s k e l e t o n . T h u s , c o n d e n s a t i o n o f T rt -l ~ -A l a w i t h e . g . 1 9 , i n t h e p r e s e n c e o f B O P a n d

D I E A , p r o d u c e d t h e a m i d e 2 6 i n 89 % y ie ld , w h i c h u p o n L A H r e d u c t io n g a v e u n e x c e p ti o n al ly t h e

s p e r m i d i n e d e r i v a ti v e 2 8 i n 7 7 % y i el d . O n t h e o t h e r h a n d, N - 9 - f lu o r e n y i m e t h o x y c a r b o n y l ( F m o c ) a ti o n 16

o f [ ~ -a la n in e p r o d u c e d c r y s t a l l i n e F m o c - ~ - A l a (2 5 ) in 8 5 % y i e ld . T h i s w a s f u r t h e r r o u t i n e l y a c t i v a t e d b y

S O C I 2 i n r e f l u x i n g b e n z~ e n e a n d t h e r e s u l t i n g c r y s t a l l i n e a c y l c h l o r i d e w a s u s e d t o a c y l a t e , i n 7 5 % y ie l d,

t h e p u t r e s c i n e d e r i v a t iv e 2 0 i n t h e p r e s e n c e o f D I E A . T h e t h u s o b t a i n e d a m i d e 2 7 w a s s e l e ct iv e l y

d e p r o t e c t e d w i th 2 0 % p i p e r i d in e ( P i p ) i n C H 2 C I 2 a n d t h e r e s u lt in g p r o d u c t w a s r e d u c e d w i th L A H t o g i v e

t h e p a r t ia l ly p r o t e c t e d s p e r m i d i n e d e r i v a t i v e 2 9 i n 6 4 % y i e ld . P r e l i m i n a r y e x p e r i m e n t s o n t h e

d e t r it y la t io n o f t h e a b o v e p r e p a r e d s p e r m i n e a n d s p e r m i d in e d e r i v a ti v e s s h o w e d t h a t t h e T i t g r o u p c a n

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5 1 9 0

b e e f fi c i e n t ly r e m o v e d w i t h T s O H . H 2 0 i n r e f lu x i n g is o p r o p a n o l , o r w i t h c a t a l y ti c h y d r o g e n o l y s i s w ith

1 0 % P d - C i n g l ac i a l A c O H / H 2 0 ( 9 : 1 ), o r 2 0 % t r i f l u o r o a c e t i c a c i d in C H 2 C I 2 . F u r t h e r a pp li ca ti ~ n s o f t h e

p r e s e n t l y d e s c r i b e d m e t h o d o l o g y a s w e l l a s b i o lo g i c a l a s s e s s m e n t o f d e t r i t y l a te d s p e r m i n e a n d

s p e r m i d i n e d e r i v a ti v e s a r e n o w i n p r o g r e s s .

cknowledgements

: F inanc ia lsup port fro m the Grcc k M inistry_~ff l lcal th i s gratclul ly acknowledged .

R E F E R E N C E S

I . A l l n e w c o m p o u n d s g a v e a n a l yt ic a l a n d s p e c t r a l d a t a i n a g r e e m e n t w i th th e p r o p o s e d s t r u c tu r e s .

Y i e l d s o f t h e r e a c t i o n s r e f e r r e d i n t h is w o r k a r e n o t o p t i m i z e d , i n g e n e r a l , k e y - in t e r m e d i a t e s fr o m

I . A H r e d u c t i o n o f a m i d e p r e c u r s o r s w e r e o b t a in e d p u r e b y r e c r y s t al l iz a t io n o r t h r o u g h r o u t i n e

F C C .

2 . B r a n d , G . ; H o s s e i n i , M . W . ; R u p p e r t , 1 .. Tetrahedron Lett. 1 9 9 4 , 3 5 , 8 6 0 9 - 8 6 1 2 a n d r e fe r e n c e s

c i t e d t h e r e i n .

3 . K a l i v r e t e n o s , A . G . ; N a k a n i s h i , K. J. Org. Chem. 1 9 9 3 , 58,6596-6608.

4 . B l a g h r o u g h , 1 . S. ; M o y a , E . Tetrahedron Lett. 1 9 9 4 , 3 5 , 2 0 5 7 - 2 (~ ) 0 .

5 . S o s n o v s k y , G ; I . u k s z o , J. Z. Naturforsch. 1 9 8 6 , 41b, 1 2 2 -1 2 9 a n d r e f e r e n c e s c i t e d t h e r e i n .

6 . I r e l ~ ri s, N . ; Y a o u a n c , J .- J .; C l e m e n t , . I. -C . : H a n d e l , H . ; d e s A b b a y e s , H .

Tetrahedron Lett.

1 9 9 3 ,

3 4 , 5 4 2 9 - 5 4 3 2 .

7 . M i t c h i n s o n , A . ; G o l d i n g , I ~ . T .; G r i M n , R . J. ; O ' S u l l i v a n , M . C . J . Chem. Soc. C h e m . Commun. 1 9 9 4 ,

2 6 1 3 - 2 6 1 4 .

8 . l ~ e v c h i n e , I . ; R a j a h , P . ; t J o r l o o , M . ; B o l l a e r t , W . ; H a m m e r s, A. Synthesis 1 9 9 4 , 3 7 - 3 9 .

9 . E d w a r d s , M . I . .; P r a k a s h , N . J .; S t e m e r i c k , I ) .M . ; S u n k a r a , S .P . ; B i t o n t i , A . J . ; D a v i s , G . F . ; 1 ) u m o n t ,

J . A . ; B e y , P. J. Med. Chem. 1 9 9 0 , 3 3 , 1 3 6 9 - 1 3 7 5 .

1 0 . B e r g e r o n , R . J. ; N e i m s , A . H . ; M c M a n i s , J .S .; H a w t h o r n e , T . R . ; V in s o n , J . R .T . ; l ~ o r t e ll , R . ; I n g e n o ,

M . J . J .

Med. Chem.

1 9 8 8 , 31 , 1 1 8 3 - 1 1 ~ ) .

1 1 . B e r g e r o n , R . J .; M c M a n i s , J .S .; l. i u , C . Z . ; F e n g , Y . ; W e i m a r , W . R . ; l . u c h e t t a , G . R . ; W u , Q . ; O r t i z -

O c ~ s i o , J .; V i n s o n , J . R . T . ; K r a m e r , 1 ) . ; P o r t e r ,

C. J. Med. Chem.

1 9 9 4 , 3 7 , 3 4 6 4 - 3 4 7 6 .

1 2 . E d w a r d s , M . I .. ; S t e m e r i c k , 1 ) .M . ; M c C a r t h y , J. R . Tetrahedron 1 9 9 4 , 5 0 , 5 5 7 9 - 5 5 9 0 .

1 3. A t h a n a s s o p o u l o s , C . ; T/avara, C . ; P a p a i o a n n o u , 1 ) .; S i n d o n a , G . ; M a i a , H.I..S.Tetrahedron, 1 9 9 5 ,

51,2679-2688 a n d r e f e r e n c e s c i t e d t h e r e i n .

1 4 . t J a r lo s , K . ; P a p a i o a n n o u , I ) . ; T h e o d o r o p o u l o s , I ) . J . Org. chem. 1 9 8 2 , 47, 1 3 2 4 - 1 3 2 6 .

t 5 . C a s t r o , I J. ; l ) o r m o y , J .- R . ; E v i n , G . ; S e l v e , C .

Tetrahedron Lett.

1 9 7 5 ,

16,

1 2 1 9 - 1 2 2 2 .

1 6 . B o l i n , I ) . R . ; S y t w u , 1 .I .; H u m i e c , F . ; M e i e n h o f f e r , J .

Int. J. Peptide Protein Res.

1 9 8 9 ,

33,353-359.

Received in France 2 6 April 1 9 9 5 ; accepted 2 June 1 9 9 5 )