Some Aspects of Organic Synthesis on Modified C-Nucleosides

4 Some Aspects of Organic Synthesis on Modified C-Nucleosides, Oxaprostaglandines, and Aminoglycoside Antibiotics

Downloaded by GRIFFITH UNIV on September 7, 2017 | http://pubs.acs.org Publication Date: June 1, 1977 | doi: 10.1021/bk-1977-0039.ch004

S. D. GERO, J. CLEOPHAX, D. MERCIER, and A. OLESKER Institute de Chimie des Substances Naturelles, CNRS, 91190 Gif sur Yvette, France For several years quite a few C-Nucleosides antibiotics have been found to display interesting antiviral and antitumoral acti vities (1-3). In these natural occurring antibiotics (Figure 1) the two heterocyclic systems are separated by a solid carbon-car bon bond. These linkages are not subject of either hydrolytic or enzymatic cleavage. The synthesis of such molecules is a diffi cult task in organic chemistry, but the preparation of such mole cules has been described by several laboratories (4-7). However, there are very few data dealing with the preparation of modified C-Nucleosides antibiotics (8-10). Considerable efforts (11-12) have also been made in the last years to replace the oxygen hetero-atom with another hetero-atom or to replace (18-20) the hydroxy-methylene or methylene groups with another hetero-atom. In the artisteromycin 1, the oxygen atom of the adenosine has been substituted (13-14) with a methy lene group, the oxygen atom of D-glucose has been replaced in the 5-thio-D-glucose 2, and in the nojirimycine 3, with a sulfur (1516) and with a nitrogen (17) hetero-atom, respectively. Oxa- and thia-prostaglandines 4 and 5 have been described in the literature (18-20). Along this line, we have been interested in recent years in our laboratory in creating synthon intermediates which can be transformed to modified C-Nucleosides and 11-oxaprostaglandines. Our approaches for these problems are outlined in Figure 2. We thought if the two functionalized epoxydes 6 and 8 could be synthesized, then they can be transformed to a modified C-Nucleo side antibiotics 7 and to the tetrahydrofuranoide system 9, and the latter then can be transformed to 11-oxaprostaglandines. These two epoxydes were unknown in the literature and we syn thesized them from the readily available D-Xylose. D-Xylose was transformed to the 2,5-anhydro-di-isobutyl-dithioacetal-D-Xylose 10, prepared by Zinner (1959) (21) and this is converted by well -established methods to the highly functionalized 11. The latter was treated with 2.5 molar of methanolic sodium methoxide and a mixture of the desired epoxydes 13 and 14 were obtained in a 70% 64

El Khadem; Synthetic Methods for Carbohydrates ACS Symposium Series; American Chemical Society: Washington, DC, 1977.

4.

Synthesis of Some

GERO E T A L .

NH,

Η

w H 0 H

£

H

v /

A,

HOHjC

ο

OH

O

OH

FORMYCIN

Ο

H

OH

H

>

C

/O.

CH Β

OH

OXOFORMYCIN

Β

Η

HOH,C


O

OH

FORMYCIN

65

Antibiotics

I

HOH,C

OH

OH

PYRAZOMYCIN

4

OH

OH

SHOWDOMYCIN

OH

OH

OXAZINOMYCIN

Figure 1

χ= ο

5 χ= s

Structures 1-5


SYNTHETIC METHODS

F O R CARBOHYDRATES

CHfcR),

ÇH(OEt),

D-Xylose

y

OH

10

/

:Η(ΟΕ5Γ^


OT

jli

»

OTs

1J

λ

ï

H(0Et)î

J If

< H $ J 0

OTs

T

s

16

15 Structures 10-16

Structures 17-23



4.

GERO E T

AL.

Synthesis of Some

Antibiotics

67

yield. T h e r a t i o o f t h e e p o x y d e s i s 35% t o 6 5 % . The s t r u c t u r e of t h e s e epoxydes has been c o n f i r m e d by p h y s i c a l methods and by chemical correlation. T h e m a j o r e p o x y d e _14 w a s t r a n s f o r m e d b y a s e r i e s o f r e a c t i o n s t o 16 w h i c h w a s d e s c r i b e d b y u s i n 1 9 6 8 (22). T h e 1Λ w a s c h o s e n f o r t h e s y n t h e s i s o f m o d i f i e d C - N u c l e o s i d e s a n d t h e e p o x y d e JL3 f o r t h e p r e p a r a t i o n o f t h e s y n t h o n 9_. Alterna t i v e l y , t h e m i n o r e p o x y d e 13^ c o u l d a l s o b e s y n t h e s i z e d b y t r e a t i n g 10 w i t h 1.2 m o l a r o f t o s y l c h l o r i d e f o l l o w e d b y t h e t r a n s f o r m a t i o n o n t r e a t m e n t w i t h m e t h a n o l i c s o d i u m m e t h o x i d e t o t h e e p o x y d e 13 obtained p r e v i o u s l y from 11. T h i s s e r i e s of r e a c t i o n s can be r e a l i z e d without the i s o l a t i o n of the i n t e r m e d i a t e s . The m o d i f i e d ( ^ - N u c l e o s i d e s have b e e n p r e p a r e d f r o m t h e m a j o r e p o x y d e _6. The l a t t e r , on t r e a t m e n t w i t h c a r b a n i o n s d e r i v e d f r o m d i t h i a n e or d i p h e n y l d i t h i o a c e t a l of formaldehyde, gave i n a regio-specific f a s h i o n 1 7 a n d 2 0 i n a y i e l d o f 88% a n d 6 8 % , r e spectively. The s t r u c t u r e of t h e s e d é r i v â t e s has been c o n f i r m e d by p h y s i c a l methods, e s p e c i a l l y w i t h NMR s p e c t r o s c o p y o f t h e i r 0 - a c e t a t e s 1 8 a n d 2 1 a n d o f t h e i r ( ) - b e n z o a t e s 19^ a n d 2 2 . B o t h 19^ a n d _22 h a v e b e e n d e s u l p h u r i z e d w i t h R a n e y N i c k e l t o t h e d e r i v a t i v e of C-methyl Z3. B o t h r e a g e n t s o p e n e d t h e e p o x y d e 6_ a t t h e p o s i t i o n 4. We w e r e u n a b l e t o d e t e c t t h e s e c o n d p o s s i b l e i s o m e r e v e n i n t r a c e amounts. 23 was s m o o t h l y h y d r o l y z e d t o t h e C ^ - f o r m y l 2 4 , w h i c h on t r e a t m e n t w i t h carboethoxy methylenetriphenylphosphorane gave 25, w h i c h on f u r t h e r t r e a t m e n t w i t h dizomethane f o l l o w e d by c h l o r i n a t i o n a n d d e h y d r o c h l o r i n a t i o n f u r n i s h e d v i a 26^ t h e carboet h o x y C - N u c l e o s i d e 27^, w h i c h w a s c o n v e r t e d o n t r e a t m e n t w i t h a m m o n i a c t o 2!8. U s i n g t h e same a p p r o a c h , a v a r i e t y o f o t h e r C N u c l e o s i d e s c a n a l s o b e p r e p a r e d . ( F i g u r e 2) T h e s y n t h o n 9_ ( F i g u r e 2 ) f o r t h e p r e p a r a t i o n o f 11-oxaprostag l a n d i n e s h a v e b e e n s y n t h e s i z e d f r o m t h e e p o x y d e _13. The epoxyde on t r e a t m e n t w i t h the c a r b o n i o n d e r i v e d from the d i p h e n y l d i t h i o a c e t a l o f f o r m a l d e h y d e g a v e t o w p r o d u c t s , _29^ a n d _ 3 1 , i n a y i e l d o f 79% a n d i n a r a t i o n o f 63% a n d 3 7 % , r e s p e c t i v e l y . The s t r u c t u r e o f t h e s e p r o d u c t s , 29 a n d 3 1 , w a s c o n f i r m e d b y NMR s p e c t r o s c o p y of t h e i r O - a c e t a t e s 3 0 a n d _32. The m i n o r o p e n i n g p r o d u c t 31 h a s a n absolute c o n f i g u r a t i o n which corresponds to the absolute configuration of the n a t u r a l l y o c c u r r i n g p r o s t a g l a n d i n e s . In the major p r o d u c t _29 t h e t w o f u n c t i o n a l i z e d s i d e c h a i n s a r e a l s o t r a n s b u t i n a meta p o s i t i o n 1, 3. T h e m i n o r p r o d u c t _32 w a s h y d r o l y s e d t o t h e a l d e h y d e _3^3, a n d t h e l a t t e r o n t r e a t m e n t w i t h d i m e t h y l ( 2 - o x o h e p t y l ) p h o s p h o n a t e f u r n i s h e d t h e u n s a t u r a t e d k e t o n e 34_, w h i c h was s e l e c t e d f o r f u r t h e r t r a n s f o r m a t i o n t o a v a r i e t y o f 11-oxaprostaglandines . I f we a r e u s i n g e p o x y d e 13 d e r i v e d f r o m e i t h e r L - X y l o s e o r D - X y l o s e ( F i g u r e 3 ) , we c a n p r e p a r e t h e t w o e n a n t i o m e r i c _35 a n d 3 6 , w h i c h c o r r e s p o n d s a t p o s i t i o n s 8 a n d 12 t o t h e a b s o l u t e conf i g u r a t i o n of the n a t u r a l and e n a n t i o m e r i c p r o s t a g l a n d i n e s . The O - A c e t a t e i n 35^ a n d 36^ c a n b e e p i m e r i z e d w i t h w e l l - e s t a b l i s h e d methods.



68

SYNTHETIC METHODS FOR CARBOHYDRATES

M U T A T I O N A L B I O S Y N T H E S I S OF A M I N O G L Y C O S I D E A N T I B I O T I C S Recent i s o l a t i o n of a v a r i e t y of aminoglycoside antibiotics, w i t h c l i n i c a l and m o l e c u l a r b i o l o g i c a l i m p o r t a n c e , has p r o v i d e d c h a l l e n g i n g p r o b l e m s t o o r g a n i c c h e m i s t s a n d b i o c h e m i s t s (23-26). I n t h e s e a n t i b i o t i c s , o u t l i n e d i n F i g u r e 4, t h e c e n t r a l m o i e t y _2d e o s y - s t r e p t a m i n e i s g l y c o s y l a t e d a t p o s i t i o n s 4 and 5 f o r the neomycin type and a t p o s i t i o n s 4 and 6 f o r the kanamycin t y p e a n t i b i o t i c s w i t h a l a r g e v a r i e t y of carbohydrate d e r i v a t i v e s . Due t o t h e i r e x t e n s i v e c l i n i c a l u s e , R - f a c t o r m e d i a t e d e n z y mes w e r e d e v e l o p e d (24, 26, 27) which i n a c t i v e these a n t i b i o t i c s b y 0- p h o s p h o r y l a t i o n , O - a d e n y l a t i o n a n d N - a c e t y l a t i o n a t t h e d i f f e r e n t p o s i t i o n s s h o w n b y t h e a r r o w s ( F i g u r e 4). Undoubtedly, the i n a c t i v a t i o n of these a n t i b i o t i c s a g a i n s t d i f f e r e n t b a c t e r i a l s t r a i n s p r o v i d e d an impetus f o r an i n t e n s i v e c h e m i c a l and b i o l o gical research. I n t h e r i b o s t a m y c i n _37, ( F i g u r e 5), the f o u r t h s u b u n i t of n e o m y c i n i s a b s e n t , a n d i n t h e b u t r i o s i n Β _38 t h e 1 - a m i n o g r o u p o f ribostamycin is acylated with L(-)-y-amino-a-hydroxybutiric acid. The p r e s e n c e o f t h i s s i d e c h a i n a t he C - l amino group o f t h e 2-deoxystreptamine confers exceptional a n t i b a c t e r i a l properties (26) on t h e b u t r i o s i n B , i n c l u d i n g i t s a c t i v i t y a g a i n s t gram n e g a t i v e b a c t e r i a - f o r i n s t a n c e , Pseudomonas a e r u g i n o s a . Due t o t h i s d i s covery, a l a r g e v a r i e t y of N - a c y l a t e d d e r i v a t i v e s of these type o f a n t i b i o t i c s h a v e b e e n s y n t h e s i z e d a n d t h e a m i k a c i n _3£ i n w h i c h t h e C - l a m i n o g r o u p o f k a n a m y c i n A i s a c y l a t e d w i t h t h e same L ( - ) γ - a m i n o - a - h y d r o x y b u t y r i c a c i d h a s b e e n d i s c o v e r e d (28). The l a t t e r i s an e x c e l l e n t a n t i b i o t i c a g a i n s t a v a r i e t y of b a c t e r i a which i n a c t i v a t e the parent kanamycine A . I n b u t i r o s i n _38 a n d i n a m i k a c i n J39 t h e c e n t r a l m o i e t y o f t h e 2 - d e o x y s t r e p t a m i n e h a s b e e n m o d i f i e d , and t h e f a c t t h a t a c t i v e a n t i b i o t i c s have been o b t a i n e d by m o d i f y i n g the c e n t r a l p a r t of these a n t i b i o t i c s suggest t h a t by m o d i f y i n g t h i s p a r t o f t h e m o l e c u l e , i n t e r e s t i n g a n d new t y p e o f a n t i b i o t i c s can be o b t a i n e d . I t i s v e r y i n t e r e s t i n g t o n o t e t h a t i n m i n o s a m i n o m y c i n 40 -a r e c e n t l y d i s c o v e r e d (29) a n t i b i o t i c - the a g l y k o n p a r t of the mole c u l e i s a 1 D - l - a m i n o - l - d e o x y - m y o i n o s i t o l , and the sugar p a r t , w h i c h i s l o c a t e d a s u s u a l a t t h e p o s i t i o n 4, i s k a s u g a m i n e . The C - l amino group i s a c y l a t e d w i t h a d i p e p t i d e . We a r e d e a l i n g i n the minosaminomycin from a b i o s y n t h e t i c p o i n t of view w i t h a mixed a n t i b i o t i c of the k a s u g a m y c i n and 2 - d e o x y s t r e p t a m i n e t y p e s . This i s the f i r s t time that jL-D-l-amino-l-deoxymyoinositol appears as a component of a m i n o g l y c o s i d e antibiotics. The t h i r d event on t h e m o d i f i c a t i o n of t h e 2 - d e o x y s t r e p t a m i n e moiety of these a n t i b i o t i c s has produced, w i t h the i s o l a t i o n of mutant s t r a i n s by R i n e h a r t and h i s c o l l e a g u e s (25, 30, 31) from Streptomyces f r a d i a e , producing neomycin-type a n t i b i o t i c s . D'imi t a n t s c o u l d not produce neomycin from the normal carbon and n i t r o gen s o u r c e s except i f a m i n o - c y c l i t o l s were added to the f e r m e n t a t i o n medium. 2 - d e o x y s t r e p t a m i n e , s t r e p t a m i n e and e p i s t r e p t a m i n e were transformed by t h i s mutant to the c o r r e s p o n d i n g antibiotics


4.

Synthesis of Some Antibiotics

GERO E T A L .

69 H

_

CH(OEt)

2

Λ


OBz

ÇHO

OB ζ

Λ

COjEt

W /

OBz

28 Structures 23-28

Figure 3


70

S Y N T H E T I C M E T H O D S F O R CARBOHYDRATES

NEOMYCIN

*CH NH


2

D

·,Purpurosomine^^,-'' CHNHRi

2

^^^^^Λ,

\

? 2-Deoxysrrepramir

,NH

ν^·0'^^

CHjOH

KANAMYCIN TOBRAMYCIN

Β R=OH

H

2

f

N

y R-.H

2

ν

Garosamine

'

OH

CM3

GEN ΤΑΜ YC IN GENTAMYCIN GENTAMYCIN

Ci R-RfCHi C R-CHj;RfΗ C^R-RfH 2

Figure 4

Figure 5



4.

GERO E T A L .

Synthesis of Some

71

Antibiotics

called hybrimycins (Figure 6). T h e s e new a n t i b i o t i c s , w i t h a modified amino-cyclitols, retained antibacterial properties (31). A l a r g e v a r i e t y o f D~~mutants ( 3 2 - 3 6 ) , u s i n g t h e same a p p r o a c h h a v e b e e n i s o l a t e d a n d u s e d f o r t h e b i o s y n t h e s i s o f new t y p e s o f antibiotics. Mutants i s o l a t e d from Micromonospora inyoensis (34), the s i s o m i c i n - p r o d u c i n g organism, which r e q u i r e the a d d i t i o n of 2-deoxy-streptamine to the fermentation broth for s i s o m i c i n production. The a d d i t i o n o f a n a l o g u e s o f 2 - d e o x y s t r e p t a m i n e to t h i s m u t a n t r e s u l t e d i n t h e f o r m a t i o n o f new a n t i b i o t i c s c a l l e d mutamicins. These m u t a m i c i n s , shown i n F i g u r e 6, p r o d u c e d by the a d d i t i o n of 2 - d e o x y s t r e p t a m i n e and 2 , 5 - d i d e o x y s t r e p t a m i n e to the fermentation broth e x h i b i t broad spectrum a n t i b i o t i c s . Most i n t e r e s t i n g l y , m u t a m i c i n 2 produced by t h e a d d i t i o n of 2,5dideoxystreptamine, e x h i b i t s s i m i l a r broad spectrum a c t i v i t y against gentamicin-sisomicin-acetylating strains. I t was c l e a r t o u s t h a t a n e n t i r e l y new a p p r o a c h i s a v a i l a b l e i n u s i n g D~mutants f o r p r o d u c i n g a n t i b i o t i c s . To u s e t h i s t y p e o f m u t a t u i n a l b i o s y n t h e s i s , we n e e d e d t h e i n d i v i d u a l c o m p o n e n t s o f t h e s e a n t i b i o t i c s , a n d i n t h e p a s t y e a r s we h a v e prepared a v a r i e t y of these substances - for i n s t a n c e : tobrosamine (37), purpurosamine ( 3 8 , 3 9 ) , l i v i d o s a m i n e (40), and a v a r i e t y of a m i n o - c y c l i t o l s r e l a t e d to 2,4-dideoxystreptamine (41). However, I would not l i k e to t a l k about the s y n t h e s i s of these s u b s t a n c e s , w h i c h w a s p a r t i a l l y d i s c u s s e d ( 4 2 ) i n my l e c t u r e a t the P h i l a d e l p h i a American C h e m i c a l S o c i e t y m e e t i n g i n 1975, but I w o u l d l i k e t o t a l k a b o u t a new b i o s y n t h e t i c m e t h o d o l o g y , n a m e l y , the m u t a t i o n a l b i o s y n t h e s i s of these a m i n o - c y c l i t o l glycoside a n t i b i o t i c s , e s p e c i a l l y the m u t a t i o n a l b i o s y n t h e s i s of neomycin (43). I t has been r e p o r t e d r e c e n t l y by R i n e h a r t (25-44) t h a t the s u b u n i t s A , B, C, D of neomycin d e r i v e d from D - g l u c o s e . The o r d e r of the assembly of t h e i r s u b u n i t s , however, never has been disclosed. R i n e h a r t s t a t e d (23,31) t h a t a D~mutants i s o l a t e d from Streptomyces f r a d i a e could not produce a n t i b i o t i c neomycin i f neamine, w h i c h are the A , Β s u b u n i t s of the neomycin, has been added to the f e r m e n t a t i o n b r o t h . F o r a c o u p l e o f y e a r s we w e r e e n g a g e d i n b i o s y n t h e t i c s t u d i e s i n t h i s f i e l d a n d we a s k e d o u r s e l v e s two q u e s t i o n s : (1) what i s t h e e x a c t o r d e r of t h e f o r m a t i o n of the 4 s u b u n i t s - A , B , C, D, - of the neomycin, and (2) when t h e f u n c t i o n a l i z a t i o n o c c u r s . Rinehart f a i l e d to produce neomycin a n t i b i o t i c , supplement i n g t h e medium o f D~mutants w i t h exogenous n e a m i n e , and t h e r e f o r e he c o n s i d e r e d as a p o s s i b l e b i o s y n t h e t i c i n t e r m e d i a t e 5 - 0 - D ribosyl-2-deoxystreptamine. S u r p r i s i n g l y enough, and c o n t r a r y t o h i s v i e w , n e a m i n e , t h e s u b u n i t A and Β o f t h e n e o m y c i n , was transformed (43), u s i n g D~mutants to neomycin ( F i g u r e 7). S u p p l e m e n t i n g t h e medium w i t h a s y n t h e t i c 5-0-D-ribosyl-2,6d i d e o x y s t r e p t a m i n e ( 4 5 ) , n e o m y c i n was n o t b i o s y n t h e s i z e d (Figure 7). This

experience,

however,

d i d not

provide

conclusive

4


evid-


72

SYNTHETIC

METHODS

FOR CARBOHYDRATES

CH,NH,

Ami n o c y c l i t o i Hybrimycin

Aj

Hybrimycin

A2

OH H

S t r e p t a m i ne

Hybrimycin Hybrimycin

"2

S t r e p t a m i ne

B£

Epi s t r e p t a m i ne

OH

H

Epi s t r e p t a m i ne

OH

CH-NH,

OH H N 2

H C RzHN 3

Ο

CH NH. 2

HN 2

R » OH

Sisomicin

R

Mutamicin

1

R = Rj

» OH

Mutamicin

la

R » Rj

•

Mutamicin

lb

R =» R^ « OH

Mutamicin

2

R *

Rj

OH

R

2

2 R

R

9

=

CH

3

" 3 = COCH, C H

» Η

Figure 6



4.

Synthesis of Some

GERO E T A L .

Antibiotics

73

Figure 7

ence whether

the

exogenous neamine was

cleaved

by

a n enzyme

pre

sent i n t h e medium t o t h e 2 - d e o x y s t r e p t a m i n e and t r a n s f o r m e d t o the neomycin. I n order to shed l i g h t whether the neamine i n c o r p orated i n t o the neomycin without cleavage i n an i n t a c t f a s h i o n , we d e c i d e d t o b i o s y n t h e s i z e (Figure 8): f i r s t , labelled

two t y p e s o f r a d i o a c t i v e neamine at both subunits A, Β with * C ; and 1 Z

secondly, a neamine l a b e l l e d only at subunit A w i t h t r i t i u m . By m i x i n g t h e s e two d i f f e r e n t l y l a b e l l e d n e a m i n e t h e r a t i o o f the t r i t i u m and l ^ C f o u n d t o be ^ H / ^ C = 1 4 . When t h e m i x t u r e o f w

a

s

1

these l a b e l l e d neamines i s g i v e n to the D~mutants of Streptomyces f r a d i a e , t h e n e o m y c i n p r o d u c e d h a d a r a d i o a c t i v i t y o f ^H/^-^C=15. Neamine i s t r a n s f o r m e d w i t h o u t c l e a v a g e to the neomycin. If the neamine might have been c l e a v e d e n z y m a t i c a l l y , and b i o s y n t h e s i z e d by D"mutants the r a t i o o f t h e r a d i o a c t i v i t y found s h o u l d have been totally different. T h i s i s t h e f i r s t t i m e , a s f a r a s we a r e a w a r e , t h a t we d e m o n s t r a t e d u n i v o c a l l y t h a t t h e n e a m i n e - p s e u d o disacchar i d e h a d been a c c e p t e d by D""mutants and i n c o r p o r a t e d w i t h o u t c l e a -


74

SYNTHETIC

14

3

s

C D-glucose H D-glucose

mix

D

0

T

r

a

o

'

a

»

S

mutant cold D O S

A-B +

A-B

NEOMYCIN

A-B-C-D

^ NEOMYCIN

>-

METHODS

A-B

FOR CARBOHYDRATES

— ^ NEAMINE A - B

ÂB CD

3

NEAMINE Â - B

1 4

H / C = 14


DOS

Figure 8

NEOMYCIN

Α-Β-C-D

NEOMYCIN

Ï-B-C-D

3

H/ C = IS ,4

vage to the antibiotic neomycin. Consequently, i n the neomycin biosynthesis the neamine must be on the biosynthetic pathway. Most probably, the third subunit C -the D-ribosyl, - and the fourth subunit D, - neosamine Β - were attached successively. Similarly, to our results, pseudo d i - and t r i - saccharides have also been transformed by D"mutants isolated from Micromonospora inyoensis or Micromonospora purpurea to sisomicin and gentamicin types antibiotics (35, 36). These studies, which w i l l be continued i n our laboratories, should have an important bearing for many academic questions on the detailed biosynthesis of these antibiotics, and also should provide a very powerful new biochemical methodology producing new type of antibiotics.

Literature Cited (1) Suhadolnik, R.J., Nucleoside antibiotics, wiley-inter science New York, N.Y., (1970). (2) Shugar, D., "Progress with Antiviral Agents", FEBS Letters, (1974), 40, 48 (supplement). (3) Giziewicz, J . , De Clercq, Ε., Luczak, Μ., Shugar, D., Bio chem., (1975), 24, 1813. (4) Buchanan, J.G., Dunn, A.D., Edgar, A.R., J.Chem. Soc., Per kin I, (1976), 68. (5) Trummlitz, G., Repke, D.B., Moffat, J.G., J.Org. Chem., (1975), 40, 3352. (6) De Las Heras, F.G., Tam, S.Y.K., Klein, R.S., Fox, J.J., J.Org.Chem., (1976), 41, 84. (7) De Bernardo, S., Weigele, M., J.Org.Chem., (1976), 41, 287. (8) Tam, H.D., Kolb, Α., Gouyette, C., Igolen, J., Dinh, S.T., J.Org.Chem., (1975), 40, 2825. (9) Jain, T.C., Russel, A.F., Moffat, J.F., J.Org. Chem. (1973), 38, 3179. (10) Barnathan, G., Tam, H.D, Kolb, Α., Igolen, J . , Eur.J.Med. Chem.Chimica Therapeutica, (1976), 11, 67



4. GERO ET AL. Synthesis of Some Antibiotics

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(11) Ritchie, R.G.S., Szarek, W.A., J.C.S. Chem.Comm., (1973), 686. (12) Paulsen, Η., and Todt, Κ., Adv.Carbohydrate Chem., (1968), 23, 115. (13) Kusaka, T., Yamamoto, H., shibata, M., Kishi, T., Mizuno, K., J.Antibiotics, (1968), 21, 255. (14) Holy, Α., Collection chechoslov.Chem.Comm., (1976), 41, 647. (15) Nayak, U.G., Whistler, R.L., J.Org.Chem., (1969), 34, 97. (16) Bushway, A.A., whistler, R.L., J.Carbohdrates-Nucleosides -nucleotids, (1975), 2, 399. (17) Inovye, S., Tsuruoka, T., Ito, T., Niida, T., Tetrahedron, (1968), 23, 2125. (18) Hanessian, S., Dextraze, P., Fougerousse, a., Guindon, Υ., Tetrahedron Letters, (1974), 3983. (19) Lourens, G.J., Koekemoer, J.M., Tetrahedron Letters, (1975), 3715. (20) Harrison, I.T., taylor, R.J.K., Fried, J.H., Tetrahedron Letters, (1975), 1165. (21) Zinner, H., Brandhoff, H., schmandke, H., Kristen, Η., Haun, R., Chem.Ber., (1959), 92, 3151. (22) Cleophax, J . , Hildesheim, J . , Williams, R.E., Gero, S.D., Bull.Soc.Chim., (1968), 1415. (23) Umezava, S., Advan.Carbohyd.Chem.Biochem., (1974), 30, 111. (24) Umezava, Η., Advan.Carbohyd.Chem.Biochem., (1974), 30, 183. (25) Rinehart, Jr. K.L., stroshane, R.M., J.Antibiotics, (1976), 29, 319. (26) Price, K.E., Godfrey, J.C., Kawaguchi, Η., Advances in Applied Microbiology, (1974), 18, 191. (27) Umezawa, Η., In Drug Action and Drug Resistance in Bacteria, Mitsuhashi, S., Ed., University Park Prss, Tokyo, (1975), 2, 211. (28) Kawaguchi, H, In Drug Action and Drug Resistance in Bacteria, S. Mitsuhashi, Ed., University Park Press, Tokyo, (1975), 2, 45. (29) Iinuma, K., Kondo, S., Maeda, Κ., Umezava, H., J.Antibiotics (1975), 28, 413. (30) Shier, W.T., Rinehart, Jr., K.L., gottlieb, D., Proc.Nat. Acad.Sci.,USA, (1969), 63, 198. (31) Shier, W.T., Schaefer, P.C., Gottlieb, D., Rinehart, Jr., K.L., Biochemistry, (1974), 13, 5073. (32) Claridge, C.A., bush, J.A., De Furia, D., Price, K.E., Devel. Indust., Microbiol., (1974), 15, 101. (33) nagaoka, Κ., Demain, A.L., (1975), 28, 627. (34) Testa, R.T., Wagman, G.H., Daniels, P.J.L., Weinstein, M.J., J.Antibiotics, (1974), 27, 917. (35) Testa, R.T., tilley, , J.Antibiotics, (1975), 28, 573. (36) Testa, R.T., Tilley, , J.Antibiotics, (1976), 29, 140. (37) Cleophax, J . , Gero, S.D., Leboul, J., Forchioni, Α., J.C.S., Chem.Comm., (1973), 710. (38) Cleophax, J . , Leboul, J., Olesker, Α., Gero, S.D., Tetrahe dron Letters, (1973), 4911.


76 (39) (40) (41) (42) (43)


(44) (45)

SYNTHETIC METHODS FOR CARBOHYDRATES Cleophax, J . , Gero, S.D., Jegou-Aumont, E., Leboul, J . , Mercier, D., forchioni, Α., J.C.S., Chem.comm., (1975), 11. Jegou, E., Cleophax, J., Leboul, J . , Gero, S.D., Carbohyd. Res., (1975), 45, 323. Cleophax, J . , Gero, S.D., Leboul, J . , Akhtar, Μ., Barnett, J.E.G., Pearce, C.J., J.Amer.Chem.Soc., in press. Gero, S.D., Cleophax, J . , Leboul, J . , Aumont, E., Olesker, Α., Abstract, 169th National Meeting of the American Chemi cal Society, Pennsylvania, (1975), Carb. 24. Pearce, C.J., Barnett, J.E.G., Anthony, C., Akhtar, Μ., Gero, S.D., Biochemical J . , in press. Rinehart, Jr., L.L., Malik, J.M., Nystrom, R.S., Stroshane, R.M., Truit, S.T., Taniguchi, Μ., rolls, J.P., Haak, W.J., Ruff, B.A., J. Amer. Chem. Soc., (1974), 96, 2263. Cleophax, J . , Mercier, D., Gero, S.D., Pearce, C.J., Bar nett, J.E.G., unpublished results.


Some Aspects of Organic Synthesis on Modified C-Nucleosides

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