Synthesis and Mutasynthesis of Pseudosaccharides Related to

21 Synthesis and Mutasynthesis of Pseudosaccharides Related to Aminocyclitol-Glycoside Antibiotics

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J. CLÉOPHAX, A. ROLAND, C. COLAS, L. CASTELLANOS, S. D. GÉRO, A. M. SEPULCHRE, and B. QUICLET Institut de Chimie des Substances Naturelles, C.N.R.S., 91190 Gif-sur-Yvette, France

The aminocyclitol glycosides enumerated in Table 1, are produced mainly by Streptomyces species but also by Micromonospora, Bacillus and even Pseudomonas species (1, 2, 3). They constitute a very important class of c l i n i c a l l y used antibiotics and provide a cover for the pathogens most commonly found in the hospital environment. To varying degrees a l l the amino-glycosides are toxic (oto and nephrotoxicity) and therefore their administration is strictly controlled. It was f i r s t noticed in 1965 (4) that some pathogenic bacteria became resistant to these antibiotics, and in subsequent years, i t was shown that the major resistance mechanism was an R-factor mediated enzymatic inactivation, resulting in O-phosphorylation, O-nucleotidylation or N-acetylation of the antibiotics at different positions (5, 6, 7). The discovery and explanation of these enzymatic inactivations led to an increased effort to find from natural sources (through soil screening programs) and through chemical modification procedures new products effective against resistant organisms. Chemical modification of already existing naturally occuring antibiotics, either by removal of certain functional groups subject to inactivating enzymes or by substitution (acylation or alkylation) of the 1-amino group of the 2-deoxystreptamine moiety, led to semi0-8412-0554-X/80/47-125-393$05.00/0 © 1980 American Chemical Society

Rinehart and Suami; Aminocyclitol Antibiotics ACS Symposium Series; American Chemical Society: Washington, DC, 1980.

AMINOCYCLITOL ANTIBIOTICS

394

TABLE 1 MAJOR DISCOVERIES


ANTIBIOTICS

OF AMINOGLYCOSIDE

(1944-1977)

YEAR

ANTIBIOTIC

1944

STREPTOMYCIN

S. GRISEUS

1949

NEOMYCIN

S. FRADIAE

1957

KANAMYCIN

S. KANAMYCETICUS

1959

PAROMOMYCIN

S. RIMOSUS F. PAROMOMYCINUS

1961

SPECTINOMYCIN

S. SPECTABILIS

1963

GENTAMICIN C

M.

1965

KASUGAMYCIN

S. KASUGAENSIS

1968

TOBRAMYCIN

S. TENEBRARIUS

1970

RIBOSTAMYCIN

S. RIBOSIDIFICUS

1970

SISOMICIN

M.

1971

LIVIDOMYCIN

S. LIVIDUS

1971

BUTIROSIN

B. CIRCULANS

1973

APRAMYCIN

S. TENEBRARIUS

1974

MINOSAMINOMYCIN

ACTINOMYCES SP

1975-77

SELDOMYCIN

S. HOFUENSIS

1976

SORBISTIN

P. SORBICINII

1977

FORTIMICIN

M. OLIVOASTEROSPORA

M = Micromonospora

PRODUCING ORGANISM

PURPUREA

INYOENSIS

; S = Streptomyces

; Β = Bacillus ;

Ρ = Pseudomonas.


21.

synthetic

derivatives

netilmicin

395

Pseudosaccharides Related to Antibiotics

CLÉOPHAX ET AL.

(10),

[dibekacin

UK 18892

1 ] , which were a c t i v e

(Π)

(8),

amikacin

and Sch 21420

(9),

( 12),

against aminoglycoside

Fig.

resistant

b a c t e r i a. In

our l a b o r a t o r y we have pursued two d i f f e r e n t


but complementary approaches chemical

synthesis

: mutasynthesis

and we w i l l

to produce p s e u d o s a c c h a r i d e s

and t o t a l

r e p o r t here our

r e l a t e d to

efforts

aminoglycoside

antibiotics. Let us f i r s t

examine the s t r u c t u r a l

the p s e u d o d i s a c c h a r i d e which e x h i b i t s timicin

B,

nocyclitol des

antibacterial

is

is

2, c o n t a i n

Except i n

a novel

named f o r t a m i n e , the o t h e r

assymetrically

1,4-diami-

2-deoxystreptamine at

position

which d i f f e r

and double bond studies

is

hydro-

functions.

The p r e r e q u i s i t e f o r s t r u c t u r e - a c t i v i t y ship

4 by

from

each o t h e r by the presence or absence of amino, xyl

for-

pseudodisacchari-

α-glycosylated

a v a r i e t y of aminohexopyranosides

of

aminoglycosides

activity.

in which the aglycone

p r e s e n t e d in F i g u r e

which

moiety of the

features

the r e a d i l y a v a i l a b i l i t y

of

or a m i n o - c y c l i t o i s and t h e i r α - g l y c o s i d e s . be o b t a i n e d by e i t h e r m u t a s y n t h e s i s

relation cyclitols

They might

or t o t a l

chemical

synthes i s. Meso 2-deoxystreptamine

and meso 2 , 5 - d i d e o x y s t r e p -

tamine can be o b t a i n e d by h y d r o l y s i s biotics 15)

or by chemical

synthesis

of natural

respectively

but they were c o n s i d e r e d u n s u i t a b l e

for

anti

(1_3, 14,

practical

chiral

synthesis.

Q u i n i c a c i d , on the o t h e r hand,

sesses

functional

groups and an a b s o l u t e

amenable to our coveted g o a l s as

starting In

this

pos

configuration

and t h e r e f o r e was

chosen

material. a r t i c l e we deal

t i o n of 2 , 6 - d i -

b r i e f l y with the p r e p a r a

and 2 ,5 , 6 - t r i d e o x y s t r e p t a m i n e s


and

3,5-

AMINOCYCLITOL ANTIBIOTICS

OH HO—*1—Ο HO

H


H,N

H0

H

Γ

|°

Î

OH H

^ ^ I

N

O

0

H

r ° ^

OH

N

H

NH

2

R = Η KANAMYCIN A Ο R:v*y-v/NH AMIKACIN H^'OH >

24 was

t h e r e was no e v i d e n c e f o r the f o r m a t i o n

^-glycoside

5

on carbon in e t h y l a -

r e s p e c t i v e l y . As

NMR data o b t a i n e d f o r

H

l

° »

12 % y i e l d

or d e u t e r i a t e d in

10 % p a l l a d i u m

26 and 26'

by a s i n

24 ( ι • » 3 ·

in the presence of a t r a c e of g l a c i a l

to compounds

in 94 %

suggested

The ^ - g l y c o s i d e

hydrogenated

mix

After

*H NMR data

the α - g l y c o s i d e

21

boron-tri-

15°C f o r another 2 h.

4.5

of

of

15 min. The r e a c t i o n

from a l c o h o l .

t i t a t i v e y i e l d using

the

-

compound was

régiospecifically

the

a catalytic

9 H z ) . The 3 anomer 25 was

5

1

A dichloroethane

The major component

this

the

compound 21 and the

a mixture of two products

crystallisation

that

using

- 20°C over

m a i n t a i n e d at

extraction

of

added to a d i c h l o r o e t h a n e s o l u t i o n

fluoride-ether is

here d e t a i l s

5-0-(3'-deoxy-a-D-H_bohexopyranosyl)2,6-

compound 23 i s

ture

example, we give

streptamine

(1 e q u i v . )

e t h e r 22 was

proceeded

the slug-

in poor y i e l d which were


D-


CLÉOPHAX E T A L .

Pseudosaccharîdes

OCOC H 6

26 R = H

5

Related to Antibiotics

27

R

28

Rι= H

1

=

OAc

R

= H

2

R

2

= OAc

26' R = D

Figure 7.



AMINOCYCLITOL

Figure 8.

Figure 9.


ANTIBIOTICS

21.

CLÉOPHAX

c h a r a c t e r i s e d as

compounds

and 28 (18 %) ( J I _ I 1

nolysed

products

Azidolysis dimethyl Downloaded by KTH ROYAL INST OF TECHNOLOGY on November 30, 2016 | http://pubs.acs.org Publication Date: August 4, 1980 | doi: 10.1021/bk-1980-0125.ch021

three silica was

gel

of 26, using

i d e n t i f i e d as

?9.

Using tives,

sodium a z i d e

of t o i u e n e - p - s u l p h o n i c (1:1)

acid.

cially,

and 6'

deoxy and 2 ' - f l u o r o thetised

(16,

31,

10),

was a l s o group

(Fig.

with

re-

antimicrobial

a range

procedure of Espe

of groups

including

pseudodisaccharides

2',3'

at di-

have been s y n -

32) . α-glycosylation

of a p s e u d o t r i s a c c h a r i d e

investigated. of t h i s

Since

class

derivative

and the

containing

; we f i r s t

33

(33)

butirosins

a

g-D-ribosyl

prepared the

tri-0-benzoyl-β-D-ribofuranosyl

5-0-

condensation

chloride

in the

bromide and m o l e c u l a r

under r e f l u x over 8 hours

treatment with g l y c a l

procedure

t h e r e are many e f f e c t i v e

31 from compound 5 by

presence of mercury ( T l ) ο (4A)

2) which

used in the r e a c t i o n .

positions

at the 5 p o s i t i o n

D-ribosyl with

deriva4-0-substi-

r e l a t e d to r i b o s t a m y c i n

antibiotics

8)

are r e l a t e d to the

The e x t e n s i o n of t h i s the s y n t h e s i s

of

(Fig.

9 have been

pseudodisaccharides 2

by

d e p i c t e d in F i g .

glycosides

and aglycones

the s t r a t e g i c

by

Saponifi-

The y i e l d of the α - g l y c o s y l a t i o n

1

of

(51 %)

between 65-90 % and depends on the nature

the g l y c a l s

(Fig.

N,N-

arose

and c y c l i t o l

p r e s e n t e d the minimum requirement f o r

for

in

gave compound 30.

a v a r i e t y of g l y c a l s

t u t e d 2-deoxystreptamine

varies

hydroge-

by r e d u c t i o n in the presence

These products

activity.

some

The major component

pseudodisaccharides

prepared.

addition

The two minorcomponents

in methanol-water

2

Hz)

2

in 81 % y i e l d which were s e p a r a t e d

c a t i o n of 29 f o l l o w e d Pt0

, _ , 1.5

110°C over 2h gave a mixture

chromatography.

elimination

In

(J

were formed which were not examined.

formamide at

products

27 ( 30 %)

9 Hz).

2

407

Related to Antibiotics

Pseudosaccharîdes

ET AL.

sieves

( 3 3 J . The l a t t e r on

23 under the usual

conditions


408

ANTIBIOTICS


AMINOCYCLITOL

Figure 10.


21. CLÉOPHAX ET AL. afforded

Pseudosaccharides Related to Antibiotics409

the unsaturated

62 % y i e l d .

pseudotrisaccharide

Using well established

converted to the trisaccharide


We feel efficient ned

methods

32, in ; 32 was

33.

that the discovery of novel and more

antibiotics

for c l i n i c a l

use might be obtai-

by the combination of the mutasynthetic and the

total

synthetic methodology. Despite that the y i e l d of

biotransformation

using idiotrophs is extremely low, mutasynthesis

might

provide a rapid information concerning the impact exerted by the mutasynthon on the antibacterial ty.

activi-

The results of our studies indicated that the re-

moval of hydroxy groups at C-6 or at C-5 and C-6, does not

affect

microbial

greatly the b i o l o g i c a l properties. The spectra

of 6-deoxyneomycins and 5.6-dideoxy-

neamine were very similar to that of neomycins and neamine,

respectively. Total

of

chemical synthesis

allows the introduction

a variety of functional groups as summarized in

Figure 9 and we hope that our methodology w i l l novel type of bioactive Financial

lead to

substances.

assistance from Institut

National de la

S a n t é et de la Recherche M é d i c a l e (INSERM) is

grateful-

ly acknowledged (Grant N° 77.205.3). Literature Cited 1

Umezawa, S. 30,

2

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111.

Cox, D.A. ; Richardson, K. ; Ross, B.C. ; Topics in A n t i b i o t i c Chemistry, Sammes P.G. E d . , Limited, England, 1977,

l,

Ellis

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RECEIVED November 15, 1979. Rinehart and Suami; Aminocyclitol Antibiotics ACS Symposium Series; American Chemical Society: Washington, DC, 1980.

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