Aminoglycoside antibiotics: synthesis of nebramine, tobramycin and 4″-epi-tobramycin

Tetrahedron

Letters

NO. 41, PP 3607 - 3610, 1977.

Perwon

Press.

Printed

in Great Britain.

AMINOGLYCOSIDE ANTIBIOTICS: SYNTHESIS OF NEBRAMINE, TOBRAMYCIN AND 4"-EPI-TOBRAMYCIN Masato Tanabe,* Dennis M. Yasuda and George Stanford Research Institute 333 Ravenswood Avenue Menlo Park, California 94025

Detre

(Received in USA 28 June 1977; received in UK for publication 30 Au@&

In a study aimed at the partial synthesis of aminoglycoside improved

spectrum

of activity,

that can be converted

to a variety

study we have synthesized naturally

occurring

Our approach

we have devised

of semi-synthetic

tobramycin

aminoglycoside

practical

naturally

occurring

efficient

conversion

of neamine

(3'-deoxyneamine).

Nebramine

with an appropriate

sugar.

key intermediates

As an example Tobramycin

4" epimer.

an

of this is a

applications.2

neamine which

is easily obtained

from

In our study, two new methods have been developed for the

to the important

is converted

Hitherto,

showing

of several

aminoglycosides.

with useful clinical

aminoglycosides.

syntheses

as well as its unnatural

starts with the pseudodisaccharide

antibiotics'

1977)

key intermediate

to tobramycin

nebramine

pseudodisaccharide

and its analogs

has only been available

nebramine3

by Ga-glycosylation by selective

hydrolysis

of tobramycin.

In the first method, tetracarbobenzyloxyneamine4 trichloroethoxycarbonyl silica gel afforded

chloride

(5 equiv.)

in pyridine

55% of the 3'-trichloroethyl

and

4' hydroxyl

of the monoester

groups

depending

-1 with 2,2_dimethoxypropane

1, m.p.

for selective

upon the reagent

esterified

at -5' for 20 hr.

carbonate

This step is the key to this route since it allows 5,6

was selectively

used.

Chromatography

165-168';

reactions

For instance,

at 3' with on

a], 33' (CHCls).

at the remaining subsequent

treatment

in DMF with pTSA at 130' gave the 5,6 isopropylidene

3607

3608

No. 41

Xa

n

No. 41

3609

intermediate

2 (95%) from which the trichloroethyl

with ammonia

in methanol

fication method method,4

to afford the isopropylidene

thus affords

that resulted

carbonate

an improved

in a difficultly

function was selectively

derivative

route to 3, previously separable

This selective

2.

prepared

removed

3' esteri:

by an alternative

mixture of 5,6 and 3',4' monoisopropylidene

derivatives. Transformation

of 2 to a nebramine

Umezawa for the conversion tosyl chloride derivative genolysis

of kanamycin

in pyridine yielded

5 (65%), m.p. 96-lOO'C, of 5 with Raney nickel

Acetylation

which was required

for selective

3'-tosylate

derivative,

synthesis

of deoxy sugar.6

the nebramine

followed

derivative

the 3'-deoxy

6n-glycosylation

derivative

nebramine

derivative

S, m.p. 177-180°,

to give tobramycin

procedure

derivative

and its analogs.

of neamine to a

by Barton and McCombie

generated

hydride proceeded

which on hydrolysis

(45%) of

of nebramine.

nearnine -15 was treated with NaH

Treatment

in methylene

sulfide-triethylamine

for the

gave a higher overall yield

-16.

acetic

of -16 with the imidoyl

chloride

and THF, followed

the 3'-thionobenzoate

smoothly

in refluxing

-17.

by -in Reduction

toluene affording

with 80% acetic acid gave the desired

nebramine

19 _*

To complete

the synthesis

we took advantage

of tobramycin

of the well established

and its congeners

use of pyranosyl

from the pseudodisaccharide

halide derivatives

group at C-2 such as a benzyl ether to insure stereoselective

Thus 8 was condensed sulfate

with the pyranosyl

in dioxane and toluene

initially with ammonia of the N-carbobenzoxy hydroxide

6_, m.p. 185-190’.

with aqueous

reactions

derivative

Hydro-

hydrolysis

of tetracarbobenzyloxy

carbamate

with tributyltin E,

of zwith

, which was converted to the iodo

19, thus being the method of choice for the preparation

with hydrogen

derivative

3' tosylation

by

Acetonide

of a 3'-thionobenzoate

of N,N-dimethylbenzamide

of the thionobenzoate

route described

the 3'-deoxy derivative

the general method developed

in OMF to give the 4',6'-cyclic

situ treatment

Selective

4, m.p. 99-103'

blocked 4'-0-acetyl

This deoxygenation

The known 5,6-cyclohexylidene

chloride methochloride

an analogous

with sodium iodide in dry OMF at 95-100' for 20 hr.

the deoxygenation

nebramine

calcium

6 to tobramycin. 5

in dioxane afforded

selectively

A second method,

cipating

followed

of 5 gave the 4' acetate 7, m.p. 90-95'.

acid gave the desired

derivative

derivative

fractions

in methanol

The resulting

formation

and benzyl blocking

followed

cyanide and

by reductive

groups with sodium and liquid ammonia.

chromatography

of a-an0mers.s

mixture was sequentially

to remove the ester function,

from ion exchange

with a nonparti-

chloride zq in the presence of mercuric (1:2).

8,

deblocked, removal

The ammonium

on Biorex 70-H+ were deacetylated

by brief

3610

I!o. 41

treatment

with boiling sodium hydroxide

chiefly of tobramycin,

although minor amounts of the 68 and C-5 isomer were also detected.lO

Silica gel chromatography properties

afforded

tobramycin

as well as antibacterial

Similar

treatment

of tobramycin

to afford a mixture, that consisted

in 1:1-dioxane-water

-13 identical with a natural

sample in physical

activity.

of 8 with the galactopyranosyl

halide -10"

ultimately

gave the 4"-epimer

14, a]D 78' (HzO).

Other analogs glycosylation12

(e.g. the 3-amino xylo derivative)

of the nebramine

It is of interest

derivative

of tobramycin

were prepared

by C-6

19 _*

to note that 4"-epi-tobramycin

exhibits

a similar antibacterial

spectrum.

and potency to that of tobramycin. REFERENCES

1.

M. Kugelman,

A. K. Mallams,

H. F. Vernay,

AND NOTES

D. F. Crowe, G. Detre, M. Tanabe,

and D. M. Yasuda.

J. Chem. Sot. fPerkin I), 1097-1118 (1976). 2.

G. Jaffe, W. Ravreby, 6. R. Meyers, and S. Z. Hirschman. 75-81 (1974).

3.

D. F. Koch and J. A. Rhoades.

4.

Antimicr.

Ag. Chemother.

5,

Antimicr. Ag. Chemother.-1970,309-313 (1971).

S. Umezawa, S. Koto, K. Tatsuta,

H. Hineno,

Y. Nishimura,

and T. Tsumura.

BUZZ. &em.

Sot.

Japan 42, 537-541 (1969). T. Miyake,

T. Tsuchiya,

and S. Umezawa.

J. Antibiotics 26, 403-406

5.

Y. Takagi,

6.

D.H.R. Barton and S. W. McCombie.

7.

T. Jikihara, T. Tsuchiya, S. Umezawa, and H. Umezawa. 3507-3510 (1973); J. Antibiotics 24_,711-712 (1971).

8.

G. Wulff and G. Rohle.

9.

S. Koto, T. Tsumura, Y. Kato, and S. Umezawa.

J. &em. SOC. Perkin

II,

(1973).

1574-1585 (1975).

BUZZ. Chem. Sot. Japan 46,

Angew Chem. Intern&. Edit 13(3),

157-216 (1974).

BUZZ. Chem.

SOC.

Japan 41, 2765-2769

(1968).

10.

We have observed with neamine and gentamine derivatives that when both the C-5 and C-6 hydroxyl groups are available for glycosysation reaction occurs predominantly at C-6.

11.

U.S. Patent 3,985,727 (Oct. 12, 1976), P.J.L. Daniels (to Schering-Plough CO.). We thank Dr. P.J.L. Daniels and Mr. C. E. Lute for providing us with this galactopyranoside intermediate,.

12.

Unpublished

results.

Acknowledgements

We thank the Schering

Corporation,

Bloomfield,

New Jersey,

for their support of this work.

We also thank Drs. P.J.L. Daniels and A. K. Mallams of the Schering helpful discussions.

Corporation

for many