The stereospecific synthesis of spectinomycin

Tetrahedron Letters No. 30, pp 2737 - 2740. @Pergamon Press Ltd. 1979. Printed in Great Britain.

THE STEREOSPECIFIC El. R. White,*

SYNTHESIS

R. C. Thomas,

R. D. Birkenmeyer, The Upjohn

OF SPECTINOMYCIN

Company,

Kalamazoo,

S. A. Mizsak Michigan

and V. H. Wiley

49001

Summary: The first synthesis of spectinomycin, a complex and sensitive antibiotic, is The synthesis, which requires only four steps from known materials, has flexibility described. for modifying either half of the molecule. Spectinomycin

(2) is an aminocyclitol

It does not have the toxicity The structure1

cyclitols. contains

a glycosylated

of a hemiketal.

Actlnomme

antibiotic

associated

of spectinomycin

actinamine

Spectinomycin

(I

usually

biological containing

is unique among the aminocyclitols

ring which

is cyclized

(2) has nine asymmetric

)

having broad spectrum

with the 2-deoxystreptamine

Spectinomycln

activity. amino-

in that it

to form a third ring by the formation

centers;

it contains

(2)

a carbonyl

at C-3'

(3)

Bose I

/ 7””

()H

~J$~.$,.CH~

C~~~~~,CH~H~~~H~.,CH3

NCH3 H

NCH3 H

(5)

(4)

and two masked sensitive

carbonyls

at C-l' and C-2'. 2

(6)

This electrophilic

to mild base which causes a benzylic

spectinoic myoinositols

acid

(4).

Acid hydrolysis

so that synthesis

OH

NCH3 H

(1) Ia which

gives actinamine

of spectinomycin

portion of the molecule

acid type of rerrangementla

from actinamine

has been synthesized

constitutes

is

to give actinofrom

a formal total

synthesis. Mild reduction which giving

have markedly

of spectinomycin diminished

the biologically

at the C-3' center gives the dihydrospectinomycins

antibiotic

inactive

activity.

Further

tetrahydrospectinomycins

2737

reduction

saturates

(5),

the C-2' center

(6),4 one isomer of which

has been

2730

synthesized mycin

30

No.

by Suami.5

intermediates

selective

Synthetic

would

oxidations.

For synthetic equivalent, involving

(3).

structure

stood by evaluation

spectinomycin

or the C-6 hydroxyl

of anomeric

effects

of five major actinamine

(1) as an achiral,

the synthetic anomeric

problem

are:

at C-2' and C-3', (d) finally, described carbonyl

meets

Condensation formamide

stereochemically

preferably

without

group.

Natural

hemiketal

and its favorable rich building

introducing

by

The occurance may be under-

"folding"

is the first

outcome would allow use of

block.

Other

key challenges

at the C-5 hydroxyl,

complex

protecting

(b) control

of of

group manipulation,

must be respected.

and offers an especially

of N,N'-dicarbobenzyloxyactinamine

The major

(anomeric

products

attractive

The synthesis method

to be

for generation

of

at C-2' and C-3'. (7)5 with nitrosodimer

gives a number of 1:l adducts

product

group of the actinamine

is formed

functional

to four possible

of the three alternatives

glycosylation

(48%) is the desired

proton at 6.2 6; [a]'$5 -59" (C, 0.7, acetone)] hydroxyl

cyclize

in cis or trans fused hemiketals. absence

of spectinomycin

these challenges

at room temperature

chromatography.

have not been reported.

as its hypothetical

( c ) use of a scheme which would allow generation of carbonyl groups

the base sensitivity

equivalents

synthesis

(a) selective

stereochemistry,

(3) might

and mild,

at the C-l' and C-2' centers as well as the preference

C-5' methyl

goals of spectinomycin

(2) based on tetrahydrospectino-

group manipulation

of tetrahydrospectinomycins

(2) and the apparent

for chair rings and an equatorial

protecting

can be envisioned

diketone

A priori,

the C-4 hyaroxyl

to spectinomycin

considerable

Such transformations

analysis

diketone

of one natural

approaches

require

ring.

in which

In addition

(8)6 in dimethyl-

which are separated

oxime

by silica gel

(9) [m/e (tetra TMS) 1063; anomeric

a-glycosylation

occurred

to the major product,

proton at 5.78 6) as well as 10% of glycosides

on the C-5

l-2% of the 6-glycoside

at C-4 or C-6 of the

CBZ (9)

(9)

actinamine. derived

The latter compounds

from L-glucose

Lemieux method7

ensures

are reactive

was utilized crucial

(IO)

because

natural

with periodate

as expected.

the known preference

chiralitylb

This antipode

for a-glycosylation

at the anomeric

center.

(8)

by the

2739

30

No.

Deoximation

of the oxime triacetate

C-2' at 99.7 and 94.6 ppm respectively [a]2,5

-65" (C, 0.9, chloroform)]

The mode of hemiketal natural

folding,

tional analysis

suggests

removal

which

of unwanted

of natural hemiketal

avoid degradation

effects

of the crude product

directly

Under

acetoxydienone hemiketal

of unnatural

(a)

stereo-

at C-3' as well as (d) introduction

potassium

is effected

bicarbonate

(ll)g requires

careful

related

by stirring

in acetonitrile

choice

4-pyrone1°

at

of conditions

(17).

and the filtrate

and then chromatography

of hemiketal

conditions

(13) which

undergoes

triacetate suffers

a second elimination

(15), having only one chiral center.

(16) which

(b) removal

salts are filtered

at C-3', C-4'

to

After

concentrated.

product

of the mother

(11).

This

liquor allows

of 55%.

to give an intermediate

the specified

and conforma-

has been involved

The next step accomplishes

(CMR and TLC) shows only one enoneacetate,

(11) is crystallized

of a total yield

the C-6 hydroxyl

series of reactions

(11) to the closely

as being un-

effects

have axial substituents

carbonyl

This remarkable

The first event in the conversion

(14).

(lo), in which

at C-4' and C-6',

the inorganic

of anomeric

in this situation.

of the enoneacetate

of the enoneacetate

(triTMS) 976 (M+) 961 (M-15),

in the next step, is assigned consideration

(10) with a slurry of anhydrous

Generation

Evaluation

of the hemiketal

m/e

triacetate' (lo)* [C-l' and

in 87% yield after column chromatography.

of the sensitive

of the hemiketal.

of the reaction,

isolation

structure

functionality

completion

enoneacetate

Further,

predominate

(c) generation

triacetate

room temperature.

is destroyed

data.

the assigned

oxygen

at C-5', folding

solvent),

is isolated

hemiketal

The three other modes of folding would

in a cis hemiketal.

and C-5'; conformational

chemistry

(CD3COCD3

which

on the basis of spectral

(9) gives a single

acetyl migration

(10) is the base induced opening

B-elimination of acetate

This intermediate

to give enolacetate

occurs

to give the Q-

collapses

to give the single enoneacetate

to a new (11).

The

No.

2740

proper

hemiketal

centers

folding

has occurred

with one remaining

Careful

hydrolysis

of the free hemiketal addition

to pyrone

to be established

of enoneacetate

GLC/MS

hydrogenolysis

as its dihydrochloride

KzHPO,

of the olefin

of the carbobenzyloxy

in methanol m/e

gives 55% (76% conversion)

(TriTMS) 814 (M+), 749 (M-15)] in

salt.

It has identical

A more direct

alternative

antibiotic.

itself,

since the acetyl group

tions.

In this case the crystalline

is reactive

for modifying

The preparation

from the convex side of the molecule groups.

The product

isomer.

natural

materials.

eight asymmetric

at C-5'.

(11) with

(12) [[a] '0" -56" (C, 1.0, CHsOH),

shows only the natural

has the flexibility

by nmr) and establishes

(17).

The final step is hydrogenation concommitant

(as judged

50

of modified

physical

in 40% yield

and biological

is hydrogenation

enough

yield

either

At the conclusion

is isolated

antibacterial

agents

properties

with the (11)

under the hydrogenation

is 35% from enoneacetate

half of the molecule

of the reaction by crystallization

of the enoneacetate

to be removed

(11).

and

condi-

This synthetic

by choice of different using this approach

scheme

starting

will be

reported. FOOTNOTES

(1)

a) b)

AND REFERENCES

P. F. Wiley, A. D. Argoudelis and H. Hoeksema, T. G. Cochran, Il. J. Abraham and L. L. Morton,

J. J.

Amer. Chem.

Chem. Sot.,

Sot.,

85,

2652 (1963). (1972).

Chem. Corn., 494

(2)

The aminoglycoside numbering system has been used so that numbering is consistent with that of the antibiotic.

(3)

T. Suami,

(4)

J. C. Knight and H. Hoeksema,

(5)

T. Suami, J. Nishiyama, 50, 2754 (1977).

(6)

H. Paulsen,

(7)

R. U. Lemieux,

(8)

NMR data for (10); PMR (CD~COCD~, 100 Hz); 2.06 (9H, s), 2.88 (3H, s), 3.12 (3H, s), 4.20 (8H, m), 5.08 (2H, s), 5.14 (2H, s), 5.82 (lH, d), 6.21 (lH, s), 7.38 6 (lOH, s). CMR (CD~COCD~): 170.8, 170.7, 170.0, 138.0, 129.2, 128.5, 99.7, 94.6, 82.7, 74.5, 71.2, 69.2, 68.5, 67.4, 66.2, 62.8, 60.5, 57.8, 31.8, 31.6, 20.6 ppm.

(9)

The enoneacetate (11) has the following physical roperties: mp 151-154', UV (C HsOH): 204 (20,950), 206, sh, (20,650), 267 nm (11,550),[~~]~~ -43" (C, 1.0, acetone). PMR PCDCl Hz): 2.07 (3H, s), 2.15 (3H, s), 3.05 (3H, s), 9.07 (3H, s), 3.50 (lH, d, J=9.4), 3.$? i;i d, J=l1.4), 4.05 (lH, d of d, J=9.4, 9.4), 4.40 (lH, br, s), 4.63 (lH, J=9.7, 7.5), 4.78 (1;. d of d, J=10.5, 10.3), 5.05 (lH, m), 5.14 (2H, s), 5.15 (2H, s), 5.18 (lH, m), 5.42 (lH, s) 5.98 (lH, s), 7.32 d (10H). CMR (CDsCOCD,): 182.5, 172.9, 169.5, 137.6, 137.5, 128.6, 127.8, 102.7, 95.5, 93.1, 75.0, 74.0, 66.8, 65.6, 60.3, 59.6, 56.7, 31.1, 20.4 ppm. m/e calcd. for C3aHs2N2012Si2, 784.3058. Found 784.3097.

S. Ogawa and H. Sano, BUZZ.

P. Stadler

J.

Clzem.

Sot.

Antibiotics,

H. Ishikawa,

Japzn,

28,

43,

of the intermediates

1843 (1970).

136 (1975).

H. Okada and T. Kinoshita,

BUZZ.

Chem.

Sot.

Japan,

and F. Tb'dter, Chem. Ber., 110, 1925 (1977).

T. L. Nagabhushan

and I. K. O'Neill,

Can. J.

Chari.,

43, 4136

(1968).

By loss of (10) 2-Ketosugar derivatives are known to give 4-pyrones under mild conditions. acetate from C-4 and C-l, Kojic acid derivatives are produced, R. W. Binkley, J. 01-g. Chem., 42, 1216 (1977). Loss of benzoate from C-4 and from C-6 has led to allomaltols, F. W. Lichtenthaler, K. Strobe1 and G. Rendel, Garb. Res., 49, 57 (1976). The ferric chloride reactive pyrone (17) was characterized as its tetraacetate. Acknowledgment: We are grateful to Dr. H. Hoeksema standards of naturally derived compounds.

(Received in USA 2 April 1979)

of The Upjohn Company

for reference