Aminocyclitol Antibiotics - American Chemical Society

6 The Stereospecific Synthesis of Spectinomycin D. R. WHITE, R. D. BIRKENMEYER, R. C. THOMAS, S. A. MIZSAK, and V. H . WILEY

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The Upjohn Company, Kalamazoo, MI 49001

Spectinomycin (1) is an aminocyclitol antibiotic marketed by The Upjohn Company as the dihydrochloride salt under the name of Trobicin . It is a broad spectrum antibiotic of moderate potency which has become especially important for the treatment of penicillin-resistant strains of gonorrhoeae. Spectinomycin does not have the oto- and nephrotoxicity which is usually associated with the 2-deoxystreptamine containing aminocyclitols. The structure of spectinomycin was determined at Upjohn by Wiley, Hoeksema, and Argoudelis (1, 2). This structure (1), shown on Figure 1, is unique among the aminocyclitols in that it contains a glycosylated actinamine ring which is cyclized to form a third ring by hemiketal formation. Spectinomycin (1) has nine asymmetric centers. It also has a carbonyl group at C-3' and two masked carbonyl groups at C-1' and C-2'. This electrophilic portion of the molecule is sensitive to mild base which causes benzylic acid type rearrangement to give actinospectinoic acid (2). ®

The aminoglycoside numbering system w i l l be used i n the i n t e r e s t of consistency when intermediates are discussed. As shown on the F i g u r e 2, stepwise r e d u c t i o n of spectinomycin u s i n g Η /Ρί (1) g i v e s dihydrospectinomycins ( 4 ) , compounds of diminished b i o l o g i c a l a c t i v i t y ( 3 ) . F u r t h e r r e d u c t i o n w i t h NaBH^ g i v e s tetrahydrospectinomycins (5) which are i n a c t i v e ( 3 ) . H y d r o l y s i s o f spectinomycin (1) w i t h m i n e r a l a c i d gives actinamine (3) (1) which has been synthesized by Suami, et ai. (4) from m y o i n o s i t o l ( 6 ) . I n 1977 Suami reported (5) a s y n t h e s i s of a tetrahydrospectinomycin ( 5 ) . However, the conversion of t e t r a hydrospectinomycin (5) t o spectinomycin (1) has not been reported. In t h e i r work on spectinomycin m o d i f i c a t i o n , Rosenbrook and coworkers have demonstrated (6) the o x i d a t i o n of N-blocked dihydrospectinomycin analogs to N-blocked spectinomycin analogs. However the DMSO o x i d a t i o n i s not s e l e c t i v e so t h a t i s o l a t e d y i e l d s are reported to be 14-18%. Synthesis of spectinomycin (1) 2

0-8412-0554-X/80/47-125-lll$05.00/0 © 1980 American Chemical Society

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

AMINOCYCLITOL ANTIBIOTICS


112

Actinamine

Figure 1.

Myoinositol

(6)

(3)

Structure and chemistry (1); absolute configuration (x-ray) (2)

A c t i n a m i n e (3)

T e t r a h y d r o s p e c t i n o m y c i n s (5)

Figure 2.


6.

113

Stereospecific Synthesis of Spectinomycin

WHITE ET AL.

from t e t r a h y d r o compounds (5) i s not a t t r a c t i v e , e i t h e r , s i n c e i t would r e q u i r e s e l e c t i v e o x i d a t i o n of the C-2 and C-3 h y d r o x y l groups o r complex p r o t e c t i n g group m a n i p u l a t i o n . S t a r t i n g from f u l l y f u n c t i o n a l i z e d sugars such a route would r e q u i r e f i r s t removal of hydroxyls at C-6 and C-4 and t h i s , taken together w i t h C-2 and C-3' o x i d a t i o n , c o n s t i t u t e s a h i g h l y i n v o l v e d adjustment i n a s i n g l e sugar r i n g . T

T

1

f

1


S y n t h e t i c Goals For these reasons, one can see that a simple method f o r generation of carbonyl groups at C-2 and C-3 i s an i n t e r e s t i n g and formidable s y n t h e t i c c h a l l e n g e . This i s l i s t e d on F i g u r e 3 along w i t h four other s y n t h e t i c g o a l s . S e l e c t i v e g l y c o s y l a t i o n at the C-5 h y d r o x y l i s e s s e n t i a l as i s c o n t r o l of anomeric stereochemistry. In a l l p l a n n i n g , the base s e n s i t i v i t y of spectinomycin must be respected. For t h i s reason, generation of the C-3 carbonyl toward the end of a s y n t h e s i s i s d e s i r a b l e . A f i f t h goal i s t o generate n a t u r a l hemiketal f o l d i n g of the h y p o t h e t i c a l diketone (7) as shown on F i g u r e 3. This i s a very i n t e r e s t i n g problem from the t h e o r e t i c a l p o i n t of view. I w i l l d i s c u s s i t i n some d e t a i l . The h y p o t h e t i c a l diketone (7) would have f r e e r o t a t i o n around the g l y c o s i d e bond and a priori might c y c l i z e to a hemiketal i n v o l v i n g e i t h e r C-4 or C-6 h y d r o x y l g i v i n g e i t h e r ois o r trans f u s i o n . The occurrence of one n a t u r a l s t r u c t u r e , to the apparent e x c l u s i o n of three o t h e r s , may be r a t i o n a l i z e d by e v a l u a t i o n of anomeric e f f e c t s at the C - l ' and C-2 centers as w e l l as the preference f o r c h a i r r i n g s and an e q u a t o r i a l C-5 methyl group. These four e f f e c t s are summarized on F i g u r e 4. Here we see the four p o s s i b l e hemiketals generated from the h y p o t h e t i c a l diketone (7) by i n v o l v i n g e i t h e r the R or S h y d r o x y l group. Consider p o s s i b l e d e s t a b i l i z a t i o n f o r c e s (a) through ( d ) . In (a) the C-2 center i s considered and d e s t a b i l i z a t i o n by the anomeric e f f e c t i s evident when the C-2 h y d r o x y l i s f o r c e d i n t o an e q u a t o r i a l p o s i t i o n r a t h e r than the p r e f e r r e d a x i a l o r i e n t a t i o n . This i s the u s u a l anomeric e f f e c t . I n (b) the anomeric e f f e c t a t the C - l center i s considered, and e i t h e r one or two oxygen lone p a i r s may be e c l i p s e d . No hemiketals are p o s s i b l e having no e c l i p s i n g of lone p a i r s . I n (c) the a x i a l o r e q u a t o r i a l d i s p o s i t i o n of the C-5' methyl group i s considered, and i n (d) t h e n e c e s s i t y of boat r i n g s i s considered as d e s t a b i l i z i n g the system. From t h i s d i s c u s s i o n one can say t h a t , w h i l e these i n f l u e n c e s (a) through (d) are probably not e q u i v a l e n t , they show why the n a t u r a l c o n f i g u r a t i o n i s most s t a b l e ; furthermore the i n f l u e n c e of e p i m e r i z a t i o n at C-5 can be estimated as being great enough t o d e s t a b i l i z e n a t u r a l hemiketal f o l d i n g toward other modes of c y c l i z a t i o n . This p e r t u r b a t i o n has been t e s t e d e x p e r i m e n t a l l y and i s p a r t of Dr. Thomas' manuscript. C e r t a i n n a t u r a l l y d e r i v e d p r o t e c t e d dihydrospectinomycin diastereomers which have been trapped as u n n a t u r a l l y f o l d e d T

1

f

1

T

T

1

f

f



114


H

S p e c t i n o m y c i n (I)

H y p o t h e t i c a l Diketone

SYNTHETIC I II III IV V

Generation

of

carbonyl

Selective glycosidation Selective Sensitivity

generation

GOALS

g r o u p s at C - 2 ' at the

C-5

and

carbonyl must

H e m i k e t a l " f o l d i n g " m u s t be

C-3'.

hydroxyl.

of n a t u r a l a n o m e r i c

of the C - 3 *

(7)

be

stereochemistry. respected.

natural.

Figure 3.

CP" CD' OH'

Destabilization Forces

-R-cis

OH{I

-R-trans

(a) E q u a t o r i a l 2'-OH (Anomeric E f f e c t ) (b) S y n - a x i a l interactions of O - C H - 0 lone p a i r s (Anomeric E f f e c t )

I

(c) A x i a l C - 5 '

Ο

(d) Boat

rings

CH

3

I

Figure 4.


6.

WHITE ET AL.

115



acetonides have been found t o r e c l o s e t o the n a t u r a l s k e l e t o n upon acetonide removal ( 7 ) . However, n a t u r a l f o l d i n g i s not i n t r i n s i c to the spectinomycin s k e l e t o n as evidenced by s t r u c t u r e (12) (wide infra) and by the subject of Dr. Thomas's manuscript. Full c o n s i d e r a t i o n of anomeric e f f e c t s and conformational e f f e c t s f o r each case i s e s s e n t i a l t o p r e d i c t the mode of f o l d i n g . N a t u r a l hemiketal f o l d i n g i s the l a s t o f f i v e major goals o f spectinomycin s y n t h e s i s and a n t i c i p a t i o n of a f a v o r a b l e outcome a l l o w s the use of actinamine (3) as an a c h i r a l , s t e r e o c h e m i c a l ^ r i c h b u i l d i n g block. Synthesis As shown on F i g u r e 5, L - g l u c a l t r i a c e t a t e (8) i s used as our s t a r t i n g m a t e r i a l ; i t can be made from L-glucose without p u r i f i c a t i o n of intermediates by the method of Roth and Pigman ( 8 ) . A d d i t i o n of N0C1 gives 90% y i e l d of the known ( 9 ) , c r y s t a l l i n e n i t r o s o d i m e r ( 9 ) . This n i t r o s o d i m e r (9) i s allowed t o r e a c t w i t h Ν,Ν'-dicarbobenzyloxyactinamine (10) i n DMF a t room temperature. S e v e r a l 1:1 adducts a r e formed which a r e separated by chromato graphy. The major product, the α-glycoside (11), i s formed i n 48% y i e l d . The preference f o r α-glycosylation i s a n t i c i p a t e d i n the use of t h i s method which was e s t a b l i s h e d by Lemieux (10). I n t h i s r e a c t i o n n a t u r a l c h i r a l i t y has been e s t a b l i s h e d a t C-1'. Among the minor f r a c t i o n s , a few percent of the $-glycoside i s u s u a l l y formed i n the r e a c t i o n and removed i n the chromatography. A l s o , up t o 10% o f g l y c o s y l a t i o n a t C-4 and C-6 hydroxyls occurs. These compounds a r e r e a c t i v e w i t h p e r i o d a t e as expected. F i n a l l y , i t should be noted t h a t the oxime a t C-2 i s a carbonyl e q u i v a l e n t . F i g u r e 6 shows t h a t deoximation occurs t o g i v e one product, a hemiketal (12) which i s i s o l a t e d i n 87% y i e l d a f t e r chromatography. NMR data show that the mode o f hemiketal f o l d i n g , which w i l l be destroyed i n the next s t e p , i s u n n a t u r a l . C o n s i d e r a t i o n o f anomeric e f f e c t s and conformational a n a l y s i s suggests the s t r u c t u r e (12) shown. The next s t e p , e f f e c t e d by r e a c t i o n w i t h anhydrous K H C O 3 , accomplishes (a) removal of unwanted f u n c t i o n a l i t y a t C-4' and C-6 , (b) removal of unnatural stereochemistry a t C-5 , (c) generation of t h e s e n s i t i v e carbonyl a t C-3 , and (d) i n t r o d u c t i o n of n a t u r a l f o l d i n g of t h e hemiketal. R e a c t i o n c o n d i t i o n s are chosen t o avoid h y d r o l y s i s of the acetate a t C-2 s i n c e the f r e e hemiketal i s r a p i d l y converted t o the r e l a t e d α-hydroxy-γpyrone (14) shown a t the bottom of F i g u r e 6. E v a l u a t i o n of the crude r e a c t i o n mixture by TLC and CMR shows that only one enonea c e t a t e i s formed. The enoneacetate (13) i s c r y s t a l l i z e d d i r e c t l y from a chloroform s o l u t i o n . A second crop of product, g i v i n g a t o t a l of 55% y i e l d , i s obtained a f t e r chromatography of the mother l i q u o r on s i l i c a g e l . A l i k e l y mechanism f o r the e l i m i n a t i o n r e a c t i o n , which guided t h i s s y n t h e s i s , i s shown on F i g u r e 7. Base encourages hemiketal f

f

f

1

f



116

^OAc OAc

2

[«Ν'

γ^^ΟΑ . OAc

mp

130-131°

[a]g

5

lit.

(8)

- 1 6 5 ° (C 2.0 , C H C I ) 3

-150° (C 1.0 , CHCI3)

(9)

CH

OH

3

CBzN


DMF 48% NCH

3

CBz

CH

3

(10)

OH OAc s

NCH3

H

CBz

(ID

m/e 1063 ( t e t r a s i l y l ) M S

OAc

- 5 9 ° (C 0 . 7 , acetone)

anomeric proton 6.2 8

OAc

Figure 5.

M g

mp 1 5 0 - 1 5 4 °

m

p

o

f

5

- 6 5 ° (C 0.9 CHCI3)

tetraacetate 2 2 0 - 2 2 1 °

[a]g5 .43° (C 1.0 acetone) Figure 6.


6.

WHITE ET AL.

117


opening to g i v e a 2-ketosugar (15) which s u f f e r s two consecutive e l i m i n a t i o n s of acetate g i v i n g an a-acetoxydienone (17). This intermediate which contains only one asymmetric c e n t e r , a t the anomeric p o s i t i o n , c l o s e s to a hemiketal (18). M i g r a t i o n of the a c e t y l group then generates the enoneacetate (13) w i t h n a t u r a l hemiketal f o l d i n g as determined by nmr. E i g h t asymmetric centers are now i n p l a c e , w i t h one remaining to be e s t a b l i s h e d at C-5 . As mentioned above the enoneacetate (13) i s s e n s i t i v e t o h y d r o l y t i c c o n d i t i o n s because of pyrone (14) formation. However, as shown on F i g u r e 8, we have found that c a r e f u l h y d r o l y s i s using ^HPO^ i n methanol at room temperature f o r 1-2 hours gives the enone (19) having a f r e e hemiketal. Even under these c o n d i t i o n s the pyrone (14) i s formed so that g e n e r a l l y the r e a c t i o n i s not run to completion. In t h i s way 55% o f the enone (19) and 28% of recovered s t a r t i n g m a t e r i a l (13) are obtained a f t e r column chromatography. One can see that the f r e e hemiketal (19) and the pyrone (14) are r e l a t e d by hemiketal opening and subsequent enolization. F i g u r e 9 shows that the l a s t step of the s y n t h e s i s i s hydrogénation of the o l e f i n from the convex s i d e of the molecule and concommitant hydrogenolysis o f the carbobenzyloxy groups. A t the c o n c l u s i o n of the r e a c t i o n GC/MS shows the major peak corresponding to the n a t u r a l a n t i b i o t i c ; no peaks correspond to p o s s i b l e s t e r e o isomers. The product (1) i s i s o l a t e d i n 40% y i e l d by c r y s t a l l i z a t i o n as the d i h y d r o c h l o r i d e s a l t . I t has i d e n t i c a l p h y s i c a l and b i o l o g i c a l p r o p e r t i e s as the n a t u r a l a n t i b i o t i c . F i g u r e 10 summarizes the s y n t h e s i s o f spectinomycin (1) from the known s t a r t i n g m a t e r i a l s . I would l i k e to p o i n t out that separate h y d r o l y s i s o f the enoneacetate (13) i s not necessary. Thus, d i r e c t hydrogénation of the enoneacetate (13) gives s p e c t i n o mycin (1) i n 35% y i e l d s i n c e the a c e t y l a t e d hemiketal i s r e a c t i v e enough to be hydrolyzed by the i s o p r o p y l a l c o h o l .


?

Summary Although the a n t i b i o t i c i s h i g h l y f u n c t i o n a l i z e d , t h i s approach r e q u i r e s minimum p r o t e c t i o n - d e p r o t e c t i o n chemistry s i n c e the scheme does not r e q u i r e s u b j e c t i n g the pseudodisaccharide t o oxidants which would a t t a c k a hydroxyl group. Only four chemical steps from known s t a r t i n g m a t e r i a l are r e q u i r e d . This i s p o s s i b l e because i n a l l except the second step more than one change toward the goal i s o c c u r r i n g ; a l l of the changes are s t e r e o s p e c i f i c . Extremely m i l d reagents are used, a l l at room temperature. F i n a l l y the scheme has f l e x i b i l i t y to modify e i t h e r h a l f of the molecule by choice of d i f f e r e n t s t a r t i n g m a t e r i a l s or by doing chemistry on some of the intermediates described.


118



(76%

b a s e d on r e c o v e r e d s t a r t i n g m a t e r i a l )

Figure 8.


6.

WHITE ET AL.

H

.'CH

2

Pd/BaS04 Pyridine 2-propanol 40%


119


Spectinomycin(l)

Figure 9.

Spectinomycin (I)

Figure 10.


3


120

Literature Cited 1. 2. 3. 4. Downloaded by UNIV OF MISSOURI COLUMBIA on April 13, 2017 | http://pubs.acs.org Publication Date: August 4, 1980 | doi: 10.1021/bk-1980-0125.ch006

5. 6. 7. 8. 9. 10.

Wiley, P. F., Argoudelis, A. D., and Hoeksema, H., J. Amer. Chem. Soc. (1963) 85, 2652. Cochran, T. G., Abraham, D. J., and Marton, L. L., J. Amer. Soc., Chem. Comm. (1972) 494. Knight, J. C. and Hoeksema, Η., J. Antibiot. (1975) 136. Suami, T., Ogawa, S., and Sano, Η., Bull. Chem. Soc. Japan (1970) 43, 1843. Suami, T., Nishiyama, S., Ishikawa, Η., Okada, Η., and Kinoshita, T., Bull. Chem. Soc. Japan (1977) 50, 2754. Rosenbrook, W., Carney, R. E., Egan, R. S. Stanaszek, R. S., Cirovic, M., Nishinaga, T., Mochida, Κ., and Mori, Y., J. Antibiot. (1978) 451. Foley, L. and Weigele, Μ., J. Org. Chem. (1978) 43, 4355. Roth, W., Pigman, W., "Methods in Carbohydrate Chemistry," Vol. II, p.405, Academic Press, New York, 1963. Paulsen, Η., Stadler, P., and Tödter, F., Chem. Ber. (1977) 110, 1925. Lemieux, R. U., Nagabhushan, T. L., and Gunner, S. W., Can. J. Chem. (1968) 43, 405.

RECEIVED

November 15, 1979.


Aminocyclitol Antibiotics - American Chemical Society

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