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3!,7f-anhydrooctose was based on a ring closure strategy which built the pyran portion of ... problem was overcome by an exchange of protective groups...
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Chapter 4

Synthetic Approaches to Bicyclic Nucleosides Total Synthesis of Octosyl Acid A and Octosyl Acid C Dimethyl Acetal

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Stephen Hanessian, John Kloss, and Tamio Sugawara Department of Chemistry, Université de Montréal, Montreal, Q u é b e c H3C 3J7, Canada

An overview of various synthetic approaches to bicyclic nucleosides such as the octosyl acids and the ezomycins is presented. Details of the total synthesis of octosyl acids A and C are disclosed. The discovery of the polyoxin group (1) of antifungal nucleoside a n t i b i o t i c s (2) spurred the attention of synthetic chemists as well as b i o l o g i s t s for a number of reasons. Their unusual s t r u c t u r a l features combined with unique b i o l o g i c a l a c t i v i t y fostered studies on many fronts (3). During their studies on the biosynthesis of the polyoxins, Isono, Crain and McCloskey (4) discovered three novel a c i d i c nucleosides which they called octosyl acid A, Β and C, ^1-^3 (Figure 1). Their structures, which were elucidated by spectroscopic and chemical means, revealed several unusual features, the most prominent being the presence of a trans-fused b i c y c l i c r i n g system i n A, Β but not C. These have been considered to be anhydrooctose uronic acid nucleosides and an analogy has been derived with c y c l i c nucleotides. Thus, viewed i n a different perspective, the octosyl acids may be considered as "carba" analogs of nucleoside S ' ^ ' - c y c l i c phosphates (4) (Figure 2). This feature may have some bearing on their b i o l o g i c a l a c t i v i t y since the adenine nucleoside analog _5 inhibited c-AMP phosphodiesterases from various sources (5). The trans-fused perhydrofuropyran system i s also encountered i n the ezomycin group of nucleoside a n t i b i o t i c s (6,7). The structures of ezomycin Αχ and A 2 are shown i n Figure 3 for comparison with the octosyl acids. U n t i l recently, these unusual classes of b i c y c l i c nucleosides had eluded the grasp of synthetic chemists. It i s clear that the main challenge i n the synthesis of these unusual nucleosides resides i n the method of b i c y c l i c ring formation. If one also considers the type of f u n c t i o n a l i t y that adorns these molecules, then the whole exercise becomes one of judicious choice of reactions and protective

c

(X)97-6156/89/0386-0064$08.25/0 1989 American Chemical Society

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

4. HANESSIAN ET AL.

Synthetic Approaches to Bicyclic Nucleosides

65

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groups. A fundamental issue i s concerned with the "timing" of certain operations. Does one start with a pyrimidine nucleoside derivative and build from there, or should the b i c y c l i c ring be constructed f i r s t and the heterocycle introduced at a later stage i n the assembly process? The two recently completed syntheses of octosyl acid A address these issues independently (8,9).

Figure 2.

Functional analogies with

cyclic-AMP.

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY

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66

8,

EZOMYCIN

A,

Figure 3.

R=OH

Structures of the ezonycins.

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

4. HANESSIAN ET AL.

Synthetic Approaches to Bicyclic Nucleosides

67

Since there have been several approaches to the construction of the 3 ,7'-anhydrooctofuranose ring system, an overview of the strategies w i l l be presented here. f

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The Anzai-Saita Approach The f i r s t attempted synthesis of compounds related to the octosyl acids was reported by Anzai and Saita (10). The strategy entailed building the pyranose ring from a suitably protected D-allofuranose (Figure 4). The c r i t i c a l c y c l i z a t i o n step was conceived as an intramolecular attack of a glycolate anion on a primary sulfonate ester. However the only product to form was epoxide 14. A l t e r n a t i ­ vely, treatment of the 6-0-tosyl derivative _13 with NaH gave approximately a 1.5 to 1 mixture of the cyclized product _16 and the epoxide 15. Attempts to remove the O-isopropylidene group under a c i d i c conditions resulted i n the degradation of the molecule to give ^8. The s e n s i t i v i t y to acid was ascribed to the highly strained trans-fused anhydrooctose ring system. Subsequently i t was thought that nucleoside formation prior to ring closure would be a viable alternative (11). Towards t h i s end, nucleoside formation from _19 gave 20_ which was further transformed into 21, although no d e t a i l s were given.

The Szarek-Kim Approach In 1976, Szarek and Kim (12) published their work related to the octosyl acids. Like the previous route, the formation of the 3 ,7 -anhydrooctose was based on a ring closure strategy which b u i l t the pyran portion of the molecule onto a pre-existing furanose (Figure 5). This approach started with aldehyde 23. Condensation with the r e a d i l y available Wittig reagent gave the α,3-unsaturated ketone 24. Borohydride reduction followed by hydrogénation gave epimeric C-7* hydroxy compounds which were not separated but instead tosylated to give 25. Removal of the acetonide and intramolecular c y c l i z a t i o n v i a S^5~~reaction produced the D-allo (25%) and the L-talo (21%) b i c y c l i c derivatives, 27 and 28. respectively. Next, a more highly functionalized Wittig reagent was employed which would lead to a 3 ,7 -anhydrooctose more closely resembling octosyl acid A (Figure 6). Wittig reaction with the protected α-hydroxy ketone gave the corresponding α,3-unsaturated ketone 29_ i n 72% y i e l d . The reaction sequence then followed a reductionhydrogenation methodology to give the tosyl derivative 30. Hydrolysis followed by attempted ring closure gave a complex mixture of products, which included the diastereomeric epoxides 32. It was assumed that the complex mixture arose from the i n s t a b i l i t y of the terminal C-8 acetate to the conditions of ring closure. This problem was overcome by an exchange of protective groups prior to c y c l i z a t i o n . Thus intermediate 30 was transformed into 3>4_ by ring opening of epoxide 33. Hydrolysis, followed by intramolecular ring closure, afforded _36 as a mixture of cyclized products i n 50% y i e l d . The two diastereomers were separated a f t e r isomerization to the prop-l-enyl derivatives 37. Selective oxidation and e s t e r i f i c a t i o n then completed the synthesis of the model anhydrooctose uronic acid, 39. !

f

f

f

1

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

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EtO,C

17

1

14 R = H 15 R = CO,Et

18 Ο

21

20

19

a. BrCH C0 Et, NaH; b. AcOH, H 0; c. TsCl, pyr.; d. NaH, e. C0(0Et) , NaH; f . H , MeOH; g. H ; h. Ac 0, pyr.; i . t r i m e t h y l s i l y l u r a c i l , SnCl^ ; j . no conditions given. 2

2

2

+

2

Figure 4.

+

2

The Anzai-Saita approach to octosyl acid A,

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

DMF;

Synthetic Approaches to Bicyclic Nucleosides

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4. HANESSIAN ET AL.

a. DCC, DMSO; b. Ph PCHCOCH ; c. NaBH^; d. Pd/C; e. TsCl, pyr f . 90% HC0 H, 0°C; g. NaH, DMF· 3

3

2

Figure 5·

The Szarek-Kim approach to octosyl acid A,

(Part I)

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

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TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY

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70

33

34

35

ο

ο

K^O

Γ$

ο

ί , Α —

^

rCi



0 - < / \ > Η

^ Ο ^ Λ β ,

36 R= CH CH=CH, r

3

M^C-iTO^OH

g

3

g

37 W'CHxCHCH,

a. f. i. 1.

NaBHt^ ; b. Pd/C; T s C l , pyr.; d. 90% HC0 H; e. NaH, DMF; NaOMe, MeOH; g. CH «CHCH ONa, CH «CHCH OH; h. 90% HC0 H, 0°C; R h C l ( P P h ) , EtOH, r e f l u x ; j . BzCl, pyr.; k. H g C l , HgO; Pt, 02, NaHC03, H20, 90°C; m. H+, MeOH. 2

2

3

F i g u r e 6.

3

2

2

2

2

2

The Szarek-Kim approach t o o c t o s y l a c i d A.

(Part I I )

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

Synthetic Approaches to Bicyclic Nucleosides

4. HANESSIAN ET AL.

71

Model Studies Directed at the Octosyl acids, Ezomyclns and Quantamycin

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In connection with the t o t a l synthesis of quantamycin (13), we adopted a different approach to the preparation of the 3',7*-anhydrooctose skeleton i n these b i c y c l i c nucleosides, namely the formation of the furanose ring onto a pre-existing pyranose ring (14). Model studies from a suitably protected D-galactose, showed that this new strategy was indeed f e a s i b l e (Figure 7). The C - a l l y l glycoside 40 was epoxidized to give a diastereomeric mixture of epoxides 4J_ which upon treatment with acid gave a diastereomeric mixture of cyclized products kl_ r e s u l t i n g from an intramolecular epoxide opening. This strategy worked equally well on the C-vinyl glycoside (14) (Figure 8). Epoxidation of 43^ afforded 44^ which, when subjected to the intramolecular epoxide opening, gave 45^ which contained the basic skeleton that could be adapted toward a synthesis of b i c y c l i c nucleosides. In order for this strategy to be applicable to either the octosyl acids or the ezomycins, however, a more highly functionalized epoxide would have to be prepared i n which the terminal position was substituted with a nucleic acid base. A s l i g h t l y modified strategy (14) was used to prepare a 3',7'-anhydrooctofuranosyl nucleoside. D-Galactose was transformed to the glycosyl bromide 50_ and then treated with allylmagnesium bromide to give the C - a l l y l D-galactopyranoside 51_ (Figure 9). Oxidation gave aldehyde 52_ which was converted to the corresponding d i t h i o a c e t a l _53. Treatment of Jx3 with N-benzoyladenine and bromine gave a 1:1 mixture of anomeric b i c y c l i c nucleosides bk_ and 55. This key transformation entailed a sequential displacement of a sulfonium intermediate. Presumably an a c y c l i c nucleoside derivative (15) i s formed f i r s t , which, after further a c t i v a t i o n with bromine, undergoes intramolecular ether formation. Unequivocal proof for the structure of the β-adeninyl nucleoside 54^was secured by X-ray crystallographic analysis (14). Although this methodology was applicable to the formation of b i c y c l i c nucleosides, the lack of stereocontrol at C - l precluded i t s further use. In addition, a hydroxy group had to be incorporated at the 2'-position. 1

An extension of this methodology was used i n another approach (16) to the octosyl acids and ezomycins (Figure 10). In this sequence, D-galactose was transformed into the 2-0-acetyl derivative 57. Transformation to the a c y c l i c nucleoside derivative and selective oxidation then gave sulfoxide 58. Elimination afforded the trans o l e f i n _59 whereupon s o l v o l y s i s followed by epoxidation and acid-catalyzed c y c l i z a t i o n produced 60_ and 6^ i n a 1:2 r a t i o respectively. The ^-NMR spectra showed each to contain a 1',2'-trans configuration, and that the minor isomer 60_ was the required 3-D-nucleoside, while the major product 61^ was the a-D-nucleoside. Since octosyl acid A has the C-5 (R) configuration, the 3-D-nucleoside 60 was subjected to configurational inversion. After protective group manipulations to give 62, oxidation gave ketone 63. It was hoped that reduction would give a net inversion of the 1

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

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TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY

40

a, MCPBA;

41

42

b. CSA, C1CH CH C1, r e f l u x . 2

2

Figure 7. Model studies for perhydrofuropyran systems.

BnO

BnO

43

BnO

44

45

OH

«Ο

o„

HO

46

a. MCPBA;

b. CSA, C1CH CH C1, reflux; 2

2

c. Pd/C.

Figure 8. Model studies for perhydrofuropyran systems.

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

Synthetic Approaches to Bicyclic Nucleosides

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4. HANESSIAN ET AL.

56

a. NaOMe, MeOH; b. BnBr, NaH, DMF; c. AcOH, H 0; d. Ac 0, pyr e. HBr, CH C l ; f . AllylMgBr, THF; g. OsO^ , Nalfy , tBuOH, H 0; h. EtSH, HC1, 0°C; i . N-Bz adenine, Br , DMF, CH C l ; j . Pd/C, cyclohexene , EtOH, r e f l u x . 2

2

2

2

2

2

2

2

Figure 9. Synthesis of a b i c y c l i c adenine nucleoside related to the octosyl acids.

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

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TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY

0

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57

58

OAc

Λ



ΒηΟ-^γ'"©

>-NH

BnO

,

59

BnO^V^"

^

0

BnO

0

N

H

°

60

61

18/

36/

R= -NH Ο

109

Λνί"^ ε

> N H

HO

110

a. Hg(0Ac) , THF; b. NaBr; c. NaBH^, 0 , DMF; d. 20% Pd(0H) /C, H , MeOH; e. Pt, 0 , NaHC0 , H 0; 90°C; f . H , MeOH; g. LiOH, H 0; h. H r e s i n , H 0. 2

2

2

+

2

2

3

2

+

2

2

Figure 19. Elaboration of the b i c y c l i c ring system of octosyl acid A.

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

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TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY

second method r e l i e s on mercury-palladium chemistry (33). This method would involve mercuration at C-5, palladium-mercury exchange, and alkenyl-palladium exchange to give the C-5 v i n y l derivative which would s t i l l have to be subjected to an oxidative cleavage. We chose to adapt a procedure developed by Miyasaka et a l (34) for the e f f i c i e n t d e r i v a t i z a t i o n at the C-5 position of dihydrouracils and then re-introducing the double bond. The dihydro derivative 111 was prepared by hydrogénation using rhodium-on-alumina i n e s s e n t i a l l y quantitative y i e l d (Figure 20). S i l y l a t i o n , formation of the lithium enolate, and quenching with ethyl chloroformate gave a 1:1 mixture of C-5 ethoxycarbonyl diastereomers 112. The double bond was re-introduced v i a a selenide addition-elimination sequence (35) to give 113 i n an o v e r a l l y i e l d of 88%. With the u r a c i l moiety successfully functionalized and protected, the f i n a l step i n the synthesis of octosyl acid A was to oxidize C-8* s e l e c t i v e l y .

This was accomplished by f i r s t removing the s i l y l protecting groups and platinum-catalyzed oxidation which gave the h a l f - e s t e r h a l f - a c i d derivative 115. Saponification, followed by a c i d i f i c a t i o n gave octosyl acid A. Dissolution of this acid i n acetone, removing a small amount of insoluble matter and p r e c i p i t a t i o n gave octosyl acid A as a white powder, mp 285-288° ( d e c ) ; [ a ] +9.8° (c 0.5, IN NaOH); reported (4), mp 290-295° (dec); [a], +13.3° (NaOH) (Figure 21). D

As can be seen, there i s some discrepancy i n the melting points and o p t i c a l rotations with the reported data (4). The small difference i n melting points, i s n e g l i g i b l e , p a r t i c u l a r l y since octosyl acid A slowly decomposes at these high temperature. The elemental analysis of our synthetic octosyl acid A^was correct for a non-hydrated compound. Secondly, i t s 400 MHz H-NMR spectrum showed no trace of any other isomer. Danishefsky, and Hungate (8) had reported [α]β +9.1° for their synthetic octosyl acid A i n good agreement with our r e s u l t s . In the l i g h t of the spectroscopic and a n a l y t i c a l data obtained, we contend that our sample of synthetic octosyl acid A i s pure and that the constants we report are r e l i a b l e . A *H NMR spectrum of synthetic octosyl acid A i s shown i n Figure 22.

Synthesis of Octosyl Acid C Dimethyl Acetal After the successful synthesis of octosyl acid A, our attention was directed towards the synthesis of octosyl acid C,_3. As shown i n Figure 23, octosyl acid C contains a cis-fused b i c y c l i c oxoperhydrofuropyran. Therefore, a synthetic strategy based on oxidation at C-5 and epimerization at C-4* i n the o r i g i n a l octosyl acid A was devised. 1

The b i c y c l i c intermediate 106 used i n the synthesis of octosyl acid A became the s t a r t i n g point for the synthesis of octosyl acid C (Figure 24). D i s i l y l a t i o n of 106 followed by hydrogenolysis liberated the C-5' hydroxyl group which was oxidized to afford the

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

4. HANESSIAN ET AL.

Synthetic Approaches to Bicyclic Nucleosides

85

f

corresponding C-5 keto derivative 118, Treatment with l,8-diazobicyclo[5.4.0]undecene i n refluxing toluene effected epimerization at C-4 to afford the cis-fused b i c y c l i c system 119, (Figure 25).

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!

With the establishment of the basic carbohydrate s k e l e t a l system of octosyl acid C, our attention was then directed toward funcionalizing the u r a c i l moiety. Protection of the keto group as i t s dimethyl acetal gave 120. Hydrogénation to the dihydro derivative 121 and carbomethoxylation v i a the enolate as previously described afforded 122 i n 70% o v e r a l l y i e l d . F i n a l l y , deprotection, oxidation and e s t e r i f i c a t i o n gave octosyl acid C dimethyl ester dimethyl acetal 125 i n 60% y i e l d . Saponification followed by treatment with a cation-exchange resin gave octosyl acid C dimethyl acetal 126. Various attempts to hydrolyze the dimethyl acetal group were unsuccessful, r e s u l t i n g i n decomposition. The H NMR spectrum of synthetic octosyl acid C dimethyl acetal i s shown i n Figure 26.

a. 5% Rh on alumina, H , MeOH; b. TBDMSiCl, E t N , DMAP, DMF; c. LDA, ClC0 Et, THF, -78°C; d. PhSeCl.pyr., CH C1 , H 0 2

2

Figure 20.

3

2

2

2

2

Carbethoxylation at the C-5 position.

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

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TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY

a. Bu^NF, THF; b. TMSC1, pyr.; c. H+ resins, MeOH; d. Pt, 0 , NaHC0 , H 0, 90°C; e. LiOH, H 0; f . H+ r e s i n s , H 0; 2

3

2

Figure 21.

2

Completion of the s y n t h e s i s

2

of o c t o s y l

a c i d A.

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

Synthetic Approaches to Bicyclic Nucleosides

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4. HANESSIAN ET AL.

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

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Ο

F i g u r e 23. A and C.

S t r u c t u r e s and p e r s p e c t i v e drawings of o c t o s y l

118

acids

119

a. TBDMSiCl, E t N , DMAP, DMF; b. 20% Pd(OH) /C, H , molecular sieves, C H 2 C I 2 ; d. DBU, P h C H 3 , r e f l u x . 3

2

2

EtOAc;

c.

PCC,

F i g u r e 24. Key s t e p s i n the t r a n s f o r m a t i o n of o c t o s y l a c i d A i n t e r m e d i a t e s en route to o c t o s y l a c i d C.

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

Synthetic Approaches to Bicyclic Nucleosides

4. HANESSIAN ET AL.

OR

ro

OR

1

" v O r —— Ο

0

"°Xc>-*Qr —

MeO

OMe

119

120

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R= TBDMSi

OR

p'

—-— "X&v?

-ΛΗ}· MeO' OMe

121

89

MeO

0

R'= H

OMe

°

123

122 R'= C0 Me 2

a. HC(0Me) , PPTS; b. 5% Rh on alumina, H , EtOAc; c. LDA, ClC02Me, THF, -78°C; d. PhSeCl.pyr., CH C1 ; H 0 ; e. Bi^NF, THF;f. Pt, 0 , NaHC0 , H 0, 90°C; g. H , MeOH; h. LiOH, HjO; i . H+ resins, H 0. 3

2

2

2

2

2

v

2

3

2

2

F i g u r e 25· F i n a l dimethyl acetal.

steps

i n the synthesis

of o c t o s y l

acid C

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

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Η

g

Μ

η κ

Μ

ο

i

η

2

Ο

Η

ο

4. HANESSIAN ET AL.

Synthetic Approaches to Bicyclic Nucleosides

91

Acknowledgment We thank NSERCC and FCAR for f i n a n c i a l assistance and the Shionogi Co., Japan for a sabbatical leave (Tamio Sugawara)

Literature Cited 1. 2. Downloaded by UNIV OF CALIFORNIA SAN DIEGO on May 5, 2013 | http://pubs.acs.org Publication Date: December 30, 1989 | doi: 10.1021/bk-1989-0386.ch004

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