Total Synthesis of the Biologically Active Form of N-Acetylneuraminic

Chapter

11

Total Synthesis of the Biologically Active Form of N-Acetylneuraminic Acid A Stereospecific Route to the Construction of N-Acetylneuraminic Acid Glycosides

Downloaded by UNIV LAVAL on July 11, 2016 | http://pubs.acs.org Publication Date: December 30, 1989 | doi: 10.1021/bk-1989-0386.ch011

Samuel J. Danishefsky and Michael P. DeNinno Department of Chemistry, Yale University, New Haven, CT 06511

The use of S-2-phenylselenopropanal in the synthesis of the naturally occurring (8R) antipode of the title compound is described. This chemistry was adapted to achieve a total synthesis of a sialic acid glycoside in a stereospecific fashion.

In the preceding chapter, (1-3) we described a total synthesis of racemic (±) Nacetylneuraminic acid (Neu5Ac). In that report we summarized the history of Neu5Ac and its involvement, via glycosides, in a host of important biological functions. We also described some preliminary studies which demonstrated the feasibility of exchanges of the methoxyl group of furyl glycosides (cf. 1 and 2) with a variety of alcohols including primary OH groups of hexose derivatives (see formation of 3 and 4). The furyl residues are readily oxidized to carboxylic acids (cf. 3 —> 3a). The sequence of exchange with a hexose based hydroxyl group, followed by oxidation, constituted a possible route to analogs of sialic acid glycosides. Adding to the attractiveness of this strategy was the finding that the exchange reaction was stereospecific, leading to equatorial glycosides of the type 4. Of course C-glycosylfurans bearing the functionality pattern suitable for construction of Neu5Ac were intermediates in our total synthesis (3). Recourse to such intermediates for the exchange reaction would provide products which are more realistic in terms of obtaining the full structural and stereochemical detail of Neu5Ac glycosides than was the case for model systems 1 and 2 described in Part I of this volume (1) Indeed, the absolute configurations of the pyranose rings of 1 and 2 are antipodal to the correspondingringof Neu5 Ac glycosides. However, the total synthesis was being conducted in the racemic series. Thus the proposition of using these advanced, fully synthetic intermediates as substrates for the exchange reaction would face the usual awkwardness in coupling a racemate with a single antipode. The goal of a total synthesis of a biologically active natural product should never be regarded as fully realized until the relevant enantiomer is obtained in homogeneous form. In the case at hand, the attainment of the goal was a particularly urgent matter, since the synthesis of Neu5Ac glycosides was the primary thrust of the effort.

c

0097-6156/89/0386-0176$06.00/0 1989 American Chemical Society

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


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DANISHEFSKY A N D DENINNO

Biologically Active Form ofNeu5Ac

177

Neu5Ac

The convergence of two findings simplified the synthesis of naturally occurring Neu5Ac (with the CsS configuration). The first discovery arose during our synthesis of racemic KDO, wherein the cyclocondensation of racemic 5 with diene 6 afforded, as the principal product, dihydropyrone 7(4). Indeed compound 7 was accompanied by varying amounts of the corresponding trans disubstituted dihydropyrone. However, the important information (not obscured by the fact that the reaction was conducted on racemic material) was the total diastereofacial connectivity, in the Cram Felkin sense (5-6). between the selenium-bearing stereogenic center of 5 and the absolute configuration of the resultant pyranose. For the synthesis of racemic KDO this connectivity was helpful in that it simplified characterization of products, but clearly was not crucial. For the program at hand, it meant that access to the appropriate (S) antipode of the aldehyde (i.e., 5S) would allow for a route to the natural form of Neu5Ac. The second finding was a disclosure from the laboratory of Paul Hopkins (2) which provided experimental protocols wherein either the S or R enantiomers of compound 5 could be obtained from ethyl lactate. Thus the combination of the discoveries of Pearson (4) and Hopkins provided the basis for a synthesis of both the naturally occurring (8R) Neu5Ac and (7R) KDO.


178

TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY

Me •Η

PhSe-

PhSe-

•Ο X

Ο


TMSO

7 X = βΟΒζ; aH 6

β

X = αΟΒζ; βΗ

The Synthesis of Neu5Ac Cyclocondensation of 5S prepared according to Hopkins with diene 6 using BF3-OEt2 in methylene chloride at -78° C afforded a 5:1 ratio of 7 to its trans isomer, 8. Compound 7 was substantially optically pure (enantiomeric homogeneity was eventually achieved after crystallization of enoate 15). The next sequence of steps was closely patterned after those employed in the racemic KDO synthesis (4). Reduction with sodium borohydride-CeCl3 (&) gave the equatorial alcohol 9 which upon methanolysis afforded 10. It is seen that the success of this smooth methanolysis reaction was a favorable precedent for the feasibility of the exchange reaction (vide infra) in that it suggested stabilization by the furan of the oxonium ion character. Compound 10 was converted to its tert-butyldimethylsilyl ether 11. Oxidative elimination of the selenoxide, derived from treating 11 with aqueous hydrogen peroxide, afforded overwhelmingly the vinyl compound 12. Treatment of 12 with osmium tetroxide afforded 13 which, upon exposure to lead tetraacetate, gave aldehyde 14. The racemic version of 14 was an intermediate in our preparation of racemic Neu5Ac Q). Accordingly, it was a simple matter to retrace these steps in the enantiomorphically homogeneous series to produce optically pure Neu5Ac. It is of interest to consider in retrospect the logic of the chirality transfers involved in this synthesis. In essence stereochemical information was passed from the stereogenic center of 5S to control the sense of emergence of the pyranose ring in compound 8. Eventually, at the stage of Z-enoate 15, stereochemical information is passedfromthe ring back to the double bond in the all critical osmylation reaction (9). The Synthesis of KDO This synthesis was accomplished using selenoaldehyde 5R. Again, cyclocondensation with 6 gave ent 7. Using the same steps as were used for the Neu5Ac synthesis, ent 7 was converted to ent 13. From there the steps to the naturally occurring (7R) antipode of KDO merely involved retracing steps followed in the synthesis of the racemate. The Synthesis of Sialic Acid Glycosides After considerable trial and error, compound 16 was identified as the latest intermediate in the Neu5Ac synthesis on which one could achieve the exchange glycosylation. The exchange reaction was carried out using four substrate alcohols. The conditions and results are shown in Table I. In the three carbohydrate cases the furan ring was converted to the corresponding methyl ester by oxidation with ruthenium tetroxide followed by esterification with diazomethane. In each case the equatorial glycoside was obtained stereospecifically. This specificity might well be the result of thermodynamic equilibration at the stage of the furan.


DANISHEFSKY A N D DENINNO

Biologically Active Form ofNeu5Ac


11.


179

180

TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY

TMSO'

7 X = βΟΒζ; oH;Y = 0 8 X = αΟΒζ; βΗ; Y = 0 9 Χ = βΟΒζ;αΗ;Υ = βΟΗ;αΗ


MeOH/H*

14

Finally, in the case of compound 17, the system was transformed to the sialic acid glycoside 20. The key step in this regard was the benzoyl migration shown as 18 -» 19. This planned axial benzoate -> equatorial benzoate rearrangement served to liberate the single axial alcohol at C5 for activation (triflylation) and displacement (tetra-N-butylammonium azide). An analogous sequence had been employed in the total synthesis of racemic Neu5Ac (3).


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DANISHEFSKY AND DENINNO

Biologically Active Form

ofNeuSAc

181

The successful application of compound 16 to the synthesis o f sialic acid glycosides points to the need for a more direct and efficient route to such systems. Partial synthesis from carbohydrate sources would be a promising alternative to total synthesis. This goal and the goal of extending the scope of the exchange reaction to include secondary sugar alcohol substrates, are now important objectives o f our laboratory. OBz


17

R 18 R = H; R* = PHCO 19 R=PhCO; R* = H

20

Acknowledgments This work was supported by P H S Grant A I 16943. A fellowship from the Corn Refiners Association, Inc. to M . P . D . is gratefully acknowledged. The K D O experiments were carried out by M r . S-h. Chen of our laboratory. N M R spectra were obtained through the auspices of the Northeast Regional N S F / N M R Facility at Y a l e University, which is supported by N S F / C h e m i s t r y D i v i s i o n Grant C H E 7916210.

Literature Cited 1. Danishefsky, S. J.; DeNinno, M. P.; Audia J. E. Chapter 10 of this volume. 2. Danishefsky, S. J.; DeNinno, M. P.; Chen, S. J. Am. Chem. Soc. In Press. 3. Danishefsky, S. J.; DeNinno, M. P. J. Org. Chem. 1981, 51, 2615. 4. Danishefsky, S. J.; Pearson, W. H.; Segmuller, B. E. J. Am. Chem. Soc. 1985, 107, 1280. 5. Cf. Ahn, N. J. Top. Curr. Chem. 1980, 88 145. 6. Danishefsky, S. J. Aldrichimica Acta 1986, 19, 59. 7. Fitzner, J. N.; Shea, R. G.; Fankhausers, J. E.; Hopkins, P. B. J. Org. Chem. 1985, 50, 417. 8. Gemal, A. C.; Luche, J. L. J. Am. Chem. Soc. 1981, 103, 5454. 9. Danishefsky, S.J.; DeNinno, M.P.; Schulte, G.A. J. Am. Chem. Soc. In Press. RECEIVED September 27, 1988


Total Synthesis of the Biologically Active Form of N-Acetylneuraminic

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