Octosyl acids

Octosyl Acids. Three octosyl uronic acid nucleosides, produced by S. cacaoi sub sp. asoensis are shown in Figure 3. The biosynthesis of (172) and (173) has been reported (1). The replacement of the pyrimidine chromophore of (171) with adenine results in a nucleoside analogue that is a competitive inhibitor of cAMP. 

Octosyl acid A (171, R = COOH) Octosyl acid B (172, R= CH2OH)... 

Total Synthesis of Octosyl Acid A and Octosyl Acid C Dimethyl Acetal... 

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 antibiotics (2) spurred the attention of synthetic chemists as well as biologists for a number of reasons. Their unusual structural features combined with unique biological activity fostered studies on many fronts (3). During their studies on the biosynthesis of the polyoxins, Isono, Crain and McCloskey (4) discovered three novel acidic nucleosides which they called octosyl acid A, B and C,... 

The trans-fused perhydrofuropyran system is also encountered in the ezomycin group of nucleoside antibiotics (6,7). The structures of ezomycin Aj and Aj are shown in Figure 3 for comparison with the octosyl acids. 

Figure A. The Anzai-Saita approach to octosyl acid A.

Model Studies Directed at the Octosyl acids, Ezomyclns and Quantamycln... 

An extension of this methodology was used In another approach (16) to the octosyl acids and ezomyclns (Figure 10). In this sequence, D-galactose was transformed Into the 2-0-acetyl derivative 57. Transformation to the acyclic nucleoside derivative and selective oxidation then gave sulfoxide 58. Elimination afforded the trans olefin 59 whereupon solvolysis followed by epoxldatlon and acid-catalyzed cycllzatlon produced and In a 1 2 ratio respectively. The H-NMR spectra showed each to contain a l, 2 -trans configuration, and that the minor Isomer was the required 6-D-nucleoslde, while the major product was the a-D-nucleoslde. 

Since octosyl acid A has the C-5 (R) configuration, the B-D-nucleoslde 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... 

Figure 9. Synthesis of a bicyclic adenine nucleoside related to the octosyl acids.

Synthetic Approaches to the Octosyl Acids from Uridine... 

Our approach to the synthesis of octosyl acid A is Illustrated using the retrosynthetlc analysis shown in Figure 13. We envisaged a cycllzatlon process that not only would give the 3, 7 -anhydrooctose blcycllc system, hut would also establish the desired... 

Figure 12. The Danishefsky-Hungate synthesis of octosyl acid A.

Figure 15. The intramolecular oxymercuration approach as a strategy for the octosyl acids.

Figure 19. Elaboration of the bicydic ring system of octosyl acid Ae...

As can be seen, there is some discrepancy in the melting points and optical rotations with the reported data (4). The small difference in melting points, is negligible, particularly 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, Its 400 MHz H-NMR spectrum showed no trace of any other Isomer. Danishefsky, and Hungate (8) had reported [alp +9.1 for their synthetic octosyl acid A in good agreement with our results. In the light of the spectroscopic and analytical data obtained, we contend that our sample of synthetic octosyl acid A is pure and that the constants we report are reliable. A NMR spectrum of synthetic octosyl acid A is shown in Figure 22. 

After the successful synthesis of octosyl acid A, our attention was directed towards the synthesis of octosyl acid C,. As shown In Figure 23, octosyl acid C contains a cls-fused bicyclic oxoperhydrofuropyran. Therefore, a synthetic strategy based on oxidation at C-5 and eplmerlzatlon at C-4 in the original octosyl acid A was devised. 

The bicyclic intermediate 106 used in the synthesis of octosyl acid A became the starting point for the synthesis of octosyl acid C (Figure 24). Disilylation of 106 followed by hydrogenolysis liberated the C-5 hydroxyl group which was oxidized to afford the... 

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