First Construction of a Saricandin Analog Corresponding to Papulacandin D

Abstract

The first total synthesis of a saricandin analog corresponding to papulacandin D has been achieved via a highly convergent synthetic strategy. A readily accessible chiral building block 3 was designed and prepared in large scale via an enantioselective reduction with pinanyl-9-BBN. The adaptability of compound 3 toward structural modifications and the highly convergent nature of the approach is illustrated in the construction of the side chain present in saricandin by Pd-catalyzed cross-coupling of 2 and 3 and sequences that include triple bond reduction of fragment C(5-16) and generation of the double bond (C4-C5) using Horner-Emmons reaction. The assembly of the spirocyclic monoglycoside with saricandin side chain is described. A practical technique for isolating the final product 1 after deprotection with TBAF is discussed. Compound 1 was evaluated for its antifungal activity in enzyme assay and cell based assays. However, in contrast the activity reported by Traxler for papulacandin D, the presence of the galactose moiety together with the short fatty acid in natural saricandin seem to be essential for the antifungal activity.

Key words

Saricandin - papulacandin - antifungal - enatioselective reduction

References and Notes

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5

The analogous papulacandin D is known as the least abundant of papulacandins family. Compound 1 has not been isolated, probably because of the extreme scarcity of the natural material.

6

The racemic building block (±)-7 was initially converted into a 1:1 mixture of 1 and its C-7 epimer following the same sequences employed for the preparation of 1 in enatiomrically pure form.

15

The reason of this selection is supported by the fact that Barrett’s approach is the only known efficient approach that delivers directly the spiroketal nucleus bearing the protecting group of choice for the generation of the correct monoester. On the other hand their study on protecting groups demonstrated that the protecting group of choice for this type of systems are O-4",O-6"-di-tert-butylsilylene, and phenol tris(triisopropylsilyl)

16

The mixture of MeOH-CH₃CN-CH₂Cl₂ solvents turned out to be very useful and was applied successfully for the purification of other polar compounds from tetrabutylammonium salts and other salts that derived from Wittig or Horner-Emmons reactions.