Conversion of cyanthiwigin U to related cyanthiwigins: total syntheses of cyanthiwigin W and cyanthiwigin Z

Abstract

The conversion of cyanthiwigin U to cyanthiwigins W and Z is described.

In 1992, two research groups independently described the isolation and structure elucidation of the first examples of the cyanthiwigins from two species of sea sponge.^1,2 Their structural features clearly placed them in the cyathane class of diterpenoids although they could be differentiated from the majority by the syn-orientation of the angular methyl groups (Figure 1, cyanthiwigin U, 1 c.f. allocyathin B₃).³

Figure 1.

Representative examples of cyathane diterpenes.

Members of the cyanthiwigin family, which has now grown to ~30 congeners^4,5,6 have been reported to have noteworthy biological activities such as action against hepatitis B virus, human immunodeficiency virus, and Mycobacterium tuberculosis as well as anti-cancer properties. In light of their biological activities and low natural abundance, the cyanthiwigins are important targets for synthesis and to date total syntheses have been reported for (−)-cyanthiwigin U, 1⁷ (+)-cyanthiwigin AC,⁸ and cyanthiwigin F, 2.⁹ In this Letter we report the total syntheses of cyanthiwigins W and Z.

Our strategy for the synthesis of cyanthiwigin W and cyanthiwigin Z is based the same two-directional tandem ROM-RCM that we have previously described for the synthesis of cyanthiwigin U (5→6, Figure 2, details of the cyanthiwigin U synthesis have been reported previously⁷). With ready access to cyanthiwigin U, we expected that a diastereoselective 1,2-reduction of the cyclopentenone would lead to cyanthiwigin W, and the combination of a diastereoselective reduction and oxidative transposition of the tertiary allylic alcohol would provide cyanthiwigin Z.

Figure 2.

Overview of the plans for the synthesis of cyanthiwigin W and cyanthiwigin Z.

To our delight, subjecting cyanthiwigin U to standard Luche reduction¹⁰ conditions led to hydride delivery from the less hindered (albeit slightly concave) β-face in high yield to furnish cyanthiwigin W and 1-epi-cyanthiwigin W (d.r. = 9:1, Scheme 1). The epimers were readily separated on silica gel, and the cyanthiwigin W obtained by this route provided data that was in accord with that reported by Hamann and co-workers.^4,11

Scheme 1.

Reagents and conditions: 1. NaBH₄, CeCl₃.7H₂O, MeOH, 95%, d.r. = 9:1.

The conversion of cyanthiwigin W to cyanthiwigin Z commenced with selective acetylation of the secondary allylic alcohol with Ac₂O/DMAP (8→9, Scheme 2). Subsequent Dauben oxidative transposition¹² of the tertiary allylic alcohol with PCC led to enone 10, and this was followed by removal of the acetate with K₂CO₃ in MeOH to yield cyanthiwigin Z¹³ in 20% overall yield from cyanthiwigin W.

Scheme 2.

Reagents and conditions: 1.Ac₂O, DMAP, CH₂Cl₂, 0 °C; 2. PCC, CH₂Cl₂, rt, 14h. 3. K₂CO₃, MeOH, rt, 3h, 20% (over 3 steps).

In conclusion, we have described the concise conversion of cyanthiwigin U to cyanthiwigins W and Z. Given the ready access to the core structures of the cyanthiwigins by either our route, or the Stoltz group’s strategy,⁹ these transformations provide an early indication of the encouraging prospects for the ready preparation of a variety of natural and unnatural cyanthiwigins in advance of biological studies.