A racemic formal total synthesis of clavukerin A using gold(I)-catalyzed cycloisomerization of 3-methoxy-1,6-enynes as the key strategy

An efficient formal total synthesis of (±)-clavukerin A was accomplished via a gold-catalyzed cycloisomerization of a 3-methoxy-1,6-enyne 5 as the key strategy followed by Rh-catalyzed stereoselective hydrogenation of the cycloheptenone 4.

From a retrosynthetic point of view, we envisioned two different approaches to the key enone intermediate 1 [3] to clavukerin A, starting from the cycloheptenone 4 (Scheme 1). In the first approach, enone 1 could be prepared by the sequential cyclization and the chemo-and stereoselective hydrogenation from cycloheptenone 4 (path A). Alternatively, enone 1 could be accessed by the hydrogenation of 4 and the subsequent cyclization (path B). The cycloheptenone 4 could then be synthesized from the enyne substrate 5 by gold(I)-catalyzed cycloisomerization.
The synthesis of enyne substrate 5 commenced with the alkylation of methyl acetoacetate with the known bromide 6 [24] to provide compound 7 in 55% yield (Scheme 2). Propargylation of 7 followed by the decarbomethoxylation with LiCl [25] gave the ketone 8 in 51% yield (over two steps). Addition of the vinyl group to this ketone gave the alkynol 9 in 90% yield as an inseparable 3:1 mixture of diastereomers. The diastereomeric ratio was determined by integration of the 1 H NMR spectrum of the crude reaction product. Subsequent methylation gave the 1,6-enyne 5 in 88% yield.
We then investigated the gold-catalyzed cycloisomerization of enyne 5 using the optimized conditions from our previous study [15]. The use of the pre-generated complex Au[P(C 6 F 5 ) 3 ] + SbF 6 − (2 mol %) provided the relatively unstable enol ether 12, which was then immediately treated with aqueous silica gel to give the ketone 4 in 93% yield over two steps. Formation of 12 was unambiguously confirmed by the analysis of or Rh)-catalyzed hydrogenations resulted in a mixture of 1 and 3. This problem was also noted in another work on the synthesis of clavukerin A [13].
Thus, we decided to investigate the alternative strategy that involved sequential hydrogenation-cyclization of 4. Initial efforts using various Pd catalysts or Wilkinson catalyst again showed poor stereoselectivity for the hydrogenation. However, with a Rh/alumina catalyst the selectivity was significantly improved and afforded the cis-ketone 3 in 94% yield with ~13:1 selectivity. The structure of 3 was unambiguously confirmed by comparison of the 1 H and 13 C data with those in the literature [3]. Because the ketone 3 was previously transformed into the enone 1 [3], synthesis of 3 represents the completion of the formal synthesis of clavukerin A.
In summary, a formal synthesis of racemic clavukerin A was accomplished via the gold(I)-catalyzed cycloisomerization of a 3-methoxy-1,6-enyne as the key strategy and stereoselective Rh-catalyzed hydrogenation. Notably, the gold(I)-catalyzed reaction was compatible with the acid-sensitive functional group. Further application of the gold(I)-catalyzed cycloisomerization reaction of 3-methoxy-1,6-enynes to the enantioselective synthesis of more structurally complex cycloheptane natural products is in progress, and will be reported in due course.

Supporting Information
Supporting Information File 1 Experimental section for the preparation of compounds 2-12, and 1 H and 13 C NMR spectra for all new compounds.