Synthetic Study toward Triterpenes from the Schisandraceae Family of Natural Products

Abstract

Triterpenoid natural products from the Schisandraceae family have long presented a significant synthetic challenge. Lancifodilactone I, a member of the family not previously synthesized, was identified as a key natural product target, from which many other members could be synthesized. We envisaged that the core ring system of lancifodilactone I could be accessed by a strategy involving palladium-catalysed cascade cyclisation of a bromoenynamide, via carbopalladation, Suzuki coupling and 8π-electrocyclisation, to synthesize the core 7,8-fused ring system. Exploration of this strategy on model systems resulted in efficient syntheses of 5,6- and 5,8-fused systems in high yields, which represent the first such cyclisation where the ynamide nitrogen atom is 'external' to the forming ring system. The enamide functionality resident in the cascade cyclisation product was found to be less nucleophilic than the accompanying tri-/tetrasubstituted alkene(s), enabling regioselective oxidations. Application of this strategy to 7,6-, and 7,8-fused systems, and ultimately the 'real' substrate, was ultimately thwarted by the difficulty of 7-membered ring closure, leading to side product formation. Nevertheless, a tandem bromoenynamide carbopalladation, Suzuki coupling and 6/8π-electrocyclisation was shown to be a highly efficient tactic for the formation of bicyclic enamides, which may find applications in other synthetic contexts.

Keywords: Suzuki coupling; cascade reaction; electrocyclisation; medium ring synthesis; natural products; total synthesis; ynamides.

Figure 1

(a) Retrosynthetic strategy towards lancifodilactone I. (b) Synthesis of 7,8-fused systems via alkyne carbopalladation/Stille coupling/8π-electrocyclisation tandem sequence, and synthesis of 5,6-fused systems via ynamide carboplladation/Suzuki coupling/6π-eletrocyclisation sequence. (c) Proposed synthesis of 5,6- or 5,8-fused ring systems with external nitrogen position, and subsequent selective oxidations.

Figure 2

Synthesis of bromoynamide 11.

Figure 3

Synthesis of (Z)-3-methylbutadienyl boronate ester 23 and application of the optimized cascade to synthesis of 5,8-fused system 13.

Figure 4

(a) Oxidations of the 5,6-fused ring system 12; (b) Oxidations of the 5,8-fused ring system 14.

Figure 5

(a) Application of the cascade to the synthesis of 7,6-fused system; (b) application of the cascade to the “real” substrate 39.