Studies for the Total Synthesis of Amphidinolide P

Abstract

A convergent, enantiocontrolled total synthesis of the 15-membered macrolide, amphidinolide P, is described. The synthesis utilizes three nonracemic components for an efficient assembly of the macrolactone in 12 steps via the longest linear pathway. Key developments include studies of the Hosomi–Sakurai reaction for the formation of the C6–C7 bond, a “ligandless” palladium-mediated Stille cross-coupling of the vinylic stannane 4 and the alkenyl bromide 5 to produce a highly functionalized dienol, and a thermally induced, intramolecular lactonization via the late-stage formation of an intermediate α-acylketene.

Potent Cytotoxic Analogs of Amphidinolides from the Atlantic Octocoral Stragulum bicolor

“…The 3 J coupling constant of 7.5-8 Hz between H-14 and H-15 suggested a dihedral angle of 160° in agreement with the anti configuration of the substituents at C-14 and C15 shown for both 1 and 2 in Figure 1B. This assignment was corroborated by the correspondence of the chemical shift of H-14 and Me-19 with those previously reported for amphidinolide P ( 5 ) and its 3-O-methyl derivative [18,20,22,23].…”

A mild preparation of alkynes from alkenyl triflates

“…When alkenyl triflates arising from methyl ketones were used as coupling partners, terminal alkynes were frequently identified as by-products. Notably, Williams et al observed similar side reactions under the Stille conditions in their synthesis of amphidinolide P. 24 We quickly realized that the formation of alkyne was irrelevant to palladium catalysis but only depended on the additive (e.g. LiCl, which is widely used in palladiumcatalyzed cross-coupling) and solvent.…”

Transesterification of Methyl 2‐Nitroacetate to Superior Esters

“…It is well known that α,α'‐unsubstituted β‐keto esters easily undergo transesterification with alcohols without the need of a catalyst; on the contrary transesterification of non enolisable α,α'‐disubstituted β‐keto esters or alkanoyl esters does not take place. This observation suggests that transesterification of β‐keto esters is facilitated by the electron‐withdrawing (EW) character of the carbonyl in geminal position to the ester group.…”