H-Bonding Mediated Asymmetric Intramolecular Diels–Alder Reaction in the Formal Synthesis of (+)-Aplykurodinone-1

Abstract

An asymmetric formal total synthesis of (+)-aplykurodinone-1 was achieved using a route, in which hydrogen bonding serves as a stereochemical control element governing the π-facial selectivity of intramolecular Diels–Alder (IMDA) reaction of an enone tethered 2-pyrone. In the IMDA process, the configuration at a stereogenic, hydroxyl bearing an α-carbon in the enone dienophile is conveyed in a highly effective manner through intramolecular hydrogen bonding with the enone carbonyl oxygen. The tricyclic lactone, generated in this process, was successfully converted to a late stage intermediate in Danishefsky’s synthesis of aplykurodinone-1.

2‐Pyrone – A Privileged Heterocycle and Widespread Motif in Nature

“…Likewise, intramolecular [4 + 2]-cycloadditions of pyrones have been established as a reliable method for the synthesis of otherwise elusive natural or pharmacological important products, even in late stages. [98,103,104] By combining the diene and dienophile moiety in one molecule, the cycloadditions can proceed regioselectively without the aid of stereodirecting catalysts due to the predefined coordination of the reactants. Snyder and co-workers, for instance, demonstrated the simple and elegant route to hydroindolines 261 which underwent subsequent hydrolysis to compounds 262, a widespread motif in natural products (Scheme 52).…”

“…Cross-coupling reactions constitute an important tool for the premeditated derivatization of pyrones in total synthesis of natural products and biologically active compounds. [104,[131][132][133] Owing to the dual aromatic and olefinic character, the pyrone scaffold can be used as the organometallic component as well as the organic halide/pseudohalide component in several renowned coupling reactions.…”

“…[140] Later, the same strategy found application in the formal synthesis of the steroidal tricyclic lactone (+)-Aplykurodinone-1 (336). [104] The same group found that dibromo pyrone 333 undergoes Stille coupling with stannanes regioselectively at either C-3 or C-5, depending on the employed reaction conditions (Scheme 69). [141] Usually, cross-couplings proceed preferred at the 3-position of dibromo pyrone 333 due to the lower electron density at C3.…”

“…Regioselective Sonogashira coupling of dibromo pyrone 333. [104,140] Scheme 69. Regioselective Stille coupling of dibromo pyrone 333.…”

Recent Applications of the Diels–Alder Reaction in the Synthesis of Natural Products (2017–2020)

“…An internal H-bond controlled the stereogenic outcome of this reaction (Scheme 41). 62 Scheme 41 Overview of the asymmetric, intramolecular Diels-Alder reaction furnishing the Danishefsky ketone 161, a known intermediate in the total synthesis of (+)-aplykurodinone-1.…”