An Improved Biomimetic Formal Synthesis of Abyssomicin C and atrop‐Abyssomicin C

Biomimetic approaches towards the synthesis of abysssomicin C and atrop‐abyssomicin C are based on a powerful intramolecular Diels–Alder reaction (IMDA) of a butenolide derivative attached to a keto‐triene side chain, where the stereogenic centers and the carbon framework are established in one step. The synthesis of the IMDA precursor is based on an ionic coupling of methyl γ‐methylene‐β‐tetronate with various aldehydes. However, the low yields of the coupling and the high sensitivity of the precursor hampered the efficiency of the developed routes and should be met. In the present work, a modified aldehyde is coupled with methyl γ‐methylene‐β‐tetronate, in a substantially higher yield. Asymmetric synthesis of this aldehyde is based on the use of the widely available and cheap Amano lipase AK. In addition, the development of a highly convenient one‐pot oxidation‐IMDA reaction protocol obviates the isolation of the sensitive IMDA‐precursor and augments the yield towards the carbocyclic skeleton of abysssomicin C and atrop‐abyssomicin C. A high‐yielding coupling of the modified aldehyde (I) with the α‐lithium salt of γ‐methylene‐β‐tetronate (II) and a one‐pot oxidation‐intramolecular Diels–Alder reaction of diol (III) to key‐intermediate (IV) is reported. The approach circumvents problems arisen by previous biomimetic approaches towards abyssomicin C and atrop‐abyssomicin C and set the base for the development of improved synthetic routes to these molecules.