Synthesis of Tricyclic Spiranoid Lactones via I₂/Sm(II)- and I₂/Pd(0)-Mediated Cyclizations of a Common Cycloalkylmethylene Precursor

Abstract

A general synthesis of phylogenetically and structurally different tricyclic angularly fused spiranoid lactones, frequently observed as scaffold segments of various biochemical compounds and drugs of natural origin, is demonstrated via controlled cyclization of simple and easily accessible cycloalkylmethylene key precursors. The rapid composition of the key architecture yields an assembly of stable bicyclic iodolactones, which are converted to form a wide range of angularly fused tricyclic scaffolds.

Stereo‐ and Regioselective Synthesis of Tricyclic Spirolactones by Diastereoisomeric Differentiation of a Collective Key Precursor

“…The next and largely intuitive step towards the formation of the desired framework was to subject iodolactone 3 to the C−C bond‐forming cyclization conditions. For this purpose, the diastereoisomeric lactones 3 a and b were separated and individually submitted to the cross‐coupling reaction in the presence of the Pd 0 ‐SIMes catalyst to generate a tricyclic product (Scheme , the cross‐coupling route) . As anticipated, compound 3 a gave rise to target 6 , the sought‐after tricyclic spirofuranone 5/5/5…”

“…To design a basic platform for the synthesis of a compact 5/5/5 scaffold, we prepared bicyclic iodolactone 3 , which is believed to be a critical intermediate for the construction of the corresponding spirofuranone (delivered from precursor I in 83 %, 67:33 d.r. ; Scheme ) . The next and largely intuitive step towards the formation of the desired framework was to subject iodolactone 3 to the C−C bond‐forming cyclization conditions.…”

“…The decomposition of methyl‐substituted anti ‐iodolactone 19 b was presumably initiated by a destabilization of the radical species 26 ; thus, β‐elimination followed by opening of the lactone prevailed to generate compound 27 . Both previously described diastereoisomers of bicyclic iodolactone 12 ( a and b ) were obtained by olefination of intermediate 28 , designed through the sequential double alkylation of cyclopentanone (Scheme ), and subsequent iodolactonization of precursor II ( 15 ) . With the goal of developing a more generalized platform, we further sought to identify common reaction conditions for anchoring other functional groups on a central ring, which would transform the resulting key precursor into the corresponding tricyclic spiranoid lactones.…”

Transition-Metal-Catalyzed Synthesis of Spirolactones

“…40 The transformation (Scheme 21, B) showed good functional group tolerance and a broad substrate scope, overcoming the difficulties of previously reported stepwise lactonization-Heck type cyclization approaches 68 → 70 (Scheme 21, A). 41 As part of the study, rarely reported palladium-catalyzed 4-exo-trig Heck type cyclizations were demonstrated, providing rapid access to oxaspiro-octanones 75 (Scheme 21, C).…”

Cascade Pd(ii)-catalyzed Wacker lactonization–Heck reaction: rapid assembly of spiranoid lactones

“…The stepwise strategy (Scheme 2) is based on the notion that, in the presence of I 2 or Br 2 and a metal-ligand system, the key cycloalkylmethylene precursor 3 generates lactone intermediate 4, and further undergoes an intramolecular cyclization to form the corresponding tricyclic spiranoid lactones 5. 8 Our previously reported sequence was designed to allow simplified access (first collective protocol) to a wide range of tricyclic spirolactones. Even though it is clearly the shortest sequence reported to date, some of its characteristics are ought to be mended.…”