A Nazarov‐Ene Tandem Reaction for the Stereoselective Construction of Spiro Compounds

Abstract

The different reactivity of trienones under Lewis and Brønsted acids catalysis was investigated, resulting in distinct cyclization products and carbon backbones that originated either from a conjugate Prins cyclization or an interrupted Nazarov cyclization. In particular, an unprecedented Nazarov cyclization tandem reaction is presented, terminating the oxyallyl cation by an ene-type reaction, and leading stereoselectively to bicyclic spiro compounds. The terminal olefin of this motif represents a useful handle for further functionalization, making it a strategic intermediate in total syntheses. The tandem Nazarov/ene cyclization was shown to be preferred over a Nazarov/[3 + 2] tandem reaction for all our substrates, independent of chain length. Deuteration studies further support the mechanistic hypothesis of the terminating ene reaction.

Asymmetric Total Synthesis of Illisimonin A

“…From 7 , spirocyclic key intermediate 6 was accessible through a B(C 6 F 5 ) 3 -catalyzed tandem-Nazarov/ene cyclization . The yield of cyclization product 6 had shown to drop during scale-up experiments, an observation we attributed to a potential retro-aldol reaction during purification on silica.…”

“…The foundation for our approach toward illisimonin A was laid by the discovery of the tandem-Nazarov/ene cyclization that produces carbocyclic spiro compounds from linear precursors like 7 in a single, diastereoselective transformation (Scheme 2a). 14 Spiro ketone 6 perfectly maps out the spiro substructure hidden inside the natural product's cage-like ring system and already contains 14 of the sesquiterpenoid's 15 carbon atoms (Scheme 1). From 6, the synthesis faced three main challenges: (I) formation of the missing C5−C6 bond (green), (II) introduction of the carboxylic carbon C11 (yellow), and (III) oxidation of three positions (C4, C7, and C14, red, Scheme 2a).…”

“…From 7, spirocyclic key intermediate 6 was accessible through a B(C 6 F 5 ) 3 -catalyzed tandem-Nazarov/ene cyclization. 14 The yield of cyclization product 6 had shown to drop during scale-up experiments, an observation we attributed to a potential retro-aldol reaction during purification on silica. A one-pot procedure with concomitant TES protection was therefore applied on large scale, affording protected spirocycle 15 as a key intermediate for our synthetic endeavor (Scheme 3a).…”

“…The foundation for our approach toward illisimonin A was laid by the discovery of the tandem-Nazarov/ene cyclization that produces carbocyclic spiro compounds from linear precursors like 7 in a single, diastereoselective transformation (Scheme a) . Spiro ketone 6 perfectly maps out the spiro substructure hidden inside the natural product’s cage-like ring system and already contains 14 of the sesquiterpenoid’s 15 carbon atoms (Scheme ).…”

Dithioallyl cation (3 + 2) cycloadditions under aprotic reaction conditions: rapid access to spiro-fused cyclopentane scaffolds

“…For methylenated cyclic enones, the cationic addition should show a predictable selectivity for the exocyclic alkene bond, and thus give a rapid access to interesting spirocarbocyclic scaffolds. 21,22 Our initial investigations of the two-step reaction scheme to elaborate spiro-fused cyclopentanes onto a cyclic enone (cf. Scheme 4) were in fact highly unpromising (Scheme 5).…”