Intramolecular Organocatalytic [3+2] Dipolar Cycloaddition: Stereospecific Cycloaddition and the Total Synthesis of (±)‐Hirsutene

Abstract

A testing ground for cyclopentannulation strategies: the triquinane natural product hirsutene is obtained through the intramolecular organocatalytic [3+2] cycloaddition of the 1,7‐enyne (E)‐1 . The cycloaddition is stereospecific: reaction of the corresponding Z isomer provides the epimeric diquinane.

Nucleophilic Phosphine Organocatalysis

“…(69)], in which a quarternary center is generated as a single diastereomer. [61] The success of the phosphine-catalyzed [3 þ 2] reaction with activated olefins led Lu and coworkers to consider other dipolarophiles such as N-tosylimines. At room temperature, triphenylphosphine catalyzed a highly regioselective cycloaddition of 2,3-butadienoates with a variety of N-tosylimines to afford pyrrolines in good to excellent yield [Eq.…”

Advances in nucleophilic phosphine catalysis of alkenes, allenes, alkynes, and MBHADs

“…22 The intramolecular [3 + 2] annulation of the advanced intermediate 42 proceeded smoothly to furnish the 5,5-fused bicyclic intermediate 43 in high yield. Late-stage reductions and oxidations completed the synthesis of (±)-hirsutene 44 .…”

“…21 This intramolecular [3 + 2] strategy was also adopted in the total synthesis of (–)-hirsutene, generating two of the three rings in the natural product. 22 Tributylphosphine can be used for systems with large steric bulk to yield annulation products efficiently (Scheme 24). Several 1,7-enynes have been subjected to the reaction conditions to render good yields of diquinanes (entries 1–3).…”

Phosphine‐Catalyzed [3 + 2] Annulation: Synthesis of Ethyl 5‐(tert‐Butyl)‐2‐Phenyl‐1‐Tosyl‐3‐Pyrroline‐3‐Carboxylate

“…5 Since Lu’s original report of such [3 + 2] annulations, many enantioselective variants of the procedure have been described, as well as several applications in the realm of natural product synthesis. 6,7 Our laboratory discovered that α-alkyl allenoates behave as 1,4-dipole–like species in novel [4 + 2] annulations with imines to form tetrahydropyridines. 8 This broadly applicable reaction has since been applied to natural product synthesis 9 and has been developed into an asymmetric process.…”