Diastereoselective Synthesis of Complex cis-Hexahydroindanes by Reductive Alkylation

Abstract

An efficient and operationally simple approach to complex cis-hexahydroindanes is reported. Upon Birch reduction of unprotected, C4-alkylated tetrahydroindanols and electrophilic trapping of the tetrasubstituted enolate, cis-fused products are formed with a new stereogenic quaternary carbon. The reaction is convergent, completely diastereoselective, and shows a broad scope with regard to the electrophile.

General Methodologies Toward cis-Fused Quinone Sesquiterpenoids. Enantiospecific Synthesis of the epi-Ilimaquinone Core Featuring Sc-Catalyzed Ring Expansion

“…For example, an attempt to reproduce the above data with cyclopentyl ethylene ketal (derived from the dione of 8 ) or the t -butyl dimethylsilyl (TBS) ether of 8 delivers cis -fused products but with noticeable reductions (>15–20%) in chemical yield. At this point, we do not rule out the possibility [ 34 ] that the more efficient transformations observed for tetrahydroindanol 8 benefit from intramolecular H atom abstraction within a radical anion intermediate formed by a kinetically favored, single-electron reduction of the enone. Molecular models do not convincingly demonstrate that the cyclopentyl hydroxyl is close enough in proximity to the β carbon to permit internal delivery, but with the potential for participation by a solvent molecule (NH 3 , Scheme 2 ) the suggested process is likely more facile than intermolecular alternatives.…”

“…The only detectable byproducts stem from protonation or O -alkylation of the putative Li enolate. The scope of this convergent reductive C–C coupling process includes both doubly ortho -substituted benzylic and allylic bromides or iodides and was communicated previously by our laboratory [ 34 ].…”

“…These studies commenced with a standard TBS protection of the free cyclopentanol (step 1, Scheme 3 ). Unprotected 9 does furnish an ene-carbinol under the forcing and precedented [ 21 ] Wittig conditions shown in step 2 (methyltriphenylphosphonium bromide, dimsyl sodium, 75 °C), but it is the exclusive result of a formal 1,5-hydride shift and subsequent cyclopentanone methylenation [ 34 ]. Avoiding Na alkoxide formation prevents this transannular, acyloin-like rearrangement [ 36 ] and leads to the desired exocyclic methylene cyclohexane 10 in good yield.…”

“…Specifically, we wanted to incorporate functionality into the Birch trapping agent that could be selectively unmasked and provide a means to direct a homogeneous hydrogenation catalyst to the α face of either unsaturated bicyclopentanone (see 10 or 11 , Scheme 3 ). Thus, 2-benzyloxy-6-chloro-3-methoxybenzyl iodide [ 34 ] was secured, containing an orthogonally protected phenol that we planned to later test as a directing group and functional handle for quinone oxidation. Under precisely the same conditions of Scheme 2 , Birch alkylation with the new electrophile gave the desired keto-alcohol in 79% yield.…”

“…A representative homologation protocol and characterization for compounds 14 and 15 are provided. Experimental procedures for structures 9 , 10 , and the ketone precursor to 17 are omitted since they have been reported elsewhere [ 34 ]. Additional details for synthesis and identification of total synthesis intermediates 8 , 11 , 12a , 12b , 16 , 17 , 18 , 19 , 20 and 21 were compiled from a previous source [ 44 ] and have been included as Supplementary Material .…”