Concise Synthesis of Norrisolide

Abstract

The marine natural product norrisolide has been synthesized in a convergent manner with a longest linear sequence of 14 steps. The hydrindane portion of the molecules is prepared through conjugate addition of a functionalized allyl group into cyclopentenone, followed by stereoselective trapping of the enolate generated from the resulting enol silyl ether with an allyl electrophile. Ring‐closing metathesis then establishes the 6–5 ring system. Likewise, selective preparation of the side chain features an enantioselective cyclopropanation of furan‐2‐one, followed by rearrangement and hydrogenation. Coupling of the two major fragments through a Shapiro reaction, followed by reduction and olefination then completes the carbon framework of the natural product. The final steps of the synthesis involve adjustments to the oxidation state of the side chain. New strategies to generate both the hydrindane core and the oxidized side chain has allowed for the more concise and efficient preparation of the natural product.

Total Synthesis of (−)-Chromodorolide B

“…Further simplification of acid 9 leads to intermediate 10 having the C 12 hydrocarbon and the highly oxidized fragment joined at a vinylic carbon of the hydrophobic fragment. 6 On the basis of our recent experience showing that fragment couplings of nucleophilic tertiary radicals with alkenes can be high yielding, 5b we envisioned a cascade sequence in which trisubstituted carbon radical B , generated by visible-light photoredox fragmentation of the N -acyloxyphthalimide substituent of intermediate 12 , 7 would couple with ( R )-4-methoxybutenolide ( 11 ) 8 to generate α-acyloxy-radical intermediate A , which was hoped would undergo intramolecular 5- exo cyclization from a conformation such as A ′ depicted in Scheme 1 that minimizes destabilizing allylic A 1,3 interactions. The cascade would then be terminated by β-fragmentation of the adjacent C–X (X = halide) bond to deliver the desired coupled product 10 .…”

“…11 In an exploratory model study, we confirmed that radical coupling at such a carbon would preferentially occur from the desired face syn to the vicinal substituent. 12 Further simplification of intermediate 12 leads to two readily available precursors: ( S , S )-trimethylhydrindanone 13 3 and ( R , R )-tartaric acid-derived acetonide 14 .…”

“…This sequence began by conversion of ketone 13 to known vinyl iodide 19 . 3 The other fragment, sensitive aldehyde 20 , is accessible in three steps from acetonide 14 . 12 A variety of standard conditions were examined for the Nozaki-Hiyama-Kishi coupling of iodide 19 with aldehyde 20 ; 18 however, only low yields (<20%) and modest diastereoselectivities (3:1) were observed.…”

Methodology for the Construction of the Bicyclo[4.3.0]nonane Core

“…Further, a sequential ring closing metathesis followed by Heck coupling was shown in 2010, giving a trans-hydrindane core for the C/D ring juncture [78]. This methodology has been applied to the synthesis of norrisolide [79]. Metathesis as a cyclization tactic has become a notable method for ring forming reactions.…”

“…Further, a sequential ring closing metathesis followed by Heck coupling was shown in 2010, giving a trans-hydrindane core for the C/D ring juncture [78]. This methodology has been applied to the synthesis of norrisolide [79]. Enyne metathesis has found an increasing interest in the synthesis of natural products (see Scheme 24) [80][81][82][83][84].…”