Development of a Concise and General Enantioselective Approach to 2,5-Disubstituted-3-hydroxytetrahydrofurans

Abstract

Concise syntheses of 2,5-disubstituted-3-hydroxytetrahydrofurans have been developed that provide access to each configurational isomer of this scaffold from a single aldol adduct. Application of these methods to the rapid preparation of (6S,7S,9S,10S)- and (6S,7S,9R,10R)-6,9-epoxynonadec-18-ene-7,10-diol, two structurally related marine epoxylipids, is reported.

Total Synthesis and Structural Revision of Laurefurenynes A and B

“…In addition, both a Mukaiyama aldol reaction,21 involving the TMS enolsilyl ether derived from methyl ketone 26 and the α‐chloroaldehyde ( R )‐ 20 , and a boron aldol reaction between 26 and ( R )‐ 20 provided very little (<5 %) of the desired product. Notwithstanding, a 1,3‐ anti ‐selective reduction of the ketone function in 30 afforded the corresponding chlorodiol (not shown) that cyclised using our AgOTf/Ag 2 O conditions12a to yield the 2,2′‐bis‐tetrahydrofuran 31 . Protection of the alcohol function in 31 as a TBS ether, followed by iodine‐silicon exchange gave the ( Z )‐vinyl iodide 32 along with small amounts of the corresponding E isomer.…”

“…Considering, however, that both stereostructures were reasonable candidates, we endeavored to develop a synthetic route to laurefurenyne A that was sufficiently flexible to permit late stage access to either stereostructure 1 or 16 . Specifically, it was envisioned that the stereochemically rich bis‐tetrahydrofuran core of the candidate stereostructures could be formed selectively through the Ag I ‐promoted cyclization of a chlorodiol 12a. The requisite chlorodiols 17 and 18 would be derived from the common ketone 19 via a lithium aldol reaction with either enantiomer of the α‐chloroaldehyde 20 ,14 followed by 1,3‐ anti ‐selective reduction of the carbonyl function 12a.…”

“…Specifically, it was envisioned that the stereochemically rich bis‐tetrahydrofuran core of the candidate stereostructures could be formed selectively through the Ag I ‐promoted cyclization of a chlorodiol 12a. The requisite chlorodiols 17 and 18 would be derived from the common ketone 19 via a lithium aldol reaction with either enantiomer of the α‐chloroaldehyde 20 ,14 followed by 1,3‐ anti ‐selective reduction of the carbonyl function 12a. The common ketone 19 should also be accessed through a similar strategy (e.g., α‐chloroaldehyde aldol, carbonyl reduction, cyclization) that builds on our previous efforts in tetrahydrofuranol synthesis 12…”

“…Luche reduction16 of the ketochlorohydrin 23 then afforded the desired 1,3‐ anti ‐diol 24 as the major component of an inseparable 5:1 mixture of diastereomers. Treatment of this purified mixture with AgOTf/Ag 2 O12a gave the tetrahydrofuranol 25 that was then protected as the corresponding TBS ether. The relative stereochemistry of 25 was assigned following analysis of 1D NOESY spectra, while comparison of 1 H NMR spectra recorded on ( R )‐ and ( S )‐MTPA esters17 of 25 and chiral GC analysis confirmed both the absolute stereochemistry and high optical purity (95 % ee ) of this material 18.…”

Recent advances in the synthesis of tetrahydrofurans and applications in total synthesis

“…Thus, an enantiospecific aldol-reduction-cyclization sequence was published in 2009, allowing an access to various diastereomers of a hydroxyl-bearing THF, all in very good yields and diastereoselectivities (Scheme 14). 47 Two diastereodivergent cyclization processes were described, one through the formation of an epoxide intermediate opened in a 5-endo-tet cyclization and leading to a global retention of configuration, and the other through a direct substitution of the chloride, leading to Walden-type inversion of configuration. Later, the same team reported a cyclization of chloropolyol in water, allowing a mild formation of THF.…”