A Scalable Stereoselective Synthesis of Scymnol

Abstract

A high-yielding, stereoselective synthesis of scymnol 1 has been carried out in five steps starting from commercially available cholic acid 2. The synthesis was designed with the aim of eventual large-scale processing. Triformyloxycholic acid chloride 4 was treated with the magnesium enolate of diethyl malonate to afford the β-keto diester, diethyl 3α,7α,12α-triformyloxy-24-oxo-5β-cholestane-26,27-dioate 5. The key step in the synthesis was the stereoselective hydrogenation of β-keto diester 5 to give the corresponding β-hydroxy diester 6 using a BINAP ruthenium(ii) catalyst. Subsequent reduction of the diester moiety and deprotection of the hydroxyl groups afforded scymnol 1.

Diastereoselective reduction of the tricarbonyl moiety in bicyclic tetramates giving pyroglutamates

“…16 In other cases, reduction was achieved via hydrogenation at high pressure. 17,18 However, treatment of Weinreb amide 9 under the reported conditions also resulted in no conversion ( Table 1, Entries 3 and 4). In an attempt to decrease the delocalisation of the system, we hypothesised that reduction of enol ether 10, accessible from the enol analogue under Mitsunobu-like conditions (diisopropyl azodicarboxylate, triphenylphosphine), 9 should have enhanced reactivity to give ether 12.…”

Synthesis of 12β-Methyl-18-nor-bile Acids

“…To a solution of tris (formyloxy)-cholic acid S1 (21.0 g, 42.6 mmol) in dry benzene (200 mL) was added oxalyl chloride (8.00 mL, 94.5 mmol) at 5 °C. After being stirred for 5 h at room temperature, the reaction mixture was concentrated, and the residue was dried under high vacuum (light-yellow foam).…”