Research and Development of an Efficient Synthesis of a Key Building Block for Anti-AIDS Drugs by Diphenylprolinol-Catalyzed Enantio- and Diastereoselective Direct Cross Aldol Reaction

Abstract

An efficient method for synthesizing 1-({[(3R,3aS,6aR)-hexahydrofuro­[2,3-b]­furan-3-yloxy]­carbonyl}­oxy)­pyrrolidine-2,5-dione (1), a key building block for HIV protease inhibitors, has been developed. A diphenylprolinol-catalyzed highly enantio- and diastereoselective cross aldol reaction of polymeric ethyl glyoxylate with an aldehyde was used as the key step. Acetalized aldol adduct was reduced with NaBH4 to give the diol intermediate in quantitative yield. The acetal exchange reaction followed by hydrogenation with Pd/C catalyst afforded 1′ in 95% yield over 2 steps. The condensation of 1′ with a carbonate gave crystalline 1 (>99/1 dr, > 99% ee) after single crystallization. This is a highly practical synthetic method since environmentally benign organocatalysis is utilized, the amount of catalyst is reduced to 3 mol %, and all of the intermediates before 1′ can be used without any purification.

Diaryl Prolinols in Stereoselective Catalysis and Synthesis: An Update

“…Different approaches have been devised to prepare this unit, although some drawbacks limited its convenient synthesis . In 2016, Ikemoto and co‐workers disclosed a practical and advantageous preparation based on the direct cross‐aldol reaction of commercially available and low cost polymeric ethyl glyoxylate with aldehydes (Scheme ) …”

“…[41] In 2016, Ikemoto and co-workers disclosed a practical and advantageous preparation based on the direct cross-aldol reaction of commercially available and low cost polymeric ethyl glyoxylate with aldehydes (Scheme 22). [42] An optimization of the original protocol was first required to maximize the conversion and stereocontrol of the model crossaldol reaction. When working under original conditions, using 4-benzyloxybutanal, a toluene solution of polymeric ethyl glyoxylate and 10 mol % of L-diphenyl prolinol 1 c, the aldol product 30 was obtained in 85 % yield, dr > 10/1 and > 95 % ee.…”

Practical Synthesis of the Bicyclic Darunavir Side Chain: (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol from Monopotassium Isocitrate

“…This compares well to the material produced by the Ikemoto process, reported at >99:1. 5 The carbonate 8 obtained from our route was then coupled to the penultimate, 4-amino- N -((2 R ,3 S )-3-amino-2-hydroxy-4-phenylbutyl)- N -isobutylbenzenesulfonamide, to furnish darunavir drug substance in a nonsolvate form. The NMR spectroscopic 17 and chromatographic properties of this material matched those of an authentic sample of darunavir.…”

Biocatalytic routes to anti-viral agents and their synthetic intermediates

“…Nonstereoselective synthesis of protected analogues of 364 required additional (enzymatic) resolution or down-stream purification of 3-OH-bis-THF. 471 Complementary to a complex stereoselective chemical synthesis of the desired (2S,3R)-364, [472][473][474] an enzymatic aldol addition would pose an interesting short synthetic strategy. With various examples discussed throughout this manuscript, biocatalytic carboligation has clearly been shown to be a powerful tool capable of rapidly accessing the complex architectures present in both anti-viral nucleoside analogues and peptidomimetics.…”