Asymmetric Formal Synthesis of (+)‐Lactacystin

Abstract

A formal synthesis of (+)‐lactacystin was achieved from commercially available isobutyraldehyde and ethyl acrylate. A Baylis–Hillman reaction, an intermolecular nucleophilic displacement under Mitsunobu conditions, a Sharpless asymmetric epoxidation, a palladium(0)‐catalyzed syn‐selective ring opening of an epoxide by treatment with an azide, a one‐pot azide reductive lactamization, and a ruthenium‐catayzed oxidation were employed as the key steps.

Applications of Mitsunobu Reaction in total synthesis of natural products

“…Then, the latter 130 was subjected into an intermolecular nucleophile substitution via Mistunobu reaction conditions (in the presence of benzoic acid, DIAD and Ph 3 P in THF) to obtain the corresponding benzoate, that was treated with K 2 CO 3 in methanol to give the corresponding allylic alcohol 131 as the main product . The latter was then converted into the appropriate epoxy alcohol 132 in several steps which is used for obtaining 4,5‐syn‐disubstituted azide 133 via a multi‐step synthesis . Next, compound 133 underwent hydrogenation H 2 gas (1 atm) in MeOH, on Pd/C and in the presence of Na 2 CO 3 and ammonium acetate to achieve the reductive lactamization in one pot manner to furnish lactam 134 in 78% yield.…”

“…Next, compound 133 underwent hydrogenation H 2 gas (1 atm) in MeOH, on Pd/C and in the presence of Na 2 CO 3 and ammonium acetate to achieve the reductive lactamization in one pot manner to furnish lactam 134 in 78% yield. The latter after several steps was transformed to, 1‐ethyl‐3‐[3‐(dimethylamino) propyl] carbodiimide hydrochloride (EDC·HCl) 135 in moderate yield (57%) Finally, the latter was converted into 127 as the desired natural product …”

Application of Two Direct C(sp3)–H Functionalizations for Total Synthesis of (+)-Lactacystin

“…Since the proteasome machinery plays an essential role in cell cycle control, differentiation, apoptosis, antigen processing, and immune response, proteasome inhibitors have emerged as important candidates for the development of pharmaceuticals and new biological tools for the study of proteasome functions . Accordingly, 1 has attracted significant attention as a synthetic target, and a number of total syntheses have been reported to date. − …”