Enantioselective Total Synthesis of the Mexicanolides: Khayasin, Proceranolide, and Mexicanolide

Abstract

The enantioselective total synthesis of the limonoids khayasin, proceranolide and mexicanolide was achieved via a convergent strategy utilizing a tactic aimed at incorporating natural products as advanced intermediates. This extended biomimetically inspired approach additionally achieved the enantioselective total synthesis of the intermediates azedaralide and cipadonoid B.

COMU: scope and limitations of the latest innovation in peptide acyl transfer reagents

“…Successful Weinreb amidation of several Boc-amino acids (63-97% yield) and aliphatic acids has been recently achieved [15,33]. In addition, the use of COMU (16) in bioconjugation, anilide, and PNA-based construct formation has been described in numerous occasions [27,[34][35][36][37][38][39].…”

Synthesis of the seco‐Limonoid BCD Ring System Identifies a Hsp90 Chaperon Machinery (p23) Inhibitor

“…[18] Duringt his time only gedunin (9)h as undergone extensive medicinalc hemistry development, but these studies have concentrated on the peripheralf unctional groups in the pursuit of identifying more active inhibitors and understanding the key pharmacophoreo ft he molecule. [19,20] In terms of accessing skeletal fragments of the limonoid skeleton, the total syntheses of only af ew limonoids have been reported[ e.g.,a ndirolide N( 6)b yN ewhouse, [21] limonin (11)b yY amashita, [22] and mexicanolide (12)b yo ur group, [23] ], along with methodological studies (e.g.,F ernµndez-Mateos, [24] Lhommet, [25] and by our group [26] ), [27] butt hese efforts did not include biological evaluation against cancer cell lines nor Hsp90m achinery.T his unfortunate situation has resulted in a lack of general understanding as to the potentiala ctive pharmacophore of thesem olecules. Inspired by this circumstance, we explored the seco-limonoid BCD ring system, focusing on developing and understanding as tructure activity relationship (SAR)a round the Hsp90 co-chaperone enzyme p23, with the aim of unearthing less complex inhibitors.Before SAR could be performed, ag eneral and flexible syntheticr oute to the BCD ring system was required.…”

“…Inspired by this circumstance, we explored the seco-limonoid BCD ring system, focusing on developing and understanding as tructure activity relationship (SAR)a round the Hsp90 co-chaperone enzyme p23, with the aim of unearthing less complex inhibitors.Before SAR could be performed, ag eneral and flexible syntheticr oute to the BCD ring system was required. This aspect was achieved,a lbeit with numerous unforeseen challenges, by drawing on our previous synthetic experiences with mexicanolide (12) [23] and gedunin (9) [26] (Scheme1).[a] Dr.D.M.P inkerton, Dr.S.C how,T .…”

“…Before SAR could be performed, ag eneral and flexible syntheticr oute to the BCD ring system was required. This aspect was achieved,a lbeit with numerous unforeseen challenges, by drawing on our previous synthetic experiences with mexicanolide (12) [23] and gedunin (9) [26] (Scheme1).…”

“…With 17 in hand the critical Fernµndez-Mateos aldol reaction [24] could be performed. Normally, this transformation proceeds in as traightforward manner,p roviding the temperature is kept below À78 8C; [23] however,s ubstantial difficulties were encounteredi ni solating the products of this reaction. Eventually,i tw as discoveredt hat lowering the temperature to À100 8Cw as required along with ar apid quench 1min after addition of the 3-furaldehyde, so as to prevent the retro-aldol on warm up.…”