Total Synthesis of a Hypothetical Macroketone of Migrastatin

Abstract

Danishefsky's macroketone, a simplified analogue of natural product Migrastatin, is one of the lead compounds with potent cancer cell migration inhibition potential. Different biological assays suggest fascin protein as the potential target. Although it was indicated through X-ray co-crystallography where the concerned macroketone analogue was found to bind in the actin-binding sites of fascin, there was a structural discrepancy, as the X-ray co-crystal structure suggested an E-olefin along with inversion of methyl stereochemistry from that of Danishefsky's macroketone. Here, we have accomplished the total synthesis of the 'hypothetical macroketone' for the first time. The TiCl 4 mediated vinylogous Mukaiyama aldol reaction is the key step in present synthesis.

Mukaiyama aldol reaction: an effective asymmetric approach to access chiral natural products and their derivatives/analogues

“…The hypothetical macroketone, which is an analogue of the migrastatin natural product, plays an effective role as an anti-cancerous agent. Considering the pharmacological importance of this analogue, Choudhury et al 138 in 2021, reported its total synthesis by utilizing the vinylogous Mukaiyama aldol reaction as one of its key steps. Initial steps involved the synthesis of compound 301 and aldehyde 303 from ( S )-4-benzyloxazolidin-2-one 300 and 2,3- O -isopropylidene- l -tartrate 302 by known methodologies.…”

“…The hypothetical macroketone, which is an analogue of the migrastatin natural product, plays an effective role as an anti-cancerous agent. Considering the pharmacological importance of this analogue, Choudhury et al 138 in Scheme 39 Synthesis of amphidinolide F 294.…”

Total Synthesis and Revision of Stereochemistry of a Natural Benzo[g]isochromene Stereodiad Isolated from Rubia philippinensis

“…For that purpose, we began our synthesis from lactone (−)-9 for MOM protection 15 using MOMCl and DIPEA in CH 2 Cl 2 to provide lactone 18, which upon treatment with NaOH in EtOH broke the six-membered lactone and employed the Mitsunobu condition to invert the secondary alcohol stereochemistry. 8 After the Mitsunobu reaction, we ended up with compounds 19 and 18 as a 3:2 non-separable diastereomeric mixture using regular column chromatography techniques. However, using a preparative HPLC technique, both diastereomers were separated, isolated, and characterized.…”

“…Aldehyde 4 was subjected for the TiCl 4 -mediated diastereoselective aldol reaction with ( S )-4-benzyl-2-oxazolidinone (+)- 5 at −78 °C in CH 2 Cl 2 to afford Evans syn aldol adduct (+)- 6 in 93% yield with 92:8 diastereomeric ratio (dr) . After removal of the chiral auxiliary using LiBH 4 in tetrahydrofuran (THF)/MeOH, the resultant diol (+)- 7 was subjected for Pd-catalyzed lactonization, where N -formyl saccharin acted as a carbonyl source to deliver lactone (+)- 8 in 69% yield. The primary alcohol of lactone (+)- 8 was oxidized by the Jones reagent to attain carboxylic acid (+)- 9 as a pale yellow solid.…”

“…For further confirmation, we planned to synthesize the isochromene acid ( 2 ) (3 R ,12 R ) and needed to compare the spectral data to the proposed one. For that purpose, we began our synthesis from lactone (−)- 9 for MOM protection using MOMCl and DIPEA in CH 2 Cl 2 to provide lactone 18 , which upon treatment with NaOH in EtOH broke the six-membered lactone and employed the Mitsunobu condition to invert the secondary alcohol stereochemistry . After the Mitsunobu reaction, we ended up with compounds 19 and 18 as a 3:2 non-separable diastereomeric mixture using regular column chromatography techniques.…”