A Simple, Efficient, and Highly Enantioselective Synthesis of MS‐153 Employing a Chiral Silane Lewis Acid‐Promoted Acylhydrazone‐Enol Ether [3+2] Cycloaddition

Abstract

Our previously reported chiral silane-promoted enol ether-acylhydrazone [3 + 2] cycloaddition reaction has been applied to a brief and efficient synthesis of the neuroprotective agent MS-153. Unsatisfactory and variable levels of efficiency and enantioselectivity with the requisite acetaldehyde-derived acylhydrazone occasioned a modification to the chiral silane Lewis acid, which led to the key cycloaddition step proceeding with excellent efficiency (85 % yield) and enantioselectivity (! 98 % ee).

Effects of MS-153 on chronic ethanol consumption and GLT1 modulation of glutamate levels in male alcohol-preferring rats

“…Nicotinoylation of the pyrazolidine product is followed by cleavage of the p -nitrobenzamide and concomitant t -butoxide elimination to provide MS-153 in 70% overall yield for the three-step sequence. Full experimental details regarding MS-153 synthesis can be found in the previous study by our group (Tran and Leighton, 2006 ).…”

Synthesis of Non-Racemic Pyrazolines and Pyrazolidines by [3+2] Cycloadditions of Azomethine Imines

“…Replacing the phenyl moiety in chiral silicon Lewis acid 41a with sterically more demanding tert -butyl group 41b resulted in significant improvement in stereoselectivity when more electrophilic N ′-ethylidene-4-nitrobenzohydrazide 44 was reacted with tert -butyl vinyl ether to provide (5 R )-3-( tert -butoxy)-5-methylpyrazolidine 45 ( Scheme 15 , Example B) in good yield of 85% and stereoselectivity (>15:1 dr , 98% ee ). Two additional synthetic steps furnished the targeted MS-153 substrate in 70% overall yield and > 99% ee ( Scheme 15 , Example B) [ 32 ]. Furthermore, a concise synthesis of manzacidin C based on the second generation [ 33 ] chiral silicon Lewis acid, which promoted diastereo- and enantioselective acylhydrazone-alkene [3+2] cycloaddition, has also been reported by the same group [ 34 ].…”

Copper(i)-catalyzed asymmetric [3 + 2] cycloaddition of N-ester acylhydrazones and β-trifluoromethyl-α,β-unsaturated ketones

“…8 Over the past few decades, several elegant enantioselective strategies have been developed to construct various chiral pyrazolidine derivatives via chiral Lewis acid catalysts using hydrazones as starting materials. 9–11 Kobayashi and co-workers reported for the first time both intra- and intermolecular asymmetric 1,3-dipolar [3 + 2] cycloaddition reactions of N -keto acylhydrazones to alkenes catalyzed by chiral zirconium/binol complexes as Lewis acid catalysts (Scheme 1b). 9 Leighton et al later reported a related intermolecular enantioselective [3 + 2] cycloaddition between acylhydrazones and enol ethers by using 1.5 equivalents of a chiral silane Lewis acid.…”

“…9 Leighton et al later reported a related intermolecular enantioselective [3 + 2] cycloaddition between acylhydrazones and enol ethers by using 1.5 equivalents of a chiral silane Lewis acid. 10 Tsogoeva reported the chiral silicon Lewis acid-catalyzed enantioselective [3 + 2] cycloaddition between N -keto acylhydrazones and cyclopentadiene (Scheme 1c). 11 Moreover, the research groups of Rueping 12 and Houk 13 as well as others 14 have established several efficient asymmetric catalytic protocols to synthesize pyrazolidines from N -keto acylhydrazones using Brønsted acids as the catalysts.…”