A Simple and General Chiral Silicon Lewis Acid for Asymmetric Synthesis:  Highly Enantioselective [3 + 2] Acylhydrazone−Enol Ether Cycloadditions

Abstract

A highly diastereo- and enantioselective [3 + 2] acylhydrazone-enol ether cycloaddition mediated by a simple chiral silane Lewis acid is described. The reactions are highly practical, as demonstrated by a larger scale (5 g of the hydrazone) reaction in which the product was obtained after recrystallization in 93% yield and 99% ee. Evidence for a stepwise mechanism and a model for the asymmetric induction are presented, as well.

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

“…The unpurified product of this reaction was simply recrystallized to provide 6 in 56 % overall yield and > 99 % ee. As we have previously demonstrated in several contexts, [22][23][24] the pseudoephedrine is recoverable by simple extraction in the work-up of the cycloaddition reaction, and in this case the pseudoephedrine was recovered in 95 % yield.…”

“…[21] Presumably due to the poor performance of the acetaldehydederived acylhydrazone, however, the acylhydrazone derived from a-phenylthioacetaldehyde was employed instead, necessitating an extra reduction step. We have shown that silane Lewis acid 1 is a highly efficient and enantioselective promoter of the acylhydrazone-enol ether [3 + 2] cycloaddition reaction, [22] and based on the success of the reaction with simple aliphatic aldehyde-derived benzoylhydrazones we expected to achieve a straightforward synthesis of MS-153 along the lines outlined in Scheme 1. In the event, however, we too experienced difficulties with the acetaldehyde-derived benzoylhydrazone, and were not able to achieve acceptable levels of efficiency and enantioselectivity.…”

“…Based upon an X-ray crystal structure obtained in prior work [23] and other mechanistic experiments, [22] …”

Mechanistic Insights into the Reaction of Enantiomerically Pure Lithiosilanes and Electrophiles: Understanding the Differences between Aryl and Alkyl Halides

“…[19] Information concerning the obtained product composition as well as the enantiomeric ratio of the product and therefore the dominating reaction mechanisms are of crucial necessity for a wider application of enantiomerically pure lithiosilanes and the synthesis of chiral silicon compounds. The synthesis of chiral silicon compounds is recently gaining importance, as silanes with a stereogenic silicon center can be used as auxiliaries for stereoselective syntheses, such as Mannich reactions, [21] cycloaddition reactions, [22] or Friedel-Crafts alkylations. [23,24] As part of our studies on functionalized lithiosilanes, we present our latest results concerning the reactions of enantiomerically pure lithiosilanes and halo electrophiles.…”

Preparation of “Si‐Centered” Chiral Silanes by Direct α‐Lithiation of Methylsilanes

“…[1] In recent years, the use of chiral silicon systems has become of particular interest due to their application as auxiliaries in stereoselective synthesis. [2] In this context, silicon groups with a stereogenic silicon center have attracted a great deal of attention owing to the high selectivities that can be achieved in a variety of reactions, such as silicon-to-element (especially carbon and silicon) chirality transfers, [3] Mannich reactions, [4] cycloaddition reactions, [5] Friedel-Crafts alkylations, [6] and aldol reactions, [7] as well as in the kinetic resolution of chiral secondary alcohols. [8] Despite this high synthetic potential of silicon-chiral silanes in preparative chemistry, many of their properties and applications are as yet not fully understood or even remain unexplored due to the extremely limited number of suitable preparation methods.…”