Second Generation of Aldol Reaction

Abstract

Since the discovery of the Mukaiyama aldol reaction more than 40 years ago, several landmark publications have inspired researchers in the field. The Mukaiyama AR is one of the most significant named reactions in organic synthesis. In the past few decades, development of the modern AR has been at the forefront in addressing the challenges of regio-, chemo-, diastereo-, and enantioselectivity in organic synthesis. All of these selectivity challenges maybe present in a single pair of reactants, thus controlling the outcome of such a process has great practical value. More than 10 years ago, our group became involved in this iconic carbon-carbon bond-forming process and attempted to very closely investigate all possible features of the AR to solve several issues still encountered by chemists, most notably the selectivity challenges mentioned above. In this context, our group initiated the second generation of the AR based on a Lewis or Brønsted acid-catalyzed process in conjunction with the use of a "super silyl" (tris(trimethylsilyl)silyl) directing group, which has demonstrated unrivalled properties in controlling the outcome of the AR. Using the extraordinary power of the super silyl group, we were able to develop new methods and concepts that broadly impacted the ability to control the selectivity attributes and thus allowed for a highly stereoselective construction of polyketide, halogenated polyketide, polypropionate, and polyol scaffolds through inter- and/or intramolecular aldolization protocols. Our diastereoselective ARs of super silyl enol ethers and aldehydes have shown great efficiency and modularity in producing exclusively and preferentially syn- or anti-adducts, creating up to four new adjacent stereocenters in a one-pot sequential manner and under mild reaction conditions. The super silyl-directed AR does not only provide a solution to stereochemistry control challenges, but also offers an efficient, modular and high yielding technique toward nontrivial construction of complex architectures with unprecedented ease. We believe that the new Lewis- or Brønsted-acid-catalyzed super-silyl-directed AR processes chronicled in our laboratories have come to maturity and now offer a "road map" for strategic stereoselective synthesis of polyketide-like units. Herein we report our recent achievements in the diastereoselective C-C bond formation, through the super-silyl-directed AR, toward the synthesis of complex and sophisticated hydroxy aldehydes. We would like to note that due to the extremely broad range of work reported in this field, only stereoselective AR involving aldehyde-derived super SEEs will be discussed in this Account.

Asymmetric assembly of high-value α-functionalized organic acids using a biocatalytic chiral-group-resetting process

“…The preparation of multifunctional chiral small molecules such as unnatural α-amino acids and α-hydroxy acids has attracted extensive attention from organic chemists because they play prominent roles in chemical synthesis, cosmetics, and pharmaceutical manufacturing 1 – 5 . Therefore, a few elegant chemical and enzymatic synthesis methods have been elaborated to provide a sufficient number of chemicals to meet market demand 6 – 9 .…”

Fluorine‐Containing Functionalized Cyclopentene Scaffolds Through Ring Contraction and Deoxofluorination of Various Substituted Cyclohexenes

“…The aldol reaction of various substituted scaffolds (e.g., amino, nitro, halogen, hydroxy, and other substituted compounds, as well as carbonyl derivatives, and some oxo esters) and its intramolecular asymmetric version are well‐known fundamental approaches for the formation of molecules with diverse structures containing an α,β‐unsaturated carbonyl moiety.…”

Development and Application of Asymmetric Organocatalytic Mukaiyama and Vinylogous Mukaiyama‐Type Reactions

“…[6] Thus,t he reaction of ketene alkyl trialkylsilyla cetals,p reparedf rom a-lithio esters and trialkylsilyl halides, with aldehydes and ketones at À78 8C, in the presence of TiCl 4 ,p roduced the corresponding b-hydroxy esters and btrialkylsilyloxy esters in good yields. [6] Thus,t he reaction of ketene alkyl trialkylsilyla cetals,p reparedf rom a-lithio esters and trialkylsilyl halides, with aldehydes and ketones at À78 8C, in the presence of TiCl 4 ,p roduced the corresponding b-hydroxy esters and btrialkylsilyloxy esters in good yields.…”