Substrate Directed Asymmetric Reactions

Abstract

Historically, reagent controlled reactions (mechanism controlled reactions) have played a significant role in the asymmetric synthesis of complex structures. In contrast, today's asymmetric synthesis is greatly dependent on substrate directed approaches. In this approach, a polar functional group, namely, a "directing group", in the vicinity of the reactive site inside the substrate has been documented to preassociate with the chiral catalyst, which exerts stereodirecting influence by directing the reacting partner toward one of the enantiotopic faces of the reaction center. Those reactions usually proceed through exceptionally ordered transition states and result in extraordinary levels of stereoselection. Within the last four decades, the substrate directed approach has become an indispensible tool for the preparation of complex chiral frameworks starting directly from relatively simple achiral substrate molecules via asymmetric induction or various resolution techniques or both. Likewise, the substrate directed approach has been applied to functionalize enantiopure substrates bearing pre-exisiting stereocenters into complex structures as a single diastereomer. A classical example is Sharpless asymmetric epoxidation of allylic alcohols in which the free hydroxy function acts as an active anchor to a dimeric Ti-catalyst that controls the stereochemical outcome of the epoxidation process by transferring the oxidant enantioselectively. The principal aim of the present review is to give a general overview of substrate directed asymmetric transformations, a topic that has not yet been documented in the form of a concise review of recently developed approaches. Due to the large number of related applications, only recent advances that have been documented within the last two decades have been reviewed. Furthermore, in the current review, we have mainly highlighted asymmetric reactions that are controlled by abundant and frequently used directing groups such as hydroxy, amide, and sulfonamide groups. In addition, selected examples of a few important substrate-directed chemo-, regio-, and diastereoselective reactions have also been included in this review.

Chiral Separations in Preparative Scale: A Medicinal Chemistry Point of View

“…In response to the exponential research in Medicinal Chemistry concerning the invention, discovery, design, identification and preparation of new biologically active compounds in enantiomerically pure form, aligned to the stricter requirements from regulatory authorities to patent new chiral drug [11], the development of methods for enantioselective production of chiral compounds as well as evaluation of their enantiomeric purity, proved to be essential. Accordingly, different enantioselective synthetic methodologies were developed [12,13] in addition to diverse analytical and preparative techniques [14,15]. Nevertheless, pure enantiomers can be achieved using several methods as illustrated in Figure 1.…”

Diastereoselective Cyclopropanation through Michael Addition‐Initiated Ring Closure between α,α‐Dibromoketones and α,β‐Unsaturated Fischer Carbene Complexes

“…In addition to biological occurrences and applications, some cyclopropanes have found use as substrates in organic synthesis through ring expansion and pericyclic reactions. From a synthetic point of view, the synthesis of substituted cyclopropanes can be realised by the manipulation of existing cyclopropanes bearing modifiable functional groups, catalytic and stoichiometric, alkene cyclopropanations. The third cyclopropanation approach, known as the Michael addition‐initiated ring closure (MIRC), relies on the 3‐exo‐tet cyclisation of the intermediate, which is formed by the reaction of the Michael acceptors with nucleophiles .…”

A Cooperative Hydrogen Bond Donor–Brønsted Acid System for the Enantioselective Synthesis of Tetrahydropyrans

“…[4] This report has been followed by several applications of chiral anion-binding catalysts in asymmetric reactions invoking oxocarbenium ion intermediates,t hough these reports are only known to be compatible with substrates that produce stabilized, conjugated ionic intermediates (such as benzylic or aromatic (pyrylium)-type intermediates). This approach would enable the substrate to recruit chiral co-catalysts [10] in as elf-assembled motif,u ltimately controlling the oxocarbenium ion geometry.T ot his end, we envisioned ar eaction design including ah ydrogen-bonding co-catalyst geared to cooperatively enhance,d efine,a nd prolong the lifetime of substrate-catalyst interactions.Foro ur initial investigations,w es elected the oxa-Pictet-Spengler reaction [11] as atest platform for our hypotheses.T o date,o nly two examples of enantioselective oxa-Pictet-Spengler reactions have been reported. [6] Notable exceptions include the use of novel highly constrained chiral imidodiphosphate-derived Brønsted acid catalysts pioneered by List, which uniquely engage non-stabilized oxocarbenium precursors in some cases through sequestration of the reactive intermediate.…”

“…This approach would enable the substrate to recruit chiral co-catalysts [10] in as elf-assembled motif,u ltimately controlling the oxocarbenium ion geometry.T ot his end, we envisioned ar eaction design including ah ydrogen-bonding co-catalyst geared to cooperatively enhance,d efine,a nd prolong the lifetime of substrate-catalyst interactions. This approach would enable the substrate to recruit chiral co-catalysts [10] in as elf-assembled motif,u ltimately controlling the oxocarbenium ion geometry.T ot his end, we envisioned ar eaction design including ah ydrogen-bonding co-catalyst geared to cooperatively enhance,d efine,a nd prolong the lifetime of substrate-catalyst interactions.…”

“…Existing strategies and proposed cooperative catalysis strategy for the control of addition facial selectivity to oxocarbeniumions.weak electrostatic ion-pairing interactions with favorable hydrogen bonds proximal to the oxocarbenium ion (Figure 1B). This approach would enable the substrate to recruit chiral co-catalysts [10] in as elf-assembled motif,u ltimately controlling the oxocarbenium ion geometry.T ot his end, we envisioned ar eaction design including ah ydrogen-bonding co-catalyst geared to cooperatively enhance,d efine,a nd prolong the lifetime of substrate-catalyst interactions.Foro ur initial investigations,w es elected the oxa-Pictet-Spengler reaction [11] as atest platform for our hypotheses.T o date,o nly two examples of enantioselective oxa-Pictet-Spengler reactions have been reported. [12] While highly selective,t hese reactions require several days to achieve acceptable conversions,w hich is likely attributable to the stability of on-cycle intermediates relative to the higherenergy oxocarbenium ions.…”