Catalytic enantioselective stereoablative reactions: an unexploited approach to enantioselective catalysis

Abstract

Approaches to the preparation of enantioenriched materials via catalytic methods that destroy stereogenic elements of a molecule are discussed. Although these processes often decrease overall molecular complexity, there are several notable advantages including material recycling, enantiodivergence and convergence, and increased substrate scope. Examples are accompanied by discussion of the critical design elements required for the success of these methods.Since the inception of enantioselective catalytic methodology, the prevailing strategic approach has relied on inducing chirality into a prochiral atom by the generation of new asymmetric centers or axes (Figure 1a). While this tactic has proven extremely effective, the number of viable prochiral functional groups is relatively limited. An alternative approach to the production of enantioenriched materials is to begin with a racemic mixture and subsequently eliminate the intrinsic stereochemistry from a portion or all of this mixture. The scope of this approach to enantioselective catalysis is as wide as the number of chiral molecules in existence. While inherently a complexity minimizing process, this approach has proven to be valuable in the synthesis of chiral building blocks and more complex synthetic targets.In 2005, we defined the term "stereoablation" in the context of an enantioconvergent reaction. 1 Our initial definition was "the conversion of a chiral molecule to an achiral molecule," based on the Oxford English Dictionary definition for ablation: "the action or process of carrying away or removing; removal." 2 Upon further consideration of the importance of such methods in enantioselective chemical transformations, we have seen fit to expand the scope of this definition to include reactions where an existing stereocenter in a molecule is destroyed, but the intermediate molecule need not be wholly achiral. 3 This revised definition thereby includes many other important advances. To date, few stereoablative strategies have been exploited for enantioselective catalysis, although notable exceptions include metal π-allyl alkylations 4 and many dynamic kinetic resolutions. 5 In this Emerging Area highlight, recent examples of novel approaches to asymmetric catalytic methods for stereoablation will be discussed. We hope to demonstrate that this is an important, though underutilized, method of asymmetric synthesis. 6When considering catalytic enantioselective stereoablative reactions, two possible regimes arise: one in which the stereoablative step is the enantioselective step (Figure 1b), and one in which stereoablation precedes the enantioselective step (Figure 1c). In the first case, a catalyst must selectively react with one enantiomer or enantiotopic group of the substrate to provide © The Royal Society of Chemistry * Fax: (+1) 626-395-8436; stoltz@caltech.edu. Additionally, ketone 4, obtained in the resolution of alcohol (±)-3, can be recycled by reduction to racemic (±)-3 in quantitative yield, allowing greater than 50% overall yield of the e...

Asymmetric Brønsted Acid Catalyzed Isoindoline Synthesis: Enhancement of Enantiomeric Ratio by Stereoablative Kinetic Resolution

“…At the same time, the yield of isoindoline 10 a decreased and higher amounts of achiral bis-indole 11 a were formed. This indicated that a stereoablative kinetic resolution [10] was occurring during the Brønsted acid catalyzed step. To confirm this, a racemic sample of Friedel-Crafts adduct 12 a was exposed to indole (8 a) in the presence of catalyst 7 f (Scheme 3).…”

“…Moreover, these investigations led to the discovery of a Brønsted acid catalyzed stereoablative kinetic resolution [10] that occurs in tandem to the Friedel-Crafts reaction and amplifies the enantiomeric ratios of the isoindoline products.…”

Asymmetrische Brønsted‐Säure‐katalysierte Synthese von Isoindolinen: Steigerung des Enantiomerenverhältnisses durch stereoablative kinetische Racematspaltung

“…Außerdem führten diese Untersuchungen zur Entdeckung einer Brønsted-Säure-katalysierten stereoablativen kinetischen Racematspaltung, [10] die parallel zur Friedel-Crafts-Reaktion verläuft und die Enantiomerenverhältnisse der Isoindoline verbessert.…”

“…Ferner wurde beobachtet, dass die Substrate und Produkte 10 h-j, die einen tert-Butylester enthalten, mit den sauren Reaktionsbedingungen dieser Methode kompatibel sind (Tabelle 3, Nr. [8][9][10] in einer geringeren Enantioselektivität reagierte (e.r. 61:39, Tabelle 3, Nr.…”

Discovery of Novel Synthetic Methodologies and Reagents during Natural Product Synthesis in the Post-Palytoxin Era

“…The fact that this reaction was found to be stereoselective but not stereospecific prompted Sorensen and co-workers to postulate a transitory allenolate ion that subsequently attacks the Weinreb amide to yield a single product 284. The fact that both isomers 283 and 285 yield the same product, 284, was considered evidence for a stereoablative 260 261,262 Along with several previously known compounds, five new alkaloids were isolated from the zoanthid extract and identified by Norte and co-workers in 1999 261 ( Figure 22). One of these alkaloids, zoanthenol (290), differed from all previously isolated zoanthamine alkaloids, such as zoanthamine (291) and norzoanthamine (292), by the presence of an aromatic ring rather than a cyclohexene moiety.…”