Enantioselective syntheses of the alkaloids (−)-aurantioclavine, (+)-amurensinine, (−)-lobeline, and (−)-and (+)-sedamine are described. The syntheses demonstrate the effectiveness of the Pd-catalyzed asymmetric oxidation of secondary alcohols in diverse contexts and the ability of this methodology to set the absolute configuration of multiple stereocenters in a single operation. The utility of an aryne C-C insertion reaction in accessing complex polycyclic frameworks is also described.

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...

Rapid resolution: A new catalyst system for the oxidative kinetic resolution of secondary alcohols leads to dramatic rate increases. This system allows the use of a diamine to provide access to either enantiomer of a range of alcohols with good selectivity factors (see scheme). This method has been applied to the formal total synthesis of (−)‐amurensinine.

A convergent and enantioselective synthesis of the natural product amurensinine is described. The synthetic strategy takes advantage of mild and selective C-H and C-C bond insertion reactions, in addition to the palladium-catalyzed aerobic oxidative kinetic resolution recently developed in these laboratories.The development of mild and selective C-H and C-C bond insertion reactions for complex molecule synthesis has the potential to enable strategic disconnections that would be inconceivable using traditional methods. 1 Because of the sheer abundance of C-H and C-C bonds in most organic molecules and the general shortage of methods to perform selective reactions on these bonds, the application of C-H and C-C activation reactions in the context of natural product synthesis has been limited. Despite these challenges, the number of examples continues to rise. 2 In this communication, we present a convergent and enantioselective synthesis of the natural product amurensinine (1) that employs mild and selective C-H and C-C bond insertion reactions as key strategic maneuvers.Amurensinine (1) is a member of the isopavine family of alkaloids, which are exemplified by a characteristic tetracyclic tetrahydroisoquinoline core structure consisting of a doubly benzannulated azabicyclo[3.2.2]nonane (Figure 1). 3,4 The isopavines exhibit important biological properties for the treatment of neurological disorders, such as Parkinson's and Alzheimer's disease. 5 To date, there has been only one reported enantioselective synthesis of amurensinine (1), which was based on a chiral auxiliary approach. 6Our retrosynthetic strategy for the preparation of amurensinine ((+)-1) commences with the disconnection of the bridging amine functionality, exposing hydroxyester 6 as a synthetic intermediate (Scheme 1). We reasoned that this chiral benzylic alcohol could be produced enantioselectively by application of the palladium-catalyzed oxidative kinetic resolution methodology, recently developed in our group. 7,8 Alcohol (±)-6 could be accessed from ketoester (±)-7, which contains the benzosuberane core carbocycle, an ideal retron for an efficient and mild C-C bond insertion reaction involving the acylalkylation of arynes, previously reported by our laboratories. 9,10 Thus, aryne 8 and β-ketoester 9 were revealed as substrates for the C-C bond insertion reaction. The former may be generated in situ from otrimethylsilyl triflate 10 ,11 and the latter by a position-selective Rh-catalyzed C-H bond insertion reaction of diazo compound 11. 12 stoltz@caltech.edu. Supporting Information Available. Experimental details are available free of charge via the Internet at http://pubs.acs.org. We began our efforts toward amurensinine ((+)-1) with the preparation of β-ketoester 9 (Scheme 2). Functionalization of (3,4-dimethoxyphenyl)acetic acid (12) by standard methods produced diazo compound 11, which was subjected to Rh 2 (OAc) 4 -catalyzed dediazotization. 13 Despite the possibility for intramolecular insertion into a number of C-H bonds at sp 3 a...

The palladium-catalyzed aerobic oxidative kinetic resolution of key pharmaceutical building blocks is described. Substrates investigated are relevant to the enantioselective preparation of Prozac ¾ , Singulair ¾ , and the promising hNK-1 receptor antagonist from Merck. The latter provides the most selective aerobic oxidative kinetic resolution yet described.