Deracemization of Quaternary Stereocenters by Pd‐Catalyzed Enantioconvergent Decarboxylative Allylation of Racemic β‐Ketoesters

Abstract

Enantioconvergent catalysis is a powerful synthetic method that converts a racemic stereogenic substrate into an enantiomerically enriched product with a theoretical yield of 100 % in a single operation.[1] Conceptually, a catalytic system for such a reaction must achieve a stereomutation [2] or stereoablation [3,4] of the substrate (or an intermediate), followed by an enantioselective conversion into product (Figure 1, compare pathways I and II). A number of catalytic processes of this type have been developed, including chemical, enzymatic, and chemoenzymatic strategies. [1,2,4] Racemic compounds that contain quaternary carbon centers are typically unsuitable substrates for enantioconvergent catalysis because of the difficulty associated with CÀC bond cleavage in the stereomutative or stereoablative process. [5,6] Herein, we describe the first catalytic system for the deracemization of quaternary carbon stereocenters. Our enantioconvergent method converts racemic a-substituted 2-carboxyallylcyclohexanones into highly enantioenriched cycloalkanones that bear quaternary stereocenters through catalytic asymmetric decarboxylative allylation.We recently reported the first catalytic asymmetric allylation methods for the synthesis of 2-alkyl-2-allylcycloalkanones (Scheme 1).[7] These reactions, based on racemic transformations reported in the early 1980s by Tsuji, [8] use enol carbonates and silyl enol ethers along with various allyl carbonates and a Pd 0 catalyst supported by a chiral phosphinooxazoline ligand (e.g., 1). [9][10][11] To demonstrate the utility of this methodology, we have started to employ these allylations as the key enantioselective reaction in multistep syntheses. In one such project, we required the substituted cyclohexenone 6 (Scheme 2). Unfortunately, the preparation of the allylation precursor 4 (R = CO 2 allyl or SiMe 3 ) was hampered by nonselective enolization of 3 to form inseparable mixtures of 4 and 5, which resulted in significant amounts of 7 after allylation.Prompted by the need for better position control in these synthetic sequences, we sought mechanistically guided alternatives to the reactions depicted in Scheme 1. To this end, we synthesized dideuterated carbonate 8 and trideuterated carbonate 9. When 8 was subjected to our standard conditions for allylation, the deuterium label was almost evenly scrambled between the termini of the allyl fragment in the product (Scheme 3 a).[12] In a separate crossover experiment, the reaction of equimolar amounts of carbonates 8 and 9 was performed under our standard allylation conditions. As expected, NMR spectroscopic analysis of the product showed deuterium scrambling between the allyl termini, but interestingly, mass spectrometric analysis of the product showed an almost perfect statistical distribution of enolate and allyl fragment pairs with four possible masses (Scheme 3 b).[12] Thus, all six possible products were formed in the reaction including those derived from crossover reactions. Although the specific details associated with the en...

Biosynthesis and Chemical Synthesis of Presilphiperfolanol Natural Products

“…With the requisite isoprenyl fragment in place, the application of the group's previously developed Pd-catalyzed asymmetric allylic alkylation methodology [47, 48] with Pd 2 (pmdba) 3 and ( S )- t -Bu-PHOX ( 101 ) smoothly provided enantioenriched vinylogous ester 102 in 91% yield and 95% ee. Conversion of the compound to acylcyclopentene 104 was achieved by employing a recently developed two-carbon ring contraction sequence.…”

The Construction of All‐Carbon Quaternary Stereocenters by Use of Pd‐Catalyzed Asymmetric Allylic Alkylation Reactions in Total Synthesis

“…In the earliest report by Stoltz in 2004, numerous chiral bidentate ligands were screened for their ability to promote high asymmetric induction in reactions with allyl enol carbonate and silyl enol ether substrates (Scheme 4). [17a] Ultimately, it was found that treatment of these substrates with the combination of ( S )- t Bu-PHOX ( 13 , Figure 2) and [Pd 2 (dba) 3 ] provided the highest degrees of enantioenrichment in the α-quaternary ketone products. Other P , N - and P , P -chelating ligands were investigated, but they proved to be less effective under the optimized conditions.…”

“…[17b,17c] The starting materials are racemates, so the destruction and reconstruction of stereochemical information through the intermediacy of a prochiral enolate must take place in order for these compounds to form asymmetric alkylation products in what has been termed a stereoablative process. [19] Despite this key mechanistic difference, these substrates demonstrated yields and levels of asymmetric induction similar to those obtained with the silyl enol ethers and enol carbonates.…”

“…After the development of a Pd·PHOX catalyst system for the catalytic construction of α-quaternary cyclic ketones, [17a] the Stoltz group sought to prepare the unique and highly substituted carbocyclic structures of dichroanone ( 46 , Scheme 7) [27] and liphagal ( 56 , Scheme 8, below). [28] Central to their divergent synthetic approach to these natural products was the preparation of bicyclic enone 41 (Scheme 7), which contains two quaternary carbons in close proximity in the cyclohexane ring.…”

“…The presence of the α′-methyl groups in the substrate did not appear to impede catalysis. Through Wacker oxidation and intramolecular aldol cyclization by previously developed protocols, [17a] bicyclic ketone 41 could be obtained in 74% yield over two steps. The key enone possesses a prevalent substitution pattern found not only in dichroanone ( 46 ) and liphagal ( 56 ), but also in many other terpenoid natural products.…”