We report a highly enantioselective, general catalytic system for the facile synthesis of tertiary stereocenters by protonation adjacent to cyclic ketones. The method relies on catalytic decarboxylative protonation of readily accessible racemic quaternary β-ketoesters. A range of substituted cycloalkanone compounds can be accessed through this process with high levels of enantioselectivity.

General homogeneous conditions for the palladium-catalyzed synthesis of carbonyl compounds with tertiary carbon stereocenters at the α-position are reported. The highly reactive catalyst tolerates a variety of substrate substitution and functionality, and generates enantioenriched cyclic ketones from racemic allyl β-ketoester starting materials.Enantioselective protonation of achiral enolates or enol equivalents is an efficient route to access carbonyl compounds with tertiary carbon stereocenters at the α-position. Several distinct methods involving chiral proton sources or chiral catalysts have been developed for the enantioselective protonation of metal enolates. 1,2 However, most of the reported methods are limited in substrate scope, few are catalytic, and together they do not provide a general solution for the enantioselective protonation of enolates. 1dPreviously, we reported a series of catalytic enantioselective allylation reactions that deliver carbonyl compounds with adjacent quaternary stereocenters from various enolate precursors (Scheme 1). 3,4 Crucial to the success of these transformations was the use of catalysts derived from Pd(0) and chiral phosphinooxazoline (PHOX) ligand 1. 5,6 Based on kinetic and mechanistic studies carried out in our laboratories as well as computational studies performed in collaboration with the W. A. Goddard group at Caltech, 7 we believe that in the course of the reaction a chiral Pd-enolate is generated in solution. We chose to explore a proton electrophile to take further advantage of this valuable intermediate for the preparation of tertiary stereocenters. 8 As a result of these studies, we reported a highly enantioselective catalytic system for the decarboxylative protonation of racemic allyl β-ketoesters in the presence of Pd(OAc) 2 , (S)-t-Bu-PHOX (1), 4 Å molecular sieves (MS), and HCO 2 H (Scheme 1). 9 Although this protocol is capable of generating cycloalkanones with excellent ee, each substrate required optimization of the amounts of 4 Å MS and HCO 2 H in order to suppress competitive allylation and maximize product ee. Moreover, the heterogeneous nature of the reaction hinders investigation of the mechanism of protonation. In response, we have sought substantially different protonation conditions to allow further development of a practical synthetic process. Herein, we report a highly enantioselective, general homogeneous catalytic system for the facile synthesis of tertiary stereocenters by protonation of ketone enolates.To achieve a homogeneous enantioselective protonation, the racemic allyl β-ketoester (±)-2 was exposed to Pd 2 (dba) 3 , (S)-t-Bu-PHOX (1), and a variety of achiral organic proton donors (Table 1). Gratifyingly, the use of dimethyl malonate did indeed lead to protonated product 3, although the ee was moderate (entry 1). Acetoacetic esters (entries 2 and 3) provided 3 in significantly higher ee than the malonate case, but at the expense of conversion. Acetylacetone derivatives (entries 4-6) were very reactive, with the more acidic a...

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Much interest has been shown in Amaryllidaceae alkaloids as synthetic targets due to their wide range of biological activities. Over 100 alkaloids have been isolated from members of the Amaryllidaceae family; most of them can be classified into eight skeletally homogeneous groups. We have succeeded in the first asymmetric total syntheses of the crinane-type alkaloids (+)-crinamine (1), (-)-haemanthidine (2), and (+)-pretazettine (3). The starting cyclohexenylamine 14 was obtained from allyl phosphonate 11c by palladium-catalyzed asymmetric amination in 82% yield and with 74% ee. The product was recrystallized from MeOH. Interestingly, (-)-14 with 99% ee was obtained from the mother liquor (74% recovery). Intramolecular carbonyl-ene reaction of (-)-10 proceeds in a highly stereoselective manner to give hexahydroindole derivative 9 as the sole product. In the Lewis-acid-catalyzed carbonyl-ene reaction, an interesting rearrangement product, 20, was isolated in high yield. From 9, (+)-crinamine was synthesized. Thus, the asymmetric total synthesis of (+)-crinamine was achieved in 10 steps from 11c, and the overall yield is 19%. The total synthesis of (-)-haemanthidine was also achieved from 9 by a short sequence of steps.

A series of bisamidine derivatives each having a ring structure in the center of the molecule was synthesized and their Factor Xa (FXa) inhibitory activities were evaluated. Among them, some indoline derivatives showed potent inhibitory activities in vitro. In particular, (R)-18a having an (R)-configuration at the 2-position of the indoline ring exhibited the most potent FXa inhibitory activity in vitro, more potent than DX-9065a. Furthermore, (R)-18a exhibited more potent anticoagulant activity than DX-9065a. We also succeeded in obtaining an X-ray crystal structure of FXa bound with (R)-18a.