Total synthesis of (18S)- and (18R)-homolargazole by rhodium-catalyzed hydrocarboxylation.

Homolargazole derivatives, in which the macrocycle of natural largazole is extended by one methylene group, were prepared by the recently developed rhodium-catalyzed hydrocarboxylation reaction onto allenes. This strategy gives access to both the (18S)- and (18R)-stereoisomers in high stereoselectivity under ligand control.

Asymmetric Diels-Alder and Ficini reactions with alkylidene ß-ketoesters catalyzed by chiral ruthenium PNNP complexes: mechanistic insight.

Hydride abstraction from the ß-position of the enolato ligand of the previously reported complex [Ru(3a-H)(PNNP)]PF(6) (5a; 3a-H is the enolate of 2-tert-butoxycarbonylcyclopentanone) with (Ph(3)C)PF(6) gives the dicationic complex [Ru(6a)(PNNP)](2+) (7a) as a single diastereoisomer, which contains the unsaturated ß-ketoester 2-tert-butoxycarbonyl-2-cyclopenten-1-one (6a) as a chelating ligand. The methyl analogue 2-methoxycarbonylcyclopentanone (3b) gives [Ru(3b-H)(PNNP)]PF(6) as a mixture of noninterconverting diastereoisomers (ester group of 3b trans to P, 5b; or to N, 5c), which were separated by column chromatography. Hydride abstraction from 5b (or 5c) yields diastereomerically pure [Ru(6b)(PNNP)](2+) (7b or 7c). Complexes 7b and 7c do not interconvert at room temperature in CD(2)Cl(2) and form opposite enantiomers of the Diels-Alder adduct upon reaction with Dane's diene (1 equiv). X-ray studies of 7a, 5b, and 5c give insight into the origin of enantioselection and the sense of asymmetric induction in the previously reported asymmetric Diels-Alder and Ficini cycloaddition reactions with 2,3-disubstituted butadienes and ynamides, respectively. Stoichiometric reactions (substrate coordination, cycloaddition, and product displacement) between [Ru(OEt(2))(2)(PNNP)](2+) (2), 6b (or 6a), and Dane's diene (15, to give estrone derivatives) or N-benzyl-N-(cyclohexylethynyl)-4-methylbenzenesulfonamide (17, to give cyclobutenamides) suggest that product displacement from the catalyst is turnover limiting.

Cu(I)- and Cu(II)-catalyzed cyclo- and Michael addition reactions of unsaturated ß-ketoesters.

The α-alkylidene ß-ketoesters 2-carbethoxycyclopentenone (1a) and ethyl 2-benzoylacrylate (1b) react with 1,2-dimethylbutadiene (2) (Diels-Alder), N-benzyl-N-(cyclohexylethynyl)-4-methylbenzenesulfonamide (3) (Ficini reaction), ethynyl(phenyl)sulfane (4) ([2 + 2] cycloaddition), and 1,2,5-trimethyl-1H-pyrrole (5) (Michael addition) in the presence of copper(I) (6) or copper(II) triflate (7) (1-2 mol %) in dichloromethane. This convenient protocol converts 1a and 1b to the corresponding cycloaddition (8-10) or Michael addition (11) products in good yields after reaction times of 0.5-3 h without requiring purified solvents or inert gas atmosphere.

Enantioselective Diels-Alder reactions of unsaturated beta-ketoesters catalyzed by chiral ruthenium PNNP complexes.

We report here dicationic ruthenium PNNP complexes that promote the enantioselective Diels-Alder reaction of alpha-methylene beta-ketoesters with various dienes. Complex [Ru(OEt2)2(PNNP)](PF6)2, formed in situ from [RuCl2,(PNNP)] and (Et3O)PF6 (2 equiv.), catalyzes the Diels-Alder reaction of such unsaturated beta-ketoesters to give novel alkoxycarbonyltetrahydro-1-indanone derivatives (nine examples) with up to 93% ee. The crystal structure of the substrate-catalyst adduct shows that the lower face of the substrate is shielded by a phenyl ring of the PNNP ligand, which accounts for the high enantioselectivity. The attack of the diene from the open re enantioface of the unsaturated beta-ketoester is consistent with the absolute configuration of the product. A useful application of this method is the reaction with Dane's diene to give estrone derivatives with up to 99% ee and an ester-exo:endo ratio of up to 145:1 (after recrystallization). Besides the enantioselective formation of all-carbon quaternary centers, this methodology is notable because unsaturated beta-ketoesters have been rarely used in Diels-Alder reactions. Furthermore, enantiomerically pure estrone derivatives are interesting in view of their potential applications, including the treatment of breast cancer.

Asymmetric Diels-Alder reactions of unsaturated beta-ketoesters catalyzed by chiral ruthenium PNNP complexes.

Cyclic alpha-unsaturated beta-ketoesters undergo cycloaddition with di- and trisubstituted butadienes to give tetrahydro-1-indanone derivatives with up to 93% ee in the presence of a ruthenium catalyst formed by activation of [RuCl(2)(PNNP)] with (Et(3)O)PF(6) (2 equiv) (PNNP = (1S,2S)-N,N'-bis[o-(diphenylphosphino)benzylidene]cyclohexane-1,2-diamine). The protocol has been used to prepare the estrone derivative (8R,13S,14S)-13-tert-butoxycarbonyl-3-methoxy-7,8,12,13,15,16-hexahydro-6H-cyclopenta[a]phenanthren-17(14H)-one as a single diastereoisomer with 85% yield and 99% ee after one crystallization step. Its absolute configuration, which has been determined by X-ray diffraction after reduction to the alcohol and esterification with camphanic chloride, is in agreement with the attack of the diene onto the open enantioface of the beta-keto ester (O-O) in the ruthenium complex [Ru(O-O)(PNNP)](2+), whose X-ray structure has been determined.