An Alkylidene Carbene C-H Activation Approach toward the Enantioselective Syntheses of Spirolactams: Application to the Synthesis of (-)-Adalinine.

A method based on in situ alkylidene carbene generation-C-H insertion reaction of 5-(3-oxobutyl)pyrrolidin-2-ones and 6-(3-oxobutyl)piperidin-2-ones is developed for the enantioselective synthesis of 1-azaspiro[4,4]non-6-ene-2-ones and 6-azaspiro[4,5]dec-1-ene-7-ones. The required 5-(3-oxobutyl)pyrrolidin-2-ones and 6-(3-oxobutyl)piperidin-2-ones are prepared from the Wacker oxidation of internal alkenes typified by 5-(but-2-enyl)pyrrolidin-2-ones and 6-(but-2-enyl)piperidin-2-ones, respectively. Excellent regioselectivity (≥92:8) is realized for the Wacker oxidation, and high yields (78-89%) of the desired lactam ketones are obtained. The results from further investigations into the Wacker oxidation suggested that the high regioselectivity of the oxidation in these lactam alkenes might be due to the participation of the lactam nitrogen via intramolecular coordination to Pd(II) during the reaction. Studies on alkylidene carbene generation-C-H insertion reaction of the lactam ketones revealed that the reaction efficiency is sensitive to the reaction temperature and the amount of lithio(trimethylsilyl)diazomethane employed, which led to the development of optimal reaction conditions for effecting alkylidene carbene generation-C-H insertion. Using the optimal reaction conditions, good to high yields (53-76%) of both γ- and δ-lactam spirocycles were obtained. The synthetic utility of the spirolactams was demonstrated by the synthesis of (-)-adalinine.

Stereoselective Syntheses of (+)-2-epi-Deoxoprosopinine, (-)-Deoxoprosophylline, (+)-cis-195A, and 2,5-Di-epi-cis-195A from a Common Chiral Nonracemic Building Block.

Approaches toward the syntheses of alkaloids belonging to the 2,6-disubstituted 3-hydroxypiperidine and cis-decahydroquinoline (cis-DHQ) classes of alkaloids are developed, starting from a common chiral nonracemic bicyclic lactam lactone (BLL). Two key δ-lactam intermediates, (5S,6S)-5-hydroxy-6-hydroxymethyl- and (5S,6S)-5-hydroxy-6-methylpiperidin-2-ones, are prepared; the latter δ-lactam is obtained via a direct decarbonylation of a bicyclic lactam lactol. The BLL is also used to prepare (4aR,5R,8aS)- and (4aR,5S,8aS)-5-methyloctahydroquinolin-2-ones, which involved a 6-exo-trig free-radical conjugate addition reaction. The stereoselectivity observed in the free-radical cyclization step is found to be governed by allylic 1,2-strain arising from the interaction of the N-(p-methoxybenzyl) group and the C6 substituent in the lactam ring of the free-radical intermediate. The effectiveness of the developed approaches is demonstrated by the asymmetric syntheses of (+)-2-epi-deoxoprosopinine, (-)-deoxoprosophylline, (+)-cis-195A, and 2,5-di-epi-cis-195A.

Mapping the mechanism of the resorcinol ring formation catalyzed by ArsB, a type III polyketide synthase from Azotobacter vinelandii.

Who's first? Aldol cyclization occurs before hydrolysis in the resorcinol ring formation catalyzed by the type III polyketide synthase, ArsB. Synthetic C(20)-TKA was not converted to alkylresorcinol by ArsB, but rather inhibited the enzyme activity, thus indicating that C(20)-TKA is not an intermediate in ArsB-catalyzed alkylresorcinol formation.

Conformational, steric and electronic effects on the site- and chemoselectivity of the metal-catalyzed reaction of N-bis(trimethylsilyl)methyl, N-(2-indolyl)methyl α-diazoamides.

The Rh(II)- and Cu(II)-catalyzed reactions of N-bis(trimethylsilyl)methyl, N-(2-indolyl)methyl α-diazoamides are investigated to delineate how conformational, steric and electronic factors influence the site- and chemoselectivity of the metallocarbenoid reaction. The N-bis(trimethylsilyl)methyl (N-BTMSM) group is found to be essential in promoting the metallocarbenoid reaction at the N-(2-indolyl)methyl moiety as well as providing subtle but effective conformational influence about the amide N-C(α) sigma bond in diazoamides carrying an N-C(α) alkoxymethyl side-chain, to afford excellent site- and chemoselectivity. In general, the metal-catalyzed reactions are found to favor metallocarbenoid addition to the indole C(2)-C(3) double bond over C-H insertion to give cyclopropanated products (tetracyclic γ-lactams); however, chemoselectivity is also affected by steric effects, as revealed in the N-[2-(3-methylindolyl)]methyl diazoamides, and to some extent by the nature of the catalyst employed, as seen in the N-C(α)-alkoxymethyl diazoamides. The tetracyclic γ-lactams are found to rearrange to give good to high yields of the tricyclic indole derivatives under the metallocarbenoid reaction conditions or under acidic conditions. The propensity of the tetracyclic γ-lactams to undergo rearrangement is found to be dependent on the nature of the α-substituent on the original diazo carbon and the indole N-substituent.

PpASCL, a moss ortholog of anther-specific chalcone synthase-like enzymes, is a hydroxyalkylpyrone synthase involved in an evolutionarily conserved sporopollenin biosynthesis pathway.

Sporopollenin is the main constituent of the exine layer of spore and pollen walls. Recently, several Arabidopsis genes, including polyketide synthase A (PKSA), which encodes an anther-specific chalcone synthase-like enzyme (ASCL), have been shown to be involved in sporopollenin biosynthesis. The genome of the moss Physcomitrella patens contains putative orthologs of the Arabidopsis sporopollenin biosynthesis genes. We analyzed available P.patens expressed sequence tag (EST) data for putative moss orthologs of the Arabidopsis genes of sporopollenin biosynthesis and studied the enzymatic properties and reaction mechanism of recombinant PpASCL, the P.patens ortholog of Arabidopsis PKSA. We also generated structure models of PpASCL and Arabidopsis PKSA to study their substrate specificity. Physcomitrella patens orthologs of Arabidopsis genes for sporopollenin biosynthesis were found to be expressed in the sporophyte generation. Similarly to Arabidopsis PKSA, PpASCL condenses hydroxy fatty acyl-CoA esters with malonyl-CoA and produces hydroxyalkyl α-pyrones that probably serve as building blocks of sporopollenin. The ASCL-specific set of Gly-Gly-Ala residues predicted by the models to be located at the floor of the putative active site is proposed to serve as the opening of an acyl-binding tunnel in ASCL. These results suggest that ASCL functions together with other sporophyte-specific enzymes to provide polyhydroxylated precursors of sporopollenin in a pathway common to land plants.

Di- and trisubstituted γ-lactams via Rh(II)-carbenoid reaction of N-Cα-branched, N-bis(trimethylsilyl)methyl α-diazoamides. Synthesis of (±)-α-allokainic acid.

Acyclic N-C(α)-branched, N-bis(trimethylsilyl)methyl (N-BTMSM) diazoamides undergo regio-, chemo-, and diastereoselective Rh(II)-carbenoid C-H insertion to give 4,5-disubstituted and 3,4,5-trisubstituted γ-lactams. The conformational influence of the N-BTMSM group and the electronic effect of the O-pivaloyl moiety of the C(α)-oxymethylene unit are essential for the observed regioselectivity. The synthesis of α-allokainic acid demonstrates the utility of the method.

Nonracemic bicyclic lactam lactones via regio- and cis-diastereocontrolled C-H insertion. Asymmetric synthesis of (8S,8aS)-octahydroindolizidin-8-ol and (1S,8aS)-octahydroindolizidin-1-ol.

The Rh(2)(MPPIM)(4)-catalyzed intramolecular C-H insertion reaction of (S)- and (R)-1-benzyl-5-(alpha-diazoacetoxy)piperidin-2-one and (S)-1-benzyl-4-(alpha-diazoacetoxy)pyrrolidin-2-one proceeds with high regioselectivity and cis-diastereoselectivity to give good yields of chiral nonracemic bicyclic lactam lactones (BLLs). For (S)- and (R)-1-benzyl-5-(alpha-diazoacetoxy)piperidin-2-one, the regioselectivity of the C-H insertion is catalyst-dependent; for example, (S)-1-benzyl-5-(alpha-diazoacetoxy)piperidin-2-one undergoes C-H insertion at C-6 preferentially when Rh(2)(5S-MPPIM)(4) is used, but with Rh(2)(5R-MPPIM)(4), C-H insertion occurs preferentially at C-4. This effect is not observed in the reaction of (S)-1-benzyl-4-(alpha-diazoacetoxy)pyrrolidin-2-one. The utility of the BLLs as chiral building blocks in alkaloid synthesis is exemplified by the synthesis of (8S,8aS)-octahydroindolizidin-8-ol and (1S,8aS)-octahydroindolizidin-1-ol.

Metal-catalyzed reaction of N-(2-indolyl)methyl, N-bis(trimethylsilyl)methyl diazoamides: an entry into the beta-carboline ring system.

The intramolecular metal-catalyzed reaction of N-(2-indolyl)methyl, N-bis(TMS)methyl diazoamides proceeds with high conformational control and chemoselectivity to give cyclopropyl derivatives, which rearrange to beta-carboline products.

Asymmetric synthesis of (+)-isofebrifugine and (-)-sedacryptine from a common chiral nonracemic building block.

The stereoselective syntheses of 2-substituted and 2,6-disubstituted 3-hydroxypiperidine alkaloids, (+)-isofebrifugine and (-)-sedacryptine, from a common, functionalized nonracemic bicyclic building block are achieved, demonstrating the flexibilty of the approach.

Regio- and diastereocontrolled C-H insertion of chiral gamma- and delta-lactam diazoacetates. Application to the asymmetric synthesis of (8S,8aS)-8-hydroxyindolizidine.

gamma- and delta-Lactam diazoacetates undergo efficient intramolecular C-H insertion catalyzed by Rh2(MPPIM)4 with excellent regioselectivity and cis-diastereoselectivity to provide synthetically useful bicyclic lactam lactones.

Competing isomerizations: a combined experimental/theoretical study of phenylpentenone isomerism.

The possible competition of Z/E versus hydrogen-shift isomerization in (E)-5-phenyl-3-penten-2-one (E-1) and (E)-5-phenyl-4-penten-2-one (E-2) was studied, both experimentally and theoretically. Iodine-catalyzed isomerization experiments and computational modeling studies show that the equilibrated system consists predominantly of E-1 and E-2, with E-2 in moderate excess, and with no detectable amounts of the Z (cis) diastereoisomers. Density functional theory (DFT) calculations corroborated the free energy difference (Delta(r) and Delta(r) were -0.7 and -1.1 kcal mol(-1), respectively), and computations of Boltzmann-weighted (1)H NMR spectra were found to be useful in confirming the assignment of the isomers. The relevance of this equilibrium to earlier work on double-bond stabilization is discussed.

The bis(trimethylsilyl)methyl group as an effective N-protecting group and site-selective control element in rhodium(II)-catalyzed reaction of diazoamides.

The intramolecular rhodium(II)-carbenoid-mediated C-H insertion reaction of structurally varied N-bis(trimethylsilyl)methyl,N-substituted diazoamides is studied. It has been found that in tertiary diazoamides the N-bis(trimethylsilyl)methyl (N-BTMSM) group is effective for conformational control about the amide N-C(O) bond; C-H insertion occurs at the other N-substituent. In C(alpha)-branched diazoamides, the N-BTMSM is found also to exert its influence on the conformational preference about the N-C(alpha) bond, which affects the regioselectivity of the C-H insertion in these systems. In unbranched diazoamides, inherent electronic effects of the N-substituent affect the regio- and chemoselectivity of the reaction; however, in branched diazoamides, electronic effects of the N-substituent and the alpha-substituent at the carbenoid carbon are subtle, but important in the deciding the eventual outcome of the reaction.

Stereoselective synthesis of the nonproteinogenic amino acid (2S,3R)-3-amino-2-hydroxydecanoic acid from (4S,5S)-4-formyl-5-vinyl-2-oxazolidinone.

(4S,5S)-4-Formyl-5-vinyl-2-oxazolidinone (4b), which is readily obtained via a zinc-silver-mediated reductive elimination of alpha-d-lyxofuranosyl phenyl sulfone (3b), is successfully converted to the naturally occurring, nonproteinogenic amino acid (2S,3R)-3-amino-2-hydroxydecanoic acid (2). Also in this study, a facile "oxazolidinone rearrangement" reaction is uncovered during the attempted formation of the (methylthio)thiocarbonate derivative of the oxazolidinone alcohol 7.

Influences of catalyst configuration and catalyst loading on selectivities in reactions of diazoacetamides. Barrier to equilibrium between diastereomeric conformations.

[reaction: see text] Stereoelectronic factors present a barrier to equilibrium between diastereomeric conformations resulting in differences in selectivity as a function of catalyst configuration. The bis(trimethylsilyl)-methyl protective group is inert to insertion but directs carbon-hydrogen insertion with enhanced enantiocontrol.

Rh(II)-Catalyzed Reaction Of Some alpha',alpha'- and beta'-Branched-O-Alkyl alpha-(Alkoxycarbonyl)-alpha-diazoacetates.

alpha',alpha'- and beta'- Branched-O-alkyl alpha-(alkoxycarbonyl)-alpha-diazoacetates 1a,b and 2a,b were prepared. The regio- and chemoselectivities in the Rh(II)-catalyzed reaction of these compounds were studied. The model systems 1a,b showed that the reactivity of the ester-substituted Rh(II) carbenoid is responsive to the nature of the Rh(II) catalyst; rhodium(II) acetamide favored insertion into the tertiary C-H bond and rhodium(II) perfluorobutyrate favored insertion into the secondary C-H bond. We also found that the nature of the O-alkyl group in the ester moiety had no influence on the reactivity of the Rh(II) carbenoid. In more complex systems such as compounds 2, it was found that rhodium(II) acetate promoted insertion into tertiary C-H bonds. Intramolecular cyclopropanation, to give 3-oxabicyclo[5.1.0]octane and 3-oxabicyclo[6.1.0]nonane products, was found to be competitive with tertiary C-H insertion; it is favored when rhodium(II) perfluorobutyrate was used as the catalyst. The Rh(II)-catalyzed reaction of 3 ("carbon" analog of 2a) resulted mainly in the cyclopentanone derivative, and no cyclopropanation product was detected. This result indicates that the ester oxygen in compounds of type 2 plays an important role in influencing the regio- and chemoselectivities of their reaction. Overall the results indicate that for compounds of a particular type of structure the regio- and chemoselectivities can be controlled via the judicious choice of the Rh(II) catalyst.