Kinetic Resolution of Racemic Aldehydes through Asymmetric Allenoate γ-Addition: Synthesis of (+)-Xylogiblactone A.

A synthesis of (+)-xylogiblactone A has been achieved from t-butyl 2-methylbuta-2,3-dienoate in a linear three-step sequence. The key elements of the synthesis include a kinetic resolution of racemic 2-silyoxyaldehyde through the allenoate γ-addition to yield the γ-adduct as a single isomer and the subsequent gold catalysis to form the butenolide core. For a general method, the kinetic resolution of several racemic 2-silyloxyaldehydes is also performed to provide products in high levels of stereoselectivity with unusual anti-Felkin-Anh addition fashion.

A Regulation of Regiodivergent Routes for Enantioselective Aldol Addition of 2-Alkyl Allenoates with Aldehydes: α-Addition versus γ-Addition.

A method for the regioselective asymmetric aldol addition of 2-alkyl allenoates with aldehydes to provide an α- or γ-adduct depending on the aldehyde pair is reported. In most cases, except enals, a mixture of a chiral bromoborane with 2-alkyl allenoates in the presence of iPr2NEt can react with aldehydes to provide efficient γ-addition products as single isomers containing axial and central chirality. On the other hand, observations indicate that enals undergo α-addition to yield highly functionalized adducts, including an α-carbon quaternary center in high levels of diastereo- and enantioselectivity.

Enantioselective Synthesis of a Furan Lignan (+)-Sylvone.

A synthesis of natural tetrahydrofuran lignan (+)-sylvone is achieved starting from methyl allenoate in 5 steps. The synthesis begins from an enantioselective aldol reaction of methyl allenoate with 3,4-dimethoxybenzaldehyde to afford α-addition aldol adduct. Key steps for the synthesis of sylvone include an oxacyclization of the α-hydroxy allenyl adduct followed by a Michael addition of a 1,3-dithiane derivative to establish a sylvone skeleton with suitable stereoselections.

Synthesis and anti-tubercular activity of 2-nitroimidazooxazines with modification at the C-7 position as PA-824 analogs.

Tuberculosis (TB) is a major global health problem, and new drug targets and scaffolds need to be identified to combat the emergence of drug resistant TB. The nitroimidazooxazine PA-824 represents a new class of bio-reductive drug to treat TB. In this study we report a 2-nitroimidazooxazine derivative with modification at the C-7 position that exhibited better activity than PA-824 against Mycobacterium tuberculosis (Mtb) H37Rv strain in vitro. From 7a as a key intermediate, we functionalized with benzyl ether (8), phenyl ether (9), benzyl carbonate (10) and benzyl carbamate (11). Among the 23 compounds produced, 8a-R (MIC=0.078 µM) with trifluoromethoxy benzyl group was 5-fold more potent than PA-824 (MIC=0.390 µM) in the in vitro assays against the wild-type Mtb, and the phenyl ether compound 9g-R (MIC=0.050 µM) exhibited the most potent antimycobacterial activity.

Asymmetric aldol reaction of allenoates: regulation for the selective formation of isomeric allenyl or alkynyl aldol adduct.

A highly stereoselective synthesis of 3-butynyl-threo-aldol adducts is achieved from the reaction of allyl allenoate with a chiral bromoborane in the presence of iPr2NEt, followed by addition of BF3·OEt2 as an additive to scavenge excess base and then aldehydes, whereas isomeric allenyl aldol adducts are formed in the absence of a Lewis acid additive from methyl allenoate.

Regulation of diastereoselectivity in the carbocyclization of allenyl (S)-N-tert-butylsulfinimines through a three-component assembly.

Allenyl sulfinimines can be stereoselectively cyclized with hexamethylditin under palladium catalysis conditions followed by a selection of additives for an activated transmetalation. Reactivity and diastereoselectivity for the cyclization strongly depend on the characteristics of additives. A highly diastereoselective synthesis of five-membered rings is achieved from the reaction of the corresponding allenyl (S)-N-tert-butylsulfinimies through the following sequence. After the distannylation of the allenyl group with hexamethylditin catalyzed by the Pd complex, stereochemical routes are additive dependent: addition of SnCl4 affords a cis ring exclusively, whereas a trans ring is formed predominantly by the introduction of B-bromocatecholborane. Extension of the methodology to the synthesis of six-membered cis rings is achieved by using B-bromocatecholborane. Stereochemical relationships of products were unambiguously deduced by X-ray crystallography.

A novel allylic transfer reaction of chirally modified 2-borylbutadiene: synthesis of chiral homoallenyl alcohols.

An enantioselective synthesis of the homoallenyl alcohols was achieved from the reaction of chiral 2-borylbutadiene with aldehydes through an allylic transfer reaction in good yields and enantioselectivities.

Efficient synthesis of dibenzo[a,c]cyclohepten-5-ones via a sequential Suzuki-Miyaura coupling and aldol condensation reaction.

A common strategy for the synthesis of a 7-membered-ring system with a Suzuki-Miyaura coupling followed by an acid/base-promoted intramolecular aldol condensation reaction has been developed. The reaction of 2'-bromoacetophenones with 2-formylphenylboronic acids in the presence of Pd(OAc)(2) and CataCXium PIntB L8 efficiently provided biaryl compounds, which were transformed to a wide array of dibenzo[a,c]cyclohepten-5-ones in excellent yields by a sequential treatment with p-TsOH, followed by 10% aq NaOH.

Regulation of cyclization for the stereoselective synthesis of substituted tetrahydrofurans and tetrahydrooxepines.

Dramatic solvent effect is observed during the cyclization of 1. Synthesis of 2 is achieved from the reaction of 1 with a hexamethylditin-catalyzed palladium complex followed by aldehydes in the presence of TMSOTf in THF, whereas 3 is formed in CH2Cl2. The method described herein is successful with various substrates 1 in good yields and high levels of diastereoselectivity.

A diastereoselective carbocyclisation of allene-hydrazones through the intramolecular allylic transfer reaction.

A diastereoselective synthesis of cyclic hydrazines was achieved from a carbocyclisation of allene-hydrazones by the Pd-catalyzed distannylation of an allene moiety, followed by the transmetallation of allylic stannane intermediates with TiCl4.

Synthesis of novel chemical probes for the study of tanshinone binding proteins.

Novel diazirine or biotin-labeled tanshinone probes were synthesized and evaluated for TRAP inhibitory activity against RANKL-induced osteoclastogenesis in RAW264.7 cells. We found that diazirine-labeled derivatives (18 and 20) are potent inhibitors of RANKL-induced osteoclastogenesis. IC50 values were 18.02 and 15.00 microM, respectively. These probes will be useful reagents for investigating tanshinone-proteins interactions.

A highly stereoselective sequential allylic transfer reaction of diene with diboronyl reagent and aldehydes promoted by nickel catalyst.

[reaction: see text] A new protocol for the sequential allylic transfer reaction of a diene with two aldehydes in the construction of cyclic systems containing four stereogenic centers is achieved in a one-pot operation. Reaction of the diene-alehyde 1 with aldehyde in the presence of the diboronyl reagent catalyzed by a nickel complex produces products 2 and 3 depending on reaction conditions in high levels of diastereoselectivity. Extension of this method to the synthesis of six-membered rings is also investigated.

Regulation of stereoselectivity using Lewis acid in the cyclization of allenic aldehydes catalyzed by palladium complex.

A highly diastereoselective synthesis of 3 is achieved from the reaction of 1 with hexamethylditin catalyzed by palladium complex in the presence of 20 mol % tris(pentafluorophenyl)borane as a Lewis acid additive for a reversal of diastereoselectivity, whereas 2 is formed in the absence of Lewis acid additive. The method described herein is successful with various substrates 1 in good yields and high levels of diastereoselectivity. [reaction: see text]

A convenient synthesis of alpha-methylene-gamma-butyrolactones from allenyl carbonyl units mediated by Mo(CO)6 through intramolecular cyclocarbonylation.

A novel procedure for the synthesis of cis-fused bicyclic alpha-methylene-gamma-butyrolactones from allenyl carbonyl functionalities via the molybdenum-mediated cyclocarbonylation is described. The use of Mo(CO)(6) with DMSO to promote reaction results in an efficient and convenient protocol through the three-component assembly in high yields.

Enantioselective synthesis of allenyl carbinols by the CBS reduction in nitroethane: dramatic solvent effect for reactivity and enantioselectivity.

Dramatic solvent effect of nitroethane was observed in the catalytic asymmetric reductions of allenyl ketones and alpha,beta-ynones using the oxazaborolidine cayalyst to yield the corresponding alcohols in high levels of enantioselectivity.

Highly diastereoselective Prins-type cyclisation of cyclopropylvinylic aldehydes mediated by TiCl4.

A novel intramolecular Prins type cyclisation of cyclopropylvinylic aldehydes promoted by TiCl(4) under mild reaction conditions to form cis-cyclic products in high yields has been accomplished.

Internal chirality transfer in the reaction of substituted cyclic (S,O)-ketene ortho esters with aldehydes catalysed by Lewis acid.

Internal chirality transfer of 1a and 1b with aldehydes in the presence of Lewis acid catalyst resulted in high diastereoselectivities in the construction of a highly functionalised acyclic system.

Silylative carbocyclization of allenyl-carbonyl units with Et3SiH catalyzed by rhodium: cis-stereoselective synthesis of homoallylic cycloalkanols.

[reaction: see text] A new procedure for the synthesis of cis-2-triethylsilylvinyl-cyclopentanols and -cyclohexanols from allenyl-aldehydes and -ketones with Et(3)SiH through rhodium-catalyzed silylative carbocyclization is described. The use of Rh(acac)(CO)(2) (1 mol %) to promote the reaction results in a mild and convenient protocol for the three-component assembly.