Practical enantioselective synthesis of lamivudine (3TC) via a dynamic kinetic resolution

A practical enantioselective synthesis of lamivudine 1 is described. A highly effective dynamic kinetic resolution of the 5-hydroxyoxathiolane, followed by chlorination and introduction of cytosine provides an efficient synthesis of lamivudine.     

Efficient enantioselective synthesis of (2R,3R)- and (2S,3S)-3-hydroxyleucines and their diastereomers through dynamic kinetic resolution

(2R,3R)- and (2S,3S)-3-Hydroxyleucines, components of cyclodepsipeptides, papuamides and polyoxypeptins, were efficiently synthesized along with their diastereomers from the corresponding β-keto-α-amino acid ester through dynamic kinetic resolution using RuCl₂(binap)-catalyzed hydrogenation.     

Asymmetric synthesis of the epimeric (3S)-3-((E)-hex-1-enyl)-2-methylcyclohexanones

The asymmetric rhodium-catalysed 1,4-addition of alkenylzirconium reagents to 2-cyclohexenone can be useful in the synthesis of 3-alkenyl-2-methylcyclohexanones, provided that formaldehyde is used in trapping the intermediate zirconium enolates. In this manner a four-step sequence leading to the two epimeric 3-hexenyl-2-methylcyclohexanones in enantiomeric form was developed.     

A scalable synthesis of (R)-3-(2-aminopropyl)-7-benzyloxyindole via resolution

(±)-3-(2-Aminopropyl)-7-benzyloxyindole 1, assembled from 7-benzyloxyindole 3 in 59% overall yield, is resolved with O,O′-di-p-toluoyl l-(2R,3R)-tartaric acid 7 into (R)-1, a key intermediate of AJ-9677 2 (selective adrenaline β₃-agonist) in 99.5% e.e. and 36% overall yield. The unwanted enantiomer (S)-1 (61.9% e.e.; recovered in 57% yield from the crystallization filtrate) can be reused in another round of resolution after its enantiomeric purity is lowered to 3.7% by Raney Co treatment under a hydrogen atmosphere.     

Reactivity of cyclooligophosphanes: synthesis and structural characterisation of cyclo-1,4-(BH3)2(P4Ph4CH2) and cyclo-1,2-(BH3)2(P5Ph5)

The borane complexes cyclo-1,4-(BH3)2(P4Ph4CH2) (3) and cyclo-1,2-(BH3)2(P5Ph5) (4) were prepared by reaction of cyclo-(P4Ph4CH2) and cyclo-(P5Ph5) with BH3(SMe2). Only the 2:1 complexes 3 and 4 were isolated, even when an excess of the borane source was used. In solution, 3 exists as a mixture of the two diastereomers (R(P)*,S(P)*,S(P)*,R(P)*)-(+/-)-3 and (R(P)*,R(P)*,R(P)*,R(P)*)-(+/-)-3. However, in the solid state the (R(P)*,S(P)*,S(P)*,R(P)*)-(+/-) diastereomer is the major stereoisomer. Similarly, while only one isomer of 4 is observed in its X-ray structure, NMR spectroscopic investigations reveal that it forms a complex mixture of isomers in solution. 3 may be deprotonated with tBuLi to give the lithium salt cyclo-1,4-(BH3)2(P4Ph4CHLi) (3 x Li), though this could not be isolated in pure form.     

Asymmetric syntheses of 3,4-syn- and 3,4-anti-3-substituted-4-aminopiperidin-2-ones: application to the asymmetric synthesis of (+)-(3S,4R)-cisapride

The conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to δ-(N-allylamino)-α,β-unsaturated esters, followed by N-deallylation and cyclisation of the resultant β,δ-diamino esters, gives the corresponding 4-aminopiperidin-2-ones as single diastereoisomers (>99:1 dr). Subsequent deprotonation with LiHMDS and functionalisation of the resultant lithium enolate gives 3,4-anti-3-substituted-4-aminopiperidin-2-ones in >99:1 dr. Alternatively, in situ oxidation of the intermediate lithium (Z)-β-amino enolates formed upon conjugate addition gives α-hydroxy-β,δ-diamino esters, which after N-deallylation and cyclisation gives the corresponding 3,4-syn-3-hydroxy-4-aminopiperidin-2-ones in >99:1 dr. The utility of this methodology was successfully demonstrated in a concise asymmetric synthesis of the gastroprokinetic agent (+)-(3S,4R)-cisapride {(+)-(3S,4R)-N(1)-[3′-(4″-fluorophenoxy)propyl]-3-methoxy-4-(2?-methoxy-4?-amino-5?-chlorobenzamido)piperidine} in nine steps from commercially available starting materials with an overall yield of 19%.     

Asymmetric synthesis of syn-aryl-(2S,3R)-2-chloro-3-hydroxy esters via an engineered ketoreductase-catalyzed dynamic reductive kinetic resolution

We report here a generic, green synthesis of 17 valuable syn-aryl-(2S,3R)-2–chloro-3–hydroxy esters(syn-(2S,3R)-1) in 73%-99% isolated yields along with 6.1:1–83:1 dr and 31%～>99% ee, through dynamic reductive kinetic resolution of racemic aryl α–chloro β-keto esters(2) catalyzed by an engineered ketoreductase which was obtained via ep PCR-based directed evolution. The hectogram scale synthesis of syn-(2S,3R)-1b at a substrate concentration of 120 g/L showcased the application potential of th...     

Diastereo- and enantioselective intramolecular C(sp3)-H arylation for the synthesis of fused cyclopentanes

All C-H bonds are not equal: The intramolecular arylation of unactivated C(sp(3))-H bonds in the presence of a chiral Pd/binepine catalyst allows the synthesis of fused cyclopentanes efficiently and in an diastereo- and enantioselective manner (see scheme).     

Synthesis,spectral characterization,molecular docking studies,biological activity of (E)-2-((E)-3-(3,4,5-trimethoxyphenyl)allylidene) and (E)-N-phenyl 2-((E)-3-(3,4,5-trimethoxyphenyl)allylidene)hydrazinecarbothioamides and their Cu(II) complexes

Two slightly distorted octahedral complexes of copper(II) with (E)-2-((E)-3-(3,4,5-trimethoxyphenyl)allylidene)hydrazinecarbothioamide (L1) common name 3,4,5-trimethoxy-cinnamaldehydethiosemicarbazone and (E)-N-phenyl-2-((E)-3-(3,4,5-trimethoxyphenyl)-allylidene)hydrazinecarbothioamide (L2) common name 3,4,5-trimethoxycinnamaldehyde-4-phenylthiosemicarbazone have been synthesized. The two free ligands and their copper(II) complexes were characterized by spectroscopic techniques like FT-IR, FT-Raman, UV, EPR, Powder X-ray diffraction and cyclic voltammetry. The EPR spectra evidenced a rhombically distorted octahedron geometry for both the copper(II) complexes. The band gap calculations for the ligands L1, L2 and their complexes Cu(L1)₂Cl₂ and Cu(L2)₂Cl₂ were found to be 2.98, 2.61, 2.66 and 2.50 eV respectively. Cu(L1)₂Cl₂ and Cu(L2)₂Cl₂ have shown 50% of viability at 80 μg/ml and 60 μg/ml. The anti-oxidant activity study revealed that the compounds are good reductants of DPPH radical. Moderate to good anti-bacterial activity is shown by the compounds against the Gram-positive and Gram-negative bacteria. Molecular docking studies have been carried out to predict the orientation and binding mode of analysis in the active site. The synthesized ligand and complex well occupy (catalytic triad and adenine-binding site) in the active site of β-ketoacyl-acyl carrier protein synthase III enzyme, and also well occupy in helix 11 (in the DCS complex) of human estrogen receptor. Moreover they form water mediated hydrogen bond and hydrogen bond with Cys530 residue.     

1-Methyl-2-((1E,3E)-4-phenylbuta-1,3-dienyl)pyridinium iodide: Synthesis,characterization, and X-ray analysis

1-Methyl-2-((1E,3E)-4-phenylbuta-1,3-dienyl)pyridinium iodide (1) is synthesized and characterized by UV-Vis, FT-IR, ¹H and ¹³C NMR, and single crystal X-ray diffraction. Compound 1 crystallizes in an orthorhombic Iba2 space group with the unit cell parameters a = 12.8236(11) Å, b = 20.1216(17) Å, c = 11.2071(10) Å, V = 2891.8(4) ų and Z = 8. X-ray diffraction indicates that the molecule of 1 displays E,E configurations with respect to the two middle C=C double bonds. The molecular structure of 1 is twisted and the dihedral angle between the pyridinium and phenyl rings is 15.0(2)°. In the crystal packing, cations form stacks in an anti-parallel V-shaped manner along the a axis through π-π interactions between pyridinium and phenyl rings.     

Stereoselective preparation of (E)-(1,2-difluoro-1,2-ethenediyl) bis[tributylstannane] and stereospecific synthesis of (E)-1,2-difluorostilbenes

[reaction: see text]. The novel bisstannane (E)-(1,2-difluoro-1,2-ethenediyl) bis[tributylstannane] 2 was stereoselectively prepared in a high overall yield through a sequential synthetic route from chlorotrifluoroethylene 1. The synthetic application of this novel bisstannane 2 was exemplified in the Pd(PPh3)4/CuI-catalyzed cross-coupling reactions with aryl iodides, yielding (E)-1,2-difluorostilbenes 3 in moderate to high yields.     

Efficient preparation of enantiomerically pure (E)-4-(tributylstannanyl)but-3-en-2-ol via lipase-mediated resolution

The practical preparation of enantiomerically pure (E)-4-(tributylstannanyl)but-3-en-2-ol 1 from 3-butyn-2-ol 2 is reported. A modified Guibé's Pd-catalyzed hydrostannation of 2 provided the racemic γ-hydroxy vinylstannane 1 in a good yield. The enzymatic esterification of 1, with an inexpensive lipozyme, afforded (R)-3 and (S)-1 with very high enantiomeric excesses and chemical yields. This procedure is suitable for the multigram scale preparation of the potential chiral building blocks, (R)-1 and (S)-1.     

Röntgenstrukturanalyse von N-((E)-2-Methyl-2-butenyl)-N-(4-methylphenylsulfonyl)-N′-(4-nitrophenyl)schwefeldiamid

X-Ray Structure Analysis of N-((E)-2-Methyl-2-butenyl)-N-(4-methylphenylsulfonyl)-N′-(4-nitrophenyl)sulfurdiamide The title compound crystallizes in the monoclinic space group P2₁/n with a = 16.893(3), b = 14.285(2), c = 18.422(4), β = 114.765(5)°, V = 4037 ų, Z = 8. The formal S? N single bonds of the diaminosulfane moiety are shortened and differ in length (1.700 and 1.644 Å). The bonds of the N? S? N group to the p-nitrophenyl and tosyl rest are also a bit shorter than single bonds. The hybridization of the N atoms of the N? S? N moiety is sp² with a tendency in the direction of sp³. Analogously to open chained sulfur diimides with respect to the N? S? N moiety an E/Z configuration can be derived. In the crystal structure the molecules are connected to one-dimensional polymers via hydrogen bridges between the nitrogen of the secondary amino group as a donor and an oxygen of the nitro group as an acceptor.     

One-Pot synthesis of (2E)- and (2E, 4E)- unsaturated carboxylic acid amides via organotellurium reagents

Di-n-butyl telluride, 2-bromoacetylisobutylamide (or 2-bromoacetylpiperidide) react directly with saturated or α,β-unsaturated aldehydes at room temperature in the presence of potassium carbonate(s) to afford (2E)-, or (2E, 4E)-unsaturated carboxylic acid amides, respectively, in excellent yields with high E stereoselectivity.     

Stereoselective synthesis of (S)-3-(methylamino)-3-((R)-pyrrolidin-3-yl)propanenitrile

(S)-3-(methylamino)-3-((R)-pyrrolidin-3-yl)propanenitrile (1) is a key intermediate in the preparation of PF-00951966, (1) a fluoroquinolone antibiotic for use against key pathogens causing community-acquired respiratory tract infections including multidrug resistant (MDR) organisms. The current work describes the development of a highly efficient and stereoselective synthesis of 1 in 10 steps with an overall yield of 24% from readily available benzyloxyacetyl chloride. Two key transformations in the synthetic sequence involve (a) catalytic asymmetric hydrogenation with chiral DM-SEGPHOS-Ru(II) complex to afford β-hydroxy amide 11b in good yield (73%) and high stereoselectivity (de 98%, ee >99%) after recrystallization and (b) S(N)2 substitution reaction with methylamine to provide diamine 14 with inversion of configuration at the 1'-position in high yield (80%), after efficient purification using a simple acid/base extraction protocol.     

An enantioselective synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid via asymmetric hydrogenation

A concise enantioselective synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid (1, Pregabalin) has been developed. The key step is the asymmetric hydrogenation of a 3-cyano-5-methylhex-3-enoic acid salt 2 with a rhodium Me-DuPHOS catalyst, providing the desired (S)-3-cyano-5-methylhexanoate 3 in very high ee. Subsequent hydrogenation of the nitrile 3 with a heterogeneous nickel catalyst provides Pregabalin 1 in excellent overall yield and purity.     

A chiral alkyltris(pyrazolyl)borate ligand: synthesis of [(Ipc)B(pz)3Mn(CO)3] and [(Ipc)B(pz)3Ru(p-cymene)]PF6 (Ipc = Isopinocampheyl)

The application of the reagent (Ipc)BCl(2) (Ipc = isopinocampheyl) in the synthesis of a new tris(pyrazolyl)borate ligand having an Ipc substituent on boron is described. The sodium salt is a convenient precursor for the preparation of the complexes [(Ipc)tris(pyrazolyl)borato]tricarbonylmanganese and [[(Ipc)tris(pyrazolyl)borato](p-cymene)ruthenium](+), whose X-ray crystal structures are reported. While little distortion of the B(pz)(3)M unit is observed in these complexes, steric interaction between the Ipc group and the 3-positions of the pyrazolyl rings is noted to lead to distortion of the angles around the B-C bond.     

Complexes of d and f Metals with 2-Methyl-3-hydroxy(amino)pyrido[1,2-a]pyrimidine-4-one. Crystal Structure of 2-Methyl-3-hydroxypyrido[1,2-a]pyrimidine-4-one

Six complexes of scandium(III), lanthanum(III), praseodymium(III), and copper(II) chlorides with 2-methyl-3-hydroxypyrido[1,2-a]pyrimidine-4-one (HL¹) and 2-methyl-3-aminopyrido[1,2-a]pyrimidine-4-one (L²), as well as hydrochloride and hydronitrate L², were isolated. The crystal and molecular structures of HL¹ were determined. HL¹ in CCl₄ solution was shown (IR data) to occur as two forms, namely, neutral and zwitterionic forms. The structures for the complexes isolated were proposed.     

Catalyst-free synthesis of (E)-2-alkenylquinoline derivatives via C(sp3)-H functionalization of 2-methylquinolines

This Letter described a facile approach to synthesize (E)-2-alkenylquinoline derivatives via C(sp³)-H functionalization of 2-methylquinolines under catalyst-free conditions. A variety of electronically and sterically diverse 2-methyl quinoline and aromatic aldehydes were well tolerated.