Stereo-conserved synthesis of syn-diarylheptanoids, active principles of Zingiber, starting from d-glucose

A highly efficient and stereo-controlled synthetic strategy has been developed to access syn-diarylheptanoids, for example, 2,3, 4, and 5b starting from d-glucose as a chiral pool. The 3-(R), 5-(S)-syn-diol stereochemistry present in these heptanoids was obtained after conserving C2 and C4 stereochemistry of d-glucose during the course of synthetic transformation. The key features of this synthetic strategy include: (i) conversion of d-glucose to a known chiral template 6 armored with the required 1,3-syn-diol stereochemistry as well as two terminal aldehyde functionalities for building up customized ‘diaryl wings’; (ii) conversion of 6 to 7 via an initial Wittig olefination at the C5-aldehyde; (iii) use of the hemiacetal 7 as a common intermediate to obtain the individual heptanoids via a second Wittig reaction at its anomeric center using appropriately chosen ylides.     

Enzymatic synthesis of optically active α-chloro-δ-hydroxy-β-ketoalkanephosphonates and reactions thereof

A novel and enzymatic approach to α-chloro-δ-hydroxy-β-ketoalkanephosphonates was developed via enantioselective CALB-catalyzed acetylation and CRL-catalyzed hydrolysis. The resultant optically active compounds provide, via Horner-Wadsworth-Emmons (HWE) reaction, chiral α,β-unsaturated ketones that are building block with potential application in organic synthesis.     

Stereoconvergent preparation of chiral vinylsilanes by cuprate substitution of α-acetoxyallylsilanes. Application to the synthesis of (S)-(+)-bishomomanicone

Enantiomerically enriched (E)- and (Z)-configured α-acetoxyallylsilanes have been prepared starting from a chiral acylsilane bearing an asymmetric unit at the silicon portion. Treatment of these compounds with organocuprates afforded the respective vinylogous substitution products in high yields and high stereoselectivities. The transformations proceed essentially by complete anti attack of the nucleophiles to the allylic acetates and predominantly via transition states leading to the (E)-configured vinylsilane products. By the proper choice of the double bond geometry in the starting material, the configuration of the newly formed stereogenic center can be controlled. The method represents a new and flexible entry into chiral vinylsilanes that can be used for subsequent transformations. As an example, the α,β-unsaturated γ-chiral, naturally occurring ketone (S)-(+)-bishomomanicone was synthesized with this method, which represents the first synthetic access to this compound.     

Stereoselective synthesis of methyl branched chiral deoxypropionate units: a new route for synthesis of insect pheromone (−)-lardolure and (2R,4R,6R,8R) 2,4,6,8-tetramethylundecanoic acid

(−)-Lardolure and (2R,4R,6R,8R)-2,4,6,8-tetramethylundecanoic acid have been synthesized via lipase catalyzed desymmetrization strategy to create two methyl chiral centers. Other key steps involved in the synthesis are Wittig reaction, Evan’s asymmetric alkylation, Grignard reaction, Pd-catalyzed isomerization of primary allylic alcohol to corresponding saturated aldehyde, and PhNO/proline catalyzed MacMillan α-hydroxylation.     

First stereoselective total synthesis of (6R)-6-[(4R,6R)-4,6-dihydroxy-10-phenyldec-1-enyl]-5,6-dihydro-2H-pyran-2-one

A stereoselective total synthesis of (6R)-6-[(4R,6R)-4,6-dihydroxy-10-phenyldec-1-enyl]-5,6-dihydro-2H-pyran-2-one is reported. The strategy utilizes an iterative Jacobsen hydrolytic kinetic resolution, ring opening with a chiral propargylic synthon and a preferential (Z)-Wittig olefination reaction and lactonization as the key steps.     

Chiral amine-induced stereoselectivity in trans-β-lactam formation via Staudinger cycloaddition

A series of chiral trans-β-lactams was obtained via Staudinger cycloaddition with low to moderate diastereoselectivity (up to 54% de) induced by a chiral amine component of the imine. It was shown that the direct connection of nitrogen to a chiral centre is crucial to induce chirality; moderate asymmetric induction was achieved by using isomeric 1-phenylethylamines, which are among the cheapest chiral sources on the market, while low diastereoselectivity was obtained from 3-aminomethylpinane, where the chiral centres are distant from nitrogen by a methylene group. It was shown, that an increase of the reaction temperature from 110 °C to 140 °C led to commensurable results but speeded-up the transformation significantly. The absolute configurations of phenylethylamine derivatives were determined by X-ray analysis of selected samples.     

Stereoselective total synthesis of almorexant

A highly stereoselective synthesis of almorexant has been achieved using (R)-tert-butanesulfinamide as a chiral source. The chiral tetrahydroisoquinoline core was constructed through allylation of chiral N-sulfinyl imine followed by ring closure of the secondary amide with a tethered halide. The chiral α-phenyl amide was introduced by means of S_N2 substitution of (S)-methyl 2-phenyl-2-(tosyloxy)acetate with chiral tetrahydroisoquinoline.     

Asymmetric addition of phenylacetylene to aldehydes catalyzed by soluble optically active polybinaphthols ligand

A chiral polymer ligand was synthesized by the polymerization of (S)-5,5′-dibromo-6,6′-dibutyl-2,2′-binaphthol (S-M-1) with (S)-2,2′-bishexyloxy-1,1′-binaphthyl-6,6′-boronic acid (S-M-2) via Pd-catalyzed Suzuki reaction. The application of the chiral polymer ligand to the asymmetric addition of phenylethynyl zinc to various aldehydes has been studied. The results show that the soluble chiral polybinaphthols ligand in combination with Et₂Zn and Ti(OⁱPr)₄ can exhibit excellent enantioselectivity for phenylacetylene addition to both aromatic and aliphatic aldehydes. The catalytically active center of the repeating unit S-1 used as a catalyst produced the opposite configuration of the propargylic alcohols to that of S-1, on the contrary, the chiral polymer gave the same configuration as the optically active binaphthol moiety of the polybinaphthols ligand. Moreover, the chiral polymer ligand can be easily recovered and reused without loss of catalytic activity as well as enantioselectivity.     

Reversal of diastereoselection in the addition of Grignard reagents to chiral 2-pyridyl tert-butyl (Ellman) sulfinimines

Addition of Grignard reagents to chiral tert-butyl sulfinimines derived from pyridine 2-carboxaldehyde affords protected 2-pyridyl amines in high yields and diastereoselectivities. The sense of chiral induction is opposite to that predicted via a chelation-controlled transition state.     

Synthesis of (+)-striatene: confirmation of its stereostructure

The first enantioselective synthesis of natural striatene (+)-1, isolated from liverwort Ptychanthus striatus, starting from commercially available (R)-Pulegone is described. Its stereostructure was confirmed by X-ray analysis of a 3,5-dinitrobenzoate derivative obtained from a key intermediate and its high optical purity was verified by chiral HPLC.     

A quantum chemical study on the mechanism of chiral N-oxides-catalyzed Strecker reaction

The mechanism for the Strecker reaction of silyl cyanide (H₃SiCN) and benzaldehyde N-methylimine (PhCHNCH₃) catalyzed by chiral 3,3′-dimethyl-2,2′-bipyridine N,N′-dioxide was investigated using the density functional theory (DFT) at the B3LYP/6-31G* level. The calculations revealed that the non-catalyzed reaction proceeded in a concerted way via a five-membered ring transition state, while the catalytic one occurred stepwisely via a hexacoordinate hypervalent silicate intermediate. It was predicted that both non-catalyzed and catalytic Strecker reactions involved two competitive reaction pathways, that is, addition followed by isomerization or isomerization followed by addition. The calculations indicated that two reaction pathways were comparable for both non-catalyzed and catalytic Strecker reactions. In the catalytic reaction, the strong electron donor (N-O) of chiral N-oxide played an important role in enhancing the reactivity and nucleophilicity of H₃SiCN by coordinating O atom to the Si atom of H₃SiCN. Chiral N-oxide could be used as a good catalyst for the reaction, which was in agreement with the experimental observations.     

First total synthesis of (+)-viroallosecurinine

The first diastereoselective chiral synthesis of (+)-viroallosecurinine, isolated from Securinega virosa as a cytotoxic alkaloid, was achieved by using a chelation-controlled addition of an alkyne moiety to the corresponding ketone, and a ring-closing metathesis, as key reactions.     

Asymmetric synthesis of macrolactin analogue

Total asymmetric synthesis of macrolactin A analogue was accomplished by the convergent strategy. Rapid access to advanced intermediate 16 through isomerization of ynone to (E,E)-conjugated dienone is a key step of this synthesis. Overall, control of all of the four stereocenters was achieved by means of asymmetric and diastereoselective reactions without using any chiral natural sources.     

Synthesis of Pd complexes bearing an enantiomerically resolved seven-membered N-heterocyclic carbene ligand and initial studies of their use in asymmetric Wacker-type oxidative cyclization reactions

The development of enantiomerically resolved, axially-chiral seven-membered N-heterocyclic carbene (⁷NHC) ligands for palladium is described. These ⁷NHC ligands are derived from enatiomerically pure 2,2′-diamino-6,6′-dimethylbiphenyl, which is transformed via a synthetic sequence consisting of ortho-arylation, N-alkylation, and cyclization to afford seven-membered-ring amidinium salts. Synthesis of the seven-membered amidinium salts benefits from microwave irradiation, and in-situ metalation of the amidinium salts yields ⁷NHC-Pd^II complexes. The chiral ⁷NHC-Pd complexes were examined as chiral catalysts under aerobic conditions in two intramolecular oxidative amination reactions of alkenes. In one case, enantioselectivities up to 63% ee were obtained, while the other substrate underwent cyclization to afford essentially racemic products. The catalytic data compare favorably to results obtained with a Pd^II catalyst bearing a chiral five-membered-ring NHC ligand and, thereby, highlight the potential significance of this new class of chiral NHC ligands.     

Stereoselective synthesis of pachastrissamine (jaspine B)

A stereoselective synthesis in enantiopure form of the natural anhydrophytosphingosine pachastrissamine (jaspine B), a metabolite isolated from sponges, is described. The chiral epoxide (R)-glycidol was the starting material. Key steps of this synthesis are a Sharpless asymmetric epoxidation, an intramolecular stereospecific epoxide opening mediated by a trichloroacetimidate group, and the formation of a tetrahydrofuran ring via intramolecular nucleophilic displacement.     

In situ synthesis of di-n-butyl l-tartrate–boric acid complex chiral selector and its application in chiral microemulsion electrokinetic chromatography

A novel procedure for in situ assembling a complex chiral selector, di-n-butyl l-tartrate–boric acid complex, by the reaction of di-n-butyl l-tartrate with boric acid in a running buffer was reported and its application in the enantioseparation of β-blockers and structural related compounds by chiral microemulsion electrokinetic chromatography (MEEKC) has been demonstrated. In order to achieve a good enantioseparation, the effect of dibutyl l-tartrate and sodium tetraborate concentration, surfactant identity and concentration, cosurfactant, buffer pH and composition, organic modifiers, as well as applied voltage and capillary length were investigated. Ten pairs of enantiomers that could not be separated with only dibutyl l-tartrate, obtained good chiral separation using the complex chiral selector; among them, seven pairs could be baseline resolved under optimized experimental conditions. The fixation of chiral centers by the formation of five-membered rings, and being oppositely charged with basic analytes were thought to be the key factors giving the complex chiral selector a superior chiral recognition capability. The effect of the molecular structure of analytes on enantioseparation was discussed in terms of molecular interaction.     

A practical approach to the fused β-carboline system. Asymmetric synthesis of indolo[2,3-a]indolizidinones via a diastereoselective intramolecular α-amidoalkylation reaction

Fused β-carboline systems, as indolo[2,3-a]indolizidinones, indolo[2,3-a]quinolizidinones, their 2-oxa analogues, and benzo[a]indolo[2,3-a]indolizidinones are prepared efficiently via an RLi addition-N-acyliminium ion cyclisation sequence on readily available imides. In an enantioselective variant of these α-amidoalkylation reactions, the addition of MeLi to a chiral non-racemic imide derived from tryptophan yielded an oxo amide, which was cyclised diastereoselectively upon treatment with BF₃·OEt₂, to afford 5,11b-trans-indoloindolizidinone in moderate yield and high ee (99%).     

Synthesis of chiral imino- and amino-imidazolium salts and of chelating amino-N-heterocyclic carbene palladium(II) complexes

A new preparation of chiral imino-imidazolium salts has been developed by condensation of chiral primary amines with 1-(2-oxo-2-phenyl-ethyl)-imidazolium salts in chloroform. This reaction gave the (E)-imino-imidazolium salts with stereoselectivities superior to 95:5. The structure of the imines were determined by NMR analyses. Reduction of the chiral (E)-imino-imidazolium salts with NaBH₄ in MeOH led to amino-imidazolium salts as a mixture of diastereomers with selectivities ranging from 84:16 to 90:10. The major diastereoisomer could be purified in some cases by crystallization and the absolute configurations were determined by X-ray diffraction. Chelating amino-N-heterocyclic carbene dichloro palladium(II) complexes were obtained in two steps via formation of the corresponding silver(I) complexes and reaction of these latters with bis(acetonitrile)dichloropalladium. Crystal structure details of a cis-dichloro amino-imidazol-2-ylidene palladium complex are presented and confirmed the formation of a six-membered Pd-metallocycle.     

First total synthesis of pro-resolving and tissue-regenerative resolvin sulfido-conjugates

The first total synthesis of the pro-resolving and tissue-regenerative resolvin sulfido-conjugates: 7S,8R,17S-RCTR1, 7S,8R,17S-RCTR2 and 7S,8R,17S-RCTR3, derived from docosahexaenoic acid, has been achieved. Two synthetic approaches are described. Chiral centers 7S and 8R were introduced in both approaches via a chiral pool strategy starting from 2-deoxy-d-ribose. The 17S chiral center was introduced either by a chiral pool strategy or by an enzymatic hydroxylation with lipoxidase. Wittig reactions, selective epoxide formation and epoxide opening with glutathione, l-cysteinylglycine and l-cysteine respectively, were the key steps in the synthesis.     

Synthesis of optically active gem-difluorocyclopropanes through a chemo-enzymatic reaction strategy

The synthesis of a chiral difluorocyclopropane building block has been accomplished using lipase-catalyzed reaction; the prochiral diacetate of cis-1,3-bishydroxymethyl-2,2-difluorocyclopropane was converted to the corresponding chiral monoacetate by the Alcaligenes lipase (lipase QL)-catalyzed hydrolysis with >99% enantiomeric excess. Enantiomerically pure trans-1,3-bishydroxymethyl-2,2-difluorocyclopropane was also obtained through the Pseudomonas cepacia SL-25 lipase (lipase SL)-catalyzed reaction. The synthesis of the chiral trans,trans-bis-gem-difluorocyclopropane derivatives has been accomplished using the same lipase technology; trans,trans-1,6-bishydroxymethyl-2,2,5,5-tetrafluorobicyclopropane was obtained in optically active form using the lipase SL-catalyzed hydrolysis of the corresponding diacetate.