A concise and general methodology for the complete asymmetric synthesis of the orthogonally protected 2-amino-1,3,4-butanetriols (ABTs)

A complete asymmetric synthesis of the orthogonally protected 2-amino-1,3,4-butanetriols I (ABTs: versatile four carbon chiral synthons) was accomplished via the regioselective asymmetric aminohydroxylation (AA) reaction and oxazoline chemistry in four to six steps from the starting olefin 1. The syn-vicinal amino alcohol functionality of I was installed by the regioselective AA reaction of the achiral olefin 1 in a single step, and the anti-vicinal amino alcohol functionality of I was derived from the syn-amino alcohol 2 by inverting the C2 hydroxy group stereochemistry through the formation and hydrolysis of the oxazoline 7. Thus, the present strategy represents the most efficient and general asymmetric synthesis of ABTs so far.     

Synthesis of the C(1)-C(16) fragment of bryostatins using an ‘ene’ reaction between an allylsilane and an alkynone

The zinc(II) iodide mediated ‘ene’ reaction between (4R)-4,5-bis-(tert-butyldimethylsilyloxy)-2-(trimethylsilylmethyl)pent-1-ene (43) and (5S,7R,9S)-5,11-dibenzyloxy-4,4-dimethyl-7,9-dihydroxy-7,9-O-isopropylideneundec-1-yn-3-one (53) gave the (E)-vinylsilane 54 with excellent stereoselectivity. Simultaneous deprotection and cyclisation via a stereoselective oxy-Michael reaction gave the bicyclic acetal 57 after treatment with trimethyl orthoformate. A synthesis of the ester 60 corresponding to the C(1)-C(16) fragment of the bryostatins was then completed by O-silylation, oxidative cleavage of the methylene group and a stereoselective condensation of the resulting ketone 59 with the chiral phosphonate 61.     

A novel and practical synthetic route for the total synthesis of lycopene

A novel route for the total synthesis of lycopene 1 is described. The synthesis is based on: (i) a condensation between 4,4-dimethoxy-3-methylbutanal 4 and methylenebisphosphonic acid tetraethyl ester 5, leading to the C6-phosphonate 6, followed by (ii) a modified Wittig-Horner reaction between 6 and 6-methyl-5-hepten-2-one 7 producing dimethoxy-3,5,9-triene 8, and (iii) another modified Wittig-Horner reaction between C15-phosphonate 2 and C10-triene dialdehyde 3 producing all-E-lycopene. The synthetic steps are easily operated and practical for the large-scale production.     

Chiral biomimetic NADH models in the benzo[b]-1,6-naphthyridine series. A novel class of stable, reactive and highly enantioselective NADH mimics

The preparation of a new class of tricyclic models 1 based on a Friedländer reaction between chiral piperidine-2,4-diones 2 and azomethine 3 is reported. Alkylation of the lactam allowed to install various pendant arms on the chiral cyclic inducer. The so-obtained mimics 1a,d,f,g,h,k were involved in the reduction of methyl benzoylformate to furnish methyl mandelate in 4-87% ee (R). The presence of a coordinating pendant arm proved to be essential to reach optimum results in terms of enantioinduction. Asymmetric reduction of 2-benzoylpyridine with mimics 1d,f,g produced α-phenyl-2-pyridinemethanol in 30-84% ee (R).     

An efficient construction of bridged chiral tetracyclic indolidines, a core structure of asperparaline, via stereocontrolled catalytic Pauson-Khand reaction

A reaction of chiral enyne 22 derived from l-proline with a catalytic amount of cobalt (0) octacarbonyl in the presence of N-methylmorphorine N-oxide gave tricyclic enone 24 in 54% yield (73% based on consumed starting material). Treatment of enone 11 with aqueous methylamine followed by silica gel afforded bridged tetracyclic indolidine 1, a common structural motif of natural metabolites, an asperparaline series of compounds and also a potential intermediate for the synthesis of a paralytic alkaloid, asperparaline C (4), in 70% yield.     

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.     

Solid state-specific and chiral lattice-controlled asymmetric photoisomerization of 3-substituted propyl cobalt complexes, and direct observation of the intermediate complex

Solid state-specific and chiral lattice-controlled asymmetric photoisomerization of 3-cyanopropyl cobaloxime complexes coordinated with chiral axial ligand, 1a-h, was found to occur with moderate to relatively high enantioselectivities (∼91%ee), even though the reaction proceeds through radical species. The enantioselectivities at a lower temperature (−78 °C) are extremely enhanced as compared to those at room temperature, in most cases.The configuration of the major enantiomer of the isomerized product is predictable from the shape of the reaction cavity, drawn based on the crystal structure of the starting material. The structure (including absolute configuration) of the intermediate 2-cyanopropyl complex was directly observed by X-ray crystallographic analyses of a single-crystal-to-single-crystal reaction of (S)-1-cyclohexylethylamine-coordinated 3-cyanopropyl cobaloxime, 1e.     

Highly enantioselective synthesis and potential biological activity of chiral novel nucleoside analogues containing adenine and naturally phenol derivatives

This paper described an efficient synthetic strategy for chiral acyclic nucleoside analogues containing both the phenoxy components of some bioactive natural compounds and a heterocyclic base. The phenoxy components with adenine moiety were incorporated into the chiral acyclic nucleoside analogues through two key synthetic tactics. Chiron 5-(R)-menthyloxy-2(5H)-furanone 5 was obtained in good yield from the cheap starting material furfural via a valuable synthetic route. The asymmetric Michael addition of 5 with adenine and the subsequent reduction reaction afforded the key chiral intermediate, 2-(R)-(9′-adeninyl)-1,4-butanediol 8. The absolute configuration of 8 was established by X-ray crystallography. The intermolecular dehydration reaction between 2-(9′-adeninyl)-1,4-butanediol 8 and phenoxy components 9 on treatment with diethyl azodicarboxylate and triphenylphosphine was carried out to give the chiral acyclic nucleoside analogues 1a-1e. The regioselectivity of the reaction was established by NMR methods, especially through ¹³C NMR shifts and NOE effect observed in the target molecule 1c, as well as by HMBC/HMQC experiments. The target compounds were tested for inhibition of cytopathogenicity against different cancer cells and exhibited potential anticancer activity.     

The enantioselective high-pressure Diels-Alder reaction of 1-methoxybuta-1,3-diene with tert-butyldimethylsilyloxyacetaldehyde catalyzed by (salen)Co(II) and (salen)Cr(III)Cl complexes

The high-pressure (10-11 kbar) reaction of 1-methoxybuta-1,3-diene (1) with tert-butyldimethylsilyloxyacetaldehyde (2), catalyzed by the chiral (salen)Co(II) 4 or (salen)Cr(III)Cl 5 complexes, has been studied. We found that the reaction afforded, in good yield (up to 90%) and both with very good diastereoselectivity (up to 92%) and enantioselectivity (up to 94% ee), the [4 + 2]cycloadducts 3, which are compounds of significant synthetic interest.     

Investigations of the stereoselectivity of the intramolecular Diels-Alder reaction of a spiculoic acid model system

Model linear precursors to the spiculoic acids were prepared and underwent thermally induced IMDA reactions. The configuration of C5 in the stereotriad was found to dominate any inherent endo/exo selectivity of the IMDA reaction. The isomer (2E,5S)-20 underwent the IMDA to give the spiculoic acid stereochemistry in 84% yield and 94% ds. The required stereotriads were synthesised using stereoselective substrate-controlled aldol reactions; an anti-boron aldol reaction, controlled by the π-facial preference of (S)-2-benzoyloxypentan-3-one ((S)-27) led to (5R)-(22) and a syn-titanium aldol reaction, under the stereocontrol of a chiral N-acylthiazolidinethione (42) led to (5S)-(22). Chain extension using standard Wittig, HWE and ‘modified’ Julia olefinations installed the diene and dienophile components giving the linear precursors to the IMDA reactions.     

A substrate controlled, very highly diastereoselective Morita-Baylis-Hillman reaction: a remote activation of the diastereofacial selectivity in the synthesis of C-3-branched deoxysugars

The Morita-Baylis-Hillman (MBH) reaction of p-nitrobenzaldehyde with C (6) acyl protected enuloside 1 in the presence of TiCl₄/TBAI yielded highly diastereoenriched C-3-branched deoxysugar derivative or MBH adduct 1′a in high yield, while reactions of unprotected enuloside 2a and C (6) alkyl protected enulosides 2d-e with p-nitrobenzaldehyde under the same conditions afforded the adducts 2′a and 2′d-e, respectively, in low yield with moderate selectivity. Several representative aromatic and aliphatic aldehydes were selected to undergo MBH reaction with 1 to give their respective adducts in very good yield with a very high diastereoselectivity. A plausible mechanism based on the assumption of a Zimmerman-Traxler-type transition state was proposed to explain the excellent selectivity observed with adducts derived from 1. The synthetic application of these adducts were shown by their stereoselective reduction to corresponding threo isomers in very good yield.     

Synthesis of novel C2-symmetric chiral crown ethers and their application to enantioselective trifluoromethylation of aldehydes and ketones

Synthesis of novel C2-symmetric chiral crown ethers and their application to enantioselective trifluoromethylation of aldehydes and ketones are discussed. The use of a series of C2-symmetric chiral crown ethers 2 or 3 derived from commercially available (R)-1,1′-bi-2-naphthol for the enantioselective trifluoromethylation of 2-naphthyl aldehyde 1a with (trifluoromethyl)trimethylsilane in the presence of a base was attempted. Iodo-substituted crown ether 2b was found to be the most effective in the model reaction. Moderate enantioselectivities were observed for the trifluoromethylation of both aryl or alkyl aldehydes and alkyl aryl ketones in 21-44% ees. Although the ees are still improvable, this is the first example of a chiral crown ether-catalyzed enantioselective trifluoromethylation reaction.     

A concise approach to (+)-1-epi-castanospermine

A concise enantioselective synthesis of (+)-1-epi-castanospermine (2) is described, which featured the use of chiral non-racemic tetramic acid derivative 5 as a synthetic equivalent of the challenging synthon A through a highly diastereoselective vinylogous Mukaiyama type reaction.     

Synthesis and characterization of a novel chiral azomethine diselenide

The first chiral diselenide 9 having an ortho-azomethine functional group has been synthesized by the reaction of bis(o-formylphenyl) diselenide with the chiral amine R(+)-(1-phenylethylamine). The chiral diselenide 9 was further characterized by derivatizing it into the corresponding selenenyl halides. The derivatives are characterized by single crystal X-ray diffraction studies. In the solid state, the bromide derivative 11 shows the strongest Se?N intramolecular interaction. The chiral azomethine diselenide 9 has been further reduced to afford the diselenide 13. The monoselenide analogues of 9 and 13 have also been synthesized.     

Stereospecific synthesis of chiral tertiary alkyl-aryl ethers via Mitsunobu reaction with complete inversion of configuration

Mitsunobu reaction of chiral tertiary alcohol (S)-2 with phenol 3 provides the desired ether (R)-1 in moderate yields at elevated temperatures (80-100°C). The S_N2 displacement pathway is evident by complete inversion of the (S)-alcohol to (R)-ether.     

Efficient and regioselective chromium(0)-catalyzed reaction of 2-substituted furans with diazo compounds: stereoselective synthesis of (2E,4Z)-2-aryl-hexadienedioic acid diesters

Pentacarbonyl(η²-cis-cyclooctene)chromium(0) (1) catalyzes efficiently reactions of diazo compounds with electron-rich furans. The reaction of 2-methoxyfuran (2) with alkyl α-diazoarylacetate (3a-g) furnishes the (2E,4Z)-2-aryl-hexadienedioic acid diesters (4a-g) in excellent yields. These reactions are highly regioselective. The cyclopropanation intermediates formed from 1 and diazo compounds 3a-g always arise from a carbene addition to the less substituted CC bond of 2. The resulting cyclopropanation product undergoes a ring opening reaction to form the corresponding (2E,4Z)-2-aryl-hexadienedioic acid diesters (4a-g). The pentacarbonylchromium(0)-catalyzed reactions of 2-alkylfuran (5a-b) with ethyl α-diazophenylacetate (3a) and 9-diazo-9H-fluorene (3h) produce the 1(E),3(E)-butadienes (6a-d) in very good yields.     

Domino routes to substituted benzoindolizines: tandem reorganization of 1,3-dipolar cycloadducts of nitrones with allenic esters/ketones and alternative cycloaddition-palladium catalyzed cyclization pathway

Reactions of C-(4-oxo-4H[1]benzopyran-3-yl)-N-phenyl nitrones (7) with allenic esters (8a-c) and allenic ketones (18a-d) furnish benzoindolizines (9a-k, 19a-d) in good yields. The formation of benzoindolizines is postulated to involve regioselective addition of 1,3-dipole to C2-C3 π bond of allenic esters/ketones followed by domino transformation of the cycloadducts, which involve an intramolecular aza Diels-Alder reaction in the intermediate C. DFT calculations of various parameters for diene and dienophile components in the proposed intermediate C have revealed that conformational constraints imposed by the alkyl groups (R=Me, Et) favor intramolecular aza-Diels-Alder cycloaddition. An alternative domino route to benzoindolizines (9a,d,g) involving sequential one-pot cycloaddition of azadienes (22a-c) with silyl-enol ether (23) followed by palladium(0)-catalyzed Heck coupling reaction has also been developed. Both these approaches represent novel domino routes for the synthesis of benzoindolizines.     

Pd-catalyzed boronations and cross-coupling reactions of aromatic cobaltadithiolene complexes with aryl halides

The Pd-catalyzed reaction of [CpCo(S2C2(Ph)(Bpin))] (1, Bpin = 4,4,5,5-tetramethyl-1,3,2-dioxaboronate) with 1-iodonaphthalene or 2-bromothiophene gave the cross-coupling product [CpCo(S2C2(Ph)(Ar))] (Ar = 1-Np (4) or 2-Th (5)), although an early paper described the reaction of 1 with 3-bromopyridine or 9-bromoanthracene (Ar = 3-Py (2) or 9-Anth (3)). The boronation of the brominated precursor [CpCo(S2C2(p-C6H4Br)(H))] (7) with Bpin-H in the presence of Pd catalyst gave the expected boronated product [CpCo(S2C2(p-C6H4Bpin)(H))] (8) but also underwent an unexpected direct boronation on the dithiolene carbon to form [CpCo(S2C2(p-C6H4Br)(Bpin))] (9). The brominated complex 7 or [CpCo(S2C2(Ph)(p-C6H4Br))] (10) was synthesized by thermal reaction and the microwave-enhanced reaction relatively gave better yield with shorter reaction time than that of the conventional heating reaction. The cross-coupling reactions of the boronated or [CpCo(S2C2(Ph)(p-C6H4Bpin))] (11) with aryl halides successfully produced the corresponding cross-coupling products such as [CpCo(S2C2(p-C6H4Py)(H))] (12) or [CpCo(S2C2(p-C6H4Anth)(H))] (13) from 8 and [CpCo(S2C2(Ph)(p-C6H4Py))] (14) from 11. The structures of 7, 9, 11, 12, 13 and 14 were determined by X-ray diffraction studies. Electronic absorption maxima (λ_max) due to dithiolene LMCT in dichloromethane solution can be modified in the range of 574-602 nm by a substituent effect on the dithiolene ring. Redox potentials obtained from CV measurement were also reported.     

Conformational chirality and chiral crystallization of N-sulfonylpyrimidine derivatives

New N-sulfonylpyrimidine derivatives 1-(p-toluenesulfonyl)uracil (1), 1-(p-toluenesulfonyl)thymine (2), 5-bromo-1-(p-toluenesulfonyl)uracil (3), 1-(methanesulfonyl)uracil (4), 1-(1-naphthylsulfonyl)uracil (5), and 1-(1-naphthylsulfonyl)thymine (6) were prepared by the condensation reaction of silylated pyrimidine derivatives with selected sulfonyl chlorides in acetonitrile. Some members of the series showed unexpected crystal properties as a consequence of their conformational chirality in the solid state. Compounds 1 and 5 exhibited chiral crystallization, which was, in the case of 1, accompanied by the formation of racemically twinned crystals regardless of the solvent used, while 5 gave a conglomerate of enantiomorphous crystals. For 2, 3, and 6, substituents at the C-5 position of the pyrimidine ring prevented chiral crystallization by influencing the crystal packing. Analysis of the crystal structures of 1, 4, and 5, reveals the influence of the arylsulfonyl group on the occurrence or absence of chiral crystallization.     

Inherently chiral calix[4]arene-based bifunctional organocatalysts for enantioselective aldol reactions

Two optical pure m-dimethylamino substituted inherently chiral calix[4]arene derivatives 8a and 8b bearing an l-prolinamido group have been synthesized by two routes, and structurally studied by the usual spectroscopic methods and X-ray crystallographic analysis. It was found that both of 8a and 8b could be utilized as bifunctional organocatalysts to efficiently promote the aldol reactions between aromatic aldehydes and ketones in the presence of acetic acid. Especially, with 8a as the catalyst, the reaction between 4-nitrobenzaldehyde and cyclopentanone at −20 °C gave the anti-aldol product up to 94% ee, while the anti-aldol product in up to 94:6 dr and 79% ee was obtained when 4-cyanobenzaldehyde was used as the aldol donor. Moreover, it was also demonstrated that the inherently chiral calixarene skeleton with (cS)-conformation in 8a was identified as the matched configuration of the stereogenic elements, and the inherently chiral moiety might play an important role in helping to stereocontrol the reaction.