3(1,3-Heterazolidin-3-yl-methyl)-1,3-oxazolidines and their reduction with borane–THF

Preparation of bis-heterazolidines bonded by a CH₂, CH₂–S–CH₂ or CH₂SCH₂SCH₂ groups through their nitrogen atoms is reported: 3-(1,3-oxazolidin-3-ylmethyl)-1,3-oxazolidine 1, 3-(4,4-dimethyl-1,3-oxazolidin-3-ylmethyl)-1,3-oxazolidine 2, 3-(1,3-diazolidin-3-ylmethyl)-1,3-diazolidine 3, 3-(1,3-thiazolidin-3-ylmethyl)-1,3-thiazolidine 4, 3-(1,3-thiazolidin-3-ylmethylsulfanylmethyl)-1,3-thiazolidine 5 and 3-(1,3-oxazolidin-3-ylmethylsulfanylmethyl-sulfanylmethyl)-1,3-oxazolidine 6. The solid state structures of 4 and 5 were determined by X-ray diffraction analyses. BH₃–THF reduction reactions of compounds 1–6 were investigated. N→BH₃ mono- and di-adducts of 1–6 were prepared and their structures calculated (ab initio 3-21G*).     

Copolymerization of cyclic ketene N,O-acetals with phenylisothiocyanate via zwitterionic intermediates

The reaction of 3-methyl-2-methylene-1,3-oxazolidine ( 1a ) and phenylisothiocyanate (PhNCS) gives 3-methyl-2-(phenylthiocarbamoyl)methylene-1,3-oxazolidine ( 3 ) whereas that of 2-isopropylidene-3-methyl-1,3-oxazolidine ( 1b ) and PhNCS gives 1:1 alternating copolymers. It is assumed that the reaction of 1b and PhNCS forms a zwitterionic intermediate ( 2b ), followed by the successive combination of 2b to give 1:1 alternating copolymers 4 and/or 5 . Consequently, it was demonstrated that the copolymerization of 1b and PhNCS proceeds via a zwitterionic mechanism with complete ring-opening to afford the 1:1 alternating copolymer 5 .     

Solid-phase synthesis of 3-aminopyrrole-2,5-dicarboxylate analogues

An efficient strategy has been developed for the solid-phase parallel synthesis of 3-aminopyrrole-2,5-dicarboxylate analogues. A library of twenty-nine 2,3,5-trisubstituted pyrroles has been synthesized on Wang resin by a 5-6 step process. The attachment of (2S,4R)-4-hydroxy-N-(PhF)proline cesium salt (PhF = 9-(9-phenylfluorenyl)) to Wang bromide resin, followed by alcohol oxidation, produced the resin-bound 4-oxo-N-(PhF)prolinate as the pyrrole precursor. Resin-bound 3-aminopyrroles were synthesized by treatment of the oxo-N-(PhF)prolinate resin with different secondary amines and diversified at the 2-position by acylation with trichloroacetyl chloride and haloform reactions with primary amines. 3-Aminopyrrole-2,5-dicarboxylates were isolated in 81-99% purity and 51-99% yields after cleavage from the resin using TFA or sodium methoxide.     

A chiral synthesis of four stereoisomers of 1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline, an inducer of Parkinson-like syndrome

Four stereoisomers of 1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline, an inducer of Parkinson-like syndrome, were synthesized by applying a new method of 1,2,3,4-tetrahydroisoquinoline (TIQ) synthesis utilizing the Pummerer reaction as a key step. The chiral centers at C-1 and C-3 were constructed by two routes starting from alaninol (3) and 1-phenylethylamine (4) as a chiral source. Enantiomerically pure 1,3-dimethyl-TIQs (1R,3S)-(2) [corrected], (1S,3R)-(ent-2) [corrected], (1S,3S)-(1) [corrected], and (1R,3R)-(ent-1) [corrected] were prepared in a stereochemically unambiguous manner from 3 in 11 steps (route I) and from 4 in 6 steps (route II). The conformations of tetrahydroisoquinoline ring in 1-methyl, 3-methyl, and 1,3-dimethyl-TIQs were discussed on the basis of their CD, 1H-NMR spectra, and steric energies.     

Ring-opening Sn2'' reactions of 7-oxanorbornenes by organolithium reagents. Regio- and stereospecific synthesis of substituted cyclohexenediols

The nucleophilic Sn2' bridge opening of 7-oxabicyclo[2.2.1] hept-5-en-2-ols with organolithium reagents occurs in a regio- and stereospecific fashion to produce 6-substituted-cyclohex-4-en-1,3-diols, regardless of the stereochemistry at C-2. A free alcohol functionality is necessary to attain complete regiocontrol of the process. The methodology is utilized to prepare an optically pure cyclohexene derivative, (+)-(1S,3S,6R)-6-n-butyl-3-methyl-cyclohex-4-en-1,3-diol (5b), as a model system.     

Syntheses in enantiopure form of four diastereoisomeric naphthopyranquinones derived from aphid insect pigments

The first syntheses are described of the four enantiopure naphthopyranquinones (1R,3R,4S)- and (1R,3R,4R)-3,4-dihydro-4,7,9-trihydroxy-1,3-dimethylnaphtho[2,3-c]pyranquinone (quinone A 1 and quinone A' 2) and their two C-3 epimers, the (1R,3S,4S)- and (1R,3S,4R)-diastereoisomers 5 and 6, using enantiopure lactate as the source of asymmetry. Key factors in these syntheses are the maintenance of stereochemical integrity throughout the sequences and intramolecular diastereoselective cyclisations of the titanium phenolates of phenolic lactaldehydes. For these cyclisations the differing degree of diastereoselectivity is explained as are the stereochemistries of the product 2-benzopyran-4,5-diols.     

Asymmetric synthesis VII: enantiospecific preparation of β-aminoalcohols from the n-cyanomethyl-4-phenyl-1,3-oxazolidine synthon

(-)-N-cyanomethyl-4-phenyl-1, 3-oxazolidine 1 has been investigated as chiral template for the enantiospecific synthesis of β-aminoalcohols. (-)-2(R)-hydroxy-3(S)-nonylamine 5a was chosen as a target molecule of the new method.     

Structural studies of 1,3-oxazolidine-containing spiropyrans

New 3’-(4-chlorophenyl)-5’,5’-dimethyl-2’-oxospiro[(2H)-chromene-2,4’-1,3-oxazolidine] was synthesized to study the donor influence of the chlorine atom at the N-phenyl substituent on the structure and photochromic properties of 1,3-oxazolidine-containing spiropyrans. Photochemical properties of synthesized 1,3-oxazolidine derivatives were studied at room temperature in toluene. The X-ray diffraction parameters for the new compound were compared with the data obtained earlier for similar spiropyrans.

     

The design and synthesis of a herbicide targeted library of N-[1-(1,3-benzoxazol-2-yl)alkyl]-6-alkyl-1,3,5-triazine-2,4-diamines

Amino acids were immobilised by attaching them via a carbamate linker to Wang resin. These intermediates were converted to 1-(1,3-benzoxazol-2-yl)alkanamines over three steps, followed by coupling with 4-alkyl-6-chloro-1,3,5-triazine-2-amines to furnish the desired N-[1-(1,3-benzoxazol-2-yl)alkyl]-6-alkyl-1,3,5-triazine-2,4-diamines. Physico-chemical property profiles were used to support design and development of a combinatorial library. The synthetic methodology described herein was validated with the production of a herbicide targeted library of 300 members.     

Solution-phase synthesis of a combinatorial library of 3-[4-(coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acid amides

The parallel solution-phase synthesis of a new combinatorial library of 3-[4-(R1-coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acid amides 9 has been developed. The synthesis involves two steps: 1) the synthesis of core building blocks - 3- [4-(coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acids, 6 - by the reaction of 3-(omega-bromacetyl)coumarins 1 with 3-amino(thioxo)methylcarbamoylpropanoic acid (5); 2) the synthesis of the corresponding 3-[4-(coumarin-3-yl)-1,3-thiazol-2-yl- carbamoyl]propanoic acids amides 9 using 1,1'-carbonyldimidazole as a coupling reagent. The advantages of the method compared to existing ones are discussed.     

Development of new calcium receptors based on oxazolidin-2-ones containing pseudopeptides

With the aim of designing a new calcium receptor, the synthesis and the conformational analysis of a small library of dipeptides having the general formula Ac-Oxx-L-Xaa-OBn [Oxx = L-Oxd, (4S,5R)-4-methyl-5-carboxyoxazolidin-2-one; D-Oxd, (4R,5S)-4-methyl-5-carboxyoxazolidin-2-one; or D-Oxac (4R)-(2-oxo-1,3-oxazolidin-4-yl)-acetic acid] is reported. Ac-L-Oxd-L-Ala-OBn was identified as the most promising compound by MS-ESI analysis and this outcome was confirmed by photoluminescence spectroscopy.     

d-生物素的不对称全合成研究(Ⅴ)

以二异丁基氢化铝使(3aS,6aR)-1,3-二苄基-四氢-4H-噻吩并[3,4-d]-咪唑-2,4(1H)-二酮(1)高立体选择性地还原成(3aS,4S,6aR)-1,3-二苄基-4-羟基-四氢-1H-噻吩并[3,4-d]-咪唑-2(3H)-酮(2),再经缩合,Witting烯化成(3aS,6aR)-1,3-二苄基-四氢-1H-噻吩并[3,4-d]咪唑-2(3)-酮-4-烯戊酸(4),后者经催化氢转移还原、脱苄即得d-生物素,以化合物1计算总产率为42%.     

New sphingolipids and a sterol from a lobophytum species of the Indian ocean

Chemical investigation of a soft coral species of the genus Lobophytum has resulted in the isolation of three new sphingolipids--(2S,3S,4R)-2-nonadecanoylamino-octadecane-1,3,4-triol (1), (2S,3R,4E,8E)-[(2'R)-2'-hydroxyheptadecanoylamino]-4,8-octadecadiene-1,3-diol (2), 1-O-(beta-D-glucopyranosyl)-(2S,3R,4E,8E)-2-[(2'R)-2'-hydroxynonadecanoylamino]-9-methyl-4,8-octadecadiene-1,3-diol (3) and a sterol--(24S)-ergost-5-en-3beta,7beta-diol (4) along with the known sphingolipid--(2S,3R,4E,8E)-2-hexadecanoylamino-4,8-octadecadien-1,3-diol (5) which showed cytotoxicity against human peripheral blood mononuclear cells (PBMC).     

Studies on the Syntheses of the Side Chains of Brassinolide and Dolicholide

(4R,5S)-2,2-Dimethyl-4-(1',2'-dimethylpropyl)-5-(1'-bromoethyl)--1,3-dioxolane(15) with the side chain of brassinolide and (4R, 5S)--2, 2-dimethyl-4-(l'-methylene-2'-methylpropyl)-5-(1'-bromoethyl) 1,3-dioxolane(14) with the side chain of dolicholide were first synthesized through 11 and 10 stepes from D-mannitol respectively. All of the intermediates 7-13 were first synthesized too.     

Trimethylsilyl-directed 1,3-dipolar cycloaddition reactions in the solid-phase synthesis of 1,2,3-triazoles

[reaction: see text] A regioselective method for the preparation of 1,5-trisubstituted 1H-1,2,3-triazoles via a 1,3-dipolar cycloaddition of 1-trimethylsilylacetylenes with organoazides is described. Immobilization of the azide on REM resin and subsequent cycloaddition afforded a 2 x 2 x 4 x 3 membered 1,5-disubstituted 1H-1,2,3-triazole library with an average purified yield of 68%.     

A parallel synthesis demonstration library of tri-substituted indazoles containing new antimutagenic/antioxidant hits related to benzydamine

A solution phase strategy for the multiple parallel synthesis of a demonstration library of indazoles is described by which regio-selectivity problems inherent to previous syntheses of this nucleus are largely overcome. Synthesis of selected components proceeded satisfactorily indicating that a fully realized library of indazole analogs could readily be produced using this methodology. Simple modifications of the basic nucleophilic aromatic substitution route unambiguously produce a range of N-1 substitutions (alkyl, aryl and aralkyl) in 50-75% yields. Next a range of substituents was introduced at the C-3 position in 50-80% yields by O-alkylation. Careful choice of reagents and reaction conditions were required to prevent by-product formation due to competing alkylation at N-2 (trace to 15% yields). When present, these contaminants were readily removed by chromofiltration. A third diversity site was sketched in at C-5 in 75-90% yield by reductive alkylation or acylation. Screening of some of the demonstration library members in vitro revealed highly active antioxidants suggesting that producing a full library would be worthwhile.     

替格瑞洛的合成工艺改进

以2-丙硫基-4,6-二氢-5-氨基嘧啶和2-{［(3aR,4S,6R,6aS)-6-氨基-2,2-二甲基四氢-3aH-环戊基［d］［1,3］二氧-4-基］氧}-1-乙醇L-酒石酸盐为原料,经C-N偶联,亲核取代和环合反应制得2-{［(3aR,4S,6R,6aS)-6-(7-氯-5-丙硫基-3H-［1,2,3］三唑［4,5-d］嘧啶-3-基)-2,2-二甲基四氢-3aH-环戊基［d］［1,3］二氧-4-基］氧}-1-乙醇(4); 4与(1R,2S)-2-(3,4-二氟苯基)环丙胺D-扁桃酸盐经亲核取代反应后酸解脱除丙酮叉保护基合成替格瑞洛,总收率58.7%,纯度99.2%,其结构经¹H NMR, MS(ESI)和XRD确证。     

Synthesis of (R)-(+)-tanikolide through stereospecific C-H insertion reaction of dichlorocarbene with optically active secondary alcohol derivatives

Stereospecific alpha C-H insertion reaction of protected chiral 1,2-glycols, (S)-1,2-isopropylidenedioxytridecane (3) and ethyl (S)-4,5-isopropylidenedioxy-pentanoate (4), prepared from (R)-glyceraldehyde acetonide (2), with dichlorocarbene generated from CHCl(3)/50% NaOH/cetyltrimethylammonium chloride (as ptc.) took place with complete retention of configuration to provide (S)-4-dichloromethyl-2,2-dimethyl-4-undecyl-1,3-dioxolane (5) and ethyl (S)-3-(4-dichloromethyl-2,2-dimethyl-1,3-dioxolan-4-yl)-propanoate (8), respectively. The ester (8) was transformed to 5 by elongation of the side chain. The glycol derivative (5) was converted into O-TBDPS-protected (S)-2-hydroxymethyl-2-undecyloxirane (16). Reaction of 16 with a cuprate reagent containing homoallylic carbon chain followed by oxidative manipulation of the terminal olefin afforded (R)-(+)-tanikolide (1).     

The reaction of 4-amino-2-oxazolines with isocyanates and isothiocyanates. Synthesis and X-ray structures of polysubstituted 2-imidazolidinones, 1,3-oxazolidines and 1,3-thiazolidines

Reactions of 4-alkylamino-2-phenyl-2-oxazolines 1 with isocyanates and isothiocyanates provide unprecedented efficient and regioselective heterocycle-heterocycle transformations. Compounds 1 reacted rapidly with tosyl isocyanate yielding directly 3-alkyl-4-benzamido-1-tosyl-2-imidazolidinones 4 in almost quantitative yields. The corresponding ureido intermediates 2 were not isolable species. However, the reactions with non-sulfonylated isocyanates or isothiocyanates were slower, leading to the expected ureido and thioureido derivatives 5, which were easily and efficiently transformed to either polysubstituted 2-imino-1,3-oxazolidine or 2-imino-1,3-thiazolidine hydrochlorides 7, respectively, by treatment with hydrochloric acid. The possible reasons for this disparity in chemical behaviour are discussed. X-ray crystallographic structures for 4-benzamido-3-methyl-1-tosyl-2-imidazolidinone 4b, 4-[1-isopropyl-3-(4-nitrophenyl)ureido]-2-phenyl-2-oxazoline 5e, (Z)-3-benzyl-4-benzamido-2-phenylimino-1,3-oxazolidine hydrochloride 7a and (Z)-3-benzyl-4-benzamido-2-phenylimino-1,3-thiazolidine hydrochloride 7b have been determined.     

Synthesis and stereochemistry of new 1,3-thiazolidine systems based on 2-amino-2-(mercaptomethyl)propane-1,3-diol: 4,4-bis(hydroxymethyl)-1,3-thiazolidines and c-5-hydroxymethyl-3-oxa-7-thia-r-1-azabicyclo[3.3.0]octanes

The thiaminalisation of 2-amino-2-(mercaptomethyl)propane-1,3-diol [‘2-(hydroxymethyl)cysteinol’] with aryl(di)aldehydes is reported. The resulting new class of 2-aryl-4,4-bis(hydroxymethyl)-1,3-thiazolidines is investigated by NMR and IR spectroscopy in tandem with DFT calculations, permitting structural assignments that are discussed in terms of conformational analysis, anomeric effects and ring-chain tautomerism. These acquired data are subsequently exploited. After treatment with formaldehyde, the subsequent (double) regio- and diastereoselective oxaminalisation of the 1,3-thiazolidine building-block affords the first non-symmetric series of a thiazolidin-oxazolidine fused system singly functionalised at the C-5 position. An unexpected rearrangement, which consists of the partial relocation of the Ar ligand from the 1,3-thiazolidine to the 1,3-oxazolidine ring, is observed as a major influence on the substitution of the Ar ring. The first single crystal X-ray analysis of the title bicyclic system, which discloses the homo- and/or heterochiral non-bonding interactions, is also presented.