Absolute structures of some naturally occurring isopropenyldihydrobenzofurans,remirol, remiridiol,angenomalin, and isoangenomalin

The absolute structures of some naturally occurring chiral 2-isopropenyl-2,3-dihydrobenzofurans, (+)-remirol (1a), (+)-remiridiol (1b), (+)-angenomalin (2), and (+)-isoangenomalin (3), were studied by respective chiral synthesis. Kinetic resolutions of racemic 2-isopropenyl-2,3-dihydrobenzofurans, 2-isopropenyl-4,6-dimethoxy-2,3-dihydrobenzofuran (4), 4-hydroxy-2-isopropenyl-2,3-dihydrobenzofuran-5-carbaldehyde (8), and 2-isopropenyl-6-(MOM)oxy-2,3-dihydrobenzofuran-5-carbaldehyde (11c), by Sharpless dihydroxylation using (DHQ)(2)AQN or (DHQD)(2)AQN gave the corresponding chiral 2-isopropenyl-2,3-dihydrobenzofurans. Chiral (S)-(+)-4 (99% ee, using (DHQD)(2)AQN) was converted to natural remirol (S)-(+)-1a and then to natural remiridiol (S)-(+)-1b. (S)-(+)-8 (97% ee, using (DHQD)(2)AQN) was converted to natural angenomalin (S)-(+)-2. (R)-(-)-11c (>99% ee, using (DHQ)(2)AQN), was converted to natural isoangenomalin (R)-(+)-3. Thus, the absolute structures of natural remirol (+)-1a and remiridiol (+)-1b and angenomalin (+)-2 were determined to be S, and the structure of natural isoangenomalin (+)-3 was R.     

Synthesis and characterization of some new C2 symmetric chiral bisamide ligands derived from chiral Feist's acid

The hemilabile chiral C2 symmetrical bidentate substituted amide ligands (1R,2R)-5(a-d) and (1S,2S)-6(a-d) were synthesized in quantitative yield from (1R,2R)-(+)-3-methylenecyclo-propane-1,2-dicarboxylic acid (1R,2R)-3 and (1S,2S)-(-)-3-methylene-cyclopropane-1,2-dicarboxylic acid (1S,2S)-3, in two steps, respectively. The chiral Feist's acids (1R,2R)-3 and (1S,2S)-3 were obtained in good isomeric purity by resolution of trans-(±)-3-methylene-cyclopropane-1,2-dicarboxylic acid from an 8:2 mixture of tert-butanol and water, using (R)-(+)-α-methylbenzyl amine as a chiral reagent. This process is reproducible on a large scale. All these new synthesized chiral ligands were characterized by 1H-NMR, 13C-NMR, IR, and mass spectrometry, as well as elemental analysis and their specific rotations were measured. These new classes of C2 symmetric chiral bisamide ligands could be of special interest in asymmetric transformations.     

2-chloro-(4R,5R)-bis[(1R,2S,5R)-menth-1-yloxycarbonyl)]-1,3,2-dioxaphospholane: a practical chiral pool-derived reagent for determining enantiomeric purity of alcohols

2-Chloro-(4 R,5 R)-bis[(1 R,2 S,5 R)-menth-1-yloxycarbonyl)]-1,3,2-dioxaphospholane is a practical reagent for reliably determining enantiomeric purity of chiral alcohols via (31)P NMR spectroscopy. The compound is available as a crystalline solid on a 20 g scale from PCl 3 and bis[(1 R,2 S,5 R)-menth-1-yl] tartrate. It is comparatively inert toward spontaneous hydrolysis under conventional laboratory conditions but undergoes quantitative substitution of alkoxide for chloride if treated with a chiral alcohol. Nonequivalent (31)P NMR signals of diastereomeric 2-alkoxy-1,3,2-dioxophospholanes were dispersed by approximately 1.4-0.1 ppm. The associated integral ratios reflected enantiomeric purities of preweighted samples of ( R)- and ( S)-1-phenylethanol, (+)- and (-)-menthol, and a set of primary, secondary, and tertiary alcohols with a precision of +/-0.4-1.0%.     

对映体纯1-甲基-7-氧杂双环[2.2.1]庚烷-2-酮的制备

1-甲基 - 7-氧杂双环 [2 .2 .1 ]庚烷 - 2 -酮 ( 1 )是萜类天然产物全合成中的重要中间体 ,能被广泛地应用于多种桉烷 ( Eudesmane)、沉香呋喃 ( Agarofuran)和降胡萝卜素 ( Norcarotenoids)等倍半萜天然产物的全合成[1,2 ] .我们以对映体纯化合物 1为原料 ,实现这类天然产物的不对称全合成 [3～ 6 ] .消旋的化合物 (± ) - 1可以 2 -甲基呋喃和 2 -氯丙烯腈为原料 ,经 3步反应得到 [2 ] .但对映体纯化合物 1的制备尚未见报道 .本文用化学拆分方法 ,成功地制备了对映体纯的 ( + ) - 1和 ( - ) - 1 ,并确定了其绝对构型 .1　结果与讨论为减…     

One-handed helical screw direction of homopeptide foldamer exclusively induced by cyclic α-amino acid side-chain chiral centers

Chiral cyclic α,α-disubstituted amino acids, (3S,4S)- and (3R,4R)-1-amino-3,4-(dialkoxy)cyclopentanecarboxylic acids ((S,S)- and (R,R)-Ac(5)c(dOR); R: methyl, methoxymethyl), were synthesized from dimethyl L-(+)- or D-(-)-tartrate, and their homochiral homoligomers were prepared by solution-phase methods. The preferred secondary structure of the (S,S)-Ac(5)c(dOMe) hexapeptide was a left-handed (M) 3(10) helix, whereas those of the (S,S)-Ac(5)c(dOMe) octa- and decapeptides were left-handed (M) α helices, both in solution and in the crystal state. The octa- and decapeptides can be well dissolved in pure water and are more α helical in water than in 2,2,2-trifluoroethanol solution. The left-handed (M) helices of the (S,S)-Ac(5)c(dOMe) homochiral homopeptides were exclusively controlled by the side-chain chiral centers, because the cyclic amino acid (S,S)-Ac(5)c(dOMe) does not have an α-carbon chiral center but has side-chain γ-carbon chiral centers.     

Chiral amines as reagents for HPLC-MS enantioseparation of chiral carboxylic acids

Mass spectrometry (MS) has become a popular analytical technique because of its high sensitivity and specificity. Therefore, the use of a chiral derivatization reagent for the MS detection seems to be efficient for the enantiomeric separation of racemates. However, the number of chiral reagents for the liquid chromatography (LC)-tandem mass spectrometry (MS/MS) analysis is very limited. The applicability of commercially available chiral amines as the derivatization reagents for the enantiomeric separation of chiral carboxylic acids is reported in this paper by using non-steroidal anti-inflammatory drugs (NSAIDs), i.e. ibuprofen, flurbiprofen, and loxoprofen. The efficiency of the chiral reagents was evaluated in terms of tagging easiness, separation by reversed-phase chromatography, and detection sensitivity by electrospray ionization (ESI)-MS/MS. Among the tested eight chiral amines, i.e. (R)-(+)-4-(3-aminopyrrolidin-1-yl)-7-(N,N-dimethylaminosulfonyl)-2,1,3-benzoxadiazole (DBD-APy), (S)-(+)-1-(2-pyrrolidinylmethyl)-pyrrolidine (PMP), L-prolinamide, (3R)-(-)-1-benzyl-3-aminopyrrolidine, (S)-(+)-1-cyclohexyl-ethylamine, (3R)-(+)-3-(trifluoroacetamido)-pyrrolidine (TFAP), (R)-(-)-1-aminoindan (AI), and (S)-(+)-tetrahydrofurfuryl-amine, DBD-APy, PMP, AI, and TFAP could be used as the chiral reagents for the enantiomeric separation of the NSAIDs. The Rs values and the detection limits of the derivatives were in the range of 1.29-3.85 and 0.57-0.96 fmol, respectively. These four reagents were applied for the determination of the NSAIDs in rat plasma.     

Stereoselective Synthesis and Complexation of a New Chiral Hybrid Phosphine-Phosphine Oxide Ligand from (S)-(+)-Prolinol

Abstract

The synthesis and the complex formation of chiral heterotopic ligands with two different binding sites each capable of bonding a different type of metal are described. The action of bis(dimethylamino) aryl phosphine on (S)-(+)-prolinol gives rise to the kinetic stereoisomer (2S,4S)-2-phenyl-1,3,2-oxazaphospholidine 1 and the thermodynamic stereoisomer (2R,4S)-2-phenyl-1,3,2-oxazaphospholidine 2. 1 is then totally converted into 2 at the end of the reaction. The Michaelis Arbuzov reaction of 2 with benzylbromide affords (R_p)-benzylaryl-(2-(S)-bromomethyl pyrrolidine-1-yl) phosphine oxide 3 in 80% yield. Compound 3 is an ideal chiral precursor for the synthesis of chiral hybrid phosphine-phosphine oxide ligands. The bromide atom is smoothly displaced by lithium diphenylphosphide to afford in 80% yield (R_p)-benzylaryl-(2-(S)-diphenylphosphinomethylpyrrolidine-1-yl) phosphine oxide 5. These reaction are proved to be totally stereoselective : the Michaelis Arbuzov reaction does not change the configuration at C2 in the proline ring. The relative configuration (R_p) of 5 (aryl = phenyl) was determinated by X-ray diffraction, from the known configuration of (S)-(+)-prolinol.     

Chiral N-alkyl-2,4,6-triphenylpyridiniums as enantioselective triplet photosensitizers. laser flash photolysis and preparative studies

Three N-alkylpyridinium photosensitizers having chiral alkyl groups have been prepared by reacting 2,4,6-triphenylpyrylium tetrafluoroborate ion with (1R,2S)-(-)-norephedrine, (S)-(+)-2-(aminomethyl)pyrrolidine, and (R)-(-)-1-cyclohexylethylamine. Laser flash photolysis allows detection of the corresponding triplet excited states that are quenched by hydrogen atom donors and electron donors. Asymmetric quenching of the chiral triplet excited state was observed using enantiomerically pure 1,2-diamino cyclohexane as quencher. Low enantiomeric excess values (up to 7%) were measured for the photochemical cyclization of 5-methyl-4-hexenoic acid to its corresponding gamma-lactone using these chiral N-alkylpyridinium as photosensitizers.     

Diastereoselective hydroxylation of 6-substituted piperidin-2-ones. An efficient synthesis of (2S,5R)-5-hydroxylysine and related alpha-amino acids

The synthesis of (2S,5R)-5-hydroxy-6-oxo-1,2-piperidinedicarboxylates (5) and related (3S,6R)-3-hydroxy-6-alkyl-2-oxo-1-piperidinecarboxylates has been developed. The approach is based on the asymmetric hydroxylation of enolates generated from the corresponding N-protected-6-substituted piperidin-2-ones. The utility of 5a as a precursor in the synthesis of (2S,5R)-5-hydroxylysine (1), an amino acid unique to collagen and collagen-like proteins, has also been demonstrated. (2S)-6-oxo-1,2-piperidinedicarboxylates (6) required for hydroxylation studies were prepared in 38-74% yield, starting from conveniently protected aspartic acid as inexpensive chiral adduct. Hydroxylation of 6 to 5 proceeds in high yield and excellent diastereoselectivity by treatment of their Li-enolate with (+)-camphorsulfonyloxaziridine at -78 degrees C. Ring opening of di-tert-butyl (2S,5R)-6-oxo-1,2-piperidinedicarboxylate ((5R)-5a) under reductive conditions afforded the corresponding 1,2-diol (17) in 91%, which was further transformed to (2S,5R)-5-hydroxylysine in four steps (84%). 17 is also a versatile intermediate in the preparation of tert-butyl (2S,5R)-2-[(tert-butoxycarbonyl)amino]-5-hydroxy-6-iodohexanoate (3) and tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-[(2R)-oxiranyl]butanoate (4), two amino acid derivatives used in the total synthesis of the bone collagen cross-link (+)-pyridinoline (2a).     

手性双二茂铁基配体的合成、表征及固体CD光谱

以甲酰基二茂铁(1)和手性1,2-二苯基乙二胺[(1R, 2R)-1,2-二苯基乙二胺(2R), (1S,2S)-1,2-二苯基乙二胺(2S)]为原料, 经缩合、还原和N-烷基化反应, 制备了一对新型手性四齿双二茂铁基配体[N,N’-二(二茂铁基甲基)-N,N’-二(2-羟基丙基)-(1R,2R)-1,2-二苯基乙二胺(5R)和N,N’-二(二茂铁基甲基)-N,N’-二(2-羟基丙基)-(1S,2S)-1,2-二苯基乙二胺(5S)]. 用元素分析、红外(IR)、质子核磁共振(1H NMR)、紫外-可见(UV-Vis)、固体圆二色(CD)光谱等对手性产物(3R-5S)进行了表征. 固体CD光谱研究表明, 配体5R(或5S)的手性特征和4R(或4S)相似而与3R(或3S)却有一定差别.     

Synthetic studies of the HIV-1 protease inhibitive didemnaketals: stereocontrolled synthetic approach to the key mother spiroketals

The stereocontrolled synthesis of (2S,4R,6R,8S,10S,1'R,1' 'R)-2(acetylhydroxymethyl)-4,10-dimethyl-8(isopropenylhydroxymethyl)-1,7-dioxaspiro[5,5]undecane (4a) and its C1' '-epimer (4b), the key mother spiroketals of the HIV-1 protease inhibitive didemnaketals from the ascidian Didemnum sp., has been carried out through multisteps from the natural (R)-(+)-pulegone, which involved the diastereoselective construction of four chiral carbon centers(C-2, C-6, C-8, and C-1') by intramolecular chiral induce.     

Chemoenzymatic synthesis of (+)-alpha-polypodatetraene and methyl (5R,10R,13R)-labda-8-en-15-oate

The reported enzymatic resolution products {acetate of (1S,4aS,8aS)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal} (8aS)-5 (>99% ee)] and [(1R,4aR,8aR)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal (8aR)-4 (98% ee) were converted to (+)-alpha-polypodatetraene (1) and methyl (5R,10R,13R)-labda-8-en-15-oate (2), respectively. For the synthesis of (5R,10R,13R)-2, chiral isoprene congener (3S)-26 corresponding to the right part of 2 was synthesized based on the lipase-assisted resolution of (+/-)-2-methyl-3- (p-methoxyphenyl)propanol (17).     

Ketopinic acid and diisoproylideneketogulonic acid as chiral ion-pair selectors in capillary electrophoresis. Enantiomeric impurity analysis of S-timolol and 1R,2S-ephedrine

1S,4R-(+)-ketopinic acid [(+)-KPA] has been introduced as a chiral selector for the separation of pharmacologically active amines by non-aqueous capillary electrophoresis (NACE). (+)-KPA gave enantioresolution for most of the compounds previously separated by 2R,3S,4R,5S-(-)-2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid [(-)-DIKGA], but with a reversed migration order. A complete enantioresolution (Rs=4.2) was obtained for timolol, a compound that could not be resolved using (-)-DIKGA as the selector. Thus, (+)-KPA was evaluated for the enantiomeric purity determination of S-timolol. A method based on pre-concentration by transient isotachophoresis (tITP) provided a limit of detection (LOD) of 0.2% R-timolol in S-timolol samples. Because of the lack of enantioresolution of ephedrine when (+)-KPA was used as the selector, a method with (-)-DIKGA has been developed and validated for determination of the enantiomeric purity of the 1R,2S enantiomer. The method gave good precision and accuracy with an LOD (S/N=3) of 0.033% for the enantiomeric impurity 1S,2R-ephedrine.     

Syntheses of the enantiomers of 1-deoxynojirimycin and 1-deoxyaltronojirimycin via chemo- and diastereoselective olefinic oxidation of unsaturated amines

Oxidation of enantiomerically pure (R)-N(1)-1'-(1'-naphthyl)ethyl-2,7-dihydro-1H-azepine with m-CPBA in the presence of HBF(4) and BnOH gave (3S,4R,5S,6S,1'R)-N(1)-1'-(1'-naphthyl)ethyl-3-hydroxy-4-benzyloxy-5,6-epoxyazepane as the major product and as a single diastereoisomer after chromatography. Elaboration of this highly functionalized intermediate via ring contraction to (2S,3R,4S,5S,1'R)-N(1)-benzyl-2-chloromethyl-3-benzyloxy-4,5-epoxypiperidine followed by regioselective epoxide ring opening, functional group manipulation, and deprotection gave (+)-1-deoxyaltronojirimycin. Alternatively, resolution of (RS,RS)-N(1)-benzyl-3-hydroxy-4-benzyloxy-2,3,4,7-tetrahydro-1H-azepine or (3RS,4SR,5RS,6RS)-N(1)-benzyl-3-hydroxy-4-benzyloxy-5,6-epoxyazepane by preparative chiral HPLC and subsequent elaboration allows access to the enantiomers of 1-deoxynojirimycin and 1-deoxyaltronojirimycin, respectively.     

A dirhodium(II)-carbenoid route to (-)- and (+)-Geissman-Waiss lactone: synthesis of (1R,7R,8R)-(-)-turneforcidine.

(-)- and (+)-Geissman-Waiss lactone, 4b, was efficiently prepared via the intramolecular C-H insertion reaction of the chiral nonracemic diazoacetates (-)-5a and (+)-5b catalyzed by dirhodium(II) tetrakis[methyl (5R and 5S)-3-phenylpropanoyl-2-imidazolidinone-5-carboxylate]. The cyclization was found to proceed with excellent regioselectivity and cis-diastereoselectivity. The bicyclic lactone (-)-4b was successfully used in the synthesis of the necine base, (-)-turneforcidine 2.     

Asymmetric synthesis,stereochemistry, and absolute configuration of 1,2-5-trimethyl-5-(2-cyanoethyl)- and 1,2,5-trimethyl-4-piperidinones

The asymmetric Michael alkylation of (–)-1,2,5-trimethyl-4-(1S-phenylethylimino)piperidine by electrondeficient alkenes proceeds with the formation of(+)-cis-(2S,5S)- and (–)-trans-(2R,5S) diastereomers of 1,2,5-trimethyl-5-(2-cyanoethyl)- and 1,2,5-trimethyl-5-(2-methoxycarbonylethyl)-4-piperidinones containing a chiral quaternary center C(₅). The spatial structure of these new chiral 4-piperidinones has been established on the basis of ¹H and ¹³C NMR spectroscopic data. The absolute configuration of the C(₂) and c(₅) chiral centers in the diastereomers has been determined by stereochemical correlation on the basis of circular dichroism data.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1369–1378, October, 1992.     

Stereoselective Synthesis of Ferrocenylamino Acids

Enantiopure ferrocenyl-β, and bis-β-amino acids [(R)-(+)-1 and (R, R)-(+)-2] were prepared from (S)-(+)-sulfinimine (3) and (S, S)-(+)-bis-sulfinimine (4) respectively. The desired sulfinimines [(S)-(+)-3 and (S, S)-(+)-4] were prepared from (S)-Andersen reagent (5) and ferrocenecarboxaldehyde (6) and 1, 1 -ferrocenedicarboxaldehyde (7).     

PREPARATION OF R-(+)-3,4-DIMETHOXYBENZYL 2-METHOXY-1-NAPHTHYL SULFOXIDE AND DIASTEREOSELECTIVE ADDITION OF LITHIATED ANION OF THIS REAGENT TO CYCLIC NITRONE. ASYMMETRIC SYNTHESIS OF OPTICAL PURE ISOQUINOLINE ALKALOIDS

Abstract

The addition of the lithium carbanion of (R)-(+)-3,4-dimethoxybenzyl 2-methoxy-1-naphthyl sulfoxide 3 to cyclic nitrone 4, under kinetically controlled conditions gave isoquinoline sulfoxide derivatives 5 and 6 in high diastereoselectivities, Under equilibrium controlled conditions poor diastereoselectivity results. The chiral (R)-(+)-3,4-dimethoxybenzyl 2-methoxy-I -naphthyl sulfoxide 3 was easily prepared by the reaction of 3.4-dimethoxyben-zylmagnesium chloride 2 with (-)-(S)menthyl 2-methoxy-naphthalenesulfinate 1 in dry benzene. This methodology allows for the synthesis of the isoquinoline alkaloid (R)-(-)-norlaudanosine 8 in three efficient synthetic steps.     

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).     

Chiral lithium amide base-mediated rearrangement of meso-cyclohexene oxides: asymmetric synthesis of amino- and aziridinocyclohexenols

Two different chiral lithium amide base routes for the synthesis of amino- and aziridino-containing cyclohexenols have been explored. The first strategy involved the diastereoselective preparation of novel meso-aziridinocyclohexene oxides and their subsequent enantioselective rearrangement using chiral bases. In this approach, the diphenylphosphinoyl nitrogen protecting group proved optimal and aziridinocyclohexenols of 47-68% ee were obtained. Of particular note was the smooth rearrangement of the epoxide to an allylic alcohol in the presence of an aziridine: under optimised chiral base conditions, the aziridine remained essentially unaffected. A second more straightforward strategy for introduction of an amino functionality was also investigated: (1S,4R,5S)- and (1R,4R,5S)-4,5-bis(tert-butyldimethylsilyloxy)cyclohex-2-enols, readily prepared in > 95% ee using a chiral base approach, were subjected to Mitsunobu substitution using a sulfonamide and Overman rearrangement.