Multigram Synthesis of a Chiral Substituted Indoline Via Copper-Catalyzed Alkene Aminooxygenation

(S)-5-Fluoro-2-(2,2,6,6-tetramethylpiperidin-1-yloxymethyl)-1-tosylindoline, a 2-methyleneoxy-substituted chiral indoline, was synthesized on multigram scale using an efficient copper-catalyzed enantioselective intramolecular alkene aminooxygenation. The synthesis is accomplished in four steps and the indoline is obtained in 89% ee (>98% after one recrystallization). Other highlights include efficient gram-scale synthesis of the (4R,5S)-di-Ph-box ligand and efficient separation of a monoallylaniline from its bis(allyl)aniline by-product by distillation under reduced pressure.     

Enantioselective trans dihydroxylation of nonactivated C-C double bonds of aliphatic heterocycles with Sphingomonas sp. HXN-200

The bacterial strain Sphingomonas sp. HXN-200 was used to catalyze the trans dihydroxylation ofN-substituted 1,2,5,6-tetrahydropyridines 1 and 3-pyrrolines 4 giving the corresponding 3,4-dihydroxypiperidines 3 and 3,4-dihydroxypyrrolidines 6, respectively, with high enantioselectivity and high activity. The trans dihydroxylation was sequentially catalyzed by a monooxygenase and an epoxide hydrolase in the strain with epoxide as intermediate. While both epoxidation and hydrolysis steps contributed to the overall enantioselectivity in trans dihydroxylation of 1, the enantioselectivity in trans dihydroxylation of the symmetric substrate 4 was generated only in the hydrolysis of meso-epoxide 5. The absolute configuration for the bioproducts (+)-3 and (+)-6 was established as (3R,4R) by chemical correlations. Preparative trans dihydroxylation of 1a and 4b with frozen/thawed cells of Sphingomonas sp. HXN-200 afforded the corresponding (+)-(3R,4R)-3,4-dihydroxypiperidine 3a and (+)-(3R,4R)-3,4-dihydroxy pyrrolidine 6b in 96% ee both and in 60% and 80% yield, respectively. These results represent first examples of enantioselective trans dihydroxylation with nonterpene substrates and with bacterial catalyst, thus significantly extending this methodology in practical synthesis of valuable and useful trans diols. Enantioselective hydrolysis of racemic epoxide 2a with Sphingomonas sp. HXN-200 gave 34% of (-)-2a in >99% ee, which is a versatile chiral building block. Further hydrolysis of (-)-2a with the same strain afforded (-)-(3S,4S)-3a in 96% ee and 92% yield. Thus, both enantiomers of 3a can be prepared by biotransformation with Sphingomonas sp. HXN-200.     

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).     

吡咯烷生物碱及相关化合物的不对称合成研究(Ⅰ)

吡咯烷生物碱及相关化合物的不对称合成研究（Ⅰ）黄培强,阮源萍（厦门大学化学系,厦门,３６１００５）关键词Ｐｒｅｕｓｓｉｎ,４－氨基－３－羟基－５－苯基戊酸,不对称合成,酰胺－α－烷基化,１．５－二苄基－４－苄氧基－２－吡咯酮（＋）－ｐｒｅｕｓｓｉｎ１...     

光学活性化合物多羟基庚酸乙酯的合成

以不对称环氧化和双羟化反应为构筑手性碳的关键步骤, 首次合成了(＋)-(2R,3S,4S,5S)-6-甲基-4,5-环氧-2,3-二羟基-庚酸乙酯(5)和(－)-(2R,3S,4R,5S)-6-甲基-2,3,4,5-四羟基-庚酸乙酯(11). 找到一条适宜于该类化合物合成的简便有效且立体选择性好的合成路线. 初步生物活性测试表明, 化合物5, 11对HL60细胞具有抑制活性.     

Influence of chirality of the preceding acyl moiety on the cis/trans ratio of the proline peptide bond

We report that the cis/trans ratio of the proline peptide bond can be strongly influenced by the chirality of the acyl residue preceding proline. Acyl moieties derived from (2S)-2,6-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (8) and (2R)-3-methoxy-2-methyl-2-(4-methyl-2-nitrophenoxy)-3-oxopropanoic acid (5) in acyl-Pro molecules influence isomerization of the proline peptide bond constraining the omega dihedral angle to the trans orientation. Structures of benzyl (2S)-1-([(2S)-2,6-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]carbonyl)-2-pyrrolidinecarboxylate (3) derived from 2D (1)H NMR conformational analysis and crystallographic data exhibit only the trans conformation of proline peptide bond. On the other hand the diastereomer 4, which contains an (R) acyl moiety, exhibits two sets of signals in (1)H NMR spectra. The signals were assigned to trans (72%) and cis (28%) conformers. Crystallographic analysis of 4 showed that only the cis conformation is present in the crystalline state. The (1)H NMR chemical shift pattern of three sets of signals observed in 2 was observed also in benzyl (2S)-1-[(2R/S)-3-methoxy-2-methyl-2-(4-methyl-2-nitrophenoxy)-3-oxopropanoyl]-2-pyrrolidinecarboxylate. (R)-Carboxylic acid 5, after coupling with (S)-ProOBn, yielded benzyl (2S)-1-[(2R)-3-methoxy-2-methyl-2-(4-methyl-2-nitrophenoxy)-3-oxopropanoyl]-2-pyrrolidinecarboxylate (6), which in DMSO-d(6) exhibited only the trans conformation of the proline peptide bond. These results suggest that in these particular cases acyl-Pro peptide bond isomerization is strongly influenced by the stereochemistry of the acyl residue preceding proline. (2S)-2,6-Dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (8) and (2R)-3-methoxy-2-methyl-2-(4-methyl-2-nitrophenoxy)-3-oxopropanoic acid (5) are promising chiral peptidomimetic building blocks that can be used as acyl moieties to force the proline peptide bond into the trans conformation in a variety of acyl-Pro molecules.     

Facile route to 3,5-disubstituted morpholines: enantioselective synthesis of O-protected trans-3,5-bis(hydroxymethyl)morpholines

[reaction: see text] (3R,5R)-1 R1 & R2 = TBDPS, (3S,5R)-2 R1 = Bn,R2 = TBDPS, (3S,5S)-3 R2 & R2 = Bn. trans-3,5-Bis(benzyl/tert-butyldiphenylsilyloxymethyl)morpholines, promising candidates for the C(2)-symmetric class of chiral reagents, were prepared with excellent optical purity. A key step in the synthesis is the coupling of a serinol derivative with 2,3-O-isopropylideneglycerol triflate or its equivalent. This methodology was extended to the synthesis of chiral trans-3-(benzyloxymethyl)-5-(tert-butyldiphenylsilyloxymethyl)morpholine, a potentially useful chiral building block.     

Two-step asymmetric synthesis of disubstituted N-tosyl aziridines having 98-100% ee: use of a phosphazene base

Unknown diaryl (1-3) and alkyl-phenyl (4, 5) N-tosyl aziridines have been successfully synthesized from pure (R,R,R,S(S))-(-)-sulfonium salt derived from Eliel's oxathiane, tosylimines 11a-f, and using a phosphazene base (EtP(2)) to generate the ylide. Both cis and trans aziridines have exceptionally high enantiomeric purities (98.7-99.9%). The (2R,3R)-configuration of trans-3 and the (2R,3S)-configuration of cis-4 have been determined by X-ray analysis using the Bijvoet method. The R-configuration found at C2 is consistent with the model and all previous results, therefore all trans-aziridines and cis-aziridines have been assigned the (2R,3R)- and the (2R,3S)-configurations, respectively. This two-step asymmetric synthesis can be easily used on gram quantities and involves no unstable/hazardous reagent. The chiral auxiliary is used in a stoichiometric amount but is recovered in high yield and reused.     

Diastereoselective synthesis of new psi[(E)-CH=CMe]- and psi[(Z)-CH=CMe]-type alkene dipeptide isosteres by organocopper reagents and application to conformationally restricted cyclic RGD peptidomimetics

Diastereoselective synthesis of new psi[(E)-CH=CMe]- and psi[(Z)-CH=CMe]-type alkene dipeptide isosteres corresponding to dipeptides having one N-methylamino acid, and application to bioactive peptides, are described. In a key reaction introducing the chiral alpha-alkyl group of the isosteres, organocopper-mediated alkylation of syn-beta-methylated gamma-mesyloxy-alpha,beta-enoate 26a afforded E- and Z-isomers of anti-S(N)2' products in a solvent-dependent manner. The resulting two isosteres, D-Phe-psi[(E)-CH=CMe]-L-Val 27a and D-Phe-psi[(Z)-CH=CMe]-L-Val 28b, which corresponded to trans- and cis-conformers of D-Phe-L-MeVal, respectively, were utilized in a structure-activity relationship study on cyclic RGD peptides 1 and 2, in company with a psi[(E)-CH=CH]-type alkene dipeptide isostere, D-Phe-psi[(E)-CH=CH]-L-Val. The cyclic isostere-containing pseudopeptides 3, 4, and 40 were synthesized and biological activity against integrin alpha(V)beta(3) and alpha(IIb)beta(3) receptors were also evaluated.     

5-羟基色胺受体激动剂(1R,2S)-(-)-2-(2-羟基苯基)-N,N-二丙基环丙胺的不对称合成

利用手性双唑啉与三氟甲磺酸亚铜催化2-甲氧基苯乙烯与重氮乙酸二环己基甲酯的不对称环丙烷化反应合成了手性环丙烷羧酸酯,用氢氧化钠对其进行选择性水解得到全反式环丙烷羧酸,其ee值经GC测定为88%.进一步经过Curtius重排、烷基化等反应及重结晶等步骤合成了光学纯的具有生理活性的环丙胺化合物1a和1b.     

Synthesis of (R)-2-methyl-4-deoxy and (R)-2-methyl-4,5-dideoxy analogues of 6-phosphogluconate as potential inhibitors of 6-phosphogluconate dehydrogenase

The synthesis of (2R)-2-methyl-4,5-dideoxy and (2R)-2-methyl-4-deoxy analogues of 6-phosphogluconate is described. The synthetic strategy relies on the Evans aldol reaction for the installation of the chiral centres in the 2- and 3-positions. The selective phosphorylation at the primary alcohol function of (2R,3S)-3,6-dihydroxy-2-methylhexanoic acid benzyl ester (5) and (2R,3S,5S)-3,5,6-trihydroxy-2-methylhexanoic acid benzyl ester (20) was achieved with dibenzyl phosphochloridate and dibenzyl phosphoiodinate respectively, working at low temperature. (2R,3S)-3-Hydroxy-2-methyl-6-phosphonoxyhexanoic acid (9) was obtained in 25% overall yield from 4-benzyloxybutanol and (2R,3S,5S)-3,5-dihydroxy-2-methyl-6-phosphonoxyhexanoic acid (28) in 10% overall yield from L-malic acid.     

多功能光学活性丁二醇衍生物的合成和结构

通过新的合成策略,以手性合成子3和具有生物活性的有机碱类化合物4为反应底物,利用Michael不对称加成反应,合成得到光学纯的5-(R)-［(1R,2S,5R)-(-)-氧基］-4-(R)-(杂环碱基)-2(5H)-呋喃酮(5). 加成物5通过还原反应得到了多功能光学活性的二醇类化合物6,产率为42%~82%,e.e.≥98%. 化合物6的化学结构得到了确认,其立体化学结构和绝对构型经X射线晶体学测定得到了确定.     

An asymmetric synthesis of (+)-grandisol, a constituent of the aggregation pheromone of the cotton boll weevil, via a kinetic resolution

A novel approach to the asymmetric synthesis of (+)-grandisol, (1R, 2S)-isopropenyl-1-methylcyclobutaneethanol, involves the use of catalytic kinetic resolution of a primary allylic alcohol, [(1RS, 5SR)-5-methylbicyclo[3.2.0]hept-2-en-2-yl] methanol. The allylic alcohol is prepared in four steps from simple achiral materials involving the use of a modified Shapiro reaction. The resolved alcohol (95% ee) is then reduced in two steps to the corresponding methyl alkene, (1S,5R)-2,5-dimethylbicyclo[3.2.0]hept-2-ene. This alkene is converted to (+)-grandisol (95% ee), in three steps, by modified literature procedures.     

光学活性3-(1′-羟基乙基)-4-乙酰氧基-β-内酰胺的立体选择性合成

(1′R,3R,4R)-N-取代-3-(1′-羟基乙基)-4-乙酰氧基-β-内酰胺(3)是合成青霉烯和碳青霉烯类β-内酰胺抗生素的关键中间体.以廉价的L-抗坏血酸为原料,制得S-缩异丙氧叉甘油醛(5),与胺反应定量转变成相应的手性亚胺(6a～6d),6与双烯酮[2+2]环加成反应,高立体选择性地合成3(S)-乙酰基-β-内酰胺(Sa～8d),其非对映体过量由类似反应的80％提高到接近100％.8a经四步反应得到目标化合物3a.     

Unprecedented oxidation of a phenylglycinol-derived 2-pyridone: enantioselective synthesis of polyhydroxypiperidines

[reaction: see text]. The phenylglycinol-derived 2-pyridone 1 undergoes m-CPBA oxidation steroselectively leading to the chiral nonracemic unsaturated bicyclic hydroxylactam 2, from which the enantioselective synthesis of (3R,5R)-3,4,5-trihydroxypiperidine (16) and the formal synthesis of the azasugar epiisofagomine are described. The enantioselective synthesis of (S)-N-Boc-3-hydroxypiperidine and (3R,4S)-3,4-dihydroxypiperidine is also reported.     

利用甘油醛进行白三烯B4中1-C～6-C及11-C～20-C片断的手性合成

本文报道由D-甘露醇和L-抗坏血酸为手性源, 通过D(+)-和L(-)-甘油醛分别合成白三烯B4中1-C～6-C片断5-(S)-苯甲酰氧基-6-氧代-己酸乙酯及11-C～20-C片断-2-(R)-叔丁基-二苯基硅氧基-癸-4-(z)-烯醛的新合成方法。     

Biomimetic iron-catalyzed asymmetric epoxidation of aromatic alkenes by using hydrogen peroxide

A novel and general biomimetic non-heme Fe-catalyzed asymmetric epoxidation of aromatic alkenes by using hydrogen peroxide is reported herein. The catalyst consists of ferric chloride hexahydrate (FeCl(3)6 H(2)O), pyridine-2,6-dicarboxylic acid (H(2)(pydic)), and readily accessible chiral N-arenesulfonyl-N'-benzyl-substituted ethylenediamine ligands. The asymmetric epoxidation of styrenes with this system gave high conversions but poor enantiomeric excesses (ee), whereas larger alkenes gave high conversions and ee values. For the epoxidation of trans-stilbene (1 a), the ligands (S,S)-N-(4-toluenesulfonyl)-1,2-diphenylethylenediamine ((S,S)-4 a) and its N'-benzylated derivative ((S,S)-5 a) gave opposite enantiomers of trans-stilbene oxide, that is, (S,S)-2 a and (R,R)-2 a, respectively. The enantioselectivity of alkene epoxidation is controlled by steric and electronic factors, although steric effects are more dominant. Preliminary mechanistic studies suggest the in situ formation of several chiral Fe-complexes, such as [FeCl(L*)(2)(pydic)]HCl (L*=(S,S)-4 a or (S,S)-5 a in the catalyst mixture), which were identified by ESIMS. A UV/Vis study of the catalyst mixture, which consisted of FeCl(3)6 H(2)O, H(2)(pydic), and (S,S)-4 a, suggested the formation of a new species with an absorbance peak at lambda=465 nm upon treatment with hydrogen peroxide. With the aid of two independent spin traps, we could confirm by EPR spectroscopy that the reaction proceeds via radical intermediates. Kinetic studies with deuterated styrenes showed inverse secondary kinetic isotope effects, with values of k(H)/k(D)=0.93 for the beta carbon and k(H)/k(D)=0.97 for the alpha carbon, which suggested an unsymmetrical transition state with stepwise O transfer. Competitive epoxidation of para-substituted styrenes revealed a linear dual-parameter Hammett plot with a slope of 1.00. Under standard conditions, epoxidation of 1 a in the presence of ten equivalents of H(2) (18)O resulted in an absence of the isotopic label in (S,S)-2 a. A positive nonlinear effect was observed during the epoxidation of 1 a in the presence of (S,S)-5 a and (R,R)-5 a.     

光学活性3-(1'-羟基乙基)-4- 乙酰氧基-β-内酰胺的立体选择 性合成

(1'R,3R,4R)-N-取代-3-(1'-羟基乙基)-4-乙酰氧基-β-内酰胺(3)是合成青霉烯和碳青霉烯类β-内酰胺抗生素的关键中间体。以廉价的L-抗坏血酸为原料,制得S-缩异丙氧叉甘油醛(5),与胺反应定量转变成相应的手性亚胺(6a～6d),6与双烯酮[2+2]环加成反应,高立体选择性地合成3(S)-乙酰基-β-内酰胺(8a～8d),其非对映体过量由类似反庆的80%提高到接近100%。8a经四步反应得到目标化合物3a。     

The nucleophilic addition of alpha-metallated 1,3-dioxanes to planar chiral cationic eta3-allylmolybdenum complexes. Synthesis of (2E,5S,6R,7E)-6-methyl-8-phenylocta-2,7-dienoic acid methyl ester, a key component of the Cryptophycins

Two adjacent stereogenic centres and a pendant alkene were constructed via nucleophilic addition of a 1,3-dioxan-4-ylcopper(I) reagent to a cationic eta3-allylmolybdenum complex as part of a synthesis of (2E,5S,6R,7E)-6-methyl-8-phenylocta-2,7-dienoic acid, a key component of the Cryptophycins. Oxidative addition of Mo(CO)(4)(THF)(2) to allyl benzoates provides an efficient synthesis of eta3-allylmolybdenum(dicarbonyl) complexes.     

Novel metal complexes containing a chiral trinitrogen isoindoline-based pincer ligand: in situ synthesis and structural characterization

The first synthesis and characterization of metal coordinated complexes containing in situ prepared chiral trinitrogen 1,3-bis(4,5-dihydrooxazol-2-ylimino)isoindoline-based pincer ligands are reported. Two zinc complexes, isolated as Zn(L)(2), where L = 1,3-bis(4,5-dihydro-4-(R)-phenyloxazol-2-ylimino)isoindoline ((R,R)-5) or 1,3-bis(4,5-dihydro-4-(S)-iso-propyloxazol-2-ylimino)isoindoline ((S,S)-6), respectively, are reported. Complexes Zn((R,R)-5)(2) and Zn((S,S)-6)(2) were prepared in situ through the condensation of phthalonitrile with enantiopure 2-amino-4-(R)-phenyloxazoline ((R)-3) or 2-amino-4-(S)-iso-propyloxazoline ((S)-4) in the presence of ZnCl(2) at 80 °C in dry toluene over 3-4 days. The characterizations of Zn((R,R)-5)(2) and Zn((S,S)-6)(2) in both the solid (X-ray crystallography) and solution (multinuclear NMR spectroscopy) states are reported.