Synthesis and structural characterization of camphanates of (−)-(2S3S,3S) and (+)-(2S,3R)-4-Phenyl-3-bromo-2-butanol diastereoisomers

The X-ray crystal structures of (–)-syn-4-phenyl-3-bromo-2-butyl camphanate (I) and (+-anti-4-phenyl-3-bromo-2-butyl camphanate (II) have been determined. Thesyn diastereoisomer of bromohydrin has the (2S,3S) absolute configuration whereas theanti diastereoisomer has the (2S,3R) absolute configuration. The crystallized derivatives I and II have been obtained by the reaction of each stereoisomer of bromohydrin, synthesized by reduction with baker's yeast, with (1S)-camphanic chloride. Crystal data: (I) C₂₀H₂₅BrO₄:M _w: 409.32; orthorhombic,P2₁2₁2₁;a=11.245(3),b=12.086(1),c=14.512(4) å; Z=4; finalR=0.053 for 1819 observed reflections. (II) C₂₀H₂₅BrO₄;M _w=409.32; monoclinic, P2₁;a=11.352(1),b=6.378(1),c=14.255(2) å,=110.38(1);Z=2; finalR=0.045 for 1672 observed reflections.     

Chemo-enzymatic synthesis of (S)-α-cyano-3-phenoxybenzyl alcohol

A chemo-enzymatic process for the preparation of (S)-α-cyano-3-phenoxybenzyl alcohol (S-CPBA), an important intermediate in the synthesis of many pyrethroids, was developed. The process consists of four stages, including lipase-mediated resolution. The first stage, the synthesis of racemic α-cyano-3-phenoxybenzyl acetate (CPBAc) from m-phenoxybenzaldehyde (m-PBA) and sodium cyanide in the presence of a phase transfer catalyst, resulted in a 75% yield with 95% purity. The second key step is the resolution of the racemic ester by a highly enantioselective lipase from Pseudomonas sp. The immobilized enzyme carried out the transesterification reaction to nearly full conversion (46% out of 50%) with an enantiomeric excess of >96%. The enzymatic reaction was accomplished in a batch system as well as in a fluidized bed column. The reaction was found to be inhibited by accumulation of the product and to a lesser extent, by the aldehyde. The separation of the enantiomerically pure alcohol from the undesired ester was performed by chromatographic techniques, as well as by extraction with hexane. The final racemization step of the (R)-ester was easily attained with the use of triethylamine in diisopropyl ether or toluene. The process was shown to be feasible on a gram scale and shows potential for scale up.     

(3S,4S)-4-氨基-3-羟基-6-甲基庚酸的合成

价廉易得的L-亮氨酸先以苄基同时保护氨基及羧基得(S)-2-(二苄胺基)-4-甲基戊酸苄酯,进而在碱性条件下与乙腈发生亲核取代反应得(S)-4-(二苄胺基)-6-甲基-3-氧代庚腈,再经硼氢化钠选择性还原羰基得(3S,4S)-4-(二苄胺基)-3-羟基-6-甲基庚腈,用双氧水氧化得(3S,4S)-4-(二苄胺基)-3-羟基-6-甲基庚酸,最后在Pd(OH)2/C-H2作用下脱掉苄基得到(3S,4S)-4-氨基-3-羟基-6-甲基庚酸,即(3S,4S)-statine。整个合成路线总产率为33.6%。     

Synthesis of 5-substituted-3-[(2′S,3′S)-3′-hydroxy-2′-hydroxymethyltetrahydrofuran-3′-yl]-1,2,4-oxadiazoles and their epimers

5-Phenyl-3-[(2′R,3′S)-3′-hydroxy-2′-dimethoxymethyltetrahydrofuran-3′-yl]-1,2,4-oxadiazole 10a and its epimer 11a, 5-methyl-3-[(2′R,3′S)-3′-hydroxy-2′-dimethoxymethyltetrahydrofuran-3′-yl]-1,2,4-oxadiazole 10b and its epimer 11b were synthesized from cyanohydrin benzoates 8a, 9a and cyanohydrin acetates 8b, 9b, respectively, by treatment with hydroxylamine in methanol via intramolecular transacylation and subsequent cyclization of the corresponding amidoximes. Hydrolysis and reduction of the dimethoxymethyl groups in the above compounds gave the desired compounds 12a, 13a, 12b and 13b.     

Synthesis of stereospecifically labeled carbohydrates: Preparation of (3S)− and (3R)-[3-2H1]ascarylose

The general problem of the synthesis of 3,6-dideoxy sugars containing stereospecifically labeled hydrogen isotope at C-3 is addressed for the specific case of ascarylose (3,6-dideoxy-L-arabino-hexose).     

Biological Evaluation and Structure Modification of （S）-3-Aminopyrrolidine Derivatives

With our interest in （S）-3-aminopyrrolidine derivatives,we further screened inhibition activities of three hit compounds on many other kinases with the results demonstrating that this series of compounds shows better anticancer activities,which might result from the main block of PI3K/Akt signaling pathway and the inhibition of Abelson murine leukemia viral oncogene homolog（ABL） kinase,as well as some epidermal growth factors.Further structure modification demonstrates that benzylsulfonyl group is the necessary functional group contributing to the biological activity that will be helpful to guiding us to optimize these （S）-3-aminopyrrolidine derivatives.     

(3S,6S)-及(3S,6R)-3-苄氧甲基-6-甲基-吗啉-2,5-二酮的 制备及其晶体结构

以2-溴丙酸和N-叔丁氧羰基-O-苄基-L-丝氨酸为起始试剂首先制得N-(2-溴丙基)-O-苄基-L-丝氨酸(BPBS), 在N,N-二甲基甲酰胺(DMF)/三乙胺(Et3N)溶剂中80 ℃经9 h后BPBS发生分子内环化反应生成(3S,6S)-3-苄氧甲基-6-甲 基-吗啉-2,5-二酮[(3S,6S)-BMMD]及(3S,6R)-BMMD共存体, 产率70%. 将所制得的共存体以乙酸乙酯为重结晶溶剂, 采用微分重结晶法, 经4次“溶解-部分重结晶”操作循环制得两种纯光学构型的(3S,6S)-BMMD和(3S,6R)-BMMD. 将两种光学纯双手性中心的BMMD分别溶于乙酸乙酯, 室温下培养得(3S,6S)-BMMD和(3S,6R)-BMMD的单晶体, 以X射线衍射法测定上述两种BMMD的分子结构.     

(1S,3S)-1,3-二苯基-1,3-丙二胺的合成

以二氯甲烷作溶剂,N-Boc保护的二氢吡唑在六甲基磷酰胺存在下与苯基格氏试剂反应,比较大量地制备了对应的四氢吡唑(4);再由4合成消旋的1,3-二苯基-1,3-丙二胺(1,总收率35%);1经L-二苯甲酰酒石酸盐拆分制得光学纯的(1S,3S)-1,3-二苯基-1,3-丙二胺,其结构经1HNMR确证。     

Asymmetric synthesis of (−)-pseudoephedrine from (2S,3S)-3-phenyloxiran-2-ylmethanol. Stereospecific interchange of amino and alcohol functions

A ring-opening reaction of N-methylaziridines with Boc₂O/NaI has been applied to the asymmetric synthesis of pseudoephedrine. 3-Methylamino-3-phenyl-1,2-propanediol 1, derived from (2S,3S)-3-phenyloxiran-2-ylmethanol, was converted into the oxazolidin-2-one 4, a precursor of pseudoephedrine. The reaction occurs with a stereospecific interchange of amino and alcohol functions.     

A Chemo-enzymatic Route for the Preparation of Chiral （S）-3-Hydroxy-3-phenylpropanoic Acid

（S）-3-Hydroxy-3-phenylpropanoic acid is a potential progenitor of optically pure tomoxetine hydrochlo- ride and fluoxetine hydrochloride which are currently available antidepressant drugs. We report here the chemical synthesis of racemic substrate （R,S）-ethyl 3-hydroxy-3-phenylpropanoate and enzymatic preparation of S-isomer of the substrate by employing Porcine pancreas lipase（PPL） as a biocatalyst. Optimum enzyme-catalyzed reaction con- ditions, such as the effects of the temperature, pH and solvents on conversion degree and enantiomeric excess, were studied. An optimal temperature of 35 ℃ and pH=7.5 are the best for the resolution of （R,S）-ethyl 3-hydroxy-3- pheylpropanoate by PPL when 0.1 mol/L phosphate buffer solution acts as a medium. This work provides a practi- cally chemo-enzvmatic oreoaration of chiral β-hvdroxv acid by PPL.     

A Convenient Synthesis of (S)-2-Methyl and (2S)-2,3-Dimethyl Butyl Phenylsulfones from (S)-(-)-3-Methyl-γ-butyrolactone

Suitably functionalized alkylphenylsulfones have been used as building blocks for the synthesis of several modified side-chains steroids¹. We describe here the synthesis of (S)-2-methyl and (2S)-2,3-dimethyl butyl phenylsulfones (4a) and (6), which can be used for the construction of the side chain of a few marine sterols² or brassinosteroids³ as well.     

Stereoselective Synthesis of [2S,3R]-β-Hydroxy Ornithine

(2S,3R)-threo-β-hydroxy ornithine has been synthesized in a stereoselective manner by the C₂ opening of epoxyalcohol 9 with benzyl isocyanate.

     

A concise synthesis of (S)-(−)-3-(2-carboxy-4-pyrrolyl)-alanine

A convergent synthesis of (S)-(−)-3-(2-carboxy-4-pyrrolyl)-alanine (CPA) 1, a non-proteinogenic amino acid is described starting from a commercially available dimethyl l-aspartate 2 in good overall yield.     

Synthesis and cytotoxicity of dinuclear platinum(Ⅱ) complexes of (1S, 3S)-1, 2, 3, 4-tetrahydroisoquinolines

A series of novel dinuclear platinum(Ⅱ) complexes with (1S, 3S)-1,2,3,4-tetrahydroisoquinolines as the ligands were synthesized as potential anticancer agents in several steps starting from commercially available L-DOPA. The cytotoxicities of the series of dinuclear platinum(Ⅱ) complexes of tetrahydroisoquinoline were tested against HCT-8, BEL-7402, A2780, MCF-7, Hela, A549 and BGC-823 cell lines by the MTT test. These complexes showed selective inhibition activity against cisplatin-insensitive cell line Skov3.     

Enantioselective preparation of (2R,3R)-(+)- and (2S,3S)-(−)-2,3-epoxy-2-methylbutanoic acids and some derivatives

(2R,3R)-(+)- and (2S,3S)-(−)-2,3-epoxy-2-methylbutanoic acids (epoxyangelic acids) were prepared from (Z)-2-methyl-2-butenoic acid using the Sharpless asymmetric epoxidation method in combination with the use of (−)- and (+)-menthol as chiral auxiliaries. Both substances, obtained in high enantiomeric excess, were characterized by spectroscopic and optical activity data. Their absolute configuration was determined by correlation with (R)-(+)-2-methyl-1,2-butanediol.     

(3S)-2,2-二甲基-3-苄氧基癸酸的合成

以 (R) pantolactone为原料 ,经还原、羟基保护、环合、开环、脱保护、氧化等 8步反应 ,合成了 (3S) 2 ,2 二甲基 3 苄氧基癸酸 ,总收率为 40 0 % .     

（3S）-2,2-二甲基-3-苄氧基癸酸的合成

以(R)-pantolactone为原料，经还原、羟基保护、环合、开环、脱保护、氧化等8步反应，合成了(3S)-2，2-二甲基-3-苄氧基癸酸，总收率为40．0％．     

(S)-叔丁基吡咯烷-3-氨基甲酸酯的合成

以L-天冬氨酸为原料,经酯、氨基保护、酯还原、取代、关环和加氢脱苄基等6步反应高效合成了(S)-叔丁基吡咯烷-3-氨基甲酸酯,总收率20%,其结构经¹H NMR, ¹³C NMR和GC确证。     

Synthesis of (S)-(−)-β-cuparenone and (S)-(−)-cuparene

A short and efficient synthesis of the title compounds is described. (S)-(−)-β-Cuparenone was prepared in 31% yield from p-tolualdehyde and mesityl oxide in eight steps. Absolute stereochemistry was established by means of a diastereoselective cyclopropanation using (R,R)-hydrobenzoin as a recoverable auxiliary.     

D-脯氨酸催化的(3S,4S)-4-氨基-3-羟基-5-苯基戊酸衍生物的合成

报道了一条合成(3S,4S)-4-氨基-3-羟基-5-苯基戊酸(Ahppa)衍生物的新路线。以氨基保护的L-苯丙氨酸为起始原料,依次经Weinreb胺缩合、还原、aldol缩合及溴仿4步反应合成了3个Ahppa衍生物,总收率5.8%~6.7%,其结构经¹H NMR, ¹³C NMR和ESI-MS确证。对反应条件进行了探讨,结果表明：催化剂D-脯氨酸用量对反应收率影响不大,对立体选择性影响较大;氨基上保护基体积较大有利于提高反应立体选择性。