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.     

Microwave-assisted multistep synthesis of functionalized 4-arylquinolin-2(1H)-ones using palladium-catalyzed cross-coupling chemistry

[reaction: see text] Biologically active 4-aryl-3-alkenyl-substituted quinolin-2(1H)-ones have been synthesized in a short and concise manner employing readily available 4-hydroxyquinolin-2(1H)-ones as intermediates. Key steps in the synthesis include the derivatization of the quinolin-2(1H)-one cores using palladium-catalyzed Suzuki and Heck reactions, installing the 4-aryl and 3-alkenyl substituents. All synthetic transformations (six steps) required for the synthesis of the desired target quinolin-2(1H)-one were carried out using controlled microwave-assisted organic synthesis.     

A concise synthesis of a very late antigen-4 antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid via reductive etherification

This contribution describes a concise synthesis to ethyl trans-[(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate (2b) as a key intermediate of very late antigen-4 (VLA-4) antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid (1). The synthesis employs a reductive etherification as a key reaction using (2S,4S)-1-benzyloxycarbonyl-4-methoxypyrrolidine-2-carboxyaldehyde (12) and trans-4-triethylsilyloxycyclohexanecarboxilic acid ethyl ester (13b). This synthesis provides 2b in 6 steps with 38% overall yield from commercially available starting material.     

Design, synthesis, and biological evaluation of a library of 1-(2-thiazolyl)-5-(trifluoromethyl)pyrazole-4-carboxamides

A library of 422 1-(2-thiazolyl)-5-(trifluoromethyl)pyrazole-4-carboxamides was prepared in five steps using solution-phase chemistry. The first step in the synthesis was the reaction of ethyl 2-ethoxymethylene-3-oxo-4,4,4-trifluorobutanoate with thiosemicarbazide, which is reported in the literature to afford a 1:1 mixture of ethyl 1-thiocarbamoyl-5-(trifluoromethyl)pyrazole-4-carboxylate and ethyl 1-thiocarbamoyl-3-(trifluoromethyl)pyrazole-4-carboxylate. We reassigned the structure of the product to be a single compound, ethyl 5-hydroxy-1-thiocarbamoyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-4-carboxylate. This common intermediate was diversified by reaction with 17 alpha-bromoketones affording, in two steps, 17 1-(2-thiazolyl)-5-(trifluoromethyl)pyrazole-4-carboxylic acids. Scavenger resins were used to facilitate formation and purification of up to 27 amides from each of these acids in the last step. In addition, the Curtius reaction was applied to 12 of the acids followed by quenching with alcohols to afford a 108-member carbamate library. Certain compounds in the two libraries were toxic to C. elegans.     

One-pot multistep Bohlmann-Rahtz heteroannulation reactions: synthesis of dimethyl sulfomycinamate

[reaction: see text] The synthesis of dimethyl sulfomycinamate, the acidic methanolysis product of the sulfomycin family of thiopeptide antibiotics, from methyl 2-oxo-4-(trimethylsilyl)but-3-ynoate is achieved in a 2,3,6-trisubstituted pyridine synthesis that proceeds with total regiocontrol in 13 steps by the Bohlmann-Rahtz heteroannulation of a 1-(oxazol-4-yl)enamine or in 12 steps and 9% yield by three-component cyclocondensation with N-[3-oxo-3-(oxazol-4-yl)propanoyl]serine and ammonia in ethanol.     

计算机辅助设计新型人脂肪酸合酶抑制剂及其抗肿瘤活性

以Orlistat为先导化合物,利用AutoDock进行计算机模拟对接,在对接结果中选择能量较低的6个结构进行合成与抗肿瘤活性筛选。以orlistat为原料,经2步反应制得苄基(2S,3S,5S)-2-己基-3,5-二羟基十六酸酯(2); 再经4步反应获得(3S,4S)-3-己基-4-［(S)-2-羟基十三烷基］氧杂环丁烷-2-酮(5); 5在EDCI作用下与酸经缩合反应合成了4个计新型人脂肪酸合酶抑制剂（6a~6d）,其中6b~6d为新化合物,其结构经¹H NMR, ¹³C NMR 和HR-MS（ESI）表征。体外初步活性测试表明：(S)-1-［(1S,2S)-3-己基-4-氧代氧杂环丁烷-2-基］十三烷-2-烟酸酯（6a）对MDA-MB-231细胞有较好的抑制作用,其IC₅₀为11.72 μmol·mL^-1,优于Orlistat(21.5 μmol·mL^-1)。     

Stereoselective synthesis of deuterated β-cyclohexenylserine, a biosynthetic intermediate of the salinosporamides

A straightforward, highly stereoselective protocol toward the synthesis of deuterium-labeled (2R,3S,4S)-β-cyclohexenylserine has been developed. Key steps are a Nozaki-Hiyama-Kishi reaction generating the stereogenic centers and a ring-closing metathesis for the construction of the cyclohexenyl ring system. The labeled amino acid was further activated as an SNAc-ester for feeding experiments.     

Total synthesis and structural elucidation of (-)-maurenone

[reaction: see text] The total synthesis of (2S,3S)-2,3-dihydro-6-[(1'S, 2'R)-2-hydroxy-1-methylbutyl]-3,5-dimethyl-2-[(1'S)-1-methylpropyl]-4H-pyran-4-one (3), the (-)enantiomer of the marine polypropionate, maurenone, was achieved in nine linear steps (13% overall yield) from (R)-2-benzylpentan-3-one ((R)-14) and (R)-2-benzoyloxypentan-3-one ((R)-15). Key fragments were synthesized using highly diastereoselective syn and anti boron aldol reactions and were coupled using a lithium-mediated aldol reaction. Trifluoroacetic acid-promoted cyclization/dehydration was then used to install the gamma-dihydropyrone ring. Eight isomers of one enantiomeric series were synthesized by coupling two ketones with each of four aldehydes. Comparison of the 13C NMR data for the eight isomers with that reported for maurenone established the relative stereochemistry of the natural product.     

Total synthesis of an immunosuppressive glycolipid, (2S,3S,4R)-1-O- (alpha-d-galactosyl)-2- tetracosanoylamino-1,3,4-nonanetriol

[reaction: see text] A practical and efficient total synthesis of (2S,3S,4R)-1-O-(alpha-d-galactosyl)-2-tetracosanoylamino-1,3,4-nonanetriol, OCH 1b, a potential therapeutic candidate for Th1-mediated autoimmune diseases, is described. The synthesis incorporates direct alkylation onto epoxide 5 and stereospecific halide ion catalyzed alpha-glycosidation reaction. A key intermediate 10 was obtained in only eight steps and 37% overall yield from commercially available d-arabitol 2, and the total synthesis of 1b was accomplished in 12 steps and 19% overall yield. This method will enable the synthesis of a variety of phytosphingolipids, especially that with the shorter sphingosine side chain than 1a, in a highly stereoselective manner.     

Total synthesis of (-)-martinellic acid via radical addition-cyclization-elimination reaction

The asymmetric total synthesis of martinellic acid, the first pyrrolo[3,2-c]quinoline alkaloid found in nature, is described. Three key steps in our synthesis of (-)-martinellic acid are the Bu(3)SnH-promoted radical addition-cyclization-elimination (RACE) reaction of an oxime ether with an alpha,beta-unsaturated ester to generate the pyrrolo[3,2-c]quinoline core, a chemoselective lactam carbonyl reduction, and guanidinylation under Mitsunobu reaction conditions. The key radical cyclization has also been investigated by using SmI(2). (-)-Martinellic acid was synthesized from commercially available methyl 4-bromo-3-methylbenzoate in fewer steps than previous syntheses and in an improved overall yield.     

The synthesis of possible hydroxylated metabolites of 2-chlorophenothiazine derivatives

The synthesis of 7-hydroxy, 8-hydroxy and 7,8-dihydroxy prochlorperazines (3a) and per-phenazines (3b) is reported. The parent ehlorophenothiazines were prepared analogously to previously reported chlorpromazine (3e) metabolite syntheses. The prochlorperazine side chain was introduced in one step using 1-(3-chloropropyl)-4-methylpiperazine and the perphenazine side chain in two steps, first reaction with 1-bromo-3-chloropropane followed by reaction with 1-piperazineethanol. The methoxymethyleneoxy O-proteetive groups were removed under mild conditions using methanolic hydrogen chloride. The preparations of 7-hydroxydesmethylprochlorperazine and 7-hydroxychlorpromazine quaternary methyl iodide are also reported.     

An improved asymmetric synthesis of malyngamide U and its 2'-epimer

An accelerated and improved asymmetric synthesis of malyngamide U (1) and its 2'-epimer (2'-epi-1) was accomplished from readily available n-hexanal, ethanolamine and (R)-(-)-carvone. The key steps involved a Johnson-Claisen rearrangement in the synthesis of an unsaturated carboxylic acid 4 and an aldol reaction in the construction of the skeleton of 1 and 2'-epi-1. There are 13 steps in the synthesis, with a 2.7% overall yield for 1 and a 0.4% yield for 2'-epi-1.     

Regioselective and diastereoselective amination with use of chlorosulfonyl isocyanate: a short and efficient synthesis of (-)-cytoxazone

The total synthesis of (-)-cytoxazone 1 was achieved in six linear steps (34% overall yield) from p-anisaldehyde. The key steps in this route are the regioselective and stereoselective introduction of a N-protected amine group, using the CSI reaction of the anti-1,2-dimethyl ether 3, and the subsequent regioselective cyclization of the N-protected amino diol 13 to give the 2-oxazolidinone unit of (-)-cytoxazone 1. [reaction: see text]     

An Improved Synthesis of Hexamethylphenalene

The synthesis of 1,3,4,6,7,9-hexamethylphenalene (2) has been improved from 15 steps to a four step procedure. The overall yield has been increased from an estimated 5% to 45%. Key steps in the synthesis are the reaction of 3,5-dimethylbenzylmagnesium chloride with 2,4-pentanedionato lithium in THF to make 5-(3,5-dimethyl-phenyl)-4-methyl-4-hydroxy-2-pentanone (5) and the Lewis acid acylation-alkation of 1,3,6,8-tetramethylnaphthalene using 3-chlorobutanoic chloride in hexane with sonication to make 1,3,4,6,7,9-hexamethyl-phenalane (2).     

Synthesis of HKI 0231B

[reaction: see text] The total synthesis of HKI 0231B (1b) was completed in 12 linear steps and 15.6% overall yield. An unusual anionic cyclization provided access to intermediate 61 and the embedded benz[cd]indol-3-(1H)-one ring system 3. Directed ortho-lithiation in the presence of a ketone followed by formylation and finally acid-catalyzed methanolysis complete the synthesis. Studies directed toward the construction and reactivity of the lactam acetal functionality present in HKI 0231A (1a) are also reported.     

Electrophile-induced ring expansions of beta-lactams toward gamma-Lactams

[reaction: see text] An efficient and straightforward route toward 3,4-cis-4-isopropenylazetidin-2-ones was developed from 4-(1-chloroalkyl)azetidin-2-ones. Starting from the latter beta-lactams, a new synthesis of pyrrolidin-2-ones was achieved. When 4-isopropenylazetidin-2-ones were treated with bromine in dichloromethane, diastereoselective electrophile-induced ring expansions toward 5-bromopyrrolidin-2-ones were performed. Further oxidation of 3-benzyloxypyrrolidin-2-ones with bromine toward 3-bromopyrrolidin-2-ones was also established. When 4-isopropenyl-beta-lactams were added to a mixture of NBS and TMSN(3), 5-azidopyrrolidin-2-ones were obtained in moderate to high yields.     

Thiopyran route to polypropionates: an efficient synthesis of serricornin

The synthesis of serricornin [(4S,6S,7S)-7-hydroxy-4,6-dimethylnonan-3-one], a sex pheromone produced by the female cigarette beetle (Lasioderma serricorne F.), in seven steps from readily available racemic 1,4-dioxa-8-thiaspiro[4.5]decane-6-carboxaldehyde (6) is described. The key steps include enantioselective aldol reaction of 6 with tetrahydrothiopyran-4-one catalyzed by 5-[(2S)-pyrrolidine-2-yl]-1H-tetrazole to fabricate the tetrapropionate skeleton, stereoselective Li(s)Bu(3)BH reduction of the resulting aldol adduct, Barton-McCombie deoxygenation, and Raney nickel desulfurization.     

Synthesis of 3-methyl-7-[2-(dimethylaminoethyl)oximino]-5-arylcyclopenta [F] Benzoxazolinones,Potential Ligands of the 5HT1D Receptors

The synthesis of 3-methyl-7-[2-(dimethylaminoethyl)oximino]-5-arylcyclopenta [f] benzoxa-zolinones, potential ligands of the 5HT_1D receptors is described through a 4 steps reaction strategy from 3-methyl-6-acetyl benzoxazolinone.     

A novel entry toward 2-imino-1,3-thiazolidines and 2-imino-1,3-thiazolines by ring transformation of 2-(thiocyanomethyl)aziridines

A new, efficient, and straightforward synthesis of 3-arylmethyl-4-chloromethyl-2-imino-1,3-thiazolidines and 2-(N-acylimino)-3-arylmethyl-4-chloromethyl-1,3-thiazolidines has been developed by ring transformation of 1-arylmethyl-2-(thiocyanomethyl)aziridines upon treatment with a catalytic amount of titanium(IV) chloride in dichloromethane. The latter 2-(thiocyanomethyl)aziridines were prepared in high yields from 1-arylmethyl-2-(bromomethyl)aziridines by reaction with potassium thiocyanate in DMF. The 2-imino-1,3-thiazolidines and 2-(N-acylimino)-1,3-thiazolidines thus obtained can be easily interconverted, either by treatment with an acid chloride and a base in ether toward 2-(N-acylimino)thiazolidines or by treatment with potassium carbonate in methanol toward N-deprotected 2-iminothiazolidines. Dehydrohalogenation of 2-(N-acylimino)-3-arylmethyl-4-chloromethyl-1,3-thiazolidines by means of potassium tert-butoxide in DMSO afforded 2-(N-acylimino)-4-methyl-2,3-dihydro-1,3-thiazolines in good yields.     

Selective palladium-catalyzed cocyclotrimerization of arynes with dimethyl acetylenedicarboxylate: A versatile method for the synthesis of polycyclic aromatic hydrocarbons

Benzyne (1a) and the substituted derivatives 4,5-difluorobenzyne (1b) and 3-methoxybenzyne (2) undergo chemoselective palladium-catalyzed [2 + 2 + 2]-cocyclotrimerization with dimethyl acetylenedicarboxylate (DMAD) to afford the corresponding phenanthrenes and/or naphthalenes. The major products are phenanthrenes if Pd(PPh(3))(4) is used as the catalyst, naphthalenes if Pd(2)(dba)(3) is used. When the method is applied to polycyclic arynes 3-6, which are generated from the corresponding o-trimethylsilylaryl triflates, the same reactivity pattern is observed: the reaction can be selectively directed either toward the cocyclization of one molecule of aryne and two molecules of alkyne or to the reaction of two molecules of aryne with one molecule of alkyne, by appropriate choice of the palladium catalyst. The synthesis of polycyclic aromatic compounds 33-39 using this methodology is reported.