Design and synthesis of a multi-detachable benzhydrylamine-resin for solid phase peptide synthesis

Peptides with C-terminal α-carboxamides were synthesized from a multi-detachable benzhydrylamine-resin containing a Boc-(4-acetoxy)benzhydryl-amine handle of unambiguous origin. The peptides bound to the new resin are stable to trifluoroacetic acid, but are cleavable by hydrogen fluoride, base and nucleophiles to give unprotected or protected peptide fragments.     

Enantioselective synthesis of a potential key intermediate for the total synthesis of fumagillin

Key intermediate, 7, of a projected total synthesis of the anti-angiogenesis compound Fumagillin 1 and the semi-synthetic analogue TNP-470 2, has been prepared in enantiomerically pure form by employing an early nucleophilic addition ring closure [NARC] sequence to construct the cyclohexene backbone.     

Facile synthesis of a key intermediate for the synthesis of prostanes and isoprostanes

An unconventional ring opening of β-sultines followed by an elimination step was achieved, leading to the formation of an important synthon for various prostanes and isoprostanes.     

Asymmetric synthesis of a chiral building block for cyclopentanoids: a novel enantioselective synthesis of preclavulone A

A new asymmetric approach to the hydroxylactone (+)-(3aR,4R,6aS)-4-(hydroxymethyl)-3a,4-dihydro-3H-cyclopenta[b]furan-2(6aH)-one (1), a key synthetic building block for cis-1,2-disubstituted five-membered ring derivatives (i.e., isoprostanes, jasmonates, and clavulones), has been described. A remarkable control of the absolute and relative configuration of the three stereocenters was achieved. Thus, the use of the Trost's asymmetric allylic alkylation strategy secured highly enantioenriched (R)-3-(nitromethyl)cyclopent-1-ene (13), which was smoothly converted to (R)-cyclopent-2-enecarboxylic acid (15) in excellent yield and high enantiomeric purity (>98% ee). 6-exo-trig atom-transfer radical cyclizations of ((R)-cyclopent-2-enyl)methyl 2-iodoacetate (12) produced exclusively the desired cis-fused delta-lactone (4aR,7aR)-hexahydro-5-iodocyclopenta[c]pyran-3(1H)-one (11), which was subsequently elaborated to hydroxylactone 1 through a stereocontrolled Pd(II)-mediated lactonization reaction. En route to preclavulone A, a putative elusive intermediate in the biosynthesis of clavulones, the synthetic utility of compound 1 was demonstrated. The key feature in this synthesis was the installation of the lower side chain via the Knochel organozinc sp3-sp C-C coupling protocol.     

Use of a mesoporous material for organic synthesis

A common problem in synthetic organic chemistry is attaining proper contact between lipophilic organic compounds and inorganic salts. Various strategies, for example, phase transfer catalysis (Starks, C. M.; Liotta, C. L.; Halpern, M. Phase Transfer Catalysis: Fundamentals, Applications and Industrial Perspectives; Chapman & Hall: New York, 1994) or use of a microheterogeneous medium such as a microemulsion (Hager, M.; Currie, F.; Holmberg, K. Organic Reactions in Microemulsions. In Colloid Chemistry II; Antonietti, M., Ed.; Topics in Current Chemistry 227; Springer-Verlag: Heidelberg, 2003; p 53) have been worked out to tackle the issue. Here, we report that mesoporous solid materials made from surfactant self-assembly can be used as medium for such reactions. The material is made from silica, and the pore size is large, relatively uniform, and can be controlled with a high degree of precision by the choice of surfactant that is being used as template (Palmqvist, A. E. C. Curr. Opin. Colloid Interface Sci. 2003, 8, 145). The pores are hydrophilic and are filled with an aqueous solution containing the inorganic salt. The porous material is dispersed in the lipophilic organic substrate, that is, 4-tert-butylbenzyl bromide, or in a hydrocarbon solution of this substrate. The reaction occurs at the hydrophilic/lipophilic interface, and, because the interface is large, the reaction is fast. A considerable advantage with this new reaction medium is that the workup procedure is extremely facile. After the reaction is completed, the solid is simply removed by filtering or centrifugation.     

Chemo-enzymatic synthesis of a multi-useful chiral building block molecule for the synthesis of medicinal compounds

Optical resolution of 2-methyl-2-nitrobut-3-en-1-ol has been accomplished using a "low-temperature lipase-catalyzed transesterification" carried out at -40 °C.     

Efficient synthesis of a side-chain extended diaminodiacid for solid-phase synthesis of peptide disulfide bond mimics

Solid-phase incorporation of diaminodiacids is one of the most effective approaches for synthesis of peptide disulfide bond mimics. One of a limitation of current diaminodiacid toolbox is that only four-atom linkage mimics are available that may not fully meet the activity optimization requirement. In this work, we developed a new diaminodiacid that contains a five-atom thioether (C–C–S–C–C) bridge for the first time. With this diaminodiacid in hand, we successfully obtained oxytocin containing new disulfide bond mimic by solid phase peptide synthesis.     

Design and synthesis of a dual linker for solid phase synthesis of oleanolic acid derivatives

A hydrophilic amino-terminated poly(ethylene glycol)-type dual linker for solid phase synthesis of oleanolic acid derivatives using trityl chloride resin was designed and synthesized for the first time. Model reactions in both liquid and solid phase were performed to show the feasibility of its selective cleavage at two different sites. The biological assay results indicated that the long and flexible alkyl ether functionality in the linker is less likely to be critical for the binding event. Following the successful solid-phase synthesis of model compounds, the potential of this dual linker in reaction monitoring and target identification is deemed worthy of further study.     

Design and synthesis of a cavitand pillar for MOFs

In this paper, we report the first example of a tetramethylene bridged cavitand with two distal methylbenzoate legs at the lower rim, adopting a unique and unprecedented equatorial equatorial (ee) configuration both in solution and in the solid state, as confirmed by NMR and single crystal X-ray diffraction. The presence of functional groups, which are potential metal binding sites in the ee configuration, makes these cavitands suitable candidates to be used as pillars in metal-organic frameworks (MOF) as specific molecular recognition units.     

Chemical synthesis of a structural gene coding for trichosanthin

A structural gene (750 bp), which codes for a type I ribosome inactivating protein, trichosanthin, has been designed according to the codon usage of highly expressed gene in E. coli and chemically synthesized. In the synthesized gene, twenty-seven unique restriction sites were evenly dispersed with an average distance between two adjacent sites less than 50 bp to facilitate a systematic investigation on structure-functional relationship of this protein by site-directed muta-genesis. To synthesize it, the whole gene was divided into three large fragments (EP, PN and NH) which were assembled from several chemical synthetic oligonucleotides by enzymatic method. The assembly of both the fragment EP from six oligonucleotides (A-F) and the fragment PN from four oligomers (G-J) was catalyzed by T4 DNA ligase in using the single stranded DNA method [Chen, H.-B. et al, Nucl. Acids Res., 18, 871(1990)]. And fragment NH was formed from three duplexes K, L and M by the classical double stranded DNA method. Finally,     

36-Dimethoxybenzocyclobutenone: a reagent for quinone synthesis

3,6-Dimethoxybenzocyclobutenone 4 is prepared in four efficient steps from 2,5-dimethoxybenzoic acid 8. The derived benzocyclobutenol 13 undergoes electrocyclic ring opening at 110–115°C to give the hydroxy-o-quinone dimethide 21, which reacts with dienophiles to give 5,8-dimethoxy-1,2,3,4-tetrahydro-1-naphthol derivadves stereoselecdvely. Since the ketone 4 can be functionalised at C-5 using electrophiles and at C-2 via hoimolytic bromination, the ring opening and cycloaddition sequence offers a flexible route to linear fused hydroquinone and quinone derivatives. In model studies, the benzocyclobutenol derivative 48 underwent thermal electrocyclic ring opening and intramolecular cycloaddition to give 49, while the analogous reaction with 52 failed due to adverse steric effects during the cycloaddition step. In photochemical experiments, attempts to generate the silyi ether 57 by in situ silylation of the dienol 55 and to prepare the benzocyclobutenol 62 via irradiation of the o-phthalaldehyde monoacetal 60 were unsuccessful.     

Ketones as a new synthon for quinoxaline synthesis

o-Phenylenediamines react with an array of ketones in PEG-400 at 60 °C under an atmosphere of air in the presence of KOH to afford the corresponding quinoxalines in good yields.     

Chiral ring a synthons for vitamin d synthesis

A unique approach to vitamin d compounds via chiral bicyclo-[3.1.0]-hexane derivatives is described.     

Diversity-oriented synthesis; a challenge for synthetic chemists

The efficient, simultaneous synthesis of structurally diverse compounds, better known as diversity-oriented synthesis (DOS), is not obvious, and remains a challenge to synthetic chemistry. This personal account details why DOS has such enormous implications for the discovery of small molecules with desired properties, such as catalysts, synthetic reagents, biological probes and new drugs, Also, I describe the evolution behind the current state-of-play of DOS.     

增感剂DPO的合成工艺研究

以苯亚磺酸钠和氯乙酸乙酯为起始原料,首先合成苯砜乙酸乙酯(Ⅰ);再与由1,1,3,3-四甲氧基丙烷与二乙胺反应得到的N,N-双乙基胺-1,3-二丙烯醋酸盐反应,得5-二乙基氨基-2-苯磺酰基-2,4-戊二烯乙酸乙酯(Ⅱ)中间体;最后与正辛醇酯交换得到目标产物5-二乙基氨基-2-苯磺酰基-2,4-戊二烯乙酸辛酯(DPO)。考察了溶剂的种类对制备化合物Ⅰ和投料比、反应温度对制备化合物Ⅱ的影响,并且通过重结晶法纯化DPO产品,最终可使产品DPO收率达到69.58%、产品纯度大于99.50%,并通过LC-MS和1H NMR对产品及中间产品进行了结构分析与确证。     

A new germanium-based linker for solid phase synthesis of aromatics: synthesis of a pyrazole library

An efficient synthesis of chlorogermane linker 12 is described. Economic introduction of germanium into this linker is accomplished by insertion of dichlorogermylene [from germanium(IV) chloride] into the homobenzylic C-Cl bond of 4-(2-chloroethyl)phenol 1. Using linker 12, transmetalation with lithiated 4-acetophenone, 3-acetophenone, and 4-(4'methoxy)biphenyl followed by Mitsunobu-type coupling to Argogel gives functionalized resins 14, 16, and 18, respectively. Treatment of resin 18 with TFA, ICl, Br2, or NCS effects clean ipso-degermylation releasing biphenyls 19-22, respectively. Resins 14 and 16 are employed for the parallel synthesis of a library of pyrazoles by enaminone formation (using Bredereck's reagent), condensative ring-closure (using a series of monosubstituted hydrazines), and cleavage (using TFA and Br2). Analysis of this library reveals the influence of the hydrazine substituent on both the regioselectivity of ring-closure and the propensity for electrophilic substitution at the 4-position of the pyrazoles during ipso-degermylative cleavage.     

Total synthesis of (+)-aspidospermidine: a new strategy for the enantiospecific synthesis of aspidosperma alkaloids

A new strategy was developed for the enantiospecific synthesis of aspidosperma alkaloids. The key steps involve a novel ketene-lactonization reaction of a chiral vinyl sulfoxide to efficiently set up the quaternary carbon center, and a tandem Michael addition-alkylation reaction sequence to form the polycyclic core structure. This new strategy was employed in the total synthesis of natural product (+)-aspidospermidine.     

In-situ synthesis of a palladium-polyaniline hybrid catalyst for a Suzuki coupling reaction

Palladium-catalyzed cross-coupling reactions are one of the most frequently used synthetic tools for the construction of new carbon-carbon bonds in organic synthesis. The present study describes the use of palladium-polyaniline composite material as a catalyst for the Suzuki coupling of aryl halides. Palladium-polyaniline nanocomposite material was synthesized using an in-situ technique in which palladium acetate and aniline hydrochloride were used as the precursors of the composite. Electron microscopy imaging showed that the palladium particles were well-dispersed within the polymer matrix and were typically 3-5 nm in diameter. The metal-polymer composite material was used as a catalyst for the coupling of phenylboronic acid with aryl halides in the presence of an inorganic base and showed excellent yield with high TOF values.