Asymmetric synthesis of macrolactin analogue

Total asymmetric synthesis of macrolactin A analogue was accomplished by the convergent strategy. Rapid access to advanced intermediate 16 through isomerization of ynone to (E,E)-conjugated dienone is a key step of this synthesis. Overall, control of all of the four stereocenters was achieved by means of asymmetric and diastereoselective reactions without using any chiral natural sources.     

Asymmetric synthesis of the highly potent anti-metastatic prostacyclin analogue cicaprost and its isomer isocicaprost

An asymmetric synthesis of the anti-metastatic prostacyclin analogue cicaprost and a formal one of its isomer isocicaprost by a new route are described. A key step of these syntheses is the coupling of a chiral bicyclic C6-C14 ethynyl building block with a chiral C15-C21 omega-side chain amide building block with formation of the C14-C15 bond of the target molecules. A highly stereoselective reduction of the thereby obtained C6-C21 intermediate carrying a carbonyl group at C15 of the side chain was accomplished by the chiral oxazaborolidine method. The chiral phosphono acetate method was used for the highly stereoselective attachment of the alpha-side chain to the bicyclic C6-C21 intermediate carrying a carbonyl group at C6. Asymmetric syntheses of the bicyclic C6-C14 ethynyl building blocks were carried out starting from achiral bicyclic C6-C12 ketones by using the chiral lithium amide method. In the course of these syntheses, a new method for the introduction of an ethynyl group at the alpha-position of the carbonyl group of a ketone with formation of the corresponding homopropargylic alcohol was devised. Its key steps are an aldol reaction of the corresponding silyl enol ether with chloral and the elimination of a trichlorocarbinol derivative with formation of the ethynyl group. In addition, a new aldehyde to terminal alkyne transformation has been realized. Its key steps are the conversion of an aldehyde to the corresponding 1-alkenyl dimethylaminosulfoxonium salt and the elimination of the latter with a strong base. Two basically different routes have been followed for the synthesis of the enantiomerically pure C15-C21 omega-side chain amide building block. The first is based on the chiral oxazolidinone method and features a highly stereoselective alkylation of (4R)-N-acetyl-4-benzyloxazolidin-2-one, and the second encompasses a malonate synthesis of the racemic amide and its efficient preparative scale resolution by HPLC on a chiral stationary phase containing column.     

Asymmetric synthesis of SMS-Phos series’ precursor and a naphthalene analogue

An efficient and high-yielding (up to 57% overall yield) asymmetric route to enantiopure P-stereogenic 1,2-bis[(o-hydroxyaryl)(phenyl)phosphino-P-borane]ethanes wherein aryl = phenyl and naphthyl, is presented. The occurring P-stereomutation is confirmed through X-ray crystal structure analysis of key intermediates.     

Asymmetric synthesis of fagomine and its congeners

The total synthesis of fagomine and its congeners 1–3 has been achieved starting from d-serine-derived Garner aldehyde 5 by catalytic ring-closing metathesis (RCM) for the construction of the piperidine ring followed by dihydroxylation.     

Asymmetric formal synthesis of schulzeines A and C

The asymmetric formal synthesis of schulzeines A and C is described. Key features of the synthesis include the efficient and stereoselective construction of the benzoquinolizidine skeleton via the aza-Claisen rearrangement-induced ring expansion of the 1-vinyl-N-glycyl-isoquinoline, which was prepared by the highly enantioselective asymmetric allylation of the 8-benzyloxy-substituted dihydroisoquinoline and by the acid-catalyzed transannulation of the resulting 10-membered lactam.     

O-磷酸酰化多肽及其类似物的化学合成

O-磷酸酰化多肽及类似物对研究和阐明蛋白质可逆磷酸化对生命活动的调节机制具有极其重要的作用,本文总结了近年来发展起来的用现代化学方法合成O-磷酸酰化多肽及类似物的有效策略,如总体磷酸化法、磷酸化单体法等,并概述了常用的磷酸化方法及磷肽类似物的合成方法等。     

Asymmetric synthesis of a new simplified dynemicin analogue equipped with a handle

The new simplified dynemicin analogue 16 was prepared enantio- and diastereoselectively in 17 steps starting from monoacetate (S) 7. It is equipped with a side arm containing a protected primary alcoholic function (`handle'), which can be used for conjugation with DNA-complexing agents or for devising new types of trigger.     

Total synthesis of Trichosanthes trypsin inhibitor and its analogue

Trichosanthes trypsin inhibitor (TTI) is a peptide consisting of 27 amino acid residues with three pairs of disulfide bonds. This paper reports the total synthesis and disulfide bond refolding of this inhibitor and its analogue. After purification, the amino acid sequence and stoichiometrical inhibitory activity against trypsin of the synthetic inhibitor were compatible with those of the natural inhibitor. The analogue of this inhibitor in which residue Met in position 6 was replaced by Ala was also synthesized. The antitrypsin activity of this synthetic analogue was also approximate to that of the natural inhibitor.     

Asymmetric synthesis of cytotoxic sponge metabolites R-strongylodiols A and B and an analogue

The asymmetric synthesis of the marine sponge natural products R-strongylodiols A R-1 and B R-2, using a minimum protection strategy, is described. Two approaches were examined and the Noyori asymmetric reduction of ynones was found to be successful for installing the chirality of the natural products. Analogue R-32 was also prepared. In addition, asymmetric alkynylation of aldehydes is briefly reviewed.     

Asymmetric synthesis of warfarin and its analogues on water

The asymmetric Michael addition of 4-hydroxycoumarin to α,β-unsaturated ketones on water without organic co-solvents is reported to be catalysed by organic primary amines. The application of enantiomerically pure (S,S)-diphenylethylenediamine affords a series of important pharmaceutically active compounds in good to excellent yields (73–98%) and with good enantioselectivities (up to 76% ee) via reactions accelerated by ultrasound. In particular, our developments led to an efficient protocol for the ‘solids on water’ formation of the anticoagulant warfarin in both enantiomeric forms. The presented scalable and environmentally friendly organocatalytic approach affords the target drug in enantiomerically pure form.     

Total synthesis of biseokeaniamides A–C and late-stage electrochemically-enabled peptide analogue synthesis

The first total synthesis of cytotoxic cyanobacterial peptide natural products biseokeaniamides A–C is reported employing a robust solid-phase approach to peptide backbone construction followed by coupling of a key thiazole building block. To rapidly access natural product analogues, we have optimized an operationally simple electrochemical oxidative decarboxylation–nucleophilic addition pathway which exploits the reactivity of native C-terminal peptide carboxylates and abrogates the need for building block syntheses. Electrochemically-generated N,O-acetal intermediates are engaged with electron-rich aromatics and organometallic reagents to forge modified amino acids and peptides. The value of this late-stage modification method is highlighted by the expedient and divergent production of bioactive peptide analogues, including compounds which exhibit enhanced cytotoxicity relative to the biseokeaniamide natural products.

A late-stage electrochemical decarboxylation enables rapid access to structural analogues of biseokeaniamides A–C, cytotoxic lipopeptide natural products.     

A facile and improved synthesis of desomorphine and its deuterium-labeled analogue

Abstract  

This work describes a convenient and improved process for the synthesis of desomorphine from codeine. The proposed method affords the highly pure opiate without the aid of chromatographic purification, and provides a simple route for the synthesis of [²H₃] deuterium-labeled desomorphine.     

Asymmetric total synthesis of botcinins C, D, and F

Stereoselective total synthesis of botcinins C, D, and F is effectively carried out through asymmetric aldol reactions, 6-endo ring closure, and SmI2-mediated 3,4-trans or -cis stereoselective intramolecular Reformatsky reaction. Rapid esterification of the main skeleton of botcinins with the chiral side chain using MNBA and DMAP produced botcinin D, an antifungal chemical against a pathogen of rice blast disease.     

Asymmetric synthesis of (+)-passifloricin A and its 6-epimer

Stereoselective total syntheses of the antiprotozoal natural product (+)-passifloricin A and its C-6 epimer have been achieved in ～5% overall yield. The strategy is based on Jacobsen epoxidation, Grubbs’ metathesis and an Evans’ intramolecular oxa-Michael reaction.     

Efficient synthesis of oligoribonucleotide and its phosphorothioate analogue using H-phosphonate approach

Efficient solid phase synthesis of oligoribonucleotide and its phosphorothioate analogue is described that utilizes the dimethoxytrityl (DMTr) for 5′-protection and t-butyldimethylsilyl (t-BDMS) group for 2′-protection of ribonucleoside monomers and the H-phosphonate coupling procedure. The synthetic cycles have been optimised to use only 8–10 fold excess of monomer at each coupling step, leading to an average coupling yield of 97%.     

Asymmetric total synthesis of dendrobatid alkaloids: preparation of indolizidine 251F and its 3-desmethyl analogue using an intramolecular Schmidt reaction strategy

Total syntheses of alkaloid 251F (1), a natural product detected from the skin extracts of the dendrobatid frog species Minyobates bombetes, and its racemic 3-desmethyl derivative (2) are reported. A Diels-Alder reaction initiated both syntheses and established four consecutive stereogenic centers. Important to the synthesis of 2 was a first-generation ozonolysis/olefination/aldol strategy to convert a [2.2.1] bicyclic acid to the [3.3.0]bicyclooctane diquinane 4b. Further elaboration to an appropriate keto azide allowed for a key intramolecular Schmidt reaction to deliver the tricyclic core of the target molecule. In a second-generation approach, a tandem ring-opening/ring-closing metathesis reaction effected an overall [2.2.1] --> [3.3.0] skeletal rearrangement to deliver diquinane 4a. In similar fashion, 4a was manipulated to an appropriate keto azide, and an intramolecular Schmidt reaction generated the core cyclic architecture of 251F.     

Asymmetric synthesis of 7-aza-phomopsolide E and its C-4 epimer

A flexible, enantioselective route to highly functionalized α,β-unsaturated δ-lactones has been applied to the synthesis of 7-aza-phomopsolide E and its C-4 epimer. This approach relies on the application of the Noyori asymmetric hydrogenation of furyl ketone to produce the secondary furyl alcohol in high enantioexcess, which can be stereoselectively transformed into α,β-unsaturated-δ-lactones by a short, highly diastereoselective oxidation and reduction sequence. DCC and acid chloride couplings were used to introduce the side chains of the two natural product analogues.     

Divergent total synthesis of penaresidin B and its straight side chain analogue

The divergent synthesis of penaresidin B and its straight side chain analogue was accomplished by constructing an azetidine ring via S_N2 type cyclization of protected 2,3-syn-3,4-syn-4-amino-1,3-dihydroxyhept-6-en-2-yl mesylate and late-stage introduction of an alkyl side chain via olefin cross-metathesis of 4-allylazetidine with readily available terminal alkenes. This synthetic route would be useful to synthesize penaresidin side chain analogues.     

A novel peptide from Apis mellifera and solid-phase synthesis of its analogue

A novel peptide designated secapin-1,was purified and characterized from Apis mellifera.The molecular weight of 25 amino acid peptide secapin-1 was found to be 2821.5625 Da by ESI-FTICR-MS.It showed high identity to secapin.The sequence of secapin-1 was determined to be YIINVPPRCPPGSKFVKNKCRVIVP by automatic Edman degradation.A disulfide bond was formed between Cys⁹ and Cys²⁰ residues.In addition,an analogue of secapin-1 was synthesized by solid phase peptide synthesis method.The synthesis product was successfully purified and identified to homogeneity by using a combination of SEC,IEC,and RP-HPLC techniques.     

Asymmetric synthesis and conformation

The configuration of the 3-alkyl substituted 1,2,3-triphenyl-1-propanones is proved through use of pseudocontact shifts using Eu(dpm)₃. The conformation of all isomers, regardless of size of R, is similar (trans vicinal protons). The relative stability of the two isomers is also independent of R up to R = t-Bu. The conformation and configuration of the hydride reduction products, the alkyl substituted 1,2,3-triphenyl-1-propanols, are elucidated through use of NMR chemical shifts, coupling constants, pseudocontact shifts, and by IR spectra. The starting materials and reduction products (with one exception) have the same conformation at relevant centers, yet the mode of hydride attack is best explained by means of a different conformation in the transition state, in which the LAH approaches over a proton at either asymmetric center.