An approach to an asymmetric synthesis of stemofoline

A stereoselective Mannich reaction between an (S)-tert-butylsulfinimine and methyl (S)-4-benzyloxy-3-methylbutanoate followed by treatment with acid and N-protection was used to prepare methyl (2R,3S)-2-[(S)-2-benzyloxy-1-methylethyl]-3-tert-butoxycarbonylamino-6-methylenedecanoate. This was taken through to methyl (4R,5S)-4-[(S)-2-benzyloxy-1-methylethyl]-5-tert-butoxycarbonylamino-3,8-dioxododecanoate which on treatment with trifluoroacetic acid cyclised stereoselectively to give (1R,2S,4R,5S)-4-[(S)-2-benzyloxy-1-methylethyl]-1-butyl-2-methoxycarbonyl-8-tert-butoxycarbonyl-3-oxo-8-azabicyclo[3.2.1]octane, a potential precursor of stemofoline. Reduction and N-deprotection of this ketone gave (1R,2S,3R,4R,5S)-4-[(S)-2-benzyloxy-1-methylethyl]-1-butyl-2-methoxycarbonyl-8-azabicyclo[3.2.1]octan-3-ol the structure of which was confirmed by X-ray diffraction.     

Sulfenic Acids from L-Cysteine Involved in the Synthesis of Alliin Analogues

Abstract

L-cysteine is a stimulating starting product for the generation of transient sulfenic acids that add to suitable acceptors, allowing formation of sulfoxides showing a biologically active residue. For instance, N-(tert-butoxycarbonyl)-L-cysteine methyl ester furnished in few steps (R)-2-tert-butoxycarbonylamino-2-methoxycarbonyl-ethanesulfenic acid, which was readily converted into (R,S _S )-(2-tert-butoxycarbonylamino-2-methoxycarbonyl-ethylsulfinyl)ethene, the methyl ester of Boc-protected nor-alliin.     

Diastereoselective amidoallylation of glyoxylic acid with chiral tert-butanesulfinamide and allylboronic acid pinacol esters: efficient synthesis of optically active γ,δ-unsaturated α-amino acids

A convenient synthesis of δ,γ-unsaturated amino acids has been developed. After a mixture of (R)-tert-butanesulfinamide and glyoxylic acid with molecular sieves in CH₂Cl₂ was stirred for 42 h at room temperature, allylboronic acid pinacol ester was added to the mixture to give (R)-2-((R)-tert-butanesulfinamido)pent-4-enoic acid with high diastereoselectivity. The corresponding reaction of (Z)-crotylboronic acid pinacol ester produced no product; however, that of (E)-crotylboronic acid pinacol ester produced (2R,3S)-2-((R)-tert-butylsulfinamido)-3-methylpent-4-enoic acid with excellent diastereoselectivity.     

Enzymatic desymmetrization of 2-amino-2-methyl-1,3-propanediol: asymmetric synthesis of (S)-N-Boc-N,O-isopropylidene-α-methylserinal and (4R)-methyl-4-[2-(thiophen-2-yl)ethyl]oxazolidin-2-one

We report herein, the novel enzymatic desymmetrization of 2-tert-butoxycarbonylamino-2-methyl-1,3-propanediol 1. This method makes it possible to prepare (S)-N-Boc-N,O-isopropylidene-α-methylserinal 3, which is a chiral building block for the synthesis of a variety of α-substituted alanine derivatives. Moreover, optically active (4R)-methyl-4-[2-(thiophen-2-yl)ethyl]oxazolidin-2-one 4, one of the key intermediates in the synthesis of a novel immunosuppressant, has been prepared by this methodology.     

Divergent and solvent dependent reactions of 4-ethoxycarbonyl-3-methyl-1-tert-butoxycarbonyl-1,2-diaza-1,3-diene with enamines

Starting from 1-tert-butyloxycarbonyl-3-methyl-4-ethoxycarbonyl-1,2-diaza-1,3-diene and β,β,β and α,β-substituted enamines a careful choice of solvents and temperatures allows the divergent synthesis of 5,6-dihydro-4H-pyridazines, 2-(1-N-boc-hydrazono-ethyl)-4-pyrrolidin-1-yl-but-3-enoic acid ethyl ester, and 1-amino-pyrroles. Moreover, some interesting conclusions about the mechanism(s) of the reaction have been drawn by careful analysis of products' structure and distribution. Thus, the reaction may proceed through a stereospecific [4+2] cycloaddition mechanism giving rise to 5,6-dihydro-4H-pyridazines or by simple addition or domino addition/cyclization pathways affording, respectively, 2-(1-N-boc-hydrazono-ethyl)-4-pyrrolidin-1-yl-but-3-enoic acid ethyl ester and 1-amino-pyrroles (formally the [3+2] cycloaddition product).     

An efficient synthesis of bislactone skeleton leading to d,l-canadensolide

A novel, stereoselective total synthesis of d,l-canadensolide by application of the two-phase reaction (Bu₄NBr, benzene-H₂O) of 2-bromohexanal with 1,1,2-ethanetricarboxylic acid 2-tert-butyl, 1-ethyl ester, 1-potassium salt (6a) is described.     

A novel intramolecular Ugi 3CC for the synthesis of N-alkyl-3-oxo-2-aryl-1,2,3,4-tetrahydropyrazino[1,2-a]indole-1-carboxamides

An intramolecular Ugi reaction of 2-(2-formyl-1H-indol-1-yl)acetic acid with aryl amines and isocyanides has been developed to produce a novel class of N-alkyl-3-oxo-2-aryl-1,2,3,4-tetrahydropyrazino[1,2-a]indole-1-carboxamides in good yields. This is the first report on intramolecular Ugi three component reaction of 2-(2-formyl-1H-indol-1-yl)acetic acid, aryl amine, and isonitrile.     

Chemoenzymatic synthesis of (3S,4S)- and (3R,4R)-3-methoxy-4-methylaminopyrrolidine

Facile chemoenzymatic enantioselective synthesis of (3S,4S)-3-methoxy-4-methylaminopyrrolidine, a key intermediate for a new quinolone antitumor compound AG-7352 has been described. This methodology illustrates the preparation of 3-azido-1-benzyloxycarbonyl-4-hydroxypyrrolidine starting from diallylamine via 1-benzyloxycarbonyl-3-pyrroline obtained by ring-closing metathesis (RCM) employing Grubbs’ catalyst. Enzymatic transesterification employing PS-C lipase gave (3S,4S)-3-azido-1-benzyloxycarbonyl-4-hydroxypyrrolidine in >99% ee, which upon methylation of the hydroxyl group followed by sequential reactions gave the desired intermediates, (3S,4S)-1-tert-butoxycarbonyl-3-tert-butoxycarbonylamino-4-methoxypyrrolidine.     

Synthesis of macrocyclic precursors of lankacidins using Stille reactions of 4-(2-iodo-alkenyl)azetidinones and related compounds for ring closure

In the context of a proposed total synthesis of lankacidins, the synthesis of 4-(2-iodo-alkenyl)azetidinones and their participation in Stille coupling reactions have been investigated. 1-tert-Butyldimethylsilyl-4-(2-iodoethenyl)azetidinone was found to undergo a Stille coupling reaction with a 3-hydroxy-1-tributylstannylhepta-1,5-diene to give an acceptable yield of the corresponding conjugated diene but the analogous reaction with a 3-tert-butyldimethylsilyloxy-1-tributylstannylhepta-1,5-diene was unsuccessful. A series of 4-[(E)-2-iodoprop-1-enyl]azetidinones, a ring-opened ester and a lactone were also found to undergo Stille reactions with 3-tributylstannylprop-2-enol albeit with variable yields. Asymmetric syntheses of methyl (2R,3R,5S)-3-tert-butyldimethylsilyloxy-2-methyl-5-(2-trimethylsilylethoxy)methoxy-6-oxohexanoate, (3R,4S)-1-tert-butyldimethylsilyl-4-[(E)-2-iodoprop-1-enyl]-3-methylazetidin-2-one, and (5S,2E,6E)-5-tert-butyldimethylsilyloxy-2-methyl-1-phenylsulfonyl-7-tributylstannylhepta-2,6-diene and their incorporation into macrocyclic precursors of the lankacidins were then investigated. Key reactions were a Julia reaction between the aldehyde and the sulfone to form the 12,13-double-bond, a stereoselective acylation of the azetidinone, and formation of macrocycles using intramolecular Stille reactions in the presence of a free hydroxyl group at C(8) (lankacidin numbering).     

Highly diastereoselective aldol additions to five-ring N,O-acetals

Highly diastereoselective aldol additions of pure (2R,4S)-2-tert-butyloxazolidinone-3,4-dicarboxylic acid 3-tert-butyl ester 4-methyl ester 1 are reported. While achiral carbonyl compounds lead to mixtures of diastereomers, the double stereodifferentiation of chiral aldehydes gave a single product isomer. The relative and absolute configurations of the aldol products were assigned by NOESY.     

Asymmetric synthesis of α,α-disubstituted α-amino alcohol derivatives

We herein report an asymmetric synthesis of α,α-disubstituted α-amino alcohol derivatives 3, key intermediates of a novel immunomodulator, using enzymatic desymmetrization of 2-alkyl-2-tert-butoxycarbonylamino-1,3-propanediols 1a and 1b. This method makes it possible to prepare a chiral analogue of FTY720 4. These synthetic procedures allow for a broad structure variation in order to evaluate structure–activity relationships and the mechanism of action for sphingosine 1-phosphate-1 (S1P₁) receptor agonist.     

Calix[4]arene Schiff bases—potential ligands for fluorescent studies

A series of novel double-armed calix[4]arene derivatives incorporating imine substituents were synthesised from the Schiff-base reaction of 25,27-bis[2-[(1-formyl-2-phenyl)oxy]ethyl]-p-tert-butylcalix[4]arene (1) with the appropriate amine or hydrazone. All compounds were characterised by various spectroscopic and analytical techniques, and in three cases, by X-ray crystallographic studies. In the case of compound 2, inclusion compounds were synthesised with both m-xylene and dimethylformamide and their X-ray structures revealed these inclusion sites—between the pendant arms and in the upper cavity, respectively. In all cases, the pendant arms are bent away from each rather than adopting a face-to-face conformation.     

Pyrroles and related compounds—XXXV: A stepwise,general synthesis of unsymmetrically substituted porphyrins

Using a new, general approach involving the stepwise progression through pyrrole, dipyrrole, tripyrrole, to tetrapyrrole, followed by cyclisation of the resulting a,c-biladiene by the copper salt method, syntheses of isocoproporphyrin tetramethyl ester (1b), coproporphyrin-III tetramethyl ester (24), protoporphyrin-IX dimethyl ester (26), 2,4,6,7-tetrakis (2-methoxycarbonylethyl)-5-methoxycarbonylmethyl-1,3,8-trimethylporphin (29) (the ester of the pentacarboxylic porphyrin recently associated with haem metabolism), rhodoporphyrin-XV dimethyl ester (27) and 2,4,7-triethyl-6-methoxycarbonyl-1,3,5,8-tetramethylporphin (28), are described.The route employs condensation of unsymmetrically substituted pyrromethanes with 2-formyl-5-methylpyrroles to give crystalline and fully characterised tripyrrene salts in high yield. These are then condensed with a second mole of a different 2-formyl-5-methylpyrrole to give very high yields of a,c-biladiene dihydrobromides; cyclisation with copper(II) chloride indimethylformamide gives copper(II) porphyrins which are demetallated in trifluoroacetic acid containing sulphuric acid to give high overall yields of the corresponding metal free porphyrins.     

Base dependent purported synthesis of congested 2-aminobenzylamines and tetrahydro-2-oxoquinazolines from 2-pyranones

An expeditious and concise synthesis of highly congested 2-amino-3-aminomethyl-5-methylsulfanyl/-sec-aminobiphenyl-4-carbonitrile 4 and 1-tert-butoxycarbonyl-6-sec-amino-8-aryl-5-cyano-2-oxo-1,2,3,4-tetrahydroquinazoline 5 has been delineated through base catalyzed ring transformation of 6-aryl-4-methylsulfanyl/-sec-amino-2H-pyran-2-one-3-carbonitrile 1 with 1,3-bis(tert-butoxycarbonylamino)-2-propanone 2, followed by TFA catalyzed hydrolysis of the intermediate [3-tert-butoxycarbonylaminomethyl-4-cyano-5-methylsulfanyl/-sec-aminobiphenyl-2-yl]carbamic acid tert-butyl ester 3 in moderate yield. The mechanism of formation of 5 has been established through isolation and transformation of the intermediate 3 to the 1-tert-butoxycarbonyl-6-sec-amino-8-aryl-5-cyano-2-oxo-1,2,3,4-tetrahydroquinazoline.     

Microwave-assisted synthesis and reverse saturable absorption of phthalocyanines and porphyrins

Soluble phthalocyanines, including tetrakis(2,9,16,23-cumylphenoxy) copper phthalocyanines (CuPc(β-CP)₄), tetrakis(1,8,15,22-cumylphenoxy) copper phthalocyanines (CuPc(α-CP)₄) as well as tetrakis(2,9,16,23-tert-butyl) copper phthalocyanines (CuPc(β-t-butyl)₄), and porphyrins (5,10,15,20-tetrakis(4-tert-butylphenyl)porphyrins; M(TBP), M=H₂, Zn, Cu, Mg, InCl, AlCl) have been quickly synthesized by microwave irradiation. Furthermore, their reverse saturable absorption have also been investigated by dissolving them in solvent or incorporating them in polymer-silica hybrid material with a sol-gel process with polyvinyl butyral and tetraethyl orthosilicate as precursors. A new method for the preparation process of phthalocyanines and porphyrins in the solids has been successfully used.     

Ugi three-component coupling reaction for the synthesis of 2-(6-oxo-11-phenyl-7,8-dihydrobenzo[b]pyrrolo[1,2-d][1,4]diazocin-5(6H)-yl)-2-phenylacetamide derivatives

A three-component, four center Ugi reaction of 3-(1-(2-aminophenyl)-5-phenyl-1H-pyrrol-2-yl)propanoic acid with aromatic aldehyde and t-butyl isocyanide has been achieved to produce a novel class of N-tert-butyl-2-(6-oxo-11-phenyl-7,8-dihydrobenzo[b]pyrrolo[1,2-d][1,4]diazacine-5(6H)-yl)-2-phenylacetamides in moderate to good yields.     

Key intermediates in the synthesis of enantiopure antagonists at NMDA receptors: a structural study

The two diastereomeric amino acid derivatives 8 (3aS,5R,6aS)-5-tert-butoxycarbonylamino-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-3,5-dicarboxylic acid diethyl ester, its epimer 9 (3aS,5S,6aS), and carboxylic acid 10 obtained by hydrolysis of 9, which are intermediates in the synthesis of novel NMDA receptor antagonists 6 and 7 (Fig. 1), have been characterized by X-ray studies at 293 K for 8 and 10, and at 100 K for 9. The configuration of the carbon binding the 5-tert-butoxycarbonylamino moiety (BOC) determines the different molecular complexity: the chain structure for 8, dimeric for 9, and chain dimers for 10. The pharmacophoric parameters in compound 8 (from which the active 7 is derived) are comparable with those observed for NMDA receptor antagonism, while 9 and 10 do not present the structural features, which match these pharmacophoric characteristics.     

Convenient synthesis of porphine from β-tetra(tert-butyl)porphyrin

β-Tetra(tert-butyl)porphyrin was prepared from 2-dimethylaminomethyl-4-tert-butylpyrrole and converted into porphine, the mother compound of porphyrins, in 64% yield. The dealkylation smoothly proceeded in aqueous sulfuric acid over 15 min at 190 °C under nitrogen.     

Efficient access to novel hexahydro-chromene and tetrahydro-pyrano[2,3-d]pyrimidine-annulated benzo-δ-sultones via a domino Knöevenagel-hetero-Diels-Alder reaction in water

An efficient catalyst-free, diastereosective synthesis of novel hexahydro-chromene and tetrahydro-pyrano[2,3-d]pyrimidine-annulated benzo-δ-sultones is described. A number of 2-formyl-4-phenyl (E)-2-phenylethenesulfonates were synthesized and underwent a one-pot domino Knöevenagel-hetero-Diels-Alder reaction, respectively, with dimedone and N,N-dimethylbarbituric acid in water, affording the desired products in moderate to excellent yields.     

Synthesis of 5-arylisoxazole- and 4,5-dichloroisothiazole-3-carboxylates derived from natural alcohols,thymol, and its synthetic analogs

Esters derived from 5-phenyl-, 5-(4-methylphenyl)-, and 5-(2,5-dimethylphenyl)-1,2-oxazole-3-carboxylic and 4,5-dichloro-1,2-thiazole-3-carboxylic acids and some natural alcohols (L-menthol, grosshemin), thymol, and synthetic analogs of the latter (4-tert-butylphenol, 4-tert-octylphenol, 2-tert-butyl-4-methylphenol) were synthesized by reactions of the corresponding alcohols with acid chlorides.