A chiral 1,4-oxazin-2-one: asymmetric synthesis versus resolution,structure, conformation and VCD absolute configuration

1,4-Oxazin-2-one 3 is obtained from 2-pinanone in 4 steps and 78% overall yield. Enantiopure (e.e. >99%) (R)-(+)-3 and (S)-(−)-3 were obtained through chiral supercritical fluid chromatography (using a semi preparative Chiralpak AS column) with almost quantitative recovery of material. The structure and the boat-conformation of the lactone ring have been determined by NMR and the absolute configuration determined by VCD.     

Enantioselective synthesis of antibiotic (+)-rancinamycin III derivative and two protected carbasugars of the α-d-talo-series from furan

The synthesis of (+)-1, a carbasugar related to rancinamycin III, has been achieved from diene (+)-3 in two steps using as the key step the transformation of alkyne (−)-2, obtained by resolution of alcohol 6, into diene (+)-3 by treatment with Na/MeOH. Moreover, reduction of the carbonyl group in (+)-1 affords diol (+)-19, in which different protection strategies of the hydroxy groups allows one to obtain, selectively, protected derivatives of α-d-carbatalopyranose (+)-4a and its 6-desoxy derivative (+)-4b to be obtained selectively.     

Stereoselective synthesis of both enantiomers of 1,4-anhydro-alditols, 1,4-anhydro-2-amino-alditols and d- and l-isonucleosides from 2,3-O-isopropylidene-d-glyceraldehyde using iodine-induced cyclization as the key step

We have stereoselectively prepared the enantiomeric 1,4-anhydro-alditols (−)-15 and (+)-15, 1,4-anhydro-2-amino-alditols (−)-19 and (+)-19, and isonucleosides (−)-22, (+)-22 and 25, from 2,3-O-isopropylidene-d-glyceraldehyde. The key step was the iodine-induced cyclization of 4-pentene-1,2,3-triols 2 and 3 to give, respectively, the tetrahydrofuran derivatives 4 and 5. In these compounds we have optimized the substitution of iodine for oxygen-bearing groups. Results were best when we used potassium superoxide as a nucleophile.     

Hydroxylated C-branched pyrrolidines, C-branched prolines and C-branched piperidines from a 2-C-methyl sugar lactone; efficient azide displacement of a tertiary triflate with inversion of configuration

The versatility of 3,4-O-isopropylidene-2-C-methyl-d-arabinonolactone [from d-erythronolactone] as a chiron for complex piperidines and pyrrolidines is illustrated by the synthesis of (2R,3S,4S)- and (2R,3S,4R)-dihydroxy-2-C-methyl prolines, 1,4-dideoxy-1,4-imino-4-C-methyl-l-ribitol and 1,4-dideoxy-1,4-imino-4-C-methyl-l-arabinitol, and isofagomine derivatives; the enantiomeric series is equally accessible from l-erythronolactone.     

Kinetic resolution of (±)-5-bromo-12-oxa-pentacyclo-[6.2.1.16,9.02,7.02,10]dodeca-4-ene-3-endo-ol and (±)-5-bromo-13-oxa-pentacyclo[6.2.2.16,9.02,7.02,10]trideca-4-ene-3-endo-ol via Pseudomonas-mediated lipase-catalyzed transesterification

The kinetic resolutions of alcohols 1 and 2 were performed using three different types of lipases. From this screening, the high ability of Lipase PS-C ‘Amano’ I in the resolution of these compounds was observed. The transesterification of the racemic alcohol 1 lead to the acetate (−)-3 with 42% yield (e.e. >99% by chiral GC) and to the alcohol (+)-1 with 39% yield after three catalytic cycles (e.e. >99% by chiral GC of the chemically obtained acetate (+)-3). The reaction of racemic alcohol 2 lead to the acetate (−)-4 with 48% yield (e.e. >99% by chiral GC) and to the alcohol (+)-2 with 32% yield after two catalytic cycles (e.e. >99% by chiral GC).     

Unusual ring contraction by substitution of 4-O-activated-pentono-1,5-lactams with cyanide. Stereospecific synthesis of 6-amino-1,4,5,6-tetradeoxy-1,4-imino-hexitols

Reaction of 4-O-sulfonylated 2,3-O-isopropylidene-d-ribo- or -d-lyxo-1,5-lactams with tetrabutylammonium cyanide gave 4-amino-5-C-cyano-4,5-dideoxy-2,3-O-isopropylidene-l-lyxo-5 or -l-ribo-15-1,4-lactams, respectively. A stereospecific ring contraction with inversion at C-4 had taken place in each case. Reduction of the cyano-lactams with LiAlH₄ gave 6-amino-1,4,5,6-tetradeoxy-1,4-imino-l-lyxo-6 or -l-ribo-16-hexitol, respectively. The 6-amino-1,4,5,6-tetradeoxy-1,4-imino-l-ribo-hexitol 16 was found to be a moderate inhibitor of α-l-fucosidase with a K_i of 110 μM.     

Synthesis of 1,4-dideoxy-1,4-imino-derivatives of d-allitol, l-allitol and d-talitol: a stereo selective approach for azasugars

A stereo selective approach for the azasugars 1,4-dideoxy-1,4-imino-d-allitol, l-allitol, and 1,4-dideoxy-1,4-imino-d-talitol is described for different olefin compounds I derived from (R)-2,3-O-isopropylidine glyceraldehyde, l-ascorbic acid, and d-isoascorbic acid by using vinyl Grignard addition, allylation, RCM, and dihydroxylation as the key steps.     

Stereo-controlled approach to pyrrolidine iminosugar C-glycosides and 1,4-dideoxy-1,4-imino-l-allitol using a d-mannose-derived cyclic nitrone

Intramolecular N-alkylation of 2,3-O-isopropylidene-5-O-methanesulfonyl-6-O-t-butyldimethylsilyl-d-mannofuranose-oxime 7 afforded a five-membered cyclic nitrone 9, which on N–O bond reductive cleavage followed by deprotection of –OTBS and acetonide functionalities gave 1,4-dideoxy-1,4-imino-l-allitol (DIA) 3. Addition of allylmagnesium chloride to nitrone 9 afforded α-allylated product 10a in high diastereoselectivity providing an easy entry to N-hydroxy-C1-α-allyl-substituted pyrrolidine iminosugar 4a after removal of protecting group, while N–O bond reductive cleavage in 10a afforded C1-α-allyl-pyrrolidine iminosugar 4b.     

Synthesis and elucidation of absolute stereochemistry of salaprinol, another thiosugar sulfonium sulfate from the ayurvedic traditional medicine Salacia prinoides

Synthesis and elucidation of absolute stereochemistry of salaprinol (3) isolated from the root and stems of Salacia prinoides, which has been used for the treatment of diabetes in India, Sri Lanka, and Southeast Asia countries, is described. Compound 3 and its 2′-epimer, epi-salaprinol (epi-3) were synthesized via the coupling reaction of a cyclic sulfate, 2-O-benzylglycerol 1,3-cyclic sulfate (5), with a thiosugar, 1,4-dideoxy-1,4-epithio-d-arabinitol (6), as the key reaction, and S configuration of the asymmetric center in the side chain of 3 was elucidated by the X-ray crystallographic analysis.     

A divergent approach for the synthesis of some polyhydroxy pyrrolidines and piperidines from ribosylamine

A simple and efficient synthesis of 1,4-dideoxy-1,4-imino-d-ribitol, 1,4-dideoxy-1,4-imino-l-lyxitol, N-benzyl derivative of d-ribitol, 3,4,5-trihydroxy-piperidine, l-4-epi-isofagomine and d-3-epi-isofagomine, which are glycosidase inhibitors has been described from the commercially available d-ribose as a starting material.     

A chemoenzymatic approach to the synthesis of the stereoisomers of a β-adrenergic receptor antagonist

The four stereoisomers of Δ²-isoxazoline 2, a β-adrenergic receptor antagonist structurally related to Falintolol 1, were prepared by an enzyme-catalyzed kinetic resolution of the unsaturated secondary alcohol (±)-7 followed by its cycloaddition to pyruvonitrile oxide. Through this strategy, diastereomeric aminoalcohols (+)-2a/(−)-2b and (−)-2a/(+)-2b were obtained in 99 and 92% enantiomeric excess, respectively. The absolute configuration to the target compounds was assigned via chemical correlation to the enantiomers of epoxides 4a and 4b, whose stereochemistry had been previously established.     

Stereoselective synthesis of 1,4-dideoxy-1,4-imino-d-allitol and formal synthesis of (2S,3R,4S)-3,4-dihydroxyproline

A stereoselective synthesis of 1,4-dideoxy-1,4-imino-d-allitol 1 and formal synthesis of (2S,3R,4S)-3,4-dihydroxyproline was achieved via the addition of vinylmagnesium bromide to the benzylimine derived from (R)-2,3-O-isopropylidene glyceraldehyde followed by N-allylation, ring-closing metathesis (RCM), and dihydroxylation.     

An efficient synthesis of 1,4-dideoxy-1,4-imino-d- and l-arabinitol and 1,4-dideoxy-1,4-imino-d- and l-xylitol from chiral aziridines

A highly efficient method for the synthesis of 1,4-dideoxy-1,4-imino-d- and l-arabinitol (d-AB1, 1 and l-AB1, 3) and 1,4-dideoxy-1,4-imino-d- and l-xylitol (d-DIX, 2 and l-DIX, 4) starting from commercially available chiral aziridines was developed. The general strategy employs a sequence involving two-carbon homologation, dihydroxylation, and regioselective aziridine ring opening/intramolecular five-membered iminosugar ring formation. The facile use of recrystallization to generate pure diastereomers makes the routes more amenable to large-scale synthesis.     

Are the absolute configurations of 2-(1-hydroxyethyl)-chromen-4-one and its 6-bromo derivative determined by X-ray crystallography correct? A vibrational circular dichroism study of their acetate derivatives

The vibrational circular dichroism (VCD) spectra of the acetate derivative, 3, of 2-(1-hydroxyethyl)-chromen-4-one, 1, and the acetate derivative, 4, of 6-bromo-2-(1-hydroxyethyl)-chromen-4-one, 2, in the CO stretching region are reported. Density functional theory (DFT) predictions of the VCD spectra of the CO stretching modes of (R)-3 and (R)-4 are in excellent agreement with the experimental spectra for (+)-3 and (+)-4, demonstrating that the absolute configurations of both molecules are (R)-(+)/(S)-(−). Since acetylation of (+)-1 and (+)-2 yields (+)-3 and (+)-4, this in turn leads to (R)-(+)/(S)-(−) for both 1 and 2. The absolute configurations of (−)-1 and (−)-2 were previously determined using X-ray crystallography to be R and S, respectively. Our results lead to the conclusion that the previously reported absolute configuration of 1 is incorrect.This work is the first to apply the ‘conformational rigidification via chemical derivatisation’ methodology to the determination of absolute configuration using VCD spectroscopy and illustrates its utility in determining the absolute configurations of chiral alcohols and, by extension, other classes of chiral molecules containing flexible functional groups.     

Asymmetric oxidation of 1,3-cyclohexadiene catalysed by chloroperoxidase from Caldariomyces fumago

Chloroperoxidase from Caldariomyces fumago catalyses the oxidation of prochiral 1,3-cyclohexadiene using TBHP as terminal oxidant. The process occurs enantioselectively and furnishes the non-racemic trans diols 1,2- and 1,4-dihydroxycyclohexene, (−)-3 and (+)-4, in good ee and yield.     

Stereo-controlled approach to pyrrolidine iminosugar C-glycosides and 1,4-dideoxy-1,4-imino-l-allitol using a d-mannose-derived cyclic nitrone

Intramolecular N-alkylation of 2,3-O-isopropylidene-5-O-methanesulfonyl-6-O-t-butyldimethylsilyl-d-mannofuranose-oxime 7 afforded a five-membered cyclic nitrone 9, which on N-O bond reductive cleavage followed by deprotection of -OTBS and acetonide functionalities gave 1,4-dideoxy-1,4-imino-l-allitol (DIA) 3. Addition of allylmagnesium chloride to nitrone 9 afforded α-allylated product 10a in high diastereoselectivity providing an easy entry to N-hydroxy-C1-α-allyl-substituted pyrrolidine iminosugar 4a after removal of protecting group, while N-O bond reductive cleavage in 10a afforded C1-α-allyl-pyrrolidine iminosugar 4b.     

Enantioselective synthesis of methyl-5(R)-fluorohept-6-ynoate

The asymmetric synthesis of propargylic fluorides, (+)-6 and (+)-3 with ee’s >95%, is reported. The first key step involves an asymmetric transfer hydrogenation of the propargylic ketone 11, using Noyori’s catalyst, to give alcohol (+)-10. The second important step is the highly stereoselective DAST mediated fluorination of the propargylic alcohol (−)-5. The ee determinations were performed using both NMR in chiral solvents and chiral GC. These propargylic fluorides appear to be useful intermediates in the preparation of fluorinated analogues of bioactive chiral molecules.     

Absolute configuration of 2-hydroxy-2-(1-naphthyl)propionic acid as determined by the 1H NMR anisotropy method

Enantiopure 2-hydroxy-2-(1-naphthyl)propionic acid (+)-2 was prepared by the stereoselective Grignard reaction of 1-naphthylmagnesium bromide with (1R,3R,4S)-menthyl pyruvate 3 or (1R,3R,4S)-8-phenylmenthyl pyruvate 4, and the absolute configuration of acid (+)-2 was unambiguously determined to be S by the ¹H NMR anisotropy method.     

Crystal and molecular structure of the levorotatory (1R,2S)-ephedrinium (S)-t-butylsulfinylacetate: a definitive proof of the absolute configuration of enantiomeric t-butyl methyl sulfoxides

The levorotatory enantiomer of t-butylsulfinylacetic acid 3 was obtained in the reaction of the α-carbanion of (+)-t-butyl methyl sulfoxide 1 with carbon dioxide. The same enantiopure form of the acid 3 was isolated from its diastereomerically pure levorotatory salt 5 with (−)-(1R,2S)-ephedrine. The structure of this salt was determined by X-ray analysis and the absolute configuration (S) at sulfur was ascribed to the t-butylsulfinylacetate anion. Consequently, the absolute configuration (S) was assigned to the acid (−)-3 and its precursor (+)-t-butyl methyl sulfoxide 1.     

Asymmetric synthesis of triepoxyzerumbol

The achiral sesquiterpene zerumbone 1, which is readily available from wild ginger, has a unique functionality and reactivity making it a convenient starting material for its conversion into useful compounds, such as paclitaxel. Optically active triepoxyzerumbol (−)-3 and its acetate (+)-4 were synthesized by lipase-catalyzed enantioselective transesterification of racemic 3. Under optimized conditions, a lipase from Alcaligenes sp. (Meito QL) catalyzed the reaction of racemic 3 with isopropenyl acetate in THF at 35 °C to afford (1S)-3 and (1R)-4 with an E-value of 79. The absolute configuration of (1R)-4 was determined by single crystal X-ray diffraction of its ester with a chlorine atom using the anomalous dispersion effect.