Stereoconvergent synthesis of N-Boc-(2R,3S)-3-hydroxy-2-phenylpiperidine

The stereoconvergent synthesis of N-Boc-(2R,3S)-3-hydroxy-2-phenylpiperidine from (R)-1-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)piperidin-2-one is described. The key steps involved are α-hydroxylation of quiral lactam with O₂, stereoconvergent reduction of (R)- or (S)-3-(benzyloxy)-piperidin-2-one with Red-Al® which afforded in both cases the trans-bicyclic oxazolidine in high stereoselectivity after chromatographic purification and a stereospecific Grignard addition to chiral bicyclic oxazolidine.     

Stereoselective synthesis of oxiranes using oxazolidines derived from 2-amino-2-deoxy-d-allose as chiral auxiliaries

The synthesis of 2,3-epoxyamide derivatives of 2-amino-2-deoxy-d-allose is described. Epoxidation of the corresponding α,β-unsaturated amides with m-CPBA took place with better stereoselectivity when an oxazolidine ring was fused to the 2,3-positions of the sugar molecule. In most cases, both stereoisomers could be isolated and characterized. The stereochemistry of the new stereogenic centers was then determined by cleavage of the oxirane moiety from the chiral auxiliary, which was also recovered.     

Synthesis of the N-(tert-butyloxycarbonyl)-O-triisopropylsilyl-d-pyrrolosamine glycal of lomaiviticins A and B via epimerization of l-Threonine

An efficient synthesis of the N-(tert-butyloxycarbonyl)-O-triisopropylsilyl-d-pyrrolosamine glycal of lomaiviticin A (1) and lomaiviticin B (2) is described. The synthesis is highlighted by the epimerization of the l-threonine-derived oxazolidine 10 to oxazolidine 11. This key epimerization reaction, which serves to establish the correct relative configuration of the carbohydrate unit, was made possible only after conformational analysis indicated that substituted oxazolidines may adopt conformations that preclude enolization.     

Convenient asymmetric synthesis of beta-trifluoromethyl-beta-amino acid, beta-amino ketones, and gamma-amino alcohols via Reformatsky and Mannich-type reactions from 2-trifluoromethyl-1,3-oxazolidines

The stereoselective syntheses of beta-trifluoromethyl-beta-amino ester, beta lactams, and beta-amino ketones starting from an oxazolidine derived from trifluoroacetaldehyde hemiacetal and (R)-phenylglycinol are reported. The Mannich-type reaction involving a chiral fluorinated iminium ion occurred in a good yield and with a higher stereoselectivity (dr up to 96:4) than that of the Reformatsky-type reaction. This straightforward strategy was applied to the short syntheses of (R)-3-amino-4,4,4-trifluorobutanoic acid, a series of novel enantiopure unprotected fluorinated beta-amino ketones, and their corresponding gamma-amino alcohols.     

A new convergent and stereoselective synthesis of 2,5-disubstituted N-acylpyrrolidines

A new synthesis of 2,5-disubstituted N-acylpyrrolidines through an S_N2′ reaction promoted by the nitrogen anion of a secondary amide onto an allylic bromide is reported. A moderate stereoselectivity, in favour of the trans heterocycle, was observed during the cyclization of a chiral precursor, while a good stereoselectivity, this time in favour of the cis one, was obtained when the second stereocentre was introduced after the cyclization step to give the same product.     

Structural and electronic effects of oxazolidine ligands derived from (1R,2S)-ephedrine in the asymmetric addition of diethylzinc to aldehydes

The purpose of this research was to determine the activity of chiral oxazolidine ligands prepared from (1R,2S)-ephedrine for the enantioselective addition of diethylzinc to aldehydes. The configuration on the newly formed C2 stereogenic center was determined as (2S) by X-ray structural analysis. Oxazolidine ligands reveal medium enantioselectivity with the ee exceeding 57%, and the yields obtained being 68–99%. The results indicate that the absolute configuration of the addition product depends not only on the N3-methyl as an important stereocontrol element but also on both the electronic and steric effects of the substrates and oxazolidine ligands.     

Solvation effects on stereochemistry of reduction of 3,3,5-trimethylcyclohexanone with lithium aluminum tri-t-butoxyhydride

Specific solvation effects on stereoselectivity in the reduction of a cyclohexanone by lithium aluminum tri-t-butoxyhydride have been studied by adding measured quantities of diethyl ether, tetrahydrofuran (THF) and methyl-substituted tetrahydrofurans to benzene solvent, and various amounts of THF to diethyl ether solvent. A steric hindrance effect in the case of bulky addends was observed, and a significant increase in stereoselectivity for less bulky addends was found. The results have been explained in terms of complexing, or steric hindrance to complexing, of the lithium cation.     

Highly enantioselective palladium-catalyzed hydrosilylation of norbornene with trichlorosilane using ferrocenyl ligands

The Pd-catalyzed hydrosilylation of norbornene with trichlorosilane using different chiral ferrocenyl ligands containing a phosphine and a pyrazole as donors was studied. Both steric and electronic factors affect stereoselectivity in this system. The combination of a sterically bulky pyrazole substituent with a π-acidic phosphine leads to an enantioselectivity of >99.5% ee. Important substrate electronic effects on stereoselectivity were observed using para-substituted styrenes.     

Using amide conformation to ‘project’ the stereochemistry of an (−)-ephedrine-derived oxazolidine: a pair of pseudoenantiomeric chiral amido-phosphine ligands

Protection of a tertiary 2-formylbenzamide as an (−)-ephedrine-derived oxazolidine both forces the amide's stereogenic Ar–CO axis to adopt one of two possible diastereoisomeric conformations and protects the formyl group from attack during amide ortho-lithiation. By functionalising the amide in the 6-position, reactive sites (such as –CHO, –SR, –PR₂ groups) may be introduced which fall under the stereochemical influence, relayed by the amide, of the (−)-ephedrine-derived oxazolidine. This ‘projection’ of stereochemistry is exemplified by a pair of amido-phosphines, members of the first ever class of non-biaryl atropisomeric ligands, which are made functionally pseudoenantiomeric by the intervention of either one or two amide groups between the (−)-ephedrine-derived oxazolidine and the PPh₂ group. The pseudoenantiomeric amido-phosphines promote the palladium-catalysed asymmetric allylation of dimethyl malonate in 82 and −53% e.e., respectively.     

Water—More Than Just a Green Solvent: A Stereoselective One‐Pot Access to All‐Chiral Tetrahydronaphthalenes in Aqueous Media

A facile and highly stereoselective construction of heavily functionalized chiral tetrahydronaphthalene skeletons fused with an oxazolidine moiety has been developed. The process involves an organocatalytic tandem Michael/nitrone formation/intramolecular [3+2] nitrone–olefin cycloaddition in aqueous media. Using rationally designed substrates, the reaction conditions have been optimized and the one‐pot process has been applied to a series of nitroolefin acrylates and aldehydes. The N‐hydroxyphenylamine component used in the second step has also been varied. The stereochemistry of one product has been verified by an X‐ray crystal structure determination. The water used in the strategy not only constitutes an environmentally benign solvent, but also helps to improve the reactivity and stereoselectivity.     

Direct conversion of 1-deoxy-1-nitroalditols to methyl glycofuranosides

Treatment of the sodium nitronate forms of 1-deoxy-1-nitrohexitols with methanolic sulfuric or hydrochloric acid at −30 °C leads to their regiospecific conversion to the corresponding methyl glycofuranosides. The reaction exhibits more pronounced stereoselectivity for 1-deoxy-1-nitroalditols with the 2,3-erythro configuration than with the 2,3-threo substrates and cis methyl glycofuranosides are the major products. The observed stereoselectivity indicates the lysis of the protonated aci-nitro form which is a two-step process consisting of nucleophilic addition to the protonated carbon-nitrogen double bond followed by the bimolecular nucleophilic substitution of the nitrogen-containing residue.     

Synthesis and thermal crosslinking of oxazolidine‐functionalized polyurethanes

A new oxazolidine derivative was obtained from phenol, 2‐amino‐2‐methylpropane‐1,3‐diol and paraformaldehyde. The reaction of this novel oxazolidine diol with phenylisocyanate lead to a urethane model compound which can be polymerized thermally by oxazolidine ring opening to give a Mannich bridge structure. Linear segmented polyurethanes were prepared by reaction of different ratios of oxazolidine diol and commercial polyethylenglycol (M_w ～ 400) with 4,4′‐methylenbis (cyclohexylisocyanate) (HMDI, 90% isomers mixture). The polyurethanes were thermally characterized and crosslinked by oxazolidine ring opening to obtain materials which showed improved thermal stability. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 4965–4973, 2007     

Diastereoselectivity in the alkylation of 4-fluoroproline methyl esters

The reaction of alkylation of cis- and trans-4-fluoro-N-Boc-l-proline methyl esters has been examined by exposing their lithium enolates to a range of alkylating agents. The process showed a high degree of facial diastereoselectivity (except when methyl iodide was used as alkylating agent), invariably giving rise to products bearing the alkyl group in anti with respect to the fluorine atom. A tentative model to account for the observed stereoselectivity is also proposed.     

Synthesis of flavonoid 2-deoxyglucosides via the Mitsunobu reaction

The Mitsunobu reaction of flavonoids and 3,4,6-tri-O-acetyl-2-deoxy-d-glucopyranose or 3,4,6-tri-O-benzyl-2-deoxy-d-glucopyranose is a very effective method for the stereoselective synthesis of flavonoid 2-deoxyglucosides. Since there is no C2 substituent on the sugar moieties, the observed α- or β-stereoselectivity was mainly controlled by the (acetyl or benzyl) protecting groups. Possible mechanistic insights are offered to explain the dual stereoselectivity.     

Calculation of possible stabilization of glycosyl carbocations in furanosides by different theoretical methods

The paper deals with the comparison of different theoretical methods for the calculation of stabilization energies of glycosyl cations from fucofuranoside glycosyl donors containing different protecting groups at atom O(3). The experimental and calculated data on stereoselectivity of glycosylation were compared. The formation of the stabilized glycosyl cations is considered as one of the possible steps of glycosylation reaction, which exerts influence on the stereoselectivity of the process and makes it possible to obtain difficultly accessible 1,2-cis-glycosides. Semi-empirical and ab initio methods without allowance for the electron correlation underestimate the stabilization energy values. The allowance for the electron correlation in the MP2 approximation, as well as the calculations by density functional theory, allowed us to obtain the data corresponding to the experimentally observed stereoselectivity.     

Stereoselective synthesis of tetrahydro-2H-[2]benzopyrano[3,4-c]pyrrol-3-ones and related compounds as precursors of serotonin 5-HT2C receptor agonists

Tetrahydro-2H-[2]benzopyrano[3,4-c]pyrrol-3-ones and the related 3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole analogues were synthesised by an intramolecular Diels-Alder reaction. The observed stereoselectivity was dependent upon the nature of the tethered dienophile as well as the judicious placement of the amide.     

Baker's yeast: production of d- and l-3-hydroxy esters

Baker's yeast grown under oxygen limited conditions and used in the reduction of 3-oxo esters results in a shift of the stereoselectivity of the yeast towards d-hydroxy esters as compared with ordinary baker's yeast. The highest degree of stereoselectivity was obtained with growing yeast or yeast harvested while growing. In contrast, the stereoselectivity was shifted towards l-hydroxy esters when the oxo esters were added slowly to ordinary baker's yeast supplied with gluconolactone as co-substrate. The reduction rate with gluconolactone was increased by active aeration. Ethyl l-(S)-3-hydroxybutanoate was afforded in >99% ee. Both enantiomers of ethyl 3-hydroxypentanoate, d-(R) in 96% ee and l-(S) in 93% ee, and of ethyl 4-chloro-3-hydroxybutanoate, d-(S) in 98% ee and l-(R) in 94% ee, were obtained. The results demonstrate that the stereoselectivity of baker's yeast can be controlled to a large extent without the use of inhibitors, heat treatment, etc.     

Oxazolinyloxiranyllithium-mediated synthesis of highly strained heterocyclic compounds

The addition reaction of α-lithiated oxazolinyloxiranes to nitrones has been investigated. 1,5,9-Trioxa-8,10-diazadispiro[2.0.4.3]undecanes formed in a completely diastereoselective manner upon treatment of α-lithiated oxiranes with nitrones. The lithiation of optically active trans and cis-oxazolinyloxiranes followed by the addition of a nitrone resulted in the formation of the same dispirocyclic compound. An explanation for the observed stereoselectivity is provided.