Search

The reaction of trimethyl(vinyl)silane 1 and dimethyl(divinyl)silane 2 with various sulfonamides in the oxidative system (tert-BuOCl + NaI) has been studied and shown to be an efficient approach for the synthesis of silylated N-heterocycles. Triflamide demonstrated the reactivity principally different from that of arenesulfonamides. With silane 1, it afforded the products of iodochlorination and bis(triflamidation) (major), whereas arenesulfonamides gave N-arenesulfonylaziridines in up to 91% yield. Silane 2 with arenesulfonamides yielded the products of mono and bis(iodochlorination), mono and bis(aziridination), and 3,5-diiodo-4,4-dimethyl-1-(arylsulfonyl)-1,4-azasilinanes. By contrast, triflamide, apart from the products of halogenation and iodotriflamidation, unexpectedly gave 3-(trifluoromethylsulfonyl)-5-(triflamido)oxazolidine as the main product. The structure of most heterocyclic products is proved by X-ray analysis. The effect of the silyl group in the substrate and of the substituent in the reagent on the course of oxidative sulfamidation is discussed by comparing with all-carbon analogues.

Classic acetyl thioester protection/deprotection methodologies are widely used in organic synthesis, but deprotection step usually requires harsh conditions not suitable for labile substrates. In this work, a new method for thioester deprotection using a thiotransesterification approach is described. Firstly, thioglycolic acid (TGA) was identified as a good deprotecting reagent in solution. In order to develop a thiol polymer-supported reagent, TGA was anchored to a PEG-based resin through an amide bond (TG-NCO-SH). Both homogeneous and heterogeneous approaches were conveniently carried out at room temperature, in aqueous buffer at pH 8. The mild conditions were suitable for alkyl and phenyl thioesters. Moreover labile thioesters containing thiazolidine and oxazolidine scaffolds, bearing amine, ester and acetal functionalities were also deprotected. The polymer-supported TGA gave better deprotection yields compared to TGA in solution, yields ranging from 61 to 90%. The feasibility of the recovery and reuse of TG-NCO-SH reagent was explored, showing it can be reused at least five times without lossing the activity.

A short and efficient strategy for the synthesis of (−)-cytoxazone, (−)-4- epi -cyoxazone and their analogues by using DDQ mediated diastereoselective intermolecular benzylic amination has been described. Immunological evaluation of their cytokine modulating activity revealed that the change of hydroxy methyl to methyl group increased the cellular immunity in in-vitro cultures. Changes in the stereochemistry of oxazolidine haven't influenced the biological activity.

Selective saturation of the conjugated C–C double bonds in the title compounds was examined in a systematic way for the first time. Many established protocols effective for similar reduction of α,β-unsaturated ketones and esters in the literature were found to be inapplicable in the present context. The most satisfactory results were finally obtained using the DIBAL-H/MeLi/CuI/HMPA/THF conditions.

A multicomponent reaction that employs an unsaturated carboxylic acid, a 1,2 or 1,3 amino alcohol and gaseous CO and H2 has been discovered. Thus, hydrocarbonylation of the carboxylic acid double bond generates a linear aldehyde, that is, immediately transformed into an oxazolidine. Further microwave assisted intramolecular lactamization delivers oxazolopiperidines with the generation of six new bonds in a one-pot single step. Bicylic, tricyclic, tetracyclic, and spirocyclic oxazolopiperidines can be prepared in good yields and acceptable stereoselection. The reaction did not occur under conventional heating even at higher temperature and pressure and for longer time, showing that microwave heating is indispensable to the process.

3-Spiropseudonucleosides, in which the heterocyclic base is a five-membered (oxazolidine, imidazolidine, thiohydantoin) or six-membered (perhydrooxazine) heterocycle, have been prepared starting from a hexofuranos-3-ulose. The method leads to good yields and is completely stereoselective. The key intermediate is a sugar iso(thio)cyanate.

Highly enantioselective asymmetric addition of terminal alkynes to various aromatic and heteroaromatic aldehydes catalyzed by the readily available, low-cost, and reusable resin-supported oxazolidine 4 together with Ti(OiPr)4 provides the chiral propargylic alcohols with good to excellent yields (up to 98%) and enantioselectivities (up to 95%). The immobilized catalyst can be recovered and used for five cycles.

In the presence of diethylzinc as a stoichiometric reductant, substoichiometric quantities of an appropriate cobalt source catalyse diastereoselective reductive aldol coupling reactions of α,β-unsaturated amides with ketones. The use of a readily available oxazolidine as a chiral auxiliary imparts high levels of asymmetric induction in these reactions.

Primary, secondary and tertiary aminodiols were synthetized regio- and stereoselectively from (−)-α-pinene 1 via α-pinene oxide 2 , (−)- trans -pinocarveol 3 and key intermediate epoxy alcohol 4 . N -Benzyl derivative 5 was transformed to spiro-fused oxazolidine 13 in a highly regioselective ring closure. Aminodiols and their derivatives 5 – 13 were applied as chiral catalysts in the enantioselective addition of diethylzinc to benzaldehyde, resulting in chiral 1-phenyl-1-propanol. The substituent effect on the nitrogen was studied in detail and the best enantioselectivity was observed in the case of N -methyl- N -benzyl-substituted derivative 8 . The phenomenon was interpreted by using molecular modelling at an ab initio level.

A number of enantiomerically pure 1,2-aminoalcohols containing tertiary nitrogen atoms bearing chiral substituents have been prepared by highly diastereoselective reductive ring cleavage of oxazolidines derived from ketones and pseudoephedrine or ephedrine. The ring cleavage occurs with retention of configuration.

The reactions of 3-phenyl-3-methylamino-1,2-propanediol 1a and 3-[(tert-butyldimethylsilyl)oxy]-1-methylamino-1-phenyl-2-propanol 1b with (CH2O)n and CH2Cl2 are appropriate procedures for the preparation of 1,3-oxazines or 1,3-oxazolidines under proper selection of kinetic or thermodynamic reaction conditions. The reaction of 1b with (CH2O)n or CH2Cl2, affords the oxazolidine 2b under kinetic conditions and then this compound can be slowly converted into 5-[(tert-butyldimethylsilyl)oxy]-3-methyl-4-phenyl-3,4,5,6-tetrahydro-2H-1,3-oxazine 3b under thermodynamic control. The mechanism proposed for this transformation and the effect of polar solvents on the acceleration of the reaction has been studied theoretically (DFT level).

The chemical synthesis, conformational analysis and receptor binding studies of novel constrained cyclosporin A (CsA) analogues are described. The selective insertion of pseudo-proline (PsiPro) systems featuring different 2-C-substituents at the oxazolidine ring exerts dramatic effects upon the backbone conformation as demonstrated by NMR analysis. It is shown that the insertion of a Psi(MeMe)pro at position 5 (Thr(5)CsA) maintains binding to cyclophilin A as well as to calcineurin and shows a 5-6 cis amide bond with all remaining amide bonds trans. The elaborated synthetic routes for generating PsiPro containing Cs derivatives pave the way for extended structure-activity relationship studies aiming at the design of potential pharmacologically active compounds with a selective activity profile. (C) 2003 Elsevier Science Ltd. All rights reserved.

Semi-empirical quantum chemical studies using PM3 suggest that the preferred reaction between a Grignard reagent and a combined aminonitrile–oxazolidine system involves initial formation of a Lewis acid–base complex between magnesium and the central nitrogen atom, followed by preferred reaction with the aminonitrile function; model studies confirm that this reaction proceeds by addition rather than substitution.

We have shown that condensation of l -cysteine methyl ester ( 8 ) and l -threonine methyl ester ( 11 ) with formaldehyde provides a convenient and efficient access to novel heterocyclic 2:3 adducts. Depending on the amino acid, the condensation leads to either the N,N′-methylenebis(thiazolidine) ( 10 , l -cys) or -(oxazolidine) ( 13 , l -thr) derivative or to its bicyclo[4.4.1]undecane isomer ( 5 , l -ser) as the major product of the reaction. The structure of 10 , 12 and 13 , was unambiguously confirmed by diffraction analysis and/or NMR spectroscopy. The latter proved to be a powerful tool to discriminate between the two possible isomers. X-Ray data emphasized the contribution of stereoelectronic effects to the structure of the above compounds.

A 3-acyl-2-(N-cyanoimino)oxazolidine derivative was found to serve as an enantioselective acylating agent for sec-alkyl amines. These reagents differentiate the enantiomers of 1-phenylethylamine derivatives up to 85% ee, and the recovered chiral auxiliary is reusable.

A flexible variant of the Pictet–Spengler reaction employing oxazinanes as synthetic equivalents of several carbonyl compounds has been developed. Using acid catalyzed one pot condensation of perhydro-1,3-heterocycles various 1,3-disubstituted and 1,2,3-trisubstituted-1,2,3,4-tetrahydro-β-carbolines (THBCs) have been synthesized diastereoselectively.

A synthetic methodology, based on N-Boc-2-acyloxazolidine chemistry combined with ring-closing metathesis, allows the preparation of enantiopure piperidinic heterocycles showing a 2-(1-hydroxyalkyl) side-chain, a pattern commonly found in natural alkaloids. Synthesis of Δ-3,4-2,6-disubstituted piperidinic rings can thus be achieved with a good 2,6-cis or -trans stereocontrol, unless the substituent located at C2 is not a phenyl group. Diastereoselective functionnalization of the Δ-3,4 alkene moiety and access to seven or eight-membered nitrogen rings are also key features of this methodology.

The reaction of TRIS with equivalent amounts of two carbonyl compounds is shown to afford, diastereoselectively, the title compounds. The results are discussed as a synthetic strategy and the stereochemistry is supported by theoretical calculations and high resolution NMR data.

Synthesis of the title compounds is examined from the diastereoselectivity point of view; their stereochemical assignments are supported by high resolution NMR data, which are used to define their chirality and isomerisation aspects.

N-Boc-oxazolidines derived from (R)-phenylglycinol and bearing a stereodefined propargylic or allylic alcohol side chain were transformed into the corresponding mesylates. Alkylation of these allylic mesylates by means of organocuprate reagents effected a regio and stereoselective 1,3-transfer of chirality. Similarly, alkylation of the propargylic mesylate gave a chiral allenyl oxazolidine. The N-Boc-2-alkenyl oxazolidines resulting from an anti SN2′ addition underwent an intramolecular bromocarbamoylation with a high level of stereocontrol upon treatment with NBS. After reaction with sodium alkoxide, the resulting cyclic urethanes gave the corresponding epoxy oxazolidines whose reactivity towards organocuprates was studied. The sequence represents an efficient synthesis of enantiopure protected aldehydes bearing three contiguous chiral centers.

Oxazolidine-2,4-diones were synthesised by tetraethylammonium hydrogen carbonate (TEAHC) promoted carboxylation of secondary carboxamides bearing a leaving group at the α-position. Several oxazolidine-2,4-diones, including clinically used malidone®, have been prepared in moderate to excellent yields as a results of a formal proton extraction-carboxylation-intramolecular SN2 one-pot sequence.

The synthesis of (−)-desoxoprosopinine and (+)-pseudoconhydrine were achieved from a common oxazolidine precursor. The three stereocenters present in (−)-desoxoprosopinine as well as the two stereocenters of (+)-pseudoconhydrine were created in highly stereoselective ways. The stereoselectivity observed during the reduction of the ketone moiety in the starting oxazolidine was dependent on the occurrence of a chelated intermediate. The others stereocenters arose from stereoselective reductions or alkylations of intermediate iminium ions.

The palladium-catalysed couplings of aryl halides and triflates with propargyl amino amides and the couplings of aryl and vinyl halides and triflates with an ethynyl oxazolidine are reported.

In the reactions of 3-amino-1,2-propanediol with aromatic aldehydes, five-component ring-chain tautomeric mixtures were formed, involving oxazolidine and oxazine C-2 epimers and the corresponding Schiff base. These multicomponent tautomeric equilibria could be described by the equation log K = ϱσ+ + log Ko, used earlier for the two- and three-component equilibria relating to only oxazine or oxazolidine rings. In the reactions of 3-amino,1,2-propanediol with aromatic aldehydes, five-component tautomeric mixtures were formed, involving oxazolidine and oxazine C-2 epimers and the corresponding Schiff base.

Modest to high levels of asymmetric induction are observed with Grignard additions to Garner type aldehydes. The resultant secondary alcohols are important precursors of chiral building blocks for asymmetric synthesis and we have demonstrated that they can be readily converted into their respective γ-hydroxy-β-amino alcohols and β-hydroxyamino acids. Additionally, aryloxy ethers, important components of many natural products, can be obtained from these precursors.

The Michael-like addition of ω-thiohydroxyesters 2 to butenolides or α.s-unsaturated lactams 1 exhibits trans -selectivity. Some of the adducts 3 undergo cyclization to novel condensed S-heterocycles 6 and the perhydrogenated thieno[2,3-c]furan 7 with s-ketoester functionality. 7 can be C-alkylated to 8 , hydrolyzed to a muscarine analog 9 and ring transformed with hydrazine to the novel dihydrothieno[3,4-c]-pyrazole 10 . A novel bicyclic pyrrolo[3,2-b]-1,4-thiazine 16 is obtained by ring transformation of the pyrrolo[2,1-b]oxazolidine 1c with 2-mercaptoaniline.

The reactivity of 2,2,4,4-tetrasubstituted-1,3-oxazolidines 1 with m-chloroperbenzoic aicd was reinvestigated. Aminoxyls 5 are isolated in good yields in ether at −15 °C, or in anhydrous dichloromethane at 0 °C. Oxaziridines 4 are promoted at room temperature, or in the presence of an acid. In any case, short reaction times prevented the degradation of aminoxyls and oxaziridines. The competition between oxaziridines 4 and aminoxyls 5 is ruled by the oxazolidine imine equilibrium.

The lithium (Z)-enolate generated from the propanamide of (S)-4-benzyl-2,2,5,5-tetra-methyloxazolidine undergoes highly lk-1,4/anti-selective Michael additions to α,β-unsaturated ester and amide acceptors. However, only poor selectivities result when either the lithium (Z)- enolates of an oxazolidine methoxyacetamide derivative or the oxazolidine α,β-unsaturated amide acceptors are used. The observed high chiral inductions in the former cases are based on the facts that syn-conformation of the enolate is involved in the transition state where the enolate and oxazolidine planes are coplanar, and that the diastereoface remote from the 4-shielding substituent of the auxiliary is open for the attack of acceptor molecules.

The propanamide and methoxyacetamide derivatives of (S)-4-benzyl-2,2,5,5-tetramethyloxazolidine, a new chirality controlling auxiliary based on the restricted rotation around amide bond, generate chiral lithium Z-enolates by lithiation. They undergo highly lk-1,4 and ul-1,4-inductive alkylations with a variety of alkylating reagents, respectively. The diastereotopic face participated in the reactions is that remote from the 4-shielding substituent of oxazolidine in the syn-conformations. Coplanarity between the enolate double bond and the oxazolidine plane in the transition state can be a major factor for the observed excellent selectivities.

Electrogenerated bases promote the carboxylation of NH-protic carboxamides bearing a leaving group at the position 2 to give oxazolidine-2,4-diones. The process is believed to involve acid-base reaction with the substrate, carboxylation of its conjugate base to the corresponding carbamate and ring-closure following intramolecular S N 2 reaction. A variety of oxazolidine-2,4-diones, including clinically used trimethadione® and malidone®, have been prepared in high to excellent yield, which established the scope and generality of this new ring-forming process.

An improved synthesis of 2-(2′-pyridyl)-2-aminoalcohols 1a and 1b, in enantiomerically pure form via 1,3-oxazolidine derivatives is presented. Some efficient and selective methods for both the cleavage of the oxazolidine ring and the removal of the N-Boc protecting group are also reported.

Hexa-2,4-dienal condensed with (-)-ephedrine to give predominantly the oxazolidine 4, which underwent a stereoselective Diels-Alder reaction with benzyl nitrosoformate to give the cycloadducts 9 and 10 in a ca 5:2 ratio. Further transformations of 9 to give the optically active mono- and tri- hydroxypiperidine derivatives 11 and 15 have also been performed.

New chirality-controlling auxiliaries, a C2-symmetric 2,2-dimethylimidazolidine and 4-chiral 2,2-dialkyloxazolidines, are readily prepared from a C2-symmetric 1,2-ethanediamine and naturally occurring α-amino acids, respectively. Conformational analysis of their N-acryloyl derivatives has been carried out on the basis of dynamic 1H NMR spectroscopy and molecular mechanics calculations using MM2 program. Proper choice of the substituents at 2-, 4-, and 5-positions, in the oxazolidine cases, leads to the most effective chiral shielding of a diastereotopic acryloyl face.

NMR studies proved that cationic species are intermediates in the acid catalyzed reaction of norephedrine-derived oxazolidanes with nucleophiles. Information was gathered on the electronic structure of the cations and its dependence on ring substitution.

Norephedrine derived 2-methoxy-2-methyl oxazolidine 2 is an efficient stereoselective acetylating agent in reactions with stereogenic silylenolethers and silylketenethiolacetals. Moderate selectivity is also obtained upon acetylation of crotyltin reagents. The present methodology compares favorably with the previously reported enantioselective Claisen-type acylations.

Two totally synthetic, racemic analogs of quinocarcin have been designed and their crystal structures determined. Both substances effect the modest cleavage of plasmid DNA. Alteration of the conformation of the reactive oxazolidine fused to the piperazine ring by selecting the stereochemistry at C-11a through synthesis drastically attenuates the relative ability of these substances to cleave DNA.

A diastereo and enantioselective synthesis of compound 11 a potential useful intermediate for the lactone portion of mevinolin and compactin was developed. Our strategy is based on the high stereoselective Michael addition of alkoxide to chiral norephedrine-derived oxazolidine 4 .

13 C NMR spectra of the atisine- and veatchine-type alkaloids, as well as certain of their derivatives, have been obtained by the Fourier transform technique at 25.03 MHz. With the help of single-frequency off-resonance proton decoupling techniques, additivity relationships, and the effects induced by certain structural changes, self-consistent assignments of nearly all the resonances have been made. The 13 C NMR spectra are also analyzed to identify skeletal features of the atisine and veatchine-type alkaloids of use in the structure determination of new C 20 -diterpenoid alkaloids. On the basis of the 13 C NMR analysis of atisine and veatchine as well as a temperature-dependence study of atisine, the existence of C-20 epimers in these alkaloids is demonstrated. A 13 C NMR study of the behavior of the oxazolidine ring of atisine in non-ionic and ionic solvents indicates that the C-20 epimers of atisine do not exist in an equilibrium mixture in solution and are not interconvertible via a zwitterion as reported earlier.

The circular dichroism of some derivatives of tetrahydro-1,3-oxazine, tetrahydro-1,4-oxazine and 1,3-oxazolidine is described, and discussed in terms of configuration and preferred conformations.

Dispiro(2,2,6,6-tetramethyl piperidine piperidine 1-oxy)-4,4'(oxazolidine 3'-oxyl)-2',1'-cydobexane] has been studied by ESR and NMR. Detailed analysis of the ESR spectrum of the frozen solution shows that the C-N bond of oxazolidine ring is equatorial relative to the chair piperidiae ring. Lande (g), dipolar (D) and hyperfine (A) tensors have been determined. Proton hyperfine splittings of cyclohexane ring have been measured by NMR at room temperature, with the results consistent with the C-N bond of oxazolidine ring being in equatorial position relative to the chair cyclobexane ring.

The tautomerism between hydroxy Schiff bases, X-C6H4CR=NCMe2CH2OH (R=H, Me, C6H5; X is a range of substituents) and X-C6H4,CR=NC6H4 (o-CH2OH), and the corresponding ring closed systems, oxazolidines and dihydrobenzoxazines, has been investigated. In all cases where equilibria can be determined the process is shown to be extremely facile, despite the fact that Baldwin's rules are contravened. Information about the structure of some of these molecules in the crystalline state is provided by solid state NMR. Previous work on the equilibration of 1-methyl-1,3-oxazolidine and its iminium tautomer in trifluoroacetic acid is shown to be complicated by trifluoroacetate formation, but the overall conclusion that this 5- endo - trig process is also rapid, appears to be correct. Some mechanistic consequences of these deductions are discussed.

The cathodic behavior of 2-pheny1-4,4-dimethyl-2-oxazoline (4), 2,4,4-trimethyl-2-oxazoline (7) and 2-(1,1-dimethylethyl)-4,4-dimethyl-2-oxazoline (8) at Hg electrodes was investigated. A reduction peak for 4 at -2.49V(SCE), was observed by cyclic voltammetry (CV). Preparative reduction of 4 at a mercury pool yielded exclusively N-benzyl-2-amino-2-methylpropanol (6) in a high yield (91%). The electrolysis procedure was simple utilizing constant current and an undivided cell, and the pH remained neutral throughout the reaction. The 2-oxazolines 7 and 8 did not exhibit CV reduction peaks and were recovered after attempts of preparative electrolysis. CV and nmr measurements indicate that the reduction of 4 involves initial formation of the corresponding oxazolidine 5 followed by ring cleavage to the easily reducible tautomeric imine 5a which reacts to give 6.

Cuprate reagents in the presence of trimethylchlorosilane add with excellent Tr-face selectivity and yield to α,β-unsafcurated ketone and aldehyde bearing In γ-position a masked aldehyde represented by the C-2 of a norephedrine-derlved oxazolidine. The title compounds are obtained in high enantlomeric excess after removal of the chiral auxiliary and of the protective group.