Diastereoselective protocols for the synthesis of 2,3-trans- and 2,3-cis-6-methoxy-morpholine-2-carboxylic acid derivatives

Two diastereoselective and straightforward protocols for the high-yielding synthesis of 2,3-trans- and 2,3-cis-6-methoxy-3-substituted morpholine-2-carboxylic esters were realized in few steps, through the condensation between 5,6-diethoxy-5,6-dimethyl-1,4-dioxan-2-one and an appropriate imine, which is the key reaction to control the C2-C3 relative stereochemistry, followed by a methanolysis/ring-closure tandem reaction sequence. In particular, 2,3-trans-morpholines derive from the R*,S*-product of the acid condensation of N-functionalized alkylimines with the silylketene acetal of the above lactone, whereas 2,3-cis-morpholines derive from the R*,R*-product of basic condensation of an N-tosylimines with the lactone.     

Stereoselective synthesis of beta-hydroxyphenylalanines using imino 1,2-Wittig rearrangement of hydroximates

The imino 1,2-Wittig rearrangement of hydroximates containing a furan ring provides a novel method for the synthesis of beta-hydroxy-alpha-amino acids. Upon treatment with LDA, hydroximates smoothly underwent the rearrangement to give Z-2-hydroxyoxime ethers in good yield, which were converted into both cis- and trans-oxazolidinones with high stereoselectivity. The cis- and trans-oxazolidinones were stereoselectively converted into erythro- and threo-beta-hydroxyphenylalanines, respectively, via the oxidative cleavage of a furan ring, ring-opening of oxazolidinone, and deprotection.     

Stereoselective synthesis of trifluoromethyl-substituted 1,2-diamines by aza-Michael reaction with trans-3,3,3-trifluoro-1-nitropropene

Aza-Michael addition of optically pure 4-phenyl-2-oxazolidinone to 3,3,3-trifluoro-1-nitropropene proceeds smoothly at low temperature with a high yield. Diastereoselectivity of the addition depends on the base used and lithiated species proved to be highly efficient affording 92% de. Optically pure 1,2-diamino-3,3,3-trifluoropropane is prepared in 58% yield from the aza-Michael addition product through a three-step procedure.     

Stereoselective synthesis of (E)-mannosylidene derivatives using the Wittig reaction

Stabilized ylides Bu(3)P=CH(EWG), where EWG is an ester or nitrile group, react with 2,3,4,6-tetra-O-benzylmannono-1,5-lactone giving high yields of mannosylidene derivatives; in contrast to the glucose and galactose analogues, the (E)-mannosylidenes are predominant (E:Z > 9:1), thus minimizing dipole-dipole repulsions in the Wittig reactions. NMR indicates chair-like conformations for solutions of the (E)-mannopyranosylidenes, but not for those (Z)-isomers where data are available (EWG = CN or CO(2)Et). X-ray crystallography shows an approximately twist-boat conformation for the tetra-O-benzyl-protected (Z)-mannosylideneacetonitrile.     

Stereoselective synthesis of C-substituted morpholine derivatives using reductive etherification reaction: total synthesis of chelonin C

A general strategy is developed for the stereoselective synthesis of C-substituted morpholine derivatives using intramolecular reductive etherification reaction. The method is extended to the first stereoselective total synthesis of (±)-chelonin C.     

Efficient and solvent-free synthesis of bis-indolylmethanes using silica gel supported aluminium chloride as a reusable catalyst

Stable and non-hygroscopic silica gel supported aluminium chloride（SiO₂-AlCl₃）,which is prepared easily from cheap and commercially available compounds was found to be an environmentally friendly heterogeneous catalyst for the condensation of indole with aldehydes and ketones to afford bis-indolylmethanes at room temperature under solvent-free conditions.The catalyst can be reused up to five times after simple washing with ether.     

Promotion of the fenton reaction by Cu2+ ions: Evidence for intermediates

The promotion of the Fenton reaction by Cu²⁺ ions has been investigated using a wide range of [Cu²⁺]. Both the disappearance of Fe²⁺ and the evolution of O₂ were followed as a function of time by quenching the reaction mixture with o‐phenanthroline or with excess Fe^{2 +} ions, respectively. Two series of experiments were performed. In one series [H₂O₂] was 5 × 10⁻⁴ mol dm⁻³, and in the other [H₂O₂] was reduced to 5 × 10⁻⁵ mol dm ⁻³. By stopping the reaction with excess Fe²⁺ ions, significant differences in the measured absorbance in the two series were observed. In the higher [H₂O₂] range, the absorbance decreased monotonically in time, due to O₂ formation during the reaction. In the lower range, an initial transient rise of the absorbance was observed, indicating the formation of spectroscopically distinct intermediates in the system. A mechanism involving the intermediates FeOCu⁴⁺ and FeOCu⁵⁺ has been set up. Rate constants of the mechanism have been determined. © 2006 Wiley Periodicals, Inc. Int J Chem Kinet 38: 725–736, 2006     

A mild and efficient synthesis of intermediates for the Pomeranz-Fritsch reaction

Reaction of 1-chloro-2,2-dimethoxyethane with sodium azide affords 1-azido-2,2-dimethoxyethane which, upon treatment with triphenylphosphine followed by aromatic aldehydes, alkyl bromides, or isocyanates, gives the corresponding dimethyl α-arylimino-, α-alkylamino-, and α-carbodiimido-acetals, respectively, in good to excellent yields.     

Stereoselective synthesis of furans by the Pd-catalyzed Oshima-Utimoto reaction

[reaction: see text]. The Pd-catalyzed coupling of acyclic allylic alcohols with vinyl ethers was examined and found to proceed with 2.5-10 mol % of catalyst and to provide cyclic acetals with good stereoselection. The reaction is tolerant of a number of functional groups and can be used to generate quaternary centers in a stereoselective fashion.     

One-pot synthesis of unsymmetrical disulfides using 1-chlorobenzotriazole as oxidant: Interception of the sulfenyl chloride intermediate

A high-yielding and low temperature one-pot procedure is described for unsymmetrical disulfide synthesis from two different thiols using 1-chlorobenzotriazole (BtCl) as oxidant. The mechanism of the coupling involves in situ trapping of the sulfenyl chloride intermediate R¹SCl by nucleophilic benzotriazole (BtH) to form R¹SBt, which protects R¹SCl from forming the homodimer R¹SSR¹. The methodology is applicable to all types of thiol (aliphatic, aromatic, heteroaromatic), with a variation developed for aliphatic-aliphatic couplings. Differentially N-protected cysteines couple to afford the unsymmetrical cystine derivatives in high yield (90%), which serves as a model for the one-pot intermolecular coupling of cysteine-containing peptides to form peptide disulfide heterodimers. Minimal exchange in aromatic-aromatic disulfide synthesis is noted on account of the mild conditions.     

Stereoselective synthesis of 2-amino-1,3,5-hexane triols using l-proline catalyzed aldol reaction

An efficient synthesis of the 2-amino-1,3,5-hexane triol pattern has been achieved by a diastereoselective aldol reaction of an amino aldehyde with acetone catalyzed by l-proline.     

Stereoselective synthesis of 3-alkylideneoxindoles using tandem In-mediated carbometalation and Pd-catalyzed cross-coupling reaction

Efficient methods for stereoselective synthesis of various (E)-, (Z)-, and disubstituted 3-alkylideneoxindoles were investigated using tandem In-mediated carbometalation and ligandless Pd-catalyzed coupling reaction.     

Intramolecular Diels-Alder reaction leading to tricyclic derivatives as intermediates of natural products synthesis

Tricyclic compounds 4a and 4b possessing a bicyclo[4.3.0] moiety, were successfully synthesized by using the intramolecular Diels-Alder reaction. The siloxy- rather than acyloxy-substituents increased the ratio of the endo-cylcoadducts 10 and 12. The oxygen substitution of 9 influenced conformation of the transition state, which was stereochemically restricted by the butenolide moiety. In addition, 9b carrying a hydroxyl group also produced 10b in a similar ratio to 9a. Compound 11 was the only exo-adduct produced in all of the entries.     

Cyclopentadienones as intermediates for the synthesis of highly functionalized biaryls

A new approach to the synthesis of substituted biaryls, via Diels-Alder reaction between cyclopentadienones and arylacetylenes, is described.     

Organic synthesis using haloboration reaction VIII. Stereo- and regioselective synthesis of [z]-1,2-dihalo-1-alkenes

[Z]-1,2-Dihalo-1-alkenes can be prepared stereo- and regioselectively in good yields from 1-alkynes by the bromoboration with tribromoborane, followed by the treatment with iodine chloride or bromine chloride in the presence of sodium acetate.     

4H-1,2-benzoxazines with electron-withdrawing substituents on the benzene ring: synthesis and application as potent intermediates for oxygen-functionalized aromatic compounds

A new general method for synthesizing functionalized 4H-1,2-benzoxazine derivatives is described. Although 4H-1,2-benzoxazine is one of the fundamental structure of the oxazine group, no general synthetic method for the heterocycle has been established. We found that 3-methoxycarbonyl-4H-1,2-benzoxazine was obtained in good yield when methyl 2-nitro-3-phenylpropionate was treated with an excess amount of trifluoromethanesulfonic acid. This methodology was also applicable for the synthesis of 4H-1,2-benzoxazine rings functionalized with various electron-withdrawing substituents on the benzene ring. Furthermore, we also show that the resulting 4H-1,2-benzoxazines can be used as precursors of functionalized o-quinone methides and multisubstituted phenols. This type of heterocycle can be a potent intermediate to oxygen-fuctionalized aromatic compounds.     

Stereoselective synthesis of novel pyrazole derivatives using tert-butansulfonamide as a chiral auxiliary

A novel chiral pyrazole derivative was developed by our research program as a potent PDE4 inhibitor for the treatment of anti-inflammatory diseases, such as asthma and chronic obstructive pulmonary disease. The asymmetric synthesis of the inhibitors carrying the pyrazole moiety, including nitrogen directly bonded to a chiral center, through a novel approach is disclosed. The key steps of the synthetic sequence begin with the preparation of chiral toluenesulfinyl imine by the condensation of (R)- and (S)-tert-butanesulfinamide with an aldehyde. Next, a corresponding chiral amine synthesis by a stereoselective addition reaction of 4-picolyl lithium to the chiral toluenesulfinyl imine is performed, followed by desulfination. The preparation of the cis-type enaminone from the addition of the enaminone to the corresponding chiral amine is then accomplished, with further transformation into the pyrazole derivatives through the amination of the enaminones and subsequent dehydro-cyclization. A total of 8 steps are completed to produce a 5.5% yield (100% ee).     

An efficient stereoselective synthesis of 4,5-trans-1,5-cis-3-oxabicyclo[3.1.0]hexan-2-ones via the iodolactonization of alkylidenecyclopropyl esters

[reaction: see text] A highly stereoselective iodolactonization of alkylidenecyclopropyl esters with iodine or N-iodosuccinimide (NIS) in aqueous CH3CN to afford 4,5-trans-1,5-cis-3-oxabicyclo-[3.1.0]hexane-2-ones is described. The reaction is very general, accommodating a wide range of substituents. A plausible mechanism that explains the essential role of water in this reaction is proposed.