Syntheses of E- and Z-2- and 4-fluorourocanic acids

Horner-Wadsworth-Emmons olefination of ring-fluorinated N-trityl-imidazole carboxaldehydes with dialkyphosphonoacetic acid esters produced ring-fluorinated imidazolyl-E- and Z-acrylate esters. Stereochemistry was controlled by choice of phoshonate. Acid catalyzed removal of trityl followed by ester saponification gave the target 2- and 4-fluoro-E- and Z-urocanic acid derivatives. These are being investigated as potential mediators of photo-immunosupression.     

Efficient synthesis of orthogonally protected anti-2,3-diamino acids

An asymmetric synthesis of anti-2,3-diamino acids is reported. The enolates of N,N-dibenzylated β³-amino esters were treated with di-tert-butyl azodicarboxylate (DBAD) to afford their N′,N″-di-Boc-2-hydrazino derivatives with excellent anti diastereoisomeric ratio. Final Boc removal and reductive cleavage of the hydrazino bond led to the expected 2,3-diamino esters having only one free amino group. In comparison with other asymmetric C-2 amination procedures, this method does not need the use of expensive chiral reagents and/or chiral auxiliaries, while leads to products which can be orthogonally protected.     

Synthesis of 2-oxazolines via boron esters of N-(2-hydroxyethyl) amides

A new, convenient, one-pot process is presented for the synthesis of 2-oxazolines in high yields (75-94%) via boron esters of N-(2-hydroxyethyl) amides. The procedure involves thermolysis of the boron esters at 240-260 °C, in the presence of solid CaO as an acid scavenger and allows the preparation of oxazolines from hydroxyethyl amides of aliphatic and aromatic monocarboxylic acids.     

Application of asymmetric phase-transfer catalysis in the enantioselective synthesis of cis-5-substituted proline esters

A simple, highly stereoselective three-step sequence for the enantioselective synthesis of cis-5-substituted proline esters is described. This sequence features an asymmetric PTC Michael addition, followed by acid catalysed imine exchange and catalytic hydrogenation. Application of this chemistry in the synthesis of the nonpeptide cholecystokinin antagonist (+)-RP-66803 11 is also described.     

A highly diastereoselective synthesis of (E)-B-2-(1-cyclopropyl-1-alkenyl)-1,3,2-dioxaborinanes. Isolation and oxidation to alkyl cyclopropyl ketones

A convenient, novel synthesis of alkyl cyclopropyl ketones based on Z-1-bromo-1-alkenylboronate esters is developed. α-Bromo-(Z)-1-alkenylboronate esters readily available from literature procedures smoothly undergo a reaction with cyclopropylmagnesium bromide in tetrahydrofuran to provide the corresponding ‘ate’ complexes. These ‘ate’ complexes undergo intramolecular nucleophilic substitution reactions to provide the corresponding (E)-1-alkenylboronate esters containing cylcopropyl moiety for the first time in good isolated yields (68-82%). The carbon skeleton present in these intermediates is confirmed by oxidation with hydrogen peroxide and sodium acetate to afford the corresponding alkyl cyclopropyl ketones in good yields (72-85%).     

Concise stereoselective synthesis of cis-3-alkoxy-2-carbomethoxy medium-ring oxacycles from (R)-3-(3-butenyl)-4-propynoyloxazolidin-2-one

A concise process for the stereoselective synthesis of chiral cis-3-alkoxy-2-carbomethoxy medium-ring oxacycles from (R)-3-(3-butenyl)-4-propynoyloxazolidin-2-one (1) was developed. The process includes five major steps: (i) hetero-Michael reaction between an alcohol and 1, (ii) stereoselective reduction of the resulting ketone, featuring stereochemical assistance of the neighboring oxazolidin-2-one group, (iii) esterification with an alkoxy acetic acid, (iv) chirality-transferring Ireland-Claisen rearrangement of the resulting 3-alkoxyallyl glycolate ester to provide a syn-2,3-dialkoxy carboxylate ester, and (v) relay ring-closing olefin metathesis to form a medium-ring ether along with the simultaneous removal of the oxazolidin-2-one moiety.     

One-pot synthesis of meso-tris-aryl-substituted N-21-methyl- and N-21-benzyl-corroles

A simple and versatile synthesis of meso-substituted N-21-alkylcorroles was achieved directly from aldehydes, pyrrole and N-alkylpyrroles via mix-condensation. Compounds inaccessible via previous routes have been obtained in acceptable yields. It was proved that meso-substituted N-21-alkylcorroles differ from N-unsubstituted corroles in absorption spectra, stability and solubility.     

Synthesis of cis-2-aryl-3-pyrrolidine carboxylic esters via diastereoselective cyclization of γ-imino esters using a TiCl4/Et3N reagent system

Facile synthesis of cis-2-aryl-3-pyrrolidine carboxylates from readily accessible γ-imino esters by intramolecular cyclization mediated by a TiCl₄/Et₃N reagent system is described.     

New stereoselective syntheses of cis- and trans-2-methyl-4-arylpiperidines

A stereoselective approach has been developed for the synthesis of cis- and trans-2-methyl-4-arylpiperidines from a common intermediate. The Ni-catalyzed hydrogenolysis of N-Boc-2-methyl-4-aryl-4-piperidinols, obtained by addition of organometallic reagents on N-Boc-2-methyl-4-piperidone, afforded the trans derivatives with up to 95% selectivity whereas the corresponding cis isomers were obtained in the presence of palladium catalysts.     

Synthesis of unnatural pentahydroxylated pyrrolizidines: 5-epi- and 5,7a-di-epi-hyacinthacine C1

Stereocontrolled synthesis of 5-epi- and 5,7a-di-epi-hyacinthacine C₁ (7 and 8), two potential glycosidase inhibitors are described using α,β-unsaturated ketone 9 as homochiral starting material. The key step in the synthesis is the highly diastereoselective dihydroxylation reaction of 9, that allows the obtention of a single bis-hydroxylated ketone (10). Further derivatization into two epimeric mesylate esters followed by internal cyclization form the pyrrolizidinic compounds 7 and 8. This type of compounds can be useful in glycobiology due to their ability to inhibit carbohydrate-processing enzymes.     

Palladium-catalyzed stereoselective synthesis of E- and Z-1,1-diaryl or triarylolefins

A stereoselective and flexible synthesis of various E- and Z-1,1-diaryl and triarylolefins 3 was achieved from readily available vinylstannanes 1 via stereospecific iodo-destannylation and subsequent palladium-catalyzed Negishi-type cross-coupling reaction with arylzinc reagents under mild conditions.     

Synthesis and odor of optically active trans-2,2,6-trimethylcyclohexyl methyl ketones and their related compounds

The synthesis characterized by cationic olefin cyclizations accomplished using ketone enol esters and odor of novel (1R,6S)- and (1S,6R)-2,2,6-trimethylcyclohexyl methyl ketones (5) are described. The stereoselective syntheses of (E)-(1R,6S)- and (E)-(1S,6R)-1-(2,2,6-trimethylcyclohexyl)-2-buten-1-one (6) and (1R,6S)-ethyl 2,2,6-trimethylcyclohexylcarboxylate (7), useful raw materials for flavor and fragrance, starting from the (1R,6S)- and (1S,6R)-5 are also described.     

Synthesis of cis-3,4-diarylpiperidines and cis-3,4-diaryltetrahydropyrans

Substituted cis-3,4-diarylpiperidines and cis-3,4-diaryltetrahydropyrans are synthesized in modest overall yields starting from 4-aryl-1,2,5,6-tetrahydropyridines and 4-aryl-1,2,5,6-tetrahydropyrans via the following sequence: (1) pinacol-type ring contraction having the combination of m-chloroperoxybenzoic acid and boron trifluoride etherate, (2) Grignard addition with arylmagnesium bromide reagents and followed by boron trifluoride etherate-mediated intramolecular ring-expanded rearrangement, and (3) hydrogenation with hydrogen on 10% palladium-activated carbon. A facile synthesis of 3,4-diarylpyridines was also described by base-induced aromatization.     

Facile stereoselective synthesis of cis- and trans-3-alkoxyazetidin-2-ones

A highly stereoselective synthesis of cis- and trans-3-alkoxy-3-phenyl/benzylthioazetidin-2-ones is described. The reaction of α-chlorosulfide-β-lactams with various alcohols catalyzed by a Lewis acid such as ZnCl₂ in the presence of molecular sieves (3-4 Å) leads to cis-3-alkoxy-3-phenyl/benzylthio-β-lactams whereas treatment of potassium 2-alkoxy-2-phenylthioethanoate with appropriate Schiff's base using POCl₃ in the presence of triethylamine leads to the formation of trans-3-alkoxy-3-phenylthioazetidin-2-ones as major products.     

Synthesis and some reductions of endo- and exo-3,6-epoxy-Δ4-tetrahydrophthalic anhydride

The synthesis of endo-3,6-epoxy-Δ⁴-tetrahydrophthalic anhydride from the endo-adduct of furan and maleic acid is described. Reduction of endo- and exo-3,6-epoxy-Δ⁴-tetrahydrophthalic anhydride with sodium borohydride gave the corresponding lactones, while catalytic hydrogenation over 10% Pd/C gave anhydride and/or hemi-acylals, depending on the solvent.     

Synthesis of trans-vaccenic acid and cis-9-trans-11-conjugated linoleic acid

The preparation of the monounsaturated fatty acid, trans-vaccenic acid 4 (TVA), using both Wittig and one-pot Julia-Kocieński olefination protocol, was achieved in good yield. Similarly a Wittig approach was employed for the stereoselective synthesis of cis-9-trans-11-conjugated linoleic acid 2 from trans-2-nonenal and (8-carboxyoctyl)triphenylphosphonium bromide 12.     

Stereoselective synthesis of cis- and trans-3-fluoro-1-phenylcyclobutyl amine

A stereoselective approach to the synthesis of cis- and trans-3-fluoro-1-phenylcyclobutylamine has been developed. Excellent stereoselectivity was obtained by the reduction of the appropriately substituted cyclobutanone to give either cis- or trans-isomers of 3-hydroxyl-1-phenylcyclobutylamine, which was stereoselectively converted to the 3-fluoro derivative.     

Synthesis of 5-endo-, 5-exo-, 6-endo- and 6-exo-hydroxylated analogues of epibatidine

A convenient, high-yield synthesis of N-Boc-7-azabicyclo[2.2.1]hept-5-en-2-one (7) was developed by SmI₂-mediated desulfonylation of 6. Thus, 5-endo-, 5-exo-, 6-endo-, and 6-exo-hydroxylated epibatidine analogues 2a,b and 3a,b were synthesized from 7 by using a Pd(PPh₃)₄-catalyzed reductive Heck coupling reaction and SmI₂-mediated reduction of the carbonyl group as the key steps. Other reaction conditions for the reductive Heck procedure and the reduction step were also investigated.     

Concise synthesis of trans- and cis-3,4-disubstituted piperidines based on regio- and stereoselective allylation of cyclopentenyl esters

3,4-Disubstituted piperidines were synthesized through anti S_N2′ allylation of 4-substituted 2-cyclopentenyl esters with reagents based on RMgX and CuX, thus allowing equal access to both trans- and cis-isomers. As an application, the paroxetine intermediate was synthesized efficiently. During the investigation, the MeOCH₂CO₂ group was found to show high reactivity in the pivotal anti S_N2′ type reaction using the reagent derived from (i-PrO)Me₂SiCH₂MgCl and CuCN.     

Stereoselective synthesis of syn-β-amino esters using the TiCl4/R3N reagent system

The reactions of benzaldehyde imines and esters with the TiCl₄/R₃N reagent system give syn-β-amino esters as the major products in 38-87% yields.