Asymmetric synthesis of (−)-(1R,7aS)-absouline

The most efficient and concise asymmetric synthesis of (?)-(1R,7aS)-absouline to date, which was accomplished in eight steps and 20% overall yield from commercially available starting materials, is described. The doubly diastereoselective conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)-amide to an enantiopure α,β-unsaturated ester derived from l-proline was employed as the key step. Subsequent hydrogenolytic N-debenzylation and acid-promoted cyclisation of the resultant β-amino ester produced the 1-aminopyrrolizidin-3-one scaffold, then reduction with DIBAL-H was followed by DCC-mediated coupling with (E)-p-methoxycinnamic acid to complete the synthesis of (?)-(1R,7aS)-absouline.     

Total synthesis of (±)-clavam-2-carboxylic acid

Racemic clavam-2-carboxylic acid has been obtained by a six-stepsynthesis from readily available starting materials.     

A straightforward route to enantiopure α-substituted derivatives of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid

High yielding and remarkably selective alkylations of a suitably protected derivative of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid are described. The fused bicyclic structure of this proline analogue greatly influences the stereochemical outcome of direct alkylation reactions taking place at the α-carbon and provides access to α-substituted analogues with retention of the configuration. The overall procedure allows the preparation of enantiopure α-substituted derivatives of this Oic isomer, suitably protected for their incorporation into peptides, in a straightforward manner.     

Design and synthesis of trans-3-aminopyran-2-carboxylic acid (APyC) and α/β-peptides with 9/11-helix

A new β-amino acid, trans-3-aminopyran-2-carboxylic acid (APyC), was designed and synthesized from (R)-glyceraldehyde derivative and used in the synthesis of α/β-peptides in a 1 : 1 alternating pattern with d-Ala. The presence of oxygen atom at the Cβ(2)-position in APyC was envisaged to provide opportunity for additional interaction. These hybrid peptides have shown the presence of 9/11-helix through extensive NMR and MD studies. The amide protons of d-Ala, in addition to participating in 9-mr H-bonding with CO of succeeding β-residue, were also involved in additional electrostatic interaction with pyran ring oxygen of preceding β-residue, which facilitated further stabilization to the 9/11-mixed helix. The study thus results in a new 'motif' for a 9/11-helix, and the first example from a cyclic β-amino acid.     

Diphenylparabanic acid as a synthon for the synthesis of α-diketones and α-ketocarboxylic acids

Diphenylparabanic acid was found to react with >2 equiv of organolithiums at -78 °C to effectively give the corresponding symmetrical α-diketones. However, upon treatment with 1 equiv of organolithium, the parabanic acid gave mainly 5-substituted 5-hydroxyimidazolidine-2,4-diones. On the other hand, Grignard reagents were less reactive toward the parabanic acid at low temperature, and selectively gave the corresponding 5-hydroxyimidazolidine-2,4-diones even if more than 1 equiv of the reagents was used. A tandem process in which the parabanic acid was first reacted with a Grignard reagent and then reacted in one-pot with an organolithium effectively gave the unsymmetrical α-diketone. 5-Substituted 5-hydroxyimidazolidine-2,4-diones were useful as versatile precursors for preparing α-ketocarboxylic acids as well as unsymmetrical α-diketones.     

Biological activity and synthesis of 5,6-dihydroxyindole-2-carboxylic acid – biosynthetic precursor of melanins (microreview)

Chemistry of Heterocyclic Compounds - The microreview considers the biological activity and methods of obtaining natural melanin pigments and their biosynthetic precursor...     

Versatile Approach for the Asymmetric Synthesis of (R)‐ and (S)‐Massoialactones

A general synthetic approach to both enantiomers, (R)‐ and (S)‐massoialactones, has been devised from commercially available (S)‐butane‐1,2,4‐triol.     

Regio- and stereoselective methods for the conversion of (2S,3R)-β-phenylglycidic acid esters to taxoids and other enantiopure (2R,3S)-phenylisoserine esters

A novel efficient method was proposed for the synthesis of enantiopure precursors of taxane-containing cytostatics, i.e., methyl esters of (2R,3S)- and (2S,3R)-N-benzoylphenylisoserine and similar taxoid esters. The method is based on the regio- and stereoselective hydrobromolysis of the corresponding trans-β-phenyl glycidate enatiomers, consecutive reactions of O-acylcarbamoylation of the obtained 3-bromohydrins, intramolecular cyclization to 4-phenyloxazolidin-2-one-5-carboxylic acid derivatives, and oxazolidinone ring opening.     

Stereocontrolled total synthesis of (±)-norpatchoulenol and two metabolites of patchouli alcohol, (±)-hydroxy patchouli alcohol and the corresponding (±)-carboxylic acid

The first total synthesis of the two biooxidation products of patchouli alcohol (2), (±)-hydroxy patchouli alcohol (3) and the corresponding (±)-carboxylic acid 4, has been achieved in highly stereoconcrolled manners. Synthesis of (±)-norpatchoulenol (1), the real odoriferous substance of patchouli oil, has been accomplished by the biogenetic route via (±)-3 and (±)-4.     

New methodology for the synthesis of enantiopure (3R,2aR)-(−)-3-phenyl-hexahydro-oxazolo[3,2-a]-pyridin-5-one: a synthesis of (S)-(+)-coniine

A new and efficient methodology for the enantiopure synthesis of (3R,2aR)-(−)-3-phenyl-hexahydro-oxazolo[3,2-a]pyridin-5-one 3 starting from (1′R)-(−)-1-(2′-hydroxy-1′-phenyl-ethyl)-(1H)-pyridin-2-one 1 is described. In addition, the enantiospecific synthesis of (S)-(+)-coniine hydrochloride 6 in good yield from 3 is reported.     

Preparation of novel pyranosyl fluorides of 3-deoxy-D-manno-2-octulosonic acid (KDO) feasible for synthesis of KDO α-glycosides

α-Ketopyranosyl fluorides, 2 and 3, of 4,5:7,8-di-O-isopropylidene KDO methyl and benzyl esters were prepared and shown to act as effective glycosyl donors. X-Ray structure analysis of 2 and ¹H NMR study established the boat (B_3,6) conformation of the di-O-isopropylidene derivatives of KDO and enabled the assignment of their anomeric configurations.     

Enantiospecific synthesis of α-amino acid semialdehydes: a key step for the synthesis of unnatural unsaturated and saturated α-amino acids

The enantiospecific synthesis of unnatural unsaturated and saturated α-amino acids based on a Wittig type reaction is described. The versatile synthetic intermediates, l-glutamic and l-aspartic acid semialdehydes, are obtained from the corresponding N,N-di-Boc-diesters, by the selective reduction of the ω-ester with DIBAL^® under controlled conditions. The semialdehydes are chemically stable for a prolonged time and react with various phosphorous ylides, under controlled conditions, to produce the enantiomerically pure unsaturated α-amino acids in high yields. The method is equally applicable to homologated diesters obtained by the presented methodology providing unsaturated amino acids with variable unsaturated positions and geometries. The corresponding saturated products can be obtained by simple hydrogenation.     

Synthesis of 3-deoxy-d-manno-2-octulosonic acid (Kdo) and d-glycero-d-talo-2-octulosonic acid (Ko) and their α-glycosides

Reaction of 2,3:5,6-di-O-isopropylidene-d-mannofuranose 1 with C-2 lithio derivatives of glyoxylate mercaptal in the presence of MgBr₂ afforded d-glycero-d-galacto-2-octulosonates 2 and 3, respectively. Their 3-O-deoxygenation led to Kdo. N-Iodosuccinimide treatment of 3 gave thioglycoside 11 directly, which was transformed into Ko derivative 12 via epimerisation of the 3-hydroxy group. 3-O-Benzoylation of 12 and then transformation into phosphite furnished 15, an efficient glycosyl donor. Reaction of 15 with 6-O-unprotected glucosamine derivative 22 as acceptor gave α-glycoside 23, which was successfully transformed either into Kdo-disaccharide 27 or into Ko-disaccharide 29.     

Lipase catalyzed regio- and stereospecific hydrolysis: chemoenzymatic synthesis of both (R)- and (S)-enantiomers of α-lipoic acid

Native lipase of Candida rugosa (EC 3.1.1.3) enantioselectively and regiospecifically hydrolyses the n-butyl ester of 2,4-dithioacetyl butanoic acid either at the carboxylic acid terminus or at the α-thioacetate to provide enantiomerically pure (R)-2,4-dithioacetyl butyric acid and (S)-butyl 2-thio-4-thioacetyl butyrate (ee >98%) while the lipase modified by treatment with diethyl p-nitrophenyl phosphate attacks only the α-thioacetate giving enantiomerically pure (S)-butyl 2-thio-4-thioacetyl butyrate. These enantiomerically pure intermediates can be used as chiral building blocks to obtain both (S)- and (R)-enantiomers of α-lipoic acid and their analogues.     

Dehydroascorbic acid (DHAA) capped magnetite nanoparticles as an efficient magnetic organocatalyst for the one-pot synthesis of α-aminonitriles and α-aminophosphonates

A dehydroascorbic acid capped magnetite (DHAA-Fe₃O₄) catalyst is prepared and used for the one-pot synthesis of α-aminonitriles and α-aminophosphonates. Different derivatives of these compounds are synthesized in good yields.     

An improved synthesis of (S)-(+)- and (R)-(−)-[2.2]paracyclophane-4-carboxylic acid

Treatment of 4-bromo[2.2]paracyclophane with n-butyllithium followed by CO₂ produced [2.2]paracyclophane-4-carboxylic acid, 1. Both enantiomeric forms [63% of (+)-(S)-1 and 48% of (−)-(R)-1] were obtained by resolution via the corresponding diastereomeric α-(p-nitrophenylethylammonium salts.     

Asymmetric synthesis of (2R,3S)-4-halo-3-benzyloxy-2-(N-methoxycarbonyl-N-benzylamino)butyronitriles as precursors for the synthesis of β-hydroxy-α-amino acids

(2R,3S)-4-Halo-3-benzyloxy-2-(N-methoxycarbonyl-N-benzylamino)butyronitriles have been prepared through an efficient three-step sequence from (2R,3S)-2-benzylamino-3-benzyloxy-4-(tert-butyldimethylsilyloxy)butyronitrile, which is readily available in diastereomerically pure form by a Strecker-type reaction of the N-benzylimine, derived from selectively protected (R)-glyceraldehyde, and trimethylsilyl cyanide. These compounds enable the facile synthesis of chiral β-hydroxy-α-amino acids containing virtually any nucleophile capable of substituting the γ-halogen atom. As an illustration of their synthetic potential, the 4-bromo derivative has been successfully converted into (1R,2R)-2-benzyloxy-1-(N-methoxycarbonyl-N-benzylamino)cyclopropanecarboxamide, which is a new conformationally restricted serine analogue, in two steps: base-induced cyclisation and subsequent hydrolysis of the nitrile group.     

Asymmetric synthesis of heteroorganic analogs of natural products 5. Synthesis of pure diastereomers and enantiomers of fluoro-substituted (2S,3R)- and (2R,3R)-β-phenylserines

A convenient method is proposed for the preparative synthesis of pure diastereomers and enantiomers of fluoro-substituted (2S,3R)- and (2R,3R)--phenylserines by the hydroxyalkylation of the Ni(II) — complex of the Schiff base of glycine with (S)-2-N-(N¹-benzylpropyl)aminobenzophenone using the corresponding fluoro-substituted benzaldehydes.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya. No. 8, pp. 1906–1913, August, 1991.     

Chemoenzymatic synthesis of Fmoc-protected (2S,3S)-2-hydroxy-3-amino acids and their application in the synthesis of an α-hydroxylated β-hexapeptide

A chemoenzymatic and stereoselective synthesis of Fmoc-protected (2S,3S)-2-hydroxy-3-amino acids from 2-furaldehyde is described as well as their application, without prior hydroxyl protection, in the solid-phase synthesis of a novel completely α-hydroxylated β-hexapeptide.