Collagen cross-links: a convenient synthesis of tert-butyl-(2S)-2-[(tert-butoxycarbonyl)amino]-4-(2-oxiranyl)butanoate

An efficient synthesis of tert-butyl-(2S)-2-[(tert-butoxycarbonyl)amino]-4-(2-oxiranyl) butanoate (5), the key intermediate for preparation of collagen cross-links (+)-pyridinoline (Pyd, 1) and (+)-deoxypyridinoline (Dpd, 2) was described from (4S)-5-(tert-butoxy)-4-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid (6) in six steps. Also, an improved synthesis of iodide (2S)-(−)-4b was presented.     

Preparation of dimethyl (R)- and (S)-2-(2-aminophenyl)-2-hydroxyethylphosphonate from anthranilic acid

An efficient synthesis of both enantiomers of dimethyl δ-amino-β-hydroxyethylphosphonate 6 has been achieved starting from anthranilic acid, through the resolution of dimethyl (±)-2-(2-N,N-dibenzylaminophenyl)-2-hydroxyethylphosphonate 9 with (S)-O-methylmandelic acid. The absolute configuration of the enantiomers 9 was assigned by the Dale and Mosher approach using the extended Newman projections and molecular mechanics.     

Enzymatic desymmetrization of 2-amino-2-methyl-1,3-propanediol: asymmetric synthesis of (S)-N-Boc-N,O-isopropylidene-α-methylserinal and (4R)-methyl-4-[2-(thiophen-2-yl)ethyl]oxazolidin-2-one

We report herein, the novel enzymatic desymmetrization of 2-tert-butoxycarbonylamino-2-methyl-1,3-propanediol 1. This method makes it possible to prepare (S)-N-Boc-N,O-isopropylidene-α-methylserinal 3, which is a chiral building block for the synthesis of a variety of α-substituted alanine derivatives. Moreover, optically active (4R)-methyl-4-[2-(thiophen-2-yl)ethyl]oxazolidin-2-one 4, one of the key intermediates in the synthesis of a novel immunosuppressant, has been prepared by this methodology.     

Enantiospecific synthesis of the sugar amino acid (2S,5S)-5-(aminomethyl)-tetrahydrofuran-2-carboxylic acid

An enantiospecific synthesis of the tetrahydrofuran amino acid (2S,5S)-5-(aminomethyl)-tetrahydrofuran-2-carboxylic acid 1 is reported. The sugar enone 2-(S)-octyl 6-O-acetyl-3,4-dideoxy-α-d-glycero-hex-3-enopyranosid-2-ulose 2a, derived from galactose, was employed as a chiral precursor. The enone 2a was converted by chemical manipulation of the functional groups into the 6-azido-2-O-tosyl-3,4,6-trideoxy-d-erythro-hexono-1,5-lactone 9 as key intermediate. Methanolysis of 9 induced the opening of the lactone and the attack of the hydroxyl group at C-5 to C-2 with the displacement of the tosylate. This reaction led to the formation of the tetrahydrofuran ring of methyl (2S,5S)-5-(azidomethyl)-tetrahydrofuran-2-carboxylate 10, which was readily converted into 1. The overall yield of the sequence was 35%, and all the intermediates and the final product have been fully characterized. In addition, the preferential conformations in solution of lactone 9 and target molecule 1 have been established.     

Chemoenzymatic synthesis of (S)-2-cyanopiperidine,a key intermediate in the route to (S)-pipecolic acid and 2-substituted piperidine alkaloids

The preparation of (S)-2-cyanopiperidine 4 provides a new access to 2-substituted piperidines. This synthesis is based on an enantioselective (R)-oxynitrilase-catalyzed reaction for the preparation of (R)-(+)-6-bromo-2-hydroxyhexanenitrile 1 and the subsequent cyclization of this compound to yield the piperidine ring. The utilization of 4 as the starting material for the synthesis of (S)-2-aminomethylpiperidine 6, (R)-(−)-coniine 10 and (S)-(−)-pipecolic acid 13 is also described.     

Synthesis of (R)-(+)-methyl 3-amino-3-(5-hydroxy-2-pyridinyl)propanoate,an analog of l-azatyrosine

A concise asymmetric synthesis of (R)-(+)-methyl 3-amino-3-(5-hydroxy-2-pyridinyl)propanoate 2, a β-amino acid analog of l-azatyrosine 1 starting from the commercially available (−)-Andersen reagent (−)-3 in good overall yield is described.     

Synthesis of (S)-, (R)-, and (rac)-2-amino-3,3-bis(4-fluorophenyl)propanoic acids and an evaluation of the DPP IV inhibitory activity of Denagliptin diastereomers

The non-proteinogenic amino acid (2S)-2-amino-3,3-bis(4-fluorophenyl)propanoic acid [(S)-1] is a key intermediate required for the synthesis of Denagliptin (2a). Denagliptin is a dipeptidyl peptidase IV (DPP IV) inhibitor that is being developed for the treatment of type-2 diabetes mellitus. A diastereoselective, cost-efficient synthetic procedure for (S)-1 was developed by alkylating a Ni(II) glycine equivalent derived from (S)-2-[(N-benzylprolyl) amino] benzophenone [(S)-BPB]. The alkylated product was then decomposed to isolate the target amino acid (S)-1 (ee >99%) and ligand (S)-BPB, which can be reused in subsequent reactions. The enantiomer (R)-1 and racemate (rac)-1 were synthesized from their corresponding Ni(II) glycine equivalents. Denagliptin diastereomers (2), derived from the key intermediates (S)-1, (R)-1, and (rac)-1 were synthesized, and their dipeptidyl peptidase IV inhibitory activities were investigated. These findings are important in the design and synthesis of DPP IV inhibitors.     

Asymmetric synthesis of (R)-[2,2-2H2]-1-aminocyclopropane-1-phosphonic acid (ACPP derivative) conformationally constrained ACC analogue using a chiral sulfinyl auxiliary

The asymmetric cyclopropanation of vinylphosphonate using (S)-dimethylsulfonium-(p-tolylsulfinyl)methylide was applied to obtain a dideuterated cyclopropyl sulfoxide. A three-step synthesis of enantiopure (+)-(1R)-1-amino-2,2-dideuteriocyclopropanephosphonic acid (+)-17-d₂ was developed.     

Asymmetric synthesis of (R)-(+)-6-(1,4-dimethoxy-3-methyl-2-naphthyl)-6-(4-hydroxyphenyl)hexanoic acid as a key intermediate for a neurodegenerative disease agent

An asymmetric synthesis of (R)-(+)-6-(1,4-dimethoxy-3-methyl-2-naphthyl)-6-(4-hydroxyphenyl)hexanoic acid 2 as a key intermediate for a neurodegenerative disease agent 1 has been developed. A key reaction was an asymmetric hydrogenation of hindered acrylic acid 13 catalyzed by the Rh-JOSIPHOS system in the presence of a base to afford a chiral acid up to 93% ee.     

Novel stereoselective syntheses of (2E,4E)-4-(4,4-dimethylpent-2-ynylidene)-N1,N5-dimethyl-N1,N5-bis(naphthalen-1-ylmethyl)pent-2-ene-1,5-diamine

We report two different synthetic approaches for the stereoselective synthesis of (2E,4E)-4-(4,4-dimethylpent-2-ynylidene)-N¹,N⁵-dimethyl-N¹,N⁵-bis(naphthalen-1-ylmethyl)pent-2-ene-1,5-diamine 1, an important impurity-reference standard for the chemical characterization of terbinafine. The diamine 1 was obtained in only six steps with a good overall yield starting from commercially available glutaconic acid.     

A short and efficient asymmetric synthesis of (1S,2R)-(+)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin hydrochloride (UH-232)

A general practical asymmetric synthesis of (1S,2R)-(+)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin hydrochloride (UH-232) was developed in a short and efficient method in high optical purity starting from commercially available 5-methoxy-1-tetralone. Asymmetric hydroboration of 5-methoxy-1-methyl-3,4-dihydronaphthalene with monoisopinocampheylborane followed by treatment with NaOH/H₂O₂ afforded key intermediate tetrahydronaphthol 4. Compound 4 was converted to the target molecule 1 using straightforward reactions.     

Synthesis of enantiomerically pure diethyl (R)- and (S)-2-hydroxy-3-(1,2,3-triazol-1-yl)propylphosphonates

The synthesis and ee determination of diethyl 3-azido-2-hydroxypropylphosphonates from 2,3-epoxypropylphosphonates have been optimised. Enantiomerically enriched diethyl (R)- and (S)-2-hydroxy-3-(1,2,3-triazol-1-yl)propylphosphonates (R)-3a–j and (S)-3a–h as well as (S)-3j were synthesised from diethyl (R)- and (S)-2,3-epoxypropylphosphonates in a reaction sequence including azidolysis followed by 1,3-dipolar cycloaddition with selected alkynes.     

Synthesis of TAK-218 using (R)-2-methylglycidyl tosylate as a chiral building block

We performed an asymmetric synthesis of (S)-2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperidinyl)methyl]-5-benzofuranamine dihydrochloride (TAK-218, 1), a compound used for the treatment of traumatic and ischemic central nervous system injuries. Oxirane 6, which was synthesized from (R)-2-methylglycidyl tosylate, was treated with aqueous trifluoroacetic acid to afford benzofuranmethanol 7 with inversion of stereochemistry at the stereogenic center. Compound 7 was converted into 1 with high enantiomeric excess in four steps.     

Preparation,molecular structures,and characteristic properties of (E)-1-(2-furyl)- and (E)-1-(2-thienyl)-2-(3-guaiazulenyl)ethylenes and (E)-1-(3-furyl)- and (E)-1-(3-thienyl)-2-(3-guaiazulenyl)ethylenes

Wittig reactions of 2-furaldehyde (20) [and thiophene-2-carbaldehyde (21)] with (3-guaiazulenylmethyl)triphenylphosphonium bromide (19) in ethanol containing NaOEt at 25 °C for 24 h under argon give (E)-1-(2-furyl)-2-(3-guaiazulenyl)ethylene (22E) and (E)-1-(2-thienyl)-2-(3-guaiazulenyl)ethylene (23E) in 53 and 36% yields. Similarly, Wittig reactions of 3-furaldehyde (29) [and thiophene-3-carbaldehyde (30)] with 19 under the same reaction conditions as for 20 and 21 afford (E)-1-(3-furyl)-2-(3-guaiazulenyl)ethylene (31E) and (E)-1-(3-thienyl)-2-(3-guaiazulenyl)ethylene (32E) in 32 and 46% yields. Molecular structures and characteristic properties as well as preparation of the title E (i.e., one of the geometrical isomers) forms, with a view to comparative study, are reported. Moreover, reactions of those conjugated π-electron systems with TCNE (=tetracyanoethylene) in benzene [and in DMF (=N,N-dimethylformamide)] at 25 °C for 24 h under argon yield unique products, possessing interesting molecular structures, respectively, whose characteristic properties and crystal structures are documented, also.     

A scalable synthesis of (R)-3-(2-aminopropyl)-7-benzyloxyindole via resolution

(±)-3-(2-Aminopropyl)-7-benzyloxyindole 1, assembled from 7-benzyloxyindole 3 in 59% overall yield, is resolved with O,O′-di-p-toluoyl l-(2R,3R)-tartaric acid 7 into (R)-1, a key intermediate of AJ-9677 2 (selective adrenaline β₃-agonist) in 99.5% e.e. and 36% overall yield. The unwanted enantiomer (S)-1 (61.9% e.e.; recovered in 57% yield from the crystallization filtrate) can be reused in another round of resolution after its enantiomeric purity is lowered to 3.7% by Raney Co treatment under a hydrogen atmosphere.     

Biohydrolysis of (S)-3-(thiophen-2-ylthio)butanenitrile

Whole-cell enzymatic hydrolysis was shown to be the choice in the preparation of (S)-3-(thiophen-2-ylthio)butanoic acid. While all chemical methods of hydrolysis failed, 12 bacterial strains expressing nitrile hydratase and amidase activities have been identified to hydrolyze (S)-3-(thiophen-2-ylthio)butanenitrile 1 directly into the corresponding acid. The substrate was also shown to be an efficient inducer of the enzymatic activity. However, it inhibited microbial growth. Acid 3 was prepared on a gram scale with the recombinant Rhodococcus erythropolis, formerly Brevibacterium sp. pYG811b as shown by sequencing of its 16S rRNA.     

Synthesis of enantiopure (R)-2-(4-methoxy-3-(3-methoxypropoxy)-benzyl)-3-methylbutanoic acid—a key intermediate for the preparation of Aliskiren

The enantioselective hydrogenation of (E)-2-(4-methoxy-3-(3-methoxypropoxy)-benzylidene)-3-methylbutanoic acid (1) to (R)-2-(4-methoxy-3-(3-methoxypropoxy)-benzyl)-3-methylbutanoic acid (2)—a key intermediate in the synthesis of the pharmacologically important renin inhibitor Aliskiren—is described. The stereochemistry of the catalytic transformation has been studied using a number of homogeneous chiral Rh(I) and Ru(II) complexes bearing ferrocene-based phosphine ligands. The highest enantioselectivity for the homogeneous hydrogenation of 1 (up to 95% ee) was achieved with a [Rh(NBD)₂]BF₄ pre-catalyst (substrate/catalyst ratio 100:1, 10 bar H₂, 40 °C, in MeOH). To bring the enantioselectivity to perfection an effective method for the isolation of the enantiopure carboxylic acid is suggested likewise.     

An efficient and stereospecific synthesis of (2S,4S)-2,4-diaminoglutaric acid

An efficient and stereospecific synthesis of (2S,4S)-2,4-diaminoglutaric acid 1 starting from trans-4-hydroxy-l-proline 2 is presented. The key step involves the combined application of ruthenium tetroxide (RuO₄) oxidation of 4-(tert-butoxycarbonylamino)proline derivatives 7 and 8 followed by regioselective ring opening of the resulting lactams 9 and 10 with 1 M LiOH.     

Studies on the syntheses of heterocyclic compounds—DCCLXII : Alternative synthesis of trans-3-(1'R*-hydroxyethyl)-4-(2',2'-dimethoxyethyl)-2-azetidinone,a synthetic intermediate of thienamycin

Synthesis of trans-3-(1'R^*-hydroxyethyl)-4-(2',2'-dimethoxyethyl)-2-azetidinone (5), an important intermediate for the synthesis of thienamycin (1), was investigated starting from the isoxazoline derivatives 3 and 9. The most effective method was catalytic hydrogenation of trans-4-t-butoxycarbonyl-3-(2,2'-dimethoxyethyl)-5-methyl-isoxazoline (9) with Adams catalyst in acetic acid, followed by trimethylsilylation of the resulting epimeric aminoesters 11A and B, cyclization with EtMgBr, and deblocking. Novel reductions of the isoxazolines with sodium borohydride and nickel chloride or with diborane followed by catalytic hydrogenation were also reported.     

Efficient synthesis of new 1-alkyl(aryl)-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrol-2(5H)-ones

The synthesis of 1-alkyl(aryl)-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrol-2(5H)-ones 5, 6a-d from 1-alkyl(aryl)-4-bromo-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrolidin-2-ones 3, 4a-d is reported. The 1-alkyl(aryl)-4-bromo-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrolidin-2-ones 3, 4a-d were obtained from regiospecific bromination of 1-alkyl(aryl)-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrolidin-2-ones 1, 2a-d with molecular bromine. The NMR and X-ray diffraction data showed that 1-alkyl(aryl)-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrolidin-2-ones were brominated at 4-position in the pyrrolidin-2-one ring.