DNA-, RNA- and self-pairing properties of a pyrrolidinyl peptide nucleic acid with a (2′R,4′S)-prolyl-(1S,2S)-2-aminocyclopentanecarboxylic acid backbone

A new pyrrolidinyl peptide nucleic acid (PNA) comprising of an alternate sequence of 4′-nucleobase-modified proline with (2′R,4′S) configuration and a (1S,2S)-2-aminocyclopentanecarboxylic acid [(2′R,4′S)-acpcPNA] backbone was synthesized and its DNA-, RNA- and self-pairing properties studied. T_m and CD studies suggested that the (2′R,4′S)-acpcPNA forms antiparallel hybrids to DNA and RNA with high sequence and direction specificity. The stability of these hybrids is comparable to those of the (2′R,4′R)-acpcPNA hybrids previously reported by our group. On the other hand, experiments with a self-complementary sequence indicated that the new (2′R,4′S)-acpcPNA forms a more stable antiparallel self-hybrid than (2′R,4′R)-acpcPNA.     

Synthesis of the constrained glutamate analogues (2S,1′R,2′R)- and (2S,1′S,2′S)-2-(2′-carboxycyclobutyl)glycines L-CBG-II and L-CBG-I by enzymatic transamination

Optically pure trans-cyclobutane analogues of glutamic acid are prepared by highly selective enzymatic transamination of a single racemic trans-cyclobutane α-ketoglutaric acid derivative 5, which is synthesized in five steps from maleic anhydride. (2S,1′R,2′R)- and (2S,1′S,2′S)-2-(2′-carboxycyclobutyl)glycines L-CBG-II and L-CBG-I are obtained using aspartate aminotransferase (AAT) and branched chain aminotransferase (BCAT), respectively.     

Determination of the absolute configuration of the male aggregation pheromone, 2-methyl-6-(4′-methylenebicyclo[3.1.0]hexyl)hept-2-en-1-ol, of the stink bug Erysarcoris lewisi (Distant) as 2Z,6R,1′S,5′S by its synthesis

Lipase-catalyzed asymmetric acetylation of a mixture of (6R,1′S,4′S,5′R)- and (6R,1′R,4′R,5′S)-7′-norsesquisabinen-4′-ol (3) afforded a separable mixture of the recovered former and the acetate of the latter. The recovered alcohol was oxidized to (6R,1′S,5′R)-sesquisabina ketone (2), whose absolute configuration could be assigned by its CD comparison with (1R,5S)-sabina ketone (4). Conversion of (6R,1′S,5′R)-sesquisabina ketone (2) to the bioactive pheromone revealed the stereostructure of the male aggregation pheromone of the stink bug Erysarcoris lewisi (Distant) to be (2Z,6R,1′S,5′S)-2-methyl-6-(4′-methylenebicyclo[3.1.0]hexyl)hept-2-en-1-ol (sesquisabinen-1-ol, 1).     

Pheromone synthesis. Part 243: Synthesis and biological evaluation of (3R,13R,1′S)-1′-ethyl-2′-methylpropyl 3,13-dimethylpentadecanoate, the major component of the sex pheromone of Paulownia bagworm, Clania variegata, and its stereoisomers

All of the four stereoisomers of (1′S)-1′-ethyl-2′-methylpropyl 3,13-dimethylpentadecanoate, the major component of the female sex pheromone of Clania variegata, were synthesized by employing olefin cross metathesis as the key reaction and starting from (R)- or (S)-2-methyl-1-butanol, (R)- or (S)-citronellal, and (S)-2-methyl-3-pentanol. Their bioassay revealed the (3R,13R,1′S)-isomer as the bioactive one, whose more efficient synthesis was achieved in two different ways by employing Wittig reaction as the key step.     

Synthesis of (3′R,5′S)-3′-hydroxycotinine using 1,3-dipolar cycloaddition of a nitrone

To synthesize (3′R,5′S)-3′-hydroxycotinine [(+)-1], the main metabolite of nicotine (2), cycloaddition of C-(3-pyridyl)nitrones 3a, 3c, and 15 with (2R)- and (2S)-N-(acryloyl)bornane-10,2-sultam [(2R)- and (2S)-8] was examined. Among them, l-gulose-derived nitrone 15 underwent stereoselective cycloaddition with (2S)-8 to afford cycloadduct 16, which was elaborated to (+)-1.     

Enantioselective total synthesis of (2R,3R,6R)-N-methyl-6-(deca-1′,3′,5′-trienyl)-3-methoxy-2-methylpiperidine, an insecticidal alkaloid

An insecticidal piperidine alkaloid, (2R,3R,6R)-N-methyl-6-(deca-1′,3′,5′-trienyl)-3-methoxy-2-methylpiperidine, was efficiently synthesized in a stereoselective manner starting from d-alanine. Chiral center at C-6 was controlled by hydrogenation of imine and side chain was introduced by Julia olefination. The absolute configuration of natural product was determined to be 2R, 3R, 6R.     

Enantioselective synthesis of (2S,3′R,7′Z)-N-(3′-hydroxy-7′-tetradecenoyl)-homoserine lactone

A concise enantioselective total synthesis of (2S,3′R,7′Z)-N-(3′-hydroxy-7′-tetradecenoyl)-homoserine lactone is described. Key feature of this protocol is a catalytic asymmetric hydrogenation and a prophenol-zinc-catalyzed diazo addition to imine reaction as genesis of chirality. Moreover, flexibility is built in the synthesis to generate enantioenriched analogs using catalytic amount of enantioenriched C₂-symmetric ligands.     

Synthesis and stereochemistry of ceramide B, (2S,3R,4E,6R)-N-(30-hydroxytriacontanoyl)-6-hydroxy-4-sphingenine, a new ceramide in human epidermis

(2S,3R,4E,6R)-N-(30-Hydroxytriacontanoyl)-6-hydroxy-4-sphingenine (1) and its (6S)-isomer (1′) were synthesized by starting from pentadecan-15-olide, the enantiomers of 1-pentadecyn-3-ol, and (S)-Garner's aldehyde. Comparison of the ¹H NMR spectra of the tetraacetyl derivatives of 1 and 1′ with that of ceramide B, a new protein-bound ceramide in human stratum corneum, revealed it to be (2S,3R,4E,6R)-1.     

Regio- and stereoselective cycloadditions of (1Z,4R,5R)-1-arylmethylidene-4-benzoylamino-3-oxo-5-phenylpyrazolidin-1-ium-2-ides to methyl methacrylate

[3+2] Cycloadditions of (1Z,4R^∗,5R^∗)-1-arylmethylidene-4-benzoylamino-3-oxo-5-phenylpyrazolidin-1-ium-2-ides 1a-e to methyl methacrylate gave the 1-CO₂Me regioisomers 3/3′, exclusively, in 1-67% yields. Stereocontrol was dependent on the ortho-substituents at the 1′-aryl group in dipole 1: ortho-unsubstituted dipoles 1a-c gave the major (1R^∗,3R^∗,5R^∗,6R^∗)-isomers 3a-c, whilst ortho-disubstituted dipoles gave the major (1R^∗,3S^∗,5R^∗,6R^∗)-isomers 3′d,e. The structures of cycloadducts were determined by NMR and X-ray diffraction.     

Highly diastereoselective chemoenzymatic synthesis of (2′R)- and (2′S)-2′-deoxy[2′-H]guanosines

In an effort to develop an efficient synthetic method of highly diastereoselective (2′R)- and (2′S)-2′-deoxy[2′-²H]guanosines, chemoenzymatic conversion was investigated. The synthesis of (2′R > 98% de)-2′-deoxy[2′-²H]guanosine was achieved by biological transdeoxyribosylation using (2′R > 98% de)-2′-deoxy[2′-²H]uridine, 2,6-diaminopurine, and Enterobacter aerogenes AJ-11125, followed by treatment with adenosine deaminase. (2′S > 98% de)-2′-Deoxy[2′-²H]guanosine was synthesized from (2′S > 98% de)-2′-deoxy[2′-²H]uridine and 2,6-diaminopurine using thymidine phosphorylase and purine nucleoside phosphorylase instead of E. aerogenes AJ-11125.     

Asymmetric syntheses of (1R,1R,5R,7R) and (1S,1R,5R,7R)-1-hydroxy-exo-brevicomin and a formal synthesis of (+)-exo-brevicomin

Asymmetric syntheses of (1R,1^′R,5^′R,7^′R) and (1S,1^′R,5^′R,7^′R)-1-hydroxy-exo-brevicomins 1 and 2, volatiles of the male mountain pine beetle, and a formal synthesis of (+)-exo-brevicomin 3, a component of the attracting pheromone system of several bark beetles have been achieved. The key steps are Birch reduction of commercially available α-picoline, selective Wittig olefination, and Sharpless asymmetric dihydroxylation.     

Stereoselective synthesis of (R)-(+)-1-methoxyspirobrassinin, (2R,3R)-(−)-1-methoxyspirobrassinol methyl ether and their enantiomers or diastereoisomers

Stereoselective synthesis of cruciferous indole phytoalexin (R)-(+)-1-methoxyspirobrassinin and its unnatural (S)-(−)-enantiomer was achieved by spirocyclization of 1-methoxybrassinin in the presence of (+)- and (−)-menthol and subsequent oxidation of the obtained menthyl ethers. Methanolysis of menthyl ethers in the presence of TFA afforded (2R,3R)-(−)-1-methoxyspirobrassinol methyl ether as well its unnatural (2S,3S)-, (2R,3S)-, and (2S,3R)-isomers.     

Diastereoselective synthesis of 1-alkyl-2,4,6-trioxoperhydropyrimidine-5-spiro-3′-(1′,2′,3′,4′-tetrahydroquinolines)

Knoevenagel products formed by the condensation of N-monoalkyl barbituric acids with o-tert-amino benzaldehydes undergo tert-amino effect reactions (T-reactions) yielding 1-alkyl-2,4,6-trioxoperhydropyrimidine-5-spiro-3′-(1′,2′,3′,4′-tetrahydroquinoline) derivatives as a mixture of (S^∗,S^∗)- and (S^∗,R^∗)-diastereomers. Mostly, the major diastereomer has the S^∗,S^∗-configuration. According to X-ray diffraction data in the solid form and NOE data in solution, diastereoselectivity of the T-reactions can be associated with the structure of the Knoevenagel products whose conformation is fixed by the strong intramolecular C-H?π interaction.     

Synthesis and absolute configuration of two diastereoisomeric (1R,2S,3R)-and (1S,2S,3R)-2-amino-1-(2-furyl)-1,3-butandiols

The synthesis of (1R, 2S, 3R) and (1S, 2S, 3R)-2-(N-benzoylamino)-1-(2-furyl)-1, 3-butandiols (15) and (16) from D-threonine is described. The assignment of absolute configuration of the newly formed asymmetric center at C-1 was based on the ¹H-NMR spectra of O-isopropylidene derivatives 17 and 18.     

An efficient and stereoselective synthesis of (3S,4R)-(−)-trans-4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine

An asymmetric conjugate addition reaction between a chiral α,β-unsaturated amido ester and ethyl-N-methylmalonamide has been used as a key step in the synthesis of (3S,4R)-(−)-trans-4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine, a key intermediate for (−)-paroxetine.     

Efficient and practical asymmetric synthesis of isopropyl (R)-3-(3′,4′-dihydroxyphenyl)-2-hydroxypropanoate and its enantiomer

The highly enantioselective synthesis of (R)-isopropyl 3-(3′,4′-dihydroxyphenyl)-2-hydroxypropanoate and its enantiomer has been achieved starting from 3,4-dihydroxybenzaldehyde. The stereogenic centers were established through asymmetric dihydroxylation of (E)-isopropyl 3,4-bis(benzyloxy) cinnamate. A convenient manipulation in selective catalytic hydrogenation and deprotection was also accomplished in HCl-ⁱPrOH employing 10% Pd/C catalyst.     

Introduction of a planar chirality onto steroid substrates: synthesis of (S) and (R)-2′-formylcymantrenyl-17α-ethynylestradiols using (S) and (R)-1-formyl-2-iodo-cymantrenes

We report the synthesis and characterisation of (S) and (R)-2′-formylcymantrenyl-17α-ethynylestradiol synthesized using the Sonogashira cross-coupling reaction between optically pure (S) and (R) 1-formyl-2-iodo cymantrenes and ethynylestradiol. (S) and (R) 1-formyl-2-iodo cymantrenes were obtained from the same precursor: (2R,4R)-4-(methoxymethyl)-2-cymantrenyl-1,3-dioxane.     

Efficient synthesis of the cyclopentanone fragrances (Z)-3-(2-oxopropyl)-2-(pent-2-en-1-yl)cyclopentanone and Magnolione

This paper describes the selective syntheses of two cis-isomer-enriched cyclopentanone fragrances: (Z)-3-(2-oxopropyl)-2-(pent-2-en-1-yl)cyclopentanone (four steps, 62% overall yield, 67% cis) and Magnolione^® (five steps, 60% overall yield, 55% cis). In addition, the asymmetric synthesis of (3aR,7aS)-5-methyl-2,3,3a,4,7,7a-hexahydro-1H-inden-1-one as well as (3a′R,7a′S)-5′-methyl-2′,3′,3a′,4′,7′,7a′-hexahydrospiro[[1,3]dioxolane-2,1′-indene] has been realized by an efficient kinetic resolution, which enables the selective synthesis of the 2S,3R-isomer-enriched 3 and 4.     

Synthetic studies on homophymine A: stereoselective synthesis of (2R,3R,4R,6R)-3-hydroxy-2,4,6-trimethyloctanoic acid

An efficient and highly stereocontrolled synthesis of (2R,3R,4R,6R)-3-hydroxy-2,4,6-trimethyloctanoic acid, the β-hydroxy acid unit that acylates the N-terminus of homophymine A, has been devised starting from iodoethane and (S,S)-pseudoephedrine propionamide in 9 steps and 36% average overall yield. Comparison of the ¹H and ¹³C NMR and optical rotation data of the resulting β-hydroxy acid with the natural fragment unambiguously verifies the configurational assignment as (2R,3R,4R,6R).     

Concise and practical synthesis of (2S,3R,4R,5R) and (2S,3R,4R,5S)-1,6-dideoxy-1,6-iminosugars

The syntheses of (2S,3R,4R,5R) and (2S,3R,4R,5S)-1,6-dideoxy-1,6 iminosugars 1a and 1b, respectively, from d-glucose are described. The key transformations in this reaction sequence include regio-selective epoxide ring opening with N-benzylamine followed by intramolecular reductive amination of amino-aldehyde.