(R)-4-menthen-3-one in the synthesis of (3S)-methylundecand (2S)-methyldec-1-ylbromides, key synthons for (S,S,S)-diprionylacetate

New capabilities for the synthetic use of (R)-4-menthen-3-one were demonstrated using as examples (3S)-methylundec- and (2S)-methyldec-1-ylbromides, key synthons for (S,S,S)-diprionylacetate (sex pheromone of pine sawflies of genera Diprion and Neodiprion).     

Synthesis of (2R,3S,4S)-4-aryl-3-hydroxyprolinols

Synthesis of (2R,3S,4S)-4-aryl-3-hydroxyprolinols has been established starting from 2-benzyloxymethylpyrrolidin-2-one framework, which is derived from commercially available trans-(2S,4R)-4-hydroxyproline. The single diastereomer having a trans–cis relative configuration with C₂ and C₃ and C₃ and C₄ is constructed in two one-pot functional group transformations of Grignard addition/dehydration and epoxidation/isomerization as the key steps in moderate yield.     

The stereochemistry of the dichlorocobalt(III) complexes with (2S,5S,9S)- and (2S,5R,9S)-trimethyltriethylenetetraamines

Dichlorocobalt(III) complexes of (2S,5S,9S)-trimethyltriethylenetetraamine (L₁) and (2S,5R,9S)-trimethyltriethylenetetraamine (L₂) have been prepared. Both L₁ and L₂ coordinate to the cobalt(III) ion to give three isomers: Λ-cis-α, Δ-cis-β, trans isomers for L₁ and Δ-cis-α, Δ-cis-β, trans isomers for L₂. Each of the trans-dichloro complexes of the two ligands have been isomerized stereospecifically to the cis-α-dichloro complex in methanol, and each of the cis-α-dichloro complexes stereospecifically to the trans-diaqua complex in water. Both the geometrical and optical inversions took place at the same time in the observed stereospecific isomerizations.     

Design, synthesis, structure and properties of an α-helix cap template derived from N-[(2S)-2-chloropropionyl]-(2S)-Pro-(2R)-Ala-(2S,4S)-4-thioPro-OMe which initiates α-helical structures

A strategy based upon removing the requirement for all of the carbonyl dipoles to align at the same time in the transition state leading to the cyclisation of N-[(2S)-2-chloropropionyl]-(2S)-Pro-(2R)-Ala-(2S,4S)-4-thioPro-OMe to a Zimm-Bragg type α-helix peptide intitator template was successful. Each amide bond of the 12-membered macrocyclic template existed in the trans-rotomeric form. Derivatives of the template were prepared by extending the C-terminus and these were characterised by NMR spectroscopy and restrained simulated annealing. In deuterochloroform solution at low temperature, separate sets of NMR signals were observed for two rapidly interconverting helical conformational isomers of the thioether macrocycle which possessed an appended trialkylammonium ion. A similar time-averaged conformation was also observed in aqueous solution. At −80 °C in d₂-dichloromethane the rate of conformational exchange was slowed sufficiently to obtain resonance assignments and NOE data separately for each isomer. In the minor isomer (40%), the four carbonyl oxygen hydrogen-bond acceptors of the template are aligned in an α-helical conformation and in the major conformer the Pro² carbonyl dipole was anti-aligned with the other three dipoles. Thus, the conformers differ in the orientation of one carbonyl group. Molecular modelling calculations showed that the minor isomer was stabilised by coulombic interactions between the trialkylammonium salt and the carbonyl group dipole moments.     

Stereoselective total synthesis of (+)-(6R,2′S)-cryptocaryalactone and (−)-(6S,2′S)-epi cryptocaryalactone

The total synthesis of (+)-(6R,2′S)-cryptocaryalactone and (−)-(6S,2′S)-epi cryptocaryalactone is reported based on stereoselective reduction of δ-hydroxy β-keto ester to install 1,3-polyol system, cis Wittig olefination, and lactonization as the key steps. The synthesis of (−)-(6S,2′S)-epi cryptocaryalactone is also reported using syn-benzylidene acetal formation and a preferential Z-Wittig olefination reaction and lactonization as the key steps.     

Stereoselective synthesis of (−)-(1R,2S)-2-aminocyclobutane-1-carboxylic acid, a conformationally constrained β-amino acid

The title compound as well as some derivatives have been synthesized for the first time in optically active form by means of a chemoenzymatic transformation used to induce asymmetry in achiral precursors. The enantio- and diastereomeric purity has been determined by HPLC and NMR techniques.     

Asymmetric synthesis of a sex pheromone (3S,5R,6S)-3,5-dimethyl-6-isopropyl-3,4,5,6-tetrahydropyran-2-one

An Oppolzer anti-aldol approach for the synthesis of the sex pheromone (3S,5R,6S)-3,5-dimethyl-6-isopropyl-3,4,5,6-tetrahydropyran-2-one is reported.     

Chemoenzymatic synthesis of (R)- and (S)-1-heteroarylethanols

A chemoenzymatic methodology for the synthesis of highly enantiomerically enriched (S)- and (R)-1-heteroarylethanols by enantioselective bioreduction with baker’s yeast of the corresponding 1-heteroarylethanones followed by three racemization free chemical steps including a Mitsunobu reaction was developed.     

Organocatalytic enantioselective synthesis of β-blockers: (S)-propranolol and (S)-naftopidil

An efficient enantioselective synthesis of β-adrenergic blockers (S)-propranolol and (S)-naftopidil with >98% ee using an l-proline-catalyzed α-aminoxylation of an aldehyde as a key step is described.     

Stereoselective synthesis of (1R,2S)-2-amino-1,3-diols from (R)-cyanohydrins

Vinyl substituted (1R,2S)-amino alcohols 5 were obtained by addition of vinyl magnesium bromide to the corresponding cyanohydrin O-trimethylsilyl ethers (R)-2. The O- and N-protected vinyl amino alcohols 6 were ozonized at −78°C in methanol yielding (1R,2S)-2-amino-1,3-diols7 in high enantiomeric and diastereomeric excesses. For purification, compounds 7 in some cases were acetylated to give the derivatives (1R,2S)-8. Racemic 6a was converted by oxidative ozonolysis at −78°C in methanolic NaOH solution to the corresponding methyl N-acetyl-β-hydroxy propanoate 9a. The configuration of (1R,2S)-8a was confirmed by x-ray crystallographic analysis.     

Preliminary studies on the synthesis of rancinamycins from nitrosugars: first total synthesis of (3S,4S,5S,6R)-5-benzyloxy-6-hydroxy-3,4-(isopropylidendioxy)-cyclohex-1-enecarbaldehyde

The first total synthesis of (3S,4S,5S,6R)-5-benzyloxy-6-hydroxy-3,4-(isopropylidendioxy)-cyclohex-1-enecarbaldehyde from d-glucose is described. The key steps of this synthesis are the stereoselective Michael addition of 2-lithio-1,3-dithiane to 3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-6-nitro--d-xilo-hex-5-enofuranose followed by the enantioselective two-step transformation of 3-O-benzyl-5,6-dideoxy-5-C-(1,3-dithian-2-yl)-6-nitro-β-l-idofuranose into (1S,2S,3S,4S,5S,6R)-5-benzyloxy-6-hydroxy-3,4-(isopropylidendioxy)-2-nitro-cyclohexanecarbaldehyde propylene dithioacetal, which was finally converted into the target compound.     

Synthesis of chiral lithium carbamates from (S)-2-(N,N-dialkyl-aminomethyl)pyrrolidines and (S)-methoxymethylpyrrolidine

A convenient synthesis of chiral lithium N-alkyl carbamates 1a–4a from chiral pyrrolidines 1–4, LiH and CO₂ is described. The yields are good to excellent. A combined experimental (¹H, ⁶Li-HOESY, cryoscopy) and theoretical study (B3LYP/6-311++G(d,p)) succeeded in assigning the predominant solution state structure of 1a.     

Enantioselective organic syntheses using chiral transition metal complexes V. (2S,3S)-Bis(dibenzophospholyl)butane, a rigid (S,S)-CHIRAPHOS analog

The P–Ph cleavage of phenyldibenzophosphole (1) with lithium in THF gives lithium dibenzophospholide (2). Reaction of 2 with ethyleneglycol ditosylate produces the known chelate ligand 1,2-bis(dibenzophospholyl)ethane (3) in good yield. Similarly, 2 and (2R,3R)-butanediol ditosylate give the new chiral chelate ligand (2S,3S)-bis(dibenzophospholyl)butane (4). Ligand exchange of [CpRu(PPh₃)₂Cl] with 3 or 4 yields the halfsandwich complexes [CpRu(C₁₂H₈PC₂H₄PC₁₂H₈)Cl] (5) and [CpRu((S,S)-C₁₂H₈PCHMeCHMePC₁₂H₈)Cl] (6). Complex 6 was characterized crystallographically (monoclinic, space group P2₁ (no. 4), a=820.6(4), b=1501.0(3), c=1172.8(6) pm, β=108.87(2)°, V=1.367(1)×10⁹ pm³, Z=2). The most conspicuous feature of the structure of 6 is the perfect coplanarity of the two dibenzophosphole moieties imposed by their steric interaction with the Cp ligand. Complex 6 and the thiophene complex [CpRu((S,S)-C₁₂H₈PCHMeCHMePC₁₂H₈)(SC₄H₄)]BF₄ (7) derived therefrom are remarkably unreactive with regard to ligand substitutions. A possible explanation is the lack of intramolecular

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–C stabilization en route to the transition state of ligand substitution. The enantiomeric purity of 6 and 7 could nevertheless be demonstrated by conversion to diastereomerically pure [CpRu((S,S)-C₁₂H₈PCHMeCHMePC₁₂H₈)((S)-CNCHMePh)]BF₄ (8).     

Asymmetric Synthesis via Acetal Templates. 14. Preparation of Enantiomerically Pure (3S,4S)- and (3S,4R)-Statine Derivatives

Several (3S,4S)- and (3S,4R)-statine derivatives have been prepared by attack of nucleophiles on crystalline, epimeric N-BOC-lactams 7a and 7b. The key step in the synthesis of the lactams was the TiCl₄-catalyzed coupling reactions of acetals derived from (R)-1,3-butanediol with allyltrimethylsilane.

Several enantiometrically pure (3S,4S- and (3S, 4R)-statine derivatives were made by sodium cyanide-catalyzed reaction of nucleophiles with the lactams 3a and 3b which were synthesized by the scheme 1 → 2 → 3.     

Total synthesis of 3,4-dihydroxyprolines, -threo- -norvaline and (2S,3R,4R)-2-amino-3,4-dihydroxytetrahydrofuran-2-carboxylic acid methyl ester

The Henry reaction between -glyceraldehyde and ethyl nitroacetate allowed the practical development of a diastereoselective synthesis of 3,4,5-trihydroxy-2-nitropentanoic acid esters, which were reduced to polyoxamic acids, which were used in a new diastereoselective synthesis of 3,4-dihydroxyprolines and new enantioselective syntheses of -threo- -norvaline and (2S,3R,4R)-2-amino-3,4-dihydroxytetrahydrofuran-2-carboxylic acid methyl ester.     

Asymmetric syntheses of protected (2S,3S,4S)-3-hydroxy-4-methylproline and 4′-tert-butoxyamido-2′-deoxythymidine

Described herein is a versatile approach to (i) (2S,3S,4S)-3-hydroxy-4-methylproline 3, a constituent of echinocandins and related oligopeptide antibiotics; (ii) (2S,3S)-3-hydroxyproline 1; (iii) (2R,3S)-3-hydroxyprolinol 5, and (iv) 4′-tert-butoxyamido-2′-deoxythymidine 6b. The method features a stepwise regio- and diastereoselective reductive furylation of the protected (3S,4S)-4-methylmalimide 10, (S)-malimide 9, and a chemoselective oxidative transformation of the furyl group to the carboxyl group as the key steps.     

A stereoselective synthesis of (2S,3R)-β-methoxyphenylalanine: a component of cyclomarin A

A stereoselective synthesis of (2S,3R)-β-methoxyphenylalanine, an amino acid contained within the cyclic peptide cyclomarin A, was successfully synthesized from Lajoie’s serine aldehyde.     

First synthesis of enantiomerically pure (1S,2S)- and (1R,2R)-1,2-diaminocyclobutanecarboxylic acid–ornithine derivative–, from racemic 2-aminocyclobutanone

An easy and efficient one-pot reaction from readily available 2-(N-Cbz) aminocyclobutanone selectively gave, by means of an asymmetric Strecker synthesis in the presence of a chiral benzylic amine, the thermodynamic 1,2-diamino nitriles. Basic hydrolysis, cleavage of the benzylic group and acidic hydrolysis of the resulting trans-1,2-diaminocyclobutanecarbonitrile gave, in a four-step sequence from the ketone, (1S,2S)- or (1R,2R)-1,2-diaminocyclobutanecarboxylic acid, ornithine derivatives. The absolute configuration has been established by X-ray analysis of the corresponding trans-diamino amide.     

Diastereoselective allylation of N-glyoxyloyl-(2R)-bornane-10,2-sultam and (1R)-8-phenylmenthyl glyoxylate: synthesis of (2S,4S)-2-hydroxy-4-hydroxymethyl-4-butanolide

The diastereoselective addition of allylsilanes and allylstannanes to N-glyoxyloyl-(2R)-bornane-10,2-sultam 1 and (1R)-8-phenylmenthyl glyoxylate 7 in the presence of Lewis acids has been studied. We obtained diastereoselectivities up to 84% and 94% for the allylation of 2 and 7, respectively. The application of the allylation products of 1 or 2 in the synthesis of 4-butanolides, for example (2S,4S)-2-hydroxy-4-hydroxymethyl-4-butanolide 13 is presented.     

(3S,4R,5R)-3-(2-Hydroxyethyl)piperidine-3,4,5-triol as an isofagomine analogue: synthesis and glycosidase inhibition study

The synthesis of (3S,4R,5R)-3-(2-hydroxyethyl)piperidine-3,4,5-triol 10 has been described from d-glucose. The base promoted cyclization for the construction of the piperdine framework is the key step of the synthesis.