A practical improvement of crystallization-induced asymmetric transformation of allene-1,3-dicarboxylates

Enantiomerically pure allene-1,3-dicarboxylates were easily synthesized by using epimerization–crystallization of dissymmetric allene compounds, which were prepared from acetone-1,3-dicarboxylates and naturally abundant chiral alcohols, that is, (−)- and (+)-menthols, borneol, and isoborneol. After scrutinizing the crystallization of several allene-1,3-dicarboxylates in the presence of triethylamine, it was found that allene-1,3-dicarboxylate carrying bornyl groups was the most easily prepared as a single isomer because of it having suitable solubility to be crystallized in hexane at 0 °C to room temperature. Diels–Alder reaction of the enantiomerically pure allene-1,3-dicarboxylates and cyclic dienes, such as N-Boc-pyrrole and cyclopentadiene, afforded endo-adducts having the same configurations at two newly generated stereogenic centers.     

Asymmetric strecker synthesis of alpha-amino acids via a crystallization-induced asymmetric transformation using (R)-phenylglycine amide as chiral auxiliary

[reaction: see text]. Diastereoselective Strecker reactions based on (R)-phenylglycine amide as chiral auxiliary are reported. The Strecker reaction is accompanied by an in situ crystallization-induced asymmetric transformation, whereby one diastereomer selectively precipitates and can be isolated in 76-93% yield and dr > 99/1. The diastereomerically pure alpha-amino nitrile obtained from pivaldehyde (R1 = t-Bu, R2 = H) was converted in three steps to (S)-tert-leucine in 73% yield and >98% ee.     

The first example of a crystallization-induced asymmetric transformation (CIAT) in the Mannich reaction

The novel synthesis of highly enantioenriched N-substituted α-amino-γ-alkyl(aryl)-γ-oxobutanoic acids is described. The process involves the combination of a crystallization-induced asymmetric transformation (CIAT) and the Mannich reaction. The role of retro-Mannich and retro-Michael reactions in the mechanism of the highly stereoselective transformation is also discussed.     

A stereoselective synthesis of (2S,4R)-δ-hydroxyleucine methyl ester: a component of cyclomarin A

(2S,4R)-δ-Hydroxyleucine methyl ester, the N-demethyl analogue of an amino acid contained within the macrocycle of cyclomarin A, was successfully synthesized using Davis’ asymmetric Strecker reaction.     

Synthesis of methyl N-Boc-(2S,4R)-4-methylpipecolate

An efficient stereoselective synthesis of fully protected (2S,4R)-4-methylpipecolic acid has been developed. The synthesis was achieved by initial asymmetric α-alkylation of glycine with a chiral iodide, affording the linear precursor as a single stereoisomer. Subsequent aldehyde formation using OsO(4)/NaIO(4) followed by immediate intramolecular cyclization afforded an enamine that was then subjected to hydrogenation to give the final compound in 23% yield over 10 steps.     

A new route to methyl (R,E)-(-)-tetradeca-2,4,5-trienoate (pheromone of Acanthoscelides obtectus) utilizing a palladium-catalyzed asymmetric allene formation reaction

[reaction: see text] A formal total synthesis of the sex attractant of male dried bean beetle, methyl (R,E)-(-)-tetradeca-2,4,5-trienoate, was achieved by a new efficient route utilizing the Pd-catalyzed asymmetric allene synthesis reaction. It was found that the atropisomeric biaryl bisphosphine (R)-segphos showed better enantioselectivity than (R)-binap in the Pd-catalyzed reaction for preparing alkyl-substituted axially chiral allenes.     

(R)-4-氰基-3-羟基丁酸乙酯的合成

研究了一条新的路线用于他汀类药物的重要中间体(R)-4-氰基-3-羟基丁酸乙酯的合成. 以廉价、易得的L-(－)-苹果酸为起始原料, 经酯化、还原、溴代和氰化四步反应得到目标化合物(R)-4-氰基-3-羟基丁酸乙酯, 合成总收率为56.7%. 所有中间体和最终产物均由ESI-MS, 1H NMR和13C NMR光谱及比旋光度表征并与文献值比较. 该方法原料易得、操作简便、收率良好, 产物容易分离纯化, 是一条适合大规模制备(R)-4-氰基-3-羟基丁酸乙酯的新合成工艺路线.     

An asymmetric synthesis of the novel H3 agonist (+)-(3R,4R)-3-(4-imidazolyl)-4-methylpyrrolidine dihydrochloride (Sch 50971)

A short, high yielding, enantioselective synthesis of the novel H₃ agonist Sch 50971 1 is described. The key enantiodifferentiating step is the 1,4-addition of a chiral N-propionyloxazolidinone to a nitroolefin.     

A new route to (2S,4R)- and (2R,4S)-4-hydroxypipecolic acid

Both enantiomers of cis-4-hydroxypipecolic acid have been prepared by asymmetric synthesis using (S)- or (R)-glycidol as the chiral source, and involving a stereoselective hydrogenation of a six-membered cyclic imine. The latter is obtained by reduction and cyclization of a cyano β-hydroxy ketone.     

Production of (2R,3S)-3-(4-methoxyphenyl)glycidic acid methyl ester using an emulsion bioreactor containing lipase fromSerratia marcescens

An emulsion bioreactor for production of (2R,3S)-3-(4-methoxyphenyl) glycidic acid methyl ester ([-]MPGM) from a racemic mixture ([±]MPGM) using the lipase fromSerratia marcescens has been proposed. Kinetics of hydrolyzing reaction and purification of (-)MPGM from the reaction mixture were investigated to provide a basis for industrial application of this bioreactor. The hydrolyzing reaction in the bioreactor proceeded at a rate that was first order in substrate concentration. The reaction rate was affected by a stirring speed and the ratio of the aqueous phase containing lipase to the toluene phase containing substrate. Phase separation after the enzymatic reaction was accomplished by addition of surfactant to the reaction mixture, and crystalline (-)MPGM with a chemical purity of 100% and optical purity of 100% enantiomeric excess was obtained in a high yield of 40–43% by concentration of the toluene solution.     

Synthesis of (R)- and (S)-4-hydroxyisophorone by ruthenium-catalyzed asymmetric transfer hydrogenation of ketoisophorone

The first synthesis of (R)- and (S)-4-hydroxyisophorone by catalytic transfer hydrogenation of ketoisophorone is reported. Ruthenium catalysts containing commercially available chiral amino alcohols afforded 4-hydroxyisophorone in up to 97% selectivity and 97% ee. (R)- or (S)-4-Hydroxyisophorones with >99% ee were isolated by crystallization. The catalyst precursors [RuCl₂((S,R)-ADPE)(η⁶-p-cymene)] ((S,R)-ADPE=(1S,2R)-amino-1,2-diphenylethanol-N) and (R_Ru)-[RuCl((S,R)-ADPE⁻¹)(η⁶-p-cymene)] (ADPE⁻¹=amino-1,2-diphenylethanolato-N,O) were isolated for the first time and the X-ray crystal structure of the latter determined.     

A fatty acid methyl ester (FAMES) analyzer

Fatty acids, as their methyl esters (FAMES), are routinely analyzed from a wide variety of plant and animal tissues and fluids. Samples have mainly been analyzed to date using capillary GC with FID detection. However, FID detection is non-specific, and open to misinterpretation. This is particularly important in the analysis of minor lipid components from, e.g. organ tissues, plasma and other body fluids, where non-FAMES impurities or contaminants can be present in relatively high amounts. This suggests that even for routine work, a mass spectral detector is necessary for the unambiguous identification–or rather, recognition–of FAMES. The FAMES analyzer we propose consists of three components: an automatic injector; a medium polarity, high-temperature stable capillary column; a mass spectrometric detector, in our case the Finnigan–MAT ion trap detector (ITD 800). Here, on-column injection allowed controlled sample transfer even for low absolute concentrations of lipids, and a column effluent splitter gave simultaneous qualititative and quantitative analysis. For automatic routine analysis, a mass spectral library routine using a tailor-made library of FAMES spectra of the most common naturally occurring fatty acids, plays an essential role. Library comparison parameters used in the standard ITD software usually give “first hit” recognition over a wide sample dynamic range (ca. 2 pg to > 200 ng in the best cases). This gives an absolute recognition even of minor lipid components, especially when combined information from mass spectra and GC retention data is used. By analogy with the now well known concept of the Amino Acid Analyzer, we propose the system described as a FAMES Analyzer. Mass spectrometers like the Finnigan MAT ITD 800 are inexpensive, reliable, sensitive, and easy to operate. Unlike the Amino Acid Analyzer, the FAMES Analyzer needs the specific detection offered by mass spectrometry because the number of acids to be analyzed, including isomers, is much greater.     

Concise asymmetric synthesis of (R)-(+)-tanikolide

A highly stereoselective total synthesis of (R)-(+)-tanikolide, a δ-lactonic marine natural product, was accomplished in seven steps from easily available starting materials with a 51% overall yield. An asymmetric synthesis of an α-hydroxy aldehyde having a stereogenic quaternary center, by the use of (S)-2-(anilinomethyl)pyrrolidine as a chiral auxiliary, was employed in a key step.