The Diels-Alder reaction is one of the most popular transformations for organic chemists to generate molecular complexity efficiently. Surprisingly, little is known about its industrial application for the synthesis of pharmacologically active ingredients, agrochemicals, and flavors and fragrances. This Review highlights selected examples, with a focus on large-scale applications (>1 kg) from a process research and development perspective.

Industrial applications of the Diels-Alder reaction.

This paper describes an effective chiral base-catalyzed biomimetic transamination of α-keto esters using simple benzyl amines. A wide variety of α-amino esters containing various functional groups can be synthesized in high enantioselectivity and reasonable yield.

Organocatalytic asymmetric biomimetic transamination: from α-keto esters to optically active α-amino acid derivatives.

A rapid and highly sensitive LC-MS-MS method for simultaneous determination of 25-hydroxyvitamin D2 125(OH)D21 and 25-hydroxyvitamin D3 125(OH)D3] in human plasma has been developed using derivatization with a Cookson-type reagent, 4-12-(6,7-dimethoxy-4-methyl-3-oxo-3,4-dihydroquinoxalyl)ethyll-1,2,4-triazoline-3,5-dione (DMEQTAD). The derivatization with DMEQTAD significantly improved the ionization efficiencies of 25(OH)D2 and 25(OH)D3 with detection limits of 20 and 12.5 fmol (8 and 5 pg) per injection, respectively. The method employed two steps of solvent extraction but did not require chromatographic purifications for sample pretreatment. The determination was carried out by mass chromatography of the protonated molecular ions formed by atmospheric pressure chemical ionization operating in the positive-ion mode after the derivatization, and 25-hydroxyvitamin D4 was used as an internal standard. The intra-assay coefficients of variation were below 4.02 and 3.24% for 25(OH)D2 and 25(OH)D3, respectively, and the analytical recoveries of both compounds were quantitative. Assay linearity was obtained in the range of 0.05-1 ng per tube and the determination limit was 3 ng/ml for a 20 microl plasma aliquot, for each compound. The developed method was applied to plasma samples obtained from volunteers, two of whom had received vitamin D2 supplementation, and gave satisfactory results.

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Simultaneous Determination of 25-Hydroxyvitamin D2 and 25-Hydroxyvitamin D3 in Human Plasma by Liquid Chromatography-Tandem Mass Spectrometry Employing Derivatization with a Cookson-Type Reagent

Die Chiralitatsubertragung bei chemischen Reaktionen mit stochiometrisch oder katalytisch verwendeten chiralen Auxiliaren wird heute haufig und erfolgreich praktiziert. Dagegen fehlt es an praktikablen und dynamischen, d. h. die ganze Reaktionssequenz einschliesenden Selektionsmodellen, die eine einfache und zuverlassige Beurteilung, Optimierung und Prognose von Selektivitaten bei asymmetrischen Synthesen ermoglichen. Entweder werden in den Modellen zu stark und einseitig sterische Erfordernisse der speziellen Eduktmolekule betont, und die Aussagen gehen nicht uber die klassischen Vorstellungen der statischen Seitendifferenzierung hinaus, oder es handelt sich um anspruchsvolle theoretische Ansatze, die wegen ihrer inharenten Randbedingungen und wegen des hohen theoretischen Aufwandes bisher keinen Eingang in die Praxis des Synthesechemikers finden konnten. Durch das Isoinversionsprinzip, das auf der Basis der Eyring-Theorie entwickelt werden konnte, ist diese Lucke geschlossen worden. Mit ihm kann der Synthetiker durch wenige Messungen der Temperaturabhangigkeit seiner Selektivitatsparameter die fur seinen Reaktionstyp charakteristische Isoinversionstemperatur Ti ermitteln, die ihm dann Aufschlus uber Fragen der Optimierung etc. gibt. Der Vorteil der Methode ist, das sie nicht nur auf Stereoselektivitaten anwendbar ist, sondern auf jede Art von Prozessen, bei denen Selektivitat (Regio-, Chemo- etc.) auf mehreren Ebenen einer Reaktionssequenz auftritt, unabhangig davon, ob es sich um Reaktionen des Grundzustandes oder um diabatische Photoprozesse handelt. Das Selektivitat auf mehreren Ebenen einer Reaktionssequenz haufiger ist, als bisher vermutet, zeigt diese Ubersicht.

Das Isoinversionsprinzip ‐ ein allgemeines Selektionsmodell in der Chemie

Identification of 8-dehydrocholesterol (cholesta-5,8-dien-3 beta-ol) in patients with Smith-Lemli-Opitz syndrome.

(24S)- and (24R)-1α,25-Dihydroxyvitamin D4 compounds and processes for preparing same. Ergosta-5,7-diene compounds which are useful intermediates in the synthesis of the 1α,25-dihydroxyvitamin D4 compounds. The D4 compounds are expected to possess an interesting pharmacological activity in association with the active-type vitamins D3 and D2.

1 alpha,25-dihydroxyvitamin D4 compounds, ergosta-5,7-diene compounds and processes for the preparation thereof

Optically active α-deuterated α-amino acids were prepared in methano-d through Zn2+-catalyzed transamination reaction between the chiral pyridoxamine analogs, (R)- or (S)-15-aminomethyl-14-hydroxy-5,5-dimethyl-2,8-dithia[9] (2,5)pyridinophane and various α-keto acids with enantiomeric excesses ranging from 40 to 94%. Aliphatic α-keto acids gave α-deuterated α-amino acids, whereas aromatic ones possessing a methylene group between the carbonyl group (ketone) and the aromatic ring underwent concomitant deuterium substitution at the active methylene group to give the amino acids deuterated at both α- and β-positions of the carboxyl group. The use of the (S)-pyridoxamine analog gave the (R)-deuterated α-amino acids in excess and vice versa. The enatiomeric excesses of the amino acids were determined through the analyses of 1H NMR spectra of the Schiff bases produced by the condensation of the amino acids with the chiral pyridoxal analog, (R)- or (S)-15-formyl-14-hydroxy-2,8-dithia[9](2, 5)pyridinophane. The a...

Asymmetric Synthesis of α-Deuterated α-Amino Acids through Nonenzymatic Transamination Reaction and the Determination of Their Enantiomeric Excesses

Disclosed are new 1α-hydroxy vitamin D₇ of formula (I) and 1α-hydroxy vitamin D₄ of formula (II) which are useful as active ingredients of pharmaceutical compositions for the treatment of osteoporosis.
 Those new compounds are synthesized starting from (22E)-5α,8α-(4-phenyl-1,2-urazolo)-6,22-ergostadien-3β-ol 3β-tert-butyl-dimethylsilyl ether and through ten process steps.

1 alpha-hydroxy vitamins D7 and D4' processes for the preparation thereof and pharmaceutical compositions

1α, 25-Dihydroxyvitamin D2 (1a) was synthesized by irradiation and subsequent thermal isomerization of (22E)-5,7,22-ergostatriene-1α,3β,25-triol (16a). The triol 16a was obtained via 22-oxo-5α,8α-(4-phenyl-3,5-dioxo-1,2,4-triazolidine-1,2-diyl)-23,24-dinor-6-cholene-1α,3β-diyl diacetate (12) starting from (22E)-5,7,22-ergostatriene-1α,3β-diyl diacetate (10), a precursor of 1α-hydroxyvitamin D2. Introduction of the new side chain with the desired stereochemistry was carried out selectively by the reductive elimination of the β-hydroxy sulfone derived from the C-22 aldehyde (12) and an optically active sulfone, prepared via (S)-2,3-dimethyl-1,3-butanediol from methyl (S)-3-hydroxy-2-methylpropionate. Similarly a C-24 epimer of 1a was synthesized.

A New and Convenient Synthesis of 1α,25-Dihydroxyvitamin D2 and Its 24R-Epimer

New 1α,25-dihydroxy vitamin D2 derivatives (22,23-dihydro-1α,25-dihydroxyvitamin D2 (2a)) and its 24R-epimer (2b), were synthesized by two procedures. 22-Oxo-5α,8α-(4-phenyl-3,5-dioxo-1,2,4-triazolidine-1,2-diyl)-23,24-dinor-6-cholene-1α,3β-diyl diacetate (8), obtainable readily from ergosterol, was converted to 22-phenylsulfonyl-5α,8α-(4-phenyl-3,5-dioxo-1,2,4-triazolidine-1,2-diyl)-1α,3β-bis(tetrahydropyranyloxy)-23,24-dinor-6-cholene (14) or 22-iodo-5α,8α-(4-phenyl-3,5-dioxo-1,2,4-triazolidine-1,2-diyl)-1α,3β-bis(tetrahydropyranyloxy)-23,24-dinor-6-cholene (16). Condensation of the C-22 sulfone (14) with (3R)-4-iodo-2,3-dimethyl-2-butanol THP ether, or the C-22 iodide (16) with (3R)-2,3-dimethyl-4-phenylsulfonyl-2-butanol THP ether followed by desulfonylation and successive deprotection gave 5,7-ergostadiene-1α,3β,25-triol (21a), which led to 2a upon irradiation and subsequent thermal isomerization. Similarly, a 24R-epimer of 2a was synthesized.

Yoji Tachibana

Papers

1 alpha,25-dihydroxyvitamin D4 compounds, ergosta-5,7-diene compounds and processes for the preparation thereof

Asymmetric Synthesis of α-Deuterated α-Amino Acids through Nonenzymatic Transamination Reaction and the Determination of Their Enantiomeric Excesses

1 alpha-hydroxy vitamins D7 and D4' processes for the preparation thereof and pharmaceutical compositions

A New and Convenient Synthesis of 1α,25-Dihydroxyvitamin D2 and Its 24R-Epimer

Syntheses of 22,23-dihydro-1α,25-dihydroxyvitamin D2 and its 24R-epimer, new vitamin D2 derivatives