Efficient and practical synthesis of optically active 5-t-butyldimethylsiloxy-2-cyclohexenone as a convenient chiral 2,5-cyclohexadienone synthon

Hikichi, Shinichi; Hareau, Georges; Sato, Fumie

doi:10.1016/s0040-4039(97)10206-4

Cited by 41 publications

(14 citation statements)

References 17 publications

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“…An intramolecular cyclization was accomplished by the Kulinkovich-type reaction. 10) Reaction of 15 with a TiCl(O i Pr) 3 / i bonyl addition reaction to give 16. Ring expansion was achieved using ferric chloride in pyridine, 11) followed by treatment with sodium acetate to yield dihydrocycloheptimidazolone 18.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and Pharmacological Activity of the Metabolites of Pratosartan

Sonegawa

Suzaka

Tomiyama

et al. 2006

CHEMICAL & PHARMACEUTICAL BULLETIN

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In the previous paper, 1) we reported the design and synthesis of Pratosartan (Chart 1), which is an orally active angiotensin II (AII) antagonist, exhibiting selective and potent antagonistic activity to AT 1 subtype. Furthermore, long duration was shown in various animal models in vivo experiment. Clinical trials of Pratosartan are now in progress as an antihypertensive agent.Clarification of the possible metabolites and their therapeutic or toxic effects during the development process of new drugs is mandatory. For this purpose, we have tried to synthesize possible metabolites in human and rat to identify their structures and activities. In a pharmacokinetic study of Pratosartan, three hydroxylated metabolites were observed as major metabolites in human and rat after oral administration. These structures were characterized on the basis of MS and NMR spectra. Metabolite 1 isolated from human urine was estimated as a hydroxylated metabolite at the propyl side chain of Pratosartan. A similar hydroxlated metabolite was also reported for Losartan.2) Metabolite 2 and 3 isolated from rat bile were estimated as 8-and 5-hydroxylated metabolites on the cycloheptane ring of Pratosartan, respectively. In this paper, we describe the synthesis of these metabolites to identify their structures and to study their pharmacological properties. ChemistryMetabolite 1 was synthesized as shown in Chart 2. Protection of 2-propyl-3H-cycloheptimidazol-4-one 4 3,4) with chloromethyl methyl ether (MOMCl) gave 5, which was treated with N-bromosuccinimide (NBS) to give the brominated product 6. The bromo group was converted to an acetoxy group using sodium acetate to yield 7. Removal of the MOM group and subsequent ester exchange of the acetate gave the corresponding alcohol 9. Hydrogenation of 9 provided 10, and it was alkylated with 11 5) to afford the desired intermediate compound 12. N-Alkylation of 3H-cycloheptimidazol-4-one in the presence of K 2 CO 3 in N,N-dimethylformamide (DMF) gave an N3-alkylated compound preferentially similarly to the biphasic reaction condition 6) and the regioisomer was separated easily by silica gel column chromatography. The N-benzylic proton of compound 12 and 20 was observed at lower field characteristically (0.4-0.5 ppm) compared to their regioisomers, which was caused by the anisotropic effect of the C4-carbonyl group. For the purpose of optical resolution, the racemic trityl compound 12 was converted to a-methoxy-a-(trifluoromethyl)phenylacetate (MTPA) 13 with (ϩ)-MTPA-Cl. 7) Each diastereomer could be separated by silica gel column chromatography. Hydrolysis of the isolated single isomer 13a gave an optically active hydroxy intermediate, and finally (ϩ)-1 was obtained by the successive deprotection of MTPA and trityl groups. Enantiomer (Ϫ)-1 was obtained from 13b in the same manner.In order to confirm the structure, the human main metabolite was led to MTPA ester (Chart 3). The human main metabolite was protected with trityl chloride to give trityl compound 12, and then it was converted to MTPA est...

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Section: Chemistrymentioning

confidence: 99%

Synthesis and Pharmacological Activity of the Metabolites of Pratosartan

Sonegawa

Suzaka

Tomiyama

et al. 2006

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…For example, the L-enantiomer is an important chiral building block for the synthesis of (−)-macrolactin A, 1 L-carnitine 2 and (R)-γ-amino-β-hydroxybutyric acid (GABOB), 3 or can be converted into (+) negamicyn 4 or to a chiral 2,5-cyclohexadienone synthon. 5 On the other hand the D enantiomer is a key chiral intermediate in the enantioselective synthesis of slagenins B and C 6 and in the total synthesis of a class of HMG-CoA reductase inhibitors 7 or can be converted into a 1,4-dihydropyridine-type β-blocker. 8 Of the two enantiomers, the (S)-is the more common and more easily available, whereas (R)-is in greater demand yet less readily available.…”

Section: Optically Active L-(r)-and D-(s)-ethyl or Methyl 4-chloro-3-mentioning

confidence: 99%

Highly enantioselective reduction of ethyl 4-chloro-3-oxobutanoate to L- and D- 3-hydroxyesters with baker’s yeast

Forni¹,

Caselli²,

Prati³

et al. 2002

Arkivoc

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Reduction with baker's yeast of ethyl or methyl 4-chloro-3-oxobutanoate in the presence of allyl bromide or allyl alcohol as additive afforded the corresponding L-and D-3-hydroxyesters. Several reduction conditions were tested, involving: different concentrations of additive; variations in the yeast/substrate ratio; the presence and absence of glucose; different preincubation periods; a range of temperatures. The best conditions gave a complete conversion of the substrate within 1-2 h and a very high enantioselectivity, 90-97% e.e., for the two enantiomers.

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“…[1,2] Wie erwartet geht das Enon 1 hochselektiv anti-1,4-Additionen mit Organokupferreagentien wie [R 2 CuLi] oder [R 2 Cu(CN)Li 2 ] ein und liefert die Verbindungen trans-2 als Hauptprodukte. Diese können leicht mit DBU oder Toluolsulfonsäure in optisch aktive 5-substituierte 2-Cyclohexenone 3 überführt werden (Schema 1).…”

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“…Ziel war dabei, die Anwendungsbreite der Reaktion durch Variation der Gruppe R in [RCu(CN)Li] zu untersuchen und die Frage zu beantworten, ob das Phänomen nur für das spezielle Edukt 1 charakteristisch ist. [1] B. Giese, B. Kopping, T. Göbel, J. Dickhaut, G. 13). Nachdem der Beweis erbracht war, daû eine Alkoxygruppe für die hohe cis-Selektivität essentiell ist, wandten wir uns der Reaktion von [nBu-Cu(CN)Li] mit 4-(tert-Butyldimethylsiloxy)-2-cyclohexenon [9] zu, um den Effekt der Position der Alkoxygruppe auf die Diastereoselektivität zu untersuchen.…”

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Eine überraschendecis-selektive 1,4-Addition von Cyanocupraten niedriger Ordnung an optisch aktives 5-(tert-Butyldimethylsilyloxy)-2-cyclohexenon

Hareau‐Vittini¹,

Hikichi²,

Sato³

1998

Angewandte Chemie

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Eine bemerkenswerte cis‐Selektivität wird bei der 1,4‐Addition von primären und sekundären Alkylcyanocupraten niedriger Ordnung an 5‐Siloxy‐ und Benzyloxy‐substituierte Cyclohexenone festgestellt. Dies ermöglicht die Synthese beider Enantiomere von 5‐Alkyl‐substituierten Cyclohexenonen, (S)‐ und (R)‐3, indem das einfach zugängliche 5‐(tert‐Butyldimethylsiloxy)‐2‐cyclohexenon 1 im ersten Schritt entweder mit einem Cyanocuprat niedriger oder höherer Ordnung umgesetzt wird. DBU=1,8‐Diazabicyclo[5.4.0]undec‐7‐en.

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Efficient and practical synthesis of optically active 5-t-butyldimethylsiloxy-2-cyclohexenone as a convenient chiral 2,5-cyclohexadienone synthon

Cited by 41 publications

References 17 publications

Synthesis and Pharmacological Activity of the Metabolites of Pratosartan

Synthesis and Pharmacological Activity of the Metabolites of Pratosartan

Highly enantioselective reduction of ethyl 4-chloro-3-oxobutanoate to L- and D- 3-hydroxyesters with baker’s yeast

Eine überraschendecis-selektive 1,4-Addition von Cyanocupraten niedriger Ordnung an optisch aktives 5-(tert-Butyldimethylsilyloxy)-2-cyclohexenon

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