L-659699, F-244, Antibiotic 1233A, 1233A, -Drug Synthesis Database

【结构式】

【药物名称】L-659699, F-244, Antibiotic 1233A, 1233A

【化学名称】12-Hydroxy-13-hydroxymethyl-3,5,7-trimethyltetradeca-2,4-dien-1,14-dioic acid 12,14-lactone
　　　　　　11-[3(R)-(Hydroxymethyl-4-oxooxetan-2(R)-yl]-3,5,7(R)-trimethyl-2(E),4(E)-undecadienoic acid

【CA登记号】29066-42-0

【分子式】C₁₈H₂₈O₅

【分子量】324.42086

【开发单位】Merck & Co. (Originator)

【药理作用】Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, HMG-CoA Reductase Inhibitors

合成路线1 合成路线2

合成路线1

The intermediate stannane derivative (XVI) has been obtained as follows: The esterification of propynoic acid (XII) with diphenyldiazomethane (XIII) in benzene gives the corresponding ester (XIV), which is then condensed with Me3Sn-Cu(CN)Li (XV) in THF/methanol to yield the desired intermediate (XVI). 3-Hydroxy-2(S)-methylpropionic acid methyl ester (I) is converted into the chiral tosylate (II) by conventional methods. The condensation of (II) with 4-pentenylmagnesium bromide (III) in THF gives the chiral tetrahydropyranyl ether (IV), which is condensed with the phosphonate (V) by means of KHMDS in THF/toluene yielding the chiral nonenoic ester (VI). The reduction of (VI) with DIBAL in the same solvent, followed by protection of the resulting alcohol with TBDPSCl and TEA in dichloromethane affords the protected diol (VII). The selective elimination of the THP protecting group, followed by reaction with TsCl and TEA in dichloromethane affords the tosylate (VIII), which is condensed with lithium acetylide (IX) in DMSO to provide the terminal acetylene (X). The deprotection of (X) with TBAF, followed by reaction with Me3Al, Cp2ZrCl2, and I2 in THF gives the omega iodoundecadienol (XI), which is condensed with the stannane derivative (XVI) by means of PdCl2 in DMF yielding the tetradecatrienoic diphenylmethyl ester (XVII). The chiral epoxidation of (XVII) with Ti(OiPr)4, BuOOH and (R,R)(+)-diisopropyl tartrate (DIPT) in dichloroethane affords the hydroxymethyl-oxirane (XVIII), which is oxidized with tetrapropylammonium perruthenate (TPAP) to provide the oxirane carbaldehyde (XIX).

参考文献中间体

【1】 Bates, R.W.; et al.; Total synthesis of the cholesterol biosynthesis inhibitor 1233A via a (Pi-allyl)tricarbonyliron lactone complex. J Chem Soc - Perkins Trans I 1999, 14, 1917.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	17128	Methyl (2S)-3-hydroxy-2-methylpropanoate	72657-23-9	C₅H₁₀O₃	详情	详情
(II)	41854	(2S)-2-methyl-4-(tetrahydro-2H-pyran-2-yloxy)butyl 4-methylbenzenesulfonate		C₁₇H₂₆O₅S	详情	详情
(III)	39424	bromo(4-pentenyl)magnesium		C₅H₉BrMg	详情	详情
(IV)	41855	(3R)-3-methyl-8-nonenyl tetrahydro-2H-pyran-2-yl ether; 2-[[(3R)-3-methyl-8-nonenyl]oxy]tetrahydro-2H-pyran		C₁₅H₂₈O₂	详情	详情
(V)	41856	methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate	88738-78-7	C₇H₉F₆O₅P	详情	详情
(VI)	41857	methyl (Z,8R)-8-methyl-10-(tetrahydro-2H-pyran-2-yloxy)-2-decenoate		C₁₇H₃₀O₄	详情	详情
(VII)	41858	tert-butyl[[(Z,8R)-8-methyl-10-(tetrahydro-2H-pyran-2-yloxy)-2-decenyl]oxy]diphenylsilane; tert-butyl(diphenyl)silyl (Z,8R)-8-methyl-10-(tetrahydro-2H-pyran-2-yloxy)-2-decenyl ether		C₃₂H₄₈O₃Si	详情	详情
(VIII)	41859	(2R,7Z)-9-[[tert-butyl(diphenyl)silyl]oxy]-2-methyl-7-nonenyl 4-methylbenzenesulfonate		C₃₃H₄₄O₄SSi	详情	详情
(IX)	17461	ethynyllithium		C₂HLi	详情	详情
(X)	41860	tert-butyl[[(Z,8R)-8-methyl-2-undecen-10-ynyl]oxy]diphenylsilane; tert-butyl(diphenyl)silyl (Z,8R)-8-methyl-2-undecen-10-ynyl ether		C₂₈H₃₈OSi	详情	详情
(XI)	41861	(2Z,8R,10E)-11-iodo-8,10-dimethyl-2,10-undecadien-1-ol		C₁₃H₂₃IO	详情	详情
(XII)	10398	2-Ethoxy-4-iodo-1-(pentyloxy)benzene; 2-Ethoxy-4-iodophenyl pentyl ether		C₁₃H₁₉IO₂	详情	详情
(XIII)	40585	1-[diazo(phenyl)methyl]benzene		C₁₃H₁₀N₂	详情	详情
(XIV)	41862	benzhydryl 2-butynoate		C₁₇H₁₄O₂	详情	详情
(XVI)	41863	benzhydryl (E)-3-(trimethylstannyl)-2-butenoate		C₂₀H₂₄O₂Sn	详情	详情
(XVII)	41864	benzhydryl (2E,4E,7R,12Z)-14-hydroxy-3,5,7-trimethyl-2,4,12-tetradecatrienoate		C₃₀H₃₈O₃	详情	详情
(XVIII)	41865	benzhydryl (2E,4E,7R)-11-[(2R,3S)-3-(hydroxymethyl)oxiranyl]-3,5,7-trimethyl-2,4-undecadienoate		C₃₀H₃₈O₄	详情	详情
(XIX)	41866	benzhydryl (2E,4E,7R)-11-[(2R,3R)-3-formyloxiranyl]-3,5,7-trimethyl-2,4-undecadienoate		C₃₀H₃₆O₄	详情	详情

合成路线2

The Wittig condensation of aldehyde (XIX) with phosphonium salt (XX) by means of KHMDS in THF/toluene gives the vinyloxirane (XXI), which is treated with diiron nonacarbonyl (XXII) in THF to yield the complex (XXIII). Oxidative decomplexation of (XXIII) with CAN in CH3CN gives the vinyl-beta-lactone (XXIV), which is treated with MCPBA and K2CO3 in CH2Cl2 to yield the epoxide (XXV). The ozonolysis of (XXV), followed by reduction with NaBH4 affords the hydroxymethyl-beta-lactone (XXVI), which is deepoxidated with SmI2 in tert-butanol/THF to provide the protected final intermediate (XXVII). Finally this compound is deprotected with TFA/CH2Cl2.

参考文献中间体

【1】 Bates, R.W.; et al.; Total synthesis of the cholesterol biosynthesis inhibitor 1233A via a (Pi-allyl)tricarbonyliron lactone complex. J Chem Soc - Perkins Trans I 1999, 14, 1917.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIX)	41866	benzhydryl (2E,4E,7R)-11-[(2R,3R)-3-formyloxiranyl]-3,5,7-trimethyl-2,4-undecadienoate		C₃₀H₃₆O₄	详情	详情
(XX)	41867	(bromomethyl)(triphenyl)phosphorane	1779-49-3	C₁₉H₁₈BrP	详情	详情
(XXI)	41868	benzhydryl (2E,4E,7R)-3,5,7-trimethyl-11-[(2R,3S)-3-vinyloxiranyl]-2,4-undecadienoate		C₃₁H₃₈O₃	详情	详情
(XXIII)	41869			C₃₃H₄₂O₄	详情	详情
(XXIV)	41870	benzhydryl (2E,4E,7R)-3,5,7-trimethyl-11-[(2R,3R)-4-oxo-3-vinyloxetanyl]-2,4-undecadienoate		C₃₂H₃₈O₄	详情	详情
(XXV)	41871	benzhydryl (E)-3-(3-methyl-3-[(2R)-2-methyl-6-[(2R,3R)-4-oxo-3-vinyloxetanyl]hexyl]-2-oxiranyl)-2-butenoate		C₃₂H₃₈O₅	详情	详情
(XXVI)	41872	benzhydryl (E)-3-(3-[(2R)-6-[(2R,3R)-3-(hydroxymethyl)-4-oxooxetanyl]-2-methylhexyl]-3-methyl-2-oxiranyl)-2-butenoate		C₃₁H₃₈O₆	详情	详情
(XXVII)	41873	benzhydryl (2E,4E,7R)-11-[(2R,3R)-3-(hydroxymethyl)-4-oxooxetanyl]-3,5,7-trimethyl-2,4-undecadienoate		C₃₁H₃₈O₅	详情	详情

Extended Information