WS-9885B, FR-182877, -Drug Synthesis Database

【结构式】

【药物名称】WS-9885B, FR-182877

【化学名称】(3R,4S,6R,6aS,7aS,9aS,10S,11S,12R,12aS,12bS,12cR)-10,12-Dihydroxy-4,6,8,11-tetramethyl-4,6,6a,7,7a,9a,10,11,12,12a,12b,12c-dodecahydro-1H,3H-3,6-etheno-as-indaceno[1,2-d]pyrano[4,3-b]pyran-1-one

【CA登记号】233256-51-4

【分子式】C₂₄H₃₂O₅

【分子量】400.51964

【开发单位】Fujisawa (Originator)

【药理作用】Antibiotics and Alkaloids, Antineoplastic Antibiotics, ONCOLYTIC DRUGS, Antimitotic Drugs, Microtubule-Stabilizing Agents

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

Preparation of fragment (VIII) is illustrated in Scheme 24509401a. Aldol condensation of aldehyde (I) with (R)-4-benzyl-3-propionyl-2-oxazolidinone (II) mediated by dibutylboron triflate gives the syn aldol adduct (III). This is converted to the Weinreb amide (IV) by treatment with N,O-dimethyl hydroxylamine in the presence of trimethylaluminium. After silylation of the secondary hydroxyl group of (IV), the resultant bis-silyl ether (V) is selectively desilylated at the primary hydroxyl group with p-toluenesulfonic acid and tetrabutylammonium bisulfate, to afford alcohol (VI). Dess-Martin oxidation of (VI) gives the aldehyde (VII), which is then subjected to Corey-Fuchs olefination with CBr4 and PPh3 to produce the gem-dibromo olefin (VIII)

参考文献中间体

【1】 Evans, D.A.; Starr, J.T.; A cascade cycloaddition strategy leading to the total synthesis of (-)-FR182877. Angew Chem. Int Ed 2002, 41, 10, 1787.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	60194	7-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4-methyl-4-heptenal	C₁₄H₂₈O₂Si	详情	详情
(II)	25713	(4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one	C₁₃H₁₅NO₃	详情	详情
(III)	60195	(4R)-4-benzyl-3-((2R,3S,6E)-9-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-2,6-dimethyl-6-nonenoyl)-1,3-oxazolidin-2-one	C₂₇H₄₃NO₅Si	详情	详情
(IV)	60196	9-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-3-hydroxy-N,2,6-trimethyl-N-(methyloxy)-6-nonenamide	C₁₉H₃₉NO₄Si	详情	详情
(V)	60197	3,9-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-N,2,6-trimethyl-N-(methyloxy)-6-nonenamide	C₂₅H₅₃NO₄Si₂	详情	详情
(VI)	60198	3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-9-hydroxy-N,2,6-trimethyl-N-(methyloxy)-6-nonenamide	C₁₉H₃₉NO₄Si	详情	详情
(VII)	60199	3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-N,2,6-trimethyl-N-(methyloxy)-9-oxo-6-nonenamide	C₁₉H₃₇NO₄Si	详情	详情
(VIII)	60352	10,10-dibromo-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-N,2,6-trimethyl-N-(methyloxy)-6,9-decadienamide	C₂₀H₃₇Br₂NO₃Si	详情	详情

合成路线2

The boron enolate aldol condensation between aldehyde (IX) and the chiral oxazolidinone (II) affords adduct (X). After conversion to the Weinreb amide (XI), addition of magnesium acetylide (XII) leads to alkynone (XIII). Diastereoselective reduction of (XIII) using DIBAL in THF furnishes diol (XIV) as the major isomer. After protection of diol (XIV) as the bis-silyl ether (XV), hydroboration of its triple bond with catecholborane, followed by alkaline work-up gives rise to the boronic acid fragment (XVI).

参考文献中间体

【1】 Evans, D.A.; Starr, J.T.; A cascade cycloaddition strategy leading to the total synthesis of (-)-FR182877. Angew Chem. Int Ed 2002, 41, 10, 1787.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	25713	(4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one		C₁₃H₁₅NO₃	详情	详情
(IX)	60351	4-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-2-butenal		C₂₀H₂₄O₂Si	详情	详情
(X)	60353	3-(6-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-3-hydroxy-2-methyl-4-hexenoyl)-4-(phenylmethyl)-1,3-oxazolidin-2-one		C₃₃H₃₉NO₅Si	详情	详情
(XI)	60354	6-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-3-hydroxy-N,2-dimethyl-N-(methyloxy)-4-hexenamide		C₂₅H₃₅NO₄Si	详情	详情
(XII)	17778	ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium	4301-14-8	C₂HBrMg	详情	详情
(XIII)	60355	8-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-5-hydroxy-4-methyl-6-octen-1-yn-3-one		C₂₅H₃₀O₃Si	详情	详情
(XIV)	60356	8-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-4-methyl-6-octen-1-yne-3,5-diol		C₂₅H₃₂O₃Si	详情	详情
(XV)	60357	4,6-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5-methyl-2-octen-7-ynyl (1,1-dimethylethyl)(diphenyl)silyl ether; 8-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-10-ethynyl-2,2,9,12,12,13,13-heptamethyl-3,3-diphenyl-4,11-dioxa-3,12-disila-6-tetradecene		C₃₇H₆₀O₃Si₃	详情	详情
(XVI)	60358	3,5-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-8-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-4-methyl-1,6-octadienylboronic acid		C₃₇H₆₃BO₅Si₃	详情	详情

合成路线3

Suzuki coupling of vinyl bromide (VIII) with boronic acid (XVI) gives bromotetraene (XVII). The methoxyamide function of (XVII) is then reduced to aldehyde (XVIII) employing DIBAL in THF. Two carbon homologation of aldehyde (XVIII) with ethyl diazoacetate leads to keto ester (XIX). Selective removal of the primary tert-butyl diphenylsilyl ether of (XIX) with tetrabutylammonium fluoride affords the allylic alcohol (XX), which is then converted into iodide (XXI) by means of I2 and PPh3.

参考文献中间体

【1】 Evans, D.A.; Starr, J.T.; A cascade cycloaddition strategy leading to the total synthesis of (-)-FR182877. Angew Chem. Int Ed 2002, 41, 10, 1787.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	15911	Ethyldiazoacetate; ethyl 2-diazoacetate	623-73-4	C₄H₆N₂O₂	详情	详情
(VIII)	60352	10,10-dibromo-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-N,2,6-trimethyl-N-(methyloxy)-6,9-decadienamide		C₂₀H₃₇Br₂NO₃Si	详情	详情
(XVI)	60358	3,5-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-8-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-4-methyl-1,6-octadienylboronic acid		C₃₇H₆₃BO₅Si₃	详情	详情
(XVII)	60422	10-bromo-3,13,15-tris{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-18-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-N,2,6,14-tetramethyl-N-(methyloxy)-6,9,11,16-octadecatetraenamide		C₅₇H₉₈BrNO₆Si₄	详情	详情
(XVIII)	60423	10-bromo-3,13,15-tris{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-18-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-2,6,14-trimethyl-6,9,11,16-octadecatetraenal		C₅₅H₉₃BrO₅Si₄	详情	详情
(XIX)	60424	ethyl 12-bromo-5,15,17-tris{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-20-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-4,8,16-trimethyl-3-oxo-8,11,13,18-icosatetraenoate		C₅₉H₉₉BrO₇Si₄	详情	详情
(XX)	60425	ethyl 12-bromo-5,15,17-tris{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-20-hydroxy-4,8,16-trimethyl-3-oxo-8,11,13,18-icosatetraenoate		C₄₃H₈₁BrO₇Si₃	详情	详情
(XXI)	60426	ethyl 12-bromo-5,15,17-tris{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-20-iodo-4,8,16-trimethyl-3-oxo-8,11,13,18-icosatetraenoate		C₄₃H₈₀BrIO₆Si₃	详情	详情

合成路线4

Intramolecular cyclization of iodide (XXI) in the presence of Cs2CO3 provides macrocycle (XXII) as an epimeric mixture. Oxidation of (XXII) with Ph2Se2O3 gives rise to the conjugated ester (XXIII), which spontaneously undergoes a sequence of transannular cycloadditions culminating in the formation of the polycyclic compound (XXIV). Complete desilylation of (XXIV) to yield (XXV) is carried out by means of HF in acetonitrile. Methylation of the vinylic bromide of (XXV) by employing trimethylboroxine under Suzuki conditions leads to (XXVI). After hydrolysis of the ethyl ester of (XXVI) under anhydrous conditions, the resultant carboxylic acid (XXVII) is finally subjected to lactonization in the presence of Mukaiyama's reagent (XXVIII) to furnish the title compound.

参考文献中间体

【1】 Evans, D.A.; Starr, J.T.; A cascade cycloaddition strategy leading to the total synthesis of (-)-FR182877. Angew Chem. Int Ed 2002, 41, 10, 1787.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XXI)	60426	ethyl 12-bromo-5,15,17-tris{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-20-iodo-4,8,16-trimethyl-3-oxo-8,11,13,18-icosatetraenoate	C₄₃H₈₀BrIO₆Si₃	详情	详情
(XXII)	60427	ethyl 10-bromo-5,7,17-tris{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-6,14,18-trimethyl-19-oxo-3,8,10,13-cyclononadecatetraene-1-carboxylate	C₄₃H₇₉BrO₆Si₃	详情	详情
(XXIII)	60428	ethyl 10-bromo-5,7,17-tris{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-6,14,18-trimethyl-19-oxo-1,3,8,10,13-cyclononadecapentaene-1-carboxylate	C₄₃H₇₇BrO₆Si₃	详情	详情
(XXIV)	60429	ethyl (1S,2R,4R,7S,8R,9R,10S,11R,12R,13S,16R,17S)-5-bromo-8,10,17-tris{[tert-butyl(dimethyl)silyl]oxy}-1,9,16-trimethyl-20-oxapentacyclo[13.4.1.0~2,13~.0~4,12~.0~7,11~]icosa-5,14-diene-14-carboxylate	C₄₃H₇₇BrO₆Si₃	详情	详情
(XXV)	60430	ethyl (1S,2R,4R,7S,8R,9R,10S,11R,12R,13S,16R,17S)-5-bromo-8,10,17-trihydroxy-1,9,16-trimethyl-20-oxapentacyclo[13.4.1.0~2,13~.0~4,12~.0~7,11~]icosa-5,14-diene-14-carboxylate	C₂₅H₃₅BrO₆	详情	详情
(XXVI)	60431	ethyl (1S,2R,4R,7R,8R,9S,10S,11R,12R,13S,16R,17S)-8,10,17-trihydroxy-1,5,9,16-tetramethyl-20-oxapentacyclo[13.4.1.0~2,13~.0~4,12~.0~7,11~]icosa-5,14-diene-14-carboxylate	C₂₆H₃₈O₆	详情	详情
(XXVII)	60432	(1S,2R,4R,7R,8R,9S,10S,11R,12R,13S,16R,17S)-8,10,17-trihydroxy-1,5,9,16-tetramethyl-20-oxapentacyclo[13.4.1.0~2,13~.0~4,12~.0~7,11~]icosa-5,14-diene-14-carboxylic acid	C₂₄H₃₄O₆	详情	详情
(XXVIII)	60433	2-chloro-1-methylpyridinium	C₆H₇ClN	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)