Mycalamide A, -Drug Synthesis Database

【结构式】

【药物名称】Mycalamide A

【化学名称】[2R-[2alpha,2[S*(S*)],5beta,6beta]]-4,8-Anhydro-3,5-dideoxy-9-C-[[hydroxy(tetrahydro-2-methoxy-5,6-dimethyl-4-methylene-2H-pyran-2-yl)acetyl]amino]-5,5-dimethyl-6-O-methyl-7,9,O-methylene-D-glycero-L-gulo-nonitol
　　　　　　N-[6(R)-[2(R),3-Dihydroxypropyl]-8(S)-methoxy-7,7-dimethyl-4a(S),8a(R)-hexahydropyrano[3,2-d]-1,3-dioxin-4(R)-yl]-2(R)-hydroxy-2-[6(R)-methoxy-2(R),3(R)-dimethyl-4-methylenetetrahydropyran-6-yl]acetamide

【CA登记号】115185-92-7

【分子式】C₂₄H₄₁NO₁₀

【分子量】503.59507

【开发单位】Harbor Branch Oceanographic Institution (Originator)

【药理作用】ANTIINFECTIVE THERAPY, Antiviral Drugs, Oncolytic Drugs

合成路线1 合成路线2

合成路线1

The methylation of the homoallyl alcohol (I) with methyl iodide and NaH in DMF gives the methyl ether (II), which is oxidized with O3, yielding the aldehyde (III). The diastereoselective allylation of (III) with the chiral borane (IV) in ethyl ether affords the homoallyl alcohol (V), which is epoxidized to the epoxide (VI). The cleavage of the epoxide (VI) with trichloromethyl carbonate provides the cyclic carbonate (VII), which is protected with Troc-Cl and pyridine and then oxidized with NaIO4, furnishing the aldehyde (VIII). The asymetric allylation of (VIII) with the chiral boronate (IX) gives the new homoallyl alcohol (X), which is treated with dimethyldioxirane (XI) to yield the epoxide (XII). Elimination of the Troc- group of (XII) with Zn/HOAc, followed by selective silylation with Tbdps-Cl and imidazole, affords the cyclized tetrahydropyran derivative (XIII), which is cyclized with P2O5 and formaldehyde, and oxidized with CrO3 and sulfuric acid to provide the bicyclic carboxylic acid (XIV).

参考文献中间体

【1】 Roush, W.R.; Marron, T.G.; Diastereoselective synthesis of N-benzoyl mycalamine, the fully elaborated trioxadecalin nucleus of mycalamide A. Control of the key N-acyl aminal stereocenter via carbamate acylation. Tetrahedron Lett 1995, 36, 10, 1581.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	43431	(1S)-1-[(4R)-2,2-diethyl-1,3-dioxolan-4-yl]-2,2-dimethyl-3-buten-1-ol	C₁₃H₂₄O₃	详情	详情
(II)	43432	(4R)-2,2-diethyl-4-[(1S)-1-methoxy-2,2-dimethyl-3-butenyl]-1,3-dioxolane; (1S)-1-[(4R)-2,2-diethyl-1,3-dioxolan-4-yl]-2,2-dimethyl-3-butenyl methyl ether	C₁₄H₂₆O₃	详情	详情
(III)	43433	(3S)-3-[(4R)-2,2-diethyl-1,3-dioxolan-4-yl]-3-methoxy-2,2-dimethylpropanal	C₁₃H₂₄O₄	详情	详情
(IV)	43434	allyl[bis[(1R,2R,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane	C₂₃H₃₉B	详情	详情
(V)	43435	(1S,3R)-1-[(4R)-2,2-diethyl-1,3-dioxolan-4-yl]-1-methoxy-2,2-dimethyl-5-hexen-3-ol	C₁₆H₃₀O₄	详情	详情
(VI)	43436	(2R,4S)-4-[(4R)-2,2-diethyl-1,3-dioxolan-4-yl]-4-methoxy-3,3-dimethyl-1-[(2S)oxiranyl]-2-butanol	C₁₆H₃₀O₅	详情	详情
(VII)	43437	(4S)-4-[(2R,4S)-4-[(4R)-2,2-diethyl-1,3-dioxolan-4-yl]-2-hydroxy-4-methoxy-3,3-dimethylbutyl]-1,3-dioxolan-2-one	C₁₇H₃₀O₇	详情	详情
(VIII)	43438	(1R,3S)-3-methoxy-2,2-dimethyl-4-oxo-1-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]butyl 2,2,2-trichloroethyl carbonate	C₁₄H₁₉Cl₃O₈	详情	详情
(IX)	43439	diethyl (4R,5R)-2-[(E)-3-(trimethylsilyl)-2-propenyl]-1,3,2-dioxaborolane-4,5-dicarboxylate	C₁₄H₂₅BO₆Si	详情	详情
(X)	43440	(1R,3S,4R,5S)-4-hydroxy-3-methoxy-2,2-dimethyl-1-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]-5-[(trimethylsilyl)oxy]-6-heptenyl 2,2,2-trichloroethyl carbonate	C₂₀H₃₃Cl₃O₉Si	详情	详情
(XI)	31501	3,3-dimethyl-1,2-dioxirane	C₃H₆O₂	详情	详情
(XII)	43441	(1R,3S,4R)-4-hydroxy-4-[(2S,3R)-3-(hydroxymethyl)oxiranyl]-3-methoxy-2,2-dimethyl-1-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]butyl 2,2,2-trichloroethyl carbonate	C₁₇H₂₅Cl₃O₁₀	详情	详情
(XIII)	43442	(4S)-4-[[(2R,4S,5R,6R)-6-((1R)-2-[[tert-butyl(diphenyl)silyl]oxy]-1-hydroxyethyl)-5-hydroxy-4-methoxy-3,3-dimethyltetrahydro-2H-pyran-2-yl]methyl]-1,3-dioxolan-2-one	C₃₀H₄₂O₈Si	详情	详情
(XIV)	43443	(4S,4aR,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxine-4-carboxylic acid	C₁₅H₂₂O₉	详情	详情

合成路线2

The Curtius degradation of carboxylic acid (XIV) with Ph2PON3 and 2-(trimethylsilyl)ethanol (A) gives the carbamate (XV), which is acylated with 2-(benzyloxy)acetyl chloride (XVI) and LiHMDS in THF, yielding the imide (XVII). The condensation of (XVII) with aldehyde (XVIII) by means of TiCl4 and DIEA in dichloromethane affords the expected adduct (XIX), which is oxidized with TFAA and DMSO in dichloromethane/DIEA, providing the beta-ketoimide (XX) as a diastereomeric mixture at the benzyloxy group. The cyclization of (XX) by means of CSA in methanol, followed by separation of the diastereomeric mixture, furnished the hydroxy tetrahydropyran derivative (XXI), which is submitted to a Swern oxidation to give the trahydropyranone (XXII). The reaction of (XXII) with diiodomethane, TiCl4 and Zn yields the exo-methylene compound (XXIII), which is desilylated with TBAF in DMF to afford intermediate (XXIV). Finally, this compound is submitted to a reductive cleavage of the benzyloxy and cyclic carbonate groups with Na/NH3 in THF/ethyl ether to furnish the target compound.

参考文献中间体

【1】 Roush, W.R.; Pfeifer, L.A.; Total synthesis of mycalamide A and 7-epi-mycalamide A. Org Lett 2000, 2, 6, 859.

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)	20323	2-(trimethylsilyl)-1-ethanol	2916-68-9	C₅H₁₄OSi	详情	详情
(XIV)	43443	(4S,4aR,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxine-4-carboxylic acid		C₁₅H₂₂O₉	详情	详情
(XV)	43444	2-(trimethylsilyl)ethyl (4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-ylcarbamate		C₂₀H₃₅NO₉Si	详情	详情
(XVI)	10493	2-(Benzyloxy)acetyl chloride; Benzyloxyacetyl chloride	19810-31-2	C₉H₉ClO₂	详情	详情
(XVII)	43445	2-(trimethylsilyl)ethyl (4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-yl[2-(benzyloxy)acetyl]carbamate		C₂₉H₄₃NO₁₁Si	详情	详情
(XVIII)	43446	(3R,4S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methylhexanal		C₁₉H₄₂O₃Si₂	详情	详情
(XIX)	43447	2-(trimethylsilyl)ethyl (4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-yl((2R,5R,6S,7R)-2-(benzyloxy)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-6-methyloctanoyl)carbamate		C₄₈H₈₅NO₁₄Si₃	详情	详情
(XX)	43448	2-(trimethylsilyl)ethyl (4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-yl((5R,6S,7R)-2-(benzyloxy)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-3-oxooctanoyl)carbamate		C₄₈H₈₃NO₁₄Si₃	详情	详情
(XXI)	43449	2-(trimethylsilyl)ethyl (4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-yl[(2S)-2-(benzyloxy)-2-[(2R,4R,5R,6R)-4-hydroxy-2-methoxy-5,6-dimethyltetrahydro-2H-pyran-2-yl]ethanoyl]ca		C₃₇H₅₇NO₁₄Si	详情	详情
(XXII)	43450	2-(trimethylsilyl)ethyl (4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-yl[(2S)-2-(benzyloxy)-2-[(2R,5S,6R)-2-methoxy-5,6-dimethyl-4-oxotetrahydro-2H-pyran-2-yl]ethanoyl]carbamate		C₃₇H₅₅NO₁₄Si	详情	详情
(XXIII)	43451	2-(trimethylsilyl)ethyl (4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-yl[(2S)-2-(benzyloxy)-2-[(2R,5R,6R)-2-methoxy-5,6-dimethyl-4-methylenetetrahydro-2H-pyran-2-yl]ethanoyl]car		C₃₈H₅₇NO₁₃Si	详情	详情
(XXIV)	43452	(2S)-N-((4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-yl)-2-(benzyloxy)-2-[(2R,5R,6R)-2-methoxy-5,6-dimethyl-4-methylenetetrahydro-2H-pyran-2-yl]ethanamide		C₃₂H₄₅NO₁₁	详情	详情

Extended Information