ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium -Drug Synthesis Database

【结构式】

【分子编号】17778

【品名】ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium

【CA登记号】4301-14-8

【分子式】C₂HBrMg

【分子量】129.23894

【元素组成】C 18.59% H 0.78% Br 61.83% Mg 18.81%

与该中间体有关的原料药合成路线共 13 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5 合成路线6 合成路线7 合成路线8 合成路线9 合成路线10 合成路线11 合成路线12 合成路线13

合成路线1

该中间体在本合成路线中的序号：(C)

By condensation of 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methylpenta-2,4-diene-1-triphenylphosphonium bromide (I) with 3-formylcrotonic acid butyl ester (II) by means of NaH in DMF to yield 9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraen-1-oic acid butyl ester (III), which is then hydrolyzed with KOH in refluxing ethanol - water. The starting products (I) and (II) are obtained as follows: 1) The methylation of 2,3,5-trimethylphenol (IV) with KOH and methyl iodide in refluxing aqueous ethanol gives 2,3,5-trimethylanisole (V), which is then carbonylated with POCl3 and DMF (A) to afford 4-methoxy-2,3,6-trimethylbenzaldehyde (VI). The condensation of (VI) with acetone (B) by means of NaOH gives 4-(4-methoxy-2,3,6-trimethylphenyl)-3-buten-2-one (VII), which by a Grignard reaction with ethynylmagnesium bromide (C) in THF is converted into 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-3-hydroxy-4-penten-1-yne (VIII). The controlled hydrogenation of (VIII) with H2 over a Pd catalyst in hexane yields 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-3-hydroxy-1,4-pentadiene (IX), which is finally treated with triphenylphosphonium bromide in benzene at 60 C to give the phosphonium salt (I). 2) The oxidation of dibutyl L-(+)-tartrate (X) with lead tetraacetate in benzene gives butyl glyoxalate (XI), which is then condensed with propionic aldehyde (D) by means of dibutylamine (E) to afford ester (II).

参考文献中间体

合成目标

【1】 Bollag, W.; et al.; Polyene derivatives. BE 0813002; DE 2414619; FR 2223037; GB 1468401; GB 1468402; JP 49126637 .
【2】 Castaner, J.; Hillier, K.; RO 10-1670. Drugs Fut 1977, 2, 11, 763.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(D)	15966	propionaldehyde	123-38-6	C₃H₆O	详情	详情
(B)	23199	2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether	67-64-1	C₃H₆O	详情	详情
(A)	33491	Dimethylformamide	68-12-2	C₃H₇NO	详情	详情
(E)	33492	N,N-dibutylamine; N-butyl-1-butanamine	111-92-2	C₈H₁₉N	详情	详情
(I)	33485	[(2E,4E)-5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2,4-pentadienyl](triphenyl)phosphonium bromide		C₃₄H₃₆BrOP	详情	详情
(II)	33486	butyl (E)-3-methyl-4-oxo-2-butenoate		C₉H₁₄O₃	详情	详情
(III)	33487	butyl (2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoate		C₂₅H₃₄O₃	详情	详情
(IV)	33479	2,3,5-trimethylphenol	697-82-5	C₉H₁₂O	详情	详情
(V)	33480	1-methoxy-2,3,5-trimethylbenzene; methyl 2,3,5-trimethylphenyl ether	20469-61-8	C₁₀H₁₄O	详情	详情
(VI)	33481	4-methoxy-2,3,6-trimethylbenzaldehyde		C₁₁H₁₄O₂	详情	详情
(VII)	33482	(E)-4-(4-methoxy-2,3,6-trimethylphenyl)-3-buten-2-one	54757-47-0	C₁₄H₁₈O₂	详情	详情
(VIII)	33483	(E)-1-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-1-penten-4-yn-3-ol		C₁₆H₂₀O₂	详情	详情
(IX)	33484	(1E)-1-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-1,4-pentadien-3-ol		C₁₆H₂₂O₂	详情	详情
(X)	33490	Dibutyl tartrate	87-92-3	C₁₂H₂₂O₆	详情	详情
(XI)	30937	butyl 2-oxoacetate		C₆H₁₀O₃	详情	详情
(C)	17778	ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium	4301-14-8	C₂HBrMg	详情	详情

合成路线2

该中间体在本合成路线中的序号：(C)

The methylation of 2,3,5-trimethylphenol (I) with MeI and KOH in 10% aqueous ethanol gives 2,3,5-trimethylanisole (II), which is formylated with DMF and POCl3 yielding 2,3,6-trimethyl-p-anisylaldehyde (III). The condensation of (III) with acetone (B) by means of NaOH affords 4-(4-methoxy-2,3,6-trimethylphenyl)but-3-en-2-one (IV), which by a Grignard reaction with ethynylmagnesium bromide (C) in THF is converted into the acetylenic alcohol (V). Partial hydrogenation of (V) with H2 over Pd/C in hexane gives dienic alcohol (VI), which is condensed with triphenylphosphine hydrobromide in benzene affording 5-(4-methoxy-2,3,6 trimethylphenyl)-3-methylpenta-2,4-diene-1-triphenylphosphonium bromide (VII). A Wittig condensation of (VII) with butyl 3-formylcrotonate (VIII) by means of NaH in DMF gives butyl 9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraenoate (IX), which is hydrolyzed with KOH in refluxing ethanol-water yielding the corresponding free acid (X). This acid is converted into the acyl chloride (XI) by treatment with PCl3 in refluxing benzene. Finally, this compound is treated with ethylamine (E) in ether. The butyl 3-formylcrotonate (VIII) is obtained as follows: The oxidation of dibutyl tartrate (XII) with lead tetraacetate in benzene gives butyl glyoxalate (XIII), which is then condensed with propionaldehyde (XIV) by heating at 110 C with dibutyl-amine (D).

参考文献中间体

合成目标

【1】 Bollag, W.; et al.; Polyene derivatives. BE 0813002; FR 2223037; GB 1468401; GB 1468402 .
【2】 Bollag, W.; et al.; Antidandruff compositions containing 9-(4-lower alkoxy-2,3,6-trilower-alkylphenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid lower alkyl amides. DE 2542366; ES 441173; FR 2330381; GB 1504350; JP 51057840; US 4021574 .
【3】 Castaner, J.; Hillier, K.; Motretinide. Drugs Fut 1978, 3, 2, 126.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(E)	10928	Ethanamine	75-04-7	C₂H₇N	详情	详情
(B)	23199	2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether	67-64-1	C₃H₆O	详情	详情
(A)	33491	Dimethylformamide	68-12-2	C₃H₇NO	详情	详情
(D)	33492	N,N-dibutylamine; N-butyl-1-butanamine	111-92-2	C₈H₁₉N	详情	详情
(I)	33479	2,3,5-trimethylphenol	697-82-5	C₉H₁₂O	详情	详情
(II)	33480	1-methoxy-2,3,5-trimethylbenzene; methyl 2,3,5-trimethylphenyl ether	20469-61-8	C₁₀H₁₄O	详情	详情
(III)	33481	4-methoxy-2,3,6-trimethylbenzaldehyde		C₁₁H₁₄O₂	详情	详情
(IV)	33482	(E)-4-(4-methoxy-2,3,6-trimethylphenyl)-3-buten-2-one	54757-47-0	C₁₄H₁₈O₂	详情	详情
(V)	33483	(E)-1-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-1-penten-4-yn-3-ol		C₁₆H₂₀O₂	详情	详情
(VI)	33484	(1E)-1-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-1,4-pentadien-3-ol		C₁₆H₂₂O₂	详情	详情
(VII)	33485	[(2E,4E)-5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2,4-pentadienyl](triphenyl)phosphonium bromide		C₃₄H₃₆BrOP	详情	详情
(VIII)	33486	butyl (E)-3-methyl-4-oxo-2-butenoate		C₉H₁₄O₃	详情	详情
(IX)	33487	butyl (2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoate		C₂₅H₃₄O₃	详情	详情
(X)	33488	(2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid		C₂₁H₂₆O₃	详情	详情
(XI)	33489	(2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoyl chloride		C₂₁H₂₅ClO₂	详情	详情
(XII)	33490	Dibutyl tartrate	87-92-3	C₁₂H₂₂O₆	详情	详情
(XIII)	30937	butyl 2-oxoacetate		C₆H₁₀O₃	详情	详情
(XIV)	15966	propionaldehyde	123-38-6	C₃H₆O	详情	详情
(C)	17778	ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium	4301-14-8	C₂HBrMg	详情	详情

合成路线3

该中间体在本合成路线中的序号：(C)

The reaction of 2,3,5-trimethylanisole (II) [prepared by alkylation of 2,3,5-trimethylphenol (I) with methyl iodide] with DMF and POCl3 affords 4-(4-methoxy-2,3,6-trimethylbenzaldehyde (V), which is condensed with propanone (B) in aqueous NaOH giving 4-(4-methoxy-2,3,6-trimethylphenyl)-but-3-en-2-one (VI). The Grignard reaction of (VI) with ethynylmagnesium bromide (C) in THF yields 5-(4-methoxy-2,3,6-trimethylphe-nyl)-3-methyl-3-hydroxypenta-4-en-1-yne (VII), which is partially hydrogenated with H2 over deactivated Pd in hexane to give 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-3-hydroxypenta-1,4-diene (VIII). The reaction of (VIII) with triphenylphosphonium hydrobromide in benzene affords 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methylpenta-2,4-diene-1-triphenylphosphonium bromide (IX). Finally, this compound is submitted to a Wittig reaction with ethyl 3,4-formylcrotonate (D) in DMF (NaH is used as base).

参考文献中间体

合成目标

【1】 Bollag, W. et al.; Polyene derivatives. DE 2414619; ES 424750; FR 2223037; GB 1468401; GB 1468402 .
【2】 Castaner, J.; Thorpe, P.; RO 10/9359. Drugs Fut 1977, 2, 3, 199.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(B)	33481	4-methoxy-2,3,6-trimethylbenzaldehyde		C₁₁H₁₄O₂	详情	详情
(D)	40061	ethyl (E)-3-methyl-4-oxo-2-butenoate	62054-49-3	C₇H₁₀O₃	详情	详情
(I)	33479	2,3,5-trimethylphenol	697-82-5	C₉H₁₂O	详情	详情
(II)	33480	1-methoxy-2,3,5-trimethylbenzene; methyl 2,3,5-trimethylphenyl ether	20469-61-8	C₁₀H₁₄O	详情	详情
(V)	23199	2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether	67-64-1	C₃H₆O	详情	详情
(VI)	33482	(E)-4-(4-methoxy-2,3,6-trimethylphenyl)-3-buten-2-one	54757-47-0	C₁₄H₁₈O₂	详情	详情
(VII)	33483	(E)-1-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-1-penten-4-yn-3-ol		C₁₆H₂₀O₂	详情	详情
(VIII)	33484	(1E)-1-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-1,4-pentadien-3-ol		C₁₆H₂₂O₂	详情	详情
(IX)	33485	[(2E,4E)-5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2,4-pentadienyl](triphenyl)phosphonium bromide		C₃₄H₃₆BrOP	详情	详情
(C)	17778	ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium	4301-14-8	C₂HBrMg	详情	详情

合成路线4

该中间体在本合成路线中的序号：(III)

The reaction of ethyl 3-(3-furyl)acrylate (I) with the cuprate t-Bu2CuCNLi2, followed by reduction with diisobutylaluminum hydride gives the tert-butylated aldehyde (II), which is condensed with ethynylmagnesium bromide (III), yielding a mixture of the syn and anti acetylenic alcohols (IV) and (V). After chromatographic separation, the undesired anti-alcohol (IV) is converted to the syn-alcohol (V) by a Mitsunobu inversion. Alcohol (V) was protected as the triethylsilyl ether and carboxylated with ethyl chloroformate affording the acetylenic ester (VI), which is cyclized with the zinc/copper enolate (VII) giving the 2-oxocyclopentenecarboxylate (VIII). The photocyclization of (VIII) with U.V. light (366 nm) yields the tetracyclic ester (IX), which is desilylated with HF and mesylated with mesyl chloride affording mesylate (X). Lactonization of (X) with PPTS gives the pentacyclic lactone (XI), which is dehydrogenated with PhSeCl and NaIO4 to the enone (XII). The opening of the cyclobutane ring of (XII) with dimethyldioxirane (DMDO) and TsOH yields the trihydroxy compound (XIII), which is treated with MeOH and TsOH to afford the bis(methyl)acetal (XIV). The deoxygenation of (XIV) through the corresponding xanthate and reduction with tributylstannane gives intermediate (XV), which is hydroxylated and acylated yielding the propionyl ester (XVI). Cyclization of (XVI) by means of LDA in THF followed by treatment with NaOMe affords a diastereomeric mixture (XVII), which is separated by chromatography. The isolated epimer (XVIII) was treated with MeOH and camphorsulfonic acid (CSA) resulting in the methanolysis of its lactone ring and formation of a new tetrahydrofuran ring providing the pentacyclic compound (XIX).

参考文献中间体

合成目标

【1】 Crimmins, M.T.; et al.; The total synthesis of (±)-ginkgolide B. J Am Chem Soc 2000, 122, 35, 8453.
【2】 Pace, J.M.; Watterson, S.H.; Nantermet, P.G.; Crimmins, M.T.; Kim-Meade, A.S.; Wagman, A.S.; Thomas, J.B.; Total synthesis of (±)-ginkgolide B. J Am Chem Soc 1999, 121, 43, 10249.

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)	37633	ethyl (E)-3-(3-furyl)-2-propenoate		C₉H₁₀O₃	详情	详情
(II)	37634	3-(3-furyl)-4,4-dimethylpentanal		C₁₁H₁₆O₂	详情	详情
(III)	17778	ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium	4301-14-8	C₂HBrMg	详情	详情
(IV)	37635	(3R,5S)-5-(3-furyl)-6,6-dimethyl-1-heptyn-3-ol		C₁₃H₁₈O₂	详情	详情
(V)	37636	(3S,5S)-5-(3-furyl)-6,6-dimethyl-1-heptyn-3-ol		C₁₃H₁₈O₂	详情	详情
(VI)	37637	ethyl (4S,6S)-6-(3-furyl)-7,7-dimethyl-4-[(triethylsilyl)oxy]-2-octynoate		C₂₂H₃₆O₄Si	详情	详情
(VIII)	37638	ethyl 2-[(1S,3S)-3-(3-furyl)-4,4-dimethyl-1-[(triethylsilyl)oxy]pentyl]-5-oxo-1-cyclopentene-1-carboxylate		C₂₅H₄₀O₅Si	详情	详情
(IX)	37639	ethyl (1S,3S,6aR)-3-(tert-butyl)-7-oxo-1-[(triethylsilyl)oxy]-2,3,8,9-tetrahydro-1H,6aH-dicyclopenta[2,3:3,4]cyclobuta[1,2-b]furan-6b(7H)-carboxylate		C₂₅H₄₀O₅Si	详情	详情
(X)	37640	ethyl (1S,3S,6aR)-3-(tert-butyl)-1-[(methylsulfonyl)oxy]-7-oxo-2,3,8,9-tetrahydro-1H,6aH-dicyclopenta[2,3:3,4]cyclobuta[1,2-b]furan-6b(7H)-carboxylate		C₂₀H₂₈O₇S	详情	详情
(XI)	37641			C₁₇H₂₀O₄	详情	详情
(XII)	37642			C₁₇H₁₈O₄	详情	详情
(XIII)	37643			C₁₇H₂₂O₇	详情	详情
(XIV)	37644			C₁₉H₂₆O₇	详情	详情
(XV)	37645			C₁₉H₂₆O₆	详情	详情
(XVI)	37646			C₂₂H₃₀O₈	详情	详情
(XVII)	37647			C₂₂H₃₀O₈	详情	详情
(XVIII)	37648			C₂₂H₃₀O₈	详情	详情
(XIX)	37649			C₂₂H₃₀O₈	详情	详情

合成路线5

该中间体在本合成路线中的序号：(B)

18-Methyl-4-oestrene-3,17-dione (I) is hydroxylated by fermentation with Penicillium raistrickii giving the 15alpha-hydroxy compound (II), which is ketalized with 2,2-dimethylpropanediol (A), triethyl orthoformate and p-toluenesulfonic acid in CH2Cl2 giving a mixture of the DELTA(5-6) and DELTA(5-10)-ketals (IIIa-b). These ketals are mesylated witn methanesulfonyl chloride in pyridine yielding the mesyl ester (IVa-b), which is treated with sodium acetate in DMF to afford the oestradiene ketal (Va-b). Finally, this compound is treated with ethynylmagnesium bromide (B) and refluxed with oxalic acid (C) in methanol.

参考文献中间体

合成目标

【1】 Hofmeister, H.; Wiechert, R.; Annen, K.; Laurent, H.; Steinbeck, H.; Steroids and pharmaceutical compositions thereof. BE 0847090; FR 2326927; GB 1569135; JP 52046060; US 4081537 .
【2】 Castaner, J.; Blancafort, P.; Gestodene. Drugs Fut 1977, 2, 12, 805.

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)	12641	Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol	126-30-7	C₅H₁₂O₂	详情	详情
(B)	17778	ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium	4301-14-8	C₂HBrMg	详情	详情
(IIIa)	33952			C₂₄H₃₆O₄	详情	详情
(IIIb)	33953			C₂₄H₃₆O₄	详情	详情
(IVa)	33954			C₂₇H₄₂O₄S	详情	详情
(IVb)	33955			C₂₇H₄₂O₄S	详情	详情
(Va)	33956			C₂₄H₃₄O₃	详情	详情
(Vb)	33957			C₂₄H₃₄O₃	详情	详情
(I)	33950	(8R,9S,10R,13S,14S)-13-ethyl-7,8,9,10,11,12,13,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione		C₁₉H₂₆O₂	详情	详情
(II)	33951	(8R,9S,10R,13S,14S,15S)-13-ethyl-15-hydroxy-7,8,9,10,11,12,13,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione		C₁₉H₂₆O₃	详情	详情
(C)	15713	Oxalic acid	144-62-7	C₂H₂O₄	详情	详情

合成路线6

该中间体在本合成路线中的序号：(B)

Ketals (IIIa-b) can also be treated with trimethylsilyl chloride in pyridine to give the trimethylsilyl derivative (VIa-b), which is then treated with ethynylmagnesium bromide (B) and oxalic acid (C) in methanol.

参考文献中间体

合成目标

【1】 Hofmeister, H.; Wiechert, R.; Annen, K.; Laurent, H.; Steinbeck, H.; Steroids and pharmaceutical compositions thereof. BE 0847090; FR 2326927; GB 1569135; JP 52046060; US 4081537 .
【2】 Castaner, J.; Blancafort, P.; Gestodene. Drugs Fut 1977, 2, 12, 805.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(B)	17778	ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium	4301-14-8	C₂HBrMg	详情	详情
(IIIa)	33952			C₂₄H₃₆O₄	详情	详情
(IIIb)	33953			C₂₄H₃₆O₄	详情	详情
(VIa)	33958			C₂₇H₄₄O₄Si	详情	详情
(VIb)	33959			C₂₇H₄₄O₄Si	详情	详情
(C)	15713	Oxalic acid	144-62-7	C₂H₂O₄	详情	详情

合成路线7

该中间体在本合成路线中的序号：(B)

Ketals (IIIa-b) can also be acetylated with acetic anhydride in pyridine to the acetate (VIIa-b), which is then treated with ethynylmagnesium bromide (B) and oxalic acid (C) in methanol.

参考文献中间体

合成目标

【1】 Hofmeister, H.; Wiechert, R.; Annen, K.; Laurent, H.; Steinbeck, H.; Steroids and pharmaceutical compositions thereof. BE 0847090; FR 2326927; GB 1569135; JP 52046060; US 4081537 .
【2】 Castaner, J.; Blancafort, P.; Gestodene. Drugs Fut 1977, 2, 12, 805.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(B)	17778	ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium	4301-14-8	C₂HBrMg	详情	详情
(IIIa)	33952			C₂₄H₃₆O₄	详情	详情
(IIIb)	33953			C₂₄H₃₆O₄	详情	详情
(VIIa)	33960			C₂₆H₃₈O₅	详情	详情
(VIIb)	33961			C₂₆H₃₈O₅	详情	详情
(C)	15713	Oxalic acid	144-62-7	C₂H₂O₄	详情	详情

合成路线8

该中间体在本合成路线中的序号：(IV)

Racemic compound.- The reaction of 1,1-diacetylcyclopropane (I) with the disilylated propargyl alcohol (II) by means of tert-butyllithium gives the monocondensation compound (III), which is treated with ethynylmagnesium bromide (IV) and CeCl3 to yield the bis acetylenic diol (V). The acylation of (V) with acetic anhydridde affords the monoacetate (VI), which is isomerized by means of [CuH(PPh3]6 to provide the allene compound (VII). The selective deprotection of (VII) gives the terminal acetylene (VIII), which is cyclized with Mo(CO)6 in refluxing DMSO/toleuene to afford the tricyclic ketone (IX). The methyletion of (IX) with CH3Li gives the monosilylated tricyclic diol (X), which is deprotected with TBAF yielding the diol (XI). The oxidation of the secondary alcohol of (XI) with Dess Martin periodinane (DMP) provides the tricyclic ketone (XII), which is finally hydroxymethylated with formaldehyde and sulfuric acid to afford the target compound as a racemic mixture.

参考文献中间体

合成目标

【1】 Brummond, K.M.; Lu, J.; A short synthesis of the potent antitumor agent (±)-hydroxymethylacylfulvene using allenic pauson-khand type cycloaddition. J Am Chem Soc 1999, 121, 21, 5087.
【2】 Brummond, K.M.; et al.; A rapid synthesis of hydroxymethylacylfulvene (HMAF) using the allenic Pauson - Khand reaction. A synthetic approach to either enantiomer of this illudane structure. J Am Chem Soc 2000, 122, 20, 4915.

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)	27116	1-(1-acetylcyclopropyl)-1-ethanone		C₇H₁₀O₂	详情	详情
(II)	27117	tert-butyl(dimethyl)silyl 3-(trimethylsilyl)-2-propynyl ether		C₁₂H₂₆OSi₂	详情	详情
(III)	27118	1-[1-[2-[[tert-butyl(dimethyl)silyl]oxy]-1-hydroxy-1-methyl-4-(trimethylsilyl)-3-butynyl]cyclopropyl]-1-ethanone		C₁₉H₃₆O₃Si₂	详情	详情
(IV)	17778	ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium	4301-14-8	C₂HBrMg	详情	详情
(V)	27119	3-[[tert-butyl(dimethyl)silyl]oxy]-2-[1-(1-hydroxy-1-methyl-2-propynyl)cyclopropyl]-5-(trimethylsilyl)-4-pentyn-2-ol		C₂₁H₃₈O₃Si₂	详情	详情
(VI)	27120	1-[1-[2-[[tert-butyl(dimethyl)silyl]oxy]-1-hydroxy-1-methyl-4-(trimethylsilyl)-3-butynyl]cyclopropyl]-1-methyl-2-propynyl acetate		C₂₃H₄₀O₄Si₂	详情	详情
(VII)	27121	3-[[tert-butyl(dimethyl)silyl]oxy]-2-[1-(1-methyl-1,2-propadienyl)cyclopropyl]-5-(trimethylsilyl)-4-pentyn-2-ol		C₂₁H₃₈O₂Si₂	详情	详情
(VIII)	27122	3-[[tert-butyl(dimethyl)silyl]oxy]-2-[1-(1-methyl-1,2-propadienyl)cyclopropyl]-4-pentyn-2-ol		C₁₈H₃₀O₂Si	详情	详情
(IX)	27123	4'-(Tert-butyldimethylsilyloxy)-5'-hydroxy-5',7'-dimethyl-2',4',5',6'-tetrahydro-1'H-spiro[cyclopropane-1,6'-inden]-2'-one		C₁₉H₃₀O₃Si	详情	详情
(X)	27124	7'-(Tert-butyldimethylsilyloxy)-2',4',6'-trimethyl-6',7'-dihydro-5'H-spiro[cyclopropane-1,5'-inden]-6'-ol		C₂₀H₃₂O₂Si	详情	详情
(XI)	27125	2',4',6'-Trimethyl-6',7'-dihydro-5'H-spiro[cyclopropane-1,5'-indene]-6',7'-diol		C₁₄H₁₈O₂	详情	详情
(XII)	27126	6'-Hydroxy-2',4',6'-trimethyl-6',7'-dihydro-5'H-spiro[cyclopropane-1,5'-inden]-7'-one		C₁₄H₁₆O₂	详情	详情

合成路线9

该中间体在本合成路线中的序号：(VII)

The chiral 6(R) isomer of 213351 has been obtained as follows: The condensation of 1,1-diacetylcyclopropane monoethylene ketal (I) with acetylenic phosphonate (II) by means of NaHMDS in THF gives the silylated pentenyne (III), which is treated with TsOH in acetone/water yielding the acetylcyclopropane (IV). The Sharpless asymetric dihydroxylation of the double bond of (IV) by means of chiral auxiliary (DHQD)2PYR, K2OsO2(OH)4, K3Fe(CN)6 and K2CO3 in tert-butanol/water affords the chiral diol (V), which is monosilylated with TBDMS-OTf providing the silyl ether (VI). The condensation of (VI) with ethynylmagnesium bromide (VII) and CeCl3 gives the diacetylenic diol (VIII), which is regioselectively acetylated with Ac2O, TEA and DMAP yielding the monoacetate (IX). The treatment of the propargylic acetate (IX) with [(PPh3)CuH]6 in methanol affords the allene (X), which is regioselectively desilylated at the terminal acetylenic group furnishing the cyclization precursor (XI). The Mo(CO)6 promoted cyclization of (XI) in refluxing toluene/DMSO gives the chiral tricyclic ketone (XII). The methylation of (XII) with MeLi yields the monosilylated diol (XIII), which is desilylated with TBAF to the chiral diol (XIV). The oxidation of (XIV) with Dess Martin periodinane (DMP) affords the chiral hydroyketone (XV), which is finally hydroxymethylated with formaldehyde and H2SO4 to furnish the target compound.

参考文献中间体

合成目标

【1】 Brummond, K.M.; et al.; A rapid synthesis of hydroxymethylacylfulvene (HMAF) using the allenic Pauson - Khand reaction. A synthetic approach to either enantiomer of this illudane structure. J Am Chem Soc 2000, 122, 20, 4915.

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)	36876	1-[1-(2-methyl-1,3-dioxolan-2-yl)cyclopropyl]-1-ethanone		C₉H₁₄O₃	详情	详情
(II)	36877	diethyl 3-(trimethylsilyl)-2-propynylphosphonate		C₁₀H₂₁O₃PSi	详情	详情
(III)	36878	trimethyl[(Z)-4-[1-(2-methyl-1,3-dioxolan-2-yl)cyclopropyl]-3-penten-1-ynyl]silane		C₁₅H₂₄O₂Si	详情	详情
(IV)	36879	1-[1-[(Z)-1-methyl-4-(trimethylsilyl)-1-buten-3-ynyl]cyclopropyl]-1-ethanone		C₁₃H₂₀OSi	详情	详情
(V)	36880	1-[1-[(1R,2R)-1,2-dihydroxy-1-methyl-4-(trimethylsilyl)-3-butynyl]cyclopropyl]-1-ethanone		C₁₃H₂₂O₃Si	详情	详情
(VI)	36881	1-[1-[(1R,2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-hydroxy-1-methyl-4-(trimethylsilyl)-3-butynyl]cyclopropyl]-1-ethanone		C₁₉H₃₆O₃Si₂	详情	详情
(VII)	17778	ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium	4301-14-8	C₂HBrMg	详情	详情
(VIII)	36882	(2R,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-[1-(1-hydroxy-1-methyl-2-propynyl)cyclopropyl]-5-(trimethylsilyl)-4-pentyn-2-ol		C₂₁H₃₈O₃Si₂	详情	详情
(IX)	36883	1-[1-[(1R,2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-hydroxy-1-methyl-4-(trimethylsilyl)-3-butynyl]cyclopropyl]-1-methyl-2-propynyl acetate		C₂₃H₄₀O₄Si₂	详情	详情
(X)	36884	(2R,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-[1-(1-methyl-1,2-propadienyl)cyclopropyl]-5-(trimethylsilyl)-4-pentyn-2-ol		C₂₁H₃₈O₂Si₂	详情	详情
(XI)	36888	(2R,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-[1-(1-methyl-1,2-propadienyl)cyclopropyl]-4-pentyn-2-ol		C₁₈H₃₀O₂Si	详情	详情
(XII)	36885			C₁₉H₃₀O₃Si	详情	详情
(XIII)	36886			C₂₀H₃₂O₂Si	详情	详情
(XIV)	36887			C₁₄H₁₈O₂	详情	详情
(XV)	26689	6(R)-6-Hydroxy-2,4,6-trimethyl-6,7-dihydro-5H-spiro[indene-5,1'-cyclopropan]-7-one; 6(R)-6-Hydroxy-2,4,6-trimethyl-6,7-dihydro-5H-spiro[indene-5,1'-cyclopropan]-7-one		C₁₄H₁₆O₂	详情	详情

合成路线10

该中间体在本合成路线中的序号：(XII)

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

合成目标

【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11

该中间体在本合成路线中的序号：(II)

Treatment of quinoline (I) with ethynylmagnesium bromide (II) in THF at low temperature, and then with 4-chlorophenyl chloroformate (III) gave carbamate (IV). Subsequent deprotection of tert-butyldimethylsilyl group with p-toluenesulfonic acid yielded allyl alcohol (V), and this was stereoselectively epoxidized with m-chloroperbenzoic acid to give epoxyalcohol (VI). Coupling of (VI) with vinyl chloride (VII) in the presence of Pd(0)-CuI catalyst provided the enediyne compound (VIII). This was oxidized with Dess-Martin periodinane reagent to the aldehyde (IX). Finally, CsF-promoted cyclization in the presence of acetic anhydride provided the title compound as a 2:1 mixture of diastereoisomers, which could not be separated.

参考文献中间体

合成目标

【1】 Unno, R.; et al.; Structure-activity relationships of cyclic enediynes related to dynemicin A-I. Synthesis and antitumor activity of 9-acetoxy enediynes equipped with aryl carbamate moieties. Bioorg Med Chem 1997, 5, 5, 883.

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)	17777	tert-butyl(dimethyl)silyl 4-quinolinylmethyl ether; 4-([[tert-butyl(dimethyl)silyl]oxy]methyl)quinoline		C₁₆H₂₃NOSi	详情	详情
(II)	17778	ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium	4301-14-8	C₂HBrMg	详情	详情
(III)	17779	1-chloro-4-[(chlorocarbonyl)oxy]benzene	7693-45-0	C₇H₄Cl₂O₂	详情	详情
(IV)	17780	4-chlorophenyl (2R)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-ethynyl-1(2H)-quinolinecarboxylate		C₂₅H₂₈ClNO₃Si	详情	详情
(V)	17781	4-chlorophenyl (2R)-2-ethynyl-4-(hydroxymethyl)-1(2H)-quinolinecarboxylate		C₁₉H₁₄ClNO₃	详情	详情
(VI)	17782	4-chlorophenyl (1aS,2S,7bS)-2-ethynyl-7b-(hydroxymethyl)-1a,7b-dihydrooxireno[2,3-c]quinoline-3(2H)-carboxylate		C₁₉H₁₄ClNO₄	详情	详情
(VII)	17783	[(Z)-4-chloro-3-buten-1-ynyl](trimethyl)silane		C₇H₁₁ClSi	详情	详情
(VIII)	17784	4-chlorophenyl (1aS,2S,7bS)-7b-(hydroxymethyl)-2-[(Z)-6-(trimethylsilyl)-3-hexene-1,5-diynyl]-1a,7b-dihydrooxireno[2,3-c]quinoline-3(2H)-carboxylate		C₂₆H₂₄ClNO₄Si	详情	详情
(IX)	17785	4-chlorophenyl (1aS,2S,7bR)-7b-formyl-2-[(Z)-6-(trimethylsilyl)-3-hexene-1,5-diynyl]-1a,7b-dihydrooxireno[2,3-c]quinoline-3(2H)-carboxylate		C₂₆H₂₂ClNO₄Si	详情	详情

合成路线12

该中间体在本合成路线中的序号：(III)

Aldehyde (II) was prepared by mono-benzylation of 1,4-butanediol (I) followed by Swern oxidation. Subsequent addition of ethynylmagnesium bromide (III) to the aldehyde function of (II) provided propargyl alcohol (IV). Kinetic resolution of the racemic alcohol (IV) by lipase-mediated acetylation in the presence of vinyl acetate produced a mixture of the (S)-acetate (V) and the unreacted (R)-alcohol (VI). The required (S)-propargyl acetate (V) was subjected to partial hydrogenation using Lindlar catalyst to furnish allyl acetate (VII), which was further hydrolyzed to the chiral alcohol (VIII). After protection of (VIII) as the silylated derivative (IX), reductive removal of the benzyl ether using lithium naphthalenide afforded the primary alcohol (X). This was then treated with methanesulfonyl chloride and triethylamine to give mesylate (XI). Ozonolysis of the double bond of (XI), followed by reductive work-up with dimethyl sulfide, yielded aldehyde (XII). This was reacted with hydroxylamine hydrochloride and Et3N in allyl alcohol (XIII) to produce the intermediate nitrone (XIV), which underwent simultaneous 1,3-dipolar cycloaddition to allyl alcohol to furnish the isoxazolopyridine (XV) as a mixture of three diastereoisomers. This mixture was then subjected to hydrogenolytic N-O bond fission, producing piperidine (XVI).

参考文献中间体

合成目标

【1】 Ooi, H.e; et al.; A concise enantioselective synthesis of antimalarial febrifugine alkaloids. Org Lett 2001, 3, 6, 953.

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)	43160	1,4-butanediol;1,4-Dihydroxybutane;1,4-Butylene glycol;Tetramethylene glycol	110-63-4	C₄H₁₀O₂	详情	详情
(II)	46170	4-(benzyloxy)butanal		C₁₁H₁₄O₂	详情	详情
(III)	17778	ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium	4301-14-8	C₂HBrMg	详情	详情
(IV)	47833	6-(benzyloxy)-1-hexyn-3-ol		C₁₃H₁₆O₂	详情	详情
(V)	47834	(1S)-1-[3-(benzyloxy)propyl]-2-propynyl acetate		C₁₅H₁₈O₃	详情	详情
(VI)	47835	(3R)-6-(benzyloxy)-1-hexyn-3-ol		C₁₃H₁₆O₂	详情	详情
(VII)	47836	(1S)-1-[3-(benzyloxy)propyl]-2-propenyl acetate		C₁₅H₂₀O₃	详情	详情
(VIII)	47837	(3S)-6-(benzyloxy)-1-hexen-3-ol		C₁₃H₁₈O₂	详情	详情
(IX)	47838	([(1S)-1-[3-(benzyloxy)propyl]-2-propenyl]oxy)(tert-butyl)diphenylsilane; benzyl (4S)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-hexenyl ether		C₂₉H₃₆O₂Si	详情	详情
(X)	47839	(4S)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-hexen-1-ol		C₂₂H₃₀O₂Si	详情	详情
(XI)	47840	(4S)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-hexenyl methanesulfonate		C₂₃H₃₂O₄SSi	详情	详情
(XII)	47841	(4S)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-oxopentyl methanesulfonate		C₂₂H₃₀O₅SSi	详情	详情
(XIII)	12234	2-Propen-1-ol; Allyl alcohol	107-18-6	C₃H₆O	详情	详情
(XIV)	47842	(5S)-5-[[tert-butyl(diphenyl)silyl]oxy]-2,3,4,5-tetrahydro-1-pyridiniumolate		C₂₁H₂₇NO₂Si	详情	详情
(XV)	47843	((4S)-4-[[tert-butyl(diphenyl)silyl]oxy]hexahydro-2H-isoxazolo[2,3-a]pyridin-2-yl)methanol		C₂₄H₃₃NO₃Si	详情	详情
(XVI)	47844	3-((3S)-3-[[tert-butyl(diphenyl)silyl]oxy]piperidinyl)-1,2-propanediol		C₂₄H₃₅NO₃Si	详情	详情

合成路线13

该中间体在本合成路线中的序号：(III)

参考文献中间体

合成目标

【1】 Ooi, H.e; et al.; A concise enantioselective synthesis of antimalarial febrifugine alkaloids. Org Lett 2001, 3, 6, 953.

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)	43160	1,4-butanediol;1,4-Dihydroxybutane;1,4-Butylene glycol;Tetramethylene glycol	110-63-4	C₄H₁₀O₂	详情	详情
(II)	46170	4-(benzyloxy)butanal		C₁₁H₁₄O₂	详情	详情
(III)	17778	ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium	4301-14-8	C₂HBrMg	详情	详情
(IV)	47833	6-(benzyloxy)-1-hexyn-3-ol		C₁₃H₁₆O₂	详情	详情
(V)	47834	(1S)-1-[3-(benzyloxy)propyl]-2-propynyl acetate		C₁₅H₁₈O₃	详情	详情
(VI)	47835	(3R)-6-(benzyloxy)-1-hexyn-3-ol		C₁₃H₁₆O₂	详情	详情
(VII)	47836	(1S)-1-[3-(benzyloxy)propyl]-2-propenyl acetate		C₁₅H₂₀O₃	详情	详情
(VIII)	47837	(3S)-6-(benzyloxy)-1-hexen-3-ol		C₁₃H₁₈O₂	详情	详情
(IX)	47838	([(1S)-1-[3-(benzyloxy)propyl]-2-propenyl]oxy)(tert-butyl)diphenylsilane; benzyl (4S)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-hexenyl ether		C₂₉H₃₆O₂Si	详情	详情
(X)	47839	(4S)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-hexen-1-ol		C₂₂H₃₀O₂Si	详情	详情
(XI)	47840	(4S)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-hexenyl methanesulfonate		C₂₃H₃₂O₄SSi	详情	详情
(XII)	47841	(4S)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-oxopentyl methanesulfonate		C₂₂H₃₀O₅SSi	详情	详情
(XIII)	12234	2-Propen-1-ol; Allyl alcohol	107-18-6	C₃H₆O	详情	详情
(XIV)	47842	(5S)-5-[[tert-butyl(diphenyl)silyl]oxy]-2,3,4,5-tetrahydro-1-pyridiniumolate		C₂₁H₂₇NO₂Si	详情	详情
(XV)	47843	((4S)-4-[[tert-butyl(diphenyl)silyl]oxy]hexahydro-2H-isoxazolo[2,3-a]pyridin-2-yl)methanol		C₂₄H₃₃NO₃Si	详情	详情
(XVI)	47844	3-((3S)-3-[[tert-butyl(diphenyl)silyl]oxy]piperidinyl)-1,2-propanediol		C₂₄H₃₅NO₃Si	详情	详情

Extended Information