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【结 构 式】 
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【药物名称】Clavepictine B 【化学名称】(3R,4S,6S,9aS)-6-[Deca-1(E),3(E)-dienyl]-4-methylperhydroquinolizin-3-ol 【CA登记号】132621-84-2 【 分 子 式 】C20H35NO 【 分 子 量 】305.50805 |
【开发单位】US Department of Health & Human Services (Originator) 【药理作用】Antibiotics and Alkaloids, Antineoplastic Antibiotics, ONCOLYTIC DRUGS |
合成路线1
The enantiopure diol (II) was prepared by the Sharpless asymmetric dihydroxylation of ethyl sorbate (I). Catalytic hydrogenation of (II) generated the gamma-lactone (III). After conversion of the hydroxyl group of (III) to the corresponding mesylate, displacement by NaN3 afforded azide (IV). Reduction of (IV) to amine gave rise to the formation of lactam (V). Sequential protection of alcohol and amide functions of (V) provided (VI), which was treated with lithium hexamethyldisilazide and Comin's reagent to furnish the aminovinyl triflate (VII). The enantiopure propargyl alcohol (X), prepared by treatment of (S)-glycidol pivalate (VIII) with lithium trimethylsilylacetylide (IX) followed by desilylation with tetrabutylammonium fluoride, was then coupled with triflate (VII) in the presence of Pd(PPh3)4 and CuI to yield adduct (XI), which was reduced to the trisubstituted piperidine (XII) by means of NaBH3CN and trifluoroacetic acid. Hydrogenation of the alkyne function of (XII) with concomitant removal of the benzyloxycarbonyl group gave (XIII). This was further protected as the allyl carbamate (XIV) by treatment with allyl chloroformate. The secondary alcohol of (XIV) was then protected as the tetrahydropyranyl ether (XV), and subsequent reductive cleavage of the pivaloyl ester with DIBAL liberated the primary alcohol (XVI).
| 【1】 Ha, J.D.; Cha, J.K.; Total synthesis of clavepictines A and B. Diastereoselective cyclization of delta-aminoallenes. J Am Chem Soc 1999, 121, 43, 10012. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 | |
| (I) | 40236 | ethyl (2E,4E)-2,4-hexadienoate | 2396-84-1 | C8H12O2 | 详情 | 详情 |
| (II) | 40237 | ethyl (E,4R,5R)-4,5-dihydroxy-2-hexenoate | C8H14O4 | 详情 | 详情 | |
| (III) | 40238 | (5R)-5-[(1R)-1-hydroxyethyl]dihydro-2(3H)-furanone | C6H10O3 | 详情 | 详情 | |
| (IV) | 40239 | (5R)-5-[(1R)-1-azidoethyl]dihydro-2(3H)-furanone | C6H9N3O2 | 详情 | 详情 | |
| (V) | 40240 | (5R,6S)-5-hydroxy-6-methyl-2-piperidinone | C6H11NO2 | 详情 | 详情 | |
| (VI) | 40241 | benzyl (2S,3R)-2-methyl-6-oxo-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C23H37NO4Si | 详情 | 详情 | |
| (VII) | 40242 | benzyl (2S,3R)-2-methyl-6-[[(trifluoromethyl)sulfonyl]oxy]-3-[(triisopropylsilyl)oxy]-3,4-dihydro-1(2H)-pyridinecarboxylate | C24H36F3NO6SSi | 详情 | 详情 | |
| (VIII) | 12235 | (2S)oxiranylmethyl pivalate | C8H14O3 | 详情 | 详情 | |
| (IX) | 16299 | Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium | 54655-07-1 | C5H9LiSi | 详情 | 详情 |
| (X) | 12236 | (2S)-2-hydroxy-4-pentynyl pivalate | C10H16O3 | 详情 | 详情 | |
| (XI) | 40243 | benzyl (2S,3R)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-hydroxy-1-pentynyl]-2-methyl-3-[(triisopropylsilyl)oxy]-3,4-dihydro-1(2H)-pyridinecarboxylate | C33H51NO6Si | 详情 | 详情 | |
| (XII) | 40244 | benzyl (2S,3R,6R)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-hydroxy-1-pentynyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C33H53NO6Si | 详情 | 详情 | |
| (XIII) | 40245 | (2R)-2-hydroxy-5-[(2S,5R,6S)-6-methyl-5-[(triisopropylsilyl)oxy]piperidinyl]pentyl pivalate | C25H51NO4Si | 详情 | 详情 | |
| (XIV) | 40246 | allyl (2S,3R,6S)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-hydroxypentyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C29H55NO6Si | 详情 | 详情 | |
| (XV) | 40247 | allyl (2S,3R,6S)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-(tetrahydro-2H-pyran-2-yloxy)pentyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C34H63NO7Si | 详情 | 详情 | |
| (XVI) | 40248 | allyl (2S,3R,6S)-6-[(4R)-5-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)pentyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C29H55NO6Si | 详情 | 详情 |
合成路线2
The required propargyl alcohol (XVIII) was obtained by Swern oxidation of alcohol (XVI) to aldehyde (XVII), followed by condensation with dimethyl (diazomethyl) phosphonate
| 【1】 Ha, J.D.; Cha, J.K.; Total synthesis of clavepictines A and B. Diastereoselective cyclization of delta-aminoallenes. J Am Chem Soc 1999, 121, 43, 10012. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVI) | 40248 | allyl (2S,3R,6S)-6-[(4R)-5-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)pentyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C29H55NO6Si | 详情 | 详情 | |
| (XVII) | 40249 | allyl (2S,3R,6S)-2-methyl-6-[(4R)-5-oxo-4-(tetrahydro-2H-pyran-2-yloxy)pentyl]-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C29H53NO6Si | 详情 | 详情 | |
| (XVIII) | 40250 | allyl (2S,3R,6S)-6-[(4R)-4-hydroxy-5-hexynyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C25H45NO4Si | 详情 | 详情 | |
| (XIX) | 40251 | allyl (2S,3R,6S)-6-(8-ethoxy-8-oxo-4,5-octadienyl)-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C29H51NO5Si | 详情 | 详情 | |
| (XX) | 40252 | allyl (2S,3R,6S)-6-(8-hydroxy-4,5-tetradecadienyl)-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C33H61NO4Si | 详情 | 详情 | |
| (XXI) | 40253 | 1-hexyl-8-[(2S,5R,6S)-6-methyl-5-[(triisopropylsilyl)oxy]piperidinyl]-3,4-octadienyl triethylsilyl ether; (2S,3R,6S)-2-methyl-6-[8-[(triethylsilyl)oxy]-4,5-tetradecadienyl]-3-[(triisopropylsilyl)oxy]piperidine | C35H71NO2Si2 | 详情 | 详情 | |
| (XXII) | 40254 | (E)-1-[(4S,6S,7R,9aS)-6-methyl-7-[(triisopropylsilyl)oxy]octahydro-2H-quinolizin-4-yl]-1-decen-4-ol | C29H57NO2Si | 详情 | 详情 | |
| (XXIII) | 40255 | (3R,4S,6S,9aS)-6-[(1E,3E)-1,3-decadienyl]-4-methyloctahydro-2H-quinolizin-3-yl triisopropylsilyl ether; (3R,4S,6S,9aS)-6-[(1E,3E)-1,3-decadienyl]-4-methyl-3-[(triisopropylsilyl)oxy]octahydro-2H-quinolizine | C29H55NOSi | 详情 | 详情 |
合成路线3
Sharpless asymmetric dihydroxylation of ethyl (E)-2-decenoate (XXIV) afforded diol (XXV) and subsequent regioselectively protection of the beta-alcohol with triisopropylsilyl triflate provided silyl ether (XXVI). Following protection of the remaining alcohol, as the corresponding tetrahydropyranyl ether, the ester group was converted to aldehyde (XXVII) by reduction with DIBAL and subsequent Swern oxidation. Condensation of (XXVII) with carbon tetrabromide in the presence of PPh3 gave dibromoolefin (XXVIII) which, upon treatment with butyllithium and further acidic deprotection, produced propargyl alcohol (XXIX). Orthoester-Claisen rearrangement of (XXIX) gave allene (XXX). Following reduction of (XXX) with DIBAL, the alcohol (XXXI) was subjected to one-carbon chain elongation by conversion to bromide and then displacement with NaCN. Reduction of the resulting nitrile (XXXII) with DIBAL gave the requisite aldehyde (XXXIII).
| 【1】 Ha, J.D.; Cha, J.K.; Total synthesis of clavepictines A and B. Diastereoselective cyclization of delta-aminoallenes. J Am Chem Soc 1999, 121, 43, 10012. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIV) | 40256 | ethyl (E)-2-decenoate | 7367-88-6 | C12H22O2 | 详情 | 详情 |
| (XXV) | 40257 | ethyl (2R,3S)-2,3-dihydroxydecanoate | C12H24O4 | 详情 | 详情 | |
| (XXVI) | 40258 | ethyl (2R,3S)-2-hydroxy-3-[(triisopropylsilyl)oxy]decanoate | C21H44O4Si | 详情 | 详情 | |
| (XXVII) | 40259 | (2R,3S)-2-(tetrahydro-2H-pyran-2-yloxy)-3-[(triisopropylsilyl)oxy]decanal | C24H48O4Si | 详情 | 详情 | |
| (XXVIII) | 40260 | (1S,2S)-4,4-dibromo-1-heptyl-2-(tetrahydro-2H-pyran-2-yloxy)-3-butenyl triisopropylsilyl ether; [[(1S,2S)-4,4-dibromo-1-heptyl-2-(tetrahydro-2H-pyran-2-yloxy)-3-butenyl]oxy](triisopropyl)silane | C25H48Br2O3Si | 详情 | 详情 | |
| (XXIX) | 40261 | (3S,4S)-4-[(triisopropylsilyl)oxy]-1-undecyn-3-ol | C20H40O2Si | 详情 | 详情 | |
| (XXX) | 40262 | ethyl (6S)-6-[(triisopropylsilyl)oxy]-3,4-tridecadienoate | C24H46O3Si | 详情 | 详情 | |
| (XXXI) | 40263 | (6S)-6-[(triisopropylsilyl)oxy]-3,4-tridecadien-1-ol | C22H44O2Si | 详情 | 详情 | |
| (XXXII) | 40264 | (7S)-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienenitrile | C23H43NOSi | 详情 | 详情 | |
| (XXXIII) | 40265 | (7S)-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienal | C23H44O2Si | 详情 | 详情 |
合成路线4
The O-silylated 4-hydroxy-delta-caprolactam (XXXIV) was reduced with borane and the resulting piperidine was protected as the N-Boc derivative (XXXV). Lithiation employing sec-butyllithium and TMEDA, followed by addition of aldehyde (XXXIII) produ-ced an inseparable 3:1 mixture of the alcohol epimers (XXXVIIa-b) and the trans-oxazolidinone (XXXVI). Acylation of the mixture with m-(trifluoromethyl)benzoyl chloride afforded a diastereomeric mixture of (trifluoromethyl)benzoates (XXXVIIIa-b), separable by column chromatography. Deprotection of the Boc group from the syn-isomer of (XXXVIII) by means of trimethylsilyl triflate and lutidine gave the free amine (XXXIX). Subsequent cyclization of (XXXIX) with AgNO3 afforded the desired cis-quinolizidine (XL) with very high diastereoselectivity. Reductive cleavage of the (trifluoromethyl)benzoyl group of (XL), followed by treatment of the free alcohol with methanesulfonyl chloride provided mesylate (XLI).
| 【1】 Ha, J.D.; Cha, J.K.; Total synthesis of clavepictines A and B. Diastereoselective cyclization of delta-aminoallenes. J Am Chem Soc 1999, 121, 43, 10012. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 13746 | 3-(Trifluoromethyl)benzoyl chloride | 2251-65-2 | C8H4ClF3O | 详情 | 详情 | |
| (XXXVIIa) | 40267 | tert-butyl (2S,3R,6R)-6-[(1S,7S)-1-hydroxy-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C43H85NO5Si2 | 详情 | 详情 | |
| (XXXVIIb) | 40268 | tert-butyl (2S,3R,6R)-6-[(1R,7S)-1-hydroxy-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C43H85NO5Si2 | 详情 | 详情 | |
| (XXXVIIIa) | 40269 | tert-butyl (2S,3R,6R)-2-methyl-6-[(1S,7S)-1-[[3-(trifluoromethyl)benzoyl]oxy]-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienyl]-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C51H88F3NO6Si2 | 详情 | 详情 | |
| (XXXVIIb) | 40270 | tert-butyl (2S,3R,6R)-2-methyl-6-[(1R,7S)-1-[[3-(trifluoromethyl)benzoyl]oxy]-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienyl]-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C51H88F3NO6Si2 | 详情 | 详情 | |
| (XXXIII) | 40265 | (7S)-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienal | C23H44O2Si | 详情 | 详情 | |
| (XXXIV) | 40278 | (5R,6S)-6-methyl-5-[(triisopropylsilyl)oxy]-2-piperidinone | C15H31NO2Si | 详情 | 详情 | |
| (XXXV) | 40279 | tert-butyl (2S,3R)-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C20H41NO3Si | 详情 | 详情 | |
| (XXXVI) | 40266 | (1R,5S,6R,8aR)-5-methyl-6-[(triisopropylsilyl)oxy]-1-[(6S)-6-[(triisopropylsilyl)oxy]-3,4-tridecadienyl]hexahydro[1,3]oxazolo[3,4-a]pyridin-3-one | C39H75NO4Si2 | 详情 | 详情 | |
| (XXXIX) | 40271 | (1R,7S)-1-[(2R,5R,6S)-6-methyl-5-[(triisopropylsilyl)oxy]piperidinyl]-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienyl 3-(trifluoromethyl)benzoate | C46H80F3NO4Si2 | 详情 | 详情 | |
| (XL) | 40272 | (1R,4S,6S,7R,9aR)-6-methyl-7-[(triisopropylsilyl)oxy]-4-[(E,3S)-3-[(triisopropylsilyl)oxy]-1-decenyl]octahydro-2H-quinolizin-1-yl 3-(trifluoromethyl)benzoate | C46H80F3NO4Si2 | 详情 | 详情 | |
| (XLI) | 40273 | (1R,4S,6S,7R,9aR)-6-methyl-7-[(triisopropylsilyl)oxy]-4-[(E,3S)-3-[(triisopropylsilyl)oxy]-1-decenyl]octahydro-2H-quinolizin-1-yl methanesulfonate | C39H79NO5SSi2 | 详情 | 详情 |
合成路线5
During the reduction of mesylate (XLI) with LiAlH4, one of the triisopropylsilyl groups was selectively removed to afford alcohol (XLII). In contrast, when the same process was applied to the anti-isomer of (XXXVIII), the desired quinolizidine (XLI) was obtained along with a high amount of rearranged product. Acetylation of alcohol (XLII) and subsequent desilylation with aqueous HF gave the allylic alcohol (XLIII). Dehydration to the desired diene (XLV) was achieved by way of the allyl sulfide (XLIV), prepared by treatment of alcohol (XLIII) with N-phenylthiophthalimide and tributylphosphine. Subsequent oxidation of (XLIV) with oxone and thermal syn elimination of the intermediate sulfoxide gave diene (XLV). Finally, the title compound was obtained by basic hydrolysis of the acetate ester of (XLV) with K2CO3 in MeOH.
| 【1】 Ha, J.D.; Cha, J.K.; Total synthesis of clavepictines A and B. Diastereoselective cyclization of delta-aminoallenes. J Am Chem Soc 1999, 121, 43, 10012. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XLI) | 40273 | (1R,4S,6S,7R,9aR)-6-methyl-7-[(triisopropylsilyl)oxy]-4-[(E,3S)-3-[(triisopropylsilyl)oxy]-1-decenyl]octahydro-2H-quinolizin-1-yl methanesulfonate | C39H79NO5SSi2 | 详情 | 详情 | |
| (XLII) | 40274 | (3R,4S,6S,9aS)-4-methyl-6-[(E,3S)-3-[(triisopropylsilyl)oxy]-1-decenyl]octahydro-2H-quinolizin-3-ol | C29H57NO2Si | 详情 | 详情 | |
| (XLIII) | 40275 | (3R,4S,6S,9aS)-6-[(E,3S)-3-hydroxy-1-decenyl]-4-methyloctahydro-2H-quinolizin-3-yl acetate | C22H39NO3 | 详情 | 详情 | |
| (XLIV) | 40276 | (3R,4S,6S,9aS)-4-methyl-6-[(E)-3-(phenylsulfanyl)-1-decenyl]octahydro-2H-quinolizin-3-yl acetate | C28H43NO2S | 详情 | 详情 | |
| (XLV) | 40277 | (3R,4S,6S,9aS)-6-[(1E,3E)-1,3-decadienyl]-4-methyloctahydro-2H-quinolizin-3-yl acetate | C22H37NO2 | 详情 | 详情 |
合成路线6
The hydrolysis of the chiral isopropylidene ketal (I) with HCl in refluxing methanol, followed by selective monosilylation of the resulting primary OH group with tert-butyldiphenylsilyl chloride, protection of the secondary OH group with MOM-Cl and Hunig base, and desilylation with HF and pyridine gives the perhydroquinolizine-4-methanol derivative (II).The reaction of the OH group of (II) with I2 and PPh3, and deiodination of the resulting iodo derivative with Bu3SnH and AIBN yields the 4-methyl derivative (III), which is condensed with trans-2-nonenal and BuLi, and treated with Na/Hg to afford the 6-(1,3-decadienyl) derivative (IV).Finally the deprotection of (IV) with HCl in refluxing methanol provides the target (+)-clavepictine B.
| 【1】 Toyooka, N.; Nemoto, H.; Application of chiral building blocks to the synthesis of drugs. Drugs Fut 2002, 27, 2, 143. |
| 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) | 51729 | (4aR,6aS,10S,11aS)-3,3-dimethyl-10-[(phenylsulfonyl)methyl]decahydro[1,3]dioxino[4,5-c]quinolizine; [(4aR,6aS,10S,11aS)-3,3-dimethyldecahydro[1,3]dioxino[4,5-c]quinolizin-10-yl]methyl phenyl sulfone | C20H29NO4S | 详情 | 详情 | |
| (II) | 51730 | [(3R,4S,6S,9aS)-3-(methoxymethoxy)-6-[(phenylsulfonyl)methyl]octahydro-2H-quinolizin-4-yl]methanol | C19H29NO5S | 详情 | 详情 | |
| (III) | 51726 | [(4S,6S,7R,9aS)-7-(methoxymethoxy)-6-methyloctahydro-2H-quinolizin-4-yl]methyl phenyl sulfone; (3R,4S,6S,9aS)-3-(methoxymethoxy)-4-methyl-6-[(phenylsulfonyl)methyl]octahydro-2H-quinolizine | C19H29NO4S | 详情 | 详情 | |
| (IV) | 51731 | (3R,4S,6S,9aS)-6-[(1E,3E)-1,3-decadienyl]-4-methyloctahydro-2H-quinolizin-3-yl methoxymethyl ether; (3R,4S,6S,9aS)-6-[(1E,3E)-1,3-decadienyl]-3-(methoxymethoxy)-4-methyloctahydro-2H-quinolizine | C22H39NO2 | 详情 | 详情 |