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【结 构 式】

【药物名称】Clavepictine A

【化学名称】Acetic acid (3R,4S,6S,9aS)-6-[deca-1(E),3(E)-dienyl]-4-methylperhydroquinolizin-3-yl ester

【CA登记号】132621-83-1

【 分 子 式 】C22H37NO2

【 分 子 量 】347.54569

【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 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
40736 bromo(hexyl)magnesium 3761-92-0 C6H13BrMg 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
(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) produced 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
17346 Benzyloxyacetaldehyde; 2-(Benzyloxy)acetaldehyde 60656-87-3 C9H10O2 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 furnished the title diene.

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

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). The deprotection of (IV) with HCl in refluxing methanol provides the secondary alcohol V), which is finally acetylated with acetic anhydride and pyridine to furnish the target (-)-clavepictine A.

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
(V) 51732 (3R,4S,6S,9aS)-6-[(1E,3E)-1,3-decadienyl]-4-methyloctahydro-2H-quinolizin-3-ol C20H35NO 详情 详情
Extended Information