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【结 构 式】 
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【分子编号】11068 【品名】(3R)-3-(Benzyloxy)tetradecanal 【CA登记号】 |
【 分 子 式 】C21H34O2 【 分 子 量 】318.49976 【元素组成】C 79.19% H 10.76% O 10.05% |
合成路线1
该中间体在本合成路线中的序号：(XI)1) The condensation of (S)-L-malic acid (I) and cyclohexanone (II) by means of boron trifluoride etherate gives the cyclic lactone (III), which is reduced by borane and treated with tert-butyldiphenylchlorosilane yielding the silyl ether (IV). The transesterification of (IV) with sodium methoxide in methanol affords 4-(tert-butyldiphenylsilyloxy)-2(S)-hydroxybutyric acid methyl ester (V), which is reduced with borane as before and esterified with naphthalenesufonyl chloride to give the sulfonate (VI). The treatment of (VI) with sodium methoxide affords the epoxide (VII), which is alkylated with decyllithium yielding 1-(tert-butyldiphenylsilyloxy)tetradecan-3(R)-ol (VIII). The benzylation of (VIII) with benzyl trichloroacetimidate (BTA) gives the benzyl ether (IX), which is desilylated with HF in acetonitrile yielding 3(R)-benzyloxytetradecan-1-ol (X). The oxidation of (X) with PDC gives 3(R)-benzyloxytetradecanal (XI), which is condensed with 1-(trimethylsilyl)-2(E)-nonene (XII) by means of a titanium dichloride complex yielding the diastereoisomeric mixture of alcohols (3R,4S,6R)- (XIII) and (3S,4S,6R)- (XIV), which are separated by column chromatography. The silylation of both isomers with tert-butyldimethylsilyl chloride affords both isomers (XV) and (XVI), which are ozonolyzed with O3 and oxidized with NaClO2 to yield the corresponding acids (XVII) and (XVIII). The desilylation of (XVII) and (XVIII) with HF in acetonitrile gives the hydroxy acids (XIX) and (XX), which are cyclized by means of benzenesulfonyl chloride and pyridine to the isomeric oxetanones (XXI) and (XXII). The unwanted isomer (XXII) can be isomerized by means of lithium diisopropylamide in THF to the correct isomer (XXI). The debenzylation of (XXI) by hydrogenation with H2 over Pd/C affords (3S,4S)-3-hexyl-4-[2(R)-hydroxytridecyl]oxetan-2-one (XXIII), which is finally condensed with N-formyl-L-leucine (XXIV) by means of diethyl azodicarboxylate (DEAD) in THF.
| 【1】 Barbier, P.; Schneider, F.; Widmer, U. (F. Hoffmann-La Roche AG); Process for the preparation of oxetanones. EP 0189577 . |
| 【2】 Prous, J.; Mealy, N.; Castaner, J.; Orlistat. Drugs Fut 1994, 19, 11, 1003. |
| 【3】 Tehim, A.; Chen, P.; Hanessian, S.; Total synthesis of (-)-tetrahydrolipstatin. J Org Chem 1993, 58, 27, 7768-81. |
| 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) | 11058 | (S)-(+)-Hydroxysuccinic acid; (S)-(+)-Malic acid; (S)-(+)-2-Hydroxybutanedioic acid; L-(-)-Apple acid | 97-67-6 | C4H6O5 | 详情 | 详情 |
| (II) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
| (III) | 11060 | 2-[(2S)-3-Oxo-1,4-dioxaspiro[4.5]dec-2-yl]acetic acid | C10H14O5 | 详情 | 详情 | |
| (IV) | 11061 | (3S)-3-(2-[[tert-Butyl(diphenyl)silyl]oxy]ethyl)-1,4-dioxaspiro[4.5]decan-2-one | C26H34O4Si | 详情 | 详情 | |
| (V) | 11062 | methyl (2S)-4-[[tert-butyl(diphenyl)silyl]oxy]-2-hydroxybutanoate | C21H28O4Si | 详情 | 详情 | |
| (VI) | 11063 | (1R)-3-[[tert-butyl(diphenyl)silyl]oxy]-1-hydroxypropyl 2-naphthalenesulfonate | C29H32O5SSi | 详情 | 详情 | |
| (VII) | 11064 | tert-Butyl(diphenyl)silyl 2-[(2S)oxiranyl]ethyl ether; tert-Butyl[2-[(2S)oxiranyl]ethoxy]diphenylsilane | C20H26O2Si | 详情 | 详情 | |
| (VIII) | 11065 | (3R)-1-[[tert-Butyl(diphenyl)silyl]oxy]-3-tetradecanol | C30H48O2Si | 详情 | 详情 | |
| (IX) | 11066 | Benzyl (1R)-1-(2-[[tert-butyl(diphenyl)silyl]oxy]ethyl)dodecyl ether; [[(3R)-3-(Benzyloxy)tetradecyl]oxy](tert-butyl)diphenylsilane | C37H54O2Si | 详情 | 详情 | |
| (X) | 11067 | (3R)-3-(Benzyloxy)-1-tetradecanol | C21H36O2 | 详情 | 详情 | |
| (XI) | 11068 | (3R)-3-(Benzyloxy)tetradecanal | C21H34O2 | 详情 | 详情 | |
| (XII) | 11069 | Trimethyl[(E)-2-nonenyl]silane | C12H26Si | 详情 | 详情 | |
| (XIII) | 11070 | (3R,4S,6R)-6-(Benzyloxy)-3-hexyl-1-heptadecen-4-ol | C30H52O2 | 详情 | 详情 | |
| (XIV) | 11071 | (3S,4S,6R)-6-(Benzyloxy)-3-hexyl-1-heptadecen-4-ol | C30H52O2 | 详情 | 详情 | |
| (XV) | 11072 | ([(1S,2R)-1-[(2R)-2-(Benzyloxy)tridecyl]-2-hexyl-3-butenyl]oxy)(tert-butyl)dimethylsilane; benzyl (1R,3S,4R)-3-[[tert-Butyl(dimethyl)silyl]oxy]-4-hexyl-1-undecyl-5-hexenyl ether | C36H66O2Si | 详情 | 详情 | |
| (XVI) | 11073 | ([(1S,2S)-1-[(2R)-2-(Benzyloxy)tridecyl]-2-hexyl-3-butenyl]oxy)(tert-butyl)dimethylsilane; benzyl (1R,3S,4S)-3-[[tert-Butyl(dimethyl)silyl]oxy]-4-hexyl-1-undecyl-5-hexenyl ether | C36H66O2Si | 详情 | 详情 | |
| (XVII) | 11074 | (2S,3S,5R)-5-(Benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-hexylhexadecanoic acid | C35H64O4Si | 详情 | 详情 | |
| (XVIII) | 11075 | (2R,3S,5R)-5-(Benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-hexylhexadecanoic acid | C35H64O4Si | 详情 | 详情 | |
| (XIX) | 11076 | (2S,3S,5R)-5-(Benzyloxy)-2-hexyl-3-hydroxyhexadecanoic acid | C29H50O4 | 详情 | 详情 | |
| (XX) | 11077 | (2R,3S,5R)-5-(Benzyloxy)-2-hexyl-3-hydroxyhexadecanoic acid | C29H50O4 | 详情 | 详情 | |
| (XXI) | 11078 | (3S,4S)-4-[(2R)-2-(Benzyloxy)tridecyl]-3-hexyl-2-oxetanone | C29H48O3 | 详情 | 详情 | |
| (XXII) | 11079 | (3R,4S)-4-[(2R)-2-(Benzyloxy)tridecyl]-3-hexyl-2-oxetanone | C29H48O3 | 详情 | 详情 | |
| (XXIII) | 11080 | (3S,4S)-3-Hexyl-4-[(2R)-2-hydroxytridecyl]-2-oxetanone | C22H42O3 | 详情 | 详情 | |
| (XXIV) | 11081 | N-Formyl-L-leucine; (2S)-2-(Formylamino)-4-methylpentanoic acid | 6113-61-7 | C7H13NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)The chiral aldehyde (XI) can also be obtained as follows: The reaction of dodecanal (XXV) with allylmagnesium bromide (XXVI) in THF gives 1-pentadecen-4-ol (XXVII) as a racemic mixture, which is esterified with 2(R)-acetoxy-2-phenylacetic acid (XXVIII) by means of dicyclohexylcarbodiimide (DCC) and dimethylaminopyridine (DMAP) to yield the diastereoisomeric mixture of esters (XXIX) and (XXX), which are separated by flash chromatography. The hydrolysis of (XXIX) and (XXX) with KOH in methanol affords the alcohols (XXXI) and (XXXII). The unwanted isomer (XXXII) can be isomerized to (XXXI) through the formation of the 4-nitrobenzoyl ester and hydrolysis with K2CO3. The benzylation of (XXXI) with benzyl bromide and KH in THF gives the benzyl ether (XXXIII), which is finally ozonolyzed to the desired aldehyde (XI) with O3 in methanol-dichloromethane.
| 【1】 Prous, J.; Mealy, N.; Castaner, J.; Orlistat. Drugs Fut 1994, 19, 11, 1003. |
| 【2】 Tehim, A.; Chen, P.; Hanessian, S.; Total synthesis of (-)-tetrahydrolipstatin. J Org Chem 1993, 58, 27, 7768-81. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 11068 | (3R)-3-(Benzyloxy)tetradecanal | C21H34O2 | 详情 | 详情 | |
| (XXV) | 11082 | Lauraldehyde; Dodecanal | 112-54-9 | C12H24O | 详情 | 详情 |
| (XXVI) | 10386 | Allyl(bromo)magnesium | 1730-25-2 | C3H5BrMg | 详情 | 详情 |
| (XXVII) | 11084 | 1-Pentadecen-4-ol | C15H30O | 详情 | 详情 | |
| (XXVIII) | 11085 | (2R)-3-Methoxy-3-oxo-2-phenylpropionic acid | C10H10O4 | 详情 | 详情 | |
| (XXIX) | 11086 | 1-methyl 3-[(1R)-1-undecyl-3-butenyl] (2S)-2-phenylpropanedioate | C25H38O4 | 详情 | 详情 | |
| (XXX) | 11087 | 1-methyl 3-[(1S)-1-undecyl-3-butenyl] (2S)-2-phenylpropanedioate | C25H38O4 | 详情 | 详情 | |
| (XXXI) | 11088 | (4R)-1-Pentadecen-4-ol | C15H30O | 详情 | 详情 | |
| (XXXII) | 11089 | (4S)-1-Pentadecen-4-ol | C15H30O | 详情 | 详情 | |
| (XXXIII) | 11090 | (4R)-4-(Benzyloxy)-1-pentadecene; Benzyl (1R)-1-undecyl-3-butenyl ether | C22H36O | 详情 | 详情 |