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WO2013185435A1 - 光学活性轴手性α-联烯醇、合成方法和用途 - Google Patents

光学活性轴手性α-联烯醇、合成方法和用途 Download PDF

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WO2013185435A1
WO2013185435A1 PCT/CN2012/084896 CN2012084896W WO2013185435A1 WO 2013185435 A1 WO2013185435 A1 WO 2013185435A1 CN 2012084896 W CN2012084896 W CN 2012084896W WO 2013185435 A1 WO2013185435 A1 WO 2013185435A1
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chiral
alcohol
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zinc
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麻生明
叶俊涛
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Shanghai Institute of Organic Chemistry of CAS
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/17—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrogenation of carbon-to-carbon double or triple bonds
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/02—Acyclic alcohols with carbon-to-carbon double bonds
    • C07C33/025—Acyclic alcohols with carbon-to-carbon double bonds with only one double bond
    • C07C33/03—Acyclic alcohols with carbon-to-carbon double bonds with only one double bond in beta-position, e.g. allyl alcohol, methallyl alcohol
    • C—CHEMISTRY; METALLURGY
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    • C07C33/05—Alcohols containing rings other than six-membered aromatic rings
    • C07C33/12—Alcohols containing rings other than six-membered aromatic rings containing five-membered rings
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    • C07C33/05—Alcohols containing rings other than six-membered aromatic rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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    • C07D307/28—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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    • C07C2601/14—The ring being saturated

Definitions

  • the invention relates to a method and a use of an optically active axial chiral ⁇ -alkenol, a simple separation and high-efficiency synthesis, in particular to a block promoted by zinc dibromide, protected by a tert-butyldiylsilyl group.
  • Dienol is a very important organic synthesis intermediate and is widely used in 2,5-di II furan (R. Geiiii, S. Geiiii, M. Albrand, BtM Soa Chim. Fr. 1972, 1946; L,- I, Oisson, A. C ⁇ aesson, Synthesis 1979, ?43; SS Nikaiii, K..-11. Chu, K. K, Wang, J, Org. Chem. 1986, 5/, 745; J. A, Mashall X.-J, Wang, J, Org. Chem, 1990, 55, 2995; J. A, ashali, X.-J. Wang, J. Org, Chem, !991, M, 4913; I, A.
  • the invention overcomes the shortcomings of the synthetic bismuth in the prior art, the low yield, the need to make the dangerous chemicals, the inconvenience of operation and the like, and provides the promotion of the zinc bismuth hydride, using the tert-butyl group.
  • the method has the advantages of short synthetic route, high yield, convenient operation, and large scale.
  • the object of the present invention is to provide a species of olefinic acid, a simple and efficient synthesis method and use thereof.
  • the axial chiral enol provided by the present invention has the following formula:
  • ⁇ C ss of a burnt group, such as a linear alkyl group, a cyclic alkyl group or a * group, etc.
  • the axial chirality of the hydrazine is ? or S type, and the carbon atom to which the hydroxy group is bonded may be: chiral or S type; when the hydrocarbon group of Q to Cw is a fatty group, the present invention provides a method for synthesizing an axial chiral ⁇ -alkenol, such as a reaction formula 2
  • chiral chiral alcohol product can be obtained by removing the protecting group from ammonium; wherein the male-protected propargyl alcohol-aldehyde: chiral secondary amine: zinc salt: four BET base gas molar ratio is! ⁇ 3: 1: 0.5 - 1.5; 1 ⁇
  • the silicon base is . ⁇ methyl silicon, ⁇ , t-butyl bis-based silicon and tert-butyl diphenyl
  • the chiral secondary amine is or its enantiomer, or its enantiomer
  • the zinc salt is zinc sulfide, barium bromide, zinc iodide, barium acetate and barium Zinc mesylate, preferably zinc desertification
  • the valve is n-butyl sputum bismuth is tetra-n-butyl sputum bismuth: hydrazine fluorinated ammonium fluoride
  • ⁇ solvent is benzene, toluene, gas benzene, p-xylene, O-xylene, m 2 ⁇ 4, preferably toluene.
  • S-synthesis has both window-axis chirality and central chirality.
  • W-axis chirality All four isomers of tt-linked secondary alcohol.
  • the highly optically active chiral ⁇ -cainol synthesized by the method of the invention can conveniently synthesize 2,5 gas furan compounds with chiral chirality and complete chirality, and can also synthesize chiral complete Dienamine and allyl malonate 3 ⁇ 4 compounds
  • the method of the invention has the advantages of short synthetic route, simple operation, easy availability of raw materials, convenient separation and purification, wide universality of substrate, total yield of 3 ⁇ 4, corresponding selectivity and '; enantioselective point.
  • the present invention overcomes the existing In the technology, the synthetic enthalpy is long, the yield is low, the reaction conditions are harsh, the demand is inconvenient, and the operation is inconvenient.
  • ZnBr 2 (169.3 mg s 0.75 mmol) was added to the dry reaction tube, dried by a heat dryer, and then ⁇ , € diphenyl brain alcohol ( -3 ⁇ 4» (258.7 mg) was added in sequence. , 1.0 nm l. 98%), tert-butyl ⁇ '. methylsilyl-protected alkynyl alcohol la (188.2 mg, ⁇ .. i mmol), dry A*(2 niL), new steamed ring Hexylformaldehyde 2a (168,6 mg, 1.5 tm3 ⁇ 4o) and dry toluene ( ⁇ tnL).
  • Example 5 The operation reference is implemented. ⁇ , (169.4 mg, 0,75 mmoS), ⁇ , ⁇ -diphenyl plycan (5 3a (258.2 mg, i.Ommol), tert-butyldimethylsilyl protected propargyl la (188 , 2 rag, ⁇ . ⁇ nimol), freshly distilled cyclopentyl formaldehyde 2cl (147.3 mg, l.Smrao), dry toluene (3 mL » TBAF-3H 2 0 (316.4 mg ; . ⁇ ! and tetra-furan ( 3 m:L)
  • Column analysis (petroleum ether / ethyl acetate - 10/1) to give a liquid-axis chiral ⁇ -alkenol (i?)-4ad (81.9 mg, 59%): 98% ee (EPLC measurement conditions) : Chmlcel AS-ll column, isobutol - 98/2
  • Embodiment 1 (3 9,2 mg 0.75 rnino), ⁇ , -.:
  • CDCK CDCK ⁇ ::: 7.35-7.14 (m, 5 H, Ar-i i ⁇ , 6.35-6.27 (m, 111, CB-C-CB).4.11 (q, J- 5.8
  • dialdehyde dicarboxylic acid 2 Ethyl vinegar (131.1 mg ; 0.75 mmol) was dissolved in 1 kg of 3 ⁇ 4 furan, and added to the reaction system under a pressure of 0 Torr over 20 minutes using a syringe. After the addition, it is stirred to 3 ⁇ 4 temperature and stirred for 12 hours. The reaction is finished.
  • a dibasic gas radical was added to the dry reaction tube in turn (6.2 mg, 0.05 mmol), and dried triethylamine (7 mg, 0.75 miiiol), chiral chiral ⁇ - Dienol (76.2 mg, 0.5 mmol, 99% ee) and dry DCM (3 ml), then the methylsulfonate gas (47 l, d.475, 0,6 i 1) Add dropwise to the reaction system within 1 minute. After the addition, the key is continued at O TF! The hour after the end of the reaction ⁇ M into lO niL water and 10 mL of two gas, alkane, separated organic, water!

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Abstract

本发明涉及一种光学活性轴手性α-联烯醇、合成方法和用途，通过二溴化锌促进剂，通过叔丁基二甲基硅基保护的炔丙醇、醛和手性α，α-二苯基脯氨醇制备高光学活性手性α-联烯醇的方法。该轴手性α-联烯醇具有如结构式（I）。本发明方法具有合成路线短、操作简单、原料易得、分离纯化方便、底物普适性广、总产率较高、对应选择性以及非对映选择性高等优点。利用本发明方法合成的高光学活性的轴手性α-联烯醇，可以很方便的合成具有中心手性且手性完全保持的2,5-二氢呋喃类化合物，同时还可以合成平性完全保持的轴手性联烯胺和联烯丙二酸酯类化合物。

Description

光学活性轴手性《联烯醇、 合成方法和用途 技术领域
本发明渉及一种萵光学活性轴手性 α-联烯醇、 简離高效合成的方法和用途， 具体涉及一种二溴化锌促进的，通过叔丁基二 φ基硅基保护的块丙醇、鏺和手性 α,α-二苯基脯¾醇制备高光 活性轴手性 α联稀醇的方法。 背：景技术
联烯醇是 类非常重耍的有机合成中间体， 广泛应用于 2,5-二 II呋喃 （R. Geiiii, S. Geiiii, M. Albrand, BtM Soa Chim. Fr. 1972, 1946； L,-I, Oisson, A. C^aesson, Synthesis 1979, ?43; S. S. Nikaiii, K..-11. Chu, K. K, Wang, J, Org. Chem. 1986, 5/, 745; J. A, Mashall X.-J, Wang, J, Org. Chem, 1990, 55, 2995; J. A, ashali, X.-J. Wang, J. Org, Chem, !991, M, 4913; I, A. Mashall, . G Pinaey, J. O ^. Chem, 1993, 58, 7180; J. A. Mashall, . H. Yu, j. F. Perkins, J. Ofg. Chem. 1995, 60, 5550; J. A. Mashall C A, Sehoii, J. Org, Chem, 1995, 6(1 5966) v 2(5/i 呋喃銅 (E. Yo«eda. T. aneko, S,-W Zhang, . Onitsuka, S. Takahaslii, ()i"g. Leii. 2000, 2, 441 ; X. Ctieng, X. Jiaiig, Y. Yu? S. M J. Org, Chem, 2008, 73, 8960)、 乙烯基氣杂环丙烷（R, W, Friesen, . Bloum, J. Org. Chem. 1 93, 58, 1653; S.-K, K g, T, Yaniaguchi, S.~j. Pyutt, Y.- Lee, T.-Q Bail, Tetrahedron Lett. 1998， 5.9, 2 !27; S. Ma, S, Zhao, J. Am. Chem. Soc. 1999, 121, 7943)、 p 素 ~β,γ-烯醛或者熾醒 （1 C, Fu, G. Own, G Cbai, S. Ma, Adv. Synth. Cafal 2008, 350, 1376; C. Fu; .1. Li, S. Ma, Ckem' Commun, 2005, 411 ; J.-Q. He5 D. Sliibaia, C. O no, S. Okamoio, Tbimhe inm LetL 20D8, 49, 6724) x U-共轭二烯 （S, Ma, G ¾¾ng, Jeirahe ron LetL 2002, 43 5723; Ύ. Deng, X. Jin, S. Ma, J, Org. Chem. 2007, 72, 590 J )·和條内醇 (Z. Lt S. Ma, Αάν. Synth. Cai l.
Mm, 349, 1225)等有机化合物的合成 同时， 联烯醇还是合成一系列 能 | 化
Figure imgf000004_0001
Saiil erg, S. B. Ross, L FagervalL A.-L. Ask, A. Qiiesson' J.
Med, Ghent 1983; 26, 103; Y. Imada, M. ishicla, K. iiisuwa, S.-I. Murahashi, T, aota, Org. Led 2ί¾)5, 7, 5837; B. M. Trost, D. R. Fandriek, D, C. Dm' h, J Am. Chem. So 2輔 S, 127, ! 4186)、 联烯丙二酸難（ M. Ogasawara, M Ikeda, X Nagaoo, T. ϊ-tayas i, J. .Am, Chem. Soc. 2001, 123, 2089; Y. Irnada, . Ueno, K. Kuts wa, S.-L Murahas i Chem. Lett 2ΘΘ2, 340； S. Ma， N. Jiao, S. Zhao, H. Eox J. Org. Ckem" 21ΪΘ2, 6"7, 2837;)、 联烯硫醇 (N, Morita, raus , Angevu Chem., L Ed 45, 1897)和联烯難或酮 (S, Ma, S. Yu, S. Yin, J. Org- Chem. 2Θ03, 68, 8996; b) S. Ma, I Liu, S. Li, B, Chen, J, Cheng, 1. Kuang, Y Liu, B. Wan, Y. Waog, J. Ye? Q, W. Yuan, S. Yu5 Synth. Caial, 2011 , 553,〗005) 化合物的遠耍前体 在 系列 o 联烯醇中， 轴手性的 α联烯醇尤为重要， 困为其轴手性能够通过手性转移的策略 转化为产物的中心手性， 从而为合成光学活性的化合物提烘了一种有效的途径 因此， 发展 ······种简单高效合成高光学活性轴手性 α-联錄醇的方法意义十分重大。. 根据文献报道， 合成轴手性 联烯辭霧要很繁琐的歩骤， 反应条件比较苛剡， 总 产率低， 且大部分方法需耍使用危险的化学品如正丁基锂 (《BuU)或乙基溴化镂 (!¾MgBr)以及艇化锂铝 (LiAi ) 操作不方便，不利于大规模合成 (L.-L Oisson, A. Claesson, Acta Chem, Scimd 1977, B31, 614; A, Claesso , L.-L Oisson, J, Am. Chem.Soc, 1979, 101, 7302; R. A. Smidi, R. L. Wbite, A. Kraivtz, J. Med Chem, !988, .i/， 1558; I. Stichler-Boiiaparte, H, Krulh, R. Lisnkwitz, C, Tsciiiersk , Li big Arm. 1996, 1375).
本发明克服了现^技术中合成歩骤长， 产率低， 需要使 ^危险化学品、 操作 不方便等缺陷，提供了 ······种二渙化锌促进的，利用叔丁基二甲基硅基保护的炔丙 醇、 醛和手性 苯基脯氣醇简单高效制备 ^光学活性轴手性 《 -联烯醇的方 法。 该方法与传统方法相比， 具^合成路线短、 产率高、 操作方便，， 适用大规模
发明内容
本发明的目的在于提供 ·····种 : 联烯醇,,簡单高效合成方法 和用途
本发明提供的一种轴手性 联烯醇具有如下的结抅式:
Figure imgf000005_0001
其中， === 〜 Css)的烧基，如直链烷基、环状烷基或 *基等； R2 === H或 〜 C ½¾基等， 如直链烷基、 环状焼基或苯基： 联姆的轴手性为 ?或 S型， 与羟 基相连 ί的碳原子可以是: 手性、 或 S型； 所述的 Q〜Cw的烃基为脂肪基时, 本发明提供的一种轴手性 α -联烯醇的合成方法， 反应式如' 2
Figure imgf000006_0001
3
, R1 、 R2、 联烯的轴手性以及与 g基相连的碳
在 i 0C 3(rc下和有机溶剂中， 以锌盐为促进剂， 以 3或:其对映体为手性 块丙醇和醛反应 5-15小时，
Figure imgf000006_0002
铵脫去 荡保护基即可得到轴手性 联條醇产物；其中，所述雄基保护的炔丙醇- 醛： 手性仲胺： 锌盐： 四 BET基氣 摩尔比为 ！〜 3: 1： 0.5 - 1.5； 1 ·
5; 所述的硅基为 .≡甲基硅基、 ί基、 叔丁基二 ¥基硅基和叔丁基二苯
'曾 - ：基； 所述的手性仲胺为 或其对映体, 优逸 或其对映体； 所述的锌盐为氣化锌、 溴化铧、 碘化锌、 醋酸铮和 観甲磺 酸锌， 优选漠化锌；所述的閥正丁基鼠化锬为四正丁基鼠化锬 Ξ:水合狻 基氟化铵 ί 溶剂为苯、 甲苯、 氣苯、对二甲苯、 邻二 甲苯、 间二 ¾ 优选甲苯 进.■ 在千燥的反应镞中加入粹盐 手性仲胺 硅基保护的炔丙醇、 醛和千燥的宵 机溶剂， 在 100-BO 'C下搅拌 5- 2«小时， 反应结束后， 过短硅胶柱得到粗产物， 降其溶于^机溶剂， o ' 下加入四正丁基氣化铵， 下羅〖45小时 < 反应结束
Figure imgf000006_0003
柱愿析分离方法纯化得到 -联烯醇 < ：计一种高效合成轴手性 联烯醇 方法， 以二漠化锌为促迸剂， 从 叔丁基.' 保护的炔丙醇、 I 和手性 α,ο 二苯基繊氣醇出发， 经过两歩操
Figure imgf000007_0001
ct-联烯醇 利用该方法， '以簡单高效地合成 有不同取代基的轴手性 α-联烯伯醇及仲醇; 型的 -二苯 脯 醇， 可 以得到联; ¾ 手性为 构型的产物， ?构 ¾的 二苯雄脑 酵 备联烯的轴手性为 S构型的产物：
S地合成同时具窗轴手性和中心手性 W轴手性 tt联烯仲醇的全部四个异构体。
利用本发明方法合成的高光学活性的轴手性 α -联婦醇，可以很方便的合成具 窗中心手性且手性完全保持的 2，5 氣呋喃类化合物， 同时还可以合成手性完全 联烯胺和联烯丙二酸酯¾化合物
本发明方法具^合成路线短、 操作简 、 原料易得、 分离纯化方便、 底物普 适性广.、 总产率较 ¾、对应选择性以及' ；对映选择 点 本发明克服了现 有技术中合成歩骤长， 产率低， 反应条件比较苛刻、 需要 品、 操作 不方便等缺陷.
具体实施方式
以下实施例有助于斑解本发明， 但不限于本发明的 :内容
实施例 1
1》ΖπΒι·2 {0.75 equiv) H
f tonllunecnneci, 11301 t ΤM'· 1OΠ h —.
y
1a 0TBS 2) TBAF3H2O (1.0 equiv} H CH2OH equiv) (1 ,5 THF, 0 't→ rt, 1.5 h {h)-4aa
Figure imgf000007_0002
68%产率， 99% ee 其中， ^ ¾示 量， mol表示摩尔， TBS《¾>r b«iySd mei:iiy!sityS)鞭示叔 某二! tM-> Cy(cydohi;xyl):表 . :ΐίϊ、ϊϋ Ι;， TBAF(tetabufyia!njBOoiu!n fh!o de)表:示 '基滅化铰， to K；表示甲苯， THF表示 ¾無呋喃， rt表示室温 ee表示
：过量 < 表示：.
在惰性气体的保护下， 向千燥的反应管中加入 ZnBr2 (169.3 mgs 0.75 mmol), 热烘枪烘干， 然后依次加入 α,€ 二苯基脑数醇( -¾» (258.7 mg, 1.0 nm l. 98%), 叔丁基 ····'.甲基硅基保护的炔闪醇 la ( 188.2 mg,〗 . i mmol)， 干燥的甲 *(2 niL), 新 蒸环己基甲醛 2a (168,6 mg, 1.5 tm¾o )和干燥的甲苯（ί tnL)。然后在反应管上插入 回流冷凝管， 放置到事先已加热到 DO sC i¾油浴中回流搅拌 10小时 冷至室温 后， 短的 胶柱过滤，20 mh乙聽洗漆，浓缩后过一根短柱 謎 /乙醚 - 50/1 } 得到叔丁基二甲基硅基保护的联烯醇粗产物 将该粗产物直接溶于四無呋喃 (3 ml), 0 °C 下加入 T8AF'3¾0 (316.0 mg, LO mmol), 然升 S靈温搅拌 1 ,5 小 时后， 向体系加入 10 mL 乙隨和 iO fflL水，分出宵机歴，水愿乙醚離取 ( 10 nil, 3), 合并 : 机层， 无水硫酸钠干燥， 浓縮， 柱层析 (^油鏠/乙酸乙顯 - ! 0/ ! ) 液体轴手性 o联烯醇 (/?)-4aa (104.0 rag, 68%): 99% ee (IIPLC 测定条件： CWm cd AS-H柱 正己烷 /异两醇 98/2,, 0.6 raL min, λ - 214 ιιη% /R (大峰） 16.0 miti. (小峰） :::: 19.2 min); [aj22 D ===: - 99,8 f === L01, CeCl3); 3H NMR {300 MHz, CD(¾) δ === 5.41-5.24 fm, .2 H, a ==C===CH), 4J 0 (d' J 2.7 Hz, 2 II OC¾)， 2.08-.L88 (m, 2 H， OH and CH from Cy), 1.82- 1.57 (m? 5 H, protons from Cy), 1.37-0.97 (m, 5 a protons from Cy); BC NMR (75 ME?., C:D(¾) δ === 201 .9， 99.7, 92.5, 6(l8f 37.(1 33,(1 32,9' 26,0， 25,9; MS (EI) m/z (%); 152 (M 0.70), 55 (100); IE (neat); v - 3326, 2923, 28505 I 6.K 1448, 1302, 1259, 1214, 1062, 1008 em ; HRMS [M";] 计算值: 152.120 L 实测值： 152.1203.
实施例 2 1ia 0TBS 2a M ¾HPh
{1.1 equiv) (1.5 equiv) (S)-3a
Figure imgf000009_0001
10 mmol
操作参考实施例 L ZnBr; (i.6 12 g 7.5 mmol), αα -二苯維脑 醇 (S> (2.585? g? lOmmoi), 叔丁基二『 基硅基保护的炔两醇 la (i.S738 g, Π nmot), 新 蒸环己基甲醛 2a (1.6831 g, 15 mmol),千燥的甲苯 (30 ml), T3 AF'3 0 (3.1563 gs lOmnw).和四 呋喃 (30mL) 柱层析 (· 油凝 /乙酸乙酷 - 15/1 (800 h)→ 10:1) 得液体轴手性 联烯醉 ( ?}-4aa (1.0624, 70%): 99% ee (HPLC 测定条件： Chira!cd AS41柱， 正己烷 /昇丙醇 8/2, 0.6 mL/mi¾ λ === 214 nm， (大峰） - 11.9 mm, /R (小峰）；：：： 12. min); [af2 :::: - .100.3 (c :: L005 CH(¾); !H刚 R (300 MHz, CDC¾) S - 5.42-5.26 (m 2 H, CHOCH), 4,11 (s, 2 H, OCH> 2.07- i. 4 (m, 1 H, CH from Cy), 1.82-1.49 (n 6 H, OH and protons from Cy), 1.36-1.00 (nx 5 H, proion.s fron Cy}.
实施例 3
Figure imgf000009_0002
操作参考实施例 i, ZnBr2 (506.8 mg, 2.25 ronol), α,α二苯基驢鼠醇 (5) 3a (775.4 rag, 3.0 mmol), 叔丁基二甲基硅基保护的炔丙醇 ia (562.4 mg, 3.3 mraol). 新熬异戊醛 2b (388.1 mg, 4.5 m \), 千燥的 ¥苯 (9 mL), TBAF-3H20 (947,3 mg,, 3.0 mm )和西 ϋ呋喃 (5 mL)<, 柱层析 (ΐϊ油醚 /乙酸乙酷 15/1)得液体轴手性 α- 联烯醇 (/i)-¾b (Π12 mg, 45%): 98% ee (HPLC 測定条件： Chiralce) AD-ί ϊ 柱， 正 己烧 /异丙醇 - 200/ L 1.0 mL/min5 λ -214 m\ ½(大峰） - 20.4 min, iR (小峰）：:: 25,3 miii); [ay-n - - 80.3 (c - L01, C!:3(:¾); Ή NM (300 MHz, CDC ) δ 5.35-5.18 (mf 2 CB-C-CB), 4.11 fs32 H5 OC¾), 2,03-1.79 (m, 3 H, Oil and a¾)， '76-1,58 (ητ I H, CE\ 0,92 (d, J :: 6.6 Hz, 6 H, two (¾;); f NMR (75 MHz' CiX ) δ - 203.6, 92,2, 0.9? 60 38.1, 28,3, 22.1; MS (E ) m/z (%)： 126 (Μ 0.2 i), 55 (100); IR {mat}: v :: 3326, 2955, 2928, 2870, 〖963, 〖466， 〖384, 1367, 1262, 1056, 1013 cm'^HRMS [ ' 计獰值： 126,1045, 实测值：〗2(U044.
实讓 4
Figure imgf000010_0001
操作参考实施例 1 ZnBfj (169.7 rag, 0.75 mmol), 二苯基脑弒醇 (5>3a
(258.8 rag, LOnimol), 叔丁基二甲基硅基保护的炔丙醇 la (188,2 mg, LI rmnol)., 新蒸正,己醛； k ( 150.4 tng,， 1 ,5 mmol), :: 燥的甲苯 (3 mL)， TBAF'3i 0 (3 i 6.2 mg,
1.0 mind)和四 呋喃 (3 mL), 柱展析 ( 油酵 /乙酸乙酯 - 10/1)得液体轴手性 α- 联烯醇 (83,0 rag, 59%}: 98% ee (HPLC 测定条件： Chiralcel AS-H 柱， £ 己烷 /异丙醇 ：::: 8/2, 0.5 mL/min, λ ---- 214 m\x (：大峰） :::： 12.2 mm, (小峰） ===】3,1 min); [aj2i D - - 78.4 (c - 1.03, CH(¾)； 5H NMR (300 MHz, CD(¾) δ 5.36-5.23 (αχ
2 Η, a: C ： Ή), 4.Π (s, 2 il OCH2), 2.09- L90 (m, 3 Oil ami CH2)、 1.49-1.23
(m, 6 H, three C¾), 0-8 (t, J - 6.5 Hz, 3 il C ); i C NMR (75 MHz, CD(¾) δ
203.0, 93,7, 91.6， 60.7, 31.2, 28,7, 28.5, 22.4, 14.0; MS (El) m/z (¾)： 140 ( \ 0.15),
55 (100); 11 (neat): v - 3345, 2956, 2928, 2857, ! ： 1464, 1417, 1379, !206, Π37,
1.111, 1.057， 1011 cm ; ORMS [M+j 计算值: 1401201, 实测值： ϊ 0. 202,
实施例 5
Figure imgf000011_0001
操作参考实施倒 。 ΖηΆΐ, (169.4 mg, 0,75 mmoS) , α，α -二苯基鋪氣醇 (5 3a (258.2 mg, i.Ommol), 叔丁基二甲基硅基保护的炔丙醇 la (188,2 rag, ί.Ι nimol), 新蒸环戊基甲醛 2cl(147.3mg, l.Smrao), 干燥的甲苯 (3mL » TBAF-3H20 (316.4 mg; .Οππηο!)和四 it呋喃 (3 m:L) 柱 析 (石油醚 /乙酸乙酯 - 10/1)得液体轴手性 α-联烯醇 (i?)- 4ad (81.9 mg, 59%): 98% ee (EPLC测定条件： Chmlcel AS-ll 柱、 异 醇 - 98/2, 0.6 m:L/ iin, λ - 214 ran, (大峰） - 13.8 mm, (小峰) - 153 mm); [α] 0 ο = - 97.2 (c = 1.02, CHC1}); lH NMR (300 MHz, CDC ) δ = 5.39-5.27 (,ra52 E, CHOCIi), 4.10 (d, J - 2.7 ilz, 2 H, OCH2)s 2.56-2.39 (m, 1 E, CH from cyclope yl), 2,07 f s, 1 il OH), 1,86-1,72 (ni.2 , CH2), 1.72-1,47 (i 4 two CH2), 1,46-1.28 (n\ 2 H, CH2); K'C NMR (75 MHz, CDCS3) δ 201.8, 98,6, 92.4, 60,7, 39.0, 32,7, 24.8; MS (El) m/z (4): 138 (f , 0.28), ?9 (100); 1R (neat): v - 3321, 2951, 2867, Ϊ 61, Ϊ451, 1420, 1207, 1009 cm]; Ϊ.固 S [ f] 计算 i: 138.1045, 实 濺值： 138.1044.
实施例 6
Figure imgf000011_0002
操作参考实施例 i。 ZnBr2 (169.5 mg? 0.75 mmol), α 二苯基薦氣醇 (258.3 rag, .Ommol), 叔丁基二甲基硅基保护的炔丙醇 la (188.2 mg，〗.1 ramoi). 新蒸正辛薩 2e (192.5 mg, ί.5 mrnol), 千燥的甲苯 (3 mL), ΤΒΑΡ-3ί¾0 (315,7 mg, LO tmm>〗)和四氛呋喃 (3 mL), 柱展析〖：石油薩 /乙酸乙觀 ：:: 15/0得液体轴手性 联烯醇 (i? ae (109.8 mg, 65%); 97% ee (HPLC 测定条件： Chiraicei AS-H 柱， ΪΕ 己貌 /异丙醇 ：:： 8/2, 0.6 mL/min, λ === 214 mnt ¼大峰》 1L】 rrio, (小峰） 12.2 roin); [ ]20ο - - 66.1 (c - 1,03、 CHC½); 5H NMR (300 MHz, CIX¾) δ - 5,37-5,22 (m, 2 B, CHOCH), 4.11 (ds J = 1.21¾ 2 H， OC¾), 2.07-1.95 (m， 2 H, CH2), 1.91 (s, !
H, OH), 1.47-1, 7 (tn; 10 Η five C ), 0.88 (t, J - 6.5 :ί¾ 311 C¾:i; NMR (75 Mi.lz， CDC13) δ - 202.9, 93.8, L6, 60.7, 31,8, 29.08, 29.06, 29,0， 28.6, 22.6, 4,0; MS (ESI): m/z 191 ( iV); 168 (M+); IR (膽 t): v :: 3320, 2956, 2925， 2855, 1964, 1463, 3420, 1379, 1140, 1056, 1012 cm'1; H MS【!νΓ] 计'算值： ½8,i5l4， 实测值： 168.1515.
― 『—― \ 1)ZnSr2 (0.75 equiv) Ph
555 ~ Λ~ \ OTSS +P rWu^Cn2teCH > Ph
卩O ^+、、Ν, ^ -Ph to!uene, 130 XMO 、- "-" , Η
1a 2f H OH 2) Τ8ΑΡ·3Η,0 (1.0 equiv) ^^^、
(1,1 equiv) ( -5 equiv) (S}-Za THF, 0 -, rt, 2 h CH2OH
(1'0，iv) 60 ;¾98%ee 操作参;％实施例】.5 Z«B (.1 9.7 mg, 0.75 mmo!), 0^-二苯¾膽養1醇(5
(258.6 mg, LOnimol), 叔丁基二甲維硅雜保护的炔丙醇 (187,9 mg, LI rmnol)., 新蒸苯丙 ¾2ί"(202.1 π¾ Ϊ.5 minol), 千燥的甲苯 (3 !iL), ΤΒΑ ·3Η20 (315.7 nig.
L0 ramol)和四缝呋喃 (3 mL), 柱擺析 (石油醒/乙羧乙 - 15/1 (320 mL)→ 10:1) 得液体轴手性 α-联烯醇 (:T)-4af (105.1 mg, 60%}: 96% ee (HPLC 測定条件：
Chiraicei AS-H 正己烷 /异丙醇 - 100/1, 1.0 mUmin, λ - 214隱, (大峰）：::：
I.9.0 miii, /R(小峰） === 20,5 mm); [af .'D === - 38.7 (c 1.05, (:HC ); 'ϊ ϊ NMR (300 MEz, a)(¾) δ - 7.32-7.13 (n\ 5 H, Ar-H), 5.34-5.21 (1, 2 H， Ci ( 'H), 3.97 (d, J - 1.2 I Iz, 2 II OC ), 2.83-2.64 (n.i, 2 I C ), 2.45-2.24 (m, 21:1, (¾■), L?g ( , 1 II, OB); !3C NM (75 MHz, CDCK) δ - 203.2, 141.3, .28,4， 128,2, 125,8； 92.7, 92, 1560,4, 35.0, 29.9; MS (ΕΪ) m/z (%): 174 (M 0.12), 1 (100); IR (neat): v - 334.1, 3026, 2923、 2856, 1 63, 1495, 1453, 1062, 1008 C I"'; ORMS [M';] 计算值： 174.1045， 实 测值： 174.1044.
实施例 8
Figure imgf000013_0001
操作参考实施例 1。
Figure imgf000013_0002
(3 9,2 mg 0.75 rnino), α, -.:
(258,7 mg, LOtnmol), 叔丁. = i:P基硅基保护的炔丙醇 ¼ (】88,1 mg, i wi), 新蒸 2-乙基丁醛 (150.4 mg', 1.5 mmol), 干燥 (3 mL TBAF-3H20 (315.8 mg, l.On wi)和四 II呋喃 (3 mL),柱 祈 (石油酸 /乙酸乙酯 15/1)得液体轴手性 «-联烯醇 (i?)-4ag (88.7 rag, 63%): 98% ee (HPLC 测定条件： Chiralcel AD-H 柱,
200/ , 1.0 mL/niiii, λ ===: 214 ran, i (大峰）：::： Ϊ9.0 min, (小峰）
22.0 iTim); [o D - --- - 92.5 (,：;■ - --- 1.0.U CH(¾); lU NMR (300 Μίίζ, CD(¾) δ === 5.32 (q, J - 6.1 Hz, 1 H, om proton from CH^OCH ), 5.14-5,04 (nx 1 il one proton from CH CH 4.11 (d, J --- 3.6 U?., 2 H, OCi b), 2.05 (s; 1 II OE\ L 5-L80 (n\ 1 H' CM), L53- L20 (m, 4 H, two C¾), 0.90 (i,J - 7.4 Hz, 6 H, two (¾) "C NMR (75 MHz, CD(¾) 5 === 202.9, 97.3, 9Ϊ.5? 6 .ίΚ 42,7, 27.5, 27.3 S 1.54, 1 L46; MS (El) m/z (%}: 140 (M 0,15), 93 (100); 111 (neat): v - 3323, 2988, 287 Ϊ, 1963, !459 1381, 1359, 1141, 1011 crn!;HRMS [K€] 计算愤： 1 0.1201, 实測值：〗4(Ui99, ——
1a 0TBS 2h
{H equiv} (1-5equiv)
Figure imgf000014_0001
操作参考实施例〖， 第 ·····'歩反应温度为 120 C。 ZnBi'2 (169.7 ing, 0.75 mmol), α;α—二苯基脯弒醇 ( -3a (258,3 nig, 1.0 mmol), 叔丁基二 ^ 硅 S保护的炔两醇 l (188.0 mg, 1.1 mmol),新蒸苯甲醛 2h (i59.5 mg, 1.5 mmol),千燥的甲苯 (3 mL),
TBAF-3H20 (315.7 mg.3.0 mnioi).和四 呋喃 (3 ra.L)t! 柱 析 (石油醚 /乙酸乙酯 -
8/1)得液体轴平性 α眹烯醇 ( -4ah (37.0 mg, 25%): 93% ee (HPLC 測定条件：
Chiralcei AD- H 柱， iE己烷 /： 丙醇 :- 8/2, 1.0 ηύΛι λ 214 (小峰) -
20. Ϊ mm, (大峰） - 21.5 mm; {(t °D：::： -2I7.S (c 0.45， CHCK): s H NMR (300 MHz,
CDCK) δ：:: 7.35-7.14 (m, 5 H, Ar-i i}, 6.35-6.27 (m, 111, CB-C-CB).4.11 (q,J- 5.8
Hz, 1 B, OCH)， 4.24 (t, J- 2.4 Hz， 1 K OCH), LS4 (s; 1 H5 OH); NMR (75 MHz,
CDCb) 6 === 204,2, 1.33,7， 128 A 127.2, Ϊ26.8, 97, L 95.8, 60.3; MS (El) m/z {%): 146
(W , 23,71), 55 (iOO); 1 (neat): 3327, 3031, 2928， 287 lf 1950, 1598, 1494, 1459,
1408, 1264, 1205, 1112.. 1072， 1009 crn"; H MS [ 'f ] 计獰值： 146.0732, 实测值：
146.0731. 实施例 10
飞 1》 ΖπΒ (0.75 equiv) H
≡≡―、、 + c CH0 + /、 )..i/yPh io , 130 t:-10h
1a 0TBS 2a 、！ 'LPh 2)TBAP3H20 (1.0 equiv) CV 〜 CH2OH (1.1 equiv) (1.5 equiv) {R 3a THF'O C rt「2h (S 4 a
{1^0 equiv) 66%产率, 99% ee 操作参考实施例 i。 Zii:Br2 (169.4 mg, 0.75 mmo), a，o！-二苯基脯氣醇
(258.3 rag, 1.0.mmol), 叔丁基二甲基硅基保护的炔丙醇 la (188.3 n¾;〗.1 m ol), 新蒸环己蕩甲酸 a (169.0 mgs 1,5 η ηοΐ), 千燥的甲苯 (3 mL), TBAF-3H20 (315,8 tng, L0mn»!)和四 a呋喃 p tnL)。柱還析 油菌乙酸乙酯 - !0/!)得液体轴手性 ct-联烯醇 (99. mg, 66%): 99% ee (BPLC 測^条件： Chiraicel AS-H 柱， ΪΕ 己貌 /异丙醇 ：:： 8/2, 0.6 niL/min, λ === 214 n t (小峰） ===: 16,0 mm, (大峰） 19.0 roin); [ ]2!ο - 100,9 ( :: 1,04, CHC ); Ή丽 R (300 MHz, CD(¾) 5 - 5,41-5,26 (α 2 H, CH^C-CH), 4,11 fs, 2 H' OC ), 2.08-1.94 fm, 1 H, CH from Cy), 1.82-1.57 (m5 6 i- OH and protons from Cy), 1 ,37-1,00 (in, 5 H, pr totis from. Cy); C NMR (75 Mi.lz， CDCh) δ - 201.8, 99.9, 2,6, 60.8, 37.0, 33.03, 32.97, 26.0, 25,9; MS (EI) /z {%)： 152 OVf; U5)? 55 (100); I (mat): v :: 3321, 2923, 2850, 1961, 1448, 1417, 1348? 1062, 1009 cn !;HRMS [Μ!] 计算值： !52.1201, 实灘值： 152.1202. 实施例】 1
？ TBS 厂 Λ ηι 1:}ZnBr2i0.756qu!v}
人、 V Ph toluene, 130 12 h c ,H ■Cy %· + CvCHO + N T'Ph „、「。,,■〜。,、 ~* + 产^^ i1.1 eq:«iv) {1.5equiv} <S)-3a THF, 0 '、- rt 12 Π H< .
(1.0 equiv 61%
Figure imgf000015_0001
(¾,R)-5ba
98% <ie, 99% ee 99% de ,99% θθ 反应式箭下面的 6i¾表示产率； de值， ¾示雜对映体过量 后面实施例相同 符号表示相同的意思 操作参考实施俩.《 ZnBr2 (1.69.3 mg, 0,75 mmol), α,ο 二笨基漏 it醇 d (258.5 mg, LO m o\)}. 叔丁基二 ^基硅基保护的炔丙醇 (士: b (277.9 mg, 1.1 mmo！),新蒸环己基 Ψ醛 2a (168,2 m , LSmjnol),干燥的 ^苯 (3 ml), TBA:F'3 0 (946.9 mgs 3.0 mftw!)和四艇呋喃 (3 mL) 柱！！析 (石油醚 /乙酸乙酯 - 25/1)得液体 轴手性 α-联烯醇 5ba (】43,5 mg, 6i%); (if,S-5 a (98% de, 99% ee), (^,!}-5^ (99% de, 98% ee) (HPLC 测定条件： CW lcd PC-2 柱， ιΕ己 ί¾异丙醇 - 98/2, 0,5 mL/min5 λ. 214 ηιΐϊ, (小峰) = .4 min, ?s(大峰) 10,3 ηιϊη, i (大峰 ) = 11,5 miii, ¾ (小峰） :: 12,6 mm);
Figure imgf000016_0001
-81,8 ( - 1,01 CHCI3); R (300 MHz, CDC ) δ - 5.33-5,19 (m, 2 H, CiiO-a i), 3.8? (s, I. ¾ ()(:H)， 2.06-1.5? (m, 12 H, OH and protons from Cy), 1.49-0.94 (n% 3 H, protons from Cy); °C NMR (75 MHz' CDCb) 6 :: 20:1,4， 200,9， 100.3, 99 95 94,9, 74,5， 73.9, 44.08, 43.97, 37,12, 37.09, 33.04, 33.01, 32.97, 28.73, 28.70, 28,3， 28.2.26,5, 26.1 U 26.07, 26,05, 26.00, 25.98, 25. 1; MS (El) m/z (%); 234 (M 2.25), 55 (100); i:R (nmt): v - 3376, 2922, 285 L !960, !448, 1083, !009 cm1: HRMS [iv 】 计算值： 234J984, 实测億: 234.1 80.
实施例 12 i C7
Figure imgf000016_0002
橾作参考实施例 L ZnBr, (169.3 mg，， 0.75 mmol), tt,(x -二.苯基脯 ¾醇 (S)-3a (258.8 rag, 1.0 rnmol), 叔丁基二甲基硅基保护的炔丙醇 le (295,7 mg, ΪΛ mrno!),新蒸环己基甲醛 2a (168,5 m , i.5 mmo),千燥的平苯 (3 mL), TBA:F'3: 0 (947.2 mg, 3,0 mmoi)和 I呋喃 (3 mL), 柱懲析 (石油醚 /乙酸乙酷 - 25/1)得液体 轴手性 "联烯醇 5ea (175.8 mg, 70%): {R(3,S)~Sc& (97% de, 98% ee); {A',„li;~5ca (98% de, 97% ee) (HPLC 測 条件： Chi ke IC ¾, 正己烷 /异两醉 - JXK3/L. 0.5 ■mL/mm, λ ---- 214 nm, (小峰） 14,0 min, (大峰） 14.8 mm, (大峰） 16,8 ηιίη, iK(小峰） 17.4 min); [afD - -70,2 (c - 1.03, CHCk): SH NMR (300 MHz, CDCh) δ ：:: 5.32-5,19 (m, 2 H， CH-C-CH), 4.30 (s, 1 H; OCH}; 2.07-1.48 im, 9 li OH aixl protons from Cy and w~C?Hw), 1.48-0.99 (rn, 15 H， protons from Cy and «-C7H{s)5 0.88 (ί, J 5.7 Ι ϊζ, 3 II, Cl¾); nC NMR. (75 MHz CD(¾) d：: 201.1, 200.7, .100.4, 99A 96,8, 96.6, 70.3, 69.8, 37.6, 37.5, 37,】, 33.04, 32.99s3i.7, 29.5, 29.4, 29.2, 26.0, 25.9, 25,44, 25.39, 22.6? 14.0; MS (El) m/z (%)： 250 (M 0,61), 55 (100); I (neat): === 3346, 2923, 2852, 961, 1448, 1134, 1047, Ϊ017 cm ; HRMS [M+] 计:鎵值: 250.2297、 实测值： 250.2298.
实施例 13
Figure imgf000017_0001
操作参考实施例 1 , ZnBr2 (169.4 mg, 0.75 mmol), tt 二苯基脑 扉 (S)-3a (258,5 mg, 1,0 mrnol), 叔丁基二甲基硅基保护的炔两醇 (±)- id (271,4 mg, 1 J 誦 οί):,新蒸环己基甲醛 2a (169,1 mg, 1.5 mmoi}，干燥的甲苯 (3 mL)， TBAF-3H20 (947,2«¾，3,01»¾0 和四氣呋喃(3 «^), 柱還析 ( 油醚/乙酸乙廳 - 15 )得液体 轴手性 α-联烯醇 5da (Ϊ67.2 mg, 73%); (I?ci,S~Sda (99% de, 99% ee}, (Ra..R, 5du (99% de, 99% ee) (HPLC 测定条件： Cbiralce! OD-H 柱， 』E己烧 /异两醇 - 98/2, 0.8 mL/min, λ 214腦, iR (大峰） === 133 m \ /R(小峰) 15,8 mk ί：小峰 ) === .19.7 mm, (大峰） 22.4 rain); [a)2l D = - 61,9 (c - 1 ,02， CHC ); Ή NMR (300 MHz, CDCli) 6 === 7,39-7.21 fm, 5 13, Ar-H), 5.47-5.39 (m, i ： H， one proton from HOOCH), 5.37-5.29 (ra5 1 H, one proton from HOC-Cil), 5.21-5,14 (m, 1 H, PliCH), 2.36 (4 J ::: 3,0 Hz, 1 H， OH), 2,07-1.93 (n% 1 H, CM from Cy), 1.81-1.57 (n% 5 H5 protons from Cy), 1.35-0.97 (m, 5 H, protons from Cy); !JC NMR (75 MHz, C::DC¾) δ - 203.2, 200.9, 143 143.0, 128,2, 127,45' 127.38, 126. L 125.9, 101 100.6, 96.93? 96.85, 72,3, 7.2,1, 37.04, 37.0 L 32.8, 25.95, 25.85; MS (El) mz (%)： 228 (M 3,11), Ϊ07 (100); IR (ileal): v 3355, 2923, 2850， 1962, 1493, 1449, 1013 era— ,
实施例 14
Figure imgf000018_0001
操作参:智实施例 L ZnBr2 (169.5 mg, 0.75 m.raol)f tt,a-二苯¾膽鉱醇 (5 3a (258.3 nig, 1.0 nimo!)? 叔丁 ¾二甲基硅基保护的炔丙醇 (?)- lb (277.9 nig, U mmol),新蒸环己基甲醛 2a (Ϊ 68,4 mg, 1.5 mrno!),千燥的甲苯 (3 L)r TBAF-3H,0 (947.2 mg? 3.0 mmol)和閥氣呋喃 (3 mL)4 柱)靈析 (Ul驗 /乙酸乙 Si - 25/ί)得液体 轴手性 α-眹烯醇 ( ,J Sba ( 131.8 mg, 56%): >99% de, >9 % ee (HPLC 测定条件： Chirakd PC-2 柱， 正己繞 /异丙醇 98/2, 0,5 niL/fflin， λ - 214 nm, iRi小峰） 0.0 % ¼大峰） - 11.4 min; [a]2S D :- -118.8 (c - 1.03, CHC¾); 'i l NMR (300 MHz. CDC¾) δ === 5.28-5.15 (n 2 E, Ce===0==CH), 3.84 (t; J --- --- 5.7 Bz, I :H, OCB), 2.04-1.54
(n% ! 2 H, OH and pix>ions from Cy)? 1.46-0.90 (m, 1 H, protons from Cy); nC NMR (75 MHz., CDC 5 - 201Λ 99.7； 94.9, 74.5, 43.9, 37.1, 33.01, 32-96， 28:7， 28.3, 26.5, 2 J, 26.00, 25,97' 25.9; MS (EI) m/z (%}: 234 (Μ÷' 1,93), 55 (100); IR (oea): v - 3373, 2922, 2851, I960, 1448, 1083, 1008 cm"!; HR S [f] 计獰值： 234J.984, 实測儘： 234,1985,
实施例 15 1 ) ZnBr2 (0.75 equiv)
u .人、、 toluene, 130 '!：■ 12 h
(R}-1c 2a
Figure imgf000019_0001
2)TBAR3H20 (3.0 equiv) H }~n~C7Hv,
98% ee {1.5 equiv) (S)-3a THF> 0 (: -- v rt, 12 h HO
(1.1 equiv) (1.0 equiv) 71% (¾,R)-5ca
99% ύ&, >99% ee 操作参考实施例 1。 ΖηΒΐ2 (169.7 mg, 0,75 mmoih α,«〜：:苯基眉tt醇 (S ?a (258.3 mg, L0 mmol), 叔丁基二 ¥基硅基保护的块丙醇 (295.5 mg, ΙΛ mmol),新蒸环己基甲醛 2a (168.4 trig,， I.Smrooi),干燥的甲苯 (3 mL), TBAF-3¾0 (947,2 mg 3.0 mmti)和四無呋喃 (3 mL) 柱歴析 (石油醚/乙酸乙酯 - --- 25/】）得液体
Figure imgf000019_0002
(178.3 rag, 71%): 99% dt% >99% ee (HPLC 测¾条件： Chirakei IC 柱， 正己 / ^两醇 === ί00/1, 0.5 mL/i:iiii， λ nm, R (小峰） 12.5 miii, (小峰）：:: 33,1 rniii, (大峰） 4,9 mio; [a]"f D - -80,8 ( - 1.04, CHC );1 : MR (300 MHz, CDCk) δ - 5,32-5.18 (m, 2 H, CHOCH), 4.10 (4 J :::: 6.0 Hz, 1 it OCH 2.06-1.92 (m, 2 H, OH mid proton from Cy), 1,81-0,99 (n% 22 H, proiosis from Cy and «- C?Ht5), 0.88 (i, J ------ 6.6 Hz, 3 i t CH3); "C NMR (75 MHz? CDCk) δ
201.1, 99.7, 96.5, 70.3, 37.4, 37.1, 33,01, 32.97, 31.7, 29.4, 29,2， 26.0, 25.% 25,4, 22,6, 14,0; MS (EI) m/z (%)； 250 (M 0.56), 55 (100); IR (aeai): v - 3345； 2923, 28S2, 1.962, 1448, 1047, 1017 cm"1: FIRMS [f】 计算值： 250.2297, 实测僚： 250,2296.
实施例 1
TBS 1)ΖπΒ¾ (0.75 equiv} Η Η
■人、 „ h toluene, 130 t> 12
98% ee {1.5equiv¾ THF, 0 C→ri 12h HO
(1.1 equiv) {1.0 equiv) 68% (¾«ft)-5ca
99% de. >99% ee 操作参考实施例 1 ZoBr2 (169.7 mg, 0.75 mmol), ct，ct-二苯基脯氣醇 (258.4 mg; L0 ramol)， 叔丁基二 Φ基硅基保护的炔丙醇 ( ?)-Jk (295,7 mg, LI aimol),新蒸环己菌甲醛 2a (168,6 mg， 1,5 mmoi),千燥的甲苯 (3 mL), TBAF-3¾0 (947,2 rag, 3.0 mmo;)和閥氛呋喃 (3 mL), 柱层析 (：石油醚 /乙酸乙酯 - 25/i)得液体 轴手性 α-眹烯醇 (SaJ^-5ca (17L1 mg, 68%): 99% de, >99¾ ee (HPLC 测定条件： Chirakei IC 柱， 正己烷 /舁丙醇 === Ϊ 00/1; 0.5 mL/mio, λ - 214謹, (大峰） - 14.8 miii, R (小峰） - 17.6 min, (小峰）：:: 18,3 min;【a】22 D - 61.8 (c - 1,07, CHC½); SH NMR (300 MHz, CDCk) - 5.33-5.18 (o¾ 2 H, CH-0 H}54.10 ( J - 2.6 H¾, 1 H, OCH), 2.07- L 3 fni 1 proton from Cy), L (s, I 11 Oi l), 1,82 00 (n 22 B, protons from Cy and C?Ht:5)? 0,88 (t, J - 6.S Hz; 3 H, CO;,); "C NMR (75 MHz, CDCla) δ - 200,7, 100.〗， 96.7, 69.7, 37.5, 37.0, 33.0, 32,9, 31.7, 29.4, 29.2, 26,0, 25,9, 25,4' 22,5' 13,9; MS (EI) m/z (%); 250 (M 0,96)' 55 (100); IR (neat): v - 3334, 2923' 2852' 1962, 1449, 1047, ΙΟΙί) cm"1; HR!vlS [Μ】 计算值： 250.2297, 实测值： 250.2299.
实施例 17
OTBS .,· ~、、 1}Zn8r2{0.?5 equiv)
L .ph t toolluueennee,, 1 T3J0U 'C, 12 h n ·"■', __ .·
(S <^ 2a H OH 2) TBAF-3H20 (d.0 equiv) H V -fiis
97% ee {1.5 equiv) (S)-3a 0？ -> rt> 12 fi Hd
ll .1 equiv) (1.0 equiv) 74% (/?a,S}-§ca
99% de, 99% ee 操作参考实施例 L ZnBr2 (169.6 mg5 0.75 mniol , α,α-二.苯基遍ffi醇 (S)-3a (258.5 mg, 1.0 mmol), 叔丁基二 f 基硅基保护的炔丙醇 (295.7 mg, LI m oi),新蒸环己基甲醛 2a (168.5 rag, 1.5 rmm)l)f 千燥的 Ψ苯 (3 l)> TBAF-3H20 (947,4 mg, 薦《ol)和四氣呋喃 (3 ml), 柱 析 油鍵 /乙酸乙纖 - 25/1)得液体 轴手性 α联烯醇 (186.2 mg, 74%)： 99% de, 99% ee (HPLC 測定条件： Chirakel i:C 柱， ίΕ己嫁 / ^丙醇 ί 00/1, 0.5 mL/niin, λ = 214 m ½ (小峰） 16,5 min, (大峰） - 17.9 min, ½(小峰） - 20.0 mm, ¾(小峰) 20,9 mm; [a] - -58.2 (c - 1.04, (： Ή( ); lU NMR (300 MHz, CDCk) δ：:: 5.32-5.18 (ηχ 2 Η, (:»:: ::CH), 4,09 (s， 1 Η, OCH), 2.07-1.90 (η% 2. Η, OH and proton from C 1.82- i.00 (ra, 22 II protons from Cy and n-C-M^ 0M (t, J - 6.6 Hz; 3 H, CH: ; "C I MR (75 MHz' CDCla) δ - 200,7, 100.2， 96.7, 69.7, 37.5, 37.1, 33.0, 32,9, 31.7, 29.5, 29.2, 26,0, 25,9, 25Λ 22,6, 14,0; MS (E!) m/z (%); 250 (M' 0.55), 55 (100); !R (neat); v：::： 3336, 2923, 2852， 1962, !448, 1123， !047, 1019 era4; HRMS [Nf ] 计算值： 250,2297, 实测傻： 250.2295.
实施例 18
〜 '人 -
(S)- 1c 2a
97% ee (1.5equiv)
Figure imgf000021_0001
(1.1 equiv) {1.0 equiv) 65% (S9>S)-5ca
99% de, >99% ee 操作参考实施例 L ZoBr2 (169.4 mg, 0.75 mmol), α，α-二苯基脯氣醇 (i?)-3a (258.3 mg, 1.0 mmol), 叔丁基二 f 基硅基保护的炔丙醇 (295.2 mg, LI mmo }f 新蒸环己基甲 l?2a (168.5 mg, j.5 mmol),千燥的 ^苯 (3 mL), TBAF-3H20 (947.2mg、3,0mmoi .和四氣呋喃 (3 mL), 柱 ¾析( 油凝 /乙酸乙 ίϋ 25/i)得液体 轴手性 联烯醇 (162,3 mg, 65%): 99% de, >99% (HPLC 溯定条件： C ira!cei :iC 柱， 正己烷 /异丙醇 100/L 0.5 mlJm x λ === 214腿, (小峰：) === 16.5 mm, /R(小峰） - 17.5 rain, ¾(小峰） - 20.1 "ι , (大峰） 21.0 i; [a]2i) D ::: ?9.4 (c - 1,04, CHCh);fH NMR (300 MH¾ CDC ) δ - 531-5.19 (m, 2 H, CH-C-CH), 4.ΙΪ (d, J :::·· 6.0 Hz, 1 11, OCH), 2,06-1,91 (m, 1 hi proton from Cy), L88 (s, 5 !1, OH), 1.81-0,99 (m, 22 H, proioiis fmm Cy and "-( :¾5), ().88 (t, J - 6.6 Ez, 3 M, C ); NMR (75 MHz, CDCb) δ - 201,1， 99,8, 96.6, 70.3, 37.5, 37 J, 33.03, 32,98, 31.8, 29.4, 29,2, 26,0, 25.9, 25,4? 22.6, 14.0; MS (Ei) m/z (%)； 250 0.71), 55 ( .100); I R (neat): v === 3343, 2923, 2852, 1962, 1448, 1120, 1048, 1020 cm"J; IIR S [M''} 计算 #1； 250.2297, 实测值： 250.2303. 实施例 19 * Ο
Figure imgf000022_0001
(R}-6
99% ee 78%, 99% ee
向千燥的反应管中依次加入轴手性 α -联烯醇 (i?)- 4aa {76.2 g, 0.5 mmoL 99% ee), 丙綱 (3 mL)和 0,05摩尔 /升的 AgN¾溶液 (i mL 0.05 mmol).然后在反应管中 插入回流冷凝管， 放置到寧先已加热到 50 的油浴中搅拌 Ϊ8小时。 冷至室温后 向反应管中加入乙酸乙 mL) 和饱和食盐水 (.10 mL)， 分出有机展， 水環乙 酸乙酯萃取 (l«mLx 3), 合并有机层， 饱和愈盐水洗涤（10 mL), ¾水硫酸钠千 燥，浓缩，柱展析 (ΐί油醚 /乙醚 40/ )得液体化合物(./?)-6(59.70 ，78%):99¾,£¾ 測定条件： Chirakel AD- H t,正己烷 /异丙醇 :::: 40()/i, 0.5 niL/mi¾ 214 iin¾ ½(大峰） - 10,2 min, (小峰) - 11.5 mm); [af ：:: - 161.8 (c :::: 1.05, CHCI5); fH
NMR (300 MHz， CDC!¾) δ - 5,90 (d， J - 6.6 Hz' 1 H, one proton from CH-CH)? 5.79
(d, J ----- 6.0 Hz、 1 H, one proton from CH===Ci;i)， 4.60 3 H, ()CH and OCi½)，
1.83-3 ,5 (n% 5 H? proiO!i from Cy), 3 ,54-3 ,38 (n% I B, proton from Cy), 1,32-0,90
( x 5 H， protons from Cy); l¾C NMR (75 MHz, CD(¾) 8 - --- --: !28.0, !26.7' 90,6, ?5.2,
43.4, 28.6, 28.4, 26.5, 26,13, 26,10; MS (El) m/z (%): 152 (Μ', 0.84), 69 (100); IR
(neat): v - 2924, 2851, 1449, 135(1 1083, 1068, 1021 mi1; HRMS M; 计算值： 152,1201,实測值： 152.1202. (参考文献； J, A. Mas alL X.-J. Wang, J Org. Chem. 1991 f 56, 4913; C. M. Sapu, I, E, Backvall, J, Dcska, Angen Chem, Int. Ed.2011, 50, 9731)
实施例 20
Figure imgf000023_0001
ee
向千燥的反应管中依次加入轴手性 o联烯醇 (/?)-½a (76.5 m 0.5 mmol, 99% ee)和 2 mL二氣 ψ烷，然后在 -15 下加入 Ν -碘代丁二酰亚胺（1240 mg， 0,55 nmiol) m l 二氣甲烷 加完后继续在 -15 下搅袢】 2 小时. 反应结束后加入 a3S305 (!CHnL)淬灭反应. 分出有,机层， 水层二氣¥烷萃取（ 0 ml x 3), 含并有 机层，饱和食盐水洗錄 aOmL),无水硫酸钠千燥，浓缩，柱层析 (石油凝 /乙謎 50/1)得液体化合物 (110.3 rog, 79%): 99% ee (HFLC 测 ¾条件： CMralcd AD-il 柱, 正己烷 /异丙醇：： 100/1, 0.3 n±/ m, λ - 214 ii , (大峰) - .12.3 min, (小峰） - 13.1 min): {u} - + 6,0 (e - 1.04, CHC ); SH NMR (300 MHz, CD( ) δ:: 626 (s, 1 il 0CH), 4.66-4.44 (in, 3 H? OCH and OC )， LS3-L57 (n% 5 H， protoii from Cy), 1.52-0.95 (ra? 6 H, protons from Cy); C NMR (75 MHz, CDC ) δ === 135.1, 93.5, 91 Al 76,9, 40,6, 30.1, 26.7, 26.3, 26.0, 24.2; MS (El) m/z (%) 278 (M 11.82), 1 5 (100); I . (neat): v - 2924, 2850, 1613, 1449, 1342, ί31ί5 128L 1234, 1178, 1102, 1087, 1067, 1019 em"; HRMS [M; 计算傲： 278.0168. 实测值: 278.01.69. (参考文献： C. I, T. Hyland, L, S. Hegedus, J Chem, 2006, ?/, 8658; B. Lfl、 X, Jiang, C. FIK S. Ma, J. Org. Chem.200 , 74, 438; J. Deska, J. E. Backvall Org. Biomol Chem, 2009, 7? 3379) 实施例 2_
Figure imgf000024_0001
99% ee 88%产率， 99% ee 在惰性气体的保护下， 向千燥的反应管中依次加入 苯基磷（197,2 mg? 0.75 mmol),叔丁氧羰基保护的对甲苯磺 II胺（163,0 rag, 0.6 ffimol),轴手性 α-联烯醇 (R) iVA (76.3 rag? 0.5 ol 99% ee) 和干燥的西氣呋喃 (2 mL), 然后将偶氣二甲 酸二:乙醋 (131.1 mg; 0.75 mmol) 溶于 1 千燥的 ¾呋喃， 在 0 Ό下利用注 射器在 20分钟内滴加到反应体系中。加究后， 然升至¾温搅拌 12小时 反应 结束^ 浓缩， 麵析 (石油觀 /乙酸:乙獺 /二氣甲烷 -15/1/0.1.) 得到叔丁氧羰基 保护的联烯胺 然后直接将其溶解在 3 raL二氣甲烷屮 , 〗 0 下加入 ()、 15 mh≡ 氣乙酸 t 视拌 2.5 小时后再加入 0.15mL: ¾乙酸, 继续视拌 2.5 小时 反应结 束后, 浓缩除去大部分三艇乙酸， 然后加入 !0 L二氣甲烷和 20 ml 饱.和 NaHC03溶液 分出有机展， 水层二氣甲烷萃取 (10 mLx 3) 合并有机 )1， 饱和 食盐水洗涤 （H) mL), 无水硫酸钠千燥， 浓缩， 柱层析 (石油醚 /乙酸乙 9/1} 得液体化合物 (134, mg, 88%, 两歩总产率）： 9% ee (ii!FLC 测定条件: Chirak i AD-H 柱， 正 β垸 /异两醇 95/5, 0,5 m.L/min5 λ-214薩' 大峰） - 36.3 mm? /R(小峰） 38.4 mill); [ ]23 0 :::: - Ϊ05.5 (c 1.07, Cl-lC ); Ίϊ NM (300 Hz. (::ί)(¾) δ 7.77 (d, J 7.8 ϊ 2 l Ax l 7.30 (d, J --- 7.5 Hz, 2 1 Ar~H }, 5.2 i-5, L2 (m, 1 H, CH-C-CB), 5.11-5.01 (n% 1 H, CB-C-CH), 4.92 (i, J :::: S3 Hz, 1 H, NH), 3,59-3,50 (m, 2 B, NC¾), 2.42 (s' 3 B, C )， 1.98-1.83 (m, 1 B, proton from Cy), 1.75-1.53 (m, 5 H, protons from Cy), 1.33-0.89 (in, 5 H：， protons fmm Cy); L'C NMR (75 MHz, CDCb) δ - 202.2, 143.2, 137.0, 129.5, 127.0， 30.3, 88,4, 42,0, 36.75 32.gs. 32.7, 25.9, 25.7, 21 .4; MS (EI) m 2 (%}: 305 (M 2.03), 55 (100); IR (neat): v - 3280, 2923 2850, 1963, 1598, 1447, 1421 , 1325, 1158, 1093 cm:5 ; HRMS Ms j 计算值： 305,1450, 实测馄： 305.1451. (参考文献： 0. Mitsunobu, M. Yaroada,
Bull Chem, Sac, Jpn, 1967, 4(K 2380; O. Miisimobo, Synthesis 198 K 1 )
C , H 1 ) MsCi (1.2 ecjuiv), NEt, (1.5 equiv)
Cy. H
DMAP (1:0 moi % . DCM, 0 ·'(: , 1 h
H 2) NaH (1.2 equiv), CH2(C02Me) (2.2 equiv)1
(i?HaaCH THF/DMSO. 0 → rt, 24 h " (R}-9、~ 99% ee 65%产率， 99 ¾Me
在,惰性气体的保护下， 向千燥的反应管中依次加入对二 基氣基毗 ¾(6.2 mg, 0.05 mmol), 干燥的三乙胺 (7 mg， 0.75 miiiol), 轴手性 α-联烯醇 (76.2 mg, 0.5 mmol, 99% ee) 和千燥的 DCM (3 ml),然后在 0 下利 注射器将 甲基磺酰氣 (47 l, d .475, 0,6 i 1)在 1 分钟内滴加到反应体系中 , 加完后鍵 续在 O TF！摔 小时 反应结束^ M入 lO niL水和 1 0 mL 二氣 ¥烷， 分出有 机 ， 水！：二氣 Φ烷举取 (iO mL x 3)， 合并t机展， 向其中加入约 2克碎冰 然 后依次用 1 M HCI (10 mL),饱和 NaHC(¾溶液 (10 mL) 和饱和食盐水 (10 mL)洗 涤， 水硫酸钠千燥， 浓缩后直接投下一歩反应 在¾外一个反应鍾 :中加入 化 钠 mg, 0.6 mmol, 60%),然后在 0 :下依次加入干 '燥的四 呋喃（1 mL), 于 燥的 DMSO (0,25 mL), 和丙二酸.二 f §( i45.5 mg, 1.1 mmoi),加宪后升¾紫温搅 用注射器在 30 mm内滴加到上述反应体系中 加完后紫温搅拌 24小时， 反应结 束后， 0 X：下加入 10 mL饱和 NH4Ci淬灭反应， 然后加入 ) mL乙醚， 分出有 机 ， 水层乙凝萃取 （iO mL 3), 合并有机层， 饱.和食盐水洗涤 （10 mL) , 无 水硫酸钠千燥， 浓縮， 柱层析 (石油離 /乙謎-: 25/1} (87.1 mg, 65%, 两歩总产率） 得液体化合物 0?>9： 99% ee (HPLC 獰 条件： Chiralce! OD 柱¥ 正己焼 /异丙 醇 1 niL/miii, λ - 214 im, (小峰) - 7.2. min, ½ (大峰) ^ 7,9 mm); [af2 v - - 85.4 (c :: 1,05， CHCk); 5Η NM (300 MHz, CDC1. 5 - 5.20-5.09 (m， 2 H， CH-C-CH), 3.74 (s, 6 H， two C >， 3,51 ( J - 7.2 Hz, 1 H; CH); 2,64-2,52 (m, 2 H, CM?), 2,01-1,85 fm, ！ H, proton from Cy), 1.79- i, 58 (m, 5 H, protons from Cy), L36-0. 6 (n% 5 H, protons from Cy): : NMR (75 MHz, CDCI3) 6 - 202.7； 169.34, 169.29, 98,9, 88.2， 52.44, 52.42， 51.2, 37,1, 32.9, 32.8, 28, lf 26.(125.9; MS (El) m/z (%} 266 (JVf， 19.00), 91 (100); IR (neat); v - 2924, 2851, 1962, 1736, 1437; 1342, 1262, 1233, I150; 1035 cm'f; HRMS [b ] 计算值： 266,1518, 实测值： 266.1516. (参考文献： Z, Zhang, C. F, Bender, :R、 A, Widenhoefer, J Am. Chem. So .2(ΜΪ7, 129, 14148)

Claims

权利要求书 i. -种轴手性《-联烯醇， 其具有
Figure imgf000027_0001
中， R¾ - 的经基， R2 - KE或 Cf〜C t, 联烯的轴手性为/? 或 S型， 相连的碳原子两'以是非手性、 /？或 S型; 所述的 C
¾为脂肪基时， ee值大于 96:
Figure imgf000027_0002
1所述的轴 性 联烯醇，其特征是所述的 Ci〜Cw的烃 基为直链烷; , C广 -C
3. 种如权利要求 1所述的轴手性 ^联烯醇的合成方法， 其特征是通过— 述歩骤获得：
Figure imgf000027_0003
在】(M )t下和有机溶剂中，以锌盐为促进剂，以( 、性仲胺， 与硅基保护的炔丙醇和醒反应 5-15小时， 过短硅跤柱后用閥正丁基氟化锬脱去 硅基保护基即可得到轴手性 联烯醇产物；
其中， 所述硅基保护的炔內醇： II： 锌盐； 四正丁基鼠化钹的糜 尔比为 、 3: 1 : 0,3〜！ ,3 : i〜5; 所述 f l3G为 Ξ Ψ基硗 ¾、 ：::： ί异
ΓΓ基 ；或叔丁基二苯基硅 所'述的手性仲胺为具有如下结 构式的 或其: ；所述的锌
Figure imgf000028_0001
渙化锌、碘化锌、 醋酸锌或 氟甲磺酸锌； 所述的四正丁基氟化铵 为四正丁基氣化铵. 水
ΐ中， !、 2 同权利耍求 1， 联烯的轴手性为/?或 S型， 与经基相连的 碳原子可以是非手性.， ？或 S型
4. 如权剁耍求 2所述的轴手性 α-联烯醇的合成方法， 其特征是在千燥的反 应器中加入锌盐、 手性仲胺-, 硅基保护的炔 ^醇 > 醛和千燥的有机溶剂， 在 100-130 ΪΓ 搅拌 5-20小时 ; 反应结束^ , 过短硅胶柱得到粗产物， 将其溶于有 机溶剂， 《) Ό下加入 正丁基概化铵， 然后在室温下搅拌 15小时。
5, 如权利耍求 3或 4所述的轴手性 α-联烯醇 ϊί 其特征是所述的 有 溶剂为苯 甲苯、 氣苯、 对二甲苯、 邻二甲苯、 间二甲苯或均 甲苯
3或 4所述的轴手性 ^联烯醇的合成方法， :征是反应产 物经过水洗涤， 取， 千燥， 浓缩或柱层析分离纯化。
7,. 如权剁要求 .所述的轴手性 联烯醇的用途， 其特征是用于合成具有中 心手性且手性 ¾全保持的 二艇呋喃类化合物、手性½全保持的轴手性联烯胺 二酸獺类化合物.,
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