2006 年第14卷合成化學(xué)Vol. 14 ,2006第6期,546~551Chinese Journal of Synthetic ChemistryNo. 6 ,546 ~551.綜合評述.C3手性合成子的合成及應(yīng)用彭煥慶'2 ,王立新' ,杜振軍' ,蔡澤貴' ,王文'( 1.中國科學(xué)院成都有機化學(xué)研究所四川成都610041 ;2. 中國科學(xué)院研究生院北京100039 )摘要:簡要介紹了兩種重要的C3手性合成子一環(huán) 氧氯丙烷( ECH )和縮水甘油( GLD )的合成方法綜述了ECH在藥物合成以及GLD在部分有機合成中的應(yīng)用。參考文獻34篇。關(guān)鍵詞:C3合成子;環(huán)氧氯丙烷;縮水甘油;合成;綜述中圖分類號:0621.3文獻標(biāo)識碼:A .文章編號: 1005-1511( 2006 )06-0546-06Syntheses and Applications of Chiral C3 SynthonsPENG Huan-qing'2 ,WANG Li-xin' ,DU Zhen-jun',CAI Ze-gui'，WANG Wen'( 1. Chengdu Institute of Organic Chemistry , Chinese Academy of Sciences , Chengdu 610041 China ;2. Graduate University of Chinese Academy of Sciences , Beijing 100039 , China ))Abstract : Synthetic methods of two C3 chiral synthon[ epichlorohydrin( ECH ) and glycido( GLD )]was introduced. The applications of ECH in drug synthesis and GLD in some organic synthesis werereviewed.34 references were cited.Keywords : C3 synthons ; chiral epichlorohydrin ; glyeidol ; synthesis ; review近年來,C3手性合成子在醫(yī)藥農(nóng)藥、香料、法和醋酸丙烯酯法其工業(yè)年產(chǎn)量約92萬噸。手液晶高分子材料等領(lǐng)域得到了廣泛的應(yīng)用其合性的ECH是1978年由Baldwin等'首次以D-甘成研究也越來越受到人們的重視。常見的C3手露醇為原料合成的收率僅為27%[( R )-ECH和性合成子為C3環(huán)氧化合物及其前體鹵代丙醇( S- )ECH的e.e.值都大于99% )。 隨后又有其它等。本文著重介紹了環(huán)氧氯丙烷( ECH ,Chart 1 )的制備手性ECH的方法陸續(xù)報道2-01。但是這在藥物合成中的應(yīng)用和縮水甘油( GLD , Chart 1 )些合成及拆分方法的收率都不高。直到1995年，在有機合成中的部分應(yīng)用。Jacobsen等7]將用于不對稱環(huán)氧化的Cr -Salen催0ClOH化劑用于ECH的拆分,得到48%的收率( 97%e.e. )。1997年Jacobsen 等81又用Co-Salen催化ECHGLDCPD劑實現(xiàn)了ECH的拆分使收率達到了40%( 98%Chart 1e.e. )。 1999年Jacobsen等9]又報道了高分子負1 ECH 的不對稱合成載的Co-Salen催化劑用于ECH的拆分，也得到了ECH的工業(yè)生產(chǎn)方法主要為丙烯高溫氯化很[中國煤化工% e.e. )。YHCNMHG*收稿日期:2006-02-16 ;修訂日期: 2006-05-25作者簡介:彭煥慶( 1981- )男漢族山東菏澤人在讀碩士主要從事醫(yī)藥中間體及相關(guān)化合物的合成研究。通訊聯(lián)系人:王立新研究員主要從事醫(yī)藥及醫(yī)藥中間體等相關(guān)功能化合物的合成、技術(shù)改進與創(chuàng)新及產(chǎn)業(yè)化研究。Tel.028 -85255208 , E-mail :wkxioc@ cioc. ac. cn第6期彭煥慶等:C3手性合成子的合成及應(yīng)用一547一2GLD及CPD的不對稱合成3 ECH在藥物合成中的應(yīng)用1942年,Fischer 等10以D-甘露醇為原料合成3.1用于芳 氧丙醇胺類藥物的合成了光學(xué)純的GLD其(R-)GLD和(S)-GLD的收率.芳氧丙醇胺類藥物是在上世紀中期發(fā)現(xiàn)的β腎分別為94%( >82% e.e. ),52%( >87% e.e. )。上腺素拮抗劑。其β受體阻斷作用比苯乙醇胺類后來Sharpless等" 1用不對稱環(huán)氧化反應(yīng)實現(xiàn)了強對β,受體具有較高的選擇性151。從該類藥物的GLD的不對稱合成,收率雖只有65%,但其通式我們可以發(fā)現(xiàn)以ECH作為合成原料是條簡捷( R- )GLD和( S- )GLD的對映選擇性都高于91%，的合成路線Scheme 1 )如已知的作用最強的β受創(chuàng)造了可以商業(yè)化的不對稱GLD的合成方法。體阻斷劑噻嗎洛爾16]特異性最高的β受體阻斷劑1990年ACROS公司12]應(yīng)用Ti與D或L酒石酸比索洛爾17]超短效β受體阻斷劑艾司洛爾18]為二異丙酯的配合物,在枯烯和雙氧水條件下首次適應(yīng)高血壓患者而開發(fā)的長效β受體阻斷劑納多洛實現(xiàn)了GLD的商業(yè)化生產(chǎn)。同時Ladner等12 ]通爾19 '等( Chart 2都是以上述方法合成的。，過酶水解拆分方法制得了手性的GLD。CPD是GLD的前體光學(xué)純的CPD主要由ECH動力學(xué)3.2用于 L-肉堿的合成水解拆分法制備。近年來也有其他不對稱合成方ECH還普遍用于L_肉堿的合成。1992 年,法報道如1999年Hollingsworth等13以( S )-3-羥Kasai等20]通過1與三甲胺水溶液同步加成消去基丁內(nèi)酯為原料合成了( R )-CPD ,收率83%反應(yīng)合成2。2與2-甲基-2-羥基丙氰反應(yīng)后經(jīng)水( >99.5% e.e. )。 2003年,Prati 等[14]以1 3-二解得3。1997 年, Kabat等211同樣用4與格氏試氯丙酮為原料合成了( R )-CPD ,收率82%( 99%劑反應(yīng)得到5。5經(jīng)三甲胺的親核取代、陰離子交換反應(yīng)氧化反應(yīng)得到6( Scheme 2 )。e.e. )。cArOH 0vNH2ROAr一Ar0丫NHR.OHScheme 1比索洛爾噻鳴洛爾是HO*艾司洛爾納多洛爾Chart 2.只30% NMes、只1. Me2C(CN)OH;2. concHCI HO2C-. cl中國煤化工HO"~HTHCNMHG_Mge1. NMe3(aq); 2. AmbedileOIRA 410(0H)- O2C~CICuBrHOrH3. O3, AcOH, then H2O24“H5Scheme 2一548一合成化學(xué)Vol. 14 ,20063.3在阿伐他汀 合成中的應(yīng)用氫氧化鈉催化下經(jīng)親核加成并同步關(guān)環(huán)制得對叔阿伐他汀鈣是由美國沃那蘭博特公司開發(fā)的丁基苯縮水甘油醚。對叔J基苯縮水甘油醚再經(jīng)HMG-CoA還原酶抑制劑類血脂調(diào)節(jié)藥。現(xiàn)為全過進一步反應(yīng)制得TX-1898等系列化合物。球銷售額最大的藥物之一。在阿伐他汀的合成中,4-氯-3~羥基丁酸酯是重要的中間體,可由3.5在 雜環(huán)化合物中的應(yīng)用ECH同氰基開環(huán)或與-氧化碳以羰基鈷為催化在雜環(huán)化合物的合成中,1 2-二活性中心或劑在醇溶液中開環(huán)得到Scheme 3 )22，該中間體1 3-二活性中心化合物的應(yīng)用非常廣泛。ECH中主要用于阿伐他汀側(cè)鏈的合成( Scheme4 )21。有3個活性中心在雜環(huán)化合物的合成上人們充OH O分應(yīng)用了這種性質(zhì)。文獻26-281以ECH為原料合0CO. MeOH, Co(CO)、cICI、成了一些雜環(huán)化合物Scheme5 )?！瓾0H+ cl美,CN3.6 同1 3-二噻烷陰離子的作用1997年,Smith 等(29 ]報道了二噻烷陰離子同Scheme 3兩種不同的端基環(huán)氧化合物一鍋法合成手性1 ,3.4在放射致敏劑合 成中的應(yīng)用5-二醇類化合物的方法。2003 年,Smith 等301又1997年,Hitoshi Hori等241用ECH為原料合報道了二噻烷陰離子同-系列的光學(xué)純的端基環(huán)成了TX-1845 ,TX-1846( Chart 3 )等高效的缺氧細氧化合物的反應(yīng)。當(dāng)他們以ECH為底物時發(fā)現(xiàn)胞放射致敏劑和血管發(fā)生抑制劑。2004 年他們25]其可以在低摩爾比的情況下較充分的同二噻烷陰又報道了TX-1898等系列放射致敏劑( Chart 3 )。離子反應(yīng)得到構(gòu)型翻轉(zhuǎn)的端基環(huán)氧化合物類化合該類藥物的合成方法是由ECH和對叔丁基苯酚在物( Scheme 6 )。QHNaCN。cnutto+ cn兒CO,BuPFPNH2Ph、HQr-CNPhHNOC'PrOH-CO2H +--- R-E0.一←R-B-CO2Bu'Scheme 4RO,B,XR0-_xNO2TX-1845: R= tert butyi:-1897: Ru ptert. butyiphenyl, X=C1TX-1899: R= p.tert. butylphemyl, X=C1TX-1846: R= P-lant. butylpbenyl:-1898: Ro p-tert butyiphenyl, X=BrTX-1900: R= p-tert- butylphenyl, X=BrChart 3- NHNH21. ECH, EtOH: 2.170 C-200 c,O,291中國煤化工-CHOECH. NH4OH, EtDHCNMH G76%. ro人aN≈C= =0ECH, Bu2Snl2 Ph3P、C83%Scheme 5第6期彭煥慶等:C3手性合成子的合成及應(yīng)用-549一合成方法來實現(xiàn)了二半乳糖縮水甘油酯的合成1.1Bul,Eb0:2.E COBnTBSQ( Scheme 7 )。- TBSBnO、3.9 CI4.2二羥 基丙酮磷酸酯( DHAP )前體的合成<-1.BuL.ELO:2.它oen。TBSODHAP在有機合成中是一個重要的親核試3.9a劑主要用于和醛加成合成鄰二醇化合物。2004.年,Meyer等3以GLD為原料經(jīng)過磷酸酯化得Scheme 6到縮水甘油磷酸酯18。18 在分子篩和三氟化硼4 GLD 的應(yīng)用的催化下同芐醇發(fā)生加成反應(yīng)后經(jīng)氧化得到DHAP前體19( Scheme 8 )。4.1半乳糖甘 油酯的合成半乳糖甘油酯類化合物是一類在植物的細胞4.3氨基-1 4-二縮水_D~戊糖醇和氨基-1 ,5-二膜和細菌的細胞壁內(nèi)分布廣泛的一類化合物。 之縮水-D-己糖醇類化合物的合成前只是在哺乳動物的睪丸和神經(jīng)系統(tǒng)細胞中發(fā)現(xiàn)光學(xué)純的氨基縮水糖醇是-類具有單糖結(jié)構(gòu)了單半乳糖甘油酯及磺化的單半乳糖甘油酯。的化合物。經(jīng)常用作氨基酸前體和很多其他有機2001年,Pahlsson等31]在結(jié)腸癌HT29線細胞中物的前體在天然化合物的全合成等領(lǐng)域得到了廣發(fā)現(xiàn)了單半乳糖縮水甘油酯及二半乳糖縮水甘油泛應(yīng)用。2003 年,Aragone 等34以GLD為原料合酯。2002 年,Lindberg等32]則以GLD為原料合成了一系列氨基-1 4-二縮水-D-_戊糖醇和氨基-1 5-成了單半乳糖縮水甘油酯及二聚半乳糖縮水甘油二縮水-D-己糖醇類化合物。他們用( R )-GLD制得酯。他們首先以7與GLD經(jīng)縮合制得8。8經(jīng)過20。20經(jīng)消去開環(huán)、醚化、環(huán)化分別制得五元環(huán)化保護基團的轉(zhuǎn)變、堿性開環(huán)等反應(yīng)步驟最后得到合物23和六元環(huán)化合物27。23和27分別經(jīng)環(huán)氧單半乳糖縮水甘油酯11。他們也應(yīng)用了同樣的化、疊氮加成、水解制得24和28Scheme9)。0Bz OBz0R ORQR2 ,OR?QOR'R?oLBz0J-SEt.RO-0C1gH31OR?OBzOR8 R=Bz10 Rl=H ; R2=Bn7十9 R=Bn+11 R'=C1gHyCO; R2_HOH 0BzQBn OBnOBn,OBn一QBz0LBrnO120Bz0BnOBn .ROLRO-OCgHssBnO--SEt廠14 R=Bz.18 R=Bn, R'=Cj5HsCO13OBn15 R=BnL -17 R-H, R'=CjsH,COScheme 7020人0H--+0- -P- -OBr中國煤化工.MHCNMHG|1819Scheme 8一550一合成化學(xué)Vol. 14 ,2006TrO-RO-QH_，RO)-→OH212223Ro_e20NH22:6228Scheme 9參考文獻[ 11] Klunde J M , KoS Y , Sharpless K B. 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