腈类Aldol反应的发展与应用

剪 瞩，醺 刖 。c， ． 墨 有机化学 YOUJI HUAXUE，1997，J7，57--61 会议论文 3"7一 f 腈类 Aldol反应的发展与应用 ’ V 盟 卢文柱 林颖晖 (香港科技大学化学系，清水湾，九龙，香港) 0 s t 。 摘要：芳香腈与醛的Aldol反应已被证明是一种合成各种反式 B一羟基腈的有效途径。该反应的反式非对映立 体选择性可用过渡态模型中的非成键立体相互作用来解释．并得到了 “．’ N和 CNMR渡谱数据的证实。本报告 通过变醛和芳香腈试剂的电子结构，调查了电子效应在决定该 Aldol反应非对映立体选择中的作用。其次．脂肪腈 反应的初步研究结果也有论及。最后，本文介绍了由口一羟基腈向各种纯非对映异构体，多功能性的开环和杂环7 一 氨基醇衍生物的转化反应。 Development and Applicaption of the Nitrile Aldol Reaction Paul R．Carlier ，Kam MoonLo，MichadM —C Lo，WeldonW —F．Lam (Department Chemistr'~HongKongUniwers D，＆ and 咖 ClearWaterBay．Kmx~xra．胁 Kong) Abstract：The role of electronice effects in determining aldol diastereo~election is investigated，by electronic perturbation of both the aldehyde and arylacetonitrile components．Secondly，a preliminary investigation of the aldol stereoselectivity of alipbatic nitriles is described．Finally we dea'nonstmte the transformation of口一hydroxy nitfiles to a variety of diastereomerlcadly pure and highly functionalized acyclic and heterocyclic 7一~Tlino alcohol derlvativez． 1 Aldol Stereochemistry of Arylacetonitriles Until recently，very little attention had been given tO the stereocbeanaistry of addition of rnetalated nitfiles tO aldehydes．[11 We have e~tablished that lithiated arylaceton itriles 1 reliably undergo anti— selective aldol reactionwithaldehydes 2，andthat to excellent selectivity(10：1～ > 50：1)can be obtained if aldehydes with bulky 2’or 3‘ bstituents are used：[2】 1．1．0 eq．uDA． o H O H Ar／~'CN 一 且 anj 娅 2．5：1·日：1 Bulky 2。 10：1·17：1 16；1->50=1 yields 70．90％ A~ignment ofthemajor diastereomers as antiⅧ madeonthe basis ofX—ray，ehemica1 correlation， and NⅣ吸．W e have demonstrated that the reaction diastereoselectivity iS dependent on solvent and concentration．the best r∞ults usually being obtained in n{F at O．o25M ．Unlike the aldol resedon of ketonez and ester derivatives。nitrile aldol diastereoselectinitie~are independent of the base used(n— BuLi，I DA，LiHMDS)．Furthermore we have e~tablished that under OLLI"conditions nitrile aldol reaction iS irreversible。and consequently that the observed selectivity iS kinetie in origin． 维普资讯 http://www.cqvip.com 有 机 化 学 1997韭 Prior t0 our work there was considerable discussion in the literature regarding the structure of metalhated nitriles． Li，15N，and 13a 幔 studies have provided the first clear picture of the ground state solution structure of lithiated phenyhacetonitrile and has established the existence of N 一1ithiated dimers 4a and 4b in Et20 and Toluene respectively．L3j Studies in THF and THF／hydrocarbon solvent mixtures were inconclusive due t0 the inability to attain slow chemical exchange above the freezing point of the solvent Based on the dependence of diasterecselectivity in THF on concentration we have peopos~ the intermediacy of both monomerlc and dimeric species，and furthem~re that the monomer displays higher diasterecselectivity than the dimer．Our current transition state modd for reaction in 1 is based on the intermecliacy of a monometlc N —lithiated nitrile．and the observed anti— selectivity iS rationalized in terms of minimization of nonbonded steric intemetions between the nitrlie substetuent Ar and the aldehyde substituent R in transition structure 5A． ：u、悖 Ph ： 悖 Ph i ／ H u 4a．L：EtaO 5A 4b：L=-q2-TMEDA lavoreO Ar a．qti- 2 Electronic Control of Diastereoselectivity It ia well recognized that electronic effects can alSO have a major influence on reaction stereoselectivity．Themostpertinent re0ent studies inthism-ea have been reported by Jacobsen．who correlated both epoxidation ％ ee and cis／trans product ratios to Hammett parameters(r ranges from 0．985 to 0．995)．L4 In the first of these studies the∞Helation was rationalized in in terms of increased steric differentiation ”late” diastercomeric transition structuras relative to the corresponding ’’early”diastereomeric transition structues．In our investigation of the nitrile aldol reaction we noficed that anti：syn selectivity degraded rapidly upon substitution of ber~aldehyde 2d with electron withdrawing groups(Table 1) Table 1 Diasrereoselectivity of Various para—substituted Benzaldehydes 1． 1．0 eq LOA． THF．-78·C． R 、 cN 2． 1■ 0_025M CN aRth＆sy．-a Anti：syn ratios m∞s by 400 MHz NMR ＼ 、 Me r=0．981 o、 t H ． NMez o＼ P=一0．560 MeO 。＼C1 ＼ ＼ ， ＼NOz 一 0 0．5 a·1 0＼ l 一口．5 0 ＼．／ 洲 维普资讯 http://www.cqvip.com 第 1期 有 机 化 学 Qualitively these results matched the expectation that rn0re reactive aldehydes should react less selectively．Following Jacobsen’s method，log(anti／syn)wan plotted versus various Hammett parameters．Adequatecorrelationwasobserved onlywity13-一(r=0．981)；correlationwas dramatically poorerwith oD丑ra(r：0．90)or口 (r=0 76o)．T11eobservedoptimtmlcorrelationwith o—isintriguing， and may be indicative of negative charge buildup at the carbonyl carbon in the transition structllre． a consequence of more advanced C—C bond making than C—O bond brcaking．Such a conclusion merits further study：however at the present time we Call simply say that synthetically useful diastere~selectivity cannot be attained with electron—ddicient benzaldehydes． It is important to point out that electronic perturbation of the nitrile does not result in a simple complementary effect on selectivity．El~-"tron rich nitriles lb and le react with aldehydes 2d and 2h with slightlylower selectivitythantheparentla，asmight be expected(Table2，entriesI一3)， TabIe 2 Efleet of Eleetronie Perturbation of Arylacetonitrile oll Aldol Diastereoseleetivity 1 la Ph 5．5：l 60：1。 2 lb 4一Me—G6H 5．3：l 22：1 3 lc 4一MeO-CoH4 5．3：1 30：ll 4 ld 4—121一CoH4 2 7：1 16：1 5 1e 1一Naphth 2．6：1 >20：1 6 lf 2一Naphth 2 3：1 >20：1 Reetiens performed usingLDA inTHF at 0．ff25M at 一 78℃ ；unle~ otherwise noted anti：syn ratioswere measured by H NMR(300 or 400 MI-k) "Ratio determined by caN11a~yGC Table 3 Diastereoseleetivity of~ iphatic Nitriles 1g～h with R’ClIO Reacticos ngIDA inTHF at 0 025M at 一 78I；；Anti：syn ratiosw eme~．sttred by NMR(300 or 400 hfⅡ七) However，electron poor nitrile ld reacts with considerably 1ess diasterece,electivlty than la．counter to our expectations(entry 4)．One possible explanation for deviation ofldfromthe expected behavioris that substitution of the nitrile with electron—withdrawing groups cfluses substantial chang e in the ground—state 8~?IXIcture of the llthiated nltrile．Paganl has demonstrated that the cyano group has a very small charge demand，and stabilizes adiacent negative charge principally by field effect and not by resollsnce．【 Therefore the degree to which negative oh~ge is delocalised into the ring should be vert sensitivetothe presenceof electron—withdrawing groups．More extensive dek~alizationofthenegative charge into the aromaticring wouldbe expectedtolengthentheN—Libond；asthisprocess continues． at N：31Tle point a solvent separated ion pair(SSIP)would result．In either case(elongated N—Li bond or SS1P)，lower aldol diestereoselectivity is anticipated as a consequence of poorer steric differentiation of the diastereomeric transition states． Naphthylic acetonitriles le and If also react with 1ower diastereoselectivity than the parent la． and presumably for the ~ffne reasDn． In these eases 维普资讯 http://www.cqvip.com 有 机 化 学 1997正 delocalization of negative c}mrge into the ring should be very extensive，since deloeali~ation would not be accompanied by a significant less of n 0nance stabilization．However．from a synthetic point of view，it is importan to note that acceptable aldol stereoselectivity can still be achieved for nitriles ld～f in reactions with tertiary aldehyde 2h(entries 4--6)． 3 Aldol Reactiml of Aliphatic Nitdles The utility of the nitrile aldoI reaction ld greatly increase if aliphafic nitriles could be shown to react wi th reliable diasterec~electivity．Thus far this goaI has not been met；in our preliminary studies diastereeaelestivity wi th aliphatic nitriles is unacceptably low and not tmiformly anti—sekestuve (Tabke 3)．The resultswithisovaleronitrile(1g)are strikinginthat changing thealdehyde r~ultain a complete reversaIindiastereoselectivity(entries1＆4)．The r~ultawith t—butylacetonitrile(1h)are ofinterestfromthe viewpointthat selectivitywith 一aldehydes is remarkably low (entries 5。6)， giventhe huge steric bulk of the t—butyl group．Useful selectivity is achieved in only one case．in whieh steric effectsare pushedtothe conceivableIimit(entry 7)Clearlythe~se selecfivities cannotbe accounted for by our transition state mode1．W e therefor~propose that the solution structure of 1ithiated aliphatic nitriles is quite different from the arylmethyl(”bensylic”)counterpart—specifically we anticipate that the lithiated aliphatic nitriles are rrlore highly aggregated．However．our preliminary attempts to generate rnore anti—selactive lower aggregates by addition of strong ly donating ligands suchasHMPAorTMEDAhave not effected the observed anti：syn ratio(entries 2。3)． 4 Synthesis of T—Alflfl~lo alcohol derivatives The 7一~ilino ether or 7一amino alcohol functional group is present in a number of important 、 antidepressants，such as the selective 5 一 }rr reuptake inhibitor Fluoxefine．[6]related drugs Tomoxetene and Nisoxetine[7l and the recently approved Venlafaxine Is]Reducti0n of aldols 3 pmvides ready access to this functional group。proceeding in gcxzd yield and without epimerizat ion： OH R R‘ a 3 【0r$们 ) 只 1．1：1 LIAIH#'AICI3 EI20．RT z HCI Ig) H 只‘ ant／-7cI4 ) syn-Tcf5∞ ) syr~7f b／ “2+ R Y d’ 只’ anti-Bb C76％) ＼。 且 snli-6a Pa 6b Cy syr~Bb 。 BrJ 6c Mes 6c ‘ ant／-6d t-Bu anO．6a 。 syr~6f Ph 且= Ph 4．MeO-Pn 2-Naphth ,qZr Yield 国 ％ 瓣 ‘ 嘲 ‘ 75％ 母 ％ 72％ O i H a R ) e ( a c g I3 e c n O ts ) ： 2cO，E，3N，cH2cI2．．7日。c ． 只—’、 rNMe2 譬HHcCHHoO，,NHaCBOH23Hc,Nr．ezfnlucx1．2．MaOH n． 7一 Amino alcohols 6 can be further transformed to the cyclic carbamates 7 in moderate yield Application of the s Lr1dard Esehweiler—Clarke protocol to anti一 6b affords the o~rreaponding tetrahydro一1．3一oxazine anti一8b in good yield；application of a modified pr~edure[ 】give the expected N ，N —dimethyl derivative anti一9bin excellent yield．ThustheNitrih AldoIReaction 维普资讯 http://www.cqvip.com 第 1期 有 机 化 学 he used t0 prepare a"rode range Df highly functionalized and stereochemically defined acyellc and hetereacyclic compounds not easily prepared by other methods． Acknowledgments：We thank Mr．Chi Yeung Kwod{or performing N3nle of the reactions listed in Table 3， and the Hong Kong Research Grants Council tor Competitive Earmarked Grants (HKUSW203／93E andHKUST588／95P) ． Referene~ and notes [1]a)Hanut~，H．；Suga．~awa，T．Ch Leu，．1982，i401 bj Kasatlma，A N．；Biktlmirov．R．Kh； 。1stikov，G．A．；Nik~aenko，A G．J．Ora． ．USSR．，1990，26， 1037． c)KaI1mT ，T．；Kieper，H ；Pieper．H．Chem．／3er．，1992，899 【2]a)Carliex，p．R．；Lo．K—M．J．Org Chem．，1994，59，4053 b)Carlier，P R．；Lo，K—M．；Lo，M．M—C．；Williams．I D J．Org．C era．，1995，60．7511． [3]Carlier．P R ；Lucht，B Ll；Coltmn，D．B．J．Am era．Soc．．1994116，11602 [4]a)Jacobsen，E N．；Zh~g．W ；Calder，M L J Am． m ．Soc，1991，113，6703． b)Jscobsm，E．N．；I)eng．L．；Furukawa，Y．；[k／iartine~．．L E Tetrahedron ，1994，50．4323． 【5]A[~tlotto，A．；Bradartmnte，S．；Paganl，G．A．J．Org．Chem．，1993，58，449． [6]R0be!ts0n．D W ；K“ m抽，J H F 1盯．R W．；Leander J．D．J． I be珥 ．1988，31，1412 [7 J a)DrugsFuture．，1986．1l，134． b)Koenig，T M．； tehet1．D Tetrah~lron Lett，1994，35，1339． [8]NIarketed undextheilanle”Effexc~”：Yard|ey，J．P ；HuSb日I ，G．E．M．；Butch，J．；Bicksl~，J．；Moyer，J．A．： Muth，E A．；A ，T．；FIetcher，H IIl；James，M．N G ；S i，A．R．J．Med．Chem ，1990．33，2899． [9]K／m．S．；Oh，C．H．；b，J．S；Aha，K．H ；Kim，Y．J．，Org Chem ．1985，50，1927． 维普资讯 http://www.cqvip.com