氨基酸的合成文档格式.docx

氨基酸的合成文档格式.docx

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2.23.2SynthesisofthekeyintermediateofthenovelrennininhibitorAliskiren

2.3Efficientsynthesesofbiologicallyimportantaminoacid

Synthesisofα-aminoacidanditsderivantfromaziridine

3．synthesisoftheaminoacidsfrom2-isopropyl-3,6-dimethoxy（or:

diethoxy）-2,5-dihydro-pyrazine

4．

4.Synthesisofα-aminoacidfromEvansReagent

1．前言

不对称合成a-氨基酸的工作自1970年代后期系统地开展起来，在其后的十余年中，发现了几十种不对称合成方法。

已经报道的a-氨基酸不对称合成方法可以分为五类，即酶合成法、αβ-脱氢氨基酸氢化或环加成法、Strecker型反应、亲电或亲核氨基化法以及亲电或亲核烷基化法，上述反应都涉及α-碳的手性控制.就立体选择性的控制方法而言，手性辅基（chiralauxiliary）方法仍占多数。

用于不对称合成a-氨基酸的手性辅基种类较多，常见的环系模板（cyclictemplates）（也叫环系手性辅基）和非环系模板（acyclictemplates）（也叫非环系手性辅基）应用手性辅基的a-氨基酸不对称合成方法

甘氨酸或丙氨酸衍生烯醇盐（enolates）的亲电烷基化是最早发展的a-氨基酸合成方法，该法变化形式丰富，研究和应用广泛，其中有几种已成为当前制备手性氨基酸的常规方法.U.Schollkopf法—从氨基酸模块开始的合成,D.Seebach法---手性中心自我再生”原理的成功应用,Y.N.Belokon法—含甘氨酸席夫碱的金属配位化合物,W.Oppolzer法---方便回收的天然手性源辅基,D.A.Evans法---一种广泛应用的手性辅基,M.J.O'

Donnell法---基于金鸡纳碱的手性相转移催化。

2.制备手性氨基酸的常用方法

2．1U.Schollkopf法---从氨基酸模块开始的合成

U.Schollkopf用L-Val和Gly缩合制得环二肽7,7与Meerwein盐（Me30+BF4-）作用得甲基醚1，经丁基锂脱质子得甘氨酸负离子8，烷基化生成9，酸水解，得手性a-氨基酸10.此法所得氨基酸的ee值可达95%以上.制备反应如Scheme1所示。

Scheme1

Example:

2.1.1U.Schollkopf法---从氨基酸模块开始的合成示例

References:

TetrahedranAsymmetry,10（1999）,4151~4156.

ToastirredsuspensionofD-valine1（117.15g,1.0mol）inTHF（1200mL）wasaddedphosgene（148.5g,0.5mol）,thetemperaturewasmaintainedat40℃withaheatingmantle.Afterthesolidinsolutiondisappeared,thesolutionwhichresultedwaspurgedwithN2for2h,thesolventwasremovedinvacuoandtheresiduewasflashedwithTHFtwice,theN-carboxyanhydridewhichformedwasdriedinthevacuumtoprovidearudeproduct2（206.37g,>

100%）,duetotheunstablenatureofthisanhydrideitwasusedimmediatelyinthenextstepwithoutfurtherpurification.

AsolutionoftheN-carboxyanhydride2（206.37g,1.44mol）inTHF（1600mL）wasaddeddropwisetoavigorouslystirredmixtureofglycineethylesterhydrochloride3（201.32g,1.44mol）,triethylamine（461mL,3.31mol）,andchloroform（2000mL）at–70℃.After3hofstirringat–70℃and2hatroomtemperature,thereactionsolutionwasfilteredtoremovethetriethylaminehydrochloride,thefiltratewasconcentrateinvacuotogivetheresidue4.Theresidue4wasaddedtoluene,thesuspensionwhichresultedwasheatedatrefluxfor12handthencooledto0℃,thebis-lactimwhichresultedwasrecoveredbyvacuumfiltration,washedwithetheranddriedundervacuumat100℃toprovidethepurecompound5.

Toastirredsolutionoftriethyloxoniumtetrafluoroborate6（1063.19g,5.60mol）inCH2Cl2wasaddedthebislactim5（291g,1.86mol）inportions,afterseveralhoursthereactionmixturebecamehomogeneous,thereactionwasstirredatroomtemperatureunderN2for3days,afterwhichasolutionofNaH2PO4andNa2HPO4inwaterwasaddedtothesolutionwithstirring,theorganicphasewasseparatedandtheaqueousphasewasre-extractedwithCH2Cl2twice.ThecombinedorganiclayersweredriedoverMgSO4,evaporatedtoremovethesolvent,theresiduewasvacuumdistilledtoprovidethepurebis-ethoxylactimether7.

n-BuLi（1.6Minhexanes,9.6mL,15.4mmol）wasaddedtoa−78°

Csolutionof（R）-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine7（3,2.5mL,14mmol）and1,3-dimethyl-2-imidazolidinone（DMEU,3.1mL,28mmol）indryTHF（140mL）.After45min,asolutionof2-bromoethyltriphenylmethylsulfide8（6.32g,16.5mmol,1.2equiv.）indryTHF（30mL）wasaddedover25min.After20hat−78°

C,thecherrycoloredreactionmixturewasquenchedwith5mLof100mmol,pH7.2phosphatebufferandwarmedtoambienttemperature.Theyellowsolutionwasconcentratedinvacuoandtheresultingresiduewaspartitionedbetweenethylacetate（EtOAc,100mL）andwater（100mL）.TheaqueouslayerwasseparatedandextractedwithEtOAc（50mL）.CombinedorganicextractsweredriedoverNa2SO4,decantedandconcentratedinvacuotogiveanoil.Purificationbyflashchromatography（5%EtOAc/hexanes）gave1.60g（47%basedonrecoveredstartingmaterial）of（2R,5S）-2-isopropyl-3,6-dimethoxy-5-[2-（tritylsulfanyl）ethyl]-2,5-dihydropyrazine9.

Compound9:

1HNMR（CDCl3）_7.42–7.38（m,5H）,7.29–7.12（m,10H）,3.96（ddd,J=7.2,3.6,3.6Hz,1H）,3.81（dd,J=3.6,3.6Hz,1H）,3.61（s,3H）,3.55（s,3H）,2.27–2.07（m,2H）,1.99–1.88（m,1H）,1.78–1.66（m,1H）,1.00（d,J=6.6Hz,3H）,0.65（d,J=6.9Hz,3H）;

13CNMR（CDCl3）_163.67,163.22,144.98,129.60,127.75,126.47,66.51,60.73,54.52,52.36,33.19,31.78,27.75,18.99,16.64;

ESMS（M+2H）2+243.2.AnalyticalHPLC（2%EtOAc/hexanes）:

Rt=7.72min

A0.50Maqueoussolutionofhydrochloricacid（10.1mL,5.06mmol,2.1equiv.）wasaddedtoasolutionof（2R,5S）-2-isopropyl-3,6-dimethoxy-5-[2-（tritylsulfanyl）ethyl]-2,5-dihydropyrazine（1.17g,2.41mmol）indioxane（10.1mL）andstirredfor6hatambienttemperature.ThesolutionwasthenadjustedtopH10withconcentratedammoniumhydroxideandextractedwithCHCl3（340mL）.Combinedorganicextractsweredried（Na2SO4）,decantedandconcentratedinvacuo.Theresidualoilwaspurifiedbyflashcolumnchromatography（5%MeOH/CH2Cl2;

Rf=0.37）toaffordmethyl（2S）-2-amino-4-（tritylsulfanyl）butanoate5asathickcolorlessoil（840mg,89%）.1HNMR（CDCl3）7.43–7.39（m,5H）,7.31–7.18（m,10H）,3.64（s,3H）,3.43–3.38（m,1H）,2.30（t,J=7.8Hz,2H）,1.80–1.70（m,1H）,1.58–1.46（m,1H）;

13CNMR（CDCl3）175.85,144.79,129.59,127.86,126.62,66.77,53.48,51.96,33.95,28.31

TheMosheramideof10waspreparedbyaddingtriethylamine（10.2mL,0.073mmol）and（R）-（−）-（-）-methoxy-（trifluoromethyl）phenylaceticacidchloride（13.6mL,0.073mmol）insuccessiontoasolutionofmethyl（2S）-2-amino-4-（tritylsulfanyl）butanoate（5,19mg,0.05mmol）inanhydrousdichloromethane（1mL）andstirredfor3hatambienttemperaturethenquenchedbyadditionofwater（100mL）.After15minofstirring,dichloromethane（20mL）wasaddedandwashedwithwater（20mL）.Theorganiclayerwasseparated,dried（Na2SO4）,decantedandconcentratedinvacuotoaffordanoilwhichwaspurifiedbyflashchromatographytoafford22mg（72%）oftheMosheramideof10.1HNMR（CDCl3）7.51–7.42（m,2H）7.35–7.15（m,18H）,6.93（d,J=8.4Hz,1H）,4.55–4.48（m,1H）,3.66（s,3H）,3.47（d,J=1.5Hz,3H）,2.25–2.15（m,1H）,2.09–1.98（m,1H）,1.83–1.71（m,1H）,1.54–1.38（m,1H）;

19FNMR（CDCl3）:

−6.15.

A0.50MLiOHsolution（9.0mL,4.5mmol,2.02equiv.）wasaddeddropwisetoasolutionofester10（772mg,1.98mmol）indioxane（9.0mL）andstirredatroomtemperaturefor3h.Thereactionmixturewasconcentratedinvacuoandtheresidualsolidwassuspendedinwater（20mL）.CarefuladjustmenttopH8with1MaqueousHClaffordedaprecipitate.Thewhitesolidthusobtainedwasfilteredanddriedunderhighvacuumat46°

CoverP2O5togive（2S）-2-amino-4-（tritylsulfanyl）butanoicacid11（,Striphenylmethyl-L-homocysteine,687mg,92%）.1HNMR（DMSO-d6）:

7.48–7.18（m,15H）,3.02（t,J=6.3Hz,1H）,2.26（t,J=5.1Hz,2H）,1.90–1.73（m,1H）,1.69–1.53（m,1H）;

13CNMR（DMSO-d6）:

169.17,144.51,129.05,127.93,126.62,65.90,53.43,30.40,28.11;

Sodiummetal（61mg,2.65mmol）wasaddedtoasuspensionofS-triphenylmethyl-L-homocysteine（11,270mg,0.72mmol）in20mLofliquidammoniaat−33℃.After1h,thereactionmixturewaswarmedtoambienttemperatureandconcentratedinvacuo.（Caution:

theproductisextremelyairsensitive.Exposuretoairshouldbekepttoaminimum.）Theresultingsolidwassuspendedindeaeratedwater（10mL）andextractedwithdeaeratedether（10mL）toremovetriphenylmethane.TheaqueouslayerwasadjustedtopH6bycarefuladditionofdeaerated47%aqueousHI.ThissolutionwasconcentratedinvacuoandanyremainingHIwasremovedbyazeotropingwithdeaeratedwater（3*10mL）.Theresiduewasstirredindeaeratedhotethanolfor15min,cooledtoambienttemperatureundernitrogenandfiltered.Thefilteredsolidwasisolatedanddriedunderhighvacuumfor15hat56℃toafford51mg（52%）ofL-homocysteine14.1HNMR（D2O）:

3.73（dd,J=7.4,5.7Hz,1H）,2.60–2.42（m,2H）,2.12–1.88（m,2H）;

13CNMR（D2O）:

174.61,53.97,34.98,20.15;

Sodiummetal（141mg,6.13mmol）wasaddedtoasuspensionof11（200mg,0.53mmol）in40mLofliquidammoniaat−33°

Candstirredfor3.5h.UnreactedsodiummetalwasquenchedbytheadditionofafewcrystalsofNH4Cl.Ammoniawasallowedtoevaporatebywarmingtoambienttemperatureandanyresidualammoniawasremovedinvacuo.Deaeratedwater（50mL）waspouredintotheflaskandthemixturewasextractedwithdeaeratedether（2*25mL）.TheaqueouslayerwasadjustedtopH7bythecarefuladditionofdeaeratedconcentratedHCl,themixturetreatedwithdecolorizingcarbon,filteredthroughCelite®

andthefilterpadwashedwithdeaeratedwater（15mL）.Theresultingfiltratewasflushedwithairfor1handleftsittingopentoairfor12h.Filtrationremovedtracesuspendedsolidsandthefiltratewasconcentratedinvacuo.Theresidualsolidwasdissolvedinwater（3mL）andfiltered.FiltratepHwasadjustedfrom9.8to5.5bycarefuladditionofconcentratedHClandallowedtostandfor30min.Thesolidthusobtainedwaswashedwithwater（3*2mL）anddriedunderhighvacuumoverP2O5at46℃togive28mg（40%）ofL-homocystine13asanoff-whitesolid.1HNMR（D2O/NaOD）:

3.15（dd,J=7.4,5.8Hz,2H）,2.58（t,J=8.0Hz,4H）,1.90–1.64（m,4H）;

13CNMR（D2O/NaOD）:

183.13,55.40,34.78,34.73;

2.1.23.2SynthesisofthekeyintermediateofthenovelrennininhibitorAliskiren

HelveticaChimicaActa,86（2003）,2848~2870.

（2S,5R）-2,5-Dihydro-3,6-dimet