唐 貝，李高偉

(1. 河南省醫(yī)藥學(xué)校,河南 開封 475001； 2. 商丘師范學(xué)院 化學(xué)系，河南 商丘 476000)

具有光學(xué)活性的α-氨基酸及其衍生物不僅是抗生素藥物、農(nóng)業(yè)化學(xué)藥品及食品添加劑的重要前體，還可以作為一種手性誘導(dǎo)劑被廣泛地應(yīng)用于不對(duì)稱合成化學(xué)中. 而不對(duì)稱Strecker 反應(yīng)是合成手性α-氨基酸最經(jīng)濟(jì)、最方便、最有效的方法之一.

1996年， LIPTON 小組首次報(bào)道了手性環(huán)二肽催化的N-二苯甲基亞胺與HCN的不對(duì)稱Strecker反應(yīng)[1]. 此后，不對(duì)稱Strecker反應(yīng)備受有機(jī)化學(xué)家關(guān)注.

1 醛亞胺的不對(duì)稱Strecker反應(yīng)

近年來，醛亞胺的不對(duì)稱Strecker反應(yīng)被有機(jī)化學(xué)家廣泛、深入地研究，許多優(yōu)秀高效的催化劑被報(bào)道，大大推動(dòng)了這一領(lǐng)域的發(fā)展.

1.1 手性噁唑硼烷催化劑

2006年，BERKESSEL小組報(bào)道了手性噁唑硼烷1催化的N-芐基亞胺與氫氰酸的不對(duì)稱Strecker反應(yīng)(圖1)，僅獲得中等的e.e.值(39%～71%)[2]，而且發(fā)現(xiàn)利用質(zhì)子化的噁唑硼烷2催化反應(yīng)時(shí)，獲得手性相反的產(chǎn)物.

1.2 手性鈦配合物催化劑

2003年，VILAIVAN小組采用N-水楊基-β-氨基醇3與Ti(Oi-Pr)4形成的配合物催化醛亞胺的不對(duì)稱Strecker反應(yīng)[3,4]，所得產(chǎn)物的e.e.值最高超過98%，發(fā)現(xiàn)手性β-氨基醇的β-位上連有Bn，i-Pr，t-Bu，或sec-Bu等體積龐大的取代基時(shí)有利于提高e.e.值.

圖1 手性噁唑硼烷催化的N-芐基醛亞胺的不對(duì)稱Strecker反應(yīng)Fig.1 Oxazaborolidine and protonated oxazaborolidine catalyzed enantioselective Strecker reaction of N-Bn aldimines

圖2 手性N-水楊基-β-氨基醇鈦(Ⅳ)配合物催化的不對(duì)稱Strecker反應(yīng)Fig.2 Chiral N-salicyl-β-amino alcohol-Ti(IV) complex catalyzed enantioselective Strecker reaction

2007年，馮小明課題組報(bào)道了辛可寧4、3,3′-二萘基-2,2′-聯(lián)苯酚5與Ti(Oi-Pr)4形成的配合物(5 mol%)催化的N-對(duì)甲苯磺?；﹣啺返牟粚?duì)稱Strecker反應(yīng)(圖3)[5-6].

圖3 自組裝鈦(IV)配合物催化的不對(duì)稱Strecker反應(yīng)Fig.3 Self-assembled Ti(IV) complex catalyzed enantioselective Strecker reaction of aldimines

研究發(fā)現(xiàn)，該催化劑所適用的底物范圍比較廣泛，芳香族醛亞胺、脂肪族醛亞胺、雜環(huán)芳香族醛亞胺及α,β-不飽和醛亞胺都能夠獲得較高的產(chǎn)率(61% ～ 99%)和e.e.值(79% ～ 97%).

2008年，HOPPE等人利用聯(lián)苯酚6與Ti(Oi-Pr)4形成的配合物催化了醛亞胺與TMSCN的不對(duì)稱Strecker反應(yīng)(圖4)[7]，獲得中等或較高的產(chǎn)率(83% ～ 94%)和e.e.值(62% ～ 89%). 實(shí)驗(yàn)發(fā)現(xiàn)，噁唑環(huán)上連有體積龐大的均三甲苯磺?；涂臻g條件要求更苛刻的烷基側(cè)鏈的聯(lián)苯酚為最佳配體，而且最佳配體會(huì)隨著底物的變化而變化.

圖4 手性 N-芳磺?；?1, 3-噁唑烷基取代聯(lián)苯酚鈦(IV)配合物催化的不對(duì)稱Strecker反應(yīng)Fig.4 Chiral N-arenesulfonyl-1, 3-oxazolidinyl substituted biphenyldiol-Ti(IV) complex catalyzed enantioselective Strecker reaction

2010年，CHAI等人發(fā)現(xiàn)由N-水楊基-β-氨基醇和部分水解的鈦醇鹽(PHTA)生成的催化劑能夠更有效地催化不對(duì)稱Strecker反應(yīng)(圖5)[8-9]. 在室溫下較短的時(shí)間內(nèi)，各種醛亞胺均可順利轉(zhuǎn)化為相應(yīng)的產(chǎn)物. 特別是氮原子被Ph2CH，Bn和 Boc保護(hù)基保護(hù)起來的醛亞胺，產(chǎn)物可獲得優(yōu)秀的e.e.值.

圖5 由手性的N-水楊基-β-氨基醇(3b)和PHTA所形成配合物催化的不對(duì)稱Strecker反應(yīng)Fig.5 Asymmetric Strecker reaction catalyzed by the catalyst generated from N-salicyl-β-amino alcohol and PHTA

1.3 手性鑭系金屬配合物催化劑

2004年，JACOBSEN課題組報(bào)道了首例用(PhPYBOX)ErCl3配合物催化的腙的不對(duì)稱氫氰化反應(yīng)(圖6)[10]. 一系列N-苯甲酰基保護(hù)的腙被成功地轉(zhuǎn)變成為相應(yīng)的產(chǎn)物，且所獲得的產(chǎn)物具有較高的產(chǎn)率和對(duì)映選擇性.

圖6 手性(PhPYBOX)ErCl3 配合物催化的腙類化合物的不對(duì)稱氫氰化反應(yīng)Fig.6 Chiral Er(III)-PYBOX complex catalyzed asymmetric hydrocyanation of hydrazones

2008年，ISHIHARA利用1, 1′-二萘基-2, 2′-二磺酸(BINSA)和La(OPh)3形成的金屬配合物催化醛亞胺的不對(duì)稱Strecker反應(yīng)(圖7)[11]. 實(shí)驗(yàn)結(jié)果表明，該體系對(duì)具有吸電子取代基、供電子取代基的芳香醛亞胺和雜環(huán)芳香醛亞胺都表現(xiàn)出良好的催化活性和手性誘導(dǎo)能力.

2009年，KARIMI和MALEKI等人將Yb(OTf)3和吡啶-2,6-雙噁唑啉形成的配合物用于N-二苯甲基醛亞胺的不對(duì)稱Strecker反應(yīng)(圖8)[12-13]. 該課題組對(duì)包括芳香醛亞胺、脂肪醛亞胺、α,β-不飽和醛亞胺在內(nèi)的各種醛亞胺進(jìn)行了實(shí)驗(yàn)，所得產(chǎn)物的e.e.值最高可達(dá)98%. 令人感興趣的是，當(dāng)吡啶環(huán)的4-位上連有一個(gè)溴原子時(shí)，對(duì)反應(yīng)產(chǎn)物的e.e.值有顯著影響.

圖7 手性二萘基二磺酸鑭(Ⅲ)配合物催化的不對(duì)稱Strecker反應(yīng)Fig.7 Chiral lanthanum(III)-binaphthyldisulfonate complex catalyzed enantioselective Strecker reaction

圖8 Yb(OTf)3-PYBOX催化的N-二苯甲基醛亞胺的不對(duì)稱Strecker反應(yīng)Fig.8 Yb(OTf)3-PYBOX catalyzed enantioselective Strecker reaction of N-benzhydryl aldimines

1.4 手性鎂配合物催化劑

在2006年和2008年，NAKAMURA、TORU及小組成員報(bào)道了手性雙噁唑啉和Mg(OTf)2配合物催化的不對(duì)稱Strecker反應(yīng)(圖9)[14]. 盡管N-(2-吡啶磺酸基)亞胺能獲得很高的產(chǎn)率和較好的對(duì)映選擇性，而N-(p-甲苯磺酸基)醛亞胺和N-芳基、N-烷基醛亞胺卻得不到想要的結(jié)果. 基于這些實(shí)驗(yàn)結(jié)果，作者推測(cè)2-吡啶磺酸基在反應(yīng)中不僅起到了活化作用，而且也起到了有效的空間立體控制作用.

圖9 手性雙噁唑啉和Mg(OTf)2配合物催化的不對(duì)稱Strecker反應(yīng)Fig.9 Chiral bis(oxazoline)-Mg(OTf)2 complex catalyzed enantioselective Strecker reaction of N-(2-pyridinesulfonyl) imines

1.5 手性釩(Ⅴ)配合物催化劑

2006年，CRAMPTON等人成功地利用salen釩配合物催化了N-芐基醛亞胺的不對(duì)稱加成反應(yīng)(圖10)[15- 16]，所得產(chǎn)物的e.e.值可達(dá)81%. 該課題組對(duì)反應(yīng)條件進(jìn)行了系統(tǒng)研究發(fā)現(xiàn)：在10 mol%催化劑、三甲基氰硅烷(1.2 equiv)、甲醇(1.2 equiv)共同存在下，N-芐基醛亞胺的不對(duì)稱Strecker反應(yīng)的e.e.值最高達(dá)75%.

2010年，KHAN小組報(bào)道了利用二聚體salen釩配合物催化的N-芐基醛亞胺的不對(duì)稱Strecker反應(yīng)(圖11)[17]. 當(dāng)使用2-甲氧基取代醛亞胺作底物時(shí)，可獲得最高的e.e. 值(94%).

1.6 手性鋁(Ⅲ)配合物催化劑

2009年，YAMAMOTO課題組報(bào)道了栓雙(8-羥基喹啉)鋁配合物在N-膦?；﹣啺放c氰基化試劑CNCOOEt的不對(duì)稱Strecker反應(yīng)中的應(yīng)用(圖12)[18]，獲得了優(yōu)秀的產(chǎn)率(80% ～ 99%)和對(duì)映選擇性(e.e. 90% ～ 98%).

圖10 手性salen釩(Ⅴ)配合物催化的N-芐基醛亞胺的不對(duì)稱Strecher反應(yīng)Fig.10 Chiral salen-V(V))complex catalyzed asymmetric addition of cyanide to N-Bn-protected aldimines

圖11 二聚體salen釩配合物催化的N-芐基醛亞胺的不對(duì)稱Strecker反應(yīng)Fig.11 Dimeric V(V)-salen complex catalyzed asymmetric Strecker reaction of N-Bn aldimines

圖12 栓雙(8-羥基喹啉)鋁(Ⅲ)配合物催化的N-膦酰基醛亞胺的不對(duì)稱Strecker反應(yīng)Fig.12 Tethered bis(8-quinolinolato)-Al(III) complex catalyzed asymmetric Strecker reaction of N-phosphonyl imines

2010年，LI等報(bào)道了N-膦?；﹣啺放cEt2AlCN的不對(duì)稱Strecker反應(yīng)(圖13)[19]. 只需加入催化量的氨基醇14或3,3′-二(4-聯(lián)苯基)聯(lián)萘酚15，各種芳香醛亞胺的不對(duì)稱Strecker反應(yīng)都能夠順利進(jìn)行，并獲得優(yōu)秀的產(chǎn)率(89% ～ 97%)和對(duì)映選擇性(e.e. 93% ～ 99%).

1.7 手性有機(jī)小分子催化劑

2007年，LIST小組首次報(bào)道了以乙酰氰化物作為氰源，硫脲16(圖14)作為催化劑的不對(duì)稱Strecker反應(yīng)[20]. 實(shí)驗(yàn)發(fā)現(xiàn)，只需添加1 ～ 5 mol%的催化劑，一系列芳香醛亞胺或脂肪醛亞胺的氰化反應(yīng)就能夠順利完成，且能獲得很高的產(chǎn)率和e.e.值(98%).

2010年，TSOGOEVA小組利用類似的手性聯(lián)萘酚磷酸17催化了腙的不對(duì)稱Strecker反應(yīng)(圖15)[21]. 實(shí)驗(yàn)結(jié)果顯示， N-4-硝基苯甲?；Ｗo(hù)脂肪腙的催化結(jié)果較好(e.e. 71% ～ 92%).

圖13 N-膦酰基醛亞胺與Et2AlCN的不對(duì)稱Strecker反應(yīng)Fig.13 Asymmetric Strecker reaction of N-phosphonyl imines with Et2AlCN in the presence of catalytic amounts of amino alcohol or BINOL derivative

圖14 硫脲催化劑Fig.14 Thiourea catalyst

圖15 手性聯(lián)萘酚磷酸催化的不對(duì)稱Strecker反應(yīng)Fig.15 Chiral phosphoric acid catalyzed asymmetric Strecker reaction of N-4-NO2-benzoyl-protected aliphatic hydrazones

2 結(jié)論與展望

近年來，有關(guān)醛亞胺的催化不對(duì)稱Strecker反應(yīng)[22-24]的研究已取得了較大成果，許多新型催化體系不斷被報(bào)道，催化活性和對(duì)映選擇性得到不斷提高. 但是目前報(bào)道的催化劑在使用范圍以及通用性等方面還存在一定的局限，因此，設(shè)計(jì)并合成出結(jié)構(gòu)新穎、催化效能更好、應(yīng)用范圍更廣泛的催化劑成為今后發(fā)展的趨勢(shì). 這對(duì)于合成具有重要生物活性的α-氨基酸具有重要意義.

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