分會

第五十三分會：手性化學(xué)

摘要

多肽是一類具有重要生物活性的物質(zhì)，可用于制作疫苗和藥物，其中非天然多肽通常表現(xiàn)出不同于天然多肽的生物活性。用固相合成法制備非天然多肽時，一般要用到N,C端雙保護(hù)的非天然氨基酸，其中N端保護(hù)基最常見的是胺基甲酸酯。α-重氮酯衍生的卡賓和胺基甲酸酯的不對稱N-H鍵插入反應(yīng)是合成氨基甲酸酯保護(hù)的非天然α-氨基酸酯的直接方法，此前人們實(shí)現(xiàn)了α-芳基和α-烯基重氮酯衍生卡賓對胺基甲酸酯N-H鍵的高對映選擇性插入反應(yīng)，但α-烷基重氮酯衍生卡賓的同類反應(yīng)仍然沒有成功的例子。這可能是由于在金屬催化下，α-烷基卡賓容易發(fā)生β-H遷移反應(yīng)得到烯烴副產(chǎn)物，而其烷基相較芳基和烯基柔性更高，造成相應(yīng)N-H鍵插入反應(yīng)的對映選擇性控制更為困難。我們發(fā)展了一種基于催化卡賓對N-H鍵的插入反應(yīng)合成非天然氨基酸酯的新方法。該方法以Tp*Cu(I)配合物與手性磷酸為催化劑，α-烷基重氮酯為卡賓前體，氨基甲酸酯為N-H鍵給體，高收率和高對映選擇性地合成了胺基甲酸酯基保護(hù)的非天然α-氨基酸酯，具有條件溫和、底物適用范圍廣、官能團(tuán)耐受性好等特點(diǎn)，豐富了非天然氨基酸的類型。該方法合成的保護(hù)的非天然氨基酸具有很好的應(yīng)用潛力，可對映選擇性保持地轉(zhuǎn)化為多種α-氨基酸衍生物，并可直接應(yīng)用于人工合成多肽。該研究拓展了N-H鍵插入反應(yīng)，豐富了非天然氨基酸類型，為非天然多肽的合成應(yīng)用和功能發(fā)現(xiàn)提供了新的物質(zhì)基礎(chǔ)。 Polypeptides are a class of substances with important biological activities that can be used to make vaccines and drugs. Unnatural polypeptides usually exhibit different biological activities from natural polypeptides. When using solid phase synthesis to prepare unnatural polypeptides, it is generally necessary to use N- and C- double protected unnatural amino acids, among which the most common N-terminal protective group is carbamate. The asymmetric N-H bond insertion reaction of carbenes derived from diazoesters with carbamates is the direct method for carbamate-protected unnatural α-amino esters. Although such reactions using α-aryl and α-alkenyl carbenes has previously been realized, there are still no successful examples of similar reactions of α-alkyl carbenes. This may be due to the α-alkyl metal carbene is prone to occur β-H migration side reaction and high flexibility of the alkyl group makes it difficult to control the enantioselectivity. Expanding on our previously reported work on catalytic asymmetric carbene insertion reactions, we have developed a method for highly enantioselective N?H bond insertion reactions of α-alkyl-α-diazoacetates and various carbamates cooperatively catalyzed by Tp*Cu(I), where Tp = (hydrotris(4,5-bromopyrazolyl)borate), and a chiral spiro phosphoric acid. These reactions provide straightforward access to unnatural optically active N-carbonate α-alkyl-α-amino esters, which are widely used in artificial peptide synthesis. This mild method uses readily available starting materials and features a broad substrate scope, good functional group tolerance, good to high yields (58?88%), and high enantioselectivities (90?96% ee). The combination of the neutral copper catalyst Tp*Cu(I) and the chiral spiro phosphoric acid ensures the success of the reaction by inhibiting a β-H migration reaction of a copper carbene intermediate and by promoting enantioselective proton transfer to an enolate intermediate.

關(guān)鍵詞

不對稱合成;N-H鍵插入反應(yīng);非天然α-氨基酸;肽合成;手性質(zhì)子梭

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