Chiral Bronsted acid catalyzed enantioselective aza-Diels-Alder reaction of Brassard's diene with imines
Chiral Bronsted acid catalyzed enantioselective aza-Diels-Alder reaction of Brassard's diene with imines
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DOI：
10.1002/anie.200601345
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发表时间：
2006-01-01
影响因子：
16.6
通讯作者：
Akiyama, Takahiko
中科院分区：
文献类型：
--
作者：
Itoh, Junji;Fuchibe, Kohei;Akiyama, Takahiko
哌啶衍生物是生物学上重要的哌啶生物碱、[1]肽和氮杂糖的前体，因此是重要的合成靶标。从药物科学以及合成有机化学的观点来看，开发用于合成光学纯形式的哌啶衍生物的新的有效方法是重要的。富电子二烯与醛亚胺的aza-Diels-桤木反应是一种高效的制备非对称哌啶衍生物的方法。[2]因此，亚胺与1-烷氧基-3-甲硅烷氧基-1，3-丁二烯及其衍生物（Danishefsky s diene）[3]的氮杂-Diels-桤木反应可除去官能化的哌啶酮。近年来，人们研究了一种催化不对称的aza-Diels-桤木反应，并获得了很高的对映选择性。[4]作为富电子二烯的另一个潜在的候选者是1，3-二甲氧基-1-（三甲基甲硅烷氧基）丁二烯1（双烯），[5]其反应提供哌啶酮衍生物（方案1）。[6]与Danishefsky的二烯相比，Escherard的二烯的研究较少。尽管Waldmann等人已经报道了与手性亚胺的氮杂-Diels-桤木反应的非对映选择性形式，其导致光学活性的哌啶酮衍生物，[7]米德兰和Koops，[8]和Kawecki，[9]的催化对映体选择性反应的双烯与亚胺，据我们所知，还没有报道。[10]双烯的高反应活性和不稳定性与其杂Diels-桤木反应的缺乏有关。最近，手性布朗斯台德酸催化，[11，12]无金属有机催化的变体，已成为一个快速增长的领域。[13]我们已经开发了由（R）-BINOL衍生的手性磷酸2作为手性布朗斯台德酸催化剂。[14与2相关的潜在问题之一在于其强酸性，[16]特别是当应用于不稳定的底物时。我们已经发现，它的吡啶鎓盐3也表现出有效的催化活性作为手性布朗斯台德酸催化剂，但比2与不稳定的底物，如双烯更相容。本文报道了手性布朗斯台德酸催化的醛亚胺与双烯1的aza-Diels-桤木反应，以高产率和良好的对映选择性（高达99%ee）得到了哌啶酮衍生物.据我们所知，这是第一个报道的不对称选择性氮杂-Diels-桤木反应的双烯醛亚胺。[17]在磷酸2的3，3 '-位上的取代基的筛选揭示了如在2a [15 c]中的9-蒽基对于氮杂-Diels-桤木反应是最有效的。因此，将衍生自苯甲醛和2-氨基-4-甲基苯酚的醛亚胺4a（R= Ph）和双烯1用2a（3mol%）在均三甲苯中在40 ℃下处理24小时。用PhCO 2 H（1当量）处理反应混合物并加热12小时，得到环加合物5a，产率72%，ee为92%（表1，条目1）。注意，只要催化剂的量为3摩尔%，就足以使反应有效地进行。有趣的是，使用等量（3mol%）的其吡啶鎓盐3显著提高了产率，具有相当的对映选择性（表1，条目2）。由芳香醛和杂芳香醛衍生的一系列醛亚胺进行氮杂-Diels-桤木反应，得到具有优异的对映选择性的环化产物（表1，条目3 -14）。原位生成的脂肪族醛亚胺也得到具有优异ee值的相应环加合物（表1，条目15、16）。5的绝对立体化学（R= p-BrC 6 H4;表1，条目3）通过X射线晶体学明确地确定。
Piperidine derivatives are precursors of the biologically important piperidine alkaloids,[1] peptides, and aza sugars, and are therefore important synthetic targets. Development of novel efficient methods for the synthesis of piperidine derivatives in optically pure form is important from the standpoint of the pharmaceutical sciences as well as synthetic organic chemistry. The enantioselective aza-Diels–Alder reaction of electron-rich dienes with aldimines provides an efficient protocol for the preparation of piperidine derivatives in scalemic form.[2] Thus, the aza-Diels–Alder reaction of an imine with 1-alkoxy-3-siloxy-1, 3-butadienes and its derivatives (Danishefsky s diene)[3] furnishes functionalized piperidinones. A catalytic asymmetric version of the aza-Diels–Alder reaction was investigated recently, and high enantioselectivity was attained.[4] Another potential candidate as an electron-rich diene is 1, 3-dimethoxy-1-(trimethylsiloxy) butadiene 1 (Brassard s diene),[5] the reaction of which provides piperidinone derivatives (Scheme 1).[6] In contrast to Danishefsky s diene, Brassard s diene has been less extensively studied. Although diastereoselective versions of aza-Diels–Alder reactions with chiral imines that lead to optically active piperidinone derivatives have been reported by Waldmann et al.,[7] Midland and Koops,[8] and Kawecki,[9] the catalytic enantioselective reaction of Brassard s diene with imines has, to the best of our knowledge, not been reported.[10] The high reactivity and lability of Brassard s diene is associated with the paucity of its hetero-Diels–Alder reaction. Recently, chiral Brønsted acid catalysis,[11, 12] a variant of metal-free organocatalysis, has become a rapidly growing area.[13] We have already developed chiral phosphoric acid 2, derived from (R)-BINOL, as a chiral Brønsted acid catalyst.[14, 15] One of the potential problems associated with 2 lies in its strong acidity,[16] in particular when applied to labile substrates. We have found that its pyridinium salt 3 also exhibits efficient catalytic activity as a chiral Brønsted acid catalyst but is more compatible than 2 with labile substrates such as Brassard s diene. Herein, we report the chiral Brønsted acid catalyzed aza-Diels–Alder reaction of aldimines with Brassard s diene 1 to afford piperidinone derivatives in high yields and with excellent enantioselectivities (up to 99% ee). To our knowledge, this is the first report of an enantioselective aza-Diels–Alder reaction of Brassard s diene with aldimines.[17]Screening of substituents at the 3, 3’-positions of phosphoric acid 2 revealed that 9-anthryl groups as in 2a [15c] were the most effective for the aza-Diels–Alder reaction. Thus, aldimine 4a (R= Ph), derived from benzaldehyde and 2-amino-4-methylphenol, and Brassard s diene 1 were treated with 2a (3 mol%) in mesitylene at À408C for 24 h. Treatment of the reaction mixture with PhCO2H (1 equiv) with heating for 12 h afforded cycloadduct 5a in 72% yield and with 92% ee (Table 1, entry 1). Note that as little as 3 mol% of the catalyst suffices for the reaction to proceed efficiently. Interestingly, use of the equivalent amount (3 mol%) of its pyridinium salt 3 improved the yield significantly with comparable enantioselectivity (Table 1, entry 2). A range of aldimines derived from aromatic and heteroaromatic aldehydes underwent the aza-Diels–Alder reaction to afford cyclization products with excellent enantioselectivities (Table1, entries3–14). Aliphatic aldimines, which were generated in situ, also gave corresponding cycloadducts with excellent ee values (Table 1, entries 15, 16). The absolute stereochemistry of 5 (R= p-BrC6H4; Table 1, entry 3) was unambiguously determined by X-ray crystallographic …