An efficient asymmetric route to 2,3-diaminobutanoic acids
An efficient asymmetric route to 2,3-diaminobutanoic acids
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DOI：
10.1021/jo9720391
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发表时间：
1998-03-20
影响因子：
3.6
通讯作者：
Janda, KD
中科院分区：
文献类型：
--
作者：
Han, HS;Yoon, J;Janda, KD
在越来越多的天然化合物中发现了非蛋白质氨基酸。因此，由于它们的蛋白酶抗性和潜在的构象限制，人们对它们在药物化学中作为拟肽物的基础材料的应用兴趣也有所增加。2，-二氨基酸家族是多种抗生素、3抗真菌二肽、4和其他生物活性化合物中发现的关键结构元素。特别是R，-二氨基丁酸，如1（图1），已经吸引了大量的合成努力，因为它们是R，-二氨基酸家族中最简单的成员，但在肽抗生素和毒素中都是关键元素。已经报道了几种合成R，-二氨基丁酸的方法。值得注意的是Schmidt及其同事报道的以苏氨酸或同素苏氨酸为起始原料，利用Mitsunobu反应条件安装第二氨基的方法。虽然这种方法是可靠的，但只有反异构体1b和1d可以从苏氨酸中获得，而同步异构体1a和1c必须从全素苏氨酸中获得。在相关研究中，Shin6a， b描述了以l -苏氨酸或d -苏氨酸为起始原料，通过双反转化学得到1的所有四种异构体1a和1c。采用完全不同的策略，Davies和他的同事6c报道了外映体1a和1d的合成，基于手性锂酰胺不对称加成到巴东酸叔丁酯上，然后用三酰叠氮引入第二个氨基。最近，1的所有四个同分异构体都是通过甲基溴化镁的亲核加成合成的，这些甲基溴化镁是由l -丝氨酸或d -丝氨酸衍生的不同保护的硝基化合物。这种方法的关键是在起始硝基上使用的保护基团策略，因为这决定了反应的立体化学结果。除了Davies概述的方法外，所有R，-二氨基丁酸的合成都需要使用旋光性R-氨基酸作为起始原料。此外，虽然Davies的方法也适用于其他R -二氨基酸的合成，但它需要化学计量量的手性试剂来完成两个关键步骤，一个Michael和亲电加成。在此，我们报道了一种高效的立体选择性合成R，-二氨基丁酸，消除了在以前的合成中发现的缺点。我们的路线利用高度对映选择性Sharpless不对称氨基羟基化（AA）反应和区域选择性开环的氮化吡啶功能。市售的巴豆酸叔丁酯(2)是我们合成的起点（方案1）。用（DHQD） 2PHAL对巴酮酸2进行功能化，以氨基甲酸苄酯为基础的Sharpless AA9反应得到了高区域选择性和对映选择性的巴酮酸3。粗产物的核磁共振氢谱显示，区域异构体的比例约为9:1，初始ee为90%，己烷/乙酸乙酯单次重结晶可将初始ee提高到bb0 ~ 99%。酯3被转化为甲烷磺酸盐4，甲烷磺酸盐4在C-2上成功转化为反r -叠氮基团。叠氮化物5的催化加氢和随后的酸水解得到对映体纯二氨基丁酸1b作为HCl盐{[R] 20 D-8.9 (c 1.0, 6 N HCl), lit. 10 [R] 20 D-11.0 (c 1.0, 6 N HCl)}。在合成同分异构体1a时，用叔丁二氧化钾将化合物4以80%的收率转化为氮杂吡啶类6。对于环开度为6，溶剂转…
Nonproteingenic amino acids have been uncovered in a growing number of naturally occurring compounds. 1 Consequently, interest in their application as building blocks for peptidomimetics in medicinal chemistry efforts has also increased due to their protease resistance and potential conformational constraints. 2 The R,-diamino acid family constitutes a key structural element found in a variety of antibiotics, 3 antifungal dipeptides, 4 and other biologically active compounds. 5 In particular, R,-diaminobutanoic acids such as 1 (Figure 1) have attracted numerous synthetic efforts, since they are the simplest member of the R,-diamino acid family yet form key elements in both peptide antibiotics and toxins. 6 Several methods for the synthesis of R,-diaminobutanoic acids have been reported. Noteworthy was a method reported by Schmidt and co-workers7 in which threonine or allo-threonine was exploited as starting materials and Mitsunobu reaction conditions were used for the installation of the second amino group. While this tact is reliable, only the anti isomers 1b and 1d are accessible from threonine, whereas the syn isomers 1a and 1c must be obtained from allo-threonine. In related studies, Shin6a, b described syntheses leading to all four isomers of 1 using L-or D-threonine as starting materials and double inversion chemistry to obtain the syn diastereomers 1a and 1c. Utilizing a completely different strategy, Davies and co-workers6c reported the synthesis of epimers 1a and 1d based on the asymmetric addition of a chiral lithium amide to tert-butyl crotonate, followed by the introduction of the second amino group using trisyl azide. Very recently, all four isomers of 1 were synthesized on the basis of the nucleophilic addition of methylmagnesium bromide to differentially protected nitrones that were derived from either L-or D-serine. 8 Critical in this approach was the protecting group strategy used on the starting nitrone, as this dictated the stereochemical outcome of the reaction.Except for the approach outlined by Davies (vide supra), all syntheses of the R,-diaminobutanoic acids have required the use of optically active R-amino acids as starting material. Furthermore, while Davies’s methodology is apt to apply toward the synthesis of other R,-diamino acids, it requires stoichiometric quantities of chiral reagents for two key steps, a Michael and an electrophilic addition. Herein, we report an efficient stereoselective synthesis of R,-diaminobutanoic acids that eliminates the drawbacks found in the previous syntheses. Our route utilizes the highly enantioselective Sharpless asymmetric aminohydroxylation (AA) reaction and regioselective ring opening of an aziridine functionality. Commercially available tert-butyl crotonate (2) was the starting point of our synthesis (Scheme 1). Crotonate 2 was functionalized using (DHQD) 2PHAL and the benzylcarbamate-based Sharpless AA9 reaction gave 3 in high regioselectivity and enantioselectivity. The ratio of the regioisomer was about 9: 1 based on 1H NMR spectrum of the crude product, and the initial ee of 90% could be easily raised to> 99% by a single recrystallization from hexane/ethyl acetate. Ester 3 was converted to its methanesulfonate 4, which was successfully transformed to the anti-R-azido species with inversion of configuration at C-2. 6c Catalytic hydrogenation and subsequent acidic hydrolysis of azide 5 gave enantiomerically pure diaminobutanoic acid 1b as its HCl salt {[R] 20 D-8.9 (c 1.0, 6 N HCl), lit. 10 [R] 20 D-11.0 (c 1.0, 6 N HCl)}. For the synthesis of the syn isomer 1a, compound 4 was converted to aziridine species 6 in 80% yield with potassium tert-butoxide. For the ring opening of 6, solvent turned …