A convenient asymmetric synthesis of 4′-α-carboxylated nucleosides
A convenient asymmetric synthesis of 4′-α-carboxylated nucleosides
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DOI：
10.1021/jo980301f
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发表时间：
1998-06-12
影响因子：
3.6
通讯作者：
Hao, XL
中科院分区：
文献类型：
--
作者：
Crich, D;Hao, XL
C-4′ R-同源核苷酸，特别是酯和酮，是目前相当感兴趣的分子。这种突出的原因之一是某些C-4′ R-酮能够阻断DNA聚合酶和逆转录酶，如HIV-1 RT，因此它们具有作为抗病毒剂的潜力。1-3或者，C4′-R-硒醇4和硫醇酯5以及C4′-R-叔丁基羰基衍生物1可作为核苷酸C4′自由基的方便且明确的前体，6核苷酸C4′自由基是博来霉素7烯二炔类抗肿瘤抗生素8、9和电离辐射降解寡核苷酸的关键。10核苷酸C4′自由基也是DNA足迹的关键中间体。[11]这些2-脱氧-4 ′ R-羰基取代核苷酸的绝大多数工作是用胸苷系列进行的。几乎毫无疑问，这些衍生的胸苷的合成3，5，12，13可以追溯到Jones关于醛1与甲醛的Cannizzaro反应得到二醇2的原始工作。14 2的反应性特征使得R-OH比β-酮更容易被保护，15这意味着R-羟甲基选择性氧化为所需的醛或酸之前必须经过漫长的三步选择性双重保护和单脱保护序列。3，5，12此外，醇如3最终氧化成酯4是困难的。5最近，我们通过PhS·加成到相应的环外糖基上，定性地证明了核苷酸C4′自由基5-9的断裂是碱基的函数。[16]要对这一观察结果进行定量，需要合成所有四种碱基的C4′酸。调整文献合成的胸苷衍生物，以适应每一个基地是不经济的，无论是在时间上还是成本上，因此，我们被驱使开发一种不对称的合成，能够提供所有四个基地，以最小的努力。此外，这种合成允许包含非标准碱基。在这里，我们提出了这样一种合成方法，其中手性来自商品化学品，L-酒石酸。我们的合成是建立在Seebach的概念的手性自我复制的基础上，例如通过烷基化的酒石酸缩醛保留的配置。17我们开始以标准方式将L-酒石酸二甲酯转化为亚环戊基缩醛10。在THF/HMPA混合物中用LDA去质子化，然后用新制备的苄氧基甲基氯（BOMCl）淬灭，以60%的分离产率提供作为单一异构体的加合物11。18然后用DIBALH选择性还原较少取代的酯，以75%产率得到醇12。重要的是，羟基酯12没有表现出内酯化的趋势，因此加强了10的烷基化发生并保留构型的观点。然后将12进行Swern氧化，得到80%的醛13，通过通常的Wittig顺序将其转化为烯烃14，产率为62%，为异构体的1：1混合物（方案1）。
C-4′ R-Homologated nucleotides, especially esters and ketones, are molecules of considerable current interest. One reason for this prominence arises from the ability of certain C-4′ R-ketones to block DNA polymerase and reverse transcriptase enzymes, such as the HIV-1 RT, and so their potential as antiviral agents. 1-3 Alternatively, the C4′-R-selenol4 and thiol esters5 and the C4′-R-tert-butylcarbonyl derivative1 serve as convenient and unambiguous precursors to nucleotide C4′ radicals, 6 which are central to the degradation of oligonucleotides by bleomycin, 7 the enediyne antitumor antibiotics, 8, 9 and ionizing radiation. 10 Nucleotide C4′ radicals are also key intermediates in DNA footprinting. 11 The vast majority of work with these 2-deoxy-4′ R-carbonyl substituted nucleotides has been conducted with the thymidine series. Almost without fail, the synthesis3, 5, 12, 13 of these ramified thymidines can be traced back to original work by Jones on the Cannizzaro reaction of aldehyde 1 with formaldehyde giving the diol 2. 14 The reactivity profile of 2 is such that the R-OH is more readily protected than the β-one, 15 which means that selective oxidation of the R-hydroxymethyl group to the desired aldehyde or acid is necessarily preceded by a lengthy three-step selective doubleprotection and monodeprotection sequence. 3, 5, 12 Moreover, the final oxidation of alcohols such as 3 to the ester 4 is difficult. 5 Recently, we have qualitatively demonstrated, by means of PhS• addition to the corresponding exocyclic glycals, that the fragmentation of nucleotide C4′ radicals 5-9 is a function of the base. 16 Quantification of this observation requires the synthesis of the C4′ acids of all four bases. Adaptation of the literature synthesis for the thymidine derivative to suit each base is not economical, neither in terms of time nor cost, and we were therefore driven to develop an asymmetric synthesis capable of providing all four bases with a minimum of effort. Furthermore, such a synthesis permits the inclusion of nonstandard bases. Here, we present such a synthesis in which the chirality is derived from the commodity chemical, L-tartaric acid.Our synthesis was built on the basis of Seebach’s concept of self-reproduction of chirality as exemplified by the alkylation of tartrate acetals with retention of configuration. 17 We began by conversion of dimethyl L-tartrate to the cyclopentylidene acetal 10 in the standard manner. Deprotonation with LDA in a THF/HMPA mixture followed by quenching with freshly prepared benzyloxymethyl chloride (BOMCl) provided the adduct 11 in 60% isolated yield as a single isomer. 18 The less substituted ester was then selectively reduced with DIBALH to give alcohol 12 in 75% yield. Importantly, the hydroxy ester 12 showed no tendency toward lactonization, so reinforcing the notion that alkylation of 10 took place with retention of configuration. Swern oxidation of 12 then gave 80% of the aldehyde 13, which was converted to the alkene 14, by the usual Wittig sequence, in 62% yield as a 1: 1 mixture of isomers (Scheme 1).