Prebiotic RNA chemistry: realising the molecular biologist's dream.

结构和分子生物学的惊人进展为“RNA世界假说”提供了支持，并为化学提供了解释RNA如何在早期地球上产生的任务。"分子生物学家的梦想"--这是由杰瑞·乔伊斯和莱斯利·奥格尔提出的一个短语--指的是一种情景，在这种情景中，益生元化学以某种方式使对映体纯的β-D-核糖核苷池变小。从核苷到RNA还有很长的路要走，但体外RNA进化的实验表明，一旦RNA出现，它的进化可能相对容易。世界上有几个研究小组正在研究简单RNA聚合酶核酶的进化，总的印象是，尽管这很困难，但有理由乐观。然而，对于β-D-核糖核苷和相应的核苷酸的生物合成的可能性，人们几乎不抱乐观态度，事实上，人们的情绪明显是悲观的。这是因为大多数尝试使用模拟早期地球化学的条件来制造核苷所产生的难以处理的混合物-“生物化学家的噩梦”。一线希望是一种被称为核糖氨基恶唑啉（RAO）的核糖衍生物，它比游离核糖更稳定，是一种潜在的核苷酸中间体。然而，如何制造RAO合成所需的核糖一直是个谜。最近，我们发现戊糖氨基恶唑啉，包括RAO，可以在绕过相应糖的反应中产生。2-氨基恶唑是乙醇醛和氰胺的缩合产物，在温和条件下与甘油醛反应，反应过程基本上是定量的，并且对RAO及其阿拉伯糖类似物具有高度立体选择性。此外，RAO从反应混合物中自发结晶，并且如果输入甘油醛的ee> 60%，则结晶的RAO是对映体纯的（Angewandte Chemie，出版中）。我们现在希望通过找到一种合理的途径来扩展这项工作，这种光学富集甘油醛，并从RAO到β-D-核苷的路线。虽然我们目前的RAO合成所需的乙醇醛和氰胺被认为是益生菌可利用的，但甘油醛不是。这是因为甘油醛相对于二羟基丙酮（DHA）是不稳定的。DHA被认为是一种前生物可用的化合物;它可以在星际介质中检测到，例如在Murchison陨石中发现。我们希望找到一种催化剂，使DHA与甘油醛平衡，因为尽管后者在平衡时只是一种次要组分，但它比DHA与2-氨基恶唑的反应快得多。因此，应该可以通过甘油醛将DHA转化为RAO。由于DHA是非手性的，但甘油醛是手性的，因此还可以找到使DHA与甘油醛的一种对映异构体的平衡比另一种更快的不对称催化剂。以这种方式，我们计划证明从DHA和2-氨基恶唑合成对映体纯的RAO。我们还想将RAO转化为核苷。RAO与氰基乙炔反应通过中间体无氢核苷产生α-胞苷。我们可以看到有两种可能的途径生成β-核糖核苷，一种来自这个无氢核苷，另一种来自α-胞苷。这两种途径都涉及立体化学转化，第一种是亲核取代，第二种是光端基异构。如果我们成功地找到从RAO到β-核糖核苷的路线，我们将应用它对映体纯RAO，从而实现分子生物学家的梦想。

Spectacular advances in structural and molecular biology have added support to the 'RNA world hypothesis', and provide a mandate for chemistry to explain how RNA might have been generated prebiotically on the early Earth. The 'molecular biologist's dream' - a phrase introduced by Jerry Joyce and Leslie Orgel - refers to a scenario in which prebiotic chemistry somehow furnishes pools of enantiopure beta-D-ribonucleosides. There is still a long way to go from such nucleosides to RNA, but the experimental demonstration of in vitro RNA evolution suggests that once RNA has arisen, its evolution might be relatively easy. Several groups worldwide are investigating the evolution of simple RNA polymerase ribozymes, and the general impression is that, although this is difficult, there is reason for optimism. There has, however, been little optimism about the chances of a prebiotic synthesis of beta-D-ribonucleosides and the corresponding nucleotides, indeed the mood has been distinctly pessimistic. This is because of the intractable mixtures that result from most attempts to make nucleosides using conditions that simulate the chemistry of the early Earth - the 'prebiotic chemist's nightmare'. The one glimmer of hope has been a derivative of ribose known as ribose amino-oxazoline (RAO), this is more stable than free ribose, and is a potential nucleotide intermediate. How to make the ribose required for RAO synthesis has been a mystery however. Very recently, we found that pentose amino-oxazolines, including RAO, can be produced in a reaction that bypasses the corresponding sugars. 2-Amino-oxazole, a condensation product of glycolaldehyde and cyanamide, reacts with glyceraldehyde under mild conditions in a remarkable process that is essentially quantitative, and is highly stereoselective for RAO and its arabinose analogue. Furthermore, the RAO crystallises spontaneously from the reaction mixture, and, if the ee of the input glyceraldehyde is > 60%, the RAO that crystallises is enantiopure (Angewandte Chemie, in press). We now want to extend this work by finding a plausible route to such optically enriched glyceraldehyde, and a route from RAO to beta-D-nucleosides. Although the glycolaldehyde and cyanamide required for our current RAO synthesis are presumed to be prebiotically available, the glyceraldehyde is not. This is because glyceraldehyde is thermodynamically unstable with respect to dihydroxyacetone (DHA). DHA is considered to be a prebiotically available compound; it can be detected in the interstellar medium and has been found in the Murchison meteorite for example. We want to find a catalyst that enables DHA to be equilibrated with glyceraldehyde because, although the latter will only be a minor component at equilibrium, it reacts much faster than DHA with 2-amino-oxazole. It should therefore be possible to convert DHA to RAO via glyceraldehyde. Since DHA is achiral, but glyceraldehyde is chiral, it should further be possible to find an asymmetric catalyst that equilibrates DHA with one enantiomer of glyceraldehyde faster than the other. In this way, we plan to demonstrate a synthesis of enantiopure RAO from DHA and 2-amino-oxazole. We also want to convert RAO to nucleosides. Reaction of RAO with cyanoacetylene produces alpha-cytidine by way of an intermediate anhydronucleoside. We can see two potential routes to beta-ribonucleosides, one from this anhydronucleoside, and the other from the alpha-cytidine. Both routes involve stereochemical inversion, the first by nucleophilic substitution, the second by photoanomerisation. If we are successful in finding a route from RAO to beta-ribonucleosides, we will apply it enantiopure RAO and thereby realise the molecular biologist's dream.