DIDEOXYNUCLEOSIDES AS POTENTIAL ANTI-AIDS DRUGS

正在进行的LMC的I期临床试验 6-amino-9-(2，3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)-9-H- 嘌呤(BetaF-Dda)引起了人们对开发的兴趣 该化合物的替代和更经济的合成。 目前，使用的方法非常昂贵，这可能 危及该化合物未来的发展，朝着可能的 临床应用。问题的症结仍然是引入 与所需的立体化学的氟原子，这一步骤是 目前在合成的非常早期阶段执行 昂贵的碳水化合物前体。在目前的调查中，我们 正在探索新的化学方法，以便在以后引入氟原子 阶段，并从价格较低的材料开始，如腺苷。 腺苷已被选为理想的起始原料，两种 为了达到我们的目标，已经制定了各种方法。问题所在 与腺苷的直接β-氟化有关 在文学中广为人知。这些是，淘汰要给予的 二脱氧二氢衍生物和脱嘌呤。我们目前的做法 从腺苷开始，围绕着构建 9-(5-0-monomethoxytrityl-beta-D-glycero-pent-3-enofuranosyl)adenine 以腺苷为原料，经两步反应得到了产率较高的目标产物。 在这种衬底上的氟化实验正在进行中。第二 方法的形式是围绕着可接近的合成 6-amino-9-(2，3-dideoxy-2-fluoro-beta-D-erythro- 5-呋喃葡萄糖)-9H-嘌呤，它是BetaF-Dda的非活性异构体， 通过不经消除的直接氟化而获得的。倒置 这种化合物的氟立体化学的计划是 通过形成相应的 6-amino-9-(5-0-monomethoxytrityl-2-fluoro-2，3-dideoxy-beta-D-glyc Ero- Pent-2-烯基呋喃糖基)腺嘌呤，然后催化氢化 形成所需苏氨酸构型的双键。

The ongoing phase I clinical trial with LMC's 6-amino-9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)-9-H- purine (betaF-ddA) has heightened the interest in developing alternative and more economical synthesis for this compound. Currently, the methods in use are very expensive, and this could jeopardize the future development of this compound towards a possible clinical use. The crux of the problem remains the introduction of the fluorine atom with the desired stereochemistry, a step which is currently performed at a very early stage of the synthesis from expensive carbohydrate precursors. In the present investigation, we are exploring new chemistry to introduce the fluorine atom at a later stage, and starting with less expensive materials, such as adenosine. Adenosine has been chosen as the ideal starting material, and two approaches have been devised to reach our goal. The problems associated with the direct beta-fluorination of adenosine are well known in the literature. These are, elimination to give dideoxydidehydro derivatives and depurination. Our current approach from adenosine has centered around the construction of 9-(5-0-monomethoxytrityl-beta-D-glycero-pent-3-enofuranosyl)adenine which was obtained in excellent yield from adenosine in two steps. Fluorination experiments on this substrate are ongoing. The second approach form is centered around the synthesis of the accessible 6-amino-9-(2,3-dideoxy-2-fluoro-beta-D-erythro- pentofuranosyl)-9H-purine, the inactive isomer of betaF-ddA, which was obtained by a direct fluorination without elimination. The inversion of the fluorine stereochemistry from this compound is planned to proceed via formation of the corresponding 6-amino-9-(5-0-monomethoxytrityl-2-fluoro-2,3-dideoxy-beta-D-glyc ero- pent-2- enofuranosyl)adenine, followed by catalytic hydrogenation of the double bond to give the desired threo-configuration.