Efficient synthesis of discodermolide

描述（由申请人提供）：本II期申请的目标是开发一种生产14-去甲甲基discodermolide的有效方法，这是一种完全合成的海绵代谢物(+)-discodermolide 3的类似物，具有令人兴奋的抗癌活性。天然产物只能从其内源性来源获得少量，并且昂贵的全合成是目前获得该化合物或生物上和商业上具有吸引力的类似物（如14-去甲酰基硅藻土）的唯一有效方法。我们已经开发了一种关键前体的合成（I期），该前体用于已建立的(+)-discodermolide的合成，使用基因工程聚酮合成酶（PKS）基因在功能化底物上操作，以提供功能和立体化学丰富的材料，这些材料被转化为所需的中间体。第二阶段以第一阶段的成功发现为基础，但避免了使用前体定向生物合成的需要。II期将提供大的聚酮片段，这些片段可以通过非常短的序列进行拆卸和重组，以获得14-去甲酰基软糖。第二阶段的具体目标是：1。我们将在黄粘球菌中产生一种截断和修饰的soraphen a类似物，该类似物将用于合成14-去甲甲基盘霉烯的高级前体。2. 我们将生产高滴度的链霉菌(2R,3S,4R,5S)-2,4-二甲基-3,5-二羟基己酸内酯。3. 我们将使用Aims 1和2的产品生产14-去甲甲基软糖。该方法的成功开发将降低合成化学所需的范围、难度和成本，使大规模商业化生产14-去甲酰基软糖酰胺可行且负担得起。

DESCRIPTION (provided by applicant): The objective of this Phase II proposal is the development of an efficient means of producing 14-normethyl discodermolide, a totally synthetic analog of the sponge metabolite (+)-discodermolide 3ossessing exciting anticancer activity. The natural product is available only in minute quantities from its endogenous source, and costly total synthesis is, at present, the only effective means of obtaining this compound or a biologically and commercially attractive analog such as 14-normethyl discodermolide. We have developed (Phase I) a synthesis of key precursors used in an established synthesis of (+)-discodermolide using genetically engineered polyketide synthase (PKS) genes operating on functionalized substrates to furnish functionally and stereochemically rich materials that were converted to the desired intermediates. Phase II builds on the successful discoveries of Phase I but avoids the need for the use of precursor directed biosynthesis. Phase II will provide large polyketide fragments that may be disassembled and then reassembled via very short sequences to gain access to 14-normethyl discodermolide. The specific aims of Phase II are: 1. We will produce in Myxococcus xanthus a truncated and modified analog of soraphen A that will be used for the synthesis of an advanced precursor of 14-normethyl discodermolide. 2. We will produce in Streptomyces coelicolor (2R,3S,4R,5S)-2,4-dimethyl-3,5-dihydroxyhexoate lactone at high titers. 3. We will use the products of Aims 1 and 2 to produce 14-normethyl discodermolide. Successful development of this methodology will reduce the extent, difficulty, and cost of the synthetic chemistry required, making large-scale commercial production of 14-normethyl discodermolide feasible and affordable.