Efficient synthesis of discodermolide

描述（由申请人提供）：本II期提案的目的是开发一种生产14-去甲甲基discodermolide的有效方法，14-去甲甲基discodermolide是海绵代谢物（+）-discodermolide 3的全合成类似物，具有令人兴奋的抗癌活性。该天然产物仅以微量从其内源来源获得，并且昂贵的全合成是目前获得该化合物或生物学和商业上有吸引力的类似物如14-去甲甲基discodermolide的唯一有效手段。我们已经开发了（阶段I）用于（+）-discodermolide的已建立的合成中的关键前体的合成，所述合成使用基因工程聚酮化合物合酶（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，所述材料被转化为所需的中间体。第二阶段建立在第一阶段的成功发现的基础上，但避免了使用前体指导的生物合成的需要。第二阶段将提供大的聚酮片段，可以通过非常短的序列分解，然后重新组装，以获得14-去甲甲基discodermolide。第二阶段的具体目标是：1。我们将在黄色粘球菌中产生一种截短和修饰的soraphen A类似物，该类似物将用于合成14-去甲甲基discodermolide的高级前体。2.我们将在天蓝色链霉菌中以高滴度生产（2 R，3S，4 R，5S）-2，4-二甲基-3，5-二羟基己酸内酯。3.我们将使用目标1和2的产物来生产14-去甲甲基discodermolide。这种方法的成功开发将减少所需的合成化学的程度、难度和成本，使得14-去甲甲基discodermolide的大规模商业生产可行且负担得起。

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.