Coupling of isoprenoid triflates with organoboron nucleophiles: synthesis and biological evaluation of geranylgeranyl diphosphate analogues.
Coupling of isoprenoid triflates with organoboron nucleophiles: synthesis and biological evaluation of geranylgeranyl diphosphate analogues.
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类异戊二烯三氟甲磺酸酯与有机硼亲核试剂的偶联：香叶基香叶基二磷酸类似物的合成和生物学评价。
DOI：
10.1016/s0968-0896(01)00390-x
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发表时间：
2002
影响因子：
3.5
通讯作者：
Gibbs,RichardA
中科院分区：
文献类型：
--
作者：
Mu,YongQi;Eubanks,LisaM;Poulter,CDale;Gibbs,RichardA
Suzuki偶联反应已用于将衍生自市售甲基硼酸的甲基引入到三氟甲磺酸乙烯酯中。这导致了全反式香叶基香叶醇（10）的简洁合成，关键步骤是钯催化的银介导的三氟甲磺酸酯8的甲基化，得到香叶基香叶酸乙酯9。该偶联方案也已用于生产新的香叶基香叶基二磷酸（GGPP）类似物3-苯基-3-去甲基香叶基香叶基二磷酸（3-PhGGPP，2d）。我们先前开发的有机铜酸酯偶联方案已用于将环丙基和叔丁基部分引入到三氟甲磺酸乙烯酯8的3-位中。然后评估了四种GGPP类似物3-乙烯基-3-去甲基香叶基香叶基二磷酸（3-vGGPP，2a）、3-环丙基-3-去甲基香叶基香叶基二磷酸（3-cpGGPP，2b）、3-叔丁基-3-去甲基香叶基香叶基二磷酸（3-tbGGPP，2c）和2d作为重组酵母蛋白-香叶基香叶基转移酶I（PGGTase I）的潜在抑制剂。基于潜在机制的抑制剂3-vGGPP和3-cpGGPP未表现出PGGT酶I的时间依赖性失活。相反，这两种类似物都是替代底物，与相应的法尼基类似物3-vFPP和3-cpFPP与PFT酶的相互作用雅阁。叔丁基和苯基类似物不是底物，而是PGGT酶I的竞争性抑制剂。注意，与3-取代的FPP类似物的行为相反，所有四种GGPP类似物与酶的结合不如天然底物紧密。
The Suzuki coupling reaction has been used to introduce a methyl group derived from commercially available methylboronic acid into a vinyl triflate. This has led to a concise synthesis of all-trans-geranylgeraniol (10), with the key step being the palladium-catalyzed, silver-mediated methylation of triflate 8 to give ethyl geranylgeranoate 9. This coupling protocol has also been used to produce the novel geranylgeranyl diphosphate (GGPP) analogue 3-phenyl-3-desmethylgeranylgeranyl diphosphate (3-PhGGPP, 2d). Our previously developed organocuprate coupling protocol has been used to introduce the cyclopropyl and tert-butyl moieties into the 3-position of vinyl triflate 8. The four GGPP analogues 3-vinyl-3-desmethylgeranylgeranyl diphosphate (3-vGGPP, 2a), 3-cyclopropyl-3-desmethylgeranylgeranyl diphosphate (3-cpGGPP, 2b), 3-tert-butyl-3-desmethyl-geranylgeranyl diphosphate (3-tbGGPP, 2c), and 2d were then evaluated as potential inhibitors of recombinant yeast protein-geranylgeranyl transferase I (PGGTase I). The potential mechanism-based inhibitors 3-vGGPP and 3-cpGGPP did not exhibit time-dependent inactivation of PGGTase I. Instead, both analogues were alternative substrates, in accord with the interaction of the corresponding farnesyl analogues 3-vFPP and 3-cpFPP with PFTase. The tert-butyl and phenyl analogues were not substrates, but were instead competitive inhibitors of PGGTase I. Note that all four of the GGPP analogues were bound less tightly by the enzyme than the natural substrate, in contrast to the behavior of the 3-substituted FPP analogues.