Manku Sukhdev, Curran Dennis P
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
J Comb Chem. 2005 Jan-Feb;7(1):63-8. doi: 10.1021/cc049899x.
Fluorous mixture synthesis was used to prepare a library of 4-alkylidene cyclopentenones starting from a mixture of four alpha-amino acid derivatives tagged with different fluorous benzyl carbamates ((F)CBz) of varying fluorine content. The amino acids were converted to the corresponding propargyl esters and then subjected to an ester-enolate Claisen rearrangement to give a mixture of allenic amino esters. The allenes were then split four ways and propargylated with different propargyl bromides to give four mixtures of alkynyl allenes. The 4-alkylidene cyclopentenones were formed by a formal [2+2+1] cycloaddition of the alkynyl allenes using catalytic [Rh(CO)2Cl]2 under CO atmosphere. Demixing by fluorous preparative HPLC, removal of the fluorous benzyl carbamates, and then exposure to HCl/ether gave the hydrochloride salts of 16 compounds as diastereomeric mixtures in 69-99% purity. Thus, after just 26 chemical steps, a library of 16 cyclopentenones was prepared by using fluorous mixture synthesis. By comparison, the same library would have required 112 steps if each compound were made individually by parallel synthesis.
使用氟代混合物合成法，从四种带有不同氟含量的氟代苄基氨基甲酸酯（(F)CBz）标记的α-氨基酸衍生物的混合物开始，制备了一系列4-亚烷基环戊烯酮。氨基酸被转化为相应的炔丙基酯，然后进行酯烯醇式克莱森重排，得到烯丙基氨基酯的混合物。然后将烯丙基化合物分成四份，并用不同的炔丙基溴进行炔丙基化反应，得到四种炔基烯丙基化合物的混合物。在CO气氛下，使用催化量的[Rh(CO)₂Cl]₂通过炔基烯丙基化合物的形式[2+2+1]环加成反应形成4-亚烷基环戊烯酮。通过氟代制备型高效液相色谱进行分离，除去氟代苄基氨基甲酸酯，然后用HCl/乙醚处理，得到16种化合物的盐酸盐，为非对映异构体混合物，纯度为69-99%。因此，仅经过26步化学反应，就通过氟代混合物合成法制备了一个包含16种环戊烯酮的化合物库。相比之下，如果通过平行合成法单独制备每种化合物，相同的化合物库将需要112步反应。
