利用對掌N-乙醛醯胺與-酮醯胺衍生物進行不對稱烯丙基加成反應

Abstract

利用烯丙基金屬化合物（allylmetal）與醛基化合物進行不對稱烯丙基加 成反應（allylation），乃是有機合成中相當重要的合成方式。反應所得到之產 物─烯丙醇，於有機合成上之應用亦相當廣泛，藉由各種不同的反應條件， 可以製備醛基、酮基、環氧化合物、γ-內酯、δ-內酯……等不同的官能基化 合物；再者，烯丙醇在許多天然物的分子（如：Laulimide（21）、LY426965 （22）……等）結構中亦為重要的一種官能基。因此，若能有效掌握產物─ 烯丙醇的「立體化學中心」，必更能增進烯丙基加成反應的應用。 本研究以對掌輔助劑camphorpyrazolidinone（112）為主架構，利用其衍 生物125 與126，進行不對稱烯丙基加成反應，並探討其立體化學中心的控 制，均獲致不錯的結果。 首先，利用N-glyoxyloyl camphorpyrazolidinone（125）進行之不對稱烯 丙基加成反應，篩選出以一當量的路易士酸Eu(OTf)3 進行催化的最佳反應條 件，亦探討溶劑的影響情況。本實驗的最高產率可達90 %，雖然立體選擇性 方面不甚理想，以非鏡像超越值為48 % de 最高。 接著，再利用-keto amide（126）之不同官能基取代化合物進行不對稱 烯丙基加成反應，更成功地篩選出以一當量路易士酸Sn(OTf)2 進行催化的最 佳反應條件，且發現不同的路易士酸會使產物的立體化學中心反轉，並就反 應機構加以推測及探討；其最高產率達95 %，非鏡像超越值更可高達95 % de 以上。Asymmetric carbonyl allylation represents one of the most useful tools for the construction of regio- and stereodefined carbon framework. The alkene functionality is readily available for further functional group transformation to give epoxides, γ-lactam, δ-lactam, ect. The Lewis acid-mediated allylation of aldehydes is a highly useful synthetic operation to form chiral secondary homoallyl alcohols and has been studied extensively. Diastereoselective allylation of camphorpyrazolidinone derived N-glyoxylate (125) and α-keto amides (126) was examined by using allyltributyltin in the presence of various Lewis acids. The chiral camphor pyrazolidinone (112) can be easiliy prepared from the known (S)-ketopinic acid (118) in three steps in total 80 % yield. This research is to study the asymmetric allylation by using camphorpyrazolidinone derived N-glyoxylate (125) as a substrate. Treatment of compound 125 with various of Lewis acids gave good chemical yield (up to 90 %) in presence of allyltributyltin but unsatisfied diastereoselectivity. On the other hand, Then camphorpyrazolidinone phenylate (126c) was used as a substrate, to our surprise, a high stereoselectivity was achieved (up to 95 % de). The absolute stereochemistry of the newly generated steregenic center was assigned as R-configuration by single crystal X-ray analysis of 126c. Therefore, the effect between diastereoselectivity and reaction rate of various α-keto amides (126a-d) were studied. A reasonable mechanism was proposed.