Pd^II‐Catalyzed Enantioselective Activation of C(sp²)H and C(sp³)H Bonds Using Monoprotected Amino Acids as Chiral Ligands

Abstract

Dedicated to Professor E. J. Corey on the occasion of his 80th birthday Enantioselective CÀH activation has been a longstanding challenge in catalysis and organic chemistry. The insertion of metal-bound carbenes or nitrenes into CÀH bonds has been employed to develop highly enantioselective carbon-carbon and carbon-nitrogen bond-forming reactions.[1] The enantioselective lithiation of C(sp 3 ) À H bonds adjacent to the nitrogen atom in N-tert-butyloxycarbonylpyrrolidine using secBuLi/(À)sparteine has provided a broadly useful method for the differentiation of prochiral C(sp 3 )ÀH bonds.[2] Investigations into the biomimetic oxidation of CÀH bonds using chiral metal-porphyrin complexes [3] and other synthetic catalysts [4] continue to provide inspiration for the development of methods for the asymmetric oxidation of C À H bonds. Remarkable progress in understanding the fundamental mechanisms of CÀH activation by means of metal insertion [5] has spurred the development of metal-catalyzed carboncarbon and carbon-heteroatom bond-forming reactions in organic molecules containing functional groups.[6] Such reactions will impact synthetic and medicinal chemistry in the context of retrosynthetic analysis [7] by providing unprecedented and more efficient strategic disconnections.[8] A major hurdle remaining in Pd II -catalyzed CÀH activation reactions, however, is the need for an external ligand that coordinates to the Pd II species and controls the chemo-, regio-, and stereoselectivity of its insertion into C À H bonds. With this in mind, we embarked on the development of a Pd II -catalyzed enantioselective CÀH activation/CÀC coupling reaction, a process previously unknown owing to the difficulty in differentiating prochiral CÀH bonds through metal insertions.

Advances in Enantioselective C–H Activation/Mizoroki-Heck Reaction and Suzuki Reaction

“…Influence of ligands on the enantioselectivities [62]. Detailed mechanism studies by Yu and coworkers suggested that using conformationally rigid chiral carboxylic acids as ligands as well as Pd II catalyst might induce the enantioselective C-H activation process.…”

“…Influence of ligands on the enantioselectivities [62]. With the optimized condition in hand, different substrates and boronic acids were investigated and the products were obtained in good yields and moderate to excellent ee (Table 1).…”

“…In 2008, a huge advance was made by Yu and coworkers [62]. They developed the Pd II /chiral mono-N-protected amino acid (MPAA) system and applied it in the desymmetrization reaction of prochiral substrates (Scheme 7).…”

O desafio da ativação das ligações C-H em síntese orgânica

“…Mesmo diante dessas dificuldades, alguns resultados importantes têm sido descritos. 55,56 O trabalho de Yu e colaboradores, 57 por exemplo, consistiu na diferenciação de ligações C-H enantiotópicas de anéis aromáticos através do uso de aminoácidos N-protegidos com grupos volumosos como ligantes na alquilação destes anéis (Esquema 15 A), sendo obtidos excessos enantioméricos de razoáveis a bons (54-95% ee).…”

“…Novamente, as seletividades voltaram a ficar entre boas e excelentes e bons rendimentos foram obtidos (Esquema 15 C), em condições semelhantes às do trabalho anterior. 57 A racionalização para a enantiosseletividade obtida nestas três reações de Yu e colaboradores segue o mesmo modelo geral, exemplificado no Esquema 15 para a equação C. A primeira parte consiste na complexação de um grupo diretor (nitrogênio piridínico ou carbonila do grupo carboxila) ao metal e na amarração deste intermediário com o ligante aminoácido, através da complexação de sua carboxila e seu nitrogênio protegido. A ativação C-H acontece quando o grupo mais volumoso (i.e., fenil) do carbono central do substrato está para o lado oposto ao da cadeia lateral do aminoácido, ou seja, forma-se o intermediário favorecido por razões estéreas.…”