Nathan Maugel

PdII-Catalyzed Enantioselective Activation of C(sp2)H and C(sp3)H Bonds Using Monoprotected Amino Acids as Chiral Ligands†

Enantioselective C H activation has been a longstanding challenge in catalysis and organic chemistry. The insertion of metal-bound carbenes or nitrenes into C H bonds has been employed to develop highly enantioselective carbon–carbon and carbon–nitrogen bond-forming reactions. The enantioselective lithiation of C(sp) H bonds adjacent to the nitrogen atom in N-tert-butyloxycarbonylpyrrolidine using secBuLi/( )sparteine has provided a broadly useful method for the differentiation of prochiral C(sp) H bonds. Investigations into the biomimetic oxidation of C H bonds using chiral metal–porphyrin complexes and other synthetic catalysts continue to provide inspiration for the development of methods for the asymmetric oxidation of C H bonds. Remarkable progress in understanding the fundamental mechanisms of C H activation by means of metal insertion has spurred the development of metal-catalyzed carbon– carbon and carbon–heteroatom bond-forming reactions in organic molecules containing functional groups. Such reactions will impact synthetic and medicinal chemistry in the context of retrosynthetic analysis by providing unprecedented and more efficient strategic disconnections. A major hurdle remaining in Pd-catalyzed C H activation reactions, however, is the need for an external ligand that coordinates to the Pd species and controls the chemo-, regio-, and stereoselectivity of its insertion into C H bonds. With this in mind, we embarked on the development of a Pd-catalyzed enantioselective C H activation/C C coupling reaction, a process previously unknown owing to the difficulty in differentiating prochiral C H bonds through metal insertions. Herein we demonstrate a proof of concept by the design of a Pd/amino acid complex capable of catalyzing asymmetric activation of prochiral C(sp) H and C(sp) H bonds to form chiral products with new C C bonds in excellent enantioselectivity [Eq. (1)].

Synthesis of (+/-)-nosyberkol (isotuberculosinol, revised structure of edaxadiene) and (+/-)-tuberculosinol.

Me(2)AlCl-catalyzed Diels-Alder reaction of N-tigloyloxazolidinone with 6,6-dimethyl-1-vinylcyclohexene selectively provided the exo adduct, which was converted to nosyberkol (isotuberculosinol) and tuberculosinol. The spectral data for nosyberkol are identical with those reported for edaxadiene, whose structure is revised accordingly.

Efficient synthesis of the tetracyclic aminoquinone moiety of marmycin A.

An efficient four-step route to the tetracyclic aminoquinone moiety of marmycin A that proceeds in 41% overall yield from 5-nitronaphthoquinone and 5-methyl-1-vinylcyclohexene will facilitate preparation of marmycin A analogues for biological evaluation. The Diels-Alder reaction gave exclusively the desired adduct that is favored by steric considerations rather than the regioisomeric adduct that is favored by electronic considerations.