Total Synthesis of ( R)-Sarkomycin Methyl Ester via Regioselective Intermolecular Pauson-Khand Reaction and Iridium-Catalyzed Asymmetric Isomerization.

A new five-step enantioselective synthesis of ( R)-sarkomycin methyl ester is described. The cyclopentane scaffold was built by a regioselective intermolecular Pauson-Khand reaction. Enantioselectivity was introduced by a novel Ir-catalyzed isomerization reaction. The last steps involved a catalytic hydrogenation of the exocylic double bond, followed by the deprotection and elimination of the amino group. This route is the shortest enantioselective synthesis of this antibiotic reported to date.

Regioselectivity of intermolecular Pauson-Khand reaction of aliphatic alkynes: experimental and theoretical study of the effect of alkyne polarization.

Generally judged poor electronic regioselectivity of alkyne insertion in intermolecular Pauson-Khand reaction (PKR) has severely restricted its synthetic applications. In our previous rational study concerning diarylalkynes (Fager-Jokela, E.; Muuronen, M.; Patzschke, M.; Helaja, J. J. Org. Chem. 2012, 77, 9134-9147), both experimental and theoretical results indicated that purely electronic factors, i.e., alkyne polarization via resonance effect, induced the observed modest regioselectivity. In the present work, we substantiate that the alkyne polarization via inductive effect can result notable, synthetically valuable regioselectivity. Computational study at DFT level was performed to disclose the electronic origin of the selectivity. Overall, the NBO charges of alkynes correlated qualitatively with regioisomer outcome. In a detailed computational PKR case study, the obtained Boltzmann distributions of the transition state (TS) populations correlate closely with experimental regioselectivity. Analysis of the TS-structures revealed that weak interactions, e.g., hydrogen bonding and steric repulsion, affect the regioselectivity and can easily override the electronic guidance.