Highly efficient molybdenum-based catalysts for enantioselective alkene metathesis

Abstract

Discovery of efficient catalysts is one of the most compelling objectives of modern chemistry. Chiral catalysts are in particularly high demand, as they facilitate synthesis of enantiomerically enriched small molecules that are critical to developments in medicine, biology and materials science. Especially noteworthy are catalysts that promote-with otherwise inaccessible efficiency and selectivity levels-reactions demonstrated to be of great utility in chemical synthesis. Here we report a class of chiral catalysts that initiate alkene metathesis with very high efficiency and enantioselectivity. Such attributes arise from structural fluxionality of the chiral catalysts and the central role that enhanced electronic factors have in the catalytic cycle. The new catalysts have a stereogenic metal centre and carry only monodentate ligands; the molybdenum-based complexes are prepared stereoselectively by a ligand exchange process involving an enantiomerically pure aryloxide, a class of ligands scarcely used in enantioselective catalysis. We demonstrate the application of the new catalysts in an enantioselective synthesis of the Aspidosperma alkaloid, quebrachamine, through an alkene metathesis reaction that cannot be promoted by any of the previously reported chiral catalysts.

Figure 1. Catalytic ring-closing metathesis of triene

1. This alkene metathesis reaction, required for total synthesis of alkaloid natural product quebrachamine, is not efficiently promoted by the available achiral or chiral molybdenum or ruthenium catalysts, indicating that significantly more effective catalysts are needed. Me, CH₃; Et, C₂H₅; Ph, C₆H₅; i-Pr, (CH₃)₂CH; and t-Bu, (CH₃)₃C. e.e., enantiomeric excess.

Figure 2. Stereoelectronic effects have a critical role in alkene metathesis reactions promoted by a molybdenum complex that bears a donor and an acceptor ligand

Such a chiral complex distorts dissymmetrically, leading to an open ligation site trans to D (see II), thus facilitating catalyst–substrate association; the donor ligand also causes a more facile decomposition of the metallacyclobutane intermediate (IV). These attributes are expected to lead to a catalyst that is substantially more effective than one that bears two electronically identical acceptor ligands (see the molybdenum complexes illustrated in Fig. 1). The high activity of a complex bearing a donor (pyrrolide) and an acceptor (aryloxide) ligand is illustrated by the efficient conversion of triene 1 to diene 2 (compare with the reaction of molybdenum-based bis-alkoxide 3 shown in Fig. 1). G, functional group.

Figure 3. Diastereoselective synthesis of stereogenic-at-Mo complexes

Such processes are achieved by efficient and stereoselective ligand exchange reactions involving enantiomerically pure aryl alcohols, derived from commercially available binaphthol, and achiral molybdenum-based bis-pyrrolides. TBS, t-butyldimethylsilyl; d.r., diastereomeric ratio.

Figure 4. Efficient and highly enantioselective synthesis of (+)-quebrachamine

The new chiral molybdenum aryloxides, represented by 13c, promote the ring-closing metathesis of 1 to afford 2 with unprecedented efficiency (see Fig. 1 for comparison with previously known catalysts). Moreover, the molybdenum-catalysed ring-closing metathesis of 1, a process that cannot be promoted by any of the available chiral molybdenum or ruthenium catalysts, proceeds with exceptionally high enantioselectivity (e.r., 98:2) in the presence of 13c. Palladium-catalysed hydrogenation of 2 affords the alkaloid natural product quebrachamine in high enantiomeric purity.