RCM Macrocyclization Made Practical:  An Efficient Synthesis of HCV Protease Inhibitor BILN 2061

Abstract

We report here that dramatic improvement of the key RCM reaction in the synthesis of HCV protease inhibitor BILN2061 can be achieved by N-substitution of the diene substrate with an electron-withdrawing group. Mechanistic studies using 1H NMR spectroscopy showed an unprecedented switch of the initiation sites and the correlation between such switch and the results of RCM, from the unmodified to the modified substrates. We also provided theoretical evidence that such modification may also increase the thermodynamic preference of the macrocyclic product over the diene substrate.

Time as a Dimension in High‐Throughput Homogeneous Catalysis

“…[34] It is now widely acknowledged that no single best catalyst exists for all substrates, [35,36] and the burgeoning number of potential catalysts (of which a selection is shown in Figure 2) means that HT screening is increasingly desirable, particularly in industrial R&D. Reaction profiles are important to assess activity, lifetime, and optimum conditions, particularly concentration, where ring-chain equilibria can partition products between the desired cyclic products and (cyclo)-A C H T U N G T R E N N U N G oligomeric species. [37,38] Although the robustness of the Grubbs class ruthenium metathesis catalysts limits the pool of potential quenching agents, several effective poisons have been reported. Included in this study (Figure 3) are ethyl vinyl ether 6, [39,40] methylimidazole 7, [41,42] acetonitrile 8, [43][44][45] and selected bidentate or tridentate proligands (9-13) with potential to deactivate the catalysts by coordination and oxidation or protonolysis.…”

“…Of key relevance from the perspective of catalyst (re)design are the structure-activity relationships that can be extracted; for example, the effect of ligands on activity and lifetime. A wide range of other parameters could be screened: for specific substrates, important examples may include the influence of protecting groups on RCM efficiency and optimal concentrations, [37,38] the influence of ligands or additives on enantioselectivity in asymmetric RCM, etc.…”

P2‐Quinazolinones and Bis‐Macrocycles as New Templates for Next‐Generation Hepatitis C Virus NS3/4a Protease Inhibitors: Discovery of MK‐2748 and MK‐6325

“…Following base-mediated hydrolysis and coupling to commercially available amine 24, the Boc group in 25 was removed, and a second amide coupling, this time to commercially available acid 26, was carried out to yield key bis-olefin 27. Based on the factors discovered at Boehringer Ingelheim during the development of BILN-2061, [30] we Boc-protected the amide NH group and then proceeded with the ring-closing metathesis (RCM) reaction, which, after removal of the two Boc protecting groups, yielded mono-macrocyclic amine 28 in an excellent yield of 95 % over three steps as a single isomer. Addition to activated carbonate 29 and vinylation led to the second RCM precursor 30 in good yield.…”

Ring-Closing Metathesis Synthesis of Medium and Large Rings: Challenges and Implications for Sustainable Synthesis

“…Protecting group-directed RCM was recently exploited by Mohaptra and coworkers in the total synthesis of an anti-malarial nonenolide [107], and by Boehringer-Ingleheim researchers in the synthesis of BILN 2061 (a protease inhibitor for the hepatitis virus containing a 15-membered macrocyclic core; Figure 13) [108,109]. A key advance in the latter synthesis was the initial observation of some sensitivity of the RCM yield to the protecting group on the amide nitrogen within 14, this leading Shu and coworkers to screen a range of such groups, as well as solvents.…”

“…Bulky silyl protecting groups have been shown to aid in cyclization of ten-membered rings precursors in the synthesis of microtubulestabilizing agents of the eleutheside family [112], although dilutions on the order of 5-10 mM were still necessary to limit oligomerization. A number of other examples have been reported in which hydroxyl protection improved RCM yields in synthesis of medium and large rings [2,107,108,113,114].…”