Inhibiting protein-protein interactions (PPIs) with synthetic molecules remains a frontier of chemical biology. Many PPIs have been successfully targeted by mimicking α-helices at interfaces, but most PPIs are mediated by non-helical, non-strand peptide loops. We sought to comprehensively identify and analyze these loop-mediated PPIs by writing and implementing LoopFinder, a customizable program that can identify loop-mediated PPIs within all protein-protein complexes in the Protein Data Bank. Comprehensive analysis of the entire set of 25,005 interface loops revealed common structural motifs and unique features that distinguish loop-mediated PPIs from other PPIs. “Hot loops,” named in analogy to protein hot spots, were identified as loops with favorable properties for mimicry using synthetic molecules. The hot loops and their binding partners represent new and promising PPIs for the development of macrocycle and constrained peptide inhibitors.

Chemical biologists commonly seek out correlations between the physicochemical properties of molecules and their behavior in biological systems. However, a new paradigm is emerging for peptides in which conformation is recognized as the primary determinant of bioactivity and bioavailability. This review highlights an emerging body of work that directly addresses how a peptide’s conformation controls its biological effects, cell penetration, and intestinal absorption. Based on this work, the dream of mimicking the potency and bioavailability of natural product peptides is getting closer to reality.

The optimization of asymmetric catalysts for enantioselective synthesis has conventionally revolved around the synthesis and screening of enantiopure ligands. In contrast, we have optimized an asymmetric reaction by modification of a series of achiral ligands. Thus, employing (S)-3,3'-diphenyl BINOL [(S)-Ph(2)-BINOL] and a series of achiral diimine and diamine activators in the asymmetric addition of alkyl groups to benzaldehyde, we have observed enantiomeric excesses between 96% (R) and 75% (S) of 1-phenyl-1-propanol. Some of the ligands examined have low-energy chiral conformations that can contribute to the chiral environment of the catalyst. These include achiral diimine ligands with meso backbones that adopt chiral conformations, achiral diimine ligands with backbones that become axially chiral on coordination to metal centers, achiral diamine ligands that form stereocenters on coordination to metal centers, and achiral diamine ligands with pendant groups that have axially chiral conformations. Additionally, we have structurally characterized (Ph(2)-BINOLate)Zn(diimine) and (Ph(2)-BINOLate)Zn(diamine) complexes and studied their solution behavior.

The asymmetric allylation of carbonyl groups to furnish homoallylic alcohols is a fundamental transformation in synthetic organic chemistry. [1±3] Several catalysts will promote the asymmetric allylation of aldehydes to give secondary homoallylic alcohols with excellent enantioselectivities. [4±15] The catalytic asymmetric allylation of ketones, however, has proven to be a more challenging transformation owing to the significant difference in reactivity between aldehydes and ketones. Thus, with one exception, [16] catalysts that promote the enantioselective allylation of aldehydes fail to catalyze the analogous reaction with ketones. In general, the enantioselective formation of quaternary stereocenters, as generated in the asymmetric allylation of ketones, is of considerable difficulty. [17,18] To compensate for the reduced reactivity of ketones, a more reactive allylating agent was needed. Baba and co-workers found that tetraallylstannane added to ketones in the presence of methanol and 200 mol % binol to give the homoallylic alcohol in up to 60 % ee. [19] An important discovery in the asymmetric allylation of ketones was recently reported by Casolari, D©Addario, and Tagliavini. [20] Their catalyst preparation involved the reaction of [Cl 2 Ti(OiPr) 2 ] and binol with allyltributylstannane. After mixing for one hour, tetraallylstannane and the substrate ketone were added.They observed the formation of the ketone allylation product with up to 65 % ee at 20 mol % binol (80 % ee with 40 mol % binol).Based on the results of the Italian team, [20] Maruoka and coworkers [16] recently reported a system for the catalytic asymmetric allylation of aldehydes with a catalyst that is based on titanium, binol, and an achiral diamine spacer (2:2:1 ratio). This catalyst (60 mol % titanium and binol) was examined in the asymmetric allylation of only two ketones, acetophenone and methyl 2-naphthyl ketone, which underwent allylation with 90 and 92 % ee, respectively. [16] More recently, Cunningham and Woodward [21] demonstrated that monothiobinaphthol will promote the allylation of acetophenone derivatives with a mixture of [RSn(allyl) 3 ]/[Sn(allyl) 4 ] (R ¼ Et, Bu) with ee values as high as 92 % (51 % yield).The ketone allylation reaction of Casolari, D'Addario, and Tagliavini [20] attracted our attention because of our interest in the mechanisms of titanium-based asymmetric Lewis acid catalysts [22±24] and the need for a more versatile and enantioselective catalyst for this important process. While investigating the catalyst structure of the Tagliavini system, we made several key observations that allowed us to develop the most general and enantioselective catalyst for the asymmetric allylation of ketones to date.We repeated the catalyst preparation of Tagliavini [20] described above in CDCl 3 to probe the nature of the (binolate)Ti species by NMR spectroscopy. Like Tagliavini and co-workers, [20] we observed the production of tributyltin chloride. However, we were surprised to find that the major titanium-containing pro...

In situ modification of Grubbs' first-generation metathesis catalyst allows for a tandem enyne metathesis/hydrovinylation that is complementary to the regioselectivity of known ruthenium-catalyzed hydrovinylations.