The isolation and total synthesis of the antimicrobial lipopeptide cerexin A1 is reported. This synthesis includes the preparation of orthogonally protected γ-hydroxylysine, utilizing a nitrile Reformatsky-type reaction as a key step to yield both diastereomers more efficiently than previously reported methods. The configuration of the β-hydroxyl in the lipid tail was determined by the use of a modified Ohrui-Akasaka approach. Furthermore, new cerexin analogues from Bacillus mycoides ATCC 21929 were isolated and characterized, revealing an ε-amino succinylation of a hydroxylysine residue that is unusual in a nonribosomal peptide synthetase product.

Heterobiaryl compounds that exhibit axial chirality are of increasing value and interest across several fields, but direct oxidative methods for their enantioselective synthesis remain elusive. Here we disclose that an iron catalyst in the presence of a chiral PyBOX ligand and an oxidant enables direct coupling between naphthols and indoles to yield atropisomeric heterobiaryl compounds with high levels of enantioselectivity. The reaction exhibits remarkable chemoselectivity and exclusively yields cross-coupled products without competing homocoupling. Mechanistic investigations enable us to postulate that an indole radical is generated in the reaction but that this is likely an offcycle event, and that the reaction proceeds through formation of a chiral Fe-bound naphthoxy radical which is trapped by a nucleophilic indole. We envision that this simple, cheap, and sustainable catalytic manifold will facilitate access to a range of heterobiaryl compounds and enable their applications across the fields of materials science, medicinal chemistry, and catalysis.Atropisomeric biaryls comprise a privileged class of compounds whose applications span the fields of medicinal chemistry, catalysis and materials science; as such, a panoply of elegant and efficient methods have been developedfor their synthesis 1 . The most convergent route to biaryls is generally the transition metal mediated cross-coupling of two partners 2,3 (although significant advances in metal-free methods have been demonstrated recently) 4 . Whilst this strategy generally results in cross-coupled products in good yields and predictable levels of chemo-and regioselectivity, these advantages may be offset by the requirement to synthesize two specifically functionalized coupling partners (Figure 1a) 5 . In principle, oxidative coupling represents a more direct, atom economic and environmentally benign approach as it creates the desired aryl-aryl linkage from two C-H bonds 6,7 . This realization has led to a significant number of oxidative homo-coupling procedures that can generate C2-symmetric BINOL-like structures in an enantioselective fashion. These include reactions mediated by transition metals including copper 8-10 , iron 11 and vanadium, 12 amongst others. However, in the absence of specific functional groups, controlling the regio-, chemo-and enantioselectivity of the corresponding hetero-couplings remains a formidable challenge, and successful examples have been limited to the synthesis of BINOL or NOBIN type scaffolds [13][14][15][16] . In particular, Katsuki

A direct, stereocontrolled synthesis of acyclic α-chloroenamides is presented. Our methodology showed good yields and substrate scope. Mechanistic insights are provided that account for the high levels of stereoselectivity reported. Subsequent synthetic manipulation of the α-chloroenamides provides direct entry to polyfunctionalized acyclic enamides, compounds of wide use in organic chemistry and the pharmaceutical industry.

Werner syndrome protein (WRN) is a multifunctional enzyme with helicase, ATPase, and exonuclease activities that are necessary for numerous DNA-related transactions in the human cell. Recent studies identified WRN as a synthetic lethal target in cancers characterized by genomic microsatellite instability resulting from defects in DNA mismatch repair pathways. WRN's helicase activity is essential for the viability of these high microsatellite instability (MSI-H) cancers and thus presents a therapeutic opportunity. To this end, we developed a multiplexed high-throughput screening assay that monitors exonuclease, ATPase, and helicase activities of full-length WRN. This screening campaign led to the discovery of 2-sulfonyl/sulfonamide pyrimidine derivatives as novel covalent inhibitors of WRN helicase activity. The compounds are specific for WRN versus other human RecQ family members and show competitive behavior with ATP. Examination of these novel chemical probes established the sulfonamide NH group as a key driver of compound potency. One of the leading compounds, H3B-960, showed consistent activities in a range of assays (IC 50 = 22 nM, K D = 40 nM, K I = 32 nM), and the most potent compound identified, H3B-968, has inhibitory activity IC 50 ∼ 10 nM. These kinetic properties trend toward other known covalent druglike molecules. Our work provides a new avenue for screening WRN for inhibitors that may be adaptable to different therapeutic modalities such as targeted protein degradation, as well as a proof of concept for the inhibition of WRN helicase activity by covalent molecules.

Heterobiaryl compounds that exhibit axial chirality are of increasing value and interest across several fields, but direct oxidative methods for their enantioselective synthesis are elusive. Here we disclose that an iron catalyst in the presence of a chiral PyBOX ligand and an oxidant enables direct coupling between naphthols and indoles to yield atropisomeric heterobiaryl compounds with high levels of enantioselectivity. The reaction exhibits remarkable chemoselectivity and exclusively yields cross-coupled products without competing homocoupling. Mechanistic investigations enable us to postulate that the reaction proceeds through selective formation of an indole radical which is trapped by a chiral iron naphthoate in a radical-anion type coupling process. We envision that this simple, cheap, and sustainable catalytic manifold will facilitate access to a range of heterobiaryl compounds and enable their applications across the fields of materials science, medicinal chemistry, and catalysis.Atropisomeric biaryls comprise a privileged class of compounds whose applications span the fields of medicinal chemistry, catalysis and materials science; as such, a panoply of elegant and efficient methods have been developedfor their synthesis 1 . The most convergent route to biaryls is generally the transition metal mediated cross-coupling of two partners 2,3 (although significant advances in metal-free methods have been demonstrated recently) 4 . Whilst this strategy generally results in cross-coupled products in good yields and predictable levels of chemo-and regioselectivity, these advantages may be offset by the requirement to synthesize two specifically functionalized coupling partners (Figure 1a) 5 . In principle, oxidative coupling represents a more direct, atom economic and environmentally benign approach as it creates the desired aryl-aryl linkage from two C-H bonds 6,7 . This realization has led to a significant number of oxidative homo-coupling procedures that can generate C2-symmetric BINOL-like structures in an enantioselective fashion. These include reactions mediated by transition metals including copper 8-10 , iron 11 and vanadium, 12 amongst others. However, in the absence of specific functional groups, controlling the regio-, chemo-and enantioselectivity of the corresponding hetero-couplings remains a formidable challenge, and successful examples have been limited to the synthesis of BINOL or NOBIN type scaffolds [13][14][15][16] . In particular, Katsuki demonstrated that iron salan complexes are effective in the enantioselective heterocoupling of naphthols 17 , and Pappo showed that chiral iron phosphate complexes act as effective precatalysts for the enantioselective synthesis of non C2-symmetric BINOLs (Figure 1b) 18 . We considered whether this oxidative cross-coupling approach could be used in the development of a method for the enantioselective synthesis of axially chiral indoles, which are emerging as a valuable member of the atropisomeric biaryl family 19-21 .