This paper describes a method for the palladium catalyzed intramolecular C-H arylation using tosylates and mesylates as electrophiles. The transformation is efficient for the synthesis of various heterocyclic motifs including furans, carbazoles, indoles, and lactams. Additionally, a protocol for the one-pot sequential tosylation/arylation of phenol derivatives is presented.

An enantioselective redox-relay Heck alkynylation of di- and trisubstituted alkenols to construct propargylic stereocenters is disclosed using a new pyridine oxazoline ligand. This strategy allows direct access to chiral β-alkynyl carbonyl compounds employing allylic alcohol substrates in contrast to more traditional conjugate addition methods.

Antibody drug conjugates are a rapidly growing form of targeted chemotherapeutics. As companies and researchers move to develop new antibody-drug conjugate (ADC) candidates, high-throughput methods will become increasingly common. Here we use advanced characterization techniques to assess two trastuzumab-DM1 (T-DM1) ADCs; one produced using Protein A immobilization and the other produced in solution. Following determination of payload site and distribution with liquid chromatography-mass spectrometry (LC/MS), thermal stability, heat-induced aggregation, tertiary structure, and binding affinity were characterized using differential scanning calorimetry (DSC), dynamic light scattering (DLS), Raman spectroscopy, and isothermal titration calorimetry (ITC), respectively. Small differences in the thermal stability of the C H 2 domain of the antibody as well as aggregation onset temperatures were observed from DSC and DLS, respectively. However, no significant differences in secondary and tertiary structure were observed with Raman spectroscopy, or binding affinity as measured by ITC. Lysine-based ADC conjugation produces an innately heterogeneous population that can generate significant variability in the results of sensitive characterization techniques. Characterization of these ADCs indicated nominal differences in thermal stability but not in tertiary structure or binding affinity. Our results lead us to conclude that lysine-based ADCs synthesized following Protein A immobilization, common in small-scale conjugations, are highly similar to equivalent ADCs produced in larger scale, solution-based methods.

An enantioselective redox-relay Heck alkynylation of di-and trisubstituted alkenols to construct propargylic stereocenters is disclosed using a new pyridine oxazoline ligand. This strategy allows direct access to chiral β-alkynyl carbonyl compounds employing allylic alcohol substrates in contrast to more traditional conjugate addition methods. Graphical abstractA convenient redox-relay Heck strategy to synthesize enantiomerically enriched β-alkynyl carbonyl compounds from allylic alcohol substrates is described. Trisubstituted allylic alcohols are also promising substrates allowing for the formation of propargylic quaternary stereocenters. KeywordsHeck reaction; alkenes; propargylic stereocenter; alkynylation Intermolecular Heck reactions generally feature the coupling of an sp 2 -hybridized reaction partner to an alkene followed by β-hydride elimination towards the site of initial migratory insertion. This formally yields a sp 2 -sp 2 carbon-carbon connection. [1] Recently, this reaction has been expanded through both substrate and catalyst design to preferentially undergo β-hydride elimination away from the site of initial migratory insertion to both set a stereocenter and allow the formation of a sp 2 -sp 3 C-C bond. [2] Specifically, our group has reported a suite of such enantioselective redox-relay Heck reactions of acyclic alkenyl Correspondence to: Matthew S. Sigman. Supporting information for this article can be found under: http://dx.doi.org/ Conflict of interestThe authors declare no conflict of interest. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript alcohols using aryldiazonium salts, [3] arylboronic acids, [4] and alkenyl triflates, [5] which provides direct preparation of carbonyl compounds that contain remote alkenyl/aryl stereocenters (Scheme 1A). However, this emerging strategy has thus far been limited to sp 2 -hybridized nucleophiles/electrophiles as coupling partners.In an effort to expand the breadth of products one can access with this approach, we selected to investigate the enantioselective Heck alkynylation of alkenols to construct propargylic stereocenters and forge sp-sp 3 C-C bonds (Scheme 1B). The successful development of an alkynyl Heck reaction would allow direct access to chiral β-alkynyl carbonyl compounds, which are versatile intermediates that have extensive applications in organic synthesis. [6] Traditionally, these types of compounds have been synthesized using enantioselective conjugate addition technologies, pioneered by Carreira, [7] Hayashi, [8] and others, through organometallic acetylide addition to α,β-unsaturated carbonyl substrates. [9] However, we envisioned that a redox-relay Heck approach that utilized allylic alcohol substrates would provide an attractive alternative to this field due to the ease of preparation, handling and improved stability of such alkenols. In addition, it was deemed possible, on the basis of our previous reports, that trisubstituted alkenols may be viable substrates. Using a traditional c...

Antibodies have been explored for decades for the delivery of small molecule cytotoxins directly to diseased cells. In antibody-directed enzyme prodrug therapy (ADEPT), antibodies are armed with enzymes that activate nontoxic prodrugs at tumor sites. However, this strategy failed clinically due to off-target toxicity associated with the enzyme prematurely activating prodrug systemically. We describe here the design of an antibody-fragment split enzyme platform that regains activity after binding to HER2, allowing for site-specific activation of a small molecule prodrug. We evaluated a library of fusion constructs for efficient targeting and complementation to identify the most promising split enzyme pair. The optimal pair was screened for substrate specificity among chromogenic, fluorogenic, and prodrug substrates. Evaluation of this system on HER2-positive cells revealed 7-fold higher toxicity of the activated prodrug over prodrug treatment alone. Demonstrating the potential of this strategy against a known clinical target provides the basis for a unique therapeutic platform in oncology.