Latest Pre-print Unveils An Unexpected Organometallic Rearrangement

Today in ChemRxiv we report an unusual and surprising organometallic rearrangement triggered by addition of Pd(TFA)2 to at alkenyl benzothiazole thioether (BT(S)). This story started two years ago. While wrapping up an in-depth study of the BT(S) directing group and its various uses in palladium(II) catalysis (ACS Catal. 2019, 9, 7626), Andrew treated a standard substrate with Pd(TFA)2. Rather than forming the PdX2(substrate)2 complex like we was with other Pd(II) salts, Andrew obtained an unusual structure where the organic ligand had undergone significant rearrangement and was now coordinated as a bidentate N,S-heterocyclic-carbene–tetrahydrothiophene—shout out to UCSD Crystallography for elucidating the structure! Andrew then teamed up with a high school intern, Matt Demer (now at UC Davis), and continued close collaboration with crystallographers Milan and Arnie from UCSD to understand the scope, limitations, and mechanism of this process. Bravo, Andrew and team!

For a link to the pre-print, click here: https://chemrxiv.org/articles/preprint/Ligand_Rearrangement_Leads_to_Tetrahydrothiophene-Functionalized_N_S-Heterocyclic_Carbene_Palladium_II_Complexes/13633301

Enantioselective 1,2-Arylfluorination via A Transient Directing Group Strategy – Pre-Print Online

Since our lab’s first paper establishing a transient directing group strategy for asymmetric Heck-type hydroarylation went online in 2019, we’ve been hard at work trying to extend this approach to three-component 1,2-difunctionalization. At long last we’ve succeeded, and we are thrilled to report the fruits of our labor: a remarkably versatile 1,2-arylfluorination reaction that can form fully substituted C(sp3)–Ar and C(sp3)–F stereo centers in up to >99% ee. Pivotal to the success of the project was use of design of experiments (DoE) to facilitate rapid optimization of reaction conditions and reaction progress kinetic analysis (RPKA) to elucidate the reaction mechanism. Hats off to Zhonglin, Luke, Mingyu, Zi-Qi, Van, and Yang on the landmark achievement!

For a link, click here: https://chemrxiv.org/articles/preprint/A_Transient_Directing_Group_Strategy_Enables_Enantioselective_Multicomponent_Organofluorine_Synthesis/13537283

Ni(COD)(DMFU) Precatalyst Paper Online

The holiday paper flurry continues! ❄️⛄️🥶 This time it’s Team Nickel, who together with collaborators at Bristol Myers Squibb describe the use of Ni(COD)(DMFU) as a well-defined, all-in-one precatalyst for alkene diarylation. This lovely red free-flowing solid can be conveniently prepared in high yield from Ni(COD)2 and is indefinitely thermally stable as long as handled in an inert-atmosphere glovebox. Congrats to the Scripps team, Nana, Van, and Omar, as well as BMS team, Steve and Martin. Here’s to another great year to come in the Scripps–BMS collaboration!

For a link to the paper, click here: https://www.thieme-connect.com/products/ejournals/abstract/10.1055/a-1344-6040

Alkoxide Decomposition Paper – In Press on Christmas Eve

‘Twas the night before Christmas 🎄 and… The final version of our paper with Bristol Myers Squibb (BMS) describing the facile decomposition of commonly used sodium alkoxide bases under air is now in press in ACS Catalysis. These bases maintain their appearance as free-flowing white or off-white solids while undergoing a complex decomposition process to various inorganic salts that is triggered by initial reaction with CO2 in the air. Congrats to the team: Bob, Aunji, Ryan, and Steve from BMS; and Joe, Van, Taeho, Omar, and Roman from Scripps!

Click here for a link to the paper: https://pubs.acs.org/doi/10.1021/acscatal.0c04124

The work first appeared as pre-print back in June: https://chemrxiv.org/articles/preprint/An_Under-Appreciated_Source_of_Reproducibility_Issues_in_Cross-Coupling_Solid-State_Decomposition_of_Primary_Sodium_Alkoxides_in_Air/12818234

Just in time for the holidays – Our [3+2] (Hetero)annulation paper is in press

Santa’s first delivery of the season has arrived 🎅 🎄 🎁 , with official acceptance and publication of our paper on [3+2] alkene (hetero)annulation in Nat. Commun. The project was carried out in collaboration with the Liu group at the University of Pittsburgh and the chemists from the Oncology Medicinal Chemistry Department at Pfizer, Inc. By taking advantage of a unique Pd(II)/Pd(IV) pathway that begins with directed nucleopalladation, this transformation conveniently furnishes indolines, dihydrobenzofurans, and indanes with trans stereochemistry across the ring juncture. The practicality of the method stems from its use of readily available alkenyl amide substrates and ambiphilic aryl halide coupling partners. Bravo to Hui-Qi, Pranali, Andrew, and Hou-Xiang from our lab, Ilia from the Liu lab, and Joyann, Shouliang, Michelle, and Indra from Pfizer.

Click here for a link to the paper: https://www.nature.com/articles/s41467-020-20182-4

The work first appeared as pre-print back in June: https://chemrxiv.org/articles/preprint/Anti-Selective_3_2_Hetero_annulation_of_Non-Conjugated_Alkenes_via_Directed_Nucleopalladation/12510038

2020 Engle Lab Holiday Party

The Engle lab continued its long-standing tradition of closing out the year with festivities—this time in Zoom format. We kicked things off with a Secret Santa gift exchange, complete with a full slate of predictions/guesses of who had whom, which were quickly debunked! Hermione enjoyed her gifts from Phillippa so much, she couldn’t resist showing off her new bow. We finished the night with several rounds of “Among Us”, rekindling our shared love of all Werewolf/Mafia-inspired games. Despite the challenges 2020 has thrown our way, we’ve gotten through it together, and we are looking forward to a safer and less Zoom-ful 2021!

Alkenyl Sulfonamide Diarylation – Now In Press

If you need something to “chew” on this Thanksgiving, look no further than our most recent collaborative paper severed by Team Nickel and Bristol Myers Squibb, accepted today for publication in ACS Catalysis. Led by second-year graduate student Omar Apolinar, the manuscript outlines the discovery and development of sulfonamides as uniquely effective nitrogen-based directing groups for the 1,2-diarylation of diverse alkenyl amine derivatives, including those with highly substituted alkenes and those where the alkene is remote from the sulfonamide. By taking advantage of the 4-cyanobenzenesulfonyl group, a close cousin of the venerable nosyl group, the sulfonamide can functional as a dual directing group and masked amine nucleophile, allowing for rapid modular synthesis of highly substituted amine products. Congrats to Omar, Van, Nana, and Joe from our lab and collaborator Mike Schmidt from BMS!

Click here for a link to the paper: https://pubs.acs.org/doi/10.1021/acscatal.0c03857

The work first appeared in pre-print form back in July: https://chemrxiv.org/articles/preprint/Sulfonamide_Directivity_Enables_Ni-Catalyzed_1_2-Diarylation_of_Diverse_Alkenyl_Amines/12642803/1

E/Z Isomerization Mechanistic Study Pre-Print Online

It has long been known that alkenes undergo isomerization—both positionally and stereochemically (E/Z)—in the presence of a palladium(II) catalyst, but the mechanistic details of this process have remained murky. In collaboration with the Blackmond lab at Scripps Research, we interrogated the mechanism of E/Z isomerization of alkenyl amides bearing an 8-aminoquinoline (AQ) directing group, which facilitates detection and characterization of otherwise short lived intermediates and suppresses positional isomerization. By leveraging a battery of techniques including in situ monitoring of intermediates, reaction kinetics, deuterium labeling, and DFT calculations, we were able to rule out several mechanistic hypotheses, with the pointing to a monometallic nucleopalladation mechanism. Congrats to Rei, Malkanthi, Mingyu, and high school intern Nhi on this work!

For a link, click here: https://chemrxiv.org/articles/preprint/Mechanistic_Studies_of_Pd_II_-Catalyzed_E_Z_Isomerization_of_Unactivated_Alkenes_Evidence_for_a_Monometallic_Nucleopalladation_Pathway/13194932

Former Postdoc De-Wei Gao Begins his Independent Academic Career

Congrats to former postdoc Dr. De-Wei Gao on his appointment as an Assistant Professor in the School of Physical Science and Technology at ShanghaiTech. De-Wei completed his Ph.D. at the Shanghai Institute of Organic Chemistry (SIOC) under the mentorship of Prof. Shu-Li You. He was a Postdoc in the Engle lab from 2016–2018, where he spearheaded our lab’s efforts in various aspects of copper catalysis. Since 2018, that time has been a Postdoc in the lab of Prof. Yi Tang at UCLA. Research in the Gao lab at ShanghaiTech will focus on selective synthesis of amino acids, peptides and proteins, the design of novel catalysts, and the development of biocompatible reactions.

To read more about the Gao group, click here: https://spst.shanghaitech.edu.cn/spst_en/2020/1010/c2939a56210/page.htm