Deconvoluting Nonlinear Catalyst-Substrate Effects in the Intramolecular Dirhodium-Catalyzed C-H Insertion of Donor/Donor Carbenes Using Data Science Tools.

Interactions between catalysts and substrates can be highly complex and dynamic, often complicating the development of models to either predict or understand such processes. A dirhodium(II)-catalyzed C-H insertion of donor/donor carbenes into 2-alkoxybenzophenone substrates to form benzodihydrofurans was selected as a model system to explore nonlinear methods to achieve a mechanistic understanding. We found that the application of traditional methods of multivariate linear regression (MLR) correlating DFT-derived descriptors of catalysts and substrates leads to poorly performing models. This inspired the introduction of nonlinear descriptor relationships into modeling by applying the sure independence screening and sparsifying operator (SISSO) algorithm. Based on SISSO-generated descriptors, a high-performing MLR model was identified that predicts external validation points well. Mechanistic interpretation was aided by the deconstruction of feature relationships using chemical space maps, decision trees, and linear descriptors. Substrates were found to have a strong dependence on steric effects for determining their innate cyclization selectivity preferences. Catalyst reactive site features can then be matched to product features to tune or override the resultant diastereoselectivity within the substrate-dictated ranges. This case study presents a method for understanding complex interactions often encountered in catalysis by using nonlinear modeling methods and linear deconvolution by pattern recognition.

One-Pot Assembly and Synthetic Applications of Geminal Acyl/Alkoxy Tetrasubstituted Allenes.

Polysubstituted allenes are useful synthetic intermediates in many applications, offering structural complexity, modularity, and their axial chirality in further transformations. While acyl and alkoxy-substituted allenes are known, there are currently few examples of allenes containing both functionalities and no reports of geminally substituted acyl/alkoxy allenes being isolated and characterized. Herein, we report the synthesis of tetrasubstituted allenes featuring a novel geminal acyl/alkoxy substitution. These unique "push-pull" allenes are bench-stable and exhibit interesting reactivity in several applications.

Divergent Asymmetric Synthesis of Panowamycins, TM-135, and Veramycin†F Using C-H Insertion with Donor/Donor Carbenes.

Panowamycins are a group of isochroman-based natural products first isolated from Streptomyces sp. K07-0010 in 2012 by Satoshi Omura and co-workers that exhibit modest anti-trypanosomal activity. Herein we demonstrate the first syntheses of these natural products and their epimers. Stereoselective dirhodium-catalyzed C-H insertion reactions with a donor/donor carbene construct the substituted isochroman core in the key bond-forming step. The syntheses are completed without the use of protecting groups and feature a late-stage Wacker oxidation. Incongruent NMR spectra between natural and synthetic samples revealed the structural misassignment of panowamycin A and veramycin F. Computational NMR studies suggested panowamycin A to be an alternate diastereomer, which was confirmed by synthesizing this isomer. Concurrent with this work, in 2021 Mahmud and co-workers came to the same conclusion with an updated NMR analysis of panowamycin A. In a divergent, asymmetric sequence, we report the synthesis of panowamycin A, panowamycin B, TM-135, and veramycin F.

Transition Metal Catalyzed Insertion Reactions with Donor/Donor Carbenes.

Donor/donor carbenes are relatively new in the field of carbene chemistry; although applications in C-H and X-H insertion reactions are few in number, they demonstrate exquisite chemo- and stereo-selectivity. Recent reports have shown that C-H, N-H, B-H, O-H, S-H, Si-H, Ge-H, Sn-H and P-H insertion reactions are feasible with a variety of transition metal catalysts, both inter- and intramolecularly. Furthermore, high degrees of diastereo- and enantioselectivity have been observed in several cases. Methods typically involve the formation of a diazo-based carbene precursor, but procedures using diazo-free metal carbenes have been developed with significant success. This Minireview covers transition-metal catalyzed insertion reactions with donor/donor and donor carbenes, providing context for future developments in this emerging field.

Enantioselective synthesis of isochromans and tetrahydroisoquinolines by C-H insertion of donor/donor carbenes.

Reports of C-H insertions forming six-membered rings containing heteroatoms are rare due to Stevens rearrangements occurring after nucleophilic attack on the carbene by a heteroatom. Using donor/donor carbenes and Rh2(R-PTAD)4 as a catalyst, we have synthesized a collection of isochroman substrates in good yield, with excellent diastereo- and enantioselectivity, and no rearrangement products were observed. Furthermore, we report the first synthesis of six-membered rings containing nitrogen by C-H insertion to form tetrahydroisoquinolines. In one case, a Stevens rearrangement product was isolated at elevated temperature from a carbamate-protected amine substrate and computational evidence suggests formation through a free ylide not bound to rhodium.

Correction: Enantioselective synthesis of isochromans and tetrahydroisoquinolines by C-H insertion of donor/donor carbenes.

[This corrects the article DOI: 10.1039/C9SC05111B.].