Divergent Asymmetric Synthesis of Panowamycins, TM‐135, and Veramycin F Using C−H Insertion with Donor/Donor Carbenes

Abstract

Panowamycins are a group of isochromanbased natural products first isolated from Streptomyces sp. K07-0010 in 2012 by Satoshi Ōmura and co-workers that exhibit modest anti-trypanosomal activity. Herein we demonstrate the first syntheses of these natural products and their epimers. Stereoselective dirhodiumcatalyzed CÀ 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 latestage 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.

Asymmetric Carbene Transfer: Enhancing Chemical Diversity for Drug Discovery

“…Jared T. Shaw's group documented the total synthesis of panowamycins, TM‐135, and Veramycin F via an asymmetric C−H insertion with donor/donor carbenes (Figure 7). [41] The carbenes, generated in situ from hydrazone 34 with MnO 2 , exhibited good stereocontrol with Rh 2 (S‐TCPTTL) 4 , maintaining stereoselectivity on a gram‐scale (>95 : 5 cis : trans , 80 : 20 dr, and 79 % yield). Subsequent transformations allowed for the synthesis of panowamycin A, panowamycin B, and Veramycin F.…”

Transition Metal‐Catalyzed Enantioselective Synthesis of Chiral Five‐ and Six‐Membered Benzo O‐heterocycles

“…Very recently, Shaw and co‐workers have applied Rh‐catalyzed insertion of donor/donor carbenes to completed the synthesis of panowamycin A, panowamycin B, and veramycin F [227] …”

“…Very recently, Shaw and co-workers have applied Rhcatalyzed insertion of donor/donor carbenes to completed the synthesis of panowamycin A, panowamycin B, and veramycin F. [227] Bi and co-workers have developed N-triftosylhydrazones which could generate the corresponding carbenes under mild conditions. In 2021, they've applied these fluoroalkyl acetophenone-derived carbene precursors 338 to asymmetric intramolecular C(sp 3 )À H insertion reaction synthesized 339 in up to 98 : 2 er (Scheme 101).…”

Palladium-catalyzed intramolecular enantioselective C(sp3)–H insertion of donor/donor carbenes

“…Donor-type metal carbenes (donor carbene and donor–donor carbene), 11 owing to the presence of a donor-substituent for stabilization of the carbene carbon center, are typically less reactive (compared with acceptor-type metal carbenes) and have attracted increasing attention. Recently, Shaw’s group 12 and our group 13 have demonstrated the utility of donor-type carbenes in an intramolecular asymmetric C(sp 3 )–H insertion reaction in the presence of rhodium and ruthenium catalysts, and diazo compounds, enynones and azaenynes could be used as carbene precursors. As part of our continuing efforts to develop asymmetric carbene transformations, 13,14 along with the unique nature of palladium carbene chemistry, we speculate that the less reactive donor-type carbene intermediate might provide a good opportunity to realize the palladium-catalyzed enantioselective insertion of a C(sp 3 )–H bond.…”