Thursday, November 21, 2024
11/21/2024
ABSTRACT Strained cyclic compounds are often used as key intermediates in the synthesis of bio-active drugs and natural products through strain-releasing reactions such as ring-expansion and ring-opening processes. While small ring ketones such as cyclobutanones have found widespread applicability in these transformations, the analogous use of cyclopropanone derivatives as substrates has seriously lagged behind, as these compounds have long been considered unsustainable synthetic intermediates due to their extreme strain and kinetic instability. This work proposes the use of 1-sulfonylcyclopropanols as a general class of stable cyclopropanone surrogates in organic synthesis, unlocking access to myriad previously inaccessible synthetic disconnections via strain-releasing reactions. These include (1) rearrangements initiated by the addition of nucleophiles, (2) transition metal-catalyzed C–C activation and deconstruction strategies, and (3) application of cyclopropanone derivatives as 1,1-cyclopropyl linchpins. We have already developed an efficient enantioselective route to these compounds and have obtained significant preliminary data in each of these types of reactions, leading to a variety of chiral synthons difficult to access by other methods. Both the electronic and steric nature of the sulfonyl moiety in these surrogates, which is acting here as a base-labile protecting group and conferring crystallinity to these compounds, is found to have a crucial impact on their rate of equilibration to cyclopropanone, highlighting their tunable reactivity and the potential for their widespread applicability as synthetic intermediates. During the funding period and using the mechanistic knowledge acquired, this technology leading to enantioenriched 1-sulfonylcyclopropanols will be extended to the formation of 1- sulfonylcyclopropylamine and hydrazines as modular precursors of chiral cyclopropanimines and hydrazones, respectively, and will allow novel access to chiral amine-containing scaffolds as well as strained chiral carbene equivalents. We firmly believe that the stability, ease of synthesis and modular character of these reagents will serve as a general solution to harvest the untapped versatility of cyclopropanones and its analogues as highly reactive building blocks in synthesis. Thus, this work will significantly expand the scope of disconnections available to chemists in the realm of strained ring activation and functionalization, evolving these severely strained derivatives from chemical curiosities to versatile synthetic intermediates, greatly contributing to streamline the production of biologically relevant organic molecules.
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