Three‐Component Coupling Reactions of Silyl Glyoxylates, Vinyl Grignard Reagent, and Nitroalkenes: An Efficient, Highly Diastereoselective Approach to Nitrocyclopentanols

Abstract

The efficient synthesis of highly substituted cyclopentanols is an important task given the prevalence of this class of compounds in nature. Nitrocyclopentanols are of particular value due to the rich chemistry associated with the nitro group [1] and their potential use as aminocyclopentitol progenitors.[2] Aminocyclopentitols have generated considerable attention because of their significant biological activity and synthetic challenges presented by their often dense functionality and contiguous chiral centers. As such, the development of a flexible synthesis of functionalized nitrocyclopentanols would be a welcome addition to the synthetic toolbox. Herein we report the three-component coupling of silyl glyoxylates, CH 2 = CHMgBr, and nitroalkenes that selectively affords (Z)-silyl enol ether products through a unique vinylogous Michael cascade. The resulting functionality enables the immediate implementation of a second-stage Henry cyclization for the expeditious, diastereoselective synthesis of functionalized nitrocyclopentanols.Silyl glyoxylates are conjunctive reagents for the union of complementary nucleophilic and electrophilic partners linked at a protected glycolic acid junction.[3] The use of these reagents in coupling reactions with alkide and hydride nucleophiles [4] and carbonyl secondary electrophiles has been documented. We endeavoured to expand the utility of silyl glyoxylate chemistry to include Michael acceptors as the secondary electrophile. Nitroalkenes were chosen by virtue of their highly electrophilic character and the synthetic versatility of the nitro functionality. The proposed transformation outlined in Scheme 1 involves the addition of vinyl Grignard to the silyl glyoxylate 1 to reveal, after [1,2]-Brook rearrangement, [5] the (Z)-metallodienolate 2. [4a,c] This intermediate could act as a transient secondary nucleophile capable of engaging the nitroalkene 4 in a vinylogous Michael addition to provide enolsilane 6. As such, the combination of 1 and CH 2 =CHMgBr would function as the synthetic equivalent of the unusual a-keto ester homoenolate synthon, perhaps by way of the C-metalated tautomer 3 of the (Z)-metallodienolate (Scheme 2). [6] An open question at the outset of this inquiry was whether a/g selectivity would exhibit electrophile dependence. Previous silyl glyoxylate-based couplings predominantly provided a-selectivity from metallodienolate intermediates. [4a,c] Moreover, the vinylogous Michael reaction of metallodienolates is infrequently deployed due to an innate kinetic preference for a-addition: evaluation of frontier-orbital densities and HOMO coefficients establish the a-carbon as the more nucleophilic site. [7] While some exceptions exist, [8] successful vinylogous Michael reactions frequently require considerable prefunctionalization to control selectivity and are almost exclusively performed with butenolide derivatives [9] and a,a-dicyanoolefins.[10] A second challenge lies in the management of the relevant rate constants. Stepwise Scheme 1. Divergent silyl glyo...

Application of the Brook Rearrangement in Tandem with Single Electron Transfer Oxidative and Radical Processes

“…Especially the Brook rearrangement, the translocation of a silyl group from a carbon atom to negatively charged oxygen atom has been recently frequently used to trigger further nucleophilic transformations with alkyl halides, epoxides, aldehydes or Michael acceptors as well as Ireland–Claisen rearrangements or [3+2] cycloadditions . The Brook rearrangement is versatile, since the silyl group can be located at varying distance to the alkoxide group, thus [1,2]‐, [1,3]‐ or [1,4]‐rearrangements are common.…”

Iodine-mediated synthesis of 3-acylbenzothiadiazine 1,1-dioxides

“…Interestingly, when 2-aminobenzenesulfonamides bearing an alknyl group were subjected to this reaction, besides the formation of 3-acylbenzothiadiazine 1,1,-dioxide skeletons, the triple bond was further transformed into an ortho -diketone functionality (Scheme 4) [27–29]. 1,2-Dicarbonyl functionalities are one of the most important skeletons found in biologically active molecules and versatile building blocks for chemical transformations [30–32]. …”

Aerobic Oxidation of Alkynes to 1,2‐Diketones by Organic Photoredox Catalysis

“…To improvet he result, ac o-solvent system [1, and DMF] was employed. DCE/DMF (2:1) was determineda st he best solventi nt erms of yield (76 %; Ta ble 1, entries [6][7][8]. Notably,t rifluoroacetic acid (TFA) was able to exert an influence on this photooxygenation ( Table 1, entry 9).…”