Stereoselective Synthesis of Tetrahydroindolizines through the Catalytic Formation of Pyridinium Ylides from Diazo Compounds

Abstract

Commercially available iron(III) and copper(I) complexes catalyzed multicomponent cycloaddition reactions between diazo compounds, pyridines, and electrophilic alkenes to give alkaloid‐inspired tetrahydroindolizidines in high yield with high diastereoselectivity. Hitherto, the catalytic formation of versatile pyridinium ylides from metal carbenes has been poorly developed; the broad utility demonstrated herein sets the stage for the invention of further multicomponent reactions in future.

Iron‐porphyrin Catalyzed Carbene Transfer Reactions – an Evolution from Biomimetic Catalysis towards Chemistry‐inspired Non‐natural Reactivities of Enzymes

“…Importantly, catalyst loadings as low as 0.01 mol‐% could be used (Scheme b). The Dowden group reported In 2016 on the iron‐catalyzed ylide formation of ethyl diazoacetate with N ‐heterocycles, which undergo a subsequent [2+3] cycloaddition reaction with dipolarophiles yielding important indolizidine heterocycles (Scheme d) . Despite these advances, enantioselective applications using organometallic iron complexes remained elusive and the application of engineered enzymatic catalysts should theoretically enable asymmetric rearrangement reactions.…”

Nucleophilic Dearomatization of Activated Pyridines

“…The 1,3-dipolar cycloaddition of pyridinium ylides with electrophilic alkenes was recently applied by Dowden and co-authors [107,108] to the synthesis of tetrahydroindolizidines. In the first paper [107], pyridinium ylides were generated in situ by a reaction of the corresponding pyridinium salt, using triethylamine as the base in dichloromethane (DCM), and then reacted with 3-alkenyloxindoles, obtaining the desired products in good or very good yields (Scheme 30).…”

“…The resulting cycloadducts showed the same relative stereochemistry of biologically active oxindole alkaloids, especially isorhynchophylline and strychnofoline. Shortly after [108], the same group reported the generation of pyridinium ylides via metallocarbenes instead of the typically employed methodology, namely the deprotonation of the corresponding salts, avoiding the production of a stoichiometric amount of the conjugate-acid waste and the alkylation step of the pyridine derivatives.…”

Development and Cycloaddition Reactivity of a New Class of Pyridine‐Based Mesoionic 1,3‐Dipole

“…[11,16] Typical synthetic approaches to these products include cyclizations with synthetic pyridine or pyrrole derivatives, [17][18][19] substitution on preformed indolizines, [20] or 1,3-dipolar cycloaddition with pyridinium ylides. [21] 2 can be considered as tabilized, mesoionic analogue to these latter 1,3-dipoles,and offers the ability to incorporate ar ange of aryl, heteroaryl and alkyl units into the 3-indolizine position from simple imines.Asan illustration of the utility of this approach, ester-substituted indolizines such as 5 (Scheme 3) has been shown by Lan and Yout ob es trong blue emitting materials of use in fluorescence imaging. [20a] In contrast to its synthesis by substitution [a] 2 formed as in Table 2 on pre-synthesized indolizines, 5 can be directly generated from 3a,animine and an alkyne.Inaddition to forming 5,the systematic tuning of each the substrates can in principle allow access to arange of new variants of these products,and from reagents that are either commercially available (e.g.…”