New Regio- and Stereoselective Cascades via Unstabilized Azomethine Ylide Cycloadditions for the Synthesis of Highly Substituted Tropane and Indolizidine Frameworks

Abstract

Multisubstituted tropanes and indolizidines have been prepared with high regio- and stereoselectivity by the [3 + 2] cycloaddition of unstabilized azomethine ylides generated from readily prepared trimethylsilyl substituted 1,2-dihydropyridines via protonation or alkylation followed by desilylation. Starting from 1,2-dihydropyridines bearing a ring trimethylsilyl substituent at the 6-position, an intermolecular alkylation/desilylation provides endocyclic unstabilized ylides that successfully undergo cycloaddition with a range of symmetrical and unsymmetrical alkyne and alkene dipolarophiles to afford densely substituted tropanes incorporating quaternary carbons in good yields and with high regio- and stereoselectivity. Additionally, an intramolecular alkylation/desilylation/cycloaddition sequence provides convenient and rapid entry to bridged tricyclic tropane skeletons, allowing for five contiguous carbon stereocenters to be set in a single experimental operation and under mild conditions. Starting from 1,2-dihydropyridines with trimethylsilylmethyl groups on nitrogen, protonation followed by desilylation generates exocyclic unstabilized ylides that undergo cycloaddition with unsymmetrical alkynes to give indolizidines with good regio- and stereoselectivity. N-Trimethylsilylmethyl 1,2-dihydropyridines can also be alkylated and subsequently desilylated to give endocyclic unstabilized ylides that undergo intermolecular cycloadditions with carbonyl compounds to give bicyclic oxazolidine products in good overall yields. Moreover, an intramolecular alkylation/desilylation/cycloaddition sequence with the N-trimethylsilylmethyl 1,2-dihydropyridines affords tricyclic indolizidines that incorporate quaternary carbons and up to five stereocenters with good to excellent regio- and diastereoselectivity.

Current Trends towards the Synthesis of Bioactive Heterocycles and Natural Products Using 1,3-Dipolar Cycloadditions (1,3-DC) with Azomethine Ylides

“…However, 1-[(trimethylsilyl)methyl] derivatives 312 furnished regio-and diastereoselectively indolizidines 313 or fused oxazolidine heterocycles 314 depending on the dipolarophile employed (Scheme 90). 131 These cascades are a powerful approach for the rapid assembly of biologically and pharmaceutically relevant nitrogen heterocycle scaffolds that are difficult to synthesize by other methods.…”

Synthesis of dehydroindolizidine-type poison-frog alkaloids via Michael-type conjugate addition

“…The stereoselectivity of the main Michael-type conjugate addition is shown in Scheme 2. An A (1,3) strain 10 was observed between the N-Cbz group and the allyl substituent at the α position. The anion attacks from the α-axial orientation were caused by stereoelectronic effects, 11 after which the enolate protonation produced a single isomer from the trisubstituted piperidine.…”

“…1,2 Several methods for the synthesis of dehydroindolizidine alkaloids have been established. [3][4][5] We have reported previously 6 the flexible synthesis of poison frog alkaloids of the 5,8-disubstituted indolizidine class. In the present study, the efficient chiral syntheses of the compounds 207E and 179 are addressed.…”

Pyridoxal-5′-phosphate–dependent bifunctional enzyme catalyzed biosynthesis of indolizidine alkaloids in fungi

“…Among them, the indolizidine alkaloids with the fused 5-and 6-membered cycles sharing a nitrogen atom seem to be highly attractive due to their intriguing structure and promising bioactivity (e.g., antibacterial, antiinflammatory, and antitumor) (Fig. 1) (3)(4)(5) as well as their elusive involvement in the producers' chemical defense (6,7). In particular, the medicinal value of some indolizidine alkaloids was showcased by the marketed anticancer drugs vinblastine and vincristine (Fig.…”

“…1A). Motivated by the observation, many groups have developed approaches to expand the chemical space of this family of alkaloids with an intention of hitting more prominent molecules (5,(8)(9)(10). Meanwhile, the diversity landscape of natural polyketide alkaloids suggests the biosynthetic versatility by the species belonging to different kingdoms (3,4,11).…”