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.

Figure 1

Endo- and exocyclic [3 + 2] cycloadditions via TMS dihydropyridines for the rapid synthesis of tropanes (eq 2-4), indolizidines (eq 5 and 7) and fused oxazolidines (eq 6).

Scheme 1. Tropanes via Intermolecular Cycloaddition of Endocyclic Azomethine Ylides with Alkyne Dipolarophiles^a

^a Yields were determined by mass balance of isolated products after chromatography and represent yields with respect to the starting dihydropyridine 1. Isomeric ratios were determined by ¹H NMR analysis of crude materials. ^b Cycloaddition performed at - −78 °C; regiochemistry assigned by 2D NMR. ^c X-ray structure shown with anisotropic displacement ellipsoids at the 50% probability level. Anion and hydrogen atoms omitted for clarity.

Scheme 2. Tropanes via Intermolecular Cycloaddition of Endocyclic Azomethine Ylides with Alkene Dipolarophiles^a

^a Yields were determined by mass balance of isolated products after chromatography and represent yields with respect to the starting dihydropyridine 1a. Isomeric ratios were determined by ¹H NMR analysis of crude materials. ^b Cycloaddition performed at 0 °C to rt. ^c Cycloaddition performed at −78 °C to rt. ^d Cycloaddition performed with CsO2CCF3 and 10 mol % of N,N′–bis[3,5–bis(trifluoromethyl)phenyl]–thiourea instead of an acetate at 0 °C to rt. ^e X-ray structure shown with anisotropic displacement ellipsoids at the 50% probability level. Anion and hydrogen atoms omitted for clarity.

Scheme 3. Bridged Tropanes via Intramolecular Cycloaddition of Endocyclic Azomethine Ylides with Tethered Dipolarophiles^a

^a Yields were determined by mass balance of isolated products after chromatography and represent yields with respect to the starting dihydropyridine 1. ^b Reaction performed at 40 °C. ^c X-ray structure shown with anisotropic displacement ellipsoids at the 50% probability level. Anion and hydrogen atoms omitted for clarity.

Scheme 4. Indolizidines via Intramolecular Cycloaddition of Exocyclic Azomethine Ylides with Alkyne Dipolarophiles^a

^a Yields were determined by mass balance of isolated products after chromatography and represent yields with respect to the starting imine 16. Isomeric ratios were determined by ¹H NMR analysis of crude materials. ^b X-ray structure shown with anisotropic displacement ellipsoids at the 50% probability level. Anion and hydrogen atoms omitted for clarity.

Scheme 5. Oxazolidines via Intermolecular Cycloaddition of Exocyclic Azomethine Ylides with Carbonyl Compounds^a

^a Yields were determined by mass balance of isolated products after chromatography and represent yields with respect to the starting dihydropyridine 8. Isomeric ratios were determined by ¹H NMR analysis of crude materials.

Scheme 6. Multicyclic Indolizidines via Intramolecular Cycloaddition of Exocyclic Azomethine Ylides with Tethered Dipolarophiles^a

^a Yields were determined by mass balance of isolated products after chromatography and represent yields with respect to the starting dihydropyridine 8. ^b X-ray structure shown with anisotropic displacement ellipsoids at the 50% probability level. Anion and hydrogen atoms omitted for clarity.