Successive Nucleophilic and Electrophilic Allylation for The Catalytic Enantioselective Synthesis of 2,4-Disubstituted Pyrrolidines

Abstract

Successive nucleophilic and electrophilic allylation mediated by the bis-Boc-carbonate derived from 2-methylene−1,3-propane diol enables formation of enantiomerically enriched 2,4-disubstituted pyrrolidines. An initial enantioselective iridium-catalyzed transfer hydrogenative carbonyl C-allylation is followed by Tsuji-Trost N-allylation using 2-nitrobenzenesulfonamide. Subsequent Mitsunobu cyclization provides the N-protected 2,4-disubstituted pyrrolidines.

Graphical Abstract

The development of catalytic asymmetric methods for the synthesis of saturated N-heterocycles^1,2 is driven by the frequency with which such structural motifs occur as substructures in FDA approved drugs,³ and the growing appreciation that stereochemical complexity improves prospects for clinical success.^4,5 Our exploration of hydrogen-mediated reductive coupling⁶ has enabled diverse methods for catalytic enantioselective C-C bond formation, including carbonyl allylation.^6d,7 In these processes, primary alcohol oxidation is balanced by C-O reductive cleavage of an allylic acetate pronucleophile resulting in the formation of a transient aldehyde-allylmetal pair, which combine to form secondary homoallylic alcohols. Based on this reactivity pattern, we envisioned an approach to N-protected 2,4-disubstituted pyrrolidines wherein the bis-Boc-carbonate derived from 2-methylene-1,3-propane diol is subjected to successive nucleophilic and electrophilic allylation (Figure 1).^8,9 While numerous bifunctional allylmetal reagents based on tin, boron or silicon have been described,¹⁰ the use of such reagents for pyrrolidine synthesis is uncommon and is soley manifested by the pioneering efforts of Trost vis-à-vis trimethylenemethane (TMM) cycloadditions of imines.^10a,11,12 Catalytic enantioselective cycloadditions of this type have been reported,^11c-f but require tailored chiral phosphoramidite ligands and are largely restricted to aryl-substituted imines.^11c,e To our knowledge, highly enantioselective syntheses of 2-alkyl-4-methylenepyrrolidines remain a largely unmet challenge. Here, we report a catalytic protocol for the synthesis of 2-alkyl-4-methylenepyrrolidines that utilizes inexpensive SEGPHOS ligands and avoids moisture sensitive imine reactants.

Figure 1.

Enantioselective pyrrolidine synthesis via successive nucleophilic and electrophilic allylation.

In an initial experiment, 4-bromobenzyl alcohol 1a (100 mol %) was exposed to bis-Boc-carbonate 2a¹³ (200 mol %) in the presence of the π-allyliridium C,O-benzoate complex derived from 4-cyano-3-nitrobenzoic acid and (S)-DM-SEGPHOS and K₃PO₄ (100 mol %) in DME (0.4 M) at 80 °C. The homoallylic alcohol 3a was generated in 58% yield and 89% ee (Table 1, entry 1). Decreased loadings of K₃PO₄ (10 mol %) led to a higher isolated yield of 3a (Table 1, entry 3). Different chiral phosphine ligands were evaluated (Table 1, entries 6–9). Optimal enantioselectivities were obtained using (S)-DM-SEGPHOS or (S)-SEGPHOS (Table 1, entries 3 and 9). It was found that a slight decrease in reaction temperature (70 °C) improved enantioselectivity without diminishing the isolated yield of 3a (Table 1, entry 11). Similar efficiencies were observed with the catalyst incorporating the 3,4-dinitro-C,O-benzoate moiety (Table 1, entry 12).

Table 1.

Selected optimization experiments in the enantioselective coupling of alcohol 1a and bis-Boc-carbonate 2a via alcohol-mediated hydrogen transfer.^a

^aYields are of material isolated by silica gel chromatography. Enantioselectivity was determined by chiral stationary phase HPLC analysis. See Supporting Information for further experimental details.

As 3,4-dinitrobenzoic acid is commercially available (and 4-cyano-3-nitrobenzoic acid is not), the optimized conditions employing (S)-Ir-III (Table 1, entry 12) were applied to the coupling of alcohols 1a–1j with bis-Boc-carbonate 2a (Table 2). Benzylic alcohols 1a–1e, the allylic alcohol geraniol 1f, and aliphatic alcohols 1g–1j delivered the respective adducts 3a–3j in good yield with excellent levels of enantioselectivity. The absolute stereochemistry of adducts 3a–3j was assigned in analogy to adduct 3i, which was determined by single crystal X-ray diffraction analysis. The conversion of alcohols 1a–1j to adducts 3a–3j represent redox-neutral processes. As illustrated by the conversion of aldehydes dehydro-1e, dehydro-1f and dehydro-1h to adducts 3e, 3f and 3h, 2-propanol-mediated reductive couplings of aldehyde reactants also proceed efficiently with high levels of enantioselectivity under identical conditions (Scheme 1).

Table 2.

Redox-neutral coupling of alcohols 1a–1j with bis-Boc-carbonate 2a to form adducts 3a–3j.^a

^aYields are of material isolated by silica gel chromatography. Enantioselectivity was determined by chiral stationary phase HPLC analysis. See Supporting Information for further experimental details.

^b(S)-Ir-II (5 mol %).

^cDME (0.2 M), 60 °C.

Scheme 1.

Reductive coupling of aldehydes dehydro-1e, dehydro-1f and dehydro-1h with bis-Boc-carbonate 2a to form adducts 3e, 3f and 3h.^a

^aYields are of material isolated by silica gel chromatography. Enantioselectivity was determined by chiral stationary phase HPLC analysis. See Supporting Information for further experimental details.

The conversion of adducts 3a–3j to the 2-substituted 4-methylenepyrrolidines 5a–5j was achieved via Tsuji-Trost allylation followed by Mitsunobu cyclization (Table 3). Whereas Tsuji-Trost allylation of para-nitrobenzenesulfonamide resulted in significant quantities of over-alkylation, corresponding reactions of ortho-nitrobenzenesulfonamide were more selective, providing the highly tractable ortho-nosyl containing adducts 4a–4j in good yield.¹⁴ Cyclization of adducts 4a–4j under Mitsunobu conditions proceeded smoothly to deliver the 2-substituted 4-methylenepyrrolidines 5a–5j.¹⁵ The enantiomeric purity of 2 pyrrolidines 5d and 5j was evaluated, which revealed no erosion in enantiomeric purity occurred upon Mitsunobu cyclization

Table 3.

Conversion of adducts 3a–3j to 4-methylenepyrrolidines 5a–5j via Tsuji-Trost allylation-Mitsunobu cyclization.^a

^aYields are of material isolated by silica gel chromatography. See Supporting Information for further experimental details.

^bAfter the first reaction was done, PPh₃ (500 mol%), DIAD (500 mol%) and THF (0.05 M) were added at 25 °C, 12 h.

To illustrate the utility of 4-methylenepyrrolidines 5a–5j, compounds 5d and 5h were subjected to a series of functional group manipulations (Scheme 2). The synthesis of carboxamide 7d from compound 5d demonstrates facile removal of the ortho-nosyl protecting group and corroborates the anticipated inversion of stereochemistry in the Mitsunobu cyclization.¹⁵ 4-Methylenepyrrolidine 5h is readily converted to the spirocyclopropane 6h,¹⁶ which embodies a structural motif evident in the FDA approved drug for the treatment of hepatitis C.¹⁷ Finally, oxidative cleavage¹⁸ of 4-methylenepyrrolidine 5h followed by exposure of the resulting ketone 7h to Deoxy-Fluor®¹⁹ delivers the gem-difluoride 8h.

Scheme 2.

Derivatization of 4-methylenepyrrolidines 5d and 5h.^a

^aYields are of material isolated by silica gel chromatography. See Supporting Information for further experimental details.

In conclusion, we report the enantioselective synthesis of 2-substituted-4-methylenepyrrolidines through successive nucleophilic and electrophilic allylation of bis-Boc-carbonate 2a. Whereas prior methods for the enantioselective synthesis of 2-substituted-4-methylenepyrrolidines involve TMM cycloadditions of moisture sensitive imine reactants and are restricted to 2-aryl-substituted adducts, the present protocol enables facile access to 2-alkyl-4-methylenepyrrolidines from highly tractable alcohol reactants.