Diastereoselective Construction of the 6-Oxa-2-azabicyclo[3.2.1]octane Scaffold from Chiral α-Hydroxyaldehyde Derivatives by the Aza-Prins Reaction

Abstract

(R)-2,3-Di-O-benzylglyceraldehyde and N-tosyl homoallylamine undergo aza-Prins cyclization to afford (1R,5S,7S)-7-[(benzyloxy)methyl]-2-tosyl-6-oxa-2-azabicyclo[3.2.1]octane in a highly diastereoselective manner through an unexpected intramolecular nucleophilic attack. Our work has opened a new route toward the asymmetric synthesis of 7-(alkyl or aryl)-6-oxa-2-azabicyclo[3.2.1]octane derivatives from chiral α-hydroxyaldehyde derivatives in one step.

The aza‐Prins Cyclization of Unfunctionalized Olefins Promoted by NHC‐Cu Complex and ZrCl4

“…trans-4-Chloro-2-(m-tolyl)-1-tosylpiperidine (trans 3f, major diastereomer, white solid): 1 : 3067, 2,966, 1,346, 1,328, 1,161, 1,093, 1,068 4-Chloro-1-tosylpiperidine (3o). Compound 3o (80.5 mg, 59% yield, oil) was prepared according to the general procedure and were purified by flash chromatography using petroleum ether/ethyl acetate (40:1) as eluent.…”

“…Compound 3o (80.5 mg, 59% yield, oil) was prepared according to the general procedure and were purified by flash chromatography using petroleum ether/ethyl acetate (40:1) as eluent. 1 4-Chloro-2-cyclohexyl-1-tosylpiperidine (3w). Compounds 3w (115.8 mg, 65% yield, trans:cis = 83:17) were prepared according to the general procedure and were purified by flash chromatography using petroleum ether/ethyl acetate (40:1) as eluent.…”

“…Chloro-2-phenyl-1-tosylpiperidine (3a). Compounds 3a (145.2 mg, 83% yield, trans:cis = 83:17) were prepared according to the general procedure and were purified by flash chromatography using petroleum ether/ethyl acetate (40:1) as eluent.trans-4-Chloro-2-phenyl-1-tosylpiperidine (trans 3a, major diastereomer, white solid):1 H NMR (400 MHz, CDCl 3 ) δ 7.68 (d, J = 7.5 Hz, 2H), 7.25 (d, J = 7.3 Hz, 7H), 5.31 (s, 1H), 3.92-3.75 (m, 2H), 2.95 (t, J = 13.9 Hz, 1H), 2.65 (d, J = 13.5 Hz, 1H), 2.36 (s, 3H), 1.80 (t, J = 14.1 Hz, 2H), 1.48 (q, J = 12.3 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 142.6, 137.0, 136.3, 128.9, 127.9, 126.4, 125.9, 125.5, 55.0, 51.8, 40.4, 36.7, 34.2, 20.5. cis-4-Chloro-2-phenyl-1-tosylpiperidine (cis 3a, minor diastereomer, oil): 1 H NMR (400 MHz, CDCl 3 ) δ 7.48 (d, J = 8.2 Hz, 2H), 7.15 (t, J = 3.7 Hz, 7H), 4.68 (t, J = 5.7 Hz, 1H), 4.05 (tt, J = 7.0, 4.0 Hz, 1H), 3.77 (ddd, J = 13.0, 9.2, 3.3 Hz, 1H), 3.41 (dt, J = 13.8, 4.9 Hz, 1H), 2.44-2.30 (m, 4H), 2.18 (dt, J = 14.4, 4.5 Hz, 1H), 2.07-1.96 (m, 1H), 1.86-1.74 (m, 1H).…”

“…4-Chloro-2-(2-methoxypheny)-1-tosylpiperidine (3b). Compounds 3b (114.1 mg, 62% yield, trans:cis = 76:24) were prepared according to the general procedure and were purified by flash chromatography using petroleum ether/ethyl acetate (40:1) as eluent.trans-4-Chloro-2-(2-methoxypheny)-1-tosylpiperidine (trans 3b, major diastereomer, white solid):1 H NMR (400 MHz, CDCl 3 ) δ 7.54 (d, J = 8.3 Hz, 2H), 7.17-7.09 (m, 3H), 6.99 (d, J = 7.5 Hz, 1H), 6.77-6.69 (m, 2H), 5.50 (d, J = 3.6 Hz, 1H), 4.00 (dt, J = 14.1, 4.0 Hz, 1H), 3.80 (tt, J = 11.4, 3.8 Hz, 1H), 3.73 (s, 3H), 3.49 (ddd, J = 14.5, 12.1, 3.2 Hz, 1H), 2.66 (dq, J = 13.3, 2.7 Hz, 1H), 2.34 (s, 4H), 2.03 (dt, J = 12.8, 2.8 Hz, 1H), 1.87-1.78 (m, 1H), 1.61 (qd, J = 12.2, 5.0 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 155.2, 142.1, 136.6, 128.5, 127.4, 126.4, 125.9, 119.1, 109.6, 54.1, 52.8, 52.0, 42.2, 38.3, 34.5, 20.5. cis-4-Chloro-2-(2-methoxypheny)-1-tosylpiperidine (cis 3b, minor diastereomer, white solid): 1 H NMR (400 MHz, CDCl 3 ) δ 7.37 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 11.2 Hz, 1H), 7.08 (d, J = 8.0 Hz, 3H), 6.77 (t, J = 7.4 Hz, 1H), 6.63-6.59 (m, 1H), 4.80 (dd, J = 8.3, 4.9 Hz, 1H), 3.96 (tt, J = 7.7, 4.2 Hz, 2H), 3.64 (s, 3H), 3.35 (ddd, J = 13.6, 7.1, 4.3 Hz, 1H), 2.34 (s, 4H), 2.32 (s, 4H), 2.20-2.07 (m, 1H), 1.97-1.85 (m, 1H).…”

“…HRMS-ESI (m/z): [M + H] + calcd for C 19 H 19 ClF 3 NO 2 S, 418.0850; found: 418.0854.4-Chloro-2-(4-nitrophenyl)-1-tosylpiperidine (3j). Compounds 3j (135.1 mg, 70% yield, trans:cis = 67:33) were prepared according to the general procedure and were purified by flash chromatography using petroleum ether/ethyl acetate (50:1) as eluent.trans-4-Chloro-2-(4-nitrophenyl)-1-tosylpiperidine (trans 3j, major diastereomer, white solid):1 H NMR (400 MHz, CDCl 3 ) δ 8.15 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 5.36 (d, J = 4.2 Hz, 1H), 3.92 (ddt, J = 14.7, 4.1, 2.2 Hz, 1H), 3.73 (tt, J = 11.9, 4.0 Hz, 1H), 2.94 (ddd, J = 15.2, 12.8, 2.8 Hz, 1H), 2.71-2.62 (m, 1H), 2.41 (s, 3H), 1.95-1.81 (m, 2H), 1.58-1.44 (m, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 147.3, 145.3, 144.1, 130.1, 127.7, 127.0, 124.1, 55.9, 52.1, 41.6, 37.8, 34.9, 21.6.cis-4-Chloro-2-(4-nitrophenyl)-1-tosylpiperidine (cis 3j, minor diastereomer, white solid):1 H NMR (400 MHz, CDCl 3 ) δ 8.06 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 4.96 (t, J = 5.1 Hz, 1H), 4.16 (p, J = 5.1, 4.6 Hz, 1H), 3.73-3.53 (m, 2H), 2.46 (dt, J = 14.7, 5.0 Hz, 1H), 2.38 (s, 3H), 2.23 (ddd, J = 14.6, 5.8, 3.8 Hz, 1H), 1.93 (ddt, J = 13.9, 8.9, 5.2 Hz, 1H), 1.83-1.74 (m, 1H).…”