Chirality Transfer in Azetidinium Ylides: An Enantioselective Route to α-Quaternary Azetidines

Abstract

Enantiomerically pure N-allyl azetidinium ions undergo a stereoselective [2,3]-sigmatropic shift to give azetidines with an α-quaternary center. These compounds are direct precursors of ­2-alkyl-2-carboxy-azetidines, a new class of constrained α-amino acids.

azetidines - nitrogen ylides - α-quaternary amino acids

References and Notes

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17

Compounds 17 and 20 were obtained as a 6:4 ratio of epimers by anionic cyclization of the corresponding chloride, obtained following a similar synthetic sequence as the one described in Scheme  [¹] . Compound 22 was obtained as the major epimer (7:3 ratio) following Scheme  [¹] .

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19

This ester was prepared by reaction of the corresponding nitrile (ref. 9a) in a mixture of EtOH-H₂SO₄ (yield 83%).

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23

The crystal structure data have been deposited at the Cambridge Crystallographic Data Centre and allocated the deposition number CCDC 703601.

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25

General Procedure for Rearrangement of Azetidinium Triflates The following procedure for the preparation of azetidine 13 is representative. To a solution of azetidinium triflate 10 (823 mg, 2.19 mmol) in dry THF (40 mL), cooled at -78 ˚C was added in one portion KOt-Bu (300 mg, 2.67 mmol). The reaction mixture was allowed to reach 0 ˚C over 3 h and was quenched by addition of H₂O and Et₂O. The reaction mixture was extracted with Et₂O, the combined organic layers were washed with brine, dried over MgSO₄, and concentrated under reduced pressure. The crude residue was examined by ^¹H NMR and showed a diastereomeric ratio of 98:2. Purification by flash chromatography (cyclohexane-EtOAc, 8:2) gave 13 as a colorless oil (461mg, 93%).
Selected Data
Compound 13: R _f  = 0.48 (cyclohexane-EtOAc, 8:2); [α]_D ^²5 -13.1 (c 0.33, CHCl₃). ^¹H NMR (300 MHz,CDCl₃): δ = 1.42 (d, J = 6.6 Hz, 3 H, Me), 2.01-2.12 (m, 1 H, CHHCH=CH₂), 2.21-2.32 (m, 1 H, CHHCH=CH₂), 2.42 (s, 3 H, NMe),
3.65 (d, J = 5.4 Hz, 1 H, H3), 3.80 (q, J = 5.5 Hz, 1 H, H4), 4.85-5.03 (m, 2 H, CHHCH=CH ₂), 5.35-5.52 (m, 1 H, CHHCH=CH₂), 7.23-7.35 (m, 5 H, Ar). ^¹³C NMR (75 MHz, CDCl₃): δ = 17.2 (CH₃), 33.9 (NMe), 36.3 (CH₂), 53.3 (C3), 61.9 (C4), 64.9 (C2), 119.9 (CN), 121.1 (CH=CH₂), 126.9, 128.3, 129.1 (CHAr), 131.0 (CH=CH₂), 135.6 (CqAr). MS (CI, NH₃): m/z = 227.1 (100) [MH⁺], 200.2 (50) [MH⁺ - HCN].
Compound 14; yield 73%, colorless oil; R _f  = 0.34 (pentane-EtOAc, 9:1); [α]_D ^²5 -64 (c 1, CH₂Cl₂). ^¹H NMR (300 MHz, CDCl₃): δ = 1.17 (d, J = 5.8 Hz, 3 H, Me), 2.38 (s, 3 H, NMe), 2.58 (appt. d, J = 5.3 Hz, 2 H, CH ₂ CH=CH₂), 3.15
(d, J = 9.1 Hz, 1 H, H3), 3.35 (q, J = 5.8 Hz, 1 H, H4),
5.11-5.22 (m, 2 H, CHHCH=CH ₂), 5.70-5.84 (m, 1 H, CHHCH=CH₂), 7.12-7.21 (m, 5 H, Ar). ^¹³C NMR (75 MHz, CDCl₃ MHz): δ = 19.6 (CH₃), 37.9 (NMe), 43.8 (CH₂), 53.9 (C3), 63.5 (C4), 71.2 (C2), 117.2 (CN), 120.2 (CH=CH₂), 127.8, 128.3, 128.6 (CHAr), 130.9 (CH=CH₂), 135.3 (CqAr). MS (CI, NH₃): m/z = 227.1 (100) [MH⁺], 200.2 (35) [MH⁺ - HCN].