Synlett 2017; 28(20): 2901-2905
DOI: 10.1055/s-0036-1591206
letter
© Georg Thieme Verlag Stuttgart · New York

Diastereoselective Lithiation of N-Benzyl Pyrroloimidazolones Derived from l-Proline Hydantoin

Kassandra Emberson, Ngan Tran, Costa Metallinos*
  • Department of Chemistry, Brock University, 1812 Sir Isaac Brock Way, St. Catharines, Ontario, L2S 3A1, Canada   Email: metallic@brocku.ca
Further Information

Publication History

Received: 07 June 2017

Accepted after revision: 18 July 2017

Publication Date:
21 August 2017 (eFirst)

Dedicated to Professor Victor Snieckus on the occasion of his 80th birthday

Abstract

An N-benzyl pyrroloimidazolone derived from l-proline hydantoin undergoes asymmetric lithiation with n-BuLi/TMEDA in toluene to give products of electrophile quench (E+) that range from 87:13 to 91:9 diastereomeric ratio (dr). All products appear to have the same relative stereochemistry as determined by transmetalation of benzylic stannanes, which gave identical major diastereomers for several products as to what was observed by direct lithiation–substitution of the starting material. X-Ray crystallography of the major diastereomer of the benzophenone adduct established (R)-configuration at the benzylic center, i.e., anti stereochemistry with respect to the imidazolone. Lithiation of a selectively deuterated analogue of the starting material according to the optimized conditions, followed by benzophenone quench, gave diastereomeric products with far lower selectivity (53:47 dr) than lithiation of the non-deuterated analogue (91:9 dr) owing to a large primary kinetic isotope effect. These preliminary results imply that metalation of the N-benzyl pyrroloimidazolone may follow an asymmetric deprotonation pathway to give a benzylic carbanion that retains its configuration during electrophile quench.

Supporting Information

 
  • References and Notes

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  • 24 Representative Example: (+)-(1R,7aS)-2-[(R)-2-Hydroxy-1,2,2-triphenylethyl]-1-[(triethylsilyl)oxy]tetrahydro-1H-pyrrolo-[1,2-c]imidazol-3(2H)-one (12e) A solution of 9 (111 mg, 0.32 mmol) and TMEDA (0.05 mL, 0.35 mmol) in PhMe (2 mL) at –78 °C was treated with n-BuLi (0.19 mL, 1.9 M in hexanes, 0.35 mmol). After stirring for 1 h the solution changed from colorless to deep yellow. The reaction mixture was quenched with a solution of benzophenone (64 mg, 0.35 mmol) in PhMe (1 mL) transferred slowly by cannula. The resulting reaction mixture was stirred for 1 h at –78 °C and slowly warmed to r.t. Water (0.5 mL) was added, and the product was extracted with Et2O (2 × 10 mL). The combined organic extract was washed with water, brine, dried over anhyd Na2SO4, and concentrated under reduced pressure. Flash column chromatography (silica gel, 90:10 hexanes/EtOAc, Rf = 0.18) gave 12e (127 mg, 76%), a colorless solid, as a 91:9 mixture of diastereomers. Recrystallization from EtOH/hexane gave the major diastereomer as fine colorless needles (>98:2 dr by 1H NMR); mp 157–158 °C (EtOH/hexane); [α]D 20 +292 (c 1.0, acetone); X-ray diffraction data (CCDC 1451575) were collected on a single crystal (0.21 × 0.20 × 0.12 mm3), obtained by crystallization from EtOH/hexanes: C32H40N2O3Si: M = 528.75 g/mol, orthorhombic, P212121, a = 9.6422(5) Å, b = 16.6071(8) Å, c = 36.8350(17) Å, V = 5898.4(5) Å3, α = 90 , β = 90 , γ = 90 , Z = 8, D c = 1.191 mg/ m3, F(000) = 2272, T = 147 (2) K; 240498 data were collected. The structure was solved by direct methods (SHELXTL) and refined by full-matrix least squares on F 2 resulting in final R, R w, and GOF [for 10465 data with F > 2σ(F)] of 0.0371, 0.0943, and 1.023, respectively, Flack parameter = 0.02(3). IR (ATR, solid): νmax = 3192, 2957, 2935, 2909, 2876, 1675, 1447, 1429, 1266, 1138 cm–1. 1H NMR (400 MHz, acetone-d 6, major isomer): δ = 8.04 (s, 1 H), 7.90 (d, 2 H, J = 7.6 Hz), 7.30 (m, 4 H), 7.17 (m, 2 H), 7.08 (m, 5 H), 6.85 (d, 2 H, J = 7.2 Hz), 5.27 (s, 1 H), 5.13 (d, 1 H, J = 7.1 Hz), 3.78 (q, 1 H, J = 7.6 Hz), 3.36 (m, 1 H), 2.87–2.80 (m, 1 H), 1.74–1.65 (m, 3 H), 1.55–1.45 (m, 1 H), 1.06 (t, 9H, J = 8.0 Hz), 0.77 (q, 6 H, J = 7.9 Hz). 13C NMR (100.7 MHz, acetone-d 6, major isomer): δ = 163.8, 148.4, 146.8, 138.0, 130.5, 129.0, 128.2, 128.1, 128.0, 127.8, 127.6, 127.5, 127.2, 80.8, 79.5, 65.6, 63.8, 47.5, 25.7, 24.9, 7.3, 5.5. Anal. Calcd for C32H40N2O3Si; C, 72.69; H, 7.62. Found: C, 72.50; H, 7.65
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  • 28 The average of two experiments that gave ratios of 56:44 and 50:50, respectively.