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

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

Key words

diastereoselective - lithiation - benzylic - imidazolone - deuteration - transmetalation - chiral auxiliary

• References and Notes

• 1 New address: Alphora Research Inc., 2395 Speakman Drive, Mississauga, Ontario, L5K 1B3, Canada; e-mail: [e-mail].
• 2a Hoppe D. Zschage O. Angew. Chem., Int. Ed. Engl. 1989; 28: 65
• 2b Hoppe D. Karstens A. Krämer T. Angew. Chem. Int. Ed. 1990; 29: 1424
• 2c Hoppe D. Krämer T. Schwark J.-R. Zschage O. Pure Appl. Chem. 1990; 62: 1999
• 2d Hoppe D. Hintze F. Tebben P. Paetow M. Ahrens H. Schwerdtfeger J. Sommerfeld P. Haller J. Guamieri W. Kolczewski S. Hense T. Hoppe I. Pure Appl. Chem. 1994; 66: 1479
• 2e Kaiser B. Hoppe D. Angew. Chem., Int. Ed. Engl. 1995; 34: 323
• 3a Beak P. Basu A. Gallagher DJ. Park YS. Thayumanavan S. Acc. Chem. Res. 1996; 29: 552
• 3b Beak P. Johnson TA. Kim DD. Lim SH. Top. Organomet. Chem. 2003; 5: 139
• 3c Hoppe D. Hense T. Angew. Chem., Int. Ed. Engl. 1997; 36: 2282
• 4 Clayden J. Organolithiums: Selectivity for Synthesis . Pergamon Press; Oxford: 2002
• 5 Kizirian J.-C. In Topics in Stereochemistry . Vol. 26. Gawley RE. Verlag Helvetica Chimica Acta; Zürich: 2010: 189
• 6 Kessar SV. Singh P. Chem. Rev. 1997; 97: 721
• 7 Schlosser M. Limat D. J. Am. Chem. Soc. 1995; 117: 12342
• 8 Faibish NC. Park YS. Lee S. Beak P. J. Am. Chem. Soc. 1997; 119: 11561
• 9 Wu S. Lee S. Beak P. J. Am. Chem. Soc. 1996; 118: 715
• 10a Barberis C. Voyer N. Roby J. Chénard S. Tremblay M. Labrie P. Tetrahedron 2001; 57: 2965
• 10b Hammerschmidt F. Hanbauer M. J. Org. Chem. 2000; 65: 6121
• 11 Oña-Burgos P. Fernández I. Roces L. Torre-Fernández L. Garcia-Granda S. Lopez-Ortiz F. Org. Lett. 2008; 10: 3195
• 12a Blake AJ. Ebden MR. Fox DN. A. Li W.-S. Simpkins NS. Synlett 1998; 189
• 12b Ariffin A. Blake AJ. Ebden MR. Li W.-S. Simpkins NS. Fox DN. A. J. Chem. Soc., Perkin Trans. 1 1999; 2439
• 13a Beak P. Du H. J. Am. Chem. Soc. 1993; 115: 2516
• 13b Basu A. Beak P. J. Am. Chem. Soc. 1996; 118: 1575
• 13c Thayumanavan S. Lee S. Liu C. Beak P. J. Am. Chem. Soc. 1994; 116: 9755
• 14a Gawley RE. Rein K. Chemburkar S. J. Org. Chem. 1989; 54: 3002
• 14b Gawley RE. J. Am. Chem. Soc. 1987; 109: 1265
• 15a Gawley RE. Zhang Q.-H. Tetrahedron 1994; 50: 6077
• 15b Elworthy TR. Meyers AI. Tetrahedron 1994; 50: 6089
• 15c Carstens A. Hoppe D. Tetrahedron 1994; 50: 6097
• 16 In both cases carbanion epimerization takes place, which does not mean that the carbanion is configurationally unstable. The final product ratio is determined by electrophile quench because of either dynamic kinetic resolution (DKR) or dynamic thermodynamic resolution (DTR). These two possibilities roughly correspond to the terms ‘ion pair’ or ‘contact species’, respectively. See ref. 5 for more details.
• 17 Metallinos C. John J. Zaifman J. Emberson K. Adv. Synth. Catal. 2012; 354: 602
• 18 Metallinos C. John J. Nelson J. Dudding T. Belding L. Adv. Synth. Catal. 2013; 355: 1211
• 19 John J. Wilson-Konderka C. Metallinos C. Adv. Synth. Catal. 2015; 357: 2071
• 20 Wilson-Konderka C. Doxtator K. Metallinos C. Adv. Synth. Catal. 2016; 358: 2599

For enanatioselective and diasteroselective lithiation of sp³-positions α to nitrogen within a pyrroloimidazolone ring, see:
• 21a Metallinos C. Xu S. Org. Lett. 2010; 12: 76
• 21b Metallinos C. Sadraei SE. Zhukovskaya N. Heterocycles 2014; 88: 347
• 22a Dakin H. Biochem. J. 1918; 12: 297
• 22b Stark G. Smyth D. J. Biol. Chem. 1963; 238: 214
• 23a See Supporting Information for full experimental procedures of all new compounds, including characterization data and copies of ¹H NMR and ¹³C NMR spectra.
• 23b The use of MeLi in place of n-BuLi for lithiation under the optimized conditions gave anti-12a in identical dr (88:12) but poor yield (5%). A better yield (63%) required prolonged lithiation time (8 h).
• 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, R_f = 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) ų, 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): ν_max = 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
• 25 Thayumanavan S. Lee S. Liu C. Beak P. J. Am. Chem. Soc. 1994; 116: 9755
• 26 9-d ₁ had >95% deuterium incorporation according to mass spectral data.
• 27 Resek JE. Beak P. J. Am. Chem. Soc. 1994; 116: 405
• 28 The average of two experiments that gave ratios of 56:44 and 50:50, respectively.