Synthesis and Evaluation of Chiral Dibenzazepinium Halide Phase-Transfer Catalysts

Abstract

Two complimentary routes to chiral dibenzazepinium halides have been developed. This has enabled the synthesis and evaluation of a range of potential phase-transfer catalysts (PTC) for asymmetric alkylation and Michael addition reactions involving glycine imine esters.

Key words

amino acids - asymmetric alkylation - phase-transfer ­catalysis - quaternary ammonium salts - Michael addition

References and Notes

• See, for example:
• 1a Lygo B. Phase-Transfer Reactions, In Rodd’s Chemistry of Carbon Compounds   Vol. V:  Elsevier Science Ltd.; Oxford: 2001.  p.101-150  
• 1b O’Donnell MJ. Asymmetric Phase-Transfer Reactions in Catalytic Asymmetric Synthesis   2nd ed.:  Ojima I. Verlag Chemie; New York: 2000. 
• 1c Shioiri T. Chiral Phase-Transfer Catalysts, In Handbook of Phase-Transfer Catalysis   Sasson Y. Neumann R. Blackie Academic and Professional; London: 1997. 
• For reviews covering recent developments in asymmetric phase-transfer catalysis, see:
• 2a Maruoka K. Org. Process Res. Dev.  2008,  12:  679 
• 2b Hashimoto T. Maruoka K. Chem. Rev.  2007,  107:  5656 
• 2c Ooi T. Maruoka K. Angew. Chem. Int. Ed.  2007,  46:  4222 
• 2d Vachon J. Lacour J. Chimia  2006,  60:  266 
• 2e O’Donnell MJ. Acc. Chem. Res.  2004,  37:  506 
• 2f Lygo B. Andrews BI. Acc. Chem. Res.  2004,  37:  518 
• 2g Maruoka K. Ooi T. Chem. Rev.  2003,  103:  3013 
• Of particular interest are approaches that are compatible with in situ generation and screening, allowing for rapid optimization of PTC activity and reaction enantioselectivity, see for example:
• 3a Kitamura K. Arimura Y. Shirakawa S. Maruoka K. Tetrahedron Lett.  2008,  49:  2026 
• 3b Lygo B. Andrews BI. Hirst JD. Melville JL. Peterson JA. Slack D. Chim. Oggi  2004,  22:  8 
• 3c Lygo B. Andrews BI. Crosby J. Peterson JA. Tetrahedron Lett.  2002,  43:  8015 
• 4a Lygo B. Allbutt B. Kirton EHM. Tetrahedron Lett.  2005,  46:  4461 
• 4b Melville JL. Lovelock KJR. Wilson C. Allbutt B. Burke EK. Lygo B. Hirst JD. J. Chem. Inf. Model.  2005,  45:  971 
• 4c Lygo B. Allbutt B. Synlett  2004,  326 
• 4d Lygo B. Allbutt B. James SR. Tetrahedron Lett.  2003,  44:  5629 
• 5 Nakajima M. Miyoshi I. Kanayama K. Hashimoto S.-I. Noji M. Koga K. J. Org. Chem.  1999,  64:  2264 
• 6 Miyaura N. Suzuki A. Chem. Rev.  1995,  95:  2457 
• 9 For a review of glycine imine chemistry see: O’Donnell MJ. Aldrichimica Acta  2001,  34:  3 
• For examples of application in target synthesis, see:
• 10a Wang Y.-G. Ueda M. Wang X. Han Z. Maruoka K. Tetrahedron  2007,  63:  6042 
• 10b Lee J.-H. Jeong B.-S. Ku J.-M. Jew S.-S. Park H.-G. J. Org. Chem.  2006,  71:  6690 
• 10c Lygo B. Slack D. Wilson C. Tetrahedron Lett.  2005,  46:  6629 
• 10d Fukuta Y. Ohshima T. Gnanadesikan V. Shibuguchi T. Nemoto T. Kisugi T. Okino T. Shibasaki M. Proc. Natl. Acad. Sci. U.S.A.  2004,  101:  5433 
• 10e Lygo B. Humphreys LD. Synlett  2004,  2809 
• 10f Kim S. Lee J. Lee T. Park H.-G. Kim D. Org. Lett.  2003,  5:  2703 
• 10g Armstrong A. Scutt JN. Org. Lett.  2003,  5:  2331 
• 10h Lygo B. Andrews BI. Tetrahedron Lett.  2003,  44:  4499 
• 10i Boeckman RK. Clark TJ. Shook BC. Org. Lett.  2002,  4:  2109 
• 12 For a discussion relating to enantiomeric enrichment of scalemic amino acid derivatives by crystallisation, see: O’Donnell MJ. Delgado F. Tetrahedron  2001,  57:  6641 
• See, for example:
• 13a Lygo B. Kirton EHM. Lumley C. Org. Biomol. Chem.  2008,  6:  3085 
• 13b Shibuguchi T. Mihara H. Kuramochi A. Sakuraba S. Ohshima T. Shibasaki M. Angew. Chem. Int. Ed.  2006,  45:  4635 
• 13c van der Werf A. Kellogg RM. Tetrahedron Lett.  1991,  32:  3727 
• See, for example:
• 14a Shibuguchi T. Mihara H. Kuramochi A. Ohshima T. Shibasaki M. Chem. Asian J.  2007,  2:  794 
• 14b Arai S. Takahashi F. Tsuji R. Nishida A. Heterocycles  2006,  67:  495 
• 14c Akiyama T. Hara M. Fuchibe K. Sakamoto S. Yamaguchi K. Chem. Commun.  2003,  1734 
• 14d O’Donnell MJ. Delgado F. Dominguez E. de Blas J. Scott WL. Tetrahedron: Asymmetry  2001,  12:  821 
• 14e Corey EJ. Noe MC. Xu F. Tetrahedron Lett.  1998,  39:  5347 

7

Representative Procedures for Route APreparation of 6- tert -Butyl-2-bromo-3-methylphenol
N-Bromosuccinimide (77.6 g, 0.44 mol) was added in batches to a solution of 4 (68.2 g, 0.42 mol) in PE (1.5 L). The resulting mixture stirred for 3 h at r.t., then filtered through silica gel, and concentrated under reduced pressure. The residue was distilled (140-145 ˚C, 1.3˙10^-³ bar) to afford the product (83.1 g, 83%) as a pale yellow oil. The residue could also be purified by chromatography on silica gel (R _f = 0.5, PE) to give the product in similar yield.
IR (neat): ν_max = 3497, 1602 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.09 (1 H, d, J = 8.0 Hz, ArH), 6.72 (1 H, d, J = 8.0 Hz, ArH), 5.90 (1 H, s, OH), 2.34 (3 H, s, CH₃), 1.38 [9 H, s, C(CH₃)₃]. ^¹³C NMR (100 MHz, CDCl₃): δ = 150.4 (C), 136.0 (C), 134.7 (C), 125.5 (CH), 121.6 (CH), 115.4 (C), 35.1 (C), 29.5 (CH₃), 23.1 (CH₃). MS (EI): m/z calcd for C₁₁H₁₅O⁷⁹Br: 242.0301; found: 242.0303 [M]⁺.
Preparation of 3,3′-Dibromo-5,5′-di- tert -butyl-2,2′-dimethyl-4,4′-dihydroxybiphenyl
Copper(I) chloride (2.40 g, 24.0 mmol) was added to a solution of TMEDA (3.84 mL, 25.0 mmol) in MeOH (600 mL). After stirring for 20 min, 6-tert-butyl-2-bromo-3-methylphenol (58.9 g, 240 mmol) was added, the mixture stirred under an air atmosphere for 3 d, then concentrated under reduced pressure. The residue was dissolved in Et₂O and filtered through silica gel. The solution was again concentrated under reduced pressure and the residue purified by chromatography on silica gel to afford unreacted starting material (36%) followed by the product (33.5 g, 58%, R _f = 0.4; PE-EtOAc, 9:1) as a colourless solid.
Mp 183-184 ˚C. IR (neat): ν_max = 3494 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 6.95 (2 H, s, ArH), 5.96 (2 H, s, OH), 2.09 (6 H, s, CH₃), 1.40 [18 H, s, C(CH₃)₃]. ^¹³C NMR (100 MHz, CDCl₃): δ = 149.5 (C), 134.2 (C), 134.1 (C), 134.0 (C), 127.6 (CH), 116.0 (C), 35.2 (C), 29.6 (CH₃), 20.9 (CH₃). MS (EI): m/z calcd for C₂₂H₂₈O₂ ^8¹Br₂: 482.0450; found: 482.0456 [M]⁺.
Preparation of 3,3′-Dibromo-5,5′-di- tert -butyl-4,4′-dimethoxy-2,2′-dimethylbiphenyl (5)
Methyl iodide (3.8 mL, 60.9 mmol) was added dropwise to a mixture of 3,3′-dibromo-5,5′-di-tert-butyl-2,2′-dimethyl-4,4′-dihydroxybiphenyl (11.8 g, 24.4 mmol) and anhyd K₂CO₃ (10.1 g, 73.1 mmol) in dry DMF (300 mL). The mixture was stirred at r.t. for 18 h, then H₂O (350 mL) added, and the solution extracted with EtOAc (2 × 200 mL). The combined extracts were washed with brine (2 × 200 mL), dried (MgSO₄), and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (R _f  = 0.3; PE-EtOAc, 49:1) to give the product (12.2 g, 98%) as a colourless solid.
Mp 105-107 ˚C. IR (neat): ν_max = 3048, 2960, 2868, 2841 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.00 (2 H, s, ArH), 3.96 (6 H, s, OCH₃), 2.10 (6 H, s, CH₃), 1.39 [18 H, s, C(CH₃)₃]. ^¹³C NMR (100 MHz, CDCl₃): δ = 155.8 (C), 141.6 (C), 137.7 (C), 135.8 (C), 127.5 (CH), 122.0 (C), 61.5 (CH₃), 35.3 (C), 31.1 (CH₃), 21.0 (CH₃). MS (EI): m/z calcd for C₂₄H₃₂O₂ ⁷⁹Br^8¹Br: 512.0743; found: 512.0752[M]⁺.
Preparation of 5,5′-Di- tert -butyl-4,4′-dimethoxy-2,2′-dimethyl-3,3′-(3,5-bistrifluoromethylphenyl)biphenyl
3,5-Bistrifluoromethylphenylboronic acid (7.56 g, 29.3 mmol) was added to a solution of 5 (5.00 g, 9.76 mmol) in degassed THF (175 mL), then degassed 2 M aq K₂CO₃ (115 mL) and Pd(PPh₃)₄ (1.13 g, 0.98 mmol) were added. The mixture was heated at 70 ˚C for 24 h under a nitrogen atmosphere, then cooled to r.t., acidified with 2 M HCl, and extracted with Et₂O (2 × 100 mL). The combined extracts were washed with brine (2 × 100 mL), dried (MgSO₄), and concentrated under reduced pressure. The residue was recystallised (Et₂O-MeOH) to afford the product (4.71 g, 62%) as a colourless solid.
Mp 183-184 ˚C. IR (neat): ν_max = 2963 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.89 (4 H, s, ArH), 7.86 (2 H, s, ArH), 7.18 (2 H, s, ArH), 3.16 (6 H, s, OCH₃), 1.76 (6 H, s, CH₃), 1.42 [18 H, s, C(CH₃)₃]. ^¹³C NMR (125 MHz, CDCl₃): δ = 156.4 (C), 141.1 (C), 140.6 (C), 137.6 (C), 133.3 (C), 133.1 (C), 131.5 (q, J = 33.5 Hz, C), 131.1 (CH), 129.2 (CH), 123.5 (q, J = 271.0 Hz, CF₃), 120.8 (q, J = 7.7 Hz, CH), 60.7 (CH₃), 35.1 (C), 31.1 (CH₃), 18.2 (CH₃). MS (EI): m/z calcd for C₄₀H₃₈F₁₂O₂: 778.2675; found: 778.2667 [M]⁺.
Preparation of 5,5′-Di- tert -butyl-4,4′-dimethoxy-2,2′-bisbromomethyl-3,3′-(3,5-bistrifluoromethylphenyl)-biphenyl (6b)
To a solution of 5,5′-di-tert-butyl-4,4′-dimethoxy-2,2′-dimethyl-3,3′-(3,5-bistrifluoromethylphenyl)biphenyl (1.85 g, 2.37 mmol) in CCl₄ (30 mL) was added NBS (0.88 g, 4.97 mmol) and AIBN (5 mg). The mixture was placed under an argon atmosphere and heated at reflux for 20 min using a 60 W light bulb (1 cm from flask). The mixture was then cooled to r.t., filtered through silica gel, and concentrated under reduced pressure to give the product (2.11 g, 95%) as a colourless solid.
Mp 90-92 ˚C. IR (neat): ν_max = 2964 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 8.15 (2 H, s, ArH), 7.98 (2 H, s, ArH), 7.96 (2 H, s, ArH), 7.40 (2 H, s, ArH), 3.95 (2 H, d, J = 10.0 Hz, CH _a H_b), 3.89 (2 H, d, J = 10.0 Hz, CH_a H _b ), 3.22 (6 H, s, OCH₃), 1.44 [18 H, s, C(CH₃)₃]. ^¹³C NMR (100 MHz, CDCl₃): δ = 157.4 (C), 143.9 (C), 138.9 (C), 135.8 (C), 134.1 (C), 132.8 (C), 131.7 (C, q, J = 33.5 Hz), 131.6 (C, q, J = 33.5 Hz), 131.1 (CH), 130.8 (CH), 130.3 (CH), 123.3 (C, q, J = 273.0 Hz), 123.3 (C, q, J = 273.0 Hz), 121.7 (CH, m), 60.9 (CH₃), 35.4 (C), 30.8 (CH₃), 30.3 (CH₂). MS (EI):
m/z calcd for C₄₀H₃₆O₂F₁₂ ^8¹Br₂: 938.0845; found: 938.0815[M]⁺.
Preparation of ( R )-2,10-Di- tert -butyl-3,9-dimethoxy-6-methyl-6-(1-naphthalen-1-ylethyl)-4,8-bis(3,5-bistri-fluoromethylphenyl)-6,7-dihydro-5 H -dibenzo[ c , e ]-azepinium Bromide (1g)
Dibromide 6b (0.57 g, 0.61 mmol) was dissolved in MeCN (15 mL) and CH₂Cl₂ (3 mL), then (R)-α-methylnaphth-1-ylamine (0.13 g, 0.67 mmol) and anhyd K₂CO₃ (0.50 g 3.60 mmol) added. The mixture was stirred at 60 ˚C for 16 h then filtered, and concentrated under reduced pressure. The residue purified by recrystallisation (PhMe) to afford the product 1g (0.45 g, 70%) as a colourless solid.
Mp 102-104 ˚C. [α]_D +78 (c 0.4, CHCl₃). IR (neat): ν_max = 2964 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 8.28 (1 H, s, ArH), 8.07 (2 H, s, ArH), 8.04 (1 H, s, ArH), 7.95 (1 H, d, J = 8.0 Hz, ArH), 7.91 (1 H, dd, J = 8.0, 1.0 Hz, ArH), 7.85 (1 H, s, ArH), 7.55 (1 H, s, ArH), 7.54 (1 H, s, ArH), 7.49 (1 H, dd, J = 7.5, 7.0 Hz, ArH), 7.39-7.28 (3 H, m, ArH), 7.07 (1 H, d, J = 8.5 Hz, ArH), 6.80 (1 H, s, ArH), 5.51 (1 H, d,
J = 15.0 Hz, NCH _a H_b), 5.20 (1 H, q, J = 6.5 Hz, CHCH₃), 4.19 (1 H, d, J = 15.0 Hz, NCH_a H _b ), 3.38 (1 H, d, J = 13.0 Hz, NCH _a H_b), 3.19 (3 H, s, OCH₃), 3.02 (3 H, s, OCH₃), 2.98 (3 H, s, NCH₃), 2.81 (1 H, d, J = 13.0 Hz, NCH_a H _b ), 1.60 [9 H, s, C(CH₃)₃], 1.46 [9 H, s, C(CH₃)₃], 1.09 (3 H, d, J = 6.5 Hz, NCHCH ₃ ). ^¹³C NMR (100 MHz, CDCl₃): δ = 158.3 (C), 128.1 (C), 147.9 (C), 147.8 (C), 137.8-119.4 (complex CAr and CF₃), 62.3 (CH), 61.2 (CH₃), 61.0 (CH₃), 59.7 (CH₂), 57.9 (CH₂), 43.2 (CH₃), 36.0 (C), 35.8 (C), 30.9 (CH₃), 30.8 (CH₃), 15.9 (CH₃). ^¹9F NMR (282 MHz, CDCl₃, referenced to CFCl₃ = 0 ppm): δ = -62.1, -62.9, -63.2, -63.3. MS (ES⁺): m/z calcd for C₅₃H₅₀F₁₂NO₂: 960.3644; found: 960.3682 [M - Br]⁺.

8

Representative Procedures for Route BPreparation of 3,3′-Dibromo-5,5′-di- tert -butyl-4,4′-dimethoxy-2,2′-bisbromomethylbiphenyl
Bromination of 5 was performed as described for 6b, to give the product (100%) as a colourless solid.
Mp 206-207 ˚C. IR (neat): ν_max = 3054, 2966, 2869 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.24 (2 H, s, ArH), 4.49 (2 H, d, J = 10.0 Hz, CHaHb), 4.19 (2 H, d, J = 10.0 Hz, CHaHb), 4.01 (6 H, s, OCH₃), 1.42 [18 H, s, C(CH₃)₃]. ^¹³C NMR (100 MHz, CDCl₃): δ = 157.3 (C), 145.1 (C), 136.3 (C), 134.6 (C), 128.5 (CH), 122.4 (C), 61.8 (CH), 35.8 (C), 33.2 (CH₂), 30.9 (CH₃). MS (EI): m/z calcd for C₂₄H₃₀O₂ ⁷⁹Br₂ ^8¹Br₂: 669.8930; found: 669.8893[M]⁺.
Preparation of ( R )-4,8-Bisbromo-2,10-di- tert -butyl-3,9-dimethoxy-6-(1-phenylethyl)-6,7-dihydro-5 H -dibenzo-[ c , e ]azepine (7a)
To a stirred solution of 3,3′-dibromo-5,5′-di-tert-butyl-4,4′-dimethoxy-2,2′-bisbromomethylbiphenyl (221 mg, 0.33 mmol) in CHCl₃ (10 mL) was added (R)-1-phenylethyl-amine (38.7 µL, 0.30 mmol) and anhyd K₂CO₃ (0.27 g, 1.98 mmol). The mixture was stirred at 60 ˚C for 18 h then filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (R _f = 0.6; Et₂O-PE, 1:4) to yield the product (160 mg, 85%) as colourless crystals.
Mp 88-92 ˚C. [α]_D ^²² +14 (c 0.7, CHCl₃). IR (neat): ν_max = 2957 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.55 (1 H, s, ArH), 7.53 (1 H, s, ArH), 7.39-7.32 (4 H, m, ArH), 7.30-7.23 (1 H, m, ArH), 4.10-3.00 (5 H, m, 2 × CH₂ and CH), 3.99 (6 H, s, OCH₃), 1.47 [18 H, s, C(CH₃)₃], 0.90 (3 H, m, CH₃). ^¹³C NMR (100 MHz, CDCl₃): δ = 156.4 (C), 146.1 (C), 144.0 (C), 137.6 (C) 135.0 (C), 128.2 (CH), 127.7 (CH), 126.8 (CH), 125.5 (CH), 122.0 (C), 61.7 (CH₃), 52.4 (CH₂), 35.5 (C), 31.0 (CH₃), 23.3 (CH₃). MS (ES⁺): m/z calcd for C₃₂H₄₀NO₂ ⁷⁹Br₂: 628.1420; found: 628.1456 [M + H]⁺.
Preparation of ( R )-2,10-di- tert -butyl-3,9-dimethoxy-6-(1-phenylethyl)-4,8-bis(3,5-bistrifluoromethylphenyl)-6,7-dihydro-5 H -dibenzo[ c , e ]azepine (8a)
Reaction of (R)-4,8-dibromo-2,10-di-tert-butyl-3,9-dimethoxy-6-(1-phenylethyl)-6,7-dihydro-5H-dibenzo-[c,e]azepine with 3,5-bistrifluoromethylphenylboronic acid was performed using the coupling procedure described above. The residue was purified by chromatography on silica gel (R _f = 0.2; CH₂Cl₂-PE, 1:4) to give the product (63%) as colourless crystals.
Mp 101 ˚C; [α]_D +1 (c 0.1, CHCl₃). IR (neat): ν_max = 2977 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 8.40-8.20 (2 H, m, ArH), 7.83 (2 H, s, ArH), 7.80-7.70 (1 H, m, ArH), 7.55 (2 H, s, ArH), 7.36 (1 H, s, ArH), 7.02-6.98 (3 H, m, ArH), 6.81-6.79 (2 H, m, ArH), 3.80-3.55 (2 H, m, CH₂), 3.20-3.05 (3 H, m, CH and CH₂), 3.09 (6 H, s, OCH₃), 1.51 [18 H, s, C(CH₃)₃], 0.95-0.80 (3 H, m, CH₃). ^¹³C NMR (100 MHz, CDCl₃): δ = 156.9 (C), 142.8 (C), 139.6 (C), 137.5 (C), 133.2-121.1 (complex C, CH, CF₃), 61.1 (CH), 60.5 (CH₃), 48.5 (CH₂), 35.3 (C), 31.0 (CH₃). MS (ES⁺): m/z calcd for C₄₈H₄₆NO₂F₁₂: 896.3331; found: 896.3455 [M + H]⁺.
Preparation of ( R )-2,10-Di- tert -butyl-3,9-dimethoxy-6-methyl-6-(1-phenylethyl)-4,8-bis(3,5-bistrifluoromethyl-phenyl)-6,7-dihydro-5 H -dibenzo[ c , e ]azepinium Iodide (2a)
Methyl iodide (200 µL, 3.2 mmol) was added to a solution of tertiary amine 8a (16 mg, 24 µmol) in CHCl₃ (1.5 mL). The mixture stirred at 60 ˚C in a sealed tube for 2 h. After cooling to r.t., the solution was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (R _f  = 0.2; CHCl₃-MeOH, 19:1) to give the product as a pale yellow solid (20.4 mg, 82%).
Mp 151-153 ˚C. [α]_D +25 (c 0.2, CHCl₃). IR (neat): ν_max = 2924 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 8.29 (1 H, s, ArH), 7.97-7.94 (2 H, m, ArH), 7.90 (1 H, s, ArH), 7.82 (1 H, s, ArH), 7.61 (1 H, s, ArH), 7.57 (1 H, s, ArH), 7.42-7.22 (3 H, m, ArH), 7.13-7.11 (1 H, m, ArH), 6.97 (2 H, d, J = 7.5 Hz, ArH), 5.32 (1 H, d, J = 15.5 Hz, CH _a H_b), 4.08 (1 H, d, J = 15.5 Hz, CH_a H _b ), 4.00-3.96 (1 H, m, CH), 3.38 (1 H, d, J = 11.5 Hz, CH _a H_b), 3.16 (3 H, s, OCH₃), 3.12 (3 H, s, OCH₃), 2.93-2.85 (4 H, m, NCH₃ and CH_a H _b ), 1.54 [9 H, s, C(CH₃)₃], 1.50 [9 H, s, C(CH₃)₃], 0.90 (3 H, m, CH₃). ^¹³C NMR (125 MHz, CDCl₃): δ = 158.2 (C), 158.1 (C), 147.9 (C), 147.6 (C), 137.9 (C), 137.7 (C), 137.5 (C), 136.8 (C), 135.2 (C), 133.3 (C, q, J = 34.0 Hz), 132.6 (C, q, J = 33.5 Hz), 132.6 (C, q, J = 33.5 Hz), 131.9 (CH), 131.8 (CH), 131.7 (C, m, obscured), 131.6 (CH), 130.9 (C), 130.1 (CH), 129.6 (CH), 129.4 (CH), 129.3 (C), 129.2 (CH), 124.7 (C), 123.3 (C), 122.9 (C, q, J = 273.0 Hz), 122.7 (C, q, J = 273.0 Hz), 122.7 (C, q, J = 274.0 Hz), 122.5 (CH), 122.4 (C, q, J = 273.0 Hz), 121.8 (CH), 70.7 (CH), 61.3 (CH₃), 61.1 (CH₃), 59.6 (CH₂), 59.3 (CH₂), 43.1 (CH₃), 35.8 (C), 35.7 (C), 30.7 (CH₃), 30.7 (CH₃), 15.3 (CH₃). MA (ES⁺): m/z calcd for C₄₉H₄₈NO₂F₁₂: 910.3488; found: 910.3453[M - I]⁺.

11

General Procedure for the Alkylation of Glycine Imine 9 with Benzyl Bromide
A mixture of the catalyst (1 mol%) and imine 9 (50 mg, 0.17 mmol) in PhMe (2 mL) was degassed, placed under nitrogen, and cooled to 0 ˚C. Benzyl bromide (35 mg, 0.20 mmol) was added followed by 15 M aq KOH (1 mL) and the mixture stirred at 0 ˚C for 3 h. The mixture was then diluted with H₂O (10 mL) and extracted with EtOAc (3 × 10 mL). The combined extracts were dried (Na₂SO₄), concentrated under reduced pressure, and purified by chromatography on silica gel (R _f = 0.5; PE-EtOAc-Et₃N, 89:10:1) to give 10 as a colourless oil.
^¹H NMR (400 MHz, CDCl₃): δ = 7.59-7.56 (2 H, m, ArH), 7.38-7.26 (6 H, m, ArH), 7.20-7.14 (3 H, m, ArH), 7.06-7.03 (2 H, m, ArH), 6.61 (2 H, d, J = 6.5 Hz, ArH), 4.11 (1 H, dd, J = 9.0, 4.5 Hz, CH), 3.23 (1 H, dd, J = 13.5, 4.5 Hz, CH _a H_b), 3.16 (1 H, dd, J = 13.5, 9.0 Hz, CH_a H _b ), 1.44 [9 H, s, C(CH₃)₃]. These ^¹H NMR data are in agreement with those previously recorded.^4d HPLC: Chiralcel OD-H (25 × 0.46 cm + guard) hexane-2-PrOH (100:1), 0.5 mL min^-¹; t _R = 14.8 min (R)-isomer; t _R = 28.2 min (S)-isomer.

15

General Procedure for the Michael Addition of Glycine Imine 11 to MVK
A mixture of imine 11 (0.12 mmol) and catalyst (1 mol%) in i-Pr₂O (4 mL) was cooled to 0 ˚C. MVK (0.24 mmol) was added followed by anhyd Cs₂CO₃ (0.06 mmol) and the mixture stirred at 0 ˚C for 2 h. The mixture was then filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (R _f = 0.2; PE-EtOAc-Et₃N, 89:10:1) to give 12 as a colourless oil.
IR (CHCl₃): ν_max = 1739, 1715, 1622 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.67-7.63 (2 H, m, ArH), 7.43-7.26 (16 H, m, ArH), 7.10-7.06 (2 H, m, ArH), 6.89 (1 H, s, CHPh₂), 4.19 (1 H, app. t, J = 6.0 Hz, NCH), 2.58-2.50 (1 H, m), 2.44-2.36 (1 H, m), 2.23-2.18 (2 H, m), 2.05 (3 H, s, Me). ^¹³C NMR (100 MHz, CDCl₃): δ = 208.0 (C), 171.0 (C), 170.7 (C), 140.0 (2 × C), 139.3 (C), 136.1 (C), 130.5 (CH), 128.8 (CH), 128.7 (CH), 128.6 (CH), 128.5 (2 × CH), 128.1 (CH), 128.0 (CH), 127.9 (CH), 127.7 (CH), 127.4 (CH), 127.0 (CH), 77.2 (CH), 64.1 (CH), 39.5 (CH₂), 29.9 (CH₃), 27.5 (CH₂). MS (CI): m/z calcd for C₃₂H₃₀NO₃: 476.2226; found: 476.2241[M + H]⁺. HPLC: Chiralpak AD (25 × 0.46 cm + guard), hexane-2-PrOH (95:5), 1.0 mL min^-¹; t _R = 23.7 min (R)-isomer; t _R = 29.5 min (S)-isomer.