Synthesis of Enantiopure Prolines via exo-Stereoselective 1,3-Dipolar ­Cycloadditions to Acetone-Derived Chiral Stabilised Azomethine Ylides

Abstract

The chiral stabilised azomethine ylide formed from condensation of the dimethyl acetal of acetone with (5S)-5-phenylmorpholinone undergoes stereoselective exo-cycloaddition reactions with a range of doubly and singly activated dipolarophiles when generated in the presence of excess MgBr₂·OEt₂. The cycloadducts can be degraded to yield enantiomerically pure proline derivatives.

Key words

ketone-derived azomethine ylide - 5,5-disubstituted prolines - Lewis acid - stereoselective cycloaddition

References and Notes

• 1 Krapcho J. Turk C. Cushman DW. Powell JR. DeForrest JM. Spitzmiller ER. Karanewsky DS. Duggan M. Rovnvak G. Schwartz J. Natarajan S. Godfrey JD. Ryono DE. Neubeck R. Atwal KS. Petrillo EW. J Med. Chem.  1988,  31:  1148 
• 2 Che Y. Marshall R. J. Org. Chem.  2004,  69:  9030 
• 3 Gil AM. Bunuel E. Jimenez AI. Cativiela C. Tetrahedron Lett.  2003,  32:  5999 
• 4 Thomas KM. Naduthambi D. Tririya G. Zondlo NJ. Org. Lett.  2005,  7:  2397 
• 5 Koskinen AMP. Helaja J. Kumpulainen TT. Koivisto J. Mansikkamaki H. Rissanen K. J. Org. Chem.  2005,  70:  6447 
• 6 Seebach D. Boes M. Naef R. Schweizer WB. J. Am. Chem. Soc.  1983,  105:  5390 
• 7a Wang Q. Tran Huu Dau M.-E. Saski A. Potier P. Tetrahedron  2001,  30:  6455 
• 7b Flamant-Rabin C. Wang Q. Chiaroni A. Sasaki A. Tetrahedron  2002,  58:  10475 
• 7c Maeda K. Miller RA. Szumigala RH. Shafiee A. Karady S. Armstrong JD. Tetrahedron Lett.  2005,  46:  1545 
• 8 Xia Q. Ganen B. Tetrahedron Lett.  2002,  43:  1597 
• 9 Arnold U. Hinderaker MP. Köditz J. Golbik R. Ulbrich-Hofmann R. Raines RT. J. Am. Chem. Soc.  2003,  125:  7500 
• 10a An SSA. Lester CC. Peng J.-L. Li Y.-J. Rothwarf DM. Welker E. Thannhauser TW. Zhang LS. Tam JP. Scheraga HA. J. Am. Chem. Soc.  1999,  121:  11558 
• 10b Magaard VW. Sanchez RM. Bean JW. Moore ML. Tetrahedron Lett.  1993,  34:  381 
• 10c Bonnett R. Clark VM. Giddey A. Todd SA. J. Chem. Soc.  1959,  2087 
• 10d Xia Q. Ganem B. Tetrahedron Lett.  2002,  43:  1597 
• 11 Elardi J. Jackson WR. Robinson AJ. Tetrahedron: Asymmetry  2005,  16:  2025 
• 12 Aldous DJ. Drew MGB. Hamelin EM.-N. Harwood LM. Jahans AB. Thurairatnam S. Synlett  2001,  1836 
• 13 Bonnett R. Clark VM. Giddey A. Todd SA. J. Chem. Soc.  1959,  2087 
• 14 Harwood LM. Manage AC. Robin S. Hopes SFG. Watkin J. Williams CE. Synlett  1993,  777 

15

Typical Experimental Procedure.
2,2-Dimethoxypropane (2 equiv) was added via syringe to a stirred solution of (5S)-5-phenylmorpholin-2-one (3, 1 equiv), dipolarophile (2 equiv), and MgBr·OEt₂ (10 equiv) in THF (10 mL per mmol substrate). The resulting mixture was stirred under nitrogen for 6 h, cooled to r.t., then quenched with aq NH₄Cl and extracted with CH₂Cl₂ (3 × 10 mL). The organic phase was washed with brine, the combined aqueous phases extracted with CH₂Cl₂ (3 × 10 mL) and the organic phases dried (MgSO₄) and concentrated in vacuo. The residue was then purified by flash column chromatography, gradient eluting with 3:1 hexane-EtOAc to pure EtOAc.

16

Representative Analytical Data. N -Methyl (2 S ,6 S ,7 S ,8 R )-9,9-Dimethyl-2-phenyl-1-aza-4-oxa[4.3.0 ^¹,6 ]bicyclononan-5-one-7,8-dicarboximide ( 5b).
Colourless crystals (61%), mp 160-163 °C; [α]_D ²⁵ -24.0 (c 0.35, CHCl₃). ¹H NMR (250 MHz, CDCl₃): δ = 7.36-7.23 (5 H, m, Ar-H), 4.43 (1 H, t, J = 5.7 Hz, 3β-H), 4.38 (1 H, d, J = 1.7 Hz, 6α-H), 4.21 (1 H, dd, J = 5.7 Hz, J′ = 11.6 Hz, 2β-H), 4.06 (1 H, dd, J = 1.6 Hz, J′ = 8.5 Hz, 7β-H), 4.00 (1 H, dd, J = 5.7 Hz, J′ = 11.6 Hz, 3α-H), 3.08 (3 H, s, NCH₃), 3.06 (1 H, d, J = 8.5 Hz, 8β-H), 1.19 (3 H, s, CH₃), 1.00 (3 H, s, CH₃). ¹³C NMR (62.5 MHz, CDCl₃): δ = 178.6, 172.1 (C=O), 139.0, 129.3, 128.5, 126.9 (C-aromatic), 71.2 (C₃), 66.1 (C₉), 60.8 (C₆), 55.2 (C₂), 54.7 (C₈), 44.9 (C₇), 26.2 (CH₃), 25.7 (NCH₃), 23.4 (CH₃). HRMS: m/z calcd for C₁₈H₂₀N₂O₄: 329.1501; found: 329.1499 [MH⁺].
Dimethyl (2 S ,6 S ,7 S ,8 R )-9,9-Dimethyl-2-phenyl-1-aza-4-oxa[4.3.0 ^¹,6 ]bicyclononan-5-one-7,8-dicarboxylate ( 5c).
Colourless oil (41%); [α]_D ²⁵ -71.3 (c 0.35, CHCl₃). ¹H NMR (250 MHz, CDCl₃): δ = 7.46-7.25 (5 H, m, Ar-H), 4.79 (1 H, d, J = 6.4 Hz, 6α-H), 4.27-4.10 (3 H, m, 2β-3α-3β-H), 3.93 (1 H, dd, J = 6.4 Hz, J′ = 7.8 Hz, 7β-H), 3.72 (3 H, CO₂Me), 3.68 (3 H, CO₂Me), 3.13 (1 H, d, J = 7.8 Hz, 8β-H), 1.11 (3 H, s, CH₃) 0.71 (3 H, s, CH₃). ¹³C NMR (62.5 MHz, CDCl₃): δ = 174.7, 172.2 (C=O), 140.8, 129.0, 128.4, 127.3 (C-aromatic), 71.5 (C₃), 65.8 (C₉), 57.8 (C₆), 57.5 (C₂), 56.7 (C₈), 52.9 (C₇), 52.0 (CO₂Me), 45.5 (CO₂Me), 26.2 (CH₃), 21.9 (CH₃). HRMS: m/z calcd for C₁₉H₂₄NO₆: 362.1603; found: 362.1613 [MH⁺].
Dimethyl (2 S ,6 S ,7 S ,8 R )-9,9-Dimethyl-2-phenyl-1-aza-4-oxa[4.3.0 ^¹,6 ]bicyclononan-5-one-7,8-dicarboxylate ( 5d).
Colourless crystals (60%); mp 105-107 °C [α]_d ²⁵ -38.0 (c 0.5, CHCl₃). ¹H NMR (250 MHz, CDCl₃): δ = 7.46-7.29 (5 H, m, Ar-H), 4.43 (1 H, d, J = 5.4 Hz, 6α-H), 4.31-4.07 (4 H, m, 2β-3α-3β-7αH), 3.77 (3 H, CO₂Me), 3.74 (3 H, CO₂Me), 3.12 (1 H, d, J = 10.8 Hz, 8β-H), 1.11 (3 H, s, CH₃), 0.71 (3 H, s, CH₃). ¹³C NMR (62.5 MHz, CDCl₃): δ = 173.7, 173.5 (C=O), 140.2, 129.0, 128.4, 127.3 (C-aromatic), 71.2 (C₃), 65.6 (C₉), 59.3 (C₆), 57.9 (C₈), 56.4 (C₂), 53.7 (C₇), 52.6 (CO₂Me), 44.7 (CO₂Me), 28.8 (CH₃), 16.8 (CH₃): HRMS: m/z calcd for C₁₉H₂₄N₂O₆: 362.1541; found: 362.1559 [MH⁺].
General Procedure for Hydrogenolysis. The cycloadduct (1 equiv) was dissolved in aq MeOH (2 mL MeOH, 0.1 mL H₂O per mmol substrate) containing TFA (1 equiv). Pearlman’s catalyst was added and the suspension was degassed then subjected to H₂ (5 bar) with stirring at r.t. for 48 h. The solution was filtered through a pad of Celite^® then the solvent removed in vacuo and the crude material purified by dry flash column chromatography (MeOH-H₂O, 1:1) or by trituration with Et₂O.
(1 S ,3a R ,6a S )-3,3-Dimethyl-4,6-dioxo-5-phenylocta-hydropyrrolo[3,4- c ]pyrrole-1-carboxylic Acid ( 6b). Colourless powder; mp 168-170 °C; [α]_D ²⁵ +51.3 (c 0.30, H₂O). ¹H NMR (250 MHz, MeOH-d ₄): δ = 7.56-7.29 (5 H, m, Ar-H), 4.70 (1 H, d, J = 4.2 Hz, 2α-H), 4.31 (1 H, dd, J = 4.2 Hz, J′ = 9.3 Hz, 3β-H), 3.59 (1 H, d, J = 9.3 Hz, 4β-H), 1.61 (6 H, s, CH₃). ¹³C NMR (62.5 MHz, MeOH-d ₄): δ = 178.6, 176.8, 174.8 (C=O), 133.6, 130.5, 130.3, 128.3 (C-aromatic), 67.9 (C₂), 62.5 (C₅), 54.9 (C₄), 49.0 (C₃), 28.4 (CH₃) 22.8 (CH₃): HRMS: m/z calcd for C₁₅H₁₆N₂O₄: 289.1188; found: 289.1193 [MH⁺].
(2 R ,3 R ,4 S )-3,4-Bis(methoxycarbonyl)-5,5-dimethyl-pyrrolidine-2-carboxylic Acid ( 6c). Colourless powder; mp 168-170 °C; [α]_D ²⁵ +10.0 (c 0.05, H₂O). ¹H NMR (250 MHz, MeOH-d ₄): δ = 4.85 (1 H, d, J = 8.2 Hz, 2α-H), 4.08 (1 H, t, J = 7.0 Hz, 3β-H), 3.76 (3 H CO₂Me), 3.74 (3 H CO₂Me), 3.51 (1 H, d, J = 8.1 Hz, 4β-H), 1.51 (3 H, s, CH₃) 1.48 (3 H, s, CH₃). ¹³C NMR (62.5 MHz, MeOH-d ₄): δ = 173.6, 171.9, 170.0 (C=O), 66.9 (C₂), 60.0 (C₅), 56.4 (CO₂Me), 48.0 (CO₂Me), 24.4 (CH₃) 20.9 (CH₃): HRMS: m/z calcd for C₁₁H₁₈NO₆: 260.1134; found: 260.1123 [MH⁺].
(2 R ,3 S ,4 S )-3,4-Bis(methoxycarbonyl)-5,5-dimethyl-pyrrolidine-2-carboxylic Acid ( 6d).
Colourless powder; [α]_D ²⁵ -2.5 (c 0.25, H₂O). ¹H NMR (250 MHz, MeOH-d ₄): δ = 4.49 (1 H, d, J = 7.4 Hz, 2α-H), 3.98 (1 H, dd, J = 7.4 Hz, J′ = 10.3 Hz, 3β-H), 3.79 (3 H CO₂Me), 3.79 (3 H s CO₂Me), 3.31 (1 H, d, J = 10.3 Hz, 4α-H), 1.64 (3 H, s, CH₃) 1.30 (3 H, s, CH₃). ¹³C NMR (62.5 MHz, MeOH-d ₄): δ = 173.3, 171.9, 170.0 (C=O), 66.8 (C₂), 60.0 (C₅), 56.4 (CO₂Me), 48.0 (CO₂Me), 24.6 (CH₃), 20.9 (CH₃). HRMS: m/z calcd for C₁₁H₁₈NO₆: 260.1134; found: 260.1126 [MH⁺].

17

Isolated as an inseparable mixture of exo-regioisomers, configuration was assigned by 2D NMR (COSY) experiments and comparison with the known endo adduct.