Synthesis of Enantiopure 4-(Dihydroxyalkyl)-β-lactams from d-Mannitol Using Ley’s BDA-Protected l-Glyceraldehyde

Abstract

Enantiomerically pure ethylene glycol derived β-lactams have been synthesized from Ley’s BDA-protected l-glyceraldehyde imines via Staudinger reaction followed by deprotection.

Key words

β-lactams - Staudinger reaction - stereoselective synthesis - chiral auxiliaries - protected glyceraldehydes

References and Notes

• For selected reviews on the use of 1,2-diacetals as chiral building blocks in organic synthesis, see:
• 1a Ley SV. Baeschlin DK. Dixon DJ. Foster AC. Ince SJ. Priepke HWM. Reynolds DJ. Chem. Rev.  2001,  101:  53 
• 1b Ley SV. Baxendale IR. Grice P. NATO Science Series (II, Mathematics, Physics and Chemistry)   Vol. 129:  Schneider M. Kluwer Academic Publishers; Netherlands: 2003.  p.235 
• 1c Ley SV. Polara A. J. Org. Chem.  2007,  72:  5943 
• 2 Ley SV. Michel P. Synthesis  2004,  147 
• Both enantiomers of glyceraldehyde acetonide are prone to racemization and rapid polymerization. See:
• 3a Hubschwerlen J. Specklin L. Higelin J. Org. Synth  1995,  72:  1 
• 3b Schmid CR. Bryant JD. Org. Synth.  1995,  72:  6 
• 4 Annunziata R. Benaglia M. Cinquini M. Cozzi F. Raimondi L. Tetrahedron  1994,  50:  5821 
• 5 Annunziata R. Benaglia M. Cinquini M. Cozzi F. Ponzini F. Bioorg. Med. Chem. Lett.  1993,  3:  2397 
• See for instance:
• 6a Hubschwerlen C. Schmid G. Helv. Chim. Acta  1983,  66:  2206 
• 6b Bose AK. Hedge VR. Wagle DR. Bari SS. Manhas MS. J. Chem. Soc., Chem. Commun.  1986,  161 
• 6c Thomas RC. Tetrahedron Lett.  1989,  30:  5239 
• 6d Alcaide B. Polanco C. Sierra MA. J. Org. Chem.  1998,  63:  6786 
• 6e Grigg R. Thornton-Pett M. Xu J. Xu LH. Tetrahedron  1999,  55:  13841 
• 7 Jarayaman M. Deshmukh ARAS. Bhawal DM.
  J. Org. Chem.  1994,  59:  932 
• 8 Palomo C. Oiarbide M. Landa A. Esnal A. Linden A. J. Org. Chem.  2001,  66:  4180 

9

General Procedure: A stirred solution of the aldehyde 1 (0.842 mmol) in anhyd Et₂O (1.6 mL) at 0 °C was treated with the corresponding amine (0.681 mmol) and molecular sieves (Merck 4 Å). After the reaction was complete, the molecular sieves were filtered and the solvent was evaporated under vacuum to yield the corresponding imine 3. Compound 3a: R = Bn; reaction time: 25 min, 0 °C, 98%. Compound 3b: R = (R)-CH(Me)(Ph); reaction time: 15 min, 0 °C, 99%. Compound 3c: R = (S)-CH(Me)(Ph); reaction time: 15 min, 0 °C, 81%.

10

General Procedure: A solution of the imine 3 (0.784 mmol) in CH₂Cl₂ (3.9 mL) was treated with Et₃N (2.359 mmol) followed by the dropwise addition of a solution of the corresponding acyl chloride (1.196 mmol) in CH₂Cl₂ (2.6 mL) at 0 °C under an argon atmosphere. After the reaction was completed, the reaction mixture was poured into H₂O (6.6 mL), stirred for 15 min, and then extracted with CH₂Cl₂ (3 × 6.6 mL). The combined organic layers were washed with 5% NaHCO₃ (2 × 2.6 mL), dried with MgSO₄ and concentrated in vacuum affording a mixture of the corresponding β-lactams 4. The major diastereoisomer was obtained by direct crystallization from the reaction mixture and purified by recrystallization from hexane-EtOAc. The minor isomer was isolated from the mother liquors by column chromatography (silica gel, hexane-EtOAc, 6:1) and further HPLC separation when it was necessary (semipreparative system, Zorbax RX-SIL column, hexane-EtOAc, 60:40; 3 mL/min). Compounds 4a,b: R = Bn, R¹ = PhO; reaction time: 25 min, 0 °C, 91%. Compounds 4c,d: R = Bn, R¹ = p-ClC₆H₄O; reaction time: 25 min, 0 °C, 72%. Compounds 4e,f: R = (R)-CH(Me)(Ph), R¹ = PhO; reaction time: 15 min, r.t., 66%. Compounds 4g,h: R = (S)-CH(Me)(Ph), R¹ = PhO; reaction time: 15 min, r.t., 61%.

11

Crystal structure analysis for 4a: mp 138-139 °C. C₂₄H₂₉NO₆, M_r = 427.48 g mol^-1. Crystallographic data (excluding structure factors) for compound 4a have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 661975. Crystal structure analysis for 4e: mp 136-137 °C. C₂₅H₃₁NO₆, M_r = 441.51 g mol^-1. Crystallographic data (excluding structure factors) for compound 4e have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 661977. Crystal structure analysis for 4g: mp 185-186 °C. C₂₅H₃₁NO₆, M_r = 441.51 g mol^-1. Crystallographic data (excluding structure factors) for compound 4g have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 661976.

12

A solution of the diastereomerically pure β-lactam 4e (0.165 mmol) in a mixture of TFA-H₂O (9:1, 1.18 mL) was stirred at r.t. for 5 min. Then the reaction mixture was evaporated under vacuum and the resulting oil was purified by column chromatography (silica gel, hexane-EtOAc, 1:2), yielding 2a as a white solid (33 mg, 61%), which was recrystallized from hexane-CH₂Cl₂; [α]_D -119.0, [α]₅₇₈ -124.5, [α]₅₄₆ -142.8, [α]₄₃₆ -257.3, [α]₅₄₆ -434.9 (c = 0.53, CH₂Cl₂, 25 °C). ¹H NMR (400 MHz, CDCl₃): δ = 7.45 (d, J = 7.2 Hz, 2 H, Ph), 7.39 (t, J = 7.2 Hz, 2 H, Ph), 7.27-7.33 (m, 3 H, Ph), 7.12 (d, J = 8.0 Hz, 2 H, Ph), 7.04 (t, J = 7.2 Hz, 1 H, Ph), 5.24 (d, J _3,4 = 5.2 Hz, 1 H, H-3), 4.82 (q, J _{1 ′′,Me} = 7.2 Hz, 1 H, H-1′′), 3.96-4.01 (m, 1 H, H-1′), 3.88 (t, J _{4,1 ′} = J _4,3 = 5.2 Hz, 1 H, H-4), 3.66 (dd, J _{2 ′a,2 ′b} = 11.2 Hz, J _{1 ′,2 ′a} = 4.0 Hz, 1 H, H-2′_a), 3.57 (dd, J _{2 ′b,1 ′} = 6.4 Hz, J _{2 ′a,2 ′b} = 11.2 Hz, 1 H, H-2′_b), 2.39 (1 H, OH), 1.78 (d, J _{Me,1 ′′} = 7.2 Hz, 3 H, Me). ¹³C NMR (100 MHz, CDCl₃): δ = 166.1 (CO), 157.4 (Ph), 141.0 (Ph), 129.7, 128.9, 127.8, 127.0 (Ph), 122.7 (Ph), 115.9 (Ph), 79.5 (C-3), 71.2 (C-1′), 63.6 (C-2′), 59.5 (C-1′′), 54.7 (C-4), 20.3 (Me).

13

2b: [α]_D -88.2, [α]₅₇₈ -92.8, [α]₅₄₆ -105.8, [α]₄₃₆ -189.8, [α]₅₄₆ -322.9 (c = 0.42, CH₂Cl₂, 25 °C). ¹H NMR (400 MHz, CDCl₃): δ = 7.26-7.38 (m, 7 H, Ph), 7.08 (d, J = 8.8 Hz, 2 H, Ph), 5.17 (d, J _3,4 = 5.2 Hz, 1 H, H-3), 4.81 (d, J _{1 ′′a,1 ′′b} = 14.8 Hz, 1 H, H-1′′_a), 4.41 (d, J _{1 ′′a,1 ′′b} = 14.8 Hz, 1 H, H-1′′_b), 4.09-4.13 (m, 1 H, H-1′), 3.84 (t, J _{4,1 ′} = J _4,3 = 5.2 Hz, 1 H, H-4), 3.74 (dd, J _{2 ′a,2 ′b} = 11.2 Hz, J _{1 ′,2 ′a} = 3.6 Hz, 1 H, H-2′_a), 3.63 (dd, J _{2 ′a,2 ′b} = 11.2 Hz, J _{1 ′,2 ′b} = 6.4 Hz, 1 H, H-2′_b). ¹³C NMR (100 MHz, CDCl₃): δ = 165.9 (CO), 155.9 (Ph), 135.5 (Ph), 129.6, 129.0, 128.4, 127.9 (Ph), 117.3 (Ph), 80.6 (C-3), 71.3 (C-1′), 63.8 (C-2′), 57.9 (C-4), 45.9 (Me). 2c: [α]_D +82.1, [α]₅₇₈ +86.0, [α]₅₄₆ +98.7, [α]₄₃₆ +177.0, [α]₅₄₆ +299.6 (c = 0.53, CH₂Cl₂, 25 °C). ¹H NMR (400 MHz, CDCl₃): δ = 7.27-7.40 (m, 7 H, Ph), 7.11 (d, J = 8.8 Hz, 2 H, Ph), 5.25 (d, J _3,4 = 5.2 Hz, 1 H, H-3), 4.77 (d, J _{1 ′′a,1 ′′b} = 14.8 Hz, 1 H, H-1′′_a), 4.22 (d, J _{1 ′′a,1 ′′b} = 14.8 Hz, 1 H, H-1′′_b), 4.05-4.09 (m, 1 H, H-1′), 3.92 (t, J _{4,1 ′} = J _4,3 = 5.2 Hz, 1 H, H-4), 3.81 (dd, J _{2 ′a,1 ′} = 3.1 Hz, J _{2 ′a,2 ′b} = 11.6 Hz, 1 H, H-2′_a), 3.65 (dd, J _{2 ′b,1 ′} = 6.4 Hz, J _{2 ′a,2 ′b} = 11.6 Hz, 1 H, H-2′_b). ¹³C NMR (100 MHz, CDCl₃): δ = 165.8 (CO), 155.6 (Ph), 134.9 (Ph), 129.6, 129.0, 128.3, 128.2 (Ph), 117.4 (Ph), 81.4 (C-3), 70.8 (C-1′), 63.9 (C-2′), 57.4 (C-4), 45.5 (C-1′′).