Synlett 2016; 27(11): 1677-1681
DOI: 10.1055/s-0035-1561942
letter
© Georg Thieme Verlag Stuttgart · New York

Stereoselectivity in the Reduction of Bicyclic Tetramates

Laia Josa-Culleré, Mark G. Moloney*, Amber L. Thompson
  • Department of Chemistry, Chemistry Research Laboratory, The University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK   Email: mark.moloney@chem.ox.ac.uk
Further Information

Publication History

Received: 11 February 2016

Accepted: 28 February 2016

Publication Date:
22 March 2016 (eFirst)

Abstract

The reduction of bicyclic tetramates can be achieved with high levels of diastereocontrol, but small changes in the substitution of the bicyclic lactam system can lead to changes in the steric bias of the concave/convex system. The tetramates and pyroglutamates prepared in this work exhibited limited antibacterial activity.

Supporting Information

 
  • References and Notes

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  • 9 Single-crystal X-ray diffraction data were collected at 150 K with an Oxford Diffraction (Rigaku) SuperNova diffractometer (using λ = 1.54180 Å) and processed with CrysAlisPro as per the SI (CIF). The structure was solved with SIR9215 and refined with CRYSTALS16 including the Flack × parameter17 which refined to –0.008(8) (unrestrained). Bayesian analysis18 of the Bijvoet pairs gave the Hooft y parameter as –0.002(4) and the probability that the structure was the correct hand of >99.99% given that the crystal is either enantiopure or a racemic twin. The asymmetric unit contains three molecules, all with the same stereochemistry. Full crystallographic data (in CIF format) is available as ESI and has been deposited with the Cambridge Crystallographic Data Centre (reference code CCDC 1452987). The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
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  • 19 General procedure for the decarboxylation of tetramic acids. Tetramic acid 2ac (1.0 equiv) and NaOH (2.0 equiv) in a 4:1:1 mixture of THF–MeOH–H2O was heated at reflux for 8 h and then cooled to room temperature. The mixture was acidified with 2 M aq HCl, extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo. The crude product was dissolved in MeCN and heated at reflux for 5 h then cooled to room temperature. The mixture was acidified with 2 M aq HCl, extracted with EtOAc, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography to give decarboxylated tetramic acids 4ac. Data for (2R,5S)-1-Aza-2-(tert-butyl)-6,8-dioxo-3-thiabicyclo[3.3.0]-octane (4b). Yield 33 mg (32%); off-white solid; mp 142–144 °C. Rf = 0.50 (50% EtOAc in CH2Cl2). [α]D 20 = +71.2 (c 0.8, CH2Cl2). IR: ν = 2960 (C–H), 1769 (C=O), 1699 (C=O) cm-1. 1H NMR (400 MHz, CDCl3): δ = 1.00 (s, 9 H, C(CH 3)3), 2.84 (t, J = 10.4 Hz, 1 H, C(4)H AHB), 3.13 (app dd, J = 22.0, 1.5 Hz, 1 H, C(7)H AHB), 3.19 (dd, J = 10.4, 7.0 Hz, 1 H, C(4)HA H B), 3.31 (d, J = 22.0 Hz, 1 H, C(7)HA H B), 4.44 (dd, J = 10.0, 7.0 Hz, 1 H, C(5)H), 5.30 (s, 1 H, C(2)H). 13C NMR (100 MHz, CDCl3): δ = 26.4 (C(CH3)3), 33.3 (C(4)), 37.8 (C(CH3)3), 43.0 (C(7)), 71.5 (C(2)), 72.4 (C(5)), 170.1 (C(8)), 203.5 (C(6)). MS (ESI+): m/z = 214.1 (MH+, 91%), 236.1 (MNa+, 100%). HRMS (ESI+): found 214.08959, C10H16NO2S requires (MH+) 214.08963.
  • 20 General procedure for the reduction of tetramic acids. NaBH4 (2.2 equiv) was added portionwise at 0 °C to a solution of tetramic acids 2ac or 4ac (1.0 equiv) and acetic acid (9.0 equiv) in anhydrous CH2Cl2. The reaction mixture was stirred at 0 °C for 15 min and then at room temperature until starting material disappeared by TLC (typically 2 h). The reaction mixture was quenched with saturated aq NaHCO3 and extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography to give the desired alcohol 3ac and 5ac. Data for (2R,5R,6S)-1-Aza-2-(tert-butyl)-6-hydroxy-5-methoxycarbonyl-8-oxo-3-thiabicyclo[3.3.0]-octane (3b). Yield 101 mg (quant.); white solid; m.p. 75–77 °C. Rf = 0.38 (50% EtOAc in CH2Cl2). [α]D 20 = +18.6 (c 1.0, CH2Cl2). IR: ν = 3380 (O–H), 2956 (C–H), 1744 (C=O), 1686 (C=O) cm-1. 1H NMR (500 MHz, CDCl3): δ = 0.92 (s, 9 H, C(CH 3)3), 2.63 (d, J = 4.5 Hz, 1 H, OH), 2.74 (dd, = 15.5, 8.0 Hz, 1 H, C(7)H AHB), 2.98 (dd, J = 16.0, 10.5 Hz, 1 H, C(7)HA H B), 3.03 (d, J = 11.5 Hz, 1 H, C(4)H AHB), 3.84 (s, 3 H, CO2CH 3), 3.90 (d, J = 11.5 Hz, 1 H, C(4)HA H B), 4.43 (ddd, J = 10.5, 8.0, 4.0 Hz, 1 H, C(6)H), 5.04 (s, 1 H, C(2)H). 13C NMR (125 MHz, CDCl3): δ = 26.6 (C(CH3)3), 38.0, 38.7 (C(4), C(CH3)3), 40.9 (C(7)), 53.1 (CO2 CH3), 72.8, C(2)), 76.6 (C(6)), 82.0 (C(5)), 171.2 (CO2CH3), 173.8 (C(8)). MS (ESI+): m/z = 274.1 (MH+, 52%), 296.1 (MNa+, 100%). HRMS (ESI+): found 296.0936, C12H19NNaO4S requires (MNa+) 296.0927. Data for (2R,5S,6S)-1-Aza-2-(tert-butyl)-6-hydroxy-8-oxo-3-thiabicyclo[3.3.0]-octane (5b). Yield 32 mg (86%); white solid; 1.9:1 mixture of diastereomers. Rf = 0.21 (50% EtOAc in CH2Cl2). IR: ν = 3369 (O–H), 2962 (C–H), 1674 (C=O) cm-1. 1H NMR (500 MHz, CDCl3) major isomer (5b’): δ = 0.96 (s, 9 H, C(CH 3)3), 2.46 (dd, J = 17.2, 3.0 Hz, 1 H, C(7)H AHB), 2.93 (dd, J = 17.2, 6.5 Hz, 1 H, C(7)HA H B), 2.97 (dd, J = 10.8, 7.2, 1 H, C(4)H AHB), 3.21 (dd, J = 10.8, 7.8 Hz, 1 H, C(4)HA H B), 4.33 (td, J = 7.5, 5.5 Hz, 1 H, C(5)H), 4.58 (ddd, J = 6.5, 5.5, 3.0 Hz, 1 H, C(6)H), 5.05 (s, 1 H, C(2)H); minor isomer (5b): δ = 0.98 (s, 9 H, C(CH 3)3), 2.51 (t, J = 10.2 Hz, 1 H, C(4)H AHB), 2.61 (dd, J = 18.0, 3.5 Hz, 1 H, C(7)H AHB), 2.83 (dd, J = 18.0, 7.5 Hz, 1 H, C(7)HA H B), 3.11 (dd, J = 10.5, 6.0 Hz, 1 H, C(4)HA H B), 4.08 (ddd, J = 10.0, 6.0, 2.0 Hz, 1 H, C(5)H), 4.29 (ddd, J = 7.5, 3.5, 2.0 Hz, 1 H, C(6)H), 5.01 (s, 1 H, C(2)H). 13C NMR (100 MHz, CDCl3) major isomer (5b’): δ = 26.5 (C(CH3)3), 30.6 (C(4)), 38.2 (C(CH3)3), 42.4 (C(7)), 66.7 (C(6)), 68.8 (C(5)), 70.8 (C(2)), 174.1 (C(8)); minor isomer (5b): δ = 26.5 (C(CH3)3), 35.0 (C(4)), 37.6 (C(CH3)3), 41.8 (C(7)), 69.5 (C(6)), 71.0 (C(2)), 73.8 (C(5)), 175.0 (C(8)). MS (ESI+): m/z = 216.1 (MH+, 97%), 238.1 (MNa+, 90%). HRMS (ESI+): found 216.10514, C10H18NO2S (MH+) requires 216.10528.