Synlett, Table of Contents Synlett 2013; 24(7): 823-826DOI: 10.1055/s-0032-1318345 letter © Georg Thieme Verlag Stuttgart · New YorkSynthesis of N-Cbz-Substituted β3-Amino Ketones Utilizing 4-Substituted 1,3-Oxazinan-6-ones Brad E. Sleebs a The Walter and Eliza Hall Institute of Medical Research, Parkville 3010, Australia b Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia , Nghi H. Nguyen c Department of Chemistry, La Trobe University, Victoria 3086, Australia Fax: +61(3)94791266 Email: tahughes@optusnet.com.au , Andrew B. Hughes* c Department of Chemistry, La Trobe University, Victoria 3086, Australia Fax: +61(3)94791266 Email: tahughes@optusnet.com.au› Author AffiliationsRecommend Article Abstract Buy Article All articles of this category Abstract Stereoselective synthesis of N-Cbz-substituted β-amino ketones exploiting the versatile 1,3-oxazin-6-one scaffold is reported. The 4-substituted 1,3-oxazinan-6-ones were enolized and acylated diastereoselectively by addition of various acyl halides. Acidic decarboxylation was then employed to smoothly transform the 5-acylated products to chiral β-amino ketones. This methodology further highlights the utility of the 1,3-oxazinan-6-one as a scaffold to access valuable synthons that are used in the peptidomimetic field. Key words Key wordsketones - amino acids - acylation - ring opening - oxazinanones Full Text References References and Notes 1a Barluenga J, Olano B, Fustero S. J. Org. Chem. 1985; 50: 4052 1b Bosch J, Rubiralta M, Domingo A, Sistaré J. J. Heterocycl. Chem. 1981; 18: 47 1c Brough P, Pécaut J, Rassat A, Rey P. Chem. Eur. J. 2006; 12: 5134 1d Fisyuk AS, Poendaev NV. Chem. Heterocycl. Compd. 2003; 39: 895 1e Fisyuk AS, Ryzhova EA, Unkovskii BV. Chem. Heterocycl. Compd. 2001; 37: 597 1f Hansen CP, Jensen AA, Balle T, Bitsch-Jensen K, Hassan MM, Liljefors T, Fralund B. Bioorg. Med. Chem. 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Tetrahedron 2012; 68: 4745 8a Sleebs BE, Hughes AB. Helv. Chim. Acta 2006; 89: 2611 8b Sleebs BE, Hughes AB. Aust. J. Chem. 2006; 58: 778 9 Sleebs BE, Hughes AB. J. Org. Chem. 2007; 72: 3340 10 Sleebs BE, Nguyen NH, Hughes AB. Tetrahedron 2013; 69: in press 11 General Procedure 1 5-Acylation of 1,3-Oxazinan-6-ones A solution of the 1,3-oxazinan-6-one 1–4 (0.1 M in dry freshly distilled THF) was cooled to –78 °C under an argon atmosphere. Then LiHMDS (1.1 equiv of a 1.0 M solution in THF) was added dropwise, and the solution was left to stir at –78 °C for 40 min. The acylating agent (3.0 equiv) was then added dropwise and stirring was continued for 3 h at –78 °C. The solution was then allowed to warm to –50 °C, and the reaction was then quenched with sat. NH4Cl solution (5 mL). The solution was diluted with EtOAc (20 mL) and washed with H2O (20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to give an oil. The oil was subjected to flash column chromatography, eluting with 5–30% EtOAc–hexane. Data for (4S,5R)-N-Benzyloxycarbonyl-4-isopropyl-5-propionyl-1,3-oxazinan-6-one (5) General Procedure 1 was followed for the acylation of oxazinanone 1 (63 mg, 0.23 mmol) with propionyl chloride (59.8 μL, 0.68 mmol), to afford the desired 5-substituted 1,3-oxazinan-6-one 5 as a clear oil (crystallized on standing; 60 mg, 80% yield); mp 82–84 °C; Rf = 0.23 (20% EtOAc–hexane); [α]D 25 +116 (c 2.17, MeOH). 1H NMR (300 MHz, CDCl3): δ = 7.33 (s, 5 H), 5.93 (d, 1 H, J = 9.9 Hz), 5.17 (s, 2 H), 4.93 (d, 1 H, J = 9.9 Hz), 4.59 (t, 1 H, J = 7.2 Hz), 3.73 (d, 1 H, J = 7.2 Hz), 2.84–2.73 (m, 1 H), 2.58–2.47 (m, 1 H), 1.88–1.77 (m, 1 H), 1.09 (t, 3 H, J = 7.2 Hz), 0.89 (d, 3 H, J = 7.2 Hz), 0.85 (d, 3 H, J = 7.2 Hz). 13C NMR (75 MHz, CDCl3): δ = 202.7 167.3, 154.5, 134.9, 128.3, 128.1, 127.8, 72.9, 68.2, 55.9, 55.1, 36.5, 31.0, 18.3, 18.1, 7.2. IR (film): νmax = 2967, 2940, 1748, 1717, 1458, 1412, 1258, 1123, 979 cm–1. HRMS (ESI–): m/z calcd for C18H23NO5 [M – H]–: 332.1503; found: 332.1496. 12 General Procedure 2Formation of the β3-Amino Ketones The oxazinanone 15–24 was dissolved in a mixture of THF–2 M HCl (1:1, 0.013 M solution), and the reaction mixture was gently heated to 50 °C for 4–6 h. The THF was then removed under reduced pressure. The aqueous solution was taken up EtOAc and washed with H2O (3 × 10 mL) followed by brine (1 × 10 mL). The organic layer was dried (MgSO4) and evaporated in vacuo to give an oil. The oil was subjected to flash column chromatography, eluting with 5–20% EtOAc–hexane. 13 Data for (5R)-(N-Benzyloxylcarbonyl-5-amino)-6-methyl-heptan-2-one (15) General Procedure 2 was followed for the hydrolysis of the 1,3-oxazinan-6-one 5 (31 mg, 0.09 mmol), and afforded the β-amino ketone 15 as a white solid (24 mg, 92% yield); mp 75–77 °C; Rf = 0.50 (30% EtOAc–hexane); [α]D 25 –3.6 (c 1.09, MeOH). 1H NMR (300 MHz, CDCl3): δ = 7.32–7.27 (m, 5 H), 5.14 (d, 1 H, J = 8.9 Hz), 5.06 (s, 2 H), 3.83–3.76 (m, 1 H), 2.61 (br d, 2 H, J = 5.7 Hz), 2.47–2.33 (m, 2 H), 1.89–1.80 (m, 1 H), 1.00 (t, 3 H, J = 7.2 Hz), 0.89 (d, 3 H, J = 4.2 Hz), 0.87 (d, 3 H, J = 4.5 Hz). 13C NMR (75 MHz, CDCl3): δ = 210.0, 155.7, 136.3, 128.1, 127.6, 127.5, 66.2, 53.2, 43.9, 35.8, 31.2, 19.1, 18.2, 7.3. IR (film): νmax = 3325, 2940, 2878, 1709, 1682, 2539, 1454, 1416, 1308. HRMS (ESI+): m/z calcd for C16H23NO3 [M + H]+: 278.1751; found: 278.1756. HPLC [Chiralpak AD-H, PE–2-PrOH (90:10), 25 °C, 254 nm]: t R (major) = 7.1 min; t R (minor) = 6.1 min, 97% ee. Supplementary Material Supplementary Material Supporting Information
