Enantioselective Total Synthesis of Ligraminol D and Ligraminol E

Abstract

As a part of our ongoing research on the synthesis of bioactive constituents or molecules by using an organocatalytic approach, enantioselective total syntheses of ligraminol D and ligraminol E were achieved starting from a commercially available nonchiral aldehyde. Key steps in this synthesis were an asymmetric α-aminoxylation of an aldehyde and a Mitsunobu reaction.

Key words

asymmetric synthesis - total synthesis - aminoxylation - ­ligraminols - Mitsunobu reaction - asymmetric catalysis

• References and Notes

• 1 Teponno RB, Kusari S, Spiteller M. Nat. Prod. Rep. 2016; 33: 1044
• 2 Kitts DD, Yuan YV, Wijewickreme AN, Thompson LU. Mol. Cell. Biochem. 1999; 202: 91
• 3 Cornwell T, Cohick W, Raskin I. Phytochemistry 2004; 65: 995
• 4 Magee PJ, Rowland IR. Br. J. Nutr. 2004; 91: 513
• 5 Liao J.-F, Huang S.-Y, Jan Y.-M, Yu L.-L, Chen C.-F. J. Ethnopharmacol. 1998; 61: 185
• 6 Della Greca M, Monaco P, Previtera L, Aliotta G, Pinto G, Pollio A. Phytochemistry 1989; 28: 2319
• 7 Lee JY, Lee JY, Yun B.-S, Hwang BK. J. Agric. Food Chem. 2004; 52: 776
• 8 Perrett S, Whitfield PJ. Phytother. Res. 1995; 9: 405
• 9 McGaw LJ, Jäger AK, van Staden J, Eloff JN. S. Afr. J. Bot. 2002; 68: 31
• 10 Kim KH, Kim HK, Choi SU, Moon E, Kim SY, Lee KR. J. Nat. Prod. 2011; 74: 2187
• 11a Gangar M, Goyal S, Hathiram V, Ramdas WA, Rao VK, Nair VA. ChemistrySelect 2017; 2: 257
• 11b Ghotekar GS, Mujahid M, Muthukrishnan M. Synthesis 2019; in press ; DOI: 10.1055/s-0037-1611919
• 12a Dalko PI, Moisan L. Angew. Chem. Int. Ed. 2001; 40: 3726
• 12b Dalko PI, Moisan L. Angew. Chem. Int. Ed. 2004; 43: 5138
• 12c Houk KN, List B. Acc. Chem. Res. 2004; 37: 487
• 12d List B. Adv. Synth. Catal. 2004; 346: 1021
• 12e Seayad J, List B. Org. Biomol. Chem. 2005; 3: 719

For reviews of proline-catalyzed asymmetric reactions, see:
• 13a List B. Synlett 2001; 1675
• 13b Movassaghi M, Jacobsen EN. Science 2002; 298: 1904
• 13c List B. Tetrahedron 2002; 58: 5573
• 13d List B. Acc. Chem. Res. 2004; 37: 548
• 14a Brown SP, Brochu MP, Sinz CJ, MacMillan DW. C. J. Am. Chem. Soc. 2003; 125: 10808
• 14b Janey JM. Angew. Chem. Int. Ed. 2005; 44: 4292
• 14c Merino P, Tejero T. Angew. Chem. Int. Ed. 2004; 43: 2995
• 14d Zhong G. Angew. Chem. Int. Ed. 2003; 42: 4247
• 14e Lu M, Zhu D, Lu Y, Hou Y, Tan B, Zhong G. Angew. Chem. Int. Ed. 2008; 47, 10013; corrigendum; Angew. Chem. Int. Ed. 2008, 47, 10187
• 14f Ramachary DB, Barbas CF. Org. Lett. 2005; 7: 1577
• 14g Hayashi Y, Yamaguchi J, Hibino K, Shoji M. Tetrahedron Lett. 2003; 44: 8293
• 14h Bøgevig A, Sundén H, Córdova A. Angew. Chem. Int. Ed. 2004; 43: 1109
• 14i Hayashi Y, Yamaguchi J, Sumiya T, Shoji M. Angew. Chem. Int. Ed. 2004; 43: 1112
• 14j Hayashi Y, Yamaguchi J, Sumiya T, Hibino K, Shoji M. J. Org. Chem. 2004; 69: 5966
• 14k Font D, Bastero A, Sayalero S, Jimeno C, Pericàs MA. Org. Lett. 2007; 9: 1943
• 14l Cambeiro XC, Martín-Rapún R, Miranda PO, Sayalero S, Alza E, Llanes P, Pericàs MA. Beilstein J. Org. Chem. 2011; 7: 1486
• 15a Markad SB, Bhosale VA, Bokale SR, Waghmode SB. ChemistrySelect 2019; 4: 502
• 15b Bhosale VA, Waghmode SB. Org. Chem. Front. 2018; 5: 2442
• 15c Bhosale VA, Markad SB, Waghmode SB. Tetrahedron 2017; 73: 5344
• 15d Bhosale VA, Waghmode SB. Tetrahedron 2017; 73: 2342
• 15e Bhosale VA, Waghmode SB. ChemistrySelect 2017; 2: 1262
• 15f Sawant RT, Waghmode SB. Tetrahedron 2009; 65: 1599
• 15g Sawant RT, Waghmode SB. Tetrahedron 2010; 66: 2010
• 15h Sawant RT, Jadhav SG, Waghmode SB. Eur. J. Org. Chem. 2010; 4442
• 15i Sawant RT, Waghmode SB. Synth. Commun. 2010; 40: 2269
• 15j Sawant RT, Waghmode SB. Synth. Commun. 2011; 41: 2385
• 15k Patil VP, Ghosh A, Sonavane R, Joshi UR, Sawant RT, Jadhav SG, Waghmode SB. Tetrahedron: Asymmetry 2014; 25: 489
• 16 Yadav JS, Singh VK, Thirupathaiah B, Reddy AB. Tetrahedron Lett. 2014; 55: 4427
• 17 Mitsunobu O, Yamada M. Bull. Chem. Soc. Jpn. 1967; 40: 2380
• 18 4-{(2R)-3-Hydroxy-2-[4-(3-hydroxypropyl)-2-methoxyphenoxy]propyl}-2-methoxyphenol (Ligraminol E) (5) To a solution of ether 16 (0.190 g) in MeOH (10 mL) was added 10% Pd/C (0.05 g), and the mixture was stirred for 12 h under H₂ (150 psi; 1.03 MPa). The catalyst was filtered off and the filtrate was concentrated under reduced pressure. A solution of the resulting crude ether (0.154 g, 0.30 mmol) in anhyd THF (5 mL) was added dropwise to a cold (0 °C) suspension of LiAlH₄ (0.025 g, 0.66 mmol) in anhyd THF (5 mL), and the suspension as stirred for 3 h at rt, then cooled to 0 °C. The reaction as quenched with sat. aq NH₄Cl (2 mL), and mixture was diluted with EtOAc (10 mL), filtered through a Celite pad under vacuum, and concentrated under reduced pressure. The crude product was purified by column chromatography [silica gel, EtOAc–hexane (3:7)] to give a sticky colourless liquid; yield: 0.119 g (93%; two steps); [α]_D ²⁵ +17.5 (c 0.103, MeOH) [Lit.^11b +18.3 (c 0.10, MeOH)]. IR (neat): 3387, 2923, 2852, 1602, 1509, 1261, 1026, 798 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 6.87–6.83 (m, 1 H), 6.81–6.76 (m, 3 H), 6.74–6.69 (m, 2 H), 4.24–4.18 (m, 1 H), 3.87 (s, 3 H), 3.86 (s, 3 H), 3.71–3.63 (m, 4 H), 3.06 (dd, J = 13.9, 6.7 Hz, 1 H), 2.90 (dd, J = 13.9, 6.9 Hz, 1 H), 2.66 (t, J = 6.9 Hz, 2 H), 1.91–1.84 (m, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 150.9, 146.5, 145.6, 144.3, 137.3, 129.7, 122.1, 121.0, 119.8, 114.4, 112.4, 112.2, 85.14, 63.4, 62.1, 55.9, 55.8, 37.3, 34.2, 31.8. HRMS (ESI, +): m/z [M + Na]⁺ calcd for C₂₀H₂₆NaO₆: 385.1627; found: 385.1628. (2S)-3-(3,4-Dimethoxyphenyl)-2-[4-(3-hydroxypropyl)-2-methoxyphenoxy]propan-1-ol (Ligraminol D) (4) A solution of ether 19 (0.115 g, 0.23 mmol) in anhyd THF (5 mL) was added dropwise to a cold (0 °C) suspension of LiAlH₄ (0.018 g, 0.48 mmol) in dry THF (5 mL) and the suspension was stirred for 3 h at r.t, then cooled to 0 °C. The reaction was quenched with sat. aq NH₄Cl (3 mL), and the mixture was diluted with EtOAc (10 mL), filtered through a Celite pad under vacuum, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 25% EtOAc–hexane) to give a sticky liquid; yield: 0.077 g (93%), [α]_D ²⁵ –24.3 (c 0.154, MeOH); {Lit.^11b –29.0 (c 0.1, MeOH); Lit.^11a +9.5 (c 0.1, MeOH)} IR (neat): 3402, 2945, 1605, 1510, 1036 cm^{– 1}. ¹H NMR (400 MHz, CDCl₃): δ = 6.82 (br s, 3 H), 6.76 (br s, 1 H), 6.68 (d, J = 0.9 Hz, 2 H), 4.25–4.19 (m, 1 H), 3.88 (s, 3 H), 3.87 (s, 3 H), 3.86 (s, 3 H), 3.69–3.67 (m, 4 H), 3.08 (dd, J = 13.9, 6.7 Hz, 1 H), 3.01–2.88 (m, 2 H), 2.66 (t, J = 6.7 Hz, 2 H), 1.91–1.84 (m, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 150.9, 148.9, 147.7, 145.5, 137.3, 130.5, 121.5, 121.0, 119.8, 112.8, 112.4, 111.3, 85.1, 63.5, 62.1, 55.9, 55.9, 55.9, 37.3, 34.2, 31.8. HRMS (ESI, +): m/z [M + Na]⁺ calcd for C₂₁H₂₈NaO₆: 399.1784; found: 399.1781.