Nucleophilic Opening of an Epoxide by a Masked Glycine Anion Equivalent: A Route to C-Glycosyl Amino Acids

Abstract

An efficient method has been developed for the synthesis of C-glycosyl amino acids through a tandem nucleophilic opening–cyclization of an l-ido-bisepoxide with the anion of Schöllkopf’s bislactim. A masked amine was introduced at the CH₂C₁-position of the resulting compound. The products are enantiopure polyfunctionalized intermediates, suitable for further synthesis of antibacterial compounds.

Key words

epoxides - ring opening - cyclizations - tandem reactions - glycosyl amino acids - medicinal chemistry

• References and Notes

• 1 Present address: Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, SI-1000 Ljubljana, Slovenia.
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For recent syntheses of liposidomycin and caprazamycin analogues, see:
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• 19 Compounds 1a and 1b; Typical Procedure A 1.51 M solution of BuLi in hexane (2.43 mL, 3.67 mmol, 1.2 equiv) was added dropwise to a solution of the Schöllkopf bislactim ether (658 μL, 3.67 mmol, 1.2 equiv) in anhyd THF (8 mL) at –78 °C under argon. The yellow solution was then stirred for 30 min. In another flask, BF₃·OEt₂ (388 μL, 3.06 mmol, 1 equiv) was added to a solution of the l-ido-bisepoxide (1 g, 3.06 mmol, 1 equiv) in anhyd THF (3 mL) at –78 °C under argon, and the mixture was stirred for 10 min. The solution of the Schöllkopf bislactim anion was then transferred to the l-ido-bisepoxide solution by using a Teflon cannula, and the mixture was stirred for 1 h at –78 °C and then overnight at –30 °C. The reaction was then quenched with sat. aq NaHCO₃, and the mixture was extracted with EtOAc (3 × 20 mL). The organic extracts were combined, washed with brine, dried (MgSO₄), and concentrated in vacuo to give a yellow oil. This crude product was purified by chromatography [silica gel, cyclohexane–EtOAc–Et₃N (8:2:3‰)] to give a mixture of diastereoisomers; yield: 880 mg (56%). A second purification by chromatography [silica gel, CH₂Cl₂–acetone–Et₃N (95:5:3‰)] gave the pure major diastereoisomer 1a as a yellow oil and the pure minor diastereoisomer 1b as a pale-yellow oil. 1a: Yellow oil; yield: 552 mg (35%); [α]_D ²⁰ +22 (c 1.0, CH₂Cl₂); R_f  = 0.53 (CH₂Cl₂–acetone, 9:1). ¹H NMR (500 MHz, CDCl₃): δ = 7.40–7.32 (m, 10 H, H_Ar), 4.63, 4.48 (AB, d, J_A,B  = 11.9 Hz, 2 H, CH₂Ph), 4.60 (AB, J_A,B  = 11.7 Hz, 2 H, CH₂Ph), 4.47–4.44 (m, 1 H, H₄), 4.20 (ddd, J_H6,H5b  = 10 Hz, J_H6,H5a  = J_H6,H8  = 3.5 Hz, 1 H, H₆), 4.13 (dd, J_H2,H1  = 3.5 Hz, J_H2,H3  = 1.5 Hz, 1 H, H₂), 4.06–4.02 (m, 1 H, H₁), 3.99 (t, J_H8,H9  = J_H8,H6  = 3.4 Hz, 1 H, H₈), 3.93 (dd, J_H3,H4  = 3.8 Hz, J_H3,H2  = 1.5 Hz, 1 H, H₃), 3.82 (dd, J_CHaOH,CHbOH  = 11.6 Hz, J_CHaOHa,H1  = 2.9 Hz, 1 H, CH_aOH), 3.74, 3.71 (2 s, 6 H, O–CH₃), 3.67 (br d, J_CHbOH,CHaOH  = 11.6 Hz, 1 H, CH_bOH), 2.74 (br s, 1 H, OH), 2.47 (ddd, J_H5a,H5b  = 13.7 Hz, J_H5a,H4  = 9.1 Hz, J_H5a,H6  = 3.5 Hz, 1 H, H_5a), 2.30 (dqq, J_H9,H10a  = J_H9,H10b  = 6.8 Hz, J_H9,H8  = 3.5 Hz, 1 H, H₉), 1.77 (ddd, J_H5b,H5a  = 13.7 Hz, J_H5b,H6  = 10.1 Hz, J_H5b,H4  = 3.5 Hz, 1 H, H_5b), 1.09 (d, J_H10a,H9  = 6.9 Hz, 3 H, H_10a), 0.76 (d, J_H10b,H9  = 6.8 Hz, 3 H, H_10b). ¹³C NMR (125 MHz, CD₃OD): δ = 163.9 (C₇), 163.4 (C_7′), 137.7, 137.6, 128.4, 128.3, 127.8, 127.7, 127.6, 127.5 (C_Ar), 83.7 (C₁), 83.5 (C₃), 83.1 (C₂), 77.6 (C₄), 71.9 (CH₂Ph), 71.3 (CH₂Ph), 62.9 (CH₂OH), 60.8 (C₈), 53.0 (C₆), 52.4 (OCH₃), 52.3 (OCH₃), 33.9 (C₅), 31.7 (C₉), 19.0, 16.7 (C₁₀). LRMS (ESI): m/z = 511.3 [M + H]⁺, 533.2 [M + Na]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₃₉N₂O₆: 511.2808; found: 511.2808; [M + Na]⁺ calcd for C₂₉H₃₈N₂NaO₆: 533.2628; found: 533.2623. 1b: Pale-yellow oil; yield: 76 mg (5%). ¹H NMR (500 MHz, CDCl₃): δ = 7.38–7.27 (m, 10 H, H_Ar), 4.62, 4.44 (AB, d, J_A,B  = 12.0 Hz, 2 H, CH₂Ph), 4.56 (AB, J_A,B  = 12.0 Hz, 2 H, CH₂Ph), 4.35 (ddd, J_H4,H3  = 7.0, J_H4,H5b  = 7.0 Hz, J_H4,H5a  = 4.5 Hz, 1 H, H₄), 4.08 (d, J_H2,H1  = 3 Hz, 1 H, H₂), 4.05 (m, 1 H, H₆), 3.99 (m, 1 H, H₁), 3.97 (dd, J_H3,H4  = 7 Hz, J_H3,H2  = 3 Hz, 1 H, H₃), 3.93 (dd, J_H8,H6  = 5.0 Hz, J_H8,H9  = 3.5 Hz, 1 H, H₈), 3.76 (dd, J_CHaOH,CHbOH  = 12.0 Hz, J_CHaOHa,H1  = 3.0 Hz, 1 H, CH_aOH), 3.68, 3.65 (2 s, 6 H, O–CH₃), 3.61 (dd, J_CHbOH,CHaOH  = 12.0 Hz, J_CHbOH,H1  = 4 Hz, 1 H, CH_bOH), 2.45 (br s, 1 H, OH), 2.39 (ddd, J_H5a,H5b  = 13.5 Hz, J_H5a,H6  = 8.0 Hz, J_H5a,H4  = 4.5 Hz, 1 H, H_5a), 2.20 (dqq, J_H9,H10a  = J_H9,H10b  = 7.0 Hz, J_H9,H8  = 3.5 Hz, 1 H, H₉), 1.69 (ddd, J_H5b,H5a  = 13.5 Hz, J_H5b,H6  = J_H5b,H4  = 7.0 Hz, 1 H, H_5b), 1.04 (d, J_H10a,H9  = 7.0 Hz, 3 H, H_10a), 0.71 (d, J_H10b,H9  = 7.0 Hz, 3 H, H_10b).
• 20 Busch K, Groth UM, Kühnle W, Schöllkopf U. Tetrahedron 1992; 48: 5607
• 21 Heidler P, Zohrabi-Kalantari V, Kaiser M, Brun R, Emmrich T, Link A. Bioorg. Med. Chem. 2009; 17: 1428
• 22 Selected Physical and Spectroscopic Data for Compound 2 Pale yellow oil; yield: 228 mg (86%); [α]_D ²⁰ +13 (c 1.0, CH₂Cl₂); R_f  = 0.52 (cyclohexane–EtOAc, 7:3). ¹H NMR (500 MHz, CD₃OD): δ = 7.77 (m, 4 H, H_Phth), 7.33–7.25 (m, 5 H, H_Ar), 7.14–7.07 (m, 5 H, H_Ar), 4.63, 4.49 (AB, J_A,B  = 12.1 Hz, 2 H, CH₂Ph), 4.42, 4.37 (AB, J_A,B  = 12.1 Hz, 2 H, CH₂Ph), 4.32–4.31 (m, 1 H, H₄), 4.12–4.08 (m, 3 H, H₁, H₂, and H₆), 3.89–3.78 (m, 4 H, H₃, H₈, and CH₂NPhth), 3.66 (s, 3 H, OCH₃), 3.63 (s, 3 H, OCH₃), 2.31 (ddd, J_H5a,H5b  = 13.1 Hz, J_H5a,H4  = 9.5 Hz, J_H5a,H6  = 4.7 Hz, 1 H, H_5a), 2.21–2.18 (m, 1 H, H₉), 1.73 (ddd, J_H5b,H5a  = 13.1 Hz, J_H5b,H6  = 9.5 Hz, J_H5b,H4  = 4.3 Hz, 1 H, H_5b), 1.02 (d, J_H10a,H9  = 7.0 Hz, 1 H, H_10a), 0.69 (d, J_H10b,H9  = 7.0 Hz, 1 H, H_10b). ¹³C NMR (125 MHz, CD₃OD): δ = 169.8 (C₇, CO_Phth), 139.4, 139.1, 135.3, 133.3, 129.4, 129.3, 129.0, 128.7 (3s), 124.24 (C_Ar), 84.6, 84.4 (C₂, C₃), 82.4 (C₁), 79.8 (C₄), 72.6 (CH₂Ph), 72.5 (CH₂Ph), 61.9 (C₈), 54.4 (C₆), 53.2 (OCH₃), 53.1 (OCH₃), 41.2 (CH₂NPhth), 35.0 (C₅), 32.8 (C₉), 19.5 (C₁₀), 17.1 (C₁₀). LRMS (ESI): m/z = 640.3 [M + H]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₃₇H₄₂N₃O₇: 640.3023; found: 640.3012.
• 23 Ojea V, Ruiz M, Shapiro G, Pombo-Villar E. J. Org. Chem. 2000; 65: 1984
• 24 Selected Physical and Spectroscopic Data for Compound 3 Very pale yellow; yield: 83 mg (73%); [α]_D ²⁰ +41 (c 1.0, MeOH). R_f  = 0.37 (EtOAc). ¹H NMR (500 MHz, CD₃OD): δ = 7.75 (m, 4 H, H_Phth), 7.32–7.25 (m, 5 H, H_Ar), 7.14–7.06 (m, 5 H, H_Ar), 4.61, 4.37 (AB, J_A,B  = 11.5 Hz, 2 H, CH₂Ph), 4.48, 4.40 (AB, J_A,B  = 11.8 Hz, 2 H, CH₂Ph), 4.16–4.10 (m, 2 H, H₁, H₄), 4.10–4.05 (m, 1 H, H₂), 3.84 (ABX, J_A,B  = 14.0 Hz, J_A,X  = 7.5 Hz, 2 H, J_B,X  = 5.0 Hz, CH₂NPhth), 3.87–3.85 (m, 1 H, H₃), 3.67 (s, 3 H, OCH₃), 3.59 (dd, J_H6,H5b  = 8.5 Hz, J_H6,5a  = 5 Hz, 1 H, H₆), 2.17 (ddd, J_H5a,H5b  = 14 Hz, J_H5a,H4  = 9 Hz, 1 H, J_H5a,H6  = 5 Hz, H_5a), 1.82 (ddd, J_H5b,H5a  = 14 Hz, J_H5b,H6  = 8.5 Hz, 1 H, J_H5b,H4  = 4 Hz, H_5b). ¹³C NMR (125 MHz, CD₃OD): δ = 177.1 (CO₂CH₃), 169.7 (CO_Phth), 139.2, 139.0, 135.3, 133.2, 129.4, 129.3, 129.0, 128.8, 128.7, 128.6, 124.2 (C_Ar), 84.4, 84.2 (C₂, C₃), 82.8 (C₁), 79.7 (C₄), 72.5 (CH₂Ph), 53.1 (C₆), 52.5 (OCH₃), 41.1 (CH₂NPhth), 34.7 (C₅). HRMS (ESI): m/z [M + H]⁺ calcd for C₃₁H₃₃N₂O₇: 545.2288; found: 545.2294.
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• 27 Selected Physical and Spectroscopic Data for Compound 5 Colourless oil; yield: 51 mg (63%); [α]_D ²⁰ +11 (c 1.02, MeOH); R_f  = 0.28 (cyclohexane–EtOAc, 7:3). ¹H NMR (500 MHz, CD₃OD): δ = 7.74–7.67 (m, 8 H, 4 H_Phth + 4 H_SiPh), 7.42–7.37 (m, 6 H, H_SiPh), 7.31–7.27 (m, 5 H, H_Ar), 7.13–7.07 (m, 5 H, H_Ar), 4.60, 4.35 (AB, d, J_A,B  = 11.6 Hz, 2 H, CH₂Ph), 4.47, 4.40 (AB, d, J_A,B  = 12.0 Hz, 2 H, CH₂Ph), 4.16–4.13 (m, 1 H, H₄), 4.13–4.06 (m, 2 H, H₁, H₂), 3.92 (dd, J_H10a,H10b  = 10.4 Hz, J_H10a,H9  = 3.4 Hz, 1 H, H_10a), 3.84 (dd, J_H10b,H10a  = 10.1 Hz, J_H10b,H9  = 3.3 Hz, 1 H, H_10b), 3.83–3.74 (m, 3 H, H₃, CH₂NPhth), 3.65 (s, 3 H, COOCH₃), 3.60–3.58 (m, 1 H, H₈), 3.52 (ddd, J_H9,H8  = 7.2 Hz, J_H9,H10a  = J_H9,H10b  = 3.4 Hz, 1 H, H₉), 3.37 (t, J_H6,H5  = 8.6 Hz, 1 H, H₆), 2.61–2.54 (m, 2 H, H₇), 2.06 (ddd, J_H5a,H5b  = 13.5 Hz, J_H5a,H6  = 8.7 Hz, J_H5a,H4  = 5.2 Hz, H_5a, 1 H), 1.86 (ddd, J_H5b,H5a  = 13.1 Hz, J_H5b,H6  = 8.7 Hz, J_H5b,H4  = 5 Hz, 1 H, H_5a), 1.04 (s, 9 H, C(CH₃)₃). ¹³C NMR (125 MHz, CD₃OD): δ = 176.4 (CO₂CH₃), 169.7 (CO_Phth), 139.2, 139.0, 136.7, 135.3, 134.2, 133.2, 131.0 (2s), 129.4, 129.3, 129.1, 129.0, 128.9 (2s), 128.8 (2s), 128.7, 124.2 (C_Ar), 84.2, 84.1 (C₂, C₃), 82.7 (C₁), 79.9 (C₄), 75.5 (2 CH₂Ph), 70.7 (C₈), 67.9 (C₉), 65.6 (C₁₀), 60.1 (C₆), 52.4 (OCH₃), 51.3 (C₇), 41.1 (CH₂NPhth), 33.3 (C₅), 27.3 [C(CH₃)₃], 14.5 [C(CH₃)₃]. LRMS (ESI): m/z = 912.4 [M + H]⁺; HRMS (ESI) m/z [M + H]⁺ calcd for C₅₁H₅₈N₅O₉Si: 912.4004; found: 912.3983.
• 28 Honcharenko D, Varghese OP, Plashkevych O, Barman J, Chattopadhyaya J. J. Org. Chem. 2006; 71: 299
• 29 Selected Physical and Spectroscopic Data for Compound 6 Colourless oil; yield: 25 mg (46%); [α]_D ²⁰ +26 (c 1.0, MeOH). R_f  = 0.46 (CH₂Cl₂–MeOH, 98:2). ¹H NMR (500 MHz, CD₃OD): δ = 7.34–7.27 (m, 10 H, H_Ar), 4.58 (AB, d, J_A,B  = 12.0 Hz, 2 H, CH₂Ph), 4.45 (AB, d, J_A,B  = 12.1 Hz, 2 H, CH₂Ph), 4.33–4.30 (m, 1 H, H₄), 4.14–4.11 (m, 1 H, H₆), 3.93 (t, J_H8,H9  = J_H8,H6  = 3.8 Hz, 1 H, H₈), 3.90–3.84 (m, 3 H, H₁, H₂, H₃), 3.68, 3.65 (2s, 6 H, OCH₃), 2.83–2.78 (m, 2 H, CH₂NH₂), 2.34 (ddd, J_H5a,H5b  = 12.7 Hz, J_H5a,H4  = 8.5 Hz, J_H5a,H6  = 3.3 Hz, 1 H, H_5a), 2.24 (dqq, J_H9,H10a  = J_H9,H10b  = 6.9 Hz, J_H9,H8  = 3.8 Hz, 1 H, H₉), 1.76 (ddd, J_H5b,H5a  = 13.1 Hz, J_H5b,H6  = 10.1 Hz, J_H5b,H4  = 3.3 Hz, 1 H, H_5b), 1.04 (d, J_H10a,H9  = 6.9 Hz, 3 H, H_10a), 0.71 (d, J_H10b,H9  = 6.9 Hz, 3 H, H_10b). ¹³C NMR (125 MHz, CD₃OD): δ = 165.8 (C₇), 165.2 (C_7′), 139.4 (2s), 129.5 (2s), 129.0, 128.9 (C_Ar), 85.9, 85.6 (C₂, C₃), 84.8 (C₁), 79.4 (C₄), 72.8 (CH₂Ph), 72.6 (CH₂Ph), 61.9 (C₈), 54.4 (C₆), 53.2 (OCH₃), 53.1 (OCH₃), 45.1 (CH₂NH₂), 35.1 (C₅), 32.9 (C₉), 19.5, 17.1 (C₁₀). LRMS (ESI): m/z = 510.3 [M + H]⁺; HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₄₀N₃O₅: 510.2968; found: 510.2962; [M + Na]⁺ calcd for C₂₉H₃₉N₃NaO₅: 532.2787; found: 532.2782.
• 30 Kotch FW, Sidorov V, Lam Y.-F, Kayser KJ, Li H, Kaucher MS, Davis JT. J. Am. Chem. Soc. 2003; 125: 15140
• 31 Selected Physical and Spectroscopic Data for Compound 7 Colourless oil; yield: 59 mg (61%); [α]_D ²⁰ +38 (c 1.0, MeOH). R_f  = 0.38 (EtOAc–MeOH, 10:1). ¹H NMR (500 MHz, CD₃OD): δ = 7.34–7.28 (m, 10 H, H_Ar), 4.57 (AB, d, J _A,_B = 11.1 Hz, 2 H, CH₂Ph), 4.43 (AB, d, J _A,_B = 11.1 Hz, 2 H, CH₂Ph), 4.12 (ddd, J_H4,H5a  = 9 Hz, J_H4,H3  = 4.5 Hz, J_H4,H5b  = 4 Hz, 1 H, H₄), 3.99–3.95 (m, 1 H, H₂), 3.93–3.86 (m, 2 H, H₁, H₃), 3.70 (s, 3 H, OCH₃), 3.66 (dd, J_H6,H5b  = 8 Hz, J_H6,H5a  = 4.5 Hz, 1 H, H₆), 3.63, 3.59 (AB from ABX, J_A,B  = 11.5 Hz, J_A,X  = 6 Hz, J_B,X  = 5.5 Hz, 2 H, CH₂OH), 2.19 (ddd, J_H5a,H5b  = 14 Hz, J_H5a,H4  = 9 Hz, J_H5a,H6  = 4.5 Hz, 1 H, H_5a), 1.86 (ddd, J_H5b,H5a  = 14 Hz, J_H5b,H6  = 8 Hz, J_H5b,H4  = 4 Hz, 1 H, H_5b). ¹³C NMR (125 MHz, CD₃OD): δ = 176.8 (CO₂CH₃), 139.4, 139.3, 129.4, 129.0, 128.9, 128.8 (C_Ar), 86.1, 84.8, 84.7 (C₁, C₂, C₃), 79.2 (C₄), 72.7, 72.5 (CH₂Ph), 63.9 (CH₂OH), 53.0 (C₆), 52.6 (OCH₃), 34.4 (C₅). HRMS: m/z [M + H]⁺ calcd for C₂₃H₃₀NO₆: 416.2073; found: 416.2065
• 32 Bonnac LF, Gao G.-Y, Chen L, Patterson SE, Jayaram HN, Pankiewicz KW. Nucleosides Nucleotides Nucleic Acids 2007; 26: 1249
• 33 Selected Physical and Spectroscopic Data for Compound 8 Colourless oil; yield: 88 mg (32%); R_f  = 0.26 (CH₂Cl₂–MeOH–Et₃N, 15:1:2‰). ¹H NMR (500 MHz, CD₃OD): δ = 4.35 (ddd, J_H4,H5a  = 7.5 Hz, J_H4,H5b  = 5.0 Hz, J_H4,H3  = 3.5 Hz, H₄, 1 H), 4.12 (ddd, J_H6,H5b  = 10.0 Hz, J_H6,H5a  = J_H6,H8  = 3.5 Hz, 1 H, H₆), 4.00 (dd, J_H2,H3  = 3.0 Hz, J_H2,H1  = 1.4 Hz, 1 H, H₂), 3.90 (m, 2 H, H₈, H₆), 3.75 (m, 1 H, H₁), 3.73 (s, 3 H, OCH₃), 3.69 (m, 2 H, CH₂OH), 2.48 (ddd, J_H5a,H5b  = 13.5 Hz, J_H5a,H4  = 7.5 Hz, J_H5a,H6  = 3.5 Hz, 1 H, H_5a), 2.16 (dqq, J_H9,H10a  = J_H9,H10b  = 6.8 Hz, J_H9,H8  = 3.5 Hz, 1 H, H₉), 1.77 (ddd, J_H5b,H5a  = 13.5 Hz, J_H5b,H6  = 10.0 Hz, J_H5b,H4  = 5.0 Hz, 1 H, H_5b), 0.99 (d, J_H10a,H9  = 6.8 Hz, 3 H, H_10a), 0.90 (d, J_H10b,H9  = 6.7 Hz, 3 H, H₁₀). ¹³C NMR (125 MHz, CD₃OD): δ = 174.3 (C₇), 162.1 (C_7′), 87.3 (C₁), 80.6 (C₃), 80.4 (C₂), 79.7 (C₄), 63.9 (CH₂OH), 59.9 (C₈), 56.5 (C₆), 53.8 (O–CH₃), 34.5 (C₅), 34.1 (C₉), 18.8, 17.5 (C₁₀). HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₄H₂₄N₂NaO₆: 339.1532 [M + Na]⁺, found: 339.1535. HRMS (ESI^–): m/z [M + H]⁺ calcd for C₁₄H₂₃N₂O₆: 315.1562 (M – H)^–, found: 315.1559.
• 34 Selected Physical and Spectroscopic Data for Compound 9 Colourless oil; yield: 666 mg (43%); R_f  = 0.18 (cyclohexane–EtOAc–Et₃N, 4:1:3‰). IR (ATR): 2974, 1691, 1455, 1366, 1307, 1236, 1182, 1093, 1035, 735, 698 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.33–7.15 (m, 10 H, H_Ar), 4.55–4.44 (m, 3 H, CH₂Ph, H₄), 4.40, 4.35 (AB, J_A,B  = 12.0 Hz, 2 H, CH₂Ph), 4.16–3.96 (m, 6 H, OCH₂CH₃, H₁, H₆), 3.96–3.88 (m, 1 H, H₂), 3.87–3.82 (m, 2 H, H₈, H₃), 3.71, 3.58 (AB from ABX, J _A,_B = 11.6 Hz, J _A,_X = 3.9 Hz, J _B,_X = 3.6 Hz, 2 H, CH₂OH), 2.78 (br s, 1 H, OH), 2.37 (ddd, J_H5a,H5b  = 13.8 Hz, J_H5a,H6  = 9.4 Hz, J_H5a,H4  = 3.5 Hz, 1 H, H_5a), 2.21 (dqq, J_H9,H10a  = J_H9,H10b  = 7.0 Hz, J_H9,H8  = 3.5 Hz, 1 H, H₉), 1.70 (ddd, J_H5b,H5a  = 13.8 Hz, J_H5b,H6  = 10.4 Hz, J_H5b,H4  = 3.7 Hz, 1 H, H_5b), 1.24–1.14 (m, 6 H, CH₃CH₂), 0.98 (d, J_H10a,H9  = 7.0 Hz, 3 H, H_10a), 0.68 (d, J_H10b,H9  = 7.0 Hz, 3 H, H_10b). ¹³C NMR (500 MHz, CDCl₃): δ = 163.6 (C₇), 163.1 (C_7′), 138.0, 137.9, 128.5, 128.4, 127.9, 127.8, 127.7, 127.6 (C_Ar), 83.8 (2s, C₂, C₃), 83.3 (C₁), 77.9 (C₄), 72.0 (CH₂Ph), 71.4 (CH₂Ph), 63.0 (CH₂OH), 60.9 (C₈), 60.8, 60.7 (CH₂CH₃), 53.2 (C₆), 34.0 (C₅), 32.0 (C₉), 19.2, 17.0 (C₁₀), 14.4 (CH₂ CH₃). LRMS (ESI): m/z (%) = 539 (100) [M + H]⁺, 1099 (10) [2M + Na]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₃₁H₄₃N₂O₆: 539.3121; found 539.3134.
• 35 Selected Physical and Spectroscopic Data for Compound 10 White solid; yield: 44 mg (48%); R_f = 0.15 (CH₂Cl₂–MeOH–Et₃N, 20:1:3‰). ¹H NMR (500 MHz, CDCl₃): δ = ¹H NMR (500 MHz, CDCl₃): 4.19 (ddd, J_H4,H5b  = 9.2 Hz, J_H4,H5a  = 5.1 Hz, J_H4,H3  = 3.5 Hz, 1 H, H₄), 4.16 (br s, 1 H, H₂), 4.18–3.99 (m, 4 H, CH₂CH₃, H₃), 3.97–3.91 (m, 1 H, CH₂CH₃,), 3.90 (dd, J_H8,H9  = 3.8 Hz, J_H8,H6  = 3.5 Hz, 1 H, H₈), 3.83 (ddd, J_H1,CHbOH  = 4.0 Hz, J_H1,CHaOH  = 3.6 Hz, J_H1,H2  = 3.0 Hz, 1 H, H₁), 3.78 (ddd, ³J_H6,H5b  = 10.6 Hz, ³ JH_6,5a  = 2.0 Hz, J_H6,H8  = 3.5 Hz, 1 H, H₆), 3.73 (dd, J_CHaOH,CHbOH  = 12.0 Hz, J_CHaOH,H1  = 3.6 Hz, 1 H, CH_aOH), 3.67 (dd, J_CHbOH,CHaOH  = 12.0 Hz, J_CHbOH,H1  = 4.0 Hz, 1 H, CH_bOH), 2.57 (ddd, J_H5a,H5b  = 14.0 Hz, J_H5a,H4  = 5.1 Hz, J_H5a,H6  = 2.0 Hz, 1 H, H_5a), 2.13 (dqq, J_H9,H10a  = J_H9,H10b  = 7.0 Hz, J_H9,H8  = 3.8 Hz, 1 H, H₉), 1.74 (ddd, J_H5b,H5a  = 14.0 Hz, J_H5b,H6  = 10.6 Hz, J_H5b,H4  = 9.2 Hz, 1 H, H_5b), 1.26–1.16 (m, 6 H, H_CH3), 0.97 (d, J_H10a,H9  = 7.0 Hz, 3 H, H_10a), 0.72 (d, J_H10b,H9  = 7.0 Hz, 3 H, H_10b). ¹³C NMR (500 MHz, CDCl₃): δ = 166.9 (C₇), 163.8 (C_7′), 87.2 (C₁), 83.0 (C₄), 80.5 (C₂), 79.6 (C₃), 64.2 (CH₂OH), 63.0 (C₈), 62.7 (CH₂CH₃), 54.0 (C6), 34.8 (C₅), 34.0 (C₉), 20.5, 18.8 (C₁₀), 15.7, 15.6 (CH₂CH₃). LRMS (ESI): m/z (%) = 359 (100) [M + H]⁺.