Asymmetric total synthesis of (−)-cebulactam A1

Abstract

The total synthesis of (−)-cebulactam A1 (3) has been achieved for the first time in 18 steps. The key steps in this synthesis included an asymmetric chelation-controlled vinylogous Mukaiyama aldol reaction for the stereoselective synthesis of the stereogenic centers at the C8 and C9 positions, an intramolecular SmI₂-mediated Reformatsky reaction for the formation of a macrocyclic lactam, and an S_N2′ reaction for the stereoselective formation of the (E)-double bond linked tetrahydropyran moiety of cebulactam A1 (3).

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Introduction

(−)-Q-1047H-R-A (1), (−)-Q-1047H-A-A (2),¹ cebulactam A1 (3)² and tetrapetalone A (4)³ represent a unique class of natural products (Fig. 1), which display a broad range of biological activities, such as antioxidant activity^1,4 of compound 1 and soybean lipoxygenase inhibitory activity⁵ for compound 4.

Fig. 1 Naturally occurring biologically active products.

In our previous communication,⁶ we achieved the total synthesis of Q-1047H-R-A (1) from Q-1047H-A-A (2) via a Na₂S₂O₄-mediated reduction (Fig. 1). In that report, we also proposed a biogenetic strategy⁷ for the total synthesis of natural products 3 and 4 from 1, involving the use of C–O and C–C bond forming reactions as the key synthetic steps, respectively (Fig. 1).

Cebulactam A1 (3) is an 11-membered macrocyclic lactam that possesses several interesting structural features, including five stereogenic centers, an isolated trisubstituted (E)-double bond, a tetrahydropyran (THP), and a hydroquinone ring system. Synthetically, it was envisaged that the THP moiety could be regio- and stereoselectively constructed from the η-hydroxy allylic alcohol in lactam A using a transition metal-mediated O-allylation⁸ or a formal S_N2′ reaction⁹ (Fig. 2).

Fig. 2 Strategy for synthesis of cebulactam A1 (3).

The most challenging aspect of this particular approach, however, would be the development of a transformation capable of discriminating the heterotopic-faces of lactam A to allow the selective installation of the C7 stereogenic center in cebulactam A1 (3). Conformational analysis of the 3D structure of lactam A (see Fig. 2) suggested that the methyl group at the C8 chiral center could be used to control the attack of the oxygen to the extent that it would occur from the backside. This facial selectivity would allow for the stereochemistry of the THP, as well as its connected double bond could be installed regio- and stereoselectively.

The realization of this strategy would allow us to adopt the chemistry that we had developed previously for our total syntheses of Q-1047H-R-A (1) and Q-1047H-A-A (2),⁶ because the 13-membered lactam A could be formed via the SmI₂-mediated Reformatsky reaction¹⁰ from B which could in turn be derived from C, D and E with sequential chelation-controlled vinylogous Mukaiyama aldol (VMAR)¹¹ and Evans aldol¹² reactions being used as the key steps for the stereoselective construction of the four stereogenic centers at C8 and C9, C4 and C5. It was also envisaged that the C2 chiral center of cebulactam A1 (3) could be stereoselectively installed during the latter stages of the total synthesis because of its tendency to epimerize under acidic, basic or even neutral conditions.⁶ Herein, we report the stereocontrolled total synthesis of (−)-cebulactam A1 (3) according to a strategy involving the SmI₂-mediated intramolecular Reformatsky-type reaction of bromoaldehyde B to form a macrolactam, and an S_N2′ reaction for the formation of the THP moiety, as shown in Fig. 2.

Results and discussion

Synthesis of Reformatsky precursor 13

Our synthesis started with the construction of amide 13 (Scheme 1). The C8 and C9 chiral centers in compound 7b were efficiently installed using our previously developed chelation-controlled VMAR.¹³ The reaction of N,O-acetal 5^13a with aldehyde 6 under the optimized conditions^13b in the presence of TiCl₄ (1.1 equiv.) in CH₂Cl₂ afforded the anti-aldol adduct 7a and the syn-aldol adduct 7b in an isolated yield of 92% as an inseparable mixture of diastereomers (1 : 20) at the C9-position. The favored formation of 7b was rationalized according to the formation of the chelation complex A, where the formation of a 6-membered chelation complex with TiCl₄ would be preferred, leading to the formation of the syn-aldol product 7b as the major product.⁶

Scheme 1 Asymmetric synthesis of amide 13.

We then proceeded with the straightforward elaboration of compound 7b to amide 13 (Scheme 2). 7b was initially protected as its methoxymethyl (MOM) ether prior to being reduced with DIBAl-H to afford aldehyde 8, and the minor diastereoisomer generated in the first step could be separated after reduction. To allow the installation of the required chirality at the C4-position, compound 8 was subsequently reacted with Evans’ oxazolidinone 9¹² to afford 10 as a single diastereoisomer in 85% yield. Compound 10 was then protected as the corresponding TBS ether using TBSOTf/2,6-lutidine, and its nitro group subsequently reduced with NaBH₄/S₈ ¹⁴ to give the corresponding amine, which was protected with an allyloxycarbonyl (Alloc) group using AllocCl/pyridine to afford 11.

Scheme 2 Synthesis of intermediate 15.

The methyl protecting groups of the phenol moieties in substrate 11 were converted to the corresponding MOM groups via an oxidative demethylation/reduction/protection sequence. The resulting MOM protected compound was then subjected to a Pd-catalyzed deprotection reaction in the presence of 1,3-dimethylbarbituric acid to allow the removal of the Alloc group¹⁵ to give 12 in 62% yield over three steps. The reduction of 12 with DIBAl-H followed by the acylation of the aniline with 2-bromopropionyl bromide and subsequent removal of the Evans chiral auxiliary gave 13 in 71% yield over the two steps.

Completion of the total synthesis

With 13 in hand, we proceeded to evaluate its performance in the SmI₂-mediated intramolecular Reformatsky reaction.¹⁶

The treatment of 13 with SmI₂ in THF under the optimized conditions⁶ at a concentration of 0.005 M under refluxing conditions gave the desired product 14 in 84% yield as a couple of diastereoisomers. We then began to explore the remainder of the total synthesis. The annulated mixture of 14 was oxidized with IBX to afford 15 as a single diastereoisomer in 68% yield. The relative stereochemistry at C2 was not assigned at this stage, because it was envisaged that this chiral center would exist in its natural form as a consequence of the epimerization process outlined above.

To complete the total synthesis, we started to investigate the development of a method for the synthesis of the THP moiety in cebulactam A1 (3), with the proposed transition metal-mediated cyclization reaction⁸ of the η-hydroxy allylic alcohol in 17 being our preferred method (Scheme 3). A variety of different methods¹⁷ were evaluated for removal of the MOM groups in 16, but none of the desired products was obtained, and it was assumed that the resulting phenol species are unstable under the reaction conditions.

Scheme 3 Attempt to synthesise cebulactam A1 (3) from 15.

We then proceeded to develop an annulation/deprotection strategy for the formation of the THP ring using the activated η-hydroxy allylic alcohol as the substrate. The hydroxyl group in 16 was converted to the corresponding mesylate 18, which was subsequently treated with TFA in CH₂Cl₂ to induce the annulation/deprotection process. Unfortunately, however, the desired reaction did not proceed effectively under any of the reaction conditions tested, with only trace amounts of cebulactam A1 (3) being observed (Scheme 4).

Scheme 4 Completion of the total synthesis.

We then attempted to convert the hydroxy group in 16 into the corresponding triflate. Pleasingly, when alcohol 16 was added to a solution of Tf₂O in CH₂Cl₂ in the presence of pyridine at 0 °C, the THP product 19 was obtained in 71% yield via a triflation/annulation/deprotection process. To complete the total synthesis, compound 19 was treated with B-bromocatecholborane at room temperature to remove its two MOM groups and give cebulactam A1 (3) in 66% yield.

The ¹H and ¹³C NMR spectral data for the synthesized cebulactam A1 (3) were in good agreement¹⁸ with those reported for the natural material.² The optical rotation of our synthesized cebulactam A1 (3) was also determined {[α]²⁰_D = −66.1° (c 1.0 in acetone)}, although similar data were not reported in the original isolation paper.

Conclusions

The first total synthesis of (−)-cebulactam A1 (3) had been completed in 18 synthetic steps, with an overall yield of 3.2% from 2,5-dimethoxy-3-nitrobenzaldehyde 6. The key synthetic transformations involved in this synthesis include a SmI₂-mediated reductive cyclization to generate the highly functionalized 13-membered lactam 14, as well as an S_N2′ reaction to assemble the double bond connected to the THP moiety of (−)-cebulactam A1 (3).

Experimental section

General methods

Unless otherwise mentioned, all reactions were carried out under a nitrogen atmosphere using Schlenk techniques. Solvent purification was conducted according to Purification of Laboratory Chemicals (D. D. Peerrin, W. L. Armarego, and D. R. Perrins, Pergamon Press, Oxford, 1980). Compound 5 was synthesized from L-phenylglycinol according to the literature.¹⁹ Compound 6 was synthesized from 2-hydroxy-5-methoxybenzaldehyde according to the literature.²⁰ All other reagents were purchased from commercial sources and used as received. Yields refer to chromatographically and spectroscopically (¹H NMR) homogeneous materials. Reactions were monitored by thin layer chromatography on plates (GF254) supplied by Yantai Chemicals (China) using UV light as a visualizing agent and iodine as a developing agent. If not specially mentioned, flash column chromatography uses silica gel (200–300 mesh) supplied by Tsingtao Haiyang Chemicals (China).

NMR spectra were recorded on Bruker Ascend 500 and Ascend 400 instruments. TMS was used as an internal standard for ¹H NMR (0 ppm), and solvent signal was used as a reference for ¹³C NMR (CDCl₃ = δ 77.0 ppm, acetone-d₆ = δ 29.84, 206.26 ppm). The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, br = broad, dd = double doublet, m = multiplet. Infrared (IR) spectra were recorded on a Thermo Nicolet Avatar 330 FT-IR spectrometer. Mass spectra were recorded on a Bruker Apex IV FTMS mass spectrometer using ESI (electrospray ionization).

Synthesis of (S)-4-benzyl-3-((4S,5R,E)-5-(2,5-dimethoxy-3-nitrophenyl)-5-hydroxy-2,4-dimethylpent-2-enoyl)oxazolidin-2-one (7b). To a solution of aldehyde 6 (2.71 g, 12.83 mmol) in dry CH₂Cl₂ (100 mL) was slowly added TiCl₄ (7.10 mL, 1 M in CH₂Cl₂, 7.10 mmol) at −78 °C, and the mixture was stirred at the same temperature for 30 min. To this solution was added a solution of vinylketene silyl N,O-acetal 5 (2.50 g, 6.45 mmol) in CH₂Cl₂ (10 mL) at −78 °C, and the reaction mixture was warmed up to room temperature and stirred for 2 h. The reaction mixture was quenched by addition of a saturated aqueous Rochelle's salt (80 mL), and the mixture was extracted with ethyl acetate (3 × 60 mL). The combined organic layers were sequentially washed with a saturated aqueous solution of NaHCO₃ (2 × 60 mL) and brine (60 mL), and then dried over anhydrous Na₂SO₄. The solvent was removed under vacuum, and the residue was purified by flash column chromatography on silica gel (hexane–ethyl acetate–CH₂Cl₂ = 4 : 1 : 1) to give colorless oil product 7b (2.870 g, 92%). R_f = 0.25 (hexane–ethyl acetate = 2 : 1); IR v_max (neat)/cm⁻¹: 3506 (br), 2931, 1785, 1685, 1531, 1352, 1298, 1217, 1048, 995, 773, 762, 703; ¹H NMR (400 MHz, CDCl₃): δ 7.42–7.25 (m, 5H), 7.25–7.13 (m, 2H), 6.02 (dd, J = 9.3, 1.4 Hz, 1H), 5.25 (dd, J = 3.9, 3.8 Hz, 1H), 4.89–4.78 (m, 1H), 4.32 (dd, J = 8.8, 8.7 Hz, 1H), 4.20 (dd, J = 9.0, 6.5 Hz, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 3.34–3.19 (m, 2H), 3.13–2.98 (m, 1H), 2.90 (dd, J = 13.6, 1 Hz), 2.08 (d, J = 1.3 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃: δ 171.3, 155.0, 154.2, 143.8, 143.5, 143.2, 139.3, 134.7, 130.2, 129.4, 128.9, 127.4, 119.0, 108.6, 70.9, 66.3, 62.5, 55.9, 55.0, 37.9, 37.4, 13.4, 12.4; HRMS (ESI): calcd for C₂₅H₂₈N₂NaO₈ [M + Na⁺] 507.1738; found 507.1734. [α]²⁰_D = +17 (1.0, CHCl₃).

Synthesis of (S)-4-benzyl-3-((4S,5R,E)-5-(2,5-dimethoxy-3-nitrophenyl)-5-(methoxymethoxy)-2,4-dimethylpent-2-enoyl)oxazolidin-2-one (8a). To a solution of 7b (5.07 g, 10.46 mmol) in dry CH₂Cl₂ (50 mL) was added DIPEA (9.5 mL, 57.48 mmol) followed by MOMCl (3.94 mL, 52.37 mmol) at 0 °C slowly, and the mixture was then stirred at room temperature for 24 h. The reaction was quenched by addition of a saturated aqueous solution of NH₄Cl (25 mL), and the mixture was extracted with CH₂Cl₂ (3 × 25 mL). The combined organic extracts were washed with brine (25 mL), and then dried over anhydrous Na₂SO₄. The solvent was removed under vacuum, and the residue was purified by flash column chromatography on silica gel (hexane–ethyl acetate–CH₂Cl₂ = 6 : 1 : 1) to give product 8a (5.34 g, 96%) as a yellowish oil. R_f = 0.40 (hexane–ethyl acetate = 2 : 1); IR v_max (neat)/cm⁻¹: 2972, 1786, 1685, 1534, 1350, 1305, 1215, 1048, 1029, 763, 703; ¹H NMR (400 MHz, CDCl₃): δ 7.36–7.22 (m, 5H), 7.21–7.16 (m, 2H), 5.90 (dd, J = 9.9, 1.4 Hz, 1H), 4.95 (d, J = 5.5 Hz, 1H), 4.68–4.53 (m, 3H), 4.23 (dd, J = 8.8, 8.0 Hz, 1H), 4.14 (dd, J = 9.0, 4.8 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.35 (s, 3H), 3.34–3.28 (m, 1H), 2.94–2.76 (m, 2H), 1.85 (d, J = 1.4 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 171.6, 155.1, 152.7, 145.0, 143.7, 138.5, 138.2, 135.1, 131.3, 129.4, 128.9, 127.3, 119.2, 108.9, 95.3, 74.6, 66.3, 62.8, 55.9, 55.9, 55.4, 38.8, 37.5, 14.5, 13.6; HRMS (ESI): calcd for C₂₇H₃₃N₂O₉ [M + H⁺] 529.2181; found 529.2184. [α]²⁰_D= +68 (1.0, CHCl₃).

Synthesis of (4S,5R,E)-5-(2,5-dimethoxy-3-nitrophenyl)-5-(methoxymethoxy)-2,4-dimethylpent-2-enal (8). To a solution of 8a (2.00 g, 3.79 mmol) in CH₂Cl₂ (40 mL) was added DIBAl-H (1 M in toluene, 7.58 mL, 7.58 mmol) at −78 °C in a drop-wise manner, and the mixture was then stirred at the same temperature for 6 h. The reaction was quenched by addition of ethyl acetate (5 mL) at −78 °C in a drop-wise manner, and the mixture was stirred at the same temperature for an additional 1 h. To this solution was added methanol (15 mL), followed by K₂CO₃ (1.05 g, 7.58 mmol) at −78 °C, and the resulting mixture was gradually warmed up to room temperature, and then stirred for 3 h. The mixture was mixed with silica gel (10 g), and the slurry was then concentrated under vacuum to remove the solvent, and the residue was purified by flash column chromatography on silica gel (hexane–ethyl acetate–CH₂Cl₂ = 8 : 1 : 1) to give product 8 (1.05 g, 79%) as a yellowish oil. R_f = 0.51 (hexane–ethyl acetate = 2 : 1); IR v_max (neat)/cm⁻¹: 2943, 1778, 1687, 1534, 1482, 1352, 1228, 1152, 1100, 1049, 1027, 993, 830, 776; ¹H NMR (400 MHz, CDCl₃): δ 9.35 (s, 1H), 7.29 (d, J = 3.1 Hz, 1H), 7.21 (d, J = 3.2 Hz, 1H), 6.41 (dd, J = 10.1, 1.3 Hz, 1H), 4.98 (d, J = 5.9 Hz, 1H), 4.60 (d, J = 6.9 Hz, 1H), 4.55 (d, J = 6.9 Hz, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.37 (s, 3H), 3.12–3.03 (m, 1H), 1.67 (d, J = 1.4 Hz, 3H), 1.14 (d, J = 6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 195.1, 155.2, 154.8, 145.0, 143.6, 139.1, 137.7, 119.2, 108.9, 94.8, 74.0, 62.8, 56.0, 39.6, 14.8, 9.2; HRMS (ESI): calcd for C₁₇H₂₃NNaO₇ [M + Na⁺] 376.1367; found 376.1369; [α]²⁰_D= +80.4 (1.0, CHCl₃).

Synthesis of (S)-4-benzyl-3-((2S,3S,6S,7R,E)-7-(2,5-dimethoxy-3-nitrophenyl)-3-hydroxy-7-(methoxymethoxy)-2,4,6-trimethylhept-4-enoyl)oxazolidin-2-one (10). To a solution of 9 (7.33 g, 31.42 mmol) in CH₂Cl₂ (60 mL) was added a solution of Bu₂BOTf in CH₂Cl₂ (35.6 mL, 35.6 mmol, 1 M) followed by Et₃N (5.24 mL, 37.59 mmol) at 0 °C under N₂, and the mixture was stirred at the same temperature for 30 min and then cooled to −78 °C. To this solution was added a solution of 8 (7.40 g, 20.94 mmol) in CH₂Cl₂ (40 mL), and the resulting mixture was then stirred at the same temperature for 3 h before the reaction mixture was warmed up to 0 °C and stirred for 1 h. The reaction was quenched by addition of a buffer solution of phosphate salts (pH = 7, 80 mL) and MeOH (80 mL), followed by addition of a mixture of MeOH in H₂O₂ (30% aqueous solution, 1 : 2 v/v, 111 mL). The resulting slurry was then stirred vigorously at room temperature for 1 h. After removing the solvent, the reaction mixture was extracted with Et₂O (3 × 100 mL), and the combined organic extracts were washed with water (2 × 50 mL), a saturated solution of NaHCO₃ (2 × 20 mL), and brine (2 × 20 mL), then dried over Na₂SO₄. The solvent was removed under vacuum, and the residue was purified by flash column chromatography on silica gel (hexane–ethyl acetate = 2 : 1 to 1 : 1) to give product 10 (10.44 g, 85%) as a colourless oil. R_f = 0.30 (hexane–ethyl acetate = 2 : 1); IR v_max (neat)/cm⁻¹: 3498, 2938, 1778, 1701, 1533, 1362, 1210, 1099, 1031, 918, 763, 751, 738, 706, 677; ¹H NMR (400 MHz, CDCl₃): δ 7.36–7.28 (m, 3H), 7.24–7.16 (m, 4H), 5.45 (d, J = 10.2 Hz, 1H), 4.81 (d, J = 7.9 Hz, 1H), 4.72–4.62 (m, 1H), 4.55 (dd, J = 19.6, 6.8 Hz, 2H), 4.29–4.14 (m, 3H), 3.87 (s, 3H), 3.85–3.76 (m, 4H), 3.35 (s, 3H), 3.21 (dd, J = 13.4, 2.9 Hz, 1H), 2.97 (s, 1H), 2.86–2.73 (m, 2H), 1.42 (s, 3H), 1.12 (d, J = 6.5 Hz, 3H), 0.79 (d, J = 7.0 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 176.8, 155.1, 152.8, 145.1, 143.7, 139.2, 134.9, 133.8, 129.3, 128.8, 127.3, 126.9, 118.8, 108.7, 94.7, 75.1, 74.5, 66.0, 62.8, 55.9, 55.7, 55.0, 39.6, 39.2, 37.5, 17.1, 13.2, 9.5; HRMS (ESI): calcd for C₃₀H₃₈N₂NaO₁₀ [M + Na⁺] 609.2419; found 609.2423; [α]²⁰_D = +63.7 (1.0, CHCl₃).

Synthesis of (S)-4-benzyl-3-((2S,3S,6S,7R,E)-3-((tert-butyldimethylsilyl)oxy)-7-(2,5-dimethoxy-3-nitrophenyl)-7-(methoxymethoxy)-2,4,6-trimethylhept-4-enoyl)oxazolidin-2-one (11a). To a solution of 10 (17.96 g, 30.62 mmol) in dry CH₂Cl₂ (100 mL) was added 2,6-lutidine (7.13 mL, 61.23 mmol) and TBSOTf (10.50 L, 45.72 mmol) at 0 °C, and the mixture was stirred at room temperature until the consumption of substrate indicated by TLC. The reaction was quenched by addition of a saturated aqueous solution of NH₄Cl (100 mL), and the mixture was extracted with CH₂Cl₂ (3 × 100 mL). The combined organic extracts were sequentially washed with HCl (2 × 100 mL, 1 N) and brine (100 mL), and finally dried over anhydrous Na₂SO₄. The solvent was removed under vacuum, and the residue was purified by flash column chromatography on silica gel (hexane–ethyl acetate = 8 : 1 to 4 : 1) to give product 11a (19.23 g, 90%) as a colourless oil. R_f = 0.68 (hexane–ethyl acetate = 1 : 1); IR v_max (neat)/cm⁻¹: 2956, 2927, 2359, 1781, 1700, 1534, 1362, 1211, 1103, 1032, 844, 838, 777, 722, 685; ¹H NMR (400 MHz, CDCl₃): δ 7.37–7.27 (m, 3H), 7.25 (d, J = 3.2 Hz, 1H), 7.20 (d, J = 7.2 Hz, 2H), 7.17 (d, J = 3.1 Hz, 1H), 5.30 (d, J = 10.0 Hz, 1H), 4.81 (d, J = 7.3 Hz, 1H), 4.52 (dd, J = 16.7, 6.9 Hz, 3H), 4.21–4.05 (m, 3H), 4.00–3.91 (m, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 3.35 (s, 3H), 3.24 (dd, J = 13.3, 2.6 Hz, 1H), 2.87–2.70 (m, 2H), 0.99 (d, J = 6.3 Hz, 6H), 0.84 (s, 9H), −0.11 (s, 3H), −0.27 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 174.7, 155.1, 152.9, 145.4, 143.8, 138.9, 135.9, 135.2, 129.4, 128.9, 127.8, 127.3, 119.1, 109.0, 94.8, 77.6, 75.0, 65.8, 62.8, 55.9, 55.6, 42.1, 38.6, 37.6, 25.7, 17.9, 16.8, 12.1, 11.9, −5.0, −5.7; HRMS (ESI): calcd for C₃₆H₅₂N₂NaO₁₀Si [M + Na⁺] 723.3283; found 723.3272; [α]²⁰_D = +64.0 (1.0, CHCl₃).

Synthesis of (S)-3-((2S,3S,6S,7R,E)-7-(3-amino-2,5-dimethoxyphenyl)-3-((tert-butyldimethylsilyl)oxy)-7-(methoxymethoxy)-2,4,6-trimethylhept-4-enoyl)-4-benzyloxazolidin-2-one (11b). To a mixture of NaBH₄ (0.480 g, 12.70 mmol) and S₈ (1.63 g, 50.84 mmol) was added THF (50 mL) in a drop-wise manner, and the mixture was stirred at room temperature for 30 min. To this solution was added a solution of 11a (1.484 g, 2.12 mmol) in THF (10 mL), and the mixture was stirred at 65 °C for 30 min. After cooling to room temperature, the reaction was quenched by addition of aqueous solution of NaOH (2 N, 30 mL), followed by addition of H₂O (30 mL). The mixture was extracted with Et₂O (2 × 30 mL) and ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (2 × 25 mL), and then dried over anhydrous Na₂SO₄. The solvent was removed under vacuum, and the residue was purified by flash column chromatography on silica gel (hexane–ethyl acetate = 4 : 1 to 2 : 1) to give product 11b (1.242 g, 87%) as a yellowish oil. R_f = 0.48 (hexane–ethyl acetate = 2 : 1); IR v_max (neat)/cm⁻¹: 2955, 1781, 1700, 1616, 1495, 1380, 1210, 1034, 837, 776, 761, 679; ¹H NMR (400 MHz, CDCl₃): δ 7.37–7.25 (m, 3H), 7.20 (d, J = 7.1 Hz, 2H), 6.24 (s, 1H), 6.17 (d, J = 2.4 Hz, 1H), 5.33 (d, J = 9.8 Hz, 1H), 4.72 (d, J = 7.6 Hz, 1H), 4.59–4.44 (m, 3H), 4.21–4.04 (m, 3H), 4.00–3.88 (m, 1H), 3.70 (d, J = 4.5 Hz, 8H), 3.38 (s, 3H), 3.23 (d, J = 13.1 Hz, 1H), 2.87–2.69 (m, 2H), 1.53 (s, 3H), 1.02 (d, J = 6.5 Hz, 3H), 0.97 (d, J = 6.6 Hz, 3H), 0.86 (s, 9H), −0.10 (s, 3H), −0.21 (s, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 174.9, 156.5, 152.9, 140.5, 140.2, 135.3, 134.7, 134.4, 129.4, 129.1, 128.9, 127.3, 101.4, 101.3, 94.2, 77.9, 75.4, 65.8, 59.7, 55.7, 55.6, 55.3, 42.2, 38.6, 37.6, 25.7, 18.0, 17.1, 11.9, 11.8, −4.9, −5.7. HRMS (ESI): calcd for C₃₆H₅₄N₂NaO₈Si [M + Na⁺] 693.3542; found 693.3531. [α]²⁰_D = +68.3 (1.0, CHCl₃).

Synthesis of allyl(3-((5R,6S,9S,E)-9-((S)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-1-oxopropan-2-yl)-6,8,11,11,12,12-hexamethyl-2,4,10-trioxa-11-silatridec-7-en-5-yl)-2,5-dimethoxyphenyl)carbamate (11). To a solution of 11b (7.47 g, 11.13 mmol) and pyridine (1.17 mL, 14.46 mmol) in anhydrous THF (50 mL) was added a solution of allyl chloroformate (1.52 mL, 14.44 mmol) in THF (10 mL) at 0 °C in a drop-wise manner, and the reaction mixture was then warmed up to room temperature, and stirred for 20 min. The reaction was worked up by filtration of the reaction mixture through a silica gel pad, and the filtrate was concentrated under vacuum, and the silica gel pad was washed with ether (50 mL). The combined filtrate was washed with brine (2 × 10 mL), and then dried over anhydrous Na₂SO₄. The solvent was removed under vacuum, and the residue was purified by flash column chromatography on silica gel (hexane–ethyl acetate = 8 : 1 to 4 : 1) to give product 11 (8.357 g, 85%) as a colourless oil. R_f = 0.60 (hexane–ethyl acetate = 2 : 1); IR v_max (neat)/cm⁻¹: 3428 (br), 2952, 1781, 1736, 1524, 1463, 1361, 1235, 1212, 1032, 839, 776, 703, 678; ¹H NMR (400 MHz, CDCl₃): δ 7.63 (s, 1H), 7.36–7.26 (m, 3H), 7.23–7.12 (m, 3H), 6.56 (d, J = 3.0 Hz, 1H), 6.06–5.93 (m, 1H), 5.38 (dd, J = 17.2, 1.3 Hz, 1H), 5.32–5.24 (m, 2H), 4.73–4.65 (m, 3H), 4.56–4.47 (m, 3H), 4.18–4.06 (m, 3H), 3.97–3.87 (m, 1H), 3.76 (s, 3H), 3.73 (s, 3H), 3.37 (s, 3H), 3.23 (dd, J = 13.3, 2.6 Hz, 1H), 2.86–2.72 (m, 2H), 1.51 (s, 3H), 1.03 (d, J = 6.6 Hz, 3H), 0.97–0.90 (m, 3H), 0.85 (s, 9H), −0.12 (s, 3H), −0.25 (s, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 174.7, 156.3, 152.9, 152.9, 140.6, 135.2, 135.0, 134.3, 132.3, 131.8, 129.3, 128.8, 128.4, 127.2, 118.1, 106.8, 103.8, 93.9, 77.6, 75.1, 65.7, 61.1, 55.6, 55.5, 55.4, 42.0, 38.8, 37.5, 25.6, 17.9, 17.2, 11.8, −5.0, −5.8; HRMS (ESI): calcd for C₄₀H₅₈N₂NaO₁₀Si [M + Na⁺] 777.3753; found 777.3777; [α]²⁰_D = +50.3 (1.0, CHCl₃).

Synthesis of allyl(3-((5R,6S,9S,E)-9-((S)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-1-oxopropan-2-yl)-6,8,11,11,12,12-hexamethyl-2,4,10-trioxa-11-silatridec-7-en-5-yl)-2,5-bis(methoxymethoxy)phenyl)carbamate (12a). To a solution of 11 (6.588 g, 8.73 mmol) in a mixed solvent of CH₃CN and H₂O (1 : 1, 200 mL) was added a solution of CAN (19.8 g, 36.11 mmol) in a mixed solvent of CH₃CN and H₂O (1 : 1, 50 mL) at 0 °C, and the mixture was then stirred at the same temperature for 30 min. The reaction was worked up by addition of Na₂S₂O₄ (13.67 g, 78.51 mmol) and NaHCO₃ (4.40 g, 52.37 mmol), and the reaction mixture was warmed up to room temperature, and stirred for an additional 10 min. To this mixture was added H₂O (100 mL), and the mixture was then extracted with Et₂O (3 × 100 mL), and the combined organic extracts were washed with brine (2 × 50 mL), and finally dried over anhydrous MgSO₄. The solvent was removed under vacuum, and the residue was dissolved in dry CH₂Cl₂ (100 mL) and the formed mixture was cooled to 0 °C. To this solution were added iPr₂NEt (15.8 mL, 95.59 mmol) and MOMCl (6.54 mL, 86.93 mmol), and the formed mixture was stirred at room temperature overnight. The reaction was quenched by addition of a saturated aqueous solution of NH₄Cl (60 mL), and the mixture was then extracted with CH₂Cl₂ (3 × 60 mL). The combined organic extracts were first washed with brine (2 × 20 mL), and then dried over anhydrous Na₂SO₄. The solvent was removed under vacuum, and the residue was purified by flash column chromatography on silica gel (hexane–ethyl acetate = 8 : 1 to 4 : 1) to give product 12a (5.05 g, 71%) as a colourless oil. R_f = 0.65 (hexane–ethyl acetate = 2 : 1); IR v_max (neat)/cm⁻¹: 3649, 3423 (br), 2957, 1785, 1741, 1540, 1473, 1455, 1209, 1076, 1029, 966, 837, 762; ¹H NMR (400 MHz, CDCl₃): δ 7.95 (s, 1H), 7.74 (s, 1H), 7.37–7.27 (m, 3H), 7.20 (d, J = 7.1 Hz, 2H), 6.68 (d, J = 2.8 Hz, 1H), 6.13–5.82 (m, 1H), 5.36 (dd, J = 17.2, 1.2 Hz, 1H), 5.29–5.21 (m, 2H), 5.12 (dd, J = 14.8, 6.6 Hz, 2H), 5.02 (d, J = 6.0 Hz, 1H), 4.90 (d, J = 6.0 Hz, 1H), 4.66 (d, J = 5.4 Hz, 2H), 4.59 (d, J = 8.1 Hz, 1H), 4.57–4.49 (m, 1H), 4.48 (s, 2H), 4.18–4.06 (m, 3H), 3.93–3.85 (m, 1H), 3.63 (s, 3H), 3.45 (s, 3H), 3.33 (s, 3H), 3.24 (dd, J = 13.3, 2.5 Hz, 1H), 2.89–2.70 (m, 2H), 1.49 (s, 3H), 1.01 (d, J = 6.6 Hz, 3H), 0.89 (d, J = 6.7 Hz, 3H), 0.86 (s, 9H), −0.13 (s, 3H), −0.24 (s, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 174.8, 154.2, 153.1, 152.9, 140.4, 135.3, 135.1, 134.9, 132.6, 132.5, 129.4, 128.9, 128.3, 127.3, 117.7, 100.7, 94.7, 94.3, 65.9, 65.6, 57.4, 55.9, 55.7, 55.7, 42.1, 38.7, 37.6, 25.8, 18.1, 17.4, 11.9, 11.6, −4.9, −5.7; HRMS (ESI): calcd for C₄₂H₆₂N₂NaO₁₂Si [M + Na⁺] 837.3964; found 837.3966; [α]²⁰_D = +62.7 (1.0, CHCl₃).

Synthesis of (S)-3-((2S,3S,6S,7R,E)-7-(3-amino-2,5-bis(methoxymethoxy)phenyl)-3-hydroxy-7-(methoxymethoxy)-2,4,6-trimethylhept-4-enoyl)-4-benzyloxazolidin-2-one (12). To a solution of 12a (2.685 g, 3.29 mmol) in anhydrous THF (40 mL) were added 1,3-dimethylbarbituric acid (0.57 g, 3.62 mmol) and Pd(PPh₃)₄ (190 mg, 0.16 mmol), and the reaction mixture was stirred at room temperature for 30 min. The reaction was quenched by removal of the solvent under vacuum, and the residue was dissolved in CH₂Cl₂ (40 mL), and the organic phase was washed with a saturated aqueous solution of NaHCO₃ (2 × 20 mL), and then dried over anhydrous Na₂SO₄. The solvent was removed under vacuum, and the residue was purified by flash column chromatography on silica gel (hexane–ethyl acetate = 4 : 1 to 2 : 1) to give product 12 (2.087 g, 87%) as a colourless oil. R_f = 0.53 (hexane–ethyl acetate = 2 : 1); IR v_max (neat)/cm⁻¹: 2930, 1781, 1701, 1618, 1491, 1454, 1361, 1210, 1149, 1074, 1029, 968, 838, 778, 703; ¹H NMR (400 MHz, CDCl₃): δ 7.41–7.31 (m, 3H), 7.25 (d, J = 7.8 Hz, 2H), 6.42 (d, J = 1.4 Hz, 1H), 6.37 (d, J = 2.6 Hz, 1H), 5.38 (d, J = 10.0 Hz, 1H), 5.15–5.07 (m, 2H), 4.98 (dd, J = 22.7, 5.7 Hz, 2H), 4.73 (d, J = 7.5 Hz, 1H), 4.62–4.49 (m, 3H), 4.27–4.11 (m, 3H), 4.03 (s, 2H), 4.00–3.93 (m, 1H), 3.66 (s, 3H), 3.48 (s, 3H), 3.41 (s, 3H), 3.30 (d, J = 13.0 Hz, 1H), 2.94–2.76 (m, 2H), 1.58 (s, 3H), 1.05 (d, J = 6.6 Hz, 3H), 1.00 (d, J = 6.7 Hz, 3H), 0.92 (s, 9H), −0.04 (s, 3H), −0.14 (s, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 174.8, 154.4, 152.9, 140.8, 138.6, 135.3, 135.2, 134.6, 129.4, 128.9, 127.3, 104.5, 103.2, 99.5, 94.6, 94.2, 77.6, 75.8, 65.8, 57.2, 55.7, 55.7, 55.6, 42.1, 38.4, 37.6, 25.7, 18.0, 17.1, 11.8, 11.6, −4.9, −5.7; HRMS (ESI): calcd for C₃₈H₅₉N₂O₁₀Si [M + H⁺] 731.3934; found 731.3951. [α]²⁰_D = +61.9 (1.0, CHCl₃).

Synthesis of 2-bromo-N-(3-((5R,6S,9S,E)-6,8,11,11,12,12-hexamethyl-9-((S)-1-oxopropan-2-yl)-2,4,10-trioxa-11-silatridec-7-en-5-yl)-2,5-bis(methoxymethoxy)phenyl)-propanamide (13). To a solution of 12 (4.544 g, 6.22 mmol) in dry CH₂Cl₂ (100 mL) was added a solution of DIBAL in CH₂Cl₂ (1 M solution, 18.6 mL, 18.6 mmol) at −78 °C slowly, and the reaction mixture was stirred at the same temperature for 3 h. To this solution was added 2-bromopropionyl bromide (1.433 mL, 13.67 mmol), and the mixture was stirred at the same temperature for 10 min. The reaction mixture was quenched by addition of a saturated aqueous Rochelle's salt (50 mL), and the resulting mixture was stirred at room temperature for 2 h and then extracted with ethyl acetate (3 × 60 mL). The combined organic extracts were washed with brine (2 × 30 mL), and then dried over anhydrous Na₂SO₄. Then the solvent was removed under vacuum, and the residue was dissolved in a mixed solvent of CH₂Cl₂ and MeOH (1 : 1, 60 mL). To this mixture was added NaHCO₃ (1.04 g, 12.38 mmol) at room temperature, and the resulting mixture was stirred at the same temperature for 5 h. The reaction was worked up by removal of the solvent under vacuum, and the residue was purified by flash column chromatography on silica gel (hexane–ethyl acetate = 8 : 1 to 4 : 1) to give product 13 (3.055 g, 71%) as a colourless oil. R_f = 0.70, 0.72 (hexane–ethyl acetate = 1 : 1); IR v_max (neat)/cm⁻¹: 3344 (br), 2931, 2855, 1702, 1604, 1534, 1453, 1398, 1152, 1101, 1030, 960, 837, 777; ¹H NMR (400 MHz, CDCl₃): δ 9.56 (d, J = 1.3 Hz, 1H), 9.01 (s, 1H), 7.98 (d, J = 2.8 Hz, 1H), 6.77 (d, J = 2.8 Hz, 1H), 5.28 (d, J = 10.1 Hz, 1H), 5.17–5.03 (m, 3H), 4.91 (d, J = 5.7 Hz, 1H), 4.61 (d, J = 8.4 Hz, 1H), 4.52–4.42 (m, 3H), 4.19 (d, J = 4.5 Hz, 1H), 3.62 (s, 3H), 3.43 (s, 3H), 3.32 (s, 3H), 2.88–2.75 (m, 1H), 2.34–2.23 (m, 1H), 1.92 (d, J = 7.0 Hz, 3H), 1.42 (s, 3H), 1.08 (d, J = 6.5 Hz, 3H), 0.82 (s, 9H), 0.70 (d, J = 6.8 Hz, 3H), −0.10 (s, 3H), −0.20 (s, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 204.5, 167.3, 153.9, 140.7, 134.9, 134.6, 131.8, 128.1, 110.5, 108.3, 100.9, 94.6, 94.2, 76.4, 75.8, 57.7, 55.9, 55.6, 50.4, 44.7, 39.1, 25.7, 22.4, 17.9, 17.5, 12.8, 7.7, −4.7, −5.6; HRMS (ESI): calcd for C₃₁H₅₂BrNNaO₉Si [M + Na⁺] 712.2487; found 712.2493.

Synthesis of (6R,7S,10S,11R,E)-7-((tert-butyldimethylsilyl)oxy)-5-hydroxy-1²,1⁵,11-tris(methoxymethoxy)-4,6,8,10-tetramethyl-2-aza-1(1,3)-benzenacycloundecaphan-8-en-3-one (14). To a solution of SmI₂ (99 mL, 0.1 M in THF, 9.90 mmol) in reflux anhydrous THF (100 mL) was added 13 (1.14 g, 1.65 mmol) in THF (10 mL) in a drop-wise manner, and the reaction mixture was stirred at the same temperature for 2 h. The reaction was quenched by addition of a saturated aqueous solution of NH₄Cl (100 mL) at room temperature followed by extraction with ethyl acetate (3 × 100 mL). The combined organic extracts were washed with brine (2 × 20 mL), and then dried over anhydrous Na₂SO₄. The solvent was removed under vacuum, and the residue was purified by flash column chromatography on silica gel (hexane–ethyl acetate = 2 : 1 to 1 : 1) to give product 14 (0.85 g, 84%) as a mixture of diastereoisomers. R_f = 0.22, 0.24 (hexane–ethyl acetate = 1 : 1); IR v_max (neat)/cm⁻¹: 2953, 2901, 2363, 1659, 1473, 1401, 1249, 1150, 1073, 1028, 966, 923, 835, 774; ¹H NMR (400 MHz, CDCl₃): δ 7.49 (s, 1H), 7.11 (d, J = 2.9 Hz, 1H), 6.87 (d, J = 2.9 Hz, 1H), 5.44 (d, J = 10.7 Hz, 1H), 5.14 (dd, J = 15.9, 6.8 Hz, 2H), 5.05 (d, J = 6.0 Hz, 1H), 4.78 (d, J = 6.0 Hz, 1H), 4.62 (s, 2H), 4.58 (d, J = 9.9 Hz, 1H), 3.56 (s, 3H), 3.45 (s, 3H), 3.41–3.35 (m, 4H), 3.05–2.93 (m, 2H), 2.64–2.55 (m, 1H), 2.51–2.40 (m, 2H), 1.29 (s, 3H), 1.22 (d, J = 7.2 Hz, 3H), 1.19 (d, J = 6.5 Hz, 3H), 1.00 (d, J = 7.0 Hz, 3H), 0.88 (s, 9H), −0.04 (s, 3H), −0.10 (s, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 178.3, 153.8, 146.7, 138.5, 138.2, 131.1, 127.9, 115.1, 113.7, 100.5, 95.0, 94.7, 79.4, 76.4, 71.5, 57.3, 55.9, 55.8, 46.7, 42.2, 40.5, 25.9, 18.1, 17.9, 16.5, 14.1, 12.7, −4.4, −5.2; HRMS (ESI): calcd for C₃₁H₅₄NO₉Si [M + H⁺] 612.3562; found 612.3571; [α]²⁰_D = +36.5 (1.0, CHCl₃).

Synthesis of (4R,6S,7S,10S,11R,E)-7-((tert-butyldimethylsilyl)oxy)-1²,1⁵,11-tris(methoxymethoxy)-4,6,8,10-tetramethyl-2-aza-1(1,3)-benzenacycloundecaphan-8-ene-3,5-dione (15). To a solution of 14 (865 mg, 1.41 mmol) in DMSO (10 mL) was added IBX (850 mg, 3.08 mmol) at room temperature, and the mixture was then stirred at the same temperature until substrate 14 disappeared as monitored by TLC. Then Et₂O (40 mL) was added and the mixture was washed with H₂O (3 × 25 mL). The aqueous phase was extracted with a mixed solvent of Et₂O and hexane (1 : 1, 3 × 80 mL). The combined organic extracts were washed with brine (2 × 30 mL), and then dried over anhydrous Na₂SO₄. The solvent was removed under vacuum, and the residue was purified by flash column chromatography on silica gel (hexane–ethyl acetate = 2 : 1 to 1 : 1) to give product 15 (593 mg, 68%) as white solids. R_f = 0.70 (hexane–ethyl acetate = 1 : 1); IR v_max (neat)/cm⁻¹: 3676, 2989, 2971, 2901, 2357, 1405, 1394, 1250, 1241, 1076, 1066, 1028 m, 879, 837, 742, 683; ¹H NMR (400 MHz, CDCl₃): δ 8.37 (s, 1H), 7.17 (d, J = 2.9 Hz, 1H), 6.83 (d, J = 2.9 Hz, 1H), 5.68 (d, J = 10.9 Hz, 1H), 5.12 (dd, J = 23.8, 6.8 Hz, 2H), 4.97 (d, J = 5.9 Hz, 1H), 4.88 (d, J = 5.8 Hz, 1H), 4.65–4.57 (m, 3H), 3.64–3.57 (m, 4H), 3.41 (s, 3H), 3.37 (s, 3H), 2.94 (dq, J = 13.6, 6.7 Hz, 1H), 2.81 (q, J = 6.8 Hz, 1H), 2.44–2.32 (m, 1H), 1.17–1.12 (m, 6H), 1.08 (d, J = 6.7 Hz, 3H), 0.89 (s, 9H), 0.88 (s, 3H), 0.00 (s, 3H), −0.10 (s, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 209.2, 174.8, 153.9, 146.9, 138.5, 136.7, 131.6, 128.7, 116.5, 114.8, 100.4, 95.1, 94.6, 76.3, 57.3, 55.9, 55.8, 53.7, 51.4, 42.2, 25.8, 18.1, 18.0, 16.3, 15.5, 12.6, −4.6, −5.2; HRMS (ESI): calcd for C₃₁H₅₂NO₉Si [M + H⁺] 610.34059; found 610.34212; [α]²⁰_D= +75.3 (1.0, CHCl₃).

Synthesis of (4R,6S,7S,10S,11R,E)-7-hydroxy-1²,1⁵,11-tris(methoxymethoxy)-4,6,8,10-tetramethyl-2-aza-1(1,3)-benzenacycloundecaphan-8-ene-3,5-dione (16). To a solution of 15 (137 mg, 0.22 mmol) in anhydrous THF (6 mL) was added a solution of HF–pyridine (0.2 mL, HF ∼ 70%, pyridine ∼ 30%) at room temperature, and the reaction mixture was then stirred at 40 °C until the substrate disappeared as indicated by TLC. The reaction was quenched by slow addition of a saturated solution of NaHCO₃ (5 mL) at room temperature followed by extraction with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with brine (20 mL), and then dried over anhydrous Na₂SO₄. The solvent was removed under vacuum, and the residue was purified by flash column chromatography on silica gel (hexane–ethyl acetate = 2 : 1 to 1 : 2) to give product 16 (49 mg, 71%) as a colourless oil. R_f = 0.45 (hexane–ethyl acetate = 1 : 2); IR v_max (neat)/cm⁻¹: 2989, 2901, 2364, 1716, 1669, 1457, 1404, 1150, 1077, 1041, 960, 759, 753, 725, 687, 681; ¹H NMR (500 MHz, CDCl₃): δ 7.59 (s, 1H), 7.17 (d, J = 3.0 Hz, 1H), 6.82 (d, J = 3.0 Hz, 1H), 5.60 (d, J = 10.7 Hz, 1H), 5.18–5.08 (m, 3H), 4.82 (d, J = 6.2 Hz, 1H), 4.62 (s, 2H), 4.58 (d, J = 10.0 Hz, 1H), 3.80 (d, J = 9.1 Hz, 1H), 3.61 (s, 3H), 3.44 (s, 3H), 3.37 (s, 3H), 3.09–3.01 (m, 1H), 2.94–2.86 (m, 1H), 2.51–2.38 (m, 1H), 1.24 (d, J = 6.9 Hz, 3H), 1.21–1.16 (m, 6H), 0.97 (s, 3H); ¹³C NMR (126 MHz, CDCl₃): δ 208.7, 173.7, 154.0, 147.1, 138.4, 137.9, 131.7, 127.5, 116.4, 114.7, 100.7, 95.0, 94.6, 76.1, 57.4, 55.9, 55.8, 50.7, 42.0, 29.7, 18.2, 15.5, 12.9; HRMS (ESI): calcd for C₂₅H₃₈NO₉ [M + H⁺] 496.2541; found 496.2539; [α]²⁰_D = +108.3 (1.0, CHCl₃).

Synthesis of (4R,6S,7S,10S,11R,E)-1²,1⁵,11-tris(methoxymethoxy)-4,6,8,10-tetramethyl-3,5-dioxo-2-aza-1(1,3)-benzenacycloundecaphan-8-en-7-yl methanesulfonate (18). To a solution of 16 (136 mg, 0.27 mmol) and Et₃N (77 μL, 0.54 mmol) in CH₂Cl₂ (5 mL) was added methanesulfonyl chloride (32 μL, 0.41 mmol) at 0 °C in a drop-wise manner, and the reaction mixture was then stirred at room temperature for 20 min. The reaction was quenched by addition of a saturated aqueous solution of NH₄Cl (5 mL), and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with brine (2 × 5 mL), and then dried over anhydrous Na₂SO₄. The solvent was removed under vacuum, and the residue was purified by flash column chromatography on silica gel (hexane–ethyl acetate = 2 : 1 to 1 : 1) to give product 18 (108 mg, 69%) as a colourless oil. R_f = 0.68 (CH₂Cl₂–MeOH = 10 : 1); IR v_max (neat)/cm⁻¹: 2930, 1719, 1676, 1672, 1654, 1363, 1176, 1150, 1026, 947; ¹H NMR (400 MHz, CDCl₃): δ 7.58 (s, 1H), 7.16 (d, J = 3.0 Hz, 1H), 6.83 (d, J = 3.0 Hz, 1H), 5.72 (d, J = 10.7 Hz, 1H), 5.19–5.08 (m, 3H), 4.81 (d, J = 6.2 Hz, 1H), 4.64–4.55 (m, 3H), 3.61 (s, 3H), 3.44 (s, 3H), 3.37 (s, 3H), 3.17–3.10 (m, 1H), 3.01 (q, J = 6.9 Hz, 1H), 2.91 (s, 3H), 2.50–2.38 (m, 1H), 1.27 (d, J = 7.0 Hz, 3H), 1.24 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 6.4 Hz, 3H), 1.07 (d, J = 1.0 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃): δ 206.56, 173.34, 154.29, 146.80, 138.2, 133.06, 131.68, 131.35, 116.27, 114.56, 100.92, 95.01, 94.6, 85.6, 75.8, 57.5, 55.9, 55.9, 51.5, 51.2, 42.3, 38.9, 17.7, 15.8, 15.8, 13.4; HRMS (ESI): calcd for C₂₆H₄₀NO₁₁S [M + H⁺] 574.2317; found 574.2313; [α]²⁰_D = +81.4 (1.0, CHCl₃).

Total synthesis of cebulactam A1 (3) from 18. To a solution of 18 (5.4 mg, 0.009 mmol) in anhydrous CH₂Cl₂ (1.5 mL) was added trifluoroacetic acid (0.5 mL) at room temperature in a drop-wise manner, and the mixture was stirred at the same temperature until substrate 18 disappeared as indicated by TLC. The reaction was worked up by removal of the solvent under vacuum, and the residue was purified by preparative TLC (hexane–ethyl acetate = 1 : 2) to give trace amounts of product 3 as yellowish solids. R_f = 0.35 (hexane–ethyl acetate = 1 : 2); IR v_max (neat)/cm⁻¹: 3675, 3263, 2989, 2901, 2355, 1714, 1652, 1602, 1394, 1250, 1066, 879, 870, 783, 694, 679; ¹H NMR (400 MHz, D6-acetone) δ 8.33 (s, 1H), 7.91 (s, 1H), 7.02 (d, J = 2.8 Hz, 1H), 6.65 (d, J = 2.8 Hz, 1H), 5.00 (dd, J = 10.0, 1.0 Hz, 1H), 4.80 (d, J = 6.4 Hz, 1H), 4.38 (dd, J = 10.0, 6.4 Hz, 1H), 4.27 (d, J = 8.5 Hz, 1H), 3.42 (q, J = 6.8 Hz, 1H), 3.22–3.15 (m, 1H), 1.87 (d, J = 1.6 Hz, 3H), 1.85–1.77 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H), 1.20 (d, J = 6.4 Hz, 3H), 1.01 (d, J = 7.2 Hz, 3H); HRMS (ESI): calcd for C₁₉H₂₄NO₅ [M + H⁺] 346.1649; found 346.1654.

Synthesis of (2R,5S,7R,14R,15S,E)-11,14-bis(methoxymethoxy)-3,5,7,15-tetramethyl-2,5-dihydro-13,2-ethanobenzo[b][1]oxa[4]azacycloundecine-6,8(7H,9H)-dione (19). To a solution of pyridine (40.4 μL, 0.50 mmol) and Tf₂O (22 μL, 0.13 mmol) in CH₂Cl₂ (5 mL) was added a solution of 16 (32 mg, 0.065 mmol) in CH₂Cl₂ (3 mL) at 0 °C slowly, and the reaction mixture was then stirred at the same temperature for 10 min. The reaction was quenched by addition of a saturated aqueous solution of NaHCO₃ (10 mL) followed by extraction with CH₂Cl₂ (3 × 10 mL). The combined organic extracts were washed with brine (20 mL), and then dried over anhydrous Na₂SO₄. The solvent was removed under vacuum, and the residue was purified by flash column chromatography on silica gel (hexane–ethyl acetate = 4 : 1 to 2 : 1) to give product 19 (20.2 mg, 71%) as a colourless oil. R_f = 0.70 (hexane–ethyl acetate = 1 : 2); IR v_max (neat)/cm⁻¹: 3694, 2968, 2931, 2360, 1718, 1683, 1482, 1378, 1147, 1079, 1028, 738, 735, 708, 683; ¹H NMR (500 MHz, CDCl₃): δ 7.08 (d, J = 2.5 Hz, 1H), 6.87–6.81 (m, 2H), 5.19 (d, J = 6.9 Hz, 1H), 5.12 (d, J = 6.9 Hz, 1H), 4.94 (q, J = 6.7 Hz, 2H), 4.71 (d, J = 9.4 Hz, 1H), 4.43 (d, J = 10.5 Hz, 1H), 4.30 (d, J = 8.2 Hz, 1H), 3.55 (s, 3H), 3.48 (s, 3H), 3.35 (q, J = 6.8 Hz, 1H), 3.33–3.25 (m, 1H), 1.96–1.85 (m, 4H), 1.35 (d, J = 6.8 Hz, 3H), 1.23 (d, J = 6.5 Hz, 3H), 1.02 (d, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃): δ 205.7, 172.8, 153.1, 143.1, 139.7, 137.1, 129.2, 123.3, 114.3, 111.3, 97.5, 95.2, 86.3, 75.9, 56.5, 56.0, 46.5, 45.3, 40.4, 18.7, 17.1, 16.00, 15.8; HRMS (ESI): calcd for C₂₃H₃₂NO₇ [M + H⁺] 434.2173; found 434.2185; [α]²⁰_D= −8.2 (1.0, CHCl₃).

Total synthesis of cebulactam A1 (3) from 19. To a solution of 19 (10 mg, 0.023 mmol) in anhydrous CH₂Cl₂ (3 mL) was added B-bromocatecholborane (0.23 mL, 0.046 mmol, 0.2 M in CH₂Cl₂) at room temperature in a drop-wise manner, and the reaction mixture was stirred at the same temperature until the substrate 19 disappeared indicated by TLC. The reaction was worked up by addition of H₂O (2 mL), and the mixture was first stirred for 20 min followed by extraction with CH₂Cl₂ (3 × 5 mL). The combined organic extracts were washed with brine (2 × 5 mL), and then dried over anhydrous Na₂SO₄. The solvent was removed under vacuum, and the residue was purified by preparative TLC (hexane–ethyl acetate = 1 : 2) to give product 3 (5.3 mg, 66%) as yellowish solids. R_f = 0.35 (hexane–ethyl acetate = 1 : 2); IR v_max (neat)/cm⁻¹: 3675, 3263, 2989, 2901, 2355, 1714, 1652, 1602, 1394, 1250, 1066, 879, 870, 783, 694, 679; ¹H NMR (500 MHz, acetone) δ 8.24 (s, 1H), 7.84 (s, 1H), 7.02 (d, J = 2.5 Hz, 1H), 6.65 (d, J = 3.0 Hz, 1H), 4.98 (d, J = 10.0 Hz, 1H), 4.72 (d, J = 6.5 Hz, 1H), 4.39 (dd, J = 10.5, 6.0 Hz, 1H), 4.27 (d, J = 8.0 Hz, 1H), 3.42 (q, J = 7.0 Hz, 1H), 3.22–3.16 (m, 1H), 1.87 (d, J = 1.0 Hz, 3H), 1.85–1.78 (m, 1H), 1.23 (d, J = 6.5 Hz, 3H), 1.20 (d, J = 6.5 Hz, 3H), 1.01 (d, J = 7.0 Hz, 3H); ¹³C NMR (126 MHz, D6-acetone) δ 206.5, 173.4, 153.9, 142.3, 140.4, 139.9, 130.5, 124.3, 113.6, 110.6, 86.9, 70.5, 47.8, 45.6, 41.9, 18.8, 17.3, 16.2, 16.2; ¹H NMR (400 MHz, D6-acetone): δ 8.33 (s, 1H), 7.91 (s, 1H), 7.02 (d, J = 2.8 Hz, 1H), 6.65 (d, J = 2.8 Hz, 1H), 5.00 (dd, J = 10.0, 1.0 Hz, 1H), 4.80 (d, J = 6.4 Hz, 1H), 4.38 (dd, J = 10.0, 6.4 Hz, 1H), 4.27 (d, J = 8.5 Hz, 1H), 3.42 (q, J = 6.8 Hz, 1H), 3.22–3.15 (m, 1H), 1.87 (d, J = 1.6 Hz, 3H), 1.85–1.77 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H), 1.20 (d, J = 6.4 Hz, 3H), 1.01 (d, J = 6.8 Hz, 3H); ¹³C NMR (100 MHz, D6-acetone) δ 206.5, 173.4, 153.9, 142.3, 140.4, 139.9, 130.5, 124.3, 113.6, 110.6, 86.9, 70.5, 47.8, 45.6, 41.9, 18.8, 17.3, 16.2, 16.1; HRMS (ESI): calcd for C₁₉H₂₄NO₅ [M + H⁺] 346.1649; found 346.1654. [α]²⁰_D = −66.1 (1.0, acetone).

Acknowledgements

This work has been supported by the National Science Foundation of China (21072006, 21072011 and 21272015), and National 863 Program (S2013AA090203).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3qo00036b

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