Stereoselective Total Synthesis of Macrolide Sch-725674 and C-7-epi-Sch-725674

Keywords

natural product synthesis - macrolides - Sch-725674 - C-7-epi-Sch-725674 - antifungal agents

Macrolactones are privileged core units in many bio­active molecules obtained from natural resources. Among them, 14-membered macrolides have received much attention because of their prominent biological activities such as antifungal and cytocidal properties. A novel 14-membered macrolide, Sch-725674, was isolated from a culture of ­Aspergillus sp (Figure [1]). Its structural identification by NMR studies and biological screening against Saccharomyces cervisiae and Candida abicans (MICs 8 and 32 μg mL^–1, ­respectively) were reported in 2005 by Yang et al.[1] Sch-725674 is a macrolactone having three free hydroxyl groups, four stereogenic centers, an (E)-α,β-unsaturated ester and an unusual n-pentyl chain. The absolute stereochemistry of Sch-725674 was reported by Curran et al. to be (4R,5S,7R,13R) by synthesizing all of its 16 isomers using a fluorous tagging protocol.[2] The structural complexity and biological importance of Sch-725674 has made it the target of synthetic chemists globally and led to its synthesis by various groups.[3]

Figure 1

As part of our ongoing research program on the synthesis of biologically active natural and synthetic compounds,[4] we herein report the stereoselective total synthesis of Sch-725674 (1) and C-7-epi-Sch-725674 (2) (Figure [1]). Our synthetic strategy consisted of Julia–Kocienski olefination, CBS reduction, HWE reaction and Shiina macrolactonization.

As shown in the retrosynthetic analysis (Scheme [1]), compound 1, could be obtained from compound 25 via Shiina macrolactonization and global deprotection of both protecting groups. Compound 25 (seco-acid) could be obtained from alkyne 11 and aldehyde 15 by a nucleophilic addition. The key precursor, alkyne fragment 11, could be obtained from (R)-benzyl glycidol and the aldehyde fragment 15 could be obtained from d-ribose.

Scheme 1 Retrosynthetic analysis

The synthesis started from commercially available (R)-benzyl glycidol 4, which, on regioselective ring opening with butyl magnesium bromide,[5] gave the corresponding secondary alcohol 5 in 86% yield, followed by silylation[6] with TBSCl and imidazole in CH₂Cl₂ to furnish compound 6 in excellent yield (Scheme [2]). Reductive debenzylation[7] of compound 6 in the presence of Pd/C (10%) in EtOAc at room temperature resulted in the formation of primary alcohol 7 in quantitative yield. The hydroxyl group was oxidized under Swern[8] conditions to furnish the aldehyde 8, which was directly subjected to Julia–Kocienski olefination[9] with sulfone 9, in the presence of KHMDS, to afford trans olefin 10 in 87% yield. The TMS deprotection of compound 10 was smoothly carried out using K₂CO₃ in MeOH to give compound 11 in 88% yield,[10] as shown in the Scheme [2].

Scheme 2 Synthesis of alkyne fragment 11 and aldehyde fragment 15. Reagents and conditions: (a) Butyl magnesium bromide (1.2 equiv), CuI (0.1 equiv), anhydrous THF, –78 °C to r.t., 1 h, 86%; (b) TBSCl, imidazole, CH₂Cl₂, 0 °C to r.t., 1.5 h, 88%; (c) H₂-Pd/C, EtOAc, 8 h, 96%; (d) (i) (COCl)₂, DMSO, CH₂C₂, –78 °C, 2 h; (ii) 9, KHMDS, anhydrous THF, –78 °C, 1 h, 80% (over two steps); (e) K₂CO₃, anhydrous MeOH, r.t., 30 min, 88%; (f) TBDPSCl, imidazole, CH₂Cl₂, 0 °C to r.t., 8 h, 86%; (g) (i) BH₃·SMe₂, THF, 0 °C to r.t., 1 h; NaOH, H₂O₂, 0 °C to r.t., 2 h, 89% (ii) (COCl)₂, DMSO, CH₂Cl₂, –78 °C, 2 h, 87%.

Synthesis of the aldehyde fragment started from commercially available d-ribose, which, by the sequential application of reported reactions led to [(4R,5S)-2,2-dimethyl-5-vinyl-1,3-dioxo lan-4-yl]methanol (12).[11] The hydroxyl group was silylated[12] with TBDPSCl / imidazole in CH₂Cl₂ to afford 13 in 86% yield. Hydroboration[13] of 13 with BH₃·Me₂S and subsequent oxidation in the presence of NaOH / H₂O₂ afforded primary alcohol 14 in 89% yield. This was oxidized under Swern conditions to afford the corresponding aldehyde 15, which was used without purification. At this stage, we coupled the two fragments alkyne 11 and aldehyde 15, in the presence of n-BuLi[14] at –78 °C, to achieve the racemic propargylic alcohol 16 and, on subsequent oxidation with

2-iodoxybenzoic acid (IBX)[15] in DMSO, to the ynone 17 in 81% yield over two steps.

The asymmetric reduction of ynone 17 was carried out using the CBS reagent[16] [(S)-(–)-2-Me-CBS-oxazaborolidine] and BH₃·Me₂S to give the desired chiral propargylic alcohol 18 in 86% yield, with excellent stereoselectivity (96:4, dr, confirmed by HPLC). The secondary alcohol was converted into its MOM ether 19 by treating with methoxy­methyl chloride[17] and DIPEA in CH₂Cl₂. Compound 19 was subjected to hydrogenation[18] in the presence of Pd/C (10%) to afford completely saturated compound 20 in 89% yield; selective desilylation[19] was then achieved by using NH₄F in anhydrous MeOH at 40 °C to afford primary alcohol 21 in 84% yield. The resulting alcohol 21 was oxidized with Dess–Martin periodinane[20] in the presence of NaHCO₃ in CH₂Cl₂ to give the corresponding aldehyde 22, which was directly subjected to Horner–Wadsworth–Emmons reaction[21] with triethyl phosphonoacetate and NaH in THF to give exclusively trans-(E)-α,β-unsaturated ester 23 in 85% yield over two steps (Scheme [3]).

Compound 23 was desilylated with HF·Py[22] in THF to afford secondary alcohol 24 in 90% yield, followed by base-­induced ester hydrolysis with LiOH to yield seco-acid 25. Seco-acid 25 cyclized into macrolide 26 under Shiina macro­lactonization[23] conditions in 80% yield over two steps. ­Removal of both acetonide and MOM ether protecting groups was achieved using trifluoroacetic acid (TFA)[24] in THF/ MeOH/ H₂O (1:2:1) mixture to afford natural product Sch-725674 (1) in 73% yield, as shown in Scheme [4].

Scheme 3 Coupling of alkyne fragment 11 and aldehyde fragment 15. Reagents and conditions: (a) n-BuLi, THF, –78 °C, 30 min; (b) IBX, DMSO, THF (1:1), 0 °C to r.t., 2 h, 81% (over two steps); (c) (S)-(–)-2-Me-CBS-oxazaborolidine (1.0 equiv), BH₃·Me₂S (1.5 equiv), THF, –40 °C, 1 h, 86%; (d) MOM-CI, DIPEA, CH₂Cl₂, 0 °C to r.t., 4 h, 87%; (e) H₂, Pd/C, EtOAc, 1 h, 89%; (f) NH₄F, MeOH, 40 °C, 1 h, 84%; (g) (i) DMP, CH₂Cl₂, NaHCO₃, 0 °C to r.t., 1 h; (ii) NaH, (OEt)₂P(O)CH₂CO₂Et, THF, 0 °C to r.t., 30 min, 85% (over two steps).

Scheme 4 Synthesis of target molecules Sch-725674 and C-7-epi-Sch725674. Reagents and conditions: (a) HF·Py, THF, 0 °C to r.t., 8 h, 90%; (b) (i) LiOH, THF/MeOH/H₂O (1:1:2), 0 °C to r.t., 3 h; (ii) MNBA, DMAP, toluene, r.t., 8 h, 80% (over two steps); (c) TFA, THF/MeOH/H₂O (2:4:1), 0 °C to r.t., 2 h, 73%.

C-7-Epi-Sch-725674 (2) was achieved by asymmetric reduction of common intermediate ynone 17, using the CBS reagent [(R)-(+)-2-Me-CBS-oxaza-borolidine] and BH₃·Me₂S in THF to give the desired chiral propargyl alcohol 18a in 83% yield, with excellent stereoselectivity (98:2, dr), the structure of which was confirmed by ¹H NMR analysis. The same reaction sequence was used (Scheme [3] and Scheme [4]) for the synthesis of the C-7-epi-Sch-725674. Global removal of the acetonide and MOM ether in macrolides 26 and 26a was carried out using TFA to afford both target compounds Sch-725674 (1) and C-7-epi-Sch-725674 (2) in good yields. The spectroscopic data and specific rotations of 1 and 2 are identical with the reported values (Table [1]).

Table 1 NMR Data for Synthetic and Natural 1

Position	Natural product [δ, ppm,in CD3OD]		Synthetic product [δ, ppm,in CD3OD]
	13C	1H (J Hz)	13C	1H (J Hz)
1	168.4		168.4
2	123.1	6.07 (dd, 15.8, 1.6)	123.1	6.08 (dd, 15.7, 1.1)
3	149.3	6.86 (dd, 15.8, 6.0)	149.3	6.87 (dd, 15.7, 5.9)
4	76.0	4.48 (ddd, 6.0, 3.0, 1.6)	76.0	4.51–4.46 (m)
5	72.9	3.84 (ddd, 6.0, 4.7, 3.0)	72.9	3.88–3.83 (m)
6	38.3	1.82 (ddd, 14.7, 6.5, 6.0), 1.65 (m)	38.3	1.83 (dt, 14.5, 5.9), 1.66 (m)
7	69.5	3.98 (q, 6.5)	69.5	4.03–3.95 (m)
8	36.8	1.36 (m)	36.8	1.36 (m)
9	25.8	1.19 (m), 1.37 (m)	25.8	1.19 (m), 1.37 (m)
10	29.5	1.15 (m), 1.40 (m)	29.5	1.15(m), 1.40 (m)
11	27.0	1.19 (m), 1.45 (m)	27.0	1.19 (m), 1.45 (m)
12	34.1	1.54 (m), 1.70 (m)	34.1	1.54 (m), 1.70 (m)
13	77.6	4.94 (dddd, 9.8, 7.5, 5.0, 2.2)	77.6	4.99–4.91 (m)
14	36.5	1.57 (m), 1.61 (m)	36.5	1.57 (m), 1.61 (m)
15	26.4	1.32 (m)	26.4	1.32 (m)
16	32.9	1.30 (m)	32.9	1.30 (m)
17	23.8	1.31 (m)	23.8	1.31 (m)
18	14.5	0.89 (t, 6.8)	14.5	0.90 (t, 6.6)

In summary, we have completed the stereoselective total synthesis of Sch-725674 (1) and C-7-epi-Sch-725674 (2) in 14 steps from commercially available d-ribose and (R)-benzyl glycidol, with an overall yield of 10.3%. The main features of the synthesis are construction of the alkyne fragment by using Julia Kocienski reaction, generation of a stereogenic center using CBS reduction, and 14-membered lactone formation using Shiina macrolactonization.

All reagents were purchased from commercial sources and were used without further purification. All reactions were performed under an inert atmosphere unless otherwise noted. THF was freshly distilled from Na/benzophenone ketyl. Petroleum ether refers to the fraction boiling in the 60–80 °C range. Column chromatography was performed on silica gel (Acme grade 60–120 mesh). All reactions were monitored by TLC to completion (Merck precoated silica gel 60 F 254 plates), visualizing with UV light, in an I₂ chamber or with phosphomolybdic acid spray. Melting points were recorded with a Büchi M-560 melting point apparatus and are uncorrected. IR spectra were recorded with a Perkin–Elmer FT-IR 240-c spectrometer. ¹H NMR spectra were recorded with a Bruker-400 MHz spectrometer in CDCl₃ and CD₃OD using TMS as internal standard, ¹³C NMR spectra were recorded on the same instrument operating at 100 MHz. Mass spectra were recorded with a Finnigan MAT 1020 mass spectrometer operating at 70 eV. Specific rotations were measured with a Rudolph Autopol IV polarimeter at 25 °C.

(R)-1-(Benzyloxy)heptan-2-ol (5)

To a stirred solution of CuI (0.34 g, 1.82 mmol) in anhydrous THF was added freshly prepared butyl-MgBr solution (2 M, 10.9 mL, 21.96 mmol) at –78 °C. The mixture was stirred for 30 min, (R)-(–)-benzyl glycidol (3 g, 18.3 mmol) was added and the mixture was stirred for 1 h. On completion, as monitored by TLC, the reaction was quenched with saturated NH₄Cl solution and the mixture was extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography using silica, eluting with EtOAc–hexane (1:9), to give compound 5 as a colorless liquid.

Yield: 3.5 g (86%); [α]_D ²⁵ –13.5 (c 1, CHCl₃).

IR (neat): 3396, 2926, 2856, 1454, 1219, 1102, 772, 698 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.38–7.26 (m, 5 H), 4.55 (s, 2 H), 3.85–3.77 (m, 1 H), 3.50 (dd, J = 9.4, 3.0 Hz, 1 H), 3.32 (dd, J = 9.3, 7.7 Hz, 1 H), 2.48–2.35 (brs, 1 H), 1.50–1.23 (m, 8 H), 0.88 (t, J = 6.8 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 137.9, 128.3, 127.6, 74.6, 73.2, 70.4, 33.0, 31.8, 25.1, 22.5, 13.9.

HRMS: m/z [M + H]⁺ calcd for C₁₄H₂₃O₂: 223.1693; found: 223.1689.

(R)-{[1-(Benzyloxy)heptan-2-yl]oxy}tert-butyldimethylsilane (6)

To a stirred solution of alcohol 5 (3.0 g, 13.5 mmol) in anhydrous ­CH₂Cl₂ (30 mL) were added imidazole (1.37 g, 20.3 mmol) and TBDMS-Cl (2.44 g, 16.2 mmol) at 0 °C and the mixture was stirred at r.t. for 2 h. After completion (monitored by TLC), the mixture was ­diluted with CH₂Cl₂ (10 mL) and washed with H₂O (10 mL), brine (5 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography ­using silica, eluting with EtOAc–hexane (0.5:9.5), to afford compound 6 as a pale-yellow oil.

Yield: 4.0 g (88%); [α]_D ²⁵ +10.5 (c 1.8, CHCl₃).

IR (neat): 3031, 2954, 2927, 2855, 1463, 1252, 1114, 835, 774, 697 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.36–7.31 (m, 4 H), 7.30–7.24 (m, 1 H), 4.52 (s, 2 H), 3.85–3.77 (m, 1 H), 3.42–3.33 (m, 2 H), 1.59–1.22 (m, 8 H), 0.88 (s, 12 H), 0.05 (s, 3 H), 0.04 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 138.5, 128.2, 127.5, 127.4, 74.8, 73.2, 71.5, 34.6, 31.9, 25.8, 24.8, 22.6, 18.1, 14.0, –4.3, –4.7.

HRMS: m/z [M + H]⁺ calcd for C₂₀H₃₇O₂Si: 337.2528; found: 337.2530.

(R)-2-[(tert-Butyldimethylsilyl)oxy]heptan-1-ol (7)

To a stirred solution of compound 6 (3.78 g, 11.3 mmol) in EtOAc (30 mL) was added Pd/C (10%, 250 mg) and the reaction mixture was stirred under hydrogen at r.t. for 12 h. After completion of the reaction (monitored by TLC), the mixture was filtered through Celite^®, and the pad was washed with EtOAc (50 mL). The filtrate was evaporated under reduced pressure and the residue was purified by flash column chromatography using silica, eluting with EtOAc–hexane (1:9), to give 7 as a colorless oil.

Yield: 2.65 g (96%); [α]_D ²⁵ –33.3 (c 1.2, CHCl₃).

IR (neat): 3394, 2954, 2927, 2856, 1464, 1253, 1098, 1046, 834, 774 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 3.76–3.70 (m, 1 H), 3.56 (dd, J = 10.9, 3.5 Hz, 1 H), 3.44 (dd, J = 10.9, 5.4 Hz, 1 H), 1.52–1.45 (m, 2 H), 1.35–1.24 (m, 6 H), 0.91 (s, 9 H), 0.89 (t, J = 7.0 Hz, 3 H), 0.09 (s, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 72.9, 66.2, 33.9, 31.9, 25.8, 24.9, 22.5, 18.0, 13.9, –4.4, –4.5.

HRMS: m/z [M + H]⁺ calcd for C₁₃H₃₁O₂Si: 247.2089; found: 247.2080.

1-Phenyl-5-{[4-(trimethylsilyl)but-3-yn-1-yl]sulfonyl}-1H-tetrazole (9)

To a stirred solution of 4-(trimethylsilyl)-but-3-yn-1-ol (2 g, 14 mmol), in anhydrous THF (30 mL) were added 5-mercapto-1-phenyl tetrazole (2.5 g, 14 mmol), PPh₃ (3.67 g, 14 mmol) and diisopropylazodicaboxylate (2.75 mL, 14 mmol) at 0 °C. The reaction mixture was stirred for 1.5 h at the same temperature and, after completion of the reaction as monitored by TLC, the reaction was quenched with saturated aq. NaHCO₃. The reaction mixture was extracted with EtOAc (2 × 20 mL) and the combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure to furnish the crude tetrazole (3.5 g). To a stirred solution of this tetrazole (3.5 g, 11.57 mmol) in EtOH (30 mL) were added (NH₄)₆Mo₇O₂₄·4H₂O (1.42 g, 1.15 mmol) and H₂O₂ (13.1 mL, 30%) at 0 °C. The reaction mixture was warmed slowly to r.t. and stirred for a further 1.5 h. After completion of the reaction (monitored by TLC), the solvent was removed under reduced pressure. The reaction was quenched with saturated aq. NaHCO₃ and the mixture was extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography using silica, eluting with ­EtOAc–hexane (1:9) mixture, to afford compound 9 as a white solid.

Yield: 3.6 g (78% over two steps).

IR (neat): 2960, 2180, 1498, 1353, 1147, 842, 769, 690 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.71–7.57 (m, 5 H), 3.90 (t, J = 7.5 Hz, 2 H), 2.93 (t, J = 7.5 Hz, 2 H), 0.14 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 153.0, 132.8, 131.5, 129.6, 125.1, 99.7, 88.4, 54.6, 14.5, –0.2.

HRMS: m/z [M + H]⁺ calcd for C₁₄H₁₉N₄O₂SSi: 335.09926; found: 335.09925.

(R , E)-tert-Butyldimethyl-{[1-(trimethylsilyl)undec-4-en-1-yn-6-yl]oxy}silane (10)

To a stirred solution of oxalyl chloride (1.35 mL, 15.8 mmol) in an­hydrous CH₂Cl₂ (5 mL) was added DMSO (2.41 mL, 33.8 mmol) slowly at –78 °C and the mixture was stirred for 30 min. Then a solution of alcohol 6 (2.6 g, 10.6 mmol) in anhydrous CH₂Cl₂ (10 mL) was added at –78 °C and the mixture was stirred for another 3 h at the same temperature. Et₃N (5.8 mL, 42.2 mmol) was added at 0 °C, the mixture was stirred for a further 45 minutes, the reaction was quenched with water (20 mL) and the mixture was extracted with CH₂Cl₂ (2 × 20 mL). The combined organic layers were washed with brine, dried over ­Na₂SO₄, filtered and concentrated to give crude aldehyde 8 as a pale-yellow syrup (2.2 g). To a stirred solution of sulfone 9 (3.6 g, 10.8 mmol) in anhydrous THF (40 mL) under argon was added KHMDS (9.9 mL 1 M, 9.9 mmol) at –78 °C and the mixture was stirred for 10 minutes. Then aldehyde 8 (2.2 g, 9.0 mmol) dissolved in anhydrous THF (10 mL) was added and the mixture was stirred for 30 min at the same temperature. The reaction mixture was warmed slowly to r.t. and stirring was continued for 1 h. The reaction was quenched with saturated aq. NH₄Cl (10 mL) and the mixture was extracted with ­EtOAc (2 × 30 mL). The combined organic layers were washed with H₂O, brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography using silica, eluting with EtOAc–hexane (0.3:9.7), to give 10 as a colorless liquid.

Yield: 2.98 g (80% over two steps); [α]_D ²⁵ –9.0 (c 1.0, CHCl₃).

IR (neat): 2956, 2929, 2856, 2177, 1467, 1250, 1076, 836, 772 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 5.68 (ddt, J = 15.2, 6.3, 1.5 Hz, 1 H), 5.51 (dtd, J = 15.2, 5.3, 0.9 Hz, 1 H), 4.12–4.04 (m, 1 H), 2.99–2.93 (m, 2 H), 1.51–1.23 (m, 8 H), 0.89 (s, 9 H), 0.88 (t, J = 5.0 Hz, 3 H), 0.16 (s, 9 H), 0.05 (s, 3 H), 0.03 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 135.5, 123.2, 104.1, 86.4, 73.0, 38.1, 31.7, 25.9, 24.9, 22.7, 22.6, 14.0, 0.06, –4.2, –4.7.

HRMS: m/z [M + Na]⁺ calcd for C₂₀H₄₀OSi₂Na: 375.2690; found: 375.2694.

(R , E)-tert-Butyldimethyl(undec-4-en-1-yn-6-yloxy)silane (11)

To a stirred solution of compound 10 (2.85 g, 8.1 mmol) in anhydrous MeOH was added K₂CO₃ (3.35 g, 24.3 mmol) at 0 °C and the mixture allowed to stir at r.t. for 20 min. After completion of the reaction, as monitored by TLC, the reaction was quenched with saturated NH₄Cl solution and the solvent was evaporated under vacuum. The reaction mixture was extracted with EtOAc (2 × 25 mL), the combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum to furnish the crude product. The crude product was purified by column chromatography using silica, eluting with EtOAc–hexane (0.5:9.5), to afford pure product 11 as a colorless liquid.

Yield: 2 g (88%); [α]_D ²⁵ –23.7 (c 0.8, CHCl₃).

IR (neat): 3313, 2955, 2928, 2856, 2178, 1464, 1252, 1075, 968, 833, 773, 630 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 5.71 (ddt, J = 15.2, 6.2, 1.6 Hz, 1 H), 5.53 (dtd, J = 15.2, 5.4, 1.0 Hz, 1 H), 4.11–4.06 (m, 1 H), 2.96–2.92 (m, 2 H), 2.09 (t, J = 2.7 Hz, 1 H), 1.52–1.40 (m, 2 H), 1.34–1.23 (m, 6 H), 0.89 (s, 9 H), 0.88 (t, J = 5.6 Hz, 3 H), 0.04 (s, 3 H), 0.03 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 135.7, 122.9, 81.5, 72.9, 70.0, 38.2, 31.7, 25.9, 24.9, 22.6, 21.2, 14.0, –4.2, –4.7.

HRMS: m/z [M + H]⁺ calcd for C₁₇H₃₃OSi: 281.2959; found: 281.2962.

tert-Butyl{[(4R,5S)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl]methoxy}diphenylsilane (13)

To a stirred solution of alcohol 12 (1.2 g, 7.6 mmol), in anhydrous CH₂Cl₂ (15 mL) were added imidazole (0.77 g, 11.4 mmol) and TBDPS-Cl (2.4 mL, 9.1 mmol) at 0 °C, followed by a catalytic amount of DMAP and the mixture was stirred at r.t. for 6 h. After completion of the reaction (monitored by TLC), the mixture was diluted with CH₂Cl₂ (10 mL), washed with H₂O (10 mL), brine (5 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography using silica, eluting with EtOAc–hexane (0.5:9.5), to give 10 as a colorless liquid.

Yield: 2.6 g (86%); [α]_D ²⁵ –3.9 (c 1.1, CHCl₃).

IR (neat): 3071, 2931, 2858, 1428, 1216, 1109, 1084, 772, 703 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.69–7.65 (m, 4 H), 7.44–7.35 (m, 6 H), 5.97–5.89 (m, 1 H), 5.36 (dt, J = 17.2, 1.0 Hz, 1 H), 5.21 (dt, J = 10.3, 0.9 Hz, 1 H), 4.68–4.63 (m, 1 H), 4.30–4.26 (m, 1 H), 3.72–3.63 (m, 2 H), 1.44 (s, 3 H), 1.37 (s, 3 H), 1.05 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 135.5, 133.6, 133.4, 133.3, 129.6, 127.6, 117.9, 108.5, 78.7, 78.4, 62.8, 27.7, 26.7, 25.3, 19.1.

HRMS: m/z [M + NH₄]⁺ calcd for C₂₄H₃₆O₃SiN: 414.2194; found: 414.2199.

2-{(4S,5R)-5-[((tert-Butyldiphenylsilyl)oxy)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl} ethan-1-ol (14)

To a stirred solution of compound 13 (2.3 g, 5.8 mmol) in anhydrous THF (30 mL) was added BH₃·SMe₂ (5.8 mL, 11.6 mmol, 2 M, THF) at 0 °C. The reaction mixture was then allowed to warm r.t. and stirred for 2 h. After consumption of starting material (monitored by TLC), the reaction mixture was cooled to 0 °C, then 3 M aq. NaOH (8 mL) was added, followed by hydrogen peroxide (2.5 mL, 33% w/w aq. solution) and the mixture was stirred for 2 h at r.t. The solvent was removed under vacuum, and the residue was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography using silica gel, eluting with EtOAc–hexane (3:7), to afford alcohol 14, as a colorless liquid.

Yield: 2.15 g (89%); [α]_D ²⁵ –29.9 (c 0.6, CHCl₃).

IR (neat): 3394, 2932, 2858, 1427, 1217, 1109, 1081, 822, 703 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.68–7.63 (m, 4 H), 7.45–7.36 (m, 6 H), 4.41–4.36 (m, 1 H), 4.26–4.20 (m, 1 H), 3.87–3.78 (m, 2 H), 3.76–3.69 (m, 1 H), 3.68–3.63 (m, 1 H), 2.41–2.36 (m, 1 H), 1.94–1.87 (m, 2 H), 1.37 (s, 3 H), 1.33 (s, 3 H), 1.05 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 133.5, 133.0, 132.9, 129.7, 127.7, 108.1, 77.6, 77.2, 62.4, 61.4, 31.4, 28.0, 26.7, 25.4, 19.1.

HRMS: m/z [M + H]⁺ calcd for C₂₄H₃₅O₄Si: 415.2290; found: 415.2294.

(R , E)-8-[(tert-Butyldimethylsilyl)oxy]-1-{(4S,5R)-5-[((tert-butyldiphenylsilyl)oxy)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl}dodec-6-en-3-yn-2-one (17)

To a stirred solution of oxalyl chloride (0.46 mL, 5.43 mmol) in an­hydrous CH₂Cl₂ (5 mL) was added DMSO (0.83 mL, 11.6 mmol) slowly at –78 °C and the mixture was stirred for 30 min. Then a solution of alcohol 14 (1.5 g, 3.62 mmol) in anhydrous CH₂Cl₂ (10 mL) was added and the mixture was stirred for another 3 h at the same temperature. Then, Et₃N (2.5 mL, 18.1 mmol) was added at 0 °C and the mixture was stirred for a further 45 minutes. The reaction mixture was diluted with water (15 mL), extracted with CH₂Cl₂ (2 × 20 mL), the combined organic layers were washed with brine, dried over Na₂SO₄, ­filtered and concentrated to give crude aldehyde compound 15 as a pale-yellow syrup (1.3 g). To a stirred solution of alkyne 11 (1.5 g, 5.35 mmol) in anhydrous THF (15 mL) was added n-BuLi (3.3 mL, 5.3 mmol, 1.6 M, hexane) at –78 °C and the mixture was stirred for 20 min. Aldehyde 15 (1.3 g, 3.15 mmol) in anhydrous THF (10 mL) was added and the reaction mixture was stirred at the same temperature for a further 1 h. The reaction was quenched with saturated aq. NH₄Cl and the mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography using silica, eluting with EtOAc–hexane (1:9), to afford 16 as an inseparable mixture of diastereoisomers as a yellow oil (yield: 1.98 g, 91%).

To a stirred solution of IBX (1.21 g, 4.32 mmol) in DMSO (10 mL) was added alcohol 16 (1.5 g, 2.16 mmol) in THF (10 mL) at 0 °C and the reaction mixture was then stirred at r.t. for 1 h. After completion of reaction (monitored by TLC), the reaction was quenched with saturated aq. Na₂S₂O₃ (6 mL) and the mixture was extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with cold water, brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography using silica gel, eluting EtOAc–hexane (0.5:9.5), to afford 17 as a ­yellow oil.

Yield: 1.35 g (81% for two steps); [α]_D ²⁵ –15.6 (c 1.0, CHCl₃).

IR (neat): 2924, 2854, 2217, 1679, 1465, 1219, 1075, 772 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.68–7.63 (m, 4 H), 7.45–7.36 (m, 6 H), 5.70 (ddt, J = 15.2, 5.8, 1.4 Hz, 1 H), 5.51 (dtd, J = 15.4, 5.6, 1.1 Hz, 1 H), 4.82–4.76 (m, 1 H), 4.28–4.22 (m, 1 H), 4.11–4.06 (m, 1 H), 3.68–3.63 (m, 2 H), 3.13–3.09 (m, 2 H), 3.07–3.01 (m, 1 H), 2.97–2.89 (m, 1 H), 1.48–1.23 (m, 14 H), 1.05 (s, 9 H), 0.89 (s, 9 H), 0.88 (t, J = 6.9 Hz, 3 H), 0.04 (s, 3 H), 0.02 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 184.8, 137.0, 135.5, 133.0, 132.9, 129.8, 127.7, 120.7, 108.3, 91.7, 82.0, 77.1, 76.8, 72.8, 62.3, 45.7, 38.0, 31.7, 27.8, 26.8, 25.8, 25.3, 24.8, 22.5, 21.8, 14.0, –4.2, –4.7.

HRMS: m/z [M + H]⁺ calcd for C₄₁H₆₃O₅Si: 691.42080; found: 691.42085.

(2S ,8R , E)-8-[(tert-Butyldimethylsilyl)oxy]-1-{(4S ,5R)-5-[((tert-­butyldiphenylsilyl)oxy)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl}dodec-6-en-3-yn-2-ol (18)

To a stirred solution of (S)-CBS (0.86 mL, 0.86 mmol, 1 M, toluene) in anhydrous THF was added a solution of ynone 17 (0.6 g, 0.86 mmol) in anhydrous THF (5 mL) at –40 °C, followed by addition of BH₃.SMe₂ (1.29 mL, 1.29 mmol, 1 M, THF) dropwise over 5 min, and the mixture was then stirred for 1.5 h at –40 °C. After completion of reaction (monitored by TLC), the reaction was quenched with MeOH (2 mL), the mixture was stirred for another 10 min and then concentrated under vacuum. The residue was purified by column chromatography using silica, eluting with EtOAc–hexane (1:9), to give alcohol 18 as a colorless oil.

Yield: 0.52 g (86%); [α]_D ²⁵ –9.9 (c 1, CHCl₃).

IR (neat): 3395, 2955, 2928, 2856, 2318, 1466, 1219, 1110, 1077, 834, 773, 703 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.69–7.64 (m, 4 H), 7.45–7.36 (m, 6 H), 5.67 (ddt, J = 15.2, 6.2, 1.5 Hz, 1 H), 5.52 (dtd, J = 15.2, 5.3, 0.9 Hz, 1 H), 4.72–4.61 (m, 2 H), 4.27–4.22 (m, 1 H), 4.11–4.04 (m, 1 H), 3.73–3.63 (m, 2 H), 3.11 (d, J = 8.5 Hz, 1 H), 3.01–2.96 (m, 2 H), 2.11–1.96 (m, 2 H), 1.50–1.21 (m, 14 H), 1.05 (s, 9 H), 0.89 (s, 9 H), 0.87 (t, J = 6.9 Hz, 3 H), 0.04 (s, 3 H), 0.02 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 135.55, 133.50, 133.0, 132.9, 129.8, 127.7, 123.4, 108.3, 82.8, 82.3, 77.5, 74.7, 73.0, 62.3, 60.9, 38.2, 36.1, 31.7, 28.0, 26.8, 25.9, 25.5, 24.9, 22.6, 21.6, 14.0, –4.1, –4.7.

HRMS: m/z [M + Na]⁺ calcd for C₄₁H₆₄O₅Si₂Na: 715.4364; found: 715.4369.

(5S ,11R,E)-11-Butyl-5-{[(4S ,5R)-5-(((tert-butyldiphenylsilyl)oxy)me­thyl)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-13,13,14,14-tetra­methyl-2,4,12-trioxa-13-silapentadec-9-en-6-yne (19)

To a stirred solution of 18 (0.4 g, 0.6 mmol ) in anhydrous CH₂Cl₂ (6 mL) at 0 °C under nitrogen, was added iPr₂NEt (0.4 mL, 2.3 mmol) dropwise. After 5 min, methoxymethyl chloride (0.09 mL, 1.14 mmol) was added dropwise and the mixture was stirred for 8 h at r.t. After completion (monitored by TLC), the reaction was quenched with saturated aq. NH₄Cl and the mixture was extracted with CH₂Cl₂ (2 × 10 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The crude residue was purified by flash column chromatography using silica, eluting with EtOAc–hexane (0.5:9.5), to afford 19 as a colorless oil.

Yield: 0.37 g (87%); [α]_D ²⁵ –18.8 (c 0.9, CHCl₃).

IR (neat): 2955, 2927, 2855, 2312, 1219, 1079, 772 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.70–7.65 (m, 4 H), 7.44–7.35 (m, 6 H), 5.65 (ddt, J = 15.2, 6.2, 1.5 Hz, 1 H), 5.51 (dtd, J = 15.2, 5.3, 0.9 Hz, 1 H), 4.98 (d, J = 6.6 Hz, 1 H), 4.60 (d, J = 6.6 Hz, 1 H), 4.58–4.55 (m, 1 H), 4.49–4.42 (m, 1 H), 4.21–4.14 (m, 1 H), 4.10–4.03 (m, 1 H), 3.74–3.61 (m, 2 H), 3.38 (s, 3 H), 2.99–2.93 (m, 2 H), 2.18–2.09 (m, 1 H), 2.04–1.95 (m, 1 H), 1.48–1.20 (m, 14 H), 1.05 (s, 9 H), 0.88 (s, 9 H), 0.87 (t, J = 5.8 Hz, 3 H), 0.03 (s, 3 H), 0.01 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 135.5, 135.4, 133.3, 133.2, 129.6, 127.6, 123.3, 107.9, 93.8, 82.9, 80.5, 77.5, 72.9, 62.5, 62.4, 55.5, 38.2, 36.4, 31.7, 28.1, 26.8, 25.9, 25.5, 24.9, 22.6, 21.5, 14, –4.2, –4.7.

HRMS: m/z [M + Na]⁺ calcd for C₄₃H₆₈O₆Si₂Na: 759.4623; found: 759.4626.

(5R,10R)-5{[(4S,5R)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-12,12,13,13-tetramethyl-10-pentyl-2,4,11-trioxa-12-silatetradecane (20)

To a stirred solution of 19 (0.3 g, 0.4 mmol) in EtOAc (8 mL) was added Pd/C (10%, 50 mg) and the reaction mixture was stirred under a ­hydrogen atmosphere at r.t. for 2 h. After completion (monitored by TLC), the mixture was filtered through Celite^® and the filter pad was washed with EtOAc (2 × 10 mL). The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography using silica, eluting with EtOAc–hexane (0.5:9.5), to give 20 as a colorless oil.

Yield: 0.27 g (89%); [α]_D ²⁵ –6.9 (c 0.8, CHCl₃).

IR (neat): 2928, 2856, 1467, 1429, 1252, 1218, 1108, 1043, 834, 772 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.69–7.63 (m, 4 H), 7.45–7.34 (m, 6 H), 4.69 (q, J = 8.8, 6.7 Hz, 2 H), 4.45–4.39 (m, 1 H), 4.18–4.12 (m, 1 H), 3.83–3.74 (m, 1 H), 3.70 (dd, J = 10.5, 7.5 Hz, 1 H), 3.65–3.57 (m, 2 H), 3.39 (s, 3 H), 1.88–1.79 (m, 1 H), 1.77–1.68 (m,1 H), 1.59–1.50 (m, 2 H), 1.44–1.23 (m, 20 H), 1.05 (s, 9 H), 0.88 (s, 12 H), 0.03 (s, 3 H), 0.03 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 135.5, 133.3, 133.2, 129.6, 127.6, 107.7, 95.9, 77.7, 75.0, 73.8, 72.3, 62.6, 55.5, 37.1, 35.4, 34.5, 32.0, 30.2, 28.1, 26.8, 25.9, 25.5, 25.4, 24.99, 24.90, 22.6, 19.1, 14.0, –4.3, –4.4.

HRMS: m/z [M + H]⁺ calcd for C₄₂H₇₃O₆Si₂: 743.5110; found: 743.5113.

{(4R,5S)-5-[(2R,8R)-8-((tert-Butyldimethylsilyl)oxy)-2-(methoxymethoxy)tridecyl]-2,2-dimethyl-1,3-dioxolan-4-yl}methanol (21)

To a stirred solution of 20 (0.21 g, 0.28 mmol) in anhydrous MeOH (5 mL) was added ammonium fluoride (0.2 g, 5.6 mmol) at r.t. The reaction mixture was warmed to 40 °C and stirred for 1 h. After completion (monitored by TLC), the reaction was quenched with saturated NH₄Cl (5 mL), solvent was removed under vacuum and the reaction mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over Na₂SO₄ filtered and concentrated under vacuum. The crude product was purified by flash column chromatography using silica, eluting with EtOAc–hexane (4:6), to obtain pure 21 as a yellow oil.

Yield: 120 mg (84%); [α]_D ²⁵ –51.1 (c 0.8, CHCl₃).

IR (neat): 3395, 2925, 2854, 1463, 1375, 1218, 1038, 834, 772 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 4.68 (q, J = 14.8, 6.8 Hz, 2 H), 4.42–4.32 (m, 1 H), 4.21–4.12 (m, 1 H), 3.83–3.69 (m, 1 H), 3.69–3.53 (m, 3 H), 3.39 (s, 3 H), 2.22–2.12 (m, 1 H), 1.81–1.22 (m, 25 H), 0.89 (s, 12 H), 0.03 (s, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 107.7, 95.8, 77.8, 75.2, 73.9, 72.3, 61.7, 55.7, 37.0, 35.0, 34.1, 32.0, 30.1, 28.1, 25.9, 25.4, 25.2, 24.9, 24.8, 22.6, 14.0, –4.4.

HRMS: m/z [M + Na]⁺ calcd for C₂₇H₅₆O₆SiNa: 527.3919; found: 527.3925.

Ethyl (E)-3-{(4R,5S)-5-[(2R,8R)-8-((tert-Butyldimethyl­silyl)oxy)-(methoxymethoxy)tridecyl]-2,2-dimethyl-1,3-dioxolan-4-yl}acrylate (23)

To a stirred solution of alcohol 21 (105 mg, 0.208 mmol) in anhydrous CH₂Cl₂ (3 mL) were added Dess–Martin periodinane (114 mg, 0.27 mmol) and NaHCO₃ (34 mg, 0.42 mmol) at 0 °C and the mixture was stirred at r.t. for 1 h. After completion (monitored by TLC), the reaction was quenched with saturated aq. Na₂S₂O₃ (10 mL) and saturated aq. NaHCO₃ (10 mL) and the mixture was extracted with CH₂Cl₂ (2 × 20 mL). The extracts were washed sequentially with water, brine, dried over Na₂SO₄, filtered and concentrated under vacuum to give the corresponding aldehyde 22, which was used in the next step without further purification. Triethyl phosponoacetate (87 mg, 0.39 mmol) was added to a stirred suspension of NaH (14 mg, 0.35 mmol) in anhydrous THF (3 mL) at 0 °C. The resulting solution was stirred for 45 min at 0 °C, then aldehyde 22 (100 mg, 0.195 mmol) in anhydrous THF (3 mL) was added and the resulting mixture was stirred at r.t. for 1 h. After completion (monitored by TLC), the reaction was quenched by adding saturated aq. NH₄Cl (10 mL), and the mixture was extracted with EtOAc (2 × 20 mL). The organic extracts were washed with brine (10 mL), dried (Na₂SO₄), filtered and concentrated under reduced pressure. The crude material was purified by column chromatography using silica, eluting with EtOAc–hexane (1:9), to give 23 as a colorless liquid.

Yield: 101 mg (85% over two steps); [α]_D ²⁵ +63.3 (c 0.5, CHCl₃).

IR (neat): 2927, 2854, 1726, 1467, 1375, 1219, 1040, 835, 772 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 6.84 (dd, J = 15.5, 5.8 Hz, 1 H), 6.07 (dd, J = 15.5, 1.4 Hz, 1 H), 4.71–4.62 (m, 2 H), 4.50–4.43 (m, 1 H), 4.21 (q, J = 14.3, 7.2 Hz, 2 H), 3.78–3.69 (m, 1 H), 3.65–3.57 (m, 1 H), 3.39 (s, 3 H), 1.61–1.20 (m, 30 H), 0.88 (s, 12 H), 0.03 (s, 3 H), 0.03 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 165.9, 143.7, 123.0, 108.7, 95.9, 77.3, 74.9, 72.3, 60.4, 55.6, 37.0, 35.8, 35.1, 32.0, 30.0, 29.6, 28.0, 25.9, 25.5, 25.3, 24.99, 24.92, 22.6, 14.2, 14.0, –4.4.

HRMS: m/z [M + H]⁺ calcd for C₃₁H₆₁O₇Si: 573.4193; found: 573.4187.

Ethyl (E)-3-{(4R,5S)-5-[(2R,8R)-8-Hydroxy-2-(methoxymethoxy)tri­decyl]-2,2-dimethyl-1,3-dioxolan-4-yl}acrylate (24)

To a stirred solution of compound 23 (95 mg) in anhydrous THF was added HF·Py (0.05 mL) at 0 °C and the reaction mixture was stirred at r.t. for 8 h. After completion of the reaction (monitored by TLC), the mixture was cooled to 0 °C and the reaction was quenched with saturated aq. NaHCO₃ (5 mL), followed by 0.05 M HCl (5 mL) and the mixture was extracted with EtOAc (2 × 10 mL). The combined organic ­layers were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography using silica, eluting with EtOAc–­hexane (3:7), to afford pure 22 as a colorless liquid.

Yield: 65 mg (90%); [α]_D ²⁵ +53.3 (c 0.2 CHCl₃).

IR (neat): 3325, 2924, 2854, 1724, 1464, 1373, 1218, 1160, 1035, 772 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 6.84 (ddd, J = 15.5, 5.9, 1.06 Hz, 1 H), 6.07 (dd, J = 15.5, 1.2 Hz, 1 H), 4.71–4.64 (m, 2 H), 4.51–4.43 (m, 1 H), 4.21 (q, J = 14.3, 7.1 Hz, 2 H), 3.77–3.70 (m, 1 H), 3.63–3.55 (m, 1 H), 3.39 (s, 3 H), 1.63–1.25 (m, 30 H), 0.89 (t, J = 6.2 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 166.0, 143.8, 122.9, 108.7, 95.9, 77.2, 74.8, 74.8, 71.8, 60.4, 55.6, 37.4, 37.3, 35.8, 35.0, 31.8, 29.7, 28.0, 25.5, 25.4, 25.3, 24.8, 22.6, 14.2, 14.0.

HRMS: m/z [M + H]⁺ calcd for C₂₅H₄₇O₇: 459.3324; found: 459.3322.

(3aR,8R,14R,15aS,E)-14-(Methoxymethoxy)-2,2-dimethyl-8-pentyl-3a,8,9,10,11,12,13,14,15,15a-decahydro-6H-[1,3]dioxolo[4,5-e][1]oxacyclotetradecin-6-one (26)

To a stirred solution of ester 24 (45 mg, 0.098 mmol) in a mixture of THF-MeOH-H₂O (4 mL, 1:1:2) was added LiOH (11 mg, 0.5 mmol) at 0°C and the mixture was stirred at r.t. for 1.5 h. After completion of the reaction (monitored by TLC), the solvent was removed under ­vacuum, the residue was extracted with Et₂O (5 mL) and the aqueous layer was acidified with 10% aqueous citric acid solution (5 mL) at 0 °C and extracted with EtOAc (2 × 10 mL). The combined organic ­layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give the crude seco-acid 25 (35 mg). To a stirred solution of 2-methyl-6-nitro benzoic anhydride (MNBA) (33 mg, 0.097 mmol) in anhydrous toluene (50 mL) was added DMAP (59 mg, 0.5 mmol), then seco-acid 25 (35 mg, 0.081 mmol) in anhydrous toluene (10 mL) was slowly added by syringe pump at r.t. over 12 h. The reaction mixture was concentrated under vacuum and the residue was purified by column chromatography using silica to afford macrolide 26 as pale-yellow oil.

Yield: 28 mg (80% over two steps); [α]_D ²⁵ +1.9 (c 1.1 CHCl₃).

IR (neat): 2922, 2852, 1725, 1465, 1219, 1038, 772 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 6.77 (dd, J = 15.7, 8.3 Hz, 1 H), 6.01 (dd, J = 15.7, 0.8 Hz, 1 H), 5.02–4.94 (m, 1 H), 4.71–4.65 (m, 2 H), 4.64–4.59 (d, J = 6.7 Hz, 1 H), 4.53–4.47 (m, 1 H), 3.78–3.70 (m, 1 H), 3.37 (s, 3 H), 1.99–1.90 (m, 1 H), 1.77–1.69 (m, 1 H), 1.69–1.21 (m, 24 H), 0.88 (t, J = 6.8 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 165.6, 143.6, 124.8, 108.7, 95.1, 77.8, 77.1, 76.0, 75.4, 73.7, 55.6, 35.3, 34.7, 33.7, 31.6, 31.5, 29.6, 29.2, 27.6, 25.0, 25.07, 25.02, 23.9, 22.5, 13.9.

HRMS: m/z [M + Na]⁺ calcd for C₂₃H₄₀O₆Na: 435.901; found: 435.2903.

(5R,6S,8R,14R,E)-5,6,8-Trihydroxy-14-pentyloxacyclotetradec-3-en-2-one

[Sch-725674 (1)]

To a stirred solution of compound 24 (20 mg, 0.05 mmol) in THF-MeOH-H₂O (2 mL, 1:2:1) mixture was added TFA (0.05 mL) in anhydrous CH₂Cl₂ (1 mL) dropwise at 0 °C. The reaction mixture was slowly warmed to r.t. and stirred for a further 2 h. After completion of the reaction (monitored by TLC), the reaction was quenched with saturated aq. NaHCO₃ (5 mL) and the mixture was extracted with EtOAc (2 × 10 mL), the combined organic layers were washed with brine, and dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography using silica, eluting with EtOAc–hexane (3:7), to afford target molecule Sch-725674 (1) as a white solid.

Yield: 11 mg (73%); mp 171–172 °C; [α]_D ²⁵ +6.2 (c 1.1, CHCl₃) {Lit.[2] +5.15 (c 0.27, MeOH)}.

IR (neat): 3395, 2921, 2857, 1704, 1463, 1276, 1219, 1079, 1004 cm^–1.

¹H NMR (400 MHz, CD₃OD): δ = 6.87 (dd, J = 15.7, 5.9 Hz, 1 H), 6.08 (dd, J = 15.7, 1.1 Hz, 1 H), 4.99–4.91 (m, 1 H), 4.51–4.46 (m, 1 H), 4.03–3.95 (m, 1 H), 3.88–3.83 (m, 1 H), 1.83 (dt, J = 14.5, 5.9 Hz, 1 H), 1.76–1.49 (m, 5 H), 1.45–1.26 (m, 11 H), 1.25–1.10 (m, 3 H), 0.90 (t, J = 6.6 Hz, 3 H).

¹³C NMR (100 MHz, CD₃OD): δ = 168.4, 149.3, 123.1, 77.6, 76.0, 72.9, 69.5, 38.3, 36.8, 36.5, 34.1, 32.9, 29.5, 27.0, 26.4, 25.8, 23.8, 14.5.

HRMS: m/z [M + H]⁺ cald for C₁₈H₃₃O₅: 329.2330; found: 329.2328.

(2R,8R,E)-8-[(tert-Butyldimethylsilyl)oxy]-1-{(4S,5R)-5-[((tert-­butyldiphenylsilyl)oxy)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl}dodec-6-en-3-yn-2-ol (18a)

This was prepared by following the procedure used for 18 (0.3 g, 0.44 mmol).

Yield: 0.25 g (83%); [α]_D ²⁵ –2.9 (c 1, CHCl₃).

IR (neat): 3395, 2955, 2926, 2855, 1466, 1219, 1110, 1076, 772 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.70–7.64 (m, 4 H), 7.46–7.35 (m, 6 H), 5.66 (ddt, J = 15.2, 6.2, 1.5 Hz, 1 H), 5.52 (dtd, J = 15.2, 5.3, 0.9 Hz, 1 H), 4.69–4.62 (m, 1 H), 4.46–4.40 (m, 1 H), 4.27–4.21 (m, 1 H), 4.10–4.03 (m, 1 H), 3.73–3.63 (m, 2 H), 3.01–2.96 (m, 2 H), 2.82–2.77 (m, 1 H), 2.09–2.02 (m, 2 H), 1.49–1.22 (m, 14 H), 1.06 (s, 9 H), 0.88 (s, 9 H), 0.87 (t, J = 6.8 Hz, 3 H), 0.04 (s, 3 H), 0.02 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 135.54, 135.50, 133.0, 132.9, 129.7, 127.7, 123.3, 108.4, 82.7, 82.1, 77.5, 77.1, 75.8, 73.0, 62.3, 61.7, 38.2, 37.6, 31.7, 28.0, 26.8, 25.9, 25.5, 24.9, 22.6, 21.6, 19.1, 14.0, –4.1, –4.7.

HRMS: m/z [M + Na]⁺ calcd for C₄₁H₆₄O₅Si₂Na: 715.4360; found: 715.4369.

(5R,11R,E)-11-Butyl-5-{[(4S,5R)-5-(((tert-butyldiphenyl­silyl)oxy)me­thyl)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-13,13,14,14-­tetramethyl-2,4,12-trioxa-13-silapentadec-9-en-6-yne (19a)

This was prepared by following the procedure used for 19 from alcohol 18a (0.2 g, 0.3 mmol).

Yield: 0.2 g (95%); [α]_D ²⁵ +5.3 (c 1.5, CHCl₃).

IR (neat): 2955, 2928, 2856, 2230, 1466, 1428, 1219, 1109 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.69–7.66 (m, 4 H), 7.44–7.35 (m, 6 H), 5.66 (ddt, J = 15.2, 6.2, 1.5 Hz, 1 H), 5.52 (dtd, J = 15.2, 5.3, 0.9 Hz, 1 H), 4.94 (d, J = 6.7 Hz, 1 H), 4.62–4.56 (m, 2 H), 4.47–4.42 (m, 1 H), 4.24–4.19 (m, 1 H), 4.09–4.04 (m, 1 H), 3.76–3.71 (m, 1 H), 3.70–3.65 (m, 1 H), 3.35 (s, 3 H), 3.01–2.96 (m, 2 H), 2.10–1.99 (m, 2 H), 1.49–1.22 (m, 14 H), 1.05 (s, 9 H), 0.88 (s, 9 H), 0.87 (t, J = 5.9 Hz, 3 H), 0.04 (s, 3 H), 0.01 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 135.6, 135.6, 133.3, 133.2, 129.6, 127.6, 123.3, 108.1, 93.9, 84.1, 79.7, 77.5, 74.3, 73.0, 64.4, 62.5, 55.5, 38.2, 35.8, 31.7, 28.1, 26.8, 25.9, 25.6, 24.9, 22.6, 21.6, 19.1, 14.0, –4.2, –4.7.

HRMS: m/z [M + Na]⁺ calcd for C₄₃H₆₈O₆Si₂Na: 759.4620; found: 759.4626.

(5S,10R)-5-{[(4S,5R)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-12,12,13,13-tetramethyl-10-pentyl-2,4,11-trioxa-12-silatetradecane (20a)

This was prepared by following the procedure used for 20 from 19a (192 mg, 0.26 mmol).

Yield: 183 mg (95%); [α]_D ²⁵ –27.9 (c 1, CHCl₃).

IR (neat): 2929, 2856, 1466, 1377, 1219, 1252, 1109, 1042, 834, 772 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.69–7.63 (m, 4 H), 7.43–7.34 (m, 6 H), 4.64 (q, J = 11.6, 6.8 Hz, 2 H), 4.31–4.25 (m, 1 H), 4.20–4.14 (m, 1 H), 3.79–3.69 (m, 2 H), 3.68–3.57 (m, 2 H), 3.36 (s, 3 H), 1.95–1.80 (m, 2 H), 1.45–1.22 (m, 22 H), 1.05 (s, 9 H), 0.88 (s, 12 H), 0.03 (s, 3 H), 0.03 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 135.56, 135.53, 133.2, 133.1, 129.7, 127.6, 107.9, 95.4, 77.7, 75.4, 74.4, 72.3, 62.6, 55.4, 37.1, 37.0, 34.1, 33.8, 32.0, 28.1, 26.8, 25.9, 25.6, 25.3, 25.0, 24.9, 22.6, 19.1, 14.0, –4.40, –4.41.

HRMS: m/z [M + H]⁺ calcd for C₄₂H₇₃O₆Si₂: 743.5116; found: 743.5113.

{(4R,5S)-5-[(2S,8R)-8-((tert-Butyldimethylsilyl)oxy)-2-(methoxymethoxy)tridecyl]-2,2-dimethyl-1,3-dioxolan-4-yl}methanol (21a)

This was prepared by following the procedure used for 21 from 20a (173 mg, 0.233 mmol).

Yield: 100 mg (86%); [α]_D ²⁵ +54.0 (c 0.5, CHCl₃).

IR (neat): 3375, 2927, 2855, 1464, 1377, 1219, 1252, 1041, 835, 772 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 4.73–4.64 (m, 2 H), 4.41–4.26 (m, 1 H), 4.20–4.13 (m, 1 H), 3.79–3.57 (m, 4 H), 3.41–3.36 (m, 2 H), 1.93–1.83 (m, 1 H), 1.79–1.63 (m, 2 H), 1.49–1.22 (m, 24 H), 0.88 (s, 12 H), 0.03 (s, 3 H), 0.03 (s, 3 H).

¹³C NMR (400 MHz, CDCl₃): δ = 108.0, 95.4, 77.8, 75.2, 73.6, 72.3, 61.6, 55.5, 37.0, 34.0, 33.4, 32.0, 30.0, 28.2, 25.9, 25.5, 25.2, 25.1, 24.9, 22.6, 14.0, –4.4.

HRMS: m/z [M + Na]⁺ calcd for C₂₇H₅₆O₆SiNa: 527.3922; found: 527.3925.

Ethyl (E)-3-{(4R,5S)-5-[(2S ,8R)-8-((tert-Butyldimethylsilyl)oxy)-2-(methoxy methoxy)tridecyl]-2,2-dimethyl-1,3-dioxolan-4-yl}acrylate (23a)

This was prepared by following the procedure used for 23 from 22a (90 mg, 0.178 mmol).

Yield: 70 mg (84%); [α]_D ²⁵ –62.4 (c 0.5, CHCl₃).

IR (neat): 2924, 2853, 1724, 1464, 1372, 1218, 1160, 1036, 984, 772 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 6.83 (dd, J = 15.5, 6.3 Hz, 1 H), 6.06 (dd, J = 15.6, 1.3 Hz, 1 H), 4.66 (td, J = 6.2, 1.3 Hz, 1 H), 4.63 (s, 2 H), 4.43–4.33 (m, 1 H), 4.20 (q, J = 14.3, 7.2 Hz, 2 H), 3.70–3.57 (m, 2 H), 3.41–3.36 (m, 3 H), 1.84–1.72 (m, 1 H), 1.63–1.54 (m, 1 H), 1.51 (s, 3 H), 1.44–1.22 (m, 24 H), 0.92–0.85 (m, 12 H), 0.03 (s, 3 H), 0.03 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 165.8, 143.3, 123.3, 108.9, 95.4, 77.3, 75.0, 74.8, 72.3, 60.4, 55.5, 37.0, 34.9, 34.0, 32.0, 30.0, 28.0, 25.9, 25.5, 25.2, 25.1, 24.9, 22.6, 14.2, 14.0, –4.4.

HRMS: m/z [M + H]⁺ calcd for C₃₁H₆₁O₇Si: 573.4190; found: 573.4187.

Ethyl (E)-3-{(4R,5S)-5-[(2S,8R)-8-Hydroxy-2-(methoxy­methoxy)tri­decyl]-2,2-dimethyl-1,3-dioxolan-4-yl}acrylate (24a)

This was prepared by following the procedure used for 24 from ester 23a (55 mg, 0.096 mmol).

Yield: 35 mg (79%); [α]_D ²⁵ –33.2 (c 0.5, CHCl₃).

IR (neat): 3385, 2923, 2853, 1723, 1463, 1373, 1218, 1034, 882, 772 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 6.83 (dd, J = 15.4, 6.3 Hz, 1 H), 6.07 (dd, J = 15.6, 1.3 Hz, 1 H), 4.73–4.59 (m, 3 H), 4.47–4.33 (m, 1 H), 4.21 (q, J = 14.3, 7.1 Hz, 2 H), 3.73–3.51 (m, 2 H), 3.44–32 (m, 3 H), 1.86–1.69 (m, 1 H), 1.63–1.49 (m, 4 H), 1.49–1.22 (m, 24 H), 0.89 (t, 3 H, J = 6.6 Hz).

¹³C NMR (100 MHz, CDCl₃): δ = 165.8, 143.4, 123.3, 108.9, 95.4, 77.2, 75.0, 74.8, 71.8, 60.5, 55.6, 37.4, 37.3, 34.9, 34.0, 31.9, 29.6, 28.0, 25.5, 25.3, 25.0, 22.6, 14.2, 14.0.

HRMS: m/z [M + H]⁺ calcd for C₂₅H₄₇O₇: 459.3320; found: 459.3322.

(3aR,8R,14S,15aS , E)-14-(Methoxymethoxy)-2,2-dimethyl-8-pentyl-­3a,8,9,10,11,12,13,14,15,15a-decahydro-6H-[1,3]dioxolo[4,5-e][1]oxacyclotetradecin-6-one (26a)

This was prepared by following the procedure used for 26 from seco-acid 25a (20 mg, 0.046 mmol).

Yield: 16 mg (84%); [α]_D ²⁵ +33 (c 1.3, CHCl₃).

IR (neat): 2923, 2853, 1721, 1460, 1379, 1219, 1041, 989, 772 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 6.80 (dd, J = 15.6, 8.9 Hz, 1 H), 6.08 (dd, J = 15.7, 0.7 Hz, 1 H), 5.05–4.97 (m, 1 H), 4.68 (dd, J = 8.4, 6.2 Hz, 1 H), 4.63–4.58 (m, 1 H), 4.57–4.46 (m, 2 H), 3.41–3.28 (m, 4 H), 1.91 (ddd, J = 14.4, 11.4, 1.4 Hz, 1 H), 1.77–1.21 (m, 25 H), 0.88 (t, J = 6.8 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 165.1, 142.1, 125.9, 108.7, 95.3, 76.8, 75.9, 75.4, 73.5, 55.6, 36.2, 34.9, 34.2, 31.6, 30.4, 28.2, 27.9, 25.28, 25.23, 25.20, 25.1, 22.5, 13.9.

HRMS: m/z [M + Na]⁺ calcd for C₂₃H₄₀O₆Na: 435.906; found: 435.2903.

(5R,6S,8S,14R,E)-5,6,8-Trihydroxy-14-pentyloxacyclotetradec-3-en-2-one [C-7-epi-Sch-725674 (2)]

This was prepared by following the procedure used for natural product Sch-725674 (1) from lactone 26a (14 mg, 0.031 mmol).

Yield: 8.5 mg (77%); [α]_D ²⁵ –39.5 (c 0.5, CHCl₃) {Lit.[2] –38.6 (c 0.24, MeOH)}.

IR (neat): 3395, 2921, 2852, 1714, 1696, 1271, 1219 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 6.95 (dd, J = 15.7, 4.2 Hz, 1 H), 6.13 (dd, J = 15.6, 1.8 Hz, 1 H), 4.99–4.89 (m, 1 H), 4.57–4.52 (m, 1 H), 3.89 (dt, J = 8.8, 2.0 Hz, 1 H), 3.44–3.34 (m, 1 H), 2.02 (ddd, J = 14.6, 8.9, 2.4 Hz, 1 H), 1.70–1.16 (m, 19 H), 0.91 (t, J = 6.8 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 169.0, 121.8, 75.5, 74.9, 72.1, 68.8, 40.4, 36.1, 35.9, 33.8, 32.9, 27.2, 26.4, 24.7, 24.5, 23.7, 14.48.

HRMS: m/z [M + H]⁺ calcd for C₁₈H₃₃O₅: 329.2331; found: 329.2328.

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