CC BY-ND-NC 4.0 · SynOpen 2019; 03(01): 26-35
DOI: 10.1055/s-0037-1611665
paper
Copyright with the author

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

Karunakar Baikadi
,
Anil Talakokkula
,
A. Venkat Narsaiah*
Organic Synthesis Laboratory, Fluoro-Agrochemicals Department, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, Telangana, India   Email: vnakkirala2001@yahoo.com   Email: vnakkirala@csiriict.in
› Author Affiliations
K.B. and A.T. are grateful to CSIR-New Delhi and UGC-New Delhi, ­respectively, for providing Fellowships, and the Minister of Science and Technology for providing financial support under DST-SERB-GAP-0563.
Further Information

Publication History

Received: 12 December 2018

Accepted after revision: 09 January 2019

Publication Date:
26 February 2019 (online)

 

Abstract

The stereoselective total synthesis of Sch-725674 in 14 ­linear synthetic steps with 10.3% overall yield is described. The synthesis started from commercially available starting materials, d-ribose and (R)-benzyl glycidol. The key reactions involved CBS reduction, Julia–­Kocienski olefination, Horner–Wadsworth–Emmons reaction, and ­Shiina macrolactonization.


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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]

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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.

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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].

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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].

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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).
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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.


#
#

Acknowledgment

The authors would like to thank the Director CSIR-IICT for providing facilities. Commun. No: IICT/Pubs./2019/067.

Supporting Information

  • References

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  • 2 Moretti JD, Wang X, Curran DP. J. Am. Chem. Soc. 2012; 134: 7963
    • 3a Bali AK, Sunnam SK, Prasad KR. Org. Lett. 2014; 16: 4001
    • 3b Sunnam SK, Prasad KR. Tetrahedron 2014; 70: 2096
    • 3c Ramakrishna K, Kaliappan KP. Org. Biomol. Chem. 2015; 13: 234
    • 3d Seetharamsingh B, Khairnar PV, Reddy DS. J. Org. Chem. 2016; 81: 290
    • 3e Sharma BM, Gontala A, Kumar P. Eur. J. Org. Chem. 2016; 1215
    • 3f Bodugam M, Javed S, Ganguly A, Torres J, Hanson PR. Org. Lett. 2016; 18: 516
    • 3g Reddy Y, Sabitha G. ChemistrySelect 2016; 1: 2156
    • 4a Nagalatha G, Narala SG, Narsaiah AV. SynOpen 2018; 2: 251
    • 4b Ghogare RS, Wadavrao SB, Narsaiah AV. Helv. Chim. Acta 2016; 99: 247
    • 4c Wadavrao SB, Ghogare RS, Narsaiah AV. Helv. Chim. Acta 2015; 98: 575
    • 4d Wadavrao SB, Ghogare RS, Narsaiah AV. Synthesis 2015; 2129
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    • 6d Narsaiah AV, Ghogare RS. Synthesis 2011; 3271
    • 6e Wadavrao SB, Ghogare RS, Narsaiah AV. Synthesis 2015; 47: 2129
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    • 7b Lowe JT, Wrona IE, Panek JS. Org. Lett. 2007; 9: 327
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    • 8b Yadav JS, Thirupathaiah B, Singh VK, Ravishashidhar V. Tetrahedron: Asymmetry 2012; 23: 931
    • 8c Nakayama Y, Maeda Y, Hama N, Sato T, Chida N. Synthesis 2016; 1647
  • 9 Das S, Kuilya TK, Goswami RK. J. Org. Chem. 2015; 80: 6467
    • 10a Yahata K, Ye N, Iso K, Ai Y, Lee J, Kishi Y. J. Org. Chem. 2017; 82: 8808
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    • 10c Ganganna B, Srihari P, Yadav JS. Tetrahedron Lett. 2017; 58: 2685
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    • 12a Rao MV, Naresh A, Saketh G, Rao BV. Tetrahedron Lett. 2013; 54: 6931
    • 12b Ghogare RS, Wadavrao SB, Narsaiah AV. Tetrahedron Lett. 2013; 54: 5674
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  • 14 Trost BM, O’Boyle BM. J. Am. Chem. Soc. 2008; 130: 16190
  • 15 Kirkham JE. D, Courtney TD. L, Lee V, Baldwin JE. Tetrahedron 2005; 61: 7219
  • 16 Hung DT, Nerenberg JB, Schreiber SL. J. Am. Chem. Soc. 1996; 118: 11054
    • 17a Tap A, Jouanneau M, Galvani G, Sorin G, Lannou M.-I, Férézoub J.-P, Ardisson J. Org. Biomol. Chem. 2012; 10: 8140
    • 17b Sabitha G, Reddy CN, Raju A, Yadav JS. Tetrahedron: Asymmetry 2011; 22: 493
  • 18 Manikanta G, Nagaraju T, Krishna PR. Synthesis 2016; 48: 4213
  • 19 Butler SC, Forsyth CJ. J. Org. Chem. 2013; 78: 3895
  • 20 Lebar MD, Baker BJ. Tetrahedron 2010; 66: 1557
  • 21 Si D, Sekara NM, Kaliappan KP. Org. Biomol. Chem. 2011; 9: 6988
    • 22a Njardarson JT, Gaul C, Shan D, Huang X.-Y, Danishefsky SJ. J. Am. Chem. Soc. 2004; 126: 1038
    • 22b Reymond S, Cossy J. Tetrahedron 2007; 63: 5918
    • 23a Jena BK, Reddy GS, Mohapatra DK. Org. Biomol. Chem. 2017; 15: 1863
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  • References

  • 1 Yang SW, Chan TM, Terracciano J, Loebenberg D, Patel M, Chu M. J. Antibiot. 2005; 58: 535
  • 2 Moretti JD, Wang X, Curran DP. J. Am. Chem. Soc. 2012; 134: 7963
    • 3a Bali AK, Sunnam SK, Prasad KR. Org. Lett. 2014; 16: 4001
    • 3b Sunnam SK, Prasad KR. Tetrahedron 2014; 70: 2096
    • 3c Ramakrishna K, Kaliappan KP. Org. Biomol. Chem. 2015; 13: 234
    • 3d Seetharamsingh B, Khairnar PV, Reddy DS. J. Org. Chem. 2016; 81: 290
    • 3e Sharma BM, Gontala A, Kumar P. Eur. J. Org. Chem. 2016; 1215
    • 3f Bodugam M, Javed S, Ganguly A, Torres J, Hanson PR. Org. Lett. 2016; 18: 516
    • 3g Reddy Y, Sabitha G. ChemistrySelect 2016; 1: 2156
    • 4a Nagalatha G, Narala SG, Narsaiah AV. SynOpen 2018; 2: 251
    • 4b Ghogare RS, Wadavrao SB, Narsaiah AV. Helv. Chim. Acta 2016; 99: 247
    • 4c Wadavrao SB, Ghogare RS, Narsaiah AV. Helv. Chim. Acta 2015; 98: 575
    • 4d Wadavrao SB, Ghogare RS, Narsaiah AV. Synthesis 2015; 2129
    • 4e Narala SG, Nagalatha G, Narsaiah AV. ARKIVOC 2018; (vii): 495
    • 5a Bonini C, Chiummiento L, Pullez M, Solladié G, Colobert F. J. Org. Chem. 2004; 69: 5015
    • 5b Huang H, Mao C, Jan S.-T, Uckun FM. Tetrahedron Lett. 2000; 41: 1699
    • 6a Dachavaram SS, Kalyankar KB, Das S. Tetrahedron Lett. 2014; 55: 5629
    • 6b Yadav JS, Lakshmi PN, Harshavardhan SJ, Reddy BV. S. Synlett 2007; 1945
    • 6c Wadavrao SB, Ghogare RS, Narsaiah AV. Tetrahedron Lett. 2012; 53: 3955
    • 6d Narsaiah AV, Ghogare RS. Synthesis 2011; 3271
    • 6e Wadavrao SB, Ghogare RS, Narsaiah AV. Synthesis 2015; 47: 2129
    • 7a Evans DA, Dow RL, Shih TL, Takacs JM, Zahler R. J. Am. Chem. Soc. 1990; 112: 5290
    • 7b Lowe JT, Wrona IE, Panek JS. Org. Lett. 2007; 9: 327
    • 8a Clyne DS, Weiler L. Tetrahedron 1999; 55: 13659
    • 8b Yadav JS, Thirupathaiah B, Singh VK, Ravishashidhar V. Tetrahedron: Asymmetry 2012; 23: 931
    • 8c Nakayama Y, Maeda Y, Hama N, Sato T, Chida N. Synthesis 2016; 1647
  • 9 Das S, Kuilya TK, Goswami RK. J. Org. Chem. 2015; 80: 6467
    • 10a Yahata K, Ye N, Iso K, Ai Y, Lee J, Kishi Y. J. Org. Chem. 2017; 82: 8808
    • 10b Kesenheimer C, Groth U. Org. Lett. 2006; 8: 2507
    • 10c Ganganna B, Srihari P, Yadav JS. Tetrahedron Lett. 2017; 58: 2685
  • 11 Davies SG, Foster EM, Lee JA, Roberts PM, Thomson JE. Tetrahedron: Asymmetry 2014; 25: 534
    • 12a Rao MV, Naresh A, Saketh G, Rao BV. Tetrahedron Lett. 2013; 54: 6931
    • 12b Ghogare RS, Wadavrao SB, Narsaiah AV. Tetrahedron Lett. 2013; 54: 5674
  • 13 Abe K, Kato K, Arai T, Rahim MA, Sultana I, Matsumura S, Toshima K. Tetrahedron Lett. 2004; 45: 8849
  • 14 Trost BM, O’Boyle BM. J. Am. Chem. Soc. 2008; 130: 16190
  • 15 Kirkham JE. D, Courtney TD. L, Lee V, Baldwin JE. Tetrahedron 2005; 61: 7219
  • 16 Hung DT, Nerenberg JB, Schreiber SL. J. Am. Chem. Soc. 1996; 118: 11054
    • 17a Tap A, Jouanneau M, Galvani G, Sorin G, Lannou M.-I, Férézoub J.-P, Ardisson J. Org. Biomol. Chem. 2012; 10: 8140
    • 17b Sabitha G, Reddy CN, Raju A, Yadav JS. Tetrahedron: Asymmetry 2011; 22: 493
  • 18 Manikanta G, Nagaraju T, Krishna PR. Synthesis 2016; 48: 4213
  • 19 Butler SC, Forsyth CJ. J. Org. Chem. 2013; 78: 3895
  • 20 Lebar MD, Baker BJ. Tetrahedron 2010; 66: 1557
  • 21 Si D, Sekara NM, Kaliappan KP. Org. Biomol. Chem. 2011; 9: 6988
    • 22a Njardarson JT, Gaul C, Shan D, Huang X.-Y, Danishefsky SJ. J. Am. Chem. Soc. 2004; 126: 1038
    • 22b Reymond S, Cossy J. Tetrahedron 2007; 63: 5918
    • 23a Jena BK, Reddy GS, Mohapatra DK. Org. Biomol. Chem. 2017; 15: 1863
    • 23b Kim H, Hong J. Org. Lett. 2010; 12: 2880
  • 24 Pandey SK, Kumar P. Tetrahedron Lett. 2005; 46: 6625

Zoom Image
Figure 1
Zoom Image
Scheme 1 Retrosynthetic analysis
Zoom Image
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%.
Zoom Image
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).
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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%.