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Heterocyclic Communications

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Volume 21, Issue 6

Issues

Synthesis of the spiroacetal fragments of spirofungins A and B, antibiotics isolated from Streptomyces violaceusniger Tü 4113

Hiroyuki Sakauchi
  • Graduate School of Environmental and Life Science, Okayama University, 1-1-1 Tsushima-Naka, Kita, Okayama 700-8530, Japan
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/ Emi Higashi / Yuko Shimizu / Mikiko Kojima / Yuko Asamitsu / Shigefumi Kuwahara / Minoru Izumi
  • Graduate School of Environmental and Life Science, Okayama University, 1-1-1 Tsushima-Naka, Kita, Okayama 700-8530, Japan
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/ Hiromasa Kiyota
  • Corresponding author
  • Graduate School of Environmental and Life Science, Okayama University, 1-1-1 Tsushima-Naka, Kita, Okayama 700-8530, Japan
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Published Online: 2015-11-28 | DOI: https://doi.org/10.1515/hc-2015-0193

Abstract

The spiroacetal [C(9)–C(20)] fragments of spirofungins A and B, antibiotics isolated from Streptomyces violaceusniger Tü 4113, were prepared from a known bromo alcohol derived from (S)-citronellal, using thermodynamically controlled iodolactonization and spiroacetalization as the key steps.

Keywords: acetylide; antibiotics; iodolactonization; selenolactonization; spiroacetalization; spirofungins A and B; Streptomyces violaceusniger Tü 4113; synthesis

Introduction

Spirofungins A and B are antifungal polyketides bearing a spiroacetal ring, isolated from culture extracts of Streptomyces violaceusniger Tü 4113 (Figure 1) [1]. Total synthesis has been achieved by several groups [2–7], and other synthetic studies have been reported to date [8–13]. In a preliminary communication, we have reported the synthesis of a spirofungins A C(9)–C(20) fragment (A core, 1) and incorrectly proposed B [(15S,18R,19S)-isomer of A] by addition reaction of a racemic alkyne Y to an optically active lactone X [8]. Later, an optically active alkyne Y has been used instead for the preparation of 1 [11]. Here we describe the synthetic details of 1 and 2 as a continuation of the previous reports [8, 11].

Spirofungins A and B, and the spiroacetal fragments prepared in this study.
Figure 1

Spirofungins A and B, and the spiroacetal fragments prepared in this study.

Results and discussion

(S)-Citronellal was converted to the known epoxy bromide 3 [14] (Scheme 1). Oxidative cleavage of the epoxy ring with NaIO4 followed by reduction with NaBH4 afforded alcohol 4 in 86% yield [15]. The resulting hydroxy group was protected with a triphenylmethyl (Tr) group to give 5, which was subjected to dehydrobromination using KOt-Bu in DMSO, leading to the olefinic compound 6. Oxidation of the double bond was performed by Lemieux-Johnson oxidation or ozonolysis to afford the aldehyde, which was treated with Ph3P=CHCO2Me to give ester 7. The ester carbonyl group was reduced using DIBAL to furnish 8, and the newly formed hydroxy group was protected as a benzyl ether to produce 9. After removal of the trityl group, the resulting alcohol 10 was oxidized to carboxylic acid 11a, the precursor for the key halolactonization. The corresponding p-methoxybenzyl and p-bromobenzyl derivatives, 11b and 11c, were also prepared.

Preparation of lactonization precursors 11a–c.
Scheme 1

Preparation of lactonization precursors 11a–c.

The trials of halolactonization are listed in Table 1. Several reagents releasing iodonium or bromonium ions were examined for 11a (entries 1–6). The desired trans-isomer was preferentially obtained using I2 under thermodynamic conditions (entry 1), but the yield was 44%. The products trans/cis-12a were easily separated using silica gel column chromatography. Attempted mercuriolactonization produced no lactonic product (entry 7). Selenolactonization [16] using PhSeCl afforded the desired lactones, trans-14a and cis-14a, in 80% yield (entry 8); however, these isomers were inseparable even after deselenenylation (Bu3SnH, Et3B, O2, THF, 85%; Scheme 2). We also tried halolactonization using the substrates with p-methoxy (11b) or p-bromo (11c) substituent on the benzene ring (entries 9–12), to change the electrostatic nature of the double bond. The yield was improved with the p-methoxy derivative 11b, but the stereoselectivity was lower (entry 10). The best result was obtained with the p-bromo derivative 11c using IBr under thermodynamic conditions (entry 12). However, the parent Bn compound trans-12a was used in the following steps due to the expected difficulty in deprotection of the p-bromobenzyl group.

Table 1

Lactonization of carboxylic acid precursors 11a–c.

Synthesis of trans-15 (= X).
Scheme 2

Synthesis of trans-15 (= X).

Deiodination of trans-12a was performed using Bu3SnH in 93% yield to give the desired lactone trans-15 (Scheme 2). The overall yield was 18% over 10 steps from 4.

The optically active alkyne 20 was prepared in a similar manner as described in the previous report (Scheme 3) [8], starting from the epoxide 16 [17]. The enantiomeric purity of 16 was increased to >99% ee after crystallization of the corresponding p-nitrobenzoyl ester. The epoxy ring of 16 was cleaved by methylation with Me3Al and the resulting diol [18] was isolated as an acetal 17 [8]. The benzyl group was removed by hydrogenolysis and the deprotected alcohol 18 was converted to the dibromo olefin 19 under Corey-Fuchs reaction conditions. Treatment of 19 with BuLi afforded the alkyne 20.

Synthesis of 20 (= Y).
Scheme 3

Synthesis of 20 (= Y).

With both fragments, trans-15 (= X) and 20 (= Y), in our hands, lithium acetylide derived from 20 (1.8 eq.) was treated with trans-15 lactone to furnish hydroxy ketone 21 in 94% yield (Scheme 4). The tautomeric hemiacetal was not observed. Selective reduction of the compound 21 triple bond using Pd/BaSO4 as a catalyst in MeOH gave the methyl acetal 22 as a single diastereomer in quantitative yield. The stereochemistry of the acetal carbon could not be determined. Finally, deprotection of the terminal acetal group under acidic conditions accompanied by spiroacetal formation produced the desired A core (1) and B core (2). The ratio of two spiroacetals (A core/B core = 1.0:2.7 or 1.0:1.9) is similar to Diaz’s results on the corresponding PMB ethers (1.0:2.3) [11]. The spectroscopic data for 2 coincides with those reported [8, 11]. Studies towards total synthesis are underway.

Synthesis of spirofungins A core (1) and B core (2).
Scheme 4

Synthesis of spirofungins A core (1) and B core (2).

Experimental

IR spectra were recorded using neat compounds on a Jasco IR Report-100 spectrometer. 1H NMR spectra were recorded with a Varian GEMINI-300 spectrometer (300 MHz) using CDCl3 as solvent and internal standard (δH 7.26 ppm). 13C NMR spectrum was recorded with a Varian Inova-600 spectrometer (150 MHz) using CDCl3 as solvent and internal standard (δC 77.00 ppm). Mass spectra in a positive ion mode (EI+) were recorded with a Jeol JMS-700 spectrometer. Merck silica gel 60 (70–230 mesh) was used for column chromatography. Merck silica gel 60 F254 (0.25 mm thickness) was used for TLC analysis. The enantiomeric purity of compound 16 (>99% ee) was determined by HPLC analysis [column Daicel Chiralcel OD (4.6×250 mm)] eluting with hexane/i-PrOH, 4:1, flow rate 1.0 mL/min at 20°C, tR = 7.60 min (ent-16) and 9.20 min (16)].

(S)-6-Bromo-4-methylhexan-1-ol (4) [15]

To a solution of epoxide 3 [14] (11 g, 47 mmol) in THF/H2O (2:1, 120 mL) was added NaIO4 (20 g, 95 mmol), and the mixture was stirred at 50°C for 4 h. After removing the precipitate by filtration, the mixture was concentrated in vacuo. The residue was diluted with ether, washed with saturated aqueous NaHCO3 solution followed by saturated aqueous Na2S2O3 solution, dried with MgSO4, and concentrated in vacuo. To a solution of the resulting crude oil in MeOH (80 mL), NaBH4 (0.62 g, 16 mmol) was gradually added at 0°C, and the mixture was stirred at 20°C for 1 h. After the pH value of the solution was adjusted to 6 with 2 m aqueous HCl, the solvent was removed in vacuo. The residue was diluted with ether, washed with water and brine, dried with MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel (hexane/EtOAc, 3:1) to give 4 (7.9 g, 40 mmol, 86%) as a colorless oil, [α]D23 = +5.0° (c = 1.2, i-Pr2O) {[α]D32 = +7.40 (c = 1.16 g/mL) [15]}; IR (film): νmax 3350, 2950, 2920, 2850, 1740, 1720, 1650, 1450, 1440, 1380, 1260, 1240, 1220, 1060 cm-1; 1H NMR: δ 0.92 (d, 3H, J = 6.6 Hz, CH3), 1.19–1.75 (m, 6H), 1.89 (m, 1H, H-4), 3.37–3.52 (m, 2H, H-6), 3.65 (t, 2H, J = 6.6 Hz, H-1). EI-HR-MS. Calcd for C7H1679BrO (M+H): m/z 195.0385. Found: m/z 195.0389.

(S)-1-Bromo-3-methyl-6-(triphenylmethyl)oxyhexane (5)

A solution of 4 (12.0 g, 61.5 mmol), pyridine (7.75 g, 8.00 mL, 98.0 mmol), triphenylmethyl chloride (18.1 g, 65.0 mmol) and DMAP (1.51 g, 12.0 mmol) in dry DMF (100 mL), was stirred at 70°C for 2 h. After cooling to room temperature the mixture was diluted with water and extracted with hexane. The organic layer was washed with 1 m aqueous HCl followed by water, dried with MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel (hexane/EtOAc, 19:1) to give 5 (26.2 g, 60.0 mmol, 98%) as a colorless oil; [α]D24 = -3.2° (c = 1.1, i-Pr2O); IR (film): νmax 3070, 3050, 3010, 2950, 2920, 2850, 1950, 1480, 1440, 1380, 1320, 1280, 1220, 1180, 1150, 1080, 1030, 1000, 900 cm-1; 1H NMR: δ 0.88 (d, 3H, J = 6.3 Hz, CH3), 1.15–1.69 (m, 6H), 1.73–1.82 (m, 1H, H-3), 3.05 (t, 2H, J = 6.6 Hz, H-6), 3.46–3.60 (m, 2H, H-1), 7.19–7.46 (m, 15H, Ph). EI-HR-MS. Calcd for C26H2979BrO (M): m/z 436.1402. Found: m/z 436.1402.

(S)-3-Methyl-6-(triphenylmethyl)oxyhex-1-ene (6)

To a solution of 5 (3.00 g, 6.86 mmol) in pentane (15 mL) was added a solution of KOt-Bu (1.54 g, 13.7 mmol) in DMSO (14 mL) at 0°C, and the mixture was stirred at room temperature for 1 h. Then the mixture was cooled to 0°C, and water (10 mL) was added. After stirring at room temperature for 30 min., the mixture was extracted with pentane. The organic layer was washed with 1 m aqueous HCl, a saturated aqueous NaHCO3 solution and then water, dried with MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel (hexane/EtOAc, 100:1) to give 6 (2.30 g, 6.55 mmol, 96%) as a colorless oil; [α]D24 = +6.8° (c = 1.0, i-Pr2O); IR (film): νmax 3050, 3000, 2950, 2910, 2850, 1630, 1590, 1480, 1440, 1410, 1380, 1360, 1310, 1220, 1180, 1150, 1070, 1030, 990, 900 cm-1; 1H NMR: δ 0.97 (d, 3H, J = 6.6 Hz, CH3), 1.33–1.38 (m, 2H), 1.57–1.65 (m, 2H), 2.02–2.11 (m, 1H, 3-H), 3.03 (t, 2H, J = 6.7 Hz, 6-H), 4.88–4.95 (m, 2H, 1-H), 5.67 (ddd, 1H, J = 7.7, 10.4, 17.3 Hz, 2-H), 7.20–7.46 (m, 15H, Ph). EI-HR-MS. Calcd for C26H28O (M): m/z 356.2140. Found: m/z 356.2141.

Methyl (2E,4S)-4-methyl-7-(triphenylmethyl)oxyhept-2-enoate (7)

Method A

A solution of 6 (5.3 g, 15 mmol), OsO4 (catalyst) and N-methylmorpholine N-oxide (3.0 g, 26 mmol) in THF/water (6:1, 30 mL) was stirred at room temperature for 3 h and then treated with a solution of NaIO4 (8.1 g, 38 mmol) in THF/water (1:1, 20 mL). After adjusting the pH of the solution to 7, it was stirred at room temperature for 18 h. After removal of precipitates by filtration, the mixture was diluted with ether, washed twice with a saturated aqueous Na2S2O3 solution, dried with Na2SO4 and concentrated in vacuo to obtain crude aldehyde.

Method B

Ozone in oxygen gas was passed through a solution of 6 (3.4 g, 9.7 mmol) in dry MeOH/dry CH2Cl2 (5:3, 80 mL) at -78°C for 30 min. Then this solution was treated with Me2S (1.5 mL) and the mixture was stirred until the temperature of the reaction reached room temperature. The mixture was concentrated in vacuo and the residue was diluted with ether, washed with water, dried with MgSO4, and concentrated in vacuo to obtain crude aldehyde.

A mixture of crude aldehyde and methyl triphenylphosphoranylideneacetate [A, 9.6 g, 30 mmol; B, 6.1 g, 19 mmol] in dry toluene [A, 80 mL; B, 40 mL] was stirred at 50°C for 20 h. The mixture was concentrated in vacuo and the residue was chromatographed on silica gel (hexane/EtOAc, 9:1) to give 7 [A, 5.1 g, 12 mmol, 83%; B, 3.4 g, 8.2 mmol, 85%, E/Z = 95:5] as a colorless oil; [α]D20 = +33° (c = 1.0, i-Pr2O); IR (film): νmax 3050, 3010, 2950, 2920, 2860, 1650, 1600, 1490, 1450, 1430, 1380, 1350, 1310, 1270, 1210, 1180, 1150, 1070, 1040, 980, 900 cm-1; 1H NMR: δ 1.03 (d, 3H, J = 6.6 Hz, CH3), 1.39–1.48 (m, 2H), 1.57–1.64 (m, 2H), 2.25 (m, 1H, 4-H), 3.04 (dt, 2H, J = 1.5, 6.5 Hz, 7-H), 3.73 (s, 3H, OCH3), 5.75 (dd, 1H, J = 1.0, 16 Hz, 2-H), 6.84 (dd, 1H, J = 8.0, 16 Hz, 3-H), 7.18–7.45 (m, 15H). EI-HR-MS. Calcd for C28H30O3 (M): m/z 414.2195. Found: m/z 414.2197.

(2E,4S)-4-Methyl-7-(triphenylmethyl)oxyhept-2-en-1-ol (8)

To a solution of 7 (12.1 g, 29.1 mmol) in dry THF (100 mL) was added DIBAL (1.0 m in toluene, 64 mL, 64 mmol) at -78°C, and the mixture was stirred at this temperature for 20 min. Then MeOH (3 mL) was added, followed by a saturated aqueous Rochelle salt solution (10 mL), and the mixture was stirred for 2 h at room temperature. Next, the mixture was diluted with ether, washed with a saturated aqueous NH4Cl solution, water and then brine, dried with MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel (hexane/EtOAc, 10:1) to give 8 (11.2 g, 29.0 mmol, quantitative yield) as a colorless oil; [α]D24 = +11°(c = 1.1, i-Pr2O); IR (film): νmax 3350, 3080, 3050, 3020, 2950, 2920, 2860, 1740, 1600, 1490, 1450, 1370, 1240, 1220, 1180, 1150, 1070, 1040, 1000, 900 cm-1; 1H NMR: δ 0.98 (d, 3H, J = 6.9 Hz, CH3), 1.31–1.39 (m, 2H), 1.58–1.66 (m, 2H), 2.10 (m, 1H, 4-H), 3.04 (dt, 2H, J = 6.7 Hz, 7-H), 4.08–4.14 (m, 3H), 5.54 (m, 2H, 2-H, 3-H), 7.23–7.46 (m, 15H, Ph). EI-HR-MS. Calcd for C27H30O2 (M): m/z 386.2246. Found: m/z 386.2248.

(2E,4S)-1-Benzyloxy-4-methyl-7-(triphenylmethyl)oxyhept-2-ene (9a)

To a suspension of NaH (60% oil dispersion, washed with hexane before use, 0.9 g, 22 mmol) in dry THF (70 mL), a solution of 8 (2.6 g, 6.7 mmol) in dry THF (15 mL) and benzyl chloride (2.9 g, 2.6 mL, 23 mmol) were added dropwise at 20°C, and the mixture was stirred at 50°C for 12 h. After cooling to 0°C, water (10 mL) was added and THF was removed in vacuo. The residue was diluted with ether, washed with a saturated aqueous NH4Cl solution, water and then brine, dried with MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel (hexane/EtOAc, 10:1) to give 9a (3.2 g, 6.7 mmol, quantitative yield) as a colorless oil; [α]D23 = +12° (c = 1.0, i-Pr2O); IR (film): νmax 3075, 3050, 3020, 2925, 2860, 1590, 1485, 1445, 1355, 1215, 1150, 1070, 1025, 970 cm-1; 1H NMR: δ 0.98 (d, 3H, J = 6.9 Hz, CH3), 1.31–1.42 (m, 2H), 1.57–1.66 (m, 2H), 2.11 (sep., 1H, J = 6.9 Hz, H-3), 3.03 (t, 2H, J = 6.6 Hz, H-7), 3.96 (d, 2H, J = 5.0 Hz, H-1), 4.50 (s, 2H, PhCH2), 5.43–5.61 (m, 2H, H-2, 3), 7.19–7.45 (m, 15H, Tr).

(4E,5S)-7-Benzyloxy-4-methylhept-5-en-1-ol (10a)

A solution of 9a (1.00 g, 2.10 mmol) in THF/1 M aqueous HCl (14:1, 30 mL) was stirred under reflux for 6 h. After removal of the solvent, the residue was diluted with ether, washed with a saturated aqueous NaHCO3 solution followed by brine, dried with MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel (hexane/EtOAc, 10:1) to give 10a (470 mg, 1.92 mmol, 91%) as a colorless oil; [α]D24 = +19° (c = 1.1, i-Pr2O); IR (film): νmax 3400, 3010, 2920, 2850, 1490, 1450, 1370, 1250, 1210, 1100, 1070, 1030, 980, 910 cm-1; 1H NMR: δ 1.02 (d, 3H, J = 6.9 Hz, CH3), 1.32–1.40 (m, 2H), 1.51–1.61 (m, 2H), 2.18 (m, 1H, 4- H), 3.63 (t, 2H, J = 1.5, 6.5 Hz, 1-H), 3.98 (d, 2H, J = 4.7 Hz, 7-H), 4.51 (s, 2H, PhCH2), 5.77–5.59 (m, 2H, 5, 6-H), 7.26–7.35 (m, 5H, Ph). EI-HR-MS. Calcd for C15H22O2 (M): m/z 234.1620. Found: m/z 234.1621.

(4E,5S)-7-Benzyloxy-4-methylhept-5-enoic acid (11a)

To a solution of 10a (5.39 g, 23.0 mmol) in acetone (30 mL) was titrated with Jones reagent (2.67 M) at 0°C until the color of the solution became pale orange, and then the mixture was stirred at room temperature for an additional 3 h. The mixture was treated with i-PrOH until the color of the solution changed to green. Then, solids were removed by filtration through a Celite pad, and the filtrate was concentrated in vacuo. The residue was diluted with ether and extracted twice with a saturated aqueous NaHCO3 solution. After acidification with 2 m aqueous HCl, the aqueous layer was extracted four times with EtOAc. The combined organic layers were washed with brine, dried with MgSO4, and concentrated in vacuo to give 11a (4.60 g, 18.5 mmol, 80%) as a pale green oil. This carboxylic acid was used in the next step without further purification. IR (film): νmax 3675–3050 (br.), 3025, 2950, 2925, 2860, 1705, 1450, 1410, 1355, 1280, 1175, 1115, 1090, 1075, 1025, 975 cm-1; 1H NMR: δ 1.03 (d, 3H, J = 6.6 Hz, CH3), 1.55–1.75 (m, 2H), 2.16–2.25 (m, 1H, 4-H), 2.31–2.37 (m, 2H, H-2), 3.98 (d, 2H, J = 4.8 Hz, H-7), 4.51 (s, 2H, PhCH2), 5.57–5.60 (m, 2H, H-5, 6), 7.35–7.40 (m, 5H, Ph).

(4S,5S,6R)-7-Benzyloxy-6-iodo-4-methylheptan-5-olide (trans-12a)

To a solution of 11a (560 mg, 2.26 mmol) in dry CH3CN (5 mL) was added I2 (1.72 g, 6.78 mmol) at 0°C, and the mixture was stirred at 0°C for 12 h. The mixture was poured into a saturated aqueous Na2S2O3 solution (1:1, 20 mL), and stirred until the color of I2 diminished. The aqueous layer was separated and extracted three times with EtOAc. The combined organic layers were washed with water and then brine, dried with MgSO4, and concentrated in vacuo. The residue was chromatographed twice on silica gel (hexane/EtOAc, 4:1) to give trans-12a (281 mg, 0.750 mmol, 33%) as a colorless oil; [α]D24 = +22° (c = 0.98, i-Pr2O); IR (film): νmax 3400, 3010, 2950, 2920, 2850, 1730, 1490, 1450, 1360, 1340, 1240, 1200, 1180, 1100, 1040 cm-1; 1H NMR: δ 1.09 (d, 3H, J = 6.6 Hz, CH3), 1.49–1.62 (m, 1H, 3-H), 1.81–1.90 (m, 1H, 3-H), 2.18–2.29 (m, 1H, 4-H), 2.38–2.65 (m, 2H, 2-H), 3.79–3.92 (m, 2H, 7-H), 4.25 (dd, 1H, J = 3.0, 8.5 Hz, 5-H), 4.50–4.59 (m, 3H, H-6, PhCH2), 7.27–7.36 (m, 5H, Ph). EI-HR-MS. Calcd for C15H19 I O3 (M): m/z 374.0379. Found: m/z 374.0457.

(4S,5R)-7-Benzyloxy-4-methylheptan-5-olide [(4S,5R)-1 or trans-15] [8]

To a solution of trans-12a (160 mg, 0.43 mmol) in dry toluene (1 mL) was added tributyltin hydride (0.64 mL, 400 mg, 1.37 mmol) at 0°C, and the mixture was stirred at room temperature for 2 h. After the mixture was diluted with ether, KF (100 mg, 1.7 mmol) was added, and the mixture was stirred at room temperature for 24 h. After removal of precipitates with a Celite pad, the filtrate was washed with brine, dried with MgSO4, and concentrated in vacuo. The residue was chromatographed twice on silica gel (hexane/EtOAc, 10:1, then 4:1) to give (4S,5R)-1 (100 mg, 0.40 mmol, 93%) as a pale yellow oil; [α]D24 = +84° (c = 1.0, i-Pr2O); IR (film): νmax 3450, 3010, 2950, 2910, 2850, 1730, 1490, 1450, 1380, 1360, 1240, 1200, 1090, 1030 cm-1; 1H NMR: δ 1.02 (d, 3H, J = 6.6 Hz, CH3), 1.49–1.62 (m, 1H, H-3), 1.68–1.96 (m, 3H, H-3, 6), 2.04–2.17 (m, 1H, H-4), 2.41–2.67 (m, 2H, H-2), 3.63–3.75 (m, 2H, H-7), 4.13 (dt, 1H, J = 2.5, 9.6 Hz, H-5), 4.51, 4.52 (s, s, 2H, PhCH2), 7.27–7.38 (m, 5H, Ph). EI-HR-MS. Calcd for C15H20O3 (M): m/z 248.1412. Found: m/z 248.1415.

(2S,3R)-1-Benzyloxy-3,4-(pentane-3,3-diyl)dioxy-2-methylbutane (17)

To a solution of 16 (800 mg, 4.12 mmol) in dry CH2Cl2 (25 mL) was added Me3Al (1.0 m in CH2Cl2, 15 mL, 15 mmol) at 20°C, and the mixture was stirred at 20°C for 14 h. After addition of 2 m aqueous HCl the mixture was stirred for 30 min. Product was extracted with EtOAc and the extract was washed with water, a saturated aqueous NaHCO3 solution followed by brine. Final concentration in vacuo gave a pale yellow oil (0.98 g) that was used in the next step without further purification. A solution of this oil (0.93 g), CuSO4 (1.5 g) and TsOH (40 mg) in diethyl ketone (8 mL) was stirred at 20°C for 18 h. The mixture was filtered through a Celite pad and concentrated in vacuo. The residue was chromatographed on silica gel (hexane/EtOAc, 10:1) to give 17 (750 mg, 2.69 mmol, 69%) as a colorless oil; 1H NMR: δ 0.89 (t, 3H, J = 7.4 Hz, CH3CH2), 0.90 (q, 3H, J = 7.4 Hz, CH3CH2), 1.04 (d, 3H, J = 6.9 Hz, 3-CH3), 1.55–1.70 (m, 4H, CH3CH2 × 2), 1.95 (m, 1H, H-2), 3.37 (d, 2H, J = 5.9 Hz, H-4), 3.64 (t, 1H, J = 7.9 Hz, H-3), 4.00 (m, 1H, H-3), 4.48 (m, 2H, CH2Ph).

(2S,3R)-3,4-(Pentane-3,3-diyl)dioxy-2-methylbutan-1-ol (18)

A suspension of 17 (3.12 g, 11.2 mmol) and Pd/C (10%, 300 mg) in EtOH (100 mL) was stirred under a hydrogen atmosphere for 2 days. The solution was filtered through a Celite pad and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel to separate 18 (950 mg, 5.05 mmol) and 17 as colorless oils. A suspension of the recovered 17 and Pd/C (10%, ca. 150 mg) in EtOH (50 mL) was stirred under a hydrogen atmosphere for 3 days. The solution was filtered through a Celite pad and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel to give 18 (1.09 g, 5.79 mmol). The combined yield was 97%; IR (film): νmax 3400, 2950, 2920, 2850, 1740, 1720, 1450, 1370, 1350, 1260, 1200, 1160, 1130, 1070, 1040, 960, 920 cm-1; 1H NMR: δ 0.88 (t, 3H, J = 7.4 Hz, CH3CH2), 0.92 (q, 3H, J = 7.4 Hz, CH3CH2), 0.99 (d, 3H, J = 6.9 Hz, 3-CH3), 1.59–1.70 (m, 4H, CH3CH2 × 2), 1.97 (m, 1H, H-2), 3.52–3.65 (m, 2H, H-1), 4.02 (dd, 1H, J = 6.3, 8.0 Hz, H-3), 4.10–4.17 (m, 2H, H-4).

(3S,4R)-1,1-Dibromo-4,5-(pentane-3,3-diyl)dioxy-3- methylpent-1-ene (19)

A suspension of 18 (152 mg, 0.807 mmol), NaHCO3 (140 mg, 1.75 mmol) and Dess-Martin periodinane (515 mg, 1.21 mmol) in dry CH2Cl2 (7 mL) was stirred at 20°C for 10 min. The mixture was diluted with Et2O and washed with a saturated aqueous Na2S2O3 solution and then a saturated aqueous NaHCO3 solution, dried with MgSO4 and concentrated in vacuo to give crude aldehyde; 1H NMR: δ 0.90 (t, 6H, J = 7.5 Hz, CH3CH2), 1.23 (m, 3H, 2-CH3), 1.59–1.65 (m, 4H, CH3CH2 × 2), 2.63 (quint, 1H, J = 6.6 Hz, H-2), 3.64 (t, 1H, J-7.5 Hz, H-4), 4.16 (m, 1H), 4.29 (q, 1H, J = 6.3 Hz), 9.74 (s, 1H, H-1).

A suspension of Zn powder (105 mg, 1.60 mmol) and PPh3 (420 mg, 1.60 mmol) in dry CH2Cl2 (2 mL) was stirred for 5 min at 20°C. After the mixture had been cooled to 0°C, a solution of CBr4 (540 mg, 1.60 mmol) in dry CH2Cl2 (2 mL) was added, and the mixture was stirred for 30 h, during which time the temperature was gradually increased to 20°C. This mixture was treated with the aldehyde described above in dry CH2Cl2 (2 mL), and the mixture was stirred for an additional 12 h. Pentane was then added and the resulting crystals were removed by filtration. The filtrate was concentrated in vacuo. The residue was chromatographed on silica gel (hexane/EtOAc, 10:1) to give 19 (201 mg, 0.586 mmol, 73%) as a colorless oil; IR (film): νmax 2960, 2930, 2860, 1610, 1450, 1380, 1360, 1350, 1330, 1270, 1230, 1200, 1170, 1130, 1080, 1060, 1020, 1000, 970, 940, 920 cm-1; 1H NMR: δ 0.86–0.95 (m, 6H, CH3CH2 × 2), 1.10 (d, 3H, J = 8.2 Hz, 3-CH3), 1.56–1.70 (m, 4H, CH3CH2 × 2), 2.66 (m, 1H, H-3), 3.68 (m, 1H, H-4), 3.92–4.02 (m, 2H, H-5), 6.25 (dd, 1H, J = 1.8, 9.6 Hz, H-2). EI-HR-MS. Calcd for C11H1979Br81BrO2 (M+H+): m/z 342.9731. Found: m/z 342.9736.

(3S,4R)-4,5-(Pentane-3,3-diyl)dioxy-3-methylpent- 1-yne (20)

To a solution of 19 (590 mg, 1.72 mmol) in dry THF (7 mL) was added BuLi (1.6 m in hexane, 3.5 mL, 5.5 mmol) at -78°C and the mixture was stirred for 30 min at -78°C. The mixture was diluted with a saturated aqueous NH4Cl solution and extracted twice with ether. The combined organic layers were washed with brine, dried with MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel (hexane/EtOAc, 10:1) to give 20 (314 mg, 1.72 mmol, quantitative yield) as a colorless oil; IR (film): νmax 3300, 2950, 2920, 2860, 2100, 1640, 1460, 1370, 1350, 1330, 1290, 1280, 1260, 1200, 1170, 1120, 1080, 960, 920 cm-1; 1H NMR: δ 0.87–0.94 (m, 6H, CH3CH2 × 2), 1.27 (d, 3H, J = 6.9 Hz, 3-CH3), 1.57–1.70 (m, 4H, CH3CH2 × 2), 2.06 (d, 1H, H-1), 2.55–2.65 (m, 1H, H-3), 3.84 (dd, 1H, J = 6.6, 8.0 Hz, H-5), 3.96 (dd, 1H, J = 6.5, 8.0 Hz, H-4), 4.13 (dd, 1H, J = 6.0, 8.0 Hz, H-5). EI-HR-MS. Calcd. for C11H17O2 (M–H+): m/z 181.1229. Found: m/z 181.1292.

(2R,3S,9S,10R)-12-Benzyloxy-10-hydroxy-3,9-dimethyl-1, 2-(pentane-3,3-diyl)dioxydodec-4-yn-6-one (21)

To a solution of 20 (91.0 mg, 0.50 mmol, 1.8 equiv.) in ether (0.9 mL) was added BuLi (1.6 m in hexane, 0.32 mL, 0.50 mmol) at -15°C and the mixture was stirred for 15 min at this temperature. This mixture was added dropwise to a solution of trans-15 (63.8 mg, 0.275 mmol) in ether (1 mL) at -15°C and the resulting mixture was stirred for 20 min at this temperature. Then the mixture was poured into a saturated aqueous NH4Cl solution and extracted with EtOAc. The organic layer was dried with MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel (hexane/EtOAc,4:1) to give 21 (111 mg, 0.258 mmol, 94%) as a colorless oil; 1H NMR: δ 0.84–0.96 (m, 12H, CH3CH2 × 2, 3,9-CH3), 1.40–1.80 (m, 9H, H-8,9,11, CH3CH2 × 2), 2.46–1.70 (m, 2H), 2.80 (quint, 1H, J = 7.3 Hz), 3.07 (br. s, 1H, OH), 3.62 (m, 2H), 3.74 (m, 1H), 3.81 (m, 1H), 4.00 (m, 1H), 4.13 (dd, 1H, J = 8.0, 6.0 Hz), 4.53 (s, 2H, CH2Ph), 7.28–7.38 (m, 5H, Ph).

(2R,3S,9S,10R)-12-Benzyloxy-6,10-epoxy-6-methoxy-3, 9-dimethyl-1,2-(pentane-3,3-diyl)dioxydodecane (22)

A suspension of 21 (18.0 mg, 0.042 mmol) and Pd-BaSO4 (catalyst) in MeOH (0.5 mL) was stirred under a hydrogen atmosphere for 15 h. The mixture was filtered through a Celite pad and concentrated in vacuo. The residue was chromatographed on silica gel (hexane/EtOAc, 4:1) to give 22 (15.6 mg, 0.035 mmol, 83.1%) as a colorless oil; 1H NMR: δ 0.83–0.92 (m, 9H, CH3CH2 × 2, 3-CH3), 1.00 (d, 3H, J = 6.5 Hz, 9-Me), 1.40–1.80 (m, 11H), 2.02 (m, 1H), 3.09 (s, 3H, OCH3), 3.36 (tt, 1H, J = 10.2, 2.1 Hz), 3.56 (dt, 1H, J = 3.0, 8.0 Hz), 3.60–3.70 (m, 2H), 3.85 (m, 1H), 4.00 (ddd, 1H, J = 8.0, 6.1, 4.2 Hz), 4.50 (s, 2H, CH2Ph), 7.28–7.38 (m, 5H, Ph). HR-MS (FAB+). Calcd for C27H44O5Na (M+Na+): m/z 471.3086. Found: m/z 471.3093.

(2R,3S,6S,8R,9S)-8-(2-Benzyloxyethyl)-3,9-dimethyl- 1.7-dioxaspiro[5.5]undecane-2-methanol [spirofungin numbering: (11R,12S,15S,19R,18S)-9-Benzyloxy-11,15: 15,19-diepoxy-12,18-dimethyldodecan-20-ol] (spirofungin A core, 1) and its 6R-epimer (spirofungin B core, 2)]

A solution of 22 (31.0 mg, 0.069 mmol) and TsOH (catalyst) in CH2Cl2 (1 mL) was stirred at 20°C for 5 min. A saturated aqueous NaHCO3 solution was then added, and the separated organic layer was dried with MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel (hexane/EtOAc, 4:1) to give 1 (4.0 mg, 0.011 mmol, 17%) and 2 (11 mg, 0.032 mmol, 46%) as colorless oils. Data for 1: 1H NMR: δ 0.85 (d, 3H, J = 6.6 Hz), 0.90 (d, 3H, J = 6.9 Hz), 1.2–1.35 (m, 2H), 1.4–1.7 (m, 8H), 1.9–2.1 (m, 2H), 2.13 (dd, 1H, J = 14.3, 3.8 Hz), 3.56–3.66 (m, 2H), 3.66–3.76 (m, 2H), 4.10 (m, 2H), 4.25 (d, 1H, J = 9.6 Hz), 4.50 (d, 1H, J = 11.8 Hz, CH2Ph), 4.56 (d, 1H, J = 11.8 Hz, CH2Ph), 7.4–7.2 (m, 5H, Ph); 13C NMR: δ 14.6 (Me), 17.8 (Me), 27.9, 29.6, 33.6, 34.8, 38.6, 42.1, 44.7, 66.9, 69.4, 72.3, 72.8, 77.2, 96.4 (C-15), 127.5 (p-Ph), 127.7 (o-Ph), 128.7 (m-Ph), 138.8 (ipso-Ph). HRMS (FAB+). Calcd for C21H33O4 (M+H+): m/z 359.2379. Found: m/z 349.2382. Data for 2: see refs. [8, 11].

Acknowledgments

Financial support was provided by Grants-in-Aid from JSPS KAKENHI (No. 17580092, 19580120, 22560112 and 25450144). Support from the Agricultural Chemical Research Foundation, the Intelligent Cosmos Foundation and the Naito Foundation is gratefully acknowledged. Our thanks are also due to the Takasago International Corporation for the gift of (S)-citronellal.

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About the article

Corresponding author: Hiromasa Kiyota, Graduate School of Environmental and Life Science, Okayama University, 1-1-1 Tsushima-Naka, Kita, Okayama 700-8530, Japan, e-mail:


Received: 2015-09-03

Accepted: 2015-10-20

Published Online: 2015-11-28

Published in Print: 2015-12-01


Citation Information: Heterocyclic Communications, Volume 21, Issue 6, Pages 337–343, ISSN (Online) 2191-0197, ISSN (Print) 0793-0283, DOI: https://doi.org/10.1515/hc-2015-0193.

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