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Synlett 2010(3): 374-378  
DOI: 10.1055/s-0029-1219185
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Thieme Chemistry Journal Awardees - Where Are They Now? Stereoselective Synthesis of Z-Configured α,β-Unsaturated Macrocyclic Lactones and Diolides by Intramolecular Julia-Kocienski Olefination

Heath E. Giesbrecht, Brian J. Knight, Nicole R. Tanguileg, Christopher R. Emerson, Paul R. Blakemore*
Department of Chemistry, Oregon State University, 153 Gilbert Hall, Corvallis, OR 97331-4003, USA
Fax: +1(541)7372062; e-Mail: paul.blakemore@science.oregonstate.edu;
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Publikationsverlauf

Received 15 October 2009
Publikationsdatum:
11. Januar 2010 (online)

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Abstract

ω-Sulfonyl aldehydes derived from the esterification of (benzothiazol-2-ylsulfonyl)acetic acid with either ω-alkenols or α,ω-diols, followed by ozonolysis or Dess-Martin oxidation as appropriate, underwent intramolecular Julia-Kocienski olefination when treated with DBU. Macrocyclic α,β-unsaturated lactones of between 12- and 19-membered ring sizes were formed successfully using this tactic (24-44% yield, Z/E ³ 3.5:1); however, diolides were selectively produced from precursors intended to target seven- to nine-membered-ring lactones (13-70% yield, ZZ/ZE ³ 2:1).

Key words

olefination - macrocycles - lactones - alkenes - sulfones

    References and Notes

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13

(Benzothiazol-2-ylsulfonyl)acetic Acid (7)
A solution of sulfanyl acid 6 (2.18 g, 9.68 mmol)¹² in EtOH (90 mL) at 0 ˚C was treated with (NH4)6Mo7O24˙4H2O (1.20 g, 0.971 mmol) and stirred for 5 min. 30 wt% aq H2O2 (67 mL, 656 mol) was then added during 3 min, and the mixture allowed to warm to r.t. and stirred for 17 h. After this time, the reaction mixture was partitioned between CH2Cl2 (100 mL) and H2O (100 mL) and the layers separated. The aqueous phase was extracted with CH2Cl2 (6 × 20 mL) and the combined organic phases washed with H2O (20 mL) and brine (20 mL), dried (Na2SO4), and concentrated in vacuo (bath temperature 25 ˚C) to afford sulfonyl acid 7 (1.99 g, 98 wt% remainder 8, 7.58 mmol, 78%) as a colorless solid; mp 131-133 ˚C. IR (KBr): 3410, 2994, 1725, 1471, 1338, 1166 cm-¹. ¹H NMR (400 MHz, acetone-d 6): δ = 8.31 (1 H, dd, J = 7.3, 1.5 Hz), 8.24 (1 H, dd, J = 7.7, 1.6 Hz), 7.75 (1 H, td, J = 7.2, 1.3 Hz), 7.71 (1 H, td, J = 7.2, 1.2 Hz), 4.82 (2 H, s) ppm. ¹³C NMR (75 MHz, acetone-d 6): δ = 167.0, 163.4, 153.4, 137.7, 129.1, 128.7, 125.9, 123.9, 59. 2 ppm. Methyl sulfone 8 (2 wt%) revealed by δH = 3.50 (3 H, s) ppm. Any attempts to recrystallize, or otherwise purify, sulfonyl acid 7 led to further unwanted decarboxylation and increased levels of 8. Formation of the peroxyacid derivative of 7 was not observed.

14

Representative Procedure: DCC Coupling of Acid 7 and 9-Decen-1-ol (Scheme 3) A stirred solution of acid 7 (6.80 g, 98 wt%, 25.9 mmol) in anhyd THF (200 mL) at 0 ˚C under Ar was treated with neat 9-decen-1-ol (3.93 g, 25.1 mmol) followed by DCC (5.72 g, 27.7 mmol). The resulting mixture was allowed to warm to r.t. and stirred for 19 h. After this time, precipitated DCU was removed by filtration and the filtrate concentrated in vacuo. The residue was purified by column chromatography (SiO2, eluting with 10% Et2O in hexanes) to afford alkenyl ester 10-12 (9.72 g, 24.6 mmol, 98%) as a pale yellow oil: IR (neat): 2929, 1738, 1639, 1471, 1346, 1157 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 8.22 (1 H, dm, J = 7.5 Hz), 8.02 (1 H, dm, J = 7.1 Hz), 7.66 (1 H, td, J = 7.2, 1.4 Hz), 7.61 (1 H, td, J = 7.2, 1.4 Hz), 5.81 (1 H, ddt, J = 17.1, 10.3, 6.6 Hz), 4.99 (1 H, dm, J = 17.2 Hz), 4.94 (1 H, dm, J = 10.2 Hz), 4.58 (2 H, s), 4.10 (2 H, t, J = 6.6 Hz), 2.03 (2 H, q, J = 6.9 Hz), 1.56-1.43 (2 H, m), 1.40-1.28 (2 H, m), 1.27-1.10 (8H, m) ppm. ¹³C NMR (75 MHz, CDCl3): δ = 165.2, 161.8, 152.6, 139.2, 137.1, 128.4, 127.9, 125.7, 122.5, 114.4, 67.0, 58.9, 33.9, 29.8, 29.3, 29.1, 29.0, 28.3, 25.7 ppm. HRMS (FAB+): m/z calcd for C19H26NO4S2: 396.1303; found: 396.1309. All other alkenyl sulfones in Scheme  [³] were similarly characterized and gave comparable spectral signatures.

16

Representative Procedure: DCC Coupling of Acid 7 and 1,6-Hexanediol (Scheme 4) A stirred solution of acid 7 (500 mg, 98 wt%, 1.90 mmol) and 1,6-hexanediol (689 mg, 5.83 mmol) in anhyd THF (5 mL) at 0 ˚C under Ar was treated with DCC (423 mg, 2.05 mmol). The resulting mixture was allowed to warm slowly to r.t. and stirred for 72 h. The mixture was filtered to remove precipitated DCU, diluted with CH2Cl2 (5 mL), and washed successively with 1 M aq NaHCO3 (2 × 5 mL) and brine (5 mL), then dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (SiO2, eluting with 40-100% EtOAc in hexanes) to yield in order of elution: the diester side-product (133 mg, 0.22 mmol, 12%), hydroxy ester 12-9 (542 mg, 1.52 mmol, 80%), and 1,6-hexanediol (181 mg, 1.53 mmol, 37% of recoverable amount).
Data for 12-9: colorless oil. IR (neat): 3406, 2935, 1741, 1471, 1343, 1154 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 8.22 (1 H, dm, J = 7.3 Hz), 8.03 (1 H, dm, J = 7.3 Hz), 7.67 (1 H, td, J = 7.3, 1.4 Hz), 7.62 (1 H, td, J = 7.3, 1.4 Hz), 4.58 (2 H, s), 4.12 (2 H, t, J = 6.5 Hz), 3.60 (2 H, t, J = 6.3 Hz), 1.59-1.42 (4 H, m), 1.30-1.18 (4 H, m) ppm. ¹³C NMR (75 MHz, CDCl3): δ = 165.0, 161.8, 152.5, 137.0, 128.4, 127.9, 125.6, 122.5, 66.8, 62.6, 58.8, 32.4, 28.2, 25.5, 25.3 ppm. HRMS (ES+): m/z calcd for C15H20NO5S2: 358.0783; found: 358.0782. All other hydroxy sulfones in Scheme  [4] were similarly characterized and gave comparable spectral signatures.

17

General Procedure: Ozonolysis and Intramolecular Olefination (Table 1, Method A)
A moderate stream of ozone was bubbled through a stirred solution of 10 (250 µmol) in CH2Cl2-MeOH (4:1, 5 mL) at -78 ˚C for 10 min. The mixture was sparged with Ar for 5 min and then treated with SMe2 (0.5 mL) and warmed to r.t. during 20 h. The solution was concentrated in vacuo and the residual crude aldehyde taken up in CH2Cl2 (12.5 mL). The solution of aldehyde (£0.02 M) was added via syringe pump during 14-18 h to a stirred 0.04 M solution of DBU (95 mg, 625 µmol, 2.5 equiv) in CH2Cl2 (15 mL) at -78 ˚C (the reaction mixture was allowed to warm slowly to r.t. during the latter half of the addition). After this time, the resulting solution was shaken with sat. aq NH4Cl (10 mL) and the layers separated. The aqueous phase was extracted with CH2Cl2 (2 × 5 mL) and the combined organic phases washed with brine (10 mL), dried (Na2SO4), and concentrated in vacuo. Purification of the residue was effected by column chromatography (SiO2, eluting with 10-15% EtOAc in hexanes).

19

Data for ( Z )-Lactones 2 (Table 1)
(Z)-2-12 (n = 7): colorless oil. IR (neat): 2920, 2850, 1734, 1717, 1700, 1457 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 6.32 (1 H, dt, J = 11.7, 8.9 Hz), 5.76 (1 H, dt, J = 11.7, 0.9 Hz), 4.23-4.19 (2 H, m), 2.47 (2 H, q, J = 7.9 Hz), 1.89-1.80 (2 H, m), 1.51-1.30 (10 H, m) ppm. ¹³C NMR (75 MHz, CDCl3): δ = 167.6, 147.7, 121.8, 66.4, 26.7, 26.3, 25.7, 25.5, 24.8, 24.7, 22.3 ppm. HRMS (EI+): m/z calcd for C11H18O2: 182.1307; found: 182.1298.
(Z)-2-13 (n = 8): colorless oil. IR (neat): 2926, 2855, 1716, 1653, 1458, 1153 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 6.15 (1 H, dt, J = 11.7, 8.5 Hz), 5.78 (1 H, dm, J = 11.8 Hz), 4.27-4.22 (2 H, m), 2.53 (2 H, qm, J = 7.6 Hz), 1.73-1.65 (2 H, m), 1.55-1.32 (12 H, m) ppm. ¹³C (100 MHz, CDCl3):
δ = 167.7, 147.0, 121.7, 65.4, 28.0, 27.3, 27.2 (2 C), 26.5, 26.3, 25.0, 24.8 ppm. HRMS (CI+): m/z calcd for C12H21O2: 197.1542; found: 197.1536. (Z)-2-15 (n = 10): colorless oil. IR (neat): 2928, 2857, 1720, 1643, 1459, 1173 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 6.13 (1 H, dt, J = 11.7, 8.0 Hz), 5.78 (1 H, dt, J = 11.7, 1.4 Hz), 4.26-4.21 (2 H, m), 2.58 (2 H, qd, J = 7.9, 1.4 Hz), 1.73-1.61 (2 H, m), 1.60-1.20 (18 H, m) ppm. ¹³C NMR (75 MHz, CDCl3): δ = 167.5, 148.2, 121.1, 64.6, 28.6, 28.4, 27.6, 27.0, 26.8, 26.63, 26.57, 26.2, 26.1, 25.2 ppm. HRMS (EI+): m/z calcd for C14H24O2: 224.1776; found: 224.1769. (Z)-2-19 (‘n = 14’): colorless oil/waxy solid. IR (neat): 2927, 2851, 1702, 1655, 1473, 1108 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 6.14 (1 H, dt, J = 11.6, 7.9 Hz), 5.77 (1 H, dm, J = 11.6 Hz), 4.17 (2 H, t, J = 5.9 Hz), 3.48-3.36 (4 H, m), 2.54 (2 H, qm, J = 7.4 Hz), 1.75-1.62 (2 H, m), 1.55-1.15 (18 H, m) ppm. ¹³C NMR (75 MHz, CDCl3): δ = 167.1, 149.0, 120.6, 70.0, 69.8, 64.0, 29.7-28.0 (8 C), 25.7 (2 C), 25.5 ppm. HRMS (EI+): m/z calcd for C17H30O3: 282.2195; found: 282.2183. Minor E-lactones revealed by: δH = ca. 6.94 (1 H, dt, J = 15.6, 7.9 Hz) ppm. ¹H NMR data for ( Z )-2-15 are in agreement with those previously reported: Hayashikoshi, T.; Abe, M.; Kurata T. Sekiyu Gakkaishi 1996, 39, 74.

20

Data for ( Z , Z )-diolides 13 (Table 1) (Z,Z)-13-14 (n = 2): waxy solid. IR (neat): 2923, 1705, 1628, 1299 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 6.24 (2 H, dt, J = 11.7, 8.7 Hz), 5.81 (2 H, dm, J = 11.7 Hz), 4.20 (4 H, t, J = 5.1 Hz), 2.77 (4 H, q, J = 8.2 Hz), 1.87-1.79 (4 H, m) ppm. ¹³C NMR (100 MHz, CDCl3): δ = 167.0, 145.5, 122.5, 63.8, 28.2, 27.1 ppm. HRMS (CI+): m/z calcd for C12H17O4: 225.1127; found: 225.1128. (Z,Z)-13-16 (n = 3): colorless oil. IR (neat): 2925, 1716, 1653, 1458, 1288 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 6.26 (2 H, dt, J = 11.7, 8.6 Hz), 5.75 (2 H, dm, J = 11.6 Hz), 4.20 (4 H, t, J = 5.6 Hz), 2.67 (4 H, qm, J = 7.5 Hz), 1.78-1.70 (4 H, m), 1.65-1.50 (4 H, m) ppm. ¹³C NMR (100 MHz, CDCl3): δ = 167.2, 146.3, 121.7, 64.3, 29.8, 29.2, 26.5 ppm. HRMS (EI+): m/z calcd for C14H20O4: 252.1362; found: 252.1370. (Z,Z)-13-18 (n = 4): colorless oil. IR (neat): 2923, 2853, 1698, 1458 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 6.18 (2 H, dt, J = 11.6, 8.3 Hz), 5.75 (2 H, dm, J = 11.6 Hz), 4.19 (4 H, t, J = 5.8 Hz), 2.61 (4 H, q, J = 7.3 Hz), 1.70-1.40 (12 H, m) ppm. ¹³C NMR (100 MHz, CDCl3): δ = 167.2, 147.7, 121.2, 64.3, 29.7, 28.9, 28.7, 26.5 ppm. HRMS (EI+): m/z calcd for C16H25O4: 281.1753; found: 281.1754.
(Z,Z)-13-24 (n = 7): colorless solid; mp 58-60 ˚C. IR (KBr): 2917, 2850, 1719, 1700, 1465 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 6.19 (2 H, dt, J = 11.7, 8.0 Hz), 5.74 (2 H, dm, J = 11.7 Hz), 4.17 (4 H, t, J = 6.0 Hz), 2.54 (4 H, q, J = 7.2 Hz), 1.75-1.60 (6 H, m), 1.50-1.20 (18 H, m) ppm. ¹³C NMR (75 MHz, CDCl3): δ = 167.3, 148.6, 120.9, 64.4, 29.5, 29.33, 29.26, 29.1, 29.0, 26.4 ppm. HRMS (EI+): m/z calcd for C22H36O4: 364.2614; found: 364.2617. Data for (E,Z)-diolides 13-14, 13-16, and 13-18, can be found in ref. 10b.

22

General Procedure: Dess-Martin Oxidation and Intramolecular Olefination (Table 1, Method B)
A solution of 12 (250 µmol) in anhyd CH2Cl2 (2 mL) was treated with DMP²¹ (160 mg, 375 µmol) and stirred for 45 min at r.t. Mixture diluted with CH2Cl2 (10 mL) and washed successively with 10 wt% aq NaHCO3 (10 mL) and brine (10 mL), dried (Na2SO4), and then concentrated in vacuo. The residual crude aldehyde was taken up in CH2Cl2 (12.5 mL) and this solution (£0.02 M) added via syringe pump during 14-18 h to a stirred 0.04 M solution of DBU (266 mg, 1.75 mmol, 7.0 equiv) in CH2Cl2 (45 mL) at r.t. After this time, the reaction mixture was quenched with sat. aq NH4Cl (10 mL) and worked up and purified as indicated above for method A (ref. 17).