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

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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• 2a Baudin JB. Hareau G. Julia SA. Ruel O. Tetrahedron Lett.  1991,  32:  1175 
• 2b Baudin JB. Hareau G. Julia SA. Lorne R. Ruel O. Bull. Soc. Chim. Fr.  1993,  130:  856 
• 2c Blakemore PR. Cole WJ. Kocienski PJ. Morley A. Synlett  1998,  26 
• Reviews:
• 2d Blakemore PR. J. Chem. Soc., Perkin Trans. 1  2002,  2563 
• 2e Plesniak K. Zarecki A. Wicha J. Top. Curr. Chem.  2007,  275:  163 
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• 3a Zajc B. Kake S. Org. Lett.  2006,  8:  4457 
• 3b Pfund E. Lebargy C. Rouden J. Lequeux T. J. Org. Chem.  2007,  72:  7871 
• For a related process, see:
• 3c del Solar M. Ghosh AK. Zajc B. J. Org. Chem.  2008,  73:  8206 
• For a review of the Horner-Wadsworth-Emmons (HWE) reaction, see:
• 4a Maryanoff BE. Reitz AB. Chem. Rev.  1989,  89:  863 
• For Z-selective variants of the HWE reaction, see:
• 4b Still WC. Gennari C. Tetrahedron Lett.  1983,  24:  4405 
• 4c Ando K. Oishi T. Hirama M. Ohno H. Ibuka T. J. Org. Chem.  2000,  65:  4745 
• For an example of Z-selective intramolecular HWE reaction, see:
• 4d Ahmed A. Hoegenauer EK. Enev VS. Hanbauer M. Kaehlig H. Oehler E. Mulzer J. J. Org. Chem.  2003,  68:  3026 
• For significant new Julia-Kocienski-type transformations employing β-sulfonyl carbonyls, see:
• 5a Nielsen M. Borch Jacobsen C. Paixao MW. Holub N. Jørgensen KA. J. Am. Chem. Soc.  2009,  131:  10581 
• 5b Cassani C. Bernardi L. Fini F. Ricci A. Angew. Chem. Int. Ed.  2009,  48:  5694 
• For example, the cytotoxic α,β-unsaturated macrolides phorboxazole A, rhizoxin D, and laulimalide. See, respectively:
• 6a Searle PA. Molinski TF. J. Am. Chem. Soc.  1995,  117:  8126 
• 6b Iwasaki S. Namikoshi M. Kobayashi H. Furukawa J. Okuda S. Chem. Pharm. Bull.  1986,  34:  1384 
• 6c Corley DG. Herb R. Moore RE. Scheuer PJ. Paul VJ. J. Org. Chem.  1988,  53:  3644 
• 7 Lafontaine JA. Provencal DP. Gardelli C. Leahy JW. J. Org. Chem.  2003,  68:  4215 
• 8 Kocienski PJ. Bell A. Blakemore PR. Synlett  2000,  365 
• 9 Aïssa C. J. Org. Chem.  2006,  71:  360 
• For related studies employing the intramolecular Wittig reaction, see:
• 10a Le Floc’h Y. Yvergnaux F. Toupet L. Grée R. Bull. Soc. Chim. Fr.  1991,  128:  742 
• 10b Le Floc’h Y. Yvergnaux F. Grée R. Bull. Soc. Chim. Fr.  1992,  129:  62 
• 11 Sawhney SN. Boykin DW. J. Org. Chem.  1979,  44:  1136 
• 12 Naya A. Kobayashi K. Ishikawa M. Ohwaki K. Saeki T. Noguchi K. Ohtake N. Chem. Pharm. Bull.  2003,  51:  697 
• Thiazo[2,3-b]benzothiazolium species have been previously identified following treatment of 6 with certain electrophilic activators. For examples, see:
• 15a Duffin GF, and Kendall JD. inventors; US  2513923. 
• 15b Lacova M. Chem. Papers  1986,  40:  95 
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• 21b Boeckman RK. Shao P. Mullins JJ. Org. Synth.  2000,  77:  141 

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 δ_H = 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: δ_H = 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 DMP^²¹ (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).