Synthesis of α-Acetyl Lactones; Access to 14-Membered Bislactones by Attempts at Direct Ring Closure

Abstract

α-Acetyl lactones are accessed by Mukaiyama-Claisen reactions. Attempts at direct 7-membered ring closure, by either intramolecular alkylation of 4-iodobutyl acetoacetate or olefin meta­thesis from allyl 2-allyl-3-oxobutanoate, afford exclusively dimeric 14-membered ring products instead of the expected caprolactones.

Key words

acylations - β-dicarbonyl compounds - lactones - macrocycles - metathesis

References

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5

3,10-Diacetyl-2,9-dioxo-1,8-dioxacyclotetradecane (5). A solution of 500 mg (1.76 mmol) iodoester 4b in 2 mL THF was added dropwise at 0 °C to a suspension of NaH (55%, 90.1 mg, 2.06 mmol) in 20 mL THF, and the reaction mixture heated to reflux overnight. Aq citric acid solution (20 mL, 20%) was added, and the mixture extracted with hexanes (3 × 10 mL). The organic phases were combined and dried over MgSO₄. The solvent was stripped off, and the crude product purified by chromatography on SiO₂ (hexanes/EtOAc, 2:1, R_f = 0.24), yielding lactone 5 as a colorless solid (37 mg, 0.12 mmol, 14%), mp 109-110 °C. Crystallization from hexanes/EtOAc afforded a product with one predominant diastereoisomer (single signal set in the NMR spectra) from which single crystals of the meso-diastereoisomer 5a could be grown. ¹H NMR (CDCl₃, 500 MHz): δ = 1.36-1.50 (m, 4 H), 1.57-1.65 (m, 2 H), 1.68-1.75 (m, 2 H), 1.77-1.84 (m, 2 H), 1.91-1.99 (m, 2 H), 2.22 (s, 6 H), 3.43 (dd, J = 11.6 Hz, J = 3.5 Hz, 2 H), 4.19-4.23 (m, 2 H), 4.27-4.31 (m, 2 H) ppm. ¹³C{¹H}-NMR (CDCl₃, 125 MHz) of the major (5a) and minor (5b) diastereoisomer: cf. Table. IR (KBr): 1728 (vs), 1705 (vs) cm^-1. MS (EI, 70 eV): m/z (%) = 312 (45) [M⁺], 270 (44), 157 (91), 139 (60), 43 (100). Anal. Calcd. for C₁₆H₂₄O₆: C, 61.53; H, 7.74. Found: C, 61.33; H, 7.70.

6

Crystallographic data (excluding structure factors) for the structures reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-176501 (5a) and no. CCDC-176500 (9a). Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax: [phone]; E-mail: [e-mail]].

15

4,11-Diacetyl-5,12-dioxo-6,13-dioxa-1,8-cyclotetra-decadiene (9). To a solution of 500 mg (2.74 mmol) ester 8 in 30 mL CH₂Cl₂, 70 mg (0.082 mmol) Ru catalyst and 40 mL CH₂Cl₂ were added. The reaction mixture was heated to reflux for 1 d, the solvent stripped off, and the residue purified by chromatography on SiO₂ (MTB/hexanes, 1:1, R_f = 0.14) to give 9 as a colorless solid (307 mg, 0.996 mmol, 73%), mp 119 °C. Crystallization from MeOH afforded a crystalline material which consists predominantly of a single diastereoisomer 9a (single ¹H and ¹³C NMR signal set). From a CH₂Cl₂ solution of this material, single crystals of 9a could be grown for the X-ray diffraction analysis. In CDCl₃ solution, 9a epimerizes to a matrix-dependent 9a/9b equilibrium mixture. ¹H NMR (CDCl₃, 500 MHz): 9a - δ = 2.242 (COCH₃, s, 3 H), 2.46₀ (3-H_B, m, 1 H), 2.651
(3-H_A, dddd, J = (-) 14.8 Hz, J = 11.3 Hz, J = 8.0 Hz,
J = 0.9 Hz, 1 H), 3.542 (4-H, dd, J = 11.3 Hz, J = 3.6 Hz, 1 H), 4.380 (7-H_B, ddt, J = (-)11.8₅ Hz, J = 5.7₅ Hz, J = 1.2 Hz, 1 H), 4.857 (7-H_A, ddd, J = (-)11.8₅ Hz, J = 7.5 Hz,
J = 0.8 Hz, 1 H), 5.633 (1-H, ddddd, J = 15.3₅ Hz, J = 7.5 Hz, J = 5.7₅ Hz, J = 1.6₅ Hz, J = 0.9 Hz, 1 H), 5.725 (2-H, ddddd, J = 15.3₅ Hz, J = 8.0 Hz, J = 5.2 Hz, J = 1.1 Hz,
J = 0.8 Hz, 1 H) ppm. ¹³C{¹H}-NMR (CDCl₃, 125 MHz) of the major (9a) and minor (9b) E,E-diastereoisomers as well as of the two E,Z-diastereoisomers (9c, 9d): cf. Table. IR (ATR): 1733 (vs), 1709 (vs), 1641 (w)cm^-1. MS (EI, 70 eV): m/z (%) = 308 (6) [M⁺], 307 (2), 155 (63), 154 (50), 137 (24), 112 (24), 111 (30), 95 (40), 94 (28), 67 (32), 43 (100). Mol. mass calcd. for C1₁₆H₂₀O₆: 308.1260; found: 308.1265 (M⁺). Anal. Calcd. for C₁₆H₂₀O₆: C, 62.33; H, 6.54. Found: C, 62.02; H, 6.42.

16

Structural Elucidation. With two asymmetric carbon atoms and two C=C double bonds, the macrolactone 9 comprises four stereogenic elements; six diastereoisomers thence are possible for compound 9, four of them chiral. The two stereocenters can be in either a rac (R,R or S,S) or meso-R,S relationship, with the acetyl groups cis or trans, respectively; the two double bonds may have E,E, E,Z, or Z,Z configuration. As Figure [2] shows, the single crystal obtained from the purified RCM product represents the meso-E,E-diastereoisomer 9a, in accord with the predominant set of eight ¹³C resonances. To unequivocally correlate X-ray diffraction with NMR solution stereochemistry, [22] another crystal was selected from the single crystal crystallization crop (0.5 × 0.3 × 0.05 mm).
On the basis of 15 unique reflexes, detected by rotation photograph, P2₁/c was determined as the space group for this crystal, which definitely established its structural identity with the single crystal on which the diffraction analysis was performed. The crystal (∼10 µg) was dissolved in CDCl₃
(0.3 mL; 10^-5 mol dm^-3 solution), and a ¹H NMR spectrum recorded immediately. Apart from a minor impurity, the spectrum displayed a clean set of seven ¹H multiplets. For the two olefinic resonances at 5.725 and 5.633 ppm (1/8- and 2/9-H), numerical analysis afforded a coupling constant of 15.3₅ Hz which is clearly in the ³ J _trans range and thus unequivocally establishes the E,E configuration. The two diastereotopic protons 7/14-H_A,H_B appear well differentiated at 4.857 and 4.380 ppm.
Upon standing at ambient temperature, though, a second signal set evolved in the NMR sample, with the O-CH_AH_B protons now almost isochronous around ∼4.6 ppm while the resonances of the other five protons appear shifted but slightly. We thence presume that the corresponding rac-E,E-diastereoisomer 9b is formed by epimerization of the stereocenters C-4 and C-11 via the respective enol tautomers. After 24 h, a ∼1:1 equilibrium is established between 9a and 9b. The position of this equilibrium is matrix-dependent, however: if sufficient crystalline material is dissolved in CDCl₃ for a ¹³C NMR spectrum, the ¹H NMR spectrum after two weeks integrates for 93:7 (9a:9b). The ¹³C spectrum displays an additional set of eight signals (cf. Table), with chemical shifts so close to those of the major isomer 9a that a change in double bond configuration is ruled out absolutely.
In an even more concentrated solution, and after 30,000 scans, two additional signal sets can be detected, in a 7:3 ratio (overall relative intensity ca. 5%) and with 16 lines each. Since this per se excludes a Z,Z configuration, these resonances were assigned to the meso-E,Z- (9c, trans) [23] and rac-E,Z-diastereoisomer (9d, cis), respectively (cf. Table). No resonances of a Z,Z-isomer were observed.

21

α-Acetyl-ε-caprolactone (2b). A solution of 0.50 mL (540 mg, 5.29 mmol) Ac₂O and 0.59 mL TiCl₄ (1.02 g, 5.37 mmol) in 10 mL CH₂Cl₂ was stirred for 20 min at -78 °C and then added to a solution of 500 mg (2.68 mmol) of silylenolether 11b in 130 mL CH₂Cl₂. The reaction mixture was stirred at -70 °C for 1 h, warmed to 23 °C, stirred for another 0.5 h, and poured into a sat. aq NaHCO₃ solution (400 mL). The mixture was neutralized with HCl (20%) and extracted successively with CH₂Cl₂ (2 × 100 mL) and EtOAc (1 × 100 mL). The organic phases were combined and dried over MgSO₄. The solvent was stripped off, and the crude product purified by filtration through SiO₂ with EtOAc, affording lactone 2b as a colorless solid (354 mg, 2.27 mmol, 85%), mp 57 °C. ¹H NMR (CDCl₃, 300 MHz): δ = 1.54-1.83 (m, 3 H), 1.94-2.07 (m, 2 H), 2.12-2.20 (m, 1 H), 2.27 (s, 3 H), 3.69 (dd, J = 10.9 Hz, J = 1.9 Hz, 1 H), 4.28 (ddd, J = 12.8 Hz, J = 9.7 Hz, J = 0.7 Hz, 1 H), 4.32-4.39 (m, 1 H) ppm. ¹³C{¹H}-NMR (CDCl₃, 125 MHz): δ = 24.89 (CH₂), 27.06 (CH₂), 28.57 (CH₂), 28.66 (CH₃), 56.67 (CH), 69.38 (CH₂), 173.05 (C), 202.60 (C) ppm. IR (KBr): 1725 (vs), 1702 (vs), 1690 (vs) cm^-1. MS (CI, CH₄): m/z (%) = 157 (100) [M⁺ + H]. Anal. Calcd. for C₈H₁₂O₃: C, 61.52; H, 7.74. Found: C, 61.48; H, 7.71.

23

The term ‘meso’ for the R,S,E,Z-diastereoisomer is misleading, since this compound is in fact chiral.