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G. Pitacco et al. / Tetrahedron: Asymmetry 11 (2000) 3263–3267
Scheme 1.
The enzymic hydrolyses of ( )-3 were carried out in aqueous solution and in a 1:9 mixture of
acetone:water,16,17 both at pH 7.4, using a series of commercially available hydrolases. The most
relevant results are summarized in Table 1.
Addition of a small amount (10%) of acetone resulted in a remarkable increase of the E18,19
value and hence in a higher enantioselectivity. In fact, using Porcine pancreatic lipase, the
corresponding lactonic acid (+)-4 was isolated with 89% e.e., whereas the use of Candida rugosa
lipase furnished the laevorotatory enantiomer (−)-4 with 82% e.e. A second enzymic resolution
carried out on these mixtures improved the e.e. of (+)-4† to 97% and that of (−)-4‡ to 99% e.e.
The e.e’s of the acids were determined by chiral HRGC of their respective ethyl esters (+)-3 and
(−)-3, obtained by esterification of the acids with EDC and HOBT. a-Chymotrypsin also proved
efficient in hydrolysing the ester group, furnishing the acid (+)-4 with 77% e.e., while Aspergillus
niger lipase, Pseudomonas sp. lipase and pig liver esterase were not enantioselective and
Pseudomonas fluorescens lipase furnished (+)-4 with only 29% e.e.
The absolute configuration of (+)-4 was determined to be S by means of CD spectroscopy.
The ethyl ester (+)-3 was reduced with sodium borohydride to a 1:1 mixture of the butanolides
(+)-7 and (+)-8 through the intermediacy of the corresponding lactonic esters (−)-5 and (+)-6,
respectively (Scheme 2). Separation of the hydroxy lactones (+)-7 and (+)-8 afforded both
diastereomers as pure compounds. A comparison was then made between the CD spectrum of
(+)-7§ and that of (3S,5S)-(+)-5-hydroxymethyl-3-methyl-4,5-dihydro-2(3H)-furanone 9.20 Both
compounds exhibited a positive Cotton effect for the np* transition [(+)-7, Dm217 +0.2; UV,
umax 210 nm, mmax 200, EtOH; (+)-9, Dm
+0.3, EtOH; UV, umax 206 nm, mmax 200, EtOH].
220
Although the g-carbon atom in (+)-7 bears a methyl group in place of a hydrogen atom, the
order of polarizability of the substituents is the same in both compounds, thus allowing a
comparison between the curves to be made.21,22 As a consequence, the absolute configuration of
(+)-7 is also (3S,5S) and that of (+)-4 is S.
† (+)-4: [h]D25=+11.8 (c 0.64, MeOH); CD: Dm202=−4.9, Dm226=+3.2 (MeOH); UV: umax 224 nm, mmax 2400 (MeOH);
1H NMR (400 MHz) l, ppm (CDCl3): 9.5 (1H, bs, OH), 6.22 (1H, dt, J 2.9, 2.4 Hz, ꢀCH), 5.66 (1H, dt, J 2.5 Hz,
ꢀCH), 3.27 (1H, dt, J 17.4, 2.4 Hz, H-3), 2.84 (1H, dt, J 17.4, 2.9 Hz, H-3), 1.65 (3H, s, Me); 13C NMR l, ppm
(CDCl3): 175.1 (s), 169.4 (s), 133.5 (s), 123.2 (t), 81.1 (s), 38.5 (t), 24.1 (q).
‡ (−)-4: ([h]2D5 −12.3 (c 0.66, MeOH), CD: Dm201=+6.6, Dm227 −3.9 (MeOH); UV: umax 224 nm, mmax 2400 (MeOH).
1
§ (+)-7: [h]2D5 +5.0 (c 0.90, EtOH); CD: Dm217 +0.2 (EtOH); UV: umax 210 nm, mmax 200 (EtOH); H NMR (400 MHz)
l, ppm (CDCl3): 3.69 (1H, d, J 12.2 Hz, CHOH), 3.43 (1H, d, J 12.2 Hz, CHOH), 2.83 (2H, m and bs, H-3, OH),
2.08 (2H, 2 pseudoquartets of an AB system, 2 H-4), 1.31 (s, 3H, Me), 1.25 (d, 3H, Me); 13C NMR l, ppm (CDCl3):
179.5 (s), 84.2 (s), 67.5 (t), 36.6 (t), 35.0 (d), 22.3 (q), 15.3 (q).