Basabe et al.
JOCArticle
SCHEME 4. Synthesis of Luffalactone and 16-Epiluffalactonea
Conversion of the furanic ring into the γ-hydroxybuteno-
lide was carried out following Faulkner’s methodology.25
Photochemical oxidation of 23 and 24 with 1O2 in the
presence of Rose Bengal irradiating with a 200 W lamp for
5 h gave the hydroxybutenolides 25 (69%) and 26 (79%).
26
Reduction with NaBH4 transformed the γ-hydroxybute-
nolide ring into the required γ-butenolide present in 4 and 27.
The spectroscopic characteristics of 4, as well as its optical
rotation [R]2D2 = þ18.2 (c = 0.27 C6H6), are identical to those
corresponding to the natural product described by Faulkner
as (þ)-luffalactone [R]2D2 = þ18.8 (c = 0.48 C6H6).
It can be concluded that the stereochemistry of (þ)-luffa-
lactone at C-16 is R. The absolute stereochemistry of this
natural product has been established as (5S,8R,9R,10S,16R).
Conclusions
Enantioselective synthesis of (þ)-luffalactone has been
accomplished, and its absolute stereochemistry is now estab-
lished. Since (þ)-luffalactone, 16-epi-luffalactone, and the
γ-hydroxybutenolides 25 and 26 have promising structures
to act as inhibitors of phospholipase A2 they will be subjected
to activity tests, which will be published in due course.
aReagents and conditions: (a) Dess-Martin periodinane, DCM; (b)
NaClO2 5%, tBuOH, NaH2PO4, 2-methyl-2-butene; (c) 2,4,6-trichlor-
obenzoyl chloride, Et3N, toluene; then DMAP; (d) O2, Rose Bengal, hν,
DCM; (e) NaBH4, EtOH.
THP group under mild acidic conditions (catalytic p-TsOH/
MeOH). At that point, with compounds 13a and 14a in our
hands, we were able to perform the required NMR studies.
Comparison between NMR spectra of each parent com-
pound and its derivative, especially the δ of H-18 (6.40 and
6.44 ppm for 13 and 13a, respectively, and 6.40 and 6.30 ppm
for 14 and 14a, respectively) confirmed the (R)-configuration
for 13 at C-16 and the (S)-configuration for 14 at the same
position (Scheme 3).
Acetylation of 13 led to 15 and, in the same way, 16 was
obtained from 14. Hydrolysis of 15 and 16 yielded the
enantiopure compounds 17 and 18, respectively. Both 17
and 18 are the key intermediates for the synthesis of luffa-
lactone and its epimeric analogue.
The synthesis of 4 was carried out separately as it is shown
in Scheme 4. The key step to reach luffalactone and 16-epi-
luffalactone from 17 and 18 is a Yamaguchi-type macro-
lactonization22 of the acids 21 and 22.
Oxidation of 17 and 18 to the corresponding acids required
two steps (Scheme 4). First, oxidation of the alcohols gave
the R,β-unsaturated aldehydes 19 and 20 using Dess-Martin
periodinane as oxidant, and second, further oxidation gave
the acids with NaClO2.23 To accomplish the lactonization
between the acid group and the tertiary alcohol of 21 and 22,
they were treated first with 2,4,6-trichlorobenzoyl chloride
and Et3N in toluene, and then with DMAP,24 obtaining the
lactones 23 and 24 with 88% and 78% yield, respectively.
Experimental Section
Methyl 8r-Acetoxy-24-(2-tetrahydropiranyloxy)-17,18,19,25-
tetranor-8,14-seco-luffol-13(Z)-en-16-oate (10). To a solution of
(2-carboxyethyl)triphenylphosphonium bromide (1.06 g, 2.56
mmol) in 12 mL of a mixture of THF/DMSO 4:1 cooled at
-5 °C was added n-BuLi dropwise 1.6 M in hexane (3.2 mL,
5.12 mmol). After the mixture was stirred for 10 min, 9 (270 mg,
0.64 mmol) was added as a solution in 12 mL of THF/DMSO 4:1
via cannula. The reaction was vigorously stirred at -5 °C for 2 h,
withprogresscontrolled byTLC. Then, 1.0 mLof MeI was added
(17 mmol), and the resulting mixture was stirred at rt overnight.
After addition of 20 mL of water, the mixture was extracted with
EtAcO and the organic layer was washed with water and brine
and dried over anhydrous Na2SO4. The crude obtained after
removal of the solvent was purified by column chromatography
eluting with hexane/EtAcO 8:2 to yield 216 mg of 10 (0.45 mmol,
70%): [R]2D2 = -8.2 (c = 0.56 CHCl3); IR (film) 2944, 2872, 1728,
1388, 1251 1126, 1023 cm-1; 1H NMR (400 MHz, CDCl3, δ ppm)
5.56 (1H, t, J = 7.1 Hz), 4.57 (1H, t, J = 3.3 Hz), 4.18 (1H, dd,
J = 11.9, 1.8 Hz), 4.03 (1H, dd, J = 11.9, 1.8 Hz), 3.88-3.83 (1H,
m), 3.68 (3H, s), 3.52-3.49(1H, m), 3.18 (2H, d, J = 7.1 Hz), 2.63
(1H, dd, J = 1.6, 12.3 Hz), 2.26-2.12 (1H, m), 1.93 (3H, s),
1.80-1.70 (1H, m), 1.70-1.65 (2H, m), 1.65-1.63 (1H, m),
1.62-1.56 (1H, m), 1.55-1.45 (6H, m), 1.52-1.48 (2H, m),
1.47 (3H, s), 1.45-1.40 (2H, m), 1.42-1.39 (1H, m), 1.25-1.15
(1H, m), 1.15-1.10 (1H, m), 1.05-0.95 (1H, m), 1.00-0.90 (1H,
m), 0.86 (3H, s), 0.84 (3H, s), 0.78 (3H, s); 13C NMR (100 MHz,
CDCl3, δ ppm) 172.8, 170.5/170.4, 140.6, 120.3, 97.8, 88.2, 64.5/
64.6, 62.3/62.4, 59.0, 55.9, 52.0, 42.1 (ꢀ2), 39.7, 39.0, 38.9, 33.6,
33.3 (ꢀ2), 30.8, 25.7, 25.2, 23.2, 21.7, 20.7, 20.2, 19.7, 18.5, 15.9;
HRMS [M þ Na] 515.3323, calcd for C29H48O6Na 515.3343.
16(R)-Acetoxy-19,25-epoxy-8,14-seco-luffola-13(Z),17(25),18-
triene-8r,24-diol (17). To a solution of 15 (18 mg, 0.036 mmol) in
3.5 mL of MeOH was added p-TsOH (2 mg, 0.01 mmol). After
being stirred at rt for 4 h, the mixture was diluted with water
(5 mL) and extracted with EtAcO. The extracts were washed with
water and brine and dried over anhydrous Na2SO4. After solvent
removal, 17 was quantitatively obtained: [R]2D2 = þ2.2 (c = 0.14
(22) (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989. (b) Haslam, E. Tetrahedron 1980, 36,
2409. (c) Mulzer, J. Comp. Org. Synth. 1991, 6, 323. (e) Meng, Q.; Hesse, M.
Top. Curr. Chem. 1992, 161, 107. (f) Thjis, l.; Egenberger, D. M.; Zwanen-
burg, B. Tetrahedron Lett. 1989, 30, 2153. (g) Hikota, M.; Tone, H.; Horita,
K.; Yonemitsu, O. Tetrahedron 1990, 46, 4613.
(23) (a) Makara, G. M.; Anderson, W. K. J. Org. Chem. 1995, 60, 5717.
(b) Babu, B. R.; Balasubramaniam, K. K. Org. Prep. Proced. Int. 1994, 26,
123.
ꢀ
(24) (a) Hartmann, B.; Kanazawa, A. M.; Depres, J.-P.; Greene, A. E.
Tetrahedron Lett. 1991, 32, 5077. (b) Ichikawa, Y.; Tsuboi, K.; Jiang, Y.;
Naganawa, A.; Isobe, M. Tetrahedron Lett. 1995, 36, 7101. (c) Marino, J. P.;
McClure, M. S.; Holub, D. P.; Comasseto, J. V.; Tucci, F. C. J. Am. Chem.
Soc. 2002, 124, 1664. (d) Chakraborty, T. K.; Ghosh, S.; Laxman, P.; Dutta,
S.; Samanta, R. Tetrahedron Lett. 2005, 46, 5447. (e) Allais, F.; Louvel,
M.-C.; Cossy, J. Synlett 2007, 3, 451.
(25) Kernan, M. R.; Faulkner, D. J. J. Org. Chem. 1988, 53, 2773.
(26) Sinhababu, A. K.; Borchardt, R. T. J. Org. Chem. 1983, 48, 2356.
J. Org. Chem. Vol. 74, No. 20, 2009 7753