2432
B. Nadal et al. / Tetrahedron Letters 50 (2009) 2430–2433
Chem. Soc. 1968, 2968–2974; (c) Weinstock, J.; Blank, J. E.; Oh, H. J.; Sutton, B.
Table 1
M. J. Org. Chem. 1979, 44, 673–675; (d) Knight, D. W.; Pattenden, G. J. Chem. Soc.,
Perkin Trans. 1 1979, 84–88; (e) Ramage, R.; Griffiths, G. J.; Sweeney, J. N. A. J.
Chem. Soc., Perkin Trans. 1 1984, 1547–1553; (f) Pattenden, G.; Turvill, M. W.;
Chorlton, A. P. J. Chem. Soc., Perkin Trans. 1 1991, 2357–2361; (g) Pattenden, G.;
Pegg, N.; Kenyon, R. J. Chem. Soc., Perkin Trans. 1 1991, 2363–2371; (h) Ahmed,
Z.; Langer, P. J. Org. Chem. 2004, 69, 3753–3757; (i) Ahmed, Z.; Langer, P.
Tetrahedron 2005, 61, 2055–2063.
Synthesis of compounds 1a–h
Entry
Ar0
Boronate
Product
Yield (%)
81
1
4a
1a
3. (a) Meunier, S.; Desage-El Murr, M.; Nowaczyk, S.; Le Gall, T.; Pin, S.; Renault, J.-
P.; Boquet, D.; Créminon, C.; Saint-Aman, E.; Valleix, A.; Taran, F.; Mioskowski,
C. ChemBioChem 2004, 5, 832–840; (b) Meunier, S.; Hanédanian, M.; Desage-El
Murr, M.; Nowaczyk, S.; Le Gall, T.; Pin, S.; Renault, J.-P.; Boquet, D.; Créminon,
C.; Mioskowski, C.; Taran, F. ChemBioChem 2005, 6, 1234–1241.
4. The antioxidant properties of variegatic acid were previously reported. See:
Kasuga, A.; Aoagi, Y.; Sugahara, T. J. Food Sci. 1995, 60, 1113–1115.
5. (a) Desage-El Murr, M.; Nowaczyk, S.; Le Gall, T.; Mioskowski, C.; Amekraz, B.;
Moulin, C. Angew. Chem., Int. Ed. 2003, 42, 1289–1293; (b) Heurtaux, B.; Lion, C.;
Le Gall, T.; Mioskowski, C. J. Org. Chem. 2005, 70, 1474–1477; (c) Desage-El
Murr, M.; Nowaczyk, S.; Le Gall, T.; Mioskowski, C. Eur. J. Org. Chem. 2006,
1489–1498; (d) Willis, C.; Bodio, E.; Bourdreux, Y.; Billaud, C.; Le Gall, T.;
Mioskowski, C. Tetrahedron Lett. 2007, 48, 6421–6424; (e) Bourdreux, Y.; Bodio,
E.; Willis, C.; Billaud, C.; Le Gall, T.; Mioskowski, C. Tetrahedron 2008, 64, 8930–
8937; (f) Mallinger, A.; Le Gall, T.; Mioskowski, C. J. Org. Chem. 2009, 74, 1124–
1129.
HO
2
3
4
4b
4c
4d
1b
1c
1d
73
60
64
Cl
F3C
CF3
6. Lacey, R. N. J. Chem. Soc. 1954, 832–839.
7. For recent syntheses of tetronic acids via Dieckmann condensation, see. ( )-
Stemonamine: (a) Zhao, Y.-M.; Gu, P.; Tu, Y.-Q.; Fan, C.-A.; Zhang, Q. Org. Lett.
2008, 10, 1763–1766; Pulvinones: (b) Bernier, D.; Moser, F.; Brückner, R.
Synthesis 2007, 2240–2248; Bernier, D.; Brückner, R. Synthesis 2007, 2249–
2272; Retipolide E, ornatipolide: (c) Ingerl, A.; Justus, K.; Hellwig, V.; Steglich,
W. Tetrahedron 2007, 63, 6548–6557; Abyssomicin C, atrop-abyssomicin C, and
abyssomicin D: (d) Nicolaou, K. C.; Harrison, S. T. J. Am. Chem. Soc. 2007, 129,
429–440.
5
6
4e
4f
1e
1f
80
50
O
8. Reviews on tetronic acids synthesis: (a) Tejedor, D.; García-Tellado, F. Org. Prep.
Proc. Int. 2004, 36, 33–59; (b) Zografos, A. L.; Georgiadis, D. Synthesis 2006,
3157–3188; (c) Schobert, R.; Schlenk, A. Bioorg. Med. Chem. 2008, 16, 4203–
S
7
8
4g
4h
1g
1h
61
61
4221.
0
9. Brandänge, S.; Flodman, L.; Norberg, ÅA J. Org. Chem. 1984, 49, 927–928.
10. Synthesis of compound 10: A solution of LiHMDS (109 mL, 1 M in THF) was
added to THF (220 mL) under nitrogen. The solution was cooled to ꢀ78 °C and
then a solution of compound 9 (11.9 g, 36.5 mmol) in THF (120 mL) was added
dropwise. The reaction mixture was stirred for 1 h at ꢀ78 °C and then allowed
to warm to room temperature over 2 h. After cooling at 0 °C, aqueous 2 N HCl
(140 mL) was added. The two layers were separated, and the aqueous layer
was extracted with AcOEt (2 ꢁ 200 mL). The combined organic layers were
dried (MgSO4) and filtered. Concentration under vacuum afforded tetronic acid
10 (10.7 g) as a pale yellow solid, which was used directly in the next step.
O
(entries 2–5). As could have been expected, the reaction involving
boronate 4f, in which the phenyl group is substituted in the para
position by the electron-withdrawing acetyl group was less effi-
cient (entry 6). Compounds 1g and 1h derived from heterocyclic
boronates 4g and 4h, containing a 3-thienyl and a 3-furanyl group,
respectively, were also prepared uneventfully (entries 7 and 8). It is
worthy of note that these cross-couplings were carried out using
iodide 6, in which the enol function was left unprotected. The anti-
oxidant properties of products 1a–h are under investigation and
will be reported in due course.
Compound 10: Mp 179–181 °C; TLC: Rf 0.35 (9:1 CH2Cl2/MeOH); ½a D20
ꢂ
+132.9 (c
1.00, MeOH); IR (KBr pellet) mmax: 3324, 3016, 2957, 2843, 2645, 1747, 1696,
1637, 1613, 1517, 1447, 1428, 1391, 1312, 1294, 1259, 1213, 1125,1032, 992,
832, 628 cmꢀ1 1H NMR (400 MHz, acetone-d6, d): 7.87 (d, 2H, J = 9.0 Hz, Ar-H),
;
6.94 (d, 2H, J = 9.0 Hz, Ar-H), 5.27 (d, 1H, J = 1.9 Hz, CHOC(O)), 4.79 (d, 1H,
J = 1.9 Hz, CHOH), 3.82 (s, 3H, OCH3), 3.80 (s, 3H, OCH3); 13C NMR (100 MHz,
acetone-d6, d): 172.4, 172.3, 170.5, 159.6, 129.5 (2C), 123.6, 114.3 (2C), 102.7,
78.6, 69.7, 55.5, 52.9; HRMS (ESI-TOF) calcd for C14H14NaO7 [M+Na]+ 317.0637,
found 317.0633.
11. Synthesis of compounds (E)-110, (Z)-11: A solution of tetronic acid 10 (1.5 g,
5.06 mmol), obtained from the previous reaction, and DMAP (91 mg,
0.253 mmol, 5 mol %) in dry CH2Cl2 (45 mL) was cooled to ꢀ18 °C.
Triethylamine (4.23 mL, 30.4 mmol, 6 equiv) was added, then trifluoroacetic
anhydride (2.15 mL, 15.2 mmol, 3 equiv) was added dropwise over 15 min. The
reaction mixture was allowed to warm to room temperature. After stirring for
16 h, 3 N HCl (15 mL) was added. After stirring for 1 h at room temperature, the
two layers were separated, and the aqueous layer was extracted with AcOEt
(2 ꢁ 15 mL). The combined organic layers were dried (MgSO4), filtered, and
concentrated under vacuum. Silica gel chromatography (90:10, then 50:50,
then 30:70 cyclohexane/acetone) afforded alkenes (E)-110 (106 mg, 7%) as a
yellow solid and (Z)-11 as an orange solid (1.13 g, 81%). (E)-110: Mp 159–
In summary, a novel synthetic access to a series of vulpinic
acids was developed. In these vulpinic acids, the lactone ring is
substituted by a 4-methoxyphenyl group, and they differ by the
nature of the aryl or heteroaryl group located in the a-ester posi-
tion. The approach relied on a convenient preparation of alkene
11 from dimethyl tartrate, involving a Dieckmann condensation,
the preparation of iodide 6 under particular conditions, and the
use of a Suzuki–Miyaura cross-coupling as the last step. This ap-
proach is complementary to the methods that we described
previously.
160 °C; TLC: Rf 0.7 (1:1 cyclohexane/acetone); IR (KBr pellet)
2923, 2845, 2594, 1780, 1680, 1635, 1604, 1513, 1440, 1353, 1280, 1251, 1188,
1157, 1093, 1042, 927, 833 cmꢀ1 1H NMR (400 MHz, CDCl3): d 13.15 (s, 1H,
mmax: 3071, 2960,
;
OH), 8.11 (d, 2H, J = 8.6 Hz, Ar-H), 6.96 (d, 2H, J = 8.6 Hz, Ar-H), 5.98 (s, 1H,
@CHCO2Me), 3.91 (s, 3H, OCH3), 3.84 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3):
d 171.5, 166.6, 159.9, 158.7, 158.2, 129.5 (2C), 121.4, 114.1 (2C), 105.6, 100.2,
55.4, 53.9; HRMS (ESI-TOF) calcd for C14H12NaO6 [M+Na]+ 299.0532, found
299.0542. (Z)-11: Mp 184-185 °C; TLC: Rf 0.1 (1:1 cyclohexane/acetone); IR
Acknowledgment
Financial support of this work by the Délégation Générale pour
l’Armement (DGA) is gratefully acknowledged.
(KBr pellet)
m
max: 3524, 3102, 3009, 2954, 2838, 1710, 1665, 1571, 1517, 1436,
1357, 1288, 1219, 1147, 1031, 957, 903, 836, 781, 651, 590 cmꢀ1
;
1H NMR
(400 MHz, acetone-d6, d): d 7.89 (d, 2H, J = 9.1 Hz, Ar-H), 7.01 (d, 2H, J = 9.1 Hz,
Ar-H), 5.91 (s, 1H, @CHCO2Me), 3.84 (s, 3H, OCH3), 3.76 (s, 3H, OCH3); 13C NMR
(100 MHz, acetone-d6, d): 168.1, 164.2, 160.8, 160.5, 153.3, 130.6 (2C), 121.9,
114.8 (2C), 106.0, 95.8, 55.7, 52.1; HRMS (ESI-TOF) calcd for C14H12NaO6
[M+Na]+ 299.0532, found 299.0524.
References and notes
1. For reviews on pulvinic acid derivatives, see: (a) Gill, M.; Steglich, W. Prog.
Chem. Org. Nat. Prod. 1987, 51, 1–317; (b) Rao, Y. S. Chem. Rev. 1976, 76, 625–
694.
2. For selected pulvinic acid derivatives syntheses, see: (a) Volhard, J. Liebigs Ann.
Chem. 1894, 282, 1–21; (b) Beaumont, P. C.; Edwards, R. L.; Elsworthy, G. J.
12. Crystallographic data (excluding structure factors) have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication
numbers CCDC 717486 for alkene (Z)-11 and CCDC 717485 for iodide 6. Copies