5158
Y. Takashima, Y. Kobayashi / Tetrahedron Letters 49 (2008) 5156–5158
copy14 (Scheme 4), thus confirming that 7 derived from 5 and 6
was free of the regioisomer 27. On the other hand, the absolute
configuration and the chirality transfer was determined at a later
stage of the synthesis because of unsuccessful purification at the
mixture of 7 and the by-product(s).
The mixture of 7 and the by-product(s) was submitted to the
conventional dihydroxylation to give the diol 14 as a diastereo-
meric mixture, which was isolated by chromatography in 75% yield
from 5. Oxidative cleavage of the diol followed by reduction of the
aldehyde intermediate in one flask afforded alcohol 15 in 82%
yield. The enantiomeric excess of 15 was 91% by chiral HPLC, and
thus chirality transfer for the allylic substitution was calculated
to be 97% or more.15
References and notes
1. Veitch, N. C. Nat. Prod. Rep. 2007, 24, 417–464.
2. Marais, J. P. J.; Ferreira, D.; Slade, D. Phytochemistry 2005, 66, 2145–2176.
3. (a) Lamartiniere, C. A. Am. J. Clin. Nutr. 2000, 71, 1705S–1707S; (b) Adlercreutz,
H.; Mousavi, Y.; Clark, J.; Hockerstedt, K.; Hamalainen, E.; Wahala, K.; Makela,
T.; Hase, T. J. Steroid Biochem. Mol. Biol. 1992, 41, 331–337.
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Chang, Y.-C.; Nair, M. G. J. Nat. Prod. 1995, 58, 1892–1896; Cf. isolation from
woods: (c) Kurosawa, K.; Ollis, W. D.; Redman, B. T.; Sutherland, I. O. J. Chem.
Soc., Chem. Commun. 1968, 1263–1294. and 1265–1267.
5. (a) Borriello, S. P.; Setchell, K. D.; Axelson, M.; Lawson, A. M. J. Appl. Bacteriol.
1985, 58, 37–43; (b) Sathyamoorthy, N.; Wang, T. T. Y. Eur. J. Cancer 1997, 33,
2384–2389; A similar study (c) Morito, K.; Hirose, T.; Kinjo, J.; Hirakawa, T.;
Okawa, M.; Nohara, T.; Ogawa, S.; Inoue, S.; Muramatsu, M.; Masamune, Y. Biol.
Pharm. Bull. 2001, 24, 351–356.
6. Muthyala, R. S.; Ju, Y. H.; Sheng, S.; Williams, L. D.; Doerge, D. R.;
Katzenellenbogen, B. S.; Helferich, W. G.; Katzenellenbogen, J. A. Bioorg. Med.
Chem. 2004, 12, 1559–1567.
7. Schmitt, E.; Dekant, W.; Stopper, H. Toxicol. In Vitro 2001, 15, 433–439.
8. Wang, X.-L.; Hur, H.-G.; Lee, J. H.; Kim, K. T.; Kim, S.-I. Appl. Environ. Microbiol.
2005, 71, 214–219.
9. Heemstra, J. M.; Kerrigan, S. A.; Doerge, D. R.; Helferich, W. G.; Boulanger, W. A.
Org. Lett. 2006, 8, 5441–5443.
10. (a) Versteeg, M.; Bezuidenhoudt, B. C. B.; Ferreira, D.; Swart, K. J. J. Chem. Soc.,
Chem. Commun. 1995, 1317–1318; (b) Versteeg, M.; Bezuidenhoudt, B. C. B.;
Ferreira, D. Tetrahedron 1999, 55, 3365–3376.
11. Kiyotsuka, Y.; Acharya, H. P.; Katayama, Y.; Hyodo, T.; Kobayashi, Y. Org. Lett.
2008, 10, 1719–1722.
An attempted demethylation and bromination of the primary
hydroxy group with BBr316 gave unidentified product(s). After sev-
eral unsuccessful trials, it was found that bromination of 15 fol-
lowed by demethylation of the methoxy bromide 16 with BBr3
successfully afforded the bromophenol 17, which without purifica-
tion was converted to equol (3) by exposure to K2CO3 in acetone in
74% yield from 16. Equol thus synthesized had 91% ee by chiral
HPLC.17 However, the specific rotation (½a 2D5
ꢀ13 (c 0.21, EtOH))
ꢃ
was inconsistent with those reported for equol of 100% and >99%
ee (½a 2D4
ꢃ
ꢀ23.0 (c not given, EtOH);8
½
a 2D4
ꢃ
ꢀ23.5 (c not given,
12. (a) Marco, J. A.; Carda, M.; Diaz-Oltra, S.; Murga, J.; Falomir, E.; Roeper, H. J. Org.
Chem. 2003, 68, 8577–8582; (b) Massad, S. K.; Hawkins, L. D.; Baker, D. C. J. Org.
Chem. 1983, 48, 5180–5182.
13. Bernstein, P. R.; Snyder, D. W.; Adams, E. J.; Krell, R. D.; Vacek, E. P.; Willard, A.
K. J. Med. Chem. 1986, 29, 2477–2483.
14. Chemical shifts of CH3 d 1.61 ppm for the former and 1.31 ppm for the latter.
15. There still remains a possibility of a few percentage racemization at the
aldehyde stage.
EtOH),9, respectively).18 Its 1H and 13C NMR spectra and mp were
consistent with those reported8,9 and the structure was also sup-
ported by the 13C APT signals.17
In summary, we established a new method to synthesize (S)-
equol (3) from L-lactate 9 in 31.6% total yield over 11 steps
(24.6% from 18 over 13 steps), which is higher than the method re-
ported.9 Since the allylic substitution (5 + 6/CuBr) is applicable to
various picolinates and ArMgBr, compounds with similar struc-
16. Pettetier, J. D.; Poirier, D. Tetrahedron Lett. 1994, 35, 1051–1054.
17. HPLC analysis (Chiralcel AD-H, hexane/i-PrOH = 90/10, 1.0 mL/min, tR
(min) = 38.7 for R-isomer, 49.4 for 1); mp 190–191 °C (lit.8 190.8 °C; lit.9
192–193 °C); ½a 2D5
ꢀ13 (c 0.21, EtOH); IR (Nujol) 3358, 1615, 1598, 1151, 1024,
ꢃ
tures to equol would be readily accessible. Furthermore, the D-iso-
829 cmꢀ1 1H NMR (300 MHz, DMSO-d6) d 2.70–2.90 (m, 2H), 2.95–3.07 (m,
;
mer is commercially available at a reasonable cost, and thus (R)-
1H), 3.89 (t, J = 10.5 Hz, 1H), 4.10–4.18 (dm, J = 8 Hz, 1H), 6.19 (d, J = 2.5 Hz,
1H), 6.28 (dd, J = 8, 2.5 Hz, 1H), 6.72 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8 Hz, 1H),
7.10 (d, J = 8.5 Hz, 2H), 9.16 (s, 1H), 9.28 (s, 1H); 13C NMR (75 MHz, DMSO-d6) d
31.3 (+), 37.2 (ꢀ), 70.2 (+), 102.5 (ꢀ), 108.0 (ꢀ), 112.6 (+), 115.2 (ꢀ), 128.3 (ꢀ),
130.1 (ꢀ), 131.6 (+), 154.5 (+), 156.1 (+), 156.5 (+).
enantiomers of equol and similar compounds are also accessible.19
Acknowledgment
18. Since sufficient chemical purity of our equol was confirmed by 1H NMR and
TLC analyses and by measurement of mp, presently we have no adequate
reason for the difference.
This work was supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Science, Sports, and Culture,
Japan.
19. Synthesis of racemic equol was reported: Gharpure, S. J.; Sathiyanarayanan, A.
M.; Jonnalagadda, P. Tetrahedron Lett. 2008, 49, 2974–2978.