Synthesis of the core bicyclic system of hyperforin and nemorosone

Article abstract of DOI:10.1016/S0040-4039(02)02693-X

A direct synthesis of analogs of hyperforin and nemorosone containing the key bicyclic unit was accomplished from 2-carboxyethylcyclohexanone and benzoylcyclohexanone. Key steps included a manganic acetate-mediated cyclization and the formation of the bet

Full text of DOI:10.1016/S0040-4039(02)02693-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 659–661
Synthesis of the core bicyclic system of hyperforin and
nemorosone
George A. Kraus,* Tuan H. Nguyen and Insik Jeon
Department of Chemistry, Iowa State University, Ames, IA 50011, USA
Received 13 November 2002; revised 25 November 2002; accepted 26 November 2002
Abstract—A direct synthesis of analogs of hyperforin and nemorosone containing the key bicyclic unit was accomplished from
2-carboxyethylcyclohexanone and benzoylcyclohexanone. Key steps included a manganic acetate-mediated cyclization and the
formation of the beta-bromo enone. © 2003 Published by Elsevier Science Ltd.
Natural products bearing
a
heavily substituted
effect that changes in structure exert on the biological
activity of hyperforin, we have developed an efficient
synthesis of the core units contained in 1 and 2.
phloroglucinol subunit are common secondary metabo-
lites.1 Despite their abundance, this class of compounds
has received little synthetic attention until the past three
years.2 The natural product hyperforin (1) was isolated
from H. perforatum.3 Recently, researchers have reported
that hyperforin may be responsible for the beneficial
effects of St. John’s wort, a commonly used botanical
dietary supplement, on mild depression.4 Nemorosone
(2) was recently isolated.5 In order to understand the
Our synthetic route began with the commercially avail-
able keto ester 3. Alkylation with allyl bromide6 followed
by intramolecular cyclization using manganic triacetate
and cupric acetate according to the method of Snider7
gave keto ester 5 in 56% yield. The keto ester 5 was
converted into the dibromide 6 in 85% yield using 2.2
equiv. of NBS and a catalytic amount of AIBN. Reaction
Scheme 1.
* Corresponding author.
0040-4039/03/$ - see front matter © 2003 Published by Elsevier Science Ltd.
PII: S0040-4039(02)02693-X

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G. A. Kraus et al. / Tetrahedron Letters 44 (2003) 659–661
Scheme 2.
of 6 with 1.1 equiv. of NBS then produced a mixture of
the bromo enone 8 and the tribromide 7. The reaction
of keto ester 5 with 3.3 equiv. of NBS afforded 7 and 8
directly, but the isolation was complicated by an
unidentified polar byproduct that was not present when
the conversion was conducted in two steps. The tribro-
mide 7 could be transformed into enone 8 by heating in
aqueous acetic acid. Overall, 8 could be obtained in
95% yield. The reaction of 8 with the sodium salt of
allyl alcohol followed by heating in a sealed tube in
toluene at 140°C to effect the Claisen rearrangement
provided triketone 9 in 45% overall yield. The structure
of 9 was established by both proton and carbon NMR,
IR and high resolution mass spectrometry (Scheme 1).8
References
1. Stevens, R. Chem. Rev. 1967, 67, 19. Fortschritte Chem.
Org. Naturstoffe 1967, 25, 63.
2. (a) Young, D. G. J.; Zeng, D. J. Org. Chem. 2002, 67,
3134–3137; (b) Spessard, S. J.; Stoltz, B. M. Org. Lett.
2002, 4, 1943–1946; (c) Usuda, H.; Kanai, M.;
Shibasaki, M. Org. Lett. 2002, 4, 859–862; (d) Nicolaou,
K. C.; Pfefferkorn, J. A.; Cao, G.-Q.; Kim, S.; Kessabi,
J. J. Am. Chem. Soc. 1999, 121, 4724–4725.
3. Gurevich, A. I.; Dobrynin, V. N.; Kolosov, M. N.;
Poprako, S. A.; Ryabova, I.; Chernov, B. K.;
Debrentzeva, N. A.; Aizeman, B. E.; Garagulya, A. D.
Antibiotiki (Moscow) 1971, 16, 510.
4. (a) Laakmann, G.; Schule, C.; Baghai, T.; Kieser, M.
Pharmacopsychiatry 1998, 31 (Suppl.), 54–59; (b) Bhat-
tacharya, S. K.; Chakrabarti, A.; Chatterjee, S. S. Phar-
macopsychiatry 1998, 31 (Suppl.), 22–29; (c) Muller, W.
E.; Singer, A.; Wonnemann, M.; Hafner, U.; Rolli, M.;
Schafer, C. Pharmacopsychiatry 1998, 31 (Suppl.), 16–
21.
5. For structure elucidation of compounds in this series,
see: Cuesta-Rubio, O.; Velez-Castro, H.; Frontana-
Uribe, B. A.; Cardenas, J. Phytochemistry 2001, 57,
279–283; Grossman, R. B.; Jacobs, H. Tetrahedron Lett.
2000, 41, 5165–5169.
We next examined a route to an analog of nemorosone.
The diketone 49 was alkylated with sodium hydride and
allyl bromide in boiling THF in 60% yield. Cyclization
with manganic acetate afforded 10 in 76% yield. Treat-
ment of 10 with 3.3 equiv. of NBS and a catalytic
amount of AIBN gave a mixture of enone 11 and
tribromide 12. Tribromide 12 was readily converted
into 11 using hot aqueous acetic acid. Enone 11 was
prepared in an overall yield of 52%. Displacement of
the bromide in 11 using sodium allyloxide provided 13
which was heated in a sealed tube at 170°C to afford
tetraketone 14 via a Claisen rearrangement. The struc-
ture assignment of 14 was supported by proton NMR,
carbon NMR, IR and high resolution mass spectrome-
try (Scheme 2).10
6. Imanishi, T.; Kurumada, T.; Maezaki, N.; Sugiyama,
K.; Iwata, C. J. Chem. Soc., Chem. Commun. 1991,
1409.
7. Cole, B. M.; Han, L.; Snider, B. B. J. Org. Chem. 1996,
61, 7832–7847.
1
The synthesis of 9 and 14 in good overall yields consti-
tutes a useful preparation of analogs of hyperforin and
nemorosonone.9 The synthetic route is direct and is
flexible enough to be extendable to a synthesis of the
natural products.
8. FTIR (thin film) 1733, 1710, 1678, 1572 cm−1; H NMR
(300 MHz, CDCl3) l 5.98–5.90 (m, 1H), 5.35–5.21 (m,
2H), 4.18 (q, J=9 Hz, 2H), 3.53 (t, J=4.5, 1H), 3.33 (d,
J=6 Hz, 2H), 2.51–2.31 (m, 2H), 2.14–1.95 (m, 2H),
1.79–1.73 (m, 2H), 1.27 (t, J=4.5 Hz, 3H); 13C NMR
(300 MHz, CDCl3) l 171.73, 164.90, 164.52, 154.02,
135.38, 118.01, 110.85, 100.97, 61.79, 43.78, 28.54, 26.52,
20.66, 19.15, 14.39; HRMS (EI) m/z calcd for
278.11610, found 278.11542.
Acknowledgements
9. Compound 4 was prepared from the reaction of the
morpholine enamine of cyclohexanone with benzoyl
chloride.
We thank Iowa State University and the Iowa State
University Center for Botanical Dietary Supplements
for partial support of this research.

G. A. Kraus et al. / Tetrahedron Letters 44 (2003) 659–661
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1
10. FTIR (thin film) 1682, 1635, 1596, 1569 cm−1; H NMR
(300 MHz, CDCl3) l 7.98 (d, J=8 Hz, 2H), 7.61 (t,
J=7.5, 1H), 7.50 (t, J=7.8, 2H), 6.02–5.89 (m, 1H),
5.36–5.20 (m, 2H), 4.57 (t, J=5.4, 1H), 3.32 (d, J=6.3,
2H), 2.59–2.50 (m, 1H), 2.40–2.30 (m, 1H), 2.13–2.03
(m, 2H), 1.79–1.67 (m, 2H); 13C NMR (300 MHz,
CDCl3) l 198.27, 164.95, 164.74, 155.23, 135.51, 135.39,
133.87, 129.06, 128.89, 117.84, 111.88, 100.86, 45.24,
28.46, 26.70, 20.51, 18.57; HRMS (EI) m/z calcd for
310.12051, found 310.12098.