Synthesis of a model system for the preparation of phloroglucinol containing natural products

Article abstract of DOI:10.1016/j.tet.2003.03.001

A model system for the synthesis of phloroglucinol containing natural products was synthesized. Key steps include a manganic acetate-mediated cyclization and the facile conversion of an alkene into a β-bromoenone.

Full text of DOI:10.1016/j.tet.2003.03.001

Tetrahedron 59 (2003) 8975–8978
Synthesis of a model system for the preparation of phloroglucinol
containing natural products
*
George A. Kraus, Elena Dneprovskaia, Tuan H. Nguyen and Insik Jeon
Department of Chemistry, Iowa State University, 2759 Gilman Hall, Ames, IA 50011, USA
Received 1 February 2003; accepted 13 March 2003
Abstract—A model system for the synthesis of phloroglucinol containing natural products was synthesized. Key steps include a manganic
acetate-mediated cyclization and the facile conversion of an alkene into a b-bromoenone.
q 2003 Elsevier Ltd. All rights reserved.
Natural products bearing a heavily substituted phloro-
glucinol subunit are common secondary metabolites.1
Recently, this class of compounds has received considerable
synthetic attention.2 The natural product hyperforin (1) was
isolated from H. perforatum.3 Nemorosone (2) was recently
isolated.4 Their challenging structure and potentially-useful
biological activity combine to make these compounds
attractive synthetic objectives. Hyperforin is a reactive
compound that undergoes cyclization reactions in the
presence of oxygen. The enolic b-diketone subunit reacts
with the prenyl groups to form hydroxyalkyl tetrahydro-
furan units or pyran units as in 3.5
Recently, researchers have reported that hyperforin may be
responsible for the beneficial effects of St. John’s wort, a
botanical dietary supplement, on mild depression.6 Other
studies related to the pharmacology of hyperforin have also
been reported.7 In order to understand the effect that
changes in structure exert on the biological activity of
hyperforin, we have developed an efficient synthesis of the
core unit contained in 1.
by palladium catalyzed oxidation10 provided enone 6.
Unfortunately, all attempts to transform either enone 6 or
its corresponding epoxide into b-diketone 7 using palladium
catalysts11 afforded either starting material or decompo-
sition products (Scheme 1).
Our initial approach began with diketone8 4. Initially, the
Michael addition of acrolein using base catalysis (DBU,
CH2Cl2; TMG, CH2Cl2; powdered KOH; Triton B, tert-
Our next approach began with keto ester 8. Alkylation of 8
butanol; K2CO3, proline, MeOH, acetone) proceeded in low
with allyl bromide and intramolecular cyclization using
yield. The product was co-produced with the dimer of
manganic triacetate and cupric acetate using the Snider12
acrolein. The use of sodium methoxide in methanol at
2788C with a trace of hydroquinone improved the yield of
protocol provided keto ester 9 in 60% yield. The
[3.3.1]bicyclononane ring system was the major product.
The isomeric [3.2.1]bicyclooctane was produced in less
than 5% yield.13 Allylic oxidation of the alkene in 9 using
the reaction to 55% yield.9 Cyclization to the bicyclic
hydroxy diketone with HCl in acetone followed by
oxidation of the mixture of diastereomeric alcohols using
PCC, SeO2 or PDC was not selective. After several
PCC afforded the triketone 5 in 62% yield. Conversion of
experiments, the bicyclic keto ester 9 was converted into
triketone 5 into the corresponding enol silyl ether followed
the dibromide 10 in 85% yield using 2.2 equiv. of NBS and
a catalytic amount of AIBN. The structural assignment of
dibromide 10 was supported by the absence of coupling
between the bridgehead hydrogen and the methine hydrogen
alpha to the bromine atom. The reaction of 10 with
Keywords: b-diketone; phloroglucinol; hyperforin.
*
Corresponding author. Tel.: þ1-515-294-7794; fax: þ1-515-294-0105;
e-mail: gakraus@iastate.edu
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.03.001

8976
G. A. Kraus et al. / Tetrahedron 59 (2003) 8975–8978
Scheme 1.
Scheme 2.
Scheme 3.
1.1 equiv. of NBS then produced a mixture of the bromo
enone 12 and the tribromide 11. Interestingly, the reaction
of keto ester 9 with 3.3 equiv. of NBS afforded 11 and 12
directly, but in lower yield. The tribromide 11 was
transformed into enone 12 with aqueous acetic acid at
1158C. Overall, 12 could be obtained in 95% yield. The
reaction of 12 with the sodium salt of allyl alcohol followed
by heating in a sealed tube in toluene at 1408C to effect the
Claisen rearrangement provided triketone 13 in 45% overall
yield from 12. The structure of 13 was established by proton
NMR, carbon NMR, IR, and mass spectrometry
(Scheme 2).14
treatment of 16 with another equivalent of NBS afforded
enone 17. Apparently, the effect of geminal dimethyl
substitution is to render the allylic bromide moiety in 16
more susceptible to conversion to 17 (Scheme 3).
Bromination of 15 with 3.5 equiv. of NBS in the presence of
molecular sieves directly afforded the bromo enone 18 in
55% yield. In this case, the tribromide was not isolated. The
13C NMR spectrum supported the production of one
regioisomer. The structure for 18 was assigned because
the chemical shift of the bridgehead hydrogen in 18 was
similar to that of the bridgehead hydrogen in a model
system.16 Substitution of the bromide with sodium allyl-
oxide followed by a Claisen rearrangement at 1408C
produced b-diketone 19 from 18 (Scheme 4).
The next objective was the preparation of an advanced
intermediate bearing the geminal dimethyl group. We were
concerned that the geminal dimethyl group might inhibit the
formation of the tribromide analogous to compound 11. The
starting material was the known keto ester 14. This
compound had been prepared in three steps by Rothberg
in his synthesis of dehydroambliol-A.15 Intramolecular
cyclization with manganic triacetate and copper acetate
produced predominately the [3.3.1]bicyclononane ring
system 15. The product from the reaction of 15 with
2.2 equiv. of NBS was the dibromide 16. To our surprise,
Scheme 4.

G. A. Kraus et al. / Tetrahedron 59 (2003) 8975–8978
8977
The use of the bromination/hydrolysis strategy efficiently
introduces the b-diketone subunit into the bicyclic ring
system. With suitably protected prenyl groups at the
bridgehead and the three-carbon bridge, this strategy is
expected to be applicable to the synthesis of 1 or 2.
Compounds 13 and 19 have been submitted for biological
evaluation.
1.2.2. Compound 15. 1H NMR (300 MHz, CDCl3) d 5.82–
5.78 (1H, m), 5.57–5.51 (1H, m), 3.65 (3H, s), 3.07–2.81
(3H, m), 2.06–1.97 (2H, m), 1.57–1.53 (1H, m), 1.19–1.10
(1H, m), 1.07 (3H, s), 1.03 (3H, s). 13C NMR (75 MHz,
CDCl3) d 209.8, 171.2, 129.5, 127.0, 64.8, 51.9, 46.7, 42.8,
36.2, 33.4, 28.5, 25.6, 25.0.
1.3. Dibromination with NBS
To a solution of alkene (1 equiv.) in CCl4, was added
AIBN (0.1 equiv.) and NBS (2.2 equiv.). The flask was
fitted with a reflux condenser and irradiated with a sun
lamp. After 30 min (monitored by TLC), the mixture was
allowed to cool to rt and filtered. The crude material was
purified by column chromatography to yield the pure
dibromide.
1. Experimental
1.1. Data for compounds
1.1.1. 5-(1-Oxo-2-methylpropyl)-1-methylbicyclo[3.3.1]-
nonane-2,9-dione (5). A solution of 1.96 g (35 mmol) of
acrolein and 4.55 g (25 mmol) of 4 in 10 mL of diethyl ether
was added dropwise at 2608C over a period of 2 h to
sodium methoxide (prepared from 10 mg of Na in 15 mL of
MeOH) containing 10 mg of hydroquinone. The resulting
mixture was kept at 2608C for another hour and then
warmed to rt (258C). Neutralization with AcOH followed by
removal of the solvent under reduced pressure gave a
residue that was dissolved in 20 mL of ether. The ether layer
was washed successively with brine, satd. NaHCO3, and
brine, and dried over anhydrous MgSO4. The residue after
concentration in vacuo was purified by silica gel column
chromatography using 5:1 hexane–ethyl acetate to provide
the adduct.
1
1.3.1. Compound 10. H NMR (300 MHz, CDCl3) d 6.52
(1H, d, J¼3.0 Hz), 5.71 (1H, d, J¼3.0 Hz), 4.28 (2H, q,
J¼9.0 Hz), 3.21 (1H, t, J¼3.0 Hz), 2.60–1.66 (6H, m), 1.31
(3H, t, J¼9.0 Hz). 13C NMR (75 MHz, CDCl3) d 201.7,
168.7, 132.3, 120.3, 63.0, 62.4, 56.2, 52.3, 36.6, 31.2, 16.7,
14.1.
1
1.3.2. Compound 16. H NMR (300 MHz, CDCl3) d 6.72
(1H, dd, J¼12.0, 3.0 Hz), 5.67 (1H, d, J¼12.0 Hz), 3.74
(3H, s), 3.48–3.51 (1H, m), 2.42–2.50 (1H, m), 2.08 (1H, tt,
J¼12.0, 3.0 Hz), 1.85 (1H, dt, J¼12.0, 3.0 Hz), 1.31 (3H, s),
1.10–1.20 (1H, m), 1.05 (3H, s). 13C NMR (75 MHz,
CDCl3) d 201.5, 168.5, 137.1, 124.6, 65.5, 63.5, 63.1, 52.7,
44.4, 34.2, 30.9, 25.9, 22.9.
A solution of 3.29 g (13.8 mmol) of adduct in acetone
(40 mL) containing 6N HCl (4 mL) was heated under reflux
for 40 min. After removing the acetone, the residue was
dissolved in 20 mL of ethyl acetate. The ethyl acetate layer
was washed successively with brine, satd. NaHCO3, and
brine and dried. The crude material was purified by column
chromatography using 4:1 hexane–ethyl acetate to provide
the aldol.
1.4. Bromination with NBS and hydrolysis to b-bromo
enones
To a solution of dibromide (1 equiv.) in CCl4, was added
AIBN (0.1 equiv.) and NBS (1.2 equiv.). The flask was
fitted with a reflux condenser and irradiated with a sun lamp.
After 30 min (monitored by TLC), the mixture was allowed
to cool to rt and filtered. The crude material was a mixture
(1:1) of tribromide and enone. Then 50% aqueous AcOH
was added and boiled for 2 h. After aqueous workup, the
enone was purified by column chromatography.
To a solution of 238 mg (1 mmol) of the aldol in CH2Cl2
(10 mL) were added 431 mg (2 mmol) of PCC and Celite
(431 mg) at rt. The mixture was stirred at rt for 3 h. It was
then filtered and concentrated. The crude material was
purified by column choromatography using 4:1 hexane–
ethyl acetate to provide the triketone 5.
1
1.4.1. Compound 11. H NMR (300 MHz, CDCl3) d 7.18
1H NMR (300 MHz, CDCl3) 1.13 (dd, J¼6, 6.3 Hz, 6H),
1.20 (d, J¼6 Hz, 3H), 1.60–1.78 (m, 4H), 1.97–2.03 (m,
1H), 2.26–2.38 (m, 2H), 2.40–2.49 (m, 1H), 2.65–2.72 (m,
1H), 2.82–2.90 (m, 1H), 2.94 (septet, J¼6 Hz, 1H). 13C
NMR (75 MHz, CDCl3) 17.3, 19.6, 20.5, 20.6, 22.8, 38.2,
38.3, 39.5, 42.8, 63.0, 211.7, 211.7, 213.7. HRMS (EI) m/z
calcd for 236.1413, found 236.1412.
(1H, s), 4.24–4.35 (2H, m), 3.56–3.58 (1H, m), 2.56–2.63
(1H, m), 1.60–2.31 (5H, m), 1.30 (3H, t, J¼9.0 Hz). 13C
NMR (75 MHz, CDCl3) d 200.1, 167.7, 139.3, 120.4, 66.4,
63.7, 62.5, 58.9, 36.9, 34.8, 17.2, 14.2.
1
1.4.2. Compound 12. H NMR (300 MHz, CDCl3) d 7.02
(1H, s), 4.32 (2H, q, J¼6.0 Hz), 3.41 (1H, t, J¼3.0 Hz),
2.36–1.61 (6H, m), 1.35 (3H, t, J¼9.0 Hz). 13C NMR
(75 MHz, CDCl3) d 201.5, 193.5, 167.3, 146.3, 137.1, 68.6,
62.7, 61.8, 33.7, 32.9, 17.8, 14.2.
1.2. Oxidative cyclization with Mn(OAc)3 and Cu(OAc)2
To a stirred solution of Mn(OAc)3 dihydrate (2 equiv.) and
Cu(OAc)2 monohydrate (1 equiv.) in degassed glacial acetic
acid at rt, was added a solution of keto ester (1 equiv.) in
glacial acetic acid. The mixture was stirred at 808C for 16 h.
After normal aqueous work-up, the crude material was
purified by column chromatography.
1
1.4.3. Compound 17. H NMR (300 MHz, CDCl3) d 7.26
(1H, d, J¼12.0 Hz) 6.52 (1H, dd, J¼9.0 Hz), 3.78 (3H, s),
3.37 (1H, t, J¼3.0 Hz), 2.16–2.27 (1H, m), 1.95–2.02 (1H,
m), 1.81 (1H, dt, J¼12.0, 3.0 Hz), 1.37 (3H, s), 1.27–1.34
(1H, m), 1.11 (3H, s). 13C NMR (75 MHz, CDCl3) d 202.2,
197.4, 168.3, 148.2, 131.9, 68.4, 62.3, 52.8, 42.2, 34.7, 27.8,
26.4, 22.9.
1.2.1. Compound 9. Identical to that reported in Ref. 12.

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G. A. Kraus et al. / Tetrahedron 59 (2003) 8975–8978
2. Young, D. G. J.; Zeng, D. J. Org. Chem. 2002, 67, 3134–3137.
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1.4.4. Compound 18. To a solution of bicyclic olefin and
crushed molecular sieves in dry CCl4, was added dry NBS
(3.5 equiv.) and AIBN (0.3 equiv.). The flask was fitted with
a reflux condenser and irradiated with a sun lamp. After 1 h
(monitored by TLC), the mixture was allowed to cool to rt
and filtered. The crude material was purified by column
chromatography to yield the bromo enone in 55% yield.
1
1.4.5. Compound 18. H NMR (300 MHz, CDCl3) d 7.05
(1H, s), 3.79 (3H, s), 3.36–3.38 (1H, m), 2.47–2.49 (1H,
m), 2.15–2.23 (1H, m), 1.98–2.03 (1H, m), 1.48 (3H, s),
1.36–1.45 (1H, m), 1.31 (3H, s). 13C NMR (75 MHz,
CDCl3) d 200.8, 193.5, 166.7, 146.1, 137.5, 74.0, 60.6, 52.5,
42.7, 34.7, 28.4, 26.7, 22.2.
4. For structure elucidation of compounds in this series, see
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5. Shan, M. D.; Hu, L. H.; Chen, Z. L. J. Nat. Prod. 2001, 64,
127–130.
1.5. Addition of sodium allyloxide and thermal Claisen
rearrangement
6. Laakmann, G.; Schule, C.; Baghai, T.; Kieser, M. Pharmaco-
psychiatry 1998, 31(Suppl.), 54–59. Bhattacharya, S. K.;
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To a solution of allyl alcohol (20 equiv.) at 08C, was added
freshly cut sodium metal (1.2 equiv.). Enone (1 equiv.) in
allyl alcohol was added and the mixture was allowed to stir
for 1 h. After aqueous work-up, the crude material was
purified by column chromatography. The allyl enol ether
was then dissolved in dry toluene and placed in a sealed
tube, where it was heated at 1408C for 7 h. Compound was
purified by column chromatography.
7. Zanoli, P.; Rivasi, M.; Baraldi, C.; Baraldi, M. Behav.
Pharmacol. 2002, 13, 645–651. Butterweck, V.; Nahrstedt,
A.; Evans, J.; Hufeisen, S.; Rauser, L.; Savage, J.; Popadak,
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1.5.1. Compound 13. FTIR (film) 1733, 1710, 1678,
1572 cm21 1H NMR (300 MHz, CDCl3) d 5.98–5.90
;
(1H, m), 5.35–5.21 (2H, m), 4.18 (2H, q, J¼9.0 Hz), 3.53
(1H, t, J¼4.5 Hz), 3.33 (2H, d, J¼6 Hz), 2.51–2.31 (2H,
m), 2.14–1.95 (2H, m) 1.79–1.73 (2H, m) 1.27 (3H, t,
J¼4.5 Hz). 13C NMR (75 MHz, CDCl3) d 171.7, 164.9,
164.5, 154.0, 135.4, 118.01, 110.9, 101.0, 61.8, 43.8, 28.5,
26.5, 20.7, 19.2, 14.4. HRMS (EI) m/z calcd for 278.11542,
found 278.11610.
8. Enders, D.; Pathak, V. N.; Wuester, P. Chem. Berichte 1992,
125, 515–524.
9. Horii, Z.; Imanishi, T.; Kim, S.-W.; Ninomiya, I. Chem.
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12. Cole, B. M.; Han, L.; Snider, B. B. J. Org. Chem. 1996, 61,
7832–7847.
1.5.2. Compound 19. FTIR (film) 1737, 1701, 1650,
1572 cm21 1H NMR (300 MHz, CDCl3) d 5.94–5.89
;
(1H, m), 5.37–5.27 (2H, m), 3.67 (3H, s), 3.35–3.33 (1H,
m), 3.31–3.28 (2H, m), 2.20–2.16 (1H, m), 2.01–1.94 (1H,
m), 1.72–1.64 (1H, m), 1.39–1.30 (1H, m), 1.25 (3H, s),
1.19 (3H, s). HRMS (EI) m/z calcd for 292.1311, found
292.1316.
13. Snider, B. B. Chem. Rev. 1996, 96, 339–363.
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16. The model system is shown below
Acknowledgements
We thank Iowa State University and the Iowa State
University Center for Botanical Dietary Supplements
(NIH grant ES12020) for partial support of this research.
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