Natural products via reetz chemistry synthesis of (±)-cuparene

Article abstract of DOI:10.1081/SCC-100104334

A concise synthesis of (±)-cuparene via Grignard, trimethylaluminum and dimethyltitanium dichloride (Reetz Alkylation) reactions to form the quaternary centers of (±)-cuparene is reported.

Full text of DOI:10.1081/SCC-100104334

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NATURAL PRODUCTS VIA REETZ CHEMISTRY
SYNTHESIS OF (±)-CUPARENE
Frank G. Favaloro a , Christina A. Goudreau a , Bradford P. Mundy b , Thomas Poon c
Sergei V. Slobodzian d & Bruce L. Jensen e
,
a Chemistry Department , Colby College , Waterville, Maine, 04901, U.S.A.
b Chemistry Department , Colby College , Waterville, Maine, 04901, U.S.A.
c Joint Science Department , Claremont McKenna, Scripps, and Pitzer Colleges ,
Claremont, California, 91711, U.S.A.
d Department of Chemistry , University of Maine , Orono, Maine, 04469, U.S.A.
e Department of Chemistry , University of Maine , Orono, Maine, 04469, U.S.A.
Published online: 16 Aug 2006.
To cite this article: Frank G. Favaloro , Christina A. Goudreau , Bradford P. Mundy , Thomas Poon , Sergei V.
Slobodzian & Bruce L. Jensen (2001) NATURAL PRODUCTS VIA REETZ CHEMISTRY SYNTHESIS OF (±)-CUPARENE, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 31:12, 1847-1855,
DOI: 10.1081/SCC-100104334
To link to this article: http://dx.doi.org/10.1081/SCC-100104334
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SYNTHETIC COMMUNICATIONS, 31(12), 1847–1855 (2001)
NATURAL PRODUCTS VIA REETZ
CHEMISTRY SYNTHESIS OF
(6)-CUPARENE
Frank G. Favaloro,a,1 Christina A. Goudreau,a,2
,3
,4
Bradford P. Mundy,a,
Thomas Poon,b,
*
*
Sergei V. Slobodzian,c and Bruce L. Jensenc,
*
aChemistry Department, Colby College, Waterville, Maine 04901
bJoint Science Department, Claremont McKenna, Scripps,
and Pitzer Colleges, Claremont, California 91711
cDepartment of Chemistry, University of Maine,
Orono, Maine 04469
ABSTRACT
A
concise synthesis of (ꢀ)-cuparene via Grignard,
trimethylaluminum and dimethyltitanium dichloride (Reetz
Alkylation) reactions to form the quaternary centers of
(ꢀ)-cuparene is reported.
INTRODUCTION
Cuparene, isolated from the liverwort, Bazzania pompeana, was char-
acterized by Matsuo, et al.5 Although several syntheses of this compound
have been reported,6 we account here a new preparation for this natural
product.
* Corresponding author.
1847
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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FAVALORO ET AL.
As a part of a separate study,7 we have been examining the use of the
Reetz reagent, dimethyltitanium dichloride,8 as a methylating agent. It has
been reported that reaction of a tertiary alcohol with the Reetz reagent
makes possible the substitution of the -OH group by -Me.9 Here we
report the use of this protocol to the synthesis of (ꢀ)-cuparene.
RESULTS AND DISCUSSION
The addition of 2-methylcyclopentanone to a Grignard reagent
prepared from 4-bromotoluene provided 3. Attempts at purification by dis-
tillation resulted in the highly competitive dehydration of 3. Since dehydra-
tion was the next step in our synthesis plan, further attempts at purification
were abandoned and the crude product was directly treated with p-toluene-
sulfonic acid in toluene, resulting in the mixture, (4a and 4b, 89:11) (48%).
The thermodynamic vs. kinetic dehydration of related systems has been
discussed.10

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1849
Without further purification, 4 was epoxidized using mCPBA in
dichloromethane at 0ꢁC. The dominant epoxide (59%) was readily sepa-
rated and purified by flash column chromatography.11 The reaction of
trimethylaluminum with the epoxide 5 in a 5:1 molar ratio in hexane at
0ꢁC under argon gave 0.52 g of the homobenzylic alcohol, 6, purified by
radial thin layer chromatography (91% purity by GC).
The alcohol precursor (6) to cuparene was added to dimethyltitanium-
dichloride, positioning the last methyl group of cuparene (7). Our spectral
data (1H-NMR, 13C-NMR and HRMS) matched previously reported spectra.
The replacement of C-OH by C-Me was extended to the simultaneous
replacement of both hydroxyl groups of a 1,2-diol.
The preparation of the 1,2-diol was accomplished in two different
ways. The obvious conversion of 4 to 8 by use of OsO4, Me3NO
and t-BuOH gave the expected cis-diol; however, it was accompanied by
significant by-product. This material exhibited unique proton and carbon

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FAVALORO ET AL.
NMR spectra with key features supporting a diketone functional group:
1H-NMR: 2.17 (s) (COCH3); 13C-NMR: 199.42, 208.61. A working struc-
ture from these and other data was developed to be 9.
This was shown to be a degradation product of the 1,2-diol by resub-
mitting the diol to reaction conditions and isolating the diketone. The struc-
ture was unambiguously confirmed by synthesis according to the procedure
of Haykawa.12 Improvement in the formation of the 1,2-diol was accom-
plished by changing the solvent from t-BuOH to MeOH, resulting in 61%
conversion to the cis-diol. In summary, we have illustrated two approaches
to (ꢀ)-cuparene through the use of the Reetz methylation.
EXPERIMENTAL
General Procedures
The 1H (400 MHz) and 13C (100 MHz) NMR spectra were determined
for CDCl3 solutions containing ca. 1% TMS as an internal standard with a
JEOL GSX-400/54 high resolution NMR spectrometer. GC/MS analyses
were performed on a Hewlett-Packard 5890 gas chromatograph coupled to
a 5970 series mass selective detector using a Supelco 2-4026 15 m ꢂ 0.25 mm
capillary column packed with SPBM-1 (0.25 mm). Preparative GC separa-
tions were performed on a Gow-Mac Series 350 gas chromatograph using a
8’ ꢂ 0.25’’ 20% Carbowax 20 M on Chrom-P80/100 mesh column. Progress
of reactions was monitored by thin layer chromatography (TLC) on com-
mercial silica gel plates (Baker-Flex IB-F using UV absorption. All reactions
were performed under argon unless stated otherwise.
Synthesis of (4-Methylphenyl)-2-methylcyclopentene (4a)
To a solution of freshly ground magnesium metal turnings (1.6 g,
0.067 mol) in 40 mL of dry ether, 3-bromotoluene (11.4 g, 0.067 mol) was
added and allowed to stir for 1.0 h. To this solution, 2-methylcyclopenta-
none (1) (5.5 g, 0.056 mol) was injected dropwise at a rate of one drop per

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1851
second and the solution was stirred for 24 h. It was quenched with wet ether,
vacuum filtered and extracted with dichloromethane. The organic layer was
dried with Na2SO4 (anhydrous), and solvent removed to give the crude
alcohol (3a) (82% pure by GC). Without purification, the alcohol was dis-
solved in toluene (20 mL) containing approximately 1.5 g of p-toluene-
sulfonic acid. This solution was heated under reflux for 3 h. The progress
of the reaction was monitored by GC/MS. Upon completion, as much
toluene as possible was removed by rotary evaporation. Using a saturated
sodium bicarbonate solution and dichloromethane, the alkenes were sepa-
rated from residual acid. The organic layer was dried with anhydrous
Na2SO4 and the product was collected as a clear colorless liquid by
Kugelrohr distillation (100ꢁC, 2.3 mm Hg), (4.7 g). GC/MS showed the
1
product to be the 13C NMR and H NMR of a purified sample of the
alkene isolated by preparative GC provided the following data: 13C NMR
d 135.78, 135.56, 134.55, 134.52, 128.70, 127.47, 40.07, 37.26, 21.81, 21.15,
15.50; 1H NMR d 7.19 (d, 2H), 7.14 (d, 2H), 2.72 (m, 2H), 2.49 (m, 2H), 2.34
(s, 3H), 1.89 (m, 2H), 1.84 (s, 3H). HRMS: measured 172.1255, calculated
172.1252.
Synthesis of 4-Methylphenyl-2-methylcyclopentane Oxide (5)
To a solution of the alkene (4), (4.2 g, 0.024 mol) in dichloromethane
(40 mL), MCPBA (57–86%) (7.6 g, 0.025 mol) was added and stirred for
24 h at 0ꢁC. The reaction was allowed to warm to room temperature over-
night. The resultant milky white mixture was washed three times with a
saturated NaHCO3 solution, and then washed with water and dried with
anhydrous Na2SO4. Removal of the solvent gave the epoxide (5) as a crude
clear yellow liquid. Purification by flash column chromatography gave the
final product (2.7 g, 59%). HRMS: measured 188.1206, calculated 188.1201.
Synthesis of 2-(4-Methylphenyl)-1,2-dimethylcyclopentanol (6)
To the epoxide (5) (1.6 g, 0.0083 mol) in hexane (150 mL), trimethyla-
luminum (8.4 mL, 0.017 mol, of a 2 M solution in hexane) was injected and
the solution was stirred for 48 h at 0ꢁC. Methanol was then injected to
quench the reaction, followed by water, and the solution was vacuum fil-
tered to remove the resulting precipitate. As much solvent as possible was
removed by rotary evaporation. The resulting solution was then extracted
with dichloromethane. The organic layer was then dried with Na2SO4
(anhydrous) and evaporated to yield the alcohol (6) (0.52 g, 91% pure

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FAVALORO ET AL.
by GC). After purification of (6) by preparative GC: 13C NMR d 144.27,
135.17, 128.54, 126.52, 82.37, 50.65, 39.06, 35.31, 25.61, 23.89, 20.90, 18.15;
1H NMR d 7.32 (d, 2H), 7.10 (d, 2H), 2.37–2.23 (m, 2H), 2.32 (s, 3H), 1.92–
1.68 (m, 2H), 1.35 (s, 3H), 1.32–1.23 (m, 2H), 0.93 (s, 3H). HRMS: meas-
ured 204.1514, calculated 204.1514.
Synthesis of (6) Cuparene (7)
Method 1: To a solution of dimethylzinc (13 mL, 0.026 mol) and
dichloromethane (10 mL), titanium tetrachloride (2.9 mL, 0.026 mol), and
then (6) (0.52 g, 0.0026 mol) was added dropwise. The reaction mixture
stirred at 0ꢁC for 24 h. Distilled water was added until it no longer reacted
and the organic layer was extracted with dichloromethane, dried with
Na2SO4 (anhydrous), and the solvent removed by rotary evaporation to
give 0.63 g of crude product. A pure sample obtained by preparative GC was
1
analyzed for structure: H NMR d 7.25 (d, 2H), 7.09 (d, 2H), 2.50 (s, 1H),
2.32 (s, 3H), 1.85–1.48 (m, 6H), 1.26 (s, 3H), 1.06 (s, 3H), 0.56 (s, 3H); 13C
NMR d 144.5, 134.71, 128.18, 126.92, 50.23, 44.20, 39.69, 36.81, 26.43,
24.37, 24.25, 20.83, 19.72. HRMS: measured 202.1729, calculated
202.1722. A search of the partial NBS Library in our data system showed
a perfect mass spectral match for the target molecule.
Synthesis of 1-(40-Methylphenyl)-2-methylcyclopentane-1,2-diol (8)
A mixture of 4 (0.5 g, 2.9 mmol), trimethylammonium N-oxide (0.42 g,
3.8 mmol), pyridine (0.5 mL), osmium tetroxide (2.5% wt t-butanol sol-
ution, 0.2 mL) and water (1 mL) were refluxed in methanol (15 mL) for
24 h. After this period, 25 mL of water were introduced to the reaction
mixture, followed by sufficient HCl to neutralize the solution. Extraction
of the organic product with ether (3 ꢂ 15 mL) was followed by sequentially
washing the extract with 10% sodium bisulfite, (20 mL), water (2 ꢂ 20 mL),
and brine (20 mL). The resulting ether layer was dried with sodium sulfate
and after filtration the solvent was removed. Hexane (10 mL) was added and
the solution was allowed to crystallize at refrigerator temperature. A crystal-
line product (0.36 g, 61%, Mp 80–83ꢁC) was obtained. H-NMR: d 0.93 s
1
(CH3, 3H), 1.66–2.11 set of multiplets (5H), 2.34 s (Ar-CH3, 3H), 2.45 m
(1H), 7.14 d (J ¼ 7.8 Hz, m-ArH, 2H), 7.39 d (J ¼ 7.8 Hz, o-ArH, 2H);
13C-NMR: d 18.47, 20.96, 24.64, 35.75, 81.89, 83.45, 126.18, 128.63,
136.86, 139.88. MS (m/z): 206 (Mþ). Anal. Calcd for C13H18O2: C, 75.69;
H, 8.80. Found: C, 76.19; H, 9.06.

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1853
Synthesis of (6) Cuparene (7)
Method 2: To a solution of dimethylzinc (12 mL, 24 mmol; 2 N,
toluene) in dichloromethane (12 mL) under a nitrogen atmosphere was
added titanium tetrachloride (2.6 mL, 23 mmol). After cooling to 0ꢁC, a
solution of 8 (250 mg, 1.2 mmol) in 5 mL of dichloromethane was injected
into the Reetz reagent. After stirring for 1 hr at ice-water temperature, the
reaction mixture was stored for 24 h in the refrigerator. Separation of the
organic layer and evaporation of solvent, giving 85 mg of product (35%)
matching authentic cuparene followed careful addition of 20 mL of water.
The Synthesis of 1-(4-Methylphenyl)-hexane-1,5-dione (9)
1-(4-Methylphenyl)-2-methylcyclopentene (0.3 g, 1.7 mmol), pyridine
(0.5 mL), trimethylammonium N-oxide dihydrate (0.22 g, 2.0 mmol),
osmium tetroxide (2.5% wt t-butanol solution, 0.1 mL) and water (1 mL)
were refluxed in t-butanol (10 mL) for 24 h. After the reflux period, 20 mL of
water were introduced into the reaction mixture. Hydrochloric acid (10%)
was added to neutralize the solution (litmus paper), and the organic fraction
was extracted with ether (3 ꢂ 10 mL). The combined ethereal extract was
washed with 10% sodium bisulfite solution (20 mL), water (2 ꢂ 20 mL) and
saturated sodium chloride solution (20 mL). The ethereal solution was dried
over sodium sulfate and the solvent was evaporated. The residue was recrys-
tallized from hexane. Yield 0.31 g (87%). Mp 89–90ꢁC. H-NMR: d 2.01
1
quintet (J ¼ 6.7 Hz, H-3, 2H), 2.17 s (COCH3, 3H), 2.42 s (ArCH3, 3H), 2.57
t (J=6.8 Hz, H-4, 2H), 2.99 t (J ¼ 7.0 Hz, H-2, 2H), 7.26 d (J¼7.7 Hz, m-
ArH, 2H), 7.88 d (J ¼ 7.7 Hz, o-ArH, 2H). 13C-NMR: d 18.26, 21.63, 29.94,
37.24, 42.62, 128.14, 129.26, 143.85, 199.42, 208.61. Anal. Calcd for
C13H16O2: C, 76.44; H, 7.90. Found: C, 76.84; H, 8.20.
ACKNOWLEDGMENTS
Support by way of a Bristol-Myers Squibb Award of Research
Corporation is gratefully acknowledged. Paul Schupf and the National
Science Foundation are acknowledged for their support of the Colby
Chemistry Computational Facilities. The Camille and Henry Dreyfus
Foundation, and Glaxo-Wellcome Foundation are also acknowledged for
their support. Dr. Joe Sears, Montana State University Mass Spectrometry
facility, Bozeman, MT, supplied HRMS data. We also acknowledge the

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FAVALORO ET AL.
continued support of the Science Division of Colby College. S.V.S and B.L.J
acknowledge support from the general research fund of the University of
Maine.
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Received in the USA September 20, 2000

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