Convenient formal synthesis of (±)-cuparene, (±)-enokipodins A and B, and (±)-cuparene-1,4-quinone

Article abstract of DOI:10.1055/s-2007-965951

A Bronsted or Lewis acid mediated semi-pinacolic rear-rangement effected on the diastereomers of cyclobutanol derivatives leads efficiently to useful intermediates in the synthesis of cuparene-type sesquiterpenes. The cyclobutanols are themselves easily o

Full text of DOI:10.1055/s-2007-965951

PAPER
999
Convenient Formal Synthesis of ( )-Cuparene, ( )-Enokipodins A and B, and
( )-Cuparene-1,4-Quinone
Synthesis of
C
r
uparene-
a
T
ype Sesqu
n
iterpenes cesco Secci,a,b Angelo Frongia,b Jean Ollivier,*a Pier Paolo Piras*b
a
Laboratoire de Synthèse organique et Méthodologie, UMR 8182, Institut de Chimie Moléculaire et des Matériaux d’Orsay,
Université Paris-Sud, 91405 Orsay, France
Fax +33(1)69156278; E-mail: jollivie@icmo.u-psud.fr
Dipartimento di Scienze Chimiche, Università di Cagliari, Complesso Universitario di Monserrato, S.S. 554, Bivio per Sestu,
09042 Monserrato, Cagliari, Italy
b
Fax +39(070)6754388; E-mail: pppiras@unica.it
Received 21 November 2006; revised 19 December 2006
O
Abstract: A Brønsted or Lewis acid mediated semi-pinacolic rear-
rangement effected on the diastereomers of cyclobutanol deriva-
tives leads efficiently to useful intermediates in the synthesis of
cuparene-type sesquiterpenes. The cyclobutanols are themselves
easily obtainable from cyclopropyl phenyl sulfide.
2
3
1
4
ref. 5b
ref. 5c
ref. 5a
ref. 4
OH
OMe
Key words: antifugal agents, aldol reactions, rearrangements, ring
expansion, ketones
R
R
a R = H
b R = OMe
5a,b
6a,b
Scheme 1
Cuparene (1) (Figure 1), found in the essential oil of
Glehnia littoralis,1 shows interesting anti-inflammatory
activity.2 Likewise, enokipodins A (2), B (3)3 and related
compounds such as cuparene-1,4-quinone (4)4 isolated in
2000 from a mushroom (Flammulina velutipes) exhibits
antimicrobial and antifungal activities.
O
SPh
1) n-BuLi, THF
–20 °C
R
SPh
PTSA
C6H6, reflux
2) 8a,b, THF
R
HO
–20 °C to r.t.
MeO
7
MeO
MeO
O
9a,b
10a,b
OH
(90%)
(92%)
a R = H
(89%)
(92%)
O
O
b R = OMe
R
O
8a,b
O
Scheme 2
O
O
HO
1
2
4
3
Subsequent addition of isopropenylmagnesium bromide
to the ketones 10a,b led to cyclobutanols 11a and 11b,
respectively, as mixtures of diastereomers. Isomers 11a
and 11a¢ were obtained in 84% yield as a 60:40 insepara-
ble mixture, while isomers 11b and 11b¢ were obtained in
88% yield as an 80:20 mixture which were separated
chromatographically (Scheme 3).
Figure 1 Cuparene-type sesquiterpenes
According to the literature,5 all these natural compounds
can be synthesized from common intermediates 5a,b pos-
sessing the same basic 3-aryl-4-methylphenyl-2,2,3-tri-
methylcyclopentanone skeleton (Scheme 1).
The relative configuration of trans-11a,b and cis-11a¢,b¢
was assigned by two-dimensional NOESY NMR spec-
troscopy. However, the semi-pinacolic rearrangement, in-
duced by catalytic p-toluenesulfonic acid in benzene11 or
by catalytic boron trifluoride etherate in dichloromethane
on a mixture of trans-11a/cis-11a¢ as well as trans-11b/
cis-11b¢, yielded cyclopentanones 5a and 5b, respective-
ly.
Applying a successful method previously described by us
in the synthesis of monoterpenoids fragranol and grandi-
sol,6 cyclopropyl phenyl sulfide 77 gave the carbinols
9a,b, after metalation and reaction with the methyl ke-
tones 8a8 or 8b,9 respectively. The carbinols then under-
went acid-catalyzed ring expansion10 to yield cyclo-
butanones 10a,b (Scheme 2).
While the synthesis of natural products 2, 3 and 4 from the
cyclopentanone 5b has been previously reported in the
literature,5b–d the synthesis of ( )-cuparene (1) from the
intermediate 5a required some additional steps. Thus,
Huang–Minlon reduction12 led to the cyclopentane 1213
which underwent demethylation to give the 3-hydroxycu-
SYNTHESIS 2007, No. 7, pp 0999–1002
Advanced online publication: 20.02.2007
DOI: 10.1055/s-2007-965951; Art ID: P13506SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
7

1000
F. Secci et al.
PAPER
The crude residue was purified by flash column chromatography
(silica gel, hexanes–Et2O, 5:1) to afford the corresponding cyclo-
propylphenylthio carbinols 9a or 9b.
R
HO
1-(2-Methoxy-4-methylphenyl)-1-[1-(phenylthio)cyclopro-
pyl]ethanol (9a)
Yellow oil; yield: 0.734 g (90%).
IR (neat): 3487, 3000, 2989, 2870 cm–1.
MeO
PTSA
C6H6, reflux
or
trans-11a (51%)
trans-11b (71%)
BrMg
10a,b
+
5a,b
THF, –40 °C
BF3⋅OEt2 (91–94%)
CH2Cl2, 0 °C
1H NMR (300 MHz, CDCl3): d = 0.97–1.09 (m, 2 H, 2H-cPr), 1.21–
1.26 (m, 1 H, H-cPr), 1.28–1.35 (m, 1 H, H-cPr), 1.72 (s, 3 H,
CH3COH), 2.18 (s, 3 H, ArCH3), 3.69 (s, 3 H, OCH3), 4.75 (br s, 1
H, OH), 6.57 (d, J = 8.4 Hz, 1 H, H-6¢ Ar), 6.86 (dd, J = 8.4, 1.5 Hz,
1 H, H-5¢ Ar), 6.96–7.08 (m, 5 H, SC6H5), 7.15 (d, J = 1.5 Hz, 1 H,
H-3¢ Ar).
13C NMR (75 MHz, CDCl3): d = 13.6 (CH2 cPr), 13.9 (CH2 cPr),
20.4 (CH3COH), 26.3 (ArCH3), 34.4 (PhSC cPr), 55.1 (OCH3), 77.2
(CH3COH), 111.8 (C-3¢ Ar), 124.1 (C-5¢ Ar), 126.3 (C Ph), 126.7
(C Ph), 127.9 (C Ph), 128.8 (C Ph), 129.5 (C-6¢ Ar), 130.1 (C-1¢ Ar),
130.8 (C Ph), 131.7 (C-4¢ Ar), 137.1 (C Ph), 154.8 (C-2¢ Ar).
R
OH
a R = H
MeO
b R = OMe
cis-11a' (33%)
cis-11b' (17%)
Scheme 3
O
Anal. Calcd for C19H22O2S (314.45): C, 72.58; H, 7.05; S, 10.20.
Found: C, 72.62; H, 7.15; S, 10.12.
BBr3
OH
CH2Cl2, 0 °C
H2NNH2
OMe
OMe
1-(2,5-Dimethoxy-4-methylphenyl)-1-[1-(phenylthio)cyclopro-
pyl]ethanol (9b)
KOH, digol
Yellow oil; yield: 0.823 g (92%).
IR (neat): 3460, 2980, 1656 cm–1.
5a
12 (75%)
6a (93%)
1H NMR (300 MHz, CDCl3): d = 1.05–1.23 (m, 2 H, 2H-cPr), 1.30–
1.34 (m, 1 H, H-cPr), 1.43–1.50 (m, 1 H, H-cPr), 1.80 (s, 3 H,
CH3COH), 2.18 (s, 3 H, ArCH3), 3.76 (s, 3 H, OCH3), 3.80 (s, 3 H,
OCH3), 4.90 (br s, 1 H, OH), 6.58 (s, 1 H, H-6¢ Ar), 6.92 (s, 1 H, H-
3¢ Ar), 7.07–7.12 (m, 5 H, SC6H5)
13C NMR (75 MHz, CDCl3): d = 13.8 (CH2 cPr), 14.0 (CH2 cPr),
15.9 (CH3COH), 26.6 (ArCH3), 34.5 (PhSC cPr), 55.8 (OCH3), 56.1
(OCH3), 78.1 (CH3COH), 112.3 (C-3¢ Ar), 114.2 (C-6¢ Ar), 125.3
(C-1¢ Ar), 127.1 (C Ph), 128.0 (C Ph), 129.0 (C Ph), 130.5 (C Ph),
131.7 (C Ph), 132.1 (C-4¢ Ar), 136.9 (C Ph), 153.0 (C-5¢ Ar), 154.6
(C-2¢ Ar).
Scheme 4
parene (6a),14 an intermediate previously used in the total
synthesis of cuparene (1)5a (Scheme 4).
In conclusion, we have developed a new and concise ac-
cess to intermediates for the efficient preparation of ( )-
cuparene, ( )-enokipolins A, B, and ( )-cuparene-1,4-
quinone. The extension of this pathway to the enantio-
selective synthesis of these biologically active natural
products is under current investigation.
FAB-MS: m/z = 367 [M + Na+].
HRMS (EI): m/z calcd for C20H24O3S: 344.2102; found: 344.2051.
Preparative column chromatography was performed on SDS flash
silica gel (35–70 mesh). IR spectra were recorded as thin films on a
FT-IR PerkinElmer Spectrum One. H NMR (300 MHz and 400
Cyclobutanones 10a,b
A solution of the cyclopropylphenylthio carbinols 9a or 9b (3
mmol) and PTSA (516 mg, 3 mmol) in wet benzene (50 mL) was
refluxed for 6 h. Then, the mixture was allowed to cool to r.t., dilut-
ed with H2O (100 mL), and washed with aq 2 N NaOH (2 × 5 mL).
The organic phase was dried (Na2SO4) and concentrated under re-
duced pressure. The crude product was readily purified by flash col-
umn chromatography (silica gel, hexanes–Et2O, 10:1) to afford the
corresponding cyclobutanones 10a or 10b.
1
MHz) and 13C NMR (63 MHz and 75 MHz) spectra were recorded
in CDCl3 on Varian 300, Bruker DRX 400 and Bruker AM 250
spectrometers and the data are reported in d (ppm) from CDCl3
(1H = 7.27 and 13C = 77). Mass spectra (electron impact or chemical
ionization) were measured with a Nermag R-10 coupled with a OK1
DP 125 gas chromatograph and a Agilent 5973 Network coupled
with a 6890N gas chromatograph. Relative percentages are shown
in brackets; high-resolution mass spectra (electron impact or elec-
trospray) were recorded with a Finnigan MAT 95S spectrometer.
Microanalyses were carried out on a Carlo Erba 1106 Elemental
Analyzer.
2-(2-Methoxy-4-methylphenyl)-2-methylcyclobutanone (10a)
Yellow oil; yield: 89%.
IR (neat): 2998, 1780, 1670 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.52 (s, 3 H, H3CC cBu), 1.98 (dt,
J = 8.7, 8.1 Hz, 1 H, H-cBu), 2.01 (dt, J = 11.4, 8.1 Hz, 1 H, H-
cBu), 2.25 (s, 3 H, ArCH3), 3.13 (t, J = 8.1 Hz, 2 H, 2H-cBu), 3.77
(s, 3 H, OCH3), 6.77 (d, J = 8.1 Hz, 1 H, H-5¢ Ar), 7.02 (d, J = 8.1
Hz, 1 H, H-6¢ Ar), 7.08 (s, 1 H, H-3¢ Ar).
13C NMR (75 MHz, CDCl3): d = 20.6 (CH3C cBu), 21.7 (ArCH3),
26.7 (CH2 cBu), 42.4 (CH2 cBu), 55.3 (OCH3), 64.6 (CH3C cBu),
111.2 (Ar C-3), 127.0 (Ar C-5¢), 128.3 (Ar C-6¢), 129.7 (Ar C-1¢),
130.5 (Ar C-4¢), 154.8 (Ar C-2¢), 213.1 (C=O).
Cyclopropyl Carbinols 9a,b
To a solution of cyclopropyl phenyl sulfide (7; 0.390 g, 26 mmol)
in anhyd THF (150 mL) was added dropwise at –20 °C, a 1.5 M so-
lution of n-BuLi (18.66 mL, 0.028 mmol) and stirring was contin-
ued at this temperature for 4 h. Then, after cooling down to –78 °C,
a solution of the ketones 8a or 8b (26 mmol) in anhyd THF (20 mL)
was added. The mixture was slowly warmed to r.t., diluted with
Et2O (100 mL) and quenched with aq NH4Cl (20 mL). The organic
phase was dried (Na2SO4) and concentrated under reduced pressure.
Synthesis 2007, No. 7, 999–1002 © Thieme Stuttgart · New York

PAPER
Synthesis of Cuparene-Type Sesquiterpenes
1001
MS (EI): m/z (%) = 204 (9, M+), 162 (67), 147 (100), 119 (58), 105
HRMS (EI): m/z calcd for C16H22O2: 246.1619; found: 246.1621.
(24) 91 (25), 77 (19).
MS (EI): m/z (%) (cis 11a¢) = 246 (4, M+), 162 (45), 147 (100), 131
Anal. Calcd for C13H16O2 (204.27): C, 76.44; H, 7.90. Found: C,
76.37; H, 7.86.
(15), 119 (79), 115 (34), 105 (15), 91 (44), 69 (33), 41 (49).
HRMS (EI): m/z calcd for C16H22O2: 246.1619; found: 246.1620.
2-(2,5-Dimethoxy-4-methylphenyl)-2-methylcyclobutanone
(10b)
Yellow oil; yield: 92%.
IR (neat): 2959, 1779, 1505 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.57 (s, 3 H, H3CC cBu), 2.03–
2.16 (m, 1 H, H-cBu), 2.24 (s, 3 H, ArCH3), 2.36–2.48 (m, 1 H, H-
cBu), 3.15 (t, J = 8.7 Hz, 2 H, H-cBu), 3.78 (s, 3 H, OCH3), 3.80 (s,
3 H, OCH3), 6.74 (br s, 1 H, H-5¢ Ar), 6.88 (br s, 1 H, H-3¢ Ar).
13C NMR (75 MHz, CDCl3): d = 22.0 (CH3CcBu), 27.0 (CH2 cBu),
28.2 (ArCH3), 42.5 (CH2 cBu), 54.5 (CH3CcBu), 55.9 (OCH3), 56.1
(OCH3), 109.4 (C-3¢ Ar), 114.6 (C-6¢ Ar), 126.0 (C-4¢ Ar), 129.1
(C-1¢ Ar), 149.5 (C-5¢ Ar), 151.6 (C-2¢ Ar), 213.5 (C=O).
trans-2-(2,5-Dimethoxy-4-methylphenyl)-2-methyl-1-(prop-1-
en-2-yl)cyclobutanol (trans-11b)
Colorless oil; yield: 71%.
IR (neat): 3429, 2966, 2867, 1464 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.48 (s, 3 H, H3CC cBu), 1.57 (s,
3 H, H3CC=CH2), 1.79–1.96 (m, 1 H, H-cBu), 2.11–2.13 (m, 1 H,
H-cBu), 2.20 (s, 3 H, ArCH3), 2.21–2.28 (m, 1 H, H-cBu), 2.35–
2,43 (m, 1 H, H-cBu), 2.90 (br s, 1 H, OH), 3.68 (s, 3 H, OCH3),
3.79 (s, 3 H, OCH3), 4.63 (br s, 1 H, H3CC=CH2), 4.88 (br s, 1 H,
H3CC=CH2), 6.52 (s, 1 H, H-5¢ Ar), 6.60 (s, 1 H, H-6¢ Ar).
13C NMR (63 MHz, CDCl3): d = 16.2 (CH3C cBu), 20.5
(H3CC=CH2), 25.3 (CH2 cBu), 26.7 (ArCH3), 29.9 (CH2 cBu), 50.7
(H3CC cBu), 55.4 (OCH3), 56.2 (OCH3), 79.8 (COH), 109.1 (Ar C-
3¢), 109.2 (C=CH2), 110.8 (C=CH2), 113.6 (Ar C-6¢), 124.1 (Ar C-
4¢), 134.1 (Ar C-1¢), 149.7 (Ar C-5'), 151.9 (Ar C-2¢).
FAB-MS: m/z = 257 [M + Na+].
HRMS (EI): m/z calcd for C14H18O3: 234.1251; found: 234.1255.
Cyclobutanols 11a,b
FAB-MS: m/z = 299 [M + Na+].
To a stirred solution of the cyclobutanols 10a or 10b (1 mmol) in
anhyd THF (45 mL), was added dropwise a 1.5 M solution of iso-
propenylmagnesium bromide in CH2Cl2 (1 mL, 1.5 mmol) at
–40 °C. Then, the mixture was allowed to warm to r.t., diluted with
Et2O (20 mL) and quenched with aq NH4Cl (5 mL). The organic
phase was dried (Na2SO4) and concentrated under reduced pressure.
The crude residue was purified by flash column chromatography
(silica gel, hexanes–Et2O, 10:1) to give from 10a a 60:40 insepara-
ble mixture of cyclobutanols trans-11a and cis-11a¢ and from 10b
an 80:20 separable mixture of cyclobutanols trans-11b and cis-
11b¢.
HRMS (EI): m/z calcd for C17H24O3: 276.17254; found: 276.17293.
cis-2-(2,5-Dimethoxy-4-methylphenyl)-2-methyl-1-(prop-1-en-
2-yl)cyclobutanol (cis-11b')
Colorless oil; yield: 17%.
IR (neat): 3429, 2966, 1504 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.30 (s, 3 H, H3CC cBu), 1.51 (s,
3 H, H3CC=CH2), 1.20–1.75 (m, 3 H, H-cBu), 1.77 (br s, 1 H, OH),
2.13 (s, 3 H, ArCH3), 2.20–2.24 (m, 1 H, H-cBu), 3.68 (s, 3 H,
OCH3), 3.71 (s, 3 H, OCH3), 4.61 (br s, 1 H, H3CC=CH2), 4.83 (br
s, 1 H, H3CC=CH2), 6.37 (s, 1 H, H-3¢ Ar), 6.60 (s, 1 H, H-6¢ Ar).
13C NMR (75 MHz, CDCl3): d = 16.2 (CH3C cBu), 22.5
(H3CC=CH2), 25.3 (CH2 cBu), 28.2 (ArCH3), 29.7 (CH2 cBu), 51.7
(H3CC cBu), 55.7 (OCH3), 56.1 (OCH3), 75.7 (COH), 108.5
(C=CH2), 109.6 (Ar C-3'), 110.1 (C=CH2), 113.6 (Ar C-6¢), 124.6
(Ar C-4¢), 132.6 (Ar C-1¢), 149.6 (Ar C-5¢), 152.1 (Ar C-2¢).
2-(2-Methoxy-4-methylphenyl)-2-methyl-1-(prop-1-en-2-yl)cy-
clobutanol (trans-11a and cis-11a¢)
Colorless oil; yield: 84% (11a/11a¢ = 60:40).
IR (neat): 3450, 2997, 1620 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.47 (s, 3 H, H3CC cBu, trans),
1.53 (s, 3 H, H3CC cBu, cis), 1.65 (s, 3 H, H3CC=CH2, trans), 1.67
(s, 3 H, H3CCH=CH2, cis), 1.71–1.78 (m, 1 H, H-cBu, cis), 1.83 (t,
J = 9.3 Hz, 1 H, H-cBu, trans), 1.93 (s, 3 H, ArCH3, cis), 2.01–2.13
(m, 1 H, H-cBu, trans), 2.26 (s, 3 H, ArCH3, trans), 2.32–2.45 (m,
2 H, H-cBu, trans), 2.34–2.45 (m, 1 H, H-cBu, cis), 2.55–2.65 (m,
2 H, H-cBu, cis), 2.87 (br s, 1 H, OH, trans), 3.22 (br s, 1 H, OH,
cis), 3.67 (s, 3 H, OCH3, trans), 3.78 (s, 3 H, OCH3, cis), 4.59 (br s,
1 H, H3CC=CH2, trans), 4.86 (br s, 1 H, H3CC=CH2, trans), 4.93 (br
s, 1 H, H3CC=CH2, cis), 5.09 (br s, 1 H, H3CC=CH2, cis), 6.65 (s, 1
H, H-3¢ Ar, cis), 6.68 (s, 1 H, H-3¢ Ar, trans), 6.71–6.82 (m, 2 H, Ar
H-5¢ and H-6¢, trans), 6.93–7.03 (m, 2 H, Ar H-5¢ and H-6¢, cis).
13C NMR (63 MHz, CDCl3): d = 16.1 (CH3C cBu, trans), 16.2
(CH3C cBu, cis), 20.5 (H3CC=CH2, trans), 22.5 (H3CC=CH2, cis),
25.3 (CH2 cBu, cis), 25.3 (CH2 cBu, trans), 26.7 (ArCH3, trans),
28.3 (ArCH3, cis), 29.6 (CH2 cBu, cis), 29.9 (CH2 cBu, trans), 49.8
(H3CC cBu, cis), 50.6 (H3CC cBu, trans), 56.1 (OCH3, cis), 56.3
(OCH3, trans), 75.7 (COH, cis), 79.8 (COH, trans), 109.2 (C=CH2,
cis), 109.7 (C=CH2, trans), 110.2 (Ar C-3¢, cis), 110.9 (C=CH2,
trans), 112.8 (Ar C-3¢, trans), 113.6 (C=CH2, cis), 128.2 (Ar C-5¢,
trans), 128.6 (Ar C-6¢, trans), 128.8 (Ar C-5¢, cis), 129.2 (Ar C-6¢,
cis), 129.4 (Ar C-1¢, trans), 129.6 (Ar C-1¢, cis), 130.3 (Ar C-4¢,
cis), 130.3 (Ar C-4¢, trans), 154.4 (Ar C-2¢, cis), 154.7 (Ar C-2¢,
trans).
FAB-MS: m/z = 299 [M + Na+].
HRMS (EI): m/z calcd for C17H24O3: 276.1725; found: 276.1731.
Cyclopentanones 5a and 5b
Method A: A solution of the cyclobutanols 11a,a¢ or 11b,b¢ (1
mmol) and PTSA (172 mg, 1 mmol) was refluxed in benzene (20
mL) for 30 min. Then, the mixture was cooled to r.t., diluted with
Et2O (100 mL) and washed with aq sat. NaHCO3 solution (2 × 10
mL) and brine (10 mL). The organic phase was dried (Na2SO4) and
concentrated under reduced pressure. The resulting crude oil was
readily purified by flash column chromatography (silica gel, hex-
anes–Et2O, 10:1) to afford the corresponding cyclopentanones 5a or
5b.
Method B: To a stirred solution of the cyclobutanols 11a,a¢ or
11b,b¢ (1 mmol) in Et2O (20 mL), BF3·OEt2 (0.5 mmol) was added
dropwise at –40 °C. After stirring for 4 h at this temperature, the
mixture was allowed to warm to r.t. and stirred for one additional
hour. Then, the mixture was diluted with Et2O (50 mL), washed
with aq sat. NaHCO3 solution (2 × 10 mL) and brine (10 mL). The
organic phase was dried (Na2SO4) and concentrated under reduced
pressure. The resulting crude oil was readily purified by flash col-
umn chromatography (silica gel, hexanes–Et2O, 10:1) to afford the
corresponding cyclopentanones 5a or 5b.
MS (EI): m/z (%) (trans 11a) = 246 (5, M+), 162 (38), 147 (100),
131 (20), 119 (69), 105 (21), 91 (47), 69 (43), 41 (64).
Synthesis 2007, No. 7, 999–1002 © Thieme Stuttgart · New York

1002
F. Secci et al.
PAPER
3-(2-Methoxy-4-methylphenyl)-2,2,3-trimethylcyclopentanone
(5a)
Yellow oil; yield: 91% (Method A); 94% (Method B).
IR (neat): 3000, 2987, 1760, 1220 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.66 (s, 3 H, CH3C-2 cPent), 1.23
(s, 3 H, CH3C-2 cPent), 1.38 (s, 3 H, CH3C-3 cPent), 1.98–2.47 (m,
1 H, H-cPent), 2.29 (s, 3 H, ArCH3), 2.41–2.54 (m, 3 H, H-cPent),
3.72 (s, 3 H, OCH3), 6.75 (d, J = 8.1 Hz, 1 H, H-5¢ Ar), 7.01 (d,
J = 8.1 Hz, 1 H, H-6¢ Ar), 7.12 (s, 1 H, H-3¢ Ar).
13C NMR (75 MHz, CDCl3): d = 20.9 (CH2 cPent), 21.8 (CH3C-2
cPent), 23.4 (CH3C-2 cPent), 29.6 (ArCH3), 32.6 (CH3C-3 cPent),
34.5 (CH2 cPent), 48.7 (CH3C-3 cPent), 52.6 (CH3CCH3), 54.2
(OCH3), 110.9 (Ar C-3¢), 127.6 (Ar C-5¢), 128.6 (Ar C-6¢), 129.2
(Ar C-1¢), 134.4 (Ar C-4¢), 155.9 (Ar C-2¢), 223.1 (C=O).
5-Methyl(-2-(1,2,2-trimethylcyclopentyl)phenol (6a, Hydroxy-
cuparene)
To a solution of the cyclopentane 12 (280 mg, 1.21 mmol) in
CH2Cl2 (20 mL) cooled at – 20 °C, was added dropwise BBr3 (303
mg, 1.21 mmol). After stirring for 3 h, the mixture was allowed to
warm to r.t. and stirred for one additional hour. The mixture was di-
luted with CH2Cl2 (50 mL), washed with aq sat. NaHCO3 solution
(2 × 5 mL), and brine (5 mL). The organic phase was dried
(Na2SO4) and concentrated under reduced pressure. The resulting
crude oil was purified by flash column chromatography (silica gel,
hexanes–Et2O, 10:1) to give the cyclopentane 6a14 (245 mg, 93%).
References
(1) Miyazawa, M.; Kurose, K.; Itoh, A.; Hiraoka, N. J. Agric.
Food Chem. 2001, 49, 5433.
MS (EI): m/z (%) = 246 (26, M+), 189 (4), 162 (56), 147 (100), 119
(2) Grainger, R. S.; Patel, A. Chem. Commun. 2003, 1072.
(3) Ishikawa, W. K.; Yamaji, K.; Tahara, S.; Fukushi, Y.;
Takahashi, K. Phytochemistry 2000, 54, 777.
(4) Paul, T.; Pal, A.; Gupta, P. D.; Mukherjee, D. Tetrahedron
Lett. 2003, 44, 737.
(5) (a) Fuganti, C.; Serra, S. J. Org. Chem. 1999, 64, 8728.
(b) Srikhrishna, A.; Srinivasa Rao, M. Synlett 2004, 374.
(c) Kuwahara, S.; Saito, M. Tetrahedron Lett. 2004, 45,
5047. (d) Saito, M.; Kuwahara, S. Biosci. Biotechnol.
Biochem. 2005, 69, 374.
(6) Bernard, A. M.; Frongia, A.; Secci, F.; Delogu, G.; Ollivier,
J.; Piras, P. P.; Salaün, J. Tetrahedron 2003, 59, 9433.
(7) Truce, W. E.; Hollister, K. R.; Lindy, L. B.; Parr, T. E.
J. Org. Chem. 1968, 33, 43.
(61), 91 (39), 77 (19), 56 (28).
Anal. Calcd for C16H22O2 (246.35): C, 78.01; H, 9.00. Found: C,
78.15; H, 9.13.
1-Methoxy-2-(1,2,2-trimethylcyclopentyl)benzene (12)
To a solution of the cyclopentanone 5a (370 mg, 1.5 mmol) in di-
ethylene glycol (digol, 25 mL), was added dropwise hydrazine hy-
drate (65 mg, 1.5 mmol) at 70 °C. After stirring for 3 h, t-BuOK
(358 mg, 3.2 mmol) was added portionwise and the temperature
was maintained for 4 h. Then, the mixture was cooled to r.t., diluted
with Et2O (50 mL), and washed with brine (2 × 5 mL). The organic
phase was dried (Na2SO4) and concentrated under reduced pressure.
The resulting crude oil was readily purified by flash column chro-
matography (silica gel, hexanes–Et2O, 10:1) to furnish the cyclo-
pentane 12; yellow oil; yield: 0.208 g (75%). We noted omissions
in the reported data of this compound.13
1H NMR (300 MHz, CDCl3): d = 0.66 (s, 3 H, CH3CCH3), 1.13 (s,
3 H, CH3C-2 cPent), 1.34 (s, 3 H, CH3C-2 cPent), 1.45–1.84 (m, 5
H, H-cPent), 2.26 (s, 3 H, ArCH3), 2.47–2.60 (m, 1 H, H-cPent),
3.75 (s, 3 H, OCH3), 6.74 (d, J = 8.1 Hz, 1 H, H-5¢ Ar), 7.00 (d,
J = 8.1 Hz, 1 H, H-6¢ Ar), 7.10 (s, 1 H, H-3¢ Ar).
(8) Harrowven, D.; Lucas, M. C.; Howes, P. D. Tetrahedron
2001, 57, 791.
(9) (a) Lecornué, F.; Paugam, R.; Ollivier, J. Eur. J. Org. Chem.
2005, 2589. (b) Shibata, S.; Nakahara, M.; Aimi, N. Chem.
Pharm. Bull. 1963, 11, 379.
(10) Trost, B. M.; Bogdanowicz, M. J. J. Am. Chem. Soc. 1971,
93, 3773.
(11) Bernard, A. M.; Frongia, A.; Piras, P. P. Chem. Commun.
2005, 3853.
(12) (a) Nagata, W.; Itazaki, H. Chem. Ind. (London) 1964, 26,
1194. (b) Pal, A.; Gupta, P. D.; Roy, A.; Mukheyee, D.
Tetrahedron Lett. 1999, 40, 4733.
13C NMR (75 MHz, CDCl3): d = 20.8 (CH3CAr), 21.1 (CH3CCH3),
23.3 (CH3CCH3), 26.3 (ArCH3), 30.0 (CH3CCH3), 40.1 (CH2CH2),
42.3 (CH2CH2), 44.2 CH2CH2), 51.3 (CH3CAr), 54.8 (OCH3),
111.0 (Ar C-3¢), 127.8 (Ar C-5¢), 129.2 (Ar C-6¢), 134.5 (Ar C-1¢),
135.9 (Ar C-4¢), 156.7 (Ar C-2¢).
(13) Inouye, Y.; Inomata, S.; Ishihara, Y.; Kakisawa, H. Bull.
Chem. Soc. Jpn. 1982, 55, 208.
(14) Toyota, M.; Koyama, H.; Asakawa, Y. Phytochemistry
1997, 46, 145.
Synthesis 2007, No. 7, 999–1002 © Thieme Stuttgart · New York