De novo synthesis of (+)-isofregenedol

Article abstract of DOI:10.1021/jo801365z

(Chemical Equation Presented) An efficient enantioselective synthesis of (+)-isofregenedol was achieved in 13 steps from commercially available cyclohexene oxide without the use of protecting groups. The tetrahydronaphthalenic core of isofregenedol was ob

Full text of DOI:10.1021/jo801365z

De Novo Synthesis of (+)-Isofregenedol
Maxime Riou and Louis Barriault*
Department of Chemistry, 10 Marie Curie, UniVersity of
Ottawa, Ottawa, Canada K1N 6N5
lbarriau@uottawa.ca
ReceiVed June 27, 2008
FIGURE 1. Structure of fregedane, isofregenedane, and labdane
diterpenes.
SCHEME 1
SCHEME 2
An efficient enantioselective synthesis of (+)-isofregenedol
was achieved in 13 steps from commercially available
cyclohexene oxide without the use of protecting groups. The
tetrahydronaphthalenic core of isofregenedol was obtained
via a gold(I)-catalyzed benzannulation recently developed
in our laboratory.
In 1991, Niemeyer and co-workers isolated from the aerial
parts of a Chilean flower, Haplopappus parVifolius, a novel
diterpene, isofregenedol (1) (Scheme 1).1 NMR spectroscopy
revealed that isofregenedol (1) possesses a substituted tetrahy-
dronaphthalene framework which is encountered in few naturally
occurring products notably in fregenedane and isofregenedane
diterpenoid family 1-3.2 Conversely, this scaffold is found in
a number of medicinally important molecules.3 On the basis of
biogenetic hypotheses, it was first proposed that the absolute
configuration at C13 was R. However, a synthesis of (+)-
isofregenedol (1) from the cationic rearrangement of labdane
diterpenes zamoranic acid (4) and sclareol (5) by Marcos and
co-workers (Figure 1) established the absolute configuration at
C13 as being S.4
Recently, we reported a novel gold(I)-catalyzed benzannu-
lation of 3-hydroxy-1,5-enynes as an efficient method to
synthesize substituted tetrahydronaphthalenes.5 A cursory in-
spection of fregenedane and isofregenedane structures prompted
us to utilize 1 as a testing ground for our new benzannulation
method. Retrosynthetically, we envisioned that 1 could be
directly synthesized from a gold(I)-catalyzed cyclization of 6
(Scheme 1). The latter could be quickly assembled from
commercially available geraniol 7 and 2,2-dimethylcyclohex-
anone 8. Herein, we reported a short and de novo synthesis of
(+)-isofregenedol (1).
The synthesis began by the enantioselective Sharpless ep-
oxidation of geraniol to give epoxide 9 in 92% yield (91% ee)
(Scheme 2).6 Tosylation of the primary alcohol followed by an
ozonolysis afforded aldehyde 10 in 84% yield. The resulting
aldehyde was then converted to the corresponding alkyne 11 in
53% yield by treatment with the modified Ohira reagent.7
Refluxing tosylate 11 in acetone in the presence of sodium
iodide gave 12 in 87% yield.
(1) Zdero, C.; Bohlmann, F.; Niemeyer, H. M. Phytochemistry 1991, 30,
3683.
(2) (a) Urones, J. G.; Marcos, I. S.; Basabe, P.; Garrido, N. M.; Jorge, A.;
Moro, R. F.; Lithgow, A. M. Tetrahedron 1993, 49, 6079. (b) Urones, J. G.;
Jorge, A.; Marcos, A. I.; Basabe, P.; Diez, D.; Garrido, N. M.; Lithgow, A. M.;
Fonseca, M. O.; Rodilla, J. M. Tetrahedron Lett. 1996, 37, 1659. (c) Urones,
J. G.; Jorge, A.; Marcos, A. I.; Basabe, P.; Laderas, M.; Diez, D.; Garrido, N. M.;
Lithgow, A. M.; Fonseca, M. O.; Rodilla, J. M.; Barata, I. G. Tetrahedron 2003,
59, 2333.
(3) Here are few examples: (a) methionine aminopeptidase-2 reversible
inhibitor: Sheppard, G. S.; Wang, J.; Kawai, M.; Fidanze, S. D.; BaMaung, N. Y.;
Erickson, S. A.; Barnes, D. M.; Tedrow, J. S.; Kolaczkowski, L.; Vasudeva, A.;
Park, D. C.; Wang, G. T.; Sanders, W. J.; Mantei, R. A.; Palazzo, F.; Tucker-
Garcia, L.; Lou, P.; Zhang, Q.; Park, C. H.; Kim, K. H.; Petros, A.; Olejniczak,
E.; Nettesheim, D.; Hajduk, P.; Henkin, J.; Lesniewski, R.; Davidsen, S. K.;
Bell, R. L. J. Med. Chem. 2006, 49, 3832. (b) Glucocorticoid receptor
agonist: Barker, M.; Clakers, M.; Copley, R.; Demaine, D. A.; Humphreys, D.;
Inglis, G. G. A.; Johnson, M. J.; Jones, H. T.; Haase, M. V.; House, D.; Loiseau,
R.; Lesley, N.; Pacquet, F.; Skone, P. A.; Shanahan, S. E.; Tape, D.; Vinader,
V. M.; Washington, M.; Uings, I.; Upton, R.; McLay, I. M.; Macdonald, S. J. F.
J. Med. Chem. 2006, 49, 4216. (c) Serotonin 5-HT7 receptor agonist: Holmberg,
P.; Sohn, D.; Leideborg, R.; Caldirola, P.; Zlatoidsky, P.; Hanson, S.; Mohell,
N.; Rosqvist, S.; Nordvall, G.; Johansson, A. M.; Johansson, R. J. Med. Chem.
2004, 47, 3927.
Treatment of 12 with zinc dust in acetic acid followed by
protection of the resulting tertiary alcohol as a TBS ether
(4) Marcos, I. S.; Laderas, M.; Diez, D.; Basabe, P.; Moro, R. F.; Garrido,
N. M.; Urones, J. G. Tetrahedron Lett. 2003, 44, 5419.
(5) (a) Grise´, C. M.; Barriault, L. Org. Lett. 2006, 8, 5905. (b) Grise´, C. M.;
Rodrigue, R. M.; Barriault, L. Tetrahedron 2008, 64, 797.
(6) (a) Hanson, R. M.; Sharpless, B. K. J. Org. Chem. 1986, 51, 1922. (b)
Taber, D. F.; Bui, G.; Chen, B. J. Org. Chem. 2001, 66, 3423.
(7) Roth, G. J.; Liepold, B.; Mu¨ller, S. G.; Bestmann, H. J. Synthesis 2004,
59.
7436 J. Org. Chem. 2008, 73, 7436–7439
10.1021/jo801365z CCC: $40.75 2008 American Chemical Society
Published on Web 08/13/2008

SCHEME 3
SCHEME 4
afforded alkyne 13 in 70% yield for two steps (Scheme 3).
Having synthesized the alkyne fragment 13, the next step was
to couple it with ketone 14. To this end, ketone 14 was prepared
via a palladium-catalyzed vinylation of 2,2-dimethylcyclohex-
anone 8 using conditions developed by Buchwald and co-
workers (Scheme 3).8 Despite various attempts to optimize the
reaction yield, the desired ketone 14 was isolated in 28% yield.9
Deprotonation of 13 with n-BuLi in THF followed by the
addition of ketone 14 produced alcohol 6 in 81%.
SCHEME 5
Having the desired 3-hydroxy-1,5-enyne 6 in our hands, the
Au(I)-catalyzed benzannulation reaction was then attempted. To
our disappointment, treatment of alcohol 6 under standard
benzannulation conditions, AuPPh3Cl (5 mol %) and AgOTf
(5 mol %), did not afford desired tetrahydronaphthalene 15 (eq
1
1). Rigorous inspection of the H NMR spectrum of the crude
grafted on the tetrahydronaphthalene framework via palladium-
catalyzed cross-coupling reactions. The second approach com-
menced by a copper-mediated addition of 2-butenemagnesium
bromide (mixture of E and Z isomers) to cyclohexene oxide 20
to give the corresponding alcohol. The latter underwent a Swern
oxidation, yielding ketone 21 as a mixture of geometrical
isomers in 82% yield over two steps (Scheme 4).10 Addition of
ethynyl magnesium bromide to ketone 21 provided 22 in 78%
yield as a mixture of diastereomers (dr ) 1:1). Gratifyingly,
exposure of 22 to the standard benzannulation conditions gave
the desired tetrahydronaphthalene 23 in 69% yield on a
multigram scale. The gem-dimethyl unit was then installed via
a benzylic oxidation with CrO3 (45% yield) followed by
treatment of the resulting ketone 24 with Me2Zn in the presence
of TiCl4 to afford 25 in 77% yield.11
A regioselective bromination of tetrahydronaphthalene 25
using bromine and a catalytic amount of Fe(0) in dichloroethane
gave the desired brominated compound in 94% yield (Scheme
5). The latter underwent a microwave-accelerated Stille cross-
coupling reaction to afford styrene 26 in 93% yield.12 The side
chain was then elongated by the use of a Suzuki reaction.
Treatment of 26 with 9-BBN followed by the addition of vinyl
iodide 27 in the presence of PdCl2(dppf) (5 mol %) and cesium
carbonate in wet DMF gave 28 in 74% yield. Reduction of the
ester group with Dibal-H led to the corresponding allylic alcohol
29, which upon exposure to Sharpless epoxidation conditions
provided epoxide 30 in 97% yield and 91% ee.4 To complete
the synthesis, alcohol 30 was converted to an iodide (I2, PPh3,
imidazole, THF), and the latter was treated with Zn in acetic
acid to yield synthetic (+)-isofregenedol (1) whose spectral data
were identical to those reported in the literature.1,4
reaction mixture showed no trace of the desired product. At
first glance, one might suggest that the steric congestion which
is exerted on the alkyne moiety by the neighboring gem-dimethyl
group could probably prevent binding of the gold catalyst. In
these circumstances, no benzannulation reaction would be
possible and other background reactions could take place. To
verify this hypothesis, 3-hydroxy-1,5-enynes 16 and 18 were
exposed to benzannulation conditions. In the first case, no
desired product was detected; again only degradation was
observed by NMR of the crude mixture (eq 2). On the other
hand, Au(I) benzannulation of 18 gave the desired product 19
in 30% yield (eq 3). One can suggest that the presence of an
extra olefinic methyl group could, even in the absence of a gem-
dimethyl substituent, prevent the benzannulation from occurring.
These results were a surprise for us since we reported Au(I)-
catalyzed benzannulation of trisubstituted 3-hydroxy-1,5-enynes
possessing an internal alkyne leading to the corresponding 1,2,3-
substituted tetrahydronaphthalenes.5 However, the inability to
cyclize 6 and 16 combined with the poor yield to obtain ketone
14 precluded pursuing this approach.
In summary, we achieved a de novo enantioselective synthesis
of (+)-isofregenedol (1) in 13 steps. The synthesis took
advantage of a Au(I)-catalyzed benzannulation to construct the
tetrahydronaphthalene framework. The application of this
After a careful examination of various scenarios, we opted
to install the gem-dimethyl group after the benzannulation
process. The side chain containing the allylic alcohol could be
(8) Chieffi, A.; Kamikawa, K.; Åhman, J.; Fox, J. M.; Buchwald, S. L. Org.
Lett. 2001, 3, 1897.
(9) We noted, with this particular substrate, that the reaction was particularly
unreliable and often produced 14 along with inseparable by products.
(10) Sauer, E. L. O.; Barriault, L. J. Am. Chem. Soc. 2004, 126, 8569.
(11) Reetz, M. T.; Westermann, J.; Kyung, S.-H. Chem. Ber. 1985, 118, 1050.
(12) Lovely, C. J.; Bhat, A. S.; Coughenour, H. D.; Gilbert, N. E.;
Brueggemeier, R. W. J. Med. Chem. 1997, 40, 3756.
J. Org. Chem. Vol. 73, No. 18, 2008 7437

silica gel column chromatography (hexanes) to afford 637 mg of
the aryl bromide as a colorless oil (94% yield): IR (neat) νmax 2968,
2930, 2869, 1554 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.40 (s, 1
H), 2.57 (t, J ) 6.5 Hz, 2 H), 2.36 (s, 3 H), 2.18 (s, 3 H), 1.83-1.78
(m, 2 H), 1.59-1.53 (m, 2 H), 1.25 (s, 6 H); 13C NMR (100 MHz,
CDCl3) δ 145.3 (C), 136.6 (C), 133.9 (C), 132.6 (C), 128.2 (CH),
123.1 (C), 38.4 (CH2), 33.9 (C), 31.9 (2xCH3), 28.5 (CH2), 19.935
(CH3), 19.5 (CH2), 16.6 (CH3); HRMS m/z calcd for C14H19Br
266.0670 (M+), found 266.0680. Step 2: A stirred solution of the
bromide (283 mg, 1.064 mmol), tributylvinyltin (560 µL, 1.916
mmol), Pd(PPh3)4 (98 mg, 0.085 mmol), and toluene (7 mL) in a
microwave cell was deoxygenated by bubbling argon through it
for 15 min. The reaction mixture was heated at 150 °C in the
microwave oven for 2 h. After cooling to room temperature, the
mixture was diluted with hexanes (25 mL) and washed with H2O
(20 mL), 10% aqueous NH4OH (20 mL), and saturated aqueous
NaCl (20 mL). The organic layer was dried and concentrated. The
residue was purified by silica gel column chromatography (hexanes)
to afford 211 mg of 26 as a pale yellow oil (93% yield): IR (neat)
method to the synthesis of other rearranged labdanes is
underway and will be reported in due course.
Experimental Section
5,6-Dimethyl-1,2,3,4-tetrahydronaphthalene (23). AgOTf (388
mg, 1.51 mmol) and Au(PPh3)Cl (747 mg, 1.51 mmol) were
transferred to a flame-dried flask containing CH2Cl2 (230 mL).
Then, a solution of 22 (4.48 g, 25.15 mmol) in CH2Cl2 (20 mL)
was added via cannula. After stirring at room temperature for 21 h,
the reaction mixture was filtered through Celite. The fritted glass
funnel was rinsed with Et2O (50 mL), and the filtrate was
concentrated. The residue was purified by silica gel column
chromatography (hexanes) to afford 2.76 g of 23 as a colorless oil
(69% yield): IR (neat) νmax 2945, 2918, 2861 cm-1; 1H NMR (400
MHz, CDCl3) δ 6.93 (d, J ) 7.7 Hz, 1 H), 6.85 (d, J ) 7.7 Hz, 1
H), 2.75 (t, J ) 6.2 Hz, 2 H), 2.66 (t, J ) 6.4 Hz, 2 H), 2.26 (s, 3
H), 2.13 (s, 3 H), 1.86-1.78 (m, 2 H), 1.77-1.71 (m, 2 H); 13C
NMR (100 MHz, CDCl3) δ 135.3 (C), 134.9 (C), 134.8 (C), 133.5
(C), 127.0 (CH), 126.5 (CH), 30.1 (CH2), 27.3 (CH2), 23.7 (CH2),
22.8 (CH2), 20.4 (CH3), 14.8 (CH3); HRMS m/z calcd for C12H16
160.1252 (M+), found 160.1267.
1
νmax 3085, 2960, 2926, 2865, 1622 cm-1; H NMR (400 MHz,
CDCl3) δ 7.32 (s, 1 H), 7.01 (dd, J ) 17.3, 10.9 Hz, 1 H), 5.51
(dd, J ) 17.3, 1.7 Hz, 1 H), 5.24 (dd, J ) 10.9, 1.7 Hz, 1 H), 2.65
(t, J ) 6.5 Hz, 2 H), 2.24 (s, 3 H), 2.15 (s, 3 H), 1.86-1.80 (m, 2
H), 1.64-1.61 (m, 2 H), 1.31 (s, 6 H); 13C NMR (100 MHz, CDCl3)
δ 143.3 (C), 136.8 (CH), 135.2 (C), 134.7 (C), 134.5 (C), 130.9
(C), 122.1 (CH), 114.9 (CH2), 38.7 (CH2), 33.9 (C), 32.0 (2xCH3),
28.7 (CH2), 16.7 (CH2), 15.8 (CH3), 15.6 (CH3); HRMS m/z calcd
for C16H22 214.1721 (M+), found 214.1730.
5,6-Dimethyl-3,4-dihydro-2H-naphthalenone (24). A 10% aque-
ous CrO3 acetic solution (23.42 mmol, 22.2 mL in AcOH/H2O)
was added to a solution of 23 (750 mg, 4.68 mmol) in glacial AcOH
(120 mL). The resulting dark brown reaction mixture was stirred
at room temperature for 2.5 h. H2O (200 mL) was added, and the
aqueous layer was extracted with Et2O (4 × 100 mL). Combined
organic phases were washed with H2O and NaHCO3 (saturated),
dried, and concentrated. The residue was purified by silica gel
column chromatography (5% EtOAc/hexanes) to afford 370 mg of
24 as a pale yellow solid (45% yield): mp 67-68.5 °C; IR (neat)
Ethyl (E)-3-methyl-5-(3,4,8,8-tetramethyl-5,6,7,8-tetrahydronaph-
thalen-2-yl)-pent-2-enoate (28). To 9-BBN (2.12 mL of a 0.5 M
solution in THF, 1.06 mmol) was added a solution of 26 (75.6 mg,
0.35 mmol) in THF (750 µL) over 2 min. The mixture was heated
under reflux for 1 h. In a separate flask, a solution of 27 (85 mg,
0.35 mmol) in DMF (500 µL) was added to a stirred mixture of
Cs2CO3 (230 mg, 0.71 mmol), PdCl2(dppf) ·CH2Cl2 (29 mg, 10 mol
%), Ph3As (11 mg, 10 mol %), DMF (1 mL), and H2O (230 µL,
36 molar equiv). The resulting mixture was stirred for 5 min. After
addition of the above THF solution, the reaction mixture was heated
at 80 °C for 2 h. After cooling down to room temperature, water
was added (3 mL) and the mixture was extracted with Et2O (3 ×
5 mL). Combined organic layers were washed with NaCl (satu-
rated), dried, and concentrated. The residue was purified by silica
gel column chromatography (10 f 50% benzene/hexanes) to afford
86 mg of 28 as a white solid (74% yield): mp 73-76 °C; IR (neat)
ν
max 2933, 2860, 1682, 1594 cm-1; 1H NMR (500 MHz, CDCl3) δ
7.83 (d, J ) 8.0 Hz, 1 H), 7.08 (d, J ) 8.0 Hz, 1 H), 2.87 (t, J )
6.2 Hz, 2 H), 2.60-2.57 (m, 2 H), 2.32 (s, 3 H), 2.20 (s, 3 H),
2.15-2.09 (m, 2 H); 13C NMR (125 MHz, CDCl3) δ 198.7 (C),
142.5 (C), 142.4 (C), 134.4 (C), 130.9 (C), 128.0 (CH), 124.5 (CH),
38.3 (CH2), 26.9 (CH2), 22.6 (CH2), 21.1 (CH3), 14.9 (CH3); HRMS
m/z calcd for C12H14O 174.1045 (M+), found 174.1044.
1,1,5,6-Tetramethyl-1,2,3,4-tetrahydronaphthalene (25). To a
solution of freshly distilled TiCl4 (625 L, 5.70 mmol) in CH2Cl2
(5 mL) at -30 °C was added Me2Zn (5.7 mL of a 1.0 M solution
in toluene, 5.70 mmol). The resulting orange mixture was stirred
at that temperature for 10 min. A solution of 24 (450 mg, 2.58
mmol) in CH2Cl2 (2.2 mL) was then added dropwise via cannula.
The dark red reaction mixture was slowly allowed to warm up to
0 °C over a period of about 2 h and was then poured onto ice water.
The aqueous layer was separated from the organic layer and
extracted with Et2O (3 × 20 mL). Combined organic phases were
washed with NaHCO3 (saturated), dried, and concentrated. The
residue was purified by silica gel column chromatography (hexanes
then 10% EtOAc/hexanes) to afford 63 mg of 24 and 376 mg of
25 as a colorless oil (77% yield; 90% yield brsm): IR (neat) νmax
2930, 2869, 1485, 1455 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.15
(d, J ) 8.0 Hz, 1 H), 6.99 (d, J ) 8.0 Hz, 1 H), 2.65 (t, J ) 6.5
Hz, 2 H), 2.26 (s, 3 H), 2.14 (s, 3 H), 1.87-1.81 (m, 2 H),
1.64-1.61 (m, 2 H), 1.29 (s, 6 H); 13C NMR (100 MHz, CDCl3)
δ 143.6 (C), 134.6 (C), 134.5 (C), 133.3 (C), 127.4 (CH), 123.9
(CH), 38.6 (CH2), 33.9 (C), 32.1 (2 × CH3), 28.4 (CH2), 20.5 (CH3),
19.7 (CH2), 15.2 (CH3); HRMS m/z calcd for C14H20 188.1565
(M+), found 188.1563.
ν
max 2929, 2867, 1716, 1650 cm-1; 1H NMR (400 MHz, CDCl3) δ
6.98 (s, 1 H), 5.72 (d, J ) 1.0 Hz, 1 H), 4.14 (q, J ) 7.1 Hz, 2 H),
2.73-2.77 (m, 2 H), 2.61 (t, J ) 6.5 Hz, 2 H), 2.31-2.35 (m, 2
H), 2.22 (d, J ) 1.0 Hz, 3 H), 2.19 (s, 3 H), 2.13 (s, 3 H), 1.77-1.83
(m, 2 H), 1.53-1.60 (m, 2 H), 1.24-1.30 (m, 9 H); 13C NMR
(100 MHz, CDCl3) δ 166.9 (C), 159.6 (C), 143.3 (C), 136.5 (C),
135.1 (C), 132.8 (C), 131.3 (C), 125.0 (CH), 115.7 (CH), 59.5
(CH2), 42.3 (CH2), 38.7 (CH2), 33.8 (C), 32.8 (CH2), 32.0 (2 ×
CH3), 28.5 (CH2), 19.7 (CH2), 19.1 (CH3), 15.7 (CH3), 15.5 (CH3),
14.4 (CH3); HRMS m/z calcd for C22H32O2 328.2402 (M+), found
328.2407.
(E)-3-Methyl-5-(3,4,8,8-tetramethyl-5,6,7,8-tetrahydronaphtha-
len-2-yl)-pent-2-enol (29). A solution of 28 (320 mg, 0.98 mmol)
in CH2Cl2 (9.8 mL) was cooled to -78 °C, and DIBAH (3.0 mL
of a 1.0 M solution in CH2Cl2, 3.00 mmol) was added dropwise
over 5 min. After stirring at -78 °C for 1 h, a 5 M solution (4 mL)
of AcOH in CH2Cl2 was added at -78 °C. The resulting mixture
was then stirred at room temperature, and 25% aqueous sodium
tartrate (5 mL) and H2O (4 mL) were added. The mixture was
extracted with CH2Cl2 (3 × 10 mL). Combined organic phases were
washed with NaHCO3 (saturated) and NaCl (saturated). The organic
layer was dried and concentrated. The residue was purified by silica
gel column chromatography (20% EtOAc/hexanes) to afford 236
mg of 29 as a pale yellow oil (84% yield): IR (neat) νmax 3335
(br), 2927, 2866, 1668 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.00
1,1,5,6-Tetramethyl-7-vinyl-1,2,3,4-tetrahydronaphthalene (26).
Step 1: To a mixture of 25 (479 mg, 2.54 mmol) and iron powder
(28 mg, 0.50 mmol) in 1,2-dichloroethane (20 mL) at 0 °C was
added Br2 (5.60 mL of a 0.50 M solution in CH2Cl2, 2.80 mmol)
dropwise. After stirring for 15 h at rt, cold water was added (10
mL). The aqueous mixture was extracted with Et2O (3 × 20 mL).
Combined organic phases were dried over anhydrous MgSO4. After
filtration and removal of the solvent, the residue was purified by
7438 J. Org. Chem. Vol. 73, No. 18, 2008

(s, 1 H), 5.47 (td, J ) 6.9, 1.2 Hz, 1 H), 4.16 (d, J ) 5.8 Hz, 2 H),
2.73-2.70 (m, 2 H), 2.62 (t, J ) 6.5 Hz, 2 H), 2.24-2.21 (m, 2
H), 2.19 (s, 3 H), 2.13 (s, 3 H), 1.83-1.78 (m, 2 H), 1.75 (s, 3 H),
1.60-1.58 (m, 2 H), 1.26 (s, 6 H), 1.14 (br, 1 H); 13C NMR (125
MHz, CDCl3) δ 143.0 (C), 139.7 (C), 137.1 (C), 134.8 (C), 132.4
(C), 131.2 (C), 124.8 (CH), 123.3 (CH), 59.3 (CH2), 40.7 (CH2),
38.5 (CH2), 33.6 (C), 33.0 (CH2), 31.9 (2xCH3), 28.3 (CH2), 19.6
(CH2), 16.4 (CH3), 15.6 (CH3), 15.3 (CH3); HRMS m/z calcd for
C20H30O 286.2297 (M+), found 286.2284.
of the corresponding iodide as a pale yellow oil (78% yield): [R]D
) +3 (c 0.023, CHCl3); IR (neat) νmax 2927, 2865, 1457, 1384,
1
1174, 1143 cm-1; H NMR (500 MHz, CDCl3) δ 7.00 (s, 1 H),
3.36 (dd, J ) 9.9, 6.0 Hz, 1 H), 3.15 (dd, J ) 8.0, 6.1 Hz, 1 H),
3.02 (dd, J ) 10.0, 8.4 Hz, 1 H), 2.70 (t, J ) 8.6 Hz, 2 H), 2.61
(t, J ) 6.4 Hz, 2 H), 2.18 (s, 3 H), 2.13 (s, 3 H), 1.88-1.78 (m, 3
H), 1.73-1.66 (m, 1 H), 1.60-1.55 (m, 2 H), 1.37 (s, 3 H), 1.26
(s, 6 H); 13C NMR (125 MHz, CDCl3) δ 143.2 (C), 136.4 (C),
134.9 (C), 132.6 (C), 131.1 (C), 124.63 (CH), 64.1 (C), 62.4 (CH),
39.4 (CH2), 38.5 (CH2), 33.6 (C), 31.9 (2 × CH3), 29.9 (CH2),
28.3 (CH2), 19.5 (CH2), 15.8 (CH3), 15.6 (CH3), 15.3 (CH3), 2.3
(CH2); HRMS m/z calcd for C20H29OI 412.1263 (M+), found
412.1237. Step 2: To a solution of the iodide (94 mg, 0.23 mmol)
in glacial AcOH (2.3 mL) was added zinc dust (196 mg, 3.00
mmol). After stirring for 1 h, wet Et2O (10 mL) was added and the
resulting mixture was filtered through a fritted glass funnel. The
filtrate was washed successively with H2O, Na2SO3 (saturated),
NaHCO3 (saturated), and NaCl (saturated), dried, and concentrated.
The residue was purified by silica gel column chromatography (10%
EtOAc/hexanes) to afford 64.5 mg of (+)-isofregenedol (1) as a
white solid (99% yield): mp 75-77 °C; [R]D ) +21 (c 0.015,
CHCl3), [R]D ) +20 (c 0.83, CHCl3) lit; IR (neat) νmax 3408 (br),
2927, 2866, 1458, 1360, 1105 cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.01 (s, 1 H), 5.99 (dd, J ) 17.3, 10.8 Hz, 1 H), 5.27 (dd, J )
17.3, 1.1 Hz, 1 H), 5.12 (dd, J ) 10.8, 1.1 Hz, 1 H), 2.68-2.58
(m, 4 H), 2.17 (s, 3 H), 2.12 (s, 3 H), 1.82-1.68 (m, 4 H),
(-)-{3-Methyl-3-[2-(3,4,8,8-tetramethyl-5,6,7,8-tetrahydronaph-
thalen-2-yl)ethyl]oxiranyl}methanol (30). To a suspension of ac-
tivated 4 Å molecular sieves (50 mg) in cold (-10 °C) CH2Cl2 (3
mL) was added L-(+)-DET (23 mg, 0.11 mmol, in 1 mL of CH2Cl2),
Ti(Oi-Pr)4 (21 mg, 0.07 mmol, in 1 mL of CH2Cl2), and TBHP
(250 µL, 1.38 mmol, 5.5 M in decane). After stirring for 10 min,
the mixture was cooled to -20 °C, and a solution of 29 (265 mg,
0.93 mmol) in CH2Cl2 (4.5 mL) was added. After stirring for 3 h,
the mixture was warmed to 0 °C and 2 mL of H2O and 1 mL of
30% aqueous NaOH saturated with solid NaCl were added. After
stirring for 10 min, the mixture was extracted with CH2Cl2 (3 ×
10 mL). Combined organic phases were dried and concentrated.
The residue was purified by silica gel column chromatography (25%
EtOAc/hexanes) to afford 271 mg of 30 as a pale yellow oil (97%
yield): [R]D ) -5 (c 0.035, CHCl3); IR (neat) νmax 3438 (br), 2925,
1
1472, 1384 cm-1; H NMR (500 MHz, CDCl3) δ 6.99 (s, 1 H),
3.81-3.77 (m, 1 H), 3.70-3.65 (m, 1 H), 2.95 (dd, J ) 6.6, 4.4
Hz, 1 H), 2.76-2.64 (m, 2 H), 2.61 (t, J ) 6.5 Hz, 2 H), 2.17 (s,
3 H), 2.12 (s, 3 H), 1.88-1.84 (m, 1 H), 1.83-1.78 (m, 2 H),
1.75-1.69 (m, 1 H), 1.60-1.58 (m, 3 H), 1.38 (s, 3 H), 1.26 (s, 6
H); 13C NMR (125 MHz, CDCl3) δ 143.1 (C), 136.3 (C), 135.0
(C), 132.6 (C), 131.2 (C), 124.8 (CH), 62.6 (CH), 61.2 (CH2), 61.0
(C), 39.4 (CH2), 38.5 (CH2), 33.6 (C), 31.9 (2 × CH3), 29.6 (CH2),
28.3 (CH2), 19.5 (CH2), 16.8 (CH3), 15.6 (CH3), 15.3 (CH3); HRMS
m/z calcd for C20H30O2 302.2246 (M+), found 302.2238; retention
time ) 6.82 min (minor enantiomer, 4.7%), 20.20 min (major
enantiomer, 95.3%).
1.60-1.57 (m, 2 H), 1.54 (s, 1 H), 1.34 (s, 3 H), 1.26 (s, 6 H); 13
C
NMR (125 MHz, CDCl3) δ 144.7 (CH), 143.1 (C), 137.4 (C), 134.9
(C), 132.3 (C), 131.3 (C), 124.9 (CH), 111.9 (CH2), 73.3 (C), 43.3
(CH2), 38.5 (CH2), 33.6 (C), 31.9 (2 × CH3), 28.9 (CH2), 28.3
(CH2), 27.9 (CH3), 19.6 (CH2), 15.5 (CH3), 15.3 (CH3); HRMS
m/z calcd for C20H30O 286.2297 (M+), found 286.2296.
Acknowledgment. We thank the University of Ottawa,
NSERC, Merck Frosst Canada, Merck and Co., Boehringer
Ingelheim, and PREA for generous funding. M.R. thanks Le
Fonds Que´becois de la Recherche sur la Nature et les Technolo-
gies (FQRNT) for a postgraduate scholarship (B2).
(+)-Isofregenedol (1). Step 1: To a solution of epoxyalcohol 30
(16.5 mg, 0.055 mmol) in benzene (1 mL) were added imidazole
(20 mg, 0.294 mmol), PPh3 (73 mg, 0.278 mmol), and I2 (70 mg,
0.276 mmol). After stirring at 25 °C for 3 h, the reaction was diluted
with Et2O (10 mL) and saturated aqueous NaHCO3 (5 mL). To
this mixture was added saturated Na2SO3 (5 mL), and the mixture
was extracted with Et2O (3 × 10 mL). The combined organic layers
were dried and concentrated. The residue was purified by silica
gel column chromatography (5% EtOAc/hexanes) to afford 16 mg
Supporting Information Available: Detailed experimental
1
procedures for 6, 9-14, and 19-22 and copies of H and 13C
NMR for all products. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO801365Z
J. Org. Chem. Vol. 73, No. 18, 2008 7439