Enantioselective total synthesis of (-)-curcuquinone via regioselective chromium-mediated benzannulation

Article abstract of DOI:10.1021/jo0500939

(Chemical Equation Presented) A short and efficient, high-yielding enantioselective total synthesis of the marine natural product (-)-curcuquinone 1 is reported involving a regioselective [3 + 2 + 1]-benzannulation reaction as the key step. Additionally, this strategy allows the isolation of curcuhydroquinone monomethyl ether 9 as an intermediate of the benzannulation reaction and its subsequent further protection toward diversified hydroquinones.

Full text of DOI:10.1021/jo0500939

and quinone moiety of curcuquinone in a completely
regioselective way, as outlined in Figure 1.5
Enantioselective Total Synthesis of
(-)-Curcuquinone via Regioselective
Chromium-Mediated Benzannulation
Ana Minatti and Karl Heinz Do¨tz*
Kekule´-Institut fu¨r Organische Chemie und Biochemie,
Rheinische Friedrich-Wilhelms Universita¨t Bonn,
Gerhard-Domagk-Strasse 1, 53121 Bonn, Germany
FIGURE 1. Retrosynthetic analysis of (-)-curcuquinone 1.
doetz@uni-bonn.de
The key substrates for the benzannulation reaction are
the propenyl methoxy chromium carbene complex 26 and
the chiral terminal acetylene 3. This unique type of metal
carbene reaction provides one of the most powerful tools
to generate densely substituted benzenoid compounds.7
It proceeds via a formal [3 + 2 + 1]-cycloaddition, which
involves an R,â-unsaturated carbene ligand (C3-synthon),
an alkyne (C2-synthon), and a carbonyl ligand (C1-
synthon) and takes place within the coordination sphere
of the chromium(0) metal center which acts as a template
(Scheme 1).
Received January 17, 2005
A short and efficient, high-yielding enantioselective total
synthesis of the marine natural product (-)-curcuquinone
1 is reported involving a regioselective [3 + 2 + 1]-benzan-
nulation reaction as the key step. Additionally, this strategy
allows the isolation of curcuhydroquinone monomethyl ether
9 as an intermediate of the benzannulation reaction and its
subsequent further protection toward diversified hydro-
quinones.
SCHEME 1. Atom Connectivity in the
Regioselective [3 + 2 + 1]-Benzannulation
Reaction toward 1 (R ) (R)-2-methylhept-2-enyl)
(-)-Curcuquinone 1, (-)-curcuhydroquinone, and (-)-
curcuphenol are aromatic bisabolene sesquiterpenoids
isolated from the Caribbean gorgonian sea plume Pseudo-
terogorgia rigida.1 Apart from displaying antibacterial
activity themselves, curcuquinone and curcuhydro-
quinone have proven to be versatile chiral building blocks
for the synthesis of related important natural products,
such as heliannuols, which represent a group of allelo-
chemical phenolic sesquiterpenes.2
Due to the common difficulty of introducing defined
absolute stereochemistry at the nonfunctionalized ben-
zylic position, only two reports on the synthesis of
optically active curcuquinone are available.3,4 However,
both routes require an enzymatic resolution as the key
step, and 50% of the synthetic material is lost at an
earlier or later stage of synthesis.
To perform the total synthesis in an enantioselective
manner, a stereoselective synthesis of the enyne 3 in
optically pure form was required (Scheme 2).
SCHEME 2. Stereoselective Synthesis of Enyne 3a
Herein, we report on the first enantioselective total
synthesis of the naturally occurring (-)-curcuquinone 1.
It represents a first convergent synthetic approach which
directly generates the quinonid core. Thus, this strategy
contrasts the customary routes starting from aromatic
precursors. From a retrosynthetic perspective, the chro-
mium-mediated benzannulation reaction was envisaged
as an efficient key-step to afford both the hydroquinone
a Reagents and conditions: (i) (D)-(-)-DIPT, Ti(O-i-Pr)4, TBHP,
CH2Cl2, MS 4 Å, -20 °C, 1 h, 87%; (ii) NaBH3CN, BF3‚OEt2, THF,
rt, 4 h, 86%; (iii) NaIO4, Bu4NIO4, H2O, CH2Cl2, 0 °C, 1 h, 95%;
(iv) CBr4, PPh3, Zn, CH2Cl2, rt, 12 h, 60%; (v) n-BuLi, THF,
-78 °C, 1 h, rt, 1 h, 99%.
(1) (a) McEnroe, F. J.; Fenical, W. Tetrahedron 1978, 34, 1661-
1664. (b) (+)-Curcuphenol has been isolated from the Jamaican sponge,
Didiscus oxeata.
(2) (a) Takabatake, K.; Nishi, I.; Shindo, M.; Shishido, K. J. Chem.
Soc., Perkin Trans. 1 2000, 1807-1808. (b) Vyvyan, J. R.; Looper, R.
E. Tetrahedron Lett. 2000, 41, 1151-1154.
10.1021/jo0500939 CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/05/2005
J. Org. Chem. 2005, 70, 3745-3748
3745

Our synthesis of the prerequisite acetylene commenced
with commercially available geraniol 4, which was epoxi-
dized asymmetrically according to Sharpless AE to
yield epoxide 5 {[R]2D5 ) +5.0° (c ) 3.0, CHCl3, lit.8b
[R]2D5 ) -5.3° (c ) 3.0, CHCl3) for the (-)-enantiomer} in
95% ee (Scheme 2).8 Lewis acid-mediated reductive ring
opening of this compound with NaBH3CN occurred at the
higher substituted center to furnish diol 6,9 which was
subjected to oxidative glycol cleavage to afford the desired
aldehyde 7.10,11 Severe difficulties were encountered in
cleaving the diol with NaIO4 in dioxane/H2O following
the procedure of Kibayashi et al., as this reaction failed
on scales bigger than 5 mmol and the removal of dioxane
turned out to be deleterious.11 Therefore, the oxidative
cleavage with NaIO4 was performed in CH2Cl2/H2O in
the presence of catalytic amounts of Bu4NIO4.12 This
procedure worked nicely even on larger scale-ups. The
racemization-free conversion of aldehyde 7 into the
terminal acetylene 3 via the dibromo olefin 8 was
achieved according to the Corey-Fuchs protocol.13
Finally, the synthesis of 1 was accomplished in 80% yield
in a benzannulation reaction of chromium carbene com-
plex 2 with properly functionalized chiral terminal
acetylene 3 (Scheme 3). The reaction occurred with
complete regioselectivity; no potential regioisomer could
be detected in the crude NMR.
reaction. Direct oxidative workup of the reaction mixture
with CAN in aqueous dichloromethane at 0 °C yielded
23
(-)-curcuquinone 1 {[R]
) -4.9° (c ) 1.09, CHCl3),
578
20
lit.3b [R]
) +4.32° (c ) 2.8, CHCl3) for the (+)-
577
enantiomer} (Scheme 3).14 The spectroscopic data for the
synthetic material were in excellent agreement with
those reported for the natural product.1 Taking advan-
tage of the inherent character of the benzannulation
reaction, the present approach allows the synthesis of
further valuable congeners. Within this context, mild
oxidation of the crude reaction mixture afforded curcu-
hydroquinone monomethyl ether 9 with an intact hydro-
quinone core as a colorless, viscous oil (Scheme 3). The
elusive primary benzannulation reaction product A bear-
ing the chromium-coordinated hydroquinone monomethyl
ether functionality could only be isolated after an in situ
benzoylation under standard conditions (Scheme 4).
SCHEME 4. Synthesis of Curcuhydroquinone
Derivatives 10, (-)-11, (-)-12, and (+)-13a
SCHEME 3. Synthesis of (-)-1 and rac-9a
a Reagents and conditions: (i) CH2Cl2, 55 °C, 2.5 h, AcBr or
(S)-MTPA-Cl, DMAP, NEt3, -20 °C to rt, 2 h, 40 or 33%,
respectively; (ii) CH2Cl2, 55 °C, 2.5 h, BzCl, DMAP, NEt3, -20 °C
to rt, 2 h, 60%; (iii) CH2Cl2, MeCN, O2, rt, 5 h, 95%.
Arenechromium complex 10 was isolated as an equi-
molar mixture of the two diastereomeric planar-chiral
metal complexes, which are direct precursors of (-)-
curcuquinone obtained by subsequent CAN oxidation.
Mild decomplexation released the free hydroquinone (-)-
11 as a colorless, viscous oil with the two phenolic groups
differentiated as methyl ether and benzoyl ester, respec-
tively. In a similar protocol, the methyl acetyl-bispro-
tected hydroquinone (-)-12 could be synthesized. Like-
wise, upon reaction with Mosher’s chloride, the corres-
ponding Mosher ester 13 was generated as a single
stereoisomer. Comparison of the respective set of 1H, 13C,
and 19F NMR signals with those of a 1:1 diastereomeric
mixture proved the overall sequence to be enantioselec-
tive. This overall ease of phenoxy group differentiation
in 9, (-)-11, and (-)-12 is of major synthetic importance
a Reagents and conditions: (i) CH2Cl2, 55 °C, 2.5 h, MeCN, O2,
rt, 1 h, 80%; (ii) CH2Cl2, 55 °C, 2.5 h, CAN, H2O, 0 °C, 30 min,
80%.
The final functionalization pattern of the product
depends on the workup conditions of the benzannulation
(3) (a) Fuganti, C.; Serra, S. J. Chem. Soc., Perkin Trans. 1 2000,
3758-3764. (b) Yoshimura, T.; Kisyuku, H.; Kamei, T.; Takabatake,
K.; Shindo, M.; Shishido, K. Arkivok 2003, 247-255.
(4) For total syntheses of racemic curcuquinone, see: (a) Sa´nchez,
I. H.; Lemini, C.; Joseph-Nathan, P. J. Org. Chem. 1981, 46, 4666-
4667. (b) Ono, M.; Yamamoto, Y.; Todoriki, R.; Akita, H. Heterocycles
1994, 37, 181-185. (c) Ono, M.; Yamamoto, Y.; Akita, H. Chem. Pharm.
Bull. 1995, 43, 553. (d) Vyryan, J. R.; Loitz, C.; Looper, R. E.; Mattingly,
C. S.; Peterson, E. A.; Staben, S. T. J. Org. Chem. 2004, 6, 2461-
2468.
(5) For recent examples on the application of the benzannulation
reaction in the total synthesis of natural products, see: (a) Rawat, M.;
Wulff, W. D. Org. Lett. 2004, 6, 329-332. (b) Roush, W. R.; Neitz, R.
J. J. Org. Chem. 2004, 69, 4906-4912. (c) Pulley, S. R.; Czako´, B.
Tetrahedron Lett. 2004, 45, 5511-5514. (d) White, J. D.; Smits, H. Org.
Lett. 2005, 7, 235-238.
(6) (a) Do¨tz, K. H.; Kuhn, W.; Ackermann, K. Z. Naturforsch. 1983,
38b, 1351-1356. (b) Fogel, L.; Hsung, R. P.; Wulff, W. D. J. Am. Chem.
Soc. 2001, 123, 5580-5581.
(7) (a) Do¨tz, K. H. Angew. Chem., Int. Ed. Engl. 1975, 14, 644-645.
For a recent review, see: (b) Minatti, A.; Do¨tz, K. H. In Topics in
Organometallic Chemistry; Do¨tz, K. H., Ed.; Springer: Heidelberg,
Germany, 2004; pp 123-157. (c) de Meijere, A.; Schirmer, H.; Duetsch,
M. Angew. Chem., Int. Ed. 2000, 39, 3964-4002. (d) Do¨tz, K. H.;
Tomuschat, P. Chem. Soc. Rev. 1999, 28, 187-198. For mechanistic
details, see: (e) Wulff, W. D.; Bax, B. M.; Brandvold, T. A.; Chan, K.
S.; Gilbert, A. M.; Hsung, R. P.; Mitchell, J.; Clardy, J. Organometallics
1994, 13, 102-126. (f) Barluenga, J.; Aznar, F.; Gutie´rrez, I.; Mart´ın,
A.; Garc´ıa-Granda, S.; Llorca-Baragano, M. A. J. Am. Chem. Soc. 2000,
122, 1314-1342.
(8) (a) The enantiomeric excess was determined by 1H NMR for the
corresponding epoxy acetate in the presence of Eu(hfc)3. (b) Gao, Y.;
Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless,
K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780. (c) Hashimoto, M.;
Harigaya, H.; Yanagiya, M.; Shirahama, H. J. Org. Chem. 1991, 56,
2299-2311.
(9) (a) Hanson, R. M. Chem. Rev. 1991, 91, 437-475. (b) Taber, D.
F.; Houze, J. B. J. Org. Chem. 1994, 59, 4004-4006.
(10) Racemic aldehyde 7 is commercially available.
(11) Yamazaki, N.; Dokoshi, W.; Kibayashi,C. Org. Lett. 2001, 3,
193-196.
(12) Corey, E. J.; Wright, S. W. J. Org. Chem. 1990, 55, 1670-1673.
(13) For the synthesis of racemic 3,7-dimethyl-6-octene-1-yne 3,
starting from racemic aldehyde 7, see: (a) Corey, E. J.; Fuchs, P. L.
Tetrahedron. Lett. 1972, 36, 3769-3772. (b) Snider, B. B.; Killinger,
T. A. J. Org. Chem. 1978, 43, 2161-2164.
(14) Attempts to determine the enantiomeric excess of the natural
product 1 did not meet with success as enantiomers of curcuquinone
could not be separated on HPLC employing standard Chiralcel OD,
OG, OB, Chiralpak AD, AS columns.
3746 J. Org. Chem., Vol. 70, No. 9, 2005

(c ) 1.0, CHCl3); GC analysis [Chirasil-Dex CB column, N2
carrier gas, 40 °C, retention times 63.6 min (S), 72.2 min (R)].
(R)-2,6-Dimethyl-5-heptenal (7).10,11 A solution of 1.72 g
(10 mmol) of 6 in 40 mL of dichloromethane was cooled to 0 °C;
0.2 g (0.46 mmol) of tetra-n-butylammonium periodate and a
solution of 4.28 g (20 mmol) of sodium periodate in 40 mL of
water cooled to 0 °C were added sequentially. After 1 h, 100 mL
of pentane was added, the layers were separated, and the organic
layer was washed with water and brine. The solvent was
evaporated under ambient pressure to yield the known title
compound 7 as a colorless liquid (1.33 g, 95%): 1H NMR
(300 MHz, CDCl3) δ 1.03 (3H, d, J ) 7 Hz), 1.35 (1H, m), 1.54
(3H, s), 1.63 (3H, s), 1.72 (1H, m), 1.97 (2H, m), 2.27 (1H, m),
5.03 (1H, t, J ) 7 Hz), 9.56 (1H, s); 13C NMR (75 MHz, CDCl3)
δ 205.0, 132.6, 123.4, 45.8, 30.6, 25.6, 25.3, 17.6 13.2.
since related protection in synthetic approaches to he-
liannuol A and D required multistep synthesis, including
resolution.2a Moreover, within the current general aim-
toward biological diversity, such structures might poten-
tially show complementary pharmaceutical and biological
activity.
In summary, we have described the first enantio-
selective total synthesis of (-)-curcuquinone 1 in 7 steps
and 20% overall yield starting from commercially avail-
able geraniol. The key features are the enantiose-
lective synthesis of the enyne 3 and the regioselective
[3 + 2 + 1]-benzannulation reaction to construct the fully
substituted aromatic core. Taking advantage of the
benzannulation key step, complementary protection pat-
terns further allow straightforward access to molecules
of higher diversity.
(R)-1,1-Dibromo-3,7-dimethyl-1,6-octadiene (8).13 Com-
pound 8 was synthesized in an analogous manner as reported:
bp 50 °C (2.5-3 × 10-2 mbar); 1H NMR (300 MHz, C6D6) δ 0.78
(3H, d, J ) 7 Hz), 1.17 (2H, m), 1.55 (3H, s), 1.69 (3H, s), 1.90
(2H, m), 2.40 (1H, m), 5.08 (1H, t, J ) 7 Hz), 6.00 (1H, d, J )
9 Hz); 13C NMR (75 MHz, CDCl3) δ 144.2, 131.9, 124.0, 87.5,
38.0, 36.3, 25.9, 25.8, 19.3, 17.8; IR (neat) ν 2964, 2927, 2852,
1616, 1454, 1377, 1117, 847, 781 cm-1; [R]D23 ) -7.8° (c ) 3.0,
CHCl3), GCMS m/z ) 296 (M+), 215, 135.
Experimental Section
(-)-Curcuquinone (1).1,3 A solution of 2 (276 mg, 1 mmol)
and 3 (204 mg, 1.5 mmol) in dichloromethane (5 mL) was
degassed by three freeze-pump-thaw cycles and warmed to
55 °C for 2.5 h under inert atmosphere. The benzannulation
reaction mixture was cooled to room temperature and slowly
added to a solution of (NO3)6Ce(NH4)2 (3.84 g, 7 mmol) in H2O
(20 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min and
extracted with dichloromethane. The organic layer was washed
with aqueous sodium bicarbonate and brine. The residue was
purified by column chromatography [n-hexane/dichloromethane,
1/1 (v/v)] to yield the title compound 1 (0.19 g, 80%) as a yellow
oil: 1H NMR (300 MHz, CDCl3) δ 1.03 (3H, d, J ) 6.8 Hz), 1.35-
1.53 (5H, m), 1.58 (3H, d, J ) 1.1 Hz), 1.89 (2H, m), 1.96 (3H, d,
J ) 1.7 Hz), 2.83 (1H, m), 4.97 (1H, t, J ) 6.9 Hz), 6.42 (1H, d,
J ) 0.9 Hz), 6.50 (1H, d, J ) 1.7 Hz); 13C NMR (75 MHz, CDCl3)
δ 188.3, 187.2, 154.0, 144.9, 133.7, 131.9, 131.0, 123.8, 35.7, 31.2,
25.7, 25.5, 19.4, 17.5, 15.2; IR (neat) ν 3272, 2966, 2926, 1657,
1610, 1452, 1241 cm-1; MS (EI) m/z ) 232 (M+), 164, 151, 122,
Curcuhydroquinone Monomethyl Ether (9). A solution
of 2 (276 mg, 1 mmol) and racemic 3 (204 mg, 1.5 mmol) in
dichloromethane (5 mL) was degassed by three freeze-pump-
thaw cycles and warmed to 55 °C for 2.5 h under inert
atmosphere. The benzannulation reaction mixture was cooled
to room temperature, diluted with acetonitrile (10 mL), and
stirred for 1 h with exposure to air. After filtration of the crude
reaction mixture through a pad of Celite, the solvent was
evaporated under reduced pressure. The pure product 9 (0.2 g,
80%) was obtained by column chromatography [n-hexane/
dichloromethane, 1/1 (v/v)] as a colorless, viscous oil: 1H NMR
(300 MHz, CDCl3) δ 1.21 (3H, d, J ) 7.0 Hz), 1.53 (3H, s) 1.54-
1.67 (5H, m), 1.93 (2H, m), 2.13 (3H, s), 2.96 (1H, m), 3.76 (3H,
s), 4.32 (1H, s), 5.11 (1H, t, J ) 7.0 Hz), 6.56 (1H, s), 6.60 (1H,
s); 13C NMR (75 MHz, CDCl3) δ 152.2, 146.5, 132.0, 130.7, 124.9,
124.6, 118.2, 109.4, 56.2, 37.4, 31.9, 26.1, 25.7, 21.2, 17.7, 15.7;
IR (neat) ν 3423, 2962, 2927, 1685, 1502, 1452, 1411, 1200 cm-1
;
69; HRMS (EI) calcd for C15H20O2 232.1463, found 232.1471;
MS (EI) m/z ) 248 (M+), 165, 151, 122, 109, 67, 55; HRMS (EI)
calcd for C16H24O2 248.1776, found 248.1769.
23
[R] ) -4.9° (c ) 1.09, CHCl3).14
578
Pentacarbonyl[methoxy(2-propenyl)carbene]chromi-
um (2).6 The known synthesis of 2 was slightly modified with
regard to the methylation. A solution of 1.81 g (15 mmol) of
2-bromopropene in 30 mL of diethyl ether was cooled to
-78 °C, and 17.6 mL (30 mmol) of a 1.7 M solution of t-BuLi in
n-hexane was added dropwise over 10 min. The resulting light-
yellow solution was stirred for 3 h at -78 °C before it was slowly
transferred via cannula to a slurry of 3.29 (15 mmol) Cr(CO)6
and 225 mL of diethyl ether kept at -60 °C. After the resulting
brown solution was stirred at -60 °C for 30 min, it was warmed
to room temperature and the solvent was evaporated under
reduced pressure. The remaining residue was dissolved in
150 mL of dichloromethane, and 3.33 g (22.5 mmol) of Me3OBF4
was added at 0 °C. The solution was warmed to room temper-
ature and stirred for 1 h. The crude reaction mixture was filtered
through a cooled pad of silica gel, and the solvent was evaporated
under reduced pressure. The known title compound 2 (2.83 g,
68%) was obtained by column chromatography (n-hexane) at
-25 °C as a red, viscous oil, which has to be stored rigorously
under argon at -78 °C: 1H NMR (300 MHz, acetone-d6) δ 1.92
(3H, m), 4.56 (3H, s), 4.82 (1H, m), 5.07 (1H, m); 13C NMR
(75 MHz, acetone-d6) δ 356.5, 225.1, 216.9, 160.0, 119.6, 68.6,
Tricarbonylchromiumhydroquinone Complex (10). A
solution of 2 (276 mg, 1 mmol) and 3 (204 mg, 1.5 mmol) in
dichloromethane (5 mL) was degassed by three freeze-pump-
thaw cycles and then warmed to 55 °C for 2.5 h under inert
atmosphere. The benzannulation reaction mixture was cooled
to room temperature and slowly added to a solution of benzoyl
chloride (154 mg, 1.1 mmol), DMAP (134 mg, 1.1 mmol), and
NEt3 (0.1 mL, 1.1 mmol) in dichloromethane (10 mL) at
-20 °C. The solution was warmed to room temperature and
stirred for
2 h. Purification by column chromatography
[n-hexane/dichloromethane, 2/1 (v/v)] afforded complex 10
(0.29 g, 60%) as a 1:1 diastereomeric mixture as a brownish oil:
1H NMR (300 MHz, CDCl3) δ 1.16-1.58 (24H, m), 1.87-2.00
(10H, m), 3.05-3.09 (6H, m), 4.90-5.08 (2H, m), 7.05-7.15 (8H,
m), 8.11-8.29 (6H, m); 13C NMR (75 MHz, CDCl3) δ 234.4, 234.3,
165.4, 165.3, 134.3, 134.3, 132.7, 132.3, 131.4, 131.3, 130.4, 130.3,
129.8, 129.1, 129.1, 128.8, 128.8, 128.5, 125.8, 125.7, 125.1, 124.9,
124.1, 123.7, 110.6, 110.2, 98.7, 98.7, 90.5, 90.4, 77.0, 75.6, 56.2,
56.1, 39.4, 36.7, 33.7, 31.8, 26.5, 26.1, 25.7, 25.4, 22.0 19.4, 19.0,
17.7, 17.7, 15.3; IR (CH2Cl2) ν 2304, 1961, 1880, 1733, 1645 cm-1
;
MS (EI) m/z ) 488 (M+), 404, 389, 345, 322, 204, 165, 105, 77;
HRMS (EI) calcd for C26H28CrO6 488.1291, found 488.1300.
(Methyl, Benzoyl)-Bisprotected Hydroquinone (-)-(11).
A solution of the two diastereomers 10 (150 mg, 0.3 mmol) in
dichloromethane (4 mL) and acetonitrile (4 mL) was stirred at
room temperature for 5 h. After filtration of the crude reaction
mixture through a pad of Celite, the solvent was evaporated
under reduced pressure. Column chromatography [n-hexane/
dichloromethane, 2/1 (v/v)] afforded pure 11 (0.1 g, 95%) as a
colorless, viscous oil: 1H NMR (300 MHz, CDCl3) δ 1.12 (3H, d,
J ) 7.0 Hz), 1.41 (3H, s), 1.48 (3H, s), 1.58 (2H, m), 1.82 (2H,
19.7; IR (n-hexane) ν 2065, 1988, 1951 cm-1
.
(R)-3,7-Dimethyl-6-octen-1-yne (3).13 Compound 3 was
synthesized in an analogous manner as reported. Purification
was carried out by distillation: bp 55 °C (15 mbar); 1H NMR
(300 MHz, C6D6) δ 1.01 (3H, d, J ) 7 Hz), 1.21-1.46 (2H, m),
1.52 (3H, s), 1.60 (3H, s), 1.83 (1H, d, J ) 2 Hz), 2.12 (2H, m),
2.25 (1H, m), 5.06 (1H, t, J ) 7 Hz); 13C NMR (75 MHz, C6D6) δ
131.8, 124.4, 88.8, 68.9, 37.2, 26.2, 25.8, 25.6, 21.1, 17.7; IR (neat)
ν 3311, 2970, 2927, 2856, 2114, 1452, 1377 cm-1; [R]D23 ) -47.5°
J. Org. Chem, Vol. 70, No. 9, 2005 3747

m), 2.12 (3H, s), 2.82 (1H, m), 3.75 (3H, s), 4.95 (1H, t, J )
7.0 Hz), 6.64 (1H, s), 6.81 (1H, s), 7.34-7.56 (3H, m), 8.10 (1H,
d, J ) 1.3 Hz), 8.13 (1H, s); 13C NMR (75 MHz, CDCl3) δ 165.6,
155.8, 141.5, 137.1, 133.3, 131.5, 130.1, 129.8, 129.5, 128.5, 128.3,
125.1, 124.3, 124.2, 108.3, 55.6, 37.6, 32.4, 26.0, 25.5, 21.2, 17.6,
15.8; IR (neat) ν 3450, 2962, 2927, 1736, 1502, 1265, 1198,
710 cm-1; MS (EI) m/z ) 352 (M+), 269, 247, 230, 215, 187, 165,
105, 77; HRMS (EI) calcd for C23H28O3 352.2038, found 352.2041;
[R]2D3 ) -14.9° (c ) 1.903, CHCl3).
was degassed by three freeze-pump-thaw cycles and warmed
to 55 °C for 2.5 h under inert atmosphere. The benzannulation
reaction mixture was cooled to room temperature and slowly
added to a solution of (S)-(+)-R-methoxy-R-trifluoromethyl-
phenylacetyl chloride (0.2 mL, 1.1 mmol), DMAP (134 mg,
1.1 mmol), and NEt3 (0.1 mL, 1.1 mmol) in dichloromethane
(10 mL) at -20 °C. The solution was warmed to room temper-
ature and stirred for 2 h. Acetonitrile (10 mL) was added, and
the reaction mixture was stirred vigorously for 20 h exposed to
air. After filtration of the crude reaction mixture through a pad
of Celite, the solvent was evaporated under reduced pressure:
1H NMR (300 MHz, acetone-d6) δ 1.01 (3H, d, J ) 7 Hz), 1.43
(3H, s), 1.48-1.64 (5H, m), 1.80 (2H, m), 2.09 (3H, s), 2.69 (1H,
m), 3.64 (3H, d, J ) 1,3 Hz), 3.79 (3H, s), 5.00 (1H, m), 6.82-
6.85 (2H, m), 7.46-7.49 (3H, m), 7.65 (2H, m); 13C NMR
(75 MHz, acetone-d6) δ 166.3, 163.3, 157.3, 141.6, 138.0, 132.9,
131.9, 130.8, 130.5, 129.5, 129.3, 128.3, 126.4, 125.9, 125.1, 124.0,
122.6, 109.1, 56.2, 56.1, 37.6, 32.8, 26.8, 25.8, 21.9, 17.7, 15.8;
19F NMR (282 MHz, acetone-d6) δ -72.7; IR (neat) ν 2962, 2929,
2854, 1761, 1501, 1457, 1398, 1268, 1244, 1200, 1178, 1122,
1020, 885, 715 cm-1; MS (EI) m/z ) 464 (M+), 290, 260, 248,
221, 189; HRMS (EI) calcd for C26H31F3O4 464.2174, found
464.2174;[R]2D5 ) +8.2° (c ) 1.53, CHCl3).
(Methyl, Acetyl)-Bisprotected Hydroquinone (-)-(12). A
solution of 2 (276 mg, 1 mmol) and 3 (204 mg, 1.5 mmol) in
dichloromethane (5 mL) was degassed by three freeze-pump-
thaw cycles and warmed to 55 °C for 2.5 h under inert
atmosphere. The benzannulation reaction mixture was cooled
to room temperature and slowly added to a solution of acetyl-
bromide (136 mg, 1.1 mmol), DMAP (134 mg, 1.1 mmol), and
NEt3 (0.1 mL, 1.1 mmol) in dichloromethane (10 mL) at
-20 °C. The solution was warmed to room temperature and
stirred for
2 h. Purification by column chromatography
[n-hexane/dichloromethane, 1/1 (v/v)] afforded compound 12
(0.12 mmol, 40%) as a colorless, viscous oil: 1H NMR (300 MHz,
CDCl3) δ 1.14 (3H, d, J ) 7.0 Hz), 1.50-1.58 (5H, m), 1.63 (3H,
s), 1.87 (2H, m), 2.12 (3H, s), 2.23 (3H, s), 2.74 (1H, m), 3.76
(3H, s), 5.04 (1H, t, J ) 7 Hz), 6.62 (1H, s), 6.71 (1H, s); 13C
NMR (75 MHz, CDCl3) δ 170.0, 155.8, 141.3, 136.9, 131.5, 125.1,
124.3, 124.1, 108.2, 55.6, 37.6, 32.4, 26.1, 25.7, 21.1, 20.8, 17.6,
15.8; IR (neat) ν 3463, 2964, 2929, 1760, 1502, 1369, 1196 cm-1
;
Supporting Information Available: General experimen-
tal details and 1H and 13C NMR spectra of known compounds
1, 3, and 5-8 and new compounds 9, 11, and 12. This material
is available free of charge via the Internet at http://pubs.acs.org.
MS (EI) m/z ) 290 (M+), 248, 165, 151, 138, 82; HRMS (EI) calcd
for C18H26O3 290.1882, found 290.1881; [R]2D5 ) -19.4° (c )
1.737, CHCl3).
(R,SAux)-Mosher Ester (+)-(13). A solution of 2 (276 mg,
1 mmol) and 3 (204 mg, 1.5 mmol) in dichloromethane (5 mL)
JO0500939
3748 J. Org. Chem., Vol. 70, No. 9, 2005