Enantioselective synthesis of (+)-majusculone

Article abstract of DOI:10.1021/jo070257g

(Chemical Equation Presented) The first enantioselective synthesis of a chamigrane sesquiterpene, (+)-majusculone, has been completed. The quaternary center was generated asymmetrically by alkylidene carbene insertion, with retention of absolute configura

Full text of DOI:10.1021/jo070257g

Enantioselective Synthesis of (+)-Majusculone
Douglass F. Taber,* M. Inthikhab Sikkander, and Pierre H. Storck
Department of Chemistry and Biochemistry, UniVersity of Delaware, Newark, Delaware 19716
taberdf@udel.edu
ReceiVed February 6, 2007
The first enantioselective synthesis of a chamigrane sesquiterpene, (+)-majusculone, has been completed.
The quaternary center was generated asymmetrically by alkylidene carbene insertion, with retention of
absolute configuration, from a diastereomerically pure ketal.
SCHEME 1
Introduction
The red algal genus Laurencia is regarded as one of the
most prolific sources of secondary metabolites, many of which
have shown interesting biological activities. For instance,
screening of an extract from Laurencia cartilaginea led to the
isolation of two new closely related bromochamigrenes 1 and
2. These metabolites showed selective and potent cytotoxicity
in the NCI 60 cell antitumor screen, with cytotoxicity profiles
that were very similar to one another.1 They were particularly
effective against the colon cancer subpanel. Remarkably,
no enantioselective synthesis of a chamigrane has yet been
reported. We report a general enantioselective approach to the
chamigrane sesquiterpenes, culminating in the first synthesis
of majusculone 3.
of 9-(bromomethylene)-1,2,5-trimethylspiro[5.5]undeca-1,7-
dien-3-one, using an approach based on the copper-catalyzed
cyclization of a diazo ketone.3 In 1991, Niwa and Yamada
reported the synthesis of a bromo chamigrene mixture.4 Ad-
ditionally, (()-R-chamigrene has been prepared independently
by Canonne5 and by Chen.6
The challenge in the synthesis of the chamigranes is the
stereocontrolled assembly of the spiro ring fusion. We envi-
sioned (Scheme 1) that (+)-majusculone 3 could be prepared
from the readily available Hagemann’s ester 8. The key step of
our retrosynthesis was the construction of the spirocyclic
quaternary center by intramolecular C-H insertion with reten-
tion of absolute configuration from the diastereomerically pure
Results and Discussion
There have been only a few syntheses of chamigranes
reported. In 1986, Martin prepared a chamigrane using intramo-
lecular bromonium induced carbocylization of an exocyclic
tetrasubstituted alkene.2 Iwata in 1988 reported the preparation
(1) (a) Rashid, M. A.; Gustafson, K. R.; Cardellina, J. H.; Boyd, M. R.
Nat. Prod. Lett. 1995, 6, 255. (b) Munro, M. H.; Luibrand, R. T.; Blunt, J.
W.; Scheuer, P. J. Bioorganic Marine Chemistry; Springer-Verlag: Berlin,
Germany, 1987; pp 93-176.
(2) Martin, J. D.; Perez, C.; Ravelo, J. L. J. Am. Chem. Soc. 1986, 108,
7801.
(3) Iwata, C.; Akiyama, T.; Miyashita, K. Chem. Pharm. Bull. 1988,
36, 2872.
(4) Niwa, H.; Yoshida, Y.; Hasegawa, T.; Yamada, K. Tetrahedron 1991,
47, 2155.
(5) Plamondon, J.; Canonne, P. Tetrahedron Lett. 1991, 32, 589.
(6) Chen, Y.-J.; Wang, C.-Y.; Lin, W.-Y. Tetrahedron 1996, 52, 13181.
10.1021/jo070257g CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/21/2007
4098
J. Org. Chem. 2007, 72, 4098-4101

EnantioselectiVe Synthesis of (+)-Majusculone
SCHEME 2
with K2CO3 (eq 1). The resulting racemic ketone was again
condensed with (R,R)-(+)-hydrobenzoin to give back the 1:1
mixture of the diastereomers 6 and 13.
Preparation of (+)-Majusculone. We were concerned about
the ability of the alkylidene carbene to insert into the very
congested methine of 6 (Scheme 3), which is also deactivated
by the two electron withdrawing ether oxygens of the ketal. In
the event, upon exposure to an excess of KHMDS, prepared
by sonicating KH in HMDS in toluene,12 the carbene generated
by R-elimination slowly (12 h at 0 °C to room temperature)
inserted into the C-H bond, yielding 5. We also observe the
1,2-rearrangement product, the alkyne 14. The power of this
approach is that the absolute configuration of the newly
generated quaternary center was now locked and could not be
altered by the acidic conditions later used to remove the ketal
protecting group.
ketal 6.7 The efficiency of such a strategy had recently been
demonstrated in our group by the enantioselective synthesis of
(-)-morphine.8 A key question was whether the alkylidene
carbene derived from 6 would insert efficiently into the very
congested target methine.
SCHEME 3
Preparation of Ketal 6. Our synthesis began with the
bromination and subsequent dehydrobromination of 3-methyl-
3-buten-1-ol 9 (Scheme 2).9 The alcohol 10 was then activated
by converting the alcohol to the benzenesulfonate ester 11 under
phase transfer conditions, to prevent the displacement of the
reactive homoallylic benzenesulfonate ester by in situ generated
chloride anion. Hagemann’s ester 8 was then alkylated with the
benzenesulfonate 11. The product ester was saponified with
LiOH‚H2O and then decarboxylated to 12 by heating with
concentrated HCl in THF.10 Conjugate addition of Me2CuLi
efficiently produced the ketone 7, which was quantitatively
condensed with (R,R)-(+)-hydrobenzoin8 to give the ketals 6
and 13 as a 1:1 mixture.
The ketals 6 and 13 were partially separated by column
chromatography, using TLC mesh silica gel, to give a
70:30 mix of the diasteromers.8 Further purification by column
chromatography was not efficient, so we investigated crystal-
lization solvents. We found that methanol was particularly
effective. The diastereomeric purity of the ketal 6 was estab-
lished by comparing 1H NMR absorptions at δ 4.75 and δ 4.53
for the methines of the ketal rings of the two diastereomers.
The relative configuration of 6 was established by X-ray
crystallography.
The mixed ketals enriched in 13 were recycled by heating
with 2 M aqueous HCl to give ketone 7,11 then epimerizing
(7) (a) Wardrop, D. J.; Bowen, E. G. Chem. Commum. 2005, 5106. (b)
Worden, S. M.; Renameditswe, M.; Hayes, C. J. Tetrahedron Lett. 2002,
43, 6011. (c) Taber, D. F.; Neubert, T. D. J. Org. Chem. 2001, 66, 143.
(8) Taber, D. F.; Neubert, T. D.; Rheingold, A. L. J. Am. Chem. Soc.
2002, 124, 12416.
(9) (a) Knudsen, C. G.; Carey, S. C.; Okamura, W. H. J. Am. Chem.
Soc. 1980, 102, 6355. (b) Cornforth, J. W.; Cornforth, R. H.; Popjak, G.;
Yengoyan, L. J. Biol. Chem. 1966, 241, 3970.
Ozonolysis of 5 followed immediately by aldol condensation
delivered the enone 15. Luche reduction13 followed by the
(10) (a) Gosh, S.; Dasgupta, R.; Charkravarty, J.; Ghatak, U. R. J. Chem.
Soc., Perkin Trans. 1 1980, 804. (b) Ghatak, U. R.; Alam, S. K.; Ray, J. K.
J. Org. Chem. 1978, 43, 4598.
(11) Aavula, B. R.; Cui, Q.; Mash, E. A. Tetrahedron: Asymmetry 2000,
11, 4681.
(12) (a) For KHMDS from KH and HMDS see: Åhman, J.; Somfai, P.
Synth. Commun. 1995, 25, 2301. (b) For KHMDS from potassium metal
and HMDS see: Chiu, K. W.; Ellenberger, D. H.; Barendt, J. M. U.S. Patent
5420322, 1995, EP 699684A2, 1996.
(13) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226.
J. Org. Chem, Vol. 72, No. 11, 2007 4099

Taber et al.
1
deprotection of the chiral ketal in 2 M aqueous HCl11 gave the
allylic alcohol 4 as a mixture of diastereomers. Addition of
1.6 M MeLi/LiBr14 to the congested ketone was difficult,15 but
with four recycles delivered the tertiary alcohol 17. Oxidation
of the secondary alcohol by the Dess-Martin periodinane gave
the enone 18. Dehydration of the tertiary alcohol with thionyl
chloride in toluene4 formed the endo and exo alkenes in a 3:1
ratio. The alkenes formed were not separable by chromatogra-
phy. Prolonged exposure to acid did not improve the endo/exo
ratio before degradation set in. Other methods for dehydration
(e.g., POCl3/pyridine) gave poorer ratios, lower yields, or both.
Allylic oxidation of the alkene mixture with chromium trioxide16
gave enantiopure (+)-majusculone 3.17 No other methods for
allylic oxidation were investigated.
(c 0.499, CHCl3); H NMR δ 7.36-7.19 (m, 10H), 6.02 (s, 1H),
4.89 (d, 1H, J ) 8.6 Hz), 4.75 (d, 1H, J ) 8.6 Hz), 2.77 (t, 1H),
2.22-2.18 (m, 2H), 1.93-1.88 (m, 2H), 1.93-1.88 (m, 2H), 1.93
(s, 3H), 1.71 (m, 1H), 1.49-1.57 (m, 4H), 1.31 (m, 1H), 1.0 (s,
6H); 13C NMR18 δ u 143.1, 139.4, 137.0, 113.1, 41.7, 41.3, 37.3,
36.5, 23.6, 19.8; 13C NMR18 δ d, 129.1, 129.0, 128.8, 128.2, 127.8,
126.4, 101.7, 87.5, 84.1, 53.6, 31.7, 22.1, 19.9; IR (film) 2949,
1948, 1878,1603 cm-1; mp 71-75 °C; CI m/z (%) 470 (2), 468
(2), 389 (16), 335 (13), 273 (23), 193 (59),177 (100), 139 (36);
HRMS calcd for C27H33O2Br (M+) 468.1664, obsd 468.1656.
Cyclopentene 5. KHMDS in toluene (0.5 M, 11.1 mL,
5.55 mmol) was added dropwise (30 min) to a stirring solution of
diastereopure ketal 6 (0.858 g, 1.83 mmol) in 1,4-dioxane (9 mL)
at 0 °C. The mixture was stirred overnight at room temperature,
and then partitioned between 30% saturated aqueous NH4Cl and
CH2Cl2. The combined organic layer was dried (Na2SO4) and
concentrated. The residue was chromatographed to yield cyclo-
pentene 5 (0.391 g, 55% yield) as a colorless sticky oil, followed
by alkyne 14 (0.113 g, 16%).
Conclusion
We have developed a general enantioselective route to the
spirocyclic chamigrene sesquiterpene skeleton, and accom-
plished the first synthesis of (+)-majusculone. The power of
intramolecular alkylidene C-H insertion to generate a spiro-
cyclic quaternary center with retention of absolute configuration
makes it a valuable tool for the synthesis of natural products of
biological interest. We believe that the enantiomerically pure
alkene 5 could be a useful intermediate for the preparation of
1 and 2 as well as other chamigrene sesquiterpenes.
Cyclopentene 5: TLC Rf 0.37 (PE/Et2O 98:2), [R]21 +86.9 (c
D
0.529, CHCl3); 1H NMR δ 7.32-7.29 (m, 7H), 7.21-7.17 (m, 4H),
5.52 (s, 1H), 4.71 (d, 1H, J ) 8.8 Hz), 4.55 (d, 1H, J ) 8.8 Hz),
2.38 (m, 4H), 1.95-1.87 (m, 3H), 1.76 (s, 3H), 1.49-1.42 (m,
1H), 1.39-1.31 (m, 1H), 1.08 (s, 3H), 0.93 (s, 3H); 13C NMR δ
142.3, 138.2,136.9, 128.3, 128.0, 127.2, 126.8, 126.6, 125.7, 114.2,
85.4, 84.7, 65.3, 38.7, 37.6, 37.1, 37.0, 33.6, 29.7, 28.6, 26.2, 25.2,
19.7, 16.9; 13C NMR (JVERT) δ u 142.2, 138.1, 136.8, 114.0, 65.2,
38.8, 37.5, 36.9, 33.3, 29.7, 28.5, 19.7; 13C NMR (JVERT) δ d
128.4, 127.9, 127.8, 126.9, 126.5, 125.6, 85.4, 85.7, 26.8, 25.2,
16.9; IR (film) 3026, 1948, 1879, 1805, 1452 cm-1; GC/MS m/z
(%) 180 (100), 107 (24), 161 (19), 121 (16), 282 (10), 388 (0.12);
HRMS calcd for C27H32O2 (M+) 387.2324, obsd 387.2324.
(1S,8R,9R)-1-[3-Pentynyl]-2,2-dimethyl-8,9-diphenyl-7,10-
Experimental Section
(1S,8R,9R)-1-[(3E)-4-Bromo-3-methyl-3-butenyl]-2,2-dimethyl-
8,9-diphenyl-7,10-dioxaspiro[6,5]decane (6). p-Toluenesulfonic
acid (0.28 g, 1.47 mmol) was added in one portion to a mixture of
ketone 7 (3.93 g, 14.4 mmol), R,R-(+)-hydrobenzoin (4.63 g,
22.0 mmol), and trimethylorthoformate (2.00 g, 18.8 mmol) in dry
CH2Cl2 (72 mL). The reaction mixture was stirred overnight at room
temperature. Solid NaHCO3 (1.5 g) was added and the mixture was
partitioned between water and CH2Cl2. The combined organic layer
was dried (Na2SO4) and concentrated. The residue was chromato-
graphed to give a 1:1 mixture of ketals (6.37 g, 98% yield) as yellow
sticky oil. The mixture (6.37 g, 14.0 mmol) was chromatographed
on TLC grade silica eluting with 0.1% Et2O/PE to give a 70:30
mix of 6 and 13 as a yellowish solid (2.85 g). The 70: 30 mixture
(2.85 g, 6.1 mmol) was dissolved in PE (2.0 mL) and concentrated
under vacuum. This residue was converted with a minimum amount
of methanol (2.0 mL) and the surface of the glass was scratched to
initiate crystallization. Once crystallization was initiated, the mixture
was allowed to sit in the refrigerator for 24 h. The supernatant was
removed by pipet and the procedure was repeated two more times.
A mixture of diastereomers 6 and 13 in a ratio of 20:1 was obtained
as a white solid (0.70 g, 79% based on ketals not recovered). The
purity of the compound was checked by 1H NMR at δ 4.75 and δ
4.53. The mixed ketals 6/13 were recovered from the supernatant
dioxaspiro[6,5]decane (14). Colorless oil (0.113 g, 16%); TLC Rf
0.21 (PE/Et2O 98:2); [R]20 +44.4 (c 0.230, CHCl3); H NMR δ
1
D
7.34-7.29 (m, 8H), 7.18-7.15 (m, 2H), 4.91 (d, 1H, J ) 8.8 Hz),
4.71 (d, 1H, J ) 8.8 Hz), 2.61-2.51 (m, 1H), 2.35-2.24 (m, 1H),
2.19 (d, 1H, J ) 12 Hz), 2.02-1.87 (m, 2H), 1.84 (t, 3H, J
) 2.6 Hz), 1.72-1.45 (m, 6H), 1.03 (s, 3H), 0.98 (s, 3H); 13C NMR
δ u 138.9, 136.5, 112.7, 79.9, 75.3, 40.9, 36.8, 35.9, 25.2, 21.45,
19.33; 13C NMR δ d 128.5, 128.4, 128.3, 127.8, 127.5, 125.9, 87.2,
83.8, 52.8, 31.3, 21.6, 3.57; IR (film) 2932, 1950, 1880, 1807, 1605
cm-1; GC/MS m/z (%) 277 (100), 199 (21), 183 (18), 171 (2.4),
152 (10); HRMS calcd for C27H32O2 (M+) 388.2402, obsd 388.2396.
Enone 15. A solution of cyclopentene 5 (2.21 g, 5.70 mmol)
and a crystal of Sudan III in dry CH2Cl2 (11 mL) was ozonized at
-78 °C until the red color faded. Nitrogen gas was bubbled for
10 min through the solution at -78 °C. The cool solution was
quenched with PPh3 (1.66 g, 6.30 mmol) and then brought to
room temperature. The solution was stirred overnight at room
temperature and then concentrated. To the residue in MeOH
(95 mL) was added 1 M NaOH (19 mL, 19.0 mmol) and the mixture
was stirred overnight at room temperature. The solution was
concentrated. The residue was partitioned between 20% saturated
aqueous NH4Cl and CH2Cl2. The combined organic layer was dried
(Na2SO4) and concentrated. The residue was chromatographed to
(5.48 g). For 6: TLC Rf 0.24 (PE/MTBE 99:1); [R]22 +23.7
D
yield enone 15 as colorless oil (1.21 g, 52% from 5). TLC Rf 0.34
(14) (a) Ashby, E. C.; Noding, S. R. J. Org. Chem. 1979, 44, 4371. (b)
Ashby, E. C.; Lin, J. J.; Watkins, J. J. Tetrahedron Lett. 1977, 18, 1709.
(15) For other examples of addition to hindered ketones, see: (a) Amigo,
C. F. D.; Collado, I. G.; Hanson, J. R.; Hernandez-Galan, R.; Hitchcock,
P. B.; Macias-Sanchez, A. J.; Mobbs, D. J. J. Org. Chem. 2001, 66, 4327.
(b) Ghosh, I.; Zeng, H.; Kishi, Y. Org. Lett. 2004, 6, 4715. (c) Srikrishna,
A.; Lakshmi, B. V.; Mathews, M. Tetrahedron Lett. 2006, 47, 2103.
(16) (a) Iwata, C.; Akiyama, T.; Miyashita, K. Chem. Pharm. Bull. 1988,
36, 2872. (b) Corey, E. J.; Fleet, G. W. J. Tetrahedron Lett. 1973, 14, 4499.
(c) Salmond, W. G.; Barta, M. A.; Havens, J. L. J. Org. Chem. 1978, 43,
2057.
1
(PE/MTBE 85:15); [R]22 +196.2 (c 0.130, CHCl3); H NMR δ
D
7.40-7.30 (m, 7H), 7.24-7.21 (m, 3H), 7.15-7.11 (m, 2H), 6.26
(d, 1H, J ) 10.4 Hz), 4.81 (d, 1H, J ) 8.8 Hz), 4.63 (d, 1H, J )
8.8 Hz), 2.93-2.84 (m, 1H), 2.53-2.41 (m, 2H), 2.20-2.08 (m,
2H), 2.00-1.94 (m, 1H), 1.84 (quint, 2H, J ) 6.2 Hz), 1.53 (m,
1H), 1.16 (s, 3H), 1.08 (s, 3H); 13C NMR δ u 200.0, 137.3, 135.5,
113.4, 49.2, 39.5, 36.3, 35.8, 44.0, 24.1, 19.2; 13C NMR δ d 131.4,
128.5, 128.3, 126.8, 126.4, 85.2, 83.9, 26.7, 26.18; the signals for
(17) (a) Suzuki, M.; Kurosawa, E.; Kurata, K. Bull. Chem. Soc. Jpn.
1987, 60, 3795. (b) Dayit, D.; Fernandez, R.; Suescun, L.; Mombru, A.
W.; Saldana, J.; Dominguez, L.; Coll, J.; Fuiji, M. T.; Manta, E. J. Nat.
Prod. 2001, 64, 1552.
(18) 13C multiplicities were determined with the aid of a JVERT pulse
sequence, differentiating the signals for methyl and methine carbons as “d”
from methylene and quaternary carbons as “u”.
4100 J. Org. Chem., Vol. 72, No. 11, 2007

EnantioselectiVe Synthesis of (+)-Majusculone
the gem dimethyl, suppressed by JVERT, come at δ 27.2 and δ
26.7 in the non-JVERT 13C NMR spectra; IR (film) 2951, 1952,
1881, 1809, 1680, 1453 cm-1; CI m/z (%) 403 (100), 385 (2), 296
(10), 224 (11), 207 (100), 180 (38), 167 (46), 135 (15); HRMS
calcd for C27H30O3 (M + H) 403.2273, obsd 403.2257.
223 (12), 207 (100), 189 (81), 121 (75), 119 (49); HRMS (M -
H) calcd 223.1698, obsd 223.1698.
7-Hydroxy-7,11,11-trimethyl[6,6]spiroundec-1-en-3-one (18).
To the tertiary alcohol 17 (13.9 mg, 0.063 mmol) in dry CH2Cl2
was added Dess-Martin reagent (28 mg, 0.066 mmol). The mixture
was stirred for 1 h at room temperature, and then the mixture was
partitioned between saturated aqueous NaHCO3 and CH2Cl2. The
combined organic layer was dried (Na2SO4) and concentrated. The
residue was chromatographed to give enone 18 as a colorless oil
Allylic Alcohol 16. NaBH4 (0.150 g, 0.0037 mol) was added
over 5 min to a solution of enone 15 (1.21 g, 0.0030 mol) and
CeCl3‚7H2O (2.24 g, 0.0060 mol) in an ice-water bath. Water
(1 mL) was added after 30 min, then the mixture was concentrated.
The residue was diluted with 3 drops of concentrated HCl in water
(25 mL), then partitioned with CH2Cl2. The combined organic layer
was dried (Na2SO4) and concentrated. The residue was chromato-
graphed to yield allylic alcohol 16 as colorless oil (1.19 g, 98%
yield). TLC Rf 0.38 (PE/MTBE 8:2), [R]22D +95.3 (c 0.635, CHCl3);
1H NMR δ 7.28-7.33 (m, 6H), 7.24-7.22 (m, 2H), 7.17-7.14
(m, 2H), 6.36-6.32 (m, 1H), 6.22 (d, J ) 10.8 Hz, 1H), 4.77 (d,
J ) 8.8 Hz, 1H), 4.63 (d, J ) 8.8 Hz, 1H), 4.05 (m, 1H), 2.34 (br
s, 1H), 2.20-2.12 (m, 1H), 1.99-1.97 (m, 2H), 1.91-1.62 (m,
7H), 1.20 (s, 3H), 0.95 (s, 3H); 13C NMR δ 137.3, 136.1, 133.6,
131.1, 128.4, 128.3, 128.1, 126.6, 114.6, 84.9, 63.3, 48.4, 38.9,
35.7, 32.0, 30.6, 26.9, 24.7, 21.7, 19.5; 13C NMR δ u 137.2, 136.0,
114.6, 48.4, 38.9, 35.6, 32.0, 30.7, 21.7, 19.5; 13C NMR δ d 133.6,
131.1, 128.4, 128.3, 128.1, 126.9, 126.6, 85.0, 84.9, 63.3; the signals
for the gem dimethyl, suppressed by JVERT, come at δ 26.9 and
(12.8 mg, 93% yield). TLC Rf 0.31 (CH2Cl2:MTBE 8:2); [R]22
D
1
+11.3 (c 0.300, CHCl3); H NMR δ 6.91 (d, 1H, J ) 12.0 Hz),
6.08 (d, 1H, J ) 12.0 Hz), 2.64-2.46 (m, 2H), 2.42-2.37 (m,
1H), 2.14-2.08 (m, 1H), 1.94-1.83 (tt, 1H), 1.80-1.67 (dd, 1H),
1.25 (s, 3H), 1.22 (s, 3H), 0.85 (s, 3H); 13C NMR δ u 154.6, 130.1,
30.5, 30.2, 25.4; 13C NMR δ d 199.9, 75.7, 47.9, 38.6, 38.5, 38.0,
36.7, 22.9, 18.5; IR (film) 3457, 2942, 1666, 1462, 1243 cm-1
;
GC/MS m/z (%) 222 (4), 204 (2), 148 (4), 137 (100), 121 (3);
HRMS calcd for C14H22O2 (M + H) 223.1698, obsd 223.1688.
(+)-Majusculone (3). To enone 18 (36 mg, 0.162 mmol) in
toluene (3 mL) was added pyridine (70 µL, 0.865 mmol) at
-78 °C. The mixture was stirred for 5 min at -78 °C. Thionyl
chloride (50 µL, 0.685 mmol) was added dropwise (2 min) to the
chilled mixture, and stirring was continued for 30 min at -78 °C.
The mixture was partitioned between ether and, sequentially, ice
water and saturated aqueous NaHCO3. The combined organic layer
was dried (Na2SO4) and concentrated. The residue was chromato-
graphed to yield a mixture of alkenes. This was then added to a
mixture of CrO3 (0.286 g, 2.86 mmol) and 3,5-dimethylpyrazole
(0.275 g, 2.86 mmol) in dry CH2Cl2 (3 mL) at -20 °C. The mixture
was stirred for 4 h at 0 °C, then partitioned between water and
Et2O. The combined organic extract was dried (Na2SO4) and
concentrated. The residue was chromatographed to yield a clear
colorless oil (17 mg). TLC Rf 0.22 (CH2Cl2/MTBE 95:5). The oil
was dissolved in 3 mL of ethanol and diluted 1000-fold. Quantita-
tive UV (lit.17a λmax 241 nm, ꢀ ) 19 900, EtOH) was used to
determine that the actual amount of (+)-majusculone was 6.7 mg
(19% from 18). [R]20D 147.2 (c 0.338, CHCl3) (lit. [R]19D ) 145 (c
δ 24.7 in the non-JVERT; IR (film) 3434, 2971, 2870, 1454 cm-1
;
CI m/z (%) 387 (2), 298 (8), 281 (2), 191 (26), 180 (100), 165 (7),
121 (6); HRMS calcd for C27H32O3 (M - OH) 387.2324, obsd
387.2322.
3-Hydroxy-11,11-dimethyl[6,6]spiroundec-1-en-7-one (4). To
a solution of allylic alcohol 16 (1.44 g, 3.56 mmol) in dry MeOH
(20 mL) was added 2 M aqueous HCl (6.00 mL, 12 mmol). The
mixture was heated to 50 °C. The reaction was monitored by TLC.
The reaction was over in 6.5 h. The mixture was partitioned between
10% saturated NaHCO3 and CH2Cl2. The combined organic layer
was dried (Na2SO4) and concentrated. The residue was chromato-
graphed to yield ketone 4 as a colorless oil (0.700 g, 94% yield).
TLC Rf 0.12 (PE:MTBE 70:30), [R]22 +19.0 (c 0.690, CHCl3);
D
1H NMR δ 5.94 (m, 2H), 4.10 (m, 1H), 2.60-2.52 (m, 1H), 2.80-
2.20 (m, 1H), 2.17-2.13 (m, 1H), 2.09-1.75 (m, 4H), 1.52-1.31
(m, 4H), 0.90 (s, 3H), 0.80 (s, 3H); 13C NMR δ u, 212.1, 41.8,
38.2, 35.2, 30.8, 28.7, 22.9, 22.7; 13C NMR δ d 135.6, 128.6, 67.28,
24.8, 22.8; IR (film) 3391, 1702, 1461, 1057 cm-1; CI m/z (%)
208 (17), 147 (13), 138 (21), 129 (34), 121 (100); HRMS cacld
for C27H30O3 (M+) 207.1385, obsd 207.1379.
1
0.965, CHCl3)); H NMR δ 6.77 (d, 1H, J ) 10.8 Hz), 6.29 (d,
1H, J ) 10.8 Hz), 5.98 (s, 1H), 2.68-2.30 (m, 6H), 2.14-2.06
(m, 1H), 1.98 (s, 3H), 1.11(d, 6H, J ) 4.4 Hz); 13C NMR δ 197.6,
197.4, 163.0, 149.8, 131.9, 127.4, 48.6, 47.3, 40.9, 35.1, 27.5, 25.5,
25.0, 23.0; 13C NMR δ u 197.7, 197.5, 48.5, 40.9, 35.0, 29.6; 13C
NMR δ d 149.8, 131.9, 127.4, 25.0, 23.1; IR (film) 3017, 2126,
1666, 1375 cm-1; CI m/z (%) 162 (100), 134 (9), 119 (19), 105
(19), 91 (63); HRMS calcd for C14H18O2 (M + H) 219.1385, obsd
219.1381.
7,11,11-Trimethyl[6,6]spiroundec-1-en-3,7-diol (17). To a
mixture of LiBr (0.109 g, mmol) and ketone 4 (120 mg,
0.576 mmol) in dry Et2O at -78 °C was added 1.5 M MeLi
(1.15 mL, 1.725 mmol) dropwise (5 min). The solution was stirred
at -78 °C for 1 h and then allowed to reach room temperature.
The mixture was partitioned between water and Et2O. The combined
organic layer was dried (Na2SO4) and concentrated. The residue
was recycled three more times and then was chromatographed to
yield tertiary alcohol 17 as colorless oil (56 mg, 65% yield) and
recovered ketone 4 (34 mg). For 17: TLC Rf 0.20 (CH2Cl2/MTBE
Acknowledgment. We thank John Dykins for high-resolu-
tion mass spectra, Glenn Yap for the X-ray crystal structure
and the National Institutes of Health (GM60287) for financial
support of this research.
Supporting Information Available: General experimental
procedures, preparation of 11, procedure for racemization, procedure
8:2); [R]20 -24.8 (c 1.515, CHCl3); 1H NMR δ 5.84 (d, J
D
1
for KHMDS preparation, X-ray crystal data for ketal 6, and H
) 10.4 Hz, 1H), 5.75 (d, J ) 10.8 Hz, 1H), 4.10 (s, 1H), 1.97-
2.13 (m, 2H), 1.89-1.74 (m, 2H), 1.63-1.34 (m, 8H), 1,19 (s,
3H), 1.11 (s, 3H), 0.77 (s, 3H); 13C NMR δ d 132.9, 132.8, 66.5,
30.6, 28.7, 24.3; 13C NMR δ u 75.2, 46.3, 37.8, 37.1, 36.9, 32.4,
21.1, 18.3; IR (film) 3377, 2936, 1464, 1327 cm-1; CI m/z (%)
and 13C NMR spectra for all new compounds and (+)-majusculone
3. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO070257G
J. Org. Chem, Vol. 72, No. 11, 2007 4101