A short synthesis of 10-hydroxy 7-spirocyclopropanated camphor

Full text of DOI:10.1021/jo0509962

A Short Synthesis of 10-Hydroxy
7-Spirocyclopropanated Camphor
Yu-Rong Yang† and Wei-Dong Z. Li*,†,‡
State Key Laboratory of Applied Organic Chemistry,
Lanzhou University, Lanzhou 730000, China, and State Key
Laboratory of Elemento-organic Chemistry, Nankai
University, Tianjin 300071, China
FIGURE 1. Synthesis of spirocyclopropanated camphor de-
rivative 2 (ref 1).
liwd@lzu.edu.cn; wdli@nankai.edu.cn
Received May 19, 2005
A short alternative synthesis of the title 10-hydroxy 7-spi-
rocyclopropanated camphor (4) en route to 10-hydroxycam-
phor (5) was achieved from cyclopentadiene-derived 4-benzyl-
oxymethylspiro[2.4]hepta-4,6-diene (6a) by a facile regioselec-
tive Diels-Alder cycloaddition with 2-chloroacrylonitrile in
an overall yield of 20%.
FIGURE 2. Fo¨hlisch synthesis of 10-hydroxycamphor (5).
SCHEME 1. A Short Synthesis of
Spirocyclopropanated Camphor 4
We have recently described an unusual γ-eliminative
cyclopropanation of C(2) endo-alkylated 9-bromocamphor
derivative 1 by the action of t-BuOK or NaH in warm
DMSO leading to a 7-spirocyclopropanated camphor
derivative 2 in generally good yield (Figure 1).1 An
apparent alternative synthesis of tricyclic structure 2
would be an endo-selective carbonyl alkylation of 7-spi-
rocyclopropanated camphor (3), which shall thus verify
the unique chemical structure of 2 unequivocally.
To the best of our knowledge, the only known relevant
synthetic approach to the ring skeleton of 3 is of a report
by Fo¨hlisch and co-workers on the synthesis of 10-
hydroxy 7-spirocyclopropanated camphor (4) en route to
10-hydroxycamphor (5) from 2-hydroxymethylated spiro-
cyclopropanated cyclopentadiene derivative 6 by a Diels-
Alder cycloaddition with 2-chloroacrylonitrile and sub-
sequent hydrogenation and basic hydrolysis.2 Spiroan-
nulated diene 6 was prepared from spirocyclopropanated
cyclopentadiene (7) through a tedious multistep proce-
dure in an overall yield of ca. 7-8% as depicted in Figure
2.2
methyl benzyl ether (NaH, THF, 0 °C f rt) proceeded
smoothly to give the alkylation product 8,5 which readily
isomerized to 8a via a sigmatropic 1,5-H-shift during the
workup.5b The crude labile cyclic diene 8a was then
alkylated with 1-bromo-2-chloroethane (NaH, DMF, 0
°C)6 to afford the desired spirocyclopropanation product
(3) For some other relevant applications in synthesis, see: (a) Corey,
E. J.; Shiner, C. S.; Volante, R. P.; Cyr, C. R. Tetrahedron Lett. 1975,
17, 1161. (b) Starr, J. T.; Koch, G.; Carreira, E. M. J. Am. Chem. Soc.
2000, 122, 8793. (c) Antczak, K.; Kingston, J. F.; Fallis, A. G. Can. J.
Chem. 1985, 63, 993. (d) Attah-Poku, S. K.; Anticzak, K.; Alward, S.
J.; Fallis, A. G. Can. J. Chem. 1984, 62, 1717. (e) Anticzak, K.;
Kingston, J. F.; Fallis, A. G.; Hanson, A. W. Can. J. Chem. 1987, 65,
114. For relevant spiro-cyclopropyl derivatives used in mechanistic
studies, see: (f) Wilcox, C. F., Jr.; Jesaitis, R. G. Tetrahedron Lett.
1967, 9, 2567. (g) Lenoir, D.; Schleyer, P. R.; Ipaktschi, J. Liebigs Ann.
Chem. 1971, 750, 28. (h) Kende, A. S.; Jenkins, J. K.; Friedrich, L. E.
J. Chem. Soc., Chem. Commun. 1971, 1215.
(4) For an alternative spiro-cyclopropanation method via a carbene
species derived from diazocyclopentadiene, see: Moss, R. A. J. Chem.
Soc., Chem. Commun. 1965, 622.
(5) Cf.: (a) Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber,
W. J. Am. Chem. Soc. 1969, 91, 5675. (b) Corey, E. J.; Koelliker, U.;
Neuffer, J. J. Am. Chem. Soc. 1971, 93, 1489.
In view of the potential usefulness of the unique
tricyclic camphor derivatives 2 and 4 in organic synthe-
sis1,3 and the lack of a practical approach for their
preparation,4 we describe in this Note an alternative
short and practical synthesis of 4 in an overall yield up
to 20% from cyclopentadiene (CPD). As shown in Scheme
1, the alkylation of freshly distilled CPD with chloro-
† Lanzhou University.
‡ Nankai University.
(1) Li, W.-D. Z.; Yang, Y.-R. Org. Lett. 2005, 7, 3107.
(2) Fo¨hlisch, B.; Bakr, D. A.; Fischer, P. J. Org. Chem. 2002, 67,
3682.
10.1021/jo0509962 CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/07/2005
8224
J. Org. Chem. 2005, 70, 8224-8227

SCHEME 2. Synthesis of Spirocyclopropanated
Camphor Derivatives 2a and 3
SCHEME 3
6a in good yield,7 which without further purification was
subjected to the facile Diels-Alder cycloaddition with
2-chloroacrylonitrile (benzene, refluxing) to furnish
regioselectively the bicyclic adduct 9 after chromato-
graphic purification on silica gel in an overall yield of
33% from CPD. The above 3-stage procedure can be
performed in a scale up to 0.1 mol without purification
of intermediates 8a and 6a.8 Hydrogenation and reduc-
tive O-debenzylation of 9 over 10% Pd/C in ethanol
produced tricyclic alcohol 10 (mp 180-182 °C) cleanly,
which was subsequently hydrolyzed under normal alka-
line conditions to give the title 10-hydroxy 7-spirocyclo-
propanated camphor (4) (mp 158-160 °C) in 60% isolated
yield from 9.
phor (3) (mp 77-79 °C) was also prepared from 4 as
shown via tosylate 4a9 in good yield.
With structurally unique and readily available 4 in
hand, we further examined the chemical reactivities of
its derivatives in view of our recent study.1 endo-Hydroxy
derivatives 12 and 13 were conveniently prepared from
4 (or its benzyl ether 4b) by carbonyl addition of an
organocerium reagent respectively (Scheme 3). Subjection
of 12 to strong basic conditions (i.e., t-BuOK or KH, DME,
18-c-6, refluxing)10 resulted in the production of C(1)-
C(2) cleavage product 14 in moderate yield.11 Similarly,
the reduction of 13 with LiAlH4 in THF led to a reductive
C(1)-C(2) cleavage product 15 predominately. The at-
tempted tandem Wagner-Meerwein rearrangement-
cyclopropyl ring opening of 1-methoxymethylcamphor
derivative 16 under mild acidic conditions furnished an
aldehydic product 17 (mixture of epimers) instead in good
yield in contrast to our previous study of 1-methyl
camphor analogues.1 These results further illustrated the
remarkable structure dependency of chemical reactivity
of the camphor series,12 i.e., an oxygenated C(10)-methyl
The synthetic 4 was readily methylated at C(2) with
methyllithium in THF and the resulting diol (inseparable
mixture of endo- and exo-methyl isomers, ratio ca. 2:1
1
by HNMR analysis) was subsequently tosylated (TsCl,
cat. DMAP, pyridine, rt.) to give endo-methyl tosylate 11
and its exo-methyl epimer (Scheme 2). Reductive deoxy-
genation of the epimeric mixture of tosylate 11 with
LiAlH4 in refluxing ether furnished the spirocyclopro-
panated camphor derivative 2a (42%, mp 80-82 °C),
identical in every respect (except optical rotation) with
the unusual cyclopropanation product [2 (R ) Me), Figure
1], obtained in our previous work,1 along with the C(2)
epimer of 2a (22%) which were separated readily by flash
chromatography on silica gel. Spirocyclopropanated cam-
(6) Better yield was achieved with this alkylating agent.
(7) Less than 5% of 5-benzyloxymethylspiro[2.4]hepta-4,6-diene,
anticipated to be formed by spirocyclopropanation at C-3 and C-4 of
the anion from 8a, was detected by 1H NMR analysis of the crude
product. The major desired product 6a might be derived from the
predominating chelated form of metal cyclopentadienide as shown
below. For some regiodegenerated alkylation (or cyclopropanation) of
alkyl-substituted cyclopentadienes, see: (a) Alder, K.; Ache, H. J.;
Flock, F. H. Chem. Ber. 1960, 93, 1888. (b) Meyer, F.; Haynes, P.;
McLean, S.; Harrison, A. G. Can. J. Chem. 1965, 43, 211. (c) McLean,
S.; Haynes, P. Tetrahedron 1965, 21, 2313. (d) Clark, R. A.; Hayles,
W. J.; Youngs, D. S. J. Am. Chem. Soc. 1975, 97, 1966. We thank one
of the reviewers for bringing these references to our attention.
(9) X-ray crystallographic data for 4a: C17H20O4S, FW 320.39,
monoclinic, space group P21/c, a ) 6.580(5) Å, b ) 19.219(15) Å, c )
12.656(10) Å, â ) 98.154(12)°, Z ) 4, dcalcd ) 1.343 g/cm3, R1(I>2σ(I))
) 0.0536, wR2(all data) ) 0.1056. See CIF file in the Supporting
Information for more details.
(10) An attempted cyclopropane-participated oxy-Cope rearrange-
ment of I to II was not observed, due probably to the poor orbital
alignment required for this electrocyclic reaction, presumably beacuse
of the tremendous inherent ring strain in I.
(8) Satisfactory spectral data were obtained, respectively; see
Experimental Section for details.
(11) The exo-hydroxy epimer of 12 was partially recovered under
similar reaction conditions.
(12) For a review, see: Money, T. Nat. Prod. Rep. 1985, 253.
J. Org. Chem, Vol. 70, No. 20, 2005 8225

7.36 (m, 5H) ppm; 13C NMR (75 MHz, CDCl3) δ 5.22, 7.89, 45.0,
48.3, 48.6, 58.7, 62.1, 64.9, 73.8, 119.5, 127.5, 127.5, 127.7, 128.4,
128.4, 134.4, 137.7, 138.5 ppm; MS (FAB) m/z [M + 1]+ found
300; HRMS (SMS) m/z [M + H]+ found 300.1159; calcd 300.1150
for C18H19OClN. (b) A solution of adduct 9 (2.0 g, 6.6 mmol) in
95% ethanol (40 mL) was charged with 10% Pd-C catalyst (400
mg) and stirred vigorously under hydrogen gas at atmospheric
pressure for 1.5 h. The catalyst was removed by filtration and
the filtrate was concentrated under reduced pressure. The
resulting hydrogenation product 10 was obtained as white solids
(1.4 g, 99%), mp 180-182 °C dec (lit. mp 180-182 °C).2 IR (film)
νmax 3502, 2952, 2876, 2242, 1446, 1073, 1039, 798 cm-1; 1H NMR
(300 MHz, CDCl3) δ 0.49-0.97 (m, 4H), 1.50-2.23 (m, 7H), 2.87-
2.94 (m, 1H), 3.63-3.89 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3)
δ 4.56, 5.74, 26.1, 27.8, 35.4, 43.1, 49.2, 55.4, 60.8, 61.9, 120.0
ppm; LRMS (EI) m/z 211 (M+, 0.3%), 106 (32), 95 (100), 91 (97),
79 (56), 77 (55); HRMS (SMS) m/z [M + H]+ found 212.0841;
calcd 212.0847 for C11H15OClN. (c) Potassium hydroxide (1.1 g,
20.0 mmol) was dissolved in DMSO (10 mL) and water (3.5 mL)
with stirring at 50 °C and allowed to cool to room temperature.
A solution of 10 (2.1 g, 9.9 mmol) in DMSO (10 mL) was added
dropwise with stirring. The mixture was heated to 70 °C for 24
h, poured into water (500 mL), and extracted with ether (3 ×
200 mL). The combined ether layers were dried with anhydrous
sodium sulfate and concentrated in vacuo. The remaining
slightly yellow viscous oil was purified by chromatography on
silica gel eluting with ethyl acetate/petroleum ether (1:40) to
afford pure product 4 as white solids (1.0 g, 60%), mp 158-160
°C dec (lit. mp 152-154 °C).2 IR (film) νmax 3456, 2955, 1734,
1173, 1058, 1011 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.42-0.63
(m, 3H), 0.77-0.84 (m, 1H), 1.50-2.12 (m, 6H), 2.37-2.46 (m,
1H), 3.51-3.64 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 4.32,
4.48, 26.8, 27.3, 35.1, 41.6, 45.3, 57.6, 59.8, 219.1 ppm; LRMS
(EI) m/z 166 (M+, 8%), 135 (36), 106 (57), 91 (90), 79 (100), 67
(67); HRMS (SMS) m/z [M + H]+ found 167.1069; calcd 167.1067
for C10H15O2.
renders the strained camphor ring system to undergo
C(1)-C(2) bond cleavage readily.
In short, an alternative short and efficient synthesis
of 10-hydroxy spirocyclopropanated camphor (4) was
realized. Further application of the unique tricyclic
camphor-like structures (i.e., 2, 3 and 4) in chemical
study would be feasible with their ready availability.
Experimental Section13
Preparation of Benzyloxymethyl Spirocyclopropanated
Cyclopentadiene Derivative 6a. (a) To a stirred suspension
of NaH (60% oil, 2.40 g, 60.0 mmol) in dry THF (45 mL) was
added slowly a solution of freshly distilled cyclopentadiene (3.96
g, 60.0 mmol) in THF (20 mL) over 20 min at 0 °C. After 30 min
of additional stirring, the resulting purple reaction mixture was
then cooled to -50 °C, to which a solution of benzyl chloromethyl
ether (11.3 g, 72.0 mmol) in 20 mL of THF was added slowly at
the same temperature over 20 min. The resulting reaction
mixture was stirred at -50 °C for 40 min, and allowed to warm
gradually to 0 °C, quenched with saturated aqueous NH4Cl (80
mL), and stirred for an additional 1 h. The organic layer was
separated, and the aqueous layer was extracted with ether (4 ×
150 mL). The combined organic phases were washed with water
(3 × 100 mL) and brine (3 × 100 mL), dried over sodium sulfate,
filtered, and concentrated under reduced pressure at room
temperature. The crude product was purified by flash chroma-
tography on silica gel (ether/hexane 1:50) to afford the alkylation
product 8a as a pale yellow liquid (10.4 g, 90%), which was used
next without further purification. 8a: 1H NMR (300 MHz,
CDCl3) δ 3.00 (s, 2H), 4.33 (s, 2H), 4.50 (s, 2H), 6.38-6.48 (m,
3H), 7.24-7.34 (m, 5H) ppm; 13C NMR (75 MHz, CDCl3) δ 41.9,
68.1, 71.7, 127.5, 127.6, 128.3, 129.3, 129.3, 131.9, 132.4, 133.1,
138.4, 145.2 ppm. (b) To a stirred suspension of NaH (60% oil,
3.20 g, 80.0 mmol) in 60 mL of dry DMF was added slowly a
solution of the above 8a (7.1 g, 38.0 mmol) and 1-bromo-2-
chloroethane (6.9 g, 49.0 mmol) in 20 mL of DMF at a speed
maintaining the temperature of the reaction mixture below 0
°C. The reaction was stirred for 30 min at 0 °C, quenched with
saturated aqueous NH4Cl (80 mL), and diluted with ether (200
mL). The organic layer was separated, and the aqueous layer
was extracted with ether (3 × 100 mL). The combined organic
portions were washed with water (4 × 100 mL) and brine (3 ×
100 mL), dried over anhydrous sodium sulfate, filtered, and
concentrated under reduced pressure. The crude product was
purified by flash chromatography on silica gel (EtOAc/petroleum
ether 1:100) to afford 6a as a pale yellow liquid (5.5 g, 68%),
which was used in the next Diels-Alder reaction without further
purification. 6a: IR (film) νmax 2921, 2852, 1088, 1066, 731, 698
Synthesis of Spirocyclopropanated Camphor Deriva-
tive 2a. (a) To a stirred solution of 4 (90.0 mg, 0.54 mmol) in
anhydrous diethyl ether (4 mL) was added dropwise CH3Li (1.0
mL, 1.6 mmol, 1.6 M in ether) under argon at -20 °C. After 1 h,
the reaction was quenched by dropwise addition of saturated
aqueous NH4Cl (1 mL), diluted, and extracted with ether. The
combined organic layers were washed with brine, dried (Na2-
SO4), and concentrated in vacuo. The residual 95 mg (98%) of a
diol was obtained as a colorless liquid, which was used in the
next step without further purification. IR (film) νmax 3359, 2947,
2869, 1168, 1014 cm-1 1H NMR (300 M Hz, CDCl3) δ 0.20-
;
0.66 (m, 8H), 1.39 (s, 3H), 1.44 (s, 3H), 1.09-2.57 (m, 18 H),
3.27-3.88 (m, 4H) ppm; 13C NMR (75 MHz, CDCl3) δ 1.7, 2.8,
5.9, 6.7, 23.2, 27.4, 27.7, 27.9, 28.2, 28.4, 35.4, 43.2, 43.9, 46.4,
50.2, 51.5, 62.5, 63.5, 80.0, 82.5 ppm; LRMS (EI) m/z 164 ([M -
18]+, 1%), 149 (18), 121 (28), 106 (100), 95 (46), 91 (66), 43 (81).
(b) To a solution of the above diol (100 mg, 0.55 mmol) in pyridine
(4 mL) was added DMAP (20 mg) and tosyl chloride (420 mg,
2.2 mmol). The mixture was stirred for 3 h at 60 °C, cooled to
room temperature, and neutralized with cold dilute HCl. The
mixture was extracted with ether, dried over anhydrous sodium
sulfate, filtered, and concentrated. Chromatography of the crude
product on silica gel eluting with ethyl acetate/petroleum ether
(1:40) provided 145 mg (80%) of tosylate 11 as a colorless oil. IR
(film) νmax 3444, 2950, 1358, 1174, 958 cm-1; 1H NMR (300 MHz,
CDCl3) δ 0.23-0.58 (m, 8H), 1.28 (s, 3H), 1.30 (s, 3H), 1.19-
2.30 (m, 16H), 2.45 (s, 6H), 3.67-4.18 (2AB, J ) 9.9, 9.3 Hz,
4H), 7.33-7.37 (m, 4H), 7.77 (d, J ) 8.1 Hz, 4H) ppm; 13C NMR
(75 MHz, CDCl3) δ 2.3, 3.2, 4.7, 5.7, 21.7, 23.8, 26.9, 27.0, 27.5,
27.7, 27.9, 35.7, 36.2, 43.2, 43.7, 46.6, 49.9, 50.7, 51.0, 69.4, 71.3,
79.0, 80.0, 127.9, 127.9, 127.9, 127.9, 129.8, 129.8, 129.9, 129.9,
132.3, 132.6, 144.7, 145.0 ppm; LRMS (EI) m/z 164 (M+, 12%),
149 (20), 121 (30), 106 (100), 91 (95); HRMS (ESI) m/z [M +
Na]+ found 359.1284; calcd 359.1288 for C18H24O4NaS. (c) To a
stirred solution of 11 (140 mg, 0.42 mmol) in anhydrous ether
(10 mL) was added LiAlH4 (100 mg, 2.6 mmol) in one portion.
The mixture was brought to reflux for 2 h, cooled to room
temperature, and quenched with dilute NaOH. The mixture was
1
cm-1; H NMR (300 MHz, CDCl3) δ 1.60-1.76 (m, 4H), 4.16 (s,
2H), 4.44 (s, 2H), 6.13 (d, J ) 5.4 Hz, 1H), 6.46-6.48 (m, 2H),
7.26-7.36 (m, 5H) ppm; 13C NMR (75 MHz, CDCl3) δ 13.6, 13.6,
37.5, 65.5, 71.3, 127.3, 127.5, 127.5, 127.7, 128.3, 128.3, 129.7,
138.3, 140.7, 144.5 ppm; LRMS (EI) m/z 212 (M+, 1%), 91(100),
77(18); HRMS (ESI) m/z [M + NH4]+ found 230.1535; calcd
230.1539 for C15H20ON.
Preparation of 10-Hydroxy Spirocyclopropanated Cam-
phor (4). (a) The above crude diene 6a (12.3 g, 58.0 mmol) and
2-chloroacrylonitrile (7.0 g, 80.0 mmol) were dissolved in dry
benzene (25 mL) and the resulting mixture was brought to 80
°C with magnetic stirring for 20 h. The brown reaction mixture
was concentrated and the residue was purified by flash chro-
matography on silica gel eluting with ethyl acetate/petroleum
ether (1:80) to afford adduct 9 as a colorless liquid (9.3 g, 54%).
IR (film) νmax 2863, 2235, 1451, 1365, 1104, 740 cm-1; 1H NMR
(300 MHz, CDCl3) δ 0.50-0.60 (m, 2H), 0.82-0.92 (m, 2H), 1.96
(d, J ) 13 Hz, 1H), 2.42 (t, J ) 3.6 Hz, 1H), 2.96 (dd, J1 ) 4.0
Hz, J2 ) 13 Hz, 1H), 3.65 (d, J ) 10 Hz, 1H), 3.88 (d, J ) 10 Hz,
1H), 4.57 (s, 2H), 6.18 (d, J ) 6.0 Hz, 1H), 6.51 (m, 1H), 7.31-
(13) For general experimental procedures, see the Supporting
Information of ref 1.
8226 J. Org. Chem., Vol. 70, No. 20, 2005

extracted with ether, dried over anhydrous sodium sulfate,
filtered, and concentrated. Chromatography on silica gel eluting
with ethyl acetate/petroleum ether (1:80) provided 30 mg (42%)
of 2a along with 15 mg (22%) of its isomer. 2a: white waxy
solids, mp 80-82 °C; IR (film) νmax 3408, 3066, 2949, 2868, 1099,
Reductive Fragmentation of Tosylate 13. To a stirred
solution of 13 (80 mg, 0.22 mmol) in anhydrous ether (10 mL)
was added LiAlH4 (50 mg, 1.3 mmol) in one portion. The mixture
was brought to reflux for 2 h, cooled to room temperature and
quenched with dilute NaOH. The slurry mixture was extracted
with ether, dried over anhydrous sodium sulfate, filtered, and
concentrated. Chromatography of the residue on silica gel eluting
with ethyl acetate/petroleum ether (1:60) provided 30 mg (75%)
of product 15 as a colorless oil. IR (film) νmax 3356, 2940, 1649,
1064 cm-1 1H NMR (300 MHz, CDCl3) δ 0.20-0.29 (m, 2H),
;
0.54-0.59 (m, 2H), 0.66 (s, 3H), 1.22 (s, 3H), 1.14-1.89 (m, 8H)
ppm; 13C NMR (75 MHz, CDCl3) δ 1.17, 4.18, 9.67, 22.3, 28.4,
31.8, 35.9, 42.5, 48.6, 49.4, 80.1 ppm; HRMS (SMS) m/z [M -
H2O + H]+ found 149.1325; calcd 149.1325 for C11H17
.
1438 cm-1 1H NMR (300 MHz, CDCl3) δ 0.47-0.89 (m, 4H),
;
Preparation of Spirocyclopropanated Camphor (3). To
a stirred solution of tosylate 4a (480 mg, 1.5 mmol) in anhydrous
ether (20 mL) was added LiAlH4 (240 mg, 6 0.0 mmol) in one
portion. The mixture was brought to reflux for 2 h, cooled to
room temperature, and quenched with dilute NaOH. The
mixture was extracted with ether, dried over anhydrous sodium
sulfate, filtered, and concentrated. Chromatography of the
resulting residue on silica gel eluting with ethyl acetate/
petroleum ether (1:60) provided 140 mg (62%) of an alcohol
intermediate. To a stirred solution of the above alcohol (60 mg,
0.39 mmol) in CH2Cl2 (5 mL) was added PCC (170 mg, 0.78
mmol). The resulting mixture was stirred for 1 h at room
temperature and filtered through a short pad of silica gel to give
50 mg (86%) of ketone 3 as waxy solids, mp 77-79 °C. IR (film)
νmax 2959, 1743, 1050 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.42-
0.53 (m, 4H), 0.75 (s, 3H), 1.46-2.38 (m, 7H) ppm; 13C NMR (75
MHz, CDCl3) δ 3.05, 3.90, 8.89, 27.2, 31.3, 36.1, 40.9, 45.0, 53.5,
218.2 ppm; LRMS (FAB) m/z 151 (M + 1).
1.25-1.68 (m, 4H), 1.73 (s, 3H), 2.02-2.10 (m, 2H), 2.45-2.51
(m, 2H), 4.09-4.13 (m, 1H), 4.30 (s, 1H), 4.57 (s, 1H), 4.82 (s,
1H), 4.96 (s, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 13.2, 16.1,
18.0, 29.4, 30.0, 32.0, 37.2, 40.8, 73.9, 97.5, 110.2, 148.4, 158.2
ppm; LRMS (FAB) m/z 193 (M + 1).
Preparation of Aldehyde 17. To a solution of 16 (50 mg,
0.28 mmol) in dry benzene (2 mL) was added p-TsOH (30 mg,
0.17 mmol), and the mixture was brought to reflux for 5 min,
diluted with ether, washed with saturated aqueous NaHCO3,
water, and brine, respectively, then dried over Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by chro-
matography on silica gel eluting with ethyl acetate/petroleum
ether (1:100) to afford 40 mg (85%) of aldehyde 17 as a colorless
oil (ratio ca. 1:1). IR (film) νmax 2953, 2869, 1716, 1669 cm-1; 1H
NMR (300 MHz, CDCl3) δ 0.20-0.69 (m, 8H), 1.17 (s, 3H), 1.23
(s, 3H), 1.25-2.13 (m, 16H), 9.47 (d, J ) 6.6 Hz, 1H), 9.62 (d, J
) 5.4 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 6.0, 6.8, 11.5,
13.4, 18.3, 20.4, 27.6, 28.4, 28.6, 28.9, 30.5, 37.7, 43.4, 45.8, 46.8,
47.3, 49.3, 51.3, 62.3, 63.8, 203.7, 206.9 ppm; LRMS (EI) m/z
164 (M+, 7%), 135 (31), 107 (43), 91 (100), 79 (91).
Preparation of Cleavage Product Enone 14. Potassium
hydride dispersion in mineral oil (4.0 mmol) was transferred into
a flask, washed with anhydrous pentane (3 × 2 mL), and
suspended in anhydrous DME (5 mL), to which a mixture of 18-
crown-6 (1.05 g, 4.0 mmol) and allylic alcohol 12 (120 mg, 0.4
mmol) in DME (3 mL) was added dropwise, and the mixture
was brought to reflux for 3 h. The reaction mixture was then
cooled to -78 °C and quenched with absolute ethanol carefully.
The resulting slurry was diluted with ether, washed with brine,
dried, and concentrated. Chromatography of the residue on silica
gel eluting with ethyl acetate/petroleum ether (1:100) gave 15
mg of enone 14 along with the recovered exo-hydroxy epimer of
Acknowledgment. We thank the National Natural
Science Foundation (Distinguished Youth Fund 29925204
and QT 20021001) for financial support. The Cheung
Kong Scholars program and the Outstanding Scholars
program of Nankai University are gratefully acknowl-
edged.
12. 14: colorless oil, IR (film) νmax 2926, 1676, 1649 cm-1 1H
;
Supporting Information Available: Experimental pro-
cedures and spectral data of compounds 4a-c, 12, 13, 13a,
16, and I; CIF file for compound 4a. This material is available
free of charge via the Internet at http://pubs.acs.org.
NMR (300 MHz, CDCl3) δ 0.62-0.77 (m, 4H), 1.41-2.03 (m, 4H),
1.86 (s, 3H), 2.32-2.50 (m, 5H), 4.31 (s, 1H), 4.59 (s, 1H), 5.77
(s, 1H), 5.93 (s, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 12.4, 17.7,
18.0, 29.7, 30.4, 31.7, 39.8, 41.5, 98.0, 124.6, 144.9, 157.3, 201.7
ppm; HRMS (ESI) m/z [M + H]+ found 191.1428; calcd 191.1430
for C13H19O.
JO0509962
J. Org. Chem, Vol. 70, No. 20, 2005 8227