Total syntheses of cladoacetals A and B: Confirmation of absolute configurations

Article abstract of DOI:10.1021/jo300923e

The first enantioselective syntheses of cladoacetals A (1a, overall yield: 16%) and B (1b, overall yield: 34%) from crotonaldehyde in nine and seven steps, respectively, have been accomplished. Sharpless asymmetric dihydroxylation, Suzuki coupling, and acid-catalyzed intramolecular acetalization were the key steps in the syntheses. The absolute configuration of natural (+)-cladoacetal A was affirmed to be 1S,3S,4R, whereas that of (-)-cladoacetal B was affirmed to be 1R,3S,4S.

Full text of DOI:10.1021/jo300923e

Article
pubs.acs.org/joc
Total Syntheses of Cladoacetals A and B: Confirmation
of Absolute Configurations
Day-Shin Hsu* and Shih-Chung Lin
Department of Chemistry and Biochemistry, National Chung Cheng University, Minhsiung, Taiwan 621
S
* Supporting Information
ABSTRACT: The first enantioselective syntheses of cladoacetals
A (1a, overall yield: 16%) and B (1b, overall yield: 34%) from
crotonaldehyde in nine and seven steps, respectively, have been
accomplished. Sharpless asymmetric dihydroxylation, Suzuki
coupling, and acid-catalyzed intramolecular acetalization were
the key steps in the syntheses. The absolute configuration of
natural (+)-cladoacetal A was affirmed to be 1S,3S,4R, whereas
that of (−)-cladoacetal B was affirmed to be 1R,3S,4S.
Scheme 1. Retrosynthetic Analysis
INTRODUCTION
■
Cladoacetals A (1a) and B (1b) have been previously isolated
from solid-substrate fermentation cultures of an unidentified
fungicolous isolate (NRRL 29097) that resembles Cladosporium
sp.1 The relative configurations displayed in Figure 1 were
Figure 1. Structure of cladoacetals A and B.
determined by NMR spectroscopy. Cladoacetals possess a
benzo-fused dioxabicyclo[4.2.1]nonene framework. Although 1a
and 1b vary only in the relative configuration at C-3, their
absolute configurations have not yet been determined.
Compound 1a shows antibacterial activity, whereas the bio-
logical activity of 1b has not been investigated. In this paper, we
report the first enantioselective syntheses of 1a and 1b, and the
determination of their absolute configurations.
A retrosynthetic analysis suggested that the desired cladoacetals A
and B could be synthesized from acetal precursors 2 via intramolecular
acetalization (Scheme 1). The key intermediates 2 couldbeobtainedby
the Suzuki coupling of boronic acid 3 and Z-vinyl bromides 4. Boronic
acid 3 could be prepared from bromoaldehyde 5 through protection of
the aldehyde and subsequent replacement of the bromide group with
boronic acid. On the other hand, 4 could be obtained from diols 6 via
protection of the 1,2-diols followed by selective hydrogenolysis; 6 could
be prepared from commercially available crotonaldehyde in two steps,
one-carbon homologation and subsequent Sharpless asymmetric
dihydroxylation of the resulting 1,1-dibromoalkene intermediate.
RESULTS AND DISCUSSION
■
Preparation of Boronic Acid 3. The boronic acid fragment
3 was prepared from 52 through a two-step sequence, as shown in
Scheme 2. Protection of the aldehyde with ethylene glycol
Received: May 7, 2012
Published: June 26, 2012
© 2012 American Chemical Society
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Scheme 2. Preparation of Boronic Acid 3
Scheme 4. Completion of the Total Synthesis of
(−)-Cladoacetal B (1b)
afforded 8, which upon lithium−halogen exchange and
subsequent treatment with trimethyl borate gave the desired
product 3 in 78% yield.
Preparation of Z-Vinyl Bromide 4b. With the necessary
boronic acid fragment in hand, we turned our attention to the
synthesis of the Z-vinyl bromide fragments. We first focused on
the synthesis of 1b because the necessary C-3 and C-4
stereocenters could be obtained directly by Sharpless asymmetric
dihydroxylation. To this end, the known (2S,3S)-diol 6b3 was
obtained in 67% yield and with 87% enantiomeric excess (ee)
from crotonaldehyde (7) via one-carbon homologation4 and the
Sharpless asymmetric dihydroxylation5 of 9 with AD-mix-α3
(Scheme 3). The resulting diol was then protected as its
recorded optical rotation ([α]25 = −173 (c 1.4, MeOH)) and
D
the literature value1 ([α]22 = −135 (c 0.6, MeOH)) were
D
identical in sign but different in magnitude. To determine
whether such a difference resulted from some technical error, the
optical rotation values for different synthetic samples were
recorded, but similar values were observed in all cases. Because of
the rigid tricyclic ring system in cladoacetals, the relative
configuration at C-1 and C-4 should be 1R* and 4S*, res-
pectively. Accordingly, we believed that only one isomer would
be formed in the acid-catalyzed intramolecular acetalization of
11. Thus, the aforementioned discrepancy in the optical rotation
is presumably due to the relatively small amount (0.9 mg) of
natural 1b isolated in previous studies and the corresponding
higher margin of error. The structure of 1b was further confirmed
by single-crystal X-ray diffraction analysis (Figure 2),11 and the
Scheme 3. Preparation of Z-Vinyl Bromide 4b
isopropylidene acetal to afford dibromoalkene 10.6 Stereo-
selective hydrogenolysis of 10 by a palladium-catalyzed n-
Bu3SnH reduction7 afforded 4b in 75% yield.
Synthesis of (−)-Cladoacetal B (1b). Suzuki−Miyaura
coupling8 of 4b and 3 yielded the desired product 11 in 81% yield
(Scheme 4). The next step was to construct the tricyclic core
structure of 1b by intramolecular acetalization. Treament of 11
with a catalytic amount of pTsOH in refluxing benzene directly
gave the desired tricyclic compound 12 in 96% yield. By
deprotection with EtSNa,9 12 was easily converted into the target
molecule 1b in 94% yield. Initial attempts to deprotect the
methyl ether by using BBr3 were unsuccessful, and only a
complex mixture was obtained. Spectroscopic data recorded for
the synthetic molecule were found to be in good agreement with
those reported for the natural product 1b.10 However, the
Figure 2. ORTEP plot of the crystal structure of cladoacetal B (1b)
(numbering is arbitrary).
absolute configuration at C-1, C-3, and C-4 was affirmed to be
1R, 3S, and 4S.
Preparation of Z-Vinyl Bromide 4a. Next, we focused our
attention on the synthesis of 1a. Because the only difference
between 1a and 1b is the relative configuration at the C-3
stereocenter, we chose (4S,5R)-15 as our target intermediate for
the synthesis of 1a. This synthesis, as shown in Scheme 5, also
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Scheme 5. Preparation of Z-Vinyl Bromide 4a
Scheme 6. Completion of the Total Synthesis of
(−)-Cladoacetal A (1a)
(Scheme 7). Transformation of the formyl and TBS protecting
groups in ent-14 into isopropylidene acetal under acidic
conditions and subsequent treatment with n-Bu3SnH in the
presence of a palladium catalyst gave Z-vinyl bromide ent-4a.
Coupling of 3 and ent-4a under Suzuki−Miyaura conditions gave
the desired product ent-16 in 78% yield. Acid-catalyzed
intramolecular acetalization of ent-16 afforded the tricyclic
compound ent-17. Finally, deprotection of the methyl ether
began with 7. One-carbon homologation and Sharpless
asymmetric dihydroxylation using AD-mix-β furnished
(2R,3R)-diol ent-6b in 63% yield and with 91% ee.12 Next,
inversion of the allylic hydroxyl group in ent-6b was achieved by
selective protection13 of the hydroxyl group at C-2, followed by
the application of Mitsunobu conditions,13 to give the desired
product (2R,3S)-14. The best selectivity in the regioselective
protection of the hydroxyl group at C-2 in ent-6b was observed
when using TBSOTf as the silylation agent at −78 °C. Poor
selectivity was observed when the reaction was carried out at a
higher temperature or used TBSCl as the silylation agent. Then,
transformation of the formyl and TBS protecting groups in 14
into isopropylidene acetal under acidic conditions14 and
subsequent treatment with n-Bu3SnH in the presence of a
palladium catalyst gave 4a in 73% yield.
Synthesis of (−)-Cladoacetal A (1a). Once 4a was
obtained, it was coupled with fragment 3 under Suzuki−Miyaura
conditions to yield the desired product 16 in 81% yield (Scheme 6).
Intramolecular acetalization of 16 under acidic conditions led to
the formation of benzo-fused dioxabicyclo[4.2.1]nonene 17 in
92% yield. Finally, deprotection of the methyl ether with EtSNa
afforded 1a in 91% yield. The spectroscopic data of the synthetic
molecule were found to be in good agreement with those reported
for the natural product 1a.10 However, the specific rotation of the
synthetic molecule ([α] 25D = −250 (c 1.4, MeOH)) was found to
be opposite to that of the natural product1 ([α] 22 D = +266 (c 1.4,
MeOH)). Thus, the absolute configuration of natural cladoacetal
A at C-1, C-3, and C-4 should be 1S, 3S, and 4R.
with EtSNa afforded the final product in 89% yield. The specific
25
D
rotation of this synthetic molecule ([α]
= +255 (c 2.7,
MeOH)) was found to be in good agreement with that of the
natural product1 ([α]22 = +266 (c 1.4, MeOH)). Thus, the
D
absolute configuration of natural cladoacetal A at C-1, C-3, and
C-4 was confirmed to be 1S, 3S, and 4R.
CONCLUSION
■
In conclusion, we have accomplished the enantioselective
syntheses of cladoacetals A (overall yield: 16%) and B (overall
yield: 34%) from crotonaldehyde in nine and seven steps,
respectively. The absolute configuration of natural (+)-cladoa-
cetal A was confirmed to be (1S,3S,4R), whereas that of
(−)-cladoacetal B was confirmed to be (1R,3S,4S).
EXPERIMENTAL SECTION
■
General Information. Unless stated otherwise, reagents were
obtained from commercial sources and used without further
purification. All reactions were performed under a nitrogen atmosphere
in anhydrous solvents, which were dried prior to use following standard
procedures. Reactions were monitored by thin-layer chromatography on
0.25 mm E. Merck silica gel plates (60F-254) using 7% ethanolic
phosphomolybdic acid as developing agent. Merck silica gel 60 (particle
size 0.04−0.063 mm) was employed for flash chromatography. Melting
points are uncorrected. IR spectra were recorded as films on KBr plates.
1HNMRspectrawereobtainedinCDCl3 unless otherwise noted at 400 MHz.
13C NMR spectra were obtained at 100 MHz. Chemical shifts were
reported in δ (ppm) using solvent resonance as the internal reference.
High resolution mass spectra (HRMS) were obtained on a TOF MS
instrument with ESI or EI source.
Synthesis of (+)-Cladoacetal A (1a). To further confirm
the absolute configuration of natural cladoacetal A, we decided to
synthesize (+)-cladoacetal A from (2S,3S)-diol 6 using the same
reagents and procedures shown in Schemes 5 and 6. Thus,
selective protection of the hydroxyl group at C-2 in 6b was
followed by the inversion of the allylic hydroxyl group under
Mitsunobu conditions to give (2S,3R)-ent-14 in 77% yield
2-(2-Bromo-6-methoxyphenyl)-1,3-dioxolane (8). p-Toluene-
sulfonic acid monohydrate (43 mg, 0.23 mmol) and ethylene glycol
(1.00 g, 16.1 mmol) were added to a solution of 5 (500 mg, 2.3 mmol) in
benzene (20 mL) at room temperature. The reaction mixture was
heated under reflux for 8 h in a Dean−Stark apparatus. The contents
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Scheme 7. Total Synthesis of (+)-Cladoacetal A (1a)
were cooled to room temperature and quenched with saturated aqueous
NaHCO3. The aqueous layer was separated and extracted with EtOAc.
The combined organic extracts were washed successively with brine,
dried over MgSO4, filtered, and concentrated under reduced pressure.
The crude product was purified by flash chromatography on silica gel
(EtOAc/hexanes = 1:10) to afford 8 (0.52 g, 86%) as a pale yellow solid:
mp 68−69 °C; IR (neat) νmax 2891, 1589, 1574, 1463, 1405, 1264, 1211,
1092, 1066, 1033, 959, 778, 730 cm−1; 1H NMR (400 MHz, CDCl3) δ
7.18 (dd, J = 8.0, 1.2 Hz, 1H), 7.14 (dd, J = 8.0, 8.0 Hz, 1H), 6.86 (dd, J =
8.0, 1.2 Hz, 1H), 6.46 (s, 1H), 4.28−4.24 (m, 2H), 4.04−4.01 (m, 2H),
3.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.8, 131.0, 126.3, 124.0,
123.6, 110.9, 101.3, 65.9, 56.1; MS (EI) m/z (% base peak) 260 (14),
258 (M+, 14), 232 (32), 230 (33), 215 (62), 213 (65), 186 (14), 149
(10), 91 (37), 73 (100); HRMS (EI) calcd for C10H1179BrO3 257.9892,
found 257.9898.
2-(1,3-Dioxolan-2-yl)-3-methoxyphenylboronic Acid (3). To a
stirred solution of 8 (100 mg, 0.38 mmol) in THF (5 mL) was added
n-BuLi (0.48 mL, 0.76 mmol, 1.6 M solution in hexane) at −78 °C. After
it was stirred at −78 °C for 30 min, trimethyl borate (0.09 mL, 0.76
mmol) was added. The resulting mixture was allowed to stir vigorously
at room temperature for 12 h. The reaction mixture was quenched with
water and separated the organic layer. The aqueous layer was extracted
with EtOAc. The combined organic extracts were washed with brine,
dried over MgSO4, filtered, and concentrated in vacuo to give 3 (65.4
mg, 76%): mp 86−88 °C; IR (neat) νmax 3417, 2954, 2929, 2898, 1574,
1458, 1336, 1261, 1068, 947, 752 cm−1; 1H NMR (400 MHz, CDCl3) δ
7.36 (dd, J = 8.8, 7.2 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 6.93 (d, J = 8.8
Hz, 1H), 6.18 (s, 1H), 5.15 (br s, 2H), 4.21−4.17 (m, 2H), 4.04−4.00
(m, 2H), 3.84 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.7, 130.6,
126.1, 124.7, 111.7, 99.0, 64.9, 55.7; MS (EI) m/z (% base peak) 224
(M+, 3), 159 (21), 139 (4), 115 (5), 103 (100), 73 (31); HRMS (EI)
calcd for C10H13BO5 224.0856, found 224.0857.
(2S,3S)-5,5-Dibromopent-4-ene-2,3-diol (6b). To a solution of
tetrabromomethane (9.47 g, 28.6 mmol) in CH2Cl2 (40 mL) was added
PPh3 (15 g, 57.2 mmol) at 0 °C, and the bright orange mixture was
stirred at 0 °C for 15 min. A solution of crotonaldehyde (7) (1 g,
14.3 mmol) in CH2Cl2 (20 mL) was added to the bright orange mixture
and stirred for 1 h. The reaction mixture was diluted with hexanes and
filtered through neutral silica gel. The filtrate was carefully concentrated
in vacuo to give dibromoalkene 9 as a yellow oil, which was used
immediately for the next step. To a flask containing AD-mix-α (20.00 g)
in tert-butyl alcohol (65 mL) and water (65 mL) at room temperature
was added methanesulfonamide (1.34 g, 14.3 mmol). The mixture was
cooled to 0 °C, and then dibromoalkene 9 was added in one portion.
The heterogeneous slurry was stirred vigorously at 0 °C for 24 h. Sodium
sulfite (20.00 g) was added at 0 °C, and the reaction mixture was allowed
to warm to room temperature. After stirring for 1 h, the mixture was
extracted with EtOAc. The combined organic extracts were washed with
brine, dried over MgSO4, and concentrated. The crude product was
purified by flash chromatography on silica gel (EtOAc/hexanes = 1:3) to
afford diol 6b (2.47 g, 67% over 2 steps) as a pale yellow solid: ee = 87%
(HPLC column Chiralcel OD; injection amount 30 μL; sample
concentration 2 mg of diol/1 mL of mobile phase solvent; mobile phase
hexane/2-propanol (95/5 v/v); flow rate 1 mL/min); [α]25 = −5.3
D
(c 28.8, CHCl3); mp 48−49 °C; IR (neat) νmax 3376, 2976, 1613, 1451,
1133, 1035, 924, 785 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.49 (d, J =
8.2 Hz, 1H), 4.14−4.10 (m, 1H), 3.76−3.73 (m, 1H), 2.55 (br s, 1H),
2.36 (br s, 1H), 1.24 (d, J = 6.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
137.5, 93.4, 76.7, 69.8, 18.8; MS (EI) m/z (% base peak) 260 (0.07), 258
(M+, 0.06), 217 (24), 215 (50), 213 (27), 181 (7), 179 (8), 137 (88),
135 (100), 133 (13), 107 (26), 105 (25), 55 (35); HRMS (EI) calcd for
C5H879Br2O2 257.8891, found 257.8894.
(4S,5S)-4-(2,2-Dibromovinyl)-2,2,5-trimethyl-1,3-dioxolane
(10). To a solution of 6b (1.00 g, 3.85 mmol) in acetone (7 mL) at room
temperature was added p-toluenesulfonic acid monohydtre (73 mg,
0.39 mmol) and 2,2-dimethoxypropane (7 mL, 58 mmol). After stirring
at room temperature for 2 h, the reaction mixture was quenched with
saturated aqueous NaHCO3 and extracted with EtOAc. The combined
organic extracts were washed with brine, dried over MgSO4, and
concentrated. The crude product was purified by flash chromatography
on silica gel (EtOAc/hexanes = 1:20) to afford 10 (1.06 g, 92%) as a
colorless oil: [α]25D = 2.3 (c 30.8, CHCl3); IR (neat) νmax 2985, 2932,
1625, 1456, 1380, 1242, 1173, 1092, 1038, 862, 811, 783 cm−1; 1H NMR
(400 MHz, CDCl3) δ 6.43 (d, J = 8.2 Hz, 1H), 4.23 (dd, J = 8.2, 8.2 Hz,
1H), 3.88 (dq, J = 8.2, 6.0 Hz, 1H), 1.42 (s, 3H), 1.38 (s, 3H), 1.33 (d,
J = 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 135.4, 109.3, 93.8, 82.1,
75.9, 27.2, 26.7, 17.0; MS (EI) m/z (% base peak) 298 (M+, 0.2), 287
(13), 285 (26), 283 (14), 258 (24), 256 (49), 254 (27), 177 (45), 175
(46), 96 (100); HRMS (ESI) calcd for C8H1379Br2O2 (M+ + H)
298.9277, found 298.9274.
(4S,5S)-(Z)-4-(2-Bromovinyl)-2,2,5-trimethyl-1,3-dioxolane
(4b). To a flame-dried flask were added palladium acetate (75 mg, 0.33
mmol) and triphenylphosphine (350 mg, 1.32 mmol) in Et2O (10 mL).
The resulting solution was stirred for 30 min, and then a solution of 10
(1.00 g, 3.3 mmol) in Et2O (10 mL) and tributyltin hydride (1 mL, 3.7
mmol) ws added. The reaction mixture was stirred for 1 h and then
diluted with water. The aqueous layer was separated and extracted with
Et2O. The combined organic extracts were washed with brine, dried over
MgSO4, filtered, and concentrated. The crude product was purified by
flash chromatography on alumina (hexanes) to afford 4b (552 mg, 75%)
as a colorless oil: [α]25D = 13.1 (c 10.0, CHCl3); IR (neat) νmax 2923,
2852, 1630, 1459, 1378, 1261, 1091, 858, 803, 755, 694 cm−1; 1H NMR
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(400 MHz, CDCl3) δ 6.42 (dd, J = 7.3, 1.4 Hz, 1H), 6.13 (dd, J = 8.1, 7.3
Hz, 1H), 4.50 (dd, J = 9.2, 8.1 Hz, 1H), 3.84 (dq, J = 9.2, 6.4 Hz, 1H),
1.44 (s, 3H), 1.40 (s, 3H), 1.34 (d, J = 6.4 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 132.0, 111.6, 109.1, 80.0, 76.4, 27.3, 26.8, 16.9; MS (EI)
m/z (% base peak) 222 (1), 220 (M+, 1), 207 (26), 205 (27), 178 (21),
176 (21), 165 (9), 163 (9), 137 (10), 135 (13), 116 (100), 97 (58);
HRMS (EI) calcd for C8H1379BrO2 220.0099, found 220.0098.
136.2, 132.5, 130.9, 129.3, 126.0, 125.5, 115.7, 99.4, 85.3, 80.0, 20.2; MS
(EI) m/z (% base peak) 204 (M+, 4), 161 (12), 160 (100), 132 (68), 131
(51), 103 (14), 91 (4), 77 (16); HRMS (EI) calcd for C12H12O3
204.0786, found 204.0780.
(2R,3R)-5,5-Dibromopent-4-ene-2,3-diol (ent-6b). To a solu-
tion of tetrabromomethane (9.47 g, 28.6 mmol) in CH2Cl2 (40 mL) was
added PPh3 (15 g, 57.2 mmol) at 0 °C, and the bright orange mixture
was stirred at 0 °C for 15 min. A solution of crotonaldehyde (7) (1 g,
14.3 mmol) in CH2Cl2 (20 mL) was added to the bright orange mixture
and stirred for 1 h. The reaction mixture was diluted with hexanes and
filtered through neutral silica gel. The filtrate was carefully concentrated
in vacuo to give dibromoalkene 9 as a yellow oil, which was used
immediately for the next step. To a flask containing AD-mix-β (20.00 g)
in tert-butyl alcohol (65 mL) and water (65 mL) at room temperature
was added methanesulfonamide (1.34 g, 14.3 mmol). The mixture was
cooled to 0 °C, and then dibromoalkene 9 was added in one portion.
The heterogeneous slurry was stirred vigorously at 0 °C for 24 h. Sodium
sulfite (20.00 g) was added at 0 °C, and the reaction mixture was allowed
to warm to room temperature. After stirring for 1 h, the mixture was
extracted with EtOAc. The combined organic extracts were washed with
brine, dried over MgSO4, and concentrated. The crude product was
purified by flash chromatography on silica gel (EtOAc/hexanes = 1:3) to
afford diol ent-6b (2.34 g, 63% over 2 steps) as a pale yellow solid: ee =
91% (HPLC column Chiralcel OD; injection amount 30 μL; sample
concentration 2 mg of diol/1 mL of mobile phase solvent; mobile phase
hexane/2-propanol (95/5 v/v); flow rate 1 mL/min); mp 54−55 °C;
(4S,5S)-(Z)-4-[2-(1,3-Dioxolan-2-yl-)3-methoxystyryl]-2,2,5-
trimethyl-1,3-dioxolane (11). A mixture of palladium acetate (6 mg,
0.027 mmol) and triphenylphosphine (28 mg, 0.1 mmol) in THF
(3 mL) was stirred at room temperature for 30 min. A solution of 4b
(30 mg, 0.13 mmol) in THF (1 mL), 3 (90 mg, 0.4 mmol) in THF
(1 mL), and a solution of K2CO3 (76 mg, 0.55 mmol) in water (1 mL)
were added to the above mixture. The reaction mixture was then heated
to 40 °C for 3 h. After cooling to room temperature, the mixture was
diluted with water. The aqueous layer was separated and extracted with
EtOAc. The combined organic extracts were dried over MgSO4, filtered,
and concentrated. The crude product was purified by flash
chromatography on silica gel (EtOAc/hexanes = 1:10) to afford 11
(35.1 mg, 81%) as a pale yellow oil: [α]25D = −181.6 (c 8.4, CHCl3); IR
(neat) νmax 2981, 2931, 2892, 1579, 1473, 1404, 1378, 1264, 1086, 1025,
957, 860, 757 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.28 (dd, J = 8.4,
7.4 Hz, 1H), 7.05 (d, J = 11.3 Hz, 1H), 6.87 (d, J = 7.4 Hz, 1H), 6.86 (d,
J = 8.4 Hz, 1H), 6.29 (s, 1H), 5.56 (dd, J = 11.3, 9.5 Hz, 1H), 4.17−4.08
(m, 3H), 3.98−3.95 (m, 2H), 3.84 (s, 3H), 3.83−3.79 (m, 2H), 1.43 (s,
3H), 1.36 (s, 3H), 1.11 (d, J = 6.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 158.7, 138.0, 135.1, 129.8, 126.7, 123.0, 122.6, 110.6, 108.2,
99.6, 78.9, 77.1, 65.5, 65.3, 55.9, 27.3, 27.2, 16.5; MS (EI) m/z (% base
peak) 320 (M+, 17), 276 (18), 245 (22), 205 (43), 186 (100), 174 (53),
161 (44), 146 (24), 115 (38), 73 (61); HRMS (EI) calcd for C18H24O5
320.1624, found 320.1621.
[α]25 = 5.4 (c 19.0, CHCl3); IR (neat) νmax 3365, 2976, 2925, 1618,
D
1
1373, 1265, 1132, 1036, 924, 870, 785 cm−1; H NMR (400 MHz,
CDCl3) δ 6.49 (d, J = 8.6 Hz, 1H), 4.12 (dd, J = 8.6, 6.6 Hz, 1H), 3.74
(dq, J = 6.6, 6.4 Hz, 1H), 2.50 (br s, 2H), 1.23 (d, J = 6.4 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 137.5, 93.3, 76.7, 69.8, 18.7; MS (EI) m/z
(% base peak) 258 (M+, 24), 256 (49), 254 (25), 243 (15), 217 (18),
215 (41), 213 (26), 199 (13), 177 (48), 175 (49), 137 (64), 135 (79),
119 (32), 117 (32), 96 (100), 58 (88); HRMS (EI) calcd for
C5H879Br2O2 257.8891, found 257.8894.
(1R,10S,11S)-3-Methoxy-11-methyl-12,13-dioxatricyclo-
[8.2.1.02,7]trideca-2(7),3,5,8-tetraene (12). To a stirred solution
of 11 (35 mg, 0.11 mmol) in benzene (10 mL) was added
p-toluenesulfonic acid monohydrate (6 mg, 0.033 mmol) at 70 °C for
1 h. After cooling to room temperature, the reaction mixture was
quenched with saturated aqueous NaHCO3. The aqueous layer was
separated and extracted with EtOAc. The combined organic extracts
were washed with brine, dried over MgSO4, filtered, and concentrated.
The crude product was purified by flash chromatography on silica gel
(EtOAc/hexanes = 1:10) to afford 12 (23 mg, 96%) as a colorless solid.
Analytically pure 12 was obtained by crystallization from CH2Cl2−
(3R,4R)-1,1-Dibromo-4-[(tert-butyldimethylsilyl)oxy]pent-1-
en-3-ol (13). To a stirred solution of ent-6b (1.0 g, 3.8 mmol) in
CH2Cl2 (15 mL) at −78 °C was added triethylamine (1.6 mL,
11.5 mmol) and TBSOTf (1.0 mL, 4.3 mmol). After stirring at −78 °C
for 3 h, the reaction mixture was diluted with water. The aqueous layer
was separated and extracted with CH2Cl2. The combined organic
extracts were washed with brine, dried over Mg2SO4, filtered, and
concentrated. The crude product was purified by flash chromatography
on alumina (EtOAc/hexanes = 1/30) to afford 13 (1.28 g, 89%) as a
colorless oil: [α]25D = −19.2 (c 25.4, CHCl3); IR (neat) νmax 3464, 2930,
hexane: mp 133−134 °C; [α]25 = −78.0 (c 10.0, CHCl3); IR (neat)
D
νmax 2965, 1580, 1466, 1269, 1243, 1196, 1058, 1016, 945, 871, 805, 747
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.21 (dd, J = 8.6, 7.6 Hz, 1H), 6.91
(s, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.81 (d, J = 8.6 Hz, 1H), 6.36 (d, J =
11.7 Hz, 1H), 6.10 (dd, J = 11.7, 5.1 Hz, 1H), 4.58 (dq, J = 6.1, 1.3 Hz,
1H), 4.44 (dd, J = 5.1, 1.3 Hz, 1H), 3.85 (s, 3H), 1.32 (d, J = 6.1 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 157.2, 135.7, 132.7, 130.9, 129.4, 127.8,
125.2, 110.8, 99.5, 85.3, 80.0, 56.0, 20.2; MS (EI) m/z (% base peak) 218
(M+, 2), 174 (100), 159 (20), 146 (52), 131 (46), 115 (8), 103 (26), 77
(15); HRMS (EI) calcd for C13H14O3 218.0943, found 218.0938.
(−)-Cladoacetal B (1b). A suspension of NaH (7 mg, 0.29 mmol) in
DMF (2 mL) was cooled to 0 °C, and EtSH (12 mg, 0.19 mmol) was
added. After stirring at 0 °C for 30 min, the 12 (20 mg, 0.09 mmol) in
DMF (2 mL) was added. The solution was heated to 120 °C for 3 h and
then cooled to room temperature. The reaction mixture was quenched
with water. The aqueous layer was separated and extracted with EtOAc.
The combined organic layers were washed with saturated aqueous
Na2S2O7, brine, dried over MgSO4, filtered, and concentrated. The
crude product was purified by flash chromatography on silica gel
(EtOAc/hexanes = 1:6) to afford cladoacetal B (1b) (17.6 mg, 74%) as a
pale yellow solid. Analytically pure 1b was obtained by crystallization
1
1619, 1471, 1377, 1257, 1067, 957, 836 cm−1; H NMR (400 MHz,
CDCl3) δ 6.45 (d, J = 8.1 Hz, 1H), 4.07−4.02 (m, 1H), 3.83−3.80
(m, 1H), 2.60 (d, J = 6.0 Hz, 1H), 1.21 (d, J = 6.0 Hz, 3H), 0.91 (s, 9H),
0.10 (s, 3H), 0.09 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 138.9, 91.6,
76.5, 70.8, 25.8, 20.0, 18.0, −4.3, −4.9; MS (ESI) m/z (% base peak) 375
(50), 373 (100), 371 (M+ − H, 53); HRMS (ESI) calcd for
C11H2179Br2O2Si (M+ − H) 370.9678, found 370.9689.
Formic Acid (R)-3,3-Dibromo-1-{(S)-1-[(tert-butyldimethyl-
silyl)oxy]ethyl}allyl Ester (14). To a stirred mixture of 13 (700 mg,
1.87 mmol) and triphenylphosphine (982 mg, 3.74 mmol) in toluene
(10 mL) was added a solution of diethyl azodicarboxylate (DEAD)
(0.6 mL, 3.74 mmol) and formic acid (0.14 mL) in toluene (10 mL)
dropwise at 0 °C. After stirring at 0 °C for 1 h, the reaction mixture was
quenched with saturated aqueous NaHCO3, and the aqueous layer was
separated and extracted with EtOAc. The combined organic layers were
washed with brine, dried over MgSO4, filtered, and concentrated. The
crude product was purified by flash chromatography on silica gel
(EtOAc/hexanes = 1:30) to afford 14 (565 mg, 75%) as a colorless oil:
[α]25D = 34.3 (c 30.4, CHCl3); IR (neat) νmax 2930, 2857, 1733, 1627,
1471, 1377, 1256, 1156, 1040, 940, 838, 777 cm−1; 1H NMR (400 MHz,
CDCl3) δ 8.05 (s, 1H), 6.51 (d, J = 8.7 Hz, 1H), 5.39 (dd, J = 8.7, 3.7 Hz,
1H), 4.02 (dq, J = 6.5, 3.7 Hz, 1H), 1.16 (d, J = 6.5 Hz, 3H), 0.89 (s, 9H),
0.07 (s, 3H), 0.06 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.7, 133.1,
95.3, 77.2, 68.8, 25.9, 25.7, 25.6, 19.5, 18.0, −4.7, −4.8; MS (EI) m/z
(% base peak) 400 (M+, 0.1), 353 (5), 250 (8), 205 (87), 189 (11), 176
from CH2Cl2−hexane: mp 220−221 °C; [α]25 = −173.1 (c 1.4,
D
MeOH); IR (neat) νmax 3296, 2970, 2925, 2853, 1581, 1464, 1290, 1118,
1054, 990, 958, 861, 806, 723 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.07
(dd, J = 8.0, 7.6 Hz, 1H), 6.88 (s, 1H), 6.81 (d, J = 7.6 Hz, 1H), 6.60 (d,
J = 8.0 Hz, 1H), 6.36 (d, J = 11.7 Hz, 1H), 6.08 (dd, J = 11.7, 5.1 Hz, 1H),
5.19 (br s, 1H), 4.60 (dq, J = 6.4, 1.2 Hz, 1H), 4.46 (dd, J = 5.1, 1.2 Hz,
1H), 1.32 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 153.2,
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(100), 161 (29), 147 (18), 133 (47), 118 (28), 104 (23), 91 (22), 77
(23); HRMS (EI) calcd for C12H2279Br2O3Si 399.9705, found 399.9708.
(4S,5R)-4-(2,2-Dibromovinyl)-2,2,5-trimethyl-1,3-dioxolane
(15). To a solution of 14 (500 mg, 1.2 mmol) in CH2Cl2 (10 mL) and
MeOH (10 mL) at room temperature was added camphorsulfonic
acid (CSA) (289 mg, 1.2 mmol) and 2,2-dimethoxypropane (6 mL,
48 mmol). After stirring at room temperature for 3 h, the reaction
mixture was quenched with saturated aqueous NaHCO3 and extracted
with EtOAc. The combined organic extracts were washed with brine,
dried over MgSO4, and concentrated. The crude product was purified by
flash chromatography on silica gel (EtOAc/hexanes = 1:20) to afford 15
separated and extracted with EtOAc. The combined organic extracts
were washed with brine, dried over MgSO4, filtered, and concentrated.
The crude product was purified by flash chromatography on silica gel
(EtOAc/hexanes = 1:10) to afford 17 (13 mg, 92%) as a pale yellow
solid. Analytically pure 17 was obtained by crystallization from
CH2Cl2−hexane: mp 103−105 °C; [α]25 = −172.2 (c 6.0, CHCl3);
D
IR (neat) νmax 2932, 1577, 1464, 1383, 1270, 1196, 1104, 1063, 966, 805,
746 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.20 (dd, J = 8.0, 7.6 Hz, 1H),
6.85 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.80 (s, 1H), 6.48 (d,
J = 11.8 Hz, 1H), 5.84 (dd, J = 11.8, 5.0 Hz, 1H), 4.63 (dd, J = 5.0, 4.6 Hz,
1H), 4.42 (dq, J = 6.2, 4.6 Hz, 1H), 3.82 (s, 3H), 1.34 (d, J = 6.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 157.1, 135.9, 132.4, 130.1, 129.5, 127.5,
(306 mg, 82%) as a colorless oil: [α]25 = −3.8 (c 40.0, CHCl3); IR
D
(neat) νmax 2985, 2933, 1613, 1455, 1380, 1218, 1174, 1092, 1040, 859,
766 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.46 (d, J = 8.7 Hz, 1H), 4.72
(dd, J = 8.7, 6.0 Hz, 1H), 4.40 (dq, J = 6.6, 6.0 Hz, 1H), 1.47 (s, 3H), 1.36
(s, 3H), 1.21 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 135.7,
108.9, 92.0, 79.2, 73.5, 28.1, 25.5, 15.2; MS (EI) m/z (% base peak) 287
(10), 285 (20), 283 (M+ − 15, 10), 258 (17), 256 (34), 254 (18), 243
(7), 213 (5), 199 (6), 177 (35), 175 (36), 135 (6), 119 (19), 117 (20),
96 (82), 58 (100); HRMS (EI) calcd for C8H1279Br2O2 297.9204, found
297.9203.
(4S,5R)-(Z)-4-(2-Bromovinyl)-2,2,5-trimethyl-1,3-dioxolane
(4a). To a flame-dried flask was added palladium acetate (22.4 mg,
0.1 mmol) and triphenylphosphine (105 mg, 0.4 mmol) in Et2O (5 mL).
The resulting solution was stirred for 30 min, and then a solution of 15
(300 mg, 1.0 mmol) in Et2O (5 mL) and tributyltin hydride (0.3 mL,
1.1 mmol) was added. The reaction mixture was stirred for 2 h and then
diluted with water. The aqueous layer was separated and extracted with
Et2O. The combined organic extracts were washed with brine, dried over
MgSO4, filtered, and concentrated. The crude product was purified by
flash chromatography on alumina (hexanes) to afford 4a (161 mg, 73%)
as a colorless oil: [α]25D = 29.3 (c 10.0, CHCl3); IR (neat) νmax 2985,
1621, 1455, 1380, 1259, 1085, 853, 802, 653 cm−1; 1H NMR (400 MHz,
CDCl3) δ 6.37 (dd, J = 7.3, 1.4 Hz, 1H), 6.19 (dd, J = 7.8, 7.3 Hz, 1H),
4.99 (ddd, J = 7.8, 6.4, 1.4 Hz, 1H), 4.44 (dq, J = 6.4, 6.1 Hz, 1H), 1.49 (s,
3H), 1.38 (s, 3H), 1.17 (d, J = 6.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 132.2, 110.2, 108.5, 77.2, 73.6, 28.2, 25.6, 15.6; MS (EI) m/z
(% base peak) 220 (M+, 0.02), 207 (9), 205 (9), 178 (7), 176 (7), 165
(3), 163 (3), 135 (2), 119 (1), 97 (23), 58 (100); HRMS (EI) calcd for
C8H1379BrO2 220.0099, found 220.0098.
125.5, 111.1, 98.7, 84.9, 78.0, 56.0, 13.6; MS (EI) m/z (% base peak) 218
(M+, 2), 174 (100), 159 (12), 146 (35), 131 (29), 115 (22), 103 (23), 91
(9), 77 (12); HRMS (EI) calcd for C13H14O3 218.0943, found 218.0939.
(−)-Cladoacetal A (1a). A suspension of NaH (5 mg, 0.21 mmol) in
DMF (2 mL) was cooled to 0 °C, and EtSH (9 mg, 0.14 mmol) was
added. After it was stirred at 0 °C for 30 min, 17 (15 mg, 0.07 mmol) in
DMF (2 mL) was added. The solution was heated to 120 °C for 3 h and
then cooled to room temperature. The reaction mixture was quenched
with water. The aqueous layer was separated and extracted with EtOAc.
The combined organic layers were washed with saturated aqueous
Na2S2O7, brine, dried over MgSO4, filtered, and concentrated. The
crude product was purified by flash chromatography on silica gel
(EtOAc/hexanes = 1:4) to afford cladoacetal A (1a) (12.8 mg, 91%) as a
colorless solid. Analytically pure 1a was obtained by crystallization from
CH2Cl2−hexane: mp 161−162 °C; [α]25D = −250.4 (c 1.4, MeOH); IR
(neat) νmax 3310, 2953, 2924, 2853, 1583, 1463, 1292, 1097, 957, 808,
749, 725 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.07 (dd, J = 8.0, 7.6 Hz,
1H), 6.82 (d, J = 7.6 Hz, 1H), 6.77 (s, 1H), 6.59 (d, J = 8.0 Hz, 1H), 6.48
(d, J = 12.0 Hz, 1H), 5.83 (dd, J = 12.0, 4.8 Hz, 1H), 5.24 (br s, 1H), 4.65
(dd, J = 4.8, 4.6 Hz, 1H), 4.43 (dq, J = 6.0, 4.6 Hz, 1H), 1.35 (d, J = 6.0
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 153.1, 136.3, 132.4, 129.9,
129.4, 125.8, 125.7, 115.9, 98.7, 84.7, 77.9, 13.6; MS (EI) m/z (% base
peak) 204 (M+, 2), 161 (11), 160 (100), 132 (55), 131 (32), 103 (10),
77 (12); HRMS (EI) calcd for C12H12O3 204.0786, found 204.0789.
(3S,4S)-1,1-Dibromo-4-[(tert-butyldimethylsilyl)oxy]pent-1-
en-3-ol (ent-13). To a stirred solution of 6b (1.0 g, 3.8 mmol) in
CH2Cl2 (15 mL) at −78 °C was added triethylamine (1.6 mL,
11.5 mmol) and TBSOTf (1.0 mL, 4.3 mmol). After stirring at −78 °C
for 3 h, the reaction mixture was diluted with water. The aqueous layer
was separated and extracted with CH2Cl2. The combined organic
extracts were washed with brine, dried over Mg2SO4, filtered, and
concentrated. The crude product was purified by flash chromatography
on alumina (EtOAc/hexanes = 1/30) to afford ent-13 (1.26 g, 88%) as a
colorless oil: [α]25D = 17.5 (c 28.0, CHCl3); IR (neat) νmax 3428, 2956,
(4S,5R)-(Z)-4-[2-(1,3-Dioxolan-2-yl)-3-methoxystyryl]-2,2,5-
trimethyl-1,3-dioxolane (16). A mixture of palladium acetate (6 mg,
0.027 mmol) and triphenylphosphine (28 mg, 0.1 mmol) in THF
(3 mL) was stirred at room temperature for 30 min. A solution of 4a
(20 mg, 0.09 mmol) in THF (1 mL), 3 (80 mg, 0.36 mmol) in THF (1 mL),
and a solution of K2CO3 (36.4 mg, 0.27 mmol) in water (1 mL) were
added to the above mixture. The reaction mixture was then heated to
40 °C for 3 h. After cooling to room temperature, the mixture was diluted
with water. The aqueous layer was separated and extracted with EtOAc.
The combined organic extracts were dried over MgSO4, filtered, and
concentrated. The crude product was purified by flash chromatography
on silica gel (EtOAc/hexanes = 1:10) to afford 16 (23.5 mg, 81%) as a
1
2887, 2859, 1622, 1462, 1257, 1143, 957, 785 cm−1; H NMR (400
MHz, CDCl3) δ 6.44 (d, J = 8.0 Hz, 1H), 4.04 (dd, J = 8.0, 4.8 Hz, 1H),
3.81 (dq, J = 6.0, 4.8 Hz, 1H), 2.57 (br s, 1H), 1.20 (d, J = 6.0 Hz, 3H),
0.90 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
138.9, 91.6, 76.5, 70.7, 25.7, 20.0, 18.0, −4.3, −4.9; MS (EI) m/z (% base
peak) 372 (M+, 0.01), 357 (13), 319 (46), 317 (51), 315 (46), 215 (48),
159 (60), 139 (35), 115 (49), 75 (100); HRMS (EI) calcd for
C11H2279Br2O2Si 371.9756, found 371.9756.
Formic Acid (S)-3,3-Dibromo-1-{(R)-1-[(tert-butyldimethyl-
silyl)oxy]ethyl}allyl Ester (ent-14). To a stirred mixture of ent-13
(500 mg, 1.33 mmol) and triphenylphosphine (701 mg, 2.7 mmol) in
toluene (10 mL) was added a solution of diethyl azodicarboxylate
(DEAD) (0.4 mL, 2.7 mmol) and formic acid (0.10 mL) in toluene (10
mL) dropwise at 0 °C. After stirring at 0 °C for 1 h, the reaction mixture
was quenched with saturated aqueous NaHCO3, and the aqueous layer
was separated and extracted with EtOAc. The combined organic layers
were washed with brine, dried over MgSO4, filtered, and concentrated.
The crude product was purified by flash chromatography on silica gel
(EtOAc/hexanes = 1:30) to afford ent-14 (414 mg, 77%) as a colorless
oil: [α]25D = −39.8 (c 21.6, CHCl3); IR (neat) νmax 2960, 2929, 2856,
1732, 1627, 1456, 1407, 1374, 1254, 1171, 1105, 1039, 940, 835, 777
cm−1; 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 6.51 (d, J = 8.7 Hz,
1H), 5.39 (dd, J = 8.7, 3.7 Hz, 1H), 4.02 (dq, J = 6.5, 3.7 Hz, 1H), 1.16
(d, J = 6.5 Hz, 3H), 0.89 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); 13C NMR
pale yellow oil: [α]25 = −39.2 (c 3.0, CHCl3); IR (neat) νmax 2982,
D
2933, 2889, 1579, 1472, 1379, 1263, 1215, 1065, 1024, 957, 853, 751
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.28 (dd, J = 8.3, 7.6 Hz, 1H), 6.98
(d, J = 11.5 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H),
6.28 (s, 1H), 5.67 (dd, J = 11.5, 9.8 Hz, 1H), 4.66 (dd, J = 9.8, 6.1 Hz,
1H), 4.21 (dq, J = 6.3, 6.1 Hz, 1H), 4.15−4.08 (m, 2H), 3.99−3.95 (m,
2H), 3.84 (s, 3H), 1.50 (s, 3H), 1.29 (s, 3H), 1.19 (d, J = 6.3 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 158.8, 138.2, 132.9, 129.9, 126.6, 122.8,
122.7, 110.6, 107.9, 99.7, 75.0, 74.3, 65.5, 65.4, 55.9, 28.5, 25.7, 15.9; MS
(EI) m/z (% base peak) 320 (M+, 40), 276 (32), 245 (23), 233 (24), 205
(59), 186 (100), 174 (74), 161 (64), 146 (34), 115 (48), 73 (75);
HRMS (EI) calcd for C18H24O5 320.1624, found 320.1627.
(1R,10S,11R)-3-Methoxy-11-methyl-12,13-dioxatricyclo-
[8.2.1.02,7]trideca-2(7),3,5,8-tetraene (17). To a stirred solution
of 16 (20 mg, 0.06 mmol) in benzene (10 mL) was added
p-toluenesulfonic acid monohydrate (4 mg, 0.023 mmol) at 70 °C for
1 h. After cooling to room temperature, the reaction mixture was
quenched with saturated aqueous NaHCO3. The aqueous layer was
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(100 MHz, CDCl3) δ 159.7, 133.1, 95.4, 77.2, 68.8, 25.9, 25.7, 19.6, 18.0,
−4.6, −4.8; MS (EI) m/z (% base peak) 400 (M+, 0.2), 383 (1), 353 (1),
251 (2), 207 (3), 191 (2), 177 (16), 161 (2), 133 (53), 117 (7), 103
(19), 89 (100), 73 (27); HRMS (EI) calcd for C12H2279Br2O3Si
399.9705, found 399.9709.
of ent-16 (50 mg, 0.16 mmol) in benzene (15 mL) was added
p-toluenesulfonic acid monohydrate (6 mg, 0.03 mmol) at 70 °C for
1 h. After cooling to room temperature, the reaction mixture was quenched
with saturated aqueous NaHCO3. The aqueous layer was separated and
extracted with EtOAc. The combined organic extracts were washed with
brine, dried over MgSO4, filtered, and concentrated. The crude product was
purified by flash chromatography on silica gel (EtOAc/hexanes = 1:10) to
afford ent-17 (29 mg, 85%) as a pale yellow solid. Analytically pure ent-17
was obtained by crystallization from CH2Cl2−hexane: mp 108−109 °C;
[α]25D = 177.2 (c 9.6, CHCl3); IR (neat) νmax 2961, 2921, 2866, 1578, 1464,
1381, 1269, 1101, 805 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.20 (dd, J =
8.1, 7.6 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.80 (s,
1H), 6.48 (d, J = 12.0 Hz, 1H), 5.84 (dd, J = 12.0, 5.0 Hz, 1H), 4.63 (dd, J =
5.0, 4.6 Hz, 1H), 4.42 (dq, J = 6.0, 4.6 Hz, 1H), 3.83 (s, 3H), 1.34 (d, J = 6.0
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 157.1, 135.9, 132.4, 130.1, 129.5,
127.5, 125.5, 111.1, 98.7, 84.9, 78.0, 56.0, 13.6; MS (EI) m/z (% base peak)
218 (M+, 0.7), 174 (100), 159 (23), 146 (86), 131 (56), 115 (29), 103 (30),
91 (1), 77 (8); HRMS (EI) calcd for C13H14O3 218.0943, found 218.0945.
(+)-Cladoacetal A (1a). A suspension of NaH (8 mg, 0.33 mmol) in
DMF (2 mL) was cooled to 0 °C and added EtSH (12 mg, 0.19 mmol).
After stirring at 0 °C for 30 min, ent-17 (20 mg, 0.09 mmol) in DMF
(2 mL) was added. The solution was heated to 120 °C for 3 h and then
cooled to room temperature. The reaction mixture was quenched with
water. The aqueous layer was separated and extracted with EtOAc. The
combined organic layers were washed with saturated aqueous Na2S2O7,
brine, dried over MgSO4, filtered, and concentrated. The crude product
was purified by flash chromatography on silica gel (EtOAc/hexanes =
1:4) to afford cladoacetal A (1a) (16.7 mg, 89%) as a colorless solid.
Analytically pure 1a was obtained by crystallization from CH2Cl2−
hexane: mp 159−160 °C; [α]25D = 255.2 (c 2.7, MeOH); IR (neat) νmax
3485, 2955, 2925, 1583, 1456, 1323, 1239, 1096, 956, 808, 727 cm−1; 1H
NMR (400 MHz, CDCl3) δ 7.05 (dd, J = 8.1, 7.6 Hz, 1H), 6.81 (d, J =
7.6 Hz, 1H), 6.77 (s, 1H), 6.55 (d, J = 8.1 Hz, 1H), 6.48 (d, J = 11.9 Hz,
1H), 5.83 (dd, J = 11.9, 5.0 Hz, 1H), 5.27 (br s, 1H), 4.65 (dd, J = 5.0, 4.7
Hz, 1H), 4.43 (dq, J = 6.4, 4.7 Hz, 1H), 1.35 (d, J = 6.4 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 153.1, 136.3, 132.4, 129.8, 129.4, 125.7,
125.6, 115.9, 98.7, 84.7, 78.0, 13.6; MS (EI) m/z (% base peak) 204 (M+,
0.7), 167 (5), 160 (100), 149 (11), 132 (50), 112 (6), 104 (6), 77 (4);
HRMS (EI) calcd for C12H12O3 204.0786, found 204.0789.
(4R,5S)-4-(2,2-Dibromovinyl)-2,2,5-trimethyl-1,3-dioxolane
(ent-15). To a solution of ent-14 (402 mg, 1.0 mmol) in CH2Cl2
(10 mL) and MeOH (10 mL) at room temperature was added
camphorsulfonic acid (CSA) (232 mg, 1.0 mmol) and 2,2-
dimethoxypropane (5 mL, 40 mmol). After stirring at room temperature
for 3 h, the reaction mixture was quenched with saturated aqueous
NaHCO3 and extracted with EtOAc. The combined organic extracts
were washed with brine, dried over MgSO4, and concentrated. The
crude product was purified by flash chromatography on silica gel
(EtOAc/hexanes = 1:20) to afford ent-15 (255 mg, 85%) as a colorless
oil: [α]25D = 7.6 (c 26.2, CHCl3); IR (neat) νmax 2991, 2937, 1623, 1458,
1379, 1217, 1089, 1043, 860, 764 cm−1; 1H NMR (400 MHz, CDCl3) δ
6.46 (d, J = 8.6 Hz, 1H), 4.71 (dd, J = 8.6, 6.1 Hz, 1H), 4.40 (dq, J = 6.4,
6.1 Hz, 1H), 1.47 (s, 3H), 1.35 (s, 3H), 1.21 (d, J = 6.4 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 135.7, 108.8, 92.0, 79.2, 73.5, 28.1, 25.5,
15.2; MS (EI) m/z (% base peak) 298 (M+, 4), 285 (12), 279 (12), 256
(14), 191 (10), 177 (18), 175 (11), 167 (24), 149 (100), 135 (8), 119
(12), 117 (12), 96 (27), 83 (24); HRMS (EI) calcd for C8H1279Br2O2
297.9204, found 297.9206.
(4R,5S)-(Z)-4-(2-Bromovinyl)-2,2,5-trimethyl-1,3-dioxolane
(ent-4a). To a flame-dried flask was added palladium acetate (22.4 mg,
0.1 mmol) and triphenylphosphine (105 mg, 0.4 mmol) in Et2O (4 mL).
The resulting solution was stirred for 30 min, and then a solution of ent-
15 (300 mg, 1.0 mmol) in Et2O (3 mL) and tributyltin hydride (0.3 mL,
1.1 mmol) was added. The reaction mixture was stirred for 2 h and then
diluted with water. The aqueous layer was separated and extracted with
Et2O. The combined organic extracts were washed with brine, dried over
MgSO4, filtered, and concentrated. The crude product was purified by
flash chromatography on alumina (hexanes) to afford ent-4a (159 mg,
72%) as a colorless oil: [α]25D = −27.6 (c 7.8, CHCl3); IR (neat) νmax
1
3092, 2974, 2929, 1375, 1214, 1027, 857, 647 cm−1; H NMR (400
MHz, CDCl3) δ 6.37 (d, J = 7.4 Hz, 1H), 6.19 (dd, J = 7.7, 7.4 Hz, 1H),
4.99 (dd, J = 7.7, 6.2 Hz, 1H), 4.44 (dq, J = 6.2, 6.2 Hz, 1H), 1.49 (s, 3H),
1.38 (s, 3H), 1.17 (d, J = 6.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
132.2, 110.1, 108.5, 77.2, 73.6, 28.2, 25.5, 15.6; MS (EI) m/z (% base
peak) 221 (M+ + H, 0.3), 207 (2), 205 (2), 193 (4), 191 (3), 167 (5),
165 (4), 163 (3), 149 (28), 127 (10), 125 (13), 123 (11), 111 (29), 97
(23), 83 (60), 57 (100); HRMS (EI) calcd for C8H1379BrO2 220.0099,
found 220.0098.
ASSOCIATED CONTENT
■
S
* Supporting Information
X-ray crystallographic data and CIF file for 1b, copies of 1H and
13C NMR for compounds 1, 3, 4, 6, 8, and 10−17. This material
is available free of charge via the Internet at http://pubs.acs.org.
(4R,5S)-(Z)-4-[2-(1,3-Dioxolan-2-yl)-3-methoxystyryl]-2,2,5-
trimethyl-1,3-dioxolane (ent-16). A mixture of palladium acetate
(10 mg, 0.045 mmol) and triphenylphosphine (47 mg, 0.18 mmol) in
THF (3 mL) was stirred at room temperature for 30 min. A solution of
ent-4a (50 mg, 0.22 mmol) in THF (2 mL), 3 (102 mg, 0.45 mmol) in
THF (2 mL), and a solution of K2CO3 (94 mg, 0.68 mmol) in water
(1.2 mL) were added to the above mixture. The reaction mixture was
then heated to 40 °C for 3 h. After cooling to room temperature, the
mixture was diluted with water. The aqueous layer was separated and
extracted with EtOAc. The combined organic extracts were dried over
MgSO4, filtered, and concentrated. The crude product was purified by
flash chromatography on silica gel (EtOAc/hexanes = 1:10) to afford
ent-16 (56.6 mg, 78%) as a pale yellow oil: [α]25D = 37.5 (c 2.6, CHCl3);
IR (neat) νmax 2981, 2890, 1581, 1463, 1260, 1073, 951, 746 cm−1; 1H
NMR (400 MHz, CDCl3) δ 7.27 (dd, J = 8.4, 7.6 Hz, 1H), 6.98 (d, J =
11.6 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 6.28 (s,
1H), 5.67 (dd, J = 11.6, 9.8 Hz, 1H), 4.66 (dd, J = 9.8, 6.1 Hz, 1H), 4.21
(dq, J = 6.4, 6.1 Hz, 1H), 4.15−4.08 (m, 2H), 3.99−3.95 (m, 2H), 3.83
(s, 3H), 1.50 (s, 3H), 1.28 (s, 3H), 1.19 (d, J = 6.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 158.7, 138.1, 132.9, 129.9, 126.6, 122.8, 122.6,
110.5, 107.8, 99.6, 74.9, 74.3, 65.5, 65.4, 55.8, 28.5, 25.7, 15.8; MS (EI)
m/z (% base peak) 320 (M+, 12), 276 (9), 245 (11), 233 (11), 205 (34),
186 (100), 174 (51), 161 (45), 146 (16), 115 (30), 73 (59); HRMS (EI)
calcd for C18H24O5 320.1624, found 320.1622.
AUTHOR INFORMATION
Corresponding Author
*E-mail: chedsh@ccu.edu.tw.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Dr. Gene-Hsiang Lee for the X-ray
crystallographic measurement. We thank the National Science
Council (NSC) of the Republic of China for financial support
(NSC 97-2113-M-194-011-MY2, NSC 99-2119-M-194-004-
MY2).
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