Total synthesis of buergerinin F and buergerinin G

Article abstract of DOI:10.1021/jo0341620

Syntheses of buergerinin F (1) and buergerinin G (2) were carried out to establish the absolute stereochemistry of these natural products. A linear sequence was used to synthesize 1 in 15 steps and 9percent overall yield from thymidine. Subsequent oxidation of 1 with ruthenium tetroxide afforded 2 in 77percent yield.

Full text of DOI:10.1021/jo0341620

CHART 1
Total Synthesis of Buergerinin F and
Buergerinin G
Jeong-Seok Han* and Todd L. Lowary*
Department of Chemistry, The Ohio State University,
Columbus, Ohio 43210
lowary.2@osu.edu
Received February 5, 2003
Abstract: Syntheses of buergerinin F (1) and buergerinin
G (2) were carried out to establish the absolute stereochem-
istry of these natural products. A linear sequence was used
to synthesize 1 in 15 steps and 9% overall yield from thy-
midine. Subsequent oxidation of 1 with ruthenium tetroxide
afforded 2 in 77% yield.
ethyl vinyl ether and p-TsOH. A 12:1 inseparable mixture
of diastereomers was formed. We also synthesized iso-
propylidene acetal 9 from 7 in good yield using standard
methods (2,2-dimethoxypropane, p-TsOH), thus produc-
ing a product with a nonstereogenic ketal carbon. How-
ever, the acetonide protecting group was not stable to a
subsequent transformation, and thus, we proceeded
instead from 8.
With a route to compound 8 in place, we continued
toward the targets by cleaving the silyl ether, affording
alcohol 10 in 92% yield. Subsequent treatment of 10 with
tosyl chloride and triethylamine afforded 11, which, when
exposed to n-Bu4NI, provided iodide 12. Reaction of 12
with vinylmagnesium bromide gave the allylfuran 13.
These transformations all proceeded efficiently, and the
conversion of 10 into 13 was achieved in 74% overall
yield. Attempts to synthesize allylfuran 13 directly from
tosylate 11 were unsuccessful.
In 2000, Zhu and co-workers reported1 the isolation of
two new natural products, buergerinin F (1) and buer-
gerinin G (2) (Chart 1), from Scrophularia buergeriana,
one of a number of Scrophularia species that are used
in Asian herbal medicine.2 To date, the biological activity
of these molecules has not been established. The struc-
tures and relative stereochemistry of these compounds
were determined using NMR spectroscopy and, in the
case of 2, X-ray crystallography. However, the absolute
stereochemistry of neither species was established. We
report here the first total syntheses of these natural
products, and establish that the stereochemistry is
1R,5S,8S in 1 and 1R,5R,8S in 2.
The final oxygen atom was introduced via a Wacker
oxidation. Thus, treatment4 of 13 with PdCl2, CuCl, and
O2 afforded the desired ketone 14 together with an
inseparable byproduct. In the 1H NMR spectrum of this
mixture of compounds, a small triplet at 9.76 ppm (J )
1.5 Hz) was present, which we attribute to aldehyde 15.
We could not, however, separate this byproduct as a pure
compound for characterization, and thus, we cannot
unequivocally prove its identity. If the assumption is
made that this byproduct is 15, an 8:1 mixture of ketone/
aldehyde was formed in the Wacker oxidation, in 64%
combined yield. A number of methods were explored,
unsuccessfully, for separation of these compounds by
chromatography. We also treated the mixture with
ethylene glycol and p-TsOH, but the resulting dioxolane
derivatives were still chromatographically inseparable.
We were, however, able to successfully separate these
compounds after reduction of the crude product with
sodium borohydride. At this stage, we obtained alcohol
16 as a single isomer5 in 70% yield. We could not,
however, isolate the reduced byproduct, presumably 17,
in quantities large enough for characterization.
Our synthesis of 1 and 2 (Scheme 1) began with the
known glycal 3, which was prepared in two steps and
65% yield from thymidine.3 Hydrogenation of the double
bond in 3 afforded alcohol 4, which was then oxidized
with pyridinium chlorochromate to provide 5 in 78% yield
over the two steps. Subsequent treatment of 5 with
vinylmagnesium bromide at -78 °C afforded tertiary
alcohol 6 in 94% yield. The stereochemistry at the
quaternary center in 6 was established by NOE experi-
ments. Irradiation of the vinyl group hydrogens gave
NOEs to hydrogens on both endocyclic methylene car-
bons. In addition, no NOE was observed between the
vinyl hydrogens and those attached to the exocyclic
methylene carbon. Taken together, these data point to
the vinyl substituent in 6 being oriented trans to the tert-
butyldiphenylsiloxymethyl group.
Having established the stereochemistry in 6, this
product was converted, in 96% yield, to diol 7 via
hydroboration. Protection of the diol as an ethylidene
acetal was achieved in 79% yield by reaction of 7 with
* To whom correspondence should be addressed (T.L.L.).
(1) Lin, S. J.; Jiang, S. H.; Li, Y. M.; Zeng, J. F.; Zhu, D. Y.
Tetrahedron Lett. 2000, 41, 1069.
With pure alcohol 16 in hand, the synthesis of 1 was
completed in two steps. First, alcohol 16 was oxidized
using pyridium chlorochromate, yielding ketone 14 in
91% yield. Finally, hydrolysis of the acetal in refluxing
(2) For example, see: (a) Kim, S. R.; Lee, K. Y.; Koo, K. A.; Sung, S.
H.; Lee, N. G.; Kim, J.; Kim, Y. C. J. Nat. Prod. 2002, 65, 1696. (b)
Qian, J.; Hunkler, D.; Rimpler, H. Phytochemistry 1992, 31, 905. (c)
Kim, S. R.; Kim, Y. C. Phytochemistry 2000, 54, 503 and references
therein.
(4) Tsuji, J.; Nagashima, H.; Nemoto, H. Org. Synth. 1984, 62, 9.
(5) We did not determine the stereochemistry at either the eth-
ylidene acetal or alcohol carbons.
(3) Cameron, M. A.; Cush, S. B.; Hammer, R. P. J. Org. Chem. 1997,
62, 9065.
10.1021/jo0341620 CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/22/2003
4116
J. Org. Chem. 2003, 68, 4116-4119

SCHEME 1a
a Reagents and conditions: (a) H2, Pd/C, CH3OH, rt, 87%; (b) PCC, NaOAc, CH2Cl2, rt, 90%; (c) vinylmagnesium bromide, THF, -78
°C, 94%; (d) 9-BBN, THF, 0 °C f rt, then NaOH, H2O2, 0 °C, 96%; (e) ethyl vinyl ether, p-TsOH, CH2Cl2, rt, 79%; (f) 2,2-dimethoxypropane,
p-TsOH, rt, 92%; (g) n-Bu4NF, THF, rt, 92%; (h) p-TsCl, Et3N, DMAP, CH2Cl2, 0 °C, 96%; (i) n-Bu4NI, toluene, rt, 77%; (j) vinylmagnesium
bromide, THF, 0 °C f rt, quantitative; (k) O2, PdCl2, CuCl, DMF, H2O, rt, 64%; (l) NaBH4, THF, rt, 70%; (m) PCC, NaOAc, CH2Cl2, rt,
91%; (n) HOAc, H2O, reflux, quantitative; (o) RuCl3‚H2O, NaIO4, NaHCO3, CCl4, acetonitrile, H2O, rt, 77%.
aqueous acetic acid afforded buergerinin F (1) in quan-
titative yield.6 Starting from thymidine, the target was
obtained in 9% overall yield in 15 steps. Oxidation of 1
with ruthenium tetroxide provided buergerinin G (2) in
77% yield.
We are unsure as to the origin of the high regioselec-
tivity observed in the oxidation of 1 to 2. Previous work7
on the mechanism of ruthenium tetroxide oxidation of
ethers has led to the proposal that the reaction proceeds
via a concerted mechanism (Figure 1), and that the
transition state is a five-membered ring adduct (e.g., 19)
involving the substrate and oxidant. We first speculated
that the oxidized carbon, C-3 in 1 (Chart 1), is more
accessible to the oxidant than C-7. However, molecular
mechanics calculations on 1 (data not shown) did not
show C-7 to be substantially more hindered than C-3. It
FIGURE 1. Proposed mechanism for RuO4 oxidation of ethers
(see ref 7).
is also possible that the necessary ring flattening that
must occur in the proposed transition state is more
readily accommodated in the furan ring containing C-3
than in the pyran ring containing C-7, which is part of a
rigid bicyclic framework.
The NMR spectra for both 1 and 2 closely matched
those previously reported1 for the natural products (see
the Supporting Information). The optical rotation mea-
sured for synthetic 1 ([R]D +39.1, c 0.9, CHCl3) was nearly
identical to that reported for the material isolated from
S. buergeriana ([R]D +40.67, c 0.431, CHCl3), thus
establishing the stereochemistry in 1 as 1R,5S,8S. The
(6) We also explored the possibility of preparing 1 directly from the
mixture of 14 and 15. Although we were successful in obtaining 1, the
material was contaminated with an inseparable byproduct, which we
believe is the cyclized product analogous to 1 that is produced from
15. In the 1H NMR spectrum of the product obtained from the
hydrolysis of the mixture of 14 and 15 was a small doublet of doublets
at 5.23 ppm (J ) 5.6, 2.4 Hz). We propose that this resonance arises
from the acetal hydrogen in the byproduct.
(7) (a) Bakke, J. M.; Frøhaug, A. E. J. Phys. Org. Chem. 1996, 9,
310. (b) Bakke, J. M.; Frøhaug, A. E. Acta Chem. Scand. 1995, 49,
615.
J. Org. Chem, Vol. 68, No. 10, 2003 4117

128.24 (2 C), 128.21 (2 C), 114.75, 83.61, 82.20, 67.40, 63.04,
41.93, 27.10 (3 C), 19.50; HRMS m/z calcd for [C23H30O3Si]Na+
405.1856, found 405.1866.
magnitude of the optical rotation measured for synthetic
2 ([R]D +33.2, c 1.0, CHCl3) matched the value reported
for the isolated natural product ([R]D +47.71, c 0.509,
CHCl3) less well. However, the signs of both rotations
are the same, and we therefore, propose that the stereo-
chemistry in 2 is 1R,5R,8S.
In conclusion, we describe here the first total syntheses
of buergerinin F (1) and buergerinin G (2) via a linear
route starting from thymidine. These syntheses allowed
us to not only confirm the proposed structures but also
identify the absolute configuration of these natural
products.
(2S,3R)-2-(tert-Butyldiphenylsilanyloxymethyl)-3-(2′-hy-
droxyethyl)tetrahydrofuran-3-ol (7). To a stirred solution of
6 (3.15 g, 8.23 mmol) in THF (15 mL) at 0 °C was added 9-BBN
(44.7 mL, 0.5 M solution in ether). The reaction mixture was
warmed to rt and stirred for 3 h before being cooled again to 0
°C. To this solution was added H2O (10 mL), followed by 2.5 M
NaOH (20 mL) and 30% H2O2 (15 mL). The reaction mixture
was stirred for 2 h and acidified with 0.3 M HCl. The product
was extracted into CH2Cl2, and the organic layer was succes-
sively washed with a saturated solution of NaHCO3 and brine
before being dried and concentrated. The product was purified
by chromatography (1:2 hexane/EtOAc) to give 7 as a white solid
(3.15 g, 96%), mp 75-77 °C: Rf 0.46 (1:2 hexane/ EtOAc); [R]D
+18.1 (c 0.9, CHCl3); 1H NMR (CDCl3, 400 MHz, δH) 7.74-7.66
(m, 4 H), 7.45-7.36 (m, 6 H), 4.08 (td, 1 H, J ) 8.4, 6.8 Hz),
4.02-3.92 (m, 3 H), 3.90-3.82 (m, 2 H), 3.56 (dd, 1 H, J ) 4.0,
3.4 Hz), 2.16 (ddd, 1 H, J ) 12.6, 6.8, 4.0 Hz), 2.06 (ddd, 1 H, J
) 14.3, 8.8, 4.4 Hz), 1.99 (ddd, 1 H, J ) 14.7, 12.6, 4.0 Hz), 1.69
(ddd, 1 H, J ) 14.4, 5.6, 3.6 Hz), 1.05 (s, 9 H); 13C NMR (CDCl3,
100.6 MHz, δC) 135.71 (2 C), 135.51 (2 C), 132.53, 132.18, 129.97,
129.92, 127.86 (2 C), 127.79 (2 C), 83.68, 82.80, 66.40, 63.47,
60.57, 40.28, 39.66, 26.71 (3 C), 19.06; HRMS m/z calcd for
[C23H32O4Si]Na+ 423.1962, found 423.1959.
Experimental Section
General Procedures. See ref 8.
(2S,3S)-2-(tert-Butyldiphenylsilanyloxymethyl)tet-
rahydrofuran-3-ol (4). Alkene 3 (1.56 g, 4.4 mmol) was dis-
solved in CH3OH (20 mL), and Pd/C (100 mg) was added. The
reaction mixture was stirred overnight under H2 and filtered
through Celite followed by rinsing with methanol. The crude
product was purified by chromatography (2:1 hexane/EtOAc) to
give 4 as a colorless syrup (1.37 g, 87%): Rf 0.32 (2:1 hexane/
1
EtOAc); [R]D +14.2 (c 1.0, CHCl3); H NMR (CDCl3, 400 MHz,
δH) 7.67-7.64 (m, 4 H), 7.44-7.35 (m, 6 H), 4.40 (quintet, 1 H,
J ) 3.1 Hz), 3.94 (dd, 2 H, J ) 8.4, 5.4 Hz), 3.82 (ddd, 1 H, J )
9.3, 4.0, 3.0 Hz), 3.75 (dd, 1 H, J ) 10.5, 4.2 Hz), 3.57 (dd, 1 H,
J ) 10.5, 6.2 Hz), 2.13 (dtd, 1 H, J ) 16.9, 8.4, 6.2 Hz), 1.87
(dtd, 1 H, J ) 13.0, 5.4, 3.2 Hz), 1.78 (br s, 1 H), 1.04 (s, 9 H);
13C NMR (CDCl3, 100.6 MHz, δC) 135.57 (2 C), 135.53 (2 C),
133.22, 133.15, 129.78, 129.75, 127.40 (2 C), 127.73 (2 C), 86.06,
74.27, 67.15, 64.76, 34.83, 26.82 (3 C), 19.20; HRMS m/z calcd
for [C21H28O3Si]Na+ 379.1700, found 379.1710.
(1S,5R)-1-(tert-Butyldiphenylsilanyloxymethyl)-7-meth-
yl-2,6,8-trioxaspiro[4.5]decane (8). To a stirred solution of 7
(520 mg, 1.3 mmol) in CH2Cl2 (10 mL) were added ethyl vinyl
ether (1.3 mL, 13.57 mmol) and p-TsOH (20 mg). After being
stirred for 24 h, the reaction mixture was diluted with CH2Cl2
and successively washed with a saturated aqueous solution of
NaHCO3 and brine before being dried and concentrated. The
product was purified by chromatography (3:1 hexane/EtOAc) to
give 8 as a colorless syrup (440 mg, 79%) as a 12:1 ratio of
1
(2S)-2-(tert-Butyldiphenylsilanyloxymethyl)dihy-
drofuran-3-one (5). A suspension of sodium acetate (8.59 g,
63.1 mmol), PCC (6.80 g, 31.6 mmol), and 4 Å molecular sieves
(4 g) in CH2Cl2 (200 mL) was stirred for 30 min, and then a
solution of 4 (3.75 g, 10.5 mmol) in CH2Cl2 (60 mL) was added.
The reaction mixture was stirred for 2 h, diluted with 1:1 ether/
hexane (300 mL), and stirred for 30 min. This suspension was
then filtered through Celite and further eluted with 1:1 ether/
hexane. The eluent was concentrated, and the residue was
purified by chromatography (4:1 hexane/EtOAc) to give 5 as a
white solid (3.34 g, 90%), mp 79-80 °C: Rf 0.37 (4:1 hexane/
isomers as determined by H NMR. Data for major isomer: Rf
0.34 (3:1 hexane/EtOAc); 1H NMR (CDCl3, 400 MHz, δH) 7.74-
7.70 (m, 4 H), 7.40-7.35 (m, 6 H), 4.81 (dd, 1 H, J ) 10.0, 5.0
Hz), 4.01-3.97 (m, 3 H), 3.84-3.73 (m, 3 H), 3.60 (dd, 1 H, J )
5.6, 5.2 Hz), 2.40 (ddd, 1 H, J ) 12.9, 7.5, 5.5 Hz), 2.15 (td, 1 H,
J ) 13.1, 5.3 Hz), 1.86 (ddd, 1 H, J ) 12.9, 8.1, 7.2 Hz), 1.42
(dd, 1 H, J ) 19.2, 5.7 Hz), 1.25 (d, 3 H, J ) 5.0 Hz), 1.06 (s, 9
H); 13C NMR (CDCl3, 100.6 MHz, δC) 135.67 (4 C), 133.75,
133.60, 129.50 (2 C), 127.58 (4 C), 93.94, 87.24, 81.33, 66.29,
64.26, 62.29, 34.39, 31.46, 26.82 (3 C), 21.22, 19.18; HRMS m/z
calcd for [C25H34O4Si]Na+ 449.2119, found 449.2114.
1
EtOAc); [R]D +61.0 (c 1.0, CHCl3); H NMR (CDCl3, 400 MHz,
(1S,5R)-1-(tert-Butyldiphenylsilanyloxymethyl)-7,7-di-
methyl-2,6,8-trioxaspiro[4.5]decane (9). To a stirred solution
of 7 (48 mg, 0.12 mmol) in 2,2-dimethoxypropane (3 mL) was
added p-TsOH (2 mg). The reaction mixture was stirred for 3 h,
and then worked up as described for the preparation of 8. The
product was purified by chromatography (2:1 hexane/EtOAc) to
give 9 as a colorless syrup (56 mg, 92%): Rf 0.52 (2:1 hexane/
δH) 7.69-7.62 (m, 4 H), 7.42-7.24 (m, 6 H), 4.50 (dt, 1 H, J )
8.8, 7.3 Hz), 4.25 (dt, 1 H, J ) 8.7, 7.6 Hz), 3.94 (dd, 1 H, J )
11.0, 2.8 Hz), 3.88 (dd, 1 H, J ) 11.0, 2.3 Hz), 3.84 (dd, 1 H, J
) 4.8, 2.2 Hz), 2.56 (t, 2 H, J ) 7.4 Hz), 1.00 (s, 9 H); 13C NMR
(CDCl3, 100.6 MHz, δC) 215.21, 135.63 (2 C), 135.57 (2 C), 132.95,
132.72, 129.80, 129.74, 127.75 (4 C), 80.37, 65.86, 64.44, 37.49,
26.67 (3 C), 19.16; HRMS m/z calcd for [C21H26O3Si]Na+ 377.1543,
found 377.1545.
1
EtOAc); [R]D +15.7 (c 1.0, CHCl3); H NMR (CDCl3, 400 MHz,
δH) 7.74-7.67 (m, 4 H), 7.42-7.34 (m, 6 H), 4.10-3.95 (m, 2 H),
3.89 (dd, 1 H, J ) 11.1, 4.0 Hz), 3.85-3.74 (m, 3 H), 3.57 (dd, 1
H, J ) 5.4, 4.2 Hz), 2.34 (ddd, 1 H, J ) 12.3, 7.7, 7.4 Hz), 2.04-
1.94 (m, 2 H), 1.45 (dt, 1 H, J ) 10.5, 3.0 Hz), 1.42 (s, 3 H), 1.29
(s, 3 H), 1.05 (s, 9 H); 13C NMR (CDCl3, 100.6 MHz, δC) 135.66
(2 C), 135.64 (2 C), 133.78, 133.67, 129.50, 129.47, 127.58 (2 C),
127.55 (2 C), 98.29, 87.82, 79.12, 66.54, 63.01, 57.42, 38.42, 31.92,
(2S,3S)-2-(tert-Butyldiphenylsilanyloxymethyl)-3-vinyltet-
rahydrofuran-3-ol (6). To a stirred solution of 5 (3.34 g, 9.4
mmol) in THF (30 mL) at -78 °C was added vinylmagnesium
bromide (18.8 mL, 1.0 M THF solution). The reaction mixture
was stirred for 2 h at -78 °C, and then a saturated aqueous
solution of NH4Cl (150 mL) was added before the solution was
extracted with ether. The organic layer was washed with brine,
dried, and purified by chromatography (3:1 hexane/EtOAc) to
give 6 as a colorless syrup (3.37 g, 94%): Rf 0.42 (3:1 hexane/
EtOAc); [R]D +3.0 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz,
δH) 7.72-7.65 (m, 4 H), 7.42-7.38 (m, 6 H), 5.92 (dd, 1 H, J )
17.1, 10.6 Hz), 5.54 (dd, 1 H, J ) 17.1, 1.5 Hz), 5.21 (dd, 1 H, J
) 10.6, 1.5 Hz), 4.25 (s, 1 H), 4.16 (ddd, 1 H, J ) 9.5, 8.0, 6.7
Hz), 4.00-3.88 (m, 3 H), 3.63 (dd, 1 H, J ) 4.2, 3.3 Hz), 2.11-
2.02 (m, 2 H) 1.04 (s, 9 H); 13C NMR (CDCl3, 100.6 MHz, δC)
140.87, 136.15 (2 C), 135.97 (2 C), 133.03, 132.65, 130.34 (2 C),
29.97, 26.81 (3 C), 24.44, 19.15; HRMS m/z calcd for [C26H36
-
O4Si]Na+ 463.2275, found 463.2270.
(1S,5R)-1-(Hydroxymethyl)-7-methyl-2,6,8-trioxaspiro-
[4.5]decane (10). To a stirred solution of 8 (420 mg, 0.98 mmol)
in THF (7 mL) was added n-Bu4NF (1.2 mL, 1.0 M THF
solution). The reaction mixture was stirred for 12 h and then
concentrated. The product was purified by chromatography (9:1
CH2Cl2/CH3OH) to give 10 as a white solid (170 mg, 92%), mp
52-54 °C. Data for major isomer: Rf 0.17 (1:6 hexane/EtOAc);
1H NMR (CDCl3, 400 MHz, δH) 4.81 (dd, 1 H, J ) 10.0, 5.0 Hz),
4.11-4.02 (m, 2 H), 3.91-3.75 (m, 4 H), 3.48 (t, 1 H, J ) 4.6
Hz), 2.52 (dd, 1 H, J ) 7.8, 4.5 Hz), 2.33 (td, 1 H, J ) 12.8, 7.3
Hz), 2.08 (td, 1 H, J ) 13.1, 5.3 Hz), 1.99 (ddd, 1 H, J ) 13.1,
(8) Gadikota, R. R.; Callam, C. S.; Lowary, T. L. J. Org. Chem. 2001,
66, 9046.
4118 J. Org. Chem., Vol. 68, No. 10, 2003

7.4, 5.9 Hz), 1.34 (td, 1 H, J ) 13.3, 1.8 Hz), 1.28 (d, 3 H, J )
5.0 Hz); 13C NMR (CDCl3, 100.6 MHz, δC) 94.38, 86.17, 83.45,
66.54, 64.14, 61.16, 34.94, 32.30, 21.29; HRMS m/z calcd for
[C9H16O4]Na+ 211.0941, found 211.0961.
(1R,5R)-1-(2′-Hydroxypropyl)-7-methyl-2,6,8-trioxaspiro-
[4.5]decane (16). A mixture of 14 and 15 (70 mg, 0.33 mmol)
was dissolved in THF (3 mL), and NaBH4 (50 mg, 1.32 mmol)
was added. The reaction mixture was stirred for 13 h, diluted
with CHCl3, successively washed with 0.1 M HCl, a saturated
aqueous solution of NaHCO3, and brine before being dried, and
concentrated. The product was purified by chromatography (1:4
hexane/EtOAc) to give 16 as a yellow oil (50 mg, 70%): Rf 0.28
(1S,5R)-1-(Tosyloxymethyl)-7-methyl-2,6,8-trioxaspiro-
[4.5]decane (11). To a stirred solution of 10 (810 mg, 4.30 mmol)
in CH2Cl2 (20 mL) at 0 °C were added Et3N (1.2 mL, 8.60 mmol),
DMAP (1.05 g, 8.60 mmol), and p-TsCl (2.46 g, 12.90 mmol).
After being stirred for 40 min at 0 °C, the reaction mixture was
diluted with CH2Cl2 and worked up as described for the
preparation of 8. The product was purified by chromatography
(1:1 hexane/EtOAc) to give 11 as a pale yellow syrup (1.41 g,
96%). Data for major isomer: Rf 0.55 (1:2 hexane/EtOAc); 1H
NMR (CDCl3, 400 MHz, δH) 7.80 (d, 2 H, J ) 8.3 Hz), 7.31 (d, 2
H, J ) 8.1 Hz), 4.74 (dd, 1 H, J ) 10.0, 5.0 Hz), 4.33 (dd, 1 H,
J ) 11.0, 3.2 Hz), 4.11 (dd, 1 H, J ) 11.0, 7.5 Hz), 4.02-3.94
(m, 2 H), 3.80-3.70 (m, 2 H), 3.67 (dd, 1 H, J ) 7.5, 3.2 Hz),
2.42 (s, 3 H), 2.34 (ddd, 1 H, J ) 13.0, 7.4, 5.7 Hz), 2.01 (td, 1 H,
J ) 13.1, 5.3 Hz), 1.86 (ddd, 1 H, J ) 13.0, 7.2, 6.8 Hz), 1.30
(ddd, 1 H, J ) 13.3, 2.1, 1.7 Hz), 1.18 (d, 3 H, J ) 5.0 Hz); 13C
NMR (CDCl3, 100.6 MHz, δC) 144.63, 133.15, 129.77 (2 C), 127.96
(2 C), 94.05, 84.30, 81.93, 69.08, 66.70, 63.99, 34.38, 31.35, 21.60,
21.02; HRMS m/z calcd for [C16H22O6S]Na+ 365.1029, found
365.1017.
1
(1:4 hexane/EtOAc); H NMR (CDCl3, 400 MHz, δH) 4.83 (dd, 1
H, J ) 10.0, 5.0 Hz), 4.10-3.99 (m, 3 H), 3.84-3.77 (m, 2 H),
3.55 (dd, 1 H, J ) 10.1, 2.7 Hz), 2.37 (ddd, 1 H, J ) 13.4, 7.8,
6.0 Hz), 1.97-1.87 (m, 2 H), 1.85-1.76 (m, 1 H), 1.69 (dt, 1 H,
J ) 14.9, 2.7 Hz), 1.30 (d, 3 H, J ) 5.0 Hz), 1.26 (dd, 1 H, J )
2.2, 1.6 Hz), 1.23 (d, 3 H, J ) 6.2 Hz), 1.20-1.13 (m, 1 H); 13C
NMR (CDCl3, 100.6 MHz, δC) 94.02, 87.45, 81.52, 67.74, 66.35,
64.20, 36.44, 33.98, 31.17, 23.54, 21.21; HRMS m/z calcd for
[C11H20O4]Na+ 239.1254, found 239.1236.
(1R,5R)-1-(2′-Oxopropyl)-7-methyl-2,6,8-trioxaspiro[4.5]-
decane (14). A suspension of sodium acetate (188 mg, 1.38
mmol), PCC (149 mg, 0.69 mmol), and 4 Å molecular sieves (100
mg) in CH2Cl2 (5 mL) was stirred for 30 min before the solution
of 16 (50 mg, 0.23 mmol) in CH2Cl2 (3 mL) was added. The
reaction mixture was stirred for 2 h, and then worked up as
described for the preparation of 5. The product was purified by
chromatography (1:4 hexane/EtOAc) to give 14 as a yellow oil
(45 mg, 91%). Data for major isomer: Rf 0.44 (1:4 hexane/EtOAc);
1H NMR (CDCl3, 400 MHz, δH) 4.82 (dd, 1 H, J ) 10.0, 5.0 Hz),
4.05-3.98 (m, 2 H), 3.92 (dd, 1 H, J ) 8.3, 4.0 Hz), 3.83-3.75
(m, 2 H), 2.80 (dd, 1 H, J ) 16.8, 8.3 Hz), 2.69 (dd, 1 H, J )
16.8, 4.0 Hz), 2.34 (ddd, 1 H, J ) 12.9, 7.6, 6.4 Hz), 2.22 (s, 3 H),
1.97-1.88 (m, 2 H), 1.28 (d, 3 H, J ) 5.0 Hz), 1.26-1.11 (m, 1
H); 13C NMR (CDCl3, 100.6 MHz, δC) 207.54, 94.02, 82.62, 81.44,
66.08, 64.16, 42.46, 34.33, 31.18, 31.02, 21.18; HRMS m/z calcd
for [C11H18O4]Na+ 237.109728, found 237.10964.
(1S,5R)-1-(Iodomethyl)-7-methyl-2,6,8-trioxaspiro[4.5]-
decane (12). To a stirred solution of 11 (1.41 g, 4.12 mmol) in
toluene (20 mL) was added n-Bu4NI (15.22 g, 41.20 mmol). The
reaction mixture was refluxed overnight, cooled, diluted with
ether (250 mL), and filtered. After concentration, the product
was purified by chromatography (2:1 hexane/EtOAc) to give 12
as a yellow oil (946 mg, 77%). Data for major isomer: Rf 0.52
1
(1:1 hexane/EtOAc); H NMR (CDCl3, 400 MHz, δH) 4.78 (dd, 1
H, J ) 10.0, 5.0 Hz), 4.05-4.00 (m, 2 H), 3.82-3.72 (m, 3 H),
3.36 (dd, 1 H, J ) 10.8, 3.2 Hz), 3.23 (dd, 1 H, J ) 10.8, 9.6 Hz),
2.40 (ddd, 1 H, J ) 13.2, 7.5, 6.0 Hz), 2.04 (td, 1 H, J ) 13.0, 5.3
Hz), 1.96 (ddd, 1 H, J ) 13.0, 7.9, 6.7 Hz), 1.30 (ddd, 1 H, J )
13.3, 2.2, 1.5 Hz), 1.25 (d, 3 H, J ) 5.0 Hz); 13C NMR (CDCl3,
100.6 MHz, δC) 94.15, 87.68, 81.48, 65.76, 64.01, 34.86, 31.82,
21.14, 2.91; HRMS m/z calcd for [C9H15O3I]Na+ 320.9958, found
320.9944.
Buergerinin F (1). Ketone 14 (40 mg, 0.19 mmol) was
dissolved in 80% acetic acid (5 mL), and the resulting solution
was stirred at 100 °C for 2 h. After cooling, the reaction mixture
was concentrated and the product was purified by chromatog-
raphy (6:1 f 1:1 hexane/EtOAc) to give 1 as a colorless oil (32
mg, 100%): Rf 0.43 (1:4 hexane/EtOAc); [R]D +39.1 (c 0.9, CHCl3)
(1R,5R)-1-Allyl-7-methyl-2,6,8-trioxaspiro[4.5]decane (13).
To a stirred solution of 12 (300 mg, 1.01 mmol) in THF (5 mL)
at 0 °C was added vinylmagnesium bromide (4.0 mL, 1. 0 M
THF solution). The reaction mixture was stirred for 7 h and
allowed to warm to rt. The reaction was worked up as described
for the preparation of 6. The product was purified by chroma-
tography (2:1 hexane/EtOAc) to give 13 as a colorless oil (200
mg, quantitative). Data for major isomer: Rf 0.54 (1:1 hexane/
EtOAc); 1H NMR (CDCl3, 400 MHz, δH) 5.91 (ddt, 1 H, J ) 17.1,
10.1, 7.0 Hz), 5.12 (ddd, 1 H, J ) 17.1, 3.4, 1.6 Hz), 5.04 (ddd, 1
H, J ) 10.5, 2.0, 1.0 Hz), 4.80 (dd, 1 H, J ) 10.0, 5.0 Hz), 4.04-
3.99 (m, 2 H), 3.80-3.68 (m, 2 H), 3.36 (dd, 1 H, J ) 7.2, 5.7
Hz), 2.39-2.30 (m, 3 H), 1.96 (td, 1 H, J ) 13.1, 5.3 Hz), 1.88
(ddd, 1 H, J ) 13.9, 8.1, 5.9 Hz), 1.27 (d, 3 H, J ) 5.0 Hz), 1.23
(ddd, 1 H, J ) 13.2, 2.1, 1.6 Hz); 13C NMR (CDCl3, 100.6 MHz,
δC) 135.92, 116.49, 93.93, 86.66, 81.20, 65.86, 64.21, 34.66, 32.91,
31.43, 21.21; HRMS m/z calcd for [C11H18O3]Na+ 221.1148, found
221.1127.
+
[lit.1 [R]D +40.67 (c 0.431, CHCl3)]; EI-MS m/z calcd for C9H14O3
170.093746, found 170.0946. The NMR data for this compound
closely matched those previously reported1 (see the Supporting
Information).
Buergerinin G (2). To a stirred solution of 1 (20 mg, 0.12
mmol) in 1:1:1 CCl4/acetonitrile/H2O (1.5 mL) were added sodium
bicarbonate (65 mg, 0.78 mmol) and sodium periodate (140 mg,
0.65 mmol). After 15 min of vigorous stirring, ruthenium chloride
hydrate (10 mg, 0.05 mmol) was added. Following 22 h of
stirring, brine was added and the product was extracted with
CH2Cl2. The organic layer was dried and concentrated, and the
product was purified by chromatography (1:4 hexane/EtOAc) to
give 2 as a white solid (17 mg, 77%): Rf 0.41 (1:4 hexane/ EtOAc);
[R]D +33.2 (c 1.0, CHCl3) [lit.1 [R]D +47.71 (c 0.509, CHCl3)];
EI-MS m/z calcd for C9H12O4+ 184.073011, found 184.0718. The
NMR data for this compound closely matched those previously
reported1 (see the Supporting Information).
(1R,5R)-1-(2′-Oxopropyl)-7-methyl-2,6,8-trioxaspiro[4.5]-
decane (14) and (1R,5R)-1-(3′-Formyloxyethyl)-7-methyl-
2,6,8-trioxaspiro[4.5]decane (15). A mixture of palladium
chloride (29 mg, 10 mol %) and cuprous chloride (164 mg, 1.66
mmol) in 3:1 DMF/H2O (4 mL) was stirred for 1 h under O2.
Alkene 13 (330 mg, 1.66 mmol) in DMF (2 mL) was added
dropwise. The reaction mixture was stirred for 24 h, poured into
a 3 M HCl solution, and extracted into ether. The organic layer
was successively washed with a saturated aqueous NaHCO3
solution and brine, before being dried, and concentrated. The
product was purified by chromatography (1:4 hexane/EtOAc) to
give 14 as a yellow oil together with a byproduct believed to be
aldehyde 15 (combined 230 mg, 64%).
Acknowledgment. This work was supported by the
National Institutes of Health and the National Science
Foundation.
Supporting Information Available: 1H and 13C NMR
spectra for all new compounds and tables comparing NMR
data for synthetic 1 and 2 vs those isolated from S. buergeri-
ana. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO0341620
J. Org. Chem, Vol. 68, No. 10, 2003 4119