Synthetic approach to analogues of the original structure of sclerophytin A

Article abstract of DOI:10.1021/jo016246j

A route to analogues of the original structure of sclerophytin A is described. The β-anomer of dideoxyribosyl nitriles 10a,b (prepared from glutamic acid) was converted into the methyl ketone 11. Addition of a silylated acetylide to 11 in diethyl ether/trimethylamine gave mainly 22a. Alkylation with methallyl halide and ozonolysis gave the ketone 24, which was then converted by hydrogenation and a second ozonolysis into the keto aldehyde 26. A two-step aldol process afforded the desired 3-pyrone 27 in good overall yield. However, several methods for the conversion of this enone 27 into the desired sclerophytin analogue 2 failed.

Full text of DOI:10.1021/jo016246j

posite enone 5 that would be produced from the furfuryl
alcohol 6. We describe herein the utilization of this route
to give the desired tricyclic core 2 and related derivatives.
Syn th etic Ap p r oa ch to An a logu es of th e
Or igin a l Str u ctu r e of Scler op h ytin A
Michael E. J ung* and J oseph Pontillo
Department of Chemistry and Biochemistry,
University of California, Los Angeles, 405 Hilgard Avenue,
Los Angeles, California 90095-1569
jung@chem.ucla.edu
Received October 29, 2001
Abstr a ct: A route to analogues of the original structure of
sclerophytin A is described. The â-anomer of dideoxyribosyl
nitriles 10a ,b (prepared from glutamic acid) was converted
into the methyl ketone 11. Addition of a silylated acetylide
to 11 in diethyl ether/trimethylamine gave mainly 22a .
Alkylation with methallyl halide and ozonolysis gave the
ketone 24, which was then converted by hydrogenation and
a second ozonolysis into the keto aldehyde 26. A two-step
aldol process afforded the desired 3-pyrone 27 in good overall
yield. However, several methods for the conversion of this
enone 27 into the desired sclerophytin analogue 2 failed.
The synthesis of the alcohol 6 began with the known
lactone acid5 7, which was reduced with borane followed
by protection of the alcohol6 as a tert-butyldiphenylsilyl
ether to give the known lactone7 8 in 90% yield over 2
steps. This was reduced to the lactol and subsequent
acetylation gave a 1:1 mixture of the crude anomeric
acetates 9 in 92% yield over 2 steps. The acetate mixture
was treated with trimethylsilyl cyanide in the presence
of catalytic tin(IV) chloride to produce, in 94% yield, a
1:1 mixture of the cyanotetrahydrofurans 10a and 10b
which was separable by column chromatography. The
structure of the cyanide 10a was confirmed by desilyl-
ation and benzoylation to give the known cyanobenzoate.8
A number of conditions, e.g., several Lewis acids and
Brønsted acids and bases that could potentially isomerize
the undesired isomer 10a to a mixture of isomers, failed.
Reexposure to the original reaction conditions (TMSCN,
SnCl4) led only to decomposition of the substrate. For-
tunately, since column chromatography was necessary
only once in the high-yielding, six-step sequence, the
desired cyanide 10b could be prepared in multigram
quantities. The cyanide was treated with methylmagne-
sium iodide, and subsequent hydrolysis of the resulting
imine provided the desired ketone 11 in 83% yield. Initial
experiments showed that the addition of 5-lithio-2-
methylfuran 12 to the ketone 11 at low temperature
resulted in the Cram chelation-controlled addition9 to
give a 3:1 mixture of the unstable furyl alcohols 13a ,b.
Octocorals have produced an array of structurally
intriguing and biologically active oxacyclic diterpenes.1
Among the large family of 2,11-cyclized cembranoid
ethers is the subclass cladiellins, which contain men-
thane-type cyclohexene rings cis-fused to 11-oxabicyclo-
[6.2.1]undecane systems. Sharma and co-workers isolated
a unique member of the cladiellin family, sclerophytin
A, from the marine soft coral Sclerophytum capitalis,
which exhibited strong cytotoxicity against the L1210 cell
line (1.0 ng/mL) and which was assigned the novel
tetracyclic diterpene structure 1.2 Because of its intrigu-
ing structure and potent cytotoxicity, we became inter-
ested in developing an efficient synthesis of this molecule
and simpler derivatives, e.g., the tricyclic core 2 contain-
ing most of the functionality of the parent molecule.
Although two groups have since successfully synthesized
this important molecule3 and have revised the structure
of sclerophytin A to that shown in structure 3,4 neverthe-
less we think that our route offers an interesting ap-
proach to this unique compound. We hypothesized that
the desired tricyclic analogue 2 could be obtained by an
internal alkylation of the enone anion with a properly
positioned leaving group X, as in 4. The enone would then
be available by functional group transposition of the op-
A model system was then employed in which the anion
of 2-methylfuran 12 was added to acetone. The crude
furyl alcohol 14 thus obtained was treated with tert-butyl
hydroperoxide in the presence of catalytic vanadyl aceto-
acetonate, which resulted in epoxidation and rearrange-
ment10 to give, after hemiketal formation, the pyranone
15. On treatment with methanol and catalytic acid, the
(1) Reviews: (a) Coll, J . C. Chem. Rev. 1992, 92, 613. (b) Wahlberg,
I.; Eklund, A.-M. In Progress in the Chemistry of Organic Natural
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(2) Sharma, P.; Alam, M. J . Chem. Soc., Perkin Trans. 1 1988, 2537.
(3) (a) Paquette, L. A.; Moradei, O. M.; Bernardelli, P.; Lange, T.
Org. Lett. 2000, 2, 1875. (b) Overman, L. E.; Pennington, L. D. Org.
Lett. 2000, 2, 2683.
(5) (a) Rouessac, F. P.; Gringore, O. H. Organic Syntheses; Wiley:
New York, 1984; Vol. 63, p 121. (b) Also commercially available from
Aldrich.
(6) Ravid, U.; Silverstein, R. M.; Smith, L. R. Tetrahedron 1978,
34, 1449.
(7) Hanessian, S.; Abad-Grillo, T.; McNaughton-Smith, G. Tetra-
hedron 1997, 53, 6281.
(8) Trifunovic, I. D. Ph.D. Dissertation, University of California,
Los Angeles, 1992.
(4) (a) Friedrich, D.; Doskotch, R. W.; Paquette, L. A. Org. Lett.
2000, 2, 1879. (b) Gallou, F.; MacMillan, D. W. C.; Overman, L. E.;
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10.1021/jo016246j CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/29/2002
6848
J . Org. Chem. 2002, 67, 6848-6851

pyranone 16 was formed in 90% yield over 3 steps. It was
then transposed to pyranone 18, e.g., by enone epoxida-
tion and Wharton fragmentation,11 to give the allylic
alcohol 17, followed by oxidation and ketal reduction to
yield the pyranone 18. Thus the pyranone 16 was treated
Since the addition of 12 to 11 had proceeded with rea-
sonable diastereoselectivity, other nucleophilic organo-
metallic reagents were considered. Addition of lithium
(trimethylsilyl)acetylide to 11 in THF proceeded in low
yield (<50%) and with no diastereoselectivity to furnish
a 1:1 mixture of the propargylic alcohols. The results did
not improve by using the Grignard reagent, changing the
solvent, or adding various Lewis acids. However, the
reaction of lithium (trimethylsilyl)acetylide in (1:1 diethyl
ether/trimethylamine), as described by Carreira and
Dubois,14 dramatically improved the diastereoselectivity
to 3:1 in favor of the chelation-controlled product 22a .
In addition, use of the corresponding organocerium
reagent15 in the mixed solvent system greatly improved
the nucleophilicity without compromising the diastereo-
selectivity of the reaction. Thus a separable 3:1 mixture
of the propargylic alcohols 22a and 22b was obtained in
86% yield after desilylation.
We next explored methods to functionalize the alkyne
or alcohol moieties of 22a to assemble the desired
pyranone system. Our success was limited to the meth-
allylation of the lithium alkoxide of 22a with methallyl
iodide (generated in situ) to give the ether 23 in 73%
yield. Attempted O-alkylation with other reagents (e.g.,
2-iodo-3-butanone or 2-iodo-3-methyl-3-butene) was un-
successful, presumably due to the sterically encumbered
nature of the propargylic alcohol. Chemoselective reduc-
tion of the alkyne in 23 was thwarted by competing
reduction of the terminal olefin. Thus a slightly longer
route was undertaken in which 23 was first subjected to
ozonolysis to give the keto alkyne 24 in 98% yield.
Catalytic hydrogenation afforded the keto alkene 25 in
89% yield. A second ozonolysis provided the unstable keto
aldehyde 26, which was immediately subjected to mild
aldol conditions16 and elimination to give the enone 27
in excellent yield (82%, 3 steps).
with hydrogen peroxide and base to provide the epoxide
19 as a single diastereomer in 85% yield. The stereo-
chemical assignment is based on a presumed antiparallel
nucleophilic attack on the anomerically locked conformer
I via a chairlike transition state via the Valls and
Toromanoff model.12 This assignment was later confirmed
by NMR analysis of the reduced alcohols and mesylates.
Surprisingly, reaction with hydrazine gave none of the
expected Wharton fragmentation product 17. Steric
hindrance about the ketone led to an alternate pathway
in which hydrazine acted as a base, causing â-elimination
and epoxide opening to give the enol 20 in 67% yield. The
epoxy ketone 19 was thus reduced with DIBAL to provide
an inseparable 5:1 mixture of the epoxy alcohols, which
were transformed to the mesylates 21a and 21b in good
yield. The mesylates were next treated with a variety of
reagents in the hope of inducing a mesylate reduction-
fragmentation sequence13 to afford 17. However, all our
attempts were unsuccessful, resulting in no reaction or
decomposition of the substrate.
(9) (a) Cram, D. J .; Abd Elhafez, F. A. J . Am. Chem. Soc. 1952, 74,
5828. (b) Cram, D. J .; Kopecky, K. R. J . Am. Chem. Soc. 159, 81, 2748.
(c) Cram, D. J .; Wilson, D. R. J . Am. Chem. Soc. 1963, 85, 1245. See
also: (d) Nakata, T.; Schmid, G.; Vranesic, B.; Okigawa, M.; Smith-
Palmer, T.; Kishi, Y. J . Am. Chem. Soc. 1978, 100, 2933. (e) Schmid,
G.; Fukuyama, T.; Akasaka, K.; Kishi, Y. J . Am. Chem. Soc. 1979, 101,
259. (f) Fukuyama, T.; Wang, C.-L. J .; Kishi, Y. J . Am. Chem. Soc.
1979, 101, 260. (g) Fukuyama, T.; Akasaka, K.; Karanewsky, D. S.;
Wang, C.-L. J .; Schmid, G.; Kishi, Y. J . Am. Chem. Soc. 1979, 101,
262.
(10) (a) Cavill, G. W.; Laing, D. G.; Williams, P. J . Aust. J . Chem.
1969, 22, 2145. (b) Achmatowicz, O.; Bukowski, P.; Szechner, B.;
Zwierzhowska, Z.; Zamojski, A. Tetrahedron 1971, 27, 1973. (c)
Lefebvre, Y. Tetrahedron Lett. 1972, 133. (d) Piancetelli, G.; Scettri,
A.; D’Auria, M. Tetrahedron Lett. 1977, 2199. (e) Piancetelli, G.; Scettri,
A.; D’Auria, M. Synthesis 1982, 245. (f) Georgiadis, M. P.; Lefebvre,
Y. Chim. Chron. 1983, 12, 45; Chem. Abstr. 1983, 99, 194770p. (g) Ho,
T.-L.; Sapp, S. G. Synth. Commun. 1983, 13, 207. (h) Antonioletti, R.;
Arista, L.; Bonadies, F.; Locati, L.; Scettri, A. Tetrahedron Lett. 1993,
34, 7089.
At this point it was necessary to install the methyl
group at the R-position of the pyranone system of 27 to
give 28. Surprisingly, treatment of 27 with a variety of
bases (e.g. LDA, LiHMDS, NaH) and methyl iodide only
(12) (a) Valls, J . Bull. Soc. Chim. Fr. 1961, 432. (b) Valls, J .;
Toromanoff, E. Bull. Soc. Chim. Fr. 1961, 758.
(13) (a) Yasuda, A.; Yamamoto, H.; Nozaki, H. Bull. Chem. Soc.
J pn. 1979, 52, 1757. (b) Attempted reagents: calcium/ammonia,
sodium naphthalide, sodium-mercury amalgam, samarium(II) iodide,
magnesium/mercury(II) chloride, and zinc/sodium iodide.
(11) Wharton, P. S.; Bohlen, D. J . Org. Chem. 1961, 26, 3615.
(14) Carreira, E. M.; Du Bois, J . Tetrahedron Lett. 1995, 36, 1209.
J . Org. Chem, Vol. 67, No. 19, 2002 6849

were isolated as a pale yellow oil, and used without further
purification.
led to decomposition. We then attempted to form the
corresponding silyl enol ether with TMSOTf in the
presence of triethylamine.17 Most of the substrate de-
composed but crude NMR and IR analysis clearly re-
vealed that an aldehyde moiety was present. It is possible
that an electrocyclic rearrangement of the intermediate
enol ether (or enolate) II gave the unstable aldehyde III,
which rapidly decomposed. This implied that the key
(2R,5S)-5-([(1,1-Dim eth yl)eth yldiph en ylsilyl]oxym eth yl)-
tetr a h yd r ofu r a n -2-ca r bon itr ile (10a ) a n d (2S,5S)-5-([(1,1-
Dim eth yl)eth yld ip h en ylsilyl]oxym eth yl)tetr a h yd r ofu r a n -
2-ca r bon itr ile (10b). To an ice-cold solution of acetates 9 (3.98
g, 9.59 mmol) in 75 mL of dichloromethane was added tri-
methylsilyl cyanide (TMSCN, 1.40 mL, 10.6 mmol), followed by
tin(IV) chloride (0.28 mL, 2.4 mmol). The solution was stirred
at 0 °C for 30 min, then quenched with ice-cold water (35 mL)
and diluted with dichloromethane (150 mL). The aqueous layer
was extracted with dichloromethane (2 × 150 mL), and the
combined extracts were washed with saturated aq NaHCO3 (150
mL) and brine (150 mL), dried over MgSO4, and evaporated to
give a yellow oil. Column chromatography on silica gel (15%
Et2O/hexane) gave cyanide 10a (1.74 g) as a colorless oil, followed
by cyanide 10b (1.70 g) as a white solid (combined yield 94%).
20
Cyanide 10a : [R]D 6° (c 3.3, CH2Cl2); IR (neat) 3071, 3049,
2957, 2932, 2891, 2859, 1472, 1428, 1391, 1190, 1113, 1074, 997,
alkylative cyclization step of the synthesis would be
compromised due to a competing electrocyclic rearrange-
ment. Hydrogenation and desilylation of 27 gave the
hydroxy dihydropyranone 30 (via 29) in 89% yield. But
all attempts at forming the enolate or enamine, e.g., the
morpholine enamine of the mesylate 31, gave no tricyclic
material, e.g., 32, but only decomposition. Thus we were
forced to abandon this route to the tricyclic core, namely
the alcohol 2.
823, 743, 704, 621 cm-1 1H NMR (CDCl3, 400 MHz) δ 7.80-
;
7.68 (m, 4H), 7.53-7.39 (m, 6H), 4.79 (dd, J ) 7.3, 3.4 Hz, 1H),
4.40-4.32 (m, 1H), 3.79 (dd, J ) 11.0, 4.0 Hz, 1H), 3.70 (dd, J
) 11.0, 4.0 Hz, 1H), 2.46-2.01 (m, 4H), 1.13 (s, 9H); 13C NMR
(CDCl3, 101 MHz) δ 135.7, 133.3, 129.8, 127.9, 119.5, 80.8, 67.0,
20
65.5, 31.7, 26.9, 26.6, 19.3. Cyanide 10b: mp 63-64 °C; [R]D
-25° (c 8.2, CH2Cl2); IR (neat) 3073, 2959, 2930, 2859, 1473,
1429, 1390, 1361, 1190, 1113, 1072, 997, 885, 601 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 7.73-7.67 (m, 4H), 7.46-7.38 (m, 6H), 4.69
(dd, J ) 7.4, 4.2 Hz, 1H), 4.21-4.13 (m, 1H), 3.76 (d, J ) 4.8
Hz, 2H), 2.39-2.21 (m, 2H), 2.15-2.01 (m, 2H), 1.10 (s, 9H);
13C NMR (CDCl3, 101 MHz) δ 135.7, 133.3, 129.8, 127.8, 119.5,
82.0, 66.5, 65.6, 32.0, 27.4, 26.8, 19.3; HRMS (CI) m/e ((M +
NH4)+) calcd for C22H31O2SiN2 383.2155, found 383.2145.
(2R,5S)-2-(1-Oxoeth yl)-5-([(1,1-d im eth yl)eth yld ip h en yl-
silyl]oxym eth yl)tetr a h yd r ofu r a n (11). To cyanide 10b (0.681
g, 1.86 mmol) in diethyl ether (12 mL) at 0 °C was added drop-
wise over 30 min methylmagnesium iodide (3.0 M in Et2O, 1.9
mL, 5.7 mmol). The mixture was stirred for an additional 5.5 h,
then treated with hydrochloric acid (1.2 M) until the mixture
was acidic (pH 2). The layers were separated, and the aqueous
layer was extracted with diethyl ether (3 × 5 mL). The combined
extracts were washed with water (2 × 15 mL) and brine (2 × 15
mL), dried over MgSO4, evaporated, and subjected to chroma-
tography on silica gel (dichloromethane) to provide ketone 11
In conclusion, we have developed an interesting method
for the production of bicyclic analogues of the original
structure of sclerophytin A and a novel synthesis of
3-pyranones.
Exp er im en ta l Section
20
(0.589 g, 83%) as a pale yellow oil. [R]D 37° (c 6.5, CH2Cl2); IR
(2RS,5S)-2-Acet yloxy-5-([(1,1-d im et h yl)et h yld ip h en yl-
silyl]oxym eth yl)tetr a h yd r ofu r a n (9). To lactone 87 (10.1 g,
28.5 mmol) in dichloromethane (120 mL) cooled to -78 °C was
added dropwise over 1.5 h diisobutylaluminum hydride (1.0 M
in dichloromethane, 34 mL, 34 mmol). The solution was stirred
for an additional 0.5 h at -78 °C, then quenched with methanol
(30 mL) and warmed to room temperature. The mixture was
diluted with saturated aq NaHCO3 (250 mL), separated, and
extracted with dichloromethane (4 × 150 mL). The combined
extracts were washed with brine (2 × 200 mL), dried over
MgSO4, and concentrated to give the lactols as viscous, colorless
oil (10.1 g, 100%), which was used without further purification.
To a mixture of the lactols (5.15 g, 14.4 mmol), triethylamine
(4.5 mL, 32 mmol), and DMAP (268 mg, 2.2 mmol) in dichloro-
(neat) 3072, 2959, 2859, 1717, 1473, 1428, 1391, 1357, 1113,
1068, 1006, 824, 743, 704, 609 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 7.72-7.66 (m, 4H), 7.47-7.36 (m, 6H), 4.79 (dd, J ) 9.9, 7.2
Hz, 1H), 4.19-4.12 (m, 1H), 3.79-3.70 (m, 2H), 2.21 (s, 3H),
2.22-2.08 (m, 1H), 2.03-1.92 (m, 2H), 1.89-1.78 (m, 1H), 1.07
(s, 9H); 13C NMR (CDCl3, 101 MHz) δ 210.8, 135.6, 133.4, 129.8,
127.7, 84.4, 81.2, 65.8, 28.9, 27.4, 26.9, 26.1, 19.3; HRMS (CI)
m/e ((M + H)+) calcd for C23H31O3Si 383.2042, found 383.2039.
(rS,2R,5S)-r-E t h yn yl-r-m et h yl-5-([(1,1-d im et h yl)et h yl-
diph en ylsilyl]oxym eth yl)tetr ah ydr ofu r an -2-m eth an ol (22b)
a n d (rR,2R,5S)-r-Eth yn yl-r-m eth yl-5-([(1,1-d im eth yl)eth -
yld ip h en ylsilyl]oxym et h yl)t et r a h yd r ofu r a n -2-m et h a n ol
(22a ). Anhydrous cerium(III) chloride powder (58.0 mg, 0.235
mmol) was stirred in THF (0.5 mL) for 2 h. The THF was
removed in vacuo, and the flask was back-filled with argon and
cooled to -78 °C. An ice-cold, 1:1 mixture of diethyl ether/
methane (25 mL) was added dropwise over
5 min acetic
anhydride (1.65 mL, 17 mmol). The solution was stirred for 3 h,
then evaporated. The residue was dissolved in ethyl acetate (100
mL), washed with saturated aq NH4Cl (75 mL), and separated.
The aqueous layer was extracted with ethyl acetate (2 × 50 mL),
and the combined extracts were washed with brine (2 × 100 mL),
dried over MgSO4, and evaporated. The acetates 9 (5.7 g, 98%)
trimethylamine (0.5 mL) was added. In
a separate flask,
n-butyllithium (1.80 M in hexanes, 0.130 mL, 0.235 mmol) was
added to trimethylsilylacetylene (33 µL, 0.235 mmol) in 1:1
diethyl ether/trimethylamine (0.5 mL) at -78 °C, stirred for 30
min, then warmed to 0 °C. The lithium trimethylsilylacetylide
solution thus formed was transferred via cannula to the ceri-
um(III) chloride suspension. The whole mixture was warmed to
0 °C, stirred for 20 min, then recooled to -78 °C. An ice-cold
solution of ketone 11 (36 mg, 0.094 mmol) in 1:1 diethyl ether/
trimethylamine (0.5 mL) was added, and the whole mixture was
stirred at -78 °C for 2 h. A spatula tip of NH4Cl was then added,
and the mixture was warmed to 21 °C. Diethyl ether (5 mL)
and water (2 mL) were added, and the mixture was separated.
(15) (a) Imamoto, T.; Sugiura, Y.; Takiyama, N. Tetrahedron Lett.
1984, 25, 4233. (b) Imamoto, T.; Kusumoto, T.; Tawarayama, Y.;
Sugiura, Y.; Mita, T.; Hatanaka, Y.; Yokoyama, M. J . Org. Chem. 1984,
49, 3904. (c) Suzuki, M.; Kimura, Y.; Terashima, S. Chem. Pharm. Bull.
1986, 34, 1531.
(16) Stork, G.; Liu, L.; Manabe, K. J . Am. Chem. Soc. 1998, 120,
1337.
(17) Simchen, G.; Kober, W. Synthesis 1976, 259.
6850 J . Org. Chem., Vol. 67, No. 19, 2002

The aqueous layer was extracted with diethyl ether (2 × 2 mL),
and the combined extracts were washed with brine (2 × 2 mL)
and dried (MgSO4). Following evaporation, the mixture of crude
propargylic alcohols was dissolved in 1 mL of methanol. Potas-
sium carbonate (33 mg, 0.24 mmol) was added, and the mixture
was stirred for 2 h. The mixture was quenched with aqueous
sat. NH4Cl (1 mL), diluted with diethyl ether (5 mL), and
separated. The aqueous layer was extracted with diethyl ether
(2 × 5 mL), and the combined extracts were washed with brine
(3 × 5 mL), dried (MgSO4), and evaporated. The residue was
subjected to chromatography on silica gel (gradient elution, 15%
Et2O/ hexane to 30% Et2O/hexane) to give alcohol 22b (8 mg)
as a viscous, colorless oil, followed by alcohol 22a (25 mg) as a
white solid (combined yield 86%).
6.9 Hz, 1H), 3.77 (dd, J ) 10.3, 5.3 Hz, 1H), 3.63 (dd, J ) 10.3,
6.2 Hz, 1H), 2.32 (s, 1H), 2.14 (s, 3H), 2.17-1.85 (m, 4H), 1.45
(s, 3H), 1.05 (s, 9H); 13C NMR (CDCl3, 101 MHz) δ 207.9, 135.7,
133.7, 129.6, 127.6, 84.2, 82.5, 80.4, 76.5, 75.4, 70.6, 66.0, 27.8,
26.9, 26.8, 23.0, 19.3 (one upfield carbon not resolved); HRMS
(CI) m/e ((M + H)+) calcd for C28H37O4Si 465.2461, found
465.2455.
(2R,5S)-2-[(R)-2-(2-Oxop r op yl)-3-b u t en -2-yl]-5-([(1,1-d i-
m eth yl)eth yldiph en ylsilyl]oxym eth yl)tetr ah ydr ofu r an (25).
To keto alkyne 24 (633 mg, 1.36 mmol) in methanol (35 mL)
was added quinoline (0.32 mL) and Lindlar catalyst (5% pal-
ladium on calcium carbonate poisoned with lead, 87 mg). The
flask was flushed with hydrogen gas. After being stirred for 15
min under hydrogen, the mixture was filtered through Celite,
evaporated, and subjected to chromatography on silica gel (5%
Et2O/benzene) to give the keto alkene 25 (565 mg, 89%) as a
20
Alcohol 22b: [R]D 16° (c 3.2, CH2Cl2); IR (neat) 3440, 3280,
3073, 2959, 2934, 2859, 1473, 1404, 1427, 1363, 1113, 1084,
1
20
1009, 988, 824, 799, 741, 704, 691, 612 cm-1; H NMR (CDCl3,
pale yellow oil. [R]D -2° (c 2.4, CH2Cl2); IR (neat) 2959, 2932,
400 MHz) δ 7.83-7.66 (m, 4H), 7.53-7.35 (m, 6H), 4.20-4.09
(m, 1H), 3.94 (dd, J ) 5.6, 5.6 Hz, 1H), 3.81 (dd, J ) 10.8, 4.6
Hz, 1H), 3.67 (dd, J ) 10.8, 4.1 Hz, 1H), 3.17 (bs, 1H), 2.30 (s,
1H), 2.26-1.84 (m, 4H), 1.50 (s, 3H), 1.08 (s, 9H); 13C NMR
(CDCl3, 101 MHz) δ 135.7, 133.3, 129.8, 127.8, 85.5, 85.3, 80.6,
72.3, 70.4, 65.6, 27.5, 27.4, 27.0, 26.9, 19.2. Alcohol 22a : mp 71-
2859, 1719, 1473, 1428, 1356, 1113, 999, 824, 741, 704, 608 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 7.89-7.60 (m, 4H), 7.55-7.30 (m,
6H), 5.82-5.71 (m, 1H), 5.18-5.28 (m, 2H), 4.12-4.03 (m, 1H),
4.00-3.86 (m, 3H), 3.70 (dd, J ) 10.4, 4.8 Hz, 1H), 3.63 (dd, J
) 10.4, 5.8 Hz, 1H), 2.12 (s, 3H), 1.96-1.73 (m, 4H), 1.26 (s,
3H), 1.06 (s, 9H); 13C NMR (CDCl3, 101 MHz) δ 208.4, 138.8,
135.6, 133.6, 129.6, 127.7, 117.1, 85.0, 80.1, 80.0, 69.5, 65.9, 27.7,
26.9, 26.8, 26.3, 19.3, 18.1; HRMS (EI) m/e (M+) calcd for
20
72 °C; [R]D -4° (c 1.5, CH2Cl2); IR (neat) 3433, 3306, 2959,
2934, 2861, 1473, 1404, 1429, 1113, 1080, 824, 743, 702 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 7.76-7.66 (m, 4H), 7.48-7.35 (m,
6H), 4.19-4.12 (m, 1H), 4.04 (dd, J ) 6.7, 6.7 Hz, 1H), 3.85 (dd,
J ) 10.9, 4.2 Hz, 1H), 3.60 (dd, J ) 10.9, 3.5 Hz, 1H), 3.26 (bs,
1H), 2.45 (s, 1H), 2.12-1.85 (m, 4H), 1.44 (s, 3H), 1.07 (s, 9H);
13C NMR (CDCl3, 101 MHz) δ 135.7, 133.2, 129.8, 127.8, 87.4,
85.6, 80.0, 70.8, 68.8, 65.5, 27.3, 26.8, 25.6, 25.1, 19.2; HRMS
(CI) m/e (M+) calcd for C25H32O3Si 408.2121, found 408.2127.
(2R,5S)-2-[R-2-(2-Meth yl-3-p r op en yloxy)-3-bu tyn -2-yl]-5-
([(1,1-d im e t h y l)e t h y ld ip h e n y ls ily l]o x y m e t h y l)t e t r a -
h yd r ofu r a n (23). To alcohol 22a (0.861 g, 2.11 mmol) and
anhydrous lithium iodide (1.13 g, 8.84 mmol) in THF (7 mL) at
-78 °C was added dropwise n-butyllithium (2.35 M in hexanes,
0.900 mL, 2.12 mmol). Stirring was continued for an additional
20 min, then HMPA (3.5 mL) was added, and the mixture was
warmed to 0 °C. Methallyl chloride (0.83 mL, 8.40 mmol) was
then added dropwise, and the mixture was warmed to 21 °C and
stirred in the dark for 4 d. The mixture was quenched with
aqueous sat. NH4Cl (5 mL), diluted with diethyl ether (10 mL),
and separated. The aqueous layer was extracted with diethyl
ether (3 × 10 mL), and the combined extracts were washed with
brine (3 × 10 mL), dried (MgSO4), and evaporated. The residue
was subjected to chromatography on silica gel (gradient elution,
10% Et2O/hexane to 30% Et2O/hexane) to give the methallyl
ether 23 (710 mg, 73%) as a colorless oil, followed by the starting
C
28H38O4Si 466.2539, found 466.2539.
(6R)-6-Meth yl-6-[(2R,5S)-5-([(1,1-d im eth yl)eth ylp h en yl-
silyloxy]m eth yl)tetr ah ydr ofu r an -2-yl]pyr an -2[3H]-on e (27).
Keto alkene 25 (548 mg, 1.17 mmol) was dissolved in a 1:1
mixture of diethyl ether/methanol (35 mL) and cooled to -78
°C. Ozone was bubbled through for 1 min, and TLC analysis
showed that all the starting material had been consumed.
Dimethyl sulfide (0.77 mL) was added, and the mixture was
slowly warmed to 21 °C, then stirred for an additional 12 h.
Evaporation of the solvent provided the crude keto aldehyde 26
as an unstable, colorless oil, which was immediately dissolved
in methanol (75 mL). To the solution was added 18-crown-6 (30
mg, 0.11 mmol) and potassium carbonate (820 mg, 5.93 mmol).
The mixture was stirred for 2.5 h, then diluted with diethyl ether
(100 mL) and washed with saturated aq NH4Cl (2 × 50 mL).
The aqueous layer was extracted with diethyl ether (2 × 50 mL),
and the combined extracts were washed with brine (2 × 100 mL),
dried (MgSO4), and evaporated. The residue was dissolved in
25 mL of dichloromethane, and DMAP (21 mg, 0.176 mmol) and
triethylamine (0.60 mL, 4.3 mmol) were added. The mixture was
cooled to 0 °C, and methanesulfonyl chloride (0.11 mL, 1.5 mmol)
was added dropwise. The mixture was warmed to 21 °C, stirred
for 3 h, then diluted with diethyl ether (100 mL) and washed
with saturated aq NH4Cl (2 × 50 mL). The aqueous layer was
extracted with diethyl ether (2 × 50 mL), and the combined
extracts were washed with brine (2 × 100 mL), dried (MgSO4),
and evaporated. Chromatography of the residue on silica gel
(20% EtOAc/hexane) provided pyranone 27 (435 mg, 82%) as a
pale yellow oil. [R]D20 -20° (c 2.2, CH2Cl2); IR (neat) 3071, 2957,
2930, 2857, 1692, 1471, 1428, 1388, 1105, 997, 824, 741, 702,
608 cm-1; 1H NMR (CDCl3, 400 MHz) δ 7.80-7.61 (m, 4H), 7.60-
7.32 (m, 6H), 7.08 (d, J ) 10.6 Hz, 1H), 6.03 (d, J ) 10.6 Hz,
1H), 4.26 (s, 2H), 4.12-4.00 (m, 1H), 4.00-3.90 (m, 1H), 3.78
(dd, J ) 10.8, 4.2 Hz, 1H), 3.66 (dd, J ) 10.8, 4.2 Hz, 1H), 2.03-
1.77 (m, 4 H), 1.43 (s, 3H), 1.06 (s, 9H); 13C NMR (CDCl3, 101
MHz) δ 194.9, 153.2, 135.6, 138.4, 129.7, 127.7, 126.3, 84.0, 80.3,
76.1, 67.5, 65.4, 26.9, 26.8, 26.5, 20.4, 19.3; HRMS (CI) m/e ((M
- H)+) calcd for C27H33O4Si 449.2155, found 449.2148.
20
alcohol 22a (215 mg, 75% conversion). [R]D 4° (c 5.7, CH2Cl2);
IR (neat) 3299, 2932, 2859, 1473, 1429, 1361, 1113, 1100, 897,
824, 741, 702 cm-1; 1H NMR (CDCl3, 400 MHz) δ 7.74-7.67 (m,
4H), 7.52-7.46 (m, 6H), 4.96 (s, 1H), 4.83 (s, 1H), 4.16-4.05 (m,
2H), 3.98-3.88 (m, 2H), 3.77 (dd, J ) 10.2, 5.2 Hz, 1H), 3.64
(dd, J ) 10.2, 6.5 Hz, 1H), 2.24 (s, 1H), 2.11-1.85 (m, 4H), 1.72
(s, 3H), 1.47 (s, 3H), 1.06 (s, 9H); 13C NMR (CDCl3, 101 MHz) δ
142.7, 135.7, 133.7, 129.5, 127.6, 111.2, 84.6, 83.5, 80.3, 75.9,
74.2, 68.1, 66.1, 28.0, 27.0, 26.9, 23.3, 19.7, 19.3; HRMS (CI)
m/e ((M + NH4)+) calcd for C29H42NO3Si 480.2934, found
480.2940.
(2R,5S)-2-[R-2-(2-Oxop r op yl)-3-b u t yn -2-yl]-5-([(1,1-d i-
m eth yl)eth yldiph en ylsilyl]oxym eth yl)tetr ah ydr ofu r an (24).
To methallyl ether 23 (163 mg, 352 mmol) in a 1:1 mixture of
diethyl ether/methanol (10 mL) was added 3 drops of Sudan Red
solution (0.1 wt % in methanol). The resulting pink solution was
cooled to -78 °C, and ozone was bubbled through just until the
solution became colorless. Dimethyl sulfide (0.15 mL) was added,
and the mixture was slowly warmed 21 °C and stirred for an
additional 6 h. Evaporation of the solvent, followed by chroma-
tography on silica gel (20% EtOAc/hexane), provided keto alkyne
24 (160 mg, 98%) as a pale yellow oil. [R]D20 -5° (c 1.5, CH2Cl2);
IR (neat) 3300, 2957, 2932, 2859, 1718, 1478, 1428, 1360, 1113,
824, 741, 704 cm-1; 1H NMR (CDCl3, 400 MHz) δ 7.85-7.63 (m,
4H), 7.50-7.33 (m, 6H), 4.30-4.05 (m, 3H), 3.96 (dd, J ) 6.9,
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (CA72684) and the Agricultural Re-
search Center of the American Cyanamid Company for
generous financial support.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for compounds 16, 19, 20, 21a b, 29, and 30 and
reactions of 11 and 31. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O016246J
J . Org. Chem, Vol. 67, No. 19, 2002 6851