Enantioselective total syntheses of slagenins A-C and their antipodes

Article abstract of DOI:10.1021/jo026773i

Full details of the total syntheses of slagenins A-C (1a-c) and their antipodes (2a-c), novel bromopyrrole alkaloids with a unique tetrahydrofuro[2,3-d]imidazolidin-2-one moiety, are described in which their absolute stereochemistry was established. The key step in the syntheses involves the efficient condensation of dihydrofuran-3-one or glyoxal with urea to construct the slagenin bicycle core.

Full text of DOI:10.1021/jo026773i

En a n tioselective Tota l Syn th eses of Sla gen in s A-C a n d
Th eir An tip od es
Biao J iang,* J ia-Feng Liu, and Sheng-Yin Zhao
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, P. R. China
jiangb@pub.sioc.ac.cn
Received November 26, 2002
Full details of the total syntheses of slagenins A-C (1a -c) and their antipodes (2a -c), novel
bromopyrrole alkaloids with a unique tetrahydrofuro[2,3-d]imidazolidin-2-one moiety, are described
in which their absolute stereochemistry was established. The key step in the syntheses involves
the efficient condensation of dihydrofuran-3-one or glyoxal with urea to construct the slagenin bicycle
core.
In tr od u ction
Several bromopyrrole alkaloids found in marine sponges
have been shown to exhibit pharmacologically useful
activities, and include c-erbB-2 kinase and cyclin-depend-
ent kinase 4 (cdk4) inhibitors, R-adrenoceptor blockers,
serotonergic receptor antagonists, antihistamine and
actomyosin ATPase activators, etc.1 Due to their interest-
ing physiological properties, the syntheses of these
compounds have attracted considerable attention from
synthetic chemists.2-4 Slagenins A-C (1a -c) (Figure 1)
comprise a group of cytotoxic secondary marine metabo-
lites recently isolated from the Okinawan sponge Agelas
nakamurai.5,6 These structurally interesting bromopyr-
role alkaloids possess a highly functionalized tetrahy-
drofuro[2,3-d]imidazolidin-2-one moiety in which the
relative stereochemistry was elucidated by 2D NMR
spectroscopy.5 Because slagenins are available in nature
in only minute amounts and may be of significant interest
for more detailed pharmacological investigations, it
F IGURE 1. Structures of slagenins A-C
became the goal of the current project to develop efficient
total syntheses for these bromopyrrole alkaloids. While
the first total synthesis of slagenins A-C was achieved
in a biomimetic pathway involving the oxidative cycliza-
tion of â-hydroxyimidazolones,7,8 their absolute stereo-
chemistries have not been determined. Herein, we report
full details of enantioselective total syntheses of slagenins
A-C and their antipodes which established their absolute
stereochemistry, and the efficient preparation of tetrahy-
drofuro[2,3-d]imidazolidin-2-one skeletons from the con-
densation of dihydrofuran-3-one or glyoxal with urea.9,10
* Corresponding author.
(1) For reviews, see: (a) Kobayashi, J .; Ishibashi, M. In The
Alkaloids: Chemistry and Pharmacology; Brossi, A., Ed.; Academic
Press: New York, 1992; Vol. 41, pp 41-124. (b) Faulkner, D. J . Nat.
Prod. Rep. 1999, 16, 155; 2002, 19, 1.
(2) (a) Daninos-Zeghal, S.; Al Mourabit, A.; Ahond, A.; Poupat, C.;
Potier, P. Tetrahedron 1997, 53, 7605. (b) Anderson, G. T.; Chase, C.
E.; Koh, Y.-h.; Stien, D.; Weinreb, S. M.; Shang, M. Y. J . Org. Chem.
1998, 63, 7594. (c) Stein, D.; Anderson, G. T.; Chase, C. E.; Koh, Y.-h.;
Weinreb, S. M. J . Am. Chem. Soc. 1999, 121, 9574. (d) Namba, K.;
Shinda, T.; Teramoto, T.; Ohfune, Y. J . Am. Chem. Soc. 2000, 122,
10708. (e) Dilley, A. S.; Romo, D. Org. Lett. 2001, 3, 1535. (f) Berre˘ e,
F.; Bleis, P. G.; Carboni, B. Tetrahedron Lett. 2002, 43, 4935.
(3) (a) Lindel, T.; Hoffmann, H. Tetrahedron Lett. 1997, 38, 8935.
(b) Lindel, T.; Hoffmann, H. Liebigs Ann./ Recl. 1997, 1525. (c) Lindel,
T.; Hochgu¨rtel, M. J . Org. Chem. 2000, 65, 2806. (d) J acquot, D. E.
N.; Hoffmann, H.; Polborn, K.; Lindel, T. Tetrahedron Lett. 2002, 43,
3699.
(4) (a) Xu, Y.-z.; Yakushijin, K.; Horne, D. A. Tetrahedron Lett. 1996,
37, 8121. (b) Xu, Y.-z.; Yakushijin, K.; Horne, D. A. J . Org. Chem. 1997,
62, 456. (c) Olofson, A.; Yakushijin, K.; Horne, D. A. J . Org. Chem.
1997, 62, 7918. (d) Olofson, A.; Yakushijin, K.; Horne, D. A. J . Org.
Chem. 1998, 63, 1248. (e) Sosa, A. C. B.; Yakushijin, K.; Horne, D. A.
J . Org. Chem. 2000, 65, 610. (f) Wiese, K. J .; Yakushijin, K.; Horne,
D. A. Tetrahedron Lett. 2002, 43, 5135.
Resu lts a n d Discu ssion
Retr osyn th etic An a lysis. Slagenins possess a cis-
fused tetrahydrofuro[2,3-d]imidazolidin-2-one moiety with
three stereogenic centers, one of which is the C11
quarternary carbon center. The key to the synthetic
scheme is the generation of the three stereogenic centers
in the moiety. In the literature, only two reports describe
the preparation of tetrahydrofuro[2,3-d]imidazolidin-2-
(7) Sosa, A. C. B.; Yakushijin, K.; Horne, D. A. Org. Lett. 2000, 2,
3443.
(8) (a) For a later account of hypothetical biogenetic mechanism
studies, see: Al Mourabit, A.; Potier, P. Eur. J . Org. Chem. 2001, 237.
(b) Kawasaki, I.; Sakaguchi, N.; Fukushima, N.; Fujioka, N.; Nikaido,
F.; Yamashita, M.; Ohta, S. Tetrahedron Lett. 2002, 43, 4377.
(5) Tsuda, M.; Uemoto, H.; Kobayashi, J . Tetrahedron Lett. 1999,
40, 5709.
(6) Several bromopyrrole alkaloids have been isolated from marine
sponge Agelas nakamurai: Uemoto, H.; Tsuda, M.; Kobayashi, J . J .
Nat. Prod. 1999, 62, 1581.
10.1021/jo026773i CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/19/2003
2376
J . Org. Chem. 2003, 68, 2376-2384

Syntheses of Slagenins A-C and Their Antipodes
SCHEME 1 a
a
Key: (a) H2, 0.1 mol % of Ru(OAc)2(R-BINAP), EtOH, 40 atm,
100 °C, 95%; (b) (1) TBDMSCl, imidazole, DMF, 45 °C; (2) NaN3,
DMF, 90 °C, 85% for two steps; (c) (1) LiOH, acetone-water, rt;
(2) H+, 95%; (d) isobutyl chlorocarbonate, NEt3, dry THF, -20 to
-10 °C; (2) 2 equiv of ethereal diazomethane, 90%; (e) DMD-
acetone, 100%.
Syn th esis of th e An tip od es.9 We began our research
on the enantioselective synthesis of slagenins with a
preparation of the key intermediate glyoxal I from
commercially available ethyl 4-chloroacetoacetate (3).
After some fruitless studies on the preparation of the
glyoxal (vide post), we turned to the synthesis of the
glyoxal I from an R-diazoketone.13 Thus, Noyori hydro-
genation of compound 3 afforded ethyl (S)-4-chloro-3-
hydroxy-butanonate (5) in 95% yield (97% ee).14,15 The
3-hydroxy group was protected as a tert-butyl dimethyl
silyl ether, and then the 4-chloro group was displaced
with azide to give ester 6.16 Ester 6 was saponified to
give acid 7, which was converted into R-diazoketone 8
via the mixed anhydride by treatment with ethereal
diazomethane.13 Oxidation of diazoketone 8 with distilled
dimethyl-dioxirane (DMD)17 in acetone quantitatively
afforded glyoxal 9,18 which appeared to be in the corre-
sponding R-keto aldehyde and its hydrate form. The
glyoxal was sensitive to air and could not be purified by
distillation or chromatography. Fortunately, the crude
product was pure enough to use in subsequent reactions
(Scheme 1).9
F IGURE 2. Retrosynthesis of slagenins A-C
one skeletons: one from reaction of 2-aminosugars with
isocyanates;11 another by oxidative cyclization of â-hy-
droxyimidazolones.7 The slagenin bicycle core can be
retrosynthesized, in the most direct way, to the conden-
sation of urea with the corresponding glyoxal I or dihy-
drofuran-3-one II based on the relevant synthesis of
dihydroxyimidazolidin and glycoluril from urea and gly-
oxal (Eq.).12 It might be expected that, due to the obvious
strain of a trans-[3.3.0]bicycle, the bicycle derived from
the condensation must be cis-fused.11 The other two of
the three stereogenic centers would be generated in an
enatioselective way induced by chiral C9 (refer to the
numbering system of slagenin) as a result of intramo-
lecular steric hindrance. So, the C9 stereogenic center
was considered to be derived, in an assured way, either
from Noyori hydrogenation of commercially available
ethyl 4-chloroacetoacetate (3) or from L-xylose (4) (Figure
2).
With the key intermediate 9 in hand, we turned our
attention to its condensation with urea. At first, we tried
to cleave the tert-butyl dimethyl silyl ether. Several
conditions were tested for the cleavage, and most gave
complex results. Finally, we found that a treatment of
the cleavage and the condensation in one pot gave out
satisfactory results (Scheme 2). Reaction of the glyoxal
9 with HF and urea in acetone-water solution gave
(13) Ihmels, H.; Maggini, M.; Prato, M.; Scorrano, G. Tetrahedron
Lett. 1991, 32, 6215.
(9) For a preliminary account of enantioselective synthesis for the
antipodes of slagenin B and C, see: J iang, B.; Liu, J .-F.; Zhao, S.-Y.
Org. Lett. 2001, 3, 4011.
(10) For a preliminary account of the enantioselective synthesis of
slagenins A∼C, see: (a) J iang, B.; Liu, J .-F.; Zhao, S.-Y. Org. Lett. 2002,
4, 3951. (b) Gurjar, M. K.; Bera, S. Org. Lett. 2002, 4, 3569.
(11) Avalos, M.; Babiano, R.; Cintas, P.; J ime´nez, J . L.; Palacios, J .
C.; Valencia, C. Tetrahedron 1993, 49, 2676.
(12) (a) Vail, S. L.; Barker, R. H.; Mennitt, P. G. J . Org. Chem. 1965,
30, 2179. (b) Gautam, S.; Katcham, R.; Nematollahi, J . Synth.
Commun. 1979, 9, 863. (c) Grillon, E.; Gallo, R.; Pierrot, M.; Boileau,
J .; Wimmer, E. Tetrahedron Lett. 1988, 29, 1015.
(14) (a) Ager, D. J .; Laneman, S. A. Tetrahedron: Asymmetry 1997,
8, 3327. (b) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1996,
7, 1919. (c) Yuasa, Y.; Tsuruta, H. Liebiegs Ann./ Recl. 1997, 1877.
(15) J iang, B.; Chen, Z. Tetrahedron: Asymmetry 2001, 12, 2835.
(16) Kobayashi, S.; Kobayashi, K.; Hirai, K. Synth. Lett. 1999, 909.
(17) (a) Adam, W.; Bialas, J .; Hadjiarapoglou, L. Chem. Ber. 1991,
124, 2377. (b) Bull, J , R.; Dekoning, P. D. Eur. J . Org. Chem. 2001,
1189. (c) Rainier, J . D.; Allcrein, S. P.; Cox, J . M. J . Org. Chem. 2001,
66, 1380.
(18) Oxidation of diazoketone 8 with DMD generated in situ from
oxone gave complex results.
J . Org. Chem, Vol. 68, No. 6, 2003 2377

J iang et al.
SCHEME 2 a
SCHEME 3 a
a
Key: (a) (1) CuSO4, H2SO4, acetone, rt, 24 h; (2) 0.1 mol/L
HCl, rt, 1 h; (b) BzCl, Py, dry CH2Cl2, 0 °C, 1 h, 80% yield from
L-xylose; (c) (1) NaH, CS2, rt, overnight, then MeI, 1.5 h, dry THF,
rt; (2) Bu3SnH, 5 mol % of AIBN, benzene, reflux, 4 h, 68% for
two steps; (d) NaOMe/MeOH, 2 h, 93%; (e) (1) TsCl, Py, CHCl3,
rt, overnight, 98%; (2) NaN3, DMF, 90 °C, overnight, 99%; (f) 1%
I2-MeOH, reflux, 18 h, 94%; (g) (from pure â-anomer of compound
16) Dess-Martin oxidation, 81%.
a
Key: (a) urea, HF, acetone-water, rt, 58%; (b) urea, 40% aq
HF, methanol, rt, yield 10a (26%), 10b and 10c (54%, a mixture,
10b/10c 9/5); (c) (1) H2, Pd/C, methanol; (2) 4-bromo-2-(trichloro-
acetyl)pyrrole, DMF, rt, for two steps (77% for 10a , 80% for 10b
and 10c).
difficult to separate by silica gel chromatography. How-
ever, we succeeded in getting some pure samples of
compounds 10b and 10c for analysis. Fortunately, we
obtained crystals of compound 10c suitable for X-ray
structure analysis.20 Complete separation of the diaster-
eomers required further elaboration of the core. There-
fore, the azido group in the mixture of 10b and 10c was
reduced to an amino group by hydrogenation over 10%
Pd/C in methanol, and the amine was then acylated with
4-bromo-2-(trichloroacetyl)pyrrole19 to give a 9:5 ratio of
compounds 2b and 2c in 80% yield for two steps. The
spectral data and specific rotations revealed that com-
pounds 2b and 2c were respective antipodes of slagenins
B and C.9 Thus, with the C9 chiral center generated from
asymmetric hydrogenation, an enantioselective synthesis
for the antipodes of slagenins A-C, which was character-
ized by construction of the slagenin bicycle core from
glyoxal 9 in a concerted pathway, was achieved.
Syn th esis of Sla gen in s A-C.10 After the successful
synthesis of antipodes of slagenins A-C, we turned our
attention to a carbohydrate-based synthesis of naturally
occurring slagenins A-C. The synthesis of the antipodes
described above suggested the absolute stereochemistries
as (9R,11R,15R) for slagenins A and B, and (9R,11S,-
15S) for slagenin C. The C9 chiral center to be introduced
into synthetic slagenins as an R-configuration was con-
sidered to be derived from L-xylose. The research for the
preparation of dihydrofuran-3-one II from L-xylose is
illustrated in Scheme 3.10a
compound 10a in 58% yield. Although compound 10a was
shown to be a simple compound by TLC analysis, it
showed itself from the proton NMR spectral data to be a
mixture of two diastereoisomers in a ratio of 5:2. How-
ever, after the reduction of intermediate 10a by hydro-
genation over 10% Pd/C in methanol and the follow-up
acylation with 4-bromo-2-(trichloroacetyl)pyrrole,19 only
a simple compound 2a was separated in 77% yield. A
plausible mechanism for this strange transformation was
arbitrarily brought forward (vide post). The NMR, IR,
and mass spectral data for compound 2a were in satis-
factory agreement with those reported for synthetic and
naturally isolated slagenin A.5,7 And the NOESY spec-
trum showed correlations for H-9 to H-10R and H-8 to
H-10â, H-15 to 11-OH, and H-10â to both 11-OH and
H-15, indicating that the bicycle of 2a was cis-fused and
that H-9, H-15, and the hydroxy group at C-11 were R-,
â-, and â-oriented, respectively. Therefore, the absolute
structure of 2a was assigned to be (9S,11S,15S)-2a .
Comparison of the negative specific rotation of 2a {[R]20
D
-7.6 (c 0.5, MeOH)} with the positive specific rotation
of naturally isolated slagenin A {[R]27 +11 (c 1.2,
D
MeOH)}5 revealed that the synthetic compound 2a was
the antipode of naturally isolated slagenin A (1a ).
A multicomponent condensation route has also been
developed to construct the slagenin core with a methoxy
group linked to the C11 quarternary carbon center
(Scheme 2). The glyoxal 9 was treated with aqueous HF
and urea in methanol at ambient temperature. After
removal of the solvent, flash chromatography afforded
two compounds. One was compound 10a , which also
showed itself from its proton NMR spectrum to be a
mixture of two diastereoisomers in a ratio of 5:2. Another
was shown by its proton NMR spectrum to be a 9:5
mixture of two diastereoisomers 10b and 10c which were
Starting from L-xylose, the 3-deoxy-L-ribose derivative
14 was prepared by adapting the reported procedures.21
Ketalization of L-xylose, in acetone in the presence of
anhydrous CuSO4 and a catalytic amount of concentrated
H2SO4, followed by selective hydrolysis with HCl (0.1 mol/
L) afforded 1,2-O-isopropylidene-R-L-xylofuranose (11).22
Selective protection of the 5-OH with BzCl in pyridine-
CH2Cl2 at 0 °C gave compound 12.23 Following conversion
of the 3-hydroxyl group to the 3-xanthate in situ, the
alcohol 12 was deoxygenated by the action of tributyltin
(19) Bromo-2-(trichloroacetyl)pyrrole was prepared from pyrrole
following the reported procedures: (a) Kitamura, C.; Yamashita, Y. J .
Chem. Soc., Perkin Trans. 1 1997, 1443. (b) Bailey, D. M.; J ohnson, R.
E.; Albertson, N. F. Organic Syntheses; Wiley: New York, 1988; Collect.
Vol. VI, p 618.
(20) ORTEP figure and tables of X-ray crystallographic data for
compound 10c can be found in the Supporting Information.
2378 J . Org. Chem., Vol. 68, No. 6, 2003

Syntheses of Slagenins A-C and Their Antipodes
SCHEME 4 a
SCHEME 5
SCHEME 6 a
a
Key: (a) (1) 0.1 mol/L of HCl, THF, reflux, 8 h; (2) urea, 0.01
a
Key: (a) urea, 5% HCl-MeOH, reflux, 10 h, 77%; (b) (1) H2,
Pd/C, methanol; (2) 4-bromo-2-(trichloroacetyl)pyrrole, DMF, rt,
80% for two steps.
mol/L of HCl, rt, 48 h, 75%; (b) (1) H2, Pd/C, methanol; (2) 4-bromo-
2-(trichloroacetyl)pyrrole, DMF, rt, 69% for two steps.
hydride and AIBN to give compound 13.24 Removal of the
benzyl protecting group was smoothly accomplished,
which afforded primary alcohol 14. Treatment of 14 with
TsCl and pyridine in CHCl3 gave the corresponding
tosylate, which was later transformed into azide 15.25
Methanolysis of azide 15 with refluxing 1% I2-MeOH,26
followed by Dess-Martin oxidation of the â-anomer of
compound 16,27 afforded the key intermediate 17 (Scheme
3).10a
With the key intermediate 17 in hand, we tried to
directly concentrate it with urea under acidic conditions.
Thus, a treatment of compound 17 with 0.1 mol/L of
aqueous HCl in THF and then condensation with urea
in situ afforded 18a and 18b in 75% yield in a ratio of
1.1:1, which could not be separated from each other by
silica gel chromatography. Undergoing the hydrogenation
of this mixture over 10% Pd/C in methanol and the follow-
up acylation with 4-bromo-2-(trichloroacetyl)pyrrole19 in
DMF, to our surprise, only a single compound 1a was
obtained in a yield of 69% (Scheme 4).10a Some further
studies were done to have a better understanding of this
transformation (vide post). The NMR (1H, 13C, and
NOESY), IR, and mass spectral data for compound 1a
were in satisfactory agreement with those reported for
naturally isolated slagenin A.5,10a Comparison of the
specific rotation of synthetic 1a {[R]20 +7.7 (c 0.8,
D
MeOH)} with that of naturally isolated slagenins A
{[R]27 +11 (c 1.2, MeOH)} further established the
D
absolute configuration of naturally isolated slagenin A
to be (9R,11R,15R)-1a .
Condensation of the compound 17 with urea and
methanol in a nonaqueous system led to the syntheses
of slagenins B and C. At the beginning, the treatment of
17 and urea in methanol with Amberlyst-15 resin as
catalyst afforded an unstable compound 19 (Scheme 5),
whose structure was proposed from its NMR data.
Finally, compound 17 was heated at reflux with urea in
5% HCl-methanol solution to afford inseparable dias-
tereoisomers 20a and 20b in a ratio of 3.8:1 with a yield
of 77% (Scheme 6).10a Following the procedure described
above (Scheme 2), slagenins B (1b) and C (1c) were
isolated by flash chromatography in 80% yield with a
ratio of 3.8:1. The NMR (1H, 13C, and NOESY), IR, and
mass spectral data for synthetic 1b and 1c were fully in
agreement with those reported for naturally isolated
slagenins B and C.5,10a Comparison of the specific rotation
of synthetic 1b {[R]20D +44.8 (c 0.5, MeOH)} with that of
naturally isolated slagenin B {[R]26D +33 (c 0.2, MeOH)}
and that of synthetic 1c {[R]20D -36.1 (c 0.8, MeOH)} with
(21) (a) Nicolaou, K. C.; Daines, R. A.; Uenishi, J .; Li, W. S.;
Papahatjis, D. P.; Chakraborty, T. K. J . Am. Chem. Soc. 1987, 109,
2208. Nicolaou, K. C.; Daines, R. A.; Uenishi, J .; Li, W. S.; Papahatjis,
D. P.; Chakraborty, T. K. 1988, 110, 4673. (b) For another report of
the preparation of compound 14 from diacetone-L-glucose, see: J ones,
M. F.; Noble, S. A.; Robertson, C. A.; Storer, R.; Highcock, R. M.;
Lamont, R. B. J . Chem. Soc., Perkin Trans. 1 1992, 1427.
(22) Baker, B. R.; Schaub, R. E. J . Am. Chem. Soc. 1955, 77, 5900.
(23) (a) Ma, T.; Pai, S. B.; Zhu, Y. L.; Lin, J . S.; Shanmuganathan,
K.; Du, J .; Wang, C.; Kim, H.; Newton, M. G.; Cheng, Y. C.; Chu, C. K.
J . Med. Chem. 1996, 39, 2835. (b) Gumina, G.; Schinazi, R. F.; Chu,
C. K. Org. Lett. 2001, 3, 4177.
(24) (a) Barton, D. H. R.; McCombie, S. W. J . Chem. Soc., Perkin
Trans. 1 1975, 1574. (b) J acobson, K. A.; Siddiqi, S. M.; Olah, M. E.;
J i, X.-d.; Melman, N.; Bellamkonda, K.; Meshulam, Y.; Stiles, G. L.;
Kim, H. O. J . Med. Chem. 1995, 38, 1720.
(25) A preparation of the antipode of compound 15 from glucose was
reported: Bentley, N.; Dowdeswell, C. S.; Singh, G. Heterocycles 1995,
41, 2499.
that of naturally isolated slagenin C {[R]25 -35 (c 0.2,
D
MeOH)} further confirmed the absolute configuration of
naturally isolated slagenins B and C to be (9R,11R,15R)-
1b and (9R,11S,15S)-1c, respectively.10a Thus, the enan-
tioselective synthesis of slagenins A∼C, which was
characterized by the efficient condensation of 2-methoxy-
dihydrofuran-3-one 17 and urea to prepare the cis-fused
tetrahydeofuro[2,3-d]imidazolidin-2-one skeleton, further
established the absolute stereochemistry of slagenins.
The direct condensation of dihydrofuran-3-one 17 with
(26) (a) Huang, B.-G.; Bobek, M. Carbohydr. Res. 1998, 308, 319.
(b) Lu, D.-M.; Min, J .-M.; Zhang, L.-H. Carbohydr. Res. 1998, 317, 193.
(27) (a) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277.
(b) Gurjar, M. K.; Ravindranadh, S. V.; Kumar, P. Chem. Commun.
2001, 917. (c) Li, N.-S.; Tang, X.-Q.; Piccirilli, J . A. Org. Lett. 2001, 3,
1025. (d) Cook, G. P.; Greenberg, M. M. J . Org. Chem. 1994, 59, 4704.
J . Org. Chem, Vol. 68, No. 6, 2003 2379

J iang et al.
SCHEME 7
SCHEME 9
SCHEME 8 a
a
Key: (a) Dibal-H, dry THF, -78 °C, 91% yield on recovery
starting materials (51% recovered starting materials, 45% obtained
aldehyde); (b) Ph3P+CH3Br-, n-BuLi, -30 °C, 79%; (c) K3[Fe(CN)6],
K2CO3, 10 mol % of OsO4, t-BuOH-H2O, 90%.
P la u sible Mech a n ism . During the course of our
syntheses of slagenin A and its antipode, it was observed
that only the thermodynamically more stable diastereo-
isomer was generated from the azide intermediate com-
prising two isomers, that is, azide 10a , which was
composed of two isomers in a ratio of 5:2, was turned into
only one diastereoisomer, the antipode of slagenin A, in
a yield of 77% (Scheme 2); azides 18a and 18b, in a ratio
of 1.1:1, were converted into only slagenin A in 69% yield
(Scheme 4).10a In the case of a 10b/10c or 20a /20b
mixture, each diastereoisomer was converted into the
corresponding antipode of slagenin or slagenin. Accord-
ingly, it was expected that the missing diastereoisomer
of slagenin A might be obtained under different condi-
tions. Thus, the mixture of azide 18a and 18b was
subjected to reduction with some phosphine. Both triphen-
ylphosphine and tri-n-butylphosphine were not reductive
enough for the azide. Finally, reduction of the azide 18a /
18b mixture was achieved with triethylphosphine in a
refluxing THF-H2O (10/1) solution. Only after evapora-
tion of the volatiles in vacuo did a one-pot treatment of
the residue with 4-bromo-2-(trichloroacetyl)pyrrole19 in
DMF afford an unseparable mixture of slagenin A (1) and
its diastereoisomer 25 in a ratio of 2.4:1 in 45% yield. At
the same time, hydyogenation of the azide over 10% Pd/C
for 3 days (a time long enough), followed by filtration
through kieselguhr and removal of the solvent in vacuo,
afforded a hygroscopic compound 26, which was directly
subjected to analysis by proton NMR and revealed to be
a single isomer (Scheme 9).
urea in a nonaqueous system, wherein the chiral furan
cycle induced the formation of the imidazolidin cycle
rather than the concerted pathway to the bicycle core
from glyoxal 9, led to an enhanced enantioselectivity and
a higher yield for the preparation of the key intermediate
to slagenins B and C.
Alter n a tive Ap p r oa ch es.28 Prior to implementing the
successful preparation of the key intermediate, prelimi-
nary studies were first conducted enlisting an R-ke-
tothioketal for glyoxal 9 (Scheme 7).9 Thus, ester 6 was
subjected to an elongation of the carbon chain with 1,3-
dithiane through umpolung to afford thioketal 21.28
However, all attempts to cleave the thioketal failed to
provide the glyoxal 9, which we attributed to the unstable
quality of glyoxals and the enhanced stability of the
thioketal with an electron-withdrawing carbonyl group.29
We also examined an approach in which the carbon
chain was elongated through a Wittig reaction (Scheme
8). Thus, ester 6 was reduced with Dibal-H at -78 °C to
give aldehyde 22,16,28 of which the carbon chain was
elongated with Wittig reagent Ph3PCH3Br.30 Dihydroxyl-
ation of the obtained alkene 2328 in 50% aqueous t-BuOH
in the presence of K3[Fe(CN)6] and a catalytic amount of
OsO4 afforded 1,2-diol 24.28,31 However, our efforts for
oxidation of compound 24 for glyoxal 9 proved fruitless.32
Presumably, this may be attributed to the unstable
quality of glyoxals and the interference of a carbonyl
group that might have been generated with the neigh-
boring hydroxy group.33
According to the observations described above, we
proposed that a conversion of one isomer to another
occurred at the amine stage. A plausible mechanism for
this conversion was arbitrarily brought forward. As is
shown in Scheme 10, the potential mechanism involves
a transformation of the endo-urea C into its exo-form C′
via the ion pair D due to the obvious intramolecular
hindrance. Some support for this mechanism was found
in the formation of ketal 19 (Scheme 5), wherein the ketal
was derived directly from urea and ketone17. Accord-
ingly, there might be an equilibrium between the labile
hemiketal A and ketone B, which was involved in an
intramolecular nucleophilic attack leading to species C
(28) Experimental details and characterization may be found in the
Supporting Information.
(29) (a) Corey, E. J .; Bock, M. G. Tetrahedron Lett. 1975, 2643. (b)
Prato, M.; Quinity, U.; Scorrano, G.; Sturaro, A. Synthesis 1982, 679.
(c) J uaristi, E.; Tapia, J .; Mendez, R. Tetrahedron 1986, 42, 1253. (d)
Cossy, J . Synthesis 1987, 1113.
(30) Wittig, G.; Scho¨llkopf, U. Organic Syntheses; Wiley: New York,
1973; Collect. Vol. V, p 751.
(31) Akashi, K.; Palermo, R. E.; Sharpless, K. B. J . Org. Chem. 1978,
43, 2063.
(32) (a) Mancuso, A. J .; Swern, D. Synthesis 1981, 165. (b) Amon,
C. M.; Banwell, M. G.; Gravatt, G. L. J . Org. Chem. 1987, 52, 4851. (c)
Ireland, R. E.; Norbeck, D. W. J . Org. Chem. 1985, 50, 2198. (d)
Newman, M. S.; Davis, C. C. J . Org. Chem. 1967, 32, 66.
(33) Tius, M. A.; Fauq, A. H. J . Am. Chem. Soc. 1986, 108, 1035.
2380 J . Org. Chem., Vol. 68, No. 6, 2003

Syntheses of Slagenins A-C and Their Antipodes
SCHEME 10
solution was stirred for more 20 min and then heated at 45
°C overnight. After cooling to ambient temperature the reac-
tion mixture was transferred into 500 mL of water. The
resulting solution was extracted with hexane. The combined
organic layers were dried (MgSO4) and concentrated to give a
yellow oil (44.5 g).
with a [2.2.1]bicycle. With a key transformation from C
to C′, amine A was converted into its diastereoisomer A′.
Con clu sion
In conclusion, the enantioselective total syntheses of
salgenins A-C and their antipodes have been accom-
plished in which their absolute stereochemistries were
established. A very direct and efficient method for
preparing the cis-fused tetrahydrofuro[2,3-d]imidazoli-
din-2-one with a quarternary carbon center either from
glyoxal or from dihydrofuran-3-one has been developed.
NaN3 (22.9 g, 0.352 mol) was added to the yellow oil solution
in 150 mL of DMF. The reaction was stirred at ambient
temperature for 1 h and then heated at 90 °C overnight. After
cooling to ambient temperature the reaction mixture was
transferred into 500 mL of water. The solution was extracted
with hexane. The combined organic layers were dried (Na2-
SO4) and concentrated to give a brown oil. The brown oil was
distilled under reduced pressure to afford the title compound
6 (38.7 g, 85%) as a yellow oil: bp 114-116 °C/140 Pa; [R]20
D
Exp er im en ta l Section
+3.4 (c 3.7, CHCl3); 1H NMR (300 MHz, CDCl3) δ 4.25 (m, 1H),
4.13 (q, J ) 7.1 Hz, 2H), 3.37 (dd, J ) 12.5, 4.3 Hz, 1H), 3.23
(dd, J ) 12.5, 5.3 Hz, 1H), 2.54 (dd, J ) 6.2, 2.2 Hz, 2H), 1.27
Gen er a l In for m a tion . Air- and water-sensitive reactions
were performed in flame-dried glassware under a nitrogen
atmosphere. Air- and moisture-sensitive reagents were intro-
duced via dry syringe and cannula. THF was distilled from
sodium benzophenone. Triethylamine was distilled from CaH2.
DMF was stored over molecular sieves. Flash chromatography
was carried out with use of 300∼400 mesh silica gel. Melting
points were recorded on WRS-1A apparatus and were uncor-
rected. 1H NMR spectra were obtained with 300-, 400-, or 600-
MHz spectrometers by using TMS (0.00) as an internal
standard. 13C NMR spectra were obtained with either 75 or
100 MHz spectrometers with use of chloroform (77.0) or DMSO
(39.43) as the internal standards. NOESY spectra were
obtained with a 400-MHz spectrometer. Optical rotations were
obtained by using the sodium D line.
(t, J ) 7.1 Hz, 3H), 0.90 (s, 9H), 0.13 (s, 3H), 0.09 (s, 3H); 13
C
NMR (75 MHz, CDCl3) δ 170.5, 68.6, 60.3, 56.2, 39.9, 25.5,
17.7, 13.9, -5.0, -5.3; IR (neat) 2105, 1737 cm-1; EIMS m/z
(rel intensity) 272 (M - Me, 0.46), 73 (100.00). Anal. Calcd
for C12H25N3O3Si: C, 50.14; H, 8.77; N, 14.62. Found: C, 50.29;
H, 8.73; N, 14.89.
(S)-4-Azido-3-(ter t-bu tyl-dim eth yl-siloxy)-bu tan oic acid
(7). To a solution of ethyl (S)-4-azido-3-(tert-butyl-dimethyl-
siloxy)-butanonate (8.62 g, 30.0 mmol) in 50 mL of acetone
was added 60 mL of aqueous LiOH (1.0 mol/L). The solution
was stirred at ambient temperature for 3.5 h. The solution
was concentrated on a rotatory evaporator to remove excess
acetone. The residual solution was acidified with HCl (2.0 mol/
L) to pH 2 and then extracted with ether. The combined
organic layers were dried (Na2SO4). After removal of the
solution the residue was purified through flash chromatogra-
Eth yl (S)-4-Ch lor o-3-h yd r oxy-bu ta n on a te (5). An au-
toclave was charged with ethyl 4-chloroaceto-acetate (3) (20.0
g, 0.122 mol) in methanol (300 mL) and was hydrogenated over
Ru(OAc)2[(R)-(-)-BINAP] (200 mg) at a pressure of 40 atm at
100 °C for 1.5 h. The reaction mixture was concentrated on a
rotatory evaporator. The residue was distilled under reduced
pressure to afford 5 (19.2 g, 95%) as a colorless oil: bp 95 °C
(3 mmHg). The enantiomeric excess of 5 was determined to
be 97% ee by HPLC analysis of the corresponding (R)-MTPA
phy to afford the title compound 7 (7.38 g, 95%) as a colorless
1
oil: [R]20 -3.5 (c 1.6, CHCl3); H NMR (300 MHz, CDCl3) δ
D
11.17 (br s, 1H), 4.16 (m, 1H), 3.28 (dd, J ) 12.5, 4.4 Hz, 1H),
3.15 (dd, J ) 12.5, 5.2 Hz, 1H), 2.50 (dd, J ) 6.2, 4.5 Hz, 2H),
0.80 (s, 9H), 0.07 (s, 3H), 0.04 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 177.3, 68.4, 56.2, 39.9, 25.5, 17.8, -4.8, -5.2; IR
(neat) 2106, 1715 cm-1; EIMS m/z (rel intensity) 260 (M + 1,
21.59), 73 (100.00). Anal. Calcd for C10H21N3O3Si: C, 46.31;
H, 8.16; N, 16.20. Found: C, 46.31; H, 8.16; N, 16.27.
ester. [R]20 +20.5 (c 5.5, CHCl3) (lit.14a for (S)-5 in 97% ee,
D
[R]20 +20.9 (c 7.71, CHCl3).
D
E t h yl (S)-4-Azid o-3-(ter t-b u t yl-d im et h yl-siloxy)-b u -
ta n on a te (6). A flame-dried 250-mL round-bottom flask
equipped with a reflux condenser was charged with ethyl (S)-
4-chloro-3-hydroxy-butanonate (26.4 g, 0.158 mol), TBDMSCl
(34.2 g, 0.227 mol), and 80 mL of redistilled DMF. The solution
was stirred at ambient temperature under a nitrogen atmo-
sphere and imidazole (34.8 g, 0.511 mol) was added in three
portions during a period of 40 min. The resulting yellow
(S)-5-Azid o-4-(ter t-bu tyl-d im eth yl-siloxy)-1-d ia zo-p en -
ta n e-2-on e (8). A flame-dried 250-mL round-bottom flask was
charged with (S)-4-azido-3-(tert-butyl-dimethyl-siloxy)-butanoic
acid (3.89 g, 15.0 mmol) and 100 mL of dry THF. The solution
was stirred at -20 °C under a nitrogen atmosphere. To this
solution was added triethylamine (2.80 mL, 20.1 mmol)
followed by isobutyl chloroformate (2.60 mL, 20.0 mmol). The
J . Org. Chem, Vol. 68, No. 6, 2003 2381

J iang et al.
solution was stirred for half an hour and then allowed to warm
to -10 °C. At this temperature ethereal diazomethane (0.4
mol/L, 75 mL, 30 mmol) was added via a dry syringe in three
portions over half an hour. The reaction mixture was stirred
at -10 °C overnignt and allowed to warm to ambient temper-
ature. It was then evaporated to a fifth of its original volume
on a rotatory evaporator with an acetic acid trap to destroy
residual diazomethane. The solution was diluted with ether
(200 mL) and washed with water, saturated aqueous NaHCO3,
and brine. The organic layer was dried (Na2SO4). After
concentration, the residue was purified through flash chro-
matography to give the title compound 8 (3.84 g, 90%) as a
chromatography afforded azide 10a (112 mg, 264 mg as total,
26%), azide 10b (23 mg), a mixture of 10b and 10c (515 mg),
and azide 10c (45 mg) all as yellow solids. Crystals suitable
for X-ray structure analysis of compound 10c were obtained
from EtOAc.20 From the proton NMR spectral data, the two
isomers (10b/10c) (583 mg as total, 54%) were assigned to be
in a ratio of 9:5.
Compound 10b: mp 110-112 °C; [R]20D -41.4 (c 1.0, CHCl3);
1H NMR (300 MHz, CDCl3) δ 6.71 (s, 1H), 6.34 (s, 1H), 5.40
(s, 1H), 4.35 (m, 1H), 3.55 (dd, J ) 13.1, 3.3 Hz, 1H), 3.40-
3.25 (m, 4H), 2.21 (dd, J ) 12.2, 5.2 Hz, 1H), 2.11 (dd, J )
12.2, 7.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 160.8, 98.7,
88.7, 76.9, 52.7, 51.5, 41.0; IR (KBr) 3233, 3084, 2092, 1724
cm-1; EIMS m/z (rel intensity) 214 (M + 1, 0.31), 182 (M -
OMe, 0.75), 157 (100.00).
Compound 10c: mp 106-109 °C; [R]20D +93.8 (c 1.1, CHCl3);
1H NMR (300 MHz, CDCl3) δ 6.72 (s, 1H), 6.48 (s, 1H), 5.27
(s, 1H), 4.38 (m, 1H), 3.41 (dd, J ) 13.1, 7.0 Hz, 1H), 3.32-
3.26 (m, 4H), 2.48 (dd, J ) 13.4, 7.3 Hz, 1H), 2.13 (dd, J )
13.4, 5.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 160.0, 98.1,
89.5, 77.5, 53.9, 50.8, 41.1; IR (KBr) 3207, 3089, 2105, 1709
cm-1; EIMS m/z (rel intensity) 182 (M - OMe, 0.74), 157
(100.00). Anal. Calcd for C7H11N5O3: C, 39.44; H, 5.20; N,
32.85. Found: C, 39.52; H, 5.03; N, 33.08.
5-O-Ben zoyl-1,2-O-isopr opyliden e-r-L-xylofu r an ose (12).
A mixture of L-xylose (15.0 g, 0.100 mol), dry CuSO4 (34.4 g,
0.216 mol), and concentrated H2SO4 (3 mL) in acetone (150
mL) was stirred at ambient temperature for 24 h. The mixture
was filtered, and the solid was washed with acetone. The
filtrate was neutralized with concentrated NH4OH, and the
resulting white solid was removed by suction filtration.
Removal of the solvent in vacuo from the filtrate gave a syrup
that was treated with aqueous HCl (0.1 mol/L, 100 mL) for 1
h at ambient temperature. The reaction was quenched with
solid NaHCO3 to a pH of 7.5. The solution was washed with
ether once, and the aqueous fraction was evaporated in vacuo
to yield a pale yellow syrup, which was dissolved in CHCl3
(100 mL) prior to drying (Na2SO4). Filtration and removal of
the solvent in vacuo afforded a pale yellow syrup (18.6 g, 0.098
mol).
yellow oil: [R]20 +0.3 (c 1.0, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 5.30 (b rs, 1H), 4.33 (m, 1H), 3.40 (dd, J ) 12.6, 4.0
Hz, 1H), 3.17 (dd, J ) 12.6, 4.7 Hz, 1H), 2.53 (d, J ) 5.6 Hz,
2H), 0.90 (s, 9H), 0.12 (s, 3H), 0.08 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 191.9, 68.8, 56.4, 55.7, 45.7, 25.6, 17.8, -4.9, -5.1;
IR (neat) 2103, 1641 cm-1; EIMS m/z (rel intensity) 283 (M,
28.27), 282 (100.00). Anal. Calcd for C11H21N5O2Si: C, 46.62;
H, 7.47; N, 24.71. Found: C, 46.70; H, 7.55; N, 24.94.
(S)-5-Azido-4-(ter t-bu tyl-dim eth yl-siloxy)-1,1-dih ydr oxy-
p en ta n e-2-on e (9).18 To a solution of R-diazoketone 8 (313
mg, 1.10 mmol) in 5.0 mL of acetone was added a DMD-
acetone solution (0.09-0.11 mol/L) in portions. The solution
was stirred at ambient temperature and the reaction was
monitored by TLC analysis. A total of 10 mL of the DMD-
acetone solution was added as the first portion and evolution
of nitrogen gas was observed. After 5 min of stirring, small
portions (0.5 mL per portion) of the DMD-acetone solution
were added before the starting material had just vanished.
The reaction mixture was concentrated to give the title glyoxal
9 (319 mg, quantitatively) as a colorless oil. It showed itself
from the proton NMR to be a mixture of the corresponding
aldehyde and its hydrate 9: [R]20 +12.9 (c 1.3, CHCl3); 1H
D
NMR (300 MHz, CDCl3) δ [9.19 (s, 0.1H) + 5.31 (m, 0.9H),
1H], 4.33 (m, 1H), 3.35 (m, 2H), 2.96 (m, 1H), 2.18 (m, 1H),
0.90 (s, 9H), 0.09 (s, 6H); IR (neat) 3421, 2105, 1733 cm-1
;
EIMS m/z (rel intensity) 289 (M, 0.53), 272 (0.79), 73 (100.00).
(5S)-5-Azid om eth yl-6a -h yd r oxy-h exa h yd r o-fu r o[2,3-d ]-
im id a zol-2-on e (10a ). To a solution of glyoxal 9 (from 596
mg, 2.10 mmol of R-diazoketone 8) and urea (155 mg, 2.58
mmol) in acetone-water (2:3, 20 mL) was added 1.80 mL of
40% aq HF. After being stirred at ambient temperature for
42 h, the resulting solution was quenched with solid K2CO3 to
a pH of 7-8. The solvent was removed in vacuo and the residue
was purified through flash chromatography to give azide 10a
(242 mg, 58%) as a yellow solid, which was assigned to be two
isomers in a ratio of 5:2 from the proton NMR spectrum: mp
Benzoyl chloride (11.4 mL, 0.098 mol) was added dropwise
over 30 min to an ice-cold solution of the syrup and pyridine
(15.9 mL, 0.196 mol) in dry CH2Cl2 (200 mL). The resulting
mixture was stirred at 0 °C for 1 h and washed with aqueous
HCl (1 mol/L, 2 × 100 mL), saturated NaHCO3 (2 × 100 mL),
and brine (2 × 100 mL) prior to drying of the organic fraction
(Na2SO4). After filtration and removal of the solvent in vacuo,
the residue was recrystallized from ether to afford the title
compound 12 as a white solid (23.5 g, 80% yield from
1
141-144 °C; H NMR (300 MHz, DMSO-d6, the two isomers
L-xylose): [R]20 -10.6 (c 1.2, CHCl3); 1H NMR (300 MHz,
are titled as a and b for clarification, a/b ) 2/5) δ 7.59 (s, 2Ha),
7.39 (s, 2Hb), 6.35 (s, 1Hb), 6.24 (s, 1Ha), 4.97 (s, 1Hb), 4.86
(s, 1Ha), 4.22 (m, 1Ha), 4.05 (m, 1Hb), 3.55 (dd, J ) 13.2, 2.9
Hz, 1Hb), 3.36-3.29 (m, 2Ha + 1Hb), 2.22 (dd, J ) 12.9, 7.3
Hz, 1Ha), 2.05 (dd, J ) 12.2, 4.2 Hz, 1Hb), 1.93-1.82 (m, 1Ha
+ 1Hb); 13C NMR (75 MHz, DMSO-d6) δ 160.4, 159.7, 93.7,
93.4, 93.1, 92.4, 77.0, 76.6, 53.5, 52.5, 42.0, 41.7; IR (KBr) 3271,
2099, 1710, 1691 cm-1; HR-ESIMS calcd for C6H9N5O3Na
222.0603, found 222.0603.
D
CDCl3) δ 8.09 (d, J ) 7.5 Hz, 2H), 7.63 (t, J ) 7.5 Hz, 1H),
7.49 (t, J ) 7.5 Hz, 2H), 5.99 (d, J ) 3.7 Hz, 1H), 4.84 (dd, J
) 12.9, 9.5 Hz, 1H), 4.63 (d, J ) 3.7 Hz, 1H), 4.44-4.39 (m,
2H), 4.20 (br s, 1H), 3.33 (d, J ) 3.7 Hz, 1H), 1.54 (s, 3H), 1.36
(s, 3H).
5-O-Ben zoyl-3-deoxy-1,2-O-isopr opyliden e-r-L-r ibofu r a-
n ose (13). NaH (0.520 g, 13.0 mmol, 60% suspension in
mineral oil) was washed twice with hexanes and added slowly
to a well-stirred and precooled (-10 °C) solution of alcohol 12
(2.75 g, 9.34 mmol) in dry THF (30 mL). Immediately there-
after, CS2 (0.90 mL, 15 mmol) was added, and the red solution
was allowed to warm to ambient temperature, at which
temperature it was stirred overnight. The reaction mixture
was then re-cooled to 0 °C and treated with methyl iodide (1.50
mL, 24.1 mmol). After being stirred at ambient temperature
for an additional 1.5 h, the yellow solution was quenched with
ice-water (100 mL) and extracted with ethyl ether. The
ethereal layers were combined, dried (Na2SO4), and concen-
trated under reduced pressure to afford the corresponding
xanthate (3.5 g) as a yellow foam. This foam was dissolved in
dry benzene (180 mL) and treated with Bu3SnH (3.60 mL, 13.4
mmol). The reaction mixture was preheated at 80 °C and
(3a S,5S,6a S)-5-Azid om et h yl-6a -m et h oxy-h exa h yd r o-
fu r o[2,3-d]im idazol-2-on e (10b)/(3aR,5S,6aR)-5-Azidom eth -
yl-6a-m eth oxy-h exah ydr o-fu r o[2,3-d]im idazol-2-on e (10c).
To a solution of glyoxal 9 (from 1.43 g, 5.06 mmol of R-diaz-
oketone 8) and urea (0.344 g, 5.73 mmol) in 66 mL of methanol
was added 9.0 mL of 40% aqueous HF. After being stirred at
ambient temperature for 35 h, the reaction was quenched with
aqueous saturated Na2CO3 to a pH of 6. Most of the methanol
was removed under reduced pressure and diluted with 200 mL
of water. The solution was extracted with ethyl acetate. The
aqueous fraction was concentrated in vacuo and the residue
was purified through flash chromatography to give azide 10a
(152 mg). On the other hand, the combined organic fractions
were dried over Na2SO4. After evaporation of the solvent, flash
2382 J . Org. Chem., Vol. 68, No. 6, 2003

Syntheses of Slagenins A-C and Their Antipodes
treated with AIBN (78 mg, 0.48 mmol) added in six portions
over a period of 3 h. After the solution was stirred for 1 h, the
solvent was removed under reduced pressure and the crude
residue was purified through flash chromatography to afford
aqueous solution of Na2S2O3 (1%, 20 mL). The mixture was
extracted with ethyl acetate, and the extract was dried (Na2-
SO4). After evaporation, the residual brown oil (336 mg, 94%)
was supposed to be a mixture of the â-anomer and the
R-anomer of compond 16 (â:R ∼ 6:1) by proton NMR analysis.
It was purified through flash chromatography to give the
â-anomer of compond 16 (282 mg, 79%) as a brown oil.
the title compound 13 (1.77 g, 68%) as a colrless oil: [R]20
D
-2.3 (c 1.9, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.06 (d, J )
7.5 Hz, 2H), 7.56 (t, J ) 7.5 Hz, 1H), 7.44 (t, J ) 7.5 Hz, 2H),
5.88 (d, J ) 3.9 Hz, 1H), 4.78 (t, J ) 3.9 Hz, 1H), 4.58-4.51
(m, 2H), 4.36 (dd, J ) 12.0, 5.7 Hz, 1H), 2.18 (dd, J ) 13.5,
3.9 Hz, 1H), 1.76 (m, 1H), 1.54 (s, 3H), 1.33 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 166.1, 132.9, 129.54, 129.51, 128.2, 111.0,
105.5, 80.0, 75.6, 65.0, 35.1, 26.5, 25.9; IR (neat) 1722, 1277
cm-1; HR-ESIMS calcd for C15H18O5Na 301.10465, found
301.10466.
â-anomer: [R]20 +37.7 (c 1.0, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 4.79 (s, 1H), 4.46 (m, 1H), 4.21 (t, J ) 3.3 Hz, 1H),
3.34 (s, 3H), 3.26 (d, J ) 6.0 Hz, 2H), 3.04 (d, J ) 3.3 Hz, 1H),
1.92 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 109.4, 78.3, 75.5,
56.2, 54.7, 35.2; IR (neat) 3427, 2103, 1284 cm-1; ESIMS m/z
196.1 [M + Na]+. Anal. Calcd for C6H11N3O3: C, 41.62; H, 6.40;
N, 24.27. Found: C, 41.62; H, 6.55; N, 24.42.
3-Deoxy-1,2-O-isop r op ylid en e-r-L-r ibofu r a n ose (14). To
a solution of ester 13 (790 mg, 2.84 mmol) in anhydrous
methanol (10 mL) was added NaOMe (230 mg, 4.26 mmol),
and the resulting solution was stirred at ambient temperature
(5R)-5-Azid om et h yl-2-m et h oxy-d ih yd r o-fu r a n -3-on e
(17). Alcohol 16 (pure â-anomer, 233 mg, 1.35 mmol) was
added to a solution of Dess-Martin periodinane (5.50 mL, 1.95
mmol, 15 wt % in CH2Cl2) at 0 °C. The mixture was allowed
to warm to ambient temperature and stirred for 18 h. The
solvent was removed in vacuo and the residue was triturated
with ethyl ether (30 mL). Following filtration through a pad
of MgSO4, the organic solution was stirred with an equal
volume of Na2S2O3‚5H2O (3.75 g) in 30 mL of aqueous
saturated NaHCO3 until the organic layer became clear (∼10
min). The organic layer was separated, washed with brine, and
dried over MgSO4. After removal of the solvent, the residue
was purified through flash chromatography to give the title
under
a nitrogen atmosphere for 2 h. The solvent was
evaporated and the residue was purified through flash chro-
matography to afford alcohol 14 (460 mg, 93%) as a colorless
solid: mp 77-78 °C; [R]20D +15.6 (c 1.3, CHCl3); 1H NMR (300
MHz, CDCl3) δ 5.74 (d, J ) 3.6 Hz, 1H), 4.67 (t, J ) 4.2 Hz,
1H), 4.24 (m, 1H), 3.77 (dt, J ) 11.7, 3.9 Hz, 1H), 3.47 (m,
1H), 2.80 (t, J ) 5.7 Hz, 1H), 1.91 (dd, J ) 13.5, 4.8 Hz, 1H),
1.74 (m, 1H), 1.42 (s, 3H), 1.23 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 111.0, 105.3, 80.5, 78.4, 62.6, 33.7, 26.5, 25.9; IR
(KBr) 3482, 3381, 1267 cm-1; HR-ESIMS calcd for C8H14O4-
Na 197.0784, found 197.0778.
ketone 17 (187 mg, 81%) as a pale yellow oil: [R]20 -39.9 (c
D
1
1.5, CHCl3); H NMR (300 MHz, CDCl3) δ 4.70 (s, 1H), 4.63
(m, 1H), 3.56 (dd, J ) 12.9, 6.9 Hz, 1H), 3.51 (s, 3H), 3.38 (dd,
J ) 12.9, 4.8 Hz, 1H), 2.67 (dd, J ) 18.9, 8.1 Hz, 1H), 2.45
(dd, J ) 18.9, 4.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 206.8,
99.1, 75.0, 56.3, 55.6, 36.5; IR (neat) 2106, 1776 cm-1; ESIMS
m/z 194.1 [M + Na]+. Anal. Calcd for C6H9N3O3: C, 42.11; H,
5.30; N, 24.55. Found: C, 42.11; H, 5.51; N, 24.51.
5-Azid o-3,5-d id eoxy-1,2-O-isop r op ylid en e-r-L-r ibofu r a -
n ose (15). p-Toluenesulfonyl chloride (950 mg, 4.98 mmol) was
added in two portions at an interval of 30 min to a solution of
alcohol 14 (570 mg, 3.27 mmol) and pyridine (0.80 mL, 9.9
mmol) in CHCl3 (10 mL). After addition, the mixture was
stirred at ambient temperature overnight. The reaction was
quenched with ice-water (30 mL) and extracted with CH2-
Cl2. The organic layer was washed with aqueous HCl (1 mol/
L), aqueous saturated NaHCO3, water, and brine in turn, and
dried (Na2SO4). The solvent was removed in vacuo and the
residue purified through flash chromatography to produce
3-deoxy-1,2-O-isopropylidene-5-O-(p-toluenesulfonyl)-R-L-ribo-
5-Azid om eth yl-6a -h yd r oxy-h exa h yd r o-fu r o[2,3-d ]im i-
d a zol-2-on e [(3a R,5R,6a R)-18a /(3a S,5R,6a S)-18b]. To a
solution of ketone 17 (52 mg, 0.30 mmol) in THF (6 mL) was
added aqueous HCl (0.1 mol/L, 0.6 mL) and the resulting
solution was heated at reflux for 8 h. The reaction mixture
was then concentrated to 1 mL (a further concentration would
result in a nigrescence product). The resulting yellow solution
was then treated with urea (22 mg, 0.37 mmol) in 6 mL of
aqueous HCl (0.01 mol/L) at ambient temperature for 48 h.
The reaction mixture was neutralized with solid NaHCO3, the
solvent was evaporated in vacuo, and the residue was purified
through flash chromatography to afford a mixture of 18a /18b
(45 mg, 75%) as a white solid (two diastereoisomers in a ratio
of 1.1:1): mp 138-141 °C; 1H NMR (300 MHz, acetone-d6, the
two isomers are arbitrarily regarded as in an equal quantity
for clarification) δ 9.60 (br s, 1H), 9.54 (br s, 1H), 7.17 (br s,
1H), 6.81 (br s, 1H), 4.57 (s, 1H), 4.55 (s, 1H), 4.24-4.13 (m,
2H), 3.37-3.27 (m, 4H), 2.87 (br s, 2H), 2.02-1.96 (m, 2H),
1.87-1.67 (m, 2H).
((5R)-5-Azid om eth yl-2,3-d im eth oxy-tetr a h yd r o-fu r a n -
3-yl)-u r ea (19). A mixture of ketone 17 (69 mg, 0.40 mmol),
urea (32 mg, 0.53 mmol), and a little Amberlyst-15 resin in
methanol (3 mL) was stirred at ambient temperature for 7
days. After removal of the solvent in vacuo, the residue was
purified through flash chromatography to give recycled ketone
17 (28 mg) and a white solid that was proposed to be urea 19
(11 mg, 11% yield and a yield of 19% based on the reacted
substrate): 1H NMR (300 MHz, CDCl3) δ 5.55 (br s, 1H), 5.27
(br s, 2H), 4.39 (m, 1H), 3.46 (s, 3H), 3.35 (s, 3H), 3.32 (d, J )
5.4 Hz, 1H), 2.57 (dd, J ) 12.9, 6.3 Hz, 1H), 1.95 (dd, J ) 12.9,
9.6 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 167.7, 102.6, 93.3,
77.6, 55.55, 55.47, 50.0, 37.5.
furanose (1.05 g, 98%) as a white solid: mp 62-63 °C; [R]20
D
1
+12.1 (c 1.4, CHCl3); H NMR (300 MHz, CDCl3) δ 7.75 (d, J
) 8.1 Hz, 2H), 7.31 (d, J ) 8.1 Hz, 2H), 5.69 (d, J ) 3.9 Hz,
1H), 4.68 (t, J ) 3.9 Hz, 1H), 4.32 (m, 1H), 4.15 (dd, J ) 10.8,
3.3 Hz, 1H), 4.04 (dd, J ) 10.8, 4.8 Hz, 1H), 2.41 (s, 3H), 2.03
(dd, J ) 13.5, 7.8 Hz, 1H), 1.70 (m, 1H), 1.43 (s, 3H), 1.26 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 144.9, 132.5, 129.7, 127.8,
111.3, 105.4, 80.1, 75.0, 69.6, 34.5, 26.6, 26.0, 21.5; IR (KBr)
1594, 1187, 1020, 959, 678 cm-1; ESIMS m/z 329.1 [M + H]+.
Anal. Calcd for C15H20SO6: C, 54.86; H, 6.14; S, 9.76. Found:
C, 54.93; H, 5.90; S, 9.96.
NaN3 (656 mg, 10.1 mmol) was added to a solution of
3-deoxy-1,2-O-isopropylidene-5-O-(p-toluenesulfonyl)-R-L-ribo-
furanose (827 mg, 2.52 mmol) in DMF (15 mL). The resulting
mixture was heated at 90 °C overnight. After removal of the
DMF in vacuo, the residue was partitioned between water and
CH2Cl2, and the combined organic extracts were dried over
Na2SO4. After removal of the solvent, the residue was purified
through flash chromatography to afford azide 15 (498 mg, 99%)
as a colorless oil: [R]20D -3.9 (c 0.9, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 5.78 (d, J ) 3.6 Hz, 1H), 4.71 (t, J ) 4.5 Hz, 1H),
4.33 (m, 1H), 3.52 (dd, J ) 13.2, 3.6 Hz, 1H), 3.21 (dd, J )
13.2, 4.8 Hz, 1H), 2.01 (dd, J ) 13.2, 4.5 Hz, 1H), 1.71 (m,
1H), 1.45 (s, 3H), 1.26 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
111.1, 105.3, 80.3, 76.5, 52.6, 35.3, 26.5, 25.9; IR (neat) 2102,
1217 cm-1; HR-ESIMS calcd for C8H13N3O3Na 222.0849, found
222.0853.
5-Azid om eth yl-6a -m eth oxy-h exa h yd r o-fu r o[2,3-d ]im i-
d a zol-2-on e [(3a R,5R,6a R)-20a /(3a S,5R,6a S)-20b]. Ketone
17 (24 mg, 0.14 mmol) was treated with urea (13 mg, 0.22
mmol) in 2 mL of 5% HCl-MeOH. After heating at reflux for
10 h, the volatiles were removed in vacuo and the residue was
Meth yl 5-Azid o-3,5-d id eoxy-r,â-L-r ibofu r a n ose (16). A
solution of azide 15 (410 mg, 2.06 mmol) in 1% I2 in MeOH
(13 mL) was heated at reflux for 18 h. The solution was then
concentrated to half of the volume and poured into a stirred
J . Org. Chem, Vol. 68, No. 6, 2003 2383

J iang et al.
purified through flash chromatography to produce a mixture
of 20a and 20b (23 mg, 77%). From the 1H NMR spectrum,
the two isomers (20a /20b) were assigned to be in a ratio of
3.8:1: mp 111-114 °C; 1H NMR (300 MHz, DMSO-d6, the two
isomers are titled as a and b for clarification, a/b ) 3.8/1)) δ
7.80 (s, 1Ha), 7.76 (s, 1Ha), 7.60 (s, 1Hb), 7.57 (s, 1Hb), 5.23
(s, 1Hb), 5.08 (s, 1Ha), 4.23 (m, 1Ha), 4.08 (m, 1Hb), 3.57 (dd,
J ) 13.2, 2.9 Hz, 1Hb), 3.34-3.22 (m, 2Ha + 1Hb), 3.15 (s,
3Hb), 3.12 (s, 3Ha), 2.30 (dd, J ) 13.0, 7.4 Hz, 1Ha), 2.12 (dd,
J ) 12.2, 4.5 Hz, 1Hb), 1.97-1.84 (m, 1Ha + 1Hb); IR (KBr)
J ) 13.2, 6.8 Hz, 1H), 1.87 (dd, J ) 13.2, 6.6 Hz, 1H); 13C NMR
(100 MHz, DMSO-d6) δ 159.7, 159.4, 126.7, 121.2, 111.7, 97.2,
94.9, 89.3, 76.0, 49.8, 42.7, 40.9; IR (KBr) 3277, 1715, 1636,
1568 cm-1; EIMS m/z (rel intensity) 328 (M - OMe, 43.30),
326 (43.65), 174 (92.13), 172 (100.00), 157 (65.47).
Sla gen in A (1a ). Following the procedure for the prepara-
tion of 2a from 10a , slagenin A (1a ) was prepared from azide
18a /18b in a yield of 69%. Slagenin A (1a ): a colorless solid;
mp 102-104 °C; [R]20D +7.7 (c 0.8, MeOH); 1H NMR (300 MHz,
DMSO-d6) δ 11.83 (s, 1H), 8.23 (t, J ) 6.0 Hz, 1H), 7.32 (s,
1H), 7.30 (s, 1H), 6.97 (s, 1H), 6.87 (s, 1H), 6.26 (br s, 1H),
4.94 (s, 1H), 4.00 (m, 1H), 3.48-3.17 (m, 2H), 2.06 (dd, J )
11.7, 4.4 Hz, 1H), 1.73 (t, J ) 11.7 Hz, 1H); 13C NMR (100
MHz, DMSO-d6) δ 159.7, 159.1, 126.7, 121.2, 111.6, 94.9, 93.3,
91.9, 76.1, 43.0, 41.5; IR (KBr) 3278, 1720, 1530 cm-1; ESIMS
m/z 367.0 and 369.0 [(M + Na)+, 1:1]; HR-ESIMS calcd for
3215, 3090, 2104, 1728, 1709 cm-1
.
(3a R,5R,6a R)-5-Am in om eth yl-6a -h yd r oxy-h exa h yd r o-
fu r o[2,3-d ]im id a zol-2-on e (26). The mixture of 18a /18b (1.1:
1)(20 mg) was hydrogenated over a little 10% Pd/C for 3 days.
Filtration through kieselguhr and removal of the solvent in
vacuo afforded crude amine 26 as a pale yellow syrup (18 mg,
100%). This crude product was subjected to proton NMR
analysis without further purification: 1H NMR (300 MHz,
DMSO-d6) δ 7.32 (s, 1H), 7.29 (s, 1H), 4.92 (s, 1H), 3.84 (m,
1H), 3.60-3.31 (m, 3H), 2.64 (br s, 2H), 2.03 (dd, J ) 12.0, 6.0
Hz, 1H), 1.74 (t, J ) 12.0 Hz, 1H).
(-)-An tip od e of Sla gen in A (2a ). Azide 10a (70 mg, 0.35
mmol) was hydrogenated over 7 mg of 10% Pd/C for 3 h.
Filtration through kieselguhr and removal of the solvent in
vacuo produced a yellow oil (58 mg). This oil was dissolved in
DMF (7 mL). To the resulting yellow solution was added
4-bromo-2-(trichloroacetyl)pyrrole (204 mg, 0.70 mmol) and the
solution turned rosy immediately. The reaction mixture was
stirred at ambient temperature overnight. The solvent was
evaporated in vacuo and the residue was dissolved with EtOAc.
The yellow organic fraction was washed with aqueous half-
saturated NaCl and dried (Na2SO4). After removal of the
solvent in vacuo, the residue was purified through flash
chromatography to afford 2a (93 mg, 77%) as a colorless
solid: mp 102-103 °C; [R]20D -7.6 (c 0.5, MeOH); 1H NMR (300
MHz, DMSO-d6) δ 11.83 (s, 1H), 8.23 (t, J ) 5.6 Hz, 1H), 7.34
(s, 1H), 7.32 (s, 1H), 6.97 (s, 1H), 6.87 (s, 1H), 6.26 (s, 1H),
4.95 (s, 1H), 4.00 (m, 1H), 3.34 (m, 2H), 2.04 (dd, J ) 11.7, 3.3
Hz, 1H), 1.71 (t, J ) 11.7 Hz, 1H); 13C NMR (75 MHz, DMSO-
d6) δ 159.7, 159.1, 126.7, 121.2, 111.6, 94.9, 93.3, 91.9, 76.1,
43.0, 41.5; IR (KBr) 3288, 1706, 1632, 1566, 1525 cm-1; ESIMS
m/z 345.0 and 347.1 [(M + H)+, 1:1], 367.0 and 369.1 [(M +
Na)+, 1:1]; HR-ESIMS calcd for C11H13N4O4Na79Br 367.0018,
found 367.0015.
(-)-An tip od e of Sla gen in B (2b) a n d (+)-An tip od e of
Sla gen in C (2c). A mixture containing 10b and 10c (13.0 mg,
0.061 mmol) was dissolved in 5 mL of methanol and a little
10% Pd/C was added. The mixture was hydrogenated under a
hydrogen atmosphere at ambient temperature for 1.5 h and
then filtered through kieselguhr. After concentration, the
resulting crude amine (12 mg, colorless solid) and 4-bromo-2-
(trichloroacetyl)pyrrole (40.0 mg, 0.137 mmol) were dissolved
in 5 mL of DMF and the solution was stirred at ambient
temperature overnight. After removal of DMF in vacuo, the
residue was dissolved in ethyl acetate (50 mL) and the solution
was washed with aqueous half-saturated NaCl and brine and
dried (Na2SO4). Flash chromatography afforded the two title
compounds 2b (11.4 mg) and 2c (6.2 mg) (17.6 mg as total,
C
11H13N4O4Na79Br 367.0018, found 367.0016.
Sla gen in A (1a )/Com p ou n d 25 [(9R,11S,15S)-isom er of
Sla gen in A]. A mixture of 18a /18b (40 mg) was treated with
triethylphosphine (0.22 mL, 1 mol/L in THF) in 2 mL of THF-
H2O (10/1). After the mixture was heated at reflux for 3 h,
the solvent was evaporated in vacuo. The residual red-orange
oil, after drying in vacuo at 40 °C for 2 h, was treated in one
pot with 4-bromo-2-(trichloroacetyl)pyrrole (90 mg, 0.31 mmol)
in DMF (2 mL) at ambient temperature overnight, followed
by the process of separation and purification described above,
to afford an unseparable mixture of slagenin A (1a ) and its
diastereoisomer 25 (31 mg, 45%) as a pale yellow solid. From
the proton NMR spectral data, the two isomers (1a /25) were
assigned to be in a ratio of 2.4:1: 1H NMR (300 MHz, DMSO-
d6, the data for compound 1a are omitted) δ 11.81(s, 1H), 8.17
(t, J ) 5.6 Hz, 1H), 7.52 (s, 1H), 7.47 (s, 1H), 6.97 (s, 1H), 6.87
(s, 1H), 6.17 (s, 1H), 4.80 (s, 1H), 4.13 (m, 1H), 3.37-3.26 (m,
2H), 2.20 (dd, J ) 13.0, 6.6 Hz, 1H), 1.86 (dd, J ) 13.0, 7.0
Hz, 1H).
Sla gen in B (1b) a n d Sla gen in C (1c). Following the pro-
cedure for the preparation of 2b and 2c from the mixture
containing 10b/10c, slagenins B (1a ) and C (1c) (1b/1c 3.8/1)
were prepared from a mixture containing 20b/20c (in a ratio
of 3.8:1) in a yield of 80%. Slagenin B (1b): mp 98-100 °C;
1
[R]20 +44.8 (c 0.5, MeOH); H NMR (400 MHz, DMSO-d6) δ
D
11.83 (s, 1H), 8.24 (t, J ) 5.9 Hz, 1H), 7.53 (s, 1H), 7.47 (s,
1H), 6.96 (s, 1H), 6.86 (s, 1H), 5.16 (s, 1H), 4.03 (m, 1H), 3.37
(m, 2H), 3.12 (s, 3H), 2.12 (dd, J ) 12.1, 4.0 Hz, 1H), 1.73 (t,
J ) 12.1 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 159.9,
159.7, 126.6, 121.3, 111.7, 97.9, 94.9, 88.4, 76.0, 50.4, 41.5, 41.3;
IR (KBr) 3274, 1712, 1637, 1567 cm-1. Slagenin C (1c): mp
1
195 °C dec; [R]20 -36.1 (c 0.8, MeOH); H NMR (300 MHz,
D
DMSO-d6) δ 11.83 (s, 1H), 8.18 (t, J ) 5.9 Hz, 1H), 7.71 (s,
1H), 7.68 (s, 1H), 6.97 (s, 1H), 6.87 (s, 1H), 5.01 (s, 1H), 4.13
(m, 1H), 3.34 (m, 2H), 3.09 (s, 3H), 2.27 (dd, J ) 12.6, 6.9 Hz,
1H), 1.89 (dd, J ) 12.6, 7.0 Hz, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 159.7, 159.4, 126.7, 121.3, 111.7, 97.2, 94.9, 89.3,
76.0, 49.8, 42.7, 40.9; IR (KBr) 3419, 3326, 3245, 3122, 1735,
1702, 1652, 1561, 1509 cm-1; EIMS m/z (rel intensity) 360 (M,
15.09), 358 (M, 15.61), 172 (93.46), 43(100.00); HR-ESIMS
calcd for C12H15N4O479Br 358.02767, found 358.02883.
Ack n ow led gm en t. We are grateful for financial
support from the Shanghai Municipal Committee of
Science and Technology. We also thank Prof. David A.
Horne (Oregon State University) for providing NMR
data for synthetic slagenin and Prof. Hongbin Zhai
(Shanghai Institute of Organic Chemistry, CAS) for
helpful discussions.
80%) both as colorless solids. Compound 2b: mp 98-100 °C;
1
[R]20 -45.4 (c 0.5, MeOH); H NMR (600 MHz, DMSO-d6) δ
D
11.78 (s, 1H), 8.21 (t, J ) 6.0 Hz, 1H), 7.48 (s, 1H), 7.44 (s,
1H), 6.96 (s, 1H), 6.86 (s, 1H), 5.16 (s, 1H), 4.05 (m, 1H), 3.40
(m, 2H), 3.13 (s, 3H), 2.14 (dd, J ) 12.0, 4.2 Hz, 1H), 1.75 (t,
J ) 12.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 159.9,
159.7, 126.6, 121.3, 111.7, 97.9, 94.9, 88.4, 76.0, 50.4, 41.5, 41.3;
IR (KBr) 3277, 1715, 1636, 1568 cm-1; ESIMS m/z 359.1 and
361.1 [(M + H)+, 1:1], 381.1 and 383.1 [(M + Na)+, 1:1]; HR-
ESIMS calcd for C12H15N4O4Na79Br 381.0174, found 381.0179.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and characterization data on compounds 21-24; ORTEP
figure and tables of X-ray crystallographic data for compound
10c. This material is available free of charge via the Internet
at http://pubs.acs.org.
Compound 2c: mp 196 °C dec; [R]20D +39.9 (c 0.75, MeOH);
1H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 8.16 (t, J ) 5.7
Hz, 1H), 7.70 (s, 1H), 7.66 (s, 1H), 6.96 (s, 1H), 6.86 (s, 1H),
4.99 (s, 1H), 4.12 (m, 1H), 3.42 (m, 2H), 3.10 (s, 3H), 2.25 (dd,
J O026773I
2384 J . Org. Chem., Vol. 68, No. 6, 2003