First Total Synthesis of 1-O-β-D-Glucopyranosyl-5-deoxyadenophorine and Its Aglycon Congener: Determination of the Absolute Configuration

Article abstract of DOI:10.1021/jo035522m

The first total synthesis of the potent glycosidase inhibitors 1-O-β-D-glucopyranosyl-5-deoxyadenophorine and its aglycon congener is described in respectively 13 steps (9% overall yield) and 9 steps (29% overall yield) from (R)-Garner aldehyde. The synthesis takes advantage of several key reactions including a diastereoselective allylation of a chiral imine, a stereoselective epoxidation, and a glycoside coupling. In addition this study established unambiguously the absolute configuration of the natural products.

Full text of DOI:10.1021/jo035522m

F ir st Tota l Syn th esis of
1-O-â-D-Glu cop yr a n osyl-5-d eoxya d en op h or in e a n d Its Aglycon
Con gen er : Deter m in a tion of th e Absolu te Con figu r a tion
Franc¸ois-Xavier Felpin,† Kamal Boubekeur,‡,§ and J acques Lebreton*,†
Laboratoire de Synthe`se Organique, CNRS UMR 6513, Universite´ de Nantes, Faculte´ des Sciences et des
Techniques, 2 rue de la Houssinie`re, BP 92208, 44322 Nantes Cedex 3, France, and Institut des
Mate´riaux J ean Rouxel, CNRS UMR 6502 Universite´ de Nantes, BP 32229, 2 rue de la Houssinie`re,
44322 Nantes Cedex 03, France
lebreton@chimie.univ-nantes.fr
Received October 15, 2003
The first total synthesis of the potent glycosidase inhibitors 1-O-â-D-glucopyranosyl-5-deoxyadeno-
phorine and its aglycon congener is described in respectively 13 steps (9% overall yield) and 9
steps (29% overall yield) from (R)-Garner aldehyde. The synthesis takes advantage of several key
reactions including a diastereoselective allylation of a chiral imine, a stereoselective epoxidation,
and a glycoside coupling. In addition this study established unambiguously the absolute configu-
ration of the natural products.
In tr od u ction
Interest in polyhydroxylated piperidines has undergone
remarkable expansion in recent years1 since the discovery
of nojirimycin 1, which displays glycosidase inhibitor
activities by glucose 2 mimicry (Figure 1) (by analogy
with the glycosyl oxocarbenium intermediate of the
enzymatic glycoside cleavage).2 The biological properties
of iminosugars can be explained by their structural
resemblance to their oxygenated analogues found in
natural substrates. Thus, due to these mimetic proper-
ties, iminosugars could be of great interest to treat a
variety of diseases such as diabetes,3 viral infections,4 and
tumor metastasis.5 As already discussed by Butters and
co-workers,6 hydrophobic substituents on iminosugars
can increase enzyme inhibitory activities. For example,
N-butyldeoxynojirimycin 3 (NB-DNJ ) has been approved
for use in Europe as therapy for Gaucher disease, a
glycolipid lysosomal storage disorder.7
F IGURE 1. Structure of nojirimycin 1, D-glucose 2, and NB-
DNJ 3.
* Address correspondence to this author. Phone: + 33 2 51 12 54
03. Fax: + 33 2 51 12 54 02.
† Laboratoire de Synthe`se Organique.
‡ Present address: LCIM2, UMR-CNRS 7071, Universite´ Pierre et
Marie Curie, 4 Place J ussieu, Case Courrier 42, 75252 Paris Cedex
05. To whom correspondence concerning the X-ray data should be
addressed. E-mail: boubekeu@ccr.jussieu.fr.
F IGURE 2. Structure of the alkaloids recently isolated by
Asano and co-workers.
§ Institut des Mate´riaux J ean Rouxel.
In this context, Asano and co-workers8 recently re-
ported the isolation of several new 6-alkyliminosugars
from Adenophora spp (Figure 2). These compounds are
rare examples of natural iminosugars containing hydro-
phobic R-1-C-substituents as the butyl- or ethyl-substi-
tuted compounds 4-8. Among them, 1-O-â-D-glucopy-
(1) (a) Asano, N. Curr. Top. Med. Chem. 2003, 3, 471-484. (b)
Compain, P.; Martin, O. R. Curr. Top. Med. Chem. 2003, 3, 541-560.
(2) Inouye, S. E.; Tsuruoka, Y.; Ito, T.; Niida, T. Tetrahedron 1968,
24, 2125-2129.
(3) Somsak, L.; Nagya, V.; Hadady, Z.; Docsa, T.; Gergely, P. Curr.
Pharm. Des. 2003, 9, 1177-1189.
(4) Greimel, P.; Spreitz, J .; Stutz, A. E.; Wrodnigg, T. M. Curr. Top.
Med. Chem. 2003, 3, 513-523.
(5) Nishimura, Y. Curr. Top. Med. Chem. 2003, 3, 575-591.
(6) (a) Platt, F. M.; Neises, G. R.; Karlsson, G. B.; Dwek, R. A.;
Butters, T. D. J . Biol. Chem. 1994, 269, 27108-27114. (b) Butters, T.
D.; van den Broek, L. A. G. M.; Fleet, G. W. J .; Krulle, T. M.; Wormald,
M. R.; Dwek, R. A.; Platt, F. M. Tetrahedron: Asymmetry 2000, 11,
113-124.
(7) Butters, T. D.; Dwek, R. A.; Platt, F. M. Chem. Rev. 2000, 100,
4683-4696.
(8) Ikeda, K.; Takahashi, M.; Nishida, M.; Miyauchi, M.; Kizu, H.;
Kameda, Y.; Arisawa, M.; Watson, A. A.; Nash, R. J .; Fleet, G. W. J .;
Asano, N. Carbohydr. Res. 2000, 323, 73-80.
10.1021/jo035522m CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/06/2004
J . Org. Chem. 2004, 69, 1497-1503
1497

Felpin et al.
SCHEME 1. Retr osyn th etic An a lysis
SCHEME 2a
ranosyl-5-deoxyadenophorine 4 was found to be a highly
potent R-glycosidase-specific inhibitor (IC50 ) 0.49-6.1
µM for R-glucosidase and IC50 ) 1.7 µM for R-galacto-
sidase). The structures as well as the relative configura-
tions of these new iminosugars were established by
extensive NMR studies.
In a previous report, we have developed a novel access
to chiral trans-2,6-dialkyl-1,2,5,6-tetrahydropyridines.9
As part of a continuing program directed toward the
synthesis of piperidine alkaloids with biological activity,10
we wished to extend our strategy to the synthesis of
iminosugars. Thus, herein we report the asymmetric total
synthesis of 1-O-â-D-glucopyranosyl-5-deoxyadenophorine
4 as well as its aglycon parent 5-named-5-deoxyadeno-
phorine 5. These first total syntheses confirm the struc-
ture assignment and their absolute configuration.
Our plan for preparing our target molecule focused on
iminosugar B, which should be a key intermediate and
on which a glycosidation reaction with glucose derivative
A would furnish 4 (Scheme 1). It was reasoned that this
aglycon compound B should be derived from tetrahydro-
pyridine 9 after oxidation of the double bond. According
to our recently described methodology,9 tetrahydropyri-
dine 9 could be obtained from commercially available
Garner aldehyde 10 by using two key reactions: a ring-
closing metathesis (RCM) reaction on the diethylenic
amine 11 and a diastereoselective allylation of a chiral
imine 12.
a
Reagents and conditions: (a) diethyl benzylphosphonate,
nBuLi, THF, -78 °C to room temperature, 14 h, 75%. (b)
Concentrated HCl, MeOH, reflux, 4 h, 98%. (c) Propanal, MgSO4,
THF, rt, 12 h, then allylmagnesium bromide, THF, Et2O, -78 to
-10 °C, 6 h, 87%.
(Scheme 2). A styryl group, known to be a good substrate
for the RCM reaction,11 was introduced to favorably
influence the diastereoselectivity in the allylation step
(vide infra). Hence, amino alcohol 14 reacted with pro-
panal to give the corresponding imine 12 on which a
diastereoselective allylation (87/13 dr) with allymagne-
sium bromide led to the diethylenic amino alcohol trans-
15. The minor cis isomer was found to be inseparable
from the trans isomer by flash chromatography at this
stage and consequently the next step was performed on
the diastereoisomeric mixture. Although the stereochem-
istry at the newly generated stereogenic center could not
be determined at this stage, the formation of amino
alcohol trans-15 as a major product was deduced from
previous results on similar structures9 and from a
mechanistic point of view. Indeed, we anticipated that
imino alcohol would react with Grignard reagent via the
Resu lts a n d Discu ssion
Syn th esis of th e Im in osu ga r Moiety. Olefination
of the Garner aldehyde 10 by a Horner-Wadworth-
Emmons reaction, using the semistabilized benzylphos-
phonate, furnished (E)-olefin 13 and occurred in a highly
stereospecific fashion. A subsequent global deprotection
of oxazolidine and Boc protecting groups afforded the
expected amino alcohol 14 in good yield (74%, 2 steps)
(9) Felpin, F.-X.; Lebreton, J . Tetrahedron Lett. 2003, 44, 527-530.
(10) (a) Felpin, F.-X.; Vo-Thanh, G.; Robins, R. J .; Villie´ras, J .;
Lebreton, J . Synlett 2000, 1646-1648. (b) Felpin, F.-X.; Girard, S.; Vo-
Thanh, G.; Robins, R. J .; Villie´ras, J .; Lebreton, J . J . Org. Chem. 2001,
66, 6305-6312. (c) Felpin, F.-X.; Lebreton, J . Tetrahedron Lett. 2002,
43, 225-227. (d) Felpin, F.-X.; Lebreton, J . J . Org. Chem. 2002, 67,
9192-9199.
(11) (a) Kirkland, T. A.; Lynn, D. M.; Grubbs, R. H. J . Org. Chem.
1998, 63, 9904-9909. (b) Garc´ıa-Fortanet, J .; Murga, J .; Carda, M.;
Marco, A. J . Org. Lett. 2003, 5, 1447-1449.
1498 J . Org. Chem., Vol. 69, No. 5, 2004

Total Synthesis of 1-O-â-D-Glucopyranosyl-5-deoxyadenophorine
SCHEME 3a
F IGURE 3. Stereoselectivity of the addition of allymagnesium
bromide over imino alcohol 12.
chelation model transition state C with a transient five-
membered ring, leading to the desired trans-adduct 15
contaminated by less than 13% of the undesired cis
isomer. Thus, the Grignard reagent attacks the less
hindered face of the imine, the Si face for the trans
addition (Figure 3).12 The relative stereochemistry was
fully confirmed later by an X-ray crystal structure (vide
infra).
With substrate 15 in hand, we focused our attention
on the RCM reaction. However, it is well-known that this
reaction was incompatible with free amines.13 Conse-
quently, the amino alcohol function was protected by
simple treatment of the diastereoisomer mixture with
carbonyldiimidazole (CDI) to give the corresponding
oxazolidinone 11 (86% yield) as its diastereoisomeric
mixture, which was not separated at this stage (Scheme
3). The next step was to construct the desired tetrahy-
dropyridine 9 by ruthenium-catalyzed intramolecular
cyclization. In this context, the mixture of oxazolidinone
11 treated with second generation Grubbs’ catalyst 16
in refluxed dichloromethane featured the formation of
tetrahydropyridine 9 in high yield. The minor cis isomer
was easily separated by flash chromatography.
a
Reagents and conditions: (a) CDI, Et3N, CH2Cl2, 18 h, 86%.
(b) [Ru]-16, CH2Cl2, 0.005 M, reflux, 1 h, 83% of trans-9 and 11%
of cis-9. (c) mCPBA, CH2Cl2, 0 °C to rt, 72 h, 86% of endo-17 and
5% of exo-17. (d) AcOH, 100 °C, 17 h, 79% of 18 and 10% of 19. (e)
K2CO3, MeOH, rt, 3 h, 95%. (f) NaH, BnBr, DMF, 0 °C to rt, 4 h,
93%. (g) 8 N NaOH, MeOH, 95 °C, 24 h, then, Cbz-Cl, CH2Cl2, 0
°C to rt, 4 h, 74%.
A significant goal of this study was the demonstration
of the utility of tetrahydropyridine as a key precursor of
iminosugar. It was envisaged that the requisite hydroxyl
functions of the desired iminosugar would be introduced
by functionalization of the olefin. So, epoxidation of the
double bond with mCPBA proceeded with good diaste-
reoselectivity (9/1 dr) in favor of the desired endo 17
isomer, as determined by extensive NOESY NMR experi-
ments and previous results obtained in our laboratory
on a similar structure.13h The desired endo-epoxide 17
was separated from its unwanted exo isomers by chro-
matography on silica gel. In contrast to previous reports
in the literature,14 the opening of epoxide 17 with acetic
acid was totally regioselective to give a mixture of
monoacetate 18 and diacetate 19 (86/14 ratio mixture,
89% combined yield). In fact, compound 19 was formed
by in situ esterification of monoacetate 18. The absolute
configuration of 18 was unambiguously confirmed by an
X-ray crystal structure (see the Supporting Information).
The mixture could easily be separated by flash chroma-
tography for analytical samples, but in our synthetic
route, the mixture was directly treated by potassium
carbonate in methanol to give quasiquantitatively the
diol 20. To achieve the synthesis of the iminosugar part
of 4, diol 20 was protected as benzyl groups by classical
treatment with NaH and BnBr in DMF (93% yield).
Finally, opening of the oxazolidinone 21 with NaOH in
refluxed MeOH, followed by trapping of the free nitrogen
with benzylchloroformate, afforded our key intermediate
22 in 74% yield over the two steps.
Tota l Syn th esis of 5-Deoxya d en op h or in e 5 a n d
Det er m in a t ion of t h e Ab solu t e Con figu r a t ion . At
this stage, it was envisaged that 20 should furnish a
direct access to 5-deoxyadenophorine 5 by cleavage of the
oxazolidinone protecting group. In addition, the optical
rotation measurement should enable the absolute con-
figuration of 5 as well as of 4 to be determined. Indeed,
by hydrolysis of 4, Asano and co-workers8 had shown that
the iminosugar part of 4 was identical to 5. Following
our strategy, a basic hydrolysis of the oxazolidinone
(12) For reviews in this field, see: (a) Bloch, R. Chem. Rev. 1998,
98, 1407-1438. (b) Alvaro, G.; Savoia, D. Synlett 2002, 651-673.
(13) For reviews on the RCM: with nitrogen-containing compounds,
see: (a) Phillips, A. J .; Abell, A. D. Aldrichim. Acta 1999, 32, 75-89.
(b) Felpin, F. X.; Lebreton, J . Eur. J . Org. Chem. 2003, 3693-3712.
See also: (c) Nguyen, S. T.; Grubbs, R. H.; Ziller, J . W. J . Am. Chem.
Soc. 1993, 115, 9856-9857. (d) Fu¨rstner, A.; Grabowski, J .; Lehmann,
C. J . Org. Chem. 1999, 64, 8275-8280. (e) Suzuki, H.; Yamazaki, N.;
Kibayashi, C. Tetrahedron Lett. 2001, 42, 3013-3015. (f) Rambaud,
L.; Compain, P.; Martin, O. R. Tetrahedron: Asymmetry 2001, 12,
1807-1807. (g) Fu¨rstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2003,
42, 308-311. (h) Felpin, F. X.; Boubekeur, K.; Lebreton, J . Eur. J . Org.
Chem. 2003, 4518-4527.
(14) (a) Takahata, H.; Banba, Y.; Ouchi, H.; Nemoto, H.; Kato, A.;
Adachi, I. J . Org. Chem. 2003, 68, 3603-3607. (b) Guanti, G.; Riva,
R. Tetrahedron Lett. 2003, 44, 357-360.
J . Org. Chem, Vol. 69, No. 5, 2004 1499

Felpin et al.
SCHEME 4a
rine 4 (13 steps, 9% overall yield) as well as its aglycon
congener 5 (9 steps, 29% overall yield) from (R)-Garner
aldehyde 10. The stereocenters were successfully ac-
cessed by several important steps including a diastereo-
selective allylation of a chiral imine, a stereoselective
epoxidation, and a regioselective opening of the epoxide.
The glycoside step was achieved by using the trichloro-
acetamidate strategy. In addition, our syntheses proved
unambiguously the absolute configuration of 1-O-â-D-
glucopyranosyl-5-deoxyadenophorine 4. Further develop-
ments toward the synthesis of iminosugars with intrigu-
ing structures remain a major challenge in our laboratory
and will be reported in due course.
a
Reagents and conditions: (a) 8 N NaOH, MeOH, 95 °C, 24 H,
88%.
function with NaOH in refluxed MeOH led cleanly to 5.
The proton and 13C NMR spectra were identical with
those reported for the natural product by Asano et al.
Furthermore, the value and sign of the optical rotation
were equally in good agreement. Consequently, the
configuration of natural 5-deoxyadenophorine 5 was
unambiguously assigned as (2R,3S,4S,6R).
Exp er im en ta l Section
(4S,1′E)-2,2-Dim eth yl-4-styr yl-3-ter t-bu tyloxyca r bon yl-
oxa zolid in e (13). A solution of diethyl benzylphosphonate
(6.95 g, 30.48 mmol) in THF (100 mL) was treated with BuLi
(15.24 mL, 1.6 M in hexane, 24.38 mmol) at -78 °C. The
resulting mixture was stirred for 30 min at -78 °C and then
a solution of aldehyde 10 (3.49 g, 15.24 mmol) in THF (35 mL)
was slowly added over 30 min. After addition, the mixture was
stirred for 2 h at -78 °C and 12 h at room temperature. The
mixture was quenched with water and diluted with Et2O. The
aqueous phase was extracted with Et2O (3×). The combined
organic extracts were washed with brine (1×), dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. Purification by flash chromatography (5% EtOAc-
petroleum ether) and crystallization in petroleum ether gave
(E)-13 (3.46 g, 75%) as colorless crystals. [R]20D +83.0 (c 0.976,
CHCl3) [lit.19 [R]20D -88.7 (c 1, CHCl3) for (R)-enantiomer]. Mp
Glycosid e Cou p lin g a n d Com p letion of th e Syn -
th esis. The major remaining task for the completion of
our target was the glycoside coupling between iminosugar
22 and a glucose derivative 23a ,b (see Scheme 5 and
Table 1). It should be noted that the current literature
regarding the coupling of iminosugars with sugar deriva-
tives is limited. First, we opted for a coupling between
22 and bromoglucose 23a . In this context, according to
the procedure described by Liu15 and co-workers, the
coupling of 22 and 23a in the presence of Hg(CN)2
proceeded with acceptable yield (38%). However, despite
several attempts, a mixture of R- and â-isomers 24 in an
approximate 3/7 ratio was isolated and was found to be
inseparable by flash chromatography. Next, we examined
a silver-based Lewis acid such as Ag(OTf)2,16 but without
success. Only starting materials were recovered. This
failure forced us to plan an alternative strategy based
on the coupling of 22 with trichloroacetimidate glucose
derivative 23b. We were very pleased to find that the
glycoside coupling in the presence of BF3‚Et2O17 pro-
ceeded stereospecifically to give the expected â-isomer 24
in 39% yield. In addition, the sole isolated side product
was compound 21, resulting from an intramolecular
cyclization, which can be recycled a few steps before.
The removal of the acetate groups with potassium
carbonate in methanol to give 25 and the subsequent
hydrogenolysis of the benzyl protecting groups afforded
1-O-â-D-glucopyranosyl-5-deoxyadenophorine 4 in 96%
1
85 °C (lit.19 mp 81 °C). IR (KBr) 1700, 2977 cm-1. H NMR δ
1.46 (s, 9H), 1.57 (s, 3H), 1.68 (s, 3H), 3.85 (dd, 1H, J ) 2.3,
8.8 Hz), 4.13 (dd, 1H, J ) 6.1, 8.8 Hz), 4.66 (m, 1H), 6.17 (dd,
1H, J ) 7.6, 15.1 Hz), 6.52 (d, 1H, J ) 15.1 Hz), 7.24-7.41
(m, 5H). 13C NMR δ 23.9, 26.8, 28.6, 59.6, 68.4, 79.9, 94.4,
126.5, 127.7, 128.7, 131.8, 136.8, 152.1. HRMS (EI) calcd for
C
18H25NO3 (M+) 303.1834, found 303.1834.
(2S,3E)-2-Am in o-4-p h en ylbu t-3-en -1-ol (14). A solution
of 13 (5.2 g, 17.16 mmol) in MeOH (55 mL) was treated with
concentrated HCl (2.7 mL, 5% v/v). After the mixture was
stirred at reflux for 4 h, the volatiles were evaporated under
reduced pressure. The residue was taken up with CH2Cl2 and
H2O and the resulting mixture was basified with solid NaOH.
The aqueous layer was extracted with CH2Cl2 (5×) and the
combined extracts were dried over anhydrous MgSO4. Removal
of the solvent left an oil that was precipitated in CH2Cl2-
petroleum ether to give 14 (2.77 g, 98%) as a white solid. Due
to its rapid degradation in air, 14 was used in the next step
yield over the two steps (Scheme 6). The H and 13C NMR
1
without further purification. [R]20 +21 (c 0.162, CHCl3). Mp
D
spectra and the optical rotation measurement were
identical with those reported for natural 4,8 and then
fully confirmed the assignment previously observed for
5-deoxyadenophorine 5 (vide supra).18
98 °C. IR (KBr) 1591, 2902, 3060, 3282, 3342 cm-1. H NMR
1
δ 1.99-2.06 (m, 3H), 3.42-3.50 (m, 1H), 3.65-3.71 (m, 2H),
6.17 (dd, 1H, J ) 6.4, 16 Hz), 6.57 (d, 1H, J ) 16 Hz), 7.20-
7.40 (m, 5H). 13C NMR δ 55.5, 66.7, 126.5, 127.8, 128.7, 130.8,
131.0, 136.8. HRMS (ESI) calcd for C10H14NO (M + H+)
164.1075, found 164.1076. Anal. Calcd for C10H13NO: C, 73.59;
H, 8.03; N, 8.58. Found: C, 73.64; H, 7.95; N, 8.49.
Con clu sion
2-(1-Eth ylbu t-3-en yla m in o)-4-p h en ylbu t-3-en -1-ol (15).
To a solution of amino alcohol 14 (1.5 g, 9.20 mmol) in THF
(15 mL) was added propanal (534 mg, 9.20 mmol) and
anhydrous MgSO4 (2 g). The mixture was stirred overnight
and filtered. The resulting mixture was slowly added over 30
min to a solution of allylmagnesium bromide (1 M in Et2O,
36.81 mmol) in THF (20 mL) cooled to -78 °C. After this
addition, the mixture was stirred for 1 h at -78 °C and slowly
allowed to warm to -10 °C over 5 h. Then, the reaction mixture
We have demonstrated the synthetic utility of trans-
2,6-dialkyl-1,2,5,6-tetrahydropyridines by the first total
syntheses of 1-O-â-D-glucopyranosyl-5-deoxyadenopho-
(15) Liu, P. S. J . Org. Chem. 1987, 52, 4717-4721.
(16) Banwell, M. G.; Ma, X.; Asano, N.; Ikeda, K.; Lambert, J . N.
Org. Biomol. Chem. 2003, 1, 2035-2037.
(17) Anzeveno, P. B.; Creemer, L. J .; Daniel, J . K.; King, C.-H. R.;
Liu, P. S. J . Org. Chem. 1989, 54, 2539-2542.
(18) During the preparation of this manuscript, a total synthesis of
adenophorine was reported: Maughan, M. A. T.; Davies, I. G.; Claridge,
T. D. W.; Courtney, S.; Hay, P.; Davis, B. G. Angew. Chem., Int. Ed.
2003, 42, 3788-3792.
(19) Imashiro, R.; Sakurai, O.; Yamashita, T.; Horikawa, H. Tetra-
hedron 1998, 54, 10657-10670.
1500 J . Org. Chem., Vol. 69, No. 5, 2004

Total Synthesis of 1-O-â-D-Glucopyranosyl-5-deoxyadenophorine
SCHEME 5
TABLE 1
26.7, 38.9, 54.6, 59.6, 65.0, 117.9, 126.5, 127.8, 128.7, 129.7,
132.3, 135.9, 136.8.
entry substrates
conditions
product
yield, %
38
3-(1-Eth yl-bu t-3-en yl)-4-styr yloxa zolid in -2-on e (11). To
a solution of the diethylenic amino alcohols 15 (3.68 g, 15.02
mmol) in CH2Cl2 (120 mL) was added Et3N (2.09 mL, 15.02
mmol) and carbonyldiimidazole (CDI) (4.87 g, 30.04 mmol).
The mixture was stirred overnight and then an additional
portion of CDI (2.44 g, 15.02 mmol) was added and the mixture
was stirred for 6 h. The solution was diluted with CH2Cl2 (10
mL) and washed with 0.5 N aqueous HCl solution (2×). The
combined aqueous phases were extracted with CH2Cl2 (3×).
The combined organic extracts were dried over anhydrous
MgSO4 and concentrated under reduced pressure. Purification
by flash chromatography (20% EtOAc-petroleum ether) gave
carbamate 11 (3.48 g, 86%) as an inseparable mixture of
diastereoisomers (trans/cis: 87/13). Pale yellow oil. IR (KBr) ν
1
23a + 22 HgCN2, 4 Å Ms,
MeNO2, toluene,
24 60%â/40%R
60 °C, 5 h
2
3
23a + 22 AgOTf2, CH2Cl2,
starting materials
-20 °C, 12 h
23b + 22 BF3‚Et2O, CH2Cl2, 24 100%â/0%R
-20 °C, 2 h
39
SCHEME 6a
1734, 2965 cm-1
.
trans-11: 1H NMR δ (ppm) 0.95 (t, 3H, J ) 7.5 Hz), 1.55-
1.88 (m, 2H), 2.23-2.32 (m, 1H), 2.44-2.55 (m, 1H), 3.53-
3.64 (m, 1H), 3.95-4.04 (m, 1H), 4.39-4.49 (m, 2H), 5.06-
5.08 (m, 1H), 5.10 (s, 1H), 5.75-5.87 (m, 1H), 6.10 (dd, 1H, J
) 8.4, 15.6 Hz), 6.61 (d, 1H, J ) 15.6 Hz), 7.30-7.41 (m, 5H).
13C NMR δ (ppm) 11.4, 24.7, 38.2, 56.2, 58.8, 67.3, 117.6, 126.7,
127.2, 127.3, 128.7, 129.0, 134.8, 135.5, 158.0.
cis-11: 1H NMR δ (ppm) 0.97 (t, 3H, J ) 7.9 Hz), 1.51-
1.78 (m, 2H), 2.23-2.55 (m, 2H), 3.67-3.73 (m, 1H), 3.95-
4.04 (m, 1H), 4.39-4.49 (m, 1H), 5.10-5.12 (m, 1H), 5.19 (s,
1H), 5.75-5.87 (m, 1H), 6.10 (dd, 1H, J ) 8.4, 15.6 Hz), 6.62
(d, 1H, J ) 15.6 Hz), 7.30-7.41 (m, 5H). 13C NMR δ (ppm)
11.4, 26.9, 36.4, 56.2, 58.4, 67.3, 117.6, 126.7, 127.2, 127.3,
128.7, 129.0, 134.5, 135.5, 158.2.
5-Eth yl-4,5,6,8a -tetr a h yd r oxa zolid in o[3,4-a ]p yr id in -3-
on e (9). To a solution of carbamates 11 (1.8 g, 6.64 mmol) in
CH2Cl2 (1400 mL) was added [Ru]-16 (284 mg, 0.33 mmol) at
room temperature. After being stirred for 1 h at reflux, the
solution was allowed to warm to room temperature and DMSO
was added (177 µL, 16.5 mmol). The solution was stirred
overnight, concentrated under reduced pressure, and purified
by flash chromatography (20% EtOAc-petroleum ether) to
give tetrahydropyridines trans-9 (921 mg, 83%) and cis-9 (122
mg, 11%) as pale yellow oils.
a
Reagents and conditions: (a) K2CO3, MeOH, THF, H2O, rt, 3
h, 98%. (b) H2, Pd(OH)2, MeOH, CH2Cl2, rt, 4 h, 98%.
trans-9: [R]20D +195.7 (c 1.555, CHCl3). IR (KBr) 1750, 2966
was hydrolyzed with saturated aqueous NH4Cl. The aqueous
phase was extracted with Et2O (4×). The combined organic
extracts were washed with brine (1×), dried over anhydrous
MgSO4, and concentrated in vacuo. The residue was purified
by flash chromatography (40% EtOAc-petroleum ether then
pure EtOAc) affording the diethylenic amino alcohols 15 (1.96
g, 87%) as an inseparable mixture of diastereoisomers (trans/
cis: 87/13). Pale yellow oil. IR (KBr) ν 1599, 1639, 2963, 3314
1
cm-1. H NMR δ 0.95 (t, 3H, J ) 7.2 Hz), 1.43-1.60 (m, 1H),
1.60-1.70 (m, 1H), 1.89-1.97 (m, 1H), 2.46-2.57 (m, 1H),
3.88-3.96 (m, 1H), 3.96 (dd, 1H, J ) 6.6, 8.1 Hz), 4.27-4.31
(m, 1H), 4.48 (app t, 1H, J ) 8.7 Hz), 5.59-5.64 (m, 1H), 5.82-
5.87 (m, 1H). 13C NMR δ 10.8, 24.6, 27.8, 49.3, 49.5, 67.9, 124.5,
126.4, 157.9. HRMS (EI) calcd for C9H13NO2 (M+) 167.0946,
found 167.0947.
cm-1
.
cis-9: [R]20D -5.8 (c 0.748, CHCl3). IR (KBr) 1750, 2966 cm-1
.
Alcohol trans-15: 1H NMR δ (ppm) 0.91 (t, 3H, J ) 7.2 Hz),
1.34-1.55 (m, 2H), 2.18-2.22 (m, 2H), 2.61-2.70 (m, 1H),
3.32-3.48 (m, 2H), 3.60-3.66 (m, 1H), 5.07 (s, 1H), 5.10-5.13
(m, 1H), 5.75-5.87 (m, 1H), 6.01 (dd, 1H, J ) 7.8, 15.9 Hz),
6.54 (d, 1H, J ) 15.9 Hz), 7.24-7.40 (m, 5H). 13C NMR δ (ppm)
10.4, 27.6, 38.0, 55.5, 59.9, 65.2, 117.3, 126.5, 127.8, 128.7,
129.8, 132.3, 135.5, 136.8.
1H NMR δ 1.00 (t, 3H, J ) 7.5 Hz), 1.72-1.86 (m, 1H), 2.04-
2.10 (m, 1H), 2.23-2.97 (m, 2H), 3.11-3.21 (m, 1H), 3.96-
3.99 (m, 1H), 4.33-4.38 (m, 2H), 5.61 (dt, 1H, J ) 1.5, 10.2
Hz), 5.91-5.95 (m, 1H). 13C NMR δ 11.5, 24.6, 29.7, 56.4, 57.2,
67.0, 127.2, 129.5, 157.6.
(5R,7R,8S,8a R)-5-Eth yl-7,8-ep oxyoxa zolid in o[3,4-a ]p i-
p er id in e-3-on e (17). To a solution of tetrahydropyridine
trans-9 (1.0 g, 5.99 mmol) in CH2Cl2 (80 mL) cooled to 0 °C
was added mCPBA (70%, 5.97 g, 23.95 mmol). The solution
was stirred for 72 h at room temperature and then hydrolyzed
with 1/1 saturated aqueous NaHCO3/10% aqueous Na2S2O3
solution. The aqueous phase was extracted with CH2Cl2 (3×),
Alcohol cis-15: 1H NMR δ (ppm) 0.91 (t, 3H, J ) 7.2 Hz),
1.34-1.55 (m, 2H), 2.00-2.33 (m, 2H), 2.61-2.70 (m, 1H),
3.32-3.48 (m, 2H), 3.60-3.66 (m, 1H), 5.07 (s, 1H), 5.10-5.13
(m, 1H), 5.58-5.70 (m, 1H), 5.90 (dd, 1H, J ) 7.6, 16 Hz), 6.50
(d, 1H, J ) 16 Hz), 7.30-7.41 (m, 5H). 13C NMR δ (ppm) 9.6,
J . Org. Chem, Vol. 69, No. 5, 2004 1501

Felpin et al.
washed with brine, dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. Purification by flash chromatography
(80% EtOAc-petroleum ether) gave endo-17 (0.942 g, 86%) as
a colorless crystal and exo-17 (54.8 mg, 5%) as a colorless oil.
and filtered. Removal of the solvent left an oil that was purified
by flash chromatography (20% EtOAc-petroleum ether, then
40% EtOAc-petroleum ether), affording compound 21 (793 mg,
93%) as a colorless oil. [R]20 +6.0 (c 1.433, CHCl3). IR (KBr)
D
ν 1734, 2965, 3031 cm-1. 1H NMR δ (ppm) 0.95 (t, 3H, J ) 7.2
Hz), 1.61-1.75 (m, 1H), 1.84 (dm, 1H, J ) 15 Hz), 1.89-2.04
(m, 1H), 2.08 (ddd, 1H, J ) 3.3, 6.9, 14.7 Hz), 3.37-3.39 (m,
1H), 3.80-3.88 (m, 2H), 4.17-4.29 (m, 3H), 4.45 (d, 2H, J )
12.3 Hz), 4.64 (dd, 2H, J ) 1.5, 11.7 Hz), 7.26-7.42 (m, 10H).
13C NMR δ (ppm) 11.5, 25.4, 26.4, 49.9, 50.1, 63.4, 71.3, 72.0,
72.1, 73.2, 127.4, 127.8, 128.0, 128.1, 128.6, 137.5, 138.0, 158.0.
HRMS (ESI) calcd for C23H27NO4 (M + H+) 382.2019, found
382.2015.
endo-17: [R]20 -13.9 (c 0.720, CHCl3). Mp 86 °C. IR (KBr)
D
1742, 2974 cm-1
.
1H NMR δ 0.93 (t, 3H, J ) 7.5 Hz), 1.46-
1.64 (m, 2H), 1.76 (ddd, 1H, J ) 1.2, 6.3, 15.6 Hz), 2.27 (dd,
1H, J ) 5.4, 15.6 Hz), 3.11-3.12 (m, 1H), 3.32 (app t, 1H, J )
4.8 Hz), 3.71 (app q, 1H, J ) 7.5 Hz), 4.14 (ddd, 1H, J ) 1.2,
5.4, 8.7 Hz), 4.33 (dd, 1H, J ) 5.4, 8.7 Hz), 4.50 (app t, 1H, J
) 8.7 Hz). 13C NMR δ 10.7, 25.5, 26.1, 47.1, 48.9, 50.0, 50.2,
65.2, 157.8. HRMS (EI) calcd for C9H13NO3 (M+) 183.0895,
found 183.0886. Anal. Calcd for C9H13NO3: C, 59.00; H, 7.15.;
N, 7.65. Found: C, 58.89; H, 7.04; N, 7.83.
Com p ou n d 22. To a solution of oxazolidinone 21 (750 mg,
1.97 mmol) in MeOH (30 mL) was added 8 N aqueous NaOH
(10 mL). After being stirred at 95 °C for 24 h, the resulting
mixture was cooled to room temperature and concentrated
under reduced pressure. The residue was taken up in CH2Cl2
(30 mL) and H2O (10 mL) and cooled to 0 °C. To this solution
was added benzyl chloroformate (0.31 mL, 2.17 mmol) and
stirring was continued for 4 h at room temperature. The
aqueous phase was extracted with CH2Cl2 (4×). The organic
extracts were dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. Purification by flash chromatography
(20% EtOAc-petroleum ether) gave 22 (712 mg, 74%) as a
exo-17: [R]20 +3.1 (c 0.381, CHCl3). IR (KBr) 1742, 2974
D
cm-1. H NMR δ 0.87 (t, 3H, J ) 7.2 Hz), 1.44-1.59 (m, 1H),
1
1.74-1.91 (m, 1H), 2.07 (d, 1H, J ) 15.6 Hz), 2.19 (ddd, 1H, J
) 2.4, 7.2, 15.6), 3.11-3.21 (m, 1H), 3.32-3.33 (m, 1H), 3.72-
3.80 (m, 1H), 4.15-4.24 (m, 2H), 4.55-4.64 (m, 1H). 13C NMR
δ 11.3, 25.7, 26.7, 48.9, 49.3, 51.5, 53.7, 65.0, 157.4.
Com p ou n d s 18 a n d 19. A solution of epoxide endo-17 (700
mg, 3.83 mmol) was heated at 100 °C in AcOH for 17 h. Then,
solvent was evaporated under reduced pressure. The residue
was purified by flash chromatography (80% EtOAc-petroleum
ether) to give acetate 18 (734 mg, 79%) and diacetate 19 (109
mg, 10%). Acetate 18 and diacetate 19 were independently
recrystallized in benzene to give colorless crystals.
colorless oil. [R]20 +45.8 (c 0.467, CHCl3). IR (KBr) ν 1684,
D
2964, 3063, 3447 cm-1. H NMR δ (ppm) 0.90 (t, 3H, J ) 7.2
1
Acetate 18: Mp 116 °C. [R]20 -15.3 (c 0.433, CHCl3). IR
Hz), 1.56-1.71 (m, 1H), 1.80-2.10 (m, 3H), 3.21 (s broad, 1H),
3.80-3.94 (m, 5H), 4.28 (dd, 1H, J ) 6.0, 10.5 Hz), 4.53 (d,
1H, J ) 12.0 Hz), 4.62-4.72 (m, 3H), 5.13-5.22 (m, 2H), 7.26-
7.36 (m, 15H). 13C NMR δ (ppm) 11.5, 27.6, 28.2, 53.6, 54.5,
63.8, 67.4, 71.4, 72.7, 75.9, 79.1, 127.5, 127.7, 127.9, 127.9,
128.1, 128.5, 128.6, 136.6, 138.0, 138.4, 156.8. HRMS (ESI)
calcd for C30H36NO5 (M + H+) 490.2594, found 490.2598.
D
(KBr) ν 1711, 1730, 2926, 3355 cm-1. 1H NMR δ (ppm) 0.91 (t,
3H, J ) 7.2 Hz), 1.49-1.63 (m, 1H), 1.73 (dd, 1H, J ) 2.7,
15.3 Hz), 1.76-1.90 (dm, 1H, J ) 2.7 Hz), 2.07 (s, 3H), 2.27
(ddd, 1H, J ) 15.3, 3.3, 6.9 Hz), 3.66 (s, broad, 1H), 3.79 (dt,
1H, J ) 15.9, 6.6 Hz), 4.04 (s broad, 1H), 4.07-4.13 (m, 1H),
4.35 (app t, 1H, J ) 8.5 Hz), 4.44 (dd, 1H, J ) 8.5, 5.1 Hz),
5.06-5.06 (m, 1H). 13C NMR δ (ppm) 11.3, 21.4, 25.5, 26.2,
49.8, 50.3, 63.4, 65.4, 70.5, 158.3, 170.0. HRMS (ESI) calcd
for C11H18NO5 (M + H+) 244.1185, found 244.1190. Anal. Calcd
for C11H17NO5: C, 54.31; H, 7.04.; N, 5.76. Found: C, 54.34;
H, 7.21; N, 5.93.
5-Deoxya d en op h or in e 5. A solution of 8 N aqueous NaOH
(2 mL) was added to a solution of diol 20 (50 mg, 0.249 mmol)
in MeOH (3 mL). The solution was stirred for 24 h at 95 °C
then evaporated under reduced pressure. The residue was
purified by flash chromatography (5% MeOH-1% Et3N-CH2-
Cl2) to give 5-deoxyadenophorine 5 (38 mg, 88%) as a colorless
oil. [R]20D +52.3 (c 0.382, H2O) [lit.8 [R]20D +50.1. (c 0.32, H2O)].
1H NMR D2O δ (ppm) 0.90 (t, 3H, J ) 7.5 Hz), 1.09-1.18 (m,
1H), 1.37-1.47 (m, 2H), 2.07 (ddd, 1H, J ) 2.7, 4.5, 12.9 Hz),
Diacetate 19: Mp 121 °C. [R]20 +36.9 (c 0.913, CHCl3). IR
D
1
(KBr) ν 1731, 1747, 2973 cm-1. H NMR δ (ppm) 0.92 (t, 3H,
J ) 7.5 Hz), 1.50-1.65 (m, 1H), 1.81-1.86 (m, 2H), 2.09 (s,
3H), 2.12 (s, 3H, 3.83-3.93 (m, 1H), 4.07 (dd, 1H, J ) 3.9, 8.7
Hz), 4.23-4.27 (m, 1H), 4.36 (app t, 1H, J ) 9 Hz), 4.90-4.91
(m, 1H), 5.00-5.03 (m, 1H). 13C NMR δ (ppm) 11.2, 20.8, 21.1,
26.1, 49.1, 49.7, 63.1, 66.6, 67.3, 157.4, 169.1, 170.0. HRMS
(ESI) calcd for C13H20NO6 (M + H+) 286.1291, found 286.1288.
Com p ou n d 20. A solution of acetate 18 (703 mg, 2.89
mmol) and diacetate 19 (94 mg, 0.330 mmol) in MeOH (50 mL)
and H2O (2 mL) was treated with K2CO3 (1.33 g, 9.66 mmol).
The resulting mixture was stirred for 3 h at room temperature.
Then, the solvent was evaporated under reduced pressure and
the residue was taken up in dry MeOH (10 mL) and filtered.
The solution was concentrated under reduced pressure and
purified by flash chromatography (EtOAc, then 80% EtOAc-
MeOH) to yield 20 (615 mg, 95%) as a white solid. Mp 157 °C.
2.81-2.87 (m, 1H), 3.25-3.32 (m, 1H), 3.65-3.85 (m, 4H). 13
C
NMR D2O δ (ppm) 12.4, 30.9, 40.5, 51.7, 59.4, 60.4, 71.6, 76.2.
Com p ou n d 24. To a solution of alcohol 22 (100 mg, 0.204
mmol) and trichloroacetimidate 23b (151 mg, 0.307) in CH2-
Cl2 (5 mL) at -30 °C was added BF3‚Et2O (33.7 µL, 0.266
mmol). After being stirred at -30 °C for 2 h, the resulting
mixture was diluted with CH2Cl2, washed with saturated
aqueous NaHCO3 (2×) and brine (1×), dried over anhydrous
MgSO4, filtered, and concentrated in vacuo. Purification by
flash chromatography (30% EtOAc-petroleum ether) gave 24
(65 mg, 39%) as a colorless oil and 21 (35 mg, 45%). [R]20D -5.8
1
(c 0.380, CHCl3). IR (KBr) ν 1695, 1750, 2963, 3032 cm-1. H
NMR δ (ppm) 0.87 (t, 3H, J ) 7.2 Hz), 1.55-1.65 (m, 1H),
1.77-2.20 (m, 15H), 3.50-4.39 (m, 10H), 4.47-4.66 (m, 4H),
4.94-5.17 (m, 5H), 7.26-7.37 (m, 15H). 13C NMR δ (ppm) 11.4,
20.7, 27.3, 28.3, 52.6, 53.6, 61.9, 67.2, 68.4, 71.2, 71.3, 71.7,
72.5, 73.1, 100.7, 127.5, 127.6, 127.7, 128.1, 128.5, 128.6, 136.8,
138.5, 138.7, 156.2, 169.5, 170.4, 170.8. HRMS (ESI) calcd for
[R]20 -21.4 (c 1.177, CHCl3). IR (KBr) ν 1719, 2972, 3365,
D
3391 cm-1. H NMR (MeOD) δ (ppm) 0.90 (t, 3H, J ) 7.5 Hz),
1
1.59-1.70 (m, 2H), 1.93-2.09 (m, 1H), 2.11 (ddd, 1H, J ) 3.3,
7.2, 14.7 Hz), 3.52-3.54 (m, 1H), 3.69 (dt, 1H, J ) 6.3, 9.9
Hz), 3.93 (dd, 1H, J ) 3, 6.6 Hz), 4.21-4.26 (m, 1H), 4.36-
4.39 (m, 1H). 13C NMR (MeOD) δ (ppm) 11.7, 27.8, 29.3, 51.2,
51.8, 65.1, 68.9, 69.3, 160.6. HRMS (ESI) calcd for C9H16NO4
(M + H+) 202.1079, found 202.1066.
C
44H54NO5 (M + H+) 820.3544, found 820.3570.
Com p ou n d 25. To a solution of compound 24 (60 mg, 73.3
µmol) in a mixture of MeOH (5 mL), THF (2 mL), and H2O
(0.2 mL) was added K2CO3 (50.5 mg, 0.366 mmol). After being
stirred at room temperature for 3 h, the mixture was diluted
with water and extracted with CH2Cl2 (4×). The combined
organic extracts were dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure. Purification by flash
Com p ou n d 21. To a stirred solution of diol 20 (450 mg,
2.24 mmol) in dry DMF (25 mL) at 0 °C was added NaH (60%
in oil, 537 mg, 13.43 mmol). After the evolution of H2 had
ceased (30 min), benzyl bromide (1.07 mL, 8.96 mmol) was
added. After being stirred for 4 h 30 at room temperature, the
mixture was quenched with water (15 mL). The aqueous layer
was extracted with ether (3×). The combined organic extracts
were washed with brine (3×), dried over anhydrous MgSO4,
chromatography gave 25 (47 mg, 98%) as a colorless oil. [R]20
D
+10.3 (c 1.05 CHCl3). IR (KBr) ν 1683, 292, 3065, 3419 cm-1
.
1H NMR δ (ppm) 0.86 (t, 3H, J ) 7.2 Hz), 1.56-1.69 (m, 1H),
1502 J . Org. Chem., Vol. 69, No. 5, 2004

Total Synthesis of 1-O-â-D-Glucopyranosyl-5-deoxyadenophorine
1.73-1.88 (m, 3H), 2.05-2.15 (m, 1H), 2.25 (s broad, 1H), 2.97
(s broad, 1H), 3.23 (s broad, 1H), 3.27-3.32 (m, 1H), 3.46-
3.58 (m, 2H), 3.76-3.91 (m, 6H), 4.07 (s broad, 1H), 4.19-
4.31 (m, 4H), 4.49-4.70 (m, 4H), 5.08 (d, J ) 15.7 Hz), 5.12
(d, J ) 15.7 Hz), 7.25-7.31 (m, 15H). 13C NMR δ (ppm) 11.4,
27.9, 28.7, 53.1, 53.5, 62.1, 67.5, 69.2, 70.2, 71.4, 72.6, 73.8,
75.8, 78.6, 103.5, 127.6, 127.8, 128.1, 128.2, 12.5, 128.6, 136.6,
138.2, 138.6, 156.7. HRMS (ESI) calcd for C36H45NO10 (M +
H+) 652.3122, found 652.3126.
1H, J ) 3.6, 10.5 Hz), 4.48 (d, 1H, J ) 7.8 Hz). 13C NMR D2O
δ (ppm) 12.4, 30.9, 40.7, 51.6, 58.9, 63.5, 68.6, 71.6, 72.4, 75.9,
76.1, 78.4, 78.7, 106.0.
Ack n ow led gm en t. This program is supported in
part by the MRT (grant for F.-X.F) and in part by the
Regional Council of the Pays-de-la-Loire. We thank Dr.
N. Asano (Hokuriku University, J apan) for providing
us NMR spectra of 1-O-â-D-glucopyranosyl-5-deoxyad-
enophorine. We are indebted to Marie-J o Bertrand for
skilled technical assistance in HPLC. Thanks are also
due to Mr. Albert Marcual (IRCOF, Rouen) for recording
high-resolution mass spectra. We are also grateful to
our colleagues Morwenna Pearson and Dr. David De-
niaud for a procedure concerning the preparation of
compound 23a .
1-O-â-D-Glu cop yr a n osyl-5-d eoxya d en op h or in e 4. To a
solution of compound 25 (40 mg, 61.4 µmol) in a mixture of
MeOH (2 mL) and CH2Cl2 (1 mL) was added Pd(OH)2 (5 mol
%) under an atmosphere of H2. After being stirred for 48 h at
room temperature, the catalyst was filtered and the solvent
was concentrated. The residue was taken up in CH2Cl2 (0.5
mL) and NaHCO3 (5.2 mg, 61.4 µmol) was added. The solution
was filtered on Millipore and the filtrate was evaporated under
reduced pressure to give 1-O-â-D-glucopyranosyl-5-deoxyad-
enophorine 4 (20.1 mg, 98%) as a colorless oil. [R]20 +17.6 (c
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
D
0.87, H2O) [lit.8 [R]20 +11.4 (c 0.33, H2O)]. 1H NMR D2O δ
D
(ppm) 0.92 (t, 3H, J ) 7.5 Hz), 1.09-1.18 (m, 1H), 1.38-1.47
(m, 2H), 2.09 (dm, 1H, J ) 12.6 Hz), 2.82-2.87 (m, 1H), 3.29-
3.57 (m, 5H), 3.67-3.78 (m, 3H), 3.89-3.96 (m, 2H), 4.11 (dd,
J O035522M
J . Org. Chem, Vol. 69, No. 5, 2004 1503