All eight stereoisomeric D-glyconic-δ-lactams: Synthesis, conformational analysis, and evaluation as glycosidase inhibitors

Article abstract of DOI:10.1021/jo000141j

An efficient and general synthetic route to all eight stereoisomeric D-glycono-δ-lactams has been developed. The strategy involves, as a key step, a stereodivergent δ-lactam formation with configurational retention or inversion at C-4 of a starting γ-lactone to lead to two epimers of δ-lactam from one parent γ-lactone. Conformations of eight glycono-δ-lactams were examined by X-ray crystallographic analysis and molecular modeling. Analyses of conformation and glycosidase-inhibition provide useful information for the design of new glycosidase inhibitors.

Full text of DOI:10.1021/jo000141j

J . Org. Chem. 2000, 65, 4871-4882
4871
All Eigh t Ster eoisom er ic D-Glycon ic-δ-la cta m s: Syn th esis,
Con for m a tion a l An a lysis, a n d Eva lu a tion a s Glycosid a se
In h ibitor s
Yoshio Nishimura,* Hayamitsu Adachi, Takahiko Satoh, Eiki Shitara, Hikaru Nakamura,
Fukiko Kojima, and Tomio Takeuchi
Institute of Microbial Chemistry, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, J apan
mcrf@bikaken.or.jp
Received February 2, 2000
An efficient and general synthetic route to all eight stereoisomeric D-glycono-δ-lactams has been
developed. The strategy involves, as a key step, a stereodivergent δ-lactam formation with
configurational retention or inversion at C-4 of a starting γ-lactone to lead to two epimers of δ-lactam
from one parent γ-lactone. Conformations of eight glycono-δ-lactams were examined by X-ray
crystallographic analysis and molecular modeling. Analyses of conformation and glycosidase-
inhibition provide useful information for the design of new glycosidase inhibitors.
In tr od u ction
The intense interest in the chemistry, biochemistry and
pharmacology of glycosidase inhibitors has grown during
the past decade due to both unraveling of the mechanism
of action of glycosidases1 and their chemotherapeutic
potential in the prevention and treatment of a variety of
diseases,2 including cancer,3 diabetes,4 AIDS,5 and influ-
enza infection.6 Glycosidase inhibitors have general
structural homology with natural glycosides, and are
traditionally polyhydroxylated six- and five-membered
heterocyclic ringssoften azacyclic rings.1-7 Various types
of inhibitors have also been designed based on a positive-
(1) (a) Elbein, A. D. Annu. Rev. Biochem. 1987, 56, 497-534. (b)
Legler, G. Adv. Carbohydr. Chem. Biochem. 1990, 48, 319-384. (c)
Sinnott, M. L. Chem. Rev. 1990, 90, 1171-1202. (d) Dwek, R. A. Chem.
Rev. 1996, 96, 683-720. (e) Davies, G.; Sinnott, M. L.; Wither, S. G.
In Comprehensive Biological Catalysis, A Mechanistic References;
Sinnott, M., Ed.; Academic Press: London, 1998; Vol. I, pp 119-208.
(2) (a) Fellows, L. E. New Sci. 1989, 123, 45. (b) Winchester, B.;
Fleet, G. W. J . Glycobiology 1992, 2, 199. (c) Karlsson, G. B.; Butters,
T. D.; Dwek, R. A.; Platt, F. M. J . Biol. Chem. 1993, 268, 570. (d) J acob,
G. S.; Bryant, M. L. Persp. Drug Dicov. Design 1993, 1, 211-224. (e)
Witczak, Z. J . In Carbohydrates in Drug Design; Witczak, Z. J ., Ed.;
Marcel Dekker: New York, 1997; pp 1-37. (f) Hughs, A. B.; Rudge, A.
J . Nat. Prod. Rep. 1994, 35.
(3) (a) Humphries, M. J .; Matsumoto, K.; White, S. L.; Molyneux,
R. J .; Olden, K. Cancer Res. 1988, 48, 1410. (b) Atsumi, S.; Nosaka,
C.; Ochi, Y.; Iinuma, H.; Umezawa, K. Cancer Res. 1993, 53, 4896. (c)
Nishimura, Y.; Satoh, T.; Kondo, S.; Takeuchi, T.; Azetaka, M.;
Fukuyasu, H.; Iizuka, Y.; Shibahara, S. J . Antibiot. 1994, 47, 840. (d)
Gross, P. E.; Baker, M. A.; Carver, J . P.; Dennis, J . W. Clin. Cancer
Res. 1995, 1, 935. (e) Nishimura, Y.; Satoh, T.; Adachi, H.; Kondo, S.;
Takeuchi, T.; Azetaka, M.; Fukuyasu, H.; Iizuka, Y. J . Med. Chem.
1997, 40, 2626.
(4) (a) Horii, S.; Fukase, H.; Matsuo, T.; Kameda, Y.; Asano, N.;
Matsui, K. J . Med. Chem. 1986, 29, 1038. (b) Yoshikuni, Y.; Ezure, Y.;
Aoyagi, Y.; Enomoto, H. J . Pharmacobio-Dyn. 1988, 111, 356. (c)
Anzeveno, P. B.; Creemer, L. J .; Daniel, J . K.; King, C.-H.; Liu, P. S.
J . Org. Chem. 1989, 54, 2539. (d) Tettersall, R. Diabet. Med. 1993, 10,
688.
F igu r e 1. Presumed oxocarbenium ions in a transition state
of hydrolysis by R- and â-glycosidases.7c,10b
charged, flattened half-chair oxocarbenium ion in a
transition state of the reaction catalyzed by glycosidase8
(Figure 1). Typical inhibitors are illustrated in Figure 2.
Excellent pioneering studies on a relationship between
structure and inhibitory activity in glycosidase inhibitors
by the Ganem group,9 Wong group7c and Vasella group10
have shown that good glycosidase inhibitors should have
(6) (a) von Itzstein, M.; Wu, W.-Y.; Kok, G. B.; Pegg, M. S.; Dyason,
J . C.; J in, B.; Phan, T. V.; Smythe, M. L.; White, H. F.; Oliver, S. W.;
Colman, P. M.; Varghese, J . N.; Ryan, M.; Woods, J . M.; Bethell, R.
C.; Hotham, V. J .; Cameron, J . M.; Penn, C. R. Nature, 1993, 363, 418.
(b) Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H.; Zhang, L.;
Swaminathan, S.; Bischofbergen, N.; Chen, M. S.; Mendel, D. B.; Tai,
C. Y.; Laver, W. G.; Stevens, R. C. J . Am. Chem. Soc. 1997, 119, 681.
(7) (a) Fellows, L. E. Chem. Ber. 1987, 23, 842. (b) Nishimura, Y. In
Studies in Natural Products Chemistry; Atta-ur-Rahman, Ed.; Elsevi-
er: Amsterdam, 1992; Vol. 10 (Part E), pp 495-583. (c) Kajimoto, T.;
Liu, K. K-C.; Pederson, R. L.; Zhong, Z.; Ichikawa, Y.; Porco, J . A.,
J r.; Wong, C.-H. J . Am. Chem. Soc. 1991, 113, 6187.
(5) (a) Karpas, A.; Fleet, G. W. J .; Dwek, R. A.; Petursson, S.;
Namgoong, S. K.; Ramsden, N. G.; J acob, G. S.; Rademacher, T. W.
Proc. Natl. Acad. Sci. U. S.A. 1988, 85, 9229. (b) Wikler, D. A.; Holan,
G. J . Med. Chem. 1989, 32, 2084. (c) Ratner, L.; Hyden, N. V.; Dedera,
D. Virology 1991, 181, 180. (d) Westervelt, P.; Gendelman, H. E.;
Patner, L. Proc. Natl. Acad. Sci. U. S.A. 1991, 88, 3097. (e) Karlsson,
G. B.; Butter, T. D.; Dwek, R. A.; Platt, F. M. J . Biol. Chem. 1993,
268, 570. (f) J acob, G. S.; Bryant, M. L. In Anti-AIDS Drug Develop-
ments: Challenges, Strategies and Prospects; Mohan, P., Baba, M. C.,
Eds.; Harwood Academic Publishers: 1995; pp 65-91.
(8) (a) Look, G. C.; Fotsh, C. H.; Wong, C.-H. Acc. Chem. Res. 1993,
26, 182. (b) Ganem, B. Acc. Chem. Res. 1996, 29, 340. (c) Hoos, R.;
Vasella, A.; Rupitz, K.; Withers, S. G. Carbohyd. Res. 1997, 298, 291.
(d) Ganem, B. In Carbohydrate Mimics; Chapleur, Y., Ed.; Wiley-
VCH: Weinheim, 1998; pp 239-258.
(9) Papandreou, G.; Tong, M. K.; Ganew, B. J . Am. Chem. Soc. 1993,
115, 11682.
10.1021/jo000141j CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/04/2000

4872 J . Org. Chem., Vol. 65, No. 16, 2000
Nishimura et al.
F igu r e 2. Representative glycosidase inhibitors.
a flattened half-chair conformation with a positive charge
character around the anomeric carbon and ring hetero-
atom, and with the correct configuration at C-2, -3, -4,
and -5 (half-chair conformation and electrostatic factors).
In the course of our study on glycosidase inhibitors,11 we
have become interested in the influence of the conforma-
tion of glycono-δ-lactams on glycosidase inhibitory activi-
ties. The known glyconolactams, D-glucono-, D-mannono-
and D-galactono-δ-lactams (7, 8, and 9) show significant
competitive inhibition against the corresponding gly-
cosidases.12-14 Mannonolactam 8 is also known to be a
better glucosidase inhibitor than gluconolactam 7.13,15
These glycono-δ-lactams were obtained by transformation
of natural azasugars 1, 3, and 5, respectively, and also
by total synthesis.12,13,16-19 Furthermore, 7 and 8 have
also been isolated from a fermentation broth of marine
actinomycete.15 Asymmetric synthesis (82% ee) of D-idono-
δ-lactam (29) was also reported.20 However, to our
knowledge, little is known about systematic study on
synthesis of all eight stereoisomeric glycono-δ-lactams
(glucono-, mannono-, galactono-, talono-, altrono-, idono-,
gulono- and allono-δ-lactam), their conformational analy-
sis, and the relationship between their conformations and
inhibitory activities. Here we report logical synthesis,
rigorous conformational analysis and evaluation of in-
hibitory activity of D-glucono- (7), D-mannono- (8), D-
galactono- (9), D-gulono- (25), D-allono- (26), D-talono-
(27), D-altrono- (28), and D-idono-δ-lactam (29) as a
fundamental probe of the half-chair conformation-inhibi-
tory activity profile.
Resu lts a n d Discu ssion
Syn th esis. Our synthetic strategy, as a key step,
involves stereodivergent δ-lactam formation with con-
figurational retention or inversion at C-4 of a starting
γ-lactone to afford two epimers of δ-lactam from one
parent γ-lactone (Scheme 1). The former δ-lactam forma-
tion has readily been achieved from 5-azido-γ-lactone 13
by well-known methods21 of usual catalytic reduction
(route a in Scheme 2). On the other hand, the latter
δ-lactam formation proved troublesome until we un-
covered that treatment of 5-azido-γ-lactone 13 with
triphenylphosphine gave the desired product 19 (route
b in Scheme 2). The latter δ-lactam formation likely
proceeded via intramolecular phosphonium-salt like the
Mitsunobu reaction:22 initial attack by triphenylphos-
phine on the azide group to form the iminophosphorane
15,23 then subsequent formation of an intramolecular
aminophosphonium-salt 16 and then an alkoxyphospho-
nium salt 17, and epimerization (SN2 type displacement
of the resulting species 17) would form the epimeric
γ-lactone 18 then leading to the desired δ-lactam 19
(route b in Scheme 2). Thus, this methodology has made
it possible to prepare efficiently all eight stereoisomeric
glycono-δ-lactams from four starting γ-lactones.
(10) (a) Ermert, P.; Vasella, A.; Weber, M.; Rupitz, K.; Withers, S.
G. Carbohyd. Res. 1993, 250, 113. (b) Heightman, T. D.; Vasella, A. T.
Angew. Chem., Int. Ed. Engl. 1999, 38, 750.
(11) (a) Nishimura, Y. In Studies in Natural Products Chemistry;
Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1995; Vol. 16, pp 495-
583. (b) Nishimura, Y.; Satoh, T.; Kondo, S.; Takeuchi, T.; Azetaka,
M.; Fukuyasu, H.; Iizuka, Y.; Shibahara, S. J . Antibiot. 1994, 47, 840.
(c) Satoh, T.; Nishimura, Y.; Kondo, S.; Takeuchi, T.; Azetaka, M.;
Fukuyasu, H.; Iizuka, Y.; Oouchi, S.; Shibahara, S. J . Antibiot. 1996,
49, 321. (d) Nishimura, Y.; Satoh, T.; Kudo, T.; Kondo, S.; Takeuchi,
T. Bioorg. Med. Chem. 1996, 4, 91. (e) Nishimura, Y.; Satoh, T.; Adachi,
H.; Kondo, S.; Takeuchi, T.; Azetaka, M.; Fukuyasu, H.; Iizuka, Y. J .
Am. Chem. Soc. 1996, 118, 3051; J . Med. Chem. 1997, 40, 2626.
(12) (a) Inouye, S.; Tsuruoka, T.; Ito, T.; Niida, T. Tetrahedron 1968,
23, 2125. (b) Fleet, G. W. J .; Carpenter, N. M.; Petursson, S.; Ramsden,
N. G. Tetrahedron Lett. 1990, 31, 409. (c) Herman, S. O.; J im, V. W.;
Upendra, K. P. Tetrahedron Lett. 1993, 34, 2527.
(13) (a) Niwa, T.; Tsuruoka, T.; Goi, H.; Kodama, Y.; Itoh, J .; Inouye,
S.; Yamada, Y.; Niida, T.; Nobe, M.; Ogawa, Y. J . Antibiot. 1984, 37,
1579. (b) Fleet, G. W.; Ramsden, N. G.; Witty, D. R. Tetrahedron 1989,
45, 319. (c) Shing, T. K. M. J . Chem. Soc., Chem. Commun. 1988, 1221.
(14) Miyake, Y.; Ebata, M. Agr. Biol. Chem. 1988, 52, 1649.
(15) Imada, C.; Okami, Y. J . Mar. Biotechnol. 1995, 2, 109.
(16) Miyake, Y.; Ebata, M. Agr. Biol. Chem. 1988, 52, 661.
(17) Hoos, R.; Naughton, A. B.; Vasella, A. Helv. Chim. Acta 1992,
75, 1802.
Synthesis of D-gulono- and allono-δ-lactams (25 and 26)
from L-mannonic acid γ-lactone (21) was performed as
outlined in Scheme 3. The synthesis began with 2,3;5,6-
(18) Overkleeft, H. S.; van Wiltenburg, J .; Pandit, U. K. Tetrahedron
1994, 50, 4215.
(19) See other synthesis of (()-mannono-δ-lactam: Cooke, G. R.;
Beholz, L. G.; Stille, J . R. J . Org. Chem. 1994, 59, 3575.
(20) Kang, J .; Lee, C. W.; Lim, G. J .; Cho, B. T. Tetrahedron: Asym.
1999, 10, 657.
(21) Paulsen, H.; Todt, K. In Advances in Carbohydrate Chemistry,
Wolfrom, M. L., Tipson, R. T., Eds.; Academic Press: New York, 1968;
Vol. 23, pp 115-232.
(22) Mitsunobu, O. Synthesis, 1981, 1.
(23) Vanltier, M.; Knouzi, N.; Carrie, R. Tetrahedron Lett. 1983, 24,
763.

Eight Stereoisomeric D-Glyconic-δ-lactams
J . Org. Chem., Vol. 65, No. 16, 2000 4873
Sch em e 1
Sch em e 2
di-O-isopropylidene-L-mannonic acid γ-lactone (30)24
readily prepared from 21. Selective removal of the 5,6-
O-isopropylidene group of 30 with acetic acid gave 2,3-
O-isopropylidene derivative 31 which was transformed
into 6-O-trityl-2,3-O-isopropylidene-L-mannonic acid γ-lac-
tone (33) via in situ formation of the cyclic stannoxane
32 by treatment with dibutyltin oxide25 and a subsequent
tritylation in good yield. Trifluoromethanesulfonylation
of 33 followed by displacement of the resultant sulfonate
with NaN3 gave the pivotal intermediate, the azide 34.
Catalytic reduction of 34 with Raney Ni straightfor-
wardly afforded the protected D-gulono-δ-lactam 35.
Removal of protecting groups of 35 by treatment with
hydrogen chloride in dioxane resulted in the crystalline
D-gulono-δ-lactam (25) in good yield. On the other hand,
treatment of 34 with triphenylphosphine in CH3CN and
a successive hydrolysis gave the desired D-allono-δ-lactam
derivative 36 in 92% yield. Then, removal of protecting
(25) (a) J enkis, I. D.; Verheyden, J . P. H.; Moffatt, J . G. J . Am. Chem.
Soc. 1971, 93, 4323. (b) Ogawa, T.; Matsui, M. Tetrahedron 1981, 37,
2363. (c) Ogawa, T.; Kaburagi, T. Carbohydr. Res. 1982, 53, 1033. (d)
Tsuda, Y.; Nishimura, M.; Kobayashi, T.; Sato, Y.; Kanemitsu, K.
Chem. Pharm. Bull. 1991, 39, 2883.
(24) Xie, M.; Berges, D. A.; Robins, M. J . J . Org. Chem. 1996, 61,
5178.

4874 J . Org. Chem., Vol. 65, No. 16, 2000
Nishimura et al.
Sch em e 3a
Sch em e 5a
a
Reagents and conditions: (a) (MeO)2CMe2, CH3COCH3, p-
TsOH, rt; (b) 80% AcOH, 30 °C; (c) (n-Bu)2SnO, PhH, MS4A, 80
°C; (d) Ph3CCl, (i-Pr)2NEt2, DMF, rt; (e) (i) (CF3SO2)2O, Py, CH2Cl2,
-40 °C, (ii) NaN3, DMF, rt; (f) H2, Raney Ni, MeOH, rt; (g) PPh3,
CH3CN, rt; H2O, rt; (h) 4 M HCl/dioxane.
a
Reagents and conditions: (a) MOMCl, (n-Bu)4NI, (i-Pr)2NEt,
70 °C; (b) 80% AcOH, 40 °C; (c) (n-Bu)2SnO, PhH, MS4A, 80 °C;
(d) Ph3CCl, (i-Pr)2NEt, DMF, rt; (e) Dess-Martin periodinane,
CH2Cl2; (f) NaBH4, MeOH/CH2Cl2; (g) (i) (CF3SO2)2O, Py, CH2Cl2,
-40 °C, (ii) NaN3, DMF, rt; (h) H2, Raney Ni, MeOH; (i) PPh3,
CH3CN, rt; H2O, rt; (j) 4 M HCl/dioxane.
Sch em e 4a
Raney Ni gave the protected D-mannono-δ-lactam 42,
while treatment with PPh3 in CH3CN followed by hy-
drolysis resulted in D-talono-δ-lactam derivative 43 as a
sole product. Acid hydrolysis of 42 straightforwardly
resulted in the crystalline D-mannono-δ-lactam (8).13,18,19
On the other hand, simultaneous removal of trityl and
isopropylidene groups in 43 by acid hydrolysis with
hydrogen chloride in dioxane proceeded unfavorably to
give many decomposed products. Removal of protecting
groups of 43 was best achieved by the two step sequences
of deprotection of trityl group by hydrogenolysis with
palladium on carbon and acid hydrolysis of the isopro-
pylidene group to afford the crystalline D-talono-δ-lactam
(27).
D-Glucono- and D-galactono-δ-lactams (7 and 9) were
synthesized as outlined in Scheme 5. The starting L-
altronic acid γ-lactone (23) was not commercially avail-
able, and therefore the desired precursor, 2,3-di-O-
(methoxymethyl)-6-O-trityl-L-altronic acid γ-lactone (52)
was prepared from D-galactonic acid γ-lactone (45).
Inversion of the stereochemistry at carbon-5 of 45 is
required for the desired 52. The readily available 5,6-O-
isopropylidene-D-galactonic acid γ-lactone (46)26 was
converted to 2,3-di-O-(methoxymethyl)-6-O-trityl-D-ga-
lactonic acid γ-lactone (50) by protection of the 2,3-diol
and 6-O-tritylation via in situ formation of the 5,6-cyclic
stannoxane. The last epimerization at carbon-5 of 50 was
best achieved by two step sequences of oxidation with
a
Reagents and conditions: (a) (MeO)2CMe2, CH3COCH3, p-
TsOH, rt; (b) 80% AcOH, rt; (c) (n-Bu)2SnO, PhH, MS4A, 85 °C;
(d) Ph3CCl, (i-Pr)2NEt, DMF, rt; (e) (i) (CF3SO2)2O, Py, CH2Cl2,
-40 °C, (ii) NaN3, DMF, rt; (f) Raney Ni, H2, MeOH/AcOEt; (g)
PPh3, CH3CN, rt; H2O, rt; (h) 4 M HCl/dioxane (i) H2/Pd-C, EtOH.
groups with acid hydrolysis yielded the crystalline D-
allono-δ-lactam (26) in good yield.
Synthesis of D-mannono- and D-talono-δ-lactams (8 and
27) from L-gulonic acid γ-lactone (22) was outlined in
Scheme 4. The key intermediate, azide 41 was prepared
from the known starting 2,3-O-isopropylidene-L-gulonic
acid γ-lactone (38)19 by sequences of reactions similar to
those mentioned above. Catalytic reduction of 41 with
(26) Fleet, G. W. J .; Son, J . C. Tetrahedron 1988, 44, 2637.

Eight Stereoisomeric D-Glyconic-δ-lactams
J . Org. Chem., Vol. 65, No. 16, 2000 4875
Sch em e 6a
galactono-, D-gulono-, and D-allono-δ-lactams (7, 9, 25,
and 26) adopt half-chair conformers, while D-mannono-,
D-talono-, and D-idono-δ-lactams (8, 27, and 29) adopt
B5,2-boat conformers. D-Altrono-δ-lactam 28 has an ex-
ceptional skew-boat conformer. The structures of all eight
glycono-δ-lactams (7-9 and 25-29) were also optimized
with PM3 in MOPAC29 using the atomic coordinates
obtained by X-ray crystallographic analysis. The opti-
mized structures with PM3/MOPAC were superimposed
well on the structures obtained by X-ray crystallographic
analysis except for 8, 27, and 29 (Figure 4). Molecules of
D-glycono-δ-lactams in the crystal structure commonly
form networks of intermolecular hydrogen bonds as well
as intramolecular hydrogen bonds28 (see Supporting
Information), and consequently, X-ray crystallographic
analysis gives the conformation of a molecule as a result
of overall inter- and intramolecular interactions. On the
other hand, the optimization of the structure with PM3/
MOPAC analyzes the conformation of one molecule
without intermolecular interactions. Therefore, the con-
formation obtained by the molecular modeling sometimes
turns out to be different from the conformation deter-
mined by the X-ray crystallographic analysis. Especially,
in the case of D-talono-δ-lactam (27), there is a large
difference of structure between the X-ray crystallographic
analysis and the molecular modeling. Intermolecular
hydrogen bonds between O(2)-H and O(5) (2.802 Å),
O(5)-H and O(2) (2.762 Å) and N-H and O(4) (2.986 Å)
as well as an intramolecular hydrogen bond between O(1)
and O(2)-H (2.689 Å) are observed in the X-ray crystal-
lographic analysis, resulting a B5,2-boat conformation. On
the other hand, a distinguishing intramolecular hydrogen
bond between O(2) and O(4)-H (1.841 Å) appears in the
molecular modeling with PM3/MOPAC, resulting in a
half-chair conformation of flap-up type. These results of
X-ray crystallographic analysis and molecular modeling
indicate that the absolute configuration at C-2 position
may play an important role in fixing the conformation
in glycono-δ-lactams. The glycono-δ-lactams with R-
configuration at C-2 position (7, 9, 25, and 26) are in a
half-chair conformation. On the other hand, the glycono-
δ-lactams with S-configuration at C-2 position (8, 27, 28,
and 29) are in a boat conformation. Molecular modeling
was next undertaken to verify the contribution of the
configurational energy at C-2 on the overall conforma-
tional energy of glycono-δ-lactams between half-chair
conformers with R-configuration and boat conformers
with S-configuration. The optimized structures of D-
glucono-, D-galactono-, D-gulono-, and D-allono-δ-lactams
(7, 9, 25, and 26) with PM3 in MOPAC which have the
half-chair conformers with R-configuration were then
optimized altering only configuration at C-2 position. The
structures obtained corresponding to D-mannono-, D-
talono-, D-idono-, and D-altrono-δ-lactams (8, 27, 29, and
28), respectively, were identical to those shown in Figure
4.
a
Reagents and conditions: (a) (MeO)2CMe2, CH3COCH3, p-
TsOH, rt; (b) MOMCl, (n-Bu)4NI, (i-Pr)2NEt, 70 °C; (c) 80% AcOH,
40 °C; (d) (n-Bu)2SnO, PhH, MS4A, 80 °C; (e) Ph3CCl, (i-Pr)2NEt,
DMF, rt; (f) (i) (CF3SO2)2O, Py, CH2Cl2, -40 °C, (ii) NaN3, DMF,
rt; (g) H2, Raney Ni, MeOH (h) PPh3, CH3CN, rt; H2O, rt; (i) 4 M
HCl/dioxane.
Dess-Martin periodinane and reduction with NaBH4 to
give 52 and 50 in a ratio of 2 to 1. Compound 52 was
transformed into the key intermediate, azide 53, by a
method similar to that mentioned above. Catalytic reduc-
tion of 53 afforded the protected D-galactono-δ-lactam 54,
and the analogous treatment of 53 with PPh3 gave
D-glucono-δ-lactam derivative 55 as the sole product. Acid
hydrolysis of 54 and 55 with hydrogen chloride in dioxane
resulted in crystalline D-galactono-δ-lactam (9)16,18 and
D-glucono-δ-lactam (7),12,17,18 respectively.
D-Altrono- and D-idono-δ-lactams (28 and 29) were
synthesized by the similar strategy from the known 5,6-
O-isopropylidene-L-galactonic acid γ-lactone (56)27 as
outlined in Scheme 6. However, in this case different from
in other cases, the δ-lactam formation using triphenyl-
phosphine afforded both the inversion isomer 63 and the
retention isomer 62 in a ratio of 3:5. It is likely that the
aminophosphonium salt 16 is more stable than the
alkoxyphosphonium salt 17 in this case (Scheme 2).
Con for m a tion a l An a lysis. Conformational analysis
was carried out by X-ray crystallographic studies. The
structures of 9 and 25-29 were solved by direct methods
(SHELX86), and the non-hydrogen atoms were anisotro-
pically refined. On the other hand, the X-ray crystal-
lographic analyses of 7 and 8 were already achieved by
Niwa et al.12 and Ogura et al.,28 respectively, and their
data were also used in this study. The ORTEP drowings
of 7-9 and 25-29 are shown in Figure 3. As shown in
Figure 3, conformations of eight glycono-δ-lactams (7-9
and 25-29) can be classified into three types of conform-
ers: boat, half-chair, and skew-boat. D-Glucono-, D-
As shown in Figure 4, when the R-configurations at
C-2 in 7, 25, and 26 were converted to the S-configura-
tions in optimization with PM3 in MOPAC, these struc-
tures were deformed simultaneously from the half-chair
conformer to the skew-boat conformer. These results
explain well why the structures with R-configuration and
S-configuration at C-2 position are the half-chair con-
former and the boat conformer, respectively. It is clearly
(27) Morgenlie, S. Carbohydr. Res. 1982, 107, 137.
(28) Ogura, H.; Furuhata, K.; Takayanagi, H.; Tsuzuno, N.; Iitaka,
Y. Bull. Chem. Soc. J pn. 1984, 57, 2687.
(29) Stewart, J . J . P. J . Comput. Chem. 1989, 10, 209, 221.

4876 J . Org. Chem., Vol. 65, No. 16, 2000
Nishimura et al.
F igu r e 3. X-ray crystal structures of eight glycono-δ-lactams.
indicated that the absolute configuration at C-2 is a chief
determining factor to fix the conformation of glycono-δ-
lactams. It is also likely that the hydrogen bond between
the lactam carbonyl and the adjacent hydroxy group at
C-2 position may make a large contribution to the overall
conformational energy: the five-membered rings of the
R-hydroxy ketones are generally effective in strong in-
tramolecular hydrogen bonding.30 However, when the
R-configuration at C-2 of 9 was converted to the S-
configuration in optimization with PM3/MOPAC, the
structure corresponding D-talono-δ-lactam (27) showed
a similar half-chair conformer to the original 9 and was
different from the structure obtained by X-ray crystal-
lographic analysis. As discussed above, this result sug-
gests that the intramolecular hydrogen bond between
S-configurational 2-OH and S-configurational 4-OH groups
make a large contribution to the overall structure in PM3/
MOPAC calculation.
An a lysis of Glycosid a se In h ibition . The inhibitory
activities of these glycono-δ-lactams against R-glucosi-
dase (baker’s yeast), â-glucosidase (almonds), R-mannosi-
dase (jack beans), â-mannosidase (snail), R-galactosidase
(30) Cho, T.; Kida, I.; Ninomiya, J .; Ikawa, S.-I. J . Chem. Soc.,
Faraday Trans. 1994, 90, 103.

Eight Stereoisomeric D-Glyconic-δ-lactams
J . Org. Chem., Vol. 65, No. 16, 2000 4877
â-glucosidase. There exists a better correlation between
the inhibitory activity against â-glucosidase and the
X-ray crystallographic structures (Figure 3) rather than
the molecular modeling structures (Figure 4). Further-
more, D-mannono-δ-lactam (8) having a boat conforma-
tion was a better inhibitor for â-glucosidase than D-glu-
cono-δ-lactam (7) having a half-chair conformation. Then,
molecular modeling of a glucopyranosyl cation in â-glu-
cosidase hydrolysis (Figure 1) was undertaken to under-
stand the structure-activity relation of the above inhibi-
tors. The structure of the glucopyranosyl cation (64) was
first optimized with PM3 in MOPAC. Three candidates,
the boat conformers (B5,2 (64a ) and B5,2 (64b)) and the
half-chair conformer of flap-up type (64c) were calculated
for the structure of the glucopyranosyl cation (Figure 5
and Table 3). Unexpectedly, the highest energy conformer
64a among these three structures more resembles D-man-
no-δ-lactam (8) which shows better inhibition for â-glu-
cosidase than D-glucono-δ-lactam (7). The discrepancy
between the calculations and the inhibitor conformations
may come from the neglect of the influence of interactions
such as hydrogen bonds between the molecule and the
active site of the enzyme in the calculation of molecular
modeling with PM3/MOPAC. D-Galactono, D-talono and
D-idono-δ-lactams (9, 27, and 29) having a S-configura-
tional at C-4 inhibited almond â-glucosidase similarly to
D-glucono and D-mannono-δ-lactams (7 and 8) having an
R-configuration at C-4, indicating that the 4-OH group
is probably not so important for binding in almond
â-glucosidase as 1-N-iminosugars (65-67) with a S-
configuration at C-4 are good inhibitors of â-glucosi-
dase.31,32 Many glycosidases are known to be nonspecific
with respect to the C-4 configuration of the sugar
moiety.33 Especially, â-glucosidases classified in family
1 have been proved to show low gluco/ galacto selec-
tivity.10b,34 The low gluco/ galacto selectivity has also been
shown in inhibition of almond â-glucosidase by the above
glycono-δ-lactams, although there are no information
whether almond â-glucosidase is classified in family 1
or not. However, the stereochemistry of C3-C4 (S and S)
is important for binding in â-galactosidase as only
D-galactono and D-talono-δ-lactams (9 and 28) among
eight glycono-δ-lactams were effective against â-galac-
tosidase. On the other hand, interestingly, mannosidases
were inhibited only by 8 among the glycono-δ-lactams
with the B5,2-conformation (Figure 3). These results
suggest that all stereochemistries of C2-C3-C4-C5 are
important for boat-form recognition in the catalytic
mechanism of â-mannosidase hydrolysis. A galactosyl
cation 69 and a mannopyranosyl cation 70 were also
calculated to be half-chair and skew-boat conformers,
respectively, by optimization with PM3/MOPAC (Figure
7, Table 3). The whole results of the structure-activity
relations seem to indicate that boat conformers as well
as half-chair ones may reflect similarly the structures of
glycopyranosyl cations in the active pockets of glycosi-
dases. On the other hand, we do not clearly understand
at this stage the reason these glycono-δ-lactams little
F igu r e 4. Optimized structures of eight glycono-δ-lactams by
PM3 in MOPAC.
(Aspergillus niger), and â-galactosidase (A. niger) were
evaluated, and the IC50 values and the inhibition con-
stants (Ki) are summarized in Tables 1 and 2. All
D-glycono-δ-lactams were proved to be competitive inhibi-
tors by Lineweaver-Burk plot, and the Ki values were
elucidated by Dixon plot. â-Glucosidase was inhibited by
D-glucono, D-mannono, D-galactono, D-talono, and D-idono-
δ-lactams (7, 8, 9, 27, and 29). â-Galactosidase was also
inhibited by D-galactono and D-talono-δ-lactams (9 and
27). On the other hand, R- and â-mannosidases were
inhibited only by D-mannono-δ-lactam (8). D-Gulono,
D-allono and D-altrono-δ-lactams (25, 26, and 28) showed
no inhibition of the glycosidases evaluated. These results
indicate that all D-glycono-δ-lactams (8, 27 and 29)
having the boat conformation in the X-ray crystallo-
graphic analysis (Figure 3) showed inhibition against
(31) Shitara, E.; Nishimura, Y.; Kojima, F.; Takeuchi, T. J . Antibiot.
1999, 52, 348.
(32) Ichikawa, Y.; Igarashi, Y. Tetrahedron Lett. 1995, 36, 4585.
(33) Skovbjerg, H.; Sjostrom, H.; Noren, O. Eur. J . Biochem. 1981,
114, 653.
(34) (a) Henrissat, B. Biochem. J . 1991, 280, 309. (b) Henrissat, B.;
Bairoch, A. Biochem. J . 1993, 293, 781. (c) Henrissat, B.; Bairoch, A.
Biochem. J . 1996, 316, 697. (d) Henrissat, B.; Davies, G. Curr. Opin.
Struct. Biol. 1997, 7, 637.

4878 J . Org. Chem., Vol. 65, No. 16, 2000
Nishimura et al.
F igu r e 5. Optimized structures of glucopyranosyl cation by PM3 in MOPAC.
Ta ble 1. In h ibitor y Activities (IC50 M) of 7-9 a n d 25-29 a ga in st Glycosid a ses
enzyme
7
8
9
25
26
27
28
29
R-glucosidasea
â-glucosidaseb
R-mannosidasec
â-mannosidased
R-galactosidasee
â-galactosidasef
NI
NI
NI
NIg
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
6.2 × 10-5
7.9 × 10-7
1.0 × 10-4
1.1 × 10-5
NI
1.6 × 10-4
1.8 × 10-4
7 × 10-5
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
1.7 × 10-5
6.2 × 10-5
Baker’s yeast. Almonds. c J ack beans. Snail. e Aspergillus nier. f Aspergillus niger. NI: no inhibition at 5.6 × 10-2 M.
a
b
d
g
Ta ble 2. Glycosid a se In h ibition Con sta n ts of 7-9, 27,
a n d 29
compd
enzyme
Ki (M)
7
8
â-glucosidase (almond)
5.1 × 10-5
5.1 × 10-7
6.8 × 10-5
9.0 × 10-6
8.5 × 10-5
4.5 × 10-6
1.2 × 10-4
1.5 × 10-5
4.6 × 10-5
â-glucosidase (almond)
R-mannosidase (jack bean)
â-mannosidase (snail)
â-glucosidase (almond)
â-galactosidase (Aspergillus niger)
â-glucosidase (almond)
â-galactosidase (Aspergillus niger)
â-glucosidase (almond)
9
27
29
F igu r e 6. 1-N-Iminosugar inhibitors with a S-configurational
4-OH group of â-glucosidase.
Ta ble 3. Ca lcu la ted P a r tia l Ch a r ge Distr ibu tion of
Glycop yr a n osyl Ca tion s
glucopyranosyl
galactopyranosyl
mannopyranosyl
atom
cation (64a )
cation (69)
cation (70)
C1
C2
C3
C4
C5
O
0.3782
0.0001
0.0468
0.0170
-0.0297
-0.0055
0.3962
-0.0240
0.0457
0.0220
0.0037
0.3384
0.0082
0.0270
0.0235
-0.0017
-0.0057
-0.0339
F igu r e 7. Optimized structures of galactosyl and mannosyl
cations (69 and 70, respectively) by PM3 in MOPAC.
affect R-glycosidases. However, it is likely that the
carbonyl groups of these glycono-δ-lactam inhibitors may
be topographically equivalent to the glycosidic oxygen
atom of the high energy transition state in â-glycosidase
rather than R-glycosidase as shown in Figure 1 and
Figure 3. Heightman and Vasella10b have elegantly
interpreted the selectivity of neutral lactone-type inhibi-
tors in the inhibition of â- over R-glycosidases by the
directionality of the hydrogen bond between the catalytic
acid and the glycosidic heteroatom of the inhibitors: in
R-glycosidases these groups are unfavorably oriented for
a strong hydrogen bond. On the whole, the inhibitory
activities of these glycono-δ-lactams having a neutral
character against glycosidases are also weaker than those
of the representative glycosidase inhibitors (1-6 and 10-
12) with a basic character (Figure 2). This indicate that
the positive charge of the inhibitors (protonation by the
glycosidases10b) plays an important role for strong binding
and recognition of glycosidases.7c,9 Thus, although the
information from three-dimensional structures of gly-
cosidase-ligand and/or inhibitor complexes in a study of
the inhibitors of influenza virus neuraminidase5,35 were
useful for the rational design of glycosidase inhibitors,
the conformational analysis of inhibitors by a combina-
tion of X-ray crystallographic study and molecular mod-
eling also provide useful information for the design of new
glycosidase inhibitors based on a transition state with
glycosyl ion character in the reaction catalyzed by gly-
cosidases.
In summary, an efficient and general synthetic route
to all eight stereoisomeric D-glycono-δ-lactams has been
developed. The strategy involves, as a key step, a novel
(35) (a) Varghese, J . N.; McKimm-Breschkin, J . L.; Caldwell, J . B.;
Kortt, A. A.; Colman, P. M. Proteins Struct. Funct. Genet. 1992, 14,
327. (b) Burmeister, W. P.; Ruigrok, R. W. H.; Cusak, S. EMBO J .
1992, 11, 49. (c) Bossart-Whitaker, P.; Carson, M.; Babu, Y. S.; Smith,
C. D.; Laver, W. G.; Air, G. M. J . Mol. Biol. 1993, 232, 1069. (d)
J anakiraman, M. N.; White, C. L.; Laver, W. G.; Air, G. M.; Luo, M.
Biochemistry 1994, 33, 8172. (e) Colman, P. M. Protein Science 1994,
3, 1687. (f) von Itzstein, M.; Dyason, J . C.; Oliver, S. W.; White, H. F.;
Wu, W.-Y.; Kok, G. B.; Pegg, M. S. J . Med. Chem. 1996, 39, 388. (g)
Chand, P.; Babu, Y. S.; Bantia, S.; Chu, N.; Cole, B.; Kotian, P. L.;
Laver, W. G.; Montgomery, J . A.; Pathak, V. P.; Petty, S. L.; Shrout,
D. P.; Walsh, D. A.; Walsh, G. M. J . Med. Chem. 1997, 40, 4030.

Eight Stereoisomeric D-Glyconic-δ-lactams
J . Org. Chem., Vol. 65, No. 16, 2000 4879
benzene (170 mL) were added dibutyltin oxide (8.29 g, 33.3
mmol) and molecular sieve 4A, and the reaction mixture was
refluxed with stirring overnight. After evaporation of the
solvent, the resulting residue was dissolved in dry DMF (170
mL). To the mixture were added triphenylmethyl chloride (12.4
g, 44.4 mmol) and N,N-diisopropylethylamine (15.5 mL, 88.8
mmol), and the mixture was stirred at room temperature for
3 h. Filtration and evaporation of the filtrate gave an oil, which
was dissolved in chloroform. The solution was washed with
water, dried over MgSO4, and filtered. Evaporation of the
filtrate gave an oil, which was subjected to column chroma-
tography on silica gel. Elution with a mixture of toluene-
methodology based on stereodivergent δ-lactam forma-
tion by configurational retention or inversion at C-4 of a
starting γ-lactone to provide two epimers of δ-lactam from
one parent γ-lactone. Conformations of eight glycono-δ-
lactams were analyzed by X-ray crystallographic studies,
and these structures were also in fair agreement with
those obtained by optimization with PM3 in MOPAC
except for D-manno, D-talono and D-idono-δ-lactams.
These conformations can be classified into three types of
conformers: boat (B5,2), half-chair of flap-up type, and
skew-boat. It is likely that the X-ray crystallographic
structure explains well the relationship between the
structure and the inhibitory activity against glycosidases.
X-ray crystallographic analysis and molecular modeling
in this study indicate that the major factor for recognition
of inhibitor in transition state by glycosidase should be
the conformation of inhibitors for â-glucosidase and the
stereochemistry of inhibitors for â-mannosidase and
â-galactosidase as well as a positive charge character.
acetone (10:1) gave 33 (9.13 g, 87%) as a colorless solid: [R]23
D
-38.4° (c 0.43, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.41 and
1.46 (3H each, s), 2.66 (1H, d, J ) 6.4 Hz), 3.40 (1H, dd, J )
5.1 and 10.2 Hz), 3.51 (1H, dd, J ) 3.4 and 10.2 Hz), 4.08 (1H,
m), 4.47 (1H, dd, J ) 3.6 and 8.3 Hz), 4.81 (1H, d, J ) 5.3 Hz),
4.91 (1H, dd, J ) 3.6 and 5.3 Hz), 7.22∼7.35 (9H, m), 7.41∼7.47
(6H, m). Anal. Calcd for C28H28O6: C, 73.02; H, 6.12. Found:
C, 72.74; H, 5.93.
5-Azid e-5-d eoxy-2,3-O-isop r op ylid en e-6-O-t r ip h en yl-
m eth yl-D-gu lon o-γ-la cton e (34). To a solution of 33 (5.0 g,
11.9 mmol) in dry CH2Cl2 (100 mL) were added dry pyridine
(3.51 mL, 43.4 mmol) and trifluoromethanesulfonic anhydride
(3.65 mL, 21.7 mmol) at -40 °C, and the reaction mixture was
stirred at -40 °C for 2 h. After dilution with chloroform, the
solution was washed with water, dried over MgSO4 and
filtered. Evaporation of the filtrate gave an oil, which was
dissolved in dry DMF (100 mL). To the solution was added
sodium azide (7.05 g, 108 mmol), and the mixture was stirred
at room-temperature overnight. Evaporation of the solvent
gave an oil, which was dissolved in ethyl acetate. The solution
was washed with water, dried over MgSO4, and filtered.
Evaporation of the filtrate gave an oil, which was subjected
to column chromatography on silica gel. Elution with a mixture
of toluene-acetone (20:1) gave 34 (2.70 g, 51%) as a colorless
Exp er im en ta l Section
Gen er a l P r oced u r es for En zym e In h ibition Assa y. The
enzymes R-glucosidase (baker’s yeast), â-glucosidase (almond),
R-mannosidase (jack beans), â-mannosidase (snail), â-galac-
tosidase (Aspergillus niger), and R-galactosidase (Aspergillus
niger) were purchased from Sigma Chemical Co. R- and
â-glucosidases were assayed using p-nitrophenyl R-D-gluco-
pyranoside (1.5 × 10-3M) and â-D-glucopyranoside (2 × 10-3M)
as substrates at pH 6.3 (0.025 M citrate-phosphate buffer) and
5.0 (0.025 M acetate buffer), respectively. R- and â-Mannosi-
dases were assayed using p-nitrophenyl R-D-mannopyranoside
(2 × 10-3M) and â-D-mannopyranoside (2 × 10-3M) as sub-
strates at pH 4.5 (0.05 M acetate buffer) and 4.0 (0.05 M
acetate buffer), respectively. R- and â-Galactosidases were
assayed using p-nitrophenyl R- and â-D-galactopyranoside (2
× 10-3M) at pH 4.0 (0.025 M citrate-phosphate buffer). The
reaction mixture contained 0.5 mL of buffer, 0.1 mL of
substrate solution and water or aqueous solution containing
the test compound. The mixture was incubated at 37 °C for 3
min, and 0.01 mL of enzyme was added. After 30 min of
reaction, 1.0 mL and 0.3 M glycine-sodium hydroxide buffer
(pH 10.5) was added and the absorbance of the liberated
nitrophenol or phenolphthalein measured at 400 or 525 nm,
respectively. The percent inhibition was calculated by the
formula (A - B)/A × 100, where A is the nitrophenol liberated
by the enzyme without an inhibitor and B is that with an
inhibitor. The IC50 value is the concentration of inhibitor at
50% of enzyme activity. Ki values were determined using six
substrate (0.25-10 mM of p-nitrophenyl â-D-glucopyranoside;
0.5-8.0 mM of p-nitrophenyl R-D-mannopyranoside; 0.25-4.0
mM of p-nitrophenyl â-D-mannopyranoside; 0.1-1.0 mM of
p-nitrophenyl â-D-galactopyranoside) and four inhibitor (usu-
ally 0-140 µM) concentrations. Ki values were also elucidated
by Dixon plot.
2,3-O-Isop r op ylid en e-L-m a n n on o-γ-la cton e (31). A solu-
tion of 3024 (17.0 g, 65.8 mmol) in 80% aqueous acetic acid
(500 mL) was stirred at room-temperature overnight. Evapo-
ration of the solvent gave an oil, which was subjected to column
chromatography on silica gel. Elution with a mixture of
chloroform-methanol (5:1) gave 31 (8.4 g, 59%) as a colorless
solid. The solid was crystallized from a mixture of ethyl
acetate-diethyl ether to give colorless crystals: mp 100-102
°C; [R]D -69.3 °C (c 0.51, acetone); 1H NMR (400 MHz, CDCl3)
δ 1.44 and 1.50 (3H each, s), 2.00 (1H, br t, J ) 5.2 Hz), 2.69
(1H, d, J ) 5.4 Hz), 3.80 (1H, dt, J ) 5.2 and 11.7 Hz), 3.95
(1H, ddd, J ) 2.9, 5.2 and 11.7 Hz), 4.06 (1H, m), 4.51 (1H,
dd, J ) 3.8 and 9.0 Hz), 4.86 (1H, d, J ) 5.7 Hz), 4.97 (1H, dd,
J ) 3.8 and 5.7 Hz). Anal. Calcd for C9H14O6: C, 49.53; H,
6.46. Found: C, 49.49; H, 6.49.
foam: [R]24 -22.4° (c 0.55, MeOH); 1H NMR (400 MHz,
D
CDCl3) δ 1.14 and 1.36 (3H each, s), 3.27 (1H, dd, J ) 3.2 and
10.0 Hz), 3.63 (1H, dd, J ) 3.2 and 10.0 Hz), 3.80 (1H, dt, J )
3.2 and 8.8 Hz), 4.21 (1H, dd, J ) 3.2 and 5.1 Hz), 4.68∼4.73
(2H, m), 7.23∼7.36 (9H, m), 7.42∼7.50 (6H, m); HRMS (FAB)
calcd for C28H27O5N3Na (MNa+) 508.1848, found 508.1819.
2,3-O-Isop r op ylid en e-6-O-tr ip h en ylm eth yl-D-gu lon o-δ-
la cta m (35). A solution of 34 (51.6 mg, 0.106 mmol) in
methanol (2.0 mL) was stirred with RaneyNi under hydrogen
atmosphere at room temperature for 4 h. After filtration,
evaporation of the filtrate gave an oil. The oil was subjected
to preparative thin-layer chromatography (PTLC) on silica gel
developed with toluene-acetone (2:1) to give 35 (38.6 mg, 79%)
as a colorless foam: [R]23 +13.1° (c 0.89, MeOH); 1H NMR
D
(400 MHz, CDCl3) δ 1.35 and 1.43 (3H each, s), 3.29 (1H, d, J
) 3.9 Hz), 3.48 (2H, dd, J ) 5.4 and 10.3 Hz), 3.70 (1H, m),
4.00 (1H, m), 4.40 (1H, dd, J ) 3.7 and 7.0 Hz), 4.49 (1H, d, J
) 7.0 Hz), 7.22-7.34 (9H, m), 7.37-7.43 (6H, m). Anal. Calcd
for C28H29NO5: C, 73.18; H, 6.36; N, 3.04. Found: C, 73.49;
H, 6.56; N, 2.75.
2,3-O-Isop r op ylid en e-6-O-tr ip h en ylm eth yl-D-a llon o-δ-
la cta m (36). To a solution of 34 (1.19 g, 2.45 mmol) in
acetonitrile (47.6 mL) was added triphenylphosphine (964 mg,
3.67 mmol), and the reaction mixture was stirred at room-
temperature overnight. After addition of water (2.4 mL), the
mixture was stirred at room-temperature overnight. Evapora-
tion of the solvent gave an oil, which was dissolved in
chloroform. The solution was washed with water, dried over
MgSO4, and filtered. Evaporation of the filtrate gave an oil.
The oil was subjected to PTLC on silica gel developed with
toluene-acetone (2:1) to give 36 (1.04 g, 92%) as a colorless
foam.
36: [R]24 +33.0° (c 0.71, MeOH); 1H NMR (400 MHz,
D
CDCl3) δ 1.39 and 1.50 (3H each, s), 2.33 (1H, d, J ) 8.0 Hz),
3.22 (1H, dd, J ) 7.8 and 9.8 Hz), 3.56 (1H, dd, J ) 3.9 and
9.8 Hz), 3.61 (1H, dt, J ) 3.9 and 7.8 Hz), 3.72 (1H, dt, J )
3.9 and 7.8 Hz), 4.44 (1H, d, J ) 6.6 Hz), 4.52 (1H, dd, J ) 3.9
and 6.6 Hz), 5.97 (1H, s), 7.20-7.35 (9H, m), 7.38-7.45 (6H,
2,3-O-Isopr opyliden e-6-O-tr iph en ylm eth yl-L-m an n on o-
γ-la cton e (33). To a solution of 31 (5.0 g, 22.9 mmol) in dry

4880 J . Org. Chem., Vol. 65, No. 16, 2000
Nishimura et al.
m). Anal. Calcd for C28H29NO5: C, 73.18; H, 6.36; N, 3.04.
Found: C, 73.37; H, 6.49; N, 2.94.
41 as in the preparation of 36 from 34; the yield was 77%:
[R]24D +3.6° (c 0.69, MeOH); 1H NMR (400 MHz, CDCl3) δ 1.40
and 1.51 (3H each, s), 2.33 (1H, s), 3.41-3.52 (3H, m), 3.92
(1H, br d, J ) 3.4 Hz), 4.40 (1H, dd, J ) 3.4 and 8.4 Hz), 4.55
(1H, d, J ) 8.4 Hz), 5.83 (1H, s), 7.22-7.35 (9H, m), 7.37∼7.43
(6H, m). Anal. Calcd for C28H29NO5: C, 73.18; H, 6.36; N, 3.04.
Found: C, 73.12; H, 6.49; N, 2.90.
2,3-O-Isop r op ylid en e-D-ta lon o-δ-la cta m (44). A solution
of 43 (330 mg, 0.727 mmol) in ethanol (6.6 mL) was stirred
with 10% Pd-C (330 mg) under hydrogen atmosphere at room-
temperature overnight. After filtration, evaporation of the
filtrate gave 44 (94 mg, 60%) as a colorless solid. The solid
was crystallized from ethanol to give colorless needles: mp
200-201 °C; [R]25D -12.3° (c 0.64, MeOH); 1H NMR (400 MHz,
CD3OD) δ 1.38 and 1.49 (3H each, s), 3.44 (1H, ddd, J ) 2.0,
6.2 and 7.5 Hz), 3.75 (1H, dd, J ) 7.5 and 11.0 Hz), 3.79 (1H,
dd, J ) 6.2 and 11.0 Hz), 4.07 (1H, dd, J ) 2.0 and 3.7 Hz),
4.46 (1H, dd, J ) 3.7 and 8.3 Hz), 4.55 (1H, d, J ) 8.3 Hz).
Anal. Calcd for C9H15NO5: C, 49.76; H, 6.96; N, 6.44. Found:
C, 50.01; H, 7.12; N, 6.31.
D-Gu lon o-δ-la cta m (25). Compound 35 (90.0 mg, 0.196
mmol) was dissolved in 4M hydrogen chloride in dioxane, and
the reaction mixture was stirred at room temperature for 6 h.
After addition of ether, the resulting precipitates were collected
and washed with ether. The solid was dissolved in water, and
the mixture was neutralized with Dowex WGR. After filtration,
evaporation of the filtrate gave an oil, which was subjected to
PTLC on silica gel developed with chloroform-methanol-30%
NH4OH (1:2:0.5 v/ v) to give 25 (25.1 mg, 88%) as an oil. The
oil was crystallized from a mixture of methanol-ethanol-H2O
to give colorless crystals: mp 163∼164 °C; [R]24D +60.5° (c 0.31,
H2O) [lit18,36 -27.0° (c 0.50, H2O) and -20.6° (c 0.65, H2O) for
L-gulono-δ-lactam: a large discrepancy of the optical rotation
value between this 25 (D-gulono-δ-lactam) and L-gulono-δ-
lactams reported by Pandit group18 and Fleet group36 is
incomprehensible, although the structure of 25 and its purity
are confirmed by X-ray crystallographic analysis and combus-
tion elemental analysis, respectively]; 1H NMR (400 MHz, D2O)
δ 3.55 (1H, m), 3.62∼3.70 (2H, m), 4.07 (1H, dd, J ) 2.7 and
4.1 Hz), 4.11 (1H, t, J ) 4.1 Hz), 4.26 (1H, d, J ) 4.1 Hz).
Anal. Calcd for C6H11NO5: C, 40.67; H, 6.25; N, 7.90. Found:
C, 40.60; H, 6.29; N, 7.75.
D-Ma n n on o-δ-la cta m (8). Compound 8 was synthesized
similarly from 42 as in the preparation of 25 from 35; the yield
was 68%. The amorphous solid was crystallized from a mixture
of ethanol and water to give colorless crystals: mp 169-171
°C (lit.13 mp 169-170 °C; 165-169 °C; 170-172 °C); [R]22
D-Allon o-δ-la cta m (26). Compound 26 was synthesized
similarly from 36 as in the preparation of 25 from 35; the yield
was 57%. The amorphous solid was crystallized from a mixture
D
+1.0° (c 1.0, H2O) (lit.13 +1.6° (H2O); +0.9° (H2O); +2.0° (H2O));
1H NMR (400 MHz, D2O) δ 3.20 (1H, dt, J ) 3.9 and 6.3 Hz),
3.53 (1H, dd, J ) 6.3 and 11.7 Hz), 3.65 (1H, dd, J ) 3.9 and
11.7 Hz), 3.69 (1H, t, J ) 6.3 Hz), 3.86 (1H, dd, J ) 3.9 and
6.3 Hz), 4.17 (1H, d, J ) 3.9 Hz).
of methanol, ethanol and water to give colorless crystals: mp
1
>265 °C dec; [R]24 +68.3° (c 0.31, H2O); H NMR (400 MHz,
D
D2O) δ 3.40 (1H, ddd, J ) 2.7, 4.4 and 9.4 Hz), 3.60 (1H, dd,
J ) 4.4 and 12.1 Hz), 3.68 (1H, dd, J ) 2.7 and 12.1 Hz), 3.88
(1H, dd, J ) 2.5 and 9.4 Hz), 4.11 (1H, d, J ) 2.5 Hz), 4.13
(1H, t, J ) 2.5 Hz). Anal. Calcd for C6H11NO5: C, 40.67; H,
6.25; N, 7.90. Found: C, 40.62; H, 6.30; N, 7.77.
D-Ta lon o-δ-la cta m (27). Compound 27 was synthesized
similarly from 44 as in the preparation of 25 from 35; the yield
was 34%. The amorphous solid was crystallized from a mixture
of methanol, ethanol and water to give colorless crystals: mp
1
151-153 °C; [R]24 +27.1° (c 0.27, H2O); H NMR (400 MHz,
2,3-O-Isop r op ylid en e-6-O-tr ip h en ylm eth yl-L-gu lon o-γ-
la cton e (40). Compound 40 was synthesized similarly from
3819 as in the preparation of 33 from 31; the yield was 97%.
The colorless solid was crystallized from a mixture of chloro-
D
D2O) δ 3.56 (1H, dt, J ) 4.9 and 5.6 Hz), 3.65 (1H, dd, J ) 4.9
and ∼12 Hz), 3.65 (1H, dd, J ) 5.6 and ∼12 Hz), 4.02 (1H, dd,
J ) 2.9 and 4.4 Hz), 4.10 (1H, d, J ) 4.4 Hz), 4.18 (1H, dd, J
) 2.9 and 5.6 Hz). Anal. Calcd for C6H11NO5: C, 40.67; H, 6.25;
N, 7.90. Found: C, 40.28; H, 6.37; N, 7.66.
form, ether and hexane to give colorless crystals: mp 160∼162
1
°C; [R]24 +18.8° (c 0.31, CHCl3); H NMR (400 MHz, CDCl3)
D
2,3-Di-O-m et h oxym et h yl-5,6,-O-isop r op ylid en e-D-ga -
la cton o-γ-la cton e (47). To a solution of 4626 (14.8 g, 67.8
mmol) in DMF (148 mL) were added N,N-diisopropylethyl-
amine (94.5 mL, 54.2 mmol), chloromethylmethyl ether (30.9
mL, 40.7 mmol) and tetra-n-butylammonium iodide (57.6 g,
15.6 mmol) at room temperature, and the reaction mixture was
stirred at 50 °C overnight. After dilution with chloroform, the
solution was washed with water, dried over MgSO4 and
filtered. Evaporation of the filtrate gave an oil, which was
subjected to column chromatography on silica gel. Elution with
δ 1.23 and 1.39 (3H each, s), 2.60 (1H, d, J ) 4.4 Hz), 3.30
(1H, dd, J ) 3.9 and 10.0 Hz), 3.54 (1H, dd, J ) 4.4 and 10.0
Hz), 4.13 (1H, m), 4.44 (1H, dd, J ) 3.4 and 5.4 Hz), 4.67 (1H,
dd, J ) 3.4 and 7.3 Hz), 4.76 (1H, d, J ) 5.4 Hz), 7.22-7.35
(9H, m), 7.43-7.48 (6H, m). Anal. Calcd for C28H28O6: C, 73.02;
H, 6.12. Found: C, 72.90; H, 6.19.
5-Azid o-5-d eoxy-2,3-O-isop r op ylid en e-6-O-t r ip h en yl-
m eth yl-D-m a n n on o-γ-la cton e (41). Compound 41 was syn-
thesized similarly from 40 as in the preparation of 34 from
33; the yield was 80%. The colorless solid was crystallized from
a mixture of toluene and acetone (2:1) gave 47 (13 g, 68%) as
a
mixture of dichloromethane and diethyl ether to give
1
a colorless foam: [R]26 -11.8° (c 0.61, CHCl3); H NMR (400
colorless crystals: mp 90∼92 °C; [R]23D +11.3° (c 0.40, CHCl3);
1H NMR (400 MHz, CDCl3) δ 1.42 and 1.44 (3H each, s), 3.40
(1H, dd, J ) 6.3 and 10.3 Hz), 3.59 (1H, dd, J ) 2.4 and 10.3
Hz), 3.79 (1H, ddd, J ) 2.4, 6.3 and 9.9 Hz), 4.36 (1H, dd, J )
3.4 and 9.9 Hz), 4.78 (1H, d, J ) 5.2 Hz), 4.85 (1H, dd, J ) 3.4
and 5.2 Hz), 7.22-7.35 (9H, m), 7.44-7.49 (6H, m). Anal. Calcd
for C28H27N3O5: C, 69.26; H, 5.60; N, 8.65. Found: C, 69.52;
H, 5.57; N, 8.79.
D
MHz, CDCl3) δ 1.37 and 1.41 (3H each, s), 3.41 and 3.46 (3H
each, s), 3.99 (1H, dd, J ) 6.8 and 8.8 Hz), 4.11 (1H, dd, J )
6.8 and 8.8 Hz), 4.20 (1H, dd, J ) 2.9 and 7.0 Hz), 4.38 (1H,
dt, J ) 2.9 and 6.8 Hz), 4.46 (1H, t, J ) 7.0 Hz), 4.53 (1H, d,
J ) 7.0 Hz), 4.73 and 4.84 (2H, ABq, J ) 6.8 Hz), 4.78 and
5.06 (2H, ABq, J ) 6.8 Hz). Anal. Calcd for C13H22O8: C, 50.97;
H, 7.23. Found: C, 51.17; H, 7.23.
2,3-Di-O-m et h oxym et h yl-D-ga la ct on o-γ-la ct on e (48).
Compound 48 was synthesized similarly from 47 as in the
preparation of 31 from 30; the yield was 93%. The solid was
crystallized from a mixture of chloroform and diethyl ether to
2,3-O-Isopr opyliden e-6-O-tr iph en ylm eth yl-D-m an n on o-
δ-la cta m (42). Compound 42 was synthesized similarly from
41 as in the preparation of 35 from 34; the yield was 65%:
[R]23 +13.7° (c 0.67, MeOH); 1H NMR (400 MHz, CDCl3) δ
D
give colorless crystals: mp 70-71 °C; [R]26 -24.3° (c 0.44,
1.36 and 1.43 (3H each, s), 2.61 (1H, br s), 3.11 (1H, dd, J )
8.3 and 9.8 Hz), 3.45 (1H, dt, J ) 3.4 and 8.3 Hz), 3.53 (1H,
ddd, J ) 3.4, 7.8 and 8.3 Hz), 3.65 (1H, dd, J ) 3.4 and 9.8
Hz), 4.23 (1H, t, J ) 7.8 Hz), 4.59 (1H, d, J ) 7.8 Hz), 6.14
(1H, s), 7.23-7.35 (9H, m), 7.37-7.43 (6H, m); HRMS (FAB)
calcd for C28H30O5N (MH+) 460.2124, found 460.2128.
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.59 (1H, br s), 3.11 (1H,
br d, J ) 5.9 Hz), 3.41 and 3.46 (3H each, s), 3.70-3.85 (2H,
m), 3.96 (1H, m), 4.28 (1H, m), 4.52-4.58 (2H, m), 4.72 and
4.85 (2H, ABq, J ) 6.8 Hz), 4.78 and 5.04 (2H, ABq, J ) 6.8
Hz). Anal. Calcd for C10H18O8: C, 45.11; H, 6.81. Found: C,
45.41; H, 6.90.
2,3-O-Isop r op ylid en e-6-O-tr ip h en ylm eth yl-D-ta lon o-δ-
la cta m (43). Compound 43 was synthesized similarly from
2,3-Di-O-m eth oxym eth yl-6-O-tr ip h en ylm eth yl-D-ga la c-
ton o-γ-la cton e (50). Compound 50 was synthesized similarly
from 48 as in the preparation of 33 from 31; the yield was
47%. The solid was crystallized from a mixture of chlororform
and diethyl ether to give colorless crystals: mp 127-128 °C;
(36) Davis, B. G.; Hull, A.; Smith, C.; Nash, R. J .; Watson, A. A.;
Winkler, D. A.; Griffiths, R. C.; Fleet, W. J . Tetrahedron: Asym. 1998,
9, 2947.

Eight Stereoisomeric D-Glyconic-δ-lactams
J . Org. Chem., Vol. 65, No. 16, 2000 4881
[R]25 -18.3° (c 0.57, CHCl3); 1H NMR (400 MHz, CDCl3) δ
D-Glu con o-δ-la cta m (7). Compound 7 was synthesized
similarly from 55 as in the preparation of 25 from 35; the yield
was 77%. The amorphous solid was crystallized from a mixture
of ethanol and water to give colorless crystals: mp 205-207
D
2.14 (1H, d, J ) 7.3 Hz), 3.25 (1H, dd, J ) 6.1 and 9.4 Hz),
3.39 (1H, dd, J ) 6.8 and 9.4 Hz), 3.38 and 3.44 (3H each, s),
4.00 (1H, m), 4.34 (1H, m), 4.50-4.56 (2H, m), 4.69 and 4.81
(2H, ABq, J ) 6.8 Hz), 4.76 and 5.03 (2H, ABq, J ) 6.8 Hz),
7.22-7.34 (9H, m), 7.40∼7.45 (6H, m). Anal. Calcd for
°C (lit.12 mp 202-204 °C; 204-205 °C; 197-199 °C; [R]22
D
+59.0° (c 0.39, H2O) (lit.12 +60° (H2O); +57° (H2O); +63°
(H2O)); 1H NMR (D2O, 400 MHz) δ 3.20-3.25 (1H, m),
3.55∼3.64 (3H, m), 3.67 (1H, dd, J ) 2.9 and 12.2 Hz), 3.82-
3.90 (1H, m).
C
29H32O8: C, 68.48; H, 6.34. Found: C, 68.62; H, 6.32.
5-Keto-2,3-d i-O-m eth oxym eth yl-6-O-tr ip h en ylm eth yl-
L-a r a bin oh exon ic a cid γ-la cton e (51). To a solution of 50
(0.923 g, 1.82 mmol) in dry CH2Cl2 (18 mL) was added Dess-
Martin periodinane (1.38 g, 3.3 mmol) at room temperature,
and the reaction mixture was stirred for 1 h. After addition of
ether, the resulting precipitates were removed by filtration.
The filtrate was evaporated to give an oil, which was subjected
to column chromatography on silica gel. Elution with a mixture
of toluene and acetone (10:1) gave 51 (0.744 g, 81%) as colorless
D-Ga la cton o-δ-la cta m (9). Compound 9 was synthesized
similarly from 54 as in the preparation of 25 from 35; the yield
was 69%. The amorphous solid was crystallized from a mixture
of ethanol and water to give colorless crystals: mp 202-204
°C (lit.16 mp 204-206 °C); [R]24D +120° (c 1.0, H2O) (lit.16 [R]23
D
+122.0° (H2O)); 1H NMR (D2O, 400 MHz) δ 3.45-3.55 (2H,
m), 3.57-3.65 (1H, m), 3.77 (1H, dd, J ) 2.2 and 10.2 Hz),
4.04 (1H, d, J ) 10.2 Hz), 4.06 (1H, dd, J ) 2.2 and ∼3 Hz).
5,6-O-Isop r op ylid en e-2,3-d i-O-m eth oxym eth yl-L-ga la c-
ton o-γ-la cton e (57). Compound 57 was synthesized similarly
from 5627 as in the preparation of 47 from 46; the yield was
oil: [R]23 +4.6° (c 0.93, CHCl3); 1H NMR (400 MHz, CDCl3) δ
D
3.29 and 3.39 (3H each, s), 4.12 and 4.05 (2H, ABq, J ) 18.1
Hz), 4.43 (1H, d, J ) 5.4 Hz), 4.47 (1H, t, J ) 5.4 Hz), 4.66
and 4.89 (2H, ABq, J ) 6.6 Hz), 4.68 (2H, s), 4.80 (1H, d, J )
5.4 Hz), 7.22-7.37 (9H, m), 7.42-7.50 (6H, m); HRMS (FAB)
calcd for C29H30O8Na (MNa+) 529.1838, found 529.1805.
81%: [R]23 +13.7° (c 0.3, CHCl3); 1H NMR (400 MHz, CDCl3)
D
δ 1.38 and 1.41 (3H each, s), 3.41 and 3.46 (3H each, s), 3.99
(1H, dd, J ) 6.8 and 8.3 Hz), 4.12 (1H, dd, J ) 6.8 and 8.3
Hz), 4.20 (1H, dd, J ) 2.9 and 6.9 Hz), 4.38 (1H, dt, J ) 2.9
and 6.8 Hz), 4.46 (1H, t, J ) 6.9 Hz), 4.53 (1H, d, J ) 6.9 Hz),
4.73 and 4.84 (2H, ABq, J ) 6.6 Hz), 4.78 and 5.07 (2H, ABq,
J ) 6.8 Hz). Anal. Calcd for C13H22O8: C, 50.97; H, 7.23.
Found: C, 51.01; H, 7.23.
2,3-Di-O-m eth oxym eth yl-6-O-tr iph en ylm eth yl-L-altr on o-
γ-la cton e (52). To a solution of 51 (6.58, 12.9 mmol) in a
mixture of CH2Cl2 (77 mL) and methanol (38 mL) was added
sodium borohydride (536 mg, 14.1 mmol) at -50 °C, and the
reaction mixture was stirred at -50 °C for 1 h. After dilution
with chloroform, the solution was washed with saturated
NH4Cl aqueous solution and water. The organic phase was
dried over MgSO4 and filtered. The filtrate was evaporated to
give an oil. The oil was subjected to PTLC on silica gel
developed with toluene-acetone (10:1) to give 52 (2.24 g, 34%)
and 50 (1.12 g, 17%) as colorless oil.
52: [R]25D +27.8° (c 0.33, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 2.62 (1H, d, J ) 5.8 Hz), 3.33 (1H, dd, J ) 5.7 and 10.2 Hz),
3.37 (1H, dd, J ) 4.3 and 10.2 Hz), 3.32 and 3.44 (3H each, s),
3.88 (1H, ddt, J ) 4.3, 5.7 and 6.3 Hz), 4.38 (1H, dd, J ) 5.0
and 6.3 Hz), 4.43 (1H, t, J ) 5.0 Hz), 4.46 (1H, d, J ) 5.0 Hz),
4.67 and 4.72 (2H, ABq, J ) 6.4 Hz), 4.74 and 5.00 (2H, ABq,
J ) 6.4 Hz), 7.22-7.35 (9H, m), 7.40∼7.45 (6H, m). Anal. Calcd
for C29H32O8: C, 68.48; H, 6.34. Found: C, 68.23; H, 6.30.
5-Azid o-5-d eoxy-2,3-d i-O-m eth oxym eth yl-6-O-tr ip h en -
ylm eth yl-D-ga la cton o-γ-la cton e (53). Compound 53 was
synthesized similarly from 52 as in the preparation of 34 from
33; the yield was 55%: [R]24D -31.1° (c 0.46, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 3.36 and 3.43 (3H each, s), 3.42 (1H, dd,
J ) 5.5 and 9.9 Hz), 3.57 (1H, dd, J ) 8.0 and 9.9 Hz), 3.76
(1H, ddd, J ) 2.2, 5.5 and 8.0 Hz), 4.23 (1H, dd, J ) 2.2 and
7.2 Hz), 4.40 (1H, t, J ) 7.2 Hz), 4.48 (1H, d, J ) 7.2 Hz), 4.65
and 4.79 (2H, ABq, J ) 6.8 Hz), 4.75 and 5.02 (2H, ABq, J )
6.8 Hz), 7.22-7.35 (9H, m), 7.41-7.46 (6H, m). Anal. Calcd
for C28H28O6: C, 73.02; H, 6.12. Found: C, 72.90; H, 6.19.
2,3-Di-O-m et h oxym et h yl-6-O-t r ip h en ylm et h yl-D-glu -
con o-δ-la cta m (54). Compound 54 was synthesized similarly
from 53 as in the preparation of 35 from 34; the yield was
64%: [R]20D +71.2° (c 0.35, MeOH); 1H NMR (400 MHz, CDCl3)
δ 3.00 (1H, t, J ) 9.2 Hz), 3.37-3.50 (2H, m), 3.43 and 3.44
(3H each, s), 3.64 (1H, t, J ) 9.3 Hz), 3.96 (1H, dd, J ) 2.9
and 9.2 Hz), 4.05 (1H, d, J ) 9.3 Hz), 4.17 (1H, d, J ) 1.0 Hz),
4.77 and 4.81 (2H, ABq, J ) 6.6 Hz), 4.80 and 5.13 (2H, ABq,
J ) 6.8 Hz), 5.94 (1H, s), 7.22-7.35 (9H, m), 7.37-7.43 (6H,
m). Anal. Calcd for C29H33NO7: C, 68.62; H, 6.55; N, 2.75.
Found: C, 68.24; H, 6.51; N, 2.74.
2,3-Di-O-m et h oxym et h yl-L-ga la ct on o-γ-la ct on e (58).
Compound 58 was synthesized similarly from 57 as in the
preparation of 31 from 30; the yield was 80%: [R]21 +25.3°
D
1
(c 0.40, CHCl3); H NMR (400 MHz, CDCl3) δ 2.73 (1H, br s),
3.21 (1H, br s), 3.41 and 3.46 (3H each, s), 3.75 (1H, dd, J )
4.9 and 11.5 Hz), 3.81 (1H, dd, J ) 6.4 and 11.5 Hz), 3.95 (1H,
m), 4.28 (1H, m), 4.51∼4.58 (2H, m), 4.72 and 4.84 (2H, ABq,
J ) 6.8 Hz), 4.78 and 5.04 (2H, ABq, J ) 6.8 Hz). Anal. Calcd
for C10H18O8: C, 45.11; H, 6.81. Found: C, 45.17; H, 7.11.
2,3-Di-O-m eth oxym eth yl-6-O-tr ip h en ylm eth yl-L-ga la c-
ton o-γ-la cton e (60). Compound 60 was synthesized similarly
from 58 as in the preparation of 33 from 31; the yield was
85%: [R]26D +17.4° (c 0.28, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 2.09 (1H, d, J ) 7.8 Hz), 3.26 (1H, dd, J ) 6.5 and 9.4 Hz),
3.39 (1H, dd, J ) 6.5 and 9.4 Hz), 3.39 and 3.45 (3H each, s),
4.01 (1H, dt, J ) 1.8 and 6.5 Hz), 4.34 (1H, m), 4.50-4.55 (2H,
m), 4.69 and 4.81 (2H, ABq, J ) 6.8 Hz), 4.77 and 5.03 (2H,
ABq, J ) 6.8 Hz), 7.22-7.34 (9H, m), 7.4-7.45 (6H, m). Anal.
Calcd for C29H32O8: C, 68.48; H, 6.34. Found: C, 68.86; H,
6.41.
5-Azid e-5-d eoxy-2,3-d i-O-m eth oxym eth yl-6-O-tr ip h en -
ylm eth yl-D-a ltr on o-γ-la cton e (61). Compound 61 was syn-
thesized similarly from 60 as in the preparation of 34 from
33; the yield was 73%: [R]24D -15.1° (c 0.36, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 3.25 and 3.43 (3H each, s), 3.39 (1H, dd,
J ) 7.3 and 10.0 Hz), 3.41 (1H, dd, J ) 5.4 and 10.0 Hz), 3.74
(1H, dt, J ) 5.4 and 7.3 Hz), 4.28 (1H, t, J ) 5.4 Hz), 4.33
(1H, t, J ) 5.4 Hz), 4.40 (1H, t, J ) 5.4 Hz), 4.58 and 4.69
(2H, ABq, J ) 6.6 Hz), 4.72 and 5.02 (2H, ABq, J ) 6.8 Hz),
7.22-7.35 (9H, m), 7.42-7.48 (6H, m). Anal. Calcd for
C
29H31N3O7: C, 65.27; H, 5.85; N, 7.87. Found: C, 65.29; H,
5.67; N, 7.96.
2,3-Di-O-m e t h oxym e t h yl-6-O-t r ip h e n ylm e t h yl-D-a l-
tr on o-δ-la cta m (62). Compound 62 was synthesized similarly
from 61 as in the preparation of 35 from 34; the yield was
72%: [R]22D -23.5° (c 0.94, MeOH); 1H NMR (400 MHz, CDCl3)
δ 3.10 (1H, t, 10.3 Hz), 3.15 (1H, d, J ) 8.3 Hz), 3.38 and 3.42
(3H each, s), 3.54-3.62 (2H, m), 3.86 (1H, dt, J ) 2.4 and 8.3
Hz), 3.92 (1H, dd, J ) 2.4 and 4.4 Hz), 4.15 (1H, d, J ) 4.4
Hz), 4.68 and 4.96 (2H, ABq, J ) 6.4 Hz), 4.73 and 4.76 (2H,
ABq, J ) 6.8 Hz), 6.04 (1H, s), 7.20-7.33 (9H, m), 7.37-7.44
(6H, m). Anal. Calcd for C29H33NO7: C, 68.62; H, 6.55; N, 2.75.
Found: C, 68.27; H, 6.26; N, 2.66.
2,3-Di-O-m eth oxym eth yl-6-O-tr ip h en ylm eth yl-D-ga la c-
ton o-δ-la cta m (55). Compound 55 was synthesized similarly
from 53 as in the preparation of 36 and 34; the yield was
67%: [R]26D +77.0° (c 0.35, MeOH); 1H NMR (400 MHz, CDCl3)
δ 2.30 (1H, m), 3.37-3.42 (2H, m), 3.40 and 3.45 (3H each, s),
3.59 (1H, dt, J ) 2.4 and 6.4 Hz), 3.87 (1H, dd, J ) 2.4 and
9.8 Hz), 4.11 (1H, m), 4.35 (1H, d, J ) 9.8 Hz), 4.76 and 4.84
(2H, ABq, J ) 6.8 Hz), 4.83 and 5.13 (2H, ABq, J ) 6.4 Hz),
5.83 (1H, s), 7.22-7.35 (9H, m), 7.37-7.43 (6H, m). Anal. Calcd
for C29H33NO7: C, 68.62; H, 6.55; N, 2.75. Found: C, 68.45;
H, 6.51; N, 2.77.
2,3-Di-O-m eth oxym eth yl-6-O-tr iph en ylm eth yl-D-idon o-
δ-la cta m (63). Compound 63 was synthesized similarly from
61 as in the preparation of 36 from 34; the yields were 30%
for 63 and 52% for 62:

4882 J . Org. Chem., Vol. 65, No. 16, 2000
Nishimura et al.
63: [R]24 -18.3° (c 0.73, MeOH); 1H NMR (400 MHz,
4.993(1) Å, Z ) 4, µ ) 11.61 cm-1, Dcalc ) 1.519 g/cm3, scan
type ) ω-2θ. X-ray diffraction experiments were carried out
at 295K on a Rigaku AFC5S diffractometer with graphite-
monochromated Cu KR radiation. Data up to 2θmax ) 126.1°
on a total of 623 reflections were collected, and the 577 with
I > 2.00σ(I) were used in the calculations.
Crystal data for 28: C6H11NO5, orthorhombic crystal system,
space group P212121, a ) 9.416(1) Å, b ) 31.905(2) Å, c )
7.543(1) Å, Z ) 12, µ ) 11.90 cm-1, Dcalc ) 1.558 g/cm3, scan
type ) ω-2θ. X-ray diffraction experiments were carried out
at 294K on a Rigaku AFC7R diffractometer with graphite-
monochromated Cu KR radiation. Data up to 2θmax ) 120.0°
on a total of 2003 reflections were collected, and the 1774 with
I > 2.00σ(I) were used in the calculations.
D
CDCl3) δ 3.38 and 3.42 (3H each, s), 3.37 (1H, dd, J ) 8.3 and
9.8 Hz), 3.47 (1H, dd, J ) 3.9 and 9.8 Hz), 3.75 (1H, ddt, J )
2.0, 3.9 and 8.3 Hz), 3.89 (1H, dt, J ) 3.9 and 5.4 Hz), 4.00
(1H, t, J ) 5.4 Hz), 4.14 (1H, d, J ) 5.4 Hz), 4.70 and 4.72
(2H, ABq, J ) 6.8 Hz), 4.74 and 5.04 (2H, ABq, J ) 6.6 Hz),
5.95 (1H, br s), 7.21-7.34 (9H, m), 7.38-7.45 (6H, m). Anal.
Calcd for C29H33NO7: C, 68.62; H, 6.55; N, 2.75. Found: C,
68.22; H, 6.43; N, 2.52.
D-Altr on o-δ-la cta m (28). Compound 28 was synthesized
similarly from 62 as in the preparation of 25 from 35; the yield
was 88%. The solid was crystallized from
a mixture of
methanol, ethanol and water to give colorless crystals: mp
1
141-143 °C; [R]26 -33.7° (c 0.30, H2O); H NMR (400 MHz,
D
D2O) δ 3.41 (1H, dt, J ) 3.0 and 5.3 Hz), 3.49 (1H, dd, J ) 5.3
and 11.9 Hz), 3.54 (1H, dd, J ) 5.3 and 11.9 Hz), 3.87 (1H,
dd, J ) 3.0 and 8.4 Hz), 4.01 (1H, t, J ) 3.0 Hz), 4.05 (1H, d,
J ) 8.4 Hz). Anal. Calcd for C6H11NO5: C, 40.67; H, 6.25; N,
7.90. Found: C, 40.25; H, 6.32; N, 7.62.
D-Id on o-δ-la cta m (29). Compound 29 was synthesized
similarly from 63 as in the preparation of 25 from 35; the yield
was 63%. The amorphous solid was crystallized from a mixture
Crystal data for 29: C6H11NO5, orthorhombic crystal system,
space group P212121, a ) 9.097(2) Å, b ) 11.426(2) Å, c )
6.981(1) Å, Z ) 4, µ ) 12.39 cm-1, Dcalc ) 1.622 g/cm3, scan
type ) ω-2θ. X-ray diffraction experiments were carried out
at 293K on a Rigaku AFC7R diffractometer with graphite-
monochromated Cu KR radiation. Data up to 2θmax ) 120.1°
on a total of 667 reflections were collected, and the 644 with
I > 2.00σ(I) were used in the calculations.
The structures were solved by the direct method using a
teXan crystallographic software package. Hydrogen atoms
were placed on the calculated positions. The refinement with
anisotropic thermal parameters converged at R ) 0.042 (Rw
) 0.058) for 25 and at R ) 0.042 (Rw ) 0.061) for 26 and R )
0.038 (Rw ) 0.050) for 28 and R ) 0.050 (Rw ) 0.074) for 30
and R ) 0.072 (Rw ) 0.101) for 31 and R ) 0.050 (Rw ) 0.068)
for 32. Atom scattering factors and dispersion corrections were
taken from the International Tables.
of methanol, ethanol and water to give colorless crystals: mp
1
202∼204 °C; [R]26 +46.3° (c 0.31, H2O); H NMR (400 MHz,
D
D2O) δ 3.52 (1H, dt, J ) 3.9 and 5.4 Hz), 3.61 (1H, dd, J ) 3.9
and 11.7 Hz), 3.65 (1H, dd, J ) 5.4 and 11.7 Hz), 3.80 (1H t,
J ) 8.1 Hz), 3.88 (1H, d, J ) 8.1 Hz), 3.91 (1H, dd, J ) 5.4
and 8.1 Hz). Anal. Calcd for C6H11NO5: C, 40.67; H, 6.25; N,
7.90. Found: C, 40.29; H, 6.23; N, 7.76.
X-r a y Str u ctu r e Deter m in a tion . Crystal data for 25:
C6H11NO5, hexagonal crystal system, space group P61, a )
6.518(1) Å, c ) 30.240(2) Å, Z ) 6, µ ) 12.12 cm-1, Dcalc
)
E n er gy Min im iza t ion Ca lcu la t ion s. The structures of
inhibitors were optimized with PM3 in MOPAC, all equipped
in a Tetronix CAChe system operated on a Power Macintosh
8100/80. The same parameter settings, which include key-
words BFGS, RHF, and PRECISE, were employed throughout
the calculations.
1.586 g/cm3, scan type ) ω-2θ. X-ray diffraction experiments
were carried out at 294K on a Rigaku AFC7R diffractometer
with graphite-monochromated Cu KR radiation. Data up to
2θmax ) 120.2° on a total of 751 reflections were collected, and
the 565 with I > 2.00 σ(I) were used in the calculations.
Crystal data for 26: C6H11NO5, orthorhombic crystal system,
space group P212121, a ) 8.952(2) Å, b ) 9.296(1) Å, c )
8.802(2) Å, Z ) 4, µ ) 12.27 cm-1, Dcalc ) 1.606 g/cm3, scan
type ) ω-2θ. X-ray diffraction experiments were carried out
at 293K on a Rigaku AFC7R diffractometer with graphite
monochromated Cu KR radiation. Data up to 2θmax ) 120.1°
on a total of 679 reflections were collected, and the 651 with
I > 2.00σ(I) were used in the calculations.
Ack n ow led gm en t. The authors are grateful to Dr.
Shinichi Kondo for his helpful discussions and encour-
agement. We are also indebted to Prof. Kazuo Naka-
mura, Showa University, for X-ray crystallographic
analysis of 9 and to Mr. Yoshio Kodama, Pharmaceuti-
cal Research Center, Meiji Seika Kaisha Ltd., for
providing the X-ray crystallographic reports of 8. Thanks
are due to Ms. Misa Ishibashi and Mr. Satoshi Shohji
for their technical assistance.
Crystal data for 27: C6H11NO5, monoclinic crystal system,
space group P21, a ) 4.6656(7) Å, b ) 10.0524(7) Å, c )
7.7257(5) Å, â ) 98.532(7), Z ) 2, µ ) 12.54 cm-1, Dcalc ) 1.642
g/cm3, scan type ) ω-2θ. X-ray diffraction experiments were
carried out at 293K on a Rigaku AFC7R diffractometer with
graphite-monochromated Cu KR radiation. Data up to 2θmax
) 120.1° on a total of 657 reflections were collected, and the
487 with I > 2.00σ(I) were used in the calculations.
1
Su p p or tin g In for m a tion Ava ila ble: 400 MHz H NMR
Spectra of 9 and 25-29) and X-ray structural information for
9 and 25-29. This material is available free of charge via the
Internet at http://www.pubs.acs.org.
Crystal data for 9: C6H11NO5, orthorhombic crystal system,
space group P212121, a ) 11.992(1) Å, b ) 12.936(2) Å, c )
J O000141J