New route to bicyclic pyrazolidinones and hydroxypyrrolidines from α,β-unsaturated sugar δ-lactones

Full text of DOI:10.1021/jo981491x

J . Org. Chem. 1999, 64, 1347-1351
1347
The introduction of a sulfonyloxy substituent to the
terminal carbon atom of the polyol side chain in 3 caused
the migration of the nitrogen atom of the hydroxylamine
fragment from C-3 to C-6 of the sugar chain and the
formation of a bicyclic compound 5. The direct reaction
of sulfonate 4 with N-benzylhydroxylamine led to the
double adduct 6 and low yield of 5 only (Scheme 1).8
It was of interest to investigate similar reactions
involving hydrazine and R,â-unsaturated δ-lactones that
have an sp3 electrophilic center at C-6 of the sugar chain.
For the present studies, we selected the lactones
D-glycero 7, D-erythro 8, and D-threo 9 having a free
hydroxy group at the terminal C-6 carbon atom. Com-
pounds 7-9 were subjected to reaction with tosyl chloride
and pyridine to afford the corresponding sulfonates 10-
12.
New Rou te to Bicyclic P yr a zolid in on es a n d
Hyd r oxyp yr r olid in es fr om r,â-Un sa tu r a ted
Su ga r δ-La cton es
J oanna Rabiczko and Marek Chmielewski*
Institute of Organic Chemistry of the Polish Academy of
Sciences, 01-224 Warsaw, Poland
Received J uly 27, 1998
There is a considerable interest in the chemistry,
synthesis, and biological activity of pyrazolidinones1,2 and
hydroxypyrrolidines.3,4 The former represent a new class
of antibacterial agents1 or interesting intermediates for
the synthesis of â-lactams,2 whereas the latter3 and their
bicyclic derivatives4 such as indolizines exhibit strong
activity as inhibitors of glycosidases and have the poten-
tial for the treatment of a variety of diseases.5
Recently, we have reported on the conjugate addition-
rearrangement of hydrazines and hydroxylamines to R,â-
unsaturated sugar δ-lactones 1, which proceeds anti to
the terminal substituent of the enelactone to afford
5-substituted pyrazolidin-3-ones 2 or 3-substituted isox-
azolidin-5-ones 3, respectively (Scheme 1).6,7
(1) (a) Claramunt, R. M.; Elguero, J . Org. Prep. Proced. Int. 1991,
23, 275. (b) Dorn, H.; Otto, A. Chem. Ber. 1968, 101, 3287. (c)
J ungheim, L. N.; Sigmund, S. K. J . Org. Chem. 1987, 52, 4007. (d)
J ungheim, L. N. Tetrahedron Lett. 1989, 30, 1889. (e) Ternansky, R.
J .; Draheim, S. E. In Recent Advances in the Chemistry of â-Lactam
Antibiotics, Chem. Soc. Special Publ. Bentley, P. H., Southgate, R.,
Eds.; Royal Society of Chemistry: Cambridge, 1989; Chapter 9, 139.
(f) Marchand-Brynaert, J .; Ghosez, L. In Recent Progress in the
Chemical Synthesis of Antibiotics; Lukacs, G., Ohno, M., Eds.; Springer-
Verlag: Berlin, 1990; 729. (g) Rutjes, F. P. J . T.; Udding, J . H.;
Hiemstra, H.; Speckamp, W. N. Heterocycles 1992, 33, 81.
The addition of hydrazine to lactones 10, 11, and 12
according to the known procedure yielded the bicyclic
pyrazolidinones 14, 15, and 16 in 65%, 60%, and 55%
yield, respectively.
Reaction of the triflate 13 with hydrazine led to a
complicated mixture of products as a result of the
coincident reaction of the nucleophile with the conjugated
system and with the sp3 electrophilic center and was not
investigated further.
Configurations at C-5 of compounds 15 and 16 were
proven by NOE experiments, whereas that of 14 was
assigned on the assumption that the steric pathway of
the hydrazine addition to all of the lactones 10-12 was
the same. An NOE experiment on 15 did not show any
interaction between H-5 (δ 4.02) and H-6 (δ 3.91) protons
whereas the experiment on 16 showed the enhancement
of the intensity of the signal H-6 (δ 3.90) by 14% when
(2) (a) Ege, S. N. J . Chem. Soc., Chem. Commun. 1968, 759; (b) J .
Chem. Soc. C 1969, 2624. (c) J ohnson, P. Y.; Hatch, C. E., III. J . Org.
Chem. 1975, 40, 909; (d) J . Org. Chem. 1975, 40, 3502. (e) Perri, S. T.;
Slater, S. C.; Toske, S. G.; White, J . D. J . Org. Chem. 1990, 55, 6037.
(f) White, J . D.; Toske, S. G. BioMed. Chem. Lett. 1993, 3, 2383.
(3) (a) Wong, Ch.-H.; Provencher, L.; Porco, J . A.; J ung, S.-H.; Wang,
Y.-F.; Chen, L.; Wang, R.; Steensma, D. H. J . Org. Chem. 1995, 60,
1492. (b) Ikota, N. Tetrahedron Lett. 1992, 33, 2553. (c) McCaig, A. E.;
Wightman, R. H. Tetrahedren Lett. 1993, 34, 3939. (d) Fleet, G. W. J .;
Witty, D. R. Tetrahedron: Asymmetry 1990, 1, 119. (e) Dell′Uno, N.;
Di Giovanni, M. Ch.; Misiti, D.; Zappla, G.; Delle Monache, G.
Tetrahrdron: Asymmetry 1996, 7, 181. (f) Cinquin, Ch.; Bortolussi, M.;
Bloch, R. Tetrahedron: Asymmetry 1996, 7, 3327. (g) J ones, D. W. C.;
Nash, R. J .; Bell, A.; Williams, J . M. Tetrahedron Lett. 1985, 26, 3125.
(h) Griffart-Brunet, D.; Langlois, N. Tetrahedron Lett. 1994, 35, 2889.
(i) Buchanan, J . G.; Edgar, A. R.; Hewitt, B. D. J . Chem. Soc., Perkin
Trans 1 1987, 2371. (j) Thompson, D. K.; Huber, Ch. N.; Wightman,
R. H. Tetrahedron 1993, 49, 3827. (k) Yoda, H.; Nakajima, T.; Takabe,
K. Tetrahedron Lett. 1996, 37, 5531. (l) Fitremann, J .; Dureault, A.;
Depezay, J .-C. Tetrahedron Lett. 1994, 35, 1201. (m) Casiraghi, G.;
Spanu, P.; Rassu, G.; Pinna, L.; Ulgheri, F. J . Org. Chem. 1994, 59,
2906. (n) Kayakiri, H.; Takase, S.; Setoi, H. Tetrahedron Lett. 1988,
29, 1725. (o) Kong, S. H.; Choi, H.-W. J . Chem. Soc., Chem. Commun.
1996, 1521. (p) Hu¨mmer, W.; Dubois, E.; Gracza, T.; J a¨ger, V. Synthesis
1997, 634. (q) Barco, A.; Benetti, S.; De Risi, C.; Pollini, G. P.;
Romagnoli, R.; Zanirato, V. Tetrahedron Lett. 1996, 37, 7599. (r)
Cardona, F.; Valenza, S.; Goti, A.; Brandi, A. Tetrahedron Lett. 1997,
38, 8097.
(4) (a) Herczegh, P.; Kovacs, I.; Sztaricskai, F. In Recent Process in
the Chemical Synthesis of Antibiotics and Related Microbial Products;
Lukacs, G., Ed., Springer-Verlag: Berlin 1994; Vol. 2, p 751. (b) Yoda,
H.; Kawauchi, M.; Takabe, K. Synlett 1998, 137. (c) Izquiardo, I.; Plaza,
M. T.; Robles, R.; Mota, A. J . Tetrahedron: Asymmetry 1998, 9, 1015.
(d) Bell, A. A.; Pickering, L.; Watson, A. A.; Nash, R. J .; Pan, Y. T.;
Elbein, A. D.; Fleet, G. W. J . Tetrahedron Lett. 1997, 38, 5869. (e)
Rodriguez, R.; Bermejo, F. Tetrahedron 1996, 37, 5581. (f) Goti, A.;
Cardona, F.; Brandi, A.; Picasso, S.; Vogel, P. Tetrahedron: Asymmetry
1996, 7, 1659. (g) Burgess, K.; Henderson, I. Tetrahedron 1992, 48,
4045. (h) Brandi, A.; Cicchi, S.; Cordero, F. M.; Frignoli, R.; Goti, A.;
Picasso, S.; Vogel, P. J . Org. Chem. 1995, 60, 6806.
(5) (a) Elbein, A. D. Annu. Rev. Biochem. 1987, 56, 497. (b) Legler,
G. Adv. Carbohydr. Chem. Biochem. 1990, 48, 319. (c) Sinnott, M. L.
Chem. Rev. 1990, 90, 1171. (d) Franck, R. W. Bioorg. Chem. 1992, 20,
77. (e) Winchester, B.; Fleet, G. W. J . Glycobiology 1992, 2, 199. (f)
Sunkara, P. S.; Taylor, D. L.; Kang, M. S.; Bowlin, T. L.; Li, P. S.;
Tyms, A. S.; Sjoerdsma, A. Lancet 1989, 1206. (g) Karlsson, G. B.;
Batters, T. D.; Dwek, R. A.; Platt, F. M. J . Biol. Chem. 1993, 268, 570.
(h) Lee, R. E.; Smith, M. D.; Nash, R. J .; Griffits, R. C.; McNeil, M.;
Grewal, R. K.; Yan, W.; Besra, G. S.; Brennan, P. J .; Fleet, G. W. J .
Tetrahedron Lett. 1997, 38, 6733. (i) Bashyal, B. P.; Fleet, G. W. J .;
Gough, M. J .; Smith, P. W. Tetrahedron 1987, 43, 3083. (j) Schneider,
M. J .; Ungemack, F. S.; Broquist, H. D.; Harris, T. M. Tetrahedron
1983, 39, 29. (k) Saul, R.; Chambers, J . P.; Molyneux, R. J .; Elbein, A.
D. Arch. Biochem. Biophys. 1983, 221, 593. (l) Eis, M. J .; Rule, C. J .;
Wu¨rzburg, B. A.; Ganem, B. Tetrahedron. Lett. 1985, 26, 5397. (m)
Ruprecht, R. M.; Mullaney, S.; Anderson, J .; Bronson, R. J . Acquired
Immune Defic. Syndr. 1989, 2, 149. (n) Newton, S. A.; White, S. L.;
Humphries, M. J .; Olden, K. Cancer Res. 1988, 48, 1410.
(6) Panfil, I.; Chmielewski, M. Heterocycles 1993, 34, 2267.
(7) Panfil, I.; Krajewski, J .; Gluzinski, P.; Stefaniak, L.; Chmielews-
ki, M. Tetrahedron 1994, 50, 7219.
(8) Socha, D.; Rabiczko, J .; Koneru, D.; Urbanczyk-Lipkowska, Z.;
Chmielewski, M. Carbohydr. Lett. 1997, 2, 349.
10.1021/jo981491x CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/26/1999

1348 J . Org. Chem., Vol. 64, No. 4, 1999
Notes
Sch em e 1
Sch em e 2
H-5 (δ 4.27) was irradiated. Consequently, a (5R) con-
figuration was assigned to 14, and (5S) to both 15 and
of addition follows previous observations.6,7,9 The conju-
gate addition-rearrangement leading to the pyrazolidin-
3-one intermediate was followed by the simultaneous
alkylation of the N-1 nitrogen atom by the terminal
tosyloxymethyl group to afford bicyclic compounds 14-
16 (Scheme 2). It is worth comparing the hydrazine
addition to lactones 10 and 11 with the similar reaction
in which both lactones reacted with N-benzylhydroxyl-
amine to give preferentially the double adduct 6.
Acetylation of compounds 14-16 gave respective di-
acetates 17-19. Methanolysis of compounds 17-19 led
to opening of the pyrazolidinone ring, yielding the cor-
responding methyl esters 20-22.
Hydrogenolysis of the N-N bond in the bicyclic pyra-
zolidinones 14-16 over Raney nickel proceeds with
difficulty. In ethanol solution, compound 15 afforded
mixture of products 24 and 25. The preparation of
ethylidene compound 24 and N-ethyl compound 25
varied, depending on the proportion of Raney nickel and
reaction conditions. Obviously, the formation of com-
pounds 24 and 25 was the result of hydrogenolysis at
the N-N bond followed by reaction of the pyrrolidine
16. These findings testified to anti approach of the
hydrazine molecule to the C-6 carbon atom of lactones
10-12. Thus, it means that the stereochemical course
(9) Frelek, J .; Panfil, I.; Urbanczyk-Lipkowska, Z.; Chmielewski, M.
Submitted for publication.

Notes
J . Org. Chem., Vol. 64, No. 4, 1999 1349
Sch em e 3
at C-2 of 24 was proven by NOE experiment, which
showed the enhancement of the intensity of the signal
H-6 (δ 2.93) by 6.2% when H-2 (δ 3.98) was irradiated.
Conversely, the signal due to H-2 was enhanced by 5.8%
when H-6 was irradiated.
nitrogen atom with acetaldehyde that was formed by the
dehydrogenation of ethanol over Raney nickel (Scheme
Hydrogenolysis of the bicyclic pyrazolidinones 14-16
in water solution over Raney nickel afforded amides 26-
28, respectively, which were characterized as di-acetates
29-31.
In this paper, we demonstrated that conjugate addi-
tion-rearrangement of hydrazine to R,â-unsaturated
sugar δ-lactones allowed a short and efficient synthesis
of bicyclic pyrazolidinones and â-D-amino acid derivatives
such as (2R,4S)-4-hydroxyhomoproline, (2S,3S,4R)-3,4-
dihydroxyhomoproline, and (2S,3R,4R)-3,4-dihydroxy-
homoproline.
Exp er im en ta l Section
1H NMR spectra were recorded at 200 and 500 MHz. Column
chromatography was performed on Merck silica gel 230-400
mesh.
3). The intermediate aminal of acetaldehyde 23 was the
precursor of both compounds 24 and 25. Configuration
The lactones 8 and 9 were obtained from ethyl 2,3-dideoxy-
R-D-erythro- and R-D-threohex-2-enopyranoside, respectively, by
standard sequences of reactions which consisted of 6-O-silylation,
followed by 4-O-benzylation, and anomeric oxidation to the
lactone stage.10,11 The lactone 10 was obtained according to the
known procedure.12
4-O-Ben zyl-2,3-d id eoxy-D-er yth r oh ex-2-en o-1,5-a ld on o-
la cton e (8). 4-O-Benzyl-6-O-tert-butyldiphenylsilyl-2,3-dideoxy-
D-erythrohex-2-eno-1,5-aldonolactone (10.0 g, 0.02 mmol) in dry
THF (100 mL) was treated with tetrabutylammonium fluoride
hydrate (6.66 g, 0.021 mmol) and stirred at room temperature
for 15 min. Subsequently, solvent was evaporated, and the crude
product was purified on silica gel to give 8 (4.21 g, 0.018 mol,
85%) as a syrup: [R]D ) +83.11° (c 1.1, CH2Cl2); IR (film) 3427,
1730 cm-1; 1H NMR (CDCl3) δ 7.40-7.31 (m, 5H), 6.89 (dd, 1H,
J ) 1.9, 10.0 Hz), 5.95 (dd, 1H, J ) 2.0, 10.0 Hz), 4.74, 4.66 (2d,
2H, J ) 11.6 Hz), 4.48 (ddd, 1H, J ) 1.9, 2.0, 10.0 Hz), 4.35
(ddd, 1H, J ) 2.7, 3.4, 10.0 Hz), 3.94 (dd, 1H, J ) 2.7, 12.6 Hz),
3.84 (dd, 1H, J ) 3.4, 12.6 Hz); MS (LSIMS, HR) m/z (M+) calcd
(10) Panfil, I.; Urbanczyk-Lipkowska, Z.; Chmielewski, M. Carbo-
hydr. Res. 1998, 306, 505.
(11) J urczak, M.; Socha, D.; Chmielewski, M. Tetrahedron 1996, 52,
1411.
(12) (a) Roth, B. D.; Roark, W. H. Tetrahedron Lett. 1988, 29, 1255.
(b) Lichtenthaler, F. W.; Klinger, F. D.; J arglis, P. Carbohydr. Res.
1984, 132, C1-C4.

1350 J . Org. Chem., Vol. 64, No. 4, 1999
Notes
for C13H15O4 235.09703, found 235.09616. Anal. Calcd for
C13H14O4: C, 66.66; H, 6.02. Found: C, 66.68; H, 6.20.
4-O-Ben zyl-2,3-d id eoxy-D-th r eoh ex-2-en o-1,5-a ld on ola c-
ton e (9). Compound 9 was obtained from 4-O-benzyl-6-O-tert-
butyldiphenylsilyl-2,3-dideoxy-D-threohex-2-eno-1,5-aldonolac-
tone according to the procedure described above: mp 81-82 °C;
[R]D ) -273.9 (c 1.0, CH2Cl2); IR (film) 3271, 1729 cm-1; 1H NMR
(CDCl3) δ 7.42-7.30 (m, 5H), 6.94 (dd, 1H, J ) 5.2, 9.8 Hz), 6.20
(d, 1H, J ) 9.8 Hz), 4.67, 4.56 (2d, 2H, J ) 11.8 Hz), 4.50 (m,
1H, J ) 3.3, 5.3, 6.7 Hz), 4.12 (dd, 1H, J ) 3.3, 5.2 Hz), 4.08
(dd, 1H, J ) 6.7, 11.9 Hz), 3.91 (dd, 1H, J ) 5.3, 11.9 Hz); MS
(LSIMS, HR) m/z (M+) calcd for C13H15O4 235.09703, found
235.09617. Anal. Calcd for C13H14O4: C, 66.66; H, 6.02. Found:
C, 66.67; H, 6.03.
2.45 (s, 3H), 2.14 (s, 3H). Anal. Calcd for C17H20N2O5: C, 61.44;
H, 6.07; N, 8.43. Found: C, 61.3; H, 6.1; N, 8.3.
(5S,6R,7R)-1,2-Dia za -6-ben zyloxy-7-h yd r oxy-3-oxo-[3.3.0]-
bicycloocta n e (16): 55%; mp 132-133 °C; [R]D ) +41.9 (c 1.6,
MeOH); IR (Nujol) 3210, 1661 cm-1; 1H NMR (CD3OD) δ 7.35-
7.25 (m, 5H), 4.69, 4.56 (2d, 2H, J ) 11.8 Hz), 4.41 (m, 1H, J )
2.6, 2.8, 5.0 Hz), 4.27 (m, 1H, J ) 5.7, 6.6, 10.5 Hz), 3.90 (dd,
1H, J ) 2.6, 5.7 Hz), 3.19 (dd, 1H, J ) 2.8, 11.5 Hz), 3.03 (dd,
1H, J ) 5.0, 11.5 Hz), 2.90 (dd, 1H, J ) 6.6, 17.2 Hz), 2.46 (dd,
1H, J ) 10.5, 17.2 Hz); MS (EI, HR) m/z (M+) calcd for
C
C
13H16N2O3 248.116093, found 248.115783. Anal. Calcd for
13H16N2O3: C, 62.89; H, 6.50; N, 11.28. Found: C, 62.6; H, 6.6;
N, 11.1.
(5S,6R,7R)-7-Acet oxy-2-a cet yl-1,2-d ia za -6-b en zyloxy-3-
oxo-[3.3.0]bicycloocta n e (19): mp 128-129 °C; [R]D ) -59.5
(c 0.6, CH2Cl2); IR (film) 1744, 1703 cm-1 1H NMR (CDCl3) δ
4-O-Ben zyl-6-O-t osyl-2,3-d id eoxy-D-er yt h r oh ex-2-en o-
1,5-a ld on ola cton e (11). Compound 11 was obtained from 8
using standard tosylation procedure: 85%, mp 75-76 °C; [R]D
;
7.39-7.29 (m, 5H), 5.34 (d, 1H, J ) 5.2 Hz), 4.79, 4.57 (2d, 2H,
J ) 12.1 Hz), 4.15 (m, 1H, J ) 5.4, 7.3, 9.9 Hz), 4.00 (d, 1H, J
) 12.5 Hz), 3.17 (dd, 1H, J ) 7.3, 18.2 Hz), 3.07 (dd, 1H, J )
5.2, 12.5 Hz), 2.66 (dd, 1H, J ) 9.9, 18.2 Hz), 2.47 (s, 3H), 2.09
(s, 3H); MS (LSIMS, HR) m/z (M + H)+ calcd for C17H20N2O5
333.145043, found 333.146821. Anal. Calcd for C17H20N2O5: C,
61.44; H, 6.07; N, 8.43. Found: C, 61.2; H, 6.5; N, 8.2.
1
) +32.1 (c 0.4, CH2Cl2); IR (film) 1742 cm-1; H NMR (CDCl3)
δ 7.81-7.32 (m, 9H), 6.85 (d, 1H, J ) 10.0 Hz), 5.95 (dd, 1H, J
) 0.9, 10.0 Hz), 4.69, 4.63 (2d, 2H, J ) 11.3 Hz), 4.48-4.36 (m,
3H, H-4,5,6), 4.19 (m, 1H), 2.45 (s, 3H); MS (LSIMS, HR) m/z
(M+) calcd for C20H21O6S 389.10590, found 389.10758. Anal.
Calcd for C20H20O6S: C, 61.84; H, 5.19. Found: C, 61.62; H, 5.24.
4-O-Ben zyl-6-O-tosyl-2,3-d id eoxy-D-th r eoh ex-2-en o-1,5-
a ld on ola cton e (12). Compound 12 was obtained from 9 using
(2R,4S)-N-Acet yla m in o-4-a cet oxy-2-m et h oxyca r b on yl-
m eth yl-p yr r olid in e (20). Compound 17 (0.01 g, 0.03 mmol)
was dissolved in methanol (2 mL) and stirred for 48 h. Subse-
quently the solvent was evaporated, and the crude product was
purified on a silica gel column using hexane-ethyl acetate 1:4
standard tosylation procedure: 87%; mp 101-102 °C; [R]D
)
-162.8 (c 1.0, CH2Cl2); IR (film) 1734 cm-1; 1H NMR (CDCl3) δ
7.85-7.23 (m, 9H), 6.87 (dd, 1H, J ) 5.4, 9.8 Hz), 6.14 (d, 1H, J
) 9.8 Hz), 4.64 (m, 1H, J ) 3.1, 6.2, 6.8 Hz), 4.58, 4.54 (2d, 2H,
J ) 11.6 Hz), 4.42 (dd, 1H, J ) 6.8, 10.3 Hz), 4.25 (dd, 1H, J )
6.2, 10.3 Hz), 4.07 (dd, 1H, J ) 3.1, 5.4 Hz), 2.45 (s, 3H); MS
(LSIMS, HR) m/z (M+) calcd for C20H21O6S 389.10590, found
v/v as an eluent to give 20 (0.006 g, 50%): mp 83-84 °C; [R]D
)
+26.0 (c 0.6, CH2Cl2); IR (film) 3454, 3184, 1738, 1664 cm-1; 1H
NMR (CDCl3) signals due to the major rotamer (63%) δ 6.30 (bs,
1H), 5.12 (m, 1H), 3.72 (bm, 1H), 3.68 (s, 3H), 3.31 (m, 1H), 2.64
(bm, 1H), 2.62 (dd, 1H, J ) 5.6, 15.4 Hz), 2.38 (dd, 1H, J ) 7.4,
15.4 Hz), 1.7-2.2 (m, 2H), 2.06, 2.06 (2s, 6H); signals due to the
minor rotamer (37%) δ 6.45 (bs, 1H), 5.12 (m, 1H), 3.84 (dd, 1H,
J ) 6.5, 10.9 Hz), 3.67 (s, 3H), 3.51 (m, 1H), 2.77 (dd, 1H, J )
4.1, 10.9 Hz), 2.67 (dd, 1H, J ) 5.7, 16.1 Hz), 2.47 (dd, 1H, J )
7.0, 16.1 Hz), 1.7-2.2 (m, 2H), 2.05, 1.91 (2s, 6H); MS (EI, HR)
m/z (M + H)+ calcd for C11H19N2O5 259.129393, found 259.128006.
Anal. Calcd for C11H18N2O5: C, 51.15; H, 7.02; N, 10.85. Found:
C, 51.2; H, 7.3; N, 10.8.
389.10883. Anal. Calcd for
Found: C, 61.67; H, 5.29.
C20H20O6S: C, 61.84; H, 5.19.
Rea ction of La cton es 10-12 w ith Hyd r a zin e. Gen er a l
P r oced u r e. The lactones 10-12 (0.13 g, 0.34 mmol) in anhy-
drous ethanol (10 mL) were treated with hydrazine (14 µL, 0.45
mmol) at room temperature. After
1 h, the mixture was
evaporated and purified on a silica gel column using ethyl
acetate-methanol 30:1 v/v as an eluent to afford compounds 14-
16, respectively.
(2S,3S,4R)-N-Acetylam in o-4-acetoxy-3-ben zyloxy-2-m eth -
oxyca r bon ylm eth yl-p yr r olid in e (21). Compound 21 was
obtained from 18 according to the procedure described for 20:
50%; syrup; [R]D ) -31.3 (c 0.5, CH2Cl2); IR (film) 3348, 1738,
(5R,7S)-1,2-Dia za -7-h yd r oxy-3-oxo-[3.3.0]bicycloocta n e
(14): 65%; mp 185-186 °C; [R]D ) +71.8 (c 0.6, MeOH); IR
(Nujol) 3346, 1665 cm-1 1H NMR (CDCl3) δ 4.54 (m, 1H, J )
;
2.7, 3.3, 5.0, 5.6 Hz), 4.20 (m, 1H, J ) 6.4, 7.3, 7.5, 9.3 Hz), 3.17
(ddd, 1H, J ) 1.0, 2.7, 11.7 Hz), 3.01 (dd, 1H, J ) 5.0, 11.7 Hz),
2.65 (dd, 1H, J ) 9.3, 17.2 Hz), 2.47 (dd, 1H, J ) 7.3, 17.2 Hz)
2.02-2.13 (m, 2H); MS (LSIMS) m/z (M + H)+ 143. Anal. Calcd
for C6H10N2O2: C, 50.69; H, 7.09; N, 19.71. Found: C, 50.6; H,
7.1; N, 19.8.
1673 cm-1 1H NMR (CDCl3) 1:1 mixture of rotamers δ 7.42-
;
7.29 (m, 5H), 6.87, 6.67 (2s, 1H), 5.36 (m, 1H), 4.66, 4.42 (2d,
1H, J ) 11.1 Hz), 4.65, 4.39 (2d, 1H, J ) 11.2 Hz), 3.93 (dd,
0.5H, J ) 6.0, 12.0 Hz), 3.82 (dd, 0.5H, J ) 4.9, 8.9 Hz), 3.74
(dd, 0.5H, J ) 5.5, 12.2 Hz), 3.72 (dd, 0.5H, J ) 5.0, 9.6 Hz),
3.65, 3.64 (2s, 3H), 3.47, 3.36 (2m, 1H), 2.87 (dd, 0.5H, J ) 2.7,
12.0 Hz), 2.84 (dd, 0.5H, J ) 2.0, 12.2 Hz), 2.59 (m, 2H), 2.49
(dd, 1H, J ) 8.1, 16.3 Hz), 2.41 (dd, 1H, J ) 6.8, 14.9 Hz), 2.17,
2.16, 2.05, 1.91 (4s, 6H). Anal. Calcd for C18H24N2O6: C, 59.33;
H, 6.64; N, 7.69. Found: C, 59.4; H, 6.8; N, 7.5.
(5R,7S)-7-Acet oxy-2-a cet yl-1,2-d ia za -3-oxo-[3.3.0]b icy-
cloocta n e (17): mp 129-130 °C; [R]D ) -53.7 (c 0.8, CH2Cl2);
1
IR (film) 1741, 1703 cm-1; H NMR (CDCl3) δ 5.44 (m, 1H, J )
1.8, 3.0, 5.7, 6.6 Hz), 4.17 (m, 1H, J ) 4.7, 7.6, 8.4, 9.9 Hz), 3.84
(ddd, 1H, J ) 1.3, 1.8, 12.1 Hz), 2.96 (dd, 1H, J ) 5.7, 12.1 Hz),
2.88 (dd, 1H, J ) 8.4, 17.9 Hz), 2.65 (dd, 1H, J ) 9.9, 17.9 Hz),
2.30 (dddd, 1H. J ) 1.3, 3.0, 7.6, 14.6 Hz), 2.21 (ddd, 1H, J )
4.7, 6.6, 14.6 Hz,), 2.48 (s, 3H), 2.08 (s, 3H). Anal. Calcd for
C10H14N2O4: C, 53.09; H, 6.24; N, 12.38. Found: C, 52.9; H, 6.4;
N, 12.3.
(2S,3R,4R)-N-Acetylam in o-4-acetoxy-3-ben zyloxy-2-m eth -
oxyca r bon ylm eth yl-p yr r olid in e (22). Compound 22 was
obtained from 19 according to the procedure described for 20:
60%; mp 125-126 °C; [R]D ) +72.1 (c 1.0, CH2Cl2); IR (film)
3226, 1732, 1662 cm-1; 1H NMR (CDCl3) major component (66%)
δ 7.42-7.29 (m, 5H), 6.18 (bs, 1H), 5.16 (m, 1H), 4.72, 4.48 (2d,
2H, J ) 11.8 Hz), 3.99 (m, 1H), 3.72 (m, 1H), 3.61 (s, 3H), 3.34
(bs, 1H), 2.55-2.80 (m, 3H), 2.08, 1.64, (2s, 6H); minor compo-
nent (34%) δ 7.42-7.29 (m,5H), 6.75 (s, 1H), 5.16 (m, 1H), 4.72,
4.49 (2d, 2H, J ) 11.8 Hz), 3.99 (m, 1H), 3.65-3.85 (m, 2H),
3.60 (s, 3H), 3.15 (dd, 1H, J ) 4.4, 11.7 Hz), 2.55-2.80 (m, 2H),
2.07, 1.87, (2s, 6H); MS (LSIMS, HR) m/z: (M+H)+ calcd for
(5S,6S,7R)-1,2-Dia za -6-ben zyloxy-7-h yd r oxy-3-oxo-[3.3.0]-
bicycloocta n e (15): 60%; mp 102-103 °C; [R]D ) +5.8 (c 0.6,
1
CH2Cl2); IR (film) 3278, 1678 cm-1; H NMR (CD3OD) δ 7.41-
7.27 (m, 5H), 4.73, 4.59 (2d, 2H, J ) 11.3 Hz), 4.46 (m, 1H, J )
4.4, 4.8, 5.1 Hz), 4.02 (m, 1H), 3.91 (dd, 1H, J ) 4.4, 4.7 Hz),
3.27 (dd, 1H, J ) 4.8, 11.8 Hz), 3.00 (dd, 1H, J ) 5.1, 11.8 Hz),
2.65 (dd, 1H, J ) 10.4, 17.6 Hz), 2.46 (dd, 1 H, J ) 7.2, 17.6
Hz). Anal. Calcd for C17H20N2O5: C, 62.88; H, 6.50; N, 11.28.
Found: C, 62.7; H, 6.5; N, 11.3.
C
C
18H25N2O6: 365.171262. Found: 365.170873. Anal. Calcd for
18H24N2O6: C, 59.33; H, 6.64; N, 7.69. Found: C, 59.4; H, 6.7;
N, 7.8.
(2S,6S,7S,R)-1,3-Diaza-7-ben zyloxy-2-m eth yl-3-oxo-[4.3.0]-
(5S,6S,7R)-7-Acet oxy-2-a cet yl-1,2-d ia za -6-b en zyloxy-3-
oxo-[3.3.0]bicycloocta n e (18): mp 76-77 °C; [R]D ) -91.5 (c
0.5, CH2Cl2); IR (film) 1740, 1704 cm-1; 1H NMR (CDCl3) δ 7.39-
7.29 (m, 5H), 5.53 (m, 1H, J ) 1.9, 4.3, 4.6 Hz), 4.68, 4.47 (2d,
2H, J ) 11.9 Hz), 3.97 (dd, 1H, J ) 1.9, 12.9 Hz), 3.96 (m, 1H),
3.88 (dd, 1H, J ) 4.7, 7.2 Hz), 3.00 (dd, 1H, J ) 4.6, 12.9 Hz),
2.95 (dd, 1H, J ) 10.0, 18.5 Hz), 2.62 (dd, 1H, J ) 6.2, 18.5 Hz),
bicyclon on a n e a n d (2S,3S,4R)-3-Ben zyloxy-2-ca r ba m oyl-
m eth yl-1-eth yl-4-h yd r oxy-p yr r olid in e (24 a n d 25). Com-
pound 15 (0.08 g, 0.32 mmol) was dissolved in anhydrous ethanol
(1 mL) and treated with Raney nickel (0.5 g suspension in
ethanol). The mixture was stirred for 1 h at room temperature
until disappearance of the substrate. Subsequently, the mixture

Notes
J . Org. Chem., Vol. 64, No. 4, 1999 1351
was filtered through Celite and evaporated. The crude product
was separated using ethyl acetate-methanol 20:1 v/v as an
eluent to afford 24 (0.029 g, 33%) and 25 (0.041 g, 45%).
24: mp 105-106 °C; [R]D ) -58.5 (c 1.3, CH2Cl2); IR (film)
C
10H16N2O4 228.11101, found 228.11020. Anal. Calcd for
C10H16N2O4: C, 52.62; H, 7.07; N, 12.27. Found: C, 52.35; H,
6.87; N, 12.12.
(2S,3S,4R)-4-Acetoxy-N-a cetyl-3-ben zyloxy-2-ca r ba m oyl-
m eth yl-p yr r olid in e (30). Compound 30 was obtained from 15
according to the procedure described above: 63%; mp 118-119
°C; [R]D ) + 20.9 (c 0.6, CH2Cl2); IR (film) 3391, 3193, 1742,
3299, 1663 cm-1 1H NMR (CDCl3) δ 7.40-7.32 (m, 5H), 6.01
;
(bs, 1H), 4.67, 4.59 (2d, 2H, J ) 11.7 Hz), 4.27 (m, 1H), 3.98 (q,
1H, J ) 5.9 Hz) 3.58 (dd, 1H, J ) 6.0, 7.5 Hz), 3.40 (dd, 1H, J
) 6.8, 10.1 Hz), 2.93 (ddd, 1H, J ) 4.7, 7.5, 9.8 Hz), 2.73 (d, 1H,
J ) 3.9 Hz), 2.58 (dd, 1H, J ) 4.7, 16.7 Hz), 2.44 (dd, 1H, J )
3.8, 10.1 Hz), 2.25 (dd, 1H, J 9.8, 16.7 Hz), 1.25 (d, 3H, J ) 5.9
Hz); MS (LSIMS, HR) m/z (M + H)+ calcd for C15H21 277.15521,
found 277.15414. Anal. Calcd for C15H20N2 O3: C, 65.20; H, 7.30;
N, 10.14. Found: C, 64.91; H, 7.41; N, 9.98.
25: mp 134-135 °C; [R]D ) +28.6 (c 0.8, CH2Cl2); IR (film)
3364, 3177, 1653, 1632 cm-1; 1H NMR (CDCl3) δ 7.83, 5.46 (2bs,
2H), 7.39-7.30 (m, 5H), 4.66, 4.59 (2d, 2H, J ) 11.4 Hz), 4.13
(q, 1H, J ) 5.5 Hz, 3.77 (bt, 1H), 3.40 (dd, 1H, J ) 5.6, 10.6 Hz),
2.94 (m, 1H), 2.89, 2.39 (2dq, 2H), 2.60 (dd, 1H, J ) 4.8, 16.3
Hz), 2.52 (bs, 1H), 2.42-2.50 (m, 2H), 1.10 (t, J ) 7.2 Hz); MS
(LSIMS, HR) m/z (M + H)+ calcd for C15H23N2O3 279.17087,
found 279.17460.
(2R,4S)-4-Acetoxy-N-a cetyl-2-ca r ba m oylm eth yl-p yr r oli-
d in e (29). Compound 14 (0.10 g, 0.7 mmol) was dissolved in
water (5 mL), treated with a suspension of Raney nickel in water
(0.3 g, pH ) 7), and stirred for 2 h until the disappearance of
the substrate. Subsequently, the mixture was filtered through
Celite which was washed with methanol. The solvents were
evaporated to dryness, and the residue was acetylated with
acetic anhydride-pyridine 1:1 mixture and stirred overnight.
Subsequently, the mixture was evaporated to dryness and
purified on a silica gel column using ethyl acetatea-methanol
1728, 1644 cm-1 1H NMR (CDCl3) δ 7.37-7.27 (m, 5H), 6.10,
;
5.32 (2bs, 2H), 5.31 (q, 1H), 4.64, 4.60 (2d, 2H, J ) 11.5 Hz),
4.41 (dd, 1H, J ) 4.3, 4.9 Hz), 4.16 (m, 1H, J ) 2.8, 4.9, 7.5 Hz),
3.80 (dd, J ) 5.5, 11.0 Hz), 3.58 (dd, 1H, J ) 4.7, 11.0 Hz), 2.73
(dd, 1H, J ) 7.5, 14.6 Hz), 2.63 (dd, 1H, J ) 2.8, 14.6 Hz), 2.09,
2.04 (2s, 6H); MS (LSIMS, HR) m/z (M + H)+ calcd for
C17H23N2O5 335.16071, found 335.16369. Anal. Calcd for
C17H22N2O5: C, 61.07; H, 6.63; N, 8.38. Found: C, 60.75; H, 6.90;
N, 8.21.
(2S,3R,4R)-4-Acet oxy-N-a cet yl-3-b en zyloxy-2-ca r b a m -
oylm eth yl-p yr r olid in e (31). Compound 31 was obtained from
16 according to the procedure described above: 53%; syrup; [R]D
) +33.7 (c 1.1, CH3OH); IR (film) 3332, 3197, 1741, 1674, 1633
cm-1; 1H NMR (CDCl3) major rotamer δ 7.38-7.29 (m, 5H), 6.00,
5.38 (2bs, 2H), 5.16 (m, 1H), 4.66, 4.59 (2d, 2H, J ) 11.3 Hz),
4.50 (m, 1H), 4.22 (dd, 1H, J ) 1.9, 5.6 Hz), 3.86 (dd, 1H, J )
4.6, 11.9 Hz), 3.44 (d, 1H, J ) 11.9 Hz), 3.12 (dd, 1H, J ) 4.4,
15.6 Hz), 2.58 (dd, 1H, J ) 8.9, 15.6 Hz), 2.07, 2.02 (2s, 6H);
minor rotamer δ 7.38-7.29 (m, 5H), 5.81, 5.46 (2bs, 2H), 4.63
(d, 1H, J ) 12.4 Hz), 3.71 (dd, 1H, J ) 4.1, 13.2 Hz); 3.65 (dd,
1H, J ) 6.3, 13.2 Hz), 2.70 (dd, 1H, J ) 8.8, 15.1 Hz), 2.42 (dd,
1H, J ) 4.8, 15.1 Hz), 2.13, 2.04 (2s, 6H); MS (EI, HR) m/z (M
+ H)+ calcd for C17H23N2O5 335.16071, found 335.16039. Anal.
Calcd C17H22N2O5: C, 61.07; H, 6.63; N, 8.38. Found: C, 60.81;
H, 6.82; N, 8.48.
40:1 v/v as an eluent to give 29 (0.092 g, 57%): syrup; [R]D
)
+28.0 (c 1.3, CH2Cl2); IR (film) 3358, 3200, 1737, 1670, 1630
1
cm-1; H NMR (CDCl3) δ 6.11, 5.40 (2bs, 2H), 5.26 (m, 1H, J )
2.1, 3.1, 4.6, 5.2 Hz), 4.37 (m, 1H, J ) 3.2, 7.5, 7.7, 7.8 Hz), 3.77
(dd, 1H, J ) 4.6, 11.9 Hz), 3.54 (m, 1H, J ) 1.5, 2.1, 11.9 Hz),
2.77 (dd, 1H, J ) 3.2, 14.3 Hz), 2.65 (dd, 1H, J ) 7.5, 14.3 Hz),
2.37 (ddd, 1H, J ) 5.2, 7.7, 14.1 Hz), 2.31 (dddd, 1H, J ) 1.5,
3.1, 7.8, 14.1 Hz), 2.05 (s, 6H); MS (EI, HR) m/z (M+) calcd for
Ack n ow led gm en t. The authors wish to thank the
State Committee for Scientific Research (grant 3T 09A
13112) for support of this work.
J O981491X