Synthesis of enantiomerically pure 1,2-diamine derivatives of 7-azabicyclo[2.2.1]heptane. New leads as glycosidase inhibitors and rigid scaffolds for the preparation of peptide analogues

Article abstract of DOI:10.1021/jo0301088

Enantiomerically pure alcohols (-)- and (+)-7-tert-butoxycarbonyl-6-endo-p-toluenesulfonyl-7-azabicyclo[2.2.1] hept-2-en-5-endo-ol ((-)-11 and (+)-11) have been obtained from the Diels-Alder adduct of N-(tert-butoxycarbonyl)pyrroel and 2-bromo-1-p-toluene

Full text of DOI:10.1021/jo0301088

Syn th esis of En a n tiom er ica lly P u r e 1,2-Dia m in e Der iva tives of
7-Aza bicyclo[2.2.1]h ep ta n e. New Lea d s a s Glycosid a se In h ibitor s
a n d Rigid Sca ffold s for th e P r ep a r a tion of P ep tid e An a logu es
Antonio J . Moreno-Vargas, Catherine Schu¨tz, Rosario Scopelliti, and Pierre Vogel*
Institut de Chimie Mole´culaire et Biologique de l’Ecole Polytechnique Fe´de´rale de Lausanne, EPFL-BCH,
CH-1015 Lausanne-Dorigny, Switzerland
pierre.vogel@epfl.ch
Received March 31, 2003
Enantiomerically pure alcohols (-)- and (+)-7-tert-butoxycarbonyl-6-endo-p-toluenesulfonyl-7-
azabicyclo[2.2.1]hept-2-en-5-endo-ol ((-)-11 and (+)-11) have been obtained from the Diels-Alder
adduct of N-(tert-butoxycarbonyl)pyrroel and 2-bromo-1-p-toluenesulfonylacetylene, including a
resolution method. These two alcohols were converted into (+)- and (-)-5-exo-amino-7-(tert-
butoxycarbonyl)-2,3-exo-isopropylidenedioxy-7-azabicyclo[2.2.1]heptane ((+)-18 and (-)-18) and (+)-
and (-)-5-endo-amino-7-(tert-butoxycarbonyl)-2,3-exo-isopropylidenedioxy-7-azabicyclo[2.2.1]heptane
((+)-19 and (-)-19) after adequate functionalization and desulfonylation steps. The corresponding
conformationally constrained bicyclic 1,2-diamines (+)-4, (-)-4, (()-5, (()-6, (+)-7, and (-)-7 were
obtained from the protected precursors 18 and 19 and evaluated as glycosidase inhibitors. Diamines
(+)-4, (-)-4, (+)-6, and (-)-6 can be seen as new nonpeptide molecular scaffolds for the design of
peptide analogues.
CHART 1
In tr od u ction
The search for better inhibitors implies the multistep
synthesis of a large number of analogues and derivatives
and their individual testing. In a recent report, we have
shown that (5R,3R,4S)-3,4-dihydroxypyrrolidin-2-yl de-
rivatives such as 1, simpler synthetic analogues of
swainsonine (2), are selective and promising R-mannosi-
dase inhibitors.1
Previously, our group had found that diamine 3 and
other 1,2- and 1,3-diamines of type A (Scheme 1) equili-
brate rapidly with aldehydes to generate dynamic librar-
ies2 of imines of type B at low concentrations (<1 mM)
and in the presence of glycosidases. There is a parallel
between the inhibitory activities of the amino-imines B
and those of the corresponding amino-amines C obtained
by reduction. This led to the invention of an efficient
combinatorial method for the discovery of glycosidase
inhibitors.3
They are new members of the sublibrary of diamines that
can be combined with aldehydes to generate dynamic
libraries of glycosidase inhibitors. These bicyclic diamines
are structurally related to calystegines, bicyclic alkaloids
that possess a nor-tropane structure bearing hydroxyl
groups varying in position and configuration. Like other
(1) Popowycz, F.; Gerber-Lemaire, S.; Demange, R.; Rodr´ıguez-
Garc´ıa, E.; Carmona-Asenjo, A. T.; Robina, I.; Vogel, P. Bioorg. Med.
Chem. Lett. 2001, 11, 2489.
(2) (a) Ganessan, A. Angew. Chem., Int. Ed. 1998, 37, 2828. (b) Lehn,
J . M. Chem. Eur. J . 1999, 5, 2455. (c) Polyakov, V. A.; Nelen, M. I.;
Nazarpack-Kandlousy, N.; Ryabov, A. D.; Eliseev, A. V. J . Phys. Org.
Chem. 1999, 12, 357. (d) Eliseev, A. V.; Lehn, J . M. Curr. Top.
Microbiol. Immunol. 1999, 213, 159. (e) Karan, C.; Miller, B. L. Drug
Discovery Today 2000, 5, 67. (f) Lehn, J . M. Science 2001, 291, 2331
and references cited therein. (g) Brady, P. A.; Bonar-Law, R. P.; Rowan,
S. J .; Suckling, C. J .; Sanders, J . K. J . Chem. Soc., Chem. Commun.
1996, 319. (h) Rowan, S. J .; Brady, P. A.; Sanders, J . K. M. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2143.
We now present the synthesis of bicyclic diamines 4-7
imitating diamines of type A (mannosidase inhibitors).
(3) Gerber-Lemaire, S.; Popowycz, F.; Rodr´ıguez-Garc´ıa, E.; Car-
mona-Asenjo, A. T.; Robina, I.; Vogel, P. ChemBiochem 2002, 5, 466.
10.1021/jo0301088 CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/10/2003
5632
J . Org. Chem. 2003, 68, 5632-5640

1,2-Diamine Derivatives of 7-Azabicyclo[2.2.1]heptane
SCHEME 1
Insertion of these moieties in appropriates sites of small
peptides produces specific three-dimensional structures
required for binding to their receptors.9 Templates of this
kind may contain diamine10 or diacid moieties11 and have
been used extensively to nucleate parallel â-sheet struc-
tures in peptides.
We consider the 5-amino-7-azabicycloheptane deriva-
tives 4 and 6 to be promising nonpeptidic molecular
scaffolds for the preparation of peptidomimetics. The exo-
diamines (-)-4 and (+)-4 would make possible the design
of reverse-turn peptide analogues as depicted with D. The
latter have the structural elements of dihydroxyproline12
(E) locked at 1,5-positions with a methylene bridge. The
conformationally rigid and nonlinear architecture of the
dihydroxyazanorbornane skeleton, apart from providing
attractive models for protein folding studies,13 may also
prevent hydrophobic collapse11c,14 of the peptide units in
the bioactive conformation. Additionally, the presence of
the hydroxyl groups can lead to enhanced stability of the
secondary structure by hydrogen bonds between the
hydroxyl groups and the peptide backbone, as it occurs
with the collagen triple helix that is stabilized by the
presence of hydroxyprolines.15
polyhydroxyalkaloids with structural resemblance to
sugars, the calystegines exhibit strong and competitive
glycosidase inhibitory activity.4 Other bicyclic alkaloids
with their nitrogen centers being bridgehead centers have
been shown to have interesting properties as glycosidase
inhibitors.5 The effect of their rigidity on their glycosidase
inhibitory activity will be evaluated here.
The incorporation into peptides of conformationally
constrained amino acids has become extremely impor-
tant, since it allows the creation of peptide analogues
with valuable physical properties and biological activity.6
Molecules containing the 7-azabicyclo[2.2.1]heptane ring
systems have become popular synthetic targets, and
several methods have been reported for their synthesis.7
These molecules are particulary attractive, as they are
rigid proline analogues and scaffolds allowing the con-
struction of peptide chains into defined regions of space.8
Resu lts a n d Discu ssion
Syn th esis of Ra cem ic 5-Am in o-7-a za n or bor n a n e
Der iva tives. The starting material for our study was
the known N-protected 7-azabicyclo[2.2.1]hept-2,5-diene16
8, which was obtained by Diels-Alder reaction between
(9) (a) Recent Advances in Peptidomimetics; Tetrahedron Symposia-
in-Print, No. 83; Aube´, J ., Guest Ed.; Pergamon Press: Oxford, 2000;
Tetrahedron 2000, 56 (50). (b) Robinson, J . A. Synlett 2000, 429. (c)
Peptides and Peptidomimetics that Adopt Folded Structures ; Symposia-
in-Print, No. 15; Kelly, J . W., Guest Ed.; Pergamon Press: Oxford,
1999; Bioorg. Med. Chem. 1999, 7 (1). (d) Hanessian, S.; McNaughton-
Smith, G.; Lombart, H.-G.; Lubell, W. D. Tetrahedron 1997, 53, 12789.
(e) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1993, 32, 1244.
(10) (a) Winningham, M. J .; Sogah, D. Y. Macromolecules 1997, 30,
862. (b) Nowick, J . S.; Smith, E. M.; Noronha, G. J . Org. Chem. 1995,
60, 7386. (c) Nowick, J . S.; Powell, E. J .; Martinez, E. J .; Smith, E. M.;
Noronha, G. J . Org. Chem. 1992, 57, 3763. (d) Kemp, D. S.; Bowen, B.
R.; Muendel, C. C. J . Org. Chem. 1990, 55, 4650.
(11) (a) Chakraborty, T. K.; Srinivasu, P.; Kumar, S. K.; Kunwar,
A. C. J . Org. Chem. 2002, 67, 2093. (b) Chitnumsub, P.; Fiori, W. R.;
Lashuel, H. A.; Diaz, H.; Kelly, J . W. Bioorg. Med. Chem. 1999, 7, 39.
(c) Ranganathan, D.; Haridas, V.; Kurur, S.; Thomas, A.; Madhusudan-
an, K. P.; Nagaraj, R.; Kumwar, A. C.; Sarma, A. V. S.; Karle, I. L. J .
Am. Chem. Soc. 1998, 120, 8448. (d) Hibbs, D. E.; Hursthouse, M. B.;
J ones, I. G.; J ones, W.; Abdul-Malik, K. M.; North, M. J . Org. Chem.
1998, 63, 1496. (e) J ones, I. G.; J ones, W.; North, M. J . Org. Chem.
1998, 63, 1505.
(4) (a) Asano, N.; Kato, A.; Miyauchi, M.; Kizu, H.; Tomimori, T.;
Matsui, K.; Nash, R. J .; Molyneux, R. J . Eur. J . Biochem. 1997, 248,
296. (b) Asano, N.; Kato, A.; Kizu, H.; Matsui, K.; Griffiths, R. C.; J ones,
M. G.; Watson, A. A.; Nash, R. J . Carbohydr. Res. 1997, 304, 173. (c)
Asano, N.; Kato, A.; Kizu, H.; Matsui, K.; Watson, A. A.; Nash, R. J .
Carbohydr. Res. 1996, 293, 195. (d) Asano, N.; Kato, A.; Yokoyama,
Y.; Miyauchi, M.; Yamamoto, M.; Kizu, H.; Matsui, K. Carbohydr. Res.
1996, 284, 169. (e) Asano, N.; Kato, A.; Oseki, K.; Kizu, H.; Matsui,
K.; Eur. J . Biochem. 1995, 229, 369. (f) Asano, N.; Oseki, K.; Tomioka,
E.; Kizu, H.; Matsui, K. Carbohydr. Res. 1994, 259, 243. (g) Molyneux,
R. J .; Pan, Y. T.; Goldmann, A.; Tepfer, D. A.; Elbein, A. D. Arch.
Biochem. Biophys. 1993, 304, 81.
(5) (a) Garc´ıa-Moreno, M. I.; Benito, J . M.; Ortiz-Mellet, C.; Garc´ıa-
Ferna´ndez, J . M. J . Org. Chem. 2001, 66, 7604. (b) Lorthiois, E.;
Meyyappan, M.; Vasella, A. Chem. Commun. 2000, 1829.
(6) (a) Hirschmann, R. Angew. Chem., Int. Ed. Engl. 1991, 30, 1278.
(b) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1993, 32, 1244.
(c) Kahn, M. Synlett 1993, 821.
(12) (a) For
a review of naturally occurring proline analogues:
(7) (a) Avenoza, A.; Barriobero, J . I.; Busto, J . H.; Cativiela, C.;
Peregrina, J . M. Tetrahedron: Asymmetry 2002, 13, 625. (b) Avenoza,
A.; Cativiela, C.; Ferna´ndez-Recio, M. A.; Peregrina, J . M. Tetrahe-
dron: Asymmetry 1999, 10, 3999. (c) Hart, B. P.; Rapoport, H. J . Org.
Chem. 1999, 64, 2050. (d) Han, W.; Pelletier, J . C.; Mersinger, L. J .;
Kettner, C. A.; Hodge, C. N. Org. Lett. 1999, 1, 1875.
(8) Conformationally constrained 7-azabicycloheptane amino acids
as proline mimetics. Han, W.; Pelletier, J .; Sahli, A.; Mersinger, L. J .;
Kettner, C. A.; Hodge, C. N. Abstracts of Papers, 213th National
Meeting of the American Chemical Society, San Francisco, April 13-
17, 1997; American Chemical Society: Washington, DC, 1997; MEDI-
011.
Mauger, A. B. J . Nat. Prod. 1996, 59, 1205. (b) Taylor, C. M.; Weir, C.
A. J . Org. Chem. 2000, 65, 1414.
(13) For reviews on protein folding, see: (a) Creighton, T. E. Proc.
Natl. Acad. Sci. U.S.A. 1988, 85, 5082. (b) Montelione, G. T.; Scheraga,
H. A. Acc. Chem. Res. 1989, 22, 70. (c) Creighton, T. E. Biochem. J .
1990, 270, 1. (d) J aenicke, R. Biochemistry 1991, 30, 3147. See also
ref 9c.
(14) Gante, J . Angew. Chem., Int. Ed. Engl. 1994, 33, 1699.
(15) Eyre, D. R. Science 1980, 207, 1315.
(16) For a review in the chemistry of 7-azabicyclo[2.2.1]hepta-2,5-
dienes, 7-azabicyclo[2.2.1]hept-2-enes, and 7-azabicyclo[2.2.1]heptanes,
see: Chen, Z.; Trudell, M. L. Chem. Rev. 1996, 96, 1179.
J . Org. Chem, Vol. 68, No. 14, 2003 5633

Moreno-Vargas et al.
SCHEME 2
SCHEME 3
2-bromoethynyl p-tolyl sulfone and N-Boc-pyrrole in 80%
yield, as described by Trudell and co-workers.17 Treat-
ment of adduct 8 with 1.1 equiv of diethylamine in the
presence of 5 equiv of triethylamine in acetonitrile,
followed by hydrolysis with 10% HCl, afforded the
known17 ketone 9 in 74% yield as a mixture of isomers
(endo/exo ) 1.2) (Scheme 1).
For the purification of compound 9 by chromatographic
methods, no methanolic solvents should be used. When
the mixture dichloromethane/methanol (60:1) was used
as an eluent, 2,5-disubstituted 3-pyrroline 10 was ob-
tained, almost quantitatively, as a result of the retro-
Claisen cleavage (or retro-Dieckman reaction) that occurs
under mild conditions (25 °C, MeOH, SiO2). This is the
consequence of the strain in bicyclic alkene 9.18
Desulfonylation of 9 employing aluminum-mercury
amalgam gave the corresponding desulfonylated ketone
in a very low yield (<10%). We thus reduced ketone 9
with LiBH4 (-78 °C, THF). This gave exclusively the
endo-alcohol 11, the relative configuration of which was
1
deduced unambiguously from its H NMR spectrum (3J
3
(H-5endo, H-4) ) 3.4 Hz, J (H-6endo, H-1) ) 3.6 Hz).19
The stereospecifity of this reduction can be explained by
involving first endo-epimerization of the tosyl group
under basic conditions that then facilitates the exo-attack
of hydride onto the ketone moiety. Stereoselective dihy-
droxylation of 11 followed by protection of the exo-diol
group afforded 13 in 75% overall yield. Mesylation of the
endo-alcohol of 13 yielded mesylate 14 (82%) (Scheme 2).
Reaction of 14 with Me3SiN3 in the presence of Bu4NF
in THF induced the expected SN2 displacement of the
mesylate by the azide anion, giving the exo-5-azido
product 15. The reaction is accompanied by the formation
of minor amounts of the 5-endo-azido-6-exo-tosylsulfonyl
isomer 16. The product ratio 15/16 diminishes on in-
creasing the temperature. These results can be inter-
preted in terms of two competitive processes: the desired
SN2 displacement of endo-mesylate 14 by the azide anion
and the â-elimination of methanesulfonic acid from 14
induced by the basic medium (fluoride anion-induced E1cb
elimination) and producing intermediate alkene 17. This
product is obtained in 90% yield on treating 14 with DBU
in CH2Cl2 at 25 °C. This product has been obtained
already by Muchowski and co-workers following another
route.20 These authors had shown that 17 adds to oxygen
nucleophiles giving mixtures of 5-exo-oxy-6-endo-tosyl
and 5-endo-oxy-6-exo-tosyl-7-azabicyclo[2.2.1]heptane de-
rivatives. When we treated 17 with Me3SiN3/Bu4NF/THF
at various temperatures, mixtures of 15 and 16 were
obtained. The 15:16 ratios, however, differed from those
obtained from 14 under identical conditions. This is
consistent with the intervention of an SN2 displacement
process that is retarded less at lower temperatures than
(17) Zhang, C.; Ballay, C. J ., II; Trudell, M. L. J . Chem. Soc., Perkin
Trans. 1 1999, 675.
(18) See, e.g.: (a) Wiberg, K. B.; Wasserman, D. J .; Martin, E. J .;
Murcko, M. A. J . Am. Chem. Soc. 1985, 107, 6019. (b) Walsh, R.; Wells,
J . M. J . Chem. Thermodynamics 1976, 8, 55.
(19) (a) Gagnaire, D.; Payo-Subiza, E. Bull. Soc. Chim. Fr. 1963,
2627. (b) Ramey, K. C.; Lini, D. C. J . Magn. Reson. 1970, 3, 94. (c)
Nelson, W. L.; Allen, D. R. J . Heterocycl. Chem. 1972, 9, 561. (d)
Kienzle, F. Helv. Chim. Acta 1975, 58, 1180. (e) Mahaim, C.; Vogel, P.
Helv. Chim. Acta 1982, 65, 866.
(20) (a) Leung-Toung, R.; Liu, Y.; Muchowski, J . M.; Wu, Y. L. J .
Org. Chem. 1998, 63, 3235. (b) Leung-Toung, R.; Liu, Y.; Muchowski,
J . M.; Wu, Y.-L. Tetrahedron Lett. 1994, 35, 1639.
5634 J . Org. Chem., Vol. 68, No. 14, 2003

1,2-Diamine Derivatives of 7-Azabicyclo[2.2.1]heptane
SCHEME 4 a
a
Reagents and conditions: (a) (i) H2, Pd/C (10%), MeOH; (ii) Na-Hg (5%), THF-MeOH, -15 °C. (b) PhCHO, NaBH(OAc)3,
1,2-dichloroethane. (c) HCl (1 M)/THF (1:1), 80 °C, 6 h.
SCHEME 5
the elimination process (Scheme 3). The structures of 15
1
and 16 were deduced from their H NMR data (Experi-
mental Section).19
Catalytic hydrogenation of azides 15 and 16, followed
by desulfonylation21 employing sodium-mercury amal-
gam (5%), led to the corresponding desulfonylated amines
18 and 19 in good-to-moderate yields. Benzylic deriva-
tives 20 and 21 were obtained in good yields from amines
18 and 19, respectively, by reductive amination with
benzaldehyde using sodium triacetoxyborohydride.22
Deprotection of compounds 18, 19, 20, and 21 under
acidic conditions afforded the corresponding unprotected
dihydrochloride diamines 4, 5, 6, and 7 quantitatively.
Obta in in g En a n tiom er ica lly P u r e 7-Aza bicyclo-
[2.2.1]h ep ta n e Der iva tives. The ease by which we
obtained alcohol 11 led us to examine the use of a
resolution technique based on enzyme-catalyzed esteri-
fication.23 Employing lipase from Candida cylindracea
and from Rhizopus oryzae as catalysts afforded low
enantioselectivity for the acetylations. We turned then
to the formation of diastereomeric esters employing (-)-
(1S,4R)-camphanic acid chloride as a resolving agent.24
The reaction of (()-11 with 2 equiv of resolving agent
gave a 1:1 mixture of diasteroisomeric esters 22 and 23
that was readly separated by flash column chromatog-
raphy on silica gel. Removal of the chiral auxiliary from
22 and 23 was realized by treating 22 and 23 with a
catalytic amount of NaOMe in MeOH-THF at 0 °C. This
afforded the enantiomerically pure â-hydroxysulfones
(-)-11 ([R]D -11.5 (c 1.0, CH2Cl2)) and (+)-11 ([R]D +11.8
(c 1.0, CH2Cl2)), respectively. Methanolysis under these
conditions allowed complete recovery of the chiral aux-
iliary as methyl camphanate.
The syntheses of enantiomerically pure 5-amino-7-
azabicyclo[2.2.1]heptanes (+)-18, (-)-18, (+)-19, and (-)-
19 were carried out starting from enantiomerically pure
alcohols (-)-11 and (+)-11 following the procedure de-
scribed for racemic mixtures (Scheme 6). We chose
compound (-)-14 for chemical correlation with the known20
vinyl sulfone (+)-17. This allowed us to assign the
absolute configuration of the series. The NMR data and
[R] value of (+)-17 were in agreement with those reported
for this compound ([R]D +13 (c 1.0, CHCl3); lit. [R]D +15
(c 1.0, CHCl3)). Moreover, the absolute configuration of
compound 23 was confirmed by X-ray diffraction.25 Enan-
tiomerically pure diamines (+)-4, (-)-4, (+)-7, and (-)-7
were synthesized from enantiomerically pure precursors
18 and 19, in good yields.
(21) For a recent review on desulfonylation, see: Najera, C.; Yus,
M. Tetrahedron 1999, 55, 10547.
(22) Abdel-Magid, A. F.; Maryanoff, C. A.; Carson, K. G. Tetrahedron
Lett. 1990, 31, 5595.
(23) (a)Santaniello, E.; Ferraboschi, P.; Grisenti, P.; Manzocchi, A.
Chem. Rev. 1992, 92, 1071. (b) Csa´ky¨, A. G.; Vogel, P. Tetrahedron:
Asymmetry 2000, 11, 4935.
(24) (a) Gerlach, H. Helv. Chim. Acta 1968, 51, 1587. (b) Sonney,
J .-M.; Vogel, P. Helv. Chim. Acta 1980, 63, 1034-1044.
(25) For the details of the X-ray structure of 23, see Supporting
Information.
J . Org. Chem, Vol. 68, No. 14, 2003 5635

Moreno-Vargas et al.
SCHEME 6
TABLE 1. In h ibitor y Activities of 1,2-Dia m in es 1, 3, (-)-4, (-)-7 (w ith Con figu r a tion s Rela ted to Th a t of
r-D-Ma n n osid es), 1,2-Dia m in es (+)-4, (+)-7 (w ith Con figu r a tion s Rela ted to th a t of r-L-Ma n n osid es), a n d Ra cem ic An a logs
(()-5 a n d (()-6 a t 1 m M Con cen tr a tion sa ,b
enzyme/inhibitor
1c
3c
(-)-4
(-)-7
(+)-4
(+)-7
(()-5
(()-6
R-galactosidase
from coffe beans
E. coli
ni
ni
ni
ni
38%
ni
ni
ni
ni
ni
ni
ni
ni
28%
ni
ni
â-galactosidase
from E. coli
Bovine liver
J ack beans
24%
26%
ni
92%
ni
76%
51%
ni
ni
ni
65%
54%
ni
ni
ni
ni
90%
ni
ni
39%
ni
74%
ni
50%
R-glucosidase maltase
80%
from yeast
ni
84%
ni
ni
33%
ni
54%
(168 µM)d
R-glucosidase isomaltase
from baker’s yeast
from Rhizopus mold
from almonds
ni
ni
98%
ni
71%
82%
ni
ni
ni
74%
ni
ni
70%
ni
amyloglucosidase
ni
41%
â-glucosidase
68%
ni
97%
93%
ni
90% (87µM)
Ki ) 55 µM (C)
37%
ni
89% (85µM)
Ki ) 117 µM (C)
36%
74%
ni
ni
ni
Caldocellum
37%
30%
saccharolyticum
R-mannosidase
from J ack beans
92%
81%
27%
ni
ni
25%
21%
ni
Ki ) 7.4 µM (C)
Ki ) 53 µM (C)
a
IC50 (in parentheses) and Ki in µM, when measured. Measured at optimal pH at 35 °C. For details of the measurements, see ref 26.
(C) ) competitive inhibition (Lineweaver-Burk plots); ni ) no inhibition. c See ref 1. IC50 evaluated for racemic (()-4.
b
d
Glycosid a se In h ibition Assa ys. We tested com-
pounds did not show any inhibitory activity at 1 mM
concentration toward the following enzymes: R-L-fucosi-
dase from bovine epididymis, R-galactosidase from As-
pergillus niger, â-galactosidases from A. niger and As-
pergillus orizae, R-glucosidase from rice, amyloglucosidase
from A. niger, R-mannosidase from almonds, â-mannosi-
dase from Helix pomatia, â-xylosidase from A. niger, â-N-
pounds (+)-4, (-)-4, (()-5, (()-6, (+)-7, and (-)-7 for their
inhibitory activities toward 24 commercially available
glycosidases. The data are summarized in Table 1 for two
R-galactosidases, three â-galactosidases, two R-glucosid-
sases, one amyloglucosidase, two â-glucosidases, and one
R-mannosidase. Unless indicated otherwise, these com-
5636 J . Org. Chem., Vol. 68, No. 14, 2003

1,2-Diamine Derivatives of 7-Azabicyclo[2.2.1]heptane
as the internal standard. Coupling constants (J ) in 1H NMR
spectra are reported in hertz.
acetylglucosaminidases from jack beans and from bovine
epididymis A and B, and R-N-acetylgalactosaminidase
from bovine liver.
(()-(2RS,5SR)-Meth yl-1-ter t-bu toxyca r bon yl-5-(p-tolu -
en esu lfon yl)m eth yl-2,5-dih ydr opyr r ol-2-car boxylate ((()-
10) (IUPAC: 1-tert-butyl 2-methyl (2RS,5SR)-5-[(4-methyl-
phenyl)sulfonyl]-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate). The
crude of (()-9,17 coming from the precedent reaction where 26
mmol of (()-8 was used, was added to silica gel in a chromato-
graphic column and eluted with 60:1 CH2Cl2/MeOH to give
(()-10 (5.2 g, 52% overall yield) as an amorphous solid: 1H
NMR (400 MHz, DMSO-d6, 353 K) δ 7.83 (d, 2 H, 3J ) 8.3),
Diamine (-)-4 with the (1S,2S,3R,4R,5R)-configuration
and its 5-endo isomer (6, not made enantiomerically pure)
were designed to imitate (2R,3R,4S)-2-aminomethylpyr-
rolidine-3,4-diol (3), a moderate and competitive inhibitor
of R-mannosidases1 (Table 1). Diamine 3 is not a selective
inhibitor, as it inhibits several other glycosidases more
or less efficiently.1 We now observe that this is also the
case for (-)-4, which in fact is a weaker R-mannosidase
inhibitor than 3. We had shown1 that upon benzylation
of the primary amine moiety of 3, which gives 1, a more
selective and more potent inhibitor of R-mannosidases
is obtained. The benzylamino analogue of (-)-4 is not a
better inhibitor than (-)-4, as shown with the data
obtained with (()-5 (Table 1). These results demonstrate
that the change in conformation and increase of rigidity
of the 7-azanorbornane (-)-4 compared with 3 are
detrimental to the R-mannosidase inhibitory activity.
This is confirmed by the observation that the endo-
benzylamino analogue (-)-7 and the nonbenzylated di-
amine (()-6 do not inhibit R-mannosidase from jack
beans and from almonds. It is now clear that systems 1
and 3 that possess a conformational greater freedom are
much better leads for the search of R-mannosidase
inhibitors than bicyclic analogues such as 4 and 6.
Unexpectedly, both enantiomers of 5-endo-benzylamino-
7-azabicyclo[2.2.1]heptane-2,3-exo-diol (-)-7 and (+)-7 are
good competitive inhibitors of â-glucosidase from al-
monds, with Ki ) 55 and 117 µM, respectively. These
diamines inhibit also, to a smaller extent, â-galactosidase
from bovine liver (65 and 90%, respectively, at 1 mM
concentration) and isomaltase from baker yeast (82 and
74%, respectively).
3
3
4
7.50 (d, 2 H, J ) 8.3), 6.14 (dt, 1 H, J ) 6.3, 2.1, J ) 2.1),
5.92 (dt, 1 H, 3J ) 6.3, 2.1, 4J ) 2.1), 4.96 (q, 1 H, J ) 2.1),
2
4.78 (m, 1 H), 4.58 (br s, 1 H), 3.94 (br d, 1 H, J ) 13.8), 3.68
(s, 3 H), 3.20 (dd, 1 H, 2J ) 13.8, 3J ) 10.4), 2.45 (s, 3 H), 1.36
(s, 9 H); 13C NMR (100.5 MHz, CDCl3, 298 K, mixture of
rotamers) δ 171.0, 170.8, 153.0, 152.8,145.5, 145.2, 137.2,132.6,
132.5, 130.5, 130.4, 128.3, 125.9, 125.5, 81.8, 81.4, 66.7, 66.3,
61.1, 59.5, 59.7, 53.0, 52.8, 28.7, 28.6, 22.0; CIMS m/z 396 [3%,
(M + H)+]. Anal. Calcd for C19H25NSO6: C, 57.71; H, 6.37; N,
3.54. Found: C, 57.44; H, 6.31; N, 3.54.
(()-(1SR,4RS,5SR,6RS)-7-ter t-Bu toxyca r bon yl-6-en d o-
p -t olu en esu lfon yl-7-a za b icyclo[2.2.1]h ep t -2-en -5-en d o-
ol ((()-11) (IUPAC: tert-butyl (1SR,4RS,5SR,6RS)-5-hydroxy-
6-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]hept-2-ene-7-
carboxylate). To a solution of (()-917 (890 mg, 2.45 mmol) in
anhydrous THF (15 mL) at -78 °C was added a solution of
LiBH4 in THF (2 M, 2.45 mmol, 1.22 mL). The mixture was
stirred for 15 min at -78 °C, and then a saturated aqueous
solution of NH4Cl was added and the mixture allowed to warm
to 20 °C under stirring. The solution was diluted with AcOEt,
washed with water and brine, and concentrated. The resulting
residue was purified by column chromatography (Et2O/light
petroleum ether, 1:1) to give (()-11 (760 mg, 85%) as a white
solid: 1H NMR (400 MHz, DMSO-d6, 323 K) δ 7.80 (d, 2 H, 3J
) 8.3), 7.45 (d, 2 H, J ) 8.3), 6.58 (dd, 1 H, 3J ) 5.7, 2.0), 6.47
(dd, 1 H, 3J ) 5.7, 2.2), 4.96 (br s, 1 H), 4.65 (m, 1 H, 3J ) 3.4,
3
7.4), 4.58 (m, 1 H), 4.42 (m, 1 H), 3.89 (dd, 1 H, J ) 7.4, 3.6),
2.43 (s, 3 H), 1.32 (s, 9 H); 13C NMR (100.5 MHz, DMSO-d6,
323 K) δ 152.6, 143.2, 137.3, 133.9, 133.5, 128.8, 127.3, 79.4,
70.1, 65.7, 63.6, 60.9, 27.0, 20.2; Anal. Calcd for C18H23NSO5:
C, 59.16; H, 6.34; N, 3.83; S, 8.77. Found: C, 59.17; H, 6.46;
N, 3.88; S, 8.75.
Con clu sion
Making use of the pioneer works of Muchowski20 and
Trudell,16,17 we have developed an efficient approach to
the synthesis of enantiomerically pure 5-exo (4) and
5-endo-amino-7-azabicyclo[2.2.1]heptane-2,3-exo-diol (6).
Exploratory inhibition studies with 24 commercially
available glycosidases have shown that both enantiomers
of 5-endo-benzylamino-7-azabicyclo[2.2.1]heptane-2,3-exo-
diol ((-)-7, (+)-7) are competitive inhibitors of â-glucosi-
dases from almonds, whereas their nonbenzylated ana-
logues 6 are not. Diamines 4 and 6 are rigid analogues
of 2-aminomethylpyrrolidine-3,4-diol (3). Contrary to
(2R,3R,4S)-2-benzylaminomethylpyrrolidine-3,4-diol (1),1
which is a good inhibitor of R-mannosidases, neither (-)-7
nor (+)-7 inhibit these enzymes, showing that the mono-
cyclic mimics of D-mannosyl cation are recognized much
better by R-mannosidase than puckered and more rigid
systems. Both enantiomers of 5-exo- (4) and 5-endo-
amino-7-azabicyclo[2.2.1]heptane-2,3-exo-diol can be
viewed as scaffolds for the construction of peptidomimet-
ics and analogues with conformational constraints.
(()-(1RS,2SR,3RS,4SR,5RS,6SR)-7-ter t-Bu toxycar bon yl-
6-en d o-p -t olu en esu lfon yl-7-a za b icyclo[2.2.1]h ep t a n e-5-
en do-2,3-exo-tr iol ((()-12) (IUPAC: tert-butyl (1RS,2SR,3RS,
4SR,5RS,6SR)-2,3,5-trihydroxy-6-[(4-methylphenyl)sulfonyl]-
7-azabicyclo[2.2.1]heptane-7-carboxylate). To a solution of (()-
11 (646 mg, 1.77 mmol) in acetone/H2O (9:1, 50 mL) were
added NMO (363 mg, 2.66 mmol) and a solution of OsO4 in
CCl4 (0.1 M, 0.8 mL). After stirring for 2 h, a saturated aqueous
solution of NaHSO3 was added. Then, the crude was extracted
with AcOEt, dried over MgSO4, concentrated under reduced
pressure, and purified by column chromatography on silica gel
(CH2Cl2/MeOH, 40:1f20:1) to give (()-12 (640 mg, 83%) as a
white solid: 1H NMR (400 MHz, 323 K CDCl3) δ 7.82 (d, 2 H,
3
3
3J ) 8.3), 7.38 (d, 2 H, J ) 8.3), 5.01 (d, 1 H, J ) 6.1), 4.68
3
(d, 1 H, J ) 6.1), 4.50 (m, 1 H,), 4.31 (m, 1 H), 4.27 (dd, 1 H,
5
3J ) 4.9, J ) 1.5), 3.74 (m, 1 H), 3.65 (br s, 1 H) 3.58 (dd, 1
3
H, J ) 9.4, 4.9), 2.49 (s, 3 H), 2.44 (br s, 1 H), 1.41 (s, 9 H);
13C NMR (100.5 MHz, CDCl3, 323 K) δ 155.6, 145.4, 137.2,
130.2, 127.9, 81.4, 69.4, 68.8, 68.3, 67.2, 64.7, 63.8, 28.1, 21.5;
CIMS m/z 417 [50%, (M + NH4)+], m/z 400 [55%, (M + H)+].
Anal. Calcd for C18H25NSO7: C, 54.12; H, 6.31; N, 3.51; S, 8.77.
Found: C, 54.15; H, 6.28; N, 3.59; S, 8.03.
(26) Appropriate p-nitrophenyl glycoside substrates buffered to
optimum pH of the enzymes were used; for details, see: (a) Brandi,
A.; Cicchi, S.; Cordero, F. M.; Frignoli, B.; Goti, A.; Picasso, S.; Vogel,
P. J . Org. Chem. 1995, 60, 6806. (b) Picasso, S.; Chen, Y.; Vogel, P.
Carbohydr. Lett. 1994, 1, 1.
(27) For reasons of simplicity, IUPAC names have not been used
systematically (see Scheme 2 for atom numbering) but are given in
parentheses in this section.
Exp er im en ta l Section 27
Gen er a l Meth od s. Chemical shifts in 1H and 13C NMR
spectra are reported in parts per million (δ) relative to the
peaks for CDCl3 (7.27 and 77.0, respectively), DMSO (2.50 and
39.5, respectively), and CD3OD (3.34 and 49.9, respectively)
J . Org. Chem, Vol. 68, No. 14, 2003 5637

Moreno-Vargas et al.
(-)-(1S,2R,3S,4R,5S,6R)-7-ter t-Bu toxyca r bon yl-6-en d o-
p-tolu en esu lfon yl-7-a za bicyclo[2.2.1]h ep ta n e-5-en d o-2,3-
exo-tr iol ((-)-12). This compound was prepared in the
manner described for (()-12 except that pure (-)-11 was used.
Yield: 80%. Mp 64-66 °C; [R]D -5 (c 1.03, CH2Cl2).
(+)-(1R,2S,3R,4S,5R,6S)-7-ter t-Bu toxyca r bon yl-6-en d o-
p-tolu en esu lfon yl-7-a za bicyclo[2.2.1]h ep ta n e-5-en d o-2,3-
exo-tr iol ((+)-12). This compound was prepared in the
manner described for (()-12 except that pure (+)-11 was used.
Yield: 82%. Mp 62-64 °C; [R]D +5.6 (c 0.97, CH2Cl2).
p-tolu en esu lfon yl-7-azabicyclo[2.2.1]h eptan e ((-)-14). This
compound was prepared in the manner described for (()-14
except that pure (-)-13 was used. Yield: 84%. Amorphous
solid. [R]D -1.0 (c 1.2, CHCl3).
(+)-(1R,2S,3R,4S,5R,6S)-7-ter t-Bu toxyca r bon yl-2,3-exo-
isopr opyliden edioxy-5-en do-m eth an o-su lfon yloxy-6-en do-
p-tolu en esu lfon yl-7-azabicyclo[2.2.1]h eptan e ((+)-14). This
compound was prepared in the manner described for (()-14
except that pure (+)-13 was used. Yield: 87%. Amorphous
solid. [R]D +1.1 (c 0.9, CHCl3).
(()-(1RS,2SR,3RS,4SR,5RS,6SR)-7-ter t-Bu toxycar bon yl-
2,3-exo-isop r op ylid en ed ioxy-6-en d o-p-tolu en esu lfon yl-7-
a za bicyclo[2.2.1]h ep ta n e-5-en d o-ol ((()-13) (IUPAC: tert-
butyl (3aRS,4SR,5RS,6SR,7RS,7aSR)-5-hydroxy-2,2-dimethyl-
6-[(4-m et h ylph en yl)su lfon yl]h exa h ydr o-4,7-epim in o-1,3-
benzodioxole-8-carboxylate). A solution of (()-12 (743 mg, 1.68
mmol) in anhydrous acetone (15 mL) containing 2,2-dimethoxy-
propane (1 mL) and PTSA monohydrate (40 mg) was stirred
at room temperature for 7-8 min. Then, a saturated aqueous
solution of NaHCO3 was added, and the crude was extracted
with AcOEt, dried over MgSO4, concentrated under reduced
pressure, and purified by column chromatography on silica gel
(CH2Cl2/MeOH, 50:1) to give (()-13 (672 mg, 91%) as a white
(()-(1SR,2RS,3SR,4SR,5RS,6SR)-5-exo-Azid o-7-ter t-bu -
toxyca r bon yl-2,3-exo-isop r op ylid en e-d ioxy-6-en d o-p-tol-
u en esu lfon yl-7-a za b icyclo[2.2.1]h ep t a n e ((()-15) (IU-
PAC: tert-butyl (3aSR,4SR,5RS,6SR,7SR,7aRS)-2,2-dimethyl-
5-[(4-methylphenyl)sulfonyl]-6-[(methylsulfonyl)oxy]hexahydro-
4,7-epimino-1,3-benzodioxole-8-carboxylate) a n d (()-(1SR,
2R S ,3S R ,4S R ,5S R ,6R S )-5-en d o-Azid o -7-t er t -b u t o x y -
ca r b on yl-2,3-exo-isop r op ylid en ed ioxy-6-exo-p -t olu en e-
su lfon yl-7-a za bicyclo[2.2.1]h ep ta n e ((()-16) (IUPAC: tert-
butyl (3aSR,4SR,5SR,6RS,7SR,7aRS)-5-azido-2,2-dimethyl-6-
[(4-m et h ylph en yl)su lfon yl]h exa h ydr o-4,7-epim in o-1,3-
benzodioxole-8-carboxylate). Mesylate (()-14 (214 mg, 0.414
mmol) was dissolved at 25 °C in THF (6 mL). Trimethylsilyl
azide (72 µL, 0.54 mmol) was added via syringe followed by a
solution of TBAF in THF (1 M, 558 µL, 0.54 mmol). The
solution was stirred for 30 min at 60 °C. Then, the mixture
was concentrated and purified by column chromatography on
silica gel (Et2O/light petroleum ether, 1:2f1:1) to give first
(()-15 (81 mg, 42%) and then (()-16 (34 mg, 17%) as white
solids. Da ta for (()-15: mp ) 128-130 °C; 1H NMR (400
1
solid: mp > 180 °C dec; H NMR (400 MHz, DMSO-d6, 323
3
3
K) δ 7.83 (d, 2 H, J ) 8.3), 7.47 (d, 2 H, J ) 8.3), 5.60 (d, 1
H, 3J ) 5.7), 5.20 (d, 1 H, 3J ) 5.6), 4.87 (d, 1 H, H-6), 4.39 (m,
5
3
1 H), 4.11 (dd, 1 H, J ) 1.2, J ) 5), 4.05 (m, 1 H), 3.95 (m,
1 H), 2.41 (s, 3 H), 1.35 (s, 9 H), 1.32, 1.27 (s each, 3 H each);
13C NMR (100.5 MHz, DMSO-d6) δ 152.6, 144.3, 137.8, 129.8,
127.9, 109.5, 79.3, 76.5, 67.4, 63.5, 63.1, 60.8, 27.8, 25.4, 24.3,
20.9; CIMS m/z 457 [41%, (M + NH4)+], m/z 440 [55%, (M +
H)+]. Anal. Calcd for C21H29NSO7: C, 57.39; H, 6.65; N, 3.19;
S, 7.29. Found: C, 57.35; H, 6.70; N, 3.24; S, 7.30.
3
MHz, DMSO-d6, 363 K) δ 7.88 (d, 2 H, J ) 8.3), 7.51 (d, 2 H,
3
3
3J ) 8.3), 4.96 (d, 1 H, J ) 5.4), 4.42 (d, 1 H, J ) 5.4), 4.36,
5
3
5
(dd, 1 H, J ) 1.7, J ) 4.9), 4.23 (d, 1 H, J ) 1.7), 4.12 (d, 1
(-)-(1S,2R,3S,4R,5S,6R)-7-ter t-Bu toxyca r bon yl-2,3-exo-
isop r op ylid e n e d ioxy-6-en d o-p -t olu e n e su lfon yl-7-a za -
bicyclo[2.2.1]h ep ta n e-5-en d o-ol ((-)-13). This compound
was prepared in the manner described for (()-13 except that
pure (-)-12 was used. Yield: 84%. Mp > 180 °C dec; [R]D -19.5
(c 0.975, CH2Cl2).
(+)-(1R,2S,3R,4S,5R,6S)-7-ter t-Bu toxyca r bon yl-2,3-exo-
isop r op ylid e n e d ioxy-6-en d o-p -t olu e n e su lfon yl-7-a za -
bicyclo[2.2.1]h ep ta n e-5-en d o-ol ((+)-13). This compound
was prepared in the manner described for (()-13 except that
pure (+)-12 was used. Yield: 82%. Mp > 180 °C dec; [R]D +18.3
(c 1.145, CH2Cl2).
3
3
H, J ) 4.2), 3.71 (t, 1 H, J ) 4.6), 2.46 (s, 3 H), 1.40 (s, 9 H),
1.34, 1.23 (s each, 3 H each); 13C NMR (100.5 MHz, DMSO-d6,
363 K) δ 152.0, 144.5, 135.0, 129.1, 126.8, 110.2, 78.9, 77.7,
76.0, 67.8, 64.6, 59.3, 59.0, 26.9, 24.3, 23.5, 19.9; CIMS m/z
465 [30%, (M + H)+]. Anal. Calcd for C21H28N4SO6: C, 54.30;
H, 6.08; N, 12.06; S, 6.90. Found: C, 54.54; H, 6.00; N, 11.94;
1
S, 6.75. Da ta for (()-16: H NMR (400 MHz, DMSO-d6, 363
3
3
K) δ 7.83 (d, 2 H, J ) 8.1), 7.50 (d, 2 H, J ) 8.1), 4.51 (d, 1
3
3
3
H, J ) 5.4), 4.45 (t, 1 H, J ) 5), 4.40 (d, 1 H, J ) 5.4), 4.37
3
(br s, 1 H), 4.28 (br s, 1 H), 3.33 (d, 1 H, J ) 4.7), 2.45 (s, 3
H), 1.39 (s, 9 H), 1.29, 1.21 (s each, 3 H each); 13C NMR (100.5
MHz, CDCl3, 298 K, mixture of rotamers) δ 153.4, 152.9, 146.3,
145.0, 134.5, 133.8, 130.8, 130.7, 129.8, 129.3, 112.4, 112.3,
82.2, 81.6, 81.2, 81.0, 78.3, 77.9, 69.4, 69.2, 61.7, 60.7, 61.0,
59.7, 59.6, 28.6, 25.5, 25.8, 24.9, 24.7, 22.1; CIMS m/z 465 [25%,
(M + H)+]. Anal. Calcd for C21H28N4SO6: C, 54.30; H, 6.08; N,
12.06. Found: C, 54.34; H, 6.24; N, 11.87.
(()-(1RS,2SR,3RS,4SR,5RS,6SR)-7-ter t-Bu toxycar bon yl-
2,3-exo-isopr opyliden edioxy-5-en do-m eth an osu lfon yloxy-
6-en do-p-tolu en esu lfon yl-7-azabicyclo[2.2.1]h eptan e ((()-
14) (IUPAC: tert-butyl (3aRS,4SR,5RS,6SR,7RS,7aSR)-2,2-
dimethyl-5-[(4-methylphenyl)sulfonyl]-6-[(methylsulfonyl)-
oxy]hexahydro-4,7-epimino-1,3-benzodioxole-8-carboxylate). To
a stirred solution of (()-13 (490 mg, 1.02 mmol) in anhydrous
pyridine (5 mL) cooled at 0 °C were added MsCl (0.15 mL, 2.04
mmol) and a catalytic amount of DMAP. After the mixture
was stirred for 12 h, a few drops of water were added, the
mixture was stirred for 15 min and concentrated. The resulting
residue was dissolved in CH2Cl2, washed with brine, dried over
MgSO4, concentrated under reduced pressure, and purified by
column chromatography on silica gel (CH2Cl2/acetone, 50:
1f40:1) to give (()-14 (431 mg, 82%) as a white solid: mp )
(-)-(1S,2R,3S,4S,5R,6S)-5-exo-Azid o-7-ter t-bu toxyca r -
bon yl-2,3-exo-isopr opyliden edioxy-6-en do-p-tolu en esu lfo-
n yl-7-a za bicyclo[2.2.1]h ep ta n e ((-)-15). This compound
was prepared in the manner described for (()-15 except that
pure (-)-14 was used. Yield: 45%. Mp 107-109 °C; [R]D -48
(c 1.1, CHCl3).
(+)-(1R,2S,3R,4R,5S,6R)-5-exo-Azid o-7-ter t-bu toxyca r -
bon yl-2,3-exo-isopr opyliden edioxy-6-en do-p-tolu en esu lfo-
n yl-7-a za bicyclo[2.2.1]h ep ta n e ((+)-15). This compound
was prepared in the manner described for (()-15 except that
pure (+)-14 was used. Yield: 46%. Mp 110-112 °C; [R]D +50
(c 1.1, CHCl3).
1
118-121 °C; H NMR (400 MHz, DMSO-d6, 333 K) δ 7.86 (d,
3
3
3
2 H, J ) 8.3), 7.52 (d, 2 H, J ) 8.3), 5.23 (d, 1 H, J ) 5.4),
3
3
5.18, (dd, 1 H, J ) 5, 9.6), 4.77 (d, 1 H, J ) 5.4), 4.46 (dd, 1
5
3
3
(+)-(1S,2R,3S,4S,5S,6R)-5-en d o-Azid o-7-ter t-bu toxyca r -
bon yl-2,3-exo-isop r op ylid en ed ioxy-6-exo-p-tolu en esu lfo-
n yl-7-a za bicyclo[2.2.1]h ep ta n e ((+)-16). This compound
was prepared in the manner described for (()-16 except that
pure (-)-14 was used. Amorphous solid. Yield: 15%. [R]D +11.6
(c 1.06, CHCl3).
H, J ) 1.2, J ) 5), 4.42 (dd, 1 H, J ) 4.6, 9.6), 4.16 (br d, 1
H, 3J ) 4.6), 3.11 (s, 3 H), 2.45 (s, 3 H), 1.39 (s, 9 H), 1.34,
1.26 (s each, 3 H each); 13C NMR (100.5 MHz, DMSO-d6, 333
K) δ 151.1, 144.4, 135.8, 129.2, 127.1, 109.4, 79.3, 75.9, 75.5,
71.2, 61.4, 59.5, 60.3, 36.5, 27.1, 24.5, 23.5, 20.2; CIMS m/z
535 [45%, (M + NH4)+]. Anal. Calcd for C22H31NS2O9: C, 51.05;
H, 6.09; N, 2.71. Found: C, 50.69; H, 6.20; N, 2.90.
(-)-(1R,2S,3R,4R,5R,6S)-5-en d o-Azid o-7-ter t-b u t oxy-
ca r b on yl-2,3-exo-isop r op ylid en ed ioxy-6-exo-p -t olu en e-
su lfon yl-7-a za bicyclo[2.2.1]h ep ta n e ((-)-16). This com-
(-)-(1S,2R,3S,4R,5S,6R)-7-ter t-Bu toxyca r bon yl-2,3-exo-
isopr opyliden edioxy-5-en do-m eth an o-su lfon yloxy-6-en do-
5638 J . Org. Chem., Vol. 68, No. 14, 2003

1,2-Diamine Derivatives of 7-Azabicyclo[2.2.1]heptane
pound was prepared in the manner described for (()-16 except
that pure (+)-14 was used. Yield: 13%. [R]D -12.6 (c 0.8,
CHCl3).
(+)-(1S,2S,3R,4R,5S)-5-en d o-Am in o-7-ter t-b u t oxyca r -
b on yl-2,3-exo-isop r op ylid en ed ioxy-7-a za b icyclo[2.2.1]-
h ep t a n e ((+)-19). This compound was prepared in the
manner described for (()-19 except that pure (-)-16 was used.
Yield: 61%. [R]D +10.7 (c 1.0, CHCl3).
(+)-(1S,2R,3S,4R)-7-ter t-Bu t oxyca r b on yl-6-p -t olu en e-
su lfon yl-2,3-exo-isop r op ylid en ed ioxy-7-a za bicyclo[2.2.1]-
h ep t-5-en e ((+)-17)20a (IUPAC: tert-butyl (3aR,4S,7R,7aS)-
2,2-dimethyl-5-[(4-methylphenyl)sulfonyl]-3a,4,7,7a-tetrahydro-
4,7-epimino-1,3-benzodioxole-8-carboxylate). To a solution of
(-)-14 (110 mg, 0.21 mmol) in anhydrous CH2Cl2 (3 mL) was
added DBU (70 mL, 0.46 mmol), and the mixture was stirred
for 15 min at room temperature. After this time, the solution
was concentrated and the resulting residue purified by column
chromatography on silica gel (Et2O/light petroleoum ether,
1:2f1:1) to give (+)-17 (83 mg, 90%) as a white foam.
(()-(1RS,2RS,3SR,4SR,5SR)-5-exo-Ben zyla m in o-7-ter t-
bu toxycar bon yl-2,3-exo-isopr opyliden edioxy-7-azabicyclo-
[2.2.1]h ep t a n e ((()-20) (IUPAC: tert-butyl (3aSR,4SR,
5SR,7RS,7aRS)-5-(benzylamino)-2,2-dimethylhexahydro-4,7-
epimino-1,3-benzodioxole-8-carboxylate). To a solution of (()-
18 (17 mg, 0.06 mmol) in anhydrous 1,2-dichloroethane (1 mL)
were added benzaldehyde (0.06 mmol, 6 µL) and NaBH(OAc)3
(18 mg, 0.08 mmol). The mixture was stirred for 1 h at 25 °C.
Then, a saturated aqueous solution of NaHCO3 was added and
the resulting solution was extracted with AcOEt. The organic
layer was dried over MgSO4 and concentrated. The residue
was purified by column chromatography on silica gel (CH2-
Cl2/MeOH, 50:1f20:1) to give (()-20 (14 mg, 63%) as a
colorless oil: 1H NMR (400 MHz, CDCl3, 298 K, mixture of
rotamers) δ 7.34-7.24 (m, 5 H), 4.43, 4.30 (2s, 1 H, H-1), 4.38,
(()-(1RS,2RS,3SR,4SR,5SR)-5-exo-Am in o-7-ter t-bu tox-
ycar bon yl-2,3-exo-isopr opyliden edioxy-7-azabicyclo[2.2.1]-
h ep ta n e ((()-18) (IUPAC: tert-butyl (3aSR,4SR,5SR,7RS,-
7a RS )-5-a m in o-2,2-dim et h ylh exa h ydr o-4,7-epim in o-1,3-
benzodioxole-8-carboxylate). To a solution of azido compound
(()-15 (98 mg, 0.21 mmol) in MeOH (6 mL) was added 10%
Pd/C (15 mg), and the resulting suspension was hydrogenated
at atmospheric pressure for 30 min. The solution was filtered
(Celite), the filter cake was rinsed with methanol, and the
combined filtrate was evaporated to provide 90 mg of crude.
The residue was dissolved in THF (4 mL)-MeOH (4 mL) and
cooled at -15 °C under N2 atmosphere. Then, finely crushed
5% sodium amalgam (0.8 g, 2.08 mmol) was added in one
portion. After 1 h and 30 min, the reaction mixture was filtered
through Celite, concentrated in vacuo, and purified by column
chromatography on silica gel (CH2Cl2/MeOH, 20:1f10:1) to
give (()-18 (36 mg, 60% overall yield) as a colorless oil: 1H
NMR (600 MHz, DMSO-d6, 333 K) δ 4.14 (d, 1 H, 3J ) 5.6),
3
4.23 (2d, 1 H, J ) 5.4), 4.13-4.09 (m, 2 H), 3.91, 3.84 (2d, 1
2
2
H, J ) 12.8), 3.76 (d, 1 H, J ) 12.8), 2.74 (m, 1 H), 1.60 (dd,
2
3
1 H, J ) 13.2, J ) 5.6), 1.55 (br s, 1 H), 1.49 (s, 9 H), 1.45,
1.27 (2s, 2 × 3 H), 1.43-1.37 (m, 1 H); 13C NMR (100.5 MHz,
CDCl3, mixture of rotamers) δ 155.5, 139.6, 128.6, 128.5, 128.3,
128.2, 127.2, 127.1, 111.4, 81.9, 81.7, 80.2, 79.7, 62.2, 61.0, 58.1,
57.2, 55.9, 55.5, 51.5, 34.1, 33.6, 28.5, 25.7, 25.6, 24.4, 24.3;
HREIMS m/z 374.2204, calcd for C21H30N2O4 374.2206.
(()-(1RS,2RS,3SR,4SR,5RS)-5-en do-Ben zylam in o-7-ter t-
bu toxycar bon yl-2,3-exo-isopr opyliden edioxy-7-azabicyclo-
[2.2.1]h ep t a n e ((()-21) (IUPAC: tert-butyl (3aSR,4SR,
5RS,7RS,7aRS)-5-(benzylamino)-2,2-dimethylhexahydro-4,7-
epimino-1,3-benzodioxole-8-carboxylate). This compound was
prepared in the manner described for (()-20 except that (()-
19 was used as starting material. Yield: 65%. Colorless oil.
1H NMR (400 MHz, DMSO-d6, 363 K) δ 7.34-7.21 (m, 5 H),
3
3
5
4.08 (d, 1 H, J ) 5.6), 4.03 (dd, 1 H, J ) 5.5, J ) 1.1), 3.77
(br s, 1 H), 2.83 (dd, 1 H, 3J ) 7.5, 3.0), 1.56 (dd, 1 H, 2J )
12.9, 3J ) 7.5), 1.41 (s, 9 H), 1.30, 1.19 (s each, 3 H each), 1.07
(m, 1 H); 13C NMR (150 MHz, DMSO-d6, 333 K) δ 154.1, 109.9,
80.7, 79.0, 77.7, 66.9, 57.3, 49.3, 35.0, 28.0, 25.3, 24.1; HREIMS
m/z 284.1755, calcd for C14H24N2O4 284.1736.
3
3
3
4.73 (d, 1 H, J ) 5.6), 4.19 (d, 1 H, J ) 5.6), 4.02 (d, 1 H, J
3
3
) 4.5), 3.99 (d, 1 H, J ) 5.9), 3.69 (s, 2 H), 3.05 (dt, 1 H, J )
2
3
10.3, 4.5), 1.95 (ddd, 1 H, J ) 12.7, J ) 10.3, 5.9), 1.38 (s, 9
H), 1.32, 1.23 (2s, 2 × 3 H), 0.82 (dd, 1 H, 2J ) 12.7, 3J ) 4.5);
13C NMR (100.5 MHz, DMSO-d6, 363 K) δ 152.5, 139.0, 126.9,
126.8, 125.4, 108.2, 80.2, 77.2, 76.3, 59.9, 58.0, 54.5, 51.0, 30.5,
27.1, 24.6, 23.5; HREIMS m/z 374.2201, calcd for C21H30N2O4
374.2206.
(-)-(1R,2R,3S,4S,5S)-5-exo-Am in o-7-ter t-bu toxyca r bo-
n yl-2,3-exo-isop r op ylid e n e d ioxy-7-a za b icyclo[2.2.1]-
h ep t a n e ((-)-18). This compound was prepared in the
manner described for (()-18 except that pure (-)-15 was used.
Yield: 58%. Colorless oil. [R]D -9.6 (c 1.4, CHCl3).
(+)-(1S,2S,3R,4R,5R)-5-exo-Am in o-7-ter t-bu toxyca r bo-
n yl-2,3-exo-isop r op ylid e n e d ioxy-7-a za b icyclo[2.2.1]-
h ep t a n e ((+)-18). This compound was prepared in the
manner described for (()-18 except that pure (+)-15 was used.
Yield: 60% yield. Colorless oil. [R]D +9.5 (c 1.25, CHCl3).
(-)-(1R,2R,3S,4S,5R)-5-en d o-Ben zyla m in o-7-ter t-b u -
toxyca r bon yl-2,3-exo-isop r op ylid en ed ioxy-7-a za bicyclo-
[2.2.1]h ep ta n e ((-)-21). This compound was prepared in the
manner described for (()-21 except that pure (-)-19 was used.
Yield: 60%. Colorless oil. [R]D -9 (c 0.8, CHCl3).
(+)-(1S,2S,3R,4R,5S)-5-en d o-Ben zyla m in o-7-ter t-bu tox-
ycar bon yl-2,3-exo-isopr opyliden edioxy-7-azabicyclo[2.2.1]-
h ep t a n e ((+)-21). This compound was prepared in the
manner described for (()-21 except that pure (+)-19 was used.
Yield: 56%. Colorless oil. [R]D +8.2 (c 0.56, CHCl3).
(()-(1RS,2RS,3SR,4SR,5RS)-5-en d o-Am in o-7-ter t-b u -
toxyca r bon yl-2,3-exo-isop r op ylid en ed ioxy-7-a za bicyclo-
[2.2.1]h ep t a n e ((()-19) (IUPAC: tert-butyl (3aSR,4SR,
5RS,7RS,7aRS)-5-amino-2,2-dimethylhexahydro-4,7-epimino-
1,3-benzodioxole-8-carboxylate). This product was prepared in
the manner described for (()-18 except that (()-16 was used
as starting material. In this case, a column chromatography
on silica gel (CH2Cl2/MeOH, 30:1f15:1) was used in the
purification. Yield: 72%. Colorless oil. 1H NMR (400 MHz,
CDCl3, 298 K, mixture of rotamers) δ 4.84 (m, 1 H), 4.23 (d, 1
H, 3J ) 5.6), 4.25, 4,15 (d each, 1 H, 3J ) 5.7), 4.19, 4.10 (d
(()-(1RS,2RS,3SR,4SR,5SR)-5-exo-Am in o-7-a za bicyclo-
[2.2.1]h ep ta n e-2,3-exo-d iol Dih yd r och lor id e ((()-4‚2HCl)
(IUPAC: (1RS,2RS,3SR,4SR,5SR)-5-ammonio-2,3-dihydroxy-
7-azoniabicyclo[2.2.1]heptane dichloride). Amine (()-18 (14
mg, 0.049 mmol) was dissolved in THF (0.5 mL)-HCl 1 M (0.5
mL), and the mixture was stirred at 80 °C for 6 h. The solvent
was evaporated and the excess HCl removed in vacuo to give
dihydrochloride of (()-4 (11 mg, 100%) as an amorphous white
solid: 1H NMR (400 MHz, CD3OD, 298 K) δ 4.24 (br s, 1 H),
3
3
each, 1 H, J ) 4.2), 3.51 (dt, 1 H, J ) 10.3, 4.5), 2.18 (ddd,
1 H, 2J ) 12.7, 3J ) 10.3, 4.2), 1.46 (s, 9 H), 1.44, 1.25 (s each,
2
3
3 H each), 1.35 (br s, 2 H), 0.73 (dd, 1 H, J ) 12.7, J ) 4.5);
13C NMR (100.5 MHz, CDCl3, 298 K, mixture of rotamers) δ
155.0, 110.1, 81.9, 81.6, 79.5, 77.6, 77.2, 62.9, 62.0, 60.0, 59.1,
49.6, 49.2, 34.0, 33.9, 28.4, 25.7, 24.3; HREIMS m/z 284.1749,
calcd for C14H24N2O4 284.1736.
3
5
3
4.22 (d, 1 H, J ) 6.2), 4.18 (dd, 1 H, J ) 1.4, J ) 5.2), 4.15
3
3
(d, 1 H, J ) 6.2), 3.80 (dd, 1 H, J ) 8.8, 4.5), 2.38 (dd, 1 H,
2J ) 14.6, 3J ) 8.8), 2.21 (dt, 1 H, 2J ) 14.6, 3J ) 4.8); 13C
NMR (100.5 MHz, CD3OD, 298 K) δ 72.7, 71.4, 69.7, 66.7, 49.5,
31.2; HRCIMS m/z 145.0974, calcd for C6H12N2O2 + H 145.0977.
(-)-(1R,2R,3S,4S,5R)-5-en d o-Am in o-7-ter t-b u t oxyca r -
b on yl-2,3-exo-isop r op ylid en ed ioxy-7-a za b icyclo[2.2.1]-
h ep t a n e ((-)-19). This compound was prepared in the
manner described for (()-19 except that pure (+)-16 was used.
Yield: 64%. Colorless oil. [R]D -11.2 (c 1.3, CHCl3).
(+)-(1R,2R,3S,4S,5S)-5-exo-Am in o-7-a za b icyclo[2.2.1]-
h ep ta n e-2,3-exo-d iol Dih yd r och lor id e ((+)-4‚2HCl). This
compound was prepared in the manner described for (()-4
J . Org. Chem, Vol. 68, No. 14, 2003 5639

Moreno-Vargas et al.
except that pure (-)-18 was used. Yield: 100%. Amorphous
solid. [R]D +7.6 (c 0.88, CH3OH).
(-)-(1S,2S,3R,4R,5R)-5-exo-Am in o-7-a za bicyclo[2.2.1]-
h ep ta n e-2,3-exo-d iol Dih yd r och lor id e ((-)-4‚2HCl). This
compound was prepared in the manner described for (()-4
except that pure (+)-18 was used. Yield: 100%. Amorphous
solid. [R]D -7.3 (c 0.695, CH3OH).
carboxylate). To a cold (0 °C) solution of (()-11 (2.66 g, 7.24
mmol) in anhydrous CH2Cl2 (100 mL) were added Et3N (2 mL,
14.46 mmol), (1S,4R)-(-)-camphanic acid chloride (3.16 g,
14.48 mmol), and a catalytic amount of DMAP. After stirring
for 2 h at room temperature, a saturated aqueous solution of
citric acid was added. The crude was extracted with CH2Cl2,
dried over MgSO4, concentrated under reduced pressure, and
purified by column chromatography on silica gel (light petro-
leum ether/AcOEt, 4:1f3:1) eluting first 22 (1.86 g, 47%) and
second 23 (1.78 g, 44%), both as white solids. Da ta for 22:
(()-(1R S ,2R S ,3S R ,4S R ,5S R )-5-exo-B e n zy la m in o -7-
a za b icyclo[2.2.1]h ep t a n e-2,3-exo-d iol Dih yd r och lor id e
((()-5‚2HCl) (IUPAC: (1RS,2RS,3SR,4SR,5SR)-5-(benzylam-
monio)-2,3-dihydroxy-7-azoniabicyclo[2.2.1]heptane dichlo-
ride). This compound was prepared in the manner described
for (()-4 except that amine (()-20 was used as starting
material. Yield: 100%. Colorless oil. 1H NMR (400 MHz, CD3-
OD, 298 K) δ 7.64 (m, 2 H), 7.49 (m, 3 H), 4.47 (s, 1 H), 4.37
(d, 1 H, 2J ) 12.9), 4.34 (d, 1 H, 2J ) 12.9), 4.22 (m, 2 H), 4.17
1
mp ) 143.5-145 °C; [R]D +25.3 (c 1, CH2Cl2); H NMR (400
3
3
MHz, CDCl3, 298 K) δ 7.79 (d, 2 H, J ) 7.9), 7.40 (d, 2 H, J
3
) 7.9), 6.77 (br s, 1 H), 6.45 (dd, J ) 5.7, 1.9), 5.89 (dd, 1 H,
3J ) 8.0, 4.2), 5.07 (br s, 1 H), 4.41 (br s, 1 H), 3.89 (dd, 1 H,
3J ) 8.0, 3.3), 2.47 (s, 3 H), 2.51-2.44 (m, 1 H), 2.06-2.03 (m,
1 H), 1.91-1.86 (m, 1 H), 1.70-1.63 (m, 1 H), 1.37 (s, 9 H),
1.13, 1.10, 1.03 (3s, 3 × 3 H); 13C NMR (100.5 MHz, CDCl3,
298 K) δ 178.5, 166.9, 154.3, 145.8, 137.4, 136.6, 133.5, 130.7,
128.3, 91.3, 82.3, 73.2, 65.9, 63.6, 62.1, 55.2, 54.7, 31.0. 29.3,
28.4, 22.1, 17.1, 17.0, 10.1. Anal. Calcd for C28H35NSO8: C,
61.63; H, 6.46; N, 2.57. Found: C, 61.42; H, 6.45; N, 2.49. Da ta
3
3
(d, 1 H, J ) 6.1), 3.90 (dd, 1 H, J ) 7.9, 5.5), 2.47-2.38 (m,
2 H); 13C NMR (100.5 MHz, CD3OD, 298 K) δ 131.9, 131.2,
130.9, 130.4, 71.8, 70.7, 67.4, 65.6, 55.5, 51.2, 29.4; HRCIMS
m/z 235.1442, calcd for C13H18N2O2 + H 235.1446.
(()-(1RS,2RS,3SR,4SR,5RS)-5-en do-Am in o-7-azabicyclo-
[2.2.1]h ep ta n e-2,3-exo-d iol Dih yd r och lor id e ((()-6‚2HCl)
(IUPAC: (1R,2R,3S,4S,5R)-5-ammonio-2,3-dihydroxy-7-azo-
niabicyclo[2.2.1]heptane dichloride). This compound was pre-
pared in the manner described for (()-4 except that amine (()-
19 was used as starting material. Yield: 100%. Amorphous
1
for 23: mp ) 135-136 °C; [R]D -38.7 (c 1, CH2Cl2); H NMR
3
(400 MHz, CDCl3, 298 K) δ 7.77 (d, 2 H, J ) 8.2), 7.40 (d, 2
3
H, 3J ) 8.2), 6.83 (br s, 1 H), 6.46 (br d, 1 H), 5.91 (dd, 1 H, J
3
) 8.1, 4.0), 5.04 (br s, 1 H), 4.45 (br s, 1 H), 3.88 (dd, 1 H, J
) 8.1, 3.4), 2.64-2.57 (m, 1 H), 2.47 (s, 3 H), 2.09-2.03 (m, 1
H), 1.93-1.87 (m, 1 H), 1.70-1.64 (m, 1 H), 1.37 (s, 9 H), 1.10,
1.09, 0.99 (3s, 3 × 3 H); 13C NMR (100.5 MHz, CDCl3, 298 K)
δ 178.2, 167.1, 154.3, 145.9, 137.5, 137.4, 133.2, 130.8, 128.3,
91.6, 82.4, 73.2, 65.8, 63.5, 62.1, 55.4, 54.6, 31.1, 29.5, 28.4,
22.1, 17.6, 17.5, 10.1. Anal. Calcd for C28H35NSO8: C, 61.63;
H, 6.46; N, 2.57. Found: C, 61.27; H, 6.50; N, 2.46.
1
3
solid. H NMR (400 MHz, CD3OD, 298 K) δ 4.52 (d, 1 H, J )
3
5
3
6.2), 4.30 (d, 1 H, J ) 6.2), 4.24 (dd, 1 H, J ) 1.4, J ) 4.6),
4.10 (d, 1 H, 3J ) 5.7), 3.92 (dt, 1 H, 3J ) 11.1, 5.0), 2.54 (ddd,
2
3
2
3
1 H, J ) 14.5, J ) 11.1, 5.7), 1.73 (dd, 1 H, J ) 14.5, J )
5.0); 13C NMR (100.5 MHz, CD3OD, 298 K) δ 73.4, 68.7, 67.6,
67.5, 47.8, 28.7; HRCIMS m/z: 145.0976. Calcd. for C6H12N2O2
+ H: 145.0977.
(-)-(1S,4R,5S,6R)-7-ter t-Bu toxyca r bon yl-6-en d o-p-tolu -
en esu lfon yl-7-a za bicyclo[2.2.1]h ep t-2-en -5-en d o-ol ((-)-
11). To a solution of 22 (1.49 g, 2.58 mmol) in anhydrous 6:1
MeOH-THF (100 mL) cooled at 0 °C, a catalytic amount of
NaOMe/MeOH (1 M) was added (pH ) 8). The solution was
stirred for 4 h at 0 °C under pH ) 8 (adding NaOMe/MeOH (1
M) when it was necessary to maintain a constant pH). Then,
Dowex resin was added until neutral pH was reached; the
solution was filtered, and the filtrate was concentrated. The
resulting residue was purified by chromatography column
chromatography (AcOEt/light petroleum ether, 1:3) to give
(-)-7 (829 mg, 88%) as a white foam. [R]D -11.5 (c 1.0, CH2-
Cl2).
(()-(1R S ,2R S ,3S R ,4S R ,5R S )-5-en d o-Be n zyla m in o-7-
a za b icyclo[2.2.1]h ep t a n e-2,3-exo-d iol Dih yd r och lor id e
((()-7‚2HCl) (IUPAC: (1RS,2RS,3SR,4SR,5RS)-5-(benzylam-
monio)-2,3-dihydroxy-7-azoniabicyclo[2.2.1]heptane dichlo-
ride). This compound was prepared in the manner described
for (()-4 except that amine (()-21 was used as starting
material. Yield: 100%. Colorless oil. 1H NMR (400 MHz, CD3-
OD, 298 K) δ 7.62 (m, 2 H), 7.50 (m, 3 H, H-3 of Ph), 4.58 (d,
1 H, 3J ) 6.2), 4.41 (d, 1 H, 2J ) 13.0), 4.34 (d, 1 H, 2J ) 13.0),
3
3
4.32 (m, 2 H), 4.08 (d, 1 H, J ) 5.7), 3.92 (dt, 1 H, J ) 10.8,
2
3
5.1), 2.45 (ddd, 1 H, J ) 14.7, J ) 10.8, 5.7), 1.79 (dd, 1 H,
2J ) 14.7, J ) 5.3); 13C NMR (100.5 MHz, CD3OD, 298 K) δ
3
132.4, 132.1, 131.4, 73.4, 68.9, 67.3, 67.1, 54.4, 53.6, 27.8;
HRCIMS m/z 235.1442, calcd for C13H18N2O2 + H 235.1446.
(+)-(1R,2R,3S,4S,5R)-5-en do-Ben zylam in o-7-azabicyclo-
[2.2.1]h ep ta n e-2,3-exo-d iol Dih yd r och lor id e ((+)-7‚2HCl).
This compound was prepared in the manner described for (()-7
except that pure (-)-21 was used. Yield: 100%. Colorless oil.
[R]D -13.5 (c 0.665, CH3OH).
(-)-(1S,2S,3R,4R,5S)-5-en do-Ben zylam in o-7-azabicyclo-
[2.2.1]h ep ta n e-2,3-exo-d iol Dih yd r och lor id e ((-)-7‚2HCl).
This compound was prepared in the manner described for (()-7
except that pure (+)-21 was used. Yield: 100%. Colorless oil.
[R]D +12.9 (c 0.315, CH3OH).
(+)-(1S,4R,5S,6R)-7-ter t-Bu toxycar bon yl-5-en do-[(1S,4R)-
ca m p h a n oyloxy]-6-en d o-p-tolu en esu lfon yl-7-a za bicyclo-
[2.2.1]h ep t-2-en e ((+)-22) (IUPAC: tert-butyl (1R,4S,5R,6S)-
5-[(4-methylphenyl)sulfonyl]-6-({[(1S,4R)-4,7,7-trimethyl-3-
oxo-2-oxa bicyclo[2.2.1]h ept -1-yl]ca r bon yl}oxy)-7-a za -
bicyclo[2.2.1]hept-2-ene-7-carboxylate) an d (-)-(1R,4S,5R,6S)-
7-ter t-Bu toxyca r bon yl-5-en d o-[(1S,4R)-ca m p h a n oyloxy]-
6-en d o-p -t olu en esu lfon yl-7-a za b icyclo[2.2.1]h ep t -2-en e
((-)-23) (IUPAC: tert-butyl (1S,4R,5S,6R)-5-[(4-methylphen-
yl)sulfonyl]-6-({[(1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo-
[2.2.1]hept-1-yl]carbonyl}oxy)-7-azabicyclo[2.2.1]hept-2-ene-7-
(+)-(1R,4S,5R,6S)-7-ter t-Bu toxyca r bon yl-6-en d o-p-tolu -
en esu lfon yl-7-a za bicyclo[2.2.1]h ep t-2-en -5-en d o-ol ((+)-
11). This compound was prepared in the manner described
for (-)-11 except that pure 23 (640 mg, 1.11 mmol) was used.
Yield: 90%. White foam after purification by column chroma-
tography on silica gel (AcOEt/light petroleum ether, 1:3). [R]D
+11.8 (c 1.0, CH2Cl2).
Ack n ow led gm en t. We are grateful to the Swiss
National Science Fondation (Grant No. 20.63667.00),
the “Office Fe´de´ral de l’Education et de la Science”
(Bern, COST D13/0001/99), and the Direccio´n General
de Investigacio´n Cient´ıfica y Te´cnica of Spain (Grant
No. BQU-2001-3779) for generous support.
Su p p or tin g In for m a tion Ava ila ble: Crystal structure
1
1
data for compound 23, H and 13C NMR spectra, H and 13C
NMR data with peak assignments, a complete list of R values,
and IR data for all the new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O0301088
5640 J . Org. Chem., Vol. 68, No. 14, 2003