Synthesis of tetrahydroxyquinolizidines: Ring-expanded analogs of the mannosidase inhibitor swainsonine

Article abstract of DOI:10.1021/jo960609b

The indolizidine azasugar swainsonine (1) is an important inhibitor of mannosidase II and has shown antitumor and immunomodulatory activity. A comparison of the structure of swainsonine and D-mannopyranose shows that swainsonine lacks the C(4) hydroxymethine group of mannose. Ring-expanded quinolizidine analogs 4 of swainsonine were prepared where the 'missing' hydroxymethine group was incorporated into the pyrrolidine ring of swainsonine between C(1) and C(8a). The quinolizidine analogs 4 resemble both D-mannopyranose and the related azasugar deoxymannojirimycin, a selective inhibitor of the glycoprotein processing enzyme mannosidase 1. D-Arabinose was converted into the ω-halo azidoalkene 13, which was subjected to thermolysis, a strategy which had been successful in an earlier synthesis of swainsonine itself. Rather than the desired quinolizidine 4, the pyridinium ion 16 was produced. An alternate synthesis of all four C(9)/C(9a) diastereomers of 4 was developed which relied on the reductive double-alkylation of epoxides bearing remote azido and chloro groups. Thus, reduction of compounds 21α, 21β, 26, and 27 resulted in the formation of the quinolizidines 22, 23, 28, and 29, which were deprotected to give the quinolizidine analogs of swainsonine (9S,9aR)-4, (9R,9aS)-4, (9S,9aS)-4, and (9R,9aR)-4, respectively. An alternate synthesis of (9R,9aR)-4 involving the reductive N-alkylation of a cyclic imine was also developed. None of the quinolizidines showed significant glycosidase activity in screens against mannosidases, glucosidases, or fucosidases. Speculation on the significance of these findings is presented.

Full text of DOI:10.1021/jo960609b

J . Org. Chem. 1996, 61, 5537-5545
5537
Syn th esis of Tetr a h yd r oxyqu in olizid in es: Rin g-Exp a n d ed An a logs
of th e Ma n n osid a se In h ibitor Sw a in son in e
William H. Pearson* and Erik J . Hembre
Department of Chemistry, The University of Michigan, Ann Arbor, Michigan 48109-1055
Received April 1, 1996X
The indolizidine azasugar swainsonine (1) is an important inhibitor of mannosidase II and has
shown antitumor and immunomodulatory activity. A comparison of the structure of swainsonine
and D-mannopyranose shows that swainsonine lacks the C(4) hydroxymethine group of mannose.
Ring-expanded quinolizidine analogs 4 of swainsonine were prepared where the “missing”
hydroxymethine group was incorporated into the pyrrolidine ring of swainsonine between C(1) and
C(8a). The quinolizidine analogs 4 resemble both D-mannopyranose and the related azasugar
deoxymannojirimycin, a selective inhibitor of the glycoprotein processing enzyme mannosidase I.
D-Arabinose was converted into the ω-halo azidoalkene 13, which was subjected to thermolysis, a
strategy which had been successful in an earlier synthesis of swainsonine itself. Rather than the
desired quinolizidine 4, the pyridinium ion 16 was produced. An alternate synthesis of all four
C(9)/C(9a) diastereomers of 4 was developed which relied on the reductive double-alkylation of
epoxides bearing remote azido and chloro groups. Thus, reduction of compounds 21R, 21â, 26, and
27 resulted in the formation of the quinolizidines 22, 23, 28, and 29, which were deprotected to
give the quinolizidine analogs of swainsonine (9S,9aR)-4, (9R,9aS)-4, (9S,9aS)-4, and (9R,9aR)-4,
respectively. An alternate synthesis of (9R,9aR)-4 involving the reductive N-alkylation of a cyclic
imine was also developed. None of the quinolizidines showed significant glycosidase activity in
screens against mannosidases, glucosidases, or fucosidases. Speculation on the significance of these
findings is presented.
In tr od u ction
might provide more potent and selective mannosidase
inhibitors. We wish to report our findings on the
synthesis and biological evaluation of ring-expanded
analogs of swainsonine.13
A number of naturally occuring polyhydroxylated in-
dolizidine, pyrrolizidine, pyrrolidine, and piperidine al-
kaloids (often referred to as “amino-sugars” or “aza-
sugars”) exhibit glycosidase inhibitory activity.1-5 At
physiological pH, the protonated amino group may mimic
the developing pyranosyl or furanosyl cation intermediate
encountered in oligosaccharide cleavage. Several of these
alkaloids are of interest for their activity against cancer,
HIV, and other disorders. Due to their ability to inhibit
glycoprotein processing enzymes, such alkaloids have also
been useful in studies on the effect of oligosaccharide
structure on glycoprotein function.3-6 Swainsonine (1)
and deoxymannojirimycin (2) are azasugar analogs of
mannose (3) and are indeed inhibitors of various
mannosidases.4,6-10 Swainsonine is an inhibitor of lyso-
somal R-mannosidases and the glycoprocessing enzyme
mannosidase II, while deoxymannojirimycin selectively
inhibits mannosidase I. Swainsonine inhibits tumor
growth and metastasis11 and exhibits immunomodulatory
activity.12 Structurally modified analogs of swainsonine
Swainsonine has been the subject of structure-activity
relationship studies, primarily involving examination of
the activity of its stereoisomers.8,14,15 Another strategy
involves the synthesis of ring-expanded or ring-contracted
analogs of swainsonine. Carpenter et al.16 and Burgess
and Henderson17 have prepared ring-contracted analogs
of swainsonine where one methylene group is missing
from the piperidine ring, i.e., pyrrolizidine analogs of
swainsonine. This modification resulted in diminished
mannosidase activity.16 A comparison of the structures
of swainsonine (1), deoxymannojirimycin (2), and D-
mannopyranose (3) shows that swainsonine lacks the
C(4) hydroxymethine group of D-mannose and deox-
ynojirimycin. This led us to consider synthesizing the
ring-expanded swainsonine analog 4 where the “missing”
(11) (a) Kino, I.; Inamura, N.; Nakahara, K.; Kiyouto, S.; Goto, T.;
Terano, H.; Kohsaka, M. J . Antibiot. 1985, 38, 936. (b) Humphries,
M. J .; Matsumoto, K.; White, S. L.; Olden, K. Proc. Natl. Acat. Sci.
U.S.A. 1986, 83, 1752. (c) Dennis, J . W. Cancer Res. 1986, 46, 5131.
(d) Humphries, M. J .; Matsumoto, K.; White, S. L.; Olden, K. Cancer
Res. 1986, 46, 5215. (e) Humphries, M. J .; Matsumoto, K.; White, S.
L.; Molyneux, R. J .; Olden, K. Cancer Res. 1988, 48, 1410. (f) Dennis,
J . W.; Koch, K.; Beckner, D. J . Natl. Cancer Inst. 1989, 81, 1028. (g)
For a recent review see: Goss, P. E.; Baker, M. A.; Carver, J . P.;
Dennis, J . W. Clin. Cancer. Res. 1995, 1, 935.
X Abstract published in Advance ACS Abstracts, J uly 15, 1996.
(1) Elbein, A. D.; Molyneux, R. J . In Alkaloids: Chemical and
Biological Perspectives; S. W. Pelletier, Ed.; Wiley: New York, 1986;
Vol. 5, pp 1-54.
(2) Elbein, A. D. Annu. Rev. Biochem. 1987, 56, 497.
(3) Elbein, A. D. FASEB J . 1991, 5, 3055.
(4) Winchester, B.; Fleet, G. W. J . Glycobiology 1992, 2, 199.
(5) Nishimura, Y. In Studies in Natural Products Chemistry; Atta-
ur-Rahman, Ed.; Elsevier: Amsterdam, 1992; Vol. 10, pp 495-583.
(6) Kaushal, G. P.; Elbein, A. D. Methods Enzymol. 1994, 230, 316.
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Acad. Sci. U.S.A. 1981, 78, 7393.
(8) Cenci Di Bello, I.; Fleet, G.; Namgoong, S. K.; Tadano, K.;
Winchester, B. Biochem. J . 1989, 259, 855.
(9) Winchester, B.; Al Daher, S.; Carpenter, N. C.; Cenci Di Bello,
I.; Choi, S. S.; Fairbanks, A. J .; Fleet, G. W. J . Biochem. J . 1993, 290,
743.
(12) (a) Hino, M.; Nakayama, O.; Tsurumi, Y.; Adachi, K.; Shibata,
T.; Terano, H.; Kohsaka, M.; Aoki, H.; Imanaka, J . J . Antibiot. 1985,
38, 926. (b) Galustian, C.; Foulds, S.; Dye, J . F.; Guillou, P. J .
Immunopharmacology 1994, 27, 165.
(13) Part of this work has been communicated: Pearson, W. H.;
Hembre, E. J . Tetrahedron Lett. 1993, 34, 8221.
(14) Winkler, D. A.; Holan, G. J . Med. Chem. 1989, 32, 2084.
(15) Elbein, A. D.; Szumilo, T.; Sanford, B. A.; Sharpless, K. B.;
Adams, C. Biochemistry 1987, 26, 2502.
(16) Carpenter, N. M.; Fleet, G. W.; Cenci di Bello, I.; Winchester,
B.; Fellows, L. E.; Nash, R. J . Tetrahedron Lett. 1989, 30, 7261.
(17) Burgess, K.; Henderson, I. Tetrahedron Lett. 1990, 31, 6949.
(10) Hughes, A. B.; Rudge, A. J . Nat. Prod. Rep. 1994, 135.
S0022-3263(96)00609-3 CCC: $12.00 © 1996 American Chemical Society

5538 J . Org. Chem., Vol. 61, No. 16, 1996
Pearson and Hembre
Sch em e 1. Retr osyn th etic An a lysis of
hydroxymethine group has been inserted into the pyr-
rolidine ring of swainsonine between C(1) and C(8a).
D-Ma n n otetr a h yd r oxyqu in olizid in e Usin g th e
ω-Ha lo Azid oa lk en e Cycliza tion Str a tegy
Sch em e 2. P r eviou s Use of th e ω-Ha lo
Azid oa lk en e Cycliza tion Str a tegy for th e Syn th esis
of (-)-Sw a in son in e
Ring-expanded analogs of castanospermine, a related
indolizidine that shows glucosidase inhibitory activity,
have been prepared and were found to retain inhibitory
activity,18 so we were optimistic that quinolizidine ana-
logs of swainsonine would be reasonable targets. We
were particularily interested to see if these quinolizidines
would prove to be selective inhibitors of the glycoprotein
processing enzyme mannosidase I. This enzyme appears
to be inhibited by structures that more closely resemble
the mannopyranose ground state conformation such as
deoxymannojirimycin. Mannosidase II, on the other
hand, appears to be inhibited by structures that mimic
the proposed mannopyranosyl cation transition state.14
Ganem and co-workers reported the preparation of (9R,-
9aR)- and (9S,9aR)-4 as part of a structure proof in a
total synthesis of castanospermine, but no biological data
were provided.19 Concurrently with the publication of our
preliminary work on the synthesis of two of the diaster-
eomers of 4,13 Rassu, Casiraghi et al., reported the
synthesis of what were originally assigned as (9R,9aR)-4
and its enantiomer,20,21 but these structures have since
been revised.22 We now wish to provide a full report of
the synthesis and glycosidase inhibitory activity of all
four C(9)/C(9a) diastereomers of 4. The following paper
describes the synthesis and biological activity of another
class of polyhydroxylated alkaloid analogs, namely the
ring-expanded analogs of the pyrrolizidine alkaloids
alexine and australine.
An In ita l Syn th etic Ap p r oa ch to th e
Qu in olizid in es 4 Usin g Azid e Cycloa d d ition
Meth od ology
Our initial synthetic strategy is shown in Scheme 1.
Based on prior work from our group,23-25 we proposed
that the ω-halo azidoalkene 5 would undergo a thermal
double-cyclization to produce 4 after suitable functional
group manipulation. Wittig chemistry would be used to
transform D-arabinose (6) into 5. The closest analogy to
the 5 f 4 transformation is our work on the synthesis of
(-)-swainsonine (1), shown in Scheme 2, which involves
a one-flask transformation of 7 to 9.23 Heating 7 caused
(1) intramolecular 1,3-dipolar cycloaddition of the azide
on to the alkene to afford a triazoline, (2) fragmentation
of the triazoline with concomitant loss of nitrogen and
1,2-hydrogen shift to produce an imine, and (3) intramo-
lecular N-alkylation of the imine to give the iminium ion
8. Without isolation, 8 was deprotonated with base to
generate an enamine which was subjected to hydrobo-
ration/oxidation in situ to produce 9 in good yield. Acidic
hydrolysis of 9 gave swainsonine (1). Extension of the
this methodology to the synthesis of 4 seemed to be a
straightforward strategy, although the stereoselectivity
of the hydroboration of the intermediate enamine was
not certain.
Scheme 3 shows our attempted implementation of the
ω-halo azidoalkene cyclization strategy. D-Arabinose (6)
was converted into the 2,3,4-tri-O-benzyl-D-arabinose (10)
by the literature procedure.26 Wittig reaction with the
known phosphonium salt 1123 gave the Z-alkene 12 with
complete stereoselectivity. A Mitsunobu reaction with
hydrazoic acid27 proved to be the best way to convert the
alcohol 12 into the azide 13 without interference from
the primary chloride. With the key ω-halo azidoalkene
13 in hand, the double-cyclization was attempted. Heat-
(18) (a) Gradnig, G.; Berger, A.; Grassberger, V.; Stuetz, A. E.;
Legler, G. Tetrahedron Lett. 1991, 32, 4889. (b) Liu, P. S.; Rogers, R.
S.; Kang, M. S.; Sunkara, P. S. Tetrahedron Lett. 1991, 32, 5853. See
also: (c) Herczegh, P.; Kova´cs, I.; Szila´gyi, L.; Sztaricskai, F.; Berecibar,
A.; Riche, C.; Chiaroni, A.; Olesker, A.; Lukacs, G. Tetrahedron 1995,
51, 2969. See also: (d) Marquart, A. L.; Podlogar, B. L.; Huber, E. W.;
Demeter, D. A.; Peet, N. P.; Weintraub, H. J . R.; Angelastro, M. R. J .
Org. Chem 1994, 59, 2092.
(19) Hamana, H.; Ikota, N.; Ganem, B. J . Org. Chem 1987, 52, 5492.
(20) Rassu, G.; Casiraghi, G.; Pinna, L.; Spannu, P.; Ulgheri, F.
Tetrahedron 1993, 49, 6627.
(21) Casiraghi, G.; Zanardi, F.; Rassu, G.; Spanu, P. Chem. Rev.
1995, 95, 1677.
(22) The data reported for (9R,9aR)-4 by Rassu, Casiraghi et al. are
not consistent with those obtained in our work (ref 13 and the current
work) or in Ganem’s work.19 Upon subsequent investigation, Casiraghi
et al. found that the critical annulation step in their work resulted in
the formation of both a pyrrolizidine and a quinolizidine derivative.
The quinolizidine reported in their paper as (9R,9aR)-4 is probably a
pyrrolizidine. The actual quinolizidine structure, not reported in their
paper, is (9S,9aS)-4. The stereochemistry of an earlier compound in
their sequence has now been reassigned based on X-ray crystal-
lography, thus explaining the S- rather than R-configuration at C(9)
and C(9a). We thank Professor Casiraghi for sharing this information
with us prior to publication.
(23) Pearson, W. H.; Lin, K.-C. Tetrahedron Lett. 1990, 31, 7571.
(24) Pearson, W. H.; Schkeryantz, J . M. J . Org. Chem. 1992, 57,
6783.
(25) Pearson, W. H.; Walavalkar, R. Tetrahedron 1994, 50, 12293.
(26) Tejima, S.; Fletcher, H. G. J . Org. Chem 1963, 28, 2999.
(27) Loibner, H.; Zbiral, E. Helv. Chim. Acta 1976, 59, 2100.

Ring-Expanded Analogs of Swainsonine
J . Org. Chem., Vol. 61, No. 16, 1996 5539
Sch em e 3. Syn th esis of th e ω-Ha lo Azid oa lk en e 13
Sch em e 4. Alter n a te Str a tegy In volvin g a
Red u ctive Dou ble-Alk yla tion
a n d Its Cycliza tion
Sch em e 5. Syn th esis of Qu in olizid in es (9S,9a R)-4
a n d (9R,9a S)-4 Usin g th e Red u ctive
Dou ble-Alk yla tion Meth od
ing 13 followed by transformations similar to those shown
in Scheme 2 failed to provide 14, instead producing the
pyridinium salt 16. Apparently, cyclization to 15 pro-
ceeded as planned, but aromatization by loss of 2 equiv
of benzyl alcohol rapidly ensued. A similar aromatization
was observed in the Polonovski reaction of castanosper-
mine tetraacetate N-oxide, where an iminium ion similar
to 15 was generated.28,29 All attempts at modifying the
cyclization of 13 (e.g., presence of mild bases, use of
different solvents, lower temperatures, or different pro-
tecting groups) failed to avoid the aromatization. Hence
we were forced to examine a slightly longer, but ulti-
mately practical alternative strategy.
stereoselective fashion. We recognized that the epoxi-
dation of these two alkenes might not be very stereose-
lective,33 but since it is not possible to predict which
diastereomer will be the most biologically active, we felt
this was not a disadvantage in this exploratory work.
Syn th esis of Qu in olizid in es (9S,9a R)-4 a n d (9R,-
9a S)-4 fr om th e cis-Ep oxy Azid es 21. Scheme 5 shows
the synthesis of two of the four possible diastereomers
of 4, namely (9S,9aR)-4 and (9R,9aS)-4. Epoxidation of
the alkene 13 with m-chloroperbenzoic acid afforded a
2.5:1 mixture of the diastereomeric cis-epoxides 21R and
21â.33,34 Without separation, the mixture of 21R/21â was
subjected to catalytic hydrogenolysis to generate the
Alter n a te Syn th etic Ap p r oa ch to th e
Qu in olizid in es 4 Usin g Ep oxid e Ch em istr y
While the ω-halo azidoalkene cyclization approach to
polyhydroxylated quinolizidines had failed, an alternate
plan using more traditional epoxide chemistry was
examined, as outlined in Scheme 4. Oxidation of 17 (X
) leaving group) to the epoxide 18 and reduction of the
azide to the primary amine 19 should afford the quino-
lizidine 20 after an intramolecular double alkylation. We
used such a reductive double-cyclization of an azido-
epoxide bearing a remote leaving group in our syntheses
of (-)-slaframine,30 (+)-7-epiaustraline,31 and (-)-7-epi-
alexine.31 Similar double-cyclizations have been reported
by others.16,32 The stereochemistry at C(9) and C(9a) of
4 will ultimately be determined by the geometry of the
alkene 17 and the diastereoselectivity of its epoxidation.
We hoped to synthesize the E- and Z-isomers of 17 in a
(32) For related one-pot double cyclizations using amino epoxides,
see: (a) Setoi, H.; Takeno, H.; Hashimoto, M. J . Org. Chem. 1985, 50,
3948. (b) Setoi, H.; Takeno, H.; Hashimoto, M. Tetrahedron Lett. 1985,
26, 4617. (c) Kim, Y. G.; Cha, J . K. Tetrahedron Lett. 1989, 30, 5721.
(d) Kim, N.-S.; Choi, J .-R.; Cha, J . K. J . Org. Chem 1993, 58, 7096. (e)
Lohray, B. B.; J ayamma, Y.; Chatterjee, M. J . Org. Chem 1995, 60,
5958. See also: (f) Poitout, L.; Le Merrer, Y.; Depezay, J .-C. Tetrahe-
dron Lett. 1994, 35, 3293. For one-pot double cyclizations using amines
with other electrophiles, see: (g) Ina, H.; Kibayashi, C. J . Org. Chem.
1993, 58, 52. (h) J irousek, M. R.; Cheung, A. W.-H.; Babine, R. E.;
Sass, P. M.; Schow, S. R.; Wick, M. M. Tetrahedron Lett. 1993, 34,
3671.
(28) Brown, R. F. C.; Collins, D. J .; Lagniton, L. M.; Smith, R. J .;
Wong, N. R. Aust. J . Chem. 1992, 45, 469.
(29) For the related aromatization of azasugars, see: Paulsen, H.
Angew. Chem., Int. Ed. Engl. 1966, 5, 495.
(30) (a) Pearson, W. H.; Bergmeier, S. C. J . Org. Chem. 1991, 56,
1976. (b) Pearson, W. H.; Bergmeier, S. C.; Williams, J . P. J . Org.
Chem. 1992, 57, 3977.
(33) For reports of similar epoxidations of allylic ethers, see: (a)
Wang, Z.; Schreiber, S. L. Tetrahedron Lett. 1990, 31, 31. (b) Erickson,
S. D.; Still, W. C. Tetrahedron Lett. 1990, 31, 4253. (c) Coutts, S. J .;
Wittman, M. D.; Kallmerten, J . Tetrahedron Lett. 1990, 31, 4301.
(31) Pearson, W. H.; Hines, J . V. Tetrahedron Lett. 1991, 32, 5513.

5540 J . Org. Chem., Vol. 61, No. 16, 1996
Pearson and Hembre
Sch em e 6. Syn th esis of Qu in olizid in es (9S,9a S)-4
a n d (9R,9a R)-4
Sch em e 7. Alter n a te Syn th esis of Qu in olizid in e
(9R,9a R)-4
25 in good yield after separation by column chromatog-
raphy.36 Selective monomesylation of the major diol 24
at the less-hindered secondary hydroxyl group was fol-
lowed by sodium hydride treatment, affording the trans-
epoxide 26 in moderate yield. The presence of DMSO
was found to be crucial for the success of the NaH-
promoted cyclization. A similar sequence on the minor
diol 25 produced the alternate trans-epoxide 27 contami-
nated with some 26, presumably due to a less regiose-
lective mesylation. Subjection of 26 to the reductive
cyclization conditions outlined above gave the quinolizi-
dine 28. Hydrogenolysis of the benzyl protecting groups
of 28 under acidic conditions afforded (9S,9aS)-4 after
ion-exchange chromatography. Reductive cyclization of
the mixture of 27 and 26 followed by separation gave the
quinolizidine 29. Deprotection as usual produced (9R,-
9aR)-4. Again, the relative stereochemistries at C(9) and
C(9a) in 28, 29, (9S,9aS)-4, and (9R,9aR)-4 were easily
1
assigned using H-NMR coupling constants.
A Selective Syn th esis of Qu in olizid in e (9R,9a R)-
4. fr om th e Diol 24. Unfortunately, the route shown
in Scheme 6 made it difficult to prepare significant
quantities of (9R,9aR)-4 for biological testing, since not
only was 25 the minor product of the osmylation, but the
closure of 25 to 27 was not very selective. Thus, we
developed an efficient way to convert the major osmyla-
tion product 24 into the minor quinolizidine (9R,9aR)-4
(Scheme 7). Selective monosilylation of 24 afforded 30.
Swern oxidation of 30 to the ketone followed by hydro-
genolysis of the azide led to the formation of the labile
cyclic imine 31. Sodium borohydride reduction of 31
followed by heating afforded the quinolizidine 32 in good
overall yield from 30. Acidic hydrogenolysis of the benzyl
groups of 32 also served to remove the silyl protecting
group, affording (9R,9aR)-4.
primary amines, which were cyclized to the separable
quinolizidines 22 and 23 upon heating. Hydrogenolysis
of the benzyl protecting groups under acidic conditions
afforded the desired quinolizidines (9S,9aR)-4 and (9R,-
9aS)-4 in excellent yield after ion-exchange chromatog-
raphy. The relative stereochemistries at C(9) and C(9a)
in 22, 23, (9S,9aR)-4, and (9R,9aS)-4 were easily assigned
using 1H-NMR coupling constants in these conformation-
ally well-behaved trans-decalin-like structures.
Syn th esis of Qu in olizid in es (9S,9a S)-4 a n d (9R,-
9a R)-4 fr om th e tr a n s-Ep oxy Azid es 26 a n d 27. In
order to prepare the remaining two C(9)/C(9a) diastere-
omers of 4, we required the trans-epoxides 26 and 27.
Attempts to prepare E-13 by other olefination methods
or by isomerization of Z-13 were unsuccessful, thus the
alkene epoxidation route was abandoned.35 Fortunately,
we were able to transform Z-13 into the desired trans-
epoxides 26 and 27 by the alternative route shown in
Scheme 6. Osmylation of 13 afforded the diols 24 and
(35) We were able to prepare a related trans alkene, ethyl (E)-
(6R,7S,8R)-9-azido-6,7,8-tris(benzyloxy)non-4-enoate, using an entirely
different synthesis. Epoxidation gave a 2:1 ratio of epoxides. The major
epoxide was transformed into (9S,9aS)-4, but this route offered no
significant advantage over the route shown in Scheme 6.
(36) Attempts to increase the stereoselectivity of the osmylation in
one direction or another using the Sharpless asymmetric dihydroxy-
lation (Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J .; J eong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.;
Xu, D.; Zhang, X.-L. J . Org. Chem. 1992, 57, 2768) failed due to poor
reactivity.
(34) Attempted J acobsen asymmetric epoxidation of 13 led to
recovered starting material (Zhang, W.; Loebach, J . L.; Wilson, S. R.;
J acobsen, E. N. J . Am. Chem. Soc. 1990, 112, 2801). Attempts to
synthesize 13 with a free allylic hydroxyl group were made in order to
attempt a Sharpless epoxidation, but the sequence became too cumber-
some to be practical.

Ring-Expanded Analogs of Swainsonine
J . Org. Chem., Vol. 61, No. 16, 1996 5541
distilled from sodium/benzophenone ketyl. Benzene, dichlo-
romethane, dimethyl sulfoxide, and triethylamine were dis-
tilled from calcium hydride. Dimethylformamide was distilled
from barium oxide at reduced pressure. Methanol and ethanol
were distilled from calcium oxide. Analytical thin layer
chromatography (TLC) was conducted on precoated silica gel
plates (Kieselgel 60 F254, 0.25 mm thickness, manufactured
by E. Merck & Co., Germany). For visualization, TLC plates
were either placed under ultraviolet light, or stained with
iodine vapor or phosphomolybdic acid solution. Elemental
analyses were performed by the University of Michigan
Department of Chemistry CHN/AA Services Branch. Assign-
Biologica l Scr een in g of th e Qu in olizid in es 4
The four diastereomers of 4 were screened for inhibi-
tory activity against a number of glycosidases.37 With
the exception of (9R,9aS)-4, which proved to be a rela-
tively weak inhibitor of R-L-fucosidase (IC50 ) 0.36 mM),
the quinolizidines were found to have little or no glycosi-
dase inhibitory activity. Less than 50% inhibition was
observed against R-mannosidase (jack bean), R-glucosi-
dase (bakers’ yeast), â-glucosidase (almond), amyloglu-
cosidase (Aspergillus niger), and R-L-fucosidase (bovine
epididymis) at concentrations up to 2 mM. For compari-
son, swainsonine (1) has been reported to inhibit the
R-mannosidase from jack bean by 50% at a concentration
of 2 µM, and deoxymannonojirimycin 2 inhibits this
enzyme by 50% at a concentration of 150 µM.14 The
quinolizidines 4 were also screened for inhibition of the
glycoprocessing enzymes glucosidase I, glucosidase II,
and mannosidase I,38 and for anticancer and anti-HIV
activity,39 but no promising activity was found. These
results contrast sharply with the glycosidase inhibitory
activity of quinolizidine analogs of castanospermine.18
We had hoped that the quinolizidines 4 would selec-
tively inhibit mannosidase I over mannosidase II, since
mannosidase I is effectively inhibited by chairlike aza-
sugars such as deoxymannojirimycin while mannosidase
II is known to be most strongly inhibited by compounds
that are able to adopt a ring-flattened conformation
resembling the proposed mannopyranosyl cation inter-
mediate which is encountered in the glycoside cleavage
process.14 While we were not able to test 4 against
mannosidase II directly, jack bean R-mannosidase is
usually a good indicator of mannosidase II activity.3
Given the preference of mannosidase II and jack bean
R-mannosidase for ring-flattened inhibitors, the failure
of the quinolizidines 4 to inhibit jack bean R-mannosidase
was not surprising due to their trans-decalin-like struc-
tures. Unfortunately, the quinolizidines 4 also failed to
inhibit mannosidase I, despite the fact that the chair
conformation of these structures mimics the mannopy-
ranose ground state conformation which appears to be
important for inhibition of this enzyme. This may
indicate that the mannosidase I binding site does not
tolerate the added steric bulk imposed by the second ring
of 4, or perhaps more likely, that mimicking the ground
state conformation of mannose is not sufficient for
mannosidase I inhibition. The greater conformational
flexibility of deoxymannojirimycin as compared to 4 may
explain the difference in the ability of these compounds
to inhibit mannosidase I.
1
ments in the H NMR spectra were made on the basis of two-
dimensional correlated off-resonance spectroscopy (COSY)
experiments. J -Modulated spin echo Fourier transform (JMOD)
13C NMR experiments are reported as (+) (for CH3 and CH)
or (-) (for CH2 and C) and are used as an alternative to off-
resonance decoupling experiments. High resolution mass
spectrometric (HRMS) measurements are accurate to within
2.2 ppm (electron impact, EI), 3.9 ppm (chemical ionization,
CI), or 3.3 ppm (fast-atom bombardment, FAB), based on
measurement of the performance of the mass spectrometer on
a standard organic sample. Flash column chromatography
was performed according to the general procedure described
by Still41 using flash grade Merck silica gel 60 (230-400 mesh).
Radial chromatography was performed on a Harrison Research
Chromatotron, using glass plates coated with Merck silica gel
60. Solvent was delivered by an FMI Lab Pump solvent
metering system. The enzymes R-mannosidase (from jack
bean), R-glucosidase (from bakers’ yeast), â-glucosidase (from
almonds), amyloglucosidase (from Aspergillus niger), and R-L-
fucosidase (from bovine epididymis), and the corresponding
p-nitrophenyl glycoside substrates were obtained from Sigma
Chemical Co. Enzyme inhibition was assayed colormetrically
by monitoring the release of p-nitrophenol from the appropri-
ate p-nitrophenyl glycoside substrate according to the proce-
dure described by Tropea et al.37
(Z)-(2R,3S,4R)-2,3,4-Tr is(ben zyloxy)-9-ch lor o-5-n on en -
1-ol (12). Potassium bis(trimethylsilyl)amide (13 mL of a 0.5
M solution in toluene, 6.5 mmol) was added to a suspension
of BrPh3P(CH2)4Cl (11)23 (2.802 g, 6.46 mmol) in THF (6.5 mL)
at 0 °C. After 30 min, the dark red-orange solution was cooled
to -78 °C, and 2,3,4-tri-O-benzyl-D-arabinopyranose (10)26
(1.076 g, 2.55 mmol) in THF (5 mL) was added. The resulting
yellow solution was allowed to warm slowly to room temper-
ature. After 6 h, the reaction was quenched with excess
acetone (5 mL) and diluted with ether (100 mL). The resulting
precipitate was removed by filtration through a bed of Celite,
rinsing with ether (50 mL). The filtrate was washed with
water (50 mL), saturated aqueous NaHCO3 (50 mL), and brine
(50 mL) and then dried (Na2SO4), filtered, and concentrated.
Chromatography (6:1 hex/EtOAc) gave 895 mg (71%) of the
title compound as a pale yellow oil. Rf ) 0.52 (2:1 hex/
EtOAc): [R]23D ) -14.0° (c 0.98, CHCl3); 1H NMR (CDCl3, 300
MHz) δ 7.4-7.2 (m, 15H), 5.58 (m, 2H), 4.73 (s, 2H), 4.47 (ABq,
J ) 11.9 Hz, ∆ν ) 91.1 Hz, 2H), 4.43 (ABq, J ) 11.4 Hz, ∆ν )
36.9 Hz, 2H), 4.42 (dd, J ) 3.5, 8.2 Hz, 1H), 3.80 (broad s,
2H), 3.69 (m, 2H), 3.45 (t, J ) 6.4 Hz, 2H) 2.30-2.00 (m, 3H),
1.84-1.74 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 138.7, 138.5,
132.7, 129.5, 128.5, 128.4, 128.2, 128.0, 127.8, 127.8, 127.7,
127.6, 82.3, 79.6, 75.1, 74.8, 72.0, 70.5, 61.5, 44.2, 32.4, 25.3;
Exp er im en ta l Section
Gen er a l Meth od s. All commercial reagents (if liquid) were
distilled prior to use. All other solid reagents were used as
obtained. Hydrazoic acid solutions were prepared according
to Wolff.40 Ca u tion : Hydrazoic acid should be handled with
extreme care. All work involving hydrazoic acid solutions were
carried out in an efficient fume hood. The solution was
transferred vial cannula, and any excess hydrazoic acid was
quenched by the addition of 10% NaOH. Tetrahydrofuran was
IR (CDCl3) 3580 (m), 3011 (s), 2873 (s), 1454 (s), 1062 (s) cm-1
;
MS (CI NH3) m/ z (rel intensity) 512 [(M + NH4)+, 5], 495 [(M
+ H)+, 3], 279 (21), 108 (43), 91 (100); HRMS calcd for
C30H35O4ClH [(M + H)+] 495.2302, found 495.2276. Anal.
Calcd for C30H35O4Cl: C, 72.79 H, 7.13. Found: C, 72.93; H,
7.36.
(Z)-(2R,3S,4R)-1-Azid o-2,3,4-t r is(b en zyloxy)-9-ch lor o-
5-n on en e (13). Hydrazoic acid40 (1.03 mL of a 1.2 M solution
in benzene, 1.24 mmol) was added to a solution of 12 (558 mg,
1.13 mmol) and PPh3 (325 mg, 1.24 mmol) in benzene (5 mL)
at 5 °C. Diethyl azodicarboxylate (216 mg, 1.24 mmol) was
added in a dropwise fashion, and the solution was allowed to
warm to room temperature (Ph3PO precipitation was ob-
(37) Tropea, J . E.; Molyneux, R. J .; Kaushal, G. P.; Pan, Y. T.;
Mitchell, M.; Elbein, A. D. Biochemistry 1989, 28, 2027.
(38) We thank Prof. Alan D. Elbein (University of Arkansas) for the
results of screening against the glucosidase I and II and mannosidase
I.
(39) The results of anti-HIV and anticancer testing were provided
by the National Cancer Institute Developmental Therapeutics Pro-
gram. Only (9S,9aR)-4 and (9R,9aS)-4 were tested in these screens.
(40) Wolff, H. In Organic Reactions; Adams, R., Ed.; Wiley: New
York, 1946; Vol. 3, pp 307-336.
(41) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

5542 J . Org. Chem., Vol. 61, No. 16, 1996
Pearson and Hembre
served). After 25 min, the solvent was removed and the
product was separated from the Ph3PO by washing the residue
with hexane. Chromatography (20:1 hex/EtOAc) gave 490 mg
of the title compound (84%) as a pale yellow oil. Rf ) 0.32
azido-epoxides 21R and 21â (2.5:1 mixture of diastereomers,
1.28 g, 2.38 mmol) in EtOH/EtOAc (1:1, 25 mL). The flask
was evacuated (aspirator) and purged with hydrogen three
times. The heterogeneous mixture was stirred at room tem-
perature under a balloon of hydrogen for 12 h, and then the
hydrogen was evacuated and the mixture was filtered through
a plug of Celite, rinsing with EtOH (10 mL). The filtrate was
transferred to a round bottom flask, K2CO3 (1.30 g) was added,
and the solution was warmed to reflux. After 12 h, the mixture
was cooled to room temperature, poured into brine, and
extracted with CH2Cl2 (3 × 20 mL). The combined organic
layers were dried (Na2SO4) and concentrated. Radial chro-
matography (4 mm silica gel plate, 1:1 to 1:10 hex/EtOAc
gradient) provided 612 mg (54%) of the quinolizidine 22 as a
pale yellow oil, followed by 250 mg (23%) of the quinolizidine
23, also as a pale yellow oil. The stereochemistry of each
quinolizidine was assigned by 1H NMR coupling constant
analysis (see supporting information). Data for 22 (major):
(10:1 hex/EtOAc); [R]23 ) -11.0° (c 1.51, CHCl3); 1H NMR
D
(CDCl3, 300 MHz) δ 7.2-7.5 (m, 15H), 5.58 (m, 2H), 4.69 (ABq,
J ) 11.4 Hz, ∆ν ) 13.5 Hz, 2H), 4.48 (ABq, J ) 11.2 Hz, ∆ν )
47.5 Hz, 2H), 4.46 (ABq, J ) 11.8 Hz, ∆ν ) 91.4 Hz, 2H), 4.39
(m, 1H), 3.83 (dt, J ) 3.0, 5.7 Hz, 1H), 3.64 (dd, J ) 4.0, 5.5
Hz, 1H), 3.47 (m, 4 H), 2.0-2.3 (m, 2H), 1.80 (m, 2H); 13C NMR
(CDCl3, 90 MHz) δ 138.3, 137.8, 132.9, 130.0, 129.1, 128.4,
128.3, 128.1, 127.9, 127.8, 127.7, 127.6, 126.1, 120.23, 120.2,
81.4, 78.7, 74.9, 73.9, 72.4, 70.2, 51.48, 44.2, 32.1, 25.1; IR
-1
(neat) 3062 (w), 3030 (m), 2866 (m), 2100 (s), 1454 (m) cm
;
MS (CI NH3) m/z (rel intensity) 537 [(M + NH4)+, 10], 492 (60),
384 (63), 348 (70), 240 (100), 150 (43), 108 (44), 91 (77); HRMS
calcd for C30H34N3O3Cl‚NH4 [(M + NH4)+] 537.2632, found
537.2632.
Rf ) 0.18 (1:1 hex/EtOAc); [R]23 ) -11.6° (c 1.09, CHCl3); 1H
1-(Ben zyloxy)-6,7,8,9-tetr a h yd r oqu in olizid in iu m Ch lo-
r id e (16). A degassed (three freeze-evacuate-thaw cycles)
solution of 13 (30 mg, 0.08 mmol) in deuterated solvent (CDCl3
or C6D6, 0.75 mL) was heated at 90 °C in a sealed NMR tube.
The reaction progress was monitored periodically by 1H NMR.
After 12.5 h (C6D6) or 15 h (CDCl3), the starting material
resonances had disappeared and had been replaced by reso-
nances for 16 and benzyl alcohol. This material was not
purified. 1H NMR (CDCl3, 360 MHz) δ 8.95 (d, J ) 5.9 Hz,
1H, H4), 7.90 (d, J ) 8.5 Hz, 1H, H2), 7.75 (dd, J ) 6.1, 8.6 Hz,
1H, H3), 7.2-7.5 (m, 20 H), 5.23 (s, 2H, OCH2Ph), 4.83 (t, J )
5.8 Hz, 2H, H6), 4.68 (s, 6H, PhCH2OH), 3.09 (t, J ) 6.6 Hz,
2H, H9), 2.08 (m, 2H), 1.95 (m, 2H); 13C NMR (CDCl3, 90 MHz)
δ 141.3 (PhCH2OH), 137.5, 134.1, 130.0, 128.9, 128.3 (PhCH2-
OH), 127.7, 127.3 (PhCH2OH), 126.9 (PhCH2OH), 126.0, 125.5,
124.9, 120.1, 72.0, 64.9 (PhCH2OH), 56.4, 23.2, 21.0, 17.3.
(2R,3R,4R,5S,6S)-1-Azido-2,3,4-tr is(ben zyloxy)-9-ch lor o-
5,6-ep oxyn on a n e (21r) a n d (2R,3R,4R,5R,6R)-1-Azid o-
2,3,4-tr is(ben zyloxy)-9-ch lor o-5,6-ep oxyn on a n e (21â). m-
Chloroperbenzoic acid (1.160 g, technical grade, 0.928 g of pure
oxidant, 5.38 mmol) was added to a cold (0 °C) solution of 13
(1.007 g, 1.94 mmol) in CH2Cl2 (8 mL), and the resulting
mixture was allowed to warm slowly to room temperature.
After 12 h, the solution was diluted with CH2Cl2 (15 mL),
washed with 10% NaOH (2 × 20 mL), 15% NH4OH (2 × 20
mL), and brine (20 mL), and then dried (Na2SO4) and concen-
trated. Chromatography (6:1 hex/EtOAc) gave 910 mg (88%)
of an inseparable mixture of R and â isomers (2.5:1 based on
1H NMR integration) as a colorless oil. The stereochemical
assignment was made by conversion to the quinolizidines (9S,-
9aR)-4 and (9R,9aS)-4 (see below). Rf ) 0.22 (6:1 hex/EtOAc);
1H NMR (CDCl3, 300 MHz) major isomer (21R): δ 7.1-7.4 (m,
15H), 4.69 (ABq, J ) 11.9 Hz, ∆ν ) 105.9 Hz, 2H), 4.65 (ABq,
J ) 11.6 Hz, ∆ν ) 54.0 Hz, 2H), 4.34 (ABq, J ) 11.2 Hz, ∆ν )
97.2 Hz, 2H), 3.81 (m, 1H), 3.3-3.7 (m, 6H), 3.10 (dd, J ) 4.5,
8.0 Hz, 1H), 2.48 (ddd, J ) 3.4, 4.4, 9.2 Hz, 1H), 1.7-2.1 (m,
2H), 1.5 (m, 1H), 1.22 (m, 1H); minor isomer (21â): δ 7.1-7.4
(m, 15H), 4.76 (ABq, J ) 11.2 Hz, ∆ν ) 27.1 Hz, 2H), 4.52
(ABq, J ) 11.4 Hz, ∆ν ) 74.8 Hz, 2H), 4.49 (ABq, J 11.7 Hz,
∆ν ) 50.2 Hz, 2H), 3.92 (ddd, J ) 2.7, 4.6, 7.5 Hz, 1H), 3.81
(m, 1H), 3.3-3.7 (m, 5H), 3.19 (dd, J ) 3.9, 8.5 Hz, 1H), 3.06
(m, 1H), 1.7-2.1 (m, 3H), 1.4 (m, 1H); 13C NMR (CDCl3, 90
MHz) δ 138.0 (â), 138.0 (â), 137.9 (â), 137.7 (R), 137.5 (R), 137.3
(R), 128.9, 128.5, 128.9, 128.8, 128.2, 128.1, 127.9, 127.8, 127.8,
127.7, 127.6, 79.6 (â), 78.2 (R), 78.1 (R), 77.9 (â), 76.3 (R), 75.0
(â), 74.3 (â), 74.0 (R), 72.5 (R), 72.3 (â), 72.1 (â), 71.6 (R), 58.2
(R), 57.9 (â), 55.5 (â), 53.7 (R + â), 50.8 (R), 44.5 (â), 44.2 (R),
30.1 (R), 29.8 (â), 25.6 (R), 25.6 (â); IR (CDCl3) 2928 (w), 2868
(w), 2104 (s), 1455 (m), 1293 (m) cm-1; MS (CI with NH3) m/ z
(rel int.) 553 ([M + NH4]+, 16), 508 (52), 474 (36), 384 (15),
120 (34), 108 (53), 91 (100); HRMS (CI with NH3) calcd for
C30H34ClN3O4‚NH4+: 553.2582, found 553.2559. Anal. Calcd
for C30H34ClN3O4: C, 67.21, H, 6.39; N, 7.84. Found: C, 67.05;
H, 6.60; N, 8.18.
D
NMR (CDCl3, 300 MHz) δ 7.2-7.5 (m, 15H), 4.90 (ABq, J )
10.6 Hz, ∆ν ) 75.5 Hz, 2H), 4.77 (s, 2H), 4.65 (ABq, J ) 12.0
Hz, ∆ν ) 14.0 Hz, 2H), 4.17 (t, J )9.6 Hz, 1H, H1), 4.10 (broad
d, J )7.8 Hz, 1H, H9), 3.79 (broad s, 1H, H3), 3.43 (dd, J )
3.1, 9.8 Hz, 1H, H2), 2.97 (dd, J ) 3.2, 12.7 Hz, 1H, H4eq), 2.72
(m, 1H, H6eq), 2.67 (d, J ) 10.7 Hz, 1H, D2O exchangeable),
1.84-2.00 (m, 5H), 1.30-1.55 (m, 2H); 13C NMR (CDCl3, 90
MHz, J MOD) δ 138.9 (-), 138.8 (-), 138.6 (-), 128.3 (+), 128.1
(+), 128.1 (+), 127.8 (+), 127.6 (+), 127.5 (+), 83.7 (+), 75.7
(-), 75.3 (+), 71.8 (-), 71.4 (+), 71.3 (-), 69.2 (+), 63.7 (+),
56.7 (-), 55.6 (-), 30.7 (-), 19.4 (-); IR (CDCl3) 3546 (w), 3066
(m), 3032 (m), 2946 (s), 2871 (s), 2813 (m) cm-1; MS (EI, 70
eV) m/z (rel intensity) 474 (M+, 2), 382 (28), 260 (24), 91 (100);
HRMS calcd for C30H35NO4H 474.2644, found 474.2631. Data
for 23 (minor): Rf ) 0.53 (10:1 CHCl3/MeOH); [R]23 ) -3.5°
D
1
(c 1.33, CHCl3); H NMR (CDCl3, 300 MHz) δ 7.25-7.45 (m,
13 H), 7.05-7.20 (m, 2H), 4.70 (ABq, J ) 12.4 Hz, ∆ν )71.3
Hz, 2H), 4.52 (ABq, J ) 12.3 Hz, ∆ν )36.1 Hz, 2H), 4.40 (d, J
) 1.8 Hz, 1H, D2O exchangeable), 4.35 (ABq, J ) 11.3 Hz, ∆ν
) 24.9 Hz, 2H), 3.98 (ddd, J ) 2.7, 4.6, 11.4 Hz, 1H, H3), 3.87
(m, 1H, H9), 3.85 (broad t, J ) 2.9 Hz, 1H, H2), 3.67 (dd, J )
2.4, 3.4 Hz, 1H, H1), 2.92 (m, 1H, H6eq), 2.89 (dd, J ) 4.5, 10.3
Hz, 1H, H4eq), 2.48 (t, J ) 10.8, 1H, H4ax), 2.24 (broad s, 1H,
H9a), 2.05-2.19 (m, 2H, H6ax and H7eq), 1.75-1.87 (m, 1H, H8eq),
1.30-1.45 (m, 2H, H7ax and H8ax); 13C NMR (CDCl3, 90 MHz,
J MOD) δ 138.6 (-), 138.5 (-), 136.3 (-), 128.7 (+), 128.6 (+),
128.4 (+), 127.9 (+), 127.8 (+), 127.6 (+), 127.6 (+), 80.7 (+),
73.5 (+), 73.1 (-), 72.5 (-), 71.7 (+), 71.2 (-), 68.7 (+), 60.7
(+), 56.9 (-), 53.8 (-), 31.6 (-), 19.2 (-); IR (CDCl3) 3477 (br
m), 3032 (m), 2945 (s), 1454 (m) cm-1; MS (CI, NH3) m/ z (rel
intensity) 474 [(M + H)+, 100], 382 (21), 260 (12), 91 (19);
HRMS calcd for C30H35NO4H 474.2644, found 474.2627.
(1R ,2R ,3R ,9S ,9a R )-1,2,3,9-T e t r a h y d r o x y q u in o lizi-
d in e [(9S,9a R)-4)]. Palladium on carbon (10%, 125 mg) was
added to a solution of the quinolizidine 22 (277 mg, 0.586
mmol) in 1% methanolic HCl (25 mL), and the resulting
heterogeneous mixture was shaken in a Paar hydrogenation
apparatus under hydrogen (45 psi). After 48 h, the hydrogen
was evacuated and the mixture was filtered through a bed of
Celite, rinsing with methanol (10 mL). The filtrate was
concentrated, and the residue was dissolved in water (1 mL)
and applied to a Dowex 1 × 8 OH- ion exchange column,
eluting with water. The I2-staining fractions were combined
and concentrated. Chromatography (50:10:1 CHCl3/MeOH/
NH4OH) provided 118 mg (99%) of the title compound as a
pale yellow oil. The stereochemistry was assigned by 1H NMR
coupling constant analysis (see supporting information). Rf
) 0.11 (4.5:1 CHCl3/MeOH); [R]23 ) -26.2° (c 1.07, EtOH);
D
1H NMR (CD3OD, 300 MHz) δ 4.09 (broad s, 1H, H9), 3.81 (dt,
J ) 1.6, 3.3 Hz, 1H, H3), 3.78 (t, J ) 9.6 Hz, 1H, H1), 2.87 (dd,
J ) 3.3, 12.3 Hz, 1H, H4eq), 2.80 (broad d, J ) 8.8 Hz, 1H,
H6eq), 2.24 (broad d, J ) 12.1 Hz, 1H, H4ax), 1.84-2.05 (m, 3H,
H7eq, H6ax and H8eq) 1.72 (broad d, J ) 9.3 Hz, 1H, H9a), 1.35-
1.49 (m, 2H, H7ax and H8ax); 13C NMR (CD3OD, 90 MHz, J MOD)
δ 76.8 (+), 70.4 (+), 69.9 (+), 69.0 (+), 64.6 (+), 61.0 (-), 56.8
(-), 32.2 (-), 20.5 (-); IR (KBr) 3501 (s), 3342 (s), 2926 (s),
2797 (m), 2757 (m), 1430 (m) cm-1; MS (EI, 70eV) m/ z (rel
(1R,2R,3R,9S,9a R)-1,2,3-Tr i-O-b en zyl-1,2,3,9-t et r a h y-
d r oxyqu in olizid in e (22) a n d (1R,2R,3R,9R,9a S)-1,2,3-Tr i-
O-ben zyl-1,2,3,9-tetr a h yd r oxyqu in olizid in e (23). Palla-
dium on carbon (10%, 130 mg) was added to a mixture of the

Ring-Expanded Analogs of Swainsonine
J . Org. Chem., Vol. 61, No. 16, 1996 5543
intensity) 203 (M+, 10), 186 (29), 185 (52), 146 (57), 113 (33),
99 (100), 96 (44), 72 (57); HRMS calcd for C9H17NO4 203.1158,
found 203.1164. Anal. Calcd for C9H17NO4HCl: C, 45.10; H,
7.58; N, 5.84. Found: C, 45.11; H, 7.44; N, 5.55.
(2R,3R,4R,5R,6S)-1-Azido-2,3,4-tr is(ben zyloxy)-9-ch lor o-
5,6-ep oxyn on a n e (26). Methanesulfonyl chloride (26 mg, 18
µL, 0.23 mmol) was added to a cold (-50 °C) solution of the
major diol 24 from above (115 mg, 0.21 mmol) and triethy-
lamine (38 µL, 27 mg, 0.27 mmol) in CH2Cl2 (1.1 mL). The
mixture was stirred for 1 h at -50 °C, then warmed slowly to
0 °C and quenched by the addition of water (5 mL). The
resulting mixture was extracted with CH2Cl2 (3 × 5 mL), and
the organic extracts were dried (MgSO4) and concentrated to
give 112 mg of the crude monomesylate. (1H NMR of the crude
residue shows the disappearance of the broad 1H OH singlet
at δ 2.32 and appearance of a sharp mesylate 3H methyl
singlet at δ 2.89.) The crude monomesylate was dissolved in
THF/DMSO (10:1, 5 mL) and cooled to 0 °C. Sodium hydride
(17 mg of a 60% suspension in mineral oil, 10 mg of pure
hydride, 0.42 mmol) was added, and the mixture was allowed
to warm to room temperature. After 12 h the reaction was
quenched by addition of saturated aqueous NH4Cl (2 mL), and
the mixture was diluted with water (10 mL) and extracted with
Et2O (2 × 15 mL). The combined organic layers were washed
with brine (10 mL), dried (MgSO4), and concentrated. Chro-
matography (10:1 to 6:1 hex/EtOAc gradient) afforded 63 mg
(56%) of trans epoxide 26 as a pale yellow oil. Rf ) 0.55 (4:1
(1R ,2R ,3R ,9R ,9a S )-1,2,3,9-T e t r a h y d r o x y q u in o lizi-
d in e [(9R,9a S)-4)]. Palladium on carbon (10%, 55 mg) was
added to a solution of the quinolizidine 23 (121 mg, 0.256
mmol) in 1% methanolic HCl (10 mL), and the resulting
heterogeneous mixture was shaken in a Paar hydrogenation
apparatus under hydrogen (45 psi). After 48 h, the hydrogen
was evacuated, and the mixture was filtered through a bed of
Celite, rinsing with methanol (10 mL). The filtrate was
concentrated, and the residue was dissolved in water (1 mL)
and applied to a Dowex 1 × 8 OH- ion exchange column,
eluting with water. The I2-staining fractions were combined
and concentrated, providing a white solid that was recrystal-
lized from EtOH to afford 48 mg (92%) of the title compound.
The stereochemistry was assigned by 1H NMR coupling
constant analysis (see supporting information). Rf ) 0.15 (2:1
CHCl3/MeOH); [R]23 ) +22.7° (c 0.73, MeOH); mp 225-230
D
1
°C dec; H NMR (CD3OD, 300 MHz) δ 4.09 (broad s, 1H, H9),
4.09 (ddd, J ) 3.2, 4.9, 11.2 Hz, 1H, H3), 3.95 (dd, J ) 1.8, 3.7
Hz, 1H, H1), 3.79 (t, J ) 3.3 Hz, 1H, H2), 2.85 (m, 1H, H6eq),
2.61 (dd, J ) 4.8, 10.5 Hz, 1H, H4eq), 2.31 (t, J )11.0 Hz, 1H,
H4ax), 2.24 (t, J ) 1.7 Hz, 1H, H9a), 2.01-2.16 (m, 2H, H6ax
and H7eq), 1.82 (m, 1H, H8eq), 1.4-1.6 (m, 2H, H7ax and H8ax);
13C NMR (CD3OD, 90 MHz) δ 76.2, 71.9, 70.8, 66.2, 61.1, 57.7,
57.2, 33.1, 20.3; IR (KBr) 3507 (s), 3332 (s), 2941 (s), 2832 (m),
2668 (m), 1443 (m) cm-1; MS (EI, 70 eV) m/ z (rel intensity)
203 (M+, 31), 185 (100), 168 (45), 146 (44), 113 (34), 99 (55),
96 (30), 72 (33); HRMS calcd for C9H17NO4 203.1158, found
203.1154. Anal. Calcd for C9H17NO4: C, 53.20; H, 8.45; N,
6.89. Found: C, 52.95; H, 8.28; N, 6.62.
hex/EtOAc): [R]23 ) 0.0° (c 1.52, CHCl3); 1H NMR (CDCl3,
D
300 MHz) δ 7.2-7.4 (m, 15 H), 4.72 (ABq, J AB ) 12.0 Hz, 2H),
4.63 (d, J ) 11.3 Hz, 1H), 4.52 (ABq, J AB ) 11.9 Hz, 2H), 4.41
(d, J ) 11.3 Hz, 1H), 3.8-3.9 (m, 2H), 3.64 (dd, J ) 13.3, 2.3
Hz, 1H), 3.52 (dt, J ) 6.5, 2.8 Hz, 2H), 3.41 (dd, J ) 13.3, 4.5
Hz, 1H), 3.36 (dd, J ) 6.9, 2.6 Hz, 1H), 2.84 (dd, J ) 6.9, 2.2
Hz, 1H), 2.78 (ddd, J ) 7.2, 3.7, 2.2 Hz, 1H), 1.83 (m, 2H),
1.68 (m, 1H), 1.39 (m, 1H); 13C NMR (CDCl3, 90 MHz) δ 138.2,
137.9, 137.6, 128.5, 128.4, 128.1, 127.9, 127.8, 79.0, 78.5, 78.1,
74.9, 73.0, 72.3, 58.5, 56.6, 50.7, 44.4, 28.8, 28.8; IR (neat) 3030
(m), 2914 (m), 2868 (m), 2100 (s), 1454 (m) cm-1; MS (CI, NH3)
(2R,3R,4R,5R,6R)-1-Azido-2,3,4-tr is(ben zyloxy)-9-ch lor o-
5,6-d ih yd r oxyn on a n e (24) a n d (2R,3R,4R,5S,6S)-1-Azid o-
2,3,4-tr is(ben zyloxy)-9-ch lor o-5,6-d ih yd r oxyn on a n e (25).
Osmium tetraoxide (0.180 mL of a 4% w/w solution in water,
7 mg, 0.03 mmol) was added to a solution of the azido-alkene
13 (300 mg, 0.58 mmol) and N-methylmorpholine N-oxide (118
mg, 0.87 mmol) in THF/t-BuOH (5:2, 3 mL). After 72 h,
sodium bisulfite (3 mL of a 10% solution) was added, and the
mixture was stirred for an additional 30 min and then diluted
with water (15 mL) and extracted with CH2Cl2 (3 × 25 mL).
The combined organic layers were dried (MgSO4) and concen-
trated. Chromatography (6:1 to 3:1 hex/EtOAc gradient) gave
40 mg (13%) of minor diastereomer 25 as a colorless oil
followed by 220 mg (69%) of major diastereomer 24 as a
colorless oil. Stereochemical assignments were made by
conversion to the quinolizidines (9S,9aS)-4 and (9R,9aR)-4 (see
below). Data for 25 (minor): Rf ) 0.40 (3:1 hex/EtOAc): 1H
NMR (CDCl3, 300 MHz) δ 7.2-7.4 (m, 15 H), 4.65-4.78 (m,
4H), 4.57 (d, J )11.3 Hz, 1H), 4.52 (d, J ) 11.3 Hz, 1H), 3.96
(dd, J ) 6.0, 4.3 Hz, 1H), 3.83 (m, 2H), 3.50 (m, 6H), 2.78 (d,
J ) 7.7 Hz, 1H), 1.90 (m, 1H), 1.75 (m, 2H), 1.66 (d, J ) 6.7
Hz, 1H), 1.39 (m, 1H); 13C NMR (CDCl3, 90 MHz, J MOD) δ
137.9 (-), 137.6 (-), 137.4 (-), 128.6 (+), 128.5 (+), 128.4 (+),
128.3 (+), 128.2 (+), 128.1 (+), 128.0 (+), 128.0 (+), 127.9 (+),
79.6 (+), 78.6 (+), 74.2 (-), 74.1 (-), 72.8 (+), 72.5 (-), 72.2
(+), 51.1 (-), 45.1 (-), 30.8 (-), 28.7 (-); IR (neat) 3462 (br,
m), 3030 (m), 2923 (m), 2866 (m), 2100 (s), cm-1; MS (CI, NH3)
m/ z (rel int) 571 ([M + NH4]+, 16), 535 (59), 490 (100), 472
(24), 402 (25), 184 (23), 120 (20), 106 (82); HRMS calcd for
C30H3635ClN3O5NH4 571.2687, found 571.2674. Data for 24
m/ z (rel int) 553 ([M + NH4]+, 41), 508 (100), 474 (53), 472
35
(50), 400 (18), 108 (44), 91 (34); HRMS calcd for C30H34
-
ClN3O4NH4 553.2582, found 553.2574. Anal. Calcd for
C30H34ClN3O4: C, 67.22, H, 6.39; N, 7.84. Found: C, 67.13;
H, 6.43; N, 7.88.
(1R,2R,3R,9S,9a S)-1,2,3-Tr i-O-b en zyl-1,2,3,9-t et r a h y-
d r oxyqu in olizid in e (28). Palladium on carbon (10%, 5 mg)
was added to a solution of the azido-epoxide 26 (30 mg, 0.06
mmol) in EtOH/EtOAc (1:1, 1 mL), and the flask was evacu-
ated (aspirator) and purged with hydrogen three times. The
resulting heterogeneous mixture was stirred under a balloon
of hydrogen for 36 h, and then the hydrogen was evacuated
and the mixture was passed through a plug of Celite, rinsing
wth EtOH (3 mL). The filtrate was transferred to a round-
bottom flask, potassium carbonate (45 mg) was added, and the
resulting mixture was heated at reflux for 12 h, cooled, poured
into water (10 mL), and extracted with CH2Cl2 (3 × 5 mL).
The combined organic layers were dried (Na2SO4) and con-
centrated. Chromatography (50:1 CHCl3/MeOH) provided 20.5
mg (77%) of the title compound as a pale yellow oil. The
1
stereochemistry was assigned by H NMR coupling constant
analysis (see supporting information). Rf ) 0.20 (50:1
CHCl3/MeOH): [R]23 ) +28.4° (c 1.41, CHCl3); 1H NMR
D
(CDCl3, 300 MHz) δ 7.25-7.45 (m, 13H), 7.2 (m, 2H), 4.72 (d,
J ) 12.4 Hz, 1H), 4.58 (d, J ) 12.2 Hz, 1H), 4.56 (d, J ) 12.4
Hz, 1H), 4.51 (d, J ) 12.2 Hz, 1H), 4.51 (d, J ) 12.2 Hz, 1H),
4.30 (d, J ) 12.2 Hz, 1H), 3.94 (ddd, J ) 12.0, 9.8, 4.4 Hz, 1H)
2.84 (dd, J ) 4.5, 10.1, Hz, 1H), 2.78 (br d, J ) 11.4 Hz, 1H),
2.51 (t, J ) 10.7 Hz, 1H), 2.01 (m, 3H), 1.61 (m, 2H), 1.22 (m,
1H), 0.81 (m, 1H), 0.72 (br s, 1H, D2O exchangeable); 1H NMR
(C6D6, 300 MHz) δ 7.0-7.5 (m, 15H), 4.75 (ABq, J AB) 12.2
Hz, ∆ν ) 58.5 Hz, 2H), 4.48 (ABq, J AB) 11.8 Hz, ∆ν ) 18.4
Hz, 2H), 4.38 (ABq, J AB) 12.1 Hz, ∆ν ) 27.8 Hz, 2H), 4.19
(ddd, J ) 2.4, 4.4, 10.9 Hz, 1H, H3), 4.15 (t, J ) 2.6 Hz, 1H,
H1), 3.98 (t, J ) 2.9 Hz, 1H, H2), 3.82 (ddd, J ) 4.5, 9.0, 11.3
Hz, 1.H, H9), 2.89 (dd, J ) 4.6, 10.0 Hz, 1H, H4eq), 2.80 (t, J )
10.5 Hz, 1H, H4ax), 2.61 (br d, J ) 11.0 Hz, 1H, H6eq), 2.24 (dd,
J ) 2.0, 9.0 Hz, 1H, H9a), 1.90 (dt, J ) 2.5, 11.8 Hz, 1H, H6ax),
1.76 (m, 1H, H8eq), 1.52 (m, 1H, H7), 1.28 (m, 1H, H7), 1.06 (m,
1H, H8ax ); 13C NMR (CDCl3, 90 MHz) δ 138.8, 137.7, 138.1,
128.8, 128.6, 128.3, 128.3, 128.2, 127.9, 127.6, 74.0, 72.7, 72.6,
72.4, 71.1, 66.7, 65.6, 55.8, 53.3, 33.5, 23.2; IR (neat) 3420 (m),
(major): Rf ) 0.30 (3:1 hex/EtOAc): [R]23 ) +4.3° (c 1.17,
D
CHCl3); 1H NMR (CDCl3, 360 MHz) δ 7.2-7.4 (m, 15 H), 4.70
(d, J ) 11.3 Hz, 1H), 4.69 (ABq, J AB ) 11.3 Hz, 2H), 4.51 (ABq,
J AB ) 11.4 Hz, 2H), 4.49 (d, J ) 11.3 Hz, 1H), 4.01 (dd, J )
4.9, 3.3 Hz, 1H), 3.83 (dt, J ) 5.7, 3.0 Hz, 1H), 3.70 (m, 3H),
3.5-3.6 (m, 4H), 2.98 (d, J ) 4.7 Hz, 1H), 2.33 (br s, 1H), 1.9-
2.0 (m, 1H), 1.65-1.8 (m, 2H), 1.4-1.5 (m, 1H); 13C NMR
(CDCl3, 90 MHz) δ 137.3, 137.2, 137.2, 128.6, 128.5, 128.3,
128.2, 128.1, 128.1, 79.5, 78.4, 78.0, 73.9, 73.8, 72.8, 72.1, 51.2,
45.2, 29.7, 28.8; IR (neat) 3448 (br m), 3030 (w), 2922 (m), 2866
(m), 2100 (s) cm-1; MS (DCI, NH3) m/ z (rel int) 571 ([M +
NH4]+, 11), 535 (40), 490 (100), 402 (25), 106 (28); HRMS calcd
for C30H36N3O535ClNH4 571.2687, found 571.2679.

5544 J . Org. Chem., Vol. 61, No. 16, 1996
Pearson and Hembre
3062 (m), 3029 (m), 2926 (s), 2857 (s), 1454 (s) cm-1; MS (EI,
70 eV) m/ z (rel int) 473 (M+, 2), 382 (48), 260 (29), 149 (18),
91 (100), 57 (18); HRMS calcd for C30H35NO4 473.2566, found
473.2547.
mixture was heated at reflux for 12 h. The mixture was cooled,
poured into brine (15 mL), and extracted with CH2Cl2 (3 × 10
mL). The resultant extracts were dried (Na2SO4) and concen-
trated. Chromatography (2:1 hex/EtOAc) provided 10 mg
(20%) of the quinolizidine 28 (see above) as a pale yellow oil
followed by 28 mg (54%) of the title compound 29 as a pale
yellow oil. The stereochemistry of 29 was assigned by 1H NMR
coupling constant analysis (see supporting information). Data
(1R,2R,3R,9S,9a S)-1,2,3,9-Tet r a h yd r oxyq u in olizid in e
[(9S,9a S)-4]. Palladium on carbon (10%, 10 mg) was added
to a solution of the quinolizidine 28 (22 mg, 0.047 mmol) in
1% methanolic HCl (2 mL) The flask was evacuated (aspirator)
and purged with hydrogen three times. The resulting hetero-
geneous mixture was stirred under a balloon of hydrogen at
room temperature for 48 h, and then the hydrogen was
evacuated and the mixture was filtered, rinsing wth MeOH
(3 mL). The filtrate was then concentrated, and the residue
was dissolved in water (2 mL) and stirred with Dowex 1 ×
8-200 -OH ion exchange resin (200 mg). After 30 min, the
mixture was filtered and the filtrate was concentrated. Chro-
matography (5:1:0.1 CHCl3/MeOH/NH4OH) gave 8.5 mg (90%)
of the title compound as a white crystalline solid. The
for 29: Rf ) 0.31 (1:1 hex/EtOAc); [R]23 ) -6.3° (c 0.95,
D
1
CHCl3); H NMR (CDCl3, 300 MHz) δ 7.2-7.5 (m, 15H), 4.99
(ABq, J ) 10.6 Hz, ∆ν ) 55.9 Hz, 2H), 4.86 (s, 1H, D2O
exchangeable), 4.79 (ABq, J ) 13.0 Hz, ∆ν ) 19.1 Hz, 2H),
4.60 (ABq, J ) 11.7 Hz, ∆ν ) 28.5 Hz, 2H), 4.16 (t, J ) 9.2
Hz, 1H, H1), 3.79 (m, J ) 4.9, 8.5, 2.9 Hz, 2H, H9 and H3),
3.52 (dd, J ) 3.2, 9.6 Hz, 1H, H2), 2.95 (dd, J ) 3.1, 12.7 Hz,
1H, H4eq), 2.72 (broad d, J ) 11.0 Hz, 1H, H6eq), 2.06 (dd, J )
1.5, 12.7 Hz, 1H, H4ax), 2.01 (m, 1H, H8eq), 1.96 (dd, J ) 2.7,
11.5 Hz, 1H, H6ax), 1.79 (t, J ) 8.5 Hz, 1H, H9a), 1.71 (app qt,
J ) ∼3.5, ∼12 Hz, 1H, H7eq), 1.59 (m, 1H, H7ax), 1.21 (m, J )
∼4, ∼11 Hz, 1H, H8ax); 13C NMR (CDCl3, 90 MHz, J MOD) δ
138.6 (-), 138.0 (-), 137.3 (-), 128.6 (+), 128.4 (+), 128.3 (+),
128.3 (+), 128.0 (+), 127.9 (+), 127.7 (+), 127.6 (+), 83.8 (+),
81.9 (+), 75.6 (-), 71.6 (-), 71.6 (+), 70.9 (+), 68.9 (+), 57.2
(-), 55.0 (-), 32.3 (-), 22.5 (-); IR (neat) 3472 (s), 3066 (m),
3029 (m), 2937 (s), 2862 (s), 2801 (m), 2734 (m), 1585 (w), 1453
(m), cm -1; MS (EI, 70 eV) m/z (rel int) 473 (M+, 1), 382 (45),
260 (29), 154 (19), 91 (100); HRMS calcd for C30H35NO4
473.2566, found 473.2548.
1
stereochemistry was assigned by H NMR coupling constant
analysis (see supporting information). Rf
) 0.23 (2:1
CHCl3/MeOH): mp 125-130 °C dec; [R]23 ) +34.7° (c 0.79,
D
1
MeOH); H NMR (CD3OD, 360 MHz) δ 4.09 (dd, J )1.8, 3.6
Hz, 1H, H1), 4.03 (ddd, J ) 3.3, 4.6, 11.3 Hz, 1H, H3), 3.90 (t,
J ) 3.1 Hz, 1H, H2), 3.68 (ddd, J ) 4.6, 9.5, 11.5 Hz, 1H, H9),
2.74 (br d, J ) 11.3 Hz, 1H, H6eq), 2.60 (dd, J ) 4.9, 10.3 Hz,
1H, H4eq), 2.34 (t, J ) 10.8 Hz, 1H, H4ax), 2.07 (dd, J ) 3.1,
11.9 Hz, 1H, H6ax), 2.0 (m, 2H, H8eq+ H9a), 1.5-1.7 (m, 2H,
H7eq+H7ax), 1.32 (dq, J ) 4.9, 11.9 Hz, 1H, H8ax); 13C NMR (CD3-
OD, 90 MHz) δ 72.4, 69.2, 67.2, 66.6, 66.5, 57.1, 56.7, 34.9,
24.3; IR (neat) 3334 (s), 2933 (m), 2854 (w), 2820 (w), 1598
(w), 1467 (w) cm-1; MS (EI, 70 eV) m/z (rel int) 203 (M+, 4),
185 (30), 146 (25), 99 (44), 72 (29), 36 (100); HRMS calcd for
C9H17NO4 203.1158, found 203.1160.
(1R ,2R ,3R ,9R ,9a R )-1,2,3,9-T e t r a h yd r oxy q u in o lizi-
d in e [(9R,9a R)-4]. Palladium on carbon (10%, 15 mg) was
added to a solution of the quinolizidine 29 (30 mg, 0.063 mmol)
in 1% methanolic HCl (3 mL). The flask was evacuated
(aspirator) and purged with hydrogen three times. The
mixture was stirred at room temperature under a balloon of
hydrogen for 48 h, and then the hydrogen was evacuated and
the mixture was filtered, rinsing with MeOH (3 mL). The
filtrate was concentrated, and the residue was dissolved in
water (2 mL) and stirred with Dowex 1 × 8-200 -OH ion
exchange resin (50 mg). After 30 min, the mixture was filtered
and the filtrate concentrated. Chromatography (8:1:0.1 CHCl3/
MeOH/NH4OH) gave 12 mg (92%) of the title compound as a
colorless oil that crystallized upon standing. The stereochem-
istry was assigned by 1H NMR coupling constant analysis (see
(2R,3R,4R,5S,6R)-1-Azido-2,3,4-tr is(ben zyloxy)-9-ch lor o-
5,6-ep oxyn on a n e (27). Methanesulfonyl chloride (50 mg, 34
µL, 0.43 mmol) was added to a cold (-50 °C) solution of the
diol 25 (200 mg, 0.36 mmol) and triethylamine (65 µL, 48 mg,
0.47 mmol) in CH2Cl2 (2 mL). The mixture was stirred for 1
h at -50 °C and then warmed slowly to 0 °C and quenched by
addition of water (5 mL). The resulting mixture was extracted
with CH2Cl2 (3 × 5 mL), dried (MgSO4), and concentrated to
give 190 mg of the crude monomesylate, which was dissolved
in THF/DMSO (10:1, 11 mL) and cooled to 0 °C. Sodium
hydride (29 mg of a 60% suspension in mineral oil, 17 mg of
pure hydride, 0.72 mmol) was added, and the mixture was
warmed to room temperature. After 12 h, the reaction was
quenched with aqueous NH4Cl (2 mL), diluted with water (10
mL), and extracted with Et2O (2 × 10 mL). The combined
organic layers were washed with brine (10 mL), dried (MgSO4),
and concentrated. Chromatography (10:1 to 5:1 hex/EtOAc
gradient) provided 75 mg (40%) of a 2.5:1 mixture of epoxides
27 and 26. The stereochemical assignment of 27 was made
by conversion to the quinolizidine (9R,9aR)-4 (see below). Data
for 27: Rf ) 0.55 (4:1 hex/EtOAc); 1H NMR (CDCl3, 300 MHz)
δ 7.15-7.40 (m, 15H), 4.86 (d, J ) 11.8 Hz, 1H), 4.5-4.7 (m,
4H), 4.31 (d, J ) 11.2 Hz, 1H), 3.84 (m, 1H), 3.68 (dd, J ) 3.0,
6.0 Hz, 1H), 3.41-3.65 (m, 4H), 3.28 (dd, J ) 2.7, 7.0 Hz, 1H),
3.05 (dd, J ) 1.9, 7.2 Hz, 1H), 2.73 (dt, J ) 2.8, 7.3 Hz, 1H),
1.7-1.9 (m, 3H), 1.37 (m, 1H); 13C NMR (CDCl3, 90 MHz) δ
138.0, 137.6, 137.5, 128.5, 128.4, 128.2, 128.0, 127.7, 79.7, 79.2,
78.5, 74.3, 72.6, 72.0, 59.3, 53.6, 51.0, 44.4, 29.0, 28.6; IR (neat)
3088 (w), 3063 (m), 3030 (m), 2918 (m), 2869 (m), 2101 (s),
1854 (w), 1878 (w), 1812 (w), 1727 (w), 1454 (m) cm-1; MS
(DCI, NH3) m/z (rel int) 553 ([M + NH4]+, 15), 508 (59), 120
(19), 108 (21), 91 (100); HRMS calcd for C30H34ClN3O4NH4
553.2582, found 553.2555.
supporting information). Rf ) 0.44 (5:1:0.1 CHCl3/MeOH/NH4-
1
OH); mp ) 150 °C; [R]23 ) -64.6° (c 1.00, MeOH); H NMR
D
(CD3OD, 300 MHz) δ 3.84 (dt, J ) 1.7, 3.3 Hz, 1H, H3), 3.82
(t, J ) 9.1 hz, 1H, H1), 3.69 (ddd, J ) 4.6, 8.5, 11.1 Hz, 1H,
H9), 3.34 9dd, J ) 3.5, 9.4 Hz, 1H, H2), 2.89 (dd, J ) 3.2, 12.5
Hz, 1H, H4eq), 2.73 (br d, J ) 11.6 Hz, 1H, H6eq), 2.30 (dd, J )
1.7, 12.5 Hz, 1H, H4ax), 2.04 (m, 1H, H6ax), 1.94 (m, 1H, H8eq),
1.66 (t, J ) 8.5 Hz, 1H, H9a), 1.64 (m, 2H, H7ax and H7eq), 1.29
(m, 1H, H8ax); 13C NMR (CD3OD, 90 MHz, J MOD) δ 76.1 (+),
75.7 (+), 74.7 (+), 70.3 (+), 69.5 (+), 60.7 (-), 56.2 (-), 33.9
(-), 23.9 (-); IR (neat) 3332 (s), 2936 (m), 2801 (m), 2752 (m)
cm-1; MS (EI, 70 eV) m/z (rel int) 203 (M+, 24), 185 (97), 168
(46), 146 (68), 128 (23), 113 (46), 99 (100), 72 (61); HRMS calcd
for C9H17NO4 203.1158, found 203.1152. Anal. Calcd for
C9H17NO4: C, 53.20; H, 8.45; N, 6.89. Found: C, 53.19; H,
8.46; N, 6.80.
(2R,3R,4R,5S,6R)-1-Azid o-2,3,4-tr is(ben zyloxy)-6-(ter t-
bu tyld im eth ylsilyl)oxy-9-ch lor o-5-h yd r oxyn on a n e (30).
tert-Butyldimethylsilyl chloride (TBDMSCl) (88 mg, 0.585
mmol) and imidazole (83 mg, 1.22 mmol) were added to a
solution of the diol 24 (270 mg, 0.487 mmol) in THF/DMF (1:
1, 3 mL) at room temperature. After 12 h, additional TBDM-
SCl (20 mg, 0.13 mmol) and imidazole (20 mg, 0.29 mmol) were
added. After 8 h, the mixture was poured into aqueous NH4-
Cl (10 mL) and extracted with Et2O (2 × 15 mL). The
combined organic layers were washed with brine, dried
(MgSO4), and concentrated. Chromatography (20:1 to 10:1
hex/EtOAc gradient) gave 287 mg (88%) of the title compound
(1R,2R,3R,9R,9a R)-1,2,3-Tr i-O-b en zyl-1,2,3,9-t et r a h y-
d r oxyqu in olizid in e (29). Palladium on carbon (10%, 10 mg)
was added to a solution of the epoxides 26 and 27 (1:2.5
mixture of diastereomers, 59 mg, 0.11 mmol), in EtOH/EtOAc
(1:1, 2 mL). The flask was evacuated (aspirator) and purged
with hydrogen three times. The heterogeneous mixture was
stirred under a balloon of hydrogen for 16 h, and then the
hydrogen was evacuated and the mixture was filtered through
as a colorless oil. Rf ) 0.45 (6:1 hex/EtOAc); [R]23 ) +10.8°
D
(c 1.39, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.2-7.4 (m, 15H),
4.73 (ABq, J ) 11.3 Hz, ∆ν ) 13.0 Hz, 2H), 4.60 (ABq, J )
11.2 Hz, ∆ν ) 62.0 Hz, 2H), 4.53 (ABq, J ) 11.8 Hz, ∆ν )
20.8 Hz, 2H), 4.07 (dd, J ) 6.2, 2.6 Hz, 1H), 3.88 (m, 2H), 3.76
a
plug of Celite, rinsing wth EtOH (6 mL). Potassium
carbonate (50 mg) was added to the filtrate, and the resulting

Ring-Expanded Analogs of Swainsonine
J . Org. Chem., Vol. 61, No. 16, 1996 5545
(m, 3H), 3.45 (m, 3H), 2.66 (d, J ) 3.0 Hz, 1H), 1.85 (m, 1H),
1.4-1.7 (m, 3H), 0.86 (s, 9H), 0.08 (s, 6H); 13C NMR (CDCl3,
90 MHz) δ 138.2, 137.9, 137.6, 128.5, 128.4, 128.3, 127.9, 127.7,
127.7, 79.2, 78.5, 77.3, 74.4, 73.1, 72.6, 72.4, 72.2, 50.8, 45.3,
28.5, 28.3, 25.8, 18.0, -4.4; IR (neat) 3503 (br w), 3030 (w),
2942 (m), 2928 (m), 2848 (m), 2100 (s) cm -1; MS (CI, NH3)
m/z (rel int) 685 ([M + NH4]+, 52), 640 (100), 604 (82), 516
(16), 106 (33); HRMS calcd for C36H5035ClN3O5SiNH4 685.3552,
found 685.3572.
compound as a colorless oil. Rf ) 0.44 (2:1 hex/EtOAc); [R]23
D
1
) -24.5° (c 1.11, CHCl3); H NMR (CDCl3, 300 MHz) δ 7.2-
7.4 (m, 15H), 4.45-4.67 (m, 6H), 4.20 (dt, J )4.3, 8.8 Hz, 1H,
H9), 4.02 (dd, J ) 3.7, 4.3 Hz, 1H, H1), 3.91 (ddd, J ) 3.2, 4.2,
8.5 Hz, 1H, H3), 3.75 (t, J ) 3.7 Hz, 1H, H2), 3.24 (dd, J ) 9.2,
11.2 Hz, 1H, H4), 2.97 (dt, J ) 3.5, 13.4 Hz, 1H, H6), 2.84 (ddd,
J ) 3.1, 11.1, 13.4 Hz, 1H, H6), 2.71 (dd, J ) 3.2, 8.8 Hz, 1H,
H9a), 2.63 (dd, J ) 4.2, 11.3 Hz, 1H, H4), 1.89 (m, 1H, H8),
1.71 (m, 1H, H7), 1.46 (m, 1H, H7), 1.32 (m, 1H, H8), 0.79 (s,
9H), -0.74 (s, 3H), -0.15 (s, 3H); 13C NMR (CDCl3, 90 MHz,
J MOD) δ 138.6 (-), 138.5 (-), 138.5 (-), 128.2 (+), 128.2 (+),
128.1 (+), 127.9 (+), 127.8 (+), 127.4 (+), 127.3 (+), 76.2 (broad,
+), 75.4 (+), 72.8 (+), 72.5 (-), 72.1 (-), 71.0 (-), 65.4 (+),
64.0 (+), 53.2 (-), 47.7 (broad, -), 34.7 (broad, -), 25.9 (+),
19.9 (-), 17.9 (-), -3.9 (+), -5.0 (+); IR (neat) 3204 (w), 2923
(s), 2850 (s), 2355 (m), 2326 (m), 1455 (m) cm-1; MS (EI, 50eV)
m/ z (rel int) 587 (M+, 3), 496 (100), 390 (20), 374 (18), 91 (71),
73 (29); HRMS calcd for C36H49NO4Si 587.3431, found 587.3439.
(1R ,2R ,3R ,9R ,9a R )-1,2,3,9-T e t r a h yd r o xy q u in o lizi-
d in e [(9R,9a R)-4] fr om 32. Palladium on carbon (10%, 15
mg) was added to a solution of the quinolizidine 32 (30 mg,
0.063 mmol) in 1% methanolic HCl (3 mL). The flask was
evacuated (aspirator) and purged with hydrogen three times.
The mixture was stirred at room temperature under a balloon
of hydrogen for 48 h, and then the hydrogen was evacuated
and the mixture was filtered, rinsing with MeOH (3 mL). The
filtrate was concentrated, and the residue was dissolved in
water (2 mL) and stirred with Dowex 1 × 8-200 -OH ion
exchange resin (50 mg). After 30 min, the mixture was filtered
and the filtrate concentrated. Chromatography (8:1:0.1 CHCl3/
MeOH/NH4OH) gave 12 mg (92%) of the title compound as a
colorless oil that crystallized upon standing. See above for
characterization.
(1R,2R,3R,9R,9aS)-1,2,3-Tr i-O-ben zyl-9-O-(ter t-bu tyldim -
eth ylsilyl)-1,2,3,9-tetr a h yd r oxyqu in olizid in e (32). A solu-
tion of dimethyl sulfoxide (80 mg, 1.0 mmol) in CH2Cl2 (1 mL)
was added to a cooled (-60 °C) solution of oxalyl chloride (65
mg, 0.51 mmol) in CH2Cl2. After 5 min, the alcohol 30 (280
mg, 0.418 mmol) was added as a solution in CH2Cl2 (1 mL).
After 10 min, triethylamine (216 mg, 2.14 mmol) was added
as a solution in CH2Cl2 (1 mL). The resulting mixture was
stirred at -60 °C for 15 min and then warmed to room
temperature and quenched by the addition of water. The
mixture was poured into Et2O (15 mL) and washed with
aqueous NH4Cl (2 × 20 mL) and brine (15 mL). The organic
layer was then dried (MgSO4) and concentrated to give 240
mg of crude azido ketone as a colorless oil. Rf ) 0.19 (10:1
1
hex/EtOAc); H NMR (CDCl3, 360 MHz) δ 7.2-7.4 (m, 15 H),
4.79 (d, J ) 3.5 Hz, 1H), 4.63 (d, J ) 11.4 Hz, 1H), 4.42 (d, J
) 11.3 Hz, 1H), 4.36 (d, J ) 11.4 Hz, 1H), 4.26 (dd, J ) 7.1,
3.5 Hz, 1H), 4.08 (dd, J ) 13.4, 2.9 Hz, 1H), 3.45 (m, 2H), 3.37
(dd, J ) 13.4, 4.3 Hz, 1H), 1.6-1.9 (m, 4H), 0.88 (s, 9H), 0.09
(s, 3H), 0.06 (s, 3H); 13C NMR (CDCl3, 90 MHz) δ 208.9, 137.7,
137.6, 137.5, 128.4, 128.4, 128.3, 128.2, 127.9, 127.9, 127.8,
79.8, 78.0, 75.9, 73.4, 73.4, 72.3, 50.5, 44.9, 31.4, 27.3, 25.8,
18.0, -4.4, -4.6; IR (neat) 2953 (m), 2929 (m), 2857 (m), 2101
(s), 1727 (m) cm-1. The crude ketone was dissolved in EtOAc/
EtOH (1:1, 15 mL), and palladium hydroxide on carbon (80
mg) was added. The flask was evacuated (aspirator) and
purged with hydrogen three times. The resulting heteroge-
neous mixture was stirred under a balloon of hydrogen for 1
h, and then the hydrogen was evacuated and the mixture was
passed through a plug of Celite, rinsing with EtOH (10 mL).
The filtrate was concentrated under reduced pressure without
heating (to avoid cyclization) to give 205 mg of the crude imine
Ack n ow led gm en t. This work was funded by the
National Institutes of Health (GM-35572). E.J .H. was
supported in part by National Research Service Award
T32 GM07767. We thank Professor J ames K. Coward
(University of Michigan) and Professor Alan D. Elbein
(University of Arkansas) for helpful discussions, and
Professor Elbein for providing us with the results of the
glycosidase I and II and mannosidase I enzyme inhibi-
tion studies.
1
31; Rf ) 0.18 (5:1 hex/EtOAc); H NMR (CDCl3, 300 MHz) δ
7.2-7.4 (m, 15H), 4.55-4.72 (m, 4H), 4.52 (ABq, J ) 12.1 Hz,
2H), 4.34 (d, J ) 4.1 Hz, 1H), 4.24 (dd, J ) 8.0, 5.1 Hz, 1H),
3.82 (m, 4H), 3.44 (t, J ) 6.3 Hz, 2H), 1.86 (m, 2H), 1.73 (m,
2H), 0.91 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H). The crude imine
was then dissolved in methanol (15 mL), cooled to 0 °C, and
treated with sodium borohydride (49 mg, 1.3 mmol). After 2
h, ethanol (20 mL) and potassium carbonate (180 mg, 1.3
mmol) were added, and the mixture was warmed to reflux (ca.
70 °C). After 3 h, the mixture was cooled to room temperature,
poured into water (40 mL), and extracted with CH2Cl2 (3 ×
30 mL). The combined organic layers were washed with brine,
dried (Na2SO4), and concentrated. Chromatography (4:1 to 2:1
hex/EtOAc gradient) provided 152 mg (62%) of the title
Su p p or tin g In for m a tion Ava ila ble: Discussion of the
1
stereochemical assignments for all quinolizidines, H and 13C
NMR spectra for compounds 4 (all four diastereomers), 12, 13,
21-30, and 32, and COSY spectra for all quinolizidines (52
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
J O960609B