Synthesis of novel glycosidase-inhibitory hydroxymethyl-substituted polyhydroxylated indolizidines: Ring-expanded analogs of the pyrrolizidine alkaloids alexine and australine

Article abstract of DOI:10.1021/jo960610a

The pyrrolizidine azasugars alexine (3) and australine (4) and their stereoisomers are glycosidase inhibitors of potential therapeutic use. Since the glycosidase inhibitory activity of azasugars is profoundly effected by ring size modification, the ring-expanded indolizidine analogs 7 (homoalexine), 8 (8-epihomoaustraline), 9 (homoaustraline), and 10 (8-epihomoalexine) were prepared. L-Xylose was converted into the diols 16, which were transformed into the nine-membered lactones 18 by Claisen rearrangment of the cyclic ketone acetal 17. Transesterification of the lactones to the hydroxy esters 19 followed by azide displacement and epoxidation gave the epoxides 21 and 31. Reductive double cyclization of these azido-epoxides followed by functional group adjustment provided the desired homologs 7-10. An alternative route involving stereoselective epoxidation of the nine-membered lactones was also examined. The homologs 7-10 were found to be good inhibiters of amyloglucosidase (Aspergillus niger). The inhibitory activities of 8 and 10 are comparable to those exhibited by castanospermine (5) and the pyrrolizidines alexine (3), australine (4), and 7-epiaustraline. Indolizidines 7-10 do not inhibit β-glucosidase (almond) or α-glucosidase (bakers' yeast). This activity parallels that exhibited by the pyrrolizidine inhibiters alexine, australine, and 7-epiaustraline, which are generally good amyloglucosidase inhibiters but relatively weak inhibitors of α-glucosidase and β-glucosidase. However, in contrast to the pyrrolizidine inhibitors which have not been reported to possess mannosidase inhibitory activity, the indolizidines 7-10 were found to inhibit α-mannosidase (jack bean), albeit weakly.

Full text of DOI:10.1021/jo960610a

5546
J . Org. Chem. 1996, 61, 5546-5556
Syn th esis of Novel Glycosid a se-In h ibitor y
Hyd r oxym eth yl-Su bstitu ted P olyh yd r oxyla ted In d olizid in es:
Rin g-Exp a n d ed An a logs of th e P yr r olizid in e Alk a loid s Alexin e a n d
Au str a lin 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 pyrrolizidine azasugars alexine (3) and australine (4) and their stereoisomers are glycosidase
inhibitors of potential therapeutic use. Since the glycosidase inhibitory activity of azasugars is
profoundly effected by ring size modification, the ring-expanded indolizidine analogs 7 (homoalexine),
8 (8-epihomoaustraline), 9 (homoaustraline), and 10 (8-epihomoalexine) were prepared. L-Xylose
was converted into the diols 16, which were transformed into the nine-membered lactones 18 by
Claisen rearrangment of the cyclic ketene acetal 17. Transesterification of the lactones to the
hydroxy esters 19 followed by azide displacement and epoxidation gave the epoxides 21 and 31.
Reductive double cyclization of these azido-epoxides followed by functional group adjustment
provided the desired homologs 7-10. An alternative route involving stereoselective epoxidation
of the nine-membered lactones was also examined. The homologs 7-10 were found to be good
inhibitors of amyloglucosidase (Aspergillus niger). The inhibitory activities of 8 and 10 are
comparable to those exhibited by castanospermine (5) and the pyrrolizidines alexine (3), australine
(4), and 7-epiaustraline. Indolizidines 7-10 do not inhibit â-glucosidase (almond) or R-glucosidase
(bakers’ yeast). This activity parallels that exhibited by the pyrrolizidine inhibitors alexine,
australine, and 7-epiaustraline, which are generally good amyloglucosidase inhibitors but relatively
weak inhibitors of R-glucosidase and â-glucosidase. However, in contrast to the pyrrolizidine
inhibitors which have not been reported to possess mannosidase inhibitory activity, the indolizidines
7-10 were found to inhibit R-mannosidase (jack bean), albeit weakly.
In tr od u ction
rally occurring compounds might provide more potent
and selective glycosidase inhibitors or new therapeutic
agents. We wish to report the synthesis and biological
evaluation of the non-natural indolizidines 7-9, com-
A number of naturally occurring polyhydroxylated
pyrrolidine, piperidine, pyrrolizidine, and indolizidine
alkaloids (often referred to as “amino-sugars” or “aza-
sugars”) exhibit glycosidase inhibitory activity.1-5 Ex-
amples include the pyrrolidine (2R,5R,3R,4R)-2,5-bis-
(hydroxymethyl)-3,4-dihydroxypyrrolidine (DMDP, 1),
the piperidine deoxynojirimycin (2), the pyrrolizidines
alexine (3) and australine (4), and the indolizidines
castanospermine (5) and swainsonine (6). At physiologi-
cal pH, the protonated amino group may mimic the
developing pyranosyl or furanosyl cation intermediate
encountered in oligosaccharide cleavage. Due to their
ability to inhibit glycoprotein processing enzymes, such
alkaloids have been useful in studies on the effect of
oligosaccharide structure on glycoprotein function.3-6
Several of these alkaloids are also of interest for their
activity against cancer, HIV, and other disorders. For
example, DMDP (1), deoxynojirimycin (2) and certain
stereoisomers of alexine (3) and australine (4) have
shown anti-HIV activity in vitro.7-9 The glucosidase
inhibitor castanospermine (5) has shown anticancer10 and
antiviral activity,11 including anti-HIV activity.12 The
mannosidase inhibitor swainsonine (6) inhibits tumor
growth and metastasis13 and exhibits immunomodulatory
activity.14 Structurally modified analogs of these natu-
(7) (a) Gruters, R. A.; Neefjes, J . J .; Tersmette, M.; De Goede, R. E.
Y.; Tulp, A.; Huisman, H. G.; Miedema, F.; Ploegh, H. L. Nature 1987,
330, 74. (b) Walker, B. D.; Kowalski, M.; Goh, W. C.; Kozarsky, K.;
Krieger, M.; Rosen, C.; Rohrschneider, L.; Haseltine, W. A.; Sodroski,
J . Proc. Natl. Acad. Sci. U.S.A. 1987, 84, 8120. (c) Tyms, A. S.; Berrie,
E. M.; Ryder, T. A.; Nash, R. J .; Hegarty, M. P.; Taylor, T. L.; Mobberly,
M. A.; Davis, J . M.; Bell, E. A.; J effries, D. J .; Taylor-Robinson, D.;
Fellows, L. E. Lancet 1987, 1025.
(8) Taylor, D. L.; Nash, R.; Fellows, L. E.; Kang, M. S.; Tyms, A. S.
Antiviral Chem. Chemother. 1992, 3, 273.
(9) For a discussion of the synthesis and biological activity of alexine,
australine, and their epimers, see: Pearson, W. H.; Hines, J . V.
Tetrahedron Lett. 1991, 32, 5513. This paper reports a synthesis of
the naturally occurring alkaloid (+)-7-epiaustraline and unnatural
alkaloid (-)-7-epialexine.
(10) (a) Humphries, M. J .; Matsumoto, K.; White, S. L.; Olden, K.
Cancer Res. 1986, 46, 5215. (b) Ostrander, G. K.; Scribner, N. K.;
Rohrschneider, L. R. Cancer Res. 1988, 48, 1091.
(11) (a) Sunkara, P. S.; Bowlin, T. L.; Liu, P. S.; Sjoerdsma, A.
Biochem. Biophys. Res. Commun. 1987, 148, 206. (b) Ruprecht, R. M.;
Mullaney, S.; Andersen, J .; Bronson, R. J . Acquired Immune Defic.
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Nash, R. J .; Taylor-Robinson, D.; Mobberley, M. A.; Ryder, T. A.;
J effries, D. J .; Tyms, A. S. Antiviral Res. 1988, 10, 11.
(12) (a) Gruters, R. A.; Neefjes, J . J .; Tersmette, M.; De Goede, R.
E. Y.; Tulp, A.; Huisman, H. G.; Miedema, F.; Ploegh, H. L. Nature
1987, 330, 74. (b) Walker, B. D.; Kowalski, M.; Goh, W. C.; Kozarsky,
K.; Krieger, M.; Rosen, C.; Rohrschneider, L.; Haseltine, W. A.;
Sodroski, J . Proc. Natl. Acad. Sci. U.S.A. 1987, 84, 8120. (c) Tyms, A.
S.; Berrie, E. M.; Ryder, T. A.; Nash, R. J .; Hegarty, M. P.; Taylor, T.
L.; Mobberly, M. A.; Davis, J . M.; Bell, E. A.; J effries, D. J .; Taylor-
Robinson, D.; Fellows, L. E. Lancet 1987, 1025.
(13) (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.
X Abstract published in Advance ACS Abstracts, J uly 15, 1996.
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S0022-3263(96)00610-X CCC: $12.00 © 1996 American Chemical Society

Ring-Expanded Analogs of Alexine and Australine
J . Org. Chem., Vol. 61, No. 16, 1996 5547
pounds which combine some of the structural features
of the alkaloids 1-6. These are the first examples of
3-(hydroxymethyl)indolizidines. From a nomenclature
standpoint, 7-9 are considered to be ring-expanded
analogs (homologs) of the alkaloids alexine (3) and
australine (4).
and australine would gain a similar increase in activity
if the less-oxygenated pyrrolidine ring were expanded to
a piperidine ring, much like swainsonine. Hence, we set
out to make the indolizidine analogs 7-10 of alexine and
australine. We chose to attempt the preparation of all
four of the C(8)/C(8a)diastereomers of these indolizidines,
since variation of the C(7) and C(7a) stereochemistry in
alexine and australine results in substantially different
biological activity.23 Indolizidine 7 is a homolog of alexine
(3), a poor inhibitor of glucosidases and galactosidas-
es,24,25 but a good inhibitor of amyloglucosidase and
thioglucosidase.26,27 Analog 8 is a homolog of 7-epiaus-
traline,9,26 a known alkaloid that is a good inhibitor of
amyloglucosidase26,28,29 and R-glucosidase26,30 and shows
anti-HIV activity.30 Indolizidine 9 is a homolog of aus-
traline (4), an inhibitor of amyloglucosidase26,28,29 and
glucosidase I29 that also shows antiviral and anti-HIV
activity.30 The analog 10 is a homolog of 7-epialexine, a
known compound whose biological activity has not been
determined.9
Resu lts a n d Discu ssion
We envisaged preparing indolizidines 7-10 using a
route analogous to that described in the preceding paper
for the synthesis of polyhydroxylated quinolizidines.31
The four diastereomers were thought to be readily
available using an azido-epoxide reductive double cy-
clization approach.20a,21,32 A retrosynthetic analysis of the
indolizidines 7-10 is shown in Scheme 1. The lactam
11 may arise from a reductive double-cyclization of the
azido-epoxide 12, which should be available by epoxida-
tion of 13.33 In order to prepare the four possible C(8)/
C(8a) diastereomers of 7-10, we would require a rela-
The alkaloids 1-6 have been the subject of structure-
activity relationship studies, primarily involving stereo-
isomeric analogs.15-18 Another strategy involves the
modification of ring sizes, where a profound effect on the
glycosidase inhibitory activity of the polyhydroxylated
alkaloids may be found. Ring-expanded quinolizidine
analogs of castanospermine have been prepared and were
found to retain inhibitory activity.19 However, ring-
expanded quinolizidine analogs of swainsonine were
found to lack inhibitory activity (see preceding paper).20
A ring-contracted pyrrolizidine analog of the indolizidine
alkaloid swainsonine was found to be four orders of
magnitude less effective as an R-mannosidase inhibi-
tor.21,22 This observation led us to propose that alexine
(23) In general, it is often difficult to predict which stereoisomer of
an azasugar will be an effective inhibitor of a certain glycosidase.2,16
(24) Nash, R. J .; Fellows, L. E.; Dring, J . V.; Fleet, G. W. J .; Derome,
A. E.; Hamor, T. A.; Scofield, A. M.; Watkin, D. J . Tetrahedron Lett.
1988, 29, 2487.
(25) Nash, R. J .; Fellows, L. E.; Plant, A. C.; Fleet, G. W. J .; Derome,
A. E.; Baird, P. D.; Hegarty, M. P.; Scofield, A. M. Tetrahedron 1988,
44, 5959.
(26) Nash, R. J .; Fellows, L. E.; Dring, J . V.; Fleet, G. W. J .; Girdhar,
A.; Ramsden, N. G.; Peach, J . M.; Hegarty, M. P.; Scofield, A. M.
Phytochemistry 1990, 29, 111.
(27) Scofield, A. M.; Rossiter, J . T.; Witham, P.; Kite, G. C.; Nash,
R. J .; Fellows, L. E. Phytochemistry 1990, 29, 107.
(28) Molyneux, R. J .; Benson, M.; Wong, R. Y.; Tropea, J . E.; Elbein,
A. D. J . Nat. Prod. 1988, 51, 1198.
(14) (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.
(15) Cenci Di Bello, I.; Fleet, G.; Namgoong, S. K.; Tadano, K.;
Winchester, B. Biochem. J . 1989, 259, 855.
(16) Winchester, B. G.; Cenci di Bello, I.; Richardson, A. C.; Nash,
R. J .; Fellows, L. E.; Ramsden, N. G.; Fleet, G. Biochem. J . 1990, 269,
227.
(17) Burgess, K.; Henderson, I. Tetrahedron 1992, 48, 4045.
(18) 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.
(19) (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.
(20) See the preceding paper in this J ournal, as well as: (a) Pearson,
W. H.; Hembre, E. J . Tetrahedron Lett. 1993, 34, 8221. See also: (b)
Hamana, H.; Ikota, N.; Ganem, B. J . Org. Chem 1987, 52, 5492. (c)
Rassu, G.; Casiraghi, G.; Pinna, L.; Spannu, P.; Ulgheri, F. Tetrahedron
1993, 49, 6627.
(29) Tropea, J . E.; Molyneux, R. J .; Kaushal, G. P.; Pan, Y. T.;
Mitchell, M.; Elbein, A. D. Biochemistry 1989, 28, 2027.
(30) (a) Fellows, L.; Nash, R. PCT Int. Appl. WO GB Appl. 89/7,-
951. Chem. Abstr. 1990, 114, 143777f. (b) Elbein, A. D.; Tropea, J . E.;
Molyneux, R. J . U.S. Pat. Appl. US 289,907. Chem. Abstr. 1990, 113,
91444p.
(31) See preceding paper in this journal. Although an azide-olefin
cyclization approach to the indolizidine backbone would not suffer the
undesired aromatization encountered in the quinolizidine work, this
chemistry was not pursued since it would allow access to only one
diastereomer of 7-10.
(32) For related one-pot double cyclizations using azido-epoxides or
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) Pearson, W. H.; Bergmeier, S. C.; Williams,
J . P. J . Org. Chem. 1992, 57, 3977. (e) Ina, H.; Kibayashi, C. J . Org.
Chem. 1993, 58, 52. (f) 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. (g) Kim, N.-S.; Choi, J .-R.; Cha, J . K. J . Org. Chem 1993, 58,
7096. (h) Poitout, L.; Le Merrer, Y.; Depezay, J .-C. Tetrahedron Lett.
1994, 35, 3293. (i) Lohray, B. B.; J ayamma, Y.; Chatterjee, M. J . Org.
Chem. 1995, 60, 5958.
(33) We initially investigated the use of an azido-chloro-alkene
epoxidation precursor similar to that used in the quinolizidine work
(see preceding paper in this journal). However, the Wittig olefination
of lactol 15 proved problematic, leading primarily to elimination
products.
(21) Carpenter, N. M.; Fleet, G. W.; Cenci di Bello, I.; Winchester,
B.; Fellows, L. E.; Nash, R. J . Tetrahedron Lett. 1989, 30, 7261.
(22) Burgess, K.; Henderson, I. Tetrahedron Lett. 1990, 31, 6949.

5548 J . Org. Chem., Vol. 61, No. 16, 1996
Pearson and Hembre
Sch em e 1. Retr osyn th esis: Red u ctive Cycliza tion
of a n Azid e Bea r in g Tw o Rem ote Electr op h ilic
Sites
on 16 to produce the E-γ,δ-unsaturated ester 19E.
Attempted orthoester-Claisen rearrangement of 16 failed
due to the formation of a seven-membered cyclic ortho-
ester which was resistant to further reaction even at high
temperatures. Although we considered other options
which would avoid the problem of the interfering hy-
droxyl group in 16, a subsequent observation made these
tactics unnecessary. Since we also required 19Z, we
explored the use of Holmes’s Claisen rearrangement
method36,37 for the synthesis of eight- and nine-membered
lactones from cyclic ketene acetals, a method known to
produce the Z-alkene isomer exclusively (i.e., 17 f 18Z
f 19Z). This strategy uses the extra hydroxyl present
in 16 to our advantage. Acetal formation with (phenylse-
leno)acetaldehyde diethylacetal38 followed by oxidation
of the selenide afforded a complex mixture of diastereo-
meric selenoxide-bearing acetals. Heating this mixture
in toluene-containing DBU caused selenoxide elimination
to give the ketene acetal 17, which suffered a Claisen
rearrangement in situ to produce a mixture of three nine-
membered lactones 18. Chromatography afforded two
fractions, the first containing the Z-alkene 18Z and an
E-alkene 18E in a 1:1 ratio. The second fraction con-
tained another E-alkene 18E′, presumably an atropiso-
mer of 18E. Indeed, continued heating of the purified
mixture of 18Z and 18E in refluxing toluene caused the
slow conversion of 18E to 18E′. In contrast to literature
precedent36,37 and predictions based on our examination
of molecular models, the Claisen rearrangment of 17
proved to be moderately E-selective rather than highly
Z-selective. The use of pure allylic alcohols 16â resulted
in a similar mixture of lactones. We have not been able
to develop a convincing rationale for this result. The low
stereoselectivity, while unexpected, was a welome turn
of events, since we required both alkene stereoisomers.
Methanolysis of the 1:1 mixture of 18Z and 18E produced
the γ,δ-unsaturated esters 19Z and 19E in 39% and 37%
yields, respectively, after separation by column chroma-
tography. Methanolysis of the atropisomeric lactone 18E′
afforded 91% of 19E. With the two requisite alkenes 19Z
and 19E in hand, we turned to completion of the
synthesis of the indolizidines 7-10.
Sch em e 2. Use of a Cla isen Rea r r a n gem en t To
In sta ll th e Alk en e
The conversion of 19E to homoalexine (7) and 8-epi-
homoaustraline (8) is shown in Scheme 3. A Mitsunobu
reaction with hydrazoic acid39 was found to be the best
way to convert the alcohol 19E into the azide 20.
Epoxidation of 20 afforded an inseparable 1:2 mixture
of the diastereomeric trans-epoxides 21R and 21â.40
Reduction of the azide to the primary amine resulted in
intramolecular epoxide opening and partial acylation of
the resultant pyrrolidine by the ester. To complete the
acylation, the mixture was heated with methanolic
sodium methoxide to afford the inseparable indolizidi-
nones 22 and 23 in a ratio that reflected the relative
tively nonstereoselective epoxidation of both geometric
isomers of 13. The γ,δ-unsaturated carboxylic acid
derivative 13 was proposed to be available by a Claisen
rearrangement of a carbohydrate-derived allylic alcohol.
The installation of the γ,δ-unsaturated carboxylic acid
by a Claisen rearrangement is shown in Scheme 2.
Commercially available L-xylose (14) was converted into
tri-O-benzyl-L-xylofuranose (15) in three steps according
to the literature procedure.34 Addition of vinylmagne-
sium bromide to 15 provided a 2:3 mixture of diastere-
omeric allylic alcohols, 16R and 16â, consistent with the
literature results in the enantiomeric D-series.35 Our
original plan was to carry out a Claisen rearrangement
(35) Boschetti, A.; Nicotra, F.; Panza, L.; Giovanni, R. J . Org. Chem.
1988, 53, 4181.
(36) Carling, R. W.; Holmes, A. B. J . Chem. Soc., Chem. Commun.
1986, 325.
(37) Curtis, N. R.; Holmes, A. B.; Looney, M. G. Tetrahedron 1991,
47, 7171.
(38) Baudat, R.; Petrzilka, M. Helv. Chim. Acta 1979, 62, 1406.
(39) Loibner, H.; Zbiral, E. Helv. Chim. Acta 1976, 59, 2100.
(40) 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.
(34) Kawana, M.; Kuzuhara, H.; Emoto, S. Bull. Chem. Soc. J pn.
1981, 54, 1492.

Ring-Expanded Analogs of Alexine and Australine
J . Org. Chem., Vol. 61, No. 16, 1996 5549
Sch em e 3. Syn th eses of Hom oa lexin e (7) a n d
8-Ep ih om oa u str a lin e (8)
Sch em e 4. An Alter n a tive Rou te to th e
In d olizid in e 23 In volvin g Ep oxid a tion of th e
La cton e 18E′
Sch em e 5. La cton e 18E P r esen ts a Differ en t
π-F a ce to th e Oxid a n t Th a n Its Atr op isom er 18E′
amounts of the epoxides 21â and 21R. The lactams 22
and 23 were reduced with borane, producing the indoliz-
idines 24 and 25 in good yield after separation by column
chromatography. Hydrogenolysis of the benzyl protecting
groups yielded the desired indolizidines homoalexine (7)
and 8-epihomoaustraline (8).
While the low stereoselectivity in the epoxidation of
19Z suited our purposes for the synthesis of both 7 and
8 for biological evaluation, we were curious about the
stereoselectivity of the epoxidation of the pure nine-
membered lactone 18E′, since models indicated that only
one π-face of the alkene would be exposed to the oxidant
(Scheme 4). Stereoselective functionalization of alkenes
from the periphery of medium-ring alkenes has been
explored by others.41 Indeed, oxidation of 18E′ gave a
single epoxide 26. Mild transesterification with methanol
yielded the alcohol 27, which was converted to the azide
21R, previously encountered as part of a mixture of
stereoisomers in Scheme 3 above. Reductive double-
cyclization of 21R gave the indolizidinone 23 (see also
Scheme 3) in good yield.
To provide evidence that 18E and 18E′ are indeed
atropisomers, we briefly studied the epoxidation of the
kinetically-formed lactone 18E (Scheme 5). An ap-
proximately equal mixture of 18Z and 18E was again
prepared by the Claisen rearrangement route (see Scheme
2). Epoxidation of this mixture gave two epoxides 28E
and 28Z which were found to be different from 26 (see
Scheme 4). While it is likely that the difference between
26 and the 28E is in the configuration of the epoxide, it
could also be due to atropisomerism. Hence, we opened
the epoxides 28E and 28Z to the hydroxy esters 29E and
29Z to remove the possibility of atropisomerism. It was
found that the hydroxy ester 29E was different from the
hydroxy ester 27 in Scheme 4, proving that 18E and 18E′
were indeed atropisomers, each presenting a different
π-face to the oxidant. The lowest energy conformation
of 18E is shown in Scheme 5. The alkene π-system is
essentially orthogonal to the mean plane of the nine-
(41) (a) Still, W. C.; Romero, A. G. J . Am. Chem. Soc. 1986, 108,
2105. (b) Schreiber, S. L.; Sammakia, T.; Hulin, B.; Schulte, G. J . Am.
Chem. Soc. 1986, 108, 2106.

5550 J . Org. Chem., Vol. 61, No. 16, 1996
Pearson and Hembre
Sch em e 6. Syn th esis of Hom oa u str a lin e (9) a n d
8-Ep ih om oa lexin e (10)
membered ring, thus explaining the high stereoselectivity
of the epoxidation.42
The conversion of 19Z to homoaustraline (9) and
8-epihomoalexine (10) is shown in Scheme 6. A Mit-
sunobu reaction with hydrazoic acid39 was used again to
convert the alcohol 19Z into the azide 30. Epoxidation
of 30 afforded an inseparable 1.4:1 mixture of the
diastereomeric cis-epoxides 31R and 31â.40 Reduction of
the azide followed by treatment with methanolic sodium
methoxide caused double cyclization, producing the in-
dolizidinones 32 and 33 in 45% and 33% isolated yields
after separation by column chromatography. Reduction
of 32 with borane gave the indolizidine 34, which was
deprotected by hydrogenolysis to afford homoaustraline
(9). Similarly, reduction of 33 gave 35, which was
deprotected to produce 8-epihomoalexine (10).
Biologica l Scr een in g of th e In d olizid in es 7-10
The four hydroxymethyl substituted indolizidines were
screened for inhibitory activity against a number of
common glycosidases that accept p-nitrophenyl glycosides
as substrates.29 All four compounds were found to to be
good inhibitors of amyloglucosidase (Aspergillus niger,
p-nitrophenyl-R-glucopyranoside as substrate): IC50 ) 75
µM (homoalexine 7), 12 µM (8-epihomoaustraline 8), 95
µM (homoaustraline 9), 4.5 µM (8-epihomoalexine 10).
Inhibition of amyloglucosidase by the indolizidine ho-
mologs 7-9 is roughly tenfold weaker than that exhibited
by the corresponding pyrrolizidines alexine (3) (IC50
)
11 µM26), 7-epiaustraline (IC50 ) 0.13 µM26), and austra-
line (4) (IC50 ) 5.8 µM,29 1.5 µM26).43 Indolizidines 7-10
do not inhibit â-glucosidase (almond) or R-glucosidase
(bakers’ yeast), exhibiting less than 50% inhibition at
inhibitor concentrations of up to 2 mM. This activity
parallels that exhibited by the pyrrolizidine inhibitors
alexine, australine, and 7-epiaustraline, which are gener-
ally good amyloglucosidase inhibitors but relatively weak
inhibitors of R-glucosidase and â-glucosidase.26,29
In contrast to the pyrrolizidine inhibitors, which do not
possess mannosidase inhibitory activity,28,29 the indoliz-
idines 7-10 were found to inhibit R-mannosidase (jack
bean) albeit weakly: IC50 ) 530 µM (7), 150 µM (8), 190
µM (9), 480 µM (10). The fact that these compounds are
mannosidase inhibitors at all is significant, since most
good mannosidase inhibitors are epimeric to 7-10 at the
carbon corresponding to C(1) (e.g. swainsonine (6)).15,18
This suggests that a similar 3-(hydroxymethyl)-substi-
tuted swainsonine analog might provide a potent man-
nosidase inhibitor. Efforts to prepare such a compound
are underway. More extensive biological testing of
compounds 7-10, including screening for anti-HIV activ-
ity, will be reported in due course.
extreme care. All work involving hydrazoic acid solutions were
carried out in an efficient fume hood. The solution was
transferred via cannula, and any excess hydrazoic acid was
quenched by the addition of 10% NaOH. Tetrahydrofuran was
distilled from sodium/benzophenone ketyl. Toluene, benzene,
dichloromethane, dimethyl sulfoxide, and triethylamine were
distilled 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. 1H NMR
spectral assignments and stereochemical determinations were
made on the basis of two-dimensional correlated off resonance
spectroscopy (COSY) experiments as well as two-dimensional
nuclear Overhauser effect spectroscopy (NOESY). J -Modu-
lated spin echo Fourier transform (J MOD) 13C NMR experi-
ments 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
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.44 Ca u tion : Hydrazoic acid should be handled with
(42) Note that the structure of 18E shown in Scheme 5 differs from
the structure of 18E′ in Scheme 4 in two ways. First, the alkene π-face
exposed to oxidant is different for each. Second, each lactone has a
different ester π-face on the periphery of the ring. Structures with the
same orientation of the ester but with different alkene π-faces exposed
were higher in energy.
(43) The biological activity of 7-epialexine has not been reported.
The screens performed by Nash et al. used potato amylose as the
substrate, rather than p-nitrophenyl-R-glucopyranoside.
(44) Wolff, H. In Organic Reactions; Adams, R., Ed.; Wiley: New
York, 1946; Vol. 3, pp 307-336.

Ring-Expanded Analogs of Alexine and Australine
J . Org. Chem., Vol. 61, No. 16, 1996 5551
(HRMS) measurements are accurate to within 2.2 ppm (elec-
tron 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 ac-
cording to the general procedure described by Still45 using flash
grade Merck Silica Gel 60 (230-400 mesh). The enzymes
R-mannosidase (from jack bean), R-glucosidase (from bakers’
yeast), â-glucosidase (from almonds), amyloglucosidase (from
Aspergillus niger), and the corresponding p-nitrophenyl gly-
coside substrates were obtained from Sigma Chemical Co.
Enzyme inhibition was assayed colorimetrically by monitoring
the release of p-nitrophenol from the appropriate p-nitrophenyl
glycoside substrate according to the procedure described by
Tropea et al.29
oil. This mixture was dissolved in toluene (400 mL) and
treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.80
mL, 1.83 g, 12.0 mmol). The resulting mixture was warmed
to reflux for 24 h and then cooled to room temperature and
concentrated. Chromatography (15:1 to 10:1 hex/EtOAc gradi-
ent) provided 660 mg (35%) of a mixture of 18Z and 18E (1:1
based on 1H NMR integration) followed by 350 mg (19%) of
pure 18E′. Data for the 18Z/18E mixture (see below for
spectra of pure 18Z): Rf ) 0.40 (4:1 hex/EtOAc); 1H NMR
(CDCl3, 360 MHz) δ 7.2-7.4 (m, 30H), 5.84 (m, 2H), 5.70 (m,
1H), 5.55 (t, J ) 10.4 Hz, 1H), 5.11 (dt, J ) 1, 7.5 Hz, 1H),
4.95 (d, J ) 10.7 Hz, 1H), 4.79 (m, 1H), 4.35-4.72 (m, 12H),
4.21 (m, 1H), 3.98 (dd, J ) 3.4, 7.2 Hz, 1H), 3.79 (m, 2H), 3.71
(dd, J ) 5.8, 9.4 Hz, 1H), 3.56 (m, 2H), 2.70 (m, 2H), 2.54 (m,
1H), 2.28-2.46 (m, 4H), 2.13 (dt, J ) 5.8, 11.1 Hz, 1H); 13C
NMR (CDCl3, 90 MHz) δ 174.2, 174.1, 138.6, 138.3, 138.2,
137.9, 137.6, 135.2, 132.4, 131.1, 128.4, 128.35, 128.30, 128.27,
128.1, 128.0, 127.8, 127.65, 127.60, 127.5, 127.3, 121.5, 82.5,
79.9, 79.1, 75.8, 75.6, 73.3, 73.0, 72.6, 71.2, 70.8, 68.0, 67.7,
33.9, 33.6, 23.9, 22.8; IR (neat) 3030 (w), 2933 (m), 2865 (m),
1742 (s), 1454 (m), 1094 (s), cm-1; MS (CI, NH3) m/ z (rel
intensity) 490 [(M + NH4)+, 100], 365 (38), 302 (29), 257 (30);
HRMS (EI, 70 eV) calcd for C30H32O5 472.2250, found 472.2240.
Anal. Calcd for C30H32O5: C, 76.25; H, 6.83. Found: C, 76.32;
H, 6.98.
(2S,3R,4R,5S)-2,5-Dih yd r oxy-1,3,4-t r is(b en zyloxy)-6-
h ep ten e (16r) a n d (2S,3R,4R,5R)-2,5-Dih yd r oxy-1,3,4-
tr is(ben zyloxy)-6-h ep ten e (16â). Prepared according to the
literature procedure for the enantiomeric series.35 Vinyl
magnesium bromide (15 mL of a 1 M solution in THF, 15
mmol) was added to a cold (0 °C) solution of 2,3,5-tri-O-benzyl-
L-xylofuranose9,34 (2.08 g, 4.94 mmol) in THF (25 mL). After
3 h, the reaction was quenched by the addition of saturated
aqueous NH4Cl (5 mL). The resulting mixture was diluted
with water (50 mL) and extracted with ether (2 × 100 mL).
The combined organic layers were washed with brine, dried
(MgSO4), and concentrated. Chromatography (3:1 to 2:1 hex/
EtOAc gradient) provided 2.16 g (97%) of diols 16R and 16â
Da ta for 18E′: Rf ) 0.32 (4:1 hex/EtOAc); [R]23 ) +63.1°
D
1
(c ) 1.27, CHCl3); H NMR (CDCl3, 300 MHz) δ 7.2-7.4 (m,
15H), 5.88 (m, 1H), 5.46 (dd, J ) 7.9, 16.7 Hz, 1H), 5.09 (t, J
) 6.9 Hz, 1H), 4.51 (ABq, J ) 12.0 Hz, ∆ν ) 74.9 Hz, 2H),
4.48 (ABq, J ) 12.1 Hz, ∆ν ) 77.3 Hz, 2H), 4.42 (s, 2H), 4.19
(d, J ) 7.8 Hz, 1H), 3.76 (s, 1H), 3.55 (dd, J ) 6.8, 9.7 Hz,
1H), 3.44 (dd, J ) 7.1, 9.7 Hz, 1H), 2.25-2.51 (m, 4H); 13C
NMR (CDCl3, 90 MHz) δ 174.7, 137.95, 137.90, 137.5, 132.2,
130.1, 128.5, 128.4, 128.3, 127.9, 127.9, 127.8, 127.7, 127.6,
81.2, 79.3, 72.9, 72.7, 71.9, 70.1, 68.7, 35.7, 29.1; IR (neat) 3030
(w), 2922 (w), 2864 (m), 1738 (s), 1454 (m), 1116 (s) cm-1; MS
(CI, NH3) m/ z (rel intensity) 490 [(M + NH4)+, 70], 473 [(M +
H)+, 13], 365 (100), 275 (43), 257 (80), 198 (47), 181 (32), 108
(91), 91 (77); HRMS calcd for C30H32O5H [(M + H)+] 473.2328,
found 473.2309. Anal. Calcd for C30H32O5: C, 76.25; H, 6.83.
Found: C, 76.20; H, 7.11.
1
as a 3:2 mixture (not separated) based on H NMR integration.
Rf ) 0.25 (2:1 hex/EtOAc); major isomer 16R: 1H NMR (CDCl3,
200 MHz) δ 7.2-7.4 (m, 15H), 5.91 (ddd, J ) 5.1, 10.5, 17.2
Hz, 1H), 5.35 (dt, J ) 1.6, 17.2 Hz, 1H), 5.18 (dt, J ) 1.6, 10.5
Hz, 1H), 4.38-4.85 (m, 7H), 4.10 (ddd, J ) ∼1, 6.8, 12.2 Hz,
1H), 3.71 (dd, J ) 1.6, 6.5 Hz, 1H), 3.57 (dd, J ) 1.9, 6.5 Hz,
1H), 3.54 (dd, J ) 6.3, 9.3 Hz, 1H), 3.42 (dd, J ) 6.6, 9.3 Hz,
1H), 3.14 (d, J ) 6.3 Hz, 1H), 3.05 (d, J ) 7.4 Hz, 1H); 13C
NMR (CDCl3, 90 MHz) δ 138.6, 138.0, 128.45, 128.40, 128.3,
128.2, 128.0, 127.9, 127.8, 127.7, 115.5, 80.2, 77.1, 74.40, 74.35,
73.2, 71.1, 70.5, 68.3; minor isomer 16â: 1H NMR (CDCl3, 200
MHz) δ 7.2-7.4 (m, 15H), 6.00 (ddd, J ) 6.1, 10.5, 17.2 Hz,
1H), 5.37 (dt, J ) 1.6, 17.2 Hz, 1H), 5.23 (dt, J ) 1.6, 10.5 Hz,
1H), 4.38-4.75 (m, 7H), 4.06 (dt, J ) 3.2, 6.2 Hz, 1H), 3.76
(dd, J ) 2.9, 5.2 Hz, 1H), 3.64 (t, J ) 5 Hz, 1H), 3.50 (dd, J )
6.1, 9.5 Hz, 1H), 3.42 (dd, J ) 6.1, 9.5 Hz, 1H), 3.09 (br d, J )
5, 1H), 2.75 (br d, J ) 6, 1H); IR (neat, mixture of isomers)
3410 (br m), 3030 (m), 2911 (m), 2864 (m), 1454 (m), 1092 (s),
Con ver sion of 18E to 18E′. A mixture of 18Z and 18E
(1.7:1, 45 mg, 0.095 mmol) was dissolved in toluene (2 mL)
and warmed to reflux. After 24 h, the solution was cooled to
room temperature and concentrated. 1H NMR of the crude
reaction mixture showed that peaks corresponding to 18Z were
still present, while peaks corresponding to 18E had nearly
dissappeared, being replaced by peaks corresponding to 18E′.
Chromatography (5:1 hex/EtOAc) provided 28 mg (62%) of a
10:1 mixture of 18Z/18E followed by 16 mg (36%) of 18E′. Data
for 18Z: Rf ) 0.40 (4:1 hex/EtOAc); 1H NMR (CDCl3, 300 MHz)
δ 7.2-7.4 (m, 15 H), 5.84 (m, 1H), 5.56 (t, J ) 10.4 Hz, 1H),
4.94 (d, J ) 10.8 Hz, 1H), 4.79 (ddd, J ) 3.9, 5.8, 8.2 Hz, 1H),
4.69 (m, 1H), 4.67 (d, J ) 10.8 Hz, 1H), 4.62 (d, J ) 11.6 Hz,
1H), 4.52 (ABq, J ) 11.8 Hz, ∆ν ) 14.1 Hz, 2H), 4.40 (d, J )
11.6 Hz, 1H), 3.98 (dd, J ) 3.7, 7.3 Hz, 1H), 3.80 (t, J ) 9 Hz,
1H), 3.71 (dd, J ) 5.8, 9.0 Hz, 1H), 2.70 (m, 2H), 2.33 (m, 1H),
2.14 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 174.0, 138.7, 138.2,
138.0, 132.3, 131.1, 128.3, 128.2, 128.0, 127.9, 125.6, 127.5,
127.4, 127.3, 82.6, 79.1, 75.8, 75.6, 73.3, 70.8, 67.8, 34.0, 24.0.
See above for 18E′ spectral data.
Meth yl (E)-(6R,7S,8S)-8-Hyd r oxy-6,7,9-tr is(ben zyloxy)-
4-n on en oa te (19E) a n d Meth yl (Z)-(6R,7S,8S)-8-Hyd r oxy-
6,7,9-tr is(ben zyloxy)-4-n on en oa te (19Z). Sodium methox-
ide (50 mg, 0.9 mmol) was added to a mixture of cis and trans
lactones 18Z and 18E (1:1 mixture of isomers, 735 mg, 1.56
mmol) in CH2Cl2/MeOH (2:1, 12 mL) at room temperature.
After 30 min, the mixture was poured into water (20 mL) and
extracted with ether (2 × 40 mL). The combined organic layers
were washed with brine (20 mL), dried (MgSO4), and concen-
trated. Chromatography (4:1 hex/EtOAc) provided 310 mg
(39%) of 19Z as a pale yellow oil, followed by 290 mg (37%) of
1066 (s) cm-1
.
The 1H- and 13C-NMR spectroscopic data
reported above are consistent with those reported by Boschetti
et al. for the enantiomers.35
(Z)-(7R,8S,9S)-7,8-Bis(ben zyloxy)-9-[(ben zyloxy)m eth yl]-
1-oxa -2-oxocyclon on -5-en e (18Z) a n d (E)-(7R,8S,9S)-7,8-
Bis(ben zyloxy)-9-[(ben zyloxy)m eth yl]-1-oxa -2-oxocyclo-
n on -5-en e (18E an d 18E′). (Phenylseleno)acetaldehyde diethyl
acetal37,38 (1.32 g, 4.82 mmol) and pyridinium p-toluene-
sulfonate (PPTS) (50 mg, 0.20 mmol) were added to a solution
of diols 16R/16â (1.80 g, 4.01 mmol) in toluene (40 mL), and
the resulting mixture was warmed to reflux. After 4.5 h, the
mixture was poured into 10% NaHCO3 (40 mL) and extracted
with ether (3 × 50 mL). The combined organic layers were
washed with brine, dried (MgSO4), and concentrated to give a
yellow oil that was found by 1H- and 13C-NMR spectroscopy
to be a complex mixture of diastereomeric acetals, Rf ) 0.38
(4:1 hex/EtOAc). The crude residue was dissolved in MeOH
(330 mL) and water (50 mL), and then NaHCO3 (0.45 g, 5.3
mmol) and sodium periodate (NaIO4) (3.09 g, 14.4 mmol) were
added. After 10 min at room temperature, a white precipitate
formed. After 2 h, the mixture was poured into water (1.2 L)
and extracted with EtOAc (3 × 400 mL). The combined
organic layers were dried (Na2SO4) and concentrated. The
residue was applied to a plug of silica gel (ca. 30 g) and was
eluted with 5:1 hex/EtOAc (100 mL) followed by 20:1 CHCl3/
MeOH (200 mL). The selenoxide-containing fractions [Rf )
0.24 (20:1 CHCl3/MeOH)] were then concentrated to give 1.5
g of a mixture of diastereomeric selenoxides as a pale yellow
19E as a pale yellow oil. Data for 19Z: Rf ) 0.21 (4:1 hex/
1
EtOAc); [R]23 ) +19.2° (c ) 1.32, CHCl3); H NMR (CDCl3,
D
360 MHz) δ 7.2-7.4 (m, 15H, ArH), 5.69 (dt, J ) 6.5, 11.0 Hz,
1H, H-4), 5.44 (dd, J ) 9.7, 11.0 Hz, 1H, H-5), 4.73 (ABq, J )
(45) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

5552 J . Org. Chem., Vol. 61, No. 16, 1996
Pearson and Hembre
11.2 Hz, ∆ν ) 130.4 Hz, 2H, OCH2Ph), 4.52 (dd, J ) 7.1, 9.7
Hz, 1H, H-6), 4.50 (ABq, J ) 11.7 Hz, ∆ν ) 74.2 Hz, 2H, OCH2-
Ph), 4.44 (ABq, J ) 11.9 Hz, ∆ν ) 20.4 Hz, 2H, -OCH2Ph),
3.85 (ddd, J ) 2.0, 6.3, 13.5 Hz, 1H, H-8), 3.66 (s, 3H, -OCH3),
3.61 (dd, J ) 2.0, 7.1 Hz, 1H, H-7), 3.45 (dd, J ) 6.1, 9.3 Hz,
1H, H-9), 3.40 (dd, J ) 6.5, 9.3 Hz, 1H, H-9), 2.51 (d, J ) 7.4
Hz, 1H, -OH), 2.4 (m, 4H, H-2 and H-3); 13C NMR (CDCl3, 90
MHz) δ 173.4, 138.5, 138.0, 133.7, 128.4, 128.35, 128.30,
128.25, 127.9, 127.8, 127.7, 127.5, 80.4, 75.3, 73.3, 70.6, 70.0,
51.6, 33.6, 23.3; IR (neat) 3500 (br m), 3030 (m), 2919 (m),
2860 (m), 1738 (s), 1093 (s) cm -1; MS (CI, NH3) m/ z (rel
intensity) 522 [(M + NH4)+, 36], 414 (27), 289 (32), 247 (100),
108 (41), HRMS calcd. for C31H36O6NH4 [(M + NH4)+] 522.2856,
found 522.2847. Anal. Calcd for C31H36O6: C, 73.79; H, 7.19.
Found: C, 73.66; H, 7.41.
See below for an alternate preparation of 21R. m-Chloroper-
oxybenzoic acid (201 mg technical grade, 160 mg pure oxidant,
0.93 mmol) was added to a cold (0 °C) solution of the trans-
azido-alkene 20 (197 mg, 0.371 mmol) in CH2Cl2 (1.9 mL), and
the mixture was allowed to warm slowly to room temperature.
After 24 h, the mixture was diluted with ether (10 mL) and
washed with 1 M NaOH (2 × 5 mL), 10% NaHCO3 (5 mL),
and brine (5 mL) and then dried (MgSO4) and concentrated.
Chromatography (6:1 hex/EtOAc) provided 135 mg (67%) of
an inseparable mixture of 21R and 21â (1:2 based on 1H and
13C NMR integration) as a colorless oil. The stereochemical
assignment of these epoxides was made by conversion to the
indolizidines 24 and 25 (see below). Rf ) 0.20 (5:1 hex/EtOAc);
1H NMR (CDCl3, 300 MHz, R indicates 21R, â indicates 21â,
integration R:â ) 1:2) δ 7.2-7.4 (m, 15HR and 15Hâ), 4.83 (d,
J ) 11.7 Hz, 1HR), 4.68 (d, J ) 11.2 Hz, 1Hâ) 4.5-4.65 (m,
5HR and 5Hâ), 3.78-3.87 (m, 2HR and 2Hâ), 3.6-3.75 (m, 2HR
and 2Hâ), 3.67 (s, 3Hâ), 3.66 (s, 3HR), 3.31 (dd, J ) 2.7, 6.8
Hz, 1Hâ), 3.26 (dd, J ) 3.2, 7.1 Hz, 1HR), 3.05 (dd, J ) 2.2,
7.1 Hz, 1HR), 2.86 (m, 1HR and 1Hâ), 2.39 (t, J ) 7.4 Hz, 2HR),
2.38 (t, J ) 7.4 Hz, 2Hâ), 1.85-2.02 (m, 1HR and 1Hâ), 1.5-
1.7 (m, 1HR and 1Hâ); 13C NMR (CDCl3, 90 MHz, R indicates
21R, â indicates 21â) δ 173.0, 137.9, 137.8, 137.7, 137.6, 137.4,
128.8, 128.41, 128.36, 128.32, 128.2, 128.1, 128.0, 127.9,
127.81, 127.78, 127.75, 127.66, 127.62, 79.6 (R), 78.9 (R), 78.2
(â), 78.2 (â), 74.9 (â), 74.2 (R), 73.4 (R), 73.2 (â), 73.0 (â), 72.3
(R), 69.6 (â), 69.3 (R), 61.1 (R), 60.6 (â), 59.2 (R), 58.3 (â), 56.3
(â), 53.3 (R), 51.7 (â), 29.9 (R), 29.8 (â), 26.6 (â), 26.5 (R); IR
Da ta for 19E: Rf ) 0.15 (4:1 hex/EtOAc); [R]23 ) -3.6° (c
D
1
) 0.72, CHCl3); H NMR (CDCl3, 360 MHz) δ 7.19-7.36 (m,
15H, ArH), 5.75 (m, 1H, H-4), 5.50 (dd, J ) 8.4, 15.7 Hz, 1H,
H-5), 4.70 (ABq, J ) 11.3 Hz, ∆ν ) 107 Hz, 2H, OCH2Ph),
4.46 (ABq, J ) 11.8 Hz, ∆ν ) 85.2 Hz, 2H, OCH2Ph), 4.44
(ABq, J ) 11.9 Hz, ∆ν ) 15.9 Hz, 2H, OCH2Ph), 4.05 (dd, J )
7.0, 7.9 Hz, 1H, H-6), 3.88 (ddd, J ) 2.4, 6.4, 12.9 Hz, 1H,
H-8), 3.66 (s, 3H, OCH3), 3.57 (dd, J ) 2.5, 6.6 Hz, 1H, H-7),
3.42 (m, 2H, H-9), 2.45 (d, J ) 6.9 Hz, 1H, OH), 2.35-2.42
(m, 4H, H-2 and H-3); 13C NMR (CDCl3, 90 MHz) δ 172.3,
138.4, 138.35, 138.0, 133.9, 128.4, 128.30, 128.28, 128.24,
127.8, 127.7, 127.5, 81.6, 80.3, 75.0, 73.3, 71.2, 70.3, 70.0, 51.6,
33.5, 27.6; IR (neat) 3470 (br m), 3030 (m), 2919 (m), 2860
(m), 1738 (s) cm-1; MS (CI, NH3) m/ z (rel intensity) 522 [(M
+ NH4)+, 45], 414 (30), 289 (39), 247 (100), 168 (42), 106 (62);
HRMS calcd for C31H36O6NH4 [(M + NH4)+] 522.2856, found
522.2859. Anal. Calcd for C31H36O6: C, 73.79; H, 7.19.
Found: C, 73.55; H, 7.40.
(neat) 3030 (m), 2920 (m), 2867 (m), 2098 (s), 1738 (s) cm-1
;
MS (CI, NH3) m/ z (rel intensity) 563 [(M + NH4)+, 42], 518
(100), 488 (27), 402 (24), 108 (24); HRMS calcd for C31H35N3O6-
NH4 [(M + NH4)+] 563.2870, found 563.2889. Anal. Calcd for
C31H35N3O6: C, 68.24; H, 6.47; N, 7.70. Found: C, 68.17; H,
6.47; N, 7.64. See below for the spectra of pure 21R.
Meth yl (E)-(6R,7S,8S)-8-Hyd r oxy-6,7,9-tr is(ben zyloxy)-
4-n on en oa te (19E) fr om P u r e 18E′. Sodium methoxide (10
mg, 0.19 mmol) was added to a solution of lactone 18E′ (55
mg, 0.12 mmol) in CH2Cl2/MeOH (2:1, 1.5 mL) at room
temperature. After 30 min, the mixture was poured into water
(5 mL) and extracted with ether (2 × 10 mL). The combined
organic layers were washed with brine (5 mL), dried (MgSO4),
and concentrated. Chromatography (3:1 hex/EtOAc) provided
53 mg (91%) of 19E as a pale yellow oil. See above for spectral
data.
(1R,2R,3R,8S,8a S)-3-[(Ben zyloxy)m eth yl]-1,2-bis(ben -
zyloxy)-8-h yd r oxyin d olizid in -5-on e (22) a n d (1R,2R,3R,-
8R,8a R)-3-[(Ben zyloxy)m eth yl]-1,2-bis(ben zyloxy)-8-h y-
d r oxyin d olizid in -5-on e (23). See below for an alternate
preparation of 23. Palladium hydroxide on carbon (25 mg) was
added to a solution of the azido epoxides 21â and 21R (2:1
mixture of diastereomers, 122 mg, 0.224 mmol) in MeOH/
EtOAc (1:1, 5 mL). The flask was evacuated (aspirator) and
purged with hydrogen three times. The mixture was stirred
under a balloon of hydrogen for 4 h, and then the hydrogen
was evacuated and the mixture was filtered, rinsing with
MeOH (5 mL). The filtrate was concentrated, and the residue
was redissolved in MeOH (15 mL). Sodium methoxide (15 mg,
0.48 mmol) was added, and the mixture was warmed to reflux.
After 24 h, the mixture was cooled to room temperature and
concentrated. Chromatography (100:1 CHCl3/MeOH) provided
86 mg (79%) of the inseparable lactams 22 and 23 (2:1 mixture
Meth yl (E)-(6R,7R,8R)-8-Azid o-6,7,9-tr is(ben zyloxy)-4-
n on en oa te (20). Hydrazoic acid (HN3)44 (0.82 mL of a 1.2 M
solution in benzene, 0.98 mmol) was added to a solution of
the alcohol 19E (248 mg, 0.491 mmol) and triphenylphosphine
(PPh3) (193 mg, 737 mmol) in benzene (2.5 mL). The resulting
mixture was cooled to 5 °C and diethyl azodicarboxylate
(DEAD) (128 mg, 0.737 mmol) was added in a dropwise
fashion. The solution was allowed to warm slowly to room
temperature. After 1.5 h, more HN3 solution (0.40 mL, 0.48
mmol), PPh3 (64 mg, 0.245 mmol), and DEAD (40 mg, 0.245
mmol) were added. After another 45 min, the solution was
diluted with hexanes (10 mL), the resulting precipitate was
filtered off, and the filtrate was concentrated without warming.
[Heating or prolonged standing at room temperature resulted
in an intramolecular 1,3-dipolar cycloaddition.] Chromatog-
raphy (10:1 hex/EtOAc) provided 214 mg (82%) of the title
1
based on H NMR integration) as an oil. The stereochemistry
of these compounds was based on the analysis of indolizidines
24 and 25 (see below). Rf ) 0.38 (20:1 CHCl3/MeOH); 1H NMR
(CDCl3, 300 MHz) (A indicates minor isomer 23, B indicates
major isomer 22) δ 7.2-7.4 [m, (15 HA + 15 HB)], 4.69 (d, J )
11.8 Hz, 1HA), 4.65 (d, J ) 12.1 Hz, 1HB), 4.63 (d, J ) 11.9
Hz, 1HB), 4.62 (d, J ) 11.8 Hz, 1HA), 4.59 (d, J ) 11.6 Hz,
1HA), 4.54 (s, 2HA), 4.48 (d, J ) 12.0 Hz, 1HB), 4.46 (d, J )
11.9 Hz, 1HB), 4.43 (d, J ) 11.6 Hz, 1HA), 4.33 (dt, J ) 3.4,
6.0 Hz, 1HA), 4.26 (m, 1HB), 4.24 (d, J ) 11.9 Hz, 1HB), 4.23
(dd, J ) 3.4, 4.8 Hz, 1HA), 4.17 (dd, J ) 4.4, 8.6 Hz, 1HB), 4.16
(s, 1HB), 4.05 (m, 1HB), 4.00 (d, J ) 3.8 Hz, 1HB), 3.96 (dd, J
) 4.8, 8.2 Hz, 1HA), 3.72 (dd, J ) 6.2, 9.4 Hz, 1HA), 3.70-3.76
(m, 1HA,), 3.64 (dd, J ) 3.6, 9.4 Hz, 1HA), 3.61 (dd, J ) 3.8,
9.0 Hz, 1HB), 3.45 (t, J ) 8.3 Hz, 1HA), 3.29 (dd, J ) 8.7, 10.5
Hz, 1HB), 2.67 (br d, J ) 2.6 Hz, 1HA) 2.48 (ddd, J ) 2.5, 6.7,
18.3 Hz, 1HA), 2.25-2.45 (m, 2HA and 2HB), 2.17 (br d, J )
3.0 Hz, 1HB), 1.95-2.10 (m, 1HA and 1HB), 1.65-1.80 (m, 1HA
and 1HB); 13C NMR (CDCl3, 75 MHz) δ 169.3 (A), 167.8 (B),
138.3, 137.51, 137.47, 128.5, 128.4, 128.32, 128.28, 128.20,
128.0, 127.9, 127.8, 127.7, 127.63, 127.59, 127.44, 87.7 (B), 83.2
(B), 80.1 (A), 78.9 (A), 73.3 (B), 73.0 (A), 71.9 (B), 71.4 (A),
70.9 (A), 70.2 (B), 68.7 (B), 66.9 (A), 66.3 (A), 65.6 (B), 64.8
(A), 62.6 (A), 61.0 (B), 30.6 (A), 30.0 (A), 29.7 (B), 29.1 (B); IR
(neat) 3362 (br m), 3031 (m), 2936 (m), 2867 (m), 1651 (s), 1621
compound as a colorless oil. Rf ) 0.33 (5:1 hex/EtOAc); [R]23
D
) -24.6° (c ) 0.24, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.2-
7.4 (m, 15H), 5.69 (m, 1H), 5.50 (dd, J ) 8.2, 15.5 Hz, 1H),
4.60 (ABq, J ) 11.2 Hz, ∆ν ) 25.8 Hz, 2H), 4.52 (ABq, J )
11.9 Hz, ∆ν ) 13.9 Hz, 2H), 4.44 (ABq, J ) 11.8 Hz, ∆ν )
77.1 Hz, 2H), 3.92 (dd, J ) 4.4, 8.1 Hz, 1H), 3.77 (m, 2H), 3.67
(dd, J ) 7.3, 10.5 Hz, 1H), 3.65 (s, 3H), 3.54 (dd, J ) 4.4, 6.5
Hz, 1H), 2.39 (m, 4H); 13C NMR (CDCl3, 90 MHz) δ 173.2,
138.2, 138.0, 137.8, 133.7, 128.4, 128.3, 128.2, 128.0, 127.7,
127.6, 81.1, 79.9, 75.0, 73.3, 70.3, 69.4, 61.5, 51.6, 33.4, 27.5;
IR (neat) 3030 (m), 2920 (m), 2864 (m), 2096 (s), 1738 (s) cm-1
;
MS (CI, NH3) m/ z (rel intensity) 502 [(M - N2+H)+, 100], 286
(15); HRMS calcd for C31H35NO5H [(M - N2+H)+] 502.2593,
found 502.2571.
Met h yl (4R,5S,6S,7R,8R)-8-Azid o-4,5-ep oxy-6,7,9-t r is-
(ben zyloxy)n on an oate (21r) an d Meth yl (4S,5R,6S,7R,8R)-
8-Azid o-4,5-ep oxy-6,7,9-tr is(ben zyloxy)n on a n oa te (21â).

Ring-Expanded Analogs of Alexine and Australine
J . Org. Chem., Vol. 61, No. 16, 1996 5553
(s), 1413 (s) cm-1; MS (CI, NH3) m/ z (rel intensity) 488 [(M +
H)+, 100], 396 (2), 108 (2); HRMS (CI, CH4 and NH3) calcd for
C30H33NO5H [(M + H)+] 488.2437, found 488.2426. See below
for spectra of pure 23.
23.1; IR (neat) 3330 (br s), 2940 (m), 2858 (w), 2807 (w), 1650
(w) cm-1; MS (CI, NH3) m/ z (rel intensity) 204 [(M + H)+, 100],
172 (9); HRMS calcd for C9H17NO4 [(M + H)+] 204.1236, found
204.1238.
(1R,2R,3R,8S,8a S)-3-[(Ben zyloxy)m eth yl]-1,2-bis(ben -
zyloxy)-8-h ydr oxyin dolizidin e (24) an d (1R,2R,3R,8R,8aR)-
3-[(Ben zyloxy)m et h yl]-1,2-b is(b en zyloxy)-8-h yd r oxyin -
d olizid in e (25). Borane-methyl sulfide complex (0.31 mL
of a 2 M solution in THF, 0.62 mmol) was added to a cool (0
°C) solution of the lactams 22 and 23 (2:1 mixture of diaster-
eomers, 71 mg, 0.15 mmol) in THF (3.9 mL). After 30 min,
the mixture was warmed to room temperature. After 6 h, the
reaction was quenched by the slow addition of EtOH (2 mL).
After 30 min, the mixture was concentrated, and the residue
was redissolved in EtOH (4 mL) and warmed to reflux. After
2 h, the mixture was cooled to room temperature and concen-
trated. Chromatography (66:33:1 to 50:50:1 hex/EtOAc/
MeOH) provided 44 mg (64%) of major diastereomer 24 as a
pale yellow oil, followed by 22 mg (32%) of minor diastereomer
25 as a pale yellow oil. Data for 24: Rf ) 0.46 (1:1 hex/EtOAc);
(1R,2R,3R,8R,8aR)-3-(Hydr oxym eth yl)-1,2,8-tr ih ydr oxy-
in d olizid in e [8-Ep ih om oa u str a lin e, (8)]. Palladium on
carbon (10%, 8 mg) and 6 N HCl (4 drops) were added to a
solution of the indolizidine 25 (16.7 mg, 0.035 mmol) in MeOH
(2 mL). The flask was evacuated (aspirator) and purged with
hydrogen three times. The mixture was stirred under a
balloon of hydrogen at room temperature for 20 h, and then
the hydrogen was evacuated and the mixture was filtered
through a cotton plug, rinsing with MeOH (2 mL). The filtrate
was concentrated, and the residue was dissolved in water and
stirred with Dowex 1 × 8 200 -OH ion exchange resin (0.5 g
dry resin). After 30 min, the mixture was filtered and the
filtrate was concentrated on a rotary evaporator. Chroma-
tography (5:1 to 3:1 CHCl3/MeOH gradient, SiO2) provided 5.3
mg (74%) of the title compound as a colorless oil. Rf ) 0.35
(2:1 CHCl3/MeOH); [R]23D ) -25.2° (c ) 0.63, MeOH); 1H NMR
(D2O, 300 MHz) δ 4.03 (app t, J ) 4 Hz, 1H), 3.96 (app t, J )
4 Hz, 1H), 3.80 (dd, J ) 4.9, 12.0 Hz, 1H), 3.73 (dd, J ) 5.0,
12.0 Hz, 1H), 3.62 (dt, J ) 4.5, 10.8 Hz, 1H), 3.05 (dd, J ) 4.6,
9.2 Hz, 1H), 2.97 (br d, J ) 12.9 Hz, 1H), 2.56-2.74 (m, 2H),
2.02 (m, 1H), 1.55-1.70 (m, 2H), 1.32 (app qd, J ) 5.4, 11.7
Hz, 1H); 13C NMR (D2O, CH3OH int std, 75 MHz) δ 80.3, 79.9,
70.7, 68.6, 67.6, 60.1, 45.6, 32.3, 20.9; IR (neat) 3225 (br s),
2932 (m), 2863 (m), 1584 (w) cm-1; MS (CI, NH3) m/ z (rel
[R]23 ) +46.9° (c ) 0.52, CHCl3); 1H NMR (CDCl3, 300 MHz)
D
δ 7.2-7.4 (m, 15H, ArH), 4.52 (ABq, J ) 12.3 Hz, ∆ν ) 78.5
Hz, 2H, OCH2Ph), 4.53 (ABq, J ) 12.0 Hz, ∆ν ) 15.7 Hz, 2H,
-OCH2Ph), 4.48 (s, 2H, OCH2Ph), 3.92 (d, J ) 4.2 Hz, 1H, H-1),
3.89 (m, 1H, H-8), 3.72 (d, J ) 4.0 Hz, 1H, H-2), 3.64 (dd, J )
5.3, 9.7 Hz, 1H, H-9a), 3.52 (dd, J ) 6.4, 9.7 Hz, 1H, H-9b),
3.13 (app dt, J ) ∼3, 10.7 Hz, 1H, H-5eq), 2.64 (app dd, J )
4, 6 Hz, 1H, H-3), 2.17 (dd, J ) 4.2, 9.0 Hz, 1H, H-8a), 2.03
(m, 1H, H-7eq), 1.96 (dd, J ) 3.8, 10.9 Hz, 1H, H-5ax), 1.52-
1.71 (m, 2H, H-6eq and H-6ax), 1.35 (d, J ) 4.0 Hz, 1H, -OH),
1.18 (app qd, J ) 5.5, 12 Hz, 1H, H-7ax); 13C NMR (CDCl3, 75
MHz) δ 138.3, 138.1, 128.5, 128.3, 128.2, 128.0, 127.8, 127.7,
127.5, 127.4, 85.1, 80.2, 73.2, 72.8, 71.4, 71.3, 71.2, 70.8, 66.8,
51.8, 33.0, 24.2; IR (neat) 3440 (br m), 3029 (m), 2935 (s), 2856
(s), 2784 (m), 1605 (w) cm-1; MS (CI, NH3) m/ z (rel intensity)
intensity) 204 [(M + H)+,100], 172 (6); HRMS calcd for C9H17
-
NO4H [(M + H)+] 204.1236, found 204.1241.
(5R,6S,7R,8S,9S)-5,6-Ep oxy-7,8-bis(ben zyloxy)-9-[(ben -
zyloxy)m eth yl]-1-oxa -2-oxocyclon on a n e (26). m-Chloro-
peroxybenzoic acid (146 mg technical grade, 117 mg pure
oxidant, 0.68 mmol) was added to a cold (0 °C) solution of 18E′
(160 mg, 0.339 mmol) in CH2Cl2 (1.7 mL), and the mixture
was allowed to warm slowly to room temperature. After 12
h, the mixture was diluted with ether (10 mL) and washed
with 1 M NaOH (2 × 5 mL), 10% NaHCO3 (5 mL), and brine
(5 mL) and then dried (MgSO4) and concentrated. Chroma-
tography (8:1 hex/EtOAc) provided 145 mg (88%) of the title
474 [(M + H)+, 61], 352 (100), 91 (48); HRMS calcd for C30H35
NO4H [(M + H)+] 474.2644, found 474.2633.
-
Da ta for 25: Rf ) 0.23 (1:1 hex/EtOAc); [R]23 ) -19.2° (c
D
) 0.13, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.2-7.4 (m, 15H,
ArH), 4.52 (ABq, J ) 12.0 Hz, ∆ν ) 50.7 Hz, 2H, OCH2Ph),
4.56 (ABq, J ) 11.9 Hz, ∆ν ) 15.2 Hz, 2H, OCH2Ph), 4.55 (s,
2H, OCH2Ph), 3.99 (dd, J ) 3.0, 5.8 Hz, 1H, H-1), 3.92 (app t,
J ) 2.7 Hz, 1H, H-2), 3.64 (dd, J ) 5.0, 9.4 Hz, 1H, H-9a),
3.52 (m, 2H, H-8 and H-9b), 3.39 (ddd, J ) 2.2, 4.6, 4.8 Hz,
1H, H-3), 2.94 (dt, J ) ∼3, 11.5 Hz, 1H, H-5eq), 2.63 (dd, J )
3.9, 8.8 Hz, 1H, H-8a), 2.51 (ddd, J ) 6.5, 9.0, 11.6 Hz, 1H,
H-5ax), 1.98-2.10 (m, 2H, -OH and H-7eq), 1.62 (m, 2H, H-6eq
and H-6ax), 1.21 (m, 1H, H-7ax); 13C NMR (CDCl3, 75 MHz) δ
138.10, 138.05, 138.00, 128.4, 128.3, 128.1, 127.9, 127.6, 87.9,
85.7, 73.4, 71.5, 71.3, 68.9, 68.6, 65.2, 46.2, 33.0, 22.8; IR (neat)
3440 (br w), 3029 (m), 2926 (s), 2856 (s), 1604 (w), 1454 (s)
cm-1; MS (CI, NH3) m/ z (rel intensity) 474 [(M + H)+, 57],
352 (100), 91 (17); HRMS calcd for C30H35NO4H [(M + H)+]
474.2644, found 474.2638.
compound as a colorless oil. Rf ) 0.47 (2:1 hex/EtOAc); [R]23
D
) -13.5° (c ) 0.95, CHCl3); 1H NMR (CDCl3, 360 MHz) δ 7.2-
7.4 (m, 15H), 5.22 (t, J ) 6.6 Hz, 1H), 4.64 (ABq, J ) 12.0 Hz,
∆ν ) 72.0 Hz, 2H), 4.44 (s, 2H), 4.40 (ABq, J ) 11.8 Hz, ∆ν )
65.2 Hz, 2H), 3.74 (app s, 1H), 3.59 (dd, J ) 6.4, 9.7 Hz, 1H),
3.48 (dd, J ) 7.3, 9.7 Hz, 1H), 3.33 (dd, J ) 1.4, 6.7 Hz, 1H),
3.14 (dt, J ) 3, 9.9 Hz, 1H), 2.68 (dd, J ) 2.6, 6.7 Hz, 1H),
2.61 (ddd, J ) 6.0, 11.2, 13.2 Hz, 1H), 2.51 (m, 1H), 2.43 (ddd,
J ) 2, 5.7, 11.2 Hz, 1H), 1.25 (ddt, J ) 4.5, 8.4, 10.8 Hz, 1H);
13C NMR (CDCl3, 90 MHz) δ 172.9, 137.7, 127.6, 137.2, 128.3,
128.1, 128.0, 127.82, 127.79, 127.67, 79.7, 78.1, 73.0, 72.2, 71.9,
71.0, 68.2, 58.4, 51.7, 32.2, 28.7; IR (neat) 3030 (w), 2868 (m),
1741 (s), 1099 (s), 1059 (s) cm-1; MS (CI, NH3) m/ z (rel
intensity) 506 [(M + NH4)+, 100), 489 [(M + H)+, 6], 397 (27),
181 (21), 108 (36), 91 (67); HRMS (CI, NH3) calcd for C30H32O6-
NH4 [(M + NH4)+] 506.2543, found 506.2535. Anal. Calcd for
C30H32O6: C, 73.75; H, 6.60. Found: C, 73.72; H, 6.68.
Met h yl (4R,5S,6R,7R,8S)-4,5-E p oxy-8-h yd r oxy-6,7,9-
tr is(ben zyloxy)n on a n oa te (27). Sodium bicarbonate (36
mg, 0.43 mmol) was added to a solution of the epoxy-lactone
26 (105 mg, 0.215 mmol) in MeOH/THF (2:1, 6.5 mL). After
3 h at room temperature, the mixture was poured into water
(10 mL) and extracted with ether (2 × 25 mL). The combined
organic layers were washed brine (10 mL) and then dried
(MgSO4) and concentrated. Chromatography (4:1 to 3:1 hex/
EtOAc gradient) provided 100 mg (89%) of the title compound
(1R,2R,3R,8S,8aS)-3-(Hydr oxym eth yl)-1,2,8-tr ih ydr oxy-
in d olizid in e [Hom oa lexin e, (7)]. Palladium on carbon
(10%, 20 mg) and 6 N HCl (4 drops) were added to a solution
of the indolizidine 24 (40 mg, 0.084 mmol) in MeOH (2 mL).
The flask was evacuated (aspirator) and purged with hydrogen
three times. The resulting heterogeneous mixture was stirred
under a balloon of hydrogen at room temperature for 20 h,
and then the hydrogen was evacuated and the mixture was
filtered through a cotton plug, rinsing with MeOH (2 mL). The
filtrate was concentrated, and the residue was dissolved in
water and stirred with Dowex 1 × 8 200 -OH ion exchange
resin (0.5 g dry resin). After 30 min, the mixture was filtered
and the filtrate was concentrated on a rotary evaporator.
Chromatography (5:1 to 3:1 CHCl3/MeOH gradient, SiO2)
provided 15 mg (88%) of the title compound as a colorless oil.
Rf ) 0.42 (2:1 CHCl3/MeOH); [R]23D ) +37.3° (c ) 0.79, MeOH);
1H NMR (D2O, 300 MHz) δ 4.11 (d, J ) 3.8 Hz, 1H), 3.87 (d,
J ) 4.6 Hz, 1H), 3.70-3.83 (m, 3H), 3.21 (br d, J ) 11.1 Hz,
1H), 2.50 (br s, 1H), 2.34 (br d, J ) 5.8 Hz, 1H), 2.04-2.21 (m,
2H), 1.79 (br d, J ) 14 Hz, 1H), 1.56 (qt, J ) 4, 13.2 Hz, 1H),
1.31 (qd, J ) 4.2, 12.4 Hz, 1H); 13C NMR (D2O, CH3OH int
std, 75 MHz) δ 79.3, 75.4, 73.9, 72.2, 65.6, 60.9, 51.5, 32.3,
as a colorless oil. Rf ) 0.27 (2:1 hex/EtOAc); [R]23 ) +14.6°
D
1
(c ) 0.65, CHCl3); H NMR (CDCl3, 300 MHz) δ 7.2-7.4 (m,
15H), 4.68 (ABq, J ) 11.8 Hz, ∆ν ) 69.8 Hz, 2H), 4.58 (ABq,
J ) 11.2 Hz, ∆ν ) 40.8 Hz, 2H), 4.46 (ABq, J ) 11.9 Hz, ∆ν )
14.8 Hz, 2H), 4.04 (ddd, J ) 2.3, 6.2, 13.4 Hz, 1H), 3.68 (dd, J
) 2.7, 5.5 Hz, 1H), 3.64 (s, 3H), 3.44 (m, 2H), 3.37 (dd, J )
5.3, 6.8 Hz, 1H), 3.06 (dd, J ) 2.1, 6.9 Hz, 1H), 2.91 (ddd, J )
2.1, 4.4, 6.5 Hz, 1H), 2.49 (d, J ) 7.4 Hz, 1H), 2.42 (t, J ) 7.5
Hz, 2H), 1.96 (ddt, J ) 4.5, 7.6, 14.4 Hz, 1H), 1.74 (app sextet,
J ) 7.2 Hz, 1H); 13C NMR (CDCl3, 90 MHz) δ 173.2, 138.0,

5554 J . Org. Chem., Vol. 61, No. 16, 1996
Pearson and Hembre
137.9, 137.8, 128.4, 128.3, 128.2, 127.9, 127.8, 127.7, 127.6,
80.0, 78.4, 74.4, 73.2, 72.4, 71.1, 69.3, 58.8, 53.9, 51.7, 30.0,
26.6; IR (neat) 3500 (w), 3030 (m), 2922 (m), 2865 (m), 1738
(s) cm-1; MS (CI, NH3) m/ z (rel intensity) 538 [(M + NH4)+,
35], 521 [(M + H)+, 29], 506 (100), 397 (25), 181 (27), 108 (41),
91 (69); HRMS (CI, NH3) calcd for C31H36O7H [(M + H)+]
521.2539, found 521.2531. Anal. Calcd for C31H36O7: C, 71.52;
H, 6.97. Found: C, 71.62; H, 7.03.
sodium bicarbonate (44 mg, 0.53 mmol) were added to a cold
(0 °C) solution of 19E (53 mg, 0.11 mmol) in CH2
Cl2 (0.5 mL),
and the mixture was allowed to warm slowly to room temper-
ature. After 24 h, the mixture was diluted with ether (5 mL)
and washed with 1 M NaOH (2 × 2 mL), 10% NaHCO3 (2 mL),
and brine (2 mL) and then dried (MgSO4) and concentrated.
Examination of the 1H NMR spectra of the crude reaction
mixture showed the presence of at least four compounds in
roughly a 1:2:3:6 ratio based on integration of the methyl ester
singlets. The two major compounds are believed to be the two
diastereomeric trans-epoxides 27 and 29E, while the minor
compounds are most likely cyclic ethers resulting from the
intramolecular opening of the epoxide by the alcohol. Com-
Met h yl (4R,5S,6S,7R,8R)-8-Azid o-4,5-ep oxy-6,7,9-t r is-
(ben zyloxy)n on a n oa te (21r). See above for an alternate
preparation of 21R. Hydrazoic acid (HN3)44 (0.29 mL of a 1.2
M solution in benzene, 0.35 mmol) was added to a solution of
the epoxy alcohol 27 (90 mg, 0.17 mmol) and triphenylphos-
phine (PPh3) (68 mg, 0.26 mmol) in benzene (0.5 mL). The
resulting mixture was cooled to 5 °C, and diethyl azodicar-
boxylate (DEAD) (45 mg, 0.26 mmol) was added in a dropwise
fashion. The solution was allowed to warm slowly to room
temperature. After 1.5 h, the mixture was concentrated.
Chromatography (10:1 hex/EtOAc) provided 78 mg (85%) of
the title compound as a colorless oil. Rf ) 0.25 (5:1 hex/EtOAc);
1
parison of the H NMR spectra of these epoxides with that of
pure 27 (prepared above as shown in Scheme 4) showed that
27 was indeed present in the mixture as the minor epoxide
product. Key resonances included δ 4.80 (d), 3.64 (s), 3.37 (dd),
3.06 (dd), 2.91 (ddd). The major component of the mixture was
assumed to be the other diastereomeric trans-epoxide 29E. A
mixture of 18Z/18E was then subjected to m-CPBA epoxida-
tion followed by lactone-opening with methanol: m-Chloro-
peroxybenzoic acid (20 mg technical grade, 16 mg pure oxidant,
0.09 mmol) was added to a cold (0 °C) solution of a mixture of
18Z and 18E (1.3:1, 13 mg, 0.03 mmol) in CH2Cl2 (0.5 mL),
and the mixture was allowed to warm slowly to room temper-
ature. After 24 h, the mixture was diluted with ether (5 mL)
and washed with 1 M NaOH (2 × 3 mL), 10% NaHCO3 (2 mL),
and brine (2 mL) and then dried (MgSO4) and concentrated to
give 13 mg of a colorless oil. The crude epoxy-lactones 28E
and 28Z were dissolved in MeOH/CH2Cl2 (2:1, 2 mL) and
treated with NaHCO3. After 12 h, brine (5 mL) was added,
and the mixture was extracted with ether (3 × 10 mL) and
then dried (MgSO4) and concentrated. Attempted silica gel
chromatography led to significant decomposition in earlier
runs. The 1H NMR spectrum of the crude hydroxy ester
mixture was compared to those of pure 27 and the epoxides
27 and 29E obtained from epoxidation of 19E (see above). No
peaks corresponding to 27 could be identified in the spectrum,
while peaks corresponding to the other trans-epoxide 29E were
present. Key resonances included δ 4.75 (d), 3.45 (m), 2.91
(m). These data indicate that the atropisomerism of 18E/18E′
involves a conformational change of the molecule that results
in the presentation of different faces of the alkene. An
additional change in the ester configuration cannot be ruled
out.
[R]23 ) -27.3° (c ) 0.97, CHCl3); 1H NMR (CDCl3, 300 MHz)
D
δ 7.2-7.4 (m, 15H), 4.70 (ABq, J ) 11.7 Hz, ∆ν ) 82.5 Hz,
2H), 4.56 (ABq, J ) 11.3 Hz, ∆ν ) 18.5 Hz, 2H), 4.53 (s, 2H),
3.82 (m, 2H), 3.71 (m, 1H), 3.66 (s, 3H), 3.64 (m, 1H), 3.26
(dd, J ) 3.2, 7.1 Hz, 1H), 3.05 (dd, J ) 2.2, 7.1 Hz, 1H), 2.83
(ddd, J ) 2.3, 3.8, 7.1 Hz, 1H), 2.39 (t, J ) 7.4 Hz, 2H), 1.97
(ddt, J ) 3.7, 7.7, 14.4 Hz, 1H), 1.56 (app sextet, J ) 7.2 Hz,
1H); 13C NMR (CDCl3, 90 MHz) δ 173.1, 137.8, 137.6, 137.4,
128.5, 128.3, 128.2, 128.0, 127.8, 127.7, 79.6, 78.9, 74.2, 73.4,
72.4, 69.3, 61.1, 59.2, 53.3, 51.7, 30.0, 26.5; IR (neat) 3030 (m),
2950 (m), 2866 (m), 2099 (s), 1732 (s), 1092 (s) cm-1; MS (CI,
NH3) m/ z (rel intensity) 518 [(M - N2 + H)+, 37], 486 (67),
402 (88), 294 (40), 186 (100), 134 (71), 108 (77), 106 (73), 91
(74), 80 (41); HRMS (CI, NH3) calcd for C31H35NO6 [(M - N2
+ H)+] 518.2543, found 518.2540. Anal. Calcd for C31H35N3-
O6: C, 68.24; H, 6.47; N, 7.70. Found: C, 68.26; H, 6.60; N,
7.69.
(1R,2R,3R,8R,8a R)-3-[(Ben zyloxy)m eth yl]-1,2-bis(ben -
zyloxy)-8-h yd r oxyin d olizid in -5-on e (23). See above for an
alternate preparation of 23. Palladium hydroxide on carbon
(20 mg) was added to a solution of the azido epoxide 21R (62
mg, 0.12 mmol) in MeOH/EtOAc (1:1, 4 mL). The flask was
evacuated (aspirator) and purged with hydrogen three times.
The resulting heterogeneous mixture was stirred under a
balloon of hydrogen at room temperature for 4 h, and then
the hydrogen was evacuated and the mixture was filtered,
rinsing with MeOH (5 mL). The filtrate was concentrated, and
the resulting residue was redissolved in methanol (10 mL).
Sodium methoxide (10 mg, 0.18 mmol) was added, and the
mixture was warmed to reflux. After 24 h, the mixture was
cooled to room temperature and concentrated. Chromatogra-
phy (25:25:1 hex/EtOAc/EtOH) provided 48 mg (82%) of the
title compound as a colorless oil. Rf ) 0.10 (25:25:1 hex/EtOAc/
Meth yl (Z)-(6R,7R,8R)-8-Azid o-6,7,9-tr is(ben zyloxy)-4-
n on en oa te (30). Hydrazoic acid (HN3)44 (0.78 mL of a 1.2 M
solution in benzene, 0.93 mmol) was added to a solution of
the alcohol 19Z (235 mg, 0.466 mmol) and triphenylphosphine
(PPh3) (183 mg, 0.698 mmol) in benzene (2.5 mL). The
resulting mixture was cooled to 5 °C and diethyl azodicar-
boxylate (DEAD) (121 mg, 0.698 mmol) was added in a
dropwise fashion. The solution was allowed to warm slowly
to room temperature. After 1.5 h, more HN3 solution (0.40
mL, 0.48 mmol), PPh3 (64 mg, 0.245 mmol), and DEAD (40
mg, 0.245 mmol) were added. After another 45 min, the
solution was diluted with hexanes (10 mL), the resulting
precipitate was filtered off, and the filtrate was concentrated
without warming. [Heating or prolonged standing at room
temperature resulted in an intramolecular 1,3-dipolar cycload-
dition.] Chromatography (10:1 hex/EtOAc) provided 210 mg
(85%) of the title compound as a colorless oil. Rf ) 0.37 (5:1
hex/EtOAc); [R]23D ) -26.0° (c ) 0.30, CHCl3); 1H NMR (CDCl3,
300 MHz) δ 7.2-7.4 (m, 15H), 5.63 (m, 1H), 5.54 (dd, J ) 9.2,
11.1 Hz, 1H), 4.62 (ABq, J ) 11.2 Hz, ∆ν ) 42.2 Hz, 2H), 4.52
(ABq, J ) 12.1 Hz, ∆ν ) 13.4 Hz, 2H), 4.48 (ABq, J ) 11.8
Hz, ∆ν ) 90.4 Hz, 2H), 4.38 (dd, J ) 4.3, 9.1 Hz, 1H), 3.81 (m,
2H), 3.68 (dd, J ) 6.8, 10.1 Hz, 1H), 3.66 (s, 3H), 3.55 (dd, J
) 4.2, 6.8 Hz, 1H), 2.25-2.40 (m, 4H); 13C NMR (CDCl3, 90
MHz) δ 173.0, 138.2, 137.9, 137.8, 132.9, 128.5, 128.4, 128.3,
128.2, 128.0, 127.7, 127.6, 81.1, 75.1, 74.2, 73.4, 70.4, 69.7, 61.6,
51.6, 33.7, 23.3; IR (neat) 3030 (m), 2923 (m), 2864 (m), 2096
(s), 1738 (s), 1091 (s) cm-1; MS (CI, NH3) m/ z (rel intensity)
EtOH); [R]23 ) -16.8° (c ) 1.12, CHCl3); 1H NMR (CDCl3,
D
300 MHz) δ 7.2-7.4 (m, 15H, ArH), 4.65 (ABq, J ) 11.8 Hz,
∆ν ) 23.3 Hz 2H, OCH2Ph), 4.53 (s, 2H, OCH2Ph), 4.51 (ABq,
J ) 11.6 Hz, ∆ν ) 46.9 Hz, 2H, OCH2Ph), 4.33 (app quintet,
J ) 3 Hz, 1H, H-3), 4.22 (t, J ) 4 Hz, 1H, H-2), 3.96 (dd, J )
4.8, 8.1 Hz, 1H, H-1), 3.72 (m, 2H, H-8 and H-9a), 3.64 (dd, J
) 3.6, 9.5 Hz, 1H, H-9b), 3.44 (t, J ) 8.2 Hz, 1H, H-8a), 2.48
(ddd, J ) 2.3, 6.3, 17.9 Hz, 1H, H-6eq), 2.38 (d, J ) 2.1 Hz,
1H, -OH), 2.31 (ddd, J ) 6.3, 11.6, 17.9 Hz, 1H, H-6ax), 2.03
(m, 1H, H-7eq), 1.75 (dt, J ) 6.4, 12 Hz, 1H, H-7ax); 13C NMR
(CDCl3, 90 MHz) δ 167.7, 138.0, 137.6, 137.4, 128.6, 128.45,
128.40, 128.1, 128.0, 127.9, 127.7, 87.7, 83.2, 73.3, 72.0, 71.9,
70.5, 68.8, 65.2, 61.0, 29.7, 28.9; IR (neat) 3360 (br m), 3030
(w), 2867 (m), 1621 (s), 1099 (s) cm-1; MS (CI, NH3) m/ z (rel
intensity) 488 [(M + H)+, 100], 108 (6), 91 (8); HRMS (CI, CH4
and NH3) calcd for C30H33NO5H [(M + H)+] 488.2437, found
488.2431.
Ep oxy-La cton e 28 a n d Ep oxy-Alcoh ol 29. To determine
whether the atropisomerism of 18E and 18E′ was due to
rotation of the alkene or the ester faces of 18E and 18E′, the
following study was carried out. First, the trans-hydroxy-
alkene 19E was epoxidized: m-Chloroperoxybenzoic acid (68
mg technical grade, 54 mg pure oxidant, 0.32 mmol) and
502 [(M - N2 + H)+, 100], 286 (12); HRMS calcd for C31H35
NO5H [(M - N2 + H)+] 502.2593, found 502.2593.
-

Ring-Expanded Analogs of Alexine and Australine
J . Org. Chem., Vol. 61, No. 16, 1996 5555
Met h yl (4S,5S,6S,7R,8S)-8-Azid o-4,5-ep oxy-6,7,9-t r is-
(ben zyloxy)n on an oate (31r) an d Meth yl (4R,5R,6S,7R,8S)-
8-Azid o-4,5-ep oxy-6,7,9-tr is(ben zyloxy)n on a n oa te (31â).
m-Chloroperoxybenzoic acid (199 mg technical grade, 160 mg
of pure oxidant, 0.92 mmol) was added to a cold (0 °C) solution
of the cis-azido-alkene 30 (195 mg, 0.368 mmol) in CH2Cl2 (1.8
mL), and the mixture was allowed to warm slowly to room
temperature. After 24 h, the mixture was diluted with ether
(10 mL) and washed with 1 M NaOH (2 × 5 mL), 10% NaHCO3
(5 mL), and brine (5 mL) and then dried (MgSO4) and
concentrated. Chromatography (10:1 hex/EtOAc) provided 150
mg (75%) of an inseparable mixture of 31R and 31â (1.4:1
based on 1H NMR integration) as a colorless oil. The stereo-
chemical assignment of these epoxides was made by conversion
to the indolizidines 34 and 35 (see below). Rf ) 0.23 (5:1 hex/
EtOAc); 1H NMR (CDCl3, 300 MHz, R indicates 31R, â
indicates 31â) δ 7.2-7.4 (m, 15HR and 15Hâ), 4.86 (d, J )
11.7 Hz, 1HR), 4.75 (d, J ) 11.2 Hz, 1Hâ), 4.65 (d, J ) 11.6
Hz, 1Hâ), 4.63 (d, J ) 11.5 Hz, 1HR), 4.45-4.58 (m, 4HR and
4Hâ), 3.65-3.95 (m, 4HR and 4Hâ), 3.71 (s, 3Hâ), 3.69 (s, 3HR),
3.53 (m, 1HR and 1Hâ), 3.41 (dd, J ) 2.3, 8.0 Hz, 1HR), 3.24
(dd, J ) 3.9, 8.4 Hz, 1Hâ), 3.15 (m, 1Hâ), 3.13 (dd, J ) 4.4,
8.0 Hz, 1HR), 2.35-2.58 (m, 2HR and 2Hâ), 1.98 (ddt, J ) 3,
8, 14 Hz, 1Hâ), 1.8 (dddd, J ) 3, 7, 8, 14 Hz, 1HR), 1.6 (dddd,
J ) 6, 8, 9, 14 Hz, 1Hâ), 1.45 (dddd, J ) 6, 8, 9, 14 Hz, 1HR);
13C NMR (CDCl3, 90 MHz, R indicates 31R, â indicates 31â) δ
173.0 (R), 172.9 (â), 137.9, 137.7, 137.6, 137.2, 128.8, 128.5,
128.5, 128.4, 128.4, 128.3, 128.3, 128.2, 128.2, 127.9, 127.8,
127.8, 127.7, 78.9 (R), 76.7 (â), 75.1 (R), 74.3 (R), 74.0 (â), 73.4
(â), 73.3 (R), 72.4 (R), 72.2 (â), 69.5 (R), 69.3 (â), 60.8 (â), 60.7
(R), 58.5 (â), 57.6 (R), 55.9 (R), 53.5 (â), 51.7 (R), 31.2 (â), 31.0
(R), 24.0 (â), 23.7 (R); IR (neat) 3030 (w), 2866 (w), 2097 (s),
1737 (s), 1092 (s) cm-1; MS (CI, NH3) m/ z (rel intensity) 563
[(M + NH4)+, 49], 518 (100), 488 (26), 402 (43), 108 (16); HRMS
calcd for C31H35N3O6NH4 [(M + NH4)+] 563.2870, found
563.2893. Anal. Calcd for C31H35N3O6: C, 68.24; H, 6.47; N,
7.70. Found: C, 68.15; H, 6.47; N, 7.47.
Da ta for 32: Rf ) 0.30 (20:1 CHCl3/MeOH); [R]23D ) -15.9°
1
(c ) 0.39, CHCl3); H NMR (CDCl3, 300 MHz) δ 7.2-7.4 (m,
15H, ArH), 4.62 (ABq, J ) 11.7 Hz, ∆ν ) 25.5 Hz, 2H, OCH2-
Ph), 4.57 (ABq, J ) 11.7 Hz, ∆ν ) 31.2 Hz, 2H, OCH2Ph), 4.51
(s, 2H, OCH2Ph), 4.40 (dt, J ) 3.5, 6.1 Hz, 1H, H-3), 4.27 (dd,
J ) 3.6, 4.7 Hz, 1H, H-2), 4.19 (dd, J ) 4.7, 7.7 Hz, 1H, H-1),
4.12 (br s, 1H, H-8), 3.78 (dd, J ) 6.3, 9.4 Hz, 1H, H-9a), 3.65
(dd, J ) 3.6, 9.4 Hz, 1H, H-9b), 3.62 (dd, J ) 2.6, 7.5 Hz, 1H,
H-8a), 2.61 (d, J ) 3.5 Hz, 1H, -OH), 2.52 (ddd, J ) 7.1, 12.0,
18.0 Hz, 1H, H-6ax), 2.30 (ddd, J ) 1, 6.9, 18.0 Hz, 1H, H-6eq),
2.1 (dddd, J ) 1.5, 4.1, 6.9, 14.0 Hz, 1H, H-7eq), 1.79 (dddd, J
) 1.8, 7.1, 12.2, 14.0 Hz, 1H, H-7ax); 13C NMR (CDCl3, 75
MHz) δ 168.4, 138.1, 137.9, 137.6, 128.4, 128.3, 128.2, 127.8,
127.7, 127.5, 82.7, 82.2, 73.2, 72.3, 71.9, 68.6, 65.8, 62.3, 60.8,
27.6, 26.2; IR (neat) 3350 (br m), 3029 (m), 2923 (m), 2864
(m), 1618 (s), 1100 (s) cm-1; MS (CI, NH3) m/ z (rel intensity)
488 [(M + H)+, 100], 398 (5); HRMS calcd for C30H33NO5H [(M
+ H)+] 488.2437, found 488.2434.
(1R,2R,3R,8S,8a R)-3-[(Ben zyloxy)m eth yl]-1,2-bis(ben -
zyloxy)-8-h yd r oxyin d olizid in e (34). Borane-methyl sul-
fide complex (0.29 mL of a 2 M solution in THF, 0.58 mmol)
was added to a cool (0 °C) solution of the lactam 32 (67 mg,
0.14 mmol) in THF (3.7 mL). After 30 min, the mixture was
warmed to room temperature. After 6 h, the reaction was
quenched by the slow addition of EtOH (2 mL). After 30 min
at room temperature, the mixture was concentrated and the
residue was redissolved in EtOH (4 mL) and warmed to reflux.
After 2 h, the mixture was cooled to room temperature and
concentrated. Chromatography (66:33:1 to 50:50:1 hex/EtOAc/
MeOH) provided 40 mg (62%) of the title compound as a pale
yellow oil. Rf ) 0.43 (1:1 hex/EtOAc); [R]23D ) +3.7° (c ) 0.38,
CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.2-7.4 (m, 15H, ArH),
4.52 (ABq, J ) 11.9 Hz, ∆ν ) 29.5 Hz, 2H, OCH2Ph), 4.52 (s,
2H, OCH2Ph), 4.50 (s, 2H, OCH2Ph), 4.13 (dd, J ) 2.4, 6.5
Hz, 1H, H-1), 3.93 (br s, 1H, H-8), 3.90 (dd, J ) 1.4, 2.4 Hz,
1H, H-2), 3.64 (dd, J ) 4.8, 9.2 Hz, 1H, H-9a), 3.49 (dd, J )
6.7, 9.2 Hz, 1H, H-9b), 3.43 (app t, J ) 5.6 Hz, 1H, H-3), 2.94
(br dd, J ) 4, 10.8 Hz, 1H, H-5eq), 2.81 (dd, J ) 1.5, 6.5 Hz,
1H, H-8a), 2.68 (br s, 1H, H-OH), 2.52 (app dt, J ) 2.8, 11.5
Hz, 1H, H-5ax), 1.90 (br d, J ) 13.5 Hz, 1H, H-7eq), 1.75 (app
qt, J ) 4.5, 13 Hz, 1H, H-6eq), 1.45 (m, J ) 13.5 Hz, 1H,
H-6ax), 1.35 (tdd, J ) 2.2, 4.7, 13.5 Hz, 1H, H-7ax); 13C NMR
(CDCl3, 75 MHz) δ 138.3, 138.1, 138.1, 128.3, 128.0, 127.6,
127.6, 127.5, 84.7, 84.5, 73.3, 72.1, 71.2, 69.3, 67.3, 66.3, 64.9,
47.6, 30.8, 19.4; IR (neat) 3475 (br m), 3029 (m), 2932 (s), 2857
(s), 1098 (s) cm-1; MS (CI, NH3) m/ z (rel intensity) 474 [(M +
(1R,2R,3R,8S,8a R)-3-[(Ben zyloxy)m eth yl]-1,2-bis(ben -
zyloxy)-8-h yd r oxyin d olizid in -5-on e (32) a n d (1R,2R,3R,-
8R,8a S)-3-[(Ben zyloxy)m eth yl]-1,2-bis(ben zyloxy)-8-h y-
dr oxyin dolizidin -5-on e (33). Palladium hydroxide on carbon
(25 mg) was added to a solution of the azido-epoxides 31R and
31â (1.4:1 mixture of diastereomers, 131 mg, 0.24 mmol) in
MeOH/EtOAc (1:1, 5 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 4 h, and then the hydrogen was
evacuated and the mixture was filtered, rinsing with MeOH
(5 mL). The filtrate was then concentrated, and the resulting
residue was redissolved in methanol (15 mL). Sodium meth-
oxide (15 mg, 0.48 mmol) was added, and the mixture was
warmed to reflux. After 24 h, the mixture was cooled to room
temperature and concentrated. Chromatography (100:1 CHCl3/
MeOH) provided 39 mg (33%) of the minor lactam 33 as a
colorless oil, followed by 54 mg (46%) of the major lactam 32
as a colorless oil. The stereochemical assignment of these
lactams was made by conversion to the indolizidines 34 and
35 (see below). Data for 33: Rf ) 0.45 (20:1 CHCl3/MeOH);
H)+, 62], 352 (100), 91 (55); HRMS (CI, CH4) calcd for C30H35
-
NO4H [(M + H)+] 474.2644, found 474.2646.
(1R,2R,3R,8R,8a S)-3-[(Ben zyloxy)m eth yl]-1,2-bis(ben -
zyloxy)-8-h yd r oxyin d olizid in e (35). Borane-methyl sul-
fide complex (0.14 mL of a 2 M solution in THF, 0.28 mmol)
was added to a cool (0 °C) solution of the lactam 33 (32 mg,
0.066 mmol). After 30 min, the mixture was warmed to room
temperature. After 6 h, the reaction was quenched by slow
addition of EtOH (1 mL). After 30 min at room temperature,
the residue was redissolved in EtOH (2 mL) and warmed to
reflux. After 2 h, the mixture was cooled to room temperature
and concentrated. Chromatography (66:33:1 to 50:50:1 hex/
EtOAc/MeOH gradient) provided 27 mg (84%) of the title
compound as a pale yellow oil. Rf ) 0.51 (1:1 hex/EtOAc);
[R]23 ) -17.5° (c ) 0.08, CHCl3); 1H NMR (CDCl3, 300 MHz)
D
δ 7.1-7.4 (m, 15H, ArH), 4.67 (d, J ) 12.0 Hz, 1H, OCH2Ph),
4.63 (d, J ) 12.0 Hz, 1H, OCH2Ph), 4.47 (d, J ) 12.0 Hz, 1H,
OCH2Ph), 4.43 (d, J ) 11.5 Hz, 1H, OCH2Ph), 4.40 (d, J )
12.0 Hz, 1H, OCH2Ph), 4.37 (m, 2H, H-8 and H-9a), 4.28 (dd,
J ) 4.5, 8.7 Hz, 1H, H-1), 4.22 (d, J ) 11.6 Hz, 1H, OCH2Ph),
4.15 (m, 2H, H-2 and H-9b), 3.99 (d, J ) 2.2 Hz, 1H, OH),
3.77 (d, J ) 4.0 Hz, 1H, H-3), 3.30 (dd, J ) 8.8, 10.5 Hz, 1H,
H-8a), 2.62 (ddd, J ) 7.7, 11.8, 17.9 Hz, 1H, H-6ax), 2.30 (ddd,
J ) 1.0, 7.4, 17.8 Hz, 1H, H-6eq), 2.03 (dddd, J ) 1.1, 3.7, 7.7,
14.0 Hz, 1H, H-7eq), 1.74 (dddt, J ) 2, 7.4, 11.8, 14.0 Hz, 1H,
H-7ax); 13C NMR (CDCl3, 75 MHz) δ 169.8, 138.3, 137.3, 135.9,
128.7, 128.4, 128.2, 127.9, 127.7, 127.5, 84.3, 77.6, 73.0, 71.5,
70.8, 66.7, 64.3, 62.4, 61.5, 28.4, 27.4, 13.8; IR (neat) 3500 (br
m), 3030 (w), 2932 (m), 2872 (m), 1644 (s), 1454 (m), 1405 (m),
1074 (s) cm-1; MS (CI, NH3) m/ z (rel intensity) 488 [(M + H)+,
100], 108 (15); HRMS (CI, CH4 and NH3) calcd for C30H33NO5H
[(M + H)+] 488.2437, found 488.2419.
[R]23 ) +10.7° (c ) 0.14, CHCl3); 1H NMR (CDCl3, 300 MHz)
D
δ 7.2-7.4 (m, 15H, ArH), 4.56 (ABq, J ) 11.9 Hz, ∆ν ) 22.3
Hz, 2H, OCH2Ph), 4.53 (ABq, J ) 11.9 Hz, ∆ν ) 18.0 Hz, 2H,
OCH2Ph), 4.48 (ABq, J ) 11.7 Hz, ∆ν ) 22.3 Hz, 2H, OCH2-
Ph), 4.23 (br s, 1H, H-8), 4.17 (s, 1H, -OH), 4.01 (d, J ) 4.5
Hz, 1H, H-1), 3.73 (d, J ) 3.8 Hz, 1H, H-2), 3.71 (dd, J ) 5.1,
9.7 Hz, 1H, H-9a), 3.52 (dd, J ) 7.0, 9.7 Hz, 1H, H-9b), 3.28
(m, 1H, H-5eq), 2.57 (ddd, J ) 4.0, 5.0, 7.0 Hz, 1H, H-3), 2.39
(d, J ) 4.4 Hz, 1H, H-8a), 1.92-3.2 (m, 2H, H-5ax and H-6eq),
1.87 (br d, J ) 13.8 Hz, 1H, H-7eq), 1.25-1.48 (m, 2H, H-6ax
and H-7ax); 13C NMR (CDCl3, 75 MHz) δ 138.30, 138.0, 137.0,
128.5, 128.3, 128.2, 127.9, 127.9, 127.7, 127.6, 127.5, 85.3, 84.3,
73.3, 71.4, 71.3, 71.3, 70.6, 67.8, 66.2, 53.5, 31.3, 20.0; IR (neat)
3515 (m), 3030 (m), 2937 (s), 2860 (s), 1454 (s), 1102 (s) cm-1
MS (CI, NH3) m/ z (rel intensity) 474 [(M + H)+, 100], 256 (9);
;

5556 J . Org. Chem., Vol. 61, No. 16, 1996
Pearson and Hembre
HRMS (CI, CH4) calcd for C30H35NO4H [(M + H)+] 474.2644,
found 474.2657.
was evacuated and the mixture was filtered through a cotton
plug, rinsing with MeOH (2 mL). The filtrate was concen-
trated, and the residue was dissolved in a minimum amount
of water and stirred with Dowex 1 × 8 200 -OH ion exchange
resin (0.5 g dry resin). After 30 min, the mixture was filtered
and the filtrate was concentrated on a rotary evaporator.
Chromatography (5:1 to 3:1 CHCl3/MeOH gradient, SiO2)
provided 10.5 mg (82%) of the title compound as a colorless
(1R,2R,3R,8S,8aR)-3-(Hydr oxym eth yl)-1,2,8-tr ih ydr oxy-
in d olizid in e [Hom oa u str a lin e, (9)]. Palladium on carbon
(10%, 18 mg) and 6 N HCl (4 drops) were added to a solution
of the indolizidine 34 (35.9 mg, 0.076 mmol) in MeOH (2 mL).
The flask was evacuated (aspirator) and purged with hydrogen
three times. The resulting mixture was stirred under a balloon
of hydrogen at room temperature for 20 h, then the hydrogen
was evacuated and the mixture was filtered through a cotton
plug, rinsing with MeOH (2 mL). The filtrate was concen-
trated and the residue was dissolved in water (2 mL) and
stirred with Dowex 1 × 8 200 -OH ion exchange resin (0.5 g
dry resin). After 30 min, the mixture was filtered and the
filtrate was concentrated on a rotary evaporator. Chroma-
tography (5:1 to 3:1 CHCl3/MeOH gradient, SiO2) provided 9.5
mg (62%) of the title compound as a colorless oil. Rf ) 0.37
(2:1 CHCl3/MeOH); [R]23D ) +16.9 (c ) 0.45, MeOH); 1H NMR
(D2O, 300 MHz) δ 4.03-4.11 (m, 2H), 4.02 (dd, J ) 5.3, 11.8
Hz, 1H), 3.88 (dd, J ) 4.8, 12.4 Hz, 1H), 3.83 (dd, 4.6, 12.4
Hz, 1H), 3.16 (dd, J ) 4.4, 8.7 Hz, 1H), 3.10 (m, 1H), 2.93 (d,
J ) 8.2 Hz, 1H), 2.80 (dt, J ) 2.4, 11.5 Hz, 1H), 1.73-195 (m,
2H), 1.53-1.63 (m, 2H); 13C NMR (D2O, CH3OH int std, 75
MHz) δ 78.1, 76.1, 68.4, 68.1, 63.4, 59.1, 47.1, 29.2, 18.2; IR
(neat) 3332 (br s), 2936 (m), 1436 (m), 1057 (m) cm-1; MS (CI,
NH3) m/ z (rel intensity) 204 [(M + H)+ 100], 186 (22), 172
(20); HRMS (CI, CH4) calcd for C9H17NO4H [(M + H)+]
204.1236, found 204.1234.
oil. Rf ) 0.45 (2:1 CHCl3/MeOH); [R]23 ) -2.0° (c ) 0.84,
D
MeOH); 1H NMR (D2O, 300 MHz) δ 4.39 (br s, 1H), 4.20 (br d,
J ) 4.5 Hz, 1H), 3.78-3.86 (m, 3H), 3.35 (br d, J ) 10.3 Hz,
1H), 2.61 (br s, 1H), 2.43 (m, 1H), 2.28 (br t, J ) 11 Hz, 1H),
1.75-1.97 (m, 2H), 1.50-1.65 (m, 2H); 13C NMR (D2O, CH3-
OH int std, 75 MHz) δ 79.1, 78.7, 73.1, 67.3, 66.4, 60.3, 52.6,
30.2, 18.9; IR (neat) 3288 (br s), 2934 (m), 1428 (m), 1069 (s)
cm-1; MS (EI, 70 eV) m/ z (rel intensity) 204 [(M + H)+, 2],
172 (100), 126 (23); HRMS (CI, CH4) calcd for C9H17NO4H [(M
+ H)+] 204.1236, found 204.1245.
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 Reserach Service Award
T32 GM07767. We thank Professor J ames K. Coward
(University of Michigan) for helpful discussions.
1
Su p p or tin g In for m a tion Ava ila ble: Photocopies of H-
NMR, 13C-NMR, COSY, and NOESY spectra for new com-
pounds 7-10, 18-27, and 30-35 (59 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.
(1R,2R,3R,8R,8aS)-3-(Hydr oxym eth yl)-1,2,8-tr ih ydr oxy-
in d olizid in e [8-Ep ih om oa lexin e, 10]. Palladium on carbon
(10%, 15 mg) and 6 N HCl (4 drops) were added to a solution
of the indolizidine 35 (29.7 mg, 0.063 mmol) in MeOH (2 mL).
The flask was evacuated (aspirator) and purged with hydrogen
three times. The mixture was stirred under a balloon of
hydrogen at room temperature for 20 h, and then the hydrogen
J O960610A