Synthesis of polyhydroxylated pyrrolizidine alkaloids of the alexine family by tandem ring-closing metathesis-transannular cyclization. (+)-Australine

Article abstract of DOI:10.1021/jo0012748

Dienes 23 and 54, prepared from epoxy alcohol 9 via oxazolidinones 15 and 51, respectively, underwent ring-closing metathesis with Grubbs's catalyst to give azacyclooctenes 26 and 55. Treatment of each azacyclooctene with m-chloroperoxybenzoic acid afforded β-epoxide 28 from 26 and α-epoxide 61 from 60. Basic hydrolysis of each of these oxazolidinones was accompanied by transannular attack at the epoxide by nitrogen, resulting in 2-(O-benzyl)-7-deoxyalexine (29) and 1,2-di-(O-benzyl)australine (62). The latter was converted to the alkaloid australine (3) upon hydrogenolysis. Attempts to effect ring-closing metathesis of dienes 37, 38, and 46 were unsuccessful, suggesting that, while one allylic oxygen substituent can be tolerated by Grubbs's catalyst, two cannot.

Full text of DOI:10.1021/jo0012748

J . Org. Chem. 2000, 65, 9129-9142
9129
Syn th esis of P olyh yd r oxyla ted P yr r olizid in e Alk a loid s of th e
Alexin e F a m ily by Ta n d em Rin g-Closin g
Meta th esis-Tr a n sa n n u la r Cycliza tion . (+)-Au str a lin e
J ames D. White* and Peter Hrnciar
Department of Chemistry, Oregon State University, Corvallis, Oregon 97331-4003
james.white@orst.edu
Received August 22, 2000
Dienes 23 and 54, prepared from epoxy alcohol 9 via oxazolidinones 15 and 51, respectively,
underwent ring-closing metathesis with Grubbs’s catalyst to give azacyclooctenes 26 and 55.
Treatment of each azacyclooctene with m-chloroperoxybenzoic acid afforded â-epoxide 28 from 26
and R-epoxide 61 from 60. Basic hydrolysis of each of these oxazolidinones was accompanied by
transannular attack at the epoxide by nitrogen, resulting in 2-(O-benzyl)-7-deoxyalexine (29) and
1,2-di-(O-benzyl)australine (62). The latter was converted to the alkaloid australine (3) upon
hydrogenolysis. Attempts to effect ring-closing metathesis of dienes 37, 38, and 46 were unsuccessful,
suggesting that, while one allylic oxygen substituent can be tolerated by Grubbs’s catalyst, two
cannot.
Ch a r t 1
In tr od u ction
Castanospermum australe, a rainforest tree found in
Queensland, Australia, and Alexa leiopetala, a legumi-
nous tree indigenous to Guyana, Surinam, Venezuela,
and the Amazon basin, are rich sources of polyhydroxy-
lated pyrrolizidine and indolizidine alkaloids. The major
alkaloidal component of these species is castanospermine
(1),1,2 a powerful inhibitor of several glucosidases,3 in-
cluding mammalian intestinal sucrosidase and the glu-
cosidase involved in lysomal glycoprotein procession.4 The
wide variety of biological activities described for castano-
spermine5 has drawn interest toward other alkaloids
present in the pods and seeds of C. australe and A.
leiopetala. Alexine (2), isolated in 1987,6 was the first
example of a polyhydroxylated pyrrolizidine alkaloid with
a C3 hydroxymethyl branch; subsequently, several other
tetrahydroxypyrrolizidines were isolated from C. aus-
trale, including australine (3),7 7,7a-diepialexine (4),8
3,7a-diepialexine (5),9 and 1,7a-diepialexine (6) (Chart
1).8,10
to specific enzymes than 1. For example, while alexine
(2) and its stereoisomer 5 are only poor inhibitors of
mammalian glucosidases,9 they display the powerful
amyloglucosidase inhibition seen with castanospermine.8
Alexine is also an effective thioglucosidase inhibitor.11
Australine (3) is a specific inhibitor of fungal amyloglu-
cosidase and glycoprotein-processing glucosidase 1, but
on the other hand no significant inhibition of â-glucosi-
The pyrrolizidines 2-6 are potent glycosidase inhibi-
tors which appear to be more selective in their binding
(1) Hohenschutz, L. D.; Bell, E. A.; J ewess, P. J .; Leworthy, D. P.;
Price, R. J .; Arnold, E.; Clardy, J . Phytochemistry 1981, 20, 811.
(2) Nash, R. J .; Fellows, L. E.; Dring, J . V.; Striton, C. H.; Carter,
D.; Hegarty, M. P. Bell, E. A. Phytochemistry 1988, 27, 1403.
(3) (a) Saul, R.; Chambers, J . P.; Molyneux, R. J .; Elbein, A. D. Arch.
Bioch. Biophys. 1983, 221, 539. (b) Elbein, A. D. CRC Crit. Rev.
Biochem. 1984, 16, 21. (c) Cenci diBello, I.; Mamm, D.; Nash, R.;
Winchester, B. in Lipid Storage Disorders; Salvayre, R.; Douste-Blazy,
L.; Gatt, S., Eds.; Plenum: New York 1988; Vol. 150, p 635.
(4) (a) Saul, R.; Ghoidoni, J . J .; Molyneux, R. J .; Elbein, A. D. Proc.
Natl. Acad.Sci. USA 1985, 82, 93. (b) Pan, Y. T.; Hori, H.; Saul, R.;
Standford, B. A.; Molyneux, R. J .; Elbein, A. D. Biochemistry 1983,
22, 3975.
(5) (a) Walker, B. D.; Kowalski, M.; Rosen, W. C.; Rohrschneider,
L. R.; Haseltine, W. A.; Sodroski, J . Proc. Natl. Acad. Sci. U.S.A. 1987,
84, 8120. (b) Sunkara, P. S.; Bowlin, T. L.; Liu, P. S.; Svoerdsma, A.
Biochem. Biophys. Res. Commun. 1987, 148, 206. (c) Ostrauder, G. K.;
Scribner, N. K.; Rohrschneider, L. R. Cancer Res. 1988, 48, 1091.
(6) 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.
(7) (a) Harris, C. H.; Harris, T. M.; Molyneux, R. J .; Tropea, J . E.;
Elbein, A. D. Tetrahedron Lett. 1989, 30, 5685. (b) Molyneux, R. J .;
Benson, M.; Wong, R. Y.; Tropea, J . E.; Elbein, A. D. J . Nat. Prod.
1988, 51, 1198. (c) 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.
(8) Simmonds, M. S. J .; Blaney, W. M.; Fellows, L. E. J . Chem. Ecol.
1990, 16, 3167.
(9) (a) Robins, D. J . J . Nat. Prod. Rep. 1990, 7, 377. (b) Nash, R. J .;
Fellows, L. E.; Dring, J . V.; Fleet, G. W. J .; Girdhar, A.; Ramsden, N.
G.; Peach, J . V.; Hegarty, M. P.; Scofield, A. M. Phytochemistry 1990,
29, 114.
(10) (a) Fellows, L.; Nash, R. Chem. Abstr. 1990, 114, 143777s. (b)
Elbein, A. D.; Tropea, J . E.; Molyneux, R. J . Chem. Abstr. 1989, 113,
91444p.
(11) (a) Scofield, A. M.; Rossiter, J . T.; Witham, P.; Kitre, G. C.;
Nash, R. J .; Fellows, L. E. Phytochemistry 1990, 29, 107. (b) Tropea,
J . E.; Molyneux, R. J .; Kaushal, C. P.; Pan, Y. T.; Mitchell, M.; Elbein,
A. D. Biochemistry 1984, 28, 2027.
10.1021/jo0012748 CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/28/2000

9130 J . Org. Chem., Vol. 65, No. 26, 2000
White and Hrnciar
Sch em e 1
dase, R- and â-mannosidase, or R- and â-galactosidase
was observed for this alkaloid.12 1,7a-Diepialexine (6)
showed only modest glucosidase 1, â-glucosidase, and
R-mannosidase inhibition but, like 4, it displayed strong
activity in a mouse gut digestive R-glucosidase assay.10
Recently, it has been shown that 3, 4, and 6 inhibit HIV-
induced synostia formation in J M cells.8,10
Structural assignments to 2,6 3,7 and 59 were made by
X-ray crystallographic analysis. Comparison of proton-
proton coupling constants in these structures showed
characteristic patterns which could be correlated with the
configuration and conformation of these molecules. How-
ever, the NMR data for australine (3), as reported by
Molyneux,9b did not fit these spectral trends and thus
prevented the formulation of more general rules which
could be used for structural assignments to other mem-
bers of this class. Although the anomalies were originally
explained by a conformational change in 3, further
investigation cast doubt on the authenticity of the
published data for this alkaloid.13 This placed the struc-
tural assignments to 4 and 6 in question since these were
made exclusively on the basis of NMR data.
second is a transannular cyclization (TC) which leads
from the derived azacyclooctene epoxide to the bicyclic
framework of a pyrrolizidine. Our RCM-TC strategy is
outlined in Scheme 1, and in a preliminary report we
described its successful application to a synthesis of
australine (3).18
The first synthetic approach toward australine (3) was
reported by Pearson,14 but due to an unfortunate error
the data which was supplied to Pearson and which was
thought to be that of natural australine was in fact that
for 4. As a consequence, Pearson mistakenly concluded
that he had synthesized 7,7a-diepialexine along with a
second stereoisomer, 7-epialexine. As later work has
revealed, Pearson had in fact prepared australine (3).
After Pearson’s synthesis, a short sequence transforming
natural castanospermine (1) to australine (3) was de-
scribed by Tyler15 which possibly mimics the proposed
biogenetic conversion of this indolizidine to the corre-
sponding C3-branched polyhydroxylated pyrrolizidine. A
synthesis of 1,7a-diepialexine (6) has been reported by
Fleet starting from L-gluconolactone,16 and recently
Denmark has completed syntheses of several members
of the class of polyhydroxylated pyrrolizidine alkaloids
employing an elegant tandem nitroalkene-cycloaddition
strategy.17
The foregoing studies indicated that, while the struc-
ture of 6 was assigned correctly, that of 7,7a-diepialexine
(4) was not. It could be surmised, based on the results of
Pearson,14 that the data originally assigned to 7,7a-
diepialexine belonged to australine (3), but the nature
of Pearson’s synthesis did not allow definitive structural
interpretation. It was this ambiguity which initially
provoked our interest in a general synthetic route to the
alexine family of polyhydroxylated pyrrolizidine alkaloids
and which directed our attention toward australine (3)
in particular.
Resu lts a n d Discu ssion
In designing a synthesis of our olefin metathesis
precursor, we sought a route which permitted flexibility
in the incorporation of oxygen functionality. R,â-Unsatur-
ated ester 7, obtained from oxidative cleavage of 1,2;5,6-
di-O-isopropylidene-D-mannitol19 followed by Wadsworth-
Emmons condensation of the derived glyceraldehyde with
ethyl diethylphosphonoacetate (Scheme 2), appeared to
be an ideal starting point for this objective. Reduction of
7 with diisobutylaluminum hydride gave allylic alcohol
820 which upon Sharpless asymmetric epoxidation in the
presence of diisopropyl L-tartrate produced epoxy alcohol
9.21 Treatment of 9 with benzyl isocyanate yielded the
urethane 10, which upon exposure to potassium tert-
butoxide underwent regiospecific intramolecular opening
of the epoxide to afford oxazolidinone 12.22 Our plan at
this stage was to utilize a known rearrangement of
glycerol acetonide derivatives in which the acetonide
migrates from a terminal to an internal 1,2-diol, thereby
liberating a primary alcohol.23 The rearrangement, which
is only successful where migration furnishes a trans
disubstituted acetonide, i.e., where oxygen substituents
in the precursor bear a syn relationship as in 12, would
position 15 for homologation to one of the two components
required for RCM. Unfortunately, the rearrangement of
12 catalyzed by Amberlyst 15 led to only a 2:1 ratio of
15:12, respectively. Although this pair of acetonides could
be separated by column chromatography and 12 recycled
through the equilibration process, it was hoped that a
more favorable ratio could be obtained by placing a less
sterically demanding substituent at the nitrogen atom.
To this end, the N-allyl urethane 11 was prepared by
reaction of 9 with allyl isocyanate, and 11 was converted
Our plan for synthesizing polyhydroxylated pyrroliz-
idines was based on two key constructions. The first of
these is ring-closing metathesis (RCM) which creates an
azacyclooctene from a functionalized dialkylamine; the
(12) Fleet, G. W. J .; Haraldsson, M.; Nash. R. J .; Fellows, L. E.
Tetrahedron Lett. 1988, 29, 5441.
(13) Wormald, M. R.; Nash, R. J .; Hrnciar, P.; White, J . D.;
Molyneux, R. J .; Fleet, G. W. J . Tetrahedron Asymm. 1998, 9, 2549.
(14) Pearson, W. H.; Hines, J . V. Tetrahedron Lett. 1991, 32, 5513.
(15) Furneaux, R. H.; Gainsford, G. J .; Mason, J . M.; Tyler, P. C.
Tetrahedron 1994, 50, 213.
(18) White, J . D.; Hrnciar, P.; Yokochi, A. F. T. J . Am. Chem. Soc.
1998, 120, 7359.
(19) Fischer, H. O. L.; Baer, E. Helv. Chim. Acta 1934, 17, 622.
(20) Marshall, J . A.; Trometer, J . D.; Cleary, D. G. Tetrahedron 1989,
45, 391.
(21) Hill, J . G.; Rossiter, B. E.; Sharpless, K. B. J . Org. Chem. 1983,
48, 3607.
(16) Choi, S.; Bruce, I.; Fairbanks, A. J .; Fleet, G. W. J .; J ones, A.
M.; Nash, R. J .; Fellows, L. E. Tetrahedron Lett. 1991, 32, 5517.
(17) Denmark, S. E.; Martinborough, E. A. J . Am. Chem. Soc. 1999,
121, 3046.
(22) Minami, N.; Ko, S. S.; Kishi, Y. J . Am. Chem. Soc. 1982, 104,
1109.
(23) Mulzer, J .; de Lasalle, P.; Friessler, A. J ustus Liebigs Ann.
Chem. 1986, 1152.

Polyhydroxylated Pyrrolizidine Alkaloids
J . Org. Chem., Vol. 65, No. 26, 2000 9131
Sch em e 2
Sch em e 3
Sch em e 4
to oxazolidinone 13 by the same procedure used with 10.
Exposure of 13 to Amberlyst 15 again gave a 2:1 ratio of
rearranged (16) to unrearranged acetonides. Since the
blocking group at the oxazolidinone nitrogen of 12 or 13
must eventually be replaced by a substituent which
provides the second alkene needed for RCM, it was
decided to explore the acetonide rearrangement of 14 in
which no substituent is present at nitrogen. The latter
was obtained by debenzylation of 12 with sodium-
ammonia,24 and when exposed to Amberlyst 15 it was
found to undergo rearrangement to 17 with the improved
ratio of 7:1. However, 17 (which could also be obtained
by debenzylation of 15) could not be separated from 14,
and for this reason it was concluded that N-benzyl
derivative 15 would provide a more satisfactory route
with pure materials. Thus, 15 was first converted to
chloro acetonide 18,25 and subsequent reaction of this
substance with sodium-ammonia removed the N-benzyl
substituent and reductively cleaved the chloro acetonide
to furnish the allylic alcohol 19 (Scheme 3).26 This was
protected as its methoxymethyl (MOM) ether 20 prior to
the next phase of the synthesis.
converted to its tosylate 22 (Scheme 4). Alkylation of the
sodium salt of 20 with 22 in the presence of tetra-n-
butylammonium iodide afforded 23 which underwent
clean ring-closing metathesis using Grubbs’s catalyst 2427
to give the azacyclooctene 25. We believe the efficiency
of this RCM is due, at least in part, to the presence of
the basal oxazolidinone to which the reacting alkenes are
tethered,28 since 1,9-azadienes in which this ring is not
present are relatively poor RCM substrates. A useful
inference drawn from the successful RCM of 23 is that
Grubbs’s catalyst 24 can tolerate at least one allylic
oxygen substituent in this system.29
A pivotal issue which now came to the fore was the
facial selectivity in epoxidation of the azacyclooctene,
since the configuration at C1 of 2 requires that oxygen
enter the â face of 25, whereas access to other pyrroliz-
idines would necessitate epoxidation at the R face. The
The pentenyl chain to be attached to the nitrogen atom
of 20 was obtained from 4-penten-1-ol (21) which was first
(24) (a) Annis, G. D.; Hebblethwaite, E. M.; Hodgson, S. T.; Hollis-
head, D. M.; Ley, S. V. J . Chem. Soc., Perkin Trans. 1 1983, 2851. (b)
Shibasaki, M.; Ishida, Y.; Iwasaki, G.; Iimori, T. J . Org. Chem. 1987,
52, 3488.
(25) Angyal, S. J .; Pickles, V. A.; Ahluwalia, R. Carbohydr. Res.
1967, 3, 300.
(27) Grubbs, R. H.; Miller, S. J .; Fu, G. C. Acc. Chem. Res. 1995,
28, 446.
(28) For a recent discussion of the templating effect on tethered
dienes in RCM to form medium-sized rings, see Maier, M. E. Angew.
Chem., Int. Ed. 2000, 39, 2073.
(29) (a) Levisalles, J .; Rudler, H.; Villemin, D. J . Organomet. 1979,
164, 251. (b) Fu, G. C.; Grubbs, R. H. J . Am. Chem. Soc. 1992, 114,
5426.
(26) Ireland, R. E.; Thaisrivongs, S.; Vanier, N.; Wilcox, C. S. J . Org.
Chem. 1980, 45, 48.

9132 J . Org. Chem., Vol. 65, No. 26, 2000
White and Hrnciar
Sch em e 5
preferred conformation of 25 according to an energy
minimization routine is one in which the double bond is
orthogonal to the allylic oxygen substituent. A directed
a syn epoxidation is therefore not possible, and in fact
the face of the double bond anti to the allylic substituent
is the more exposed. In accord with this assessment,
epoxidation of MOM ether 25 with m-chloroperoxybenzoic
acid gave exclusively the epoxide of â configuration (vide
infra). Although, this favorable outcome was countered
by difficulty in removing the MOM protecting group
without damage to the epoxide, reversal of the epoxida-
tion-deprotection sequence easily solved this problem.
Alcohol 26, obtained in quantitative yield after removal
of the MOM ether from 25, underwent epoxidation to give
27 as the sole product.
Our intention with 27 was to effect a one-pot cleavage
of the oxazolidinone and transannular attack at the
epoxide with the derived nitrogen anion to yield a
pyrrolizidine directly. Unfortunately, the free hydroxyl
group of 27 interfered with this plan, and all efforts to
complete the transannular cyclization phase of our RCM-
TC agenda from this epoxide were unsuccessful. Benzy-
lation of 27 not only circumvented this obstacle but gave
us a crystalline derivative 28 whose exposure to lithium
hydroxide in aqueous ethanol led in high yield to 29, the
benzyl ether of 7-deoxyalexine.30 The crystal structure
of 28 is shown in Figure 1.
Although 7-deoxyalexine has not been reported as a
member of the family of naturally occurring hydroxylated
pyrrolizidines, the success exemplified in our synthesis
of 29 encouraged us to launch our RCM-TC strategy at
alexine (2) itself. In principle, this requires only a minor
modification to 22 which incorporates an additional
oxygen substituent at C3 prior to N-alkylation of 20. The
revised plan was put into motion starting from (S)-malic
acid (30) which was first transformed to acetonide 31 and
then to R-hydroxy-γ-lactone 32 by a known procedure
(Scheme 5).31 After protection of the hydroxyl group of
32 as its MOM ether 33, the lactone was reduced to lactol
34, and this was reacted with triphenylphosphonium
methylide to afford the pentenol 35. Tosylation of this
alcohol gave 36 which was used in an efficient N-
alkylation of oxazolidinone 20 to furnish RCM substrate
37. A parallel route in which 32 was converted to a tert-
butyldimethylsilyl ether rather than 33 was less suc-
cessful and met its demise when silyl migration to the
liberated primary alkoxide was found to occur during the
Wittig reaction. With expectations of emulating the
successful RCM of 23, diene 37 was exposed to Grubbs’s
catalyst 24 under a variety of conditions. No azacy-
clooctene was produced, nor was an attempted RCM with
diol 38 any more productive.
Sch em e 6
pared from lactone 39 via 40 and was converted to its
triflate 42 (Scheme 6). Next, oxazolidinone 19 was
protected at both the nitrogen and the hydroxyl function
as its bis-Boc derivative 43 (Scheme 7). Treatment of 43
with sodium ethoxide effected cleavage of both the
oxazolidinone and the carbonate (but not the urethane)
to yield diol 44, which was transformed to benzylidene
acetal 45. Alkylation of 45 with triflate 42 afforded RCM
substrate 46 in excellent yield; however, this substance
like 37 and 38 was completely unreactive toward Grubbs’s
catalyst 24. The failure of 37, 38, and 46, in contrast to
23, to undergo RCM must be attributed to interference
by the bis allylic oxygen functionality with initial forma-
tion of the ruthenium-olefin complex from which sub-
sequent metathesis must flow. It emphasizes the care
with which RCM substrates must be designed,32 and in
the context of a general RCM-TC strategy for synthesis
of pyrrolizidines such as 2-6 it stipulates that oxygen
Suspecting that the pair of allylic MOM ethers could
be responsible for the failure of 37 to undergo RCM,29
a
new metathesis substrate was designed in which these
protecting groups were no longer present. A further
modification was made in which the oxazolidinone tem-
plate was replaced by a cycle linking the two oxygen
substituents in the butenyl chain, thus providing a more
rigid platform at one terminus of the RCM candidate.28
First, (S)-3-p-methoxybenzylpent-4-en-1-ol (41) was pre-
(30) For a recent synthesis of 7-deoxyalexine, see Yoda, H.; Asai,
F.; Takabe, K. Synlett 2000, 1001.
(31) Green, D. L. C.; Kiddle, J . J .; Thompson, C. M. Tetrahedron
1995, 51, 2865.
(32) For discussion of this point, see Armstrong, S. K. J . Chem. Soc.,
Perkin Trans 1 1998, 371.

Polyhydroxylated Pyrrolizidine Alkaloids
J . Org. Chem., Vol. 65, No. 26, 2000 9133
Sch em e 7
Sch em e 9
Sch em e 8
substitution should be positioned at only one of the two
allylic sites in the alkenyl chains of the RCM candidate.
The disappointing RCM results with 37, 38, and 46
caused us to realign an earlier plan for synthesis of
australine (3), and alcohol 15 was selected as the starting
point for a new approach to our RCM substrate. Swern
oxidation33 of 15 afforded aldehyde 47 which upon Wittig
olefination gave 48 (Scheme 8). Unfortunately, the
intended N-debenzylation of 48 with sodium-ammonia
was complicated by reductive elimination of the aceto-
nide,24 resulting in the useless allylic alcohol 49. In an
attempt to circumvent this problem, debenzylation was
carried out on 15, but the primary alcohol of this
unprotected oxazolidinone proved exceptionally difficult
to oxidize to an aldehyde.
The impasse presented by 48 was circumvented by
incorporating the butenyl chain required for RCM prior
to formation of the oxazolidinone, so that removal of a
protecting group at the nitrogen atom was no longer
required. The isocyanate from Curtius rearrangement34
of the acyl azide prepared from 4-pentenoic acid was
reacted in situ with 9 to give the urethane 50 in excellent
yield (Scheme 9). Upon exposure to potassium tert-
butoxide, 50 underwent smooth intramolecular displace-
ment of the epoxide to form oxazolidinone 5122 in which
the stereogenic oxygen substituents are in the same syn
relationship as in 14. This configuration set the stage
for migration of the acetonide from the terminal position
to the internal dioxolane,23 a rearrangement which was
again efficiently catalyzed by Amberlyst 15 resin and
which yielded a 2:1 mixture favoring 52 over 51. The
primary alcohol of 52 released in this migration was
oxidized33 to aldehyde 53, and Wittig olefination then
furnished the RCM substrate 54.
It was hoped that the two five-membered rings of 54
would impose a degree of conformational immobilization
on this structure which would be advantageous for
RCM,28 and indeed treatment of the diene with Grubbs’s
catalyst 24 led to azacyclooctene 55 in excellent yield.
The extent to which the acetonide of 54 assists RCM can
be gauged by comparison of the conditions used in this
case (room temperature, 5 h) with those necessary for
RCM of 25 (60 °C, 18 h). The conformation of 55 now
became a matter of importance, since in contrast to 26
an epoxide must be introduced from the R face of the
double bond. Molecular modeling suggested that the
eight-membered ring of 55 exists preferentially in a
conformation which places all of the substituents in an
equatorial orientation, and an AM 1 optimized geometry
for the diol derived from 55 clearly shows that the R face
of the double bond is more exposed to attack in this
conformation.18 In fact, epoxidation of 55 with m-chloro-
peroxybenzoic acid produced a single epoxide whose
structure was confirmed as 56 by X-ray crystallographic
analysis (Figure 2).
(33) Mancuso, A. J .; Huang, S.-L.; Swern, D. J . Org. Chem. 1978,
43, 2480.
(34) Smith, P. A. S. Org. React. 1946, 3, 337.

9134 J . Org. Chem., Vol. 65, No. 26, 2000
White and Hrnciar
Sch em e 10
F igu r e 1. ORTEP diagram for 28. Ellipsoids are drawn at
the 30% probability level.
Sch em e 11
F igu r e 2. ORTEP diagram for 56. Ellipsoids are drawn at
the 30% probability level.
The acetonide which had provided impetus to the RCM
of 54 now proved to be an encumbrance for the transan-
nular cyclization of 56. A conformational reorganization
of the eight-membered ring shown in Figure 1 must take
place in order to orient the nitrogen for internal displace-
ment of the epoxide, and while this would be quite
feasible if the acetonide were not present, the trans fusion
of a five-membered ring imposes a significant barrier on
this process. Not surprisingly, removal of the acetonide
from 56 without compromising the epoxide proved to be
impossible, and it was therefore decided to return to 55
in order to avoid this cul-de-sac. Diol 57, obtained by
hydrolysis of 55 with 48% aqueous hydrobromic acid
(Scheme 10), now became the substrate for epoxidation,
and based on the conformation shown in Figure 1, it was
again predicted that attack by peracid would take place
from the R side of the double bond. This assertion would
appear to run counter to the generally accepted dictum
of Henbest35 who demonstrated that allylic alcohols exert
a strong directing influence upon epoxidation with per-
acids. However, it is known that the Henbest rule is
inoperative in medium rings, and that a trans orientation
of epoxide and alcohol is often the result even in systems
with significantly more flexibility than 57.36 In line with
this reasoning, epoxidation of 57 gave a single product
58 whose configuration was established by correlation
with acetonide 56. Unfortunately, 58 resisted all at-
tempts at opening the oxazolidinone, so that an unlatched
nitrogen never had the opportunity for transannular
attack on the epoxide in this molecule. This failure is to
be contrasted with base treatment of 55, which readily
yielded amino alcohol 59, and it was concluded from this
result that successful TC would only be possible where
the vicinal diol of 58 was blocked.
Revision of the final steps to 3 necessitated a return
to 56 which was converted to its bis benzyl ether 60
(Scheme 11). Epoxidation of 60 again gave a single
stereoisomer which, in this case, was nicely crystalline;
X-ray crystallographic analysis confirmed the anticipated
stereochemistry of 61 as shown.18 With the stage now set
(36) Itoh, T.; J itsukawa, K.; Kaneda, K.; Teranishi, S. J . Am. Chem.
Soc. 1979, 101, 159.
(35) Henbest, H. B.; Wilson, R. A. L. J . Chem. Soc. 1957, 1958.

Polyhydroxylated Pyrrolizidine Alkaloids
J . Org. Chem., Vol. 65, No. 26, 2000 9135
lution of 10 (41.8 mg, 0.136 mmol) in dry THF (10 mL)
maintained at -10 °C was added a 1 M solution of potassium
tert-butoxide in tert-BuOH (272 mL, 0.272 mmol), and the
mixture was stirred for 2 h at 0 °C. The reaction was quenched
with a saturated solution of NH4Cl (1 mL), and the mixture
was extracted with EtOAc (4 × 10 mL). The combined organic
extracts were washed with a saturated solution of NaCl, dried
over anhydrous Na2SO4, and concentrated under reduced
pressure. Chromatography of the residue (4 g of silica gel,
EtOAc-hexane, 2:1) afforded 53.1 mg (84%) of 12 as a pale
yellow solid: mp 70-73 °C; [R]2D3 -14.6 (c 4.55, CHCl3); IR
(neat) 3433, 2994, 1738, 1445, 1382, 1269, 1220, 1147, 1069
for transannular cyclization to a pyrrolizidine, 61 was
reacted with a variety of bases which were expected to
first open the oxazolidinone. Of these, only lithium
hydroxide was fully satisfactory, and this led to a
quantitative yield of di-O-benzylaustraline (62). The
facile conversion of 61 to 62 would imply that the
transient lithiated amino alcohol generated upon expo-
sure of 61 to hydroxide places the nucleophilic nitrogen
in an especially favorable orientation for 1,5-displacement
at the epoxide, so that inversion at the epoxide center
undergoing attack and conservation of the other C-O
bond results in the (7S,7aR) configuration of australine.
This stereochemical arrangement is also characteristic
of other pyrrolizidine alkaloids such as 5 and 6 which
could therefore be accessed via a similar TC strategy. The
importance of a lithiated species for the TC step became
evident when the analogous sodio derivative, prepared
from 61 with sodium ethoxide, underwent transannular
reaction. In this case, bicyclic amino ether 63 was the
major product resulting from attack at the epoxide by
the liberated alkoxide rather than by nitrogen. Interest-
ingly, the attack by alkoxide occurs in the opposite regio
sense to that operating along the pathway to 62. The
divergent behavior of lithio and sodio intermediates
derived from 61 can be rationalized in terms of the
diminished affinity of sodium (compared to lithium)
cation for coordination with oxygen, thus rendering the
alkoxide more nucleophilic.
Final hydrogenolysis of 62 over Pearlman’s catalyst
removed both benzyl groups and furnished (+)-australine
(3) in quantitative yield. The synthesized material was
identical in all respects, including optical rotation, with
a sample of natural australine provided by Professor G.
W. J . Fleet of Oxford University. It was also clear from
careful comparison of our NMR data for 3 that this
substance was distinct from stereoisomers 4, 5, and 6, a
point which has recently received more detailed scru-
tiny.13 Comparison of our australine with the substance
which Pearson had synthesized and which he had er-
roneously believed to be 7,7a-diepialexine14 showed that
they were identical.
1
cm-1; H NMR (300 MHz, CDCl3) δ 1.33 (s, 3H), 1.43 (s, 3H),
2.45 (d, J ) 6 Hz, 1H), 3.62-3.68 (m, 1H), 3.75-3.86 (m, 2H),
3.94-3.99 (m, 2H), 4.18-4.28 (m, 2H), 4.51 (dd, J ) 7, 9 Hz,
1H), 4.84 (d, J ) 15 Hz, 1H), 7.29-7.42 (m, 5H); 13C NMR (75
MHz, CDCl3) δ 25.3, 26.3, 46.6, 58.0, 63.1, 66.0, 67.5, 75.7,
110.3, 128.2, 128.3, 129.2, 136.0, 159.2; MS (CI) m/z 308 (M+
+ 1), 278, 250, 176, 151, 129, 91; HRMS (CI) m/z 308.1500
(calcd for C16H22NO5: 308.1498).
(4R)-3-Allyl-4-[(2R)-[(4R)-2,2-d im eth yl-1,3-d ioxola n -4-
yl](h yd r oxym eth yl]-1,3-oxa zolid in -2-on e (13). To a solu-
tion of 11 (40 mg, 0.16 mmol) in dry THF (15 mL) maintained
at -10 °C was added a 1 M solution of potassium tert-butoxide
in tert-BuOH (280 mL, 0.28 mmol), and the mixture was
stirred for 2 h at 0 °C. The reaction was quenched with a
saturated solution of NH4Cl, and the product was extracted
with EtOAc (3 × 8 mL). The combined organic extracts were
washed with a saturated solution of NaCl, dried over anhy-
drous Na2SO4, and concentrated under reduced pressure.
Chromatography of the residue (6 g of silica gel, EtOAc-
hexane, 2:1) afforded 36.8 g (92%) of 13 as a colorless oil:
[R]2D3 -18.6 (c 2.12, CHCl3); IR (neat) 3438, 2989, 2935, 1733,
1450, 1367, 1264, 1230, 1147, 1069 cm-1; 1H NMR (300 MHz,
CDCl3) δ 1.34 (s, 3H), 1.44 (s, 3H), 2.81 (d, J ) 6 Hz, 1H), 3.67
(dd, J ) 8, 19 Hz, 1H), 3.78-3.85 (m, 2H), 3.87-3.96 (m, 1H),
4.02-4.06 (m, 2H), 4.14-4.23 (m, 1H), 4.28 (t, J ) 9 Hz, 1H),
5.23 (s, 1H), 5.26-5.28 (m, 1H), 5.72-5.85 (m, 1H); 13C NMR
(75 MHz, CDCl3) δ 25.4, 26.3, 45.2, 58.3, 63.1, 66.1, 67.3, 75.9,
110.2, 119.0, 132.4, 158.8; MS (CI) m/z 258, 228, 199, 170, 140,
125; HRMS (CI) m/z 258.1340 (calcd for C12H20NO5: 258.1341).
(4R)-4-[(2R)-[(4R)-2,2-Dim et h yl-1,3-d ioxola n -4-yl](h y-
d r oxy)m eth yl]-1,3-oxa zolid in -2-on e (14). Anhydrous am-
monia (100 mL) was condensed into a 250 mL two-necked flask
containing a solution of 12 (1.14 g, 3.71 mmol) in THF (7 mL)
maintained at -78 °C. To this mixture was added sodium
metal until a blue color persisted. The solution was stirred
for 2 h at -78 °C and was quenched with solid NH4Cl. The
ammonia was evaporated, and the residue was extracted with
a EtOAc-MeOH (5%) mixture (3 × 10 mL). The extract was
filtered through Celite, and the filtrate was concentrated under
reduced pressure. Chromatography of the residue (40 g of silica
gel, EtOAc-hexane, 2:1) afforded 0.69 (85%) of 14 as a
colorless solid: mp 109-112 °C; [R]2D3 -2.5 (c 1.96, CHCl3); IR
(neat) 3198, 2983, 1772, 1440, 1381, 1244, 1059, 946 cm-1; 1H
NMR (300 MHz, CDCl3) δ 1.35 (s, 3H), 1.44 (s, 3H), 3.20 (d, J
) 7 Hz, 1H), 3.58-3.64 (m, 1H), 3.92-3.97 (m, 2H), 4.06 (t, J
) 7 Hz, 1H), 4.14-4.19 (m, 1H), 4.45 (t, J ) 9 Hz, 1H), 4.48-
4.59 (m, 1H), 6.81 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 25.2,
26.3, 55.3, 65.8, 67.3, 71.3, 75.5, 110.0, 160.9; MS (CI) m/z 218
(M+ + 1), 202, 188, 160, 142, 116, 109, 98, 88, 86, 84, 73; HRMS
(CI) m/z 218.1029 (calcd for C9H16NO5: 218.1028).
In summary, a general strategy for synthesis of hy-
droxylated pyrrolizidines bearing a C3 alkyl substituent
has been devised in which an azacyclooctene precursor
is generated by ring-closing metathesis. Stereoselective
epoxidation of this azacyclooctene and transannular
opening by nitrogen produces a pyrrolizidine in which
hydroxyl configurations are set unambiguously. A limita-
tion of this strategy is the inability of RCM to accom-
modate two allylic oxygen substituents in the diene
substrate. Future attempts to remove this deficiency will
focus on RCM of precursors bearing hydroxyl surrogates
such as silicon substituents.
Exp er im en ta l Section
(4S)-3-Ben zyl-4-[(4R,5R)-5-(h ydr oxym eth yl)-2,2-dim eth -
yl-1,3-d ioxola n -4-yl]-1,3-oxa zolid in -2-on e (15). To a solu-
tion of 12 (1.19 g, 3.87 mmol) in dry acetone (80 mL) was added
Amberlyst 15 resin (ca. 100 mg), and the mixture was stirred
for 18 h at room temperature. The mixture was filtered and
the filtrate was neutralized with solid NaHCO3 (2 g). The
resulting solution was concentrated, and the residue was
chromatographed (160 g of silica gel, EtOAc-hexane, 1:1) to
afford 761 mg (64%) of 15 as a colorless solid: mp 89-92 °C;
[R]2D3 -6.30 (c 1.73, CHCl3); IR (neat) 3438, 2984, 1743, 1440,
Melting points are uncorrected. Chemical ionization (CI)
high and low resolution mass spectra (HRMS and MS) were
obtained using a source temperature of 120 °C and CH4 as
the ionizing source. Perfluorokerosene was used as a reference.
Column chromatography was carried out on silica gel 60 (70-
230 mesh). Unless otherwise indicated, reactions were carried
out under a nitrogen atmosphere. Solvents were dried by
distillation over sodium/benzophenone (Et2O, THF) or over
CaH2 (CH2Cl2).
1
(4R)-3-Ben zyl-4-[(2R)-[(4R)-2,2-d im eth yl-1,3-d ioxola n -
4-yl](h yd r oxy)m eth yl]-1,3-oxa zolid in -2-on e (12). To a so-
1250, 1098, 1030 cm-1; H NMR (400 MHz, CDCl3) δ 1.35 (s,
3H), 1.44 (s, 3H), 3.57-3.62 (m, 1H), 3.62-3.73 (m, 2H), 3.78-

9136 J . Org. Chem., Vol. 65, No. 26, 2000
White and Hrnciar
3.83 (m, 1H), 4.18 (dd, J ) 2, 8 Hz, 1H), 4.25 (d, J ) 17 Hz,
1H), 4.27 (d, J ) 15 Hz, 1H), 4.34 (dd, J ) 6, 9 Hz, 1H), 4.83
(d, J ) 15 Hz, 1H), 7.28-7.37 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 27.0, 27.2, 46.9, 54.5, 62.3, 62.7, 75.2, 110.1, 128.2,
128.5, 129.0, 135.0, 158.6; MS (CI) m/z 308 (M+ + 1), 250, 176,
151, 129, 114, 91, 84; HRMS (CI) m/z 308.1500 (calcd for
residue was extracted with a EtOAc-MeOH (5%) mixture. The
extract was filtered through a short column of silica gel, and
the filtrate was concentrated under reduced pressure. Chro-
matography of the residue (15 g of silica gel, EtOAc-hexane,
2:1) gave 54 mg (61%) of 19 as a colorless solid: mp 85-89
°C; [R]2D3 -10.1 (c 1.36, CHCl3); IR (neat) 3345, 1743, 1421,
1250, 1064 cm-1
; 1H NMR (300 MHz, CDCl3) δ 3.27 (br s, 1H),
C
16H22NO5: 308.1498). Anal. Calcd for C16H21NO5: C, 62.53;
H, 6.89; N, 4.56. Found: C, C, 62.26; H, 6.86; N, 4.80.
3.89-3.95 (m, 1H), 4.23-4.27 (m, 1H), 4.32-4.41 (m, 2H), 5.30
(d, J ) 10 Hz, 1H), 5.41-5.47 (m, 1H), 5.72-5.83 (m, 1H), 6.60
(s br, 1H); 13C NMR (75 MHz, CDCl3) δ 56.4, 66.0, 72.7, 118.6,
135.1, 161.1; MS (CI) m/z 144 (M+ + 1), 131, 129, 114, 109,
103, 86, 71; HRMS (CI) m/z 144.0660 (calcd for C6H10NO3:
144.0661).
(4R)-3-Allyl-4-[(4R,5R)-5-(h ydr oxym eth yl)-2,2-dim eth yl-
1,3-d ioxola n -4-yl]-1,3-oxa zolid in -2-on e (16). To a solution
of 13 (35.0 mg, 0.136 mmol) in dry acetone (20 mL) was added
Amberlyst 15 resin (ca. 10 mg), and the mixture was stirred
for 18 h at room temperature. The mixture was filtered, and
the filtrate was neutralized with solid NaHCO3 (20 mg). The
mixture was filtered through a short column of silica gel, and
the filtrate was concentrated under reduced pressure. Chro-
matography of the residue (5 g of silica gel, EtOAc-hexane,
1:1) gave 22.4 mg (64%) of 16 as a colorless oil: [R]2D3 -13.9 (c
1.10, CHCl3); IR (neat) 3443, 2989, 2925, 1738, 1450, 1377,
(4R)-4-[(1S)-1-(Met h oxym et h oxy)-2-p r op en yl]-1,3-ox-
a zolid in -2-on e (20). To a solution of 19 (20 mg, 0.140 mmol)
and dimethoxymethane (123 µL, 1.40 mmol) in dry CHCl3 (15
mL) was added P2O5 (25 mg), and the mixture was stirred at
ambient temperature until TLC analysis indicated ca. 80%
conversion to a new product. The supernatant was decanted
from the solid residue and was neutralized with solid NaHCO3
(30 mg). The mixture was filtered, and the filtrate was
concentrated under reduced pressure. Chromatography of the
residue (3 g of silica gel, EtOAc-hexane, 1:1) afforded 20 mg
(75%) of 20 as a colorless solid: mp 140-144 °C; [R]2D3 +80.8
(c 0.73, CHCl3); IR (neat) 3306, 2915, 1758, 1240, 1142, 1040
1259, 1084, 1044, 1000 cm-1 1H NMR (300 MHz, CDCl3) δ
;
1.41 (s, 3H), 1.45 (s, 3H), 3.65-3.84 (m, 4H), 3.97-4.02 (m,
1H), 4.18-4.24 (m, 2H), 4.29-4.38 (m, 2H), 5.24-5.32 (m, 2H),
5.73-5.93 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 27.0, 27.2,
45.4, 54.8, 62.3, 62.7, 75.1, 110.1, 119.0, 132.2, 158.2; MS (CI)
m/z 258 (M+ + 1), 242, 228, 200, 182, 156, 141, 131, 126; HRMS
(CI) m/z 258.1341 (calcd for C12H20NO5: 258.1341).
cm-1 1H NMR (300 MHz, CDCl3) δ 3.39 (s, 3H), 3.89-3.94
;
(m, 1H), 4.02 (t, J ) 6 Hz, 1H), 4.41 (dd, J ) 5.9 Hz, 1H), 4.47
(t, J ) 7 Hz, 1H), 5.41-5.47 (m, 3H), 5.62-5.73 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ 54.3, 55.4, 67.1, 78.7, 94.1, 122.3,
133.1, 159.5; MS (CI) m/z 188 (M+ + 1), 170, 158, 156, 140,
126, 82; HRMS (CI) m/z 188.0923 (calcd for C8H14NO4:
188.0928).
(4S)-4-[(4R,5R)-5-(Hyd r oxym eth yl)-2,2-d im eth yl-1,3-d i-
oxola n -4-yl]-1,3-oxa zolid in -2-on e (17). Anhydrous ammonia
(25 mL) was condensed into a 50 mL, two-necked flask
containing a solution of 15 (130 mg, 0.423 mmol) in THF (2
mL) maintained at -78 °C. To the mixture was added sodium
metal until a blue color persisted. The mixture was stirred
for 2 h at -78 °C and quenched with solid NH4Cl. The
ammonia was evaporated, and the residue was extracted with
a EtOAc-MeOH (5%) mixture (3 × 5 mL). The extract was
filtered through Celite and the filtrate was concentrated under
reduced pressure. Chromatography of the residue (10 g of silica
gel, EtOAc-hexane, 2:1) yielded 75 mg (82%) of 17 as a
colorless oil: [R]2D3 -1.0 (c 1.50, CHCl3); IR (neat) 3365, 2984,
4-P en ten yl 4-Meth ylben zen esu lfon a te (22). A solution
of 4-penten-1-ol (21, 45 mL, 0.24 mmol), p-toluenesulfonyl
chloride (81.2 mg, 0.426 mmol), triethylamine (77 mL, 0.55
mmol), DMAP (4 mg), and CHCl3 (2 mL) was stirred for 3 h
at ambient temperature. An aqueous solution of HCl (5%, 2
mL) was added, and the organic phase was separated, washed
with a saturated solution of NaCl, dried over anhydrous Na2-
SO4, and concentrated under reduced pressure to yield pure
as an oil 22: IR (neat) 3070, 2911, 1648, 1604, 1360, 1177,
1097, 988, 928, 824 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.68-
1.76 (m, 2H), 201-2.10 (m, 2H), 2.44 (s, 3H), 4.02 (t, J ) 6
Hz, 1H), 4.93 (s, 1H), 4.95-4.97 (m, 1H), 5.63-5.73 (m, 1H),
7.34 (d, J ) 8 Hz, 1H), 7.78 (d, J ) 8 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 21.8, 28.2, 29.5, 70.0, 116.0, 128.1, 130.0, 133.4,
136.1, 144.9; MS (CI) m/z 3070, 2911, 1648, 1604, 1360, 1177,
1097, 988, 928, 824; HRMS (CI) m/z 241.0899 (calcd for
2940, 1793, 1255, 1044 cm-1 1H NMR (300 MHz, CDCl3) d
;
11.38 (s, 6H), 3.68-3.71 (m, 1H), 3.79-3.94 (m, 4H), 4.41 (dd,
J ) 5, 9 Hz, 1H), 4.52 (t, J ) 8 Hz, 1H), 6.85 (br s, 1H); 13C
NMR (75 MHz, CDCl3) δ 27.0, 54.8, 62.7, 68.3, 79.9, 81.1,
109.8, 160.5; HRMS (CI) m/z 218.1030 (calcd for C9H16NO5:
218.1028
(4R)-3-Ben zyl-4-[(4R,5S)-5-(ch lor om eth yl)-2,2-dim eth yl-
1,3-d ioxola n -4-yl]-1,3-oxa zolid in -2-on e (18). To a solution
of 15 (261 mg, 0.850 mmol) and HMPT (0.310 mL, 1.70 mmol)
in THF (30 mL) maintained at -78 °C under an argon
atmosphere was added CCl4 (0.82 mL, 8.50 mmol), and the
mixture was stirred for 4 h at -78 °C. The temperature of the
reaction mixture was gradually raised to 60 °C, and stirring
was continued for 12 h. The mixture was filtered through a
short column of silica gel and the filtrate was concentrated
under reduced pressure. Chromatography of the residue (10
g of silica gel, EtOAc-hexane, 1:4) afforded 230 mg (83%) of
18 as a colorless oil: [R]D23 -100.0 (c 0.87, CHCl3); IR (neat)
1758, 1437, 1375, 1242, 1071 cm-1; 1H NMR (300 MHz, CDCl3)
δ 1.34 (s, 3H), 1.44 (s, 3H), 3.44 (dd, J ) 7, 11 Hz, 1H), 3.60
(dd, J ) 4, 11 Hz, 1H), 3.70-3.76 (m, 1H), 3.86-3.91 (m, 1H),
4.17 (dd, J ) 2, 7 Hz, 11H), 4.24-4.33 (m, 2H), 4.81 (d, J ) 15
Hz, 1H), 7.28-7.41 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 26.9,
27.2, 44.2, 46.8, 55.2, 62.3, 76.2, 77.0, 110.9, 127.8, 128.3, 128.5,
129.0, 135.8, 158.3; MS (CI) m/z 326 (M+ + 1), 268, 213, 176,
169, 91; HRMS (CI) m/z 326.1160 (calcd for C16H21ClNO4:
326.1159). Anal. Calcd for C16H20ClNO4: C, 58.99; H, 6.19; Cl,
10.88. Found: C, 59.26; H, 6.30; Cl, 10.52.
C
12H17O3S: 241.0894). This compound was used immediately
for alkylation of 20.
(4R)-4-[(1S)-1-(Meth oxym eth oxy)-2-p r op en yl]-3-(4-p en -
ten yl)-1,3-oxa zolid in -2-on e (23). To a solution of 20 (7.3 mg,
0.039 mmol) in dry THF (2 mL) were added NaH (50 wt %
dispersion in mineral oil, 8 mg, 0.390 mmol), tetra-n-butylam-
monium iodide (1 mg), and 22 (12.2 mg, 0.055 mmol). The
mixture was stirred for 16 h at 70 °C, and the reaction was
quenched with a saturated solution of NH4Cl. The organic
phase was separated, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. Chromatography of the
residue (2 g of silica gel, EtOAc-hexane, 3:1) yielded 7.0 mg
(70%) of 23 as a colorless oil: [R]2D3 +91.3 (c 0.53, CHCl3); IR
(neat) 2920, 1753, 1435, 1235, 1167, 1044, 922 cm-1; 1H NMR
(400 MHz, CDCl3) δ 1.61-1.79 (m, 2H), 2.08-2.13 (q, J ) 7
Hz, 1H), 2.99-3.19 (m, 1H), 3.32 (s, 3H), 3.58-3.66 (m, 1H),
3.85-3.89 (m, 1H), 4.21-4.29 (m, 3H), 4.55 (d, J ) 7 Hz, 1H),
4.69 (d, J ) 7 Hz, 1H), 4.99-5.08 (m, 2H), 5.39-5.45 (m, 2H),
5.62-5.71 (m, 1H), 5.79-5.86 (m, 1H); 13C NMR (100 MHz,
CDCl3) d 26.4, 31.0, 41.7, 56.2, 57.8, 62.8, 75.0, 94.4, 115.6,
120.7, 133.0, 137.6, 158.6; MS (CI) m/z 256 (M+ + 1), 226, 224,
196, 194, 180, 170, 156, 154, 126, 110, 100, 95, 86; HRMS (CI)
m/z 256.1550 (calcd for: C13H22NO4: 256.1549).
(4R)-4-[(1S)-1-H yd r oxy-2-p r op en yl]-1,3-oxa zolid in -2-
on e (19). Anhydrous ammonia (40 mL) was condensed into a
100 mL, two-necked flask containing a solution of 18 (44 mg,
0.145 mmol) in THF (2 mL) maintained at -78 °C. To the
mixture was added sodium metal until the blue color persisted.
The reaction was stirred for 3 h at -78 °C and was quenched
with solid NH4Cl. The ammonia was evaporated, and the
(10S,10a R)-10-(Meth oxym eth oxy)-1,5,6,7,10,10a -h exa -
h yd r o[1,3]oxa zolo[3,4-a ]a zocin -3-on e (25). To a solution of
23 (6.30 mg, 0.025 mmol) in CH2Cl2 (4 mL) under an argon

Polyhydroxylated Pyrrolizidine Alkaloids
J . Org. Chem., Vol. 65, No. 26, 2000 9137
atmosphere was added Grubbs’s catalyst (24, 4.5 mg, 5.50
mmol), and the mixture was stirred for 18 h at 60 °C. The
mixture was concentrated under reduced pressure, and the
residue was chromatographed (3 g of silica gel, EtOAc-hexane,
1:1) to give 4.12 mg (75%) of 25 as a colorless oil: [R]2D3 +89.7
(c 0.38, CHCl3); IR (neat) 2931, 2847, 1758, 1455, 1420, 1375,
1241, 1162, 1112, 1042, 993 cm-1; 1H NMR (400 MHz, CDCl3)
δ 1.40-1.48 (m, 1H), 2.10-2.31 (m, 3H), 2.85-2.93 (m, 1H),
3.42 (s, 3H), 3.46-3.52 (m, 1H), 3.73 (dd, J ) 5, 14 Hz, 1H),
4.29 (dd, J ) 5, 9 Hz, 1H), 4.38-4.46 (m, 2H), 4.78 (d, J ) 7
Hz, 1H), 4.57 (d, J ) 6 Hz, 1H), 5.58 (dd, J ) 6 Hz, 1H), 5.77-
5.84 (m, 1H); 13C NMR (100 MHz, CDCl3) d 24.0, 26.5, 42.9,
56.5, 61.3, 66.8, 76.1, 94.9, 131.8, 132.2, 159.1; MS (CI) m/z
228 (M+ + 1), 214, 198, 194, 182, 166, 154, 138, 122, 97, 83;
HRMS (CI) m/z 228.1236 (calcd for C11H18NO4: 228.1236).
(10S,10a R)-10-H yd r oxy-1,5,6,10,10a -h exa h yd r o[1,3]-
oxa zolo[3,4-a ]a zocin -3-on e (26). To a solution of 25 (6.0 mg,
0.026 mmol) in CH3CN (1 mL) was added an aqueous solution
of HBr (48%, 1 drop), and the mixture was stirred for 2 h at
ambient temperature. The mixture was neutralized with solid
NaHCO3 and filtered through a short column of silica gel. The
filtrate was concentrated under reduced pressure, and the
residue was chromatographed (2 g of silica gel, EtOAc-hexane,
2:1) to furnish 4.5 mg (94%) of 26 as a colorless oil: [R]D23
+28.6 (c 1.26, CHCl3); IR (neat) 3321, 2935, 1738, 1465, 1377,
1245, 1074 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.37-1.47 (m,
1H), 2.08-2.24 (m, 3H), 2.17 (s, 3H), 2.58 (br s, 1H), 2.85-
2.95 (m, 1H), 3.39-3.47 (m, 1H), 3.69 (dd, J ) 5, 14 Hz, 1H),
33.39-4.46 (m, 2H), 5.64-5.72 (m, 2H); 13C NMR (75 MHZ,
CDCl3) δ 23.9, 26.3, 42.7, 62.4, 67.0, 71.7, 129.9, 134.2, 159.4;
MS (CI) m/z 184 (M+ + 1), 170, 140, 122, 96, 88, 70; HRMS
(CI) m/z 184.0971 (calcd for C9H14O3N: 184.0974).
(1aR,8aR,9R,9aS)-9-Hydr oxyoctah ydr o[1,3]oxazolo[3,4-
a ]oxir en o[2,3-d ]a zocin -6-on e (27). To a solution of 26 (12.0
mg, 0.066 mmol) in CH2Cl2 (2 mL) was added m-chloroper-
oxybenzoic acid (50 wt %, 56.5 mg, 0.162 mol), and the mixture
was stirred for 7 h at ambient temperature. Methyl sulfide
(50 µL) and solid NaHCO3 (40 mg) were added, and the
reaction was stirred for a further 1 h at ambient temperature.
The mixture was filtered through a short column of silica gel,
and the filtrate was concentrated under reduced pressure.
Chromatography of the residue (2 g of silica gel, EtOAc-
hexane, 3:1) gave 9.6 mg (74%) of 27 as a colorless crystalline
solid: [R]2D3 +34.2 (c 0.88, CH3CN); IR (neat) 3292, 2915,
1714, 1450, 1264, 1250, 1079 cm-1; 1H NMR (400 MHz, CDCl3)
1.19-1.38 (m, 1H), 1.61-1.68 (m, 1H), 2.14-2.23 (m, 1H),
2.96-3.04 (m, 2H), 3.06-3.11 (m, 1H), 3.59 (dd, J ) 7, 10 Hz,
1H), 3.66-3.72 (m, 1H), 3.88 (dd, J ) 5, 14 Hz, 1H), 4.35 (dd,
J 6, 9 Hz, 1H), 4.46 (t, J ) 9 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 23.0, 23.7, 43.9, 55.2, 58.4, 59.2, 65.8, 74.8, 158.9;
HRMS (CI) m/z 200.0925 (calcd for C9H14NO4: 200.0923).
(1aR,8aR,9R,9aR)-9-(Ben zyloxy)octah ydr o[1,3]oxazolo-
[3,4-a ]oxir en o[2,3-d ]a zocin -6-on e (28). A mixture of 27 (3.0
mg, 0.015 mmol), benzyl bromide (20 mL, 0.168 mmol), and
tetra-n-butylammonium iodide (1 mg) in THF (2 mL) was
stirred for 4 h at ambient temperature. A saturated solution
of NH4Cl was added, and the product was extracted with
EtOAc (3 × 2 mL). The combined organic extracts were washed
with a saturated solution of NaCl, dried over anhydrous Na2-
SO4, and concentrated under reduced pressure. Chromatog-
raphy of the residue (3 g of silica gel, EtOAc-hexane, 1:1)
produced 4.3 mg (98%) of 28 as colorless prisms: mp 78-80
°C; [R]2D3 +64.2 (c 0.24, CHCl3); IR (neat) 2911, 2842, 1763,
1454, 1426, 1377, 1259, 1147, 1003 cm-1; 1H NMR (400 MHz,
CDCl3) δ 1.20-1.31 (m, 1H), 1.61-1.70 (m, 2H), 2.05-2.23 (m,
2H), 2.96-3.05 (m, 2H), 3.36 (dd, J ) 7, 10 Hz, 1H), 3.69-
3.75 (m, 1H), 3.88 (dd, J ) 5, 14 Hz, 1H), 4.15 (dd, J ) 6, 9
Hz, 1H), 4.43 (t, J ) 9 Hz, 1H), 4.61 (d, J ) 11 Hz, 1H), 4.90
(d, J ) 11 Hz, 1H), 7.31-7.53 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 23.1, 23.7, 44.1, 53.0, 57.1, 58.7, 66.2, 71.9, 80.6,
127.9, 128.4, 128.5, 128.8, 137.2, 158.8; HRMS (CI) m/z
290.1389 (calcd for C16H20NO2: 290.1391).
8.6 mmol) in a EtOH-H2O mixture (0.5 mL) was added LiOH
(3.6 mg, 0.086 mmol), and the solution was stirred for 24 h at
96 °C. The mixture was concentrated under reduced pressure
and was extracted with CHCl3 (5 × 0.5 mL). The combined
organic extracts were dried over anhydrous Na2SO4 and
concentrated under reduced pressure to afford 2.2 mg (92%)
of 29 as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 1.80-
1.89 (m, 1H), 1.91-2.07 (m, 3H), 2.84-2.94 (m, 1H), 3.01 (q,
J ) 8 Hz, 1H), 3.24 (br s, 1H), 3.55-3.67 (m, 1H), 3.73 (dd, J
) 6, 12 Hz, 1H), 3.89 (dd, J ) 3, 12 Hz, 1H), 3.95-3.96 (m,
1H), 4.08-4.09 (m, 1H), 4.61 (d, J ) 12 Hz, 1H), 4.66 (d, J )
12 Hz, 1H), 7.28-7.37 (m, 5H); HRMS (CI) m/z 280.1548 (calcd
for C15H22NO3: 280.1548).
2-[(4S)-2,2-Dim eth yl-5-oxo-1,3-dioxolan -4-yl]acetic Acid
(31). To a solution of (S)-malic acid (30, 300 mg, 2.24 mmol)
in 2,2-dimethoxypropane (20 mL) was added camphorsulfonic
acid (10 mg), and the mixture was stirred for 18 h at room
temperature. Sodium acetate was added to the mixture, and
stirring was continued for a further 1 h. The mixture was
filtered, and the filtrate was concentrated under reduced
pressure. Crystallization of the residue from a CHCl3-hexane
mixture afforded 331 mg (85%) of 31 as a colorless oil: [R]D23
+4.0 (2.82 CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.57 (s, 3H),
1.63 (s, 3H), 2.86 (dd, J ) 7, 18 Hz, 1H), 3.00 (dd, J ) 4, 21
Hz, 1H), 4.72 (dd, J ) 4, 7 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 26.0, 27.0, 36.2, 70.6, 111.6, 172.0, 174.9; MS (CI) m/z 175
(M+ + 1), 1Å57, 147, 131, 117, 103, 89; HRMS (CI) m/z 175.0606
(calcd for C7H11O5: 175.0606).
(3S)-3-Hyd r oxyd ih yd r o-2(3H)-fu r a n on e (32). To a solu-
tion of 31 (2.00 g, 11.5 mmol) in THF (150 mL) maintained at
0 °C was added a 1 M solution of BH3 in THF (14.0 mL, 14.0
mmol) dropwise over 45 min. The mixture was stirred for 2 h
at 0 °C and for 18 h at room temperature, MeOH (30 mL) was
added, and the mixture was stirred for a further 1 h at room
temperature. Volatiles were removed under reduced pressure,
the residue was dissolved in CHCl3 (40 mL), and camphorsol-
fonic acid (1 g) was added. The mixture was stirred for 10 h
at room temperature and filtered, and the filtrate was con-
centrated under reduced pressure. Chromatogaphy of the
residue (80 g of silica gel, EtOAc-hexane, 2:1) gave 0.840 g
(72%) of 32 as a colorless oil: [R]2D3 -69.7 (c 0.93, CHCl3); IR
(neat) 3413, 2916, 1773, 1231, 1181, 1132, 1017 cm-1; 1H NMR
(300 MHz, CDCl3) δ 2.22-2.39 (m, 1H), 2.56-2.66 (m, 1H),
4.19-4.28 (m, 1H), 4.40-4.55 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 31.0, 65.4, 67.6, 178.3; MS (CI) m/z 103 (M+ + 1),
91, 85, 75, 71; HRMS (CI) m/z 103.0396 (calcd for C4H7O3:
103.0395).
(3S)-3-(Meth oxy)d ih yd r o-2(3H)-fu r a n on e (33). To a so-
lution of 32 (120 mg, 1.17 mmol) and dimethoxymethane (1.00
mL, 11.3 mmol) in CHCl3 (5 mL) was added P2O5 (ca. 50 mg),
and the mixture was stirred for 5 h at room temperature. The
organic phase was separated, neutralized with with solid
NaHCO3, and filtered. The filtrate was concentrated under
reduced presure, and the residue was chromatographed (15 g
of silica gel, EtOAc-hexane, 1:3) to furnish 165 mg (96%) of
33 as a colorless oil: [R]D23 -122.4 (c 2.59, CHCl3); IR (neat)
2935, 1792, 1460, 1391, 1240, 1157, 1064, 1025 cm-1; 1H NMR
(300 MHz, CDCl3) δ 2.23-2.36 (m, 1H), 2.53-2.63 (m, 1H),
3.43 (s, 3H), 4.20-4.28 (m, 1H), 4.40-4.47 (m, 2H), 4.72 (d, J
) 7 Hz, 1H), 4.96 (d, J ) 7 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 30.1, 56.1, 65.3, 70.4, 96.1, 175.1; MS (CI) m/z 147 (M+ + 1),
130, 117, 115, 87, 71; HRMS (CI) m/z 147.0657 (calcd for
C6H11O4: 147.0657).
(3S)-3-(Meth oxym eth oxy)tetr a h yd r o-2-fu r a n ol (34). To
a solution of 33 (0.880 g, 5.47 mmol) in dry CH2Cl2 (30 mL)
maintained at -78 °C was added a 1.5 M solution of DIBALH
in toluene (4.0 mL, 6 mmol), and the mixture was stirred for
30 min at -78 °C. Solid NH4Cl (0.4 g) and MeOH (1 drop) were
added, and the mixture was filtered through a short column
of silica gel which was subsequently rinsed with a EtOAc-
MeOH (5%) mixture. The filtrate was concentrated under
reduced pressure, and the residue was chromatographed (20
g of silica gel, EtOAc-hexane, 1:1) to afford 0.621 g (76%) of
34 as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 1.91-2.30
(1R,2R,3R,7a S)-Ben zyloxy-3-(h yd r oxym eth yl)h exa h y-
d r o-1H-p yr r olizin e-1,2-d iol (29). To a solution of 28 (2.5 mg,

9138 J . Org. Chem., Vol. 65, No. 26, 2000
White and Hrnciar
gave 16 mg (93%) of 38 as a colorless oil: [R]2D3 +11.4 (c 1.63,
(m, 4H), 3.38 (s, 3H), 3.41 (s, 3H), 3.80-3.88 (m, 1H), 4.01-
4.17 (m, 5H), 4.66 (s, 2), 4.68-4.74 (m, 2H), 5.31 (d, J ) 4 Hz,
1H), 5.40 (s, 1H). This material was used immediately for the
conversion to 35.
CHCl3); IR (neat) 3420, 2956, 1730, 1432, 1273, 1155, 1026,
934 cm-1 1H NMR (400 MHz, CDCl3) δ 1.17-1.81 (m, 1H),
;
1.85-1.93 (m, 1H), 3.03 (br s, 2H), 3.47 (t, J ) 7 Hz, 1H), 3.87-
3.91 (m, 1H), 4.18-4.27 (m, 3H), 4.45-4.46 (m, 1H), 5.12 (d,
J ) 10 Hz, 1H), 5.25-5.32 (m, 2H), 5.47 (dd, J ) 1, 18 Hz,
1H), 5.72-5.80 (m, 1H), 5.87-5.95 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 35.0, 40.0, 60.2, 69.9, 70.7, 115.0, 118.3, 135.0,
140.4, 159.8; MS(CI) m/z 228 (M+ + 1), 210, 170, 156, 144,
116, 112, 88, 71. Anal. Calcd for C11H17NO4: C, 58.14; H, 7.54;
N, 6.16. Found: C, 57.90; H, 7.59; N, 6.42.
(3S)-3-(Meth oxym eth oxy)-4-p en ten -1-ol (35). To a sus-
pension of methyltriphenylphosphonium bromide (222 mg,
0.62 mmol) in THF (40 mL) maintained at 0 °C under an argon
atmosphere was added a 0.5 M solution of KHMDS in toluene
(1.86 mL, 0.93 mmol), and the mixture was stirred for 30 min
at 0 °C. The mixture was then cooled to -78 °C, and a solution
of 34 (85.2 mg, 0.380 mmol) in THF (0.5 mL) was added. The
mixture was stirred for 10 h at room temperature, and the
reaction was quenched with a saturated solution of NH4Cl (5
mL). The mixture was extracted with Et2O (3 × 10 mL), and
the combined organic extracts were washed with a saturated
solution of NaCl, dried over anhydrous Na2SO4, and concen-
trated under reduced pressure. Chromatography of the residue
(4 g of silica gel, EtOAc-hexane, 1:3) gave 142.4 mg (65%) of
35 as a colorless oil: [R]D23 -120.5 (c 1.25, CHCl3); IR (neat)
3424, 2955, 2891, 1650, 1474, 1162, 1108, 1040, 927 cm-1; 1H
NMR((300 MHz, CDCl3) δ 1.84 (q, J ) 6 Hz, 2H), 2.01 (br s,
1H), 3.41 (s, 3H), 3.72-3.87 (m, 2H), 4.27 (q, J ) 6 Hz, 1H),
4.57 (d, J ) 7 Hz, 1H), 4.72 (d, J ) 7 Hz, 1H), 5.20-5.29 (m,
2H), 5.68-5.80 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 37.9,
55.8, 60.2, 76.5, 94.2, 117.6, 137.8; HRMS (CI) m/z 146.0941
(calcd for C7H14O3: 146.0942);
(3S)-3-[(4-Met h oxyb en zyl)oxy]d ih yd r o-2(3H )-fu r a n -
on e (39). To a solution of 32 (59.2 mg, 0.405 mmol) and
p-methoxybenzyl 2,2,2-trichloroacetimidate (228 mg, 0.810
mmol) in dry CH2Cl2 (10 mL) was added a 1 M solution of
trifluoromethanesulfonic acid in CH
2Cl2 (12 µL, 0.0120 mmol),
and the mixture was stirred for 4 h at ambient temperature.
The reaction was neutralized with solid NaHCO3 (10 mg), the
mixture was filtered, and the filtrate was concentrated under
reduced pressure. Chromatography of the residue (12 g of silica
gel, EtOAc-hexane, 1:3) gave 83 mg (92%) of 39 as a colorless
oil: [R]2D3 -56.3 (c 4.73 CHCl3); IR (neat) 2925, 1772, 1733,
1611, 1513, 1259, 1176, 1137, 1035 cm-1; 1H NMR (300 MHz,
CDCl
3) δ 2.20-2.32 (m, 1H), 2.38-2.49 (m, 1H), 3.81 (s, 3H),
4.13-4.25 (m, 2H), 4.41 (dt, J ) 4, 8 Hz, 1H), 4.67 (d, J ) 11
Hz, 1H), 4.87 (d, J ) 11 Hz, 1H), 6.89-6.92 (m, 2H), 7.30-
7.34 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 30.1, 55.5, 65.7,
72.0, 72.2, 113.9, 114.1, 129.1, 130.1, 159.7, 175.3; MS (CI)
m/z 222 (M+ + 1), 162, 137, 126, 121, 98; HRMS (CI) m/z
222.0891 (calcd for C12H14O4: 222.0892).
(3S)-3-(Meth oxym eth oxy)-4-pen ten yl 4-Meth ylben zen e-
su lfon a te (36). A solution of 35 (151 mg, 1.03 mmol),
p-toluenesulfonyl chloride (0.197 g, 1.03 mmol), DMAP (10 mg),
and triethylamine (0.216 mL, 1.54 mmol) in dry CH2Cl2 (20
mL) was stirred for 3 h at ambient temperature. An aqueous
solution of HCl (2%, 15 mL) was added, and the organic phase
was separated, washed with water and a saturated solution
of NaCl, dried over Na2SO4, and concentrated under reduced
pressure. Chromatography of the residue (20 g of silica gel,
EtOAc-hexane, 1:3) afforded 284 mg (92%) of 36 as a colorless
oil: [R]2D3 -51.6 (c 1.29, CHCl3); IR (neat) 2950, 2876, 1596,
(3S)-3-[4-Meth oxyben zyl)oxy]tetr ah ydr o-2-fu r an ol (40).
To a solution of 39 (93.6 mg, 0.412 mmol) in CH2Cl2 (15 mL)
maintained at -78 °C was added a 1 M solution of DIBALH
in hexanes (0.50 mL, 0.50 mmol), and the mixture was stirred
for 30 min at -78 °C. Solid NH4Cl and MeOH (1 drop) were
added, and the mixture was filtered through a short column
of silica gel, which was subsequently rinsed with a EtOAc-
MeOH (5%) mixture. The filtrate was concentrated under
reduced pressure, and the residue was chromatographed (10
g of silica gel, EtOAc-hexane, 1:1) to afford 57.3 mg (60%) of
40 as a colorless oil: IR (neat) 3404, 2890, 16116, 1518, 1255,
1127, 1044 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.92-2.25 (m,
4H), 3.79 (s, 3H), 3.80 (s, 3H), 3.97-4.09 (m, 4H), 4.48-4.56
(m, 4H), 5.30 (d, J ) 4 Hz, 1H), 5.41 (s, 1H), 6.85-6.91 (m,
2H), 7.25-7.28 (m, 2H). This material was used immediately
for the conversion to 41.
1
1357, 1192, 1040, 922, 849 cm-1; H NMR (300 MHz, CDCl3)
δ 1.79-2.01 (m, 2H), 2.46 (s, 3H), 3.30 (s, 3H), 4.06-4.25 (m,
3H), 4.47 (d, J ) 7 Hz, 1H), 4.63 (d, J ) 7 Hz, 1H), 5.15-5.21
(m, 2H), 5.55-5.67 (m, 1H), 7.35 (d, J ) 8 Hz, 2H), 7.80 (d, J
) 8 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 21.8, 34.9, 55.8,
67.2, 73.6, 94.1, 118.5, 128.1, 130.0, 133.3, 137.2, 145.0; MS
(CI) m/z 301 (M+ + 1), 239, 215, 201, 173, 155, 99, 68; HRMS
(CI) m/z 301.1109 (calcd for C14H21O5S: 301.1109).
(4R)-3-[(3S)-3-(Met h oxym et h oxy)-4-p en t en yl]-4-[(1S)-
1-(m eth oxym eth oxy)-2-pr open yl]-1,3-oxazolidin -2-on e (37).
To a solution of 20 (5.0 mg, 0.027 mmol) in benzene (0.5 mL)
were added NaH (50 wt % dispersion in mineral oil, 6.4 mg,
0.133 mmol), tetra-n-butylammonium bromide (ca. 1 mg), and
a solution of 36 (12.7 mg, 0.035 mmol) in benzene (0.1 mL).
The resulting mixture was refluxed for 10 h, after which the
volatiles were removed under reduced pressure, and the
residue was chromatographed (4 g of silica gel, EtOAc-hexane,
1:5) to yield 7.1 mg (84%) of 37 as a colorless oil: [R]2D3 +39.9
(c 3.03, CHCl3); IR (neat) 2920, 1758, 1426, 1235, 1152, 1108,
1030, 927 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.84-1.93 (q, J
) 8 Hz, 2H), 3.17-3.32 (m, 1H), 3.36 (s, 3H), 3.39 (s, 3H),
3.67-3.79 (m, 1H), 3.86-3.97 (m, 1H), 4.21-4.32 (m, 3H), 4.57
(d, J ) 7 Hz, 2H), 4.70 (d, J ) 7 Hz, 2H), 5.21-5.33 (m, 2H),
5.37-5.48 (m, 2H), 5.60-5.79 (m, 2H). 13C NMR (75 MHz,
CDCl3) δ 32.9, 38.9, 55.8, 56.1, 58.0, 62.9, 75.1, 75.6, 94.2, 94.4,
118.1, 120.7, 132.9, 137.5, 158.5; MS (CI) m/z 316 (M+ + 1),
284, 254, 240, 210, 184, 170, 156, 130, 100; HRMS (CI) m/z
316.1760 (calcd for C15H26NO6: 316.1760).
(4R)-3-[(3S)-3-Hyd r oxy-4-p en ten yl]-4-[(1S)-1-h yd r oxy-
2-p r op en yl]-1,3-oxa zolid in -2-on e (38). To a solution of 37
(36 mg, 0.114 mmol) in CH3CN (3 mL) was added an aqueous
solution of HBr (48%, 3 drops), and the mixture was stirred
for 1 h at ambient temperature. Solid NaHCO3 (20 mg) was
added, and stirring was continued for 30 min. The mixture
was filtered through a short column of silica gel, and the
filtrate was concentrated under reduced pressure. Chroma-
tography of the residue (5 g of silica gel, EtOAc-hexane, 5:1)
(3S)-3-[(4-Meth oxyben zyl)oxy]-4-p en ten -1-ol (41). To a
stirred suspension of methyltriphenylphosphonium bromide
(271 mg, 0.760 mmol) in THF (20 mL) cooled to 0 °C was added
a 0.5 M solution of KHMDS in toluene (2.3 mL, 1.13 mmol),
and the mixture was stirred for 30 min at 0 °C. The solution
was then cooled to -78 °C, and a solution of 40 (85.2 mg, 0.380
mmol) in THF (0.5 mL) was added. The mixture was allowed
to warm to ambient temperature, was stirred for 18 h, and
then was quenched with a saturated solution of NH4Cl (5 mL).
The mixture was extracted with Et2O (3 × 8 mL), and the
combined organic extracts were washed with a saturated
solution of NaCl, dried over anhydrous Na2SO4, and concen-
trated under reduced pressure. Chromatography of the residue
(4 g of silica gel, EtOAc-hexane, 1:3) gave 180.0 mg (67%) of
41 as a colorless oil: [R]D23 -56.0 (c 1.42, CHCl3); IR (neat)
1
3412, 2929, 1624, 1513, 1248, 1039, 827 cm-1; H NMR (300
MHz, CDCl3) δ 1.74-1.92 (m, 2H), 2.15 (br s, 1H), 3.69-3.78
(m, 2H), 3.81 (s, 3H), 3.97-4.05 (m, 1H), 4.30 (d, J ) 11 Hz,
1H), 4.57 (d, J ) 11 Hz, 1H), 5.25 (s, 1H), 5.29-5.30 (m, 1H),
5.74-5.86 (m, 1H), 8.87-6.90 (m, 2H), 7.24-7.27 (m, 2H);13C
NMR (75 MHz, CDCl3) δ 37.9, 55.5, 60.9, 70.1, 79.8, 114.1,
117.6, 129.6, 130.1, 130.4, 138.4, 159.4; MS (CI) m/z 222 (M+
+ 1), 203, 175, 149, 137, 121, 109, 85; HRMS (CI) m/z 222.1256
(calcd for C13H18O3: 222.1256).
ter t-Bu tyl (4R)-4-{(1S)-1-[(ter t-Bu toxyca r bon yl)oxy]-2-
p r op en yl}-2-oxo-1,3-oxa zolid in e-3-ca r boxyla te (43). To a
solution of 19 (8.2 mg, 0.057 mmol) in CH2Cl2 (0.5 mL) were
added triethylamine (18 mL, 0.129 mmol), di-tert-butyl carbon-

Polyhydroxylated Pyrrolizidine Alkaloids
J . Org. Chem., Vol. 65, No. 26, 2000 9139
ate (41.2 mL, 0.183 mmol), and DMAP (2 mg), and the mixture
was stirred for 1 h at room temperature. The solution was
concentrated under reduced pressure, and the residue was
chromatographed (1 g of silica gel, EtOAc-hexane, 1:8) to give
18.4 mg (93%) of 43 as a colorless oil: [R]2D3 +47.7 (c 1.36,
CHCl3); IR (neat) 2979, 2935, 1826, 1796, 1752, 1371, 1279,
2.99-3.32 (m, 2H), 3.62-3.73 (br s, 1H), 3.79 (s, 3H), 4.13 (br
s, 1H), 4.24 (d, J ) 11 Hz, 1H), 4.52 (d, J ) 11 Hz, 1H), 5.25
(d, J ) 10 Hz, 1H), 5.33 (d, J ) 15 Hz, 1H), 5.36 (d, J ) 15 Hz,
1H), 5.50-5.69 (m, 2H), 5.84-5.95 (m, 1H), 6.88 (d, J ) 8 Hz,
2H), 7.26 (d, J ) 8 Hz, 2H), 7.35-7.37 (m, 3H), 7.49-7.51 (m,
2H); HRMS (CI) m/z 494.2909 (calcd for C30H40NO5: 494.2906).
1254, 1162, 1132, 1088 cm-1 1H NMR (300 MHz, CDCl3) δ
;
(4S,5R)-5-[4S)-3-Ben zyl-2-oxo-1,3-oxa zolid in -4-yl]-2,2-
d im eth yl-1,3-d ioxola n e-4-ca r ba ld eh yd e (47). To a solution
of oxalyl chloride (22.0 mL, 0.252 mmol) in CH2Cl2 (0.5 mL)
maintained at -78 °C was added a solution of DMSO (32.8
mL, 0.462 mmol) in CH2Cl2 (0.5 mL), followed after 2 min by
a solution of 15 (64.5 mg, 0.210 mmol) in CH2Cl2 (0.1 mL).
The mixture was stirred for 30 min at -78 °C, and triethyl-
amine (0.146, 0.0105 mmol) was added. Stirring was continued
for 2 h at -78 °C, and the mixture was concentrated under
reduced pressure. The residue was taken up into EtOAc (15
mL), and the solution was filtered through a short column of
silica gel. The filtrate was concentrated under reduced pres-
sure, and the residue was chromatographed (12 g of silica gel,
EtOAc-hexane, 1:1) to afford 47.4 mg (74%) of 47 as a colorless
oil: [R]2D3 -27.0 (c 2.52, CHCl3); IR (neat) 2988, 2935, 1752,
1435, 1264, 1220., 1103, 712 cm-1; 1H NMR (400 MHz, CDCl3)
δ 1.35 (s, 3H), 1.61 (s, 3H), 3.94-3.98 (m, 1H), 4.06 (d, J ) 6
Hz, 1H), 4.28-4.36 (m, 4H), 4.90 (d, J ) 15 Hz, 1H), 7.31-
7.50 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 25.3, 26.4, 47.1,
54.8, 62.6, 76.1, 80.6, 111.9, 128.1, 128.9, 129.1, 135.7, 158.7,
202.3; MS (CI) m/z 306 (M+ + 1), 304, 248, 178, 176, 95, 91,
89, 83, 73; HRMS (CI) m/z 306.1343 (calcd for C16H20NO5N:
306.1341).
1.47 (s, 9H), 1.57 (s, 9H), 4.24 (d, J ) 9 Hz, 1H), 4.33 (d, J )
9 Hz, 1H), 4.34 (d, J ) 9 Hz, 1H), 4.37-4.42 (m, 1H), 5.37 (d,
J ) 10 Hz, 1H), 5.41-5.49 (m, 1H), 5.72-5.78 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ 27.8, 28.1, 56.9, 61.7, 74.0, 83.5, 84.5,
119.6, 131.2, 149.2, 151.9, 152.8; MS (CI) m/z 344 (M+ + 1),
321, 232, 216, 188, 170, 144, 126, 86; HRMS (CI) m/z 344.1707
(calcd for C16H26NO7: 344.1709).
ter t-Bu tyl (1R,2S)-2-Hydr oxy-1-(h ydr oxym eth yl)-3-bu te-
n ylca r ba m a te (44). To a solution of 43 (13.6 mg, 0.039 mmol)
in dry EtOH (1 mL) was added a 2 M solution of NaOEt in
EtOH (60 µL, 0.120 mmol), and the mixture was stirred for 7
h at ambient temperature. The reaction was quenched with
solid NH4Cl (40 mg), the mixture was filtered, and the filtrate
was concentrated under reduced pressure. Chromatography
of the residue (1.5 g of silica gel, EtOAc-hexane, 2:1) yielded
6.2 mg (72%) of 44 as a colorless oil: [R]2D3 -5.4 (c 1.10,
CHCl3); IR (neat) 3389, 2972, 2928, 1703, 1512, 1368, 1262,
1
1162, 1066 cm-1; H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H),
3.08 (br s, 2H), 3.63 (s br, 1H), 3.68-3.71 (m, 1H), 3.92 (dd, J
) 4, 11 Hz, 1H), 4.36 (br s, 1H), 5.24-5.27 (m, 1H), 5.36-5.41
(m, 1H), 5.42 (br s, 1H), 5.88-5.99 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 28.3, 55.0, 62.3, 74.7, 116.5, 137.4, 156.2; MS
(CI) m/z 218 (M+ + 1), 202, 188, 172, 162, 144, 118, 114, 104,
100; HRMS (CI) m/z 218.1391 (calcd for C10H20NO4: 218.1392).
(4S)-3-Ben zyl-4-[(4R,5R)-2,2-d im eth yl-5-vin yl-1,3-d iox-
ola n -4-yl]-1,3-oxa zolid in -2-on e (48). To a suspension of
methyltriphenylphosphonium bromide (83.6 mg, 0.178 mmol)
in THF (15 mL) was added a 1.6 M solution of n-BuLi in
hexanes (0.11 mL, 0.18 mmol), and the resulting solution was
stirred for 30 min at 0 °C. The mixture was cooled to -78 °C,
and a solution of 47 (27.2 mg, 0.089 mmol) in THF (0.1 mL)
was added. The mixture was gradually warmed to 60 °C,
stirred for a further 18 h, and then diluted with EtOAc (20
mL) and filtered through a short column of silica gel. The
filtrate was concentrated under reduced pressure, and the
residue was chromatographed (5 g of silica gel, EtOAc-hexane,
1:7) to give 17.2 mg (64%) of 48 as a colorless oil: [R]2D3 -22.7
(c 2.37, CHCl3); IR (neat) 2979, 1762, 1430, 1235, 1083, 717
ter t-Bu tyl (2R,4S,5R)-2-P h en yl-4-vin yl-1,3-d ioxa n -5-yl-
ca r ba m a te (45). A solution of 44 (19.0 mg, 0.087 mmol),
benzaldehyde dimethylacetal (26.2 µL, 0.1.75 mmol), and
camphorsulfonic acid (2 mg) in CH2Cl2 (1 mL) was stirred for
6 h at ambient temperature. NaHCO3 (10 mg) was added, and
the mixture was stirred for a further 1 h and was filtered. The
filtrate was concentrated under reduced pressure, and the
residue was chromatographed (2 g of silica gel, EtOAc-hexane,
1:10) to afford 24.2 mg (96%) of 45 as a colorless oil: [R]D23
-29.6 (c 1.55, CHCl3); IR (neat) 3360, 2979, 1694, 1528, 1308,
1
1235, 1171, 1020 cm-1; H NMR (300 MHz, CDCl3) δ 1.46 (s,
9H), 3.58-3.65 (m, 1H), 3.73 (br s, 1H), 4.31 (d, J ) 8 Hz,
1H), 4.38 (dd, J ) 5, 10 Hz, 1H), 5.31 (dd, J ) 1, 10 Hz, 1H),
5.43 (d, J ) 17 Hz, 1H), 5.23 (s, 1H), 5.92-6.09 (m, 1H), 7.32-
7.41 (m, 3H), 7.50-7.53 (m, 2H); 13C NMR (75 MHz, CDCl3) δ
28.5, 47.9, 70.1, 82.3, 101.2, 119.2, 126.4, 128.5, 129.2, 134.7,
137.8; MS (CI) m/z 250, 172, 151, 144, 107, 83, 69; HRMS (CI)
m/z 306.1703 (calcd for C17H24dNO4: 306.1705).
1
cm-1; H NMR (300 MHz, CDCl3) δ 1.37 (s, 3H), 1.46 (s, 3H),
3.77-3.82 (m, 1H), 3.90 (dd, J ) 2, 8 Hz, 1H), 4.01 (t, J ) 8
Hz, 1H), 4.20-4.31 (m, 3H), 4.84 (d, J ) 15 Hz, 1H), 5.27 (d,
J ) 16 Hz, 1H), 5.31 (d, J ) 23 Hz, 1H), 5.69-5.80 (m, 1H),
7.29-7.38 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 26.8, 27.0,
47.0, 53.6, 62.5, 78.4, 78.5, 110.0, 120.2, 128.2, 128.4, 130.0,
134.7, 135.9, 158.5; MS (CI) m/z 304 (M+ + 1), 246, 176, 127,
61; HRMS (CI) m/z 304.1549 (calcd for C17H22NO4: 304.1549).
ter t-Bu tyl (3S)-3-[(4-Meth oxyben zyl)oxy]-4-p en ten yl-
[(4S,5R)-2-ph en yl-4-vin yl-1,3-dioxolan -5-yl]car bam ate (46).
To a solution of 41 (10 mg, 0.045 mmol) in triethylamine (31
mL, 0.225 mmol) and CH2Cl2 (1 mL) was added trifluo-
romethanesulfonic anhydride (9.8 mL, 0.058 mmol), and the
mixture was stirred for 1 h at 0 °C. An aqueous solution of
HCl (5%, 1 mL) was added, and the organic phase was
separated, washed with a saturated solution of NaCl, dried
over anhydrous Na2SO4, and concentrated under reduced
pressure to afford 15.3 mg of 42 which was not further purified.
(4R)-4-[(1S,2E)-1-Hyd r oxy-2-bu ten yl]-1,3-oxa zolid in -2-
on e (49). Anhydrous ammonia (7 mL) was condensed into a
25 mL two-necked flask containing a solution of 48 (44.0 mg,
0.145 mmol) in THF (0.5 mL) maintained at -78 °C. Sodium
metal was added to the solution until a blue color persisted,
and the solution was stirred for 2 h at -78 °C. The reaction
was quenched with solid NH4Cl, the ammonia was evaporated,
and the residue was extracted with a EtOAc-MeOH (5%)
mixture (3 × 5 mL). The combined extracts were filtered
through a short column of silica gel, and the filtrate was
concentrated under reduced pressure. Chromatography of the
residue (2 g of silica gel, EtOAc-hexane, 1:1) yielded 15.1 mg
(66%) of 49 as a colorless oil: [R]2D3 +0.1 (c 0.90, CHCl3); IR
(neat) 3326, 2925, 1748, 1421, 1250, 1157, 1044 cm-1; 1H NMR
(300 MHz, CDCl3) δ 1.73 (d, 3H), 3.14 (br s, 1H), 3.84-3.90
(m, 1H), 4.12 (br s, 1H), 4.31-4.44 (m, 2H), 5.40 (ddd, J ) 2,
7, 8 Hz, 1H), 5.79-5.91 (m, 1H), 6.23 (br s, 1H); 13C NMR (75
MHz, CDCl3) δ 18.1, 56.5, 66.6, 73.3, 128.1, 131.2, 160.7; MS
(CI) m/z 158 (M+ + 1), 140, 128, 114, 96, 86, 71; HRMS (CI)
m/z 158.0817 (calcd for C7H12NO3: 158.0817).
To a solution of 45 (3.8 mg, 0.013 mmol) in THF (0.5 mL)
was added NaH (50 wt % dispersion in mineral oil, 6.2 mg,
0.14 mmol), and the mixture was stirred at room temperature
for 1 h. The solution was cooled to -78 °C, and a solution of
42 (5.1 mg, 0.019 mmol) in THF (0.2 mL) was added. The
mixture was warmed to room temperature, stirred for a further
10 h, and then was quenched with a saturated solution of NH4-
Cl (0.5 mL). The mixture was extracted with CH2Cl2 (3 × 1
mL), and the combined organic extracts were washed with a
saturated solution of NaCl, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. Chromatography of the
residue (1 g of silica gel, hexanes-EtOAc, 10:1) gave 5.4 mg
(82%) of 46 as a colorless oil: IR (neat) 2962, 2926, 1694, 1509,
{(2S ,3R )-3-[(4R )-2,2-Dim e t h yl-1,3-d ioxola n -4-yl]oxi-
r a n yl}m eth yl 3-Bu ten ylca r ba m a te (50). To a solution of
4-pentenoic acid (1.03 mL, 10.0 mmol) in benzene (20 mL) were
1365, 1247, 1139, 1108 cm-1
1.48-1.57 (m, 9H), 1.64-1.82 (m, 2H), 2.01-2.13 (m, 2H),
;
1H NMR (300 MHz, CDCl3) δ

9140 J . Org. Chem., Vol. 65, No. 26, 2000
White and Hrnciar
added diphenylphosphoryl azide (1.85 mL, 8.6 mmol) and
triethylamine (2.4 mL, 17.2 mmol), and the mixture was
stirred for 2 h at ambient temperature. The mixture was
filtered through a short column of silica gel (6 g) which was
subsequently rinsed with dry benzene (20 mL). The filtrate
was warmed to 90 °C and stirred for 1.5 h. The temperature
of the mixture was then lowered to 60 °C, and 9 (0.50 g, 2.87
mmol) was added followed by triethylamine (1 mL). The
mixture was stirred for 18 h at 60 °C and was concentrated
under reduced pressure. Chromatography of the residue (40
g of silica gel, EtOAc-hexane, 1:1) furnished 0.72 g (92%) of
50 as a colorless oil: [R]D23 -20.3 (c 0.69, CHCl3); IR (neat)
reduced pressure. The residue was taken up into dry EtOAc
(15 mL), and the solution was filtered through a short column
of silica gel. The filtrate was concentrated under reduced
pressure, and the residue was chromatographed (20 g of silica
gel, EtOAc-hexane, 1:1) to give 47.4 mg (59%) of 53 as a
colorless oil: [R]2D3 -15.7 (c 1.15, CHCl3); IR (neat) 2979,
2925, 1748, 1435, 1367, 1264, 1215 cm-1; 1H NMR (300 MHz,
CDCl3) δ 1.35 (s, 3H), 1.,54 (s, 3H), 2.29-2.46 (m, 2H), 3.20-
3.29 (m, 1H), 3.62-3.71 (m, 1H), 4.06 (d, J ) 6 Hz, 1H), 4.10-
4.16 (m, 1H), 4.16-4.36 (m, 4H), 5.07-5.17 (m, 2H), 5.73-
5.82 (m, 1H), 9.88 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 25.3,
26.3, 31.7, 42.2, 55.3, 62.5, 76.4, 80.4, 111.9, 117.7, 134.7, 158.5,
202.7; MS (CI) m/z 270 (M+ + 1), 228, 21, 170, 140, 129, 100;
HRMS (CI) m/z 270.1340 (calcd for C13H20NO5: 270.1341).
3345, 2989, 1723, 1548, 1377, 1255, 1230, 1152, 1065 cm-1
;
1H NMR(300 MHz, CDCl3) δ 1.34 (s, 3H), 1.40 (s, 3H), 2.21-
2.28 (m, 2H), 2.94-2.96 (m, 1H), 3.16-3.18 (m, 1H), 3.21-
3.27 (m, 2H), 3.79-3.86 (m, 1H), 3.96 (dd, J ) 6, 12 Hz, 1H),
4.02-4.11 (m, 2H), 4.35 (dd, J ) 3, 12 Hz, 1H), 4.90 (br s, 1H),
5.06-5.12 (m, 2H), 5.66-5.80 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ 25.7, 26.4, 34.2, 40.2, 53.0, 55.9, 64.2, 66.1, 75.1,
110.2, 117.2, 135.1, 156.0; MS (CI) m/z 272 (M+ + 1), 256, 230,
214, 154, 117, 112, 99, 83; HRMS (CI) m/z 272.1497 (calcd for
(4R)-3-(3-Bu ten yl)-4-[(4R,5R)-2,2-d im eth yl-5-vin yl-1,3-
d ioxola n -4-yl]1,3-oxa zolid in -2-on e (54). To a suspension of
methyltriphenylphosphonium bromide (443 mg, 1.24 mmol) in
dry THF (5 mL) was added a 0.5 M solution of KHMDS in
toluene (2.34 mL, 1.17 mmol), and the mixture was stirred
for 30 min at 0 °C. The mixture was cooled to -78 °C, and a
solution of 53 (0.167 g, 0.620 mmol) in THF (1 mL) was added.
The reaction was allowed to gradually warm to room temper-
ature and was stirred for an additional 18 h. EtOAc (30 mL)
was added, the solution was filtered through a short column
of silica gel, and the filtrate was concentrated under reduced
pressure. Chromatography of the residue (5 g of silica gel,
EtOAc-hexane, 1:1) yielded 323 mg (74%) of 54 as a colorless
oil: [R]2D3 +2.4 (c 1.51, CHCl3); IR (neat) 2981, 1748, 1425,
C
13H22NO5: 272.1498).
(4R)-3-(3-Bu ten yl)-4-[(2R)-[(4R)-2,2-d im eth yl-1,3-d iox-
ola n -4-yl](h yd r oxy)m eth yl]-1,3-oxa zolid in -2-on e (51). To
a solution of 50 (0.72 g, 2.65 mmol) in dry THF (100 mL) was
added a 1 M solution of potassium tert-butoxide in tert-BuOH
(4.23 mL, 0.42 mmol), and the mixture was stirred for 2 h at
-10 °C. The reaction was quenched with a saturated NH4Cl
solution (10 mL), and the mixture was extracted with EtOAc
(3 × 30 mL). The combined organic extracts were washed with
a saturated solution of NaCl, dried over anhydrous Na2SO4,
and concentrated under reduced pressure. Chromatography
of the residue (40 g of silica gel, EtOAc-hexane, 2:1) afforded
0.45 g (63%) of 51 as a pale yellow solid: mp 69-75 °C;
[R]2D3 +10.1 (c 1.12, CHCl3); IR (neat) 3399, 2984, 2930, 1738,
1445, 1377, 1264, 1226, 1167, 1074 cm-1; 1H NMR (300 MHz,
CDCl3) δ 1.36 (s, 3H), 1.45 (s, 3H), 2.29-2.42 (m, 2H), 2.72 (d,
J ) 6 Hz, 1H), 3.11-3.23 (m, 1H), 3.54-3.64 (m, 1H), 3.76-
3.86 (m, 2H), 3.93-4.03 (m, 1H), 4.05-4.13 (m, 2H), 4.27 (t, J
) 9 Hz, 1H), 4.49 (dd, J ) 6, 9 Hz, 1H), 5.09 (dd, J ) 1, 6 Hz,
1H), 5.14 (dd, J ) 1, 6 Hz, 1H), 5.72-5.85 (m, 1H); 13C NMR
(75 MHz, CDCl3) δ 25.4, 26.3, 32.0, 41.7, 58.6, 63.3, 66.5, 67.8,
75.8, 110.3, 117.8, 135.0, 159.0; MS (CI) m/z 272 (M+ + 1),
242, 230, 214, 199, 153, 139, 127; HRMS (CI) m/z 272.1997
(calcd for C13H22O5: 272.1999).
1370, 1221, 1082, 1037 cm-1 1H NMR (300 MHz, CDCl3) δ
;
1.42 (s, 3H), 1.44 (s, 3H), 2.27-2.46 (m, 2H), 3.20-3.29 (m,
1H), 3.59-3.69 (m, 1H), 3.93 (dd, J ) 2, 8 Hz, 1H), 3.98-4.09
(m, 2H), 4.20-4.31 (m, 2H), 5.06-5.14 (m, 2H), 5.34 (d, J )
21 Hz, 1H), 5.39 (d, J ) 28 Hz, 1H), 5.73-5.90 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 26.6, 26.7, 31.6, 41.8, 53.9, 62.3, 78.2,
78.8, 109.7, 117.3, 120.2, 134.6, 158.0; MS (CI) m/z 268 (M+
1), 226. 210, 168, 140, 127, 97, 86, 69; HRMS (CI) m/z 268.1550
+
(calcd for C14H22NO4: 268.1549).
(3a R,11a R,11bR)-2,2-Dim eth yl-3a ,6,7,11,11a ,11b-h exa -
h yd r o[1,3]d ioxolo[4,5-c][1,3]oxa zolo[3,4-a ]a zocin -9-on e
(55). To a stirred solution of 54 (6.0 mg, 0.022 mmol) in CH2Cl2
(4.5 mL) under an argon atmosphere was added Grubbs’s catalyst
(24, 4.6 mg, 5.6 mmol), and the mixture was stirred at room
temperature for 5 h. The mixture was concentrated under
reduced pressure, and the residue was chromatographed (1 g
of silical gel, EtOAc-hexane, 1:2) to give 5.1 mg (90%) of 55
as a colorless oil: [R]2D3 -7.1 (c 1.47, CHCl3); IR (neat) 2984,
(4R)-3-(3-Bu t en yl)-4-[(4R,5R)-5-(h yd r oxym et h yl)-2,2-
d im eth yl-1,3-d ioxola n -4-yl]-1,3-oxa zolid in -2-on e (52). To
a solution of 51 (230 mg, 0.85 mmol) in dry acetone (25 mL)
was added Amberlyst 15 resin (ca. 20 mg), and the mixture
was stirred for 18 h at room temperature. The mixture was
filtered, and the filtrate was treated with solid NaHCO3 (50
mg) and stirred for 1 h. The solution was filtered, and the
filtrate was concentrated under reduced pressure. Chroma-
tography of the residue (40 g of silica gel, EtOAc-hexane, 1:1)
gave 143 mg (62%) of 52 as a colorless solid: mp 76-80 °C;
[R]2D3 +10.1 (c 1.12, CHCl3); IR (neat) 3428, 2994, 1738, 1450,
1
1763, 1421, 1372, 1220, 1079, 874 cm-1; H NMR (300 MHz,
CDCl3) δ 1.40 (s, 3H), 1.43 (s, 3H), 2.36-2.56 (m, 2H), 3.15-
3.24 (m, 1H), 3.57 (t, J ) 9 Hz, 1H), 3.67-3.74 (m, 1H), 4.34-
4.44 (m, 2H), 4.68-4.73 (m, 1H), 5.57-5.68 (m, 1H), 5.76 (dd,
J ) 5, 12 Hz, 1H); 13C NMR (75 MHz, d6-acetone) δ 27.0, 27.3,
29.1, 44.3, 58.0, 67.3, 77.7, 83.3, 109.8, 128.2, 130.6, 159.2; MS
(CI) m/z 240.1235 (calcd for C12H18NO4: 240.1236).
(3a R,3bS,4a S,10a R,10bR)-2,2-Dim eth ylocta h yd r o[1,3]-
d ioxolo[4,5-c][1,3]oxa zolo[3,4-a ]oxir en o[2,3-e]a zocin -8-
on e (56). A solution of 55 (12.5 mg, 0.052 mmol) and
m-chloroperoxybenzoic acid (50 wt %, 54.0 mg, 0.157 mol) in
CH2Cl2 (0.7 mL) was stirred for 18 h at room temperature.
The mixture was treated with methyl sulfide (50 µL) and a
saturated solution of Na2CO3 (0.5 mL), and stirring was
continued for 30 min. The organic phase was separated, the
aqueous solution was extracted with dichloromethane (4 × 1
mL), and the combined organic extracts were dried over
anhydrous Na2SO4 and concentrated under reduced pressure.
The residue was chromatographed (1 g of silica gel, EtOAc-
hexane, 1:1) to give 6.2 mg (64%) of 56 as colorless needles:
mp 156-159 °C; [R]2D3 +2.1 (c 0.62, CHCl3); IR (neat) 2984,
1
1377, 1250 cm-1; H NMR (300 MHz, CDCl3) δ 1.42 (s, 3H),
1.43 (s, 3H), 2.28-2.44 (m, 2H), 3.19-3.28 (m, 1H), 3.57-3.83
(m, 4H), 4.05 (t, J ) 8 Hz, 1H), 4.21 (d, J ) 8 Hz, 1H), 4.29 (d,
J ) 7 Hz, 2H), 5.06-5.15 (m, 2H), 5.72-5.82 (m, 1H); 13C NMR
(75 MHz, CDCl3) δ 27.0, 27.2, 31.9, 41.9, 55.1, 62.5, 62.7, 75.7,
77.0, 110.0, 117.6, 134.9, 158.4; MS (CI) m/z 272 (M+ + 1),
230, 214, 167, 149, 137, 113, 95, 89; HRMS (CI) m/z 272.1497
(calcd for C13H22NO5: 272.1498).
(4R,5R)-5-[(4R)-3-(3-Bu t en yl)-2-oxo-1,3-oxa zolid in -4-
yl]-2,2-d im eth yl-1,3-d ioxola n e-4-ca r ba ld eh yd e (53). To a
solution of oxalyl chloride (0.10 mL, 1.15 mmol) in CH2Cl2 (3.0
mL) maintained at -78 °C was added a mixture of DMSO (0.15
mL, 2.11 mmol) and CH2Cl2 (0.75 mL), followed after 3 min
by a solution 52 (216 mg, 0.80 mmol) in CH2Cl2 (1 mL). The
mixture was stirred for 30 min at -78 °C, and triethylamine
(0.15 mL, 0.010 mmol) was added. Stirring was continued for
2 h at -78 °C, and the mixture was concentrated under
1
2926, 1767, 1377, 1250, 1216, 1079, 863 cm-1; H NMR (300
MHz, CDCl3) δ 1.40 (s, 3H), 1.46 (s, 3H), 1.64-1.80 (m, 2H),
2.41-2.49 (m, 1H), 3.09-3.17 (m, 3H), 3.60-3.66 (m, 1H),
1.64-1.80 (m, 2H), 2.41-2.49 (m, 1H), 3.09-3.17 (m, 3H),
3.60-3.66 (m, 1H), 3.73-3.81 (m, 2H), 3.93-4.03 (m, 1H), 4.37
(dd, J ) 8, 9 Hz, 1H), 4.46 (dd, J ) 3, 9 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 26.9, 27.0, 27.6, 41.4, 52.1, 55.9, 57.2, 67.0,

Polyhydroxylated Pyrrolizidine Alkaloids
J . Org. Chem., Vol. 65, No. 26, 2000 9141
78.5, 79.9, 110.6, 159.0; MS (CI) m/z 256 (M+ + 1), 240, 198,
with a saturated solution of NaCl, dried over anhydrous Na2-
SO4, and concentrated under reduced pressure. The residue
was chromatographed (15 g of silica gel, EtOAc-hexane, 1:2)
to give 160 mg (84%) of 60 as a colorless oil: [R]2D3 +22.8 (c
1.33, CHCl3); IR (neat) 3023, 2920, 2861, 1753, 1460, 1421,
1215, 1079, 751 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.26-2.37
(m, 1H), 2.39-2.44 (m, 1H), 3.10-3.16 (m, 1H), 3.43-3.52 (m,
1H), 3.76 (dd, J ) 5, 13, 1H), 4.17 (dd, J ) 1, 8 Hz, 1H), 4.18-
4.33 (m, 3H), 4.51 (d, J ) 12 Hz, 1H), 4.58 (d, J ) 11 Hz, 1H),
4.73 (d, J ) 11 Hz, 1H), 5.14 (d, J ) 11 Hz, 1H), 5.71-5.82
(m, 2H), 7.28-7.39 (m, 10 H); 13C NMR (100 MHz, CDCl3) δ
27.1, 44.0, 58.8, 68.6, 71.3, 76.0, 78.9, 81.6, 127.8, 128.2, 128.5,
128.6, 128.7, 133.2, 138.0, 138.2, 159.9;MS (CI) m/z 380 (M+
+ 1), 279, 272, 182, 149, 107, 91; HRMS (CI) m/z 380.1862
(calcd for C23H26NO4: 380.1862).
182, 123, 85, 83, 68; HRMS (CI) m/z 256.1184 (calcd for C12H18
-
NO5: 256.1185).
(9R,10R,10aR)-9,10-Dih ydr oxy-1,5,6,9,10,10a-h exah ydr o-
[1,3]oxa zolo[3,4-a ]a zocin -3-on e (57). To a solution of 55
(170 mg, 0.797 mmol) in CH3CN (20 mL) was added an
aqueous solution of HBr (48%, 1 mL), and the mixture was
stirred for 1 h at ambient temperature. Volatiles were removed
under reduced pressure, and the residue was taken up into
acetonitrile (20 mL). To the solution was added solid NaHCO3,
and the mixture was stirred for 30 min at ambient tempera-
ture and then was filtered through a short pad of silica gel
which was subsequently rinsed with a EtOAc-MeOH (5%)
mixture. The filtrate was concentrated under reduced pressure
to leave 140 mg (99%) of 57 as a colorless oil which was not
further purified: [R]2D3 +4.2 (c 0.67, CH3CN); IR (neat) 3412,
(1a S,7a R,8R,9S,9a S)-8,9-Bis(ben zyloxy)octa h yd r o[1,3]-
oxa zolo[3,4-a ]oxir en o[2,3-e]a zocin -5-on e (61). A solution
of 60 (160 mg, 0.422 mmol) and m-chloroperoxybenzoic acid
(50 wt %) (0.58 g, 1.68 mmol) in CH2Cl2 (5 mL) was stirred for
6 h at ambient temperature and then was treated with Me2S
(100 µL). Stirring was continued for 15 min, and the solution
was washed with a saturated solution of Na2CO3 and a
saturated solution of NaCl, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. Chromatography of the
residue (10 g of silica gel, EtOAc-hexane, 1:2) afforded 125
2936, 1736, 1435, 1222, 1080 cm-1 1H NMR (400 MHz, d6-
;
acetone) δ 2.29-2.38 (m, 2H), 3.13-3.22 (m, 2H), 3.48-3.58
(m, 3H), 3.81 (d, J ) 1 Hz, 1H), 4.22-4.25 (m, 1H), 4.30 (dd,
J ) 8, 8 Hz, 1H), 4.41 (dd, J ) 2, 8 Hz, 1H), 5.54-5.62 (m,
2H); 13C NMR (400 MHz, CDCl3) δ 27.6, 45.1, 59.5, 69.2, 71.6,
126.9, 136.1, 161.2; MS (CI) m/z 200 (M+ + 1), 182, 166, 149,
138, 93, 69; HRMS (CI) m/z 200.0923 (calcd for C9H14O4N:
200.0928).
(1a S ,7a R ,8R ,9S ,9a R )-8,9-Dih yd r oxyoct a h yd r o[1,3]-
oxa zolo[3,4-a ]oxir en o[2,3-e]a zocin -5-on e (58). To a solu-
tion of 57 (4.1 mg, 0.021 mmol) in THF (1 mL) was added
m-chloroperoxybenzoic acid (50 wt %, 14 mg, 0.041 mmol), and
the mixture was stirred for 7 h at ambient temperature. The
mixture was treated with methyl sulfide (10 mL) and solid
Na2CO3 (15 mg), and stirring was continued for 1 h. The
suspension was filtered through a short column of silica gel,
which was subsequently rinsed with a EtOAc-MeOH (5%)
mixture, and the filtrate was concentrated under reduced
pressure. The residue was chromatographed (1 g of silica gel,
EtOAc-MeOH, 10:1) to give 2.7 mg (62%) of 58 as colorless
prisms: mp 92-96 °C; 1H NMR (300 MHz, CDCl3) δ 1.32-
1.52 (m, 1H), 2.18-2.26 (m, 1H), 2.78 (dd, J ) 4,7 Hz, 1H),
2.91-2.98 (m, 1H), 3.10 (m, 1H), 3.22-3.40 (m, 3H), 3.91 (dt,
J ) 5, 14 Hz, 1H), 4.19-4.26 (m, 1H), 3.45 (d, J ) 14 Hz, 1H)
HRMS m/z 216.0871 (calcd for C9H14NO5: 216.0872).
mg (75%) of 61 as colorless needles: mp 127-129 °C; [R]D23
+
48.6 (c 0.72, CHCl3); IR (neat) 2911, 2847, 1758, 1465, 1420,
1
1215, 1137, 1074 cm-1; H NMR (400 MHz, CDCl3) δ 1.39-
1.50 (m, 2H), 2.37-2.40 (m, 1H), 3.08-3.19 (m, 3H), 3.44 (t, J
) 7 Hz, 1H), 3.52-3.59 (m, 2H), 4.04 (dt, J ) 5, 14 Hz, 1H),
4.24 (dd, J ) 1, 9 Hz, 1H), 4.32 (dd, J ) 7, 9 Hz, 1H), 4.59 (d,
J ) 11 Hz, 1H), 4.72 (d, J ) 11 Hz, 1H), 4.97 (d, J ) 11 Hz,
1H), 5.16 (d, J ) 11 Hz, 1H), 7.19-7.43 (m, 10 H); 13C NMR
(100 MHz, CDCl3) δ 27.2, 42.7, 51.9, 57.2, 58.4, 68.8, 73.1, 76.7,
79.3, 81.8, 128.0, 128.2, 128.3, 128.6, 128.8, 137.7, 138.2, 160.4;
MS (CI) m/z 396 (M+ + 1), 380, 306, 184, 165, 113, 107, 91,
79. Anal. Calcd for C23H25NO5: C, 69.86; H, 6.37; N, 3.54.
Found: C, 70.02; H, 6.39; N, 3.60.
(1S,5R,6R,7R,7aR)-6,7-Bis(ben zyloxy)-5-(h ydr oxyeth yl)-
h exa h yd r o-1H-p yr r olizin -1-ol (1,2-Di-(O-ben zyl)a u str a -
lin e, 62). To a solution of 61 (50 mg, 0.126 mmol) in EtOH-
H2O (1:1, 20 mL) was added LiOH-H2O (53 mg, 1.26 mmol),
and the mixture was stirred for 18 h at 94 °C. The mixture
was extracted with CHCl3 (3 × 5 mL), and the combined
organic extracts were washed with a saturated solution of
NaCl, dried over anhydrous Na2SO4, and concentrated under
reduced pressure to give 47 mg (100%) of pure 62 as a colorless
oil: [R]2D3 +13.2 (c 0.94, CHCl3); IR (neat) 3389, 2876, 1465,
[(3a R,4R,9a R)-2,2-Dim et h yl-3a ,4,5,6,7,9a -h exa h yd r o-
[1,3]d ioxolo[4,5-c]a zocin -4-yl]m eth a n ol (59). To a solution
of 55 (12 mg, 0.050 mmol) in EtOAc (10 mL) was added a 0.5
M solution of sodium ethoxide in EtOH (1 mL), and the
mixture was stirred for 18 h at 70 °C. The mixture was
concentrated under reduced pressure, and the residue was
treated with a saturated solution of NH4Cl (2 mL). The mixture
was extracted with CHCl3 (4 × 5 mL), and the combined
organic extracts were washed with a saturated solution of
NaCl and dried over anhydrous Na2SO4. Volatiles were
removed under reduced pressure to afford 11 mg (100% of
virtually pure 59 as a colorless oil: [R]2D3 -14.4 (c 0.50,
CHCl3); IR (neat) 3370, 2920, 1738, 1465, 1372, 1235, 1142,
1074 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.41 (s, 3H), 1.42 (s,
3H), 2.06-2.30 (m, 1H), 2.35-2.42 (m, 1H), 2.68-2.73 (m, 1H),
2.89 (ddd, J ) 4, 12, 12, 1H), 2.99 (ddd, J ) 1, 6, 8 Hz, 1H),
3.20 (d, J ) 9 Hz, 1H), 3.27 (dd, J ) 8, 10 Hz, 1H), 3.78 (dd,
J ) 5, 10 Hz, 1H), 4.54 (t, J ) 7 Hz, 1H), 5.60-5.67 (m, 1H),
5.90-5.94 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 27.1, 27.2,
28.7, 47.0, 58.2, 64.4, 78.5, 82.7, 109.5, 127.4, 130.9; MS (CI)
m/z 214 (M+ + 1), 182, 162, 156, 138, 124, 119, 95, 91; HRMS
(CI) m/z 214.1443 (calcd for C11H20NO3: 214.1443).
1
1142, 1074, 1040, 747, 707 cm-1; H NMR (300 MHz, CDCl3)
δ 1.93-1.99 (m, 2H), 2.74 (q, J ) 8 Hz, 1H), 2.98-3.01 (m,
1H), 3.14-3.19 (m, 1H), 3.52 (dd, J ) 5, 5 Hz, 1H), 4.59 (d, J
) 2 Hz, 2H), 4.64 (d, J ) 4, 7 Hz, 1H), 4.13-4.19 (m, 2H),
4.33 (dd, J ) 5, 5 Hz, 1H), 4.59 (d, J ) 2 Hz, 2H), 4.64 (d, J )
11 Hz, 1H), 4.75 (d, J ) 11 Hz, 1H), 7.28-7.40 (m, 10H); 13C
NMR (75 MHz, CDCl3) δ 37.0, 51.9, 60.8, 71.3, 71.7, 72.5, 72.9,
73,0.1, 81.4, 85.2, 128.0, 128.1, 128.7, 138.0, 138.3; MS(CI) m/z
370(M+ + 1), 338, 262, 229, 207, 135, 107, 91, 79, 69; HRMS
(CI) m/z 370.2018 (calcd for C22H28NO4: 370.2018).
(1R,2R,3R,7S,7a R)-3-(Hyd r oxym eth yl)h exa h yd r o-1H-
p yr r olizid in e-1,2,7-tr iol. Au str a lin e (3). A suspension of 62
(26 mg, 0.07 mmol) and Pd(OH)2/C (20%, 10 mg) in MeOH (2
mL) was stirred for 24 h under a hydrogen atmosphere. The
mixture was filtered through a short column of silica gel, and
the filtrate was concentrated under reduced pressure to
furnish 13.4 mg (100%) of 3 as a colorless oil: [R]2D3 +16.6 (c
1.37, MeOH); IR (neat) 3331, 2915, 1621, 1426, 1118, 1049
cm-1; 1H NMR (400 MHz, CDCl3) δ 1.92-2.01 (m, 1H), 2.02-
2.06 (m, 1H), 2.72-2.78 (m, 2H), 3.15-3.22 (m, 2H), 3.63 (dd,
J 6, 12 Hz, 1H), 3.81 (dd, J ) 3, 12 Hz,1H), 3.91 (t, J ) 9 Hz,
1H), 4.25 (t. J ) 8 Hz, 1H), 4.39 (s, 1H); 13C NMR (100 MHz,
D2O) δ 35.4, 52.1, 62.9, 69.8, 70.8, 71.0, 73.4, 79.1; MS (CI)
m/z 190 (M+ + 1), 184, 172, 158, 152, 140, 112, 99; HRMS (CI)
m/z 190.1079 (calcd for C8H16NO4: 190.1079).
(9R,10R,10a R)-9,10-Bis(ben zyloxy)-1,5,6,9,10,10a -h exa -
h yd r o[1,3]oxa zolo[3,4-a ]a zocin -3-on e (60). To a solution of
56 (100 mg, 0.502 mmol) in dry THF (10 mL) were added KH
(50 wt % suspension in mineral oil, 220 mg, 4.50 mmol) and
tetra-n-butylammonium iodide (10 mg), and the mixture was
stirred for 30 min at ambient temperature. Benzyl bromide
(200 mL, 1.68 mmol) was added, and the mixture was warmed
to 50 °C and stirred for 2 h. The mixture was treated with a
saturated solution of NH4Cl (3 mL) and extracted with CHCl3
(4 × 4 mL), and the combined organic extracts were washed

9142 J . Org. Chem., Vol. 65, No. 26, 2000
White and Hrnciar
Ack n ow led gm en t. We are grateful to Professor
Alexandre Yokochi of this Department for X-ray crystal
structures of 56 and 61; to Professor George Fleet of
Oxford University, Dr. Robert Nash of The Institute of
Grassland and Environmental Research Aberystwyth,
Wales, and Dr. Russell J . Molyneux, USDA, Albany,
California, for samples and spectra of natural austra-
line; and to Professor Scott Denmark, University of
Illinois, and Professor William H. Pearson, University
of Michigan, for helpful correspondence. Financial sup-
port was provided by the National Institutes of Health
(GM58889).
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for 7-20, 22, 23, 25-29, 31-41, 43-63, australine
(3), X-ray crystallographic data for 28, 56, and 61. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O0012748