A concise sequential photochemical-metathesis approach for the synthesis of (+)-castanospermine and possible uniflorine-A stereoisomers

Article abstract of DOI:10.1016/j.tet.2005.07.014

A recently developed strategy for polyhydroxylated indolizidine ring construction has been applied to the synthesis of (+)-castanospermine and possible isomers of uniflorine-A. The routes to these targets rely on the use of the earlier discovered photocyclization reaction of pyridinium perchlorate in a concise route for preparation of a key N-allylacetamidocyclopentendiol intermediate. Ring rearrangement metathesis of this substance gives an allyl-tetrahydropyridine, which is then transformed to the targets by execution of regio- and stereo-controlled hydroxylation processes followed by indolizidine ring construction.

Full text of DOI:10.1016/j.tet.2005.07.014

Tetrahedron 61 (2005) 8888–8894
A concise sequential photochemical-metathesis approach for the
synthesis of (C)-castanospermine and possible
uniflorine-A stereoisomers
*
Zhiming Zhao, Ling Song and Patrick S. Mariano
Department of Chemistry, University of New Mexico, Albuquerque, NM 87131, USA
Received 31 May 2005; revised 5 July 2005; accepted 6 July 2005
Available online 28 July 2005
Abstract—A recently developed strategy for polyhydroxylated indolizidine ring construction has been applied to the synthesis of (C)-
castanospermine and possible isomers of uniflorine-A. The routes to these targets rely on the use of the earlier discovered photocyclization
reaction of pyridinium perchlorate in a concise route for preparation of a key N-allylacetamidocyclopentendiol intermediate. Ring
rearrangement metathesis of this substance gives an allyl-tetrahydropyridine, which is then transformed to the targets by execution of regio-
and stereo-controlled hydroxylation processes followed by indolizidine ring construction.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Members of the polyhydroxylated indolizidine, natural
product family have received continuous intense scrutiny
from synthetic chemists owing to their densely function-
alized, stereochemically rich structures and their bio-
medically relevant physiological properties.1 Recently,2
we described a unique and stereochemically flexible
strategy for synthesis of functionalized indolizidines that
relies on the combined use of photochemical and ring
rearrangement metathesis (RRM) reactions in key ring
building steps. The overall approach, outlined in Scheme 1,
begins with the preparation of 4-amino-3,5-cyclopentendiol
Scheme 1.
derivative
1 through photocyclization reaction of
a-D-mannosidase and mannosidase II inhibitor, (K)-
swainsonine (8). In the approach to this target (Scheme 2),
regiocontrolled RRM reaction of allylacetamidocyclo-
pentene 4 was employed to produce the tetrahydropyridine
5. As a result of A1,3-strain between the N-acetyl and 6-allyl
groups, the corresponding acetate derivative exists pre-
dominantly in the diaxial conformation 6, in which both
faces of the endocyclic alkene group are blocked.
Consequently, dihydroxylation of the exocyclic olefin in 6
takes place selectively to produce the requisite precursor 7
in the route to (K)-swainsonine.
pyridinium perchlorate.3,4 Transformation of this sub-
stances to N-acetamido-N-allylcyclopentenes 2 is then
followed by ruthenium alkylidene5 catalyzed RRM
reactions6 to generate the corresponding 6-allyltetrahydro-
pyridines 3. The RRM derived products contain an array of
exocyclic and endocyclic alkene and potentially differen-
tiated alcohol functionalities, which can be manipulated to
both introduce the groups required for indolizidine ring
formation and install target functionality.
In an earlier publication,2 we described the advent of this
strategy and its application to the synthesis of the potent
Broad application of this strategy to a variety of naturally
occurring, biomedically important indolizidines requires
that methods be available to selectively manipulate the
endocyclic alkene moiety in the RRM derived 6-allyl-
tetrahydropyridine intermediates. (C)-Castanospermine, an
Keywords: Pyridinium salt photochemistry; Ring rearrangement metath-
esis; Polyhydroxylated indolizidines.
*
Corresponding author. Tel.: C1 5052776390; fax: C1 5052776202;
e-mail: mariano@unm.edu
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.014

Z. Zhao et al. / Tetrahedron 61 (2005) 8888–8894
8889
Scheme 2.
excellent glycosidase inhibitor,7 is one of a group of targets,
which can be approached by using this design variation. As
depicted in Scheme 3, a possible route to (C)-castano-
spermine would employ RRM reaction of the N-acetamido-
N-allylcyclopentene 9 to generate the tetrahydropyridine 11.
Based on A1,3-strain considerations, the alcohol derivative
12 should exist in the diaxial conformation, in which the C-5
hydroxyl is perfectly aligned to guide selective a-face
epoxidation of the internal alkene moiety. Trans-diaxial
epoxide ring opening would then set the stage for
cyclization to produce the tetrahydroxylated indolizidine
skeleton of castanospermine. Importantly, this general
strategy can be employed to design concise, stereoselective
routes for the preparation of pentahydroxylated indolizi-
dines that are potentially related to the incorrectly identified
glycosidase inhibitor, uniflorine-A.8 For this purpose,
hydroxyl guided epoxidation of 12 and epoxide ring
opening would be followed by dihydroxylation of the
exocyclic olefin and indolizidine ring formation (Scheme 3).
2. Results and discussion
2.1. Synthesis of (C)-castanospermine
Earlier, we reported that RRM reaction of the enantiomeri-
cally enriched cis,-trans-N-allylacetamidocyclopentendiol
derivative 9, produced from pyridine by using a photo-
chemical-enzymatic desymmetrization-alcohol inversion
sequence, proceeds smoothly (93%) to furnish the corre-
sponding 6-allyltetrahydropyridine 11.2 This highly regio-
selective process is performed by using the second
generation, Grubbs ruthenium alkylidene catalyst 105 in
the presence of ethylene (Scheme 3). X-ray crystallographic
analysis of endocyclic allylic alcohol 12, generated by
treatment of 11 with TBAF, clearly demonstrates that it
exists in the diaxial conformation. This preference results
from relief of A1,3-strain caused by interactions between the
N-acetyl and 6-allyl side chain in the alternative diequatorial
conformation. A consequence of this preference is that the
endocyclic hydroxyl group in 12 can be used advan-
tageously to guide regio- and stereo-selective dihydroxyl-
ation reaction of the endocyclic alkene moiety. In the
context of the current targets, the hydroxyl group is
employed to direct selective epoxidation of 12 to produce
the corresponding epoxy-alcohol 13. Trans-diaxial ring
opening of 13 under mild basic conditions then furnishes the
trans,trans,trans-trihydroxy-piperidine 14. Benzylation of
14 provides the tetrabenzyl ether 15 (Scheme 4), which
serves as the key intermediate in routes to castanospermine
and the possible uniflorine-A diastereomers.
Several approaches were explored to transform 15 to the
corresponding terminal alcohol. The best method (albeit not
fully satisfactory) for performing this operation was found
to be one using the hydroboration–oxidation protocol.
Accordingly, treatment of 15 with the BH3–THF complex
followed by NaOH–H2O2 oxidation produces the alcohol 16
(Scheme 5). Surprisingly the N-acetyl group is fortuitously
removed under these conditions.9 As expected this process
also forms a minor amount of the N-ethyl analog of 16 by
way of reduction of the amide group. An attempt to
minimize this unwanted side reaction by using 9-BBN was
not successful; 15 is recovered when treated with this
Scheme 3.

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Z. Zhao et al. / Tetrahedron 61 (2005) 8888–8894
Scheme 4.
Scheme 5.
hydroboration agent. Indolizidine ring formation takes place
when 16 is subjected to typical Mitsunobo cyclization
conditions (DEAD–PPh3) to yield indolizidine 17. Hydro-
genolytic removal of the benzyl protecting groups then
generates the target, (C)-castanospermine. The physical
and spectroscopic properties of the synthetic material match
those reported for the natural product.10
Pyne to make the reasonable suggestion that ‘uniflorine-A,
if it is an indolizidine alkaloid, has the same H-1
stereochemistry as castanospermine’; that is, that H-1 and
H-8a have a syn relationship.8b
2.2. Pentahydroxylated indolizidines potentially related
to uniflorine-A
A novel pentahydroxylated indolizidine, uniflorine-A, was
recently isolated from the tree Eugenia uniflora L. whose
leaves are used in folk medicine as antidiarrhetics,
antirheumatics and antidiabetics.8a The structure/stereo-
chemistry of this substance was assigned by Arisawa and his
co-workers8a as 18 based on NMR spectroscopic data.
Recently, Pyne and his co-workers8b synthesized the
putative uniflorine-A 18 by using an elegent pathway
starting with L-xylose. However, the 1H and 13C NMR data
of the synthetic material did not match those reported for the
natural product by the Arisawa group. One significant
difference between the natural and synthetic materials was
Based on Pyne’s conclusion, uniflorine-A could be one of
the two pentahydroxylated indolizidines 19 or 20, both of
which have the trans,trans,trans-piperidine ring stereochem-
istry and syn relationships between H-1 and H-8a. The
preparation of one of these, indolizidine 20, was reported in
1996 by Fleet and his co-workers.11 A comparison of their
spectroscopic data with those reported by Arisawa (Table 1)
indicates that uniflorine-A is not 20. To our knowledge,
indolizidine 19 has not been prepared previously. Owing to
the potentially interesting biomedical properties of
uniflorine-A and the fact that its structure/stereochemistry
remains undefined, we have applied the RRM based
strategy described above to the synthesis of the respective
1
found in their H NMR spectra. Specifically, the H1–H8a
coupling constant reported for uniflorine-A is 4.5 Hz while
that of the synthetic material 18 is 7.7 Hz, as expected for
the anti-relationship of these protons. This difference led
Table 1. 1H NMR spectroscopic data (D2O) for uniflorine-A and the pentahydroxy-indolizidines 18–20
Chemical shifts (ppm)
Coupling constants (Hz)
Uniflorine-A8a
4.18
4.35
2.98
3.04
3.61
3.76
2.76
3.81
188b
3.82
4.11
3.26
2.20
3.01
2.09
3.46
3.20
3.25
2.08
19
2011
4.06
4.24
2.54
2.71
2.95
1.91
3.42
3.12
3.47
2.01
Uniflorine-A8a
4.5
4.5
5.1
5.1
7.7
7.7
9.0
6.4
3.8
12.1
11.8
188b
7.3
7.5
6.8
6.8
9.2
9.0
9.0
10.9
5.5
10.5
10.7
19
0
6.3
6.3
4.4
10.2
9.1
9.1
9.1
5.2
10.3
10.9
2011
5.3
3.5
8.1
2.1
9.7
9.5
9.1
10.6
5.1
10.7
10.6
H1
H2
H3
H3
H5
H5
H6
H7
H8
H8a
4.08
4.25
2.63
2.88
2.96
1.91
3.42
3.13
3.48
2.01
H1–H2
H1–H8a
H2–H3
H2–H3
H8a–H8
H8–H7
H7–H6
H6–H5
H6–H5
H3–H3
H5–H5
3.94
3.14

Z. Zhao et al. / Tetrahedron 61 (2005) 8888–8894
8891
Scheme 6.
unknown and known pentahydroxylated indolizidines 19
and 20.
chemistry. In addition, the ability to develop concise
stereocontrolled routes to members of the polyhydroxylated
indolizidine family has been exploited in the synthesis of the
interesting glycosidase inhibitor (C)-castanospermine.
Finally, by using this chemistry we have demonstrated
that the natural product uniflorine-A does not possess the
pentahydroxylated indolizidine stereostructures represented
by 19 and 20.
The divergent route to both targets (Scheme 6) begins
with the protected piperidine 15. Stereocontrolled
catalytic osmylation of this substance cleanly produces
the corresponding diol 21. Amide hydrolysis and
Mitsunobo cyclization is then employed to transform
21 to the pentahydroxy-indolizidine derivative 22,
which serves as a direct precursor (benzyl deprotection)
of the known indolizidine 20.11 Indolizidine 19, is also
generated from 22 by using Mitsunobo hydroxyl
inversion to form 23 followed by hydrogenolytic benzyl
deprotection.
4. Experimental
4.1. General
Each reaction was run under a dry nitrogen atmosphere. All
reagents were obtained from commercial sources and used
without further purification, and all solvents were dried by
The physical and spectroscopic properties of 19 do not
match those reported for uniflorine-A. Significant differ-
ences are found between the melting points and optical
rotations of the synthetic material (mp 114–116 8C, [a]025
C22.7 (c, 0.07, H2O))8a and naturally occurring substance
(mp 175–178 8C, [a]0 K4.4 (c, 1.2, H2O)). Equally different
1
using the standard procedures. H and 13C NMR spectra
were recorded by using CDCl3 solutions, unless specified
otherwise, and chemical shifts are reported in ppm relative
1
to CHCl3 (7.24 ppm for H and 77.0 ppm for 13C), which
1
are the H and 13C NMR spectra of 19 and uniflorine-A
was used as a chemical shift internal standard for samples in
CDCl3. For spectra recorded on d6-acetone solutions,
chemical shifts are reported in ppm relative to d5-acetone
(2.05 ppm for 1H and 29.92 ppm for 13C). For spectra
recorded using d4-methanol, chemical shifts are reported in
ppm relative to d3-methanol (3.31 ppm for 1H and
49.15 ppm for 13C). 13C NMR resonance assignments
were aided by the use of the DEPT-135 technique to
determine numbers of attached hydrogens. All compounds
were isolated as oils unless otherwise specified and their
purities were determined to be O90% by 1H and 13C NMR
analysis. Column chromatography was performed by using
230–400 mesh silica gel as absorbent.
(Table 1). Moreover, the properties reported for the natural
product are not equivalent to those reported earlier for 20 by
Fleet and his co-workers (Table 1).11 To insure that the
differences between the properties of the natural product and
those determined for 19 and 20 are not a consequence of
different protonation state, the hydrochloride salts of the of
19 and 20 were prepared. As with their neutral counterparts,
the spectroscopic data for these salts do not match those
obtained for uniflorine-A. Based on these results, we
conclude that the glycosidase inhibitor uniflorine-A isolated
by Arisawa and his co-workers does not have the structure
and/or stereochemistry found in either of the three
pentahydroxy indolizidines 18–20.
4.1.1. 1-Acetyl-2-(1-benzyloxyallyl)-3-hydroxy-4,5-
epoxypiperidine 13. To a stirred solution of the known2
allylic alcohol 12 (29 mg, 0.10 mmol) in 3 mL of CH2Cl2 at
0 8C was added vanadyl acetylacetonate (2 mg, 0.01 mmol)
and 0.07 mL (5–6 M in decane) of tBuOOH. The resulting
mixture was stirred at 25 8C for 5 h, diluted with 1 mL of
satd NaHSO3 and CHCl3. The CHCl3 layer was separated,
washed with satd NaHSO3, satd NaHCO3 and satd NaCl,
3. Conclusions
The studies described above demonstrate the unique
preparative potential of the strategy for functionalized
indolizidine synthesis, that is, based on pyridinium salt
photochemistry and ring rearrangement metathesis

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Z. Zhao et al. / Tetrahedron 61 (2005) 8888–8894
dried and concentrated in vacuo giving a residue, which was
subjected to column chromatography (silica gel, 1:1
acetone/hexane) to yield 15 mg (50%) of the epoxide 13.
[a]2D5 C26.6 (c, 0.13, CHCl3); 1H NMR (mixture of
rotamers) 7.34–7.20 (m, 5H), 5.72–5.68 (m, 1H), 5.46 (d,
JZ10.0 Hz, 1H), 5.36 (d, JZ16.6 Hz, 1H), 4.80 (d, JZ
15.4 Hz, 1H), 4.58 (d, JZ11.9 Hz, 1H), 4.23 (dd, JZ3.9,
11.9 Hz, 1H), 3.98–3.94 (m, 1H), 3.76 (m, 1H), 3.42 (m,
1H), 3.41 (m, 1H), 2.91 (d, JZ15.3 Hz, 1H), 2.71 (d, JZ
9.0 Hz, 1H), 2.07 (s, 3H); 13C NMR rotamer A 172.3, 137.3,
134.7, 128.4, 127.9, 127.8, 127.6, 121.5, 78.4, 70.1, 62.6,
61.8, 52.6, 51.1, 36.5, 21.7; rotamer B 172.4, 137.3, 134.4,
128.4, 127.9, 127.8, 127.6, 119.5, 80.4, 71.1, 64.2, 58.5,
52.6, 49.7, 42.1, 21.9; HRMS (FAB) m/z 326.1358 (MC
Na), calcd for C17H23NO5Na 326.1363.
3 M NaOH and 1 mL of 30% hydrogen peroxide were
added. The solution was stirred at 25 8C for 3 h and
extracted with CHCl3. The CHCl3 extracts were dried and
concentrated in vacuo giving a residue, which was subjected
to column chromatography (silica gel, 1:2 acetone/hexane)
1
to give 33 mg (31%) of 16. H NMR 7.36–7.21 (m, 20H),
4.99 (d, JZ10.7 Hz, 1H), 4.91 (d, JZ11.1 Hz, 1H), 4.82 (d,
JZ10.7 Hz, 1H), 4.69 (d, JZ10.9 Hz, 1H), 4.64 (d, JZ
11.7 Hz, 1H), 4.50 (d, JZ11.1 Hz, 1H), 4.35 (d, JZ
11.1 Hz, 1H), 4.09 (d, JZ11.1 Hz, 1H), 4.05 (d, JZ6 Hz,
1H), 3.75 (t, JZ11.4 Hz, 2H), 3.58 (t, JZ9 Hz, 1H), 3.51
(m, 1H), 3.46 (t, JZ9.5 Hz, 1H), 3.35 (m, 1H), 3.19 (dd, JZ
8.1 Hz, 13.8 Hz, 1H), 2.49–2.43 (m, 2H), 2.16 (m,1H); 13C
NMR 138.5, 138.3, 138.2, 137.9, 128.4, 128.0, 127.9, 127.9,
127.7, 127.5, 87.1, 80.8, 79.8, 75.8, 75.2, 72.8, 72.8, 70.6,
62.3, 55.3, 46.6, 34.2; HRMS (FAB) m/z 590.2894 (MC
Na), calcd for C36H41NO5Na 590.2877.
4.1.2. 1-Acetyl-2-(1-benzyloxyallyl)-3,4,5-hydroxypiper-
idine 14. A solution of epoxide 13 (46 mg, 0.15 mmol) in
1 mL of water containing sodium benzoate (6 mg,
0.04 mmol) was stirred at 130 8C for 12 h, cooled and
concentrated in vacuo giving a residue, which was subjected
to column chromatography (silica gel, 3:2 acetone/hexane)
to yield 27 mg (55%) of the triol 14. [a]2D5 C7.2 (c, 0.1,
4.1.5. 1,6,7,8-Tetrabenzyloxyindolizidine 17. A solution
of 16 (20 mg, 0.035 mmol) in 2 mL THF containing PPh3
(14 mg, 0.053 mmol), DEAD (9 mg, 0.05 mmol) was stirred
at 25 8C for 12 h, diluted with satd NaHCO3, and extracted
with ethyl acetate. The ethyl acetate extracts were washed
with satd NaCl, dried and concentrated in vacuo giving a
residue, which was subjected to column chromatography
(silica gel, 1:2 EA/hexane) to yield 18 mg (93%) of 17.
[a]2D5 C35.28 (c, 0.01, CHCl3) (lit.10 [a]2D5 C32 (c, 1.0,
CHCl3)); the spectroscopic data for this substance matched
those previously reported.10 1H NMR (C6D6) 7.43–7.16 (m,
20H), 5.18 (d, JZ6.5 Hz, 1H), 5.15 (d, JZ6.9 Hz, 1H), 5.01
(d, JZ11.3 Hz, 1H), 4.92 (d, JZ11.7 Hz, 1H), 4.57 (abq,
JZ12 Hz, 2H), 4.40 (d, JZ11.7 Hz, 1H), 4.27 (t, JZ
9.2 Hz, 1H), 4.18 (d, JZ11.7 Hz, 1H), 4.02–3.97 (m, 1H),
3.89 (ddd, JZ5.0, 4.2, 9.5 Hz,1H), 3.76 (t, JZ8.9 Hz, 1H),
3.24 (dd, JZ5.0, 10.4 Hz, 1H), 2.97 (m, 1H), 2.08 (dd, JZ
4.9, 9.4 Hz, 1H), 1.99 (t, JZ10.3 Hz, 1H), 1.89 (dd, JZ8.6,
17.3 Hz, 1H), 1.86–1.79 (m,1H), 1.75–1.69 (m,1H); 13C
NMR 139.1, 138.9, 138.4, 138.1, 128.3, 128.3, 128.2, 128.1,
127.8, 127.4, 87.5, 79.1, 77.3, 75.6 (2), 74.2, 72.8, 71.6,
70.5, 54.5, 52.4, 29.7.
1
CH3OH); H NMR (mixture of rotamers) 7.51–7.23 (m,
5H), 5.86–5.82 (m, 1H), 5.48–5.41 (m, 2H), 4.59 (d, JZ
11.9 Hz, 1H), 4.47–4.40 (m, 1H), 4.29–4.25 (m, 1H), 3.96
(d, JZ10 Hz, 1H), 3.85 (s, 1H), 3.80 (s, 1H), 3.65 (d, JZ
15.2 Hz, 1H), 3.31 (s, 1H), 2.83 (d, JZ14.1 Hz, 1H), 2.19 (s,
3H); 13C NMR rotamer A 175.7, 139.8, 137.1, 129.5, 129.1,
128.7, 121.4, 77.3, 71.2, 70.5, 69.9, 69.8, 66.1, 39.7, 22.2;
rotamer B 174.3, 140.0, 137.4, 129.4, 129.1, 128.7, 120.5,
78.3, 71.9, 71.2, 71.1, 70.0, 60.0, 46.3, 22.2; HRMS (FAB)
m/z 344.1482 (MCNa), calcd for C17H23NO5Na 344.1468.
4.1.3. 1-Acetyl-2-(1-benzyloxyallyl)-3,4,5-benzyloxy-
piperidine 15. To a solution of triol 14 (180 mg,
0.60 mmol) in 10 mL DMF at 0 8C was added sodium
hydride (95%, 86 mg, 3.4 mmol), After stirring at 0 8C for
30 min, 0.5 mL of benzyl bromide was added and the
solution was stirred for 2 h, diluted with ethyl acetate,
washed with satd NaCl, dried and concentrated in vacuo
giving a residue, which was subjected to column
chromatography (silica gel, 1:2 EA/hexane) to give
4.1.6. (C)-Castanospermine. A solution of 17 (15 mg,
0.027 mmol) in 3 mL ethyl acetate and 3 mL MeOH
containing palladium chloride (22 mg, 0.013 mmol) under
an atmosphere of hydrogen (1 atm) was stirred for 4 h at
25 8C, filtered through Celite. The filtrate was concentrated
in vacuo giving a residue, which was subjected to ion-
exchange chromatography (Dowex 1-X8, OHK form, 100–
200 mesh, eluted with water) to yield 5 mg (91%) of
(C)castanospermine. [a]2D5 C20.6 (c, 0.05, H2O) (lit.10
[a]D25 C70 (c, 0.33, H2O)). The 1H and 13C NMR spectra of
the synthetic material matched those reported previously.10
1H NMR (D2O) 4.24 (m, 1H), 3.64 (m, 2H), 3.35 (m, 1H),
3.19 (m, 1H), 3.14 (m, 1H), 2.35(m, 1H), 2.23 (m, 1H),
2.10–2.02 (m, 2H), 1.74–1.72 (m, 1H); 13C NMR 79.1, 71.4,
70.2, 69.7, 69.0, 55.4, 51.6, 32.8.
330 mg (94%) of 15. [a]2D5 C35.8 (c, 0.17, CHCl3); H
1
NMR (mixtures of rotamers) 7.32–7.12 (m, 20H), 5.78–5.70
(m, 0.4H), 5.62–5.55(m, 0.6H), 5.31 (d, JZ10.2 Hz, 0.6H),
5.25 (d, JZ10.1 Hz, 0.4H), 5.16 (t, JZ15.3 Hz, 1H), 4.72
(d, JZ11.7 Hz, 1.3H), 4.68 (d, JZ12.4 Hz, 1.2H), 4.60 (d,
JZ12.1 Hz, 1H), 4.54 (m, 2.2H), 4.41 (m, 2.9H), 4.21(d,
JZ12.0 Hz, 0.6H), 4.07 (m, 1.5H), 3.92 (d, JZ9.2 Hz,
0.6H), 3.77 (m, 0.4H), 3.61 (m, 2.5H), 3.51 (m, 1H), 2.75 (d,
JZ14.7 Hz, 0.6H), 2.15 (s, 2.3H), 2.11 (s, 1.3H); 13C NMR
rotamer A 171.6, 138.1, 137.8, 128.0, 127.7, 127.1, 120.7,
75.5, 73.1, 73.0, 71.2, 70.7, 70.2, 69.5, 61.6, 35.6, 21.6;
rotamer B 170.6, 137.7, 137.4, 127.9, 127.5, 127.4, 118.2,
81.1, 78.6, 78.3, 74.3, 73.4, 72.8, 70.8, 56.2, 45.1, 21.3;
HRMS (FAB) m/z 614.2879 (MCNa), calcd for
C38H41NO5Na 614.2877.
4.1.7. 2-(1-Benzyloxy-2,3-dihydroxypropyl)-3,4,5-benzyl-
oxypiperidine 21. To a solution of 15 (290 mg,
0.049 mmol) and NMO (172 mg, 1.47 mmol) in 30 mL
acetone was added OsO4 (0.7 mL, 7 mg in 10 mg/ml 1:1
acetone/water). The resulting solution was stirred for 4 h at
25 8C diluted with 3 mL satd Na2S2O5, stirred for 30 min,
4.1.4. 2-(1-Benzyloxy-3-hydroxypropyl)-3,4,5-benzyloxy-
piperidine 16. To a solution of 15 (110 mg, 0.186 mmol) in
3 mL of THF was added BH3$THF (0.5 mmol) at 0 8C. The
resulting solution was stirred at 0 8C for 3 h and 0.5 mL of

Z. Zhao et al. / Tetrahedron 61 (2005) 8888–8894
8893
1
and filtered. The filtrate was concentrated in vacuo giving a
residue, which was subjected to column chromatography
(silica gel, 1:1 acetone/hexane) to yield 240 mg (78%) 21
along with 20 mg (6.5%) of the uncharacterized dia-
hexane) to yield 62 mg of the inverted benzoate ester. H
NMR 8.06 (d, JZ8.1 Hz, 2H), 7.56–7.50 (m, 1H), 7.50–
7.34 (m, 2H), 7.33–7.13 (m, 20H), 5.49 (m, 1H), 5.01 (d,
JZ11.0 Hz, 1H), 4.93 (d, JZ11.5 Hz, 1H), 4.86 (t, JZ
11.5 Hz, 2H), 4.71 (d, JZ11.0 Hz, 1H), 4.59 (abq, JZ
11.0 Hz, 2H), 4.37 (m, 1H), 4.18 (d, JZ4.5 Hz, 1H), 3.92 (t,
JZ9.1 Hz, 1H), 3.85–3.70 (m, 1H), 3.65–3.55 (m, 2H), 3.31
(dd, JZ4.2 Hz, 9.4 Hz, 1H), 2.5 (dd, JZ4.1, 9.5 Hz, 1H),
2.35 (dd, JZ5.2, 10.2 Hz, 1H), 2.12 (t, JZ10.3 Hz, 1H);
13C NMR 165.6, 138.7 (2), 138.2, 137.3, 133.2, 129.5,
128.3, 128.2, 128.1, 127.8, 127.7, 127.6, 127.5, 127.3, 87.2,
82.1, 78.8, 76.4, 76.2, 75.5, 74.5, 72.8, 71.3, 69.3, 58.7,
54.2.
stereomeric diol. [a]2D5 C50.8 (c, 0.14, CHCl3); H NMR
1
7.35–7.17 (m, 20H), 5.43 (s, 1H), 4.99 (d, JZ11.7 Hz, 1H),
4.80 (abq, JZ6.5 Hz, 2H), 4.63 (dd, JZ4.2, 11.6 Hz, 2H),
4.55 (d, JZ9.2 Hz, 1H), 4.50 (d, JZ8.3 Hz, 1H), 4.39 (d,
JZ11.4 Hz, 1H), 4.07 (d, JZ11.4 Hz, 1H), 3.75 (d, JZ
6.4 Hz, 1H), 3.73–3.66 (m, 7H), 3.38 (br s, 1H), 2.16 (s,
3H); 13C NMR 173.2, 138.1, 137.9, 137.4, 128.5, 128.4,
128.0, 127.8, 127.6, 127.3, 85.3, 81.7, 79.2, 75.1, 74.7, 74.6,
74.3, 71.4, 70.1, 63.5, 57.0, 47.2, 21.3; HRMS (FAB) m/z
648.2912 (MCNa), calcd for C38H43NO7Na 648.2932.
A solution of the inverted ester (60 mg, 0.11 mmol) in
10 mL MeOH containing sodium methoxide (54 mg,
1 mmol) was stirred for 12 h at 25 8C, diluted with 1 mL
of water, and concentrated in vacuo giving a residue, which
was subjected to column chromatography (silica gel, 1:1
acetone/hexane) to yield 44 mg (73%) of 23. [a]2D5 C16.2
(c, 0.04, CHCl3); 1H NMR 7.33–7.20 (m, 20H), 4.99 (d, JZ
10.9 Hz, 1H), 4.84 (abq, JZ11.1 Hz, 2H), 4.68–4.60 (m,
4H), 4.50 (d, JZ11.6 Hz, 1H), 4.32 (t, JZ6.2 Hz, 1H), 3.89
(dt, JZ4.6, 9.2 Hz, 2H), 3.73–3.68 (m, 1H), 3.60–3.52 (m,
2H), 3.26 (dd, JZ4.9, 10.5 Hz, 1H), 2.45 (dd, JZ4.6,
9.3 Hz, 1H), 2.08–2.03 (m, 2H); 13C NMR 139.0, 138.8,
138.3, 137.6, 128.3, 128.3, 127.9, 127.8, 127.3, 87.4, 85.2,
78.9, 77.0, 75.6, 75.3, 72.8, 71.3, 69.3, 61.7, 54.3; HRMS
(FAB) m/z 588.2740 (MCNa), calcd for C36H39NO5Na
588.2720.
4.1.8. 1,6,7,8-Tetrabenzyloxy-2-hydroxyindolizidine 22.
A solution of 21 (120 mg, 0.19 mmol) in 4 mL THF and
4 mL 6 N HCl was stirred at 70 8C for 4 h, cooled and
concentrated in vacuo to give a residue. A solution of the
residue in 3 mL anhydrous pyridine containing 0.2 g
molecular sieves, PPh3 (63 mg, 0.24 mmol) and DEAD
(42 mg, 0.24 mmol) was stirred at 0 8C for 4 h, diluted with
satd NaHCO3 and extracted with CHCl3.The CHCl3 extracts
were washed with satd NaCl, dried and concentrated in
vacuo to yield a residue, which was subjected to column
chromatography (silica gel, 1:2 EA/hexane) to give 80 mg
(74%) of 22. [a]2D5 C40 (c, 0.032, CHCl3); 1H NMR 7.49–
7.18 (m, 20H), 5.07 (d, JZ11.3 Hz, 1H), 5.03 (d, JZ
11.0 Hz, 1H), 4.83 (d, JZ10.9 Hz, 1H), 4.69–4.64 (m, 4H),
4.58 (d, JZ11.0 Hz, 1H), 4.32 (br s, 1H), 4.18 (t, JZ5.6 Hz,
1H), 3.90 (m, 1H), 3.78 (m, 1H), 3.62 (m, 1H), 3.29 (dd, JZ
4.8, 10.5 Hz, 1H), 3.22 (br s, 1H), 3.04 (d, JZ8.9 Hz, 1H),
2.35 (dd, JZ6.3, 10.3 Hz, 1H), 2.15 (m, 1H), 1.94 (t, JZ
11.9 Hz, 1H); 13C NMR 138.9, 138.7, 138.3, 137.2, 128.5,
128.4, 128.4, 127.9, 127.1, 87.6, 79.1, 78.1, 76.8, 75.5, 74.4,
74.2, 72.8, 70.4, 69.9, 62.7, 54.2; HRMS (FAB) m/z
588.2702 (MCNa), calcd for C36H39NO5Na 588.2720.
4.1.11. 1,2,6,7,8-Pentahydroxyindolizidine 19. A solution
of 23 (42 mg, 0.074 mmol) in 3 mL EA and 3 mL MeOH
containing palladium chloride (22 mg, 0.013 mmol). The
mixture under an atmosphere of hydrogen (1 atm) was
stirred at 25 8C for 4 h and filtered through Celite. The
filtrate was concentrated in vacuo giving a residue, which
was subjected to ion-exchange chromatography (Dowex
1-X8, OHK form, 100–200 mesh, eluted with water) to
yield 15 mg (98%) of 19, mp 114–116 8C, [a]2D5 C22.7 (c,
0.07, H2O); 1H NMR (D2O) 4.21 (t, JZ6.3 Hz, 1H), 4.12 (d,
JZ4.3 Hz, 1H), 3.64–3.58 (m, 2H), 3.51 (dd, JZ7.1,
10.3 Hz, 1H), 3.38 (t, JZ9.1 Hz, 1H), 3.19 (dd, JZ5.2,
10.9 Hz, 1H), 2.37 (dd, JZ4.4, 10.2 Hz, 1H), 2.19–2.14 (m,
2H); 13C NMR 81.2, 79.6, 78.9, 72.3, 71.7, 70.9, 61.9, 57.7;
HRMS (FAB) m/z 228.0841 (MCNa), calcd for
C8H15NO5Na 228.0842.
4.1.9. 1,2,6,7,8-Pentahydroxyindolizidine 20. A solution
of 22 (32 mg, 0.057 mmol) in 3 mL EA and 3 mL MeOH
containing palladium chloride (22 mg, 0.013 mmol) under
an atmosphere of hydrogen (1 atm) was stirred at 25 8C for
4 h and filtered through Celite. The filtrate was concentrated
in vacuo giving a residue, which was subjected to ion-
exchange chromatography (Dowex 1-X8, OHK form, 100–
200 mesh, eluted with water) to yield 11 mg (94%) of 20.
[a]2D5 C37.9 (c, 0.013, H2O) (lit.11 [a]2D5 C66.5 (c, 1.33,
1
H2O)). The H and 13C NMR spectra of this substance
matched those reported earlier.11 1H NMR (D2O) 4.26 (m,
1H), 4.08 (m, 1H), 3.50–3.41 (m, 2H), 3.13 (t, JZ9.1 Hz,
1H), 2.97 (dd, JZ5.1, 10.8 Hz, 1H), 2.73 (dd, JZ2.1,
11.0 Hz, 1H), 2.48 (dd, JZ8.1, 10.7 Hz, 1H), 2.00 (dd, JZ
3.5, 9.7 Hz, 1H), 1.90 (t, JZ10.6 Hz, 1H); 13C NMR (D2O)
81.1, 72.6, 72.2, 72.0, 71.6, 71.1, 61.8, 57.6.
Acknowledgements
Financial support for this work by the National Science
Foundation and a generous gift from Dijindo Molecular
Technologies is greatly appreciated. We thank Professor
Stephen G. Pyne for informative discussion about this effort
and Professor George W. J. Fleet for kindly providing
spectra for indolizidine 20.
4.1.10. 1,6,7,8-Tetrabenzyloxy-2-hydroxyindolizidine 23.
A solution of 22 (60 mg, 0.11 mmol), benzoic acid (26 mg,
0.22 mmol), PPh3 (58 mg, 0.022 mmol) and DEAD (37 mg,
0.22 mmol) in 3 mL THF was stirred at 25 8C for 12 h,
diluted with satd NaHCO3 and extracted with CHCl3. The
CHCl3 extracts were washed with satd NaCl, dried and
concentrated in vacuo to give a residue, which was
subjected to column chromatography (silica gel, 1:2 EA/
Supplementary data
Supplementary data associated with this article can be

8894
Z. Zhao et al. / Tetrahedron 61 (2005) 8888–8894
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014. Contained in the supplementary data are H and 13C
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