Syntheses of pyrrolizidines and indolizidines from α,β-unsaturated sugar δ-lactones via Dieckmann condensation

Article abstract of DOI:10.1016/S0040-4020(02)00005-4

Both N-methoxycarbonylmethyl- and N-methoxycarbonylethyl-derivatives of dihydroxy-(D)-homoproline were subjected to the intramolecular ester condensation to yield ketoesters of pyrrolizidine and indolizidine series, respectively. The former ketoester was transformed into derivative related to anstraline, while the latter were transformed into the natural lentiginosine as well as its 2-epi-, and 7-hydroxy-2-epi-derivatives.

Full text of DOI:10.1016/S0040-4020(02)00005-4

TETRAHEDRON
Pergamon
Tetrahedron 58 -2002) 1433±1441
Syntheses of pyrrolizidines and indolizidines from
a,b-unsaturated sugar d-lactones via Dieckmann condensation
p
Â
Joanna Rabiczko, Zo®a Urbanczyk-Lipkowska and Marek Chmielewski
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Received 3 September 2001; revised 27 November 2001; accepted 20 December 2001
AbstractÐBoth N-methoxycarbonylmethyl- and N-methoxycarbonylethyl-derivatives of dihydroxy--d)-homoproline were subjected to the
intramolecular ester condensation to yield ketoesters of pyrrolizidine and indolizidine series, respectively. The former ketoester was
transformed into derivative related to australine, while the latter were transformed into the natural lentiginosine as well as its 2-epi-, and
7-hydroxy-2-epi-derivatives. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Some time ago, Buchanan et al.4 accomplished the synthesis
of -1)-crotonecine 114 via initial Dieckmann condensation
followed by an additional four-step reaction sequence. The
work of Buchanan's group3 has prompted us to investigate
in detail the analogous Dieckmann condensation approach
to the synthesis of pyrrolizidine and indolizidine
alkaloids,5±7 starting from -d)-homoproline 8.
Recently, we have reported on the conjugate addition-
rearrangement of hydrazine to the a,b-unsaturated sugar
d-lactones 1±3. This transformation constitutes a short
and ef®cient route to the bicyclic pyrazolidinones 4±6, as
well as the corresponding mono- and dihydroxy--d)-homo-
proline derivatives 7±9,1 via hydrogenolysis of the N±N
bond. Compounds 7±9 represent highly functionalized
b-amino acids that are suitable for the syntheses of a variety
of natural products. Enantioselective syntheses of b-amino
acids and their synthetic applications have recently been
reviewed.2
2. Results and discussion
Methanolysis of -d)-homoproline 8 led to the hydrochloride
10 which was silylated at the oxygen atom to give
compound 11 in 74% overall yield. N-Alkylation of salt
10 with methyl bromoacetate resulted in formation of the
diester 12 in 66% yield. N-Alkylation could also be
accomplished using trimethylsilyl bromoacetate. During
work-up, the unstable TMSester underwent facile
hydrolysis to provide the corresponding free acid 13
directly.
The presence of a free hydroxyl group in both 12 and 13
offered the possibility of epimerization at the C-4 carbon
atom under Mitsunobu conditions, which allowed for easy
modi®cation of the stereochemistry of the starting proline
10. In the case of diester 12, epimerization proceeded via
p-nitrobenzoate 15 which was later saponi®ed to give 16. In
the case of acid 13 the epimerization reaction was accom-
panied by an intramolecular cyclization resulting in the
formation of lactone 17.
Depending on the direction of Dieckmann condensation,
application of the Buchanan's methodology3 to 14 should
provide an entry to the skeleton of either heliotridine 188 or
australine 19.9
Keywords: d-lactones; Dieckmann condensation; pyrrolizidines; indolizi-
dines.
Corresponding author. Tel.: 148-22-6323789; fax: 148-22-6326681;
e-mail: chmiel@icho.edu.pl
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020-02)00005-4

1434
J. Rabiczko et al. / Tetrahedron 58 -2002) 1433±1441
Reduction of ketoester 21 under an oxygen-free argon
atmosphere followed by acetylation of the resulting diol
yielded pyrrolizidine 22. Compound 22 is a structural and
con®gurational isomer of pyrrolizidines such as australine
19. The stereochemistry assigned to 22 was corroborated by
NOE experiments indicating the existence of a spin±spin
interaction between H-5, H-6 and H-7a protons. Irradiation
of the H-6 signal -at d 5.22) caused enhancement of reso-
nances of H-7a -d 3.82) by 1.5%, H-5 -d 3.04) by 2.9%, and
H-7 -d 2.29) by 4.5%. We detected no spin±spin inter-
actions between H-6 and H-70 -d 1.69) and between H-70
and H-7a protons. The presence of these NOE effects
corroborates the con®guration assigned to structure 22.
The regiochemistry of the Dieckmann condensation
reported by Buchanan's group3 is a direct consequence of
the presence of a lactone ring, that allows for the desired
direction of the condensation reaction exclusively. In our
case, however, formation of a carbanion next to the nitrogen
atom is preferred. As a result, the insertion of the ketoester
fragment occurs at the 5,6- and not at the 6,7-position.
Consequently, the reaction yielded products with the
skeleton of australine 19, and not heliotridine 18.
We decided to investigate whether it would be possible to
alter the direction of ester condensation by increasing the
electrophilicity of the carbonyl group. We speculated that
such an increase could result from attachment of an activa-
tor, such as a thiophenol moiety, to the nitrogen atom.
In the case of compound 14, our attempts to apply the
standard conditions of the Dieckmann condensation that
promote formation of the ®ve-membered rings -use of
sodium or potassium ethoxide,7,10 t-BuOK,11 TiCl4,12 NaH
in toluene13 or diethyl ether,14 K in toluene,15 TMS2NLi16)
were mostly unsuccessful. Sodium hydride in boiling
benzene13 in the presence of catalytic amount of methanol
resulted in racemization at C-2 via a retro-Michael mechan-
ism leading to the formation of a 1:1 mixture of 14 and 20
-Scheme 1).
In order to obtain thiophenol derivative 24, ester 11 was
treated with thiophenyl chloroacetate 2317 in the presence
of pyridine and DMAP. The crude post-reaction mixture
was directly treated with TMS2NLi at 2788C to give
indolizidinone 26 and ester 24 in a ratio of about 2:1, respec-
tively, and in 82% overall yield. Compound 26 was identi-
®ed, after standard acetylation, as the indolizidinone 27. The
presence of both compounds 24 and 26 as products of the
ester condensation suggested that the original reaction of
ester 11 with thiophenyl chloroacetate 23 led to a mixture
of ester 24 and amide 25. Subsequently, in the presence of
lithium amide, N-chloroacetyl derivative 25 underwent ester
condensation to give indolizidinone 26, while ester 24
remained unchanged. An attempt to force the Dieckmann
An acceptable yield for the Dieckmann condensation -58%)
was ®nally achieved by employing TMS2NNa -1 M in THF)
at 2788C -Scheme 2). The observed regiochemistry of this
reaction was opposite to that reported by Buchanan's
group.3 Ketoester 21, found to be air-sensitive in the
presence of base, was isolated as a sole product.
Scheme 1.
Scheme 2.

J. Rabiczko et al. / Tetrahedron 58 -2002) 1433±1441
1435
Scheme 3.
condensation with ester 24 at higher temperature led to
decomposition of the substrate -Scheme 3).
Diester 28 which is a homologue of 14, formally obtained
by an addition of one more carbon atom to the substituent at
the nitrogen atom, should provide an entry to indolizidines
by the Dieckmann cyclization. Addition of methyl acrylate
to the amino group in ester 11, carried out under standard
conditions18 led to the diester 28 which could be easily
transformed into lentiginosine 29 and related compounds.
Lentiginosine 29,19 isolated from Astragalus lentiginosus,
2-epi-lentiginosine 30,20 isolated from Rhizoctomia
lenguminicola and 7-hydroxy-lentiginosine 3121 are all
highly active glycosidase inhibitors. Syntheses of 29,22
3023 and 3121,22f,g have been already reported several times
in the past.
We established that the b-keto-ester moiety in the major
product 32 can be reduced stepwise with NaBH4 in metha-
nolic solution. Four equivalents of NaBH4 for 15 min at 08C
gave partially reduced ester 34. When the reduction was
carried out at room temperature, with 8 equiv. of NaBH4
for 30 min, both carbonyl functions in ketoester 32 were
reduced to give diol 35, which was identi®ed as diacetate
36. Separate reduction of monoester 34 under the same
conditions led also to diol 35.
The con®guration of diacetate 36 was assigned by NOE
experiments in C6D6 solution which showed enhancement
of the intensity of the H-8a signal -at dˆ2.50) by 6% when
signal of H-7 -dˆ4.93) was irradiated and, conversely, the
signal of H-7 was enhanced by 7% when H-8a resonance
was irradiated. NOE experiments did not show any inter-
action between H-6 and H-7 protons. The observed high
stereoselectivity of ketoester 32 reduction and con®guration
found at both C-6 and C-7 in the reduction products 34 and
35 suggest an exo-approach of the hydride anion and
thermodynamic control of the methoxycarbonyl group
position.
Our attempts to induce the Dieckmann cyclization using
diester 28 carried out under standard conditions that
should promote the formation of the six-membered ring
-use of CH3ONa in toluene,24 NaH in benzene with
catalytic amount MeOH,12 K2CO3/18-crown-6 in toluene25)
were unsuccessful. The use of -TMS)2NNa in THF26 led to
the formation of the expected cyclization product in a
low yield -20%). Finally, a satisfactory result was
obtained when condensation was carried out using LDA in
THF at 2788C. A mixture of two isomeric ketoesters
existing as enols 32 and 33, in approximate ratio 3:1,
was obtained in 87% yield. Esters 32 and 33 were
Decarboxylation of the mixture of enol esters 32 and 33 in
DMSO in the presence of the catalytic amounts of water and
NaCl led to the formation of indolizinone 37 in 92% yield.27
Reduction of ketoester 37 with l-Selectride, followed by
acetylation, gave acetate 39 as the sole product. Deoxygena-
tion of ketoester 37 by the modi®ed Wolff±Kishner
1
separated by chromatography and identi®ed by H NMR
spectroscopy.

1436
J. Rabiczko et al. / Tetrahedron 58 -2002) 1433±1441
The transformations of diesters 14 and 28 presented above
illustrate a convenient synthetic approach to pyrrolizidines
and indolizidines with the -S)-con®guration at the bridge-
head carbon atom -C-7a or C-8a, respectively). The con-
®guration at this carbon atom is a direct consequence of
the stereochemistry of conjugate addition-rearrangement
of hydrazine to the lactones 1±3 with -d)-con®guration.
Recently, we have reported on the skeletal rearrangement
leading from lactone 43 to the bicyclic compound 45.30
Conjugate addition-rearrangement of N-benzylhydroxyl-
amine to lactone 43 gave isoxazolidin-5-one 44 which, in
turn, was tosylated at the terminal hydroxy group to yield
mixture of bicyclic lactones 45 and 46. Lactone 45 has
-l)-homoproline structure -Scheme 4).
Elucidation of the possible reaction pathway leading to
these lactones has been proposed by us.30 Transamination
of bicyclic lactone 45 led to the formation of amide 47.
Further debenzylation and detosylation of amide 47 with
sodium in liquid ammonia followed by the treatment of
resulting intermediate with 2,2-dimethoxypropane and
methanolic HCl yielded ®nal ester 48. Ester 48 represents
an entry point to the pyrrolizidines and indolizidines having
-R)-con®guration of the bridgehead carbon atom. The
modest overall yield of the transformation of adduct 43
into ester 48 and the presence of non-regiospeci®c -iso-
propylidene group) protection of its two hydroxy groups
does limit, however, the attractiveness of this reaction
sequence when considering further synthetic transforma-
tions leading toward swainsonine 49 and related
compounds.
Figure 1. X-Ray structure of 1-O-benzyl-lentiginosine -42) with crystal-
lographic numbering scheme.
procedure,22d,28 involving formation of the tosylhydrazone
followed by its reduction in situ with NaBH3CN, afforded
the 2-epi-lentiginosine derivative 40 in 89% yield. The silyl
ether in indolizine 40 was removed by treatment with
TBAF. The resulting 1-O-benzyl-2-epi-lentiginosine 41,
treated with p-nitrobenzoic acid under Mitsunobu con-
ditions followed by saponi®cation of the intermediate
p-nitrobenzoate, gave 1-O-benzyl-lentiginosine 42. The
structure and absolute con®guration of 42 was proved by
X-ray crystallography -Fig. 1).29 It should be noted that the
X-ray crystallographic structure of lentiginosine or a simple
derivative has not been reported yet. Hydrogenolysis of the
benzyl ether in ether 42 with sodium in liquid ammonia led
to natural -1)-lentiginosine 29.
In summary, we have demonstrated that -d)-homoproline
derivatives can be employed as attractive starting materials
for the syntheses of pyrrolizidines and indolizidines via
Dieckmann condensations. This attractiveness was exempli-
®ed by the synthesis of pyrrolizidine 22 related to australine,
and indolizidines such as natural -1)-lentiginosine 29 -a
Scheme 4.

J. Rabiczko et al. / Tetrahedron 58 -2002) 1433±1441
1437
potent inhibitor of amyloglucosidases) as well as
structurally related derivatives 38 and 41. An early attempt
to ®nd an access to the related -l)-homoproline derivatives
did not result in a fully satisfactory solution.
3.76 -m, 1H, H-5a), 3.71, 3.65 -2s, 6H, 2OCH3), 3.47 -m,
1H, H-2), 3.54, 3.41 -2d, 2H, Jˆ17.2 Hz, H-10a,10b), 3.35
-dd, 1H, Jˆ5.8, 12.2 Hz, H-3), 2.71 -dd, 1H, Jˆ4.8,
10.3 Hz, H-5b), 2.56 -dd, 1H, Jˆ5.3, 15.2 Hz, H-100b),
2.48 -dd, 1H, Jˆ6.8, 15.2 Hz, H-100b); MS-LSIMS, HR)
m/z -M1H)1 calcd for C17H24NO6: 338.16037; found:
338.16483.
3. Experimental
3.1. General
3.1.3. -2S,3S,4R)-3-Benzyloxy-N-carboxymethyl-4-
hydroxy-2-methoxycarbonylmethyl-pyrrolidine -13).
Compound 13 was obtained according to the procedure
described above using TMSbromoacetate; syrup,
[a]Dˆ241.5 -c 0.6, CH3OH); IR -nujol): 3390, 1744,
È
Melting points were determined using a Ko¯er hot-stage
apparatus with microscope. 1H NMR spectra were recorded
on a Bruker Avance 500 and Varian Gemini AC-200
spectrometers for CDCl3 or C6D6 solutions using tetra-
methylsilane as an internal standard and are expressed as
d values. IR spectra were recorded on a Perkin±Elmer FT-
IR Spectrum 2000 spectrophotometer. Mass spectra were
determined using an AMD 604 Inectra GmbH spectrometer.
Optical rotation was measured using a JASCO P 3010
polarimeter at ambient temperature. Column chromatography
was performed using Merck silica gel -230±400 mesh). All
solvents were dried and puri®ed by standard techniques.
1627 cm21 1H NMR -CD3OD) d: 4.76, 4.54 -2d, 2H,
;
Jˆ11.7 Hz, Bn), 4.39 -m, 1H, H-4), 3.87 -dd, 1H, Jˆ3.8,
8.0 Hz, H-3), 4.01, 3.78 -2d, 2H, Jˆ16.0 Hz, H-10a,10b),
3.79 -m, 2H, H-2,5a), 3.65 -s, 3H, OCH3), 3.26 -dd, 1H,
Jˆ2.9, 12.6 Hz, H-5b), 2.87 -d, 2H, H-100a,100b); MS
-LSIMS, HR) m/z -M1H)1 calcd for C16H22NO6:
324.14471; found: 324.14539.
3.1.4.
-2S,3S,4R)-3-Benzyloxy-4-tert-butyldimethyl-
siloxy-2,N-bis-methoxycarbonylmethyl)-pyrrolidine -14).
Silyl ether 11 -0.20 g, 0.53 mmol) in THF -10 mL) was
treated with TEA -163 mL, 1.17 mmol), methyl bromo-
acetate -54 mL, 0.58 mmol) and stirred for 5 h at room
temperature. Subsequently, it was evaporated and puri®ed
by chromatography using hexane±ethyl acetate 3:2 v/v as
an eluant to give 14 -0.20 g, 86%); syrup, [a]Dˆ212.9 -c
Compound 5 was prepared according to the procedure
described earlier.1
3.1.1. -2S,3S,4R)-3-Benzyloxy-4-tert-butyldimethylsiloxy-
2-methoxycarbonylmethyl-pyrrolidine -11). Compound
5 -0.20 g, 0.81 mmol) in water -2 mL) was treated with
aqueous Raney nickel suspension -600 mg, pH 7). Resulted
mixture was stirred for 1.5 h at room temperature. Subse-
quently, solution was ®ltered through Celite and evaporated.
The crude compound 8 was treated with 10% HCl in
methanol -5 mL) and stirred for 4 h. Solvents were removed
under reduced pressure and the crude hydrochloride 10 was
dissolved in acetonitrile -10 mL), treated with imidazole
-0.22 g, 9.24 mmol) and t-butyldimethylsilyl chloride
-0.18 g, 1.20 mmol). The mixture was stirred overnight at
room temperature. Subsequently, the solvent was evapo-
rated and the crude product was puri®ed by chromatography
using hexane±ethyl acetate 4:1 v/v and 1% Et3N as an
eluant to give 11 -0.23 g, 74%), syrup, [a]Dˆ2101.9 -c
1
0.6, CH2Cl2); IR -®lm): 1739 cm21; H NMR -CDCl3) d:
4.75, 4.52 -2d, 2H, Jˆ11.9 Hz, Bn), 4.27 -m, 1H, H-4), 3.69,
3.60 -2s, 6H, 2OCH3), 3.62 -t, 1H, Jˆ4.6 Hz, H-3), 3.57,
3.37 -2d, 2H, Jˆ16.8 Hz, H-10a,10b), 3.36 -dd, 1H, Jˆ5.5,
9.4 Hz, H-5a), 3.25 -m, 1H, H-2), 2.66 -dd, 1H, Jˆ6.6,
9.4 Hz, H-5b), 2.54 -dd, 1H, Jˆ5.5, 15.2 Hz, H-100a), 2.45
-dd, 1H, Jˆ7.0, 15.2 Hz, H-100b), 0.90, 0.09, 0.07 -3s, 15H,
TBS); MS -LSIMS, HR) m/z -M1H)1 calcd for
C23H38NO6Si: 452.24684; found: 452.24548.
3.1.5.
-2S,3S,4S)-3-Benzyloxy-4-hydroxy-N-methoxy-
carbonylmethyl-pyrrolidine -16). A solution of TPP
-0.230 g, 0.89 mmol) and DEAD -140 mL, 0.89 mmol) in
dry THF -5 mL) was stirred for 30 min at room temperature
and then p-nitrobenzoic acid -0.15 g, 0.89 mmol) was
added. Stirring was continued for additional 30 min and
then compound 12 -0.10 g, 0.29 mmol) in THF -1 mL)
was added. The mixture was kept at room temperature for
4 h. Subsequently, solvent was evaporated and residue was
extracted with ethyl ether -4£10 mL). Extracts were
combined, washed, dried and evaporated. The crude 15
was treated with methanol -5 mL) and K2CO3 -0.05 g,
0.32 mmol). After disappearance of the p-nitrobenzoate
-15 min), the mixture was ®ltered through Celite and evapo-
rated. The residue was puri®ed by chromatography using
hexane±ethyl acetate 4.5:1 v/v as an eluant to afford 16
-0.07 g, 73%); syrup, [a]Dˆ110.7 -c 1.4, CH2Cl2); IR
1
0.4, CH2Cl2); IR -®lm): 3372, 1738, 1683 cm21; H NMR
-CDCl3) d: 4.74, 4.44 -2d, 2H, Jˆ12.0 Hz, Bn), 4.24 -m,
1H, H-4), 3.64 -s, 3H, OCH3), 3.60 -m, 1H, H-2), 3.45 -dd,
1H, Jˆ4.5, 7.0 Hz, H-3), 3.11 -dd, 1H, Jˆ4.5, 11.5 Hz,
H-5b), 2.93 -dd, 1H, Jˆ4.0, 11.5 Hz, H-5b), 2.62 -dd, 1H,
Jˆ4.0, 16.0 Hz, H-10a), 2.32 -dd, 1H, Jˆ9.0, 16.0 Hz,
H-10b), 0.91 -s, 9H, t-Bu), 0.09, 0.10 -2s, 6H, SiMe2); MS
-ESI-TOF, HR) m/z -M1H)1 calcd for C20H34NO4Si:
380.2252; found: 380.2223.
3.1.2.
-2S,3S,4R)-3-Benzyloxy-4-hydroxy-2,N-bis-
-methoxycarbonylmethyl)-pyrrolidine -12). Hydro-
chloride 10 obtained as above from 5 -0.90 g, 0.81 mmol)
was dissolved in THF -10 mL) and treated with TEA
-163 mL, 1.17 mmol) and methyl bromoacetate -54 mL,
0.58 mmol). The mixture was stirred for 5 h at room
temperature. Subsequently, it was evaporated and puri®ed
by chromatography using hexane±ethyl acetate 3:2 v/v as
an eluant to afford 12 -0.18 g, 66%); syrup, [a]Dˆ113.3 -c
1.6, CH2Cl2); IR -®lm): 3485, 1733 cm21; 1H NMR -CDCl3)
d: 4.66, 4.62 -2d, 2H, Jˆ11.5 Hz, Bn), 4.17 -m, 1H, H-4),
1
-®lm): 3420, 1739 cm21; H NMR -CDCl3) d: 4.64, 4.57
-2d, 2H, Jˆ11.8 Hz, Bn), 4.11 -m, 1H, H-4), 3.86 -m, 1H,
H-3), 3.70, 3.65 -2s, 6H, 2OCH3), 3.59, 3.31 -2d, 2H,
Jˆ16.8 Hz, H-10a,10b), 3.13 -d, 1H, Jˆ10.1 Hz, H-5a),
3.05 -m, 1H, H-2), 2.94 -dd, 1H, Jˆ4.6, 10.1 Hz, H-5b),
2.63 -m, 2H, H-100a,100b); MS -LSIMS, HR) m/z -M1H)1
calcd for C17H24NO6: 338.16037; found: 338.16091.

1438
J. Rabiczko et al. / Tetrahedron 58 -2002) 1433±1441
3.1.6.
-5S,6S,7S)-1-Aza-3-benzyloxy-4-oxa-3-oxo-7-
3.1.9. -1S,2R,5S,6S,7aS)-6-Acetoxy-5-acetoxymethyl-1-
benzyloxy-2-tert-butyldimethylsiloxy-pyrrolizidine -22).
Compound 14 -0.25 g, 0.55 mmol) in dry THF -3 mL)
was cooled to 2788C under argon and treated with
TMS2NNa -1.32 mL, 0.6 M solution in toluene,
0.66 mmol). The mixture was stirred for 1 h. Subsequently,
it was diluted with CH2Cl2 -10 mL), washed with saturated
aq. NaHCO3, dried and evaporated. The crude 21 was
dissolved in MeOH -2 mL), cooled to 08C under argon
and treated with NaBH4 -0.21 g, 5.5 mmol). The mixture
was stirred for 0.5 h, then ®ltered through Celite and evapo-
rated. The residue was acetylated with acetic anhydride±
pyridine mixture 1:2 v/v -10 mL) with addition of DMAP
-3 mg). After 4 h, the mixture was evaporated and residue
puri®ed by chromatography using hexane±ethyl acetate 9:1
v/v as an eluant to afford 22 -0.19 g, 73%); colorless syrup,
methoxycarbonylmethyl-bicyclo[3.2.1] octane -17). A
solution of TPP -0.20 g, 0.75 mmol) and DEAD -118 mL,
0.75 mmol) in dry THF -4 mL) was stirred at room tempera-
ture for 30 min and then treated with compound 15 -0.08 g,
0.35 mmol) in THF -1 mL). The mixture was kept at room
temperature for 20 h. Subsequently, it was evaporated and
puri®ed by chromatography using hexane±ethyl acetate 4:1
v/v as an eluant to give 17 -0.06 g, 82%); syrup,
[a]Dˆ116.2 -c 0.9, CH2Cl2); IR -®lm): 1743 cm21; H
1
NMR -CDCl3) d: 4.78 -d, 1H, Jˆ1.6 Hz, H-6), 4.65, 4.51
-2d, 2H, Jˆ11.8 Hz, Bn), 3.86 -dd, 1H, Jˆ2.1, 4.8 Hz, H-5),
3.71 -s, 3H, OCH3), 3.67 -d, 2H, Jˆ0.8 Hz, H-2a,2b), 3.45
-m, 1H, H-7), 3.32 -dd, 1H, Jˆ2.1, 12.3 Hz, H-8a), 3.10 -dd,
1H, Jˆ12.3 Hz, H-8b), 2.69 -dd, 1H, Jˆ6.6, 14.7 Hz,
H-10a), 2.62 -dd, 1H, Jˆ9.6, 14.7 Hz, H-10b); MS-EI,
HR) m/z M1 calcd for C16H19NO5: 305.12631; found:
305.12401.
1
[a]Dˆ230.6 -c 0.9, CH2Cl2); IR -®lm): 1743 cm21; H
NMR -C6D6) d: 5.22 -m, 1H, H-6), 4.63, 4.42 -2d, 2H,
Jˆ12.1 Hz, Bn), 4.31 -m, 1H, Jˆ3.1, 4.1, 4.4 Hz, H-2),
4.16 -dd, 1H, Jˆ5.6, 11.2 Hz, CHAHBOAc), 4.05 -dd, 1H,
Jˆ6.8, 11.2 Hz, CHAHBOAc), 3.82 -m, 1H, H-7a), 3.52 -dd,
1H, Jˆ4.1, 7.0 Hz, H-1), 3.36 -dd, 1H, Jˆ3.1, 11.1 Hz,
H-3), 3.05 -m, 1H, H-5), 2.77 -dd, 1H, Jˆ4.4, 11.1 Hz,
H-30), 2.28 -ddd, 1H, Jˆ6.2, 7.7, 13.9 Hz, H-7), 1.81 -s,
3H, OAc), 1.69 -m, 1H, H-70), 1.66 -s, 3H, OAc), 1.08,
0.20, 0.18 -3s, 15H, TBS); MS -LSIMS, HR) m/z
-M1H)1 calcd for C25H40NO6Si: 478.26249; found:
478.26264.
3.1.7. -2R,3S,4R)-3-Benzyloxy-4-tert-butyldimethylsiloxy-
2,N-bis-methoxycarbonylmethyl)-pyrrolidine -20). To a
suspension of 60% NaH in mineral oil -0.016 g,
0.39 mmol) in benzene -1 mL) under nitrogen compound
14 -0.055 g, 0.12 mmol) in benzene -1 mL) and methanol
-10 mL) was added. The mixture was re¯uxed for 4 h and
then it was cooled to the room temperature, neutralized with
acetic acid -250 mL), and poured into saturated solution of
NaHCO3. The mixture was extracted with chloroform
-3£20 mL). The extract was washed, dried and evaporated.
The crude product was separated by chromatography using
hexane±ethyl acetate 2:1 v/v as an eluant to give 14
-0.025 g, 45%) and 20 -0.027 g, 49%); syrup,
3.1.10.
-2S,3S,4R)-3-Benzyloxy-4-tert-butyldimethyl-
siloxy-N-thiophenylcarbonylmethyl-2-methoxycarbonyl-
methyl-pyrrolidine -24) and -2S,3S,4R)-7-acetoxy-1-
benzyloxy-2-tert-butyldimethylsiloxy-6-chloro-5-oxo-6-
eno-indolizidine -27). Compound 11 -0.20 g, 0.53 mmol) in
dry THF -52 mL) was treated with TEA -177 mL,
1.27 mmol), thiophenyl chloroacetate -23; 0.12 g,
0.64 mmol) and DMAP -5 mg). The mixture was stirred
for 20 h at room temperature. Subsequently, solvent was
evaporated and residue was ®ltered through silica gel bed
using hexane±ethyl acetate 4:1 v/v as an eluant. After
evaporation of the solvent resulted mixture -24 and 25)
was dissolved in THF -5 mL), cooled to 2788C and treated
under nitrogen with TMS2NLi -650 mL, 1 M hexane solu-
tion, 0.65 mmol) and left for 15 min. Subsequently, acetic
acid -250 mL) and acetic anhydride±pyridine mixture 1:2
-10 mL) were added. After 2 h, the solvents were removed
under reduced pressure and the mixture was separated by
chromatography using hexane±ethyl acetate 4:1 v/v as an
eluant to afford 24 -0.08 g, 28%) and 27 -0.13 g, 54%).
[a]Dˆ215.3 -c 0.2, CH2Cl2); IR -®lm): 1739 cm21; H
1
NMR -CDCl3) d: 4.75, 4.50 -2d, 2H, Jˆ11.7 Hz, Bn),
4.45 -m, 1H, H-4), 4.08 -dd, 1H, Jˆ4.0, 6.4 Hz, H-3),
3.68, 3.57 -2s, 6H, 2OCH3), 3.65 -m, 1H, H-2), 3.60, 3.43
-2d, 2H, Jˆ17.9 Hz, H-10a,10b), 3.04 -dd, 1H, Jˆ3.9,
9.6 Hz, H-5a), 2.99 -dd, 1H, Jˆ5.5, 9.6 Hz, H-5b), 2.76
-dd, 1H, Jˆ6.4, 16.6 Hz, H-100a), 2.57 -dd, 1H, Jˆ7.0,
16.6 Hz, H-100b), 0.91, 0.08, 0.07 -3s, 15H, TBS); MS
-LSIMS, HR) m/z -M1H)1 calcd for C23H38NO6Si:
452.24684; found: 452.24506.
3.1.8. -1S,2R,5S,7aS)-1-Benzyloxy-2-tert-butyldimethyl-
siloxy-5-methoxycarbonyl-6-oxo-pyrrolizidine
-21).
Compound 14 -0.07 g, 0.15 mmol) in dry THF -2 mL)
under nitrogen was cooled to 2788C and treated with
sodium bis-trimethylsilylamide -TMS2NNa; 180 mL, 1 M
in THF, 0.18 mmol). After 1 h the mixture was poured
into saturated aq. NaHCO3 and extracted with CH2Cl2
-3£10 mL). The extract was washed, dried, evaporated
and puri®ed by chromatography using hexane±ethyl acetate
6:1 v/v as an eluant to give 21 -0.04 g, 58%), syrup,
[a]Dˆ291.6 -c 0.4, CH2Cl2); IR -®lm): 3362, 1749,
1
Compound 24: syrup, [a]Dˆ218.5 -c 0.8, CH2Cl2); H
NMR -CDCl3) d: 4.70, 4.65 -2d, 2H, Jˆ12.1 Hz, Bn),
4.37 -ddd, 1H, Jˆ3.6, 4.5, 9.5 Hz, H-5), 4.32 -ddd, 1H,
Jˆ4.0, 6.6, 7.6 Hz, H-2), 3.79 -dd, 1H, Jˆ2.5, 3.9 Hz,
H-3), 3.64 -m, 3H, H-10a, H-5a,5b), 3.59 -s, 3H, OCH3),
3.51 -dd, 1H, Jˆ7.8, 9.5 Hz, H-10b), 2.88 -dd, 1H, Jˆ3.7,
16.2 Hz, H-100a), 2.36 -dd, 1H, Jˆ9.5, 16.2 Hz, H-100b),
0.90, 0.08, 0.07 -3s, 15H, TBS); MS -LSIMS, HR) m/z
-M1Na)1 calcd for C28H39NO5SiNa: 552.22059; found:
552.22050.
1705 cm21 1H NMR -CDCl3) d: 4.70, 4.47 -2d, 2H,
;
Jˆ11.9 Hz, Bn), 4.52 -ddd, 1H, Jˆ1.3, 4.3, 5.0 Hz, H-2),
4.27 -m, 1H, Jˆ6.5, 6.8, 8.6 Hz, H-7a), 3.82 -s, 1H, H-5),
3.81 -dd, 1H, Jˆ5.0, 12.8 Hz, H-3), 3.76 -s, 3H, OCH3),
3.44 -dd, 1H, Jˆ4.3, 8.6 Hz, H-1), 3.20 -dd, 1H, Jˆ1.1,
12.8 Hz, H-3), 2.38 -dd, 1H, Jˆ6.8, 13.9 Hz, H-7), 2.34
-dd, 1H, Jˆ6.5, 13.9 Hz, H-70), 0.91, 0.11, 0.10 -3s, 15H,
TBS); MS -ESI-TOF, HR) m/z -M1Na)1 calcd for
C22H33NO5SiNa: 442.2044; found: 442.2031.
Compound 27: mp 124±1258C; [a]Dˆ295.7 -c 0.6,
CH2Cl2); IR -®lm): 1771, 1669, 1639 cm21 1H NMR
;

J. Rabiczko et al. / Tetrahedron 58 -2002) 1433±1441
1439
-CDCl3) d: 4.73 -m, 1H, H-2), 4.73, 4.43 -2d, 2H,
Jˆ11.8 Hz, Bn), 4.11 -m, 1H, H-8a), 3.59 -m, 3H,
H-1,3,30), 2.67 -dd, 1H, Jˆ5.7, 16.6 Hz, H-8), 2.60 -dd,
1H, Jˆ13.6, 16.6 Hz, H-80), 2.26 -s, 3H, OAc), 0.90, 0.12,
0.11 -3s, 15H, TBS); MS -LSIMS, HR) m/z -M1H)1 calcd
for C23H33NO5SiCl: 446.18165; found: 446.17986.
3.05 -dd, 1H, Jˆ7.0, 11.0 Hz, H-5), 2.61 -dd, 1H, Jˆ3.5,
12.0 Hz, H-6), 2.52 -dd, 1H, Jˆ6.5, 12.0 Hz, H-60), 2.44 -m,
2H, H-30,50), 0.90 -s, 9H, t-Bu), 0.11, 0.09 -2s, 6H, SiMe2);
MS -LSI MS, HR) m/z -M1H)1 calcd for C23H36NO5Si:
434.2363; found: 434.2357.
3.1.13.
-1S,2R,6S,7S,8aS)-3-Benzyloxy-2-tert-butyl-
3.1.11.
-2S,3S,4R)-3-Benzyloxy-4-tert-butyldimethyl-
dimethylsiloxy-7-hydroxy-6-methoxy-carbonyl-indolizi-
dine -34). To a solution of compound 32 -0.040 g,
0.09 mmol) in methanol -1 mL) at 08C, NaBH4 -0.014 g,
0.36 mmol) was added over 5 min with stirring. Stirring
and low temperature was maintained for 10 min and then
the mixture was allowed to warm to room temperature.
Subsequently, saturated NaCl solution -5 mL) was added
and mixture extracted with chloroform -3£10 mL). The
extracts were dried and evaporated. The residue was puri-
®ed by chromatography using hexane±ethyl acetate 7:3 v/v
as an eluant to give 34 -0.031 g, 78%); syrup, [a]Dˆ258.8
siloxy-N--20-methoxycarbonylethyl)-2-methoxycarbonyl-
methyl-pyrrolidine -28). Compound 11 -0.15 g,
0.39 mmol) in ethanol -5 mL) was treated with NEt3
-324 mL, 2.3 mmol) and methyl acrylate -100 mL,
1.17 mmol). The mixture was stirred for 20 h at room
temperature. Subsequently, the solvent was removed
under reduced pressure and residue puri®ed by chromato-
graphy using hexane±ethyl acetate 7:3 v/v as an eluant to
afford 28 -0.16 g, 86%); syrup, [a]Dˆ24.2 -c 1.0, CH2Cl2);
IR -®lm): 1739 cm21; H NMR -CDCl3) d: 4.74, 4.53 -2d,
1
2H, Jˆ12.0 Hz, Bn), 4.21 -m, 1H, H-4), 3.63 -t, 1H,
Jˆ4.5 Hz, H-3), 3.66, 3.61 -2s, 6H, 2OCH3), 3.16 -dd,
1H, Jˆ5.5, 9.0 Hz, H-5a), 3.08 -m, 2H, H-10a,2), 2.74
-m, 1H, H-10b), 2.53 -dd, 1H, Jˆ7.5, 9.0 Hz, H-5b), 2.47
-dd, 1H, Jˆ5.0, 15.0 Hz, H-100a), 2.44 -m, 2H, H-20a,b),
2.37 -dd, 1H, Jˆ7.5, 15.0 Hz, H-100b), 0.91 -s, 9H, t-Bu),
0.08, 0.07 -2s, 6H, SiMe2); MS -LSIMS, HR) m/z
-M1Na)1 calcd for C24H39NO6SiNa: 488.2444; found:
488.24652.
-c 0.2, CH2Cl2); IR -®lm): 3461, 1739 cm21 1H NMR
;
-CDCl3) d: 4.75, 4.44 -2d, 2H, Jˆ12.0 Hz, Bn), 4.39 -m,
1H, H-7), 4.35 -q, 1H, Jˆ6.5 Hz, H-2), 3.73 -m, 1H, H-1),
3.71 -s, 3H, OCH3), 3.36 -m, 2H, H-3,6), 3.01 -dd, 1H,
Jˆ3.5, 10.0 Hz, H-5), 2.63 -m, 1H, H-8), 2.53 -d, 1H,
Jˆ2.5 Hz, H-50), 2.35 -dd, 1H, Jˆ6.0, 9.5 Hz, H-30), 2.15
-dt, 1H, Jˆ3.0, 13.5 Hz, H-8a), 1.24 -m, 1H, H-80), 0.91 -s,
9H, t-Bu), 0.09, 0.08 -2s, 6H, SiMe2); MS -LSIMS, HR) m/z
-M1H)1 calcd for C23H38NO5Si: 436.2519; found:
436.2515.
3.1.12. -1S,2R,8aS)-1-Benzyloxy-2-tert-butyldimethyl-
siloxy-7-hydroxy-6-methoxycarbonyl-6-eno-indolizidine
-32) and -1S,2R,8aS)-1-benzyloxy-2-tert-butyldimethyl-
siloxy-7-hydroxy-8-methoxycarbonyl-7-eno-indolizidine
-33). To the solution of diisopropylamine -78 mL,
0.56 mmol) in dry THF -2 mL), cooled to 2788C under
argon n-BuLi -2.5 M in hexane, 234 mL, 0.51 mmol) was
added. After 20 min, a solution of diester 28 -0.120 g,
0.26 mmol) in THF -1 mL) was added. The mixture was
stirred at 2308C for 30 min. Then, while stirring for
15 min, temperature was allowed to rise to room tempera-
ture. Subsequently, the mixture was poured into saturated
aq. NaHCO3 and extracted with CH2Cl2 -3£10 mL).
Combined extracts were washed, dried, and evaporated.
The residue was separated by chromatography using
hexane±ethyl acetate 5:1 v/v as an eluant to afford 32
-0.072 g, 65%) and 33 -0.025 g, 22%).
3.1.14. -1S,2R,6S,7S,8aS)-7-Acetoxy-6-acetoxymethyl-1-
benzyloxy-2-tert-butyldimethylsiloxy-indolizidine -36).
Compound 34 -0.020 g, 0.04 mmol) in methanol -1.5 mL)
was treated with NaBH4 -0.012 g, 0.32 mmol). The mixture
was stirred at room temperature for 30 min and ®ltered
through Celite. Filtrate was evaporated under reduced pres-
sure and crude product 35 was acetylated using Ac2O/Py
mixture. The post-reaction mixture was evaporated and
puri®ed by chromatography to give 36 -0.016 g, 73%);
syrup, [a]Dˆ212.6 -c 0.2, CH2Cl2); IR -®lm): 1744 cm21
;
1H NMR -CDCl3) d: 4.69 -m, 1H, H-7), 4.74, 4.43 -2d, 2H,
Jˆ12.0 Hz, Bn), 4.34 -q, 1H, Jˆ6.5 Hz, H-2), 4.06 -dd, 1H,
Jˆ3.0, 11.5 Hz, H-10a), 3.98 -dd, 1H, Jˆ6.0, 11.5 Hz,
H-10b), 3.44 -t, 1H, Jˆ7.5 Hz, H-1), 3.34 -dd, 1H, Jˆ6.5,
9.5 Hz, H-3), 3.07 -dd, 1H, Jˆ10.5, 17.0 Hz, H-5), 2.34 -m,
2H, H-8,8a), 2.25 -dd, 1H, Jˆ6.0, 9.5 Hz, H-30), 2.05 -m,
2H, H-5,6), 2.05, 2.03 -s, 6H, 2Ac), 1.25 -m, 1H, H-80), 0.91
-s, 9H, t-Bu), 0.09, 0.08 -2s, 6H, SiMe2); 1H NMR -C6D6) d:
4.93 -dt, 1H, Jˆ5.0, 11.0 Hz, H-7), 4.75, 4.43 -2d, 2H,
Jˆ12.0 Hz, Bn), 4.25 -m, 1H, H-2), 4.15 -dd, 1H, Jˆ3.5,
11.5 Hz, H-10a), 4.11 -dd, 1H, Jˆ6.5, 11.5 Hz, H-10b), 3.34
-m, 1H, H-1), 3.29 -m, 1H, H-3), 2.96 -dd, 1H, Jˆ4.5,
11.0 Hz, H-5), 2.61 -ddd, 1H, Jˆ2.5, 5.0, 11.5 Hz, H-8),
2.50 -ddd, 1H, Jˆ2.5, 8.0, 11.5 Hz, H-8a), 2.30 -dd, 1H,
Jˆ5.5, 9.0 Hz, H-30), 2.20 -m, 1H, H-6), 1.93 -t, 1H,
Jˆ11.0 Hz, H-50), 1.78, 1.76 -2s, 6H, 2Ac), 1.40 -m, 1H,
H-80), 1.07 -s, 9H, t-Bu), 0.15, 0.13 -2s, 6H, SiMe2); MS
-LSIMS, HR) m/z -M1H)1 calcd for C26H42NO6Si:
492.2781; found: 492.2763. Reduction of ester 32 under
the above conditions yielded 36 -89%) directly.
Compound 32: syrup, [a]Dˆ2137.4 -c 0.7, CH2Cl2); IR
1
-®lm): 1746, 1722, 1662, 1621 cm21; H NMR -CDCl3) d:
11.98 -s, 1H, OH), 4.77, 4.47 -2d, 2H, Jˆ12.0 Hz, Bn), 4.36
-q, 1H, Jˆ6.0 Hz, H-2), 3.75 -s, 3H, OCH3), 3.60 -d, 1H,
Jˆ13.5 Hz, H-5), 3.50 -t, 1H, Jˆ7.0 Hz, H-1), 3.45 -dd, 1H,
Jˆ6.0, 10.0 Hz, H-3), 2.91 -dt, 1H, Jˆ2.0, 13.5 Hz, H-50),
2.64 -m, 1H, H-8a), 2.54 -ddd, 1H, Jˆ1.5, 4.0, 17.5 Hz,
H-8), 2.41 -dd, 1H, Jˆ5.5, 10.0 Hz, H-30), 2.23 -m, 1H,
H-8), 0.92 -s, 3H, t-Bu), 0.11, 0.10 -2s, 6H, SiMe2); MS
-LSIMS, HR) m/z -M1H)1 calcd for C23H36NO5Si:
434.2363; found: 434.2344.
Compound 33: syrup, [a]Dˆ254.4 -c 1.2, CH2Cl2); IR
1
-®lm): 1745, 1718, 1656, 1615 cm21; H NMR -CDCl3) d:
4.42 -q, 1H, Jˆ6.0 Hz, H-2), 4.74, 4.34 -2d, 2H, Jˆ11.0 Hz,
Bn), 3.66 -m, 1H, H-1), 3.57 -s, 3H, OCH3), 3.41 -dd, 1H,
Jˆ6.5, 9.5 Hz, H-3), 3.27 -m, 1H, H-8a), 3.17 -m, 1H, H-8),
3.1.15. -1S,2R,8aS)-1-Benzyloxy-2-tert-butyldimethyl-
siloxy-7-oxo-indolizidine -37). To a mixture of 32/33
-0.15 g, 0.33 mmol) dissolved in DMSO -2 mL), water

1440
J. Rabiczko et al. / Tetrahedron 58 -2002) 1433±1441
-18 mL, 0.99 mmol) and NaCl -0.030 g, 0.49 mmol) were
added. While stirring, the mixture was kept at 130±1408C
under nitrogen for 4 min. Subsequently, it was poured into
water and extracted with dichloromethane -3£10 mL). The
extracts were dried and evaporated, residue was subject to
chromatographic puri®cation using hexane±ethyl acetate
9:1 v/v as an eluant to give 37 -0.12 g, 92%); syrup,
3.1.18. -1S,2R,8aS)-1-Benzyloxy-2-hydroxy-indolizidine
-41). Compound 40 -0.20 g, 0.55 mmol) in dry THF
-5 mL) was treated with TBAF hydrate -0.21 g,
0.66 mmol) and stirred for 30 min. The mixture was poured
into water and extracted with toluene -3£10 mL). Combined
extracts were dried and evaporated. The crude product was
puri®ed by chromatography using hexane±ethyl acetate 4:1
v/v as an eluant to give 41 -0.13 g, 96%); syrup,
1
[a]Dˆ235.2 -c 0.5, CH2Cl2); IR -®lm): 1719 cm21; H
1
NMR -CDCl3) d: 4.76, 4.43 -2d, 2H, Jˆ12.0 Hz, Bn),
4.42 -q, 1H, Jˆ6.5 Hz, H-2), 3.52 -t, 1H, Jˆ7.0 Hz, H-1),
3.41 -dd, 1H, Jˆ6.5, 9.5 Hz, H-3), 3.18 -m, 1H, H-50), 2.61
-m, 2H, H-8,8a), 2.47 -m, 2H, H-6,60), 2.35 -dd, 1H, Jˆ7.0,
9.5 Hz, H-30), 2.33 -m, 1H, H-5), 2.13 -dd, 1H, Jˆ11.5,
13.5 Hz, H-80), 0.92 -s, 9H, t-Bu), 0.12, 0.10 -2s, 6H,
SiMe2); MS -LSIMS, HR) m/z -M1H)1 calcd for
C21H34NO3Si: 376.2308; found: 376.2318.
[a]Dˆ270.5 -c 0.8, CH2Cl2); IR -®lm): 3416 cm21; H
NMR -CDCl3) d: 4.67, 4.59 -2d, 2H, Jˆ11.5 Hz, Bn),
4.19 -m, 1H, H-2), 3.52 -dd, 1H, Jˆ7.0, 8.0 Hz, H-1),
3.45 -dd, 1H, Jˆ6.5, 10.0 Hz, H-3), 2.96 -m, 1H, H-5),
2.18 -dd, 1H, Jˆ5.0, 10.0 Hz, H-30), 2.03 -m, 2H,
H-50,8a), 1.93 -m, 2H, H-8), 1.78 -m, 1H, H-7), 1.62 -m,
1H, H-6), 1.47 -m, 1H, H-60), 1.21 -m, 1H, H-70,80); MS
-LSIMS, HR) m/z -M1H)1 calcd for C15H22NO2: 248.1650;
found: 248.1635.
3.1.16.
-1S,2R,7R,7aR)-7-Acetoxy-1-benzyloxy-2-tert-
butyldimethylsiloxy-indolizidine -39). Compound 37
-0.10 g, 0.27 mmol) in dry THF -2 mL) was cooled to
2788C under argon and treated with l-Selectride -810 mL,
1 M in THF, 0.81 mmol). After 1 h mixture was diluted with
THF -10 mL), treated with 3N NaOH -3 mL), 30% H2O2
-1 mL) and saturated K2CO3 -2 mL). The mixture was stir-
red for 5 min. Subsequently, organic layer was separated,
dried and evaporated. The residue was treated with acetic
anhydride±pyridine mixture 1:2 v/v -3 mL) and DMAP
-2 mg). After 4 h the mixture was poured into ice/water
and extracted with CH2Cl2. The extract was dried, evapo-
rated and puri®ed by chromatography to give 39 -0.10 g,
87%); colorless oil, [a]Dˆ253.6 -c 1.6, CH2Cl2); IR
3.1.19. -1S,2S,8aS)-1-Benzyloxy-2-hydroxy-indolizidine
-1-O-benzyl-lentiginosine) -42). A solution of Ph3P
-0.16 g, 0.60 mmol) in THF -3 mL) was treated with
DEAD -95 mL, 0.60 mmol) and stirred for 30 min at room
temperature. Subsequently, p-nitrobenzoic acid -0.10 g,
0.60 mmol) was added and, after 30 min, compound 41
-0.050 g, 0.20 mmol) in THF -1 mL) was added. The
mixture was kept at room temperature until disappearance
of the substrate -4 h) and then it was poured into saturated
aq. NaHCO3 and extracted with ethyl ether -4£10 mL).
Combined extracts were dried and evaporated. Residue
was dissolved in methanol -5 mL) and treated with K2CO3
-0.03 g, 0.22 mmol). The p-nitrobenzoate disappeared after
10 min. Reaction mixture was ®ltered through Celite,
evaporated and puri®ed by chromatography using hexane±
ethyl acetate 4:1 v/v to afford 42 -0.041 g, 82%); mp 112±
1
-®lm): 1740 cm21; H NMR -C6D6) d: 4.90 -m, 1H, H-7),
4.75, 4.41 -2d, 2H, Jˆ11.9 Hz, Bn), 4.23 -m, 1H, Jˆ5.4,
6.5, 6.6 Hz, H-2), 3.44 -dd, 1H, Jˆ6.6, 7.9 Hz, H-1), 3.25
-dd, 1H, Jˆ6.5, 9.0 Hz, H-3), 2.73 -m, 1H, H-5), 2.46 -m,
2H, H-8,8a), 2.26 -dd, 1H, Jˆ3.4, 9.0 Hz, H-30), 1.95 -m,
2H, H-50,80), 1.78 -s, 3H, OAc), 1.70 -m, 1H, H-6), 1.50 -m,
1H, H-60), 1.04, 0.12, 0.10 -3s, 15H, TBS); MS -LSIMS,
HR) m/z -M1H)1 calcd for C23H38NO4Si: 420.25701;
found: 420.25760.
1138C; [a]Dˆ236.0 -c 1.2, CH2Cl2); IR -®lm): 3143 cm21
;
1H NMR -CDCl3) d: 4.70, 4.59 -2d, 2H, Jˆ12.0 Hz, Bn),
4.07 -dd, 1H, Jˆ1.5, 6.0 Hz, H-2), 3.52 -dd, 1H, Jˆ1.5,
7.5 Hz, H-1), 2.98 -m, 1H, H-5), 2.87 -d, 1H, Jˆ10.5 Hz,
H-3), 2.53 -dd, 1H, Jˆ6.0, 10.5 Hz, H-30), 1.98 -m, 2H,
H-50,8a), 1.89 -m, 1H, H-8), 1.88 -m, 1H, H-7), 1.62 -m,
1H, H-6), 1.54 -m, 1H, H-60), 1.26 -m, 2H, H-70,80); MS
-LSIMS, HR) m/z -M1H)1 calcd for C15H22NO2: 248.1650;
found: 248.1643.
3.1.17. -1S,2R,8aS)-1-Benzyloxy-2-tert-butyldimethyl-
siloxy-indolizidine -40). Compound 37 -0.060 g,
0.16 mmol) was dissolved in DMF -2 mL), treated with
tosylhydrazine -0.060 g, 0.32 mmol) and catalytic amount
of p-TsOH -2.5 mg). The mixture was heated at 1008C
under argon for 1 h. Subsequently it was treated with
NaBH3CN -0.040 g, 0.64 mmol) and heated for additional
2 h. The mixture was then cooled to room temperature,
poured into saturated aq. NaHCO3 and extracted with
toluene -3£10 mL). The extracts were washed, dried and
evaporated. The crude product was puri®ed by chromato-
graphy using hexane±ethyl acetate 9:2 v/v as an eluant to
afford 40 -0.052 g, 89%); syrup, [a]Dˆ285.8 -c 1.2,
CH2Cl2); 1H NMR -CDCl3) d: 4.77, 4.44 -2d, 2H,
Jˆ12.0 Hz, Bn), 4.31 -dd, 1H, Jˆ6.5, 12.0 Hz, H-2), 3.42
-m, 1H, H-1), 3.34 -dd, 1H, Jˆ6.5, 9.5 Hz, H-3), 2.95 -m,
1H, H-5), 2.22 -dd, 1H, Jˆ6.0, 9.5 Hz, H-30), 2.12 -m, 2H,
H-8a), 2.05 -m, 2H, H-50), 1.96 -m, 1H, H-8), 1.77 -m, 1H,
H-7), 1.62 -m, 1H, H-6), 1.47 -m, 1H, H-60), 1.26 -m, 1H, H-
70), 1.14 -m, 1H, H-80), 0.91 -s, 9H, t-Bu), 0.10, 0.09 -2s,
6H, SiMe2); MS -LSIMS, HR) m/z -M1H)1 calcd for
C21H36NO2Si: 362.2515; found: 362.2536.
3.1.20. -1S,2S,8aS)-1,2-Dihydroxy-indolizidine, -1)-
lentiginosine -29). Compound 42 -0.10 g, 0.405 mmol) in
liquid ammonia -2 mL) was cooled to 2788C and treated
with sodium -19 mg, 0.83 mmol). Mixture was stirred for
30 min and treated with NH4Cl until disappearance of color.
Ammonia was then evaporated, residue dissolved in THF
and ®ltered through Celite. The solvent was evaporated and
residue recrystallized from ethyl acetate±hexane mixture to
yield 29 -0.05 g, 78%); mp 106±1078C, [a]Dˆ13.1 -c 0.7,
MeOH), lit.22c mp 1068C, [a]Dˆ13.0 -c 0.7, MeOH), lit.22d
mp 106±1078C, [a]Dˆ13.2 -c 0.27, MeOH), lit.22h mp
1078C; [a]Dˆ12.8 -c 0.28, MeOH). Spectral data of 29
were identical with those reported previously.22
3.1.21. -2R,3S,4R)-3-Benzyloxy-2-carbamoylmethyl-4-
hydroxy-N-tosyl-pyrrolidine -47). Compound 45 -0.15 g,
0.36 mmol) in THF -1 mL) was treated with 25% aqueous
ammonia -2 mL). The mixture was stirred overnight. Subse-
quently, it was evaporated and puri®ed on a silica gel

J. Rabiczko et al. / Tetrahedron 58 -2002) 1433±1441
1441
Compernolle, F.; Hoornaert, G. J. J. Chem. Soc., Perkin
Trans. 1 1992, 1035±1042.
column using hexane±ethyl acetate 3:2 v/v as an eluant to
give 47 -0.14 g, 88%); colorless syrup; [a]Dˆ170.0 -c 0.4,
CH2Cl2); IR -®lm): 3455, 3361, 1667, 1598 cm21; 1H NMR
-CDCl3) d: 5.97, 5.61 -2Bs, 2H, NH2), 4.60, 4.51 -2d, 2H,
Jˆ11.5 Hz, Bn), 4.18 -m, 1H, H-4), 3.89 -dd, 1H, Jˆ4.6,
8.9 Hz, H-2), 3.70 -dd, 1H, Jˆ4.6, 7.4 Hz, H-3), 3.45 -dd,
1H, Jˆ3.7, 11.5 Hz, H-5a), 3.25 -dd, 1H, Jˆ5.3, 11.5 Hz,
H-5b), 2.94 -s, 1H, H-1a), 2.92 -d, 1H, Jˆ2.1 Hz, H-10b),
2.43 -s, 3H, Ts); MS -LSIMS, HR) m/z -M1H)1 calcd for
C20H25N2O5: 405.1484; found: 405.1486.
12. Deshmukh, M. N.; Gangakhedkar, K. K.; Kumar, U. S. Synth.
Commun. 1996, 26, 1657±1661.
13. Denmark, S. E.; Forbes, D. C.; Hays, D. S.; DePue, J. S.;
Wilde, R. G. J. Org. Chem. 1995, 60, 1391±1407. Barbour,
R. H.; Robins, D. J. J. Chem. Soc., Perkin Trans. 1 1985,
2475±2478.
14. Chauvin, A.; Fabron, J.; Yahia, M. O. A.; Pastor, R.; Cambon,
A. Tetrahedron 1990, 46, 6705±6714.
15. Makosza, M.; Nieczypor, P.; Grela, K. Tetrahedron 1998, 54,
10827±10836.
3.1.22.
-2R,3S,4R)-3,4-O-Isopropylidene-2-methoxy-
methoxycarbonylmethyl-pyrrolidine -48). Compound 47
-0.09 g, 0.22 mmol) in THF -1 mL) was cooled to 2788C
and treated with sodium -0.05 g, 2.2 mmol) in liquid
ammonia -10 mL). The mixture was stirred at 2308C for
30 min. Subsequently, it was treated with NH4Cl until
disappearance of the color. Ammonia was evaporated,
residue dissolved in THF -5 mL) and treated with 2,2-
dimethoxypropane -31 mL, 0.31 mmol) and 10% solution
of HCl in methanol -3 mL). The mixture was stirred for
24 h. Subsequently the mixture was evaporated and puri®ed
by chromatography using hexane±ethyl acetate 1:4 v/v as
an eluant to afford 48 -0.043 g, 89%); colorless syrup;
[a]Dˆ230.6 -c 1.0, CH2Cl2); IR -®lm): 3356, 1668,
16. -a) Suzuki, T.; Sato, E.; Unno, K.; Kametani, T. J. Chem. Soc.,
Perkin Trans. 1 1986, 2263±2268. -b) Chenera, B.; Chuang,
Ch.-P.; Hart, D. J.; Loi, Ch.-S. J. Org. Chem. 1992, 57, 2018±
2029. -c) Suemune, H.; Maeda, K.; Kato, K.; Sakai, K.
J. Chem. Soc., Perkin Trans. 1 1994, 3441±3448.
17. Imamoto, T.; Kodera, M.; Yokoyama, M. Synthesis 1982,
134±136.
18. Bhide, R.; Mortezaei, R.; Scilimati, A.; Sih, C. J. Tetrahedron
Lett. 1990, 31, 4827±4830.
19. Pastuszak, I.; Molyneux Russel, J.; James, L. F.; Elbein, A. D.
Biochemistry 1990, 29, 1886±1891.
20. Harris, T. M.; Harris, C. M.; Hill, J. E.; Ungemach, F. S.;
Broquist, H. p.; Wickwire, B. M. J. Org. Chem. 1987, 52,
3094±3098.
1
1575 cm21; H NMR -CDCl3) d: 4.69 -dd, 1H, Jˆ4.1,
5.6 Hz, H-3), 4.61 -m, 1H, H-4), 3.67 -s, 3H, OMe), 3.03
-m, 1H, H-2), 2.99 -d, 1H, Jˆ13.4 Hz, H-10a), 2.69 -dd, 1H,
Jˆ7.4, 16.4 Hz, H-5a), 2.61 -dd, 1H, Jˆ3.9, 13.4 Hz,
H-10b), 2.58 -dd, 1H, Jˆ6.4, 16.4 Hz, H-5b), 1.27, 1.41
-2s, 6H, CMe2); MS-ESI-TOF, HR) m/z -M1H)1 calcd
for C10H18NO4: 216.1221; found: 216.1245.
21. Goti, A.; Cardona, F.; Brandi, A.; Picasso, S.; Vogel, P.
Tetrahedron: Asymmetry 1996, 7, 1659±1674.
22. -a) Yoda, H.; Kitayama, H.; Katagiri, T.; Takabe, K.
Tetrahedron: Asymmetry 1993, 4, 1455±1456. -b) Yoda, H.;
Kawanchi, M.; Takabe, K. Synlett 1998, 137±138. -c) Ha,
D.-C.; Yun, C.-S.; Lee, Y. J. Org. Chem. 2000, 65, 621±
623. -d) Cordero, F.; Cicchi, S.; Goti, A.; Brandi, A.
Tetrahedron Lett. 1994, 35, 949±952. -e) Brandi, A.; Cicchi,
S.; Cordero, F. M.; Frignoli, R.; Goti, A.; Picasso, S.; Vogel, P.
J. Org. Chem. 1995, 60, 6806±6812. -f) Goti, A.; Cardona, F.;
Brandi, A. Synlett 1996, 761±763. -g) McCaig, A. E.;
Meldrum, K. P.; Wightman, R. H. Tetrahedron 1998, 54,
9429±9446. -h) Giovannini, R.; Marcantoni, E.; Petrini, M.
J. Org. Chem. 1995, 60, 5706±5707. -i) Gurjar, M. K.; Ghosh,
L.; Syamalu, M.; Jayasree, V. Tetrahedron Lett. 1994, 35,
8872±8875. -j) Nukui, S.; Sodecka, M.; Sasai, H.; Shibasaki,
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Acknowledgements
The authors wish to thank the State Committee for Scienti®c
Research, Grant 7 T09A 022 21 for support of this work.
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