Synthesis of polyhydroxyindolizidines from 5,6-dihydro-2H-pyran-2-one

Article abstract of DOI:10.1016/S0008-6215(01)00265-8

(1aR,5aR,5bS,6S,7S)-6,7-Di-tert-butoxy-5-oxo-pyrrolidino[1,2-b]isoxazolidino [4,5-c]tetrahydropyran (8) prepared by (1,3)-dipolar cycloaddition of the cyclic nitrone 6 derived from tartaric acid to 5,6-dihydro-2H-pyran-2-one (7) was transformed into indolizidine 11 via a sequence of reactions involving methanolysis of the lactone ring, intramolecular alkylation of the nitrogen atom promoted by a carbontetrabromide-triphenylphosphine mixture and hydrogenolysis of the N-O bond. Decarboxylation of 11 provided known 7-hydroxylentiginosine derivative 14, whereas oxidative decarboxylation gave indolizidine 15 structurally related to castanospermine.

Full text of DOI:10.1016/S0008-6215(01)00265-8

Carbohydrate Research 336 (2001) 315–318
www.elsevier.com/locate/carres
Note
Synthesis of polyhydroxyindolizidines from
5,6-dihydro-2H-pyran-2-one
Dariusz Socha, Margarita Jurczak, Marek Chmielewski*
Institute of Organic Chemistry of the Polish Academy of Sciences, PL-01-224 Warsaw, Poland
Received 16 August 2001; accepted 5 October 2001
Abstract
(1aR,5aR,5bS,6S,7S)-6,7-Di-tert-butoxy-5-oxo-pyrrolidino[1,2-b]isoxazolidino[4,5-c]tetrahydropyran (8) prepared
by (1,3)-dipolar cycloaddition of the cyclic nitrone 6 derived from tartaric acid to 5,6-dihydro-2H-pyran-2-one (7)
was transformed into indolizidine 11 via a sequence of reactions involving methanolysis of the lactone ring,
intramolecular alkylation of the nitrogen atom promoted by a carbontetrabromide–triphenylphosphine mixture and
hydrogenolysis of the NꢀO bond. Decarboxylation of 11 provided known 7-hydroxylentiginosine derivative 14,
whereas oxidative decarboxylation gave indolizidine 15 structurally related to castanospermine. © 2001 Elsevier
Science Ltd. All rights reserved.
Keywords: 1,3-Dipolar cycloaddition; (3S)-tert-Butoxy-1-pyrroline N-oxide; 7-Hydroxylentiginosine
Owing to a wide range of biological appli-
cations, iminosugars such as castanospermine
(1),1 swainsonine (2)2 and lentiginosine (3)3
become attractive synthetic targets for many
laboratories (Scheme 1).4
It has been shown that (1,3)-dipolar cy-
cloaddition of cyclic nitrones 4–65 derived
from tartaric acid to olefins offers a particu-
larly attractive entry to indolizidines such as
lentiginosine (3) and its derivatives.4,6
Recently we have reported on highly effec-
tive cycloaddition of the nitrone 6 to 5,6-dihy-
dro-2H-pyran-2-one (7).7 The reaction
proceeds exclusively via the exo approach of
the dipole to the re–re side of the lactone to
afford adduct 8 in 91% yield (Scheme 2).
The strategy of the indolizidine synthesis via
nitrones 4–6 has been reported by Brandi’s6c
and Wightman’s6d groups. As substrates, 3-
buten-1-ol6c and benzyl 3-butenoate6d have
been used, respectively. The high effectiveness
of (1,3)-dipolar cycloaddition of 6 to 7, higher
than those reported previously6c,6d, prompted
us to examine transformation of the adduct 8
into selected indolizidines (Scheme 2).
Scheme 1.
The lactone ring in 8 can be easily opened
in methanol in the presence of anhydrous
K2CO3 to afford hydroxyester 9 in 53% yield
whereas unreacted 8 (34%) was recovered.
* Corresponding author. Tel.: +48-22-6323789; fax: +48-
22-6326681.
E-mail address: chmiel@icho.edu.pl (M. Chmielewski).
0008-6215/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(01)00265-8

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D. Socha et al. / Carbohydrate Research 336 (2001) 315–318
acid 12, readily available by saponification of
11 with lithium hydroxide, was transformed
into ester 13 which in situ was decarboxylated
under argon using t-butylmercaptan to afford
14 in 64% yield. The use of tributyltin hydride
as a free radical promotor in the same reac-
tion gave a worse result. Compound 14 has
been transformed in the past by Brandi’s
group into lentiginosine 36c by deoxygenation
at C-7 and deprotection of t-butyl ethers or
into 7-hydroxylentiginosine 166c,8 by deprotec-
tion of t-butyl ethers (Scheme 4).
Scheme 2.
Decarboxylation of compound 13 with t-
butylmerkaptan, performed in the presence of
air, led to the introduction of a hydroxy func-
tion to the C-8 carbon atom in 40% yield.
Owing to sterical preferences, formation of
compound 15 proceeds with retention of
configuration at C-8. Compound 15 depro-
tected with trifluoroacetic acid provides in-
dolizidine 17 which was characterized as
tetraacetate 18 (Scheme 4).
Scheme 3.
In summary, we reported a formal, highly
stereoselective approach to lentiginosine 3,
and to 7-hydroxylentiginosine 16. We de-
scribed also the synthesis of indolizidine 17
which is a structural isomer of castanosper-
mine 1.
Scheme 4.
The terminal hydroxy group in 9, similar to
the Brandi’s6c approach, may be used for in-
tramolecular alkylation of the nitrogen atom.
An attempt to introduce a bromine atom of
the hydroxy group using the carbontetra-
bromide–triphenylphosphine procedure gave
a tricyclic ammonium salt 10 which, without
isolation, was subjected to hydrogenolysis of
the NꢀO bond to yield indolizidine 11
(Scheme 3).
Compound 11 has at C-1, -2, -7 and -8a
carbon atoms configurations of known 7-hy-
droxylentiginosine 16.6c,8 The additional
methoxycarbonyl function at C-8 can be re-
moved by decarboxylation, or oxidatively de-
carboxylated in order to introduce a new
hydroxy group.
We investigated several classical decarboxy-
lation conditions of free acid 12.9 Due to the
presence of the hydroxy group in the b-posi-
tion, significant decomposition of the sub-
strate was noticed. The best result was
obtained by application of Barton’s N-hy-
droxy-thiopyrolidinone methodology.10 Free
1. Experimental
1H NMR spectra were recorded on a
Brucker DRX 500 Avance Spectrometer. IR
spectra were obtained on an FT-IR-1600
Perkin–Elmer spectrophotometer. Rotations
were measured with a JASCO P 3010 digital
polarimeter. Mass spectra were determined
with AMD 604 Inectra GmbH and PerSeptive
Biosystems Mariner spectrometers. Column
chromatography was performed on E. Merck
Silica Gel 230–400 mesh.
Nitrone 6 was obtained by the known pro-
cedure.5a Synthesis of 8 has been described
earlier.7
(2R,3R,3aS,4S,5S)-4,5-Bis-tert-butoxy-2-
(2% - hydroxyethyl) - 3 - methoxycarbonyl - hexa-
hydropyrrolo[1,2-b]isoxazole (9).—A solution
of lactone 8 (0.68 g, 2.08 mmol) in dry MeOH
(20 mL) was treated with anhyd K2CO3 (0.14
g, 1.04 mmol) at rt and stirred. The progress

D. Socha et al. / Carbohydrate Research 336 (2001) 315–318
317
(1S,2S,7R,8R,8aS)-1,2-Bis-tert-butoxy-8-
carboxy-7-hydroxy-indolizidine (12).—To a
stirred solution of ester 11 (0.18 g, 0.53 mmol)
in a mixture 3:1 THF–water (5 mL) was
added LiOH (0.33 g, 0.8 mmol). The resulting
reaction mixture was stirred at rt for 24 h.
Subsequently the solution was diluted with
mixture 1:1 THF–MeOH (15 mL), filtered
with Florisil while free carboxylic acid was
liberated, dried over MgSO4 and evaporated.
The residue was purified by chromatography
to afford 12 (0.15 g, 89%); colorless oil; [h]D
+38.0° (c 1.0, CHCl3); IR (film): 3348, 1596
of the reaction was monitored by TLC. When
ca. 2/3 of the substrate was converted into 9 (2
h), the mixture was diluted with CH2Cl2 (100
mL) and filtered through Celite. Subsequently
the filtrate was washed with 1 M aq NaHSO4
(15 mL) and brine, dried and concentrated.
Chromatographical
purification
afforded
methyl ester 9 (0.4 g, 53% yield) and recovered
lactone 8 (0.23 g, 34%). Compound 9: color-
less oil; [h]D +86.9° (c 1.0, CHCl3); IR (film):
1
3441, 1739 cm−1; H NMR (CDCl3): l 4.60
(dt, 1 H, H-2), 3.91 (dd, 1 H, J3,3a 5.7, J3a,4 3.1
Hz, H-3a), 3.89 (m, 1 H, H-5), 3.83 (bt, 1 H,
H-4), 3.79–3.72 (m, 1 H, H-2%a,2%b), 3.73 (s, 3
H, OCH3), 3.52 (dd, 1 H, J2,3 7.3 Hz, H-3),
3.50 (dd, 1 H, J5,6a 5.4, J6a,6b 11.9 Hz, H-6a),
2.95 (dd, 1 H, J5,6b 5.7 Hz, H-6b); 13C NMR
(CDCl3): l 171.42, 80.96, 76.83, 76.61, 74.21,
74.05, 73.43, 60.75, 60.40, 56.23, 51.99, 32.25,
28.55, 28.39; EI/HR MS: m/z: 382.2210,
1
cm−1; H NMR (Py-d5): l 4.45–4.30 (bm, 2
H, H-1,H-7), 4.06 (dt, 1 H, H-2), 3.02 (dd, 1
H, J2,3 3.1, J3,3% 9.8 Hz, H-3), 3.02–2.93 (bm, 2
H, H-8,8a), 2.89 (t, 1 H, J2,3% 9.6 Hz, H-3%),
2.80 (bs, 1 H, H-5), 2.49 (bt, 1 H, H-5%), 1.98
(bm, 1 H, H-6), 1.91 (m, 1 H, H-6%), 1.32, 1.18
(2s, 18 H, 2 t-Bu). ESI/HR MS: m/z:
330.2278, [M+H]+; Calcd for C17H32NO5:
330.2275.
[M+Na]+;
382.2200.
Calcd
for
C18H33NNaO6:
(1S,2S,7R,8aS) - 1,2 - Bis - tert - butoxy - 7-
hydroxy-indolizidine (14).—A solution of acid
12 (40 mg, 0.12 mmol) in MeCN (4 mL) was
treated with N-hydroxy-pyridin-2-thione (18
mg, 0.14 mmol), DCC (29 mg, 0.14 mmol)
and DMAP (17 mg, 0.14 mmol) and stirred at
50 °C under an Ar atmosphere. After disap-
pearance of the substrate (about 2 h) the
reaction mixture was subjected to reduction
by tert-butylthiol. To the reaction mixture
was added tert-butylthiol (40 mL, 0.36 mmol)
and the mixture was stirred for 1 h at 50 °C
under an Ar atmosphere. Subsequently, it was
evaporated to dryness. The crude product was
purified by chromatography to give 14 (22 mg,
64% yield); mp=117–119 °C, lit.8 118–
119 °C; [h]D +49.7° (c 0.45, CHCl3), lit.8 [h]D
(1S,2S,7R,8R,8aS)-1,2-Bis-tert-butoxy-7-
hydroxy-8-methoxycarbonyl-indolizidine (11).
—Compound 9 (0.30 g, 0.84 mmol) in dry
pyridine (8 mL) was treated with
triphenylphosphine (0.44 g, 1.67 mmol) and
carbon tetrabromide (0.29 g, 0.87 mmol). The
mixture was stirred at rt until disappearance
of the substrate (3 h), then evaporated to
dryness, dissolved in MeOH (10 mL) and
shaken under hydrogen (70 psi) for 2 h in the
presence of Pd(OH)2–C. Subsequently the
suspension was filtered and concentrated. The
crude product was purified by chromatogra-
phy to give 11 (0.21 g, 72%); colorless oil; [h]D
+22.2° (c 1.0, CHCl3); IR (film): 3443, 1739
1
cm−1; H NMR (CDCl3): l 3.91 (dt, 1 H, J1,2
+53.0° (c 1.05, CHCl3); IR (film): 3391 cm−1
;
3.0, J2,3 2.7, J2,3% 6.9 Hz, H-2), 3.85 (dd, 1 H,
J1,8a 4.8 Hz, H-1), 3.81 (m, 1 H, H-7), 3.74 (s,
3 H, OCH3), 2.95 (ddd, 1 H, J5,6 2.4, J5,6% 4.2,
J5,5% 12.3 Hz, H-5), 2.90 (dd, 1 H, J3,3% 9.9 Hz,
H-3), 2.69 (dd, 1 H, H-3%), 2.49–2.43 (m, 2 H,
H-8,8a), 2.34 (dd, 1 H, J5%,6 2.9, J5%,6% 12.5 Hz,
H-5%), 1.83 (m, 1 H, H-6), 1.68 (dt, 1 H, J6%,7
11.7, J6,6% 12.5 Hz, H-6%), 1.19, 1.18 (2s, 18 H,
2 t-Bu); 13C NMR (CDCl3): l 173.26, 83.22,
78.32, 74.23, 73.81, 72.01, 66.68, 58.56, 52.63,
51.58, 48.47, 31.02, 28.94, 28.83; ESI/HR MS:
m/z: 366.2258, [M+Na]+; Calcd for
C18H33NNaO5: 366.2251.
1H NMR (CDCl3): l 3.84 (ddd, 1 H, J1,2 4.0,
J2,3 1.7, J2,3% 7.2 Hz, H-2), 3.67 (dd, 1 H, J1,8a
8.5 Hz, H-1), 3.59 (m, 1 H, H-7), 2.93 (m, 1
H, H-5), 2.90 (dd, 1 H, J3,3% 10.0 Hz, H-3),
2.43 (dd, 1 H, H-3%), 2.19 (m, 1 H, H-8), 1.97
(m, 1 H, H-5%), 1.87 (m, 1 H, H-6), 1.82 (m, 1
H, H-8a), 1.61 (m, 1 H, H-6%), 1.28 (bq, 1 H,
H-8); 13C NMR (CDCl3): l 83.24, 77.97,
73.85, 73.68, 69.82, 65.40, 61.16, 50.57, 37.97,
34.26, 29.25, 28.71; ESI/HR MS: m/z:
286.2382, [M+H]+; Calcd for C16H32NO3:
286.2395.

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D. Socha et al. / Carbohydrate Research 336 (2001) 315–318
1
cm−1; H NMR (CDCl3): l 5.17 (dd, 1 H, J1,2
(1S,2S,7R,8R,8aS) - 1,2 - Bis - tert - butoxy-
2.2, J1,8a 7.1 Hz, H-1), 5.08 (t, 1 H, J7,8 9.4,
J8,8a 9.6 Hz, H-8), 5.02 (ddd, 1 H, J2,3 1.0, J2,3%
6.3 Hz, H-2), 4.80 (ddd, 1 H, J6,7 5.3, J6%,7 11.5
Hz, H-7), 3.02 (bd, 1 H, H-3), 2.99 (ddd, 1 H,
J5,6 2.4, J5,6% 4.7, J5,5% 11.5 Hz, H-5), 2.75 (dd, 1
H, J3,3% 11.0 Hz, H-3%), 2.30 (dd, 1 H, H-8a),
2.22 (ddd, 1 H, J5%,6 2.8, J5%,6% 12.5 Hz, H-5%),
2.06 (m, 1 H, H-6), 1.81 (m, 1 H, J6,6% 11.5 Hz,
H-6%), 2.09, 2.03, 2.02, 1.98 (4s, 12 H, 4 Ac);
ESI/HR MS: m/z: 380.1307, [M+Na]+;
Calcd for C16H23NNaO8: 380.1316.
7,8-dihydroxy-indolizidine (15).—A solution
of acid 12 (40 mg, 0.12 mmol) in MeCN (4
mL) was treated with N-hydroxy-pyridin-2-
thione (18 mg, 0.14 mmol), DCC (29 mg, 0.14
mmol) and DMAP (17 mg, 0.14 mmol) and
stirred at 50 °C. After disappearance of the
substrate (about 2 h) the reaction mixture was
subjected to reduction by tert-butylthiol. To
the reaction mixture was added tert-butylthiol
(40 mL, 0.36 mmol) and the mixture was
stirred for 1 h at 50 °C. Subsequently it was
evaporated to dryness. The crude product was
purified by chromatography to give 15 (14 mg,
39% yield); mp=133–135 °C, [h]D +29.0° (c
Acknowledgements
1
0.5, CHCl3); IR (film): 3411 cm−1; H NMR
The authors wish to thank the State Com-
mittee for Scientific Research, Grant 7 T09A
022 21 for support of this work and Professor
Alberto Brandi for scientific discussion.
(CDCl3): l 4.01 (dd, 1 H, J1,2 3.9, J1,8a 7.9 Hz,
H-1), 3.89 (ddd, 1 H, J2,3 2.1, J2,3% 7.0 Hz,
H-2), 3.50 (t, 1 H, J7,8 8.4, J8,8a 8.9 Hz, H-8),
3.42 (ddd, 1 H, J7,6 4.8, J7,6% 11.2 Hz, H-7),
2.96 (dd, 1 H, J3,3% 10.0 Hz, H-3), 2.87 (m, 1
H, H-5), 2.74 (bs, 1 H, H-8a), 2.54 (dd, 1 H,
H-3%), 2.09 (bt, 1 H, H-5%), 1.87 (m, 1 H, H-6),
1.70 (tdd, 1 H, J5,6% 4.5, J3%,6% 12.5, J6,6% 12.5 Hz,
H-6%), 1.29, 1.19 (2s, 18 H, 2 t-Bu); ESI/HR
MS: m/z: 324.2104, [M+Na]+; Calcd for
C16H31NNaO4: 324.21457. Acetate: colorless
oil; [h]D +3.5° (c 0.3, CHCl3); IR (film): 1740
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cm−1; H NMR (CDCl3): l 5.14 (t, 1 H, J7,8
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(1S,2S,7R,8R,8aS) 1,2,7,8-Tetraacetoxy-
indolizidine (18).—A solution of indolizidine
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with 1:1 Ac2O–pyridine mixture in the pres-
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quently the mixture was evaporated and the
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give 18 (5.5 mg, 66%); colorless syrup; [h]D
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