Total synthesis of (+)-hyacinthacine A2 based on SmI 2-induced nitrone umpolung

Article abstract of DOI:10.1021/jo048237r

(Chemical Equation Presented) A concise total synthesis of (+)-hyacinthacine A₂, a polyhydroxylated pyrrolizidine alkaloid, is described using our recently discovered inversion of the C-N bond polarity in nitrones. In the key step, the diastere

Full text of DOI:10.1021/jo048237r

SCHEME 1. Retrosynthetic Approach to
Polyhydroxylated Pyrrolizidines
Total Synthesis of (+)-Hyacinthacine A2
Based on SmI2-Induced Nitrone Umpolung
Ste´phanie Desvergnes, Sandrine Py,*
and Yannick Valle´e
LEDSS, UMR 5616 CNRS Institut de Chimie Mole´culaire
de Grenoble - FR 2607 Universite´ Joseph Fourier,
B.P. 53, 38041 Grenoble, France
sandrine.py@ujf-grenoble.fr
Received October 7, 2004
We have recently described the first samarium diio-
dide-induced umpolung of nitrones, which become able
to undergo reductive coupling with carbonyl derivatives6
and R,â-unsaturated esters.7 The latter methodology
opens a direct route to γ-N-hydroxylamino esters. As in
principle γ-lactams should be easily obtained from the
corresponding γ-N-hydroxylamino esters, we became
interested in using sugar-derived cyclic nitrones to
develop a new access to functionalized pyrrolizidines,
following the retrosynthetic approach outlined in Scheme
1. Our strategy relied on the assembly of the sugar-
derived A-ring of pyrrolizidines (including the nitrogen
atom) with the three carbons necessary to complete
B-ring formation, in a tandem process. Although it could
be anticipated that in the key step the chain would be
introduced preferentially on the less hindered R-face, the
stereochemical outcome of this still uninvestigated reac-
tion was of interest.8 Depending on the selectivity of the
reductive coupling step, a new route to either alexines
or hyacinthacines would be designed.
A concise total synthesis of (+)-hyacinthacine A2, a polyhy-
droxylated pyrrolizidine alkaloid, is described using our
recently discovered inversion of the C-N bond polarity in
nitrones. In the key step, the diastereoselective reductive
coupling of a L-xylose-derived cyclic nitrone with ethyl
acrylate allowed the assembly of the bicyclic core of the
target molecule, by way of a tandem formation of the C-C
and C-N bonds. The method opens a novel, short, and
general route for the synthesis of other pyrrolizidine alka-
loids.
While 7-deoxyalexine (1)9 is a synthetic product for
which biological activity has not been investigated yet,
hyacinthacine A2 (2) is a representative member of the
Owing to the importance of carbohydrate processing
enzymes in pathologies such as diabetes, cancer, or AIDS,
selective inhibition of these enzymes represents a prom-
ising therapeutic strategy.1 Iminosugars have rapidly
emerged as candidates of choice for inhibiting both
glycosidases2 and glycosyltransferases.3 In particular, a
great deal of attention has been focused on their bicyclic,
conformationally constrained analogues, which often
exhibit better selectivity toward specific enzymes.2 As the
natural polyhydroxylated pyrrolizidines and their syn-
thetic analogues are part of this class of potential
inhibitors, many synthetic efforts have been directed
toward their preparation.4,5 However, most of the re-
ported methodologies are lengthy and/or lead to low
selectivity.
(4) For recent reviews on isolation and chemistry of polyhydroxyl-
ated pyrrolizidines, see: (a) Casiraghi, G.; Zanardi, F.; Rassu, G.;
Pinna, L. Org. Prep. Proc. Int. 1996, 28, 643-682. (b) Liddell, J. R.
Nat. Prod. Rep. 2001, 18, 441-447. (c) Yoda, H. Curr. Org. Chem. 2002,
6, 223-243. See also ref 2c.
(5) For selected examples of stereoselective syntheses, see: (a) Ikota,
N.; Nakagawa, H.; Ohno, S.; Nogushi, K.; Okuyama, K. Tetrahedron
1998, 54, 8985-8998. (b) Denmark, S. E.; Hurd, A. R. J. Org. Chem.
2000, 65, 2875-2886. (c) Denmark, S. E.; Herbert, B. J. Org. Chem.
2000, 65, 2887-2896. (d) Pearson, W. H.; Hines, J. V. J. Org. Chem.
2000, 65, 5785-5793. (e) Yoda, H.; Katoh, H.; Takabe, K. Tetrahedron
Lett. 2000, 41, 7661-7665. (f) Romero, A.; Wong, C.-H. J. Org. Chem.
2000, 65, 8264-8268. (g) White, J. D.; Hrnciar, P. J. Org. Chem. 2000,
65, 9129-9142. (h) Goti, A.; Cicchi, S.; Cacciarini, M.; Cardona, F.;
Fedi, V.; Brandi, A. Eur. J. Org. Chem. 2000, 3633-3645. (i) Denmark,
S. E.; Cottell, J. J. J. Org. Chem. 2001, 66, 4276-4284. (j) Goti, A.;
Cacciarini, M.; Cardona, F.; Cordero, F. M.; Brandi, A. Org. Lett. 2001,
3, 1367-1369. (k) Izquierdo, I.; Plaza, M. T.; Franco, F. Tetrahedron:
Asymmetry 2002, 13, 1581-1585.
(1) (a) Goss, P. E.; Baker, M. A.; Carver, J. P.; Dennis, J. W. Clin.
Cancer Res. 1995, 1, 935-944. (b) Jung, K.-H.; Schmidt, R. R.
Carbohydrate-Based Drug Discovery; Wong, C.-H., Ed.; John Wiley and
Sons: New York, 2003; pp 609-659.
(2) (a) Stu¨tz, A. E. Iminosugars as Glycosidase Inhibitors: Nojiri-
mycin and Beyond; Wiley-VCH: Weinheim, 1999. (b) Heightman, T.
D.; Vasella, A. T. Angew. Chem., Int. Ed. 1999, 38, 750-770. (c) Asano,
N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron:
Asymmetry 2000, 11, 1645-1680.
(3) Compain, P.; Martin, O. R. Curr. Top. Med. Chem. 2003, 3, 541-
560.
(6) Masson, G.; Py, S.; Valle´e, Y. Angew. Chem., Int. Ed. 2002, 41,
1772-1775.
(7) (a) Masson, G.; Cividino, P.; Py, S.; Valle´e, Y. Angew. Chem.,
Int. Ed. 2003, 42, 2265-2268. (b) Riber, D.; Skrydstrup, T. Org. Lett.
2003, 5, 229-231.
(8) For a previous example of diastereoselective reductive coupling
involving an R-alkoxy nitrone see: Masson, G.; Zeghida, W.; Cividino,
P.; Py, S.; Valle´e, Y. Synlett 2003, 1527-1529.
(9) (a) Yoda, H.; Asai, F.; Takabe, K. Synlett 2000, 1001-1003. (b)
Izquierdo, I.; Plaza, M. T.; Robles, R.; Franco, F. Tetrahedron: Asym-
metry 2001, 12, 2481-2487.
10.1021/jo048237r CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/19/2005
J. Org. Chem. 2005, 70, 1459-1462
1459

SCHEME 2
natural pyrrolizidine alkaloids family. It was isolated
from the bulbs of Muscari armeniacum (Hyacinthaceae)10
and exhibits selective inhibition of amyloglucosidase from
Aspergillus niger (IC50 8.6 µM). The first synthesis of
hyacinthacine A2 was accomplished in 2001.11 Then two
other syntheses appeared in the literature during the
course of our work,12 and yet another approach targeted
an advanced synthetic intermediate to hyacinthacine
A2.13 The synthetic strategies by the groups of Goti12a and
Tamura13 also involved a cyclic sugar-derived nitrone as
the key intermediate that was used in a 1,3-dipolar
cycloaddition process.
syloxy oxime 5 with tetrabutylammonium triphenyldif-
luorosilicate (TBAT)18 often led to substantial amounts
of unprotected oxime 6 as a side product, even when
using freshly opened bottles of TBAT or previously dried
material (P2O5, desiccator). Next, we found that heating
(methanol reflux) the mesyloxy oxime 6 in the presence
of hydroxylamine hydrochloride and sodium hydrogen
carbonate offered better results in terms of yields and
reproducibility and led to nitrone 7 as a white, crystalline
product, in 92% yield (Scheme 2).
19
This nitrone was then treated with SmI2 and ethyl
acrylate in THF at -78 °C, in the presence of water,
under conditions previously optimized for the reductive
coupling of nitrones with R,â-unsaturated esters.7a Under
these conditions, the expected N-hydroxypyrrolidine 8
was smoothly obtained, in 64% yield and with good
stereoselectivity (dr ) 90:10). Considering the well-
known propensity of N-hydroxylamines to be reduced to
amines in the presence of SmI2,20 we next thought to
prepare pyrrolizidinone 10 in a single step. Thus, when
TLC control showed total consumption of the starting
nitrone (ca. 3 h), excess SmI2 was added to the reaction
mixture, which was then warmed to room temperature.
Under these conditions, a mixture of amine 9 and lactam
10 was obtained, in variable proportions. Treating the
crude mixture with potassium carbonate in EtOH/H2O
induced total conversion of 9 to 10 which, after purifica-
tion by chromatography, was isolated in 59% overall
yield.
Herein, we wish to highlight a novel aspect of the
reactivity of such nitrones in the presence of SmI2, i.e.,
their ability to be transformed into R-azanucleophilic
species.
Our synthesis started with the preparation of nitrone
7
12a,14 from L-xylose, an unnatural but not too expensive
sugar. Thus, 2,3,5-tri-O-benzyl-L-xylofuranose15 was se-
quentially reacted with O-tert-butyldiphenylsilylhydroxyl-
amine16 and then with mesyl chloride, with the aim of
using Tamura’s method for selective cyclization of γ-me-
syloxy oximes.13,17 However, in our hands this method
proved poorly reproducible, and treatment of the γ-me-
(10) Asano, N.; Kuroi, H.; Ikeda, K.; Kizu, H.; Kameda, Y.; Kato,
A.; Adachi, I.; Watson, A. A.; Nash, R. J.; Fleet, G. W. J. Tetrahedron:
Asymmetry 2000, 11, 1-8.
(11) Rambaud, L.; Compain, P.; Martin, O. R. Tetrahedron: Asym-
metry 2001, 12, 1807-1809.
(12) (a) Cardona, F.; Faggi, E.; Liguori, F.; Cacciarini, M.; Goti, A.
Tetrahedron Lett. 2003, 44, 2315-2318. (b) Izquierdo, I.; Plaza, M. T.;
Franco, F. Tetrahedron: Asymmetry 2003, 14, 3933-3935.
(13) Toyao, A.; Tamura, O.; Takagi, H.; Ishibashi, H. Synlett 2003,
35-39.
(17) Tamura, O.; Toyao, A.; Ishibashi, H. Synlett 2002, 1344-1346.
(18) Pilcher, A. S.; DeShong, P. J. Org. Chem. 1996, 61, 6901-6905.
(19) (a) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc.
1980, 102, 2693-2698. (b) Kagan, H. B. Tetrahedron 2003, 59, 10351-
10372. (c) Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. Rev. 2004,
104, 3371-3403. (d) In this work 0.1 M solutions of SmI2 in THF were
prepared as described in: Curran, D. P.; Zhang, W.; Dowd, P.
Tetrahedron 1997, 53, 9023-9042.
(14) Carmona, A. T.; Wightman, R. H.; Robina, I.; Vogel, P. Helv.
Chim. Acta 2003, 86, 3066-3073.
(15) Behr, J.-B.; Erard, A.; Guillerm, G. Eur. J. Org. Chem. 2002,
1256-1262.
(16) Battaro, J.; Bedford, C. D.; Dodge, A. Synth. Commun. 1985,
15, 1333-1335.
(20) Kende, A. S.; Mendoza, J. S. Tetrahedron Lett. 1991, 32, 1699-
1702.
1460 J. Org. Chem., Vol. 70, No. 4, 2005

MgSO4 (3.7 g) under argon. The suspension was stirred at reflux
temperature for 5 min, and then O-tert-butyldiphenylsilylhy-
droxylamine (3.1 g, 11.42 mmol) and pyridinium p-toluene-
sulfonate (60 mg) were added. The reaction mixture was heated
at the same temperature for 30 min, and then it was filtered.
The filtrate was washed with a saturated aqueous solution of
NaHCO3 and with brine and dried over MgSO4 to give a residue,
which upon column chromatography over silica gel (pentane/
AcOEt 9/1, 4/1, then 1/1) yielded the oxime 4 (4.05 g, 79%) as
an oil: 1H NMR (CDCl3) δ 1.10 (s, 9H), 2.41 (d, 1H, J ) 6.5 Hz),
3.39 (d, 2H, J ) 6 Hz), 3.71 (dd, 1H, J ) 3, 6 Hz), 3.95-4.04 (m,
1H), 4.18 (dd, 1H, J ) 6, 8 Hz), 4.24 (d, AB system, 1H, J ) 12
Hz), 4.40 (s, 2H), 4.51 (d, AB system, 1H, J ) 12 Hz), 4.52 (d,
AB system, 1H, J ) 12 Hz), 4.69 (d, AB system, 1H, J ) 12 Hz),
7.15-7.35 (m, 21H), 7.65-7.73 (m, 4H); 7.79 (d, 1H, J ) 8 Hz);
13C NMR (CDCl3) d 19.7, 27.5, 70.0, 71.4, 73.7, 74.6, 76.8, 79.1,
128.0-128.8, 130.2, 133.8, 133.9, 136.0, 137.9, 138.3, 138.4,
154.7; MS (DCI) m/z 674 (100) [M + H]+; IR ν (cm-1) 3551, 3476,
3461, 3069, 3037, 2931, 2857, 1959, 1878, 1804, 1722, 1582,
1495, 1453, 1110. Anal. Calcd for C42H47O5NSi: C, 74.85; H, 7.03;
N, 2.08. Found: C, 74.68; H, 6.99; N, 2.08.
2,3,5-Tri-O-benzyl-4-methanesulfonyl-L-xylofuranose Ox-
ime (6). To a solution of oxime 4 (4.05 g, 6.02 mmol) in CH2Cl2
(18 mL) placed at 0 °C under argon atmosphere were added
successively triethylamine (1.3 mL, 9.34 mmol) and mesyl
chloride (556 µL, 7.03 mmol). The solution was stirred for 30
min, and then water (5 mL) was added. The aqueous layer was
extracted three times with CH2Cl2. The organic layers were
washed with brine, dried over MgSO4, and concentrated under
vacuum to give a residue, which upon column chromatography
over silica gel (pentane/AcOEt 9/1, 4/1, then 1/1) yielded the
mesylate 5 (4.205 g, 93%: 3/1 mixture of E/Z isomers) as an oil.
To a solution of mesylate 5 (4.87 g, 5.60 mmol) in THF (180 mL)
placed at 0 °C under argon was added tetrabutylammonium
fluoride (6.6 mL, 1 M solution in THF, 6.6 mmol). The reaction
mixture was stirred for 5 min at 0 °C, and then the solvent was
removed under vacuum. The residue was dissolved in ethyl
acetate, water was added, and the aqueous layer was extracted
three times with ethyl acetate. The organic layers were washed
with brine, dried over MgSO4, and concentrated under vacuum
to give a residue, which upon column chromatography over silica
gel (pentane/AcOEt 9/1, 4/1, then 1/1) yielded the oxime 6 (2.5
g, 87%: 2/1 mixture of E/Z isomers) as an oil: 1H NMR (CDCl3)
δ 2.86 (s, 0.9H), 2.91 (s, 2.1H), 3.44 (dd, 0.33H, J ) 5.5, 11.5
Hz), 3.53 (dd, 0.66H, J ) 5.5, 11.0 Hz), 3.90 (t, 0.66H, J ) 5.5
Hz), 4.08-4.21 (m, 1.33H), 4.25-4.69 (m, 6H), 4.86-4.95 (m,
1.33H), 6.94 (d, 0.33H, J ) 5.5 Hz), 7.23-7.29 (m, 15H), 7.45
(d, 1H, J ) 8 Hz); 13C NMR (CDCl3) δ 38.1, 38.3, 68.6, 71.1,
71.9, 73.3, 75.0, 75.2, 75.2, 77.7, 78.7, 80.7, 81.5, 127.8-128.5,
136.6-137.3, 149.0, 151.0; MS (DCI) m/z 514 (100) [M + H]+,
531 (92) [M + NH4]+, 418 (29) [M - OMs]+; IR ν (cm-1) 3425,
3090, 3061, 3032, 2937, 2865, 1962, 1897, 1824, 1605, 1496,
1453, 1365, 1169, 1067.
FIGURE 1. ORTEP diagram for compound 11.
At this stage of the synthesis, the configuration of the
new stereocenter in the molecule (C-7a) had to be
determined, but NOE experiments on either 8, 9, or 10
did not prove informative. Fortunately, reduction of 10
to the corresponding pyrrolizidine 11 by LiAlH4 afforded
a nicely crystalline product which could be analyzed by
X-ray diffraction21 (Figure 1). This analysis showed
unambiguously that the reductive addition took place on
the face opposite to the C-2 and C-4 substituents in the
nitrone, affording the product with a trans configuration,
i.e., related to the hyacinthacine family.
Deprotection of the benzyl groups was then accom-
plished as previously described11 to afford after proper
neutralization (+)-hyacinthacine A2, in 19% overall yield
from L-xylose. The synthetic product exhibited physical
and spectral properties identical to the data reported for
the natural product.
In conclusion, the synthesis of hyacinthacine A2 de-
scribed herein illustrates the potential of our novel,
convergent methodology based on nitrone umpolung. This
method complements favorably the well-known 1,3-
cycloaddition processes and opens the field for the syn-
thesis of other polyhydroxypyrrolizidines starting from a
variety of sugar-derived cyclic nitrones. In particular, it
should be useful for the preparation of new analogues of
the natural pyrrolizidine alkaloids bearing substituents
at C-7 that, to the best of our knowledge, have not been
accessible via 1,3-cycloaddition. The preparation of new
B-ring substituted hyacinthacines is currently under
investigation in our laboratories, and their biological
evaluation will hopefully lead to a better understanding
of the structural requirements for glycosidase and gly-
cosyltransferase inhibition.
Nitrone 712a,14 ((2R,3R,4R)-3,4-Bis-benzyloxy-2-benzyl-
oxymethyl-3,4-dihydro-2H-pyrrole 1-Oxide). To a solution
of oxime 6 (170 mg, 0.33 mmol) in a 4:1 mixture of methanol
and water (3.75 mL) were added NaHCO3 (233 mg, 2.77 mmol)
and hydroxylamine hydrochloride (184 mg, 2.65 mmol). The
reaction mixture was heated overnight at reflux temperature.
After concentration under vacuum, the residue was dissolved
in CH2Cl2, and water was added. The aqueous layer was
extracted three times with CH2Cl2, and the organic layers were
washed with brine, dried over MgSO4, and concentrated under
vacuum to give a residue, which upon column chromatography
over silica gel (pentane/AcOEt 9/1, 4/1, then 1/1) yielded the
nitrone 7 (124 mg, 92%) as a white solid: mp 91-93 °C (lit.14
mp 88-90 °C); [R]20 -42 (c 1.3, CHCl3) (lit.14 [R]20 -41.7 (c
Experimental Section
2,3,5-Tri-O-benzyl-L-xylofuranose O-tert-Butyldiphenyl-
silyloxime (4). Methyl 2,3,5-tri-O-benzyl-R,â-L-xylofuranoside
3
22 (12.3 g, 28.3 mmol) in acetic acid (160 mL) and 1 M aqueous
H2SO4 (40 mL) was heated at 100 °C for 1 h. After cooling, the
mixture was diluted with CH2Cl2 (250 mL), and the organic layer
was washed with 5 N NaOH and then with brine, dried over
MgSO4, and concentrated under vacuum to yield 2,3,5-tri-O-
benzyl-L-xylofuranose as an oil, which was used without puri-
fication in the next step. To a solution of 2,3,5-tri-O-benzyl-L-
xylofuranose (3.2 g, 7.62 mmol) in dry toluene (31 mL) was added
D
D
1
1.00, CH2Cl2)); H NMR (CDCl3) δ 3.80 (dd, 1H, J ) 3, 10 Hz),
4.04 (m, 1H), 4.08 (dd, 1H, J ) 5, 10 Hz), 4.41 (dd, 1H, J ) 2,
3.5 Hz), 4.54 (d, AB system, 1H, J ) 12 Hz), 4.57 (d, 2H, J ) 3
Hz), 4.58 (s, 2H), 4.64 (d, AB system, 1H, J ) 12 Hz), 4.69 (t,
1H, J ) 2 Hz), 6.91 (s, 1H); 7.30-7.38 (m, 15H); 13C NMR
(CDCl3) δ 66.6, 72.1, 72.3, 73.9, 77.9, 80.8, 83.2, 128.1-129.0,
133.1, 137.5, 137.7, 138.1; MS (DCI) m/z 418 (100) [M + H]+,
(21) See Supporting Information.
(22) Secrist, J. A., III; Tiwari, K. N.; Shortnacy-Fowler, A. T.;
Messini, L.; Riordan, J. M.; Montgomery, J. A.; Meyers, S. C.; Ealick,
S. E. J. Med. Chem. 1998, 41, 3865-3871.
J. Org. Chem, Vol. 70, No. 4, 2005 1461

420 (31) [M + H - O]+; IR ν (cm-1) 3045, 2873, 1959, 1878, 1820,
1589, 1497, 1453, 1088. Anal. Calcd for C26H27O4N: C, 74.80; H,
6.52; N, 3.35. Found: C, 74.59; H, 6.56; N, 3.28.
4.32 (dd, 1H, J ) 4, 5 Hz), 4.45-4.61 (m, 6H), 7.27-7.30 (m,
15H); 13C NMR (CDCl3) δ 25.6, 33.0, 58.4, 63.5, 69.1, 72.0, 72.1,
73.0, 86.9, 88.9, 127.3, 128.3, 137.6-138.0, 174.6; MS (DCI) m/z
458 (100) [M + H]+; IR ν (cm-1) 3090, 3063, 3031, 2857, 1967,
1878, 1820, 1698, 1101. Anal. Calcd for C29H31O4N: C, 76.12; H,
6.83; N, 3.06. Found: C, 76.25; H, 6.88; N, 3.11.
3-((2R,3R,4R,5R)-3,4-Bis-benzyloxy-5-benzyloxymeth-
ylpyrrolidin-2-yl)propionic Acid Ethyl Ester (8). A stirred
and carefully deoxygenated solution of the nitrone 7 (102 mg,
0.245 mmol) in dry THF (5 mL) was cooled to -78 °C under
argon. Freshly distilled ethyl acrylate (37 µL, 0.34 mmol),
degassed water (35 µL, 1.96 mmol), and a 0.088 M solution of
SmI2 in THF (8.4 mL, 0.74 mmol) were then added. The
temperature was kept at -78 °C during 3 h, and then air was
introduced until disappearance of the blue color of the reaction
mixture, whereupon a saturated aqueous solution of Na2S2O3
(5 mL) and ethyl acetate (15 mL) were added. The yellow
mixture was extracted with AcOEt (3 × 20 mL), and the
combined organic layers were washed with a saturated aqueous
solution of NaCl (20 mL), dried over MgSO4, filtered, and
concentrated in vacuo. Purification of the resulting residue by
chromatography on silica gel (pentane/AcOEt 4/1, then 1/1)
afforded the expected N-hydroxypyrrolidine ester 8 (82 mg; 64%:
90:10 mixture of diastereomers) as a colorless oil: 1H NMR
(CDCl3) δ 1.21 (t, 3H, J ) 7 Hz), 1.83-1.97 (m, 1H), 2.07-2.19
(m, 1H), 2.40 (t, 2H, J ) 7 Hz), 3.15 (lq, 1H, J ) 6.5 Hz), 3.52-
3.60 (m, 2H), 3.78 (m, 1H), 3.85 (dd, 1H, J ) 3, 6.5 Hz), 3.97 (t,
1H, J ) 3 Hz), 4.09 (q, 2H, J ) 7 Hz), 4.43 (d, AB system, 1H,
J ) 12 Hz), 4.50 (s, 2H), 4.52 (s, 2H), 4.57 (d, AB system, 1H, J
) 12 Hz), 6.39 (s, 1H), 7.27-7.31 (m, 15H); 13C NMR (CDCl3) δ
14.1, 23.9, 31.0, 60.3, 68.0, 69.0, 70.0, 71.5, 71.7, 73.2, 84.6, 86.1,
127.6-128.3, 137.9, 138.0, 138.1, 174.0; MS (DCI) m/z 520 (100)
[M + H]+; IR ν (cm-1) 3428, 3087, 3062, 3028, 2930, 2873, 1730,
1091. Anal. Calcd for C31H37O6N: C, 71.65; H, 7.18; N, 2.70.
Found: C, 71.66; H, 7.02; N, 2.73.
(5R,6R,7R,7aR)-6,7-Bis-benzyloxy-5-benzyloxymethyl-
hexahydropyrrolizin-3-one (10). A stirred and carefully
deoxygenated solution of the nitrone 7 (380 mg, 0.91 mmol) in
dry THF (18.5 mL) was cooled to -78 °C under argon. Freshly
distilled ethyl acrylate (139 µL, 1.28 mmol), degassed water (136
µL, 7.56 mmol), and a 0.1 M solution of SmI2 in THF (28 mL,
2.8 mmol) were then added. The temperature was kept at -78
°C during 3 h, and after checking by TLC that the starting
nitrone had been completely converted, excess samarium diio-
dide was added (28 mL, 2.8 mmol) and the temperature was
allowed to reach room temperature overnight. The reaction was
then quenched by introduction of air, and then a saturated
aqueous solution of Na2S2O3 (10 mL) and ethyl acetate (30 mL)
was added. The yellow mixture was extracted with AcOEt (3 ×
30 mL), and the combined organic layers were washed with a
saturated aqueous solution of NaCl (20 mL), dried over MgSO4,
filtered, and concentrated in vacuo. The residue, containing a
mixture of pyrrolidine 9 and pyrrolizidinone 10, was dissolved
in ethanol (20 mL) and treated with a solution of potassium
carbonate (150 mg, 1.17 mmol) in water (5 mL) during 2 days.
The mixture was then concentrated in vacuo, and the residue
was extracted with ethyl acetate (3 × 20 mL). The combined
organic layers were washed with brine, dried over MgSO4, and
concentrated in vacuo. Purification of the resulting residue by
chromatography on silica gel (CH2Cl2/MeOH: 99/1, then 95/5)
afforded the expected pyrrolizidinone 10 (246 mg; 59%) as a
colorless oil: 1H NMR (CDCl3) δ 1.70-1.88 (m, 1H), 2.17-2.42
(m, 2H), 2.56 (td, 1H, J ) 10, 16 Hz), 3.50-3.63 (m, 2H), 3.70
(dd, 1H, J ) 5, 7 Hz), 3.88 (q, 1H, J ) 7 Hz), 4.05-4.12 (m, 1H),
(1R,2R,3R,7aR)-1,2-Bis-benzyloxy-3-benzyloxymethyl-
hexahydropyrrolizine (11). A solution of pyrrolizidinone 10
(60 mg, 0.13 mmol) in THF (5 mL) was cooled to 0 °C under
argon, and then lithium aluminum hydride (9 mg, 0.25 mmol)
was added. The reaction mixture was stirred during 5 h at reflux
temperature, and then it was quenched with water (9 µL), an
aqueous 15% solution of NaOH (9 µL), and water (36 µL) and
stirred for 1 h. Then sodium sulfate was added, the mixture was
stirred for 1 h and filtered through Celite, and the filtrate was
concentrated under vacuum to give a residue, which upon
column chromatography over alumina (pentane/AcOEt 9/1, 4/1,
then 1/1) yielded the pyrrolizidine 11 (46 mg, 79%) as a white
solid: mp 47.5 °C; [R]20 -5 (c 1, CHCl3); 1H NMR (CDCl3) δ
D
1.61-2.01 (m, 4H), 2.76 (td, 1H, J ) 7, 10 Hz), 2.94 (td, 1H, J )
5, 7 Hz), 3.05 (td, 1H, J ) 6, 10 Hz), 3.45 (dt, 1H, J ) 6, 7 Hz),
3.51 (dd, 1H, J ) 7, 10 Hz), 3.59 (dd, 1H, J ) 5, 10 Hz), 3.80 (t,
1H, J ) 6 Hz), 4.06 (dd, 1H, J ) 6, 7 Hz), 7.26-7.31 (m, 15H);
13C NMR (CDCl3) δ 25.8, 31.7, 55.1, 67.4, 68.3, 71.9, 72.1, 72.5,
73.2, 85.7, 88.9, 127.4-128.3, 138.3, 138.4, 138.5; MS (DCI) m/z
444 (100) [M + H]+; IR ν (cm-1) 3069, 3029, 2921, 2857, 1949,
1872, 1803, 1495, 1451, 1101. Anal. Calcd for C29H33O3N: C,
78.52; H, 7.50. Found: C, 78.43; H, 7.83.
(+)-Hyacinthacine A2 (2). To a solution of pyrrolizidine 11
(60 mg, 0.14 mmol) in a 4:1 mixture of methanol and THF (10
mL) was added Pd/C 10% (24 mg). After the reaction flask was
purged with hydrogen, 10 drops of HCl 6 N were added and the
reaction mixture was stirred for 4 days at room temperature
under hydrogen. The mixture was then filtered through Celite,
and the filtrate was concentrated under vacuum. The residue
was dissolved in a minimum of water and stirred with DOWEX
1X8 resin (OH- form) until pH ) 11.55. After filtration, the
filtrate was concentrated under vacuum to give spectroscopically
pure hyacinthacine A2 (2) (18.5 mg, 79%): [R]20 +19.9 (c 0.97,
D
MeOH) [lit.10 [R]25D +20.1 (c 0.44, H2O); lit.11 [R]25D +12.5 (c 0.4,
H2O); lit.12a [R]25D +12.7 (c 0.13, H2O); lit.12b [R]25D +10.5 (c 0.6,
H2O)]; 1H NMR (D2O) δ 1.70-2.00 (m, 4H), 2.66-2.77 (m, 2H),
2.85-2.93 (m, 1H), 3.10-3.17 (m, 1H), 3.61-3.81 (m, 4H); 13C
NMR (D2O) δ 27.3, 32.6, 57.6, 66.0, 68.8, 72.0, 80.2, 83.1; MS
(DCI) m/z 174 (100) [M + H]+; IR ν (cm-1) 3354, 2956, 2920,
2866, 1124.
Acknowledgment. We are grateful to Drs. O.
Martin and P. Compain for helpful discussions. Drs. C.
Philouze and A. Durif are thanked for performing the
X-ray analysis of compound 11. This work was sup-
ported by the CNRS and the Universite´ Joseph Fourier.
S.D. thanks the LEDSS for financial support.
Supporting Information Available: General procedures,
copies of spectra for compounds 8-11 and for synthetic (+)-
hyacinthacine A2 (2), as well as crystallographic data for
compound 11. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO048237R
1462 J. Org. Chem., Vol. 70, No. 4, 2005