Intramolecular cycloadditions of nittones derived from 1-allyl-2- pyrrolecarbaldehyde as a route to racemic and enantiopure pyrrolizidines and indolizidines

Article abstract of DOI:10.1021/jo9810415

A version of the intramolecular nitrone cycloaddition strategy, using 2- pyrrolecarbaldehyde as starting material, has been developed to synthesize new pyrrolizidines and indolizidines structurally related to biologically active alkaloids. The target molecules have been accessible in racemic as well as enantiopure form.

Full text of DOI:10.1021/jo9810415

J . Org. Chem. 1998, 63, 9279-9284
9279
In tr a m olecu la r Cycloa d d ition s of Nitr on es Der ived fr om
1-Allyl-2-p yr r oleca r ba ld eh yd e a s a Rou te to Ra cem ic a n d
En a n tiop u r e P yr r olizid in es a n d In d olizid in es
Alberto Arnone,† Gianluigi Broggini,‡ Daniele Passarella,‡ Alberto Terraneo,‡ and
Gaetano Zecchi*,‡
Dipartimento di Chimica Organica e Industriale dell’Universita`, Via Golgi 19, 20133, Milano, Italy, and
Centro CNR per lo Studio delle Sostanze Organiche Naturali, Via Mancinelli 7, 20131, Milano, Italy
Received J une 1, 1998
A version of the intramolecular nitrone cycloaddition strategy, using 2-pyrrolecarbaldehyde as
starting material, has been developed to synthesize new pyrrolizidines and indolizidines structurally
related to biologically active alkaloids. The target molecules have been accessible in racemic as
well as enantiopure form.
In tr od u ction
dition reactions of nitrone intermediates.4 Two intramo-
lecular versions of the same strategy, which could be in
principle more efficient in terms of stereoselectivity, are
also known: the first one is directed to the synthesis of
indolizidines and uses (S)-5-(hydroxymethyl)-2-pyrroli-
done as primary chiral material;5 the second one deals
with a synthetic entry to pyrrolizidines starting from (S)-
proline.6
Pyrrolizidine and indolizidine alkaloids are endowed
with a vaste range of potent biological activities.1 Several
of them (e.g., isoretronecanol (1), petasinecine (2), swain-
sonine (3), and castanospermine (4)) have been proven
glycosidase inhibitors and constitute promising antiviral
and antitumoral agents.2
The present paper describes a new approach to the
pyrrolizidine and indolizidine skeletons, essentially based
upon the intramolecular cycloaddition of nitrones derived
from 1-allyl-2-pyrrolecarbaldehyde (5) (Scheme 1). Al-
though the reactivity of similar nitrones has been inves-
tigated,7 its potential in alkaloid synthesis has not been
exploited. In addition, other authors have turned their
attention to the behavior of nitrones derived from 1-allyl-
2-indolecarbaldehyde.8
(3) Robins, D. J . Nat. Prod. Rep. 1995, 413. Michael, J . P. Nat. Prod.
Rep. 1995, 535. Liddell, J . R. Nat. Prod. Rep. 1996, 187. Michael, J . P.
Nat. Prod. Rep. 1997, 21.
In view of these features as well as of the exotic
provenance and the scarsity of natural samples, there is
a great impulse toward the synthesis of such alkaloids
and structurally related unnatural compounds.3 To
attain this goal, various authors have employed cycload-
(4) (a) Tufariello, J . J .; Lee, G. E. J . Am. Chem. Soc. 1980, 102, 373.
(b) Chastanet, J .; Roussi, G. Heterocycles 1985, 23, 653. (c) Ito, M.;
Kibayashi, C. Tetrahedron 1991, 45, 9329. (d) Herczegh, I.; Kovacs, I.;
Szilagyi, L.; Varga, T.; Dinya, Z.; Sztaricskai, F. Tetrahedron Lett. 1993,
34, 1211. (e) McCaig, A. E.; Wightman, R. H. Tetrahedron Lett. 1993,
34, 3939. Hall, A.; Meldrum, K. P.; Therond, P. R.; Wightman, R. H.
Synlett 1997, 123. (f) Cordero, F. M.; Cicchi, S.; Goti, A.; Brandi, A.
Tetrahedron Lett. 1994, 35, 949. Goti, A.; Cardona, F.; Brandi, A.;
Picasso, F.; Vogel, P. Tetrahedron: Asymmetry 1996, 7, 1659. Cordero,
F. M.; Machetti, F.; De Sarlo, F.; Brandi, A. Gazz. Chim. Ital. 1997,
127, 5. Goti, A.; Fedi, V.; Nannelli, L.; De Sarlo, F.; Brandi, A. Synlett
1997, 577.
* Author to whom correspondence should be addressed. Tel: (39)
2-70635727. Fax: (39) 2-2364369. E-mail: mabuck@icil64.cilea.it.
† Centro CNR.
‡ Universita`.
(1) Warren, F. L. In The Alkaloids Chemistry and Physiology;
Manske, R. H. F., Ed.; Academic Press: New York, 1970; Vol. 12, p
319. Mattocks, A. R. Chemistry and Toxicology of Pyrrolizidine
Alkaloids; Academic Press: New York, 1986. Elbein, A. D.; Molineux,
R. J . In Alkaloids: Chemical and Biological Perspectives; Pelletier, S.
W., Ed.; Wiley: New York, 1987; Vol. 5, Chapter 1.
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J .; McGowan, L. S.; Gordon, M. M. J . Med. Chem. 1985, 28, 687.
Gruters, R. A.; Neefjes, J . J .; Tersmette, M.; de Goede, R. A. Y.; Tulp,
A.; Huisman, H. G.; Miedema, F.; Ploegh, H. L. Nature 1987, 330, 74.
Cenci di Bello, I.; Fleet, G.; Namgoong, S. K.; Tadano, K.-I.; Winchester,
B. Biochem. J . 1989, 259, 855. Pastuszak, I.; Molineux, R. J .; J ames,
L. F.; Elbein, A. D. Biochemistry 1990, 29, 1886. Winchester, B.; Fleet,
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J . P.; Dennis, J . W. Clin. Cancer Res. 1995, 1, 935. Das, P. C.; Roberts,
J . D.; White, S. L.; Olden, K. Oncol. Res. 1995, 7, 425. Wong, C.-H.;
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1995, 34, 521. Granier, T.; Gaiser, F.; Hintermann, L.; Vasella, A. Helv.
Chim. Acta 1997, 80, 1443.
(5) (a) Collins, I.; Fox, M. E.; Holmes, A. B.; Williams, S. F.; Baker,
R.; Forbes, I. J .; Thompson, M. J . Chem. Soc., Perkin Trans. 1 1991,
175. (b) Holmes, A. B.; Smith, A. L.; Williams, S. F. J . Org. Chem.
1991, 56, 1393. (c) Collins, I.; Nadin, A.; Holmes, A. B.; Long, M. E.;
Man, J .; Baker, R. J . Chem. Soc., Perkin Trans. 1 1994, 2205. (d)
Rudge, A. J .; Collins, I.; Holmes, A. B.; Baker, R. Angew. Chem., Int.
Ed. Engl. 1994, 33, 2320.
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Chem. 1991, 56, 2775. (b) Hassner, A.; Singh, S.; Sharma, R.; Maurya,
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Corsaro, A.; Librando, V.; Rescifina, A.; Romeo, R.; Romeo, G.
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10.1021/jo9810415 CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/14/1998

9280 J . Org. Chem., Vol. 63, No. 25, 1998
Arnone et al.
Sch em e 1
F igu r e 1. Bridged-ring (A) and fused-ring (B) transition
states for the intramolecular cycloaddition of nitrone 6.
Sch em e 2
Resu lts a n d Discu ssion
(A) Syn th esis of Ra cem ic Com p ou n d s. The reac-
tion of aldehyde 5 with the commercially available
benzylhydroxylamine gave the desired nitrone 6 in 52%
yield. Heating the latter in refluxing toluene led to the
isomeric cycloadducts 7 and 8 in 57 and 34% yields,
1
respectively.9 Both H and 13C NMR spectra showed that
compound 7 exists as a 4:1 mixture of two invertomers,
in agreement with literature precedents for encumbered
N-substituted isoxazolidines.10 The observed coalescence
temperature (28 °C) corresponds to an inversion energy
barrier of ca. 15 kcal/mol.11 MM+ calculations12 have
shown the invertomer having the benzyl group in pseudo-
axial position more stable by 1.3 kcal/mol in comparison
with that having the same pendant in pseudoequatorial
position.
The behavior of nitrone 6 deserves a few comments.
The isomeric products 7 and 8 reflect two opposite
regiochemical trends of the cycloaddition, both of which
however give exclusively a cis relationship of the new
stereocenters. The latter outcome is clearly the conse-
quence of geometric restraints and constitutes an intrin-
sic advantage of intramolecular nitrone cycloadditions
with respect to the intermolecular ones. The predomi-
nance of the bridged-ring product 7 is worthy of noting
because only fused-ring products have been found in the
intramolecular cycloaddition of nitrones derived from
N-alkenyl-2-prolinaldehyde.6c,d It may be that, because
of the rigid angular disposition imparted by the planar
pyrrole nucleus, the fused-ring transition state increases
in energy thereby becoming competitive with the usually
unfavored bridged-ring transition state (Figure 1). As
molecular models indicate, this is not the case for the
more flexible pyrrolidine nucleus of proline. MM+
calculations, assuming a distance of 2.7 Å between the
reaction centers, have estimated the transition state B
higher in energy of 0.8 kcal/mol with respect to A.
Significantly, in the case of the analogous structures
containing a pyrrolidine ring, the same computational
approach has indicated an energy difference of 16.5 kcal/
mol in favor of the fused-ring transition state of type B.
At this point, we submitted the above cycloadducts 7
and 8 to hydrogenolytic treatment with the idea of (i)
removing the benzyl group, (ii) opening the isoxazolidine
ring, and (iii) saturating the pyrrole nucleus. Prelimi-
nary experiments showed a marked influence by both the
catalyst and the reaction conditions. Upon hydrogena-
tion in methanol in the presence of 10% Pd/C at rt and
15 psi of pressure, compound 7 gave after 6 h the amino
alcohol 9 and the alcohol 10 in 12 and 50% yields,
respectively (Scheme 2). The loss of the primary amino
group, although rather disappointing, is not unespected
due to its pseudobenzylic position. However, when the
hydrogenolytic treatment of 7 was prolonged until 48 h,
we isolated the isomeric 6-hydroxyindolizidines 13 (25%)
and 14 (22%).13 Compound 8 was found more reluctant
toward hydrogenation. Under the conditions indicated
above, it gave after 24 h the amino alcohol 12 as the only
product, the species 11 being isolable at short time (3
h). Saturation of the pyrrole nucleus proceeded slowly
and partially under these conditions, but it was facili-
tated by the additional presence of hydrogen chloride,
which allowed the obtainment of 2-hydroxypyrrolizidine
(15) in 51% yield.14
Structural assignments to the fully hydrogenated
products required homonuclear and heteronuclear shift
correlations. Significantly, the bridgehead hydrogen
resonates at 3.57 ppm in 15, in accord with the cis
(9) When the reaction of 5 with benzylhydroxylamine was carried
out at high temperature, compounds 7 and 8 could be obtained without
isolating the intermediate nitrone 6. However, the overall yields were
less satisfactory.
(10) Gru¨nanger, P.; Vita-Finzi, P. Isoxazoles; Wiley: New York,
1991; p 679.
(13) No improved result was observed by using Pd(OH)2 as catalyst.
(14) Attempts to isolate 13-15 as hydrochlorides gave highly
hygroscopic solids difficult to handle and to characterize. The satura-
tion of the pyrrole nucleus of 8 was also observed, without the presence
of hydrogen chloride, using acetic acid as solvent. However, under these
conditions, the isolation of the product suffered from a drawback due
to the combination of its basicity and volatility.
(11) Kessler, H. Angew. Chem., Int. Ed. Engl. 1970, 9, 219.
(12) HyperChem program (4.1 version, Autodesck, Inc.).

Intramolecular Cycloadditions of Nitrones
J . Org. Chem., Vol. 63, No. 25, 1998 9281
Ta ble 1. Selected Con n ectivities Esta blish ed by NOE Differ en ce Stu d ies
protons affected (%) in compound
proton
irradiated
18
19
Me
Ph
HL
HC
HG
HC(3.5), HI(4), HL(7.5), Ph(2.5)
HC(<0.5), HI(1.5), HL(8), Me(1)
HC(0.5), HI(1.5), HG(3), Me(1,5), Ph(4.5)
HI(2.5), HL(0.5), Me(0.5)
HC(<0.5), HI(<0.5), HL(7), Ph(2)
HC(4), HI(2.5), HL(8), Me(1)
HC(1), HI(1), HC(<0.5), Me(2), Ph(4.5)
HI(2), HL(1), Ph(2)
HF(4.5), HH(20), HI(3.5), HL(3)
HF(4.5), HH(18), HI(3), HL(<0.5)
Sch em e 3
junction of the rings, and at less than 1.90 ppm in 13
and 14, thus indicating in both isomers a diaxial trans
disposition with respect to the lone electron pair on the
nitrogen. The distinction between the diastereoisomers
13 and 14 was possible because H-6 shows two coupling
constants of 10.1 Hz typical of trans diaxial interactions
in compound 13, while it exhibits four vicinal couplings
of ca. 2.4 Hz indicating its equatorial disposition in
compound 14. On the other hand, in the case of 15, the
1,3-syn relationship between H-2 and H-7a was estab-
lished unequivocally by 2D NOE measurements.15
(B) Syn th esis of En a n tiop u r e Com p ou n d s. The
second part of this paper is concerned with the asym-
metric synthesis of the new pyrrolizidines and indoliz-
idines just described in the first part. As a device aimed
at this goal, we ideated the use of an enantiopure
hydroxylamine and chose (R)-N-(1-phenylethyl)hydroxyl-
amine (16) in view of its benzylic nature as well as of its
ready accessibility.16 Actually, the reaction of aldehyde
5 with 16 gave the optically active nitrone 17 in 48% yield
(Scheme 3). Heat treatment of the latter resulted in a
mixture of four products, all of which were obtained in
pure state by means of column chromatography. Ana-
lytical and spectral data were consistent with two dia-
stereoisomeric bridged-ring cycloadducts and two dia-
stereoisomeric fused-ring cycloadducts. The proportion
between the two types of structures (ca. 2:1) is rather
similar to that found in the intramolecular cycloaddition
of N-benzylnitrone (6). Within each diastereoisomeric
pair, the observed ratio (ca. 4:3) corresponds to a moder-
ate asymmetric induction by the homochiral pendant. It
is to be added that the major bridged-ring cycloadduct
exists as a 3:2 mixture of two invertomers with a
coalescence temperature of 35 °C. Conversely, the minor
bridged-ring cycloadduct exists as one largely predomi-
nant invertomer (10:1).
F igu r e 2. Preferred conformations and absolute configura-
tions of the diastereoisomeric cycloadducts 18 and 19.
The absolute stereochemistry of the diastereoisomeric
bridged-ring cycloadducts 18 and 19 was elucidated by
1H NMR. Observed NOE enhancements (Figure 2, Table
1) are consistent if (i) the N-pendant assumes preferably
a pseudoaxial conformation with the smallest substituent
at the benzylic carbon (i.e., HL) oriented toward the inner
concavity of the molecule and (ii) the newly formed
stereocenters possess the absolute configurations de-
picted in the formulas. This conclusion agrees with the
marked shielding effect exerted by the Ph ring on HC in
compound 19, but not in compound 18. Sizable mutual
NOEs between HL and HG were also observed in com-
pound 18 because of the rapid conversion to the minor
invertomer having the N-pendant positionated pseu-
doequatorially; the corresponding NOEs were smaller in
compound 19 according to the negligeable extent of the
minor invertomer. MM+ calculations have shown that,
on assuming the absolute configurations of 18, the
N-invertomer having the pendant disposed pseudoaxially
is preferred of only 0.6 kcal/mol with respect to that
having the pendant disposed pseudoequatorially. Con-
versely, on assuming the absolute configuration of 19,
the energy difference between pseudoaxial and pseu-
doequatorial dispositions rises to 3.4 kcal/mol in favor of
the former one.
(15) For previous NMR studies of pyrrolizidines and indolizidines
see refs 4b, 5c, 6b, 6d, and the following: (a) J ones, T. H.; Blum, M.
S.; Fales, H. M.; Thompson, C. R. J . Org. Chem. 1980, 45, 4778. (b)
Belmont, S. E.; Polniaszek, R. P. J . Org. Chem. 1990, 55, 4688. (c)
Bond, T. J .; J enkins, R.; Ridley, A. C.; Taylor, P. C. J . Chem. Soc.,
Perkin Trans. 1 1993, 2241. (d) Logie, C. G.; Grue, M. R.; Liddell, J .
R. Phytochemistry 1994, 37, 43.
In the case of the diastereoisomeric fused-ring cycload-
ducts 20 and 21 (Figure 3), NOE enhancements between
HF and HI (2%) clearly demonstrates their cis relation-
ship. Moreover, in compound 20 the presence of NOE
(16) Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron 1985, 41, 3455.

9282 J . Org. Chem., Vol. 63, No. 25, 1998
Arnone et al.
temperature for 1 h. A solution of 5 (2.1 g, 15.5 mmol) in Et2O
(100 mL) was added, and the resulting mixture was stirred
for 24 h. After filtration and evaporation of the solvent under
reduced pressure, the residue was chromatographed on a silica
gel column with AcOEt as eluent to give 1.9 g (52%) of 6. For
6: mp 108-109 °C (from hexane/benzene); 1H NMR (δ, CDCl3,
300 MHz) 4.43 (br d, J ) 5.0 Hz, 2H), 4.79 (dd, J ) 1.2, 17.1
Hz, 1H), 5.00 (s, 2H), 5.09 (dd, J ) 1.2, 10.3 Hz, 1H), 5.80
(ddt, J ) 4.9, 10.3, 17.1, 1H), 6.26 (dd, J ) 2.7, 3.6 Hz, 1H),
6.76 (dd, J ) 1.3, 2.7 Hz, 1H), 7.21 (s, 1H), 7.36-7.43 (m, 5H),
7.82 (dd, J ) 1.3, 3.6 Hz, 1H); MS m/z 240 (M+). Anal. Calcd
for C15H16N2O: C, 74.96; H, 6.72; N, 11.66. Found: C, 75.03;
H, 6.61; N, 11.74.
F igu r e 3. Preferred conformations and absolute configura-
tions of the diastereoisomeric cycloadducts 20 and 21.
In tr a m olecu la r Cycloa d d ition of Nitr on e 6. A solution
of 6 (1.7 g, 7.1 mmol) in toluene (150 mL) was refluxed for 24
h. The solvent was evaporated under reduced pressure and
the residue was chromatographed on a silica gel column with
AcOEt-light petroleum (1:1) as eluent. The first fractions
gave 0.58 g (34%) of (3aR*,8bR*)-1-benzyl-1,3a,4,8b-tetrahy-
dro-3H-isoxazolo[3,4-a]pyrrolizine (8) as an oil: 1H NMR (δ,
CDCl3, 300 MHz) 3.85 (dd, J ) 4.0, 8.3 Hz, 1H), 3.88-3.95
(m, 1H), 3.98 (dd, J ) 3.3, 10.6 Hz, 1H), 4.03 and 4.12 (AB, J
) 13.3 Hz, 2H), 4.16 (dd, J ) 8.0, 10.6 Hz, 1H), 4.27 (br s,
1H), 4.50 (br s, 1H), 5.71-5.81 (m, 1H), 6.21-6.25 (m, 1H),
6.54-6.58 (m, 1H), 7.25-7.45 (m, 5H); 13C NMR (δ, CDCl3, 75
MHz) 50.9 (d), 51.0 (t), 60.3 (t), 67.7 (d), 72.5 (t), 101.3 (d),
113.5 (d), 114.3 (d), 127.4 (s), 127.4 (d), 128.3 (d), 129.1 (d),
137.1 (s); MS m/z 240 (M+). Anal. Calcd for C15H16N2O: C,
74.96; H, 6.72; N, 11.66. Found: C, 74.89; H, 6.63; N, 11.55.
The last fractions contained 0.97 g (57%) of (1R*,4S*)-2-benzyl-
1,2,4,5-tetrahydro-1,4-methanopyrrolo[2,1-d][1,2,5] oxadiaz-
epine (7) isolated as an oil: 1H NMR (δ, CDCl3, 300 MHz)
{major conformer} 2.25 (d, J ) 10.9 Hz, 1H), 2.80 (ddd, J )
4.5, 6.6, 10.9 Hz, 1H), 3.53 and 3.58 (AB, J ) 13.2 Hz, 2H),
4.00 (d, J ) 12.5 Hz, 1H), 4.13 (d, J ) 12.5 Hz, 1H), 4.29 (d,
J ) 4.5 Hz, 1H), 4.76 (br d, J ) 6.6 Hz, 1H), 5.94-6.00 (m,
1H), 6.15-6.21 (m, 1H), 6.63-6.69 (m, 1H), 7.20-7.41 (m, 5H),
{minor conformer} 2.17-2.23 (m, 1H), 2.62-2.76 (m, 1H),
3.50-4.30 (overlapping, 5H), 4.90-4.98 (m, 1H), 5.79-5.84 (m,
1H), 6.02-6.13 (m, 1H), 6.44-6.57 (m, 1H), 7.20-7.41 (m, 5H);
13C NMR (δ, CDCl3, 75 MHz) {major conformer} 36.5 (t), 53.3
(t), 56.3 (d), 59.1 (t), 72.7 (d), 106.9 (d), 108.0 (d), 119.9 (d),
127.1 (d), 127.4 (s), 128.3 (d), 129.0 (d), 137.6 (s) {minor
conformer} 32.1 (t), 52.4 (t), 56.7 (d), 63.0 (t), 73.8 (d), 103.2
(d), 108.3 (d), 119.4 (d), 127.2 (d), 127.4 (s), 128.3 (d), 129.0
(d), 137.1 (s); MS m/z 240 (M+). Anal. Calcd for C15H16N2O:
C, 74.96; H, 6.72; N, 11.66. Found: C, 75.05; H, 6.84; N, 11.81.
Hyd r ogen a tion of 7 for 6 h . Pd/C (10%, 0.31 g, 0.3 mmol)
was added to a solution of 7 (0.36 g, 1.5 mmol) in MeOH (40
mL). The mixture was stirred under H2 for 6 h. After
filtration through Celite, the solvent was evaporated under
reduced pressure and the residue was chromatographed on a
silica gel column. Elution with CHCl3/MeOH (19:1) gave 0.10
g (50%) of 6-hydroxy-5,6,7,8-tetrahydroindolizidine (10) as an
oil: 1H NMR (δ, CDCl3, 300 MHz) 1.75 (br s, 1H, missing after
deuteriation), 1.90 (dddd, J ) 6.0, 7.1, 7.9, 13.3 Hz, 1H), 2.04
(dddd, J ) 2.7, 6.0, 7.0, 13.3 Hz, 1H), 2.79 (ddd, J ) 6.0, 7.9,
16.4 Hz, 1H), 2.96 (ddd, J ) 6.0, 7.0, 16.4 Hz, 1H), 3.81 (dd, J
) 6.4, 12.0 Hz, 1H), 4.11 (dd, J ) 4.2, 12.0 Hz, 1H), 4.21-4.30
(m, 1H), 5.85 (dd, J ) 1.5, 3.5 Hz, 1H), 6.14 (dd, J ) 2.5, 3.5
Hz, 1H), 6.50 (dd, J ) 1.5, 2.5 Hz, 1H); 13C NMR (δ, CDCl3, 75
MHz) 19.4 (t), 29.3 (t), 51.6 (t), 65.7 (d), 104.1 (d), 108.4 (d),
118.8 (d), 127.7 (s); IR (Nujol) 3380 cm-1; MS m/z 137 (M+).
Anal. Calcd for C8H11NO: C, 70.04; H, 8.08; N, 10.21.
Found: C, 69.95; H, 8.01; N, 10.15. Subsequent elution with
CHCl3/MeOH/30% NH3 (10:1:1) gave 0.027 g (12%) of (6R*,8S*)-
8-amino-6-hydroxy-5,6,7,8-tetrahydroindolizine (9) as an oil:
1H NMR (δ, CDCl3, 300 MHz) 1.90 (ddd, J ) 3.0, 3.1, 14.0 Hz,
1H), 2.14 (ddd, J ) 2.9, 3.4, 14.0 Hz, 1H), 2.33 (br s, 3H,
missing after deuteriation), 3.95 (dd, J ) 3.2, 12.7 Hz, 1H),
4.22 (br d, J ) 12.7 Hz, 1H), 4.38-4.41 (m, 1H), 4.55 (br dd,
J ) 3.1, 3.4 Hz, 1H), 6.06 (dd, J ) 1.5, 3.5 Hz, 1H), 6.19 (dd,
J ) 2.5, 3.5 Hz, 1H), 6.59 (dd, J ) 1.5, 2.5 Hz, 1H);13C NMR
(δ, CDCl3, 75 MHz) 33.2 (t), 43.6 (d), 53.4 (t), 66.4 (d), 105.4
(d), 108.4 (d), 120.4 (d), 130.3 (s); IR (Nujol) 3240, 3290, 3350
Sch em e 4a
a
Key: (a) H2 Pd/C, MeOH, 6 h; (b) H2 Pd/C, MeOH, 24 h; (c)
H2 Pd/C, MeOH, 48 h; (d) H2 Pd/C HCl, MeOH, 24 h.
(1%) between the Me protons and HG as well as the
shielding effect exerted by the facing Ph on HC are only
compatible with the (S,S) stereochemistry.
At the final stage of our work, we submitted the
optically active cycloadducts 18-21 to catalytic hydro-
genation, following the conditions adopted in the case of
the analogous N-benzyl derivatives 7 and 8. In this way,
both enantiomers of compounds 10 and 12-15 became
available (Scheme 4). The enantiomeric purity was
determined in a few cases, namely (+)-13 and (-)-13,
upon functionalization by (+)-(2R,3R)-dibenzoyltartaric
anhydride and subsequent NMR analysis at 300 MHz of
the resulting monoester. It was proven to be total within
the experimental error limits (>98%).
Con clu sion s
In summary, we have shown that nitrones derived
from 1-allyl-2-pyrrolcarbaldehyde are useful intermedi-
ates for a valuable synthesis of pyrrolizidines and in-
dolizidines structurally related to bioactive alkaloids. The
accessibility of both racemic and enantiopure molecules
must be emphasized. However, in addition to the already
acquired goals, developments and improvements can be
devised. The first one is the synthesis of more function-
alized structures, which could be plausibly obtained from
substrates having appropriate substituents at the pyrrole
ring and/or at the allylic moiety. The second point is
concerned with a better degree of asymmetric induction,
which may hopefully be achieved by using a homochiral
sugar-derived hydroxylamine. Work is in progress in
both of these directions.
Exp er im en ta l Section
Melting points are not corrected. Analytical and spectro-
scopic instruments were as described in detail in a recent
paper.17
Compounds 57 and 1616 were prepared according to the
literature methods.
N-[(1-Allylp yr r ol-2-yl)m et h ylid en e]b en zen em et h a n -
a m in e N-Oxid e (6). A suspension of N-benzylhydroxylamine
hydrochloride (3.0 g, 18.8 mmol), Al2O3 (30.0 g), and NaHCO3
(2.1 g, 25 mmol) in Et2O (150 mL) was stirred at room
(17) Broggini, G.; Zecchi, G. Tetrahedron: Asymmetry 1997, 8, 1431.

Intramolecular Cycloadditions of Nitrones
J . Org. Chem., Vol. 63, No. 25, 1998 9283
cm-1; MS m/z 152 (M+). Anal. Calcd for C8H12N2O: C, 63.12;
H, 7.95; N, 18.41. Found: C, 62.99; H, 7.84; N, 18.53.
Hyd r ogen a tion of 7 for 48 h . Pd/C (10%, 0.14 g, 0.13
mmol) was added to a solution of 7 (0.14 g, 0.58 mmol) in
MeOH (25 mL). The mixture was stirred under H2 for 48 h.
After filtration through Celite, the solvent was evaporated
under reduced pressure and the residue was chromatographed
on a silica gel column with CHCl3/MeOH (1:3) as eluent. The
first fraction gave 0.020 g (25%) of (6R*,8aR*)-6-hydroxy-
1,2,3,5,6,7,8,8a-octahydroindolizidine (13) as an oil: 1H NMR
(δ, CDCl3, 300 MHz) 1.20-1.40 (overlapping, 3H, H-1, H-7,
H-8), 1.60-1.92 (overlapping, 6H, H-1, H-2, H-2, H-5ax, H-8,
H-8a), 2.00-2.07 (m, 1H, H-7), 2.15 (dt, J ) 8.7, 8.7 Hz, 1H,
H-3), 2.38 (br s, 1H, OH, missing after deuteriation), 2.98 (dt,
J ) 1.7, 8.7 Hz, 1H, H-3), 3.24 (ddd, J ) 1.5, 4.1, 10.1, 1H,
H-5eq), 3.84 (tt, J ) 4.1, 10.1 Hz, 1H, H-6);13C NMR (δ, CDCl3,
75 MHz) 22.2 (t, C-2), 29.1 (t, C-1 or C-8), 30.2 (t, C-1 or C-8),
34.6 (t, C-7), 54.3 (t, C-3), 60.6 (t, C-5), 64.3 (d, C-8a), 68.3 (d,
C-6); IR (Nujol) 3360 cm-1; MS m/z 141 (M+). Anal. Calcd
for C8H15NO: C, 68.03; H, 10.71; N, 9.92. Found: C, 68.08;
H, 10.59; N, 9.99. The next fraction gave 0.018 g (22%) of
(6R*,8aS*)-6-hydroxy-1,2,3,5,6,7,8,8a-octahydroindolizine (14)
as an oil: 1H NMR (δ, CDCl3, 300 MHz) 1.30-1.91 (overlap-
ping, 9H, H-1, H-1, H-2, H-2, H-7, H-7, H-8, H-8, H-8a), 2.09
(dt, J ) 9.1, 9.1 Hz, H-3), 2.15 (dd, J ) 2.4, 11.2 Hz, 1H, H-5ax),
2.40 (br s, 1H, OH, missing after deuteriation), 2.97 (dt, J )
2.4, 9.1 Hz, 1H, H-3), 3.07 (ddd, J ) 2.3, 2.4, 11.2 Hz, H-5eq),
3.88 (br quintet, J ) 2.4 Hz, 1H, H-6); 13C NMR (δ, CDCl3, 75
MHz) 21.4 (t, C-2), 26.4 (t, C-1 or C-8), 31.1 (t, C-1 or C-8),
31.6 (t, C-7), 54.6 (t, C-3), 59.4 (t, C-5), 64.8 (d, C-8a), 66.0 (d,
C-6); IR (Nujol) 3360 cm-1; MS m/z 141 (M+). Anal. Calcd
for C8H15NO: C, 68.03; H, 10.71; N, 9.92. Found: C, 67.89;
H, 10.61; N, 10.04.
Hyd r ogen a tion of 8 w ith ou t HCl. Pd/C (10%, 0.11 g, 0.1
mmol) was added to a solution of 8 (0.12 g, 0.5 mmol) in MeOH
(18 mL). The mixture was stirred under H2 for 24 h. After
filtration through Celite, the solvent was evaporated under
reduced pressure and the residue was chromatographed on a
silica gel column with CHCl3/MeOH (19:1) as eluent to obtain
0.052 g (68%) of (1R*,2R*)-1-amino-2,3-dihydro-1H-pyrrolizine-
2-methanol (12) as an oil: 1H NMR (δ, CDCl3, 300 MHz) 2.55
(br s, 3H, missing after deuteriation), 3.05 (dddt, J ) 3.6, 7.0,
7.4, 7.6 Hz, 1H), 3.85 (dd, J ) 7.0, 11.8 Hz, 1H), 3.95 (dd, J )
3.6, 11.8 Hz, 1H), 3.98 (d, J ) 7.6, 2H), 4.56 (d, J ) 7.4 Hz,
1H), 5.90 (dd, J ) 1.1, 3.5 Hz, 1H), 6.23 (dd, J ) 2.5, 3.5 Hz,
1H), 6.58 (dd, J ) 1.1, 2.5 Hz, 1H); 13C NMR (δ, CDCl3, 75
MHz) 47.3 (t), 47.8 (d), 51.5 (d), 62.5 (t), 99.9 (d), 113.2 (d),
115.1 (d), 140.8 (s); IR (Nujol) 3175, 3280, 3350 cm-1; MS m/z
152 (M+). Anal. Calcd for C8H12N2O: C, 63.12; H, 7.95; N,
18.41. Found: C, 63.08; H, 8.02; N, 18.49.
When the hydrogenation was stopped after 3 h, (1R*,2R*)-
1-(benzylamino)-2,3-dihydro-1H-pyrrolizine-2-methanol (11)
was isolated in 20% yield as an oil: 1H NMR (δ, CDCl3, 300
MHz) 1.92 (br s, 2H, missing after deuteriation), 3.08-3.22
(m, 1H), 3.84 (dd, J ) 7.3, 11.9 Hz, 1H), 3.90 and 4.02 (AB, J
) 12.9 Hz, 2H), 3.97 (dd, J ) 4.1, 11.9 Hz, 1H), 3.97 (d, J )
8.2 Hz, 2H), 4.26 (d, J ) 7.5 Hz, 1H), 5.96 (dd, J ) 1.0, 3.5 Hz,
1H), 6.23 (dd, J ) 2.5, 3.5 Hz, 1H), 6.61 (dd, J ) 1.0, 2.5 Hz,
1H), 7.27-7.35 (m, 5H); IR (Nujol) 3250, 3280 cm-1; MS m/z
242 (M+). Anal. Calcd for C15H18N2O: C, 74.34; H, 7.49; N,
11.57. Found: C, 74.40; H, 7.61; N, 11.48.
Hyd r ogen a tion of 8 in th e P r esen ce of HCl. Compound
8 (0.10 g, 0.42 mmol) was dissolved in a 0.04 N solution of
HCl in MeOH (10 mL) and treated with 10% Pd/C (0.090 g,
0.084 mmol). The mixture was stirred under H2 for 24 h. After
filtration through Celite, the solvent was evaporated under
reduced pressure. The residue was treated with 50% NaOH
and extracted with CH2Cl2. After the evaporation of the
solvent, the crude product was chromatographed on a silica
gel column with CH2Cl2/MeOH/30% NH3 (5:1:1) as eluent to
obtain 0.030 g (51%) of (2R*,7aS*)-2,3,5,6,7,7a-hexahydro-1H-
pyrrolizine-2-methanol (15) as an oil: 1H NMR (δ, CDCl3, 300
MHz) 1.12 (dt, J ) 9.0, 12.0 Hz, 1H, H-1), 1.41-1.53 (m, 1H,
H-7), 1.68-1.98 (overlapping, 4H, H-6, H-6, H-7, OH, 3H after
deuteriation), 2.11 (dt, J ) 6.3, 12.0 Hz, 1H, H-1), 2.24 (dd, J
) 9.2, 10.5 Hz, 1H, H-3), 2.48 (ddddt, J ) 6.1, 6.3, 6.4, 9.0,
10.5 Hz, 1H, H-2), 2.59 (dt, J ) 6.2, 10.5 Hz, 1H, H-5), 2.96
(dt, J ) 6.2, 10.5 Hz, 1H, H-5), 3.24 (dd, J ) 6.4, 9.2 Hz, 1H,
H-3), 3.57 (dddd, J ) 6.3, 6.4, 9.0, 10.5 Hz, 1H, H-7a), 3.64 (d,
J ) 6.1 Hz, 2H, CH2OH); 13C NMR (δ, CDCl3, 75 MHz) 25.7
(t, C-6), 32.3 (t, C-7), 36.1 (t, C-1), 44. 8 (d, C-2), 54.8 (t, C-5),
58.3 (t, C-3), 64.7 (t, CH2OH), 65.8 (d, C-7a); IR (Nujol) 3380
cm-1; MS m/z 141 (M+). Anal. Calcd for C8H15NO: C, 68.03;
H, 10.71; N, 9.92. Found: C, 67.90; H, 10.65; N, 9.81.
(R)-N-[(1-Allylp yr r ol-2-yl)m eth ylid en e]-r-m eth ylben -
zen em eth a n a m in e N-Oxid e (17). A suspension of 5 (1.50
g, 11.1 mmol), 16 (1.54 g, 11.2 mmol) and Al2O3 (15.0 g) in
Et2O (40 mL) was stirred at room temperature for 5 d. After
filtration and evaporation of the solvent under reduced pres-
sure, the residue was chromatographed on a silica gel column
with AcOEt as eluent to give 1.36 g (48%) of 17: mp 122-124
°C (from hexane/benzene); [R]2D5 ) +12.5 (c ) 0.18, CHCl3); 1H
NMR (δ, CDCl3, 300 MHz) 1.88 (d, J ) 6.6 Hz, 3H), 4.46 (br d,
J ) 4.9 Hz, 2H), 4.85 (br d, J ) 17.1 Hz, 1H), 5.10 (q, J ) 6.6
1H), 5.11 (br d, J ) 10.3 Hz, 1H), 5.80 (ddt, J ) 4.9, 10.3, 17.1
Hz, 1H), 6.26 (dd, J ) 2.7, 3.6 Hz, 1H), 6.76 (dd, J ) 1.3, 2.7
Hz, 1H), 7.31 (s, 1H), 7.35-7.49 (m, 5H), 7.82 (dd, J ) 1.3, 3.6
Hz, 1H); MS m/z 254 (M+). Anal. Calcd for: C16H18N2O: C,
75.55; H, 7.14; N, 11.02. Found: C, 75.59; H, 7.05; N, 10.94.
In tr a m olecu la r Cycloa d d ition of Nitr on e 17. A solu-
tion of 17 (0.96 g, 3.8 mmol) in toluene (70 mL) was refluxed
for 24 h. The solvent was evaporated under reduced pressure,
and the residue was chromatographed on a silica gel column
with AcOEt/light petroleum (1:1) as eluent. The first fraction
gave 0.086 g (9%) of (+)-(RR,3aR,8bR)-1-(R-phenylethyl)-1,-
3a,4,8b-tetrahydro-3H-isoxazolo[3,4-a]pyrrolizine (21) as an
1
oil: [R]D ) +48.9 (c ) 0.190, CHCl3); H NMR (δ, CDCl3, 300
MHz) 1.51 (d, J ) 6.6 Hz, 3H, Me), 3.74 (dd, J ) 4.7, 8.2 Hz,
1H, H-3), 3.82 (ddddd, J ) 3.5, 4.7, 7.3, 7.9, 8.1 Hz, 1H, H-3a),
3.94 (dd, J ) 3.6, 10.6 Hz, 1H, H-4), 4.03 (q, J ) 6.6 Hz, 1H,
CHMe), 4.08 (dd, J ) 8.1, 10.6 Hz, 1H, H-4), 4.14 (dd, J ) 7.3,
8.2 Hz, 1H, H-3), 4.55 (d, J ) 7.9 Hz, 1H, H-8b), 5.91 (dd, J )
1.4, 3.5 Hz, 1H, H-8), 6.26 (dd, J ) 2.7, 3.5 Hz, 1H, H-7), 6.56
(dd, J ) 1.4, 2.7 Hz, 1H, H-6), 7.22-7.45 (m, 5H, Ph);13C NMR
(δ, CDCl3, 75 MHz) 22.0 (q), 50.2 (d), 50.7 (t), 63.9 (d), 66.1
(d), 71.7 (t), 101.0 (d), 113.7 (d), 113.9 (d), 127.4 (s), 127.5 (d),
127.8 (d), 128.5 (d), 143.2 (s); MS: m/z 254 (M+). Anal. Calcd
for C16H18N2O: C, 75.55; H, 7.14; N, 11.02. Found: C, 75.45;
H, 7.15; N, 10.91. The second fraction contained 0.12 g (12%)
of (+)-(RR,3aS,8bS)-1-(R-phenylethyl)-1,3a,4,8b-tetrahydro-3H-
isoxazolo[3,4-a]pyrrolizine (20) isolated as an oil: [R]D ) +10.3
(c ) 0.18, CHCl3);1H NMR (δ, CDCl3, 300 MHz) 1.50 (d, J )
6.3 Hz, 3H, Me), 3.80 (ddddd, J ) 2.9, 3.0, 7.3, 7.8, 8.0 Hz,
1H, H-3a), 3.83 (dd, J ) 3.0, 8.9 Hz, 1H, H-3), 3.93 (dd, J )
2.9, 10.6 Hz, 1H, H-4), 3.95 (q, J ) 6.3 Hz, 1H, CHMe), 4.10
(dd, J ) 7.8, 10.6 Hz, 1H, H-4), 4.22 (dd, J ) 8.0, 8.9 Hz, 1H,
H-3), 4.54 (d, J ) 7.3 Hz, 1H, H-8b), 5.38-5.58 (m, 1H, H-8),
6.13-6.22 (m, 1H, H-7), 6.45-6.52 (m, 1H, H-6), 7.27-7.45
(m, 5H, Ph); 13C NMR (δ, CDCl3, 75 MHz) 21.9 (q), 50.0 (d),
50.8 (t), 63.7 (d), 66.1 (d), 71.5 (t), 100.7 (d), 113.4 (d), 113.7
(d), 127.4 (s), 127.4 (d), 127.6 (d), 128.4 (d), 143.0 (s); MS m/z
254 (M+). Anal. Calcd for C16H18N2O: C, 75.55; H, 7.14; N,
11.02. Found: C, 75.67; H, 7.26; N, 11.11. The third fraction
gave 0.32 g (33%) of (+)-(RR,1S,4R)-2-(R-phenylethyl)-1,2,4,5-
tetrahydro-1,4-methanopyrrolo[2,1-d][1,2,5]oxadiazepine (18)
1
as an oil: [R]D ) +33.3 (c ) 1.0, CHCl3); H NMR (δ, CDCl3,
300 MHz) {major conformer} 1.32 (d, J ) 6.5 Hz, 3H, Me),
2.25 (br d, J ) 11.0 Hz, 1H, H-10), 2.79-2.84 (m, 1H, H-10),
3.13 (q, J ) 6.5, 1H, CHMe), 3.94 (br d, J ) 13.2 Hz, 1H, H-5),
4.05 (br d, J ) 13.2 Hz, 1H, H-5), 4.55 (br d, J ) 4.3 Hz, 1H,
H-1), 4.64 (br d, J ) 6.2 Hz, 1H, H-4), 6.11-6.14 (m, 1H, H-9),
6.21-6.23 (m, 1H, H-8), 6.64-6.69 (m, 1H, H-7), 7.40-7.45
(m, 5H, Ph), {minor conformer} 1.49 (d, J ) 6.5 Hz, 3H, Me),
2.19 (br d, J ) 11.1 Hz, 1H, H-10), 2.55-2.62 (m, 1H, H-10),
3.77 (q, J ) 6.5 Hz, 1H, CHMe), 3.94 (br d, J ) 13.2 Hz, 1H,
H-5), 4.13 (br d, J ) 13.2 Hz, 1H, H-5), 4.16 (br s, 1H, H-1),
4.95 (br s, 1H, H-4), 5.65-5.70 (m, 1H, H-9), 6.05-6.09 (m,
1H, H-8), 6.47-6.52 (m, 1H, H-7), 7.18-7.41 (m, 5H, Ph); 13
NMR (δ, CDCl3, 75 MHz) {major conformer} 21.4 (q), 36.1 (t),
C

9284 J . Org. Chem., Vol. 63, No. 25, 1998
Arnone et al.
53.0 (t), 54.5 (d), 63.0 (d), 72.0 (t), 106.3 (d), 107.8 (d), 119.7
(d), 126.7 (d), 127.0 (d), 127.4 (s), 128.0 (d), 144.3 (s), {minor
conformer} 21.2 (q), 31.8 (t), 52.1 (t), 55.0 (d), 66.5 (d), 73.8
(d), 102.7 (d), 108.0 (d), 119.1 (d), 126.7 (d), 127.3 (d), 127.4
(s), 128.5 (d), 143.3 (s); MS m/z 254 (M+). Anal. Calcd for
(-)-(6S,8a S)-6-H yd r oxy-1,2,3,5,6,7,8,8a -oct a h yd r oin -
d olizid in e (13). Obtained in 28% yield from 19 according to
the procedure described for the racemate. [R]D ) -23.4 (c )
0.16, CHCl3). Anal. Calcd for C8H15NO: C, 68.03; H, 10.71;
N, 9.92. Found: C, 68.11; H, 10.85; N, 10.06.
C
16H18N2O: C, 75.55; H, 7.14; N, 11.02. Found: C, 75.63; H,
(-)-(6R,8a S)-6-H yd r oxy-1,2,3,5,6,7,8,8a -oct a h yd r oin -
d olizin e (14). Obtained in 24% yield from 19 according to
the procedure described for the racemate. [R]D ) -26.6 (c )
0.16, CHCl3). Anal. Calcd for C8H15NO: C, 68.03; H, 10.71;
N, 9.92. Found: C, 67.94; H, 10.58; N, 9.80. Treatment of
(-)-14 with (+)-(2R,3R)-dibenzoyltartaric anhydride, as de-
scribed for its enantiomer, gave the crude monoester: 1H NMR
(δ, CD3OD, 300 MHz) 1.45-2.15 (overlapping, 11H), 3.10-3.65
(overlapping, 2H), 5.15 (broad s, 1H), 6.10 (broad s, 1H), 6.22
(broad s, 1H), 7.40-7.70 (m, 6H), 7.96-8.18 (m, 4H); MS m/z
481 (M+).
(+)-(1S,2S)-1-Am in o-2,3-dih ydr o-1H-pyr r olizin e-2-m eth -
a n ol (12). Obtained in 66% yield from 20 according to the
procedure described for the racemate. [R]D ) +20.2 (c ) 0.10,
CHCl3). Anal. Calcd for C8H12N2O: C, 63.12; H, 7.95; N,
18.41. Found: C, 63.25; H, 7.79; N, 18.29.
7.03; N, 11.13. The last fraction contained 0.23 g (24%) of (+)-
(RR,1R,4S)-2-(R-phenylethyl)-1,2,4,5-tetrahydro-1,4-methano-
pyrrolo[2,1-d][1,2,5]oxadiazepine (19) isolated as an oil: [R]D
) +25.4 (c ) 0.10, CHCl3);1H NMR (δ, CDCl3, 300 MHz, T )
-40 °C) 1.42 (d, J ) 6.4 Hz, 3H, Me), 2.14 (br d, J ) 10.9 Hz,
1H, H-10), 2.79 (ddd, J ) 4.8, 6.5, 10.9 Hz, 1H, H-10), 3.28 (q,
J ) 6.4 Hz, 1H, CHMe), 3.98 (br d, J ) 12.0 Hz, 1H, H-5),
4.12 (br d, J ) 12.0 Hz, 1H, H-5), 4.11 (br d, J ) 4.8 Hz, 1H,
H-1), 4.82 (ddd, J ) 2.1, 2.2, 6.5 Hz, 1H, H-4), 5.61 (dd, J )
1.4, 3.5 Hz, 1H, H-9), 6.14 (dd, J ) 2.7, 3.5 Hz, 1H, H-8), 6.64
(dd, J ) 1.4, 2.7 Hz, 1H, H-7), 7.21-7.34 (m, 5H, Ph); 13C NMR
(δ, CDCl3, 75 MHz) 23.1 (q), 36.3 (t), 53.2 (t), 54.6 (d), 63.4 (d),
72.5 (d), 107.3 (d), 107.7 (d), 119.4 (d), 127.1 (d), 127.4 (s), 127.7
(d), 128.1 (d), 143.1 (s); MS m/z 254 (M+). Anal. Calcd for
C
16H18N2O: C, 75.55; H, 7.14; N, 11.02. Found: C, 75.49; H,
7.05; N, 10.91.
(-)-(1R,2R)-1-Am in o-2,3-dih ydr o-1H-pyr r olizin e-2-m eth -
a n ol (12). Obtained in 59% yield from 21 according to the
procedure described for the racemate. [R]D ) -20.7 (c ) 0.10,
CHCl3). Anal. Calcd for C8H12N2O: C, 63.12; H, 7.95; N,
18.41. Found: C, 62.98; H, 8.12; N, 18.32.
(+)-(2R,7a S)-2,3,5,6,7,7a -Hexa h yd r o-1H-p yr r olizin e-2-
m eth a n ol (15). Obtained in 46% yield from 20 according to
the procedure described for the racemate. [R]D ) +20.5 (c )
0.10, CHCl3). Anal. Calcd for C8H15NO: C, 68.03; H, 10.71;
N, 9.92. Found: C, 67.86; H, 10.58; N, 10.08.
(-)-(2S,7a R)-2,3,5,6,7,7a -Hexa h yd r o-1H-p yr r olizin e-2-
m eth a n ol (15). Obtained in 52% yield from 21 according to
the procedure described for the racemate. [R]D ) -20.8 (c )
0.34, CHCl3). Anal. Calcd for C8H15NO: C, 68.03; H, 10.71;
N, 9.92. Found: C, 68.15; H, 10.87; N, 9.84.
(+)-(6R)-6-Hyd r oxy-5,6,7,8-tetr a h yd r oin d olizid in e (10).
Obtained in 68% yield from 18 according to the procedure
described for the racemate. [R]D ) +36.1 (c ) 0.14, CHCl3).
Anal. Calcd for C8H11NO: C, 70.04; H, 8.08; N, 10.21.
Found: C, 69.92; H, 7.98; N, 10.11.
(-)-(6S)-6-Hyd r oxy-5,6,7,8-tetr a h yd r oin d olizid in e (10).
Obtained in 65% yield from 19 according to the procedure
described for the racemate. [R]D ) -31.1 (c ) 0.18, CHCl3).
Anal. Calcd for C8H11NO: C, 70.04; H, 8.08; N, 10.21.
Found: C, 70.16; H, 8.16; N, 10.29.
(+)-(6R,8a R)-6-H yd r oxy-1,2,3,5,6,7,8,8a -oct a h yd r oin -
d olizid in e (13). Obtained in 27% yield from 18 according to
the procedure described for the racemate. [R]D ) +23.1 (c )
0.17, CHCl3). Anal. Calcd for: C8H15NO: C, 68.03; H, 10.71;
N, 9.92. Found: C, 67.95; H, 10.60; N, 9.81.
(+)-(6R,8a S)-6-H yd r oxy-1,2,3,5,6,7,8,8a -oct a h yd r oin -
d olizin e (14). Obtained in 21% yield from 18 according to
the procedure described for the racemate. [R]D ) +24.7 (c )
0.16, CHCl3). Anal. Calcd for: C8H15NO: C, 68.03; H, 10.71;
N, 9.92. Found: C, 67.87; H, 10.83; N, 9.79. A solution of
(+)-14 (10 mg, 0.07 mmol) and (+)-(2R,3R)-dibenzoyltartaric
anhydride (24 mg, 0.07 mmol) in CH2Cl2 (2 mL) was stirred
for 48 h. The solvent was evaporated to give the crude
monoester: 1H NMR (δ, CD3OD, 300 MHz) 1.50-2.30 (over-
lapping, 11H), 3.10-3.55 (overlapping, 2H), 5.06-5.14 (m, 1H),
5.71 (d, J ) 5.6 Hz, 1H), 5.79 (d, J ) 5.6 Hz, 1H), 7.42-7.67
(m, 6H), 7.98-8.12 (m, 4H); MS m/z 481 (M+).
Ack n ow led gm en t. Thanks are due to MURST and
CNR for financial support.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra for compounds 7-10, 12-15, and 18-21 as well
as of two-dimensional NMR spectra for compounds 13-15 (30
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
J O9810415