Synthesis of enantiopure 3-substituted pyrroline N-oxides by highly regioselective oxidation of the parent hydroxylamines: A mechanistic rationale

Article abstract of DOI:10.1021/jo962372p

The syntheses of four new, differently O-substituted 3-hydroxypyrroline N-oxides and the first 3-amino analogue have been performed by the use of a strategy involving double nucleophilic displacement of the corresponding dimesylates by hydroxylamine and oxidation of the resulting 1-hydroxypyrrolidines. The regioselectivity data of the oxidation reactions nicely confirm the mechanistic hypothesis, which explains the dependence on the electronic nature of the substituent. The trend of the regioselectivity ratio has useful predictive value. Practical complete regioselection has been obtained by substitution with a benzoyloxy functionality. The O-allyl-substituted nitrone is not stable in the reaction conditions, undergoing immediately an intramolecular cycloaddition reaction with complete stereocontrol and inversion of regio- and stereoselectivity with respect to the intermolecular case.

Full text of DOI:10.1021/jo962372p

J . Org. Chem. 1997, 62, 3119-3125
3119
Syn th esis of En a n tiop u r e 3-Su bstitu ted P yr r olin e N-Oxid es by
High ly Regioselective Oxid a tion of th e P a r en t Hyd r oxyla m in es: A
Mech a n istic Ra tion a le
Andrea Goti,* Stefano Cicchi, Valentina Fedi, Luca Nannelli, and Alberto Brandi*
Centro di Studio C.N.R. sulla Chimica e la Struttura dei Composti Eterociclici e loro Applicazioni
(CSCEA), Dipartimento di Chimica organica “Ugo Schiff”, Universita` di Firenze, via G. Capponi 9,
I-50121 Firenze, Italy
Received December 18, 1996X
The syntheses of four new, differently O-substituted 3-hydroxypyrroline N-oxides and the first
3-amino analogue have been performed by the use of a strategy involving double nucleophilic
displacement of the corresponding dimesylates by hydroxylamine and oxidation of the resulting
1-hydroxypyrrolidines. The regioselectivity data of the oxidation reactions nicely confirm the
mechanistic hypothesis, which explains the dependence on the electronic nature of the substituent.
The trend of the regioselectivity ratio has useful predictive value. Practical complete regioselection
has been obtained by substitution with a benzoyloxy functionality. The O-allyl-substituted nitrone
is not stable in the reaction conditions, undergoing immediately an intramolecular cycloaddition
reaction with complete stereocontrol and inversion of regio- and stereoselectivity with respect to
the intermolecular case.
Sch em e 1
In tr od u ction
Enantiomerically pure five-membered cyclic nitrones
substituted with protected hydroxy functionalities1 have
been recently used as new chiral building blocks for the
synthesis of natural and unnatural polyhydroxy-
indolizidines,1d,2 potential glycosidase inhibitors.3 Di-
substituted nitrones 1 (Scheme 1), derived from un-
expensive L-tartaric acid, and the corresponding enan-
tiomers, have been applied quite extensively.1b,c,2 Ni-
trones 1 were obtained from the starting acid by two
alternative strategies (Scheme 1),1a-c whose convenience
depends on the choice of the protecting groups. Route a
requires immediate protection of the secondary hydroxyl
groups, followed by reduction of the ester, tosylation, and
ring-closure with hydroxylamine.1a In our hands, this
route proved to be more efficient and reproducible when
the nature of the protecting groups is compatible with
the reaction conditions. This was not the case of silyl
protecting groups, which have the tendency to migrate
to the primary hydroxy groups in the reduction step.
When protection by silyl groups is desired, route b, which
consists of initial ring-closure to a pyrrolindione and
successive reduction and protection,1b,c should be used
instead. Both strategies require in the last step an
oxidation to nitrone, of a hydroxylamine4 and of an
amine,5 respectively. However, no matter of selectivity
Sch em e 2
X Abstract published in Advance ACS Abstracts, April 15, 1997.
(1) (a) Cicchi, S.; Ho¨ld, I.; Brandi, A. J . Org. Chem. 1993, 58, 5274.
(b) Ballini, R.; Marcantoni, E.; Petrini, M. J . Org. Chem. 1992, 57, 1316.
(c) Brandi, A.; Cicchi, S.; Goti, A.; Koprowski, A.; Pietrusiewicz, K. M.
J . Org. Chem. 1994, 59, 1315. (d) Cicchi, S.; Goti, A.; Brandi, A. J .
Org. Chem. 1995, 60, 4743.
(2) (a) Brandi, A.; Cicchi, S.; Cordero, F. M.; Frignoli, R.; Goti, A.;
Picasso, S.; Vogel, P. J . Org. Chem. 1995, 60, 6806. (b) Giovannini, R.;
Marcantoni, E.; Petrini, M. J . Org. Chem. 1995, 60, 5706. (c) Mc Caig,
A. E.; Wightman, R. H. Tetrahedron Lett. 1993, 34, 3939. (d) Goti, A.;
Cardona, F.; Brandi, A.; Picasso, S.; Vogel, P. Tetrahedron: Asymm.
1996, 7, 1659. (e) Goti, A.; Cardona, F.; Brandi, A. Synlett 1996, 761.
(3) Reviews: (a) Elbein, A. D. Annu. Rev. Biochem. 1987, 56, 497.
(b) Vogel, P. Chim. Oggi 1992, 10, 9. (c) Winchester, B.; Fleet, G. W.
J . Glycobiology 1992, 2, 199. (d) Legler, G. Adv. Carbohydr. Chem.
Biochem. 1990, 48, 319. (e) Fellows, L. E. Chem. Br. 1987, 23, 842. (f)
Fellows, L. E. New Sci. 1989, 123, 45.
arises in these oxidations, since the nitrone precursors
possess a C2 symmetry.
On the contrary, the question of regioselectivity arose
in the oxidation of hydroxylamine 3, synthesized by a
modification of route a starting from L-malic acid.1d
However, a practicable 9:1 ratio in favor of nitrone 4, with
respect to its regioisomer 5, was obtained in the first
example of this strategy (Scheme 2).1d The high regio-
isomeric ratio of the hydroxylamine to nitrone oxidation
(5) (a) Murahashi, S.-I.; Shiota, T. Tetrahedron Lett. 1987, 28, 2383.
(b) Murahashi, S.-I.; Mitsui, H.; Shiota, T.; Tsuda, T.; Watanabe, S. J .
Org. Chem. 1990, 55, 1736. (c) Marcantoni, E.; Petrini, M.; Polimanti,
O. Tetrahedron Lett. 1995, 36, 3561. (d) Goti, A.; Nannelli, L.
Tetrahedron Lett. 1996, 37, 6025.
(4) (a) Hamer, J .; Macaluso, A. Chem. Rev. 1964, 64, 473. (b) Goti,
A.; De Sarlo, F.; Romani, M. Tetrahedron Lett. 1994, 35, 6571.
S0022-3263(96)02372-9 CCC: $14.00 © 1997 American Chemical Society

3120 J . Org. Chem., Vol. 62, No. 10, 1997
Goti et al.
Sch em e 3a
Sch em e 4a
has been related to the electron-withdrawing properties
of the OtBu group, which stabilizes a developing negative
charge on the R-carbon atom. Consistently with this
interpretation, alkyl groups at C-3 gave a scarce 1.8-
2:1 selectivity.1d Meanwhile, Murahashi has obtained a
somewhat lower 6.8:1 ratio in the direct oxidation of the
3(R)-OTBDMS-substituted pyrrolidine to the correspond-
ing nitrones.6
In this Article we report the synthesis of a series of
3-hydroxypyrroline N-oxides substituted at the oxygen
with a variety of different groups and also of a related
3-amino-substituted nitrone. The results of the oxidation
reactions furnish a tool to predict the selectivity of the
oxidation and to choose the appropriate protecting group
in order to obtain synthetically useful selectivities.
physical data of 8b and 9b with those previously reported
for the enantiomeric nitrones.6 The measured 8/9 ratio
was 5:1 for the nitrones having the free hydroxy groups
and 12:1 for the OTBDMS substituted ones. It is
noteworthy that this ratio is almost double than the one
obtained by Murahashi and co-workers for formation of
the enantiomeric nitrones by direct oxidation of the
corresponding pyrrolidine,6 suggesting a higher selectiv-
ity for the HgO oxidation of hydroxylamines.
While the major nitrone 8b was easily separated from
its regioisomer 9b, analogous separation failed in the case
of 8a . Moreover, all the compounds 7a , 8a , and 9a are
very polar and hardly recoverable from the reaction
mixtures, which might partly account for the low yields
of nitrones obtained. However, nitrone 8a was obtained
as a pure solid in good overall yield by desilylation of 8b
with fluoride ions (Scheme 3), while direct deprotection
of nitrone 4 failed. Use of CsF in absolute EtOH7 gave
the best results in the deprotection of 8b, whereas TBAF
in THF made the nitrone purification difficult by the
presence of ammonium salts as side-products. The same
procedure on nitrone 9b gave the hydroxy nitrone 9a .
The allyl protecting group was interesting in both
mechanistic and synthetic aspects, as it is slightly less
electron-donating and encumbered than t-Bu and, at the
same time, contains a dipolarophile for internal trapping
of the nitrone moiety (Scheme 4).
Resu lts a n d Discu ssion
As already pointed out, the synthesis of silylated
nitrones of type 1 by route a is prevented by scrambling
of the silicon moiety when primary hydroxy groups are
present. In order to avoid this drawback, the direct
deprotection of dimesylate 2 with trifluoroacetic acid was
attempted with success (Scheme 3). The alcohol 6a was
then protected with chloro-tert-butyldimethylsilane to
give the corresponding silyl ether 6b. Both dimesylates
6 were converted into a mixture of the regioisomeric
nitrones 8 and 9 by a one-pot, two-step procedure via the
corresponding hydroxylamines 7 (Scheme 3). The latter
compounds are difficult to purify and were only charac-
terized spectroscopically by 1H NMR and oxidized in situ
with yellow HgO.4a Structural assignment to nitrones 8
and 9 could be easily made on the basis of the different
shape and chemical shifts of the proton signals for
hydrogen atoms on C-2 and C-3 in 8 with respect to the
corresponding on C-2 and C-4 in 9. Both protons gave
less-coupled signals in 8 than in 9, and the proton
attached at the substituted carbon atom was significantly
more deshielded in 8 (∆δ > 0.5 ppm). The structural
assignment was finally confirmed by comparison of
Allyl derivatization of the hydroxy group of 6a was only
possible through allyl trichloroacetimidate,8 which avoids
basic conditions. Double nucleophilic displacement of the
mesylate 10 and oxidation gave a mixture of nitrone 13
(7) Desilylation with CsF in THF failed due to the low solubility of
the cesium salt, which, on the contrary, is the most soluble alkaline
fluoride in absolute EtOH: Rand, L.; Swisher, J . V.; Cronin, C. J . J .
Org. Chem. 1962, 27, 3505.
(6) Murahashi, S.-I.; Imada, Y.; Ohtake, H. J . Org. Chem. 1994, 59,
6170.
(8) Wessel, H.-P.; Iversen, T.; Bundle, D. R. J . Chem. Soc., Perkin
Trans. 1 1985, 2247.

Synthesis of Enantiopure 3-Substituted Pyrroline N-Oxides
J . Org. Chem., Vol. 62, No. 10, 1997 3121
Sch em e 5
F igu r e 1. Preferred transition states for the inter- and
intramolecular cycloadditions to 3-OR-substituted nitrones.
Sch em e 6a
the furo[2,3-b]pyrrole skeleton (Scheme 4).13 Mesylation
and hydrogenation of the major cycloadduct 18 afforded
the hydroxypyrrolizidine 22 (Scheme 5).1d,2c,e,14
and cycloadduct 14 in 1:9 ratio (Scheme 4). The nitrone
12 was not even observed in the reaction mixture after
oxidation, since it underwent completely intramolecular
trapping to 14, while its regioisomer 13 was unreactive
in the same conditions. Complete regio- and stereo-
selectivity was attained in the intramolecular cyclo-
addition to furnish exclusively the cycloadduct 14, a
result that is reverse and complementary with the
analogous intermolecular cycloaddition. Indeed, cyclo-
addition of nitrone 8b to allyl alcohol 17 gave a mixture
of four cycloadducts 18-21 in a 23:5:4:1 ratio, independ-
ently on the reaction temperature (Scheme 5). Assign-
ment of the relative stereochemistry to all the adducts
18-21 was possible on the basis of 2D NOESY spectra
and comparison with analogous cycloaddition products.1c,d,2
All the adducts 18-21 derived from the regiochemical
approach opposite to the intramolecular version and the
major one was the exo-anti adduct (Figure 1).1c,d,2,9 The
cycloaddition of nitrone 8a to allyl alcohol gave the
related adducts in a 23:4:2:1 ratio,10 showing that the
protecting group has virtually no influence on the dia-
stereoselective approaches of the reactants.11
Finally, the benzoyl protecting group was considered
as a candidate to further stabilize an incipient R-anion
in the pyrrolidine ring. Standard benzoylation of 6a gave
the ester 23 which was cyclized and oxidized as usual
(Scheme 6). Oxidation of hydroxylamine 24 gave selec-
tively the nitrone 25, no trace of its regioisomer being
1
detectable by H NMR in the crude reaction mixture.
In order to achieve a more complete picture of depend-
ence on substituents of the regiochemistry of oxidation,
extension of the same process to the nitrogen-substituted
diol 26 was attempted (Scheme 7). Diol 2615 was
obtained in two steps from L-aspartic acid as previously
reported.16 The subsequent reactions were complicated
by formation of several side products, probably due to
the reported equilibrium of dimesylate 27 with aziri-
dinium ion 28, prone to undergo several different trans-
formations,17 and no intermediate 27 or 29 could be
isolated in pure form (Scheme 7). However, completion
of the three-step process in situ allowed the isolation and
characterization of the expected nitrones 30 and 31,
although in very low yield, which were formed in a 4:1
ratio (Scheme 7).
The same nitrone 30 was synthesized from diol 26 by
a different route, according to Scheme 8. Monomesyl-
ation occurred mainly at the less encumbered position
to give the intermediate 32, as previously reported.18 This
monomesylate was directly oxidized in situ by the Swern
procedure to afford the aldehyde 33, which was obtained
chemically pure in 25% yield from 26 by flash column
chromatography on silica. The following oximation gave
Formation of the adduct 14 in the intramolecular
version is ascribed to a high preference for an endo-syn
transition state, due to the constraint imposed by the
short three-atom connecting chain (Figure 1).12
The synthetic utility of both intra- and intermolecular
processes has been exemplified by the conversion of
cycloadducts 14 and 18 to the novel nitrogen heterocycles
16 and 22. Methylation and reductive isoxazolidine ring-
opening of 14 gave the bicyclic amino alcohol 16 having
(13) (a) Fraser, R. R.; Lin, Y. S. Can. J . Chem. 1968, 46, 801. (b)
Koizumi, T.; Hirai, H.; Yoshii, E. J . Org. Chem. 1982, 47, 4004.
(14) (a) Tufariello, J . J . Acc. Chem. Res. 1979, 12, 396. (b) Tufariello,
J . J .; Tette, J . P. J . Org. Chem. 1975, 40, 3866.
(15) (a) Gmeiner, P. Arch. Pharm. (Weinheim) 1991, 324, 551. (b)
Pedrocchi-Fantoni, G.; Servi, S. J . Chem. Soc., Perkin Trans. 1 1992,
1029.
(16) Gmeiner, P.; J unge, D.; Ka¨rtner, A. J . Org. Chem. 1994, 59,
6766.
(17) Gmeiner, P.; Orecher, F.; Thomas, C.; Weber, K. Tetrahedron
Lett. 1995, 36, 381.
(9) Syn and anti refer to the approaches of dipolarophile from the
same or the opposite face of the substituent at C-3 of the nitrone,
respectively.
(10) Nannelli, L. Tesi di Laurea, Universita` di Firenze, 1996.
(11) However, the cycloaddition of but-3-en-1-ol to nitrone 4 gave
only the exo adducts in 8:1 ratio,1d suggesting that selectivity strongly
depends on minor changes in dipolarophiles.
(12) Padwa, A. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A.,
Ed.; J ohn Wiley: New York, 1984; Vol. 2, p 277.
(18) Gmeiner, P.; Ka¨rtner, A. Synthesis 1995, 83.

3122 J . Org. Chem., Vol. 62, No. 10, 1997
Goti et al.
Sch em e 7a
Ta ble 1. Regioselective Ra tios in th e HgO Oxid a tion of
3-Su bstitu ted 1-Hyd r oxyp yr r olid in es
hydroxyl-
amine
yield
(%)
R
nitrones
ratio
reference
Me
Ph
(S)-NBn2
(S)-OH
34
37
29
7a
3
11
7b
24
35, 36
38, 39
30, 31
8a , 9a
4, 5
1.8
2
4
5
9
90
95
1d
1d
12a this work
24b this work
(S)-OtBu
80
100
1d
(S)-O-allyl
(S)-OTBDMS
(S)-OCOPh
12,c 13
8b, 9b
25
9
this work
12
>20
64b this work
50b this work
a
On a three-step reaction from the diol. b On a two-step reaction
from the dimesylate. c Calculated as the intramolecular cycload-
duct.
Sch em e 8a
F igu r e 2. Representation of orbital interaction of the 3-sub-
stituent with the trans hydrogen atom.
Sch em e 9
directly the nitrone 30 in quantitative yield by nucleo-
philic attack of the intermediate oxime nitrogen to the
carbon atom bearing the mesylate moiety.19 However,
the obtained nitrone was largely racemized, as proved
by the lower specific optical rotation with respect to the
nitrone obtained by oxidation of the hydroxylamine 29.
The observed partial racemization might have occurred
at the level of the intermediate aldehyde, since R-amino
aldehydes are known to suffer of configurational labil-
ity.20 Proof of this hypothesis derived from 1H NMR
spectra of the aldehyde 33 in the presence of the shift
reagent Yb(hfc)3, which showed the splitting of the
HsCdO signals. On the other hand, Reetz and co-
workers have reported the obtainment of configuration-
ally stable (at room temperature) R-dibenzylamino alde-
hydes by Swern oxidation of the corresponding alcohols,
but the aldehydes were used without purification and no
mention about configurational instability on purification
was made.21 Indeed, when the crude aldehyde 33 was
treated directly with hydroxylamine without purifi-
cation, the nitrone 30 was obtained enantiomerically
pure, proving that racemization had occurred during
chromatography of 33. The three-step in situ conversion
of diol 26 afforded nitrone 30 in 24% overall yield
(Scheme 8).
The results of the regioselectivity of oxidation of
3-substituted N-hydroxypyrrolidines are summarized in
Table 1.
Examination of these data shows a direct correlation
of the regioselectivity with the electronegativity of the
substituent. Steric effects seem to play only a minor
role,22 e.g. in enhancing the regioselectivity ratio from
hydroxylamine 3 with respect to the unprotected 7a .
These findings reinforce our reported mechanistic hy-
pothesis for the oxidation of hydroxylamines in a two-
step process (Scheme 9).1d,23 The substituents might play
their role in the second, rate-determining step by stabi-
lizing the incipient negative charge on the R carbon atom
by σC-H f σ*C-R donation (Figure 2). The greater is the
ability of the substituent in stabilizing the negative
charge, the higher the regioselectivity in the oxidation
reaction. The importance of the stereoelectronic effects
on the proton trans to the substituent, represented in
Figure 2 in both MO and VB notations, has already been
demonstrated by isotopic labeling.1d
(19) (a) Stork, G.; Darling, S. D.; Harrison, I. T.; Wharton, P. S. J .
Am. Chem. Soc. 1962, 84, 2018. (b) Stempel, A.; Douvan, I.; Sternbach,
L. H. J . Org. Chem. 1968, 33, 2963.
(20) See for example: (a) Hanson, G. H.; Lindberg, T. J . Org. Chem.
1985, 50, 5399. (b) Danishefsky, S.; Kobayashi, S.; Kerwin, J . F. J .
Org. Chem. 1982, 47, 1983. (c) Garner, P. J . Org. Chem. 1986, 51, 2609.
(d) Fehrens, J . A.; Castro, B. Synthesis 1983, 676. (e) Coj, D. H.; Hocart,
S. J .; Sasaki, Y. Tetrahedron 1988, 44, 835.
(22) Tufariello, J . J .; Lee, G. E. J . Am. Chem. Soc. 1980, 102, 373.
(23) (a) LeBel, N. A.; Post, M. E.; Hwang, D. J . Org. Chem. 1979,
44, 1819. (b) Asrof Ali, Sk.; Wazeer, M. I. M. Tetrahedron Lett. 1992,
33, 3219. (c) Asrof Ali, Sk. Tetrahedron Lett. 1993, 34, 5325. (d) Asrof
Ali, Sk. J . Chem. Res. (M) 1994, 301.
(21) Reetz, M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem., Int.
Ed. Engl. 1987, 26, 1141.

Synthesis of Enantiopure 3-Substituted Pyrroline N-Oxides
J . Org. Chem., Vol. 62, No. 10, 1997 3123
filtered and concentrated. The residue was purified by flash
column chromatography, eluent ethyl acetate, to give the
protected dimesylate 6b (2.61 g, 6.9 mmol, 84%) which
crystallized on standing. Mp 41-42 °C. Rf 0.44; [R]22D ) -13.3
(c 1.54, CHCl3); 1H NMR: δ 4.45-4.25 (m, 2H), 4.13 (m, 3H),
3.05 (s, 3H), 3.03 (s, 3H), 2.10 (m, 2H), 0.90 (s, 9H), 0.13 (s,
3H), 0.12 (s, 3H); 13C NMR: δ 72.3 (d), 67.1 (t), 66.1 (t), 38.0
(q, 2C), 34.1 (t), 26.2 (q, 3C), 17.8 (s), -4.0 (q), -4.5 (q); IR:
3029, 1171 cm-1; MS: m/ z (rel intensity) 376 (M+, 0.02), 249
(3), 153 (100). Anal. Calcd for C12H28O7S2Si: C, 38.28; H, 7.49.
Found: C, 38.70, H, 7.40.
Con clu sion s
From the synthetic point of view, very useful levels of
regioselectivity have been achieved for the synthesis of
the oxygen substituted nitrones, up to a complete selec-
tivity with the benzoate substituted one. The scale in
Table 1 also has a useful predictive value for the
selectivity to be expected in presence of a certain sub-
stituent. The obtainment of the amino-substituted ni-
trone 30 might prove useful for the construction of amino
indolizidinols and pyrrolizidinols related to the parent
polyhydroxy derivatives.1d,2 Finally, the facile and
straightforward assembly of a polycyclic skeleton as in
14 and 16 by the intramolecular version of cycloaddition
to this family of nitrones has been demonstrated. Ap-
plication of the inter- and intramolecular cycloaddition
methodologies to this family of enantiopure cyclic ni-
trones24 for the synthesis of natural products is underway
in our group.
3(S)-3-[(ter t-Bu t yld im et h ylsilyl)oxy]-N-h yd r oxyp yr -
r olid in e (7b) was obtained from 6b (520 mg, 1.38 mmol)
according to the general procedure and pure enough to be used
for the following step. A sample purified by chromatography
on silica, eluent ethyl acetate, afforded an analytically pure
1
oil. Rf 0.54; [R]20 ) -0.1 (c 1.58, CHCl3); H NMR: δ 4.47
D
(m, 1H), 3.32-3.14 (m, 2H), 3.02 (m, 1H), 2.97 (dd, J ) 12.0,
4.0 Hz, 1H), 2.20 (m, 1H), 1.75 (m, 1H), 0.86 (s, 9H), 0.04 (s,
6H); 13C NMR: δ 70.9 (d), 67.2 (t), 57.4 (t), 33.2 (t), 25.7 (q,
3C), 18.0 (s), -4.8 (q), -4.9 (q); IR: 3157, 1462 cm-1; MS: m/ z
(rel intensity) 215 (M+ - H2, 7), 83 (60), 75 (100), 73 (83). Anal.
Calcd for C10H23NO2Si: C, 55.25; H,10.66; N, 6.44. Found: C,
55.65; H, 10.99; N, 6.02.
Exp er im en ta l Section
(3S)-3-[(ter t-Bu tyld im eth ylsilyl)oxy]-1-p yr r olin e N-Ox-
id e (8b) a n d (4S)-4-[(ter t-Bu tyld im eth ylsilyl)oxy]-1-p yr -
r olin e N-Oxid e (9b). A 12:1 mixture of nitrones 8b and 9b
was obtained by the oxidation of 7b (256 mg, 1.18 mmol)
according to the general procedure. Separation of the regio-
isomeric nitrones by flash column chromatography, eluent
ethyl acetate, gave 8b (174 mg, 59%) and 9b (14 mg, 5%) as
pure solid compounds, which were recrystallized from petro-
leum ether. 8b: mp 74-75 °C. Rf 0.21; [R]21D ) -62.3 (c 1.04,
For instruments and generalities see ref 1d.
Gen er a l P r oced u r e for th e Syn th esis of N-Hyd r oxy-
p yr r olid in es b y Nu cleop h ilic Disp la cem en t of Di-
m esyla t es. A suspension of the dimesylate and hydroxyl-
amine hydrochloride (4 equiv) in triethylamine (8 mL/mmol)
was heated at reflux for 2-3 h. Triethylamine was then
evaporated off, and the resulting white solid was washed
thoroughly with diethyl ether. Ethereal extracts were then
concentrated to give the crude N-hydroxypyrrolidines.
Gen er a l P r oced u r e for th e Syn th esis of 2H-P yr r olin e
N-Oxid es by Oxid a tion of N-Hyd r oxyp yr r olid in es. Yel-
low mercury oxide (4 equiv) was added in portions to an ice-
cooled solution of the N-hydroxypyrrolidine in CH2Cl2 (10 mL/
mmol). The suspension was then stirred at room temperature
for 2-3 h. The reaction mixture was filtered through Celite
and concentrated to give the crude regioisomeric nitrones.
(2S)-2-H yd r oxy-1,4-b is[(m et h a n su lfon yl)oxy]b u t a n e
(6a ). A solution of (2S)-2-tert-butoxy-1,4-bis[(methansulfonyl)-
oxy]butane1d (2, 4.0 g, 12.5 mmol) in trifluoroacetic acid (4.6
mL, 60 mmol) was stirred at room temperature for 1 h. The
acid was distilled off at reduced pressure, and the residue was
recrystallized from CH2Cl2/Et2O 1:1 to give the pure title
CHCl3); [R]22 ) -59.8 (c 1.03, CH3OH) [lit. for the (R)-
D
enantiomer:6 mp 73.8-75.5 °C; [R]28D ) +55.9 (c 1.14, CH3OH)];
1H NMR: δ 6.83 (q, J ) 1.7 Hz, 1H), 5.01 (m, 1H), 4.15 (m,
1H), 3.86 (m, 1H), 2.56 (m, 1H), 2.08 (m, 1H), 0.89 (s, 9H),
0.09 (s, 6H); 13C NMR: δ 135.5 (d), 72.1 (d), 61.3 (t), 30.9 (t),
25.6 (q, 3C), 18.0 (s), -4.7 (q), -4.8 (q); IR: 1586, 1251 cm-1
;
MS: m/ z (rel intensity) 215 (M+, 16), 75 (100). Anal. Calcd
for C10H21NO2Si: C, 55.77; H, 9.83; N, 6.50. Found: C, 55.67;
H, 9.70; N, 6.20. 9b: mp 67.5-68.5 °C. Rf 0.06; [R]23D ) +46.5
(c 0.92, CH3OH) [lit. for the (R)-enantiomer:6 mp 72.1-72.9
°C; [R]28D ) -50.9 (c 1.14, CH3OH)]; 1H NMR: δ 6.88 (m, 1H),
4.64 (m, 1H), 4.12 (m, 1H), 3.80 (m, 1H), 3.01 (ddd, J ) 18.8,
4.4, 2.1 Hz, 1H), 2.62 (d, J ) 18.8 Hz, 1H), 0.88 (s, 9H), 0.08
(s, 6H); 13C NMR: δ 133.7 (d), 70.5 (d), 66.4 (t), 40.0 (t), 25.6
(q, 3C), 17.9 (s), -4.9 (q, 2C); IR: 1595, 1255 cm-1; MS: m/ z
(rel intensity) 215 (M+, 1), 101 (74), 75 (100). Anal. Calcd for
C10H21NO2Si: C, 55.77; H, 9.83; N, 6.50. Found: C, 56.07; H,
10.00; N, 6.39.
compound 6a (2.77 g, 10.5 mmol, 84%). Mp 65-66 °C. [R]20
D
) -17.9 (c 1.82, CH2Cl2); 1H NMR: δ 4.54-4.06 (m, 5H), 3.09
(s, 3H), 3.05 (s, 3H), 2.57 (br, 1H), 2.10-1.80 (m, 2H); 13C
NMR: δ 73.0 (d), 66.1 (t), 65.6 (t), 37.5 (q), 37.3 (q), 32.1 (t);
IR: 3615, 3410 (br), 3015, 1200 cm-1; MS: m/ z (rel intensity)
262 (M+, 2), 97 (92), 79 (100), 57 (100). Anal. Calcd for
C6H14O7S2: C, 27.47; H, 5.38. Found: C, 27.12, H, 5.30.
(2S)-2-[(ter t-Bu tyldim eth ylsilyl)oxy]-1,4-bis[(m eth an su l-
fon yl)oxy]bu ta n e (6b). tert-Butyldimethylchlorosilane (1.57
g, 10.4 mmol) was added at 0 °C to a solution of 6a (2.15 g,
8.2 mmol) and imidazole (562 mg, 8.2 mmol) in DMF (10 mL).
The mixture was stirred at rt for 1 d and then diluted with
water and extracted repeatedly with diethyl ether. The
collected organic phases were dried over Na2SO4 and then
(3S)-3-Hyd r oxy-1-p yr r olin e N-Oxid e (8a ) a n d (4S)-4-
Hyd r oxy-1-p yr r olin e N-Oxid e (9a ). A 5:1 mixture of ni-
trones 8a and 9a (24 mg, 24%) was obtained according to the
general procedures by treatment of dimesylate 6a (262 mg, 1
mmol) with hydroxylamine and direct oxidation of the result-
ing mixture.
Syn th esis of (3S)-3-Hyd r oxy-1-p yr r olin e N-Oxid e (8a )
by Dep r otection of 8b. A solution of 8b (800 mg, 3.71 mmol)
and cesium fluoride (733 mg, 4.83 mmol) in absolute EtOH
(41 mL) was stirred at rt for 18 h. The solvent was removed
in vacuo, and flash chromatography of the resulting mixture,
eluent AcOEt/MeOH 1:1, afforded the desired nitrone 8a (333
mg, 3.3 mmol, 90%) as a solid, which was recrystallized from
(24) For some recent examples on the synthesis and use of different
chiral, enantiomerically pure, cyclic nitrones, see: (a) Golik, J .; Wong,
H.; Krishnan, B.; Vyas, D. M.; Doyle, T. W. Tetrahedron Lett. 1991,
32, 1851. (b) Tronchet, J . M. J .; Zosimo-Landolfo, G.; Balkadjian, M.;
Ricca, A.; Zse´ly, M.; Barbalat-Rey, F.; Cabrini, D.; Lichtle, P.; Geoffroy,
M. Tetrahedron Lett. 1991, 32, 4129. (c) Grigg, R.; Markandu, J .;
Perrior, T.; Surendrakumar, S.; Warnock, W. J . Tetrahedron 1992, 48,
6929. (d) Herczegh, P.; Kova´cs, I.; Szila´gyi, L.; Varga, T.; Dinya, T.;
Sztaricskai, F. Tetrahedron Lett. 1993, 34, 1211. (e) Berranger, T.;
Langlois, Y. J . Org. Chem. 1995, 60, 1720. (f) de March, P.; Figueredo,
M.; Font, J .; Gallagher, T.; Mila´n, S. J . Chem. Soc., Chem. Commun.
1995, 2097. (g) van den Broek, L. A. G. M. Tetrahedron 1996, 52, 4467.
(h) Katagiri, N.; Okada, M.; Kaneko, C.; Furuya, T. Tetrahedron Lett.
1996, 37, 1801. (i) Ishikawa, T.; Tajima, Y.; Fukui, M.; Saito, S. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1863. (j) Tamura, O.; Gotanda, K.;
Terashima, R.; Kikuchi, M.; Miyawaki, T.; Sakamoto, M. J . Chem. Soc.,
Chem. Commun. 1996, 1861.
ethyl acetate. 8a : mp 105-107 °C. Rf 0.36; [R]21 ) -136.4
D
(c 0.94, CHCl3); 1H NMR: δ 7.01 (m, 1H), 4.98 (m, 1H), 4.31-
4.17 (m, 1H), 3.94-3.80 (m, 1H), 3.60-3.20 (br, 1H), 2.72-
2.54 (m, 1H), 2.25-2.10 (m, 1H); 13C NMR: δ 137.7 (d), 71.4
(d), 61.4 (t), 30.1 (t); IR: 3317 (br), 1586, 1245 cm-1; MS: m/ z
(rel intensity) 101 (M+, 37), 85 (62), 83 (100), 71 (64). Anal.
Calcd for C4H7NO2: C, 47.57; H, 6.98; N, 13.86. Found: C,
47.22; H, 7.05; N, 13.48.
Syn th esis of (4S)-4-Hyd r oxy-1-p yr r olin e N-Oxid e (9a )
by Dep r otection of 9b. The same procedure as above on
nitrone 9b (14 mg, 0.065 mmol) with cesium fluoride (20 mg,
0.13 mmol) afforded nitrone 9a (5 mg, 0.049 mmol, 76%) as a

3124 J . Org. Chem., Vol. 62, No. 10, 1997
Goti et al.
white solid. 9a : mp 115-116 °C. Rf 0.18; [R]20 ) +87.7 (c
then hydrogenated under pressure (70 psi) at rt for 12 h. The
crude reaction mixture was filtered over Celite and passed in
a column filled with Amberlyst-A26. After removal of the
solvent in vacuo, the product was purified on silica, eluent
CH2Cl2/CH3OH 20:1, to afford the pure amino alcohol 16 (141
mg, 1.12 mmol, 65%) as an oil. Rf 0.15; [R]20D ) -45.7 (c 1.07,
D
1
0.18, CHCl3); H NMR: δ 6.93 (q, J ) 1.9 Hz, 1H), 4.66 (t, J
) 6.0 Hz, 1H), 4.30 (br, 1H), 4.20 (m, 1H), 3.88 (d, J ) 15.1
Hz, 1H), 3.09 (m, 1H), 2.73 (d, J ) 18.7 Hz, 1H); 13C NMR: δ
134.3 (d), 70.5 (d), 65.7 (t), 39.6 (t); IR: 3275 (br) cm-1; MS:
m/ z (rel intensity) 101 (M+, 81), 83 (10), 72 (100). Anal. Calcd
for C4H7NO2: C, 47.57; H, 6.98; N, 13.86. Found: C, 47.32;
H, 7.06; N, 13.50.
1
CHCl3); H NMR: δ 4.67 (q, J ) 7.0 Hz, 1H), 4.06 (dd, J )
11.7, 2.9 Hz, 1H), 4.03-3.76 (AB part of an ABX system, 2H),
3.75 (dd, J ) 11.7, 4.0 Hz, 1H), 3.17 (t, J ) 7.1 Hz, 1H), 3.05
(ddd, J ) 10.2, 6.7, 3.4 Hz, 1H), 2.41 (s, 3H), 2.28 (dt, J ) 5.8,
10.2 Hz, 1H), 2.20-1.93 (m, 2H), 1.88-1.70 (m, 1H); 13C
NMR: δ 84.2 (d), 77.2 (d), 72.6 (d), 68.0 (t), 59.8 (t), 56.3 (t),
43.7 (q), 31.3 (t); IR: 1213 cm-1; MS: m/ z (rel intensity) 157
(M+, 11), 156 (16), 98 (100). Anal. Calcd for C8H15NO2: C,
61.12; H, 9.62; N, 8.91. Found: C, 61.00; H, 9.67; N, 9.37.
Cycloa d d ition of Nitr on e 8b to Allyl Alcoh ol (17). A
mixture of nitrone 8b (174 mg, 0.81 mmol) and allyl alcohol
(17, 1.5 mL) was heated at reflux for 3 d. Excess alcohol was
distilled off under reduced pressure to leave a crude mixture
of adducts 18-21 in a 23:5:4:1 ratio (by 1H NMR). Separation
by flash column chromatography, eluent ethyl acetate/
petroleum ether 8:1, gave the major adduct 18 (111 mg, 0.41
mmol, 50%) as a pure oil, adduct 19 containing some impuri-
ties of 18 (33 mg), and an inseparable mixture of adducts 20
and 21 (24 mg), for a 76% total yield in recovered cycloadducts.
A reaction run at 27 °C for 10 d gave a mixture of the adducts
18-21 (64% yield) in roughly the same ratio.
(2S)-2-(Allyloxy)-1,4-bis[(m eth a n su lfon yl)oxy]bu ta n e
(10). Trifluoromethanesulfonic acid (5 mL) was added por-
tionwise during 2 d to a solution of dimesylate 6a (2.25 g, 8.6
mmol) and allyltrichloroacetimidate8 (5.2 g, 17.2 mmol) in
CH2Cl2 (80 mL). The solution was stirred at rt for additional
5 d and then washed with H2O and saturated NaHCO3. After
removal of the solvent, the crude product was purified by
passage over a short pad of silica gel, eluent ethyl acetate/
petroleum ether 1:1, to give the desired allyloxy dimesylate
10 (1.5 g, 5.0 mmol, 58%) as a liquid. Rf 0.32; [R]22 ) -29.4
D
1
(c 0.97, CHCl3); H NMR: δ 5.90 (ddt, J ) 16.7, 10.8, 5.7 Hz,
1H), 5.35-5.17 (m, 2H), 4.46-4.28 (m, 3H), 4.28-3.98 (m, 3H),
3.85-3.73 (m, 1H), 3.05 (s, 3H), 3.02 (s, 3H), 2.05-1.93 (m,
2H); 13C NMR: δ 133.9 (d), 117.9 (t), 72.5 (d), 71.3 (t), 69.9 (t),
65.9 (t), 37.6 (q), 37.3 (q), 31.2 (t); IR: 3015, 1358, 1171 cm-1
;
MS: m/ z (rel intensity) 245 (M+ - OCH2CHdCH2, 3), 97 (100),
79 (100). Anal. Calcd for C9H18O7S2: C, 35.75; H, 6.00.
Found: C, 35.40, H, 6.02.
(3S)-3-(Allyloxy)-N-h yd r oxyp yr r olid in e (11). The hy-
droxylamine 11 was synthesized from 10 (1.5 g, 5.0 mmol)
under standard conditions. Purification by passage over a
short pad of silica, eluent ethyl acetate, gave 11 (330 mg, 2.28
mmol, 46%) as a pure oil. Rf 0.35; [R]26D ) +8.6 (c 0.74, CHCl3);
1H NMR: δ 8.36 (br, 1H), 5.88 (ddt, J ) 17.2, 10.2, 5.2 Hz,
1H), 5.30-5.12 (m, 2H) 4.18 (m, 1H), 4.05-3.90 (m, 2H), 3.29-
2.97 (m, 4H), 2.25-2.00 (m, 1H), 2.00-1.70 (m, 1H); 13C
NMR: δ 134.6 (d), 116.9 (t), 77.2 (d), 70.2 (t), 64.3 (t), 57.2 (t),
(2R ,3a R ,4S )-4-[(t er t -Bu t yld im e t h ylsilyl)oxy]-2-(h y-
d r oxym eth yl)h exa h yd r op yr r olo[1,2-b]isoxa zole (18). Rf
0.24; [R]21 ) -17.2 (c 1.27, CHCl3); 1H NMR: δ 4.17 (m, 1H),
D
4.07 (dt, J ) 5.8, 3.0 Hz, 1H), 3.70 (dd, J ) 11.8, 2.9 Hz, 1H),
3.60-3.52 (m, 1H), 3.56 (dd, J ) 11.8, 5.2 Hz, 1H), 3.32 (m,
2H), 2.43 (m, 1H), 2.27-2.05 (m, 2H), 1.80-1.60 (br, 1H),
1.73-1.62 (m, 1H), 0.88 (s, 9H), 0.06 (s, 6H); 13C NMR: δ 79.1
(d), 77.7 (d), 74.6 (t), 64.4 (d), 55.1 (t), 35.9 (t), 33.9 (t), 25.7 (q,
29.6 (t); IR: 3001, 1346, 1205 cm-1. Anal. Calcd for C7H13
-
3C), 17.9 (s), -4.7 (q), -4.8 (q); IR (CCl4): 3447, 1248 cm-1
;
MS: m/ z (rel intensity) 273 (M+, 1), 216 (13), 149 (18), 71 (48),
57 (100). Anal. Calcd for C13H27NO3Si: C, 57.10; H, 9.95; N,
5.12. Found: C, 57.37; H, 9.92; N, 4.78.
NO2: C, 58.72; H, 9.15; N, 9.78. Found: C, 58.84; H, 9.24; N,
9.78.
(4S)-4-(Allyloxy)-1-p yr r olin e N-Oxid e (13) a n d (2a R,
6a S,6bS)-P er h yd r o-1,4-d ioxa -4a -a za cyclop en ta [cd ]p en -
ta len e (14). Oxidation of the hydroxylamine 11 was ac-
complished in standard conditions, but the reaction mixture
was then stirred at rt for additional 14 h. After removal of
the solvent, the crude product was passed over a short pad of
silica, eluent ethyl acetate, to afford the pure cycloadduct 14
(240 mg, 1.7 mmol, 90%) and, by elution with methanol, the
(2S ,3a S ,4S )-4-[(t er t -Bu t yld im e t h ylsilyl)oxy]-2-(h y-
d r oxym eth yl)h exa h yd r op yr r olo[1,2-b]isoxa zole (19). Rf
0.22; 1H NMR: δ 4.13-4.07 (m, 2H), 3.88-3.81 (m, 1H), 3.76-
3.53 (m, 2H), 3.44-3.24 (m, 2H), 2.60-2.42 (m, 1H), 2.31-
2.14 (m, 2H), 1.92-1.60 (m, 2H), 0.88 (s, 9H), 0.06 (s, 6H); 13
C
NMR: δ 79.5 (d), 78.1 (d), 75.6 (t), 62.3 (d), 55.0 (t), 36.0 (t),
33.4 (t), 25.7 (q, 3C), 18.0 (s), -4.7 (q), -4.8 (q). (2S,3a R,4S)-
4-[(t er t -Bu t yld im e t h ylsilyl)oxy]-2-(h yd r oxym e t h yl)-
h exa h yd r op yr r olo[1,2-b]isoxa zole (20). Rf 0.08; 1H
NMR: δ 4.50-4.18 (m, 2H), 3.83-3.68 (m, 2H), 3.57 (dd, J )
11.7, 5.1 Hz, 1H), 3.23-3.10 (m, 2H), 2.90-2.80 (br, 1H), 2.45-
2.37 (m, 1H), 2.11-2.03 (m, 2H), 1.95-1.85 (m, 1H), 0.88 (s,
9H), 0.06 (s, 6H); 13C NMR: δ 78.6 (d), 72.1 (d), 69.2 (t), 63.5
(d), 53.4 (t), 34.1 (t), 31.2 (t), 25.7 (q, 3C), 18.0 (s), -4.7 (q),
-4.8 (q). (2R,3a S,4S)-4-[(ter t-Bu tyld im eth ylsilyl)oxy]-2-
(h yd r oxym eth yl)-h exa h yd r op yr r olo[1,2-b]isoxa zole (21).
Rf 0.08; 1H NMR: δ 4.48-4.15 (m, 2H), 3.88-3.63 (m, 3H),
3.47-3.35 (m, 1H), 3.02-2.85 (m, 1H), 2.90-2.80 (br, 1H),
2.52-2.48 (m, 1H), 2.15-1.98 (m, 2H), 1.91-1.83 (m, 1H), 0.88
(s, 9H), 0.06 (s, 6H); 13C NMR: δ 79.2 (d), 73.3 (d), 69.0 (t),
63.0 (d), 52.8 (t), 34.1 (t), 30.6 (t), 25.8 (q, 3C), 18.0 (s), -4.7
(q), -4.8 (q).
nitrone 13 (27 mg, 0.18 mmol, 10%). 14: [R]20 ) +58.5 (c
D
0.37, CH2Cl2); 1H NMR: δ 4.36 (dt, J ) 1.6, 4.8 Hz, 1H), 4.18
(dd, J ) 8.4, 4.8 Hz, 1H), 4.09 (t, J ) 8.4 Hz, 1H), 3.89 (dd, J
) 9.4, 1.5 Hz, 1H), 3.75 (dd, J ) 9.4, 5.1 Hz, 1H), 3.70 (dd, J
) 8.8, 7.3 Hz, 1H), 3.30-3.10 (m, 3H), 2.10 (dddd, J ) 13.7,
5.9, 3.7, 1.6 Hz, 1H), 1.85 (dddd, J ) 13.7, 9.4, 7.6, 4.6 Hz,
1H); 13C NMR: δ 83.1 (d), 75.8 (d), 71.6 (t), 70.5 (t), 52.4 (t),
51.0 (d), 30.0 (t); IR (CH2Cl2): 3043, 1096 cm-1; MS: m/ z (rel
intensity) 141 (M+, 89), 68 (93), 55 (100). Anal. Calcd for
C7H11NO2: C, 59.56; H, 7.85; N, 9.92. Found: C, 59.57; H,
7.72; N, 9.46. 13: 1H NMR: δ 6.86 (m, 1H), 6.00-5.80 (m,
1H), 5.36-5.20 (m, 2H), 4.44-4.33 (m, 1H), 4.20-4.08 (m, 1H),
4.04-3.90 (m, 3H), 3.12-2.92 (m, 1H), 2.86-2.70 (m, 1H); 13
C
NMR: δ 133.5 (d), 133.0 (d), 117.8 (t), 72.0 (d), 69.9 (t), 67.6
(t), 36.4 (t); MS: m/ z (rel intensity) 141 (M+, 100), 83 (24).
Anal. Calcd for C7H11NO2: C, 59.56; H, 7.85; N, 9.92.
Found: C, 59.43; H, 7.90; N, 9.54.
(1S,6R,7aR)-1-[(ter t-Bu tyldim eth ylsilyl)oxy]-6-h ydr oxy-
1H-h exa h yd r op yr r olizin e (22). Triethylamine (72 µL, 0.51
mmol) and methanesulfonyl chloride (29 µL, 0.38 mmol) were
added at 0 °C to a solution of cycloadduct 18 (94 mg, 0.34
mmol) in CH2Cl2 (2 mL). The mixture was reacted at rt for
15 min under stirring and then concentrated. The resulting
crude product was dissolved in CH3OH (18 mL) and poured
into a Parr bottle. 10% Palladium on charcoal (50 mg) was
added, and the mixture was hydrogenated at a Parr apparatus
at 45 psi. After 1 d the suspension was filtered over Celite
and Amberlyst A-26 and the filter washed thoroughly with
CH3OH. Removal of the solvent in vacuo gave an oil which
was purified by flash column chromatography, eluent CH3OH
+ 5% NH4OH, to afford the desired pyrrolizidine 22 (62 mg,
(3S,3a S,6a S)-3-(Hyd r oxym eth yl)-4-m eth yl-h exa h yd r o-
fu r o[2,3-b]p yr r ole (16). The adduct 14 (240 mg, 1.7 mmol)
was reacted with methyl iodide (1.37 mL, 22 mmol) in C6H6
(3 mL) at rt for 12 h. After removal of the solvent, the crude
ammonium salt 15 was obtained and subjected to hydrogena-
tion without any further purification. 1H NMR: δ 6.05 (t, J
) 6.7 Hz, 1H), 5.18 (dt, J ) 3.7, 6.7 Hz, 1H), 4.81 (dd, J ) 9.6,
6.6 Hz, 1H), 4.57 (dt, J ) 12.4, 8.3 Hz, 1H), 4.36 (dd, J ) 9.6,
2.7 Hz, 1H), 4.22-3.96 (m, 4H), 4.01 (s, 3H), 2.92-2.77 (m,
1H), 2.50-2.35 (m, 1H); 13C NMR: δ 87.3 (d), 83.2 (d), 76.9
(t), 73.4 (t), 68.1 (t), 52.3 (d), 48.9 (q), 29.5 (t).
The crude salt 15 was dissolved in CH3OH (15 mL) and
added with 10% Pd on charcoal (100 mg). The suspension was
70%) as an oil. [R]21 ) +33.0 (c 0.74, CHCl3); 1H NMR: δ
D

Synthesis of Enantiopure 3-Substituted Pyrroline N-Oxides
J . Org. Chem., Vol. 62, No. 10, 1997 3125
4.44 (quint, J ) 5.4 Hz, 1H), 4.15 (q, J ) 4.7 Hz, 1H), 3.35-
3.18 (m, 3H), 2.90-2.75 (m, 1H), 2.60-2.50 (m, 1H), 2.31-
2.00 (m, 3H), 1.82-1.69 (m, 1H), 1.64-1.51 (m, 1H), 0.88 (s,
9H), 0.06 (s, 6H); 13C NMR: 78.3 (d), 72.5 (d), 71.3 (d), 62.0
(t), 53.2 (t), 38.5 (t), 34.1 (t), 25.8 (q, 3C), 18.0 (s), -4.6 (q),
system, J ) 13.7 Hz, 4H), 2.45-2.13 (m, 2H); 13C NMR: δ
139.0 (s, 2C), 136.6 (d), 129.0 (d, 8C), 127.9 (d, 2C), 62.4 (d),
62.2 (t), 55.1 (t, 2C), 21.9 (t); IR (CCl4): 3029, 2955, 1575, 1236
cm-1; MS: m/ z (rel intensity) 280 (M+, 2), 263 (8), 91 (100).
Anal. Calcd for C18H20N2O: C, 77.11; H, 7.19; N, 9.99.
1
-4.7 (q); IR (CCl4): 3352, 1248 cm-1
.
Anal. Calcd for
Found: C, 77.16; H, 7.39; N, 9.59. 31: Rf 0.03; H NMR: δ
C13H27NO2Si: C, 60.65; H, 10.57; N, 5.44. Found: C, 60.20;
H, 10.70; N, 5.22.
7.38-7.21 (m, 10H), 6.90-6.85 (m, 1H), 4.02-3.83 (m, 3H),
3.60 (A2B2 system, J ) 13.6 Hz, 4H), 2.79 (m, 2H); 13C NMR:
δ 138.2 (s, 2C), 134.7 (d), 128.6 (d, 4C), 128.5 (d, 4C), 127.4 (d,
2C), 63.5 (d), 53.9 (t, 2C), 53.6 (t), 31.8 (t); IR: 3032, 1595,
1263 cm-1; MS: m/ z (rel intensity) 280 (M+, 3), 279 (4), 223
(16), 196 (18), 132 (28), 106 (88), 91 (100), 65 (80).
(2S )-2-(Be n zoyloxy)-1,4-b is[(m e t h a n su lfon yl)oxy]-
bu ta n e (23). Benzoyl chloride (921 µL, 7.94 mmol) was added
dropwise at 0 °C to a solution of dimesylate 6a (1.73 g, 6.61
mmol), triethylamine (1.1 mL, 7.94 mmol), and 4-(dimethyl-
amino)pyridine (40.4 mg, 0.33 mmol) in THF (15 mL). The
mixture was reacted at rt for 3.5 h and then diluted with H2O
and extracted with CH2Cl2. The organic phase was dried over
Na2SO4, filtered, and concentrated in vacuo. Separation of the
crude product by flash column chromatography, eluent CH2Cl2/
CH3OH 25:1, gave the ester 23 (2.42 g, 100%) as a white solid
which was recrystallized from AcOEt/(iPr)2O. Mp 68-69 °C.
(2S)-2-(N,N-Diben zyla m in o)-4-[(m eth a n su lfon yl)oxy]-
bu ta n -1-a l (33). Triethylamine (167 µL, 1.2 mmol) and
methanesulfonyl chloride (85 µL, 1.1 mmol) were added to a
solution of the diol 26 (285 mg, 1 mmol) in CH2Cl2 (5 mL)
cooled at -15 °C, and the mixture was reacted at this
temperature for 1 h. The solution was then concentrated to
complete precipitation of the formed salt. The supernatant
was added at -60 °C to a solution previously prepared by
addition of DMSO (156 µL, 2.2 mmol) dissolved in CH2Cl2 (1
mL) to a solution of (COCl)2 (94 µL, 1.1 mmol) in CH2Cl2 (1
mL) at -60 °C. After 20 min, triethylamine (613 µL, 4.4 mmol)
has been added and the mixture stirred for additional 10 min.
Saturated NaHCO3 has been added, and the product was
extracted with diethyl ether. The organic phase was dried over
Na2SO4 and concentrated to give the crude aldehyde 33.
Purification by flash column chromatography on silica, eluent
CH2Cl2, gave the pure aldehyde 33 (90 mg, 0.25 mmol, 25%)
partially racemized (23% ee measured by integration of the
aldehydic proton signals in the 1H NMR spectrum recorded
Rf 0.43; [R]25 ) -29.6 (c 1.00, CHCl3); 1H NMR: δ 8.08-8.03
D
(m, 2H), 7.65-7.58 (m, 1H), 7.51-7.44 (m, 2H), 5.51 (m, 1H),
4.57-4.32 (m, 4H), 3.04 (s, 3H), 3.01 (s, 3H), 2.33-2.24 (m,
2H); 13C NMR: δ 165.7 (s), 133.6 (d), 129.7 (d, 2C), 129.0 (s),
128.6 (d, 2C), 69.2 (t), 68.2 (d), 65.2 (t), 37.7 (q), 37.4 (q), 30.3
(t); IR: 3014, 1721, 1265 cm-1; MS: m/ z (rel intensity) 271
(M+ - OSO2CH3, 2), 105 (100), 77 (57). Anal. Calcd for
C13H18O8S2: C, 42.62; H, 4.95. Found: C, 42.45; H, 5.03.
3(S)-3-(Ben zoyloxy)-N-h yd r oxyp yr r olid in e (24). The
hydroxylamine 24 was prepared from dimesylate 23 (366 mg,
1 mmol) according to the general procedure. A portion of the
crude product, purified by flash column chromatographhy,
eluent ethyl acetate, afforded 24 as a white solid, which was
recrystallized from ethyl acetate/pentane. Mp 125 °C dec. Rf
in presence of 0.65 equiv of Yb(hfc)3). Rf 0.47; [R]18 ) -44.2
D
(c 0.74, CHCl3); 1H NMR: δ 9.73 (s, 1H), 7.41-7.25 (m, 10H),
4.41-4.33 (m, 1H), 4.30-4.16 (m, 1H), 3.74 (A2B2 system, J )
13.5 Hz, 4H), 3.39 (dd, J ) 7.7, 5.5 Hz, 1H), 2.86 (s, 3H), 2.21-
2.03 (m, 2H); 13C NMR: δ 202.9 (d), 138.4 (s, 2C), 128.9 (d,
4C), 128.6 (d, 4C), 127.6 (d, 2C), 67.1 (t), 63.0 (d), 55.0 (t, 2C),
37.2 (q), 23.7 (t); IR: 3031, 1728 cm-1; MS: m/ z (rel intensity)
332 (M+ - CHO, 65), 236 (57), 149 (67), 91 (100), 65 (74). Anal.
Calcd for C19H23NO4S: C, 63.14; H, 6.41; N, 3.88. Found: C,
63.23; H, 6.70; N, 3.41.
0.35; [R]25 ) +3.7 (c 0.77, CH3OH); 1H NMR: δ 8.06-8.02
D
(m, 2H), 7.60-7.39 (m, 3H), 6.35 (br, 1H), 5.53 (m, 1H), 3.53-
3.03 (m, 4H), 2.56-2.34 (m, 1H), 2.14-1.96 (m, 1H); 13C
NMR: δ 166.2 (s), 132.1 (d), 129.6 (d, 2C), 128.6 (s), 128.3 (d,
2C), 73.5 (d), 64.1 (t), 57.0 (t), 30.0 (t); IR: 3585, 1274 cm-1
;
MS: m/ z (rel intensity) 207 (M+, 1), 105 (100), 85 (56), 77 (80).
Anal. Calcd for C11H13NO3: C, 63.76; H, 6.32; N, 6.76.
Found: C, 63.37; H, 6.33; N, 6.30.
(3S)-3-(Ben zoyloxy)-1-p yr r olin e N-Oxid e (25). Oxida-
tion of 24 according to the general procedure furnished
exclusively the nitrone 25 (103 mg, 0.50 mmol, 50% from 23)
as a pure solid after flash column chromatography, eluent
(3S)-3-(N,N-Diben zyla m in o)-1-p yr r olin e N-Oxid e (30)
by Rea ction of Ald eh yd e 33 w ith Hyd r oxyla m in e. NH2-
OH‚HCl (10 mg, 0.14 mmol) and K2CO3 (39 mg, 0.28 mmol)
were added to a solution of the aldehyde 33 (47 mg, 0.13 mmol)
in CH3OH (4 mL). The mixture was stirred at rt for 30 min,
H2O and CH2Cl2 were added, and the organic phase was
separated and dried over Na2SO4. The crude product (36 mg,
0.13 mmol, 100%) was chemically pure by comparison of its
NMR spectra with those of the nitrone 30 obtained by the
alternative procedure (see above), and its specific optical
rotation ([R]22D ) -24.2 (c 0.85, CHCl3)) confirmed the occurred
partial racemization.
ethyl acetate/methanol 20:1. Mp 100-101 °C. Rf 0.25; [R]25
D
) -147.7 (c 1.04, CHCl3); 1H NMR: δ 8.03-7.99 (m, 2H), 7.63-
7.41 (m, 3H), 7.09 (d, J ) 1.8 Hz, 1H), 6.02 (dd, J ) 7.7, 1.8
Hz, 1H), 4.35-4.20 (m, 1H), 4.06-3.92 (m, 1H), 2.91-2.71 (m,
1H), 2.47-2.33 (m, 1H); 13C NMR: δ 165.8 (s), 133.5 (d), 131.8
(d), 129.6 (d, 2C), 129.0 (s), 128.5 (d, 2C), 74.3 (d), 61.4 (t),
27.0 (t); IR: 1719, 1578, 1256 cm-1; MS: m/ z (rel intensity)
205 (M+, 19), 122 (89), 105 (100), 84 (93), 83 (74), 77 (49). Anal.
Calcd for C11H11NO3: C, 64.38; H, 5.40; N, 6.83. Found: C,
64.14; H, 5.54; N, 6.93.
The same reaction carried out on the crude aldehyde 33
gave, after removal of the solvent in vacuo, a crude product
which was purified by flash column chromatography, eluent
CH2Cl2/CH3OH 30:1. Nitrone 30 (66 mg, 0.24 mmol, 24% from
diol 26) was collected chemically and enantiomerically pure.
(3S)-3-(N,N-Diben zyla m in o)-1-p yr r olin e N-Oxid e (30)
an d (4S)-4-(N,N-Diben zylam in o)-1-pyr r olin e N-Oxide (31).
Methanesulfonyl chloride (0.895 mL, 11.6 mmol) was added
dropwise to an ice-cooled solution of the diol 2615,16 (1.50 g,
5.2 mmol) and triethylamine (1.76 mL, 12.6 mmol) in CH2Cl2
(45 mL). The mixture was reacted at -10 °C for 1 h and then
allowed to warm to rt. After removal of the solvent in vacuo,
the crude mixture was treated according to the general
procedure for formation of the cyclic hydroxylamine. The
resulting crude yellow oil was then oxidized under standard
conditions to the crude regioisomeric nitrones 30 and 31.
Separation by flash column chromatography, eluent CH2Cl2/
CH3OH 30:1, afforded pure 30 (129 mg, 0.46 mmol, 9%) and
31 still contaminated with some of the major nitrone (43 mg,
0.15 mmol, 3%). 30: mp 127-128 °C. Rf 0.08; [R]21D ) -87.4
Mp 127-128 °C; [R]21 ) -88.5 (c 0.79, CHCl3). Anal. Calcd
D
for C18H20N2O: C, 77.11; H, 7.19; N, 9.99. Found: C, 76.82;
H, 7.18; N, 9.64.
Ack n ow led gm en t. The authors thank C.N.R. (Con-
siglio Nazionale delle Ricerche - Italy, Progetto Strate-
gico “Tecnologie Chimiche Innovative”) and M.U.R.S.T.
(Ministero dell’Universita` e della Ricerca Scientifica e
Tecnologica - Italy) for financial support. Technical
assistance from Mrs. B. Innocenti and Mr. S. Papaleo
is gratefully acknowledged.
1
(c 0.73, CHCl3); H NMR: δ 7.36-7.24 (m, 10H), 6.87 (q, J )
1.8 Hz, 1H), 4.38-4.26 (m, 1H), 4.12-3.85 (m, 2H), 3.64 (A2B2
J O962372P