Aziridine ring-opening reactions with chiral enolates. Stereocontrolled synthesis of 5-substituted-3-methyl-pyrrolidin-2-ones

Article abstract of DOI:10.1021/jo0103571

A procedure for performing stereocontrolled aziridine ring-opening reactions with chiral enolates derived from (S,S)-(+)-pseudoephedrine amides has been developed leading to γ-aminoamides in good yields. The diastereoselectivity of the reaction becomes controlled by the presence of the chiral auxiliary on the enolate, although the stereogenic center contained in the structure of the aziridine has a striking influence on the stereochemical course of the reaction which results in the presence of the corresponding matched and mismatched combinations. Besides, the sense of the asymmetric induction of the chiral auxiliary has resulted to be the opposite to the one found with other type of electrophiles, although it is in good agreement with the trend observed in the reaction of the same kind of enolates with epoxides. Finally, the obtained γ-aminoamide adducts were converted into enantiopure γ-amino acids, γ-aminoesters, and pyrrolidin-2-ones using easy to perform and high yielding reactions.

Full text of DOI:10.1021/jo0103571

J . Org. Chem. 2001, 66, 5801-5807
5801
Azir id in e Rin g-Op en in g Rea ction s w ith Ch ir a l En ola tes.
Ster eocon tr olled Syn th esis of
5-Su bstitu ted -3-m eth yl-p yr r olid in -2-on es
J ose L. Vicario, Dolores Bad´ıa,* and Luisa Carrillo
Departamento de Quı´mica Orga´nica II, Facultad de Ciencias, Universidad del Pa´ıs Vasco/ Euskal
Herriko Unibertsitatea, P.O. Box 644, E-48080 Bilbao, Spain
qopbaurm@lg.ehu.es
Received April 4, 2001
A procedure for performing stereocontrolled aziridine ring-opening reactions with chiral enolates
derived from (S,S)-(+)-pseudoephedrine amides has been developed leading to γ-aminoamides in
good yields. The diastereoselectivity of the reaction becomes controlled by the presence of the chiral
auxiliary on the enolate, although the stereogenic center contained in the structure of the aziridine
has a striking influence on the stereochemical course of the reaction which results in the presence
of the corresponding matched and mismatched combinations. Besides, the sense of the asymmetric
induction of the chiral auxiliary has resulted to be the opposite to the one found with other type of
electrophiles, although it is in good agreement with the trend observed in the reaction of the same
kind of enolates with epoxides. Finally, the obtained γ-aminoamide adducts were converted into
enantiopure γ-amino acids, γ-aminoesters, and pyrrolidin-2-ones using easy to perform and high
yielding reactions.
In tr od u ction
Chiral aziridines have found widespread applications
in synthetic organic chemistry, and therefore, they have
shown to be important intermediates for the stereocon-
trolled synthesis of nitrogen-containing molecules such
as amino acids, heterocycles or alkaloids, among others.1
F igu r e 1.
As a consequence of the ring strain present in the
in an stereoselective fashion.5 In this regard, most of
these papers refer to particular substrates and only a
recent work by Enders et al. reports a general procedure
for performing stereocontrolled aziridine ring-opening
reactions using aza-enolates derived from chiral SAMP/
RAMP hydrazones.5d
Therefore, taking into account that (S,S)-(+)-pseu-
doephedrine, a cheap and commercially available reagent
in both enantiomeric forms, has been recently used as
chiral auxiliary in reactions of enolates with several
electrophiles yielding the corresponding adducts with an
extremely high degree of stereoselection.6 In connection
with our studies in the field of the asymmetric synthesis,
we wanted to assess the ability of (S,S)-(+)-pseudoephe-
drine amide enolates to promote stereocontrolled ring-
opening reactions with aziridines providing a straight-
forward access to γ-aminocarbonyl compounds. However,
considering that both aziridine and enolate contain
stereogenic centers in their structure, the double asym-
metric induction in the ring-opening reaction warrants
in depth investigation (Figure 1).
molecule, the chemistry of aziridines is mainly dominated
by nucleophilic ring-opening reactions2 and in this con-
text, many examples can be found in the literature in
which nitrogen, sulfur and carbon nucleophiles have
shown to react efficiently with different kind of aziridines
opening a straightforward access to a wide number of
functionalized nitrogen compounds.3
Although the use of organometallic reagents in ring-
opening reactions of aziridines is well documented, the
number of examples found in the literature in which
metal enolates are employed as nucleophiles is still very
limited,4,5 particularly when the aforementioned enolate-
promoted aziridine ring-opening reaction was carried out
* Corresponding author.
(1) Pearson, W. H.; Lian, B. W.; Bergmeier, S. C. In Aziridines and
Azirines: Monocyclic, in Comprehensive Heterocyclic Chemistry II;
Padwa, A., Ed.; Pergamon Press: Oxford, 1996; Vol. 1A, p 1-60.
(2) Ham, G. E. J . Org. Chem. 1964, 29, 3052.
(3) For recent reviews on aziridine ring-opening reactions:(a) Kasai,
M.; Kono, M. Synlett 1992, 778. (b) Tanner, D. Angew. Chem., Int. ed.
Engl. 1994, 33, 599. (c) Rayner, C. M. Synlett 1997, 11. (d) McCoull,
W.; Davis, F. A. Synthesis 2000, 1347.
(4) (a) Stamm, H.; Weib, R. Synthesis 1986, 395. (b) Stamm, H.;
Weib, R. Synthesis 1986, 392. (c) J ones, D. S.; Srinivasan, A.; Kasina,
S.; Fritzberg, A. R.; Wilkening, D. W. J . Org. Chem. 1989, 54, 1940.
(d) Lygo, B. Synlett 1993, 764.
(5) (a) Bergmeier, S. C.; Lee, W. K.; Rapoport, H. J . Org. Chem. 1993,
58, 5019. (b) Katagiri, T.; Takahashi, M.; Fujiwara, Y.; Ihara, H.;
Uneyama, K. J . Org. Chem. 1999, 64, 7323. (c) J oly, J . G.; Peeters, K.;
Mao, H.; Brossette, T.; Hoornaert, G. J .; Compernolle, F. Tetrahedron
Lett. 2000, 41, 2223. (d) Enders, D.; J aneck, C. F.; Raabe, G. Eur. J .
Org. Chem. 2000, 3337. (e) Iwamoto, K.; Kojima, M.; Chatani, N.;
Murai, S. J . Org. Chem. 2001, 66, 169.
In this paper, the reaction between (S,S)-(+)-pseu-
doephedrine propionamide enolate with a variety of chiral
(6) (a) Myers, A. G.; McKinstry, L. J . Org. Chem. 1996, 61, 2428.
(b) Myers, A. G., Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D.J .;
Gleason, J . L. J . Am. Chem. Soc. 1997, 119, 6496. (c) Vicario, J . L.;
Bad´ıa; D.; Dom´ınguez, E.; Crespo, A.; Carrillo, L. Tetrahedron Lett.,
1999, 40, 7123. (d) Vicario, J . L.; Bad´ıa, D.; Dom´ınguez, E.; Rodr´ıguez,
M.; Carrillo, L. J . Org. Chem. 2000, 65, 3754. (e) Vicario, J . L.; Bad´ıa,
D.; Carrillo, L. Org. Lett., in press.
10.1021/jo0103571 CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/26/2001

5802 J . Org. Chem., Vol. 66, No. 17, 2001
Vicario et al.
Sch em e 1a
monosubstituted aziridines of specific absolute configura-
tions is reported. The double asymmetric induction
process has been studied in order to determine the
optimal combination of reagents for the reaction to
proceed with the highest possible degree of stereoselec-
tion and the so obtained γ-aminoamide adducts will be
converted into chiral nonracemic γ-amino acids, esters,
and pyrrolidin-2-ones using easy to perform and high
yielding transformations. γ-Amino acids are important
compounds in biochemical processes related to Parkinson
disease and epilepsia7 and also they have recently been
employed for the synthesis of modified peptide ana-
logues.8 Pyrrolidin-2-ones have been widely used in
organic synthesis as chiral auxilaries9 and have shown
to be versatile intermediates in the asymmetric synthesis
of natural compounds.10
Resu lts a n d Discu ssion
a
In a first test reaction, propionamide 1, prepared by a
previously reported procedure,6b was deprotonated with
2 equiv of LDA at -78 °C and reacted with activated
N-tosylaziridine 2a at 0 °C in the presence of 5 equiv of
LiCl yielding, after 1 h reaction time, a 88:12 mixture of
both possible diastereoisomers 3a and 3′a , which could
be easily separated by flash column chromatography and
fully characterized. Lowering the temperature to -20 °C
increased the 3a /3′a ratio to 94:6 however, at lower
temperatures (-40 °C), no reaction was observed. These
optimized conditions were extended to the use of other
chiral monosubstituted N-tosylaziridines with different
configurations11 yielding the corresponding γ-aminoamide
adducts in good yields and with a variable degree of
diastereoselection (Scheme 1, Table 1). The absolute
configuration of the newly created stereogenic center was
determined on the final pyrrolidin-2-one derivatives 6a -
h , as outlined in the discussion.
Reagents and Conditions: (i) 1. LDA, LiCl, THF, -78 °C; 2.
2a -h , THF, -20 °C.
Ta ble 1. Dia ster eoselective Rin g-op en in g Rea ction of
Azir id in es 2a -h w ith th e Lith iu m En ola te of 1
entry
product
R
(%) yielda
3/3′b
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
Ph
88
89
87
93
91
86
90
85
96/4
89/12
93/7
Me
i-Pr
Bn
95/5
Ph
75/25
85/15
77/33
70/30
Me
i-Pr
Bn
3g
3h
a
b
Global yield as a mixture of diastereoisomers. Calculated by
HPLC (Chiralcel OD column, UV detector, hexane/i-PrOH 85:15,
0.80 mL/min).
enolates with alkyl halides,6b epoxides6a and imines,6e but
contrasts the reaction of the same enolates with alde-
hydes5d or tert-butyl azodicarboxylate,6c in which the
presence of LiCl was not necessary. We believe that the
electrophilic character of aziridines is insufficient to
undergo ring-opening with the nucleophile and reactivity
enhancement on the enolate species, provided by the
presence of lithium salts as has previously been re-
ported,12 is required for the reaction to proceed.
In all cases it was observed that the ring-opening
reaction was regioselective, in the sense that only the
products arising from the attack of the enolate at the less
substituted carbon atom of the aziridine ring were
obtained. Regarding the diastereoselectivity of the reac-
tion, it should be noted that the stereochemistry of the
stereogenic center at the R-carbon atom of the final major
γ-aminoamide adducts 3a -h was the same in all cases
regardless the configuration of the starting aziridine.
Therefore, it would appear that the stereochemical course
of the reaction is controlled by the chiral auxiliary linked
to the enolate species. However, the configuration of the
starting aziridine has a striking influence on the dias-
tereoselectivity of the reaction because, as illustrated in
Table 1. Reaction of aziridines 2a -d with the (S) con-
figuration at their stereogenic center proceeded with a
It should be pointed out that the presence of LiCl was
necessary in the reaction medium as in its absence, only
starting materials were recovered. This behavior has also
been observed in the reaction of pseudoephedrine amide
(7) (a) Rinehart, J . K. L.; Kishore, V.; Nagarajan, S.; Lake, R. J .;
Gloer, J . B.; Bozich, F. A.; Li, K.-M.; Malekza, J . R. E.; Todsen, W. L.;
Munro, M. H.; Sullins, D. W.; Sakai, R. J . Am. Chem. Soc. 1987, 109,
6846. (b) Petit, G. R.; Kamano, Y.; Herald, C. L.; Tuinman, A. A.;
Boettner, F. E.; Kizu, H.; Schmidt, J . M.; Baczynskyj, J .; Tomer, K.;
Bontems, R. J . J . Am. Chem. Soc. 1987, 109, 6833. (c) J ouin, P.; Poncet,
J .; Dufour, M.-N.; Pantaloni, A.; Castro, B. J . Org. Chem. 1989, 54,
617. (d) Burke, J . R.; Silverman, R. B. J . Am. Chem. Soc. 1991, 113,
9329. (e) Nanavati, S. M.; Silverman, R. B. J . Am. Chem. Soc. 1991,
113, 9341
(8) (a) Hintermann, T.; Gademann, K.; J aun, B.; Seebach, D. Helv.
Chim. Acta 1998, 81, 983. (b) Hanessian, S.; Luo, X.; Schaum, R.;
Michnick, S. J . Am. Chem. Soc. 1998, 120, 8569.
(9) For a review: Seyden-Penne, J . Chiral Auxiliaries and Ligands
in Asymmetric Synthesis; Wiley-Interscience: New York, 1994.
(10) For some examples see (a) Giovanni, A.; Savoia, D.; Umani-
Ronchi, A. J . Org. Chem. 1989, 54, 228. (b) Winkler, J . D.; Hersberger,
P. M. J . Am. Chem. Soc. 1989, 111, 4852. (c) Hamada, Y.; Hara, O.;
Kawai, A.; Kohno, Y.; Shioiri, T. Tetrahedron 1991, 40, 8635. (d)
Burgess, L. E.; Meyers, A. I. J . Org. Chem. 1992, 57, 1656. (e)
Ba¨nzinger, M.; McGarrity, J . F.; Meul, T. J . Org. Chem. 1993, 58, 4010.
(f) Ezquerra, J .; Pedregal, C.; Rubio, A.; Vaquero, J . J .; Matia, M. P.;
Mart´ın, J .; D´ıaz, A.; Navio, J . L. G. J . Org. Chem. 1994, 59, 4237. (g)
Herdeis, C.; Hubmann, H. P.; Lotter, H. Tetrahedron: Asymmetry
1994, 5, 351. (h) Yoda, H.; Kitayama, H.; Katagiri, T.; Takabe, K.
Tetrahedron 1995, 48, 3313. (i) McAlohan, H.; Stevenson, P. J .
Tetrahedron: Asymmetry 1995, 6, 239. (j) Liddell, J . R. Nat. Prod. Rep.
1996, 13, 187. (k) Kanazawa, A.; Gillet, S.; Delair, P.; Greene, A. E. J .
Org. Chem. 1998, 63, 4660. (l) Snider, B. B.; Ahn, Y.; Foxman, B. M.
Tetrahedron 1999, 40, 3339.
(12) For the effect of LiCl in the reaction of pseudoephedrine amide
enolates, see: Ru¨ck, K. Angew. Chem., Int. ed. Engl. 1995, 34, 433-
435. See also: Henderson, K. W.; Dorigo, A. E.; Liu, Q.-Y.; Williard,
P. G.; Schleyer, P. R.; Bernstein, P. R. J . Am. Chem. Soc. 1996, 118,
1339-1347 and references therein.
(11) Aziridines 2a -h were prepared according to a previously
reported procedure: Berry, M. B.; Braig, D. Synlett 1992, 41.

Aziridine Ring-Opening Reactions
J . Org. Chem., Vol. 66, No. 17, 2001 5803
Sch em e 2a
a
Reagents and Conditions: (i) 4 M H2SO4/dioxane, reflux. (ii)
MeOH, conc HCl, reflux.
Ta ble 2. γ-Am in o Acid s 4a -h , γ-Am in oester s 5a -h , a n d
P yr r olid in -2-on es 6a -h P r ep a r ed
F igu r e 2.
(%)
(%)
(%)
entry
R
product yielda product yieldb product yieldc
high degree of diastereoselection. On the other hand,
diastereoselection decreased when the corresponding
enantiomeric (R) aziridines 2e-h were used. Therefore,
it can be concluded that the enolate derived from (S,S)-
(+)-pseudoephedrine propionamide 1 and (S) aziridines
2a -d form a matched combination leading to γ-aminoa-
mides with a relative 1,3-syn configuration 3a -d in good
de. On the contrary, the same enolate and (R) aziridines
2e-h form a mismatched combination leading to the
corresponding adducts with a relative 1,3-anti configu-
ration 3d -h with poor diastereoselection.
Analysis of the sense of the asymmetric induction
exerted by the chiral auxiliary (S,S)-(+)-pseudoephedrine
on the newly created stereogenic center at the R-carbon
of the γ-aminoamides 3a -h , reveals that the attack of
the aziridine electrophile on the enolate π-face occurs
from the opposite face to the observed for reactions
between similar enolates and electrophiles such as alkyl
halides,6b aldehydes,6d imines,6e or dialkyl azodicarbox-
ylates6c (see Figure 2). However, this trend is in ac-
cordance with the observed facial selectivity in the ring-
opening reaction of epoxides with pseudoephedrine amide
enolates and the same matched-mismatched correlation
was found.6a,13
1
2
3
4
5
6
7
8
Ph
4a
4b
4c
4d
4e
4f
85
87
90
93
82
87
87
85
5a
5b
5c
5d
5e
5f
94
89
90
91
92
93
91
93
6a
6b
6c
6d
6e
6f
77
72
74
76
75
73
71
71
Me
i-Pr
Bn
Ph
Me
i-Pr
Bn
4 g
4h
5 g
5h
6 g
6h
a
Yield of product 4 after standard acid-base purification.
b Yield of product 5 after flash column chromatography purification
and with ee>99% as calculated by chiral HPLC under conditions
optimized for a racemic standard (Chiralcel OD column, UV
detector, hexane/i-PrOH 90:10, 1.00 mL/min). c Yield of product 6
after flash column chromatography purification and with ee>99%
as calculated by chiral HPLC under conditions optimized for a
racemic standard (Chiralcel OD column, UV detector, hexane/i-
PrOH 93:7, 0.75 mL/min)..
Sch em e 3a
Next, we proceeded to convert the obtained R-methyl-
γ-aminoamides 3a -h to the target γ-amino acids, esters,
and pyrrolidin-2-ones. The chiral auxiliary was cleanly
removed by hydrolysis using 4 M H2SO4 in refluxing
dioxane providing the corresponding R-methyl-γ-amino
acids 4a -h in good yield (Scheme 2, Table 2). Further-
more, the chiral auxiliary, (S,S)-(+)-pseudoephedrine,
could be recovered in optically pure form from the
extracts of the basic aqueous layer after workup and
crystallization from hexane/EtOAc 1:1 in ca. 86% yield,
allowing its recycling for further purposes. The acids
4a -h were esterified by treatment with refluxing metha-
nol under acid catalysis, affording R-methyl-γ-ami-
noesters 5a -h in excellent yields after flash chromatog-
raphy. Esters 5a-h appeared to be single diastereoisomers
with >99% ee as determined by 1H NMR and chiral
HPLC analyses of the crude reaction mixtures.14 This
indicated that both the hydrolysis and esterification steps
a
Reagents and Conditions: (i) LHMDS, THF, -20 °C.
proceeded without racemization of either of the stereo-
genic centers of the starting amides 3a -h .
Finally, the R-methyl-γ-aminoesters 5a -h were sub-
mitted to base-promoted cyclization15 by treatment with
LHMDS in THF at -20 °C affording the 5-substituted
3-methyl-1-tosyl-pyrrolidin-2-ones 6a -h in good yields
and as a single diastereoisomers in >99% ee (determined
1
by H NMR and chiral HPLC). This indicates that the
cyclization procedure proceeded without racemization of
either of the stereogenic centers present in the starting
compounds (Scheme 3, Table 2).
With these cyclic derivatives of known stereochemistry
at the C5 stereogenic center in hand, we proceeded to
determine the absolute configuration of the newly created
stereogenic center in the aziridine ring-opening reaction
(13) (a) Askin, D.; Volante, R. P.; Ryan, K. M.; Reamer, R. A.;
Shinkai, I. Tetrahedron Lett. 1988, 29, 4245.
(14) For example, a racemic sample (()-5a to be used as standard
to optimize the HPLC separation conditions was prepared by hydroly-
sis/esterification of a 1:1 mixture of 3a and 3′e.
(15) Guanti, G.; Narisano, E.; Banfi, L. Tetrahedron Lett. 1987, 28,
4331.

5804 J . Org. Chem., Vol. 66, No. 17, 2001
Vicario et al.
and filtered and the solvent was removed in vacuo to yield a
yellowish oil which was flash column chromatographed (hex-
anes/ethyl acetate 2:8) affording diastereomerically pure amide
3a as a colorless oil. An analytically pure sample was obtained
after crystallization in Et2O Yield: 83%. Mp: 89-91 °C (Et2O).
[R]D20: +122.7 (c ) 0.2, CH2Cl2). IR (KBr): 3355; 1607; 1342,
1
1165. H NMR (δ, ppm) (2:1 rotamer ratio; *indicates minor
rotamer resonances): 0.94* (d, 3H, J ) 6.7 Hz); 1.07-1.20 (m,
6H); 2.00* (s, 3H); 2.34 (s, 3H); 2.20 (m, 1H); 2.74 (s, 3H); 2.83
(m, 1H); 2.91* (s, 3H); 2.99 (m, 1H); 3.63* (m, 1H); 3.80 (d,
1H, J ) 10.2 Hz); 3.96 (m, 1H); 4.16* (m, 1H); 4.45-4.56 (m,
2H); 5.62* (d, 1H, J ) 5.7 Hz); 5.70 (d, 1H, J ) 6.0 Hz); 7.16-
7.43 (m, 9H). 13C NMR (δ, ppm) (2:1 rotamer ratio; *indicates
minor rotamer resonances): 14.1*; 14.8; 15.0*; 15.9; 22.8;
23.0*; 25.2; 27.3*; 38.2; 38.4; 47.8; 48.0*; 49.3; 49.5*; 58.3;
74.8*; 75.6; 123.3; 123.5*; 125.8*; 125.9; 126.4; 126.6*; 126.8;
127.0*; 127.2; 127.4*; 128.1*; 128.2; 128.5*; 128.6; 128.7;
129.5*; 135.1*; 136.4; 137.3; 138.1*; 141.6*; 142.1; 143.6*;
143.7; 175.2*; 176.0. MS (EI) m/z (rel int): 338 (2), 294 (100).
Anal. Calcd for C28H34N2O4S: C, 67.99; H, 6.93; N, 5.66.
Found: C, 68.10; H, 7.01; N, 5.58.
[2S,4S,1′S,2′S]-(+)-N,2-Dim eth yl-N-(2′-ph en yl-2′-h ydr oxy-
1′-m e t h y le t h y l)-4-(p -t o lu e n e s u lfo n y la m in o )p e n t a n -
a m id e (3b). Yield: 78%. [R]D20: +26.8 (c ) 0.4, CH2Cl2). IR
(CHCl3): 3353; 1600; 1341, 1163. 1H NMR (δ, ppm) (5:4
rotamer ratio; *indicates minor rotamer resonances): 0.59 (d,
3H, J ) 6.3 Hz); 0.80* (d, 3H, J ) 6.4 Hz); 0.91* (d, 3H, J )
7.5 Hz); 0.99 (d, 3H, J ) 7.4 Hz); 1.02 (m, 3H); 1.07* (m, 1H);
1.12 (m, 1H); 1.51* (m, 1H); 1.98 (m, 1H); 2.00 (m, 1H); 2.23*
(m, 1H); 2.34 (s, 3H); 2.36 (s, 3H); 2.84 (s, 3H); 2.93 (s, 3H);
3.22 (m, 1H); 3.33 (m, 1H); 4.31-4.46 (m, 2H); 5.53* (d, 1H, J
) 10.3 Hz); 5.75 (d, 1H, J ) 6.9 Hz); 7.18-7.50 (m, 7H); 7.64-
7.72 (m, 2H). 13C NMR (δ, ppm) (5:4 rotamer ratio; *indicates
minor rotamer resonances): 13.3*; 14.4; 15.4; 17.4*; 17.8*;
18.0; 21.4; 22.0; 26.8; 27.0*; 31.4*; 32.3; 34.6; 40.8; 40.9*; 48.0*;
49.5; 75.6; 76.3*; 126.4*; 126.8; 126.9; 127.2*; 127.5*; 128.1;
128.3*; 128.7; 129.4*; 129.5; 138.6; 138.9*; 141.1*; 141.8;
143.2*; 142.9; 178.5*; 178.8. MS (EI) m/z (rel int): 432 (M+,
1), 189 (100). Anal. Calcd for C23H32N2O4S: C, 63.86; H, 7.46;
N, 6.48. Found: C, 63.93; H, 7.50; N, 4.45.
[2S ,4R ,1′S ,2′S ]-(+)-N ,2-D im e t h y l-N -(2′-p h e n y l-2′-
h yd r oxy-1′-m et h ylet h yl)-4-(p -t olu en esu lfon yl)h exa n a -
m id e (3c). Yield: 80%. [R]D20: +36.1 (c ) 0.2, CH2Cl2). IR
(CHCl3): 3353; 1600; 1341, 1163. 1H NMR (δ, ppm) (3:2
rotamer ratio; *indicates minor rotamer resonances): 0.47-
0.62 (m, 6H); 0.82-0.99 (m, 6H); 1.07-1.57 (m, 3H); 2.11 (m,
1H); 2.22 (s, 3H); 2.24* (s, 3H); 2.54* (m, 1H); 2.65 (s, 3H);
2.79* (s, 3H); 3.01 (m, 1H); 3.37 (m, 1H); 4.24-4.51 (m, 2H);
4.72-4.78* (m, 2H); 5.56 (d, 1H, J ) 8.9 Hz); 5.64* (d, 1H, J
) 8.2 Hz); 7.03-7.40 (m, 7H); 7.57-7.62 (m, 2H). 13C NMR
(δ, ppm) (3:2 rotamer ratio; *indicates minor rotamer reso-
nances): 8.8*; 9.2; 13.1; 13.9*; 14.9*; 15.5; 16.6*; 16.8; 17.1*;
18.3; 19.4*; 20.9; 26.3; 26.5*; 30.9*; 31.5; 31.7; 31.8; 33.3*; 33.6;
56.1*; 56.8; 75.2; 75.4*; 126.2*; 126.3; 126.9; 127.0*; 127.7;
127.8; 128.1*; 128.9; 129.0*; 129.2; 138.8; 138.9*; 141.0*; 141.7;
142.2*; 142.3; 177.6*; 178.0. MS (EI) m/z (rel int): 252 (66),
155 (100). Anal. Calcd for C25H36N2O4S: C, 65.19; H, 7.88; N,
6.08. Found: C, 65.10; H, 7.97; N, 6.03.
[2S,4R,1′S,2′S]-(+)-N,2-Dim eth yl-5-p h en yl-N-(2′-p h en -
yl-2′-h yd r oxy-1′-m eth yl-eth yl)-4-(p-tolu en esu lfon yla m i-
n o)p en ta m id e (3d ). Yield: 88%. [R]D20: +52.6 (c ) 0.2,
CH2Cl2). IR (CHCl3): 3358; 1603; 1340, 1160. 1H NMR (δ, ppm)
(4:3 rotamer ratio; *indicates minor rotamer resonances):
0.93-0.98 (m, 6H); 1.07-1.15 (m, 2H); 1.64* (m, 1H); 1.76 (m,
1H); 2.09* (m, 2H): 2.34* (s, 3H); 2.37 (s, 3H); 2.45 (m, 2H);
2.78 (m, 1H); 2.83 (s, 3H); 2.95* (s, 3H); 3.35 (m, 1H); 3.57*
(m, 1H); 4.08* (m, 1H); 4.56-4.75 (m, 2H); 5.73* (m, 1H); 5.95
(d, 1H, J ) 8.5 Hz); 6.81-6.91 (m, 2H); 7.14-7.60 (m, 10H);
7.65* (d, 2H, J ) 8.0 Hz); 7.75 (d, 2H, J ) 8.0 Hz). 13C NMR
(δ, ppm) (4:3 rotamer ratio; *indicates minor rotamer reso-
nances): 12.8; 13.7*; 16.6*; 17.3; 20.5*; 20.9; 30.5*; 31.2; 33.8;
36.9*; 37.4; 39.7; 41.4; 41.6*; 53.1*; 54.5; 74.4; 74.8*; 125.7*;
126.1; 127.3*; 126.9; 127.1*; 127.3; 127.6*; 127.9; 128.0*; 128.2;
128.4*; 128.6; 128.7; 129.1*; 129.2*; 129.8; 137.3*; 137.6; 138.2;
138.3*; 140.9*; 141.4; 142.3*; 142.5; 177.9*; 178.0. MS (EI) m/z
F igu r e 3. Observed nOe effects and proposed structure for
pyrrolidin-2-ones 6a and 6e.
with the help of nOe difference experiments (see Figure
3). Thus, the observation of an intense nOe effect between
H5 and one of the two diastereotopic protons at C4 as well
as between H3 and the other diastereotopic proton at C4
for pyrrolidin-2-one 6a suggested a relative 1,3-trans
configuration between both CH3 and Ph substituents.
Furthermore, taking into account that C5 had the R
configuration (from aziridine 2a ), the configuration of the
stereogenic center at C3 had to be 3S. On the contrary,
pyrrolidin-2-one 6e, which had a 5S configuration, showed
an intense nOe effect between H5 and one of the two
diastereotopic protons at C4 as well as between H3 and
the same proton at C4 suggesting a 1,3-cis relative
configuration for both substituents and thus the 3S
configuration at the newly created stereogenic center in
the ring-opening reaction. This analysis was further
extended to the remaining pyrrolidin-2-ones 6a-h , γ-ami-
noamides 3a -h , γ-amino acids 4a -h , and γ-aminoesters
5a -h .
Con clu sion s
In summary, a procedure for performing diastereose-
lective ring-opening reactions of monosubstituted N-
tosylaziridines with (S,S)-(+)-pseudoephedrine amide
enolates has been developed. The reaction proceeds with
variable diastereoselectivity, depending on the configu-
ration of the starting aziridine, although the stereochem-
ical outcome of the reaction is controlled by the chiral
auxiliary. The best combination of reagents, namely
(S,S)-pseudoephedrine propionamide enolate and (S)-
aziridines yielded the ring-opening products with an
excellent degree of diastereoselection. The resulting
γ-aminoamide adducts were finally converted into chiral
γ-amino acids, γ-aminoesters, and pyrrolidin-2-ones which
were obtained in excellent yields and in almost enantio-
merically pure form.
Exp er im en ta l Section
Gen er a l P r oced u r e for th e Rin g-Op en in g Rea ction of
Azir id in es w ith (S,S)-(+)-P seu d oep h ed r in e P r op ion a -
m id e Lith iu m En ola te. Syn th esis of [2S,4R,1′S,2′S]-(+)-
N,2-Dim eth yl-4-p h en yl-N-(2′-p h en yl-2′-h yd r oxy-1′-m eth -
yleth yl)-4-(p-tolu en esu lfon yla m in o)bu ta m id e (3a ).16
A
solution of propionamide 1 (1.00 g, 4.52 mmol) in dry THF (15
mL) was slowly added to a cooled (-78 °C) suspension of LDA
(9.04 mmol) and LiCl (0.96 g, 22.60 mmol) in dry THF (20 mL).
The mixture was stirred at this temperature for 1 h and
allowed to reach room temperature. The mixture was cooled
again to -20 °C at which temperature a THF (20 mL) solution
of aziridine 2a (1.36 g, 4.52 mmol) was dropwise added within
20 min and the resulting solution was stirred for 2 h at this
temperature. The mixture was quenched with a saturated
NH4Cl solution (50 mL), extracted with CH2Cl2 and the
combined organic fractions were collected, dried over Na2SO4
(16) For general experimental procedures see: Vicario, J . L.; Bad´ıa;
D.; Dom´ınguez, E.; Carrillo, L. J . Org. Chem. 1999, 64, 4610.

Aziridine Ring-Opening Reactions
J . Org. Chem., Vol. 66, No. 17, 2001 5805
(rel int): 155 (72), 91 (100). Anal. Calcd for C29H36N2O4S: C,
68.47; H, 7.13; N, 5.51. Found: C, 68.51; H, 7.19; N, 5.45.
47.9; 126.6; 126.8; 127.9; 128.1; 129.3; 136.6; 138.8; 143.2;
184.3. MS (EI) m/z (rel int): 331 (M+, 55), 155 (100).
[2S,4S]-(-)-2-Met h yl-4-(p -t olu en esu lfon yla m in o)p en -
ta n oic Acid (4b). Yield: 87%. [R]D20: -25.9 (c ) 0.2, CH2-
[2S,4S,1′S,2′S]-(+)-N,2-Dim eth yl-4-p h en yl-N-(2′-p h en yl-
2′-h yd r oxy-1′-m eth yl-eth yl)-4-(p-tolu en esu lfon yla m in o)-
bu ta m id e (3e). Yield: 67%. [R]D20: +88.4 (c ) 0.2, CH2Cl2).
IR (CHCl3): 3355; 1617; 1348, 1163. 1H NMR (δ, ppm): 0.91-
1.12 (m, 6H); 1.17-1.25 (m, 2H); 2.13 (m, 1H); 2.33 (s, 3H);
2.90 (s, 3H); 3.06 (m, 1H); 3.44 (m, 1H); 4.41-4.55 (m, 2H);
5.77 (d, 1H, J ) 9.5 Hz); 6.81-7.39 (m, 12H); 7.66 (d, 2H, J )
8.0 Hz). 13C NMR (δ, ppm): 14.1; 17.6; 20.5; 31.8; 33.3; 37.1;
40.4; 54.9; 74.8; 125.2; 125.6; 126.5; 126.9; 127.3; 127.9; 128.0;
128.9; 136.3; 137.1; 141.4; 142.2; 176.3. MS (EI) m/z (rel int):
338 (9), 294 (100). Anal. Calcd for C29H36N2O4S: C, 68.47; H,
7.13; N, 5.51. Found: C, 68.55; H, 7.06; N, 5.59.
1
Cl2). IR (CHCl3): 3453; 1711; 1343, 1160. H NMR (δ, ppm):
0.90 (d, 3H, J ) 6.7 Hz); 1.06 (d, 3H, J ) 7.0 Hz); 1.35 (m,
1H); 1.76 (m, 1H); 2.35 (s, 3H); 2.54 (m, 1H); 3.33 (m, 1H);
5.10 (m, 1H); 7.21 (d, 2H, J ) 8.2 Hz); 7.67 (d, 2H, J ) 8.2
Hz). 13C NMR (δ, ppm): 17.2; 21.0; 21.8; 35.8; 40.4; 48.3; 126.6;
129.5; 138.3; 143.1; 182.0. MS (EI) m/z (rel int): 285 (M+, 28),
155 (100).
[2S,4R]-(-)-2,5-Dim eth yl-4-(p-tolu en esu lfon yla m in o)-
h exa n oic Acid (4c). Yield: 90%. [R]D20: -8.6 (c ) 0.1, CH2-
1
Cl2). IR (CHCl3): 3450; 1711; 1340, 1166. H NMR (δ, ppm):
0.71 (d, 6H, J ) 6.8 Hz); 0.97 (d, 3H, J ) 6.9 Hz); 1.26 (m,
1H); 1.57 (m, 2H); 2.31 (s, 3H); 2.38 (m, 1H); 3.10 (m, 1H);
5.48 (m, 1H); 7.15 (d, 2H, J ) 7.9 Hz); 7.65 (d, 2H, J ) 7.9
Hz). 13C NMR (δ, ppm): 16.2; 17.3; 17.9; 21.1; 31.4; 34.4; 35.4;
51.3; 126.3; 129.5; 138.3; 142.4; 181.3. MS (EI) m/z (rel int):
313 (M+, 10), 189 (100).
[2S,4R]-(-)-2-Meth yl-5-ph en yl-4-(p-tolu en esu lfon ylam i-
n o)p en ta n oic Acid (4d ). Yield: 87%. [R]D20: -26.4 (c ) 0.2,
CH2Cl2). IR (CHCl3): 3451; 1710; 1341, 1164. 1H NMR (δ,
ppm): 1.03 (d, 3H, J ) 7.1 Hz); 1.39 (m, 1H); 1.76 (m, 1H);
2.37 (s, 3H); 2.58 (m, 1H); 2.86 (m, 2H); 3.52 (m, 1H); 5.30 (m,
1H); 7.02-7.24 (m, 5H); 7.36 (d, 2H, J ) 8.1 Hz); 7.72 (d, 2H,
J ) 8.1 Hz). 13C NMR (δ, ppm): 16.2; 21.4; 36.3; 37.8; 41.8;
51.5; 126.2; 126.6; 128.4; 129.1; 129.4; 136.6; 137.9; 142.5;
180.4. MS (EI) m/z (rel int): 361 (M+, 28), 91 (100).
[2S,4S]-(+)-2-Meth yl-4-ph en yl-4-(p-tolu en esu lfon ylam i-
n o)bu ta n oic Acid (4e). Yield: 82%. [R]D20: +44.3 (c ) 0.2,
CH2Cl2). IR (CHCl3): 3455; 1710; 1341, 1163. 1H NMR (δ,
ppm): 1.08 (d, 3H, J ) 7.1 Hz); 2.39 (s, 3H); 2.71 (m, 1H);
3.12 (m, 1H); 3.21 (m, 1H); 3.33 (m, 1H); 4.58 (m, 1H); 7.02-
7.21 (m, 5H); 7.33 (d, 2H, J ) 8.1 Hz); 7.62 (d, 2H, J ) 8.1
Hz). 13C NMR (δ, ppm): 14.4; 21.6; 42.1; 45.3; 48.8; 126.3;
126.7; 127.9; 128.2; 129.5; 136.4; 138.9; 143.2; 184.1. MS (EI)
m/z (rel int): 331 (M+, 48), 155 (100).
[2S,4R,1′S,2′S]-(-)-N ,2-Dim e t h yl-N -(2′-p h e n yl-2′-h y-
d r oxy-1′-m et h ylet h yl)-4-(p -t olu en esu lfon yla m in o)p en -
20
ta n a m id e (3f). Yield: 73%. Mp: 86-89 °C (Et2O). [R]D
:
-23.5 (c ) 0.1, CH2Cl2). IR (KBr): 3350; 1601; 1342, 1160. 1H
NMR (δ, ppm): 0.71 (d, 3H, J ) 6.5 Hz); 1.02 (d, 3H, J ) 7.2
Hz); 1.07 (d, 3H, J ) 7.3 Hz); 1.11-1.18 (m, 2H); 2.09 (m, 1H);
2.34 (s, 3H); 3.03 (s, 3H); 3.15 (m, 1H); 3.49 (m, 1H); 4.58 (d,
1H, J ) 7.6 Hz); 4.99 (m, 2H); 7.28-7.66 (m, 7H); 7.98 (d, 2H,
J ) 8.2 Hz). 13C NMR (δ, ppm): 14.6; 15.7; 18.5; 21.0; 21.6;
31.8; 33.9; 42.1; 49.2; 75.6; 126.6; 127.0; 127.9; 128.5; 129.2;
137.2; 141.7; 143.3; 177.1. MS (EI) m/z (rel int): 432 (M+, 5),
189 (100). Anal. Calcd for C23H32N2O4S: C, 63.86; H, 7.46; N,
6.48. Found: C, 63.81; H, 7.51; N, 4.53.
[2S ,4S ,1′S ,2′S ]-(+)-N ,2,5-Tr im e t h yl-N -(2′-p h e n yl-2′-
h yd r oxy-1′-m e t h yle t yl)-4-(p -t olu e n e su lfon yla m in o)-
20
h exa n a m id e (3g). Yield: 68%. Mp: 103-105 °C (Et2O). [R]D
:
+12.3 (c ) 0.3, CH2Cl2). IR (KBr): 3350; 1618; 1344, 1158. 1H
NMR (δ, ppm): 0.50 (d, 3H, J ) 6.7 Hz); 0.62 (d, 3H, J ) 6.7
Hz); 0.87 (d, 3H, J ) 6.7 Hz); 1.09 (d, 3H, J ) 6.7 Hz); 1.12-
1.36 (m, 2H); 2.08 (m, 1H); 2.36 (s, 3H); 2.88 (s, 3H); 3.09 (m,
1H); 3.15 (m, 1H); 4.77 (m, 2H); 5.49 (m, 1H); 7.09 (d, 2H, J )
8.0 Hz); 7.19-7.44 (m, 5H); 7.67 (d, 2H, J ) 8.0 Hz). 13C NMR
(δ, ppm): 14.3; 17.5; 17.8; 17.9; 19.9; 21.3; 29.5; 31.6; 32.7;
36.3; 57.9; 74.0; 126.2; 126.9; 127.4; 127.8; 129.9; 138.1; 141.3;
142.5; 177.3. MS (EI) m/z (rel int): 252 (41), 91 (100). Anal.
Calcd for C25H36N2O4S: C, 65.19; H, 7.88; N, 6.08. Found: C,
65.23; H, 7.81; N, 6.00.
[2S,4R]-(-)-2-Met h yl-4-(p -t olu en su lfon yla m in o)p en -
ta n oic Acid (4f). Yield: 87%. [R]D20: -13.5 (c ) 0.1, CH2-
1
Cl2). IR (CHCl3): 3453; 1710; 1341, 1160. H NMR (δ, ppm):
0.97 (d, 3H, J ) 6.5 Hz); 1.02 (d, 3H, J ) 7.2 Hz); 1.34 (m,
1H); 1.79 (m, 1H); 2.41 (s, 3H); 2.52 (m, 1H); 3.31 (m, 1H);
5.08 (sa, 1H); 7.23 (d, 2H, J ) 8.0 Hz); 7.75 (d, 2H, J ) 8.0
Hz). 13C NMR (δ, ppm): 17.6; 21.5; 21.9; 35.6; 40.8; 48.6; 126.8;
129.4; 137.7; 142.6; 180.9. MS (EI) m/z (rel int): 285 (M+, 31),
155 (100).
[2S,4S,1′S,2′S]-(+)-N,2-Dim eth yl-5-p h en yl-N-(2′-p h en yl-
2′-h yd r oxy-1′-m eth yl-eth yl)-4-(p-tolu en esu lfon yla m in o)-
20
p en ta m id e (3h ). Yield: 56%. Mp: 98-101 °C (Et2O). [R]D
:
+97.5 (c ) 0.1, CH2Cl2). IR (KBr): 3350; 1611; 1348, 1161. 1H
NMR (δ, ppm): 0.80-0.90 (m, 6H); 1.02-1.23 (m, 2H); 2.11
(m, 1H); 2.31 (s, 3H); 2.43-2.51 (m, 2H): 2.88 (s, 3H); 3.01
(m, 1H); 3.28 (m, 1H); 4.33-4.54 (m, 2H); 5.48 (d, 1H, J ) 9.5
Hz); 6.81-7.52 (m, 12H); 7.78 (d, 2H, J ) 8.0 Hz). 13C NMR
(δ, ppm): 14.2; 17.5; 20.9; 31.3; 32.4; 38.9; 39.2; 41.3; 52.1;
74.3; 125.7 125.9; 126.2; 126.5; 127.4; 127.8; 128.3; 128.8;
136.2; 137.5; 141.2; 142.3; 176.5. MS (EI) m/z (rel int): 329
(3), 91 (100). Anal. Calcd for C29H36N2O4S: C, 68.47; H, 7.13;
N, 5.51. Found: C, 68.55; H, 7.06; N, 5.59.
[2S,4S]-(+)-2,5-Dim et h yl-4-(p -t olu en su lfon yla m in o)-
h exa n oic Acid (4g). Yield: 87%. [R]D20: +36.3 (c ) 0.3, CH2-
1
Cl2). IR (CHCl3): 3453; 1706; 1339, 1163. H NMR (δ, ppm):
0.63 (d, 3H, J ) 6.8 Hz); 0.94 (d, 3H, J ) 7.0 Hz); 1.07 (d, 3H,
J ) 7.0 Hz); 1.45 (m, 1H); 2.00 (m, 1H); 2.33 (s, 3H); 2.42 (m,
2H); 3.35 (m, 1H); 4.29 (m, 1H); 7.22 (d, 2H, J ) 8.1 Hz); 7.85
(d, 2H, J ) 8.1 Hz). 13C NMR (δ, ppm): 14.3; 15.6; 20.0; 21.6;
27.5; 30.3; 37.8; 51.4; 127.6; 129.3; 135.5; 144.7; 180.5. MS (EI)
m/z (rel int): 313 (M+, 12), 189 (100).
Gen er a l P r oced u r e for th e Hyd r olysis of Am id es 3a -
h . Syn th esis of [2S,4R]-(+)-2-Meth yl-4-p h en yl-4-(p-tolu -
en esu lfon yla m in o)bu ta n oic Acid (4a ). A solution of γ-ami-
noamide 3a (0.33 g, 1.16 mmol) in dioxane (10 mL) was slowly
added over a cooled (0 °C) 4 M H2SO4 solution (10 mL). When
the addition was complete the mixture was refluxed for 5 h.
The reaction was quenched with water, carefully basified to
pH ) 12 and washed with EtOAc. The aqueous layer was
carefully driven to pH ) 3 and extracted with CH2Cl2 (3 × 20
mL). After drying (Na2SO4), filtering and removing the solvent
from the basic organic extracts it was possible to recover, after
crystallization (hexanes/EtOAc) pure (+)-(S,S)-pseudoephe-
drine in 83% yield. The collected organic acidic extracts were
dried over Na2SO4 and filtered and the solvent was removed
in vacuo yielding the wanted acid as a colorless oil. Yield: 85%.
[R]D20: +21.6 (c ) 0.3, CH2Cl2). IR (CHCl3): 3455; 1710; 1341,
1163. 1H NMR (δ, ppm): 1.11 (d, 3H, J ) 7.0 Hz); 2.45 (s, 3H);
2.77 (m, 1H); 3.02 (m, 1H); 3.17 (m, 1H); 3.35 (m, 1H); 4.65
(m, 1H); 6.95-7.19 (m, 5H); 7.28 (d, 2H, J ) 8.2 Hz); 7.65 (d,
2H, J ) 8.2 Hz). 13C NMR (δ, ppm): 14.2; 21.3; 42.3; 44.7;
[2S,4S]-(+)-2-Meth yl-5-ph en yl-4-(p-tolu en esu lfon ylam i-
n o)p en ta n oic Acid (4h ). Yield: 85%. [R]D20: +38.9 (c ) 0.1,
CH2Cl2). IR (CHCl3): 3450; 1710; 1341, 1162. 1H NMR (δ,
ppm): 1.03 (d, 3H, J ) 6.9 Hz); 1.41 (m, 1H); 1.87 (m, 1H);
2.45 (s, 3H); 2.62 (m, 1H); 2.71 (m, 2H); 3.41 (m, 1H); 4.78 (m,
1H); 7.01-7.28 (m, 5H); 7.23 (d, 2H, J ) 8.1 Hz); 7.70 (d, 2H,
J ) 8.1 Hz). 13C NMR (δ, ppm): 16.3; 21.2; 35.4; 37.5; 41.2;
51.7; 126.1; 126.5; 128.3; 128.7; 129.6; 136.5; 137.6; 142.5;
181.3. MS (EI) m/z (rel int): 361 (M+, 31), 91 (100).
Gen er a l P r oced u r e for th e Ester ifica tion of Acid s 4a -
h . Syn th esis of [2S,4R]-(+)-Meth yl 2-m eth yl-4-p h en yl-4-
(p-tolu en esu lfon yla m in o)bu ta n oa te (5a ). A solution of acid
4a (0.98 g, 2.82 mmol) in MeOH (15 mL) was added concd HCl
(5 mL) and the mixture was refluxed for 12 h. The reaction
was quenched with water (20 mL) and extracted with CH2Cl2
(3 × 15 mL). After drying (Na2SO4), filtering and removing
the solvent from the collected organic fractions ester 5a was
isolated after flash column chromatography purification (hex-
anes/EtOAc 1:1). Yield: 94%. [R]D20: +10.3 (c ) 0.2, CH2Cl2).

5806 J . Org. Chem., Vol. 66, No. 17, 2001
Vicario et al.
1
IR (CHCl3): 3450; 1712; 1341, 1160. H NMR (δ, ppm): 1.13
for C16H25NO4S: C, 58.69; H, 7.70; N, 4.28. Found: C, 58.76;
H, 7.77; N, 4.21.
(d, 3H, J ) 7.0 Hz); 2.41 (s, 3H); 2.76 (m, 1H); 2.98 (m, 1H);
3.15 (m, 1H); 3.36 (m, 1H); 3.42 (s, 3H); 4.57 (m, 1H); 6.98 (m,
2H); 7.21 (m, 3H); 7.26 (d, 2H, J ) 8.2 Hz); 7.63 (d, 2H, J )
8.2 Hz). 13C NMR (δ, ppm): 14.3; 21.1; 42.4; 44.5; 47.7; 51.1;
126.6; 126.9; 127.7; 128.2; 129.3; 136.4; 138.8; 143.0; 174.6.
MS (EI) m/z (rel int): 361 (M+, 1), 91 (100). Anal. Calcd for
[2S,4S]-(+)-Meth yl 2-Meth yl-5-ph en yl-4-(p-tolu en esu lfo-
n yla m in o)p en ta n oa te (5h ). Yield: 93%. [R]D20: +68.4 (c )
0.5, CH2Cl2). IR (CHCl3): 3457; 1714; 1342, 1163. 1H NMR (δ,
ppm): 1.05 (d, 3H, J ) 6.8 Hz); 1.43 (m, 1H); 1.85 (m, 1H);
2.43 (s, 3H); 2.65 (m, 3H); 3.47 (m, 1H); 3.60 (s, 3H); 5.02 (m,
1H); 7.03 (m, 2H); 7.15 (m, 3H); 7.26 (d, 2H, J ) 8.0 Hz); 7.64
(d, 2H, J ) 8.0 Hz). 13C NMR (δ, ppm): 16.2; 21.0; 35.5; 37.7;
41.3; 51.8; 53.3; 126.2; 126.6; 128.3; 128.8; 129.4; 136.9; 137.7;
142.6; 177.5. MS (EI) m/z (Int. Rel.): 375 (M+, 4), 91 (100).
Anal. Calcd for C20H25NO4S: C, 63.97; H, 6.71; N, 3.73.
Found: C, 64.07; H, 6.79; N, 3.68.
C
19H23NO4S: C, 63.13; H, 6.41; N, 3.88. Found: C, 63.21; H,
6.38; N, 3.93.
[2S,4S]-(-)-Meth yl 2-m eth yl-4-(p-tolu en esu lfon yla m i-
n o)p en ta n oa te (5b). Yield: 89%. Mp: 78-80 °C (Hexanes/
AcOEt 1:1). [R]D20: -19.7 (c ) 0.1, CH2Cl2). IR (KBr): 3450;
1715; 1347, 1165. 1H NMR (δ, ppm): 0.89 (d, 3H, J ) 6.5 Hz);
1.01 (d, 3H, J ) 7.0 Hz); 1.37 (m, 1H); 1.78 (m, 1H); 2.35 (s,
3H); 2.51 (m, 1H); 3.30 (m, 1H); 3.60 (s, 3H); 5.19 (d, 1H, J )
8.9 Hz); 7.23 (d, 2H, J ) 8.2 Hz); 7.71 (d, 2H, J ) 8.2 Hz). 13C
NMR (δ, ppm): 16.8; 21.3; 21.6; 36.1; 40.8; 48.1; 51.6; 126.8;
129.4; 138.1; 143.0; 177.2. MS (EI) m/z (rel int): 299 (M+, 3),
91 (100). Anal. Calcd for C14H21NO4S: C, 56.16; H, 7.07; N,
4.68. Found: C, 56.20; H, 7.15; N, 4.63.
[2S,4R]-(-)-Met h yl 2,5-d im et h yl-4-(p -t olu en esu lfon -
yla m in o)h exa n oa te (5c). Yield: 90%. [R]D20: -6.3 (c ) 0.2,
CH2Cl2). IR (CHCl3): 3454; 1710; 1341, 1164. 1H NMR (δ,
ppm): 0.65 (d, 6H, J ) 6.8 Hz); 0.91 (d, 3H, J ) 6.9 Hz); 1.30
(m, 1H); 1.58 (m, 2H); 2.30 (s, 3H); 2.36 (m, 1H); 3.11 (m, 1H);
3.53 (s, 3H); 5.40 (d, 1H, J ) 9.0 Hz); 7.16 (d, 2H, J ) 7.9 Hz);
7.67 (d, 2H, J ) 7.9 Hz). 13C NMR (δ, ppm): 16.3; 17.0; 17.7;
21.1; 31.2; 34.0; 35.6; 51.4; 56.7; 126.5; 129.1; 138.5; 142.6;
176.9. MS (EI) m/z (rel int): 327 (M+, 1), 91 (100). Anal. Calcd
for C16H25NO4S: C, 58.69; H, 7.70; N, 4.28. Found: C, 58.61;
H, 7.63; N, 4.36.
[2S,4R]-(-)-Met h yl 2-m et h yl-5-p h en yl-4-(p -t olu en e-
su lfon yla m in o)p en ta n oa te (5d ). Yield: 91%. Mp: 138-141
°C (n-Pentane). [R]D20: -19.9 (c ) 0.5, CH2Cl2). IR (KBr): 3453;
1715; 1342, 1164. 1H NMR (δ, ppm): 0.98 (d, 3H, J ) 7.0 Hz);
1.45 (m, 1H); 1.80 (m, 1H); 2.39 (s, 3H); 2.60 (m, 3H); 3.51 (m,
1H); 3.63 (s, 3H); 5.24 (m, 1H); 6.98 (m, 2H); 7.18 (m, 3H);
7.24 (d, 2H, J ) 8.0 Hz); 7.73 (d, 2H, J ) 8.0 Hz). 13C NMR (δ,
ppm): 16.3; 21.1; 35.8; 37.5; 41.4; 51.4; 53.3; 126.1; 126.6;
128.1; 128.9; 129.3; 136.9; 137.9; 142.8; 177.1. MS (EI) m/z (rel
int): 375 (M+, 1), 91 (100). Anal. Calcd for C20H25NO4S: C,
63.97; H, 6.71; N, 3.73. Found: C, 64.01; H, 6.61; N, 3.79.
[2S,4S]-(+)-Meth yl 2-m eth yl-4-p h en yl-4-(p-tolu en esu l-
fon yla m in o)bu ta n oa te (5e). Yield: 92%. [R]D20: +72.3 (c )
0.1, CH2Cl2). IR (CHCl3): 3450; 1712; 1341, 1160. 1H NMR (δ,
ppm): 1.10 (d, 3H, J ) 7.0 Hz); 2.39 (s, 3H); 2.78 (m, 1H);
3.02 (m, 1H); 3.11 (m, 1H); 3.36 (m, 1H); 3.45 (s, 3H); 4.52 (m,
1H); 7.00 (m, 2H); 7.25 (m, 3H); 7.33 (d, 2H, J ) 8.2 Hz); 7.63
(d, 2H, J ) 8.2 Hz). 13C NMR (δ, ppm): 14.3; 21.4; 42.5; 44.5;
47.6; 51.2; 126.6; 126.8; 127.5; 128.4; 129.1; 136.4; 138.7; 143.0;
174.5. MS (EI) m/z (rel int): 361 (M+, 1), 91 (100). Anal. Calcd
for C19H23NO4S: C, 63.13; H, 6.41; N, 3.88. Found: C, 63.09;
H, 6.51; N, 3.79.
Gen er a l P r oced u r e for th e La cta m iza tion of Ester s
5a -h . Syn th esis of [3S,5R]-(-)-3-Meth yl-5-p h en yl-1-(p-
tolu en esu lfon yl)p yr r olid in -2-on e (6a ). A solution of LH-
MDS (1.02 mmol) in THF was slowly added over a cooled (-20
°C) solution of 5a (0.37 g, 1.02 mmol) in dry THF (15 mL).
The mixture was stirred for 45 min at this temperature and
quenched with a 4 M HCl solution (15 mL). The mixture was
extracted with CH2Cl2 (3 × 10 mL) and the collected organic
fractions were dried over Na2SO4 and filtered and the solvent
was removed in vacuo yielding pyrrolidin-2-one 6a after flash
column chromatography purification (hexanes/EtOAc 8:2).
Yield: 74%. Mp: 88-91 °C (n-Pentane). [R]D20: -4.7 (c ) 0.1,
1
CH2Cl2). IR (KBr): 1720; 1343, 1162. H NMR (δ, ppm): 0.73
(d, 3H, J ) 7.3 Hz); 2.46 (s, 3H); 2.89 (m, 1H); 3.53 (dt, 1H, J
) 3.1, 8.3 Hz); 4.02 (dd, 1H, J ) 3.2, 6.8 Hz); 4.15 (dd, 1H, J
) 6.8, 8.3 Hz); 6.91 (m, 2H); 7.19 (m, 3H); 7.33 (d, 2H, J ) 8.1
Hz); 7.96 (d, 2H, J ) 8.1 Hz). 13C NMR (δ, ppm): 10.7; 21.6;
41.2; 42.6; 51.2; 127.1; 127.3; 127.9; 128.6; 129.6; 134.8; 138.4;
145.2; 175.0. MS (EI) m/z (rel int): 329 (M+, 2), 118 (100). Anal.
Calcd for C18H19NO3S: C, 65.63; H, 5.81; N, 4.25. Found: C,
65.72; H, 5.85; N, 4.28.
[3S,5S]-(+)-3,5-Dim eth yl-1-(p-tolu en esu lfon yl)p yr r oli-
20
d in -2-on e (6b). Yield: 77%. Mp: 98-100 °C (Et2O). [R]D
:
+86.4 (c ) 0.01, CH2Cl2). IR (KBr): 1725; 1340, 1163. 1H NMR
(δ, ppm): 1.43 (d, 3H, J ) 6.5 Hz); 1.55 (d, 3H, J ) 6.1 Hz);
1.82 (m, 2H); 2.41 (s, 3H); 2.69 (m, 1H); 4.30 (m, 1H); 4.98 (d,
1H, J ) 8.7 Hz); 7.31 (d, 2H, J ) 8.0 Hz); 7.96 (d, 2H, J ) 8.0
Hz). 13C NMR (δ, ppm): 14.5; 15.6; 21.5; 25.7; 36.7; 59.6; 128.5,
129.7; 135.5; 144.5; 177.2. MS (EI) m/z (rel int): 267 (M+, 2),
188 (100). Anal. Calcd for C13H17NO3S: C, 58.40; H, 6.41; N,
5.24. Found: C, 58.49; H, 6.50; N, 5.29.
[3S,5R]-(+)-3-Met h yl-5-(1-m et h ylet h yl)-1-(p -t olu en e-
su lfon yl)p yr r olid in -2-on e (6c). Yield: 72%. Mp: 112-115
°C (Et2O). [R]D20: +78.6 (c ) 0.1, CH2Cl2). IR (KBr): 1722; 1343,
1161. 1H NMR (δ, ppm): 0.64 (d, 3H, J ) 6.8 Hz); 0.90 (d, 3H,
J ) 7.0 Hz); 1.12 (d, 3H, J ) 7.0 Hz); 1.39 (m, 1H); 2.21 (m,
1H); 2.42 (s, 3H); 2.48 (m, 1H); 2.75 (m, 1H); 4.26 (dt, 1H, J )
3.9, 7.8 Hz); 7.31 (d, 2H, J ) 8.1 Hz); 7.94 (d, 2H, J ) 8.1 Hz).
13C NMR (δ, ppm): 13.9; 15.3; 18.0; 21.4; 25.5; 29.0; 36.3; 62.7;
128.3; 129.8; 135.6; 144.5; 177.4. MS (EI) m/z (rel int): 295
(M+, 1), 155 (100). Anal. Calcd for C15H21NO3S: C, 60.99; H,
7.17; N, 4.74. Found: C, 61.11; H, 7.25; N, 4.88.
[3S,5R]-(+)-5-Ben zyl-3-m et h yl-1-(p -t olu en esu lfon yl)-
p yr r olid in -2-on e (6d ). Yield: 76%. Mp: 143-145 °C (Et2O).
[R]D20: +73.7 (c ) 0.1, CH2Cl2). IR (KBr): 1722; 1342, 1160.
1H NMR (δ, ppm): 1.05 (d, 3H, J ) 7.1 Hz); 1.41 (m, 2H); 2.13
(m, 2H); 2.36 (m, 1H); 2.43 (s, 3H); 2.63 (dd, 1H, J ) 10.0,
12.8 Hz); 3.84 (dd, 1H, J ) 3.6, 12.8 Hz); 4.45 (m, 1H); 7.21-
7.35 (m, 7H); 8.02 (d, 2H, J ) 8.1 Hz). 13C NMR (δ, ppm): 16.0;
21.6; 31.5; 36.7; 42.4; 59.5; 126.8; 128.1; 128.2; 128.6; 129.5;
136.2; 136.7; 144.9; 176.7. MS (EI) m/z (rel int): 343 (M+, 3),
155 (100) Anal.Calcd for C19H21NO3S: C, 66.45; H, 6.16; N,
4.08. Found: C, 66.54; H, 6.11; N, 4.17.
[3S,5S]-(+)-3-Met h yl-5-p h en yl-1-(p -t olu en esu lfon yl)-
p yr r olid in -2-on e (6e). Yield: 71%. [R]D20: +88.6 (c ) 0.2, CH2-
Cl2). IR (CHCl3): 1720; 1343, 1162. 1H NMR (δ, ppm): 0.82
(d, 3H, J ) 7.3 Hz); 2.49 (s, 3H); 3.11 (m, 1H); 3.48 (dt, 1H, J
) 2.9, 11.0 Hz); 4.04 (dd, 1H, J ) 2.9, 8.8 Hz); 4.31 (dd, 1H, J
) 8.8, 11.0 Hz); 7.03 (m, 2H); 7.18 (m, 3H); 7.30 (d, 2H, J )
8.1 Hz); 8.00 (d, 2H, J ) 8.1 Hz). 13C NMR (δ, ppm): 10.7;
21.6; 41.2; 42.6; 51.2; 127.1; 127.3; 127.9; 128.6; 129.6; 134.8;
138.4; 145.2; 175.0. MS (EI) m/z (rel int): 329 (M+, 1), 118
[2S,4R]-(-)-Meth yl 2-m eth yl-4-(p-tolu en esu lfon yla m i-
n o)p en ta n oa te (5f). Yield: 93%. [R]D20: -9.2 (c ) 0.2, CH2-
1
Cl2). IR (CHCl3): 3457; 1713; 1343, 1160. H NMR (δ, ppm):
0.95 (d, 3H, J ) 6.5 Hz); 1.07 (d, 3H, J ) 7.2 Hz); 1.31 (m,
1H); 1.76 (m, 1H); 2.39 (s, 3H); 2.54 (m, 1H); 3.31 (m, 1H);
3.60 (s, 3H); 4.98 (d, 1H, J ) 8.7 Hz); 7.25 (d, 2H, J ) 8.0 Hz);
7.71 (d, 2H, J ) 8.0 Hz). 13C NMR (δ, ppm): 17.7; 21.3; 21.7;
35.7; 40.9; 48.2; 51.5; 126.8; 129.5; 137.9; 143.0; 176.7. MS (EI)
m/z (rel int): 299 (M+, 3), 91 (100). Anal. Calcd for C14H21
-
NO4S: C, 56.16; H, 7.07; N, 4.68. Found: C, 56.21; H, 7.00;
N, 4.59.
[2S,4S]-(+)-Met h yl 2,5-d im et h yl-4-(p -t olu en esu lfon -
yla m in o)h exa n oa te (5g). Yield: 91%. Mp: 112-114 °C (n-
heptane). [R]D20: +52.4 (c ) 0.2, CH2Cl2). IR (KBr): 3455; 1710;
1
1340, 1165. H NMR (δ, ppm): 0.61 (d, 3H, J ) 6.8 Hz); 0.91
(d, 3H, J ) 7.0 Hz); 1.02 (d, 3H, J ) 7.0 Hz); 1.59 (m, 1H);
2.08 (m, 1H); 2.34 (s, 3H); 2.44 (m, 2H); 3.30 (m, 1H); 3.53 (s,
3H); 4.20 (dd, 1H, J ) 3.6, 9.3 Hz); 7.23 (d, 2H, J ) 8.1 Hz);
7.86 (d, 2H, J ) 8.1 Hz). 13C NMR (δ, ppm): 15.1; 15.9; 18.8;
21.3; 27.7; 30.8; 36.9; 51.2; 62.6; 127.9; 129.1; 135.5; 144.6;
176.3. MS (EI) m/z (rel int): 327 (M+, 1), 155 (100). Anal. Calcd

Aziridine Ring-Opening Reactions
J . Org. Chem., Vol. 66, No. 17, 2001 5807
(100). Anal. Calcd for C18H19NO3S: C, 65.63; H, 5.81; N, 4.25.
Found: C, 65.72; H, 5.85; N, 4.28.
135.7; 144.7; 177.0. MS (EI) m/z (rel int): 295 (M+, 3), 155
(100). Anal. Calcd for C15H21NO3S: C, 60.99; H, 7.17; N, 4.74.
Found: C, 58.31; H, 6.53; N, 5.18.
[3S,5R]-(-)-3,5-Dim eth yl-1-(p-tolu en esu lfon yl)p yr r oli-
20
d in -2-on e (6f). Yield: 75%. Mp: 119-121 °C (Et2O). [R]D
:
[3S,5S]-(+)-5-Ben zyl-3-m et h yl-1-(p -t olu en esu lfon yl)-
p yr r olid in -2-on e (6h ). Yield: 71%. [R]D20: -95.3 (c ) 0.1,
CH2Cl2). IR (CHCl3): 1723; 1342, 1161. 1H NMR (δ, ppm): 1.00
(d, 3H, J ) 6.9 Hz); 1.64 (m, 2H); 2.11 (m, 2H); 2.37 (m, 1H);
2.43 (s, 3H); 2.81 (dd, 1H, J ) 9.4, 13.3 Hz); 3.34 (dd, 1H, J )
3.3, 13.3 Hz); 4.49 (m, 1H); 7.21-7.35 (m, 7H); 7.98 (d, 2H, J
) 8.1 Hz). 13C NMR (δ, ppm): 14.7; 21.6; 31.6; 35.5; 40.0; 58.7;
126.9, 128.1, 128.2, 128.6, 129.3; 135.8; 136.2; 144.9; 175.7.
MS (EI) m/z (rel int): 343 (M+, 1), 155 (100). Anal. Calcd for
-13.7 (c ) 0.1, CH2Cl2). IR (KBr): 1728; 1340, 1164. 1H NMR
(δ, ppm): 1.11 (d, 3H, J ) 7.0 Hz); 1.16 (d, 3H, J ) 6.6 Hz);
2.11 (m, 2H); 2.43 (s, 3H); 2.83 (m, 1H); 4.28 (m, 1H); 7.27 (d,
2H, J ) 8.0 Hz); 7.91 (d, 2H, J ) 8.0 Hz). 13C NMR (δ, ppm):
14.5; 15.7; 21.5; 25.8; 36.5; 59.6; 128.3; 129.5; 135.6; 144.7;
177.3. MS (EI) m/z (rel int): 267 (M+, 1), 188 (100). Anal. Calcd
for C13H17NO3S: C, 58.40; H, 6.41; N, 5.24. Found: C, 58.31;
H, 6.53; N, 5.18.
[3S,5S]-(+)-3-Met h yl-5-(1-m et h ylet h yl)-1-(p -t olu en e-
su lfon yl)p yr r olid in -2-on e (6g). Yield: 73%. Mp: 86-89 °C
(Et2O). [R]D20: +75.7 (c ) 0.1, CH2Cl2). IR (KBr): 1725; 1342,
1161. 1H NMR (δ, ppm): 0.62 (d, 3H, J ) 6.8 Hz); 0.89 (d, 3H,
J ) 6.9 Hz); 1.10 (d, 3H, J ) 7.1 Hz); 1.37 (m, 1H); 2.19 (m,
2H); 2.39 (s, 3H); 2.74 (m, 1H); 4.24 (dt, 1H, J ) 4.0, 7.9 Hz);
7.27 (d, 2H, J ) 8.1 Hz); 7.90 (d, 2H, J ) 8.1 Hz). 13C NMR (δ,
ppm): 13.9; 15.2; 18.0; 21.5; 25.3; 29.0; 36.3; 62.9; 128.1, 129.3;
C19H21NO3S: C, 66.45; H, 6.16; N, 4.08. Found: C, 66.39; H,
6.23; N, 4.01.
Ack n ow led gm en t . Financial support from the
Basque Government (a fellowship to J .L.V. and Project
GV00170.30-7307/19) is gratefully acknowledged.
J O0103571