Synthesis of chiral amino epoxyaziridines: Useful intermediates for the preparation of chiral trisubstituted piperidines

Article abstract of DOI:10.1021/jo0490806

Chiral aminoalkyl epoxyaziridine 1 is synthesized in high yield and diastereoselectivity from L-serine. Ring opening of epoxyaziridine I with primary amines is carried out with total chemo- and regioselectivity, affording chiral polyfunctionalized piperid

Full text of DOI:10.1021/jo0490806

Syn th esis of Ch ir a l Am in o Ep oxya zir id in es: Usefu l In ter m ed ia tes
for th e P r ep a r a tion of Ch ir a l Tr isu bstitu ted P ip er id in es
J ose´ M. Concello´n,*,† Estela Riego,† Ignacio A. Rivero,*,‡ and Adria´n Ochoa‡
Departamento de Qu´ımica Orga´nica e Inorga´nica, Facultad de Qu´ımica, Universidad de Oviedo,
J ulia´n Claverı´a 8, 33071 Oviedo, Spain, and Centro de Graduados e Investigacio´n del Instituto
Tecnolo´gico de Tijuana, Blvd. Industrial s/ n, Mesa de Otay, Tijuana, B.C., Me´xico 22000
jmcg@sauron.quimica.uniovi.es
Received J une 2, 2004
Chiral aminoalkyl epoxyaziridine 1 is synthesized in high yield and diastereoselectivity from
L-serine. Ring opening of epoxyaziridine 1 with primary amines is carried out with total chemo-
and regioselectivity, affording chiral polyfunctionalized piperidines 8. The structure of these
trisubstituted piperidines is established by NMR studies.
In tr od u ction
Recently, we have reported the preparation of the
pseudo-C2-symmetric (2R,4R)- and (2S,4S)-N,N-dibenzyl-
1,2:4,5-diepoxypentan-3-amine (amino diepoxides) from
serine, in enantiomerically pure form,5 and the synthesis
of chiral amino aziridines from 1-aminoalkyl chloro-
methyl ketones.6 On the basis of these methodologies,
we wish to report the preparation of a new family of
highly functionalized enantiopure compounds, such as
(2S,1′R,2′R)-1-benzyl-2-[1′-(dibenzylamino)-2′,3′-epoxypro-
pyl]aziridine 1 (amino epoxyaziridine).7 Taking into ac-
count the different reactivity of oxirane and aziridine
rings with nucleophiles, we studied their behavior with
primary amines, obtaining functionalized hydroxylated
piperidines 8.
Polyfunctionalized chiral building blocks, which are
defined as molecules having at least one stereogenic
center and more than one chemically differentiated
functional group, have played significant roles in asym-
metric synthesis and the synthesis of biologically and
pharmacologically active molecules,1 such as functional-
ized heterocyclic compounds. Therefore, the development
of novel synthetic units is highly desired to obtain
functional compounds.
In this regard, the piperidine ring systems,2 and
specifically, hydroxylated piperidine alkaloids,3 constitute
a large family of naturally occurring substances, many
of which possess important biological activities.3e Hence,
the development of new methods for the synthesis of
these piperidine derivatives in an enantiomerically pure
way constitutes an area of current interest.4
Resu lts a n d Discu ssion
Our synthetic strategy to prepare the amino ep-
oxyaziridine 1 was based on the transformation of the
ester function of the serine derivative 2 into an aziridine
ring and, then, oxirane ring formation from the hydroxyl
group (Scheme 1). Thus, as a first step, the R-amino-R′-
chloro ketone 35 was prepared from the methyl N,N-
dibenzylated O-protected ester 2,8 by reaction with in situ
generated chloromethyllithium at -78 °C, in high yield
(93%, Scheme 1). Treatment of ketone 3 with benzyl-
amine in the presence of TiCl4 at room temperature gave
the R-amino ketimine 4, which was immediately trans-
formed into the amino aziridine 5 by reduction of 4 with
NaBH4 at -30 °C, and further treatment with MeLi. That
* To whom correspondence should be addressed. Fax: 34-98-510-
34-46.
† Universidad de Oviedo.
‡ Instituto Tecnolo´gico de Tijuana.
(1) (a) Hanessian, S. Total Synthesis of Natural Products: the
‘Chiron’ Approach; Pergamon: Oxford, UK, 1983. (b) Banfi, L.; Guanti,
G. Synthesis 1993, 1029.
(2) For a review, see: (a) Wang, C.-L. J .; Wuonola, M. A. Org. Prep.
Proced. Int. 1992, 24, 585. (b) Angle, S. R.; Breitenbucher, J . G. In
Studies in Natural Products Chemistry; Atta-ur-Rahman, Ed.; Elsevi-
er: Amsterdam, The Netherlands, 1995; Vol. 16, pp 453-502. (c)
Leclercq, S.; Daloze, D.; Braekman, J .-C. Org. Prep. Proced. Int. 1996,
28, 501. (d) Nadin, A. Contemp. Org. Synth. 1997, 4, 387. (e) Bailey,
P. D.; Millwood, P. A.; Smith, P. D. Chem. Commun. 1998, 633. (f)
Laschat, S.; Dickner, T. Synthesis 2000, 1781.
(3) (a) Fodor, G. B.; Colasanti, B. In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1985;
Vol. 3, Chapter 1, pp 1-90. (b) Elbein, A. D.; Molyneux, R. J . In
Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.;
Wiley: New York, 1987; Vol. 5, Chapter 1, pp 1-54. (c) Takahata, H.;
Momose, T. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: San
Diego, CA, 1993; Vol. 44, Chapter 3, pp 189-256. (d) Schneider, M. J .
In Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W.,
Ed.; Pergamon: Oxford, UK, 1996; Vol. 10, Chapter 2, pp 155-299.
(4) Some recent synthesis of hydroxylated piperidines: (a) Davis,
F. A.; Chao, B.; Rao, A. Org. Lett. 2001, 3, 3169. (b) Celestini, P.;
Danieli, B.; Lesma, G.; Sacchetti, A.; Silvani, A.; Passarella, D.; Virdis,
A. Org. Lett. 2002, 4, 1367. (c) Singh, R.; Ghosh, S. K. Tetrahedron
Lett. 2002, 43, 7711. (d) Ma, D.; Ma, N. Tetrahedron Lett. 2003, 44,
3963.
(5) Concello´n, J . M.; Riego, E.; Rodr´ıguez-Solla, H.; Plut´ın, A. M. J .
Org. Chem. 2001, 66, 8661.
(6) Concello´n, J . M.; Bernad, P. L.; Riego, E.; Garc´ıa-Granda, S.;
Force´n-Acebal, A. J . Org. Chem. 2001, 66, 2764.
(7) Previously, other epoxyaziridines have been described: (a) Marco,
J . A.; Sanz, J . F.; Vogel, E.; Schwartzkopff-Fischer, B.; Schmickler,
H.; Lex, J . Tetrahedron Lett. 1990, 31, 999. (b) O’Brien, P.; Pilgram,
C. D. Tetrahedron Lett. 1999, 40, 8427. (c) Schilling, S.; Rinner, U.;
Chan, C.; Ghiviriga, I.; Hudlicky, T. Can. J . Chem. 2001, 79, 1659. (d)
Paleo, M. R.; Aurrecoechea, N.; J ung, K.-Y.; Rapoport, H. J . Org. Chem.
2003, 68, 130.
(8) Laib, T.; Chastanet, J .; Zhu, J . J . Org. Chem. 1998, 63, 1709.
10.1021/jo0490806 CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/17/2004
6244
J . Org. Chem. 2004, 69, 6244-6248

Synthesis of Chiral Amino Epoxyaziridines
SCHEME 1. Syn th esis of Am in o Ep oxya zir id in e 1
SCHEME 2. Syn th esis of
3-Hyd r oxy-4,5-d ia m in op ip er id in es 8
reduction process was carried out with total diastereo-
1
selectivity (de >95%, H NMR 300 MHz).9
Once the aziridine ring was prepared, we proceeded
to construct the oxirane cycle through the careful oxida-
tion of the free hydroxyl group in compound 6, under
Swern conditions, and iodomethylation of the resulting
R-amino aldehyde 7, with in situ generated iodomethyl-
lithium at -78 °C. The ring closure of the obtained
lithium alcoholate took place spontaneously under these
reaction conditions, yielding the product 1 in 87% yield
1
and 93% de (300 MHz H NMR).
Since all the intermediate compounds (3-7) were
obtained with a high degree of purity, they could be used
without further purification. This allowed the isolation
of 1 in good yield (43% after 6 steps).
On the basis of our earlier studies which examined the
nonchelation controlled reduction of chiral R-dibenzyl-
amino ketimines6 and the addition of iodomethyllithium
to R-aminoaldehydes,10 the absolute configuration of
amino epoxyaziridine 1 is believed to be (2S,1′R,2′R).11
Furthermore, we assumed that synthesis of 1 pro-
ceeded with keeping of the integrity of the preexistent
asymmetric carbon at the starting material. This as-
sumption is based on previously described preparations
of amino aziridines from amino chloromethyl ketones,6
amino epoxides from R-aminoaldehydes and iodometh-
yllithium,10 and amino diepoxides from serine.12 No
racemization took place in these syntheses.13
It is noteworthy that all the carbon atoms of ep-
oxyaziridine 1 are differently functionalized. Moreover,
the oxirane and the aziridine rings have different reac-
tivity: the oxirane ring is more easily opened by nucleo-
philes than nonactivated aziridine. Hence, this compound
could be used as a new chiral building block in the
synthesis of enantiopure compounds. To illustrate this
synthetic potential, the amino epoxyaziridine 1 was
treated with some primary amines in the presence of
lithium perchlorate14 at room temperature, affording
TABLE 1. Syn th esis of
3-Hyd r oxy-4,5-d ia m in op ip er id in es 8
entry
product
R
yield (%)a
1
2
3
4
5
8a
8b
8c
8d
8e
n-propyl
allyl
benzyl
cyclohexyl
(S)-Ph(Me)CH
60
78
66
70
65
a
Isolated yield after column chromatography based on the
starting epoxyaziridine 1.
chiral hydroxylated piperidines 8 as sole products in good
yields (Scheme 2, Table 1).
Although no ring activation has been observed in
amino aziridines with lithium perchlorate in ring-opening
reactions,15 formation of compounds 8 can be explained
by successive openings of the oxirane and the aziridine
rings by the amine, at less substituted carbons in
compound 1.
Thereby, the oxirane ring would be opened at the less
hindered position according to previous works,5,14 afford-
ing the diamino alcohol 9 (Scheme 2). This intermediate
could react through the hydroxyl group (Scheme 3, path
a) or through the amine function (Scheme 3, paths b, and
c), yielding tetrahydrofurans A, pyrrolidines B, or pip-
eridines 8, respectively. However, trisubstituted pip-
eridines 8 were detected as sole reaction products (300
(9) Only one diastereoisomer was visible by 1H and 13C NMR spectra
(300 MHz) of compound 5.
(10) Barluenga, J .; Baragan˜a, B.; Concello´n, J . M. J . Org. Chem.
1995, 60, 6696.
(11) N,N-Dibenzylamino carbonyl compounds react with nucleo-
philes, in absence of Lewis acids, with a nonchelation control. See:
Reetz, M. T. Chem. Rev. 1999, 99, 1121.
(12) Synthesis of ketone 3 from 2 proceeded with no detectable
racemization, which was determined by chiral HPLC in the synthesis
of amino diepoxides from serine. See ref 5.
1
MHz H NMR). Therefore, the amine function in inter-
mediate 9 participates in a nucleophilic attack to the
aziridine ring at the less hindered position, affording the
piperidine ring.
(13) No racemization is observed in the use of N,N-dibenzylamino
carbonyl compounds as electrophiles. See ref 10.
(14) N,N-Dibenzylamino epoxides are opened with amines, using
lithium perchlorate as catalyst: Concello´n, J . M.; Cuervo, H.; Ferna´n-
dez-Fano, R. Tetrahedron 2001, 57, 8983.
(15) Previously, we studied the ring opening of nonactivated ami-
noaziridines with nucleophiles, using different acids [see: (a) Concello´n,
J . M.; Riego, E. J . Org. Chem. 2003, 68, 6407. (b) Concello´n, J . M.;
Riego, E.; Sua´rez, J . R. J . Org. Chem. 2003, 68, 9242], but no reaction
was observed in the presence of LiClO4.
J . Org. Chem, Vol. 69, No. 19, 2004 6245

Concello´n et al.
SCHEME 3. P r oba ble P r od u cts of th e Rin g
Op en in g of In ter m ed ia te 9
F IGURE 1. Conformational equilibrium of piperidines 8.
interactions between H-4 and H-3 and the absence of
NOE between H-4 and H-5 support the configuration of
piperidines. Therefore, since the original asymmetric
center in serine (C-4 in 8) has not been involved in any
process, the absolute configuration of 8 is (3S,4R,5S).
This stereochemistry is also in agreement with the
proposed ring-opening mechanism.
In conclusion, we have described the synthesis of the
optically active amino epoxyaziridine 1 with high di-
astereoselectivity and good yield. The synthetic route is
simple, and the starting material (serine) is readily
available. Likewise, the usefulness of 1 as a new chiral
building block has been proved, affording chiral trisub-
stituted piperidines in totally chemoselective form.
SCHEME 4. Rin g Op en in g of 1 w ith Dieth yla m in e
Exp er im en ta l Section
(2R)-(Z)-N,N-Diben zyl-3-(ben zylim in o)-1-[(ter t-bu tyld i-
m eth ylsila n yl)oxy]-4-ch lor obu ta n -2-a m in e (4). A solution
of TiCl4 (0.18 mL, 1.65 mmol) in dry hexane was added
dropwise to a stirred solution of 3 (1.30 g, 3 mmol) in dry
diethyl ether (30 mL) at 0 °C. Benzylamine (1.31 mL, 12 mmol)
was added to the resulting solution over 5 min with stirring.
After being stirred at room temperature for 2 h, the mixture
was filtered through a pad of Celite and the solvents were
removed in vacuo yielding the corresponding crude ketimine
4. Due to instability of 4 no further purification was attempted,
and it was characterized by IR and NMR spectroscopy: 1H
NMR (CDCl3, 300 MHz) δ 7.34-7.27 (15 H, m), 4.63 (2 H, d,
J ) 16.2 Hz), 4.30 (1 H, dd, J ) 10.8, 7.7 Hz), 4.13 (1 H, dd,
J ) 10.8, 5.1 Hz), 3.95 (2 H, d, J ) 10.8 Hz), 3.90 (2 × 2 H, d,
J ) 13.1 Hz), 3.73 (1 H, dd, J ) 7.7, 5.1 Hz), 0.98 (9 H, s), 0.15
(3 H, s), 0.12 (3 H, s); 13C NMR (CDCl3, 75 MHz) δ 165.7 (C),
140.0 (C), 139.6 (C), 129.2, 128.2, 128.1, 127.4, 126.9, and 126.5
(6 × CH), 63.0 (CH), 61.2 (CH2), 54.6 (CH2), 34.5 (CH2), 26.0
(CH3), 18.2 (C), -5.4 (CH3); IR (neat) 1662.
The structures of ring-opening products were estab-
lished based on IR and 13C and NOESY NMR experi-
ments. To reject some possible structures of 8, compound
8a was acetylated. The IR spectra of this product showed
bands at 1735 and 1643 cm-1, characteristic of ester and
amide groups, respectively. Consequently, the tetrahy-
drofuran A (Scheme 3) was ruled out, since it would
contain two amide functions.
Therefore, the amine group acts as a nucleophile for a
second time, as the use of diethylamine can also prove
because the corresponding intermediate 9 was isolated
(Scheme 4).
On the other hand, two methine groups in the 13C NMR
spectrum of 8a were moved to lower fields in the
acetylated derivative (from 63.9 and 51.5 to 67.0 and 55.3
ppm, respectively), which could indicate that the hydroxyl
and secondary amine functions could be joined to these
carbons. Thus, structure B (Scheme 3) would not explain
this behavior, and the ring-opening product would cor-
respond to the six-member heterocycle 8. Moreover,
NOESY experiments showed correlation between gemi-
nal hydrogens of the C-2 and C-6 methylenes. This
correlation is observed in six-member cyclic molecules,
due to a conformational equilibrium that produces an
exchange of the environment of methylene protons
(Figure 1, I and II).16 Hence, all these data can support
the assigned structures for compounds 8.
(2S,1′R)-1-Ben zyl-2-{1′-(d ib en zyla m in o)-2′-[(ter t-b u -
tyld im eth ylsila n yl)oxy]eth yl}a zir id in e (5). To a -30 °C
stirred solution of the ketimine 4 (1.56 g, 3 mmol) in methanol
(15 mL) was added NaBH4 (0.23 g, 6.0 mmol). After being
stirred at the same temperature for 3 h, the mixture was
quenched with a saturated aqueous solution of NH4Cl (15 mL)
and extracted with diethyl ether (3 × 15 mL). The combined
organic layers were dried (Na2SO4), filtered, and concentrated
in vacuo. The residue was dissolved in dry THF and treated
with MeLi (4.1 mL of 1.5 M solution in diethyl ether, 6.2
mmol). The crude product 5 was examined by 1H NMR to give
a de >95%. Flash column chromatography over silica gel
(hexane:ethyl acetate) provided pure compound 5: Rf 0.30
(hexane/ethyl acetate 10/1); [R]22 -20.0 (c 1.2, CHCl3); 1H
D
Finally, configurational assignments of piperidine 8
were established by 1H NMR coupling constants analysis
and NOESY experiments of 8a ,c. The H-4 signal (2.39
ppm for 8a , 2.45 ppm for 8c) shows J ) 10.6, 1.8 Hz in
8a and J ) 10.3, 1.7 Hz in 8c, corresponding to a trans
relative configuration between H-4 and H-5 and cis for
H-4 and H-3. Furthermore, the observation of NOE
NMR (CDCl3, 200 MHz) δ 7.42-7.23 (15 H, m), 3.88-3.71 (6
H, m), 3.54 (2 H, d, J ) 12.9 Hz), 2.49 (1 H, q, J ) 5.9 Hz),
1.82 (1 H, ddd, J ) 6.4, 5.9, 3.3 Hz), 1.71 (1 H, d, J ) 3.3 Hz),
1.39 (1 H, d, J ) 6.4 Hz), 0.96 (9 H, s), 0.07 (6 H, s); 13C NMR
(CDCl3, 75 MHz) δ 140.8 (C), 139.2 (C), 128.8, 128.6, 128.3,
127.8, 127.1, and 126.2 (6 × CH), 65.1 (CH2), 63.8 (CH2), 61.3
(CH), 54.9 (CH2), 38.4 (CH), 31.6 (CH2), 25.8 (CH3), 18.1 (C),
-5.6 (CH3), -5.7 (CH3); IR (neat) 3084, 3062, 3028. Anal. Calcd
for C31H42N2OSi: C, 76.49; H, 8.07; N, 5.76. Found: C, 76.05;
H, 8.21; N, 5.80.
(16) Perrin, C.; Dwyer, T. Chem. Rev. 1990, 90, 935.
6246 J . Org. Chem., Vol. 69, No. 19, 2004

Synthesis of Chiral Amino Epoxyaziridines
(2S,1′R)-1-Ben zyl-2-[1′-(diben zylam in o)-2′-h ydr oxyeth yl]-
a zir id in e (6). A solution of 5 (1.46 g, 3 mmol) in THF (30
mL) was stirred with (Bu4N)F (9 mL of 1 M solution in THF,
9 mmol) at room temperature for 2 h. The reaction mixture
was diluted with water (30 mL) and extracted with CH2Cl2 (3
× 10 mL). Removal of the solvent followed by purification by
flash column chromatography over silica gel (1/1 hexane/ethyl
acetate) provided pure compound 6: Rf 0.20 (hexane/ethyl
acetate 3/1); [R]22D -57.9 (c 1.10, CHCl3); 1H NMR (CDCl3, 300
MHz) δ 7.36-7.21 (15 H, m), 3.60-3.41 (2 H, m), 3.56 (2 × 2
H, d, J ) 13.1 Hz), 3.50 (2 H, d, J ) 12.8 Hz), 2.72-2.67 (1 H,
m), 1.75-1.73 (2 H, m), 1.44 (1 H, d, J ) 6.2 Hz); 13C NMR
(CDCl3, 75 MHz) δ 139.3 (C), 138.4 (C), 128.8, 128.7, 128.3,
127.9, 127.3, and 126.8 (6 × CH), 64.8 (CH2), 59.5 (CH), 58.7
(CH2), 53.5 (CH2), 36.3 (CH), 30.6 (CH2); IR (neat) 3419. Anal.
Calcd for C25H28N2O: C, 80.61; H, 7.58; N, 7.52. Found: C,
80.78; H, 7.49; N, 7.60.
(2S,1′R)-1-Ben zyl-2-[1′-(diben zylam in o)-2′-oxoeth yl]azir -
id in e (7). A solution of dry DMSO (0.50 mL, 7.04 mmol) in
dry CH2Cl2 (2.8 mL) was added dropwise to a -63 °C solution
of oxalyl chloride (0.31 mL, 3.52 mmol) in dry CH2Cl2 (2.8 mL)
over 10 min. The mixture was stirred at the same temperature
for 5 min and a solution of 6 (3.2 mmol) in dry CH2Cl2 (23
mL) was added within 10 min. The reaction was stirred for
an additional 20 min, and then treated carefully with triethyl-
amine (1.4 mL, 16 mmol) in CH2Cl2 (5 mL) over 15 min. The
mixture was stirred for another 30 min. Water was then added
and the aqueous layer was extracted with additional CH2Cl2
(3 × 20 mL). The organic layers were combined, washed with
saturated NaCl solution (50 mL), and dried over Na2SO4. The
solvents were removed in vacuo, yielding the R-aminoaldehyde
7. Due to instability of the aldehyde 7 no further purification
was attempted, and it was characterized by IR and NMR
spectroscopy: 1H NMR (CDCl3, 200 MHz) δ 9.60 (1 H, s), 7.50-
7.26 (15 H, m), 3.64 (2 × 2 H, d, J ) 13.3 Hz), 3.56 (2 H, d, J
) 12.6 Hz), 2.92 (1 H, d, J ) 8.0 Hz), 2.01-1.92 (1 H, m), 1.67
(1 H, d, J ) 3.3 Hz), 1.61 (1 H, d, J ) 6.4 Hz); 13C NMR (CDCl3,
50 MHz) δ 202.0 (CH), 139.0 (C), 138.6 (C), 129.0, 128.9, 128.4,
128.1, 127.4, and 127.0 (6 × CH), 69.8 (CH), 64.9 (CH2), 54.8
(CH2), 34.6 (CH), 31.5 (CH2); IR (neat) 1695, 1680.
temperature for 48 h and then the reaction was hydrolyzed
with H2O (30 mL) and extracted with dichloromethane (3 ×
10 mL). The combined organic layers were dried (Na2SO4),
filtered, and concentrated in vacuo. The crude product was
chromatographed on silica gel, which was saturated with
triethylamine (3/1 hexane/ethyl acetate) to provide a pure
product.
(3S,4R,5S)-5-Ben zylam in o-4-diben zylam in o-3-h ydr oxy-
1-p r op ylp ip er id in e (8a ): Rf 0.68 (ethyl acetate/hexane 3/1);
[R]22 +33.5 (c 0.3, CH2Cl2); 1H NMR (CDCl3, 200 MHz) δ
D
7.32-7.09 (15 H, m), 4.30 (1 H, br s), 3.86 (2 × 2 H, AB system,
J ) 14.4 Hz), 3.71 (2 H, AB system, J ) 13.2 Hz), 3.20-3.04
(2 H, m), 2.94-2.87 (1 H, m), 2.39 (1 H, dd, J ) 10.6, 1.8 Hz),
2.30 (2 H, t, J ) 7.8 Hz), 2.00 (1 H, dd, J ) 11.4, 0.8 Hz), 1.70
(1 H, t, J ) 11.4 Hz), 1.51-1.34 (2 H, m), 0.86 (3 H, t, J ) 7.3
Hz); 13C NMR (CDCl3, 50 MHz) δ 140.3 (C), 140.1 (C), 128.4,
128.3, 128.2, 126.9, and 126.8 (5 × CH), 63.9 (CH), 62.3 (CH),
59.7 (CH2), 59.1 (CH2), 58.5 (CH2), 54.4(CH2), 52.3 (CH2), 51.5
(CH), 19.8 (CH2), 11.6 (CH3); IR (neat) 3472, 3310; MS, m/z
444 (M+ + 1, 4), 385 (6), 337 (38), 247 (57), 146 (100).
(3S,4R,5S)-1-Allyl-5-b en zyla m in o-4-d ib en zyla m in o-3-
h yd r oxyp ip er id in e (8b): Rf 0.55 (ethyl acetate); [R]22D +57.9
1
(c 0.19, CH2Cl2); H NMR (CDCl3, 200 MHz) δ 7.30-7.10 (15
H, m), 5.85-5.66 (1 H, m), 5.20-5.05 (2 H, m), 4.28 (1 H, t, J
) 1.8 Hz), 3.84 (2 × 2 H, AB system, J ) 14.7 Hz), 3.70 (2 H,
AB system, J ) 13.2 Hz), 3.21-3.08 (2 H, m), 3.00 (2 H, d, J
) 6.6 Hz), 2.88 (1 H, br s), 2.41 (1 H, dd, J ) 10.2, 1.8 Hz),
2.02 (1 H, d, J ) 9.8 Hz), 1.73 (1 H, t, J ) 11.8 Hz); 13C NMR
(CDCl3, 50 MHz) δ 139.9 (C), 139.7 (C), 134.2 (CH), 128.2,
128.1, 127.9, 126.6, and 126.5 (5 × CH), 117.9 (CH2), 64.1 (CH),
62.2 (CH), 60.5 (CH2), 59.5 (CH2), 58.3 (CH2), 54.3 (CH2), 52.2
(CH2), 51.3 (CH); IR (neat) 3445, 3314, 1639; MS, m/z 442 (M+
+ 1, 10), 335 (25), 245 (90), 146 (100). Anal. Calcd for
C
29H35N3O: C, 78.87; H, 7.99; N, 9.52. Found: C, 78.68; H,
8.17; N, 9.50.
(3S,4R,5S)-1-Ben zyl-5-ben zyla m in o-4-d iben zyla m in o-
3-h yd r oxyp ip er id in e (8c): Rf 0.74 (hexane/ethyl acetate 3/1);
[R]20 +33.1 (c 0.7, CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ
D
7.39-7.20 (20 H, m), 4.30 (1 H, br s), 3.89 (2 × 2 H, AB system,
J ) 14.3 Hz), 3.70 (2 H, AB system, J ) 13.2 Hz), 3.56 (2 H,
AB system, J ) 10.1 Hz), 3.20-3.15 (2 H, m), 2.92 (1 H, d, J
) 10.2 Hz), 2.47 (1 H, d, J ) 10.2 Hz), 2.08 (1 H, d, J ) 10.8
Hz), 1.78 (1 H, t, J ) 11.6 Hz); 13C NMR (CDCl3, 75 MHz)
140.2 (C), 140.0 (C), 137.8 (C), 128.8, 128.4, 128.3, 128.2, 128.0,
127.3, 126.9, and 126.8 (8 × CH), 64.2 (CH), 62.3 (CH), 61.8
(CH2), 59.6 (CH2), 58.3 (CH2), 54.2 (CH2), 52.1 (CH2), 51.2 (CH);
IR (neat) 3483, 3312; MS, m/z 492 (M+ + 1, 6), 385 (42), 295
(100), 146 (73).
(2S,1′R,2′R)-1-Ben zyl-2-[1′-(d iben zyla m in o)-2′,3′-ep oxy-
p r op yl]a zir id in e (1). To a -78 °C stirred solution of R-ami-
noaldehyde 7 (1.19 g, 3.2 mmol) and diiodomethane (0.77 mL,
9.6 mmol) in dry THF (10 mL) was added methyllithium (6.4
mL of a 1.5 M solution in diethyl ether, 9.6 mmol) dropwise
over 5 min. After being stirred at -78 °C for 30 min, the
mixture was allowed to warm to room temperature. Stirring
was continued for 1 h and then the reaction was hydrolyzed
with a saturated aqueous solution of NH4Cl (5 mL) and
extracted with diethyl ether (3 × 10 mL). The combined
organic layers were dried (Na2SO4), filtered, and concentrated
in vacuo. The crude epoxyaziridine 1 was examined by 1H
NMR to give a de of 93%. The crude product was chromatog-
raphied on silica gel, which was saturated with triethylamine
(3/1 hexane/ethyl acetate) to provide pure compound 1: Rf 0.43
(3S,4R,5S)-5-Ben zyla m in o-4-d ib en zyla m in o-1-cyclo-
h exyl-3-h yd r oxyp ip er id in e (8d ): Rf 0.48 (ethyl acetate);
[R]22 +40.9 (c 0.09, CH2Cl2); 1H NMR (CDCl3, 200 MHz) δ
D
7.37-7.10 (15 H, m), 4.30-4.20 (1 H, m), 3.84 (2 × 2 H, AB
system, J ) 14.2 Hz), 3.71 (2 H, AB system, J ) 12.8 Hz),
3.18-3.06 (2 H, m), 2.86 (1 H, d, J ) 10.6 Hz), 2.50 (1 H, br
s), 2.36 (1 H, dd, J ) 10.2, 1.8 Hz), 2.24 (1 H, d, J ) 11.4 Hz),
1.99 (1 H, t, J ) 11.4 Hz), 1.80-1.55 (4 H, m), 1.25-0.98 (6 H,
m); 13C NMR (CDCl3, 50 MHz) δ 139.8 (C), 128.2, 128.1, 127.9,
126.6, and 126.5 (5 × CH), 63.7 (CH), 63.3 (CH), 62.7 (CH),
55.6 (CH2), 54.8 (CH2), 54.3 (CH2), 52.3 (CH2), 52.2 (CH), 29.2
(CH2), 28.6 (CH2), 26.1 (CH2), 25.9 (CH2), 25.8 (CH2); IR (neat)
3450, 3313; MS, m/z 484 (M+ + 1, 22), 377 (80), 287 (100), 236
(38), 146 (60). Anal. Calcd for C32H41N3O: C, 79.46; H, 8.54;
N, 8.69. Found: C, 79.28; H, 8.37; N, 8.50.
(hexane/ethyl acetate 3/1); [R]22 -37.1 (c 0.92, CHCl3); 1H
D
NMR (CDCl3, 200 MHz) δ 7.50-7.21 (15 H, m), 3.73 (2 × 2 H,
d, J ) 13.8 Hz), 3.51 (2 H, s), 3.10-3.05 (1 H, m), 2.63 (1 H,
dd, J ) 5.1, 4.1 Hz), 2.49 (1 H, dd, J ) 5.1, 2.8 Hz), 2.26 (1 H,
dd, J ) 8.5, 4.6 Hz), 1.93-1.84 (1 H, m), 1.62 (1 H, d, J ) 3.3
Hz), 1.40 (1 H, d, J ) 6.4 Hz); 13C NMR (CDCl3, 75 MHz) δ
140.2 (C), 138.8 (C), 138.6 (C), 128.9, 128.6, 128.3, 128.0, 127.3,
and 126.6 (6 × CH), 64.9 (CH2), 61.5 (CH), 54.7 (CH2), 53.6
(CH), 44.6 (CH2), 36.0 (CH), 31.3 (CH2); IR (neat) 3028. Anal.
Calcd for C26H28N2O: C, 81.21; H, 7.34; N, 7.29. Found: C,
81.00; H, 7.41; N, 7.17.
(3S,4R,5S,1′S)-5-Ben zyla m in o-4-d ib en zyla m in o-3-h y-
d r oxy-1-(1′-p h en ylet h yl)p ip er id in e (8e): Rf 0.70 (ethyl
1
acetate/methanol 1/1); [R]20 +50.3 (c 0.16, CH2Cl2); H NMR
D
Gen er a l P r oced u r e for th e Rea ction of (2S,1′R,2′R)-1-
Be n zyl-2-[1′-(d ib e n zyla m in o)-2′,3′-e p oxyp r op yl]a zir i-
d in e (1) w ith Am in es. To a room temperature stirred
solution of 1 (0.38 g, 1.0 mmol) in dry acetonitrile (20 mL) was
successively added LiClO4 (0.11 g, 1.0 mmol) and the corre-
sponding amine (1.2 mmol). Stirring was continued at room
(CDCl3, 200 MHz) δ 7.40-7.05 (20 H, m), 4.23 (1 H, br s), 3.82
(2 × 2 H, AB system, J ) 14.2 Hz), 3.64 (2 H, AB system, J )
13.2 Hz), 3.18-2.98 (3 H, m), 2.97-2.86 (1 H, m), 2.34 (1 H,
dd, J ) 10.6, 1.6 Hz), 1.99 (1 H, d, J ) 11.4 Hz), 1.66 (1 H, t,
J ) 9.9 Hz), 1.32 (3 H, d, J ) 6.8 Hz); 13C NMR (CDCl3, 50
MHz) 142.1 (C), 139.8 (C), 128.4, 128.1, 128.0, 127.9, 127.2,
J . Org. Chem, Vol. 69, No. 19, 2004 6247

Concello´n et al.
126.9, 126.6, and 126.5 (8 × CH), 63.9 (CH), 62.8 (CH), 62.4
(CH), 56.2 (CH2), 55.3 (CH2), 54.2 (CH2), 52.1 (CH2), 51.6 (CH),
17.8 (CH3); IR (neat) 3481, 3313; MS, m/z 506 (M+ + 1, 30),
399 (45), 309 (100), 236 (25), 146 (38). Anal. Calcd for
63.3 (CH), 57.7 (CH2), 54.9 (CH2), 46.9 (CH2), 37.5 (CH), 32.5
(CH2), 11.9 (CH3); IR (neat) 3316, 2968; MS, m/z 458.0 (M+
+
1, 40), 385 (100), 329 (65), 210 (88).
C
34H39N3O: C, 80.75; H, 7.77; N, 8.31. Found: C, 81.62; H,
Ack n ow led gm en t. This research was supported by
the Ministerio de Ciencia y Tecnolog´ıa (BQU2001-3807).
J .M.C. thanks Carmen Ferna´ndez-Flo´rez for her time,
and E.R. thanks the Ministerio de Ciencia y Tecnolog´ıa
for a predoctoral fellowship.
7.51; N, 8.40.
(2S,1′R,2′S)-1-Ben zyl-2-[(1′-d ib en zyla m in o-3′-d iet h yl-
a m in o-2′-h yd r oxy)p r op yl]a zir id in e (9f): Rf 0.35 (dichlo-
romethane/methanol 9/1); [R]20 -33.9 (c 0.12, CH2Cl2); 1H
D
NMR (CDCl3, 200 MHz) δ 7.50-7.15 (15 H, m), 3.78-3.71 (1
H, m), 3.66 (2 × 2 H, AB system, J ) 13.8 Hz), 3.55 (2 H, AB
system, J ) 13.2 Hz), 2.70 (1 H, dd, J ) 13.2, 4.0 Hz), 2.59-
2.35 (4 H, m), 2.15 (1 H, t, J ) 7.8 Hz), 1.97 (1 H, dd, J )
13.2, 10.2 Hz), 2.01-1.91 (1 H, m), 1.76 (1 H, d, J ) 3.4 Hz),
1.48 (1 H, d, J ) 6.4 Hz), 0.93 (6 H, t, J ) 7.4 Hz); 13C NMR
(CDCl3, 50 MHz) 140.0 (C), 138.9 (C), 128.8, 128.6, 128.3,
128.1, 127.7, 127.0, and 126.4 (7 × CH), 67.3 (CH), 64.9 (CH2),
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and spectroscopic data for diacetylated compound of 8a ,
13C NMR spectra of 4-7, 1, 8a -e, and diacetylated 8a , and
1
NOESY H NMR spectra of 8a ,c. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O0490806
6248 J . Org. Chem., Vol. 69, No. 19, 2004