An enantioselective entry to substituted 6-membered nitrogen heterocycles from chiral pyridinium salts via selective epoxidation of tetrahydropyridine intermediates

Article abstract of DOI:10.1055/s-2000-8712

Epoxidation reactions of chiral 2- and 2,6-substituted 1,2,5,6-tetrahydropyridines 6, 11, 12 and 21 proceed with good to high stereoselectivity and excellent yields using pertrifluoroacetic acid as reagent. Epoxides such as 15, 16 and 19 are unstable but they can be deprotonated by LDA to give allylic alcohols such as 28, 30 or 32. These alcohols turned out to be potentially useful synthons, whose further oxidation or conversion to enones (29, 31) allows, in principle, introduction of a number of substituents on the piperidine ring. In particular, this is exemplified by a five-steps synthesis, from chiral tetrahydropyridine 6, of tetrasubstituted piperidine 7 in 26% overall yield.

Full text of DOI:10.1055/s-2000-8712

SPECIAL TOPIC
2117
An Enantioselective Entry to Substituted 6-Membered Nitrogen Heterocycles
from Chiral Pyridinium Salts via Selective Epoxidation of Tetrahydropyridine
Intermediates
Laurent Gil,a Delphine Compère,b Bérangère Guilloteau-Bertin,b Angèle Chiaroni, b Christian Marazano*b
aDepartamento de quimica, ICEB, Universidad Federal de Ouro Preto, Campus Morro de Cruzeiro, 35400.00, Ouro-Preto, MG, Brazil
bInstitut de Chimie des Substances Naturelles, C.N.R.S., Avenue de la Terrasse, 91198 Gif-Sur-Yvette CEDEX, France
Fax +33169077247; E-mail: marazano@icsn.cnrs-gif.fr
Received 3 August 2000
potentially used for introduction of further functionalities,
Abstract: Epoxidation reactions of chiral 2- and 2,6-substituted
thus allowing an enantioselective access to a number of
1,2,5,6-tetrahydropyridines 6, 11, 12 and 21 proceed with good to
highly substituted piperidines.
high stereoselectivity and excellent yields using pertrifluoroacetic
acid as reagent. Epoxides such as 15, 16 and 19 are unstable but they
can be deprotonated by LDA to give allylic alcohols such as 28, 30
or 32. These alcohols turned out to be potentially useful synthons,
these tetrahydropyridines 2 to give epoxides 3 with good
whose further oxidation or conversion to enones (29, 31) allows, in
principle, introduction of a number of substituents on the piperidine
In this paper, we now report such an extension of our strat-
egy, which consists of controlled oxidation reactions of
to high diastereoselectivity. These epoxides are rather un-
stable but can be easily converted to useful synthons such
as allylic alcohols 4 or enones 5 with complete regioselec-
tivity.
ring. In particular, this is exemplified by a five-steps synthesis, from
chiral tetrahydropyridine 6, of tetrasubstituted piperidine 7 in 26%
overall yield.
Key words: alkaloids, chiral auxiliaries, enones, epoxidations, pro-
tonations
As an example of the application, we also present a short
enantioselective synthesis, starting from tetrahydropyri-
dine 6 (Scheme 2), of the highly substituted piperidine 7,
a derivative, which can be considered as an azasugar
equivalent of L-idose.4
The control of the enantioselective synthesis of substitut-
ed six-membered nitrogen heterocycles has been the sub-
ject of much attention due to the importance of this motif
in the field of alkaloid synthesis and medicinal chemis-
try.1 We have recently introduced2 a new general ap-
proach to these intermediates, which starts from chiral
pyridinium salts 1 (Scheme 1), readily obtained using the
Zincke procedure. This methodology proceeds via highly
reactive dihydropyridine species.
OH
OAc
HO
HO
OH
AcO
OAc
Me
5 steps,
N
Me
26% yield
Me
Ph
O
CH2OH
N
H
H
6
7
L-idose
Scheme 2
O
oxidation
NH2
R1
R2
+
R4
N
R3
For epoxidation studies, we first prepared, from salts 8
and 9 (Scheme 3), a set of chiral tetrahydropyridines (6,
10, 11a and 12) according to our reported procedure.3a
R4
N
R3
N
H
X -
H
R1
R2
R1
R2
R1
R2
H
H
2
1
3
After preliminary experiments, pertrifluoroacetic acid
was selected as the most convenient epoxidizing agent.5
Using this procedure, it is necessary to work both on tet-
rahydropyridine salts as starting materials and to treat the
crude reaction mixture with sodium sulfite in order to
avoid formation of undesirable N-oxides. We first studied
reactions of tetrahydropyridines 6 and 10 under these con-
ditions. Interestingly, the temporary nitrogen protection
of these derivatives by prior addition of an acid resulted in
the formation of two diastereoisomeric ammonium salts
(13a, b for 6 and 14a, b for 10, Scheme 4). The diastere-
oisomeric ratio of these salts was easily evaluated by 1H
NMR spectroscopy in CDCl3. Thus tetrahydropyridine 6
gave salts 13a and 13b in a 80:20 ratio while tetrahydro-
pyridine 10 gave salts 14a and 14b with no selectivity
O
OH
R3
B—
oxidation
R4
N
R3
R4
N
R1
R2
R1
R2
H
H
4
5
Scheme 1
Reactions of salts 1 with Grignard reagents offer in partic-
ular a very short entry to 2-alkyl or 2,6-dialkyl substituted
tetrahydropyridines 2.3 The presence of a double bond in
these heterocycles is of particular interest since it can be
Synthesis 2000, No. 14, 2117–2126 ISSN 0039-7881 © Thieme Stuttgart · New York

2118
L. Gil et al.
SPECIAL TOPIC
We next studied, as a second model, epoxidation of tet-
rahydropyridine 11a possessing a phenylethanol side
chain and its corresponding acetate derivative 11b or me-
thyl ether 11c (Scheme 5). The results are summarized in
the table in Scheme 5. Yields of unstable diastereoisomer-
ic epoxide mixtures are again practically quantitative. Al-
beit less evident than for the epoxidation of
tetrahydropyridines 6 and 10, the diastereomeric excess
observed for protonated species 17a-c and 18 a-c (60-
70%) roughly corresponded to that of the formed epoxides
19a-c and 20a-c (40-60%). The stereochemistry of the
major isomers 19 was again deduced from X-ray analysis
of a derivative of 19c (vide infra).
+
+
Cl -
N
N
-
n-C12H25OSO3
9
H
8
Me
Ph
H
Ph
OH
1- MeMgCl
2- NaBH4
1- MeMgCl
2- NaBH4
1- MeMgCl
NaBH4
2- (Me)3SiCH2MgCl
Si
N
Me
N
N
H
Me
N
Me
H
Me
H
Me
Ph
H
Ph
Ph
Ph
OH
11a
OH
6
10
12
O
O
Scheme 3
i
ii-iv
Me
+
11a-c
+
+
N
+
N
Me
TfO—
H
TfO—
H
N
Me
N
Me
H
H
(50:50 ratio). Epoxidation of the mixture of salts 13 and
14 gave couples of epoxides 15a/15b and 16a/16b in
83:17 and 52:48 ratios, respectively, as measured by GC
and GC-MS analysis. Thus, in both cases, the diastereoi-
someric ratio of obtained epoxides was found to be prac-
tically identical to the diastereoisomeric ratio of
ammonium salts.
H
H
Ph
Ph
Ph
Ph
OR
OR
OR
OR
20a-c
17a-c
18a-c
19a-c
R
H
salts (% ratio); de
epoxides (%ratio); de
19a (71), 20a (29); 42%
19b (70), 20b (30); 40%
19c (80), 20c (20); 60%
17a (84), 18a (16); 68%
17b (80), 18b (20); 60%
17c (85), 18c (15); 70%
COCH3
CH3
O
O
i
ii-iv
Me
6
+
+
+
+
N
Me
N
TfO–
Me
N
Me
N
Me
O
TfO–
Me
H
H
H
Reagents and conditions: (i) CF3CO2H, CH2Cl2; (ii) CF3CO3H,
CH2Cl2, 0 °C, 1.5 h; (iii) Na2SO3; (iv) NaHCO3
Me
Ph
Me
Ph
H
H
H
Ph
Ph
Scheme 5
15a
15b
13a
13b
O
H
ii-iv
i
Protonation and epoxidation of tetrahydropyridines 12
and 21 (Scheme 6) afforded practically in each case only
one ammonium salt and a single epoxide 22 or 23, respec-
tively (checked by GC and GC-MS, which showed only
traces of minor epoxides). These epoxides were not isolat-
ed but reduced and acetylated to give acetates 24 (75%
yield from 12) or 25 (20% yield from 21). The lower yield
observed for the latter derivative 25 is attributed to a com-
peting oxidation of the exocyclic double bond. These re-
sults must be completed by our recent report3a on the
completely selective oxidation of tetrahydropyridine 26,
which gave, using this procedure, a three steps access to
indolizidine 27. Thus, this remarkable epoxidation selec-
tivity observed for 2,6-trans dialkyl substituted series ap-
pears as a quite general phenomenon. It is also closely
similar to the excellent selectivity also observed for the
epoxidation of a related quinolizidine.5,6
+
+
+
10
+
TfO–
Me
N
N
N
N
TfO–
Me
H
H
H
Me
Ph
16b
Me
Ph
16a
H
H
Ph
14a
Ph
14b
Reagents and conditions: (i) CF3CO2H, CH2Cl2; (ii) CF3CO3H,
CH2Cl2, 0 °C, 10 min; (iii) Na2SO3; (iv) NaHCO3; 15a/15b = 80/20;
16a/16b ª 50/50
Scheme 4
The yield of the epoxide mixture was practically quantita-
tive, but separation of each isomer turned to be very diffi-
cult due to the instability of these products, which gave
mainly isomeric diols after chromatography over silica
gel or alumina. Nevertheless, it was possible to isolate a
pure sample of epoxide 15a by chromatography over alu-
mina, albeit in low yield. The relative stereochemistry of
this last compound was deduced from X-ray analysis of a
further derivative (vide infra) and this allowed unambigu-
ous stereochemical assignments for isomeric epoxides
15a and 15b. However, the structures of isomers 16a and
16b could not be distinguished.
The relationship between the observed diastereomeric ex-
cess of ammonium salts and epoxides is likely to be inter-
preted as a directing effect of the ammonium proton,
which also activates the peracid. Such a mechanism is de-
picted in Scheme 7 for the epoxidation of salts 15. Albeit
this interpretation has to be taken with care, it is however
Synthesis 2000, No. 14, 2117–2126 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
An Enantioselective Entry to Substituted 6-Membered Nitrogen Heterocycles
2119
enone 29 in quantitative yield. The same sequence applied
to epoxides 13a, b afforded a 50:50 mixture of inseparable
alcohols 30, which, after oxidation gave a single new
chiral enone 31. Methoxy derivative 32a was obtained as
crystals (47% yield) suitable for an X-ray analysis.9 The
structure of this product is represented in Figure 1. This
result allowed us to determine the relative stereochemistry
of the major epoxides obtained in these series (see
Scheme 5). In addition, the coupling constant of H-2 and
O
OAc
Me
1- H+
Me
Si
Si
Si
N
N
N
Me
1- LiAlH4
2- Ac2O
H
H
H
2- CF3CO3H
Ph
Ph
Ph
OH
OAc
OH
12
22
24
(75% overall from 12)
O
OAc
1
H-3 (JH2-H3 deduced from H NMR spectra, see experi-
mental) is between 4.2 Hz and 5.3 Hz for major allylic al-
cohols.
1- H+
Me
2- CF3CO3H
1- LiAlH4
2- Ac2O
N
N
Me
N
Me
H
H
H
Ph
Ph
OH
21
Ph
OAc
OH
OH
25
OH
Me
O
23
LDA, THF
crude 15a-b
(20% overall from 21)
Swern
Me
+
O
N
N
N
Me
Me
ref 3a
ref 3a
Me
Ph
Me
Ph
Me
Ph
29
OH
H
H
H
O
N
Me
N
Me
O
H
N
Me
H
28a (60% de)
28b
Ph
Ph
OH
OH
OH
O
LDA, THF
26
27
Swern
crude 13a-b
N
N
Scheme 6
Me
Ph
Me
Ph
H
H
in good agreement with the recent observation of such di-
recting effects during the epoxidation of allylic alkeny-
lammonium salts.7,8 As a consequence, it is reasonable to
deduce the absolute stereochemistry of the main ammoni-
um salt, formed by treatment of the tetrahydropyridines
with acids, from the stereochemistry of the main obtained
epoxide. Such an assumption was used for stereochemical
assignments of salts 13a and 17a-c.
30 (0% de)
31
OH
Me
OH
Me
LDA, THF
+
N
N
H
crude 17b-18b
H
Ph
Ph
OMe
OMe
32a (60% de)
32b
Scheme 8
O
H
Ph
δ−
CF3
Me
O
H
O
+
δ+
N
H
H
N
+
H
Me
Ph
Me
O
δ−
O
H
δ+
Me
O
CF3
attack on salt 15a (major)
attack on salt 15b (minor)
Scheme 7
As we already noticed, all epoxides obtained from our tet-
rahydropyridines were too unstable to be isolated (ring
opening to give diols). Accordingly, we used the crude
mixture of these derivatives for further transformations. In
particular, it was found that treatment with LDA gave po-
tentially useful new allylic alcohols in good yields
(Scheme 8). Thus, under these conditions a crude mixture
of epoxides 15a, b gave derivatives 28a and 28b, respec-
tively, which were separated over alumina. Major alcohol
28a was thus obtained as a crystalline product in 52%
overall yield from tetrahydropyridine 6. Swern oxidation
of the crude mixture of alcohols 28a, b gave a single
Figure 1 X-Ray structure of derivative 32a
Synthesis 2000, No. 14, 2117–2126 ISSN 0039-7881 © Thieme Stuttgart · New York

2120
L. Gil et al.
SPECIAL TOPIC
We also briefly investigated the conditions in which in-
version of configuration of alcohol at position 3 could be
accomplished, using derivative 28a as a model (Scheme
9). In our hands, this transformation turned to be unsuc-
cessful. For example, reaction with triflic anhydride in the
presence of 2,6-di-tert-butyl pyridine10 in CH2Cl2, fol-
lowed by addition of one equivalent of sodium benzoate,
resulted in formation of benzoic ester 35 with complete
retention of configuration at C-3. Ester saponification of
35 gave back only alcohol 28a. This result is likely to be
interpreted as a double inversion process involving inter-
mediate formation of triflate 33 and aziridinium 34.11 Re-
duction of enone 29 was also unsuccessful, giving again
alcohol 28a with an excellent selectivity.
Me
OH
Me
OH
Me
N
N
Me
+
MeMgCl, THF, - 78 °C
Me
Me
Ph
62%
H
H
O
Ph
2
37
36 (major)
dr= 80 : 20
N
Me
Me
Ph
H
Me
O
Me
O
+
29
N
Me
N
Me
Me2CuLi, THF, 0 °C
Me
Ph
Me
H
H
85%
Ph
38 (major)
39
dr= 75 : 25
Scheme 10
OCOPh
OSO2CF3
i
3
ii
+
28a
N
Me
N
Me
N
Me
OAc
3
OAc
Me
Ph
4
Me
Ph
CF3SO3
34
Me
Ph
OAc
Me
OAc
H
H
H
2
-
+
crude 15a-b
N
N
Me
33
35
Me
Ph
Me
H
H
Ph
O
OH
iii
41
40
3
OAc
N
OAc
N
N
Me
N
Me
O
OH
AcO
OAc
Me
OH
AcO
OAc
Me
Ph
Me
H
H
+
Ph
N
Me
N
Me
Me
29
28a (90% de)
Me
Ph
Me
Ph
Me
Ph
Me
H
H
H
H
Ph
43
44
Reagents and conditions: (i) Triflic anhydride, 2,6-di-tert-butyl pyri-
dine, CHCl3; (ii) PhCO2Na; (iii) LiAlH4, THF or NaBH4, MeOH
28a
42
Scheme 9
OAc
OAc
AcO
OAc
Me
AcO
OAc
Me
Enones such as 29 are potentially useful synthons for in-
troduction of substituents on the ring by formation of new
carbon-carbon bonds. Albeit we did not study this aspect
in details, some preliminary results are summarized in
Scheme 10. As expected, reaction of enone 29 with meth-
ylmagnesium chloride gave two alkylated alcohols 36 and
37, while the corresponding organocopper reagent gave
two ketones 38 and 39. The regioselectivity is excellent
and the diastereomeric excess is appreciable (60% and
50%, respectively). Attribution of reaction stereochemis-
try is only tentative in this case. We assumed that the pre-
ferred attack of the organometallic reagent proceeded on
the face opposite to that of the methyl group in position 2
by analogy with the hydride reduction of ketone 29 (see
Scheme 9).
N
H
N
H
7
45
OH
OH
HO
HO
OH
HO
OH
Me
O
CH2OH
N
H
L-idose
deoxyfuconojirimycin
Scheme 11
3 and 4 (JH2-H3 = 4.8 Hz and JH3-H4 = 10.0 Hz for 40; JH2-
H3 = 8.5 Hz and JH3-H4 = 8.7 Hz for 41).
We finally turned our attention toward the synthesis of
polyhydroxylated piperidines (Scheme 11). Ring opening
of a crude mixture of epoxides 15a, b in refluxing acetic
acid, followed by acetylation, gave a mixture of two
trans-diacetates 40 and 41 in 67% yield and a 60:40 ratio.
Stereochemistry of these products was assigned on the ba-
sis of 1H NMR coupling constants observed for protons 2,
Trifluoroperacetic acid epoxidation of allylic alcohol 28a
gave a mixture of diasteoisomeric epoxides 42 in a 68:32
ratio (undetermined stereochemistry). Treatment of these
epoxides with acetic acid followed by acetylation gave
two triacetates 43 and 44 in approximately the same ratio.
These derivatives were separated by chromatography and
Synthesis 2000, No. 14, 2117–2126 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
An Enantioselective Entry to Substituted 6-Membered Nitrogen Heterocycles
2121
4.3 mmol) in CH2Cl2 (20 mL). After further stirring for 1.5 h at
0 °C, was added a mixture of salts 13a and 13b (dr = 80:20), ob-
tained from tetrahydropyridine 6 (361 mg, 1.8 mmol) and trifluoro-
acetic acid (0.34 mL, 4.5 mmol) in dry CH2Cl2 (3 mL). The ice bath
was removed and the reaction mixture was stirred for 10 min. Sat.
Na2SO3 was then added and the organic layer separated, washed
with NaHCO3 and H2O, dried (Na2SO4), and concentrated in vacuo
to provide a mixture of isomeric epoxides 15a and 15b (370 mg,
95% yield, dr = 83:17) as a colorless oil. Due to their instability
(ring opening giving diols) the mixture of epoxides was used with-
out further purification. A small sample of each isomer can be iso-
lated by chromatography over alumina albeit in low yield.
recovered in 59% and 29% yield, respectively, from 28a.
The stereochemistry of triacetate 43 was deduced from an
X-ray analysis, which is depicted in Figure 2.12
Major Isomer 15a
[a]D +40° (c 1.33, CHCl3).
1H NMR (250 MHz, CDCl3): d = 7.30 (m, 5H, ArH), 3.84 (q, 1H,
J = 6.7 Hz), 3.27 (m, 1H), 3.04 (m, 2H), 2.62 (ddd, 1H, J = 12.5,
7.7, 4.9 Hz), 2.24 (ddd, 1H, J = 12.5, 5.2, 5.2 Hz), 1.90 (m, 2H),
1.34 (d, 3H, J = 6.7 Hz), 1.20 (d, 3H, J = 6.2 Hz).
13C NMR (62.89 MHz, CDCl3): d = 143.2, 128.2, 127.6, 126.9,
57.5, 56.2, 52.3, 49.6, 37.4, 25.2, 21.6, 12.8.
MS (EI): m/z = 217 (M+, 15), 202 (75), 105 (100).
HRMS (EI): m/z calcd for C14H19NO (M+): 217.1467. Found:
217.1477.
Figure 2 X-ray structure of derivative 43
Minor Isomer 15b
1H NMR (250 MHz, CDCl3): d = 7.27 (m, 5H), 4.04 (q, 1H, J = 7.0
Hz), 3.21 (m, 1H), 2.97 (q, 1H, J = 6.8 Hz), 2.88 (d, 1H, J = 4.2 Hz),
2.62 (m, 1H), 2.21 (m, 1H), 1.80-2.08 (m, 2H), 1.40 (d, 3H, J = 7.0
Hz), 1.30 (d, 3H, J = 6.8 Hz).
13C NMR (62.89 MHz, CDCl3): d = 141.0, 128.0, 127.5, 126.9,
57.8, 56.7, 51.1, 50.2, 37.1, 25.7, 20.0, 17.2.
This X-ray analysis allowed us to secure stereochemical
assignments for epoxide 15a (see Scheme 4). It also al-
lowed us to attribute the structure 44 to the minor triace-
tate, since the ring opening of the epoxides 42 normally
proceeds in a trans manner. Finally, catalytic hydrogena-
tion of 43 and 44 afforded piperidine 7, which can be con-
sidered as an azasugar equivalent of L-idose, and
piperidine 45, respectively, an acetate protected deriva-
tive of the glucosidase inhibitor deoxyfuconojirimycin.
MS (EI): m/z = 217 (M+, 15), 202 (90), 105 (100).
(1R,2S,2R,6S)-2-(2-Methyl-7-oxa-3-azabicyclo[4.1.0]hept-3-yl)-
2-phenylethanol (19a)
Trifluoroacetic anhydride (2.17 mL, 15 mmol) was added dropwise
to a solution of 50% hydrogen peroxide (0.44 mL, 7.5 mmol) in
CH2Cl2 (25 mL) at 0 °C. After stirring at 0 °C for 1.5 h, a solution
of tetrahydropyridine 11a (332 mg, 1.53 mmol) and trifluoroacetic
acid (0.29 mL, 3.82 mmol) in dry CH2Cl2 (3 mL) was added drop-
wise. The ice bath was removed and the mixture was stirred for
0.5 h. The reaction mixture was then extracted as for epoxides 15a,
b to give isomeric epoxides 19a and 20a (340 mg, 95% yield,
dr = 71:29) as a colorless oil.
We hope that the reported results will be useful in under-
standing the stereochemical aspects concerning the epoxi-
dation of N-alkyl substituted tetrahydropyridines. These
new results also extend the synthetic possibilities offered
by our methodological approach, starting from new chiral
pyridinium salts. If the observed selectivities are not al-
ways perfect, this is compensated by very short syntheses
of rather complex products, starting from easily available
intermediates and using simple procedures.
MS (CI): m/z = 234 [M+H]+ (100), 216 [MH-H2O]+ (18).
HRMS (CI): m/z calcd for C14H20NO2 (MH+): 234.1494. Found:
234.1491.
NMR data for each epoxide can be deduced from the NMR spectra
of the crude mixture.
Experiments involving organometallics were carried out in dried
glassware under a positive pressure of dry N2. THF and Et2O were
distilled from sodium benzophenone ketyl. Methyl magnesium
chloride, vinyl magnesium chloride and methyllithium were pur-
chased from Aldrich. Column chromatography: silica gel 60,
0.070-0.200 (SDS) or aluminiumoxide 90, 0.063-0.200 (Merck).
NMR spectra were recorded on a Bruker AC-200, AC-AC-250 or
AC-300. Mass spectra were recorded on a AEI MS-50 (EI) or AEI
MS-9 (CI) spectrometer. Optical rotations were measured on a Per-
kin-Elmer 14 at 20 °C.
Major Epoxide 19a
1H NMR (250 MHz, CDCl3): d = 7.22-7.38 (m, 5H), 3.71-3.83 (m,
3H), 3.43 (m, 1H), 3.27 (m, 1H), 3.13 (t, 1H, J = 4.5 Hz), 2.68 (ddd,
1H, J = 13.5, 11.5, 3.9 Hz), 2.48 (m, 1H), 1.93 (tdd, 1H, J = 14.7,
5.3, 2 Hz), 1.79 (m, 1H), 1.14 (d, 3H, J = 6.7 Hz).
13C NMR (62.89 MHz, CDCl3): d = 141.0, 128.6, 128.3, 127.6,
66.1, 63.3, 54.9, 52.0, 48.0, 36.9, 23.8, 12.6.
(1R,1R,2S,6S)-(+)-2-Methyl-3-(1-phenylethyl)-7-oxa-3-azabicy-
clo[4.1.0]heptane (15a)
Trifluoroacetic anhydride (1.2 mL, 8.6 mmol) was added dropwise,
at 0 °C, to a stirred solution of 50% hydrogen peroxide (0.25 mL,
Minor Epoxide 20a
1H NMR (250 MHz, CDCl3): d = 7.22-7.38 (m, 5H), 3.96 (dd, 1H,
J = 6.9, 5.4 Hz), 3.78 (m, 2H), 3.43 (m, 1H), 3.30 (m, 1H), 2.93 (br
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L. Gil et al.
SPECIAL TOPIC
d, 1H, J = 4.1 Hz), 2.60 (m, 2H), 1.98 (m, 1H), 1.78 (m, 1H), 1.18
(d, 3H, J = 6.8 Hz).
(ddd, 1H, J = 13.4, 10.9, 3.7 Hz), 2.43 (m, 1H), 1.98 (m, 1H), 1.70
(m, 1H), 1.15 (d, 3H, J = 6.7 Hz).
13C NMR (62.89 MHz, CDCl3): d = 140.5, 128.3, 128.2, 127.3,
66.2, 62.4, 55.9, 51.0, 50.8 (2C), 36.6, 23.8, 15.0 (2C).
13C NMR (75.47 MHz, CDCl3): d = 142.3, 128.3, 128.1, 127.2,
75.3, 63.6, 59.1, 54.9, 52.2, 49.3, 37.2, 23.2, 12.9.
(1R,1R,2S,6S)-3-(2-Acetoxy-1-phenylethyl)-2-methyl-7-oxa-3-
azabicyclo[4.1.0]heptane (19b)
Use of the above epoxidation procedure (preparation of epoxides
19a, 20a) starting from tetrahydropyridine 11b gave a mixture of
isomeric epoxides 19b and 20b (80 mg, 95% yield, dr = 71:29) as a
colorless oil:
Minor Isomer 20c
1H NMR (300 MHz, CDCl3): d = 7.20-7.40 (m, 5H), 4.09 (dd, 1H,
J = 6.3, 5.2 Hz), 3.75 (dd, 1H, J = 9.8, 5.2 Hz), 3.68 (dd, 1H,
J = 9.8, 6.3 Hz), 3.45 (q, 1H, J = 7.0 Hz), 3.34 (s, 3H), 3.31 (m, 1H),
2.94 (d, 1H, J = 4.2 Hz), 2.53 (ddd, 1H, J = 12.2, 8.7, 4 Hz), 2.36
(dt, 1H, J = 12.2, 5.2 Hz), 1.92 (m, 1H), 1.72 (m, 1H), 1.28 (d, 3H,
J = 7 Hz).
MS (EI): m/z = 202 (M+-C3H5O2, 100).
13C NMR (75.47 MHz, CDCl3): d = 141.7, 128.1, 127.9, 126.8,
72.5, 61.3, 58.9, 56.6, 51.2, 50.3 (2C), 37.2, 25.2, 17.9 (2C).
MS (CI): m/z = 276 [M+H]+ (100), 260 [MH-CH4]+ (10), 216
[MH-C2H4O2]+ (30), 94 (60).
HRMS (CI): Calcd for C16H22NO3 (MH+): 276.1600. Found:
276.1603.
(1R,2R,5S,6S)-5-Acetoxy-6-methyl-2-trimethylsilanylmethyl-1-
(1-phenyl-2-ethanolacetate)-piperidine (24)
Trifluoroacetic anhydride (0.48 mL, 3.4 mmol) was added dropwise
to a solution of 50% hydrogen peroxide (0.1 mL, 1.7 mmol) in
CH2Cl2 (6 mL) at 0 °C. After stirring at 0 °C for 1.5 h, a solution of
tetrahydropyridine 12 (102 mg, 0.34 mmol), trifluoroacetic acid
(0.06 mL, 0.84 mmol), in CH2Cl2 (3 mL) was added dropwise. The
ice bath was removed and the mixture was stirred for 1.8 h. The re-
action was then extracted as for epoxides 15a, b to give practically
pure epoxide 22 in nearly quantitative yield. This unstable crude ep-
oxide was dissolved in THF, an excess of LiAlH4 was added, and
the resulting mixture refluxed for 3 h. After cooling, an excess of
EtOAc was carefully added, followed by MeOH. Filtration over
Celite using MeOH as eluent gave a crude alcohol, which, after re-
moval of solvent under reduced pressure, was treated overnight
with Ac2O (0.5 mL) and pyridine (1 mL). After evaporation, the res-
idue was chromatographed over alumina using a mixture of EtOAc/
heptane. Piperidine 24 (103 mg, 0.25 mmol, 75% yield) was isolat-
ed as a colorless oil:
1H NMR (300 MHz, CDCl3): d = 7.20-7.35 (m, 5H), 4.55 (t, 1H,
J = 7.2 Hz), 4.40 (m, 3H), 3.15 (m, 2H), 1.96 (s, 3H), 1.90 (s, 3H),
1.45-1.70 (m, 3H), 1.15 (m, 1H), 1.02 (d, 3H, J = 6.7 Hz), 0.90 (dd,
1H, J = 13.8, 3.4 Hz), 0.80 (dd, 1H, J = 13.8, 11.3 Hz), 0.00 (s, 9H).
13C NMR (75.47 MHz, CDCl3): d = 171.0, 170.4, 140.9, 128.3,
128.1, 127.0, 72.4, 63.6, 56.7, 49.1, 48.5, 31.7, 25.0, 21.4, 20.8,
12.2, -0.37.
NMR data for each epoxide can be deduced from the NMR spectra
of the crude mixture.
Major Epoxide 19b
IR (neat): n = 2978, 2939, 2844, 1740, 1678, 1492, 1451, 1425,
1382, 1234, 1042 cm-1.
1H NMR (250 MHz, CDCl3): d = 7.20-7.40 (m, 5H), 4.42 (dd, 1H,
J = 11.2, 5.1 Hz), 4.20 (dd, 1H, J = 11.2, 6.4 Hz), 3.93 (dd, 1H,
J = 6.4, 5.1 Hz), 3.32 (m, 2H), 3.14 (t, 1H, J = 4.4 Hz), 2.62 (ddd,
1H, J = 14.5, 10.8, 3.8 Hz), 2.40 (m, 1H), 2.00 (m, 1H), 1.97 (s, 3H),
1.75 (m, 1H), 1.20 (d, 3H, J = 6.7 Hz).
13C NMR (62.89 MHz, CDCl3): d = 170.8, 141.0, 128.5, 128.2,
127.6, 65.7, 62.4, 54.9, 52.1, 49.4, 37.3, 23.4, 20.9, 12.6 (2C).
Minor Epoxide 20b
IR (neat): n = 2978, 2939, 2844, 1740, 1678, 1492, 1451, 1425,
1382, 1234, 1042 cm-1.
1H NMR (250 MHz, CDCl3): d = 7.20-7.40 (m, 5H), 4.51 (dd, 1H,
J = 11.5, 5.9 Hz), 4.38 (dd, 1H, J = 11.5, 6.4 Hz), 4.21 (dd, 1H,
J = 6.4, 5.9 Hz), 3.46 (q, 1H, J = 6.8 Hz), 3.27 (m, 1H), 2.95 (d, 1H,
J = 4.1 Hz), 2.55 (ddd, 1H, J = 12.3, 8.4, 4.1 Hz), 2.38 (dt, 1H,
J = 12.3, 5.3 Hz), 2.02 (m, 1H), 2.02 (s, 3H), 1.72 (m, 1H), 1.29 (d,
3H, J = 6.8 Hz).
13C NMR (62.89 MHz, CDCl3): d = 171.0, 140.6, 128.3, 127.9,
127.2, 63.6, 60.4, 56.4, 51.2, 50.5 (2C), 37.2, 25.0, 21.2, 17.6.
MS (EI): m/z = 202 (M+-C3H5O2, 100).
MS (CI): m/z = 406 [M+H]+ (58), 346 [M-OAc]+ (100).
HRMS (CI): m/z calcd for C22H36NO4Si (MH+): 406.2414. Found:
406.2389.
(1R,1R,2S,6S)-3-(2-Methoxy-1-phenylethyl)-2-methyl-7-oxa-3-
azabicyclo[4.1.0]heptane (19c)
Use of the above epoxidation procedure (preparation of epoxides
19a, 20a) starting from tetrahydropyridine 11c (231 mg, 1 mmol)
gave a mixture of isomeric epoxides 19c and 20c (240 mg, 97%
yield, dr = 80:20) as a colorless oil:
MS (EI): m/z = 202 (M+-C2H5O, 100).
MS (CI): m/z = 248 [M+H]+ (100), 216 [MH-CH3OH]+ (12).
(1R,2R,5S,6S)-5-Acetoxy-6-methyl-2-vinyl-1-(1-phenyl-2-etha-
nol-acetate)-piperidine (25)
Tetrahydropyridine 21 (170 mg, 0.7 mmol) was treated using the
same procedure as for preparation of piperidine 24, to give piperi-
dine 25 (48 mg, 0.14 mmol, 20% yield) as a colorless oil.
1H NMR (250 MHz, CDCl3): d = 7.25-7.45 (m, 5H), 5.88 (ddd, 1H,
J = 20.0, 10.0, 2.75 Hz), 5.25 (dt, 1H, J = 20.0, 2.0 Hz), 5.12 (dd,
1H, J = 10.0 Hz, 2.0 Hz), 4.45-4.55 (m, 4H), 3.55 (dt, 1H, J = 8.75,
2.75 Hz), 3.10 (dq, 1H, J = 6.5, 4.5 Hz), 2.00 (s, 3H), 1.98 (s, 3H),
1.60-1.75 (m, 4H), 1.08 (d, 3H, J = 6.7 Hz).
HRMS (CI): Calcd for C15H22NO2 (MH+): 248.1650. Found:
248.1638.
13C NMR (75.47 MHz, CDCl3): d = 140.6, 128.4, 127.2, 116.5,
72.9, 62.7, 59.7, 56.0, 49.2, 31.7, 24.3, 21.0 (2C), 11.2.
MS (EI): m/z = 345 (M+, 2) 272 (100).
NMR data for each epoxide can be deduced from the NMR spectra
of the crude mixture.
Major Isomer 19c
1H NMR (300 MHz, CDCl3): d = 7.20-7.40 (m, 5H), 3.84 (t, 1H,
J = 5.0 Hz), 3.62 (dd, 1H, J = 10.0, 5.0 Hz), 3.57 (dd, 1H, J = 10.0,
5.0 Hz), 3.31 (m, 2H), 3.25 (s, 3H), 3.11 (t, 1H, J = 4.4 Hz), 2.61
(1R,2S,3S)-(+)-2-Methyl-1-(1-phenylethyl)-1,2,3,6-tetrahydro-
pyridin-3-ol (28a)
To a solution of diisopropylamine (1.48 mL, 10.58 mmol) in dry
THF (5 mL) at 0 °C under Ar was added n-BuLi (1.6 M in hexane,
Synthesis 2000, No. 14, 2117–2126 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
An Enantioselective Entry to Substituted 6-Membered Nitrogen Heterocycles
2123
6.6 mL, 10.58 mmol) and the resulting mixture was stirred for
15 min at 0 °C. To the above solution was then introduced slowly a
mixture of epoxides 15a and 15b (919 mg, 4.23 mmol) in dry THF
(6 mL) and the ice bath was removed. After 1.5 h of stirring, the re-
action was quenched with sat. NH4Cl and extracted with CH2Cl2.
The organic layer was dried (Na2SO4), filtered, and concentrated in
vacuo. The residue was purified by chromatography over alumina
with heptane/EtOAc (94:6 to 86:14) to give major alcohol 28a
(472 mg, 52% yield) as a white solid and alcohol 28b (80 mg, 9%
yield) as a yellow oil.
MS (EI): m/z = 215 (M+, 10), 148 (13), 105 (100).
MS (CI): m/z = 216 (MH+).
Anal. Calcd for C14H17NO: C, 78.10; H, 7.96; N, 6.51. Found: C,
77.95; H, 7.84; N, 6.49.
(1R)-1-(1-Phenylethyl)-1,6-dihydro-2H-pyridin-3-one (31)
Obtained from a mixture epoxides 13a, b using the above proce-
dure:
[a]D 0° (c 0.90, CHCl3).
IR (neat): n = 1689 cm-1.
1H NMR (300 MHz, CDCl3): d = 7.30 (m, 5H), 7.01 (ddd, 1H,
J = 9.9, 3.8, 3.5 Hz), 6.10 (ddd, 1H, J = 9.9, 2.0, 2.0 Hz), 3.59 (q,
1H, J = 6.7 Hz), 3.25 (m, 2H), 3.17 (m, 2H), 1.42 (d, 3H, J = 6.7
Hz).
13C NMR (75.47 MHz, CDCl3): d = 196.3, 149.1, 142.0, 128.5,
127.6, 127.4, 63.8, 58.7, 49.6, 19.1.
MS (EI): m/z = 201 (M+, 52), 186 (50), 134 (18), 105 (100), 68 (44).
HRMS (EI): m/z calcd for C13H15NO (M+): 201.1153. Found:
Major Isomer 28a
White crystals of 28a were obtained from dry Et2O/heptane: mp 102
°C; [a]D +94° (c 1.06, CHCl3).
IR (CDCl3): n = 3606, 2983, 2938, 2790, 1457, 1375 cm-1.
1H NMR (250 MHz, CDCl3): d = 7.20-7.40 (m, 5H), 5.79 (dddd,
1H, J = 10, 4.1, 2.1, 2.1 Hz), 5.60 (dm, 1H, J = 10.0 Hz), 4.31 (m,
1H), 3.75 (q, 1H, J = 6.6 Hz), 3.35 (dm, 1H, J = 17.3 Hz), 2.97 (qd,
1H, J = 6.6, 5.3 Hz), 2.94 (dm, 1H, J = 17.3 Hz), 1.86 (m), 1.35 (d,
3H; J = 6.6 Hz), 0.84 (d, 3H, J = 6.6 Hz).
13C NMR (62.89 MHz, CDCl3): d = 145.3, 128.6, 128.0, 127.3,
127.1 (3C), 68.6, 60.4, 52.7, 44.7, 21.9, 4.4.
201.1161.
MS (EI): m/z = 217 (M+, 8), 148 (30), 105 (100), 44 (90).
(1R,2S,3S)-(+)-1-(2-Methoxy-1-phenylethyl)-2-methyl-1,2,3,6-
tetrahydropyridin-3-ol (32a)
Anal. Calcd for C14H19NO: C, 77.37; H, 8.81; N, 6.45. Found: C,
77.34; H, 8.66; N, 6.49.
The mixture of epoxides 17b and 18b (189 mg, 0.76 mmol) was
subjected to the same procedure as for the synthesis of allylic alco-
hol 28a and 28b. The residue was purified by chromatography over
alumina with heptane/EtOAc (94:6 to 86:14) to give major alcohol
32a (89 mg, 47% yield) as a white solid, and minor alcohol 32b
(16 mg, 8.5% yield) as a yellow oil.
Minor Isomer 28b
[a]D -17° (c 1.39, CHCl3).
IR (neat): n = 3677, 2975, 2940, 1445, 1395, 1368 cm-1.
1H NMR (250 MHz, CDCl3): d = 7.28 (m, 5H), 5.87 (m, 2H), 3.62
(q, 1H, J = 6.6 Hz), 3.52 (m, 1H), 3.48 (dd, 1H, J = 17.0, 2.3 Hz),
2.93 (d, 1H, J = 17.0 Hz), 2.83 (dq, 1H, J = 6.7, 2 Hz), 2.54 (br d,
1H, J = 10.6 Hz), 1.36 (d, 3H, J = 6.6 Hz), 0.74 (d, 3H, J = 6.7 Hz).
13C NMR (62.89 MHz, CDCl3): d = 145.0 (C arom.), 129.1, 128.6,
127.2, 126.0, 68.8, 60.9, 54.4, 44.9, 21.9, 7.0.
MS (EI): m/z = 217 (M+, 25), 148 (42), 105 (100), 44 (22).
HRMS (EI): m/z calcd for C14H19NO (M+): 217.1467. Found:
Major Isomer 32a
White crystals of 32a were obtained from dry Et2O/heptane: mp 82
°C; [a]D +42° (c 1.95, CHCl3).
IR (CDCl3): n = 3594, 2990, 2927, 2882, 1452, 1381 cm-1.
1H NMR (300 MHz, CDCl3): d = 7.20-7.40 (m, 5H), 5.09-5.23 (m,
2H), 4.21 (m, 1H), 4.00 (dd, 1H, J = 6.0, 5.6 Hz), 3.78 (dd, 1H,
J = 9.9, 6.0 Hz), 3.67 (dd, 1H, J = 9.9, 5.6 Hz), 3.39 (qd, 1H,
J = 6.5, 4.2 Hz), 3.33 (s, 3H), 2.78-2.94 (m, 2H), 1.90 (m, 1H), 1.13
(d, 3H, J = 6.5 Hz).
217.1456.
13C NMR (75.47 MHz, CDCl3): d = 141.4, 128.4, 128.1, 128.0,
(1R,2S)-(+)-2-Methyl-1-(1-phenylethyl)-1,6-dihydro-2H-pyri-
din-3-one (29)
127.2 (3C), 73.7, 69.0, 62.7, 59.1, 54.4, 46.0, 9.4.
MS (CI): m/z = 248 [M+H]+ (100), 230 [MH-H2O]+ (60), 216
To a solution of oxalyl chloride (0.135 mL, 1.58 mmol) in dry
CH2Cl2 (2.4 mL) was added dropwise at -78 °C a solution of
DMSO (0.246 mL, 3.47 mmol) in dry CH2Cl2 (3 mL) and the mix-
ture was stirred at this temperature for 10 min. To the above solution
was added dropwise a mixture of allylic alcohols 28a and 28b
(172 mg, 0.79 mmol) in dry CH2Cl2 (1.5 mL) and the mixture was
stirred at -78 °C for 15 min. Et3N (0.75 mL, 10.4 mmol) was then
added and the solution allowed to warm to r.t. Distilled H2O (8 mL)
was added and the reaction stirred for 10 min. CH2Cl2 was added
and the organic layer washed with H2O, dried (Na2SO4), and con-
centrated in vacuo to give pure ketone 29 (166.6 mg, 98% yield).
White crystals of 29 were obtained from dry pentane: mp 61 °C;
[a]D +138° (c 1.37, CHCl3).
[MH-CH3OH]+ (15).
Anal. Calcd for C15H21NO2: C, 72.84; H, 8.56; N, 5.66. Found: C,
72.75; H, 8.62; N, 5.66.
Minor Isomer 32b
Mp 74 °C; [a]D -63° (c 0.88, CHCl3).
IR (neat): n = 3675, 2991, 2932, 2876, 1450, 1401, 1372 cm-1.
1H NMR (300 MHz, CDCl3): d = 7.20-7.36 (m, 5H), 5.85 (m, 1H),
5.68 (ddd, 1H, J = 9.8, 4.1, 2.2 Hz), 3.73 (m, 3H), 3.52 (dd, 1H,
J = 12.9, 6.9 Hz), 3.47 (qd, 1H, J = 6.6, 2.3 Hz), 3.29 (s, 3H), 2.83
(ddd, 1H, J = 18, 4.1, 2.1 Hz), 2.73 (m, 1H), 0.95 (d, 3H, J = 6.6
Hz).
13C NMR (75.47 MHz, CDCl3): d = 141.6, 129.2, 128.6, 128.0,
127.6, 125.8 (3C), 76.0, 68.8, 65.9, 59.0, 55.6, 46.0, 8.4.
IR (CDCl3): n = 1669 cm-1.
1H NMR (300 MHz, CDCl3): d = 7.30 (m, 5H), 6.98 (ddd, 1H,
J = 10.0, 4.9, 2 Hz), 6.04 (ddd, 1H, J = 10.0, 2.1, 2.1 Hz), 3.82 (q,
1H, J = 6.6 Hz), 3.65 (ddd, 1H, J = 19.9, 4.9, 1.6 Hz), 3.41 (ddd,
1H, J = 19.9, 2.4, 2.4 Hz), 3.38 (q, 1H, J = 7.0 Hz), 1.39 (d, 3H,
J = 6.6 Hz), 1.06 (d, 3H, J = 7.0 Hz).
13C NMR (75.47 MHz, CDCl3): d = 199.7, 147.7, 143.9, 128.7,
127.4, 127.2, 126.3, 60.0, 59.7, 44.4, 21.7, 9.2.
MS (CI): m/z = 248 [M+H]+ (100), 230 [MH-H2O]+ (7), 216 [MH-
CH3OH]+ (10).
HRMS (CI): m/z calcd for C15H22NO2 (MH+): 248.1651. Found:
248.1660.
Synthesis 2000, No. 14, 2117–2126 ISSN 0039-7881 © Thieme Stuttgart · New York

2124
L. Gil et al.
SPECIAL TOPIC
(1R,2S,3S)-(+)-2,3-Dimethyl-1-(1-phenylethyl)-1,2,3,6-tetrahy-
dropyridin-3-ol (36)
1H NMR (400 MHz, CDCl3): d = 7.27 (m, 5H), 5.00 (m, 1H), 4.96
(dd, 1H, J = 10.0, 4.8 Hz), 3.73 (q, 1H, J = 6.5 Hz), 3.21 (dq, 1H,
J = 6.9, 4.8 Hz), 2.88 (ddd, 1H, J = 12.5, 5.3, 2.7 Hz), 2.60 (ddd,
1H, J = 12.5, 12.5, 2.9 Hz), 2.03 (m, 1H), 2.02 (s, 3H), 1.95 (s, 3H),
1.71 (dddd, 1H, J = 12.5, 12.5, 10.5, 5.2 Hz), 1.32 (d, 3H, J = 6.5
Hz), 0.93 (d, 3H, J = 6.9 Hz).
13C NMR (75.47 MHz, CDCl3): d = 170.1, 170.8, 145.3, 128.5,
127.0, 126.9, 73.3, 69.8, 59.6, 52.5, 39.5, 29.8, 22.6, 21.2, 21.1, 5.9.
MS (CI): m/z = 320 (MH+).
MS (EI): m/z = 319 (M+, 22), 304 (100), 260 (59), 105 (100).
Ketone 29 (151 mg, 0.70 mmol) was dissolved in dry THF (4 mL)
and the solution was cooled to -78 °C under Ar. To the above solu-
tion was then introduced dropwise a 2 M commercial solution of
methylmagnesium chloride (1.2 mL, 2.1 mmol). The reaction was
stirred for 20 min at -78 °C, warmed to r.t. and stirred at this tem-
perature for 1.5 h. The reaction was quenched with sat. NH4Cl and
extracted with CH2Cl2. The organic layer was dried (Na2SO4), fil-
tered, and concentrated in vacuo to give a mixture of allylic alcohols
36 and 37 in a 79:21 ratio. The residue was purified by chromatog-
raphy over alumina with heptane/EtOAc (100:0 to 90:10) to furnish
major alcohol 36 (73 mg, 45% yield) and minor alcohol 37 (14 mg,
8.5% yield) as yellow oils.
HRMS (EI): m/z calcd for C18H25NO4 (M+): 319.1784. Found:
319.1789.
Minor Isomer 41 (colourless oil)
[a]D +93° (c 0.81, CHCl3).
Major Isomer 36
[a]D +53° (c 0.48, CHCl3).
IR (neat) n = 3606, 2976, 2936, 1454, 1373 cm-1.
1H NMR (300 MHz, CDCl3): d = 7.28 (m, 5H), 5.67 (ddd, 1H,
J = 10.0, 4.0, 2.2 Hz), 5.51 (dm, 1H, J = 10.0 Hz), 3.69 (q, 1H,
J = 6.6 Hz), 3.34 (ddd, 1H, J = 17.2, 4.0, 2.0 Hz), 2.89 (ddd, 1H,
J = 17.2, 2.3, 2.3 Hz), 2.63 (qd, 1H, J = 6.5, 0.9 Hz), 1,50 (br m,
1H), 1.33 (d, 3H, J = 6.6 Hz), 1.31 (s, 3H), 0.84 (d, 3H, J = 6.5 Hz).
13C NMR (75.47 MHz, CDCl3): d = 143.9, 131.8, 128.4, 127.6,
127.0, 125.3, 71.9, 60.6, 57.8, 44.8, 28.3, 22.0, 4.9.
IR (neat): n = 2982, 2838, 2811, 1744, 1495, 1452, 1368, 1251,
1232, 1049 cm-1.
1H NMR (300 MHz, CDCl3): d = 7.28 (m, 5H), 4.74 (dd, 1H,
J = 8.7, 8.5 Hz), 4.58 (ddd, 1H, J = 10.7, 8.7, 4.8 Hz), 4.24 (q, 1H,
J = 7.0 Hz), 3.00 (ddd, 1H, J = 11.7, 3.9, 3.9 Hz), 2.35 (dq, 1H,
J = 8.5, 6.1 Hz), 2.02 (s, 3H), 2.01 (m, 1H), 2.00 (m, 1H), 1.99 (s,
3H), 1.63 (m, 1H), 1.45 (d, 3H, J = 7.0 Hz), 1.20 (d, 3H, J = 6.10
Hz).
13C NMR (75.47 MHz, CDCl3): d = 170.5, 170.3, 139.8, 128.0,
128.0, 127.1, 75.9, 73.0, 56.7, 55.9, 42.5, 29.3, 21.1, 21.0, 19.4,
15.6.
MS (EI): m/z = 231 (M+, 19), 148 (100), 105 (100), 84 (80).
HRMS (EI): m/z calcd for C15H21NO (M+): 231.1623. Found:
MS (CI): m/z = 320 (MH+).
231.1621.
MS (EI): m/z = 319 (M+, 15), 304 (67), 260 (24), 105 (100).
HRMS: (EI): m/z calcd for C18H25NO4 (M+): 319.1784. Found:
Minor Isomer 37
[a]D +9° (c 2.97, CHCl3).
IR (neat) n = 3675, 2982, 2939, 1645, 1454, 1376 cm-1.
319.1774.
1H NMR (250 MHz, CDCl3): d = 7.28 (m, 5H), 5.73 (ddd, 1H,
J = 9.7, 4.2, 1.8 Hz), 5.63 (dm, 1H, J = 9.7 Hz), 3.62 (q, 1H, J = 6.5
Hz), 3.48 (ddd, 1H, J = 17.5, 4.2, 1.9 Hz), 3.41 (br m, 1H), 2.87
(dm, 1H, J = 17.5 Hz), 2.57 (q, 1H, J = 6.7 Hz), 1.37 (d, 3H, J = 6.5
Hz), 1.01 (s, 3H), 0.75 (d, 3H, J = 6.7 Hz).
13C NMR (62.89 MHz, CDCl3): d = 144.8, 131.4, 128.7, 127.3,
126.7, 69.9, 60.9, 58.7, 44.8, 23.2, 22.1, 5.5.
Mixture of Epoxides 42
Trifluoroacetic anhydride (1 mL, 7 mmol) was added dropwise to a
solution of 50% hydrogen peroxide (0.12 mL, 2.09 mmol) in
CH2Cl2 (20 mL) at 0 °C. After 1.5 h at 0 °C under stirring was added
a solution of allylic alcohol 28a (90.4 mg, 0.416 mmol) and trifluo-
roacetic acid (0.1 mL, 1.25 mmol) in CH2Cl2 (2 mL). The ice bath
was removed and the reaction mixture was stirred for 0.5 h. Treat-
ment under the conditions used for preparation of epoxides 15a and
15b gave a mixture of diastereoisomeric epoxides 42 (94.5 mg, 97%
yield, 68:32 ratio) as a colorless oil.
MS (EI): m/z = 232 (MH+, 45), 231 (M+, 40), 148 (65), 105 (100).
HRMS (EI): m/z calcd for C15H21NO (M+): 231.1623. Found:
231.1620.
MS (EI): m/z = 233 (M+, 25), 232 (26), 218 (39), 105 (100).
HRMS (EI): Calcd for C14H19NO2 (M+): 233.1415. Found:
233.1398.
(1R,2S,3R,4R)-(-)-3,4-Diacetoxy-2-methyl-1-(1-phenylethyl)-
piperidine (40)
The mixture of epoxides 15a and 15b (236 mg, 1.08 mmol) was dis-
solved in HOAc (4 mL) and this solution was refluxed for 0.5 h. Af-
ter removal of solvent under reduced pressure, the residue was
dissolved in anhyd pyridine (5 mL) and Ac2O (1 mL, 10.8 mmol).
After stirring overnight at r.t., the reaction mixture was diluted with
Et2O and washed four times with H2O. The organic phase was dried
(Na2SO4) and concentrated in vacuo to give a mixture of diacetates
40 and 41 in a 60:40 ratio (GC analysis). The residue was purified
by chromatography over alumina using heptane/EtOAc (100:0 to
92:8) to furnish diacetate 40 (133 mg, 40% yield) and diacetate 41
(89 mg, 26% yield).
The two epoxides can be distinguished by NMR.
Major Isomer
1H NMR (250 MHz, CDCl3): d = 7.20-7.40 (m, 5H), 3.91 (q, 1H,
J = 6.9 Hz), 3.82 (m, 1H), 3.30 (dd, 1H, J = 3.9, 3.3 Hz), 3.17 (br d,
1H, J = 3.9 Hz), 3.06 (d, 1H, J = 13.7 Hz), 2.91 (dd, 1H, J = 13.7,
3.3 Hz), 2.81 (qd, 1H, J = 6.7, 3.6 Hz), 1.70 (m, 1H), 1.37 (d, 3H,
J = 6.9 Hz), 1.03 (d, 3H, J = 6.7 Hz).
13C NMR (50.32 MHz, CDCl3): d = 143.4, 128.5, 127.5, 127.1,
69.1, 57.8, 54.3, 54.2 (2C), 51.7, 43.3, 20.5, 10.3.
MS (EI): m/z = 233 (M+, 25), 232 (26), 218 (39), 105 (100).
HRMS (EI): m/z calcd for C14H19NO2 (M+): 233.1415. Found:
233.1398.
Major Isomer 40 (colourless oil)
[a]D -5° (c 0.30, CHCl3).
IR (neat) n = 2975, 2819, 2257, 1740, 1492, 1454, 1371, 1251,
1232, 1053 cm-1.
Minor Isomer
1H NMR (250 MHz, CDCl3): d = 7.20-7.40 (m, 5H), 3.89 (m, 1H),
3.74 (q, 1H, J = 6.7 Hz), 3.46 (ddd, 1H, J = 4.2, 4.2, 1.2 Hz), 3.36
Synthesis 2000, No. 14, 2117–2126 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
An Enantioselective Entry to Substituted 6-Membered Nitrogen Heterocycles
2125
(dd, 1H, J = 4.2, 2.9 Hz), 3.04 (d, 1H, J = 13.6 Hz), 2.97 (br d, 1H,
J = 13.6 Hz), 2.76 (qd, 1H, J = 6.7, 5.6 Hz), 2.00 (m, 1H), 1.34 (d,
3H, J = 6.7 Hz), 1.00 (d, 3H, J = 6.7 Hz).
washed with pentane and filtered over silica gel. Removal of solvent
under reduced pressure afforded piperidine hydrochloride 7◊HCl
(20.1 mg, 90%) as a light yellow oil.
13C NMR (62.89 MHz, CDCl3): d = 144.2, 128.6, 127.5, 127.2,
68.9, 59.3, 54.7, 53.7 (2C), 51.9, 42.7, 21.6, 7.5.
Free Base 7
[a]D +10° (c 0.91, CHCl3).
(1R,2S,3R,4R,5S)-(+)-3,4,5-Triacetoxy-2-methyl-1-(1-phenyl-
ethyl)-piperidine (43)
IR (neat): n = 2976, 2932, 2257, 1741, 1371, 1253, 1232 cm-1.
1H NMR (300 MHz, CDCl3): d = 5.13 (dd, 1H, J = 5.9, 5.4 Hz), 4.76
(dd, 1H, J = 5.9, 3.5 Hz), 4.69 (ddd, 1H, J = 5.4, 5.4, 3.8 Hz), 3.26
(qd, 1H, J = 6.9, 3.5 Hz), 3.11 (dd, 1H, J = 14.3, 3.8 Hz), 2.97 (dd,
1H, J = 14.3, 5.4 Hz), 2.10 (s, 3H), 2.08 (s, 3H), 2.07 (s, 3H), 1.12
(d, 3H, J = 6.9 Hz).
13C NMR (62.89 MHz, CDCl3): d = 170.0, 169.9, 169.4, 70.9, 68.8,
68.4, 49.2, 44.0, 21.1, 20.9, 20.9, 15.5.
The mixture of epoxides 42 (94.4 mg, 0.405 mmol) was dissolved
in HOAc (4 mL) and the solution was stirred overnight at r.t. and
then refluxed for 1 h. After evaporation of the solvent to dryness, the
residue was dissolved in anhyd pyridine (5 mL) and Ac2O (1 mL,
10.8 mmol) was added. This solution was left overnight at r.t. and
then diluted with CH2Cl2. The organic phase was washed with H2O
and evaporated at reduced pressure to afford a mixture of isomers
43 and 44 in a 68:32 ratio. Chromatography over alumina (heptane/
EtOAc, 95:5 to 91:9) gave the major isomer 43 (89 mg, 59% yield)
as a white solid and the minor isomer 44 (45 mg, 29% yield) as a
colorless oil. White crystals of 43 were obtained from dry Et2O/hep-
tane.
MS (CI): m/z = 274 (MH+).
HRMS (CI): m/z calcd for C12H20NO6 (MH+): 274.1290. Found:
274.1308.
References
Isomer 43
(1) Husson, H. -P.; Royer, J. Chem. Soc. Rev. 1999, 28, 383.
Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem. Commun.
1998, 633.
Meyers, A. I.; Brengel, G. P. Chem. Commun. 1997, 1.
(2) Wong, Y. -S.; Marazano, C.; Gnecco, D.; Génisson, Y.;
Chiaroni, A.; Das, B. C. J. Org. Chem.1997, 62, 729.
Génisson, Y., Mehmandoust, M.; Marazano, C.; Das, B. C.
Heterocycles 1994, 39, 811.
Génisson, Y.; Marazano, C.; Mehmandoust, M.; Gnecco, D.;
Das, B. C. Synlett 1992, 431.
(3) a) Guilloteau-Bertin, B.; Compère, D.; Gil, L.; Marazano, C.;
Das, B. C. Eur. J. Org. Chem. 2000, 1391.
Mp: 130-132 °C; [a]D +1° (c 1.63, CHCl3).
IR (neat): n = 2979, 1745, 1455, 1437, 1372, 1252, 1229 cm-1.
1H NMR (300 MHz, CDCl3): d = 7.19-7.36 (m, 5H), 5.25 (dd, 1H,
J = 10.2, 9.9 Hz), 5.02 (ddd, 1H, J = 10.5, 9.9, 5.9 Hz), 4.94 (dd,
1H, J = 10.2, 5.5 Hz), 3.76 (q, 1H, J = 6.5 Hz), 3.24 (qd, 1H,
J = 6.8, 5.5 Hz), 3.21 (dd, 1H, J = 11.7, 5.9 Hz), 2.54 (dd, 1H,
J = 11.7, 10.5 Hz), 2.03 (s, 3H), 2.02 (s, 3H), 1.95 (s, 3H), 1.33 (d,
3H, J = 6.5 Hz), 0.97 (d, 3H, J = 6.8 Hz).
13C NMR (50.32 MHz, CDCl3): d =170.5, 170.2, 169.8, 144.7,
128.6, 127.2, 126.8, 71.9, 71.3, 71.0, 59.7, 51.7, 43.4, 22.4, 20.9,
20.9, 5.7.
MS (EI): m/z = 377 (M+, 2.5), 362 (19), 317 (14), 105 (100), 43 (74).
MS (CI): m/z = 378 (MH+).
HRMS (CI): m/z calcd for C20H28NO6 (MH+): 378.1916. Found:
b) Barbier, D.; Marazano, C.; Riche, C.; Das, B. C.; Potier, P.
J. Org. Chem. 1998, 63, 1767.
c) Génisson, Y.; Marazano, C.; Das, B. C. J. Org. Chem. 1993,
58, 2052.
(4) Azasugars are important biologically active compounds as
glycosidases inhibitors, for a review and references see:
Heightman, T. D.; Vasella, A. T. Angew. Chem., Int. Ed. Engl.
1999, 38, 750.
(5) Quick, J.; Khandelwal, Y.; Meltzer, P. C.; Weinberg, J. S. J.
Org. Chem.1983, 48, 5199.
378.1933.
Isomer 44
[a]D -27.5° (c 3.09, CHCl3).
IR (neat): n = 2979, 1745, 1455, 1437, 1372, 1252, 1229 cm-1.
(6) Structures of the epoxides 22 and 23 were deduced by analogy
with these precedent results and by an extensive NMR study
(nOe’s) of derivative 25.
(7) Asensio, G.; Boix-Bernardini, C.; Andreu, C.; Gonzalez-
Nunez, M. E.; Mello, R.; Edwards, J. O.; Carpenter, G. B. J.
Org. Chem. 1999, 64, 4705.
(8) The rather significant difference in this relationship observed
for epoxidation of tetrahydropyridines 11 can be tentatively
attributed to a competing (but small) directing effect of the
phenylethanol side chain oxygen function.
1H NMR (300 MHz, CDCl3): d = 7.20-7.38 (m, 5H), 5.21 (dd, 1H,
J = 3.5, 2.3 Hz), 5.12 (ddd, 1H, J = 9.5, 9.5, 4.5 Hz), 4.75 (dd, 1H,
J = 9.5, 3.5 Hz), 4.13 (q, 1H, J = 7.0 Hz), 3.28 (dd, 1H, J = 11.3, 4.5
Hz), 2.62 (dq, 1H, J = 6.4, 2.3 Hz), 2.14 (s, 3H), 2.04 (s, 3H), 1.97
(dd, 1H J = 11.3, 9.5 Hz), 1.97 (s, 3H), 1.46 (d, 3H, J = 7.0 Hz),
1.19 (d, 3H, J = 6.4 Hz).
13C NMR (50.32 MHz, CDCl3): d = 171.0, 170.4, 170.2, 139.8,
128.2, 127.8, 127.2, 72.5, 72.2, 69.0, 55.9, 54.7, 47.2, 21.1, 20.9,
20.8, 19.1, 15.3.
MS (EI): m/z = 377 (M+, 3.5), 362 (23), 317 (11), 105 (100), 43 (72).
MS (CI): m/z = 378 (MH+).
HRMS (CI): m/z calcd for C20H28NO6 (MH+): 378.1916. Found:
(9) Crystal data of 32a: Colorless crystal (0.15 x 0.35 x 0.45 mm)
recrystallized from Et2O/heptane mixture. C15H21NO2,
MW = 247.33. Orthorhombic system, space group P212121,
Z = 4, a = 5.297 (2), b = 9.563 (3), c = 27.540 (10) Å,
V = 1395 Å3, dC = 1.178 g cm-3, F(000) = 536, l (Mo
Ka) = 0.7107 Å; m = 0.077 mm-1; 2640 data measured on a
Philips PW1100 diffractometer of which 1468 unique
(Rint = 0.030) and 1114 observed with I ≥ 2.0 s(I). Structure
solved with SHELX76 and refined with SHELXL93. Hydrogen
atoms riding. Refinement converged to R(Fo) = 0.0376 for the
observed Fo and wR(Fo2) = 0.1158 for all the 1468 data with
goodness-of-fit S = 1.065. Residual electron density between
-0.12 and 0.13 eÅ-3. All crystallographic results have been
378.1920.
(2S,3R,4R,5S)-(+)-3,4,5-Triacetoxy-2-methylpiperidine (7)
Triacetate derivative 43 (27 mg, 0.072 mmol) was dissolved in a
mixture of EtOH (1.5 mL), EtOAc (1.5 mL) and 20% aqueous HCl
(1 mL). The resulting homogeneous solution was hydrogenated in a
Parr apparatus at 4.5 psi, in the presence of a catalytic amount of
10% palladium on charcoal, during 14 h. After filtration over Celite
and removal of solvent under reduced pressure, the residue was
Synthesis 2000, No. 14, 2117–2126 ISSN 0039-7881 © Thieme Stuttgart · New York

2126
L. Gil et al.
SPECIAL TOPIC
deposited at the Cambridge Crystallographic Data Centre,
U.K., as Supplementary Material (CIF file). (Sheldrick, G. M.
(1986), SHELXS86, Program for the Solution of Crystal
Structures, University of Göttingen, Germany; Sheldrick, G.
M. (1993), SHELXL93, Program for the Refinement of Crystal
Structures, University of Göttingen, Germany (Program for
the Solution of Crystal Structures, University of Göttingen,
Germany; Sheldrick, G. M. (1993), SHELXL93, Program for
the Refinement of Crystal Structures, University of Göttingen,
Germany).
group P212121, Z = 4, a = 7.209 (5), b = 11.513 (7), c = 25.893
(12) Å, V = 2149 Å3, dC = 1.167 g cm-3, F(000) = 808, l (Cu
Ka) = 1.5418 Å; m = 0.71 mm-1; 2908 data measured on a
Nonius CAD-4 diffractometer of which 2163 unique
(Rint = 0.075) and 1485 observed with I ≥ 2.0 s(I). Structure
solved with SHELX76 and refined with SHELXL93. Hydrogen
atoms riding. Refinement converged to R(Fo) = 0.0783 for the
observed Fo and wR(Fo2) = 0.2654 for all the 2163 data with
goodness-of-fit S = 1.030. Residual electron density between
-0.28 and 0.39 eÅ-3. All crystallographic results have been
deposited at the Cambridge Crystallographic Data Centre,
U.K., as Supplementary Material (CIF file). (Sheldrick, G. M.
(1986), SHELXS86, Program for the Refinement of Crystal
Structures, University of Göttingen, Germany; Sheldrick, G.
M. (1993), SHELXL93, Program for the Refinement of Crystal
Structures, University of Göttingen, Germany).
(10) Used of this highly hindered, non nucleophilic base is
rendered necessary since pyridine itself reacted with the
intermediate triflate 33 or aziridinium 34 to give a pyridinium
salt.
(11) Deduced from a 1H NMR spectroscopy study of the reaction
in CDCl3 (apparition of a downfield proton at 5.8 ppm,
tentatively H3, JH2-H3 = 2 Hz).
(12) Crystal data of 43: Small colorless needle (0.07 x 0.20 x 0.26
mm) recrystallized from an Et2O/heptane mixture.
C20H27NO6, MW = 377.43. Orthorhombic system, space
Article Identifier:
1437-210X,E;2000,0,14,2117,2126,ftx,en;C03200SS.pdf
Synthesis 2000, No. 14, 2117–2126 ISSN 0039-7881 © Thieme Stuttgart · New York