Synthesis of substituted 5-(3-hydroxypropyl)pyrrolidin-2-ones and pyrrolizidinones from nitroethane via C3 functionalized 5,6-dihydro-4H-1,2- oxazines: A novel approach to some analogues of the antidepressant Rolipram

Article abstract of DOI:10.1055/s-0029-1216806

Easily accessible [(5,6-dihydro-4H-1,2-oxazin-3-yl)methyl]malonates 1 were converted into substituted 5-(3-hydroxypropyl) pyrrolidin-2-ones 2 and pyrrolizidinones 3, which are versatile products and intermediates for organic and bioorganic chemistry. The

Full text of DOI:10.1055/s-0029-1216806

PAPER
1999
Synthesis of Substituted 5-(3-Hydroxypropyl)pyrrolidin-2-ones and Pyrrolizi-
dinones from Nitroethane via C3 Functionalized 5,6-Dihydro-4H-1,2-oxazines:
A Novel Approach to Some Analogues of the Antidepressant Rolipram
D
iastereoselective
l
Synthe
e
sis of Subs
x
tituted
a
-Pyr
e
rolidone
D
e
y
rivative
s
from
Nitr
Y
oethane u. Sukhorukov, Alexey V. Lesiv, Yulia A. Khomutova, Sema L. Ioffe,* Vladimir A. Tartakovsky
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prosp. 47, 119991 Moscow, Russian Federation
Fax +7(499)1355328; E-mail: iof@ioc.ac.ru
Received 29 January 2009; revised 26 February 2009
furans,4 and pyrroles.3 However, it is evident that the syn-
thetic potential of dihydrooxazines 1 is not exhausted by
these examples. Herein we would like to report the use of
dihydrooxazines 1 in the synthesis of diastereomerically
Abstract: Easily
accessible
[(5,6-dihydro-4H-1,2-oxazin-3-
yl)methyl]malonates 1 were converted into substituted 5-(3-hy-
droxypropyl)pyrrolidin-2-ones 2 and pyrrolizidinones 3, which are
versatile products and intermediates for organic and bioorganic
chemistry. The synthetic sequence suggested includes stereoselec- pure 5-(3-hydroxypropyl)pyrrolidin-2-ones 2 and pyr-
rolizidinones 3 (Figure 1).5
tive two-step reduction of an oximino fragment, followed by in-
tramolecular cyclization involving one of the CO2Me groups and
decarboxylation in the last stage. The efficiency of this strategy was
H
demonstrated by the stereoselective synthesis of pyrrolizidinone
rac-4, a highly efficient analogue of antidepressant Rolipram, from
nitroethane.
R1
H
O
N
H
R1
O
N
R2
OH
Key words: 5,6-dihydro-4H-1,2-oxazines, reduction, pyrrolidones,
pyrrolizidinones, Rolipram
R2
R4
R4
2
R3
3
Recently we reported a simple and efficient approach to
the synthesis of diastereomerically pure 5,6-dihydro-4H-
1,2-oxazines 1, bearing a fragment CH2FG [FG =
CH(CO2Me)2, Scheme 1] at C3, starting from nitroethane
and other simple precursors.1 The resulting six-membered
cyclic oxime ethers 1 can be considered as perspective re-
agents for the preparation of a variety of versatile poly-
functionalized products.
O
H
MeO
O
N
rac-4
Figure 1
Products of types 2 and 3 have considerable interest as
valuable intermediates for the total synthesis of pyrrolizi-
dine alkaloids, such as pseudoheliotridane,6 isoretro-
necanol,7 and platynecine,8 as well as some biologically
active products (e.g., highly selective EP4 antagonists9).
Furthermore, many heterocycles of types 2 and 3 possess
their own high biological activity.10 Thus, racemic pyr-
rolizidinone 4 (Figure 1) is several times more active as a
cAMP-specific phosphodiesterase (PDE IV) inhibitor
than the known antidepressant Rolipram.11
We have now demonstrated the application of dihydroox-
azines 1 in the synthesis of unnatural g-amino acids deriv-
atives,2 oxaazaspirononanones,3 substituted dihydro-
R1
EtNO2
R2
R3
Me
O
R1CHO
R3
R2
N
O
R4
R4
Me3SiBr, Et3N
Scheme 2 shows the proposed three-step sequence for the
transformation of cyclic oxime ethers 1 into pyrrolidi-
nones 2 or pyrrolizidinones 3 (depending on the nature of
the substituents at C6 of the oxazine ring). This method
includes the selective reduction of a C=N bond (step 1),
the subsequent hydrogenolysis of an N–O bond in inter-
mediates 5, followed by pyrrolidinone ring closure (step
2) and, finally, removal of a CO2Me group, attached to the
pyrrolidinone ring (step 3).
R1
R1
R2
R3
R2
R3
FG
Br
CH2(CO2Me)2
t-BuOK
N
N
O
O
R4
R4
1
FG = CH(CO2Me)2
R1 = Alk, Ar, OAlk; R2, R3 = H, Alk, Ar; R4 = H, Alk, OAlk, Ar
Scheme 1
Ring contraction of 5,6-dihydrooxazines to pyrrolidines is
known to occur during the hydrogenolysis of six-mem-
bered cyclic oxime ethers, bearing an alkoxy group at
C6.12 However, in the synthetic scheme suggested here
another process, an intramolecular cyclization involving
SYNTHESIS 2009, No. 12, pp 1999–2008
Advanced online publication: 12.05.2009
DOI: 10.1055/s-0029-1216806; Art ID: P01509SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
9

2000
A. Yu. Sukhorukov et al.
PAPER
CO2Me
O
CO2Me
R1
O
H
H
R1
R1
R2
R3
40 bar H2
Ra-Ni
R1
CO2Me
CO2Me
R2
R3
CO2Me
CO2Me
O
NaBH3CN
N
H
N
or
6
MeOH, r.t., 3 h
step 2
6
R2
AcOH
step 1
NH
N
OH
R2
R4
O
R4
R4
R3
R4
1
5
20 min (for 1a–e)
2 h (for 1f,g)
R3 = OAlk
R3, R4 ≠ OAlk
7' and 7''
+
R1
8' and 8''
R2
R3
CO2Me
DMSO, NaBr
H2O, reflux
step 3
step 3
N
25 min for 2
45 min for 3
O
O
R4
6
3
2
Scheme 2
one of the CO2Me groups of the FG fragment, is used according to a known procedure (NaBH3CN, AcOH, 2
(Schemes 1 and 2).
h).2
As for the formation of the bicyclic skeleton in products Selective catalytic hydrogenation of the N–O bond in ox-
3, single examples of their synthesis using an approach azines 5 (step 2, Scheme 2) furnishes products 7 or 8,
similar to that indicated in Scheme 2 are known in the lit- which differ from the target heterocycles 2 and 3 in the
erature.5
presence of an additional CO2Me group. The nature of the
resulting product, 7 or 8, depends on the structure of the
tetrahydrooxazine 5. Catalytic hydrogenation of tetrahy-
drooxazines 5a–e, which do not possess an alkoxy substit-
uent at C6 (R3, R4 ≠ OAlkyl), in the presence of Raney
nickel in methanol causes the reductive cleavage of the
N–O bond and subsequent intramolecular cyclization of
the corresponding amine with one of the CO2Me groups.
Due to these transformations, hydroxy-pyrrolidinones 7
are formed as nearly equimolar mixtures of diastereomers
(7¢ and 7¢¢) differing in the configuration of the stereo-
center at C3 bearing the CO2Me group. In the hydrogena-
tion of oxazine 5d reductive dehalogenation of a chlorine
atom in the aromatic ring also occurs (see Table 1, entry
4).
The yields of target and intermediate products are collect-
ed in Table 1 and the optimized procedures for the synthe-
sis are illustrated in Scheme 2.
Stereoselective reduction of the C=N bond in dihydroox-
azines 1 (step 1, Scheme 2) was accomplished with sodi-
um cyanoborohydride in acetic acid.2 Recently it was
shown,2 that the products of this transformation, 3,4-
trans-tetrahydrooxazines 5, are unstable under the reduc-
tion conditions, undergoing an intramolecular ring closure
between the nitrogen atom and CO2Me group to give bi-
cyclic derivatives 6.13 Now by decreasing the reaction
time from two hours to 20 minutes we were able to obtain
individual products 5 in good to high yields. Over the in-
dicated reaction time nearly full conversion of the starting
material was observed in most of the examples with the
amount of cyclization products being very small. Tetrahy-
drooxazines 5f,g with R3 = OAlkyl, which are more stable
towards the intramolecular cyclization to 6, were prepared
Catalytic hydrogenation of tetrahydrooxazines 5f,g, bear-
ing an alkoxy substituent at C6 (R3 = OAlkyl), results in
consecutive closures of pyrrolidine and pyrrolidinone
rings (Schemes 2 and 3).
Table 1 Synthesis of Products 2 and 3
Entry
Dihydrooxazine R1
R2
R3
R4
Final product Product [yield (%)]
[yielda (%)]
2a [58]
2b [65]
2c [60]
–
Step 1
Step 2
Step 3
2a [94]
2b [91]
2c [83]
–
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
Me
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
H
5a [82]
5b [76]
5c [83]
5d [70]
5e [47c]
5f [82]
5g [81]
7a [75]
7b [94]
7c [87]
7bb [69]
7e [84]
8f [57]
8g [60]
Ph
4-MeOC6H4
4-ClC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
(CH2)4
2e [39]
3f [41]
3g [42]
2e [99]
3f [87]
3g [86]
H
H
OEt
H
1g
OMe
Me
a Yield of isolated product based on 1.
b The product of hydrogenation is 7b due to reductive dehalogenation of the chlorine attached to the phenyl ring.
c Yield of isolated product based on converted 1e (conversion of 1e: 56%).
Synthesis 2009, No. 12, 1999–2008 © Thieme Stuttgart · New York

PAPER
Diastereoselective Synthesis of Substituted a-Pyrrolidone Derivatives from Nitroethane
2001
The final stage, removal of the CO2Me group (step 3,
Scheme 2), was realized by refluxing the products 7 or 8
in wet dimethyl sulfoxide in the presence of sodium bro-
mide.16 As a result, the target 5-(3-hydroxypropyl)pyrro-
lidin-2-ones 2 and pyrrolizidinones 3 were obtained from
products 7 and 8, respectively. Thus, dihydrooxazines 1
were converted into target products 2 or 3 in 39–65%
overall yields in three steps.
An
O
An
6
CO2Me
CO2Me
CO2Me
H2, catalyst
NH2
A
NH
R
3 = OAlk
CO2Me
R4
R3
O
R4
5f,g
An
An
H2, catalyst
3
The efficiency of the suggested approach towards the syn-
thesis of a-pyrrolidone derivatives from simple molecules
was demonstrated by the stereoselective total synthesis of
racemic product 4 (Figure 1). Pyrrolizidinone 4 was
shown to be four times more active than the known drug
Rolipram.17
5
R4
R4
N
N
H
CO2Me
CO2Me
MeO2C
MeO2C
C
B
An = 4-MeOC6H4
Details of our strategy for the synthesis of pyrrolizidinone
4 are illustrated in Scheme 4. We started from the known
aldehyde 9 available from isovanillin,18 nitroethane, and
ethyl vinyl ether. These reagents were converted into cy-
8
Scheme 3
In the transformation 5f,g into 8f,g the reductive oxazine clic nitronate 11 according to the two-step protocol devel-
ring contraction to pyrrolidine, apparently, is a multistep oped by S. E. Denmark.19a,b The nitronate 11 was isolated
process (Scheme 3), which involves the hydrogenolysis as the diastereomerically pure 4,6-trans-isomer (trace
of an N–O bond, leading to intermediate A, subsequent re- amount of the corresponding 4,6-cis-isomer can be sepa-
cyclization of A to dihydropyrrolidine B and the reduction
of B to pyrrolidine C.2,14 Intramolecular cyclization of C
furnishes a mixture of diastereomeric pyrrolizidinones 8¢
and 8¢¢ isolated in good yield by column chromatogra-
phy.15
rated from 11 by column chromatography). Silylation of
nitronate 11 with excess bromotrimethylsilane/triethyl-
amine mixture and subsequent nucleophilic substitution
of bromine with the CH(CO2Me)2 fragment according to
a literature method1a provided dihydrooxazine 1h, the key
intermediate in the synthesis of rac-4, possessing the
OMe
OMe
OMe
O
OMe
O
O
O
Me3SiBr (5 equiv)
Et3N (1.5 equiv)
EtNO2
CH2(CO2Me)2
CH2=CHOEt
Me
O
CH2Cl2
–78 °C, 24 h
Br
t-BuOK, DMF
60–80 °C
2 h
NH4OAc
reflux
Me
CH2Cl2, SnCl4
–94 °C
then workup
H
N
O
H
N
EtO
O
NO2
EtO
O
9
12, 54%
10, 90%
11, 85%
OMe
OMe
O
OMe
OMe
O
O
O
1. 40 bar H2
Ra-Ni, MeOH
3 h
NaBH3CN
H
H
CO2Me
NH CO2Me
AcOH
2 h
CO2Me
CO2Me
N
H
N
MeO2C
N
O
EtO
O
CO2Me
EtO
O
CO2Me
13
8h
5h, 99%
1h, 80%
2. DMSO, NaBr
H2O, reflux
71%
OMe
O
total yield of rac-4 from 9: 23%
H
N
rac-4
O
Scheme 4
Synthesis 2009, No. 12, 1999–2008 © Thieme Stuttgart · New York

2002
A. Yu. Sukhorukov et al.
PAPER
whole carbon skeleton of the target molecule. Diastereo- Fortunately, under the decarboxylation conditions both
selective reduction of the C=N bond in 1h with sodium products 13 and 8h were converted smoothly into the tar-
cyanoborohydride in acetic acid according to the proce- get pyrrolizidinone rac-4. This allows the transformation
dure listed in Scheme 2 and Table 1 provided the expected of 5h to rac-4 to be performed in one technological step
3,4-trans-tetrahydrooxazine 5h in quantitative yield. in 71% yield without isolation of intermediate heterocycle
However, we failed to realize selective hydrogenation of 8h. Thus, target pyrrolizidinone rac-4 was obtained in
product 5h to 8h under the conditions applied for the re- seven steps in 23% overall yield from aldehyde 9 and ni-
duction of oxazines 5f,g (Scheme 2). Here in addition to troethane.
the desired pyrrolizidinone 8h, pyrrolidine 13 was detect-
ed in the reaction mixture (ration 8h/13 ~1.9:1.0). Appar-
ently, this indicates that the cyclization of 13 to 8h is
slower than the corresponding transformation in case of
The previous synthesis of rac-4 from aldehyde 9 is also
quite efficient (6 steps, 16.9% yield),11 but it is not stereo-
selective and requires a chromatographic separation of
diastereomers (c.a. 2:1 in favor of rac-4) in the last step of
the synthesis.
model oxazines 5f,g.
18
OMe21
20
Cl
18
15
Me
17
16
14
9
10
7
Me
H''
CO2Me
8
17
16
19
18
H
4
3
H'
5
6
12
15
3
11
4
9
7
8
9
10
5
6
2NH CO2Me
10
7
3
11
1
O
14
Me
15
3
8
CO2Me
1 NH2
OH
CO2Me
9
10
17
3
4
13
Me
7
9
7
10
5
6
13Me
8
CO2Me
12
11
8
CO2Me
2NH CO2Me
12Me
4
5a
14
4
16
13
1
O
5
6
15
14
O
5
6
11
12
12
7a'
Me
11
2NH
CO2Me
2NH CO2Me
14
1
O
5d
1
O
5e
13 Me
Me13
5b
Me
15
OMe
18
17
OMe20
19
OMe
14
16
15
17
14
Me
H''
16
H
18
H'
13
4
14
15
7
8
9
H''
11
5
6
17
10
3
11
H
12
14
1 NH2
OH
CO2Me
H'
H''
16
H
13
Me
4
H
3
2
4
7
10
11
H
5
6
3
H' 10
8
12Me
CO2Me
5
4
1
11
4
7
8
9
1 HN 2
OH
15
12
9
13
Me
5
6
7
9
3
O
11
10
14
13
5
6
3
7a''
N
6
7
CO2Me
8
HN2
13
2
CO2Me
1
OH
12 Me
10
1 NH
OH
O
Me
8
9
12Me
CO2Me
7b' and 7b''
O
O
O
7c' and 7c''
7e' and 7e''
8f' and 8f''
OMe16
OMe16
16
18
OMe
15
OMe
17
15
15
15
14
13
Me12
H
16
14
13
14
14
H'
H'
15
H''
13
H''
13
12
12
4
12
7
12
3
5
14H
H
4
5
3
4
5
H
3
2
8
H
H
11
6
11
Me
2
H''
H'
4
9
H''
H'
10
Me
1 HN2
OH
1
1
7
9
3
4
13
12
Me
5
6
4
7
9
7
9
6
8
N
6
N
5
6
3
3
2
5
6
1 HN2
OH
11 Me
H
8
8
10
Me
H
10
7
HN2
10
11
7
O
10
Me
1
OH
2e
1 HN
2a
10
8
9
8
9
11 Me
OH
CO2Me
O
8g''
O
O
CO2Me
O
8g'
11 Me
2b
O
O
2c
14
OMe
13
OMe
16
16
OMe
10
OMe
13
OMe
13
12
13
7
12
12
O
18
17
6
O
14
15
18
17
8
9
14
15
12
19
12
11
10
19
H'
11
13
9
H'
11
11
10
11
H''
5
10
H''
H'
10
4
5
3
3
2
4
5
7
H
4
3
H
1
7
2
9
Me
Me
1
N
1
4
2
Me
4
1
O
5
6
3
6
3
Br
6
N
5
6
H
2 N
H''
8
7
8
8
8
9
Me
1
O
11
7
2N
9
Me
NO2
O
O
O
3g
O
10
O
3f
12
21
15
21
17
OMe
OMe
12
13
OMe
18
18
17
O
19
20
23
11 O
14
3
22
O
24
19
20
23
24
22
16
9
H'
H''
H'
10
16
16
15
17
18
9
10
7
15
4
5
H
CO2Me
9
10
8
7
2
4
1
3
5
6
CO2Me
8
4
11
12
N
2 NH CO2Me
7
6
3
2 N
13
5
6
H''
1
14
Me
11
12
8
13
1
14
O
O
CO2Me
Me
O
O
rac-4
5h
O
1h
Figure 2
Synthesis 2009, No. 12, 1999–2008 © Thieme Stuttgart · New York

PAPER
Diastereoselective Synthesis of Substituted a-Pyrrolidone Derivatives from Nitroethane
2003
carried out in a steel autoclave (Parr instrument) with external stir-
ring.
It is likely that the synthesis of rac-4 presented here can
be realized in an asymmetric variant by generation of an
analogue of nitronate 11 with a chiral auxiliary at C6. This
can be achieved by employing a chiral vinyl ether in the
[4+2] cycloaddition with nitroalkene 10; preparations of
chiral six-membered cyclic nitronates and dihydroox-
azines are given in the literature.19
Tetrahydrooxazines 5; General Procedure
NaBH3CN (0.19 g, 3 mmol for 1a–d, 0.57 g, 9 mmol for 1e) was
added to a stirred soln of oxazine 1 (1 mmol) in AcOH (4.4 mL) un-
der argon. The mixture was kept stirring at r.t. for 20 min (for 1a–
e) or 2 h (for 1h) and poured into a mixture of EtOAc (200 mL) and
sat. aq K2CO3 (200 mL). The aqueous phase was back-extracted
with EtOAc (2 ꢀ 50 mL); the combined organic layers were washed
brine (50 mL) and dried (Na2SO4). The solvent was evaporated in
vacuo and the residue was immediately subjected to column chro-
matography (silica gel, EtOAc–hexane, 1:5 to 1:3). Yields of prod-
ucts are presented in Table 1.
The structure of final (2–4) and intermediate (1h, 5, 7, 8,
10–12) products was confirmed by elemental analysis
and NMR spectroscopy data (1H, 13C, INEPT, for number-
ing see Figure 2), as well as by the chemical transforma-
tions depicted in Schemes 2 and 4. The 3,4-trans-
configuration of tetrahydrooxazines 5a–h was established
from the analysis of coupling constants of protons at C3
and C4 under the standard hypothesis that tetrahydroox-
azine ring occupies a chair-type conformation. In further
transformations of products 5a–h (Schemes 2 and 4), the
relative configuration of substituents at C3 and C4 is not
affected. This was confirmed by 2D NOESY experiments
for products 3g and 8g. The unambiguous assignment of
signals in NMR spectra of diastereomers 7 and 8 was
guided by 2D NMR experiments COSY, HSQC, and
NOESY (for characteristic correlations see the experi-
mental section).
Dimethyl rel-2-{[(3S,4R)-4,6,6-Trimethyltetrahydro-2H-1,2-ox-
azin-3-yl]methyl}malonate (5a)
Mp 35–37 °C; Rf = 0.52 (EtOAc–hexane, 1:1).
1H NMR (500 MHz, COSY, CDCl3): d = 0.91 (d, J = 5.9 Hz, 3 H,
15-CH3), 1.16 and 1.25 (2 s, 6 H, 13-CH3, 14-CH3), 1.26 (m, 1 H,
H5ax), 1.50 (m, 1 H, H4), 1.58 (dd, J = 12.5, 3.7 Hz, 1 H, H5), 1.69
(ddd, J = 14.9, 9.6, 5.9 Hz, 1 H, H7), 2.34 (ddd, J = 14.9, 8.5, 3.0
Hz, 1 H, H7), 2.53 (ddd, 1 H, J = 9.6, 9.6, 3.0 Hz, H3ax), 3.66 (dd,
J = 8.8, 5.9 Hz, 1 H, H8), 3.73 and 3.74 (2 s, 6 H, 10-CH3, 12-CH3),
5.90 (br, 1 H, 2-NH).
13C NMR (75 MHz, HSQC, CDCl3): d = 18.2 (C15), 21.6 and 29.3
(C13, C14), 29.3 (C7), 31.1 (C4), 44.2 (C5), 48.7 (C8), 52.5 and
52.6 (C10, C12), 62.1 (C3), 74.7 (C6), 169.8 and 170.2 (C9, C11).
In conclusion, stepwise reduction of readily available di-
hydrooxazines 1 bearing the CH2CH(CO2Me)2 fragment
at C3 can be considered as an efficient approach to the
synthesis of diastereomerically pure substituted 5-(3-hy-
droxypropyl)pyrrolidin-2-ones 2 and pyrrolizidinones 3,
versatile products and precursors of biologically active
molecules. Great synthetic potential of the above-men-
tioned approach was demonstrated by the synthesis of
Anal. Calcd for C13H23NO5: H, 8.48; C, 57.13; N, 5.12. Found: H,
8.29; C, 57.22; N, 5.09.
Dimethyl rel-2-{[(3S,4S)-6,6-Dimethyl-4-phenyltetrahydro-2H-
1,2-oxazin-3-yl]methyl}malonate (5b)
Oil; Rf = 0.60 (EtOAc–hexane, 1:1).
1H NMR (500 MHz, COSY, CDCl3): d = 1.19 and 1.33 (2 s, 6 H,
13-CH3, 14-CH3), 1.62 (ddd, J = 15.0, 10.0, 6.1 Hz, 1 H, H7), 1.72
pyrrolizidinone rac-4, a highly active analogue of the an- (dd, J = 13.3, 5.3 Hz, 1 H, H5), 1.76 (dd, J = 13.3, 11.1 Hz, 1 H,
H5), 1.92 (ddd, J = 15.0, 8.1, 3.2 Hz, 1 H, H7), 2.60 (ddd, J = 11.1,
tidepressant Rolipram. It is evident that other analogues of
10.5, 5.3 Hz, 1 H, H4ax), 3.14 (ddd, J = 10.5, 10.0, 3.0 Hz, 1 H,
rac-4 should be available by this synthetic route as well.
H3ax), 3.50 (dd, J = 8.1, 6.1 Hz, 1 H, H8), 3.62 and 3.64 (2 s, 6 H,
10-CH3, 12-CH3), 4.85 (br, 1 H, 2-NH), 7.14–7.28 (m, 5 H, H16,
1D and 2D NMR spectra were recorded at r.t. on Bruker DRX-500
H17, H18).
1
(1H (500.13 MHz), H-1H COSY, HSQC (J = 145 Hz), NOESY
13C NMR (75 MHz, HSQC, CDCl3): d = 21.5 and 29.3 (C13, C14),
29.5 (C7), 44.2 (C5), 44.4 (C4), 48.6 (C8), 52.5 and 52.6 (C10,
C12), 60.2 (C3), 74.6 (C6), 126.9, 127.6 and 128.8 (C14, C15,
C16), 142.1 (C15), 169.5 and 170.1 (C9, C11).
(mixing time 900 ms), Bruker AM-300 (13C 75.13 MHz, INEPT)
and WM-250 (13C 62.9 MHz, INEPT) NMR spectrometers for 0.1–
0.2 M solns in CDCl3. The chemical shifts (1H and 13C) are given in
relative to the solvent signal.20 All NMR experiments were per-
formed using standard methods and Bruker NMR technique soft-
ware. Elemental analyses were performed by the Analytical Center
of the Moscow Chemical Lyceum and Analytical Laboratory of In-
stitute of Organic Chemistry. Melting points were determined on a
Kofler melting point apparatus (uncorrected). Analytical TLC was
performed on Merck silica gel plates with QF-254. Visualization
was accomplished with UV light or with soln of ninhydrin in EtOH.
Glacial AcOH and DMSO were recrystallized twice. CH2Cl2 (tech-
nical grade), MeCN (technical grade), Et3N, and Me3SiBr were re-
distilled from CaH2. Hexane and EtOAc for chromatography and
extractions and MeOH for hydrogenation were technical grade and
distilled without drying agents. Column chromatography was per-
formed using Merck Kieselgel 40–60 mm 60A silica gel. NaBH3CN
(Sigma-Aldrich), Raney Nickel (50% slurry in H2O) (Acros), ethyl
vinyl ether (Acros), dimethyl malonate (Acros), nitroethane
(Acros), SnCl4 (Acros) were purchased from commercial sources
and used as received. Initial oxazines 1a–g1 and 5f,g2 were prepared
according to literature procedures. Catalytic hydrogenations were
Anal. Calcd for C18H25NO5: H, 7.51; C, 64.46; N, 4.18. Found: H,
7.67; C, 64.29; N, 4.06.
Dimethyl rel-2-{[(3S,4S)-4-(4-Methoxyphenyl)-6,6-dimethyl-
tetrahydro-2H-1,2-oxazin-3-yl]methyl}malonate (5c)
1H and 13C NMR data are consistent with previously reported data.2
Dimethyl rel-2-{[(3S,4S)-4-(4-Chlorophenyl)-6,6-dimethyl-
tetrahydro-2H-1,2-oxazin-3-yl]methyl}malonate (5d)
Oil; Rf = 0.60 (EtOAc–hexane, 1:1).
1H NMR (500 MHz, COSY, CDCl3): d = 1.19 and 1.33 (2 s, 6 H,
13-CH3, 14-CH3), 1.60 (ddd, J = 14.7, 10.3, 6.2 Hz, 1 H, H7), 1.71
(d, J = 8.5 Hz, 2 H, H5), 1.90 (ddd, J = 14.7, 8.5, 3.1 Hz, 1 H, H7),
2.58 (ddd, J = 10.3, 8.5, 8.5 Hz, 1 H, H4), 3.10 (ddd, J = 10.3, 10.3,
3.1 Hz, 1 H, H3), 3.51 (dd, J = 8.5, 6.2 Hz, 1 H, H8), 3.64 and 3.66
(2 s, 6 H, 10-CH3, 12-CH3), 4.80 (br, 1 H, 2-NH), 7.09 and 7.27 (2
d, J = 8.9 Hz, 4 H, H16, H18).
Synthesis 2009, No. 12, 1999–2008 © Thieme Stuttgart · New York

2004
A. Yu. Sukhorukov et al.
PAPER
13C NMR (75 MHz, HSQC, CDCl3): d = 21.5 and 29.3 (C13, C14),
29.5 (C7), 43.9 (C4), 44.2 (C5), 48.5 (C8), 52.6 and 52.7 (C10,
C12), 60.1 (C3), 74.6 (C6), 129.0 (C16, C17), 132.6 and 140.6
(C15, C18), 169.5 and 170.1 (C9, C11).
1 H, H5), 1.70 (m, 1 H, H4), 1.90 (ddd, J = 13.3, 9.6, 7.7 Hz, 1 H,
H7¢), 2.43 (ddd, J = 13.3, 7.2, 3.3 Hz, 1 H, H7¢¢), 3.00 (br, 1 H, 1-
OH), 3.36 (dd, J = 9.6, 3.3 Hz, 1 H, H8), 3.53 (ddd, J = 7.7, 7.5, 7.2
Hz, 1 H, H3), 8.19 (br, 1 H, 2-NH).
Anal. Calcd for C18H24ClNO5: H, 6.54; C, 58.46; N, 3.79. Found: H,
6.52; C, 58.47; N, 3.77.
13C NMR (75 MHz, HSQC, CDCl3): d (selected signals) = 18.3
(C14), 28.3 and 31.7 (C12, C13), 30.1 (C7), 34.8 (C4), 48.5 (C5),
48.8 (C8), 52.5 (C11), 59.7 (C3), 70.3 (C6).
Dimethyl rel-2-{[(3S,4S,4aR,8aR)-4-(4-Methoxyphenyl)octahy-
dro-2H-1,2-benzoxazin-3-yl]methyl}malonate (5e)
Mp 127–128 °C; Rf = 0.43 (EtOAc–hexane, 1:1).
Characteristic 2D-NOESY correlations: H3/H7¢¢, H7¢/H8.
Unassigned signals for both isomers:
1H NMR (500 MHz, CDCl3): d = 3.72 and 3.73 (2 s, 3 H, 11-CH3).
13C NMR (75 MHz, CDCl3): d = 170.4, 170.5, 172.6 and 172.7 (C9,
C10).
1H NMR (300 MHz, CDCl3): d = 1.05–1.21, 1.24–1.36, 1.65–1.68,
1.84–1.90, 2.03–2.10 (5 m, 1 H, 4 H, 1 H, 1 H, 1 H, H13, H14, H15,
H16), 1.60 (ddd, J = 14.7, 9.9, 6.0 Hz, 1 H, H7), 1.84 (ddd, J = 14.7,
8.1, 3.1 Hz, 1 H, H7), 2.26 (ddd, J = 11.4, 5.9, 4.4 Hz, 1 H, H5), 2.61
(dd, J = 11.4, 10.6 Hz, 1 H, H4), 3.19 (ddd, J = 10.6, 9.9, 3.1 Hz, 1
H, H3), 3.48 (dd, J = 8.1, 6.0 Hz, 1 H, H8), 3.63 and 3.65 (2 s, 6 H,
10-CH3, 12-CH3), 3.77 (s, 3 H, 21-CH3), 3.92 (ddd, J = 12.5, 5.1,
4.8 Hz, 1 H, H6), 4.86 (br, 1 H, 2-NH), 6.84 (d, J = 8.1 Hz, 2 H,
H19), 7.04 (d, J = 8.1 Hz, 2 H, H18).
Pyrrolidones 7b
1
Oil; mixture of diastereomers, 7b¢/7b¢¢, 1.2:1.0. H and 13C NMR
spectra are consistent with those previously reported for 7b pre-
pared directly from dihydrooxazine 2b.3
13C NMR (62 MHz, INEPT, CDCl3): d = 19.8, 24.1, 25.0, 26.8 and
29.9 (C7, C13, C14, C15, C16), 40.3 and 44.3 (C4, C5), 48.6 (C8),
52.4 and 52.5 (C10, C12), 55.1 (C21), 61.1 (C3), 77.5 (C6), 114.0
(C19), 128.7 (br, C18), 132.1 (C17), 158.3 (C20), 169.5 and 170.1
(C9, C11).
Methyl rel-(3S,5S)-5-[(1S)-3-Hydroxy-3-methyl-1-phenyl-
butyl]-2-oxopyrrolidine-3-carboxylate (7b¢)
1H NMR (500 MHz, COSY, NOESY, CDCl3): d (selected
signals) = 1.80 (m, 1 H, H7¢¢), 1.89 (m, 1 H, H7), 1.95 (m, 1 H, H7¢),
2.05 (dd, J = 14.8, 5.2 Hz, 1 H, H5), 2.90 (ddd, J = 9.5, 5.9, 5.2 Hz,
1 H, H4), 3.05 (br, 1 H, 1-OH), 3.35 (dd, J = 10.3, 9.1 Hz, 1 H, H8),
3.70 (m, 1 H, H3), 7.15–7.31 (m, 5 H, H15, H16, H17).
Anal. Calcd for C21H29NO6: H, 7.47; C, 64.43; N, 3.58. Found: H,
7.78; C, 64.26; N, 3.64.
13C NMR (75 MHz, HSQC, CDCl3): d (selected signals) = 31.4
(C7), 47.8 (C4), 48.8 (C8), 52.6 (C11), 59.0 (C3), 70.6 (C6), 126.9
(C17).
Hydrogenation of Tetrahydrooxazines 5; General Procedure
Raney nickel (c.a. 0.05 g, washed with MeOH) was placed in a test
tube equipped with a magnetic stirrer and charged with a soln of ox-
azine 5 (0.47 mmol) in MeOH (5.0 mL). The test tube was placed
in steel autoclave which was then flushed and filled with H2 to a
pressure of 40 bar. After stirring the mixture at r.t. for 3 h, the auto-
clave was slowly depressurized and the catalyst was filtered off.
The solvent was evaporated in vacuo and the residue was subjected
to column chromatography (for products 8f and 8g, silica gel,
EtOAc–hexane, 1:5 to 1:3 to 1:1 to 1:0) or filtered thorough a short
pad of silica gel (for products 7a–c,e, EtOAc–hexane, 1:1 to EtOAc
to MeOH). Yields of products are presented in Table 1.
Characteristic 2D-NOESY correlations: H3/H7¢¢, H7¢¢/H8.
Methyl rel-(3R,5S)-5-[(1S)-3-Hydroxy-3-methyl-1-phenyl-
butyl]-2-oxopyrrolidine-3-carboxylate (7b¢¢)
1H NMR (500 MHz, COSY, NOESY, CDCl3): d (selected
signals) = 1.80 (m, 1 H, H7¢), 1.89 (m, 1 H, H5), 1.92 (m, 1 H, H5),
2.08 (m, 1 H, H7¢¢), 2.80 (ddd, J = 9.2, 6.1, 5.0 Hz, 1 H, H4), 3.05
(br, 1 H, 1-OH), 3.22 (dd, J = 9.5, 4.2 Hz, 1 H, H8), 3.86 (ddd,
J = 9.2, 7.0, 7.0 Hz, 1 H, H3), 7.15–7.31 (m, 5 H, H15, H16, H17).
13C NMR (75 MHz, HSQC, CDCl3): d (selected signals) = 30.6
(C7), 47.7 (C4), 48.4 (C8), 52.6 (C11), 59.5 (C3), 70.6 (C8), 126.9
(C17).
Pyrrolidones 7a
Mp 114–119 °C; mixture of diastereomers, 7a¢/7a¢¢, 1.3:1.0.
Characteristic 2D-NOESY correlations: H3/H7¢¢, H7¢/H8.
Anal. Calcd for C12H21NO4: H, 8.70; C, 59.24; N, 5.76. Found: H,
9.04; C, 59.28; N, 5.76.
Unassigned signals for both isomers:
1H NMR (500 MHz, CDCl3): d = 1.01, 1.08, 1.19 and 1.20 (4 s, 6 H,
12-CH3, 13-CH3), 3.68 and 3.72 (2 s, 3 H, 11-CH3), 8.45 and 8.70
(2 br, 1 H, 2-NH).
13C NMR (75 MHz, CDCl3): d = 27.8, 28.0 and 31.9 (C12, C13),
48.2 and 48.7 (C5), 128.1, 128.2, 128.9 (C15, C16), 142.9 and 143.0
(C14), 170.4, 173.3 and 173.4 (C9, C10).
Methyl rel-(3S,5S)-5-[(1R)-3-Hydroxy-1,3-dimethylbutyl]-2-
oxopyrrolidine-3-carboxylate (7a¢)
1H NMR (500 MHz, COSY, NOESY, CDCl3): d (selected
signals) = 0.91 (d, J = 6.6 Hz, 3 H, 14-CH3), 1.18 and 1.22 (2 s, 6
H, 12-CH3, 13-CH3), 1.31 (m, 1 H, H5), 1.57 (dd, J = 14.5, 13.8 Hz,
1 H, H5), 1.78 (m, 1 H, H4), 2.09 (ddd, J = 12.7, 11.0, 9.1 Hz, 1 H,
H7¢), 2.32 (ddd, J = 12.7, 8.6, 6.6 Hz, 1 H, H7¢¢), 3.00 (br, 1 H, 1-
OH), 3.28 (ddd, J = 9.1, 8.6, 6.6 Hz, 1 H, H3), 3.39 (dd, J = 11.0,
8.6 Hz, 1 H, H8), 8.36 (br, 1 H, 2-NH).
Pyrrolidones 7c
Oil; mixture of diastereomers, 7c¢/7c¢¢, 1.0:1.1.
13C NMR (75 MHz, HSQC, CDCl3): d (selected signals) = 18.5
(C14), 28.1 and 31.9 (C12, C13), 30.5 (C7), 34.8 (C4), 48.5 (C5),
48.8 (C8), 52.5 (C11), 59.1 (C3), 70.3 (C6).
Anal. Calcd for C18H25NO5: H, 7.51; C, 64.46; N, 4.18. Found: H,
7.63; C, 64.33; N, 4.10.
Methyl rel-(3S,5S)-5-[(1S)-3-Hydroxy-1-(4-methoxyphenyl)-3-
methylbutyl]-2-oxopyrrolidine-3-carboxylate (7c¢)
Characteristic 2D-NOESY correlations: H3/H7¢¢, H7¢¢/H8.
1H NMR (500 MHz, COSY, NOESY, CDCl3): d (selected
signals) = 1.80 (m, 1 H, H7¢¢), 1.85–1.90 (m, 2 H, H5), 1.98 (m, 1
H, H7¢), 2.70 (br, 1 H, 1-OH), 2.82 (ddd, J = 8.8, 6.4, 6.4 Hz, 1 H,
H4), 3.33 (dd, J = 9.1, 10.1 Hz, 1 H, H8), 3.63 (ddd, J = 8.8, 8.7, 6.9
Hz, 1 H, H3), 3.75 (s, 3 H, 18-CH3).
Methyl rel-(3R,5S)-5-[(1R)-3-Hydroxy-1,3-dimethylbutyl]-2-
oxopyrrolidine-3-carboxylate (7a¢¢)
1H NMR (500 MHz, COSY, NOESY, CDCl3): d (selected
signals) = 0.86 (d, J = 7.4 Hz, 3 H, 14-CH3), 1.18 and 1.22 (2 s, 6
H, 12-CH3, 13-CH3), 1.31 (m, 1 H, H5), 1.55 (dd, J = 14.4, 13.6 Hz,
Synthesis 2009, No. 12, 1999–2008 © Thieme Stuttgart · New York

PAPER
Diastereoselective Synthesis of Substituted a-Pyrrolidone Derivatives from Nitroethane
2005
13C NMR (75 MHz, HSQC, CDCl3): d (selected signals) = 31.3
(C7), 46.9 (C4), 48.6 (C8), 52.6 (C11), 55.2 (C18), 59.1 (C3), 70.6
(C6), 114.2 (C16).
both isomers), 3.72, 3.76 and 3.77 (3 s, 6 H, 9-CH3, 15-CH3, both
isomers), 3.82 (ddd, J = 9.9, 9.5, 9.5 Hz, 1 H, H2, major isomer),
4.08 (ddd, J = 9.9, 9.5, 9.5 Hz, 1 H, H2, minor isomer), 6.86 (d,
J = 8.4 Hz, 2 H, H13, both isomers), 7.12 (d, J = 8.4 Hz, 2 H, H12,
minor isomer), 7.15 (d, J = 8.4 Hz, 2 H, H12, major isomer).
Characteristic 2D-NOESY correlations: H3/H7¢¢, H7¢¢/H8.
Methyl rel-(3R,5S)-5-[(1S)-3-Hydroxy-1-(4-methoxyphenyl)-3-
methylbutyl]-2-oxopyrrolidine-3-carboxylate (7c¢¢)
13C NMR (75 MHz, INEPT, CDCl3): d = 29.4, 29.8, 35.0 and 35.4
(C4, C6), 41.2 and 41.3 (C5), 50.2, 50.5, 52.1, 52.4, 52.5 and 53.1
(C3, C7, C9), 55.1 (C15), 65.7 and 66.6 (C2), 114.1 (C13), 128.0
and 128.1 (C12), 130.4 and 130.5 (C11), 158.7 (C14), 168.7, 169.0,
170.2 and 170.3 (C8, C10).
1H NMR (500 MHz, COSY, NOESY, CDCl3): d (selected
signals) = 1.80 (m, 1 H, H7¢), 1.85–1.90 (m, 2 H, H5), 2.04 (m, 1 H,
H7¢¢), 2.70 (br, 1 H, 1-OH), 2.73 (ddd, J = 8.9, 7.0, 4.6 Hz, 1 H, H4),
3.20 (dd, J = 9.5, 4.4 Hz, 1 H, H8), 3.75 (s, 3 H, 18-CH3), 3.85 (ddd,
J = 8.9, 7.3, 7.0 Hz, 1 H, H3).
Anal. Calcd for C16H19NO4: H, 6.62; C, 66.42; N, 4.84. Found: H,
6.88; C, 66.34; N, 4.69.
13C NMR (75 MHz, HSQC, CDCl3): d (selected signals) = 30.4
(C7), 46.8 (C4), 48.3 (C8), 52.6 (C11), 55.2 (C18), 59.5 (C3), 70.6
(C6), 114.2 (C16).
Pyrrolizidinones 8g
Oil; Rf = 0.22 (EtOAc–hexane, 1:1); mixture of diastereomers,
8g¢/8g¢¢, 1.4:1.0.
Characteristic 2D-NOESY correlations: H3/H7¢¢, H7¢/H8.
Anal. Calcd for C17H21NO4: H, 6.98; C, 67.31; N, 4.62. Found: H,
7.28; C, 66.73; N, 4.36.
Unassigned signals for both isomers:
1H NMR (500 MHz, CDCl3): d = 1.02, 1.05 and 1.15 (3 s, 6 H, 12-
CH3, 13-CH3), 3.68 and 3.71 (2 s, 3 H, 11-CH3), 6.83 (d, J = 8.8 Hz,
2 H, H16), 7.08 and 7.10 (2 d, J = 8.8 Hz, 2 H, H15), 8.29 and 8.54
(2 br, 1 H, 2-NH).
13C NMR (75 MHz, CDCl3): d = 27.9, 28.1, 31.7 and 31.8 (C12,
C13), 48.0 and 48.5 (C5), 129.0, 129.1 (C15), 134.6 and 134.9
(C14), 158.3 and 158.4 (C17), 170.4, 173.2 and 173.3 (C9, C10).
Methyl rel-(2S,5S,7S, 7aS)-7-(4-Methoxyphenyl)-5-methyl-3-
oxohexahydro-1H-pyrrolizine-2-carboxylate (8g¢)
1H NMR (500 MHz, COSY, NOESY, CDCl3): d (selected
signals) = 1.86 (ddd, J = 12.4, 12.2, 9.1 Hz, 1 H, H4¢¢), 2.28 (ddd,
J = 12.9, 10.9, 7.3 Hz, 1 H, H6¢), 2.38 (ddd, J = 12.9, 8.8, 6.9 Hz, 1
H, H6¢¢), 2.67 (ddd, J = 12.4, 6.9, 6.5 Hz, 1 H, H4¢), 2.87 (ddd,
J = 12.2, 9.8, 6.9 Hz, 1 H, H3), 3.77 (m, 1 H, H7), 3.87 (ddd, J = 9.8,
7.3, 6.9 Hz, 1 H, H2), 3.99 (m, 1 H, H5).
Methyl rel-(3S,5S)-5-{(S)-[(1R,2R)-2-Hydroxycyclohexyl](4-
methoxyphenyl)methyl}-2-oxopyrrolidine-3-carboxylate (7e¢)
and Methyl rel-(3R,5S)-5-{(S)-[(1R,2R)-2-Hydroxycyclohex-
yl](4-methoxyphenyl)methyl}-2-oxopyrrolidine-3-carboxylate
(7e¢¢)
13C NMR (75 MHz, HSQC, CDCl3): d (selected signals) = 21.1
(C11), 29.6 (C6), 44.5 (C4), 50.3 (C5), 51.0 (C3), 52.8 (C7), 55.3
(C16), 66.0 (C2), 114.2 (C14), 128.1 (C13), 158.7 (C15).
Characteristic 2D-NOESY correlations: H2/H6¢¢, H6¢¢/H7, H6¢/H3,
H3/H4¢, H4¢/H5, H4¢¢/11-CH3.
Mp 193–198 °C; mixture of isomers, 1.3:1.0.
1H NMR (300 MHz, CDCl3): d = 0.98–1.34, 1.44–1.65, 1.73–1.83,
1.90–1.99 (4 m, 11 H, H7, H12, H13, H14, H15, H5, both isomers),
2.50 (m, 1 H, H4, both isomers), 3.05–3.12 (m, 2 H, H8, minor iso-
mer and 1-OH, major isomer), 3.31 (dd, J = 11.0, 8.8 Hz, 1 H, H8,
major isomer), 3.47 (br, 1 H, 1-OH, minor isomer), 3.69 and 3.70 (2
s, 3 H, 11-CH3, both isomers), 3.78 (s, 3 H, 20-CH3, both isomers),
3.86 (ddd, J = 9.2, 8.4, 6.6 Hz, 1 H, H3, major isomer), 4.19 (m, 2
H, H6, both isomers and H3, minor isomer), 6.83 (d, J = 7.9 Hz, 2
H, H18, both isomers), 7.02 (d, J = 7.9 Hz, 2 H, H17, both isomers),
7.72 (br, 1 H, 2-NH, minor isomer), 7.95 (br, 1 H, 2-NH, major iso-
mer).
13C NMR (75 MHz, INEPT, CDCl3): d = 19.7, 25.3, 25.9, 31.8,
33.0, 33.6 (C7, C12, C13, C14, C15), 46.9, 47.8, 48.1, 48.3 (C4,
C8), 52.4, 52.5, 53.0, 53.2 (C5, C11), 55.2 (C20), 55.4 and 55.7
(C3), 66.6 and 66.8 (C6), 113.8 (C18), 129.4 and 129.6 (C17), 132.9
and 133.3 (C16), 158.3 (C19), 170.4, 170.5, 172.5 and 172.8 (C9,
C10).
Methyl rel-(2R,5S,7S,7aS)-7-(4-Methoxyphenyl)-5-methyl-3-
oxohexahydro-1H-pyrrolizine-2-carboxylate (8g¢¢)
1H NMR (500 MHz, COSY, NOESY, CDCl3): d (selected
signals) = 1.86 (m, 1 H, H4¢¢), 2.01 (ddd, J = 13.1, 9.5, 7.3 Hz, 1 H,
H6¢), 2.53 (ddd, J = 13.1, 6.9, 1.7 Hz, 1 H, H6¢¢), 2.67 (ddd,
J = 12.4, 6.9, 6.5 Hz, 1 H, H4¢), 2.72 (ddd, J = 9.9, 7.3, 6.9 Hz, 1 H,
H3), 3.55 (dd, J = 9.5, 1.7 Hz, 1 H, H7), 3.99 (m, 1 H, H5), 4.15
(ddd, J = 9.9, 7.3, 6.9 Hz, 1 H, H2).
13C NMR (75 MHz, HSQC, CDCl3): d (selected signals) = 21.0
(C11), 29.8 (C6), 44.9 (C4), 50.3 (C5), 51.3 (C3), 53.2 (C7), 55.3
(C16), 65.1 (C2), 114.2 (C14), 128.1 (C13), 158.7 (C15).
Characteristic 2D-NOESY correlations: H2/H6¢¢, H6¢/H7, H3/H4¢,
H4¢/H5, H4¢¢/11-CH3.
Unassigned signals for both isomers:
1H NMR (500 MHz, CDCl3): d = 1.34 and 1.36 (2 d, J = 6.6 Hz,
J = 6.0 Hz, 3 H, 11-CH3), 3.77 and 3.80 (2 s, 6 H, 9-CH3, 16-CH3),
6.88 (d, J = 9.2 Hz, 2 H, H14), 7.14 and 7.16 (2 d, J = 9.2 Hz,
J = 8.5 Hz, 2 H, H13).
Anal. Calcd for C20H27NO5: H, 7.53; C, 66.46; N, 3.88. Found: H,
7.53; C, 66.49; N, 3.91.
Methyl rel-(2S,7R,7aR)-7-(4-Methoxyphenyl)-3-oxohexahydro-
1H-pyrrolizine-2-carboxylate (8f¢) and Methyl rel-(2R,7R,7aR)-
7-(4-Methoxyphenyl)-3-oxohexahydro-1H-pyrrolizine-2-car-
boxylate (8f¢¢)
Mp 63–66 °C; Rf = 0.11 (EtOAc–hexane = 1:1); mixture of isomers,
1.2:1.0.
1H NMR (300 MHz, CDCl3): d = 2.04 (ddd, J = 13.2, 9.5, 7.3 Hz, 1
H, H6, major isomer), 2.17–2.31, 2.34–2.42 and 2.44–2.58 (3 m, 4
H, H4, H6, both isomers), 2.69 (ddd, J = 11.4, 9.5, 7.3 Hz, 1 H, H3,
minor isomer), 2.84 (ddd, J = 11.4, 9.5, 7.0 Hz, 1 H, H3, major iso-
mer), 3.32 (m, 1 H, H5, both isomers), 3.53–3.68 (m, 2 H, H8, H5,
13C NMR (75 MHz, CDCl3): d = 52.2 and 52.6 (C9), 130.4 and
130.5 (C12), 168.9, 169.1, 170.4 and 170.5 (C8, C10).
Decarboxylation of Products 7 and 8; General Procedure
H2O (0.018 mL, 1.0 mmol) was added to a soln of 7 or 8 (0.5 mmol)
and NaBr (0.052 g, 0.5 mmol) in DMSO (7.0 mL) and the mixture
was gently refluxed for 25 min (for 7) or 45 min (for 8). Then the
solvent was evaporated in vacuo (100 °C/0.67 mbar) and the residue
was subjected to column chromatography (silica gel, EtOAc–hex-
ane, 1:3 to 1:1 to 1:0 to EtOAc–MeOH, 10:1 to 5:1). Yields of prod-
ucts are presented in Table 1.
Synthesis 2009, No. 12, 1999–2008 © Thieme Stuttgart · New York

2006
A. Yu. Sukhorukov et al.
PAPER
rel-(5S)-5-[(1R)-3-Hydroxy-1,3-dimethylbutyl]pyrrolidin-2-one
(2a)
rel-(7S,7aS)-7-(4-Methoxyphenyl)hexahydro-3H-pyrrolizin-3-
one (3f)
Mp 59–63 °C; Rf = 0.51 (EtOAc–MeOH, 3:1).
Mp 79–81 °C; Rf = 0.65 (EtOAc–MeOH, 3:1).
1H NMR (300 MHz, COSY, HSQC, CDCl3): d = 0.90 (d, J = 6.6
Hz, 3 H, 12-CH3), 1.18 and 1.23 (2 s, 6 H, 10-CH3, 11-CH3), 1.33
(dd, J = 14.9, 5.1 Hz, 1 H, H5), 1.58 (dd, J = 14.9, 4.8 Hz, 1 H, H5),
1.69 (m, 2 H, H4, H7), 2.10 (m, 1 H, H7), 2.28 (m, 2 H, H8), 3.36
(ddd, J = 8.1, 7.7, 7.3 Hz, 1 H, H3), 3.44 (br, 1 H, 1-OH), 8.11 (br,
1 H, 2-NH).
13C NMR (75 MHz, INEPT, HSQC, CDCl3): d = 18.3 (C12), 26.0
(C7), 31.3 (C8), 28.1 and 31.7 (C10, C11), 34.8 (C4), 48.6 (C5),
61.1 (C3), 70.1 (C6), 178.5 (C9).
1H NMR (300 MHz, COSY, NOESY, HSQC, CDCl3): d = 1.83
(dddd, J = 12.8, 10.3, 9.5, 7.0 Hz, 1 H, H6), 2.15–2.19 (m, 2 H, H4¢¢,
H6), 2.42–2.53 (m, 2 H, H4¢, H7), 2.64–2.79 (m, 2 H, H3, H7), 3.31
(dd, J = 11.2, 10.3 Hz, 1 H, H5¢¢), 3.61 (ddd, J = 11.2, 10.3, 8.1 Hz,
1 H, H5¢), 3.78 (s, 3 H, 13-CH3), 3.89 (ddd, J = 9.9, 7.3, 7.0 Hz, 1
H, H2), 6.86 (d, J = 8.6 Hz, 2 H, H11), 7.13 (d, J = 8.6 Hz, 2 H,
H10).
13C NMR (75 MHz, INEPT, HSQC, CDCl3): d = 25.5 (C6), 34.8
(C7), 35.4 (C4) 40.9 (C5), 50.6 (C3), 55.2 (C13), 67.8 (C2), 114.1
(C11), 128.1 (C10), 131.0 (C9), 158.6 (C12), 174.7 (C8).
Anal. Calcd for C10H19NO2: H, 10.34; C, 64.83; N, 7.56. Found: H,
10.41; C, 64.67; N, 7.75.
Characteristic 2D-NOESY correlations: H2/H10, H4¢¢/H10,
H4¢¢/H5¢¢, H4¢/H5¢C.
rel-(5S)-5-[(1S)-3-Hydroxy-3-methyl-1-phenylbutyl]pyrrolidin-
2-one (2b)
Mp 118–121 °C; Rf = 0.64 (EtOAc–MeOH, 3:1).
Anal. Calcd for C14H17NO2: H, 7.41; C, 72.70; N, 6.06. Found: H,
7.62; C, 72.05; N, 6.05.
1H NMR (300 MHz, COSY, HSQC, CDCl3): d = 1.08 and 1.21 (2
s, 6 H, 10-CH3, 11-CH3), 1.51–1.70 (m, 2 H, H7), 1.96 (dd, J = 14.7,
6.6 Hz, 1 H, H5), 2.06 (dd, J = 14.7, 4.4 Hz, 1 H, H5), 2.16–2.24 (m,
2 H, H8), 2.83 (ddd, J = 9.6, 6.6, 4.4 Hz, 1 H, H4), 3.35 (br, 1 H, 1-
OH), 3.77 (ddd, J = 9.6, 7.3, 7.3 Hz, 1 H, H3), 7.16–7.32 (m, 5 H,
H13, H14, H15), 8.33 (br, 1 H, 2-NH).
13C NMR (75 MHz, INEPT, CDCl3): d = 26.8 (C7), 30.9 (C8), 27.9
and 31.9 (C10, C11), 47.8 (C4), 48.3 (C5), 60.9 (C3), 70.4 (C6),
126.6, 128.1 and 128.6 (C13, C14, C15), 143.4 (C12), 178.9 (C9).
rel-(5S,7S,7aS)-7-(4-Methoxyphenyl)-5-methylhexahydro-3H-
pyrrolizin-3-one (3g)
Oil; Rf = 0.64 (EtOAc–MeOH, 3:1).
1H NMR (300 MHz, COSY, NOESY, CDCl3): d = 1.34 (d, J = 5.9
Hz, 3 H, 9-CH3), 1.75–1.90 (m, 2 H, H6, H4¢¢), 2.15–2.25 (dddd,
J = 13.2, 9.5, 6.6, 2.2 Hz, 1 H, H6), 2.45 (ddd, J = 16.1, 9.5, 2.2 Hz,
1 H, H7), 2.63–2.78 (m, 3 H, H3, H4¢, H7), 3.79 (s, 3 H, 14-CH3),
3.97 (ddd, J = 9.5, 7.3, 7.3 Hz, 1 H, H2), 4.01 (m, 1 H, H5), 6.86 (d,
J = 8.2 Hz, 2 H, H12), 7.14 (d, J = 8.2 Hz, 2 H, H11).
Anal. Calcd for C15H21NO2: H, 8.56; C, 72.84; N, 5.66. Found: H,
8.56; C, 72.74; N, 5.33.
13C NMR (75 MHz, INEPT, CDCl3): d = 21.3 (C9), 25.4 (C6), 34.8
(C7), 44.7 (C4), 49.7 and 51.3 (C3, C5), 55.3 (C14), 67.0 (C2),
114.1 (C12), 128.1 (C11), 131.0 (C10), 158.6 (C13), 174.8 (C8).
rel-(5S)-5-[(1S)-3-Hydroxy-1-(4-methoxyphenyl)-3-methylbu-
tyl]pyrrolidin-2-one (2c)
Mp 128–132 °C; Rf = 0.61 (EtOAc–MeOH, 3:1).
Characteristic 2D-NOESY correlations: H11/H2, H11/H4¢¢,
H4¢¢/9-CH3.
Anal. Calcd for C15H19NO2: H, 7.81; C, 73.44; N, 5.71. Found: H,
7.62; C, 73.14; N, 5.43.
1H NMR (300 MHz, CDCl3): d = 1.03 and 1.15 (2 s, 6 H, 10-CH3,
11-CH3), 1.48–1.68 (m, 2 H, H7), 1.88 (dd, J = 14.7, 7.0 Hz, 1 H,
H5), 1.97 (dd, J = 14.7, 4.0 Hz, 1 H, H5), 2.10–2.22 (m, 2 H, H8),
2.74 (ddd, J = 9.2, 7.0, 4.0 Hz, 1 H, H4), 3.29 (br, 1 H, 1-OH), 3.67
(ddd, J = 9.2, 7.3, 7.0 Hz, 1 H, H3), 3.74 (s, 3 H, 16-CH3), 6.80 (d,
J = 8.4 Hz, 2 H, H14), 7.06 (d, J = 8.4 Hz, 2 H, H13), 8.16 (br, 1 H,
2-NH).
13C NMR (75 MHz, INEPT, CDCl3): d = 26.5 (C7), 30.8 (C8), 27.9
and 31.7 (C10, C11), 46.8 (C4), 48.0 (C5), 55.1 (C16), 60.8 (C3),
70.3 (C6), 113.9 (C14), 128.9 (C13), 135.1 (C12), 158.1 (C15),
178.8 (C9).
Cyclopentyl 2-Methoxy-5-[(E)-2-nitroprop-1-enyl]phenyl
Ether (10)
To a soln of aldehyde 9h18 (5.5 g, 25.0 mmol) in nitroethane (50
mL) was added NH4OAc (1.9 g, 25.0 mmol) and AcOH (22.5 mL).
The mixture was heated at 90 °C with vigorous stirring for 7 h, then
cooled to r.t. and poured into a mixture of H2O (25 mL) and EtOAc
(50 mL). The aqueous phase was back-extracted with EtOAc (3 ꢀ
50 mL); the combined organic layers were washed with H2O (25
mL) and brine (50 mL) and dried (Na2SO4). The solvent was evap-
orated in vacuo and the crude product was recrystallized (MeOH) to
give 10 (6.23 g, 90%) as yellow crystals; mp 69–73 °C.
Anal. Calcd for C16H23NO3: H, 8.36; C, 69.29; N, 5.05. Found: H,
8.45; C, 69.15; N, 5.05.
1H NMR (300 MHz, CDCl3): d = 1.56–1.69 and 1.76–1.98 (2 m, 2
H, 6 H, H12, H13), 2.46 (s, 3 H, 1-CH3), 3.87 (s, 3 H, 10-CH3), 4.76
(m, 1 H, H11), 6.91 (d, J = 8.3 Hz, 1 H, H8), 6.95 (s, 1 H, H5), 7.04
(d, J = 8.3 Hz, 1 H, H9), 8.02 (s, 1 H, H3).
rel-(5S)-5-{(S)-[(1R,2R)-2-Hydroxycyclohexyl](4-methoxyphe-
nyl)methyl}pyrrolidin-2-one (2e)
Mp 213–218 °C; Rf = 0.61 (EtOAc–MeOH, 3:1).
1H NMR (300 MHz, COSY, HSQC, CDCl3): d = 1.10–1.18 (m, 1
H, H12), 1.25–1.36 (m, 2 H, H7, H12), 1.46 (m, 1 H, H11), 1.54–
1.69 (m, 6 H, H5, H7, H10, H11, H13), 1.92–2.00 (m, 1 H, H10),
2.03–2.10 (m, 1 H, H8), 2.12–2.24 (m, 1 H, H8), 2.49 (dd, J = 9.2,
9.0 Hz, 1 H, H4), 3.78 (s, 3 H, 18-CH3), 3.95 (ddd, J = 9.0, 7.0, 5.9
Hz, 1 H, H3), 3.99 (br, 1 H, 1-OH), 4.19 (s, 1 H, H6), 6.82 (d, J = 8.2
Hz, 2 H, H16), 7.00 (d, J = 8.2 Hz, 2 H, H15), 7.73 (br, 1 H, 2-NH).
13C NMR (75 MHz, INEPT, HSQC, CDCl3): d = 19.8 (C11), 25.3
(C12), 26.0 (C13), 28.4 (C7), 30.8 (C8), 33.6 (C10), 47.5 (C5), 53.4
(C4), 55.1 (C18), 57.3 (C3), 66.0 (C6), 113.7 (C16), 129.5 (C15),
133.7 (C14), 158.2 (C17), 178.4 (C9).
13C NMR (75 MHz, INEPT, CDCl3): d = 14.0 (C1), 24.0 and 32.7
(C12, C13), 55.9 (C10), 80.5 (C11), 111.6 (C8), 116.3 (C5), 123.9
(C9), 124.7 (C4), 133.9 (C3), 145.5, 147.6 and 151.7 (C2, C6, C7).
Anal. Calcd for C15H19NO4: H, 6.91; C, 64.97; N, 5.05. Found H,
6.82; C, 64.93; N, 5.14.
rel-(4S,6S)-4-[3-(Cyclopentyloxy)-4-methoxyphenyl]-6-ethoxy-
3-methyl-5,6-dihydro-4H-1,2-oxazin-2-ium-2-olate (11)
To a soln of nitroalkene 10 (1.5 g, 5.4 mmol) in CH2Cl2 (50 mL) at
–94 °C was added SnCl4 (0.63 mL, 5.4 mmol) under a dry argon at-
mosphere followed by ethyl vinyl ether (1.0 mL, 10.8 mmol). After
10 min at –94 °C an additional portion of ethyl vinyl ether (0.5 mL,
5.4 mmol) was added and the resulting mixture was poured into a
Anal. Calcd for C18H25NO3: H, 8.31; C, 71.26; N, 4.62. Found: H,
8.14; C, 71.12; N, 4.68.
Synthesis 2009, No. 12, 1999–2008 © Thieme Stuttgart · New York

PAPER
Diastereoselective Synthesis of Substituted a-Pyrrolidone Derivatives from Nitroethane
2007
mixture of sat. aq K2CO3 (200 mL) and EtOAc (200 mL). The aque-
ous phase was back-extracted with EtOAc (2 ꢀ 50 mL); the com-
bined organic layers were washed with H2O (50 mL) and brine (50
mL) and dried (Na2SO4). The solvent was evaporated in vacuo and
the residue was subjected to column chromatography (silica gel,
EtOAc–hexane, 1:5 to 1:3 to 1:1) to give nitronate 11 (1.6 g, 85%)
as a white solid. The minor fraction (0.19 g, Rf = 0.15, EtOAc–hex-
ane, 1:1) contained a mixture of 11 and the corresponding 4,6-cis-
isomer (~1.7:1.0).
3.91 (dd, J = 7.7, 7.7 Hz, 1 H, H8), 4.77 (m, 1 H, H22), 5.10 (dd,
J = 2.6, 2.2 Hz, 1 H, H6), 6.68 (d, J = 1.8 Hz, 1 H, H16), 6.73 (dd,
J = 8.3, 1.8 Hz, 1 H, H20), 6.83 (d, J = 8.3 Hz, 1 H, H19).
13C NMR (75 MHz, INEPT, CDCl3): d = 15.0 (C14), 24.0, 32.6,
32.7 and 33.5 (C5, C7, C23, C24), 36.6 (C4), 47.9 (C8), 52.5 (C10,
C12), 56.0 (C21), 63.5 (C13), 80.4 (C22), 95.5 (C6), 112.4, 114.8
and 120.6 (C16, C19, C20), 131.9 (C15), 148.1 and 149.3 (C17,
C18), 157.8 (C3), 169.3 and 169.4 (C9, C11).
Anal. Calcd for C24H33NO8: H, 7.18; C, 62.19; N, 3.02. Found: H,
7.16; C, 62.40; N, 3.07.
Mp 90–92 °C; Rf = 0.23 (EtOAc–hexane, 1:1).
1H NMR (300 MHz, CDCl3): d = 1.20 (t, J = 7.0 Hz, 3 H, 9-CH3),
1.49–1.61 and 1.71–1.87 (2 m, 8 H, H18, H19), 1.79 (s, 3 H, 7-
CH3), 2.02 (ddd, J = 14.1, 11.0, 2.6 Hz, 1 H, H5), 2.18 (ddd,
J = 14.1, 7.3, 2.2 Hz, 1 H, H5), 3.60–3.72 (m, 2 H, H4, H8), 3.75 (s,
3 H, 16-CH3), 3.99 (m, 1 H, H8), 4.68 (m, 1 H, H17), 5.29 (dd,
J = 2.9, 2.2 Hz, 1 H, H6), 6.58 (d, J = 2.2 Hz, 1 H, H11), 6.65 (dd,
J = 8.3, 2.2 Hz, 1 H, H15), 6.75 (d, J = 8.3 Hz, 1 H, H14).
Dimethyl rel-2-{[(3S,4S,6S)-4-[3-(Cyclopentyloxy)-4-methoxy-
phenyl]-6-ethoxytetrahydro-2H-1,2-oxazin-3-yl]methyl}mal-
onate (5h)
Tetrahydrooxazine 5h was prepared in 99% yield according to the
same procedure used for the reduction of dihydrooxazines 1f,g;2 mp
99–102 °C; Rf = 0.47 (EtOAc–hexane, 1:1).
13C NMR (75 MHz, INEPT, CDCl3): d = 14.8 (C9), 17.3 (C7), 23.8,
32.5 and 34.1 (C5, C18, C19), 39.9 (C4), 55.8 (C16), 64.7 (C8),
80.2 (C17), 100.8 (C6), 112.1, 114.1 and 120.1 (C11, C14, C15),
123.3 (C3), 132.0 (C10), 147.9 and 149.4 (C12, C13).
1H NMR (300 MHz, CDCl3): d = 1.28 (t, J = 7.3, 7.0 Hz, 3 H, 14-
CH3), 1.52–1.66 and 1.76–2.01 (2 m, 12 H, H5, H7, H23, H24), 2.66
(ddd, J = 11.0, 10.6, 5.5 Hz, 1 H, H4), 3.20 (ddd, J = 11.0, 10.6, 2.2
Hz, 1 H, H3), 3.54 (m, 1 H, H13), 3.64 and 3.67 (s and m, s, 7 H,
H8, 10-CH3, 12-CH3), 3.79 (m, 1 H, H13), 3.80 (s, 3 H, 21-CH3),
4.76 (m, 1 H, H22), 4.84 (s, 1 H, H6), 5.26 (br, 1 H, 2-NH), 6.67 (s,
1 H, H16), 6.69 (d, J = 8.8 Hz, 1 H, H20), 6.80 (d, J = 8.8 Hz, 1 H,
H20).
13C NMR (75 MHz, INEPT, CDCl3): d = 15.1 (C14), 23.9, 29.7,
32.7, and 37.1 (C5, C7, C23, C24), 41.9 (C4), 48.4 (C8), 52.3 and
52.5 (C10, C12), 56.0 (C21), 60.1 (C3), 63.5 (C13), 80.3 (C22),
98.0 (C6), 112.1, 114.3 and 119.3 (C16, C19, C20), 134.1 (C15),
147.6 and 148.8 (C17, C18), 169.4 and 170.2 (C9, C11).
Anal. Calcd for C19H27NO5: H, 7.79; C, 65.31; N, 4.01. Found: H,
7.79; C, 65.21; N, 4.06.
rel-(4S,6S)-3-(Bromomethyl)-4-[3-(cyclopentyloxy)-4-methoxy-
phenyl]-6-ethoxy-5,6-dihydro-4H-1,2-oxazine (12)
To a soln of nitronate 11 (0.345 g, 0.989 mmol) and Et3N (0.21 mL,
1.48 mmol) in CH2Cl2–MeCN (10:1, 2.0 mL) was added Me3SiBr
(0.65 mL, 4.94 mmol) at –78 °C under a dry argon atmosphere. The
mixture was kept with occasional shaking at –78 °C for 24 h, then
poured into a mixture of sat. aq K2CO3 (100 mL) and EtOAc (100
mL). The aqueous phase was back-extracted with EtOAc (1 ꢀ 80
mL); the combined organic layers were washed with H2O (50 mL)
and brine (50 mL) and dried (Na2SO4). The solvent was evaporated
in vacuo and the residue was subjected to column chromatography
(silica gel, EtOAc–hexane, 1:10 to 1:5) to give 12 (0.22 g, 54%).
Further elution (EtOAc–hexane, 1:1) provided unreacted nitronate
11 (0.11 g, 34%).
Anal. Calcd for C24H35NO8: H, 7.58; C, 61.92; N, 3.01. Found: H,
7.68; C, 62.02; N, 3.21.
rel-(7S,7aS)-7-[3-(Cyclopentyloxy)-4-methoxyphenyl]hexa-
hydro-3H-pyrrolizin-3-one (rac-4)
Reduction of 5h (0.205 g, 0.44 mmol) was accomplished by the pro-
cedure for hydrogenation of oxazines 5a–g listed above. 1H NMR
analysis of the crude product obtained after filtration of the mixture
and evaporation showed the presence of pyrrolizidinone 8h (ratio of
isomers 1.2:1.0) and pyrrolidine 13, ca. 1.9:1.0, respectively. This
mixture was dissolved in DMSO (6.2 mL) and the soln was heated
at 100–140 °C for 30 min. Then it was cooled and NaBr (0.045 g,
0.44 mmol) and H2O (0.016 mL, 0.88 mmol) were added. The mix-
ture was gently refluxed for 45 min. The solvent was evaporated in
vacuo (100 °C/0.67 mbar) and the residue was subjected to column
chromatography (silica gel, EtOAc–hexane, 1:3 to 1:1 to 1:0 to
EtOAc–MeOH, 10:1) to give pyrrolizidinone 4 (0.098 g, 71%); mp
65–66 °C (Lit.11 64–66 °C); Rf = 0.71 (EtOAc–MeOH, 1:3). The 1H
NMR spectrum is consistent with that previously reported for pyr-
rolizidinone rac-4.11
1H NMR (300 MHz, COSY, NOESY, HSQC, CDCl3): d = 1.54–
1.65 and 1.76–1.95 (2 m, 2 H, 7 H, H6, H17, H18), 2.15–2.30 (m, 2
H, H4¢¢, H6), 2.43–2.53 (m, 2 H, H4¢, H7), 2.63–2.79 (m, 2 H, H3,
H7), 3.31 (dd, J = 11.0, 10.3 Hz, 1 H, H5¢¢), 3.61 (ddd, J = 11.0, 9.2,
8.8 Hz, 1 H, H5¢), 3.81 (s, 3 H, 13-CH3), 3.89 (ddd, J = 9.5, 7.3, 7.0
Hz, 1 H, H2), 4.75 (m, 1 H, H16), 6.72 (s, 1 H, H10), 6.73 (d, J = 8.1
Hz, 1 H, H14), 6.82 (d, J = 8.1 Hz, 1 H, H13).
Mp 60–62 °C; Rf = 0.70 (EtOAc–hexane, 1:1).
1H NMR (300 MHz, CDCl3): d = 1.25 (t, J = 7.0 Hz, 3 H, 9-CH3),
1.58–1.69 and 1.79–1.96 (2 m, 8 H, H18, H19), 2.11 (ddd, J = 13.2,
10.6, 2.6 Hz, 1 H, H5), 2.25 (ddd, J = 13.2, 8.1, 2.4 Hz, 1 H, H5),
3.63 (m, 1 H, H8), 3.64 (d, J = 9.9 Hz, 1 H, H7), 3.83 (s, 3 H, 16-
CH3), 3.86–4.00 (m, 2 H, H4, H8), 3.91 (d, J = 9.9 Hz, 1 H, H7),
4.75 (m, 1 H, H17), 5.18 (dd, J = 2.6, 2.2 Hz, 1 H, H6), 6.74 (s, 1 H,
H11), 6.76 (d, J = 8.1 Hz, 1 H, H15), 6.83 (d, J = 8.1 Hz, 1 H, H14).
13C NMR (75 MHz, INEPT, CDCl3): d = 15.0 (C9), 24.0, 30.9, 32.5
and 32.7 (C5, C7, C18, C19), 33.4 (C4), 56.0 (C16), 63.6 (C8), 80.3
(C17), 96.1 (C6), 112.4, 115.0 and 120.4 (C11, C14, C15), 130.8
(C10), 148.0 and 149.4 (C12, C13), 158.3 (C3).
Anal. Calcd for C19H26BrNO4: H, 6.36; C, 55.35; N, 3.40. Found: H,
6.50; C, 55.36; N, 3.54.
Dimethyl rel-2-{[(4S,6S)-4-[3-(Cyclopentyloxy)-4-methoxyphe-
nyl]-6-ethoxy-5,6-dihydro-4H-1,2-oxazin-3-yl]methyl}mal-
onate (1h)
Dihydrooxazine 1h was prepared from bromide 12 in 80% yield by
general procedure described in ref. 1a.
1H NMR (300 MHz, CDCl3): d = 1.22 (t, J = 7.3, 7.0 Hz, 3 H, 14-
CH3), 1.55–1.64 and 1.79–1.94 (2 m, 8 H, H23, H24), 2.03 (ddd,
J = 13.6, 9.9, 2.2 Hz, 1 H, H5), 2.20 (ddd, J = 13.6, 7.3, 2.6 Hz, 1
H, H5), 2.53 (dd, J = 16.9, 7.7 Hz, 1 H, H7), 2.63 (dd, J = 16.9, 7.7
Hz, 1 H, H7), 3.47 and 3.59 (2 m, 2 H, H13), 3.69 (s, 6 H, 10-CH3,
12-CH3), 3.79 (dd, J = 9.9, 7.3 Hz, 1 H, H4), 3.83 (s, 3 H, 21-CH3),
13C NMR (75 MHz, INEPT, HSQC, CDCl3): d = 23.9 (C18), 25.5
(C6), 32.7 (C17), 34.7 (C7), 35.2 (C4), 40.9 (C5), 50.8 (C3), 56.0
(C15), 67.7 (C2), 80.5 (C16), 112.1, 114.3 and 119.1 (C10, C13,
C14), 131.5 (C9), 147.7 and 149.1 (C11, C12), 174.7 (C8).
Characteristic 2D-NOESY correlations: H10/H2, H10/H4¢¢,
H4¢¢/H5¢¢, H4¢/H5¢.
Synthesis 2009, No. 12, 1999–2008 © Thieme Stuttgart · New York

2008
A. Yu. Sukhorukov et al.
PAPER
(11) Brackeen, M. F.; Cowan, D. J.; Stafford, J. A.; Schoenen, F.
J.; Veal, J. M.; Domanico, P. L.; Rose, D.; Strickland, A. B.;
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(12) See, for example: Tsoungas, P. G. Heterocycles 2002, 57,
915; and references cited therein.
(13) Products of this cyclization, hexahydropyrrolizidinones 6,
could not be reduced to the corresponding pyrrolidones 7 at
stage 2.2
Acknowledgment
This study was supported by Russian Foundation for Basic
Research (project no. 06-03-32607). The authors also thank the
Public Charity Foundation for the Support of National Science for
a Ph.D. studentship.
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Synthesis 2009, No. 12, 1999–2008 © Thieme Stuttgart · New York