Intermolecular one-pot cyclization of formyl-pyrroles of amino acid esters with norephedrine: stereoselective routes to new tricyclic pyrrole-pyrazine-oxazole fused structures

Article abstract of DOI:10.1016/j.tetasy.2006.09.020

The treatment of esters of amino acids with dimethoxytetrahydrofuran furnished pyrrole derivatives of amino acid esters. The Wilsmeier-Haack formylation followed by the reaction of the formylated pyrroles with norephedrine afforded a selective formation of the tricyclic pyrrole-pyrazine-oxazole fused structures in one step via the formation of an oxazoline structure and intramolecular lactam formation. Pyrrole-pyrazine-oxazole fused structures were achieved in good yields. The cyclization reaction for the formation of an oxazole ring worked selectively to form only one stereoisomer. The configuration of the newly generated stereogenic center in the oxazole ring is dependent on the stereogenic centers of norephedrine.

Full text of DOI:10.1016/j.tetasy.2006.09.020

Tetrahedron: Asymmetry 17 (2006) 2625–2631
Intermolecular one-pot cyclization of formyl-pyrroles of amino
acid esters with norephedrine: stereoselective routes to new
tricyclic pyrrole–pyrazine–oxazole fused structures
Ayhan S. Demir,a,* N. Tuna Subasia and Ertan Sahinb,
aDepartment of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
bDepartment of Chemistry, Faculty of Arts and Sciences, Atatu¨rk University, 25240 Erzurum, Turkey
Received 18 July 2006; accepted 21 September 2006
Abstract—The treatment of esters of amino acids with dimethoxytetrahydrofuran furnished pyrrole derivatives of amino acid esters. The
Wilsmeier–Haack formylation followed by the reaction of the formylated pyrroles with norephedrine afforded a selective formation of
the tricyclic pyrrole–pyrazine–oxazole fused structures in one step via the formation of an oxazoline structure and intramolecular lactam
formation. Pyrrole–pyrazine–oxazole fused structures were achieved in good yields. The cyclization reaction for the formation of an oxa-
zole ring worked selectively to form only one stereoisomer. The configuration of the newly generated stereogenic center in the oxazole
ring is dependent on the stereogenic centers of norephedrine.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
derivative of alanine 3a according to published proce-
dures.4 This homochiral pyrrole formation process was
carried out without racemization. Several procedures are
described in the literature for the formylation of a pyrrole
ring. The Wilsmeier–Hack formylation of the pyrrole was
carried out by using the procedure, given in the experimen-
tal, to obtain the highest yield for the desired isomer of the
product.5 2-Formylpyrrole 4a was obtained in a 77% yield
together with 3-formyl derivative 5a and undefined
products.
Nitrogen-containing heterocycles have always constituted a
subject of great interest due to their wide presence in
biologically important compounds.1 As part of ongoing
research directed toward the development of pyrrole-based
heterocyclic compounds, we have already reported efficient
methods for the construction and functionalization of
pyrrole ring systems.2 In an effort to expand upon access
to new heteropolycycles, we studied the reaction of pyrrole
derivatives with norephedrine toward inter- and intramo-
lecular cyclizations in order to obtain interesting hetero-
polycyclic compounds with oxazole–pyrrole–pyrazine
structures. These polycyclic structures are present in natu-
ral products, especially in alkaloids.3 Particular interest has
come from the selective aspect of the process during intra-
and intermolecular cyclizations.
2-Formylpyrrole 4a was refluxed with (ꢀ)-norephedrine
(ꢀ)-6 to form the corresponding amine via the reduction
of the intermediate imine to synthesize the norephedrine-
based chiral ligands with multiple stereogenic centers.
However, by refluxing norephedrine with 2-formyl pyrrole,
the tricyclic fused structure 8 was obtained. Spectral anal-
ysis of the product showed that any imine formation failed
and the product was identified as a tricyclic pyrrole–pyra-
zine–oxazole fused structure as shown in Scheme 1. This
reaction was repeated several times with the enantiomers
of alanine and (ꢀ)- and (+)-norephedrine with stereoiso-
meric products 7 and 8 obtained in comparable yields
(72–75%).
2. Results and discussion
In an initial reaction, alanine methyl ester 2a was reacted
with dimethoxytetrahydrofuran 1 to form the pyrrole
*
Corresponding author. Tel.: +90 312 2103242; fax: +90 312 2103200;
e-mail: asdemir@metu.edu.tr
As shown in Table 1, the reaction was carried out with the
representative esters of amino acids and enantiomers of
To whom correspondence should be addressed concerning the X-ray
structure.
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.09.020

2626
A. S. Demir et al. / Tetrahedron: Asymmetry 17 (2006) 2625–2631
O
N
+
H2N
*
OCH3
OCH3
H3CO
OCH3
O
R
*
R
O
3
1
2a R: Me
b
c
d
i
-Pr
Ph
Bn
POCl3/DMF
OH
O
10
*
*
1
9
8
10a
10b
O
O
2
NH2
N
*
N
6
N
*
7
3
N
OCH3
5
OCH3
O
*
6
4
R
R
*
5
*
4
R
7-14
O
O
Scheme 1.
norephedrine and the corresponding tricyclic pyrrole–
pyrazine–oxazole fused structures were obtained in 71–
77% yields.
of the ˜C@N– planar group. As a result, during the forma-
tion of the oxazoline ring, the bulky phenyl and pyrrole can
be arranged in the trans position, to avoid steric interac-
tions as shown in Scheme 2.
The configuration of the new stereogenic center was
assigned on the basis of the NMR spectroscopic data.
The NOE and NOESY showed that in all four isomers 7
and 8, the (C-10b)–H lies on the same side as the CH3
and the phenyl groups of norephedrine, any positive
NOE being not registered between (C-10b)–H and (C-2)–
H nor (C-3)–H. The structural determination experiments
were carried out with other amino acid derived products
with the stereochemical results in agreement with what
was found for alanine derived products. The assignment
of the stereochemistry of the newly formed center was also
assigned from the X-ray crystallographic data from
(R,S,S,R)-12, as shown in Figure 1. It seems that the ste-
reocenters of norephedrine are responsible for the stereo-
chemical outcome of the products at the newly formed
center, but not the stereocenter of the amino acid moiety.6
3. Conclusion
The synthesis of the pyrrole derivative of amino acid esters
followed by Vilsmeier–Haack formylation furnished C-2
formylated pyrrole derivatives of amino acid esters as the
major products. The C-2 formylated pyrroles are refluxed
with norephedrine and the products identified as tricyclic
pyrrole–pyrazine–oxazole fused structures in high yields.
According to the NMR and X-ray experiment, the oxazole
ring formation step proceeded selectively to give only one
stereoisomer. The configuration of the newly generated ste-
reogenic center in the oxazole ring depends on the chirality
centers of norephedrine.
The configuration of the tricyclic structure (R,S,S,R)-12
was determined by X-ray crystal structure analysis
(Fig. 1a). The compound crystallizes in the non-centrosym-
metric chiral space group P212121 (no. 19) with Z = 4; it
contains the C10(R), C16(S), C8(S), C7(R) chiral centers.
Although it is generally not a stable form, pyrazine ring
has the boat conformation; C16 and C10 lie out of the plane
and on the same side of the plane containing C15, N2, C11,
and N1. Deviation for C16 and C10 from the least square
4. Experimental
4.1. Materials and methods
NMR spectra were recorded on a Bruker DPX 400. Chem-
ical shifts d are reported in parts per million relative to
CHCl3 (1H: d = 7.27), CDCl3 (13C: d = 77.0), and CCl4
(13C: d = 96.4) as the internal standards. Column chroma-
tography was conducted on silica gel 60 (40–63 lm). TLC
was carried out on aluminum sheets pre-coated with silica
gel 60F254 (Merck), and the spots were visualized with UV
light (k = 254 nm). Optical rotations were measured with a
˚
plane is 0.169 and 0.135 A, respectively. The pyrrole ring
is planar but the oxazole ring has a slightly distorted enve-
lope conformation. Maximum deviation from the mean
˚
plane is 0.167 A for C8 [Cremer and Pople puckering
Kruss P3002RS automatic polarimeter.
¨
parameters7 Q(2) = 0.273(3) A, phi(2) = 261.1(5)ꢁ]. The
˚
chains of molecules running parallel to the short a axis
4.2. X-ray crystal structure analysis of (R,S,S,R)-12
are linked by conventional hydrogen bonds (Fig. 1b)
i
ii
˚
˚
[C10ꢁ ꢁ ꢁO2 = 3.194(4) A and C14ꢁ ꢁ ꢁO2 = 3.342(4) A; sym-
A single crystal suitable for X-ray structural analysis was
obtained by EtOAc/hexane. A white crystal of dimensions
0.25 · 0.17 · 0.15 mm was mounted on a glass fiber. X-ray
diffraction intensity data collection and cell refinement
were performed on Rigaku R-AXIS RAPID IP diffracto-
metry codes: (i) ꢀ1 + x, y, z; (ii) 2 ꢀ x, ꢀ1/2 + y, 1/2 ꢀ z].
Most probably, during the cyclization of the imine inter-
mediate, the OH attack preferentially occurs on the Si face

A. S. Demir et al. / Tetrahedron: Asymmetry 17 (2006) 2625–2631
2627
Table 1. Synthesis of tricyclic heterocycles
Entry Amino acid ester 2
2-Formylpyrrole 4, yielda (%)
Norephedrine 6
(1R,2S)
Pyrrole–pyrazine–oxazole-product
Yielda,b (%)
O
N
N
1
(R)-2a
(R)-4a
72
O
(2R,3S,6R,10bR)-7
2
3
(S)-2a
(S)-2a
(S)-4a
(1S,2R)
(1R,2S)
(2S,3R,6S,10bS)-7
75
74
O
N
N
(S)-4a, 77
O
(2R,3S,6S,10bR)-8
(2S,3R,6R,10bS)-8
4
5
(R)-2a
(R)-2b
(R)-4a, 76
(R)-4b
(1S,2R)
(1R,2S)
75
76
O
N
N
O
(2R,3S,6R,10bR)-9
6
7
8
9
(S)-2b
(S)-2b
(R)-2b
(R)-2c
(S)-4b
(1S,2R)
(1R,2S)
(1S,2R)
(1R,2S)
(2S,3R,6S,10bS)-9
77
71
74
71
O
N
N
(S)-4b, 76
(R)-4b, 73
(R)-4c
O
(2R,3S,6S,10bR)-10
(2S,3R,6R,10bS)-10
O
N
N
O
(2R,3S,6R,10bR)-11
10
11
(S)-2c
(S)-2c
(S)-4c
(1S,2R)
(1R,2S)
(2S,3R,6S,10bS)-11
73
73
O
N
N
(S)-4c, 73
O
(2R,3S,6S,10bR)-12
12
13
(R)-2c
(R)-2d
(R)-4c, 74
(R)-4d
(1S,2R)
(1R,2S)
(2S,3R,6R,10bS)-12
72
74
O
N
N
O
(2R,3S,6R,10bR)-13
(continued on next page)

2628
A. S. Demir et al. / Tetrahedron: Asymmetry 17 (2006) 2625–2631
Table 1 (continued)
Entry
14
Amino acid ester 2
2-Formylpyrrole 4, yielda (%)
(S)-4d
Norephedrine 6
(1S,2R)
Pyrrole–pyrazine–oxazole-product
Yielda,b (%)
73
(S)-2d
(2S,3R,6S,10bS)-13
O
N
N
15
16
(S)-2d
(R)-2d
(S)-4d, 76
(R)-4d, 76
(1R,2S)
(1S,2R)
71
73
O
(2R,3S,6S,10bR)-14
(2S,3R,6R,10bS)-14
a Isolated yields.
b Newly generated stereogenic centers are assigned according to the unique reaction and the structure information from NOE experiments and the X-ray
diffraction structure of (2R,3S,6S,10bR)-12.
meter equipped with a graphite monochromator. A total of
at 291(2) K, of which 2891 reflections had I > 2r(I) and
were used in the structural solution and refinements. The
corrections for Lp factors and empirical absorption were
applied to the intensity data. The structure was solved by
direct methods and refined on F2 using a full matrix
least-squares technique (SHELXS-97 and SHELXL-97).8 The
non-hydrogen atoms were also refined by a full-matrix
least-squares technique, anisotropically, and the hydrogen
atoms were included but not refined. The final cycle of
the full-matrix least-squares refinement was based on
3741 observed reflections and 237 parameters. Conver-
gence with unweighted and weighted agreement factors
5505 unique reflections were collected using Mo Ka
˚
(k = 0.71073 A) radiation by the oscillation scan technique
was achieved at R = 0.079 Rw = 0.116 ðw ¼ 1=½rðF 2oÞþ
2
ð0:0325PÞ þ 0:1214PꢂÞ where P ¼ ðF 2o þ 2F c2Þ=3, The max-
imum and minimum peaks on the final difference Fourier
3
˚
map correspond to 0.120 and ꢀ0.120 e A . Crystal data
for (R,S,S,R)-7c: empirical formula, C22H20N2O2; formula
weight, 344.4; calculated density, 1.27 g/cm3; volume (V),
3
˚
1807.6.(2) A ; crystal system, orthorhombic; space group,
P212121 (no: 19); Z = 4; unit cell dimensions, a = 6.569
(5), b = 13.099 (5), c = 21.007 (5); absorption coefficient,
0.082 mm ꢀ1 ; index ranges, ꢀ9 6 h 6 9, ꢀ17 6 k 6 18,
ꢀ29 6 l 6 30; F(000), 728; hmax = 30.5; GOF, 1.077; Flack
parameter, 0.05(2).
Final atomic coordinates of the crystal, along with lists of
anisotropic thermal parameters, hydrogen coordinates,
bond lengths, and bond angles, have been deposited with
the Cambridge Crystallographic Data Centre as supple-
mentary publication no. CCDC-609449. Data can be
obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cam-
bridge, CB2 1EZ, UK (fax: (+44) 1223 336 033; e-mail:
deposit@ccdc.cam.cn; web: http//www.ccdc.cam.ac.uk).
Figure 1. (a) ORTEP view of (R,S,S,R)-12 with displacement ellipsoids
drawn at the 50% probability level. (b) Hydrogen bonded chains, viewed
along the b axis. Dashed lines represent C–Hꢁ ꢁ ꢁO bonds. H atoms not
involved in hydrogen bonding have been omitted. Selected bond lengths
4.3. General procedure for the synthesis of pyrrole
derivatives 3
Amino acid ester (10 mmol) was dissolved in 5 mL of
water. To this solution 2,5-dimethoxytetrahydrofuran
(12 mmol), glacial AcOH (4 mL), and dichloroethane
(30 mL) were added at room temperature. The reaction
mixture was refluxed for 3 h. The two layers were then sep-
˚
(A), bond angles (ꢁ) and torsion angles (ꢁ): C10–O1 1.403(3), C10–N2
1.460(3), O2–C15 1.231(3), C7–C6 1.513(4), C1–C6 1.379(3), N1–C16
1.449(3), C10–O1–C7 110.7(2), N1–C16–C15 110.2(2), C10–N2–C8
109.8(2), O2–C15–N2 123.1(3), C5–C6–C7–O1 ꢀ33.0(2), C7–O1–C10–
N2 4.6(2), N2–10–C11–N1 ꢀ25.9(3), C10–C11–N1–C14 179.5(2).

A. S. Demir et al. / Tetrahedron: Asymmetry 17 (2006) 2625–2631
2629
H
Pyrrole ring
OH
H
H
N
N
O
O
N
H3C
H3C
Ph
HN
COOCH3
N
Ph
Ph
H
H3C
H
O
CH3
CH3
Scheme 2.
arated and the aqueous layer extracted three times with
CHCl3. The organic phases were combined and dried over
MgSO4. The solvent was removed under reduced pressure
and the crude product was purified by flash column
chromatography (1:3, EtOAc/hexane).
179.5. Anal. Calcd for C11H15NO3 (209.24): C, 63.14; H,
7.23; N, 6.69. Found: C, 63.35; H, 7.48; N, 6.42.
4.7. (R)-Methyl-2-(2-formyl-1H-pyrrol-1-yl)-2-phenyl
acetate 4c
White solid (1.80 g, 74% yield). Mp = 88.7–89.7 ꢁC.
4.4. General procedure for the synthesis of pyrrole-2-
carboxaldehyde derivatives 4
25
½aꢂD ¼ ꢀ104:4 (c 0.2, CHCl3). IR (KBr): 3116, 2960,
1
2847, 1755, 1651, 1466, 1381, 1212, 1000, 763 cmꢀ1. H
NMR (400 MHz, CDCl3) d (ppm): 3.79 (s, 3H), 6.18 (t,
J = 3.1 Hz, 1H), 6.84 (s, 1H), 6.97 (m, 2H), 7.35 (m, 2H),
7.41 (m, 3H), 9.55 (s, 1H). 13C NMR (100 MHz, CDCl3)
d (ppm): 52.4, 63.2, 109.9, 125.2, 128.8, 129.1, 130.1,
131.7, 134.1, 169.8, 179.4. Anal. Calcd for C14H13NO3
(243.26): C, 69.12; H, 5.39; N, 5.76. Found: C, 69.33; H,
5.42; N, 5.62.
Phosphoryl chloride (10 mmol) was added to ice-cold
DMF (10 mmol) over 15 min. The reaction mixture was
allowed to warm to room temperature diluted with CH2Cl2
(20 mL) and cooled again to 0 ꢁC. Pyrrole (5 mmol) was
dissolved in 10 mL CH2Cl2 and this solution added drop-
wise over 1 h, while the temperature was kept at 0 ꢁC. After
the addition was complete, the reaction mixture was
refluxed for 30 min. After the reflux was completed, the
reaction mixture was cooled to 10 ꢁC and hydrolyzed with
sodium acetate solution (3.15 g NaOAc in 15 mL water).
The phases were separated and the aqueous phase was
extracted three times with ether. The combined organic
layer was washed with a saturated sodium carbonate until
no CO2 evolved. The organic layer was then dried over
MgSO4. After evaporation of the solvent, the crude prod-
uct was purified by flash column chromatography (1:5,
EtOAc/hexane).
4.8. (S)-Methyl-2-(2-formyl-1H-pyrrol-1-yl)-3-phenyl-
propanoate 4d
25
Yellow oil (1.95 g, 76% yield). ½aꢂD ¼ þ8:8 (c 0.2, CHCl3).
IR (neat): 3116, 2960, 1658, 1412, 1080, 751, 702 cmꢀ1. 1H
NMR (400 MHz, CDCl3) d (ppm): 3.30 (ddd, J1 = 5.6 Hz,
J2 = 14.1 Hz, J3 = 19.7 Hz, 2H), 3.66 (s, 3H), 5.99 (s, 1H),
6.12 (m, 1H), 6.79 (m, 1H), 6.92 (m, 2H), 7.09 (m, 3H), 9.36
(s, 1H). 13C NMR (100 MHz, CDCl3) d (ppm): 40.1, 52.8,
63.9, 109.3, 120.3, 121.6, 122.3, 126.2, 127.4, 127.5, 128.9,
129.3, 136.7, 170.7, 170.8. Anal. Calcd for C15H15NO3
(257.28): C, 70.02; H, 5.88; N, 5.44. Found: C, 69.82; H,
5.61; N, 5.23.
4.5. (S)-Methyl-2-(2-formyl-1H-pyrrol-1-yl)propanoate 4a5a
25
Orange oil (1.40 g, 77% yield). ½aꢂD ¼ ꢀ87:5 (c 0.2, CHCl3).
IR (neat): 2846, 1660, 1412, 1214, 1085, 753 cmꢀ1 1H
.
NMR (400 MHz, CDCl3) d (ppm): 1.67 (d, J = 7.4 Hz,
3H), 3.67 (s, 3H), 5.82 (q, J = 7.3 Hz, 1H), 6.22 (t,
J = 3.3 Hz, 1H), 6.88 (d, J = 3.5 Hz, 1H), 7.07 (s, 1H),
9.44 (s, 1H). 13C NMR (100 MHz, CDCl3) d (ppm): 18.0,
52.4, 55.2, 110.2, 113.5, 125.1, 128.5, 171.2, 179.3. Anal.
Calcd for C9H11NO3 (181.19): C, 59.66; H, 6.12; N, 7.73.
Found: C, 59.81; H, 6.25; N, 7.61.
4.9. General procedure for the synthesis of pyrrole–pyrazine–
oxazole fused cyclic structures 7–14
Formylated pyrrole (3 mmol) was dissolved in 10 mL of
dry benzene. To this solution was added norephedrine
(503 mg, 3.33 mmol) in 10 mL dry benzene under argon.
The reaction mixture was refluxed under a Dean Stark
trapp apparatus and monitored by TLC (24–36 h). The
organic layer was separated and dried over MgSO4. After
evaporation of solvent, the crude product was purified by
flash column chromatography (EtOAc/hexane, 1:6).
4.6. (S)-Methyl-2-(2-formyl-1H-pyrrol-1-yl)-3-methyl-
butanoate 4b
25
Yellow oil (1.59 g, 76% yield). ½aꢂD ¼ þ1:5 (c 1.1, CHCl3).
IR (neat): 2966, 1662, 1208, 1030, 753 cmꢀ1
.
1H NMR
4.10. (2R,3S,6R,10bR)-3,6-Dimethyl-2-phenyl-2,3-dihydro-
10bH-[1,3]oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-5[6H]-one 7
(400 MHz, CDCl3) d (ppm): 0.71 (d, J = 6.7 Hz, 3H),
0.94 (d, J = 6.7 Hz, 3H), 2.31 (m, 1H), 3.68 (s, 3H), 5.91
(d, J = 9.5 Hz, 1H), 6.21 (dd, J1 = 2.9 Hz, J2 = 3.7 Hz,
1H), 6.82 (dd, J1 = 1.6 Hz, J2 = 3.9 Hz, 1H), 7.30 (s, 1H),
9.45 (s, 1H). 13C NMR (100 MHz, CDCl3) d (ppm): 18.5,
19.2, 33.1, 52.1, 63.7, 110.6, 125.0, 129.7, 132.0, 170.9,
25
Yellow oil (610 mg, 72% yield). ½aꢂD ¼ ꢀ7:2 (c 0.2, CHCl3).
IR (neat): 2962, 1659, 1413, 1260, 1087, 802 cmꢀ1 1H
.
NMR (400 MHz, CDCl3) d (ppm): 0.87 (d, J = 7.0 Hz,
3H), 1.55 (d, J = 7.2 Hz, 3H), 4.63 (q, J = 7.1 Hz, 1H),

2630
A. S. Demir et al. / Tetrahedron: Asymmetry 17 (2006) 2625–2631
4.76 (p, J = 6.7 Hz, 1H), 5.09 (d, J = 5.6 Hz, 1H), 6.15 (t,
J = 3.2 Hz, 1H), 6.20 (broad s, 1H), 6.24 (s, 1H), 6.56 (s,
1H), 7.27 (m, 5H). 13C NMR (100 MHz, CDCl3) d
(ppm): 14.0, 21.4, 54.3, 55.9, 80.6, 81.0, 105.1, 110.0,
118.1, 124.1, 126.2, 127.9, 128.4, 136.4, 166.3. Anal. Calcd
for C17H18N2O2 (282.34): C, 72.32; H, 6.43; N, 9.92.
Found: C, 72.44; H, 6.62; N, 9.71.
4.14. (2R,3S,6R,10bR)-2,6-Diphenyl-3-methyl-2,3-dihydro-
10bH-[1,3]oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-5[6H]-one 11
White solid (723 mg, 71% yield). Mp = 140.5–141.5 ꢁC.
25
½aꢂD ¼ ꢀ63:0 (c 0.1, CHCl3). IR (KBr): 3059, 1664, 1449,
1
1313, 1199, 1071, 719 cmꢀ1. H NMR (400 MHz, CDCl3)
d (ppm): 0.79 (d, J = 6.8 Hz, 3H), 4.77 (p, J = 6.6 Hz,
1H), 5.16 (d, J = 5.5 Hz, 1H), 5.78 (s, 1H), 6.14 (s, 1H),
6.29 (m, 1H), 6.34 (br s, 1H), 6.68 (s, 1H), 6.98 (d,
J = 7.3 Hz, 2H), 7.31 (m, 8H). 13C NMR (100 MHz,
CDCl3) d (ppm): 14.0, 54.5, 63.5, 80.6, 81.2, 105.1, 110.3,
125.1, 125.3, 126.2, 126.6, 127.9, 128.2, 128.4, 128.4,
129.0, 129.1, 136.2, 136.6, 164.4. Anal. Calcd for
C22H20N2O2 (344.41): C, 76.72; H, 5.85; N, 8.13. Found:
C, 76.61; H, 5.77; N, 7.88.
4.11. (2R,3S,6S,10bR)-3-Methyl-6-isopropyl-2-phenyl-2,3-
dihydro-10bH-[1,3]oxazolo[3,2-(2R,3S,6S,10bR)-3,6-
dimethyl-2-phenyl-2,3-dihydro-10bH-[1,3]oxazolo[3,2-a]-
pyrrolo[2,1-c]pyrazin-5[6H]-one 8
25
Yellow oil (627 mg, 74% yield). ½aꢂD ¼ ꢀ58:1 (c 0.1,
CHCl3). IR (neat): 2962, 1659, 1413, 1260, 1087,
1
802 cmꢀ1. H NMR (400 MHz, CDCl3) d (ppm): 0.87 (d,
4.15. (2R,3S,6S,10bR)-2,6-Diphenyl-3-methyl-2,3-dihydro-
10bH-[1,3]oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-5[6H]-one 12
J = 7.0 Hz, 3H), 1.56 (d, J = 7.2 Hz, 3H), 4.64 (q,
J = 7.1 Hz, 1H), 4.76 (p, J = 6.7 Hz, 1H), 5.10 (d, J =
5.5 Hz, 1H), 6.16 (t, J = 3.2 Hz, 1H), 6.20 (broad s, 1H),
6.24 (s, 1H), 6.58 (s, 1H), 7.27 (m, 5H). 13C NMR
(100 MHz, CDCl3) d (ppm): 14.1, 21.4, 54.3, 55.9, 80.5,
81.0, 105.1, 110.0, 119.7, 123.3, 126.2, 127.9, 128.4, 136.3,
166.4. Anal. Calcd for C17H18N2O2 (282.34): C, 72.32; H,
6.43; N, 9.92. Found: C, 72.51; H, 6.61; N, 9.69.
White solid (754 mg, 73% yield). Mp = 139.8–140.8 ꢁC.
25
½aꢂD ¼ ꢀ75:4 (c 0.1, CHCl3). IR (KBr): 3059, 1664, 1449,
1
1313, 1199, 1071, 719 cmꢀ1. H NMR (400 MHz, CDCl3)
d (ppm): 0.82 (d, J = 6.9 Hz, 3H), 4.77 (p, J = 6.7 Hz,
1H), 5.16 (d, J = 5.4 Hz, 1H), 5.79 (s, 1H), 6.14 (s, 1H),
6.31 (m, 1H), 6.35 (br s, 1H), 6.70 (s, 1H), 6.98 (d,
J = 7.5 Hz, 2H), 7.31 (m, 8H). 13C NMR (100 MHz,
CDCl3) d (ppm): 13.9, 54.5, 63.5, 80.5, 81.2, 105.1, 110.3,
119.6, 125.1, 126.2, 126.5, 127.9, 128.4, 128.4, 128.9,
129.0, 129.0, 136.2, 136.5, 164.4. Anal. Calcd for
C22H20N2O2 (344.41): C, 76.72; H, 5.85; N, 8.13. Found:
C, 76.55; H, 5.70; N, 7.97.
4.12. (2R,3S,6S,10aR)-3-Methyl-6-isopropyl-2-phenyl-2,3-
dihydro-10bH-[1,3]oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-
5[6H]-one
25
Yellow oil (661 mg, 71% yield). ½aꢂD ¼ ꢀ57:4 (c 0.4,
CHCl3). IR (neat): 2969, 1666, 1452, 1358, 1200, 1068,
4.16. (2R,3S,6R,10bR)-6-Benzyl-3-methyl-2-phenyl-2,3-
dihydro-10bH-[1,3]oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-
5[6H]-one 13
752 cmꢀ1 1H NMR (400 MHz, CDCl3) d (ppm): 0.87
.
(dd, J1 = 6.8 Hz, J2 = 9.5 Hz, 6H), 1.0 (d, J = 6.9 Hz,
3H), 2.12 (sextet, J = 6.7, 1H), 4.29 (d, J = 6.2 Hz, 1H),
4.75 (p, J = 6.8 Hz, 1H), 5.05 (d, J = 5.6 Hz, 1H), 6.12 (t,
J = 3.1 Hz, 1H), 6.19 (d, J = 3.3 Hz, 1H), 6.24 (s, 1H),
6.54 (t, J = 1.8 Hz, 1H), 7.25 (m, 5H). 13C NMR
(100 MHz, CDCl3) d (ppm): 13.1, 17.4, 18.4, 33.1, 53.1,
65.2, 79.3, 80.3, 103.6, 108.1, 118.9, 124.7, 125.1, 126.8,
127.3, 135.3, 164.1. Anal. Calcd for C19H22N2O2
(310.39): C, 73.52; H, 7.14; N, 9.03. Found: C, 73.31; H,
7.11; N, 8.86.
25
Orange oil (795 mg, 74% yield). ½aꢂD ¼ ꢀ8:3 (c 0.8,
CHCl3). IR (neat): 3059, 1660, 1451, 1214, 1079,
1
749 cmꢀ1. H NMR (400 MHz, CDCl3) d (ppm): 0.64 (d,
J = 6.8 Hz, 3H), 3.22 (ddd, J1 = 4.2 Hz, J2 = 13.5 Hz,
J3 = 47.2 Hz, 2H), 4.67 (m, 2H), 4.88 (t, J = 4.4 Hz, 1H),
4.98 (d, J = 5.7 Hz, 1H), 6.03 (m, 1H), 6.19 (t,
J = 3.4 Hz, 1H), 6.58 (t, J = 2.1 Hz, 1H), 6.66 (d,
J = 7.1 Hz, 2H), 7.06 (t, J = 7.6 Hz, 2H), 7.18 (m, 6H).
13C NMR (100 MHz, CDCl3) d (ppm): 13.3, 41.6, 53.9,
60.7, 80.2, 80.6, 104.4, 110.4, 117.7, 125.9, 126.16, 126.4,
127.1, 127.6, 127.8, 128.2, 128.3, 129.1, 134.4, 136.6,
163.7. Anal. Calcd for C23H22N2O2 (358.43): C, 77.07; H,
6.19; N, 7.82. Found: C, 76.88; H, 6.23; N, 7.52.
4.13. (2R,3S,6R,10bR)-3-Methyl-6-isopropyl-2-phenyl-2,3-
dihydro-10bH-[1,3]oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-
5[6H]-one 10
25
Yellow oil (707 mg, 76% yield). ½aꢂD ¼ ꢀ28:2 (c 0.1,
4.17. (2R,3S,6S,10bR)-6-Benzyl-3-methyl-2-phenyl-2,3-
dihydro-10bH-[1,3]oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-
5[6H]-one 14
CHCl3). IR (neat): 2969, 1666, 1452, 1358, 1200, 1068,
752 cmꢀ1. H NMR (400 MHz, CDCl3) d (ppm): 0.82 (d,
1
J = 6.4 Hz, 3H), 0.96 (dd, J = 6.9 Hz, 6H), 2.21 (sextet,
J = 6.7, 1H), 4.31 (d, J = 5.8 Hz, 1H), 4.77 (p, J =
6.3 Hz, 1H), 5.07 (d, J = 5.6 Hz, 1H), 6.14 (t, J = 2.9,
1H), 6.22 (br s, 1H), 6.25 (s, 1H), 6.56 (s, 1H), 7.28 (m,
5H). 13C NMR (100 MHz, CDCl3) d (ppm): 14.2, 18.9,
20.2, 34.4, 55.9, 67.3, 82.7, 82.4, 104.2, 109.4, 120.4,
126.6, 126.6, 128.5, 128.7, 135.4, 165.3. Anal. Calcd for
C19H22N2O2 (310.39): C, 73.52; H, 7.14; N, 9.03. Found:
C, 73.39; H, 7.23; N, 8.78.
25
Orange oil (763 mg, 71% yield). ½aꢂD ¼ ꢀ23:0 (c 0.3,
CHCl3). IR (neat): 3059, 1660, 1451, 1214, 1079,
749 cmꢀ1. H NMR (400 MHz, CDCl3) d (ppm): 0.73 (d,
1
J = 6.9 Hz, 3H), 3.32 (ddd, J1 = 4.1 Hz, J2 = 13.5 Hz,
J3 = 49.6 Hz, 2H), 4.76 (m, 2H), 4.99 (t, J = 4.3 Hz, 1H),
5.07 (d, J = 5.8 Hz, 1H), 6.14 (m, 1H), 6.30 (t,
J = 3.1 Hz, 1H), 6.69 (m, 1H), 6.76 (d, J = 7.4 Hz, 2H),
7.17 (t, J = 7.4 Hz, 2H), 7.30 (m, 6H). 13C NMR

A. S. Demir et al. / Tetrahedron: Asymmetry 17 (2006) 2625–2631
2631
Chapters 3 and 4; (h) Gilchrist, T. L. J. Chem. Soc., Perkin
Trans. 1 2001, 1, 2491.
(100 MHz, CDCl3) d (ppm): 13.3, 41.6, 53.8, 60.6, 80.1,
80.6, 104.4, 110.4, 117.7, 125.9, 126.2, 126.4, 127.1, 127.6,
127.8, 128.2, 128.3, 129.1, 134.4, 136.6, 163.7. Anal. Calcd
for C23H22N2O2 (358.43): C, 77.07; H, 6.19; N, 7.82.
Found: C, 76.82; H, 5.91; N, 7.61.
2. (a) Aydogan, F.; Demir, A. S. Tetrahedron 2005, 61, 3019; (b)
Aydogan, F.; Demir, A. S. Tetrahedron: Asymmetry 2004, 15,
259; (c) Demir, A. S.; Akhmedov, I. M.; Sesenoglu, O.;
Alpturk, O.; Apaydin, S.; Gercek, Z.; Ibrahimzade, N. J.
Chem. Soc., Perkin Trans. 1 2001, 1162, and references cited
therein; (d) Demir, A. S.; Emrullahoglu, M. Tetrahedron 2005,
61, 10482; (e) Demir, A. S.; Emrullahoglu, M. Tetrahedron
2006, 62, 1452.
Acknowledgments
3. (a) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Paladino, G.
Tetrahedron 2005, 61, 1077–1082; (b) Likhosherstov, A. M.;
Filippova, O. V.; Peresada, V. P.; Kryzhanovskii, S. A.;
Vititnova, M. B.; Kaverina, N. V.; Reznikov, K. M. Pharm.
Chem. J. 2003, 37, 6–9 (Translation of Khimiko-Farmatsev-
ticheskii Zhurnal); (c) Kobayashi, Y.; Kutsuma, T.; Morinaga,
K. Chem. Pharm. Bull. 1971, 19, 2106–2115; (d) Guttmann, S.;
Huguenin, R. Ger. Offen. DE 2029447, 1971; (e) Stadler, P.;
Hauth, H.; Wersin, G.; Guttmann, S.; Hofmann, A.; Stuetz,
P.; Willems, H. Fr. FR 1588541, 1970; (f) Sprio, V.; Aiello, T.;
Fabra, I. Ann. Chim. 1966, 56, 866–873.
The financial support from the Scientific and Technical
Research Council of Turkey (TUBITAK), the Turkish
Academy of Sciences (TUBA), the Turkish State Planning
Organization, and the Middle East Technical University is
gratefully acknowledged. The authors are indebted to
Department of Chemistry and Ataturk University, Turkey,
¨
for NOE experiments (Dr. Cavit Kazaz) and the use of X-
ray diffractometer purchased under grant number 2003/219
of University research fund.
¨
4. (a) Jefford, C. W.; Sienkiewicz, K.; Thornton, S. R. Tetrahe-
dron Lett. 1994, 35, 4759–4762; (b) Lellouche, J.-P.; Senthil,
G.; Joseph, A.; Buzhansky, L.; Bruce, I.; Bauminger, E. R.;
Schlesinger, J. J. Am. Chem. Soc. 2005, 127, 11998–12006.
5. (a) Abell, A. D.; Hoult, D. A.; Jamieson, E. J. Tetrahedron
Lett. 1992, 33, 5831–5832; (b) Unaleroglu, C.; Aydin, A. E.;
Demir, A. S. Tetrahedron: Asymmetry 2006, 17, 742–749.
6. The products are separated by flash column chromatography
from the crude mixture. The remaining part was a mixture of
undefined products. Many attempts were made to find out
whether other possible minor isomers are formed or not, but
without success. This work is still under investigation.
7. Cremer, D.; Pople, J. A. J. Am. Chem. Soc. 1975, 97, 1354–
1358.
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