Synthesis and photooxygenation of homochiral 2-methylpyrrole derivatives of chiral amino alcohols: Simple, selective access to chiral bicyclic lactams

Article abstract of DOI:10.1016/j.tetasy.2003.11.011

Homochiral 2-methylpyrrole derivatives are synthesized in high yields starting from chiral amino alcohols and 5-chloro-3-pentene-2-one. The photooxygenation of these compounds in the presence of a photosynthesizer furnishes the pyrrolooxazolone structures in high diastereoselectivities. In all of the examples, trans-isomers are formed as the major products.

Full text of DOI:10.1016/j.tetasy.2003.11.011

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 259–265
Synthesis and photooxygenation of homochiral 2-methylpyrrole
derivatives of chiral amino alcohols: simple, selective access to
chiral bicyclic lactams
Feray Aydogana,b and Ayhan S. Demira,*
aDepartment of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
bDepartment of Chemistry, Yildiz Technical University, 34010 Davutpasa, Istanbul, Turkey
Received 26 September 2003; revised 5 November 2003; accepted 13 November 2003
Abstract—Homochiral 2-methylpyrrole derivatives are synthesized in high yields starting from chiral amino alcohols and 5-chloro-
3-pentene-2-one. The photooxygenation of these compounds in the presence of a photosynthesizer furnishes the pyrrolooxazolone
structures in high diastereoselectivities. In all of the examples, trans-isomers are formed as the major products.
Ó 2003 Elsevier Ltd. All rights reserved.
1. Introduction
Dye sensitized pyrrole photooxygenation followed by
solvolysis of the formed endo-peroxide in methanol
yielded lactam 2. Such products are formed when the
pyrrole a-position is free or substituted by an alkyl,
formyl, carbomethoxy, or acyl group.7
Singlet oxygen is capable of oxidizing a wide range of
substrates. However, only very limited success has been
achieved in terms of applying these reactions to practical
organic synthesis.1 One of the problems associated with
these photooxidations is low chemoselectivity. The
photooxygenation of heterocycles is important because
heterocyclic systems such as pyrroles,2 imidazoles,3 and
other heterocycles4 are involved in photobiosynthesis
and other biological processes. Photooxidations of
pyrroles often produce a mixture of products derived
from both (1,2)- and (1,4)-oxygen addition. Wasserman
et al. recently showed that when both electron-releasing
and electron-withdrawing groups are substituted on the
hetero ring, oxidations can take place with more con-
trol.5 The photooxidation of N-substituted pyrroles, to
form hydroxylactams of type 1, has been applied by
Franck and Auerbach.6
Previously, we reported a new synthetic method for the
efficient preparation of 2-substituted pyrrole derivatives
3 from haloenones and amines, and amino alcohols and
amino acids. This cyclization works without any race-
mization.8 Recently, we also showed that the homochi-
ral 2-methylpyrroles can be converted into unsaturated
c-lactams 4 in good yields using singlet oxygen.9
Herein, attention is focused on the singlet oxygen oxi-
dation of 2-methyl substituted homochiral pyrroles 6
that are derived from various amino alcohols 5, in which
the nitrogen atom is carrying chiral groups, in order to
obtain chiral bicyclic lactams 8 (Scheme 1).
A number of reports have demonstrated the synthetic
utility of chiral bicyclic lactams. These systems have
provided access to a number of enantiomerically pure
materials bearing quaternary carbon centers including
cyclobutanes, cyclopentenones, cyclohexanes, and
cyclohexenones. They are also used as starting materials
by the formal total synthesis of some natural prod-
ucts.10;11 Some methods have already been published
reporting the synthesis of these bicyclic lactams starting
from different compounds,11;12 but the most relevant
synthetic route to these bicyclic lactams involves heating
R1
O
O
O
N
R
OH
N
R
N
N
OMe
R1
R2
R1
R2
*
*
1
2
3
4
* Corresponding author. Fax: +90-3122101280; e-mail: asdemir@
metu.edu.tr
0957-4166/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.11.011

260
F. Aydogan, A. S. Demir / Tetrahedron: Asymmetry 15 (2004) 259–265
NH2
O
Lit.8
OH
Cl
+
N
OH
5a
6a
1O2, CH2Cl2
O
O
N
OH
O
OH
O
O
O
N
O
N
N
O
O
O
OH
N
(S,R)-8a
(S,S)-8a
7
Scheme 1.
the appropriate anhydride with a chiral 2-amino alco-
hol. The subsequent reduction of these imides followed
by the treatment of the resulting alcohols with TFA
provides the bicyclic lactams.13 Only a few cis-bicyclic
lactams have been described and some of these com-
pounds are commercially available. As far as we know,
no work has been previously published for the synthesis
of trans-isomers of these compounds.
Carrying out the reaction with (R)-6a provided the
enantiomers (R,R)-8a and (R,S)-8a. The reaction of rac-
6a gave trans-rac-8a as the major product (Scheme 1).
Identification of the isomeric products was easily per-
formed by using NMR techniques, GC–MS, and HPLC.
As shown in Table 1, different homochiral 2-methyl-
pyrroles, synthesized from amino alcohols and the
amino acid ester, were used as starting materials and the
corresponding bicyclic lactams isolated in comparable
yields (47–56%). According to the spectroscopic data,
the bicyclic lactams were obtained as a diastereomeric
mixture with a similar selectivity as described for
(S,RS)-8a (Table 1). Starting from (R)-6e the corre-
sponding bicyclic lactam 8e was obtained in a 55% yield
with which it was possible to separate the diastereomers
by flash column chromatography to give both isomers
(R,S)-8e and (R,R)-8e in their enantiomerically pure
form. In the case of 6f, both enantiomers of the amino
alcohol are commercially available and the bicyclic lac-
tams (S,RS)-8f and (R,RS)-8f can be synthesized start-
ing from both the enantiomers of 6f. The flash column
chromatographic separation of the isomers supplied all
of the possible enantiomers of 8f diastereomerically
pure. The enantiomers were analyzed by HPLC using a
chiral column (Scheme 2).
2. Results and discussion
The reaction of amino alcohols and the esters of amino
acids 5a–g with 5-chloro-3-pentene-2-one provided the
2-methylpyrrole derivatives 6a–g in 75–95% yields
without any racemization as previously reported8
(Scheme 1). The oxygenation of (S)-6a was performed
using several methods of singlet oxygen generation.2;14
In most cases, a low yield of bicyclic lactam was
obtained. The best yield of bicyclic lactam was gained by
using the following conditions: The oxidation of (S)-6a
in dichloromethane took place at rt in the presence of
TPP in a stream of oxygen under irradiation with a
150 W sodium lamp. The color of the reaction mixture
turned from violet to green in 10–20 min. The reaction
was monitored by TLC and GC–MS. After all of the
starting material was consumed (1 h), the solvent was
removed and the product separated by flash column
The photooxygenation of 6g only gave the bicyclic lac-
tam with a primary hydroxy group. No cyclization was
observed with the secondary hydroxy group. In accor-
dance with this result, the oxidation reaction of pyrrole
9, which was derived from norephedrine, mainly sup-
plied the c-lactam elimination product 10. Only a trace
amount of cyclization product, which was detected by
GC–MS, was obtained under the above mentioned
reaction conditions (Scheme 3). Sterical hindrance is
likely the reason for this result.
1
chromatography. According to the H and 13C NMR
spectra, along with the MS, the major product was
identified as 3-isopropyl-7a-methyl-2,3-dihydropyr-
rolo[2,1b][1,3]oxazol-5(7aH)-one as a diastereomeric
mixture with a 49% yield along with tarry residues from
a mixture of oxidation and polymeric products. The
structural assignment was carried out by using NMR
techniques (NOESY, HMBC) and also by the compar-
ison of their data with a known, commercially available
compound. The major isomer was identified as (S,S)-8a
and the minor (S,R)-8a (the spectroscopic data of this
isomer is identical with a commercially available com-
pound). As shown in Scheme 1, the formation of the
trans-product is favored.
The products were derived from a reactive endo-perox-
ide intermediate 7 (Scheme 1), which was formed by the
1
1,4-addition of O2 to 6. Thus, 7 was able to undergo
alcoholysis to form a hydroperoxides. The latter was
then decomposed to yield 8.

F. Aydogan, A. S. Demir / Tetrahedron: Asymmetry 15 (2004) 259–265
261
Table 1. Pyrrolooxazole derivatives
Amine compounds 5
Pyrrole compounds 6
Yield
(%)
Pyrrolooxazole
compounds 8
Yield
(%)
React. time
(min)
Isomer ratioa
NH2
OH
O
N
N
O
92
49
60
S,R/S,S 1:5
OH
(S)-5a
(S)-6a
(R)-6a
rac-6a
(S,RS)-8a
(R,RS)-8a
rac-8a
(R)-5a
rac-5a
93
92
54
47
50
60
R,S/R,R 1:5
cis/trans 1:6
NH2
OH
O
O
90
56
50
S,R/S,S 1:5
N
N
(S,RS)-8b
N
O
OH
(S)-5b
(S)-6b
NH2
OH
95
51
60
R,S/R,R 1:5
N
O
OH
(R)-5c
(R)-6c
(R,SR)-8c
NH2
78
50
45
S,R/S,S 1:4
OH
N
OH
(S)-5d
(S)-6d
(S,RS)-8d
NH2
O
N
OH
84
55
60
R,S/R,R 1:6
(separated)
N
O
OH
(R)-5e
(R)-6e
(R,SR)-8e
NH2
O
OH
N
75
N
O
53
90
S,S/S,R 1:5
(separated)b
C2H5O2C
(S)-5f
OH
C2H5O2C
C2H5O2C
(S)-6f
(S,RS)-8f
NH2
O
OH
N
O
N
79
48
90
R,R/R,S 1:5
(separated)b
C2H5O2C
OH
(R)-5f
C2H5` 2C
(R)-6f
C2H5O2C
(R,RS)-8f
NH2
O
OH
N
O
N
81
54
90
(S,S,S/S,S,R)
1:3
OH
OH
(S,S)-5g
OH
OH
(S,S,RS)-8g
(S,S)-6g
a Determined by 1H NMR spectroscopy.
b The enantiomers were analyzed by HPLC using chiral column (Chiralcel OD), UV detection at 254 nm, eluent: hexane/2-propanol 9:1, flow rate
0.80 mL minꢀ1, 20 °C.

262
F. Aydogan, A. S. Demir / Tetrahedron: Asymmetry 15 (2004) 259–265
N
N
HO
OC2H5
C2H5O
OH
O
O
(S)-6f
(R)-6f
O
+
O
N
O
O
+
O
O
N
O
O
N
N
C2H5O
C2H5O
OC2H5
OC2H5
O
O
O
O
(S,S)-8f
(Minor)
(S,R)-8f
(Major)
(R,R)-8f
(Minor)
(R,S)-8f
(Major)
Scheme 2.
(mesh size 40–63 lm). GC–MS spectra were determined
on a phenomenex Zebron ZB-5 capillary column [5%
phenylmethylsiloxane, 30 m, 250 lm; TGC (injec-
tor) ¼ 250 °C, TMS (ion source) ¼ 200 °C, time program
(oven): T0 min ¼ 60 °C, T3 min ¼ 60 °C, T14 min ¼ 280 °C
300 °C (heating rate 20 °C minꢀ1), T25 min ¼ 300 °C, MS:
EI, 70 eV]. Optical rotations were measured with a
Perkin–Elmer 241 polarimeter. Melting points were
measured on a Gallenkamp melting point apparatus in
an open capillary. 2-Methylpyrrole derivatives were
synthesized according to the recently published proce-
dure.8 The synthesis of 6a and 9 (described previously)
and all spectroscopic data were in agreement with
published values.8a;9 Enantiomeric excesses were deter-
mined by HPLC analysis using a Thermo Quest (TSP)
LC–MS equipped with an appropriate optically active
column, as described in the footnotes of the corre-
sponding tables.
N
O
N
Ph
Ph
OH
(1R,2S)-9
(1S,2R)-9
(heating rate 20 °C minꢀ1), T19 min ¼ 280 °C, T20 min
¼
OH
(1S,2R)-10
(1S,2R)-10
Scheme 3.
The mechanism of formation of the bicyclic lactam from
the endo-peroxide is either the direct nucleophilic
involvement of –OH in an endo-peroxide decomposition
mode or an open Zwitter ion is attached by –OH as
shown in Scheme 1. The stereocontrolled formation of
an intermediate can result from the stereoselective 1,4-
1
addition of O2 to the pyrrole ring to form the endo-
peroxide followed by stereoselective intramolecular
alcoholysis to form the bicyclic lactam. It should be
noted that the mechanistic details of the present reaction
are still under investigation.
4.2. General procedure for photooxygenation
A solution of pyrrole (1 mmol) and TPP (20 mg) in
dichloromethane (200 mL) was irradiated with a 150 W
sodium lamp in a water-cooled vessel with O2 passed
through the solution. The color of the mixture changed
from violet to green in 10–20 min. The reaction was
monitored by TLC and GC–MS. The solvent was then
evaporated and the crude product purified by way of
column chromatography (1:3 EtOAc/hexane) to pro-
duce the product.
3. Conclusion
In summary, the simple homochiral 2-methylpyrroles,
derived from chiral amino alcohols, can be converted
selectively into bicyclic lactams with good diastereo-
meric ratio and chemical yields using singlet oxygen.
The diastereomers can then be separated by using col-
umn chromatography. These bicyclic lactams with a
quaternary stereocenter are valuable intermediates for
many different bioactive compounds.
4.2.1. (S)-2-(2-Methyl-1H-pyrrol-1-yl)butan-1-ol (S)-6b.
20
Light yellow oil (414 mg). ½aꢁ ¼ )20.7 (c 4.1, CHCl3);
D
1H NMR (400 MHz, CDCl3): d 0.70 (t, J ¼ 7:3 Hz, 3H,
CH3), 1.52 (m, 1H, CHA), 1.63 (m, 1H, CHB), 2.11 (s,
3H, CH3), 2.33 (br s, 1H, OH), 3.47 (m, 2H, CH2), 3.76
(m, 1H, CH), 5.71 (s, 1H, @CH), 5.92 (s, 1H, @CH),
6.39 (s, 1H, @CH); 13C NMR (100 MHz, CDCl3): d
11.0, 12.8, 25.5, 59.7, 66.3, 106.5, 108.0, 115.7, 129.7.
Anal. Calcd for C9H15NO (153.12): C, 70.55; H, 9.87; N,
9.14.
4. Experimental
4.1. General methods
NMR spectra were recorded on a Bruker DPX 400.
Column chromatography was conducted on silica gel 60

F. Aydogan, A. S. Demir / Tetrahedron: Asymmetry 15 (2004) 259–265
263
4.2.2. (R)-2-(2-Methyl-1H-pyrrol-1-yl)propan-1-ol (R)-
6c. Light yellow solid (396 mg). Mp 70–73 °C;
106.4, 119.4, 127.0, 127.5, 128.2, 129.1, 143.8. Anal.
Calcd for C14H17NO2 (231.13): C, 72.70; H, 7.41; N,
6.06.
20
D
½aꢁ ¼ )9.6 (c 1.2, CHCl3); 1H NMR (400 MHz,
CDCl3): d 1.32 (d, J ¼ 6:9 Hz, 3H, CH3), 1.42 (s, 1H,
OH), 2.17 (s, 3H, CH3), 3.60 (d, J ¼ 6:3 Hz, 2H, CH2),
4.14 (m, 1H, CH), 5.73 (s, 1H, @CH), 5.97 (s, 1H,
@CH), 6.51 (s, 1H, @CH); 13C NMR (100 MHz,
CDCl3): d 12.6, 18.0, 53.1, 67.5, 107.1, 108.3, 115.5,
129.0. Anal. Calcd for C8H13NO (139.10): C, 69.03; H,
9.41; N, 10.06.
4.2.8. (S,RS)-3-Isopropyl-7a-methyl-2,3-dihydropyrrolo-
[2,1b][1,3]oxazol-5(7aH)-one (S,RS)-8a. Yellow oil
20
D
(89 mg). ½aꢁ ¼ )6 (c 2.0, CHCl3); IR (CHCl3): m 2989,
1717, 1642 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d for
(S,S)-8a 0.76 (d, J ¼ 6:7 Hz, 3H, CH3), 1.16 (d,
J ¼ 6:4 Hz, 3H, CH3), 1.42 (s, 3H, CH3), 2.65 (m, 1H,
CH), 3.32 (m, 1H, CHA), 3.57 (m, 1H, CHB), 4.03 (m,
1H, CH), 5.87 (d, J ¼ 5:7 Hz, 1H, @CH), 6.91 (d,
J ¼ 5:7 Hz, 1H, @CH); for (S,R)-8a 0.86 (d, J ¼ 6:6 Hz,
3H, CH3), 1.01 (d, J ¼ 6:6 Hz, 3H, CH3), 1.47 (s, 3H,
CH3), 2.65 (m, 1H, CH), 3.57 (m, 1H, CHA), 3.98 (m,
1H, CHB), 4.17 (m, 1H, CH), 5.91 (d, J ¼ 5:7 Hz, 1H,
@CH), 6.93 (d, J ¼ 5:7 Hz, 1H, @CH); 13C NMR
(100 MHz, CDCl3): d for (S,S)-8a 19.2, 22.7, 23.3, 25.7,
65.0, 73.3, 101.1, 129.4, 150.1, 174.2; for (S,R)-8a 19.6,
20.8, 33.2, 62.7, 74.0, 100.6, 128.2, 150.8, 177.7; MS
(m=z) (rel abund): 181 [Mþ] (20), 165(96), 150(100),
137(100), 122(64), 109(98), 93(98), 80(86). Anal. Calcd
for C10H15NO2 (181.11): C, 66.27; H, 8.34; N, 7.73.
4.2.3. (S)-3-Cyclohexyl-2-(2-methyl-1H-pyrrol-1-yl)pro-
20
pan-1-ol (S)-6d. Light yellow oil (518 mg). ½aꢁ ¼ )25.9
D
(c 3.4, CHCl3); 1H NMR (400 MHz, CDCl3): d 0.73 (m,
2H, CH2), 0.96 (m, 4H, CH2), 1.21 (br s, 1H, OH), 1.42
(m, 6H, CH2), 1.59 (m, 1H, CH), 2.07 (s, 3H, CH3), 3.51
(m, 2H, CH2), 3.99 (m, 1H, CH), 5.64 (br s, 1H, @CH),
5.90 (m, 1H, @CH), 6.39 (m, 1H, @CH); 13C NMR
(100 MHz, CDCl3): d 12.8, 26.3, 26.5, 26.8, 33.3, 34.2,
34.3, 39.8, 55.4, 67.1, 106.8, 108.3, 115.7, 129.5. Anal.
Calcd for C14H23NO (221.18): C, 75.97; H, 10.47; N,
6.33.
4.2.4. (R)-3-Phenyl-2-(2-methyl-1H-pyrrol-1-yl)propan-
20
D
1-ol (R)-6e. Light yellow oil (542 mg). ½aꢁ ¼ +73.2 (c
4.2.9. (S,RS)-3-Ethyl-7a-methyl-2,3-dihydropyrrolo-[2,1b]-
[1,3]oxazol-5(7aH)-one (S,RS)-8b. Yellow oil (94 mg).
4.0, CHCl3); 1H NMR (400 MHz, CDCl3): d 1.77 (s, 3H,
CH3), 2.08 (br s, 1H, OH), 2.75 (m, 1H, CHA), 2.84 (m,
1H, CHB), 3.60 (m, 2H, CH2), 4.01 (m, 1H, CH), 5.60
(m, 1H, @CH), 5.96 (m, 1H, @CH), 6.54 (m, 1H, @CH),
6.79 (m, 2H, ArH), 7.06 (m, 3H, ArH); 13C NMR
(100 MHz, CDCl3): d 12.4, 39.5, 59.8, 65.5, 106.7, 108.5,
115.6, 127.0, 128.8, 129.3, 130.0, 138.1. Anal. Calcd for
C14H17NO (215.13): C, 78.10; H, 7.96; N, 6.51.
20
D
½aꢁ ¼ +27.5 (c 2.0, CHCl3); IR (CHCl3): m 2989, 1719,
1
1644 cmꢀ1; H NMR (400 MHz, CDCl3): d for (S,S)-8b
0.97 (t, J ¼ 7:3 Hz, 3H, CH3), 1.42 (s, 3H, CH3), 1.63
(m, 1H, CHA), 2.30 (m, 1H, CHB), 3.54 (m, 2H, CH2),
4.15 (m, 1H, CH), 5.87 (d, J ¼ 5:6 Hz, 1H, @CH), 6.92
(d, J ¼ 5:6 Hz, 1H, @CH); for (S,R)-8b 0.97 (t,
J ¼ 7:3 Hz, 3H, CH3), 1.48 (s, 3H, CH3), 1.63 (m, 2H,
CH2), 3.54 (m, 1H, CHA), 3.73 (m, 1H, CHB), 3.86 (m,
1H, CH), 5.91 (d, J ¼ 5:6 Hz, 1H, @CH), 6.93 (d,
J ¼ 5:6 Hz, 1H, @CH); 13C NMR (100 MHz, CDCl3): d
for (S,S)-8b 12.1, 21.1, 23.3, 59.6, 75.5, 101.3, 129.4,
150.2, 174.2; for (S,R)-8b 11.5, 23.1, 28.1, 58.1, 74.8,
100.7, 128.1, 151.2, 177.9; MS (m=z) (rel abund): 167
[Mþ] (4), 151(37), 136(100), 122(9), 109(43), 93(25),
80(66). Anal. Calcd for C9H13NO2 (167.21): C, 64.65; H,
7.84; N, 8.38.
4.2.5. (S)-Ethyl-3-hydroxy-2-(2-methyl-1H-pyrrol-1-yl)-
20
D
propanoate (S)-6f. Yellow oil (443 mg). ½aꢁ ¼ )37.8 (c
1
5.2, CHCl3); H NMR (400 MHz, CDCl3): d 1.18 (t,
J ¼ 7:0 Hz, 3H, CH3), 2.15 (s, 3H, CH3), 2.39 (br s, 1H,
OH), 3.83 (m, 1H, CHA), 4.03 (m, 1H, CHB), 4.12 (m,
2H, CH2), 4.63 (t, J ¼ 6:6 Hz, 1H, CH), 5.77 (br s, 1H,
@CH), 5.97 (m, 1H, @CH), 6.55 (br s, 1H, @CH); 13C
NMR (100 MHz, CDCl3): d 12.9, 18.5, 53.1, 66.5, 73.4,
107.2, 108.6, 115.5, 129.4, 170.7. Anal. Calcd for
C10H15NO3 (197.11): C, 60.90; H, 7.67; N, 7.10.
4.2.10. (R,SR)-3-7a-Dimethyl-2,3-dihydropyrrolo[2,1b]-
[1,3]oxazol-5(7aH)-one (R,SR)-8c. Yellow oil (78 mg).
20
D
½aꢁ ¼ )42.1 (c 0.9, CHCl3); IR (CHCl3): m 2987, 1719,
1
4.2.6. (R)-Ethyl-3-hydroxy-2-(2-methyl-1H-pyrrol-1-yl)-
propanoate (R)-6f. Light yellow oil. ½aꢁ ¼ +37.9 (c 5.2,
1642 cmꢀ1; H NMR (400 MHz, CDCl3): d for (R,R)-8c
20
D
1.42 (s, 3H, CH3), 1.48 (d, J ¼ 6:7 Hz, 3H, CH3), 3.50
(m, 1H, CHA), 3.75 (m, 1H, CHB), 4.16 (m, 1H, CH),
5.89 (d, J ¼ 5:7 Hz, 1H, @CH), 6.94 (d, J ¼ 5:7 Hz, 1H,
@CH); for (R,S)-8c 1.31 (d, J ¼ 6:7 Hz, 3H, CH3), 1.51
(s, 3H, CH3), 3.80 (m, 1H, CHA), 3.98 (m, 1H, CHB),
4.16 (m, 1H, CH), 5.90 (d, J ¼ 5:7 Hz, 1H, @CH), 6.92
(d, J ¼ 5:7 Hz, 1H, @CH); 13C NMR (100 MHz,
CDCl3): d for (R,R)-8c 13.9, 23.3, 53.1, 76.9, 101.3,
129.6, 150.4, 174.3; for (R,S)-8c 20.7, 27.4, 52.0, 76.1,
100.8, 128.1, 151.2, 177.9; MS (m=z) (rel abund): 153
[Mþ] (1), 137(100), 122(74), 107(30), 93(61), 79(38).
Anal. Calcd for C8H11NO2 (153.18): C, 62.73; H, 7.24;
N, 9.14.
CHCl3).
4.2.7. (S,S)-2-(2-Methyl-1H-pyrrol-1-yl)-1-phenylpropan-
1,3-diol (S)-6g. Colorless solid (561 mg). Mp 160–161 °C;
20
D
½aꢁ ¼ +34.7 (c 0.7, MeOH); 1H NMR (400 MHz,
DMSO-d6): d 1.63 (s, 3H, CH3), 3.58 (m, 1H, CHA), 3.84
(m, 1H, CHB), 3.97 (m, 1H, CH), 4.59 (br s, 1H, OH),
4.96 (d, J ¼ 3:5 Hz, 1H, CH), 5.21 (br s, 1H, OH), 5.49
(s, 1H, @CH), 5.80 (m, 1H, @CH), 6.81 (br s, 1H,
@CH), 7.02 (m, 2H, ArH), 7.14 (m, 3H, ArH); 13C
NMR (100 MHz, CDCl3): d 12.3, 62.6, 63.1, 72.6, 105.5,

264
F. Aydogan, A. S. Demir / Tetrahedron: Asymmetry 15 (2004) 259–265
4.2.11. (S,RS)-3-(Cyclohexylmethyl)-7a-methyl-2,3-dihy-
dropyrrolo[2,1b][1,3]oxazol-5(7aH)-one (S,RS)-8d. Col-
yellow oil (14 mg). HPLC (Chiralcel OD): tR ¼ 26:9 min;
20
½aꢁ ¼ +102.0 (c 0.4, CHCl3); IR (CHCl3): m 2983, 1719,
D
20
D
orless oil (118 mg). ½aꢁ ¼ +21.8 (c 0.9, CHCl3); IR
1637 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d 1.24 (t,
(CHCl3): m 2989, 2979, 1719, 1642 cmꢀ1
;
1H NMR
J ¼ 7:1 Hz, 3H, CH3), 1.47 (s, 3H, CH3), 4.15 (m, 3H,
CH2+CHA), 4.26 (m, 1H, CHB), 4.40 (m, 1H, CH), 5.97
(d, J ¼ 5:8 Hz, 1H, @CH), 7.00 (d, J ¼ 5:8 Hz, 1H,
@CH); 13C NMR (100 MHz, CDCl3): d 14.4, 22.3, 57.3,
62.0, 73.3, 101.9, 129.2, 150.4, 168.6, 174.5.
(400 MHz, CDCl3): d for (S,S)-8d 1.14 (m, 6H, CH2),
1.42 (s, 3H, CH3), 1.61 (m, 7H, CH2+CH), 3.40 (m, 1H,
CHA), 3.72 (m, 1H, CHB), 4.12 (m, 1H, CH), 5.87 (d,
J ¼ 5:7 Hz, 1H, @CH), 6.91 (d, J ¼ 5:7 Hz, 1H, @CH);
for (S,R)-8d 1.14 (m, 6H, CH2), 1.49 (s, 3H, CH3), 1.61
(m, 7H, CH2+CH), 3.40 (m, 1H, CHA), 3.80 (m, 1H,
CHB), 3.95 (m, 1H, CH), 5.90 (d, J ¼ 5:7 Hz, 1H,
@CH), 6.91 (d, J ¼ 5:7 Hz, 1H, @CH); 13C NMR
(100 MHz, CDCl3): d for (S,S)-8d 23.7, 26.6, 26.9, 33.3,
34.1, 34.6, 36.2, 43.1, 56.2, 75.8, 101.1, 129.4, 150.4,
173.8; for (S,R)-8d 23.7, 26.6, 33.2, 33.4, 35.2, 43.0, 54.5,
75.0, 101.1, 128.4, 151.1, 177.2; MS (m=z) (rel abund):
235 [Mþ] (6), 220(16), 204(100), 191(6), 138(24), 122(58),
109(28), 93(56), 80(34). Anal. Calcd for C14H21NO2
(235.32): C, 71.46; H, 8.99; N, 5.95.
4.2.16. (R,S)-Ethyl-7a-methyl-5-oxo-2,3,5,7a-tetrahydro-
pyrrolo[2,1b][1,3]oxazole-3-carboxylate (R,S)-8f. Light
yellow oil (82 mg). HPLC (Chiralcel OD): tR ¼ 27:1 min;
20
½aꢁ ¼ )40.8 (c 0.4, CHCl3).
D
4.2.17. (R,R)-Ethyl-7a-methyl-5-oxo-2,3,5,7a-tetrahydro-
pyrrolo[2,1b][1,3]oxazole-3-carboxylate (R,R)-8f. Light
yellow oil (12 mg). HPLC (Chiralcel OD): tR ¼ 28:2 min;
20
½aꢁ ¼ )108.9 (c 0.5, CHCl3).
D
4.2.12. (R,R)-3-Benzyl-7a-methyl-2,3-dihydropyrrolo-
[2,1b][1,3]oxazol-5(7aH)-one (R,R)-8e. Colorless oil
20
D
(101 mg). ½aꢁ ¼ )50.8 (c 0.3, CHCl3); IR (CHCl3): m
4.2.18. (S,S,RS)-3-[Hydroxy(phenyl)methyl]-7a-methyl-
2,3-dihydropyrrolo[2,1b][1,3]oxazol-5(7aH)-one (S,S,RS)-
3013, 2978, 1707, 1637 cmꢀ1
;
1H NMR (400 MHz,
20
D
CDCl3): d 1.43 (s, 3H, CH3), 2.69 (m, 1H, CHA), 3.64
(m, 1H, CHB), 3.85 (m, 1H, CH), 3.93 (m, 2H, CH2),
5.93 (d, J ¼ 5:7 Hz, 1H, @CH), 6.95 (d, J ¼ 5:7 Hz, 1H,
@CH), 7.13 (m, 3H, ArH), 7.19 (m, 2H, ArH); 13C
NMR (100 MHz, CDCl3): d 21.4, 32.4, 56.8, 73.5, 99.7,
125.0, 127.1, 127.2, 127.5, 136.8, 148.7, 172.6; MS (m=z)
(rel abund): 229 [Mþ] (30), 198(12), 137(100), 109(66),
90(90), 77(42). Anal. Calcd for C14H15NO2 (229.11): C,
73.34; H, 6.59; N, 6.11.
8g. Colorless oil (132 mg). ½aꢁ ¼ +74.1 (c 1.2, CHCl3);
IR (CHCl3): m 3013, 2978, 1707, 1637 cmꢀ1; H NMR
1
(400 MHz, CDCl3): d for (S,S,S)-8g 1.45 (s, 3H, CH3),
3.60 (d, J ¼ 7:9 Hz, 1H, CHA), 3.80 (m, 1H, CHB), 4.00
(m, 1H, CH), 4.91 (dd, J ¼ 3:3, 6.3 Hz, 1H, CH), 6.01
(d, J ¼ 5:7 Hz, 1H, @CH), 6.98 (d, J ¼ 5:7 Hz, 1H,
@CH), 7.26 (m, 5H, ArH); for (S,S,R)-8g 1.64 (s, 3H,
CH3), 3.60 (d, J ¼ 7:9 Hz, 1H, CHA), 3.69 (m, 1H,
CHB), 4.00 (m, 1H, CH), 4.76 (d, J ¼ 9:3 Hz, 1H, CH),
6.03 (d, J ¼ 5:7 Hz, 1H, @CH), 7.10 (d, J ¼ 5:7 Hz, 1H,
@CH), 7.26 (m, 5H, ArH); 13C NMR (100 MHz,
CDCl3): d for (S,S,S)-8g 24.5, 64.7, 72.7, 84.8, 102.3,
127.0, 128.8, 129.1, 129.0, 139.8, 151.1, 174.8; for
(S,S,R)-8g 22.9, 57.6, 67.1, 73.5, 100.4, 126.7, 128.7,
128.8, 129.1, 137.8, 152.4, 175.8; MS (m=z) (rel abund):
244 [M)1] (1), 226(3), 149(5), 138(100), 122(17), 108(51),
96(94), 76(86). Anal. Calcd for C14H15NO3 (245.27): C,
68.56; H, 6.16; N, 5.71.
4.2.13. (R,S)-3-Benzyl-7a-methyl-2,3-dihydropyrrolo-
[2,1b][1,3]oxazol-5(7aH)-one (R,S)-8e. Colorless oil
20
D
(16 mg). ½aꢁ ¼ +11.0 (c 0.2, CHCl3); IR (CHCl3): m
3013, 2978, 1707, 1637 cmꢀ1
;
1H NMR (400 MHz,
CDCl3): d 1.43 (s, 3H, CH3), 2.82 (m, 1H, CHA), 3.07
(m, 1H, CHB), 3.95 (m, 2H, CH2), 4.15 (m, 1H, CH),
5.92 (d, J ¼ 5:7 Hz, 1H, @CH), 6.93 (d, J ¼ 5:7 Hz, 1H,
@CH), 7.18 (m, 5H, Ar); 13C NMR (100 MHz, CDCl3):
d 23.3, 40.6, 57.3, 73.3, 100.8, 126.6, 128.0, 128.9, 129.7,
137.3, 151.3, 178.0.
4.2.19. 1-[(1S,2R)-2-Hydroxy-1-methyl-2-phenylethyl]-5-
methylene-1,5-dihydro-2H-pyrrol-2-one (1R,2S)-10.9 Yel-
20
low oil. ½aꢁ ¼ +14.5 (c 5.5, CHCl3); IR (CHCl3): m 2986,
D
4.2.14. (S,R)-Ethyl-7a-methyl-5-oxo-2,3,5,7a-tetrahydro-
pyrrolo[2,1b][1,3]oxazole-3-carboxylate (S,R)-8f. Light
1715, 1640 cmꢀ1; 1H NMR (400 MHz, CDCl3): d 1.27 (d,
J ¼ 7:0 Hz, 3H, CH3), 3.92 (m, 1H, CH), 4.74 (s, 2H,
CH2), 4.86 (s, 1H, CH), 5.08 (s, 1H, OH), 6.08 (d,
J ¼ 4:6 Hz, 1H, @CH), 6.84 (d, J ¼ 5:7 Hz, 1H, @CH),
7.27 (m, 5H, ArH); 13C NMR (100 MHz, CDCl3): d
12.2, 56.6, 75.5, 97.9, 125.4, 126.5, 127.8, 128.2, 138.0,
142.5, 145.8, 172.1. Anal. Calcd for C14H15NO2
(229.27): C, 73.34; H, 6.59; N, 6.11. Found: C, 73.48; H,
6.47; N, 6.01.
yellow oil (80 mg). HPLC (Chiralcel OD): tR ¼ 26:5 min;
20
½aꢁ ¼ +44.6 (c 0.6, CHCl3); IR (CHCl3): m 2983, 1719,
D
1637 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d 1.24 (t,
J ¼ 7:1 Hz, 3H, CH3), 1.57 (s, 3H, CH3), 4.18 (m, 2H,
CH2), 4.29 (m, 2H, CH2), 4.50 (m, 1H, CH), 5.96 (d,
J ¼ 5:7 Hz, 1H, @CH), 7.00 (d, J ¼ 5:7 Hz, 1H, @CH);
13C NMR (100 MHz, CDCl3): d 14.5, 22.2, 57.0, 62.0,
72.5, 101.7, 127.7, 151.5, 170.4, 176.9; Anal. Calcd for
C10H13NO4 (211.21): C, 56.86; H, 6.20; N, 6.63.
4.2.20. 1-[(1R,2S)-2-Hydroxy-1-methyl-2-phenylethyl]-5-
methylene-1,5-dihydro-2H-pyrrol-2-one (1S,2R)-10.9 Yel-
4.2.15. (S,S)-Ethyl-7a-methyl-5-oxo-2,3,5,7a-tetrahydro-
pyrrolo[2,1b][1,3]oxazole-3-carboxylate (S,S)-8f. Light
20
low oil. ½aꢁ ¼ )14.4 (c 5.5, CHCl3).
D

F. Aydogan, A. S. Demir / Tetrahedron: Asymmetry 15 (2004) 259–265
265
€
ꢀ
8. (a) Demir, A. S.; Akhmedov, I. M.; Sßeßsenoglu, O.;
Acknowledgements
_
€
Alpturk, O.; Apaydın, S.; Gerßcek, Z.; Ibrahimzade, N. J.
Chem. Soc., Perkin Trans. 1 2001, 1162; (b) Demir, A. S.;
Akhmedov, I. M.; Tanyeli, C.; Gerßcek, Z.; Gadzhili, R. A.
Tetrahedron: Asymmetry 1997, 5, 753.
Financial support was funded by the Middle East
Technical University (BAP-2003), the Scientific and
Technical Research Council of Turkey (TUBITAK), the
Turkish Academy of Sciences (TUBA), the Turkish
State Planning Organization (DPT), and the Yildiz
Technical University is gratefully acknowledged.
9. Demir, A. S.; Aydogan, F.; Akhmedov, I. M. Tetrahedron:
Asymmetry 2002, 13, 601.
10. (a) Romo, D.; Romine, J. L.; Midura, W.; Meyers, A. I.
Tetrahedron 1990, 46, 4951; (b) Meyers, A. I.; Fleming,
S. A. J. Am. Chem. Soc. 1986, 108, 306; (c) Meyers,
A. I.; Garland, R. J. J. Am. Chem. Soc. 1984, 106,
1146.
References and notes
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