Asymmetric synthesis of 1-benzyl-2-((S)-2′,2′-dimethyl-1′,3′-dioxolan-4′-yl)-1H-pyrrole using chiral imines

Article abstract of DOI:10.1016/j.tetasy.2006.07.008

A new synthesis of chiral alkyl pyrroles and pyrrolines has been achieved in an easy straightforward way, using the addition of organometallics to chiral imines.

Full text of DOI:10.1016/j.tetasy.2006.07.008

Tetrahedron: Asymmetry 17 (2006) 2260–2264
Asymmetric synthesis of 1-benzyl-2-((S)-20,20-dimethyl-
10,30-dioxolan-40-yl)-1H-pyrrole using chiral imines
*
´
´
´
David Dıez, Ana B. Anton, Pilar Garcıa, Marta G. Nunez, Narciso M. Garrido,
˜
Rosalina F. Moro, Isidro S. Marcos, Pilar Basabe and Julio G. Urones
Dpto. de Quı´mica Orga´nica, Facultad de Ciencias Quimicas, Universidad de Salamanca, 37008 Salamanca, Spain
Received 2 July 2006; accepted 5 July 2006
Available online 23 August 2006
Abstract—A new synthesis of chiral alkyl pyrroles and pyrrolines has been achieved in an easy straightforward way, using the addition of
organometallics to chiral imines.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
studied methodology,8 that has been used by Reissig
et al. for the synthesis of non-chiral pyrroles,9a and more
recently reported the synthesis of pyrrole 17 as a side
product in the synthesis of enantiopure amino polyols
and pyrrolidines derivatives was reported.9b We have been
interested in the addition of vinylsulfones to imines derived
from (R)-glyceraldehyde for the synthesis of aminoacid
derivatives, Figure 2.10,11
Pyrroles and pyrrolines are heterocycles present in many
bioactive natural1 and therapeutic compounds,2 new or-
ganic materials3 and anion binding agents.3d Monopyrrolic
compounds are particularly important4 due to their pres-
ence in ionophores as Routiennocin, 15 while nucleus 2 is
present in many alkaloids of the Senecio family of plants
(Fig. 1).6
MOMO
HOOC
MOMO
OH
NHBoc
Ref. 10
O
OH
OH
COOH
N
SO2Ph
4
5
O
O
N
N
H
N
O
Bn
17
O
O
NBn
O
OH
Ph
O
O
3
2
NHBoc
O
SO2Ph
Ref. 11
Routiennocin, 1
6
Figure 1.
Ph
Figure 2.
Therefore many syntheses of pyrroles have been described,7
although to the best of our knowledge, no synthesis of chi-
ral 2-(10-hydroxyalkyl) pyrroles has been reported. The
addition of organometallic to chiral imines is a very well
2. Results and discussion
The addition of the lithium anion of 7 to acetone has
previously been used by us, for the synthesis of a variety
of tetrahydropyran and tetrahydrofuran derivatives.12
*
Corresponding author. Tel.: +34 923 294474; fax: +34 923 294574;
e-mail: ddm@usal.es
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.07.008

D. Dı´ez et al. / Tetrahedron: Asymmetry 17 (2006) 2260–2264
2261
Hence we decided to study the addition of this anion under
8
9
different conditions13 to imine 3 (Scheme 1).
a
NHBn
4
65%
1
61%
a
NHBn
3´
3´
O
O
O
O
O
O
OR
OR
O
O
O
NBn 1´
NHBn
NHBn
4
O
3
+
n-BuLi
R
1´
R
OTHP 11
+
OTHP 10
OH
Br
13
15
OH
Br
12
14
OTHP
1
OTHP
OTHP
7
8
9
b
42%
b
40%
H
H
3´
O
3´
O
2
Entry Additive Tª/ºC Solvent Yield Ratio 8/9
5
O
O
5
+
+
2
N
N
N
1
2
3
4
-
-20
-20
-20
50
THF
THF
THF
56
77
45
55
50 / 50
54 / 46
10 / 90
22 / 78
Bn
Bn
Bn
35 / 5
13 / 29
BF3Et2O
CeCl3
ZnMe2
O
1´
O
1´
c
17
c
18
16
Toluene
40%
40%
Scheme 1.
Scheme 2. Reagents: (a) H2, Lindlar catalyst, EtOAc, rt; (b) 1. TsOH,
MeOH, 2. CBr4, PPh3, DCM, then NEt3; (c) DDQ, DCM.
In our hands, the best ratio achieved was at ꢀ20 ꢁC in THF
as solvent and with the addition of CeCl3 (entry 3),
although in low yield. In order to determine the stereo-
chemistry of compounds 8 and 9, obtained in the addition
reaction, they were separated by column chromatography
and transformed into the known compounds.
4. Experimental
4.1. General
Unless otherwise stated, all chemicals were purchased in
the highest purity commercially available and were used
without further purification. IR spectra were recorded on
a AVATAR 370 FT-IR Thermo Nicolet spectropho-
tometer. 1H and 13C NMR spectra were performed in
CDCl3 and referenced to the residual peak of CHCl3 at d
When compounds 8 and 9 were hydrogenated using Lind-
lar catalyst, they gave the cis-olefins 10 and 11, respectively,
in good yield. Compounds 10 and 11 were deprotected
under dilute conditions14 to the corresponding alcohols
12 and 13. These alcohols were submitted without purifica-
tion, to a one-pot reaction. They were then treated sepa-
rately with CBr4 and PPh3 in dichloromethane and when
the reaction was complete as shown by TLC, an equivalent
of Et3N was added, to give a mixture of pyrroline 16 and
pyrrole 17 from bromide 14 in a 35/5 ratio and pyrroline
18 and pyrrole 17 in a 29/13 ratio from bromide 15 in mod-
1
7.26 ppm and d 77.0 ppm, for H and 13C, respectively,
using Varian 200 VX and Bruker DRX 400 instruments.
Chemical shifts are reported in d ppm and coupling
constants (J) are given in hertz. MS and HRMS were
performed in a QSTAR XL spectrometer using electro-
spray technique. Optical rotations were determined in a
Perkin–Elemer 241 polarimeter in 1 dm cells. Diethyl ether,
THF and benzene were distilled from sodium, and dichloro-
methane was distilled under argon from CaH2.
erate yield for the three steps. Pyrroline 18 has previously
15
´
been synthesized by Dıaz-de-Villegas and Galvez et al.
and so the stereochemistry of the addition compounds to
the imine 3 and pyrrolines 16 and 18 is confirmed. The ste-
reochemistry of pyrrole 17 came from the starting material.
Pyrrolines 16 and 18 were transformed separately to pyr-
role 17 by treatment with DDQ in DCM. Pyrrole 17 was
obtained as well without separation of pyrrolines that im-
prove the yields. Although the synthesis of pyrrole 17 has
been described previously as a side product,9b this method-
ology improves the yield and converts this compound into
a chiral synthon that can be used in asymmetric synthesis
(Scheme 2).
4.2. Procedures of the addition reaction to imine 3
Additive: none. n-BuLi 1.6 M (27.4 mL, 43.8 mmol) was
added to a solution of 7 (7.16 g, 51.1 mmol) in THF
(100 mL) at ꢀ20 ꢁC. After 10 min, imine 3 (3.20 g,
14.6 mmol) was added to the reaction flask via cannula as
a solution in THF (29 mL). The reaction mixture was left
to stir overnight at ꢀ20 ꢁC ! rt under Ar before the addi-
tion of saturated ammonium chloride solution (16 mL).
The product was extracted into EtOAc (3·). The organic
extracts were combined, washed with brine, dried over
anhydrous Na2SO4, filtered and the solvent removed in va-
cuo. The resultant oil was submitted to flash silica column
chromatography (hexane–EtOAc, 9:1) to yield 1.41 g
(3.94 mmol, 27%) of 8 and 1.52 g (4.23 mmol, 29%) of 9.
3. Conclusion
In conclusion a new methodology for the synthesis of chiral
2-substituted alkylpyrroles and pyrrolines has been opened.
All compounds can be obtained in both enantiomeric
forms, by choosing the appropriate starting material, add-
ing more versatility to this synthesis. Further development
using this methodology is ongoing.
Additive: BF3Et2O. To a solution of compound 7 (1.14 g,
8.15 mmol) in THF (16.3 mL), n-BuLi 1.6 M (4.4 mL,
7.0 mmol) was slowly added at ꢀ20 ꢁC under Ar with

2262
D. Dı´ez et al. / Tetrahedron: Asymmetry 17 (2006) 2260–2264
stirring. After 10 min, the reaction mixture was cooled to
ꢀ78 ꢁC and BF3Et2O (0.9 mL, 7.0 mmol) was added to
the solution and the mixture was stirred for 10 min. Imine
3 (510 mg, 2.33 mmol) was then added and the mixture stir-
red for 1 h at ꢀ78 ꢁC before addition of NaOH 10% solu-
tion (12 mL). The product was extracted into Et2O (3·).
The organic extracts were combined, washed with brine,
dried over anhydrous Na2SO4, filtered and the solvent
was removed in vacuo. The resultant oil was submitted to
flash silica column chromatography (hexane–EtOAc, 8:2)
to yield 642 mg (1.78 mmol, 77%) of 8 and 9.
96.6 (C-100), 109.9 (C-20), 127.3 (Cpara–Ph), 128.5 and
128.6 (Cortho and Cmeta–Ph), 139.6 (Cipso–Ph). MS, ESI:
382 [M+Na]+, 360 [M+H]+ 221; HRMS (ESI): calculated
for C21H30NO4, [M+H]+: 360.2169; found 360.2152.
4.2.2. Tetrahydropyranyl derivative of (S)-4-(benzylamino)-
4-((S)-20,20-dimethyl-10,30-dioxolan-40-yl)but-2-yn-1-ol, 9.
20
½aꢁD ¼ ꢀ59:0 (c 1.25, CHCl3). IR (film) m (cmꢀ1): 3150–
3600, 2985, 2940, 2870, 1735, 1669, 1458, 1378, 1263,
1212, 1157, 1087, 1026. 1H NMR (CDCl3, 200 MHz) d
(ppm): 1.32 (6H, s, 2Me-20), 1.42–1.79 (6H, m, 2H-200,
2H-300, 2H-400), 3.42–3.54 (2H, m, H-4, HA-500), 3.83 and
4.07 (1H each, 2d, J = 13.2 Hz, –CH2Ph), 3.78–3.88 (1H,
m, HB-500), 3.92 (1H, dd, J = 5.6 and 8.4 Hz, HA-50),
4.02–4.08 (1H, m, HB-50), 4.15–4.26 (1H, m, H-40), 4.30
(2H, s, H-1), 4.76–4.86 (1H, m, H-100), 7.22–7.36 (5H, m,
–CH2Ph). 13C NMR (CDCl3, 50 MHz) d (ppm): 19.3 (C-
300), 25.5 (C-400), 26.9 (2Me-20), 30.4 (C-200), 50.8 (–CH2Ph),
52.3 (C-4), 54.3 (C-1), 62.2 (C-500), 67.1 (C-50), 77.5 (C-40),
82.1 (C-3), 82.6 (C-2), 96.9 (C-100), 110.3 (C-20), 127.6
(Cpara–Ph), 128.7 (Cmeta–Ph), 128.8 (Cortho–Ph), 138.4
(Cipso–Ph). MS, ESI: 382 [M+Na]+, 360 [M+H]+.
HRMS (ESI): calculated for C21H30NO4, [M+H]+:
360.2169; found: 360.2168.
Additive: CeCl3. Cerium chloride (1.7 g, 6.9 mmol) was
placed in a 100 mL flask and was heated with stirring at
140 ꢁC in vacuo for 30 min and cooled. Dry THF (4 mL)
was added with stirring under Ar and stirring was contin-
ued for 2 h. The resulted suspension was then cooled to
ꢀ78 ꢁC, and the previously formed organolithium com-
pound (6.9 mmol) was added with stirring. After being
kept at the same temperature for 10 min, imine 3
(500 mg, 2.3 mmol) in THF (4.6 mL) was added and the
mixture stirred overnight at ꢀ78 ꢁC ! rt. The reaction
mixture was then treated with saturated ammonium
chloride solution, filtered through Celite and the product
extracted into EtOAc (3·). The organic extracts were
combined, washed with brine, dried over anhydrous
Na2SO4, filtered and the solvent was removed in vacuo.
The resultant oil was submitted to flash silica column chro-
matography (hexane–EtOAc, 8:2) to yield 371 mg
(1.03 mmol, 45%) of 8 and 9.
4.2.3. Tetrahydropyranyl derivative of (R,Z)-4-(benzyl-
amino)-4-((S)-20,20-dimethyl-10,30-dioxolan-40-yl)but-2-en-1-
ol, 10. To a solution of 8 (367 mg, 1.03 mmol) in dry ethyl
acetate (5.2 mL) was added the Lindlar catalyst (142 mg).
The mixture was stirred for 10 min before the addition of
quinoline (115 lL, 1.13 mmol). The mixture was left to stir
under hydrogen for 24 h. It was then filtered through Celite
and the solvent was evaporated in vacuo. The product was
Additive: ZnMe2. In a flask under an inert Ar atmosphere,
alkyne 7 (881 mg, 5.7 mmol) was dissolved in anhydrous
toluene (20 mL). A 2.0 M solution of ZnMe2 in toluene
(2.15 mL, 5.7 mmol) was then carefully added, and the
resulting mixture was stirred at rt for 30 min. Imine 3
(500 mg, 2.3 mmol) was then added via cannula as a solu-
tion in toluene (3 mL), and the temperature was increased
to 50 ꢁC. The resulting solution was stirred for 24 h. The
reaction was quenched with water. The aqueous phase
was extracted with CH2Cl2 (3·), and the organic phase
washed with brine and dried over anhydrous Na2SO4.
The evaporation of the solvent under reduced pressure fur-
nished the crude product, which was purified by flash col-
umn chromatography to yield 454 mg (1.27 mmol, 55%)
of 8 and 9.
purified by column chromatography (hexane/EtOAc 9:1)
20
to yield 241 mg (0.67 mmol, 65%) of 10. ½aꢁD ¼ þ6:4 (c
1.38, CHCl3). IR (film) m (cmꢀ1): 3200–3600, 2990, 2935,
1
2875, 1725, 1684, 1448, 1383, 1258, 1202, 1127. H NMR
(CDCl3, 200 MHz) d (ppm): 1.33 (3H, s, Me-20), 1.40
(3H, s, Me-20), 1.38–1.85 (6H, m, 2H-200, 2H-300, 2H-400),
2.45 (1H, br s, NH), 3.42–3.48 (1H, m, HA-500), 3.62 (1H,
dd, J = 4.6 and 9.6 Hz, H-4), 3.64, 3.66 and 3.90 (2H, 3d,
J = 13.4 Hz, –CH2Ph), 3.75–3.85 (1H, m, HB-500), 3.92–
4.05 (2H, m, 2H-50), 4.16 (2H, d, J = 6.9 Hz, H-1), 4.16–
4.32 and 4.26–4.32 (1H, 2m, H-40), 4.55–4.60 (1H, m,
1H-100), 5.44 (1H, dd, J = 9.7 and 11.2 Hz, H-3), 5.90
(1H, dt, J = 6.9 and 12.1 Hz, H-2), 7.19–7.35 (5H, m,
–CH2Ph). 13C NMR (CDCl3, 50 MHz) d (ppm): 19.3 (C-
300), 25.0 (Me-20), 25.3 (C-400), 26.2 (Me-20), 30.5 (C-200),
50.7 (–CH2Ph), 55.6 (C-4), 62.1 (C-1), 63.1 and 63.2 (C-
500), 66.0 (C-50), 77.8 (C-40), 98.1 and 98.2 (C-100), 109.0
4.2.1. Tetrahydropyranyl derivative of (R)-4-(benzylamino)-
4-((S)-20,20-dimethyl-10,30-dioxolan-40-yl)but-2-yn-1-ol, 8.
20
½aꢁD ¼ þ16:3 (c 0.9, CHCl3), IR (film) m (cmꢀ1): 3150–
3600, 2940, 2865, 1453, 1373, 1263, 1197, 1127, 1067,
1021; 1H NMR (CDCl3, 200 MHz) d (ppm): 1.10–1.95
(6H, m, 2H-200, 2H-300, 2H-400), 1.34, 1.43 and 1.51 (6H,
3s, 2Me-20), 3.42–3.61 (1H, m, HA-500), 3.80 and 4.05 (1H
each, 2d, J = 12.8 Hz, –CH2Ph), 3.76–3.94 (1H, m, HB-
500), 3.94–4.14 (2H, m, 2H-50), 4.15–4.24 (1H, m, H-40),
4.27 (1H, d, J = 4.4 Hz, H-4), 4.34 (2H, s, 2H-1), 4.76–
4.82 and 4.82–4.89 (1H, 2m, H-100), 7.18–7.42 (5H, m,
–CH2Ph); 13C NMR (CDCl3, 50 MHz) d (ppm): 19.0 and
19.2 (C-300), 25.5 (C-400), 26.6 (Me-20), 30.4 (C-200), 31.5
(Me-20), 51.4 (–CH2Ph), 51.9 (C-4), 54.4 (C-1), 61.9 and
62.0 (C-500), 67.0 (C-5), 77.6 (C-40), 81.3 (C-3), 83.8 (C-2),
(C-20), 127.0 (Cpara–Ph), 128.1 (Cmeta–Ph), 128.4 (Cortho
–
Ph), 130.5 (C-3), 131.1 and 131.2 (C-2), 139.7 (Cipso–Ph).
MS, ESI: 362 [M+H]+, 278. HRMS (ESI): calculated for
C21H32NO4, [M+H]+: 362.2326; found: 362.2335.
4.2.4. Tetrahydropyranyl derivative of (S,Z)-4-(benzyl-
amino)-4-((S)-20,20-dimethyl-10,30-dioxolan-40-yl)but-2-en-1-
ol, 11. To a solution of 9 (300 mg, 0.84 mmol) in dry ethyl
acetate (8.4 mL) was added the Lindlar catalyst (117 mg).
The mixture was stirred for 10 min before the addition of
quinoline (108 lL, 0.92 mmol). The mixture was left to stir
under hydrogen for 20 h. It was then filtered through Celite

D. Dı´ez et al. / Tetrahedron: Asymmetry 17 (2006) 2260–2264
2263
and the solvent was evaporated in vacuo. The product was
purified by column chromatography (hexane–EtOAc 6:4)
purified by column chromatography (hexane/EtOAc 8:2)
to yield 63.5 mg (0.23 mmol, 56%) of 13. The yield
20
to yield 185 mg (0.51 mmol, 61%) of 11. ½aꢁD ¼ ꢀ13:9 (c
improved when diol 13 was not submitted to chromato-
20
1.02, CHCl3). IR (film) m (cmꢀ1): 3327, 2984, 2940, 1496,
1455, 1370, 1259, 1211, 1157, 1119, 1063, 1027, 905, 849,
815, 738. 1H NMR (CDCl3, 200 MHz) d (ppm): 1.32
(3H, s, Me-20), 1.35 and 1.36 (3H, 2s, Me-20), 1.47–1.87
(6H, m, 2H-200, 2H-300, 2H-400), 2.20 (1H, br s, NH), 3.42–
3.53 (2H, m, H-4 and HA-500), 3.61, 3.62 and 3.88 (2H,
3d, J = 13.4 Hz, –CH2Ph), 3.65–3.75 (1H, m, HA-50),
3.77–3.85 (1H, m, HB-500), 3.90–4.07 (3H, m, HB-50 and
H-1), 4.15–4.20 and 4.23–4.30 (1H, 2m, H-40), 4.57–4.59
(1H, m, H-100), 5.38 (1H, t, J = 10.6 Hz, H-3), 5.86 (1H,
dt, J = 6.9 and 12.2 Hz, H-2), 7.18–7.36 (5H, m, –CH2Ph).
graphy. ½aꢁD ¼ ꢀ0:7 (c 0.67, CHCl3). IR (film) m (cmꢀ1):
1
3600–3100, 2986, 2921, 2866, 1463, 1381, 1216, 1079. H
NMR (CDCl3, 200 MHz) d (ppm): 1.32 (3H, s, Me-20),
1.34 (3H, s, Me-20), 3.35–3.60 (2H, br s, NH and OH),
3.42 (1H, t, J = 8.4 Hz, H-4), 3.95 and 3.65 (1H each, 2d,
J = 13.2 Hz, –CH2Ph), 3.70 (1H, dd, J = 5.8 and 8.4 Hz,
HA-50), 3.98 (1H, dd, J = 6.2 and 8.4 Hz, HB-50), 4.18
(2H, d, J = 5.4 Hz, H-1), 4.05–4.26 (1H, m, 1H-40), 5.33–
5.43 (1H, m, H-3), 5.86 (1H, dt, J = 5.4 and 11.8 Hz, H-
2), 7.26–7.34 (5H, m, –CH2Ph). 13C NMR (CDCl3,
50 MHz) d (ppm): 25.7 (Me-20), 27.1 (Me-20), 50.9
(–CH2Ph), 58.3 (C-4), 59.8 (C-1), 66.9 (C-50), 78.4 (C-40),
109.9 (C-20), 127.5 (Cpara–Ph), 128.4 (C-3), 128.8 (Cortho
and Cmeta–Ph), 135.3 (C-2), 139.5 (Cipso–Ph).
13
C NMR (CDCl3, 50 MHz) d (ppm): 19.4 (C-300), 25.4 (C-
400), 25.5 (Me-20), 26.8 (Me-20), 30.5 (C-200), 50.8 (–CH2Ph),
57.6 (C-4), 62.1 and 62.2 (C-1), 63.2 and 63.4 (C-500), 66.6
(C-50), 78.2 (C-4), 98.2 and 98.3 (C-100), 109.5 (C-20),
126.9 (Cpara,–Ph), 128.1 (Cmeta–Ph), 128.3 (Cortho–Ph),
130.9 and 131.0 (C-3), 131.4 and 131.5 (C-20), 140.0
(Cipso–Ph). MS, ESI: 362 [M+H]+, 278. HRMS (ESI):
calculated for C21H32NO4, [M+H]+: 362.2326; found:
362.2323.
4.2.7. (S)-1-Benzyl-2,5-dihydro-2-((S)-20,20-dimethyl-10,30-
dioxolan-40-yl)-1H-pyrrole, 16. To
a solution of 12
(68.3 mg, 0.25 mmol) in DCM (1.7 mL) were added PPh3
(70.8 mg, 0.27 mmol) and CBr4 (89.6 mg, 0.27 mmol).
The mixture was left to stir for 30 min before the addition
of Et3N (105 lL, 0.75 mmol). The solution was stirred for
2 h, then diluted with DCM and washed with an HCl (2 M)
solution (2·), sodium bicarbonate (5%) solution (2·), water
and saturated brine. The organic phase was dried with
anhydrous sodium sulfate, filtered and the solvent removed
in vacuo. The product was purified by column chromato-
graphy (hexane–EtOAc 8:2) to yield 3.2 mg (0.012 mmol,
4.2.5. (R,Z)-4-(Benzylamino)-4-((S)-20,20-dimethyl-10,30-dio-
xolan-40-yl)but-2-en-1-ol, 12. To a solution of 10 (113 mg,
0.31 mmol) in MeOH (11.4 mL) was added a catalytic
amount of p-toluensulfonic acid monohydrate. The mix-
ture was left to stir for 1 h. The solution was then diluted
with EtOAc, and washed with a solution of sodium bicar-
bonate (5%), water and saturated brine. The organic phase
was dried with anhydrous sodium sulfate, filtered and the
solvent removed in vacuo. The product was purified by col-
umn chromatography (hexane–EtOAc 6:4) to yield 40 mg
5%) of 17 and 22.7 mg (0.09 mmol, 35%) of 16.
20
½aꢁD ¼ þ138:4 (c 0.41, CHCl3). IR (film) m (cmꢀ1): 2990,
1
2935, 2870, 2789, 1378, 1217, 1157, 1067, 966. H NMR
(CDCl3, 200 MHz) d (ppm): 1.34 (3H, s, Me-20), 1.44
(3H, s, Me-20), 3.25 (1H, ddt, J = 2.2, 2.2, 4.0 and 14 Hz,
HA-5), 3.66 and 4.14 (1H each, 2d, J = 13.6 Hz, –CH2Ph),
3.60–3.67 (1H, m, HB-5), 3.82 (1H, dd, J = 6.2 and 8.2 Hz,
HA-50), 3.87–3.98 (1H, m, H-2), 4.00 (1H, dd, J = 6.6 and
8.0 Hz, HB-50), 4.06–4.20 (1H, m, H-40), 5.66–5.72 (1H, m,
H-3), 5.85–5.89 (1H, m, H-4), 7.23–7.33 (5H, m, –CH2Ph).
13C NMR (CDCl3, 50 MHz) d (ppm): 25.1 (Me-20), 26.7
(Me-20), 59.8 (–CH2Ph), 61.0 (C-5), 65.9 (C-50), 72.6 (C-
2), 77.2 (C-40), 109.4 (C-20), 127.0 (C-3 and Cpara–Ph),
128.6 (Cortho and Cmeta–Ph), 129.8 (C-4), 140.2 (Cipso–Ph).
MS, ESI: 260[M+H]+, 202. HRMS (ESI): calculated for
[M+H]+: 260.1645; found: 260.1655.
(0.14 mmol, 46%) of 12. Yield was improved when diol
20
12 was not submitted to chromatography. ½aꢁD ¼ ꢀ99:2
(c 1.27, CHCl3). IR (film) m (cmꢀ1): 3100–3600, 2986,
1
2926, 2871, 1682, 1463, 1370, 1266, 1211, 1151, 1030. H
NMR (CDCl3, 200 MHz) d (ppm): 1.34 (3H, s, Me-20),
1.41 (3H, s, Me-20), 2.60 (2H, br s, OH and NH), 3.51–
3.61 (1H, m, H-4), 3.67 and 3.89 (1H each, 2d,
J = 13.2 Hz, –CH2Ph), 3.78–3.94 (1H, m, HA-50), 4.07
(2H, d, J = 6.4 Hz, 2H-1), 4.01–4.16 (2H, m, H-40, HB-
50), 5.45 (1H, dd, J = 9.2 and 11.4 Hz, H-3), 5.98 (1H, dt,
J = 6.6 and 11.0 Hz, H-2), 7.22–7.35 (5H, m, –CH2Ph).
13C NMR (CDCl3, 50 MHz) d (ppm): 25.3 (Me-20), 26.5
(Me-20), 51.1 (–CH2Ph), 56.7 (C-4), 58.8 (C-1), 67.1
(C-50), 77.3 (C-40), 109.6 (C-20), 127.5 (Cpara–Ph), 128.4
(Cmeta–Ph), 128.7 (Cortho–Ph), 131.5 (C-3), 133.7 (C-2),
139.9 (Cipso–Ph). MS, ESI: 278 [M+H]+, 220. HRMS
(ESI): calculated for C16H24NO3, [M+H]+: 278.1751;
found: 278.1754.
4.2.8. (R)-1-Benzyl-2,5-dihydro-2-((S)-20,20-dimethyl-10,30-
dioxolan-40-yl)-1H-pyrrole, 18. To
a solution of 13
(106.6 mg, 0.38 mmol) in DCM (2.5 mL) was added PPh3
(109.6 mg, 0.42 mmol) and CBr4 (138.8 mg, 0.42 mmol).
The mixture was left to stir for 30 min before the addition
of Et3N (160 lL, 1.14 mmol). The solution was stirred
overnight, then diluted with DCM and washed with a
HCl (2 M) solution (2·), sodium bicarbonate (5%) solution
(2·), water and saturated brine. The organic phase was
dried with anhydrous sodium sulfate, filtered and the
solvent removed in vacuo. The product was purified by
column chromatography (hexane–EtOAc 8:2) to yield
4.2.6. (S,Z)-4-(Benzylamino)-4-((S)-20,20-dimethyl-10,30-di-
oxolan-40-yl)but-2-en-1-ol, 13. To a solution of 11 (148
mg, 0.41 mmol) in MeOH (15 mL) was added a catalytic
amount of p-toluensulfonic acid monohydrate. The
mixture was left to stir for 45 min. The solution was then
diluted with EtOAc, and washed with a solution of sodium
bicarbonate (5%), water and saturated brine. The organic
phase was dried with anhydrous sodium sulfate, filtered
and the solvent was removed in vacuo. The product was
12.5 mg (0.048 mmol, 13%) of 17 and 28.2 mg (0.11 mmol,
20
29%) of 18. ½aꢁD ¼ ꢀ73:0 (c 0.63, CHCl3). 1H NMR
(CDCl3, 200 MHz) d (ppm): 1.34 (3H, s, Me-20), 1.39

2264
D. Dı´ez et al. / Tetrahedron: Asymmetry 17 (2006) 2260–2264
(3H, s, Me-20), 3.22 (1H, dddd, J = 2.1, 2.1, 4.2, 14.7 Hz,
HA-5), 3.64 and 4.19 (1H each, 2d, J = 13.8 Hz, –CH2Ph),
3.71 (1H, dddd, J = 1.8, 3.6, 5.4, 14.7 Hz, HB-5), 3.87–3.97
(3H, m, H-2 and 2H-50), 4.09–4.16 (1H, m, H-40), 5.68–5.72
(1H, m, H-3), 5.75–5.82 (1H, m, H-4), 7.19–7.38 (5H, m,
–CH2Ph). 13C NMR (CDCl3, 50 MHz) d (ppm): 25.2
(Me-20), 26.5 (Me-20), 60.9 (C-5), 66.2 (C-50), 71.94 (C-2),
79.16 (C-40), 108.9 (C-20), 126.8 (C-3), 127.8 (C-4), 128.3
(Cortho and Cmeta–Ph), 128.9 (Cpara–Ph), 140.2 (Cipso–Ph).
2. (a) O’Toole-Colin, K.; Getzel, A.; Argenti, A.; Evans, M. A.;
Smith, D. C.; Dalglish, G. A.; Rifat, S.; Wilson, D. L.;
Taylor, B. M.; Miott, U.; Glersaye, J.; Lam, K. S.; McCra-
nor, B. J.; Berkowitz, J. D.; Miller, R. B.; Lukens, J. R.;
Krumpe, K.; Gupton, J. T.; Burnham, B. S. Molecules 2004,
9, 135, and references cited therein; (b) Huffman, J. W. Curr.
Med. Chem. 1999, 6, 705–720.
3. (a) Lee, C. F.; Yang, L. M.; Hwu, T. Y.; Feng, A. S.; Tseng,
J. C.; Luh, T. Y. J. Am. Chem. Soc. 2000, 122, 4992; (b)
Domingo, V. M.; Aleman, C.; Brillas, E.; Julia, L. J. Org.
Chem. 2001, 66, 4058; (c) Curran, D.; Grimshaw, J.; Perera,
S. D. Chem. Soc. Rev. 1991, 20, 391; (d) Sessler, J. L.;
Camiolo, S.; Gale, P. A. Coord. Chem. Rev. 2003, 240, 17.
4. Gossauer, A. Monopyrrolic Natural Compounds Including
Tetramic Acid Derivatives. In Forstschritte der Chemie
Organischer Naturstoffe; Herz, W., Falk, H., Kirby, G. W.,
Eds.; Springer: Wien, 2003; Vol. 86, pp 1–188.
4.2.9. 1-Benzyl-2-((S)-20,20-dimethyl-10,30-dioxolan-40-yl)-
1H-pyrrole, 17. To a solution of 16 and 18 (41.4 mg,
0.16 mmol) in DCM (1 mL) was added DDQ (36.3 mg,
0.16 mmol) under Ar at rt. The mixture was stirred for
30 min. Solvent was then evaporated under reduced pres-
sure. The product was purified by column chromatography
´
´
5. Dıez-Martın, D.; Kotecha, R. N.; Ley, S. V.; Mantegani, S.;
(hexane–EtOAc 9:1) to yield 16.5 mg (0.064 mmol, 40%) of
´
Menendez, J. C.; Organ, H. M.; White, A. D. Tetrahedron
20
17. ½aꢁD ¼ ꢀ20:7 (c 0.83, CHCl3). IR (film) m (cmꢀ1): 2990,
1992, 48, 7899.
1
2920, 2850, 1448, 1368, 1303, 1212, 1162, 1052. H NMR
6. (a) McNab, H.; Thornley, C. J. Chem. Soc., Perkin Trans. 1
2000, 3584; (b) Jakupovic, J.; Grenz, M.; Bohlmann, F.;
Niemeyer, H. M. Phytochemistry 1991, 30, 2691.
7. (a) Bellur, E.; Laanger, P. Tetrahedron Lett. 2006, 47, 2151,
and references cited therein; (b) Sundber, R. J. In Compre-
hensive Heterocyclic Chemistry II; Katrizky, A. R., Rees, C.
W., Scriven, E. S. V., Eds.; Pergamon Press: Oxford, 1996;
Vol. 2, pp 119–206; (c) Yang, Q.; Li, X.-Y.; Xiao, W.-J. P.
Tetrahedron Lett. 2006, 47, 3893.
(CDCl3, 200 MHz) d (ppm): 1.38 (3H, s, Me-20), 1.41
(3H, s, Me-20), 3.94–4.12 (2H, m, 2H-50), 4.99 (1H, t,
J = 6.6 Hz, H-40), 5.14 and 5.27 (1H each, 2d,
J = 16.2 Hz, –CH2Ph), 6.13–6.22 (2H, m, H-3 and H-4),
6.68–6.71 (1H, m, H-5), 7.03–7.08 (2H, m, Hmeta–Ph),
7.20–7.38 (3H, m, Hortho and Hpara–Ph). 13C NMR (CDCl3,
50 MHz) d (ppm): 26.2 (Me-20), 26.9 (Me-20), 50.9
(–CH2Ph), 68.6 (C-50), 70.6 (C-40), 107.8 (C-3 and
C-4), 109.7 (C-20), 123.7 (C-5), 126.8 (Cmeta–Ph), 127.7
(Cpara–Ph), 128.9 (Cortho–Ph), 129.3 (C-2), 138.4 (Cipso–Ph).
MS, ESI: 280 [M+Na]+, 245, 200, 149. HRMS (ESI):
calculated for [M+Na]+: 280.1308; found: 280.1311.
´
8. (a) Badorrey, R.; Cativiela, C.; Dıaz-de-Villegas, M. D.;
´
Galvez, J. A. Synthesis 1997, 747; (b) Badorrey, R.; Cativiela,
´
´
C.; Dıaz-de-Villegas, M. D.; Galvez, J. A. Tetrahedron 1997,
´
53, 1411; (c) Badorrey, R.; Cativiela, C.; Dıaz-de-Villegas, M.
´
D.; Galvez, J. A. Tetrahedron 2002, 58, 341; (d) Badorrey, R.;
´
´
´
Cativiela, C.; Dıaz-de-Villegas, M. D.; Dıez, R.; Galvez, J. A.
Eur. J. Org. Chem. 2003, 2268; (e) Bloch, R. Chem. Rev. 1998,
98, 1407, and references cited therein.
Acknowledgements
9. (a) Amombo, M. O.; Hausherr, A.; Reissig, H.-U. Synlett
1999, 1871; (b) Pulz, R.; Schade, W.; Reissig, H.-U. Synlett
2003, 405.
Financial support for this work came from the E.F.S.;
Spanish MEC (CTQ2005-06813/BQU) and Junta de Cas-
´
´
10. Dıez, D.; Garcıa, P.; Moro, R. F.; Marcos, I. S.; Basabe, P.;
Garrido, N. M.; Broughton, H. B.; Urones, J. G. Synthesis
2005, 3327.
´
tilla y Leon (Spain) (SA045A05). The authors also thank
´
Dr. A. M. Lithgow for the NMR spectra and Dr. Cesar
Raposo for the mass spectra. M.G.N. is grateful for a
FPU doctoral fellowship of the Spanish MEC.
´
´
11. Dıez, D.; Garcıa, P.; Marcos, I. S.; Basabe, P.; Garrido, N.
M.; Broughton, H. B.; Urones, J. G. Tetrahedron 2005, 61,
11641.
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