Catalytic asymmetric Michael reactions of dibenzyl malonate to α,β-unsaturated N-acylpyrroles using a La(O-iPr)3/Ph-linked-BINOL complex

Article abstract of DOI:10.1016/j.tetlet.2007.02.112

Catalytic asymmetric Michael reactions of a malonate to acyclic α,β-unsaturated N-acylpyrroles as ester equivalent acceptors are described. A La(O-iPr)₃/(S,S)-linked-BINOL complex, which is suitable for Michael addition to cyclic enones, is not

Full text of DOI:10.1016/j.tetlet.2007.02.112

Tetrahedron Letters 48 (2007) 2815–2818
Catalytic asymmetric Michael reactions of dibenzyl
malonate to a,b-unsaturated N-acylpyrroles
using a La(O-iPr)3/Ph-linked-BINOL complex
So-Young Park, Hiroyuki Morimoto, Shigeki Matsunaga* and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
Received 7 February 2007; revised 22 February 2007; accepted 26 February 2007
Available online 28 February 2007
Abstract—Catalytic asymmetric Michael reactions of a malonate to acyclic a,b-unsaturated N-acylpyrroles as ester equivalent
acceptors are described. A La(O-iPr)3/(S,S)-linked-BINOL complex, which is suitable for Michael addition to cyclic enones, is
not suitable for acyclic a,b-unsaturated N-acylpyrroles. A new (S,S)-Ph-linked-BINOL chiral ligand was developed to improve
enantioselectivity, and a La(O-iPr)3/(S,S)-Ph-linked-BINOL complex with the addition of HFIP afforded Michael adducts in good
yield and enantioselectivity (up to 96% ee).
Ó 2007 Elsevier Ltd. All rights reserved.
The Michael reaction is one of the most useful carbon–
O
X = OH:
S,S)-linked-BINOL 1a
carbon bond-forming reactions, and the development of
catalytic enantioselective variants has been an impor-
tant topic of study over the last decade.1 Previously,
(
HO
OH
X
X = -Ph:
S,S)-Ph-linked-BINOL 1b
HO
(
we reported that
a La(O-iPr)3/linked-BINOL 1a
X = -H: ligand 1c
(Fig. 1) = 1:1 complex is effective for catalytic asymmet-
ric Michael reaction of malonates to cyclic enones, giv-
ing Michael adducts in up to 99% ee.2,3 Its application
to acyclic substrates, however, is limited to a few enones,
and it is not applicable to acyclic a,b-unsaturated esters.
Despite recent progress in asymmetric Michael reactions
to enones and nitroalkenes,4,5 the use of acyclic carbox-
ylic acid derivatives as acceptors in combination with
1,3-dicarbonyl donors is still limited.6–9 Kanemasa
et al. (malononitrile and 1,3-diketones),6 Jacobsen and
co-workers (malononitrile and cyano esters),7 Evans
et al. (b-keto esters),8 and Takemoto and co-workers
(malononitrile and cyano esters)9 recently reported ele-
gant systems giving Michael adducts from acyclic car-
boxylic acid derivatives in high enantioselectivity. The
use of malonates as donors, however, is rare.10,11 Herein
we report a catalytic asymmetric Michael reaction of a
malonate to a,b-unsaturated N-acylpyrrole derivatives.
R =
R
O
OH
OH
ligand 1d
HO
HO
t
Bu
F C
CF
3
3
OH
t
Bu ligand 1e
ligand 1f
Figure 1. Structures of (S,S)-linked-BINOL 1a, (S,S)-Ph-linked-
BINOL 1b and other non-C2-symmetric linked-BINOL derivatives
1c–f.
A new Ph-substituted linked-BINOL 1b (Fig. 1) was
effective for high enantioselectivity.
We recently reported the utility of a,b-unsaturated N-
acylpyrroles in asymmetric conjugate additions.12–14
Therefore, we initiated our studies with a,b-unsaturated
N-acylpyrrole 2 and dibenzyl malonate 3 using the
La(O-iPr)3/linked-BINOL 1a = 1:1 complex. The opti-
mization studies of the reaction conditions are summa-
rized in Table 1. With N-acylpyrrole 2a, only trace
amount of product was obtained at ꢀ20 °C (entry 1).
Keywords: Asymmetric catalysis; Lanthanide; Linked-BINOL; Mich-
ael reaction.
*
Corresponding authors. Tel.: +81 3 5841 4830; fax: +81 3 5684 5206
(M.S.); e-mail addresses: smatsuna@mol.f.u-tokyo.ac.jp; mshibasa@
mol.f.u-tokyo.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.112

2816
S.-Y. Park et al. / Tetrahedron Letters 48 (2007) 2815–2818
Table 1. Optimization of reaction conditions
OH
OR
a
O
X
ref. 16
OR
Ph
(S)-BINOL
La(O-i-Pr)
3
Ph
(10 mol %)
S,S)-ligand 1a or 1b
(10 mol %)
N
n-Pr
O
R
X
(
2
+
CO Bn
2
N
5: R = MOM
6: R = MOM
DME, –20 °C, 40 h
CO Bn
CO Bn
2
2
4
(1 equiv)
O
Br
RO
RO
CO Bn
2
b
OR RO
Ph RO
3
+
6
Entry N-Acylpyrrole X Ligand Additive Yield (%) % ee
1
2
H- : 2a
1a
1a
—
—
Trace
70
—
8
7: R = MOM
8: R = MOM
1b: R = H
O
c
EtO
: 2b
(S,S)-Ph-linked-BINOL
O
3
4
1a
1a
—
—
40
50
32
41
Scheme 1. Reagents and conditions: (a) (i) t-BuLi, THF, ꢀ78 °C; then
DMF, ꢀ78 °C–rt, 4 h; (ii) NaBH4, MeOH/THF, 0 °C–rt, 12 h, 77%
yield (two steps from 5); (b) NaH, 7; then 6, DMF, rt, 10 h, 83% yield;
(c) p-TsOHÆH2O (cat.), MeOH/CH2Cl2, 40 °C, 24 h, 94% yield.
Me N
2
: 2c
O
N
: 2d
5
6
7
8
9
2d
1b
1c
1d
1e
1f
—
—
—
—
—
HFIPa
23
83
80
81
92
78
86
40
18
2
10
80
ate the catalyst turnover step by efficiently protonating
the intermediate La-enolate species to dissociate
Michael product 4.
2d
2d
2d
2d
2d
The substrate scope and limitations are summarized in
Table 2. Both linear (2d and 2e) and branched (2f) alk-
yl-substituted N-acylpyrroles gave good enantioselec-
tivity. With branched substrate 2f, however, 20 mol %
of catalyst and 2 equiv of malonate 3 were required to
achieve good conversion. With alkenyl substituents,
the 1,4-addition proceeded predominantly over 1,6-
addition, affording products 4g and 4h in high ee (entry
4: 96% ee, entry 5: 92% ee). b-Aryl-substituted N-acyl-
pyrroles 2i and 2j were also applicable, although
20 mol % catalyst was required for good conversion
(entries 6–7).
10
1b
a 0.1 equiv of HFIP (1,1,1,3,3,3-hexafluoroisopropanol) was added.
To improve the reactivity of N-acylpyrrole, N-acylpyr-
roles 2b–2d with an electron-withdrawing group at the
2’-position were examined, and N-acylpyrrole 2d pro-
duced promising reactivity and enantioselectivity. With
2d, the reaction proceeded at ꢀ20 °C and Michael
adduct 4d was obtained in 50% yield and 41% ee after
40 h (entry 4). Further screening of the reaction condi-
tions using ligand 1a, with alterations in the solvent, me-
tal, malonate, and reaction temperature, did not afford
satisfactory results. Therefore, we modified the chiral
ligand. We hypothesized that the bulkiness around the
lanthanide metal center is important for improving
enantioselectivity. Based on our recent report that
non-C2-symmetric linked-BINOL derivatives are effec-
tive in Zn-catalyzed reactions15 and on Katsuki’s salen
ligand containing a binaphthyl group,16 we designed
non-C2-symmetric Ph-linked-BINOL 1b (Fig. 1). The
synthetic scheme of (S,S)-Ph-linked-BINOL 1b is sum-
marized in Scheme 1. Compound 5 and 7 were synthe-
sized from BINOL by following the reported
procedures.3a,16 A coupling reaction of 6 and 7, followed
by removal of the MOM group afforded 1b in good
yield. As expected, ligand 1b improved enantioselectivity
(86% ee, Table 1, entry 5), although reactivity decreased
significantly (23% yield). In contrast, sterically less hin-
dered non-C2-symmetric linked-BINOL derivatives 1c–
1f, which were utilized in Zn-catalyzed reactions,15
showed less satisfactory enantioselectivity (entries 6–9,
1c–1f), albeit in better reactivity than 1b. Ligand 1b
was selected for further studies in terms of enantioselec-
tivity. The reaction rate was improved by the addition
of 1,1,1,3,3,3-hexafluoroisopropanol (HIFP),17 while
maintaining good enantioselectivity (78% yield,
80% ee, entry 10). We assume that HIFP would acceler-
Although we and others have reported various useful
transformations of N-acylpyrrole units,12–14,18 transfor-
mation of the present amide-substituted N-acylpyrrole
unit has not been reported. Gratifyingly, the transfor-
mations of the Michael adducts proceeded smoothly un-
der mild conditions, as shown in Scheme 2. The amide-
substituted N-acylpyrrole unit is more readily cleaved
than the non-substituted N-acylpyrrole unit.12,13 Meth-
anolysis was promoted by 10 mol % of Er(OTf)3 at
room temperature, giving ester 9 in 96% yield.19 Thio-
ester 10 was obtained in 76% yield by treatment with
EtSLi. Amide 11 was obtained in 92% yield by treatment
with amineÆHCl salt and imidazole. Amide 12 was also
obtained in 82% yield by treatment with pyrrolidine at
25 °C. Treatment with NaBH4 gave cyclized compound
13 in 85% yield.
In summary, we developed a new La(O-i-Pr)3/Ph-
linked-BINOL 1b = 1:1 complex for the catalytic asym-
metric Michael reaction of dibenzyl malonate 3 to
a,b-unsaturated 20-amide-substituted N-acylpyrroles.
The use of sterically hindered (S,S)-Ph-linked-BINOL
1b was essential for high enantioselectivity, giving
Michael adducts in 76–87% yield and in 78–96% ee.20
Further application of (S,S)-Ph-linked-BINOL 1b is
ongoing.

S.-Y. Park et al. / Tetrahedron Letters 48 (2007) 2815–2818
Table 2. Michael reaction of various a,b-unsaturated N-acylpyrroles
2817
La(O-
S,S)-1b (x mol %)
i-Pr) (x mol %)
3
(
O
X
O
R
X
malonate 3 (y equiv)
CO Bn
N
R
HFIP (0.1 equiv)
2
N
DME, –20 ºC, 40 h
2
4
CO Bn
2
O
X =
N
Entry
N-Acylpyrrole R
Product
Conditionsa
Yieldb (%)
% eec
1
2
3
4
5
6
7
2d: n-Pr
2e: Me
2f: Cyclohexyl
2g: –CH@CHCH3
2h: –CH@CH(CH2)2CH3
2i: Ph
2j: 4-Cl–C6H4
4d
4e
4f
4g
4h
4i
A
A
B
B
A
B
B
78
85
87
80
83
76
80
80
90
88
96
92
78
86
4j
a Conditions A: 10 mol % of La(O-iPr)3, 10 mol % of (S,S)-1b, and 1 equiv of malonate 3 were used; Conditions B: 20 mol % of La(O-iPr)3, 20 mol %
of (S,S)-1b, and 2 equiv of malonate 3 were used.
b Isolated yield.
c Determined by chiral HPLC analysis.
O
n-Pr
Springer: Berlin, 1999; (b) Krause, N.; Hoffmann-Ro¨der,
A. Synthesis 2001, 171; (c) Sibi, M. P.; Manyem, S.
Tetrahedron 2000, 56, 8033; (d) Hayashi, T.; Yamasaki, K.
Chem. Rev. 2003, 103, 2829; (e) Christoffers, J.; Baro, A.
Angew. Chem., Int. Ed. 2003, 42, 1688.
CO Bn
2
MeO
9d
O
Me
CO Bn
2
CO Bn
2
a
EtS
c
10e
CO Bn
2
2. Malonates as donors: (a) Kim, Y. S.; Matsunaga, S.; Das,
J.; Sekine, A.; Ohshima, T.; Shibasaki, M. J. Am. Chem.
Soc. 2000, 122, 6506; (b) Matsunaga, S.; Ohshima, T.;
Shibasaki, M. Tetrahedron Lett. 2000, 41, 8473; (c) Takita,
R.; Ohshima, T.; Shibasaki, M. Tetrahedron Lett. 2002,
43, 4661; b-Keto-esters as donors: (d) Majima, K.; Okada,
A.; Takita, R.; Ohshima, T.; Shibasaki, M. J. Am. Chem.
Soc. 2003, 125, 15837.
3. Synthesis of linked-BINOL 1a: (a) Matsunaga, S.; Das, J.;
Roels, J.; Vogl, E. M.; Yamamoto, N.; Iida, T.; Yama-
guchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122,
2252; A review of linked-BINOL: (b) Shibasaki, M.;
Matsunaga, S. Chem. Soc. Rev. 2006, 35, 269.
b
O
N
O
n-Pr
O
R
MeO
CO Bn
2
CO Bn
2
N
N
CH
CO Bn
2
3
CO Bn
2
11d
4d: R = n-Pr
4e: R = Me
d
O
n-Pr
e
CO Bn
2
N
O
CO Bn
12d
2
CO Bn
2
O
13d
n-Pr
4. For selected recent examples with 1,3-dicarbonyl donors
using chiral metal catalysts, see: (a) Hamashima, Y.;
Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124,
11240; (b) Barnes, D. M.; Ji, J.; Fickes, M. G.; Fitzgerald,
M. A.; King, S. A.; Morton, H. E.; Plagge, F. A.; Preskill,
M.; Wagaw, S. H.; Wittenberger, S. J.; Zhang, J. J. Am.
Chem. Soc. 2002, 124, 13097, and references cited therein;
(c) Watanabe, M.; Ikagawa, A.; Wang, H.; Murata, K.;
Ikariya, T. J. Am. Chem. Soc. 2004, 126, 11148, and
references cited therein; (d) Taylor, M. S.; Zalatan, D. N.;
Lerchner, A. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2005,
127, 1313; (e) Evans, D. A.; Seidel, D. J. Am. Chem. Soc.
2005, 127, 9958. For other examples including organocat-
alytic Michael reactions, see reviews in Refs. 1 and 5.
5. For organocatalytic Michael reactions to enones and
nitroalkenes, see general reviews and references cited
therein: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int.
Ed. 2004, 43, 5138; (b) Acc. Chem. Res. 2004, 37, special
issue (Houk, K. N., Eds.; List, B); (c) Lelais, G.;
MacMillan, D. W. C. Aldrichim. Acta 2006, 39, 79; (d)
Connon, S. J. Chem. Eur. J. 2006, 12, 5418; (e) Enders, D.;
Scheme 2. Transformations of N-acylpyrrole unit; Reagents and
conditions: (a) Er(OTf)3 (10 mol %), MeOH/CH3CN, 25 °C, 24 h,
96% yield; (b) EtSLi (1.5 equiv), THF, 0 °C, 15 min, 77% yield; (c)
N,O-dimethylhydroxylamineÆHCl (3 equiv), imidazole (9 equiv),
CH2Cl2, 0 °C, 22 h, 92% yield; (d) pyrrolidine (2.2 equiv), THF,
25 °C, 1 h, 82% yield; (e) NaBH4, MeOH/THF, 0 °C, 1 h, 85% yield.
Acknowledgements
We thank financial support by Grant-in-Aid for Spe-
cially Promoted Research and Grant-in-Aid for Encour-
agements for Young Scientists (B) (S.M.) from JSPS and
MEXT. H.M. thanks JSPS Research Fellowships for
Young Scientists. We thank Mr. H. Noda and Dr. T.
Yoshida for their generous supports for ligand 1b and
substrates synthesis.
Grondal, C.; Huttl, M. R. M. Angew. Chem., Int. Ed.
¨
2007, 46, 1570. See also reviews in Ref. 1.
References and notes
6. (a) Kanemasa, S.; Ito, K. Eur. J. Org. Chem. 2004, 4741;
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Asymmetry 2003, 14, 635; (c) Ito, K.; Hasegawa, M.;
Tanaka, J.; Kanemasa, S. Org. Lett. 2005, 7, 979.
1. (a) Recent reviews: Comprehensive Asymmetric Catalysis,
1st ed.; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.,

2818
S.-Y. Park et al. / Tetrahedron Letters 48 (2007) 2815–2818
7. (a) Raheem, I. Z.; Goodman, S. N.; Jacobsen, E. N. J.
Scheidt, K. A.; Johnston, J. N.; Willis, M. C. J. Am.
Chem. Soc. 2001, 123, 4480.
Am. Chem. Soc. 2004, 126, 706; (b) Taylor, M. S.;
Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 11204.
8. Evans, D. A.; Thomson, R. J.; Franco, F. J. Am. Chem.
Soc. 2005, 127, 10816.
9. (a) Hoashi, Y.; Okino, T.; Takemoto, Y. Angew. Chem.,
Int. Ed. 2005, 44, 4032; (b) Inokuma, T.; Hoashi, Y.;
Takemoto, Y. J. Am. Chem. Soc. 2006, 128, 9413.
10. Highly enantioselective organocatalytic asymmetric
Michael addition of manolates to a,b-unsaturated alde-
hydes was recently reported. (a) Brandau, S.; Landa, A.;
14. For other application of pyrrole carbinol as useful
building blocks, see: (a) Dixon, D. J.; Scott, M. S.;
Luckhurst, C. A. Synlett 2003, 2317; (b) Dixon, D. J.;
Scott, M. S.; Luckhurst, C. A. Synlett 2005, 2420; Use of
N-acylpyrrole as donor, see also: (c) Harada, S.; Handa,
S.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed.
2005, 44, 4365.
15. Synthesis and utility of non-C2-symmetric linked-BINOL
derivatives: (a) Yoshida, T.; Morimoto, H.; Kumagai, N.;
Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed.
2005, 44, 3470; (b) Shibasaki, M.; Matsunaga, S. J.
Organomet. Chem. 2006, 691, 2089.
16. (a) Sasaki, H.; Irie, R.; Hamada, T.; Suzuki, K.; Katsuki,
T. Tetrahedron 1994, 50, 11827; (b) Sasaki, H.; Irie, R.;
Katsuki, T. Synlett 1994, 356; See also: (c) Kawabata, H.;
Omura, K.; Uchida, T.; Katsuki, T. Chem. Asian J. 2007,
2, 248, and references cited therein.
17. HFIP effects in asymmetric catalysis: see, Refs. 2c and 12c.
See also: (a) Evans, D. A.; Rovis, T.; Kozlowski, M. C.;
Downey, W.; Tedrow, J. S. J. Am. Chem. Soc. 2000, 122,
9134, and references cited therein; (b) Kitajima, H.; Ito,
K.; Katsuki, T. Tetrahedron 1997, 53, 17015; (c) Kawara,
A.; Taguchi, T. Tetrahedron Lett. 1994, 35, 8805; (d)
Zhou, J.; Tang, Y. J. Am. Chem. Soc. 2002, 124, 9030.
18. For transformations of 20-CN-substitued N-acylpyrroles,
see: Hodous, B. L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124,
10006.
´
Franzen, J.; Marigo, M.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2006, 45, 4305, and references cited therein; For
related Michael addition of b-keto esters and/or a-cyano
esters to a,b-unsaturated aldehydes: (b) Wu, F.; Hong, R.;
Khan, J.; Liu, X.; Deng, L. Angew. Chem., Int. Ed. 2006,
45, 4301, and references cited therein; With Pd-catalyst: (c)
Hamashima, Y.; Hotta, D.; Umebayashi, N.; Tsuchiya,
Y.; Suzuki, T.; Sodeoka, M. Adv. Synth. Catal. 2005, 347,
1576; For other early works, see also, phase transfer
catalyst: (d) Ooi, T.; Miki, T.; Taniguchi, M.; Shiraishi,
M.; Takeuchi, M.; Maruoka, K. Angew. Chem., Int. Ed.
2003, 42, 3796; Metal catalysts: (e) Motoyama, Y.; Koga,
Y.; Kobayashi, K.; Aoki, K.; Nishiyama, H. Chem. Eur. J.
2002, 8, 2968; (f) Yamaguchi, M.; Shiraishi, T.; Hirama,
M. J. Org. Chem. 1996, 61, 3520.
11. Michael reaction of a malonate to ethyl crotonate using
chiral Al–Li–BINOL catalyst is reported, although enantio-
selectivity is not determined, see: (a) Tabatabaeian, K.;
Mamaghani, M.; Pourahamad, A. Rus. J. Org. Chem.
2001, 37, 1287; For Al–Li–BINOL (ALB) complex, see a
review: (b) Shibasaki, M.; Sasai, H.; Arai, T. Angew.
Chem., Int. Ed. 1997, 36, 1236.
19. For Sm(OTf)3-catalyzed methalolysis of imides, see:
´
Evans, D. A.; Trotter, B. W.; Coleman, P. J.; Coˆte, B.;
Dias, L. C.; Rajapakse, H. A.; Tyler, A. N. Tetrahedron
1999, 55, 8671, see also, Refs. 7 and 9.
12. Use of a,b-unsaturated N-acylpyrroles in catalytic asym-
metric conjugate additions: (a) Matsunaga, S.; Kinoshita,
T.; Okada, S.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126,
7559; (b) Yamagiwa, N.; Qin, H.; Matsunaga, S.; Shiba-
saki, M. J. Am. Chem. Soc. 2005, 127, 13419; (c) Mita, T.;
Sasaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2005, 127, 514; (d) Kinoshita, T.; Okada, S.; Park, S.-R.;
Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed.
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Chem. Commun. 2005, 3213; (f) Matsunaga, S.; Qin, H.;
Sugita, M.; Okada, S.; Kinoshita, T.; Yamagiwa, N.;
Shibasaki, M. Tetrahedron 2006, 62, 6630; Application to
diastereoselective 1,4-addition reactions: (g) Arai, Y.;
Kasai, M.; Ueda, K.; Masaki, Y. Synthesis 2003, 1511.
13. Properties of N-acylpyrroles were reported by Evans and
co-workers in detail: (a) Evans, D. A.; Borg, G.; Scheidt,
K. A. Angew. Chem., Int. Ed. 2002, 41, 3188; Use of enol
silane derived from N-acylpyrrole: (b) Evans, D. A.;
Johnson, D. S. Org. Lett. 1999, 1, 595; (c) Evans, D. A.;
20. Representative procedure of catalytic asymmetric Michael
reaction: To a solution of (S,S)-Ph-linked-BINOL 1b
(10 mg, 15 lmol) in THF (0.2 mL) was added La(O-iPr)3
(0.2 M in THF, 75 lL, 15 lmol). The mixture was stirred
for 30 min at 25 °C, then the solvent was removed under
reduced pressure. The residue was dried in vaccuo for 5 h
to remove iPrOH to afford La-1b catalyst. To the La-1b
catalyst was added DME (0.25 mL), and then the mixture
was cooled to ꢀ20 °C. To the solution were added HIFP
(15 lmol), N-acylpyrrole 2 (0.15 mmol), and then malon-
ate 3 (0.15 mmol), and the reaction mixture was stirred at
ꢀ20 °C for 40 h. The mixture was quenched with sat. aq.
NH4Cl, and extracted with ethyl acetate. The organic layer
was washed with brine and dried over Na2SO4. After
evaporation, the residue was purified by flash silica gel
column chromatography to afford Michael adduct 4.
Absolute configuration of Michael adduct 4j was deter-
mined after conversion into N-acylpyrrole moiety into a
known methyl ester, see Ref. 10a.