Intramolecular Pauson-Khand reaction of optically active aza-Baylis-Hillman adducts

Article abstract of DOI:10.1016/j.tetlet.2010.02.115

The intramolecular Pauson-Khand reaction of aza-Baylis-Hillman adducts, which were prepared through the thio-Michael/imino-aldol domino reaction of optically active sulfinimines, was examined and gave optically active cis- and trans-pyrrolidine-fused cyclopentenones in a stereoselective manner.

Full text of DOI:10.1016/j.tetlet.2010.02.115

Tetrahedron Letters 51 (2010) 2329–2331
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Tetrahedron Letters
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Intramolecular Pauson–Khand reaction of optically active aza-Baylis–Hillman
adducts
Shingo Ishikawa a, Fumiaki Noguchi a, Hidemitsu Uno b, Akio Kamimura a,
*
a Department of Applied Molecular Bioscience, Graduate School of Medicine, Yamaguchi University, Ube 755-8611, Japan
b Department of Chemistry, Graduate School of Science and Technology, Ehime University, Matsuyama 790-8577, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The intramolecular Pauson–Khand reaction of aza-Baylis–Hillman adducts, which were prepared through
the thio-Michael/imino-aldol domino reaction of optically active sulfinimines, was examined and gave
optically active cis- and trans-pyrrolidine-fused cyclopentenones in a stereoselective manner.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 26 January 2010
Revised 16 February 2010
Accepted 22 February 2010
Available online 24 February 2010
The aza-Baylis–Hillman reaction is one of the most potentially
useful synthetic methods because it provides b-amino- -methy-
lene esters, which are regarded as useful synthetic building blocks,
in one step from ,b-unsaturated carbonyl compounds and imi-
Letter, we describe a new process to carry out intramolecular Pau-
son–Khand methodology through optically active aza-Baylis–Hill-
man adducts derived from aliphatic imines. The method will
provide a potentially useful synthesis of aza-heterocyclic com-
pounds. It is remarkable that an alkyl substituent at the C3 position
induced cis-selectivity in the Pauson–Khand reaction products
preferentially; the selectivity is opposite to similar Pauson–Khand
reactions starting from other electron-deficient alkenes.6,5c
The optically active aza-Baylis–Hillman adducts 1 were pre-
pared from chiral sulfinimines and tert-butyl acrylate by the proce-
dure previously reported.3a The conversion to intramolecular
Pauson–Khand precursors 3 was achieved through S-oxidation to
sulfonamines 2 followed by propargylation under basic conditions
(Scheme 1).3b For example, the adduct 1a, obtained in 57% yield
(94% de) through the domino reaction, was oxidized by treatment
with m-CPBA at room temperature to give sulfonamine 2a in 97%
yield. The N-propargylation of 2a gave the Pauson–Khand precur-
sor 3a in 84% yield. The enantiomeric excess of 2a was estimated
to be 92%, which was determined by HPLC analysis with ChiralPak
IC (entry 1). The optical purity of these compounds was almost the
same and no significant epimerization occurred during the trans-
formation. The results are summarized in Table 1.
With desired precursors 3 in-hand, we examined the Pauson–
Khand reaction of 3a under various conditions. Commercially
available Co2(CO)8 was used as a catalyst (Scheme 2). The results
are summarized in Table 2. The use of 100 mol % of Co2(CO)8 pro-
vided the desired adduct 4a in 77% yield, while the reduction of
catalyst amounts to 60 mol % decreased the yield 4a to 19% (entries
1 and 2). To improve the yield of 4a, we applied Yang’s reaction
conditions7 and employed 60 mol % of (N,N,N,N)-tetramethylthio-
urea (TMTU); adduct 4a was isolated in 85% yield (entry 4). Thus,
a reduction of the amount of Co2(CO)8 was successfully achieved
when a sufficient amount of TMTU coexisted in the reaction mix-
ture. For example, when the amount of Co2(CO)8 was reduced to
10 mol % compound 4a was obtained in 84% yield provided that
60 mol % of TMTU was present in the reaction mixture (entry 5).
a
a
nes.1 Although a number of reports have been published for the
catalytic asymmetric modification of aza-Baylis–Hillman reaction,
so far most examples are limited to the use of aromatic imines
and only a few examples are successfully applicable to aliphatic
imines.2 To overcome this drawback, we have recently developed
a useful preparation of optically active aza-Baylis–Hillman adducts
via the thio-Michael/imino-aldol domino reaction of chiral sulfini-
mines, which gives aza-Baylis–Hillman adducts derived from ali-
phatic imines in a highly enantioselective manner.3a This is a
promising methodology because of its usefulness in the conversion
of a wide range of aliphatic imines to chiral aza-Baylis–Hillman ad-
ducts. We have already applied the transformation to the synthesis
of heterocyclic compounds, and successfully achieved the formal
synthesis of (À)-trachelanthamidine.3b The formed chiral b-amino
esters would also be useful for the preparation of pyrrolidine ring-
fused cyclopentenones through the intramolecular Pauson–Khand
reaction, which is recognized as a powerful tool for the construc-
tion of cyclopentenone frameworks through [2+2+1] cyclizations.4
The reaction has received much attention due to its potential appli-
cability in the synthesis of complex molecules.5 Although the origi-
nal cobalt complex-catalyzed Pauson–Khand reaction requires an
excess of Co2(CO)8 to proceed to completion,4 various catalytic
Pauson–Khand reactions with using other transition metals have
been reported in the past decade. We thought that the optically
active aza-Baylis–Hillman adducts prepared using our methodol-
ogy would provide good precursors for the intramolecular
Pauson–Khand reaction after facile N-propargylation. To our
knowledge there are few such examples of the Pauson–Khand
reaction starting from chiral aza-Baylis–Hillman adducts. In this
* Corresponding author. Tel.: +81 836 85 9231; fax: +81 836 85 9201.
E-mail address: ak10@yamaguchi-u.ac.jp (A. Kamimura).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.115

2330
S. Ishikawa et al. / Tetrahedron Letters 51 (2010) 2329–2331
O
S
Ts
R
Ts
R
NH
N
p-Tol
NH
i
ii
CO2t-Bu
CO2t-Bu
CO2t-Bu
R
2
3
1
Scheme 1. Reagents and conditions: (i) m-CPBA, CH2Cl2, rt; (ii) propargyl bromide, K2O3, DMF.
Table 1
Table 2
Preparation of intramolecular Pauson–Khand precursors 3
The Pauson–Khand reaction of 3a
Entry
R
2; Yielda (%)
3; Yielda (%)
Entry
Co2(CO)8 (mol %)
TMTU (mol %)
4a; Yield (%)a
1
2
3
4
5
6
7
Pr
Bu
i-Bu
i-Pr
c-C6H11
p-Tol
p-ClC6H4
2a; 97 (92)
2b; 82 (92)
2c; 97 (99)
2d; 100 (96)
2e; 90 (94)
2f; 92 (99)
2g; 98 (99)
3a; 84 (92)
3b; 86 (92)
3c; 82 (99)
3d; 86 (94)
3e; 90 (94)
3f; 84 (92)
3g; 94 (92)
1
2
3
4
5
100
60
60
60
10
0
0
10
60
60
77
19
59
85
84
a
Isolated yield.
a
Isolated yield. Enantiomeric excesses are in parentheses. Ee values were
determined by HPLC analyses (ChiralPak-IC, hexane/2-propanol 80:20).
Table 3
The Pauson–Khand reaction of 3
Entry
R
4
Yielda (%)
cis/transb
However, the reaction under these conditions was unreproducible
unless freshly opened dicobalt complex was used. This is probably
due to the slow decomposition of Co2(CO)8. Therefore, we used
60 mol % of Co2(CO)8 in order to examine the generality of the
reaction.
1
2
3
4
5
6
7
Pr
Bu
i-Bu
i-Pr
c-C6H11
p-Tol
p-ClC6H4
4a
4b
4c
4d
4e
4f
85 (86)
62 (90)
66 (96)
45 (96)
59 (90)
83 (94)
82 (90)
75/25
77/23
74/26
86/14
80/20
37/63
29/71
The cyclization of other precursors also took place smoothly
(Scheme 3). The results are summarized in Table 3.8 For example,
the Pauson–Khand product 4b was obtained in 62% yield (entry
2). Compound 4b was obtained as a mixture of two stereoisomers,
whose ratio was estimated to be 77/23 by 1H NMR analysis. Chiral
HPLC analysis revealed that the optical purity of the major isomer
of 4b was estimated to be 90% ee. This value was slightly lower
than the ee value of the starting material 3b (92% ee). Thus, the dis-
cussed procedure provided optically active bicyclic compounds
from asymmetric aza-Baylis–Hillman adducts. The diastereoselec-
tivity of the reactions was about 3:1 for compounds that had pri-
mary alkyl groups at the R position (entry 1–3), and 4:1 or 7:1
for the compounds that had secondary alkyl groups at the R posi-
tion (entry 4 and 5). It is remarkable that cis-selectivity was ob-
served in the intramolecular Pauson–Khand reaction. This
selectivity was opposite to that reported by Ichikawa and co-work-
ers, who showed that the reaction progressed dominantly in a
C3–C3a trans-selective manner.5c On the other hand, when an
aromatic group occupied the R position, trans-selectivity was
observed (entries 6 and 7). For example, the Pauson–Khand adduct
4f was obtained in 83% yield as a mixture of cis/trans isomers in a
ratio of 37:63. Thus, the stereoselectivity of the intramolecular
Pauson–Khand reaction depended on the R substituent, and the
selectivity was switched from cis to trans as the substituent at
the R position changed from aliphatic to aromatic.
4g
a
Isolated yield. Enantiomeric excesses for major isomer are in parentheses. Ee
values were determined by HPLC analyses (ChiralPak-IC, hexane/2-propanol 80:20).
Determined by 1H NMR.
b
two diastereomers, which were separated by careful flash column
chromatography. The major isomer of 4e gave good crystals for X-
ray analysis, which indicated a cis configuration between C3 and
C3a unambiguously.9 The major isomer of 4g was also isolated
and X-ray analysis clearly showed a trans configuration between
C3 and C3a positions.10
It should be mentioned that the 1H NMR signal at the C6 posi-
tion (the vinylic proton in
a,b-unsaturated alkene unit) in the
cis-isomers showed a remarkable upfield shift. For example, these
signals appeared at 5.25 ppm for cis-4e and 4.5 ppm for cis-4f,
while they appeared around 6.1 ppm for the corresponding trans
isomers. X-ray crystallographic analysis for cis-4e and trans-4g
clearly showed that the protons in the cis-isomer are located above
the plane of the phenyl ring of the N-tosyl group and the strongly
affected by the ring current of the aromatic ring. Thus, it is ex-
pected that the preferred conformation of the cis-isomer will offer
a very good bias for controlling a nucleophilic attack at the C6a car-
bon. An investigation of this is underway.
The stereochemistry of the adduct 4 was determined by X-ray
crystallographic analyses. For example, compound 4e contained
In conclusion, we have succeeded in forming pyrrolidine
ring-fused cyclopentenones by means of an intramolecular
1atm CO
Ts
N
TsN
TsN
Co2(CO)8
O
O
TMTU
toluene/reflux
CO2t-Bu
CO2t-Bu
cis-4a
cis/trans = abt 3:1
CO2t-Bu
3a
trans-4a
Scheme 2.

S. Ishikawa et al. / Tetrahedron Letters 51 (2010) 2329–2331
2331
Ts
R
6a
6
6a
6
N
i
Ts
N
O
Ts
N
O
+
C3
C3a
C3a
C3
CO2t-Bu
CO2t-Bu
cis-4
(major)
CO2t-Bu
trans-4
R
R
Scheme 3. Reagents and conditions: (i) 60 mol % CO2(CO)8, 60 mol % TMTU, 1 atm CO, toluene, reflux, 16 h.
6. For reviews on the Pauson–Khand reaction of electron-deficient alkenes, see:
(a) Rivero, M. R.; Adrio, J.; Carretero, J. C. Synlett 2005, 26–41; (b) Rivero, M. R.;
Adrio, J.; Carretero, J. C. Eur. J. Org. Chem. 2002, 2881–2889.
7. Tang, Y.; Deng, L.; Zhang, Y.; Dong, G.; Chen, J.; Yang, Z. Org. Lett. 2005, 7, 593–
595.
Pauson–Khand reaction starting from readily available optically
active aza-Baylis–Hillman adducts. The stereoselectivity of the
reaction depended on the R substituent; a moderate to high
cis-selectivity is obtained when an alkyl group is placed at the R
position, while an approximate ratio of 1:2 is obtained for the
trans-isomer when an aromatic group occupies the R position. Fur-
ther investigations to elaborate the scope and extend the applica-
tions of this methodology are in progress in our laboratory.
8. The Pauson–Khand reaction of 3e: typical procedure. Under CO atmosphere, a
mixture of 3e (155.8 mg, 0.36 mmol), TMTU (28.7 mg, 0.22 mmol), and
Co2(CO)8 (75.6 mg, 0.22 mmol) in degassed toluene (10 mL) was heated at
refluxing temperature for 16 h. The reaction mixture was concentrated in
vacuo and the residue was purified by flash chromatography (silica gel/
hexane–EtOAc 10:1 then 5:1) to give 4e in 59% yield (97.1 mg). trans-4e and
cis-4e were separated by further careful chromatography. trans-4e: oil; 1H
NMR (500 MHz, CDCl3) d 7.77 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 6.10 (s,
1H), 4.64 (d, J = 4.3 Hz, 1H), 4.22 (d, J = 16.4 Hz, 1H), 4.09 (d, J = 16.4 Hz, 1H),
3.08 (s, 1H), 2.57 (d, J = 17.8 Hz, 1H), 2.52 (d, J = 17.8 Hz, 1H), 2.40 (s, 3H), 1.76–
1.56 (m, 4H), 1.50–1.04 (m, 7H), 1.23 (s, 9H); 13C NMR (126 MHz, CDCl3) d
206.4, 177.6, 169.4, 143.5, 136.1, 129.4, 127.9, 126.5, 83.1, 66.7, 63.8, 46.9, 44.3,
43.1, 40.6, 31.9, 28.6, 27.4, 26.2, 26.0, 21.4. cis-4e: white solid; mp 127.8–
128.0 °C; 1H NMR (500 MHz, CDCl3) d 7.63 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 7.9 Hz,
2H), 5.25 (s, 1H), 4.53 (d, J = 15.4 Hz, 1H), 4.32 (d, J = 15.4 Hz, 1H), 3.36 (d,
J = 8.6 Hz, 1H), 3.22 (d, J = 17.2 Hz, 1H), 2.40 (s, 3H), 2.05–1.62 (m, 8H), 1.43 (s,
9H), 1.27–1.05 (m, 4H); 13C NMR (126 MHz, CDCl3) d 206.3, 174.5, 168.5, 144.6,
134.0, 129.7, 127.8, 124.1, 83.6, 74.2, 62.8, 50.4, 48.2, 40.5, 30.9, 29.9, 27.7,
26.5, 26.2, 26.1, 21.4; Anal. Calcd for C25H33NO5S: C, 65.33; H, 7.24; N, 3.05.
Found: C, 65.03; H, 7.20; N, 3.02.
9. Crystallographic data (excluding structure factors) for the structures cis-4e
have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication numbers CCDC759538. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK [fax: +44(0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
10. Crystallographic data (excluding structure factors) for the structures trans-4g
have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication numbers CCDC759539. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [fax: +44(0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
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