Asymmetric intramolecular Pd(II)-catalysed amidocarbonylation of unsaturated amino alcohols

Article abstract of DOI:10.1016/j.tetasy.2009.10.024

The first example of an asymmetric carbonylative bicyclisation of racemic N-protected 1-amino-pent-4-ene-3-ols (±)-1 catalysed by palladium(II) with chiral bis(oxazoline) ligands was investigated. The kinetic resolution of (±)-1 in the presence of chiral

Full text of DOI:10.1016/j.tetasy.2009.10.024

Tetrahedron: Asymmetry 20 (2009) 2720–2723
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Tetrahedron: Asymmetry
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Asymmetric intramolecular Pd(II)-catalysed amidocarbonylation
of unsaturated amino alcohols
Peter Koóš a, Ivan Špánik b, Tibor Gracza a,
*
a Department of Organic Chemistry, Slovak University of Technology, Radlinského 9, SK-812 37 Bratislava, Slovakia
b Department of Analytical Chemistry, Slovak University of Technology, Radlinského 9, SK-812 37 Bratislava, Slovakia
a r t i c l e i n f o
a b s t r a c t
Article history:
The first example of an asymmetric carbonylative bicyclisation of racemic N-protected 1-amino-pent-4-
ene-3-ols ( )-1 catalysed by palladium(II) with chiral bis(oxazoline) ligands was investigated. The kinetic
resolution of ( )-1 in the presence of chiral catalyst, p-benzoquinone in acetic acid under carbon monox-
ide atmosphere afforded enantiomerically enriched derivatives of 2-oxa-6-azabicyclo[3.3.0]octan-3-ones
(R,R)-2 and (S,S)-2, respectively.
Received 30 September 2009
Accepted 22 October 2009
Available online 24 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Geissman–Waiss lactone8), which is an important intermediate
in the synthesis of a number of necine bases9 (pyrrolizidine alka-
The intramolecular palladium(II)-catalysed carbonylation of
unsaturated polyols is an important transformation of alkenes into
bisheterocyclic lactones.1 Early examples of this domino reaction;
Pd(II)-promoted cyclisation—intramolecular amidocarbonylation
were described for 3-hydroxypent-4-enyl- and 5-hydroxyhex-6-
enylamides providing cis- and/or trans-fused bicyclic lactones,
and involving the pyrrolidine-2 and/or piperidine2,3 structural
motif, respectively (Scheme 1). Such a transformation of enantio-
merically pure substrates has found numerous applications as
the key step in the total syntheses of natural compounds and
useful chirons containing saturated azaheterocyclic skeleton
loids), the application of enantioselective palladium(II)-catalysed
bicyclisation as the key reaction offers an asymmetric alternative
to the existing synthetic routes.10 Following reports on the non-
enantioselective carbonylation of unsaturated aminopolyols,1g,5–7
and/or of racemic2,3 and enantiomerically pure,4 simple amino
alcohols, we attempted to extend this to a kinetic resolution of
racemic N-protected 1-aminopent-4-ene-3-ols ( )-1.
Typically, the carbonylation of alkenyl amino alcohols is cata-
lysed by 10 mol % of the palladium(II)-salt in the presence of an
oxidant (CuCl2, p-benzoquinone, CuCl2/O2). Generally, the most
efficient catalytic system for the intramolecular amino/amidocarb-
onylation of unsaturated aminopolyols, originally developed for
the Wacker process, contains palladium(II) chloride as a catalyst,
copper(II) chloride as an oxidant and sodium acetate in acetic acid
as a buffer, the reaction taking place under a carbon monoxide
atmosphere (balloon) at room temperature. The N-protected
1-aminopent-4-ene-3-ols 1 afforded under these reaction condi-
tions the corresponding 2-oxa-6-azabicyclo[3.3.0]octan-3-ones 2
in good yields2–7 following the usual cis-ring formation pattern,
but an asymmetric version of this type of reaction has not been re-
ported so far. To the best of our knowledge, previously reported
work on related asymmetric Wacker-type oxidations have been
limited to the monocyclisation of alkenols and alkynols.11 Sasai
et al.12 described an enantioselective intermolecular amidocarb-
onylation of pentenyl amine derivatives catalysed by Pd(II)-chiral
SPRIX—complexes to form pyrrolidin-2-yl-acetic methyl esters in
good yields with moderate enantioselectivity. There is no report
in the literature, related to the enantioselective carbonylative
bicyclisation of unsaturated amino alcohols. Recently, we have re-
ported on the asymmetric intramolecular oxycarbonylation of
unsaturated diols catalysed by chiral palladium(II) complexes.13
The kinetic resolution of racemic pent-4-ene-1,3-diol in the
(Geissman–Waiss lactone,4 homo-DLX,5 homo-
L
-ido-DMAP,5
homo-l-DNJ,6 homo-
L
-ido-l-DNJ,6 calvine and epicalvine7).
CO (balloon)
PdCl2 (0.1 equiv.)
O
OH
O
R
CuCl2 (3 equiv.)
AcONa (3 equiv.)
AcOH
R
N
NH
PG
PG
R = OH, protected OH (OP), H
PG = Ts, Z, Boc, Bn
Scheme 1. Intramolecular Pd(II)-catalysed amino/amidocarbonylation of unsatu-
rated amino alcohols.
For the synthesis of the enantiomerically pure N-protected
(1R,5R)-2-oxa-6-azabicyclo[3.3.0]octane-3-one (+)-2 (N-protected
* Corresponding author. Tel.: +421 2 593 25 160; fax: +421 2 529 68 560.
E-mail address: tibor.gracza@stuba.sk (T. Gracza).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.10.024

P. Koóš et al. / Tetrahedron: Asymmetry 20 (2009) 2720–2723
2721
presence of Pd(OAc)2-{(R,S)-indabox}, p-benzoquinone in acetic
acid under carbon monoxide atmosphere afforded enantiomeri-
cally enriched (1R,5R)-2,6-dioxabicyclo[3.3.0]octan-3-one in 29%
yield and 62% ee.
Initially, the optimised catalytic system for the kinetic resolution of
unsaturated 1,3-diols was examined.13 Racemic 1-tosylaminopent-
4-ene-3-ol ( )-1a was chosen as a model substrate for screening
the reaction conditions (Table 1). The transformation was carried
*
Herein, we report a study on the enantioselectivity of carbony-
lative bicyclisation of N-protected 1-aminopent-4-ene-3-ols ( )-1
promoted by chiral Pd(II) complexes.
out with different chiral PdX2–(L ) complexes, p-benzoquinone in
acetic acid under a carbon monoxide atmosphere (balloon). Chiral
palladium(II)-complexes were generated in situ from PdX2 and a
slight excess of chiral ligands L*. In accordance with the kinetic res-
olution process, the 50% conversion was maintained by use of
0.5 equiv of p-benzoquinone. Conversion control was made by GC
2. Results and discussion
using HP5 (30 m, id 0.25 mm, film thickens 0.125 lm) stationary
Having obtained preliminary results on the use of chiral Pd(II)-
complexes in the oxycarbonylative kinetic resolution of pent-4-
ene-1,3-diol,13a we focused on the asymmetric Pd(II)-catalysed
amidocarbonylation of alkenyl amines. In the case of the amino
alkenols, the nature of the amino-protecting group had been found
to be essential for optimal adjustment of the N-nucleophilicity, in
order to favour the cyclisation step over the competing N-Pd
complexation.2–5 We had proposed to use p-toluenesulfonyl, ben-
zyloxycarbonyl and tert-butyloxycarbonyl, respectively, as N-pro-
tecting groups in order to decrease the affinity of amino function
to Pd(II)-species. The substrates, N-protected amino alcohols
( )-1, were obtained from acetonitrile adopting a known route. Fol-
lowing the reaction sequence, a condensation of acetonitrile lith-
ium enolate with acrolein,14 LiAlH4-mediated reduction of
nitrile15 and a final protection of amino group with TsCl,16 ZCl17
and Boc2O,18 respectively, amides ( )-1 were readily prepared in
good yields [( )-1a (32%), ( )-1b (41%), ( )-1c (29%) overall]. We
then prepared lactones ( )-2 as racemic standards for GC analysis.
Thus, amino alcohols ( )-1 were submitted to amidocarbonylation,
carried out under standard conditions,2–5 that is, with palla-
dium(II) chloride, copper(II) chloride and sodium acetate in acetic
acid under carbon monoxide atmosphere at normal pressure and
room temperature. The corresponding pyrrolidinolactones ( )-
2a–c were obtained in 90%, 88% and 89% yield, respectively, with
noteworthy chemo-, regio- and cis-diastereoselectivity. The struc-
tures of ( )-2a–c were established using NMR spectroscopy. All
the spectroscopic and physical data of our samples were in good
agreement with those reported in the literature.3,4,19
phase. The bicyclic product 2 was separated by flash chromatogra-
phy and the enantiomeric excess determined by GC analysis with a
ChirasilDex (permethylated-b-cyclodextrin) stationary phase
(2.5 m, id 0.25 mm, film thickens 0.25 lm).
*
As shown in Table 1, the reaction catalysed with PdCl2–(L )
(entries 1, 6, 11, 14) and Pd(BF4)2–(L*) complexes (entries 3, 13
and 16) afforded only racemic lactone 2a. Moderate selectivities
were achieved using Pd(OAc)2-[bis(oxazolines) A, B, C] (entries
2, 5 and 7) catalysts. It is apparent that the catalytic activity of
the palladium complexes in the present reaction was strongly
dependent upon the nature of the anionic part of the catalyst.
Generally, the enantioselectivity of the reaction was increased
by the use of bis(oxazolines)-ligands A–E. The best selectivity
(66% ee) was noted with Pd(OAc)2-{(R,S)-indabox} (entry 7), how-
ever the transformation proceeded with low conversion. The use
of palladium catalysts with ligands A, B, D and E under the same
reaction conditions furnished product 2a in comparable yields
(14–21%), but with lower enantioselectivities (34–60% ee, entries
2, 5, 8 and 9). It is significant, that the reaction proceeding in the
presence of S-configured bis(oxazoline) E provided enriched lac-
tone (ꢀ)-2, while the opposite enantiomer D preferred the forma-
tion of (+)-2. The PdX2-complexes with ligands F–H have been
shown to be inactive as catalysts for the transformation (entries
10–16).
Based on the results with N-tosyl derivative ( )-1a, our atten-
tion was turned to the screening of the other suitable protected
amino alcohols (Table 2). The choice of 1-benzyloxycarbonyl- and
1-tert-butyloxycarbonylaminopent-4-ene-3-ols ( )-1b,c gave us
an advantage of straightforward determination of the absolute
Next, we have examined several palladium(II) salts, chiral
ligands and reoxidants for the bicyclisation of ( )-1a–c (Scheme 2).
CO (balloon)
PdX2 (0.05 equiv.)
OH
O
O
*
L
(0.075 equiv.)
(S)-1
+
p-benzoquinone (0.5 equiv.)
N
NH
PG
PG
( )-1a = Ts
b = Z
(R,R)-2
c = Boc
O
O
O
N
O
O
O
*
L
=
Ph
Ph
Ph
N
N
N
N
N
Ph
Ph
Ph
A
B
C
NMe2
PPh2
O
O
O
O
N
(Tol)2P
Fe
N
N
N
N
P(Tol)2
R2
R1
R2
R1
D: R1 = H, R2 = i-Pr
E: R1 = i-Pr, R2 = H
G
F
H
Scheme 2. Kinetic resolution of N-protected 1-aminopent-4-ene-3-ols ( )-1 in the asymmetric Pd(II)-catalysed amidocarbonylation.

2722
P. Koóš et al. / Tetrahedron: Asymmetry 20 (2009) 2720–2723
Table 1
Kinetic resolution of 1-tosylaminopent-4-ene-3-ol ( )-1a in the asymmetric Pd(II)-catalysed amidocarbonylation
Entry
X
Ligand
Conditions
Conversion (%)
Yielda (%)
eeb (%)
[a] (25 °C) (c, CHCl3)
D
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Cl
Ac
Ac
Ac
Bc
25 °C, 48 h
17 °C, 41 h
20 °C, 45 h
20 °C, 120 h
17 °C, 48 h
20 °C, 96 h
16 °C, 17 h
20 °C, 21 h
20 °C, 42 h
40 °C, 24 h
40 °C, 32 h
20 °C, 48 h
20 °C, 48 h
22 °C, 24 h
40 °C, 96 h
19 °C, 240 h
37
22
52
16
33
30
25
17
22
23
42
32
20
100
<5
<5
26
21
33
14
26
21
21
15
21
23
36
30
16
92
—
0
60
26
26
40
0
66
34
34
9
0
15
9
0
0
—
AcO
BF4
Cl
AcO
Cl
AcO
AcO
AcO
AcO
Cl
AcO
BF4
Cl
ꢀ28 (0.21)
ꢀ11 (0.12)
+13 (0.12)
Bc
—
—
Cc
Cc
ꢀ32 (0.17)
D20
E20
Fc
+23 (0.14)
ꢀ22 (0.15)
+4.3 (0.21)
Fc
—
—
—
—
—
—
H21
H21
Gc
AcO
BF4
Gc
Gc
—
0
a
b
c
Isolated yield after flash column chromatography.
Enantiomeric excesses were determined using gas chromatography with chiral stationary phase (see Section 4).
Commercially available.
Table 2
Kinetic resolution of N-protected 1-aminopent-4-ene-3-ol ( )-1a,b,c in asymmetric Pd(II)-catalysed amidocarbonylation
Entry Diol
Ligand Conditions
Conversion (%) Yielda (%)
eeb (%)
62
Lactone
1
2
3
( )-1b
C
C
A
BQ (0.5 equiv), AcOH, 22 °C, 48 h
22
11
20
20
8
(R,R)-
2bc
(R,R)-
2b
(R,R)-
2b
( )-1b
( )-1b
BQ (0.5 equiv), AcOH, 28 °C, 42 h
BQ (0.5 equiv), AcOH, 27 °C, 42 h
68
73
18
4
5
6
7
8
( )-1a
( )-1a
( )-1a
( )-1a
( )-1a
( )-1a
( )-1a
C
C
BQ (0.5 equiv), THF, 22 °C, 192 h
BQ (0.5 equiv), CH2Cl2, 27 °C, 42 h
BQ (1.0 equiv), AcOH, 25 °C, 91 h
<5
<5
>95
50
—
—
—
76
40
—
—
—
0
60
—
—
—
—
( )-2a
(-)-2a
—
—
(ꢀ)-2a
—
A
—
—
A
BQ (1.0 equiv), Pd(OAc)2 (0.1 equiv), ligand (0.12 equiv), AcOH, 29 °C, 24 h
Duroquinone (1.0 equiv), AcOH, 25 °C, 192 h
Tetrachlorobenzoquinone (1.0 equiv), AcOH, 29 °C, 312 h
BQ (1.0 equiv), Pd(OAc)2 (0.1 equiv), ligand (0.12 equiv), CH2Cl2/AcOH (1:1),
ꢀ15 °C, 144 h
9
10
—
5
—
—
26
11
12
( )-1c
( )-1c
A
C
BQ (1.0 equiv), CH2Cl2, 29 °C, 24 h
BQ (1.0 equiv), CH2Cl2, 20 °C, 48 h
71
85
65
68
26
33
(R,R)-2c
(R,R)-2c
a
b
c
Isolated yield after flash column chromatography.
Enantiomeric excesses were determined using gas chromatography with chiral stationary phase (see Section 4).
½ ꢁ ¼ ꢀ40 (c 0.21, CHCl3).
a 2D5
configuration of known lactones 2b,c, together with the pleasing
option of N-deprotection to Geissman–Waiss’s precursor by
hydrogenolysis (Scheme 2). The absolute configuration of the lac-
tones 2b,c was assigned by comparison of the specific rotation va-
and we found that the catalytic system containing Pd(OAc)2
(0.1 equiv), ligand (0.14 equiv) and p-BQ (1.0 equiv), with respect
to substrate ( )-1a, increased the conversion and yield of the
reaction (entries 6 and 7). Finally, the choice of reoxidant was in-
spected: the replacement of p-benzoquinone by either duroqui-
none or tetrachlorobenzoquinone had a detrimental effect on the
desired transformation of 1 to 2 and only complex reaction mix-
tures were obtained (entries 8 and 9). Unfortunately, when the
reaction was performed at lower temperature (ꢀ15 °C), it did not
improve the enantioselectivity (entry 10).
lue with the literature data {for (R,R)-2b: ½a D25
ꢁ
¼ ꢀ122 (c 4.7,
CHCl3);4
½
a 2D4
ꢁ
¼ ꢀ115 (c 1.12, CHCl3);9f,22
½ ꢁ
a 3D2
¼ ꢀ170 (c 0.7,
CHCl3);23 for (S,S)-2b: ½a 2D5
ꢁ
¼ þ123 (c 1.14, CHCl3);4
½
a 2D6
ꢁ
¼ þ123
(c 1.14, CHCl3);9f,22
½
a 2D8
ꢁ
¼ þ109 (c 1.10, MeOH);24 for (R,R)-2c:
½
a 3D1
a 2D0
ꢁ
¼ ꢀ127 (c 0.4, CH2Cl2);10o
½
a 2D7
ꢁ
¼ ꢀ131 (c 1.0, CHCl3);10p
½
ꢁ
¼ ꢀ150 (c 0.5, CHCl3);25 for (S,S)-2c: ½a 2D7
¼ þ96 (c 0.43,
ꢁ
CH2Cl2);10m
½
a 2D8
ꢁ
¼ þ134 (c 1.02, CHCl3)26]}. In the next set of
3. Conclusions
experiments, the catalytic system and solvent was scrutinised
using the most effective Pd(OAc)2-{(R,S)-indabox (C)} and
Pd(OAc)2-{2,20-methylenebis[(4R,5S)-4,5-diphenyloxazolin-2-yl]
(A)} catalysts (see Table 2). First, we looked at the nature of amino-
protecting group of substrates ( )-1b,c to compare the selectivity
with that observed for N-tosylated alcohol ( )-1a and found the
benzyloxycarbonyl moiety to be an equally suitable one (62–73%
ee, entries 1–3) in contrast with tert-butyloxycarbonyl (entries
11 and 12). It is notable that the attempts to perform the bicyclisa-
tion of 1a to 2a using dichloromethane or tetrahydrofuran as
solvents failed totally (entries 4 and 5). Next, we decided to inves-
tigate the relative stoichiometry of reagents used in the reaction
In conclusion, we have developed an enantioselective amido-
carbonylative bicyclisation of alkenyl aminoalcohols catalysed by
in situ prepared chiral palladium(II) complexes. This is the first
example of a kinetic resolution process of racemic unsaturated
amino alcohols of the title reaction. The N-protected 2-oxa-6-aza-
bicyclo[3.3.0]octan-3-ones (R,R)-2b and (ꢀ)-2 (derivatives of the
Geissman–Waiss lactone) were obtained in 20–40% yields with
60–73% ee. Further studies to improve the performance of asym-
metric catalysts for this transformation are now currently under
way.

P. Koóš et al. / Tetrahedron: Asymmetry 20 (2009) 2720–2723
2723
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Bajracharya, G. B.; Suzuki, T.; Onitsuka, K.; Sasai, H. Tetrahedron: Asymmetry
2007, 18, 919–923; (m) Arai, M. A.; Arai, T.; Sasai, H. Org. Lett. 1999, 1, 1795–1979.
12. Shinohara, T.; Arai, M. A.; Wakita, K.; Arai, T.; Sasai, H. Tetrahedron Lett. 2003,
44, 711–714.
*
and (L )PdCl2
A chiral ligand (0.075–0.12 equiv) in CH2Cl2 (1 mL) was added to
the solution of Pd(OAc)2, or Pd(MeCN)2Cl2 (0.025–0.1 equiv) in
CH2Cl2 (1 mL), respectively. The mixture was stirred for 15 min to
give a clear solution and CH2Cl2 was removed in vacuo. The resulting
chiral palladium complex was dissolved in glacial AcOH (2 mL), and
substrate ( )-1 (1.0 equiv, 0.42 mmol) and p-benzoquinone (0.5–
1.0 equiv) in AcOH (2 mL) were added. The flask was purged with
CO from a balloon and the reaction mixture was vigorously stirred
until the deposition of black palladium was observed (approx. 1–
2 days). The solvent was evaporated and the crude product purified
by flash column chromatography.
4.2. Asymmetric amidocarbonylation of ( )-1 with (L*)Pd(BF4)2
*
and (L )PPh3Pd(BF4)2
A chiral ligand (0.12 equiv) in CH2Cl2 (1 mL) was added to a solu-
tion of Pd(MeCN)2Cl2 (0.1 equiv) in CH2Cl2 (1 mL). The mixture was
stirred for 15 min to give a clear solution. This solution was added to
a mixture of AgBF4 (0.2 equiv) in CH2Cl2 (1 mL). Precipitated AgCl
was removed and the filtrate was concentrated. In the synthesis of
(L*)PPh3Pd(BF4)2, in addition PPh3 (0.1 equiv) was added and stirred
for 30 min before concentration in vacuo. The solid was dissolved in
glacial AcOH (2 mL), and substrate ( )-1 (1.0 equiv, 0.42 mmol) and
p-benzoquinone (0.5–1.0 equiv) in AcOH (2 mL) were added. The
flask was purged with CO from the balloon and the mixture was stir-
red vigorously until black palladium was observed (approx. two
days). The solvent was then evaporated and the crude product puri-
fied by flash column chromatography. The spectroscopic and physi-
cal data were in good agreement with those reported.3,4,19
The general conversion control of purified products was per-
formed on Agilent 5980 series II gas chromatograph equipped with
split/splitless injector (250 °C, split ratio 1:50) and FID detector
(250 °C). Hydrogen with optimal velocity 40 cm/s was used as
a carrier gas. The oven was operated under temperature pro-
gramme 180 °C (25 min)–10 °C/min–240 °C (5 min). The enantio-
meric excess was determined using the same gas chromatograph
using hydrogen with velocity 85 cm/s a carrier gas and tempera-
ture programme 60 °C (2 min)–3.5 °C/min–190 °C.
13. (a) Kapitán, P.; Gracza, T. ARKIVOC 2008, viii, 8–17; (b) Kapitán, P.; Gracza, T.
Tetrahedron: Asymmetry 2008, 19, 38–44.
Acknowledgements
14. Itoh, T.; Mitsukura, K.; Kanphai, W.; Takagi, Y.; Kihara, H.; Tsukube, H. J. Org.
Chem. 1997, 62, 9165–9176.
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16. Evans, P. A.; Holmes, A. B.; Russell, K. J. Chem. Soc., Perkin Trans. 1 1994, 3397–
3409.
17. Jäger, V.; Hümmer, W.; Stahl, U.; Gracza, T. Synthesis 1991, 769–776.
18. Ewing, W. R.; Harris, B. D.; Bhat, K. L.; Joullie, M. M. Tetrahedron 1986, 42,
2421–2428.
This work was supported by Slovak Grant Agencies (VEGA, Slo-
vak Academy of Sciences and Ministry of Education, Bratislava,
project No. 1/0236/09, and APVV, Bratislava, project No. APVV-
20-000305).
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