Asymmetric synthesis of γ-siloxyenamides via chiral auxiliary-mediated diaseteroselective coupling of ynamides, aldehydes, and silane by nickel catalyst

Article abstract of DOI:10.3987/COM-10-S(E)122

A nickel-catalyzed diastereoselective three-component coupling of optically active oxazolidinone-derived ynamides, aldehydes, and silane is described. The reaction proceeded via stereoselective formation of oxanickelacycle to give γ-siloxyenamide derivati

Full text of DOI:10.3987/COM-10-S(E)122

HETEROCYCLES, Vol. 82, No. 2, 2011
1181
HETEROCYCLES, Vol. 82, No. 2, 2011, pp. 1181 - 1187. © The Japan Institute of Heterocyclic Chemistry
Received, 6th September, 2010, Accepted, 4th October, 2010, Published online, 6th October, 2010
DOI: 10.3987/COM-10-S(E)122
ASYMMETRIC SYNTHESIS OF !-SILOXYENAMIDES VIA CHIRAL
AUXILIARY-MEDIATED DIASETEROSELECTIVE COUPLING OF
YNAMIDES, ALDEHYDES, AND SILANE BY NICKEL CATALYST
Nozomi Saito, Tomoyuki Katayama, and Yoshihiro Sato*
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812,
Japan. E-mail: biyo@pharm.hokudai.ac.jp
Abstract – A nickel-catalyzed diastereoselective three-component coupling of
optically active oxazolidinone-derived ynamides, aldehydes, and silane is
described.
The reaction proceeded via stereoselective formation of
oxanickelacycle to give !-siloxyenamide derivatives in a highly diastereoselective
manner.
This paper is dedicated to Professor Albert Eschenmoser on the occasion of his 85th birthday.
Ynamides, electron-rich alkynes, show unique reactivity and have been recognized as versatile synthetic
units in recent organic chemistry.1 Among the various reactions of ynamides, transformation of
ynamides using transition metal catalysts has attracted much attention recently, and various excellent
examples have been reported.1,2 In this context, we demonstrated nickel-catalyzed multicomponent
coupling of oxazolidinone-derived ynamides 1, aldehydes 2, and silane 3 (Scheme 1).3 This reaction
proceeded through oxanickelacycle I formed by oxidative addition of 1 and 2 to a zero-valent nickel
complex to give !-siloxyenamide derivative 4 in a highly regioselective manner.4 Herein we report
asymmetric synthesis of !-siloxyenamide derivatives via diastereoselective three-component coupling of
ynamides having a chiral auxiliary, aldehydes and silane.5
O
O
H
OSiEt3
R2
O
O
IMes
Ni
cat. Ni(0)-IMes
O
O
+
H
R2
Et3SiH (3)
N
N
N
O
O
R1
2
R1
N
N
4
R1
R2
1
I
IMes
Scheme 1

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HETEROCYCLES, Vol. 82, No. 2, 2011
First, the coupling reaction of phenylalanine-derived ynamide 5aa, aldehyde 2a and Et3SiH (3) was
carried out in the presence of a Ni(0)-SIMes catalyst generated from Ni(cod)2, SIMes·HBF4 and KOtBu in
situ in THF overnight (Table 1, run 1). As a result, the !-siloxyenamide derivative 6aaa was obtained in
79% yield and with 66% de. Encouraged by these results, the effects of substituents on the
oxazolidinone ring on the diastereoselectivity were examined (runs 2-6). The reaction of ynamide 5ba
prepared from phenylglycine with 2a and Et3SiH (3) gave 6baa in 85% yield, 70% de (run 2). When
ynamide 5ca having an isobutyl group on the oxazolidinone was reacted with 2a and 3, the
diastereoselectivity was increased to 84% (run 3). Surprisingly, the reaction of alanine-derived ynamide
5da having the smallest methyl group on the oxazolidinone ring showed excellent diastereoselectivity,
and the corresponding coupling product 6daa was obtained in 98% yield, 91% de (run 4). On the other
hand, the reaction of ynamide derived from valine 5ea did not proceed probably due to the steric
bulkiness of the isopropyl group (run 5). Moreover, when ynamide 5fa prepared from aminoindanol
was employed, !-siloxyenamide 6faa was obtained in 93% yield, 92% de (run 6).
Table 1. Effect of Substituents on the Oxazolidinone Ring.a
10 mol% Ni(cod)2
OSiEt3
*
nBu
O
O
10 mol% SIMes·HBF4
O
12 mol% KOtBu
N
N
O
2 equiv Et3SiH (3)
THF, rt, overnight
nBu
CO2Me
5
6
O
+
N
N
H
BF4
SIMes·HBF4
CO2Me
2a
de (%)b
run
ynamide
yield (%)
1
2
3
4
5
5aa (R1 = Bn)
5ba (R1 = Ph)
5ca (R1 = iBu)
5da (R1 = Me)
5ea (R1 = iPr)
6aaa: 79
6baa: 85
6caa: 86
6daa: 98
6eaa: 0
66
70
84
91
-
O
O
N
R1
nBu
O
O
N
6
6faa: 93
92
5fa
nBu
a
Reaction procedure: A solution of ynamide 5 (0.50 mmol) in THF (3.0 mL) was added to a
solution of aldehyde 2a (3 equiv to 5), Et3SiH (3, 2 equiv to 5), Ni(cod)2 (10 mol% to 5),
SIMes·HBF4 (10 mol% to 5), and KOtBu (12 mol% to 5) in THF (2.0 mL) over a period of 7 h
by a syringe pump at room temperature. After the slow addition was finished, the reaction
mixture was stirred overnight. The reaction mixture was concentrated, and the residue was
purified by flash column chromatography on silica gel to give 6. b Diastereomeric excess (de)
was determined by 1H-NMR (400 MHz or 500 MHz) analysis.

HETEROCYCLES, Vol. 82, No. 2, 2011
1183
All absolute configurations of the methyne carbon in the predominant diastereomer of the coupling
products 6 were determined through derivation of 6daa, as shown in Scheme 2. Thus, treatment of the
coupling product 6daa (91% de) with O3 gave !-hydroxyketone (+)-7, which was reduced by Zn(BH4)2 to
give diol 8 as an inseparable mixture of diastereomers.
The diol 8 was treated with
2,2-dimethoxypropane to give the corresponding acetonides cis-9 and trans-9 in 74% and 5% yields,
respectively. After confirmation of the stereochemistry of cis-9 by NOE experiments, cis-9 was
transformed into dibenzoate of 1-arylhexane-1,2-diol 10, whose absolute configurations were determined
to be 1S and 2R-configurations by the CD exciton chirality method.6 Therefore, it was found that the
major diastereomer in 6daa has an S-configuration at the methyne carbon. Furthermore, all other
coupling products 6aaa-6caa and 6faa could be also converted into (+)-7 in a manner similar to that for
6daa. These result indicate that the predominant diastereomer of 6aaa-6caa and 6faa also has an S
configuration at the methyne carbon.
OH
Ar
nBu
OH
Ar
nBu
MeO OMe
O3, then PPh3
CH2Cl2
Zn(BH4)2
THF
6daa
(91% de)
HO
O
PPTS, CH2Cl2
8: 95%
(major:minor = 9:1)
(+)-7: 59%
NOE
O
OBz
H
1) TsOH/MeOH
nBu
O
H
2R
Ar
1S
Ar
2) BzCl
Ar =
nBu
OBz
10: 89% from cis-9
CO2Me
cis-9: 74%
+ trans-9: 5%
Scheme 2
Coupling reactions of various alanine-derived ynamides and aldehydes were investigated and the results
are summarized in Table 2. The reaction of 5da and aromatic aldehydes 2b-d with Et3SiH (3) in the
presence of a Ni(0)-SIMes catalyst afforded the coupling products 6dab-6dad in high yields and in high
diastereoselectivity (runs 1-3). An aliphatic aldehyde 2e was also applicable to the coupling with 5da
and 3, giving 6dae in 75% yield as a single diastereomer (run 4). On the other hand, ynamides 5db-5de
having various substituents on the alkyne part were reacted with 2a and Et3SiH (3) by Ni(0)-SIMes to
give the corresponding "-siloxyenamides 6dba-6dea, respectively in good yields and in a highly
diastereoselective manner (runs 5-8).7

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HETEROCYCLES, Vol. 82, No. 2, 2011
Table 2. Coupling of Various Ynamides and Aldehydes.a
OSiEt3
O
O
O
O
cat. Ni(0)-SIMes
+
N
R3
*
N
O
H
R3
Et3SiH (3), THF, rt
R2
R2
2
Me
Me
5
6
de (%)b
run
ynamide
aldehyde
yield (%)
1
2
3
4
5
6
7
8
5da (R2 = nBu)
2b (R3 = C6H5)
2c (R3 = 4-CF3CC6H4) 6dac: 97
2d (R3 = 2-naphtyl)
2e (R3 = CH2CHMe2)
6dab: 95
91
84
90
5da
5da
6dad: 93
5da
5db (R2 = Me)
5dc (R2 = CH2OTBS)
5dd (R2 = CH2CH2OTBS) 2a
5de (R2 = CH2CH2OMOM) 2a
6dae: 75 >99
2a (R3 = 4-MeO2CC6H4) 6dba: 88
85
90
94
91
2a
6dca: 93
6dda: 83
6dea: 73
a Reaction procedure: A solution of ynamide 5 (0.50 mmol) in THF (3.0 mL) was added to
a solution of aldehyde 2a (3 equiv to 5), Et3SiH (3, 2 equiv to 5), Ni(cod)2 (10 mol% to 5),
SIMes·HBF4 (10 mol% to 5), and KOtBu (12 mol% to 5) in THF (2.0 mL) over a period of
7 h by a syringe pump at room temperature. After the slow addition was finished, the
reaction mixture was stirred overnight. The reaction mixture was concentrated, and the
residue was purified by flash column chromatography on silica gel to give 6.
b Diastereomeric excess (de) was determined by 1H-NMR (400 MHz or 500 MHz) analysis.
The absolute configuration at the methyne carbon of the coupling products 6 in Table 2
was tentatively assigned as S-configuration by the analogy to that of 6daa.
It is well known that nickel-catalyzed reductive coupling of alkyne and aldehyde proceeds via the
formation of oxanickelacycle generated by oxidative cycloaddition of alkyne and aldehyde to a
zero-valent nickel complex.8,9 Moreover, Jamison and Houk recently reported that the oxidative
cycloaddition is the rate-determining step of the alkyne-aldehyde coupling and controls the
regioselectivity of formation of the oxanickelacycle.10 Therefore, the most significant step for the
diasteroselection of this coupling of chiral ynamides and aldehydes was also thought to be the oxidative
cycloaddition stage (Scheme 3). First, both the #-orbital of the triple bond and lone-pair electrons of the
carbonyl group in ynamide 5, aldehyde 2 and ligand (SIMes) would coordinate to the nickel center, and
two possible tetracoordinate complexes 11 and 12, in which the R1 group on the oxazolidinone ring
should be oriented to avoid steric interaction with the bulky SIMes ligand, could be formed. Then
oxidative cycloaddition from each tetracoordinate complex would occur to afford oxanickelacycle 13 or
14. However, the formation of 14 from 12 seems to be less favorable than the formation of 13 because
of steric repulsion between the R3 group in the aldehyde and the bulky SIMes ligand. Thus, nickelacycle
13 would be formed preferably as compared with 14. Therefore, the coupling reaction would
predominantly proceed via oxanickelacycle 13, and (S)-6 was obtained as a major diastereomer through
$-bond metathesis of 13 with Et3SiH (3) followed by reductive elimination. On the other hand,
diastereoselectivity of the reaction of ynamides having a bulkier R1 group such as 5aa-5ca decreased in

HETEROCYCLES, Vol. 82, No. 2, 2011
1185
contrast to that of 5da having a methyl group as described above. It is thought that formation of 13 from
5aa-5ca might be less favorable than the reaction of 5da due to steric interaction between the hindered R1
group and the R3 group. Therefore, it is thought that contribution of the reaction pathway via 14
increased and the diastereoselectivity of the coupling diminished.
R1
O
OSiEt3
O
R1
O
O
Et3SiH (3)
N
R3
(S)
R3
H
O
N
H
N
O
R2
R2
Ni
SIMes
O
Ni
R1
(S)-6
major diastereomer
*
O
SIMes
R2
11
R3
13
H
5 + 2
R1
O
Ni(0)-SIMes
OSiEt3
O
R1
O
O
Et3SiH (3)
N
3
(R)
N
R
H
N
H
O
O
R2
R2
Ni
SIMes
O
Ni
*
R1
(R)-6
minor diastereomer
O
SIMes
R3
R2
14
12
R3
H
Scheme 3
In summary, nickel-catalyzed three-component coupling of chiral oxazolidinone-derived ynamides,
aldehydes and silane was developed. The reaction proceeds through the formation of oxanickelacycle to
afford "-siloxyenamide derivatives in a highly regio- and stereoselective manner.
ACKNOWLEDGEMENTS
This work was partly supported by a Grant-in-Aid for Science Research on Priority Areas (No. 19027005
and 20036005, Synergy of Elements) from MEXT, Japan and a Grant-in-Aid for Scientific Research (B)
(No. 19390001) from JSPS. N.S. acknowledges the Akiyama Foundation and the Research Foundation
for Pharmaceutical Sciences for financial support.
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HETEROCYCLES, Vol. 82, No. 2, 2011
2. For our reports on transition metal catalysis based on ynamide as a platform, see: (a) N. Saito, Y.
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7. Typical Procedure for the Nickel-Catalyzed Coupling of Ynamide, Aldehyde, and Et3SiH
(Table 2, run 4). To a solution of Ni(cod)2 (14 mg, 0.050 mol), SIMes·HBF4 (20 mg, 0.050 mmol),
and KOtBu (6.8 mg, 0.061 mmol) in THF (3.0 mL) were added 2e (0.16 mL, 1.5 mmol) and 3 (0.16
mL, 1.1 mmol) at 0 °C, and the mixture was stirred at the same temperature for 10 min. To the
mixture was added a solution of 5da (91 mg, 0.50 mmol) in THF (2.0 mL) over a period of 7 h by a
syringe pump at room temperature. After the slow addition was finished, the reaction mixture was
stirred at room temperature overnight. The mixture was concentrated, and the residue was purified
by flash column chromatography on silica gel (hexane/AcOEt = 8/1) to give 6dae (144 mg, 75%) as
26
1
a colorless oil. [!]D -37.8° (c 0.22, CHCl3); IR (neat) 1761, 1236 cm-1; H NMR (500 MHz,
CDCl3) % 0.58-062 (m, 6H), 0.89 (d, J = 4.0 Hz, 3 H), 0.91 (d, J = 4.6 Hz, 3 H), 0.91 (d, J = 3.4 Hz,
3 H), 0.95 (t, J = 8.0 Hz, 9 H), 1.25 (d, J = 6.3 Hz, 3H), 1.29-1.45 (m, 6H), 1.69 (m, 1H), 1.99-2.9
(m, 2H), 3.94 (dd, J = 8.0, 5.2 Hz, 1H), 4.07 (m, 1H), 4.17 (dd, J = 8.0, 4.6 Hz, 1H), 4.44 (t, J = 8.3
Hz, 1H), 5.97 (s, 1H); 13C NMR (125 MHz, CDCl3) % 4.7, (3C), 6.8 (3C), 13.8, 18.5, 22.2, 23.0, 23.3,
24.1, 26.7, 30.4, 46.5, 52.4, 68.8, 73.2, 117.9, 139.2, 156.0; EI-LRMS m/z 354 [(M-Et)+], 326, 298,
251; EI-HRMS calcd for C19H36NO3Si [(M-Et)+] 354.2464, found 354.2458.
8. For nickel-catalyzed coupling of normal alkyne, aldehyde and silane via oxanickelacycle
intermediate, see: (a) G. M. Mahandru, G. Liu, and J. Montgomery, J. Am. Chem. Soc., 2004, 126,
3698; (b) K. Sa-ei and J. Montgomery, Org. Lett., 2006, 8, 4441; (c) M. R. Chaulagain, G. J.
Sormunen, and J. Montgomery, J. Am. Chem. Soc., 2007, 129, 9568; For related nickel-catalyzed
reductive coupling of alkyne and aldehyde in the presence of Et2Zn or Et3B as a reducing reagent,
see: (d) E. Oblinger and J. Montgomery, J. Am. Chem. Soc., 1997, 119, 9065; (e) W.-S. Huang, J.

HETEROCYCLES, Vol. 82, No. 2, 2011
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Chan, and T. F. Jamison, Org. Lett., 2000, 2, 4221.
9. Recently, oxanickelacyclopentene from zero-valent nickel, aldehyde, and alkyne was isolated and its
structure was elucidated by X-ray analysis. See: S. Ogoshi, T. Arai, M. Ohashi, and H. Kurosawa,
Chem. Comunn., 2008, 1347.
10. P. R. McCarren, P. Liu, P. H.-Y. Cheong, T. F. Jamison, and K. N. Houk, J. Am. Chem. Soc., 2009,
131, 6654.