Catalytic asymmetric addition of alkynylzinc reagents to nitrones

Article abstract of DOI:10.1246/cl.2007.44

The catalytic asymmetric addition of alkynylzinc reagents, which were prepared in situ from dimethylzinc and 1-alkynes, to nitrones was achieved by utilizing di(t-butyl) (R,R)-tartrate as a chiral auxiliary to afford the corresponding optically active (R)

Full text of DOI:10.1246/cl.2007.44

44
Chemistry Letters Vol.36, No.1 (2007)
Catalytic Asymmetric Addition of Alkynylzinc Reagents to Nitrones
Atsuko Konishi, Weilin Wei, Masato Kobayashi, Shuhei Fujinami,
Yutaka Ukaji,ꢀ and Katsuhiko Inomataꢀ
Division of Material Sciences, Graduate School of Natural Science and Technology,
Kanazawa University, Kakuma, Kanazawa 920-1192
(Received July 19, 2006; CL-060815; E-mail: inomata@cacheibm.s.kanazawa-u.ac.jp)
The catalytic asymmetric addition of alkynylzinc reagents,
Table 1. Catalytic asymmetric addition of an alkynylzinc re-
agent to a nitrone 2a in the presence of a product-like additive 5a
which were prepared in situ from dimethylzinc and 1-alkynes,
to nitrones was achieved by utilizing di(t-butyl) (R,R)-tartrate
as a chiral auxiliary to afford the corresponding optically active
(R)-N-(ꢀ-substituted)propargylic hydroxylamines. By the addi-
tion of methylzinc salt of a product-like racemic hydroxylamine,
enantioselectivity of the N-propargylic hydroxylamines was
enhanced up to 96% ee.
Yield of 4aa ee of 4aa Yield of 6
/%c
Entry
5
mb
nb
/%
/%
1
2
3
4
5
6
7
8
9
racemic 0.2
0
87
80
93
90
85
86
94
83
83
83
88
76
68
72
83
83
60
73
72
45
62
61
51
21
4
5
3
2
3
3
1
4
2
2
7
3
racemic 0.2 0.1
racemic 0.2 0.2
racemic 0.2 0.3
R
S
0.2 0.3
0.2 0.3
racemic 0.2 0.4
racemic 0.1
racemic 0.1 0.1
racemic 0.1 0.2
racemic 0.1 0.3
The catalytic asymmetric C–C bond formation via nucleo-
philic addition of a C-nucleophile to imine functions provides
one of the most important method for synthesizing optically ac-
tive amines, which are versatile building blocks for the optically
active nitrogen-containing compounds. Especially, the addition
of alkynyl nucleophile has a strategic advantage to produce more
functionalized nitrogen-containing substances.1 However, the
catalytic methods for the preparation of optically active propar-
gylic amines are still limited.2 Very recently we have reported a
stoichiometric enantioselective nucleophilic addition of alkynyl-
zinc reagent to nitrones by utilizing tartaric acid ester as a
chiral auxiliary.3 Herein, we describe a catalytic enantioselective
addition of alkynylzinc reagents to acyclic nitrones utilizing
di(t-butyl) (R,R)-tartrate as a chiral auxiliary.
First the catalytic addition reaction of alkynylzinc reagent
to N-(benzylidene)benzylamine N-oxide (2a) was examined
in CH2Cl2 at 0 ꢁC; i.e., in the presence of 0.2 molar amount of
bis(methylzinc) salt of di(t-butyl) (R,R)-tartrate [(R,R)-DTBT]
1, prepared in situ from 0.2 molar amount of (R,R)-DTBT and
0.4 molar amount of dimethylzinc, the nitrone 2a was treated
with phenylacetylene (3a) and dimethylzinc (Scheme 1).1b,4
The reaction proceeded smoothly to give the corresponding
(R)-N-propargylic hydroxylamine 4aa with the enantioselectivi-
ty of 68% ee as shown in Table 1 (Entry 1). This result suggested
that the zinc salt 1 can work as a catalyst. Previously we found
that a product-like additive enhances the enantioselectivity in
the stoichiometric addition reaction.3 Then, the effect of the
product-like additive was examined also in the present catalytic
0
10
11
12
S
0
0.2
aSee ref. 5. bThe italicized m and n indicate the molar amounts of 1 and 5
as depicted in Scheme 1, respectively. cEnantioselectivities were deter-
mined by HPLC analysis (Daicel Chiralcel OD-H).
reaction. Namely, to a mixture of 0.2 molar amount of bis-
(methylzinc) salt of (R,R)-DTBT 1 and 0.2 molar amount of
methylzinc salt 5 derived from racemic p-methoxyphenyl-
substituted N-propargylic hydroxylamine 4ba and dimethylzinc,
1.0 molar amount of dimethylzinc, nitrone 2a and phenylacetyl-
ene (3a) were subsequently added. The enantioselectivity was
again enhanced from 68 to 83% ee (Entry 3). Next, the amount
of the product-like additive 5 was investigated. As shown in
Table 1, the use of 0.2 or 0.3 molar amount of 5 gave almost
the same enantioselection (Entries 1–4 and 7). Using 0.3 molar
amount of 5, more reproducible result was realized (Entry 4).
In order to confirm how the reaction proceeds, the time-
courses of the reactions corresponding to Entries 1 and 4 in
Table 1 were observed. In the catalytic reaction without the ad-
ditive 5 (Figure 1a), enantioselectivity was lower at the initial
stage and it was slightly increased as the reaction proceeded.
At later stage of the reaction, a part of the addition product
cyclized to give the corresponding 4-isoxazoline 6.4a,6 By the
100
%
100
%
b)
a)
80
60
40
20
0
80
60
40
20
0
0
5
10 15 20
h
h
10 15 20
0
5
Figure 1. The time-course of the formation of 4aa. a) Corre-
sponding to Entry 1 in Table 1. b) Corresponding to Entry 4 in
Table 1.
Scheme 1.
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.1 (2007)
45
By the addition of a product-like racemic substrate, the asym-
metric amplification was observed, and the corresponding N-
propargylic hydroxylamines were obtained with excellent enan-
tioselectivities.9
MeZnO
1) 0.3
Bn
N
An
racemic-5
2) 1.0 Me2Zn
t
MeZnO
MeZnO
CO2 Bu
HO
R1
Bn
Ph
N
0.2
t
CO2 Bu
The present work was financially supported in part by
a Grant-in-Aid for Scientific Research on Priority Areas ‘‘Ad-
vanced Molecular Transformations of Carbon Resources’’ from
The Ministry of Education, Culture, Sports, Science and
Technology (MEXT), a Grant-in-Aid for Scientific Research
(C) from Japan Society for the Promotion of Science (JSPS),
and NOVARTIS Foundation (Japan) for the Promotion of
Science.
O
Bn
N
R2
3) 1.0
1
4
2
3
R1
H
4) 1.0 HC CR2
0 °C, T h
Scheme 2.
Table 2. The asymmetric addition of alkynylzinc reagents to
nitrones 2 in the presence of a product-like racemic additivea
Dedicated to Professor Teruaki Mukaiyama on the occasion
of his 80th birthday.
Entry
R1
2
a
R2
3
a
Solvent T/h
4
Yield/% ee/%
1
2
3
4
5
6
7
Ph
Ph
CH2Cl2 16 aa
90
89
62
92
80
84
70
87
73
77
57
83b
83b
75b
91b
91b
95b
90b
90b
90b
96d
88b
Et2O
THF
19
20
References and Notes
1
a) J. Blanchet, M. Bonin, L. Micouin, Org. Prep. Proced. Int. 2002,
34, 467. b) P. Aschwanden, E. M. Carreira, Acetylene Chemistry,
ed. by F. Diederich, P. J. Stang, R. R. Tykwinski, Wiley-VCH,
Weinheim, 2005, Chap. 3.
toluene 14
xylene 17
EtPh
cumeme 17
14
2
a) J. F. Traverse, A. H. Hoveyda, M. L. Snapper, Org. Lett. 2003, 5,
3273. b) C. Koradin, N. Gommermann, K. Polborn, P. Knochel,
Chem. Eur. J. 2003, 9, 2797. c) C. Wei, J. T. Mague, C.-J. Li, Proc.
8c pMeOC6H4
9
10
11e
b
c
d
a
Ph
Ph
Ph
SiMe3
a
a
a
b
EtPh
EtPh
EtPh
toluene
13 ba
18 ca
19 da
pBrC6H4
oBrC6H4
Ph
Natl. Acad. Sci. 2004, 101, 5749. d) T. F. Knopfel, P. Aschwanden,
¨
7
ab
T. Ichikawa, T. Watanabe, E. M. Carreira, Angew. Chem., Int. Ed.
2004, 43, 5971. e) N. Gommermann, P. Knochel, Chem. Commun.
2005, 4175. f) A. M. Taylor, S. L. Schreiber, Org. Lett. 2006,
8, 143. g) F. Colombo, M. Benaglia, S. Orlandi, F. Usuelli, G.
Celentano, J. Org. Chem. 2006, 71, 2064. h) A. Bisai, V. K. Singh,
Org. Lett. 2006, 8, 2405. i) P. Aschwanden, C. R. J. Stephenson, E. M.
Carreira, Org. Lett. 2006, 8, 2437. j) N. Gommermann, P. Knochel,
Chem. Eur. J. 2006, 12, 4380.
W. L. Wei, M. Kobayashi, Y. Ukaji, K. Inomata, Chem. Lett. 2006,
35, 176.
a) S. Pinet, S. U. Pandya, P. Y. Chavant, A. Ayling, Y. Vallee, Org.
Lett. 2002, 4, 1463. b) L. Zani, S. Alesi, P. G. Cozzi, C. Bolm, J.
Org. Chem. 2006, 71, 1558.
aSee ref. 5. bEnantioselectivity was determined by HPLC analysis (Daicel
Chiralcel OD-H). cA methylzinc salt of racemic-4aa was used as an addi-
tive instead of 5. dEnantioselectivity was determined by HPLC analysis
(Daicel Chiralcel OJ-H). eThe reaction was carried out at rt.
addition of a product-like additive 5 (Figure 1b), induction
time was not observed and the enantioselectivity was constantly
high from the initial stage. In addition, the cyclization to the 4-
isoxazoline 6 was rather retarded.
3
4
The influence of the stereochemistry of the additive 5 was
investigated. When 0.2 molar amount of methylzinc salt (R)-
or (S)-5 derived from the corresponding optically pure (R)- or
(S)-4ba7 and dimethylzinc was used as an additive instead of
racemic-5, the enantioselectivity was surprisingly decreased
(Entries 5 and 6). Furthermore, it was found that reduction of
the amount of methylzinc salt of (R,R)-DTBT 1 to 0.1 molar
amount decreased the catalytic efficiency (Entries 8–11), and
poor chiral induction was observed by the use of the only
additive 5 without the methylzinc salt of (R,R)-DTBT 1 (Entry
12). It is noteworthy that this reaction does not proceed in an
autocatalytic way, since (R)-4aa was formed by using (S)-5.
Next, the addition reactions were carried out in several
solvents (Table 2, Entries 1–7). The enantioselectivity was de-
creased in THF (Entry 3), but remarkably increased in aromatic
solvents (Entries 4–7). It was found that ethylbenzene was a
choice of solvent to afford 4aa with excellent enantioselectivity
of 95% ee (Entry 6).8 The several other asymmetric additions of
acetylides to nitrones 2 in the presence of racemic-5 were also
carried out to furnish the corresponding N-propargylic hydroxyl-
amines 4 with excellent enantioselectivities (Entries 8–11).
The absolute configurations of 4aa and 4ba were deter-
mined to be R by chemical correlation3 and X-ray crystallo-
graphic analysis,7 respectively. The stereochemistries of other
products were tentatively assigned to be also R.
5
6
7
The numbers in front of the reagents in Schemes 1 and 2 indicate
molar amounts of the reagents used.
P. Aschwanden, D. E. Frantz, E. M. Carreira, Org. Lett. 2000, 2,
2331.
The optically pure (S)-N-propargylic hydroxylamine 4ba, was
obtained as follows: The enantiomerically rich (S)-4ba (93% ee), ob-
tained by asymmetric addition using a stoichiometric amount of (S,S)-
DTBT,3 was treated with (S)-camphanic chloride and Et3N in the
presence of a catalytic amount of 4-(N,N-dimethylamino)pyridine in
CH2Cl2 to give the corresponding ester (74%). Recrystallization from
toluene/hexane gave the diastereomerically pure ester. The absolute
configuration of the ester was determined to be S,S by X-ray crystallo-
graphic analysis of its single crystal. Crystal data of the ester–toluene
˚
(1:1): C40H41NO5, FW 615.77, triclinic, P1, a ¼ 6:194ð1Þ A, b ¼
10:686ð2Þ A, c ¼ 13:007ð2Þ A, ꢀ ¼ 91:913ð4Þꢁ, ꢁ ¼ 91:046ð5Þꢁ,
˚
˚
ꢂ ¼ 99:929ð6Þꢁ, V ¼ 847:4ð3Þ A , Z ¼ 1. Dcalcd ¼ 1:207 g/cm3.
3
˚
R ¼ 0:042 (Rw ¼ 0:059) for 5909 reflections with I > 3:00ꢃðIÞ and
416 variable parameters. Reduction of the optically pure ester by
LiAlH4 gave the optically pure (S)-4ba (99%). The optically pure
(R)-4ba was obtained in a similar manner.
8
9
The enhancement of enantioselectivity by a product-like additive 5
was confirmed even when the asymmetric addition was carried out
in ethylbenzene: The reaction in ethylbezene without additive 5 under
the same conditions of Entry 1 in Table 1 (the reaction was quenched
after stirring for 14 h) gave 4aa in 76% yield with the enantioselectiv-
ity of 84% ee.
Examples for asymmetric amplification by a product-like additive:
K. Soai, J. Synth. Org. Chem. Jpn. 2004, 62, 673; B. M. Trost, A.
Fettes, B. T. Shireman, J. Am. Chem. Soc. 2004, 126, 2660.
As described above, a catalytic asymmetric addition of
alkynylzinc reagents to acyclic nitrones has been developed.
Published on the web (Advance View) December 9, 2006; doi:10.1246/cl.2007.44