Asymmetric addition of alkynylzinc reagents to nitrones utilizing tartaric acid ester as a chiral auxiliary

Article abstract of DOI:10.1246/cl.2006.176

The asymmetric addition of alkynylzinc reagents, prepared in situ from dialkylzinc 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)-α-substituted proparg

Full text of DOI:10.1246/cl.2006.176

176
Chemistry Letters Vol.35, No.2 (2006)
Asymmetric Addition of Alkynylzinc Reagents to Nitrones
Utilizing Tartaric Acid Ester as a Chiral Auxiliary
Weilin Wei, Masato Kobayashi, Yutaka Ukaji,ꢀ and Katsuhiko Inomataꢀ
Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University,
Kakuma, Kanazawa 920-1192
(Received November 9, 2005; CL-051390; E-mail: inomata@cacheibm.s.kanazawa-u.ac.jp)
The asymmetric addition of alkynylzinc reagents, prepared
Table 1. Asymmetric addition of alkynylzinc reagents to 2a
in situ from dialkylzinc and 1-alkynes, to nitrones was achieved
by utilizing di(t-butyl) (R,R)-tartrate as a chiral auxiliary to af-
ford the corresponding optically active (R)-ꢀ-substituted propar-
gylic N-hydroxylamines. By the addition of product-like N-hy-
droxylamine, unprecedented enhancement of enantioselectivity
was observed to afford the N-hydroxylamines up to 95% ee.
Entry
M1
M2
R1
1
R2
Yield/% ee/%a
The development of efficient methods for C–C bond forma-
tion by asymmetric nucleophilic additions to a C=N bond is
quite important.1 The asymmetric addition of acetylides to
imines is a useful method for the production of chiral propargyl-
amines, which are versatile building blocks for the optically ac-
tive nitrogen-containing compounds2 and can be also encoun-
tered as part of biologically active compounds.3 Although sever-
al diastereoselective methods for nucleophilic addition of acety-
lides had been reported,2,4 asymmetric addition of acetylides to
C=N bond is still regarded as one of the challenging problems
especially in terms of availability of chiral auxiliaries.5 Among
the imine compounds, nitrone seems to be a promising candidate
because it possesses an electronegative oxygen, which can acti-
vate C=N bond and strongly coordinate to metals. We have al-
ready reported enantioselective nucleophilic addition of dialkyl-
zinc and Reformatsky-type reagent to nitrones with isoquinoline
skeleton by utilizing tartaric acid ester as a chiral auxiliary.6,7
Herein, we wish to describe an enantioselective addition of alky-
nylzinc reagents to acyclic nitrones utilizing tartaric acid ester as
a chiral auxiliary.8
First the addition reaction of alkynylzinc reagent to N-(ben-
zylidene)benzylamine N-oxide (2a) was examined in CH2Cl2 at
0 ꢁC; i.e., in the presence of 1.0 molar amount of biszinc salt of
diisopropyl (R,R)-tartrate 1A, derived in situ from 1.0 molar
amount of diisopropyl (R,R)-tartrate and 2.0 molar amounts of
diethylzinc,9 the nitrone 2a was treated with phenylacetylene
(3a) and diethylzinc. After the usual workup, the corresponding
(R)-propargylic N-hydroxylamine 4aa was obtained with the
enantioselectivity of 73% ee as shown in Table 1, Entry 1. As
a dialkylzinc for salt formation of tartrate and alkynylzinc re-
agent, dimethylzinc was slightly more effective than diethylzinc
or diisopropylzinc (Entries 1–3). Bulkiness of dialkylzinc, which
generated the alkynylzinc, scarcely influenced the enantioselec-
tivity (Entries 3 and 4). More Lewis acidic bromozinc salts 1D
and 1E showed rather low enantioselection (Entries 1, 5, and
6). The influence of the ester group in bis(methylzinc) salt of tar-
trate was also investigated. The use of the esters derived from
primary alcohols 1F and 1G afforded the product 4aa with lower
selectivities (Entries 7 and 8). It was found that t-butyl ester was
the best choice to afford the N-hydroxylamine 4aa with 82% ee
(Entry 9).
1
2
3
4
5
6
7
8
9
ZnEt
ZniPr
ZnMe ZnMe iPr
ZnMe ZnMe iPr
ZnEt
ZniPr
iPr
iPr
A
B
C
C
D
E
F
Et
74
58
86
88
48
61
83
77
89
73
73
78
78
iPr
Me
Et
ZnBr
ZnBr
ZnBr
ZnEt
iPr
iPr
Et
7b
Et
11
47
60
82
ZnMe ZnMe Me
ZnMe ZnMe Et
ZnMe ZnMe tBu
Me
Me
Me
G
H
aEnantioselectivities were determined by HPLC analysis (Daicel
Chiralcel OD-H). b(S)-Enantiomer was mainly obtained.
Next, in order to confirm how the reaction proceeded, the
time course of the reaction corresponding to Entry 9 in Table 1
was observed (Table 2). Surprisingly, enantioselectivity was in-
creased remarkably after around 8 h, suggesting that (R)-enan-
tiomer was selectively produced after the induction time.
Based on this observation, if the product at initial stage of
the reaction was added into the original reaction, the ee of the
product could be enhanced without the induction time. In order
to distinguish the product of the reaction and the additive, a
product-like substrate was added to the reaction. Namely, a mix-
ture of 1.2 molar amounts of bis(methylzinc) salt of di(t-butyl)
(R,R)-tartrate (1H) and 1.2 molar amounts of dimethylzinc
was treated with 0.2 molar amount of racemic p-methoxyphen-
Table 2. The time-course of the production of 4aa
Entry
T/h
Yield/%
ee/%
1
2
3
4
5
2
4
2
10
13
70
89
—
47
49
79
82
8
19
24
Copyright Ó 2006 The Chemical Society of Japan

Chemistry Letters Vol.35, No.2 (2006)
177
selectivities were realized.13 Further investigation for the present
peculiar asymmetric amplification by the racemic additive is
now on progress in our laboratory.
Table 3. The asymmetric addition of alkynylzinc reagents to
nitrones 2 in the presence of product-like additive
The present work was financially supported in part by
Grant-in-Aid for Scientific Research from Japan Society for
the Promotion of Science (JSPS).
References and Notes
1
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Entry
1
2d pMeOC6H4
R3
Ph
2
R4
3 T/h 4
Yielda ee (Yield ee)b
2
3
a
b
c
Ph
Ph
Ph
Ph
a
a
a
a
18 aa 75 94c (89 82)
39 ba 80 92e (70 74)
18 ca 92 91e (57 77)
18 da 67 95c (71 78)
3
pBrC6H4
oBrC6H4
Ph
4
d
a
a
5
6f
pMeC6H4 b 18 ab 70 86e (58 76)
nC6H13 14 ac 62 79c (48 57)
Ph
c
aIsolated yields/%. bIsolated yields/% and enantioselectivities/% ee
in parentheses were the results of the reaction carried out without the
product-like additive under the same conditions as that of Entry 9 in
Table 1. cEnantioselectivity/% ee was determined by HPLC analysis
d
(Daicel Chiralcel OJ-H). The racemic 4aa was used as an additive
instead of the racemic 4ba. eEnantioselectivity/% ee was determined
f
by HPLC analysis (Daicel Chiralcel OD-H). 0.2 Molar amount of
Me2Zn was added in the step 1). Pre-reacted mixture of 1.0 molar
amount of Me2Zn and 1.0 molar amount of acetylene 3c was added
in the step 4); the reaction was carried out at rt.
4
5
P. Ascwanden, E. M. Carreira, Acetylene Chemistry, ed. by F.
Diederich, P. J. Stang, R. R. Tykwinski, Wiley-VCH, Weinheim,
2005, Chap. 3.
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C=N bond: a) D. E. Frantz, R. Fassler, C. S. Tomooka, E. M.
¨
Carreira, Acc. Chem. Res. 2000, 33, 373. b) J. F. Traverse, A. H.
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Inomata, Synlett 2003, 1075.
yl-substituted product-like additive 4ba,10 followed by addition
of 1.0 molar amount of the nitrone 2a and phenylacetylene (3a).
As expected, the enantioselectivity was enhanced from 82 to
94% ee (Table 3, Entry 1). The several asymmetric additions
of acetylides to nitrones 2 in the presence of the product-like
additive were also carried out to furnish the corresponding ꢀ-
substituted propargylic N-hydroxylamines 4 with excellent
enantioselectivities (Entries 2–6). By comparison with the reac-
tion without the product-like additive (the results were shown in
parentheses), the dramatic enhancement of the enantioselection
was observed.
6
7
8
Enatioselective addition of Reformatsky-type reagent to imines was
also developed: Y. Ukaji, S. Takenaka, Y. Horita, K. Inomata,
Chem. Lett. 2001, 254.
Addition of alkynylzinc reagents, prepared in situ from 1-alkynes
and zinc reagents, to nitrones: S. Pinet, S. U. Pandya, P. Y. Chavant,
The absolute configuration of the propargylic N-hydroxyl-
amine 4aa was confirmed to be R by chemical correlation.
Namely, 4aa (76% ee) was transformed to the 1,3-diphenyl-1-
25
propylamine derivative 5 (½ꢀꢂD ꢃ41 (c 0.23, MeOH), ꢃ55 (c
A. Ayling, Y. Vallee, Org. Lett. 2002, 4, 1463; R. Fassler, D. E.
¨
Frantz, J. Oetiker, E. M. Carreira, Angew. Chem., Int. Ed. 2002,
0.23, CHCl3)), and its absolute configuration was determined
to be S by the comparison with specific optical rotation of
´
41, 3054; S. K. Patel, S. Py, S. U. Pandya, P. Y. Chavant, Y. Vallee,
15
Tetrahedron: Asymmetry 2003, 14, 525, and Ref 5a.
M. Hayashi, K. Ono, H. Hoshimi, N. Oguni, Tetrahedron 1996, 52,
7817.
the known (R)-5 (100% ee; ½ꢀꢂD þ54:4 (c 2.6, MeOH))
9
(Scheme 1).11,12 The absolute configurations of other propargylic
N-hydroxylamines 4 were tentatively assigned to be R.
10 p-Methoxyphenyl-substituted substrate 4ba was selected as an
additive due to easy separation from the product 4aa.
11 A. L. Manna, V. Ghislandi, P. B. Hulbert, P. M. Scopes, Farmaco,
Ed. Sci. 1967, 22, 1037.
12 Other data of specific rotation of 5: M. J. Burk, Y. M. Wang, J. R.
Lee, J. Am. Chem. Soc. 1996, 118, 5142, supporting information,
As described above, an attractive asymmetric addition of
alkynylzinc reagents to acyclic nitrones has been developed.
By the addition of product-like substrate, the excellent enantio-
25
25
(R) (96.9% ee), ½ꢀꢂD þ67 (c 0.22, MeOH), ½ꢀꢂD þ31:8 (c
0.10, CHCl ); D. Enders, J. H. Kirchhoff, J. Kobberling, T. H.
¨
Peiffer, Org. Lett. 2001, 3, 1241, supporting information, (R)
(50% ee), ½ꢀꢂD þ5:0 (c 0.30, CHCl3).
3
26
13 Examples for asymmetric amplification by 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.
Scheme 1.
Published on the web (Advance View) January 7, 2006; DOI 10.1246/cl.2006.176