Zinc-mediated radical reaction of glyoxylic oxime ether and hydrazone in aqueous media: Asymmetric synthesis of α-amino acids

Article abstract of DOI:10.1016/S0957-4166(03)00529-9

Alkyl radical addition to glyoxylic oxime ether and hydrazone in aqueous media was studied using zinc dust as a radical initiator. The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding alkylated prod

Full text of DOI:10.1016/S0957-4166(03)00529-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2857–2859
Zinc-mediated radical reaction of glyoxylic oxime ether and
hydrazone in aqueous media: asymmetric synthesis of a-amino
acids
Masafumi Ueda,a Hideto Miyabe,b Azusa Nishimura,a Hisako Suginoa and Takeaki Naitoa,*
aKobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan
bGraduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Received 3 March 2003; accepted 28 April 2003
Abstract—Alkyl radical addition to glyoxylic oxime ether and hydrazone in aqueous media was studied using zinc dust as a
radical initiator. The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding
alkylated products with good diastereoselectivities, which could be converted into enantiomerically pure a-amino acids.
© 2003 Elsevier Ltd. All rights reserved.
Zinc-mediated carbon–carbon bond-forming reactions
in aqueous media have attracted considerable interest
from both economical and environmental points of
view.1 Among various types of known zinc-mediated
reactions,1 zinc-mediated radical reactions have cap-
tured much recent attention, because of the exceptional
tolerance of functional groups.2
isopropylated product 2 was obtained in 96% yield. The
reaction probably proceeds through the radical path-
way based on a single-electron transfer from zinc as
reported previously.4 It is noteworthy that reduction
and hydrolysis of the oxime ether group were not
observed under present reaction conditions.
The carbon–nitrogen double bond has emerged as a
radical acceptor.3 However, zinc-mediated radical reac-
tions of imine derivatives have not been widely studied
so far. Our recent studies show that N-sulfonylimines
are excellent radical acceptors for the aqueous-medium
reaction using zinc as a single-electron transfer radical
initiator.4 As part of our program directed toward the
development of environmentally benign synthetic reac-
tion in aqueous media5 employing imines as a substrate,
we now report for the first time zinc-mediated radical
addition to the Oppolzer’s camphorsultam derivatives
of water-resistant glyoxylic oxime ethers and hydra-
zones for asymmetric synthesis of a-amino acids.
As a preliminary experiment, we first examined the
zinc-mediated isopropyl radical addition to achiral gly-
oxylic oxime ether 1, because it has shown high reactiv-
ity toward radical additions in our recent studies
(Scheme 1).6 To a suspension of oxime ether 1, metallic
unactivated Zn, and i-PrI in MeOH was added drop-
wise saturated aq. NH4Cl at 20°C. After the reaction
mixture has been stirred at 20°C for 15 min, the desired
Scheme 1.
Expecting that the comparison of zinc-mediated reac-
tions with indium-mediated reactions5a,b would lead to
instructive suggestions regarding radical initiators such
as zinc and indium, we next investigated diastereoselec-
tive radical additions to oxime ether 3 having camphor-
sultam as a chiral auxiliary (Scheme 2 and Table 1). We
recently reported indium-mediated alkyl radical addi-
tion to oxime ether 3 in aqueous media.5a,b The addi-
tion reactions to 3 were run in saturated aq. NH4Cl
even in the absence of an organic co-solvent. In con-
trast to indium-mediated reactions,5b the zinc-mediated
reaction of 3 with an isopropyl radical proceeded
smoothly to give the isopropylated product 4a in 64%
yield, after being stirred for only 0.5 h (entry 1).
* Corresponding author. Tel: (+81) 78-441-7554; fax: (+81) 78-441-
7556; e-mail: taknaito@kobepharma-u.ac.jp
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00529-9

2858
M. Ueda et al. / Tetrahedron: Asymmetry 14 (2003) 2857–2859
Scheme 2.
Table 1. Alkyl radical addition to chiral oxime ether 3
Entry
R
Time (h)
Product
Yield (%)a
De (%)b
1c
2d
3c
i-Pr
c-Pentyl
t-Bu
0.5
2
1
4a
4b
4c
64
74 (11)
81
75
78
73
a Combined yields of diastereomers. Yield in parentheses was for the recovered starting material 3.
b Diastereoselectivities were determined by 1H NMR analysis of crude product.
c Reactions of oxime ether 3 (0.11 mmol) were carried out with RI (0.55 mmol) and Zn (0.77 mmmol) in sat. aq. NH4Cl (0.4 mL).
d Reaction of oxime ether 3 (0.11 mmol) was carried out with c-pentyl iodide (0.55 mmol×2) and Zn (0.77 mmmol) in sat. aq. NH4Cl (0.4 mL).
Table 2. Alkyl radical addition to chiral hydrazone 5a
However, the diastereoselectivity of the zinc-mediated
reactions was lower than that obtained by previous
Entry
R
Product
Yield (%)b
De (%)c
indium-mediated reactions. The absolute configuration
at the newly formed stereocenter of major product 4a
was determined to be R by conversion into authentic
N-Cbz-D-valine.7 Other alkyl iodides were also exam-
ined as an alkyl radical precursor. Not only a sec-
ondary cyclopentyl radical but also a bulky tertiary
butyl radical worked well under similar reaction condi-
tions to give the corresponding adducts 4b and 4c in
good yields (entries 2 and 3).
1
2
3
i-Pr
c-Pentyl
t-Bu
6a
6b
6c
73 (7)
58 (40)
84
86
86
>95
a Reactions of hydrazone 5 (0.11 mmol) were carried out with RI
(0.55 mmol), Zn (0.77 mmmol) in sat. aq. NH4Cl (0.4 mL) and
CH2Cl2 (0.1 mL).
b Combined yields of diastereomers. Yields in parentheses were for
the recovered starting material 5.
c Diastereoselectivities were determined by 1H NMR analysis.
Expecting that the bulky diphenyl amino group on the
imino nitrogen atom of
5 would enhance the
the desired product 6c was obtained as a single
diastereoselectivities, we next examined the diastereose-
lective radical addition to hydrazone 5 as a congener of
radical acceptor (Scheme 3). The hydrazone 5 was
easily prepared by condensation of methyl (E)-
diphenylhydrazono acetate with (1R)-(+)-2,10-cam-
phorsultam in the presence of trimethylaluminum.
Screening the reaction conditions showed that the
biphasic reaction conditions using saturated aq. NH4Cl
and CH2Cl2 were effective for the radical reaction of
hydrazone 5. As expected, the diastereoselectivities
observed in the reaction of hydzone 5 were better than
those obtained by the reaction of oxime ether 3 (Table
2). The isopropyl radical addition to hydrazone 5 gave
the isopropylated product 6a in 73% yield with 86% de,
accompanying with 7% yield of the starting material 5
(entry 1). A cyclopentyl radical worked well (entry 2).
In the case of tert-butyl radical addition, 84% yield of
diastereomer (entry 3).8
We finally converted the isopropylated product 6a into
a-amino acid 7 (Scheme 4). The cleavage of the NꢀN
bond of diastereomerically pure product 6a which was
readily obtained by preparative TLC was successfully
achieved by hydrogenolysis in the presence of Pearl-
man’s catalyst and camphorsulfonic acid. Subsequently,
protection with CbzCl and hydrolysis using 1M LiOH
gave N-Cbz-D-valine 7 in 61% yield from 6a without
any loss of enantiomeric excess.
In conclusion, we have established the diastereoselective
zinc-mediated alkyl radical addition to imine deriva-
tives such as oxime ether and hydrazone in aqueous
media. The reactions proceeded with good diastereose-
lectivities, providing access to a range of a-amino acid.
Scheme 3.

M. Ueda et al. / Tetrahedron: Asymmetry 14 (2003) 2857–2859
2859
Scheme 4.
Acknowledgements
Damm, W.; Roth, M.; Zehnder, M. Synlett 1992, 441–443;
(g) Erdmann, P.; Scha¨fer, J.; Springer, R.; Zeitz, H.-G.;
Giese, B. Helv. Chim. Acta 1992, 75, 638–644.
We thank Grant-in-Aid for Young Scientists (B) from
The Ministry of Education, Culture, Sports, Science
and Technology and the Science Research Promotion
Fund of the Japan Private School Promotion Founda-
tion for research grants.
3. For reviews, see: (a) Friestad, G. K. Tetrahedron, 2001, 57,
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Chem., Jpn. 2001, 59, 35–41; (c) Radicals in Organic Syn-
thesis, Vol. 1 and 2; Renaud, P.; Sibi, M. P. Wiley-VCH:
Weinheim, 2001.
4. Miyabe, H.; Ueda, M.; Naito, T. Chem. Commun. 2000,
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8. A typical experimental procedure of alkyl radical addition
to hydrazone 5: To a suspension of hydrazone 5 (0.11
mmol), RI (0.55 mmol), Zn (0.77 mmmol) and CH2Cl2
(0.1 mL) was added dropwise aqueous sat. NH4Cl (0.4
mL) at 20°C. After being vigorously stirred at the same
temperature for 22 h, the reaction mixture was neutralized
with sat. NaHCO3 and extracted with CH2Cl2. The
organic phase was dried over MgSO4 and concentrated
under reduced pressure. Purification of the residue by
preparative TLC (hexane/AcOEt 3:1) afforded desired
product 6 in the yields shown in Table 2.