Highly diastereoselective radical addition to glyoxylic oxime ether: Asymmetric synthesis of α-amino acids

Article abstract of DOI:10.1039/a704562j

A high degree of stereocontrol in radical addition to the Oppolzer's camphor sultam derivative of glyoxylic oxime ether was achieved, providing a convenient method for preparing a variety of enantiomerically pure α-amino acids.

Full text of DOI:10.1039/a704562j

View Article Online / Journal Homepage / Table of Contents for this issue
Highly diastereoselective radical addition to glyoxylic oxime ether: asymmetric
synthesis of a-amino acids
Hideto Miyabe, Chikage Ushiro and Takeaki Naito*
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658, Japan
O
O
A high degree of stereocontrol in radical addition to the
Oppolzer’s camphor sultam derivative of glyoxylic oxime
ether was achieved, providing a convenient method for
preparing a variety of enantiomerically pure a-amino
acids.
NOBn
NHOBn
i
N
N
SO2
SO2
R
Me
Me
Me
Me
5
6
a R = Pri
b R = Et
c R = But
d R = Bui
ii, iii
Asymmetric induction in free radical-mediated reactions of
acyclic systems is a subject of current interest.1 Oxime ethers
are well known to be excellent radical acceptors because of the
extra stabilisation of the intermediate aminyl radical provided
by the lone pair on the adjacent oxygen atom.2 We now describe
the first example of an efficient and diastereoselective carbon
radical addition to acyclic oxime ethers which was successfully
applied to the novel asymmetric synthesis of a-amino acids.
Studies on the radical reaction of oxime ethers have
concentrated on radical cyclisation,3 except for a few out-
standing examples of intermolecular radical reaction.4 There-
fore, stereocontrol in intermolecular radical addition to oxime
ethers is a challenging problem. Prior to exploring dias-
tereoselective radical addition to acyclic oxime ethers, we first
investigated competitive reactions using two types of oxime
ether in order to survey the intermolecular reactivity of oxime
ethers with carbon radicals. Treatment of a 1:1 mixture of
glyoxylic oxime ether 1 and aldoxime ether 2 with isopropyl
radical, generated from PriI, Bu3SnH and Et3B as a radical
initiator, at 278 °C for 30 min gave the isopropylated product
3 in 78% yield with no detection of the other adduct 4 (Scheme
1). As expected, the addition of an isopropyl radical to 2 under
the same reaction conditions did not take place and 90% of the
starting compound 2 was recovered. These results suggest that
the carbon radical does not add to the aldoxime ether 2, but does
add to glyoxylic oxime ether 1 even at 278 °C.
HO2C
NH2
R
e R = c-hexyl
7
Scheme 2 Reagents and conditions: i, RI, Bu3SnH, Et3B, 30 min; ii,
Mo(CO)6; iii, LiOH
reaction temperature, solvent and Lewis acid. The ster-
eoselectivity for 6a was shown to be dependent on the reaction
temperature, thus changing the temperature from 20 to 278 °C
led to an effective increase in the diastereoselectivity to 94 :6
(entry 2). The replacement of CH2Cl2 with Et2O as solvent led
to higher selectivity, comparable to or better than that obtained
by the known addition of organometallic reagents to the oxime
ethers (entry 4).5,6 Although the addition of Lewis acids as an
additive did not dramatically influence the degree of stereo-
selectivity, the presence of BF3·OEt2 in CH2Cl2 was found to be
useful for asymmetric induction (entry 5). The absolute
configuration at the newly formed stereocentre of the major
product was determined to be R by converting the adduct 6a into
authentic d-valine 7a. The reductive cleavage of the nitrogen–
oxygen bond of 6a by treatment with Mo(CO)67 and subsequent
removal of the sultam auxiliary by standard hydrolysis8
afforded the enantiomerically pure d-valine 7a without any loss
Table 1 Radical addition to the oxime ether 5a
We then extended the carbon radical addition to the
Oppolzer’s camphor sultam derivative of glyoxylic oxime ether
55 which would allow access to a wide range of enantiomer-
ically pure natural and unnatural a-amino acids (Scheme 2).
The reaction of 5 with PriI, Bu3SnH and Et3B in CH2Cl2 at
20 °C proceeded smoothly to give a 86 :14 diastereomeric
mixture of the desired isopropylated product 6a accompanying
by a small amount of the ethylated product 6b, which would be
formed by a competitive reaction with ethyl radical generated
from Et3B and O2 (Table 1, entry 1). In the absence of PriI,
treatment of 5 with Bu3SnH and Et3B afforded exclusively the
corresponding ethylated product 6b as the result of a similar
stereoselective radical reaction. In order to optimise the reaction
conditions, we then investigated the reaction by varying the
Yieldd
(%)
Entry RIb
Lewis acidc Solvent
Selectivitye
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
PriI
PriI
PriI
PriI
PriI
PriI
PriI
PriI
EtI
none
none
none
none
BF3·OEt2
Et2AlCl
Zn(OTf)2
Yb(OTf)3
none
BF3·OEt2
none
BF3·OEt2
none
CH2Cl2
CH2Cl2
toluene
Et2O
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
CH2Cl2
Et2O
CH2Cl2
Et2O
76f
73f
74f
71f
80f
57f
81f
74f
54
86:14
94:6
93:7
96:4
96:4
90:10
94:6
92:8
96:4
95:5
> 98:2
> 98:2
97:3
97:3
96:4
96:4
EtI
80
ButI
ButI
BuiI
BuiI
25f
83f
39f
83f
74f
86f
MeO2C
NOBn
MeO2C
Pri
NHOBn
BF3OEt2
CH2Cl2
Et2O
CH2Cl2
H
H
c-HexylI none
c-HexylI BF3·OEt2
1
i
3
Et
NOBn
Et
Pri
NHOBn
a Reaction was carried out with Bu3SnH (2.5 equiv.) and Et3B in hexane (5
equiv.) under N2 at 20 °C (entry 1). Other reactions were carried out at
278 °C (entries 2–16). b 5 equiv. of RI was used. c 2 equiv. of Lewis acid
was used. d Isolated yields of major diastereomer 6a–f. e Diastereoselectiv-
ities were determined by 1H NMR analysis. f The ethylated product 6b was
obtained in 3–22% yield.
H
H
2
4
Scheme 1 Reagents and conditions: i, PriI (1.1 equiv.), Bu3SnH (1.1 equiv.),
Et3B (1.1 equiv.), CH2Cl2, 278 °C, 30 min
Chem. Commun., 1997
1789

View Article Online
R•
Footnote and References
* E-mail: taknaito@kobepharma-u.ac.jp
O
O
1 D. P. Curran, N. A. Porter and B. Giese, Stereochemistry of Radical
Reactions, VCH, Weinheim, 1996. For recent reviews: W. Smadja,
Synlett, 1994, 1; N. A. Porter, B. Giese and D. P. Curran, Acc. Chem. Res.,
1991, 24, 296.
2 S. E. Booth, P. R. Jenkins, C. J. Swain and J. B. Sweeney, J. Chem. Soc.,
Perkin Trans. 1, 1994, 3499.
N
S
NOBn
O
Me
Me
R•
Figure 1
3 For some recent examples: D. L. J. Clive and J. Zhang, Chem. Commun.,
1997, 549; J. Marco-Contelles, G. Balme, D. Bouyssi, C. Destabel,
C. D. Henriet-Bernard, J. Grimaldi and J. M. Hatem, J. Org. Chem., 1997,
62, 1202; G. E. Keck and T. T. Wager, J. Org. Chem., 1996, 61, 8366; G.
J. Hollingworth, G. Pattenden and D. J. Schulz, Aust. J. Chem., 1995, 48,
381; J. L. Chiara, J. Marco-Contelles, N. Khiar, P. Gallego, C. Destabel
and M. Bernabe´, J. Org. Chem., 1995, 60, 6010; M. Santagostino and
J. D. Kilburn, Tetrahedron Lett., 1995, 36, 1365; J. W. Grissom and
D. Klingberg, J. Org. Chem., 1994, 59, 7876; K. A. Parker and D. Fokas,
J. Org. Chem., 1994, 59, 3927; T. Naito, K. Tajiri, T. Harimoto,
I. Ninomiya and T. Kiguchi, Tetrahedron Lett., 1994, 35, 2205;
E. W. Della and A. M. Knill, Aust. J. Chem., 1994, 47, 1833.
4 B. Bhat, E. E. Swayze, P. Wheeler, S. Dimock, M. Perbost and
Y. S. Sanghvi, J. Org. Chem., 1996, 61, 8186; S. Kim, I. Y. Lee,
J.-Y. Yoon and D. H. Oh, J. Am. Chem. Soc., 1996, 118, 5138; D. J. Hart
and F. L. Seely, J. Am. Chem. Soc., 1988, 110, 1631.
of stereochemical purity. High chemical yield and diastereo-
selectivity were also observed in radical additions using
different radical precursors such as ethyl, tert-butyl, isobutyl
and cyclohexyl iodides (entries 9–16).
The stereochemical features of this reaction can be rational-
ised in terms of steric control in the conformationally restricted
sultam derivative 5. The s-cis conformation of 5 would be
preferred due to repulsion between the oxime ether and sulfonyl
groups, thus alkyl radical addition takes place predominantly
from the less hindered p-face of the oxime derivative 5, as
indicated (Fig. 1).
The traditional addition of anionic carbon nucleophiles to
oxime ethers has been widely investigated as a carbon–carbon
bond forming reaction with excellent stereoselectivity, although
the addition is frequently plagued by the abstraction of
a-protons adjacent to the carbon–nitrogen double bond, the
lability of the nitrogen–oxygen bond, and the poor electro-
philicity of the oxime ether group.9 We suggest that many of
these fundamental problems would be solved by the newly
found mild addition of strictly neutral species such as uncharged
free radicals.
Acknowledgement is made to the Ministry of Education,
Science, Sports and Culture of Japan and the Science Research
Promotion Fund of the Japan Private School Promotion
Foundation for research grants.
5 S. Hanessian and R.-Y. Yang, Tetrahedron Lett., 1996, 37, 5273.
6 Y. Yamamoto and W. Ito, Tetrahedron, 1988, 44, 5415; J.-C. Fiaud and
H. B. Kagan, Tetrahedron Lett., 1970, 1813.
7 S. Cicchi, A. Goti, A. Brandi, A. Guarna and F. De Sarlo, Tetrahedron
Lett., 1990, 31, 3351; M. Nitta and T. Kobayashi, J. Chem. Soc., Perkin
Trans. 1, 1985, 1401.
8 W. Oppolzer, O. Tamura and J. Deerberg, Helv. Chim. Acta, 1992, 75,
1965.
9 N. Risch and M. Arend, Stereoselective Synthesis, ed. G. Helmchen,
R. W. Hoffmann, J. Mulzer and E. Schaumann, Thieme, Stuttugart, New
York 1966, vol. 3, p. 1876; R. A. Volkmann, Comprehensive Organic
Synthesis, ed. B. M. Trost, Pergamon Press, Oxford 1991, vol. 1,
p. 355.
Received in Cambridge, UK, 30th June 1997; 7/04562J
1790
Chem. Commun., 1997