Highly diastereoselective radical addition to oxime ethers: Asymmetric synthesis of β-amino acids

Article abstract of DOI:10.1021/ol990688o

(Matrix presented) Highly diastereoselective alkyl radical addition to Oppolzer's camphorsultam derivatives of oxime ethers provided a convenient method for preparing the enantiomerically pure α,β-dialkyl-β-amino acids. The phase-transfer-catalyzed alkyla

Full text of DOI:10.1021/ol990688o

ORGANIC
LETTERS
1999
Vol. 1, No. 4
569-572
Highly Diastereoselective Radical
Addition to Oxime Ethers: Asymmetric
Synthesis of â-Amino Acids
Hideto Miyabe, Kayoko Fujii, and Takeaki Naito*
Kobe Pharmaceutical UniVersity, Motoyamakita, Higashinada, Kobe 658-8558, Japan
taknaito@kobepharma-u.ac.jp
Received May 25, 1999
ABSTRACT
Highly diastereoselective alkyl radical addition to Oppolzer’s camphorsultam derivatives of oxime ethers provided a convenient method for
preparing the enantiomerically pure r,â-dialkyl-â-amino acids. The phase-transfer-catalyzed alkylation was an excellent method for the selective
monoalkylation of the N-(â-oximino)acyl derivative of Oppolzer’s sultam, with no detection of dialkylated products. In the presence of BF ‚
3
OEt2, the carbon radical addition to the oxime ethers proceeded smoothly to give the r,â-dialkyl-â-amino acid derivatives with excellent
diastereoselectivity.
Stereocontrol in free radical-mediated carbon-carbon bond-
forming reactions has been of great importance in organic
synthesis.1 The carbon-nitrogen double bond of imine
derivatives has attracted significant attention as an excellent
radical acceptor in the radical cyclizations, and thus numer-
ous, powerful synthetic methods for the intramolecular
carbon-carbon bond construction have been reported.2 In
contrast, however, only two studies have been directed
toward stereocontrol in the intermolecular carbon radical
addition to imine derivatives.3,4 Bertrand’s and our group
recently reported studies on stereocontrol in the radical
addition to activated imine derivatives such as glyoxylic
oxime ethers and imines,5 which were successfully used for
the novel asymmetric synthesis of R-amino acids.3,4 However,
a general solution to the problem of stereoselection in the
intermolecular radical addition to unactivated imine deriva-
tives has remained elusive. Following our studies on the
synthesis of R-amino acids,6 we now describe a novel
asymmetric synthesis of R,â-dialkyl-â-amino acids based on
the highly diastereoselective carbon radical addition to the
unactivated oxime ethers bearing Oppolzer’s camphorsultam.
As shown below, the radical reaction is rapid and can be
easily carried out very conveniently at room temperature
without any special precautions such as drying, degassing,
and purification of solvents and reagents.7
In a preliminary study, the auxiliary of choice was
Oppolzer’s camphorsultam since it had shown good char-
acteristics in our previous work on the radical addition to
glyoxylic oxime ethers.3 The camphorsultam derivative of
oxime ether 1 would be flexible to allow access to a wide
range of R,â-dialkyl-â-amino acids.8,9 Oxime ether 1 was
(1) For reviews, see: (a) Renaud, P.; Gerster, M. Angew. Chem., Int.
Ed. Engl. 1998, 37, 2562. (b) Giese, B.; Kopping, B.; Go¨bel, T.; Dickhaut,
J.; Thoma, G.; Kulicke, K. J.; Trach, F. Org. React. (N.Y.) 1996, 48, 301.
(c) Ryu, I.; Sonoda, N.; Curran, D. P. Chem. ReV. 1996, 96, 177. (d) Curran,
D. P.; Porter, N. A.; Giese, B. In Stereochemistry of Radical Reactions:
Concepts, Guidelines, and Synthetic Applications; VCH: Weinheim, 1996.
(2) For reviews, see: (a) Naito, T. Heterocycles 1999, 50, 505. (b) Fallis,
A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543.
(6) (a) Miyabe, H.; Fujishima, U.; Naito, T. J. Org. Chem. 1999, 64,
2174. (b) Miyabe, H.; Ueda, M.; Yoshioka, N.; Naito, T. Synlett 1999, 465.
(c) Miyabe, H.; Yoshioka, N.; Ueda, M.; Naito, T. J. Chem. Soc., Perkin
Trans. 1 1998, 3659.
(3) Miyabe, H.; Ushiro, C.; Naito, T. Chem. Commun. 1997, 1789.
(4) Bertrand, M. P.; Feray, L.; Nouguier, R.; Stella, L. Synlett 1998, 780.
(5) Glyoxylic oxime ethers and imines are activated by the adjacent
electron-withdrawing substituent.
(7) All radical reactions were run in commercially available solvents and
with reagents not requiring any special precautions.
(8) For a review on asymmetric synthesis of â-amino acids, see: Cardillo,
G.; Tomasini, C. Chem. Soc. ReV. 1996, 117.
10.1021/ol990688o CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/07/1999

readily prepared by treatment of ethyl 1-[N-(phenylmethoxy)-
imino]propionate10 with (1S)-(-)-2,10-camphorsultam in the
presence of trimethylaluminum in boiling 1,2-dichloroethane
(Scheme 1). The screening of several methods for the anionic
equiv) as a phase-transfer catalyst in 5 N NaOH/CH2Cl2 at
20 °C for 1 h (Table 1). In the case of benzylation using
Table 1. PTC-Catalyzed Alkylation of 1a
product
Scheme 1
entry
R1
(% yield)b ratioc R,Z:R,E:S,Z selectivityd
1
2
3
Bn
4-NO2-benzyl 2b (98)
propargyl 2c (90)
2a (99)
15.7:1.0:1.3
7.6:1.0:1.0
9.7:1.2:1.0
>95% de
>95% de
>95% de
a Alkylation reaction of 1 was carried out with R1Br (1.1 equiv) and
Bu4NBr (0.1 equiv) in 5 N NaOH/CH2Cl2 at 20 °C. b Combined yields.
The diastereomerically pure materials (R,Z)-2a-c were obtained in ca. 60-
80% yields after recrystallization. c Ratios were determined by 1H NMR
analysis. d Diastereoselectivities of 2a-c are for the selectivities after
recrystallization.
benzyl bromide, the desired monobenzylated oxime ether 2a
was obtained in 99% combined yield in favor of the (R,Z)-
isomer (entry 1).13 The diastereomerically pure oxime ether
(R,Z)-2a was easily obtained by recrystallization from
hexane/AcOEt.14 The E/Z-isomers with respect to the
geometry of the oxime ether group were easily determined
1
by H NMR spectroscopy.15 The absolute configuration of
the major product was determined to be R by X-ray analysis
of (R,Z)-2a. The other diastereomerically pure monoalkylated
products (R,Z)-2b and (R,Z)-2c could be also obtained under
similar reaction conditions after the recrystallization (entries
2 and 3).16
We first investigated the ethyl radical addition to the oxime
ethers (R,Z)-2a-c by using triethylborane as an ethyl radical
source under several reaction conditions (Table 2). We
alkylation of sultam compounds showed that the phase-
transfer-catalyzed reaction was an excellent method for the
selective monoalkylation of the active methylene in sultam
derivative 1 with no detection of dialkylated products.11,12
All alkylations of sultam derivative 1 were run by using alkyl
bromides (1.1 equiv) and tetrabutylammonium bromide (0.1
Table 2. Ethyl Radical Addition to 1 and 2
(9) Among the different types of radical acceptors containing a carbon-
nitrogen double bond, oxime ethers are well-known to be excellent radical
acceptors because of the extra stabilization of the intermediate aminyl radical
provided by the adjacent oxygen atom. See: (a) Miyabe, H.; Torieda, M.;
Inoue, K.; Tajiri, K.; Kiguchi, T.; Naito, T. J. Org. Chem. 1998, 63, 4397.
(b) Iserloh, U.; Curran, D. P. J. Org. Chem. 1998, 63, 4711. (c) Boiron,
A.; Zillig, P.; Faber, D.; Giese, B. J. Org. Chem. 1998, 63, 5877. (d) Marco-
Contelles, J.; Balme, G.; Bouyssi, D.; Destabel, C.; Henriet-Bernard, C.
D.; Grimaldi, J.; Hatem, J. M. J. Org. Chem. 1997, 62, 1202. (e) Clive, D.
L. J.; Zhang, J. Chem. Commun. 1997, 549. (f) Keck, G. E.; Wager, T. T.
J. Org. Chem. 1996, 61, 8366. (g) Bhat, B.; Swayze, E. E.; Wheeler, P.;
Dimock, S.; Perbost, M.; Sanghvi, Y. S. J. Org. Chem. 1996, 61, 8186. (h)
Kim, S.; Lee, I. Y.; Yoon, J.-Y.; Oh, D. H. J. Am. Chem. Soc. 1996, 118,
5138. (i) Hollingworth, G. J.; Pattenden, G.; Schulz, D. J. Aust. J. Chem.
1995, 48, 381. (j) Chiara, J. L.; Marco-Contelles, J.; Khiar, N.; Gallego,
P.; Destabel, C.; Bernabe´, M. J. Org. Chem. 1995, 60, 6010. (k)
Santagostino, M.; Kilburn, J. D. Tetrahedron Lett. 1995, 36, 1365. (l)
Kiguchi, T.; Tajiri, K.; Ninomiya, I.; Naito, T.; Hiramatsu, H. Tetrahedron
Lett. 1995, 36, 253.
product
entry oxime ether solvent T (°C) (% yield)c selectivityd
1
2
3
4
5
6
7
(R,Z)-2a
(R,Z)-2a
(R,Z)-2a
(R,Z)-2b
(R,Z)-2b
(R,Z)-2c
1
CH2Cl2
CH2Cl2
toluene
CH2Cl2
toluene -78a
CH2Cl2
CH2Cl2
-78a
3a A (95)
20b 3a A (99)
20b 3a A (99)
>95% de
>95% de
>95% de
>95% de
>95% de
>95% de
5% de
-78a
3bA (66)
3bA (72)
3cA (43)
3d A (84)
-78a
-78a
a Radical addition at -78 °C was carried out with BF3‚OEt2 (9 equiv)
and Et3B in hexane (9 equiv). b Radical addition at 20 °C was carried out
with BF3‚OEt2 (5 equiv) and Et3B in hexane (5 equiv). c Isolated yields.
1
d Diastereoselectivities were determined by H NMR analysis.
(10) Ethyl 1-[N-(phenylmethoxy)imino]propionate was readily prepared
from commercially available ethyl 3,3-diethoxypropionate and O-benzy-
loxyamine hydrochloride. See: Macchia, M.; Menchini, E.; Nencetti, S.;
Orlandini, E.; Rossello, A.; Belflore, M. S. Il Farmaco 1996, 51, 255.
(11) (a) Kim, B. H.; Curran, D. P. Tetrahedron 1993, 49, 293. (b)
Oppolzer, W. Pure Appl. Chem. 1990, 62, 1241. (c) Oppolzer, W. Pure
Appl. Chem. 1988, 60, 39. (d) Oppolzer, W. Tetrahedron 1987, 43, 1969.
(12) For some examples of the phase-transfer-catalyzed reaction, see:
(a) O’Donnell, M. J.; Wu, S.; Huffman, J. C. Tetrahedron 1994, 50, 4507.
(b) Oppolzer, W.; Bienayme´, H.; Genevois-Borella, A. J. Am. Chem. Soc.
1991, 113, 9660. (c) Oppolzer, W.; Moretti, R.; Thomi, S. Tetrahedron
Lett. 1989, 30, 6009.
recently reported the potentiality of BF3‚OEt2 as a Lewis
acid in achieving the intermolecular radical addition to
(13) The stereochemical feature of this reaction can be rationalized in
terms of stereoelectronic effect in the chelated (Z)-enolate anion as proposed
by Oppolzer et al. See reference 11.
(14) Full characterization data of all obtained compounds and general
experimental procedures are given in the Supporting Information.
570
Org. Lett., Vol. 1, No. 4, 1999

unactivated oxime ethers.17 As indicated in our previous
studies, the activation of the oxime ether group by BF3‚OEt2
was essential for the successful radical addition reaction of
oxime ethers (R,Z)-2a-c. In the presence of BF3‚OEt2, the
reaction of (R,Z)-2a with triethylborane in CH2Cl2 proceeded
smoothly within 15 min even at -78 °C to give a 95% yield
of the ethylated product 3aA (Table 2, entry 1), while no
reaction occurred in the absence of BF3‚OEt2. The diastereo-
meric purity of (R,Z)-2a was found to be not less than 95%
the case of (R,Z)-2a-c, the conformer A minimizing A1,3-
strain effects would be favored (Figure 1). Additionally, the
1
de by H NMR analysis of the crude products. The high
diastereoselectivity and chemical yield were still maintained
in the reaction at 20 °C (entry 2). It should be noted that the
unactivated oxime ether having acidic R-hydrogen reacted
smoothly with a carbon radical. In regard to the solvent
effect, the replacement of CH2Cl2 with a nonpolar aromatic
solvent such as toluene was also effective for the radical
reaction to give the ethylated product 3aA in 99% yield with
excellent diastereoselectivity (entry 3). The absolute con-
figuration at the newly formed stereocenter of the ethylated
product 3aA was determined to be S by X-ray analysis.
Hydrogenolysis of the benzyloxy group of 3aA in the
presence of Pd(OH)2 in MeOH, subsequent protection of the
resulting amine with benzyloxycarbonyl chloride, and final
removal of the sultam auxiliary by standard hydrolysis18
afforded the enantiomerically pure R,â-dialkyl-â-amino acid
4 in 60% overall yield from 3aA without any loss of
stereochemical purity (Scheme 2). Excellent diastereoselec-
Figure 1. 1,2-Asymmetric induction.
stable conformation was also supported by the crystal
structure resulting from X-ray analysis of (R,Z)-2a. Thus,
an ethyl radical addition takes place predominantly from the
less-hindered π-face of oxime ethers activated by BF3, in
which the bulky alkyl group (R1) shields the opposite face.
To investigate the generality and practicality of this
reaction, the present procedure was successfully extended
to the radical addition reactions using different radical
precursors (Table 3). The isopropyl radical addition to (R,Z)-
Table 3. Alkyl Radical Addition to 2a
Scheme 2
entry
oxime
R2
product
% yieldb selectivityc
1
2
3
4
5
6
(R,Z)-2a
(R,Z)-2a
(R,Z)-2a
(R,Z)-2a
(R,Z)-2a
(R,Z)-2b
i-Pr
3a B
3a C
3a D
3a E
3a F
3bB
70
57
59
50
20 (39)d
40 (16)
>95% de
>95% de
>95% de
>95% de
>95% de
>95% de
c-hexyl
c-pentyl
s-Bu
i-Bu
i-Pr
a Radical addition was carried out with R2I (30 equiv), BF3‚OEt2 (9
equiv), and Et3B in hexane (9 equiv) in toluene at 20 °C. b Isolated yields;
yields in parentheses are for the recovered starting material. c Diastereo-
selectivities were determined by 1H NMR analysis. d Ethylated product 3aA
was also obtained in 29% yield.
tivities were also observed in the radical addition to different
radical acceptors (R,Z)-2b and 2c containing a 4-nitrobenzyl
group or a carbon-carbon triple bond to afford the ethylated
products 3bA and 3cA with slightly low efficiencies (entries
4-6). In the case of radical addition to the oxime ether 1,
the ethylated product 3dA was obtained with low diastereo-
selectivity, probably because the approaching radical was
too far away from the sultam (entry 7). Thus, the high
stereocontrol in the radical addition to (R,Z)-2a-c was
regarded as the result of high 1,2-asymmetric induction. In
2a was run in toluene at 20 °C for 15 min by using isopropyl
iodide and Et3B in the presence of BF3‚OEt2 (entry 1). As
expected, the reaction proceeded smoothly in the absence
of tin hydride to give a good yield of isopropylated products
3aB with a high level of diastereoselectivity.19 Other
secondary alkyl radicals also worked well under similar
reaction conditions, allowing facile incorporation of structural
variety (entries 2-4). A low chemical yield was obtained in
the reaction using an unstable primary alkyl radical such as
(15) In general, the signals due to the imino hydrogen of the E-oxime
ether are shifted downfield by the influence of the alkoxy group of the
oxime ether moiety. See: McCarty, C. G. In The Chemistry of Functional
Groups; The chemistry of the carbon-nitrogen double bond; Patai, S., Ed.;
John Wiley & Sons Inc.: New York, 1970; pp 383-392.
(16) The absolute configuration of major products 2b and 2c was assigned
(19) The reaction proceeded via a route involving the iodine atom-transfer
process between isopropyl iodide and ethyl radical generated from Et3B.
In this reaction, Et3B acts as a radical initiator and a radical terminator to
trap the intermediate benzyloxy radical. Thus, the radical chain reaction
proceeds via the regeneration of the ethyl radical by the simple procedure,
which does not require the tedious workup to remove the tin residues from
the reaction mixture. See refs 4, 6b, and 6c.
1
to be R since their H NMR data showed similarity with that of (R,Z)-2a.
(17) (a) Miyabe, H.; Shibata, R.; Ushiro, C.; Naito, T. Tetrahedron Lett.
1998, 39, 631. (b) Miyabe, H.; Shibata, R.; Sangawa, M.; Ushiro, C.; Naito,
T. Tetrahedron 1998, 54, 11431.
(18) Oppolzer, W.; Tamura, O.; Deerberg, J. HelV. Chim. Acta 1992,
75, 1965.
Org. Lett., Vol. 1, No. 4, 1999
571

an isobutyl radical because of the competitive formation of
a significant amount of the ethylated products 3aA as a
byproduct, which were formed by the reaction with the ethyl
radical generated from Et3B (entry 5). Similar trends were
observed in our previous studies on the radical addition to
activated glyoxylic oxime ethers.6 The isopropyl radical
addition to oxime ether having a 4-nitrobenzyl group (R,Z)-
2b also proceeded in excellent diastereoselectivity under
similar reaction conditions (entry 6).
ethers presents new opportunities for stereoselective synthesis
of R,â-dialkyl-â-amino acids.
Acknowledgment. We wish to thank 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. We also
thank Dr. H. Hiramatsu and Dr. K. Aoe, Tanabe Seiyaku
Co., Ltd, for X-ray analysis.
In conclusion, we have succeeded in the asymmetric
synthesis of R,â-dialkyl-â-amino acids based on the phase-
transfer-catalyzed alkylation of Oppolzer’s camphorsultam
derivative followed by the highly diastereoselective carbon
radical addition to the resulting oxime ethers. The stereo-
control in the carbon-carbon bond construction through the
intermolecular carbon radical addition to unactivated oxime
Supporting Information Available: General experimen-
tal procedures and characterization data for obtained com-
pounds 1, 2a-c, 3aA-3bB, and 4. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL990688O
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Org. Lett., Vol. 1, No. 4, 1999