Enantioselective radical addition reactions to the C=N bond utilizing chiral quaternary ammonium salts of hypophosphorous acid in aqueous media

Article abstract of DOI:10.1039/b613045c

An enantioselective addition of alkyl radicals to glyoxylate oxime ether mediated by Cinchona alkaloid derived chiral ammonium salts of hypophosphorous acid, QP and QDP, has been developed. The Royal Society of Chemistry.

Full text of DOI:10.1039/b613045c

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Enantioselective radical addition reactions to the CLN bond utilizing
chiral quaternary ammonium salts of hypophosphorous acid in aqueous
media
Dae Hyan Cho and Doo Ok Jang*
Received (in Cambridge, UK) 8th September 2006, Accepted 21st September 2006
First published as an Advance Article on the web 12th October 2006
DOI: 10.1039/b613045c
An enantioselective addition of alkyl radicals to glyoxylate
oxime ether mediated by Cinchona alkaloid derived chiral
ammonium salts of hypophosphorous acid, QP and QDP, has
been developed.
Table 1 Radical addition reactions to glyoxylic oxime ether under
various reaction conditions
The formation of a carbon–carbon bond is extremely important in
organic synthesis, especially the asymmetric formation of a
carbon–carbon bond. Radical addition reactions have become a
powerful and versatile tool for forming new carbon–carbon bonds
because the reactions can be accomplished under mild and neutral
reaction conditions in which a broad range of functional groups of
polyfunctionalized molecules is compatible.1 Considerable effort
has been devoted to the development of asymmetric radical
reactions, and the majority of the asymmetric radical reactions
have been accomplished using chiral auxiliaries.2 However, recent
progress has shown that the stereochemistry of radical reactions
could be controlled without using chiral auxiliaries. Although this
development was achieved mainly during radical conjugate
addition promoted by chiral Lewis acids, which formed the chiral
environment by coordinating the substrates,3 there have been no
reports on asymmetry induction in radical reactions through a
p-stacking and/or hydrogen bonding chiral environment.4
Here we report on the development of an enantioselective
radical addition reaction to glyoxylate oxime ether for the
preparation of a-amino acids5 under mild reaction conditions
with chiral quaternary ammonium salts of hypophosphorous acid
in aqueous media.
Isolated
yield (%)
of 2a (2b)
QP
(equiv.)
iPrI
(equiv.)
Et3B
(equiv.)
Entry
1
2
3
4
5
6
7
8
a
5
5
2
2
2
2
2
2
30
5
5
0
0
5
5
5
1
1
1
1
0.5
0.5
0.5
0.5
b
87 (0)
85 (10)
86 (7)
0 (54)
0 (12)
83 (7)
50a
23b
The reaction was carried out in water. The reaction was carried
out in CH2Cl2.
iPrI decreased, the addition adduct 2b produced by the addition
reaction of ethyl radical to 1 increased. We performed the same
reaction by varying the ratios of QP, iPrI and Et3B to establish the
optimal reaction conditions for radical addition reactions. Optimal
reaction conditions were established with 2 equiv. of QP, 5 equiv.
of iPrI, and 0.5 equiv. of Et3B in aqueous CH2Cl2 (entry 6).{ The
reaction was also carried out in pure water or CH2Cl2 affording
50% and 23% yields of the addition product 2a, respectively
(entries 7 and 8). It is inferred that low yields of the addition
product 2a are attributed to the low solubility of the substrate in
water or QP in CH2Cl2. The addition product 2a was converted
into its ester derivative 3a in 80% yield when treated9 with Ph3P–
CCl3CN and MeOH–Et3N to determine the enantiomeric ratio
(er), which was found to be 21 : 79 by HPLC analysis (Table 2,
entry 1).
Hypophosphorous acid has been used as a radical chain carrier
and a radical hydrogen source in radical reactions.6 We assumed
that quaternary ammonium hypophosphites prepared from
H3PO2 and chiral amines such as Cinchona alkaloids7 can readily
generate radicals from alkyl halides and form the chiral
environment. We also assumed that they play a role as surfactants
that would result in an increase in the solubility of the organic
substrates in aqueous media.8
The quaternary ammonium hypophosphites QP and QDP were
readily prepared as white solid by mixing quinine or quinidine with
an equimolar amount of H3PO2 at room temperature. First, the
reaction of glyoxylate oxime ether (1), which was generated in situ
i
with PrI, was carried out in a biphasic dichloromethane–water
system in the presence of QP using Et3B/O2 as an initiator at room
temperature (Table 1). The reaction proceeded smoothly to afford
the addition adduct 2a in 87% yield (entry 1). As the amount of
With these optimal reaction conditions established, addition
Department of Chemistry, Yonsei University, Wonju, 220-710, Korea.
E-mail: dojang@yonsei.ac.kr; Fax: +82 337602208; Tel: +82 337602261
reactions of various alkyl halides to 1 were carried out. The results
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Chem. Commun., 2006, 5045–5047 | 5045

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Table 2 Enantioselective alkyl radical addition to glyoxylic oxime
ether in the presence of QP
Scheme 1
Isolated
yielda (%)
3 (Yield
(%))
erb of 3
R : S
Entry
RI
Product
1
2
3
4
5
a
iPr-I
2a
2c
2d
2e
2f
83 (7)
3a (80)
3c (81)
3d (83)
3e (82)
3f (85)
21 : 79
21 : 79
1 : .99
1 : .99
40 : 60
cHex-I
tBu-I
80 (10)
60 (30)
45 (35)
50 (25)
1-Ad-I
nOct-I
b
The yield in parenthesis is for 2b. Enantiomeric ratio was
determined by HPLC analysis using chiral column (Daicel
Chiralpak AD-H) with hexane–isopropanol as the solvent.
a
are presented in Table 2. The reaction of secondary alkyl halides
afforded the addition products in high yields with high er values
(entries 1 and 2). In the case of tertiary alkyl halides, moderate
chemical yields with extremely high er values were obtained
without a trace of other enantiomers (entries 3 and 4). However,
the reaction with primary alkyl halides such as 1-octyl iodide gave
a low chemical yield with low enantioselectivity (entry 5).
Fig. 1 Model to explain enantioselectivity.
The absolute configuration of the addition adduct allows a
plausible rationalization for the observed si-face attack of the alkyl
radical on the substrate 1 involving p-stacking and hydrogen
bonding as shown in Fig. 1. The substrate 1 is bound to QP by
hydrogen bonds between N–H and CLO/CLN in 1 with a CO/CN
s-cis planar conformation and also through p-stacking. In this
arrangement, the re-face of CLN bond is blocked by the quinoline
ring of QP. An alkyl radical then attacks the CLN bond from the
si-face to afford the addition product.
Next, we investigated the radical addition reaction to 1 in
aqueous solvent with quaternary ammonium hypophosphite,
QDP, prepared from quinidine and H3PO2 (Table 3). The reaction
proceeded smoothly to furnish the addition adducts, although
compared to QP, QDP gave relatively lower enantioselectivity,
when secondary and primary alkyl halides were used as substrates
(entries 1, 2 and 5). However, with the tertiary halides, only one
enantiomer was observed under these conditions (entries 3 and 4).
The absolute configuration of the addition adduct 3a was
established by conversion to 4 and by synthesis from known
compounds, D-Val–OH and L-Val–OH independently. 3a was
converted into an amino ester by subsequent treatment with Raney
Ni/H2 and Zn/HOAc. After it was treated with Fmoc-Cl, 4 was
obtained in 56% overall yield from 3a. The major enantiomer in 4,
which was prepared in the presence of QP, was found to have an
S-configuration (Scheme 1).
In conclusion, we have synthesized chiral quaternary ammo-
nium hypophosphites that can be used for enantioselective radical
addition reactions for preparing a-amino acids in aqueous media.
The reactions afforded high yields of the addition products with a
high enantioselectivity that can be attained without using metals.
The reagents used in the research are inexpensive and less toxic
than metal containing compounds, and the reaction affords an
easy work-up process and mild reaction conditions. Especially, the
chiral amines were recycled after treating with a base such as
KOH.
This work was supported by Korea Research Foundation
Grant (KRF-2004-041-C00211).
Notes and references
Table 3 Enantioselective alkyl radical addition to glyoxylic oxime
ether in the presence of QDP
{ General procedure: A mixture of BnONH2?HCl (1 equiv.), glyoxylic acid
(1 equiv.), and QP or QDP in CH2Cl2–H2O (1 : 1) was stirred at room
temperature for 1 h under argon. The alkyl halide (5 equiv.) was added,
followed by Et3B (0.5 equiv., 1 M in hexane). Air (40 mL) was added
through a syringe needle (using a syringe pump) to the reaction mixture at
room temperature over 4 h. After evaporation of the solvent, the residue
was purified by flash column chromatography on silica gel affording the
radical addition product.
Isolated
yielda (%)
3 (Yield
(%))
erb of 3
R : S
Entry
RI
Product
1 (a) B. Giese, B. Kopping, T. Go¨bel, J. Dickhaut, G. Thoma, K. J. Kulicke
and F. Trach, Org. React., 1996, 48, 301; (b) W. Motherwell and D. Crich,
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2 For reviews on stereoselective radical reactions, see: (a) G. Bar and
A. Parsons, Chem. Soc. Rev., 2003, 32, 251; (b) B. Gue´rin, W. W. Ogilvie
and Y. Guindon, in Radicals in Organic Synthesis ed. P. Renaud and
1
2
3
4
5
a
iPr-I
2a
2c
2d
2e
2f
82 (10)
82 (9)
62 (27)
47 (37)
48 (30)
3a (81)
3c (80)
3d (82)
3e (79)
3f (79)
62 : 38
72 : 28
.99 : 1
.99 : 1
58 : 42
cHex-I
tBu-I
1-Ad-I
nOct-I
b
The yield in parenthesis is for 2b. Enantiomeric ratio was
determined by HPLC analysis using chiral column (Daicel
Chiralpak AD-H) with hexane–isopropanol as the solvent.
a
5046 | Chem. Commun., 2006, 5045–5047
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Chem. Commun., 2006, 5045–5047 | 5047