Protecting/radical translocating chiral auxiliaries: A new concept in radical-mediated asymmetric synthesis

Full text of DOI:10.1021/jo981836b

9162
J . Org. Chem. 1998, 63, 9162-9163
Ta ble 1. Ra d ica l Deu ter a tion of 2, 3, 5, a n d 6 w ith
Bu 3Sn D Accor d in g to Eq 1
P r otectin g/Ra d ica l Tr a n sloca tin g Ch ir a l
Au xilia r ies: A New Con cep t in
Ra d ica l-Med ia ted Asym m etr ic Syn th esis
pre-
T
prod- H-transfera yieldb
entry cursor
R
RR (°C) uct
(%)
(%)
drc
Luc Giraud and Philippe Renaud*
1
2
3
4
5
6
7
8
9
2
2
3
3
5
5
H
H
H
H
Me
Me
Me
H
H
80
10
7
7
8
8
9
9
9
10
10
96
41
44
28
95
64
95
97
77
81
83
76
78
80
83
53
88
79
60:40
73:27
89:11
96:4
64:36
80:20
86:14d
84:16f
98:2f
Universite´ de Fribourg, Institut de Chimie Organique, Pe´rolles,
CH-1700 Fribourg, Switzerland
Me 80
Me 10
H
H
H
80
10
10
Received September 10, 1998
5
1-Amidoalkyl radicals are highly interesting intermediates
for the synthesis of biologically active compounds such as
alkaloids, unusual amino acids, and other nitrogen-contain-
ing molecules.1,2 However, the generation of these radicals
is often problematic due to the instability of the radical
precursors. Excellent results have been obtained by using
translocation of hydrogen atoms.3 The development of
protecting/radical translocating (PRT) groups4,5 represents
an efficient and attractive method for the generation of
1-amidoalkyl radicals.6-17 We present here the first ex-
amples where the PRT group also plays the role of a chiral
auxiliary.18-21 This approach has been applied to the prepa-
ration of R-alkylated amino acid and 1-substituted primary
amine derivatives. The general strategy is outlined in
Scheme 1; the amido-substituted radical B is generated from
the initial aryl radical A via a 1,5-hydrogen atom transfer.
This approach involves three components: lactic acid C
(more precisely lactamide) as primary source of chirality,
2-halobenzaldehyde D as radical precursor/secondary source
of chirality,22 and finally an alkyl halide E as carbon skeleton
for the final amine.
6e
6e
Me Me 80
Me Me 10
a
Percentage of translocated product, the rest to 100% being the
b
product of direct reduction. Isolated yields of reduced product
(translocation and direct reduction). c Determined by 1H and 2H
NMR. In trifluoroethanol instead of benzene. e Starting from
d
6-cis/6-trans 65:35. f Identical ratios of diastereomers were ob-
tained for the cis and trans isomers.
Sch em e 1
(1) Renaud, P.; Giraud, L. Synthesis 1996, 913-926.
(2) Easton, C. J . Chem. Rev. 1997, 97, 53-82.
(3) For a useful discussion of the preparative aspect of radical translo-
cation reactions, see: Curran, D. P.; Shen, W. J . Am. Chem. Soc. 1993,
115, 6051-6059.
(4) For the definition of the PRT-groups, see: Curran, D. P.; Kim, D.;
Liu, H. T.; Shen, W. J . Am. Chem. Soc. 1988, 110, 5900-5902.
(5) Curran, D. P.; Xu, J . Y. J . Am. Chem. Soc. 1996, 118, 3142-3147.
(6) Snieckus, V.; Cuevas, J .-C.; Sloan, C. P.; Liu, H. T.; Curran, D. P. J .
Am. Chem. Soc. 1990, 112, 896-898.
It was anticipated that the stereochemical outcome of the
radical reactions would be controlled by the stereogenic
acetal center and not by the R-center of lactic acid. Therefore,
and for the sake of simplicity, the first experiments were
run with a simple model system derived from glycolic acid.
The radical precursors 2 and 3 were prepared by acetaliza-
tion of glycolamide with 2-bromobenzaldehyde followed by
N-alkylation of the oxazolidinone 1 with ethyl bromoacetate
and ethyl 2-bromopropionate, respectively (Scheme 2). Simi-
larly, the racemic and the enantiopure radical precursors 5
and 6 were prepared from racemic and (S)-lactamide. The
oxazolidinone 4 was isolated as a cis/trans 66:34 mixture of
isomers, which were N-alkylated. The cis and trans dia-
stereomers of 5 were separated by column chromatography,
and the reactions were run with the major cis isomer. The
radical precursor 6 was used as a 65:35 cis/trans mixture.
The reduction of the radical precursors 2, 3, 5, and 6 with
tributyltin deuteride was first examined (eq 1), results are
summarized in Table 1. The diastereoselectivities were
(7) Denenmark, D.; Hoffmann, P.; Winkler, T.; Waldner, A.; De Mes-
maeker, A. Synlett 1991, 621-624.
(8) Denenmark, D.; Winkler, T.; Waldner, A.; De Mesmeaker, A. Tetra-
hedron Lett. 1992, 33, 3613-3616.
(9) Williams, L.; Booth, S. E.; Undheim, K. Tetrahedron 1994, 50, 13697-
13708.
(10) Sato, T.; Mori, T.; Sugiyama, T.; Ishibashi, H.; Ikeda, M. Heterocycles
1994, 37, 245-248.
(11) Sato, T.; Kugo, Y.; Nakaumi, E.; Ishibashi, H.; Ikeda, M. J . Chem.
Soc., Perkin Trans. 1 1995, 1801-1809.
(12) Murakami, M.; Hayashi, M.; Ito, Y. Appl. Organomet. Chem. 1995,
9, 385-397.
(13) Booth, S. E.; Benneche, T.; Undheim, K. Tetrahedron 1995, 51,
3665-3674.
(14) Weinreb, S. M. J . Heterocycl. Chem. 1996, 33, 1437.
(15) Ikeda, M.; Kugo, Y.; Sato, T. J . Chem. Soc., Perkin Trans. 1 1996,
1819-1824.
(16) Ikeda, M.; Kugo, Y.; Kondo, Y.; Yamazaki, T.; Sato, T. J . Chem. Soc.,
Perkin Trans. 1 1997, 3339-3344.
(17) Rancourt, J .; Gorys, V.; J olicoeur, E. Tetrahedron Lett. 1998, 39,
5339-5342.
(18) A related approach using a radical translocating chiral auxiliary
has been reported; however, the diastereoselectivity of the reaction has not
been determined: Baldwin, J . E.; Brown, D.; Scudder, P. H.; Wood, M. E.
Tetrahedron Lett. 1995, 36, 2105-2108.
(19) A diastereoselective process involving a 1,5-hydrogen atom trans-
location starting from chiral â-amino acid derivatives has been reported:
Beaulieu, F.; Arora, J .; Veith, U.; Taylor, N. J .; Chapell, B. J .; Snieckus, V.
J . Am. Chem. Soc. 1996, 118, 8727-8728.
(20) For reactions of 1-amidoalkyl radicals controlled by a N-centered
chiral auxiliary, see: Yamamoto, Y.; Onuki, S.; Yumoto, M.; Asao, N. J .
Am. Chem. Soc. 1994, 116, 421-422.
(21) Pearson, W. H.; Lindbeck, A. C.; Kampf, J . W. J . Am. Chem. Soc.
1993, 115, 2622-2636.
(22) This approach is related to the principle of self-generation of
stereocenters developed and reviewed by Seebach: Seebach, D.; Sting, A.
R.; Hoffmann, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 2708-2748.
measured by 1H and 2H NMR. The experiments with the
10.1021/jo981836b CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/13/1998

Communications
J . Org. Chem., Vol. 63, No. 25, 1998 9163
Sch em e 2
Ta ble 2. Ra d ica l Allyla tion of 2, 3, 5, a n d 6 w ith Meth yl
2-[(Tr ibu tylsta n n yl)m eth yl]p r op en oa te a t 80 °C
Accor d in g to Eq 2
Sch em e 3
pre-
cursor
prod-
uct
yielda
(%)
entry
R
RR
drb
1
2
3
4
2
2
3
5
H
H
H
Me
H
H
Me
H
11
11
12
13
59
61
74
85
66:34
84.16c
98:2
72:28
a
b
Isolated yields. Determined by 1H and 2H NMR. c At 10 °C.
glycolamide derivatives (Table 1, entries 1-4) showed that
1,5-hydrogen transfers were occurring with a satisfactory
efficiency at 80 °C (Table 1, entries 1 and 3). The transfer
was less efficient at 10 °C (Table 1, entries 2 and 4), but the
diastereoselectivity was enhanced (entries 1 vs 2 and 3 vs
4). The only detected side products were the products of
direct reduction. Interestingly, the alanine derivative 3 (RR
) Me) gave much higher diastereoselectivities (up to 96:4
at 10 °C) than the glycine derivative 2 (RR ) H). This trend
was confirmed with the lactamide-derived radical precursors
5 and 6 (Table 1, entries 5-9). With these two compounds,
the ratio of hydrogen transfer was in all cases superior to
64%. The glycine derivative 5 gave moderate stereoselec-
tivities at 80 °C (Table 1, entry 5, dr 64:36). However, a much
better stereocontrol was achieved at 10 °C (Table 1, entry
6, dr 80:20). The reaction in trifluoroethanol was even
slightly more stereoselective (Table 1, entry 7, dr 86:14). The
reaction of the alanine derivative 6 (cis/trans 65:35) gave
an excellent diastereoselectivity at 10 °C (Table 1, entry 9,
cis dr 98:2, trans dr 98:2). The major cis and trans products
have the opposite configuration at the newly formed stere-
genic center (R center) (see the Supporting Information).
This confirms the hypothesis that the stereoselectivtiy is
fully controlled by the acetal center.
and 4) which is noticeably enhanced at 10 °C (Table 2, entry
2, dr 84:16) and (b) high selectivity with the alanine
derivative 3 (Table 2, entry 3, dr 98:2).
The relative configuration of 10 was established by
comparison with an authentic sample prepared by an
alternative synthesis starting from ethyl L-(-)-lactate and
ethyl L-(+)-alanine hydrochloride (see the Supporting In-
formation). The relative stereochemistry of the other prod-
ucts has not been proved but attributed by analogy (same
reaction topicity). A possible rationalization of the stereo-
chemical outcome is given in Scheme 3. The radical inter-
mediate exists preferentially in the E conformation (model
F ). We assume that the radical lies in this conformation
because it minimizes dipole-dipole interactions between the
ester and the amide moiety.23 Moreover, the minor Z
conformer (model G) is further destabilized when RR is a
methyl group by steric repulsion with the phenyl group. This
explains the observed enhancement of stereoselectivity when
RR is a methyl group relative to a hydrogen atom.
In conclusion, we have demonstrated that oxazolidinones
prepared from lactic acid and 2-bromobenzaldehyde are
suitable for the generation of glycinyl and alaninyl radicals
and for the control of the stereochemistry of the subsequent
reactions. Relative to classical methods of alkylation of
amino acids, this approach offers promising opportunities
for the synthesis of cyclic amino acids by taking advantage
of unique radical cyclizations. Further work in this direction
is currently underway.
A series of allylation reactions was conducted with methyl
2-[(tributylstannyl)methyl]propenoate (eq 2). The results are
Ack n ow led gm en t . This work was supported by the
Fonds National Suisse de la Recherche Scientifique.
Su p p or tin g In for m a tion Ava ila ble: Detailed experimental
procedures and spectral data (1H NMR, 13C NMR, IR, MS, and
elemental analyses) for compounds 1-13 and assessment of the
relative configuration of 10 by chemical correlation (13 pages).
shown in Table 2. The desired products 11-13 are formed
in satisfactory yields (59-85%). The diastereoselectivities
are higher than the corresponding deuteration, but the same
trends can be observed: (a) moderate diastereocontrol with
the glycine derivative 2 and 5 at 80 °C (Table 2, entries 1
J O981836B
(23) A similar model has been proposed for a related acyliminium ion
mediated reaction: Roth, E.; Altman, J .; Kapon, M.; Benishai, D. Tetrahe-
dron 1995, 51, 801-810.