Synthesis of β-Substituted α-Amino Acids via Lewis Acid Promoted Radical Conjugate Additions to α,β-Unsaturated α-Nitro Esters and Amides

Article abstract of DOI:10.1021/ol036461h

(Martix presented) β-Substituted α,β-unsaturated α-nitro esters and amides undergo radical conjugate additions when treated with an appropriate Lewis acid. Deuterium studies revealed that the acidic α-stereocenter of the α-nitro ester products does not racemize under strictly controlled workup conditions. The α-nitro amides did racemize significantly during chromatography, but this could be greatly minimized by subjecting the crude adducts to subsequent transformations. The conjugate addition products can be elaborated into β-substituted α-amino acids in two simple steps.

Full text of DOI:10.1021/ol036461h

ORGANIC
LETTERS
2004
Vol. 6, No. 3
449-452
Synthesis of â-Substituted r-Amino
Acids via Lewis Acid Promoted Radical
Conjugate Additions to r,â-Unsaturated
r-Nitro Esters and Amides
G. S. C. Srikanth and Steven L. Castle*
Department of Chemistry and Biochemistry, Brigham Young UniVersity,
ProVo, Utah 84602
scastle@chem.byu.edu
Received December 18, 2003
ABSTRACT
â-Substituted r,â-unsaturated r-nitro esters and amides undergo radical conjugate additions when treated with an appropriate Lewis acid.
Deuterium studies revealed that the acidic r-stereocenter of the r-nitro ester products does not racemize under strictly controlled workup
conditions. The r-nitro amides did racemize significantly during chromatography, but this could be greatly minimized by subjecting the crude
adducts to subsequent transformations. The conjugate addition products can be elaborated into â-substituted r-amino acids in two simple
steps.
â-Substituted R-amino acids are present in several peptidic
natural products;1 additionally, they are of interest as
conformationally constrained analogues of R-amino acids.2
Accordingly, several methods have recently been devised
for their preparation,3 including some that employ conjugate
additions to R,â-unsaturated amino acid precursors.3h-j We
were attracted to this strategy but mindful of the fact that
the organometallic reagents normally employed in these
reactions would be incompatible with complex peptides such
as the projected intermediates in our synthesis of the
antimitotic natural product Celogentin C.4 Thus, we turned
our focus to radical conjugate additions, which have been
skillfully used by Sibi to construct â-unsubstituted R-amino
acids.5 Herein, we report that â-substituted R,â-unsaturated
R-nitro esters and amides are viable substrates in Lewis acid
promoted radical conjugate additions.6 Significantly, we have
discovered that racemization of the labile R-stereocenter of
the resulting adducts7 can be prevented in many cases. This
result suggests the possibility of using this method in a
(1) (a) Suzuki, H.; Morita, H.; Iwasaki, S.; Kobayashi, J. Tetrahedron
2003, 59, 5307. (b) Kobayashi, J.; Suzuki, H.; Shimbo, K.; Takeya, K.;
Morita, H. J. Org. Chem. 2001, 66, 6626. (c) Leung, T.-W. C.; Williams,
D. H.; Barna, J. C. J.; Foti, S.; Oelrichs, P. B. Tetrahedron 1986, 42, 3333.
(2) Gibson, S. E.; Guillo, N.; Tozer, M. J. Tetrahedron 1999, 55, 585.
(3) (a) O’Donnell, M. J.; Cooper, J. T.; Mader, M. M. J. Am. Chem.
Soc. 2003, 125, 2370. (b) Bull, S. D.; Davies, S. G.; Garner, A. C.; Mujtaba,
N. Synlett 2001, 781. (c) Soloshonok, V. A.; Tang, X.; Hruby, V. J.; Van
Meervelt, L. Org. Lett. 2001, 3, 341. (d) Burtin, G.; Corringer, P.-J.; Young,
D. W. J. Chem. Soc., Perkin Trans. 1 2000, 3451. (e) Tamura, O.; Yoshida,
S.; Sugita, H.; Mita, N.; Uyama, Y.; Morita, N.; Ishiguro, M.; Kawasaki,
T.; Ishibashi, H.; Sakamoto, M. Synlett 2000, 1553. (f) Medina, E.; Moyano,
A.; Perica`s, M. A.; Riera, A. HelV. Chim. Acta 2000, 83, 972. (g) Burk, M.
J.; Gross, M. F.; Martinez, J. P. J. Am. Chem. Soc. 1995, 117, 9375. (h)
Han., G.; Lewis, A.; Hruby, V. J. Tetrahedron Lett. 2001, 42, 4601. (i)
Acevedo, C. M.; Kogut, E. F.; Lipton, M. A. Tetrahedron 2001, 57, 6353.
(j) Liang, B.; Carroll, P. J.; Joullie´, M. M. Org. Lett. 2000, 2, 4157.
(4) Castle, S. L.; Srikanth, G. S. C. Org. Lett. 2003, 5, 3611.
(5) Sibi, M. P.; Asano, Y.; Sausker, J. B. Angew Chem., Int. Ed. 2001,
40, 1293.
(6) For a review of Lewis acid promoted radical reactions, see: Renaud,
P.; Gerster, M. Angew. Chem., Int. Ed. 1998, 37, 2562. For a comprehensive
treatise on the uses of radicals in organic synthesis, see: Radicals in Organic
Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: New York, 2001.
(7) The pKa of ethyl nitroacetate has been measured as 5.62. For
discussions of the chemistry of these acidic compounds, see: Shipchandler,
M. T. Synthesis 1979, 666.
10.1021/ol036461h CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/14/2004

diastereo- and enantioselective synthesis of â-substituted
R-amino acids.
Our initial investigations of radical conjugate additions to
R,â-unsaturated R-nitro esters (1)8 are summarized in Table
1. We employed p-methoxyphenyl-substituted nitro ester 1a
lization,12 use of this material in the radical conjugate
additions also provided 2a-c as 1:1 diastereomeric mixtures.
Finally, attempted radical conjugate additions to nitro ester
1d bearing an aliphatic â-substituent resulted in complex
mixtures.
Having established the viability of esters 1a-c as sub-
strates in radical conjugate additions, we next examined the
performance of the corresponding R,â-unsaturated R-nitro
amides 413 in this reaction. Amides 4a-c were each obtained
as a single olefin isomer of undetermined configuration; the
Z-isomers are arbitrarily depicted in Table 2. The solvent
Table 1. Radical Conjugate Additions of Ester Substrates
Table 2. Radical Conjugate Additions of Amide Substrates
substrate
Lewis acid
equiv i-PrI
product
yield (%)a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1c
1c
1d
1d
MgBr2‚OEt2
ZnCl2
ZnCl2
25
5
12
25
5
12
12
5
5
5
5
5
3a
3a
2a
2a
3a
2a
2a
nrb
2b
2b
2b
nrb
60
60
85
85
60
70
80
Zn(OTf)2
Yb(OTf)3
Yb(OTf)3
Cu(OTf)2
MgBr2‚OEt2
ZnCl2
La(OTf)3
Sm(OTf)3
Yb(OTf)3
ZnCl2
substrate
Lewis acid
time (h)
5:6
yield (%)a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4c
4c
4c
MgBr2‚OEt2
Zn(OTf)2
Cu(OTf)2
Yb(OTf)3
Sm(OTf)3
La(OTf)3
Zn(OTf)2
Cu(OTf)2
Yb(OTf)3
Zn(OTf)2
Cu(OTf)2
Yb(OTf)3
2
1
1
1
1
1
3
3
3
4
4
4
0:100
86:14
52:48
28:72
25:75
25:75
84:16
44:56
25:75
89:11
44:56
25:75
82
92
70
62
54 (64)
50 (64)
84
52
58
85
58
65
15
15
5
2c
85
7,49
MgBr2‚OEt2
MgBr2‚OEt2
ZnCl2
2c,3c
nrb
nrb
5
80
46
30
1
a For reactions of 1a, yields were calculated from H NMR because of
persistent tin byproducts. All other yields are for isolated materials. b Neither
product observed.
a Sum of the isolated yields of 5 and 6. Yields in parentheses are based
on recovered 4. Adducts 5a-c were obtained as a 1:1 mixture of
diastereomers.
as our test substrate for isopropyl radical addition under
reaction conditions developed by Sibi for R,â-unsaturated
N-acyl oxazolidinones.9 We found that 1,4-reduction10
product 3a11 was formed in reactions employing MgBr2‚OEt2
as the Lewis acid promoter. Reduction was also observed
with ZnCl2 and Yb(OTf)3, but the conjugate addition product
2a could be obtained by increasing the amount of i-PrI from
5 to 12 equiv. Radical conjugate addition products were also
obtained with phenyl- and p-fluorophenyl-substituted nitro
esters 1b and 1c. Substrate 1c provided a mixture of
conjugate addition adduct 2c and reduction product 3c when
MgBr2‚OEt2 was employed as the Lewis acid, whereas 2c
was the sole product with ZnCl2. Compounds 1a-c were
used as ca. 2:1 mixtures of olefin isomers, and adducts 2a-c
were formed as 1:1 mixtures of diastereomers. Although
isomerically pure Z-1a-c could be obtained via recrystal-
was changed to CH2Cl2/Et2O 1:1 in order to facilitate
solubility of the substrate-Lewis acid complexes, and the
amount of i-PrI was held constant at 5 equiv. Zn(OTf)2 was
the superior Lewis acid for all three substrates, affording
adducts 5 as the major products along with minor amounts
of reduced compounds 6. In contrast, Cu(OTf)2-mediated
reactions delivered roughly equimolar amounts of 5 and 6,
whereas the use of lanthanide triflates provided 6 as the major
product. The increased levels of reduction of amides 4
relative to esters 1 may be attributed to tighter binding of
the amides to Lewis acids creating more electrophilic
complexes.14 Sibi has observed similar reductions when
strong Lewis acids were employed in radical conjugate
addition studies.9 Additionally, all amides 5 were obtained
(8) Fornicola, R. S.; Oblinger, E.; Montgomery, J. J. Org. Chem. 1998,
63, 3528.
(9) Sibi, M. P.; Ji, J.; Sausker, J. B.; Jasperse, C. P. J. Am. Chem. Soc.
1999, 121, 7517.
(10) Nozaki, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn. 1991,
64, 2585.
(12) The olefin stereochemistry of Z-1a was determined by X-ray
crystallography. We thank Dr. John F. Cannon for this experiment.
(13) Preparation of these compounds is detailed in Supporting Informa-
tion. The synthesis was based on the following report: Fenk, C. J.
Tetrahedron Lett. 1999, 40, 7955.
(11) Nakamura, S.; Uchiyama, M.; Ohwada, T. J. Am. Chem. Soc. 2003,
125, 5282.
(14) Urabe, H.; Yamashita, K.; Suzuki, K.; Kobayashi, K.; Sato, F. J.
Org. Chem. 1995, 60, 3576.
450
Org. Lett., Vol. 6, No. 3, 2004

as 1:1 mixtures of diastereomers despite the fact that a single
olefin isomer of 4 was used in each reaction, an observation
identical to our findings with esters 2.
The nitro moieties of adducts 2 and 5 can be transformed
into protected amines 7 and 8 via a simple two-step sequence
(Scheme 1). Thus, radical conjugate addition to R,â-
2 can be prevented in most cases and minimized in others
by simply conducting the workup with dilute acid.
On the other hand, radical conjugate additions to amides
4a-c with Bu3SnD were characterized by extensive D-H
exchange (32-57%). Use of more concentrated acid in the
workup failed to decrease hydrogen incorporation. NMR
studies implicated the amide hydrogen in this exchange.15
1
Additionally, examination of the H NMR spectra of crude
d-5a-c revealed that the D-H exchange was taking place
during SiO2 chromatography. Accordingly, we removed this
step from our procedure and subjected the adducts to
hydrogenation followed by N-Cbz protection immediately
after workup.16 We were pleased to discover that this greatly
attenuated the D-H exchange, as R-protons were not
detected in the 1H NMR spectrum of d-8b and were observed
at low levels (4% and 11%) in the spectra of d-8a and d-8c.
Therefore, of the six substrates examined in this study, only
one (4c) exhibited >4% D-H exchange.
These deuterium studies indicate that the lack of diaste-
reoselectivity in radical conjugate additions to isomerically
pure 1 and 4 is not due to epimerization at the R-stereocenter
of the products. Rather, it appears that the initially formed
â-stereocenter does not exert any influence over the sub-
sequent hydrogen atom abstraction step. Although the lack
of substrate stereocontrol limits the current utility of our
method, it actually bodes well for the discovery of a chiral
Lewis acid controlled, diastereo- and enantioselective syn-
thesis of â-substituted R-amino acids via this protocol. In
addition to setting the â-stereochemistry, a suitable chiral
Lewis acid would be expected to control the configuration
at the R-position without interference from the newly
established â-stereocenter.17
Scheme 1. Conversion of Adducts into Protected Amino
Acids
unsaturated R-nitro esters 1 and amides 4 is a useful method
for the synthesis of â-substituted R-amino acid derivatives.
Moreover, the successful use of amides 4 as substrates
suggests that the reaction could be carried out on a peptide.
However, application of this protocol to natural product or
complex molecule synthesis necessitates development of a
diastereo- and enantioselective version. A requirement for
such a reaction is inhibition of racemization of the sensitive
R-stereocenters of 2 and 5. To determine if this is possible,
we performed radical conjugate additions to 1 and 4 with
Bu3SnD to see if deuterium would be retained in 2 and 5
(Table 3).
In summary, we have demonstrated that R,â-unsaturated
R-nitro esters and amides undergo Lewis acid promoted
radical conjugate additions, affording â-substituted R-amino
acid derivatives. Competitive reduction is more pronounced
with amides, presumably as a result of the tighter substrate-
Lewis acid complexes. Importantly, we have discovered
workup conditions that prevent or minimize deprotonation
of the extremely acidic R-center of nitro esters 2 and amides
5, thereby indicating the feasibility of asymmetric radical
conjugate additions to these substrates provided a suitable
chiral Lewis acid can be identified. Furthermore, we note
that in some instances selective epimerization of the R-nitro
amide stereocenter in a complex peptide adduct could be
used advantageously to obtain a thermodynamic product.
Consequently, we envision a variety of applications for these
Table 3. Incorporation and Retention of Deuterium in 2 and 5
substrate
time (h)
workup
H2O
H incorporation (%)a
1c
1c
1b
1a
4a
4b
4c
3
3
3
3
1
3
3
10
4
0.25 N HCl
0.25 N HCl
0.25 N HCl
1 N HCl
ndb
ndb
4
1 N HCl
ndb
1 N HCl
11
a Measured by 1H NMR of d-2a-c or d-8a-c (see text). b Not detected.
(15) 1H NMR spectra recorded immediately after isolation of d-5a-c
exhibited amide N-H signals attenuated by an amount consistent with the
extent of hydrogen incorporation at the R-position. Over time, the nitrogen-
bound deuterium exchanged with protons derived from trace moisture and
the amide signals returned to their normal levels of intensity. Unfortunately,
attempts to block this exchange by performing radical conjugate additions
on protected or tertiary amides have been unsuccessful. The N-Boc derivative
of 4a afforded reduction product exclusively, whereas N-PMB and N-Me
versions were unreactive.
(16) Reductions of crude d-5a-c were sluggish as a result of the presence
of tin byproducts, requiring ca. 3 wt equiv of 10% Pd/C.
(17) Sibi has successfully used a chiral Lewis acid to control the
stereochemistry at both the R- and â-positions in radical conjugate additions
to R,â-unsaturated N-acyl oxazolidinones: Sibi, M. P.; Chen, J. J. Am.
Chem. Soc. 2001, 123, 9472.
When we conducted this experiment with electron-poor
ester substrate 1c, we observed modest levels of hydrogen
incorporation (10%) at the R-center when water was used
in the workup. Fortunately, when the same reaction was
worked up with 0.25 N HCl instead of water, the amount of
D-H exchange dropped significantly. With nitro esters 1b
and 1a, R-protons were not observed in the 1H NMR spectra
of d-2b and d-2a. Thus, racemization of acidic R-nitro esters
Org. Lett., Vol. 6, No. 3, 2004
451

radical conjugate additions in amino acid and peptide
synthesis. Studies to delineate the full scope of this method
are in progress and will be reported in due course.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank Brigham Young University
for support of this work.
OL036461H
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Org. Lett., Vol. 6, No. 3, 2004