SmI(2)-promoted radical addition of nitrones to alpha,beta-unsaturated amides and esters: synthesis of gamma-amino acids via a nitrogen equivalent to the ketyl radical.

Article abstract of DOI:10.1021/ol027386y

[reaction: see text] Alkyl nitrones undergo radical addition reactions to a series of alpha,beta-unsaturated amides and esters when subjected to samarium diiodide via a nitrogen equivalent to a ketyl radical anion. This reaction conveniently provides acce

Full text of DOI:10.1021/ol027386y

ORGANIC
LETTERS
2003
Vol. 5, No. 2
229-231
SmI2-Promoted Radical Addition of
Nitrones to r,â-Unsaturated Amides and
Esters: Synthesis of γ-Amino Acids via
a Nitrogen Equivalent to the Ketyl
Radical
Ditte Riber and Troels Skrydstrup*
Department of Chemistry, UniVersity of Aarhus, Langelandsgade 140,
8000 Aarhus C, Denmark
ts@chem.au.dk
Received December 2, 2002
ABSTRACT
Alkyl nitrones undergo radical addition reactions to a series of r,â-unsaturated amides and esters when subjected to samarium diiodide via
a nitrogen equivalent to a ketyl radical anion. This reaction conveniently provides access to a variety of functionalized γ-amino acids. The
methodology was extended to the asymmetric synthesis of 4-substituted γ-amino acids, via the nitrone radical addition reaction to acrylates/
amides possessing a chiral auxiliary.
The reduction of aldehydes or ketones by low-valent transi-
tion-metal complexes to ketyl radicals and their subsequent
intra- or intermolecular addition to R,â-unsaturated esters
or amides is well-documented and therefore a useful synthetic
organic transformation (Scheme 1a).1 Above all, the lan-
thanide-based one-electron reducing agent, samarium di-
iodide, has been found to be one of the most effective
reagents for promoting such reactions under mild reaction
conditions, and in many cases leads to products with high
diastereoselectivities.2 On the other hand, analogous reactions
with imines or related systems possessing a carbon-nitrogen
double bond are scarce, largely due to the difficulties in
reducing such functionalities to their corresponding ketyl-
type radical intermediate under mild conditions.3-7
Scheme 1
Recently, alkyl and aryl nitrones were reported to undergo
low-temperature pinacol-type heterocoupling with carbonyl
compounds promoted by samarium diiodide.8 Evidence was
(1) Gansa¨uer, A.; Bluhm, H. Chem. ReV. 2000, 100, 2771 and references
therein.
(2) For recent reviews on the application of SmI2 in organic synthesis,
see: (a) Steel, P. G. J. Chem. Soc., Perkin Trans. 1 2001, 2727. (b) Krief,
A.; Laval, A.-M. Chem. ReV. 1999, 99, 745. (c) Molander, G. A.; Harris,
C. R. Chem. ReV. 1996, 96, 307. (d) Molander, G. A.; Harris, C. R.
Tetrahedron 1998, 54, 3321. (e) Skrydstrup, T. Angew. Chem., Int. Ed.
Engl. 1997, 36, 345. (f) Molander, G. A. Org. React. 1994, 46, 211.
10.1021/ol027386y CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/31/2002

provided for the preferential reduction of the CdN bond,
suggesting the presence of an intermediate R-heteroatom-
substituted carbon radical. If this mechanism is indeed valid,
it should be possible to intercept the carbon radical species
with electron-deficient alkenes. In this report, we reveal our
preliminary efforts in this area demonstrating the ability of
alkyl N-benzylnitrones to undergo intermolecular radical
addition to R,â-unsaturated amides and esters when treated
with SmI2, thereby providing a useful entry to 4-substituted
γ-amino acids alone or as constituents of small mixed R,γ-
peptides (Scheme 1b). This work represents the first practical
application of a nitrogen equivalent of the intermolecular
ketyl radical addition reaction.
Table 1. SmI2-Promoted Addition of Nitrones to
R,â-Unsaturated Amides and Estersa
Initial experiments were carried out with the cyclohexyl
N-benzylnitrone and the methyl ester of N-acryloylglycine,
as illustrated in Table 1. A 0.1 M etheral solution of SmI2
was added dropwise to a 1:1 solution of the nitrone and
acrylamide in THF cooled to -78 °C. After stirring for 12
h, work up and column chromatography led to a 65% yield
of the N-hydroxylated dipeptide analogue possessing a
γ-amino acid unit (entry 1).9 Inclusion of a proton source
(e.g. t-BuOH) did not lead to an improvement. At higher
temperatures competitive reduction and dimerization of the
acrylamide was observed indicating the close reactivity of
the two substrates with the low-valent lanthanide reagent and
the fine balance of selectivity that is achieved at lower
temperatures.
Other examples are illustrated in Table 1. With the
N-acryloylphenylalanine derivative as shown in entry 2, the
γ,R-dipeptide was obtained in a 53% yield as an approxi-
mately 2:1 diastereomeric mixture. Other alkyl nitrones also
provided peptide analogues under similar conditions (entries
3 and 4). Even coupling to the N-acryloyl derivative of
LeuPheOMe proved feasible, as illustrated in entry 5,
furnishing the tripeptide analogue in 47% yield. A dipeptide
possessing a 2,4-disubstituted γ-amino acid unit was obtained
with good diastereoselectivity from the addition of the
cyclohexyl nitrone to N-methacryloylglycine (entry 6). The
(3) Only imines prepared from aryl aldehydes or ketones have so far
been reported to undergo reduction by SmI2. For some examples, see: (a)
Machrouhi, F.; Namy, J.-L. Tetrahedron Lett. 1999, 40, 1315. (b) Annun-
ziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Raimondo, L. Tetrahedron
Lett. 1998, 39, 3333. (c) Taniguchi, N.; Uemura, M. Synlett 1997, 51. (d)
Imamoto, T.; Nishimura, S. Chem. Lett. 1990, 1141. (e) Enholm, E. J.;
Forbes, D. C.; Holub, D. P. Synth. Commun. 1997, 27, 1483.
(4) Hydrazones or oximes prepared from alkyl aldehydes are not reduced
by SmI2 even in the presence of HMPA. See: (a) Fallis, A. G.; Sturino, C.
F. J. Am. Chem. Soc. 1994, 116, 7447. (b) Fallis, A. G.; Brinza, I. M.
Tetrahedron 1997, 53, 17543. (c) Riber, D.; Hazell, R.; Skrydstrup, T. J.
Org. Chem. 2000, 65, 5382 and references therein.
(5) The electroreductive coupling of two closely related aromatic imines
to methyl acrylate represents the only examples previously reported for
this reaction, Shono, T.; Kise, N.; Kunimi, N.; Nomura, R. Chem. Lett.
1991, 2191.
(6) Surrogates to imines for generating R-amino radicals with SmI2 and
their application in intramolecular cyclizations have been reported. (a)
Katritzky, A. R.; Feng, D. M.; Qi, M.; Aurrecoechea, J. M.; Suero, R.;
Aurrekoetxea, N. J. Org. Chem. 1999, 64, 3335. (b) Aurrecoechea, J. M.;
Fernandez, A.; Gorgojo, J. M.; Saornil, C. Tetrahedron 1999, 55, 7345.
(7) For other work on the generation and application of R-amino radicals,
see: Renaud, P.; Giraud, L. Synthesis 1996, 913.
(8) Masson, G.; Py, S.; Valle´e, Y. Angew. Chem., Int. Ed. 2002, 41,
1772.
(9) For other applications of SmI2 for the synthesis of modified peptides,
see: Ricci, M.; Blakskjær, P.; Skrydstrup, T. J. Am. Chem. Soc. 2000, 122,
12413.
a For full experimental details, see the Supporting Information. b Isolated
yields after column chromatography. c Reaction performed in the presence
of 2 equiv of t-BuOH.
successful coupling of the same nitrone with the N-acryloyl
derivative of (2R,3S)-aminohydroxydihydroindane (entry 7)
provides entry to a new class of compounds possessing
structural similarities to the potent HIV protease inhibitor,
indinavir.10 Extrapolation of the same radical addition
230
Org. Lett., Vol. 5, No. 2, 2003

reactions to R,â-unsaturated esters was more rewarding
(entries 8-10) with yields up to 70% in two examples. In
contrast to the acrylamides, t-BuOH is required in these
couplings for successful C-C bond formation.11 In the latter
two cases, the diastereoselectivity proved even higher than
seen with the methacyrlamide in entry 6. Even generation
of a quaternary carbon center is feasible, though in somewhat
reduced yield (entry 11).
Scheme 3
The products obtained from this reaction suggest the
formation of a ketyl-like intermediate as illustrated in Scheme
2. Coordination of the lanthanide metal center to the carbonyl
Scheme 2
group and activation is followed by the 1,4-addition step.
There is also the possibility that the good Lewis acid ability
of SmI2 or other salts formed under the reaction conditions
catalyzed the cycloaddition of the nitrone to the C-C double
bond followed by SmI2-mediated deoxygenation at the
R-position. However, deoxygenation at the R-position of
esters with SmI2 in general requires the presence of strongly
coordinating solvents such as HMPA, which augments the
reducing power of the divalent lanthanide reagent.2f In
addition, the nitrone cycloaddition step would be expected
to afford products of the opposite regioisomer.12
found to undergo predominant cyclization to 6 upon chro-
matography; however, a three-step transformation led to the
quantitative formation of the Boc-protected γ-amino acid
derivative 7.14
In conclusion, we have demonstrated that alkyl nitrones
undergo addition reactions to R,â-unsaturated amides and
esters upon reduction with SmI2, providing an imine equiva-
lent to the well-known radical addition reactions of aldehydes
and ketones. This reaction provides access to variously
substituted γ-amino acids and preliminary studies have
revealed that such amino acids can be prepared with high
enantiomeric excesses. Efforts are underway to examine the
efficiency of other chiral auxiliaries, as well as their
generality.
Finally, attempts were made to extend this methodology
for the preparation of optically active 4-substituted γ-amino
acids, by initially examining the addition of nitrone 1 to
acrylates/acrylamides 3a-d possessing a chiral auxiliary
(Scheme 3). Of the four chiral auxiliaries tested, (1R,2S)-
N-methylephedrine proved to be the most effective leading
to a 9:1 diastereomeric ratio of the γ-amino acid derivative
4d. The same high diastereoselectivity could be obtained for
the nitrone 2 leading to derivative 5.13 Compound 5 was
Acknowledgment. We thank the Danish National Science
Foundation (THOR program), The University of Aarhus, and
the Carlsberg Foundation for generous financial support.
(10) For a recent and extensive review on protease inhibitors, see: Leung,
D.; Abbenante, G.; Fairlie, D. P. J. Med. Chem. 2000, 43, 305.
(11) In the addition reactions to the acrylamides, the amide proton may
serve as the protonation source for the resulting enolate formed, hence
explaining the observation that the presence of t-BuOH does not affect the
yields of these reactions.
(12) Gothelf, K. V.; Jørgensen, K. A. Chem. ReV. 1998, 98, 863.
(13) Fukuzawa and co-workers reported this chiral auxiliary to be the
most effective in the asymmetric preparation of γ-lactones with high
enantiomeric excesses by SmI2-promoted ketyl radical addition reactions.
Fukuzawa, S.-i; Seki, K.; Tatsuzawa, M.; Mutoh, K. J. Am. Chem. Soc.
1997, 119, 1482.
Supporting Information Available: Experimental pro-
cedure and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL027386Y
(14) Schmidt, U.; Riedl, B.; Haas, G.; Griesser, H.; Vetter, A.; Wein-
brenner, S. Synthesis 1993, 216.
Org. Lett., Vol. 5, No. 2, 2003
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