Inter- and intramolecular addition reactions of electron-deficient alkenes with alkyl radicals, generated by SET-photochemical decarboxylation of carboxylic acids, serve as a mild and efficient method for the preparation of γ-amino acids and macrocyclic l

Article abstract of DOI:10.1021/ol9019277

Inter- and Intramolecular additions of alkyl radicals, generated by SET photochemical decarboxylation reactions of free carboxylic acids, to electron-deficient alkenes take place under mild conditions as part of efficient routes for the formation of NBoc

Full text of DOI:10.1021/ol9019277

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4652-4655
Inter- and Intramolecular Addition
Reactions of Electron-Deficient Alkenes
with Alkyl Radicals, Generated by
SET-Photochemical Decarboxylation of
Carboxylic Acids, Serve as a Mild and
Efficient Method for the Preparation of
γ-Amino Acids and Macrocyclic
Lactones
Yasuharu Yoshimi,* Miho Masuda, Tomoyuki Mizunashi, Keisuke Nishikawa,
Kousuke Maeda, Nobumasa Koshida, Tatsuya Itou, Toshio Morita, and
Minoru Hatanaka*
Department of Applied Chemistry and Biotechnology, Graduate School of Engineering,
UniVersity of Fukui, 3-9-1 Bunkyo, Fukui 910-8507, Japan
yyoshimi@u-fukui.ac.jp; mhatanak@iwate-med.ac.jp
Received August 19, 2009
ABSTRACT
Inter- and intramolecular additions of alkyl radicals, generated by SET photochemical decarboxylation reactions of free carboxylic acids, to
electron-deficient alkenes take place under mild conditions as part of efficient routes for the formation of N-Boc γ-amino acids and macrocyclic
lactones.
Inter- and intramolecular radical additions to alkenes serve
as the basis for useful methods for C-C bond formation.1
The use of decarboxylation reactions of carboxylic acid
groups in amino acids and peptides as sources for key radical
intermediates has also attracted great interest.2 Transforma-
tions involving both of these processes typically employ the
(1) (a) Giese, B. Radicals in Organic Synthesis: Formation of Carbon-
Carbon Bonds; Pergamon: Oxford, 1986. (b) Fossey, J.; Lefort, D.; Sorba,
J. Free Radicals in Organic Chemistry; Wiley: Chichester, UK, 1995. (c)
Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH:
Weinheim, 2001. (d) Zard, S. Z. Radical Reactions in Organic Synthesis;
Oxford University Press: New York, 2003. (e) Srikanth, G. S. C.; Castle,
S. L. Tetrahedron 2005, 61, 10377.
(2) (a) Barton, D. H. R.; Herve, Y.; Potier, P.; Thierry, J. J. Chem. Soc.,
Chem. Commun. 1984, 1298. (b) Renaud, P.; Giraud, L. Synthesis 1996,
913. (c) Griesbeck, A. G.; Heinrich, T.; Oelgemoller, M.; Lex, J.; Molis,
A. J. Am. Chem. Soc. 2002, 124, 10972. (d) Yoon, U. C.; Jin, Y. X.; Oh,
S. W.; Park, C. H.; Park, J. H.; Campana, C. F.; Cai, X.; Duesler, E. N.;
Mariano, P. S. J. Am. Chem. Soc. 2003, 125, 10664. (e) Saavedra, C.;
Hernandez, R.; Boto, A.; Alvarez, E. J. Org. Chem. 2009, 74, 4655.
10.1021/ol9019277 CCC: $40.75
Published on Web 09/14/2009
 2009 American Chemical Society

Barton decarboxylation procedure to form alkyl radicals by
homolysis of thiohydroxamic esters under either thermal or
photochemical conditions.3 One limitation of this approach
stems from the fact that esterification of carboxylic acids is
required in order to produce the thiohydroxamic ester
precursors. Consequently, a technique that involves direct
generation of alkyl radicals from free carboxylic acids under
mild conditions would make the approach more efficient.
In a recent report,4 we described results which show that
aliphatic carboxylic acids undergo decarboxylation to form
alkyl free radicals when subjected to redox-photosensitized
reaction conditions5 employing phenanthrene (Phen) and 1,4-
dicyanobenzene (DCB) (Scheme 1). This process is promoted
Decarboxylative addition reactions between N-Boc-R-amino
acids and a variety of electron-deficient alkenes were examined
(Table 1) initially to determine the scope of the process.
Table 1. Intermolecular Radical Addition of 1 to 2 via
SET-Photochemical Decarboxylationa
Scheme 1
entry
amino acid
alkene
adduct (yield,b %)
1
2
1a
1a
1a
1a
1b
1b
1b
1c
1c
1c
1d
1d
1d
2a
2b
2c
2d
2a
2b
2c
2a
2b
2c
2a
2b
2c
3aa (85)
3ab (41)
3ac (57)
3ad (60)
3ba (83)
3bb (48)
3bc (43)
3ca (74)
3cb (36)
3cc (60)
3da (88)
3db (57)
3dc (52)
3c
4d
5
6
7c
8
9
10c
11
12
13c
by single-electron transfer (SET) from the carboxylate ion
to the cation radical, formed by SET from the singlet excited
state of Phen to DCB. This process leads to the formation
of carboxyl radicals that rapidly lose carbon dioxide to
produce alkyl free radicals.6 Alkyl radicals, formed in this
manner, react by hydrogen atom transfer with a thiol or by
addition to the cogenerated anion radical of DCB to yield
the respective reduction or substitution products. These
findings, which demonstrate that the SET photochemical
route can be used to efficiently generate alkyl radicals from
free aliphatic carboxylic acids under mild conditions, led us
to investigate a novel approach to inter- and intramolecular
radical additions to alkenes.
a The photoreaction was carried out with Phen (1.2 mmol), DCB (1.2
mmol), 1 (1.2 mmol), and 2 (1.2 mmol) in aqueous CH3CN solution
(CH3CN, 54 mL; H2O, 6 mL) using a 100-W high-pressure mercury lamp
under argon atmosphere for 6 h. b Isolated yield. c Irradiation time is 8 h.
d In the presence of 1 equiv of NaOH.
Irradiation of an aqueous acetonitrile solution (CH3CN/H2O )
9:1) containing Phen (20 mM), DCB (20 mM), N-Boc-L-valine
1a (20 mM), and acrylonitrile 2a (20 mM) with a 100-W high-
pressure mercury lamp through a Pyrex filter (λ > 280 nm)
under an argon atmosphere for 6 h at room temperature was
found to promote formation of the adduct 3aa as a racemic
mixture in 85% yield along with near-quantitative recovery
(>90%) of Phen and DCB (entry 1, Table 1). This reaction
proceeds smoothly, and only 1 equiv of 2a is required. The
presence of 1 equiv of NaOH in the photoreaction mixture
accelerates the reaction. In this case, a similar yield of 3aa is
obtained even when a shorter irradiation time (3 h) is employed.
Other electron-deficient alkenes, such as ethyl acrylate 2b,
acrylic acid 2c, and phenyl vinyl sulfone 2d, participate in this
process to yield the corresponding adducts 3ab, 3ac, and 3ad
in moderate yields (entries 2-4). However, no adducts are
formed when electron-rich alkenes, such as ethyl vinyl ether
and allyl alcohol, are used. Importantly, moderate to good yields
of adducts are obtained when other amino acids, including
N-Boc-L-phenylalanine 1b, N-Boc-L-serine 1c, and N-Boc-L-
proline 1d, are subjected to the photoreaction conditions in the
presence of the electron-deficient alkenes 2a-c (entries 5-13).
It is important to point out that the adduct formation takes place
(3) (a) Barton, D. H. R.; Crich, D.; Kretzschmar, G. J. Chem. Soc., Perkin
Trans. 1 1986, 39. (b) Barton, D. H. R.; Herve, Y.; Potier, P.; Thierry, J.
Tetrahedron 1987, 43, 4297. (c) Crich, D.; Quintero, L. Chem. ReV. 1989,
89, 1413. (d) Garner, P.; Anderson, J. T.; Dey, S.; Youngs, W. J.; Galat,
K. J. Org. Chem. 1998, 63, 5732.
(4) (a) Yoshimi, Y.; Itou, T.; Hatanaka, M. Chem. Commun. 2007, 5244.
(b) Itou, T.; Yoshimi, Y.; Morita, T.; Tokunaga, Y.; Hatanaka, M.
Tetrahedron 2009, 65, 263.
(5) (a) Pac, C.; Nakasone, A.; Sakurai, H. J. Am. Chem. Soc. 1977, 99,
5806. (b) Majima, T.; Pac, C.; Nakasone, A.; Sakurai, H. J. Am. Chem.
Soc. 1981, 103, 4499. (c) Ohashi, M.; Nakatani, K.; Maeda, H.; Mizuno,
K. Org. Lett. 2008, 10, 2741. (d) Ohashi, M.; Nakatani, K.; Maeda, H.;
Mizuno, K. J. Org. Chem. 2008, 73, 8348.
(6) For SET-photochemical decarboxylation of carboxylic acids, see:
(a) Libman, J. J. Am. Chem. Soc. 1975, 97, 4139. (b) Mariano, P. S. Acc.
Chem. Res. 1983, 16, 130. (c) Chiu, F. T.; Ullrich, J. W.; Mariano, P. S. J.
Org. Chem. 1984, 49, 228. (d) Karauchi, Y.; Nobuhara, N.; Ohga, K. Bull.
Chem. Soc. Jpn. 1987, 59, 897. (e) Tsujimoto, K.; Nakao, N.; Ohashi, M.
J. Chem. Soc., Chem. Commun. 1992, 366. (f) Griesbeck, A. G.; Henz, A.;
Peters, K.; Peters, E. M.; Schnering, H. G. Angew. Chem., Int. Ed. 1995,
34, 474. (g) Yokoi, H.; Nakano, T.; Fujita, W.; Ishiguro, K.; Sawai, Y.
J. Am. Chem. Soc. 1998, 120, 12453. (h) Griesbeck, A. G.; Hoffmann, N.;
Warzecha, K. D. Acc. Chem. Res. 2007, 40, 128.
Org. Lett., Vol. 11, No. 20, 2009
4653

smoothly even with the unprotected hydroxyl group containing
serine derivative 1c (entries 8-10). Also noteworthy is the fact
that the photoreactions of 1a-d with acrylic acid 2c for 8 h
give the corresponding N-Boc-γ-amino acids (entries 3, 7, 10,
and 13). This finding suggests that the difference between the
pKa values of the starting N-Boc-R-amino acids 1a-c and the
product γ-amino acids 3ac, 3bc, 3cc, and 3dc is sufficiently
large to prevent yield diminishing decarboxylation reactions of
the products. Overall, the results show that a variety of N-Boc-
γ-amino acids can be prepared directly by reactions between
N-Boc-R-amino acids and acrylic acid.
acid 10, prepared in a 84% yield starting from the macro-
cyclic lactone 8 and using a four-step route (I + II). Ring-
opening of 8 promoted by treatment with KOH followed by
MOM protection of the carboxylic acid group leads to
formation of the alcohol 9. Esterification of 9 with acryloyl
chloride followed by MOM deprotection gives the alkene-
tethered carboxylic acid 10. Photocyclization reaction of 10
(1 mM) in the presence of NaOH (1 mM), Phen, and DCB,
occurs smoothly to form the macrocyclic lactone 11 in 84%
yield (step III). The efficiency of this process decreases (73,
61, 51, 29% yields of 11) when higher concentrations of 10
(2, 3, 4, 5 mM) are used. Repetition of a similar reaction
sequence (I + II + III) starting with 11 produces the two-
carbon elongated macrocyclic lactone 12 in good yield.
Similarly, the 21 membered macrocyclic lactone 15 is
generated when the 17 membered lactone 13 is subjected to
the ring-opening-radical cyclization sequence. The results
of this investigation show that macrocyclic lactones with
desired ring sizes can be obtained by employing this novel
radical cyclization method.
The synthetic utility of the process described above was
demonstrated by its application to radical addition reactions
of the N-protected peptides (Scheme 2). Photoreactions of
Scheme 2
In order to gain information about the mechanism of the
radical addition process, a deuterium incorporation experi-
ment was carried out (Scheme 4). Irradiation of a mixture
Scheme 4. Deuterium Incorporation Experiment Using D2O
the N-Boc-GlyVal-OH dipeptide 4 and N-Boc-GlyValVal-
OH tripeptide 6 with acrylonitrile 2a, promoted by using
the conditions described above, take place smoothly to
produce the respective adducts 5 and 7.
Intramolecular radical addition reactions of carboxylic
acid, bearing tethered electron-deficient alkenes, were in-
vestigated next (Scheme 3). The first substrate explored was
of N-Boc-amino acid 1a, acrylonitrile 2a, Phen, and DCB
in a 1:9 mixture of D2O and acetonitrile was found to
generate adduct d-3aa which contains a deuterium atom at
the position R to the cyano group. This finding shows that
the R-cyano anion serves as the ultimate intermediate in the
pathway for adduct formation (Scheme 5). Thus, decarboxy-
Scheme 3
Scheme 5. Plausible Mechanism
lation of carboxylate ions, induced by the photogenerated
cation radical of Phen, produces alkyl radicals 16 that react
with electron-deficient alkenes to produce adduct radicals
4654
Org. Lett., Vol. 11, No. 20, 2009

17. The processes are terminated by SET from the anion
radical of DCB, formed in the initial SET event, to the adduct
radicals 17 to produce anions 18 that undergo protonation
to yield the adducts.
enlargement pathway that is based upon the radical cycliza-
tion methodology. Further investigations of the scope,
limitations, and applications of this methodology are cur-
rently in progress.
In conclusion, the results of this effort demonstrate that
alkyl free radicals, generated from free carboxylic acids via
a photochemically promoted SET-decarboxylation pathway,
undergo inter- and intramolecular additions to electron-
deficient alkenes. The photoreactions proceed under mild
conditions to generate N-Boc-γ-amino acids starting from
N-Boc-R-amino acids. In addition, macrocyclic lactones of
various ring sizes can be obtained by using a stepwise ring
Acknowledgment. This work was supported by a Mit-
subishi Gas Chemical Company Award in Synthetic Organic
Chemistry, Japan.
Supporting Information Available: Experimental pro-
cedures and characterization. This material is available free
of charge via the Internet at http://pubs.acs.org.
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