Photolysis of diacyl peroxides: A radical-based approach for the synthesis of functionalized amino acids

Article abstract of DOI:10.1021/ol035125y

(Matrix presented) Photolysis of the amino acid derived symmetrical and unsymmetrical diacyl peroxides at 254 nm at low temperature (-78 to -196°C) generates various bis(amino acids) in a concise manner and with orthogonal protection. The methodology was

Full text of DOI:10.1021/ol035125y

ORGANIC
LETTERS
2003
Vol. 5, No. 16
2963-2965
Photolysis of Diacyl Peroxides: A
Radical-Based Approach for the
Synthesis of Functionalized Amino
Acids
M. Daniel Spantulescu, Rajendra P. Jain, Darren J. Derksen, and
John C. Vederas*
Department of Chemistry, UniVersity of Alberta, Edmonton, Alberta, Canada T6G 2G2
john.Vederas@ualberta.ca
Received June 18, 2003
ABSTRACT
Photolysis of the amino acid derived symmetrical and unsymmetrical diacyl peroxides at 254 nm at low temperature (−78 to −196 °C) generates
various bis(amino acids) in a concise manner and with orthogonal protection. The methodology was applied to the synthesis of (4R)-5-propyl-
L-leucine (PrLeu), a component of HUN-7293.
Thermal or photochemical decompositions of diacyl perox-
ides are well-studied reactions that in principle provide an
extremely useful method of carbon-carbon bond formation
starting from two carboxylic acids (Figure 1).1 In practice,
potential of this chemistry remains relatively unexplored,
especially for synthesis of chiral molecules bearing multiple
heteroatoms and functional groups.3c Our interest in diami-
nopimelic acid (DAP) derivatives as antimicrobial enzyme
inhibitors4 and also in cross-linking of linear peptides to
replace cysteine disulfides with diaminosuberic acid moieties5
led us to examine low-temperature photolysis of peroxides
derived from protected glutamic and/or aspartic acids. We
(1) For leading references, see: (a) Ryzhkov, L. R. J. Org. Chem. 1996,
61, 2801-2808. (b) Fujimori, K.; Hirose, Y.; Oae, S. J. Chem. Soc., Perkin
Trans. 2 1996, 405-412. (c) Radziszewski, J. G.; Nimlos, M. R.; Winter,
P. R.; Ellison, G. B. J. Am. Chem. Soc. 1996, 118, 7400-7401. (d) Linhardt,
R. J.; Murr, B. L.; Montgomery, E.; Osby, J.; Sherbine, J. J. Org. Chem.
1982, 47, 2242-2251.
(2) Warning: Although larger diacyl peroxides cannot be detonated, small
diacyl peroxides with e7 carbons on each side (e.g., diacetyl peroxide)
can be explosive and hazardous. As scrambling of acyl groups can occur
during preparation, coupling of small acyl groups (e.g., acetyl) should be
avoided. For example of scrambling, see: Staab, H. A.; Rohr, W.; Graf, F.
Chem. Ber. 1965, 98, 1128-1133.
(3) (a) Feldhues, M.; Scha¨fer, H. J. Tetrahedron 1985, 41, 4213-4235.
(b) Feldhues, M.; Scha¨fer, H. J. Tetrahedron 1986, 42, 1285-1290. (c)
Lomo¨lder, R.; Scha¨fer, H. J. Angew. Chem., Int. Ed. Engl. 1987, 26, 1253-
1254.
(4) (a) For a review, see: Cox, R. J.; Sutherland, A.; Vederas, J. C.
Bioorg. Med. Chem. 2000, 8, 843-871. (b) Sutherland, A.; Vederas, J. C.
J. Chem. Soc., Chem. Commun. 2002, 224-225.
(5) Stymiest, J. L.; Mitchell, B. F.; Wong, S.; Vederas, J. C. Org. Lett.
2003, 5, 47-49.
Figure 1. Decomposition of diacyl peroxides with radical coupling.
the approach is not often used because of the perception that
all diacyl peroxides are explosive2 and the recurring observa-
tion that extensive side reactions (e.g., hydrogen abstraction)
and crossover radical coupling products occur. However, in
1985 Scha¨fer and co-workers reported the low temperature
(-78 °C) photolysis of aliphatic diacyl peroxides for the
efficient synthesis of long chain aliphatic hydrocarbons.3 The
10.1021/ol035125y CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/10/2003

mediated coupling of protected amino acids with 2-meth-
oxyprop-2-yl hydroperoxide,8 acidic deprotection of the
resultant peresters 2, and acylation of the corresponding
peracids 3 with another protected amino acid (DCC/MeCN).
The diacyl peroxides 4 are stable to shock and can be stored
for several weeks at -20 °C without decomposition (espe-
cially as solutions in ethyl acetate).
To avoid generation of complex mixtures and crossover
products, the photolysis reactions on the peroxides are best
done on neat substrates (solids as well as oils, no solvent)3
at either -78 °C (Ar atmosphere) or -196 °C (N2 atmo-
sphere) with a 254-nm UV lamp (typical reaction times are
2-5 days).9 In this fashion, cage recombination of the
resulting alkyl radicals is enhanced as movement of the
reactive partners is relatively constrained.3 Higher temper-
atures or frozen solutions (e.g., dioxane, alcohols, water)
afford numerous side products and low yields. Thus, pho-
tolysis of the symmetrical diacyl peroxides (+)-4a and (+)-
4b generates enantiomerically pure derivatives of diamino-
adipate (+)-5a and diaminosuberate (+)-5b, respectively.
Photolysis of unsymmetrical diacyl peroxides (+)-4c and
(+)-4d produces optically pure diaminopimelate derivatives,
(+)-5c and (+)-5d, which are orthogonally protected, with
no detectable crossover products (i.e. diaminoadipates or
diaminosuberates).
Some starting material is generally recovered even after
prolonged (2-5 days) irradiation, possibly because of
photoprotection of lower substrate layers by strata above
them. Although optimal ratios of surface area to layer
thickness may be substrate-dependent and have not yet been
determined, photolyses on ca. 0.5 mmol are readily ac-
complished using a 100-mL beaker as the reaction vessel.
In this regard, benzyl and Cbz protecting groups are
compatible with the photolysis method, but Fmoc moieties
hinder facile cleavage of the diacyl peroxide, as does an
aromatic acyl group directly attached to the peroxide oxygen.
An alternative approach to symmetrical amino acids is Kolbe
electrolysis10 of suitably protected aspartic or glutamic acids
having a free distal carboxyl.11 However, coupling of two
different partners by electrolysis usually generates complex
mixtures and very low yields of desired products.12 The
present method offers an attractive alternative.
Figure 2. Synthesis and photolysis of amino acid derived diacyl
peroxides.
now report that this offers facile access to complex amino
acids6 with surprising stereocontrol at the intermediate radical
center.
Stereocontrol in the photolysis step is demonstrated by
synthesis of (4R)-5-propyl-L-leucine (PrLeu13 derivative 9,
Both symmetrical and unsymmetrical diacyl peroxides of
amino acids served as starting materials for this study. The
symmetrical diacyl peroxides of the suitably protected
aspartic or glutamic acids 1 can be synthesized by activation
of the carboxyl group with DCC and coupling with 0.5 equiv
of urea-hydrogen peroxide (UHP)7 (Figure 2). The unsym-
metrical diacyl peroxides 4 (n * m) are available by DCC-
(7) Cooper, M. S.; Heaney, H.; Newbold, A. J.; Sanderson, W. R. Synlett
1990, 533-535.
(8) Dussault, P.; Sahli, A. J. Org. Chem. 1992, 57, 1009-1012.
(9) All reactions were conducted with a 0.9-A UV lamp. The apparatus
is extremely simple. For reactions at -78 or -85 °C, the substrate can be
placed on the bottom of an open 500-mL capacity measuring cylinder
immersed in a cooling bath, while for reactions at -196 °C, the substrate
can be placed on the bottom of an open beaker sunk in a dewar of liquid
N2, with irradiation directly from above.
(10) For review on Kolbe electrolysis, see: Scha¨fer, H. J. Angew. Chem.,
Int. Ed. Engl. 1981, 20, 911-934.
(6) For selected references on amino acid synthesis, see: (a) Williams,
R. M. In Organic Chemistry Series, Volume 7: Synthesis of Optically ActiVe
R-Amino Acids; Baldwin, J. E., Magnus, P. D., Eds.; Pergamon Press:
Oxford, 1989. (b) Burk, M. J.; Gross, M. F.; Martinez, J. P. J. Am. Chem.
Soc. 1995, 117, 9375-9376. (c) Myers, A. G.; Gleason, J. L.; Yoon, T.;
Kung, D. W. J. Am. Chem. Soc. 1997, 119, 656-673. (d) Petasis, N. A.;
Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445-446. (e) Ishitani, H.;
Komiyama, S.; Hasegawa, Y.; Kobayashi S. J. Am. Chem. Soc. 2000, 122,
762-766.
(11) Nutt, R. F.; Strachan, R. G.; Veber, D. F.; Holly, F. W. J. Org.
Chem. 1980, 45, 3078-3080.
(12) (a) Hiebl, J.; Kollmann, H.; Rovenszky, F.; Winkler, K. Bioorg.
Med. Chem. Lett. 1997, 7, 2963-2966. (b) Hiebl, J.; Blanka, M.; Guttman,
A.; Kollmann, H.; Leitner, K.; Mayrhofer, G.; Rovenszky, F.; Winkler, K.
Tetrahedron 1998, 54, 2059-2074.
(13) Boger, D. L.; Keim, H.; Oberhauser, B.; Schreiner, E. P.; Foster,
C. A. J. Am. Chem. Soc. 1999, 121, 6197-6205.
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Org. Lett., Vol. 5, No. 16, 2003

Figure 4. Syntheses of serine (16a) and homoserine (16b).
1.5:1 diastereomeric ratio. Lower yields in the photolysis
reaction are due to the formation of Boc-allylglycine (10)
as a byproduct (26-34%). To probe the possible effect of
the second chiral center in 9 on the stereochemical outcome
of the photolysis reaction, the corresponding syn-diastereomer
(-)-13 was synthesized starting from pyrrolidin-2-one
derivative 11.17 Photolysis of neat (-)-13 at -196 °C again
generates primarily the product showing retention of con-
figuration during coupling, (+)-14 (dr 5:1).
The photolysis is readily extended to amino acid peresters.
DCC-mediated coupling of protected aspartic or glutamic
acids with tert-butyl hydroperoxide provides the correspond-
ing peresters 15a,b in quantitative yields. Photolysis as before
forms the corresponding protected serine ((-)-16a, 54%
yield) and homoserine derivatives ((+)-16b, 89% yield). In
conclusion, photolysis of glutamate- or aspartate-derived
diacyl peroxides or peresters is a concise method for the
synthesis of functionalized optically pure amino acids,
including orthogonally protected bis(amino acids). These
C-C bond-forming reactions are safe, do not require
complex apparatus,9 and show surprising stereocontrol.
Current investigations on the scope and limitations of this
method as well as applications to synthesis of cyclic peptides
will be reported later.
Figure 3. Syntheses of (2S,4R)-5-propyl-L-leucine (9) and its
isomer 14.
Figure 3), a component of HUN-7293 (a potent inhibitor of
vascular cell adhesion molecule 1 (VCAM-1) exhibiting anti-
inflammatory properties).14 Conversion of Boc-Glu-OBzl-
(OH) (6) into its R-methyl ester and subsequent alkylation
with LiHMDS/MeI gives the anti-isomer 7 of â-methyl-
glutamate.15 Hydrogenolysis and treatment with pervaleric
acid16/DCC affords diacyl peroxide (+)-8. Photolysis of neat
8 at -85 °C produces (-)-9 in 53% yield along with its
(4S)-isomer in 4.3:1 diastereomeric ratio.
The retention of configuration at C4 in the photolysis
reaction is confirmed by comparison (1H NMR in C6D6) of
(-)-9 with its syn-diastereomer ((4R)-5-propyl-D-leucine, the
enantiomer of (+)-14), synthesized by an approach closely
related to that of Boger and co-workers.13 The diastereomeric
ratio in the photolysis reaction can be improved to 5.1:1 at
-196 °C (50% yield of 9). In contrast, photolysis of neat 8
at 20 °C in open atmosphere gives 30% yield of 9 with a
Acknowledgment. Financial support from Boehringer
Ingelheim Canada, the Natural Sciences and Engineering
Research Council of Canada (NSERC), and the Canada
Research Chair in Bioorganic and Medicinal Chemistry is
gratefully acknowledged.
Supporting Information Available: Typical experimen-
tal procedures and spectroscopic data of diacyl peroxides
and photolysis products. This material is available free of
charge via the Internet at http://pubs.acs.org.
(14) Foster, C. A.; Dreyfuss, M.; Mandak, B.; Meingassner, J. G.;
Naegeli, H. U.; Nussbaumer, A.; Oberer, L.; Scheel, G.; Swoboda, E.-M.
J. Dermatol. 1994, 21, 847-854.
(15) Hanessian, S.; Margarita, R. Tetrahedron Lett. 1998, 39, 5887-
5890.
OL035125Y
(16) Effkemann, S.; Pinkernell, U.; Neumu¨ller, R.; Schwan, F.; Engel-
hardt, H.; Karst, U. Anal. Chem. 1998, 70, 3857-3862.
(17) Gu, Z.-Q.; Lin, X.-F.; Hesson, D. P. Bioorg. Med. Chem. Lett. 1995,
5, 1973-1976.
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