Solid-phase intermolecular radical reactions 2: Synthesis of C-glycopeptide mimetics via a novel acrylate acceptor

Article abstract of DOI:10.1021/ol025846h

A novel tetrafluorophenol-linked acrylate is reported as an activated acceptor for intermolecular radical reactions. Addition of alkyl radicals led to pure products in good yields. We include here the first syntheses of C1- and C6-linked glycosides using

Full text of DOI:10.1021/ol025846h

ORGANIC
LETTERS
2002
Vol. 4, No. 10
1775-1777
Solid-Phase Intermolecular Radical
Reactions 2: Synthesis of
C-Glycopeptide Mimetics via a Novel
Acrylate Acceptor
Stephen Caddick,* Daniel Hamza, Sjoerd N. Wadman,† and Jonathan D. Wilden
Centre for Biomolecular Design and Drug DeVelopment, The Chemistry Laboratory,
UniVersity of Sussex, Falmer, Brighton, BN1 9QJ, UK
s.caddick@sussex.ac.uk
Received March 8, 2002
ABSTRACT
A novel tetrafluorophenol-linked acrylate is reported as an activated acceptor for intermolecular radical reactions. Addition of alkyl radicals
led to pure products in good yields. We include here the first syntheses of C1- and C6-linked glycosides using a solid-phase radical methodology.
The field of solid-phase organic synthesis has recently seen
the advent of a new class of reactions, namely, radical
chain processes. The merits of free radical chemistry long
evident in solution1 are now being applied in conjunction
with solid-phase technology to provide a wide range of both
intermolecular2-4 and intramolecular5 solid-phase radical
transformations. Our interests center on the particular
advantages offered by intermolecular radical reactions. In
the field of solution-phase radical chemistry, such transfor-
mations have traditionally relied upon chain conditions,
thereby maintaining a low concentration of radicals. This
position is tenable when the synthetically important bond-
forming processes are faster than any other step in the chain
process, and in the intramolecular mode, these conditions
are usually met.
However, in the case of intermolecular radical reactions,
more care needs to be taken to avoid unwanted side-reactions.
This can often limit both the scope of transformations
possible and the attainable yields. We have been keen to
address these issues using a solid-phase methodology and
reason that with an appropriately designed system, side-
reactions occurring in solution will not compromise the yield
or purity of the desired transformation on resin.
* Corresponding author.
† Current Address: High Throughput Chemistry, GlaxoSmithKline,
Stevenage, Herts, SG1 2NY, UK.
(1) Motherwell, W. B.; Crich, D. Free Radical Chain Reactions in
Organic Synthesis: Academic Press: New York, 1991. Giese, B. Radicals
in Organic Synthesis: Formation of Carbon-Carbon Bonds; Pergamon
Press: Oxford, 1986. Curran, D. P. Synthesis 1988, 419, 489.
(2) Sibi, M.; Chandramouli, S. V. Tetrahedron Lett. 1997, 38, 8929.
Miaybe, H.; Fujishma, Y.; Naito, T. J. Org. Chem. 1999, 64, 2174.
(3) Ganesan, A.; Zhu, X. W. J. Comb. Chem. 1999, 1, 157.
(4) Enholm, E. J.; Gallagher, M. E.; Jiang, S. J.; Batson, W. A. Org.
Lett. 2000, 2, 3355.
Following the success of our work on the addition of
sulfonyl radicals to unactivated acceptors,6 we have concen-
trated on the use of an activated acceptor for the addition of
carbon-centered radicals. We were particularly interested in
(5) Routledge, A.; Abell, C.; Balasubramanian, S. Synlett, 1997, 61. Du,
X. H.; Armstrong, R. W. J. Org. Chem. 1997, 62, 5678.
(6) Caddick, S.; Hamza, D.; Wadman, S. N. Tetrahedron Lett. 1999,
40, 7285-7288
10.1021/ol025846h CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/24/2002

applying our methodology toward the synthesis of C-
glycosides and C-glycopeptides. This field is currently
expanding with a number of C-linked glycopeptide libraries
appearing in the recent literature.7-9 The choice of linker
was governed by our desire to lessen the reactivity differential
between primary, secondary, and tertiary carbon-centered
radical additions while also developing a generic method for
the synthesis of certain classes of C-linked glycopeptides.
Others have shown how Wang acrylate can be utilized as
an acceptor in radical additions.3 However, it is interesting
to note that these additions were not reported using tributyltin
hydride and AIBN (although Enholm et al. have reported
free-radical allyl transfers using allyl tributyltin on soluble
non-cross-linked resins4). Others have reported difficulties
when using the more conventional conditions with activated
acceptors on solid supports.10 There are also problems
associated with using Wang acrylate when the addition does
not proceed to completion since acrylic acid is not released
cleanly from the resin under conditions required for product
cleavage.
We decided to use the tetrafluorophenol linker 3 to address
these problems for a variety of reasons. First, the acrylate
acceptor is expected to have enhanced activity over a
conventional acrylate ester due to the strong electron-
withdrawing effects of the fluoro-aromatic moiety. Second,
we anticipate that the release of products into solution by a
range of nucleophiles would provide an extra point of product
diversity and can be exploited in a combinatorial library as
shown recently.11 The corollary of this is that an array of
saturated amides can be synthesized by radical addition and
subsequent nucleophilic amine cleavage. Finally, since the
cleavage reaction is responsible for introducing the product
diversity essential for library generation, the radical addition
need only be carried out upon a single acceptor, reducing
the requirement for method development.
Loading for the phenol was assessed by acetylation (excess
acetic anhydride/Et3N, DCM, 16 h) and cleavage (4-methyl-
benzylamine, 2 equiv, DCM, 16 h); subsequent loadings and
yields quoted are based on this calculation. Formation of
acrylate ester 3 was carried out in DMF by sequential
addition of acrylic acid, DMAP, and DIC.
We began by examining the addition of simple alkyl
radicals to acceptor 3 (Scheme 1, Table 1).
Table 1
entry
R-X
R-NH2
product yield %a
1
2
3
4
5
6
7
8
9
t-butyl iodide
n-butyl iodide
isopropyl iodide
cyclohexyl iodide
phenethyl iodide
4-Me-BnNH2
4-Me-BnNH2
4-Me-BnNH2
4-Me-BnNH2
4-Me-BnNH2
4a
4b
4c
4d
4e
4f
4gb
4h b
4ib
4jb
4k b
4lb
98
79
99
78
68
68
53
44
57
21
16
37
cyclopentyl iodide 4-Me-BnNH2
5
5
5
5
5
6
4-Me-BnNH2
PheOEt
TrpOMe
TyrOMe
SerOMe
PheOEt
10
11
12
a Isolated yields. b Column chromatography was required for analytical
purity.
These reactions proceeded smoothly on resin with yields
as quoted in Table 1 based on the loading of 3. In the case
of entries 1-6, product purification was limited to removal
of excess amine either by washing the organic phase with 2
M HCl or filtration of the solution through an SCX solid-
phase extraction cartridge. These results demonstrate the
reactivity of acrylate acceptor 3 as well as the advantages
of the solid-phase approach, with good to excellent yields
reported for tertiary, secondary, and primary radicals (4a-
f).12
The next stage of our research saw the application of this
technology to the synthesis of C-linked glycosides. Radical
addition of 6-iodo-1,2:3,4-O-diisopropylidene-R-l-fucopy-
ranose 5 to acceptor 3 followed by cleavage with a selection
of amines, including amino acid derivatives, afforded
products 4g-l in moderate yields as shown in Scheme 2
and Table 1 (entries 7-12).
Since we began this work, synthesis of the tetrafluorophe-
nol linker 2 has been reported11 and some of our methodology
has been adapted accordingly. Aminomethyl-polystyrene
resin 1 was coupled to 2,3,5,6-tetrafluoro-4-hydroxy-benzoic
acid under standard conditions as shown below (Scheme 1).
Scheme 1a
The synthesis of C-linked glycosides via solid-phase
radical methodology has not, to our knowledge, been
(7) Arya, P.; Kutterer, K. M. K.; Barkley, A. J. Comb. Chem. 2000, 2,
120-126.
(8) Eniade, A.; Murphy, A. V.; Landreau, G.; Ben, R. N. Bioconjugate
Chem. 2001, 12, 817-823.
(9) Peri, F.; Cipolla, L.; Rescigno, M.; La Ferla, B.; Nicotra, F.
Bioconjugate Chem. 2001, 12, 325-328.
(10) Yim, A.-M.; Vidal, Y.; Viallefont, P.; Martinez, J. Tetrahedron Lett.
1999, 40, 4535.
(11) Salvino, J. M.; Kumar, N. V.; Orton, E.; Airey, J.; Kiesow, T.;
Crawford, K.; Mathew, R.; Krolikowski, P.; Drew, M.; Engers, D.;
Krolikowski, D.; Herpin, T.; Gardyan, M.; McGeehan, G.; Labaudiniere,
R. J. Comb. Chem. 2000, 691-697.
(12) For a discussion on the effects of substituents on the rates and yields
of tin-mediated radical additions to various electron-deficient alkenes, see:
Giese, B. Angew. Chem., Int. Ed. Engl. 1983, 22, 753-764; 1985, 24, 553-
565.
a Reaction conditions: (a) 3.5 equiv of 2,3,5,6-tetrafluoro-4-
hydroxy-benzoic acid, 3.5 equiv of EDC, 7 equiv of DIPEA, DCM,
16 h; repeat using 2/3 of the amount of (b) 5 equiv of acrylic acid,
5 equiv of DIC, 0.2 equiv of DMAP, DMF; (c) 5 equiv of RI, 5
equiv of Bu3SnH, 1 equiv of AIBN, toluene, 100 °C, 1.5 h; (d) 3
equiv of R′NH2, DCM, 16 h.
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Org. Lett., Vol. 4, No. 10, 2002

Scheme 2a
Scheme 3a
a Reaction conditions: (a) 5.0 equiv of 6, 5.0 equiv of Bu3SnH,
1.0 equiv of AIBN, toluene, 100 °C, 2 h; (b) 2.0 equiv of
RNH2‚HCl, 2.0 equiv of Et3N, CH2Cl2, 16 h.
a Reaction conditions: (a) 5.0 equiv of 5, 5.0 equiv of Bu3SnH,
1.0 equiv of AIBN, PhMe, 100 °C, 2 h; (b) 2.0 equiv of RNH2‚HCl,
2.0 equiv of Et3N, CH2Cl2, 16 h.
intermolecular radical additions. Despite the low yields in
some cases, this work represents, to our knowledge, the first
successful synthesis of C-glycosides on a solid phase using
a free-radical methodology. We have recently demonstrated
that the analogous, solution-phase, pentafluorophenol esters
are surprisingly stable species and may be isolated and
characterized. We are therefore pursuing a complementary
solution-phase approach to our methodology and also plan
to extend the solid-phase approach to the synthesis of
glycopeptide libraries.
previously reported, and despite the relatively low yields of
entries 10 and 11, the examples outlined in Table 1 represent
a novel means of accessing a range of interesting C-linked
glycopeptide mimetics.
Radical chemistry has classically been used in the forma-
tion of C-linked glycosides at the anomeric center.13 We were
interested in extending our methodology to this important
area.
The addition of 2,3,4,6-tetra-O-acetyl-R-D-glucopyranosyl
bromide to resin-bound acceptor 3 followed by cleavage with
phenylalanine ethyl ester afforded the desired C-linked
glycopeptide 4k in 37% isolated yield (Scheme 3). Numerous
attempts were made to improve the yields of entries 10-12.
We believe that the low yields in these cases may be
attributed to poor recovery of the reaction products from the
resin. It may be the case that the high steric demand of the
product does not easily allow free diffusion of the molecule
out of the resin matrix.
Acknowledgment. We thank the EPSRC and Glaxo-
SmithKline for generous financial support of this work. We
also thank the Association for International Cancer Research,
BBSRC, Novartis, and AstraZeneca for the support of our
program and the University of Sussex for providing funds
to establish the Centre for Biomolecular Design and Drug
Development. We also gratefully acknowledge the contribu-
tions of Dr. Tony Avent, Dr. Ali Abdul-Sada, and the EPSRC
Mass Spectroscopy Service at Swansea.
In conclusion, we have developed a novel activated
acrylate linker and successfully performed a range of
Supporting Information Available: Full characterization
data for the cleaved products. This material is available free
of charge via the Internet at http://pubs.acs.org.
(13) Keck, G. E.; Enholm, E. J.; Kachensky, D. F. Tetrahedron Lett.
1984, 25, 1867.
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