A fluorous-tagged "safety catch" linker for preparing heterocycles by ring-closing metathesis

Article abstract of DOI:10.1021/ol802848j

A fluorous-tagged "safety catch" linker is described for the synthesis of heterocycles with use of ring-closing metathesis. The linker facilitiates the purification of metathesis substrates, the removal of the catalyst, the functionalization of the produc

Full text of DOI:10.1021/ol802848j

ORGANIC
LETTERS
2009
Vol. 11, No. 4
915-918
A Fluorous-Tagged “Safety Catch”
Linker for Preparing Heterocycles by
Ring-Closing Metathesis
Catherine O’Leary-Steele,† Christopher Cordier,† Jerome Hayes,‡
Stuart Warriner,† and Adam Nelson*,†
School of Chemistry and Astbury Centre for Structural Molecular Biology, UniVersity
of Leeds, Leeds, LS2 9JT, United Kingdom, and Chemical DeVelopment,
GlaxoSmithKline, Old Powder Mill, Leigh, Tonbridge,
Kent, TN11 9AN, United Kingdom
a.s.nelson@leeds.ac.uk
Received December 15, 2008
ABSTRACT
A fluorous-tagged “safety catch” linker is described for the synthesis of heterocycles with use of ring-closing metathesis. The linker facilitiates
the purification of metathesis substrates, the removal of the catalyst, the functionalization of the products, and the release of only metathesis
products. The synthesis of a range of heterocycles is described.
Ring-closing metathesis has revolutionalized organic syn-
thesis.1 Ruthenium complexes are particularly functional
group tolerant,2 but the catalyst residues often need to be
scavenged.3 Recently, we developed a fluorous-tagged linker
for synthesizing heterocycles by metathesis but a fluorous-
tagged catalyst was needed to allow easy product purifica-
tion.4 We now describe a fluorous-tagged “safety catch”5
linker that facilitates the synthesis, purification, and func-
tionalization of metathesis products without the use a
fluorous-tagged catalyst (Scheme 1). We use the term
“linker” to describe compounds (e.g., 1) which are func-
tionalized to yield metathesis substrates (e.g., 2).
It was envisaged that functionalization of 1 (f 2) would
be followed by removal of excess reagents by fluorous-solid
phase extraction6 (F-SPE). Initiation of a metathesis cascade
would be expected at the terminal alkene7 of 2 (f 3).
Cyclization (f 4) would be followed by a second ring-
closing metathesis (f 5) in which a catalytically active
methylene complex was regenerated.8 Crucially, the product
5 would still be fluorous-tagged; F-SPE would thus allow
† University of Leeds.
‡ GlaxoSmithKline.
(1) (a) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199. (b)
Chattopadhyay, S. K.; Karmakar, S.; Biswas, T.; Majumdar, K. C.;
Rahaman, H.; Roy, B. Tetrahedron 2007, 63, 3919. (c) Gradillas, A.; Pe´res-
Castells, J. Angew. Chem., Int. Ed. 2006, 45, 6086.
(2) Grubbs, R. H. Handbook of Metathesis, Wiley-VCH: Weinheim,
Germany, 2003.
(4) (a) Leach, S. G.; Cordier, C. J.; Morton, D.; McKiernan, G. J.;
Warriner, S.; Nelson, A. J. Org. Chem. 2008, 73, 2752. (b) Morton, D.;
Leach, S.; Cordier, C.; Warriner, S.; Nelson, A. Angew. Chem., Int. Ed.
2009, 48, 104.
(3) For example, see: (a) Ahn, Y. M.; Yang, K.; Georg, G. I. Org. Lett.
2001, 3, 1411. (b) Maynard, H. D.; Grubbs, R. H. Tetrahedron Lett. 1999,
40, 4137. (c) Galan, B. R.; Kalbarczyk, K. P.; Szczepankiewicz, S.; Keister,
J. B.; Diver, S. T. Org. Lett. 2007, 9, 1203. (d) Matsugi, M.; Curran, D. P.
J. Org. Chem. 2005, 70, 1636. (e) Yao, Q.; Zhang, Y. J. Am. Chem. Soc.
2004, 126, 74.
(5) Patek, M.; Lebl, M. Biopolymers 1999, 47, 353.
(6) Zhang, W.; Curran, D. P. Tetrahedron 2006, 62, 11837.
(7) (a) Ulman, M.; Grubbs, R. H. Organomet. 1998, 17, 2484. (b)
Wallace, D. J. Angew. Chem., Int. Ed. 2005, 44, 1912.
10.1021/ol802848j CCC: $40.75
Published on Web 01/27/2009
2009 American Chemical Society

Scheme 1
.
Design of the Fluorous-Tagged “Safety Catch”
Scheme 2.
Validation of the Design of the Linker 1a
Linker 1
a GII is Grubbs’s second generation catalyst.
linker 1. Finally, Fukuyama-Mitsunobu reaction with Ns-
BocNH, and deprotection, gave the fluorous-tagged sulfon-
amide 18.
Scheme 3
.
Preparation of the Fluorous-Tagged Linkers 1 and
18a
removal of the metathesis catalyst and removal of the excess
reagents in subsequent functionalization steps. Finally, acetal
cleavage would release only metathesis products (e.g., 6) (and
not unreacted substrates such as 2) from the fluorous tag.
The fluorous-tagged linker 1 was, therefore, designed to be
a “safety catch”5 linker since the cleavage step should release
only metathesis products.
To validate the design, we prepared the trienes 8 and 9
from a known glucose derivative (see the Supporting
Information). Treatment of 8 and 9 (4 mM in CH2Cl2) with
6 mol % Grubbs’s second generation catalyst gave the
expected metathesis products 10 and 11 (Scheme 2). Thus,
irrespective of the initiation site,7 the metathesis cascade
proceeded smoothly, cleaving the central dihyropyran ring.
The study validated the “safety catch” linker design since
hydrolysis of the resulting acyclic acetals would yield the
required dihydropyran products.
a For the definition of RF, see Scheme 1.
The linkers 1 and 18 were functionalized with a range of
reactants (see Figure 1, Table 1, and the Supporting Informa-
tion). Thus, the substrates were prepared by using the
Fukuyama-Mitsunobu reaction,10 allylation, silaketal forma-
tion,11 or esterification. In general, the fluorous-tagged
products were purified by F-SPE alone, and the purities were
determined by HPLC.
Scheme 3 describes the synthesis of the linkers 1 and 18.
Reaction of the anion of 12 with ethyl R-bromomethyl
acrylate,9 and reduction, gave the allylic alcohol 13. A
Fukuyama-Mitsunobu reaction10 between 13 and the sulf-
onamide4 14, and deprotection, gave the fluorous-tagged
The cascade reactions of a range of the metathesis
substrates were successful (Table 1). Six- and seven-
(9) Villieras, J.; Rambaud, M. Org. Synth. 1988, 66, 220.
(10) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995,
36, 6373.
(8) Moriggi, J.-D.; Brown, L. J.; Castro, J. L.; Brown, R. C. D. Org.
Biomol. Chem 2004, 2, 835.
(11) Cordier, C.; Morton, D.; Leach, S.; Woodhall, T.; O‘Leary-Steele,
C.; Warriner, S.; Nelson, A. Org. Biomol. Chem. 2008, 6, 1734.
916
Org. Lett., Vol. 11, No. 4, 2009

Table 1. Heterocycle Synthesis by Functionalization of the Linker, Metathesis, and Release (See Scheme 1 for the Definitions of RF
and R′F)
a Method A: reactant (4 equiv), PPh3 (4 equiv), DEAD (4 equiv), THF, rt then F-SPE. Method B: (i) Hoveyda-Grubbs second generation catalyst,
CH2Cl2, reflux; (ii) P(CH2OH)3, Et3N then silica; (iii) F-SPE. Method C: 3% TFA in CH2Cl2, rt then F-SPE. Method D: (i) NaH, THF, 0 °C; (ii) allyl
bromide, rt; (iii) MeOH then F-SPE; b See Scheme 1 for the definitions of RF and R′F. c Unless otherwise stated, isolated yield of product. d Mass of product
after F-SPE. e Purity (%) determined by HPLC after F-SPE. f 10 equiv of the sulfonamide, PPh3, and DEAD were used. g In the presence of an ethylene
atmosphere. h Not undertaken.
complex cascade reactions in which two new heterocyclic
rings were formed were also successful (entries 4 and 5).
Unlike with our previous linker,4 it was not possible to
prepare eight- or nine-membered heterocycles (see the
Supporting Information for the substrates studied); instead,
dimerization was competitive with cyclization and, hence,
release from the linker. Six metathesis products [26-31
(R ) H)] were released directly from the linker by
treatment of the correponding metathesis products with
3% TFA in CH2Cl2 (entries 1-6, Table 1).
The metathesis products could also be functionalized
before release from the fluorous tag (see Table 2 and Figure
2). In each case, the excess reagents were removed by
F-SPE only. Thus, removal of the o-nitrophenylsulfonyl
group from 26 (R ) R′F), derivatization, and release from
Figure 1. Reactants used to derivatize the linkers 1 and 18.
membered nitrogen and oxygen heterocycles were formed
in good to excellent yield. In the case of the terminal
alkyne substrate (entry 6), the reaction was performed
under an ethylene atmosphere,12 and a 53% yield of the
fluorous-tagged product 31 (R ) R′F) was obtained. More
(12) Lloyd-Jones, G. C.; Margue, R. G.; de Vries, J. G. Angew. Chem.,
Int. Ed. 2005, 44, 7442.
Org. Lett., Vol. 11, No. 4, 2009
917

Table 2. Functionalisation of the Metathesis Products and Release from the Fluorous Taga
starting
material
functionalization
methodb
mass recoveryc/%
(purityd/%)
cleavage
methodb
entry
purity/%
product
product
yielde/%
1
2
3
4
5
26 (R ) R′F)
26 (R ) R′F)
26 (R ) R′F)
29 (R ) R′F)
36 (R ) R′F)
94
94
>99
>99
87
A
C
E
D
A
33 (R ) R′F)
34 (R ) R′F)
35 (R ) R′F)
36 (R ) R′F)
37 (R ) R′F)
87 (>90)
B
B
B
B
B
33 (R ) H)
34 (R ) H)
35 (R ) H)
36 (R ) H)
37 (R ) H)
82
67f
57f
59
67
86 (87)
79 (>95)
a See Scheme 1 for the definition of R′F. b Method A: (i) PhSH, DBU, MeCN; (ii) BnNCO; (iii) F-SPE. Method B: (i) 3% TFA in CH2Cl2; (ii) F-SPE.
Method C: (i) PhSH, DBU, MeCN; (ii) Ac2O, pyridine; (iii) F-SPE. Method D: (i) 4-phenyl-[1,2,4]-triazole-3,5-dione, CH2Cl2; (ii) F-SPE. Method E: (i)
PhSH, DBU, MeCN; (ii) DMAP and isoxazole-5-carbonyl chloride; (iii) F-SPE. c Mass of product after F-SPE only. d Purity (%) determined by HPLC after
F-SPE only. e Isolated yield of purified product. f Isolated yield of product over 2 steps.
the fluorous tag yielded the tetrahydropyridines 33 (R )
H), 34 (R ) H), and 35 (R ) H) (entries 1-3).
Alternatively, the diene 29 (R ) R′F) underwent efficient
Diels-Alder reaction with 4-phenyl-[1,2,4]-triazole-3,5-
dione to yield 36 (R ) R′F): the resulting adduct could
either be released directly from the fluorous tag [f 36
(R ) H), entry 4] or after deprotection and derivatization
[f 37 (R ) H), entry 5].
In summary, we have developed a linker for the synthesis
of arrays of heterocylic products using metathesis cascade
reactions. The design of the fluorous-tagged linker allowed
(a) easy purification of metathesis substrates; (b) easy
removal of the catalyst from the metathesis products; (c)
functionalization of the products before release; and (d) the
release of only metathesis products.
Acknowledgment. We thank the Wellcome Trust,
EPSRC, Leeds University and GSK for funding, and Stuart
Leach and Daniel Morton (University of Leeds) for
discussions.
Supporting Information Available: Details of all ex-
perimental procedures, including unsuccessful metathesis
substrates, and NMR spectra for all novel compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 2. Derivatized metathesis products after release from the
fluorous tag, R ) H.
OL802848J
918
Org. Lett., Vol. 11, No. 4, 2009