A fluorous-tagged linker from which small molecules are released by ring-closing metathesis

Article abstract of DOI:10.1021/jo7026273

(Chemical Equation Presented) A fluorous-tagged linker for the parallel synthesis of small- and medium-ring and macrocyclic nitrogen heterocycles using ring-closing metathesis is described. The linker was designed such that "cyclization-release" of the cyclic heterocyclic products was coupled with liberation of the active catalyst. The design of the linker was validated using a non-fluorous-tagged model. A wide range of unsaturated alcohols were used as reagents to functionalize afluorous-tagged sulfonamide, (Z)-{N-[4-(2-(N′-3,3,4,4,5,5,6,6,7,7,8,8,9,9,-10,10,10- heptadecafluorodecyl)-4-methylsulfonamido)methylallyloxy]but-2-enyl} -2-nitrobenzene-sulfonamide, using Fukuyama-Mitsunobu reactions; in each case, fluorous-solid-phase extraction (F-SPE) was used to purify the functionalized linker from the excess reagents. In general, the "cyclization-release" of cyclic products was triggered using a light-fluorous tagged derivative of the Grubbs-Hoveyda second-generation catalyst. After the metathesis step, F-SPE was used to purify released cyclic compounds from the fluorous-tagged linker and the fluorous-tagged catalyst. The scope and limitations of the approach were determined using a range of substrates which probed different aspects of the functionalization and metathesis steps. In the study as a whole, a wide range of small- and medium-ring and macrocyclic nitrogen heterocycles were prepared using polyene and polyenyne metathesis cascades.

Full text of DOI:10.1021/jo7026273

A Fluorous-Tagged Linker from Which Small Molecules Are
Released by Ring-Closing Metathesis
Stuart G. Leach, Christopher J. Cordier, Daniel Morton, Gordon J. McKiernan,
Stuart Warriner, and Adam Nelson*
School of Chemistry and Astbury Centre for Structural Molecular Biology, UniVersity of Leeds,
Leeds LS2 9JT, UK
a.s.nelson@leeds.ac.uk
ReceiVed December 18, 2007
A fluorous-tagged linker for the parallel synthesis of small- and medium-ring and macrocyclic nitrogen
heterocycles using ring-closing metathesis is described. The linker was designed such that “cyclization-
release” of the cyclic heterocyclic products was coupled with liberation of the active catalyst. The design
of the linker was validated using a non-fluorous-tagged model. A wide range of unsaturated alcohols
wereusedasreagentstofunctionalizeafluorous-taggedsulfonamide,(Z)-{N-[4-(2-(N′-3,3,4,4,5,5,6,6,7,7,8,8,9,9,-
10,10,10-heptadecafluorodecyl)-4-methylsulfonamido)methylallyloxy]but-2-enyl}-2-nitrobenzene-
sulfonamide, using Fukuyama-Mitsunobu reactions; in each case, fluorous-solid-phase extraction (F-
SPE) was used to purify the functionalized linker from the excess reagents. In general, the “cyclization-
release” of cyclic products was triggered using a light-fluorous tagged derivative of the Grubbs-Hoveyda
second-generation catalyst. After the metathesis step, F-SPE was used to purify released cyclic compounds
from the fluorous-tagged linker and the fluorous-tagged catalyst. The scope and limitations of the approach
were determined using a range of substrates which probed different aspects of the functionalization and
metathesis steps. In the study as a whole, a wide range of small- and medium-ring and macrocyclic
nitrogen heterocycles were prepared using polyene and polyenyne metathesis cascades.
Introduction
Ring-closing metathesis has revolutionalized the synthesis of
small- and medium-ring and macrocyclic compounds.1 Ruthe-
nium and molybdenum complexes have been developed as well-
defined catalysts and are widely used to catalyze ring-closing
metathesis reactions in organic synthesis.2 The functional group
tolerance of the ruthenium-based catalysts 1-3 (Figure 1) is
particularly remarkable, and these catalysts have been used
widely in the synthesis of highly functionalized products. Ring-
closing metathesis has been exploited as a key step in the
FIGURE 1. Some catalysts for alkene metathesis.
formation of an exceptional range of small- and medium ring
and macrocyclic natural products including callystatin,3 lauren-
cin,4 salicylihalamide A,5 migrastatin,6 and epothilone A.7
The removal of ruthenium residues from the products of many
metathesis reactions can often be problematic. A range of
* To whom correspondence should be addressed. Tel: +44 (0)113 343 6502.
Fax: +44 (0)113 343 6565.
(1) (a) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199-2238. (b)
Chattopadhyay, S. K.; Karmakar, S.; Biswas, T.; Majumdar, K. C.;
Rahaman, H.; Roy, B. Tetrahedron 2007, 63, 3919-3952. (c) Arisawa,
M.; Nishida, A.; Nakagawa, M. J. Organomet. Chem. 2006, 691, 5109-
5121. (d) Gradillas, A.; Pe´res-Castells, J. Angew. Chem., Int. Ed. 2006, 45,
6086-6101.
(2) (a) Grubbs, R. H. Handbook of metathesis; Wiley-VCH: Weinheim,
Germany, 2003. (b) Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012-
3043.(c) Furstner, A. Alkene metathesis in organic synthesis; Springer: New
York, 1998. (d) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A.
H. J. Am. Chem. Soc. 2000, 122, 8168-8179.
10.1021/jo7026273 CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/08/2008
J. Org. Chem. 2008, 73, 2753-2759
2753

Leach et al.
SCHEME 1. Design of a Fluorous-Tagged Linker for the “Cyclization-Release” of Cyclic Molecules Prepared by Ring-Closing
Metathesis
protocols have been developed to allow metathesis catalysts to
be scavenged.8 A polar isocyanide has been used to deactivate
and facilitate the purification of metathesis products.9 In
addition, metathesis catalysts have been developed which are
polymer- or ionic liquid-supported,10 or functionalized with a
heavy or light fluorous tag.11
In this paper, we describe the design and development of a
fluorous-tagged linker for the parallel synthesis of cyclic small
molecules using ring-closing metathesis as the key step. We
also demonstrate that the linker may be used to prepare
structurally diverse examples of nitrogen heterocycles, a class
of molecules with highly varied biological function. The design
features of the linker, 4, are summarized in Scheme 1. The
toluenesulfonyl group was incorporated to allow easy HPLC
analysis after the functionalization step. The linker bears a
perfluorooctyl chain such that, after use of excess reagents in
the functionalization step, purification by fluorous-solid-phase
extraction (F-SPE) would be possible.12 The use of fluorous-
tagged substrates in array chemistry can be highly effective as
the products may be purified rapidly from excess reagents by
F-SPE, a procedure which can be performed in parallel.13 Thus,
it was envisaged that the linker 4 would be appended with
terminal alkene or alkyne substituent to yield a substrate (e.g.,
6) for a ring-closing metathesis cascade. In this paper, we
describe the use of Fukuyama-Mitsunobu reactions14 to prepare
the cyclization precursors.
Most importantly, however, the linker was designed with a
“cyclization-release”15 strategy in mind: crucially, this strategy
was expected to release only the required cyclic metathesis
products from the fluorous tag. Furthermore, to facilitate removal
of the metathesis catalyst from the required product, we planned
to use a fluorous-tagged catalyst such as f-3 (Figure 2).11a
Initiation of each metathesis cascade was expected to occur at
the terminal alkene (e.g., f 7).16 Ring-closing metathesis should
(3) (a) Crimmins, M. T.; King, B. W. J. Am. Chem. Soc. 1998, 120,
9084-9085.
(4) (a) Crimmins, M. T.; Emmitte, K. A. Org. Lett. 1999, 1, 2029-
2032. (b) Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999, 121,
5653-5660.
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Y.; Esser, L.; De Brabander, J. K. Angew. Chem., Int. Ed. 2000, 39, 4308-
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A.; Dierkes, T.; Thiel, O. R.; Blanda, G. Chem. Eur. J. 2001, 7, 5286-
5298. (e) Wu, Y.; Liao, X.; Wang, R.; Xie, X.-S.; De Brabander, J. K. J.
Am. Chem. Soc. 2002, 124, 3245-3253. (f) Smith, A. B., III; Zheng, J.
Tetrahedron 2002, 58, 6455-6471.
(6) Gaul, C.; Njardarson, J. T.; Danishefsky, S. J. J. Am. Chem. Soc.
2003, 125, 6042-6043. (b) Reymond, S.; Cossy, J. Eur. J. Org. Chem.
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Angew. Chem., Int. Ed. Engl. 1997, 36, 166-168.
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9069-9072.
(8) (a) Ahn, Y. M.; Yang, K.; Georg, G. I. Org. Lett. 2001, 3,1411-
1413. (b) Maynard, H. D.; Grubbs, R. H. Tetrahedron Lett. 1999, 40, 4137-
4140.
(13) Zhang, W.; Lu, Y.; Nagashima, T. J. Comb. Chem. 2005, 7, 893-
(9) Galan, B. R.; Kalbarczyk, K. P.; Szczepankiewicz, S.; Keister, J. B.;
Diver, S. T. Org. Lett. 2007, 9, 1203-1206.
897.
(14) (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995,
36, 6373-4. (b) Olsen, C. A.; Witt, M.; Hansen, S. H.; Jaroszewski, J. W.;
Franzyk, H. Tetrahedron 2005, 61, 6046-6055. (c) Rew, Y.; Goodman,
M. J. Org. Chem. 2002, 67, 8820-8826.
(15) Moriggi, J.-D.; Brown, L. J.; Castro, J. L.; Brown, R. C. D. Org.
Biol. Chem 2004, 2, 835-844.
(16) (a) Ulman, M.; Grubbs, R. H. Organometallics 1998, 17, 2484-
2489.(b) Wallace, D. J. Angew. Chem., Int. Ed. 2005, 44, 1912-1915.
(10) (a) Nguyen, S. T.; Trnka, T. M. In Handbook of Metathesis; Grubbs,
R. H., Ed.; Wiley-VCH: Weinheim, Germany, 2003; Vol. 1, pp 61-94.
(b) Harned, A. M.; Probst, D. A.; Hanson, P. R. In Handbook of Metathesis;
Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, Germany, 2003; Vol. 2, pp
361-402.
(11) (a) Matsugi, M.; Curran, D. P. J. Org. Chem. 2005, 70, 1636-
1642. (b) Yao, Q.; Zhang, Y. J. Am. Chem. Soc. 2004, 126, 74-75.
2754 J. Org. Chem., Vol. 73, No. 7, 2008

Fluorous-Tagged Linker for Ring-Closing Metathesis
SCHEME 2. Synthesis of a Model Linker To Validate the
“Cyclization-Release” Strategy
FIGURE 2. Fluorous-tagged derivative of Grubbs-Hoveyda second-
generation catalyst.
FIGURE 3. Definition of the fluorous-tagged substituent RF.
then release only cyclized products from the fluorous-tagged
linker (e.g., f 8 + 9). Previously, Brown has shown that the
efficiency of a solid-supported linker was greatly improved when
the active catalyst was released directly back into solution.15
Thus, we also designed the linker such that a subsequent ring-
closing metathesis reaction (f 10) would release the catalyti-
cally active methylene complex efficiently.
Immediately after the reaction, the required cyclic products
(e.g., 9) would be contaminated with the remnant of the
fluorous-tagged linker (10), the ruthenium-based catalyst, and
any unreacted substrates (such as 6 or even 4). It was envisaged
that a F-SPE would allow effective removal of the fluorous-
tagged components: the required product (e.g., 9) would then
be eluted in the organic fraction. The design of the linker should,
therefore, allow (a) the efficient synthesis of the metathesis
precursors (e.g., 6); (b) the “cyclization-release” of the required
cyclic metathesis products (e.g., 9); (c) the purification of the
required product from the remaining catalyst and the remnants
of the linker (10); and (d) our approach to be applied in the
parallel synthesis of libraries of cyclic small molecules.
facilitate its synthesis on a large scale. Alkylation of the alcohol
19 using the allylic bromide 12 gave the acrylate 20, which
was reduced to yield the corresponding alcohol 21. Reaction
of the alcohol 21 with the fluorous-tagged toluenesulfonamide
22, itself prepared by Fukuyama-Mitsunobu reaction, was
followed by deprotection to give the crystalline fluorous-tagged
alcohol 23. Finally, the alcohol 23 was converted into the
fluorous-tagged sulfonamide 4 (Scheme 3).
Results and Discussion
To validate the design of the fluorous-tagged linker 4, we
prepared the non-fluorous-tagged model 15 (Scheme 2). It was
expected that reactions of 15 would test two features of the linker
design: the “cyclization-release” of the required cyclic prod-
ucts, and the subsequent release of the active catalyst from the
fluorous-tagged linker. Hence, alkylation of the alcohol17 11
using the allylic bromide18 12 gave the acrylate 13 which was
reduced to yield the corresponding alcohol 14. Benzylation and
detritylation gave the alcohol 15.
The allylic alcohol 15 was functionalized using a Fukuyama-
Mitsunobu reaction to yield the sulfonamide 16. Treatment of
the triene 16 (2.1 mM in CH2Cl2) with 3 mol % Grubbs-
Hoveyda second generation catalyst 3 for 4 h at 45 °C triggered
the expected metathesis cascade, and the cyclic sulfonamide
18a was obtained in >98% yield. In addition, a second ring-
closing metathesis step yielded the required cyclic ether 17 in
83% yield, a process which must also release the active catalyst.
We next prepared the fluorous-tagged linker 4 which we had
designed for the parallel synthesis of small molecules using a
ring-closing metathesis reaction. Many of the intermediates in
the preparation of the linker 4 were crystalline, which would
The fluorous-tagged linker 4 was functionalized by Fuku-
yama-Mitsunobu reaction with the unsaturated alcohols 24a-l
(Table 1; see the Supporting Information for the synthesis of
novel substrates). A wide range of unsaturated substrates were
investigated: the allylic alcohols 24a,b (entries 1 and 2), the
homoallylic alcohols 24c,d (entries 3 and 4), the longer
unsaturated alcohols 24e,f (entries 5 and 6) and the propargylic
alcohols 24g-i (entries 7-9). In addition, the reactions of the
chiral cyclic alcohols 24j-l, each prepared from the corre-
sponding meso diol (see the Supporting Information), were also
studied (entries 10-12). In each case, the functionalized
fluorous-tagged product was purified by F-SPE alone, and its
1
purity was determined by analytical HPLC and 500 MHz H
NMR spectroscopy.
In general, the functionalization reactions proceeded ef-
ficiently within 1 h in THF with 4 equiv of the alcohol 24,
triphenylphosphine, and DEAD. The products of many Mit-
sunobu reactions19a are notoriously difficult to purify; however,
by using a fluorous-tagged substrate, the excess reagents were
efficiently removed in each case by F-SPE. The allylic alcohols
24b (entry 2, Table 1) and 24j-l (entries 10-12) underwent
(17) Herna´ndez, A.-I.; Balzarini, J.; Karlsson, A.; Camarasa, M.-J.; Pe´rez-
Pe´rez, M. J. J. Med. Chem, 2002, 45, 4254-4263.
(18) Villieras, J.; Rambaud, M. Org. Synth. 1988, 66, 220.
J. Org. Chem, Vol. 73, No. 7, 2008 2755

Leach et al.
SCHEME 3. Preparation of the Fluorous-Tagged Linker 4
for the “Cyclization-Release” of Cyclic Small Molecules
in Table 2. In each case, the purity of the metathesis substrate,
which had been purified by F-SPE alone, is specified. The
“cyclization-cleavage” of the metathesis substrates (ca. 1 mM
in CH2Cl2, 45 °C) was catalyzed by 3 mol % of the fluorous-
tagged second-generation Grubbs-Hoveyda catalyst f-3 (entries
1-8 and 10-13). The reactions were monitored by thin layer
chromatography, and additional 3 mol% portions of catalyst
were added as required. The crude reaction mixtures were
diluted with 80:20 methanol-water, the dichloromethane re-
moved by evaporation, and the remaining fluorophobic solutions
were loaded directly onto F-SPE cartridges. The modified
procedure avoided the formation of concentrated solutions of
the metathesis products and the catalyst f-3 prior to F-SPE
purification. Following F-SPE, the organic fractions were
analyzed by HPLC to give some insight into the efficiency of
the cyclization process. Where analytically pure products had
not been previously synthesized, the product of the metathesis
reaction was purified by column chromatography.
The ring-closing metatheses of the allylic and homoallylic
substrates, prepared from the allylic and homoallylic alcohols
24a-d, yielded the corresponding N-sulfonyl dihydropyrroles
18a,b and tetrahydropyridines 18c,d (entries 1-4, Table 2). In
these cases, HPLC analysis of the crude products after F-SPE
alone showed that the cyclization process, with release of the
products from the fluorous support, had proceeded efficiently.
In the synthesis of 18a, the fluorous-tagged dihydrofuran 10
was isolated from the fluorous fraction in 96% yield, demon-
strating that the linker had functioned as proposed in Scheme
1. Furthermore, our approach enabled the synthesis of medium-
ring and macrocyclic nitrogen heterocycles. The syntheses of
the medium-ring heterocycles, 18e and 18m, proceeded rather
efficiently (entries 5 and 13). Indeed, with the modified workup
procedure, the dimerization of 18e was not observed, and a
higher yield of product was obtained. The macrocyclization to
yield 18f was less efficient, though the required product was,
nonetheless, obtained in 24% yield (entry 6).
The metatheses of the propargylic substrates were more
problematic (entries 7-9, Table 2). The metatheses of the
substrates prepared from the propargylic alcohols 24g,h were
performed under an ethylene atmosphere,22 and rather poor
yields of the required products 18g,h were observed (entries
7-8). With the substrate derived from 24i (entry 9), the method
was more successful with second generation Grubbs-Hoveyda
catalyst 3: at the end of the reaction, the catalyst was effectively
removed using a water-soluble phosphine, P(CH2OH)3,8b and a
78% yield of the diene 18i was obtained.
clean SN2 (rather than SN2′) substitution; with the allylic
alcohols, 24j-l, clean inversion of configuration was observed.
However, a greater excess of the alcohols 24c,d (10 equiv) was
required to drive the functionalization step and, even under these
conditions, the product contained some (5-9%) of unfunction-
alized linker 4 (entries 3 and 4). Presumably, this observation
stemmed from the propensity of the homoallylic systems to
eliminate, reducing the efficiency of clean substitution.19 In
addition, we also noted the efficient functionalization of the
fluorous-tagged allylic alcohol 23 with the sulfonamide 25 (entry
13).
In preliminary experiments, concentration of the crude
products of some of the metathesis reactions prior to F-SPE,
was found to lead to dimerization.20 For example, the metathesis
substrate derived from 24e was metathesized (3 mol % f-3, CH2-
Cl2, 45 °C, 18 h), concentrated, and then purified by F-SPE
and flash chromatography: the required product 18e (18%) was
obtained along with an inseparable mixture (23%) of cyclic
dimers. Similarly, the metathesis of the substrate derived
from 24h was performed under an ethylene atmosphere and
yielded the required product 18h (30%) along with a dimer21
(11%).
The metathesis cascades of the substrates derived from 24j-l
gave the chiral heterocyclic products 18j-l (entries 10-11 and
12a).23 The enantiomerically enriched product 18j, whose two
(21) The structure of the dimeric product obtained after concentration
of the crude reaction mixture, and purification by F-SPE and column
chromatography is
In order to avoid the dimerization of some products, a
modified protocol was devised for use in subsequent experi-
ments. Our results using this modified protocol are summarized
(19) (a) Hughes, D. L. Org. React. 42, 375-376. (b) Dias, L. C.; Diaz,
G.; Ferriera, A. A.; Meira, P. R.R.; Ferreria, E. Synthesis 2003, 4, 603-
622. (c) Mulzer, J.; Angermann, A.; Schubert, B.; Seilz, C. J. Org. Chem.
1986, 51, 5294-5299.
(20) For examples of ring-expanding metathesis reactions, see: (a) Lee,
C. W.; Choi, T.-L.; Grubbs, R. H. J. Am. Chem. Soc. 2002, 124, 3224-
3225. (b) Zheng, X.; Jones, C. W; Weck M. J. Am. Chem. Soc. 2007, 129,
1105-12. (c) Zhang, W.; Moore, J. S; Angew. Chem., Int. Ed. 2006, 45,
4416-4439.
(22) For mechanistic study of the effect of ethylene on ring-closing enyne
metathesis, see: Lloyd-Jones, G. C.; Margue, R. G.; de Vries, J. G. Angew.
Chem., Int. Ed. 2005, 44, 7442-7447.
(23) For similar metathesis cascade reactions conducted in solution phase,
see: (a) Choi, T.-L.; R. H. Grubbs, Chem. Commun. 2001, 2648-2649.
(b) Dochnahl, M.; Schulz, S. R.; Blechert, S. Synlett 2007, 16, 2599-2601.
(c) Zuercher, W. J.; Hashimoto, M.; Grubbs, R. H J. Am. Chem. Soc. 1996,
118, 6634-6640.
2756 J. Org. Chem., Vol. 73, No. 7, 2008

Fluorous-Tagged Linker for Ring-Closing Metathesis
TABLE 1. Functionalization of the Fluorous-Tagged Linkers 4 and 23 (See Figure 3 for the Definition of the Fluorous-Tagged Substituent
RF)*
*Methods: A1: (i) linker 4 (0.025 M), alcohol 24 (4 equiv), DEAD (4 equiv), PPh3 (4 equiv), THF, 0 °C, 1 h; (ii) F-SPE; A2: (i) linker 4 (0.025 M),
alcohol 24 (10 equiv), DEAD (4 equiv), PPh3 (4 equiv), THF, 0 °C, 1 h; (ii) F-SPE; A3: (i) linker 23 (0.025 M), sulfonamide 23 (4 equiv), DEAD (4 equiv),
PPh3 (4 equiv), THF, 0 °C, 1 h; (ii) F-SPE; B: TBAF, THF; F-SPE. a Yield of product purified by F-SPE only. The purity of the compound is shown
in parentheses and was determined by analytical HPLC. b HPLC analysis revealed that the linker 4 was present (entry 3: 9%; entry 4: 5%). c Yield and
purity after method A1.
five-membered rings were formed in the cascade, was obtained
in >98% yield (entry 10, Table 2). The metathesis cascades of
the substrates derived from the cycloheptenols 24k,l resulted
in moderate yields of the products 18k,l (entries 11 and 12a).
The metathesis of the unsilylated substrate derived from
24l was slightly lower yielding than the silylated substrate and
gave the product 18l′ in 50% yield (compare entries 12a and
12b).
J. Org. Chem, Vol. 73, No. 7, 2008 2757

Leach et al.
TABLE 2. “Cyclization-Release” of Heterocyclic Products by Ring-Closing Metathesis (See Figure 3 for the Definition of the
Fluorous-Tagged Substituent RF)*
*Methods: C1: (i) substrate (ca. 1 mM), catalyst f-3, CH2Cl2, 45 °C; (ii) add 80:20 methanol-water then remove CH2Cl2 by evaporation; (iii) F-SPE;
C2: (i) substrate (ca. 1 mM), catalyst 3, CH2Cl2, 45 °C; (ii) Et3N (86 equiv), P(CH2OH)3 (86 equiv) then silica (iii) filter through a Celite pad; (iv) column
chromatography. a See Table 1 for the determination of the purity of the functionalized linkers. b Yield of product purified by F-SPE and column
chromatography. The numbers in parentheses are the percentage mass recovery and the purity, determined by analytical HPLC, after F-SPE alone. c The
products obtained after F-SPE were analyzed by HPLC after F-SPE and compared with analytically pure samples prepared separately. d The fluorous-
tagged metathesis product 10 was isolated in 96% yield. e The reaction was monitored by thin layer chromatography, and the catalyst was added in 3 mol
% portions as required. f The reaction was performed under an ethylene atmosphere. g With f-3, the organic fraction was noticably brown following F-SPE:
on concentration, the required product 18i was observed to decompose (TLC) and was obtained in 17% yield. h Not applicable.
2758 J. Org. Chem., Vol. 73, No. 7, 2008

Fluorous-Tagged Linker for Ring-Closing Metathesis
HPLC). The catalyst f-3 (1.5 mg, 3 mol %) was added to a stirred
solution of the metathesis precursor (56 mg, 0.053 mmol) in
dichloromethane (ca. 1 mM) at 45 °C and the reaction mixture
heated at 45 °C. Heating was continued until completion was
indicated by TLC. The reaction mixture was allowed to cool to
room temperature and 80:20 MeOH-H2O (equivalent volume to
the dichloromethane used) was added. The dichloromethane was
removed under reduced pressure to give the crude product, as a
solution in MeOH-H2O, which was purified by F-SPE to give
the crude bicycle 18j (18 mg, >98% by mass; 98% purity by
analytical HPLC) as a colorless oil: Rf 0.32 (50:50 petrol-EtOAc);
Conclusions
We have described the development of a novel fluorous-
tagged linker for application in the parallel synthesis of libraries
of cyclic small molecules using ring-closing metathesis. To
demonstrate its synthetic scope, the fluorous-tagged linker was
functionalized with a wide range of unsaturated alcohols using
the Fukuyama-Mitsunobu reaction; in each case, F-SPE was
used to purify the functionalized linker from the excess reagents.
The design of the linker was such that “cyclization-release”
of cyclic products, triggered using a light-fluorous tagged
derivative of the Grubbs-Hoveyda second-generation catalyst,
was coupled with the regeneration of the active catalyst. After
metathesis, F-SPE was used to separate the released cyclic
compounds from the fluorous-tagged linker and catalyst.
Our investigations have demonstrated the efficiency and
generality of a fluorous-tagged linker strategy in the synthesis
of heterocycles using ring-closing metathesis. The rapid syn-
thesis of a wide range of small- and medium-ring and macro-
cyclic heterocycles, and the facile purification steps involved,
provides a strong foundation for the synthesis of more complex
molecules using the same strategy. Indeed, the application of a
fluorous-tagged linker in the diversity-oriented synthesis of more
complex, natural product-like molecules will be described in
due course.
[R]20+12.4 (c 1.0, CHCl3); IR (film) 3087, 3021, 2912, 2852,
D
1
1585 and 1543; H NMR (300 MHz) 7.94-7.89 (1 H, m, H-3′′),
7.74-7.60 (3 H, m, H-4′′, H-5′′ and H-6′′), 5.97 (1 H, ddd, J 6.4,
4.4 and 2.1, H-4′), 5.87 (1 H, ddd, J 6.4, 3.6 and 1.5, H-4), 5.80 (1
H, ddd, J 6.4, 3.6, 2.3, H-3), 5.70 (1 H, ddd, J 6.4, 3.8 and 1.8,
H-3′), 5.02-4.93 (1 H, m, H-2), 4.97-4.78 (1 H, m, H-2′), 4.61-
4.56 (2 H, m, H-5), 4.32 (1 H, ddd, J 14.8, 4.4 and 2.3, H-5′A),
4.19 (1 H, app ddt, J 14.8, 5.1 and 2.1, H-5′B), 2.24 (1 H, dt, J
14.1 and 3.6, methylene HA) and 1.82 (1 H, dt, J 14.1 and 8.5); δC
(75 MHz, CDCl3) 133.9, 132.4, 132.0, 131.5, 130.3, 130.1, 126.8,
124.6, 123.7, 121.0 (C-3, C-4, C-3′, C-4′, Ar), 84.0 (C-2′), 75.3
(C-5′), 66.7 (C-2), 55.8 (C-5) and 42.8 (methylene); m/z (ES) 359.0
([M + Na]+, 52), 253.0 (100), 186.0 (79) (found [M + Na]+,
359.0684 C15H16N2O5S requires [M + Na]+, 359.0672).
Acknowledgment. We thank EPSRC and the Wellcome
Trust for funding and James Titchmarsh for HPLC analyses.
Experimental Section
Supporting Information Available: Details of all experimental
procedures including syntheses of the HPLC standards and the
cyclic unsaturated alcohols 24j,k, 1H NMR spectra and HPLC
(2R,2′R)-2-(2′,5′-Dihydrofuran-2′-ylmethyl)-1-(2′′-nitrobenze-
nesulfonyl)-2,5-dihydro-1H-pyrrole 18j. Diethyl azodicarboxylate
(37 µL, 0.234 mmol, 4 equiv) was added to a stirred solution of
the fluorous-tagged sulfonamide 4 (55 mg, 0.058 mmol), triph-
enylphosphine (61 mg, 0.234 mmol, 4 equiv) and the alcohol 24j
(33 mg, 0.234 mmol, 4 equiv) in THF (2 mL, 25 mM) at 0 °C.
The reaction mixture was allowed to warm to room temperature
and was stirred for 1 h. The solvent was removed under reduced
pressure to give a crude product which was purified by F-SPE to
give a crude product (58 mg, 94% by mass; 96% purity by analytical
chromatograms for the functionalized fluorous linkers, 1H and 13
C
NMR spectra of all purified compounds, HPLC chromatograms of
the heterocyclic compounds directly after F-SPE purification, and
1
500 MHz H NMR spectra and HPLC data acquired during the
synthesis of the heterocycle 18j from the alcohol 24j. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO7026273
J. Org. Chem, Vol. 73, No. 7, 2008 2759