Synthesis of arrays using low molecular weight MPEG-assisted mitsunobu reaction

Article abstract of DOI:10.1021/co100091n

Triphenylphosphine tagged with a short poly(ethyleneglycol)-ω- monomethyl ether chain (light MPEG, 10-16 ethylenoxy units, ^MTPP-G2) and an MPEG-tagged version of diethyl azodicarboxylate (^MDEAD) have been used to prepare a 20 member library of esters, ethers, and sulfonamides, with cLogP?s in the range of 1.4-5.7 on a 0.1 mmol scale. Removal of MPEG-tagged side products was achieved by MPEG-assisted solid-phase extraction (MSPE) on prepacked silica columns to give the products in good yield and high purity.

Full text of DOI:10.1021/co100091n

RESEARCH ARTICLE
pubs.acs.org/acscombsci
Synthesis of Arrays Using Low Molecular Weight MPEG-Assisted
Mitsunobu Reaction
Marek Figlus,† Natalie Wellaway,‡ Anthony W. J. Cooper,‡ Steven L. Sollis,‡ and Richard C. Hartley*,†
†WestCHEM Department of Chemistry, University of Glasgow, Glasgow, G12 8QQ, United Kingdom
‡GSK Medicines Centre, Gunnels Wood Rd, Stevenage, SG1 2NY, United Kingdom
S Supporting Information
b
ABSTRACT: Triphenylphosphine tagged with a short poly-
(ethyleneglycol)-ω-monomethyl ether chain (light MPEG,
10ꢀ16 ethylenoxy units, MTPP-G2) and an MPEG-tagged
version of diethyl azodicarboxylate (MDEAD) have been used
to prepare a 20 member library of esters, ethers, and sulfona-
mides, with cLogP’s in the range of 1.4ꢀ5.7 on a 0.1 mmol scale.
Removal of MPEG-tagged side products was achieved by
MPEG-assisted solid-phase extraction (MSPE) on prepacked
silica columns to give the products in good yield and high purity.
KEYWORDS: triphenylphosphine, Mitsunobu reaction, cLogP, solid-phase extraction
’ INTRODUCTION
together as they are required to react with each other to form an
intermediate analogous to betaine 4 (Scheme 2). Of course, a
solid-supported phosphine can be combined with an azadicarbox-
ylate removed by another method to avoid chromatography,3,4 or
vice versa,5 but this requires additional manipulation. The hetero-
geneous nature of reactions can also be an issue as intrinsic
reactivity of the supported reagent6,7 in a given solvent depends
on the nature of the polymer, the size of its cavities, bead size/
shape and loading, and there can be mixing problems and
mechanical damage to resins. In a direct comparison between
solid-supported TPP (2.1 mmol gꢀ1, 1% cross-linked diphenyl-
phosphinopolystyrene) and TPP itself in the bromination of 2,4-
dimethoxybenzyl alcohol using carbon tetrabromide, it was found
that while the initial rate of reaction was similar, the overall con-
version was lower for solid-supported TPP, presumably because
not all the phosphine groups were accessible.8 Variability in the
behavior of different batches of the same solid-supported reagents
has also been noted as a problem,7 and this is a particular issue
because the chemical purity of solid-supported reagents are not
easily checked.
To overcome these difficulties, reagents that allow homoge-
neous reaction in solution and have properties that assist removal
have been investigated.1 Di-2-methoxyethyl azodicarboxylate has
been introduced as a water-soluble reagent9 and di-tert-butyl
azodicarboxylate decomposes in aqueous acid into gaseous prod-
ucts.10 Removal of the phosphine is more problematic: phos-
phines derived from pyridine or N,N-dimethylaniline can be
washed away with aqueous acid after reaction,11 but this process
is less useful in drug discovery where many compounds contain a
basic nitrogen atom. Alternatively, a precipitation tag can be
The Mitsunobu reaction is one of the most common ways of
making a carbon-heteroatom bond in synthetic organic chem-
istry and is widely used in drug discovery.1 Generally, a combina-
tion of triphenylphosphine (TPP) and diethyl azodicarboxylate
(DEAD) is used to convert an alcohol 1 and a weak acid 2 into a
substitution product 3, triphenylphosphine oxide (TPPO) and
dicarboethoxyhydrazine (DCEH, Scheme 1). The mechanism
involves TPP and DEAD combining to give the betaine inter-
mediate 4 (Scheme 2). Reaction between betaine 4, the weak
acid 2 and the alcohol 1 generates DCEH and the alkoxypho-
sphonium salt 5. The nucleophilic anion of this salt then displaces
the TPPO leaving group by a concerted mechanism to give the
substitution product 3. A range of phosphines and azodicarbox-
ylates can be used, and tributylphosphine and di-isopropylazo-
dicarboxylate (DIAD) are common alternatives to TPP and
DEAD. The weak acid employed generally has a pKa between 2
and 11, though there are examples of even weaker acids being
successful, and can have O, N, S or C as the nucleophilic atom. The
range of nucleophilies, the mild, near neutral reaction conditions,
and the stereochemical control makes the Mitsunobu reaction an
attractive synthetic method. However, purification of products
after Mitsunobu reactions can be problematic, the TPPO and
DCEH produced by the reaction are often difficult to remove
from the desired product by chromatography, and there are
potentially traces of four starting materials in the crude mixture.
There have been many attempts to overcome the purification
problems associated with TPP, TPPO, DEAD, and DCEH, and
these have been reviewed comprehensively.1 The most popular
approach is to use a solid-supported phosphine or azodicarbox-
ylate, which can be removed after reaction by simple filtration, in
polymer-assisted solution-phase synthesis.2 The most obvious
problem is that two solid-supported reagents cannot be used
Received: December 20, 2010
Revised:
March 11, 2011
Published: March 25, 2011
r
2011 American Chemical Society
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RESEARCH ARTICLE
Scheme 1. Mitsunobu Reaction
Figure 1
Scheme 2. General Mechanism of Mitsunobu Reaction
Figure 2. MPEG interactions with silica.
Figure 3. MPEG-tagged reagents for the Mitsunobu reaction.
used, so that the phosphine and phosphine oxide are precipitated
upon switching to a nonpolar solvent such as diethyl ether, and
are then removed by filtration.12ꢀ15 However, coprecipitation of
polar compounds can also occur. Very recently, Mitsunobu reac-
tions in solution followed by a ring-opening metathesis reaction to
scavenge the spent reagents onto a solid support has been reported.16
Fluorous technology, in which a perfluoroalkyl group acts as a
“phase tag” assisting purification, is now very widely employed in
solution-phase synthesis.17,18 Fluorous DEAD and fluorous TPP
have been used in the Mitsunobu reaction and these, together
with the fluorous DCEH and TPPO arising from them, are con-
veniently removed by solid-phase extraction on fluorous silica
gel (silica gel with a fluorocarbon bonded phase) eluting with
methanolꢀwater.19 The use of two tagged reagents together and
the simplicity of the purification procedure make this an attrac-
tive approach. The main problem is cost. Fluorous silica retails at
about 15 times the price of ordinary silica,20 and the fluorous tags
themselves are also expensive.
Recently, we introduced light-MPEG-assisted organic synthe-
sis (MPAOS) where reagents tagged with low molecular weight or
“light” poly(ethyleneglycol)-ω-monomethyl ether (MPEGꢀOH,
8ꢀ19 ethylenoxy units, average MW 550) are used in homo-
geneous solution-phase reactions before being removed by solid-
phase extraction on normal silica (MSPE) eluting with DCM or
EtOAc to give pure products (Figure 1).21 The MPEG-tagged
reagents and biproducts remain attached to silica in the aprotic
solvents, ethyl acetate and dichloromethane,21,22 as MPEG has
multiple hydrogen-bond acceptor sites that interact with mul-
tiple hydrogen-bond donors on the surface of the silica, but
no hydrogen-bond donor sites to interact with aprotic solvents
(Figure 2). In addition to the cost-saving of using normal silica,
MPEGꢀOH is inexpensive even when purchased from a
standard supplier of laboratory fine chemicals ($0.15 per mmol)
and is prepared industrially from ethylene oxide on a very large
scale for cosmetics and household uses (Carbowax). MPAOS
does not rely on precipitation in nonpolar solvents with the
danger of coprecipitation of polar compounds; indeed, the
reagents are soluble in a wide range of solvents including
nonpolar solvents like diethyl ether and tert-butyl methyl ether.
Unlike batches of solid-supported reagents, the chemical purity
of the MPEG-tagged compounds is easily checked by 1H NMR
spectroscopy using the methyl signal of the MPEG as an internal
reference (δ 3.4), so potential failed arrays resulting from
defective reagent are avoided.
Among the reagents we reported were MPEG-tagged TPP
(MTPP, Figure 3) and MPEG-tagged DEAD (MDEAD, Figure 3)
and we demonstrated that they could be used together in
Mitsunobu reactions to give esters 6-8 in high yields and high
purity following MSPE, and a wash with base in the case of ester 8
(Scheme 3).21 MSPE was conducted using 10 g of silica for every
1 g of solvent-free unpurified material and eluting the product with
EtOAc, leaving MPEG-tagged materials on the column. We now
report the adaptation of this chemistry for the synthesis of arrays.
’ RESULTS AND DISCUSSION
The first stage in adapting the chemistry for array synthesis was to
optimize the routes to the MPEG-tagged reagents for larger scale
synthesis. Originally, MTPP had been prepared by reacting
MPEGꢀOH 9 with excess R,R0-dibromo-p-xylene and then react-
ing the benzylic bromide 10 with the phenoxide derived from a
phenolic analogue 11 of TPP, prepared by our adaptation21 of the
literature method13 (Scheme 4). Thus, an extra xylyl unit was in-
cluded, which effectively decreased the loading. We have now found
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RESEARCH ARTICLE
Scheme 3. MPEG-Assisted Mitsunobu Reaction
Scheme 5. Synthesis of MTPP-G2
Scheme 4. Synthesis of MTPP
Scheme 6. Synthesis of MDEAD
that a more scalable alternative is to make a compact second genera-
tion MPEG-tagged TPP (TPP-G2)23 by converting MPEGꢀOH 9
into MPEG-I 12 and displacing the iodide (Scheme 5).
MDEAD had originally been prepared by converting MPEGꢀ
OH 9 into the chloroformate 13, and reacting the latter with a
large excess of hydrazine to give amide 14 (Scheme 6).21 Re-
action with ethyl chloroformate then gave the MDCEH, which
could be oxidized easily with bromine to give MDEAD itself. We
have now optimized this route by converting chloroformate 13
directly into MDCEH with ethyl carbazate in good yield. The oxi-
dation of MDCEH was also optimized and was found to be faster
when an excess of pyridine and bromine were used.
The synthesis of arrays demands the standardization of reaction
and purification conditions and of equipment, and the minimiza-
tion of solvent. Although the best results for the Mitsunobu re-
actions are obtained when either the acid or alcohol is in excess
and can easily be removed, e.g. a volatile alcohol or an acid that is
removed by a wash with aqueous base, and such conditions are
generally employed to illustrate new methods (see Scheme 3
above), we wished to use a more demanding test for our chemistry,
bearing in mind that the two reacting components may be of
equal value. Therefore, coupled products were obtained using a
1:1 ratio of reactants and without the inconvenience of an aqueous
wash. Under these conditions, MSPE would remove the poten-
tial contaminants resulting from the reagents, but may leave con-
tamination from starting alcohol or acid. We chose to synthesize
0.1 mmol of product and to use for purification commercially
available prepacked columns of 5 g of silica with a 20 mL reservoir.
When arrays are prepared for drug discovery, the library
members generally have clogP’s in the range of 1ꢀ5,24 i.e. there
are relatively polar members in the library. This presented us with
a significant problem, EtOAc was insufficiently polar to elute the
more polar compounds in this range in a reasonable volume of
solvent (less than the reservoir volume). We scanned a variety of
solvent combinations and found that EtOAc-MeOH (95:5),
DCM-MeOH (95:5) and DCM-acetone (5:1) were all suffi-
ciently polar. However, all caused some elution of the lighter
fractions of MPEG. We noted that different chain lengths formed
discrete spots on silica TLC plates when DCM-acetone (5:1) was
used as the eluent, while solvent systems containing protic solvents
led to streaking on TLC on silica. Clearly, acetone is sufficiently
polar to overcome the entropic effect and allow elution of MPEG
even though it is incapable of hydrogen-bonding to the MPEG, but
the difference in behavior on TLC is consistent with different effects
from aprotic and protic solvents.
Chromatography of MTPP-G2 removed both the lighter chain
lengths and the heavier chain lengths to give MTPP-G2 with a
narrower range of ethylenoxy units (10ꢀ16 by ESI-MS) and a
loading of 1.04 mmol gꢀ1 (by microanalysis). Similarly, narrow-
MW-range MDCEH was obtained by chromatography and
converted into MDEAD bearing 9ꢀ16 ethylenoxy units (by
ESI-MS) having a loading of 1.22 mmol gꢀ1. Using these MPEG
reagents, MSPE was effective on the crude mixtures produced by
overnight reaction between 0.1 mmol of acid, 0.1 mmol of
alcohol, 1.5 equiv of narrow-MW-range TPP-G2 and 1.8 equiv
of narrow-MW-range MDEAD in THF. Following solvent eva-
poration, MSPE of the crude using 15 mL of EtOAc-MeOH
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RESEARCH ARTICLE
Table 1. Array Using a 1:1 Ratio of Alcohols and Weak Acids
a Yields are calculated by isolated mass/MW of desired product. b Purities are mass ratios derived from the mole ratios of starting materials and product
determined by 1H NMR spectroscopy. There are no significant side products.
(95:5) gave products with complete removal of MPEGylated
compounds. A small array of compounds (Table 1) was pro-
duced in this way using alcohols 15ꢀ18 and weakly acidic
compounds AꢀE. The library members had clogP’s25 in the
range 1ꢀ6 and are arranged in Table 1 so that the least polar is
top left and the most polar bottom right. There is a weak inverse
relationship between polarity and yield, but all coupling partners
gave product. The effectiveness of MSPE is well illustrated
by the spectra of compound 17A before and after MSPE
(Figure 4).
Our objective was to provide a methodology that would enhance
the toolkit of procedures available to medicinal chemists.26 This
drove the selection of substrates including the incorporation of
fluoroaromatics (fluorine is an important bioisostere of hydrogen
for blocking metabolism27). The procedure was successful for
carboxylic acids (A and D), phenols (B and C) and the sulfon-
amide E. The weak acids A, C and D are bifunctional, containing
a potential site for palladium-catalyzed cross coupling and amination
reactions,28 a masked carboxylic acid, and a masked amine,
respectively. Primary alcohols 15-18 were chosen to reflect a
range of types of substrate: a masked amine, a hindered benzylic
alcohol, a heterocyclic alcohol with potential for elimination, and
a polar heterocyclic alcohol with a Lewis basic nitrogen atom,
respectively. Although derivatives of alcohol 15 bearing a Boc
protected amine are relatively nonpolar, the polarity of depro-
tected derivatives would be considerably lower (see clogP values
in parentheses, Table 1), and the same is true of derivatives of
acid D. Finally, the polar heterocyclic alcohol 18 was selected to
demonstrate the utility of the method for the preparation of highly
functionalized molecules with “drug-like” molecular properties.
In summary, we have demonstrated that light-MPEG-tagged
reagents are useful and inexpensive tools for the synthesis of
arrays by the Mitsunobu reaction.
’ EXPERIMENTAL PROCEDURES
General Comments on Synthesis and Characterization of
MPEG Reagents21. Each MPEG-tagged compound is actually
comprised of functionally identical compounds with different
MPEG chain lengths. Thus, for each tagged compound the
molecular ions appear as a series of peaks in the pneumatically
assisted ESI-MS corresponding to M þ Kþ, M þ Naþ, or M þ Hþ
with a difference of 44 amu between adjacent peaks in each series.
The distribution of chain lengths was identified from such a series
in each case and when reporting the ESI-MS, the 100% peak
corresponds to the most intense peak in a series and all other in-
tensities are reported relative to it. For each tagged compound, the
HRMS was determined for the compound with twelve ethylene
glycol units (n = 12). The average MW of the starting MPEGꢀOH
9 (i.e., 550) was used to calculate notional yields of the MPEG-
tagged compounds, assuming no change in the distribution of chain
lengths. The loadings of MTPP-G2 and MDEAD were determined
by microanalysis from percentage phosphorus or nitrogen, respec-
tively. The purity of each MPEG-tagged compound was established
by 1H NMR spectroscopy comparing the integration of the methyl
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Figure 4. MSPE illustrated: 1H NMR spectrum of ester 17A before (top) and after MSPE (bottom).
1
group of the MPEG to signals for the tagged reagent, and from the
absence of unexpected peaks in the 13C NMR spectra.
General Procedure for the Preparation of Library Mem-
with their characterization data and H and 13C NMR spectra,
characterization data for all library members, together with their
13C NMR spectra, and their H NMR spectra after MSPE and
1
bers. Narrow-MW-range MTPP-G2 (144 mg, 1.04 mmol gꢀ1
,
when fully purified, and the 1H NMR spectrum of a very impure
sample of ester 17A, prepared by employing the conditions used
for the library generation but using DIAD and TPP instead of
MDEAD and MTPP. This information is available free of charge
via the Internet at http://pubs.acs.org/.
0.15 mmol) in dry THF (0.25 mL) was added to a solution of an
alcohol 15-18 (0.1 mmol) and an acid A-E (0.1 mmol) in dry
THF (0.5 mL) followed by the MDEAD (151 mg, 1.19 mmol gꢀ1
,
0.18 mmol) in dry THF (0.25 mL) under nitrogen. The mixture
was stirred overnight (20 h). Solvent was evaporated and the
residue dissolved in EtOAc-MeOH (95:5, 0.5 mL). The resulting
solution was loaded onto a cartridge of silica [5 g, 20 mL reservoir
volume, which had been prewashed with EtOAC (15 mL) prior to
the use], washing onto the surface of the silica with a further
0.5 mL EtOAc-MeOH (95:5). The reservoir was filled and the
product eluted by gravity under normal pressure. A total of
15 mL of eluent was collected from the cartridge (>16 mL should
not be used as elution of MPEG-supported compounds may occur).
Solvent was evaporated, the sample weighed and analyzed by
1H NMR spectroscopy (data presented in Table 1). A pure sample
was then obtained using an automated purification system.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: Richard.Hartley@glasgow.ac.uk.
Funding Sources
Engineering and Physical Sciences Research Council and
GlaxoSmithKline U.K. for funding (EP/F068174/1).
’ REFERENCES
(1) Review: Swamy, K. C. K.; Kumar, N. N. B.; Balaraman, E.;
Kumar, K. V. P. P. Mitsunobu and Related Reactions: Advances and
Applications. Chem. Rev. 2009, 109, 2551–2651.
’ ASSOCIATED CONTENT
(2) Ley, S. V., Ladlow, M., Vickerstaffe, E. In Exploiting Chemical
Diversity for Drug Discovery; Bartlett, P. A., Entzeroth, M., Eds.; The
Royal Society of Chemistry: Cambridge, U.K., 2006; Chapter 1, pp
3ꢀ32.
S
Supporting Information. Experimental details for the
b
preparation of MPEG-tagged compounds 12, MDCEH, MDEAD
and MTPP-G2 (including fractionation procedures), together
284
dx.doi.org/10.1021/co100091n |ACS Comb. Sci. 2011, 13, 280–285

ACS Combinatorial Science
RESEARCH ARTICLE
(3) Barrett, A. G. M.; Roberts, R. S.; Schr€oder, J. Impurity Annihilation:
Chromatography-Free Parallel Mitsunobu Reactions. Org. Lett. 2000, 2,
2999–3001.
(21) Figlus, M.; Tarruella, A. C.; Messer, A.; Sollis, S. L.; Hartley,
R. C. Low Molecular Weight MPEG-assisted Organic Synthesis. Chem.
Commun. 2010, 46, 4405–4407.
(22) Low molecular weight MPEG has been used to tag intermedi-
ates in the solution-phase synthesis of oligosaccharides:(a) Hanashima,
S.; Inamori, K.; Manabe, S.; Taniguchi, N.; Ito, Y. Systematic Synthesis
of Bisubstrate-Type Inhibitors of N-Acetylglucosaminyltransferases.
Chem.—Eur. J. 2006, 12, 3449–3462. and references therein.(b) Jiang,
L.; Hartley, R. C.; Chan, T.-H. Use of Low Molecular Weight Poly-
ethylene Glycol Linker for Polymer-Supported Solution Synthesis of
Oligosaccharides. Chem. Commun. 1996, 2193–2194.
(23) A heavy MPEG version of this compound has recently been
reported and its silver complexes used in NMR studies: Bergbreiter, D. E.;
Yang, Y.-C. Variable-Temperature NMR Studies of Soluble Polymer-
Supported Phosphine-Silver Complexes. J. Org. Chem. 2010, 75, 873–878.
(24) Leeson, P. D.; Springthorpe, B. The Influence of Drug-like
Concepts on Decision-making in Medicinal Chemistry. Nature Rev.
Drug Discovery 2007, 6, 881–890.
(25) ClogP was calculated using Daylight clogP, version 4.81, Day-
light Chemical Information Systems, Inc., 28202 Cabot Road, Suite 300,
Laguna Niguel, CA 92677.
(26) Cooper, T. W. J.; Campbell, I. B.; Macdonald, S. J. F. Factors
Determining the Selection of Organic Reactions by Medicinal Chemists
and the Use of These Reactions in Arrays (Small Focused Libraries).
Angew. Chem., Int. Ed. 2010, 49, 8082–8091.
(4) Pelletier, J. C.; Kincaid, S. Mitsunobu Reaction Modifications
Allowing Product Isolation without Chromatography: Application to a
Small Parallel Library. Tetrahedron Lett. 2000, 41, 797–800.
(5) Lan, P.; Porco, J. A., Jr.; South, M. S.; Parlow, J. J. The
Development of a Chromatography-Free Mitsunobu Reaction: Synthe-
sis and Applications of an Anthracene-Tagged Phosphine Reagent.
J. Comb. Chem. 2003, 5, 660–669.
(6) Egelhaaf, H.-J.; Rademann, J. Understanding Supported Reac-
tions in Spherical Compartments: A General Algorithm To Model and
Determine Rate Constants, Diffusion Coefficients, and Spatial Product
Distributions. J. Comb. Chem. 2005, 7, 929–941.
(7) Czarnik, A. W. Solid-Phase Synthesis Supports Are Like Sol-
vents. Biotechnol. Bioeng. (Comb. Chem.) 1998, 61, 77–79.
(8) Chen, C. H.-T.; Zhang, W. Fluorous Reagents and Scavengers
Versus Solid-Supported Reagents and Scavengers, a Reaction Rate and
Kinetic Comparison. Mol. Diversity 2005, 9, 353–359.
(9) Hagiya, K.; Muramoto, N.; Misaki, T.; Sugimura, T. DMEAD: A
New Dialkyl Azodicarboxylate for the Mitsunobu Reaction. Tetrahedron
2009, 65, 6109–6114.
(10) Kiankarimi, M.; Lowe, R.; McCarthy, J. R.; Whitten, J. P.
Diphenyl 2-Pyridylphosphine and Di-tert-butyl Azodicarboxylate: Con-
venient Reagents for the Mitsunobu Reaction. Tetrahedron Lett. 1999,
40, 4497–4500.
(11) (a) Camp, D.; Jenkins, I. D. The Use of a Phosphine Containing
a Basic Group in the Mitsunobu Esterification Reaction. Aust. J.
Chem. 1988, 41, 1835–1839. (b) Von Itzstein, M.; Mocerino, M.
(27) Review: B€ohm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn,
B.; M€uller, K.; Obst-Sander, U.; Stahl, M. Fluorine in Medicinal
Chemistry. ChemBioChem. 2004, 5, 637–643.
(28) Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E.; Wiley: New York, 2002.
(p-Dimethylaminophenyl)diphenylphosphine:
A
More Practical
Phosphine in the Mitsunobu Reaction. Synth. Commun. 1990,
20, 2049–2057.
(12) Ginisty, M.; Roy, M.-N.; Charette, A. B. Tetraarylphospho-
nium-Supported Carbodiimide Reagents: Synthesis, Structure Optimi-
zation and Applications. J. Org. Chem. 2008, 73, 2542–2547.
(13) Sieber, F.; Wentworth, P.; Toker, J. D.; Wentworth, A. D.;
Metz, W. A.; Reed, N. N.; Janda, K. D. Development and Application of a
Poly(ethyleneglycol)-Supported Triarylphosphine Reagent: Expand-
ing the Sphere of Liquid-Phase Organic Synthesis. J. Org. Chem. 1999,
64, 5188–5192.
(14) Roller, S.; Zhou, H.; Haag, R. High-Loading Polyglycerol
Supported Reagents for Mitsunobu- And Acylation-Reactions
and Other Useful Polyglycerol Derivatives. Mol. Diversity 2005, 9,
305–316.
(15) Harned, A. M.; He, H. S.; Toy, P. H.; Flynn, D. L.; Hanson, P. R.
Multipolymer Solution-Phase Reactions: Application to the Mitsunobu
Reaction. J. Am. Chem. Soc. 2005, 127, 52–53.
(16) Maity, P. K.; Rolfe, A.; Samarakoon, T. B.; Faisal, S.; Kurtz,
R. D.; Long, T. R.; Sch€atz, A.; Flynn, D. L.; Grass, R. N.; Stark, W. J.;
Reiser, O.; Hanson, P. R. Monomer-on-Monomer (MoM) Mitsunobu
Reaction: Facile Purification Utilizing Surface-Initiated Sequestration.
Org. Lett. 2011, 13, 8–10.
(17) Dandapani, S.; Curran, D. P. Fluorous Mitsunobu Reagents and
Reactions. Tetrahedron 2002, 58, 3855–3864.
(18) Handbook of Fluorous Chemistry; Gladysz, J. A., Curran, D. P.,
Horvꢀath, I. T., Eds.; Wiley-VCH: Weinheim, Germany, 2004.
(19) Review of recent libraries including those using fluorous
synthesis and reagents: Dolle, R. E.; Le Bourdonnec, B.; Worm, K.;
Morales, G. A.; Thomas, C. J.; Zhang, W. Comprehensive Survey of
Chemical Libraries for Drug Discovery and Chemical Biology: 2009.
J. Comb. Chem. 2010, 12, 765–806.
(20) On the basis of the advertised price in dollars of 1 kg ofFluoroFlash
silica (40 μm particle size) from a specialist supplier of fluorous chemicals
and 1 kg of silica (35ꢀ70 μm particle size, 60 Å) from a supplier of fine
chemicals and chromatographic materials, both accessed online fourth
March 2011. Many research institutes and universities already buy silica
in bulk at a considerably lower cost.
285
dx.doi.org/10.1021/co100091n |ACS Comb. Sci. 2011, 13, 280–285