In summary, we have demonstrated light-MPEG-assisted
organic synthesis (MPAOS) for the first time, as a new and
inexpensive way of simplifying solution phase synthesis
using only standard glassware and normal silica. We have
simultaneously provided a whole toolkit of supported reagents
for the preparation of esters, amides and ureas. MPAOS
should be easy to automate, and the light-MPEG toolkit
should greatly facilitate the synthesis of arrays of compounds
for drug discovery.
Scheme 4 Urea synthesis using an MPEG-supported electrophilic
scavenger.
The Mitsunobu reaction is particularly important.19 It uses the
combination of TPP and diethyl azadicarboxylate (DEAD) to
convert an alcohol into a triphenylphosphine oxide (TPPO)
leaving group while simultaneously generating a nucleophilic
anion from a weak acid. Unfortunately, the TPPO and
reduced DEAD produced by the reaction are often difficult
to remove from the desired product by chromatography. On
the other hand, our MPEG-supported versions of these
reagents MTPP and MDEAD and the side products produced
from them are easily removed by MSPE, so that carboxylic
acid 14 is converted into esters 15 and 16 in high yield, and
similarly alcohol 17 gives ester 18 in high purity following
MSPE (and an alkaline aqueous wash in the case of ester 18,
Scheme 5).
EPSRC, GSK, ERASMUS and AGAUR for funding, and
the University of Barcelona and the Technical University of
Kaiserslautern for allowing ACT and AM to travel.
Notes and references
1 R. E. Dolle, B. Le Bourdonnec, A. J. Goodman, G. A. Morales,
C. J. Thomas and W. Zhang, J. Comb. Chem., 2009, 11, 739.
2 Reviews: (a) A. Solinas and M. Taddei, Synthesis, 2007, 2409;
(b) F. Z. Dorwald, Organic Synthesis on Solid Phase, Wiley-VCH,
¨
Weinheim, 2000.
3 Reviews and examples: (a) S. Kim, A. Tsuruyama, A. Ohmori and
K. Chiba, Chem. Commun., 2008, 1816; (b) M. Ginisty, M.-N. Roy
and A. B. Charette, J. Org. Chem., 2008, 73, 2542; (c) W. Miao and
T. H. Chan, Acc. Chem. Res., 2006, 39, 897; (d) Handbook of
Fluorous Chemistry, ed. J. A. Gladysz, D. P. Curran and
´
I. T. Horvath, Wiley-VCH, Weinheim, 2004; (e) M. Zhang,
P. Vedantham, D. L. Flynn and P. R. Hanson, J. Org. Chem.,
2004, 69, 8340.
4 Review of soluble PEG-supported reagents: T. J. Dickerson,
N. N. Reed and K. D. Janda, Chem. Rev., 2002, 102, 3325.
5 L. Jiang, R. C. Hartley and T. H. Chan, Chem. Commun., 1996, 2193.
6 (a) S. Hanashima, K. Inamori, S. Manabe, N. Taniguchi and
Y. Ito, Chem.–Eur. J., 2006, 12, 3449; (b) S. Hanashima,
S. Manabe and Y. Ito, Angew. Chem., Int. Ed., 2005, 44, 4218;
(c) S. Hanashima, S. Manabe, K. Inamori, N. Taniguchi and
Y. Ito, Angew. Chem., Int. Ed., 2004, 43, 5674; (d) Y. Ito and
S. Manabe, Chem.–Eur. J., 2002, 8, 3076; (e) H. Ando, S. Manabe,
Y. Nakahara and Y. Ito, J. Am. Chem. Soc., 2001, 123, 3848;
(f) H. Ando, S. Manabe, Y. Nakahara and Y. Ito, Angew. Chem.,
Int. Ed., 2001, 40, 4725.
Finally, 1,3-arylmethyltriazenes are alternative reagents to
diazomethane for the mild methylation of carboxylic acids.20
The MPEG-version of this reagent MAMT methylates a range
of acids to give methyl esters 19–23 in good yield and high
purity following MSPE (Scheme 6).
7 L. Jiang and T. H. Chan, Can. J. Chem., 2005, 83, 693.
8 Light-MPEG has other attractive solubility properties which have
been exploited in enzymatic reactions: (a) M. Nogawa,
M. Shimojo, K. Matsumoto, M. Okudomi, Y. Nemoto and
H. Ohta, Tetrahedron, 2006, 62, 7300; (b) M. Shimojo,
K. Matsumoto, M. Nogawa, Y. Nemoto and H. Ohta, Tetrahedron
Lett., 2004, 45, 6769.
Scheme 5 Mitsunobu reactions using MPEG-supported reagents.
9 S. V. Ley, M. Ladlow and E. Vickerstaffe, in Exploiting Chemical
Diversity for Drug Discovery, ed. P. A. Bartlett and M. Entzeroth,
The Royal Society of Chemistry, Cambridge, 2006, ch. 1, pp. 3–32.
10 F. Sieber, P. Wentworth, J. D. Toker, A. D. Wentworth,
W. A. Metz, N. N. Reed and K. D. Janda, J. Org. Chem., 1999,
64, 5188.
11 S. Roller, H. Zhou and R. Haag, Mol. Diversity, 2005, 9, 305.
12 e.g. J. Keilitz and R. Haag, Eur. J. Org. Chem., 2009, 3272.
13 H. Shen, A. M. Jawaid and P. T. Snee, ACS Nano, 2009, 3, 915.
14 This is a known compound (see ref. 5 and 7) but has not been used
as a scavenger previously.
15 Review: E. Valeur and M. Bradley, Chem. Soc. Rev., 2009, 38, 606.
16 Y. Kiso and H. Yajima, J. Chem. Soc., Chem. Commun., 1972, 942.
17 Solid-supported version of this reagent: E. Valeur and M. Bradley,
Chem. Commun., 2005, 1164.
18 W. Zhang, C. H.-T. Chen and T. Nagashima, Tetrahedron Lett.,
2003, 44, 2065.
19 Reviews: (a) K. C. K. Swamy, N. N. B. Kumar, E. Balaraman and
K. V. P. P. Kumar, Chem. Rev., 2009, 109, 2551; (b) R. Dembinski,
Eur. J. Org. Chem., 2004, 2763.
20 J. Rademann, J. Smerdka, G. Jung, P. Grosche and D. Schmid,
Angew. Chem., Int. Ed., 2001, 40, 381.
Scheme 6 Methylation of carboxylic acids using MPEG-supported
arylmethyltriazene.
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 4405–4407 | 4407