Reagent-controlled domino synthesis of skeletally-diverse compound collections

Article abstract of DOI:10.1039/b717635j

An efficient reagent-controlled methodology for generating highly substituted diverse scaffolds from a common substrate has been developed; thus, treatment of a common precursor with different desilylating reagents, such as ammonium fluoride, caesium fluo

Full text of DOI:10.1039/b717635j

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Reagent-controlled domino synthesis of skeletally-diverse compound
collectionsw
¨
Herbert Waldmann,*ab Marc Kuhn,ab Wei Liuab and Kamal Kumar*ab
Received (in Cambridge, UK) 14th November 2007, Accepted 10th December 2007
First published as an Advance Article on the web 4th January 2008
DOI: 10.1039/b717635j
An efficient reagent-controlled methodology for generating
highly substituted diverse scaffolds from a common substrate
has been developed; thus, treatment of a common precursor with
different desilylating reagents, such as ammonium fluoride,
caesium fluoride and PPTS, triggers different domino reaction
sequences, yielding highly substituted pyridines, phenols and
benzopyrans, respectively; the substituent patterns of these
scaffolds provide further opportunities for library development.
(TBAF) led to a retro-aldol reaction, thereby hydrolyzing 1
to formylchromone and b-ketoesters.
The use of diverse sets of small molecules in chemical biology
studies has led to new insights into various biological phe-
nomena.1–6 For the development of such compounds, Diver-
sity-Oriented Synthesis (DOS)4 and Biology-Oriented
Synthesis (BIOS)5,6 of compound collections are efficient
approaches. In both approaches, structural complexity and
diversity is often generated by means of multi-step sequences
employing skeletally-differentiating transformations of com-
mon precursors. Here we report on the development of new
structurally-diversifying domino reaction7 sequences, giving
access to highly substituted pyridines, benzopyrans or phenols
from a common intermediate.
Fig. 1 Substrate for domino reactions with diverse reactive sites.
Attempted tert-butyldimethylsilyl (TBS) deprotection of 1
using TBAF under dry conditions was also unsuccessful.
Upon employing another desilylating reagent, i.e. ammonium
fluoride, at room temperature, single products were formed
(TLC control) within an hour, which after purification (silica
gel column chromatography) were identified by spectroscopic
techniques (NMR, DEPT, HRMS) to be pyridines
(Scheme 1).8
4
Substrates capable of entering domino sequences must have
diverse reactive sites, at which different chemical reactions can
take place in a sequential manner. We envisioned employing
Under these reaction conditions, the TBS ether remained
intact (4, Scheme 1). Extending the reaction time and raising
the temperature (60 1C) led to clean removal of the protecting
group (1 - 5; Scheme 1). Further, saponification of the esters
with 1 M NaOH provided the corresponding substituted
pyridine carboxylic acids (6, Scheme 1; for a tabular survey
of the synthesized compounds see the ESIw).
Chromanylidene-b-ketoesters 7 with short alkyl chains
(R4 = Me or H) were also cleanly transformed to the
corresponding substituted pyridines 8 by means of the domino
route described above. The corresponding pyridine carboxylic
acids, 9, were obtained after hydrolysis of the esters with 1 M
NaOH (Scheme 1). Formation of the pyridine ring proceeded,
most likely, by means of the initial conversion of e.g.
b-ketoester 1 into enamine 2, which then attacks the activated
C-2 position in the chromone (2-3, Scheme 1). Rearrange-
ment was accompanied by opening of the chromone, and
aromatization resulted in the formation of pyridine 4. Overall,
this domino sequence provided high yields of substituted
pyridines (see the ESIw).
appropriately substituted 3-chromanylidene-b-ketoesters
1
(Fig. 1) as key intermediates for the establishment of new
domino sequences. These compounds contain electrophilic
centers, e.g. C2 and C10, where nucleophiles can attack, and
also nucleophilic centers such as C40 and OH (after deprotec-
tion). Furthermore, the C30 ketone provides an entry into
imine–enamine chemistry. Moreover, desilylating the alcohol
at C70 could possibly induce the formation of six-membered
hemiacetals. Thus, these substrates can potentially enter into
various different reaction pathways. Initially, we planned to
desilylate the alcohol and determine if the formation of
hemiacetals is followed by further reactions at the different
electrophilic centers available in these molecules. Using the
standard desilylating reagent tetrabutylammoniumfluoride
a Max-Planck-Institut fur Molekulare Physiologie, Abteilung
¨
Chemische Biologie, Otto-Hahn-Straße 11, 44227 Dortmund,
Germany
b Universitat Dortmund, Fachbereich 3, Chemische Biologie,
The reactions detailed above demonstrate that electrophilic
centers, especially C2 (Fig. 1), can be easily attacked by
nucleophiles in a sequential way. So as to determine whether
an alkoxide, generated by the desilylation of 1, attacks at C2
or triggers other cascade processes, we used CsF as a desilylat-
ing reagent. Thus, chromanylidene intermediates 1 and 7 were
¨
Otto-Hahn Straße 6, 44227 Dortmund, Germany. E-mail:
Kamal.Kumar@mpi-dortmund.mpg.de. E-mail:
Herbert.Waldmann@mpi-dortmund.mpg.de; Fax: +49 231-133-2499
w Electronic supplementary information (ESI) available: Experimental
details and spectroscopic data for selected compounds. See DOI:
10.1039/b717635j
ꢀc
This journal is The Royal Society of Chemistry 2008
Chem. Commun., 2008, 1211–1213 | 1211

View Article Online
Scheme 3 Domino synthesis of benzopyrans.
tion from substrate 1. To enter such a reaction pathway, a
desilylating reagent may be required that provides conditions
suitable for acetal formation. Based on this assumption
pyridinium para-toluene sulfonate (PPTS) was employed as
the desilylating reagent. Interestingly, treatment of silyl ethers
1 with PPTS in methanol at 65 1C for 36 h led to the formation
of benzopyrans 18 (Scheme 3). However, transesterification of
the substrates occurred, which could be successfully avoided
by reducing the reaction time to 24 h. This finding provided
another cascade route to a different scaffold, around which a
new compound collection could be readily generated. As in the
cases described above, the hydrolysis of the ester groups with
sodium hydroxide provided the corresponding carboxylic
acids in good yields.
Scheme 1 Domino synthesis of substituted pyridines: (a) NH4F (10.0
equiv.), MeOH, r.t., 1–3 h; (b) NH4F (10.0 equiv.), MeOH, 60 1C,
6–10 h; (c) 1 M NaOH, MeOH/THF (1 : 2), r.t., 16 h.
treated with CsF in DMF. Interestingly, we observed the
formation of substituted phenols 13 under these reaction
conditions in moderate to good yields (see the ESI for a
tabular survey of the resultsw).
At least two equivalents of CsF were required to obtain
good to excellent yields of 13. Again, hydrolysis of the ester
moiety in the products yielded carboxylic acids 14 in high
yields (Scheme 2). Mechanistically, a caesium enolate may
have been formed after removal of the TBS group and added
to C2 of the chromone, forming a C–C bond (10-11, Scheme
2). Subsequent ring opening (11-12) and aromatization gave
rise to phenols 13, which were obtained in deprotected forms
(Scheme 2).
Under these reaction conditions, the TBS group is removed,
and the liberated alcohol 15 cyclizes to the ketone, yielding the
expected hemiacetal 16 (Scheme 3), which eliminates water to
form the dihydropyran 17. An intramolecular cyclization
followed by aromatization leads to benzopyrans 18. This
domino sequence provides a clear advantage over the reported
multi-step synthesis of similar molecules, which involves the
generation of 1,3-bis(trimethylsilyloxy)-7-chlorohepta-1,3-
dienes (3 steps) followed by additional steps to yield benzo-
pyrans.9
These two domino processes (Scheme 1 and Scheme 2)
provided highly substituted phenols and pyridines, which
could be further diversified for compound collection synthesis.
However, we did not observe the expected hemiacetal forma-
To gain further insight into the reaction mechanism, the
reaction between 1 (R3 = (S)-Me) and PPTS in methanol was
stopped after 1 h, and the major product quickly purified by
flash column chromatography. Interestingly, the product ob-
tained in this case was not the benzopyran but the chroma-
nomethylidene-substituted dihydropyran 17a (Scheme 4),
which appears to be the precursor of the benzopyran (Scheme
3). Stirring 17a under the same reaction conditions, i.e. with
PPTS in methanol at 65 1C for 24 h, yielded exclusively the
Scheme 2 Domino synthesis of substituted phenols.
1212 | Chem. Commun., 2008, 1211–1213
Scheme 4 From dihydropyran to benzopyran.
ꢀc
This journal is The Royal Society of Chemistry 2008

View Article Online
Angew. Chem., Int. Ed., 1998, 37, 688–749; (e) P. Stahl and H.
Waldmann, Angew. Chem., Int. Ed., 1999, 38, 3710–3713.
2 For examples from our laboratories, see: (a) P. Deck, D. Pendzia-
lek, M. Biel, M. Wagner, B. Popkirova, B. Ludolph, G. Kragol, J.
Kuhlmann, A. Giannis and H. Waldmann, Angew. Chem., Int. Ed.,
2005, 44, 4975–4980; (b) T. Lessmann, M. G. Leuenberger, S.
Menninger, M. Lopez-Canet, O. Muller, S. Huemmer, J. Bor-
¨
mann, K. Korn, E. Fava, M. Zerial, T. U. Mayer and H.
Waldmann, Chem. Biol., 2007, 14, 443–451; (c) A. B. Garcia, T.
Lessmann, J. D. Umarye, V. Mamane, S. Sommer and H. Wald-
mann, Chem. Commun., 2006, 3868–3870; (d) S. Roettger and H.
Waldmann, Eur. J. Org. Chem., 2006, 2093–2099; (e) O. Barun, K.
Kumar, S. Sommer, A. Langerak, T. U. Mayer, O. Muller and H.
¨
Waldmann, Eur. J. Org. Chem., 2005, 4773–4788; (f) M. Manger,
M. Scheck, H. Prinz, J. P. von Kries, T. Langer, K. Saxena, H.
Schwalbe, A. Furstner, J. Rademann and H. Waldmann, Chem-
¨
BioChem, 2005, 6, 1749–1753; (g) M. A. Koch, L.-O. Wittenberg,
S. Basu, D. A. Jeyaraj, E. Gourzoulidou, K. Reinecke, A. Oder-
matt and H. Waldmann, Proc. Natl. Acad. Sci. U. S. A., 2004, 101,
16721–16726; (h) O. Barun, S. Sommer and H. Waldmann, Angew.
Chem., Int. Ed., 2004, 43, 3195–3199; (i) B. Meseguer, D. Alonso-
Scheme 5 Diversification of substituted pyridine molecules.
Dıaz, N. Griebenow, T. Herget and H. Waldmann, Angew. Chem.,
´
corresponding benzopyran 18a, thus confirming the inter-
mediacy of dihydropyrans.
Int. Ed., 1999, 38, 2902–2906; (j) B. Sauerbrei, V. Jungmann and H.
Waldmann, Angew. Chem., Int. Ed., 1998, 37, 1143–1146; (k) P.
Stahl, L. Kissau, R. Mazitschek, A. Giannis and H. Waldmann,
Angew. Chem., Int. Ed., 2002, 41, 1174–1178; (l) I. Reis-Correa Jr,
The skeletally-differentiating domino approach described
above provided molecules with various functionalities, which
could be explored for adding further diversity to the com-
pound collections. To this end, the phenol moiety in substi-
tuted pyridines 8 was converted to intermediate esters 20 by
treatment with bromoacetic acid esters. Saponification of 20
yielded the pyridine dicarboxylic acids 21 in good yields
(Scheme 5). Coumarin, as a ‘‘privileged’’ scaffold, shows
multiple biological properties, especially anti-HIV and anti-
biotic activities.10 To add this scaffold to the molecular
architecture of the library, the substituted pyridines 8 were
readily converted to the coumarin-substituted pyridine car-
boxylates by a one pot procedure (see the ESIw). Alkylation of
8 with diverse acetic acids, followed by a base-mediated
condensation, yielded the desired coumarin-substituted pyr-
idine carboxylates 22, and subsequent saponification led to the
corresponding acids 23 (Scheme 5).
A. Noren-Mueller, H.-D. Ambrosi, S. Jakupovic, K. Saxena, H.
¨
¨
Schwalbe, M. Kaiser and H. Waldmann, Chem.–Asian J., 2007, 2,
1109–1126; (m) V. Mamane, A. B. Garcia, J. D. Umarye, T.
Lessmann, S. Sommer and H. Waldmann, Tetrahedron, 2007, 63,
5754–5767; (n) M. A. Koch, A. Schuffenhauer, M. Scheck, S.
Wetzel, M. Casaulta, A. Odermatt, P. Ertl and H. Waldmann,
Proc. Natl. Acad.Sci. U. S. A., 2006, 103, 10606–10611; (o) B.
Meseguer, D. Alonso-Diaz, N. Griebenow, T. Herget and H.
Waldmann, Chem.–Eur. J., 2000, 6, 3943–3957; (p) L. Kissau, P.
Stahl, R. Mazitschek, A. Giannis and H. Waldmann, J. Med.
Chem., 2003, 46, 2917–2931.
3 R. Breinbauer, I. R. Vetter and H. Waldmann, Angew. Chem., Int.
Ed., 2002, 41, 2878–2890.
4 (a) G. C. Micalizio and S. L. Schreiber, Angew. Chem., Int. Ed.,
2002, 41, 3272–3276; (b) D. S. Tan, Nature Chem. Biol., 2005, 1,
74–84; (c) P. Arya, R. Joseph, Z. Gan and B. Rakic, Chem. Biol.,
2005, 12, 163–180.
5 A. Noren-Muller, I. Reis-Correa, Jr, H. Prinz, C. Rosenbaum,
¨
¨
K. Saxena, H. J. Schwalbe, D. Vestweber, G. Cagna, S. Schunk,
O. Schwarz, H. Schiewe and H. Waldmann, Proc. Natl. Acad. Sci.
U. S. A., 2006, 103, 10606–10611.
6 (a) M. A. Koch and H. Waldmann, Drug Discovery Today, 2005,
10, 471–483; (b) S. Wetzel, A. Schuffenhauer, S. Roggo, P. Ertl and
H. Waldmann, Chimia, 2007, 61, 355–360.
In conclusion, we have discovered efficient reagent-con-
trolled domino processes that led to structurally-diverse func-
tionalized molecules in a complementary manner. The general
approach to synthesizing different compound collections from
a common intermediate by control with different reagents
should provide efficient access to collections of small molecules
for chemical biology and medicinal chemistry research.
7 L. F. Tietze, Chem. Rev., 1996, 96, 115–136.
8 For similar pyridine syntheses, see: (a) G. Haas, J. L. Stanton, A.
V. Sprecher and W. Paul, J. Heterocycl. Chem., 1981, 18, 607–612;
(b) G. Sabitha, Aldrichimica Acta, 1996, 29, 15–25 and references
cited therein.
9 V. T. H. Nguyen, B. Appel and P. Langer, Tetrahedron, 2006, 62,
7674–7686.
10 (a) R. D. H. Murray, J. Mendez and S. A. Brown, The Natural
´
Notes and references
1 (a) M. D. Burke, E. M. Berger and S. L. Schreiber, Science, 2003,
302, 613–618; (b) D. R. Spring, Chem. Soc. Rev., 2005, 34, 472–482;
(c) J. R. Peterson and T. J. Mitchison, Chem. Biol., 2000, 9,
1275–1285; (d) K. Hinterding, D. Alonso-Diaz and H. Waldmann,
Coumarins: Occurrence, Chemistry and Biochemistry, Wiley, New
York, 1982; (b) T. Yamaguchi, T. Fukuda, F. Ishibashi and M.
Iwao, Tetrahedron Lett., 2006, 47, 3755 and references cited
therein.
ꢀc
This journal is The Royal Society of Chemistry 2008
Chem. Commun., 2008, 1211–1213 | 1213