Solid-phase synthesis of combinatorial libraries based on enatiomerically pure (1S,2S,4R,5S)-4,5-dihydroxycyclohexan-1,2-dicarboxylic acid scaffolds

Article abstract of DOI:10.1016/S0014-827X(02)01306-X

The conditions for solid-phase functionalization of the new enantio-pure scaffold 1 to give libraries of general formula 4 have been derived.

Full text of DOI:10.1016/S0014-827X(02)01306-X

Il Farmaco 57 (2002) 861Á864
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www.elsevier.com/locate/farmac
Short Communication
Solid-phase synthesis of combinatorial libraries based on
enatiomerically pure (1S,2S,4R,5S)-4,5-dihydroxycyclohexan-1,2-
dicarboxylic acid scaffolds
Daniela Arosio a, Anna Bernardi a,*, Donatella Dellavecchia a, Fabrizio Micheli b,
Alessandra Pasquarello b
a Dipartimento di chimica organica e industriale, universita` di Milano, Via Venezian 21, 20133 Milan, Italy
b GlaxoSmithKline SpA, Medicines Research Center, Via Fleming 4, 37135 Verona, Italy
Received in revised form 24 June 2002; accepted 6 July 2002
Abstract
The conditions for solid-phase functionalization of the new enantio-pure scaffold 1 to give libraries of general formula 4 have
been derived.
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# 2002 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
Keywords: Cyclohexanediols; Enantiopure compounds; Polyfunctional scaffolds; Solid-phase synthesis
The synthesis of large libraries of novel compounds is
often based on the combinatorial functionalization
(decoration) of template scaffolds anchored to insoluble
supports [1]. Many heterocyclic and carbocyclic scaf-
folds have been used to this end, and the introduction of
new molecular scaffolds with a high potential of
molecular diversity is of great interest for the production
of new collections of compounds.
single chair conformation, and can fix the substituents
in a predetermined disposition.
In this paper we report on the use of compound 1 for
the solid-phase generation of libraries of type 4 (Scheme
1). In a first approach (Scheme 2), the equatorial
function of 1 (RꢀMe) was protected as an allylether,
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the axial one as dimethyl-t-butylsilyl ether, and the
carboxy groups were demasked to allow solid-phase
anchoring.
We have recently reported the facile synthesis of the
The scaffold was attached to solid-phase using a
commercially available PAL-PS resin [4], which gave
better loading results than PS- or Tentagel based Rink
amide resins (Scheme 2). As expected, a 1:1 regioiso-
meric mixture of 8 and 9 was obtained, as shown by
nanoprobe NMR analysis of the resin and MS/HPLC
analysis of the cleavage (20% TFA) mixture. This
three polyfunctional enantio-pure cyclohexanes 1Á3
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(Fig. 1) [2]. These molecules have several properties
that make them ideal for the use as scaffolds for the
production of combinatorial libraries of highly diverse
molecules with potential pharmaceutical activity. They
have low molecular weight, which allows their decora-
tion with many building blocks without violating
Lipinski’s rule [3], they contain four potential points
of diversification (the two hydroxy and two carboxy
groups) and they can be easily attached on solid-phase.
Furthermore, the three diastereoisomeric scaffolds are
conformationally defined molecules that populate a
* Corresponding author
E-mail address: anna.bernardi@unimi.it (A. Bernardi).
Fig. 1. The polyfunctional scaffolds 1Á3.
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0014-827X/02/$ - see front matter # 2002 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
PII: S 0 0 1 4 - 8 2 7 X ( 0 2 ) 0 1 3 0 6 - X

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D. Arosio et al. / Il Farmaco 57 (2002) 861Á864
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Scheme 3. Solid-phase functionalization of the free carboxy group. (a)
DIC, DMAP, CH2Cl2 ÁROH 1:1; (b) PyBOP, DIPEA, DMF, pirro-
lidine.
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(Scheme 3). Selective deprotection of the hydroxy group
functionalities was then studied (Scheme 4).
Scheme 1. General scheme of the library generation.
The deallylation of 10Á
achieved in high yields and purity using Pd(PPh3)4 in
CH2Cl2ÁAcOHÁN-methylmorpholine [5]. The desilyla-
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15 to give 16Á21 could be
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tion of the amides 14 and 15 also occurred uneventfully
using 1 M TBAF in THF to give 22 and 23. However,
under these conditions the esters 10Á13 were found to be
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unstable, and were extensively hydrolyzed before desi-
lylation could take place. None of the experimental
conditions attempted, using more diluted TBAF solu-
tion, shorter reaction times, or buffered Fꢁ solutions
(1:1 TBAFÁ
unwanted hydrolysis. Therefore this approach could
only be used for the synthesis of the library 4a (X3, X4ꢀ
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AcOH or Et3N×/3HF) could prevent the
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NR1R2), and the reaction sequence of Scheme 5 had to
be followed.
The free axial hydroxy group of 22 and 23 was
Scheme 2. Solid-phase anchoring of the fully protected scaffold. (a)
Compound 5 see ref. [2b], TBDMSCl, DMF, imidazole (96%); (b)
LiOH, MeOHÁH2O 3:1; (c) PyBOP, DIPEA, DMF, PAL-PS resin.
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transformed in the benzoate 24, 25 (X1ꢀ
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Ph) or in
problem can be circumvented by differentiating the
carboxy group functionalities before loading onto the
resin, using the diasteroselective hydrolysis of 1 that we
have recently described [2b]. However, all the prelimi-
nary solid-phase chemistry and library rehearsals re-
ported in this paper were carried out on regioisomeric
mixtures of compounds.
carbamate 26, 27 (X1ꢀArNH). This latter transforma-
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tion was initially attempted using p-NO2 phenylchlo-
roformate followed by reaction with benzylamine.
However, upon cleavage, the product was found to be
contaminated by 15Á
which could not be eliminated. Eventually the carba-
mates were synthesized in good yields and ꢀ85% purity
using ArNCO in the presence of stoichiometric amounts
of DMAP [6]. Deallylation of 24Á27 was performed
under the conditions described for 10Á15, and the
equatorial hydroxy group was in turn functionalized as
/20% of PNP-containing impurities,
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The first reaction carried out on solid-phase was the
functionalization of the free carboxy group, which was
/
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transformed into an ester 10Á
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13, or an amide 14Á15
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Scheme 4. Diol deprotection from 10 to 15. (a) (PPh3)4Pd, NMM, AcOH, DCM; (b) 1 M TBAF in THF.

D. Arosio et al. / Il Farmaco 57 (2002) 861Á
/864
863
Scheme 7. Scheme for the synthesis of the library of ester 4b. (a) X1ꢀ
Ph: PhCO2H, DIC, DMAP, DCM; X1ꢀNHAr: ArNCO, DMAP,
DCM; (b) (PPh3)4Pd, NMM, AcOH, DCM; (c) X2ꢀPh: PhCO2H,
DIC, DMAP, DCM; X2ꢀNHAr: ArNCO, DMAP, DCM; (d) 20%
TFA in DCM, 2% Me2S scavenger.
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/
/
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a benzoate 28Á
(X2ꢀPhNH) following the procedure described above.
TFA cleavage from the PAL resin (20% TFA, 2% Me2S)
yielded compounds 36Á43 in ꢀ80% purity by MS/
HPLC.
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31 (X2ꢀ
/
Ph) or a carbamate 32Á35
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/
/
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In order to synthesize the library of esters 4b, loading
of the unprotected diacid 44 onto the PAL resin was
attempted (Scheme 6). Under the usual reaction condi-
tions (2 equiv. of diacid, PyBOP, DIPEA, 18 h) a 1:1
mixture of 45 and 46 was cleanly obtained.
Scheme 5. Scheme for the synthesis of the library of amides 4a. (a)
X1ꢀPh: PhCO2H, DIC, DMAP, DCM; X1ꢀNHAr: ArNCO,
DMAP, DCM; (b) (PPh3)4Pd, NMM, AcOH, DCM; (c) X2ꢀPh:
PhCO2H, DIC, DMAP, DCM; X2ꢀNHAr: ArNCO, DMAP, DCM;
(d) 20% TFA in DCM, 2% Me2S scavanger.
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The two acids could be activated with PyBOP and
treated with pirrolidine to give the corresponding
amides 22 and 23. However attempts to synthesize the
ester 47 and 48 via carboxy group activation with DIC,
followed by reaction with MeOH and DMAP led to the
formation of byproducts possibly due to the internal
competition of the free hydroxy group in 46. The
transformation was cleanly accomplished using TMSÁ
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diazometane [7] in 1:1 THFÁMeOH (Scheme 6).
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Further manipulation of these substrates using the
same protocols discussed for 22 and 23 led to the desired
ester 53Á
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60, in a ꢀ80% purity by MS/HPLC (Scheme
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7).
In conclusion, conditions have been defined by which
largely diverse libraries of type 4 can be built starting
from the polyfunctional scaffold 1. Several hundred
compounds are being prepared using this strategy and
will be tested for biological activity.
1. Definitions and abbreviations
Scheme 6. Solid-phase anchoring of the partially protected scaffold.
(a) LiOH, MeOHÁH2O 3:1; (b) PyBOP, DIPEA, DMF, PAL-PS resin;
(c) PyBOP, DIPEA, pirrolidine, DMF; (d) TMSCHN2, MeOHÁTHF
1:1.
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DCM
DIC
dichloromethane
diisopropylcarbodiimide
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864
D. Arosio et al. / Il Farmaco 57 (2002) 861Á864
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boxylic acid, Tetrahedron Asymmetry 10 (1999) 3403Á3407;
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DIPEA
DMAP
DMF
NMM
PAL-PS
N,N-diisopropylethylamine
4-(dimethylamino)pyridine
N,N-dimethylformamide
(b) A. Bernardi, D. Arosio, L. Manzoni, D. Dellavecchia, F.
Micheli, A. Pasquarello, P. Seneci, Stereoselective synthesis of
conformationally constrained cyclohexanediols: a set of molecular
scaffolds for the synthesis of glycomimetics, J. Org. Chem. 66
4-methylmorpholine
5-(4-(9-fluorenylmethyloxycarbonil)amino-
methyl-3,5-dimetoxyphenoxy)-valeric acid-
polystirenic resin
(benzotriazol-1-yloxy)tripyrrolidinophos-
phonium hexafluorophosphate
tetrabutylammonium fluoride
(2001) 6209Á6216.
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[3] C.A. Lipinski, F. Lombardo, B.W. Dominy, P.J. Feeney, Experi-
mental and computational approaches to estimate solubility and
permeability in drug discovery and development settings, Adv.
Drug Deliv. Rev. 23 (1997) 3.
PyBOP
TBAF
[4] F. Albericio, N. Kneib-Cordonier, S. Biancalana, L. Gera, R.I.
Masada, D. Hudson, G. Barany, Preparation and application of
the 5-(4-(9-fluorenylmethyloxycarbonil)aminomethyl-3,5-dimetox-
yphenoxy)-valeric acid (PAL) handle for the solid-phase synthesis
of C-terminal peptide amides under mild conditions, J. Org. Chem.
TBDMSCl tert-butyldimethylsilyl chloride
TFA trifluoroacetic acid
THF Tetrahydrofuran
TMSCHN2 (trimethylsilyl)diazomethane
55 (1990) 3730Á3743.
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[5] S.A. Kates, S.B. Daniels, N.A. Sole, G. Barany, F. Albericio, in:
R.S. Hodges, J.A. Smith (Eds.), Peptides, Chemistry, Structure and
Biology Proceedings of 13th American Peptide Symposium,
ESCOM, Leiden, 1994, p. 113.
References
[6] C. Kallus, T. Opatz, T. Wunberg, W. Schmidt, S. Henke, H. Kunz,
Combinatorial solid-phase synthesis using
five-dimension-diversity scaffold, Tetrahedron Lett. 40 (1999)
7783Á7786.
D-galactose as a chiral
[1] See, for instance H. Richter, A. Trantwein, T. Walk, G. Jung, The
use of templates in combinatorial chemistry for the solid-phase
synthesis of multiple core structure libraries, in: G. Jung (Ed.),
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[7] D. Seyferth, H. Menzel, A.W. Dow, T. Flood, Trimethylsilyl-
Combinatorial Chemistry, Wiley-VCH, 1999, pp. 229Á256.
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substituded-diazoalkane. I. Trimethylsilyldiazomethane, J. Orga-
[2] (a) A. Bernardi, D. Arosio, D. Dellavecchia, F. Micheli, Improved
synthesis of both enantiomers of trans-cyclohex-4-ene-1,2-dicar-
nomet. Chem. 44 (1972) 279Á289.
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