Macrolactone-based dynamic combinatorial libraries of cholate monomers bearing recognition functionality

Article abstract of DOI:10.1016/S0040-4039(00)01866-9

Dynamic combinatorial libraries were generated incorporating new pyridine and dimethylaniline containing monomers. These libraries were analyzed using ¹H NMR and HPLC-UV-MS. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01866-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 10171–10174
Macrolactone-based dynamic combinatorial libraries of
cholate monomers bearing recognition functionality
Philip S. Lukeman* and Jeremy K. M. Sanders
University Chemical Laboratory, University of Cambridge, Lensfield Rd, Cambridge CB2 1EW, UK
Received 3 August 2000; accepted 23 October 2000
Abstract
Dynamic combinatorial libraries were generated incorporating new pyridine and dimethylaniline
containing monomers. These libraries were analyzed using 1H NMR and HPLC–UV–MS. © 2000
Published by Elsevier Science Ltd.
Keywords: combinatorial chemistry; molecular recognition; macrocyclization.
In the process of expanding our group’s work on templating dynamic combinatorial libraries
(DCLs),1 we have now synthesized monomers Sp and Sd. The monomers were designed to
function as isosteres of the deoxycholic acid monomer Sa (Fig. 1) with directional recognition
functionality specific for metal centers. We have also devised conditions for the quantitative
analysis of libraries.
Figure 1. Deoxycholate monomers utilized in DCL formation
In earlier work, when a 5 mM solution of Sa in toluene was exposed to the reversible
macrolactonization conditions developed for DCL formation, primarily cyclic dimer, trimer and
tetramer were formed. The product distribution changed upon addition of alkali metal ions2
indicating that a template effect was occurring. An ESI-MS study of the interaction between
* Corresponding author. Present address: Department of Chemistry, New York University, 29 Washington Place,
New York, NY 10003, USA. Tel: +1 212 998 8394; fax: +1 212 260 7905; e-mail: phil.lukeman@nyu.edu
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01866-9

10172
alkali metal ions and the individual constituents of these DCLs provided a correlation with the
observed product distribution changes.3
With this result in hand, we wished to increase the range of templates available to steroidal
monomers. Incorporating a pyridyl unit into Sp would allow the use of co-ordination chemistry
as a more sophisticated templating tool than the essentially directionless electrostatic interac-
tions that operated previously with alkali metal ions. The Sd monomer would act as a control
in these reactions—this monomer, bearing a tertiary amine, should bind less strongly than the
pyridine unit in Sp to carefully chosen metal centers.
Synthesis of Sp and Sd was straightforward (Fig. 2). Acetimidates 1 and 2 were prepared
using literature conditions4 from the corresponding alcohols. Methyl deoxycholate-3%-acetate
was reacted under previously developed2 acid catalyzed conditions with the acetimidate 1 to
form 3. This intermediate was coupled with 4-trimethylstannylpyridine5 under Stille coupling
conditions6 to form the biaryl compound, which was then deprotected under basic conditions to
provide Sp.
,
Figure 2. Synthesis of Sp and Sd. (i) 1 or 2 (1.2 equiv.), CCl4, C6H12, F3CSO3H (0.05 equiv.), 4 A molecular sieves,
rt, 3 h, 70%; (ii) 4-trimethylstannylpyridine (2 equiv.), Pd(PPh3)4 (0.05 equiv.), toluene, reflux, 48 h, 70%; (iii)
4-(N,N-dimethylamino) phenylzincbromide (1.1 equiv.), Pd(PPh3)4 (0.05 equiv.), THF, rt, 2 h, 65%; (iv) KOMe (2
equiv.), MeOH, THF, rt, 1 h, 90%
The analogous Stille reaction was carried out to synthesize Sd and this resulted in a product
which was extremely laborious to purify. The organozinc compound of 4-bromodimethylaniline7
also reacted sluggishly under Negishi8 conditions with 3. Using iodo intermediate 4 under the
same reaction conditions provided the biaryl that was essentially free of contaminants. This
intermediate was deprotected under standard conditions to provide Sd. All new compounds gave
1
satisfactory H and 13C NMR, IR, HRMS and HPLC analyses.9
Cyclization of the monomers at 5 mM utilizing our standard thermodynamic macrolactoniza-
tion conditions provided DCLs containing >90% dimer, trimer and tetramer, as demonstrated
by HPLC–MS and 1H NMR. Cyclization of Sp provided
a
40:50:10 ratio of
dimer:trimer:tetramer, while Sd gave 25:50:25. The decrease in dimer in the case of Sd relative
to Sp was probably caused by repulsion between the electron rich aniline rings, or steric
repulsion between the dimethylamine groups.
Individual samples of cyclic species Sp2, Sp3, Sp4, Sd2, Sd3 and Sd4 were separated from DCL
reaction mixtures using preparative TLC. The spectroscopic (1H NMR) and chromatographic

10173
(RP-HPLC) properties of these compounds confirmed the identity of the cyclization
components.
Cyclizing a 1:1 mixture of Sp and Sd at 5 mM total monomer concentration resulted in a
1
DCL containing at least 16 species, as demonstrated by ESI-MS. A H NMR spectrum of the
DCL at 600 MHz showed a well resolved set of signals corresponding to the 12bH protons in
the dimers Sp2, SpSd and Sd2. Integration of these signals indicated the expected 1:2:1 ratio of
these macrocycles. All other ‘fingerprint’ signals corresponding to other protons in the mixed
macrocycles were too closely spaced for accurate integration.
To fully quantitate this DCL, we turned to HPLC. After much experimentation, a reverse
phase column (Supelco ABZ+ C16 alkylamide) was found to give the best separation of DCL
components. A two-stage gradient elution was employed utilizing mixtures of MeCN (with 5%
i
aqueous HCO2H) and PrOH (with 5% aqueous HCO2H). The oligomers were cleanly separated
in a 70 minute HPLC run (Fig. 3), and their relative quantities ascertained by integration of the
UV absorptions. Individual UV spectra of each peak displayed the expected ratios of maxima
at 260 and 290 nm corresponding to the absorptions of the phenylpyridine and phenylaniline
ring systems. Additionally, use of ESI-MS allowed examination of each peak’s mass spectrum
and these were also found to be in accordance with predicted values.
Figure 3. HPLC–MS of the Sp+Sd DCL
We attempted to template these reactions utilizing coordination to either zinc(II) porphyrins
or Pt(II). Complexes of Sp with Pt(II) or electron deficient Zn(II) porphyrins such as tetra-
kis(meso-phenyl) octachloroporphyrin and tetrakis(meso-trifluoromethyl) porphyrin were syn-
thesized. When these complexes were exposed to our DCL forming conditions no macrolactones
were observed and reduction byproducts of the template molecule were formed.

10174
Utilizing the more electron rich Zn(II) tetraphenylporphyrin resulted in competitive binding
of the catalyst to the porphyrin and necessitated the addition of excessive amounts of catalyst
to drive the reaction to completion. Analysis of these DCLs showed no appreciable shift in the
oligomer distributions.
Through these studies it has become clear that the present transesterification reaction
conditions severely limit the scope of the molecular recognition chemistries available to template
DCLs. Utilization of milder bond-breaking and making chemistry appears to be the key to
successful templating of DCLs using complex structures. These studies10,11 are currently under-
way.
Supplementary information: HPLC methods and characterizations of monomers/oligomers are
available upon request.
Acknowledgements
P.S.L. thanks the EPSRC (UK), the Newton Trust and Sidney Sussex College Cambridge for
financial support.
References
1. Cousins, G. R. L.; Poulsen, S. A.; Sanders, J. K. M. Curr. Opin. Chem. Biol. 2000, 4, 270.
2. Brady, P. A.; Sanders, J. K. M. J. Chem. Soc., Perkin Trans. 1 1997, 3237.
3. Brady, P. A.; Sanders, J. K. M. New J. Chem. 1998, 22, 411.
4. Patil, V. J. Tetrahedron Lett. 1996, 37, 1481.
5. Clyde-Watson, Z.; Vidal-Ferran, A.; Twyman, L. J.; Walter, C. J.; McCallien, D. W. J.; Fanni, S.; Bampos, N.;
Wylie, R. S.; Sanders, J. K. M. New J. Chem. 1998, 22, 493.
6. Scott, W. J.; Stille, J. C. Acc. Chem. Res. 1988, 21, 47.
7. Amatore, C.; Jutand, A.; Negri, S.; Fauvarque, J. F. J. Organometal. Chem. 1990, 390, 389.
8. Negishi, E. I. J. Org. Chem. 1977, 42, 1821.
1
9. Selected analytical data: Sp monomer. H NMR (400 MHz, CDCl3): 8.62 (2H, d, J=6.1 Hz, pyaH
6
), 7.61 (2H,
), 4.33–4.66 (2H, ABq, ArCH2), 3.71
6
). HRMS (ES): 574.3904 (M+H)+ C37H52NO4 requires
d, J=12.5 Hz, AraH
(1H, m, 12bH), 3.64 (3H, s, CO2CH3
574.3896.
Sd monomer. H NMR: 7.54 (2H, d, J=8.1 Hz, mArH
oArH), 6.80 (2H, d, J=8.7 Hz, anaH), 4.32–4.61 (2H, ABq, J=11.6 Hz, ArCH
s, CO2CH3), 3.57 (1H, m, 3bH), 2.99 (6H, s, N(CH3 2
) ). HRMS (+FAB): 601.4130 (M−CH2)+ C39H55NO4 requires
601.4186.
6
), 7.43–7.52 (4H, d+d, J=6.1 Hz+12.5 Hz, pybH
6
+ArbH
6
6
6
6
), 3.56 (1H, brm, 3bH
1
6
), 7.51 (2H, d, J=8.7 Hz, anbH
6
), 7.39 (2H, d, J=8.1 Hz,
), 3.66 (3H,
6
6
6
2), 3.71 (1H, m, 12bH
6
6
6
6
10. Cousins, G. R. L.; Poulsen, S. A.; Sanders, J. K. M. Chem. Commun. 1999, 1575.
11. Simpson, M. G.; Watson, S. P.; Feeder, N.; Davies, J. E.; Sanders, J. K. M. Org. Lett. 2000, 2, 1435.
.
.