1,3-allylic strain as a strategic diversification element for constructing libraries of substituted 2-arylpiperidines

Article abstract of DOI:10.1002/anie.201007133

Flipping diversity: Minimization of 1,3-allylic strain (A^{1, 3} strain) is a recurring element in the design of a stereochemically and spatially diverse collection of 2-arylpiperidines. A^{1, 3} strain guides the regioselective addition of nucleophiles and N-substituents leverage A ^{1, 3} strain to direct each stereoisomer to two different conformer populations, thus doubling the number of library members. Copyright

Full text of DOI:10.1002/anie.201007133

Communications
DOI: 10.1002/anie.201007133
Heterocycles
1,3-Allylic Strain as a Strategic Diversification Element for
Constructing Libraries of Substituted 2-Arylpiperidines**
Thomas C. Coombs, Gerald H. Lushington, Justin Douglas, and Jeffrey Aubꢀ*
Screening approaches to probe molecules for drug discovery
require access to high-quality, small-molecule libraries. One
contemporary challenge in providing such access is the
construction of libraries that maximize the coverage of
chemical (functional group), stereochemical, and spatial
diversity in a given chemotype.[1] Although the problem of
functional group diversity has been addressed since the
earliest days of combinatorial chemistry and parallel syn-
thesis, the incorporation of stereochemical diversity and,
more broadly, shape diversity has required the development
of new strategies. These include the use of spatially diverse
scaffolds or the pre-construction of stereochemically diverse
building blocks that are then combined to afford final
products (“build-couple-pair”[2] is an example of this).
Herein we describe a conformational switching approach
toward shape-diverse piperidine libraries in which the pres-
ence or absence of 1,3-allylic strain (A1,3 strain)[3] is leveraged
to enhance both 1) scaffold diversity by regiodivergent open-
Scheme 1. Use of A1,3 strain to control constitutional (2,4- vs. 2,5-Ar/
Nu relationship), stereochemical (cis vs. trans), and conformational
diversity in piperidine libraries. Functional group diversity arises from
variations in Ar, Nu, and R.
ing of epoxide intermediates and 2) the conformational space
of the final library through the simple expedient of changing
the nature of nitrogen substitution.[4] The concept is illus-
trated in Scheme 1 for a series of substituted 2-arylpiper-
idines. For a given epoxide isomer, the conformation of the
piperidine ring will depend on whether the N1 atom is sp3
hybridized (Ar preferring an equatorial position because of
the minimization of 1,3-diaxial interactions) or sp2 (Ar
preferring axial position because of A1,3 strain in the
equatorial isomer).[5] Nucleophilic addition to the epoxide
would then take place according to the Fꢀrst–Plattner
principle[6] (trans-diaxial opening), leading to two constitu-
tional isomers from this epoxide intermediate (2,4- versus 2,5-
cis Ar/Nu relationships). Stereochemical diversity would then
follow by applying the same principles to the alternative
epoxide diastereomer, affording the analogous 2,4- and 2,5-
trans isomers. Once prepared—and likely following the
downstream introduction of functional group diversity—the
compounds in the library could then be substituted at N by a
different set of alkyl or acyl substituents, thus leading to a
doubling of the library members through conformational
diversity.
We chose to demonstrate this approach by preparing a
library based on the triazole-containing piperidines shown in
Scheme 2 (selected because the arylpiperidine chemotype
appears in a number of bioactive compounds and is therefore
a desirable library scaffold for broad screening).[7] To a first
approximation, the expected conformations in one such
library are shown (four isomers bearing two different
N groups), thus demonstrating the range of conformational
and configurational space covered by these compounds.
To demonstrate the value of 1,3-allylic strain in scaffold
preparation, we first carried out the stereochemically and
constitutionally differentiated scaffold syntheses shown in
Scheme 3. Four 2-aryl-1,2,3,6-tetrahydropyridines were con-
structed from substituted benzaldehydes[8] in two steps by
bisallylation/N-acylation and subsequent ring-closing me-
tathesis. The N-acylated derivatives underwent highly stereo-
selective epoxidation reactions, presumably because the top
faces as drawn were blocked by the aromatic groups in the
most stable conformations.[5] By using m-CPBA or methyl-
[*] Dr. T. C. Coombs, Prof. Dr. J. Aubꢀ
Chemical Methodologies and Library Development Center
University of Kansas, Delbert M. Shankel Structural Biology Center
2121 Simons Drive, West Campus, Lawrence, KS 66047 (USA)
Fax: (+1)785-864-4496
E-mail: jaube@ku.edu
Homepage: medchem.ku.edu/faculty/Aube
Dr. G. H. Lushington
Molecular Graphics Laboratory, University of Kansas
Lawrence, KS 66047 (USA)
Dr. J. Douglas
NMR Laboratory, University of Kansas
Lawrence, KS 66047 (USA)
[**] This work was supported by the National Institute of General
Medical Sciences (P50 69663).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201007133.
2734
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 2734 –2737

Scheme 2. Conformational diversity of targeted library containing sp3
and sp2 hybridized N-substituted versions of scaffolds A and B. In all,
eight idealized conformers (four amines and four amides, all piper-
idines as chairlike conformation) are shown in the two overlays.
Details, including the calculations of individual structures, are pro-
vided in the Supporting Information.
(trifluoromethyl)dioxirane,[9] the epoxidation from the less-
hindered bottom alkene face afforded anti-epoxides 3 (after
DBU-mediated Fmoc removal) and 5.[10] Alternatively, NBS/
H2O produced an uncharacterized bromohydrin intermedi-
ate,[11] resulting from trans-diaxial addition of H2O to the
bromonium ion formed on the less-hindered bottom alkene
face. Treatment with base delivered the corresponding syn-
epoxides 4 and 6.[12]
Both NH and N-acylated epoxy piperidines were pre-
pared as each was expected to react through the divergent
conformations shown in Scheme 3b to provide regioisomeric
nucleophilic addition products according to the well-estab-
lished Fꢀrst–Plattner principle of trans-diaxial epoxide ring
opening.[6a] In this way, allylic strain controlled both the
stereochemical and regiochemical outcome of scaffold syn-
thesis, delivering all four isomers of the trans-4,5-disubstituted
2-arylpiperidines desired for the targeted library. In only one
stereochemical series was no selectivity obtained: epoxide 6
gave an essentially 1:1 mixture because of competing
electronic and stereoelectronic preferences for this epoxide
(see the Supporting Information for details). However, even
in this case, we were able to isolate more than 700 mg
quantities of the desired NH azido alcohols in high purity (as
was the case for all 16 of the desired scaffolds) for further
diversification.
The scaffolds were decorated by removal of the Boc group
(if present) and either subsequent reductive alkylation or
N acylation, and finally, a copper-induced triazole formation
step (Scheme 4).[13] For this initial, speculative screening
library, we chose a relatively small number of substituents that
represent a range of aliphatic and aromatic diversity at the
newly introduced positions. The total number of compounds
Scheme 3. Preparation of scaffold precursors by A) tetrahydropiperi-
dine synthesis and B) stereoselective epoxidation reactions and allylic
strain control of regiochemistry of epoxide ring opening (general
reaction conditions for azidation: NaN3, NH4Cl, MeOH/H2O (3:1),
608C). Boc=tert-butoxycarbonyl, Fmoc=9-fluorenylmethyloxycarbonyl,
mCPBA=meta-chloroperbenzoic acid, NBS=N-bromosuccinimide,
THF=tetrahydrofuran.
targeted in these steps, where R1 and R2 were one of the three
substituents shown, was 16 ꢁ 9 ꢁ 2 = 288 compounds. After
parallel synthesis, the library was prepared for screening by
mass-directed HPLC purification, yielding ultimately 268
compounds in greater than 90% purity (UV) and greater than
10 mg quantities. All compounds were characterized by high-
resolution mass spectrometry.
A subset of 32 compounds (16 amines and the 16
corresponding amides), comprising four substitution patterns
for each of the four stereochemical and constitutional
isomers, was subjected to conformational analysis by
1H NMR spectroscopy using coupling constant analysis. The
data revealed that each functionalized amino/piperidine
Angew. Chem. Int. Ed. 2011, 50, 2734 –2737
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
2735

Communications
Scheme 4. Scaffold diversification. PS-Pip=polystyrene-based piperi-
dine.
isomer adopted the same conformation in solution, regardless
of the substituents appended to the core. The same held true
for the corresponding amides.
The conformational profiles of the eight stereochemical
families of the triazole-containing piperidines (4 amines and 4
amides) are shown in Figure 1.[14] Figure 1a shows overlays of
each amino/piperidine (blue) paired with the corresponding
amido/piperidine (green) counterpart, highlighting the con-
formational differences achieved through the introduction of
1,3-allylic strain. Three of the four families of amino/
piperidines adopted chair conformations, thus placing the 2-
aryl substituents in the equatorial position. The 2,4-trans
family of amino/piperidines exhibited a slight distortion from
an ideal chair conformation, while still placing the 2-aryl
substituents in a pseudoequatorial position. The correspond-
ing 2,5-cis and 2,4-trans families of amido/piperidines adopted
the opposite chair conformations, thus placing the 2-aryl
substituents in the axial position. However, rather than
adopting chair conformations and placing all three non-
hydrogen substituents (Ph, OH, triazole) in axial positions,
the 2,5-trans amido/piperidines exhibited twistlike conforma-
tions, and the 2,4-cis amido/piperidines adopted boat con-
formations. Thus, each of the eight compounds in the family
presents the piperidine substituents in a unique three-dimen-
sional array. Taken together, these compounds (and by
extension the entire library that they represent) comprise a
shape-diverse collection with predictable three-dimensional
shapes for use in biological screening and the development of
structure–activity relationship (SAR) studies (Figure 1b).
Through these efforts, we have demonstrated a useful
protocol for maximizing the stereochemical diversity in a
piperidine library using a limited number of scaffolds and
building blocks. This approach features the use of 1,3-allylic
strain for controlling both the ring opening of epoxide
precursors and, thus, constitutional isomerism, as well as the
conformations of the final library members. In so doing, a
library of 268 druglike compounds having predictable con-
formations has been prepared. The compounds prepared in
this work are being scrutinized by high-throughput screening
whereas the concepts utilized in the present case are currently
Figure 1. a) Overlays contrasting amino/piperidine conformation
(blue) with the corresponding amido/piperidine conformation (green)
for each isomeric pair (NMR). b) Overlay showing the chemical space
occupied by the entire library. For each case: Ar=Ph, R1 =2-thiophene,
R2 =CH2OBz. For individual conformational analyses, see the Support-
ing Information. Bz=benzoyl.
being applied to the construction of other heterocyclic
libraries.
Received: November 12, 2010
Revised: January 13, 2011
Published online: February 23, 2011
Keywords: compound libraries · heterocycles ·
.
strained molecules · synthetic methods
[1] For examples of stereochemical diversity in library design, see:
a) D. A. Annis, O. Helluin, E. N. Jacobsen, Angew. Chem. 1998,
110, 2010 – 2012; Angew. Chem. Int. Ed. 1998, 37, 1907 – 1909;
b) A. M. Misske, H. M. R. Hoffmann, Chem. Eur. J. 2000, 6,
3313 – 3320; c) O. Arjona, R. Menchaca, J. Plumet, J. Org. Chem.
2001, 66, 2400 – 2413; d) B. A. Harrison, T. M. Gierasch, C.
2736
www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 2734 –2737

Neilan, G. W. Pasternak, G. L. Verdine, J. Am. Chem. Soc. 2002,
124, 13352 – 13353; e) T. O. Schrader, M. L. Snapper, J. Am.
Chem. Soc. 2002, 124, 10998 – 11000; f) M. D. Burke, S. L.
Schreiber, Angew. Chem. 2004, 116, 48 – 60; Angew. Chem. Int.
Ed. 2004, 43, 46 – 58; g) Y.-k. Kim, M. A. Arai, T. Arai, J. O.
Lamenzo, E. F. Dean, III, N. Patterson, P. A. Clemons, S. L.
Schreiber, J. Am. Chem. Soc. 2004, 126, 14740 – 14745; h) S.
Krishnan, S. L. Schreiber, Org. Lett. 2004, 6, 4021 – 4024; i) J. C.
Wong, S. M. Sternson, J. B. Louca, R. Hong, S. L. Schreiber,
Chem. Biol. 2004, 11, 1279 – 1291; j) A. B. Beeler, D. E. Acqui-
lano, Q. Su, F. Yan, B. L. Roth, J. S. Panek, J. A. Porco, J. Comb.
Chem. 2005, 7, 673 – 681; k) B. Clique, A. Ironmonger, B.
Whittaker, J. Colley, J. Titchmarsh, P. Stockley, A. Nelson,
Org. Biomol. Chem. 2005, 3, 2776 – 2785; l) S. Das, L.-S. Li, S.
Abraham, Z. Chen, S. C. Sinha, J. Org. Chem. 2005, 70, 5922 –
5931; m) D. P. Curran, Q. Zhang, C. Richard, H. Lu, V. Gudipati,
C. S. Wilcox, J. Am. Chem. Soc. 2006, 128, 9561 – 9573; n) S.
Shang, H. Iwadare, D. E. Macks, L. M. Ambrosini, D. S. Tan,
Org. Lett. 2007, 9, 1895 – 1898; o) I. E. Wrona, J. T. Lowe, T. J.
Turbyville, T. R. Johnson, J. Beignet, J. A. Beutler, J. S. Panek, J.
Org. Chem. 2009, 74, 1897 – 1916; p) L. Liu, P. E. Floreancig,
Angew. Chem. 2010, 122, 3133 – 3136; Angew. Chem. Int. Ed.
2010, 49, 3069 – 3072.
[4] For the use of 1,3-allylic strain in controlling the stereochemistry
of 2,4-disubstituted piperidines, see: a) P. S. Watson, B. Jiang, B.
Scott, Org. Lett. 2000, 2, 3679 – 3681; for an alternative approach
to triazole-containing piperidine scaffolds, see: b) H. Schramm,
W. Saak, C. Hoenke, J. Christoffers, Eur. J. Org. Chem. 2010,
1745 – 1753.
[5] a) I. S. Kim, J. S. Oh, O. P. Zee, Y. H. Jung, Tetrahedron 2007, 63,
2622 – 2633; b) E. E. Sugg, J. F. Griffin, P. S. Portoghese, J. Org.
Chem. 1985, 50, 5032 – 5037; c) H. Paulsen, K. Todt, Angew.
Chem. 1966, 78, 943 – 944; Angew. Chem. Int. Ed. Engl. 1966, 5,
899 – 900; d) F. Johnson, Chem. Rev. 1968, 68, 375 – 413.
[6] a) A. Fꢀrst, P. A. Plattner, Helv. Chim. Acta 1949, 32, 275 – 283;
b) C. J. Monceaux, P. R. Carlier, Org. Lett. 2010, 12, 620 – 623.
[7] D. A. Horton, G. T. Bourne, M. L. Smythe, Chem. Rev. 2003, 103,
893 – 930.
[8] Benzaldehyde substitution patterns were chosen from the top
tier of the Topliss chart: J. G. Topliss, J. Med. Chem. 1972, 15,
1006 – 1011.
[9] a) D. Yang, Acc. Chem. Res. 2004, 37, 497 – 505; b) D. Yang, M.-
K. Wong, Y.-C. Yip, J. Org. Chem. 1995, 60, 3887 – 3889.
[10] Boc-protected tetrahydropyridine epoxidation with m-CPBA
gave low and irreproducible yields of epoxide 5.
[11] a) F. Zhang, Z. J. Song, D. Tschaen, R. P. Volante, Org. Lett.
2004, 6, 3775 – 3777; b) A. J. Pearson, S. Y. Hsu, J. Org. Chem.
1986, 51, 2505 – 2511.
[12] Ratios were determined as shown in Scheme 3 for all examples
where Ar= Ph. For other Ar groups, the corresponding inter-
mediates were not isolated nor were the ratios determined prior
to isolation of the final azido alcohols.
[13] V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless,
Angew. Chem. 2002, 114, 2708 – 2711; Angew. Chem. Int. Ed.
2002, 41, 2596 – 2599.
[14] Details of the conformational analyses and depictions of the
individual isomers are provided in the Supporting Information.
[2] a) T. Nielsen, S. Schreiber, Angew. Chem. 2008, 120, 52 – 61;
Angew. Chem. Int. Ed. 2008, 47, 48 – 56; b) D. Pizzirani, T. Kaya,
P. A. Clemons, S. L. Schreiber, Org. Lett. 2010, 12, 2822 – 2825;
c) L. A. Marcaurelle, E. Comer, S. Dandapani, J. R. Duvall, B.
Gerard, S. Kesavan, M. D. Lee, H. Liu, J. T. Lowe, J.-C. Marie,
C. A. Mulrooney, B. A. Pandya, A. Rowley, T. D. Ryba, B.-C.
Suh, J. Wei, D. W. Young, L. B. Akella, N. T. Ross, Y.- L. Zhang,
D. M. Fass, S. A. Reis, W.-N. Zhao, S. J. Haggarty, M. Palmer,
M. A. Foley, J. Am. Chem. Soc. 2010, 132, 16962 – 16976.
[3] R. W. Hoffmann, Chem. Rev. 1989, 89, 1841 – 1860.
Angew. Chem. Int. Ed. 2011, 50, 2734 –2737
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
2737