Synthesis of a tetrasubstituted tetrahydronaphthalene scaffold for α-helix mimicry via a MgBr2-catalyzed Friedel-Crafts epoxide cycloalkylation

Article abstract of DOI:10.1021/ol402334j

α-Helices are ubiquitous protein recognition elements that bind diverse biomolecular targets. The synthesis of a small molecule scaffold to present the side chains of an α-helix is described. The 1,3,5,7-tetrasubstituted 1,2,3,4-tetrahydronaphthalene scaf

Full text of DOI:10.1021/ol402334j

ORGANIC
LETTERS
2013
Vol. 15, No. 18
4892–4895
Synthesis of a Tetrasubstituted
Tetrahydronaphthalene Scaffold for
r‑Helix Mimicry via a MgBr2‑Catalyzed
FriedelꢀCrafts Epoxide Cycloalkylation
Devan Naduthambi, Santosh Bhor, Michael B. Elbaum, and Neal J. Zondlo*
Department of Chemistry and Biochemistry, University of Delaware, Newark,
Delaware 19716, United States
zondlo@udel.edu
Received August 14, 2013
ABSTRACT
R-Helices are ubiquitous protein recognition elements that bind diverse biomolecular targets. The synthesis of a small molecule scaffold to
present the side chains of an R-helix is described. The 1,3,5,7-tetrasubstituted 1,2,3,4-tetrahydronaphthalene scaffold, providing mimicry of the i,
iþ3, and iþ4 positions of an R-helix, was synthesized using a novel MgBr2-catalyzed FriedelꢀCrafts epoxide cycloalkylation as the key step. Each
position may be differentiated via O-alkylation after scaffold synthesis, generating a diversity-oriented approach to readily synthesize
proteomimetics for different targets.
R-Helices are fundamental protein secondary structure
elements that are broadly utilized in biomolecular
recognition.1 Proteinꢀprotein, proteinꢀDNA, and proteinꢀ
RNA interactions employ R-helices as critical recognition
epitopes. Inhibitors of R-helical protein interactions have
considerable potential as therapeutics for a wide range of
diseases.2
In R-helix-mediated recognition, the primary role of the
R-helix is to organize the side chains for interaction with
the target, with the protein typically undergoing a disorder-
to-order transition. The protein backbone normally does
not directly interact with the target molecule, instead
primarily serving as a scaffold to organize side chains
for target recognition. In view of its scaffolding role, the
protein backbone could be replaced with an organic scaf-
fold that can similarly present the equivalent protein side
chain functionalities. In an R-helical proteomimetic ap-
proach, protein sequence information can be directly
applied to inhibitor design, resulting in the rapid develop-
ment of lead compounds.
A series of elegant R-helix proteomimetics for a range
of biomedically important protein targets has been de-
veloped.2,3 We sought to develop a novel scaffold for
R-helical proteomimetics that would incorporate the fol-
lowing properties: (1) presentation of the side chains along
one R-helical face over two helical turns; (2) strong con-
formational preferences in the scaffold while retaining
sufficient flexibility to adapt to a broad range of protein
interfaces; (3) rapid synthesis of target molecules from a
universal scaffold; (4) facile incorporation of a wide range
of functional groups via readily available compounds; (5)
inclusion of a functionalizable handle to modulate electro-
statics and solubility and to use as a linker for subsequent
experiments; and (6) chirality to potentially increase target
specificity.
(1) Jochim, A. L.; Arora, P. S. Mol. BioSyst. 2009, 5, 924–926.
(2) (a) Cummings, C. G.; Hamilton, A. D. Curr. Opin. Chem. Biol.
2010, 14, 341–346. (b) Haridas, V. Eur. J. Org. Chem. 2009, 5112–5128.
(c) Davis, J. M.; Tsou, L. K.; Hamilton, A. D. Chem. Soc. Rev. 2007, 36,
326–334. (d) Garner, J.; Harding, M. M. Org. Biomol. Chem. 2007, 5,
3577–3585. (e) Jochim, A. L.; Arora, P. S. ACS Chem. Biol. 2010, 5, 919–
923. (f) Bullock, B. N.; Jochim, A. L.; Arora, P. S. J. Am. Chem. Soc.
2011, 133, 14220–14223. (g) Azzarito, V.; Long, K.; Murphy, N. S.;
Wilson, A. J. Nat. Chem. 2013, 5, 161–173.
r
10.1021/ol402334j
Published on Web 09/09/2013
2013 American Chemical Society

We identified a tetrasubstituted tetrahydronaphthalene
as a promising scaffold for R-helix mimicry (Figure 1). In
this scaffold, the oxygens are equivalent to the R carbon
of the protein backbone, with side chains readily added
to the scaffold as electrophiles in standard substitution
chemistry. Moreover, this scaffold has two major ring
conformations, allowing mimicry of both ideal and non-
ideal R-helices.
The 1,3,5,7-oxygen-tetrasubstituted ring system of the
scaffold has not previously been described. However, a
straightforward synthesis from the inexpensive compound
1 or the commercially available compound 4 was envi-
sioned. Grignard addition to the aldehyde 4, followed
by protection and epoxidation, yielded 7 as a precursor
electrophile for synthesis of the bicyclic system (Scheme 1).
In the original approach to the 6,6-bicyclic system, an
aryl-brominated variant of 7 was converted to a Grignard
reagent in order to effect intramolecular nucleophilic ad-
dition to the epoxide. Despite good precedence for this
reaction in model systems, that reaction proceeded poorly.
However, surprisingly, product formation was observed
after quenching the Grignard reagent. Those results were
suggestive of an electrophilic aromatic substitution reac-
tion with the epoxide mediated by Mg(II). Reaction of
Figure 1. (a) A tetrahydronaphthalene scaffold to mimic the
i, iþ3, and iþ4 residues over 2 turns of an R-helix. The O is
designed to be equivalent to the CR on the protein. (b) Scaffold
(R0 = R3 = R4 = H) structure, with the major ring conforma-
tions of the trans and cis diastereomers shown. OꢀO distances in
the proteomimetic are nearly identical to the CRꢀCR distances
in a canonical R-helix: the benzylic O, when in a pseudoaxial
˚
conformation, is 5.2ꢀ5.8 A from the phenolic oxygens. When
7 with MgBr2 OEt2 (Scheme 2) resulted in the formation
of the cycloalkylation products 8 and 9 as a mixture
of diastereomers, proceeding effectively to generate the
3
the benzylic O is in a pseudoequatorial conformation, the
˚
corresponding distances are 4.9ꢀ6.1 A, similar to those found
in the nonideal R-helices often observed in recognition R-helices.
Rotation about the CꢀO bonds provides flexibility in binding
to different helical interfaces at a modest cost in conforma-
(3) (a) Xuereb, H.; Maletic, M.; Gildersleeve, J.; Pelczer, I.; Kahne,
D. J. Am. Chem. Soc. 2000, 122, 1883–1890. (b) Orner, B. P.; Ernst, J. T.;
Hamilton, A. D. J. Am. Chem. Soc. 2001, 123, 5382–5383. (c) Ernst, J. T.;
Kutzki, O.; Debnath, A. K.; Jiang, S.; Lu, H.; Hamilton, A. D. Angew.
Chem., Int. Ed. 2002, 41, 278–281. (d) Kutzki, O.; Park, H. S.; Ernst,
J. T.; Orner, B. P.; Yin, H.; Hamilton, A. D. J. Am. Chem. Soc. 2002, 124,
11838–11839. (e) Ernst, J. T.; Becerril, J.; Park, H. S.; Yin, H.; Hamilton,
A. D. Angew. Chem., Int. Ed. 2003, 42, 535–539. (f) Minter, A. R.;
Brennan, B. B.; Mapp, A. K. J. Am. Chem. Soc. 2004, 126, 10504–10505.
(g) Rodriguez, A. L.; Tamrazi, A.; Collins, M. L.; Katzenellenbogen,
J. A. J. Med. Chem. 2004, 47, 600–611. (h) Davis, J. M.; Truong, A.;
Hamilton, A. D. Org. Lett. 2005, 7, 5405–5408. (i) Yin, H.; Fredrick,
K. K.; Liu, D.; Wand, A. J.; DeGrado, W. F. Org. Lett. 2006, 8, 223–225.
(j) Kim, I. C.; Hamilton, A. D. Org. Lett. 2006, 8, 1751–1754. (k)
Becerril, J.; Hamilton, A. D. Angew. Chem., Int. Ed. 2007, 46, 4471–
4473. (l) Rodriguez, J. M.; Hamilton, A. D. Angew. Chem., Int. Ed. 2007,
46, 8614–8617. (m) Zhou, H. B.; Collins, M. L.; Gunther, J. R.;
Comninos, J. S.; Katzenellenbogen, J. A. Bioorg. Med. Chem. Lett.
2007, 17, 4118–4122. (n) Volonterio, A.; Moisan, L.; Rebek, J., Jr. Org.
Lett. 2007, 9, 3733–3736. (o) Restorp, P.; Rebek, J., Jr. Bioorg. Med.
Chem. Lett. 2008, 18, 5909–5911. (p) Gunther, J. R.; Moore, T. W.;
Collins, M. L.; Katzenellenbogen, J. A. ACS Chem. Biol. 2008, 3, 282–
286. (q) Saraogi, I.; Incarvito, C. D.; Hamilton, A. D. Angew. Chem., Int.
tional entropy. (c) Overlay of the trans scaffold (gray, R0
=
R3 = R4 = Me) with residues 19ꢀ23 of the p53 activation domain
(cyan; backbone and Phe19, Leu22, and Trp23 side chains shown).4
All chiral compounds synthesized herein are racemates.
6-endo products in CH2Cl2. The reaction proceeded poor-
ly in coordinating solvents. Other Lewis acids (AlCl3,
FeCl3, ZnCl2) were also ineffective.
FriedelꢀCrafts epoxide cycloalkylation reactions have
previously been described using several strong Lewis acid
catalysts, including SnCl4, BF3, and TiCl4, as well as a
recent major advance using AuCl3.5 These reactions all
generated the 6-endo products. In our case, the use of
SnCl4 or BF3 resulted in decomposition of the starting
material and AuCl3 was cost-prohibitive on a preparative
scale. The MgBr2-catalyzed FriedelꢀCrafts epoxide
€
Ed. 2008, 47, 9691–9694. (r) Maity, P.; Konig, B. Org. Lett. 2008, 10,
1473–1476. (s) Parent, A. A.; Gunther, J. R.; Katzenellenbogen, J. A.
J. Med. Chem. 2008, 51, 6512–6530. (t) Gunther, J. R.; Parent, A. A.;
Katzenellenbogen, J. A. ACS Chem. Biol. 2009, 4, 435–440. (u)
Cummings, C. G.; Ross, N. T.; Katt, W. P.; Hamilton, A. D. Org. Lett.
2009, 11, 25–28. (v) Hebda, J. A.; Saraogi, I.; Magzoub, M.; Hamilton,
A. D.; Miranker, A. D. Chem. Biol. 2009, 16, 943–950. (w) Shaginian, A.;
Whitby, L. R.; Hong, S.; Hwang, I.; Farooqi, B.; Searcey, M.; Chen, J.;
Vogt, P. K.; Boger, D. L. J. Am. Chem. Soc. 2009, 131, 5564–5572.
(x) Williams, A. B.; Weiser, P. T.; Hanson, R. N.; Gunther, J. R.;
Katzenellenbogen, J. A. Org. Lett. 2009, 11, 5370–5373. (y) Plante, J. P.;
Burnley, T.; Malkova, B.; Webb, M. E.; Warriner, S. L.; Edwards, T. A.;
Wilson, A. J. Chem. Commun. 2009, 5091–5093. (z) Marimganti, S.;
Cheemala, M. N.; Ahn, J.-M. Org. Lett. 2009, 2009, 4418–4421. (aa)
Tosovska, P.; Arora, P. S. Org. Lett. 2010, 12, 1588–1591. (ab) Campbell,
F.; Plante, J. P.; Edwards, T. A.; Warriner, S. L.; Wilson, A. J. Org.
Biomol. Chem. 2010, 8, 2344–2351. (ac) Adler, M. J.; Hamilton, A. D.
J. Org. Chem. 2011, 76, 7040–7047. (ad) Thompson, S.; Hamilton, A. D.
Org. Biomol. Chem. 2012, 10, 5780–5782. (ae) Cummings, C. G.;
Hamilton, A. D. Tetrahedron 2013, 69, 1663–1668.
(4) Kussie, P. H.; Gorina, S.; Marechal, V.; Elenbaas, B.; Moreau, J.;
Levine, A. J.; Pavletich, N. P. Science 1996, 274, 948–953.
(5) (a) Taylor, S. K.; Hockerman, G. H.; Karrick, G. L.; Lyle, S. B.;
Schramm, S. B. J. Org. Chem. 1983, 48, 2449–2452. (b) Taylor, S. K.;
Davisson, M. E.; Hissom, B. R.; Brown, S. L.; Pristach, H. A.; Schramm,
S. B.; Harvey, S. M. J. Org. Chem. 1987, 52, 425–429. (c) Nagumo, S.;
Miyoshi, I.; Akita, H.; Kawahara, N. Tetrahedron Lett. 2002, 43, 2223–
2226. (d) Shi, Z. J.; He, C. J. Am. Chem. Soc. 2004, 126, 5964–5965. (e)
Ueki, H.; Kitazume, T. J. Org. Chem. 2005, 70, 9354–9363. (f) Marcos,
R.; Rodriguez-Escrich, C.; Herrerias, C. I.; Pericas, M. A. J. Am. Chem.
Soc. 2008, 130, 16838–16839. (g) Liu, Y. X.; Li, X. B.; Lin, G.; Xiang, Z.;
Xiang, J.; Zhao, M. Z.; Chen, J. H.; Yang, Z. J. Org. Chem. 2008, 73,
4625–4629. (h) Nagumo, S.; Miura, T.; Mizukami, M.; Miyoshi, I.; Imai,
M.; Kawahara, N.; Akita, H. Tetrahedron 2009, 65, 9884–9896. (i) Li,
G.-X.; Qu, J. Chem. Commun. 2010, 46, 2653–2655. (j) Bandini, M.;
Emer, E.; Tommasi, S.; Umani-Ronchi, A. Eur. J. Org. Chem. 2006,
3527–3544. (k) Krake, S. H.; Bergmeier, S. C. Tetrahedron 2010, 66,
7337–7360.
Org. Lett., Vol. 15, No. 18, 2013
4893

Scheme 3. Brief Analysis of the Scope of MgBr2-Catalyzed
FriedelꢀCrafts Cycloalkylation Reactions
Scheme 1. Synthesis of the Cycloalkylation Precursor 7
a This transformation was alternatively accomplished via mCpBA,
Et2O, 48 h, rt, 32% (1:1.3 diastereomer ratio).
Scheme 2. MgBr2-Catalyzed FriedelꢀCrafts Cycloalkylation
Scheme 4. Examination of One Possible Mechanism
of MgBr2-Catalyzed Cycloalkylation Reaction via the
Bromohydrin
cycloalkylation is a practical alternative approach using
inexpensive, nontoxic reagents and mild conditions, allow-
ing product formation with sensitive starting materials.6
We briefly investigated the scope of this reaction in the
attempted synthesis of alternative scaffolds (Scheme 3).
Not surprisingly, no product formation was observed with
the contracted compound 10, similar to results in model
compounds with SnCl4.5a,b However, the homologated
compound 11, synthesized via the cascade approach of
Lubell to generate homoallylic ketones,7 underwent cy-
cloalkylation to yield the expected 6-exo (Baldwin) pro-
duct, albeit in poor yield. We also examined this reaction in
a related simpler compound 34, which proceeded readily.
The bromohydrin (e.g., 13) was the major side product
in these reactions.8 The cycloalkylation reaction mecha-
nism could potentially involve direct Lewis acid activation
of the epoxide, as observed previously, or could alterna-
tively proceed via attack on the bromohydrin or its alk-
oxide. In order to investigate this possibility, the isolated
bromohydrin 13 was subjected to reaction conditions,
using MgBr2, or alternatively using EtMgBr to generate
the magnesium alkoxide (Scheme 4). In both conditions,
no product formation was observed, consistent with Lewis
acid activation of the epoxide as the reaction mechanism.
Scheme 5. EtMgBr-Mediated FriedelꢀCrafts Cycloalkylation
Scheme 6. Synthesis of General Scaffolds for R-Helix Mimicry
(6) Ueki and Kitazume (ref 5e) observed a 3% yield of Friedelꢀ
Crafts epoxide cycloalkylation product with MgBr2 using difluorovinyl
epoxides in the only identified precedent for this reaction.
(7) Hansford, K. A.; Dettwiler, J. E.; Lubell, W. D. Org. Lett. 2003, 5,
4887–4890.
(8) The isolated bromohydrin 13 was readily converted to the starting
material epoxide 7 (1:1 mixture of diastereomers) in quantitative yield
with NaH.
Interestingly, EtMgBr also effectively mediated the ep-
oxide cycloalkylation (Scheme 5), producing 8 and 9 with
the trans diastereomer 8 asthe major product (dr1.8:1 8:9),
4894
Org. Lett., Vol. 15, No. 18, 2013

Scheme 7. Partial Alkylation to Differentiate the Scaffolds and the Positions on the R-Helix Mimica
a Synthesis of the cis diastereomers is described in the Supporting Information. All compounds are racemates.
in contrast to the MgBr2-catalyzed reaction which gener-
ated the cis diastereomer as the major product (dr 1:1.7).
Analysis of starting material and product as a function
of time under EtMgBr reaction conditions revealed an
increase in dr of both the starting material and product
over time, suggesting epimerization as the basis for the change
in the diastereomer ratio. This reaction was critically depen-
dent on noncoordinating solvents (CH2Cl2 and DCE), and
with Grignard reagents prepared in Et2O yielding cycloalk-
ylation product, but with no desired product formation
observed for Grignard reagents prepared in THF.
Scaffold synthesis proceeded readily from the mixture of
8 and 9 (Scheme 6), via alcohol modification to form 14 as
a mixture of diastereomers. A carboxylate was incorpo-
rated to specifically modulate electrostatics and solubility
and as a handle for further conjugation. Subjection of
14 to global deprotection with TBAF yielded two alter-
native general scaffolds for R-helix mimicry, 15 and 16,
which were separable. 2-D NMR analysis (Supporting
Information) allowed assignment of the relative stereo-
chemistry of both compounds and revealed that in 15 the
benzylic O is predominantly in a pseudoaxial conformation,
whereas in 16 the benzylic O is in a pseudoequatorial con-
formation (Figure 1b). The difference in the major conforma-
tions of 15 and 16 suggests that each scaffold will present
attached side chains with alternative geometries, as desired.
A primary goal of this work is the synthesis of a general
scaffold for R-helix mimicry that could be rapidly converted
to R-helix mimics of a variety of biological targets. In order
to demonstrate the ready functionalization of the general
scaffold, we sought to synthesize small molecules that could
be mimics of a series of short linear motifs that bind their
target via short R-helices. Our initial targets were the
FXXLF motif present in the androgen receptor coactivator;
the FXXLL motif present in transcription activation do-
mains such as NF-κB p65; and the LXXLL motif of the
estrogen receptor coactivator.3g,k,p,s,t,x,z,9
The synthesis of small molecules to mimic each of these
short linear motifs proceeded readily in two to three steps
from the general scaffold, generating four lead compounds
for three different targets in eight total steps (Scheme 7). In
addition, the analogous compounds derived from the cis
diastereomer of the general scaffold were similarly synthe-
sized (Supporting Information).
The incorporation of side chain equivalents in the final
steps of the synthesis, combined with the use of simple
alkylation chemistry and the wide availability of diverse
electrophiles, suggests the expeditious application of this
approach to a broad range of diverse targets. In addition,
lead optimization should proceed readily using electro-
philes to represent unnatural amino acids. Our efforts in
the application of this strategy to control proteinꢀprotein
interactions will be reported in due course.
Acknowledgment. We thank the NIH (RR17716) and
the University of Delaware for funding. We thank Gasirat
Tririya for preliminary work in the development of alter-
native approaches. We thank Anil Pandey for experimen-
tal assistance. We thank Professor Barry Trost (Stanford)
for helpful discussion.
(9) (a) Uesugi, M.; Nyanguile, O.; Lu, H.; Levine, A. J.; Verdine,
G. L. Science 1997, 277, 1310–1313. (b) McInerney, E. M.; Rose, D. W.;
Flynn, S. E.; Westin, S.; Mullen, T.-M.; Krones, A.; Inostroza, J.;
Torchia, J.; Nolte, R. T.; Assa-Munt, N.; Milburn, M. V.; Glass,
C. K.; Rosenfeld, M. G. Genes Dev. 1998, 12, 3357–3368. (c) Uesugi,
M.; Verdine, G. L. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 14801–14806.
(d) He, B.; Minges, J. T.; Lee, L. W.; Wilson, E. M. J. Biol. Chem. 2002,
277, 10226–10235. (e) He, B.; Wilson, E. A. Mol. Cell. Biol. 2003, 23,
2135–2150. (f) Ravindranathan, P.; Lee, T. K.; Yang, L.; Centenera,
M. M.; Butler, L.; Tilley, W. D.; Hsieh, J. T.; Ahn, J. M.; Raj, G. V. Nat.
Commun. 2013, 4, article 1923.
Supporting Information Available. Experimental pro-
cedures, characterization data, and NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 18, 2013
4895