Folding propensity of cyclohexylether-δ-peptides

Article abstract of DOI:10.1021/ol048861q

(Chemical Equation Presented) Linear (n = 2-18) and cyclic oligomers (n = 3-8) of a cyclohexylether-δ-amino acid (COA) were prepared in high yield and stereopurity. CD spectra of the linear oligomers were indicative of secondary structure formation. X-ray crystal structures of cyclic COA oligomers revealed hydrophobic packing and internal 5- and 10-membered-ring hydrogen bonds. Ether and amide oxygens reside preferably in an ap orientation. This conformational locking is apparently broken by a C-2 substituent in an asymmetric cyclotrimer, for which a zeolithe-like tubular structure was found.

Full text of DOI:10.1021/ol048861q

ORGANIC
LETTERS
2004
Vol. 6, No. 19
3269-3272
Folding Propensity of
Cyclohexylether-δ-peptides
Hans-Dieter Arndt,†,‡ Burkhard Ziemer,† and Ulrich Koert*
,§
Humboldt-UniVersita¨t zu Berlin, Institut fu¨r Chemie, Brook-Taylor-Str. 2,
D-12489 Berlin, Germany, and Philipps-UniVersita¨t Marburg, Fachbereich Chemie,
Hans-Meerwein-Str., D-35032 Marburg, Germany
koert@chemie.uni-marburg.de
Received June 16, 2004
ABSTRACT
Linear (n ) 2−18) and cyclic oligomers (n ) 3−8) of a cyclohexylether-δ-amino acid (COA) were prepared in high yield and stereopurity. CD
spectra of the linear oligomers were indicative of secondary structure formation. X-ray crystal structures of cyclic COA oligomers revealed
hydrophobic packing and internal 5- and 10-membered-ring hydrogen bonds. Ether and amide oxygens reside preferably in an ap orientation.
This conformational locking is apparently broken by a C-2 substituent in an asymmetric cyclotrimer, for which a zeolithe-like tubular structure
was found.
Oligomers capable of folding into defined secondary struc-
tures have received considerable attention recently.1 Among
them the â-, γ-, and δ-peptides,1,2 as well as a growing array
of aromatic amide oligomers,1,3 are most prominent. Oligo-
mers featuring heteroatoms in the backbone remain com-
paratively unexplored, with the exception of sugar amino
acids,4 R-aminoxy acids,5 and R-hydrazino acids.6
(3) Recent examples: (a) Jiang, H.; Le´ger, J.-M.; Huc, I. J. Am. Chem.
Soc. 2003, 125, 3448-3449. (b) Hecht, S.; Khan, A. Angew. Chem., Int.
Ed. 2003, 42, 6021-6024. (c) Estroff, L. A.; Incarvito, C. D.; Hamilton,
A. D. J. Am. Chem. Soc. 2004, 126, 2-3. (d) Jiang, H.; Dolain, C.; Leger,
J.-M.; Gornitzka, H.; Huc, I. J. Am. Chem. Soc. 2004, 126, 1034-1035.
(e) Goto, H.; Heemstra, J. M.; Hill, D. J.; Moore, J. S. Org. Lett. 2004, 6,
889-892. (f) Yang, X. W.; Yuan, L. H.; Yamamoto, K.; Brown, A. L.;
Feng, W.; Furukawa, M.; Zeng, X. C.; Gong, B. J. Am. Chem. Soc. 2004,
126, 3148-3162.
(4) Review: (a) Gruner, S. A. W.; Locardi, E.; Lohof, E.; Kessler, H.
Chem. ReV. 2002, 102, 491-514. Recent examples: (b) Chakraborty, T.
K.; Srinivasu, P.; Bikshapathy, E.; Nagaraj, R.; Vairamani, M.; Kiran Kumar,
S.; Kunwar, A. C. J. Org. Chem. 2003, 68, 6257-6263. (c) van Well, R.
M.; Marinelli, L.; Altona, C.; Erkelens, K.; Siegal, G.; van Raaij, M.;
Llamas-Saiz, A. L.; Kessler, H.; Novellino, E.; Lavecchia, A.; van Boom,
J. H.; Overhand, M. J. Am. Chem. Soc. 2003, 125, 10822-10829. (d) Smith,
M. D.; Claridge, T. D. W.; Sansom, M. S. P.; Fleet, G. W. J. Org. Biomol.
Chem. 2003, 1, 3647-3655. (e) Grotenbreg, G. M.; Timmer, M. S. M.;
Llamas-Saiz, A. L.; Verdoes, M.; van der Marel, G. A.; van Raaij, M. J.;
Overkleeft H. S.; Overhand, M. J. Am. Chem. Soc. 2004, 126, 3444-3446.
(5) (a) Yang, D.; Qu, J.; Li, W.; Zhang, Y.-H.; Ren, Y.; Wang, D.-P.;
Wu, Y.-D. J. Am. Chem. Soc. 2003, 125, 14452-14457. (b) Yang, D.; Qu,
J.; Li, W.; Wang, D.-P.; Ren, Y.; Wu, Y.-D. J. Am. Chem. Soc. 2003, 125,
14452-14457.
† Humboldt-Universita¨t zu Berlin.
‡ Current address: MPI fu¨r molekulare Physiologie, Otto-Hahn-Str. 11,
D-44227 Dortmund, Germany.
§ Philipps-Universita¨t Marburg.
(1) Reviews: (a) Seebach, D.; Matthews, J. L. J. Chem. Soc., Chem.
Commun. 1997, 2015-2022. (b) Gellman, S. H. Acc. Chem. Res. 1998,
31, 173-180. (c) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem.
ReV. 2001, 101, 3219-3232. (d) Hill, D. J.; Mi’o, M. J.; Prince, R. B.;
Hughes, T. S.; Moore, J. S. Chem ReV. 2001, 101, 3893-4011. (e) Sanford,
A. R.; Gong. B. Curr. Org. Chem. 2003, 7, 1649-1659. (f) Huc, I. Eur. J.
Org. Chem. 2004, 69, 17-29. (g) Balbo Block, M. A.; Kaiser, C.; Khan,
A.; Hecht, S. Top. Curr. Chem. 2004, in press.
(2) Recent examples: (a) Gademann, K.; Hane, A.; Rueping, M.; Jaun,
B.; Seebach, D. Angew. Chem., Int. Ed. 2003, 42, 1534-1537. (b)
Langenhan, J. M.; Guzei, I. A.; Gellman, S. H. Angew. Chem., Int. Ed.
2003, 42, 2402-2405. (c) Bru¨ckner, A. M.; Chakraborty, P.; Gellman, S.
H.; Diederichsen, U. Angew. Chem., Int. Ed. 2003, 42, 4395-4399. (d)
Sharma, G. V. M.; Reddy, K. R.; Krishna, P. R.; Sankar, A. R.; Narsimulu,
K.; Kumar, S. K.; Jayaprakash, P.; Jagannadh, B.; Kunwar, A. C. J. Am.
Chem. Soc. 2003, 125, 13670-13671. (e) Hayen, A.; Schmitt, M. A.;
Ngassa, F. N.; Thomasson, K. A.; Gellman, S. H. Angew. Chem., Int. Ed.
2004, 43, 505-510. (f) Zhao, X.; Jia, M. X.; Jiang, X. K.; Wu, L. Z.; Li,
Z. T.; Chen, G. J. J. Org. Chem. 2004, 69, 270-279.
10.1021/ol048861q CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/25/2004

Scheme 1. Synthesis of Discrete COA Oligomersa
Figure 1. Overlay of normalized CD spectra of COA oligomers
5-10 at constant concentration of residues: c ) 1/n mM for n )
2, 3, 4, 6, 8, 12 in (a) H2O/CH3CN 75:25 or (b) n-hexane/i-PrOH
95:5.
yields by recursive fragment couplings from the stereopure
building blocks 5 and 6 using standard solution-phase peptide
technology (Scheme 1). Interestingly, albeit dimer 5 was a
solid, all of the higher linear oligomers 6-10 (n ) 3-12)
were found to be noncrystalline and freely soluble in many
solvents.
Severe signal overlap in the spectra of the homooligomeric
peptides prohibited the extraction of sufficient 3-D informa-
tion from NMR spectra. Therefore, CD spectra of the
peptides were recorded for characterization (Figure 1). In
going from dimer 5 to dodecamer 10, strong negative (I, ca.
182 nm) and positive (II, 198 nm) bands developed with
increasing chain length in polar protic solvents. In nonpolar
organic solvents the bands I and II were equally observed,
but an additional positive band (III) at 218 nm appeared
with increasing chain length.
It can be concluded that a higher ordered structure is
formed in either case. Whereas in polar solvents a single
species seems to predominate, a more complex fold (or
mixture) is realized for the COA-δ-peptides in nonpolar
solvents. Although some resemblance with reported CD
spectra for helical oligomers was apparent, notably, with
â-peptide helices,1c more structural information was needed,
and we turned our attention to cyclic COA-δ-peptides.
Toward this end, the free amino acids resulting from C-
and N-terminal deprotection of 6-9 were cyclized using
HATU/HOAt.12 Good yields of the cyclic δ-peptides 11-
14 were obtained (Scheme 2) under high-dilution conditions.
Even the largest compound 14 (ring size, 48 atoms) was
isolated in 45% yield, with the shorter COA-δ-peptides
giving better results. Notably, no products resulting from
premature oligomerization (dimers, trimers) were detected.
The observation of the rather facile ring closures indicated
an apparent reduction in the degrees of freedom for the
cyclization precursors (vide infra). However, a strictly helical
preorganization should lead to an increased propensity for
oligomerization instead of cyclization for the longer ether-
δ-peptides (especially 9) and was therefore deemed less likely
at this point.
a (a) Cat. TFA, MeOH; (b) BrCH2COOtBu, NaOH, cat. TBABr,
toluene; (c) TFA/CH2Cl2 1:1; (d) PivCl, NEt3; (e) 3, H2, 5% Pd/C,
MeOH; (f) 4, DMF, 0 °C; (g) HOBt, EDC, EtN(iPr)2, CH2Cl2.
We have studied THF7,8 as well as cyclohexylether-δ-
amino acids9 (COAs) as building blocks in artificial ion
channels.8,9 Cyclohexylether-δ-amino acids have been found
to induce novel ion channel properties when inserted into
the gramicidin A peptide sequence.9 To gain insight into the
secondary structure forming (“foldamer”) properties of ether-
δ-amino acids, a study of COA oligomers was initiated. Of
particular interest was the influence of the ether oxygens on
the resulting δ-peptide’s conformation.
Toward this goal COA oligomers from n ) 2-12 were
independently synthesized, purified, and characterized (Scheme
1). The synthesis was initially based on Jacobsen’s asym-
metric ring opening of cyclohexene oxide.10 Azide 1 (93%
ee) was desilylated and alkylated under phase-transfer
conditions11 to yield δ-amino acid monomer 3 on a 30-g
scale. The dimerization to 5 was best achieved via the mixed
anhydride 4, as normal peptide coupling conditions (HOBt/
EDC, HATU) were hampered by δ-lactam formation to
variable degrees. Dipeptide 5 was obtained isomerically pure
by crystallization9 and then extended to tripeptide 6 in the
same fashion. At this stage, diastereomeric impurities could
be removed by chromatography.
To avoid the cumbersome accumulation of minor stereo-
isomers, the higher COA oligomers were assembled in high
(6) Lelais, G.; Seebach, D. HelV. Chim. Acta 2003, 86, 4152-4168.
(7) (a) Schrey, A.; Osterkamp, F.; Straudi, A.; Rickert, C.; Wagner, H.;
Koert, U.; Herrschaft, B.; Harms, K. Eur. J. Org. Chem. 1999, 2977-2990.
(b) Koert, U. J. Prakt. Chem. 2000, 342, 325-333.
(8) (a) Schrey, A.; Vescovi. A.; Knoll, A.; Rickert, C.; Koert, U. Angew.
Chem., Int. Ed. 2000, 39, 900-902. (b) Fidzinski, P.; Knoll, A.; Rosenthal,
R.; Schrey, A.; Vescovi, A.; Koert, U.; Wiederholt, M.; Strauss, O. Chem.
Biol. 2003, 10, 35-43. (c) Vescovi, A.; Knoll, A.; Koert, U. Org. Biomol.
Chem. 2003, 1, 2983-2997.
As opposed to their linear counterparts 5-10, the cyclic
COA-δ-peptides 11-14 were found to be solids of low
(9) Arndt, H.-D.; Knoll, A.; Koert, U. Angew. Chem., Int. Ed. 2001, 40,
2076-2078.
(10) Mart´ınez, L. E.; Leighton, J. L.; Carsten, D. H.; Jacobsen, E. N. J.
Am. Chem. Soc. 1995, 117, 5897-5898.
(12) (a) Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397-4398. (b)
Ehrlich, A.; Heyne, H.-U.; Winter, R.; Beyermann, M.; Haber, H.; Carpino,
L. A.; Bienert, M. J. Org. Chem. 1996, 61, 8831-8838.
(11) Pietraszkiewicz, M.; Jurczak, J. Tetrahedron 1984, 40, 2967-2970.
3270
Org. Lett., Vol. 6, No. 19, 2004

Scheme 2. Synthesis of Cyclic COA Oligomersa
a (a) (i) 50% TFA, (ii) H2, 5% Pd/C, MeOH, (iii) slow addition
(6 h) to HATU, HOAt, EtN(iPr)2, CH2Cl2/DMF 10:1; (b) NaH,
MeI, DMF.
solubility, indicating a high tendency for aggregation.13
Crystallization efforts led mainly to microcrystalline powders
or high levels of included solvent. Both facts prohibited X-ray
structure elucidation up to now.
In an attempt to break the apparent aggregational ten-
dency,14 the cyclic trimer 11 was permethylated at the amide
nitrogens to yield cycle 15 devoid of H-bond donors (Scheme
2). Gratifyingly, 15 could be obtained from acetone in single
crystals suitable for X-ray structure analysis (Figure 2). Two
molecules of 15 with very similar conformations are located
with a molecule of acetone in the asymmetric unit. The
conformation of 15 is nonsymmetric15 and dominated by the
N-Me groups, which adopt a ap orientation with regard to
the neighboring C-H bond. Two amide bonds are found in
the cis-configuration, leading to a general saddle-shaped
molecule. The acetone molecules line up in channel-like
voids formed by the packing of the rigid saddles of 15.
Interestingly, no stable single crystals could be obtained in
the absence of acetone.
Figure 2. Crystal structure analysis of methylated cyclotrimer 15.
(Top) Conformation in the solid state; only one molecule is shown.
H-atoms at ring junctions are highlighted in gray. (Bottom) Crystal
packing viewed along the B-axis. The two non-symmetry-related
molecules of 15 in the asymmetric unit are color coded in blue
and orange, and acetone molecules are color coded in yellow.
acetyl chloride to yield 17 and its diastereomer, which were
easily separated by chromatography or crystallization. KOtBu
induced the ring closure to ether 18, which was characterized
by X-ray crystallography. The auxiliary group was then
removed with HCOOH17 (18 f 19), and the amide nitrogen
was derivatized with Z-Cl to give amide 20. Lactam 19 was
independently synthesized from 1 for comparison, confirming
all stereochemical assignments. Lactam 20 was found to be
quite sensitive under enolate alkylation conditions and prone
to overalkylation. However, the alkylation proceeded with
excellent stereocontrol (149:1) using LiHMDS under stoi-
chiometric conditions.18
Ring opening of 21 with LiOOH19 then provided C-2
benzyl-substituted δ-amino acid monomer 22. Elongation
with COA dimer 4 gave the δ-tripeptide 23. After C- and
N-terminal deprotection this was cyclized under the same
conditions as the COA oligomers to cyclo-δ-peptide 24 in
86% isolated yield. This exceptional yield indicates that
δ-peptide 23 must be conformationally set up very well for
cyclization.
It was reasoned that breaking the symmetry and repetitive-
ness of individual oligomers might not only result in more
disperse NMR signals but moreover lead to materials with
local orientation and ultimately better folding properties. We
decided to explore C-2 substitution, as present in the THF
and THP amino acids.7 Initial attempts to alkylate monomer
3 led to unseparable mixtures. Additionally, we were unable
to obtain 3 or its precursors in an enantiopure form via the
present route. Therefore, an alternative route was developed
(Scheme 3).
Cyclohexene oxide 16 was ring opened16 with readily
available (S)-phenethylamine and derivatized with chloro-
(13) Interestingly, the cyclotrimers 11 and 15 were found to form stable
1:1 adducts with KI, which were freely soluble in CH2Cl2.
(14) Ghadiri, M. R.; Kobayashi, K.; Granja, J. R.; Chaha, R. K.; McRee,
D. E. Angew. Chem., Int. Ed. Engl. 1995, 34, 93-95.
(15) In solution, compound 15 does not adopt an averaged C3-symmetric
conformation. As a result of slowly interconverting amide bond rotamers,
a complex mixture of conformers is observed.
(17) Semple, J. E.; Joullie´, M. M.; Lysenko, Z.; Wang, P. C. J. Am.
Chem. Soc. 1980, 102, 7505-7510.
(18) A base-catalyzed equilibration of C-2 cannot be ruled out at this
point. The stereochemistry was initially deduced from characteristic NOE
data and later confirmed by the X-ray structure of 24.
(19) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737-1739.
(16) de Parrodi, C. A.; Juaristi, E.; Quintero, L.; Clara-Sosa, A.
Tetrahedron: Asymmetry 1997, 8, 1075-1082.
Org. Lett., Vol. 6, No. 19, 2004
3271

Scheme 3. Synthesis of Asymmetric Cyclic COA Trimer 24a
a (a) (S)-1-Phenylethylamine, LiClO4, CH3CN, ∆; (b) ClCH2COCl,
NEt3, CH2Cl2; (c) KOtBu, THF, 0 °C; (d) HCOOH, ∆; (e) BuLi,
Z-Cl, -78 °C; (f) LiHMDS, BnBr, -78 °C; (g) LiOOH, THF/
H2O; (h) 5, H2, 5% Pd/C, MeOH, then 22, HATU, HOAt, EtN(iPr)2,
DMF; (k) 50% TFA; (h) H2, 5% Pd/C, MeOH, (l) slow addition (6
h) to HATU, HOAt, EtN(iPr)2, CH2Cl2/DMF 10:1.
Figure 3. Crystal structure analysis of asymmetric trimer 24. (Top)
Conformation in the solid state; intramolecular five-membered-ring
H-bonds are dashed, 10-membered-ring H-bond is dotted. (Bottom)
Crystal packing viewed along the crystallographic A-axis. Residual
electron density in the channels is omitted for clarity.
In summary, the present data suggests that ether-δ-amino
acids lacking C-2 substituents will adopt one low-energy
conformation featuring a five-membered-ring H-bond to the
preceding residue oxygen, dominating the general secondary
structure. This linearization reduces the degrees of freedom
in solution, corroborated by the rather facile cyclization
reactions. C-2 substitution obviously breaks this preference
and gives rise to a more complex folding pattern. This may
become a viable tool for inducing long-range H-bond
formation in cyclohexyl ether-δ-peptides. In extension the
breaking of symmetry and repetitiveness could lead to much
better organized foldamers in the future.
The sensitive single crystals of 24 grown from wet CHCl3
could be analyzed by X-ray crystallography (Figure 3).
Again, the cyclopeptide 24 adopts a saddle-like conformation
in the crystal but is folded in the opposite direction as 15.
In the unsubstituted COA subunits the glycolic amide
portions in 24 adopt a sp orientation. Such a five-membered
ring H-bond to the ether oxygen was observed before in the
crystal structure of dimer 59 and is also present in R-aminoxy
acid peptides.5 On the other hand, the C-2 substituted ether-
δ-amino acid assumes a conformation where the Bn sub-
stituent avoids syn-pentane strain.20 This allows the amide
function to rotate and form a transannular, 10-membered-
ring H-bond, as well as a connective H-bond with the next
molecule in the crystal. Hydrophobic packing of these chains
then leads to a zeolithe-like structure with narrow channels
along the a-axis.
Acknowledgment. This research was supported by the
Volkswagen Stiftung, the Fonds der Chemischen Industrie,
and the Pinguin Stiftung. We thank Prof. Dr. J. Liebscher
(HU-Berlin) for the use of his CD spectrometer and P.
Neubauer for skilful assistance in X-ray crystallography.
The channels are filled with partially ordered water
molecules (12/cell). It is interesting to note, that the channels
are not formed by a perpendicular stacking of rings.
Supporting Information Available: GC and HPLC
traces for 1 and 21, crystal structures of 18 and 19,
experimental procedures, and analytical data. This material
is available free of charge via the Internet at http://pubs.acs.org.
(20) (a) Tsuzuki, S.; Scha¨fer, L.; Goto, H.; Jemmis, E. D.; Hosoya, H.;
Siam, K.; Tanabe, K.; Osawa, E. J. Am. Chem. Soc. 1991, 113, 4665-
4671. (b) Hoffmann, R. W. Angew. Chem., Int. Ed. 2000, 39, 2054-2070.
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