Helix persistence and breakdown in oligoureas of metaphenylenediamine: Apparent diastereotopicity as a spectroscopic marker of helix length in solution

Article abstract of DOI:10.1021/ja805758v

Oligomeric ureas derived from m-phenylenediamine with chain lengths of up to seven urea linkages were made by iterative synthetic pathways. Three families were synthesized: 4 and 20, bearing a terminal chiral sulfinyl group; 24, bearing a terminal rotatio

Full text of DOI:10.1021/ja805758v

Published on Web 10/10/2008
Helix Persistence and Breakdown in Oligoureas of
Metaphenylenediamine: Apparent Diastereotopicity as a
Spectroscopic Marker of Helix Length in Solution
Jonathan Clayden,*,† Lo¨ıc Lemie`gre,†,‡ Gareth A. Morris,† Mark Pickworth,†
Timothy J. Snape,†,§ and Lyn H. Jones|
School of Chemistry, UniVersity of Manchester, Oxford Road, Manchester M13 9PL, United
Kingdom, and Pfizer Central Research, Sandwich CT12 3NT, United Kingdom
Received July 23, 2008; E-mail: clayden@man.ac.uk
Abstract: Oligomeric ureas derived from m-phenylenediamine with chain lengths of up to seven urea
linkages were made by iterative synthetic pathways. Three families were synthesized: 4 and 20, bearing
a terminal chiral sulfinyl group; 24, bearing a terminal rotationally restricted amide group, and 30 bearing
a terminal achiral bromophenyl group. The distal end of the oligomers was capped with an N-benzyl group
1
to act as a diastereotopic probe. With a terminal sulfinyl group, the H NMR signals arising from the CH2
group of the diastereotopic probe remained anisochronous even when separated from the stereogenic
center by up to 24 bonds (in 20c). With a rotationally restricted amide, anisochronicity was no longer apparent
beyond 17 bond lengths (in 24c). No anisochronicity was observable with a terminal bromophenyl group.
We interpret these results as indicating that the oligoureas of short lengths adopt a defined helical secondary
structure in solution, but that in longer oligomers the helicity breaks down and transmission of chirality in
these systems is limited to about 24 bond lengths. We propose that “apparent diastereotopicity”
(anisochronicity) provides a general empirical method for identifying secondary structure in solution.
Introduction
exploited as a means of communicating stereochemical informa-
tion over long (nanometer-scale) distances,11,12 a chemical
The absolute control of the configuration of new stereogenic
centers has been for several decades a central goal of synthetic
chemistry.1 Comparable stereochemical control over conforma-
tion, particularly of acyclic molecules, is a more nebulous aim
toward which slow progress has been made in recent years.2
Substitution patterns have been manipulated to induce defined
conformational features in alkyl3 and silyl4 chains; methods have
been developed for the control of slowly interconverting
conformers (or atropisomers),5-9 and the propagation of a chiral
influence through global conformational control10 has been
analogue of biological allostery. With respect to structurally
repetitive compounds, numerous classes of foldamerssoligomers
with a well-defined conformationshave been reported.13,14
Many classes of foldamers, even those made of achiral mono-
mers, adopt well-defined, typically helical, conformations in the
solid state.13,15,16 Some of these have been proposed to retain helical
conformations in solution as well, but determining the extent of
(5) Betson, M. S.; Clayden, J.; Helliwell, M.; Johnson, P.; Lai, L. W.;
Pink, J. H.; Stimson, C. C.; Vassiliou, N.; Westlund, N.; Yasin, S. A.;
Youssef, L. H. Org. Biomol. Chem. 2006, 4, 424.
(6) Clayden, J. Chem. Commun. 2004, 127.
† University of Manchester.
(7) (a) Clayden, J.; Lai, L. W. Angew. Chem., Int. Ed. 1999, 38, 2556.
(b) Clayden, J.; Johnson, P.; Pink, J. H.; Helliwell, M. J. Org. Chem.
2000, 65, 7033. (c) Clayden, J.; Lai, L. W. Tetrahedron Lett. 2001,
42, 3163. (d) Clayden, J.; Lai, L. W.; Helliwell, M. Tetrahedron 2004,
60, 4399. (e) Betson, M. S.; Clayden, J.; Lam, H. K.; Helliwell, M.
Angew. Chem., Int. Ed. 2005, 44, 1241. (f) Clayden, J.; Westlund,
N.; Frampton, C. S.; Helliwell, M. Org. Biomol. Chem. 2006, 4, 455.
(g) Clayden, J.; Vallverdu´, L.; Helliwell, M. Org. Biomol. Chem. 2006,
4, 2106.
‡ Current address: Ecole Nationale Supe´rieure de Chimie de Rennes,
CNRS UMR6226 “Sciences Chimiques de Rennes”, Av. G. Leclerc, 35700
Rennes, France.
§ Current address: School of Pharmacy, Maudland Building, University
of Central Lancashire, Preston PR1 2HE, U.K.
| Pfizer Central Research.
(1) Eliel, E. L.; Wilen, S. H., Stereochemistry of Organic Compounds;
Wiley: New York, 1994.
(2) Hoffmann, R. W. Angew. Chem., Int. Ed. 2000, 39, 2054.
(3) (a) Yamamoto, Y.; Nemoto, H.; Kikuchi, R.; Komatsu, H.; Suzuki, I.
J. Am. Chem. Soc. 1990, 112, 8598. (b) Alder, R. W; Anderson, K. R.;
Benjes, P. A.; Butts, C. P.; Koutentis, P. A.; Orpen, A. G. Chem.
Commun. 1998, 309. (c) Stenkamp, D.; Hoffmann, R. W; Go¨ttlich, R
Eur. J. Org. Chem. 1999, 2929. (d) Hoffmann, R. W.; Caturla, F.;
Lazaro, M. A.; Framery, E.; Bernabeu, M. C.; Valancogne, I.;
Montalbetti, C. A. G. N. New J. Chem. 2000, 24, 187. (e) Carlier,
P. R.; Zhang, Y.; Slebodnick, C.; Lo, M. M.-C.; Williams, I. D. J.
Org. Chem. 2006, 71, 8835. (f) O’Hagan, D.; Rzepa, H. S.; Schu¨ler,
M.; Slawin, A. M. Z. Beilstein J. Org. Chem. 2006, 2, 19. (g)
Hanessian, S.; Chahal, N.; Giroux, S. J. Org. Chem. 2006, 71, 7403.
(4) Fukuzawa, A.; Tsuji, H.; Tamao, K. J. Am. Chem. Soc. 2006, 128,
6800.
(8) (a) Clayden, J.; Mitjans, D.; Youssef, L. H. J. Am. Chem. Soc. 2002,
124, 5266. (b) Betson, M. S.; Clayden, J.; Helliwell, M.; Mitjans, D.
Org. Biomol. Chem. 2005, 3, 3898. (c) Clayden, J.; Worrall, C. P.;
Moran, W.; Helliwell, M. Angew. Chem., Int. Ed. 2008, 47, 3234.
(9) Betson, M. S.; Bracegirdle, A.; Clayden, J.; Helliwell, M.; Lund, A.;
Pickworth, M.; Snape, T. J.; Worrall, C. P. Chem. Commun. 2007,
754.
(10) Clayden, J.; Vassiliou, N. Org. Biomol. Chem. 2006, 4, 2667.
(11) (a) Clayden, J.; Pink, J. H.; Yasin, S. A. Tetrahedron Lett. 1998, 39,
105. (b) Clayden, J.; Kenworthy, M. N.; Youssef, L. H. Tetrahedron
Lett. 2000, 41, 5171. (c) Clayden, J.; Lai, L. W.; Helliwell, M.
Tetrahedron: Asymmetry 2001, 12, 695. (d) Clayden, J.; Lund, A.;
Youssef, L. H. Org. Lett. 2001, 3, 4133. (e) Clayden, J.; Vallverdu´,
L.; Helliwell, M. Chem. Commun. 2007, 2357.
9
10.1021/ja805758v CCC: $40.75
2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 15193–15202 15193

A R T I C L E S
Clayden et al.
helicity in solution in systems where conformational interconversion
is rapid poses a significant challenge.17 In some cases, these
foldamers have been shown to adopt absolute helicity dependent
only on stereochemistry present at one terminus.18-21 An estimation
of the fidelity with which such oligomers respond, in solution, to
a terminal chiral influence is given by circular dichroism studies,20-22
though generally only qualitative information about helicity is
provided. Remotely stereoselective reactions23 imply a degree of
conformational control,12,24 and the “chain length dependence
test”25 can give evidence of conformationally ordered structures.
If diastereoisomeric conformers interconvert slowly on the NMR
time scale direct measurement of conformational ratios may be
possible.19,21 However, when helix inversion is fast on the NMR
time scale, it becomes difficult to establish (a) the extent to which
the solution state conformation of the oligomer is helical and (b)
the level of control obtained over the absolute helicity of the
oligomer. (Absolute helicity (the adoption of specifically M or P
helicity) most commonly results from chiral monomers which result
in handed helices.16 Cooperative effects mean that the “degree”
of chirality required to provide a high level of helical control can
be very smallseven H vs D.26 Likewise, not every monomer needs
to be chiral for induction to be effectivesthe principle of “sergeants
and soldiers” means that achiral monomers follow suit if chiral
monomers are dispersed among them.27)
Figure 1. Fast and slow interconversion of enantiomeric and diastereo-
isomeric helices.
In this paper we propose that, even for oligomers undergoing
fast conformational change, NMR methods can still provide a
qualitative, empirical indication of the degree to which a molecule
adopts a helical conformation in solution. Consider two enantio-
meric interconverting helices carrying a pair of terminal protons
Ha and Hb (Figure 1a) The protons are rendered diastereotopic by
virtue of the chirality of the helix: slow (i.e., k , π∆ν/ꢀ2, where
∆ν is the chemical shift difference between Ha and Hb)28 inter-
conversion between the M and P helices will give rise to
anisochronous signals (an AB system), as has been observed for
example by Huc29 and others. Fast interconversion (i.e., k . π∆ν/
ꢀ2) will however average the environments of Ha and Hb and these
protons will appear isochronous (a 2H singlet).
Attaching a chiral controlling element X* to the terminus
of the helix generates a diastereoisomeric pair of structures
(Figure 1b). Now, even if the helices undergo fast intercon-
version, Ha and Hb remain diastereotopic by virtue of the
presence of X*. However, the apparent diastereotopicitys
the spectroscopically observed anisochronicitysof Ha and Hb
due to the direct effect of X* will decrease rapidly as the
oligomeric chain is lengthened, and direct interaction between
X* and the geminal pair Ha, Hb is lost. Nonetheless, if X* is
able to bias the equilibrium such that one of the diastereo-
isomeric helices M or P predominates, then Ha and Hb remain
in diastereomeric environments due to the local influence of
the unequally populated helix conformations: they remain
anisochronous and will still appear as an AB system, in
principle irrespective of the distance from X*, and irrespec-
tive of the rate of helix inversion. In practice of course
anisochronicity will be under the control of a range of other
factors,30 but it can safely be assumed that persistence of
apparent diastereotopicity significantly beyond the maximum
range usually observed in acyclic systems (>8 bond lengths,
say31) indicates a degree of helicity in the solution state
conformation. If however, as the helix lengthens, the
conformation becomes disordered such that X* can no longer
control the local chiral environment of Ha and Hb via the
helix, then the signal arising from the diastereotopic pair of
protons will collapse to a 2H singlet. The chemical shift
difference ∆ν between Ha and Hb may thus be useful as a
chain-length dependent25 empirical measure of the distance
over which the helicity of an oligomer persists in solution.
OligoureassPreliminary Study. We chose to apply this
proposed technique to a series of oligomeric ureas of structures
(12) Clayden, J.; Lund, A.; Vallverdu´, L.; Helliwell, M. Nature (London)
2004, 431, 966.
(13) (a) Hecht, S.; Huc, I. Foldamers; Wiley-VCH: Weinheim, 2007. (b)
Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S.
Chem. ReV. 2001, 101, 3893.
(14) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173.
(15) Huc, I. Eur. J. Org. Chem. 2004, 17.
(16) (a) Nakano, T.; Okamoto, Y. Chem. ReV. 2001, 101, 4013. (b)
Cornelissen, J. H. L. M.; Rowan, A. E.; Nolte, R. J. M.; Sommerdijk,
N. A. J. M. Chem. ReV. 2001, 101, 4039.
(17) Dolain, C; Gre´lard, A.; Laguerre, M.; Jiang, H.; Maurizot, V.; Huc, I.
Chem.-Eur. J. 2005, 11, 6135.
(18) (a) Akazome, M.; Ishii, Y.; Nireki, T.; Ogura, K. Tetrahedron Lett.
2008, 49, 4430. (b) Maeda, K.; Yashima, E. Top. Curr. Chem. 2006,
265, 47. (c) Yahima, E; Maeda, K.; Nishimura, T. Chem.-Eur. J.
2004, 10, 43. (d) Jiang, H.; Dolain, C.; Le´ger, J.-M.; Gornitzka, H.;
Huc, I. J. Am. Chem. Soc. 2004, 125, 1034. (e) Mizutami, T.; Sakai,
N.; Yagi, S.; Takagishi, T.; Kitagawa, S.; Ogoshi, H. J. Am. Chem.
Soc. 2000, 122, 748. (f) Pengo, B.; Formaggio, F.; Crisma, M.;
Toniolo, C.; Bonora, G. M.; Broxterman, Q. B.; Kamphuis, J.; Saviano,
M.; Iacovino, R.; Rossi, F.; Benedetti, E. J. Chem. Soc., Perkin Trans.
2 1998, 1651. (g) Benedetti, E.; Saviano, M.; Iacovino, R.; Pedone,
C.; Santini, A.; Crisma, M.; Formaggio, F.; Toniolo, C.; Broxterman,
Q. R.; Kamphuis, J. Biopolymers 1998, 433.
(19) Hu, H.-Y.; Xiang, J.-F.; Yang, Y.; Chen, C.-F. Org. Lett. 2008, 10,
1275.
(20) Pijper, D.; Feringa, B. L. Angew. Chem., Int. Ed. 2007, 46, 3693.
(21) Dolain, C.; Jiang, H.; Le´ger, J.-M.; Guionneau, P.; Huc, I. J. Am. Chem.
Soc. 2005, 127, 12943.
(22) (a) Miyagawa, T.; Furuko, A.; Maeda, K.; Katagiri, H.; Furusho, Y.;
Yashima, E. J. Am. Chem. Soc. 2005, 127, 5018. (b) Mazaleyrat, J.-
P.; Wright, K.; Gaucher, A.; Toulemonde, N.; Wakselman, M.; Oancea,
S.; Peggion, C.; Formaggio, F.; Setnicka, V.; Keiderling, T. A.;
Toniolo, C. J. Am. Chem. Soc. 2004, 126, 12874. (c) Inai, Y.; Komori,
H. Biomacromolecules 2004, 5, 1231. (d) Ousaka, N.; Inai, Y.; Okabe,
T. Biopolymers 2006, 83, 337. (e) Komori, H.; Inai, Y. J. Org. Chem.
2007, 72, 4012.
(23) (a) Mikami, K.; Shimizu, M.; Zhang, H.-C.; Maryanoff, B. E.
Tetrahedron 2001, 57, 2917. (b) Mitchell, H. J.; Nelson, A.; Warren,
S. J. Chem. Soc., Perkin Trans. 1 1999, 1899.
(24) (a) Noe, C. R.; Knollmu¨ller, M.; Ettmayer, P. Angew. Chem., Int. Ed.
1988, 27, 1379. (b) Jianfeng, Y.; RajanBabu, T. V.; Parquette, J. R.
J. Am. Chem. Soc. 2008, 130, 7845.
(25) Stone, M. T.; Heemstra, J. M.; Moore, J. S. Acc. Chem. Res. 2006,
39, 11.
(28) Sandstro¨m, J. Dynamic NMR Spectroscopy; Academic Press: London,
1982.
(26) Green, M. M.; Reola, C.; Mun˜oz, B.; Reidy, M. P. J. Am. Chem. Soc.
1988, 110, 4063.
(29) Maurizot, V.; Dolain, C.; Leydet, Y.; Le´ger, J.-M.; Guionneau, P.;
Huc, I. J. Am. Chem. Soc. 2004, 126, 10049.
(27) Green, M. M.; Reidy, M. P.; Johnson, R. J.; Darling, G.; O’Leary,
D. J.; Willson, G. J. Am. Chem. Soc. 1989, 111, 6452.
(30) Jennings, W. B. Chem. ReV. 1975, 75, 307.
(31) Schramm, M. P.; Rebek, J. New J. Chem. 2008, 32, 794.
9
15194 J. AM. CHEM. SOC. VOL. 130, NO. 45, 2008

Helix Persistence and Breakdown in Oligoureas
A R T I C L E S
Scheme 2. Synthesis of the Sulfoxide Terminusa
a (a) Boc2O, THF, ∆ 60 h; (b) H2, Pd/C, THF, i-PrOH, rt, 16 h; (c)
2-BrC6H4NCO, CH2Cl2, rt, 14 h; (d) NaH, THF, 0 °C, 1 h; MeI rt, 60 h;
(e) n-BuLi, THF, -90 °C, 1 min; (R)-t-BuSS(O)t-Bu, THF, -90 °C - rt,
18 h; (f) CF3CO2H, CH2Cl2, rt, 12 h.
Figure 2. X-ray crystal structure of 1 [R1 ) H, R2 ) s-Bu].36
Scheme 3. Synthesis of the N-Benzyl Terminusa
Figure 3. Conformational preferences in ureas.
Scheme 1. Preliminary Synthesis of Three Sulfinyloligoureasa
a (a) THF, rt, 16 h; (b) H2, Pd/C, THF, i-PrOH, rt, 18 h; (c)
p-NO2C6H4OCOCl, py, THF, rt, 18 h.
Previous work9 had shown that an enantiomerically pure
arylsulfinyl or t-butylsulfinyl group placed adjacent to the ArC-N
bond of an N-arylurea is able to exert powerful control over
the orientation of the urea function (Figure 3). Alignment of
dipoles and steric effects combine to ensure that 2, for example,
adopts the conformation 2A in preference to 2B with >95:5
selectivity (Figure 3). (For related examples of the use of sulfinyl
groups to control bond orientation, see refs 5, 8, and 39.) We
hoped that this conformational controlling effect, combined with
the known preference for helicity in oligoureas, would allow
the sulfinyl group to control the helicity of the urea in solution.
Sulfinyl groups have proved to be widely effective in remotely
stereocontrolled reactions.40
a 1.n-BuLi,THF,-90°C;2.(1S,2R,5S)-(+)-menthyl-(RS)-p-tolylsulfinate.
related to 1. Fully N-substituted N,N′-diaryl ureas are known to
adopt in general a conformation which places the aromatic rings
close in space32spresumably due to π-stacking33sand kinetic and
thermodynamic aspects of bond rotation in simple N,N′-diaryl ureas
have been determined.34,35 Oligomeric ureas of N,N-dimethyl-m-
phenylenediamine (such as the triureas 1, Figure 2) have been
reported to adopt helical conformations in the solid state (Figure
236 shows the X-ray crystal structure of 1 [R1 ) H, R2 ) s-Bu]),
and on the basis of upfield shifts in their NMR spectra, they have
beenassignedstacked,possiblyhelicalconformationsinsolution.36-38
In connection with attempts to use the propagation of a stereo-
chemical influence within non-hydrogen bonded molecules to allow
transmission of information in the form of stereochemistry,10,12
we became interested in whether these oligo-ureas were indeed
helical in solution, and if so whether their conformation could be
controlled by a terminal chiral monomer.
We had to hand36 three oligoureas 3a-c bearing a terminal
2,6-diethylphenyl group, and a simple halogen metal exchange
followed by quench with (1S, 2R, 5S)-(+)-menthyl-(RS)-p-
tolylsulfinate41 converted the bromo substituent to a tolylsulfinyl
group (Scheme 1). We used the sulfoxides 4a-c as a “proof of
principle” before embarking on a more elaborate synthesis of a
larger set of oligoureas. Because of slow rotation in the 2,6-
diethylphenyl ring, the two ethyl groups of 3 may be rendered
diastereotopic by virtue of the chirality of the helix. However,
in 3 they appear as a single set of peaks, either because of fast
helix interconversion or because of the lack of ordered
(35) Clayden, J.; Lemie`gre, L.; Pickworth, M.; Jones, L. Org. Biomol.
Chem. 2008, 2908.
(36) Clayden, J.; Lemie`gre, L.; Helliwell, M. J. Org. Chem. 2007, 72, 2302.
(37) Tanatani, A.; Kagechika, H.; Azumaya, I.; Fukutomi, R.; Ito, Y.;
Yamaguchi, K.; Shudo, K. Tetrahedron Lett. 1997, 38, 4425.
(38) Lewis, F. D.; Kurth, T. L.; Hattan, C. M.; Reiter, R. C.; Stevenson,
C. D. Org. Lett. 2004, 6, 1605.
(32) (a) Lepore, G.; Migdal, S.; Blagdon, D. E.; Goodman, M. J. Org.
Chem. 1973, 38, 2590. (b) Lepore, U.; Castronuovo Lepore, G.; Ganis,
P.; Germain, G.; Goodman, M. J. Org. Chem. 1976, 41, 2134. (c)
Yamaguchi, K.; Matsumura, G.; Kagechika, H.; Azumaya, I.; Ito, Y.;
Itai, A.; Shudo, K. J. Am. Chem. Soc. 1991, 113, 5474. (d) Kurth,
T. L.; Lewis, F. D. J. Am. Chem. Soc. 2003, 125, 13760.
(33) Bhosale, S.; Sisson, A. L.; Sakai, N.; Matile, S. Org. Biomol. Chem.
2006, 3031.
(39) Clayden, J.; Stimson, C. C.; Keenan, M. Synlett 2005, 1716.
(40) (a) Garc´ıa Ruano, J. L; Ferna´ndez-Iba´n˜ez, M. A.; Maestro, M. C;
Rodr´ıguez-Ferna´ndez, M. M. J. Org. Chem. 2005, 70, 1796. (b)
Arroyo, Y.; Rodriguez, F.; Santos, M.; Sanz Tejedor, M. A.; Garc´ıa
Ruano, J. L. J. Org. Chem. 2007, 72, 1035.
(34) Adler, T.; Bonjoch, J.; Clayden, J.; Font-Bard´ıa, M.; Pickworth, M.;
Solans, X.; Sole´, D.; Vallverdu´, L. Org. Biomol. Chem. 2005, 3173.
(41) Andersen, K. K. Tetrahedron Lett. 1962, 93.
9
J. AM. CHEM. SOC. VOL. 130, NO. 45, 2008 15195

A R T I C L E S
Clayden et al.
Scheme 4. Construction of Oligoureasa
a (a) PhNCO, THF, rt, 14 h; (b) NaH, THF, 0 °C, 1 h; BnBr, rt, 10 h; (c) 8 and/or 11, DMAP, THF, rt, 16 h; (d) NaH, THF, 0 °C, 1 h; MeI, rt, 14 h;
(e) THF, rt, 18 h (32 h with 10); (f) H2, Pd/C, i-PrOH, THF, rt, 18 h; (g) CF3CO2H, CH2Cl2, rt, 15 h; (h) p-NO2C6H4OCOCl, py, THF, rt, 18 h. Note that
compounds are represented here for claritysno assumptions about true solution conformations are implied.
conformation. In 4 however, diastereotopicity is evident in the
ethyl groups of 4a (the two terminal methyl triplets differ in
chemical shift by 0.09 ppm) but for 4b and 4c peak separation
between these triplets is essentially zero.
9
15196 J. AM. CHEM. SOC. VOL. 130, NO. 45, 2008

Helix Persistence and Breakdown in Oligoureas
A R T I C L E S
To investigate in more detail the effects of structure and chain
length on apparent diastereotopicity we chose to simplify the
diastereotopic probe to an N-benzyl group and also to make
two further changes to 4: first, we were concerned that the
particularly bulky 2,6-diethylphenyl group might perturb π-stack-
ing of the terminal ring of the oligomer.35 Second, it had
previously been noted that in some situations t-butylsulfinyl
groups exert significantly greater conformational controlling
effects than arylsulfinyl groups.9
We set out therefore to build oligoureas 20a-f carrying at one
terminus a t-butylsulfoxide substituent, and at the other a dia-
stereotopic reporter group in the form of an N-phenyl-N-benzyl
urea. Two obstacles meant that the route needed to be more
elaborate than the iterative chain extension previously used for
simple unfunctionalised compounds. First, oligoureas containing
multiple NH groups tended to be intractable,36 necessitating gradual
N-methylation during the synthesis of the oligomers rather than
global methylation at the end of the synthesis. Second, incompat-
ibilities between (a) the (acidic,42 toward BuLi) N-benzyl dia-
stereotopic marker group and the (basic) conditions required for
the introduction of the sulfoxide substituent, and (b) between the
sulfoxide and the reductive hydrogenation conditions required
during the chain extension (reduction of nitro to amino groups),
meant that the two termini of the oligomers had to be separately
synthesized before a late coupling step.
Table 1. Apparent Diastereotopicity in the NCHaHbPh Signal of Sulfinylureas 20
9
J. AM. CHEM. SOC. VOL. 130, NO. 45, 2008 15197

A R T I C L E S
Clayden et al.
Scheme 5. Synthesis of Amidoureasa
a (a) PhNCO, THF, rt, 14 h; (b) NaH (1.2 equiv.), THF, rt, 20 min; MeI (1.5 eqiuv.), rt, 16 h; (c) NaH, THF, rt, 20 min; BnBr, rt, 16 h; (d) m-NO2C6H4NCO,
THF, rt, 18 h; (e) Boc2O, THF, ∆, 14 h; NaH, MeI, rt, 10 h; CF3CO2H, CH2Cl2, rt, 2 h; (f) 11, DMAP, THF, ∆, 12 h; NaH, THF, MeI, rt, 16 h (g) H2, Pd/C,
MeOH, THF, rt, 18 h.
Synthesis of the Sulfinyloligoureas. The sulfoxide terminus
was constructed as shown in Scheme 2. The monoprotected
diamine 6 was converted into bromourea 7. Halogen-lithium
exchange required very low temperature to avoid decomposition;
quenching with Ellman’s di-tert-butylthiosulfinate43 gave the
sulfoxide in enantiomerically pure form (by HPLC) which was
deprotected to yield aniline 8.
The N-benzyl terminus required for all but the simplest member
of the series 20a was made as shown in Scheme 3. Urea formation
from N-benzylaniline and 3-nitrophenyl isocyanate gave 9 which
was reduced to aniline 10 and converted to reactive carbamate 11
by acylation with p-nitrophenyl carbamyl chloride.
The diurea 20a was made simply by addition of sulfinylaniline
8 to phenylisocyanate and N-benzylation of the product (Scheme
4). The next member of the series, triurea 20b was made by
acylation of the same sulfinylaniline 8 with the benzylated
reactive carbamate 11, followed by N-methylation of the
resulting urea 12b.
For the remaining members of the series it was necessary to
synthesize separately a central oligourea section 14, which was
then sequentially capped with the N-benzyl terminus to yield
16 and the sulfoxide terminus to yield 19 and hence 20. Scheme
4 shows how this central section was built up for various chain
lengths. First, monoprotected m-phenylendiamine 6 was added
to 3-nitrophenyl isocyanate to yield, after methylation, 13d.
Monourea 13d was then treated under our published urea chain
extension conditions36 to yield the diurea 13d and the triurea
13e. Oligoureas bearing multiple NH groups soon become
intractable, insoluble powders, so with each chain growth step
the ureas 13 were methylated. Deprotection of each member of
the series 13 yielded anilines 14d-f. At this stage, the N-benzyl
terminus was introduced: acylation of the mono-, di- and triureas
14d-f with reactive carbamate 11 yielded tri-, tetra- and
pentaureas 15d-f. An analogous diurea member of this series
15c was obtained by chain extension of 10 with m-nitrophen-
ylisocyanate 9. Again, for ease of handling it was necessary to
methylate the remaining nonalkylated urea nitrogens of 15,
yielding fully methylated di-, tri-, tetra- and pentaureas 16c-f.
These ureas were prepared for capping with the sulfoxide
terminus by reduction to the amines 17 followed by formation
of the reactive carbamates 18. Acylation of sulfinyl aniline 8
by 18c-f yielded tetra-, penta-, hexa- and heptaureas 19c-f.
A final methylation yielded the remaining members of the family
of oligoureas 20: tetraurea 20c, pentaurea 20d, hexaurea 20e
and heptaurea 20f.
NMR Studies of Sulfinylureas. 1H NMR spectra of the
sulfinylureas 20a-f were obtained at either 300 or 500 MHz at
a concentration of ca. 10 mg mL-1 in deuterated chloroform,
benzene, toluene, methanol or DMSO at 23 °C. The form of
the NCHaHbPh signal at ca. δ 4.9-4.6 was examined, and
representative examples are illustrated shown in Table 1, which
also tabulates the chemical shift difference, ∆δ, in ppb, between
the two anisochronous signals, which was established by
modeling the AB system using the commercial software gNMR.
When diastereotopicity was apparent, the signal took the form
of an AB system, J ) 14.7 Hz. In other cases, a 2 H singlet
was observed.
Clear AB systems were evident for the diurea 20a and the
triurea 20b (though surprisingly 20a displays a 2H singlet in
chloroform). In tetraurea 20c the diastereotopic probe lies 24
bond-lengths from the sulfinyl group, and in most solvents
appeared as a 2 H singlet. Nonetheless, in CDCl3, a clear, very
9
15198 J. AM. CHEM. SOC. VOL. 130, NO. 45, 2008

Helix Persistence and Breakdown in Oligoureas
A R T I C L E S
Table 2. Apparent Diastereotopicity in the NCHaHbPh Signal of Amidoureas 24a
a Minor peaks visible in the NMR spectra are due to small amounts of inseparable impurities.
strongly coupled, AB system is evident. The outer lines of the
AB system are clearly located ca. 15 Hz from the central line,
clearly distinguishable from the natural abundance 13C coupled
differences between coupled protons in these compounds by
using homonuclear INADEQUATE experiments with very long
(up to 1 s) evolution delays. Long evolution delays are needed
because the effect of strong coupling is to shift the optimum
delay for double quantum excitation to longer times;44 in the
limit of very strong coupling the optimum total delay is of the
order of T2. In principle this is a very sensitive test, capable of
detecting very small shift differences, since double quantum
coherence between two spins can only be created if they are
distinguishable. Unfortunately the detection of intramolecular
double quantum coherence, which requires that the two spins
involved have (slightly) different chemical shifts, is confounded
by the potential presence of intermolecular double quantum
coherence arising from the very weak long-range dipolar
1
doublet with JCH ) 138 Hz. The form of the AB signal
remained essentially unchanged over a range of temperatures
from -90 to +23 °C. It was also independent of concentration,
appearing the same at 1/2, 1/4, and 1/8 dilutions of the original
concentration.
Urea 12b is the incompletely methylated analogue of 20b
and in contrast with 20b its NCHaHbPh signal is a 2H singlet.
Penta-, hexa- and heptaureas 20d-f displayed no apparent
diastereotopicity in their NCHaHbPh signals in a variety of
solvents and at a variety of temperatures. A number of attempts
were made to detect the presence of unresolved chemical shift
9
J. AM. CHEM. SOC. VOL. 130, NO. 45, 2008 15199

A R T I C L E S
Clayden et al.
siently chiral conformations provided enantiomeric conformers
interconvert slowly on the NMR time scale, so even achiral
molecules adopting transient helical conformations may be
studied by our method. In order to explore this feature, we made
a series of oligoureas 24 terminated simply by a “conformational
anchor”san amide group whose bond rotation is slow on the
NMR time scale5,46 and which therefore prevents rapid helix
inversion.
Figure 4. Conformation of an amido urea.
Amidourea 21 and its congeners have been shown to adopt
a single relative conformation 21A in solution (Figure 4),9 and
in the solid state the amide and the urea dipoles are orientated
anti to one another as shown.9 Based on previous studies,6,46
we expected the rate of interconversion at ambient temperature
of the two enantiomeric anti conformations of 21 to be too fast
for 21 to be considered a chiral molecule, but slow enough for
the NMR spectrum of 21 to lie in the slow exchange regime.
N-Benzyl urea 24a was made from 22 by regioselective
methylation followed by benzylation (Scheme 5). The signal
for the NCH2Ph group of 24a was evident as a clear AB system,
an observation fully consistent with slow (t1/2 > ca. 0.01 s) Ar-
CO rotation.
Scheme 6. Synthesis of Bromoureas and a Sulfonyl Ureaa
A further series of amidooligoureas 24 based on this structure
were built up as shown in Scheme 5. Amine 25 was acylated
with 11 to give the diurea 24b. The stability of the amide
substituent meant that a simple series of homologations36 of
amine 22 using 3-nitrophenylisocyanate, followed by reduction,
gave unsubstituted ureas 27 and 29, each of which was acylated
with 11 and globally methylated to yield triurea 24c and
tetraurea 24d. For the simplicity of the route, global methylation
was reserved until the final step. However, the intractability of
the intermediate ureas meant that overall yields were low.
1
NMR Studies of Amidoureas. As with the sulfinylureas, H
NMR spectra of the amidoureas 24a-d were obtained at either
300 or 500 MHz at a concentration of ca. 10 mg mL-1 in
deuterated chloroform or other solvents at 23 °C. Representative
examples of the form of the NCHaHbPh signal at ca. δ 4.9-4.6
are illustrated in Table 2, which also tabulates the chemical shift
difference, ∆δ, in ppb, between the two anisochronous signals.
In the monourea 24a, with only a 5-bond separation between
the diastereotopic probe and the rotationally restricted amide,
an AB system (J ) -14.7 Hz) with peak separation of nearly
0.5 ppm was observed. This separation dropped to 20 ppb in
the diurea 24b (13 bonds from amide to probe) but interestingly
rose again to 65 ppb in the triurea 24c, possibly because the
influences of the amide and the helix on the relative chemical
shifts of Ha and Hb are opposed in sign. In the tetraurea 24d, in
every solvent tried, and at low temperature in CDCl3, toluene
or deuteromethanol, a 2 H singlet was observed.
a (a) 11, DMAP, THF, rt, 12 h; (b) NaH, THF, 0 °C, 1 h; MeI, rt, 15 h;
(c) 18c, DMAP, THF, rt, 12 h; (d) 17c, THF, rt, 16 h; (e) H2, Pd/C, THF,
i-PrOH, rt, 16 h; (f) 2-BrC6H4NCO, THF, rt, 16 h; (g) m-CPBA, CH2Cl2,
rt, 12 h.
Synthesis of Bromooligoureas. As a further control, we
synthesized a series of three oligoureas devoid of a terminal
chiral group of any type, namely bromooligoureas 30a-c.
(Ar-N bond rotation in related simple 2-bromoureas takes place
with a barrier of around 55 kJ mol-1and a half-life for bond
rotation of around 5 ms at 25 °C.24,35) Diurea and triurea 30a
and 30b were made by addition of 2-bromoaniline to 11 and
18c, respectively, followed by global methylation; tetraurea 30c
interaction between blocks of spins in different spatial regions
of the sample.45 Such effects are most commonly seen in very
concentrated samples, typically in protiated solvents such as
H2O, but can be detected at much lower concentrations if, as
here, suitably sensitive methods are employed. A diagnostic
difference between intra- and intermolecular coherence is that
the amplitudes of signals deriving from the former scale linearly
with concentration, and those for signals deriving from the latter
scale quadratically; a more direct solution to the problem would
be the use of magic angle gradient pulses.
(42) Clayden, J.; Dufour, J. Tetrahedron Lett. 2006, 47, 6945.
(43) Weix, D. J.; Ellman, J. A. Org. Lett. 2003, 5, 1317.
(44) Freeman, R.; Bax, A. J. Magn. Reson. 1980, 41, 507.
Synthesis of Amidooligoureas. Unlike circular dichroism,
apparent diastereotopicity is independent of homochirality and
must apply equally to both enantiomerically enriched and to
racemic samples. Furthermore, just as NMR will detect tran-
(45) (a) Levitt, M. H. Concepts Magn. Res. 1995, 8, 77. (b) Warren, W. S.;
Richter, W.; Reotti, A. H.; Farmer, B. T. Science 1993, 262, 2005.
(46) Ahmed, A.; Bragg, R. A.; Clayden, J.; Lai, L. W.; McCarthy, C.; Pink,
J. H.; Westlund, N.; Yasin, S. A. Tetrahedron 1998, 54, 13277.
9
15200 J. AM. CHEM. SOC. VOL. 130, NO. 45, 2008

Helix Persistence and Breakdown in Oligoureas
A R T I C L E S
Figure 5. CD spectra of 4a-c.
Figure 6. CD spectra of 20a-f.
was synthesized as shown in Scheme 6: aminodiurea 17c was
chain-extended with m-nitrophenyl isocyanate, reduced to the
amine, added to 2-bromophenyl isocyanate and methylated. A
further oligourea devoid of chirality was made by oxidizing the
sulfoxide 20b to sulfone 33.
to an AB system of peak separation 75 ppb at -50 °C,
presumably because Ar-N bond rotation becomes slow at this
temperature. 2-Substituted ureas adopt twisted conformations,34,35
and the helicity of 33 at low temperature may be governed by
the resulting transient Ar-N axis.
Circular Dichroism Spectroscopy. CD spectra were obtained
for the sulfinyl ureas 4a-c and 20a-f in solution in chloroform
(Figures 5 and 6). All show distinctive features in the region
250-350 nm which we take to indicate opposite helicity induced
by the RS sulfoxide of 4 and the SS sulfoxide of 20. In both
NMR Studies of Bromooligoureas 30. The NCH2Ph groups
1
of all three bromoureas 30a-c displayed singlets in their H
NMR spectra in various solvents at ambient temperature and at
-90 °C. This signal in the spectrum of sulfone 33 however,
while appearing as a singlet at room temperature, decoalesced
9
J. AM. CHEM. SOC. VOL. 130, NO. 45, 2008 15201

A R T I C L E S
Clayden et al.
tions,35 and the lack of apparent diastereotopicity in 12b (Table
1) is consistent with disruption of the helix in this type of
unalkylated structure. Beyond four or five stacked rings, it seems
that entropic effects take over and disorder within the secondary
structuresin other words, the presence of further rapidly
interconverting alternative conformerssdilutes the effect of the
chiral terminus to the point where only singlets are observed.
We discount as unlikely the possibility that the helix persists
but that ∆δ is zero by chance, since singlets were observed in
a wide variety of solvents and at a variety of temperatures.
It is interesting to note the way that apparent diastereotopicity
in the sulfoxides 20 and amides 24 drops off markedly from
484 ppb in the monourea 24a to between 20 and 85 ppb in all
of the di- and triureas 20a,b and 24b,c. It seems possible that
this degree of anisochronicity represents the local influence of
the helix, while the greater degree of anisochronicity observed
in 24a is a result of the diastereotopic probe falling into the
direct local influence of the amide group itself. Anisochronicity
appears to be only weakly dependent on solvent, in accord with
the suggestion that order in these structures arises from π-π
stacking interactions.
Figure 7. Stacked, helical conformation proposed for 20c.
series there is a general trend toward less intense CD bands as
the helix lengthens, in agreement with our assumption that there
is a loss of helicity in longer oligomers.
Discussion
The NMR data from sulfinylureas 20 and amidoureas 24
show that the diastereotopic probe remains under the influ-
ence of the terminal substituent even when separated by up
to about 24 bond lengths. In the absence of secondary
structure within the oligomer, this would be an unprecedent-
edly remote effect for an acyclic molecule, and the distance
over which the environmental influence of the chiral group
is projected makes it clear that the ureas adopt a well-defined
structure over these lengths. The lack of observable diaster-
eotopicity in 30 discounts the possibility that diastereotopicity
arises because of the oligourea structure alone. We also rule
out the possibility that the apparent diastereotopicity arises
from an intermolecular (head-to-tail, say) interaction for two
reasons. First, the apparent diastereotopicity remained con-
stant with decreasing concentration. Second, mixing together
equimolar amounts of achiral triurea 30b and chiral triurea
20b did not induce anisochronicity in the NMR signal arising
from the NCH2Ph group of 30b.
Solid state evidence and previous observations of upfield
chemical shifts suggesting Ar-Ar stacking,36,37 lead us to
conclude that such N-alkylated aromatic oligoureas of up to
four stacked rings adopt a chiral secondary structurespresumably
a helixsin solution, and that this helix may have its relative
stereochemistry (and absolute stereochemistry in the case of the
sulfoxides) determined by a terminal sulfinyl or amido group.
The stacked helical structure we propose for 20c is illustrated
in Figure 7. Unmethylated ureas adopt “open” (exo) conforma-
Conclusion
Inclusion of a terminal diastereotopic probe remote from a
chiral influence can give qualitative information about ordered
chiral secondary structure in solution. When applied to oli-
goureas built from m-phenylenediamine monomers, the tech-
nique suggests order persists for oligomer lengths of up to about
four or five monomer units. We are currently seeking to apply
the technique more widely to the functional application of
foldamer conformation in solution.
Acknowledgment. We are grateful to the EPSRC, the
Leverhulme Trust, and to Pfizer Ltd for support. We thank Prof.
Andrew Doig and Dr. Jordi Sola´ for assistance with the CD
spectroscopy.
Supporting Information Available: Experimental procedures
and characterization data for all compounds reported in this
paper. This information is available free of charge via the
Internet at http://pubs.acs.org.
JA805758V
9
15202 J. AM. CHEM. SOC. VOL. 130, NO. 45, 2008