Relaying stereochemistry through aromatic ureas: 1,9 and 1,15 remote stereocontrol

Article abstract of DOI:10.1039/b817527f

The well-defined conformation of an N,N′-diarylurea allows a chiral sulfinyl substituent to influence diastereoselectivity in the formation of new stereogenic centres up to 14 bond lengths away. The Royal Society of Chemistry.

Full text of DOI:10.1039/b817527f

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Relaying stereochemistry through aromatic ureas: 1,9 and 1,15 remote
stereocontrolw
Jonathan Clayden,*a Mark Pickwortha and Lyn H. Jonesb
Received (in Cambridge, UK) 6th October 2008, Accepted 10th November 2008
First published as an Advance Article on the web 26th November 2008
DOI: 10.1039/b817527f
The well-defined conformation of an N,N0-diarylurea allows
a chiral sulfinyl substituent to influence diastereoselectivity
in the formation of new stereogenic centres up to 14 bond
lengths away.
Although control of configuration at new stereogenic centres
Scheme 1 Conformation of simple ureas.
remains a major goal of synthetic chemists, the ability to
achieve stereochemical control over conformation, particularly
in acyclic molecules, is far less well developed. Recent progress
in the area has included the development of conformationally-
defined oligomers (‘‘foldamers’’),1 elucidation of the factors
governing the conformation of substituted alkyl chains2 and
the development of methods for the control of slowly inter-
converting conformers (atropisomers).3 Our own work has
addressed control of orientation of C–C, C–N and C–O bonds
using the stereochemical influence (steric and/or electronic)
of appropriately chosen nearby stereogenic centres.4,5 The
achievement of high levels of conformational control has
allowed the enantioselective synthesis of new non-biaryl
atropisomers,6 and is a key feature of systems designed
to mediate the remote communication of stereochemical
information.7,8
In this paper, we now report that N,N0-diaryl ureas may be
used to relay stereochemical information over long distances.
We chose to use N,N0-diaryl ureas as a conformationally con-
trollable ‘‘scaffold’’ for three reasons. Firstly, their C–N bond
rotations are typically slow on the NMR timescale,9,10 facilitat-
ing spectroscopic characterisation of conformational preferences
and interconversions. Secondly N,N0-diaryl-N,N0-dialkyl ureas
adopt a well-defined conformation about the urea N–CO bonds,
with the two aromatic rings lying cis to one another.11 As a
result, extended polyurea structures apparently adopt p-stacked,
helical conformations.12–14 Finally, the lithiation chemistry
associated with the ureas facilitates their synthesis.15
A well-defined conformation in solution is generally a pre-
requisite for high levels of stereoselectivity.7,16 Incorporation
into 2 of a prochiral stereogenic centre would allow explora-
tion of the possibility that the stereochemical influence of the
sulfoxide group might be relayed and amplified by its effect on
Ar–N conformation.17
Scheme 2 illustrates our synthesis of two ureas, 7 and 9,
containing a 2-formyl group. Aldehyde 7 showed only one set
1
of H NMR signals in toluene solution over the full range of
temperatures ꢀ90 to +105 1C, suggesting that it assumes a
uniform conformation not only about the C–N bond marked a
but also that marked b. Its X-ray crystal structure showed that
it adopts the conformation 7A in the solid state (Fig. 1), in
which the sulfinyl and formyl groups are arranged anti across
the urea linker. However previous results had indicated only
low levels of conformational selectivity in the relative orienta-
tion of the two Ar–N bonds in 2,20 disubstituted N,N0-diaryl
ureas,9 so it was important to rule out the possibility that the
single set of peaks might be due to rapid interconversion
between the two conformers 7A and 7B rather than thermo-
dynamic preference for 7A. We therefore made 9 from 4 via 8
(Scheme 2). The 1H NMR signals due to Ha–d of 9 were
broadened at room temperature and decoalesced to a pair of
AB systems at ca. ꢀ30 1C, with diastereotopicity arising from
slow rotation about Ar–N bond b. Lineshape analysis9
allowed us to estimate a barrier for rotation about the Ar–N
bond adjacent to the formyl group of 9 of 55.6 ꢁ 1.1 kJ molꢀ1
at ꢀ30 1C, a figure consistent with those calculated for related
structures.9,10 Since compounds closely related to 7 but with
The perpendicular conformation adopted by 2-substituted
ureas 1 with simple achiral substituents X and Y is evident in
their NMR spectra: the enantiomeric Ar–N conformers inter-
convert slowly on the NMR timescale.9,10 We recently showed
that levels of conformational control in ureas 2 carrying a
2-sulfinyl group (R = Ar or t-Bu) were sufficiently high that
the minor conformer 2B was undetectable by NMR
(Scheme 1).5
a School of Chemistry, University of Manchester, Oxford Road,
Manchester, UK M13 9PL. E-mail: Clayden@man.ac.uk
b Pfizer Central Research, Sandwich, Kent, UK CT12 3NT
w Electronic supplementary information (ESI) available: Experimental
details and characterisation data for new compounds. CCDC 703570
and 703571. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b817527f
Scheme 2 Synthesis of 2-formyl substituted ureas.
Chem. Commun., 2009, 547–549 | 547
ꢂc
This journal is The Royal Society of Chemistry 2009

View Article Online
Table 1 Diastereoselectivity in nucleophilic attack
Solvent, additive Yield (%) Ratio 10a : 10ba
Entry SM Nu
1
2
3
4
5
6
7
8
7
7
7
7
7
7
7
7
7
7
7
7
PhMgBr
PhMgBr
PhMgBr
PhMgBr
RMgBrc
PhMgBr
THF
THF, ꢀ90 1C
96
85
80
40–60
50–95
80 : 20
88 : 12
87 : 13
CH2Cl2
THF + LAb
THF
78 : 22–86 : 14
60 : 40–80 : 20
495 : 5
495 : 5
495 : 5
495 : 5
495 : 5
495 : 5
90 : 10
60 : 40
60 : 40
75 : 25
80 : 20
82 : 18
88 : 12
85 : 15
495 : 5
o5 : 95
THF, DMPUd 95
Scheme 3 1,9 Stereocontrol by nucleophilic attack on acylureas.
MeMgBr THF, DMPUd 65
EtMgCl
BuMgCl
THF, DMPUd 45
THF, DMPUd 80
9
non-uniform conformation about a bond equivalent to axis a
show clear doubling of peaks in their 1H NMR spectra,5,18 we
deduce that conformational non-uniformity about either bond
10
11
12
13
14
15
16
17
18
19
20
21
i-BuMgBr THF, DMPUd 65
c-PnMgBr THF, DMPUd 90
vinylMgBr THF, DMPUd 71
1
11 LiAlH4
11 NaBH4
11 LiBEt3H THF
11 LiBEt3H CH2Cl2
11 Lis-Bu3BH THF
11 Lis-Bu3BH CH2Cl2
11 RedAl
11 RedAl
11 i-Bu2AlH CH2Cl2
THF
EtOH
65
85
60
65
85
80
90
95
95
a or bond b would be evident in the H NMR spectrum of 7.
Encouraged by the apparent high level of conformational
control in 7, we treated this aldehyde with a series of nucleo-
philes (Scheme 3), hoping to see correspondingly good levels
of 1,9 remote stereoselectivity. The results are tabulated in
Table 1, entries 1–12. In general, Grignard reagents gave
moderate to good diastereoselectivity (entries 1, 5), which
could be improved to some extent by reducing the temperature
(entry 2) or by changing to a less coordinating solvent (entry 3).
Addition of Lewis acids (entry 4) had little effect, but by
contrast addition of the powerfully coordinating co-solvent
DMPU led to near perfect selectivity for diastereoisomer 10a
in almost every case (entries 6–12). This result strongly
suggests that while chelated transition states can yield good
levels of diastereocontrol, saturation of chelation effects by
DMPU is the most effective way of gaining the highest levels
of selectivity in these reactions.
THF
CH2Cl2
a
b
Determined by 1H NMR. Lewis acid (LA) = ZnBr2, Et2AlCl, AlMe3,
c
MgBr2.OEt2, BF3.OEt, TiCl4, Ti(Oi-Pr)3Cl. Grignards listed in entries
7–12. Remaining material consists mainly of the benzylic alcohol reduc-
d
tion product of 7. DMPU = N,N0-dimethylpropylideneurea.
The stereochemistry of products 10 was deduced by X-ray
crystallography of the major diastereoisomer 10a (R = Ph).
Given the consistently high levels of selectivity in entries 6–12
we assume that other nucleophiles react with the same sense of
diastereoselectivity. We propose that this remote diastereo-
selectivity arises through a transition state in which the
nucleophile attacks the less hindered face of the aldehyde as
it lies in the favoured conformation 7a (Fig. 1).19
Fig. 2 (a) X-Ray crystal structure of 10a (Nu = Ph)z and (b)
rationales for diastereoselective nucleophilic attack on 11 (R = Ph).
A remarkable complete reversal of selectivity was evident
when DIBAL was used in CH2Cl2 solvent: 10b (Nu = Ph) was
formed with high yield and selectivity. Presumably this is
brought about by coordination between Al and O during the
reduction, promoting adoption of an alternative reactive
conformation which minimises interaction between the
coordinated CQO and the urea (Fig. 2).20
More extended oligoureas adopt a stacked helical structure
in the solid state,12,13 and we have recently reported NMR
evidence that short oligomers (up to four urea linkages) adopt
a helical structure in solution,14 though we were unable to
quantify the population of the helical conformer relative to
Oxidation of the alcohols 10 (Nu = Ph) gave the ketone 11,
which was reduced back to a mixture of alcohols 10 with a
range of reducing agents, as indicated in Table 1, entries
13–21. In most cases (entries 13–20) selectivity again lay in
favour of 10a (Nu = Ph), with the degree of selectivity having
a clear dependence on the steric bulk of the reducing agent.
We propose that these selectivities, culminating in 495 : 5
observed with RedAl in CH2Cl2, are the result of the
unhindered trajectory for attack on what we presume to be
the favoured conformation of 11, shown in Fig. 2.19
Fig. 1 (a) X-Ray crystal structure of 7 (showing conformer 7A);z
(b) assumed preferred conformation of a 2-formyl urea; rationale for
diastereoselective nucleophilic attack on 7.
Scheme 4 Elongating the urea.
ꢂc
This journal is The Royal Society of Chemistry 2009
548 | Chem. Commun., 2009, 547–549

View Article Online
4 M. S. Betson, J. Clayden, M. Helliwell, P. Johnson, L. W. Lai,
J. H. Pink, C. C. Stimson, N. Vassiliou, N. Westlund, S. A. Yasin
and L. H. Youssef, Org. Biomol. Chem., 2006, 4, 424.
5 M. S. Betson, A. Bracegirdle, J. Clayden, M. Helliwell, A. Lund,
M. Pickworth, T. J. Snape and C. P. Worrall, Chem. Commun.,
2007, 754.
6 J. Clayden, C. P. Worrall, W. Moran and M. Helliwell, Angew. Chem.,
Int. Ed., 2008, 47, 3234; J. Clayden, D. Mitjans and L. H. Youssef,
J. Am. Chem. Soc., 2002, 124, 5266; J. Clayden, P. Johnson, J. H. Pink
and M. Helliwell, J. Org. Chem., 2000, 65, 7033; J. Clayden and
L. W. Lai, Angew. Chem., Int. Ed., 1999, 38, 2556; J. Clayden,
L. W. Lai and M. Helliwell, Tetrahedron, 2004, 60, 4399.
7 J. Clayden and N. Vassiliou, Org. Biomol. Chem., 2006, 4,
2667.
Scheme 5 1,15 Remote diastereocontrol.
other conformers. Diastereoselectivity provides an empirical
indication of the degree to which conformation is non-
random, and we set out to make a series of oligimeric ureas
terminated, like monourea 7, by a sulfoxide and by a reactive
carbonyl substituent. The synthesis of the diurea 14, a sub-
strate for potential 1,15-stereochemical control, is shown in
Scheme 4. We used the strategy of chain elongation with
3-nitrophenyl isocyanate,13,14 followed by reduction to the
aniline 12 and trapping with 2-bromophenylisocyanate,
converting 13 to 14 using enantiomerically enriched
di-t-butylthiosulfinate. If 14 adopts a stacked, helical struc-
ture, we expect its conformation to approximate to that shown
as 14A.13
8 J. Clayden, A. Lund, L. Vallverdu´ and M. Helliwell, Nature
(London), 2004, 431, 966; J. Clayden, A. Lund and
L. H. Youssef, Org. Lett., 2001, 3, 4133; J. Clayden,
M. N. Kenworthy and L. H. Youssef, Tetrahedron Lett., 2000,
41, 5171; J. Clayden, J. H. Pink and S. A. Yasin, Tetrahedron Lett.,
1998, 39, 105; J. Clayden, L. W. Lai and M. Helliwell, Tetrahedron:
Asymmetry, 2001, 12, 695; J. Clayden, N. Westlund,
C. S. Frampton and M. Helliwell, Org. Biomol. Chem., 2006, 4,
455.
9 J. Clayden, L. Lemiegre, M. Pickworth and L. Jones, Org. Biomol.
Chem., 2008, 6, 2908.
10 T. Adler, J. Bonjoch, J. Clayden, M. Font-Bardı
X. Solans, D. Sole and L. Vallverdu, Org. Biomol. Chem., 2005, 3,
3173.
´
a, M. Pickworth,
´
´
11 G. Lepore, S. Migdal, D. E. Blagdon and M. Goodman, J. Org.
Chem., 1973, 38, 2590; U. Lepore, G. Castronuovo Lepore,
P. Ganis, G. Germain and M. Goodman, J. Org. Chem., 1976,
41, 2134; K. Yamaguchi, G. Matsumura, H. Kagechika,
I. Azumaya, Y. Ito, A. Itai and K. Shudo, J. Am. Chem. Soc.,
1991, 113, 5474; T. L. Kurth and F. D. Lewis, J. Am. Chem. Soc.,
2003, 125, 13760.
12 A. Tanatani, H. Kagechika, I. Azumaya, R. Fukutomi, Y. Ito,
K. Yamaguchi and K. Shudo, Tetrahedron Lett., 1997, 38, 4425;
F. D. Lewis, T. L. Kurth, C. M. Hattan, R. C. Reiter and
C. D. Stevenson, Org. Lett., 2004, 6, 1605.
Aldehyde 14 was treated with a selection of nucleophiles
under comparable conditions to those used for 7, but in
most cases diastereoselectivities close to 1 : 1 were observed.
With PhMgBr in CH2Cl2 in the presence of DMPU, however,
a pair of alcohols 15 was obtained in 90% yield with a
diastereoisomeric ratio of 65 : 5 (Scheme 5). A selectivity
of the order of 2 : 1 is moderate by any standards, but to
attain any selectivity over 14 bond lengths is nonetheless
noteworthy.21
13 J. Clayden, L. Lemiegre and M. Helliwell, J. Org. Chem., 2007, 72,
2302.
14 J. Clayden, L. Lemiegre, G. A. Morris, M. Pickworth, T. J. Snape
and L. H. Jones, J. Am. Chem. Soc., 2008, 130, 15193.
15 J. Clayden, H. Turner, M. Pickworth and T. Adler, Org. Lett.,
2005, 7, 3147; J. Clayden, H. Turner, M. Helliwell and E. Moir,
J. Org. Chem., 2008, 73, 4415; J. Clayden and J. Dufour, Tetra-
hedron Lett., 2006, 47, 6945; J. Clayden, J. Dufour, D. Grainger
and M. Helliwell, J. Am. Chem. Soc., 2007, 129, 7488; J. Clayden
and U. Hennecke, Org. Lett., 2008, 10, 3567.
The diastereoisomers of 15 were oxidised to ketone 16 and
then reduced back to 15 using the same reducing agents as
shown in Table 1. Low selectivities were obtained,22 but as
before, an inversion of sense occurred on exchanging simple
hydride reducing agents for DIBAL in CH2Cl2. This latter
reagent returned a ratio of 30 : 70 of the two diastereoisomeric
alcohols, another example of ca. 2 : 1 stereocontrol over 14
bond lengths.
16 K. Mikami, M. Shimizu, H.-C. Zhang and B. E. Maryanoff,
Tetrahedron, 2001, 57, 2917.
17 For other recent examples of ‘‘remote’’ stereocontrol (44 bond
Our aim in this paper has been to show that well-defined
conformational control of otherwise flexible molecules allows
remote control of diastereoselectivity. In the oligoureas we use
as our substrates, it is evident that conformational control
begins to degrade rapidly after the second urea subunit is
incorporated, a result which suggests that the well-defined
conformations seen in the crystal structures of these
compounds is not mirrored in solution.
lengths) using
M. A. Fernandez-Iba
Fernandez, J. Org. Chem., 2005, 70, 1796; J. L. Garcı
A. M. Martın-Castro, F. Tato and C. J. Pastor, J. Org. Chem.,
2005, 70, 7346; Y. Arroyo, F. Rodriguez, M. Santos, M. A. Sanz
Tejedor and J. L. Garcıa Ruano, J. Org. Chem., 2007, 72, 1035.
a
sulfoxide, see: J. L. Garcı
nez, M. C. Maestro and M. M. Rodrı
a Ruano,
´
a
Ruano,
´
´
´
guez-
´
´
´
´
18 P. V. Jog, R. E. Brown and D. K. Bates, J. Org. Chem., 2003, 68,
8240.
19 For a discussion of selectivity in related additions to atropisomeric
ureas, see ref. 15b and to atropisomeric amides, see: J. Clayden,
C. McCarthy, N. Westlund and C. S. Frampton, J. Chem. Soc.,
Perkin Trans. 1, 2000, 1363. Our reasoning here is based on the
assumption that both conformers have approximately equal reac-
tivity. For a discussion of the application of the Winstein–Holness
equation in comparable situations, see: J. I. Seeman, Chem. Rev.,
1983, 83, 83; N. S. Zefirov, Tetrahedron, 1977, 33, 2719.
20 J. Clayden, N. Westlund, R. L. Beddoes and M. Helliwell, J. Chem.
Soc., Perkin Trans. 1, 2000, 1351.
Notes and references
z Crystallographic data for 7 and 10a (Nu = Ph) has been deposited
with the Cambridge Crystallographic Data Centre, deposition
numbers 703570 and 703571.
1 S. Hecht and I. Huc, in Foldamers, Weinheim, 2007; D. J. Hill,
M. J. Mio, R. B. Prince, T. S. Hughes and J. S. Moore, Chem. Rev.,
2001, 101, 3893; S. H. Gellman, Acc. Chem. Res., 1998, 31,
173.
21 The current ‘‘record’’ for remote stereochemical control stands at
1,23 (ref. 8). For examples of 41,10 stereochemical control, see
refs. 8 and 16.
2 R. W. Hoffmann, Angew. Chem., Int. Ed., 2000, 39, 2054.
3 J. Clayden, Chem. Commun., 2004, 127.
22 Stereochemistry of 15 was assigned by analogy with 10. Ketone 16
exists as a mixture of conformers by H NMR.
1
ꢂc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 547–549 | 549