Amino acid based chiral N-amidothioureas. Acetate anion binding induced chirality transfer

Article abstract of DOI:10.1039/c1cc14995d

N-Amidothioureas generated from amine-dimethylated natural l-phenylalanine and its d-enantiomer bearing a chiral carbon that is by 2 atoms or 3 chemical bonds away from the anion binding site establish chiral communication upon acetate anion binding to the thiourea moiety.

Full text of DOI:10.1039/c1cc14995d

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COMMUNICATION
Amino acid based chiral N-amidothioureas. Acetate anion binding
induced chirality transferw
Fang Wang,a Wen-Bin He,a Jin-He Wang,a Xiao-Sheng Yan,a Ying Zhan,a Ying-Ying Ma,b
Li-Cai Ye,a Rui Yang,b Fu Cai,a Zhao Lia and Yun-Bao Jiang*a
Received 11th August 2011, Accepted 7th September 2011
DOI: 10.1039/c1cc14995d
N-Amidothioureas generated from amine-dimethylated natural
L-phenylalanine and its D-enantiomer bearing a chiral carbon
that is by 2 atoms or 3 chemical bonds away from the anion
binding site establish chiral communication upon acetate anion
binding to the thiourea moiety.
Thiourea has recently received increasing attention as an
organocatalyst,1 in addition to the classic role in the anion
receptor,2 operating via its double hydrogen bonding inter-
action with the reaction substrate. In particular, using thiourea
as the major component of organocatalysts for enantio-
selective catalysis or kinetic resolution of enantiomers has
Scheme 2 Anion binding with PLTU and the resultant hydrogen
made available a variety of chiral thioureas (for typical
examples, see Scheme 1), in which the chiral centre is directly
linked to the thioureido –NH group. We recently showed that
N-amidothioureas exhibited substantially enhanced anion
affinity despite the twisted N–N single bond that breaks the
electronic communication between the thiourea and N-amide
moieties.3 This was attributed to a conformation change
bonding network. Magnetically nonequivalent gemini CH2 protons
(Ha and Hb) next to the chiral a-carbon bearing proton Hc are shown.
Dashed line in L-/D-PLTU indicates the 5-membered ring intra-
molecular hydrogen bond in PLTU and the rest of the dashed lines
in the anion binding complex represent hydrogen bonds in the hydrogen
bonding network.3 L-BPTU and L-PATU are two control molecules of
L-PLTU for identifying the contribution of the 5-membered ring
intramolecular hydrogen bond in PLTU. ‘‘*’’ in the molecular structure
indicates the chiral carbon centre.
around the N–N single bond upon anion binding to the
thiourea moiety that affords a hydrogen bonding network in
the anion binding complex (Scheme 2). We therefore envisaged
that if the easily available a-amino acids are employed to
generate the corresponding N-amidothioureas, the hydrogen
bonding network in the anion binding complex may help the
chiral communication in the N-amidothioureas upon anion
binding. This would allow us to create a family of structurally
diverse thiourea-based chiral organocatalysts from the easily
available chiral sources, in which the chiral carbon centre is by
2 atoms or 3 chemical bonds away from the nearest thioureido
–NH group (Scheme 2). Here we report our first attempt by
taking phenylalanine as the a-amino acid based chiral source.
The amine group in the amino acid moiety was dimethylated
for two reasons, i.e. the synthetic feasibility since the primary
amine group may react with the other reactant isothiocyanate
employed in the preparation of the final N-amidothiourea and
the introduction of a bulky group to minimize structural
flexibility.4 We found that with L-/D-PLTUs (Scheme 2),
derived from the natural L-phenylalanine and its enantiomer
D-phenylalanine, respectively, chiral communication occurs
upon their binding to acetate anion.
Scheme 1 Selected reported examples of chiral thioureas for enantio-
selective organocatalysis and kinetic resolution.
a Department of Chemistry, College of Chemistry and Chemical
Engineering, and the MOE Key Laboratory of Analytical Sciences,
Xiamen University, Xiamen 361005, China.
E-mail: ybjiang@xmu.edu.cn; Fax: +86 592 218 5662;
Tel: +86 592 218 8372
b College of Chemistry and Chemical Engineering, Southwest
University, Chongqing 400715, China
w Electronic supplementary information (ESI) available: Synthesis
(Scheme S1) and characterization of PLTUs (optimized conformation
in Scheme S2), BPTU and PATU and spectral titration traces and data
(Figs. S1–S11). See DOI: 10.1039/c1cc14995d
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N-amide moiety with the thiourea moiety.3 Surprisingly, a
bisignate CD couplet was developed upon anion binding, with
positive and negative Cotton effects at 296 nm and 260 nm,
respectively, while the original CD signals of the a-amino acid
residue disappeared. The CD couplet is of excitonic nature since
it appears at the wavelength of 270 nm that is close to the
absorption maximum of the anion binding complex (Fig. 1),5
which means that the two chromophores, chiral amide and
thiourea are now coupled in the anion binding complex. This
is a clear indication of the conformation change in L-PLTU upon
anion binding that allows transmission of the chirality from the
N-amide to the thiourea moiety in the anion binding complex.
The fact that, while the absorption spectrum of D-PLTU under-
went practically the same variations in the presence of acetate
anion, the CD spectra exhibit a mirror-imaged variation profile
as that of the L-PLTU (Fig. S1) confirms that the chirality is
transferred from the N-amide moiety of the chiral a-amino acid
origin. It was encouraging to find that, with (E)-4,40-(diazene-1,
2-diyl)dibenzoate (ADA) that has an absorption window far
beyond that of the anion binding complex of L-PLTU, CD signals
corresponding to the intrinsic absorption of the ADA chromo-
phore were observed (Fig. 3). This confirms that the chirality of
the L-PLTU is transferred to the relatively remote chromophore
in ADA anion that is bound to the thiourea moiety in PLTU and
that totally the ADA-L-PLTU complex turns to be chiral.
The acetate-binding induced electronic communication in
L-PLTU was also supported by NMR titrations. PLTU contains
two gemini protons (Ha and Hb, Scheme 2) next to the chiral
a-carbon. They are magnetically nonequivalent, therefore splitting
in their NMR signals reflecting structural rigidity around the
chiral centre.6 We monitored the NMR spectra of L-PLTU in
CD3CN in the presence of acetate anion. The observation that
the NMR signals of the thioureido –NH protons underwent a
downfield shift and broadening while those of the aromatic
protons of the thiourea moiety exhibited opposite shifting pro-
files confirms the hydrogen bonding nature of the interaction of
acetate anion with thiourea in L-PLTU 3h (full NMR traces given
in Fig. S4 (ESIw)). More importantly, the splitting of the Ha and
Hb signals was found to be enlarged with increasing concen-
tration of acetate anion (Fig. 2 and Fig. S5 (ESIw)), which points
Fig. 1 Absorption (a) and CD (b) spectra of L-PLTU in CH3CN in
the presence of tetrabutylammonium acetate. [L-PLTU] = 40 mM.
Fig. 2 Portion of 1H NMR traces of L-PLTU in CD3CN in the presence
of acetate anion of increasing equivalence from bottom to top. [PLTU] =
10 mM. Signal of Ha is later mixed with and interfered by those of
(n-Bu)4N+ cation. For numbering of Ha, Hb and Hc see Scheme 2.
PLTUs were easily prepared from L-/D-phenylalanine (Scheme
S1, ESIw). Fig. 1 shows the absorption and CD spectra of
L-PLTU in acetonitrile in the presence of acetate anion as a
model anion. Substantial changes in both spectra probe the
interaction of acetate anion with the thiourea receptor, which
1
is confirmed by H NMR titrations (Fig. 2). In the absorption
titration traces an isosbestic point at 240 nm was observed
(Fig. 1a). This means a clean binding interaction of acetate anion
with L-PLTU. The new absorption at 296 nm is the charge
transfer band of the anion binding complex in which the anion/
N-aminothiourea binding moiety is the electron donor while the
N-amido moiety is within the acceptor.3 The occurrence of the
charge transfer was supported by an upfield shift of the NMR
signal of the a-CHc proton of L-PLTU in CD3CN in the presence
of acetate (Fig. 2). It was observed that in the absence of the
anion, L-PLTU only exhibits CD signals at 240 nm and 220 nm
(Fig. 1b) that are due to the chiral a-amino acid residue,5 whereas
at the absorption region around 265 nm of the thiourea moiety it
is CD silent. This observation suggests that the thiourea moiety
in L-PLTU remains achiral or that the chirality of the a-amino
acid residue is not transferred, which is consistent with the
previous conclusion of the twisted nature of the N–N single
bond that breaks the electronic communication of the chiral
Fig. 3 Absorption (a, L-PLTU) and CD (b, L-PLTU; c, D-PLTU)
spectra of PLTU in CH3CN in the presence of trans-ADA anion.
[PLTU] = 40 mM; [ADA] = 0–5 mM (a) and 0–30 mM (b, c). The
absorption beyond 325 nm (a) originates mainly from the chromo-
phore in ADA anion (Fig. S2, ESIw) and the CD signals at 365 nm
(b, c) are due to bound ADA (Fig. S3, ESIw).
c
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to enhanced magnetic nonequivalence upon anion binding to the
thiourea moiety. It hence follows that the rigidity around the
chiral a-carbon centre is increased, which nicely coincides with
the formation of the hydrogen bonding network in the anion
binding complex (Scheme 2). Taking together the observations of
chirality transfer from a-carbon to the thiourea moiety in the
anion binding complex (Fig. 1 and 3) and the anion binding
induced rigidity increase around the a-carbon (Fig. 2 and
Fig. S5 (ESIw)), it appears that a mutual communication between
acetate anion and chiral a-carbon in PLTU is established in the
PLTU–AcOꢀ binding complex.
This work has been supported by the NSFC (20835005 and
J1030415) and the MOST of China (2011CB910403). Professor
Hui Zhang of Xiamen University is appreciated for her
instructive discussions on the CD spectra.
Notes and references
1 For most recent reviews see (a) Z. G. Zhang and P. R. Schreiner,
Chem. Soc. Rev., 2009, 38, 1187–1198; (b) Y. Sohtome, N. Takemura,
K. Takada, R. Takagi, T. Iguchi and K. Nagasawa, Chem.–Asian J.,
2007, 2, 1150–1160; (c) A. G. Doyle and E. N. Jacobsen, Chem. Rev.,
2007, 107, 5713–5743; For recent examples of organocatalysis see:
(d) B. Tan, N. R. Candeias and C. F. Barbas III, Nat. Chem., 2011, 3,
473–477; (e) J. Wang and B. L. Feringa, Science, 2011, 331, 1429–1432;
(f) J. Luo, H. Wang, X. Han, L.-W. Xu, J. Kwiatkowski, K.-W. Huang
and Y. Lu, Angew. Chem., Int. Ed., 2011, 50, 1861–1864; (g) Q. Guo,
M. Bhanushali and C.-G. Zhao, Angew. Chem., Int. Ed., 2010, 49,
9460–9464; (h) H. Uehara, R. Imashiro, G. Hernandez-Torres and
C. F. Barbas III, Proc. Natl. Acad. Sci. U. S. A., 2010, 107,
20672–20677; (i) Y. Sohtome, S. Tanaka, K. Tanaka, T. Yamaguchi
and K. Nagasawa, Angew. Chem., Int. Ed., 2010, 49, 9254–9257;
(j) R. Imashiro, H. Uehara and C. F. Barbas III, Org. Lett., 2010,
12, 5250–5253; (k) X.-F. Wang, Q.-L. Hua, Y. Cheng, X.-L. An,
Q.-Q. Yang, J.-R. Chen and W.-J. Xiao, Angew. Chem., Int. Ed., 2010,
49, 8379–8383; (l) X.-Q. Dong, H.-L. Teng, M.-C. Tong, H. Huang,
H. Y. Tao and C.-J. Wang, Chem. Commun., 2010, 46, 6840–6842;
(m) R. P. Singh, B. M. Foxman and L. Deng, J. Am. Chem. Soc., 2010,
132, 9558–9560; (n) A. R. Brown, W.-H. Kuo and E. N. Jacobsen,
J. Am. Chem. Soc., 2010, 132, 9286–9288; (o) S. J. Zuend,
M. P. Coughlin, M. P. Lalonde and E. N. Jacobsen, Nature, 2009,
461, 968–971; For recent examples of kinetic resolution, see:
(p) E. G. Klauber, C. K. De, T. K. Shah and D. Seidel, J. Am. Chem.
Soc., 2010, 132, 13624–13626; (q) C. K. De, E. G. Klauber and
D. Seidel, J. Am. Chem. Soc., 2009, 131, 17060–17061.
2 (a) J. L. Sessler, P. A. Gale and W.-S. Cho, Anion
Receptor Chemistry, RSC Publishing, 2006; (b) P. A. Gale, Chem.
Commun., 2011, 47, 82–86; (c) P. A. Gale, Chem. Soc. Rev., 2010, 39,
3746–3771; (d) R. M. Duke, E. B. Veale, F. M. Pfeffer, P. E. Kruger
and T. Gunnlaugsson, Chem. Soc. Rev., 2010, 39, 3936–3953;
(e) A.-F. Li, J.-H. Wang, F. Wang and Y.-B. Jiang, Chem. Soc.
Rev., 2010, 39, 3729–3745; (f) T. Gunnlaugsson, M. Glynn,
G. M. Tocci, P. E. Kruger and F. M. Pfeffer, Coord. Chem. Rev.,
2006, 250, 3094–3117; (g) V. Amendola, D. Esteban-Gomez,
L. Fabbrizzi and M. Licchelli, Acc. Chem. Res., 2006, 39,
343–353; (h) P. A. Gale, Acc. Chem. Res., 2006, 39, 465–475.
3 (a) F.-Y. Wu, Z. Li, Z.-C. Wen, N. Zhou, Y.-F. Zhao and
Y.-B. Jiang, Org. Lett., 2002, 4, 3203–3205; (b) L. Nie, Z. Li,
J. Han, X. Zhang, R. Yang, W.-X. Liu, F.-Y. Wu, J.-W. Xie,
Y.-F. Zhao and Y.-B. Jiang, J. Org. Chem., 2004, 69, 6449–6454;
(c) F.-Y. Wu, Z. Li, L. Guo, X. Wang, M.-H. Lin, Y.-F. Zhao and
Y.-B. Jiang, Org. Biomol. Chem., 2006, 4, 624–630; (d) W.-X. Liu
and Y.-B. Jiang, Org. Biomol. Chem., 2007, 5, 1771–1775;
(e) W.-X. Liu and Y.-B. Jiang, J. Org. Chem., 2008, 73,
1124–1127; (f) Z. Li, Z. Liu, Q.-X. Liao, Z.-B. Wei, L.-S. Long
and Y.-B. Jiang, C. R. Chim., 2008, 11, 67–72; (g) R. Yang,
W.-X. Liu, H. Shen, H.-H. Huang and Y.-B. Jiang, J. Phys. Chem.
B, 2008, 112, 5105–5110; (h) W.-X. Liu, R. Yang, A.-F. Li, Z. Li,
Y.-F. Gao, X.-X. Luo, Y.-B. Ruan and Y.-B. Jiang, Org. Biomol.
Chem., 2009, 7, 4021–4028; (i) Q.-Q. Jiang, B. Darhkijav, H. Liu,
F. Wang, Z. Li and Y.-B. Jiang, Chem.–Asian J., 2010, 5, 543–549.
4 (a) H. Maekawa, G. Ballano, C. Toniolo and N.-H. Ge, J. Phys.
Chem. B, 2011, 115, 5168–5182; (b) P. G. Vasudev, S. Chatterjee,
N. Shamala and P. Balaram, Chem. Rev., 2011, 111, 657–687.
5 (a) N. Berova, K. Nakanishi and R. W. Woody, Circular Dichromism,
Principles and Applications, Wiley-VCH, New York, 2nd edn, 2000;
(b) N. Berova, L. D. Bari and G. Pescitelli, Chem. Soc. Rev., 2007, 36,
914–931.
Referring to the intramolecular hydrogen bonding (IHB) in
peptide backbones bearing repeating 2,2-dimethylglycine residues
(AiB),4,6 a 5-membered ring IHB between a-NMe2 and amido
–NH proton (dashed line in L-/D-PLTU, Scheme 2) was assumed
possible. We hence examined whether this IHB, if exists, may
facilitate chirality transfer. Calculations do suggest such an IHB
(Scheme S2, ESIw), which is also supported by NMR data of
L-PLTU in DMSO-d6/CD3CN binary solvents. It was observed
that while the signals of the thioureido –NHs were sensitive to the
solvent composition, that of the amido –NH proton was less
sensitive (Fig. S6, ESIw), suggesting that an IHB involves this
proton.3e In order to probe the role of this IHB in chirality transfer,
we prepared two control compounds of L-PLTU in that the amine
group in the L-phenylalanine residue was derived into benzoyl-
amide or replaced with a methyl group (L-BPTU and L-PATU,
respectively, Scheme 2). With L-BPTU a ‘‘PhCQOꢁꢁꢁHNC(O)’’
7-membered ring IHB (the g-turn7) was concluded from its COSY
and NOESY spectra and the –NH chemical shifts in DMSO-d6/
CD3CN as a function of solvent composition (Figs. S7–S9, ESIw).
The fact that, while the absorption spectrum of BPTU in CH3CN
underwent a similar variation in the presence of acetate anion, the
CD spectrum showed a different variation profile (Fig. S10, ESIw)
from that of PLTU (Fig. 2) means that the 5-membered ring IHB
in PLTU indeed plays a role in the chirality transfer in its anion
binding complex. This was further supported by the observation
that the CD spectrum of L-PATU, in which no such an IHB is
present, underwent a variation profile (Fig. S11, ESIw) very
different from those observed with L-PLTU (Fig. 1) and L-BPTU
(Fig. S10, ESIw), despite the fact that the absorption spectra varied
similarly (Fig. 1a and Figs. S10a and S11a (ESIw)).
In summary, we developed a new kind of chiral thioureas,
the a-amino acid phenylalanine based N-amidothioureas,
L-/D-PLTUs, in which the a-carbon chiral center is by 2 atoms
or 3 chemical bonds away from the thiourea moiety, yet upon
acetate anion binding the chirality was transferred to the
thiourea moiety and the bound anion. We showed that a
mutual communication between the thiourea moiety and the
chiral center was established via anion hydrogen-bonding to
the thiourea moiety. We found that the 5-membered ring IHB
between the a-NMe2 and the amido –NH proton in PLTUs
was important for the efficient remote chirality transfer. Since
these chiral N-amidothioureas can be easily made available
from natural a-amino acids of diverse structural and func-
tional characters, they would be of potential significance in
enantioselective organocatalysis and other functions as
well. Extended investigations into the peptide based
N-amidothioureas would allow long-distance chirality transfer
to be evaluated.
6 (a) J. Clayden, A. Castellanos, J. Sola and G. A. Morris, Angew.
Chem., Int. Ed., 2009, 48, 5962–5965; (b) J. Sola, M. Helliwell and
J. Clayden, J. Am. Chem. Soc., 2010, 132, 4548–4549.
7 E. J. Cocinero, P. C¸ arc¸ abal, T. D. Vaden, J. P. Simons and
B. G. Davis, Nature, 2011, 469, 76–80.
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11786 Chem. Commun., 2011, 47, 11784–11786
This journal is The Royal Society of Chemistry 2011