Simple transformation of crystalline chiral natural anions to liquid medium and their use to induce chirality

Article abstract of DOI:10.1039/b600816j

New chiral ionic liquids can be prepared simply by combining the tetra-n-hexyl-dimethylguanidinium cation with readily available chiral anions and used as an asymmetric inducing agent as demonstrated for catalytic Rh(ii) carbenoid C-H insertion and Sharpless dihydroxylation. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b600816j

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Simple transformation of crystalline chiral natural anions to liquid
medium and their use to induce chirality{
Lu´ıs C. Branco,a Pedro M. P. Gois,a Nuno M. T. Lourenc¸o,a Vanya B. Kurtevaa and Carlos A. M. Afonso*b
Received (in Cambridge, UK) 19th January 2006, Accepted 13th April 2006
First published as an Advance Article on the web 10th May 2006
DOI: 10.1039/b600816j
In the course of continuous effort in the development and
application of room temperature ionic liquids, ILs,6 based on the
combination of organic cations and inorganic and organic anions,
we observed that tetra-alkyl-dimethylguanidinium cations [dmg]
are potential candidates for the creation of a new generation of ILs
due to peculiar solubility properties and a high thermal and
chemical stability.7 Despite containing 27 carbon atoms, the [dmg]
cation tetra-n-hexyl-dimethylguanidinium [(di-h)2dmg] is less prone
to crystallize even in the presence of anions which are persistently
solid in combination with different cations. This notable property
allows the development of a new, simple and efficient strategy to
synthesize new chiral ionic liquids (CILs)8 by simple exchange of
the [(di-h)2dmg] Cl salt with natural or easily functionalized chiral
natural anions. In Scheme 1 are presented the chiral ionic liquids
(CILs) prepared and the physical properties determined, namely
the viscosity and the glass transition temperature (Tg). Noticeably,
New chiral ionic liquids can be prepared simply by combining
the tetra-n-hexyl-dimethylguanidinium cation with readily
available chiral anions and used as an asymmetric inducing
agent as demonstrated for catalytic Rh(II) carbenoid C–H
insertion and Sharpless dihydroxylation.
Living systems use chirality as an important tool in biodiversity to
create a large range of architecturally sophisticated complex
structures. As a result of the large-scale creation of chiral centers
by living organisms, they produce a diverse range of chiral organic
polyfunctional molecules which become available in the earth in
large quantities such as cellulose, starch, carbohydrates, aminoa-
cids and steroids. The creation of chiral molecules in vivo, in vitro
or in the traditional chemical fashion is mainly performed in
homogeneous conditions where the solvent used plays an
important role not only in the asymmetric induction but also in
heat transfer and transport of molecules to the reactive center.
Different but complementary strategies have been established for
the production of chiral compounds. One of the most popular
approaches is the resolution of racemic mixtures in which the
traditional crystallization is still one of the most successful
procedures.1 Another important method is based on the chemical
manipulation of already existing chiral natural compounds, chiral
synthons.2 The creation of chiral centers can be achieved by several
chemical reactions where the enantioselectivity is induced using
chiral auxiliaries, readily obtained by chemical manipulation of
chiral natural and non-natural compounds,2 by asymmetric
catalysis based on organometallic catalysts,3 organocatalysis4 and
biocatalysis where enzymes and antibodies are used.5 Such
methodologies are highly appealing not only for the high degree
of enantioselectivities and atom efficiency achieved, but also due to
the possibility of recycling the catalyst and chiral auxiliary. Here is
described a new and remarkably simple methodology to generate
new chiral centers under homogeneous conditions using non-
volatile chiral ionic liquids readily available from the unique
combination of crystalline chiral salts, common in nature, used as
anion and a guanidinium unit that acts as cation.
aREQUIMTE, Departamento de Qu´ımica, Faculdade de Cieˆncias e
Tecnologia da Universidade Nova de Lisboa, Quinta da Torre, 2829-516,
Caparica, Portugal
Scheme 1 Chiral ionic liquids (CILs) prepared by combination of readily
a
accessible chiral anions with ([(di-h)2dmg]) cation. Salt [(di-h)2dmg] Cl,
bCQFM, Departamento de Engenharia Qu´ımica e Biolo´gica, Instituto
Superior Te´cnico, Av. Rovisco Pais, 1049-001, Lisboa, Portugal.
E-mail: carlosafonso@ist.utl.pt; Fax: (+) 351 218464455;
Tel: (+) 351 218417627
b
M+[chiral anion] (2 eq), dichloromethane, rt, 24 h. Observed glass
transition temperature (Tg, uC) and viscosity (g, cP at 25 uC) for
[(di-h)2dmg] X2: X = [(S)-mand], Tg = 256.9, g = 1633.3; X = [lactic],
Tg = 272.9, g = 247.6; X = [Boc-ala], Tg = 237.5, g = 749.1; X = [quinic],
Tg = 263.6, g = 998.2; X = [(S)-CSA], Tg = 244.3, g = 417.0; X =
[Ac-prol-OH], Tg = 232.7, g = 4913.6.
{ Electronic supplementary information (ESI) available: Detailed experi-
mental procedures and spectral data of new compounds. See DOI:
10.1039/b600816j
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Chem. Commun., 2006, 2371–2372 | 2371

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The examples of asymmetric induction described here
demonstrate that one simple approach to create new chiral
centers can be used to perform established reactions in
homogeneous ionic liquid media based on the use of readily
available chiral natural anions, usually crystalline, and the
appropriate tetra-alkyl-dimethylguanidinium cation which
presents a very low tendency to crystallize. This new chiral
medium, due to being ionic, moderately viscous and non-
volatile, opens new opportunities not only to induce chirality
by performing different reactions in this medium but also in
other areas such as chiral sensors, chiral selectors for mass
spectrometry (e.g. matrix for MALDI), chiral resolution based
on membrane technology and on different types of chromato-
graphic methods such as GLC or capillary electrophoresis. The
possibility to effect simple chemical transformation on other
crystalline and readily accessible chiral natural compounds
such as carbohydrates in order for them to become anions and
then moderately viscous liquids in combination with the
appropriate [dmg] cation opens new opportunities in the broad
area of chirality.
Scheme 2 Induction of chirality by chiral ionic liquids (CILs) in: i) C–H
insertion of a-diazo-acetamides catalyzed by Rh2(OAc)4 and ii) Sharpless
AD. a Rh2(OAc)4 (1 mol%), [(di-h)2dmg][(R)-mand] (0.3 g), 1 (0.15 mmol),
110 uC, 3 h. b Alkene (0.5 mmol), K2OsO2(OH)4 (0.5 mol%), NMO (1 eq),
[(di-h)2dmg] [quinic] (0.3 mL), rt, 24 h.
We thank Fundac¸a˜o para a Cieˆncia e Tecnologia and FEDER
for financial support. We gratefully acknowledge Solchemar Lda
company (http://www.solchemar.com) for providing some of the
ionic liquids.
the CIL with lactate as anion has low viscosity and has a lower Tg
value. All the CILs prepared are stable thermally (up to 220 uC)
and are liquids at room temperature.
In order to test the effectiveness in inducing chirality in
asymmetric reactions of this new class of chiral ionic liquids,9 we
performed their evaluation as the reaction medium in the following
transformations: carbenoid intramolecular C–H insertion of
a-phosphono-a-diazo-acetamides catalyzed by Rh2(OAc)4 and
Sharpless asymmetric dihydroxylation (AD) (Scheme 2).
Notes and references
1 (a) F. Toda, in Green Separation Processes: Fundamentals and
Applications, C. A. M. Afonso, J. P. S. G. Crespo (Eds), Wiley-VCH,
Weinheim, 2005; (b) C. A. M. Afonso and J. G. Crespo, Angew. Chem.,
Int. Ed., 2004, 43, 5293.
2 R. S. Atkinson, Stereoselective Synthesis, John Wiley, Chichester, 1995.
3 I. Ojima, (Ed.), Catalytic Asymmetric Synthesis, 2nd ed., Wiley-VCH,
New York, 2000.
4 P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2004, 43, 5138.
5 K. Faber, Biotransformations in Organic Chemistry, 5th ed., Springer-
Verlag, Berlin, 2004.
6 (a) R. D. Rogers, K. R. Seddon, (Eds); Ionic Liquids; Industrial
Applications for Green Chemistry, ACS Symposium Series 818, ACS,
Washington DC, 2002; (b) P. Wasserscheid and T. Welton. Ionic Liquids
in Synthesis, VCH-Wiley, Weinheim, 2002; (c) K. R. Seddon, Nat.
Mater., 2003, 2, 1; (d) J. Dupont, R. F. de Souza and P. A. Z. Suarez,
Chem. Rev., 2002, 102, 3667; (e) C. F. Poole, J. Chromatogr., A, 2004,
1037, 49; (f) N. Jain, A. Kumar, S. Chauhan and S. M. S. Chauhan,
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Using the CIL [(di-h)2dmg][(R)-mand] instead of the traditional
organic solvent, 1,2-dichloroethane, under routine conditions
(110 uC, 3 h) in the presence of Rh2(OAc)4 catalyst, the in situ
formation of Rh(II) carbenoid from 1 originates the c-lactam 2 in
72% yield (trans/cis 67/33) (Scheme 2i) with
a moderate
enantiomeric excess (ee 27%), nevertheless, this constitutes an
improvement when compared with the result obtained when the
chiral Rh2((R)-mandelate)4 catalyst (ee 18%) was used.10 The
asymmetric induction probably occurs as a result of in situ ligand
exchange and the chiral solvent environment.
The Sharpless osmium-catalyzed asymmetric dihydroxylation
(AD)11 is a very powerful methodology for the preparation of
chiral vicinal diols and amino alcohols. The success of the
asymmetric induction requires the use of one chiral ligand
consisting of two cinchona alkaloid units attached to one core
unit. Generally in the case of 4-methylmorpholine-N-oxide (NMO)
as co-oxidant, a slow addition of the olefin is required in order to
eliminate the secondary catalytic cycle effect. Interestingly, using
the CILs [(di-h)2dmg][quinic], in the absence of the Sharpless chiral
ligand and without slow addition of the olefin, the diols 3 and 4
were obtained in high yields (95 and 92%) and high enantiomeric
excesses (ee 85 and 72%) (Scheme 2ii). It should be mentioned that
the observed yields and enantioselectivities are similar to the ones
obtained using the chiral ligand [DHQD]2PHAL in t-BuOH/H2O
(1 : 1) by adding the olefin at once (80% yield and 73% ee for 4).12
Using a catalytic amount (5 mol%) of the CIL [(di-h)2dmg][quinic]
dissolved in t-BuOH/H2O (1 : 1) lower yields (81%) and
enantioselectivities (40%) were obtained for 4.
7 N. M. M. Mateus, L. C. Branco, N. M. T. Lourenc¸o and C. A. M.
Afonso, Green Chem., 2003, 5, 347.
8 (a) C. Baudequin, J. Baudoux, J. Levillain, D. Cahard, A. C. Gaumont
and J. C. Plaquevent, Tetrahedron: Asymmetry, 2003, 14, 3081; (b)
C. Baudequin, D. Bre´geon, J. Levillain, F. Guillen, J.-C. Plaquevent and
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J. Feder-Kubis, Chem.–Eur. J., 2005, 11, 4441; (e) K. Fukumoto,
M. Yoshizawa and H. Ohno, J. Am. Chem. Soc., 2005, 127, 2398; (f)
G. Tao, L. He, N. Sun and Y. Kou, Chem. Commun., 2005, 3562.
9 (a) B. Pe´got, G. Vo-Thanh, D. Gori and A. Loupy, Tetrahedron Lett.,
2004, 45, 6425; (b) J. Ding, V. Desikan, X. Han, T. L. Xiao, R. Ding,
W. S. Jenks and D. W. Armstrong, Org. Lett., 2005, 7, 335; (c) Z. Wang,
Q. Wang, Y. Zhang and W. Bao, Tetrahedron Lett., 2005, 46, 6457.
10 P. M. P. Gois, N. R. Candeias and C. A. M. Afonso, J. Mol. Catal. A:
Chem., 2005, 227, 17.
11 R. A. Johnson and K. B. Sharpless, in Catalytic Asymmetric Synthesis,
2nd ed.; I. Ojima (Ed.); p. 357, VCH, Weinheim, 2000.
12 L. C. Branco and C. A. M. Afonso, J. Org. Chem., 2004, 69, 4381.
2372 | Chem. Commun., 2006, 2371–2372
This journal is ß The Royal Society of Chemistry 2006