(1-Naphthyl)(trifluoromethyl) O-carboxy anhydride as a chiral derivatizing agent: Eclipsed conformation enforced by hydrogen bonding

Article abstract of DOI:10.1021/ol801930m

(Chemical Equation Presented) The preparation of the (1-naphthyl) (trifluoromethyl) O-carboxy-anhydride 1 and its use as a chiral derivatizing agent with several α-chiral primary amines are reported. The very large Δδ^RS values observed in ¹H NMR have been correlated with a marked preference of the corresponding α-hydroxy-amides for the eclipsed conformation. In comparison, the related O-methylated amides are shown to adopt staggered conformations, which substantiates the critical role of intramolecular hydrogen bonding in maximizing the anisotropic effect.

Full text of DOI:10.1021/ol801930m

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4669-4672
(1-Naphthyl)(trifluoromethyl) O-Carboxy
Anhydride as a Chiral Derivatizing
Agent: Eclipsed Conformation Enforced
by Hydrogen Bonding
Olivier Thillaye du Boullay, Aure´lie Alba, Fatima Oukhatar, Blanca Martin-Vaca,*
and Didier Bourissou*
Laboratoire He´te´rochimie Fondamentale et Applique´e du CNRS (UMR 5069)
UniVersite´ Paul Sabatier, 118, route de Narbonne, 31062 Toulouse Cedex 09, France
dbouriss@chimie.ups-tlse.fr
Received August 19, 2008
ABSTRACT
The preparation of the (1-naphthyl)(trifluoromethyl) O-carboxy-anhydride 1 and its use as a chiral derivatizing agent with several r-chiral
primary amines are reported. The very large ∆δRS values observed in 1H NMR have been correlated with a marked preference of the corresponding
r-hydroxy-amides for the eclipsed conformation. In comparison, the related O-methylated amides are shown to adopt staggered conformations,
which substantiates the critical role of intramolecular hydrogen bonding in maximizing the anisotropic effect.
The growing interest for enantioselective synthesis in chemi-
cal and pharmaceutical fields has stimulated the development
of simple and inexpensive methods for the determination of
the enantiomeric excess of chiral compounds and the
assignment of the absolute configuration of stereogenic
centers. In this context, the use of chiral derivatizing agents
(CDA) combined with multinuclear NMR analyses is one
of the most efficient methods.1 The MTPA and MPA
derivatives introduced by Mosher2 and Trost,3 respectively,
(Figure 1) have led to spectacular results especially with
R-chiral primary amines and secondary alcohols. Further
improvements have been possible exploiting the structural
versatility of R-arylcarboxylic acids, as is nicely illustrated
by the BPG4 and CFTA5 compounds.6
Current efforts focused on new CDA aim at increasing
both their reactivity and resolution efficiency.7 In this regard,
(2) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. (b)
Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543.
(3) (a) Trost, B. M.; Bunt, R. C.; Pulley, S. R. J. Org. Chem. 1994, 59,
4202. (b) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.;
Balkovec, J. M. J. Org. Chem. 1986, 51, 2370.
(1) Seco, J. M.; Quin˜oa´, E.; Riguera, R. Chem. ReV. 2004, 104, 17.
(4) Seco, J. M.; Quin˜oa´, E.; Riguera, R. J. Org. Chem. 1999, 64, 4669.
10.1021/ol801930m CCC: $40.75
Published on Web 09/25/2008
2008 American Chemical Society

using N-(nitroaryl)prolines (NPP) as CDA.10 As the result
of intramolecular hydrogen bonding between the amide
hydrogen and proline nitrogen atoms (Figure 2, adduct D),
significantly larger chemical shift differences (∆δRS) values
were obtained than with MPA and MTPA derivatives.
From a synthetic viewpoint, R-hydroxy-amides C can be
readily accessed by reacting R-chiral primary amines with
O-carboxy anhydrides (OCA).11-13 The (1-naphthyl)(tri-
fluoromethyl) OCA 1 was thus considered a promising CDA.
Here we report its synthesis (in both racemic and enantio-
merically pure forms) and its derivatization with several
R-chiral primary amines. The very large ∆δRS values
Figure 1. Structure of representative R-arylcarboxylic acid deriva-
tives used as CDA (X ) OH or Cl).
it is well-established that the eclipsed vs staggered conforma-
tions of the corresponding adducts have a major influence
on the anisotropic effect induced by the aryl moiety.4,5,8,9
Riguera et al. reported an elegant illustration of this
phenomenon in the derivatization of R-chiral primary amines
with MPA. The addition of barium(II) salts was demonstrated
to shift the conformation of the ensuing amides from
staggered to eclipsed, resulting in a significant increase of
the anisotropic effect (Figure 2, compounds A and B).8a In
1
observed in H NMR have been correlated with a marked
preference of the R-hydroxy-amides for the eclipsed con-
formation, as deduced from detailed spectroscopic analyses
performed on the R-methylbenzylamine adducts 2a/2b. In
comparison, the related O-methylated adducts 4a/4b (ob-
tained from the MTPA analog 3) are shown to adopt a
staggered conformation, which substantiates the critical role
of intramolecular hydrogen bonding in enforcing the eclipsed
conformation.
The OCA 1 was readily prepared in racemic form from
the corresponding R-hydroxy-acid and isolated in 68% yield
after recrystallization.14 Reaction of 1 with (R)-R-methyl-
benzylamine15 afforded an equimolar mixture of R-hydroxy-
amides 2a and 2b that were separated by silica-gel chroma-
tography and fully characterized (Scheme 1). Notably, the
Scheme 1. Reaction of rac-1 with (R)-R-Methylbenzylamine
Figure 2. Control of the amide conformation by complexation to
Ba2+ (A/B) or by intramolecular hydrogen bonding (C and D).
principle, the conformational equilibrium may also be
controlled by replacing the methoxy group of the MTPA/
MPA models by a hydroxyl group, thanks to the formation
of a hydrogen bond between the proximal OH and CdO
moieties (Figure 2, compound C). Note that a somewhat
related approach has been recently studied by Choi et al.
two diastereomers are readily distinguishable in the 1H NMR
spectrum, with differences in chemical shifts up to 0.26 ppm
(5) (a) Takeuchi, Y.; Segawa, M.; Fujisawa, H.; Omata, K.; Lodwig,
S. N.; Unkefer, C. J. Angew. Chem., Int. Ed. 2006, 45, 4617. (b) Takahashi,
T.; Fukushima, A.; Tanaka, Y.; Takeuchi, Y.; Kabuto, K.; Kabuto, C. Chem.
Comm. 2000, 787.
(10) Ahn, H. C.; Choi, K. Org. Lett. 2007, 9, 3853.
(11) Reaction of OCA with primary or secondary amines has been
demonstrated to yield R-hydroxy-amides. (a) Toyoka, K.; Takeuchi, Y.;
Kubota, S. Heterocycles 1989, 29, 5. (b) Branch, C. L.; Finch, S. C.; Pearson,
M. J. J. Chem. Soc., Perkin Trans. 1 1985, 1491. (c) Sinay, P. Carbohydr.
(6) For recent examples of CDA different from R-arylcarboxylic acids,
see: (a) Pe´rez-Fuertes, Y.; Kelly, A. M.; Johnson, A. L.; Arimori, S.; Bull,
S. D.; James, T. D. Org. Lett. 2006, 8, 609. (b) Rodr´ıguez-Escrich, S.; Popa,
D.; Jimeno, C.; Vidal-Ferran, A.; Perica´s, M. A. Org. Lett. 2005, 7, 3829.
(7) For recent examples reporting alternative coupling methodologies
see: (a) Porto, S.; Seco, J. M.; Espinosa, J. F.; Quin˜oa´, E.; Riguera, R. J.
Org. Chem. 2008, 73, 5714. (b) Katritzky, A. R.; Mohapatra, P. P.;
Fedoseyenko, D.; Duncton, M.; Steel, P. J. J. Org. Chem. 2007, 72, 4268.
(8) (a) Garc´ıa, R.; Seco, J. M.; Va´zquez, S. A.; Quin˜oa´, E.; Riguera, R.
J. Org. Chem. 2006, 71, 1119. (b) Latypov Sh., K.; Seco, J. M.; Quin˜oa´,
E.; Riguera, R. J. Am. Chem. Soc. 1998, 120, 877. (c) Seco, J. M.; Latypov
Sh., K.; Quin˜oa´, E.; Riguera, R. J. Org. Chem. 1997, 62, 7569. (d) Latypov
Sh., K.; Seco, J. M.; Quin˜oa´, E.; Riguera, R. J. Org. Chem. 1996, 61, 8569.
(e) Latypov Sh., K.; Seco, J. M.; Quin˜oa´, E.; Riguera, R. J. Org. Chem.
1995, 60, 1538.
Res. 1971, 16, 113
.
(12) O-carboxy-anhydrides have also been involved recently for the
dynamic kinetic resolution of monosubstituted R-hydroxy carboxylic acids:
Tang, T.; Deng, L. J. Am. Chem. Soc. 2002, 124, 2870
.
(13) As part of a research program on biodegradable polymers, we have
recently reported the remarkable reactivity of the OCAs derived from lactic
and glutamic acids towards Ring-Opening Polymerization, giving access
to poly(R-hydroxy-acids) in very mild conditions: (a) Bonduelle, C.; Martin-
Vaca, B.; Cossío, F. P.; Bourissou, D. Chem.-Eur. J. 2008, 14, 5304. (b)
Thillaye du Boullay, O.; Bonduelle, C.; Martin-Vaca, B.; Bourissou, D.
Chem. Commun. 2008, 1786. (c) Thillaye du Boullay, O.; Marchal, E.;
Martin-Vaca, B.; Cossío, F. P.; Bourissou, D. J. Am. Chem. Soc. 2006,
(9) The situation may be further complicated if different rotamers with
opposite anisotropic effects coexist in solution.
128, 16442
(14) See Supporting Information.
.
4670
Org. Lett., Vol. 10, No. 20, 2008

for the methyl group and 0.58 ppm for the Hortho of the phenyl
ring. These values are markedly larger than those usually
observed, with previous CDA typically leading to ∆δRS
<
0.21 ppm for the methyl group of ArCH(Me)NH2 (Ar )
phenyl, para-tolyl, 1-naphthyl).2-5,8d,16 To rationalize the
large ∆δRS values obtained with 1, we sought to determine
the conformations of 2a and 2b.
The absolute configuration (S,R) of 2b was first deduced
from an X-ray diffraction analysis (Figure 3), suitable crystals
Figure 4. NOE interactions observed for 2a and 2b in NOESY
and 19F{1H} HOESY experiments.
This hydrogen bond, which enforces the eclipsed confor-
mation, is likely to explain the large ∆δRS observed between
2a and 2b by maximizing the anisotropic effect of the
naphthyl group (Figure 5). In this regard, the OCA 1
markedly differs from other CDA that usually favor the
staggered conformation. The situation encountered in 2a/2b
is reminiscent of the eclipsed conformation induced by
Riguera et al. upon complexation of both oxygen atoms of
MPA-derived amides with barium(II) salts.8a
Figure 3. Molecular structure of 2b.
being obtained from pentane solution at 0 °C. This study
also provided the first indication of the conformation of the
R-hydroxy-amide. As expected, the C-C(dO)-NH-CR
skeleton is almost perfectly planar, the amide fragment adopts
a Z conformation and the vicinal N-H/C-H bonds are
approximately antiperiplanar (HNCH torsion angle 152.4°).
In addition, the O-C-CdO fragment adopts a synperiplanar
(sp) conformation (OCCO torsion angle 13.6°), indicating
the presence of an intramolecular hydrogen bond.17 As a
result of this eclipsed conformation, the 1-naphthyl and
trifluoromethyl groups eclipse the methyl and phenyl groups,
respectively.
According to multinuclear NMR and IR analyses, the sp-Z
conformation observed for 2b in the solid state is also favored
in CDCl3 solution for both diastereomers 2a and 2b. Indeed,
3
the JHH coupling constants (8.0 Hz) are diagnostic for an
antiperiplanar arrangement of the vicinal N-H and C-H
bonds (3JHH ) 7.0-9.0 Hz).4,16,18 In addition, NOESY and
19F{1H} HOESY experiments unambiguously supported the
eclipsed sp conformation, cross-relaxation peaks being
observed for the CF3 group and Hperi atom of the naphthyl
on the one hand, and the CH3 group and Hortho of the phenyl
on the other hand (Figure 4). Lastly, the presence of an
intramolecular hydrogen bond between the OH and CdO
groups is supported by the sharp signals observed for the
1
Figure 5
.
Extended Newman projections of 2a/2b and H NMR
spectra (aromatic and methyl regions) of 2a/2b illustrating the
eclipsed conformation and the resulting strong anisotropic effect
of the naphthyl ring.
1
hydroxyl group both in H NMR (δOH ) 5.28 ppm for 2a
At this stage, one may argue that the larger anisotropic
effect of the naphthyl versus the phenyl ring19 could also
have a significant effect. This prompted us to investigate the
1-naphthyl analogue 3 of MTPA (Scheme 2).14 The spec-
troscopic study performed on the corresponding O-meth-
ylated amides derived from the (R)-R-methylbenzylamine 4a/
4b, revealed a preference for a staggered conformation with
the MeO-C-CdO fragment adopting an antiperiplanar
and 5.37 ppm for 2b) and in IR (νOH ) 3421 cm-1 for 2a
and 2b), no noticeable displacements being detected upon
dilution.
(15) The R-methylbenzylamine was chosen as a representative R-chiral
primary amine available in enantiopure form and presenting diagnostic
signals 1H NMR.
(16) Chinchilla, R.; Falvello, L. R.; Na´jera, C. J. Org. Chem. 1996, 61,
7285.
(17) The hydrogen atom of the hydroxyl group could be positioned
between the two oxygen atoms without any constraint.
(18) Helmchen, G.; Ott, R.; Sauber, K. Tetrahedron Lett. 1972, 37, 3873.
(19) Latypov Sh., K.; Seco, J. M.; Quin˜oa´, E.; Riguera, R. J. Org. Chem.
1995, 60, 504.
Org. Lett., Vol. 10, No. 20, 2008
4671

Scheme 2. Reaction of 3 with (R)-R-Methylbenzylamine
conformation. As a result, very low ∆δRS are observed in
1
the H NMR spectra (0.01 ppm for the methyl group),
confirming thus the critical role played by the hydrogen bond
in 2a and 2b.
To further substantiate the utility of OCA-1, enantiomeri-
cally pure forms (S)-1 and (R)-1 were prepared after
resolution of the R-hydroxy-acid precursor with R-methyl-
benzylamine (ee >99.6% after three recrystallizations in
2-propanol).14,20 A range of R-chiral primary amines with
diverse structures were then reacted with both rac-1 and (S)-
1, and the resulting ∆δRS values were determined (Figure
6). The proton chemical shift differences follow the same
trend for all the prepared R-hydroxy-amides, and are all
consistent with the eclipsed hydrogen-bonded conformation
established with R-methylbenzylamine. This includes the
amino-alcohol adduct 11, illustrating (i) the complete
selectivity of OCA 1 for amines vs alcohols in the absence
of coupling reagents and (ii) its applicability to substrates
featuring hydroxyl groups also susceptible to hydrogen-
bonding toward the amide moiety. Moreover, all the obtained
∆δRS values are significantly larger than those reported with
classical CDA such as MTPA, MPA and even surpass those
achieved with NPP.10
Figure 6.
∆δRS values obtained for diastereomeric amides 5-11
[R ) COC(OH)CF3(1-naphthyl)] derived from the corresponding
R-chiral primary amines. (1H NMR spectra were recorded at 25
°C, in CDCl3)].
conformations are enforced by intramolecular hydrogen
bonding. As a result, the anisotropic effect of the naphthyl
group is much larger than in the related O-methylated amides
for which the staggered conformation is classically favored.
Accordingly, this OCA may be considered as a promising
CDA and further improvements may be expected in both
reactivity and resolution efficiency by varying the substitution
pattern.
Acknowledgment. The CNRS and UPS are warmly
acknowledged for financial support of this work. Discussions
with Y. Robin (ISOCHEM) are sincerely appreciated. We
also thank P. Lavedan (NMR), C. Zedde (HPLC), Dr. S.
Bontemps, and Dr. H. Gornitzka (X-ray diffraction analyses)
for their assistance.
In conclusion, the (1-naphthyl)(trifluoromethyl) O-car-
boxyanhydride 1 was found to induce considerable 1H NMR
differentiation with a wide range of R-chiral primary amines.
In marked contrast to related CDA such as MTPA and MPA,
the use of 1 leads to O-unprotected adducts in which eclipsed
Supporting Information Available: Experimental details,
spectroscopic characterization for all new compounds, and
crystallographic data for 2a and 4a.This material is available
free of charge via the Internet at http://pubs.acs.org.
(20) The absolute configuration of enantiomerically pure 1 was deter-
mined by derivatization with (R)-R-methylbenzylamine and comparison with
1
the known adducts 2a/2b by H NMR.
OL801930M
4672
Org. Lett., Vol. 10, No. 20, 2008