(S)-2-[(R)-fluoro(phenyl)methyl]oxirane: A general reagent for determining the ee of α-chiral amines

Article abstract of DOI:10.1021/ol051110j

(Chemical Equation Presented) (S)-2-[(R)-Fluoro(phenyl)methyl]oxirane is a new, synthetic, yet enantiopure, chiral resolution reagent, readily obtained from enantiopure (2S,3S)-phenylglycidol, that reacts with a variety of α-chiral primary and secondary a

Full text of DOI:10.1021/ol051110j

ORGANIC
LETTERS
2005
Vol. 7, No. 18
3829-3832
(S)-2-[(R)-Fluoro(phenyl)methyl]oxirane:
A General Reagent for Determining the
ee of
r-Chiral Amines
Sergi Rodr´ıguez-Escrich,†,‡ Dana Popa,† Ciril Jimeno,† Anton Vidal-Ferran,*,†,§ and
Miquel A. Perica`s*,†,‡
Institute of Chemical Research of Catalonia (ICIQ), AV. Pa¨ısos Catalans s/n,
43007 Tarragona, Spain, Departament de Qu´ımica Orga`nica, UniVersitat de
Barcelona, c/ Mart´ı i Franque`s 1-11, 08008 Barcelona, Spain, and ICREA
mapericas@iciq.es; aVidal@iciq.es
Received May 12, 2005
ABSTRACT
(S)-2-[(R)-Fluoro(phenyl)methyl]oxirane is a new, synthetic, yet enantiopure, chiral resolution reagent, readily obtained from enantiopure (2S,3S)-
phenylglycidol, that reacts with a variety of
r-chiral primary and secondary amines in a straightforward manner through a regioselective
ring-opening. Diastereomeric products are easily identified and quantified by 19F, 1H, and 13C NMR and by HPLC, which makes this fluorinated
compound a most versatile reagent for the analysis of scalemic mixtures of amines.
Since enantiopure compounds are increasingly important in
the chemical and pharmaceutical sciences due to their
particular properties, and especially because one enantiomer
usually behaves differently than its counterpart when inter-
acting with a biological system,1,2 the need to develop fast
and efficient methods to determine the enantiomeric com-
position of a synthetic scalemic mixture is in demand. Chiral
chromatographic methods (HPLC, GC) have simplified and
quickened the analysis of many products,3 but chiral station-
ary phases are expensive and much more sensitive to physical
and chemical agression than regular chromatography col-
umns. Moreover, their use always implies trial-and-error
iterations to optimize the phase and separation conditions,
whenever it is possible to separate the compounds. Therefore,
the classical use of resolution reagents chemically bonded
to the individual components of the mixture to be analyzed
is still in use.4 These methods are very reliable and can be
adapted to several common techniques such as NMR or
HPLC with no need of any modification. In some cases, it
is even possible to determine the absolute configuration of
the new compound.4d Thus, the development of new resolu-
tion reagents with improved properties is of practical interest.
It is generally admitted that resolution reagents should
fulfill the following requisites in order to achieve general
interest: (a) straightforward preparation to make it easily
accessible to most chemists, (b) fast and clean reactivity
toward the substrate to be analyzed, and (c) absence of kinetic
† Institute of Chemical Research of Catalonia.
‡ Universitat de Barcelona.
§ ICREA.
(1) (a) Chirality in Industry; Collins, A. N., Sheldrake, G. N., Crosby,
J., Eds.; John Wiley and Sons: Chichester, 1992. (b) Chirality in Industry
II; Collins, A. N., Sheldrake, G. N., Crosby, J., Eds.; John Wiley and Sons:
Chichester, 1997.
(2) (a) Ikunaka, M. Chem. Eur. J. 2003, 9, 379. (b) Wandrey, C.; Liese,
A.; Kihumbu, D. Org. Proc. Res. DeV. 2000, 4, 286.
(3) (a) Anderson, M. E.; Aslan, D.; Clarke, A.; Roeraade, J.; Hagman,
G. J. Chromat. A 2003, 1005, 83. (b) Davankov, V. A. Pure Appl. Chem.
1997, 69, 1469.
(4) (a) Toyo’oka, T. Current Pharm. Anal. 2005, 1, 57. (b) Bhushan,
R.; Brueckner, H. Amino Acids 2004, 27, 231. (c) Toyo’oka, T. Methods
Mol. Biol. 2004, 243, 231. (d) For a review, see: Seco, J. M.; Quin˜oa´, E.;
Riguera, R. Chem. ReV. 2004, 104, 17. For a most recent account, see:
Freire, F.; Seco, J. M.; Quin˜oa´, E.; Riguera, R. J. Org. Chem. 2005, 70,
3778.
10.1021/ol051110j CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/10/2005

Scheme 1. Preparation of Resolution Reagent 1 from
(2S,3S)-Phenylglycidyl p-Toluenesulfonate (2)
Table 1. Yields and Main NMR Signals Associated to the
CHF Group of Diastereomers Obtained by Reaction with the
Derivatization Reagent 1
resolution to ensure that the enantiomeric ratio determined
corresponds to that of the original sample. Moreover, the
more techniques that are able to distinguish the diastereomers
formed, the easier the determination will be. In this respect
it is desirable that NMR-active heteroatoms, such as 19F, are
embedded in the structure in addition to 1H and 13C in order
to facilitate the analysis by NMR techniques.5 In much the
same manner, the presence of UV-active groups (aromatic
rings) that allow simple detection in conventional HPLC is
also an advantage.
In this paper, we present a new derivatization reagent, (S)-
2-[(R)-fluoro(phenyl)methyl]oxirane (1),6 that can be readily
prepared from (2S,3S)-phenylglycidyl tosylate (2) which, in
turn, ultimately arises from the Sharpless epoxidation of
cinnamyl alcohol with inexpensive natural tartrate ligands.
Regioselective and stereospecific ring opening of 2 with
BF3 yielded (2S,3R)-3-fluoro-2-hydroxy-3-phenylpropyl p-
toluenesulfonate (3),7 which was converted into 1 in es-
sentially quantitative yield by intramolecular nucleophilic
displacement induced by lithium tert-butoxide (Scheme 1).
This procedure allows for the preparation of enantiopure 1
on a multigram scale without any difficulty.8,9 To our
knowledge, 1 is the first chiral derivatizing agent introduced
through the ring-opening of an epoxide that has been
successfully tested.
With fluoroepoxide 1 in hand, the ring-opening of the
epoxide with R-chiral primary amines was next tested. This
class of amines is present in many natural substances and in
active pharmaceutical ingredients, so that the development
of methods for the easy and reliable determination of their
enantiomeric composition is a matter of interest. We found
(Scheme 2) that either upon conventional heating or micro-
wave irradiation the epoxide ring opening with rac-R-methyl
benzylamine (4a) took place in excellent yield and with
complete regioselectivity using lithium perchlorate as a
promoter10 and THF as the solvent. Microwave irradiation
consistently afforded higher yields, and few decomposition
a Isolated yield after flash chromatography. b No signal separation.
c Experimental conditions: 10 mol % of Cu(BF4)2‚6H2O, acetonitrile, 2 h,
75 °C (MW).
byproducts were observed compared to the thermal reaction;
therefore, this activation was preferentially used thereafter.
The optimized procedure for complete conversion of the
amine under scrutiny consisted, thus, in irradiating with
microwaves the mixture of 0.7 equiv of racemic amine (4),
1 equiv of enantiopure terminal epoxide, and 1 equiv of
LiClO4 in THF at for 90 min, with the maximum temperature
set at 75 °C, in a pressure tube. We applied this procedure
to a family of structurally diverse racemic amines and
recorded in all cases 1H, 13C, and 19F NMR spectra in order
Scheme 2. Reaction of 1 with R-Chiral Amines
3830
Org. Lett., Vol. 7, No. 18, 2005

Figure 1. Most suitable nuclei for diastereomeric composition
estimation in amines 5.
to find out the most convenient way to determine the
diastereomeric composition (Table 1).
Very interestingly, all three distinct nuclei present at the
fluorine bearing chiral center were differentially perturbed
by the chiral center R to nitrogen, which is located four bonds
away, and originated different sets of signals for each
diastereomer (Figure 1).
19F NMR was superior in all cases, since only two sets of
clearly separated signals, remote from those due to the initial
fluoroepoxide, appeared in the spectra. These signals allowed
easy integration and, hence, a simple evaluation of diaster-
eomeric (enantiomeric) composition. As mentioned above,
1
the H and 13C NMR spectra also presented sets of signals
corresponding to the methyne moiety showing good line
separation and making their integration feasible.
We have collected in Table 1 a summary of the studied
1
amines (4a-i) and the chemical shifts for the 19F, H, and
13C signals corresponding to the considered center in the two
diastereomers formed by the ring-opening reaction. As an
example of signal separation, the regions of the 1H, 13C, and
19F NMR spectra of interest for analytical purposes of 5a
obtained from racemic 4a and from (S)-4a are shown in
Figure 2.
From a preparative point of view, the reaction worked
nicely for both acyclic (4a,b) and cyclic (4c,d) primary
amines, somewhat lower yields being recorded with long-
chain amines (4e). Even a more functionalized substrate like
4f, also containing an alcohol and ether functions,11 could
be successfully used in the ring-opening of 1. Racemic
ephedrine 4g could be used as substrate as well, showing
how secondary amines with extra functional groups (alcohol)
are able to react with fluoroepoxide 1. Phenylalanine methyl
Figure 2. NMR spectra of the CHF region of the R-methyl
benzylamine compound, 5a (partially resolved after flash chroma-
tography), and (S)-5a.
(5) For key references on some F-containing chiral derivatizating agents,
see the following. MTPA: (a) Dale, L. A.; Mosher, H. S. J. Am. Chem.
Soc. 1973, 95, 512. (b) Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org.
Chem. 1973, 38, 2143. CFTA and CFPA: (c) Takeuchi, Y. J. Fluorine
Chem. 2000, 105, 215 and references therein. AFPA: (d) Apparu, M.; Ben
Tiba, Y.; Le´o, P.-M.; Hamman, S.; Coulombeau, C. Tetrahedron: Asym-
metry 2000, 11, 2885 and references therein. (e) Hamman, S.; Barrelle,
M.; Tetaz, F.; Beguin, C. G. J. Fluorine Chem. 1987, 37, 85. ATEA: (f)
Pirkle, W. H.; Simmons, K. A. J. Org. Chem. 1981, 46, 3239. TFLA: (g)
Kubota, T.; Kanega, J.; Katagiri, T. J. Fluorine Chem. 1999, 97, 213.
(6) Patent pending
(7) Islas-Gonza´lez, G.; Puigjaner, C.; Vidal-Ferran, A.; Moyano, A.;
Riera, A.; Perica`s, M. A. Tetrahedron Lett. 2004, 45, 6337.
(8) Methods to prepare rac-1: (a) Chehidi, I.; Chaabouni, M. M.;
Baklouti, A. Tetrahedron Lett. 1989, 30, 3167. (b) Gabriel, B.; Gounelle,
Y.; Jullien, J. Bull. Soc. Chim. Fr. 1969, 521.
ester and â-amino butanoic acid methyl ester (products 5h
and 5i) were suitable substrates as well. In this way, the
enantiomeric composition of a wide variety of nitrogen-
containing compounds could be analyzed using the present
method.
To ensure that no kinetic resolution happened while the
reaction was in course, the reaction crudes were analyzed at
different conversion levels for R-methyl benzylamine. In all
cases, the ring-opening product was a perfect 1:1 mixture
of diastereomers. In addition, the use of either enantiopure
or racemic amines led to the same yields of ring-opening
products under identical conditions.
(9) A method to prepare enantiopure 1 using a chiral auxiliary: Bravo,
P.; Piovosi, E.; Resnati, G. J. Chem. Soc., Perkin Trans. 1 1989, 1201.
(10) Chini, M.; Crotti, P.; Flippin, L. A.; Gardelli, C.; Giovani, E.;
Macchia, F.; Pineschi, M. J. Org. Chem. 1993, 58, 1221.
(11) Puigjaner, C.; Vidal-Ferran, A.; Moyano, A.; Perica`s, M. A.; Riera,
A. J. Org. Chem. 1999, 64, 7902.
It must be pointed out that other NMR signals are also
suitable for the determination of the diastereomeric (enan-
Org. Lett., Vol. 7, No. 18, 2005
3831

Table 2. Comparison of Analysis Methods on the 95% and
85% ee Samples of 4a
method
95% ee
85% ee
weighting (R-methylbenzylamine)
95.7
96.0
95.9
95.7
94.6
95.2
86.6
87.3
87.0
85.0
85.6
85.3
GCa (R-methyl benzylamine)
mean
HPLCb (5a)
19F NMR (5a)
mean
a Supelco â-DEX column. b Zorbax-Sil column.
Although we have devoted a considerable computational
effort to the analysis of the conformational preferences of
the diastereomers of 5, the precise reasons for the excellent
signal separation observed in most cases cannot be fully
accounted for at this moment. However, the structures of
the lowest energy conformers of 5a calculated by DFT
(B3LYP hybrid functional with 6-31G* basis set) strongly
suggest that intramolecular hydrogen bonding between the
fluorine atom, the hydroxyl, and/or the amine can help in
freezing the conformational flexibility of these compounds
and, hence, facilitate analytical differentiation.
Figure 3. 19F NMR spectra of 5a obtained from (top) 85% and
(bottom) 95% ee (S)-R-methyl benzylamine, 4a.
tiomeric) composition, but the CHF signals already discussed
are in general more separated, appear in a cleaner zone of
the spectra, and are much easier to assign.
In summary, the readily available enantiopure fluoro-
epoxide 1 has been shown to be a most convenient reagent
for the fast and reliable determination of enantiomeric
composition of R-chiral primary amines. The reaction
involved in the analysis, the nucleophilic ring-opening of
an epoxide, has not been used before in this context and
could, in principle, be extended for the determination of the
enantiomeric composition of other chiral nucleophiles.
Further work in this area, now in progress in our laboratories,
will be reported in due course.
In practice, the analytical use of 1 involves greatly
simplified conditions. Once it has been established that no
kinetic resolution is taking place during the ring opening of
1 by primary amines, and since the diagnostic 19F NMR
signals of the diastereomeric amines 5 occur in a clean
spectral region, it is not necessary to use stoichiometric
amounts of fluoroepoxide 1 with respect to the amine to be
analyzed. When 20 mol % of fluoroepoxide is used, the chiral
derivatizing reagent is completely consumed within 15 min
and the reaction crude can be directly submitted to 19F NMR
analysis, without any intermediate purification. In this way,
enantiomeric purities up to 95% on 4a have been easily
determined with less than 1% error, as shown in Figure 3
and Table 2.
In addition to the NMR-based determinations of diaster-
eomeric composition, it is also generally possible to separate
the diastereomers of 5a-h by HPLC, using a commercial
Zorbax-Sil column and a UV-vis detector. The HPLC
retention times for the diastereomers of the prepared ring-
opening products are also provided in the Supporting
Information.
Acknowledgment. We thank DGI-MCYT (Grant No.
BQU2002-02459), DURSI (Grant No. 2001SGR50), Fun-
dacio´n Ramon Areces, and ICIQ Foundation for financial
support.
Supporting Information Available: Experimental pro-
cedures and characterization of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL051110J
3832
Org. Lett., Vol. 7, No. 18, 2005