10030 J. Am. Chem. Soc., Vol. 122, No. 41, 2000
Weix et al.
it extends the ability to distinguish configurations of chiral
centers from the previous limit, n ) 3, to n ) 7. For the
methylalkanols Et(Me)CH(CH2)nOH, it extends the limit from
n ) 3 to n ) 4.20,21
It also analyzes carboxylic acids. Three points are significant
in this regard. The first is that reagent 5 is effective, for it is
one of very few reported for the analyses of chiral acids.8 Second
is that of the few previously studied reagents, only one has been
reported to distinguish chiral centers that are remote from the
carboxyl group.8b,22 Although the compounds tested before are
different from those tested here, Table 4 shows that reagent 5
distinguishes chiral centers that are even further from the
carboxyl than the furthest analyzed before. The situation is
similar when chromatographic methods are considered.23 Third
is that the linker used here, 2-aminophenol, or related linkers
have not previously been used as auxiliaries with other reagents
that analyze alcohols and amines. The linker is short and should
therefore keep the attached centers of chirality within or near
the groove of the [5]HELOL ligand.
The mechanism by which the phosphorus atom distinguishes
the chirality of the remote centers is not known, but the three-
point rule26 implies that the distinction, when for example
molecules 1 are bonded to 5, originates from the relationships
between both the remote phenyl and methyl groups and the
helical structure. A model in which O(CH2)8CH3 in its all-trans
extended conformation is bonded to 5 (at X) was constructed
by means of the Macromodel computer program. It shows that
at least the first three carbon atoms must lie within the
[5]HELOL groove. Substituents even on the fourth carbon must
interact with the [5]HELOL skeleton, and if the chain either
does not point straight out along [5]HELOL’s C2 axis or if it
folds back, substituents even further away will as well. If the
chain folds into the groove, the interactions within the HELOL
ligand can be extended considerably. Figure 5 suggests that in
the case of 1 when n ) 7, the benzene ring at the penultimate
carbon in the conformation of lowest energy lies within the
helicene cleft in both diastereomers, oriented with an edge
perpendicular to the terminal aromatic ring and near to that ring
and to the phosphorus. The pictured model appears reasonable
because benzene rings commonly adopt edge-to-face orienta-
tions.27,28,29 Figure 5 also implies that the terminal methyl group
of the alkoxy chain points away from the helicene structure not
Figure 5. Conformations of minimum energy of (M,M)-5 with X )
O(CH2)7CHPhMe when the side chain has (a) the (R)-configuration
and (b) the (S)-configuration. Hydrogens and methoxyl groups have
been deleted for clarity. Oxygen atoms are shown as speckled and
phosphorus as striped.
ee was 61.2 ( 0.1% [the (S)-isomer predominating].16 The
analyses show the (S)-â-citronellol to be >98% enantiomerically
pure, the (R)-â-citronellol to be >98% enantiomerically pure,
and the ee of the mixture to be 60.3 ( 2%. These data also
show that the enantiomeric purity of the [5]HELOL reagent was
g98%.
To analyze why 5 is effective in distinguishing the stereo-
chemistry of remote chiral centers, calculations were made to
find the conformations of lowest energy for the two diastere-
omers of 5 in which X was O(CH2)7CHPhMe. The Macromodel
V.6.0 program17 with AMBER* force field,18 operating on a
Silicon Graphics-O2 computer, was used for the conformational
searches. Initially, a structure of local minimum energy was
calculated for 5 (X ) O(CH2)7CHPhMe) in the selected solvent.
The structure was then subjected to a Metropolis Monte Carlo
conformational search using the standard parameters in Mac-
romodel. No parts of the molecule were constrained. The
conformations of lowest energy found for the two diastereomers
are displayed in Figure 5.
The results of these calculations showed that in the conforma-
tion of globally minimum energy, the (R) alkoxy chain lies
within the cleft of the helicene whether the solvent is water or
chloroform. When water was the selected solvent, all the other
conformations within 2 kcal/mol of the global minimum (there
were two) were also folded like this. However, when the solvent
was chloroform, 40% of the other conformations within 2 kcal/
mol of the global minimum (there were five) had the alkoxy
chain extended, with the phenyl and methyl groups outside the
cleft.19
(20) The reagent used for Et(Me)CH(CH2)3OH was R-cyano-R-fluo-
rophenylacetic acid.4
(21) Reagents 2a (in this experiment, NMe2 took the place of the pictured
Cl) and 2b are reported not to distinguish the enantiomers of 4-methylhex-
anol.3a,5 They do distinguish those of 2-methylbutanol, as does 33b and a
related reagent (Wu, R.; Odom, J. D.; Dunlap, R. B.; Silks, L. A., III
Tetrahedron: Asymmetry 1999, 10, 1465).
Discussion
(22) (a) Silks, L. A., III; Peng, J.; Odom, J. D.; Dunlap, R. B. J. Chem.
Soc., Perkin Trans. 1 1991, 2495. (b) Salvatore, B. A.; Smith, A. B., III
Tetrahedron Lett. 1994, 35, 1329.
The data in Tables 1-4 imply that [5]HELOL chlorophos-
phite (5, X ) Cl), presumably because it binds molecules within
a helical groove, is by far the most sensitive probe there is for
remote chirality. When combined with alcohols of structure 1,
(23) Chromatography on a chiral column was used to resolve lipoic acid.24
A binaphthyl column was used to separate the 3,5-dinitroanilides of the
4-phenylvaleric acids.25
(24) Fadnavis, N. W.; Koteshwar, K. Tetrahedron: Asymmetry 1997, 8,
337.
(25) Oi, S.; Ono, H.; Tanaka, H.; Matsuzaka, Y.; Miyano, S. J.
Chromatogr. A 1994, 659, 75.
(26) (a) Pirkle, W. H.; Pochapsky, T. C. Chem. ReV. 1989, 89, 347. (b)
Pirkle, W. H.; House, D. W. J. Org. Chem. 1979, 44, 1957. (c) Taylor, D.
R.; Maher, K. J. Chromatogr. Sci. 1992, 30, 67.
(16) Measured by the weights of the (R) and (S) materials that were
combined. The analyses of the (R) and (S) materials show that any slight
deviation from their enantiopurity cannot significantly change the calculated
ee.
(17) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput.
Chem. 1990, 11, 440.
(27) Hunter, C. A. Chem. Soc. ReV. 1994, 23, 101.
(18) (a) AMBER: Cornell, W. D.; Cieplak, P.; Bayly, C. I.; Gould, I.
R.; Merz, K. M., Jr.; Ferguson, D. M.; Spellmeyer, D. C.; Fox, T.; Caldwell,
J. W.; Kollman, P. A. J. Am. Chem. Soc. 1995, 117, 5179. (b) AMBER* is
a variation used in the Macromodel program, ref 17.
(19) When the solvent was water, there were only two conformers within
4 kcal/mol of the global minimum, but when CHCl3, there were five within
2 kcal/mol of the global minimum and eight total within 3 kcal/mol.
(28) (a) Mu¨ller-Dethlefs, K.; Hobza, P. Chem. ReV. 2000, 100, 143 and
references therein. (b) Boyd, D. R.; Evans, T. A.; Jennings, W. B.; Malone,
J. F.; O’Sullivan, W.; Smith, A. J. Chem. Soc., Chem. Commun. 1996, 2269
and references therein.
(29) The reasons are unclear (see: Kim, E.-I.; Paliwal, S.; Wilcox, C.
S. J. Am. Chem. Soc. 1998, 120, 11192, references therein, and refs 27 and
28a), and molecular mechanics calculations do not account for them.27