oxyacetic acid (9-AMA, 4) with racemic pentane-2-thiol
(chosen as model compound for the screening, Figure 1a).
Figure 2. Partial 1H NMR spectra of the (R)- and (S)-MPA
thioesters of (S)-butane-2-thiol (5) (CDCl3, 250.13 MHz).
and the corresponding ∆δRS signs. These results can be
explained on the basis of the presence, in each diastereo-
meric thioester, of NMR relevant conformer/s in equilibria
where the shielding effect produced by the phenyl ring of
the auxiliary affects mainly one of the substituents (L1 or
L2) of the thiolsthe one located closer to itsthus serving to
connect the configuration of the auxiliary part with that of
the thiol.
Figure 1. (a) CDAs 1-4 selected for this study and ∆δRS absolute
values (ppm, Me groups, italic) of their thioesters with pentane-
2-thiol (CDCl3, 250.13 MHz). (b) CDAs 16-19 and ∆δRS values
(ppm, italic) of butane-2-thiol thioesters (CDCl3, 250.13 MHz).
A combination of theoretical studies and experimental
evidence led to the identification of the significant conform-
ers. A short account follows.
We performed geometry and energy calculations6 on
dihedral angles Φ1 [O-CR-CPh-CPh], Φ2 [O-CR-CdO],
Φ3 [OdC-S-CR′],7 and Φ4 [(O)C-S-CR′-H] belonging
to the MPA thioesters of methanethiol and butane-2-thiol
(both taken as model compounds).
The resulting scenario shows equilibria between two
predominant species of conformers that are named, according
to the geometry of Φ2 at the MPA moiety, synperiplanar
(sp, minor) and antiperiplanar (ap, major and NMR relevant).
The situation depicted resembles that of the MPA derivatives
of amines (Figure 4a).8
MPA (1) generated the largest separation of chemical shifts
between diastereomeric thioesters, and as a result, it was
selected to continue the studies.
Next, we decided to examine the NMR behavior of the
(R)- and the (S)-MPA thioester derivatives of a series of thiols
of known absolute configuration and see ifsjust as in the
case of secondary alcohols, primary amines, and other
functional groupssa correlation between the absolute con-
figuration and the NMR chemical shifts was present.
Figure 2 shows the 1H NMR spectra of the MPA
derivatives of (S)-butane-2-thiol (5). It is easily observable
that the signal corresponding to CH3(1) is more shielded in
the (S)- than in the (R)-MPA thioester. The opposite situation
holds for CH2(3) and CH3(4), which are more shielded in
the (R)- than in the (S)-MPA thioester. These differences of
chemical shifts expressed as ∆δRS show a positive sign for
CH3(1) (∆δRS ) +0.07 ppm) and a negative sign for CH2-
(3) and CH3(4) (∆δRS ) -0.05 and -0.06 ppm, respectively).
(6) DFT (B3LYP/6-31G*) both in gas and solution (PCM) with Gauss-
ian03. See: Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin,
K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A.
D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A.
G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian
03, revision C.02; Gaussian, Inc.: Wallingford, CT, 2004.
1
Likewise, the H NMR spectra of the (R)- and the (S)-
MPA thioesters of the structurally diverse thiols 6-15 of
known configuration (Figure 3) showed signs of ∆δRS for
protons of the side chains (L1 and L2) identical to those with
the same spatial relationship in 5 (positive for L1 and negative
for L2).
This distribution of ∆δRS signs is coherent for all the thiols
studied and correlates with the configuration; therefore, it
can be used to determine the absolute stereochemistry of
the thiol. Figure 3 shows the spatial arrangement of L1/L2
(7) Conformational analysis on simple thioesters had previously shown
that the cis planar form around the Φ3 angle was the prevailing conformation
in a variety of solvents. See: (a) Nagy, P. I.; Tejada, F. R.; Sarver, J. G.;
Messer, W. S., Jr. J. Phys. Chem. A 2004, 108, 10173. (b) Deerfield, D.
W., II; Pedersen, L. G. J. Mol. Struct. (THEOCHEM) 1995, 358, 99. (c)
Reve´n, M. F.; Boese, R.; Ve´dova, C. O. D.; Oberhammer, H.; Willner, H.
J. Org. Chem. 2006, 71, 616.
(5) A value of ∆δRS for a given substituent is the difference between its
chemical shift in the (R)-CDA derivative minus that in the (S)-CDA
derivative.
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Org. Lett., Vol. 9, No. 24, 2007