2
J. Soponpong et al. / Tetrahedron Letters xxx (xxxx) xxx
Fig. 1. Structures of THENA and THENA-d2.
Fig. 2. ORTEP diagram of the major disorder conformation of one of the two
symmetry-independent molecules in the crystal structure of (S,S)-7b (drawn with
30% probability displacement ellipsoids).
dented [14] and exo-deuteration could be confirmed, based on
the disappearance of the J-coupling between the exo-proton H-3
and the bridgehead proton H-4 [15].
To determine the absolute configuration of an enantiopure sec-
ondary alcohol of interest, it was first coupled with THENA-d2 to
form a pair of diastereomers. As shown in Fig. 3, the array of O–
a
C –CO–O–C*–H bonds of the THENA-d2 ester was assigned to be
in a plane, called the THENA plane [5a]. Accordingly, the 1H NMR
chemical shifts of the protons in the alcohol substituent on the
same side of this plane as the rigid aromatic group of the
THENA-d2 entity will shift to a lower field, because of the deshield-
ing anisotropic effect. In contrast, the protons of the alcohol sub-
stituent on the other side of the THENA plane are further away
from the aromatic ring, and their chemical shifts will be influenced
less. Thus, the protons on substituent L2 in the (S,?) [16] THENA-d2
ester (Fig. 3b) and on L1 in the (R,?) THENA-d2 ester (Fig. 3c) are
deshielded to different extents, which results in negative and pos-
Scheme 1. Preparation of optically active THENA-d2 (R)-(À)-2 and (S)-(+)-2.
Reagents and conditions: (a) 1,2-dichloroethane, reflux, overnight, 88%; (b) D2,
Pd/C, CH2Cl2, 30 °C, 99%; (c) KOH (5 eq), MeOH:1,4-dioxane (1:1), rt, overnight, 80%;
itive signs for the chemical shift difference values (D ; Dd
dSR SR = d(-
(d) (i) (COCl)2, DMF (cat.), CH2Cl2, 0 °C to rt, 3 h; (ii) L-phenylalaninol, NEt3, DMAP
(cat.), CH2Cl2, rt, overnight, (R,S)-7a (31%) and (S,S)-7b (30%); (e) KOH (30 eq),
MeOH:1,4-dioxane (1:1), reflux, overnight, 90% and 98% for (R)-(À)-2 and (S)-(+)-2,
respectively.
S,?) À d(R,?)) for protons on the substituents L1 and L2, respectively
(Fig. 3d).
In accordance with the above concept, THENA-d2 (R)-(À)-2 and
(S)-(+)-2 were activated with oxalyl chloride before treatment with
a variety of optically active secondary alcohols to generate a
diastereomeric pair of (R,?)- and (S,?)-THENA-d2 esters 8–27 in
moderate yields. The chemical shifts of the protons in the alcohol
substituent of each corresponding diastereomer were used to cal-
by column chromatography to provide pure diastereomeric com-
pounds (R,S)-7a [10] and (S,S)-7b [11] in 31% and 30% yield, respec-
tively. Each diastereomer was then hydrolyzed to finally obtain
optically active THENA-d2 (R)-(À)-2 (90%) and (S)-(+)-2 (98%).
Compound (S,S)-7b provided a good single crystal suitable for
X-ray diffraction analysis [12]. The asymmetric unit contains two
molecules of the same enantiomer with very similar conformations
and slight disorder of the benzyl entity. As shown in Fig. 2, the
culate the chemical shift difference values (
Dd
SR). If the signs of
the
D
dSR values for most of the protons on one side of the alcohol
substituent (as separated by THENA plane) were negative, this
group was assigned as substituent L1 in the model (Fig. 3d). Con-
D
dSR
a
versely, the other side of the alcohol substituent, where the
alignment of the amide C@O and the C –O is anti-periplanar
values for most of the protons were positive, was assigned as sub-
stituent L2. Overall, the absolute configurations determined by the
THENA-d2 method were found to be identical when compared with
the known configurations of the chiral secondary alcohols (8–27)
used for testing (Fig. 4).
Not only can THENA-d2 be used in the assignment of the abso-
lute configuration of chiral secondary alcohols, the high field
region in the 1H NMR spectra of these compounds is less compli-
cated. For example, comparison of the high field regions in the
[13]. Although the absolute configuration of the molecule could
not be confirmed independently by the diffraction experiment,
the known configuration of the L-(S)-phenylalaninol used as a
resolving agent could be applied in constructing the model for
the crystal structure refinement, from which it was possible to con-
firm the absolute configuration of THENA-d2 as the (S)-isomer. It
should be noted that the position of deuterium cannot be con-
firmed by X-ray crystallography. However, the syn hydrogenation
at the exo-position of the bridge of the [2.2.1] alkene was prece-
Please cite this article as: J. Soponpong, K. Dolsophon, C. Thongpanchang et al., Application of deuterated THENA for assigning the absolute configuration of