Conformational analysis of spiro-bis-dithiepins: A peculiar case of axial chirality

Article abstract of DOI:10.1021/ol062172s

(Figure Presented) Spiro-bis-dithiepins are synthesized via dehydrative ring expansion in α-hydroxyalkyl spiro-bis-dithianes. Atypical of spiranes possessing axial chirality, the two most stable conformers of substituted spiro-bis-dithiepin have virtually

Full text of DOI:10.1021/ol062172s

ORGANIC
LETTERS
2006
Vol. 8, No. 22
5121-5124
Conformational Analysis of
Spiro-bis-dithiepins: A Peculiar Case of
Axial Chirality
Edmir O. Wade, Roman A. Valiulin, Leslie A. Ruybal, and Andrei G. Kutateladze*
Department of Chemistry and Biochemistry,
UniVersity of DenVer, DenVer, Colorado 80208
akutatel@du.edu
Received September 1, 2006
ABSTRACT
Spiro-bis-dithiepins are synthesized via dehydrative ring expansion in
r-hydroxyalkyl spiro-bis-dithianes. Atypical of spiranes possessing
axial chirality, the two most stable conformers of substituted spiro-bis-dithiepin have virtually colinear double bonds; i.e., each enantiomer
exists in a form of two energy degenerate syn and anti conformations. Because of the high polarizability of the vinyl sulfide moiety, spiro-
bis-dithiepins bearing electron-withdrawing substituents offer access to two-state systems possessing large dipole moments, which can be
modulated by conformational events.
A photoinduced 1,3-hydrogen shift in substituted 6,7-
dihydro-5H-[1,4]dithiepins and associated modulation of the
electronic properties of this highly polarizable system make
dithiepins a promising framework for advanced materials.1
Conjoining two dithiepin moieties via a spiro connection
offers an even more sophisticated framework, with the
potential for photoinduced modulation of the properties of
both local π-systems, which are aligned according to the
conformational bias of the two seven-membered heterocycles.
Since the original Gerlach account2 of axial chirality in spiro-
[4.4]nonane-1,6-dione, the predominate description of these
spiranes included their two cycles residing in perpendicular
planes, with the symmetry of each lifted by asymmetric
substitution in the opposite ring. Although this depiction is
always valid for a time-averaged structure, we find that the
actual conformational preferences in the dihydrodithiepin
moiety produce a rather peculiar picture. In this Letter, we
report on synthesis and experimental and theoretical con-
formational analyses of spiro-bis-dithiepins.
As outlined in Scheme 1, the target bis-dithiepins 5 were
synthesized via a two-step process: the addition of lithiated
spiro-bis-methyldithiane 1 to aromatic aldehydes followed
by dehydrative ring expansion, catalyzed by toluenesulfonic
acid.3 The first addition step produces up to 7% of monoad-
(1) Wan, Y.; Kurchan, A. N.; Kutateladze, A. G. J. Org. Chem. 2001,
66 (5), 1894.
(2) Gerlach, H. HelV. Chim. Acta 1968, 51, 1587.
10.1021/ol062172s CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/05/2006

Scheme 1
Figure 1. HPLC trace for enantioseparation of 5f on a Chiralcel
OD chiral chromatography column.
unsubstituted 6,7-dihydro-5H-[1,4]dithiepin is 0.9 kcal/mol
more stable than the chair conformer. It was therefore not
unexpected that in the spiro-bis-dithiepin the most stable
conformers have both rings in the twist conformation. What
*Starting from the monoacetal of terephthalaldehyde.
ducts 2, which also are readily converted into spiro-
dithianodithiepins 4.
Bisaldehyde 5f, synthesized from the monoacetal of
terephthalaldehyde, is a primary synthon for the facile post
modifications shown in Scheme 2. It is readily condensed
Figure 2. DFT structures of the two bis-twist conformers of the
unsubstituted spiro-bis-dithiepin: (A) the coplanar conformer (|)
and (B) the cross conformer ( ). Bis-twist-(|) is 1.7 kcal/mol more
stable than bis-twist-( ) at the B3LYP/6-311++G(3df) level of
theory.
Scheme 2
is unique about the spiro-bis-dithiepin framework is that there
are two ways in which the bis-twist arrangement can be
realized (Figure 2): (i) with the two double bonds perpen-
dicular to each other, which we denote as ( ), and (ii) with
(3) At the first addition step, some amount of monoadduct is always
formed together with bisadduct 3. To improve the bis/mono ratio, we
deviated from the classic Corey-Seebach procedure for preparation of
dithiane anions (Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231) by
generating the bisanion at room temperature for 30 min, before quenching
the reaction with a carbonyl compound to furnish 2. (a) General Procedure
for Preparation of 3: Butyllithium (5 mL, 8 mmol, 1.6 M) was added to
0.5 g (2 mmol) of 3,9-dimethyl-2,4,6,10-tetrathiaspiro[5.5]undecane, and
the mixture was stirred at room temperature for 30 min. A solution of a
substituted benzaldehyde (4.4 mmol) in 10 mL of freshly distilled THF
was added to the mixture, and the solution was stirred for 2 h at room
temperature, quenched with 20 mL of saturated NH4Cl(aq), and extracted
with dichloromethane (20 mL × 2). The organic layers were combined
and dried over anhydrous sodium sulfate. The solvent was removed under
a vacuum, and the crude product was purified by column chromatography
(3f was synthesized starting from the monoacetal of terephthalaldehyde and
deprotected with AcOH before dehydrative ring expansion into sprio-bis-
dithiepin; for details refer to Supporting Information). (b) General Procedure
for Preparation of 5: 0.1 g (0.2 mmol) of bisadduct 3 was dissolved in
toluene, and a catalytic amount of p-toluenesulfonic acid (0.1 equiv) was
added. The reaction mixture was refluxed with a Dean-Stark trap for 12
h, then allowed to cool to room temperature. The remaining toluene was
removed under a vacuum. The resulting oil was washed with saturated NH4-
Cl(aq) and extracted with dichloromethane (15 mL × 2). The organic
extracts were combined and dried over anhydrous sodium sulfate. The
solvent was removed under a vacuum, and the crude residue was
chromatographed.
with nitriles to yield tetraenes 6-8, possessing polarized
π-systems, or converted into imines 9-11 in reactions with
substituted anilines.4 Imine 12 was synthesized with enan-
tiopure S-(-)-R-phenylethyl amine in an attempt to separate
the enantiomers of 5f. For the same reason, diethyl L-(+)-
tartrate was used in preparation of bisacetal 13. In both cases,
the resulting diastereomers showed insufficient differences
in physical properties for their separation. However, direct
separation of enantiomers 5f on a chiral chromatography
column, Chiracel OD, was successful (Figure 1).
According to our DFT computational studies, the half-
twist conformer (from here on “twist”) of the parent
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Org. Lett., Vol. 8, No. 22, 2006

the double bonds nearly coplanar (|). The lattersin cases
when the dithiepin moieties carry nonsymmetrically substi-
tuted double bondssgives rise to syn and anti conformations.
Another feature is that the conformational equilibrium is
hardly affected by substitution at the double bond but rather
is governed by the intrinsic properties of the parent (i.e.,
unsubstituted) spiro-bis-dithiepin (Table 1). Among other
(not shown) lies 3 kcal/mol above the bis-twist-(|); i.e., it is
very similar in energy to the twist-chair intermediate.
To experimentally determine the barrier of the conforma-
tional equilibration in 5f, a variable-temperature (VT) NMR
experiment was carried out (Figure 4a). At 20 °C, confor-
Table 1. B3LYP/6-31G(d) Relative Energies and Dipole
Moments of 5f and 18
dipole moment (D)
bis-twist:
rel energya
X
Y
Z
total
syn-(|)-5f
anti-(|)-5f
( )-5f
syn-(|)-18
anti-(|)-18
( )-18
0.06
(0.0)
1.55
0.35
(0.0)
1.77
0.00
0.00
0.47
0.00
0.00
5.07
0.00
1.75
7.19
0.00
2.76
0.00
2.16
2.06
0.00
0.53
4.35
5.07
2.16
2.75
7.19
0.53
5.16
-0.19
a In kcal/mol.
things, this implies that the syn and anti conformations are
nearly energy degenerate for various spiro-bis-dithiepins
substituted at the double bond.
B3LYP/6-311++G(3df) computations reveal that the bis-
twist-(|) to bis-twist-( ) conformational flip occurs via a
twist-chair intermediate (Figure 3). The highest-energy
Figure 4. (a) VT-NMR for 5f: 20 to -90 °C at ∆T ) 5°, CD2-
Cl2. (b) Eyring plot and (c) a 2.8 ppm multiplet (black) simulated
with two pairs of doublets (J ) 14.1 Hz) with equal intensity (red).
mational dynamics are fast and all four pairs of methylenic
protons show as a broad singlet at 3.5 ppm. Lowering the
temperature causes this peak to decoalesce into two reso-
nances (pseudoaxial and pseudoequatorial methylene pro-
tons), approximately 1.2 ppm apart. At -90 °C, the higher-
field 4H multiplet is best simulated as two pairs of doublets
of equal intensity, with a geminal spin-spin coupling
constant of 14.1 Hz (Figure 4c). This is consistent with two
C2-symmetric conformers, syn and anti bis-twist-(|), present
in equal or nearly equal concentrations. Line shape analysis
of the NMR data produced a set of rate constants, which
were plotted according to the Eyring equation (Figure 4b)
to yield the following activation parameters: ∆Hq ) 10.2
( 1.2 kcal/mol and ∆Sq ) 3.5 ( 2.4 eu. This is in very
good agreement with our DFT computational results for the
spiro-bis-dithiepin core.
The long axis of the 4-formylphenyl moiety, primarily
responsible for the direction of the local dipole in 5f, forms
a 148° angle with the chiral axis of the spiro-bis-dithiepin
core. As a result, the dipole moments of the syn and anti
bis-twist-(|)-5f conformers do not differ much from each
other (Table 1).
Figure 3. Energy profile (rel kcal/mol) for bis-twist-(|) to bis-
twist-( ) interconversion at the B3LYP/6-311++G(3df) level of
theory.
The anti to syn conformational flip can more efficiently
modulate the dipole moment of a system, in which local
dipoles are more orthogonal to the long axis of the molecule.
One solution, which potentially can achieve this objective,
is to conjugate dithiepins’ double bonds with a carbonyl
directly. With this in mind, we have developed a straight-
forward synthetic approach to such R,â-unsaturated ketones
starting with R-diketones (Scheme 3).
transition state (TS1) is found at 10.9 kcal/mol above the
coplanar conformer, which is consistent with a previously
reported 12.6 kcal/mol energy barrier for the conformational
flip in a related benzodithiepin.5 The bis-chair conformation
(4) This chemistry and related photochemical transformations will be
reported in detail elsewhere.
(5) Von Bredow, K.; Friebolin, H.; Kabuss, S. Org. Magn. Reson. 1970,
2, 43.
Org. Lett., Vol. 8, No. 22, 2006
5123

syn conformer is rather large, 7.2 D, and directed almost
exclusively along the Y axis (Figure 5 and Table 1). In the
Scheme 3
Figure 5. Local dipole alignment in syn (top) and anti (bottom)
bis-twist-(|)-18.
A plausible mechanism of the 17 to 18 transformation
involves a tandem ring expansion, i.e., (i) 1,2-sulfur migration
producing the dithiepin ring, reciprocated by (ii) a 2,1-
naphthyl migration furnishing fused six-membered cyclo-
hexadienone (Scheme 4).6
anti conformer, the dipole moment is 14 times smaller, due
to canceling in the XY plane. Its residual value of 0.53 in
the Z direction is primarily due to the slight deviation of the
double bonds from coplanarity.
Experimental studies are underway to isolate individual
enantiomers of 18 and to determine if solvent polarity or an
external electric field could modulate their chiroptical
properties. Changes in polarizability and hyperpolarizabilities
in spiranes 6-11 and their photochromic properties, due to
a photoinduced 1,3-hydrogen shift, are also being investi-
gated.
Scheme 4
Acknowledgment. We thank the National Science Foun-
dation and the donors of the Petroleum Research Fund,
administered by the American Chemical Society, for sup-
porting this research.
The carbonyl groups in 18 are perpendicular to the chiral
axis of the molecule. The computed dipole moment of the
Supporting Information Available: Spectral information
and synthetic and computational details. This material is
available free of charge via the Internet at http://pubs.acs.org.
(6) A reviewer suggested an alternative mechanism: the alkene, formed
via dehydration of the first species shown in Scheme 4, is protonated to
give the S-stabilized cation which undergoes 1,2-naphthyl migration
concomitant with â-sulfur participation. C-S cleavage followed by proton
loss gives the observed product.
OL062172S
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Org. Lett., Vol. 8, No. 22, 2006