A remarkable cyclization of TADDOL-bisthioacetate under oxidative conditions

Article abstract of DOI:10.1007/s00706-010-0410-5

Attempted oxidation of a TADDOL-derived bisthioacetate resulted in a rather unexpected and remarkable cyclization and deprotection reaction, giving a thiolane-1,1-dioxide as the main product. Systematic in situ ESI-HRMS studies revealed a bicyclic, highly

Full text of DOI:10.1007/s00706-010-0410-5

Monatsh Chem (2010) 141:1347–1351
DOI 10.1007/s00706-010-0410-5
ORIGINAL PAPER
A remarkable cyclization of TADDOL-bisthioacetate
under oxidative conditions
•
Mario Waser Manuela Haunschmidt
•
Markus Himmelsbach
Received: 8 October 2010 / Accepted: 13 October 2010 / Published online: 30 October 2010
Ó Springer-Verlag 2010
Abstract Attempted oxidation of a TADDOL-derived
bisthioacetate resulted in a rather unexpected and remarkable
cyclization and deprotection reaction, giving a thiolane-1,
1-dioxide as the main product. Systematic in situ ESI-HRMS
studies revealed a bicyclic, highly acid labile key interme-
diate of this reaction. Supported by force field calculations,
the high sensitivity of this intermediate was judged to be due
to the formation of a highly strained trans-configured
bicyclo[3.3.0]skeleton.
in Mukaiyama aldol reactions. As this elegant approach
and the suggested mechanism provide a very useful
methodology for the general activation of carbonyl groups
towards a variety of nucleophiles, the synthesis of analo-
gous sulfonimides based on different chiral sources is an
opportunity to broaden the scope of this strategy.
Among the easily available natural chiral sources, tar-
taric acid (1) has obtained a prominent position not only for
historical reasons, but especially due to the fact that both
enantiomers are readily available from natural sources.
Thus, 1 has become a valuable and cheap source of primary
chiral information for asymmetric catalysis. Tartaric acid
derived tetraaryl-2,2-dimethyl-1,3-dioxolan-4,5-dimetha-
nol (TADDOL, 2) and analogous compounds are easily
synthesized and extraordinarily versatile chiral auxiliaries
which have found numerous and widespread applications
as chiral ligands in asymmetric metal-catalyzed transfor-
mations (for a leading review about TADDOLs see [5]; for
a recent review see [6]). Surprisingly, their use as chiral
organocatalysts (avoiding the use of precious or potentially
toxic metals) has so far been limited to a few applications
only [7–10].
Keywords Oxidation Á Molecular modeling Á
Cyclization Á Mass spectrometry Á Tartaric acid Á
Organocatalysis
Introduction
Amongst the various ways of creating enantiomerically
enriched products, catalytic methods are nowadays consid-
ered to be the most appealing because the use of
stoichiometric amounts of valuable chiral reagents can be
avoided. Besides enzymatic and metal-catalyzed asymmetric
transformations, the use of sub-stoichiometric amounts of
organic molecules (organocatalysts) has proven to possess
an enormous potential [1–3].
As part of a program aimed at the synthesis of novel
tartaric acid derived organocatalysts, we therefore targeted
the synthesis of the chiral disulfonimide 3 starting from the
readily available chiral source 1 (Fig. 1). The synthesis of
this compound and its use as a chiral organocatalyst would
not only broaden the field of tartaric acid derived catalysis
but also the field of chiral counterion directed applications.
Recently List et al. [4] described the application of
chiral binol-based disulfonimides as chiral counteranions
M. Waser (&)
Institute of Organic Chemistry, Johannes Kepler University
Linz, Altenbergerstraße 69, 4040 Linz, Austria
e-mail: mario.waser@jku.at
Results and discussion
M. Haunschmidt Á M. Himmelsbach
The syntheses of TADDOL derivatives were thoroughly
investigated over the last few decades [5, 6]. Variations of
Institute of Analytical Chemistry, Johannes Kepler University
Linz, Altenbergerstraße 69, 4040 Linz, Austria
123

1348
M. Waser et al.
Fig. 1 Retrosynthetic analysis for the disulfonimide 3
the aryl substituents or in the ketal group have to be
introduced early in the synthesis of TADDOLs from 1,
whereas functionalizations of the hydroxyl groups are most
commonly achieved via conversion of 2 to the dichloro
compound 4 which can then be treated with different
nucleophiles (so far mainly nitrogen-, sulfur-, and oxygen-
containing nucleophiles have been reported in literature [5,
11–13]).
Fig. 3 Attempted synthesis of 3 giving the thiolanes 8 and 9 instead
performic acid (generated in situ by treatment of HCOOH
with H2O2) at room temperature resulted in full conversion
of 6. However, detailed NMR and HRMS analysis of the
obtained product showed that no desired disulfonic acid 7
was formed. Instead, the reaction led to the formation of a
mixture of the cyclic sulfoxide 8 and the corresponding
sulfone 9 (ratio *1:4) exclusively after 12 h reaction time.
After 20 h reaction time, no sulfoxide was detected any-
more and 9 was isolated in 55% yield after column
chromatography (Fig. 3). Also the use of peracetic acid did
not give any disulfonic acid 7 but several decomposition
products and small amounts of 8 and 9, whereas peroxide-
mediated oxidation under slightly basic conditions did not
result in any conversion at all.
For the synthesis of the disulfonimide 3 a direct
approach via synthesis of the dithiol 5 and subsequent
oxidation followed by imide formation appears to be the
most straightforward one. However, investigations by
Seebach et al. [5, 11] showed that synthesis of 5 is rather
difficult and, furthermore, this dithiol is prone to the for-
mation of a disulfide bond under oxidative conditions.
Therefore we decided to introduce the sulfur functionality
via formation of a bisthioacetate (giving compound 6). As
thioacetates are known to be easily oxidized to sulfonic
acids upon treatment with a variety of oxidants (e.g. per-
acids or dioxirane) [14–16] this approach should give
access to the disulfonic acid 7, one step away from the
target 3 (Fig. 2).
This remarkable formation of the thiolane products 8
and 9 was unexpected as, to the best of our knowledge, no
comparable single-step transformation has been reported so
far. Besides the unexpected cyclization forming the thio-
lane ring, the cleavage of the acetonide under these
reaction conditions is also remarkable. Normally the
TADDOL acetonide group is known to be rather stable
under acidic conditions, surviving acidic work-up without
any problem [5]. In addition, the ketal proved to be rather
stable even under the acidic conditions during the synthesis
of 6 at 50 °C (some unidentified by-products have been
formed, so a partial cleavage can not be excluded), whereas
during the oxidation reaction full hydrolysis occurred at
much lower temperature. Accordingly, there must be a
significant decrease in stability of the dioxolane ring during
this sequence, making it more sensitive towards acid-
mediated cleavage.
Synthesis of 6 could be achieved by treatment of 4
(synthesized according to Ref. [11]) with an excess of
thioacetic acid (HSAc) at 50 °C in moderate yield (36%,
not optimized). It is worth noting that neither treatment of 4
with stoichiometric amounts of thioacetic acid nor with
KSAc or Hg(SAc)2 gave any conversion.
Oxidation of 6 was first attempted using OxoneÒ
(2KHSO5ÁKHSO4ÁK2SO4) under a variety of conditions but
no conversion was obtained. Treatment with an excess of
To get a clearer picture of this reaction, in situ mass
spectrometry studies and force field calculations were
undertaken. Several possible intermediates for the conversion
of 6 to 9 might be possible. Out of a variety of possible
reaction mechanisms, two pathways seemed to be the most
probable: ketal cleavage first (due to the acidic reaction
conditions) followed by cyclization and subsequent oxidation
Fig. 2 Intended synthesis of 3 via the bisthioacetate 6
123

Remarkable cyclization of TADDOL-bisthioacetate
1349
and MMX yielded similar results). From these minimum
energy conformations, the relative stabilities of the
dioxolane rings of the three compounds were calculated
without minimization after replacing the substituents for H,
just leaving the comparable (4S,5S)-2,2,4,5-tetramethyl-
1,3-dioxolane conformations A (derived from the mini-
mum energy conformation of 2), B (derived from the
minimum energy conformation of 6), and C (derived from
the minimum energy conformation of 12), for comparison
of their relative steric energies. It was found that the
dioxolane rings A and B were significantly more stable
than C (A: 142, B: 172, and C: 188 kJ/mol). This result
can be rationalized by considering the contribution of the
individual steric energy components, especially bond
stretching, angle bending, and torsion. It was shown that
the bond lengths in the dioxolane rings are approximately
the same in 2 and 6, whereas in the case of 12 the C–C
bond between the bridgehead atoms is remarkably shorter
Fig. 4 Proposed pathways for the conversion of 6 to 9
(path A, Fig. 4), or cyclization first followed by ketal cleav-
age and oxidation (path B, Fig. 4).
We therefore carried out the reaction and monitored its
progress by electrospray ionization high resolution mass
spectrometry (ESI-HRMS). After 15–30 min at 0 °C we
were able to clearly identify the bicyclic intermediate 12 as
its Na and K adducts in the positive ion mode with accuracies
of 1.29 and 3.12 ppm. Furthermore, at this point of the
reaction, small amounts of the sulfoxide 8 were already
detected (besides unconverted starting material 6). Warming
up the reaction mixture to room temperature, after further
30 min significant amounts of sulfoxide 8 accompanied by
traces of sulfone 9 were detected. During all these mea-
surements no ketal cleavage product 10 could be detected. In
addition, the bicyclic intermediate 12 was hardly detectable
at ambient temperature, indicating the high instability of this
compound under the acidic reaction conditions.
˚
(1.50 A) in comparison to the monocyclic 2 (1.54 A) and 6
˚
˚
(1.55 A). It is worth noting that the calculated value for 2 is
in accordance with published X-ray structures of 2 [17, 18].
Comparing the bond (a) and dihedral (u) angles of the
TADDOL-derived conformations A–C with the values of
the force field minimized most stable conformation of
(4S,5S)-2,2,4,5-tetramethyl-1,3-dioxolane (D), significant
differences were observed. The dihedral angles (u) of the
O–C–C–O bond of 2 (A, u = 38°) and 6 (B, u = 37°)
were slightly smaller compared to D (u = 40°) while the
bicyclo-derived structure C showed the highest torsion
(u = 43°). Comparing the bond angles at the two stereo-
genic centers even more striking differences were
observed. TADDOL (2) (=A) showed only a small defor-
mation compared to the optimized conformation D, mainly
due to the steric repulsion of the phenyl groups. However,
the bisthioacetate (6)-derived B already showed a higher
angle distortion, explaining the higher steric energy of
B compared to A. Finally, the trans-configured bicy-
clo[3.3.0]skeleton of 12 leads to a significant angle
deformation at the bridgehead carbons (Fig. 5).
These studies unambiguously proved that the reaction
proceeds via pathway B (Fig. 4), with the bicyclic com-
pound 12 as a key intermediate (12 is a known compound
synthesized by Seebach et al. [13]).
The remarkable cyclization step most probably proceeds
via oxidation of one thioacetate group first (giving the
corresponding mono-sulfonic acid), followed by a desulf-
onation, intramolecular SN1 cyclization, and deacetylation
sequence resulting in 12. The high tendency of 6 to
undergo this cyclization might be due to the easy formation
of a highly reactive tertiary carbocation under acidic con-
ditions, thus facilitating the desulfonation and favoring the
intramolecular cyclization. However, none of the possible
highly reactive intermediates in this step could be detected
during our HRMS investigations, making an exact deter-
mination of the mechanism and a proof of this hypothesis
impossible.
The increased sensitivity of the dioxolane ring may be
due to the highly strained trans-configured bicyclo[3.3.0]
skeleton, which destabilizes the ketal moiety significantly
as compared to monocyclic TADDOL derivatives. Mole-
cular mechanics calculations support this hypothesis.
Therefore, the conformations of 2, 6, and the intermediate
12 were optimized by using the MMFF94 force field (MM3
Fig. 5 Force field calculations revealed the conformational differ-
ences between the monocyclic 2 and 6 and the bicyclic 12
123

1350
M. Waser et al.
S,S’-((4R,5R)-2,2-Dimethyl-1,3-dioxolane-4,5-
diyl)bis(diphenylmethylene) diethanethioate
Accordingly, the enhanced acid-sensitivity of the trans-
configured bicyclic compound 12 is due to a high bond angle
deformation and bond compression resulting in a signifi-
cantly higher ring strain in comparison to the monocyclic 2
and 6. The driving force of the hydrolysis is therefore
derived from the considerable relief of strain energy.
(6, C35H34O4S2)
A mixture of 390 mg (R,R)-4 (0.775 mmol) and 2.25 cm3
AcSH was stirred at 50 °C for 15 h, cooled, and extracted
with aqueous NaHCO3 (sat.) and EtOAc. The organic layer
was washed with brine, dried over Na2SO4, and evaporated
to dryness. Purification by column chromatography (silica
gel, hexanes/EtOAc = 5:1) yielded 162 mg (36%) 6 as a
white solid. M.p.: 192–196 °C; 1H NMR (500 MHz,
CDCl3): d = 7.58 (d, J = 7.4 Hz, 4H, Ar–H), 7.42–7.12
(m, 16H, Ar–H), 5.95 (s, 2H, –CH–), 2.17 (s, 6H,
–COCH3), 0.35 (s, 6H, –CH3) ppm; 13C NMR (125
MHz, CDCl3): d = 194.0 (–CO–), 144.8 (Ar–C), 140.3
(Ar–C), 131.8 (Ar–C), 131.3 (Ar–C), 127.9 (Ar–C), 127.5
(Ar–C), 126.5 (Ar–C), 126.4 (Ar–C), 110.8 (C(CH3)2),
79.9 (–CH–), 65.4 (CPh2), 31.1 (–COCH3), 28.0 (–CH3)
ppm; HRMS (ESI?): m/z calcd for C35H34O4S2 ? Na:
605.1791 [M ? Na]?, found: 605.1785; [a]2D0 = -282°
cm2 g-1 (c = 3.4, CHCl3).
Conclusion
The attempted synthesis of the disulfonic acid 7 by oxidation
of the bisthioacetate 6 failed completely, giving the unex-
pected sulfone 9 as the major product instead. In situ
ESI-HRMS investigations proved that this unique reaction
proceeds via the bicyclic intermediate 12. No further inter-
mediates of this surprising cyclization could be detected. As a
result of its highly strained trans-configured bicyclic skeleton,
intermediate 12 was found to be extraordinarily acid-sensi-
tive, resulting in full hydrolysis of the acetonide group under
mild conditions. This instability was also corroborated
by force field calculations which showed that the bicy-
clo[3.3.0]skeleton of 12 is highly strained and therefore the
dioxolane ring is significantly more labile to ring-opening
reactions than usually is the case for TADDOLs. Thus, as
a result of their reduced stability, bicyclo[3.3.0]-based
TADDOL derivatives seem to be less suited for further
applications in chiral catalysis (the comparably high acid
sensitivity of a pyrrolidine-containing TADDOL-derived
bicyclo[3.3.0]skeleton was recently reported [19]).
(3R,4R)-2,2,5,5-Tetraphenyltetrahydrothiophene-3,4-
diol-1,1-dioxide (9, C28H24O4S)
A mixture of 8 cm3 HCOOH and 0.8 cm3 H2O2 (30%) was
stirred at room temperature for 1 h, cooled to 0 °C, and a
solution of 72 mg 6 (0.124 mmol) in 4 cm3 CH2Cl2 was
added dropwise (15 min). The mixture was slowly warmed
up to room temperature (1 h) and stirred for an additional
19 h. The mixture was neutralized with aqueous Na2CO3
(sat.) and extracted with CH2Cl2 twice. The combined
organic layers were washed with brine, dried over Na2SO4,
and evaporated to dryness. Purification by column chro-
matography (silica gel, hexanes/EtOAc = 3:1) yielded 31
mg (55%) 9 as an oily residue. 1H NMR (500 MHz,
CDCl3): d = 7.63–7.48 (m, 8H, Ar–H), 7.37–7.10 (m,
12H, Ar–H), 5.18 (s, 2H, –CH–) ppm; 13C NMR (125
MHz, CDCl3): d = 136.4 (Ar–C), 134.9 (Ar–C), 132.0
(Ar–C), 130.0 (Ar–C), 129.1 (Ar–C), 128.8 (Ar–C), 128.5
(Ar–C), 128.0 (Ar–C), 80.7 (CPh2), 74.1 (–CH–) ppm;
HRMS (ESI?): m/z calcd for C28H24O4S ? NH4:
Experimental
Melting points were measured on a Kofler melting point
1
microscope (Reichert, Vienna). H and 13C NMR spectra
were recorded on a Bruker Avance DRX 500 MHz spec-
trometer using a TXI cryoprobe with z-gradient coil. Typical
resolutions and chemical shift precisions were 1 Hz for 1H
and 0.8 Hz for 13C. All NMR spectra were referenced to the
solvent peak. High resolution mass spectra were obtained by
using an Agilent 6520 Q-TOF mass spectrometer with an ESI
source and an Agilent G1607A coaxial sprayer. All analyses
were made in the positive ionization mode. Purine (exact
mass for [M ? H]? = 121.050873) and 1,2,3,4,5,6-hexa-
kis(2,2,3,3-tetrafluoropropoxy)-1,3,5,2,4,6-triazatriphosph-
inane (exact mass for [M ? H]? = 922.009798) were used
for internal mass calibration. [a]2D0 values were recorded on a
Perkin Elmer 241 MC Polarimeter. Force field calculations
were done with Pcmodel 9.0 (Serena Software). All chem-
icals were purchased from commercial suppliers and used
without further purification. (R,R)-TADDOL dichloride (4)
was synthesized starting from L-tartaric acid according to
Ref. [11].
474.1734 [M ? NH4]?, found: 474.1736; [a]2D0
-199.5° cm2 g-1 (c = 0.6, CHCl3).
=
Acknowledgments This work was supported by the FWF (Austrian
Science Funds) Project No. P22508-N17. We are grateful to Dr.
Christoph Etzlstorfer for his support with the force field calculations,
and Prof. Dr. Norbert Mu¨ller and Prof. Dr. Heinz Falk for inspiring
discussions.
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