Fluxional sulfonyl derivatives of troponoids and colchicinoids

Article abstract of DOI:10.1016/S0040-4039(03)00122-9

In what represents the first examples of fluxional sulfonyl derivatives, the tosyl group in the couple 4-isopropyltropone/6-isopropyltropone (3/4), the tosyl or mesyl groups in the couple colchicine/isocolchicine (5/6 or 7/8), and the tosyl group in the couples of colchicinoids 9/10 and 11/12, were observed to undergo thermally-induced shift between the two tropolone-like oxygen atoms, likely via a bipyramidal intermediate; recycling of tosylates or mesylates of biologically inactive isocolchicinoids into the corresponding tosylates or mesylates of biologically active colchicinoids affords synthetic value to the unselective tosylation or mesylation of colchiceine.

Full text of DOI:10.1016/S0040-4039(03)00122-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1895–1897
Fluxional sulfonyl derivatives of troponoids and colchicinoids
Marino Cavazzaa,* and Francesco Pietrab
aDipartimento di Chimica e Chimica Industriale, Universita` di Pisa, via Risorgimento 35, I-56100 Pisa, Italy
bVia della Fratta 9, I-55100, Lucca, Italy
Received 10 December 2002; revised 3 January 2003; accepted 7 January 2003
Abstract—In what represents the first examples of fluxional sulfonyl derivatives, the tosyl group in the couple 4-isopropyltropone/
6-isopropyltropone (3/4), the tosyl or mesyl groups in the couple colchicine/isocolchicine (5/6 or 7/8), and the tosyl group in the
couples of colchicinoids 9/10 and 11/12, were observed to undergo thermally-induced shift between the two tropolone-like oxygen
atoms, likely via a bipyramidal intermediate; recycling of tosylates or mesylates of biologically inactive isocolchicinoids into the
corresponding tosylates or mesylates of biologically active colchicinoids affords synthetic value to the unselective tosylation or
mesylation of colchiceine. © 2003 Elsevier Science Ltd. All rights reserved.
In 2-acetoxytropone (1a) and analogues, migration of
the acyl group via intramolecular attack at the carbonyl
carbon by the cycloheptatrienone carbonyl oxygen pro-
ceeds very rapidly even at low temperatures, as indi-
oxy-6-isopropyltropone (4)3 (Chart 1). That this is an
equilibrium mixture was proven by isolating pure 4 and
subjecting it to a similar procedure, by which the same
1:0.9 mixture of 3 and 4 was obtained. Similar observa-
tions were made with either the tosylates (5/6)4
1
cated by a marked temperature dependence of their H
and the
NMR and 13C NMR spectra in the 203–298 K range.1
mesylates (7/8)5 in the colchicine/isocolchicine system,
and with tosylates in the neocolchicine/pseudocol-
chicine and 5,6-didehydro-7-deacetamidocolchicine/5,6-
didehydro-7-deacetamidoisocolchicine systems (9/106
and 11/127 respectively) (Chart 2). In the equilibrium
mixtures of compounds obtained on heating pure com-
pounds in the 100–140°C temperature range, the pre-
vailing isomer (by about 2.4:1) bears a double bond
between C7a and C12a.
In contrast with the acetyl group, the tosyl group has
never been described to impart fluxional behavior to
suitable systems to which it is bound, such as the
troponoids, e.g. 2-tosyloxytropone (2a).2 Therefore, it is
interesting to have observed, and report here, fluxional
behavior for tosylates and mesylates of both troponoids
and colchicinoids, albeit under forcing conditions.
Thus, the tosylate of b-thujaplicine (2-tosyloxy-4-iso-
propyltropone, 3)3 in DMF at 100°C in about 2.5 h was
observed to change into a 1:0.9 mixture with 2-tosyl-
The equilibrium processes (for which rate coefficients
are given in Table 1) could be disentangled into for-
ward and backward reaction on the basis of the equi-
librium position. The activation parameters, determined
in the 100–140°C temperature range (Table 2), are
similar for all fluxional processes examined,8 the largest
deviation being observed for the mesylates of the col-
chicine/isocolchicine system (7/8), which show a slightly
higher enthalpy of activation, for both the forward and
the backward reaction, than the other sulfonates.
The data in Table 2 show that fluxionality with tosyl
group is typified by about 2.5 fold higher activation
energy than the acyl group, evaluated as about 11 kcal
mol−1 for 1a.1 The NMR spectra of the above tosylates
are therefore temperature independent in the normally
accessible range, which explains why these fluxional
processes have passed unnoticed with systems such as
2a/2b which give undistinguishable isomers.
Chart 1.
Keywords: colchicinoids; troponoids; tosylates; mesylates; tosyl or
mesyl migration.
* Corresponding author. Fax: 39 050 20237; e-mail: marcav@
dcci.unipi.it
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00122-9

1896
M. Ca6azza, F. Pietra / Tetrahedron Letters 44 (2003) 1895–1897
the mechanism of nucleophilic substitution at the sul-
fonyl sulfur atom has been actively investigated, a
clear cut position in favor of either a two-step process
(with a trigonal bipyramidal intermediate having nega-
tively-charged oxygen atoms at the apical positions) or
a one-step process (with entering and leaving group at
the apical position of a trigonal bipyramidal transition
state) was never taken.9 The latter configuration is
difficult to conceive for the reactions described here,
because collinear entering and leaving tropolonate-like
oxygen atoms would give rise to a prohibitively highly
strained transition state. Rather, a trigonal bipyrami-
dal intermediate having negatively-charged oxygen
atoms at the apical positions, as outlined above, can
be easily accommodated for the reactions described
here: molecular mechanics calculations by the
MMFF94 force field for the hypothetical bipyramidal
intermediate for fluxional system 2a/2b (1) indicate
low strain. Higher rates in DMF than toluene for the
3/4 equilibrium system (Table 1) are consistent with
the highly polarized character of the rate limiting tran-
sition state that can be envisaged from the intermedi-
ate in Figure 1.
Chart 2.
These tosyl migrations may allow recycling biologi-
cally-inactive isocolchicinoids into biologically-active
colchicinoids. This affords synthetic value to the unse-
lective tosylation or mesylation of colchiceine, which
remains the easiest intermediate step towards a variety
of colchicinoids.4,6
These processes can be mechanistically described as a
shift of the tosyl or mesyl group via intramolecular
nucleophilic attack at the sulfur atom by the cyclohep-
tatrienone carbonyl oxygen. To this concern, although
Table 1. Rate coefficients for the equilibriation reactions in DMF
Equilibrating compounds
k1 (s−1 105)a
118°C
k−1 (s−1 105)a
100°C
140°C
100°C
118°C
140°C
3/4
3/4
5/6
7/8
9/10
11/12
3.490.1
19.7
16.0b
30.0
36.5
27.7
28.9
89
3.990.1
22.7
18.0b
13.0
17.7
10.2
8.4
107
5.890.1
6.590.1
5.290.1
3.590.1
172
214
150
87
2.390.1
3.390.1
1.990.1
1.490.1
72
107
60
36
a k1 and k−1 represent first-order rate coefficients for the direct (e.g. 3“4) and the reverse (e.g. 4“3) reactions.
b Measured in toluene.
Table 2. Activation parameters for the equilibration reactions in DMF
Equilibrating compounds
DH"25° (kcal/mol)a
DS"25° (e.u.)a
DH"25° (kcal/mol)b
DS"25° (e.u.)b
3/4
5/6
7/8
9/10
11/12
24.3
25.3
26.1
25.1
23.8
−14.1
−10.4
−8.1
−11.2
−15.2
24.7
25.7
26.0
25.8
23.8
−12.8
−11.2
−9.7
−11.4
−16.9
a Activation parameters for the direct reaction.
b Activation parameters for the reverse reaction.

M. Ca6azza, F. Pietra / Tetrahedron Letters 44 (2003) 1895–1897
1897
J(5,3)=1.6, H5), 2.05 (heptet, J=6.6, isopropyl methyne),
1.74 (s, tosyl methyl), 0.74 (d, J=6.6, isopropyl methyl
groups). Therefore, the isomer with higher m.p. could be
assigned structure 4.
4. Staretz, M. P.; Bane Hastie, S. J. Org. Chem. 1991, 56,
428–432.
5. Cavazza, M.; Veracini, C. A.; Pietra, F. J. Chem. Soc.,
Perkin Trans. 2 1992, 2201–2204.
6. Cavazza, M.; Zandomeneghi, M.; Pietra, F. J. Chem. Soc.,
Perkin Trans. 1 2002, 560–564.
7. Compounds 11 and 12 were prepared by tosylation of
5,6-didehydro-7-deacetamidocolchiceine (Kouroupis, P.;
Hansen, H.-J. Helv. Chim. Acta 1995, 78, 1247-1277). The
reaction mixture was subjected to TLC on silica gel with
Et2O. The Rf 0.57 band gave 12 while the Rf 0.61 band
gave 11. Compound 11: lH (CDCl3) 7.96 (d, J=8.4), 7.38
(d, J(12,11)=10.2, H12), 7.37 (d, J =8.4), 7.21 (s, H8),
7.05 (d, J(11,12)=10.2, H11), 6.56 (s, H4), 6.54 (dd,
J(5,6)=10.1, J(5,7ax)=1.4, H5), 6.20 ( m, H6), 3.96, 3.93
and 3.65 (three s, OMe), 3.05 (m, H7eq and H7ax), 2.48 (s,
tosyl methyl), lC (CDCl3): 181, 154.4, 145.2, 137.4, 133.9,
129.9, 129.7, 128.7, 107.0, 61.7, 56.4, 39.3, 22.3. Com-
pound 12: lH (CDCl3) 7.96 (d, J=8.5), 7.58 (s, H8), 7.38
(d, J(12,11)=13.2, H12), 6.91 (d, J(11,12)=13.2, H11),
6.66 (s, H4), 6.59 ( dd, J(5,6)=9.6, J(5,7ax)=1.4, H5), 6.23
(ddd, J(6,5)=9.6, J(6,7eq) =12.4, J(6,7ax)=1.8, H6), 3.95,
3.93 and 3.74 (three s, OMe), 3.07 (dd, J(7eq,6)=12.4,
J(7eq,7ax)=6.0, H7eq), 2.52 (dd, J(7ax,7eq)=6.0, J(7ax,6)=
1.8, H7ax), 2.45 (s, tosyl methyl), dC(CDCl3): 178.5, 153.7,
152.2, 145.6, 142.7, 141.4, 138.9, 135.4, 133.8, 133.6, 130.9,
129.8, 128.9, 106.7, 61.6, 56.3, 37.5, 22.1.
Figure 1. MMFF94-calculated least-strained hypothetical
bipyramidal intermediate for the intramolecular shift of the
tosyl group with tropolone tosylate.
8. Kinetics measurements were carried out with about 10−3
mol L−1 solutions in dry DMF. The solutions, sealed in
vials, were heated in a thermostatic bath and were
analysed by HPLC under UV detection. For the 5/6
system a RP-18 250 mm column, with MeCN/H2O 6:4,
flow rate 1 mL/min, gave retention times 4.8 min for 6 and
5.2 min for 5. For both systems 7/8 and 9/10 a CN 250
mm column, eluent AcOEt, flow rate 1 mL/min, gave
retention times 3.12 min for 8, 3.4 min for 7, 3.5 min for
9 and 4.0 min for 10. A CN 250 mm column with
AcOEt/hexane 6:4, flow rate 1 mL/min, gave retention
times 3.36 min for 4, 4.03 min for 3, 3.56 min for 12 and
4.11 for 11.
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were obtained. The 1H NMR spectrum of the isomer
characterized by a lower m.p. (79–81°C) supports the
structure previously assigned to 3. 2-Tosyloxy-4-isopropyl-
tropone (3): lH (C6D6) 8.12 (d, J=8.4), 7.42 (d, J(3,5)=
1.6, H3), 6.80 (d, J(7,6)=12.2, H7), 6.68 (d, J=8.4), 6.17
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