Table 1 Variation of product distribution with temperature and solvent
and this was the bis-THF 9. This product was also exclusively
formed from the cyclisation of tetrol 8†, which produces the
same episulfonium ion intermediate. This kind of bis-THF
motif is common among biologically active natural products,
most notably the annonaceous acetogenins.8
On one occasion some of the Z isomer of alkene 6 was carried
through the AD/anti reduction sequence as an impurity. In this
case a small amount of another cyclic product crystallised out
from the cyclisation reaction mixture. This was shown by X-ray
crystallography to be the centrosymmetric trans-fused bis-THP
10 (Fig. 3), which results from cyclisation of the corresponding
anti meso-tetrol. A similar bis-THP was desymmetrised by
Nelson in a formal synthesis of hemibrevetoxin B.9 Resubmit-
ting this bis-THP to the cyclisation conditions resulted in its
conversion to an equilibrium mixture with meso bis-THF 11
(Scheme 4).
Solvent
Temp./°C
% THF 12
% THP 13
CH2Cl2
CHCl3
Toluene
Toluene
Toluene
Toluene
40a
61a
30
60
80
50
67
22
28
34
40
50
33
78
72
66
60
100
a reflux
We were very interested to observe that the position of the
equilibrium was affected by both temperature and solvent, as
summarised in Table 1. In a less polar solvent (toluene), the
fused bis-THP 12 becomes the major product (in marked
contrast with the cyclisation of diastereomeric tetrol 2 and with
our earlier work on triols such as 1), whereas increasing the
temperature favours the bis-THF 13. This is consistent with the
bis-THF being more polar and higher in entropy than the fused
bis-THP. From this data estimates of DH and DS for the
reaction could be calculated (DH 210.5 kJ mol21, DS 224.3 J
mol21 K21).
This property can be exploited to synthesise either ring
system in useful synthetic yields from the same tetrol starting
material, by choosing appropriate reaction conditions. The
unwanted isomer can be recycled to further increase the overall
yield.
Fig. 3 Centrosymmetric by-product.
In conclusion, the acid-catalysed phenylsulfanyl migration
reaction can be used to create two rings simultaneously and
interesting bicyclic systems can be synthesised by this method.
The selectivity of the cyclisation depends on both ster-
eochemistry and reaction conditions.
Notes and references
Scheme 4 Reagents: i. Amberlyst, CDCl3, 60 °C.
†
Synthesised in low yield from trans-1,4-dibromobut-2-ene.
Crystal data for 10: C24H30O2S2, M = 414.60, monoclinic, space group
Cyclisation of the all syn tetrol 3 produced a mixture of
products (Scheme 5). Under the same conditions as those used
initially for tetrol 2 (Amberlyst, CH2Cl2, reflux) a 1 : 1
equilibrium mixture of bis-THF 12 and fused bis-THP 13 was
formed. The two products could be easily separated by
chromatography, and re-submitting either product to the
original reaction conditions resulted in the same 1 : 1 ratio. The
structure of the cis-fused bis-THP 13 was confirmed by X-ray
crystallography (Fig. 4).
P2(1)/c (no. 14), a = 7.2728(4), b = 5.6573(3), c = 26.5782(16) Å, b =
96.130(2)°, U = 1087.29(11) Å3, Z = 2, m(Mo-Ka) = 0.262 mm21, 5145
reflections measured at 180(2) K using an Oxford Cryosystems Cryostream
cooling apparatus, 1861 unique (Rint = 0.044); R1 = 0.050, wR2 = 0.114
[I > 2s(I)]. The structure was solved with SHELXS-97,10 and refined with
SHELXL-97.10 CCDC 216120.
Crystal data for 13: C24H30O2S2, M = 414.60, monoclinic, space group
P2(1) (no. 4), a = 9.7835(3), b = 11.2223(4), c = 10.6280(3) Å, b =
109.981(2)°, U = 1096.64(6) Å3, Z = 2, m(Mo-Ka) = 0.260 mm21, 6935
reflections measured at 180(2) K using an Oxford Cryosystems Cryostream
cooling apparatus, 4285 unique (Rint = 0.041); R1 = 0.038, wR2 = 0.072
[I > 2s(I)]. Absolute structure parameter 20.04(6). The structure was
solved with SHELXS-97,10 and refined with SHELXL-97.10 CCDC
graphic data in .cif or other electronic format.
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Scheme 5 Reagents: Amberlyst, CH2Cl2, reflux, 72 h.
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Fig. 4 Crystal structure of THP 13.
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