Fig. 1
product, though THP 18 did account for 17% of the equilib-
rium.
The rearrangement of the triols 7 and 8 required careful
handling (presumably due to the benzylic hydroxy group). The
2,4anti,4,5syn triol 7 rearranged exclusively to THF 19 after
being heated to reflux in dichloromethane for 24 h (Scheme 5).
The 2,4syn,4,5syn triol 8, however, had to be rearranged at rt (3
days) to avoid decomposition. Again, the THF 20 was the only
isolated product.
Scheme 7 Reagents: i, (MeO)3CMe, C5H6N+ TsO2, CH2Cl2, rt; ii, TsOH,
CH2Cl2, rt.
after the two-step reaction sequence, the THP 24 with an axial
acetate (the alternative THF 25 contains an unfavourable
2,3-syn relationship) (Scheme 6). Finally, in this series of
compounds, the 2,4anti,4,5syn-triol 13 gave a single product after
treatment with trimethylorthoacetate and PPTS: the bicyclic
orthoester 26. Attempts to repeat the reaction at higher
temperatures, or with longer reaction times, led only to
decomposition products that were not characterised. It is
interesting to note the stabilising effect of an exo-methyl group
on these compounds. When triol 11 (with 2,4-anti ster-
eochemistry) was reacted with the same reagent system no
bicyclic orthoester intermediate was observed; presumably an
endo-methyl group here destabilises the orthoester intermediate
(if the corresponding orthoester forms at all).
Scheme 5 Reagents: i, TsOH, CH2Cl2, 40 °C; ii, TsOH, CH2Cl2, rt.
The products of the kinetically controlled orthoester re-
arrangement reported in the preceding communication2 were
equilibrated with toluene p-sulfonic acid in dichloromethane
with the aim of converting the unrearranged7 THFs to THPs.
Reactions of the triols in the lactic acid series turned out to be
very substrate dependent. Rearrangement of the 2,4syn,4,5anti
triol 10 under kinetic conditions gave the unrearranged THF 22
as the major product (Scheme 6). Equilibration with toluene p-
sulfonic acid gave only a 74+26 mixture of the rearranged THP
21 and unrearranged THF 22. The inference here could be that
it is unfavourable for the sulfur to occupy an axial position,
indeed sufficiently unfavourable that it can partly overcome the
driving force for ‘downhill’ migration.8 The 2,4anti,4,5anti-triol
11 behaved quite differently; after equilibration of an initial
THF–THP mixture the only product identified was the THP 23,
with methyl, acetoxy and phenylsulfanyl groups all occupying
equatorial positions (Scheme 6). The 2,4syn,4,5syn-triol 12 gave,
The triols 7 and 8, each containing a benzylic hydroxy group,
behaved similarly to their analogues in the lactic acid series.
Triol 7 was converted into the THP 27, bearing an axial acetate,
and triol 8 gave only the bicyclic orthoester 28, which was not
successfully transformed into the target heterocycles
(Scheme 7).
In summary, we have demonstrated that for the general class
of triols under investigation THFs are formed as thermody-
namic products when toluene p-sulfonic acid is used as the
catalyst. This is attributed to the 1,3-diaxial interactions which
exist in the THPs when one of the C–C bonds of the tertiary
migration origin is forced to enter an axial environment. The
orthoester reaction was shown to be general apart from triols
with 2,4anti,4,5syn stereochemistry in which case the inter-
mediate bicyclic orthoester is overstabilised by a 6-exo
substituent. The subsequent equilibration of the product mixture
gives THPs as exclusive products in all cases except for triol
precursors with 2,4syn,4,5anti stereochemistry.
We thank the EPSRC and AstraZeneca for a grant to D. H.
Notes and references
1 D. House, F. Kerr and S. Warren, Chem. Commun., 2000, 1779 (DOI:
10.1039/b005342m).
2 D. J. Fox, D. House, F. Kerr and S. Warren, Chem. Commun., 2000, 1781
(DOI: 10.1039/b005341o).
3 H. C. Kolb, M. S. VanNieuwenhze and K. B. Sharpless, Chem. Rev.,
1994, 94, 2483.
4 K.-M. Chen, G. E. Hardtmann, K. Prasad, O. Repic˘ and M. J. Shapiro,
Tetrahedron Lett., 1987, 28, 155.
5 D. A. Evans, K. T. Chapman and E. M. Carreira, J. Am. Chem. Soc., 1988,
110, 3560.
6 E. P. Lodge and C. H. Heathcock, J. Am. Chem. Soc., 1987, 109, 3353.
7 By ‘unrearranged’ we mean a product in which the phenylsulfanyl group
remains bound to the same carbon as it was before the cyclisation, i.e. a
product that has not undergone a [1,2]-PhS rearrangement.
8 By ‘downhill’ we refer to the phenylsulfanyl group undergoing a [1,2]
shift from a more substituted to a less substituted carbon atom. Sulfanyl
groups generally only move ‘downhill’; in exceptional cases they may
undergo ‘flat’ migration, i.e. from one secondary centre to another. For
more details see: D. J. Fox, D. House and S. Warren, Angew. Chem., Int.
Ed. Engl., manuscript in preparation.
Scheme 6 Reagents: i, (MeO)3CMe, C5H6N+ TsO2, CH2Cl2, rt; ii, TsOH,
CH2Cl2, 40 °C.
1784
Chem. Commun., 2000, 1783–1784