Scheme 2. Stereoselection in Prins-Pinacol Reactions
Assembling 12-Oxatricyclo[6.3.1.02,7]dodecanes
Figure 2. Comparison of the oxatricyclic ring systems 3 and 4
contained in aspergillin PZ (1) and 1,5-epoxysalvial-4(14)-ene (2).
dodecane moiety requires that the Prins cyclization takes
place by a boat topography (Scheme 2). Cyclization occurring
through a chair topography would afford an 12-oxatricyclo-
[6.3.1.02,7]dodecane having the configuration found in the
congeneric unit of 1,5-epoxysalvial-4(14)-ene (2). In general,
Prins cyclizations that form six-membered rings occur by
chair topographies,5 which has been the case in previous
Prins-pinacol reactions reported from our laboratories.1 In
the reaction pathways analyzed in Scheme 2, we conjectured
that the chair process might be disfavored because of the
cofacial disposition of the two six-membered rings in the
conversion 8 f 9 (Scheme 2).
by the addition of hydropyran aldehyde 10 (Scheme 3).7 The
resulting 4:1 mixture of alcohols 12 and 15 was separated
by HPLC, and the resulting pure epimers were silylated to
provide Prins-pinacol precursors 13 and 16. The relative
configuration of these epimers was confirmed by single-
crystal X-ray analysis of the p-nitrobenzoyl ester derivative
14 of alcohol 12.9
Scheme 3. Synthesis of Prins-Pinacol Precursors 13 and 16a
Scheme 1. Retrosynthetic Analysis of Aspergillin PZ (1)
a Reagents and conditions: (i) t-BuLi, then 11, THF, -78 °C;
(ii) TESCl, imidazole, DMF, rt; (iii) 4-nitrobenzoyl chloride, pyr,
DMAP, CH2Cl2.
As there was no precedent for the projected Prins-pinacol
reaction 7 f 6, we set out to explore the feasibility of this
transformation in simpler systems. Synthesis of the first
model substrate was accomplished by halogen-lithium
exchange of 1-iodocyclohexene6 (11) with t-BuLi, followed
Cyclohexenyl acetals 13 and 16 were exposed to several
Lewis acids in order to initiate their Prins-pinacol conver-
sions. Transformations of acetal 16 were found to be cleanest
in the presence of SnCl4. For example, reaction of 16 with
0.5 equiv of SnCl4 in CH2Cl2 for 0.5 h at 0 °C provided a
mixture of the 12-oxatricyclo[6.3.1.02,7]dodecane aldehyde
17 (33%) and 13-oxatricyclo[7.3.1.00,0]tridecan-8-one 19
(55%) (Scheme 4).8 In contrast, exposure of 13 to identical
reaction conditions afforded a complex mixture of products
(4) This strategy has been employed widely in the synthesis of alkaloids
containing the isoindolone unit such as cytochalasin D and aspochalasin
C; see: (a) Harkin, S. A.; Jones, R. H.; Tapolczay, D. J.; Thomas, E. J.
Chem. Soc., Perkin. Trans. 1 1989, 489-497. (b) Craven, A. P.; Dyke, H.
J.; Thomas, E. J. Tetrahedron 1989, 45, 2417-2429. (c) Thomas, E. J.;
Watts, J. P. Chem. Soc., Perkin. Trans. 1 1999, 3285-3290.
(5) For reviews of Prins cyclizations, see: (a) Arundale, E.; Mikeska,
L. A. Chem. ReV. 1952, 52, 505-555. (b) Snider, B. B. In The Prins
Reaction and Carbonyl Ene Reactions; Trost, B. M., Fleming, I., Heathcock,
C. H., Ed.; Pergamom Press: New York, 1991; Vol. 2, pp 527-561.
(6) Barton, D. H. R.; Bashiardes, G.; Fourrey, J.-L. Tetrahedron 1988,
44, 147-162.
(7) Jurczak, J.; Bauer, T.; Tetrahedron 1986, 42, 5045-5052.
(8) Prins-pinacol reaction of the TIPS analogue of 16 under similar
conditions provided oxatricyclic products 17 and 19 in a 3:1 ratio (1H NMR
analysis).
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Org. Lett., Vol. 6, No. 21, 2004