cyclization and no desired crossed product could be obtained
by using In(OTf)3.
Gratifyingly, InBr3 was discovered to be the highly
efficient Lewis acid to promote this Prins cyclization and
the yields were dependent on the amount of InBr3 employed
(Table 1, entries 1, 2, and 3), with the best condition being
Scheme 1. Prins Cyclization of γ-Brominated Homoallylic
Alcohol with Aldehydes
Table 1. Prins Cyclization of (Z)-1 with Aldehydes
tetrasubstituted THP rings in moderate to high yields with
excellent stereoselectivity and our explorations toward their
synthetic value. To our best knowledge, our method is the
first stereoselective dibromo-THP construction via Prins
cyclization that results in a cis configuration of bromine
atoms. Other approaches to dibromo-THP rings were realized
via bromination of dihydropyrans, and only trans addition
products were obtained.7
γ-Brominated homoallylic alcohol (Z)-1 and cyclohexan-
ecarboxaldehyde were selected for the optimization of
reaction conditions (Scheme 2). Indium-based Lewis acids,
Scheme 2. Prins Cyclization of (Z)-1 with
Cyclohexanecarboxaldehyde and Analysis of the
Stereochemistry
a Isolated yield. b 0.2 equiv of InBr3 was employed. c 0.5 equiv of InBr3
was employed. d Reaction time was 25 h.
such as InCl3, In(OTf)3, and InBr3, were employed to mediate
the Prins cyclization at 0 °C in CH2Cl2. No Prins product
could be formed when InCl3 was utilized to promote this
1.0 equiv of InBr3 with 1.2 equiv of TMSBr8 in CH2Cl2 at
0 °C to afford 2a in 95% yield as a single isomer (Table 1,
entry 3). This cyclization proceeded smoothly with high
stereoselectivity and introduced four stereogenic centers into
the product in one step. 2,4,6-cis-5-trans THP ring 2a was
expected to be constructed with an axial bromine substituent
at the 5 position and the other three substituents occupying
equatorial positions. This was confirmed by the crystal
structure of 2a9 (Figure 1). We thus predict that all-cis-
(3) (a) Arundale, E.; Mikeska, L. A. Chem. ReV. 1952, 51, 505-555.
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(6) (Z)-1 was prepared in 62% yield by using hydrocinnamaldehyde to
trap allylic anion generated from allyl bromide in the presence of LDA
and zinc bromide.5a (E)-1 was prepared in three steps: (1) propargylation
of trialkylsilyl propargyl bromide with hydrocinnamaldehyde mediated with
indium and indium bromide (60%),5c (2) DIBAL-H reduction converting
the triple bond into the cis double bond (64%),5d and (3) bromination
(90%).5e,f
(7) (a) Woods, G. F.; Temin, S. C. J. Am. Chem. Soc. 1950, 72, 139-
143. (b) Dale, W. J.; Sisti, A. J. J. Am. Chem. Soc. 1954, 76, 81-82. (c)
Brown, R. K.; Srivastava, R. M.; Sweet, F.; Murry, T. P. J. Org. Chem.
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(8) Our initial investigations revealed that TMSBr serves as a bromide
source. No reaction occurred when only TMSBr was used as promoter.
With a stoichiometric amount of InBr3 as the sole promoter, only a trace
amount of the product could be observed when (Z)-1 was reacted with
cyclohexanecarboxaldehyde; for (E)-1 only 21% yield was obtained.
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Org. Lett., Vol. 9, No. 11, 2007