however it should be noted that the presence of the chiral
counterion means that all four product-generating transi-
tion state structures are unequal in energy and therefore
a priori the enantiomeric composition of 3 and 4 need not
olefin faces are (Si, Re) and (Re, Si). The cyclization of (E)
and (Z) isomers can be said to have the same (or opposite)
sense of enantioselection only if one focuses on one
trigonal carbon. This catalyst system consistently delivers
Brþ to the C(4)-Si face, regardless of whether that face is
also C(5)-Si or C(5)-Re (Figure 1). We hypothesize that
this outcome reflects which substituent on the double bond
dominates the chiral recognition and that since the config-
uration of the tetrahydrofuran is conserved (Scheme 2,
C(4) of 1, C(2) of 3), the dominant recognition feature is
the tethered hydroxyl group. This sense of recognition is
tentatively hypothesized to result from hydrogen bonding
to the phosphate group, analogous to what is proposed in
certain Mannich reactions14 (Figure 1).
be equal (Scheme 3). For example if kReꢀendo/kReꢀexo
>
k
Siꢀendo/kSiꢀexo then kinetic resolution would occur,
increasing the er of 3a at the expense of lower er of 4a and
a lower ratio of 3a:4a.11 Any background reaction would
also produce mostly racemic 4a.
The greater proportion of exo cyclization of Z alkenes
compared to E alkenes is a property of the substrate,
independent of the selectivity of the catalyst system. This
phenomenon has been observed in many different electro-
phile-initiated olefin cyclization reactions3b,5,12 and epox-
ide opening reactions.13 The transition structure for 6-endo
cyclization of Z alkenes, ii, experiences unfavorable 1,3-
diaxial interactions that are absent in the 5-exo cyclization
transition structure iii as well as in the 6-endo transition
structure for E alkenes (Scheme 4).
Scheme 4
Figure 1. Absolute sense of enantioselectivity and postulated
substrateꢀcatalyst interaction.
The racemization of bromonium ions by olefin-to-olefin
transfer is not important in the current catalyst system. A
4-fold increase in reaction concentration led to a negligible
decrease in the enantiomeric composition of 3a (93:7 to
90:10). This drop suggests that olefin-to-olefin transfer
may be occurring to some extent, but either it is substan-
tially slower than cyclization at 0.1 M or the equilibrium
ratio of bromonium ions is favorably high. All other
experiments were conducted at 0.025 M, where associative
transfer should be 16 times slower, and the erosion of
enantioselectivity should be negligible.
In conclusion, an enantioselective bromocycloetherifi-
cation of 5-arylpentenols has been developed using a chiral
Brønsted acid and an achiral Lewis base to provide good
yield and enantiomeric induction. High site selectivity was
achieved by a combination of substrate and catalyst con-
trol. Further studies to expand the scope, improve the
selectivity, and understand the mechanism of this trans-
formation are ongoing.15
Acknowledgment. We are grateful to the National
Institutes of Health (R01 GM82535) for financial support
and to Dr. D. Kalyani for assistance and helpful discus-
sions. M.T.B. thanks the University of Illinois for a
Seemon H. Pines Graduate Fellowship.
Comparing the absolute configurations of the (E)- and
(Z)-derived products offers a clue about the origin of
enantioselection. The two trigonal carbons that constitute
the (Z) olefin faces are (Si, Si) and (Re, Re) whereas the (E)
(11) This analysis finds analogy in the divergence of enantioselec-
tivity for trans and cis epoxides in the Jacobsen epoxidation of Z alkenes.
Zhang, W.; Lee, N. H.; Jacobsen, E. N. J. Am. Chem. Soc. 1994, 116, 425.
(12) (a) Julia, M. M.; Guy-Roualt, A. C. R. Hebd. Seances Acad. Sci.
1964, 258, 3728. (b) Parker, K. A.; O’Fee, R. J. Am. Chem. Soc. 1983,
105, 654. (c) Ting, P. C.; Bartlett, P. A. J. Am. Chem. Soc. 1984, 106,
2668. (d) Bongini, A.; Cardillo, G.; Orena, M.; Sandri, M.; Tomasini, C.
J. Org. Chem. 1986, 51, 4905.
(13) (a) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang,
C.-K. J. Am. Chem. Soc. 1989, 111, 5330. (b) Nicolaou, K. C.; Prasad,
C. V. C.; Somers, P. K.; Hwang, C.-K. J. Am. Chem. Soc. 1989, 111,
5335.
Supporting Information Available. Full experimental
procedures, analyses, characterization data, and crystal-
lographic data for 3e. This material is available free of
(14) Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am. Chem.
Soc. 2007, 129, 6756.
(15) While this manuscript was under review, a similar study by
Shi et al. appeared. Huang, D.; Wang, H.; Xue, F.; Guan, H.; Li, L.;
Peng, X.; Shi, Y. Org. Lett. 2011, 13, 6350.
Org. Lett., Vol. 14, No. 1, 2012
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