We next turned our attention to the envisioned {1,6}-
TCAGC using the 13-membered (E,E)-1b for the purpose
of catalyst optimization (Table 2). (R,R)-6a and (S,S)-6d,
members of the copper(II)bis(oxazoline) family of chelat-
ing C2-symmetric Lewis acids,17 are known catalysts for
the catalytic asymmetric GosteliꢀClaisen rearrangement
(CAGC) at ambient temperature. Additionally, the stereo-
differentiating substituents (R) and the ligands (L) were
varied to modulate selectivity and reactivity; selected ex-
amples are summarized in Table 2. (R,R)-6a (R = Ph, L =
H2O) proved to be an effective catalyst for a rt {1,6}-
TCAGC providing trans-5b in high yields and diastereo-
selectivies (dr = 92:8) but offered only low enantioselec-
tivities (13% ee) (entry 1). (R,R)-6b (R = Ph, L = PhOH)
demonstrated faster conversion but otherwise did not bias
the stereoselectivity (entry 2). An increase in enantioselec-
tivity (70% ee) was obtained with (R,R)-6c (R = Bn, L =
PhOH) but at the expense of a slightly lower diastereo-
selectivity (dr = 87:13) (entry 3).18 For the known (S,S)-6d
(R = t-Bu, L = H2O), the enantioselectivity eventually
reached synthetically useful levels (>98% ee) (entry 4).
Subsequent experiments using the previously unreported
(S,S)-6e (R = t-Bu, L = CF3CH2OH) or (S,S)-6f (R =
t-Bu, L = PhOH) resulted in comparable enantioselectiv-
ities but increased turnover (entries 5 and 6). It was then
found possible to reduce the catalyst loading to 5 mol %
for (S,S)-6f by prolonging the reaction time (entry 7). The
increase in enantioselectivity (>98% ee) observed with the
catalysts (S,S)-6d,e,f (R = t-Bu) was accompanied by a
significantly diminshed diastereoselectivity (dr = 83:17).
A subtle dependence of diastereoselectivity on the ring size
was observed when 12-membered (E,E)-1a and 14-mem-
bered (E,E)-1c were subjected to the standard protocol using
(S,S)-6f as the catalyst. In detail, using either 15 or 2.5 mol %
of (S,S)-6f, the {1,6}-TCAGC of (E,E)-1a provided the
8-membered 5a with low diastereoselectivity, but excellent
enantioselectivity (dr = 62:38, >97% ee) (entry 8); (E,E)-1c
underwent the enantioselective {1,6}-TCAGC to afford
the 10-membered 5c without any noticeable diastereos-
electivity (dr = 51:49, > 98% ee) (entries 9 and 10).
Table 2. {1,6}-TCAGC of (E,E)-1a: Variation of Catalyst
Structurea
time
(h)
yield
(%)b
ee
(%)d
entry
substrate
catalyst
drc
1
(E,E)-1b
(E,E)-1b
(E,E)-1b
(E,E)-1b
(E,E)-1b
(E,E)-1b
(E,E)-1b
(E,E)-1a
(E,E)-1c
(E,E)-1c
(R,R)-6a
(R,R)-6b
(R,R)-6c
(S,S)-6d
(S,S)-6e
(S,S)-6f
(S,S)-6f
(S,S)-6f
(S,S)-6f
(S,S)-6f
5
97e
92
70
90g
87
87
86
98
95
86
92:8
13
2
1.5
1.5
72
18
18
26
2
92:8
13
70f
3
87:13
83:17
83:17
83:17
83:17
62:38
51:49
51:49
4
>98
>98
>98
>98
>97
>98
>98
5
6
7h
8i
9
18
48
10j
a Experiments conducted with 0.08 mmol (E,E)-1aꢀc in 1,2-dichloro-
ethane at ambient temperature. Catalysts prepared as described in the
Supporting Information. b Isolated yield after purification by chroma-
tography. c trans-5/cis-5, ratio determined by NMR. d ee for the major
diastereomer determined by chiral HPLC. The absolute configuration
was assigned based on the accepted TS model for the CAGC. e 39% yield
after 1.5 h with 56% of (E,E)-1b recovered. f In favor of the (1S,2R)-
trans-5b diastereomer. g 66% yield after 18 h with 33% of (E,E)-1b
recovered. h 0.05 equiv of (S,S)-6f. i Identical outcome using 0.025 equiv
of (S,S)-6f after 18 h. j 0.05 equiv of (S,S)-6f.
We next studied the influence of the double bond con-
figuration on the chemo- and diastereoselectivity of the
{1,6}-TCAGC (Table 3). In general, the difference be-
tween the 13-membered (E,E)-1b and its double bond
isomers was substantial; in particular, varying reactivities,
diastereoselectivities, and the formation of the inseparable
byproduct 7were observed. In detail, attempts to catalyze the
{1,6}-TCAGC of (Z,E)-1b using (S,S)-6d (R = t-Bu,
L = H2O) led to a miniscule conversion, even after 3 days,
and the formation of a 1:1 mixture of diastereomers (entry 1).
A faster conversion to a nearly 1:1:1 mixture of diastereomers
and 7 was observed using (S,S)-6e (R = t-Bu, L =
CF3CH2OH) or (S,S)-6f (R = t-Bu, L = PhOH) (entries
2 and 3). Somewhat surprinsingly in light of the results from
the {1,6}-TGC (Table 1, entry 7), using 15 or even 30 mol %
of (S,S)-6f, (E,Z)-1b was reluctant to undergo the {1,6}-
TCAGC and only small amounts of a roughly 1:1 mixture of
cis- andtrans-5b contaminated with traces of 7were obtained
(entry 4). In contrast, attempts to realize the {1,6}-TCAGC
of (Z,Z)-1b led to the expected low conversion via a boat-like
TS structure to afford cis-5b and the formation of 7 via the
nonconcerted pathway (entry 5).
(9) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885–888.
(10) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89,
5505–5507.
(11) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
(12) (a) Paquet, F.; Sinay, P. J. Am. Chem. Soc. 1984, 106, 8313–8315.
(b) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
2183–2186.
(13) Assignment of the double bond configuration by NOE experi-
ments; see Supporting Information for details.
(14) Rehbein, J.; Leick, S.; Hiersemann, M. J. Org. Chem. 2009, 74,
1531–1540.
(15) Rehbein, J.; Hiersemann, M. J. Org. Chem. 2009, 74, 4336–4342.
(16) Funk has reported the uncatalyzed {1,6}-transannular Irelandꢀ
Claisen rearrangement of an 11-membered lactone containing an
E-configured double bond. In the event, the 7-membered rearrangement
product was isolated as a mixture of diastereomers (trans/cis = 59:41);
see: Abelman, M. M.; Funk, R. L.; Munger, J. D. J. Am. Chem. Soc.
1982, 104, 4030–4032.
(17) Desimoni, G.; Faita, G.; Jørgensen, K. A. Chem. Rev. 2011, 111,
PR284–PR437.
(18) The intriguing reversal in enantioface differentiation by going
from 6a (R = Ph) to 6c (R = Bn) or 6d (R = tert-Bu) is documented in
the literature; see: (a) Johanssen, M.; Jørgensen, K. A. J. Org. Chem.
1995, 60, 5757–5762 (HDA reaction). (b) Evans, D. A.; Rovis, T.;
Kozlowski, M. C.; Downey, C. W.; Tedrow, J. S. J. Am. Chem. Soc.
2000, 122, 9134–9142 (MukaiyamaꢀMichael reaction), and ref 1m
(GosteliꢀClaisen rearrangement).
4116
Org. Lett., Vol. 14, No. 16, 2012