Highly Diastereoselective Cycloisomerization of Acyclic Trienones. the Interrupted Nazarov Reaction

Full text of DOI:10.1021/jo9803030

2430
J . Org. Chem. 1998, 63, 2430-2431
Sch em e 1
High ly Dia ster eoselective Cycloisom er iza tion
of Acyclic Tr ien on es. Th e In ter r u p ted
Na za r ov Rea ction
J ohn A. Bender, Alan E. Blize, Cindy C. Browder,
So¨ren Giese, and F. G. West*
Department of Chemistry, University of Utah,
Salt Lake City, Utah 84112
Received February 23, 1998
In the pursuit of synthetic efficiency,1 high value is placed
on transformations that create several new stereocenters
and bonds in a single operation, in high yield and with good
stereocontrol. The reorganization of polyolefinic reactants
into fused polycyclic products under cationic conditions
exemplifies these ideals and has proven especially useful in
the construction of multiple six-membered rings,2 but ap-
plication of cation-olefin cyclizations to cyclopentanoid
synthesis has been less common.3 We previously described
photocyclizations of pyran-4-ones bearing pendant olefin or
arene nucleophiles to furnish functionalized diquinanes and
hydrindans.4 While yielding large increases in molecular
complexity, certain aspects of this chemistry reduced its
appeal: irradiation in trifluoroethanol raised concerns about
scale-up, and necessary installation of an angular hydroxyl
in the products was usually not desirable.5 The Nazarov
cyclization proceeds via oxyallyl intermediates analogous to
those produced photochemically from pyran-4-ones;6 how-
ever, reports of nucleophilic trapping of this intermediate
are limited to a few cases of unexpected solvent capture.7
We report here the first examples of deliberate trapping of
the Nazarov oxyallyl intermediate via cationic cyclization
onto pendant olefins, a process that efficiently converts
acyclic, achiral trienones into diquinanes with the net
formation of two new carbon-carbon bonds and four or five
new stereocenters.
responding organolithium or Grignard reagents, and the
resultant dienols were oxidized to the required dienone
substrates 3a -f with BaMnO4.
With these substrates in hand, common Lewis acids were
surveyed,10 and BF3‚OEt2 was found to cleanly effect the
desired transformation. When dienone 3a was treated with
BF3‚OEt2 in CH2Cl2 at -78 °C and then slowly warmed to
room temperature, a single new product was formed (eq 1).
Trienone substrates were easily prepared using standard
transformations (Scheme 1). Starting from readily available
aldehydes 1a 8 and 1b,9 Horner-Emmons olefination fol-
lowed by DIBAL reduction and TPAP/NMO oxidation led
to enals 2a and 2b. These materials, along with com-
mercially available citral 2c, were alkylated with the cor-
Upon workup, isolation, and analysis, the material was
found to lack all alkene and carbonyl moieties and to have
a molecular weight consistent with hydrated starting mate-
rial. The product was identified as hemiketal 4a , as
confirmed by X-ray diffraction analysis.11 All of the prepared
substrates were subjected to these reaction conditions, and
the results are summarized in Table 1. This process, termed
the “interrupted Nazarov reaction”, provides good isolated
yields of the polycyclic hemiketal products 4 with complete
diastereoselectivity when the dienone and alkene trap are
linked by a two-carbon tether, and the dienone is substituted
at both R positions (entries 1-4).
The proposed mechanism for formation of 4 is shown in
Scheme 2. Complexation of the Lewis acid by the carbonyl
of the dienone 3 results in the expected four-electron
conrotatory electrocyclic closure, establishing a new C-C
bond, one or two stereocenters, and a new oxyallyl cation 5.
The cation is then trapped by the pendant olefin in a 5-exo
cyclization, establishing a second C-C bond, two more
stereocenters, and a tertiary carbocation (6). To explain the
eventual oxygenation present at the site of the tertiary
carbocation, we envisage its subsequent capture by the boron
(1) (a) Hudlicky, T. Chem. Rev. 1996, 96, 3. (b) Wender, P. A.; Miller, B.
L. In Organic Synthesis: Theory and Applications; Hudlicky, T., Ed.; J AI
Press: Greenwich, CT, 1993; Vol. 2, pp 27-66.
(2) Reviews: (a) Taylor, S. K. Org. Prep. Proc. Int. 1992, 24, 245. (b)
Sutherland, J . K. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 341-377. (c) Bartlett,
P. A. In Asymmetric Synthesis; Morrison, J . D., Ed.; Academic Press: New
York, 1984; Vol. 3, pp 341-409.
(3) Examples: (a) Mehta, G.; Rao, K. S.; Reddy, M. S. J . Chem. Soc.,
Perkin Trans. 1 1991, 693. (b) Wender, P. A.; Correira, C. R. D. J . Am.
Chem. Soc. 1987, 109, 2523. (c) Amupitan, J . A.; Scovell, E. G.; Sutherland,
J . K. J . Chem. Soc., Perkin Trans. 1 1983, 755. (d) J ohnson, W. S.; Daub,
G. W.; Lyle, T. A.; Niwa, M. J . Am. Chem. Soc. 1980, 102, 7800. (e) Lansbury,
P. T.; Demmin, T. R.; DuBois, G. E.; Haddon, V. R. J . Am. Chem. Soc. 1975,
97, 394.
(4) (a) West, F. G.; Fisher, P. V.; Arif, A. M. J . Am. Chem. Soc. 1993,
115, 1595. (b) West, F. G.; Willoughby, D. W. J . Org. Chem. 1993, 58, 3796.
(5) For an exception, see: Amann, C. M.; Fisher, P. V.; Arif, A. M.; West,
F. G. J . Org. Chem., in press.
(6) (a) Habermas, K. L.; Denmark, S. E.; J ones, T. K. Org. React. (N.Y.)
1994, 45, 1. (b) Denmark, S. E. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5, pp 751-784. (c)
Ramaiah, M. Synthesis 1984, 529. (d) Santelli-Rouvier, C.; Santelli, M.
Synthesis 1983, 429.
(7) (a) Hirano, S.; Takagi, S.; Hiyama, T.; Nozaki, H. Bull. Chem. Soc.
J pn. 1980, 53, 169. (b) Shoppee, C. W.; Cooke, B. J . A. J . Chem. Soc., Perkin
Trans. 1 1972, 2271.
(8) Marbet, R.; Saucy, G. Helv. Chim. Acta 1967, 50, 2095.
(9) Takano, S.; Chiba, H.; Kudo, J .; Takahashi, M.; Ogasawara, K.
Heterocycles 1967, 26, 2461.
(10) Both TiCl4 and SnCl4 caused oligomerization of the starting materi-
als at -78 °C. FeCl3 provided the desired products, but in lower overall
yield than with BF3‚OEt2.
(11) A similar hemiketal product was observed as a side product during
diene trapping of an alkoxyallyl cation: Harmata, M.; Elomari, S.; Barnes,
C. L. J . Am. Chem. Soc. 1996, 118, 2860.
S0022-3263(98)00303-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/24/1998

Communications
J . Org. Chem., Vol. 63, No. 8, 1998 2431
Ta ble 1. Cycloisom er iza tion of Dien on es 3a -f to
P olycyclic Hem ik eta ls 4a -fa
are presumed to be epimeric at the position adjacent to the
hemiketal via a bicyclic enol intermediate, but with the same
relative stereochemistry at the other stereogenic centers. In
support of this, the major diasteromer was reduced with
DIBAL to the crystalline diol 8 and the relative stereochem-
istry rigorously determined by X-ray diffraction analysis (eq
2). From this, it can be inferred that the 6-exo cyclization
largely follows the same stereochemical course as the 5-exo
cyclizations of substrates 3a -d .
yield of
entry dienone
R1
R2
R3
R4
n
4b (%)
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
H
H
H
H
H
CH3
CH3 CH3
CH3 C(CH3)3
H
H
1
1
1
1
2
1
75
89c
73
62
42d
e
CH3 CH2CH3 CH3
CH3
CH3 CH3
CH3
-(CH2)4-
H
H
H
a
See eq 1. Standard procedure: BF3‚OEt2 (4.0 equiv) was added
dropwise to a stirring solution of 3 (10 mM) in CH2Cl2 at -78 °C.
The reaction mixture was allowed to warm to room temperature
and stirred for 5 min and then quenched with H2O and subjected
b
to a standard aqueous workup. Isolated yields after chromatog-
d
raphy. c Only 2.0 equiv of BF3‚OEt2 was used. A 5:1 ratio of
epimerizable diastereomers was obtained. e Multiple unidentified
products were obtained.
The resistance of 3f to cycloisomerization is also notable
(entry 6). Systematic variation of reaction conditions re-
sulted only in multiple products that could not be character-
ized. It is possible that â-disubstitution sterically impedes
the initial electrocyclic closure; however, there are many
reports of highly substituted dienones undergoing successful
Nazarov cyclizations.12 A more likely explanation involves
the lack of R and R′ disubstitution. This should substantially
increase the populations of undesired “sickle” (s-cis/s-trans)
and “w” (s-cis/s-cis) conformations at the expense of the “u”
(s-trans/s-trans) conformation required for the cyclization,
permitting alternative reaction pathways to compete with
electrocyclization. Also, to the extent that Nazarov cycliza-
tion occurs, greater positive charge density should reside at
the more distant, substituted carbon of the oxyallyl system,
thus reducing the efficiency of the subsequent cation-olefin
cyclization. Efforts to develop a more complete understand-
ing of these substituent effects are ongoing.
Sch em e 2
We have described the first examples using the Nazarov
oxyallyl intermediate to initiate cationic cyclizations. This
process converts simple trienones to functionalized polycyclic
products under straightforward conditions. Four or five
stereocenters are set with high control during a cascade of
events: (1) electrocyclic conrotatory closure, (2) cation-olefin
cyclization via a compact transition state, and (3) face-
selective enol ether protonation. Efforts are underway to
probe the scope of this new cycloisomerization, including the
use of other trapping groups and the development of
methods for controlling absolute stereochemistry, and their
results will be disclosed at a future date.
enolate oxygen. This final ring closure can only occur if the
carbocation is endo-disposed, which results from cationic
cyclization of 5 to 6 exclusively via a compact transition
state. Upon aqueous workup, the strained enol ether 7 is
hydrated with selective protonation from the convex face to
form the last stereocenter, resulting in hemiketal 4.
When the tether length was increased by one carbon, the
hemiketal was produced in diminished yield and as a 5:1
ratio of diastereomers (entry 5). We experienced initial
difficulty in assigning the relative stereochemistry of these
diastereomers; however, during a 2D NMR experiment on
the major diastereomer, we noted the gradual appearance
of the minor diastereomer. We then showed that a pure
sample of the major diastereomer and an enriched sample
of the minor diastereomer in CDCl3 each equilibrated to a
5:1 ratio of diastereomers over a 4 d period. The isomers
Ack n ow led gm en t. Support by the NIH (GM44720) is
gratefully acknowledged. We thank the University of Utah
for a University Research Fellowship (J .A.B.), Fonds der
Chemischen Industrie for a Kekule´ Fellowship (S.G.), and
Drs. Atta Arif (University of Utah) and Charles Campana
(Siemens, Inc.) for their assistance in obtaining X-ray
crystallographic data for compounds 4a and 8.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and physical data for 2a ,b, 3a -f, 4a -e and 8, NMR spectra
for 2a ,b, 3b-d , and 4a ,e, and ORTEP structures and positional
parameters for 4a and 8 (20 pages).
(12) See, for example: (a) Denmark, S. E.; Habermas, K. L.; Hite, G. A.
Helv. Chim. Acta 1988, 71, 168. (b) Mehta, G.; Krishnamurthy, N. J . Chem.
Soc., Chem. Commun. 1986, 1319. (c) Crisp, G. T.; Scott, W. J .; Stille, J . K.
J . Am. Chem. Soc. 1984, 106, 7500.
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