A novel cycloisomerization of tetraenones: 4+3 Trapping of the Nazarov oxyallyl intermediate [11]

Full text of DOI:10.1021/ja9837001

876
J. Am. Chem. Soc. 1999, 121, 876-877
Scheme 1a
A Novel Cycloisomerization of Tetraenones: 4+3
Trapping of the Nazarov Oxyallyl Intermediate
Yong Wang, Atta M. Arif, and F. G. West*
Department of Chemistry, UniVersity of Utah
315 South 1400 East, Rm. Dock
Salt Lake City, Utah 84112-0850
ReceiVed October 23, 1998
Among the approaches to medium sized rings, cycloadditions
stand out for their ability to generate these structures in a single
step from simple fragments.1,2 For example, [4+3]-cycloadditions
employing oxyallyl units and 1,3-dienes offer an attractive route
to cycloheptane adducts containing several useful handles for
further functionalization.1 We3 and others4 have noted that [4+3]-
cycloadditions of cyclic oxyallyls provide access to eight-
membered or larger rings via keto-bridged intermediates (eq 1).
a Reagents and conditions: (a) O3, MeOH, -78 °C; then TsOH, room
temperature; then NaHCO3, Me2S; (b) (EtO)2P(dO)CH2CHdCH2, BuLi,
THF, -78 °C; then 1a or 1b and HMPA; (c) HCl, THF, room
temperature; (d) CH2dC(CH3)MgBr, THF, 0 °C; (e) DMSO, (ClCO)2,
CH2Cl2, -78 °C; Et3N, 0 °C; (f) LDA, THF, -60 °C; then RCHO; then
MsCl, Et3N; then DBU, THF.
The required precursors (pyran-4-ones or 2-halocyclopentanones
bearing pendant dienes) and the conditions for their conversion
to the short-lived oxyallyl intermediates (UV irradiation or
treatment with LiClO4 in ether) place some constraints on these
approaches. Our recent observations that the oxyallyl cation
formed during Nazarov cyclization of cross-conjugated dienones
can be intercepted with a variety of intra- and intermolecular
olefinic nucleophiles5 prompted us to investigate the viability of
the corresponding 4+3 trapping with dienes. Here we report the
preliminary results of these studies, a high-yield entry into
polycyclic products via Lewis acid-catalyzed cycloisomerization
of simple, acyclic tetraenone precursors.
Preparation of the initially examined tetraenone substrates was
straightforward (Scheme 1). Ozonolysis of cyclohexene or cy-
cloheptene with the Schreiber protocol6 provided differentiated
dialdehyde synthons 1a and 1b. Homologation to the dienes 2a,b
was accomplished with high E/Z selectivity by using a variation
of the Yamamoto method.7 Acetal hydrolysis,8 Grignard addition,
oxidation, and an eliminative aldol addition completed the
synthesis of 6a-d. The E-geometry of the trisubstituted alkenes
in 6 was confirmed by the observation of nOe interactions between
protons of R and the nearest methylene group of the tether in the
2D NOESY NMR spectra.
Substrate 6b was exposed to a variety of Lewis acids (BF3‚
OEt2, TiCl4, SnCl4, AlCl3, Me3SiOTf) to effect the Nazarov
electrocyclization, and FeCl3 in CH2Cl2 at -30 °C was found to
be optimal (Scheme 2).9 Under these conditions, [4+3]-cycload-
ducts 7b and 8b were obtained in a combined 72% yield (1.3:1
ratio). An identical result could be achieved by using as little as
0.2 equiv of Lewis acid.10 An nOe interaction between the
indicated protons in the 2D NOESY spectrum of 7b provided
strong support for that relative stereochemistry. A similar interac-
tion was not seen with diastereomer 8b. On this basis, we
tentatively assigned the stereochemistry shown, epimeric at the
bridgehead methine. The structure of 8b was confirmed by X-ray
diffraction analysis. Notably, two of the four possible diastere-
omeric cycloadducts, 9 and 10, were not isolated. The observed
product ratio appears to derive from a high diastereofacial
selectivity in the cycloaddition, with preferred approach from the
less hindered face of the cyclic oxyallyl cation, but only modest
selectivity for endo vs exo orientation of the diene and oxyallyl.
Replacement of the phenyl substituent of 6b with methyl (6a)
had very little effect on the outcome of the reaction: a 1.3:1 ratio
of 7a and 8a was obtained in slightly lower (65%) yield.11a
HoweVer, homologous substrates 6c-d each furnished a single
diastereomeric cycloadduct, 8c and 8d, in 67 and 75% yields,
respectiVely. Complete diastereofacial selectivity was obtained
as before, but complete exo selectivity was also seen in these
cases.11b The large impact of an additional methylene group in
the tether is surprising. The origins of this effect are not clear at
(1) (a) Hosomi, A.; Tominaga, Y. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5, pp 593-
615. (b) Rigby, J. H.; Pigge, F. C. Org. React. 1997, 51, 351-478. (c) Harmata,
M. In AdVances in Cycloaddition; Lautens, M., Ed.; JAI Press Inc.: Greenwich,
1997; Vol. 4, pp 41-86. (d) Harmata, M. Tetrahedron 1997, 53, 6235.
(2) (a) Rigby, J. H. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, pp 617-643. (b)
Sieburth, S. McN.; Cunard, N. T. Tetrahedron 1996, 52, 6251.
(3) West, F. G.; Hartke-Karger, C.; Koch, D. J.; Kuehn, C. E.; Arif, A. M.
J. Org. Chem. 1993, 58, 6795.
(4) For recent examples, see: (a) Harmata, M.; Elomari, S. E.; Barnes, C.
L. J. Am. Chem. Soc. 1996, 118, 2860. (b) Harmata, M.; Elahmad, S.; Barnes,
C. L. J. Org. Chem. 1994, 59, 1241. (c) Cha, J. K.; Jin, S.-J.; Choi, J.-R.; Oh,
J.; Lee, D. J. Am. Chem. Soc. 1995, 117, 10914. (d) Kim, H.; Ziani-Cherif,
C.; Oh, J.; Cha, J. K. J. Org. Chem. 1995, 60, 792.
(5) (a) Bender, J. A.; Blize, A. E.; Browder, C. C.; Giese, S.; West, F. G.
J. Org. Chem. 1998, 63, 2430. (b) Giese, S.; West, F. G. Tetrahedron Lett.
1998, 8393. (c) Browder, C. C.; West, F. G. submitted for publication.
(6) Claus, R. E.; Schreiber, S. L. Org. Synth. 1985, 64, 150.
(7) (a) Ikeda, Y.; Ukai, J.; Ikeda, N.; Yamamoto, H. Tetrahedron 1987,
43, 723. (b) Wang, Y.; West, F. G. Manuscript in preparation.
(8) Aldehyde 3a had been prepared previously by other routes: (a) Craig,
D.; Geach, N. J.; Pearson, C. J.; Slawin, A. M. Z.; White, A. J. P.; Williams,
D. J. Tetrahedron 1995, 51, 6071. (b) Wulff, W. D.; Powers, T. S. J. Org.
Chem. 1993, 58, 2381. (c) Smith, D. A.; Houk, K. N. Tetrahedron Lett. 1991,
32, 1549. (d) Segi, M.; Takahashi, M.; Nakajima, T.; Suga, S.; Sonoda, N.
Synth. Commun. 1989, 19, 2431. (e) Oppolzer, W.; Dupuis, D. Tetrahedron
Lett. 1985, 26, 5437. (f) Roush, W. R.; Hall, S. E. J. Am. Chem. Soc. 1981,
103, 5200.
(9) (a) For a discussion of the use of anhydrous FeCl3 in silicon-directed
Nazarov reactions, see: Denmark, S. E.; Jones, T. K. J. Am. Chem. Soc. 1982,
104, 2642. Other Lewis acids: (b) Tsuge, O.; Kanemasa, S.; Fujiwara, I.;
Wada, E. Bull. Chem. Soc. Jpn. 1987, 60, 325. (c) Santelli, M.; Dulcere, J.-
P.; Morel-Fourrier, C. J. Am. Chem. Soc. 1991, 113, 8062. (d) Marino, J. P.;
Linderman, R. J. J. Org. Chem. 1981, 46, 3696.
(10) We are aware of only one other example of the use of catalytic amounts
of Lewis acid in the Nazarov reaction.5b
(11) (a) The stereochemistry of 7a and 8a was assigned based on close
spectral analogy to 7b and 8b. (b) The stereochemistry of 8d was rigorously
determined by X-ray diffraction analysis, and that of 8c was assigned based
on close spectral analogy to 8d.
10.1021/ja9837001 CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/15/1999

Communications to the Editor
J. Am. Chem. Soc., Vol. 121, No. 4, 1999 877
Scheme 2
Scheme 3a
a Reagents and conditions: (a) CH2dC(CH3)MgBr, THF, 0 °C; (b)
DMSO, (ClCO)2, CH2Cl2, -78 °C; Et3N, 0 °C; (c) LDA, THF, -60 °C;
then PhCHO; then MsCl, Et3N; then DBU, THF; (d) CH2dNMe2Cl, Et3N,
CH2Cl2; then SiO2; (e) cyclohexenyllithium, THF, -78 °C; (f) Dess-
Martin periodinane, CH2Cl2, NaHCO3.
this time and merit further study, though preliminary analysis
suggests unfavorable interactions between the diene unit and the
tether may be significantly different in the endo and exo transition
states.12
and we were interested in what effect this would have on the
diastereoselectivity. In the event, the usual conditions furnished
endo and exo cycloadducts 7f and 8f in a ratio of 1.4:1 and in
near quantitative yield. Thus, substituents at either â position of
the cyclic oxyallyl intermediate exert a powerful bias for approach
of the diene from the opposite face, but three-carbon tether once
again led to low exo/endo selectivity.
We have described a new class of tandem reactions, involving
an initial Nazarov-type electrocyclic closure of a 1,4-dien-3-one,
followed by intramolecular [4+3]-cycloaddition of the resulting
oxyallyl cation with a pendant 1,3-diene. The stereocenter set
during the electrocyclization leads to complete facial selectivity
in the subsequent cycloaddition, and high exo selectivity can be
obtained in the cycloaddition of substrates containing a four-
carbon tether. This process converts acyclic, achiral reactants into
complex, tricyclic products in good to excellent yield, with the
concomitant formation of three new carbon-carbon bonds and
up to five new stereocenters. Additional studies of the scope of
this reaction and its application to complex targets containing these
skeletons will be reported elsewhere.
Two other examples possessing alternative substitution patterns
were examined (Scheme 3). Substrate 6e, containing an additional
methyl substituent on the 1,3-diene, was prepared from aldehyde
3c in analogous fashion to the previously described route (Scheme
1). Application of the standard conditions for tandem electrocy-
clization/[4+3]-cycloaddition led to three products in a combined
yield of 74%. Exo cycloadduct 8e was obtained as the major
product along with trace quantities of 7e. An additional product,
13, was also isolated. This formal 3+2 adduct is presumed to
arise from a stepwise nucleophilic trapping of the oxyallyl,
followed by enolate closure onto the resulting allylic carbocation.13
Its formation solely from 6e may be a consequence of the greater
nucleophilicity of the substituted diene, as well as the more
sterically demanding [4+3] transition state.
Finally, aldehyde 3a was converted to tetraenone 6f by a
variation on the standard sequence. In this case, an unsubstituted
methylene group was introduced14 prior to the addition of
cyclohexenyllithium, and the resulting tetraenol was oxidized by
using the Dess-Martin conditions.15 Unlike 6a-e, this substrate
lacked a â substituent on the proximal alkene of the dienone
system, but was substituted on both carbons of the distal alkene,
Acknowledgment. We thank NIH for their generous support of this
research and Dr. Charles Mayne for invaluable assistance with high-field
NMR experiments.
Supporting Information Available: Experimental procedures and
physical data for 2-8 and 13 and X-ray data for 8b and 8d (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
(12) Endo and exo refer to the orientation of the diene in relation to the
central carbon of the oxyallyl unit. There is some precedent for greater exo/
endo selectivity in intramolecular [4+3]- and [4+4]-cycloadditions: (a)
Harmata, M.; Herron, B. F. J. Org. Chem. 1993, 58, 7393. (b) Sieburth, S.
McN.; Hiel, G.; Lin, C.-H.; Kuan, D. P. J. Org. Chem. 1994, 59, 80. (c)
Sieburth, S. McN.; Chen, J.; Ravindran, K.; Chen, J. J. Am. Chem. Soc. 1996,
118, 10803.
(13) For related examples of stepwise 3+2 trapping of cyclic oxyallyl
cations by 1,3-dienes, see: (a) Harmata, M.; Carter, K. W. Tetrahedron Lett.
1997, 38, 7985. (b) Giguere, R. J.; Tassely, S. M.; Rose, M. I.; Krishnamurthy,
V. V. Tetrahedron Lett. 1990, 31, 4577. We have also observed this type of
reactivity with simple alkene traps.5c
JA9837001
(14) Takano, S.; Inomata, K.; Samizu, K.; Tomita, S.; Yanase, M.; Suzuki,
M.; Iwabuchi, Y.; Sugihara, T.; Ogasawara, K. Chem. Lett. 1989, 1283. The
reaction was not complete after stirring for 3 days following the literature
procedure; however, we have found that the reaction went to completion in
12 h in the presence of silica gel.
(15) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. (b)
Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.