Nazarov-initiated diastereoselective cascade polycyclization of aryltrienones [20]

Full text of DOI:10.1021/ja991215f

J. Am. Chem. Soc. 1999, 121, 7443-7444
7443
Scheme 1
Nazarov-Initiated Diastereoselective Cascade
Polycyclization of Aryltrienones1
John A. Bender, Atta M. Arif, and F. G. West*
Department of Chemistry
UniVersity of Utah
315 S. 1400 East, Rm. Dock
Salt Lake City, Utah 84112-0850
ReceiVed April 16, 1999
Cationic olefin polycyclizations2-4 occupy a special position
among synthetic methods employing tandem or domino-type
reactions.5 The elegant work of Johnson and others has demon-
strated the effectiveness of this approach in the construction of
sterol skeletons and related structures.6 We have recently noted
that alkenes and conjugated dienes may function as effective traps
of the oxyallyl cation formed upon electrocyclization during the
Nazarov reaction.7,8 These observations prompted an examination
of the corresponding cascade polycyclization processes, in which
a pendant alkene would function as a reactivity relay between
the oxyallyl unit and a terminating aryl moiety. Here we describe
our initial result, a high-yield and diastereoselective method for
the construction of tetra- or pentacyclic skeletons from simple
aryl trienone precursors.
The necessary substrates 2a-e were easily prepared from the
known aldehyde 19 through a five-step sequence (Scheme 1).
Conditions for effecting the desired cyclization were then
examined. Treatment of 2b with protic acid led to the “traditional”
Nazarov cyclization product 3, while 2a furnished hydrindenone
4 in the presence of BF3‚OEt2. In each case, the desired
polycyclization process had been truncated, diverting to elimina-
tion products either at the point of the oxyallyl intermediate A or
the tertiary cation B resulting from 6-endo cyclization. Exclusive
formation of the exocyclic olefin isomer 4 from B is surprising,10
suggesting a possible intramolecular proton-transfer mechanism.
We have observed that cation elimination pathways predomi-
nate only at higher temperatures.7c This suggested the use of a
stronger Lewis acid in conjunction with a low temperature for
the initial electrocyclization. After a survey of several Lewis acids
and conditions, we found that the use of TiCl4 at -78 °C cleanly
produced cascade polycyclization products 5, with no apparent
admixture of elimination products 3 and 4 (eq 1). As noted in
Table 1, substrates 2b-e provided the tetra- or pentacyclic
products 5b-e in good to excellent yields. Importantly, this
efficient conVersion was accomplished with complete diastereo-
selectiVity in all cases, establishing up to six contiguous stereo-
centers in a single step. One apparent limitation is the requirement
for R-substitution on the acyclic portion of the dienone, as
evidenced by the exclusive oligomerization of unsubstituted
substrate 2a.
The high concentration of overlapping aliphatic protons made
structural elucidation by NMR methods difficult. Fortunately,
pentacycle 5d was isolated as a crystalline solid and its structure
unambiguously assigned by single-crystal X-ray diffraction
analysis. The structures of the closely related 5b,c,e were assigned
by analogy. The trans B/C ring fusion is expected based upon
precedented cationic polycyclization processes,4 and the cis C/D
ring fusion is consistent with simpler 6-endo cyclization examples.7c
The relationship between the C/D bridgehead proton and R2 on
the neighboring carbon is established by the conrotatory cycliza-
tion mandated by orbital symmetry considerations (Scheme 2).
Finally, the trans disposition of R1 relative to R2 results from
(1) Presented in preliminary form: Bender, J. A.; West, F. G. Abstracts of
Papers, 213th National Meeting of the American Chemical Society, San
Francisco, CA, April 1997; American Chemical Society: Washington, DC,
1997; ORGN 585.
(2) For recent examples of cationic cascade reactions in total syntheses,
see: (a) Corey, E. J.; Luo, G.; Lin, L. S. Angew. Chem., Int. Ed. 1998, 37,
1126. (b) Corey, E. J.; Luo, G. L.; Lin, L. S. J. Am. Chem. Soc. 1997, 119,
9927. (c) Corey, E. J.; Lin, S. J. Am. Chem. Soc. 1996, 118, 8765. (d) Corey,
E. J.; Wood, H. B., Jr. J. Am. Chem. Soc. 1996, 118, 11982. (e) Romero, A.
G.; Leiby, J. A.; Mizak, S. A. J. Org. Chem. 1996, 61, 6974. (f) Burke, S. D.;
Kort, M. E.; Strickland, S. M. S.; Organ, H. M.; Silks, L. A., III. Tetrahedron
Lett. 1994, 35, 1503. (g) Harring, S. R.; Livinghouse, T. Tetrahedron 1994,
50, 9229.
(3) For an interesting variant involving radical cation-initiated cyclizations,
see: Heinemann, C.; Demuth, M. J. Am. Chem. Soc. 1997, 119, 1129.
(4) Reviews: (a) Johnson, W. S. Tetrahedron 1991, 47 (41), xi-xxiv. (b)
Sutherland, J. K. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 341-377.
(5) (a) Bunce, R. A. Tetrahedron 1995, 51, 13103. (b) Tietze, L. F.; Beifuss,
U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131. (c) Ho, T.-L. Tandem Organic
Reactions; Wiley: New York, 1992.
(6) (a) Fish, P. V.; Johnson, W. S. Tetrahedron Lett. 1994, 35, 1469.
Johnson, W. S.; Hughes, L. R.; Carlson, J. L. J. Am. Chem. Soc. 1979, 101,
1281. (b) Johnson, W. S.; Bunes, L. A. J. Am. Chem. Soc. 1976, 98, 5597. (c)
Johnson, W. S.; Chen, Y.-Q.; Kellogg, M. S. J. Am. Chem. Soc. 1983, 105,
6653.
(7) (a) Bender, J. A.; Blize, A. E.; Browder, C. C.; Giese, S.; West, F. G.
J. Org. Chem. 1998, 63, 2430. (b) Wang, Y.; Arif, A. M.; West, F. G. J. Am.
Chem. Soc. 1999, 121, 876. (c) Browder, C. C.; West, F. G. Synlett. 1999, In
press.
(8) Recent reviews of the Nazarov reaction: (a) Habermas, K. L.; Denmark,
S. E.; Jones, T. K. Org. React. 1994, 45, 1. (b) Denmark, S. E. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Perga-
mon: Oxford, 1991; Vol. 5, pp 751-784.
(9) Brinkmeyer, R. S. Tetrahedron Lett. 1979, 207.
(10) In the BF3-mediated 6-endo cyclization of Nazarov-derived oxyallyl
cations bearing a simple 1,1-disubstituted alkene, elimination of the tertiary
cation typically leads to a mixture of exo- and endocyclic olefin products.7c
10.1021/ja991215f CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/27/1999

7444 J. Am. Chem. Soc., Vol. 121, No. 32, 1999
Table 1. Cycloisomerization of Aryltrienones 2a
Communications to the Editor
Scheme 2
substrate
R1
R2
product
yield (%)b
c
2a
2b
2c
2d
2e
H
Me
Me
-(CH2)4-
-(CH2)5-
H
H
Et
5a
5b
5c
5d
5e
-
99
73d
98
74d
a See eq 1. Standard procedure: A CH2Cl2 solution of 2 was cooled
to -78 °C and treated with 1.1 equiv of TiCl4. After 5 min, the reaction
was quenched with brine. Standard aqueous workup and chromatog-
raphy yielded 5. b Isolated yields after chromatography. In all cases, 5
was isolated as a single diastereomer. c The expected product 5a was
not observed; instead, an apparent oligomeric material was isolated.
d Products 5c and 5e were accompanied by small amounts of 7c (23%)
and 7e (15%), respectively.
exclusive protonation of the titanium enolate 6 from the more
accessible convex face of the hydrindan ring system, as we have
noted previously.7a,c
The yields of polycyclization products 5c and 5e were eroded
slightly in comparison to the others, and in each of these cases
we also isolated a second minor product. The spectral data for
these products (7c,e) were puzzling, as they clearly retained a
monosubstituted phenyl group and possessed a cyclopentenone
ring, consistent with the simple Nazarov product 3 described
above. However, the intervening trisubstituted alkene was no
longer present, and the formerly allylic methyl group now
appeared as a doublet in the upfield aliphatic region of the proton
NMR spectrum. We believe these compounds to be the products
of a minor hydride-shift pathway, which would furnish 7c and
7e as indicated. Products of this type have also been observed in
simple 6-endo cyclizations analogous to these.7c The origin of
the apparent dependence on substituents is not clear and will be
investigated in detail in future studies.
polycycles 5 in high yield and with complete diastereoselectivity.
Minor products are also isolated in two cases, apparently resulting
from a surprising transannular hydride transfer following 6-endo
cyclization. Studies focusing on the construction of other poly-
cyclic frameworks are underway and will be reported elsewhere.
Acknowledgment. We thank the National Institutes of Health for
support of this work and the University of Utah for a University Research
Fellowship (J.A.B.).
Supporting Information Available: Experimental procedures, physi-
cal data and NMR spectra for 2a-e, 3, 4, 5b-e, 6c,e and synthetic
intermediates, and X-ray data for 5d (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
The work described here presents a novel application of the
Nazarov cyclization as an initiating step for a cascade polycyc-
lization. Readily prepared aryl trienones 2 can be converted to
JA991215F