Polyene cyclization promoted by the cross-conjugated α-carbalkoxy enone system. Observation on a putative 1,5-hydride/1,3-alkyl shift under lewis acid catalysis

Article abstract of DOI:10.1021/ol702631q

Polyene cyclization of compounds 3 and 4 under catalysis with AlCl ₃ and/or SnCl₄ gave rise to complex bicyclic products 8 and 9, structures of which were highly unexpected, and X-ray analyses were invoked for unambiguously structura

Full text of DOI:10.1021/ol702631q

ORGANIC
LETTERS
2008
Vol. 10, No. 1
121-123
Polyene Cyclization Promoted by the
Cross-Conjugated -Carbalkoxy Enone
r
System. Observation on a Putative
1,5-Hydride/1,3-Alkyl Shift under Lewis
Acid Catalysis
Ho-Hsuan Chou,† Huang-Min Wu,† Jen-Dar Wu,† Tai Wei Ly,‡ Ning-Wei Jan,†
Kak-Shan Shia,*,§ and Hsing-Jang Liu*,†
Department of Chemistry, National Tsing Hua UniVersity, Hsinchu, Taiwan 30013,
R.O.C., Actimis Pharmaceuticals, Inc., 10835 Road to the Cure, Suite 200,
San Diego, California 92121, and DiVision of Biotechnology and Pharmaceutical
Research, National Health Research Institutes, Miaoli County 350, Taiwan, R.O.C.
ksshia@nhri.org.tw
Received October 30, 2007
ABSTRACT
Polyene cyclization of compounds 3 and 4 under catalysis with AlCl3 and/or SnCl4 gave rise to complex bicyclic products 8 and 9, structures
of which were highly unexpected, and X-ray analyses were invoked for unambiguously structural identification. Mechanistically, a tandem
σ
-bond rearrangement process, including an unusual through-space 1,5-hydride or 1,3-alkyl shift as a key operation, is proposed.
Nature’s inexhaustible ability to construct molecules of ex-
tremely high degrees of intricacy and structural complexity
has been a constant fascination for synthetic organic chemists.
This unique facility for bioorganic synthesis, oftentimes from
the simplest building blocks, is equaled by no other. Deeply
rooted in this efficient synthesis machinery is the seemingly
simple paradigm of cation-promoted cyclization and bond
migration processes.1-7 This is highly evident in the well-
accepted biosynthetic process of a plethora of secondary
metabolites.
In our quest for the establishment of efficient protocols
for accessing decalin and other polycyclic systems by
mirroring nature-driven cyclization processes, we discovered
that â-keto esters 1 and 2 could undergo effective Lewis
acid-catalyzed intramolecular cyclization, giving rise to
decalin systems in high yields.8-11 Further investigation into
this interesting process led to the generation of positional
analogue 3 and its homologue 4, each possessing the
terminal olefin at the R′-position. These compounds were
individually subjected to the optimized cyclization conditions
as delineated in the preceding work.8
† National Tsing Hua University.
‡ Actimis Pharmaceuticals, Inc.
§ National Health Research Institutes.
(1) Bartlett, P. A. in Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: Orlando, 1984; Vol. 3, pp 341-409.
(2) Johnson, W. S. Bioorg. Chem. 1976, 5, 51.
(3) Vandewalle, M.; Clerq, P. D. Tetrahedron 1985, 41, 1767.
(4) vanTamelen, E. E. Acc. Chem. Res. 1975, 8, 152.
(5) Goldsmith, D. J.; Philips, F. J. Am. Chem. Soc. 1969, 91, 5862.
(6) van der Gen, A.; Weidhaup, K.; Swoboda, J. J.; Dunathan, H.;
Johnson, W. S. J. Am. Chem. Soc. 1973, 95, 2656.
Surprisingly, the anticipated polyene cyclization product
of the individual reactions was not formed; instead, a
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molecule bearing a peculiar skeleton was obtained, the
structure of which could only be ascertained unambiguously
by X-ray crystallographic analysis. These structures as well
as our proposed mechanistic rationalization for their forma-
tion are described herein.
Starting from 4,4-dimethylcyclohexanone, compound 3
was readily prepared via four key operations as illustrated
in Scheme 1. Dimethylhydrazone 5, formed in good yield
Compound 4 was prepared following a similar synthetic
sequence as described for compound 3 with the exception
that allyl bromide was replaced with 1-butenyl bromide in
the alkylation step. As in the case of compound 3, when
compound 4 was treated with AlCl3 (2 equiv) or SnCl4 (2
equiv) for 2 h at room temperature, the polyene cyclization
process occurred smoothly, affording product 9 in ca. 75%
yield, which was identified spectroscopically and further
explicated by X-ray crystallographic studies as follows.
Our proposed mechanism for the formation of 9 (Scheme
3) proceeds from the cationic intermediate upon cyclization
Scheme 1
Scheme 3
(85%) under standard conditions, was deprotonated with
n-butyl lithium and alkylated with allyl bromide to give
R-allylic cyclohexanone 6 in 81% yield. This was followed
by carbomethoxylation (6 f 7) and DDQ oxidation to
provide compound 3 in 63% over two steps. Enone 3 thus
obtained was treated with aluminum trichloride (2 equiv)
for 48 h at room temperature, giving rise to the cyclic
compound 8 exclusively in 70% yield, the structure of which
was determined unambiguously by an X-ray analysis. A
plausible mechanistic rationale is proposed in Scheme 2.
of the terminal olefin to the activated enone system. Again,
a cascade of the σ-bond shift process involving 1,5-hydride,
1,2-methyl, and 1,2-methylene shifts followed by the de-
composition of the metaloxy complex is proposed. The
relative configuration of 9 was unambiguously confirmed
by the X-ray analysis of its corresponding crystalline diol
10,13 readily provided by reduction of 9 with lithium
aluminum hydride in excellent yield (92%).
Although the mechanistic rationales for the formation of
these structurally novel products 8 and 9 seem reasonable
(vide supra), in terms of reactions performed under standard
chemical environment, the chemistry described above is
unique in that one sole product is produced in rather high
yield. Typically, chemical processes involving numerous
bond shifts yield a multitude of products per reaction and
are individually low yielding. The mechanistic rationale
invoked for the generation of the resulting products may be
atypical for the conditions applied but not entirely unprec-
edented as similar mechanistic pathways have been reported
for some electron-deficient olefinic/acetylenic14 and structur-
ally highly constrained systems.15 However, strictly speaking,
the through-space 1,5-hydride shift proposed for the titled
system is somewhat more exotic in that those described in
above literatures are limited to substrates containing a
C(sp3)-H bond adjacent to a heteroatom (N, O) or an acti-
vated tertiary benzylic C(sp3)-H bond as a hydride donor16
so that the ensuing carbocation can be stabilized by electron
Scheme 2
Following the formation of an aluminoxy complex, a cascade
of σ-bond migrations comprising 1,2-hydride, 1,3-methyl,
and 1,2-methine shifts is envisioned, culminating in the
formation of the bicycle[3.3.1]nonane 8.12
(7) Majetich, G.; Khetani, V. Tetrahedron Lett. 1990, 31, 2243.
(8) Liu, H. J.; Sun, D.; Shia, K. S. Tetrahedron Lett. 1996, 37, 8073.
(9) Liu, H. J.; Sun, D. Tetrahedron Lett. 1997, 38, 6159.
(10) Liu, H. J.; Sun, D.; Shia, K. S. J. Chin. Chem. Soc. 1999, 46, 453.
(11) Liu, H. J.; Sun, D.; Roa-Gutierrez, F.; Shia, K. S. Lett. Org. Chem.
2005, 2, 364.
(12) CCDC 261323 (8) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via www.ccdc.
cam.ac.uk/conts/retrieving.html or deposite@ccdc.cam.ac.uk.
(13) CCDC 261324 (10) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via www.ccdc.
cam.ac.uk/conts/retrieving.html or deposite@ccdc.cam.ac.uk.
122
Org. Lett., Vol. 10, No. 1, 2008

delocalization; this carbocation-stabilized capacity may serve,
in part, as the essential driving force to facilitate the 1,5-
hydride shift in these systems. Nevertheless, the mechanistic
pathways proposed in Schemes 2 and 3, though occurring
without intermediacy of the extra stabilizing force, are
considered quite normal in the living system and commonly
adopted in elucidating the biosynthetic courses of the
secondary metabolites, for example, trichodiene and illudins
M and S, etc.17
of R,â-unsaturated cross-conjugated cyclohexenone systems
as achieved under a purely chemical environment. The results
indicated that the multiple σ-bond migration process, an
enzymatic process prevalent in nature, might potentially take
place under typical chemical reaction conditions and thus
should not be entirely excluded nor considered aberrant in
the elucidation of product formation.
Acknowledgment. We are grateful to the National
Science Council of the Republic of China and National
Health Research Institutes for financial support.
In conclusion, we report here the observation of a highly
ordered, organized, and deep-seated rearrangement process
(14) (a) Pastine, S. J.; McQuaid, K. M.; Sames, D. J. Am. Chem. Soc.
2005, 127, 12180. (b) Pastine, S.; Sames, D. Org. Lett. 2005, 7, 5429. (c)
Nijhuis, W. H. N.; Verboom, W.; Reinhoudt, D. N. J. Am. Chem. Soc.
1987, 109, 3136. (d) Noguchi, M.; Yamada, H.; Sunagawa, T. J. Chem.
Soc., Perkin Trans. 1 1998, 3227. (e) D´ıaz, D.; Mart´ın, V. S. Org. Lett.
2000, 2, 355. (f) D´ıaz, D.; Mart´ın V. S. Tetrahedron Lett. 2000, 41, 743.
(15) (a) Rademacher, P.; Mohr, P. C. Org. Biomol. Chem. 2007, 5, 2698.
(b) Kawai, H.; Takeda, T.; Fujiwara, K.; Suzuki, T. J. Am. Chem. Soc.
2005, 127, 12172. (c) Wo¨lfling, J.; Frank, EÄ .; Schneider, G.; Tietze, L. F.
Eur. J. Org. Chem. 2004, 90. (d) Krohn, K.; Flo¨rke, U.; Ho¨fker, U.;
Tra¨ubel, M. Eur. J. Org. Chem. 1999, 3495. (e) Heathcock, C. H.; Hansen,
M. M.; Ruggeri, R. B.; Kath, J. C. J. Org. Chem. 1992, 57, 2544.
(16) For a recent review, see: Tobisu, M.; Chatani, N. Angew. Chem.,
Int. Ed. 2006, 45, 1683.
Supporting Information Available: Detailed experi-
mental procedures and characterization data for all new
compounds described in this paper are provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL702631Q
(17) Mann, J. Secondary Metabolism, 2nd ed.; Atkins, P. W., Holker, J.
S. E., Holliday, A. K., Ed.; Clarendon Press: Oxford, England, 1987; pp
95-172.
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