Synthesis of [4.6.4.6]fenestradienes and [4.6.4.6]fenestrenes based on an 8π-6π-cyclization-oxidation cascade

Article abstract of DOI:10.1021/ja800691c

Fenestranes are regarded as a particularly challenging synthetic targets, and only few syntheses have been reported in the recent past. These rare compounds of synthetic and theoretical interest are a class of tetracyclic skeletons, defined as doubly a,a-bridged spiroalkanes. The reported results are focused on the synthesis of new and original [4.6.4.6]fenestradienes 3a-f and [4.6.4.6]fenestrenes 4a-e. Our approach implies the formation of this tetracyclic structure by a reaction cascade, based on consecutive transformations starting from the trienyne 1a-f: an initial soft hydrogenation using a P-2 Nickel catalyst at room temperature, followed by a conrotatory 8p electrocyclization and a disrotatory 6p electrocyclization and a final oxidation. Several examples of this type of new compounds are described in this Communication. Copyright

Full text of DOI:10.1021/ja800691c

Published on Web 03/19/2008
Synthesis of [4.6.4.6]Fenestradienes and [4.6.4.6]Fenestrenes
Based on an 8π-6π-Cyclization-Oxidation Cascade
Catherine Hulot, Gaëlle Blond, and Jean Suffert*
Faculté de Pharmacie, UniVersité Louis Pasteur de Strasbourg, (LC01 UMR 7175 CNRS/ULP),
74 Route du Rhin, 67401 Illkirch/Strasbourg, France
Received February 4, 2008; E-mail: jean.suffert@pharma.u-strasbg.fr
Scheme 1. Structure of [4.6.4.6]Fenestradienes 3a-f,
[4.6.4.6]Fenestrenes 4a-e (For details see Table 1.)
The fenestranes comprise a structurally and theoretically
fascinating class of organic molecules in which a quaternary
carbon is shared by four rings. Found in natural products such
as laurenene and in a wide range of targets of theoretical interest,
these polycyclic scaffolds have attracted much synthetic interest
over the past 35 years.1 These studies have focused mainly on
the energetic consequences of forcing the tetravalent carbon
common to the tetracyclic network toward a strained planar
geometry. Several impressive syntheses of fenestranes with
improved step economy and efficiency have been reported.2
Notwithstanding these advancements, the introduction of
methods that access novel fenestranes is central to exploiting
these polycycles as ligands for catalysis, materials, and drug
discovery opportunities. An especially important attribute of
smaller ring fenestranes is that they provide a scaffold for the
display of pharmaceutically relevant functionalities in a unique,
spatially and conformationally defined fashion. Toward this end,
we describe herein a step-economical synthesis of a new family
of substituted fenestradienes 3a-f and fenestrenes 4a-e. These
novel systems 4a-e are obtained directly, in a one-pot operation,
through a remarkable cascade starting with the Ni-catalyzed
semihydrogenation of trienynes 1a-f readily prepared from diol
2 in six steps and in good overall yield (Scheme 1).3
Scheme 2. Proposed Mechanism for the Formation of 3a
Several classical catalysts (Lindlar, Zn(0)/CuBr, NiCl2/
NaBH4, Ni(OAc)2 ·4H2O-BER),4 well-known for their ability
to partially hydrogenate a triple bond, were selected and tested
on the model substrate 1a. Unexpectedly, in all cases, only traces
of compound 3a were isolated. Gratifyingly, when P-2 Ni5
(Ni(OAc)2 ·4(H2O), 1 equiv; NaBH4, 1 equiv; EDA, 3.5 equiv;
EtOH, H2 1 atm, 16 h, room temp) was used, compound 1a
was almost completely consumed and a new cyclized product
3a was formed in 88% yield. Scheme 2 illustrates the proposed
mechanism for the remarkable conversion of 1a to the observed
[4.6.4.6]fenestradiene 3a. Partial reduction of the alkyne
functionality in 1a generates tetraene 5a, which can undergo
an 8π-conrotatory electrocyclization to form cyclooctatriene 6a.
This intermediate then undergoes a 6π-disrotatory electrocyclic
cyclization to provide 3a as the sole product isolated in this
reaction sequence. No traces of intermediates 5a or 6a were
detected during the process. Of particular interest was the nature
of the cyclized product. The reaction was stereoselective, and
only one diastereomer of the [4.6.4.6]fenestradiene was obtained
with the relative configuration shown in Scheme 2 as determined
by NOESY experiments.
Scheme 3. Spontaneous Cyclization of 3a to 4a in the Presence of
Air/O2 or m-CPBA
4a can be explained by a spontaneous oxidation of the highly
reactive [4.6.4.6]fenestradiene 3a with molecular oxygen. To
confirm the oxidation sequence, 3a was submitted to 1 equiv
of m-CPBA in CH2Cl2 at 0 °C; compound 4a was isolated in
pure form in 63% yield. These experiments suggest that epoxide
7 is generated as a nonisolable intermediate, which leads to 4a
by an SN′ attack of the dimethylcarbinol on the double bond of
When compound 3a was stored at -20 °C under air for
several hours, it reacted slowly with O2 to give a new product
that possesses all characteristic data corresponding to the
[4.6.4.6]fenestrene 4a (Scheme 3). Exemplary of the novel
chemistry of strained fenestranes, the transformation of 3a into
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10.1021/ja800691c CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
and complexity. The extension of this reaction sequence to other
systems has also been investigated. In all cases the fenestradienes
3a-f were obtained from 1a-f in very good yields (63–93%)
in view of the complexity of the reaction sequence. Only 3a
was stable enough to be purified by chromatography on silica
gel treated with Et3N. Due to the high purities of the crude
reaction products and their sensitivity to silica gel, compounds
3b-d were not purified by chromatography but directly engaged
into the m-CPBA oxidation step producing 4b-d in good yields
(62–68%). Compound 4e was obtained in 35% yield in two
steps.
Figure 1. X-ray crystal structure of the 3,5-dinitrobenzoate derivative 8.
The majority of hydrogens are omitted for clarity.
Table 1. Synthesis of [4.6.4.6]Fenestradienes 3a-f and
[4.6.4.6]Fenestrenes 4a-e
In conclusion, we have reported a means of preparing a new
family of [4.6.4.6]fenestradienes, and [4.6.4.6]fenestrenes through
a unique 8πf6πf[O2-oxi] cascade electrocyclization sequence.
The high yields and the limited number of steps of the reaction
sequence render this process very attractive for the synthesis
of new fenestranes. Further extensions of this chemistry to the
rapid and efficient syntheses of compounds of significant
structural complexity are underway in our laboratory.
Acknowledgment. Dedicated to Prof. Paul A. Wender
(Stanford University) on the occasion of his 60th birthday. We
thank the CNRS for financial support, the MNERT (C.H.) for
fellowships, and Prof. Marc Snapper (Boston College) for
helpful discussions.
Supporting Information Available: Full experimental details
are available. This material is available free of charge via the
Internet at http://pubs.acs.org.
References
(1) For reviews in this field see: Keese, R. Chem. ReV. 2006, 106, 4787. (b)
Kuck, D. Chem. ReV. 2006, 106, 4885. (c) Venepalli, B. R.; Agosta, W. C.
Chem. ReV. 1987, 87, 399. (d) For review on total syntheses of laurenene
see Mehta, G.; Srikrishna, A. Chem. ReV. 1997, 97, 671.
(2) (a) Hoeve, W. T.; Wynberg, H. J. Org. Chem. 1980, 45, 2925. (b) Wolff,
S.; Agosta, W. C. J. Org. Chem. 1981, 46, 4821. (c) Deshpande, M. N.;
Jawdosiuk, M.; Kubiak, G.; Venkatachalam, M.; Weiss, U.; Cook, J. M.
J. Am. Chem. Soc. 1985, 107, 4786. (d) Rao, V. B.; George, C. F.; Wolff,
S.; Agosta, W. C. J. Am. Chem. Soc. 1985, 107, 5733. (e) Deshpande, M. N.;
Wehrli, S.; Jawdosiuk, M.; Guy, J. T.; Bennett, D. W., Jr.; Cook, J. M. J.
Org. Chem. 1986, 51, 2437. (f) Crimmins, M. T.; Mascarella, S. W. J. Am.
Chem. Soc. 1986, 108, 3435. (g) Crimmins, M. T.; DeLoach, J. A. J. Am.
Chem. Soc. 1986, 108, 800. (h) Wolff, S.; Venepalli, B. R.; George, C. F.;
Agosta, W. C. J. Am. Chem. Soc. 1988, 110, 6785. (i) Brinker, U. H.;
Schrievers, T.; Xu, L. J. Am. Chem. Soc. 1990, 112, 8609. (j) Mehta, G.;
Rao, K. S. J. Org. Chem. 1988, 53, 425. (k) Koteswar Rao, Y.; Nagarajan,
Y. M. J. Org. Chem. 1989, 54, 5678. (l) Grieco, P. A.; Brandes, E. B.;
McCann, S.; Clark, J. D. J. Org. Chem. 1989, 54, 5849. (m) Wender, P. A.;
von Geldern, T. W.; Levine, B. H. J. Am. Chem. Soc. 1988, 110, 4858. (n)
Wender, P. A.; deLong, M. A.; Wireko, F. C. Acta Crystallogr. 1997, C53,
954. (o) Gerber, R.; Keese, R. Tetrahedron Lett. 1992, 33, 3987. (p) de
Meijere, A. Chem. ReV. 2000, 100, 2739. (q) Kulinkovich, O. G.; de Meijere,
A. Chem. ReV. 2000, 100, 2789. (r) Yet, L. Chem. ReV. 2000, 100, 2963. (s)
Tsuji, J. Transition Metal Reagents and Catalysts; Wiley & Sons: Sussex,
U.K., 2000. (t) Beller, M.; Bolm, C., Eds. Transition Metals for Organic
Synthesis; Wiley-VCH: Weinheim, Germany, 1998. (u) Nakamura, I.;
Yamamoto, Y. Chem. ReV. 2004, 104, 2127. (v) Zeni, G.; Larock, R. C.
Chem. ReV. 2004, 104, 2285. (w) Hartwig, J. F. In ComprehensiVe
Coordination Chemistry II; McCleverty, J. A., Meyer, T. J. Eds.; Elsevier:
Oxford, U.K., 2004; Vol. 9, p 369.
a P-2 Ni, 1 equiv, EDA, EtOH, H2, 1 atm. b m-CPBA, NaHCO3,
CH2Cl2, 0 °C, 20 min-1 h. c Yield determined by 1H-NMR on the
crude. d Yield of isolated product after chromatography. e Neat, under
air/O2. f Not determined. g Yield for the two steps (a, b) from 1e. h The
product 3b was contaminated by 30% of inseparable 1b.
the epoxide 7 as shown in Scheme 3. The stereochemistry
observed for this transformation is completely controlled by the
shape of the three contiguous CBD ring and the intramolecular
attack of the hydroxy group onto the double bond occurred from
thelesshinderedfaceofthemolecule.Theresulting[4.6.4.6]fenes-
trene 4a is stable and can be purified by classical silica gel
chromatography. The structure of 4a was elucidated by extensive
1H and 13C NMR analysis and high resolution mass spectrum
analysis (MS-MS). Structural confirmation was obtained
through X-ray crystallographic analysis of the 3,5-dinitroben-
zoate derivative 8 (Figure 1). This X-ray structure shows
significant distortion of the central quaternary carbon atom that
is attributable to the size and configuration of the fused rings.
The two important orthogonal bond angles R and ꢀ are
respectively widened to 118° and 124°.
(3) (a) Suffert, J.; Salem, B.; Klotz, P. J. Am. Chem. Soc. 2001, 123, 12107. (b)
See Supporting Information.
(4) (a) Hayashi, R.; Fernandez, S.; Okamura, W. H. Org. Lett. 2002, 4, 851. (b)
Mulzer, J.; Berger, M. J. Org. Chem. 2004, 69, 891. (c) Yoshida, M.;
Sugimoto, K.; Ihara, M. Org. Lett. 2004, 6, 1979. (d) Brown, C. A. J. Org.
Chem. 1970, 35, 1900. (e) Choi, J.; Yoon, M. Tetrahedron Lett. 1996, 37,
1057.
(5) (a) Brown, C. A.; Ahuja, V. K. J. Chem. Soc., Chem. Comm. 1973, 553. (b)
Brown, C. A.; Ahuja, V. K. J. Org. Chem. 1973, 38, 2226.
(6) (a) Kuck, D. In AdVances in Theoretically Interesting Molecules; Thummel,
R. P., Ed.; JAI Press: Greenwich, CT, 1998; Vol. 4, p 81. (b) Brunvoll, J.;
Guidetti-Grept, R.; Hargittai, I.; Keese, R. HelV. Chim. Acta 1993, 76, 2838.
(c) Thommen, M.; Keese, R.; Förtsch, M. Acta Crystallogr. 1996, C52, 2051.
(d) Wang, J.; Thommen, M.; Keese, R. Acta Crystallogr. 1996, C52, 2311.
(e) Denmark, S. E.; Montgomery, J. I. Angew. Chem., Int. Ed. 2005, 4, 3732.
These high values can be compared to those of the corre-
sponding angles, determined by X-ray analysis in several
fenestranes, that are widened between 116° and 134.9° for the
most representative ones.6 To the best of our knowledge, this
sequence represents the first reported 8πf6πf[O2-oxi] cy-
clization cascade to highly substituted fenestrenes of this type
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