An expeditious and atom-economical synthesis of a new generation of substituted [4.6.4.6]fenestradienes

Article abstract of DOI:10.1002/anie.201107934

With finesse and strain: Highly strained derivatives of fenestranes, [4.6.4.6]fenestradienes, have been prepared using a remarkable reaction cascade featuring a 4-exo-dig cyclocarbopalladation, a Sonogashira-type coupling, a regioselective alkynylation, and an 8π/6π electrocyclization sequence. Copyright

Full text of DOI:10.1002/anie.201107934

Angewandte
Chemie
DOI: 10.1002/anie.201107934
Synthetic Methods
An Expeditious and Atom-Economical Synthesis of a New Generation
of Substituted [4.6.4.6]Fenestradienes**
Mꢀlanie Charpenay, Aꢁcha Boudhar, Gaꢂlle Blond, and Jean Suffert*
The development of step-economical reactions to access
novel structures of biological, material, therapeutic, or
theoretical interest is one of the most challenging areas of
synthetic chemistry today.[1] In most bond-forming reactions
only one or two bonds are formed at a time, but by triggering
a cascade of reactions many bonds can be formed in one
operation and thus simple starting materials can be efficiently
converted into highly sophisticated complex structures. Ach-
ieving complexity with such brevity is indeed a key character-
istic of the ideal and green synthesis.[2] Toward these ends, we
have focused our attention on developing facile routes to
unusual scaffolds to prepare structurally diverse materials of
potential theoretical and biological value.[3]
Fenestranes have been examined by different research
groups from both a theoretical and a synthetic perspective
Scheme 1. A one-pot synthesis of substituted [4.6.4.6]fenestradienes.
because of their unique structure and occurrence in nature,
and their unexplored potential as molecular scaffolds, probes,
and materials.[4] Several syntheses of fenestranes have been
reported and since the appearance of the earliest contribu-
tions in this field, access to these compounds has improved in
terms of the number of steps required and overall yield.[5]
Intramolecular arene–olefin photo-cycloadditions,[6] photo-
induced [2+2] cycloadditions,[7] transition-metal-induced cyc-
lizations,[8] and cascade cyclizations[9] are some of the power-
ful methods that have been used to generate this class of
compounds.
phine (TDMPP), and a similar method developed by
Gevorgyan and Rubina for the palladium-catalyzed head-
to-head dimerization of aryl acetylenes (Scheme 2).[12] The
high regio- and stereoselectivities of these reactions were
attributed to the strong steric influence of the ester group R2
and specific agostic interactions between the ortho proton of
the aromatic ring and the palladium center, respectively.
A new approach to the fenestranes was recently demon-
strated by our group.[10] Although, fenestradienes 4 were
obtained in excellent yields, the method required the use of
tin compounds, a sensitive nickel(0) catalyst, and hydrogen,
and the intermediate trienyne species 3 was prone to
polymerization if not handled with special care (Scheme 1).
We herein report a one-step procedure that overcomes these
problems and provides facile access to substituted fenestra-
dienes 2 directly from alkenyl bromides 1 (Scheme 1). Our
approach was inspired by a method developed by Trost et
al.[11] for the selective synthesis of head-to-tail enynes in the
presence of Pd(OAc)2 and tris(2,6-dimethoxyphenyl)phos-
Scheme 2. Head-to-tail and head-to-head synthesis of enynes accord-
ing to Trost et al.,[11] and Rubina and Gevorgyan.[12]
Our new method is based on a remarkable cascade
reaction that involves a 4-exo-dig cyclocarbopalladation,
a Sonogashira-type coupling, a regioselective alkynylation
of a disubstituted triple bond, and 8p/6p electrocyclizations.
In accordance with our previous results, an initial Sonoga-
shira-type reaction of alkenyl bromide 1 should generate 7,[13]
which based on the work of the Trost[11] and Gevorgyan[12]
groups, should be converted into 9 upon regioselective attack
of an appropriate terminal alkyne. The highly unsaturated
compound 9 could then collapse through a cascade rearrange-
ment to give fenestradiene 10 (Scheme 3).
[*] M. Charpenay, A. Boudhar, Dr. G. Blond, Dr. J. Suffert
Facultꢀ de Pharmacie, Universitꢀ de Strasbourg
UMR 7200 CNRS/UDS, 74 Route du Rhin, Strasbourg (France)
E-mail: jean.suffert@unistra.fr
Homepage: http://www-chimie.u-strasbg.fr/~lsb/
[**] We thank the CNRS and the MENRT for financial support to M.C.,
Prestwick Chemical-Illkirch France for a CIFRE grant to A.B., Prof.
Paul A. Wender and Prof. Marc L. Snapper for stimulating discus-
sions, and Dr. Lydia Brelot (Service de Cristallographie, Institut de
Chimie de Strasbourg) for X-ray crystallographic analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107934.
Angew. Chem. Int. Ed. 2012, 51, 4379 –4382
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4379

.
Angewandte
Communications
Scheme 4. Preparation of propargylic amines 1b–d.
Two side-products, the cyclooctatriene 11 and the trienyne 7,
were observed in variable amounts in several cases (Table 1),
but could be easily separated from 2 by using silica gel flash
chromatography. As well as fenestradiene 2, in seven cases
(entries 3, 4, 6, 7, 10, 13, and 14), trienynes 7c, 7d, 7 f, 7g, 7j,
7m, and 7n were also isolated and in nine cases (entries 1–4,
6, 8–10, and 13), cyclooctatrienes 11a, 11b, 11c, 11d, 11 f, 11h,
11i, 11j, and 11m were also isolated. Despite a screen of
reaction conditions, the formation of these products could not
be avoided, as they are formed in competition with the
fenestradienes, which represent the kinetic products (see
below).
To rationalize the above results, we proposed the mech-
anistic pathway depicted in Scheme 5. After an initial
4-exo-dig cyclocarbopalladation of the alkenyl bromide 1a
to produce the palladium derivative 12, a Sonogashira-type
reaction could occur to form 13. This highly unsaturated
trienyne 13 could then react with a second equivalent of the
enyne 6 to afford the hydrido palladium intermediate 14,
which could then undergo rapid reductive elimination to
Scheme 3. Retrosynthetic approach to fenestradienes 10.
We describe herein the preparation of new fenestradienes
2a–n from the alkenyl bromides 1 using a one-pot cascade
reaction of the type described above (Scheme 1). The highly
substituted members of this new family of fenestradienes are
reasonably stable at room temperature and do not oxidize and
cyclize, as was the case for the first generation of fenestra-
dienes (5), which were obtained through a reduction of
trienyne 3 using a P2-Ni catalyst[17] (Scheme 1). They repre-
sent the first examples of fenestradienes 2 possessing a con-
jugated trienyne and variable substituents that can be used for
further elaboration. Alkenyl bro-
mide 1a was chosen as a suitable
model substrate for this study and
was easily prepared from 2-bromo-
Table 1: Synthesis of substituted fenestradienes 2.[a]
cyclohexenone by
a previously
reported sequence of four steps in
good overall yield.[14] The propar-
gylic amine derivatives 1b, 1c, and
1d were prepared in two or four
steps from 1a (Scheme 4).
As summarized in Table 1, the
alkenyl bromides 1a–d, were
treated with Pd(OAc)2 (5 mol%),
PPh3 (10 mol%), CuI (10 mol%),
and diisopropylamine and after
heating (90–1008C) using a micro-
wave, afforded, in a single five-step
process, the stable and diastereo-
merically pure fenestradienes 2a–n.
The yields were strongly influenced
by the structure of both starting
materials. A variety of enynes 6
reacted with dioxolane 1a to give
[4.6.4.6]fenestradienes 2a–h in
Entry
1
R2
H
R3
R4
2
Yield
[%][b]
7
Yield 11
Yield
[%][b]
[%][b]
1
2
1a
1a CH3
CH2NHBoc
H
H
H
2a
2b
43
73
–
–
–
–
11a
11b
25
15
3[c]
1a
1a
H
H
H
H
2c
2d
39
59
7c
7d
47
25
11c
9
8
4
11d
5
6
1a CH3 (E)-CH2OH
1a CH3 (E)-CH2OTBDMS
1a CH3
1a
1d CH3
H
H
2e
2 f
68
72
40
46
72
40
80
59
–
–
–
–
10
–
36
15
22
–
–
7
–
7 f
7g
–
–
7j
–
8
30
–
–
29
–
11 f
–
11h
11i
11j
–
7[c]
8[d]
9
H
(Z)-CH2OTBDMS 2g
H
CH2CH2Ph
H
H
H
H
H
2h
2i
2j
10
11
12
13
14
1d CH3 (E)-CH2OTBDMS
moderate
to
good
yields
1c CH3
1c CH3
1b CH3
1d CH3
H
H
H
H
2k
(entries 1–8). When amines 1b–d
were subjected to the same reaction
conditions, the corresponding fen-
estradienes 2i–n, including an
allylic amine (entries 9–14) were
(Z)-CH2OTBDMS 2l
H
(Z)-CH2OTBDMS 2n
–
–
–
2m 48
7m 20
7n 48
11m
–
45
[a] Reaction Conditions: Enyne 6 (3 equiv), Pd(OAc)2 (5 mol%), CuI (10 mol%), PPh3 (10 mol%),
iPr2NH, MW, D, 60 min. [b] Yields of isolated products after chromatography. [c] Reaction time of 120
obtained in good yields (40–80%). min was used. [d] Reaction time of 30 min was used.
4380 www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 4379 –4382

Angewandte
Chemie
zoate derivative of 2d (compound 17, Figure 1).[15] This X-ray
structure exhibited a significantly distorted central quater-
nary carbon atom that is attributable to the size and
configuration of the fused rings. The associated orthogonal
Figure 1. X-ray crystal analysis of the 3,5-dinitrobenzoate derivative 17.
Thermal ellipsoids are set at 50% probability and hydrogen atoms
have been removed for clarity.
bonds angles, a and b, are 1268 and 1228, respectively, thus
making this compound one of the most distorted members of
the fenestrane family to be reported in the literature.[16] DFT
calculations, which were carried out on related com-
pounds,[10b] imply that the relative configuration of the centers
in 2a–n arises from a 6p electrocyclization that proceeds in
a direction that is dictated by the shape of the three
contiguous ABC rings of the cyclooctriene 16.
When the reaction of compound 1a was conducted at
1308C in the presence of 3 equivalents of the enyne 18,
palladium acetate, PPh3 and copper iodide, the cycloocta-
triene 11b was cleanly obtained in very good yield (98%)
without any trace of the corresponding fenestradiene
(Scheme 6). As anticipated by our previous studies, the
inferred torquoselectivity of the 8p electrocyclization reac-
tion that is required for the formation of 11b is opposite to
that required for the cascade reaction toward fenestradiene.
Undoubtedly, the cyclooctatriene 11b represents the thermo-
dynamically more stable product in this reaction. The
isolation of 11b, albeit in only 26% yield, when the
fenestradiene 2b was heated to 1308C using microwave
Scheme 5. Mechanistic proposal for the regioselective preparation of
substituted fenestradienes.
regenerate Pd0. We believe that the high regioselectivity of
the alkynylation is controlled by chelation of the metal to the
proximate allylic alcohol or amine, which is in the a position
to the triple bond; this chelation stabilizes intermediate 14.
Compound 15 cannot be isolated because it undergoes
spontaneous and torquoselective conrotatory 8p electrocyc-
lization to give cyclooctatriene 16, the relative stereochem-
istry of which would be in accordance with our previous
results.[10b] The postulated cyclooctatrienes 16, would undergo
further reaction in the form of a torquoselective disrotatory
6p electrocyclic process to generate the [4.6.4.6]fenestra-
dienes 2a–h.
Notably, the addition of one equivalent of enyne 6,
followed by microwave irradiation, then the addition of
a second equivalent of 6 (or any other structurally different
enyne) under the same reaction conditions, did not produce
any of the corresponding fenestradiene. More importantly,
when a trienyne of type 13 (obtained by the reaction of
1.2 equivalents of 6 with 1a) was subjected to the reaction
conditions with 1.2 equivalents of enyne 6, fenestradiene 2
was not obtained; the starting material was fully recovered.
The presence of at least 2.5 equivalents of enyne 6 at the
beginning of the process is therefore essential for the reaction
to proceed in the desired manner.
The [4.6.4.6]fenestradienes 2a–n were isolated in diaste-
reomerically pure form and were characterized using NMR
spectroscopy, including the analysis of NOESY experiments,
and mass spectrometry. Structural confirmation was obtained
through X-ray crystallographic analysis of the 3,5-dinitroben-
Scheme 6. Thermodynamic/kinetic control of the reaction.
Angew. Chem. Int. Ed. 2012, 51, 4379 –4382
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
4381

.
Angewandte
Communications
[4] For excellent reviews in this field see a) R. Keese, Chem. Rev.
2006, 106, 4787 – 4808; b) B. R. Venepalli, W. C. Agosta, Chem.
Rev. 1987, 87, 399 – 410; for a review on total syntheses of
laurenene, see: c) G. Mehta, A. Srikrishna, Chem. Rev. 1997, 97,
671 – 720.
irradiation for 30 minutes, supports this hypothesis. This low
yield can be explained by the existence of other transforma-
tive pathways involving the fenestradiene 2b at 1308C. This
behavior was found to be general for all other fenestradienes
subjected to similar reaction conditions. The amino-substi-
tuted fenestradienes 2i–n are more kinetically stable than the
corresponding hydroxy derivatives 2a–h as inferred by the
higher temperatures that were required for the transforma-
tion of the former into their corresponding cyclooctatrienes
11.
[5] a) W. Ten Hoeve, H. Wynberg, J. Org. Chem. 1980, 45, 2925 –
2930; b) S. Wolff, W. C. Agosta, J. Org. Chem. 1981, 46, 4821 –
4825; c) M. N. Deshpande, M. Jawdosiuk, G. Kubiak, M.
Venkatachalam, U. Weiss, J. M. Cook, J. Am. Chem. Soc. 1985,
107, 4786 – 4788; d) V. B. Rao, C. F. George, S. Wolff, W. C.
Agosta, J. Am. Chem. Soc. 1985, 107, 5733 – 5739; e) M. N.
Deshpande, S. Wehrli, M. Jawdosiuk, J. T. Guy, Jr., D. W.
Bennett, J. M. Cook, J. Org. Chem. 1986, 51, 2436 – 2444;
f) M. T. Crimmins, S. W. Mascarella, J. Am. Chem. Soc. 1986,
108, 3435 – 3438; g) M. T. Crimmins, J. A. DeLoach, J. Am.
Chem. Soc. 1986, 108, 800 – 806; h) S. Wolff, B. R. Venepalli, C. F.
George, W. C. Agosta, J. Am. Chem. Soc. 1988, 110, 6785 – 6790;
i) U. H. Brinker, T. Schrievers, L. Xu, J. Am. Chem. Soc. 1990,
112, 8609 – 8611; j) G. Mehta, K. S. Rao, J. Org. Chem. 1988, 53,
425 – 427; k) Y. Koteswar Rao, M. Nagarajan, J. Org. Chem.
1989, 54, 5678 – 5683; l) P. A. Grieco, E. B. Brandes, S. McCann,
J. D. Clark, J. Org. Chem. 1989, 54, 5849 – 5851.
[6] a) P. A. Wender, T. M. Dore, M. A deLong, Tetrahedron Lett.
1996, 37, 7687 – 7690; b) P. A. Wender, M. A. deLong, F. C.
Wireko, Acta Crystallogr. Sect. C 1997, 53, 954 – 956; c) C. S.
Penkett, J. A. Woolford, I. J. Day, M. P. Coles, J. Am. Chem. Soc.
2010, 132, 4 – 5.
[7] P. Gerber, R. Keese, Tetrahedron Lett. 1992, 33, 3987 – 3988.
[8] a) A. de Meijere, Chem. Rev. 2000, 100, 2739 – 3282; b) O. G.
Kulinkovich, A. de Meijere, Chem. Rev. 2000, 100, 2789 – 2834;
c) J. Tsuji, Transition Metal Reagents and Catalysts, Wiley,
Chichester, 2000; d) Transition Metals for Organic Synthesis
(Eds.: M. Beller, C. Bolm), Wiley-VCH, Weinheim, 1998; e) I.
Nakamura, Y. Yamamoto, Chem. Rev. 2004, 104, 2127 – 2198;
f) G. Zeni, R. C. Larock, Chem. Rev. 2004, 104, 2285 – 2309;
g) J. F. Hartwig in Comprehensive Coordination Chemistry II,
Vol. 9 (Eds.: J. A. McCleverty, T. J. Meyer), Elsevier, Oxford,
UK, 2004, pp. 369 – 398.
In conclusion, we have herein reported a new method for
the preparation of [4.6.4.6]fenestradienes that involves, in
À
a one pot reaction, an unprecedented 4-exo-dig C C bond
formation, a Sonogashira-type coupling, a regioselective
alkynylation, and a 8p/6p electrocyclization cascade reaction.
The exceptional efficiency of this process is highlighted by the
limited number of steps that were required to synthesize these
structurally complex products. These fenestranes are unusual
as suggested in part by their highly strained bond angles.
Further extension of this chemistry to the rapid and efficient
synthesis of similar compounds, for example, those bearing
five- or seven-membered rings or the use of cycloalkyl
iodides, triflates or substituted cyclohexenyl bromide as
substrates are underway. DFT calculations will also be carried
out to understand more fully the observed regio- and
torquoselectivity.
Received: November 10, 2011
Published online: March 21, 2012
Keywords: cascade reactions · electrocyclic reactions ·
.
fenestradiene · palladium · strained molecules
[9] a) D. H. Kim, S. U. Son, Y. K. Chung, S. G. Lee, Chem. Commun.
2002, 56 – 57; b) U. K. Son, K. K. H. Park, Y. K. Chung, J. Am.
Chem. Soc. 2002, 124, 6838 – 6839.
[10] a) C. Hulot, G. Blond, J. Suffert, J. Am. Chem. Soc. 2008, 130,
5046 – 5047; b) C. Hulot, S. Amiri, G. Blond, P. Schreiner, J.
Suffert, J. Am. Chem. Soc. 2009, 131, 13387 – 13398.
[11] B. M. Trost, J. L. Gunzner, T. Yasukata, Tetrahedron Lett. 2001,
42, 3775 – 3778.
[12] M. Rubina, V. Gevorgyan, J. Am. Chem. Soc. 2001, 123, 11107 –
11108.
[1] a) P. A. Wender, B. L. Miller, Nature 2009, 460, 197 – 201;
b) S. H. Bertz, T. J. Sommer, Org. Synth. Theory Appl. 1993, 2,
67 – 92; c) M. Malacria, Chem. Rev. 1996, 96, 289 – 306; d) K. H.
Ang, S. Brꢀse, A. G. Steinig, F. E. Meyer, A. Llebaria, K. Voigt,
A. de Meijere, Tetrahedron 1996, 52, 11503 – 11528; e) H.
Henniges, F. E. Meyer, U. Schick, F. Funke, P. J. Parsons, A.
de Meijere, Tetrahedron 1996, 52, 11545 – 11578; f) P. A.
Wender, J. M. Nuss, D. B. Smith, A. Suarez-Sobrino, J. Vagberg,
D. Decosta, J. Bordner, J. Org. Chem. 1997, 62, 4908 – 4909.
[2] For reviews on cascade and metal-mediated reactions, see:
a) P. A. Wender, B. L. Miller, Org. Synth. Theory Appl. 1993, 2,
27 – 66; b) L. F. Tietze, G. Brasche, K. M. Gericke, Domino
Reactions in Organic Synthesis, Wiley-VCH, Weinheim, 2006;
c) T. J. J. Mꢁller, Top. Organomet. Chem. 2006, 19, 149 – 205;
d) J.-C. Wasilke, S. J. Obrey, R. T. Baker, G. C. Bazan, Chem.
Rev. 2005, 105, 1001 – 1020; e) K. C. Nicolaou, D. J. Edmonds,
P. G. Bulger, Angew. Chem. 2006, 118, 7292 – 7344; Angew.
Chem. Int. Ed. 2006, 45, 7134 – 7186; f) M. Lautens, W. Klute, W.
Tam, Chem. Rev. 1996, 96, 49 – 92; g) H.-W. Frꢁhauf, Chem. Rev.
1997, 97, 523 – 596; h) M. A. J. Duncton, G. Pattenden, J. Chem.
Soc. Perkin Trans. 1 1999, 1235 – 1246; i) L. Yet, Chem. Rev. 2000,
100, 2963 – 3007; j) S. Garcia-Rubın, J. A. Varela, L. Castedo, C.
Saa, Org. Lett. 2009, 11, 983 – 986.
[13] M. Charpenay, A. Boudhar, A. Siby, S. Schigand, G. Blond, J.
Suffert, Adv. Synth. Catal. 2011, 353, 3151 – 3156.
[14] a) B. Salem, P. Klotz, J. Suffert, Synthesis 2004, 298 – 307; b) C.
Bour, G. Blond, B. Salem, J. Suffert, Tetrahedron 2006, 62,
10567 – 10581; c) C. Bour, J. Suffert, Org. Lett. 2005, 7, 653 – 656.
[15] CCDC 827789 (17) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
[16] V. B. Rao, C. F. George, S. Wolff, W. C. Agosta, J. Am. Chem.
Soc. 1985, 107, 5732 – 5739.
[17] C. A. Brown, V. K. Ahuja, J. Chem. Soc. Chem. Commun. 1973,
553 – 554.
[3] a) N. A. Petasis, M. A. Patane, Tetrahedron 1992, 48, 5757 – 5821;
b) G. Mehta, V. Singh, Chem. Rev. 1999, 99, 881 – 930.
4382
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 4379 –4382