An atom-economical and stereoselective domino synthesis of functionalised dienes

Article abstract of DOI:10.1002/chem.201300776

Open sesame: A direct synthesis of functionalised and stereodefined dienes, relying on a domino allylic alkylation/electrocyclic ring-opening sequence, is reported. This method allows concise access to doubly vinylogous esters. A further systematic study

Full text of DOI:10.1002/chem.201300776

COMMUNICATION
DOI: 10.1002/chem.201300776
An Atom-Economical and Stereoselective Domino Synthesis
of Functionalised Dienes
Caroline Souris, Marco Luparia, Frꢀdꢀric Frꢀbault, Davide Audisio, Christophe Farꢁs,
Richard Goddard, and Nuno Maulide*[a]
The thermal 4p-electrocyclic ring opening of cyclobutenes,
a symmetry-allowed, conrotatory transformation leading to
butadienes, is a well-established subset of pericyclic reac-
tions.[1,2] This process generates either (E,Z)- or (Z,E)-diene
We have recently studied the allylic alkylation of lactone
1[4] with stabilised (or “soft”) carbon-centred nucleophiles
(Scheme 2a).[5] Cognisant of the considerable body of work
concerning the use of phenols as nucleophilic entities for al-
lylic alkylation,[6,7] we investigated such species as a means
products from
a cis-3,4-disubstituted cyclobutene, and
(E,E)- or (Z,Z)-diene products from a trans-3,4-disubstitut-
ed cyclobutene (Scheme 1).
Scheme 1. Conrotatory electrocyclic ring opening of substituted cis- and
trans-cyclobutenes.
Scheme 2. Prior work and unexpected formation of dienes 2.
to gain access to interesting heterofunctionalised cis-cyclo-
The inward or outward rotation of the C3 and C4 sub-
stituents of the cyclobutene starting materials, crucial in de-
termining the geometry of the diene products, can be pre-
dicted by a set of torquoselectivity rules deduced by
Houk.[3] Sterically demanding and electron-donating groups
tend to rotate outward, whereas smaller and electron-with-
drawing substituents prefer inward rotation. Therefore ster-
eochemical information can be translated faithfully from
3,4-disubstituted cyclobutenes to the corresponding diene
products. Nevertheless, the general preference of dienyl sys-
tems for an all-E geometrical configuration means that iso-
merisation of the initially formed products often plagues
such diene syntheses, particularly in cases in which substitu-
ents A and B are an electronically antagonistic pair (see
Scheme 1).
butene products. To our surprise, reaction of the sodium salt
of phenols with lactone 1 under catalysis by [PdACTHNUTRGNE(UNG PPh3)4] led
cleanly to the (Z,E)-dienes 2, formed as single reaction
products (Scheme 2b). The direct formation of stereode-
fined, functionalised dienes under mild conditions and with
complete atom economy warranted further investigation.
We report herein a methodology for direct synthesis of geo-
metrically defined dienes bearing challenging substitution
patterns, and their use in atom economical domino sequen-
ces that increase structural complexity in a synthetically
useful manner.
At first, we evaluated the scope of this transformation
with respect to both the nucleophile and electrophile. As de-
picted in Scheme 3, a variety of phenols can be employed in
this transformation, leading to the corresponding (Z,E)-5-ar-
yloxydienyl carboxylic acids 2 in good to excellent yields.
Noteworthy is the use of unusual nucleophiles such as pen-
tafluorophenol, for which a much diminished nucleophilicity
can be anticipated due to strong electronic deactivation.[8]
Additionally, alkyl- or aryl-substituted lactones such as 1b–
d, readily available by photoisomerisation of the corre-
sponding 3-substituted-2-pyrones,[9] also undergo a domino
allylic alkylation/4p electrocyclic ring opening reaction.
[a] C. Souris, Dr. M. Luparia, Dr. F. Frꢀbault, Dr. D. Audisio,
Dr. C. Farꢁs, Dr. R. Goddard, Dr. N. Maulide
Max-Planck-Institut fꢂr Kohlenforschung, Kaiser-Wilhelm-Platz 1
45470 Mꢂlheim an der Ruhr (Germany)
Fax : (+49)2083062999
E-mail: maulide@mpi-muelheim.mpg.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300776.
Chem. Eur. J. 2013, 00, 0 – 0
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Scheme 5. Domino allylic alkylation/4p electrocyclic ring opening of lac-
tone 1a.
ed intermediate cyclobutene, thereby triggering its sponta-
neous ring opening (Scheme 5).[15,16]
At this juncture, the direct formation of functionalised
diene products decorated with synthetically useful function-
ality, through an atom economical allylic alkylation/4p elec-
trocyclic ring opening sequence, appeared to hold potential
as a general concept. This piqued our interest towards ex-
ploring the ring opening of cyclobutene adducts in a broader
sense.
In the event, thermolysis of readily available cis- and
trans-cyclobutenes 4[5c] led to the corresponding geometrical-
ly defined dienes (Z,E)- or (E,E)-5 (Scheme 6).[10]
Eager to obtain more information about the factors influ-
encing ring-opening and realising that this system provides a
unique opportunity to systematically study stereochemical
and electronic parameters, we prepared cis/trans pairs of
Scheme 3. Scope of phenol nucleophiles and lactone electrophiles in the
domino diene synthesis. Yields refer to analytically pure, isolated com-
pounds.
Scheme 4. Selected examples of X-ray structures of dienoic (Z,E)-5-ary-
loxydienyl carboxylic acids 2a and 2i.
Single-crystal X-ray analysis of (Z,E)-5-aryloxydienyl car-
boxylic acids derivatives 2 allowed unambiguous structural
assignments of all products (Scheme 4).[10]
It is important to note that all diene products were ob-
tained in geometrically pure (Z,E)-configuration (>95:5)
after a simple acid–base extractive work-up, highlighting the
mildness of the reaction conditions and the simplicity of this
procedure.
This strictly palladium-catalysed transformation (as no
product is observed when the catalyst is absent)[11] delivers
doubly vinylogous esters for which known synthetic proce-
dures are typically cumbersome, multistep, low-yielding se-
quences[12–14] and achieves a formal aryloxy anion addition
to pyrone with extrusion of a hypothetical carboxylate leav-
ing group.[11] Importantly, the thermodynamically more
stable (E,E)-configured aryloxydienes can be obtained by a
simple iodine-catalysed isomerisation.[11] It appears reasona-
ble to infer that the simultaneous presence of the electron-
releasing aryloxy moiety and the carboxylic acid residue
impart “push–pull” character to the putative cis-disubstitut-
Scheme 6. Thermal ring opening of cis- and trans-disubstituted cyclobu-
tenes 4, 6 and 8 at 908C in CDCl2CDCl2, as monitored by H NMR spec-
troscopy.
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Domino Synthesis of Functionalised Dienes
COMMUNICATION
methyl esters and amides 6 and 8 from acids 4 and investi-
gated their thermal electrocyclic transformation by means of
1H NMR spectroscopy. The results are presented graphically
in Scheme 6.
As a general tendency, the cis-cyclobutenes underwent
electrocyclic ring opening faster than their trans-analogues,
as expected based on strain release considerations.[17] The
trends observed within each sub-group of either cis- or
trans- cyclobutene derivatives, on the other hand, are more
unusual. In the cis series, the free carboxylic acid cis-4 un-
derwent ring opening at the fastest rate (t1/2 =16.3 min)
whereas the corresponding methyl ester cis-6 and N-benzy-
lamide cis-8 were considerably slower (t1/2 of 40.6 and
90.0 min, respectively). Surprisingly, that trend was reversed
in the trans-cyclobutene series. In this case, the free carbox-
ylic acid trans-4 is the compound with the slowest ring open-
ing (t1/2 =198.0 min) whereas the methyl ester trans-6 and N-
benzylamide trans-8 show almost identical behaviour (t1/2 of
105.0 and 113.6 min, respectively). To the best of our knowl-
edge, the observation of such effects is unprecedented in
prior studies of cyclobutene ring opening. We believe that
both the notorious deceleration of the ring opening of trans-
4 and the acceleration of its cis-4 counterpart are connected
to subtle changes in the hydrogen-bonding modes of its car-
boxylic acid moiety.[18]
Scheme 7. Domino electrocyclic ring opening/Diels–Alder cycloaddition.
Yields are for isolated, analytically pure compounds. d.r. refers to the
centre marked with *. d.r.=diastereomeric ratio
Having ascertained the stereoselectivity and the total ab-
sence of byproducts of these transformations, we sought to
exploit them in the context of more complex sequences. In
particular, the prospect of coupling the electrocyclic ring
opening with further pericyclic reactions was appealing. To
bring this idea to practice, trans-cyclobutene methyl ester 6
was heated in the presence of N-phenylmaleimide. The de-
sired exo-cycloadduct 10 was isolated as a single diaster-
eoisomer in 76% yield (Scheme 7a).[19]
We further designed trans-cyclobutenes 11a,b, containing
a tethered olefin, as substrates for sequential electrocyclic
ring opening-intramolecular Diels–Alder reaction (Sche-
me 7b). At the onset, we were uncertain about the stereo-
chemical outcome of this domino cycloaddition sequence,
since literature precedents demonstrate that very subtle
steric and electronic factors control this issue in related sys-
tems.[20] As shown, both substrates led to the desired bicyclic
compounds in good yields,[10] with remarkable stereoselectiv-
ity being observed for the transformation of trans-cyclobu-
tene 11b into decalin cycloadduct 13b.[13] It is instructive to
notice how the stereochemical information initially inscribed
in two stereocentres of the cyclobutene ring is ultimately
translated in multiple contiguous stereocentres in cycload-
ducts 10 and 13.
As shown, thermolysis of dienes 16 in toluene led to the
stereoselective formation of the desired tricyclic compounds
17.[10] The structures of 13b and 17a were confirmed by X-
ray crystallography (Scheme 9). Both electron-withdrawing
and electron-releasing groups were well tolerated and vari-
ous substitution patterns in the aromatic ring were possible
in this transformation. The remarkable increases of molecu-
lar complexity depicted in Schemes 7 and 8, coupled with
the near complete atom economy of the synthetic sequences
portrayed render these transformations appealing. In partic-
ular, the structure of cycloadducts 17a–e is closely related to
the Euglobal natural product family as well as Isocymobar-
batol (Scheme 8).[22]
In summary, we have developed an atom economical
domino synthesis of functionalised and stereodefined dienes.
This method hinges on an allylic alkylation/4p electrocyclic
ring-opening sequence and allows direct access to doubly vi-
nylogous esters bearing challenging substitution patterns. A
systematic investigation of electrocyclic ring-opening rates
along a series of substrates revealed interesting trends and
an unprecedented “anomalous” carboxylic acid effect. This,
in turn, enabled the design of reaction sequences that dra-
matically increase structural complexity from the simplest of
reagents.
In spite of the numerous literature reports detailing
scarce reactivity of push–pull dienes in the context of [4+2]-
cycloadditions,[21] aryloxydienes 14 also proved to be compe-
tent partners for Diels–Alder cycloaddition as depicted in
Scheme 8a. This prompted us to investigate the use of o-al-
lylated-phenols as nucleophiles in the domino diene synthe-
sis, hoping that the resulting pendant olefin could engage in
a subsequent, thermal [4+2]-cycloaddition (Scheme 8b).
Acknowledgements
We are grateful to the Max-Planck Society and the Max-Planck-Institut
fꢂr Kohlenforschung for generous funding of our research programs. This
work has been supported by the Deutsche Forschungsgemeinschaft
Chem. Eur. J. 2013, 00, 0 – 0
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N. Maulide et al.
[1] a) R. B. Woodward, R. Hoff-
mann, Angew. Chem. 1969, 81,
797–869; Angew. Chem. Int. Ed.
Engl. 1969, 8, 781–839; b) E. N.
Marwell, Thermal Electrocyclic
Reactions, Academic press, New
York, 1980, Chapter 5, pp. 124–
213; c) T. Durst, L. Breau in
Comprehensive Organic Synthesis,
Vol. 5 (Eds.: B. M. Trost, I. Flem-
ing, L. A. Paquette), Pergamon,
Oxford,
1991,
pp. 665–697;
d) J. C. Namyslo, D. E. Kauf-
mann, Chem. Rev. 2003, 103,
1485–1537. For an interesting
review on biosynthetic and biomi-
metic electrocyclisations, see:
e) C. M. Beaudry, J. P. Malerich,
D. Trauner, Chem. Rev. 2005, 105,
4757–4778.
[2] For examples of eletrocyclic ring
opening of cyclobutenes in the
context of natural products syn-
thesis, see: a) B. M. Trost, P. G.
McDougal, J. Org. Chem. 1984,
49, 458–468; b) K. C. Nicolaou,
J. A. Vega, G. Vassilikogiannakis,
Angew. Chem. 2001, 113, 4573–
4577; Angew. Chem. Int. Ed.
2001, 40, 4441–4445; c) S. L.
Schreiber, C. Santini, J. Am.
Chem. Soc. 1984, 106, 4038–4039.
[3] a) W. Kirmse, N. G. Rondan,
K. N. Houk, J. Am. Chem. Soc.
1984, 106, 7989–7991; b) N. G.
Rondan, K. N. Houk, J. Am.
Chem. Soc. 1985, 107, 2099–2111;
c) K. Rudolf, D. C. Spellmeyer,
K. N. Houk, J. Org. Chem. 1987,
52, 3708–3710; d) S. Niwayama,
K. N. Houk, Tetrahedron Lett.
1992, 33, 883–886; e) S. Niwaya-
Scheme 8. Diels–Alder reactions of push–pull aryloxy-dienes. The d.r. values were determined by NMR analy-
sis of the crude mixture and refer to the centre marked with *. Isolated yields refer to intramolecular cycload-
dition reaction. Numbers in brackets refer to yields based on recovered starting material. d.r.=diastereomeric
ratio
ma, J. Org. Chem. 1996, 61, 640–646; f) W. R. Dolbier, H. Koroniak,
K. N. Houk, C. M. Sheu, Acc. Chem. Res. 1996, 29, 471–477; g) S.
Niwayama, E. A. Kallel, D. C. Spellmeyer, C. M. Sheu, K. N. Houk,
J. Org. Chem. 1996, 61, 2813–2825.
[4] E. J. Corey, J. Streith, J. Am. Chem. Soc. 1964, 86, 950–951.
[5] a) F. Frꢀbault, M. Luparia, M. T. Oliveira, R. Goddard, N. Maulide,
Angew. Chem. 2010, 122, 5807–5811; Angew. Chem. Int. Ed. 2010,
49, 5672–5676; b) M. Luparia, D. Audisio, N. Maulide, Synlett 2011,
735; c) M. Luparia, M. T. Oliveira, D. Audisio, F. Frꢀbault, R. God-
dard, N. Maulide, Angew. Chem. 2011, 123, 12840–12844; Angew.
Chem. Int. Ed. 2011, 50, 12631–12634; d) D. Audisio, M. Luparia,
M. T. Oliveira, D. Kluett, N. Maulide, Angew. Chem. 2012, 124,
7426–7429; Angew. Chem. Int. Ed. 2012, 51, 7314–7316.
[6] a) Handbook of Organopalladium Chemistry for Organic Synthesis,
Vol. 2 (Ed.: E- I. Neigishi), Wiley, New York, 2002; b) J. Tsuji, Palla-
dium Reagents and Catalysis, Wiley, Chichester, 2004, pp. 431–479;
c) B. M. Trost, M. L. Crawley, Chem. Rev. 2003, 103, 2921–2943;
d) B. M. Trost, D. L. VanVranken, Chem. Rev. 1996, 96, 395–422.
For the use of heteroatom nucleophiles in allylic alkylation, see:
e) B. M. Trost, T. Zhang, J. D. Sieber, Chem. Sci. 2010, 1, 427–440.
[7] For selected examples of phenols as nucleophiles in allylic alkyla-
tion, see: a) B. M. Trost, F. D. Toste, J. Am. Chem. Soc. 1999, 121,
4545–4554; b) R. C. Larock, N. H. Lee, Tetrahedron Lett. 1991, 32,
6315–6318; c) C. Goux, M. Massacret, P. Lhoste, D. Sinou, Organo-
metallics 1995, 14, 4585–4593; d) B. M. Trost, T. R. Verhoeven, J.
Am. Chem. Soc. 1980, 102, 4730–4743; e) B. M. Trost, F. D. Toste, J.
Scheme 9. Stereochemical assignment of the major diastereoisomers of
13b and 17a using X-ray crystallography.
(Grant MA-4861/3-1) and the Alexander van Humboldt Foundation (Fel-
lowship to M. L.). The project “Sustainable Chemical Synthesis (Sus-
ChemSys)” is co-financed by the European Regional Development Fund
(ERDF) and the state of North Rhine-Westphalia, Germany, under the
Operational Programme “Regional Competitiveness and Employment”
2007–2013. Invaluable assistance from our HPLC, NMR (B. Gabor, C.
Wirtz, D. Bartels) and X-ray departments is acknowledged.
Keywords: allylic alkylation
· cyclobutene · dienes ·
electrocyclic reactions · palladium
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Domino Synthesis of Functionalised Dienes
COMMUNICATION
Am. Chem. Soc. 1998, 120, 815–816; f) B. M. Trost, F. D. Toste, J.
Am. Chem. Soc. 1999, 121, 3543–3544; g) C. Goux, P. Lhoste, D.
Sinou, Synlett 1992, 725–727; h) B. M. Trost, M. K. Brennan, Org.
Lett. 2007, 9, 3961–3964.
Youcef, C. Boucheron, S. Guillarme, S. Legoupy, D. Dubreuil, F.
Huet, Synthesis 2006, 633–636.
[16] For spontaneous ring opening of cyclobutenes, see: a) F. Binns, R.
Hayes, S. Ingham, S. T. Saengchantara, R. W. Turner, T. W. Wallace,
Tetrahedron 1992, 48, 515–530; b) F. Binns, R. Hayes, K. J. Hodg-
etts, S. T. Saengchantara, T. W. Wallace, C. J. Wallis, Tetrahedron
1996, 52, 3631–3658; c) H. M. Sheldrake, T. W. Wallace, C. P.
Wilson, Org. Lett. 2005, 7, 4233; d) S. Ingham, R. W. Turner, T. Wal-
lace, J. Chem. Soc. Chem. Commun. 1985, 1664–1666; e) S. Ogawa,
D. Urabe, Y. Yokokura, H. Arai, M. Arita, M. Inoue, Org. Lett.
2009, 11, 3602–3605.
[8] To the best of our knowledge, pentafluorophenol was only employed
once in palladium-catalysed allylic alkylation: J. Lçfstedt, K. Narhi,
I. Dorange, J. E. Bꢄckvall, J. Org. Chem. 2003, 68, 7243–7248.
[9] F. Frꢀbault, M. T. Oliveira, E. Wçstefeld, N. Maulide, J. Org. Chem.
2010, 75, 7962–7965.
[10] The structures of compounds 2a, 2i, (E,E)-5, 13b and 17a were con-
firmed by single-crystal X-ray analysis. CCDC 878396 (2a), CCDC
878398 (2i), CCDC 887605 ((E,E)-5), CCDC 866302 (13b) and
CCDC 887606 (17a), respectively, contain the supplementary crys-
tallographic data for this paper. This data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data request/cif. For additional X-ray data, see
Supporting Information.
[11] See Supporting Information for details and control experiments.
[12] For the synthesis of (E,E)-5-alkoxyypenta-2,4-dienoic acid and de-
rivatives through glutaconaldehyde anion, see: a) R. R. Schmidt,
Synthesis 1982, 958–962. Horner–Wadsworth–Emmons olefination:
b) E. J. J. Grabowski, R. L. Autrey, Tetrahedron 1969, 25, 4315–
4330; c) J. Maddaluno, J. d’Angelo, Tetrahedron Lett. 1983, 24, 895–
898; d) A. Lubineau, H. Bienaymꢀ, J. Le Gallic, J. Chem. Soc.
Chem. Commun. 1989, 1918–1919; e) P. H. Dussault, Q. Han, D. G.
Sloss, D. J. Symonsbergen, Tetrahedron 1999, 55, 11437–11454;
f) I. H. Aspinall, P. M. Cowley, G. Mitchell, C. M. Raynor, R. J.
Stoodley, J. Chem. Soc. Perkin Trans. 1 1999, 2591–2599. Transition-
metal catalysed processes: g) R. M. Moriarty, W. R. Epa, A. K.
Awasthi, J. Am. Chem. Soc. 1991, 113, 6315–6317; h) Y. Hatamoto,
S. Sakaguchi, Y. Ishii, Org. Lett. 2004, 6, 4623–4625; i) I. T. Crouch,
T. Dreier, D. E. Frantz, Angew. Chem. 2011, 123, 6252–6256;
Angew. Chem. Int. Ed. 2011, 50, 6128–6132. For a critical compari-
son between the syntheses of 5-amino and 5-alkoxypenta-2,4-dienoic
acid, see: j) C. D. Vanderwal, J. Org. Chem. 2011, 76, 9555–9567.
[17] For an exception, see ref. [2b].
[18] The (Z,E) and (E,E) configurations for products 5, 7 and 9 were
readily distinguishable from signature J couplings of 11.1–11.3 Hz
and 15.0–15.4 Hz, respectively and chemical shifts at position 3 of
6.5–6.6 and 7.3 ppm, respectively.
[19] Interestingly, when cyclobutene methyl ester cis-6 was used in this
transformation under identical or harsher conditions, only unreacted
(Z,E)-diene was recovered.
[20] a) F. Nꢄf, R. Decorzant, W. Thommen, Helv. Chim. Acta 1979, 62,
114–118; b) R. K. Boeckman, T. E. Barta, J. Org. Chem. 1985, 50,
3421–3423; c) S. Handa, K. Jones, C. G. Newton, D. J. Williams, J.
Chem. Soc. Chem. Commun. 1985, 1362–1363; d) Y.-T. Lin, K. N.
Houk, Tetrahedron Lett. 1985, 26, 2517–2520; e) A. Ichihara, H. Ka-
wagishi, N. Tokugawa, S. Sakamura, Tetrahedron Lett. 1986, 27,
1347–1350; f) G. H. Posner, R. D. Crouch, C. M. Kinter, J.-C. Carry,
J. Org. Chem. 1991, 56, 6981–6987.
[21] a) J. E. Baldwin, T. D. W. Claridge, A. J. Culshaw, F. A. Heupel, V.
Lee, D. R. Spring, R. C. Whitehead, Chem. Eur. J. 1999, 5, 3154–
3161 and ref. [12j]. For examples of Diels–Alder reaction with
push–pull dienes, see: b) M. Yoshimatsu, M. Hibino, M. Ishida, G.
Tanabe, O. Muraoka, Chem. Pharm. Bull. 2002, 50, 1520–1524; c) V.
Branchadell, M. Sodupe, R. M. Ortuno, A. Oliva, D. Gomez-Pardo,
A. Guingant, J. d’Angelo, J. Org. Chem. 1991, 56, 4135–4141; d) S.
DalenÅon, R. A. Youcef, M. Pipelier, V. Maisonneuve, D. Dubreuil,
F. Huet, S. Legoupy, J. Org. Chem. 2011, 76, 8059–8063. See also
refs. [12b], [12f] and [13].
[13] ACHTUNGTRENNUNG(Z,E)-5-Aryloxypenta-2,4-dienoic acid or derivatives have been ob-
tained only through Still-Gennari olefination protocols: a) P. M.
Cowley, R. J. Stoodley, Tetrahedron Lett. 1994, 35, 7853–7856; b) J.
Mathew, K. Farber, H. Nakanishi, M. Qabar, Tetrahedron Lett. 2003,
44, 583–586; c) M. J. Alves, F. T. Costa, V. C. M. Duarte, A. G.
Fortes, J. A. Martins, N. M. Micaelo, J. Org. Chem. 2011, 76, 9584–
9592.
[22] For Euglobal Ia: a) M. Kozuka, T. Sawada, F. Kasahara, E. Mizuta,
T. Amano, T. Komiya, M. Goto, Chem. Pharm. Bull. 1982, 30, 1952–
1963; b) M. Takasaki, T. Konoshima, K. Fujitani, S. Yoshida, H.
Nishimura, H. Tokuda, H. Nishino, A. Iwashima, M. Kozuka, Chem.
Pharm. Bull. 1990, 38, 2737–2739. For 4-isocymobarbatol, see:
c) M. E. Wall, M. C. Wani, G. Manikumar, H. Taylor, T. J. Hughes,
K. Gaetano, W. H. Gerwick, A. T. Mcphail, D. R. Mcphail, J. Nat.
Prod. 1989, 52, 1092–1099; d) M. E. Wall, J. Nat. Prod. 1992, 55,
1561–1568.
[14] For a recent review on diene synthesis, see: M. De Paolis, I. Cha-
taigner, J. Maddaluno, Top. Cur. Chem. 2012, 327, 87–146.
[15] For spontaneous ring opening of push–pull cyclobutenes, see: a) N.
Gauvry, F. Huet, J. Org. Chem. 2001, 66, 583–588; b) M. E. Gour-
del-Martin, F. Huet, J. Org. Chem. 1997, 62, 2166–2172; c) R. A.
Received: February 27, 2013
Published online: && &&, 0000
Chem. Eur. J. 2013, 00, 0 – 0
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N. Maulide et al.
Diene Synthesis
C. Souris, M. Luparia, F. Frꢀbault,
D. Audisio, C. Farꢁs, R. Goddard,
N. Maulide* ................... &&&& — &&&&
An Atom-Economical and Stereoselec-
tive Domino Synthesis of Functional-
ised Dienes
Open sesame: A direct synthesis of
functionalised and stereodefined
dienes, relying on a domino allylic
alkylation/electrocyclic ring-opening
sequence, is reported. This method
allows concise access to doubly vinylo-
gous esters. A further systematic study
of ring-opening rates of carbon-substi-
tuted cyclobutenes allowed the design
of substrates amenable to sequential
pericyclic reactions (see scheme).
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6
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