Boronated enynes as versatile sources of stereodefined and skeletally diverse molecules

Article abstract of DOI:10.1021/ol070400s

The application of a one-pot palladium-catalyzed cycloisomerization of enynes 1/Diels-Alder cycloaddition/allylboration sequence efficiently generates tricyclic structures with complete control of the four stereogenic centers. Ruthenium and platinum catal

Full text of DOI:10.1021/ol070400s

ORGANIC
LETTERS
2007
Vol. 9, No. 9
1717-1720
Boronated Enynes as Versatile Sources
of Stereodefined and Skeletally Diverse
Molecules
Alain Hercouet,† Fabienne Berre´e,† Chia Hui Lin,† Lo
1
ıc Toupet,‡ and
Bertrand Carboni*,†
Inge´nie´rie Chimique et Mole´cules pour le ViVant, Sciences Chimiques de Rennes, UMR
6226, and Groupe Matie`re condense´e et Mate´riaux, UMR 6626, CNRS-UniVersite´ de
Rennes 1, Campus de Beaulieu, 35042 Rennes CEDEX, France
bertrand.carboni@uniV-rennes1.fr
Received February 16, 2007
ABSTRACT
The application of a one-pot palladium-catalyzed cycloisomerization of enynes 1/Diels−Alder cycloaddition/allylboration sequence efficiently
generates tricyclic structures with complete control of the four stereogenic centers. Ruthenium and platinum catalysts perform distinct
transformations providing other isomeric boron-substituted cyclic compounds.
Diversity-oriented synthesis, which emerged from genomics
and proteomics research, aims to synthesize series of small
molecules with structural complexity and diversity for use
in systematic explorations in biology.1 Following the pio-
neering work of Schreiber et al., many developments have
been recently reported in this field.2 One possible strategy
involves the conversion of a common substrate into a range
of products having different structural cores.3 Transition-
metal-catalyzed cycloisomerizations of enynes and multi-
component processes both constitute very attractive and
powerful tools to prepare a wide range of diversely substi-
tuted polycyclic compounds and are particularly well adapted
to the demands of diversity-oriented synthesis. On the other
hand, the reactivity and the functional group tolerance of
boronic esters have led to an increasing use of these
compounds in synthetic organic chemistry, for example, in
tandem reactions involving dienyl- or diynylboronates.4 As
a part of our ongoing program related to new multicomponent
processes involving boronic acids and their derivatives,5 we
reasoned that boronated enynes 1 could be used as versatile
† Inge´nie´rie Chimique et Mole´cules pour le Vivant.
‡ Groupe Matie`re condense´e et Mate´riaux.
(1) Schreiber, S. L Science 2000, 287, 1964. For a discussion of the use
of DOS to explore biology, see: Schreiber, S. L. Chem. Eng. News 2003,
81, 51.
(2) Moulin, E.; Barluenga, S.; Totzke, F.; Winssinger, N. Chem. Eur. J.
2006, 12, 8819. Adriaenssens, L. V.; Austin, C. A.; Gibson, M.; Smith, D.;
Hartley, R. C. Eur. J. Org. Chem. 2006, 4998. Fitzmaurice, R. J.; Etheridge,
Z. C.; Jumel, E.; Woolfson, D. N.; Caddick, S. Chem. Commun. 2006, 4814.
Kotha, S.; Mandal, K.; Tiwari, A.; Mobin, S. M. Chem. Eur. J. 2006, 12,
8024. Wyatt, E. E.; Fergus, S.; Galloway, W. R.; Bender, A.; Fox, D. J.;
Plowright, A. T.; Jessiman, A. S.; Welch, M.; Spring, D. R. Chem. Commun.
2006, 3296. Freifeld, I.; Holtz, E.; Dahmann, G.; Langer, P. Eur. J. Org.
Chem. 2006, 3251. Oikawa, M.; Naito, S.; Sasaki, M. Tetrahedron Lett.
2006, 47, 4763. Lu, K.; Huang, M.; Xiang, Z.; Liu, Y.; Chen, J.; Yang, Z.
Org. Lett. 2006, 8, 1193.
(4) (a) For a pioneering work, see: Vaultier, M.; Truchet, F.; Carboni,
B.; Hoffmann, R. W.; Denne, I. Tetrahedron Lett. 1987, 28, 4169. (b) For
recent reviews, see: Hilt, G.; Bolze, P. Synthesis 2005, 2091. Carboni, B.;
Carreaux, F. In Boronic Acids; Hall, D. G., Ed.; Wiley-VCH: Weinheim,
2005; pp 343-376. (c) See also more recently: Kim, M.; Lee, D. Org.
Lett. 2005, 7, 1865. De, S.; Welker, M. E. Org. Lett. 2005, 7, 2481.
Yamamoto, Y.; Ishii, J.-I.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2005,
127, 9625. Yamamoto, Y.; Hattori, K.; Ishii, J.; Nishiyama, H. Tetrahedron
2006, 62, 4294. Hilt, G.; Hesse, W.; Harms, K. Org. Lett. 2006, 8, 3287.
(5) Gao, X.; Hall, D.; Deligny, M.; Favre, A.; Carreaux, F.; Carboni, B.
Chem. Eur. J. 2006, 12, 3132. Berre´e, F.; Debache, A.; Marsac, Y.; Collet,
B.; Girard-Le Bleiz, P.; Carboni, B. Tetrahedron 2006, 62, 4027. Debache,
A.; Boumoud, B.; Amimour, M.; Belfaitah, A.; Rhouati, S.; Carboni, B.
Tetrahedron Lett. 2006, 47, 5697.
(3) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46.
For a recent and elegant application of this strategy, see: Kumagai, N.;
Muncipito, G.; Schreiber, S. L. Angew. Chem., Int. Ed. 2006, 45, 3635.
10.1021/ol070400s CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/05/2007

sources of stereodefined and skeletally diverse small mol-
ecules.6 We first started with the palladium-catalyzed syn-
thesis of 1,3-dienes, pioneered by Trost et al.7 and report
herein our preliminary results concerning a one-pot sequential
three-component cycloisomerization/Diels-Alder/allylbora-
tion sequence. As an extension of this study, we also present
two examples of ruthenium and platinum cycloisomerization
reactions, which give access to other isomeric cyclic boronic
esters.
The enynes 1a,b were first synthesized from (E)-3-chloro-
1-propenylboronic ester8 by addition of an excess of the
corresponding primary amines, followed by tosylation.
Similarly, N-propargylbenzylamine and propargyl malonate
directly afforded, respectively, 1c and 1e in 46% and 76%
yield. For 1d, the N-benzyl derivative was acylated with
2-propynoic acid in the presence of DCC and DMAP. The
oxygenated enyne 1f was best prepared in 65% yield by
monohydroboration of dipropargylether with diisopinocam-
pheylborane, followed by dealkylation with an excess of
acetaldehyde and transesterification with pinacol (Scheme
1). All of these enynes have controlled E double bond
Enyne 1a was first selected as test substrate for the
cycloisomerization reaction. Among several palladium
sources, Pd2(dba)3‚CHCl3/PPh3/AcOH gave best results,
whereas yields and purities were lower with Pd(OAc)2/PPh3
or Pd(OAc)2/([bis(benzylidene)ethylenediamine]. The con-
version of 1a to the 1,3-diene 2a was complete after 2 h at
room temperature (85% yield, measured by 1H NMR
spectroscopy of the crude reaction mixture in the presence
of an internal standard). The Z geometry of 2a was
determined to be by NOE experiments. For other enynes,
1e,f, full conversions were readily achieved under the same
experimental conditions, whereas 18 h at room temperature
and 2 h at 50 °C were necessary for 1c and 1b, respectively.
It should be noted that significant amounts of non-boronated
diene (≈30%) were produced in the case of the malonate
derivative 1e.9 For 1d, the only product observed in the crude
reaction product was the dimer 3, even if the cycloisomer-
ization was carried out in the presence of N-phenylmaleimide
to trap the expected diene (Scheme 2).10
Scheme 2. Palladium-Catalyzed Cycloisomerization of Enynes
1
Scheme 1. Preparation of Boronated Enynes 1
a Yield estimated by 1H NMR spectroscopy of the crude reaction
mixture with 4-nitroanisole as an internal standard. bAfter purifica-
tion by chromatography on silica gel.
Although stable in solution, partial decomposition of
dienes 2 was observed throughout purification by chroma-
tography on silica gel, which led us to carry out the following
step in the same pot without removing the palladium catalyst.
Compound 2a readily underwent Diels-Alder reaction with
N-phenylmaleimide and maleic anhydride to yield the
stereochemistry due to the hydroboration step used for the
introduction of the boronate group.
(6) For some reviews on cycloisomerization of enynes, see: Ma, S.; Yu,
S.; Gu, Z. Angew. Chem., Int. Ed. 2006, 45, 200. Bruneau, C. Angew. Chem.,
Int. Ed. 2005, 44, 2328. Lloyd-Jones, G. C. Org. Biomol. Chem. 2003, 1,
215. Trost, B. M.; Frederiksen, M. U.; Rudd, M. T. Angew. Chem., Int. Ed.
2005, 44, 6630. Aubert, C.; Buisine, O.; Malacria, M. Chem. ReV. 2002,
102, 813. Trost, B. M.; Toste, D.; Pinkerton, A. B. Chem. ReV. 2001, 101,
2067.
(7) Trost, B. M.; Dong, L.; Schroeder, G. M. J. J. Am. Chem. Soc. 2005,
127, 10259 and references therein.
(8) Lombardo, M.; Morganti, S.; Tozzi, M.; Trombini, C. Eur. J. Org.
Chem. 2002, 2823.
(9) We have no explanation for this different behaviour, compared with
other enynes. Such a protodeboronation is often associated with metal-
catalyzed reactions of boronic acids. Only the boronated allylboronate 4
can react with the aldehyde, and the final product was easily separated from
the non-boronated Diels-Alder cycloadduct.
(10) This behaviour could be attributed to the presence of an electron-
withdrawing group in position 2 of 2d that favors the dimerization process.
See, for example: McIntosh, J. M.; Sieler, R. A. J. Org. Chem. 1978, 43,
4431.
1718
Org. Lett., Vol. 9, No. 9, 2007

Scheme 3. Diels-Alder Cycloaddition of Diene 2a
Table 1. Cycloisomerization /Diels-Alder Cycloaddition/
Allylboration Sequence
corresponding cycloadducts 4a and 4b in 77% and 83% yield
as single diastereoisomers. The relative configurations of the
three stereogenic centers were attributed on the basis of
NOESY experiments and are in agreement with an endo
approach as expected4a (Scheme 3). The use of a boronic
ester derived from (+)-pinanediol did not lead to significant
asymmetric induction.
Having in hand an efficient access to new tricyclic
allylboronates, we then focused our attention to their addition
to aldehydes and, in order to prevent tedious intermediate
purification, decided to carry out the palladium-catalyzed
cycloisomerization/Diels-Alder cycloaddition/allylboration
sequence in the same pot (Table 1). When N-phenylmale-
imide and maleic anhydride were employed, a successful
three-component process occurred in high yields, with
complete control of stereochemistry. An X-ray crystal
structure determination of 5 confirmed the assignments
previously proposed for the allylboronate 4a and established
the relative configuration of the R1CH(OH) created in the
last step, in agreement with a chairlike six-membered
transition state.11 For 9, a spontaneous intramolecular cy-
clization was observed, as previously reported,4a whereas
4-phenyl triazolidinedione produced a mixture of products,
partially as a result of the competitive addition of the starting
azo compound to the intermediate Diels-Alder cycloadduct,
instead of the expected addition to benzaldehyde.12 The
presence of a methyl group in an R-position to the triple
bond of the starting enyne 1b caused an important decrease
in the reactivity of the corresponding cyclic allylboronate,
probably due to steric hindrance. Only minor amounts of
expected allylic alcohol 12 were obtained, even after heating
in toluene at reflux overnight, although the Diels-Alder
cycloadduct has been quite quantitatively produced after 50
°C for 5 h.
In addition to these palladium-catalyzed cycloisomeriza-
tions, many other skeletal reorganizations are also commonly
associated with enynes. To illustrate the potential of enynes
1 in such reactions, we selected ruthenium and platinum
catalysts to perform distinct transformations providing other
isomeric boron-substituted cyclic compounds (Scheme 4).13
In the presence of Grubbs II catalyst, 1a was readily con-
verted to the corresponding cyclic diene 16, which gave the
a Isolated yields. b Isolated as its methyl ester. c Mixture of two diaste-
reoisomers (60/40). d Isolated with the addition product to 4-phenyl tria-
zolidinedione and another unidentified byproduct. e The Diels-Alder
cycloadduct, as a single diastereoisomer, was recovered unchanged. f Low
yield due to partial deborylation in the cycloisomerisation step.
(11) See Supporting Information for X-ray cristallographic analysis of
5.
(12) Zhang, A.; Kan, Y.; Jiang, B. Tetrahedron 2001, 57, 2305.
(13) For other reports dealing with metal-catalyzed synthesis of dienyl-
boronic esters, see: ref 4c and Renaud, J.; Graf, C. D.; Oberer, L. Angew.
Chem., Int. Ed. 2000, 39, 3101. Micalizio, G. C.; Schreiber, S. L. Angew.
Chem., Int. Ed. 2002, 41, 3272.
Diels-Alder cycloadduct 17 with N-phenylmaleimide in
good yield. Unfortunately, the allylboration with benzalde-
hyde failed even refluxing in toluene. However, oxidation
was efficiently carried out and afforded the alcohol 18 that
Org. Lett., Vol. 9, No. 9, 2007
1719

expected bicyclo[4.1.0]heptene derivative 19, with a minor
amount (5-10%) of product originating from the metathesis
pathway.14 The presence of a boron-substituted cyclopropane
makes it possible to envisage the further creation of new
carbon-carbon bonds by Suzuki-Miyaura cross-coupling
reaction.
Scheme 4. Skeletal Reorganizations of Enyne 1a with Further
Functional Transformations
In summary, three-component reactions of boronated
enynes, activated alkenes, and aldehydes were found to afford
stereodefined tricyclic compounds. The association of the
enyne moiety, which can be engaged in various metal-
catalyzed cycloisomerization reactions, with the boronate
group, for further post-functionalization, should allow the
construction of a range of stereodefined and skeletally diverse
molecules from common organoboron precursors.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data of all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL070400S
could be a useful partner in allylic substitution reactions.
(14) Fu¨rstner, A.; Stelzer, F.; Szillat, H. J. J. Am. Chem. Soc. 2001, 123,
Platinium-catalyzed cycloisomerization of 1a provided the
11863.
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Org. Lett., Vol. 9, No. 9, 2007