Metal-Free Access to Fully Substituted Skipped
Diynes. An Efficient Chemodifferentiating A2BB′
4CR Manifold
David Tejedor,*,† Sara Lo´pez-Tosco,†
Javier Gonza´lez-Platas,§ and Fernando Garc´ıa-Tellado*,†
Instituto de Productos Naturales y Agrobiolog´ıa, Consejo
Superior de InVestigaciones Cient´ıficas, Astrof´ısico Francisco
Sa´nchez 3, 38206 La Laguna, Tenerife, Spain, and SerVicio de
Difraccio´n de Rayos X, Departamento de F´ısica Fundamental II
& Instituto UniVersitario de Bioorga´nica Antonio Gonza´lez,
UniVersidad de La Laguna, Astrof´ısico Francisco Sa´nchez 2,
38204 La Laguna, Tenerife, Spain
FIGURE 1. (a) General structure of skipped diynes (1,4-diynes) and
tertiary skipped diynes 4. (b) A2BB′ 4CR manifold for the synthesis of
tertiary skipped diynes 4. A, B ) components; B′ ) component B
incorporated in a differentiated manner; 4CR ) four-component
reaction.
fgarcia@ipna.csic.es; dtejedor@ipna.csic.es
ReceiVed April 11, 2007
mentary metal-free access to these structures in accordance with
the more environmentally friendly tendencies in organic syn-
thesis should be desirable. Herein we report on our results on
the design and development of a metal-free A2BB′ 4CR
approach to these systems.7 This synthetic manifold constructs
tertiary skipped diynes by a triethylamine triggered reaction of
terminal conjugated alkynes and acid chlorides in a modular
and efficient manner (Figure 1b). The resulting tertiary 1,4-
diynes incorporate two identical units of the alkynoate (A2) and
two chemodifferentiated units of the acid chloride (B and B′)
in their structure. While the conjugated character of the two
alkyne units offers an additional reactivity profile to these
scaffolds (reactivity domain), the chemodifferentiated incorpora-
tion of the two units of acid chloride introduces a convenient
degree of diversity in the final structure (diversity domain).
In the last 5 years, we have been involved in the design and
development of new ABB′ 3CRs based on the catalytic
A metal-free chemodifferentiating A2BB′ 4CR manifold for
the modular synthesis of tertiary skipped diynes is described.
The manifold performs a triethylamine triggered reaction of
alkyl propiolates and acid chlorides to assemble two units
of each component in the form of two propargylic alkynoates,
a tertiary alcohol, and an ester. A differentiated incorporation
of the two acid chloride components ensures functional
diversity in the final structure. In addition, the presence of
two connected propargylic alkynoates provides a reactive
platform for complexity generation.
(2) For selected examples, see: (a) Livingston, R.; Cox, L. R.; Odermatt,
S.; Diederich, F. HelV. Chim. Acta 2002, 85, 3052-3077. (b) Livingston,
R. C.; Cox, L. R.; Gramlich, V.; Diederich, F. Angew. Chem., Int. Ed. 2001,
40, 2334-2337. (c) Maurette, L.; Godard, C.; Frau, S.; Lepetit, C.;
Soleilhavoup, M.; Chauvin, R. Chem.-Eur. J. 2001, 7, 1165-1170. (d) Van
Ornum, S. G.; Bruendl, M. M.; Cao, H.; Reddy, M.; Grubisha, D. S.; Bennet,
D. W.; Cook, J. M. J. Org. Chem. 2000, 65, 1957-1971. (e) An, Y.-Z.;
Rubbin, Y.; Schaller, C.; McElvany, S. W. J. Org. Chem. 1994, 59, 2927-
2929.
(3) For selected reviews, see: (a) de Meijere, A.; Kozhushkov, S. I. Top.
Curr. Chem. 1999, 201, 1-42. (b) Diederich, F.; Gobbi, L. Top. Curr. Chem.
1999, 201, 44-79. (c) Scott, L. T.; Cooney, M. J. Macrocyclic Homocon-
jugated Polyacetylenes. In Modern Acetylene Chemistry; Stang, P. J.,
Diederich, F., Eds.; VCH: Weinheim, Germany, 1995; Chapter 9, pp 321.
(4) For a review, see: Durand, S.; Parrain, J.-L.; Santelli, M. J. Chem.
Soc., Perkin Trans. I 2000, 253-273.
(5) For selected recent examples, see: (a) Kessabi, J.; Beaudegnies, R.;
Jung, P. M. J.; Martin, B.; Montel, F.; Wendeborn, S. Org. Lett. 2006, 8,
5629-5632. (b) Montel, F.; Beaudegnies, R.; Kessabi, J.; Martin, B.; Muller,
E.; Wendeborn, S.; Jung, P. M. J. Org. Lett. 2006, 8, 1905-1908.
(6) For a review, see: Tedeschi, C.; Saccavini, C.; Maurette, L.;
Soleilhavoup, M.; Chauvin, R. J. Organomet. Chem. 2003, 670, 151-169.
(7) Multicomponent reactions designated as A2BB′ 4CR are defined as
bimolecular processes that, using only two different starting materials (A
and B), are able to generate a product whose structure incorporates two
identical units of component A and two chemodifferentiated units of
component B. For a tutorial review, see: Tejedor, D.; Garc´ıa-Tellado, F.
Chem. Soc. ReV. 2007, 36, 484-491.
Skipped diynes are linear C5 structural units composed of
two triple bonds connected by an sp3 carbon center (Figure 1a).
This naturally occurring structural motif1 is a very well
appreciated synthon for the construction of novel carbon-rich
structures2,3- as well as a valuable precursor of the 1,4-cis,cis-
diene units present in many bioorganic relevant molecules.4 The
main synthetic approaches to these systems rely on the cross-
coupling reactions of metal-alkynylides and propargylic elec-
trophiles.5 A plethora of structurally diverse 1,4-diynes have
been obtained by using this well-established strategy.6 Although
this methodology is general and with wide scope, a comple-
† CSIC.
§ Universidad de La Laguna.
(1) For some examples, see: (a) Lim, Y. J.; Lee, C.-O.; Hong, J.; Kim,
D.-K.; Im, K. S.; Jung, J. H. J. Nat. Prod. 2001, 64, 1565-1566. (b) Chill,
L.; Miroz, A.; Kashman, Y. J. Nat. Prod. 2000, 63, 523-526. (c) Lim, Y.
J.; Kim, J. S.; Im, K. S.; Jung, J. H.; Lee, C.-O.; Hong, J.; Kim, D.-K. J.
Nat. Prod. 1999, 62, 1215-1217. (d) Kim, J. S.; Lim, Y. J.; Im, K. S.;
Jung, J. H.; Shim, C. J.; Lee, C.-O.; Hong, J.; Lee, H. J. Nat. Prod. 1999,
62, 554-559.
10.1021/jo070764y CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/09/2007
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J. Org. Chem. 2007, 72, 5454-5456