Collins et al.
often employ two different functional groups that come together
to form the cycle. Normally these reactions do not create
stereocenters because the influence of the macrocyclic structure
on their formation is difficult to predict.3 The Yamaguchi
macrolactonization is an excellent example of such a reaction
that under optimized conditions favors macrocyclization to form
a lactone.4,5 While the synthetic strategy described above is both
convergent and aesthetically pleasing, it can be improved. A
more efficient approach would be to develop macrocyclization
reactions that would not only form the macrocycle but also, in
doing so, create new important functionality present in the
natural product in a stereo-, regio-, and chemoselective fashion.
In addition, it would be important to develop reactions that result
in the formation of carbon-carbon (C-C) bonds. This would
result in an increase in convergence and a more efficient
synthesis as much more complexity would be possible per
synthetic operation. Macrocyclizations to form C-C bonds that
result in an increase in molecular complexity have become
increasingly important. The macrocyclic Ni-catalyzed coupling
of aldehydes and alkynes6 and the Ru-catalyzed cycloisomer-
ization7 reaction are examples of reactions that can undergo
macrocyclization and produce significant levels of new func-
tionality in the process.
prompted the development of macrocyclic alkyne metathesis
as an alternative.14
Although the use of olefin metathesis in natural product
synthesis is well-established, the use of en-yne metathesis is
relatively poorly explored. This is surprising for a number of
reasons. There has been an increased amount of study dedicated
to understanding the mechanism of en-yne metathesis and how
it can be exploited to afford substituted cyclic molecules.15,16
Most importantly, en-yne metathesis differs from olefin and
alkyne metathesis in that it has the potential to form a multitude
of different products using the same relatively simple function-
alities of an alkene and alkyne. In macrocyclic en-yne metath-
esis, it is possible to afford both endo and exo products that
possess different carbon connectivities.17 The complexity of the
resulting products is multiplied when considering that each
cyclization mode could afford both E- and Z-isomers.18 The exo
mode of metathesis can also be rendered more complex if
combined with a tandem cross-metathesis. Despite this flex-
ibility, the ability to form a variety of products can also be
problematic. Macrocyclic en-yne metathesis rarely affords a sole
thermodynamic product with complete selectivity. This can lead
to problems in purification of the desired product as the products
often possess similar physical properties. Indeed, there is
significant potential in macrocyclic en-yne metathesis; however,
the challenge is to develop methods to control the products
formed, via either substrate or catalyst control.16b
Olefin metathesis has emerged as one of the “go-to” methods
for macrocycle formation, especially as it forms a new C-C
bond.8,9 Despite this advantage, it is still influenced by ring strain
and entropic factors that can be difficult to overcome.10 At times,
this can force a reexamination of the synthetic route and a return
to a more “traditional” retrosynthetic disconnection.11 It is also
possible that the intermediate preceding macrocyclization can
also adopt conformations that are unfavorable toward macro-
cyclization.12 This has stimulated the development of imagina-
tive new routes to coercing ring closure by olefin metathesis
employing relay ring closing metathesis.13 The difficulty in
controlling the isomeric distribution of products has also
An additional level of complexity can be introduced into the
macrocyclization process when strained systems are formed. In
such cases, the restricted rotation of functional groups such as
aromatic or heteroaromatic groups can result in the formation
of an element of planar chirality. This is not uncommon as there
are many classes of biologically active natural products that
possess strained macrocycles, many of which exhibit elements
of planar chirality.19 In such cases, conformational controlling
elements or “gearing elements” are employed to help promote
successful cyclization.20 In a strict sense, the term “geared
molecule” makes reference to molecules where a level of strain
is present because of unavoidable steric crowding, the result of
which is a rigidified structure typically incorporating bonds
exhibiting restricted rotation. Although the term “gearing effect”
or “gearing element” has become increasingly used to describe
(3) For some examples of macrocyclization reactions that do create
stereocenters, see: (a) Doyle, M. P.; Hu, W.-H. Chin. J. Chem. 2001, 19,
22-29. (b) Doyle, M. P.; Hu, W.; Phillips, I. M.; Wee, A. G. Org. Lett.
2000, 2, 1777-1779. (c) Doyle, M. P.; Hu, W. J. Org. Chem. 2000, 65,
8839-8847.
(4) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989-1993.
(5) For other examples of procedures for macrolactonization, see: Moslin,
R. M.; Jamison, T. F. J. Am. Chem. Soc. 2006, 128, 15106-15107.
(6) (a) Knapp-Reed, B.; Mahandru, G. M.; Montgomery, J. J. Am. Chem.
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T. F. J. Am. Chem. Soc. 2005, 127, 4297-4307.
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