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| Figure 1. The allene molecule. |
I have just read an advance article from Angew. Chem. Int.
Ed., about an atom-economical, rhodium-catalyzed cyclization reaction [1]. The
researchers have found that, with the use of a chiral and modified DIOP ligand,
they could carry out asymmetric cyclizations, which resulted in the formation
of large-sized cyclic esters known as macrolactones. Certainly, this is a hot
research area, yet there are a number of reasons why I am so excited about this
article, and I would like to share with you here.
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| Figure 2. The rhodium-catalyzed asymmetric cyclization. |
First, the reaction involves the use of the interesting
allene functionality (Figure 1 and 2). This 3-carbon component is not only fascinating in terms
of its structure, but it has also found a lot of applications in the areas of
transition metal catalysis or phosphine / NHC-type organocatalysis. The allene
functionality can form complexes with a number of metals – rhodium, palladium
and gold are some examples that immediately come up to my mind. In many cases,
the outcome of the catalytic reaction will lead to the generation of an olefin
structure. In this paper, it is an exocyclic olefin, and it can be used for
further functionalizations. Cross-coupling, metathesis, epoxidation or aziridination
followed by organocopper / cuprate coupling or nucleophilic substitutions – all
these diverse reactions can be used to build up a side-chain at the cyclic structure,
and thus infer interesting chemical or biological properties to the final
compound.
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| Figure 3. Cyclic peptide synthesis. |
The target compound class, macrolactone, is an extremely
biologically-relevant type of molecules, and they have been intensely studied
in the field of natural product chemistry and drug discovery. While the rhodium
methodology could provide access to numerous macrolactone targets, what
fascinated me even more was the fact that the method could be used in the
synthesis of cyclic peptides (Figure 3). Indeed, the researchers have shown their method
to be tolerant to a number of sensitive functional groups, and they have also
employed their methods in the synthesis of some depsipeptide targets. This
novel method should enter the arsenal of methods that can ‘close up’ a peptide
chain, such as peptide stapling via metathesis, Pd-catalyzed
cycloisomerization, or simply an amide bond formation. In this case, the
exocyclic olefin I have mentioned can find further use, because a spacer can be
attached through that part, and this should facilitate easy separation if the reaction
condition calls for it, for example, if the compound is attached to a solid
support for automated synthesis. And, I believe a great research direction is
to explore whether this method can be carried out in an aqueous or a more bio-friendly
solvent system. This catalytic reaction has the benefit that it can be carried
out at room temperature, which is ideal for temperature sensitive
bio-molecules. Thus, not only we can make useful cyclic peptides from it, we
may even employ this method to generate synthetic protein architectures, which
can then be further investigated for biological applications.
All in all, this work is just brilliant and the reaction
makes my day!
by Ed Law
7/7/2016
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| Figure 4. Use of sugar allenes in the synthesis of furanose sugar derivatives. Taken from [2]. |
P.S. Speaking of the use of allene, I have also read another
article from Angew. Chem. Int. Ed. [2], which is about the synthesis of a
number of furanose sugars via the use of some ‘sugar allenes’, via a (1) Pd-catalyzed
hydroalkoylation, (2) Ru-catalyzed ring closing metathesis, and (3) Os-catalyzed
dihydroxylation sequence (Figure 4). Also worth a read.
1. Enantioselective Rhodium-Catalyzed Atom-Economical
Macrolactonization
Stephanie Ganss and Bernhard Breit
Angew. Chem. Int. Ed., 2016, asap, DOI:
10.1002/anie.201604301
2. De Novo Synthesis of Furanose Sugars: Catalytic Asymmetric
Synthesis of Apiose and Apiose Containing Oligosaccharides
Mijin Kim, Soyeong Kang and Young Ho Rhee
Angew. Chem. Int. Ed., 2016, asap, DOI: 10.1002/anie.201604199
