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Review of 'Organocatalysts for enantioselective synthesis of fine chemicals: definitions, trends and developments'

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3
A review covering organocatalysis worthwhile reading, but with room for improvements.
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    Rated 2.5 of 5.
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    Rated 3 of 5.
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    Rated 3 of 5.
Level of comprehensibility:
    Rated 2 of 5.
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Organocatalysts for enantioselective synthesis of fine chemicals: definitions, trends and developments

Organocatalysis, that is the use of small organic molecules to catalyse organic transformations, has been included among the most successful concepts in asymmetric catalysis and it has been used for the enantioselective construction of C-C, C-N, C-O, C-S, C-P, and C-halide bonds. Since the seminal works in early 2000, the scientific community has been paying an ever-growing attention to the use of organocatalysts for the synthesis, with high yields and remarkable stereoselectivities, of optically active fine chemicals of interest for the pharmaceutical industry. A brief overview is here presented about the two main classes of substrate activation by the catalyst: covalent organocatalysis and non-covalent organocatalysis, with a more stringent focus on some recent outcomes in the field of the latter and of hydrogen-bond-based catalysis. Finally, some successful examples of heterogenisation of organocatalysts are also discussed, in the view of a potential industrial exploitation.
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    Review information

    10.14293/S2199-1006.1.SOR-CHEM.AGZIIB.v1.RBBNKB

    This work has been published open access under Creative Commons Attribution License CC BY 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Conditions, terms of use and publishing policy can be found at www.scienceopen.com.

    Review text

    Today, the concept of molecular chirality has been known for exactly two centuries and, ever since, there has been a continuous learning of what the implications of this phenomenon are. In this regard, one area that has seen a rather dramatic development over the period comprising the most recent 30-50 years is our understanding of the interactions between molecules and receptors in live organisms, e.g. human beings. Here, a cornerstone has been the growing insight of the key role that stereochemical aspects of pharmacologically active compounds are playing with regard to the biological response elicited. It is against this backdrop that the need for efficient methodologies to prepare chemical compounds with defined stereochemistry has increased exponentially and in this context organocatalysis, the subject of this paper, has appeared as a valuable tool capable of demonstrating real usefulness. The authors capture aspects of the specific technologies that are at the disposal to potential users and achieve this by categorizing the various approaches based largely on mechanistic considerations as defined by the type of interaction between substrate and the small molecule organocatalyst. This way of presenting the subject matter is not without problems. Admittedly, a trained organic chemist will find pleasure in reading a paper where the narrative is based on chemical and structural features. However, if the ambition is to go outside this targeted audience, then the uptake of the "story" will be severely hampered. What way to present the topic is more a question that only the authors can comment on: Who did you have in mind when writing your article?

    In order to emphasize the strength of organocatalysis, comparisons with two other catalytic techniques - the use of (transition) metals in homogenous phase and enzymes, respectively - are made, however, without managing to convincingly prove why one is better than another. It is in this discussion (p. 2) where the statement in reference to enzymes is made that they possess "attractive features.........such as limited stability........and low efficiency"??? How the authors have arrived at this position in their analysis is a mystery and would demand some thorough explanation! Whilst talking about drawbacks it seems as a good opportunity to bring forward the use of varying font sizes for specifically the structural formulae - a very irritating and totally unnecessary bad habit (compare for example Fig 3 with Fig 7). At the same time it is worthwhile to point out that a phenyl group has erroneously been included in the iminium intermediate of Fig 7b (the enal is acrolein and not its Ph-congener). Likewise, in compound # 17, the letter t has been separated from where it should sit, namely together with the E above (Et). In catalyst 58, the regiopositions of the nitro-substituents on the two phenyl rings is not specified.

    One aspect of organocatalysis that is notoriously left out is as discussion on how to ensure that the auxiliary (e.g. a thiourea or a prolinol derivative) is efficiently removed from the reaction system. This is indeed a challenging problem when running transformations in the presence of organometallic species and also when the catalyst is an enzyme so it is a very relevant question to address here as well, something which the authors fail to deliver throughout. Gratifyingly, however, the topic of scale up of organocatalytic reactions is briefly described (p. 10) where one interesting option seems to be via a heterogenization strategy. The literature cited is covering the subject matter well - even if it is not entirely comprehensive. There are some entries that for reasons of completeness should have been included: The landmark work by Hajos and Wiechert from the early 1970s is only referenced via the paper written by the former. Likewise, the seminal work by Biot in 1815 (200th anniversary!) should be honoured by citing the original work and not only work from 1992. Furthermore, ref 65 seems to be missing from the running text and ref 66 (p. 8) is inserted using a wrong format. On p. 9, the independent work of Terada and Akiyama, respectively is honoured without citing the relevant papers of both scientists as only the latter has been shown this favor (ref #71) - one might ask for what reason?

    All in all a review paper well worth reading, but where there is obvious room for improvement and corrections. This could for example be focused on the poor synchronization between running text and Figures and Schemes where there is an annoying need to constantly leave the page you happen to be reading to have a look at the artwork one or a few pages further on.

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