Tetrahedron report 1249Applications of Claisen condensations in total synthesis of natural products. An old reaction, a new perspective
Graphical abstract
Introduction
The Claisen condensation is a carbon–carbon coupling reaction that happens through the treatment of two esters or one ester and another carbonyl substrate by a strong base to generate a,β-keto ester or a,β-diketone [1]. After, this reaction is entitled Rainer Ludwig Claisen, who first reported his research on the reaction in 1887 [[2], [3], [4]]. A plausible mechanism for the reaction is demonstrated in Scheme 1. The reaction was carried on via the treatment of the an enolate anion (2), arising from removing of an α-proton using base, with carbonyl carbon of the (other) ester (3) to form the compound 4 along with the elimination of alkoxy group to generate the compound 5, which the resultant alkoxy group subsequently separated the second α-proton of the 5 to produce an extremely resonance-stabilized enolate anion (6). Finally, β-keto ester or β-diketone (7) was achieved by the addition of aqueous acid [5].
There are various types of Claisen condensation such as [6,7]:
- (a)
Classic Claisen condensation is a self-condensation reaction of the same two molecules of a substrate including an enolizable ester (8) (Scheme 2).
- (b)
Mixed (crossed) Claisen condensation is used for the treatment of an enolizable ester or ketone (10) with nonenolizable ester (11) (Scheme 3).
- (c)
Dieckmann condensation is an intramolecular reaction of a molecule bearing two ester moieties (13) to produce usually a stable 5- or 6-membered cyclic β-keto ester (14) (Scheme 4).
Notably, a full equivalent of the base, often lithium diisopropylamide (LDA), sodium hydride (NaH) or an alkoxide, is needed for different types of Claisen condensations and when an alkoxide is utilized as the requirement base, it must be similar to the alcohol segment of the ester to avoid product mixtures arising from ester interchange [[8], [9], [10]].
In spite of importance of role of Claisen condensation as a name reaction its usefulness in the total of natural products has been largely overlooked and limited to biology which has been previously, reviewed [11]. Due to our interested in the applications of name reactions in organic synthesis [[12], [13], [14], [15], [16], [17]], asymmetric synthesis [[18], [19], [20], [21]], and total synthesis of natural products [19,20,22,23], in this review we wish to underscore the recent applications of the Claisen condensation as a key step in total synthesis of natural products, especially alkaloids, polyketides, terpenes, and flavonoids.
Section snippets
Alkaloids
Alkaloids are a class of natural products that include mainly basic nitrogen atoms. This type of compounds also contains some corresponding structures with neutral and even poor acidic properties [24]. Alkaloids are plant metabolites with a nitrogen-containing scaffold, alkali-like chemical reactivity, and various biological potencies [25]. The alkaloids comprise a very wide range of important medicinal compounds such as opiates as famous drugs. Alkaloids are originated from a broad diversity
Conclusion
In this review, we have described the Claisen condensation, as one of the most important and exclusive tools utilized in the total synthesis of natural products. Owing to the lower enolization ability of simple esters (pKa ∼25) in comparison with aldehydes and ketones (pKa ∼19–21), the C–C bond generation require more difficult conditions. Hence, various routs have been presented for simple esters enolization such as the system by TiCl4–amine reagents led to enolate production from aldehydes,
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
The authors are thankful to Alzahra University Research Council for partial financial supports.
Majid M. Heravi was born in 1952 in Mashhad, Iran. He received his B.Sc. degree from the National University of Iran in 1975 and his M.Sc. and Ph.D. degrees from Salford University, England, in 1977 and 1980. He completed his doctoral thesis under the supervision of the late Jim Clarck. He started his career as a research fellow in Daroupakhsh (a pharmaceutical company) in 1981 Tehran, Iran and joined as an assistant professor at Ferdowsi University of Mashhad, Iran, in 1983 and was promoted to
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Majid M. Heravi was born in 1952 in Mashhad, Iran. He received his B.Sc. degree from the National University of Iran in 1975 and his M.Sc. and Ph.D. degrees from Salford University, England, in 1977 and 1980. He completed his doctoral thesis under the supervision of the late Jim Clarck. He started his career as a research fellow in Daroupakhsh (a pharmaceutical company) in 1981 Tehran, Iran and joined as an assistant professor at Ferdowsi University of Mashhad, Iran, in 1983 and was promoted to associate professor in 1993 and full professor in 1997. In 1999 he moved to Alzahra University of Tehran, Iran as professor of chemistry where he is still working. He has previously been a visiting professor at UC Riverside, California, USA and Hamburg University, Hamburg, Germany. His research interests focus on “Heterocyclic Chemistry”,” Catalysis”, “Organic Methodology and Green Synthetic Organic Chemistry”.