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Ester Coupling Reactions – an Enduring Challenge in the Chemical Synthesis of Bioactive Natural Products

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Ester Coupling Reactions – an Enduring Challenge in the Chemical Synthesis of Bioactive Natural Products Natural Product Reports Ester Coupling Reactions – an Enduring Challenge in the Chemical Synthesis of Bioactive Natural Products Journal: Natural Product Reports Manuscript ID: NP-REV-08-2014-000106.R2 Article Type: Review Article Date Submitted by the Author: 30-Nov-2014 Complete List of Authors: Tsakos, Michail; Aarhus University, Chemistry Schaffert, Eva; Aarhus University, Chemistry Clement, Lise; Aarhus University, Chemistry Villadsen, Nikolaj; Aarhus University, Chemistry Poulsen, Thomas; Aarhus University, Chemistry Page 1 of 25Journal Name Natural Product Reports Dynamic Article Links ► Cite this: DOI: 10.1039/c0xx00000x www.rsc.org/xxxxxx ARTICLE TYPE Ester Coupling Reactions– an Enduring Challenge in the Chemical Synthesis of Bioactive Natural Products Michail Tsakos, a Eva S. Schaffert, a Lise L. Clement,a Nikolaj L. Villadsen a and Thomas B. Poulsen a* Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX 5 DOI: 10.1039/b000000x Covering: up to 2014 In this review we investigate the use of complex ester fragment couplings within natural product total synthesis campaigns. We first outline the different biosynthetic and chemical strategies for performing complex ester couplings and on this mechanistic background we then present and discuss a collection of 10 successful examples from the literature. 1 Introduction 1. Introduction 2 Biosynthesis of Esters For many, the first encounter with organic chemistry is in the 2.1 Polyketide and non-Ribosomal Peptide Biosynthesis teaching laboratories in high school or junior years at university, 2.2 Chain Release 50 where one of the favorite experiments involves the formation of ‡ 15 2.2.1 Condensation and Thioesterase Domains low molecular weight carboxylate esters, compounds with a 2.2.2 Thioesterase Catalytic Mechanism distinctive panel of smells. Albeit simple from a synthetic 2.3 Ester Fragment Couplings during Biosynthesis perspective, such experiments carry the potential for important 2.4 Baeyer-Villiger Monooxygenases molecular insights as concerns an understanding of how very 3 Classic Activation Modes 55 small changes in structure can drastically impact the biology, i.e. our perception, of molecules. How do a few extra methyl groups 20 3.1 Acyl Halides 3.2 Carbodiimides change the smell of a compound from glue-like to strawberry or banana? 3.3 Yamaguchi Anhydrides Ester bonds are present in biological molecules, but they are 3.4 Mitsunobu Couplings 60 notably absent from information-storing (DNA/RNA) and 3.5 Ketene Intermediates functional (proteins) biopolymers. The evolutionary logic may 25 4 Representative Complex Ester Couplings in Total have favored, above all, stability in these biomolecules and thus Synthesis of Natural Products weeded out the presence of ester functionalities as a consequence 4.1 Steglich Variants of their potential hydrolytic lability.1 The domain of biology 4.1.1 Ramoplanin A2 65 dominated by ester bonds is the metabolites. In particular, esters 4.1.2 Pipecolidepsin A are key linking groups in many primary lipid metabolites, but 30 4.1.3 Iriomoteolide-3a they also constitute a class-defining functionality in many 4.2 Acyl Halide Approach secondary metabolites, notably macrocyclic lactones belonging to 4.2.1 Halipeptin A the cyclodepsipeptide and polyketide classes. 4.2.2 Cruentaren A 70 In spite of the apparent simplicity, the construction of ester bonds 4.3 Alternative Coupling Reagents often constitutes the most challenging synthetic operation in 35 4.3.1 MA026 efforts aimed at preparing such complex natural products. Nature 4.3.2 Daptomycin has developed her own synthetic logic for constructing 4.3.3 FK228 ester/lactone linkages mainly as the final transformation along 4.4 Yamaguchi Method 75 complex enzymatic assembly lines and this strategy has been 4.4.1 (+)-Migrastatin mimicked by organic chemists in the form of macrolactonization 40 4.4.2 (-)-Laulimalide reactions. This area has recently been reviewed. 2 In the absence of 4.5 Mitsunobu Method Natures amazing small molecule factories, macrolactonization is 4.5.1 Leucascandrolide A unfortunately not a general synthetic solution. Nature also 4.5.2 Pochonin C 80 constructs ester bonds in complex settings through e.g. Bayer- 4.6 Overview and Analysis Villiger type oxidations of ketone functionalities and despite the 45 5 Emerging Methods alternative retrosynthetic disconnections enabled by the synthetic 6 Conclusion This journal is © The Royal Society of Chemistry [year] [journal] , [year], [vol] , 00–00 | 1 Natural Product Reports Page 2 of 25 version of this type of reaction, the applications in complex odorants of the teaching laboratories, important neurotransmitters molecule synthesis remains relatively rare, especially in the case 35 such as acetylcholine, lipids of all kinds, to complex terpenoids of macrocyclic targets. Whether the impetus being strategic (Taxol), polyketides (Erythromycin) and cyclodepsipeptides considerations or a lack of alternative options, intermolecular (FK228 and Rapamycin, Fig. 1). In this section we will outline 5 ester coupling reactions remain a recurrent transformation within the enzymatic mechanisms employed during biosyntheses of natural product total synthesis campaigns, however in the ester-containing metabolites and discuss the different activation crowded and functionality-rich molecular environment of 40 strategies that Nature has developed. Focus will remain on the complex natural products, such couplings can present formidable complex secondary metabolites. This section will also include a challenges. In this review we will refer to these reactions as short introduction to the logic of assembly-line biosynthesis. 10 “complex ester couplings” in order to differentiate them from e.g. 2.1 Polyketide and non-Ribosomal Peptide Biosynthesis acetylations or other simple ester formations. 3 Our agenda is an analysis of the area of complex ester fragment The biosyntheses of macrocyclic lactones are performed by coupling reactions. As most of the examples fall within the 45 polyketide synthase (PKS), non-ribosomal peptide synthase classes of macrocyclic lactones, a large part of the review is (NRPS), or PKS-NRPS-hybrid assembly lines, where a cluster of 15 devoted to this class of molecules, but other examples will be enzymes catalyze the connection of simple building blocks in a included as appropriate. A key intention is to point out techniques linear fashion. 4 Recent authoritative reviews are available that and procedures (the small tricks) that allow for boosting cover this area in high detail.4,5,6 In short, for PKS the building reactivity within the classic modes of activation. Curiously, as the 50 blocks consist of malonyl, methylmalonyl and acetyl, activated introduction of new synthetic methodology in many areas of via a thioester linkage to coenzyme A. Units are iteratively 20 organic chemistry has expanded dramatically, the methods incorporated via a Claisen condensation followed by optional employed for performing (complex) ester couplings have seen reduction(s) and elimination to give rise to a variety of different much less development. Considering the importance of this two-carbon extensions of the chain, as is exemplified by the functionality, this testifies to a problem that is not easy to 55 macrocyclic precursor, 6-deoxyerythronolide B, of the antibiotic address. In the end of the review, we will present a number of Erythromycin (Scheme 1). 25 new approaches to the synthesis of ester/lactone bonds that hold NRPS incorporate amino acids, both proteinogenic and non- potential for further development into mechanistically novel and proteinogenic, and to a lesser extent other small carboxylic acids. reliable methods for performing challenging ester fragment Amino acids are activated by adenylation followed by chain couplings. 60 extension through amide bond formation. Several modifications can then occur to the amino acid unit, giving rise to an enormous O structural diversity from the shuffling of relatively few different O Me Me types of enzymes ordered in a specific assembly line. Many O Me HO OH Me O Me Me O NH O OH NMe 2 natural product macrocyclic lactones are synthesized by PKS- OH Me HO O O O O Me 65 NRPS hybrid assembly lines ( e.g. Rapamycin, Fig 1). Throughout OH H Me the biosynthesis a thioester bond links the growing linear HO O O OMe O O O Me Me molecule to the assembly line until the last unit releases the chain Taxol Erythromycin O OH O (Scheme 1). OMe Me Me HO O Me N Me O Me Me Me 70 2.2 Chain Release MeO Me H Acetylcholine O O 2.2.1 Condensation and Thioesterase Domains Me N Me 7,8 O O OH O NH H Three different termination strategies are known (Scheme 2). N Me O Reductive cleavage through an NAD(P)H-coupled reaction O H O O O O MeO HO NH results in formation of an aldehyde. The aldehyde will normally Me NH 8 O OMe Me S O 75 undergo further modification. A condensation domain can use a S Me Me nucleophile, intra- or intermolecularly, to cleave the thioester Me Me bond, releasing the assembly product. Condensation reactions are Rapamycin FK228 most common in chain elongation, but can also function as chain Me Me O O O termination. One role of the condensation enzymes is to position N P Me 80 the thioester and the nucleophile in close proximity. A histidine Me O O O O Me residue is situated close to the reaction site and is believed to O function as a proton acceptor/donor to promote the coupling 9,10 1,2-dipalmitoyl-sn -glycero-3-phosphocholine reaction. The most common releasing units are thioesterases (TEs) 30 Figure 1 Examples of ester-containing natural products. 85 (Scheme 1-2), resulting in either macrocyclization or hydrolytic cleavage. The mechanism of hydrolysis and cyclization is the 2. Biosynthesis of Esters same, the essential deviation is the substrate binding pocket. A As mentioned in the introduction, many classes of metabolites binding pocket that favors cyclization needs to be hydrophobic in contain ester functionalities.
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