Abstract
Structurally complex macrolide natural products, isolated from a variety of marine and other sources, continue to provide a valuable source of targets for the synthetic chemist to embark. In this account, we provide the recent progress and pathways in the total synthesis of macrolides and discussed the synthesis of (+)-neopeltolide, aspergillide D, miyakolide and acutiphycin natural products.
Keywords
- macrolide
- aldolization
- macrolactonization
- ring closing metathesis
- coupling reactions
- total synthesis
1. Introduction
Macrolides are a class of antibiotics that consist of a large macrocyclic lactone ring attached to deoxy sugars. These antibiotics are bacteriostatic in nature and act by inhibiting protein synthesis of bacteria. These are obtained mainly from certain actinomycetes genus, such as
The construction of macrocyclic structures is a recurrent and challenging problem in synthetic organic chemistry. Theoretically, macrocyclic systems can be generated by cyclization of open, long chain precursors or by cleavage of internal bonds in polycyclic systems. In the course of synthesis, numerous problems are encountered to achieve target molecules. Despite the several problems, however, recent interest in the chemistry of macrolide antibiotics and other biologically active macrolactones and macrolactams resulted in the discovery and development of several new synthetic methods for macrolide formation. In this chapter, total synthesis of some of the macrolides is discussed with scrupulous emphasis on the key macrolide ring forming reactions.
2. Synthetic strategy for macrolide synthesis
In the polyoxomacrolide ring, generally we will observe the 1,3-diol systems as a core. There are two synthetic approaches for the edifice of 1,3-diols which are illustrated here. They are asymmetric aldol reaction and the other one is asymmetric epoxide and epoxide ring-opening.
2.1 Aldolization
Asymmetric synthesis of β-hydroxy ketones by aldol reactions of ketones with aldehydes is the general and efficient method for the synthesis of 1,3-diol systems and is of great interest in the field of total synthesis. By using the range of chiral ketones, highly diastereoselective
A highly efficient and extensively used method for diastereoselective aldol reactions is the Evans aldol reaction using boron enolate derived from a chiral imide [4, 5]. Upon treatment of imide
2.2 Asymmetric epoxidation and dihydroxylation
The asymmetric epoxidation of allylic alcohols introduced by Katsuki and Sharpless in 1980 has tremendous applications in the synthesis of various compounds [7]. The Sharpless asymmetric epoxidation (AE) is the efficacious reagent in the synthetic organic chemistry particularly in the synthesis of variety of natural products. Epoxidation is carried out from allylic alcohols
The Sharpless dihydroxylation [8] is another tool used in the enantioselective preparation of 1,2-diols (
Stereoselective ring-opening of 2,3-epoxy alcohols
The logic of macrocyclization in natural product synthesis can be investigated by different strategies; some of them are Prins reaction [10], lactonization [11, 12], ring closing metathesis [13], Wittig reaction [14], Horner Wadsworth Emmons (HWE) reaction [15], Julia-Kocienski reaction [16], metal-mediated cross coupling reaction [17], etc. However, it is true that there is no universal macrocyclization method is reliable in the total synthesis of natural products.
2.3 Macrolactonization
Macrolactonization is the one of the effective and popular methods in the synthesis of macrolactones. The method is based on the lactonization of the corresponding seco-acid. Thus various methods are reported in the literature for the macrolactone synthesis, some of the most commonly used methods are Corey-Nicolaou [18], Shiina [19], Yamaguchi [20], Mitsunobu [21], Keck-Boden [22], and Mukaiyama [23] macrolactonizations (Figure 8).
Hansen et al. [24] reported the synthesis of (−)-aplyolide A from
Narasaka et al. [25] used the Mukaiyama method for the effective construction of macrocycle ring from corresponding seco-acid
Enev et al. [26] in his studies towards the total synthesis of laulimalide, crucial Yamaguchi macrolactonization was employed on the ynoic seco-acid
In the synthetic studies towards the synthesis of colletodial, Keck et al. [27] effectively used DCC-DMAP protocol for the macrolactonization of
Mitsunobu macrolactonization protocol based on the activation of the seco-acid alcohol
In the total synthesis of iejimalide by Schweitzer et al. [29], Shiina macrolactonization (2-methyl-6-nitro benzoic anhydride/DMAP) is used as the key step for the construction of macrolactone
2.4 Ring-closing olefin metathesis
In recent years, ring closing metathesis (RCM) has become one of the most paramount tools in synthetic organic chemistry especially in the field of total synthesis of macrolide natural products [13, 30, 31]. Furthermore, RCM is becoming the most popular way to construct large rings and has the advantage of being compatible with a wide range of functional groups such as ketones, ethers, esters, amides, amines, epoxides, silyl ethers, alcohols, thioesters, etc. In view of this, among the several reagents developed by Grubbs, Shrock, and Chauvin, the catalysts
Here, some of the applications of ring closing metathesis in the total synthesis of macrolides salicylihalamide A [32],
2.5 Palladium catalyzed coupling reactions
Palladium-catalyzed coupling reactions have gained more attention in recent years in the field of organic chemistry. In this course, Suzuki reaction using organoboron compounds [37], Heck reaction using alkenes [38], Stille reaction with organostannate [39, 40], Sonogashira reaction with terminal alkyne [41] and Tsuji-Trost reaction with π-allylpalladium intermediate [42, 43], etc. are the most frequently employed reactions in the total synthesis of macrolide natural products. Some of them are depicted here.
Tortosa and co-workers [44] in the synthesis of (+)-superstolide A, Suzuki macrocyclisation approach is used for the construction of 24-membered macrocyclic octane
The first application of the Heck cyclisation to a macrocyclic substrate was reported by Ziegler and co-workers [45] in 1981 during the synthesis of aglycone of the macrocyclic antibiotic carbomycin B. They achieved the cyclisation to the model substrate
Stille macrocyclisation as illustrated below used as the key step in the total synthesis of the biselyngbyolide A by Tanabe et al. [46] using Pd2(dba)3 and lithium chloride in DMF (Figure 19).
The utility of Sonogashira macrocyclisation in the first total synthesis of penarolide sulfate A1, an α-glucosidase inhibitor is demonstrated by Mohapatra and co-workers [47]. The macrocyclisation was successfully achieved from compound
Towards the total synthesis of antibiotic natural product A26771B, Trost and co-workers [48] effectively constructed the macrolactone
In the end game of total synthesis of macrolides, glycosidation to the aglycon also have more significance. Thus, a wide variety of methods are reported for glycosidation in the literature [49, 50].
3. Total synthesis of selected macrolides
In this section, the total synthesis of selected macrolides is discussed: (+)-neopeltolide (
3.1 (+)-Neopeltolide
(+)-Neopeltolide is a 14-membered macrolide isolated from north coast of Jamaica by Wright and coworkers from a deep water sponge [51]. It was tested for
In 2013, Ghosh et al. [53] in their total synthesis adopted the retrosynthetic pathway as follows. Disconnection of O▬C bond of the oxazole side chain would give acid which can undergo Mitsunobu esterification. Yamaguchi macrolactonization of acid would in turn give the desired macrolactone. The tetrahydropyran ring in acid could be constructed via a hetero Diels-Alder reaction between aldehyde and silyloxy diene ether using Jacobsen’s chromium catalyst.
The synthesis of the macrolactone ring of (+)-neopeltolide began with commercially available 3-methyl glutaric anhydride as shown in the scheme. 3-methyl glutaric anhydride,
After the completion of requisite silyloxy diene, hetero-Diels Alder reaction of tosyl oxyacetaldehyde,
3.2 Paterson strategy
Paterson and coworkers [54] reported the synthesis of neopeltolide as follows. Aldehyde was synthesized starting from known β-keto ester,
3.3 Ulanovskaya strategy
The synthesis of neopeltolide by Ulanovskaya et al. [55] is depicted as follows, Prins desymmetrization of diene
3.4 Aspergillide-D
Bao and coworkers in 2013 isolated 16-membered macrolide, aspergillide D, from the extract of
The retrosynthetic analysis of aspergillide D was depicted as shown above, macrolactone could be synthesized from seco acid via intramolecular Shiina esterification. For the total synthesis of Aspergillide D, the acid fragment was synthesized from commercially available D-ribose which was transformed to lactol
Acid
3.5 Miyakolide
Evan’s strategy of bond connections & key reactions in the synthesis of
4. Conclusions
A number of new macrolide antibiotics with fascinating biological activities have been isolated everyday with the unique and complex structures have been determined with extensive spectroscopic studies. Toward the total synthesis of such macrolide antibiotics, very efficient synthetic strategies and various new methodologies are also developed. Recent advances in macrolide synthesis based on newly developed strategies and methodologies are noteworthy. Further synthetic studies on macrolide antibiotics will make an immense contribution to progress in both organic and medicinal chemistry.
Acknowledgments
The author wishes to thank Vice Chancellor, Dean R & D, VFSTRU for constant support and encouragement. The author wishes to express his gratitude to Prof. V. Anuradha and other staff members of chemistry department, Vignan for the fruitful discussion. IntechOpen OAPF is greatly acknowledged.
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