Total Synthesis of Macrolides

*Chebolu Naga Sesha Sai Pavan Kumar*

## **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 *Streptomyces* and related species. The original macrolide complex, erythromycin A, was isolated in 1952 as a natural product of *Saccharopolyspora erythraea* (formerly *Streptomyces erythreus*). Other examples include clarithromycin, azithromycin, telithromycin, cethromycin, modithromycin, etc. Macrolides structurally contain three characteristic parts in every molecule, that is, a macrocyclic lactone ring, multiple ketone & hydroxyl group, and two deoxy sugars attached by glycosidic bond. According to the carbon number of lactone ring, macrolides are classified into several types. That is, 12-membered ring, 13-membered ring, 14-membered ring, 15-membered ring, 16-membered rings, etc. (**Figure 1**). Out of these, most of the antibiotic drugs comprised of 14-membered and 16-membered lactone rings.

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.


**Figure 1.**

*Classification of macrolide antibiotics.*

## **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.

> Weinreb amide, etc. In contrast, addition of a Lewis acid to the boron enolate provides either *anti*-diol **3** or non-Evans 1,2-*syn*-aldol **4** with excellent diastereos-

*Macrolide antibiotics: evidence for the chemists interested in the stereochemistry of the Aldol reaction.*

The asymmetric epoxidation of allylic alcohols introduced by Katsuki and Sharpless in 1980 has tremendous applications in the synthesis of various

electivity [6] (**Figure 4**).

*Total Synthesis of Macrolides*

*DOI: http://dx.doi.org/10.5772/intechopen.87898*

**Figure 3.**

**Figure 4.**

**161**

*Evan's Aldol strategy.*

**2.2 Asymmetric epoxidation and dihydroxylation**

## **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 *syn* and *anti* aldol products are produced using various boron enolates [1–3]. Some of the reagents shown below (**Figure 2**) direct the relative and absolute stereochemistry of C▬C bond formation between various achiral and chiral ketones, thus providing a ubiquitous synthetic tool for macrolide synthesis (**Figure 3**).

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 **1** with *n*-Bu2BOTf and *i*-Pr2NEt in CH2Cl2 followed by addition of aldehyde, aldol reaction proceeds smoothly in stereoselective manner through the chelation transition state to attain 1,2-*syn*-aldol adduct **2** in high yield and with excellent diastereoselectivity. After the reaction, the chiral auxiliary is cleaved by hydrolysis to acid, then reduction to aldehyde or alcohol, conversion to

**Figure 2.** *Reagents for asymmetric Aldol reactions.*

*Total Synthesis of Macrolides DOI: http://dx.doi.org/10.5772/intechopen.87898*

**Figure 3.** *Macrolide antibiotics: evidence for the chemists interested in the stereochemistry of the Aldol reaction.*

Weinreb amide, etc. In contrast, addition of a Lewis acid to the boron enolate provides either *anti*-diol **3** or non-Evans 1,2-*syn*-aldol **4** with excellent diastereoselectivity [6] (**Figure 4**).

## **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

**Figure 4.** *Evan's Aldol strategy.*

**2. Synthetic strategy for macrolide synthesis**

epoxide and epoxide ring-opening.

*Classification of macrolide antibiotics.*

*Organic Synthesis - A Nascent Relook*

**2.1 Aldolization**

**Figure 1.**

synthesis (**Figure 3**).

**Figure 2.**

**160**

*Reagents for asymmetric Aldol reactions.*

In the polyoxomacrolide ring, generally we will observe the 1,3-diol systems as a

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 *syn* and *anti* aldol products are produced using various boron enolates [1–3]. Some of the reagents shown below (**Figure 2**) direct the relative and absolute stereochemistry of C▬C bond formation between various achiral and chiral ketones, thus providing a ubiquitous synthetic tool for macrolide

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 **1** with *n*-Bu2BOTf and *i*-Pr2NEt in CH2Cl2 followed by addition of aldehyde, aldol reaction proceeds smoothly in stereoselective manner through the chelation transition state to attain 1,2-*syn*-aldol adduct **2** in high yield and with excellent diastereoselectivity. After the reaction, the chiral auxiliary is cleaved by hydrolysis to acid, then reduction to aldehyde or alcohol, conversion to

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 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 **5** with *tert*-butyl hydroperoxide in the presence of Ti(O*i*Pr)4. The resulting epoxide stereochemistry is determined by the enantiomer of the chiral tartrate ester (usually diethyl tartrate or diisopropyl tartrate) employed in reaction. When ()-diester is used, β-epoxide **6** is obtained, while (+)-diester produces α-epoxide **7** (**Figure 5**).

The Sharpless dihydroxylation [8] is another tool used in the enantioselective preparation of 1,2-diols (**9a**/**9b**) from olefins (**8**). This reaction is performed with osmium catalyst and a stoichiometric oxidant (e.g., K3Fe(CN)6 or NMO). Enantioselectivity is produced by the addition of enantiomerically-enriched chiral ligands [(DHQD)2PHAL also called AD-mix-β, (DHQ)2PHAL also called AD-mix-α or their derivatives] (**Figure 6**). These reagents are also commercially available as stable and not so expensive.

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

Macrolactonization is the one of the effective and popular methods in the syn-

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

thesis of macrolactones. The method is based on the lactonization of the

method is reliable in the total synthesis of natural products.

Mukaiyama [23] macrolactonizations (**Figure 8**).

**2.3 Macrolactonization**

*Stereoselective ring-opening of epoxy alcohols.*

*DOI: http://dx.doi.org/10.5772/intechopen.87898*

*Total Synthesis of Macrolides*

**Figure 7.**

**Figure 8.**

**163**

*Some of the popular methods used for macrolactonization.*

Stereoselective ring-opening of 2,3-epoxy alcohols **10** is extremely valuable for the synthesis of different functionalized compounds [9]. A wide range of nucleophiles such as secondary amine, alcohol, thiol, azide and carboxylic acid predominantly at C-3 position to give 1,2-diol **11** (**Figure 7**).

**Figure 5.** *Sharpless asymmetric epoxidation strategy.*

**Figure 6.** *Sharpless asymmetric dihydroxylation.*

*Total Synthesis of Macrolides DOI: http://dx.doi.org/10.5772/intechopen.87898*

#### **Figure 7.**

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 **5** with *tert*-butyl hydroperoxide in the presence of Ti(O*i*Pr)4. The resulting epoxide stereochemistry is determined by the enantiomer of the chiral tartrate ester (usually diethyl tartrate or diisopropyl tartrate) employed in reaction. When ()-diester is used, β-epoxide

The Sharpless dihydroxylation [8] is another tool used in the enantioselective preparation of 1,2-diols (**9a**/**9b**) from olefins (**8**). This reaction is performed with

Enantioselectivity is produced by the addition of enantiomerically-enriched chiral ligands [(DHQD)2PHAL also called AD-mix-β, (DHQ)2PHAL also called AD-mix-α or their derivatives] (**Figure 6**). These reagents are also commercially available as

Stereoselective ring-opening of 2,3-epoxy alcohols **10** is extremely valuable for the synthesis of different functionalized compounds [9]. A wide range of nucleophiles such as secondary amine, alcohol, thiol, azide and carboxylic acid predomi-

**6** is obtained, while (+)-diester produces α-epoxide **7** (**Figure 5**).

nantly at C-3 position to give 1,2-diol **11** (**Figure 7**).

stable and not so expensive.

*Organic Synthesis - A Nascent Relook*

**Figure 5.**

**Figure 6.**

**162**

*Sharpless asymmetric dihydroxylation.*

*Sharpless asymmetric epoxidation strategy.*

osmium catalyst and a stoichiometric oxidant (e.g., K3Fe(CN)6 or NMO).

*Stereoselective ring-opening of 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**).

*Some of the popular methods used for macrolactonization.*

Hansen et al. [24] reported the synthesis of ()-aplyolide A from **12** in which they adopted the Corey-Nicolaou macrolactonisation as the key step with 78% yield (**Figure 9**).

Narasaka et al. [25] used the Mukaiyama method for the effective construction of macrocycle ring from corresponding seco-acid **13** in the synthesis of Prostaglandin F-lactone (**Figure 10**).

Enev et al. [26] in his studies towards the total synthesis of laulimalide, crucial Yamaguchi macrolactonization was employed on the ynoic seco-acid **14** and then reducing the triple bond obtained the desired macrolactone **15** (**Figure 11**).

In the synthetic studies towards the synthesis of colletodial, Keck et al. [27] effectively used DCC-DMAP protocol for the macrolactonization of **16** to precursor of colletodial **17** (**Figure 12**).

Mitsunobu macrolactonization protocol based on the activation of the seco-acid alcohol **18** to **19** using diisopropyl azodicarboxylate (DIAD) and triphenylphosphine is used in the total synthesis of natural product (+)-amphidinolide K by Williams

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 **21** in moderate yield. Even the yield is somewhat low, other methods failed to construct the lactone while Shiina protocol worked

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 **A**–**D** represents two generations of ruthenium complexes, while **E** is the molybdenum Shrock catalyst (**Figure 15**). **A** is popularly known as Grubbs first generation catalysts, **B** and **C** are Grubbs second generation catalysts and **D** is

and Meyer [28] (**Figure 13**).

*Total Synthesis of Macrolides*

*DOI: http://dx.doi.org/10.5772/intechopen.87898*

successfully from **20** (**Figure 14**).

*Mitsunobu esterification in the total synthesis of (+)-amphidinolide K.*

**Figure 13.**

**Figure 14.**

**Figure 15.**

**165**

**2.4 Ring-closing olefin metathesis**

*Various catalysts for ring closing metathesis.*

*Shiina macrolactonization towards the synthesis of iejimalide B.*

**Figure 9.**

*Application of Corey-Nicolaou macrolactonisation.*

**Figure 10.** *Mukaiyama method in the synthesis of prostaglandin F-lactone.*

**Figure 11.** *Yamaguchi protocol in the synthesis of laulimalide.*

**Figure 12.** *Keck et al. lactonisation for the synthesis of colletodial.*

*Total Synthesis of Macrolides DOI: http://dx.doi.org/10.5772/intechopen.87898*

Mitsunobu macrolactonization protocol based on the activation of the seco-acid alcohol **18** to **19** using diisopropyl azodicarboxylate (DIAD) and triphenylphosphine is used in the total synthesis of natural product (+)-amphidinolide K by Williams and Meyer [28] (**Figure 13**).

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 **21** in moderate yield. Even the yield is somewhat low, other methods failed to construct the lactone while Shiina protocol worked successfully from **20** (**Figure 14**).

**Figure 13.**

Hansen et al. [24] reported the synthesis of ()-aplyolide A from **12** in which they adopted the Corey-Nicolaou macrolactonisation as the key step with 78% yield

Narasaka et al. [25] used the Mukaiyama method for the effective construction of macrocycle ring from corresponding seco-acid **13** in the synthesis of Prostaglan-

Enev et al. [26] in his studies towards the total synthesis of laulimalide, crucial Yamaguchi macrolactonization was employed on the ynoic seco-acid **14** and then reducing the triple bond obtained the desired macrolactone **15** (**Figure 11**). In the synthetic studies towards the synthesis of colletodial, Keck et al. [27] effectively used DCC-DMAP protocol for the macrolactonization of **16** to precursor

(**Figure 9**).

**Figure 9.**

**Figure 10.**

**Figure 11.**

**Figure 12.**

**164**

din F-lactone (**Figure 10**).

*Organic Synthesis - A Nascent Relook*

of colletodial **17** (**Figure 12**).

*Application of Corey-Nicolaou macrolactonisation.*

*Mukaiyama method in the synthesis of prostaglandin F-lactone.*

*Yamaguchi protocol in the synthesis of laulimalide.*

*Keck et al. lactonisation for the synthesis of colletodial.*

*Mitsunobu esterification in the total synthesis of (+)-amphidinolide K.*

**Figure 14.** *Shiina macrolactonization towards the synthesis of iejimalide B.*

#### **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 **A**–**D** represents two generations of ruthenium complexes, while **E** is the molybdenum Shrock catalyst (**Figure 15**). **A** is popularly known as Grubbs first generation catalysts, **B** and **C** are Grubbs second generation catalysts and **D** is

**Figure 15.** *Various catalysts for ring closing metathesis.*

Hoveyda-Grubbs catalyst. The choice of the catalysts can be used in the synthetic organic transformations based on the reactivity of the substrate, and other reaction condition parameters. Substitution in the aromatic ring of **D** has given rise to a new family of third generation catalyst.

Tortosa and co-workers [44] in the synthesis of (+)-superstolide A, Suzuki macrocyclisation approach is used for the construction of 24-membered macrocy-

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 **25** in 55% yield, by slow addition to a solution of PdCl2(MeCN)2, Et3N and

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

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 **28** with catalytic Pd(PPh3)4 and CuI in Et2NH at room temperature (**Figure 20**). Towards the total synthesis of antibiotic natural product A26771B, Trost and co-workers [48] effectively constructed the macrolactone **31** (**Figure 21**) by the use of bidentate phosphine ligand (1,4-bis(diphenylphosphino)butane (DPPB)).

formic acid in MeCN at ambient temperature (**Figure 18**).

clic octane **23** (**Figure 17**).

*Total Synthesis of Macrolides*

*DOI: http://dx.doi.org/10.5772/intechopen.87898*

chloride in DMF (**Figure 19**).

**Figure 17.**

**Figure 18.**

**Figure 19.**

**167**

*Suzuki macrocyclisation in the synthesis of superstolide A.*

*Heck cyclisation in the synthesis of carbomycin B.*

*Stille macrocyclisation in the total synthesis of biselyngbyolide A.*

Here, some of the applications of ring closing metathesis in the total synthesis of macrolides salicylihalamide A [32], *trans*-resorcylide [33], (+)-lasiodiplodin [34], oximidine III [35], and Sch 38516 [36] by various metathesis catalysts have been illustrated (**Figure 16**).

**Figure 16.** *Some of the applications of ring closing metathesis in total synthesis of macrolides.*

#### **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.

#### *Total Synthesis of Macrolides DOI: http://dx.doi.org/10.5772/intechopen.87898*

Hoveyda-Grubbs catalyst. The choice of the catalysts can be used in the synthetic organic transformations based on the reactivity of the substrate, and other reaction condition parameters. Substitution in the aromatic ring of **D** has given rise to a new

Here, some of the applications of ring closing metathesis in the total synthesis of macrolides salicylihalamide A [32], *trans*-resorcylide [33], (+)-lasiodiplodin [34], oximidine III [35], and Sch 38516 [36] by various metathesis catalysts have been

family of third generation catalyst.

*Organic Synthesis - A Nascent Relook*

**2.5 Palladium catalyzed coupling reactions**

*Some of the applications of ring closing metathesis in total synthesis of macrolides.*

Some of them are depicted here.

**Figure 16.**

**166**

Palladium-catalyzed coupling reactions have gained more attention in recent

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.

years in the field of organic chemistry. In this course, Suzuki reaction using

illustrated (**Figure 16**).

Tortosa and co-workers [44] in the synthesis of (+)-superstolide A, Suzuki macrocyclisation approach is used for the construction of 24-membered macrocyclic octane **23** (**Figure 17**).

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 **25** in 55% yield, by slow addition to a solution of PdCl2(MeCN)2, Et3N and formic acid in MeCN at ambient temperature (**Figure 18**).

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 **28** with catalytic Pd(PPh3)4 and CuI in Et2NH at room temperature (**Figure 20**).

Towards the total synthesis of antibiotic natural product A26771B, Trost and co-workers [48] effectively constructed the macrolactone **31** (**Figure 21**) by the use of bidentate phosphine ligand (1,4-bis(diphenylphosphino)butane (DPPB)).

**Figure 17.** *Suzuki macrocyclisation in the synthesis of superstolide A.*

**Figure 18.** *Heck cyclisation in the synthesis of carbomycin B.*

**Figure 19.** *Stille macrocyclisation in the total synthesis of biselyngbyolide A.*

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 alde-

The synthesis of the macrolactone ring of (+)-neopeltolide began with commer-

After the completion of requisite silyloxy diene, hetero-Diels Alder reaction of

tosyl oxyacetaldehyde, **43** with **42** using chiral chromium catalyst (**44**) gave tetrahydropyranone, **45** in 83% yield (**Figure 23**). After protection of ketone group in **45** as ketal and displaced the tosylate to nitrile **46** using NaCN in DMF. Nitrile **46** was hydrolysed to acid and on deprotection of ketone to afford ketone **47**. Intramolecular Yamaguchi macrolactonization attained the key macrolactone **48** in 40% yield. Olefin **48** was subjected to hydrogenation with 10% Pd/C to give saturated compound and on reduction with NaBH4/EtOH to attain alcohol **49**. Next, the synthesis of unsaturated oxazole side chain **50** is started with known alkyne with LDA and Bu3SnCl to obtain the alkynyl stannate, which on hydrozirconation gave the carbamate in 38% yield. Crucial Stille cross coupling of carbamate with iodooxazole using Pd(MeCN)2Cl2 in DMF gave oxazole which can be easily

cially available 3-methyl glutaric anhydride as shown in the scheme. 3-methyl glutaric anhydride, **36** was desymmetrized using PS-30 'Amano' lipase to obtain acid. The resulting acid was treated with borane-dimethyl sulfide complex to afford alcohol, **37**. Alcohol **37** was oxidized to corresponding aldehyde by Swern oxidation and then protected to its acetal, **38**. Ester of **38** was then reduced to alcohol and on Swern oxidation obtained aldehyde and the resulting aldehyde was subjected to Brown's allylation protocol using (+)-Ipc2BOMe and allyl magnesium bromide to attain alcohol, **39**. Alcohol **39** was methylated with MeI, and on Lemieux-Johnson oxidation gave aldehyde and on Brown's allylation protocol afforded alcohol, **40**. Acetal protection was deprotected and the aldehyde was converted to α,β-unsaturated ketone, **41** using standard Horner-Wadsworth-Emmons olefination conditions. Secondary alcohol in **41** was then protected with TESOTf to obtain the

hyde and silyloxy diene ether using Jacobsen's chromium catalyst.

silyloxy diene, **42** in excellent yield (**Figure 22**).

*Total Synthesis of Macrolides*

*DOI: http://dx.doi.org/10.5772/intechopen.87898*

**Figure 22.**

**169**

*Synthesis of silyloxy diene 42 fragment.*

#### **Figure 20.**

*Sonogashira macrocyclisation in the synthesis of penarolide sulfate A1.*

**Figure 21.** *Tsuji-Trost lactonization for the synthesis of A26771B.*

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 (**32**), aspergillide D (**33**) and briefly about miyakolide (**34**) and acutiphycin (**35**).

#### **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 vitro* antiproliferative activity against several cancer cell lines comprising A549 human lung adenocarcinoma, NCI/ADR-RES ovarian sarcoma and P388 murine leukemia and shows IC50 values 1.2, 5.1 and 0.56 nM. Besides this, neopeltolide also exhibits anti-fungal activity against *Candida albicans* [52]. The complexity of the structure with six chiral centres, tetrahydropyran ring, and an oxazole-bearing unsaturated side chain and its efficacious biological activity led to several total syntheses, few of them are discussed below.

#### *Total Synthesis of Macrolides DOI: http://dx.doi.org/10.5772/intechopen.87898*

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, **36** was desymmetrized using PS-30 'Amano' lipase to obtain acid. The resulting acid was treated with borane-dimethyl sulfide complex to afford alcohol, **37**. Alcohol **37** was oxidized to corresponding aldehyde by Swern oxidation and then protected to its acetal, **38**. Ester of **38** was then reduced to alcohol and on Swern oxidation obtained aldehyde and the resulting aldehyde was subjected to Brown's allylation protocol using (+)-Ipc2BOMe and allyl magnesium bromide to attain alcohol, **39**. Alcohol **39** was methylated with MeI, and on Lemieux-Johnson oxidation gave aldehyde and on Brown's allylation protocol afforded alcohol, **40**. Acetal protection was deprotected and the aldehyde was converted to α,β-unsaturated ketone, **41** using standard Horner-Wadsworth-Emmons olefination conditions. Secondary alcohol in **41** was then protected with TESOTf to obtain the silyloxy diene, **42** in excellent yield (**Figure 22**).

After the completion of requisite silyloxy diene, hetero-Diels Alder reaction of tosyl oxyacetaldehyde, **43** with **42** using chiral chromium catalyst (**44**) gave tetrahydropyranone, **45** in 83% yield (**Figure 23**). After protection of ketone group in **45** as ketal and displaced the tosylate to nitrile **46** using NaCN in DMF. Nitrile **46** was hydrolysed to acid and on deprotection of ketone to afford ketone **47**. Intramolecular Yamaguchi macrolactonization attained the key macrolactone **48** in 40% yield. Olefin **48** was subjected to hydrogenation with 10% Pd/C to give saturated compound and on reduction with NaBH4/EtOH to attain alcohol **49**. Next, the synthesis of unsaturated oxazole side chain **50** is started with known alkyne with LDA and Bu3SnCl to obtain the alkynyl stannate, which on hydrozirconation gave the carbamate in 38% yield. Crucial Stille cross coupling of carbamate with iodooxazole using Pd(MeCN)2Cl2 in DMF gave oxazole which can be easily

**Figure 22.** *Synthesis of silyloxy diene 42 fragment.*

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

In this section, the total synthesis of selected macrolides is discussed: (+) neopeltolide (**32**), aspergillide D (**33**) and briefly about miyakolide (**34**) and

(+)-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 vitro* antiproliferative activity against several cancer cell lines comprising A549 human lung adenocarcinoma, NCI/ADR-RES ovarian sarcoma and P388 murine leukemia and shows IC50 values 1.2, 5.1 and 0.56 nM. Besides this, neopeltolide also exhibits anti-fungal activity against *Candida albicans* [52]. The complexity of the structure with six chiral centres, tetrahydropyran ring, and an oxazole-bearing unsaturated side chain and its efficacious biological activity led to several total

glycosidation in the literature [49, 50].

*Tsuji-Trost lactonization for the synthesis of A26771B.*

*Organic Synthesis - A Nascent Relook*

acutiphycin (**35**).

**168**

**Figure 20.**

**Figure 21.**

**3.1 (+)-Neopeltolide**

**3. Total synthesis of selected macrolides**

*Sonogashira macrocyclisation in the synthesis of penarolide sulfate A1.*

syntheses, few of them are discussed below.

Paterson and coworkers [54] reported the synthesis of neopeltolide as follows. Aldehyde was synthesized starting from known β-keto ester, **51**, which on treatment with (*S*)-BINAP-Ru (II) catalyst under Noyori asymmetric hydrogenation to afford (13*S*)-alcohol. The alcohol on TBS protection and DIBAL reduction of the ester produced the enantiopure aldehyde **52**. Aldehyde **52** was subjected to Brown's methallylation using 2-methyl propene and ()-Ipc2BOMe furnished the desired C11 alcohol with 94:6 dr, and the alcohol was methylated into the methyl ether **53** by NaH, MeI. Methyl ether **53** was subjected to ozonolysis to obtain methyl ketone and on Horner Wadsworth Emmons reaction with trimethyl phosphonoacetate to attain ester **54** in E/Z isomers (75,25). Esters **54** were reduced to its alcohol by DIBAL-H and on subsequent oxidation with Dess-Martin periodinane produced aldehyde **55**. Next, organo catalytic hydride reduction of enal **55** using MacMillan strategy with imidzolidinone catalyst **56**. TFA (20 mol%) and Hantzch ester furnished as 1,4-reduction product **57** with 76:24 of epimers at C9 stereocentre (**Figure 25**). Further, Jacobsen asymmetric hetero Diels-Alder reaction between **57** and known 2-silyloxy diene **58** produced *cis*-tetrahydropyranone **60** in 60% yield using chiral tridentate chromium (III) catalyst **59**. On PMB deprotection and further oxidation of alcohol to corresponding acid followed by TBS deprotection furnished seco-acid **61**. Macrolactonization of **61** under standard Yamaguchi conditions afforded macrolactone **62** in 80% yield. Reduction of macrolactone **62** to the alcohol with NaBH4 in MeOH followed by Mitsunobu esterification with the oxazole side chain **50** achieved (+)-neopeltolide (**32**) in 52% yield (**Figure 26**).

The synthesis of neopeltolide by Ulanovskaya et al. [55] is depicted as follows, Prins desymmetrization of diene **63** followed by benzyl protection and Wacker oxidation of alkene afforded ketone **64**. Formation of boron enolate from ketone and on addition of aldehyde **65** gave the anticipated aldol product with >98:2 diastereoselectivity, which was treated with Ph3P=CH2 (Wittig methylenation) followed by cleavage of dioxolone by acidic work-up afforded ketone **66** in 75%

**3.3 Ulanovskaya strategy**

*Total Synthesis of Macrolides*

*DOI: http://dx.doi.org/10.5772/intechopen.87898*

*Synthesis of aldehyde 57.*

**Figure 25.**

**171**

**Figure 23.**

*Hetero-Diels-Alder reaction for the synthesis of tetrahydropyrarone moiety.*

**Figure 24.** *Completion of synthesis of (+)-neopeltolide.*

converted to desired side chain **50**. The target neopeltolide compound was furnished by standard Mitsunobu esterification of **49** with acid **50** (**Figure 24**).

#### **3.2 Paterson strategy**

#### *Total Synthesis of Macrolides DOI: http://dx.doi.org/10.5772/intechopen.87898*

Paterson and coworkers [54] reported the synthesis of neopeltolide as follows. Aldehyde was synthesized starting from known β-keto ester, **51**, which on treatment with (*S*)-BINAP-Ru (II) catalyst under Noyori asymmetric hydrogenation to afford (13*S*)-alcohol. The alcohol on TBS protection and DIBAL reduction of the ester produced the enantiopure aldehyde **52**. Aldehyde **52** was subjected to Brown's methallylation using 2-methyl propene and ()-Ipc2BOMe furnished the desired C11 alcohol with 94:6 dr, and the alcohol was methylated into the methyl ether **53** by NaH, MeI. Methyl ether **53** was subjected to ozonolysis to obtain methyl ketone and on Horner Wadsworth Emmons reaction with trimethyl phosphonoacetate to attain ester **54** in E/Z isomers (75,25). Esters **54** were reduced to its alcohol by DIBAL-H and on subsequent oxidation with Dess-Martin periodinane produced aldehyde **55**. Next, organo catalytic hydride reduction of enal **55** using MacMillan strategy with imidzolidinone catalyst **56**. TFA (20 mol%) and Hantzch ester furnished as 1,4-reduction product **57** with 76:24 of epimers at C9 stereocentre (**Figure 25**). Further, Jacobsen asymmetric hetero Diels-Alder reaction between **57** and known 2-silyloxy diene **58** produced *cis*-tetrahydropyranone **60** in 60% yield using chiral tridentate chromium (III) catalyst **59**. On PMB deprotection and further oxidation of alcohol to corresponding acid followed by TBS deprotection furnished seco-acid **61**. Macrolactonization of **61** under standard Yamaguchi conditions afforded macrolactone **62** in 80% yield. Reduction of macrolactone **62** to the alcohol with NaBH4 in MeOH followed by Mitsunobu esterification with the oxazole side chain **50** achieved (+)-neopeltolide (**32**) in 52% yield (**Figure 26**).

**Figure 25.** *Synthesis of aldehyde 57.*

### **3.3 Ulanovskaya strategy**

The synthesis of neopeltolide by Ulanovskaya et al. [55] is depicted as follows, Prins desymmetrization of diene **63** followed by benzyl protection and Wacker oxidation of alkene afforded ketone **64**. Formation of boron enolate from ketone and on addition of aldehyde **65** gave the anticipated aldol product with >98:2 diastereoselectivity, which was treated with Ph3P=CH2 (Wittig methylenation) followed by cleavage of dioxolone by acidic work-up afforded ketone **66** in 75%

converted to desired side chain **50**. The target neopeltolide compound was furnished by standard Mitsunobu esterification of **49** with acid **50** (**Figure 24**).

*Hetero-Diels-Alder reaction for the synthesis of tetrahydropyrarone moiety.*

**3.2 Paterson strategy**

*Completion of synthesis of (+)-neopeltolide.*

**Figure 24.**

**170**

**Figure 23.**

*Organic Synthesis - A Nascent Relook*

yield. Ketone **66** was selectively reduced to *syn*-alcohol using Et2BOMe and NaBH4 followed by ester hydrolysis gave acid which was subjected to Yamaguchi macrolactonization to furnish desired macrolactone **67**. Alkene in **67** was hydrogenated using Pd/C to afford desired alcohol **68** as a major product. Alcohol **68** was subjected to Mitsunobu conditions, followed by hydrolysis with K2CO3 in MeOH to get the inversion product. Subsequent methylation with MeO3BF4 & hydrogenolysis of benzyl ether achieved desired macrolide **49**. The final coupling of fragment **49** with oxazole side chain **50** with standard Mitsunobu conditions furnished target (+)-neopeltolide **32** (**Figure 27**).

**3.4 Aspergillide-D**

*Total Synthesis of Macrolides*

*DOI: http://dx.doi.org/10.5772/intechopen.87898*

**Figure 28.**

**173**

*Synthesis of acid fragment 71.*

Bao and coworkers in 2013 isolated 16-membered macrolide, aspergillide D, from the extract of *Aspergillus* sp. SCSGAF 0076 [56]. Aspergillide D macrolactone contains four chiral centres, α,β-unsaturation, three hydroxyl groups and the first

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 **69** by using three step sequence, that is, catalytic amount of H2SO4 & acetone to form acetonide which on reduction with NaBH4 and on oxidative cleavage of the diol with NaIO4. The lactol was subjected to Wittig type olefination using PPh3=CH2 and the obtained primary alcohol **70** was oxidized to carboxylic acid **71** by using TEMPO/ BAIB conditions (**Figure 28**). The synthesis of alcohol fragment was started with mono-PMB protection **73** of commercially available 1,8-octane diol **72** and the other alcohol was converted to racemic allyl alcohol **74** by Swern oxidation and subsequent treatment of aldehyde with vinyl magnesium bromide in the presence of CuI. The allylic alcohol **74** was subjected to standard Sharpless kinetic resolution conditions by using ()-DIPT & Ti(O*i*Pr)4 to obtain enantiomeric epoxy alcohol **75**. Upon MOM protection **76** to the secondary alcohol **75** and PMB deprotection produced **77**, which on oxidation with Dess-Martin periodinane to afford aldehyde. Aldehyde was converted to olefin **78** by treating PPh3=CH2 in THF. **78** was cleaved

Acid **71** and alcohol **79** fragments were coupled together under Yamaguchi esterification conditions afforded diene ester **80** in 65% yield. Intramolecular RCM was employed on diene ester by using Grubbs'second generation catalyst in refluxing CH2Cl2 to produce the requisite macrolactone **81**. Double bond in **81** was hydrogenated by using PtO2 in MeOH to attain saturated lactone **82**. Lactone **82** was

Ph3P=CHCO2Et in C6H6 afforded α,β-unsaturated ester **83**. The ester was converted

reduced with DIBAL-H to afford lactol which on further treatment with

to carboxylic acid **84** by LiOH in THF/H2O which on adopting key Shiina's

total synthesis was reported by Jena et al. in 2017 as follows [57].

to alcohol **79** by reduction with LAH in THF (**Figure 29**).

**Figure 26.** *Total synthesis of (+)-neopeltolide.*

**Figure 27.** *Alternate synthesis of (+)-neopeltolide.*

## **3.4 Aspergillide-D**

yield. Ketone **66** was selectively reduced to *syn*-alcohol using Et2BOMe and NaBH4

macrolactonization to furnish desired macrolactone **67**. Alkene in **67** was hydrogenated using Pd/C to afford desired alcohol **68** as a major product. Alcohol **68** was subjected to Mitsunobu conditions, followed by hydrolysis with K2CO3 in MeOH to

hydrogenolysis of benzyl ether achieved desired macrolide **49**. The final coupling of fragment **49** with oxazole side chain **50** with standard Mitsunobu conditions

followed by ester hydrolysis gave acid which was subjected to Yamaguchi

get the inversion product. Subsequent methylation with MeO3BF4 &

furnished target (+)-neopeltolide **32** (**Figure 27**).

*Organic Synthesis - A Nascent Relook*

**Figure 26.**

**Figure 27.**

**172**

*Alternate synthesis of (+)-neopeltolide.*

*Total synthesis of (+)-neopeltolide.*

Bao and coworkers in 2013 isolated 16-membered macrolide, aspergillide D, from the extract of *Aspergillus* sp. SCSGAF 0076 [56]. Aspergillide D macrolactone contains four chiral centres, α,β-unsaturation, three hydroxyl groups and the first total synthesis was reported by Jena et al. in 2017 as follows [57].

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 **69** by using three step sequence, that is, catalytic amount of H2SO4 & acetone to form acetonide which on reduction with NaBH4 and on oxidative cleavage of the diol with NaIO4. The lactol was subjected to Wittig type olefination using PPh3=CH2 and the obtained primary alcohol **70** was oxidized to carboxylic acid **71** by using TEMPO/ BAIB conditions (**Figure 28**). The synthesis of alcohol fragment was started with mono-PMB protection **73** of commercially available 1,8-octane diol **72** and the other alcohol was converted to racemic allyl alcohol **74** by Swern oxidation and subsequent treatment of aldehyde with vinyl magnesium bromide in the presence of CuI. The allylic alcohol **74** was subjected to standard Sharpless kinetic resolution conditions by using ()-DIPT & Ti(O*i*Pr)4 to obtain enantiomeric epoxy alcohol **75**. Upon MOM protection **76** to the secondary alcohol **75** and PMB deprotection produced **77**, which on oxidation with Dess-Martin periodinane to afford aldehyde. Aldehyde was converted to olefin **78** by treating PPh3=CH2 in THF. **78** was cleaved to alcohol **79** by reduction with LAH in THF (**Figure 29**).

Acid **71** and alcohol **79** fragments were coupled together under Yamaguchi esterification conditions afforded diene ester **80** in 65% yield. Intramolecular RCM was employed on diene ester by using Grubbs'second generation catalyst in refluxing CH2Cl2 to produce the requisite macrolactone **81**. Double bond in **81** was hydrogenated by using PtO2 in MeOH to attain saturated lactone **82**. Lactone **82** was reduced with DIBAL-H to afford lactol which on further treatment with Ph3P=CHCO2Et in C6H6 afforded α,β-unsaturated ester **83**. The ester was converted to carboxylic acid **84** by LiOH in THF/H2O which on adopting key Shiina's

**Figure 28.** *Synthesis of acid fragment 71.*

macrolactonization protocol to provide the desired mactrolactone **85** in 51% yield. On deprotection of acetonide with CuCl2.2H2O gave diol **86** and removal of MOM

Evan's strategy of bond connections & key reactions in the synthesis of **34** is

Smith's strategy [59] & Moslin's strategy of acutiphycin [60] is shown below

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

*Key reactions and strategies in the synthesis of miyakolide and acutiphycin.*

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.

group, the synthesis of aspergillide D **33** was achieved (**Figure 30**).

**3.5 Miyakolide**

*Total Synthesis of Macrolides*

*DOI: http://dx.doi.org/10.5772/intechopen.87898*

illustrated [58].

**3.6 Acutiphycin**

**4. Conclusions**

**Figure 31.**

organic and medicinal chemistry.

**Acknowledgements**

**175**

(**Figure 31**).

**Figure 29.** *Synthesis of alcohol fragment 79.*

**Figure 30.** *Completion of synthesis of aspergillide D.*

*Total Synthesis of Macrolides DOI: http://dx.doi.org/10.5772/intechopen.87898*

macrolactonization protocol to provide the desired mactrolactone **85** in 51% yield. On deprotection of acetonide with CuCl2.2H2O gave diol **86** and removal of MOM group, the synthesis of aspergillide D **33** was achieved (**Figure 30**).

## **3.5 Miyakolide**

Evan's strategy of bond connections & key reactions in the synthesis of **34** is illustrated [58].

## **3.6 Acutiphycin**

**Figure 29.**

**Figure 30.**

**174**

*Completion of synthesis of aspergillide D.*

*Synthesis of alcohol fragment 79.*

*Organic Synthesis - A Nascent Relook*

Smith's strategy [59] & Moslin's strategy of acutiphycin [60] is shown below (**Figure 31**).

**Figure 31.** *Key reactions and strategies in the synthesis of miyakolide and acutiphycin.*

## **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.

## **Acknowledgements**

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.

**References**

pp. 301-320

pp. 249-297

401a031

[5] Gage JR, Evans DA.

[1] Cowden CJ, Paterson I. Asymmetric Aldol reactions using boron enolates. Organic Reactions. 1997;**51**:1-200. DOI:

*DOI: http://dx.doi.org/10.5772/intechopen.87898*

of the American Chemical Society. 1980;

[9] Caron M, Sharpless KB. Titanium isopropoxide-mediated nucleophilic openings of 2,3-epoxy alcohols. A mild procedure for regioselective ringopening. The Journal of Organic Chemistry. 1985;**50**:1557-1560. DOI:

[10] Crane EA, Scheidt KA. Prins type macrocyclizations as an efficient ringclosing strategy in natural product synthesis. Angewandte Chemie, International Edition. 2010;**49**: 8316-8326. DOI: 10.1002/

[11] Parenty A, Moreau X, Campagne J-M. Macrolactonizations in the total synthesis of natural products. Chemical Reviews. 2006;**106**:911-939. DOI:

[12] Parenty A, Moreau X, Niel G, Campagne J-M. Update 1 of: Macrolactonizations in the total

[13] Gradillas A, Perez-Castells J. Macrocyclization by ring-closing metathesis in the total synthesis of natural products: Reaction conditions and limitations. Angewandte Chemie International Edition. 2006;**45**: 6086-6101. DOI: 10.1002/anie.

synthesis of natural products. Chemical Reviews. 2013;**113**:PR1-PR40. DOI:

[14] Nicolaou KC, Harter MW, Gunzner JL, Nadin A. The Wittig and related reactions in natural product synthesis. Liebigs Annalen. 1997;**1997**(7): 1283-1301. DOI: 10.1002/jlac.19971997

[15] Bisceglia JA, Orelli LR. Recent applications of the Horner-Wadsworth-

**102**:4263-4265. DOI: 10.1021/

ja00214a053

10.1021/jo00209a047

anie.201002809

10.1021/cr0301402

10.1021/cr300129n

200600641

0704

[2] Kim BM, Williams SF, Masamune S. The Aldol reaction: Group III enolates. In: Trost BM, Fleming I, editors. Comprehensive Organic Synthesis. Oxford, UK: Pergamon Press; 1991.

[3] Paterson I, Cowden CJ, Wallace DJ. Stereoselective Aldol reactions in the synthesis of polyketide natural products. In: Otera J, editor. Modern Carbonyl Chemistry. Weinheim, Germany: Wiley-VCH; 2000.

[4] Evans DA, Nelson JV, Vogel E, Taber TR. Stereoselective Aldol condensations via boron enolates. Journal of the American Chemical Society. 1981; **103**:3099-3111. DOI: 10.1021/ja00

Diastereoselective Aldol condensation using a chiral oxazolidinone auxiliary: (2S\*3S\*)-3-hydroxy-3-phenyl-2 methylpropanoic acid. Organic Syntheses. 1990;**68**:83-91. DOI: 10.15227/orgsyn.068.0083

[6] Walker MA, Heathcock CH. Extending the scope of the Evans asymmetric aldol reaction: Preparation of anti and "Non-Evans" Syn aldols. Journal of Organic Chemistry. 1991;**56**: 5747-5750. DOI: 10.1021/jo00020a006

[7] Katsuki T, Sharpless KB. The first practical method for asymmetric epoxidation. Journal of the American Chemical Society. 1980;**102**:5974-5976.

Asymmetric induction in the reaction of osmium tetroxide with olefins. Journal

DOI: 10.1021/ja00538a077

**177**

[8] Hentges SG, Sharpless KB.

10.1002/0471264180.or051.01

*Total Synthesis of Macrolides*

## **Author details**

Chebolu Naga Sesha Sai Pavan Kumar Division of Chemistry, Department of Sciences and Humanities, Vignan's Foundation for Science, Technology and Research, Guntur, Andhra Pradesh, India

\*Address all correspondence to: pavaniict@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

Anuradha and other staff members of chemistry department, Vignan for the fruit-

ful discussion. IntechOpen OAPF is greatly acknowledged.

*Organic Synthesis - A Nascent Relook*

**Author details**

**176**

Chebolu Naga Sesha Sai Pavan Kumar

provided the original work is properly cited.

\*Address all correspondence to: pavaniict@gmail.com

Division of Chemistry, Department of Sciences and Humanities, Vignan's

Foundation for Science, Technology and Research, Guntur, Andhra Pradesh, India

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

[1] Cowden CJ, Paterson I. Asymmetric Aldol reactions using boron enolates. Organic Reactions. 1997;**51**:1-200. DOI: 10.1002/0471264180.or051.01

[2] Kim BM, Williams SF, Masamune S. The Aldol reaction: Group III enolates. In: Trost BM, Fleming I, editors. Comprehensive Organic Synthesis. Oxford, UK: Pergamon Press; 1991. pp. 301-320

[3] Paterson I, Cowden CJ, Wallace DJ. Stereoselective Aldol reactions in the synthesis of polyketide natural products. In: Otera J, editor. Modern Carbonyl Chemistry. Weinheim, Germany: Wiley-VCH; 2000. pp. 249-297

[4] Evans DA, Nelson JV, Vogel E, Taber TR. Stereoselective Aldol condensations via boron enolates. Journal of the American Chemical Society. 1981; **103**:3099-3111. DOI: 10.1021/ja00 401a031

[5] Gage JR, Evans DA. Diastereoselective Aldol condensation using a chiral oxazolidinone auxiliary: (2S\*3S\*)-3-hydroxy-3-phenyl-2 methylpropanoic acid. Organic Syntheses. 1990;**68**:83-91. DOI: 10.15227/orgsyn.068.0083

[6] Walker MA, Heathcock CH. Extending the scope of the Evans asymmetric aldol reaction: Preparation of anti and "Non-Evans" Syn aldols. Journal of Organic Chemistry. 1991;**56**: 5747-5750. DOI: 10.1021/jo00020a006

[7] Katsuki T, Sharpless KB. The first practical method for asymmetric epoxidation. Journal of the American Chemical Society. 1980;**102**:5974-5976. DOI: 10.1021/ja00538a077

[8] Hentges SG, Sharpless KB. Asymmetric induction in the reaction of osmium tetroxide with olefins. Journal

of the American Chemical Society. 1980; **102**:4263-4265. DOI: 10.1021/ ja00214a053

[9] Caron M, Sharpless KB. Titanium isopropoxide-mediated nucleophilic openings of 2,3-epoxy alcohols. A mild procedure for regioselective ringopening. The Journal of Organic Chemistry. 1985;**50**:1557-1560. DOI: 10.1021/jo00209a047

[10] Crane EA, Scheidt KA. Prins type macrocyclizations as an efficient ringclosing strategy in natural product synthesis. Angewandte Chemie, International Edition. 2010;**49**: 8316-8326. DOI: 10.1002/ anie.201002809

[11] Parenty A, Moreau X, Campagne J-M. Macrolactonizations in the total synthesis of natural products. Chemical Reviews. 2006;**106**:911-939. DOI: 10.1021/cr0301402

[12] Parenty A, Moreau X, Niel G, Campagne J-M. Update 1 of: Macrolactonizations in the total synthesis of natural products. Chemical Reviews. 2013;**113**:PR1-PR40. DOI: 10.1021/cr300129n

[13] Gradillas A, Perez-Castells J. Macrocyclization by ring-closing metathesis in the total synthesis of natural products: Reaction conditions and limitations. Angewandte Chemie International Edition. 2006;**45**: 6086-6101. DOI: 10.1002/anie. 200600641

[14] Nicolaou KC, Harter MW, Gunzner JL, Nadin A. The Wittig and related reactions in natural product synthesis. Liebigs Annalen. 1997;**1997**(7): 1283-1301. DOI: 10.1002/jlac.19971997 0704

[15] Bisceglia JA, Orelli LR. Recent applications of the Horner-WadsworthEmmons reaction to the synthesis of natural products. Current Organic Chemistry. 2012;**16**:2206-2230. DOI: 10.2174/138527212803520227

[16] Chatterjee B, Bera S, Mondal D. Julia-Kocienski olefination: A key reaction for the synthesis of macrolides. Tetrahedron: Asymmetry. 2014;**25**:1-55. DOI: 10.1016/j.tetasy.2013.09.027

[17] Ronson TO, Taylor RJK, Fairlamb IJS. Palladium-catalysed macrocyclisations in the total synthesis of natural products. Tetrahedron. 2015; **71**:989-1009. DOI: 10.1016/j. tet.2014.11.009

[18] Corey EJ, Nicolaou KC. Efficient and mild lactonization method for the synthesis of macrolides. Journal of the American Chemical Society. 1974;**96**: 5614-5616. DOI: 10.1021/ja00824a073

[19] Shiina I, Kubota M, Ibuka R. A novel and efficient macrolactonization of ωhydroxycarboxylic acids using 2 methyl-6-nitrobenzoic anhydride (MNBA). Tetrahedron Letters. 2002;**43**: 7535-7539. DOI: 10.1016/S0040-4039 (02)01819-1

[20] Inanaga J, Hirata K, Saeki H, Katsuki T, Yamaguchi M. A rapid esterification by means of mixed anhydride and its application to largering lactonization. Bulletin of the Chemical Society of Japan. 1979;**52**: 1989-1993. DOI: 10.1246/bcsj.52.1989

[21] Kurihara T, Nakajima Y, Mitsunobu O. Synthesis of lactones and cycloalkanes. Cyclization of ω-hydroxy acids and ethyl α-cyano-ωhydroxycarboxylates. Tetrahedron Letters. 1976;**17**:2455-2458. DOI: 10.1016/0040-4039(76)90018-6

[22] Boden EP, Keck GE. Proton-transfer steps in Steglich esterification: A very practical new method for macrolactonization. The Journal of

Organic Chemistry. 1985;**50**:2394-2395. DOI: 10.1021/jo00213a044

[31] Grubbs RH, Miller SJ, Fu GC. Ringclosing metathesis and related processes in organic synthesis. Accounts of Chemical Research. 1995;**28**:446-452.

*DOI: http://dx.doi.org/10.5772/intechopen.87898*

[38] Heck RF, Nolley JP. Palladiumcatalyzed vinylic hydrogen substitution reactions with aryl, benzyl, and styryl halides. The Journal of Organic Chemistry. 1972;**37**:2320-2322. DOI:

[39] Heravi MM, Mohammadkhani L. Recent applications of Stille reaction in total synthesis of natural products: An update. Journal of Organometallic Chemistry. 2018;**869**:106-200. DOI: 10.1016/j.jorganchem.2018.05.018

[40] Milstein D, Stille JK. Palladiumcatalyzed coupling of tetraorganotin compounds with aryl and benzyl halides. Synthetic utility and

mechanism. Journal of the American Chemical Society. 1979;**101**:4992-4998.

[41] Sonogashira K, Tohda Y, Hagihara N. A convenient synthesis of acetylenes: Catalytic substitutions of acetylenic hydrogen with bromoalkenes, iodoarenes and bromopyridines. Tetrahedron Letters. 1975;**16**:

4467-4470. DOI: 10.1016/S0040-4039

[42] Trost BM, Fullerton TJ. New synthetic reactions. Allylic alkylation. Journal of the American Chemical Society. 1973;**95**:292-294. DOI: 10.1021/

[43] Trost BM. Cyclizations via

[new synthetic methods (79)]. Angewandte Chemie International Edition in English. 1989;**28**:1173-1192.

DOI: 10.1002/anie.198911731

[45] Ziegler FE, Chakraborty UR, Weisenfeld RB. A palladium-catalyzed carbon-carbon bond formation of

10.1021/ja710238h

palladium-catalyzed allylic alkylations

[44] Tortosa M, Yakelis NA, Roush WR. Total synthesis of (+)-superstolide A. Journal of the American Chemical Society. 2008;**130**:2722-2723. DOI:

DOI: 10.1021/ja00511a032

(00)91094-3

ja00782a080

10.1021/jo00979a024

[32] Wu Y, Esser L, De Brabander JK. Revision of the absolute configuration of salicylihalamide A through asymmetric total synthesis. Angewandte Chemie, International Edition. 2000;**39**: 4308-4310. DOI: 10.1002/1521-3773 (20001201)39:23%3C4308::aidanie4308%3E3.0.CO;2-4

[33] Garbaccio RM, Stachel SJ, Baeschlin

asymmetric synthesis of radicicol and monocillin I. Journal of the American

10903-10908. DOI: 10.1021/ja011364+

[34] Furstner A, Seidel G, Kindler N. Macrocycles by ring-closing metathesis, XI: Syntheses of (R)-(+)-lasiodiplodin, zeranol and truncated salicylihalamides. Tetrahedron. 1999;**55**:8215-8230. DOI: 10.1016/S0040-4020(99)00302-6

[35] Wang X, Bowman EJ, Bowman BJ, Porco JA. Total synthesis of the

salicylate enamide macrolide oximidine III: Application of relay ring-closing metathesis. Angewandte Chemie International Edition. 2004;**43**: 3601-3605. DOI: 10.1002/

[36] Xu Z, Johannes CW, Salman SS, Hoveyda AH. Enantioselective total synthesis of antifungal agent Sch 38516. Journal of the American Chemical Society. 1996;**118**:10926-10927. DOI:

Stereoselective synthesis of arylated (E)-alkenes by the reaction of alk-1 enylboranes with aryl halides in the presence of palladium catalyst. Journal of the Chemical Society, Chemical Communications. 1979;**1979**(19): 866-867. DOI: 10.1039/C39790000866

anie.200460042

10.1021/ja9626603

**179**

[37] Miyaura N, Suzuki A.

DK, Danishefsky SJ. Concise

Chemical Society. 2001;**123**:

DOI: 10.1021/ar00059a002

*Total Synthesis of Macrolides*

[23] Mukaiyama T, Usui M, Saigo K. The facile synthesis of lactones. Chemistry Letters. 1976;**5**:49-50. DOI: 10.1246/ cl.1976.49

[24] Hansen TV, Stenstrom Y. First total synthesis of ()-aplyolide A. Tetrahedron: Asymmetry. 2001;**12**: 1407-1409. DOI: 10.1016/S0957-4166 (01)00250-6

[25] Narasaka K, Maruyama K, Mukaiyama T. A useful method for the synthesis of macrocyclic lactone. Chemistry Letters. 1978;**7**:885-888. DOI: 10.1246/cl.1978.885

[26] Enev VS, Kaehlig H, Mulzer J. Macrocyclization via allyl transfer: Total synthesis of laulimalide. Journal of the American Chemical Society. 2001;**123**: 10764-10765. DOI: 10.1021/ja016752q

[27] Keck GE, Boden EP, Wiley MR. Total synthesis of (+)-colletodial: New methodology for the synthesis of macrolactones. The Journal of Organic Chemistry. 1989;**54**:896-906. DOI: 10.1021/jo00265a033

[28] Williams DR, Meyer KG. Total synthesis of (+)-amphidinolide K. Journal of the American Chemical Society. 2001;**123**:765-766. DOI: 10.1021/ja005644l

[29] Schweitzer D, Kane JJ, Strand D, McHenry P, Tenniswood M, Helquist P. Total synthesis of iejimalide B. An application of the Shiina macrolactonization. Organic Letters. 2007;**9**:4619-4622. DOI: 10.1021/ ol702129w

[30] Majumdar KC, Rahaman H, Roy B. Synthesis of macrocyclic compounds by ring closing metathesis. Current Organic Chemistry. 2007;**11**:1339-1365. DOI: 10.2174/138527207782023166

### *Total Synthesis of Macrolides DOI: http://dx.doi.org/10.5772/intechopen.87898*

[31] Grubbs RH, Miller SJ, Fu GC. Ringclosing metathesis and related processes in organic synthesis. Accounts of Chemical Research. 1995;**28**:446-452. DOI: 10.1021/ar00059a002

Emmons reaction to the synthesis of natural products. Current Organic Chemistry. 2012;**16**:2206-2230. DOI:

*Organic Synthesis - A Nascent Relook*

Organic Chemistry. 1985;**50**:2394-2395.

[23] Mukaiyama T, Usui M, Saigo K. The facile synthesis of lactones. Chemistry Letters. 1976;**5**:49-50. DOI: 10.1246/

[24] Hansen TV, Stenstrom Y. First total

Mukaiyama T. A useful method for the synthesis of macrocyclic lactone. Chemistry Letters. 1978;**7**:885-888. DOI:

[26] Enev VS, Kaehlig H, Mulzer J. Macrocyclization via allyl transfer: Total synthesis of laulimalide. Journal of the American Chemical Society. 2001;**123**: 10764-10765. DOI: 10.1021/ja016752q

[27] Keck GE, Boden EP, Wiley MR. Total synthesis of (+)-colletodial: New methodology for the synthesis of macrolactones. The Journal of Organic Chemistry. 1989;**54**:896-906. DOI:

[28] Williams DR, Meyer KG. Total synthesis of (+)-amphidinolide K. Journal of the American Chemical Society. 2001;**123**:765-766. DOI:

[29] Schweitzer D, Kane JJ, Strand D, McHenry P, Tenniswood M, Helquist P. Total synthesis of iejimalide B. An

macrolactonization. Organic Letters. 2007;**9**:4619-4622. DOI: 10.1021/

[30] Majumdar KC, Rahaman H, Roy B. Synthesis of macrocyclic compounds by ring closing metathesis. Current Organic Chemistry. 2007;**11**:1339-1365. DOI: 10.2174/138527207782023166

DOI: 10.1021/jo00213a044

synthesis of ()-aplyolide A. Tetrahedron: Asymmetry. 2001;**12**: 1407-1409. DOI: 10.1016/S0957-4166

[25] Narasaka K, Maruyama K,

cl.1976.49

(01)00250-6

10.1246/cl.1978.885

10.1021/jo00265a033

10.1021/ja005644l

ol702129w

application of the Shiina

[16] Chatterjee B, Bera S, Mondal D. Julia-Kocienski olefination: A key reaction for the synthesis of macrolides. Tetrahedron: Asymmetry. 2014;**25**:1-55. DOI: 10.1016/j.tetasy.2013.09.027

[17] Ronson TO, Taylor RJK, Fairlamb

macrocyclisations in the total synthesis of natural products. Tetrahedron. 2015;

[18] Corey EJ, Nicolaou KC. Efficient and mild lactonization method for the synthesis of macrolides. Journal of the American Chemical Society. 1974;**96**: 5614-5616. DOI: 10.1021/ja00824a073

[19] Shiina I, Kubota M, Ibuka R. A novel and efficient macrolactonization of ωhydroxycarboxylic acids using 2 methyl-6-nitrobenzoic anhydride (MNBA). Tetrahedron Letters. 2002;**43**: 7535-7539. DOI: 10.1016/S0040-4039

[20] Inanaga J, Hirata K, Saeki H, Katsuki T, Yamaguchi M. A rapid esterification by means of mixed anhydride and its application to largering lactonization. Bulletin of the Chemical Society of Japan. 1979;**52**: 1989-1993. DOI: 10.1246/bcsj.52.1989

[21] Kurihara T, Nakajima Y, Mitsunobu

cycloalkanes. Cyclization of ω-hydroxy

[22] Boden EP, Keck GE. Proton-transfer steps in Steglich esterification: A very

hydroxycarboxylates. Tetrahedron Letters. 1976;**17**:2455-2458. DOI: 10.1016/0040-4039(76)90018-6

macrolactonization. The Journal of

O. Synthesis of lactones and

acids and ethyl α-cyano-ω-

practical new method for

**178**

IJS. Palladium-catalysed

tet.2014.11.009

(02)01819-1

**71**:989-1009. DOI: 10.1016/j.

10.2174/138527212803520227

[32] Wu Y, Esser L, De Brabander JK. Revision of the absolute configuration of salicylihalamide A through asymmetric total synthesis. Angewandte Chemie, International Edition. 2000;**39**: 4308-4310. DOI: 10.1002/1521-3773 (20001201)39:23%3C4308::aidanie4308%3E3.0.CO;2-4

[33] Garbaccio RM, Stachel SJ, Baeschlin DK, Danishefsky SJ. Concise asymmetric synthesis of radicicol and monocillin I. Journal of the American Chemical Society. 2001;**123**: 10903-10908. DOI: 10.1021/ja011364+

[34] Furstner A, Seidel G, Kindler N. Macrocycles by ring-closing metathesis, XI: Syntheses of (R)-(+)-lasiodiplodin, zeranol and truncated salicylihalamides. Tetrahedron. 1999;**55**:8215-8230. DOI: 10.1016/S0040-4020(99)00302-6

[35] Wang X, Bowman EJ, Bowman BJ, Porco JA. Total synthesis of the salicylate enamide macrolide oximidine III: Application of relay ring-closing metathesis. Angewandte Chemie International Edition. 2004;**43**: 3601-3605. DOI: 10.1002/ anie.200460042

[36] Xu Z, Johannes CW, Salman SS, Hoveyda AH. Enantioselective total synthesis of antifungal agent Sch 38516. Journal of the American Chemical Society. 1996;**118**:10926-10927. DOI: 10.1021/ja9626603

[37] Miyaura N, Suzuki A. Stereoselective synthesis of arylated (E)-alkenes by the reaction of alk-1 enylboranes with aryl halides in the presence of palladium catalyst. Journal of the Chemical Society, Chemical Communications. 1979;**1979**(19): 866-867. DOI: 10.1039/C39790000866 [38] Heck RF, Nolley JP. Palladiumcatalyzed vinylic hydrogen substitution reactions with aryl, benzyl, and styryl halides. The Journal of Organic Chemistry. 1972;**37**:2320-2322. DOI: 10.1021/jo00979a024

[39] Heravi MM, Mohammadkhani L. Recent applications of Stille reaction in total synthesis of natural products: An update. Journal of Organometallic Chemistry. 2018;**869**:106-200. DOI: 10.1016/j.jorganchem.2018.05.018

[40] Milstein D, Stille JK. Palladiumcatalyzed coupling of tetraorganotin compounds with aryl and benzyl halides. Synthetic utility and mechanism. Journal of the American Chemical Society. 1979;**101**:4992-4998. DOI: 10.1021/ja00511a032

[41] Sonogashira K, Tohda Y, Hagihara N. A convenient synthesis of acetylenes: Catalytic substitutions of acetylenic hydrogen with bromoalkenes, iodoarenes and bromopyridines. Tetrahedron Letters. 1975;**16**: 4467-4470. DOI: 10.1016/S0040-4039 (00)91094-3

[42] Trost BM, Fullerton TJ. New synthetic reactions. Allylic alkylation. Journal of the American Chemical Society. 1973;**95**:292-294. DOI: 10.1021/ ja00782a080

[43] Trost BM. Cyclizations via palladium-catalyzed allylic alkylations [new synthetic methods (79)]. Angewandte Chemie International Edition in English. 1989;**28**:1173-1192. DOI: 10.1002/anie.198911731

[44] Tortosa M, Yakelis NA, Roush WR. Total synthesis of (+)-superstolide A. Journal of the American Chemical Society. 2008;**130**:2722-2723. DOI: 10.1021/ja710238h

[45] Ziegler FE, Chakraborty UR, Weisenfeld RB. A palladium-catalyzed carbon-carbon bond formation of

conjugated dienones: A macrocyclic dienone lactone model for the carbomycins. Tetrahedron. 1981;**37**: 4035-4040. DOI: 10.1016/S0040-4020 (01)93278-8

[46] Tanabe Y, Sato E, Nakajima N, Ohkubo A, Ohno O, Suenaga K. Total synthesis of biselyngbyolide A. Organic Letters. 2014;**16**:2858-2861. DOI: 10.1021/ol500996n

[47] Mohapatra DK, Bhattasali D, Gurjar MK, Khan MI, Shashidhara KS. First asymmetric total synthesis of penarolide sulfate A1. European Journal of Organic Chemistry. 2008;**2008**(36):6213-6224. DOI: 10.1002/ejoc.200800680

[48] Trost BM, Brickner SJ. Palladiumassisted macrocyclization approach to cytochalasins: A synthesis of antibiotic A26771B. Journal of the American Chemical Society. 1983;**105**:568-575. DOI: 10.1021/ja00341a043

[49] Toshima K, Tatsuta K. Recent progress in O-glycosylation methods and its application to natural products synthesis. Chemical Reviews. 1993;**93**: 1503-1531. DOI: 10.1021/cr00020a006

[50] Danishefsky SJ, Bilodeau MT. Glycals in organic synthesis: The evolution of comprehensive strategies for the assembly of oligosaccharides and glycoconjugates of biological consequence. Angewandte Chemie International Edition in English. 1996; **35**:1380-1419. DOI: 10.1002/ anie.199613801

[51] Wright AE, Botelho JC, Guzman E, Harmody D, Linley P, McCarthy PJ, et al. Neopeltolide, a macrolide from a lithistid sponge of the family Neopeltidae. Journal of Natural Products. 2007;**70**:412-416. DOI: 10.1021/np060597h

[52] Altmann KH, Carreira EM. Unraveling a molecular target of macrolides. Nature Chemical Biology. 2008;**4**:388-389. DOI: 10.1038/nchem bio0708-388

[53] Ghosh AK, Shurrush KA, Dawson ZL. Enantioselective total synthesis of macrolide (+)-neopeltolide. Organic & Biomolecular Chemistry. 2013;**11**: 7768-7777. DOI: 10.1039/C3OB41541D

[54] Paterson I, Miller NA. Total synthesis of the marine macrolide (+) neopeltolide. Chemical Communications. 2008;**2008**(39): 4708-4710. DOI: 10.1039/B812914B

[55] Ulanovskaya OA, Janjic J, Suzuki M, Sabharwal SS, Schumacker PT, Kron SJ, et al. Synthesis enables identification of the cellular target of leucascandrolide A and neopeltolide. Nature Chemical Biology. 2008;**4**:418-424. DOI: 10.1038/ nchembio.94

[56] Bao J, Xu XY, Zhang XY, Qi SH. A new macrolide from a marine-derived fungus *Aspergillus* sp. Natural Product Communications. 2013;**8**:1127-1128. DOI: 10.1177%2F1934578X1300800825

[57] Jena BK, Reddy GS, Mohapatra DK. First asymmetric total synthesis of aspergillide D. Organic & Biomolecular Chemistry. 2017;**15**:1863-1871. DOI: 10.1039/c6ob02435a

[58] Evans DA, Ripin DHB, Halstead DP, Campos KR. Synthesis and absolute assignment of (+)-miyakolide. Journal of the American Chemical Society. 1999; **121**:6816-6826. DOI: 10.1021/ja990789h

[59] Smith AB III, Chen SS-Y, Nelson FC, Reichert JM, Salvatore BA. Total syntheses of (+)-acutiphycin and (+) trans-20,21-didehydroacutiphycin. Journal of the American Chemical Society. 1997;**119**:10935-10946. DOI: 10.1021/ja972497r

[60] Moslin RM, Jamison TF. Highly convergent total synthesis of (+) acutiphycin. Journal of the American Chemical Society. 2006;**128**: 15106-15107. DOI: 10.1021/ja0670660

**181**

**Chapter 9**

**Abstract**

Complexes

available, non-toxic and economical.

cyclization reactions, polymerization

In singlet carbene, a lone pair of electron occupies sp2

**1. Introduction**

Catalytic Activity of Iron

*Badri Nath Jha, Nishant Singh and Abhinav Raghuvanshi*

Recent research towards development of more efficient as well as cost effective catalyst as a substitute to traditional precious metal catalysts has witnessed significant growth and interest. Importance has been given to catalyst based on 3d-transition metals, especially iron because of the broad availability and environmental compatibility which allows its use in various environmentally friendly catalytic processes. N-Heterocyclic carbene (NHC) ligands have garnered significant attention because of their unique steric and electronic properties which provide substantial scope and potential in organometallic chemistry, catalysis and materials sciences. In the context of catalytic applications, iron-NHC complexes have gained increasing interest in the past two decades and could successfully be applied as catalysts in various homogeneous reactions including C–C couplings (including biaryl cross-coupling, alkyl-alkyl cross-coupling, alkyl-aryl cross-coupling), reductions and oxidations. In addition to this, iron-NHC complexes have shown the ability to facilitate a variety of reactions including C-heteroatom bond formation reactions, hydrogenation and transfer-hydrogenation reactions, polymerization reactions, etc. In this chapter, we will discuss briefly recent advancements in the catalytic activity of iron-NHC complexes including mono-NHC, bis-NHC (bidentate), tripodal NHC and tetrapodal NHC ligands. We have chosen iron-NHC complexes because of the plethora of publications available, increasing significance, being more readily

**Keywords:** N-heterocyclic carbene (NHC), singlet carbenes, triplet carbenes, percent buried volume (% Vbur), *σ-donation*, *π-donation*, CO complexes, NO complexes, halide complexes, donor-substituted NHCs, pincer motifs, scorpionato motifs, macrocyclic ligands, piano stool motifs, iron-sulfur clusters, C-C bond formations, allylic alkylations, C-X (heteroatom) bond formations, reduction reactions,

Story of N-heterocyclic carbene builds up from an unstable non-isolable reactive species to a stable and highly flourished ligand for the synthesis of a variety of organometallic compounds and many important catalytic reactions. Based on the orbital occupancy of the electrons, carbenes can be classified as singlet and triplet carbenes.


N-Heterocyclic Carbene

## **Chapter 9**

conjugated dienones: A macrocyclic dienone lactone model for the carbomycins. Tetrahedron. 1981;**37**: 4035-4040. DOI: 10.1016/S0040-4020

*Organic Synthesis - A Nascent Relook*

2008;**4**:388-389. DOI: 10.1038/nchem

[53] Ghosh AK, Shurrush KA, Dawson ZL. Enantioselective total synthesis of macrolide (+)-neopeltolide. Organic & Biomolecular Chemistry. 2013;**11**: 7768-7777. DOI: 10.1039/C3OB41541D

[54] Paterson I, Miller NA. Total synthesis of the marine macrolide (+)-

Communications. 2008;**2008**(39): 4708-4710. DOI: 10.1039/B812914B

[55] Ulanovskaya OA, Janjic J, Suzuki M, Sabharwal SS, Schumacker PT, Kron SJ, et al. Synthesis enables identification of the cellular target of leucascandrolide A and neopeltolide. Nature Chemical Biology. 2008;**4**:418-424. DOI: 10.1038/

[56] Bao J, Xu XY, Zhang XY, Qi SH. A new macrolide from a marine-derived fungus *Aspergillus* sp. Natural Product Communications. 2013;**8**:1127-1128. DOI: 10.1177%2F1934578X1300800825

[57] Jena BK, Reddy GS, Mohapatra DK. First asymmetric total synthesis of aspergillide D. Organic & Biomolecular Chemistry. 2017;**15**:1863-1871. DOI:

[58] Evans DA, Ripin DHB, Halstead DP, Campos KR. Synthesis and absolute assignment of (+)-miyakolide. Journal of the American Chemical Society. 1999; **121**:6816-6826. DOI: 10.1021/ja990789h

[59] Smith AB III, Chen SS-Y, Nelson FC, Reichert JM, Salvatore BA. Total syntheses of (+)-acutiphycin and (+) trans-20,21-didehydroacutiphycin. Journal of the American Chemical Society. 1997;**119**:10935-10946. DOI:

[60] Moslin RM, Jamison TF. Highly convergent total synthesis of (+) acutiphycin. Journal of the American

15106-15107. DOI: 10.1021/ja0670660

Chemical Society. 2006;**128**:

neopeltolide. Chemical

nchembio.94

10.1039/c6ob02435a

10.1021/ja972497r

bio0708-388

[46] Tanabe Y, Sato E, Nakajima N, Ohkubo A, Ohno O, Suenaga K. Total synthesis of biselyngbyolide A. Organic Letters. 2014;**16**:2858-2861. DOI:

[47] Mohapatra DK, Bhattasali D, Gurjar MK, Khan MI, Shashidhara KS. First asymmetric total synthesis of penarolide sulfate A1. European Journal of Organic Chemistry. 2008;**2008**(36):6213-6224.

[48] Trost BM, Brickner SJ. Palladiumassisted macrocyclization approach to cytochalasins: A synthesis of antibiotic A26771B. Journal of the American Chemical Society. 1983;**105**:568-575.

DOI: 10.1002/ejoc.200800680

DOI: 10.1021/ja00341a043

[49] Toshima K, Tatsuta K. Recent progress in O-glycosylation methods and its application to natural products synthesis. Chemical Reviews. 1993;**93**: 1503-1531. DOI: 10.1021/cr00020a006

[50] Danishefsky SJ, Bilodeau MT. Glycals in organic synthesis: The evolution of comprehensive strategies for the assembly of oligosaccharides and

glycoconjugates of biological consequence. Angewandte Chemie International Edition in English. 1996;

**35**:1380-1419. DOI: 10.1002/

lithistid sponge of the family Neopeltidae. Journal of Natural Products. 2007;**70**:412-416. DOI:

[52] Altmann KH, Carreira EM. Unraveling a molecular target of macrolides. Nature Chemical Biology.

10.1021/np060597h

**180**

[51] Wright AE, Botelho JC, Guzman E, Harmody D, Linley P, McCarthy PJ, et al. Neopeltolide, a macrolide from a

anie.199613801

(01)93278-8

10.1021/ol500996n
