Strategies and Methods for the Synthesis of Anticancer Natural Product Neopeltolide and its Analogs

Abstract

Neopeltolide, isolated in 2007, with its novel structural features and potent anti cancer cell proliferation activity, has attracted a tremendous amount of synthetic efforts. This review briefly and chronologically summarizes each of the synthesis with the main focus on the strategies and methodologies for the construction of its cis-tetrahydropyran-containing macrolactone core.

1. INTRODUCTION

Natural products have always been valuable sources and inspirations for life-saving drug discovery.[1] Macrolide natural products are one of the most important families. Among them, tetrahydropyran (THP) and tetrahydrofuran (THF)-containing macrolides are a diverse subfamily of macrolides with a wide range of biological activities, particularly anticancer activity.[2] Neopeltolide (1) is a complex THP-containing macrolide isolated by Wright and co-workers in 2007 from a deep-water sponge of the family of Neopeltidae.[3] Its structure was first proposed as 1a, which was later revised to 1b and confirmed by total synthesis work. Structurally, neopeltolide and leucascandrolide A (2) [4] share a large portion of substructures, including the acid side chain (cf. 3) and part of their macrolactone ring systems.

Biologically, neopeltolide was revealed to be an extremely potent anti-proliferation compound against several cancer cell lines including P388 murine leukemia (IC₅₀ = 0.56 nM), A-549 human lung adenocarcinoma (IC₅₀ = 1.2 nM), and NCI-ADR-RES human ovarian sarcoma (IC₅₀ = 5.1 nM). It also showed strong cytostatic inhibitory effects in PANC-1 pancreatic and DLD-1 colorectal cell lines. Additionally, neopeltolide also exhibits potent antifungal activity against pathogenic yeast Candida albicans.

The structural complexity and potent anticancer activity of neopeltolide have attracted a great amount of synthetic efforts since its isolation. Many elegant syntheses have been developed. These syntheses have facilitated the structure-activity relationship study of its in vitro anticancer activity. More importantly, through total synthesis and target identification of the synthetic sample, Kozmin and co-workers have revealed that neopeltolide may inhibit mitochondrial ATP synthesis and identified cytochrome bc1 complex as the principle cellular target,[5] which provided the molecular basis for the potent antiproliferative activity of neopeltolide and related analogs.

2. SYNTHESIS

This review briefly summarizes the key strategies and methodologies of each synthesis with focus on the THP-containing macrolactone core synthesis. The synthesis of the side chain (cf. 3) will not be discussed here.[6]

The Panek Total Synthesis

Shortly after the isolation of neopeltolide, Panek and co-workers completed the first total synthesis in 2007 (Scheme 1) and revised the stereochemical assignment of the C₁₁ and C₁₃ stereogenic centers of neopeltolide (1a vs 1b, Figure 1).[7] Their synthesis commenced with compounds 4 and 5, which contain the C₉ stereocenter and C₁₃ stereocenter of neopeltolide, respectively. After 4 and 5 were converted to 6, Evans-Tishchenko reduction[8] was used to introduce the C₁₁ carbon center (d.r. 14:1) and the resulting alcohol was further transformed to 7. Upon treatment of compounds 7 and 8 with triflic acid, a [4+2] annulation took place smoothly to build dihydropyran 9, which was further advanced to seco-acid 10. Yamaguchi macrolactonization[9] provided macrolactone 12 in 44% yield. Oxymercuration followed by demercuration converted 12 to 13. The latter was advanced to neopeltolide (1b) with a sequence of esterification and Still-Gennari olefination.[10]

Scheme 1.

The Panek synthesis (2007)

Figure 1.

Structures of neopeltolide and leucascandrolide A

The Scheidt Total Synthesis

In the same year, Scheidt and co-workers completed an elegant total neopeltolide and revised its structure assignment as well (Scheme 2).[11] Their synthesis features a Mitsunobu reaction to install the side chain and a Prins-type macrocyclization to synthesize the THP-containing macrolactone core in one operation. As delineated in Scheme 2, a Ti(IV)-(S)-BINOL-catalyzed asymmetric aldol reaction was employed to introduce the C₃ stereocenter in intermediate 18. Compound 19 (derived from Noyori asymmetric hydrogenation) and 20 carrying the C₁₃ and C₉ stereocenters of neopeltolide, respectively, were eventually united together to provide compound 21, which underwent an Evans-Tishchenko reduction followed by methylation and removal of benzoate to produce 22. Scheidt and co-workers used a Yamaguchi reaction to join 22 and 18. The resulting ester was then transformed to aldehyde 23, which upon treatment with Sc(OTf)₃, underwent an efficient Prins-type macrocyclization to build the THP ring and the macrocyclic ring system in one step and provided compound 24 in 40% yield. The latter was then converted to neopeltolide smoothly via a sequence of decarboxylation, reduction and Mitsunobu esterification.

Scheme 2.

The Scheidt synthesis (2007)

The Maier Total Synthesis

In 2008, Maier and co-workers first reported a formal synthesis of neopeltolide followed by a total synthesis.[12] As summarized in Scheme 3, starting from aldehyde 26, which was synthesized from Noyori asymmetric hydrogenation followed by DIBAL-H reduction, a Leighton asymmetric allylation[13] was used to synthesize compound 28 with the C₁₁ stereocenter. After 28 was converted to α,β-unsaturated thioester 29, a Feringa-Minnaard reaction enabled the introduction of the C₉ methyl group in a stereoselective manner.[14] Reduction of thioester 31 afforded aldehyde 32. The latter underwent a Prins reaction with homoallylic alcohol 33 (again derived from a Leighton asymmetric allylation) to provid tetrahydropyran product 34 in 72% yield (d.r. 8:1). After 34 was converted to seco-acid 35, Maier and co-workers used a Yamaguchi macrolactonization to synthesize 36, which was then advanced to neopeltolide via MOM-deprotection and Mitsunobu reaction. Notably, Maier and co-workers have provided insightful SAR information about the acid side chain’s effect on neopeltolide’s anticancer activity. A slightly more potent analog has been identified.

Scheme 3.

The Maier synthesis (2008)

The Lee Total Synthesis

In the same year, Lee and co-workers reported an elegant total synthesis of neopeltolide featuring a Prins-type macrocyclization as a key step to build the THP-macrolactone in one step (Scheme 4).[15] Their synthesis started with a crotyl transfer reaction from 38 to aldehyde 37. The resulting homoallylic alcohol was further converted to 39 via benzyl protection and ozonolysis. They then used a titanium (IV)-mediated diastereoselective methallylation followed by esterification with 41 to synthesize 42 which was equipped with a directing group for the next hydroformylation. The substrate-directed hydroformylation of 42 preferentially produced desired aldehyde 43, which was further converted to dimethyl acetal 44. Removal of the benzyl-protecting group followed by DCC promoted esterification with acid 45 gave ester 46. After oxidative removal of the PMB-protecting group, a Prins-type macrocyclization took place smoothly to set up two stereocenters (C₅ and C₇) and the THP-macrolactone core in one step and provided 48 in good yield, which was converted to neopeltolide shortly. Notably, Lee and co-workers also developed an alternative Prins-cyclization to synthesize 48.

Scheme 4.

The Lee synthesis (2008)

The Kozmin Total Synthesis

In 2008, Kozmin and co-workers reported an elegant total synthesis of neopletolide as well as a simplified analog of leucascandrolide A (Scheme 5).[5] More importantly, they have shown that neopeltolide and leucascandrolide A may inhibit mitochondrial ATP synthesis and identified cytochrome bc1 complex as the principle cellular target, which provided the molecular basis for the potent antiproliferative activity of neopeltolide and leucascandrolide A. Their synthesis initiated with a Prins desymmetrization of 49 to form the THP-ring. Benzyl protection followed by Wacker oxidation converted the Prins cyclization product to ketone 50. Boron enolate promoted aldol reaction between 50 and 51 gave 52 in high stereoselectivity at C₁₁ (>98:2). While the stereochemical outcome at C₁₁ is opposite from what is required for the synthesis of neopeltolide, this new stereocenter facilitated the introduction of the C₁₃ stereocenter via a 1,3-syn selective reaction (cf. 53→54) and was inverted to the desired one via a Mitsunobu reaction at a later stage. Yamaguchi macrolactonization was used to build the 14-membered lactone in preference of a more strained 12-membered lactone. Kozmin and co-workers then developed a diastereoselective hydrogenation to introduce the C₉ stereocenter by taking advantage of macrocyclic stereochemical control and product 56 was obtained in 61% yield (d.r. 3:1), which was advanced to 25 then to neopeltolide smoothly with two Mitsunobu reactions as the key transformations.

Scheme 5.

The Kozmin synthesis (2008)

The Fuwa and Sasaki Total Synthesis

Fuwa, Sasaki and co-workers reported their first generation total synthesis of neopeltolide in 2008 as well (Scheme 6).[16] Their synthesis features a B-alkyl Suzuki cross coupling to unite compounds 57 and 58 to provide diene 59, which underwent a ring closing metathesis reaction followed by hydrogenation to provide product 60 with the desired cis-THP ring. The latter was further advanced to seco-acid 61. Again, Yamaguchi reaction was used to prepare the macrolactone ring. The macrocyclization product was transformed to neopeltolide upon removal of BOM-protecting group and Mitsunobu reaction with 3.

Scheme 6.

The Fuwa and Sasaki synthesis (2008 and 2010)

In 2010, Fuwa and Sasaki reported their second-generation synthesis, which features a hydroxyl group directed cross-metathesis over a ring closing metathesis to convert 62 to 64.[17] After protection group adjustment, DBU-promoted intramolecular oxa-conjugate addition of 65 afforded compound 66 in 73% yield (d.r. >20:1). The latter underwent Yamaguchi esterification with alcohol 68 to give diene 69 in excellent yield. Ring closing metathesis using the Grubbs second-generation catalyst built the macrocyclic ring. The RCM product was converted to 25 with a one-pot hydrogenation to remove both the BOM-protecting group and the double bond. Notably, unlike Kozmin’s case of hydrogenation of the exo-methylene group, a single diastereomer was obtained in Fuwa and Sasaki’s case with an internal double bond. The two synthetic approaches allowed Fuwa, Sasaki and co-workers to extensively explore the structure-activity relationship of neopeltolide’s anticancer activity.[18]

The Paterson Total Synthesis

Paterson and Miller reported their total synthesis of neopeltolide in 2008 (Scheme 7).[19] Unlike the previous syntheses, they used an asymmetric hetero-Diels-Alder reaction to construct the THP-ring. Their synthesis started with aldehyde 70, which underwent Brown methallylation with 71 followed by methylation to provide 72. The latter was advanced to aldehyde 73 shortly. Paterson and Miller employed a MacMillan organocatalytic hydride reduction to introduce the C₉ stereocenter while with 76:24 diastereoselectivity. With aldehyde 75 in hand, they used a Jacobsen asymmetric hetero-Diels-Alder reaction between 75 and 76 to provide 78 in 78% yield with Cr(III) catalyst 77. The latter was advanced to 79, then to neopeltolide with a Yamaguchi macrolactonization and a Mitsunobu reaction as the key steps.

Scheme 7.

The Paterson synthesis (2008)

The Taylor Formal Synthesis

The Taylor group at the University of Notre Dame developed a radical cyclization strategy to build the cis-THP-ring and completed a formal synthesis of neopeltolide.[20] As shown in Scheme 8, their synthesis started with commercially available compound 80 containing the C₉ stereocenter, which was furnished to 81. They employed the Soderquist asymmetric allylation[21] to install the C₇ alcohol, which was further protected as BOM-ether 83. Compound 83 was then linked with β-hydroxylsulfide 84 using the Rychnovsky method to produce β-hydroxy ketone 85 in 92% yield.[22] Evans-Tishchenko reduction of 85 introduced the C₁₁ alcohol with excellent stereoselectivity. The newly generated alcohol was converted to the desired methyl ether 86. The highlight of the Taylor synthesis is an iodo-ether transfer reaction to convert 86 to 87 with the desired C₅ stereocenter in 71% yield (d.r. >20:1). The ether transfer reaction also released the C₇ alcohol for the next oxa-conjugate addition to 88 to provide compound 89, which underwent a radical reaction to form compound 90 with the desired cis-THP-ring in excellent yield and selectivity. Compound 90 was then quickly advanced to Panek’s intermediate 13. Again, Yamaguchi macrolactonization was used to build the neopeltolide macrolactone.

Scheme 8.

The Taylor synthesis (2008)

The Roulland Total Synthesis

The saga of neopeltolide synthesis continues in the year of 2009. Roulland and Guinchard developed an elegant total synthesis featuring a tandem ene-yne coupling followed by oxa-Michael addition to construct the cis-THP-ring of neopeltolide.[23] As shown in Scheme 9, 1,2-addition of Grignard reagent 92 to Weinreb amide 91 (prepared using asymmetric hydrogentation as key step) followed by Evans-Tishchenko reduction provided compound 93 in excellent yield. Esterification of the latter followed by ring-closing metathesis gave α,β-unsaturated lactone 94, which was converted to aldehyde 95 with a substrate-controlled hydrogenation to introduce the C₉ stereocenter as a key step. In^III-catalyzed asymmetric propargylation reaction with 96 converted 95 to homopropargylic alcohol 97.[24] This reaction occurred with a full stereoselective transfer of the trimethylsilylpropynyl group from chiral alcohol 96 to 95. Roulland and Guinchard then developed an efficient Rucatalyzed tandem alkyne-enal coupling/stereoselective oxa-Michael addition sequence to convert 97 to 99. The latter, upon a sequence of oxidative cleavage of the C-C double bond, oxidation of the aldehyde to carboxylic acid, Yamaguchi macrolactonization, stereoselective ketone reduction and Mitsunobu reaction, was advanced to neopeltolide.

Scheme 9.

Roulland synthesis (2009)

The Hong Formal Synthesis

Hong and co-workers developed a tandem allylic oxidation/oxa-Michael addition to synthesize 2,6-cis-tetrahydropyrans and applied it nicely to a formal synthesis of neopeltolide (Scheme 10).[25] Their synthesis started with sequential coupling of dithiane 100 with iodide 101 and (R)-epichlorohydrin followed by epoxide opening to provide 102. After removal of the thioketal, Evans-Tishchenko reduction provided the desired anti-1,3-diol, which was methylated to give product 103. They then used Sharpless dihydroxylation to introduce the C₇ stereocenter. The resulting diol was further converted epoxide 105. Again, dithiane coupling was used to connect 105 and 106 to provide key intermediate 107. Upon treatment of MnO₂, the allylic alcohol of 107 was oxidized to an α,β-unsaturated aldehyde to trigger an oxa-Michael addition to form the 2,6-cis-THP ring. Further oxidation with the condition of MnO₂, DBU, and 108 in methanol converted the resulting aldehyde to ester 109. This allylic oxidation/oxa-Michael reaction/oxidation sequence was chemoselective and stereoselective. After hydrolysis of 109, Shiina macrolactonization was used to synthesize the neopeltolide macrolactone, which was further converted to known alcohol 25 upon thio-ketal removal and reduction of the resulting ketone.

Scheme 10.

The Hong synthesis (2009)

The Floreancig Total Synthesis

Floreancig and co-workers have developed an oxidative C-C bond formation for the synthesis of cis-THP ring in the presence of macrocycles. They further applied this strategy to the total synthesis of neopeltolide and its analogs (Scheme 11).[26] Their synthesis commenced with a convergent approach to unite three building blocks 112, 113, and 114 together via an etherification and Sonogashira cross coupling to provide compound 115. They then used a Pt(DVDS)-mediated intramolecular hydrosilylation followed by Tamao oxidation to convert one of the alkyne groups to a ketone (cf. 115→116) in a regioselective fashion. Again, Evans-Tishchenko reduction was used to install the C₁₁ stereocenter. Compound 116 was then advanced to seco-acid 117, which underwent a Yamaguchi macrolactonization to provide 12-membered lactone 118 in 72% yield. The synthesis of the oxidative cyclization precursor 119 was accomplished by a ruthenium-mediated addition of HOAc across the alkyne in 82% with 5:1 regioselectivity. DDQ oxidation of 119 promoted the oxidative carbocation cyclization to form the desired cis-THP ring. The resulting product was then converted to 79 via macrocycle-controlled hydrogenation, which was further converted to neopeltolide via NaBH₄ reduction and Mitsunobu reaction.

Scheme 11.

The Floreancig synthesis (2009)

The Yadav Formal Synthesis

Yadav and co-workers started with chiral pool (S)-citronellol (120), which contains the C₉ stereocenter of neopeltolide (Scheme 12).[27] After (S)-citronellol was advanced to aldehyde 121 via oxidative degradation, a Prins cyclization of 121 and (S)-pent-4-ene-1,2-diol (122) was utilized to set up the C₁₁ and C₁₃ stereocenter in one operation. The unwanted stereocenter from 122, after serving as a chiral auxiliary in the Prins cyclization step was removed with a reductive elimination of iodide 124. The open chain product 125 was further converted to 126, a key intermediate for Lee’s synthesis. Following Lee’s Prins macrocyclic protocol, Yadav and co-workers completed a formal synthesis of neopeltolide in 2009.

Scheme 12.

The Yadav synthesis (2009)

The Jennings Formal Synthesis (−)-Neopeltolide

The Jennings’ synthesis was reported in 2010 (Scheme 13).[28] Jennings and co-worker developed two synthetic approaches to synthesize 127. One involves a Reformatsky reaction; the other one involves a ring closing metathesis to form the 6-membered lactone. Substrate-controlled hydrogenation converted 127 to 128 and introduced the C₉ stereocenter. After advancing 128 to 129, they used a Brown asymmetric allylation followed by cross metathesis catalyzed by the second-generation Grubbs catalyst to produce 131. Following the Evans protocol for the diastereoselective synthesis of 1,3-syn-diols,[29] ester 131 was converted to 132 with the treatment of benzaldehyde and catalytic amount of KOtBu. After converting 132 to 133, Jennings and co-worker used a stereoselective reduction with the combination of TFA/Et₃SiH to synthesize 134 with the desired cis-THP ring in 70% yield with excellent diastereoselective (d.r. >20:1). Compound 134 was successfully converted to the neopeltolide macrolactone ent-13 with Yamaguchi reaction as a key transformation.

Scheme 13.

Jennings synthesis (2010)

The She Formal Synthesis

She and co-workers from Lanzhou University report an elegant synthesis of the neopeltolide macrolactone in 2011 (Scheme 14).[30] Their synthesis commenced with an efficient iridium-catalyzed double asymmetric carbonyl allylation developed by the Krische group to convert 1,3-propanediol 136 to the C₂-symmetric diol 138 in 72% yield.[31] The latter was then subjected to the Semmelhack’s palladium-catalyzed alkoxycarbonylation reaction[32] to provide tetrahydropyran 139 in excellent yield and stereoselectivity (d.r. > 20:1). After 139 was furnished to 140, Shiina’s protocol was used to connect 140 and 68 together and provide diene 141. Ring closing metathesis catalyzed by Hoveyda-Grubbs second-generation catalyst converted 141 to macrocyclic compound 142, which was further advanced to known intermediate 25 upon removal of the benzyl-protecting group and the unsaturated double bond in one pot.

Scheme 14.

The She synthesis (2011)

The Sharma Formal Synthesis

Sharma and co-workers synthesized both 143 and 144 from chiral pool L-malic acid (Scheme 15).[33] After DDC coupling of them, a ring closing metathesis was used to form the 14-membered macrocyclic ring with a different disconnection from the She and Fuwa/Sasaki syntheses. After oxidative removal of the PMB-protecting group, they developed an elegant transannular oxy-mercuration of 146 to build the cis-THP ring and provide 147 in 84% yield and excellent selectivity. Notably, poor diastereoselectivity was obtained when a related transannular iodo-etherification was employed. Radical removal of mercury followed by hydrolysis of MOM-ether converted 147 to the Panek intermediate 13.

Scheme 15.

The Sharma synthesis (2012)

The Raghavan Formal Synthesis

Raghavan and co-worker used the MacMillan’s organocatalytic hydride reduction catalyzed by 74 to reduce enal 148 to introduce the C₉ stereocenter and produce aldehyde 149 (Scheme 16).[34] Hetero-Diels-Alder reaction catalyzed by (S,S)-Cr(III)-salen between 149 and the Danishefsky diene 150 proceeded smoothly to produce 151 in 75% yield with high stereoselectivity at C₇. The C₇ stereocenter controls the reduction of the carbonyl group of 151 by the Luche protocol to introduce the C₅ stereocenter, which was transferred to C₃ via a Claisen rearrangement (cf. 152→153). The Claisen product was further advanced to 154. Treatment of 154 with LDBB and aldehyde 70 gave an epimeric mixture of alcohols, which were oxidized by IBX to yield ketone 155. After several functional group manipulations, 155 was converted to the Panek seco-acid 10, then to macrolactone 12 uneventfully.

Scheme 16.

The Raghavan synthesis (2012)

The S. Ghosh Formal Synthesis

The S. Ghosh’s synthesis started with known alcohol 156, which was converted to 157 with two Jacobsen hydrolytic kinetic resolutions as key steps to introduce the C₁₁ and C₁₃ stereocenters (Scheme 17).[35] Compound 157 was then condensed with ketophosphonate 158 by a Horner-Wadsworth-Emmons reaction to provide enone 159 in 77% yield. The authors then developed a palladium(II)-catalyzed oxa-Michael reaction to build the cis-THP ring and product 160 was produced in 48% yield accompanied by 12% of the undesired stereoisomer. Uneventfully, compound 160 was advanced to the known enone 79 with a Yamaguachi macrolactonization as the key step to form the macrolactone ring.

Scheme 17.

The S. Ghosh synthesis (2012)

The A. Ghosh Total Synthesis

The A. Ghosh group at Purdue University completed an elegant total synthesis of neopeltolide in 2013 (Scheme 18).[36] Their synthesis commenced with an enzymatic desymmetrization of 3-methylglutaric anhydride 161 using PS-30 “Amano” lipase to introduce the C₉ stereocenter. The reduced product 162 was then converted to 163 with two Brown asymmetric allylations as key steps to install the C₁₁ and C₁₃ stereocenters. Compound 163 was further converted to 164 equipped with a diene functional group for the next hetero-Diels-Alder reaction to build the cis-THP ring. The Jacobsen Cr(III)-catalyst 166 served well to catalyze the hetero-Diels-Alder reaction between 164 and 165 to provide 167 in 83% yield. Notably, this hetero-Diels-Alder reaction is very sensitive to the length of the aldehyde side chain. After 167 was advanced to seco-acid 168, Yamaguchi macrolactonization was used to synthesize macrolactone 79, which was then converted to neopeltolide shortly.

Scheme 18.

The A. Ghosh synthesis (2013)

The Dai Synthesis of 9-Demethylneopeltolide[37]

We recently developed a palladium-catalyzed alkoxycarbonylative macrolactonization method to synthesize various THP-containing macrolactones with different ring sizes and functional groups (Scheme 19, 169→170). This reaction also worked smoothly for the macrolactonization of tertiary alcohols. To demonstrate its application in synthesizing complex natural products and their analogs, we used it to synthesize 9-demethylneopeltolide, a simplified analog of neopeltolide but with similar anti-cancer activity as neopeltolide. When substrate 171 was subjected to the palladium-catalyzed alkoxycarbonylative macrolactonization conditions, desired product 172 was produced in 58% yield with excellent cis-selectivity. Compound 172 was then converted to 9-demethylneopeltolide 174 via a sequence of ketal removal, NaBH₄ reduction and Mitsunobu reaction. The palladium-catalyzed alkoxycarbonylative macrolactonization enabled the installation of the cis-THP-ring and the macrolactone ring in one operation. Carbon monoxide was used as the carbonyl sources. No pre-carboxylate synthesis is required.

Scheme 19.

The Dai synthesis of 9-demethylneopeltolide (2014)

The Hoveyda Total Synthesis of Neopeltolide

Very recently, Hoveyda and co-workers have reported an elegant total synthesis of neopeltolide.[38] Their synthesis started with an enantioselective boron conjugate addition catalyzed by chiral N-heterocyclic carbene 176 to convert 175 to 177 with the desired C₁₃ stereocenter. The latter was then advanced to known intermediate 68 quickly with a sequence of 1,2-addition, Evans-Tishchenko reduction, methylation and hydrolysis. They synthesized tetrahydropyran 181 with a powerful enantioselective ring-opening cross-metathesis involving oxabicyclic alkene 178 and vinyl ether 179 in the presence of Mo MAP complex 180. Upon hydrolysis and oxidation, 181 was converted to acid 182, which was then coupled with alcohol 68 to provide diene 183. The latter underwent ring-closing metathesis smoothly with Mo bis(aryloxide) 184 as catalyst and product 142 was produced in 89% yield in gram-scale, which was further advance to neopeltolide with a sequence of hydrogenation and Mitsunobu reaction. Notably, Hoveyda and co-workers also developed a short and stereoselective route to synthesize linear acid 3 featuring two highly Z-selective cross-metathesis steps to construct the two cis-double bonds of acid 3.

3. CONCLUSION

Since its isolation in 2007, neopeltolide has aroused many interests in the fields of organic synthesis, chemical biology, and anticancer drug discovery, due to its intriguing structure and potent anticancer activity. Many elegant syntheses have been developed. These syntheses have enabled (i) the elucidation of its correct structure, (ii) preparation of sufficient material for biological evaluations, (iii) identification of its potential cellular targets, (iv) establishment of structure-activity relationship, (v) identification of simplified analogues with similar biological activity, and (vi) development of different strategies and novel synthetic methodologies. These practices demonstrated the importance of total synthesis. They also paved the way for future anticancer drug discovery based on neopeltolide and related natural products.

Scheme 20.

The Hoveyda synthesis (2014)