Epoxide-Based Synthetic Approaches toward Polypropionates and Related Bioactive Natural Products

Polypropionate units are a common structural feature of many of the natural products in polyketides, some of which have shown a broad range of antimicrobial and therapeutic potential. Polypropionates are composed of a carbon skeleton with alternating methyl and hydroxy groups with a specific configuration. Different approaches have been developed for the synthesis of polypropionates and herein we include, for the first time, all of the epoxide-based methodologies that have been reported over the years by several research groups such as Kishi, Katsuki, Marashall, Miyashita, Prieto, Sarabia, Jung, McDonald, etc. Several syntheses of polypropionate fragments and natural products that employed epoxides as key intermediates have been described and summarized in this review. These synthetic approaches involve enatio- and diastereoselective synthesis of epoxides (epoxy-alcohols, epoxy-amides, and epoxy-esters) and their regioselective cleavage with carbon and/or hydride nucleophiles. In addition, we included a description of the isolation and biological activities of the polypropionates and related natural products that have been synthetized using epoxide-based approaches. In conclusion, the epoxide-based methodologies are a non-aldol alternative approach for the construction of polypropionate.


Introduction
All living organisms have the capacity to transform and interconvert a variety of molecules using two types of metabolic pathways, primary and secondary metabolism, with this review focusing primarily on the latter. In general, the majority of organisms produce different kinds of secondary metabolites in a limited distribution and play an important role in the well-being of the producer [1]. Polyketides are secondary metabolites derived from the acetate pathway and are an important large family of natural products biosynthesized by animals, bacteria, fungi, and plants. This process occurs through the Claisen condensation of C 3 -units catalyzed by the enzyme polyketide synthases (PKSs) [2]. Polyketides include groups of fatty acids, aromatic compounds (e.g., anthraquinones, tetracyclines), and polypropionates ( Figure 1). Polypropionates are further classified into subgroups including macrolide antibiotics, linear polyketides, and polyethers [3]. In fact, more than 10,000 polyketides have been reported and about 1% of them possess drug activity (typically antibiotic, anticancer, antifungal, antiparasitic, immunomodulatory action, and cholesterol lowering agents), which is approximately five times more bioactive than the average of other natural product families [3,4]. Around 20% of the top-selling, small-molecule drugs are polyketides [5]. The propionate unit consists of an aliphatic chain with alternating methyl and hydroxy groups with a specific configuration at each carbon ( Figure 2). For decades, the construction of polypropionate chains has attracted the great interest of synthetic organic chemists due to the challenge represented by the elaboration of their array of contiguous asymmetric centers. As the number of stereocenters increases, the difficulty of synthesizing these compounds also increases. In 1987, the term "stereo-n-ad" was introduced by Hoffman, in which n refers to the number of asymmetric carbons within the propionate chain [6]. For example, three and five chiral centers represent a stereotriad and stereopentad, respectively. Aldol type reactions represent one of the primarily used methods for the regio-, stereo-, and enantioselective formation of propionates that has been developed [7][8][9]. Furthermore, other methods for the stereoselective assembly of long sequences of stereocenters in polypropionates have been developed. These methods include crotylations [10][11][12], allenylations [13][14][15], selective radical processes [16][17][18][19], sequential substitutions [20,21], epoxide ring openings [22][23][24][25], Diels-Alder [26], and others [27][28][29][30] (Figure 3). In this review, we describe the structures, classification, and antimicrobial activities of approximately thirty polypropionate natural products that have been synthesized using epoxide-based approaches by different research groups from 1980 to 2020. Some research groups reported their epoxide-based methodologies for a partial and/or total synthesis of polypropionates. Therefore, this review describes and depicts the general epoxide-based approach of each group including key steps to construct the polypropionate units, an example in the synthesis of a polypropionate fragment, and all the polypropionate fragments and/or natural products reported by each group. The propionate unit consists of an aliphatic chain with alternating methyl and hydroxy groups with a specific configuration at each carbon ( Figure 2). For decades, the construction of polypropionate chains has attracted the great interest of synthetic organic chemists due to the challenge represented by the elaboration of their array of contiguous asymmetric centers. As the number of stereocenters increases, the difficulty of synthesizing these compounds also increases. In 1987, the term "stereo-n-ad" was introduced by Hoffman, in which n refers to the number of asymmetric carbons within the propionate chain [6]. For example, three and five chiral centers represent a stereotriad and stereopentad, respectively. Aldol type reactions represent one of the primarily used methods for the regio-, stereo-, and enantioselective formation of propionates that has been developed [7][8][9]. Furthermore, other methods for the stereoselective assembly of long sequences of stereocenters in polypropionates have been developed. These methods include crotylations [10][11][12], allenylations [13][14][15], selective radical processes [16][17][18][19], sequential substitutions [20,21], epoxide ring openings [22][23][24][25], Diels-Alder [26], and others [27][28][29][30] (Figure 3). The propionate unit consists of an aliphatic chain with alternating methyl and hydroxy groups with a specific configuration at each carbon ( Figure 2). For decades, the construction of polypropionate chains has attracted the great interest of synthetic organic chemists due to the challenge represented by the elaboration of their array of contiguous asymmetric centers. As the number of stereocenters increases, the difficulty of synthesizing these compounds also increases. In 1987, the term "stereo-n-ad" was introduced by Hoffman, in which n refers to the number of asymmetric carbons within the propionate chain [6]. For example, three and five chiral centers represent a stereotriad and stereopentad, respectively. Aldol type reactions represent one of the primarily used methods for the regio-, stereo-, and enantioselective formation of propionates that has been developed [7][8][9]. Furthermore, other methods for the stereoselective assembly of long sequences of stereocenters in polypropionates have been developed. These methods include crotylations [10][11][12], allenylations [13][14][15], selective radical processes [16][17][18][19], sequential substitutions [20,21], epoxide ring openings [22][23][24][25], Diels-Alder [26], and others [27][28][29][30] (Figure 3). In this review, we describe the structures, classification, and antimicrobial activities of approximately thirty polypropionate natural products that have been synthesized using epoxide-based approaches by different research groups from 1980 to 2020. Some research groups reported their epoxide-based methodologies for a partial and/or total synthesis of polypropionates. Therefore, this review describes and depicts the general epoxide-based approach of each group including key steps to construct the polypropionate units, an example in the synthesis of a polypropionate fragment, and all the polypropionate fragments and/or natural products reported by each group.  In this review, we describe the structures, classification, and antimicrobial activities of approximately thirty polypropionate natural products that have been synthesized using epoxide-based approaches by different research groups from 1980 to 2020. Some research groups reported their epoxide-based methodologies for a partial and/or total synthesis of polypropionates. Therefore, this review describes and depicts the general epoxidebased approach of each group including key steps to construct the polypropionate units, an example in the synthesis of a polypropionate fragment, and all the polypropionate fragments and/or natural products reported by each group. Macrolides are a large family of polypropionates in which the majority exhibit antibiotic activity, and their structure is characterized by a range of 12-, 14-, 16-, 18-, or 22-membered macrocyclic lactone rings. For example, methymycin 1 ( Figure 4) is a 12-membered macrolide antibiotic biosynthesized by Streptomyces venezuelae [31]. Prelog-Djerassi 2 ( Figure 4) is a 6-membered polypropionate lactone that was obtained as a degradation product of 1 and retains the configuration of the four chiral centers corresponding to the C1-C7 polypropionate fragment. Erythromycin A 3a ( Figure 4) is a 14-membered macrolide antibiotic produced by Saccharolyspora erythraea and was isolated in 1952 [1]. Erythromycins show activity against Gram-positive bacteria, penicillin resistant Staphilococus strains, and are used to treat infections of Legionella pneumophilia. The mechanism of action consists in the inhibition of the protein biosynthesis in the organism. The structure was elucidated by spectroscopic methods and confirmed by X-ray crystallography [32]. Erythromycin A 3a attaches at the C3 and C5 two sugars, D-desoamine and L-cladinose, respectively, and the aglycone structure. It is worth noting that erythronolide A 3b does not have the corresponding glycoside linkages.  Another group of macrolides named ansa lactams, possess an aromatic ring (naphthalene, naphthoquinone, or benzene) connected to the aliphatic chain in non-adjacent positions. Rifamycin S 15 ( Figure 5) is a member of the lactam ansa macrolide antibiotic that was isolated from Norcodia mediterranei in 1951 [66,67]. This macrolactam 15 consists of twenty-four-member rings that contain a naphthoquinone portion that is connected by an aliphatic polypropionate chain with eight consecutive stereogenic centers. Rifamycins    Lankamycin 5a (Figure 4) was collected from a soil sample and isolated from various Streptomyces species: first in 1960 by Gäumann et al. from Streptomyces violaceoniger [33] and later in 1969 by Namiki et al. from the Kuji District of Ibari Prefecture, Japan from S. spinichromogenes var. kujimyceticus [34]. In addition, Kinashi et al. reported that Streptomyces rochei 7434AN4 produces lankamycin 5a and other structurally unrelated polyketide antibiotics [35]. Lankamycin 5a shows moderate inhibitory activities against Mycobacteria [34] and Gram-positive bacteria such as Staphylococcus aureus, Bacillus subtilis, and Micrococcus luteus [36,37]. The relative structure of the neutral 14-membered macrolide antibiotic lankamycin 4a was determined by Keller et al. [38]. The molecule consists of a lactone ring, 11-acetyllankolide, which contains a polypropionate fragment with twelve stereogenic centers. The structure of lankamycin 4a has two sugar moieties, in which D-chalcose is bound at the C5 and the 4-O-acetyl-L-arcanose is bound at C3 [39]. Lankanolide 4b (Figure 4) is the aglycon of 4a. Elaiophylin 5 ( Figure 4) is a 16-membered macrodiolide isolated from different cultures of Streptomyces malonosporus and belongs to a group of C2-symmetrical macrodiolides [40]. The elaiophylin 5 structure was determined by extensive chemical degradation and nuclear magnetic resonance (NMR) studies, while X-ray crystallographic analysis revealed the relative and absolute stereochemistry [41]. The structure of 5 consists of a macrolactone, an intramolecular hemiacetal, and a polypropionate fragment with nine asymmetric carbons. Macrolide 5 exhibited potent antimicrobial activity against several strains of Gram-positive bacteria including Bacillus subtilis, Staphylococcus aureus, and Corynebacterium diphtheriae. It also revealed anthelmintic activity against Trichonomonas vaginalis [42,43].

Isolation, Structural Characterization, and Antimicrobial Activities of Polypropionates
Bafilomycin A 1 6 ( Figure 4) was isolated in 1983 by Wagner from a broth of Streptomyces griseus [44]. Its relative stereochemistry was determined by Corey and Ponder in 1984 using extensive NMR analysis, and confirmed in 1987 using X-ray crystallography [45,46]. The structure of 6 represents a 16-membered macrolide with a tetraene core, a cyclic hemiacetal, a C14 methoxy, and a C23-isopropyl group within its polypropionate chain. Bafilomycin A 1 6 exhibited potent antifungal and antibacterial activity and is also the first known inhibitor of Vacuolar H + -ATPase (VATPase) [47]. Protomycinolide IV (7) (Figure 4) is the aglycone of Mycinamicins [48]. It is a 16-membered macrolide isolated from Micromonospora griseorubida sp. nov. that possesses excellent activity against Gram-positive bacteria [49]. The protomycinolide IV (7) structure is characterized by a short polypropionate chain that contains four chiral carbons of the six in total, a conjugate ketone, and macrocyclic lactone.
Scytophycin C 11 ( Figure 4) is a 22-membered macrolide isolated in 1986 by Moore et al., from the terrestrial blue-green alga Scytonema pseudohofmanni [56]. The structure of 11 contains 15 stereogenic centers, a dihydropyran ring bearing two trans-substituted side chains, a polypropionate chain, and a terminal N-methyl-N-vinylformamide moiety. Scytophycin C 11 exhibited potent activity against a variety of human carcinoma cell lines including solid tumors [57].
Lobophorolide 12 (Figure 4) was isolated from the Caribbean brown algae Lobophora variegata by Kubanek et al. in 2003 [58]. They characterized the lobophorolide 12 structure using IR, NMR, and MS analysis, which consists of a 22-membered macrolactone that has attached an aliphatic side chain with a tetrahydropyran ring-termini. Lobophorolide 12 displayed antifungal activity against D. salina and L. thalassiae as well as a high cytotoxicity toward the colon tumor cell line HCT-116 (IC 50 = 0.03 µg/mL) [59].
The isolation of mycalolides was reported in 1989 by Fusetani et al. from a sponge of the genus Mycale [60]. Mycalolide A 13 ( Figure 4) has a 25-membered macrolide ring that incorporates the tris-oxazole, attached to an aliphatic polyketide side chain that contains eight of the eleven stereogenic centers present in this compound [61]. The relative and absolute configuration were determined through a combination of chemical degradation, extensive NMR analysis, and correlation experiments [62]. Mycalolide A 13 exhibits potent antifungal activity against a wide array of pathogenic fungi and cytotoxicity toward B-16 melanoma cells (IC 50 = 0.5-1.0 ng/mL). It was also shown that it selectively inhibits the actomyosin Mg 2+ -ATPase, acting as an acting-depolymerizing agent [63]. Swinholides A-C (14a-c) ( Figure 5) was isolated from the marine sponge Theonella swinhoei [64]. The structure consists of a 44-membered dimeric macrolide, with four tetrahydropyran rings, two conjugated double bonds connected to each ester, and the polypropionate chains had nine chiral centers [65]. Swinholides 14a-c exhibit high cytotoxic activity against a variety of tumor cells and possess antifungal activities [50].
Another group of macrolides named ansa lactams, possess an aromatic ring (naphthalene, naphthoquinone, or benzene) connected to the aliphatic chain in non-adjacent positions. Rifamycin S 15 ( Figure 5) is a member of the lactam ansa macrolide antibiotic that was isolated from Norcodia mediterranei in 1951 [66,67]. This macrolactam 15 consists of twenty-four-member rings that contain a naphthoquinone portion that is connected by an aliphatic polypropionate chain with eight consecutive stereogenic centers. Rifamycins have shown activity against Gram-positive and Gram-negative bacteria with the most valuable activity toward Mycobacterium tuberculosis, leprosy, and meningitis. Rifamycin activity works through the inhibition of the DNA-dependent RNA polymerase and at high concentration through the inhibition of the RNA-dependent DNA polymerase of retroviruses [1,68].
The streptovaricin anasamycin antibiotics A-K were first isolated from Streptomyces spectabilis in 1957 by Siminoff [69]. Streptovaricins 16 ( Figure 5) showed activity against Gram-positive, Gram-negative bacteria, and Mycobacterium tuberculosis [70]. Ten years later, Rinehart et al. was able to characterize the macrolactams by NMR, chemical derivatization studies, and X-ray analysis [71]. The structures of streptovaricin A 16a, D 16b, and U 16e ( Figure 5) consist of a napthoquinoid core and a polypropionate chain with nine contiguous stereogenic centers, five of which have a challenging all-anti relative configuration [72]. Interestingly, the streptovaricin U 16e ansa segment replaced the C10 carbomethoxy for a methyl group and streptovarcin A 16a has two tertiary alcohols at the C6 and C14 positions. Streptovaricin D 16b inhibits the RNA-directed DNA polymerase and was the most active against reverse transcriptase (0.25 µmol/mL for 70% inhibition) in comparison to all of the streptovaricins [73]. Streptovaricin U 16e is a unique, open-chain streptovaricin that inhibits Rauscher leukemia virus RNA-dependent DNA polymerase (40% inhibition at 200 µg/mL) [74]. Protostreptovaricins I-V were isolated after various chromatographic purifications of fractions from the streptovarin complex [75]. The protostreptovaricins are precursors of streptovaricins that are active inhibitors of reverse transcriptase. The ansa chain of 16e and protostreptovaricin I 16c and II 16d ( Figure 5) were the same and only differed in the substitution of the napthoquinoid core. In fact, streptovaricin U 16e is most likely the result of the enzymatic hydrolysis of protostreptovaricin I 16c by S. spectabilis.

Polyene Macrolides
Polyene macrolides are a larger group of macrolides characterized by the presence a series of conjugated E double bonds and the macrolactone is in the range of 26-38 atom Polyenes have antifungal properties, and the medicinally important ones include the he taene amphotericin B 20 ( Figure 5)   The ansamycin antibiotic trienomycin A 17 ( Figure 5) was isolated and purified by Komiyama et al. in 1985 from the culture broth of Streptomyces sp. No. . Komiyama reported the physico-chemical characteristics, molecular formula, and biological activities against HeLa S 3 (IC 50 = 0.1 µg/mL) and PLC hepatoma (IC 50 = 0.01 µg/mL) cells in vitro [76]. Then, the structures of trienomycins A 17, B, and C were determined based on their spectroscopical and chemical properties [77,78]. Trienomycins are unique ansamycin lactams with a stereotriad polypropionate segment, a triene, an 1,3,5-trisubstituted benzene, and N-hexahydrobenzoylalanine moieties in the structure. Trienomycins do not exhibit antimicrobial activity against bacteria, fungi, or yeasts. In 1995, Otake et al. isolated trienomycins A 17, B, and C Streptomyces rishiriensis T-23. They also characterized the structure of this mycotrienin antibiotic by NMR studies and reported cytotoxicity against L-5178Y (IC 50 = 0.11 µg/mL) cells in vitro [79].  (18), from a soil sample collected in Japan and produced by Streptomyces sp. 87-397 [80]. They reported the physico-chemical properties, NMR spectra, molecular formula, and biological activities of the oxo pentaene 18 [81]. The polyene 18 ( Figure 5) showed cytotoxicity against tumor cells lines K-562 and HL-60, inhibiting human leukemia, and was active against filamentous fungi, yeast, and bacteria. Macrolide structure 18 consists of a conjugated pentaene and a large segment of 1,3-polyols. Roflamycoin 19 (formerly named flavomycoin) ( Figure 5) is a 36-membered polyene macrolide that was isolated from Streptomyces roseoflavus and has antifungal activity [82]. Schlegel et al. determined the structure using spectroscopic and chemical degradation methods [83], and then reported the absolute configuration using the 13C acetonide method and synthetic correlation [84]. The structure consists of a conjugated pentaene, a ketone at C17, and a long 1,3-diol chain. Roflamycoin 19 is an ion channel-forming antibiotic that increases the membrane permeability only in the case of sterol-containing membranes. The channels are potential-dependent, have a short lifetime, and high conductance [85]. Amphotericin B 20a ( Figure 5) is a polyene antifungal antibiotic that consists of a 38-membered macrolide that was isolated from Streptomyces nodosus from the Orinoco River in Tembladora, Venezuela [86]. Amphotericin 20a is active against yeasts and most fungi including Cryptococcus neoformans, Candida albicans, Sporotrichum, Blastomyces dermatitidis, Histoplasma capsulatum, Coccidioides immitis, and Aspergillus fumigatus. In addition, 20a is used for the treatment of cryptococcosis, histoplasmosis, disseminated candidiasis, coccidioidomycosis, North American blastomycosis, aspergillosis, and sporotrichosis [87]. The structure of 20a was elucidated in 1970 employing chemical manipulations and MS studies [88]. The absolute configuration of 20a was established using X-ray single-crystal analysis [89]. The structure of macrolactone 20a consists of a steretetrad polypropionate portion, 1,3-polyol segments, a cyclic hemiacetal substituted with a carboxylic acid, and a conjugated heptaene. Amphoterolide B 20b ( Figure 5) is the aglycone of Amphotericin B 20a.

Linear Polypropionates
Macrolide formation does not always occur during biosynthesis in some organisms such as marine mollusks, microorganisms, terrestrial plants, and insects, and produce a rare class of polyketide metabolites that can be classified as linear polypropionates [90]. (+)-Discodermolide 21 ( Figure 6) is a linear polypropionate that contains a six-membered lactone that was isolated from the Caribbean marine sponge Discodermia dissolute [91]. This natural product has been approved for clinical trials regarding antitumoral activity and has also shown strong antimitotic, antifungal, and immunosuppressant activity [92]. The structure of 21 contains an amide and a polypropionate segment with 13 chiral centers. The absolute configuration was determined by analyzing the NMR data and X-ray results in 1990 [93]. Discodermolide 21 exhibited strong cytotoxicity against murine P388 leukemia and human lung adenocarcinoma A549 cell lines [90]. Zincophorin 22 ( Figure 6) was isolated from a strain of Streptomyces griseus and the structure consists of a linear polyketide that contains a tetrahydropyran ring and an methylester termini [94]. This zinc-binding antibiotic (ionophore) possesses a remarkable in vitro activity against Grampositive bacteria as well as against Clostridium coelchii and influenza WSN/virus [95]. (−)-Serricornin (4,6-dimethyl-7-hydroxy-nonan-3-one) 23 ( Figure 6) is a sex pheromone of a female cigarette beetle (Lasiodema serricorw F.) that has been isolated and structurally characterized by chemical and spectroscopic evidence by Chuman et al. in 1979 [96]. Myriaporones ( Figure 6) have been isolated from the western Mediterranean Sea marine organism bryozoan Myriapora truncata [97]. The NMR, IR, and FAB/MS data analysis were employed to determine the structures and stereochemistry of each myriaporone (1, 2, 3/4). Interestingly, myriaporones 3/4 (24) ( Figure 6) were isolated as inseparable equilibrium mixture of acyclic and cyclic isomers, respectively. In 2004, the research group of Echavarren reported the total synthesis of all myriaporones and the relative and absolute configurations of these cytotoxic compounds [98]. Myriaporones 3/4 (24) were the most active and showed 88% inhibition of L1210 murine leukemia cells at 0.2 µg/mL [97]. Crocacins A-D (25a-d) ( Figure 6) are unusual secondary metabolites in which the biosynthesis of the structure consists of a mixture of polypropionate and peptide building blocks [99]. They are potent antifungal and cytotoxic compounds isolated from myxobacteria Chondromyces crocatus and the bacteria Chrondomyces pediculatusi by Reichenbach et al., which named the structures of 25 as (Z)-enamides [100]. The structure of crocacins 25a-d has a common polypropionate steretetrad fragment (C16-C19) and the conjugated (E,E)-dienamide motif (C11-C15). The relative configuration of crocacins 25a-d was confirmed by Jansen et al. in 1999 [101]. Their absolute configuration was later confirmed by its first total synthesis in 2000 by Rizzacasa et al. [102]. Only crocacins A 25a and D 25a have shown high biological inhibition of the electron transport chain in a beef heart mitochondrial respiration assay. They also inhibited the growth of several yeast and fungi in vitro such as Plasmopara viticola and Phytophthora infestans [103]. Dolabriferols 26a-c ( Figure 6) were isolated by Gavagnin et al., from the anaspidean mollusk Dolabrifera dolabrifera [104]. The structure of dolabriferol was determined by spectral methods and the relative stereochemistry was determined by X-ray analysis and consisted of two polypropionate subunits linked by an ester. Similar compounds, dolabriferol B 26b and C 26c, were isolated by Rodriguez et al., from a Caribbean mollusk Dolabrifera dolabrifera from Puerto Rico and characterized using spectral data and X-ray analysis [105]. Dolabriferol, in general, did not display any significant activity with the exception of Dolabriferol B 26b and 26c at a concentration of 128 µg/mL, which showed an inhibitory activity (39% and 93%, respectively) against Mycobacterium tuberculosis H37Rv. Sakuda et al., in 1996, isolated aflastatin A 27 ( Figure 6) from Streptomyces sp. MRI142, which is an inhibitor of aflatoxin biosynthesis, but does not inhibit the growth of Aspergillus parasiticus [106]. First, they reported the preliminary structure of 27 after employing chemical degradation and spectroscopic analysis, and later confirmed and revised the absolute configuration of all 29 chiral centers [107,108]. The tetramic acid derivative 27 consists of a long and linear polyol and polypropionate chain with a tetrahydropyran ring moiety.
Streptomyces sp. MRI142, which is an inhibitor of aflatoxin biosynthesis, but does not inhibit the growth of Aspergillus parasiticus [106]. First, they reported the preliminary structure of 27 after employing chemical degradation and spectroscopic analysis, and later confirmed and revised the absolute configuration of all 29 chiral centers [107,108]. The tetramic acid derivative 27 consists of a long and linear polyol and polypropionate chain with a tetrahydropyran ring moiety.

Polyethers
Polyether antibiotics are a large group of secondary metabolites that show a broad spectrum of bioactivities such as antibacterial, antifungal, antiparasitic, antiviral, and tumor cell cytotoxicity [109]. These are characterized by the presence of several tetrahydrofuran, tetrahydropyran, and oxepane all-trans fused rings. Gymnocin-A 28 ( Figure 7) is

Polyethers
Polyether antibiotics are a large group of secondary metabolites that show a broad spectrum of bioactivities such as antibacterial, antifungal, antiparasitic, antiviral, and tumor cell cytotoxicity [109]. These are characterized by the presence of several tetrahydrofuran, tetrahydropyran, and oxepane all-trans fused rings. Gymnocin-A 28 ( Figure 7) is classified as a polycyclic ether and was isolated from the red tide dinoflagellate, Gymnodinium mikimotoi, at Kushimoto Bay, Japan in 2002 [110]. The structure of gymnocin-A 28 was determined by NMR and FAB/MS spectrometry and consists of a linear array of 14 fused ether rings and a 2-methyl-2-butenal side-chain. The absolute configuration was assigned via Mosher ester analysis. Gymnocin-A 28 showed potent cytotoxicity (IC 50 = 1.3 µg/mL) against mouse leukemia P388 cells [111]. Muamvatin 29 ( Figure 7) is a marine polypropionate that contains a unique 2,4,6-trioxaadamantane ring skeleton that was isolated from the Fijian pulmonated mollusc Siphonaria normalis by Ireland et al. in 1986 [112]. They elucidated the structure by employing NMR analysis, specifically, the relative stereochemistry of the trioxaadamantane ring (tricyclic ketal) constituents was determined based on the results of a two-dimensional NOE experiment. The absolute configuration of (+)-muamvatin 29 was determined by chemical degradation studies [113] and after the total synthesis of 29 reported by Paterson and Perkins in 1993 [114]. Yamada et al. reported the isolation of two new polypropionates, auripyrones A 30a and B 30b (Figure 7), from the sea hare Dolabella auricularia (Aplysiidae) collected in Mie Prefecture, Japan [115]. They characterized 30a and 30b by employing spectroscopic analyses including NOESY. The structures of 30a and 30b consist of polycyclic polypropionates that contain a δ-pyrone ring and a spiroketal moiety. Auripyrones A 30a and B 30b exhibited cytotoxicity against HeLa S 3 cells with IC 50 = 0.26 and 0.48 µ/mL, respectively. Tautomycin 1 (31) (Figure 7) was isolated from Streptomyces spiroverticillatus from a soil sample collected in Jiangsu Province, China [116]. The name of tautomycin was chosen because it exists in a tautomeric mixture in solution. Compound 31 exhibited strong antifungal activity against Sclerotinia sclerotiorum, and induced morphological change (blebbing) of the human erythroid leukemia cell K562. Compound 31 is also a potent inhibitor of the spread of human myeloid leukemia cell HL60 [116], and the protein phosphatases type 1 and type 2A [117]. The structure of polyether 31 consists of 13 chiral centers and was determined by chemical degradation and conformational calculations [118]. Other characteristic structural features of tautomycin 1 31 are the tetramic acid derivative termini linked to an ester, internal and terminal ketones, and a polypropionate spiroketal moiety. Aplysiatoxin 32 (Figure 7) was first isolated and purified from the marine gastropod mollusc Stylocheilus longicauda and the structure of 32 was elucidated employing UV-Vis, NMR, IR, and MS data analysis and chemical degradation [119]. The absolute configuration of 32 was established using optical, NMR, X-ray crystallographic analysis, and an examination of the degradation products of 32 [120]. The macrolactone 32 has a tetrahydropyran-tetrahydropyran (THP-THP) spiro system and side chain with a bromo phenol moiety. Aplysiatoxin 32 and related metabolites have shown to be potent tumor promoters [121].

Other Related Polypropionates
Bengamide E 33 (Figure 7) was first isolated from an undescribed Jaspidae sponge collected in the Benga lagoon of the Fiji Islands. The structure and stereochemistry including the chirality of the substituted ɛ-caprolactam ring of bengamide E 33 was established by comparing the structure of the analogs bengamides A and B through extensive spectroscopic studies and chemical degradation. Bengamide E 33 was also extracted and characterized from Jaspis cf. coriacea from Fiji [122] and Pachastrissa sp. from Djibouti [123]. Bengamide 33 has shown in vitro cytotoxic activity against the MDA-MB-435 (IC50 = 4-7 nM) human breast carcinoma cell line and also demonstrated an in vitro anthelminthic activity [122]. Multiplolide A 34 (Figure 7) is a ten-membered lactone (decalactone) that was isolated from the broth of Xylaria multiplex BCC 1111 [124]. In 2001, the structure of

Other Related Polypropionates
Bengamide E 33 (Figure 7) was first isolated from an undescribed Jaspidae sponge collected in the Benga lagoon of the Fiji Islands. The structure and stereochemistry including the chirality of the substituted E-caprolactam ring of bengamide E 33 was established by comparing the structure of the analogs bengamides A and B through extensive spectroscopic studies and chemical degradation. Bengamide E 33 was also extracted and characterized from Jaspis cf. coriacea from Fiji [122] and Pachastrissa sp. from Dji-bouti [123]. Bengamide 33 has shown in vitro cytotoxic activity against the MDA-MB-435 (IC 50 = 4-7 nM) human breast carcinoma cell line and also demonstrated an in vitro anthelminthic activity [122]. Multiplolide A 34 ( Figure 7) is a ten-membered lactone (decalactone) that was isolated from the broth of Xylaria multiplex BCC 1111 [124]. In 2001, the structure of 34 was elucidated by employing spectroscopic and spectrometric analysis, but the relative configuration of the epoxide moiety could not be assigned. Then, in 2008, the absolute configuration was assigned after the total synthesis of 34 [125]. Multiplolide A 34 exhibited antifungal activity against Candida albicans (IC 50 = 7 µg/mL).

Kishi (Pioneer)
It was 1979 when Kishi reported a stereo-and regioselective method for the synthesis of propionates from allylic alcohols [126,127]. The synthetic approach started from chiral aldehydes such as 35 to induce stereoselectivity, which after 4-steps was converted into chiral allylic alcohol 36 ( Figure 8). Adduct 36 was then treated with mCPBA to form epoxide 37 in a 97% yield. This epoxide was then regioselectively opened to form propionate 38 using LiCu(Me) 2 in a 95% yield. Grignard reagents such as (CH 2 =CHMgBr) can also be used to increase the propionate backbone to produce terminal olefins that can be further functionalized ( Figure 8). In simple terms, Kishi's approach to propionates relies on the use of mCPBA as the epoxidating agent [128] and either the Gilman or Grignard reagents for the alkylation step. It is important to note that Kishi was also able to synthesize all four diastereomers by either the pioneer epoxide approach or through hydroboration-oxidation conditions (Figure 8, middle) [126,127]. To validate the scope, Kishi and coworkers worked on the total synthesis of rifamycin S [129][130][131] and the partial synthesis of narasin and salinomycin [132] (Figure 8, bottom).
for the alkylation step. It is important to note that Kishi was also able to synthesize all four diastereomers by either the pioneer epoxide approach or through hydroboration-oxidation conditions (Figure 8, middle) [126,127]. To validate the scope, Kishi and coworkers worked on the total synthesis of rifamycin S [129][130][131] and the partial synthesis of narasin and salinomycin [132] (Figure 8, bottom).

Katsuki
A few years later (1989), Katsuki and coworkers reported a different approach toward polypropionates [133]. Katsuki's approach is based on an epoxide ring-opening using 2-lithio-1,3-dithiane [134]. Figure 9 shows the synthetic sequence, which starts from a dithianative epoxide ring opening of 46 to produce dithioacetal 47. This intermediate was treated with iodomethane to allow an alkylative desulfurization that released an alde-

Katsuki
A few years later (1989), Katsuki and coworkers reported a different approach toward polypropionates [133]. Katsuki's approach is based on an epoxide ring-opening using 2-lithio-1,3-dithiane [134]. Figure 9 shows the synthetic sequence, which starts from a dithianative epoxide ring opening of 46 to produce dithioacetal 47. This intermediate was treated with iodomethane to allow an alkylative desulfurization that released an aldehyde, which was then oxidized with NaClO 2 to afford carboxylic acid 48. Then, esterification with CH 2 N 2 , followed by α-methylation and a reduction with lithium aluminum hydride, produced the expected propionate 49. Further elaboration of intermediate 49 produced the rifamycin S fragment 50. It is worth noting that Katsuki utilized either VO(acac) 2 or WO 5 ·HMPA for epoxidations [133]. Furthermore, the same synthetic approach was used during a formal total synthesis of aplysiatoxin 32; this methodology could also be used to synthesize dibromoaplysiatoxin (Figure 9, bottom right).

Marshall
In 1998, Marshall reported the addition of chiral allenylstannanes such as 53 to chiral aldehydes (e.g., 52) to produce homopropargylic alcohols with two contiguous anti-anti stereocenters ( Figure 10, top left) in an 87% yield [135]. The homopropargylic alcohol 54 was then reduced with Red-Al to allylic alcohol 55. Then, using Sharpless asymmetric epoxidation conditions, the expected product 56 was observed with an 87:13 dr. The addition of Me2Cu(CN)Li2 opened the epoxide by regio-and stereoselective addition of a methyl group to afford polypropionate 57 in an 85% yield. Finally, the protection and deprotection sequences delivered zincophorin's C7-C13 fragment (58). Likewise, this reiterative epoxidation-methyl cuprate sequence to transform allylic alcohols into polypropionates was used to prepare rifamycin-S's C21-C27 fragment (60), albeit employing other enantiomers during the initial allenylstannane addition (Figure 10, middle) [135]. Due to the fact that by using chiral allenylstannanes, five carbons can be added to the backbone in a single step, so this polypropionate approach is efficient and useful for the synthesis of natural products. For instance, Marshall and coworkers reported the total synthesis of (+)-discodermolide with an excellent stereocontrol observed [136]. They also reported the stereoselective synthesis of bafilomycin A1′s C15-25 fragment, this time using allenylzinc as the key reagent (Figure 10, bottom) [137].

Marshall
In 1998, Marshall reported the addition of chiral allenylstannanes such as 53 to chiral aldehydes (e.g., 52) to produce homopropargylic alcohols with two contiguous anti-anti stereocenters ( Figure 10, top left) in an 87% yield [135]. The homopropargylic alcohol 54 was then reduced with Red-Al to allylic alcohol 55. Then, using Sharpless asymmetric epoxidation conditions, the expected product 56 was observed with an 87:13 dr. The addition of Me 2 Cu(CN)Li 2 opened the epoxide by regio-and stereoselective addition of a methyl group to afford polypropionate 57 in an 85% yield. Finally, the protection and deprotection sequences delivered zincophorin's C7-C13 fragment (58). Likewise, this reiterative epoxidation-methyl cuprate sequence to transform allylic alcohols into polypropionates was used to prepare rifamycin-S's C21-C27 fragment (60), albeit employing other enantiomers during the initial allenylstannane addition (Figure 10, middle) [135]. Due to the fact that by using chiral allenylstannanes, five carbons can be added to the backbone in a single step, so this polypropionate approach is efficient and useful for the synthesis of natural products. For instance, Marshall and coworkers reported the total synthesis of (+)-discodermolide with an excellent stereocontrol observed [136]. They also reported the stereoselective synthesis of bafilomycin A1 s C15-25 fragment, this time using allenylzinc as the key reagent (Figure 10, bottom) [137].

Miyashita
Miyashita was one of the major contributors to publications related to the synthesis of fragments and natural products containing polypropionate subunits. His methodology relies on the use of trimethylaluminum for the regio-and stereospecific methylation of epoxides. In 1991, his group reported a new iterative method for the construction of polypropionate chains from epoxy acrylates [138]. The method takes advantage of optically active epoxy acrylates that can undergo stereospecific methylation with 10 equiv. of (Me)3Al to afford highly diastereoselective adducts. For example, the (E)-epoxy acylate 61 produced anti adduct 62, while the (Z)-epoxy acylate 63 gave syn adduct 64 (Figure 11, top) in very high yields and diastereoselectivity. It is important to note that having adjacent chiral centers does not affect the yields or diastereoselectivity [138]. Using this stereospecific methylation approach, Miyashita and co-workers synthesized Prelog-Djerassi lactone 2 in six synthetic steps (Figure 11, middle) [139]. They also reported the formal synthesis of protomycinolide IV 7 [139]. In addition, several other fragments and/or natural products have been prepared by Miyashita et al. For instance, the following polypropionate-containing-natural products: (−)-serricornin 23 [140], rifamycins 15 [141], streptovaricin U 16c [142], protostreptovaricin I and II (16c-d) [142], scytophycin C 11 [143][144][145], swinholides A-C 14a-c [146], tedanolide 9 [147], lepranthin 8 [148], and venturicidins 10ac [149] were all prepared from epoxides and trimethylaluminum for the regio-and stereospecific methylation (Figure 11, bottom). It is worth noting that Miyashita also reported

Miyashita
Miyashita was one of the major contributors to publications related to the synthesis of fragments and natural products containing polypropionate subunits. His methodology relies on the use of trimethylaluminum for the regio-and stereospecific methylation of epoxides. In 1991, his group reported a new iterative method for the construction of polypropionate chains from epoxy acrylates [138]. The method takes advantage of optically active epoxy acrylates that can undergo stereospecific methylation with 10 equiv. of (Me) 3 Al to afford highly diastereoselective adducts. For example, the (E)-epoxy acylate 61 produced anti adduct 62, while the (Z)-epoxy acylate 63 gave syn adduct 64 (Figure 11, top) in very high yields and diastereoselectivity. It is important to note that having adjacent chiral centers does not affect the yields or diastereoselectivity [138]. Using this stereospecific methylation approach, Miyashita and co-workers synthesized Prelog-Djerassi lactone 2 in six synthetic steps (Figure 11, middle) [139]. They also reported the formal synthesis of protomycinolide IV 7 [139]. In addition, several other fragments and/or natural products have been prepared by Miyashita et al. For instance, the following polypropionatecontaining-natural products: (−)-serricornin 23 [140], rifamycins 15 [141], streptovaricin U 16c [142], protostreptovaricin I and II (16c-d) [142], scytophycin C 11 [143][144][145], swinholides A-C 14a-c [146], tedanolide 9 [147], lepranthin 8 [148], and venturicidins 10a-c [149] were all prepared from epoxides and trimethylaluminum for the regio-and stereospecific methylation (Figure 11, bottom). It is worth noting that Miyashita also reported the use of m-chloroperoxybenzoic acid (mCPBA) for highly stereoselective epoxidations of chiral allylic alcohols [150] and organoselenium reagents for a chemoselective reduction of epoxides [151]; both important methodologies for the synthesis of polypropionates. of chiral allylic alcohols [150] and organoselenium reagents for a chemoselective reduction of epoxides [151]; both important methodologies for the synthesis of polypropionates.

Prieto
Prieto's methodology is a relatively simple substrate-control approach and consists of three reiterative steps: (1) regioselective cleavage of epoxide 71 with an organoaluminium or organomagnesium reagents; (2) cis or trans reduction of the resulting alkyne 72; (3) syn or anti epoxidation of the homoallylic alcohol 73 [152,153] to subsequently produce the 3,4-epoxyalcohol 74. The application of the reiterative three step methodology produced a new propionate unit 75 ( Figure 12). The absolute stereochemistry of the polypropionate fragment was introduced during the synthesis of the first epoxide for step one by employing the Sharpless asymmetric epoxidation [154]. The relative configuration of the methyl groups is defined by the cis/trans geometry of the epoxide precursor, which in turn is defined by the geometry of the alkene precursors. The configuration of the secondary hydroxy groups is defined by the configuration of the epoxide precursors. In 2009, Prieto et al. reported the stereoselective synthesis of the very challenging all-anti, the C6-C10 polypropionate chain 83 of streptovaricin U 16e (Figure 12) [155]. For this, the syn-selective epoxidation of cis-homoallylic alcohols 77 and 79 were obtained by either applying the iodocarbonation/methanolysis procedure [40,156] or the VO(acac) 2 catalyzed epoxidation reaction [153,157]. Then, the regioselective cleavage of epoxides 76, 79, and 81 with a propynyl aluminum reagent followed by a cis reduction produced homoallylic alcohols 77, 79, and 82 in good yields. Furthermore, the incorporation of the copper-catalyzed Grignard epoxide cleavage reaction [158] for the cleaving of epoxide 76 to complement the alkynyl alane approach [25,25,159,160] was also developed.

Prieto
Prieto's methodology is a relatively simple substrate-control approach and consis of three reiterative steps: (1) regioselective cleavage of epoxide 71 with an organoalumin ium or organomagnesium reagents; (2) cis or trans reduction of the resulting alkyne 7 (3) syn or anti epoxidation of the homoallylic alcohol 73 [152,153] to subsequently produc the 3,4-epoxyalcohol 74. The application of the reiterative three step methodology pro duced a new propionate unit 75 ( Figure 12). The absolute stereochemistry of the polypro pionate fragment was introduced during the synthesis of the first epoxide for step one b employing the Sharpless asymmetric epoxidation [154]. The relative configuration of th methyl groups is defined by the cis/trans geometry of the epoxide precursor, which i turn is defined by the geometry of the alkene precursors. The configuration of the second ary hydroxy groups is defined by the configuration of the epoxide precursors. In 200 Prieto et al. reported the stereoselective synthesis of the very challenging all-anti, the C6 C10 polypropionate chain 83 of streptovaricin U 16e (Figure 12) [155]. For this, the syn selective epoxidation of cis-homoallylic alcohols 77 and 79 were obtained by either apply ing the iodocarbonation/methanolysis procedure [40,156] or the VO(acac)2 catalyze epoxidation reaction [153,157]. Then, the regioselective cleavage of epoxides 76, 79, an 81 with a propynyl aluminum reagent followed by a cis reduction produced homoallyl alcohols 77, 79, and 82 in good yields. Furthermore, the incorporation of the copper-cat lyzed Grignard epoxide cleavage reaction [158] for the cleaving of epoxide 76 to compl ment the alkynyl alane approach [25,25,159,160] was also developed.   To demonstrate the synthetic usefulness of this non-aldol approach for the elaboration of polypropionate-containing natural products, they applied a linear three-reaction sequence to the stereoselective construction of the stereohexads corresponding to the C15-C10 84 [158], C5-C12 85 [161], and C15-C8 86 [161] polypropionate chains of streptovaricin D 16b including the C10 carbomethoxy functionality needed for the elaboration (Figure 13). Prieto also reported the C5-C10 87 [160] and triad C12-C16 88 [161] fragments of elaiophylin 5, in addition to the stereotetrad C22-C27 89 [158] fragment of rifamycin S 15 ( Figure 13). In 2012, the linear, convergent, and enantioselective synthesis of the C14-C25 90 fragment of bafilomycin A 1 6 was reported in a 16% overall yield. The process consisted of eight steps in its longest linear sequence (Figure 13) using a dithiane substitution reaction to the coupling of the corresponding linear fragments [162]. This group has reported the convergent synthesis of optically active and common precursors of the C1-C5/C15-C11 segment 91a,b of lankanolide 4b [157] (Figure 13) and the convergent precursor for the C3-C9/C12-C18 fragments 92a,b of dolabriferol B 26b (Figure 13) [161]. They also reported a second-generation methodology in 2014 to introduce the hydroxymethyl moiety found at the C16 of tedanolide 9 and C18 of myraporone 3/4 (24) [159]. Specifically, they constructed an optically active stereotetrad 92 that is a common intermediate for the elaboration of C6-C9 93a and C14-C7 93b aliphatic chains of tedanolide 9 and myraporone 3/4 (24), respectively ( Figure 13). The most recent paper reported by Prieto et al. describes the enantioselective and stereoselective synthesis of several polypropionate chains, which include the C15-C20 segment 94 of crocacin 25 and the polypropionate chains of C22-C27 95, mycalolide A 13, and C19-C24 95 of the lobophorolide 12 natural products ( Figure 13) [161]. In summary, this reiterative, linear, and convergent methodology has demonstrated the versatility to synthesize stereotriads, stereotretrads, and stereohexads with regio-, enantio-, and diastereoselectivity in polypropionate natural products.

Sarabia
More recently, the group of Sarabia reported the stereoselective synthesis of polypropionatetype frameworks utilizing an epoxy amide-based strategy ( Figure 14) [163]. The reiterative methodology of Sarabia consists of four consecutive steps: sulfur ylide reaction, oxirane opening, protection, and reduction of amide. The starting material is a chiral aldehyde 97 that is reacted with a sulfur ylide 98 in a stereoselective fashion induced by the presence of an asymmetric center at the α-position of aldehyde 97 ( Figure 14). The resulting trans epoxyamide 99 is then subjected to the epoxide opening reaction mediated by a methyl organocuprate reagent, followed by the protection of the resulting alcohol as a silyl ether and the reduction of the amide to the alcohol. At this point, the oxidation of the alcohol provided a new aldehyde 100, which was ready for the application of a second reaction sequence. This sequence provided the anti-relative configuration between the chiral centers present in the resulting polypropionate chain 101 (Figure 14). A collection of different chiral aldehydes was subjected to reaction with sulfur ylide. The majority showed remarkable stereofacial differentiation, providing a major diastereomer, in contrast to other aldehydes that displayed poor to no stereoselectivity. Despite the difficulties encountered for the preparation of some epoxide amides with respect to the diastereomeric yields, Sarabia was able to prepare various stereo-n-ads such as 108 including the synthesis of the C5-C17 polypropionate chain of streptovaricin U 109 ( Figure 14) [164]. In 2010, Sarabia and co-workers reported on the stereoselective preparation of bengamide E 33 and analogs using chiral sulfur ylides [165]. Specifically, they achieved the synthesis of the tetraol polyketide fragment present in bengamide E 33 by using two trans-epoxides synthesized by employing Sharpless asymmetric epoxidation (SAE). This was then followed by conversion into epoxyamides to apply the oxirane-ring-opening process with alkylborates, catalyzed by palladium (0) to yield the corresponding ring opened syn-diol products (Figure 14) [166].

Jung
Jung et al. developed a "non-aldol aldol" protocol for the synthesis of polypropionates that involves the stereoselective olefination of the aldehyde 110, followed by a hydride reduction to produce the allylic alcohol 111. Sharpless asymmetric epoxidation of 111 yielded epoxy alcohol 112 ( Figure 15) [24,167,168]. Silylation of the primary alcohol in 112 and the final Lewis acid catalyzed the rearrangement of the epoxy silyl ether 113, generating the desired syn or anti propionate unit product 114. The epoxy silyl ether epoxide 112 is activated with the Lewis acid TBSOTf, and an intramolecular hydride transfer cleaves the epoxide 113, generating an optically active aldehyde 114 (Figure 15). E-allylic alcohols like 111 generate syn adducts whereas Z-allylic epoxides generate anti adducts.

Jung
Jung et al., developed a "non-aldol aldol" protocol for the synthesis of polypropionates that involves the stereoselective olefination of the aldehyde 110, followed by a hydride reduction to produce the allylic alcohol 111. Sharpless asymmetric epoxidation of 111 yielded epoxy alcohol 112 ( Figure 15) [24,167,168]. Silylation of the primary alcohol in 112 and the final Lewis acid catalyzed the rearrangement of the epoxy silyl ether 113, generating the desired syn or anti propionate unit product 114. The epoxy silyl ether epoxide 112 is activated with the Lewis acid TBSOTf, and an intramolecular hydride transfer cleaves the epoxide 113, generating an optically active aldehyde 114 ( Figure 15). E-allylic alcohols like 111 generate syn adducts whereas Z-allylic epoxides generate anti adducts. In 1999, Jung et al. examined the Lewis acid promoted rearrangements of several allylic epoxides and their derivatives as a method for the preparation of compounds that can be used in the synthesis of natural products such as Tedanolides [167]. Jung et al., first reported the total synthesis of auripyrone B 30a from the known epoxide 120 in 18 steps and a 17% overall yield. They employed a non-aldol Lewis acid catalyzed rearrangement of an epoxy silyl ether strategy combined with a Paterson aldol process ( Figure 15) [168]. In 2010, Jung et al. also reported the total synthesis of auripyrone B 30b in only 20 steps in an 8% yield starting from optically active epoxy silyl ether 115 using a syn non-aldol aldol/anti cuprate opening strategy to produce the C8-C12 polypropionate fragment 119 ( Figure 15) [169].

McDonald
In 2002, McDonald and co-workers reported a new strategy for the construction of alternating 1,3-polyols based on two parts. The first, cross-coupling of six-carbon alkynol 122 (nucleophile) and the six-carbon epoxyalkynol 123 (electrophile) modules by epoxide opening. Second, the resulting internal alkyne 124 was hydrated to form 125 and then reduced with either 1,3-anti-15 or syn-stereoinduction to form the polyol fragment 126 ( Figure 16) [170]. They reported the preparation of the C13-C27 polyol fragment 134 of the macrolide polyne RK-397 18. The cross-coupling between terminal alkyne 127 with epoxide 128 produced the dialkyne 129. The hydration-reduction of the resulting internal alkyne in 129 produced the polyol fragment 130, which was then coupled with epoxide 131. The synthesis concluded with regio-and stereoselective synthesis of the polyol fragment 133 (Figure 16) [170]. In another paper, McDonald and co-workers reported the synthesis of the C9-C27 polypropionate fragment 134, which is the degradation product of aflastatin A 27 using the alkyne-epoxide cross-coupling strategy [171]. Particularly, the polypropionate fragments 134 and 135 were obtained by employing the stereoselective vanadium catalyzed and iodocarbonation/methanolysis epoxidations, respectively.

McDonald
In 2002, McDonald and co-workers reported a new strategy for the construction of alternating 1,3-polyols based on two parts. The first, cross-coupling of six-carbon alkynol 122 (nucleophile) and the six-carbon epoxyalkynol 123 (electrophile) modules by epoxide opening. Second, the resulting internal alkyne 124 was hydrated to form 125 and then reduced with either 1,3-anti-15 or syn-stereoinduction to form the polyol fragment 126 (Figure 16) [170]. They reported the preparation of the C13-C27 polyol fragment 134 of the macrolide polyne RK-397 18. The cross-coupling between terminal alkyne 127 with epoxide 128 produced the dialkyne 129. The hydration-reduction of the resulting internal alkyne in 129 produced the polyol fragment 130, which was then coupled with epoxide 131. The synthesis concluded with regio-and stereoselective synthesis of the polyol fragment 133 (Figure 16) [170]. In another paper, McDonald and co-workers reported the synthesis of the C9-C27 polypropionate fragment 134, which is the degradation product of aflastatin A 27 using the alkyne-epoxide cross-coupling strategy [171]. Particularly, the polypropionate fragments 134 and 135 were obtained by employing the stereoselective vanadium catalyzed and iodocarbonation/methanolysis epoxidations, respectively.

Lipshutz
Lipshutz and co-workers, in 1984, described a two-step methodology for the formation of all syn-1,3-polyols 146. They employed the vinyl-lithium-based higher order cyano-cuprates to cleave the monosubstituted epoxide 143 and 145, followed by epoxidation of the resulting homoallylic alkenol 144 ( Figure 17) [172,173]. An alternative methodology for the synthesis of polypropionate chains was also reported by Lipshutz and Barton in 1988 starting with the regiospecific cleavage of epoxide 143 with the cis-or transpropenyl high order cuprates (Figure 17) [174]. The cleavage of the disubstituted 3,4epoxy alcohol 147 yielded the desired polypropionate products 148 and 149 in variable regioselectivities. In contrast, the epoxide cleavage with the vinyl cuprate reagent enhanced the regioselectivity at latter stages, providing 1,3-diol exclusively. In this sequence,

Lipshutz
Lipshutz and co-workers, in 1984, described a two-step methodology for the formation of all syn-1,3-polyols 146. They employed the vinyl-lithium-based higher order cyanocuprates to cleave the monosubstituted epoxide 143 and 145, followed by epoxidation of the resulting homoallylic alkenol 144 ( Figure 17) [172,173]. An alternative methodology for the synthesis of polypropionate chains was also reported by Lipshutz and Barton in 1988 start-ing with the regiospecific cleavage of epoxide 143 with the cisor trans-propenyl high order cuprates ( Figure 17) [174]. The cleavage of the disubstituted 3,4-epoxy alcohol 147 yielded the desired polypropionate products 148 and 149 in variable regioselectivities. In contrast, the epoxide cleavage with the vinyl cuprate reagent enhanced the regioselectivity at latter stages, providing 1,3-diol exclusively. In this sequence, the epoxidation of the homoallylic alcohols was achieved in high stereoselectivities using the iodocarbonation/methanolysis sequence, while the VO(acac) 2 protocol was also quite efficient. In 1988, Lipshutz and co-workers also reported on the construction of the desired all syn-polyol array 153 and 156 by employing the coupling reaction between dithiane 150 with epoxides 151 and 154 to obtain the products 152 and 155, respectively. Hydrolysis of dithianes followed by a highly syn-selective LiAlH 4 -LiI reduction method produced all of the syn-polyols 153 and 155 ( Figure 17). In 1989, this epoxide and dithiane coupling strategy was applied to the construction in an optically pure form of the C12-C35 fragment 157 of the 36-membered polyene macrolide roflamycoin 19. Unfortunately, the stereochemistry of the eleven chiral centers in this year was unknown and they assumed that 19 had all of its polyhydroxyl groups in a syn-relationship ( Figure 17) [175].

Nicolaou
Nicolao and Uenishi, in 1982, reported an approach that utilizes the allylic alcohol 158 as a starting material, converted in epoxyalcohol 159 by the SAE reaction. This was then converted into the γ,δ-epoxy-α,β-unsaturated ester 160 before a regioselective hy-

Nicolaou
Nicolao and Uenishi, in 1982, reported an approach that utilizes the allylic alcohol 158 as a starting material, converted in epoxyalcohol 159 by the SAE reaction. This was then converted into the γ,δ-epoxy-α,β-unsaturated ester 160 before a regioselective hydride reduction with DIBAL to afford the allylic and homoallylic alcohol 161 ( Figure 18) [176]. The application of the aforementioned sequence generated the 1,3-syn-polyol fragment 162. Years later, Nicolaou and co-workers reported the synthesis of various key building blocks 170 to 173 toward the total synthesis of amphotericin B 20a and amphoterolide B 20b (Figure 18) [177]. They envisaged a convergent synthesis to construct polyol fragments 170 and 172. To achieve this, 163 was converted into epoxide 164 by the SAE reaction, then Swern oxidation followed by the Witting reaction, which produced the conjugated epoxy ester 165. A protection-deprotection strategy provided 167, which was then converted into the epoxide 168. The hydride reduction of 168 provided the syn-1,3-diol unit 169, which is the common precursor for the divergent synthesis of 170 and 172 polyol fragments ( Figure 18). For the synthesis of the fragment 172 present, Nicolaou employed an epoxide cleavage reaction with two organometallic reagents; Et 2 AlC≡CCH 2 OTBDPS and CH 2 =CHMgBr catalyzed by copper, and SAE as the key step for its elaboration. The total synthesis of amphotericin B 20a and amphoterolide B 20b was achieved by the efficient coupling of 170, 171, 172, and 173 fragments by employing four aldehyde-phosphonate type condensation reactions and an esterification reaction [178].

Polypropionate Synthesis by Others
Aside from the synthetic approach toward polypropionates by the research groups described above, there are other research groups that have contributed to this field with one or two publications (also see Table 1). Figure 19 depicts several natural products that these research groups have targeted, with reports varying from the synthesis of fragments

Polypropionate Synthesis by Others
Aside from the synthetic approach toward polypropionates by the research groups described above, there are other research groups that have contributed to this field with one or two publications (also see Table 1). Figure 19 depicts several natural products that these research groups have targeted, with reports varying from the synthesis of fragments to total syntheses. With few exceptions, these other methods are analogs to the synthetic approaches described above, since they follow slightly modified protocols and somewhat different starting materials. However, they do complement the epoxide-approach toolkit. In 1979, Corey reported the use of an epoxide intermediate to construct the C15-C29 chain of rifamycin 15 ( Figure 19) [179]. However, it was not until 1982 when he disclosed that a vinyl cuprate was used to open the epoxide [180]. A year earlier (1981), Lipshutz documented the use of high order mixed organocuprates in substitution reactions at unactivated secondary centers [181,182]. In 1982, Lipshutz also documented their reactivity toward epoxides [183], followed by their application in other organic reactions [176,184,185] and the synthesis of fragments of polypropionates [175]. In 1989, Yonemitsu et al. described an alternative synthesis toward two fragments C1-C5/C9-C15 of erythronolide A 3b via regio-and stereoselective reductive ring opening. The key of their methodology was to utilize trisubstituted epoxides (the methyl group pre-installed) and B 2 H 6 as a reducing agent [186]. Schreiber also reported stereochemical studies of epoxides toward the ansa chain of streptovaricin A 16a. He also took advantage of trisubstituted epoxides but used an intramolecular ring opening facilitated by a nearby urethane that was deprotected with Et 2 AlCl [187]. In 1993, Yadav et al. also utilized trimethylaluminum, an epoxy acrylate intermediate to synthesize fragment C9-C16 of trienoycin A 17 [188]. In addition, Zhai used Me 2 CuLi to open chiral allylic epoxides [189], Haddad used organocuprates and organoaluminium reagents [190], Sato used NaBH 4 to open trisubstituted trimethylsilyl epoxides [191], Mulzer used high order organo cyanocuprates to open two consecutive epoxides [192], and Tan used SmI 2 to reduce epoxides and MeMgCl or Me 3 Al to ringopen the epoxide while installing the methyl group [193]. More recently (2020), Kaliappan employed palladium mediated stereoselective reduction (ring opening) of the trisubstituted epoxide 174 to produce propionate 175 in a 68% yield [194]. It is important to note that this is the first example of palladium chemistry used to construct polypropionates, which led to the synthesis of the C1-C10 fragment of muamvatin 29 (Figure 19, middle). Table 1. Summary of the formal and total syntheses of polypropionates and related natural products by research group (chronological order).

Group
Year Fragment Natural Product Ref.  Figure 19. Natural products synthesized following the epoxide-based approaches (several authors).  Figure 19. Natural products synthesized following the epoxide-based approaches (several authors).

Other Epoxide Based-Syntheses of Polyols and Polyethers
It is well-known that all of the methodologies described above are paired with the aldol chemistry developed by Evans and others. Nonetheless, Evans also reported the use of epoxides for the synthesis of polyethers such as ferensimycin B 176 [199]. In this case, a neighboring hydroxy group performed an intramolecular epoxide ring opening to form an ether, which in turn could lead to polyethers after a few iterations. Lipshutz also contributed with his high order cuprate protocol for the synthesis of polyols [200] such as roflamycoin 19 [174,176] (Figures 17 and 19). Isobe also utilized Grignard or Gilman reagents to regioselective open epoxides to either form polypropionates or polyethers such as tautomycin 1 31 [197] (Figure 19). DIBAL and REDAL were the reducing agents of choice by Nicolaou for the regioselective reduction of chiral disubstituted epoxides [177] toward polyols such as amphoterecin B 20a and amphotheronolide B 20b [178] (Figures 18 and 19). The total synthesis of multiplolide A 34 was reported by Meshram et al. Treating a disubstituted epoxide with Sc(OTf) 3 and water afforded the expected diol in good yield [196]. Aside from the well-known Sharpless dihydroxylation reaction to make polyols, he also used Red-Al to open epoxides in his search for synthetic alternatives toward polyols [201]. Furthermore, Jamison reacted a polyepoxide with water at 60 • C for days to produce a polyether intermediate used to construct the HIJK rings of gymnocin A 28 [198] (Figure 19, bottom) and Table 1.

Conclusions
This manuscript describes the isolation and characterization of approximately 30 polypropionate and related natural products that have shown antimicrobial activities against bacteria, fungi, and yeast. Some of the polypropionates also displayed cytotoxicity against different types of cancer lines. The first epoxide-based methodology for polypropionate synthesis was reported by Kishi and collaborators in 1980 and was applied to the first synthesis of the ansa chain of rifamycin S 15. Kishi's five step methodology was based on Sharpless asymmetric epoxidation followed by lithium dimethyl cuprate ring opening to construct the propionate units. Yamagishi et al. reported the synthesis of two types of Kishi's intermediates, one for the construction of the ansa chain of rifamycin S 15 and the other for the formal synthesis of the aplysiatoxin 32 C1-C21 fragment, based on the stereoselective vanadium-catalyzed or tungsten-based epoxidations of cis-homoallylic alcohols and the asymmetric epoxidation of allylic alcohols. Marshall et al. were also influenced by the pioneering work of Kishi and employed a Lewis acid mediated allenylmetal addition to chiral aldehydes followed by the Kishi reiterative asymmetric epoxidationmethyl cuprate sequence. The research groups of Miyashita (1992 to 2011) and Prieto (2004 to 2017) applied their epoxide-alkynylaluminum cleavage approaches to the formal and total synthesis of several polypropionate natural products in common. Miyashita's group employed the regiospecific cleavage of γ,δ-epoxy acrylates with trimethylaluminum as the key steps while Prieto's reiterative methodology reported the stereoselective vanadiumcatalyzed epoxidation of homoallylic alcohols, followed by the epoxide-ring opening with alkynylaluminum reagents or alkenyl Grignards as the crucial steps for the elaboration of propionate motifs. Remarkably, McDonald's group developed a cross-coupling with elaborated alkynyllithium and epoxyalkyne fragments to construct long polypropionate chains with good regioselectivity. Jaminson was the only group that employed SAE for the construction of trans-syn-fused polycyclic ethers by an epoxide-opening cascade reaction promoted by water. The groups of Nicolaou and Yonemitzu based their epoxide methodology on the regioselective hydride ring-opening trisubstituted 2,3-epoxyalcohols for the construction of the 1,3-polyols and polypropionate fragments, respectively. Lipshutz and Nicolaou based their epoxide-cleavage methodologies to the stereoselective synthesis of 1,3-diols motifs found in polyene macrolides. The most recent report was made in 2020 by Kaliappan et al., which reported the synthesis of the polypropionate fragment of Muamvatin using palladium chemistry to open their epoxide. The most successful organometallic reagents to introduce methyl groups by the cleavage of epoxides were Me 3 Al and Me 2 CuLi. Indeed, the Kishi, Marshall, Sarabia, Jung, and Isobe groups employed a methyl cuprate reagent, while Miyashita and Yadav selected the methyl aluminum reagent to construct the polypropionate fragments. Particularly, the Yamagishi, Prieto, Isobe, and Lipshutz groups reported the cleavage of hindered 3,4-epoxy alcohols with dithianes for the convergent synthesis of long polypropionate and polyol chains.
It is important to note that most of the reviewed synthetic approaches were developed/reported a few decades ago, with a clear decline in the number of publications in the past decade. However, it is believed that this review should help to put these methods back into the limelight. Thus, an incremental interest on the topic is expected in the near future, particularly for methods utilizing transition metals or mild reaction conditions.
In brief, this review condenses the known reports of epoxide-based approaches toward polypropionates, which are attractive structural motifs in synthetic organic chemistry and the total synthesis of natural products. As described above, the presence of propionate moieties in natural products has shown good antimicrobial activity. Therefore, it is believed that the known literature and this review will be beneficial in the design of novel approaches and the synthesis of other important natural products in the near future.