Progress in the total synthesis of inthomycins

The inthomycin family of antibiotics, isolated from Streptomyces strains, are interesting molecules for synthesis due to their characteristic common oxazole polyene chiral allylic β-hydroxycarbonyl fragments and significant biological activities. The full structural motif of the inthomycins is found in several more complex natural products including the oxazolomycins, 16-methyloxazolomycin, curromycins A and B, and KSM-2690. This review summarises the application of various efforts towards the synthesis of inthomycins and their analogues systematically.


Introduction
Inthomycins, alternatively known as phthoxazolins, are a class of compounds in which a methylene-interrupted oxazolyltriene unit is conjugated to a chiral β-hydroxycarbonyl center of an amide functionality. Inthomycin A ((+)-1), the first member of the inthomycin family, was isolated by Omura's group from the strain of Streptomyces sp. OM-5714 in 1990 [1]. Then, the following year, Henkel and Zeek had reported the reisolation of inthomycin A ((+)-1) and the first isolation of inthomycin B ((+)-2) from the strain of Streptomyces sp. Gö 2, and proved inthomycin A ((+)-1) to be identical with phthoxazolin A ((+)-1) [2]. Later, the reisolation of inthomycin B ((+)-2) and inthomycin C ((-)-3) was reported by Omura's group in 1995 [3]. Inthomycin A ((+)-1) displays moderate antifungal activity against cellulose-containing Phytophthora parasitica and Phytophthora capsici [4]. Inthomycins were reported to possess many interesting biological properties, which include the specific inhibition of the cellular biosynthesis [1,4], in vitro antimicrobial activity [4,5], and anticancer activity against human prostate cancer cell lines [6,7]. A recent study suggested that the close analogue (+)-11 of inthomycin C was found to exhibit proteasome inhibition activity [8]. The skeletal structures of inthomycins A-C (1-3) are embodied in several other naturally occurring compounds, such as neooxazolomycin (4), oxazolomycins A-C (5, 6) [9][10][11][12][13][14], curromycins (7) [15], and KSM-2690 (8) [16] (Figure 1). Owing to their various biological activities and characteristic closely related structural motifs, they have generated immense interest among the chemists. Over the past two decades, a wide variety of synthetic strategies have been dedicated towards the synthesis of the inthomycin class of antibiotics. An earlier report on the total synthesis of oxazolomycins provides an overview of the author's synthetic efforts toward neooxazolomycin (4), oxazolomycin A (5a), and related antibiotics [17]. The recent review of Lee has mainly focused on the application of copper(I) salt and fluoridepromoted Stille coupling reactions in the synthesis of bioactive molecules including inthomycins A-C (1-3) [18]. The present review provides a systematic summary of synthetic strategies for the synthesis of inthomycins and their analogues over the period of 1999 to present.

Rewiew Synthesis
Undoubtedly, the unique skeleton of inthomycins has acted as an inspiration for the development of new synthetic methodolo-gies. Many methods have been developed for the synthesis of inthomycins since their first isolation in 1990 [1]. Most of the reported methods have been directed towards inthomycin C (3) due to its thermodynamically more favored 4E,6E,8E-triene system. The regiochemical issues of installing the conjugated triene system, which is susceptible to cis-trans isomerization, have been longstanding problems in the area of inthomycins. The problems are more acute for the construction of enantioenriched β-hydroxycarbonyl units as evident from the recent reports [19][20][21]. Since the pioneering works of Henaff and Whiting [19,20], several racemic and asymmetric total syntheses of inthomycins A-C (1-3) have been carried out in many research groups ( Figure 2). However, only four synthetic strategies that lead to the total synthesis of all three members of inthomycins A-C (1-3) are available ( Figure 2, route b, d, h, and i) [21][22][23][24].
Although the overall yield of this route was very low, this work certainly established the basis for the future enantioselective syntheses of inthomycins and related natural products.
In 2002, Moloney et al. described an efficient synthetic route using the Stille coupling reaction as the key step to accomplish the synthesis of phenyl analogues of inthomycins [36]. These triene moieties are a sub-unit of the oxazolomycin class of antibiotics. To prepare the phenyl analogue of racemic inthomycin C (rac-3), at first, the phosphonate 28 was prepared using a Claisen condensation of ethyl propionate (25) followed by methylation of 26a, treatment with bromine in acetic acid, and then triethyl phosphite. Next, compound 28 was treated with sodium hydride followed by aldehyde 29 [37] to give (E,E)-dienyl stannane 30 in 50% yield. The key Stille coupling between 30 and vinyl iodide 31, prepared by Takai reaction [38] of phenylacetaldehyde, in presence of PdCl 2 (MeCN) 2 produced (E,E,E)-Scheme 2: Moloney's synthesis of the phenyl analogue of inthomycin C ((rac)-3). triene 32 in 84% yield. Finally, NaBH 4 reduction of 32 gave alcohol (rac)-13, in which the triene moiety is analogous to inthomycin C ((rac)-3) and oxazolomycin B (5b) (Scheme 2).
After the successful application of the Stille reaction to construct the (E,E,E)-triene system (rac)-13 in a stereoselective manner, attention was then focused on the development of an analogous strategy towards the (Z,Z,E)-and (Z,E,E)-triene systems present in oxazolomycin A (5a) and oxazolomycin C (5c), respectively. The key steps were i) synthesis of dienyl halides, ii) synthesis of the required vinylstannane and iii) Stille coupling between them (Scheme 3) [39]. The required divinyl halides 36 were prepared, starting from phenylacetaldehyde (33), by using the Takai [38] or Wittig procedures [40] as shown in Scheme 3 (68% of a 3.3:1 mixture of (E,E)/(Z,E)-36b and 69% yield of a 8:1 mixture of (Z,E)/(E,E)-36a, respectively). Aldehyde 35 was then converted into dibromide 37 using PPh 3 /CBr 4 followed by stereoselective palladium-catalyzed monoreduction according to the literature available protocol [41] to give vinyl bromide 38 in 76% yield (Z/E as 99:1 mixture). Iodide 15a [42] was prepared stereoselectively from propargyl alcohol following the literature procedure, and the free hydroxy group was then protected as its TBDMS ether to produce 39 in 99% yield.
In 2006, R. J. K. Taylor and co-workers reported the first total synthesis of inthomycin B ((+)-2) using a Stille coupling of a stannyl-diene with an oxazole vinyl iodide unit followed by a Kiyooka ketene acetal/amino acid-derived oxazaborolidinone procedure as its cornerstones (Scheme 4) [43]. In the beginning, oxazole 45 was prepared in good yield (86%) by treating ethyl glyoxylate with tosyl methyl isocyanate (TosMIC) in the presence of K 2 CO 3 at 80 °C [44]. The reduction of the ethyl ester of 45 followed by NBS treatment gave unstable bromide 46 [45], which was immediately coupled to (E)-1,2-bis(tri-n-butylstannyl)ethene (47) using catalytic Pd 2 dba 3 in refluxing THF to produce iodide 48 in 46% yield. The coupling partner (Z,E)-(+)-54 was prepared enatioselectively from the known (E)-3-(tributylstannyl)propenal (49) [46] using a four-step sequence. Treatment of 49 with the Still-Gennari bis-trifluoroethoxy phosphonate reagent 50 proceeded stereoselectively to give ester 51 in excellent yield (94%). Subsequent DIBAL-H reduction of ester 51 followed by tetrapropylammonium perruthenate (TPAP) oxidation afforded aldehyde (Z,E)-52 as a single isomer in 83% yield over two steps. The asymmetric aldol reaction aldehyde (Z,E)-52 with silyl ketene acetal 53 in the presence of oxazaborolidinone derived from N-tosyl-ʟvaline and BH 3 ·THF generated the desired alcohol (Z,E)-(+)-54 in 74% yield and 64% ee. Next, a wide range of catalysts/conditions were screened for the crucial Stille coupling between iodide 48 and (Z,E)-(+)-54 to overcome the problems of isomerization of the (Z,E,E)-triene unit of the desired products. Finally, PdCl 2 (CH 3 CN) 2 (1 mol %) in DMF was found to smoothly deliver the required triene (+)-55 in quantitative yield. After many unsuccessful attempts of direct conversion of methyl ester (+)-55 into the corresponding primary amide, acetylation of acid 56a followed by acid chloride formation of acetate 56b and in situ ammonium hydroxide treatment was found to be fruitful to produce inthomycin B (+)-2 in reason-able yield (Scheme 4). This synthetic route introduced the chiral entry to any member of the inthomycin family for the first time.

Soon after, a subsequent collaboration between the Hale and Hatakeyama groups demonstrated that inthomycin C ((-)-3) has (3R)-and not (3S)-stereochemistry
Recently, Burton's group developed some efficient and tin-free total syntheses of all three inthomycins A-C ((+)-1, (+)-2, and (−)-3) using a Suzuki or Sonogashira cross-coupling of the (E)or (Z)-alkenyl iodides 130 with the dienylboronic ester 128 as key step (Schemes [18][19][20][21][22]. Initially, (E)-pent-2-en-4-yn-1-ol (124) was smoothly converted into the desired bromide derivative 125 [67] in two simple steps. The bromide 125 was then reacted with pre-lithiated oxazole derivative 120 [68,69] under optimized conditions to produce coupled product 126. The selective deprotection of the TMS group of 126 was found to be extremely challenging. The commonly used conditions provided the allene as a major product instead of the desired product. Ultimately, the mono-desilylated product 127 was obtained in 85% yield by using sodium sulfide in a mixture of THF and water. Next, the zirconium-catalyzed hydroboration of the terminal acetylene in 127 gave (E,E)-128 in good yield and with complete stereocontrol (Scheme 18).
To accomplish the key Suzuki coupling of dienylboronic ester 128, the necessary alkenyl iodides (Z)-and (E)-130 were prepared from the propargyl alcohol (14) in good yields using a four-step sequence such as Negishi's (Z) and (E)-stereoselec-tive isomerization of the terminal alkyne followed by iodinolysis [19,70,71], oxidation to the corresponding aldehydes and enantioselective Kiyooka-Mukaiyama aldol reaction followed by TES protection of the resulting alcohols (Scheme 19).

Conclusion
This review highlighted reports on the various synthetic efforts for both the formal and total synthesis of racemic and enantiopure inthomycins A-C (1-3). These compounds have three key structural features: an oxazole ring, a triene system, and an amide moiety with a chiral, hydroxylated carbon at the β-position. These interesting structures accompanied by their promising biological activities and the lack of natural sources have made inthomycins an attractive target in the synthetic organic community to work intensively in this area. The synthesis of simple looking inthomycins is challenging due to the unusually interposed functional groups and isomerizable double bonds in the conjugated triene moiety. Various stereoselective cross-coupling reactions such as Stille, Suzuki, or Sonogashira or Suzuki-Miyaura have been utilized to construct the geometrically distinctive polyene systems of inthomycins A-C (1-3). The elegant work of R. J. K. Taylor [21,43], Ryu [50], Donohoe [57], and Burton [23] demonstrated the power of the Mukaiyama−Kiyooka aldol reactions to install the asymmetric center of inthomycins. Alternatively, Hatakeyama and Kim's groups employed an asymmetric β-lactone synthesis and an asymmetric ynone reduction protocol for the construction of the stereogenic center of inthomycins, respectively [22,24]. Despite these recent advances, the development of novel methods for the regio-and stereocontrolled synthesis of inthomycins, inthomycin-embedded natural products, and their synthetic analogues with better biological outcomes is of strategic importance and being continued for further discovery.

Funding
The author gratefully acknowledges the financial assistance of the Science & Engineering Research Board (TAR/2018/ 000904), New Delhi, India.