untitled European Journal of Chemistry 6 (3) (2015) 357‐366 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2015 Atlanta Publishing House LLC ‐ All rights reserved ‐ Printed in the USA http://dx.doi.org/10.5155/eurjchem.6.3.357‐366.1267 European Journal of Chemistry Journal webpage: www.eurjchem.com Oxetanes as versatile building blocks in the total synthesis of natural products: An overview Ahmed Mahal * Department of Chemistry of the Natural Products, School of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131 Napoli, Italy * Corresponding author at: Department of Chemistry of the Natural Products, School of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131 Napoli, Italy. Tel.: +39.081.678550. Fax: +39.081.678532. E‐mail address: ahmed.salem@unina.it (A. Mahal). REVIEW INFORMATION ABSTRACT DOI: 10.5155/eurjchem.6.3.357‐366.1267 Received: 27 April 2015 Accepted: 01 June 2015 Published online: 30 September 2015 Printed: 30 September 2015 Oxetane ring plays an important role as main core in naturally occurring compounds and has many applications in pharmaceutical industries and synthetic organic chemistry. In this review, we report a brief survey of using the oxetane ring as versatile precursors in the total synthesis of natural products. Many approaches such as cyclization, addition, oxidation, reduction, elimination, protection as well as deprotection reactions utilized to synthesize of most important oxetane‐containing natural products involving taxol, (±)‐merrilactone A, (±)‐ oxetin, L‐oxetanocin, (+)‐(Z)‐laureatin and L‐oxetanocin are also covered. We describe in this review the most common total synthesis approaches have been yet applied to synthesis of most important oxetane‐containing natural products. The review is also included isolation, structure Identification of these oxetane‐containing natural products. The biological activity of oxetane‐containing natural products due to the oxetane ring is also defined. KEYWORDS Oxetane Anti‐tumor Drug discovery Small molecules Natural products Heterocyclic synthesis Cite this: Eur. J. Chem. 2015, 6(3), 357‐366 1. Introduction One of most important example as anti‐tumor drug is Paclitaxel (Taxol) in which has the oxetane four‐memberd D‐ ring can be essential for biological activity of Paclitaxel (Taxol) [1]. Oxetane ring has also found in many other natural products such as oxetin, oxetanocin, and many other examples of oxetane containing natural products (Figure 1) [2,3]. Thromboxane A2 is a compound belonging to Throm‐ boxane type which is obtained by activated platelets. Half‐life of Thromboxane A2 is very short about 30 seconds in Plasma [3]. Mitrephorone A is a diterpenoids having an oxetane ring with ketone moieties was isolated in 2005 from Mitrephora Glabra Scheff by Oberlies and his co‐workers and shown an activity as anticancers [4]. Maoyecrystal I is a diterpenoids was isolated from Isidon japonicus and the structure was confirmed by using spectroscopic methods. Sun and his co‐workers reported that the cytotoxity against K562 cells could be due to oxetane ring existed in the structure of Maoyecrystal I [5]. Dictyoxetane is a diterpenoid was first isolated in 1985 by Clardy and his co‐workers from brown algae Dictyoatadi‐ chotoma in Indian Ocean. Unusual structure of Dictyoxetane has attracted much attention to be synthesized [6‐10]. Bradyoxetin is a symmetrical bis‐oxetane ring has shown to be signaling molecule for Bradyrhizobium japonicum involved in symbiotic gene regulation [11]. We aim in this study to shed light on the oxetane as useful building blocks for the synthesis of some important biologically active oxetane‐containing natural products. 2. Oxetane as building blocks for synthesis of L‐oxetanocin The first isolation of Oxetanocin was in 1986 from the soil‐ bacterium Bacilus megaterium NK84‐0218 [12] Oxetanocin has shown an activity to inhibit the HIV‐virus that causes the AIDS disease [13]. Many approaches have described the total synthesis of Oxetanocin [14‐19]. Oxetanocin has attracting much attention due to its high biological activity. Chu and his co‐workers have achieved the total synthesis of L‐Oxetanocin (Scheme 1) in 16 steps and 2.8% overall yield [20] avoiding the use of Lewis acid since they used coupling reaction between the oxetane ring and nucleobase. Starting from protected L‐xylose was converted in 8 steps to protected derivative 2 [20,21]. Deprotection of derivative 2 to lactol 3 followed by oxidation of compound 3 to lactone 4. In order to get a convenient yield, this step was completed using amended procedure [22] upon control of pH to be between 4.5‐4.8. 358 Mahal / European Journal of Chemistry 6 (3) (2015) 357‐366 Figure 1. Oxetane‐containing natural products. O OH HO OH OH O OBn ORO O 1 R=H 2 R=Bn NaH, TBAI, BnBr, 89% O OBn OBnOH HOO OBn OBnOR O O HOOC OBn OBn NaOH 72% 4 R=H 5 R=Ms MsCl, Py, 96% L-xylose 3 Br2, BaCO3 72% HCl, Dioxane 99% 7 steps 52% 6 -isomer 7 Scheme 1 Mesylation of lactone 4 to compound 5 followed by ring contraction to yield acids 6 and 7 (3:1) (73%) [20,23]. The acids 6 and 7 underwent one‐pot reaction to afford epimeric thiopyridyl oxetanes 8 in 30% yield. The coupling reaction of compound 8 was resulted the protected derivatives 9 and 10 (2:3) in 61% yield. Removing of benzyl protected group yielded compounds 11 and 12 and then hydrogenation reaction was achieved using palladium black to result Oxetanocin and its α‐isomer 13 in 90% yield (Scheme 2). 3. Oxetane as building blocks for synthesis of (±)‐oxetin Oxetin is an amino acid antimetabolite was isolated in 1984 from the fermentation broth of a Streptomyces sp. OM‐ 2317 with herbicidal and antibacterial activity [24,25]. It has (2R,3S) configuration as was confirmed by X‐ray crystallo‐ graphy. Total synthesis of Oxetin has accomplished by many groups [25,26]. Bach and his co‐workers have showed an efficient method to synthesis of Oxetin (Rac‐1) in four steps with an overall yield 14% [27]. They have been started from available n‐butyl glyoxylate 14 [28] underwent a stereo‐ selective Paternò‐Büchi reaction with 2 equivalent of available enecarbamate [29] to afford diastereomericlly pure oxetane 15 in yields of 28‐35% (Scheme 3). Catalytic hydrogenolysis was used to remove the N‐benzyl group which led to yield the n‐butyl ester 16 (50%) and its methyl derivative 17 (17%). Mahal / European Journal of Chemistry 6 (3) (2015) 357‐366 359 Scheme 2 Scheme 3 Oxetin was obtained in a good yield by removal of protected amine of compound 16 followed by saponification of compound 18 as shown in Scheme 4. Scheme 4 4. Oxetane as building blocks for synthesis of (±)‐ merrilactone A Merrilactone A was isolated from Illicium merrillianum in 2000 by Fukuyama and co‐workers and has shown an intriguing neurotrophic activity in the cultures of fetal rat cortical neurons [30]. The crystal structure of Merrilactone A has identified to be a sesquiterpene possessing two γ‐lactones as well as an oxetane ring. Due to the biological activity of Merrilactone A, many synthetic methodologies have applied to the total synthesis of Merrilactone A [31‐36], among of these was total synthesis of (±)‐Merrilactone A by Inoue and his co‐ workers in 2003 based on ring reducing of meso‐diketone [32]. Unnatural enantiomer of Merrilactone A has synthesized by Inoue and his co‐workers in 2006 [37]. Fukuyama and his co‐workers have reported a new approach to synthesis of core skeletons of Merrilactone A [38‐40]. They were aimed to construct the core of meso‐diketone therefore, they have started from [2+2] photocycloaddition between compound 19 and compound 20 which afforded the compound 21 [41,42]. Compound 21 was reducing to form double bond and followed by LAH‐reduction of the anhydride yielded meso‐diol, 22. Converting two hydroxyl groups into benzyl ethers and then dihydroxylation has achieved to afford compound 23. A one‐ pot reaction [43] of Swern oxidation/allylation (compound 23, 24 and 25) afforded compound 25αα as the major isomer since cis‐introduction of allyl groups occurred from α‐face, this step has accomplished in one step to avoid the hydrolysis of diketone in aqueous workup. Ring‐closing metathesis reaction [44‐47] of compound 25 yielded bicyclo[4.2.0]octyl system 26, then the reaction underwent upon treating with Pb(OAc)4 in situ [48] to afford eight membered ring 27 (Scheme 5). The target compound 28 was selectively obtained from the reaction of compound 27 with LiN(TMS)2 in THF at ‐100 °C (Scheme 6). Furthermore, they have optimized reaction conditions in order to get the best ratio of the target compound (Table 1). Table 1. Reaction conditions of target compound 28. Entry Reagents and conditions Ratio 28 Ratio 29 Combined yield, % 1 LiN(TMS)2, THF, ‐110 °C 3.1 1.0 85 2 LiN(TMS)2, THF, ‐40 °C 2.6 1.0 78 3 MgBrN(TMS)2, Et2O, RT 1.0 3.0 81 4 LiN(TMS)2, Et3N, toluene, ‐78 °C 1.0 5.1 79 5 DBU, CH2Cl2, 0 °C 1.1 1.0 63 360 Mahal / European Journal of Chemistry 6 (3) (2015) 357‐366 Scheme 5 Scheme 6 α‐Epoxide 30 was produced as a result of epoxidation reaction of compound 28 which converted to compound 31 through 2 steps involving epoxide ring opening with DBU and then IBX oxidation [49,50]. α‐bromoacetal was added to compound 31 to yield compound 32 as a 4:1 mixture of diastereomers (Scheme 7). Radical cyclization using Bu3SnH and BEt3 [51,52] produced a highly yield of 5‐exo cyclized product 33 [53‐55] although the steric effect around C9. They have transformed 33α into 33β using acidic ethanol. The compound 34 which has all of the carbons of 1 in place was synthesized by the regioselective silyl enol formation from 33β and then reacted with Eschenmoser reagent followed by m‐CPBA [56]. Two steps was used in order to prepare enol ether 35, first upon treatment with TFA/H2O and the second step using mesylation and base induced elimination as shown in Scheme 8. L‐Selectride was used to reduce enone 35 followed by an in situ triflation of the resultant enolate [57,58] which resulted compound 36. Reduction of compound 36 by using palladium afforded olefin 37 [59]. The isomer benzyl ethers 38 was generated by reduction reaction using DIBAL at ‐78 °C. The tetraol 40 was obtained by birch reduction of benzyl ethers 38 afforded triol 39 in which was hydrated (Scheme 9). Mahal / European Journal of Chemistry 6 (3) (2015) 357‐366 361 Scheme 7 . Scheme 8 They were regio‐ and chemo‐selectivities oxidized C11 and C12 alcohol by Fetizon oxidation [60,61] afforded bis‐lactone 41. Epoxidation of bis‐lactone 41 using dimethyldioxirane [62,63] yielded compound 42, then treatment with acidic condition afforded the natural product of (±)‐merrilactone A via epoxide‐opening oxetane formation (Scheme 10) [30,31]. 5. Oxetane as building blocks for synthesis of (+)‐(Z)‐ laureatin Laureatin is a metabolite of the red algae was first isolated from Laurencia nipponica Yamada in 1968 by Irie and his co‐ workers with larvarcidal activity in a mosquitos [64,65]. Three approaches have been described the total synthesis of Laureatin [66‐68]. Suzuki and his co‐workers were reported the first total synthesis of Laureatin based on biosynthesis pathway which was proposed by Murai’s group [69‐71] as shown in Scheme 11. They have attempted to prepare laureatin starting from α,ά‐trans‐oxocene core 43, the first attempt was failed to convert oxocene 6 to bicyclic skeletons and instead of that, tetrahydrofuran derivative was produced. The second trial was used cyclization of hydroxyl epoxide. The compound 44 was obtained by protection of hydroxyl group of oxocene 43, followed by removal of benzyl protecting group of compound 44 afforded compound 45. Epoxidation of compound 45 was preceded through β‐selectivity to yield compound 46 up to 96%. Upon treatment of compound 46 with aqueous KOH in DMSO [72] led to regioselective 4‐exo cyclization which resulted laureatin bicyclic system 47. The compound 47 was then protected using pivaloyl chloride to afford compound 48 as shown in Scheme 12. The complete conversion of compound 49 was obtained by mesylation of compound 48 and then using of CsOAc and 18‐ crown‐6 in toluene [73]. 362 Mahal / European Journal of Chemistry 6 (3) (2015) 357‐366 Scheme 9 Scheme 10 Scheme 11 Mahal / European Journal of Chemistry 6 (3) (2015) 357‐366 363 Scheme 12 Scheme 13 Removal of protecting groups of the acetyl and SEM led to form two hydroxyl groups 50 which subjected to bromination reaction via SN2 using Murai’s procedure [74] to yield dibromide 51 (Scheme 13). After reduction of pivaloyl group in compound 51 to hydroxyl group in 96% yield, the C‐C bond forming proceeded as the following steps [75]: Oxidation using Dess‐Matin peridinane (93%), then reacted with CBr4 and HMPT in THF (93%) [76] and stereoselective hydrogenolysis of 1,1‐ dibromoalkene by Uenishi’s approach (82%) [77], followed by sonogashira coupling of the Z‐1‐bromoalkene (90%) [78]. TBS group in compound 52 was removed to afford final target of (+)‐(Z)‐laureatin (Scheme 14). 6. Oxetane as building blocks for synthesis of taxol Taxol [79], is anticancer natural product drug was first isolated from the cytotoxic methanolic extract of the bark of T. brevifolia [80]. It has shown a very good activity as clinical agent [81,82] for the treatment of breast [83], ovarian [84‐87], skin [88,89], lung [90‐92], and head and neck [93] cancers. Taxol was approved in 1993 by FDA for treatment of breast and ovarian cancers [94]. To date, seven methods was used in description the total synthesis of taxol [94‐103]. Nicolaou and his co‐workers were reported total synthesis of taxol and in 1994 [104‐107]. They were described the construction of oxetane ring which was more challenging in the total synthesis of taxol in two pathways based on a taxoid skelton achieved by Potier’s group [108] and on a C ring model system performed by Danishefsky’s group [109]. Danishefsky’s approach [109] was started from intermediate 55 which was obtained either by silylation of compound 54 with TESCl‐pyridine or from degradation of 10‐ deacetylbaccatin III [104]. Selectively removal of acetate group at C‐20 was by using K2CO3 in MeOH to yield triol 56. The new hydroxyl group of triol 56 was selectively protected with TMSCl afforded compound 57 which was subjected to the triflation produced triflate silyl ether 58. Oxetane ring 59 was obtained upon treatment with (silica gel, CH2Cl2) accompanied by desilylation of C20‐hydroxyl group followed by internal SN2 displacement of the triflate as shown. 364 Mahal / European Journal of Chemistry 6 (3) (2015) 357‐366 Scheme 14 Scheme 15 Potier’s approach was involved the same diol 55 which was converted into hydroxyl mesylate 60 followed by selective deacetylated at position 20 to afford diol 61. The diol 61 was allowed to heating in refluxing butanone afforded oxetane ring 59 (Scheme 15). 4. 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