Cyclization reactions macrolactonization

The synthesis of the disaccharide subunit 85 of tricolorin A, a cytotoxic resin glycoside isolated from lpomoea tricolor, provides a unique opportunity to compare the efficiency of an RCM-based macro cyclization reaction with that of a more conventional macrolactonization strategy. Furthermore, this specific target molecule challenges the compatibility of the catalysts with various functional groups. 

For initial laboratory investigations, a reaction concentration of 0.3-0.4 M may be a good starting point. More dilute conditions will be needed to minimize selected intermolecular reactions for some relatively slow reactions, such as 3-lactam cyclization and macrolactonization. The optimal manufacturing concentration has been described as greater than 10% [14], and should be adjusted for the process needs. 

Zinc(O) is capable of reducing alkyl halides. The interplay of the reductive action of zinc and the ability of aluminum Lewis acids to activate the carbonyl group enabled effective generation of aluminum enolates from a-bromo carbonyl compounds (Scheme 6.25) [45]. This method is convenient for aldol cyclization reaction, producing macrolactones in moderate to high yields. Note that the possibility of a zinc enolate, rather than the aluminum enolate, promoting the actual reactions could not be excluded. 

Intramolecular lactonization can also be carried out with DCCI and DMAP. As with most other macrolactonizations, the reactions must be carried out in rather dilute solution to promote the intramolecular cyclization in competition with inter-molecular reaction, which leads to dimers or higher oligomers. A study with 15-hydroxypentadecanoic acid demonstrated that a proton source is beneficial under these conditions and found the hydrochloride of DMAP to be convenient.130... 

In parallel investigations, Danishefsky and coworkers accomplished the preparation of the 16-membered lactone of a model epothilone system via an alternative C9,C10 disconnection [14] (Scheme 4). In this case, coupling of epoxy-alcohol 17 with acids 18a and 18b afforded trienes 19a and 19b respectively. RCM of 19a under the influence of ruthenium initiator 3 produced dienes 20a as a 1 1 mixture of Z -isomers. Under identical conditions, cyclization of 19b produced a single product 20b (tentatively assigned as the Z-isomer). The variable stereoselectivity observed in these reactions was inconsequential since the olefinic functionality could be reduced to afford the corresponding saturated macrolactones. Schrock s molybdenum initiator 1 promoted the cyclization of 19a and 19b with similar efficacy [14]. 

Aldol reaction of keto-acid 21 with aldehyde 10 and esterification of the resulting acids with alcohol 22 led rapidly to cyclization precursor 23 and its 6S,7R-diastereomer (not shown). RCM using ruthenium initiator 3 (0.1 equiv) in dichloromethane (0.0015 M) at 25 °C afforded macrolactones 24a and 24b in a 1.2 1 ratio. Deprotection and epoxidation of the desired macrolactone, 24a, afforded epothilone A (4) via 25a (epothilone C) (Scheme 5). Varying a number of reaction parameters, such as solvent, temperature and concentration, failed to improve significantly the Z-selectivity of the RCM. However, in the context of the epothilone project, the formation of the E-isomer 24b could actually be viewed as beneficial since it allowed preparation of the epothilone A analog 26 for biological evaluation. 

Synthesis of 12- and 13-membered sulfur-containing lactones by homolytic macrocyclization of mercaptoacetic esters and alkynes has been investigated [95S307]. Reaction of the mercaptoester 245 with alkynes using triethyl borane radical initiation gave the macrolactones 247 and 248 in low yield [95TL2293], Remote asymmetric induction is observed during the cyclization. 

By use of chelating tri- and tetramines 59 or 60 Kharasch additions can be performed in 65-75% yield using 0.3-10 mol% FeCl2 as the catalyst (Fig. 13) [116, 117]. The same catalysts are very efficient to promote otherwise difficult ATRC of co-alkenyl trichloroacetates 58 providing five-membered lactone 61 by 5-exo cycli-zation in 55% yield and eight- to ten-membered lactones 62 by 8-10-endo cyclizations in 34-50% yield, respectively. Even oo-allyl oligo(ethyleneoxy) trichloroacetates underwent radical macrolactonization reactions in 56-60% yield with 10 mol% of catalyst. 

Although Bu2SnO is a powerful catalyst for cyclization of co-hydroxy and co-amino carboxylic acids [294], treatment of co-hydroxy trifluoroethyl esters with Bu jSnOMe catalysis resulted in macrolactonization and/or diolide formation in different ratios, depending on chain lengths and reaction conditions (Scheme 12.166) [295]. In this reaction inter- and/or intramolecular transesterification occurred between trifluoroethyl esters and alkoxytrialkyltin generated by rapid exchange of the alkoxytin catalyst with the terminal alcohol. By use of this procedure as a final key step a 12-membered macrocyclic otonecine diester was obtained (Scheme 12.167) [296]. 

Macrocyclic motifs are usually essential for the unique biological properties of natural products. In most cases, linear NRP and PK scaffolds are cyclized to form macrolactones or macrolactams prior to further post-modification. Macrocyclization is usually carried out by cyclases towards the end of elongation. For example, in the biosynthesis of the antibiotic tyrocidine A, a linear enzyme-bound decapeptide is cyclized via an intramolecular SN2 reaction between the N-terminal amine nucleophile and the C-terminal thioester, which is covalently linked to the synthase [reactions (a) and (b), Scheme 8.3] [22], This cyclase shows great versatility. Not only does it catalyze the formation of macrolactams of ring sizes from 18 to 42 atoms from... 

Aldol reactions involving aluminum species are considered to be of less synthetic value because of the ambiguous isomerization of the aldol products, under the influence of the Lewis-acidic aluminum species. Efforts have been made to generate an aluminum enolate in a regiospecific manner. Addition of dialkylchloroalane and zinc to a mixture of an a-halo ketone (126) and an aldehyde leads to the formation of enolate (127), which subsequently reacts with the aldehyde, as shown in Scheme 53.71 This method is applicable to the construction of medium to large rings by intramolecular aldol cyclization of various a-bromocarboxylates of u)-hydroxy aldehydes (e.g. BiCHRC02(CH2) CH0 where — 9, 11 or 12 and R = H or Me). The macrolactonization proceeds in reasonable yield, as shown in Scheme 53. 

Mitsunobu et al. [46] reported an efficient macrolactonization using diethyl azodicarboxylate (DEAD) and Ph3P. In the case of (o-hydroxy acids having a secondary alcohol, this cyclization takes place with inversion of the configuration of the alcohol. In the total synthesis of latrunculin A (82) and B, the Mitsunobu reaction was used for the macrolactonization of the seco-acid 81 with inversion of the secondary alcohol [47]. 

The intramolecular HWE cyclizations using phosphonoacetate (t-PrOLi or LHMDS, HMPA, THF-PhH) or ketophosphonate (NaH, DME or Na, PhMe) under high dilution conditions were developed as variable methods for the construction of macrolactones by Stork and Nakamura [89] and Nicolaou et al. [90], respectively. The very mild and efficient conditions for the intramolecular HWE reaction of (3-ketophosphonate or phosphonoacetate were reported (1) treatment with K2CO3, in the presence of 18-crown-6 [91], or (2) treatment with tertiary amines such as EtjN or Hunig s base in the presence of LiBr or LiCl [92]. These methods are applied to the total synthesis of polyene macrolides [93a-95] such as amphotericin B (170) [96] and polyoxomacrolides [97-100]. 

A variety of specialized reagents have been developed for macrolactonization reactions. Two of the more important are the Corey-Nicolaou reagent, 2,2 -dipyridyl disulfide (232)10 jjjg Mukaiyama reagent, which is 2-chloro-l-methylpyridinium iodide (233). A number of related reagents have been developed, including imidazole disulfide 234 [2,2 -dithio-(4-ferf-butyl-l-isopropylimidazole)]l 2 and imidazole 235 [N-(trimethylsilyl)imidazole].l 3 All of these reagents are effective for the cyclization of co-hydroxy acids, as shown in Table 6.1. For comparison, available cyclization results with DEAD and 234 are included. In this table, a hydroxy acid is converted to a lactone (219). 

The first total syntheses of racemic zearalenone (rac-479) were reported in the 1960s by the Merck and Syntex research groups (364, 365). In their multistep synthesis routes of the seco acid, the double bond was introduced by a Wittig reaction, but the required ( )-configured double bond was not formed selectively and the yields of the following lactonization were very low. The yields of macrolactonization were improved remarkably by Corey (360) and Masamune (361) using new activation methods for carboxylic acids (366). In aU the syntheses of zearalenone, the macrolide was formed by lactonization, but numerous possibilities are evident for the cyclization step. Figure 9.4 illustrates some different approaches to the synthesis of zearalenone (367). 

Figure 3.102 Possible schemes for formation of the 2,3-trans double bond of the macrolactone produced from the chm PKS. (a) Two-step reduction and dehydration of the full-length polyketide chain prior to release from the PKS enzyme and cyclization (b) post-PKS reduction and dehydration of the macrolactone showing two different points at which these reactions may occur.

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