Seco-acid lactonization

The 13,17-seco-acid lactone (258), obtained from a Baeyer-Villiger oxidation of 5a-androstan-17-one has been reduced to yield 13,17-seco-5a-androstan-13a,17-diol, whose diacetate on pyrolysis furnished the endocyclic seco-olefin (259 R = OAc) as the major reaction product. A minor product is the corresponding A12 13-olefin.115 Hydrolysis of the acetate (259 R = OAc) to its alcohol (259 R = OH) and formation of the tosylate and the iodide (259 R = I), followed by reaction with lithium dimethylcuprate, afforded a route to A1314-13,17-seco-5a-D-homoandrostene (259 R = Me). The [17a,17a,17a-[2H3]androstene (259 R = CD3) was prepared by treating the iodide (259 R = I) with lithium perdeuteriodimethyl-cuprate. 

Sorm" " found that when cholesterol acetate (67) is oxidized by chromic acid in acetic acid-water at 55°, crystalline keto seco-acid (69) is obtained in 25-30 % yield from the mother liquors after removal of successive crops of 7-ketocholesterol acetate (68). Reaction of keto acid (69) with benzoyl chloride in pyridine gives a dehydration product, shown" to be the )5-lactone... 

Elaboration of triol 88b to bryostatin 7 requires chemoselective hydrolysis of the Cl methyl ester in the presence of the C7 and C20 acetates, macrolide formation, installation of the C13 and C21 methyl enoates, and, finally, global deprotection. The sequencing of these transformations is critical, as attempts to introduce the C21 methyl enoate to form the fully functionalized C-ring pyran in advance of macrolide formation resulted in lactonization onto the C23 hydroxyl. In the event, trimethyltin hydroxide promoted hydrolysis [73] of the Cl carboxylate of triol 88b, and subsequent trie thy lsilylation of the C3 and C26 hydroxyls each occurs in a selective fashion, thus providing the seco-acid 89. Yamaguchi macrolacto-nization [39] proceeds uneventfully to provide the macrolide 67 in 66 % yield (Scheme 5.14). 

Macrolactonization.1 High dilution is usually essential for macrolactonization, but the 14-membered lactone, 9-dihydroerythronolide A (3), can be obtained in almost quantitative yield by lactonization of the seco-acid 2 via the mixed anhydride formed with 2,4,6-trichlorobenzoyl chloride (1) with triethylamine and 4-dimethyl-... 

This method was used to effect lactonization of the protected seco acids of 7-epibre-feldine A (5) in 74% yield. 

Macrolactonizathn with inversion. Lactonization of the optically active seco-acid 1 with P(C sH,), and DEAD followed by hydrolysis of the acetonide group gives the cyclic dilactonc colletodiol (2), formed with inversion of configuration at the hydroxyl-bearing carbon. Lactonization of 1 with 2,4,6-trichlorobenzoyl chloride and tdethylamine (9, 478-479) furnishes 6-epicolletodiol after deprotection. 

In the synthesis of brefeldin A 92) by Gais and Lied [54], seco acid 90 was lactonized to 91 with the push-pull acetylene 93 (Scheme 31) in 71% yield (Scheme 30). The mechanism is outlined in Scheme 31. 

The hydroxy part of a hydroxy acid can also be activated for macrolactonization. Vedejs et al. [60] applied such a strategy to the synthesis of the macrocychc pyrrolizidine alkaloid monocrotaline 108). Thus, the seco acid derivative 106 was first mesylated with MsCl/EtjN in dichloromethane, and the crude product was added over 3 h to an excess of tetrabutylammonium fluoride trihydrate in acetonitrile at 34 °C to effect ring carboxy deprotection and ring closure to give 107 in 71% yield (Scheme 36). It has been noted that the active intermediate of this kind of lactonization may be an allylic chloride rather than a mesylate [61a], In addition, an intramolecular nucleophilic displacement process of chloride from an a-chloro ketone moiety by a remote carboxylate has been recently reported as an efficient approach to macrocychc keto lactones [61 bj. 

The same structural requirements have bren recently recognized by Stork and Rychovsky [65] in the course of the total synth is of (+)-(9S)-dihydroery-thronolide A, though a different ring closure method was employed. In addition, a further structural requirment for efficient lactonization has been found. Seco acids 114 and 115 failed to lactonize while seco acid 116 was cyclized using the DCC-DMAP method to lactone //7 in 64% yield (Scheme 39). The explanation is as follows The conformation in solution of the C(8)-C(ll) portion of 117 is shown in Fig. 1, in which a 1,3-diaxial interaction is present between and C(8). Therefore, when R is an alkyl group, the resulting severe interaction should make cyclization of the seco acid very unfavorable. 

The formation of mixed anhydrides, which in some cases may be isolated, is an established method. For instance, racemic zearalenone (352) has been obtained by treating the seco-acid (351) with trifluo-roacetic anhydride (equation 126). Similarly, antimycin A3 has been prepared. A more modem procedure makes use of Yamaguchi s 2,4,6-benzoyl chloride esterification. For example, a synthesis of methynolide is based on the lactonization of the alkynic seco-acid (353) to (354 equation 127). 

A more complex hydroxy acid is lactonized in a synthesis of (9S)-9-dihydroerythronolide A, albeit in low yield (equation 128). By acid treatment (356) is deprotected to give the desired target molecule. The presence of jp -centers in the seco-acid obviously facilitates lactonization, as shown by the preparation of the mycinolide V precursor (357 equation 129). A mixed carbonate is used in the synthesis of the tylonolide precursor (358 equation 130). ° In general, DMAP catalysis is helpful in the ring closing step in most cases. 

Hikota, M., Tone, H., Horita, K., Yonemitsu, O. Chiral synthesis of polyketide-derived natural products. 31. Stereoselective synthesis of erythronolide A by extremely efficient lactonization based on conformational adjustment and high activation of seco-acid. Tetrahedron 1990, 46, 4613 628. 

Not surprisingly. Bycroft reported failure to effect formation of the macrocycle from the seco acid via an intramolecular lactonization. All attempts at the use of either DCC or trifluoroacetic anhydride under a variety of conditions failed... 

Intermediate 113 was transformed into the trimethylsilyl methyl ketone 119 in quantitative yield via the acid chloride, followed by the addition of trimethylsilylmethyl lithium (Scheme 2.13). Subsequent Peterson olefination of aldehyde 108 with 119 resulted in the required unsaturated ketone 120 in 95% yield. Subsequent desilylation and thioester hydrolysis afforded a 97% of the seco acid 121. Lactonization was achieved in 32% yield via the phosphoric acid-mixed anhydride, however this procedure also formed about 25% of the dimeric bis lactone. Following removal of the acetonide under the action of acid, a nonselective oxidation with RuCl2(Ph3P)3 produced a 1 1 mixture of the natural... 

A unique approach to the stereochemical complexities of erythronolide A was developed by Deslongchamps as outlined in Scheme 2,19. The methyl ester of erythronolide A seco acid (212) was dehydrated to form the cyclic ketal 213. A multistep oxidation of the side chain then gave aldehyde 214 which, when condensed with the zirconium enolate of methyl propionate, afforded a 10 1 ratio of aldol diastereomers, the major being 213. Furthermore, aldehyde 214 could easily be converted into the y-lactone 215. 

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