Yamaguchi synthesis, 8-lactones

Scheme 13.40. Prelog-Djerassi Lactone Synthesis M. Yamaguchi and Co-Workers3...

With both building blocks 103 and 109 in hand, the total synthesis of lb was completed as shown in Scheme 17. Coupling of acid 103 and alcohol 109 under Yamaguchi conditions to give ester 110 and subsequent desilylation followed by chemoselective oxidation provided hydroxy acid 111. Lactonization of the 2-thiopyridyl ester derived from 111 in the presence of cupric bromide produced the macrodiolide 112 in 62% yield, which was finally converted to pamamycin-607 (lb) via one-pot azide reduction/double reductive AT-methylation. In summary, 36 steps were necessary to accomplish the synthesis of lb from alcohols 88 and 104, sulfone 91, ketone 93, and iodide rac-97. 

In fact, the sensitive disubstituted alkene of 14 turned out to not be stable to the subsequent A1C1, coupling conditions, so the alkene and the secondary alcohol were protected together as the bromoether 15. Condensation of the derived enol ether 16 with the sulfone 2 in the presence of DTBMP (2,6-di-/-butyl-4-methylpyridine) then gave 17. Yamaguchi lactonization followed by regeneration of the alkene by zinc reduction completed the synthesis of 1. 

With the full complement of stereogenic centres required, the 1,3-diol (11) was then taken through a protection/ deproteclion sequence to afford the corresponding diacetoxy alcohol (13), thereby completing the formal synthesis of (+)-PDLA. The remaining steps in the total synthesis followed the route employed by Yamaguchi and co-workers/ Diacetoxy alcohol (13) was oxidised with RuClj/NalO to provide acid (14), which underwent concomitant lactonisation to (15) under saponification conditions. The primary alcohol (15) was then oxidised to afford (+)-Prelog-Djerassi lactonic acid in an overall 9 % yield, with all spectroscopic data in accord with the literature values. 

One final example of acylation of alkynes by lactones forms part of the synthesis of neomethynolide by Yamaguchi. The Prelog-Djerassi lactone serves as the acylating agent (equation 49). The functionalized alkynide undergoes addition very selectively at the lactonic carbonyl group, despite the presence of a relatively unhindered primary ester. ... 

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). 

YAMADA Coupling reagent 430 YAMAGUCHI Lactonization reagent 431 YAMAZAKI Cyanoandme synthesis 432 Yamamoto 177... 

An enantioselective total synthesis of epothilone A 837 using multifunctional asymmetric catalysis has been achieved [614]. Suzuki cross-coupling of fragment A 835 with fragment C 836 followed by Yamaguchi lactonization as key steps leads to an enantiocontrolled synthesis of epothilone A 837. During the synthesis of fragment A, reaction of an aldehyde 832 with TMS-acetylide affords an alcohol, which... 

Takadoi M, Yamaguchi K, Terashima S (2003) Synthetic studies on himbacine, a potent antagonist of the muscarinic M2 subtype receptor. Part 2 synthesis and muscarinic M2 subtype antagonistic activity of the novel himbacine congeners modified at the C-3 position of lactone moiety. Bioorg Med Chem 11 1169-1186... 

Pietruszka [75] reported the total synthesis of a series of solandelactones (A-H) by the coupling reaction of the lactone 78, the key intermediate, with side chains 79 and 80 (Scheme 5.27). Lactone 78 was prepared by cyclization of the seco-acid 77 under Yamaguchi conditions in good yield (85%). Finally, the Nozaki-Hiyama-Kishi coupling of the unsaturated lactone aldehyde or its saturated counterpart with the iodide 79 or 80 afforded solandelactones A-H in good yields as separable diastereomeric mixtures (ratio 2 1). 

Aggarwal performed the stereoselective total synthesis of solandelactones E and F by a stereocontrolled allylboration reaction of the eight-membered lactone 83, which was prepared by cyclization of 81 (Scheme 5.28) [76]. Treatment of the seco-acid 81 under Yamaguchi conditions according to the protocol previously established by Martin et al. [73] and Pietruszka [75] for a similar reaction resulted in the formation of the target lactone 82 in good yield. 

Wills first accomphshed the total synthesis of 6a using the Yamaguchi lactonization to form the medium-sized lactone of 6a (Scheme 5.31) [80]. Lactonization of 87 was achieved by employing Yamaguchi s mixed-anhydride method to form the corresponding lactone 88 [26]. Although the preparation of the nine-membered lactone moiety can be difficulL smooth lactonization was accomphshed because the cis double bond provides both enthalpic and entropic assistances to this process, in contrast with cychzation of a saturated ring. 

Datta reported the formal synthesis of (6a) by preparation of the nine-membered lactone that possesses a cyclopropane moiety as one of the functionalities (Scheme 5.35) [86]. Cyclization of the seco-acid 95 under Yamaguchi conditions... 

---