Formal total synthesis of (+)-zaragozic acid C through an Ireland-Claisen rearrangement
Formal total synthesis of (+)-zaragozic acid C through an Ireland-Claisen rearrangement
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DOI：
10.1002/anie.200602507
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发表时间：
2006-01-01
影响因子：
16.6
通讯作者：
Rizzacasa, Mark A.
中科院分区：
文献类型：
--
作者：
Bunte, Jens O.;Cuzzupe, Anthony N.;Rizzacasa, Mark A.
The hydrolysis of the methyl ketal in 14 proved troublesome as most acidic methods caused extensive decomposition of the substrate. Eventually, we found that acetolysis (Ac2O, TFA, 08C)[26] cleanly gave the diacetate 16 as a 2: 1 mixture of anomers. Higher temperatures also resulted in acetolysis of the benzyl groups. The anomeric acetate could now be readily cleaved with dilute acid and oxidation gave the lactone 17. Selective acetate methanolysis followed by TMS protection provided the spirobislactone core precursor 4 in good yield. With the required spirobislactone 4 in hand, we then synthesized the iodide 5 required for the C1 side chain as outlined in Scheme4. Thus, an Evans aldol reaction [27] between the boron enolate derived from oxazolidinone 18 and aldehyde 19 [28] proceeded in excellent yield and stereoselectivity (> 95% de) to afford adduct 20. Reductive removal of the chiral auxiliary provided diol 21, which was converted into the primary monotosylate and treatment of this with nBuLi resulted in oxetane formation.[8a] Ring opening of the oxetane with PhLi in the presence of a Lewis acid gave alcohol 22 in good overall yield. We found that the synthesis and isolation of the oxetane gave better yields than the one-pot process reported by Carreira and Du Bois.[8a] Benzyl group protection proceeded best with NaHMDS as the base to afford ether 23, and fluoride-induced desilylation followed by conversion of the primary alcohol into the iodide [29] gave the side-chain fragment 5 in excellent yield. The final steps to the zaragozic acid C intermediate 2 are outlined in Schemes 5 and 6. Treatment of 5 with tBuLi [30] in a Et2O/hexane solvent mixture at À788C generated the lithium anion, which selectively added to spirolactone 4 at the C1 carbonyl group (2.2: 1 ratio of addition products; 72% yield). Treatment of the C1 addition product with acidic methanol, however, gave the methyl ketals 3 as a separable mixture and only a trace (2% yield) of the desired 2, 8-dioxa-[3.2. 1] bicyclooctane. We surmised that the slow step in the acid-catalyzed process may be opening of the lactone ring and therefore decided that a decrease in electron density would assist the methanolysis. Therefore, alkene 3 was oxidatively cleaved and oxidation [31] followed by methylation afforded methyl ester 24 along with a by-product 25, as a result of oxidation of the side-chain O4’benzyl protecting group.[32] To our delight, treatment of a mixture of ketals 24 with 0.1 m sulfuric acid in boiling methanol resulted in the formation of the desired zaragozic acid core system 26 in 44% yield along with recovered methyl ketals 24 (85% based on recovered
