Kuehneromycins

Table 1. Effect of mniopetals and kuehneromycin A of the reverse transcriptases (RT)...

As the total synthesis of mniopetal E (5) was compleated, we next focused our attention on mniopetal F (6) and kuehneromycin A (7) as synthetic targets. The retrosynthesis of 6 and 7 is shown in Scheme 13. We anticipated that the IMDA reaction of the substrate G would proceed favorably via a chair-like enrfo-transition state F, which would lead to the desired adduct E. In general, a substituent neighboring the dienophile part would dispose of the sterically less-demanding equatorial orientation in the transition state. However, the trialkyl-... 

Entries 1, 2, 8, or 9). On the other hand, the silyl ethers 90-94 provided the desired endo-adduct A predominantly (Entries 3-7). In the case of the bulkier silyl ethers 93 and 94, the n-facial selectivity significantly decreased (Entries 6 and 7 compared to 3-5). As anticipated, by employing the silyl ethers 90-92 for the IMDA reaction, the desired cycloadduct A for the syntheses of mniopetal F and kuehneromycin A was obtained stereoselectively. 

We next investigated the total synthesis of kuehneromycin A (7). Partial hydrolysis of 111 in trifluoroacetic acid (TFA) gave alcohol, which was oxidized to keto-lactone 112 (Scheme 18). Treatment of 112 with TFA followed by triethylamine caused unexpected decarboxylation, providing a mixture of kuehneromycin B (113) and panudial (114), which are known as natural products related to 7 [3]. The synthesis of... 

In summary, we completed the total syntheses of (-)-mniopetal F (6) and (-)-kuehneromycin A (7) in their natural forms. Our total synthesis feature a the highly ewdoselective IMDA reaction using some substrates carrying a trialkylsilyloxy group at C-l. The n-facial selectivity in the IMDA reaction was controlled by the stereoelectronic effect of the silyloxy group adjacent to the dienophile part. 

Jauch achieved the short and elegant total synthesis of mniopetals during almost the same period in which our total syntheses were reported [36-41]. We briefly introduce Jauch s achievements on this subject. The key step of his synthesis was the IMDA reaction of 2-substituted butenolide 124 (Scheme 20), which was prepared by the diastereoselective PhSeLi-induced Baylis-Hillman reaction of 122 and Feringa s butenolide 123 [99]. The cycloadduct of this IMDA reaction 125 was transformed into kuehneromycin A and mniopetals E and F, respectively. 

Thus, Jauch effectively synthesized kuehneromycin A, mniopetal E, and mniopetal F by a strategy employing a new variant of the Baylis-Hillman reaction. 

Research by J. Jauch showed that in the case of highiy base-sensitive substrates the Baylis-Hillmann reaction can be carried out by using lithium phenylselenide, which is a strong nucieophile but oniy weakiy basic. This variant of the reaction is highly diastereoselective and was successfully applied to the total synthesis of kuehneromycin... 

Jauch, J. A short total synthesis of kuehneromycin A. Angew, Chem, Int, Ed, Engl, 2000, 39, 2764-2765. 

Follotving the quite recent discovery of the broad range of biological activities exhibited by members of the sesquiterpene-based drimane family, namely mnio-petals, kuehneromycins, and marasmanes, a solid-phase approach towards a common key intermediate has recently been disclosed [408]. This supported synthesis offers the additional advantage of potential access to libraries of compounds with the same sesquiterpenoid skeleton. 

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