A total synthesis of (−)-callipeltoside A (1) has been achieved. The core macrocycle was made via a dual macrolactonization/pyran hemiketal formation reaction, which was developed to circumvent issues related to the reversible nature of acylketene formation from β-keto lactone substrates. Initial approaches to the core of the natural product that revolved around ring-closing metathesis (RCM) and relay ring-closing metathesis (RRCM) reactions are also described.

Thermal generation of acylketenes in diol-containing substrates results in dual macrocyclization/ pyran-hemiketal formation. This transformation expands the scope of acylketene macrolactonizations and their application to the synthesis of complex macrolides. Triol and even tetrol substrates also have been closed in highly regioselective fashion. Additionally, the challenging macrolactonization of a tertiary alcohol was achieved. Keywordsacylketenes; regioselective macrolactonization; concerted addition Acylketenes (2) are often employed as electrophiles to trap alcohols to construct β-ketoesters 4 via concerted addition [i] of the hydroxylic nucleophile to produce the transient enol 3 (Scheme 1). [ii] Thermolysis of 1,3-dioxin-4-one derivatives 1 is the most common method used for generation of 2. [iii] Boeckman pioneered the application of these reactive species in the context of complex molecule synthesis. [iv] Namely, macrocyclic lactones (and lactams) can be constructed by intramolecular reactions of hydroxy-(or amino-)containing acylketenes. [v] Correspondence to: Thomas R. Hoye, hoye@umn.edu. Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author. As part of our research program directed toward the synthesis of complex pyran-containing macrolides (cf., 5 and 6, Figure 1), we have expanded the scope of this powerful transformation [vi] by exploring the use of substrates containing multiple hydroxyl groups. [vii] The mechanism of addition of hydroxylic nucleophiles to acylketene allows for this process to be highly regioselective, as reported here for substrates containing up to four free hydroxyl groups. As we report here, this reagent-and catalyst-free transformation allows for rapid, direct, and selective construction of the macrolactone/pyran-hemiketal substructure units present in callipeltoside A (5) [viii] and lyngbyaloside B (6). [ix] We chose the prototypical substrate 7 [x] for use in testing the concept of dual macrolactonization/pyran-hemiketal formation (Scheme 2). When this diol was heated in benzene at 80 °C the macrolactone/pyran 8 was cleanly formed (as an ca. 9:1 ratio of 8 to its C3-anomer) in 80% isolated yield. NIH Public AccessWhile we do not know the exact sequence of events leading to 8, if the distal C13-hydroxyl group in acylketene 9 were to add in a concerted 1,4-addition, [i] the enol-lactone 10 would be formed. Rapid tautomerization followed by hemiketal formation within ketone 11 would account for formation of 8. Alternative intermediates or processes can be envisioned for this transformation of 7 to 8. i) Hemiketal formation in 9 prior to lactonization would give 12, which could further cyclize to the macrolactone/pyran 8. We presume that the acylketene 9 would lactonize considerably faster than the simple ketene 12 [e.g., water reacts with acetylketene (AcCH=C=O) ~42,000 times faster than with ketene (H 2 C=C=O) itself]. [xi] Moreover, there are no intermediates involved in the 9 to 10 transfo...

Silver (I) activation of thioacetoacetates in the presence of ketones produces 1,3-dioxin-4-ones. Mechanistic studies addressing the intermediacy of an acylketene intermediate are described.

N-Acyl-2-oxazolidinones are ring-opened by lithium iodide and decarboxylated in the presence of a mild proton source. Further reaction with an amine base provides 2-oxazolines. The transformation is general for oxazolidinones unsubstituted in the 5 position and occurs under mild conditions (25-50 degrees C). These results complement the existing methods for this transformation by allowing lower temperatures and/or avoiding metal catalysts.

Oxazole derivatives R 0220Decarboxylative Isomerization of N-Acyl-2-oxazolidinones to 2-Oxazolines. -The mild and general method for the isomerization proceeds without epimerization. -(MAY, A. E.; WILLOUGHBY, P. H.; HOYE*, T. R.; J. Org. Chem. 73 (2008) 8, 3292-3294; Dep. Chem., Univ. Minn., Minneapolis, MN 55455, USA; Eng.) -Jannicke 35-120