Dual Macrolactonization/Pyran–Hemiketal Formation via Acylketenes: Applications to the Synthesis of (−)‐Callipeltoside A and a Lyngbyaloside B Model System

Abstract

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...

Total Synthesis of (−)-Callipeltoside A

“…The relative amount of 40 increased over time. This suggests that the unimolecular lactonization of the acylketene 37 outcompetes its trapping by water and that the ketolactone 39 is able to revert via 38 to acylketene 37 22. While concentration effects are undoubtedly also important, it is relevant that i) addition of an O–H bond to an acylketene is a concerted event (cf., 37 to 38 )23 and ii) the O–H bond dissociation energy of water is substantially higher than those of alcohols (119 vs. 104–107 kcal mol −1 ) 24.…”

Bond formations by intermolecular and intramolecular trappings of acylketenes and their applications in natural product synthesis

“…As a model system, Boeckman first explored the solvolytic capture of the acylketene intermediate derived from dioxinone substrate 102 . 43 When this compound was heated in toluene to 110 °C in the presence of methanol, bicyclic β-keto ester 103 was isolated in 54% yield (Scheme 30). The intra-molecular Diels–Alder reaction proceeds via the more stable endo transition state, which imparts greater than 10 : 1 diastereoselectivity in the formation of bicycle 103 .…”

Synthetic studies to lyngbouilloside: a phosphate tether-mediated synthesis of the macrolactone core

“…4, 5,6 In 2008, Cossy and coworkers, reported the first stereoselective synthesis of the carbon backbone of 1 using a pivotal cross-metathesis (CM) between the C1–C8 and C9–C13 fragments. 4a In 2009, Ley and coworkers reported a synthesis of the lyngbouilloside macrolactone core using a late-stage ring-closing metathesis (RCM)/hydrogenation sequence for macrocyclization, and also brought to light stereochemical issues regarding this natural product.…”

“…4, 5,6 In 2008, Cossy and coworkers, reported the first stereoselective synthesis of the carbon backbone of 1 using a pivotal cross-metathesis (CM) between the C1–C8 and C9–C13 fragments. 4a In 2009, Ley and coworkers reported a synthesis of the lyngbouilloside macrolactone core using a late-stage ring-closing metathesis (RCM)/hydrogenation sequence for macrocyclization, and also brought to light stereochemical issues regarding this natural product. 4b In 2012, Cossy and coworkers confirmed the stereochemical issues in their first total synthesis of the lyngbouilloside aglycon using a pivotal acylketene macrolactonization of a tertiary methyl carbinol (C13 in 1 ) to circumvent fundamental issues associated with macrolactonizations of sterically encumbered alcohols.…”

“…4a In 2009, Ley and coworkers reported a synthesis of the lyngbouilloside macrolactone core using a late-stage ring-closing metathesis (RCM)/hydrogenation sequence for macrocyclization, and also brought to light stereochemical issues regarding this natural product. 4b In 2012, Cossy and coworkers confirmed the stereochemical issues in their first total synthesis of the lyngbouilloside aglycon using a pivotal acylketene macrolactonization of a tertiary methyl carbinol (C13 in 1 ) to circumvent fundamental issues associated with macrolactonizations of sterically encumbered alcohols. 5 In addition, Cossy proposed a revised structure of lyngbouilloside with stereochemical reassignment of the C11 stereogenic center having an epimeric C11 stereogenic center and thus a syn C10/C11 relationship.…”