An enantioselective total synthesis of both enantiomers of caryophyllene-type sesquiterpenoid pestalotiopsin A has been achieved, thereby establishing the absolute stereochemistry of natural (+)-pestalotiopsin A. Highlights of the synthesis include a [2 + 2] cycloaddition of N-propioloyl Oppolzer's camphorsultam and ketene dialkyl acetal and subsequent highly stereoselective 1,4-hydride addition/protonation, an aldol reaction of functionalized bicyclic lactone with aldehyde, an efficient intramolecular Nozaki-Hiyama-Kishi (NHK) reaction for the construction of the highly strained (E)-cyclononene ring, and a palladium-catalyzed reduction of allylic mesylate with retention of the E configuration.
In 1996 two highly oxygenated caryophyllene sesquiterpenoids, pestalotiopsins A (1) and B (2) (Scheme 1), were isolated by Sugawara and co-workers from Pestalotiopsis sp., an endophytic fungus associated with the bark and leaves of Taxus brevifolia (the Pacific yew).[1] Later, several related natural products were found from the species of Pestalotiopsis.[2] Among them, pestalotiopsin A showed cytotoxicity and immunosuppressive activity in the mixed lymphocyte reaction. The structures of the pestalotiopsins were determined by extensive spectroscopic studies and finally confirmed by X-ray crystallographic analysis; however, the absolute stereochemistry remained unclear. Pestalotiopsin A (1) consists of an unprecedented oxatricyclic structure bearing seven stereogenic centers and it is comprised of a cyclobutane ring fused with both an (E)-cyclononene ring and a g-lactol unit. In contrast, bicyclic pestalotiopsin B (2) exists as a mixture of two atropisomers at the C4ÀC5 carbon-carbon double bond. The synthetically formidable structure of 1 has attracted considerable attention among chemists concerned with natural product synthesis. The research groups of Procter, [3] Paquette, [4] and Markó, [5] in addition to our group, [6] have reported a number of synthetic studies of 1. Herein, we describe the first total synthesis of (À)-pestalotiopsin A (1) and the assignment of its absolute configuration as the antipode of natural pestalotiopsin A.Since embarking on this research we have devoted our efforts to the efficient formation of the strained (E)-cyclononene moiety in 1. Although early attempts were unsuccessful, [7] we envisioned that a Nozaki-Hiyama-Kishi (NHK) reaction approach [8] would enable efficient (E)-cyclononene ring formation. As shown in Scheme 1, we considered 1 could be synthesized by using the intramolecular NHK reaction of aldehyde/alkenyl iodide 3 as a key step and subsequent deoxygenation of the newly formed hydroxy group at C3. The formation of 3 would, in turn, be achieved by the aldol reaction of functionalized bicyclic lactone 4 and g-iodo-b,gunsaturated aldehyde 5, both in high enantioenriched forms. We expected that stereogenic centers at C7 and C8 of 3 would be introduced stereoselectively as desired in the aldol process by taking advantage of the 2-oxabicyclo[3.2.0]heptan-3-one structure of 4. This bicyclic g-lactone 4, in turn, would be prepared from a highly enantioenriched cyclobutane derivative analogous to that described in our preliminary report. [6] Earlier we reported [6] the asymmetric synthesis of functionalized cyclobutanes which featured the [2+2] cycloaddition of the N-propioloyl derivative of Oppolzers camphorsultam (6) (Scheme 2) and ketene bis(trimethylsilyl) acetal. However, the bis(trimethylsilyl) acetal moiety was not stable under the conditions used for the removal of the camphorsultam, and it gave rise to some additional steps for the conversion of the cyclobutane derivativeinto the bicyclic lactone intermediate. To overcome this disadvantage, ketene dialkyl acetal...
In 1996 two highly oxygenated caryophyllene sesquiterpenoids, pestalotiopsins A (1) and B (2) (Scheme 1), were isolated by Sugawara and co-workers from Pestalotiopsis sp., an endophytic fungus associated with the bark and leaves of Taxus brevifolia (the Pacific yew).[1] Later, several related natural products were found from the species of Pestalotiopsis.[2] Among them, pestalotiopsin A showed cytotoxicity and immunosuppressive activity in the mixed lymphocyte reaction. The structures of the pestalotiopsins were determined by extensive spectroscopic studies and finally confirmed by X-ray crystallographic analysis; however, the absolute stereochemistry remained unclear. Pestalotiopsin A (1) consists of an unprecedented oxatricyclic structure bearing seven stereogenic centers and it is comprised of a cyclobutane ring fused with both an (E)-cyclononene ring and a g-lactol unit. In contrast, bicyclic pestalotiopsin B (2) exists as a mixture of two atropisomers at the C4ÀC5 carbon-carbon double bond. The synthetically formidable structure of 1 has attracted considerable attention among chemists concerned with natural product synthesis. The research groups of Procter, [3] Paquette, [4] and Markó, [5] in addition to our group, [6] have reported a number of synthetic studies of 1. Herein, we describe the first total synthesis of (À)-pestalotiopsin A (1) and the assignment of its absolute configuration as the antipode of natural pestalotiopsin A.Since embarking on this research we have devoted our efforts to the efficient formation of the strained (E)-cyclononene moiety in 1. Although early attempts were unsuccessful, [7] we envisioned that a Nozaki-Hiyama-Kishi (NHK) reaction approach [8] would enable efficient (E)-cyclononene ring formation. As shown in Scheme 1, we considered 1 could be synthesized by using the intramolecular NHK reaction of aldehyde/alkenyl iodide 3 as a key step and subsequent deoxygenation of the newly formed hydroxy group at C3. The formation of 3 would, in turn, be achieved by the aldol reaction of functionalized bicyclic lactone 4 and g-iodo-b,gunsaturated aldehyde 5, both in high enantioenriched forms. We expected that stereogenic centers at C7 and C8 of 3 would be introduced stereoselectively as desired in the aldol process by taking advantage of the 2-oxabicyclo[3.2.0]heptan-3-one structure of 4. This bicyclic g-lactone 4, in turn, would be prepared from a highly enantioenriched cyclobutane derivative analogous to that described in our preliminary report. [6] Earlier we reported [6] the asymmetric synthesis of functionalized cyclobutanes which featured the [2+2] cycloaddition of the N-propioloyl derivative of Oppolzers camphorsultam (6) (Scheme 2) and ketene bis(trimethylsilyl) acetal. However, the bis(trimethylsilyl) acetal moiety was not stable under the conditions used for the removal of the camphorsultam, and it gave rise to some additional steps for the conversion of the cyclobutane derivativeinto the bicyclic lactone intermediate. To overcome this disadvantage, ketene dialkyl acetal...
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