Total Synthesis of (−)‐Pestalotiopsin A

Abstract

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...

Studies for the Synthesis of Xenicane Diterpenes. A Stereocontrolled Total Synthesis of 4-Hydroxydictyolactone

“…While new opportunities have explored the synthesis of medium-ring carbocycles using ring-closing metathesis,14 the formation of cyclononenes has presented problems for some RCM strategies 15. On the other hand, two groups have independently described recent results for Nozaki-Hiyama-Kishi cyclizations directed toward pestalotiopsin, a caryophyllene sesquiterpenoid 16. In classic studies by Professor E. J. Corey, the use of the Grob fragmentation was devised to address the synthesis of (±)-caryophyllene 17.…”

Recent advances in the application of the Oppolzer camphorsultam as a chiral auxiliary

“…39 For the synthesis of chiral fluorinated amino acids, dehydroamino acid 51 with both phthalimide and camphorsultam moieties were reacted with various perfluoroalkyl iodides. Phthalimide was added in the a-addition 40 to the already prepared N-propioloyl derivatives of Oppolzer's camphorsultam 41 50 to afford the dehydroamino acid 51 in good yield. The hydroperfluoroalkylation of 51 proceeded smoothly to afford the required products 52a-e in good yield and with high stereoselectivity.…”

Addition of Vinylmetallic Reagents to Chiral 2‐Formyltetrahydrofuran

“…[22] In the total synthesis of pestalotiopsin A, the macrocyclization proceeded through an intramolecular NHK reaction and provided the product in excellent chemical yield and diastereoselectivity. [23] In this work, compounds 1a and 2 were employed as models to compare experimental methods for the diastereoselective formation of allylic alcohol 3 (see Scheme 1). Three procedures were examined as possible approaches, that is, a chelate-controlled organometallic addition, a carboalumination, and an NHK reaction.…”