Asymmetric Total Synthesis of the Indole Diterpene Alkaloid Paspaline

Abstract

An enantioselective synthesis of the indole diterpenoid natural product paspaline is disclosed. Critical to this approach was the implementation of stereoselective desymmetrization reactions to assemble key stereocenters of the molecule. The design and execution of these tactics are described in detail, and a thorough analysis of observed outcomes is presented, ultimately providing the title compound in high stereopurity. This synthesis provides a novel template for preparing key stereocenters in this family of molecules, and the reactions developed en route to paspaline present a series of new synthetic disconnections in preparing steroidal natural products.

Indole diterpenoid natural products as the inspiration for new synthetic methods and strategies

“…The first topic presented pertains to arguably the most complex member of this natural product family, penitrem D. The synthesis of penitrem D by the Smith group features the use of an innovative fragment coupling/indole synthesis methodology. 7 Next, recent efforts toward the related compounds, emindole SB 8 and paspaline, 9 by Johnson and Pronin, respectively, are discussed. We then highlight the Baran synthesis of dixiamycin B, 10 which has led to the considerable advancement of electrochemical methods in organic synthesis.…”

Recent Applications of Rh‐ and Pd‐Catalyzed C(sp3)–H Functionalization in Natural Product Total Synthesis

“…A comparison of Johnson's synthesis of (–)‐paspaline ( 106 ; Scheme a) and Sorensen's synthesis of (–)‐jiadifenolide ( 107 ; Scheme b) illustrates the strengths and limitations of this approach . In Johnson's total synthesis of (–)‐paspaline ( 106 ), oxime 109 is subjected to catalytic Pd(OAc) 2 and (diacetoxyiodo)benzene to generate acetate 110 in 79 % yield and with high diastereocontrol (Scheme a) . On the other hand, Sorensen and co‐workers were not as successful in achieving stereoselective acetoxylation in their synthesis of (–)‐jiadifenolide ( 107 ) .…”

Local Desymmetrization through Diastereotopic Group Selection: An Enabling Strategy for Natural Product Synthesis

“…[7] In the course of the synthesis, intermediate 15 was synthesized by a route that took advantage of enantiotopic group discrimination via a biocatalytic reduction. Moving forward from 15 , application of the Sanford C–H activation [6] allowed the completely diastereselective acetoxylation of the equatorial methyl group to give 16 .…”

“…In 2011, Leighton and coworkers reported a convergent and stereoselective synthesis of zincophorin methyl ester ( 28 ) (Scheme 6). [9] Using Shi's asymmetric epoxidation, [10] Pagenkopf's epoxide-opening alkynylation, [11] and a NaH-promoted dehydrogenative silylation, the authors assembled the key substrate 23 .…”