Total Syntheses of Aromatic Abietane Diterpenoids Utilizing Advances in the Pummerer Rearrangement

Abstract

The first total syntheses of triptobenzene T, vitexifolin C, 4- epi-triptobenzene L, triptobenzene L, and nepetaefolin F have been accomplished through an enantioselective, common intermediate approach and have enabled the confirmation and/or establishment of the absolute stereochemistry of each natural product synthesized. Application of three new and/or underutilized Pummerer reaction pathways proved critical to the synthetic work. A proline sulfonamide-catalyzed Yamada-Otani reaction was used to access the highly functionalized cyclohexane A ring core, including the C all-carbon quaternary stereocenter. Additionally, the importance of the A ring unsaturation for controlling the stereoselectivity during the C alkylation is showcased.

Diverse Types of Diterpenoids with an Aromatized C Ring from the Twigs of Podocarpus imbricatus

“…The abietane skeleton as represented by 1 – 3 , which originated from a pimarane skeleton by a 1,2-shift of the methyl group from C-13 to C-15, is believed to be the precursor for co-isolated semperviranes ( 4 – 9 ), totaranes ( 10 – 12 ), a C-17 norabietane ( 13 ), and an icetexane ( 14 ). The sempervirane and totarane types of diterpenoids are derived probably from abietane-type precursors by a series of reactions, including a 1,2-shift of the isopropyl group, oxidations, and aromatization. , The C-17 norabietane diterpenoid ( 13 ) stems from an abietane precursor by the loss of a 17-methyl group via a possible oxidative degradation . The icetexane diterpenoid ( 14 ) was likely produced by a key reaction of a ring-expanding rearrangement from an abietane precursor, followed by oxidative modifications …”

“…25,26 The C-17 norabietane diterpenoid (13) stems from an abietane precursor by the loss of a 17-methyl group via a possible oxidative degradation. 5 The icetexane diterpenoid (14) was likely produced by a key reaction of a ring-expanding rearrangement from an abietane precursor, followed by oxidative modifications. 27 Zika virus (ZIKV), a mosquito-borne flavivirus, can cause infections with symptoms, including fever, rash, conjunctivitis, muscle and joint pain, malaise, and headache.…”

“…Diterpenoids, constituting a large family of secondary metabolites, are distributed widely among a variety of plants. , The C ring-aromatized ones comprise both a large number and diverse structural types of this compound category, showing intriguing biological activities. − Podocarpus (Euphorbiaceae) comprises more than 100 species, and seven of these grow in mainland China . Previous chemical studies on this genus have resulted in the identification of many diterpenoids, of which the aromatic abietanes have accounted for a large percentage. − These diterpenoids exhibit a wide spectrum of bioactivities, including antitumor, anti-inflammatory, antimicrobial, and antiviral effects, and are of great interest to study. − Podocarpus imbricatus Blume, mainly distributed in southern China, Myanmar, Vietnam, and Indonesia, is rich in diterpenoids. , In this study, 14 new diterpenoids with an aromatized C ring, including three abietane diterpenoids ( 1 – 3 ), as well as four biogenetically related diterpenoids of sempervirane ( 4 – 9 ), totarane ( 10 – 12 ), a C-17 norabietane ( 13 ), and an icetexane ( 14 ) type, were isolated from an ethanol extract of the twigs of P. imbricatus .…”

Pummerer Synthesis of Chromanes Reveals a Competition between Cyclization and Reductive Chlorination

“…Classic Pummerer cyclizations using aromatic rings as nucleophiles are extremely limited (Scheme b), presumably because of the competition between nucleophiles and the byproducts obtained but also because β-hydrogens are undesirable because their elimination causes the formation of vinyl sulfides. Recently, Carter and coworkers took advantage of this fact by applying the vinyl sulfides effectively in a Pummerer cyclization; unfortunately, the use of β-chiral centers is impractical in Carter’s method. Another problem is the use of highly deactivated aromatic rings (carrying electron-withdrawing groups (EWGs)) as nucleophiles, whereas they are almost unreactive in all aforementioned situations.…”

Pummerer Cyclization Revisited: Unraveling of Acyl Oxonium Ion and Vinyl Sulfide Pathways

“…The discovery of the acyl oxonium ion pathway should provide the synthetic community with access to a highly reactive electrophilic moiety which will enable its further exploration. In the following paper, we detail our application of these discoveries to the efficient, enantioselective total synthesis of multiple members of the abietane diterpenoids …”