Quaternary-centre-guided synthesis of complex polycyclic terpenes

Abstract

The presence of a quaternary centre-a carbon with four other carbons bonded to it-in any given molecule can have a substantial chemical and biological impact. In many cases, it can enable otherwise challenging chemistry. For example, quaternary centres induce large rate enhancements in cyclization reactions-known as the Thorpe-Ingold effect-which has application in drug delivery for molecules with modest bioavailability 1. Similarly, the addition of quaternary centres to a drug candidate can enhance both its activity and its metabolic stability 2. When present in chiral ligands 3 , catalysts 4 and auxiliaries 5 , quaternary centres can guide reactions toward both improved and unique regio-, stereo-and/or enantioselectivity. However, owing to their distinct steric congestion and conformational restriction, the formation of quaternary centres can be achieved reliably by only a few chemical transformations 6,7. For particularly challenging casesfor example, the vicinal all-carbon 8 , oxaand aza-quaternary centres 9 in molecules such as azadirachtin 10,11 , scopadulcic acid A 12,13 and acutumine 14-the development of target-specific approaches as well as multiple functional-group and redox manipulations is often necessary. It is therefore desirable to establish alternative ways in which quaternary centres can positively affect and guide synthetic planning. Here we show that if a synthesis is designed such that each quaternary centre is deliberately leveraged to simplify the construction of the next-either through rate acceleration or blocking effects-then highly efficient, scalable and modular syntheses can result. This approach is illustrated using the conidiogenone family of terpenes as a representative case; however, this framework provides a distinct planning logic that is applicable to other targets of similar synthetic complexity that contain multiple quaternary centres.

Development and Elucidation of a Pd‐Based Cyclization–Oxygenation Sequence for Natural Product Synthesis

“…Nevertheless, our hope was that the α‐quaternary center in the alkyl–Pd II intermediate 5 might enable its interception by an oxygen nucleophile through intermolecular capture by precluding any intramolecular reactions such as β–H elimination; such a strategy has proven successful in promoting other types of challenging reductive eliminations –. In fact, we recently achieved one example of such a functionalization as part of a total synthesis of conidiogenol ( 16 ) and related family members in which 14 was obtained directly from 13 following an initial C−C bond construction through migratory insertion, leading to a similarly situated quaternary center . Herein, we delineate the development and scope of this overall reaction process, one that is capable of affording a range of architectures with a variety of terminating oxygen‐based nucleophiles with complete diastereocontrol.…”

Reductive Cross-Coupling of Vinyl Electrophiles

“…of the englerins by Cook and Tao (Scheme 23c), 64 and the synthesis of the conidiogenol skeleton by the Snyder group (Scheme 23d). 65 The combination of Ni(0) catalyst with Et 3 SiH as a hydride source also proved effective in reductive Heck vinylation reactions. This catalytic system was applied by Cook and co-workers for the synthesis of (-)-geissoschizol 66 and Yang and co-workers for the concise synthesis of (±)-arbornamine (Scheme 24).…”

Synthesis of Cyclohexane-Angularly-Fused Triquinanes

“…In 2019, the Snyder group completed the second total synthesis of conidiogenones and conidiogenols, which featured their concept of quaternary-center-guided synthesis for complex polycyclic skeletons, which involved sequential annulation of each ring, starting from the C ring of the cyclopianes. 10 As outlined retrosynthetically in Scheme 5, conidiogenone B (5), which was an intermediate in the syntheses of both 2 and 8 by Tu and co-workers (Scheme 4), could be accessed by intramolecular reductive Heck coupling of 26, the side chain of which could be prepared by homoallylation of aldehyde 27 (Scheme 5). The triquinane skeleton of 27 could be established by a series of C-C bond formation steps from cyclopentanone 29 via triflated diquinane 28, in which the stereoselectivity and regioselectivity in the formation of 28 resulted from the quaternary center of 29.…”