Strong Bases and Weak Anions in Catalytic C–H Insertion Reactions of Vinyl Carbocations

Wigman, Benjamin; Popov, Stasik; Bagdasarian, Alex L.; Shao, Brian; Benton, Tyler R.; Williams, C. G.; Fisher, Steven P.; Lavallo, Vincent; Houk, K. N.; Nelson, Hosea M.

doi:10.26434/chemrxiv.7453223.v1

“…Unfortunately, use of our reported . 29 However, we were gratified to find that pairing mild inorganic bases with metal/WCA salts yielded polycyclic products, albeit in low yields (entries 3 -5). Utilization of stoichiometric LiClO4 was found to produce the cyclized terpene products in reduced yield, presumably due to promiscuous oxidative reactivity, as aromatic species such as cadalene were observed in the reaction mixture (entry 6, see Supporting Information).…”

Section: Resultsmentioning

confidence: 99%

Terpene Tail-to-Head Polycyclization Mediated by Small Molecule Catalysts: A Weakly-Coordinating Anion Approach

Burch

¹

,

Bagdasarian²,

Hooshmand³

et al. 2020

Preprint

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Biomimetic total synthesis has played a pivotal role in the development of synthetic organic chemistry. In particular, efforts aimed at mimicking the head-to-tail (HT) cation–π cyclization cascades invoked in terpene biosynthesis, such as those catalyzed by type-II cyclases, have led to a multitude of new synthetic methods, chemical concepts, and total syntheses over the past century. Conversely, synthetic methodology that mimics tail-to-head (TH) cation–π cyclization cascades, mediated by Mg2+ type-I terpene cyclases, remains elusive in organic synthesis, despite key roles in the biosynthesis of privileged therapeutic molecules such as taxol and artemesinin. Here we report that Li+/weakly-coordinating anion (WCA) salts catalyze the TH polycyclization of linaloyl fluoride, leading to high-yielding mixtures of polycyclic terpene natural products including cedrenes, cadinadiene, epizonarene, and 𝛿-selinene. The examples reported herein are the first small molecule-catalyzed TH polycyclization reactions enabling the shortest (formal) total synthesis of (±)-artemisinin. Moreover we apply this strategy to the diterpene geranyllinaloyl fluoride, resulting in a two-step total synthesis of the tricyclic core of the gersemiols (named here as α-gersemiene), a recently discovered class of marine diterpenoid natural products.

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“…25,26 Discouraged by the lack of selectivity and poor efficiency, we posited that the incompatibility of R3Si + /WCA catalysts with dichloromethane and olefinic substrates was responsible for the poor reaction outcome. 28 These findings led us to explore the use of Li + /WCA catalysts with (E)-nerolidyl fluoride (11) 29 However, we were gratified to find that pairing mild inorganic bases with metal/WCA salts yielded polycyclic products, albeit in low yields (entries 3 -5). Utilization of stoichiometric LiClO4 was found to produce the cyclized terpene products in reduced yield, presumably due to promiscuous oxidative reactivity, as aromatic species such as cadalene were observed in the reaction mixture (entry 6, see Supporting Information).…”

Section: Resultsmentioning

confidence: 99%

Terpene Tail-to-Head Polycyclization Mediated by Small Molecule Catalysts: A Weakly-Coordinating Anion Approach

Burch

¹

,

Bagdasarian²,

Hooshmand³

et al. 2020

Preprint

Self Cite

1

0

View full text Add to dashboard Cite

Biomimetic total synthesis has played a pivotal role in the development of synthetic organic chemistry. In particular, efforts aimed at mimicking the head-to-tail (HT) cation–π cyclization cascades invoked in terpene biosynthesis, such as those catalyzed by type-II cyclases, have led to a multitude of new synthetic methods, chemical concepts, and total syntheses over the past century. Conversely, synthetic methodology that mimics tail-to-head (TH) cation–π cyclization cascades, mediated by Mg2+ type-I terpene cyclases, remains elusive in organic synthesis, despite key roles in the biosynthesis of privileged therapeutic molecules such as taxol and artemesinin. Here we report that Li+/weakly-coordinating anion (WCA) salts catalyze the TH polycyclization of linaloyl fluoride, leading to high-yielding mixtures of polycyclic terpene natural products including cedrenes, cadinadiene, epizonarene, and 𝛿-selinene. The examples reported herein are the first small molecule-catalyzed TH polycyclization reactions enabling the shortest (formal) total synthesis of (±)-artemisinin. Moreover we apply this strategy to the diterpene geranyllinaloyl fluoride, resulting in a two-step total synthesis of the tricyclic core of the gersemiols (named here as α-gersemiene), a recently discovered class of marine diterpenoid natural products.

show abstract

“…25,26 Discouraged by the lack of selectivity and poor efficiency, we posited that the incompatibility of R3Si + /WCA catalysts with dichloromethane and olefinic substrates was responsible for the poor reaction outcome. 28 These findings led us to explore the use of Li + /WCA catalysts with (E)-nerolidyl fluoride (11) 29 However, we were gratified to find that pairing mild inorganic bases with metal/WCA salts yielded polycyclic products, albeit in low yields (entries 3 -5). Utilization of stoichiometric LiClO4 was found to produce the cyclized terpene products in reduced yield, presumably due to promiscuous oxidative reactivity, as aromatic species such as cadalene were observed in the reaction mixture (entry 6, see Supporting Information).…”

Section: Resultsmentioning

confidence: 99%

Terpene Tail-to-Head Polycyclization Mediated by Small Molecule Catalysts: A Weakly-Coordinating Anion Approach

Burch

¹

,

Bagdasarian²,

Hooshmand³

et al. 2020

Preprint

Self Cite

0

View full text Add to dashboard Cite

Biomimetic total synthesis has played a pivotal role in the development of synthetic organic chemistry. In particular, efforts aimed at mimicking the head-to-tail (HT) cation–π cyclization cascades invoked in terpene biosynthesis, such as those catalyzed by type-II cyclases, have led to a multitude of new synthetic methods, chemical concepts, and total syntheses over the past century. Conversely, synthetic methodology that mimics tail-to-head (TH) cation–π cyclization cascades, mediated by Mg2+ type-I terpene cyclases, remains elusive in organic synthesis, despite key roles in the biosynthesis of privileged therapeutic molecules such as taxol and artemesinin. Here we report that Li+/weakly-coordinating anion (WCA) salts catalyze the TH polycyclization of linaloyl fluoride, leading to high-yielding mixtures of polycyclic terpene natural products including cedrenes, cadinadiene, epizonarene, and 𝛿-selinene. The examples reported herein are the first small molecule-catalyzed TH polycyclization reactions enabling the shortest (formal) total synthesis of (±)-artemisinin. Moreover we apply this strategy to the diterpene geranyllinaloyl fluoride, resulting in a two-step total synthesis of the tricyclic core of the gersemiols (named here as α-gersemiene), a recently discovered class of marine diterpenoid natural products.

show abstract

Strong Bases and Weak Anions in Catalytic C–H Insertion Reactions of Vinyl Carbocations

Cited by 5 publications

References 23 publications

Terpene Tail-to-Head Polycyclization Mediated by Small Molecule Catalysts: A Weakly-Coordinating Anion Approach

Terpene Tail-to-Head Polycyclization Mediated by Small Molecule Catalysts: A Weakly-Coordinating Anion Approach

Terpene Tail-to-Head Polycyclization Mediated by Small Molecule Catalysts: A Weakly-Coordinating Anion Approach

Terpene Tail-to-Head Polycyclization Mediated by Small Molecule Catalysts: A Weakly-Coordinating Anion Approach

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