Unified Synthesis of 10-Oxygenated Lycopodium Alkaloids: Impact of C₁₀-Stereochemistry on Reactivity

Abstract

The pronounced impact of the C10 stereochemistry on the successful construction of a polycyclic Lycopodium alkaloid scaffold has been explored. A wide range of reaction conditions and functionality were investigated to control a keto sulfone Michael addition to construct the C7-C12 linkage. An unexpected, overriding impact of the C10 stereochemistry in stereoselectivity and reaction rate in the Michael addition was observed. Furthermore, divergent reactivity of a conformationally accelerated, intramolecular Mannich cyclization based on the C10 stereochemistry was discovered. The successful execution of this synthetic route resulted in the total synthesis of all three known 10-oxygenated Lycopodium alkaloids: 10-hydroxylycopodine, paniculine, and deacetylpaniculine.

Second-Generation Synthesis of (+)-Fastigiatine Inspired by Conformational Studies

“…Lycopodium alkaloids have inspired synthetic chemists for generations . Himeradine A has attracted the interest of organic chemists. , The structurally similar lyconadine family of natural products have generated a great deal of interest and a variety of creative synthetic strategies . Syntheses of Lycopodium alkaloids has been recently reviewed …”

Lycopodium Alkaloids: An Intramolecular Michael Reaction Approach

“…Successful completion of the synthesis of 10-hydroxylycopodines also provided a platform to explore the 10S stereochemistry toward our long-term aspirations of the total synthesis of himeradine A (14) (Scheme 28). 54 We commenced the synthetic campaign with the enantiomer of compound 157 (10S-diol) and using similar chemistry as depicted in Scheme 24. Using the framework described for the intramolecular Michael reaction for its C10 epimer, we screened a range of reaction conditions with achiral additives and chiral organocatalysts on the 10S series in order to probe its reactivity.…”

Organophotoredox-Catalyzed Reductive Tetrafluoroalkylation of Alkenes

“…All liquid alkenes were distilled prior to use. Compounds (3-methylbut-3-en-1-yl)benzene (1b), 26 4,4-diphenyl-1-butene (1c), 27 1-allylnapthalene (1d), 28 1-allyl-3,4-dimethoxybenzene (1e), 29 N-allylphthalimide (1f), 28 o-allyloxyacetophenone (1h), 30 4-(but-3-en-1-yl)benzonitrile (1i), 31 allylbenzoate (1j), 32 5-(benzyloxy)-1-pentene (1k), 33 (but-3-ene-1-sulfonyl)benzene (1l), 34 4-[(2-methoxyethoxy)methoxy]but-1-ene (1m), 35 diethyl (but-3-en-1-yl)phosphonate (1n), 36 vinylcyclohexene (1o), 37 N-(tertbutoxycarbonyl)allylamine (1p), 38 pent-4-en-1-yl benzoate (1s), 39 2-bromo-2,2-difluoroethyl benzoate (2v), 5a 4CzIPN, 40 and 3DPA2FBN 41 were synthesized according to literature procedures.…”