Beyond the Isoprene Pattern: Bifunctional Polyene Cyclizations.

Polyene cyclizations are capable of producing molecular complexity in a single step. While classical systems are limited to simple alkyl substitution patterns only, bifunctional polyenes take advantage of the unique reactivity of higher-functionalized alkenes. Here, we highlight the potential of these variants for the synthesis of structurally complex polycycles involving unprecedented termination steps. We also want to provide a stimulus for the development of novel modes of cyclization that involve bifunctional units to enable efficient synthesis of yet inaccessible natural products.

Bifunctional Polyene Cyclizations: Synthetic Studies on Pimarane Natural Products.

Polyene cyclizations generate molecular complexity from a linear polyene in a single step. While methods to initiate these cyclizations have been continuously expanded and improved over the years, the majority of polyene substrates are still limited to simple alkyl-substituted alkenes. In this study, we took advantage of the unique reactivity of higher-functionalized bifunctional alkenes. The realization of a polyene tetracyclization of a dual nucleophilic aryl enol ether involving a transannular endo-termination step enabled the total synthesis of the tricyclic diterpenoid pimara-15-en-3α-8α-diol. The highly flexible and modular route allowed for the preparation of a diverse library of cyclization precursors specifically designed for the total synthesis of the tetracyclic nor-diterpenoid norflickinflimiod C. The tetracyclization of three diversely substituted allenes enabled access to complex pentacyclic products and provided a detailed insight into the underlying reaction pathways.

A Transannular Polyene Tetracyclization for Rapid Construction of the Pimarane Framework.

Polyene cyclizations are one of the most powerful and fascinating chemical transformations to rapidly generate molecular complexity. However, cyclizations employing heteroatom-substituted polyenes are rare. Described here is the tetracyclization of a dual nucleophilic aryl enol ether involving an unprecedented transannular endo-termination step. In this transformation, five stereocenters, two of which are quaternary, four carbon-carbon bonds, and four six-membered rings are formed from a readily available cyclization precursor. The realization of this cyclization enabled short synthetic access to the tricyclic diterpenoid pimara-15-en-3α-8α-diol.

Iterative assembly line synthesis of polypropionates with full stereocontrol.

The polypropionate motif is ubiquitous, being characteristic of the most important family of natural products for human health, the polyketides. Numerous strategies have been devised to construct these molecules with high stereocontrol, but certain stereoisomers remain challenging to prepare. We now describe the development of an iterative assembly line strategy for the construction of polypropionates. An assembly line strategy for the synthesis of deoxypolypropionates has already been described. However, the introduction of carbinol units required the development of new building blocks and new reaction conditions. This has been achieved by the use of enantioenriched lithiated α-chlorosilanes [1-((2'-lithiochloromethyldimethylsilyl)-methyl)-2-(methoxymethyl)-pyrrolidine], thus enabling the programmed synthesis of polypropionates in a fully stereocontrolled manner, including the stereochemically challenging anti-anti isomers. The versatility of the approach is exemplified in its extension to the synthesis of 1,3-related polyols. The methodology now allows access to a much wider family of polyketide natural products with stereochemistry being dialled in at will.