Martin Fleck

Total Synthesis of Punctaporonin C by a Regio‐ and Stereoselective [2+2]‐Photocycloaddition

The unique sesquiterpene punctaporonin C was synthesized starting from commercially available 7-tert-butoxynorbornadiene in a linear sequence of 29 steps and with an overall yield of 0.65%. Key step of the synthesis was an intramolecular [2+2]-photocycloaddition, in which the two vinylic double bonds in a 1,3-divinyl-2-cyclopentyl tetronate were differentiated by reaction with the photoexcited tetronate. The reaction gave regio- and diastereoselective access to the tricyclic core skeleton of punctaporonin C in 63% yield. Additional studies related to the tetronate [2+2]-photocycloaddition revealed that even diastereotopic vinylic double bonds in a 1,3-divinyl-2-cyclopentyl tetronate can be differentiated (d.r. up to 78:22). In the further course of the total synthesis the complete tetracyclic oxatetracyclo[6.3.2.0(1, 4).0(5, 12)]tridecane skeleton of punctaporonin C was established by an intramolecular aldol reaction, closing a seven-membered oxepane ring. The nucleophilic methyl ketone employed in this step was generated by Wacker oxidation of the vinylic double bond, which was not involved in the [2+2]-photocycloaddition. Several reactions employed in the synthetic sequence required adaptation to the rigid skeleton of punctaporonin C, for example, the reduction of a mesylate, the alkylation of a cyclobutane carboxylate, or the methyl addition to a prostereogenic carbonyl group.

Total Synthesis of the Tetracyclic Sesquiterpene (±)‐Punctaporonin C

Although a hypothesis on the biosynthesis of the punctaporonins has been put forward, and the biand tricyclic punctaporonins A, B, and D have been accessed synthetically, a total synthesis of punctaporonin C has not yet been reported. An intrinsic problem is the annulation of the fourmembered ring to the highly substituted tetrahydrofuran moiety. An intermolecular [2+2] photocycloaddition with simultaneous formation of the C1 C2 and C3 C4 bonds is impossible, as neither of the two potential reaction partners can display a suitable chromophore. For related, carbanalogous scaffolds, for example, the tricyclo[6.2.0.0]decane scaffold of kelsoene, the intermolecular [2+2] photocycloaddition is feasible, as an enone serves as the chromophore. Herein, we report the first total synthesis of racemic ( )-punctaporonin C, as well as a photochemical route to skeletonA by a selective intramolecular [2+2] photocycloaddition of a tetronate and subsequent aldol ring closure. Retrosynthetically (Scheme 2), punctaporonin C (1) was traced back to ketone I, in which the two hydroxy groups at C6 and C7 were to be protected orthogonally (PG= protecting group), and in which the carbonyl group was to serve as a precursor for the tertiary alcohol at C9. An intramolecular enolate alkylation was planned for the ring closure to form the unusual bridged oxepane. These considerations led to compound II as a precursor, which was chosen to enable the construction of an acetyl group (C9, C10) by a Wacker oxidation. The carbon skeleton of the tricyclic compound II could be formed from lactone III, if a complete reduction of the carboxylic carbon atom to a methyl group was taken in account. The other methyl group at C2 of punctaporonin C was to be introduced by the alkylation of lactone IV to give III. Lactone IV could obviously be formed through an intramolecular [2+2] photocycloaddition, with the decisive question being whether and how the two terminal double bonds in a precursor molecule could be distinguished. In preliminary studies on the [2+2] photocycloaddition, no selectivity was observed when ether was used as the solvent, and the wrong regioisomer was formed preferentially in the presence of cyclodextrins. However, we now discovered that 1,3-divinyl-2-cyclopentyltetronates with a polar substituent at the 4-position undergo the cycloaddition in protic solvents to give predominantly the desired regioisomer. Indeed, the product 3, which was required for the planned synthesis, was obtained from substrate 2 with acceptable selectivity (75:25; Scheme 3). We presume that the acetoxy group becomes sterically demanding as a result of hydrogen bonding with the solvent and resides in a pseudoequatorial position in the envelope 2’. As a consequence, the tetronate group and one of the two terminal double bonds are ideally positioned for an intramolecular [2+2] photocycloaddition. The facial and simple diastereoselectivity of the photoreaction were perfect: A single diastereoisomer was obtained. The starting material for the successful total synthesis of punctaporonin C (Scheme 4) was the knownmeso epoxide 4 Scheme 1. Structure of punctaporonin C (1) and its core skeleton A with the cyclobutane ring highlighted. Scheme 2. Retrosynthetic analysis of punctaporonin C (1).

Regioselective [2 + 2]-photocycloaddition reactions of chiral tetronates—influence of temperature, pressure, and reaction medium

The intramolecular [2 + 2]-photocycloaddition of the 1,3-divinyl-2-cyclopentyl tetronates was performed under various conditions to give perfect diastereoselectivity and a regioselectivity of up to 85/15 in the presence of gamma-cyclodextrin by differentiating the two chemically very similar double bonds of .