Spirotryprostatin B

Total synthesis

The first total synthesis was accomplished in 2000 by the Danishefsky group at Columbia University, with a number of other syntheses following shortly thereafter by Williams, Ganesan, Fuji, Carreira, Horne, Overman, and most recently Trost.

From a synthetic point of view, the most challenging structural features of the molecule are the C3 spirocyclic ring juncture and the adjacent prenyl-substituted carbon. Approaches toward preparing the skeleton of spirotryprostatin B have varied considerably.

Danishefsky spirotryprostatin B synthesis :[[Image:Danishefsky spirotryprostatinB synthesis.png|339px|Danishfesky spirotryprostatin B synthesis]]

In the Danishefsky synthesis, an amine derived from tryptophan was condensed with an aldehyde, triggering a Mannich-type reaction wherein the pendant oxindole acted as a nucleophile toward the intermediate iminium species.

Williams spirotryprostatin B synthesis :[[Image:Williams spirotryprostatinB synthesis.png|412px|Williams spirotryprostatin B synthesis]]

The synthesis by the Williams group utilized a 3-component coupling reaction. A secondary amine was combined with an aldehyde to form an intermediate azomethine ylide, which underwent a 1,3-dipolar cycloaddition with an unsaturated oxindole also present in the reaction mixture.

Ganesan spirotryprostatin B synthesis :[[Image:Ganesan spirotryprostatinB synthesis.png|466px|Ganesan spirotryprostatin B synthesis]]

Ganesan made use of a biomimetic strategy in his synthesis of spirotryprostatin B. An indole was treated with N-bromosuccinimide to trigger an oxidative rearrangement, forming the quaternary stereocenter in a diastereoselective manner.

Fuji spirotryprostatin B synthesis :[[Image:Fuji spirotryprostatinB synthesis.png|404px|Fuji spirotryprostatin B synthesis]]

In the synthesis developed by the Fuji group, the stereochemistry at the spirocyclic carbon was established by a nitroolefination reaction. An oxindole with pendant prenyl group was reacted with a nitroolefin bearing a chiral leaving group.

Carreira spirotryprostatin B synthesis :[[Image:Carreira spirotryprostatinB synthesis.png|387px|Carreira spirotryprostatin B synthesis]]

The Carreira group made use of a magnesium iodide promoted annulation reaction in their approach toward spirotryprostatin B. An oxindole bearing a cyclopropane was reacted with an imine in the presence of the magnesium iodide, triggering the ring-expansion reaction.

Horne spirotryprostatin B synthesis :[[Image:Horne spirotryprostatinB synthesis.png|420px|Horne spirotryprostatin B synthesis]]

Horne's synthesis of spirotryprostatin B also made use of a Mannich-type process, wherein a chloro-indole served as the pro-nucleophile. The cyclization was triggered by treating the pendant imine with the acyl chloride derived from proline. The resulting iminium species was attacked by the chloro-indole, forming the spirocyclic bond.

Overman spirotryprostatin B synthesis :[[Image:Overman spirotryprostatinB synthesis.png|434px|Overman spirotryprostatin B synthesis]]

The Overman group utilized a Heck reaction to prepare the molecule. An iodo-aniline with a tethered alkene was subjected to palladium catalysis. The intermediate palladium-allyl species was intercepted by the pendant amide nitrogen to generate the prenyl stereocenter in the same reaction.

Trost spirotryprostatin B synthesis :[[Image:Trost spirotryprostatinB synthesis.png|433px|Trost spirotryprostatin B synthesis]]

In the synthesis developed by the Trost group, the stereochemistry at the spirocyclic ring juncture is established by a decarboxylation-prenylation sequence, reminiscent of the Carroll reaction. Here, a prenyl ester serves as both the nucleophile and electrophile precursor. Upon treatment with a chiral palladium catalyst the prenyl group ionizes and decarboxylates. The resulting ion pair subsequently recombines to generate the prenylated product. Notably, double bond migration occurs and the prenyl group is attacked at the oxindole carbon.

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References

1. "KNApSAcK Metabolite Information - C00016255". www.knapsackfamily.com.