Studien zur Totalsynthese der Spirochensilide

authored by

Dennis Lübken

supervised by

Markus Kalesse

Abstract

This doctoral thesis describes synthetic work towards the triterpenoids spirochensilide A and B that were isolated in 2015 from abies chensiensis by Gao and coworkers. Spirochensilide A shows weak inhibition (30%) of the NO production (12.5 µg/mL). These two triterpenoids differ in the absolute configuration of the secondary alcohol at C-3 in the A-ring. This work consists of four different retrosynthetic analyses of spirochensilide A and B including synthetic work towards each of it. The aimed intramolecular construction of the all-anti unit of three methyl groups and the quaternary spiro center at C-8 was investigated. The unit of three all-anti methyl groups was constructed by a Claisen rearrangement in the first retrosynthetic approach. A polyene cyclization was investigated for the construction of the A,B rings as well as for the all carbon quaternary spiro center at C-8 in an first and second approach. A third retrosynthetic path aimed at a semipinacol rearrangement of a tertiary allylic alcohol to build up the C-8 all carbon quaternary spiro center. Starting from (S)-methyl-Wieland-Miescher ketone the desired trans-hydrindane was obtained in ten steps. The key step of this sequence was a ring contraction effected by a photo Wolff rearrangement followed by an in situ ozonolysis of the intermediary ketene. The required C,D ring was obtained in a sequence of nine steps with an intramolecular aldol condensation for the closure of the D ring. The tertiary allylic alcohol was synthesized and investigations towards the envisioned semipinacol rearrangement were undertaken. The desired spiroketone could be obtained in a very low yield. Further Experiments could show a similar semipinacol rearrangement at a model system. In a fourth retrosynthetic approach the construction of the all carbon quaternary spiro center at C-8 was investigated by an intramolecular aldol addition. Furthermore, in context of this work synthetic studies towards the sesquiterpene coumarins penisarin A and B were initiated. These two natural products were isolated by Li et al. in 2020 from an endophytic Penicillium sp. KMU18029 and show cytotoxic activity against human cancer cell lines HL-60 (IC50 = 3.6 µM) and SMMC-7721 (IC50 = 3.7 µM) in first in vitro evaluations. Penisarin A and B possess two adjacend all carbon quaternary centers. Starting from the trans-hydrindane, which was synthesized towards the synthesis of the spirochensilides, sesquiterpene unit of penisarin A and B could be obtained.

Organisation(s)

Institute of Organic Chemistry

Type

Doctoral thesis

No. of pages

461

Publication date

2021

Publication status

Published

Sustainable Development Goals

SDG 3 - Good Health and Well-being

Electronic version(s)

https://doi.org/10.15488/11467 (Access: Open)