Harringtonolide

Total Synthesis of the Diterpenoid (+)-Harringtonolide.[Pubmed:27529411]

Angew Chem Int Ed Engl. 2016 Sep 12;55(38):11638-41.

Described herein is the first asymmetric total synthesis of (+)-Harringtonolide, a natural diterpenoid with an unusual tropone imbedded in a cagelike framework. The key transformations include an intramolecular Diels-Alder reaction and a rhodium-complex-catalyzed intramolecular [3+2] cycloaddition to install the tetracyclic core as well as a highly efficient tropone formation.

Synthesis of Tetracyclic Diterpenoids with Pharmacologic Relevance.[Pubmed:26728618]

Curr Pharm Des. 2016;22(12):1767-807.

This review covers the chemical reactions, synthesis, and biological activities of tetracyclic diterpenoids including ent-kauranes, ent-beyeranes, ent-atisanes, ingenanes, tyglianes, stemodanes, stemaranes, sordarin, salvileucalin B, Harringtonolide and hainanolidol. It comprises of the un-reviewed references from the year 2000.

Stereoselective total synthesis of hainanolidol and harringtonolide via oxidopyrylium-based [5 + 2] cycloaddition.[Pubmed:23930656]

J Am Chem Soc. 2013 Aug 21;135(33):12434-8.

The tetracyclic carbon skeleton of hainanolidol and Harringtonolide was efficiently constructed by an intramolecular oxidopyrylium-based [5 + 2] cycloaddition. An anionic ring-opening strategy was developed for the cleavage of the ether bridge in 8-oxabicyclo[3.2.1]octenes derived from the [5 + 2] cycloaddition. Conversion of cycloheptadiene to tropone was realized by a sequential [4 + 2] cycloaddition, Kornblum-DeLaMare rearrangement, and double elimination. The biomimetic synthesis of Harringtonolide from hainanolidol was also confirmed.

Asymmetric synthesis of the oxygenated polycyclic system of (+)-harringtonolide.[Pubmed:22339261]

Org Lett. 2012 Mar 2;14(5):1270-3.

A straightforward asymmetric synthesis of the cage oxygenated structure of (+)-Harringtonolide has been accomplished for the first time. The key steps involved (i) a templated stereoselective IMDA reaction to build a highly functionalized cyclohexene ring D, (ii) functionalization of the cycloadduct, (iii) ring-closing metathesis providing the five-membered ring C, and finally (iv) a challenging one-step cascade cyclization of an epoxy-alcohol toward the target structure, whose mechanism was investigated.

Synthesis of novel molecular probes inspired by harringtonolide.[Pubmed:21537512]

Org Biomol Chem. 2011 Jun 21;9(12):4570-9.

A novel Harringtonolide-inspired scaffold containing a cycloheptatriene ring and two fused cyclopentane rings has been synthesised from simple starting materials. The scaffold, containing a similar substitution pattern and relative stereochemistry to the complex diterpenoid, has been enumerated into a small library of derivatives. One of these library members has been converted into a sub-library of substituted triazoles using copper-catalysed azide-alkyne cycloaddition (click) chemistry. The scaffold may be useful in drug discovery or in the preparation of additional molecular probes for chemical biology.

Further studies of the norditerpene (+)-harringtonolide isolated from Cephalotaxus harringtonia var. drupacea: absolute configuration, cytotoxic and antifungal activities.[Pubmed:18523925]

Planta Med. 2008 Jun;74(8):870-2.

Harringtonolide (= hainanolide) is a complex polycyclic fused norditerpene isolated from CEPHALOTAXUS HARRINGTONIA var. DRUPACEA. In spite of its appealing biological properties - we measured an IC (50) of 43 nM on KB cells and a significant antifungal activity - its absolute configuration has not yet been firmly established. This was done herein using X-ray anomalous scattering after bromination of the tropone ring, unambiguously giving the stereochemistry 5 R,6 R,7 S,13 S,14 S,15 R,16 R. Detailed IN VITRO biological measurements are provided.

Model studies toward the synthesis of the bioactive diterpenoid, harringtonolide.[Pubmed:18019538]

Org Biomol Chem. 2007 Aug 21;5(16):2627-35.

In model studies towards the synthesis of Harringtonolide, the construction of the tropone moiety via arene cyclopropanation was investigated. The installation of the lactone ring was accomplished by way of a Diels-Alder cycloaddition of various indenones and a-pyones. The incorporation of the key bridge methyl group and subsequent control of its stereochemistry is also outlined.