Jonathan Sperry

Natural products containing a nitrogen-nitrogen bond.

As of early 2013, over 200 natural products are known to contain a nitrogen-nitrogen (N-N) bond. This report categorizes these compounds by structural class and details their isolation and biological activity.

Isolation, biological activity and synthesis of benzannulated spiroketal natural products.

Covering: up to late 2009 A review of the isolation, biological activity and synthesis of natural products containing a benzannulated spiroketal moiety is provided.

Natural products targeting telomere maintenance

Telomeres are repetitive sequences of DNA found at the ends of chromosomes which determine and restrict the number of replications a cell can undertake. In the majority of cancer cells, telomerase has been found to maintain the length of telomeres, conferring cell immortality and prevention of cell senescence. With the ready availability of assays to detect telomerase activity, numerous telomerase inhibitors have been discovered from a variety of natural sources. This article gives an outline of these natural product-based telomerase inhibitors and their inspiration for analogue design.

Pyranonaphthoquinone Derivatives of Eleutherin, Ventiloquinone L, Thysanone and Nanaomycin A Possessing a Diverse Topoisomerase II Inhibition and Cytotoxicity Spectrum

A series of pyranonaphthoquinone derivatives related to the known topoisomerase II inhibitor eleutherin 1 have been shown to act as specific topoisomerase II catalytic inhibitors, with several analogues displaying greater potency than the natural product itself. Amongst the compounds tested were the natural products ventiloquinone L 4 and thysanone 8 with a diverse range of topoisomerase II inhibition properties being observed. Interestingly, the natural products are generally weaker inhibitors than their synthetic counterparts, emphasising that subtle changes in the basic molecular structure of a natural product led to significant changes in the inhibition profile. It has also been demonstrated for the first time that analogues related to nanaomycin A and cardinalin-type dimeric pyranonaphthoquinones exhibit potent topoisomerase II inhibitory properties. With respect to structural features, it appears that the nature of the substituents at C1 on the pyran ring and oxygenated substituents on the aryl ring are critical for anti-topoII activity. Importantly, the topoisomerase II inhibition strength does not correlate well with the measured cytotoxicity against yeast, indicating that other molecular features in the pyranonaphthoquinone family must be considered for the design and use of this structural class as highly specific topoisomerase II inhibitors.

Enantioselective synthesis of pyranonaphthoquinone antibiotics using a CBS reduction/cross-metathesis/oxa-Michael strategy.

The enantioselective syntheses of deoxydihydrokalafungin (5), cis-deoxydihydrokalafungin (6) and deoxykalafungin (7) are reported. The strategy was based on 4 key reactions: (1) CBS reduction of prochiral ketone 10 to introduce chirality at C-1, (2) radical allylation of quinone 9a, (3) cross-metathesis of dimethoxynaphthalene 13 with methyl acrylate, and (4) intramolecular oxa-Michael addition of alcohol 8 to form the core naphthopyran ring system. This novel approach delivers naphthopyrans possessing the natural trans-stereochemistry observed in the pyranonaphthoquinone family of antibiotics.

Total Synthesis of the Initially Reported and Revised Structures of the Neuroprotective Agent Palmyrolide A

The total syntheses of the initially reported and revised structures of the neuroprotective agent palmyrolide A are reported. The key macrocyclization step was achieved using a sequential ring closing metathesis/olefin isomerization reaction. The synthetic work described herein serves to confirm the recent structural revision of this unusual natural product.

Total Synthesis of the Photoprotecting Dipyrrolobenzoquinone (+)-Terreusinone

The first synthesis of (+)-terreusinone 1, a dipyrrolobenzoquinone with a potent UV-A protecting capability, is described. Key transformations include a one-pot Larock indolization-Sonogashira coupling reaction and the hydroamination of an unsubstituted ortho-alkynylaniline catalyzed by a cationic gold(I) complex. The synthesis proceeds in eight steps from commercially available starting materials, confirming the structure and absolute configuration of the natural product.

Synthesis of the Tetracyclic Core of Berkelic Acid Using Gold(I)-Catalyzed Hydroarylation and Oxidative Radical Cyclizations

A synthetic approach to the tetracyclic core of berkelic acid is reported using gold(I)-catalyzed intramolecular hydroarylation and oxidative radical cyclizations to effect the key ring-forming steps. The carboxylic acid was introduced via a late-stage palladium-catalyzed carbonylation to afford the core tetracycle with the correct relative stereochemistry for the natural product.

Biomimetic studies towards the cardinalins: synthesis of (+)-ventiloquinone L and an unusual dimerisation

Studies towards the biomimetic synthesis of cardinalin 3 are described. Despite the successful enantioselective synthesis of the monomeric pyranonaphthoquinone ventiloquinone L, it subsequently failed to undergo a proposed biomimetic homodimerisation to cardinalin 3 using a range of oxidants. However, treatment of a related naphthopyran with cerium ammonium nitrate (CAN) facilitated a tandem biaryl bond formation-oxidative demethylation sequence furnishing a dimeric pyranonaphthoquinone that had exclusively dimerised at C6. The nature of this unusual sequence is discussed and the product subsequently converted to the C6 regioisomer of cardinalin 3.

Toward an asymmetric synthesis of the dimeric pyranonaphthoquinone antibiotic crisamicin A.

A full account of our efforts toward an asymmetric synthesis of crisamicin A are presented. The key steps include a Hauser-Kraus annulation of a cyanophthalide with a chiral enone-lactone, a stereoselective cyclization-reduction to install the pyran unit, and a Suzuki homocoupling to forge the key biaryl bond. This work has culminated in the asymmetric synthesis of a dimer bearing the complete carbon skeleton of the dimeric pyranonaphthoquinone natural product crisamicin A.