Paul A. Hume

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 virgatolide B.

The first total synthesis of the benzannulated spiroketal virgatolide A is presented. Key features include sp(3)-sp(2) Suzuki coupling of an enantiomerically enriched β-trifluoroboratoamide and an aryl bromide, regioselective intramolecular carboalkoxylation, and a 1,3-anti-selective Mukaiyama aldol reaction followed by global deprotection/cyclization with regioselectivity governed by internal hydrogen bonding.

The Bioreductive Alkylation of DNA by Kalafungin: A Theoretical Investigation

The thermochemical cascades for the bioreductive alkylation of DNA by kalafungin were calculated using density functional theory (DFT). Guanine (G) was used as a model nucleotide. According to the calculations both one- and two-electron reduction of kalafungin is possible in vivo. Furthermore, a clear pathway was found for both mono- and bis-alkylations of G with the former favoured. Alkylation at C-8 position of G is considerably more exothermic than on the N2-exocyclic amine. In the absence of experimentally identified adduct structures of kalafungin, the results presented here support the idea that this compound readily forms covalent bonds with DNA resulting in pro-mutagenic lesions.

Unexpected Direct Synthesis of N-Vinyl Amides through Vinyl Azide–Enolate [3+2] Cycloaddition

The unexpected synthesis of industrially important N-vinyl amides directly from aldehydes and α,β-unsaturated N-vinyl amides from esters is reported. This reaction probably proceeds through an initial [3+2] azide-enolate cycloaddition involving a vinyl azide generated in situ. A survey of the reaction scope and preliminary mechanistic findings supported by quantum computational analysis are reported, with implications for the future development of atom-efficient amide synthesis. Intriguingly, this study suggests that (cautious) reevaluation of azidoethene as a synthetic reagent may be warranted.

Total Synthesis of Virgatolide B via Exploitation of Intramolecular Hydrogen Bonding

A full account of the enantioselective total synthesis of virgatolide B is reported. Key features of the synthesis include an sp(3)-sp(2) Suzuki-Miyaura cross-coupling of a β-trifluoroboratoamide with an aryl bromide, regioselective intramolecular carboalkoxylation, and a 1,3-anti-selective Mukaiyama aldol reaction. Intramolecular hydrogen bonding governed the regioselectivity of the key spiroketalization step, affording the natural product as a single regioisomer.

Divergent Reactivity via Cobalt Catalysis: An Epoxide Olefination

Cobalt salts exert an unexpected and profound influence on the reactivity of epoxides with dimethylsulfoxonium methylide. In the presence of a cobalt catalyst, conditions for epoxide to an oxetane ring expansion instead deliver homoallylic alcohol products, corresponding to a two-carbon epoxide homologation/ring-opening tandem process. The observed reactivity change appears to be specifically due to cobalt salts and is broadly applicable to a variety of epoxides, retaining the initial stereochemistry. This transformation also provides operationally simple access to enantiopure homoallylic alcohols from chiral epoxides without use of organometallic reagents. Tandem epoxidation-homologation of aldehydes in a single step is also demonstrated.

Total Synthesis of an Isatis indigotica-Derived Alkaloid Using a Biomimetic Thio-Diels–Alder Reaction

A biomimetic thio-Diels-Alder reaction between a dienylthiadiazole and 3-thioisatin leads to the Isatis indigotica-derived alkaloid (1), along with its diastereomer 2. This synthetic study, supported by molecular modeling, establishes the viability of the proposed biosynthesis by thio-Diels-Alder cycloaddition, a very rare reaction in nature. Moreover, the results described infer that the diastereomer 2 is an as-yet undiscovered natural product present in Isatis indigotica.

Effective Conversion of Amide to Carboxylic Acid on Polymers of Intrinsic Microporosity (PIM-1) with Nitrous Acid

Carboxylate-functionalised polymers of intrinsic microporosity (C-PIMs) are highly desirable materials for membrane separation applications. The recently reported method to afford C-PIMs was via an extensive base hydrolysis process requiring 360 h. Herein, a novel and effective method to convert PIM-CONH2 to C-PIM using nitrous acid was studied. The chemical structure of C-PIM was characterised by 1H NMR, 13C NMR, FTIR, elemental analysis, UV-Vis, TGA and TGA-MS. Complete conversion from amide to carboxylic acid groups was confirmed. Decarboxylation of C-PIM was also successfully studied by TGA-MS for the first time, with a loss of m/z 44 amu (CO2) observed at the first degradation stage. TGA also revealed decreased thermal stability of C-PIM relative to PIM-CONH2 under both N2 and air atmosphere. Gel permeation chromatography (GPC) analysis showed continuous molecular weight degradation of C-PIM with extended reaction time. Aromatic nitration was also observed as a side reaction in some cases.

Synthesis of Psychrophilin E

The first total synthesis of psychrophilin E, a potent antiproliferative cyclic tripeptide isolated from Aspergillus versicolor ZLN-60, is reported herein. Key features of the synthesis include the installation of an amide bond between the indole-nitrogen of tryptophan and an anthranilic acid residue, and a high yielding macrolactamization of the linear tripeptide to the desired macrocycle.

Total Synthesis of the Fungal Metabolite Virgatolide B

Abstract This account describes the total synthesis of the title compound, a polyketide metabolite with in vitro antitumor activity. A first-generation approach involving an sp 3 –sp 2 Suzuki cross-coupling reaction of a chiral trifluoroboratoamide and a rotationally symmetric aryl bromide successfully established the carbon framework required to construct the spiroketal core of the molecule. However, removal of the phenolic protecting groups with concomitant spiroketalization could not be achieved. A revised strategy was therefore devised, employing different protecting groups and incorporating greater functionality on the aryl bromide coupling partner. Suzuki cross-coupling, extension of the carbon backbone using a diastereoselective Mukaiyama aldol reaction and deprotection/cyclization furnished the spiroketal ring system. The final transformation required was carboalkoxylation of the aromatic ring to form the phthalide subunit present in the molecule. This manipulation was difficult to achieve due to competing protodehalogenation. Finally, a reordering of synthetic events provided access to virgatolide B by exploitation of an intramolecular hydrogen-bonding interaction in order to control the regioselectivity of the spiroketalization process.