Exploratory studies towards a total synthesis of the unusual bridged tetracyclic Lycopodium alkaloid lycopladine H

A strategy for a total synthesis of the structurally novel Lycopodium alkaloid lycopladine H has been investigated. Key steps that have been tested include: 1. a regioselective Diels-Alder cycloaddition of nitroethylene with an o-quinone ketal to produce the bicyclo[2.2.2]octane moiety of the alkaloid; 2. a stereoselective Henry reaction to generate the requisite functionality and configuration at C-5; 3. a stereoselective catalytic hydrogenation of a trisubstituted alkene to set the C-15 methyl configuration.     

An approach to the total synthesis of the marine ascidian metabolite perophoramidine via a halogen-selective tandem Heck/carbonylation strategy

A halogen-selective tandem intramolecular Heck/carbonylation reaction has been developed for the construction of the C,E,F-ring system and the C20 quaternary center found in perophoramidine (1). This process can be effected in good yields in the presence of both the chlorine and bromine atoms found in the natural product. In addition, it is possible to introduce the quaternary center at C4 in a stereoselective manner by a lactone enolate alkylation, using NaH and allyl bromide. [reaction: see text]     

Polycyclic ethers and an unexpected dearomatisation reaction during studies towards the bioactive alkaloid,perophoramidine

The bioactive alkaloid natural product perophoramidine and the related family of compounds known as the communesins have inspired the synthesis community for more than a decade. Many of the elegant approaches have required the synthesis of complex intermediates that have not always reacted in the expected manner. In this study we describe a series of cyclic ether-containing precursors that were prepared during our synthetic studies towards these natural products. Attempts to open the cyclic ether ring and trap the resulting stabilised carbocation with a carbon nucleophile ultimately led to the preparation of a diallyl-substituted all carbon quaternary centre. Subsequent attempts to differentiate between the two allyl groups resulted in a relatively clean transformation to an unexpected compound. Extensive structural characterisation, including small molecule X-ray crystallography, showed that a dearomatisation reaction had occurred.     

A chemoenzymatic total synthesis of the Amaryllidaceae alkaloid narseronine

A 15-step and fully stereocontrolled total synthesis of the title alkaloid 1 has been accomplished using the enantiomerically pure and enzymatically-derived cis-1,2-dihydrocatechol 2 as starting material. The final and pivotal step involved the intramolecular hetero-Michael addition of secondary amine 16 to a tethered enone moiety followed by trapping of the resulting enolate through its reaction with an adjacent ester residue.     

Towards a biomimetic synthesis of schischkiniin: assembling the bis-dihydropyrazinone cycloaddition precursor

The final step in the biosynthesis of the natural product schischkiniin is proposed to be a photochemically driven [2+2]-cycloaddition between two dihydropyrazinone units tethered to a 1,1′-bisindole. Herein, we describe the extensive efforts aimed at synthesizing the cycloaddition precursor 2, which has been obtained as its di-Boc protected derivative 30. Two bidirectional approaches were examined, both starting with the diallylated hydrazobenzene 19 undergoing two simultaneous intramolecular Heck cyclizations to give 3,3′-dimethylene-1,1′-bisindoline (20), which was readily converted to the 1,1′-bisindole-3,3′-dicarbaldehyde (14) by a bromination–hydrolysis–oxidation sequence. In the initial approach, the simultaneous addition of the pyrazinyl Grignard 15 to dicarbaldehyde 14 followed by reduction and demethylation was successful, but the imines in the resulting bis-pyrazinone 5 could not be selectively reduced to the cycloaddition precursor 2. A revised route involving simultaneous Horner–Wadsworth–Emmons reactions between dicarbaldehyde 14 and phosphonoglycine 23 followed by reduction gave 1,1′-bistryptophan 25, which underwent two consecutive thermally driven amidations to the bisamide 27. Acid-mediated cyclization of 27 gave the di-Boc protected cycloaddition precursor 30, from which the Boc groups could not be removed under a variety of conditions. These results provide a platform for an eventual biomimetic synthesis of 1, as well as demonstrating that 1,1′-bisindoles are sturdy heterocyclic motifs capable of surviving lengthy synthetic sequences.     

Synthetic studies toward melotenine A

Attempts to the construction of B/C ring and E ring in melotenine A are described. Based on para-dienone chemistry, a tactical application of tandem aminolysis/aza-Michael addition reaction was made to access highly functionalized building blocks with the pyrrolo[2,3-d]carbazole tetracyclic unit (A/B/C/D ring). Albeit negative results for assembling the dihydroazepine unit (E ring) by using the proposed fragmentation reaction of gem-dihalocyclopropanes, an alternative strategy based on ring closing metathesis was evolved to forge the E ring possessing a twisted 1,3-diene unit embedded in the rigid skeleton of melotenine A.     

A practical formal synthesis of camptothecin

The synthesis of the DE ring of camptothecin using simple and inexpensive starting materials, employing an addition elimination reaction and selective esterification of an aliphatic carboxylic acid as key steps is described.     

Model studies toward a synthesis of asperaculin A: exploration of iterative intramolecular Pauson-Khand reaction based strategies to access the dioxa[5.5.5.6]fenestrane framework

A concise strategy, involving tandem intramolecular Pauson-Khand reactions (IPKRs) on a readily available ene-diyne precursor, to access the dioxa-fenestrane framework is delineated.     

Antimycobacterial natural products: synthesis and preliminary biological evaluation of the oxazole-containing alkaloid texaline

Texaline, an antimycobacterial oxazole-containing alkaloid previously isolated from Amyris texana and A. elemifera, and related compounds have been synthesized in order to explore aspects of the structure-antituberculosis activity relationship. While texaline was found to be inactive in our assays, simpler diaryloxazoles were more active whilst also exhibiting modest toxic selectivity, leading to their identification as potential lead compounds.     

A total synthesis of spiruchostatin A

We achieved the total synthesis of the histone deacetylase inhibitor spiruchostatin A, as the prelude to the preparation of a combinatorial library of its analogues. Two key reactions were an asymmetric acetate aldol reaction using a Zr-enolate and macrolactonization using the Shiina method.     

A study of Heck cyclization reactions to form phenanthridine ring systems

A survey of conditions for the palladium catalyzed intramolecular Heck cyclization of protected amines has shown that the Herrmann-Beller palladacycle can be exploited under ‘cationic’ conditions to provide a robust and rapid route (<2 h) to the synthesis of single double bond isomer phenanthridines in excellent yield (76-99%). In addition, the same cyclization can be performed under ‘neutral’ conditions to provide phenanthridines with a double bond isomer profile suitable for exploitation in diversity-based applications. We have also shown that the highly reactive (^tBu₃P)₂Pd catalyst can induce cyclization at low temperatures (≤50 °C), giving similar results to the ‘neutral’ conditions, and offering an alternative pathway for sensitive substrates.     

First total synthesis of the marine steroid alkaloid plakinamine B

The first total synthesis of the marine steroid alkaloid plakinamine B (1) was accomplished in seven steps starting from known aldehyde 3. Key steps in this synthesis are the attachment of a vinylpyridine side chain by an aldol reaction, a chemoselective reduction of a pyridinium salt to a vinyl tetrahydropyridine, and the introduction of the 3α-methylamino group under Mitsunobu conditions. Plakinamine B and some of its precursors with amino or pyridinium side chains show significant antimicrobial activities.     

Kingamide A, a new indole alkaloid from the ascidian Leptoclinides kingi

Chemical investigation of the CH₂Cl₂/MeOH extract from the Australian ascidian Leptoclinideskingi led to the isolation of a new brominated indole alkaloid, kingamide A (1). The planar structure of kingamide A was elucidated following the interpretation of 1D/2D NMR and MS data, and the absolute configuration was determined using Marfey’s method. This is the first report of a natural product from L. kingi.     

Formal total synthesis of the cytotoxic marine ascidian alkaloid haouamine A

[reaction: see text] Described is a convergent 13-step synthesis of a pentacyclic compound which has previously been transformed into haouamine A, therefore constituting a formal total synthesis of this unique marine alkaloid.     

Recent progress toward the total synthesis of humulanolides

The humulanolides are a series of sesquiterpene lactones, most of which have unique and challenging structure. The humulanolides have exhibited anticancer activity. The combinations of fascinating structural motifs and promising pharmacological properties have prompted significant interest in the synthetic community. In this review, we provide a summary of recent progress regarding the total synthesis of humulanolides.     

Reinvestigation on total synthesis of kaitocephalin and its isomers

Aldol reaction of 2,5-disubstituted pyrrolidine 3b with (R)-Garner aldehyde followed by Sharpless asymmetric dihydroxylation and other four reactions afforded mesylate 8a, which was introduced by an amide group via three ordinary transformations to provide amide 9a. Careful deprotection with AlCl₃/Me₂S and subsequent HPLC purification furnished kaitocephalin.     

The total synthesis of (-)-callystatin A

Callystatin A is a prominent member of a class of natural products which display promising growth inhibition of cancer cells in their biological profile. The challenging structure and the interesting biological activity of (-)-callystatin A fueled our interest in the synthesis of this marine natural product. We achieved the total synthesis using a highly convergent approach joining four subunits together with a Wittig olefination, a selective Heck reaction and an aldol reaction as the pivotal steps. The aldol reaction as one of the final transformations during the synthesis opens fast access to a variety of structural analogues and circumvents tedious protecting group manipulations. Here we report an improved synthesis utilizing a modified vinyl iodide which shortens the synthesis by two steps. Additionally, first biological results will be reported.     

An approach to total synthesis of the cylindricine B pyridoquinoline subclass of tricyclic marine ascidian alkaloids

Employing an intramolecular N-acylketiminium ion/olefin hetero Diels-Alder reaction, and a ring closing metathesis of a vinyl chloride as pivotal steps, it is possible to directly access the pyridoquinoline tricyclic ring system of the marine alkaloids cylindrines B and J.     

A de novo Diels-Alder strategy toward the novel pentacyclic natural product fluostatin C: a concise synthesis of 6-deoxyfluostatin C

A conceptually new Diels-Alder approach, involving a diene moiety grafted on a preformed epoxyquinone platform and a 4-hydroxy-indenone as the dienophile, delivers the pentacyclic framework of fluostatin C in one key step.