2010-Present Natural Products

2017

2,3-Dihydropyrrolo[1,2-a]quinazolin-5(1H)-one  An improved, scalable synthetic route to the quinazolinone natural product 2,3-dihydropyrrolo[1,2-a]-quinazolin-5(1H)-one is reported. The applicability of this method to analogue synthesis and the synthesis of related natural products is explored. Finally, reactivity of the scaffold to a variety of electrophilic reagents, generating products stereoselectively, is reported. See: On the synthesis and reactivity of 2,3-dihydropyrrolo[1,2-a]quinazolin-5(1H)-ones C.L. Sutherell and S.V. Ley Synthesis201749, 135-144.

2016

Beauvericin, bassianolide and enniatin C  Flow chemistry has been successfully integrated into the synthesis of a series of cyclooligomeric depsipeptides of three different ring sizes including the natural products beauvericin, bassianolide and enniatin C. A reliable flow chemistry protocol was established for the coupling and macrocyclisation to form challenging N-methylated amides. This flexible approach has allowed the rapid synthesis of both natural and unnatural depsipeptides in high yields, enabling further exploration of their promising biological activity. See: Synthesis of natural and unnatural cyclooligomeric depsipeptides enabled by flow chemistry D. Lücke, T. Dalton, S.V. Ley, Z.E. Wilson Chem. Eur. J. 201622, 4206-4217.

2015

Plantazolicin A and B  Plantazolicin A, a linear decacyclic natural product, exhibits desirable selective activity against the causative agent of anthrax toxicity. The total synthesis of plantazolicin A and its biosynthetic precursor plantazolicin B was successfully achieved by an efficient, unified, and highly convergent route featuring dicyclizations to form 2,4-concatenated oxazoles and the mild synthesis of thiazoles from natural amino acids. This represents the first synthesis of plantazolicin B and includes the first complete characterization data for both natural products.we have developed an efficient, unified strategy for the total syntheses for both thiazole/oxazole natural product plantazolicin A and its biosynthetic precursor plantazolicin B. This was achieved through application of solution-phase peptide coupling chemistry, with step-efficient multiple oxazole formations as well as the application of a readily scalable preparation of the thiazole fragments from natural amino acids. Late-stage introduction of the N-terminus dimethylation allowed access to both natural products through a unified approach. See: and Total syntheses of linear polythiazole/oxazole plantazolicin A and its biosynthetic precursor plantazolicin B Z.E. Wilson, S. Fenner, S.V. Ley Angew. Chem. Int. Edn. 201554, 1284-1288 and The total synthesis of the bioactive natural product Plantazolicin A and its biosynthetic precursor Plantazolicin B S. Fenner, Z.E. Wilson, S.V. Ley, Chem. Eur. J. 201622, 15902-15912.

Isoborreverine  Flow chemistry is widely used in synthetic chemistry and it has increasingly been applied to complex natural product synthesis. However, to date flow chemistry has not found a place in the area of biomimetic synthesis. Here we show the syntheses of borrerine derived alkaloids, indicating that we can use biomimetic principles in flow to prepare complex architectures in a single step. See: Facilitating biomimetic syntheses of borrerine derived alkaloids by means of flow-chemical methods S.B. Kamptmann, S.V. Ley Aust. J. Chem201568, 693-696.

2014

Spirangien A methyl ester and spirodienal A  Over the past decade, the integration of synthetic chemistry with flow processing has resulted in a powerful platform for molecular assembly that is making an impact throughout the chemical community. We have demonstrated the extension of these tools to encompass complex natural product synthesis by developing a number of novel flow-through processes for reactions commonly encountered in natural product synthesis programs to achieve the first total synthesis of spirodienal A and the preparation of spirangien A methyl ester. Highlights of the synthetic route include an iridium-catalyzed hydrogenation, iterative Roush crotylations, gold-catalyzed spiroketalization and a late-stage cis-selective reduction. See: Accelerating spirocyclic polyketide synthesis using flow chemistry S. Newton,  C.F. Carter, C.M. Pearson, L.C. Alves, H. Lange, P. Thansandote, S.V. Ley,  Angew. Chem. Int. Edn. 201453, 4915-4920.

Nazlinine  Judicious choice of flow electrochemistry as an enabling technology has permitted the rapid generation of a small library of unnatural relatives of this biologically active molecule. Furthermore, by conducting the key electrochemical Shono oxidation in a flow cell, the loading of electrolyte can be significantly reduced to 20 mol % while maintaining a stable, broadly applicable process. See: Expedient preparation of nazlinine and a small library of indole alkaloids using flow electrochemistry as an enabling technology M.A. Kabeshov, B. Musio, P.R.D. Murray, D.L. Browne, S.V. Ley Org. Lett.  201416, 4618-4621.

2013

(–)-Hennoxazole A  The syntheses of natural products O-methyl siphonazole and (–)-hennoxazole A were accomplished using a combination of batch and flow procedures. Key oxazole-containing fragments were prepared using solid-supported reagents and flow technologies to facilitate the overall syntheses of these molecules and highlight the advantages of incorporating enabling technologies into natural product synthesis. See: Synthesis of (-)-hennoxazole A: integrating batch and flow chemistry methods A. Fernández, Z.G. Levine, M. Baumann, S. Sulzer-Mossé, C. Sparr, S. Schläger, A. Metzger, I.R. Baxendale, S.V. Ley, Synlett, 201324, 514-518.

Spongistatin 2  An improved route to the EF fragment of the spongistatins has been developed and employed in a synthesis of spongistatin 2. The C48–C51 diene side chain, which lacks the chlorine substituent present in spongistatin 1, presented some compatibility issues during target assembly. These were overcome by implementing a late stage Stille cross coupling to construct the diene portion of the natural product. See: Synthesis of spongistatin 2 employing a new route to the EF fragment H. Kraus, A. Français, M. O’Brien, J.R. Frost, A. Diéguez-Vázquez, A. Polara, N. Baricordi, R. Horan, D-S. Hsu, T. Tsunoda, S.V. Ley, Chem. Sci. 20134, 1989-1994.

2012

Callipeltosides A, B and C  The callipeltosides were isolated by Minale and co-workers from the marine sponge Callipelta sp. in 1996. They contain 14 stereocentres, an unusual trans-configured chlorocyclopropane ring conjugated to a dieneyne motif and a 14-membered macrolactone ring. The natural products differ only in the sugar unit which is attached to a common aglycon core. The synthesis towards the aglycon core includes a gold-catalysed cyclisation, an Oppolzer-Radinov alkenyl metal addition and a Yamaguchi macrolactonisation. Completion of these natural products resulted in confirmation that all members of the callipeltoside family contained l-configured sugars and represented the first total synthesis of callipeltoside B. See: Total synthesis of callipeltosides A, B and C J.R. Frost, C.M. Pearson, T.N. Snaddon, R.A. Booth, S.V. Ley, Angew. Chem. Int. Ed. 201251, 9366-9371 and Callipeltosides A, B and C: total syntheses and structural confirmation J.R. Frost, C.M. Pearson, T.M. Snaddon, R.A. Booth, R.M. Turner, J. Gold, D.M. Shaw, M.J. Gaunt, S.V. Ley Chem. Eur. J. 201521, 13261-13277.

(–)-Enniatin B  A nine-step (longest linear) batch total synthesis of the cyclic hexadepsipeptide (−)-enniatin B is described. The synthesis minimizes precipitation during reaction conditions for adaptability to flow synthesis. The route was used to prepare >100 mg of the natural product. See: A total synthesis of the ammonium ionophore (–)-enniatin B D.X. Hu, M. Bielitza, P. Koos, S.V. Ley, Tetrahedron Lett. 201253, 4077-4079.

Millingtonine A  A total synthesis of millingtonine A, a diglycosylated alkaloid, has been accomplished. Millingtonine A possesses a unique racemic tricyclic core structure not known from any other natural or synthetic source until now. The synthesis features a key bond-forming radical Ueno–Stork cyclization to form the heterocyclic core. See: A total synthesis of millingtonine A J. Wegner, S.V. Ley, A. Kirschning, A-L. Hansen, J. Montenegro Garcia, I.R. Baxendale, Org. Lett. 201214, 696-699.

2011

O-Methyl siphonazole  The bisoxazole containing natural product O-methyl siphonazole was assembled using a suite of microreactors via a flow-based approach in concert with traditional batch methods. The use of a toolbox of solid-supported scavengers and reagents to aid purification afforded the natural product in a total of nine steps. See: An integrated flow and batch-based approach for the synthesis of O-methyl siphonazole M. Baumann, I.R. Baxendale, M. Brasholz, J.J. Hayward, S.V. Ley, N. Nikbin Synlett, 201110, 1375-1380.

Pseudomonas quinolone signal (PQS) Expedient syntheses of Pseudomonas quinolone signal (PQS) and related structural analogues using microwave and flow methods are reported. See: Microwave and flow syntheses of Pseudomonas Quinolone Signal (PQS) and analogues J.T. Hodgkinson, W.R.J.D. Galloway, S. Saraf, I.R. Baxendale, S.V. Ley, M. Ladlow, M. Welch, D.R. Spring, Org. Biomol. Chem20119, 57-61.

Isobongkrekic acid and bongkrekic acid  The first convergent total synthesis of isobongkrekic acid is reported involving three different stereospeci€c palladium cross-couplings for the formation of the diene units. Access to bongkrekic acid by this route is also demonstrated. These syntheses involve the formation of several potentially general building blocks. See: Total synthesis of iso- and bongkrekic acids: natural antibiotics displaying potent antiapoptotic properties A. Francais, A. Leyva-Pérez, G. Etxebarria-Jardi, J. Peña, S.V. Ley, Chem. Eur. J201117, 329-343 and Total synthesis of the anti-apoptotic agents Iso- and bongkrekic acids A. Francais, A. Leyva, G. Etxebarria-Jardi, I. R. Baxendale, S.V. Ley, Org. Lett201012, 340-343.

Subereomollines A and B  The first total syntheses of (+)- and (-)-subereamollines A and B are reported. The enantiomeric forms of the natural products were obtained by preparative chiral HPLC separation of the corresponding racemates. See: Total synthesis of subereomollines A and B J.W. Shearman, R. M. Myers, J.D. Brenton, S.V. Ley, Org. Biomol. Chem20119, 62-65.

2010

Total synthesis of chloptosin: a dimeric cyclohexapeptide Here we describe in full our investigations into the synthesis of the dimeric cyclohexapeptide chloptosin in 17 linear steps. Particularly, this work features an organocatalytic tandem process for the synthesis of the embedded piperazic acids, in which a differentially protected azodicarboxylate is used together with pyrrolidinyl tetrazole as the catalyst. The central biaryl bond is being formed by Stille coupling of two sterically demanding ortho-chloropyrroloindole fragments. The inherent flexibility of the synthetic strategy proved beneficial as the route could be adjusted smoothly during the progression of the synthesis programme. See:  Total synthesis of chloptosin A.J. Oelke, D.J. France, T. Hofmann, G. Wuitschik, S.V. Ley, Angew. Chem. Int. Ed201049, 6139-6142 and Total synthesis of chloptosin: a dimeric cyclohexapeptide A.J. Oelke, F. Antonietti, L. Bertone, P.B. Cranwell, D.J. France, R.J.M. Goss, T. Hoffman, S. Knauer, S.J. Moss, P.C. Skelton, R.M. Turner, G. Wuitschik, S.V. Ley, Chem. Eur. J201117, 4183-4194.

Combretastatin A-4  The generally accepted view is that the 3,4,5-trimethoxy-substituted aromatic A-ring of combretastatin A-4 (CA-4) and its analogues should be conserved in order to maintain biological activity through enforcing an active molecular conformation. Contrary to this, we have found that substituting the larger meta-methoxy groups of CA-4 with smaller halogen atoms results in compounds that are equipotent or more potent than CA-4 itself in vitro. See: Antivascular and anticancer activity of dihalogenated A-ring analogues of combretastatin A-4 T.M. Beale, R.M. Myers, J.W. Shearman, D.S. Charnock-Jones, J.D. Brenton, F.V. Gergeley, S.V. Ley, Med. Chem. Commun20101, 202-208.

Ianthelline, 5-bromoverongamine and JBIR-44  The total syntheses of the bromotyrosine-derived natural products ianthelline, 5-bromoverongamine and JBIR-44 are described and their cytotoxic activity in a cervical cancer (HeLa) cell line and human umbilical vein endothelial cells (HUVECs) are reported.  Total syntheses of the bromotyrosine-derived natural products ianthelline, 5-bromoverongamine and JBIR-44 J.W. Shearman, R.M. Myers, T.M. Beale, J.D. Brenton, S.V. Ley, Tetrahedron Lett201051, 4812-4814.