• Callipeltosides A, B and C: Total Syntheses and Structural Confirmation
• Accelerating Spirocyclic Polyketide Synthesis using Flow Chemistry
• Total Synthesis of the Protein Phosphatase Inhibitor Okadaic Acid
• Synthesis of Azadirachtin: A Long but Successful Journey
• Total Synthesis of Rapamycin
• Total Synthesis of Spongistatin I: A New Synthetic Strategy Exploiting its Latent Pseudo Symmetry
• The total synthesis of the bioactive natural product Plantazolicin A and its biosynthetic precursor Plantazolicin B
• Total synthesis of chloptosin: a dimeric cyclohexapeptide
• Total Synthesis of Five Thapsigargins – Guaianolide Natural Products Exhibiting Subnanomolar SERCA Inhibition
• Multi-step Application of Immobilized Reagents and Scavengers: A Total Synthesis of Epothilone C

• The Callipeltoside Story in Marine Natural Products: Topics in Heterocyclic Chemistry (2020)
• Engineering Chemistry to Enable Bioactive Small Molecule Discovery in Chemical and Biological Synthesis: Enabling Approaches for Understanding Biology (2018)
• Engineering chemistry for the future of organic synthesis (2018)
• Enabling technologies for the future of chemical synthesis (2016)
• Accelerating spirocyclic polyketide synthesis using flow chemistry (2014)
• Flow chemistry syntheses of natural products (2013)
• The evolution of immobilised reagents and their application in flow chemistry for the synthesis of natural products and pharmaceutical compounds (2012)
• Piperazic acid-containing natural products: isolation, biological relevance and total synthesis (2011)
• The Azadirachtin Story (2008)
• The Changing Face of Organic Synthesis (Chimia, 2008)
• Total Synthesis Studies Towards the Macrocyclic Pipercolic Natural Products FK 506, Antascomycins and Rapamycin (2008)
• Natural Products as an Inspiration for the Discovery of New High Throughput Chemical Synthesis Tools (2007)
• A Fascination with 1,2-Diacetals (2007)
• Solid Supported Reagents in Multi-Step Flow Synthesis (2007)
• Polymer-Supported Reagents and Scavengers in Synthesis (2006)
• The Use of Polymer Supported Reagents and Scavengers in the Synthesis of Natural Products (2006)
• Synthesis of Alkaloid Natural Products using Solid-Supported Reagents and Scavengers (2005)
• Development of Methods Suitable for Natural Product Synthesis: The Azadiractin Story  (2005)
• Organic Synthesis in a Changing World (2002)
• New Tools and Concepts in Modern Organic Synthesis (2002
• The Development and Application of Supported Reagents for Multi-step Organic Synthesis (2001)
• 1,2- Diacetals: A New Opportunity for Organic Synthesis (2001)
• Sweet Dreams: New Strategies and Methods for Complex Oligosaccharide Assembly  (2000)
• Use of the Temporary Connection in Organic Synthesis (2000)

2020

Goniothalamin  An integrated batch and continuous flow process has been developed for the gram-scale synthesis of goniothalamin. This styryl lactone exhibits important antiproliferative and cytotoxic effects on several tumor cell types, such as lung, breast, kidney, prostate, liver, and leukemia. See: Integrated Batch and Continuous Flow Process for the Synthesis of Goniothalamin J. C. Pastre, P. R. D. Murray, D. L. Browne, G. A. Brancaglion, R. S. Galaverna, R. A. Pilli, S. V. Ley, ACS Omega 2020, 5, 18472–18483. (http://doi.org/10.1021/acsomega.0c02390).

2017

Bengazole C and E  The bengazoles are marine natural products with unique structure, containing two oxazole rings flanking a single carbon. They show very potent antifungal activity. The total syntheses of bengazole C and E are described following a convergent route which involves diastereoselective cycloaddition of an appropriately substituted nitrile oxide with a butane-1,2-diacetal-protected alkenediol as the key step. See:  Total Synthesis of the Potent Antifungal Agents Bengazole C and E A. Enríquez-Garcia and S.V. Ley, Coll. Czech. Chem. Comm. 2009, 74, 887-900.

2008

(–)-Epipyriculol  A convenient synthesis of the phytotoxic natural product epipyriculol has been accomplished in 17 steps from methyl l-tartrate. The synthetic strategy is based upon the use of a butanediacetal-protected scaffold as central core from which the alkenyl side chains were assembled. See: A New Synthesis of (-)-Epipyriculol: a Phytotoxic Metabolite A. Levya, F.E. Blum and S.V. Ley, Tetrahedron, 2008, 64, 4711-4717.

1-Tigloyl-3-acetyl-11-methoxy-azadirachtinin, vepaol, desacetylazadirachtin and isovepaol  The synthesis of five natural products isolated from the Indian neem tree Azadirachta indica, is reported from a common intermediate. The judicious choice of transacetalization conditions allows efficient access to both the azadirachtinin and the azadirachtin skeletons. See: Synthesis of Natural Products from the Indian Neem Tree Azadirachta indica G.E. Veitch, A. Pinto, A. Boyer, E. Beckmann, J.C. Anderson and S.V. Ley, Org. Lett., 2008, 10, 569-572.

Niacin   Niacin (3-picolinic acid), which is extensively used as vitamin B₃ in foodstuffs and as a cholesterol-lowering agent, along with other oxygenated products of the picolines, 4-methylquinoline, and a variety of pyrimidines and pyridazines, may be produced in a single-step, environmentally benign fashion by combining single-site, open-structure, heterogeneous catalysts with a solid source of active oxygen, namely acetyl peroxyborate (APB), in the absence of an organic solvent.  See: Facile, One-Step Production of Niacin (Vitamin B3) and other Nitrogen-Containing Pharmaceutical Chemicals with a Single-Site Heterogeneous Catalyst R. Raja. J.M. Thomas, M. Greenhill-Hooper, S.V. Ley, and F.A. Almeida Paz, Chem. Eu. J., 2008, 14, 2340-2348.

2007

Azadirachtin  We describe in full the first synthesis of the potent insect antifeedant azadirachtin through a highly convergent approach. An O-alkylation reaction is used to unite decalin ketone and propargylic mesylate fragments, after which a Claisen rearrangement constructs the central C8C14 bond in a stereoselective fashion. The allene which results from this sequence then enables a second critical carboncarbon bond forming event whereby the [3.2.1] bicyclic system, present in the natural product, is generated via a 5-exo-radical cyclisation process. Finally, using knowledge gained through our early studies into the reactivity of the natural product, a series of carefully designed steps completes the synthesis of this challenging molecule. See: Synthesis of Azadirachtin: A Long but Successful Journey G.E. Veitch, E. Beckmann, B.J. Burke, A. Boyer, S.L. Maslen and S.V. Ley, Angew. Chem. Int. Ed. 2007, 46, 7629-7632 and The Azadirachtin Story G.E. Veitch, A. Boyer and S.V. Ley, Angew. Chem. Int. Ed., 2008, 47, 9402-9429 and The Synthesis of Azadirachtin: A Potent Insect Antifeedant S.V. Ley, A. Abad-Somovila, J.C. Anderson, C. Ayats, R. Bänteli, E. Beckmann, A. Boyer, M.G. Brasca, A. Brice, H. Broughton, B.J. Burke, E. Cleator, D. Craig, A.A. Denholm, T. Durand-Reville, L.B. Gobbi, M. Gröbel, B.L. Gray, R.B. Grossmann, C.E. Gutteridge, N. Hahn, S.L. Harding, D.C. Jennens, P.J. Lovell, H.J. Lovell, M.L. de la Puente, H.C. Kolb, W-J Koot, S.L. Maslen, C.F. McCusker, A. Mattes, A.R. Pape, A. Pinto, D. Santfianos, J.S. Scott, S.C. Smith, A.Q. Somers, C.D. Spilling, F. Stelzer, P.L. Toogood, R.M. Turner, G.E. Veitch, A. Wood, C. Zumbrunn, Chem. Eur. J., 2008, 14, 10683-10704.

Rapamycin  Rapamycin is a macrocyclic natural product, established as a potent immunosuppressant and currently of interest to the scientific community as the framework for a series of novel anticancer drugs. Extensive studies have culminated in a new convergent total synthesis of 1, which features a number of group-derived methodologies and an unusual catechol-templating strategy for the construction of the challenging macrocyclic core. See: Total Synthesis of Rapamycin M.L. Maddess, M.N. Tackett, H. Watanabe, P.E. Brennan, C.D. Spilling, J.S. Scott, D.P. Osborn and S.V. Ley, Angew. Chem., Int. Ed. 2007, 46, 591-597 and Total Synthesis of Rapamycin S.V. Ley, M.N. Tackett, M.L. Maddess, J.C. Anderson, P.E. Brennan, M.W. Cappi, J.P. Heer, C. Helgen, M. Kori, C. Kouklovsky, S.P. Marsden, J. Norman, D.P. Osborn, M.Á. Palomero, J.B.J. Pavey, C. Pinel, L.A. Robinson, J. Schnaubelt, J.S. Scott, C.D. Spilling, H. Watanabe, K.E. Wesson and M.C. Willis, Chem. Eur. J., 2009, 15, 2874-2914.

Bengazole B  The bengazoles are a family of marine natural products that display potent antifungal activity and a unique structure, containing two oxazole rings flanking a single carbon atom. Total syntheses of bengazole A and B are described, which contain a sensitive stereogenic centre at this position between the two oxazoles. Additionally, the synthesis of 10-epi-bengazole A is reported. Two parallel synthetic routes were investigated, relying on construction of the 2,4-disubstituted oxazole under mild conditions and a diastereoselective 1,3-dipolar cycloaddition. Our successful route is high yielding, provides rapid access to single stereoisomers of the complex natural products and allows the synthesis of analogues for biological evaluation. See: Total Synthesis of Potent Antifungal Marine Bisoxazole Natural Products Bengazoles A and B J.A. Bull, E.P. Balskus, R.A.J. Horan, M. Langner and S.V. Ley, Chem. Eur. J. 2007, 13, 5515-5538.

Thapsivillosin C, thapsivillosin F, trilobolide and nortrilobolide  We describe the total synthesis of five guaianolide natural products: thapsigargin, thapsivillosin C, thapsivillosin F, trilobolide and nortrilobolide. Prodrug derivatives of thapsigargin have shown selective in vivo cytotoxicity against prostate tumours and the need for further investigation of this phenomenon highlights the importance of these total syntheses. The first absolute stereochemical assignment of thapsivillosin C is also delineated. See: Total Synthesis of Five Thapsigargins – Guaianolide Natural Products Exhibiting Subnanomolar SERCA Inhibition S.P. Andrews, M. Ball, F. Wierschem, E. Cleator, S. Oliver, K. Högenauer, O. Simic, A. Antonello, U. Hünger, M.D. Smith and S.V. Ley, Chem. Eur. J., 2007, 13, 5688-5712.

Thapsigargin  The enantioselective total synthesis of thapsigargin, a potent, selective inhibitor of the Ca2+ pump SERCA, is described. Starting from ketoalcohol 8, key steps involve regioselective introduction of the internal olefin at C4−C5, judicious protecting group choice to allow chelation-controlled reduction at C3, and chemoselective introduction of the angelate ester function at C3-O. A selective esterification approach completes the total synthesis in a total of 42 steps. See: Total Synthesis of Thapsigargin, A Potent SERCA Pump Inhibitor M. Ball, S.P. Andrews, F. Wierschem, E. Cleator, M.D. Smith and S.V. Ley, Org. Lett. 2007, 9, 663-666.

2006

Oxomaritidine  A flow process for the multi-step synthesis of the alkaloid natural product (¬±)-oxomaritidine is described, mediated through the use of microfluidic pumping systems that progress material through various packed columns containing immobilized reagents, catalysts, scavengers or catch and release agents; our route involves the combination of seven separate synthetic steps linked into one continuous sequence utilizing flow chemistry. See: A Flow Process for the Multi-Step Synthesis of the Alkaloid Natural Product Oxomaritidine: A New Paradigm for Molecular Assembly I.R. Baxendale, J. Deeley, C.M. Griffiths-Jones, S.V. Ley, S. Saaby and G. Tranmer, J. Chem. Soc., Chem. Commun. 2006, 2566-2568.

Grossamide  This article describes the first enantioselective total synthesis of 2-aryl-2,3-dihydro-3-benzofurancarboxyamide neolignan, grossamide (1) using a fully automated and scalable flow reactor. See:  Preparation of the Neolignan Natural Product Grossamide by a Continuous Flow Process I.R. Baxendale, C.M. Griffiths-Jones, S.V. Ley and G.K. Tranmer, Synlett 2006, 427-430.

Bengazole A  Candidate for Candida: A high-yielding and versatile synthesis of bengazole A has been developed; the first to provide access to a single stereoisomer of the natural product. Key steps include the construction of the 2,4-disubstituted oxazole under mild conditions and a diastereoselective 1,3-dipolar cycloaddition. See: Stereocontrolled Total Synthesis of Bengazole A: A Marine Bisoxazole Natural Product Displaying Potent Antifungal Properties J.A. Bull, E.P. Balskus, R.A.J. Horan, M. Langner and S.V. Ley,  Angew. Chem. Int. Ed. 2006, 45, 6714-6718 and  Total Synthesis of Potent Antifungal Marine Bisoxazole Natural Products Bengazoles A and B J.A. Bull, E.P. Balskus, R.A.J. Horan, M. Langner and S.V. Ley, Chem. Eur. J. 2007, 13, 5515-5538.

2005

Antascomicin B  The structurally enticing antascomicin B, which exhibits potent immunosuppressant-antagonizing properties, has a complex polyketide structure. Key steps in its enantioselective total synthesis include a transannular catechol-templated Dieckmann reaction to assemble the challenging tricarbonyl functionality and a butanediacetal-directed allegation. See: Total Synthesis of Antascomicin B D.E.A. Brittain, C.M. Griffiths-Jones, M.R. Linder, M.D. Smith, C. McCusker, J.S. Barlow, R. Akiyama, K. Yasuda and S.V. Ley, Angew. Chem., Int. Ed., 2005, 44, 2732-2737.

Spongistatin I  The challenging structure and potent growth inhibition properties against a variety of human cancer cell lines make Spongistatin 1 (1) an exciting target for total synthesis. Enantioselective total synthesis has been achieved by exploiting a latent element of pseudo-symmetry (pseudo-C₂ axis) within the ABCD bis(spiroketal) fragment (red substructure). See: Total Synthesis of Spongistatin I: A New Synthetic Strategy Exploiting its Latent Pseudo Symmetry M. Ball, M.J. Gaunt, D.F. Hook, A.S. Jessiman, S. Kawahara, P. Orsini, A. Scolaro, A.C. Talbot, H.R. Tanner, S. Yamanoi and S.V. Ley, Angew. Chem. Int. Ed., 2005, 44, 5433-5438 and Azeotropic Reflux Chromatography: An Efficient Solution to a Difficult Separation in the Scale-up of Spongistatin I M. O’Brien, A. Dieguez-Vázquez, D-S. Hsu, H. Kraus, Y. Sumino and S.V. Ley, Org. Biomol. Chem., 2008, 6, 1159-1164.

Hair crab pheromone  A stereoselective synthesis of a ceramide sphingolipid as a potential sex pheromone of the hair crab Erimacrus isenbeckii is reported using diastereoselective alkylation and aldol reactions of butane-2,3-diacetal (BDA) desymmetrised glycolic acid building blocks as the key synthetic steps. See: Synthesis of a Ceramide Sphingolipid as a Potential Sex Pheromone of the Hair Crab Erimacrus isembeckii using Butane-2,3-diacetal Desymmetrised Glycolic Acid Building Blocks D.J. Dixon, S.V. Ley, S. Lohmann and T.D. Sheppard, Synlett., 2005, 481-484.

(+)-Plicane and (-)-obliquine  Two new naturally occurring amaryllidaceae alkaloids have been synthesized, using a divergent approach facilitated by the use of polymer-supported reagents and scavengers. See: Synthesis of the Alkaloid Natural Products (+)-Plicane and (–)-Obliquine using Polymer Supported Reagents and Scavengers I.R. Baxendale and S.V. Ley, Ind. Eng. Chem. Res., 2005, 44, 8588-8592.

10-Hydroxyasimicin  Orthogonal and modular templating is an effective basis for the preparation of the biologically active annonaceous acetogenin 10-hydroxyasimicin. The versatile tartrate-derived 2,3-butanediacetal building block together with a highly diastereoselective hetero-Diels–Alder approach to the butenolide unit were usefully employed in this novel synthetic route. See: The Total Synthesis of the Annonaceous Acetogenin, 10-Hydroxyasimicin G.L. Nattrass, E. Diez, M. McLachlan, D.J. Dixon and S.V. Ley, Angew. Chem. Int. Ed., 2005, 44, 580-584.

2004

(+)-Okaramine  The first total synthesis of (+)-okaramine C is described. Our previously described selenocyclisation-oxidative deselenation sequence was used to establish a 3a-hydroxy-pyrrolo[2,3- b]indole core, which was modified by selective epimerisation to the common pyrrolo[2,3- b]indole of the okaramines. See: A Concise Total Synthesis of (+) Okaramine C, E. Cleator, P.R. Hewitt and S.V. Ley, Org. Biomol. Chem., 2004, 2, 2415-2417.

Histone Deacetylase Inhibitor  The polymer-assisted solution phase synthesis (PASP) of an array of histone deacetylase (HDAc) inhibitors is described. HDAc inhibitors have considerable potential as new anti-proliferative agents. Selected compounds were shown to inhibit both human endothelial cell proliferation, and the formation of tubules (neovascularisation) in an in vitro model of angiogenesis. See: Polymer-Assisted Multistep Solution Phase Synthesis and Biological Screening of Histone Deacetylase Inhibitors A. Bapna, M. Ladlow, E. Vickerstaff, B.H. Warrington, T-P. Fan and S.V. Ley, Org. Biomol. Chem., 2004, 2, 611-620.

2003

(–)-Gloeosporone  The synthesis of the germination self-inhibitor (‚àí)-gloeosporone is reported. The embedded 1,7-diol motif in the product is constructed by an ironcarbonyl tether controlled Mukaiyama aldol reaction. The key step in the synthesis is the reductive removal of the ligating iron species by treatment of an acetoxycomplex 6 with lithium naphthalene. See: Synthesis of (-)-Gloeosporone, a Fungal Autoinhibitor of Spore Germination using a π-Allyltricarbonyliron Lactone Complex as a Templating Architecture for 1,7-Diol Construction E. Cleator, J. Harter, C.J. Hollowood and S.V. Ley, Org. Biomol. Chem., 2003, 1, 3263 and The Synthesis of (-)-Gloeosporone, a Potent Fungal Autoinhibitor of Spore Germination using a pi-Allytricabonyl iron Lactone Complex and a New Reductive Decomplexation Procedure for the Installation of the Embedded 1,7-Diol Component of the Natural Product E. Cleator, J. Harter and S.V. Ley, Heterocycles, 2004, 62, 619-633.

(–)-Norarmepavine  We describe, in full, the enantioselective synthesis of the tetrahydrobenzylisoquinoline alkaloid (-)-norarmepavine (1) in 77% e.e. This compound was prepared using solid-supported reagents and scavengers in multi-step sequences of reactions to give materials that required no conventional purification at the individual steps. See: Enantioselective Synthesis of the Tetrahydrobenzylisoquinoline Alkaloid (-)-Norarmepavine using Polymer-Supported Reagents I.R. Baxendale, T.D. Davidson S.V. Ley and R.H. Perni, Heterocycles, 2003, 60, 2707-2715.

Herbarumin II  The total synthesis of phytotoxic nonenolide herbarumin II has been achieved by implementation of butane diacetal (BDA)-desymmetrised glycolate building blocks. Three of the four stereogenic centres present in the key coupling fragments were generated from both enantiomeric forms of the BDA building block in highly diastereoselective alkylation and aldol reactions. See: The Use of Butane Diacetals of Glycolic Acid as Precursors for the Synthesis of the Phytotoxic Camodulin Inhibitor Herbarumin II E. Diez, D.J. Dixon, S.V. Ley, A. Polara and F. Rodríguez, Helv.Chim. Acta., 2003, 86, 3717-3729 and Total Synthesis of the Phytotoxic Agent Herbarumin II using Butane Diacetals of Glycolic Acid as Building Blocks E. Diez, D.J. Dixon, S.V. Ley, A. Polara and F. Rodriguez, Synlett., 2003, 1186.

Polysphorin, oxosurinamensin, rhaphidecursinol B and (–)-surinamensin  A general asymmetric route to both enantiomers of polysphorin has been developed. The route utilizes polymer-supported reagents, catalysts and scavengers to minimise the need for aqueous work-up and chromatography. This includes application of a method to scavenge 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and a “catch-and-release” procedure to extract the resultant diol following Sharpless asymmetric dihydroxylation. A novel enzymatic selective protection and investigations of a new asymmetric dihydroxylation using microencapsulated osmium tetroxide were also investigated during the course of this study. See: The Synthesis of the Anti-Malarial Natural Product Polysphorin and Analogues using Polymer-Supported Reagents and Scavengers A-L. Lee and S.V. Ley, Org. Biomol. Chem., 2003, 1, 3957.

Epothilone C and A  A total synthesis of epothilone C with concomitant formal synthesis of epothilone A is described, using immobilized reagents and scavengers to effect multistep synthetic transformations and purifications. See:  A Total Synthesis of Epothilones using Solid-Supported Reagents and Scavengers R.I. Storer, T. Takemoto, P.S. Jackson and S.V. Ley, Angew. Chem. Int. Edn., 2003, 42, 2521 and Multi-step Application of Immobilized Reagents and Scavengers: A Total Synthesis of Epothilone C R.I. Storer, T. Takemoto, P.S. Jackson, D.S. Brown, I.R. Baxendale and S.V. Ley, Chem. Eur. J., 2004, 10, 2529-2547.

2002

Argyrine B  The total synthesis of Argyrin B is presented using a synthetic plan that is convergent and flexible and conserves the stereogenic centers. The unusual amino acid 4-methoxy tryptophan was obtained via an enzymatic resolution. Cyclization followed by oxidative elimination of the phenylseleno cysteine to the sensitive dehydroalanine afforded synthetic Argyrin B. See: Total Synthesis of the Cyclic Peptide Argyrine B S.V. Ley and A. Priour, Eur. J. Org. Chem., 2002, 3995 and Total Synthesis of the Cyclic Heptapeptide Argyrin B: A New Potent Inhibitor of T-Cell Independent Antibody Formation S.V. Ley, A. Priour and C. Heusser, Org. Lett., 2002, 4, 711.

(+)-Plicamine  In this report we describe in full the total synthesis of the amaryllidaceae alkaloid (+)-plicamine 1 including a model compound study. In both cases the compounds were prepared using solid-supported reagents and scavengers in multi-step sequences of reactions to give materials which required no conventional purification but could be carried on to the next synthetic step. See: Total Synthesis of the Amaryllidaceae Alkaloid (+)-Plicamine and its Unnatural Enantiomer by using Solid-Supported Reagents and Scaveners in a Multistep sequence of Reactions I.R. Baxendale, S.V. Ley and C. Piutti, Angew. Chem. Int. Edn., 2002, 41, 2194 and Total Synthesis of the Amaryllidacea Alkaloid (+)-Plicamine using Solid-Supported Reagents I.R. Baxendale, S.V. Ley, C. Piutti and M. Nesi, Tetrahedron, 2002, 58, 6285.

Taurospongin A  The total synthesis of taurospongin A by two new approaches has been achieved where pi-allyltricarbonyliron lactone complexes have been used to control highly stereoselective additions of the nucleophiles to a carbonyl unit located in the side chain of these complexes. See: Synthesis of Taurospongin A: A Potent Inhibitor of DNA Polymerase and HIV Reverse Transcriptase using p-Allyltricarbonyliron Lactone Complexes C.J. Hollowood, S.V. Ley and S.Yamanoi, J. Chem. Soc., Chem. Common. 2002, 1624 and Use of π-Allyltricarbonyliron Lactone Complexes in the Synthesis of Taurospongin A: A Potent Inhibitor of DNA Polymerase β and HIV Reverse Transcriptase C.J. Hollowood, S.V. Ley and S. Yamanoi, Org. Biomol. Chem. 2003, 1, 1664.

Polycephalin C  The total synthesis of the polyenoyltetramic acid polycephalin C is described. Key steps of the synthesis include a double Swern oxidation, double Takai reaction and a double Stille reaction. In addition, the absolute stereochemistry of the ring junction has been determined by synthesis of both isomers and comparison of their CD spectra with natural polycephalin C. See: Total Synthesis of Polycephalin C and Determination of the Absolute Configurations at the 3”, 4” Ring Junction D.A. Longbottom, A.J. Morrison, D.J. Dixon and S.V. Ley, Angew. Chem., Int. Edn., 2002, 41, 2786 and Total Synthesis of the Polyenoyltetramic Acid Polycephalin C D.A. Longbottom, A.J. Morrison, D.J. Dixon and S.V. Ley, Tetrahedron, 2003, 59, 6955.

Nornicotine and nicotine  The sequential use of solid-supported reagents and scavengers has led to an efficient synthesis of the natural products nornicotine, nicotine and further fuctionalised derivatives. Also reported is a diastereoselective route to both enantiomers of nicotine. See: Synthesis of Nornicotine, Nicotine and Other Functionalised Derivatives Using Solid-Supported Reagents and Scavengers I.R. Baxendale, G. Brusotti, M. Matsuoka and S.V. Ley, J. Chem. Soc., Perkin Trans. 1, 2002, 143.

Didemniserinolipid B  En route to proving the absolute and relative stereochemistry, through synthesis, of (+)-didemniserinolipid B, the first natural serinolipid isolated from a tunicate Didemnum sp., it was discovered that the isolated natural product was in fact the 31-sulfate configured 8R,9R,10R,13S,30S. This structural reassignment was only possible after the development of a microwave-assisted method for the sulfation of unreactive hydroxyl groups. See: Synthesis, Structure Revision and Absolute Configuration of Didemniserinolipid B, a Serinol Marine Natural Product from a Tunicate Didemnum sp., H. Kiyota, D.J. Dixon, C.K. Luscombe, S. Hettstedt and S.V. Ley, Org. Lett., 2002, 4, 3223.

2001

Carpanone  Polymer-supported reagents have been applied to the synthesis of the natural product carpanone resulting in a clean and efficient synthesis without the requirement for conventional purification techniques. A new polymer-supported transition metal isomerisation catalyst is also reported. See: A Concise Synthesis of the Natural Product Carpanone using Solid-Supported Reagents and Scavengers I.R. Baxendale, A.-L. Lee and S.V. Ley, Synlett, 2001, 1482 and A Concise Synthesis of Carpanone using Solid-Supported Reagents and Scavengers I.R. Baxendale, A-L. Lee and S.V. Ley, J. Chem. Soc., Perkin Trans. 1, 2002, 1850.

2000

Equisetin  A short stereoselective synthesis of the Fusarium toxin equisetin, a potent inhibitor of HIV-1 integrase enzyme is described, using as the key step a stereoselective intramolecular Diels–Alder reaction of a fully conjugated E,E,E-triene with a trisubstituted unsaturated β-ketothioester. See: A Short Stereoselective Total Synthesis of the Fusarium Toxin Equisetin L. T. Burke, D.J. Dixon, S.V. Ley and F. Rodríguez, Org. Lett., 2000, 2, 3611 and Total Synthesis of the Fusarium Toxin Equisetin L.T. Burke, D.J. Dixon, S.V. Ley and F. Rodríguez, Org. Biomol. Chem., 2005, 3, 274-280.

CMI-977  A short and efficient synthesis of the potent 5-lipoxygenase inhibitor CMI-977 is described using as the key step a stereoselective anomeric oxygen to carbon rearrangement of an alkynyl stannane tetrahydrofuranyl ether derivative mediated by boron trifluoride ether ate. See: A Short and Efficient, Stereoselective Synthesis of the Potent, Orally Active Anti-Histamine Agent CMI-977 D.J. Dixon, S.V. Ley, D.J. Reynolds and M. Chorgharde, Syn. Commun., 2000, 30, 1955.

Muricatetrocin  The total synthesis of the potential antitumour agent muricatetrocin C has provided an ideal stage for the exploitation and development of new chemistry. A convergent synthetic strategy has been realised incorporating three distinct pieces of methodology, these include a highly diastereoselective hetero-Diels–Alder reaction to construct the butenolide terminus, an oxygen to carbon rearrangement to install the trans-2,5-disubstituted tetrahydrofuran ring and a spatial desymmetrisation process to afford the anti-diol unit. See: The Total Synthesis of the Annonaceous Acetogenin Muricatetrocin C D.J. Dixon, S.V. Ley and D. J. Reynolds, Angew. Chem., Int. Ed. 2000, 39, 3622 and The Total Synthesis of the Annonaceous Acetogenin Muricatetrocin C, D.J. Dixon, S.V. Ley, D.J. Reynolds, Chem. Eur. J. 2002, 8, 1621.

(+)-Aspicilin  A short and efficient synthesis of the polyhydroxylated macrolactone (+)-aspicilin using a stereoselective lithium perchlorate mediated addition of allyltributyltin to the equatorially disposed carboxaldehyde (derived from (R‘,R‘,R,S) butane diacetal protected butane tetrol as the key step is described. Terminal group manipulation and Masamune−Roush olefination using a phosphonate ester followed by macrocyclization via ring closing metathesis afforded the natural product after partial hydrogenation and global deprotection. See:  A Short and Efficient Steroselective Synthesis of the Polyhydroxylated Macrolactone (+)-Aspicilin D.J. Dixon, A.C. Foster and S.V. Ley, Org. Lett., 2000, 2, 123 and The Total Synthesis of (+)-Aspicilin using 2,3-Butane Diacetal Protected Butane Tetrols via a Chiral Memory Protocol D.J. Dixon, A.C. Foster and S.V. Ley, Can. J. Chem., 2001, 79, 1668.

α– and β-Zearalenol  A highly stereoselective synthesis of the natural products α- and β-zearalenol 1 and 2 has been achieved using π-allyltricarbonyliron lactone complexes to control the 1,5-stereochemical relationship of the oxygen functionalities found in these resorcylic macrolides. See: The Use of π-Allyltricarbonyliron Lactone Complexes in the Synthesis of the Resorcylic Macrolides α- and β- Zearalenol S.V. Ley and S. Burckhardt, J. Chem. Soc., Perkin Trans. 1, 2000, 3028 and The Use of π-Allyltricarbonyliron Lactone Complexes in the Synthesis of the Resorcyclic Macrolides and Zearalenol S. Burckhardt and S.V. Ley, J. Chem. Soc., Perkin Trans. 1, 2002, 874.

L-Galactosylated SLe(x) Undecasaccharide  Galactosylated dimeric sialyl Lewis X (SLe^x) has been prepared employing a combination of chemical and enzymatic synthetic methods. GDP-l-galactose has been chemically synthesised. Enzymatic transfer of l-galactose onto the acceptor (Sia-α2,3-Gal-β1,4-GlcNAc-β1,3/6)₂-Man-α1-OMe was achieved using the human α-1,3-fucosyltransferase V. See: Chemoenzymatic Synthesis of L-Galactosylated Dimeric Sialyl Lewis Structures Employing a-1,3-Fucosyltransferase V, A. Düffels, L.G. Green, R. Lenz, S.V. Ley, S. P. Vincent and C-H. Wong, Bioorg. Med. Chem., 2000, 8, 2519.

(±)-Epibatidine  A ten-step synthesis of (±)-epibatidine is described, using an organised array of polymer supported reagents and sequestering agents in a successive manner. No chromatographic purification steps are required to afford the product in >90% purity. See: Synthesis of the potent analgesic compound (±)-epibatidine using an orchestrated multi-step sequence of polymer supported reagents J. Habermann, S.V. Ley, J.S. Scott, J. Chem. Soc., Perkin Trans. 1, 1999, 1253-1256.

(±)-Oxomaritidine and (±)-epimaritidine  The concise synthesis of the alkaloids (±)-oxomaritidine and (±)-epimaritidine in high yield are described, which employs a sequence of five- and six-step reactions respectively, using solely polymer supported reagents in an orchestrated successive manner. See: Synthesis of the alkaloids (±)-oxomaritidine and (±)-epimaritidine using an orchestrated multi-step sequence of polymer supported reagents S.V. Ley, O. Schucht, A.W. Thomas, P.J. Murray, J. Chem. Soc., Perkin Trans. 1, 1999, 1251-1252 and A Flow Process for the Multi-Step Synthesis of the Alkaloid Natural Product Oxomaritidine: A New Paradigm for Molecular Assembly I.R. Baxendale, J. Deeley, C.M. Griffiths-Jones, S.V. Ley, S. Saaby and G. Tranmer, J. Chem. Soc., Chem. Commun. 2006, 2566-2568.

Erythroskyrine  The first total synthesis of erythroskyrine, a polyenoyltetramic acid mycotoxin and principal pigment of Penicillium Islandicum Sopp., is described using a palladium(II) catalysed oxycarbonylation to create the furan-derived bicyclic portion and the phosphonate ester to furnish both the polyenoyl chain and the N-methyl(S)-valine derived tetramic acid terminus. See: Total synthesis of the polyenoyl tetramic acid mycotoxin erythroskyrine D.J. Dixon, S.V. Ley, T. Gracza, P. Szolcsanyi, J. Chem. Soc., Perkin Trans. 1 1999, 839-842.

Physarorubinic acid  The total synthesis of physarorubinic acid, a polyenoyltetramic acid plasmoidal pigment from Physarum polycephalum, is described in a series of steps from (E)-3-iodoacrylic acid 6 and employs aminolysis of the pentaene thioester 11 as a key synthetic step. Lacey–Dieckmann cyclisation and subsequent deprotection then affords physarorubinic acid 1 in high yield and purity. See: Total synthesis of the plasmoidal pigment physarorubinic acid, a polyenoyl tetramic acid D.J. Dixon, S.V. Ley, D.A. Longbottom, J. Chem. Soc., Perkin Trans. 1 1999, 2231-2232.

Glycodelin glycans  The concise synthesis of nine diantennary oligosaccharides by chemical and chemoenzymatic protocols is presented. The compounds display Lewis X, Lewis Y, sialyl Lewis X and T-antigen epitopes supported on a 3,6-branched trimannose core. They derive from the glycans of the human glycoproteins Glycodelin-A and Glycodelin-S believed to be involved in regiospecific suppression of the female immune system. See: Synthesis of glycans from the glycodelins: two undeca-, two deca-, three nona-, and octa- and a heptasaccharide, D Depré, A. Düffels, L.G. Green, R. Lenz, S.V.Ley, C-H. Wong, Chem. Eur. J. 1999, 5, 3326-3340.

1233A  The total synthesis of the beta-lactone cholesterol synthase inhibitor 1233A (1) is described employing the oxidative decomplexation of a (π-allyl)tricarbonyliron lactone (2) as the key synthetic step. See: Total synthesis of the cholesterol biosynthesis synthase inhibitor 1233A via a π-Allyltricarbonyliron Lactone Complex S.V. Ley, R.W. Bates, E. Fernández-Megía, S.V. Ley, K. Rück-Braun, D.M.G. Tilbrook, J. Chem. Soc., Perkin Trans. 1 1999, 1917-1926.

1998

Okadaic acid  The total synthesis of the protein phosphatase inhibitor okadaic acid 1 is reported using a convergent coupling strategy of three components, all of which may be prepared using chemistry developed in our laboratories. See: Total synthesis of the protein phosphatase inhibitor okadaic acid S.V Ley, A C. Humphries, H. Eick, R. Downham, A.R. Ross, R.J. Boyce, J.B.J. Pavey, J. Pietruszka, J. Chem. Soc., Perkin Trans. 1 1998, 3907-3912.

(+)-Goniodiol  A high-yielding enantioselective total synthesis of the bioactive styryllactone (+)-goniodiol has been realised, starting from readily available (S)-glycidol. A key step is an oxygen-to-carbon rearrangement of a silyl enol ether linked via an anomeric centre, facilitating the rapid and diastereoselective construction of this functionalised system. See: A total synthesis of (+)-Goniodiol using an anomeric oxygen-to-carbon rearrangement D.J. Dixon, S.V. Ley and E.W. Tate, J. Chem. Soc., Perkin Trans. 1 1998, 3125-3126 and A Highly Enantioselective Total Synthesis of (+)-Goniodiol E.W. Tate, D.J. Dixon and S.V. Ley, Org. Biomol. Chem. 2006, 4, 1698-1706.

Glycosylphosphatidylinositol anchor  Six building blocks, six reaction steps: The recently developed innovative methodology facilitated the convergent synthesis of the complex oligosaccharide core 1 (shown here with protecting groups) for the total synthesis of a glycosylphosphatidylinositol (GPI) anchor. The key factors are the tuning of the reactivity of the building blocks by using 1,2-diacetal protecting groups and the desymmetrization of glycerol and myo-inositol with a chiral bis(dihydropyran). See: Rapid assembly of oligosaccharides: total synthesis of a glycosylphosphatidylinositol anchor of Trypanosoma brucei D.K. Baeschlin, A. Chaperon, V. Charbonneau, L.G. Green, S.V. Ley, U. Lücking, E. Walther, Angew. Chem., Int. Ed. Engl., 1998, 3423-3428 and 1,2-Diacetals in Synthesis: Total Synthesis of a Glycosylphosphatidylinositol Anchor of Trypanosoma brucei D.K. Baeschlin, A.R. Chaperon, L.G. Green, M.G. Hahn, S.J. Ince, S.V. Ley, Chem. Eur.J., 2000, 6, 172.

1997

(+)-D-Conduritol B  Using (2S,2’S)-2,2′-diphenyl-6,6′-bi(3,4-dihydro-2 H-pyran) to effect a simultaneous protection–resolution of a myo-inositol derivative, a new synthesis of (+)-D-conduritol B has been achieved. See: Dispiroketals in synthesis. Part 23. A new route to (+)-D-conduritol B from myo-inositol J.E. Innes, P.J. Edwards, S.V. Ley, J. Chem. Soc., Perkin Trans. 1 1997, 795-796.

High Mannose Type Nonasaccharide  The high-mannose nonasaccharide is part of the glycoprotein gp 120 of the viral coat of HIV-1. The mannan portion of this triantennary glycan was prepared by a number of consecutive glycosidation steps without the need for any protecting-group manipulation. This was achieved by carefully tuning the reactivity of the glycosyl donors by employing our cyclohexane-1,2-diacetal (CDA) methodology. The method was further extended with one-pot procedures for oligosaccharide synthesis, thus reducing the number of steps to form the protected nonasaccharide from the monosaccharide building blocks to five. See: A new strategy for oligosaccharide assembly exploiting cyclohexane-1,2-diacetal methodology: an efficient synthesis of a high mannose type nonasaccharide P. Grice, S.V. Ley, J. Pietruszka, H.M.I. Osborn, H.W.M. Priepke, S.L. Warriner, Chem. Eur. J. 1997, 3, 431-440 and Synthesis of High-Mannose Type Neoglycolipids Active Targeting of Liposomes to Macrophages for Gene Therapy A. Düffels, L. G. Green, S.V. Ley and A.D. Miller, Chem. Eur. J., 2000, 6, 1416.

1996

Tetronasin  Studies towards the synthesis and biosynthesis of tetronasin, an acyltetronic acid ionophore are described, together with an account of some novel methodology which is more widely applicable for the synthesis of other acyltetronic acids. See: Synthesis and chemistry of the ionophore antibiotic tetronasin S.V. Ley, J.A. Clase, D.J. Mansfield, H.M.I. Osborn, J. Heterocyclic Chem. 1996, 33, 1533-1544 and Synthesis of the acyltetronic and acid ionophore tetronasin (ICI M139603) S.V. Ley, D.S. Brown, J.A. Clase, H.M.I. Osborn, D. Wadsworth, E.S. Stokes, A.J. Fairbanks, J. Chem. Soc., Perkin Trans. 1,1998, 2259-2276.

1995

β-dimorphecolic acid  A highly enantioselective synthesis of beta-dimorphecolic acid 1 is reported. The synthesis features a diastereoselective reduction of the ketone 4, in which the tricarbonyliron lactone tether induces a 1,5 transfer of chirality, followed by a stereoselective decarboxylation to create all the stereochemical elements of 1. Selective oxidation of the primary alcohol in the diol 17 serves to introduce the acid functionality. See: Synthesis of β-dimorphecolic acid exploiting highly stereoselective reduction of side-chain carbonyl group of a π-allyltricarbonyliron lactone complex S.V. Ley and G. Meek, J. Chem. Soc., Chem. Commun. 1995, 1751-1752 and Synthesis of β-dimorphecolic acid exploiting highly  stereoselective reduction of a side-chain carbonyl group in a π-allyltricarbonyliron lactone complex S.V. Ley, G. Meek, J. Chem. Soc. Perkin Trans. 1 1997, 1125-1134.

1994

Immunodominant epitope of group specific polysaccharide of group B Streptococci  The reactivity of sugars in glycosylation reactions can be tuned by the cyclohexane-1,2-diacetal (CDA) protecting group. In the efficient synthesis of trisaccharide 1 from three monosaccharide units, no functional group conversions are necessary between glycosylation steps. See: A Facile One-pot Synthesis of a Trisaccharide Unit from the Common Polysaccharide Antigen of the Group B Streptococci using Cyclohexane-1,2-diacetal Protected Rhamnosides S.V. Ley and H.W.M. Priepke, Angew. Chem., Int. Ed. Engl. 1994, 33, 2292.

1993

(+)-Milbemycin a1  The total synthesis of the antiparasitic spiroketal macrolide (+)-milbemycin a1 is reported, following Julia sulfone anion coupling of the sulfone 3 with a northern hemisphere aldehyde 2 and subsequent functional group elaboration. See: Total synthesis of the spiroketal macrolide (+)-milbemycin a1 S. V. Ley, A. Madin and N. Monck, Tetrahedron Lett. 1993, 34, 7479.

1992

CP-61,405 (routiennocin)  The total synthesis of the spiroketal ionophore antibiotic routiennocin (CP-61,405) employing π-allyltricarbonyl iron lactone complexes is described. These complexes were used as precursors for the preparation of substituted 2-phenylsulphonyl pyrans which, in turn, were coupled with iodoacetonides to afford spiroketals. Elaboration of the spiroketals by tetra-n-propylammonium perruthenate (TPAP) oxidation and coupling with 2-lithio-1-[beta-(trimethylsilyl)ethoxymethyl] pyrrole followed by further oxidation, deprotection, oxidation and benzoxazole formation afforded the natural product. The preparation of the amino phenol fragment necessary for benzoxazole formation involved a novel amination procedure using benzeneselenenic anhydride and hexamethyldisilazane followed by samarium diiodide reduction. See: Total synthesis of ionophore antibiotic CP-61,405 (routiennocin) D. Díez-Martin, N.R. Kotecha, S.V. Ley, S. Mantegani, J.C. Menéndez, H.M. Organ, A.D. White, B.J. Banks, Tetrahedron, 1992, 48, 7899; Total synthesis of the carboxylic acid ionophore antibiotic CP-61,405 (routiennocin): preparation of the inherent spiroketal unit via a reverse coupling process D. Diez-Martin, N.R. Kotecha, S.V. Ley, J.C. Menendez, Synlett, 1992, 399 and Total synthesis of the carboxylic acid ionophore antibiotic CP-61,405 (routiennocin) N.R. Kotecha, S.V. Ley, S. Mantegani, Synlett, 1992, 395.

Pseudo-alpha-d-glucopyranose  Cis-3,5-Cyclohexadiene-1,2-diol, derived from benzene by microbial transformation using Pseudomonas putida, was converted to the enzyme inhibitor pseudo-alpha-D-glucopyranose. See: Microbial oxidation in synthesis: preparation of pseudo-alpha-D-glycopyranose from benzene L. L. Yeung and S.V. Ley, Synlett, 1992, 291.

1991

Norruspoline and ruspolinone  Several 2-phenylsulphonyl-piperidines and -pyrrolidines were prepared from the corresponding N-acyl aminals by treatment with benzenesulphinic acid. On reaction with various carbon nucleophiles these sulphones gave good yields of substitution products. Typical nucleophiles used in these studies were organometallic reagents derived from Grignard reagents and zinc halide together with silyl enol ethers, silyl ketene acetals, allylsilanes and trimethylsilyl cyanide in the presence of a Lewis acid. These methods were employed in the synthesis of two natural product alkaloids; norruspoline and ruspolinone. See: Substitution reactions of 2-phenylsulphonyl-piperidines and -pyrrolidines with carbon nucleophiles: Synthesis of the pyrrolidine alkaloids norruspoline and ruspolinone D.S. Brown, P. Charreau, T. Hansson, S.V. Ley, Tetrahedron, 1991, 47, 1311.

Avermectin B1a  A highly convergent total synthesis of the anthelmintic macrolide avermectin B1a is described. The key features of this synthesis include the introduction of the C(11)–C(15) portion by selective ring opening of a symmetrical 1,4-bis-epoxide followed by reaction with the anion derived from the 3-methyl-2-(1-methylpropyl)-6-phenylsulphonylpyran to afford the ‘northern’ C(11)–C(25) fragment. Coupling of the derived C(11)–C(25) aldehyde unit with a C(1)–C(10)‘southern’ fragment was achieved via a novel deconjugative vinyl sulphone anion sequence. Macrolactonisation and subsequent introduction of the 3,4-double bond gave the aglycone portion. The oleandrosyloleandrose disaccharide was introduced by a novel silver-mediated coupling between the 5-acetylated aglycone and the thiocarbonylimidazolide. Final deacetylation was accomplished using Super-Hydride to give the natural product. See: Total synthesis of the anthelmintic macrolide avermectin B1a S.V. Ley, A. Armstrong, D. Díez-Martín, M.J. Ford, P. Grice, J. Knight, H.C. Kolb, A. Madin, C.A. Marby, S. Mukherjee, A.N. Shaw, A.M.Z. Slawin, S. Vile, A.D. White, D.J. Williams, M.Woods, J. Chem. Soc., Perkin Trans. 1 1991, 667-692 and See: The Champagne Route to Avermectins and Milbemycins in Strategy and Tactics in Organic Synthesis Vol. 3, S.V. Ley and A. Armstrong, T. Lindberg, Ed. Acad. Press, 1991, 273-291.

(–)-Heliotridane and (–)-isoretronecanol  A novel synthesis of the pyrrolizidine alkaloids (-)-heliotridane and (-)-isoretronecanol is described. The key steps involve the conversion of a proline-derived carbamate into the pi-allyltricarbonyliron lactam complex and the exhaustive carbonylation of this to give the pivotal intermediate gamma-lactam. See: Synthesis of the alkaloids (−)-heliotridane and (−)-isoretronecanol via π-allyltricarbonyliron lactam complexes G. Knight and S.V. Ley, Tetrahedron Lett. 1991, 32, 7119.

Agglomerin A and (±)-carolinic acid  A variety of O-methyl-3-acyl tetronates were prepared in good yield from the corresponding acid chlorides via a palladium catalyzed acylation of O-methyl 3-(tri-n-butylstannyl) tetronates. This new synthetic method was then exploited for the total synthesis of the novel antibiotic agglomerin A, as well as the fungal metabolite (±) carolinic acid. See: The total synthesis of agglomerin a and (¬±)-carolinic acid: a general method for the preparation of 3-acyl tetronic acids via direct acylation of o-methyl 3- stannyl tetronates S.V. Ley, M.L. Trudell, D.J. Wadsworth, Tetrahedron, 1991, 47, 8285.

Valilactone  Synthesis of the esterase inhibitor valilactone is reported employing the oxidation of π-allyltricarbonyliron lactone complexes with ceric ammonium nitrate to afford the inherent β-lactone ring. See: Synthesis of the β-lactone esterase inhibitor valilactone using π-allyltricarbonyliron lactone complexes R.W. Bates, R. Fernández-Moro, S.V. Ley, Tetrahedron Lett.1991, 32, 2651 and The use of p-allyltricarbonyliron lactone complexes in the synthesis of b-lactone esterase inhibitor (–)-valilactone R.W. Bates, R. Fernández-Moro and S.V. Ley, Tetrahedron, 1991, 47, 9929.

1990

L-(–)-Oleandrose  L-(-)-Oleandrose (2,6-dideoxy-3-O-methyl-arabino-hexose) was prepared in only three steps from (S)-(-)-methyl lactate and (3-butenylsulphonyl)benzene, without the use of protecting groups. A stereocontrolled reduction and a thermodynamically controlled exchange reaction afforded the required arabino configuration. See: An efficient three step synthesis of L(-)-oleandrose from S(-)-methyl lactate M.J. Ford and S.V. Ley, Synlett, 1990, 771.

(+)-Conduritol F A synthesis of the naturally occurring cyclohexenetetrol (+)-conduritol F and its unnatural antipode has been developed in five steps from benzene using Pseudomonas putida oxidation to introduce the necessary cis-1,2-diol functionality. See: Microbial oxidation in synthesis: concise preparation of (+)-conduritol F from benzene S.V. Ley and A.J. Redgrave, Synlett, 1990, 393.

1989

Inositol-1-phosphate and inositol-1,4,5-trisphosphate  The novel 6-deoxy, 6-deoxy-6-fluoro and 6-deoxy-6-methyl myo-inositol 1,4,5-trisphosphate derivatives were derived from benzene via microbial oxidation to cis-1,2-dihydroxycyclohexa-3,5-diene and conversion through to the key epoxyacetonide. See: Microbial oxidation in synthesis: preparations of 6-deoxy cyclitol analogues of myo-inositol 1,4,5-trisphosphate from benzene S.V. Ley, M. Parra-Alvarez, A.J. Redgrave, F. Sternfeld, Tetrahedron Lett. 1989, 30, 3557-3560.

Milbemycin β₁  The successful sulfone anion stabilised coupling of a monocyclic C-1 to C-10 unit with the “northern hemisphere” C-11 to C-25 fragment of the milbemycins produces a compound which may be further elaborated in fourteen steps to the macrocyclic natural product (+) – milbemycin β₁. See:  Total synthesis of (+)-milbemycin b1 N.J. Anthony, A. Armstrong, S.V. Ley, A. Madin, Tetrahedron Lett. 1989, 30, 3209-3212 and  A highly convergent total synthesis of the spiroacetal macrolide (+)-milbemycin b1 S.V. Ley, N.J. Anthony, A. Armstrong, M.G. Brasca, T. Clarke, C. Greck, P. Grice, A.B. Jones, B. Lygo, A. Madin, R.N. Sheppard, A.M.Z. Slawin, D.J. Williams, Tetrahedron 1989, 45, 7161-7194.

1988

Fuligorubin A  The use of t-butyl-3-oxobutanthioate and t-butyl 4-diethylphosphono-3-oxobutanthioate for the preparation of homologated derivatives suitable for amination in the presence of silver (I) trifluoroacetate to afford the corresponding beta-ketoamides is discussed. In particular Wadsworth-Emmons coupling reactions with various carbonyl compounds gave good yields of E-substituted products. Many of the beta-ketoamides were shown to be suitable precursors for 3-acyltetramic acids using a Dieckmann cyclisation with tetra-n-butyl ammonium fluoride as the cyclising base. These new reactions were applied to the total synthesis of the polyene 3-acyltetramic acid fuligorubin A.  See: Use of t-butyl 4-diethylphosphono-3-oxobutanethioate for tetramic acid synthesis: total synthesis of the plasmodial pigment fuligorubin A S.V. Ley, S.C. Smith and P.R. Woodward, Tetrahedron Lett. 1988, 29, 5829-5832 and Further reactions of t-butyl 3-oxobutanthioate and t-butyl 4-diethylphosphono-3-oxobutanthioate: carbonyl coupling reactions, amination, use in the preparation of the 3-aceyltetramic acids and application to the total synthesis of fuligorubin A S.V. Ley, S.C. Smith, P.R. Woodward, Tetrahedron, 1992, 48, 1145.

1987

(+)-and (-)-Pinitol  Microbial oxidation with Pseudomonas putida of benzene affords cis-1,2-dihydroxycyclohexa-3,5-diene which may be converted in five steps and 49% overall yield to (±)-pinitol. Resolution of an intermediate alcohol with menthoxyacetyl chloride provides optically pure materials which may be independently transformed to (+)- or (-)-pinitol. Demethylation conditions for pinitol together with further reactions of related compounds were investigated. See: Microbial oxidation in synthesis: a six step preparation of (+)-pinitol from benzene S.V. Ley, S. Taylor, F. Sternfeld, Tetrahedron Lett. 1987, 28, 225-226 and Microbial oxidation in synthesis: preparation of (+)-and (–)-pinitol from benzene S.V. Ley and F. Sternfeld, Tetrahedron 1989, 45, 3463-3476.

Carolic, carlosic and carlic acids  Dianions generated from S-t-butyl acetothioacetate were alkylated with a variety of electrophiles at the gamma-carbon centre. Treatment of the alkylated products with 2-hydroxy esters in the presence of silver(I) salts gave transesterified acetoacetate derivatives in good yields. These acetoacetates were cyclised efficiently to acyltetronic acid derivatives using tetrabutyl ammonium fluoride in THF solution at room temperature. By an appropriate choice of substituents the total syntheses of the fungal metabolite natural products carlosic, carolic, and carlic acids have been achieved. See: Preparation of acyltetronic acids using t-butyl acetothioacetate: total synthesis of the fungal metabolites carolic, carlosic and carlic acids P.M. Booth, C.M.J. Fox, S.V. Ley, J. Chem. Soc., Perkin Trans. 1 1987, 121-129.

1986

Indolactam V  A synthesis of the macrolactam tumour promoter indolactam V is described in 11 steps from 4-aminoindole. See: Synthetic approaches to the teleocidin-related tumour promoters: a total synthesis of indolactam V S.E. de Laszlo, S.V. Ley and R.A. Porter, J. Chem. Soc., Chem. Commun. 1986, 344-346.

Pheromones from Dacus oleae and Paravespula vulgaris  Reaction of 3,4-dihydro-2H-pyran or 2-methoxytetrahydropyran with benzenesulphinic acid gave 2-benzenesulphonyl tetrahydropyran. Deprotonation followed by alkylation with carbonyl compounds or halides gave cyclic enol ether addition products by spontaneous elimination of benzenesulfinic acid. Interception of the initial addition products with aldehydes by reductive desulfonylation to give alkylated tetrahydropyran derivatives proeeeded in moderate yield using sodium naphthalenide. Several of the cystic enol ether addition products were further converted to spiroketals including syntheses of natural product pheromones from Dacus oleae and Paravespula vulgarise. See: Alkylation reactions of anions derived from 2-benzenesulphonyl tetrahydropyran and their application to spiroketal synthesis S.V. Ley, B. Lygo, F. Sternfeld, A. Wonnacott, Tetrahedron 1986, 42, 4333-4342.

1985

Parasorbic acid, carpenter bee pheromone malyngolide  Preparation of three delta-lactonic natural products, parasorbic acid, the carpenter bee pheromone and malyngolide has been achieved from π-allyltricarbonyliron lactone complexes as the key synthetic intermediates. See: Natural product synthesis using π-allyltricarbonyliron lactone complexes: synthesis of parasorbic acid, the carpenter bee pheromone and malyngolide A.M. Horton and S.V. Ley, J. Organometallic Chem. 1985, 285, C17-C20.

Norcardicin A  A short five-step synthesis, in 79% overall yield, of (–)-3-Oxo-1 -[(p-benzyloxyphenyl) benzyloxy-carbonylmethyl]azetidin-2-one, a precursor for nocardicin synthesis has been developed from isoprene monoepoxide. The key steps of the procedure rely on the efficient transformation of 2–4-n3-(1-formyloxy-2-methylbut-3-en-2-ylato)tricarbonyliron into the corresponding diastereoisomeric lactam complexes using D-(–)-benzyl-(p-benzyloxyphenyl)glycinate and ZnCl2·TMEDA and their oxidation with CAN to 3-isopropenylazetidinone derivatives. See: Use of π-allyltricarbonyliron lactam complexes in the preparation of nocardicin derivatives: synthesis of (–)-3-oxo-1-[(p-benzyloxyphenyl)-benzyloxycarbonylmethyl]azetidin-2-one S.T. Hodgson, D.M. Hollinshead, S.V. Ley, C.M.R. Low, D.J. Williams. J. Chem. Soc., Perkin Trans. 1 1985, 2375-2381.

Nonacetic acid   See: Synthetic applications of ynes, enes and ones; organoselenium-mediated cyclisation reactions in organic synthesis S.V. Ley, Chem. and Ind. 1985, 101-106.

(+)-Thienamycin  The pi-allyltricarbonyliron lactone complex, formed by reaction of E-1,2-epoxy-2-methyl-6,6-dimethoxyhex-3-ene with co-ordinatively unsaturated iron carbonyl species, was reacted with benzylamine to give a lactam complex by an Sn’-like mechanism. This complex upon oxidation with Ce(IV) afforded cis-3-isopropenyl-4-[(2′,2′-dimethoxy)ethyl]-N-benzylazetidin-2-one which was chemically modified into trans-3-(1′-hydroxyethyl)-4-[(2′,2-dimethoxy)ethyl] azetidin-2-one, a key intermediate previously used in the synthesis of the antibiotic thienamycin. Similar reaction with (S)-(-)-alpha-methylbenzylamine afforded a separable mixture of diastereoisomeric iron lactam complexes. These complexes could be individually converted to the corresponding optically active ?-lactam derivatives and, hence, are precursors for the synthesis of either natural (+)-thienamycin or unnatural (-)-thienamycin. See:  Synthesis of the β-lactam antibiotic (+)-thienamycin via an intermediate π-allyltricarbonyliron lactone complex S.T. Hodgson, D.M. Hollinshead, S.V. Ley, Tetrahedron 1985, 41, 5871-5878.

1984

Indanomycin  The total synthesis of the ionophore antibiotic X-14547A (indanomycin) is described by using a convergent strategy. 2-Ethylvalerolactone was converted into ethyl (E,E,E)-11-[[(beta-3-methoxy)ethoxy]methoxy]-6-ethyl- 2,7,9-undecatrienoate in eight steps. Intramolecular Diels-Alder reaction of 8 at 110 oC followed by deprotection to give the racemic tricyclic lactone proceeded with very high stereoselectivity (>90%)and in 38% overall yield from 2-ethylvalerolactone. The tricyclic lactone was resolved via the diastereomeric amides to provide the optically pure lactones. Reaction with 1-pyrrolyl magnesium bromide gave the pyrrolyl carbonyl derivative whose structure was determined by X-ray crystallography. Alternatively, the optically pure lactone was reacted with 2-lithio-14[(trimethylsilyl)ethoxy]methyl]pyrrole to give the corresponding N-SEM protected pyrrolyl carbonyl. Elaboration afforded the phenylsulfone which constituted an appropriate right-hand fragment suitable for later coupling. Synthesis of the left-hand tetrahydropyranyl-unsaturatedaldehyde was achieved by using levoglucosan(1,6-anhydroglucopyranose) as the starting material. Coupling with the lithio anion followed by trapping with benzoyl chloride gave the benzoyloxy phenyl sulfones. Reduction of these with sodium amalgam stereoselectively afforded the E,E-diene. The synthesis was completed by deprotection and hydrolysis to afford the antibiotic X-14547A (indanomycin). See: Total synthesis of the ionophore antibiotic X-14547A (indanomycin) M.P. Edwards, S.V. Ley, S.G. Lister, B.D. Palmer, D.J. Williams, J. Org. Chem. 1984, 49, 3503-3516 and Novel rearrangement of the ionophore antibiotic X-14547 (indanomycin) and related derivatives induced by lithium tetrafluoroborate M.P. Edwards and S.V. Ley, J. Chem. Soc., Perkin Trans. 1 1984, 1761-1763.

(2S,8R)-8-methyl-2-phenyl-1,7-dioxaspiro[5.5]undecan-4(R)-ol  Alkenyl hydroxyketones undergo cyclisation via their hemiacetal form, in the presence of N-phenylselenophthalimide (NPSP) and a Lewis acid, to give the corresponding phenylseleno-substituted spiroacetals. Using this methodology the synthesis of trans- and cis-2-methyl-1,6-dioxaspiro-[4.4]nonane, trans- and cis-2-ethyl-1,6-dioxaspiro[4,4]nonane (chalcogran), trans- and cis-2-methyl-1,6-dioxaspiro[4,5]decane, trans-7-methyl-1,6-dioxaspiro[4.5]decane, trans-2-methyl-1,7-dioxaspiro[5.5]undecane, and (2S,8R)-8-methyl-2-phenyl-1,7-dioxaspiro[5.5]undecane-4-one has been achieved, after reductive removal of selenium using Raney-nickel in diethyl ether. Compound is the principal aggregation pheromone from Pityogenes chalcographus(L), whilst compounds (3) and (4) constitute the pheromone components of the common wasp, Paravespula vulgaris. The structure of the spiroacetal (6) was determined as a result of X-ray crystallography of a later derivative, obtained by sodium borohydride reduction of the spiroacetal. See: Synthesis of spiroacetals using organoselenium mediated cyclisation reactions, x-ray molecular structure of (2S, 8R)-8-methyl-2-phenyl-1,7-dioxaspiro-[5.5]undecan-4(R)-ol A.M. Doherty, S.V. Ley, B. Lygo, D.J. Williams, J. Chem. Soc., Perkin Trans. 1 1984, 1371-1377.

1983

Ajugarin I  The first total synthesis of the polyoxygenated diterpene insect antifeedant ajugarin I has been achieved by a route which involves a new method for the construction of 3-substituted-delta-2-butenolides. See: The total synthesis of the clerodane diterpene insect antifeedant, ajugarin I S.V. Ley, N.S. Simpkins, A.J. Whittle, J. Chem. Soc., Chem. Commun. 1983, 503-505 and Total synthesis of the insect antifeedant ajugarin I and degradation studies of related clerodane diterpenes P.S. Jones, S.V. Ley, N.S. Simpkins, A.J. Whittle, Tetrahedron 1986, 42, 6519-6534.

Isodrimeninol, drimenin and danilol  The stereospecific preparation of various 1-vinyl-2,6,6-trimethylcyclohex-1-enes (6) as potential diene precursors in the Diels-Alder reaction with dimethyl acetylenedicarboxylate have been investigated. The reaction of the parent diene (6a) with dimethyl acetylenedicarboxylate affords an adduct (18) in 94% yield. This species was reductively isomerised using 10%Pd/C/H2 and a mineral acid to give a trans- fused decalin diester (19). Reduction of (19) with lithium aluminium hydride afforded Il4,4a,5,6,8,8a- octahydro-5,8,8a-trimethyl-l P14aa,8a-naphthalene-l,2-dimethanol(24) a key starting material for the highly efficient syntheses of five drimane sesquiterpene natural products, cinnamolide (1), polygodial (2), isodrimeninol (3), drimenin (4), and warburganal (5). Microbial oxidation reactions using C. elegans or A. niger of (2), (24), and (1) gave good yields of the corresponding 3p-hydroxy derivatives, (30), (31), and (32). Several other unusually substituted drimane derivatives are reported. See: The Diels-Alder route to drimane related sesquiterpenes; synthesis of cinnamolide, polygodial, isodrimeninol, drimenin, and warburganal D.M. Hollinshead, S.C. Howell, S.V. Ley, M. Mahon, N.M. Ratcliffe, P.A. Worthington, J. Chem. Soc., Perkin Trans. 1 1983, 1579-1589.

1982

Hirsutene A short synthesis of the sesquiterpene hirsuteness has developed in which the key step involved intramolecular cyclization of a β-oxoester to an alkene using N-phenylselenophthalimide and tin terrachloride. See: A short synthesis of (+/-)-hirsutene involving the use of an organoselenium mediated cyclization reaction S.V. Ley and P. J. Murray, J. Chem. Soc., Chem. Commun. 1982, 1252-1253 and Total synthesis of the sesquiterpene hirsutene using an organoselenium-mediated cyclisation reaction S.V. Ley, P.J. Murray, B.D. Palmer, Tetrahedron 1985, 41, 4765-4769.

Massoialactone  A variety of tricarbonyliron lactone complexes undergo thermal decomposition upon warming in deoxygenated solvents to give products arising from decarbonylation, decarboxylation, and rearrangement pathways. The products of the reactions were characterised by spectroscopic or X-ray crystallographic methods, or in some cases, by independent synthesis. Mechanisms to account for the various transformations are also proposed (massoialactone). See: Thermal rearrangement reactions of tricarbonyliron lactone complexes G.D. Annis, S.V. Ley, C.R. Self, R. Sivaramakrishnan, D.J. Williams, J. Chem. Soc., Perkin Trans. 1 1982, 1355-1361.

(cis-6-Methyltetrahydropyran-2-yl) acetic acid  A short stereospecific synthesis of (cis-6-methyltetrahydropyran-2-yl)acetic acid has been achieved from readily available starting materials using a novel organoselenium-mediated cyclization of alkenyl-substituted β-oxoesters. See: Synthesis of (cis-6-methyltetrahydropyran-2-yl) acetic acid involving the use of an organoselenium mediated cyclization reaction S.V. Ley, B. Lygo, H. Molines, J.A. Morton, J. Chem. Soc., Chem. Commun. 1982, 1251-1252; Synthesis of (+/-)cis-6-methyltetrahydropyran-2-yl acetic acid a natural product from Viverra civetta using organoselenium-mediated cyclisation reactions S.V. Ley, B. Lygo, H. Molines, J. Chem. Soc., Perkin Trans. 1, 1984, 2403-2405 and Diastereoselective Oxygen to Carbon Rearragements of Anomerically Linked Enol Ethers and the Total Synthesis of (+)-S,S-(cis-6-Methyltetrahydropyran-2-yl)acetic Acid a Component of Civet D.J. Dixon, S.V. Ley and E.W. Tate, J. Chem. Soc., Perkin Trans. 1, 2000, 2385.

Methyl-1,6-dioxaspiro[4,5]decane  Three naturally occurring methyl-1,6-dioxaspiro[4.5]decanes have been prepared in good yield using organoselenium mediated reactions during the crucial cyclization process. See: Synthesis of methyl-1,6-dioxaspiro[4,5]decanes using organoselenium mediated cyclisation reactions S.V. Ley and B. Lygo, Tetrahedron Lett 1982, 23, 4625-4628 and Alkylation reactions of anions derived from 2-benzenesulphonyl tetrahydropyran and their application to spiroketal synthesis S.V. Ley, B. Lygo, F. Sternfeld, A. Wonnacott, Tetrahedron 1986, 42, 4333-4342.

1981

Cinnamolide and polygodial  Starting from 2,6,6-trimethyl-1-vinylcyclohex-1-ene a short synthesis of the sesquiterpenes cinnamolide and polygodial has been achieved with 60% and 57% overall yields, respectively. Synthesis of cinnamolide and polygodial S.C. Howell, S.V. Ley, M. Mahon, P.A. Worthington, J. Chem. Soc., Chem. Commun. 1981, 507-508 and The Diels-Alder route to drimane related sesquiterpenes; synthesis of cinnamolide, polygodial, isodrimeninol, drimenin, and warburganal D.M. Hollinshead, S.C. Howell, S.V. Ley, M. Mahon, N.M. Ratcliffe, P.A. Worthington, J. Chem. Soc., Perkin Trans. 1 1983, 1579-1589.

Euryfuran, confertifolin and valdiviolide  Trans-3,4,4a,5,6,7,8,8a-Octahydro-5,5,8a-trimethylnaphthalene-1 (2H)-one was converted into the drimane sesquiterpene euryfuran in 59% yield. Euryfuran was then used as a starting material for the synthesis of two other drimane natural products, confertifolin and valdiviolide. The preparation of valdiviolide constitutes the first total synthesis of this molecule. See: Synthesis of euryfuran, valdiviolide and confertifolin S.V. Ley and M. Mahon, Tetrahedron Lett. 1981, 22, 4747-4750 and Synthesis of the drimane-related sesquiterpenes euryfuran, confertifolin and valdiviolide S.V. Ley and M. Mahon, J. Chem. Soc. Perkin Trans. 1 1983, 1379-1381.

Warburganal  From readily available starting materials a short stereospecific synthesis of the biologically active molecule warburganal has been achieved in 20% overall yield. See: Synthesis of (+/-)-warburganal S.V. Ley and M. Mahon, Tetrahedron Lett. 1981, 22, 3909-3912 and The Diels-Alder route to drimane related sesquiterpenes; synthesis of cinnamolide, polygodial, isodrimeninol, drimenin, and warburganal D.M. Hollinshead, S.C. Howell, S.V. Ley, M. Mahon, N.M. Ratcliffe, P.A. Worthington, J. Chem. Soc., Perkin Trans. 1 1983, 1579-1589.