• Continuous flow synthesis enabling reaction discovery (2024)
• The Evolution of Flow Chemistry: An Opinion on Factors Driving Innovation (2023)
• Process Intensification: From Green Chemistry to Continuous Processing in Sustainable Organic Synthesis: Tools and Strategies (2021 - Print ISBN978-1-83916-203-9; ePub eISBN978-1-83916-485-9).
• Formation and Utility of Reactive Ketene Intermediates Under Continuous Flow Conditions (2021)
• Living with our machines: Towards a more sustainable future (2020)
• A tutored discourse on microcontrollers, single board computers and their applications to monitor and control chemical reactions (2020)
• Engineering chemistry for the future of organic synthesis (2018)
• Taming hazardous chemistry by continuous flow technology (2016)
• The ‘Internet of Chemical Things‘ (2015)
• Machine-assisted organic synthesis (2015)
• Organic synthesis: march of the machines (2015)
• Flow chemistry meets advanced functional materials (2014)
• Continuous flow chemistry: a discovery tool for new chemical reactivity patterns (2014)
• Camera enabled techniques for organic synthesis (2013)
• On being green: can flow chemistry help? (2012)
• Less well Known enabling technologies for organic synthesis (2011)
• Lab of the future: the importance of remote monitoring and control (2011)
• The changing face of organic synthesis (2010)
• Practical Organocatalysis with (S)- and (R)-5 Pyrrolidin-2-yl-1H-tetrazoles (2008)
• A Fascination with 1,2-Diacetals (2007)
• Asymmetric Organocatalysis (2006 - ISBN-978-3-527-31399-0, 211-216)
• Synthesis of the Thapsigargins (2004)
• 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)
• Multistep Organic Synthesis using Solid Supported Reagents and Scavengers: A New Paradigm in Chemical Library Generation (2000)
• π-Allyltricarbonyliron lactone complexes in organic synthesis: a useful and conceptually unusual route to lactones and lactams (1996)
• Tetrapropylammonium perruthanate, Pr4N+RuO4- TPAP: a catalytic oxidant for organic synthesis (1994)
• Tricarbonyliron lactone complexes in organic synthesis (1994)
• The Champagne Route to Avermectins and Milbemycins (1991)

We have used extensively irontricarbonyl lactone complexes as a conceptually new bond forming process to lactones and lactams.  These complexes also served as key entry points to 1,5 and 1,7 remote stereo-control and as precursors to various natural products.  

See π-Allyltricarbonyliron lactone complexes in organic synthesis: a useful and conceptually unusual route to lactones and lactams S.V. Ley, L.R. Cox, G. Meek, Chem. Rev. 1996, 96, 423-442.

Related Publications:

• Tetracyanoethylene addition to iron tricarbonyl complexes of substituted cyclooctatetraenes. Regioselectivity considerations during formation of the 2,3,4,10-tetrahapto adducts L.A. Paquette, S.V. Ley, S. Maiorana, D.F. Schneider, M.J. Broadhurst, R.A. Boggs, J. Am. Chem. Soc. 1975, 97, 4658-4667.
• The formation of unusual sultones during the rearrangement reactions of bicyclic ketones D.S. Brown, H. Heaney, S.V. Ley, K.G. Mason, P. Singh, Tetrahedron Lett. 1978, 41, 3937-3940.
• Isolation characterisation and oxidation of isomeric ferralactone complexes G.D. Annis, S.V. Ley, R. Sivaramakrishnan, A.M. Atkinson, D. Rogers, D.J. Williams, J. Organometallic Chem. 1979, 182, C11-C14.
• Formation of β-lactams from tricarbonyliron lactones complexes G.D. Annis, E.M. Hebblethwaite, S.V. Ley, J. Chem. Soc., Chem. Commun. 1980, 297-298.
• Thermal decomposition of tricarbonyliron lactone complexes G.D. Annis, S.V. Ley, C.R. Self, R. Sivaramakrishnan, J. Chem. Soc., Chem. Commun. 1980, 299-299.
• Preparation of lactones via tricarbonyliron lactone complexes G.D. Annis, S.V. Ley, C.R. Self, R. Sivaramakrishnan, J. Chem. Soc., Perkin Trans. 1 1981, 270-277.
• 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.
• Synthesis of β-lactams from π-allyltricarbonyliron lactone complexes G.D. Annis, E.M. Hebblethwaite, S.T. Hodgson, D.M. Hollinshead, S.V.Ley, J. Chem. Soc., Perkin Trans. 1 1983, 2851-2856.
• π-Allyltricarbonyliron lactone complexes in synthesis: application to the synthesis of the β-lactam antibiotic (+)-thienamycin S.T. Hodgson, D.M. Hollinshead, S.V. Ley, J. Chem. Soc., Chem. Commun. 1984, 494-496.
• Fe2(CO)9 in tetrahydrofuran or under sonochemical conditions as convenient routes to π-allyltricarbonyliron lactone complexes A.M. Horton, D.M. Hollinshead, S.V. Ley, Tetrahedron 1984, 40, 1737-1742.
• Natural product synthesis via π-allyltricarbonyliron lactone complexes G.D. Annis, E.M. Hebblethwaite, S.T. Hodgson, A.M. Horton, D. M. Hollinshead, S.V. Ley, C.R. Self, R. Sivaramakrishnan, 2nd SCI/RSC Medicinal Chemistry Symposium. Special Publication, No. 50, 1984, 148-161.
• 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.
• 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.
• 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.
• Application of ultrasound to the preparation of tricarbonyliron diene complexes S.V. Ley, C.M.R. Low, A.D. White, J. Organometallic Chem. 1986, C13-C16.
• Organic synthesis with tricarbonyliron lactone complexes S.V. Ley, Phil. Trans. R. Soc. Lond. 1988, 326, 633-640.
• Alkenylcyclic sulphites as novel precursors for the preparation of pi-allyltricarbonyliron lactone complexes M. Caruso, J.G. Knight and S.V. Ley, Synlett, 1990, 224.
• Assessment of butene-1,4-diols as starting materials for the preparation of p-allyltricarbonyliron lactone complexes R.W. Bates, D. Diez-Martin, W.J. Kerr. J.G. Knight, S.V. Ley And A. Sakellaridis, Tetrahedron, 1990, 46, 4063.
• Total synthesis of avermectin B1a: synthesis of the C11-C25 spiroacetal fragment D. Díez-Martín, P. Grice, H.C. Kolb, S.V. Ley, A. Madin, Synlett 1990, 326-328.
• 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.
• 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.
• 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.
• Synthesis of the alkaloids (−)-heliotridane and (−)-isoretronecanol via π-allyltricarbonyliron lactam complexes G. Knight and S.V. Ley, Tetrahedron Lett. 1991, 32, 7119.
• 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.
• Tricarbonyliron lactone complexes in organic synthesis S.V. Ley, Pure and Appl. Chem. 1994, 66, 1415.
• Diastereoselective addition reactions to carbonyl groups in the side-chain of p-allyltricarbonyliron lactone complexes S.V. Ley, G. Meek, K-H Metten, C. Pique, J. Chem. Soc., Chem. Commun. 1994, 1931.
• Diastereoselective additions to aldehyde groups in the side-chain of π-allyltricarbonyliron lactone complexes S.V. Ley and G. Meek, J. Chem. Soc., Chem. Commun. 1996, 317-318.
• π-Allyltricarbonyliron lactone complexes in organic synthesis: a useful and conceptually unusual route to lactones and lactams S.V. Ley, L.R. Cox, G. Meek,  Chem. Rev. 1996, 96, 423-442.
• Diastereoselective addition reactions of allylstannanes to carbonyl groups in the side-chain of π-allyltricarbonyliron lactone complexes S.V. Ley and L. Cox, J. Chem. Soc., Chem. Commun. 1996, 657-658.
• 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.
• 1,5-Asymmetric induction of chirality: highly diastereoselective addition reactions of organoaluminium reagents into ketone groups in the side-chain of π-allyltricarbonyliron lactone complex S.V. Ley, L.R. Cox, G. Meek, K.-H. Metten, C. Pique, J. Worrall, J. Chem. Soc., Perkin Trans. 11997, 3299-3314.
• 1,5 Asymmetric induction of chirality: highly diastereoselective synthesis of homoallylic tertiary alcohols by the Lewis acid-mediated addition of allylstannanes into ketones in the side-chain of π-allyltricarbonyliron lactone complexes L.R. Cox and S.V. Ley, J. Chem. Soc., Perkin Trans. 11997, 3315-3326.
• 1,5 Asymmetric induction of chirality: diastereoselective addition of organoaluminium reagents and allylstannanes to aldehyde groups in the side-chain of π-allyltricarbonyliron lactone complexes S.V. Ley, S. Burckhardt, L.R. Cox, G. Meek, J. Chem. Soc., Perkin Trans. 1 1997, 3327-3338.
• Highly diastereoselective synthesis of β-hydroxy carbonyl compounds using π-allyltricarbonyliron lactone complexes: a formal 1,7 asymmetric induction of chirality in a Mukaiyama Aldol reaction S.V. Ley and L.R. Cox, J. Chem. Soc., Chem. Commun. 1998, 227-228.
• A novel decomplexation of π-allyltricarbonyliron lactone complexes using borohydride reagents: a new route to stereodefined acyclic 1,5-diols and 1,5,7-triols S.V. Ley, S. Burckhardt, L.R. Cox and, J. M. Worrall, J. Chem. Soc., Chem. Commun., 1998, 229-230.
• Mukaiyama Aldol reactions of π-allyltricarbonyliron lactone and lactam complexes bearing trimethylsilyl enol ether side-chains: not just formal but genuine 1,7-induction of chirality S.V. Ley, L.R. Cox, B. Middleton, J.M. Worrall, J. Chem. Soc., Chem. Commun. 1998, 1339-1340.
• Tricarbonyliron complexes: an approach to acyclic stereocontrol L.R. Cox and S.V.Ley, J. Chem. Soc. Rev. 1998, 27, 301-314.
• A new route to functionalised π-allyltricarbonyliron lactam complexes from aziridines and their use in steroselective synthesis and oxidative conversion to β-lactams S.V. Ley and B. Middleton, J. Chem. Soc., Chem. Commun. 1998, 1995-1996.
• Double diastereodifferentiation in the Mukaiyama aldol reactions of π-allyltricarbonyliron lactone complexes; 1,7-vs 1,2-asymmetric induction S.V. Ley, L.R. Cox, J.M. Worrall, J. Chem. Soc., Perkin Trans. 1 1998, 3349-3354.
• New building blocks for efficient and highly diastereoselective polyol production: synthesis and utility of (R,R,S,S)-and (S,S,R,R,)-2,3-butane diacetal protected butane tetrol derivatives J. Barlow, D.J. Dixon, A.C. Foster, S.V. Ley, D.R. Reynolds, J. Chem. Soc., Perkin Trans. 1 1999, 1627-1630.
• 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.
• Reductive Decomplexation of p-Allyltricarbonyliron Lactone Complexes: A New Route to Stereodefined Acyclic 1,5-Diols and 1,5,7-Triols S.V. Ley, S. Burckhardt, L.R. Cox and J.M. Worrall, J. Chem. Soc., Perkin Trans. 1, 2000, 211.
• 1,7- Asymmetric Induction of Chirality in a Mukaiyama Aldol Reaction using p-Allyltricarbonyliron Lactone Complexes: Highly Diastereoselective Synthesis of α-Substituted β-Hydroxy Carbonyl Compounds S.V. Ley and E.A. Wright, J. Chem. Soc., Perkin Trans. 1, 2000, 1677.
• 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.
• 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.
• 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. Commun., 2002, 1624.
• Reductive Decomplexation of p-Allyltricarbonyliron Lactone Complexes: A New Route to Stereo-defined 1,7-Diols and 2,3-Diene-1,7-diols S.V. Ley and C.J. Hollowood, J. Chem. Soc., Chem. Commun., 2002, 2130.
• 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.
• Reductive Decomplexation of π-Allyltricarbonyliron Lactone Complexes using Sodium Naphthalenide as a Route to Stereodefined 1,7-diols and 2,3-diene-1,7-diols C.J. Hollowood and S.V. Ley, Org. Biomol. Chem., 2003, 1, 3197.
• 1,5-Asymmetric Induction of Chirality using π-Allyltricarbonyliron Lactone Complexes: Highly Diastereoselective Synthesis of α-Functionalised Carbonyl Compounds C.J. Hollowood, S.V. Ley, and E.A. Wright, Org. Biomol. Chem., 2003, 1, 3208.
• 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.

While 1,2-diacetals have been known in the literature since 1938, their specific application in organic synthesis has taken time to develop. It seems remarkable to us that given the importance of acetals, carbonyl compounds and diols that aspects of the chemistry have not been discovered previously; yet, that is the case.  We have pioneered the use of dispiroketals 1 in synthesis and have reviewed this topic in detail.   We have also extensively investigated the use of 1,2-diacetals 2 which provide alternative opportunities for selective diol protection and for reactivity control.  Readers are directed to these reviews^1, 2  as this constitutes a major research area for the group.

1.   1,2- Diacetals: A New Opportunity for Organic Synthesis S.V. Ley, D.K. Baeschlin, D.J. Dixon, A.C. Foster, S.J. Ince, H.W.M. Priepke and D.J. Reynolds, Chem. Rev., 2001, 101, 53.

2.   A Fascination with 1,2-Diacetals S.V. Ley and A. Polara, J. Org. Chem., 2007, 72, 5943-5959.

Oxidation processes feature in a very wide range of our synthesis research programs.  Listed below is a selection of the reactions and reagents that we have developed over the years.

24. Oxidation of phenols to ortho-quniones using diphenylseleninic anhydride D.H.R. Barton, A.G. Brewster, S.V. Ley, M.N. Rosenfeld, J. Chem. Soc., Chem. Commun. 1976, 985-986.

25. Experiments on the synthesis of tetracycline part 15. Oxidation of phenols and ring A. Model phenols to O-hydroxydienones with benzeneseleninic anhydride D.H.R. Barton, S.V. Ley, P.D. Magnus, M.N. Rosenfeld, J. Chem. Soc., Perkin Trans. 1 1977, 567-572.

36. Oxidation of aldehyde hydrazones, hydrazo compounds and hydroxylamines with benzeneseleninic anhydride D.H.R. Barton D.J. Lester, S.V. Ley, J. Chem. Soc. Chem. Commun. 1978, 276-277.

40. Oxidation of alcohols using benzeneseleninic anhydride D.H.R. Barton, A.G. Brewster, R.A.H.F. Hui, D.J. Lester, S.V. Ley, T.G. Back, J. Chem. Soc., Chem. Commun. 1978, 952-954.

43. Preparation of aldehydes and ketones by oxidation of benzylic hydrocarbons with benzeneselenininic anhydride D.H.R. Barton, R.A.H.F. Hui, D.J. Lester, S.V. Ley, Tetrahedron Lett. 1979, 20, 3331-3334.

45. Bis(p-methoxyphenyl) telluroxide: a new mild oxidising agent D.H.R. Barton, S.V. Ley, C.A. Meerholz, J. Chem. Soc., Chem. Commun. 1979, 755-756.

52. Oxidation of ketone and aldehyde hydrazones, oximes and semi- carbazones and of hydroxylamines and hydrazo compounds using benzeneseleninic anhydride D.H.R. Barton, D.J. Lester, S.V. Ley, J. Chem. Soc., Perkin Trans. 1 1980, 1212-1217.

62. Oxidation of phenols, pyrocatechols, and hydroquinones to ortho-quinones using benzeneseleninic anhydride D.H.R. Barton, A.G. Brewster, S.V. Ley, C.M. Read, M.N. Rosenfeld, J. Chem. Soc., Perkin Trans. 1 1981, 1473-1476.

65. Diaryl telluroxides as new mild oxidising reagents S.V. Ley, C.A. Meerholz, D.H.R. Barton, Tetrahedron 1981, 37, 213-223.

73. Oxygen atom transfer from iodlybenzene to diphenyl diselenide: a convenient catalytic method for dehydrogenation of steroidal 3-ketones D.H.R. Barton, J. Morzycki, W.B. Motherwell, S.V. Ley, J. Chem. Soc., Chem. Commun. 1981, 1044-1045.

82. Oxidation of benzylic hydrocarbons with benzeneseleninic anhydride and related reactions D.H.R. Barton, R.A.H.F. Hui, S.V. Ley, J. Chem. Soc., Perkin Trans. 1 1982, 2179-2185.

97. Oxo complexes of ruthenium (VI) and (VII) as organic oxidants G. Green, W.P. Griffith, D.M. Hollinshead, S.V. Ley, M. Schrader, J. Chem. Soc., Perkin Trans. 1 1984, 681.

131. 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.

141. Preparation and use of tetra-n-butylammonium perruthenate (TBAP reagent) and tetra-n-propylammonium perruthenate (TPAP reagent) as new catalytic oxidants for alcohols W.P. Griffiths, S.V. Ley, G.P. Whitecombe, A.D. White, J. Chem. Soc., Chem. Commun. 1987, 1625-1627.

153. Microbial oxidation in synthesis. Preparation from benzene of the cellular secondary messenger myo-inositol-1,4,5-trisphosphate (IP3) and related derivatives S.V. Ley and F. Sternfeld, Tetrahedron Lett. 1988, 29, 5305-5308.

163. Microbial oxidation in synthesis: preparation of (+)-and (–)-pinitol from benzene S.V. Ley and F. Sternfeld, Tetrahedron 1989, 45, 3463-3476.

165. 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.

179. TPAP: tetra-n-propylammonium perruthenate, a mild and convenient oxidant for alcohols W.P. Griffith and S.V. Ley, Aldrichimica Acta, 1990, 23, 13-19

189. Microbial oxidation in synthesis: preparation of myo-inositol phosphates and related cyclitol derivatives from benzene S.V. Ley, M Parra, A.J. Redgrave, F. Sternfeld, Tetrahedron, 1990, 46, 4995.

196. A new ruthenium(VI) oxidant: preparation, x-ray crystal structure and properties of (Ph4P)[RuO2(OAc)Cl2] W.P. Griffith, J.M. Jolliffe, S.V. Ley and D.J. Williams, J. Chem. Soc., Chem. Commun., 1990, 1219.

218. Microbial oxidation in synthesis: preparation of novel 3-substituted cis- cyclohexa-3,5-diene-1,2-diol derivatives from (1s,2s)-3-bromocyclohexa-3,5- diene-1,2-diol S.V. Ley, A.J. Redgrave, S.C. Taylor, S. Ahmed, D.W. Ribbons, Synlett, 1991, 741.

227. Oxidation of activated C-H bonds adjacent to heteroatoms: oxidation adjacent to oxygen of alcohols by chromium reagents by S.V. Ley and A. Madin in Comprehensive Organic Synthesis. Pergamon Press, 1991, 7, 251.

230. Microbial oxidation in synthesis: preparation of pseudo-alpha-D-glycopyranose from benzene L. L. Yeung and S.V. Ley, Synlett, 1992, 291.

276. Tetrapropylammonium perruthanate, Pr4N+RuO4- TPAP: a catalytic oxidant for organic synthesis S.V. Ley, S.P. Marsden, J. Norman, W.P. Griffith, Synthesis, 1994, 639.

335. Polymer supported perruthenate (PSP): a new oxidant for clean organic synthesis B. Hinzen and S.V. Ley, J. Chem. Soc., Perkin Trans. 1 1997, 1907-1908.

340. Tetra-n-propylammonium perruthenate (TPAP)-catalysed oxidations of alcohols using molecular oxygen as a co-oxidant R. Lenz and S.V. Ley, J. Chem. Soc., Perkin Trans. 1 1997, 3291-3292.

350. Polymer supported perruthenate (PSP): clean oxidation of primary alcohols to carbonyl compounds using oxygen as cooxidant B. Hinzen, R. Lenz, S.V. Ley, Synthesis 1998, 977-979.

374. Polymer supported hypervalent iodine reagents in ‘clean’ organic synthesis with potential applications in combinatorial chemistry S.V. Ley, A.W. Thomas, H. Finch, J. Chem. Soc., Perkin Trans. 1 1999, 669-672.

376. 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.

438. Solid-Supported Reagents for the Oxidation of Aldehydes to Carboxylic Acids T. Takemoto, K. Yasuda and S.V. Ley, Synlett, 2001, 1555.

440. Tetra-N-Propylammonium Perruthenate: A Case Study in Catalyst Recovery and Reuse Involving Tetraalkylammonium Salts S.V. Ley, C. Ramarao and M.D. Smith, J. Chem. Soc., Chem. Commun., 2001, 2278.

459. A Clean Conversion of Aldehydes to Nitriles using a Solid-Supported Hydrazine I.R. Baxendale, S.V. Ley and H.P. Sneddon, Synlett, 2002, 775.

495. Microencapsulation of Osmium Tetroxide in Polyurea S.V. Ley, C. Ramarao, A-L. Lee, N. Østergaard, S.C. Smith and I.M. Shirley, Org. Lett., 2003, 5, 185.

513. A Sequential Tetra-n-propylammonium Perruthenate-Wittig Oxidation R.N. MacCoss, E.P. Balskus, S.V. Ley, Tetrahedron Lett., 2003, 44, 7779.

595. 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.

644. The Changing Face of Organic Synthesis S.V. Ley and I.R. Baxendale, Chimia, 2008, 62, 162-168.

695. KMnO4 mediated oxidation as a continuous flow process J. Sedelmeier, S.V. Ley, I.R. Baxendale, M. Baumann, Org. Lett., 2010, 12, 3618-3621.

713. Oxidation reactions in segmented and continuous flow chemical processing using a N-(tert Butyl)phenylsulfinimidoyl chloride monolith H. Lange, M.J. Carpenter, A.X. Jones, C.J. Smith, N. Nikbin, I.R. Baxendale, S.V. Ley, Synlett 2011, 6, 869-873.

736. The oxygen mediated continuous flow synthesis of 1,3-butadiynes using Teflon AF-2400 to effect gas-liquid contact T.P. Peterson, A. Polyzos, M. O’Brien, T. Ulven, I.R. Baxendale, S.V. Ley, Chem. Sus. Chem. 2012, 5, 274-277.

749. On being green: can flow chemistry help? S.V. Ley, Chem. Rec. 2012, 12, 378-390.

769. A continuous flow solution to achieving efficient, aerobic anti-Markovnikov Wacker oxidation S.L. Bourne, S.V. Ley, Adv. Synth. Catal. 2013, 355, 1905-1910.

775. Sustainable flow Oppenauer oxidation of secondary benzylic alcohols with a heterogeneous zirconia catalyst R. Chorghade, C. Battilocchio, J.M. Hawkins, S.V. Ley, Org. Lett. 2013, 15, 5698-5701.

786. Continuous flow chemistry: a discovery tool for new chemical reactivity patterns J. Hartwig, J.B. Metternich, N. Nikbin, A. Kirschning, S.V. Ley, Org. BioMol. Chem. 2014, 12, 3611.

798. The rapid synthesis of oxazolines and their heterogeneous oxidation to oxazoles under flow conditions S. Glockner, D.N. Tran, R.J. Ingham, S. Fenner, Z.E. Wilson, C. Battilocchio, S.V. Ley Org. Biomol. Chem. 2015, 13, 207.

835. Taming hazardous chemistry by continuous flow technology M. Movsisyan, E.I.P. Delbeke, J.K.E.T. Berton, C. Battilocchio, S.V. Ley, C.V. Stevens, Chem. Soc. Rev. 2016, 45, 4892-4928.

855. Continuous direct anodic flow oxidation of aromatic hydrocarbons to benzyl amides M.A. Kabeshov, B. Musio and S.V. Ley, React. Chem. Eng., 2017, 2, 822-825.

874.  C–H functionalisation of aldehydes using light generated, non-stabilised diazo compounds in flow P. Dingwall, A. Greb, L. N. S. Crespin, R. Labes, B. Musio, J.S. Poh, P. Pasau, D. C. Blakemore and S. V. Ley Chem. Comm. 2018, 54, 11685 – 11688.  (http://dx.doi.org/10.1039/c8cc06202a).

880.  Direct Oxidation of Csp3−H bonds using in Situ Generated Trifluoromethylated Dioxirane in Flow M. Lesieur, C. Battilocchio, R. Labes, J. Jacq, C. Genicot, S. V. Ley and P. Pasau Chem. Eur. J., 2019, 25, 1203-1207. (https://doi.org/10.1002/chem.201805657).

902. Exploring the chemical space of phenyl sulfide oxidation by automated optimization P. Mueller,   A. Vriza,   A. D. Clayton,   O.S. May,   N. Govan,   S. Notman,  S. V. Ley,   T. W. Chamberlain  and  R. Bourne, React. Chem. Eng. 2023, 8, 538-542. (https://doi.org/10.1039/d2re00552b).

907.  Continuous flow synthesis enabling reaction discovery A.I. Alfano, J. García-Lacuna, O. M. Griffiths,  S.V. Ley and  M. Baumann.  Chem. Sci., 2024, 15, 4618-4630. (https://doi.org/10.1039/D3SC06808K).

Polymer-Supported Reagents (selected publications only)

The use of polymer-supported reagents and scavengers provides an attractive and practical method for the clean and efficient preparation of novel chemical entities. These methods can be extended in a multistep fashion to provide access to more complex structures, including biologically active natural products. In our major review we covered all known supported reagents, catalysts and scavenging agents as useful directory to assist with future synthesis planning in the chemical community. Our group has a long track record in the pioneering development and application of polymer-supported reagents in organic synthesis and here we provide a few examples of our work in this area.

DEVELOPMENT OF POLYMER-SUPPORTED REAGENTS

Polymer-supported iridium catalyst
We prepared a polymer-supported iridium catalyst and used in the isomerisation of the double bonds in aryl allylic derivatives with excellent trans selectivity and without the need for conventional work-up procedures.

Polymer-supported thiolating agent
We developed a thiolating reagent for the conversion of carbonyls to thiocarbonyls and demonstrated its use on a range of amides. Secondary or tertiary amides were converted cleanly and efficiently through to the corresponding thioamides and primary amides were converted to the corresponding nitriles. While reactions could be aided by conventional heating, we found that if microwave heating was used, in the presence of an ionic liquid, enhanced reaction rates are achieved.

Polymer-supported perruthenate
Steve Ley was the inventor of the widely used TPAP oxidation agent, and of course we had to prepare a polymer supported perruthenate reagent. We used it in the conversion of primary and secondary alcohols to aldehydes and ketones, respectively, which afforded pure products without the need for conventional work-up procedures.

THE POLYMER-SUPPORTED REAGENT APPROACH TO NATURAL PRODUCT SYNTHESIS

The use of polymer-supported reagents in our group is extensive, particularly as we now incorporate them into our flow chemistry projects. What we offer are a few discussions on a limited number of natural products that we have synthesised using polymer-supported reagents. At their time, these syntheses were often “world-firsts” and were major landmarks for us early on. These are a few examples excerpted from one of our book chapter reviews.

Oxomaritidine and Epimaritidine  
Our first serious application of supported reagents for natural product synthesis was published in 1999 [1]. We reported concise routes to two amaryllidaceae alkaloids; oxomaritidine (1) and epimaritidine (2) in just five and six steps, respectively. Supported reagents, featured in all of the steps, were used in a sequential fashion and led to pure products following a simple filtration to remove spent reagents.

The route began with the quantitative oxidation of 3,4-dimethoxybenzyl alcohol (3) to the corresponding aldehyde 4 using our own polymer-supported perruthenate (PSP), a catalytic oxidant [2]. Next, the reductive amination of aldehyde 4 was achieved firstly by coupling with the phenolic amine 5 and followed by reduction using a polymer-supported borohydride reagent to furnish the corresponding secondary amine 6 under previously optimised conditions [3].  Amine 6 was protected as trifluoroacetate 7 by treatment with trifluoroacetic anhydride and immobilized dimethylaminopyridine (PS-DMAP) as the catalyst and base. The resulting product 7 underwent smooth oxidative coupling to the spirodienone 8 using polymer-supported hypervalent iodine diacetate, a reagent developed specifically for the task [4]. In order to guarantee good conversion in this process, it was essential to use trifluoroethanol as the solvent. Finally, a wet carbonate ion-exchange resin simultaneously deprotected and initiated cyclisation (via conjugate addition) to give the first of the natural products, oxomaritidine (1), in essentially quantitative yield after filtration and solvent evaporation. Subsequent stereoselective reduction of oxomaritidine (1), using an immobilized copper boride (or nickel boride) equivalent, delivered the second natural product epimaritidine (2) in an excellent 50% overall yield over the six step sequence. The synthesis was scaleable to deliver gram quantities.

Epibatidine
The potent analgesic alkaloid epibatidine (18) [5] isolated from the Equadorian poison frog Epipedobates tricolour, was a more challenging compound to synthesize using immobilization techniques. This synthesis involved the orchestrated employment of 10 polymer-supported reagents and scavengers to give epibatidine (18) in greater than 90% purity without any chromatographic steps.

The synthesis began by transforming the commercially available acid chloride 19 to aldehyde 20. This was achieved in a two-step process by reduction of the acid chloride to the intermediate alcohol with polymer-supported borohydride, then partial re-oxidation by the PSP reagent to deliver aldehyde 20. Alternative immobilized oxidants such as supported permanganate [6] and diacetoxyiodobenzene were equally efficient. Oxidants such as Magtrieve (magnetised CrO₂ and MnO₂), although performing the reaction, were less suitable as they required considerably longer reaction times. Aldehyde 20 then underwent straightforward conversion to the nitrostyrene 21. A Henry reaction promoted by the basic Amberlite resin (IRA 420 OH^– form) and followed by elimination of an intermediate trifluoroacetate using polymer-supported diethylamine as a base gave 21. By NMR analysis at each stage, products were shown to be better than 95% pure. In an important modification to the above sequence of reactions, it was found that by the incorporation of supported reagents contained in sealed porous polymer pouches the conversion of chloride 19 to nitrostyrene 21 was possible in a one-pot operation. Thus, when an individual reaction was deemed to be complete the pouch was simply removed, washed with solvent, and the next reagent pouch added to the flask. This process obviated the need for filtration between individual steps.

In the next phase of the synthesis, a regioselective Diels-Alder reaction of nitrostyrene 21 with 2-tert-butyldimethylsilyloxybutadiene in a sealed tube at 120 ^oC and work-up with a volatile acid (TFA) to hydrolyse the intermediate enol ether gave ketone 22 exclusively as the trans-substituted product.  Stereoselective reduction of the carbonyl and corresponding mesylate formation gave 23, again using an immobilized suite of reagents.  Selective reduction of the nitro 23 to amine 24 in the presence of other sensitive functionalities was next achieved using polymer-supported nickel boride. Treatment of amine 24 with PS-BEMP initiated an intramolecular displacement of the mesylate which, following a scavenging step with a polystyrene aminomethyl resin to remove excess mesylate, yielded the natural product precursor 25. Epimerisation to epibatidine (18) was readily achieved by microwave heating in the presence of potassium tert-butoxide. The natural product was ultimately isolated by a catch-and-release technique.

Plicamine
Much of the above constitutes the preparation of relatively simple structures. However, these syntheses actually helped prepare the ground for more challenging targets such as the synthesis of the alkaloid (+)-plicamine (27) [7]. Extensive use of parallel optimisation methods and focussed microwave techniques, to achieve fast reaction times, were used to complete the total synthesis in just six weeks without rehearsal of any reactions using conventional solution-phase methods or separation techniques. In this respect this synthesis stands out. Please refer to the full details of the work [8] which describes how the route (in multi-gram quantities) can be modified to afford analogues or generate related structural scaffolds for further chemical decoration. Also of note is that since this synthesis relied on a single asymmetric centre in the starting material to control all the others, by use of the opposite enantiomer, the unnatural (–)-plicamine enantiomer can also be prepared and examined for biological activity.

Polymer-supported hypervalent iodine reagent performed well to convert phenol 28 to spirodienone 29. Nafion-H (fluorosulfonic acid resin) catalysed the final cyclisation of &nbsp29 to form the tricyclic core of the natural product in virtually quantitative yield. After stereo- and regioselective reduction of 30 using supported borohydride, the very hindered intermediate alcohol was methylated by treatment with trimethylsilyl diazomethane and supported sulfonic acid resin to give 31. This process is very mild and is to be recommended in difficult situations. The remaining steps to (+)-plicamine from 31 were relatively straightforward. However, the final oxidation of amine 32 to (+)-plicamine required significant development. This was eventually achieved using CrO₃ and 3,5-dimethylpyrazole followed by scavenging with Amberlyst 15 resin. The chromium salts were efficiently removed by filtration through a mixed bed containing Varian Chem Elut CE 1005 and Montmorillonite K10 clay to give (+)-plicamine (27).

The route to plicamine was also be diverted at an earlier stage to afford two further natural products, plicane (33) and obliquine (34) [9]. The ability to divert material in this way is attractive and was facilitated by using immobilized reagent methods. These more advanced syntheses clearly illustrated the opportunities created by embracing these methods for multi-step transformations.

Carpanone
The deceptively complex natural product carpanone (41) was made from commercially available sesamol in a relatively simple set of reactions using immobilized reagents.

After allylation of sesamol using allyl bromide and PS-BEMP, the product underwent an extremely clean Claisen rearrangement using a combination of toluene and an ionic liquid to absorb the energy from an external microwave source. These binary conditions were simple to operate, since after heating then cooling, the mixture was separated using a simple liquid handler to remove the product-containing toluene layer. The ionic liquid can also be recovered and re-used in further experiments. The toluene fraction containing 42 was then used directly in the double bond isomerisation reaction to yield conjugated compound 43. This was achieved stereoselectively (11:1 trans:cis) by use of a new immobilised iridium catalyst 44 [10] developed specifically for this project. However, it has also been shown to be general for other double bond isomerisations at room temperature [11].  Lastly following original work by Chapman using other oxidants, the phenolic styrene was converted to carpanone (41) by application of a modified Jacobsen Salen cobalt complex under catalytic conditions with molecular oxygen. After scavenging with a carbonate resin to remove unreacted phenols and a trisamine resin to remove an unwanted aldehyde by-product, the crystalline natural product was obtained in excellent yield and purity. Mechanistically, carpanone was finally formed by oxidative dimerisation through carbon coupling of the phenol (43) followed by a highly stereoselective intramolecular Diels-Alder reaction.

Epothilones
The epothilones have generated wide interest in the broad scientific community owing to their ability to inhibit tumour cell proliferation by inducing mitotic arrest through microtubules stabilization. Owing to this activity, they have also become principal targets for many synthesis groups. Indeed they provide an excellent platform to explore the full armoury of supported reagents and scavengers for complex molecule synthesis. The epothilones lend themselves well to convergent synthetic approaches as they can be easily disconnected to more manageable fragments for analogue development; a crucial aspect of pharmaceutical drug programmes. For the synthesis of epothilone C (66) and epothilone A (67) by epoxidation, a convergent synthesis plan was devised that would require the coupling of three major fragments 68, 69 and 70.  An important criterion for this route was conducting the work in an efficient and clean manner using only immobilized reagents, scavengers and catch-and-release techniques. The overall aim was to avoid chromatography, crystallisation, distillation and water washes which are common in conventional approaches to these molecules.  Consequently, using only immobilized reagents, scavengers and catch-and-release techniques can achieve this goal [12].

In the full paper on this work, a number of alternative routes to the various fragments were reported [13]. Three routes to fragment A (68) were investigated, but the one shown in below was the shortest, the most efficient, and also proved to be the most easily scaled.  The key feature was the formation of the C2-C3 bond with concomitant introduction of the desired C3 stereocentre by application of an asymmetric Mukaiyama aldol reaction. In this synthesis, the aldol reaction progressed in excellent yield to give the alcohol 71 with an enantiomeric excess of 92%. This was achieved using a complex of borane with N-tosylphenylalanine as the chiral ligand. Work-up of this reaction required the addition of a minimum amount of water and a boron selective scavenger Amberlite IRA-743 to quench the reaction and remove the contaminating boric acid. Filtration and solvent removal produced a suspension of amino acid and aldol product 71.  However, the insolubility of the N-protected amino acid in non-polar solvents allowed dissolution of the desired aldol product. Subsequent filtration enabled the amino acid to be recovered and recycled whilst concentration of the filtrate gave the purified alcohol 71. After protection as its tert-butyldimethylsilylenol ether 72 and reaction with (trismethylsilylmethyl)lithium followed by a scavenger quench using a carboxylic acid resin, direct filtration and solvent removal yielded the ketone 73.  α-Methylation of ketone 73 via its lithium enolate and work-up again with a polymer-supported carboxylic acid gave fragment A (68) in just six steps from commercially available starting material.

The preparation of the second key coupling partner fragment B (69) was achieved in just five steps from the commercially available bromide (–)-(R)-3-bromo-2-methyl-1-propanol (74). Protection of the alcohol as its THP-ether using a polymeric sulfonic acid followed by Finkelstein halide exchange gave iodide 75. Homologation of alkyl iodide 75 with a cuprate derived from 3-butenylmagnesium bromide produced the corresponding alkene 76. Addition of a carboxylic acid resin and the trisamine resin quenched the reaction and scavenged dissolved copper salts. Finally after deprotection of the THP acetal, the resulting alcohol was oxidised to the fragment B aldehyde 69. Several oxidants were investigated for this process, but the most expedient proved to be pyridinium chlorochromate PCC on basic alumina.

The final fragment C (70) was constructed  in a convergent fashion from (S)-α-hydroxyl-g-lactone (77) and the chloromethyl triazole hydrochloride (78). Lactone 77 was therefore elaborated to ketone 79. Ketone 79 was coupled with a phosphonate derived from thiazole 78 via a highly stereoselective Horner-Wadsworth-Emmons reaction. A polymer-supported aldehyde was used to scavenge any excess phosphonate from this reaction to yield the bis-TBS protected adduct 80. TBS-protected diol 80 was taken through to fragment C by previously described steps. Ultimately iodide 70 was captured onto a polymer-supported triphenylphosphine to produce Wittig salt 81 as the coupling precursor.

With all the fragments now in hand, the final fusion of the components began. Previously, the stereoselective aldol coupling of fragments A and B to form the C6-C7 bond was shown to be highly sensitive to proximal and remote functionality in both fragments. In this work, although bearing close similarity to previous studies, the coupling of ketone 68 with the aldehyde 69 was a novel combination. Using LDA as a base this aldol coupling proceeded in quantitative yield with better than 13:1 stereoselectivity for the desired product. An acetic acid quench was followed by treatment with a diamine functionalised polymer. This resin served two purposes; to remove the excess acid and to sequester a small amount of unreacted aldehyde.

The elaborated adduct 82 was then silyl-protected and the double bond cleaved by ozonolysis. Work-up of the intermediate ozonide was achieved by application of immobilized triphenylphosphine. This is an excellent procedure as the triphenylphosphine oxide produced in normal solution work-ups and in Wittig chemistry causes practical difficulties that often require multiple chromatographic separations to obtain pure material.  Here simple filtration was sufficient. The resin bound phosphonium salt 81derived from fragment C was treated with an excess of sodium hexamethyldisilazide (NaHMDS) followed by washing with anhydrous THF to give an isolable salt-free ylide. This was coupled stereoselectively to give the cis-olefin which required application of a dilute methanolic solution of camphorsulfonic acid to effect selective removal of the primary TBS-protecting group to give the free alcohol 84. This process required a separate scavenging step using an immobilized carbonate resin to remove the acid with the volatile MeOTBS by-product being removed under reduced pressure.

Catalytic tetra-N-propylammonium perruthenate (TPAP) oxidation of alcohol 84 followed by filtration through a pad of silica gel to remove morpholine and ruthenium by-products gave an intermediate aldehyde which was immediately oxidised to the corresponding acid using a previously developed modified Pinnick procedure [14]. Finally, selective desilylation prior to macrocyclisation was finally achieved found using tetrabutyl ammonium fluoride (TBAF) solution to afford intermediate 85. Immobilized versions of fluoride or other acidic resins led to complex mixtures. As a consequence of using the TBAF procedure, an aqueous extraction was necessary, and this gave pure deprotected alcohol 85. This was the first and only water wash used in the whole synthesis to this point. The final steps to epothilone A (67) simply required application of the Yamaguchi macrolactonisation procedure using PS-DMAP and a catch-and-release purification to produce epothilone C. Upon epoxidation with DMDO, epothilone A was obtained.

Without a doubt, this synthesis constitutes a triumph for the utility of supported reagents and scavenging techniques for multi-step complex molecule assembly. The high stereoselectivity and overall yield in this synthesis of epothilone A compares well with the best of all of the previous and conventional, routes. By the discussed route, the target molecule was delivered in 29 steps, with the longest linear sequence being only 17 steps from readily available materials.

Also check out ref 15 on accelerating spirocyclic polyketide synthesis using flow chemistry.

1. 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

2. (a) Polymer supported perruthenate (PSP): a new oxidant for clean organic synthesis B. Hinzen and S.V. Ley J. Chem. Soc., Perkin Trans. 1 1997, 1907-1908 (b) Polymer supported perruthenate (PSP): clean oxidation of primary alcohols to carbonyl compounds using oxygen as cooxidant B. Hinzen, R. Lenz, S.V. Ley Synthesis 1998, 977-979

3. Use of polymer supported reagents for clean multi-step organic synthesis: preparation of amines and amine derivatives from alcohols for use in compound library generation S.V. Ley, M. Bolli, B. Hinzen, A-G. Gervois, B.J. Hall J. Chem. Soc. Perkin Trans. 1, 1998, 2239-2242

4. Polymer supported hypervalent iodine reagents in ‘clean’ organic synthesis with potential applications in combinatorial chemistry S.V. Ley, A.W. Thomas, H. Finch J. Chem. Soc. Perkin Trans. 1 1999, 669-672

5. 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

6. Clean five-step synthesis of an array of 1,2,3,4,-tetra-substitued pyrroles using polymer supported reagents M. Caldarelli, J. Habermann, S. V. Ley J. Chem. Soc. Perkin Trans. 1 1999, 107-110

7.   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, C. Piutti Angew. Chem. Int. Edn., 2002, 41, 2194

8.  Total synthesis of the amaryllidacea alkaloid (+)-plicamine using solid-supported reagents I.R. Baxendale, S.V. Ley, C. Piutti, M. Nesi, Tetrahedron, 2002, 58, 6285.

9. 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. A polymer-supported iridium catalyst for the stereoselective isomerisation of double bonds I.R. Baxendale, A-L Lee, S.V. Ley Synlett, 2002, 516

11. 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

12. A total synthesis of epothilones using solid-supported reagents and scavengers R.I. Storer, T. Takemoto, P.S. Jackson, S.V. Ley Angew. Chem. Int. Edn., 2003, 42, 2321

13. 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, S.V. Ley Chem. Eur. J. 2004, 10, 2529-2547

14. Solid-supported reagents for the oxidation of aldehydes to carboxylic acids T. Takemoto, K. Yasuda, S.V. Ley Synlett 2001, 1555

15. 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. 2014, 53, 4915-4920

Our group has had a long lasting interest in using biotransformation to effect interesting and important chemical transformations. From the early days we were attracted by using biotransformations to achieve oxidation processes which were difficult by conventional methods. Illustrative of these reactions is the direct conversion of the natural product polygodiol to he drimane daniol sesquiterpene using a microbial oxidase Cunninghamella elegans. Noteworthy in this example is the selective high-yielding oxidation at C-3 while simultaneously effecting selective reduction of the vinylic aldehyde substituent.

Our group was also the first to point out the power of using microbial dioxygenase Pseudomonas putida to disrupt the aromatic sextet by oxygenation of arenes to lead to useful building blocks for natural product synthesis.

Recently we have shown that simple N-isovanillyltyramine derivatives undergo double oxidative biotransformations using the enzyme, tyrosinase, giving the corresponding hydroxylated dibenzoazocanes whereby we have formed a new C-C bond and installed a new hydroxyl group on one of the aromatic rings.

We have also used polymer-supported enzymes in continuous flow conditions. In this case pig liver esterase which we report in the first total synthesis of 2-aryl-2,3-dihydro-3-benzofurancarboxyamide neolignan, grossamide in 91% yield using a fully automated and scalable flow reactor.

Polymer-supported pig liver esterase was also used for the resolution of meso-diesters. The enzyme can be recovered quantitatively from the reaction mixture by filtration and reused without significant loss of activity. Further transformation of the resulting enantiomerically enriched carboxylic acids through the application of polymer-supported reagents and scavengers provides a number of GABA-analogues.

Publications

91. 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 and P.A. Worthington
J. Chem. Soc., Perkin Trans. 1, 1983, 1579-1589

131. Microbial oxidants in synthesis: a six step preparation of pinitol from benzene S.V. Ley, S. Taylor, F. Sternfeld Tetrahedron Lett. 1987, 28, 225-226

153. Microbial oxidation in synthesis. Preparation from benzene of the cellular secondary messenger myo-inositol-1,4,5-trisphosphate (IP3) and related derivatives S.V. Ley and F. Sternfeld, Tetrahedron Lett. 1988, 29, 5305-5308.

163. Microbial oxidation in synthesis: preparation of (+)-and (-)-pinitol from benzene S.V. Ley and F. Sternfeld Tetrahedron 1989, 45, 3463-3476

165. 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.

190. Microbial oxidation in synthesis: concise preparation of (+)-conduritol F from benzene S.V. Ley and A.J. Redgrave, Synlett, 1990, 393.

218. Microbial oxidation in synthesis: preparation of novel 3-substituted cis- cyclohexa-3,5-diene-1,2-diol derivatives from (1s,2s)-3-bromocyclohexa-3,5- diene-1,2-diol S.V. Ley, A.J. Redgrave, S.C. Taylor, S. Ahmed, D.W. Ribbons, Synlett, 1991, 741.

244. Microbial oxidation in synthesis: preparation of a potential insulin mimic from benzene S.V. Ley and L.L. Yeung, Synlett, 1992, 997.

334. Identification of azadirachtin in tissue-cultured cells of neem (Azadirachta indica) A.P. Jarvis, E.D. Morgan, S.A. van der Esch, F. Vitali, S.V. Ley, A.R. Pape, Nat. Prod. Lett. 1997, 10, 95-98.

472. Application of polymer-supported enzymes and reagents in the synthesis of γ-aminobutyric acid GABA analogues I.R. Baxendale, M. Ernst, W-R. Krahnert, S.V. Ley Synlett 2002, 1641-1644

585. Preparation of the neolignan natural product grossamide by a continuous flow process I.R. Baxendale, C.M. Griffiths-Jones, S.V. Ley, G.K. Tranmer Synlett 2006, 427-430

694. Enzymatic oxidative cyclisation reactions leading to dibenzoazocanes F. Tozzi, S.V.Ley, M.O. Kitching, I.R. Baxendale Synlett 2010, 13, 1919-1922

823. An orthogonal biocatalytic approach for the safe generation and use of HCN in a multistep continuous preparation of chiral O-acetylcyanohydrins A. Brahma, B. Musio, U. Ismayilova, N. Nikbin, S.B. Kamptmann, P. Siegert, G.E. Jeromin, S.V. Ley, M. Pohl Synlett 2016, 27, 262-266.

860.  Rapid, selective and stable HaloTag-LbADH immobilization directly from crude cell extract for the continuous biocatalytic production of chiral alcohols and epoxides J. Döbber, M. Pohl, S. V. Ley and B. Musio React.Chem.Eng., 2018, 3, 8–12.

895.  Enzymatic pretreatment of recycled grease trap waste in batch and continuous-flow reactors for biodiesel production, N.N. Tran, M. Escribà Gelonch, S. Liang, Z. Xiao, M. Mohsen Sarafraz, M. Tišma, H-J. Federsel, S.V. Ley, V. Hessel, Chemical Engineering Journal, 2021, 426, 131703. (https://doi.org/10.1016/j.cej.2021.131703).

Sulfone chemistry has played a wide role in much of our work.  The use of these methods in the construction of c-c bonds at anomeric carbon atoms and their use in natural product synthesis is particularly interesting.

Related Publications:

• Preparation and reactions of 2-benzenesulphonyltetrahydropyran S.V. Ley, B. Lygo, A. Wonnacott, Tetrahedron Lett. 1985, 26, 535-538.
• 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.
• Direct substitution of 2-benzenesulphonyl cyclic ethers using organozinc reagents D.S. Brown and S.V. Ley, Tetrahedron Lett. 1988, 29, 4869.
• Preparation of cyclic ether acetals from 2-benzenesulphonyl derivatives: a new mild glycosidation procedure D.S. Brown, S.V. Ley, S. Vile, Tetrahedron Lett. 1988, 29, 4873-4876.
• Substitution reactions of 2-benzenesulphonyl cyclic ethers with silyl enol ethers promoted by aluminium trichloride D.S. Brown, S.V. Ley, M. Bruno, Heterocycles 1989, 28, (Special Issue No. 2), 773-777.
• Substitution reactions of 2-benzenesulphonyl cyclic ethers with carbon nucleophiles D.S. Brown, M. Bruno, R.J. Davenport, S.V. Ley, Tetrahedron 1989, 45, 4293-4308.
• 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.
• Direct substitution of 2-benzenesulphonyl-piperidines and -pyrrolidines by carbon nucleophiles: synthesis of the pyrrolidine alkaloid ruspolinone D.S. Brown, T. Hansson and S.V. Ley, Synlett, 1990, 48.
• Total synthesis of avermectin B1a: synthesis of the C11-C25 spiroacetal fragment D. Díez-Martín, P. Grice, H.C. Kolb, S.V. Ley, A. Madin, Synlett 1990, 326-328.
• Direct substitution of 2-phenylsulphonyl pyrrolidines, -piperidines, -tetrahydrofurans and -tetrahydropyrans by alkylorganometallic reagents in dichloromethane D.S. Brown, P. Charreau, S.V. Ley, Synlett, 1990, 749.
• 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.
• Use of phenylsulphonylmethano ethers in synthesis: a new versatile route to substituted cyclic ethers P. Charreau, S.V. Ley, T.M. Vettiger, S.Vile, Synlett, 1991, 415.
• 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.
• Total synthesis of the carboxylic acid ionophore antibiotic CP-61,405 (routiennocin) N.R. Kotecha, S.V. Ley, S. Mantegani, Synlett, 1992, 395.
• 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.
• 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 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.
• Preparation of arylsulfonyl chlorides by chlorosulfonylation of in situ generated diazonium salts using a continuous flow reactor L. Malet-Sanz, J. Madrzak, S.V. Ley, I.R. Baxendale, Org. Biomol. Chem. 2010, 8, 5324-5332.
• Photoredox Generation of Sulfonyl Radicals and Coupling with Electron Deficient Olefins Y. Chen, N. McNamara, O. May, T. Pillaiyar, D. C. Blakemore, and S. V. Ley, Org. Lett. 2020, 22, 5746–5748. (https://doi.org/10.1021/acs.orglett.0c01730).
• Automated Multi-Objective Reaction Optimisation: Which Algorithm Should I Use?  P. Müller,  A. D. Clayton, J. Manson, S. Riley, O. S. May,  N. Govan, S. Notman, S. V. Ley,  T. W. Chamberlain and R. A. Bourne, Reac. Chem. Eng. 2022, 7, 987-993. (https://doi.org/10.1039/d1re00549a).
• Exploring the chemical space of phenyl sulfide oxidation by automated optimization P. Mueller,   A. Vriza,   A. D. Clayton,   O.S. May,   N. Govan,   S. Notman,  S. V. Ley,   T. W. Chamberlain  and  R. Bourne, React. Chem. Eng. 2023, 8, 538-542. (https://doi.org/10.1039/d2re00552b).
• Photoredox-Catalyzed Preparation of Sulfones Using Bis-Piperidine Sulfur Dioxide – An Underutilized Reagent for SO₂Transfer O.M. Griffiths, H.A. Esteves, D.C. Emmet and S.V. Ley Chem. Eur.J.,2024, 30, e202303976 (6 pages). (https://doi.org/10.1002/chem.202303976).

Photo catalysed processes are popular strategies for molecular assembly and especially photoredox cycles.  Scale up of these processes benefits from the incorporation of flow chemistry technologies.

842. Visible light activation of boronic esters enables efficient photoredox C(sp2)-C(sp3) cross-couplings in flow F. Lima, M.A. Kabeshov, D.N. Tran, C. Battilocchio, J. Sedelmeier, G. Sedelmeier, B. Schenkel, S.V. Ley, Angew. Chem. Int. Ed. 2016, 55, 14085-14089.

857.  Visible-Light-Mediated Annulation of Electron-Rich Alkenes and Nitrogen-Centered Radicals from N-Sulfonylallylamines: Construction of Chloromethylated Pyrrolidine Derivatives L.N.S. Crespin, A. Greb, D.C. Blakemore, and S.V. Ley J. Org. Chem. 2017, 82, 13093−13108.

863.  Mimicking the surface and prebiotic chemistry of early Earth using flow chemistry D. J. Ritson, C. Battilocchio, S.V. Ley and J. D. Sutherland Nature Communications 2018, 9, 1821 [DOI:10.1038/s41467-018-04147-2 | www.nature.com/naturecommunications].

866.  Organic photocatalysis for the radical couplings of boronic acid derivatives in batch and flow F. Lima, L. Grunenberg, H.B.A. Rahman, R. Labes, J. Sedelmeier and S.V. Ley Chem. Commun., 2018, 54, 5606-5609.

877.  Photochemical Homologation for the Preparation of Aliphatic Aldehydes in Flow Y. Chen, M. Leonardi, P. Dingwall, R. Labes, P. Pasau, D. C. Blakemore, and S. V. Ley J. Org. Chem., 2018, 83 (24), 15558–15568. (https://doi.org/10.1021/acs.joc.8b02721).

881.  Enabling Synthesis in Fragment-Based Drug Discovery by Reactivity Mapping: Photoredox-Mediated Cross-Dehydrogenative Heteroarylation of Cyclic Amines R. Grainger, T. D. Heighten, S. V. Ley, F. Lima, and C. N. Johnson Chem. Sci., 2019, 10, 2264-2271. (http://dx.doi.org/10.1039/c8sc04789h).

882.  A Photoredox Coupling Reaction of Benzylboronic Esters and Carbonyl Compounds in Batch and Flow Y. Chen, O. May, D. C. Blakemore, and S. V. Ley Org. Lett. 2019, 21, 6140−6144. (https://doi.org/10.1021/acs.orglett.9b02307).

883.  A New World for Chemical Synthesis? S. V. Ley, Y. Chen, D.E. Fitzpatrick,  and O. May, CHIMIA 2019, 73, 792-802. (https://doi.org/10.2533/chimia.2019.792).

888.  Photoredox Generation of Sulfonyl Radicals and Coupling with Electron Deficient Olefins Y. Chen, N. McNamara, O. May, T. Pillaiyar, D. C. Blakemore, and S. V. Ley, Org. Lett. 2020, 22, 5746–5748. (https://doi.org/10.1021/acs.orglett.0c01730).

901.  Multicomponent Direct Assembly of N-Heterospirocycles Facilitated by Visible-Light-Driven Photocatalysis O. M. Griffiths and S. V. Ley, J. Org. Chem. 2022, 87, 13204−13223.(https://doi.org/10.1021/acs.joc.2c01684).

905.  Photoredox-Catalyzed Preparation of Sulfones Using Bis-Piperidine Sulfur Dioxide – An Underutilized Reagent for SO2Transfer O.M. Griffiths, H.A. Esteves, D.C. Emmet and S.V. Ley Chem. Eur. J.,2024, 30, e202303976 (6 pages). (https://doi.org/10.1002/chem.202303976).

907.  Continuous flow synthesis enabling reaction discovery A.I. Alfano, J. García-Lacuna, O. M. Griffiths,  S.V. Ley and  M. Baumann.  Chem. Sci., 2024, 15, 4618-4630. (https://doi.org/10.1039/D3SC06808K).

The use of gases in synthesis is attractive for scale-up opportunities.  However, new technologies to  safely handle reactive gases are needed.  We highlight below some of the procedures we have introduced in our work:

• Flow ozonolysis using a semi-permeable Teflon™ AF-2400 membrane to effect gas-liquid contact M. O’Brien, I.R. Baxendale, S.V. Ley, Org. Lett. 2010, 12, 1596-1598.
• A palladium wall coated microcapillary reactor for use in continuous flow transfer hydrogenation C.H. Hornung, B. Hallmark, M.R. Mackley, I.R. Baxendale, S.V. Ley, Adv. Synth. Catal. 2010, 352, 1736-1745.
• The continuous flow synthesis of carboxylic acids using CO2 in a tube-in-tube gas permeable membrane reactor A. Polyzos, M. O’Brien, T. Pugaard-Petersen, I.R. Baxendale, S.V. Ley, Angew. Chem. Int. Ed. 2011, 50, 1190-1193.
• Hydrogenation in flow: homogenous and heterogeneous catalysts using Teflon AF-2400 to effect gas-liquid contact at elevated pressure M. O’Brien, N. Taylor, A. Polyzos, I.R. Baxendale, S.V. Ley Chem. Sci. 2011, 2, 1250-1257.
• Teflon AF-2400 mediated gas-liquid contact in continuous flow methoxycarbonylations and in-line FTIR measurement of CO Concentration P. Koos, U. Gross, A. Polyzos, M. O’Brien, I.R. Baxendale, S.V. Ley, Org. Biomol. Chem. 2011, 9, 6903-6908.
• Syngas mediated C-C bond formation in flow: selective rhodium catalysed hydroformylation of styrenes S. Kasinathan, S.L. Bourne, P. Tolstoy, P. Koos, M. O’Brien, R.W. Bates, I.R. Baxendale, S.V. Ley, Synlett 2011, 2648-2651.
• The oxygen mediated continuous flow synthesis of 1,3-butadiynes using Teflon AF-2400 to effect gas-liquid contact T.P. Peterson, A. Polyzos, M. O’Brien, T. Ulven, I.R. Baxendale, S.V. Ley, Chem. Sus. Chem. 2012, 5, 274-277.
• The continuous flow processing of gaseous ammonia using a Teflon AF-2400 tube in tube reactor: the synthesis of thioureas and in-line titrations D.L. Browne, M. O’Brien, P. Koos, P.B. Cranwell, A. Polyzos, S.V. Ley, Synlett 2012, 1402-1406.
• Asymmetric homogenous hydrogenation in flow using tube-in-tube reactor S. Newton, S.V. Ley, E.C. Arce, D. Grainger, Adv. Synth. Catal. 2012, 354, 1805-1812.
• Flow synthesis using gaseous ammonia in a Teflon AF 2400 tube in tube reactor: Paal-Knorr formation and gas concentration measurement with in-line titration P.B. Cranwell, M. O’Brien, D. Browne, P. Koos, A. Polyzos, M. Pêna López, S.V. Ley, Org. Biomol. Chem. 2012, 10, 5774-5779.
• Flow chemistry syntheses of styrenes, unsymmetrical stilbenes and branched aldehydes S.L. Bourne, M. O’Brien, S. Kasinathan, P. Koos, P. Tolstoy, D.X. Hu, R.W. Bates, B. Martin, B. Schenkel, S.V. Ley, ChemCatChem., 2013, 5, 159-172.
• Camera enabled techniques for organic synthesis S.V. Ley, R.J. Ingham, M. O’Brien, D.L. Browne, Beilstein J. Org. Chem. 2013, 9, 1051-1072.
• A continuous flow solution to achieving efficient, aerobic anti-Markovnikov Wacker oxidation S.L. Bourne, S.V. Ley, Adv. Synth. Catal. 2013, 355, 1905-1910.
• Scaling-up of continuous flow processes with gases using a tube-in-tube reactor: in-line titrations and fanetizole synthesis with ammonia J. Pastre, D.L. Browne, M. O’Brien, S.V. Ley, Org. Proc. Res. Dev. 2013, 17, 1183-1191.
• A general continuous flow method for palladium catalysed carbonylation reactions using single and multiple tube-in-tube gas-liquid microreactors U. Gross, P. Koos, M. O’Brien, A. Polyzos, S.V. Ley, Eur. J. Org. Chem. 2014, 6418-6430.
• Flow chemistry: intelligent processing of gas-liquid transformations using a tube-in-tube reactor M. Brzozowski, M. O’Brien, S.V. Ley,  A. Polyzos Acc. Chem. Res. 2015, 48, 349-362.
• An orthogonal biocatalytic approach for the safe generation and use of HCN in a multistep continuous preparation of chiral O-acetylcyanohydrins A. Brahma, B. Musio, U. Ismayilova, N. Nikbin, S.B. Kamptmann, P. Siegert, G.E. Jeromin, S.V. Ley, M. Pohl Synlett 2016, 27, 262-266.
• Controlled generation and use of CO in flow S.V.F. Hansen, Z.E. Wilson, T. Ulven, S.V. Ley React. Chem. Eng. 2016, 1, 280-287.
• Taming hazardous chemistry by continuous flow technology M. Movsisyan, E.I.P. Delbeke, J.K.E.T. Berton, C. Battilocchio, S.V. Ley, C.V. Stevens, Chem. Soc. Rev. 2016, 45, 4892-4928.
• Flow synthesis of cyclobutanones via [2 + 2] cycloaddition of keteneiminium salts and ethylene gas C. Battilocchio, G. Iannucci, S. Wang, E. Godineau, A. Kolleth, A. De Mesmaeker and S.V. Ley, React. Chem. Eng., 2017, 2, 295-298.
• A New World for Chemical Synthesis? S. V. Ley, Y. Chen, D.E. Fitzpatrick,  and O. May, CHIMIA 2019, 73, 792-802.
• Living with our machines: Towards a more sustainable future S. V. Ley, Y. Chen, D. E. Fitzpatrick and O. S. May Current Opinion in Green and Sustainable Chemistry 2020, 25, 100353.
• Process Intensification: From Green Chemistry to Continuous Processing, C. Battilocchio, S.V. Ley and E. Godineau in Sustainable Organic Synthesis: Tools and Strategies S. Protti and A. Palmieri (Eds.). RSC, 2021, 522-548 (Ch. 19). Print ISBN978-1-83916-203-9; ePub eISBN978-1-83916-485-9.
• Photoredox-Catalyzed Preparation of Sulfones Using Bis-Piperidine Sulfur Dioxide – An Underutilized Reagent for SO2Transfer O.M. Griffiths, H.A. Esteves, D.C. Emmet and S.V. Ley Chem. Eur.J.,2024, 30, e202303976 (6 pages).