guest editorial for asymmetric synthesis on large scale special issue

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Published: August 24, 2011 r2011 American Chemical Society 1088 dx.doi.org/10.1021/op200214d | Org. Process Res. Dev. 2011, 15, 10881088 EDITORIAL pubs.acs.org/OPRD Guest Editorial for Asymmetric Synthesis on Large Scale Special Issue I t has been four years since our last special feature on asym- metric synthesis on large scale. Thus, it is time to once again dedicate an issue to this topic and to see if the favored methods from 2007 are still the favored methods today. In the past four years the chemical and, in particular, the pharmaceutical industry has faced ever increasing challenges of addressing not only economics and process safety but also to deliver on: 9 greenor more sustainable processes (special feature 2011, issue 4) 9 the tighter regulations around control of genotoxic impu- rities (special feature 2010, issue 4) 9 the trend towards greater complexity in pharmaceutically active molecules. For these reasons the bar to dene an acceptable large scale synthesis continues to rise and in turn provides the driver to develop more ecient methods for delivery of chiral molecules. A recent review (J. Med. Chem. 2011, 54, 3451) indicated that at least a third of compounds generated by medicinal chemistry groups contain at least one chiral centre, highlighting the importance of the controlled introduction of such chiral centres on large scale. In reading the submitted papers, we see the majority of papers are from the Pharmaceutical industry; however there are also contributions from academic laboratories and chemical compa- nies. The most prevalent reaction presented is the catalytic asymmetric hydrogenation, and the most common structural motif targeted is an amino acid (either R or β). Asymmetric hydrogenations in various dierent guises feature in the papers by Praquin, Grayson, Campeau, Challenger, Matsumura, Fox, and Goto. Substrates for the hydrogenation include enamides, enamines, benzophenones, and a tetrasubstituted alkene. Two papers use chiral pool starting material in their approaches, either to introduce the single stereocentre (Scott) or to build additional stereocentres via diastereoselective transformations (Tang). Single examples use Sharpless asymmetric dihydroxylation (Erhard), chiral cyclopropanation (Pibworth), and Ellman chemistry (Pibworth). A nice example of Seebachs self-regeneration of stereocenters proce- dure is illustrated in the paper by Wang. The two papers from Wulare dierent in approach, in that they focus on ligand design and synthesis, followed by application to two dierent catalytic reactions. We were interested to note that for the most part asymmetric biocatalytic reactions were largely absent from the papers we have received for this issue. Grayson et al. compare an asymmetric hydrogenation approach to β-phenylalanine derivatives with enzy- matic resolutions using either lipases or acyclases. However no examples of the more recently developed asymmetric reduction or nonresolution approaches using enzymes were submitted (although a number of papers did appear in the special issue on biocata- lysis earlier this year, 2011, issue 1). This suggests that despite the considerable advances that have occurred in the area of ketoreduc- tase and transaminase reactions over the past ve years, these reactions have yet to feature signicantly in larger scale reactions. In a similar way, transformations employing organocatalysis are also not seen in this collection of papers, despite the large number of academic groups working in the area. We hope the readership of OPRD will nd this collection of papers both interesting and inspiring, and that the process community continues to work towards solving the remaining challenges around asymmetric synthesis. We will be particularly keen to see if a comparable issue ve years from now embraces a larger range of asymmetric transformation than we see today. Debra Wallace Department of Process Chemistry Merck Research Laboratories, P.O. Box 2000 Rahway, New Jersey 07065, United States. E-mail: [email protected]. Phone: 001 732 594 3041. Stephen Challenger Chemical Research & Development Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, U.K. E-mail: stephen. challenger@pzer.com. Special Issue: Asymmetric Synthesis on Large Scale 2011

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Page 1: Guest Editorial for Asymmetric Synthesis on Large Scale Special Issue

Published: August 24, 2011

r 2011 American Chemical Society 1088 dx.doi.org/10.1021/op200214d |Org. Process Res. Dev. 2011, 15, 1088–1088

EDITORIAL

pubs.acs.org/OPRD

Guest Editorial for Asymmetric Synthesis on Large Scale Special Issue

It has been four years since our last special feature on asym-metric synthesis on large scale. Thus, it is time to once again

dedicate an issue to this topic and to see if the favored methodsfrom 2007 are still the favored methods today. In the past fouryears the chemical and, in particular, the pharmaceutical industryhas faced ever increasing challenges of addressing not onlyeconomics and process safety but also to deliver on:9 “green” or more sustainable processes (special feature2011, issue 4)9 the tighter regulations around control of genotoxic impu-rities (special feature 2010, issue 4)9 the trend towards greater complexity in pharmaceuticallyactive molecules.For these reasons the bar to define an acceptable large scale

synthesis continues to rise and in turn provides the driver todevelop more efficient methods for delivery of chiral molecules.A recent review (J. Med. Chem. 2011, 54, 3451) indicated that atleast a third of compounds generated by medicinal chemistrygroups contain at least one chiral centre, highlighting theimportance of the controlled introduction of such chiral centreson large scale.In reading the submitted papers, we see the majority of papers

are from the Pharmaceutical industry; however there are alsocontributions from academic laboratories and chemical compa-nies. The most prevalent reaction presented is the catalyticasymmetric hydrogenation, and the most common structuralmotif targeted is an amino acid (either R or β). Asymmetrichydrogenations in various different guises feature in the papersby Praquin, Grayson, Campeau, Challenger, Matsumura, Fox,and Goto. Substrates for the hydrogenation include enamides,enamines, benzophenones, and a tetrasubstituted alkene. Twopapers use chiral pool starting material in their approaches, eitherto introduce the single stereocentre (Scott) or to build additionalstereocentres via diastereoselective transformations (Tang). Singleexamples use Sharpless asymmetric dihydroxylation (Erhard), chiralcyclopropanation (Pibworth), and Ellman chemistry (Pibworth). Anice example of Seebach’s self-regeneration of stereocenters proce-dure is illustrated in the paper byWang. The two papers fromWulffare different in approach, in that they focus on ligand design andsynthesis, followed by application to two different catalytic reactions.We were interested to note that for the most part asymmetric

biocatalytic reactions were largely absent from the papers we havereceived for this issue. Grayson et al. compare an asymmetrichydrogenation approach to β-phenylalanine derivatives with enzy-matic resolutions using either lipases or acyclases. However noexamples of the more recently developed asymmetric reduction ornonresolution approaches using enzymeswere submitted (althougha number of papers did appear in the special issue on biocata-lysis earlier this year, 2011, issue 1). This suggests that despite theconsiderable advances that have occurred in the area of ketoreduc-tase and transaminase reactions over the past five years, thesereactions have yet to feature significantly in larger scale reactions.In a similar way, transformations employing organocatalysis are also

not seen in this collection of papers, despite the large number ofacademic groups working in the area.We hope the readership of OPRD will find this collection of

papers both interesting and inspiring, and that the processcommunity continues to work towards solving the remainingchallenges around asymmetric synthesis. We will be particularlykeen to see if a comparable issue five years from now embraces alarger range of asymmetric transformation than we see today.

Debra Wallace

Department of Process ChemistryMerck Research Laboratories, P.O.Box 2000 Rahway, New Jersey 07065, United States. E-mail:[email protected]. Phone: 001 732 594 3041.

Stephen Challenger

Chemical Research & Development Sandwich Laboratories,Ramsgate Road, Sandwich, Kent CT13 9NJ, U.K. E-mail: [email protected].

Special Issue: Asymmetric Synthesis on Large Scale 2011