A total synthesis is the complete chemical synthesis of complex organicmolecules from simple, commercially available petrochemical or natural precursors.[2] Total synthesis may be accomplished either via a linear or convergent approach. In a linear synthesis—often adequate for simple structures—several steps are performed one after another until the molecule is complete; the chemical compounds made in each step are called synthetic intermediates.[2] Most often, each step in a synthesis refers to a separate reaction taking place to modify the starting compound. For more complex molecules, a convergent synthetic approach may be preferable, one that involves individual preparation of several "pieces" (key intermediates), which are then combined to form the desired product.[citation needed] Convergent synthesis has the advantage of generating higher yield, compared to linear synthesis.
Each step of a synthesis involves a chemical reaction, and reagents and conditions for each of these reactions must be designed to give an adequate yield of pure product, with as few steps as possible.[10] A method may already exist in the literature for making one of the early synthetic intermediates, and this method will usually be used rather than an effort to "reinvent the wheel". However, most intermediates are compounds that have never been made before, and these will normally be made using general methods developed by methodology researchers. To be useful, these methods need to give high yields, and to be reliable for a broad range of substrates. For practical applications, additional hurdles include industrial standards of safety and purity.[11]
Methodology research usually involves three main stages: discovery, optimisation, and studies of scope and limitations. The discovery requires extensive knowledge of and experience with chemical reactivities of appropriate reagents. Optimisation is a process in which one or two starting compounds are tested in the reaction under a wide variety of conditions of temperature, solvent, reaction time, etc., until the optimal conditions for product yield and purity are found. Finally, the researcher tries to extend the method to a broad range of different starting materials, to find the scope and limitations. Total syntheses (see above) are sometimes used to showcase the new methodology and demonstrate its value in a real-world application.[12] Such applications involve major industries focused especially on polymers (and plastics) and pharmaceuticals. Some syntheses are feasible on a research or academic level, but not for industry level production. This may lead to further modification of the process. [13]
Most complex natural products are chiral,[14][15] and the bioactivity of chiral molecules varies with the enantiomer.[16] Historically, total syntheses targeted racemic mixtures, mixtures of both possible enantiomers, after which the racemic mixture might then be separated via chiral resolution.
In the later half of the twentieth century, chemists began to develop methods of stereoselective catalysis and kinetic resolution whereby reactions could be directed to produce only one enantiomer rather than a racemic mixture. Early examples include stereoselective hydrogenations (e.g., as reported by William Knowles[17] and Ryōji Noyori,[18] and functional group modifications such as the asymmetric epoxidation of Barry Sharpless;[19] for these specific achievements, these workers were awarded the Nobel Prize in Chemistry in 2001.[20] Such reactions gave chemists a much wider choice of enantiomerically pure molecules to start from, where previously only natural starting materials could be used. Using techniques pioneered by Robert B. Woodward and new developments in synthetic methodology, chemists became more able to take simple molecules through to more complex molecules without unwanted racemisation, by understanding stereocontrol, allowing final target molecules to be synthesised as pure enantiomers (i.e., without need for resolution). Such techniques are referred to as stereoselective synthesis.
Synthesis design
Elias James Corey brought a more formal approach to synthesis design, based on retrosynthetic analysis, for which he won the Nobel Prize for Chemistry in 1990. In this approach, the synthesis is planned backwards from the product, using standard rules.[21] The steps "breaking down" the parent structure into achievable component parts are shown in a graphical scheme that uses retrosynthetic arrows (drawn as ⇒, which in effect, mean "is made from").
More recently,[when?] and less widely accepted, computer programs have been written for designing a synthesis based on sequences of generic "half-reactions".[22]
^Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.; Schenker, K. (1954). "The Total Synthesis of Strychnine". Journal of the American Chemical Society. 76 (18): 4749–4751. doi:10.1021/ja01647a088.
^Wender, Paul A.; Badham, Neil F.; Conway, Simon P.; Floreancig, Paul E.; Glass, Timothy E.; Gränicher, Christian; Houze, Jonathan B.; Jänichen, Jan; Lee, Daesung (1997-03-01). "The Pinene Path to Taxanes. 5. Stereocontrolled Synthesis of a Versatile Taxane Precursor". Journal of the American Chemical Society. 119 (11): 2755–2756. doi:10.1021/ja9635387. ISSN 0002-7863.
^Holton, Robert A.; Somoza, Carmen; Kim, Hyeong Baik; Liang, Feng; Biediger, Ronald J.; Boatman, P. Douglas; Shindo, Mitsuru; Smith, Chase C.; Kim, Soekchan (1994-02-01). "First total synthesis of taxol. 1. Functionalization of the B ring". Journal of the American Chemical Society. 116 (4): 1597–1598. doi:10.1021/ja00083a066. ISSN 0002-7863.
^Nicolaou, K. C.; Yang, Z.; Liu, J. J.; Ueno, H.; Nantermet, P. G.; Guy, R. K.; Claiborne, C. F.; Renaud, J.; Couladouros, E. A. (1994-02-17). "Total synthesis of taxol". Nature. 367 (6464): 630–634. Bibcode:1994Natur.367..630N. doi:10.1038/367630a0. PMID 7906395. S2CID 4371975.
^Danishefsky, Samuel J.; Masters, John J.; Young, Wendy B.; Link, J. T.; Snyder, Lawrence B.; Magee, Thomas V.; Jung, David K.; Isaacs, Richard C. A.; Bornmann, William G. (1996-01-01). "Total Synthesis of Baccatin III and Taxol". Journal of the American Chemical Society. 118 (12): 2843–2859. doi:10.1021/ja952692a. ISSN 0002-7863.
^. www.org-chem.org. Archived from the original on 2011-07-27. Retrieved 2016-11-20.
^March, J.; Smith, D. (2001). Advanced Organic Chemistry, 5th ed. New York: Wiley.[page needed]
^Carey, J.S.; Laffan, D.; Thomson, C. & Williams, M.T. (2006). "Analysis of the reactions used for the preparation of drug candidate molecules". Org. Biomol. Chem. 4 (12): 2337–2347. doi:10.1039/B602413K. PMID 16763676. S2CID 20800243.{{cite journal}}: CS1 maint: uses authors parameter (link)
^Nicolaou, K. C.; Hale, Christopher R. H.; Nilewski, Christian; Ioannidou, Heraklidia A. (2012-07-09). "Constructing molecular complexity and diversity: total synthesis of natural products of biological and medicinal importance". Chemical Society Reviews. 41 (15): 5185–5238. doi:10.1039/C2CS35116A. ISSN 1460-4744. PMC3426871. PMID 22743704.
^Chen, Weiming; Suo, Jin; Liu, Yongjian; Xie, Yuanchao; Wu, Mingjun; Zhu, Fuqiang; Nian, Yifeng; Aisa, Haji A.; Shen, Jingshan (2019-03-08). "Industry-Oriented Route Evaluation and Process Optimization for the Preparation of Brexpiprazole". Organic Process Research & Development. 23 (5): 852–857. doi:10.1021/acs.oprd.8b00438. ISSN 1083-6160. S2CID 104375334.
^Blackmond, Donna G. (2016-11-20). "The Origin of Biological Homochirality". Cold Spring Harbor Perspectives in Biology. 2 (5): a002147. doi:10.1101/cshperspect.a002147. ISSN 1943-0264. PMC2857173. PMID 20452962.
^Welch, CJ (1995). Advances in Chromatography. New York: Marcel Dekker, Inc. p. 172.
^Nguyen, Lien Ai; He, Hua; Pham-Huy, Chuong (2016-11-20). "Chiral Drugs: An Overview". International Journal of Biomedical Science. 2 (2): 85–100. ISSN 1550-9702. PMC3614593. PMID 23674971.
^Knowles, William S. (2002-06-17). "Asymmetric Hydrogenations (Nobel Lecture)". Angewandte Chemie International Edition. 41 (12): 1998–2007. doi:10.1002/1521-3773(20020617)41:12<1998::AID-ANIE1998>3.0.CO;2-8. ISSN 1521-3773. PMID 19746594.
^Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.; Akutagawa, S.; Sayo, N.; Saito, T. (1989). "Stereoselective hydrogenation via dynamic kinetic resolution". Journal of the American Chemical Society. 111 (25): 9134–9135. doi:10.1021/ja00207a038.
^Gao, Yun; Klunder, Janice M.; Hanson, Robert M.; Masamune, Hiroko; Ko, Soo Y.; Sharpless, K. Barry (1987-09-01). "Catalytic asymmetric epoxidation and kinetic resolution: modified procedures including in situ derivatization". Journal of the American Chemical Society. 109 (19): 5765–5780. doi:10.1021/ja00253a032. ISSN 0002-7863.
^Service. R.F. (2001). "Science Awards Pack a Full House of Winners". Science. 294 (5542, October 19): 503–505. doi:10.1126/science.294.5542.503b. PMID 11641480. S2CID 220109249.
^Todd, Matthew H. (2005). "Computer-aided Organic Synthesis". Chemical Society Reviews. 34 (3): 247–266. doi:10.1039/b104620a. PMID 15726161. S2CID 4668678.
organic, synthesis, this, article, about, artificial, synthesis, organic, compounds, journal, organic, syntheses, synthesis, organisms, biosynthesis, this, article, needs, additional, citations, verification, please, help, improve, this, article, adding, citat. This article is about artificial synthesis of organic compounds For the journal see Organic Syntheses For synthesis in organisms see Biosynthesis This article needs additional citations for verification Please help improve this article by adding citations to reliable sources Unsourced material may be challenged and removed Find sources Organic synthesis news newspapers books scholar JSTOR March 2016 Learn how and when to remove this template message Organic synthesis is a special branch of chemical synthesis and is concerned with the intentional construction of organic compounds 1 Organic molecules are often more complex than inorganic compounds and their synthesis has developed into one of the most important branches of organic chemistry There are several main areas of research within the general area of organic synthesis total synthesis semisynthesis and methodology Contents 1 Total synthesis 2 Methodology and applications 3 Stereoselective synthesis 4 Synthesis design 5 See also 6 References 7 Further reading 8 External linksTotal synthesis EditMain article Total synthesis A total synthesis is the complete chemical synthesis of complex organic molecules from simple commercially available petrochemical or natural precursors 2 Total synthesis may be accomplished either via a linear or convergent approach In a linear synthesis often adequate for simple structures several steps are performed one after another until the molecule is complete the chemical compounds made in each step are called synthetic intermediates 2 Most often each step in a synthesis refers to a separate reaction taking place to modify the starting compound For more complex molecules a convergent synthetic approach may be preferable one that involves individual preparation of several pieces key intermediates which are then combined to form the desired product citation needed Convergent synthesis has the advantage of generating higher yield compared to linear synthesis Robert Burns Woodward who received the 1965 Nobel Prize for Chemistry for several total syntheses 3 e g his 1954 synthesis of strychnine 4 is regarded as the father of modern organic synthesis Some latter day examples include Wender s 5 Holton s 6 Nicolaou s 7 and Danishefsky s 8 total syntheses of the anti cancer therapeutic paclitaxel trade name Taxol 9 Methodology and applications EditThis section needs additional citations for verification Please help improve this article by adding citations to reliable sources Unsourced material may be challenged and removed March 2016 Learn how and when to remove this template message Each step of a synthesis involves a chemical reaction and reagents and conditions for each of these reactions must be designed to give an adequate yield of pure product with as few steps as possible 10 A method may already exist in the literature for making one of the early synthetic intermediates and this method will usually be used rather than an effort to reinvent the wheel However most intermediates are compounds that have never been made before and these will normally be made using general methods developed by methodology researchers To be useful these methods need to give high yields and to be reliable for a broad range of substrates For practical applications additional hurdles include industrial standards of safety and purity 11 Methodology research usually involves three main stages discovery optimisation and studies of scope and limitations The discovery requires extensive knowledge of and experience with chemical reactivities of appropriate reagents Optimisation is a process in which one or two starting compounds are tested in the reaction under a wide variety of conditions of temperature solvent reaction time etc until the optimal conditions for product yield and purity are found Finally the researcher tries to extend the method to a broad range of different starting materials to find the scope and limitations Total syntheses see above are sometimes used to showcase the new methodology and demonstrate its value in a real world application 12 Such applications involve major industries focused especially on polymers and plastics and pharmaceuticals Some syntheses are feasible on a research or academic level but not for industry level production This may lead to further modification of the process 13 Stereoselective synthesis EditMain article Chiral synthesis This section needs additional citations for verification Please help improve this article by adding citations to reliable sources Unsourced material may be challenged and removed March 2016 Learn how and when to remove this template message Most complex natural products are chiral 14 15 and the bioactivity of chiral molecules varies with the enantiomer 16 Historically total syntheses targeted racemic mixtures mixtures of both possible enantiomers after which the racemic mixture might then be separated via chiral resolution In the later half of the twentieth century chemists began to develop methods of stereoselective catalysis and kinetic resolution whereby reactions could be directed to produce only one enantiomer rather than a racemic mixture Early examples include stereoselective hydrogenations e g as reported by William Knowles 17 and Ryōji Noyori 18 and functional group modifications such as the asymmetric epoxidation of Barry Sharpless 19 for these specific achievements these workers were awarded the Nobel Prize in Chemistry in 2001 20 Such reactions gave chemists a much wider choice of enantiomerically pure molecules to start from where previously only natural starting materials could be used Using techniques pioneered by Robert B Woodward and new developments in synthetic methodology chemists became more able to take simple molecules through to more complex molecules without unwanted racemisation by understanding stereocontrol allowing final target molecules to be synthesised as pure enantiomers i e without need for resolution Such techniques are referred to as stereoselective synthesis Synthesis design EditElias James Corey brought a more formal approach to synthesis design based on retrosynthetic analysis for which he won the Nobel Prize for Chemistry in 1990 In this approach the synthesis is planned backwards from the product using standard rules 21 The steps breaking down the parent structure into achievable component parts are shown in a graphical scheme that uses retrosynthetic arrows drawn as which in effect mean is made from More recently when and less widely accepted computer programs have been written for designing a synthesis based on sequences of generic half reactions 22 See also EditOrganic Syntheses journal Methods in Organic Synthesis journal Electrosynthesis Automated SynthesisReferences Edit Cornforth JW 1993 02 01 The Trouble With Synthesis Australian Journal of Chemistry 46 2 157 170 doi 10 1071 ch9930157 a b Nicolaou K C Sorensen E J 1996 Classics in Total Synthesis New York VCH page needed Nobelprize org www nobelprize org Retrieved 2016 11 20 Woodward R B Cava M P Ollis W D Hunger A Daeniker H U Schenker K 1954 The Total Synthesis of Strychnine Journal of the American Chemical Society 76 18 4749 4751 doi 10 1021 ja01647a088 Wender Paul A Badham Neil F Conway Simon P Floreancig Paul E Glass Timothy E Granicher Christian Houze Jonathan B Janichen Jan Lee Daesung 1997 03 01 The Pinene Path to Taxanes 5 Stereocontrolled Synthesis of a Versatile Taxane Precursor Journal of the American Chemical Society 119 11 2755 2756 doi 10 1021 ja9635387 ISSN 0002 7863 Holton Robert A Somoza Carmen Kim Hyeong Baik Liang Feng Biediger Ronald J Boatman P Douglas Shindo Mitsuru Smith Chase C Kim Soekchan 1994 02 01 First total synthesis of taxol 1 Functionalization of the B ring Journal of the American Chemical Society 116 4 1597 1598 doi 10 1021 ja00083a066 ISSN 0002 7863 Nicolaou K C Yang Z Liu J J Ueno H Nantermet P G Guy R K Claiborne C F Renaud J Couladouros E A 1994 02 17 Total synthesis of taxol Nature 367 6464 630 634 Bibcode 1994Natur 367 630N doi 10 1038 367630a0 PMID 7906395 S2CID 4371975 Danishefsky Samuel J Masters John J Young Wendy B Link J T Snyder Lawrence B Magee Thomas V Jung David K Isaacs Richard C A Bornmann William G 1996 01 01 Total Synthesis of Baccatin III and Taxol Journal of the American Chemical Society 118 12 2843 2859 doi 10 1021 ja952692a ISSN 0002 7863 Taxol The Drama behind Total Synthesis www org chem org Archived from the original on 2011 07 27 Retrieved 2016 11 20 March J Smith D 2001 Advanced Organic Chemistry 5th ed New York Wiley page needed Carey J S Laffan D Thomson C amp Williams M T 2006 Analysis of the reactions used for the preparation of drug candidate molecules Org Biomol Chem 4 12 2337 2347 doi 10 1039 B602413K PMID 16763676 S2CID 20800243 a href Template Cite journal html title Template Cite journal cite journal a CS1 maint uses authors parameter link Nicolaou K C Hale Christopher R H Nilewski Christian Ioannidou Heraklidia A 2012 07 09 Constructing molecular complexity and diversity total synthesis of natural products of biological and medicinal importance Chemical Society Reviews 41 15 5185 5238 doi 10 1039 C2CS35116A ISSN 1460 4744 PMC 3426871 PMID 22743704 Chen Weiming Suo Jin Liu Yongjian Xie Yuanchao Wu Mingjun Zhu Fuqiang Nian Yifeng Aisa Haji A Shen Jingshan 2019 03 08 Industry Oriented Route Evaluation and Process Optimization for the Preparation of Brexpiprazole Organic Process Research amp Development 23 5 852 857 doi 10 1021 acs oprd 8b00438 ISSN 1083 6160 S2CID 104375334 Blackmond Donna G 2016 11 20 The Origin of Biological Homochirality Cold Spring Harbor Perspectives in Biology 2 5 a002147 doi 10 1101 cshperspect a002147 ISSN 1943 0264 PMC 2857173 PMID 20452962 Welch CJ 1995 Advances in Chromatography New York Marcel Dekker Inc p 172 Nguyen Lien Ai He Hua Pham Huy Chuong 2016 11 20 Chiral Drugs An Overview International Journal of Biomedical Science 2 2 85 100 ISSN 1550 9702 PMC 3614593 PMID 23674971 Knowles William S 2002 06 17 Asymmetric Hydrogenations Nobel Lecture Angewandte Chemie International Edition 41 12 1998 2007 doi 10 1002 1521 3773 20020617 41 12 lt 1998 AID ANIE1998 gt 3 0 CO 2 8 ISSN 1521 3773 PMID 19746594 Noyori R Ikeda T Ohkuma T Widhalm M Kitamura M Takaya H Akutagawa S Sayo N Saito T 1989 Stereoselective hydrogenation via dynamic kinetic resolution Journal of the American Chemical Society 111 25 9134 9135 doi 10 1021 ja00207a038 Gao Yun Klunder Janice M Hanson Robert M Masamune Hiroko Ko Soo Y Sharpless K Barry 1987 09 01 Catalytic asymmetric epoxidation and kinetic resolution modified procedures including in situ derivatization Journal of the American Chemical Society 109 19 5765 5780 doi 10 1021 ja00253a032 ISSN 0002 7863 Service R F 2001 Science Awards Pack a Full House of Winners Science 294 5542 October 19 503 505 doi 10 1126 science 294 5542 503b PMID 11641480 S2CID 220109249 Corey E J Cheng X M 1995 The Logic of Chemical Synthesis New York Wiley page needed Todd Matthew H 2005 Computer aided Organic Synthesis Chemical Society Reviews 34 3 247 266 doi 10 1039 b104620a PMID 15726161 S2CID 4668678 Further reading EditCorey EJ Cheng X M 1995 The Logic of Chemical Synthesis New York NY John Wiley amp Sons ISBN 978 0471115946 External links Edit Wikimedia Commons has media related to Organic syntheses The Organic Synthesis Archive Chemical synthesis database https web archive org web 20070927231356 http www webreactions net search html https www organic chemistry org synthesis Prof Hans Reich s collection ofnatural product syntheses Chemical synthesis semantic wiki Retrieved from https en wikipedia org w index php title Organic synthesis amp oldid 1119831076, wikipedia, wiki, book, books, library,
