The Info List - Organic Synthesis

--- Advertisement ---

ORGANIC SYNTHESIS is a special branch of chemical synthesis and is concerned with the construction of organic compounds via organic reactions . Organic molecules often contain a higher level of complexity than purely inorganic compounds, so that the synthesis of organic compounds 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 _.


* 1 Total synthesis * 2 Methodology and applications * 3 Stereoselective synthesis * 4 Synthesis design * 5 See also * 6 References * 7 Further reading * 8 External links


Main article: Total synthesis

A total synthesis is the complete chemical synthesis of complex organic molecules from simple, commercially available (petrochemical ) or natural precursors. 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. 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.

Robert Burns Woodward , who received the 1965 Nobel Prize for Chemistry for several total syntheses (e.g., his 1954 synthesis of strychnine ), is regarded as the father of modern organic synthesis. Some latter-day examples include Wender\'s , Holton\'s , Nicolaou\'s , and Danishefsky\'s total syntheses of the anti-cancer therapeutic, paclitaxel (trade name, Taxol ).


_ 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 )_

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 little work as possible. 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.

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 optimum 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. Such applications involve major industries focused especially on polymers (and plastics) and pharmaceuticals.


Main 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, and the bioactivity of chiral molecules varies with the enantiomer . 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 and Ryōji Noyori , and functional group modifications such as the asymmetric epoxidation of Barry Sharpless ; for these specific achievements, these workers were awarded the Nobel Prize in Chemistry in 2001. 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 pure enantiomers (i.e., without need for resolution). Such techniques are referred to as _stereoselective synthesis _.


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. 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, and less widely accepted, computer programs have been written for designing a synthesis based on sequences of generic "half-reactions".


* _ Organic Syntheses _ * _ Methods in Organic Synthesis _ * Electrosynthesis


* ^ _A_ _B_ Nicolaou, K. C. ; Sorensen, E. J. (1996). _Classics in Total Synthesis_. New York: VCH . * ^ Dighe, Nachiket (2010). "Convergent synthesis: A strategy to synthesize compounds of biological interest" (PDF). _Der Pharmacia Lettre_. 2: 318–328. * ^ "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.; 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. ISSN 0002-7863 . doi :10.1021/ja9635387 . * ^ 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. ISSN 0002-7863 . doi :10.1021/ja00083a066 . * ^ 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. PMID 7906395 . doi :10.1038/367630a0 . * ^ 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. ISSN 0002-7863 . doi :10.1021/ja952692a . * ^ " Taxol – The Drama behind Total Synthesis". _www.org-chem.org_. Retrieved 2016-11-20. * ^ March, J.; Smith, D. (2001). _Advanced Organic Chemistry, 5th ed_. New York: Wiley . * ^ 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: 2337–2347. PMID 16763676 . doi :10.1039/B602413K . 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. ISSN 1460-4744 . doi :10.1039/C2CS35116A . * ^ Blackmond, Donna G. (2016-11-20). "The Origin of Biological Homochirality" . _Cold Spring Harbor Perspectives in Biology_. 2 (5): a002147. ISSN 1943-0264 . PMC 2857173  _. PMID 20452962 . doi :10.1101/cshperspect.a002147 . * ^ 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 : IJBS_. 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. ISSN 1521-3773 . doi :10.1002/1521-3773(20020617)41:123.0.CO;2-8 . * ^ Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.; Akutagawa, S.; Sayo, N.; Saito, T. "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. ISSN 0002-7863 . doi :10.1021/ja00253a032 . * ^ Service. R.F. (2001). "Science Awards Pack a Full House of Winners" (print, online science news). _Science_. 294 (5542; October 19): 503–505. PMID 11641480 . doi :10.1126/science.294.5542.503b . Retrieved 2 March 2016. * ^ Corey, E. J. ; Cheng, X-M. (1995). _The Logic of Chemical Synthesis_. New York: Wiley . * ^ Todd, Matthew H. (2005). "Computer-aided Organic Synthesis". _ Chemical Society Reviews _. 34 (3): 247–266. PMID 15726161 . doi :10.1039/b104620a .


* Corey EJ ; Cheng, X-M (1995). _The Logic of Chemical Synthesis_. New York, NY: John Wiley & Sons . ISBN 978-0471115946 .


_ Wikimedia