Organic synthesis

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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

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 structuresseveral 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

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

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]

See also

Related Research Articles

Elias James Corey American chemist

Elias James "E.J." Corey is an American organic chemist. In 1990, he won the Nobel Prize in Chemistry "for his development of the theory and methodology of organic synthesis", specifically retrosynthetic analysis. Regarded by many as one of the greatest living chemists, he has developed numerous synthetic reagents, methodologies and total syntheses and has advanced the science of organic synthesis considerably.

In organic chemistry, the Diels–Alder reaction is a chemical reaction between a conjugated diene and a substituted alkene, commonly termed the dienophile, to form a substituted cyclohexene derivative. It is the prototypical example of a pericyclic reaction with a concerted mechanism. More specifically, it is classified as a thermally-allowed [4+2] cycloaddition with Woodward–Hoffmann symbol [π4s + π2s]. It was first described by Otto Diels and Kurt Alder in 1928. For the discovery of this reaction, they were awarded the Nobel Prize in Chemistry in 1950. Through the simultaneous construction of two new carbon–carbon bonds, the Diels–Alder reaction provides a reliable way to form six-membered rings with good control over the regio- and stereochemical outcomes. Consequently, it has served as a powerful and widely applied tool for the introduction of chemical complexity in the synthesis of natural products and new materials. The underlying concept has also been applied to π-systems involving heteroatoms, such as carbonyls and imines, which furnish the corresponding heterocycles; this variant is known as the hetero-Diels–Alder reaction. The reaction has also been generalized to other ring sizes, although none of these generalizations have matched the formation of six-membered rings in terms of scope or versatility. Because of the negative values of ΔH° and ΔS° for a typical Diels–Alder reaction, the microscopic reverse of a Diels–Alder reaction becomes favorable at high temperatures, although this is of synthetic importance for only a limited range of Diels-Alder adducts, generally with some special structural features; this reverse reaction is known as the retro-Diels–Alder reaction.

Aldol reaction

The aldol reaction is a means of forming carbon–carbon bonds in organic chemistry. Discovered independently by the Russian chemist Alexander Borodin in 1869 and by the French chemist Charles-Adolphe Wurtz in 1872, the reaction combines two carbonyl compounds to form a new β-hydroxy carbonyl compound. These products are known as aldols, from the aldehyde + alcohol, a structural motif seen in many of the products. Aldol structural units are found in many important molecules, whether naturally occurring or synthetic. For example, the aldol reaction has been used in the large-scale production of the commodity chemical pentaerythritol and the synthesis of the heart disease drug Lipitor.

Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially-available precursors. It usually refers to a process not involving the aid of biological processes, which distinguishes it from semisynthesis. The target molecules can be natural products, medicinally-important active ingredients, or organic compounds of theoretical interest.

Enantioselective synthesis

Enantioselective synthesis, also called asymmetric synthesis, is a form of chemical synthesis. It is defined by IUPAC as: a chemical reaction in which one or more new elements of chirality are formed in a substrate molecule and which produces the stereoisomeric products in unequal amounts.

In chemistry, stereoselectivity is the property of a chemical reaction in which a single reactant forms an unequal mixture of stereoisomers during a non-stereospecific creation of a new stereocenter or during a non-stereospecific transformation of a pre-existing one. The selectivity arises from differences in steric effects and electronic effects in the mechanistic pathways leading to the different products. Stereoselectivity can vary in degree but it can never be total since the activation energy difference between the two pathways is finite. Both products are at least possible and merely differ in amount. However, in favorable cases, the minor stereoisomer may not be detectable by the analytic methods used.

Chiral pool is a "collection of abundant enantiopure building blocks provided by nature" used in synthesis. Contributors to the chiral pool are amino acids, sugars, and terpenes. Their use improves the efficiency of total synthesis. Not only does the chiral pool contribute a premade carbon skeleton, their chirality is preserved in the remainder of the reaction sequence.

Trimethylsilyl

A trimethylsilyl group (abbreviated TMS) is a functional group in organic chemistry. This group consists of three methyl groups bonded to a silicon atom [−Si(CH3)3], which is in turn bonded to the rest of a molecule. This structural group is characterized by chemical inertness and a large molecular volume, which makes it useful in a number of applications.

Trögers base

Tröger's base is a white solid tetracyclic organic compound. structure and formula of (CH3C6H3NCH2)2CH2. Tröger's base and its analogs are soluble in various organic solvents and strong acidic aqueous solutions due to their protonation.

Biocatalysis

Biocatalysis refers to the use of living (biological) systems or their parts to speed up (catalyze) chemical reactions. In biocatalytic processes, natural catalysts, such as enzymes, perform chemical transformations on organic compounds. Both enzymes that have been more or less isolated and enzymes still residing inside living cells are employed for this task. Modern biotechnology, specifically directed evolution, has made the production of modified or non-natural enzymes possible. This has enabled the development of enzymes that can catalyze novel small molecule transformations that may be difficult or impossible using classical synthetic organic chemistry. Utilizing natural or modified enzymes to perform organic synthesis is termed chemoenzymatic synthesis; the reactions performed by the enzyme are classified as chemoenzymatic reactions.

Chiral auxiliary

A chiral auxiliary is a stereogenic group or unit that is temporarily incorporated into an organic compound in order to control the stereochemical outcome of the synthesis. The chirality present in the auxiliary can bias the stereoselectivity of one or more subsequent reactions. The auxiliary can then be typically recovered for future use.

Longifolene is the common chemical name of a naturally occurring, oily liquid hydrocarbon found primarily in the high-boiling fraction of certain pine resins. The name is derived from that of a pine species from which the compound was isolated, Pinus longifolia

Danishefsky Taxol total synthesis

The Danishefsky Taxol total synthesis in organic chemistry is an important third Taxol synthesis published by the group of Samuel Danishefsky in 1996 two years after the first two efforts described in the Holton Taxol total synthesis and the Nicolaou Taxol total synthesis. Combined they provide a good insight in the application of organic chemistry in total synthesis.

A carbometalation is any reaction where a carbon-metal bond reacts with a carbon-carbon π-bond to produce a new carbon-carbon σ-bond and a carbon-metal σ-bond. The resulting carbon-metal bond can undergo further carbometallation reactions or it can be reacted with a variety of electrophiles including halogenating reagents, carbonyls, oxygen, and inorganic salts to produce different organometallic reagents. Carbometalations can be performed on alkynes and alkenes to form products with high geometric purity or enantioselectivity, respectively. Some metals prefer to give the anti-addition product with high selectivity and some yield the syn-addition product. The outcome of syn and anti- addition products is determined by the mechanism of the carbometalation.

Jacobsens catalyst

Jacobsen's catalyst is the common name for N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminomanganese(III) chloride, a coordination compound of manganese and a salen-type ligand. It is used as an asymmetric catalyst in the Jacobsen epoxidation, which is renowned for its ability to enantioselectively transform prochiral alkenes into epoxides. Before its development, catalysts for the asymmetric epoxidation of alkenes required the substrate to have a directing functional group, such as an alcohol as seen in the Sharpless epoxidation. This compound has two enantiomers, which give the appropriate epoxide product from the alkene starting material.

Enders SAMP/RAMP hydrazone-alkylation reaction

The Enders SAMP/RAMP hydrazone alkylation reaction is an asymmetric carbon-carbon bond formation reaction facilitated by pyrrolidine chiral auxiliaries. It was pioneered by E. J. Corey and D. Enders in 1976, and was further developed by D. Enders and his group. This method is usually a three-step sequence. The first step is to form the hydrazone between (S)-1-amino-2-methoxymethylpyrrolidine (SAMP) or (R)-1-amino-2-methoxymethylpyrrolidine (RAMP) and a ketone or aldehyde. Afterwards, the hydrazone is deprotonated by lithium diisopropylamide (LDA) to form an azaenolate, which reacts with alkyl halides or other suitable electrophiles to give alkylated hydrazone species with the simultaneous generation of a new chiral center. Finally, the alkylated ketone or aldehyde can be regenerated by ozonolysis or hydrolysis.

Camphorsultam

Camphorsultam, also known as bornanesultam, is a crystalline solid primarily used as a chiral auxiliary in the synthesis of other chemicals with a specific desired stereoselectivity. Camphorsultam is commercially available in both enantiomers of its exo forms: (1R)-(+)-2,10-camphorsultam and (1S)-(−)-2,10-camphorsultam.

Ugis amine

Ugi’s amine is a chemical compound named for the chemist who first reported its synthesis in 1970, Ivar Ugi. It is a ferrocene derivative. Since its first report, Ugi’s amine has found extensive use as the synthetic precursor to a large number of metal ligands that bear planar chirality. These ligands have since found extensive use in a variety of catalytic reactions. The compound may exist in either the 1S or 1R isomer, both of which have synthetic utility and are commercially available. Most notably, it is the synthetic precursor to the Josiphos class of ligands.

Cobalt(II)–porphyrin catalysis is a process in which a Co(II) porphyrin complex acts as a catalyst, inducing and accelerating a chemical reaction.

Edwin Vedejs Latvian-American professor of chemistry

Edwin Vedejs was a Latvian-American professor of chemistry. In 1967, he joined the organic chemistry faculty at University of Wisconsin. He rose through the ranks during his 32 years at Wisconsin being named Helfaer Professor (1991–1996) and Robert M. Bock Professor (1997–1998). In 1999, he moved to the University of Michigan and served as the Moses Gomberg Collegiate Professor of Chemistry for the final 13 years of his tenure. He was elected a fellow of the American Chemical Society in 2011. After his retirement in 2011, the University of Michigan established the Edwin Vedejs Collegiate Professor of Chemistry Chair. Vedejs died on December 2, 2017, in Madison, Wisconsin.

References

  1. Cornforth, JW (1993-02-01). "The Trouble With Synthesis". Australian Journal of Chemistry. 46 (2): 157–170. doi: 10.1071/ch9930157 .
  2. 1 2 Nicolaou, K. C.; Sorensen, E. J. (1996). Classics in Total Synthesis . New York: VCH.[ page needed ]
  3. "Nobelprize.org". www.nobelprize.org. Retrieved 2016-11-20.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. "Taxol – The Drama behind Total Synthesis". www.org-chem.org. Archived from the original on 2011-07-27. Retrieved 2016-11-20.
  10. March, J.; Smith, D. (2001). Advanced Organic Chemistry, 5th ed. New York: Wiley.[ page needed ]
  11. 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.CS1 maint: uses authors parameter (link)
  12. 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.
  13. 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.
  14. 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.
  15. Welch, CJ (1995). Advances in Chromatography. New York: Marcel Dekker, Inc. p. 172.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. Corey, E. J.; Cheng, X-M. (1995). The Logic of Chemical Synthesis. New York: Wiley.[ page needed ]
  22. Todd, Matthew H. (2005). "Computer-aided Organic Synthesis". Chemical Society Reviews . 34 (3): 247–266. doi:10.1039/b104620a. PMID   15726161.

Further reading