Total Synthesis of Any Natural Product - Report Example

Total Synthesis of Aflatoxin B2 Introduction Aflatoxins are a group of acutely toxic mycotoxins produced naturally by a group of fungus known as Aspergillus. Aflatoxin compounds are highly toxic and are capable of causing serious damages to the liver and kidney leading to cirrhosis, hemorrhage or degeneration of the liver. Other organs that may also be affected are the gall bladder, gut, pancreas and the lungs if ingested. Aflatoxin is important in our environment and society at large due to its poisonous effects on food and has been used as biological weapon in wars. There are different types of Aflatoxins: aflatoxin B1, aflatoxin M1, aflatoxin G1, aflatoxin B2 aflatoxin M2 and aflatoxin G2. However, this report focuses on the total synthesis of aflatoxin B2. The target molecule for this library report is Aflatoxin B2 which was selected from a publication entitled “Studies in Mycological Chemistry. Part XXII. Total Synthesis of (±)-Aflatoxin-B2” from the Journal of the Chemical Society C: Organic of the year 1968 on page 22. The authors of this publication are Robert, Sheppard, Roffey and Knight. Total synthesis of Aflatoxin B2 The total synthesis of aflatoxin B2 is a multistep process and sequence that was reported first by Robert et al (22). In this initial synthesis, they began with a tricyclic compound in which. The compound was taken through condensation with diethyl beta-oxoadipate which resulted into the formation of lactone. The ethyl ester formed was hydrolyzed followed by formation of acid chloride with oxalyl chloride. This was then taken through acylation process without further purification to yield racemic aflatoxin B2. The second total synthesis was published in 1990 by a group of scientists (Trost and Dean, 3090). They began with the intermediate by first regioselectively de-iodinating the intermediate compound to give a free alcohol. The free alcohol was then protected using benzyl ether followed by exchange of a metal halogen with n-BuLi. The products were then followed by transmetalation with lithium 2-thienylcyno curate. The final addition of cuprate unto the cyclopentanone resulted into benzyl ether. A five ringed species was then produced by cleavage of the benzyl ether through hydrolysis process. This product was then taken through oxidation process to produce aflatoxin B2. The first enantioselective total synthesis of aflatoxin B2 was first presented by Zhou and Corey in 2005. They began by tricyclic compound addition between 2,3-Dihydrofuran and a Quinone in the presence of a Corey-Bakshi-Shibata (CBS) catalyst. The products go to the second reaction in which there is orthoformylation in a duff reaction resulting into the formation of hydroxyl group. The second stage is an esterification of the hydroxyl group formed with triflic in order to add a triflate protecting group to the aldehyde formed. This step is very important since it enhances the reaction of the aldehyde group. The aldehyde group then reacts with methylmagnesiumbromide to form alcohol. The alcohol formed is then taken through an oxidation process using Dess-Martin periodinane to form a ketone. The ketone is then taken through an esterification process using a Baeyer-Villiger oxidation to form a simple ester. The triflic acid group is then removed from the esterified compound through a reduction process in the presence of Raney nickel to form an alcohol. The last step is a combined coupling reaction of the alcohol with zinc carbonate and the trans-esterification between ethyl ester group and the phenol group (Gang & Corey, 11958). The alternate and most recent synthesis of aflatoxin B2 was published in 2005 by Gang and Core (11958). The difference between this step and the previous one is what the scholars referred to as Dotz benzannulation. In this alternate synthesis the bromohydrin is formed as a result of dehydration of the intermediate product followed by cyclization mediated by cobalt . This is followed by ozonolysis to form hydrazine. The Dotz reaction processor is then formed from the removal of hydrazine from the compound by reduction and formation of Chromium-carbonyl. The Dotz precursor then reacts with alkyne followed by oxidation and hydrogenation. The second step is pyrolysis which yields protected and free alcohol which is then protected as a triflate. The removal of the triflate through oxidation result into deprotection of silyl ether yielding aflatoxin B2. Considering the above two alternate methods for total synthesis of aflatoxin B2, we can see that the Dotz reaction is efficient in terms of providing a ready access to the pivotal intermediate which is necessary for the total synthesis of aflatoxin B2. However, it only precedes in a moderate yield of about 30% thus its convergent nature. This convergent nature finally leads to the most important and highly functionalized intermediate dilutes its initial ready access pivotal intermediate. It is also important to note that silicon substituent controls the regiochemistry of the first Dotz reaction and avails a facile way through the selective protection as well as deoxygenation of a hydroquinone intermediate can easily be achieved. The Dotz reaction is also limited by the fact that it holds potential limitations since it cannot be effectively applied in electronically mismatched or congested alkyne partners. Sometimes the reaction may call for the use of stabilizing substituents. The first enantioselective total synthesis of aflatoxin B2 is therefore most effective. It is a highly enantioselective 3,2 cycloaddition reaction between 1,4 benzoquinones with 2,3 dihydrofuran in the presence of chiral oxazaborolidinium triflimidate as a catalyst. This is highly effective since it allows rapid access to a variety and different phenolic tricycles. In this regard enantiometric excess ranges from ninety one to ninety eight percent. This new methodology is also effective since it demonstrate a short synthesis of the essential pentacyclic natural product which is aflatoxin B2. This synthesis also gives room for broader applications of different catalysts in the multi-step synthesis. It is therefore the best alternative for the total synthesis of aflatoxin B2. This article has advanced the overall study in organic chemistry since it outlines the principles of organic chemistry in the multi step synthesis. The principle such as cycloaddition forms the first step involving quinone and 2, 3-Dihydrofuran. This is the formation of a cyclic compound by unsaturated molecules leading to the net reduction in the bonds. In this synthesis, there is also etherification of hydroxyl group with triflic anhydride to form esters. These are compounds derived from the reaction between oxoacid and the hydroxyl and in this particular reaction by condensing acids and alcohols. There are also a number of organic redox reactions involving different compounds in the synthesis pathway. Generally, this multi step synthesis of aflatoxin B2 combines a number of organic chemistry principles to eventually get the final product. Conclusions The total synthesis of aflatoxin B2 serves different purposes just like the other compounds targeted in the organic chemistry. First, this synthesis is important in advancing the overall study of organic chemistry for the study of different complex compounds with respect to their structure and the evidence from spectroscopy. Second, Synthesis of Aflatoxin B2 is a demonstration of the new organic chemistry concepts in the study of reagents and reaction pathways. This is essential for nature since it reveals the derivatives of molecular products not found in nature in substantial amounts and can therefore be exploited and used in different ways. In this respect, total synthesis of aflatoxin B2 serves as an alternative for commercially isolating exploiting compounds from their natural sources. Aflatoxin B2 in particular adds another perspective since it is suspected that it has been produced in large quantities from biological sources as part of efforts by some countries to use it a biological weapon due to its toxicity. Ability of total synthesis of this molecule is therefore interesting and may define the future of many nations in years to come. While Aflatoxin B2 is a toxin that is not of any commercial importance, it is expected that scientific research would explore possible uses such as pesticide, herbicide, and insecticide and so on. Works Cited Gang, Zhou, and E.J. Corey. "Short, Enantioselective Total Synthesis Of Aflatoxin B2 Using An Asymmetric [3+2]-Cycloaddition Step." Journal Of The American Chemical Society 34 (2005): 11958. Roberts, John C., et al. "Studies In Mycological Chemistry. Part XXII. Total Synthesis of (±)-Aflatoxin-B2." Journal of the Chemical Society C: Organic (1968): 22. Trost, Barry M., and F. Dean Toste. "Palladium Catalyzed Kinetic And Dynamic Kinetic Asymmetric Transformations Of Gamma-Acyloxybutenolides: Enantioselective Total Synthesis Of (+)-Aflatoxin B1 And B(Sub 2A)." Journal Of The American Chemical Society 10 (2003): 3090 Read More