Synthesis and retrosynthetic analysis

For additional practice on Synthesis and Retrosynthetic Analysis, go to MasteringChemistry where the following tutorials are available ... 

Synthesis and Retrosynthetic Analysis Retrosynthesis of 2-Pentanone Using Reactions of Carbonyl Compounds... 

Students are introduced to synthetic chemistry and retrosynthetic analysis early in the book (Chapters 6 and 7, respectively), so they can start designing multistep syntheses early in the course. Nine special sections on synthesis design, each with a different focus, are introduced at appropriate intervals. There is a new tutorial on synthesis and retrosynthetic analysis that includes some examples of complicated multistep syntheses from the literature. 

Corey, E. J. Bakshi, R. K. Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551. Elias 1. Corey (1928—) was bom in Metbuen, Massacbusetts. After earning bis Pb.D. at MET from John Sbeeban at age 22, be began bis independent academic career at tbe University of Illinois in 1950 and moved to Harvard University in 1959. Corey won tbe Nobel Prize in Chemistry in 1990 for development of novel methods for the synthesis of complex natural compounds and retrosynthetic analysis. He is still carrying out active research at Harvard. Prof. Corey has been a consultant to Pfizer for more than 50 years. 

In your first semester of organic chemistry you studied regiochemistry and retrosynthesis. The type of director (o-p or m) is an important aspect of this regiochemistry that you need to consider in any synthesis or retrosynthetic analysis problem. 

Typical LC molecules that exhibit SmC and/or SmCA phase are shown in Figure 1. As readily seen, the LC compounds consist of optically active 1,1,1-trifluoro-2-alkanols which contribute to the stabilization of the SmCA phase and thus play key roles of these LC materials. Accordingly methods for the l,l,l-trifluoro-2-alkanols have been the target of organic synthesis. Conventional retrosynthetic analysis of the trifluoro alcohols leads to (1) resolution of l,l,l-trifIuoro-2-alkanols by chemical or enzymatic methods, (2) asymmetric reduction of l,l,l-trifluoro-2-alkanones, or (3) asymmetric carbonyl addition of carbonaceous nucleophiles. Indeed, at present, the enzymatic resolution through the hydrolysis of the carboxylates of l,l,l-trifluoro-2-alkanols prevails. Other methods remain yet to be studied. 

The retrosynthetic analysis of a target compound is a systematic approach in developing a synthesis plan starting with the target structure and working backward to available starting materials. 

In the last fifteen years macrolides have been the major target molecules for complex stereoselective total syntheses. This choice has been made independently by R.B. Woodward and E.J. Corey in Harvard, and has been followed by many famous fellow Americans, e.g., G. Stork, K.C. Nicolaou, S. Masamune, C.H. Heathcock, and S.L. Schreiber, to name only a few. There is also no other class of compounds which is so suitable for retrosynthetic analysis and for the application of modem synthetic reactions, such as Sharpless epoxidation, Noyori hydrogenation, and stereoselective alkylation and aldol reactions. We have chosen a classical synthesis by E.J. Corey and two recent syntheses by A.R. Chamberlin and S.L. Schreiber as examples. 

When planning the synthesis of a compound using an organometallic reagent or indeed any synthesis the best approach is to reason backward from the product This method is called retrosynthetic analysis Retro synthetic analysis of 1 methylcyclohexanol suggests it can be prepared by the reaction of methylmagnesmm bromide and cyclohexanone... 

On the basis of this retrosynthetic analysis design a synthesis of N methyl 4 phenylpipendine (compound A where R = CH3 R = C6H5) Present your answer as a series of equations show ing all necessary reagents and isolated intermediates... 

Methodology for the enantioselective synthesis of a broad range of chiral starting materials, by both chiral catalytic and controller-directed processes, is rapidly becoming an important factor in synthesis. The varied collection of molecules which are accessible by this technology provides another type of chiral S-goal for retrosynthetic analysis. 

Ex-Target Tree. (EXTGT Tree) A branching tree structure formed by retrosynthetic analysis of a target molecule (treetop). Such trees grow out from a target and consist of nodes which correspond to the structures of intermediates along a pathway of synthesis. 

The importance of biotin in nutrition and increasing commercial needs combine to suggest the need for short and economical synthesis. Retrosynthetic analysis using cysteine as SM goal suggested a number of synthetic pathways for study, one of which has been demonstrated as shown below. 

Methoxatin, now known as coenzyme PQQ, was originally obtained from methylotrophic bacteria but is now known to be a mammalian cofactor, for example, for lysyl oxidase and dopamine p-hydroxylase. The first synthesis of this rare compound was accomplished by the route outlined below. In the retrosynthetic analysis both of the heterocyclic rings were disconnected using directly keyed transforms. 

Retrosynthetic analysis of antheridic acid produced a totally different plan of synthesis from that which had been employed for the structurally related target gibberellic acid. The synthesis of antheridic acid, which included a number of novel steps, allowed definitive assignment of structure and revised stereochemistry at C(3). 

Despite the structural relationship between ginkgolide B and bilobalide, retrosynthetic analysis of the latter produced a totally different collection of sequences. A successful synthesis of bilobalide was implemented using a plan which depended on stereochemical and FG-based strategies. A process for enantioselective synthesis was based on an initial enantioselective Diels-Alder step in combination with a novel annulation method. 

Venustatriol, a marine-derived antiviral agent, as with many polyether structures, is a straightforward problem for retrosynthetic analysis. The major issues, clearance of stereocenters and topologically strategic disconnection, were readily resolved to generate the pathway of synthesis described below. 

---