Stereochemistry multistep synthesis

A new multistep synthesis of ( )-reserpine (109) has been published by Wender et al. (258). The key building block of the synthesis is cw-hexahydroiso-quinoline derivative 510, prepared by the extension of the previously elaborated (259) Diels-Alder addition-Cope rearrangement sequence. Further manipulation of 510 gave 2,3-secoreserpinediol derivative 512, which already possesses the required stereochemistry in ring E. Oxidative cyclization of 512 yielded 3-isoreserpinediol (513), which was transformed by the use of simple reaction... 

If you don t know your reactions, you can t possibly solve a multistep synthesis problem. Knowing the reactions includes the reactants, products, conditions, regiochemistry, and stereochemistry. Flashcards are a useful means of learning the reactions. On the front side of the card, write the reactants and conditions, and on the reverse side, write the products, regiochemistry, and stereochemistry. Learn the cards in one direction first (identifying what s on the back based on what you see on the front), and then learn them in reverse (knowing what s on the front when you look at the back). You must know the reactions backwards and forwards. (Shuffle the deck often.)... 

After finishing a multistep synthesis problem, spend some time working on another problem or task. Then come back and check each step in both the forward and the reverse direction. You should pay particular attention to both the regiochemistry and the stereochemistry of each step. In addition, if one of the steps involves a molecule with more than one functional group, make sure the reaction only alters the desired functional group. 

Despite the difficulty in controlling the stereochemistry of the ring-fusion center as well as the low yields of the multistep synthesis, which lead to serious drawbacks of these strategies, a large variety of such bicyclic compounds could be synthesized that mimic the central dipeptide of / -turns in general and in particular the Xaa-Pro dipeptide as trans isomer [106,114-118]. A few examples of such dipeptide mimetics are shown in Fig. 11.11. 

Two other methods toward the manzamines have been reported recently. A preliminary report by Baldwin s group at Oxford of a biomimetic approach described the preparation of a key tricycle, which bears a resemblance to likely natural product precursors to the manzamines (153). A multistep synthesis from Overman s group at the University of California at Irvine, featuring an intermolecular Mannich reaction, starts from D-(-)quinic acid, thus setting the absolute stereochemistry (154). 

In designing a multistep synthesis, one must consider aspects of stereochemistry as well as functionality. In the chapters dealing with individual reactions, many examples were given in which the aspects of stereochemistry were a direct consequence of the reaction mechanism. For example, hydroboration-oxidation involves a syn addition followed by oxidation with retention of configuration. The generalization, widely but not universally correct, that reagents attack molecules from the sterically less hindered side was also illustrated on numerous occasions. 

Each of these syntheses of aphidicolin provides an example of the utilization of stereochemistry established in an early intermediate to control subsequent stereochemistry as the synthesis is completed. This represents the control of relative stereochemistry, and the syntheses as a whole are diastereoselective. The final products are racemic materials. Most syntheses which have been completed to date have been of racemic materials, in which control of relative stereochemistry has been sufficient. As discussed in Section 11.3, the synthesis of a substance in optically pure form requires that either a catalyst, a reagent, or one of the starting materials be optically active. Diastereoselective syntheses, such as those discussed in Schemes 11.21-11.24, can be made enantioselective if an early intermediate can be obtained in optically active form by some enantioselective process. The advantage of establishing optical purity early in a multistep synthesis is that all the material subsequently formed by diastereospecific processes will possess the desired absolute stereochemistry. A resolution or other enantioselective process introduced late in a synthetic scheme can transform only one half of the material to the desired product. 

There are many routes available for the synthesis of aziridine 2-carboxylic acids, however there are few reactions which yield enantiomerically pure products. These compounds (especially those with cis-stereochemistry) are especially useful for the synthesis of bioactive molecules556. There is thus significant effort in this area of synthesis557,558, but most methods are lengthy multistep procedures. Recently, a simple, one-pot procedure, utilizing imines, has been developed for the asymmetric synthesis of c/s-N-substituted aziridine-2-carboxylic acids via a Darzens-type reaction (equation 154)559. 

Of the numerous other aziridine syntheses, there are several multistep procedures from alkenes. Though not strictly within the scope of this review, the practising chemist will wish to consider their merits alongside the rect syntheses, and the main possibilities are summarized in Scheme 8. There are several good recent reviews, - and two older compilations remain very useful. - Syntheses of those intermediates of Scheme 8 accessible from alkenes are described in later sections of tiie present review, and syntheses of epoxides (Volume 6, Chapter 1.1 and Volume 7, Chapters 3.1 and 3.2) and triazolines (Volume 5, Ch ter 3.1) are described elsewhere in Comprehensive Organic Synthesis . It is important to note that by careful choice of route one can either commence with alkene (14) and retain the cisitrans stereochemistry in the resulting aziridine (16), or start with alkene (13) and change the cisitrans relatitm-ships of the substituents. 

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