Multistep synthesis protecting groups

Purpose To demonstrate principles of multistep synthesis, protecting groups, and... 

The base-catalyzed reaction of nitroalkanes and sugar-based aldehydes (the Henry reaction) is one of the most common procedures for the lengthening of the carbon skeleton of a carbohydrate.16 The mild reaction conditions required for the formation of C C bonds by this method are usually compatible with most of the protective groups and masked functionalities involved in multistep synthesis from sugars.17... 

These desiratives have been useful for gas chromatographic and mass spectral analyses, but since they are very sensitive to hydrolysis, their use as protecting group in multistep organic synthesis become limited. But since trimethylsilyl ethyl derivatives are more stable towards hydrolysis and can be easily removed under very mild conditions, they are more useful for protection of amines and carboxylic acids. 

A number of methods are available to dequaternize heterocyclic and related compounds. Dealkylation methods may be desired for various reasons which include (a) removing a protecting group in a multistep synthesis and (b) activating a molecule for nucleophilic substitution by quaternization and then removing the group after substitution. 

Dithianes are readily prepared from aldehydes (for an overview, see 1,3-dithianes as protecting group) and offer high stability towards acids and bases. Therefore, use of the S,S-acetal unit is especially useful in multistep synthesis. A crucial step is the hydrolysis of S,S-acetals, the difficulty of which is due to the excellent nucieophilicity of sulfur. 

Perfluorosulfonates have been demonstrated as a valuable fluorous syn-thon. In multistep synthesis, the perfluorooctanesulfonyl tag plays three roles 1) as a protecting agent for the hydroxyl group 2) as a fluorous tag to facilitate intermediate purification and 3) as an activating group to promote the coupling reaction. 

Many chemical processes take place between one or two reactants, and in principle all such reactions will equilibrate. In practice, however, the actual preparative procedures proceed irreversibly and very high yields of pure products can result if no competing events parti-cipate.f l A usual multistep synthesis where the product is formed from three or more educts consists of a number of successive reaction steps. The intermediate product of each step is isolated, purified, and reacted with the next educt in a further reaction step, until the final product is formed. In many syntheses, particularly in those of peptide derivatives and related compounds, some of the participating functional groups are activated, while others are protected and later deprotected.t l The more preparative steps that are carried out, the more work there is to be accomplished toward obtaining the final desired product, and the overall yields of the final products decrease with each additional step. 

The use of an expandase to convert penicillins to cephalosporins (9.36) also replaced a more expensive multistep chemical synthesis.238 Penicillin acylase has also been used to remove phenylacetyl protecting groups from amines in the synthesis of oligonucleotides.239... 

Lithium/ammonia reduction was also utilized in a multistep synthesis of a 4-norsteroid starting from 2,3,7,7a-tetrahydro-l//-indene-l,5(67/)-one40. In this case the introduced acetal protecting group is inert in the single electron transfer reduction. 

The next steps in the synthesis include the multistep conversion of E)-15 into 16, subsequent cleavage of the silyl ether protecting group, and cyclization of 17, which cannot be isolated, to provide hexacyclic 18. With the reductive removal of the sulfonamide Magnus et al. arrived at their first goal, the total synthesis of the Wieland-Gumlich aldehyde (2). The conclusion of the total synthesis of strychnine is also within reach the authors succeed in converting 2 into the natural prod-... 

It is interesting that iron carbonyl can be used as a protecting group for dienes. Iron diene complex 491, for example, reacted with 492 in a Mukaiyama aldol reaction (sec. 9.4,C), giving an 81% yield of 493 and 494 in an 84 16 ratio.32 in a synthesis of heptitol derivatives,322 Pearson protected tropone as the iron tricarbonyl derivative (495), and prepared 496 using a multistep sequence before deprotecting the diene to give 497. 

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