Manipulation functional group

Organic Chemistry An Intermediate Text, Second Edition, by Robert V. Hoffman ISBN 0-471-45024-3 Copyright 2004 John Wiley Sons, Inc. 

Very often these reactions are traditional and illustrative, but they are not necessarily the best way to manipulate a particular functional group. Many traditional methods have been replaced, in practice, by newer reactions or reagents which offer certain advantages over older methods. In general, these advantages have to do with mild conditions, selectivity, generality, and/or experimental simplicity. Nevertheless all types of functional group interconversions, new or old, are still based fundamentally on the ideas that have been developed earlier in this book. 

The discussion which follows is organized in the following fashion. First a common undergraduate text was used to provide a list of standard or traditional preparations for the major functional groups dealt with herein. Most of these reactions should be familiar because they are the ones learned (or not learned) in the undergraduate course in organic chemistry. Although these methods will be listed and perhaps discussed briefly, the discussion in no way serves as a review of these methods. 

The main focus of this chapter will be to introduce the most widely used and practical ways (or real ways) to introduce the major functional groups. These latter methods have practical synthetic value and are usually the first choices in real laboratory situations, but often they differ from the standard list of preparations. What is important is that these first-choice methods must be integrated into die methods previously encountered so that a wider view of how to manipulate functional groups is achieved. 

Carboxylic acids have a relatively high oxidation level (+3), and thus a majority of synthetic mediods to access carboxylic acids are oxidative in nature. Traditional preparations include die following  

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Sometimes the orientation of two substituents m an aromatic compound precludes Its straightforward synthesis m Chloroethylbenzene for example has two ortho para directing groups m a meta relationship and so can t be prepared either from chloroben zene or ethylbenzene In cases such as this we couple electrophilic aromatic substitution with functional group manipulation to produce the desired compound... 

A similar intramolecular Diels-Alder strategy was employed in an efficient synthesis to an appropriately functionalized hydrindanone nucleus (212). After functionalization, Diels-Alder cyclization, and appropriate functional group manipulation, this hydrindanone was converted into ( )-cortisone. The overall process afforded ( )-cortisone in a total of 18 chemical steps in approximately 3% yield. 

Similarly, W-methyl-D-aspartate (NMDA) antagonists 32 with analgesic activity were prepared, again using the Meth-Cohn quinoline synthesis as the key entry reaction, subsequent functional group manipulation giving the desired target compound. 

The completion of the synthesis of intermediate 27 now only requires a few straightforward functional group manipulations. 

The construction of the five contiguous stereocenters required for a synthesis of compound 3 is now complete you will note that all of the substituents in compound 5 are positioned correctly with respect to the carbon backbone. From intermediate 5, the completion of the synthesis of the left-wing sector 3 requires only a few functional group manipulations. Selective protection of the primary hydroxyl group in 5 as the corresponding methoxymethyl (MOM) ether, followed by benzylation of the remaining secondary hydroxyl, provides intermediate 30 in 68 % overall yield. It was anticipated all along that the furan nucleus could serve as a stable substi-... 

Through some conventional functional group manipulations, intermediate 5 could be derived from compound 9. Retrosynthetic disassembly of intermediate 9, in the manner illustrated in Scheme 2, furnishes the benzyloxymethyl ether of (/ )-/ -hydroxyisobutyral-dehyde (10) as a potential precursor and introduces the interesting... 

The synthetic challenge is now reduced to the preparation of intermediates 2-4. Although intermediates 3 and 4 could potentially be derived in short order from very simple precursors (see Scheme 4), intermediate 2 is rather complex, particularly with respect to stereochemistry. Through a short sequence of conventional functional group manipulations, it is conceivable that aldehyde 2 could be derived from intermediate 9. Hydrolysis and keta-lization reactions could then permit the formation of 9 from intermediate 11, the cyclic hemiaminal of the highly stereo-defined acyclic molecule, intermediate 12. 

The completion of the synthesis of key intermediate 2 requires only a straightforward sequence of functional group manipulations. In the presence of acetone, cupric sulfate, and camphorsulfonic acid (CSA), the lactol and secondary hydroxyl groups in 10 are simultaneously protected as an acetonide (see intermediate 9). The overall yield of 9 is 55 % from 13. Cleavage of the benzyl ether in 9 with lithium metal in liquid ammonia furnishes a diol (98% yield) which is subsequently converted to selenide 20 according to Grie-co s procedure22 (see Scheme 6a). Oxidation of the selenium atom... 

With a secure route to pentacyclic amine 2, the completion of the total synthesis of 1 requires only a few functional group manipulations. When a solution of 2 in ethanol is exposed to Pd-C in an atmosphere of hydrogen, the isopropenyl double bond is saturated. When a small quantity of HCI is added to this mixture, the hydro-genolysis of the benzyl ether is accelerated dramatically, giving alcohol 15 in a yield of 96%. Oxidation of the primary alcohol in 15 with an excess of Jones reagent, followed by Fischer esterification, gives ( )-methyl homosecodaphniphyllate [( )-1] in an overall yield of 85 % from 2. 

Through a short sequence of functional group manipulations, compound 6 could be elaborated from allylic alcohol 7, the projected product of a Wharton fragmentation4 of epoxy ketone 8 (vide infra). In turn, compound 8 could be derived from enone 9. In the synthetic direction, a Michael addition5 of hydroperoxide anion to enone 9 would be expected to take place from the less hindered side of the molecule. Epoxy ketone 8 would fhen form upon collapse of the intermediate enolate with concomitant expulsion of hydroxide ion (see arrows, Scheme 2). 

The completion of the synthesis of gilvocarcin V (2) only requires a few functional group manipulations. Hydrogenolysis of the four benzyl groups, followed by acetylation of the liberated hydroxyl groups, provides 30 in 68 % overall yield. After cleavage of the MOM ether in 30 with bromotrimethylsilane, application... 

Compound 14 can be dismantled in a productive fashion by ret-rosynthetic cleavage of the indicated bonds (see Scheme 4). The intermolecular attack of the amino group in 15 upon the keto function in 16 would be expected to result in the formation of the desired oxime ether after loss of a water molecule. A few functional group manipulations would then complete the synthesis of intermediate 14. A valuable structural feature of 15 is the C-2 oxygen substituent. Although this oxygen atom is not expressed in the natural product, it would certainly play an important role in our... 

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