The Deprotection and Deprotonation

The aspects discussed in the preceding section elucidated the part of work to be finished in batches before starting — more or less automatically — a Merrifield peptide synthesis with its returning cycles of operations on each stage of the process. 

The polymer support, loaded with a well-known amount of the first C-terminal amino acid, has to be preswollen and washed with an appropriate solvent, e.g., dichloromethane, before the repetitive procedure of the Merrifield synthesis is initiated with the cleavage of the temporary N-terminal protecting group to liberate the first amino function. Deprotect-ing reagents and fission products are washed out with an inert solvent. The completion of these steps has to be monitored by a suitable procedure [92,95] to prevent undesired side reactions. Assuming that the temporary N-terminal protecting group was cleaved by acid. 

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These compounds are the opposite of the dithians much easier to hydrolyse but more difficult to make and use. t-BuLi was needed for the deprotonation and the rest of the synthesis was straightforward. Note the high yield in the deprotection and that the aldol is unambiguous only the ketone 37 can enolise and the aldehyde is more electrophilic. 

Although deprotonation of simple 1,3-dithiolanes at the 2 position is usually accompanied by cycloreversion to the alkene and dithiocarboxylate, this does not occur for the 2-ethoxycarbonyl compound 55. The anion of this is readily generated with LDA and undergoes conjugate addition to a,(3-unsaturated ketones, esters, and lactones to give, after deprotection, the a,8-diketoester products 56 (73TL2599). In this transformation 55 therefore acts as an equivalent of Et02C-C(0) . 

Dieter developed a flexible two step synthesis of substituted pyrroles involving initial Beak deprotonation of /ert-butoxycarbonyl (Boc) amines 36 followed by addition of CuX-2LiCl (X = -Cl, -CN) to afford a-aminoalkylcuprates. Such cuprates undergo conjugate addition reactions to a,(3-alkynyl ketones affording a,(3-enones 37, which upon treatment with PhOH/TMSCl undergo carbamate deprotection and intramolecular cyclization to afford the pyrroles 38 . 

Converting furfuraldehyde into its 1,3-dithian-2-y] derivative by reacting it with propane-1,3-dithiol could also be the basis of a route to furoin. Once deprotonated. this forms an acyl anion equivalent that could be reacted with a second equivalent of the aldehyde and then protonated and deprotected to yield furoin ... 

Besides simple enones and enals, less reactive Michael acceptors like /3,/3-disubstituted enones, as well as a,/3-unsaturated esters, thioesters, and nitriles, can also be transformed into the 1,4-addition products by this procedure.44,44a,46,46a The conjugate addition of a-aminoalkylcuprates to allenic or acetylenic Michael acceptors has been utilized extensively in the synthesis of heterocyclic products.46-49 For instance, addition of the cuprate, formed from cyclic carbamate 53 by deprotonation and transmetallation, to alkyl-substituted allenic esters proceeded with high stereoselectivity to afford the adducts 54 with good yield (Scheme 12).46,46a 47 Treatment with phenol and chlorotrimethylsilane effected a smooth Boc deprotection and lactam formation. In contrast, the corresponding reaction with acetylenic esters46,46a or ketones48 invariably produced an E Z-mixture of addition products 56. This poor stereoselectivity could be circumvented by the use of (E)- or (Z)-3-iodo-2-enoates instead of acetylenic esters,49 but turned out to be irrelevant for the subsequent deprotection/cyclization to the pyrroles 57 since this step took place with concomitant E/Z-isomerization. 

Intramolecular conjugate additions with nitriles 244 have been performed by deprotonation with n-BuLi in the presence of 12-crown-4 at room temperature, giving mainly indolizidine and quinolizidine derivatives 245 with the cyano group in an axial orientation (Scheme 67)395. The deprotection of the final dithioacetal has been achieved with bis(trifluoroacetoxy)iodobenzene396. 

The synthesis of the coupling partner (enone 124) began in the manner reported by Noda [70] (Scheme 30). Thus, starting with commercially available acetylacetaldehyde dimethylacetal (125), the dithiane protection of both the ketone and the dimethyl acetal units under acidic conditions afforded compound 131 in 86% yield as a white crystalline solid. Deprotonation with n-BuLi, followed by the addition of / -benzyl glycidyl ether (132) provided an 80% yield of the hydroxyl ether 133. Deprotection of the dithiane moiety with HgCb in acetonitrile and water revealed the two carbonyl units, which underwent spontaneous cyclization to the enone 124. Spectroscopic data for this compound were in complete agreement with the published data [70]. 

Deprotonation with n-butyllithium and addition of aldehyde 148 generated alcohol 149 as a 2 l-diastereomeric mixture. Again the stereochemistry at the newly created center was corrected by an oxidation reduction sequence via ketone 151. This time the chiral reduction had to be performed with using Corey s oxazaborolidine catalysts (19). In this way both the (31 )- and (3S)-diastereomer of alcohol were available. LAH-reduction of (3S)-149 led to the -alkene 150 which was eventually oxidized to aldehyde 154 after protection-deprotection via 152 and 153. Addition of the potassium salt of pyrone 131 gave 155 as a 4 l-epimeric mixture. Removal of the PMB protective group led to selective destruction of the minor diastereomer, so that a 95 5-mixture in favor of the desired stereoisomer 156 was obtained (Scheme 26). 

In the case of tosylates of secondary amines, the effect of bases appears to be more harmful for the stability of the amine moiety in the course of the electrolysis. Here, the deprotonation process involves a proton located in the a-position to the nitrogen atom and may lead37 therefore to an anionic elimination. The formation of an imine and its further degradation during the work-up are the principal causes of the low yields when the deprotection process is conducted without a sufficient amount of a proton source. By... 

In the lithiated dicarbamate 111 of (S)-2-(dibenzylamino)-l,4-butanediol (derived from L-aspartic acid) the 4-carbamoyloxy group also possesses a high tendency for intramolecular complexation [Eq. (31)] [75, 76]. The favorable equatorial positions of the dibenzylamino and 1-carbamate groups are displayed in the transition state of the deprotonation. When treated with sec-butyl-lithium in ether or THE, the bicyclic chelate complex 111 is formed exclusively by removal of the pro-S-IH atom. Trapping of 111 by many types of electrophiles gives stereohomogeneous substitution products 112 [Eq. (31), Table 3]. Since deprotection proceeds easily by the usual means, anion 111 constitutes a synthetic equivalent of the synthon 114. No deprotonation in the 4-position was detected, however this can be achieved by protecting the pro-S-lH by conversion to deuterium (see below and Sect. 2.5). 

In 1985, O Malley et al. published the total syntheses of rac-averufin (103) and rac-nidurufin (104) (65). These are both early precursors of the aflatoxins in their biosynthesis. Nidurufin (104) is the direct successor of averufin (103) and the direct precursor of versiconal hemiacetal acetate (12, see Scheme 2.1). Nidurufin (104) and averufin (103) are accessible by the same synthesis route only the two last steps differ firom each other (see Scheme 2.17). The first reaction was a double Diels-Alder reaction with dichloro-p-benzoquinone (97) and two equivalents of diene 98. Then, three of the four alcohol functions were selectively MOM-protected (—> 99). The remaining alcohol was converted into the allyl ether and then subjected to a reductive Claisen rearrangement, followed by MOM-protection of the redundant alcohol ( 100). By addition/elimination of PhSeCl, 101 was formed. Deprotonation of t-butyl 3-oxobutanoate, followed by reaction with 101 yielded the pivotal intermediate 102. This could be converted into rac-averufin (103) by deprotection of the alcohols and decarboxylation at the side chain. The last step was a p-TsOH-catalyzed cyclization to give 103. By treating 102 with /m-CPBA, the double bond is epoxidized. rac-Nidurufin (104) was then formed by cyclization of this epoxide under acidic conditions. 

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