Second Deprotection

From the initial deprotection, a few strategies have been delineated to further heterofunctionaUze cyclodextrins through successive deprotections. 

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Fig. 15.4.58. Solution NMR spectra of products formed at each stage of solid phase synthesis of oligoethers (Fig. 15.4.59) on a linear soluble support A, soluble chloromethylated polystyrene B, attachment or coupling step C, deprotection step D, activation step E, elongation or second coupling step F, second deprotection step (see Ref. 91).

Fig. 13.15), through a commonly applicable methodology (635). The synthesis sequence (Scheme 13.8) involved manipulation of a silyl-protected 4-hydroxycyclohex-2-enone (902) through several steps to the 2-bromo-3-carboxymethyl ester 905, then reaction of this species with the aldehyde 906 to form the intermediate benzophenone 907. This product was first desilylated, then de-allylated, with a second deprotection followed by an in situ cyclization of the phenolic intermediate, to give blennolide C (897) and the diastereomer 908 in an approximately 2 1 diastereomeric ratio, after 11 steps from cyclohexenone 258 (635). 

A second deprotection strategy employs the rapid and irreversible reaction of the tt-aUylpaUadium complex with tri-n-butyltin hydride in the presence of an acid (Scheme 8). Alternatively, sodium borohydride has been used to reduce the rr-allylpalladium com-plex.f Both of these methods have been used in the in situ deprotection/acylation of... 

This methodology has been appHed to perbenzylated ycydodextrin, but the selectivity is lower and two regioisomers 6A,6D and 6A,6E are obtained. This is due to the bigger size of the primary rim, making the steric hindrance of the aluminum derivatives too small to direct the second deprotection [65]. 

Scheme 9.38 Selective second deprotection on deoxy-a-cyclodextrin.

Scheme 9.39 Selective second deprotection on bridged-a-cyclodextrin.

In the case of fS-cyclodextrin, the lack of symmetry makes the duplication of the double de-O-benzylation more challenging. Indeed, if we consider that the second deprotection wiU take place on opposite positions, de-O-benzylation can lead to four regioisomers. 

The use of chiral ketones for the protection of diols serves two purposes first, diol protection is accomplished, and second, symmetrical intermediates are converted to chiral derivatives that can be elaborated further, so that when the diol is deprotected, the molecule retains chirality. ... 

Nevertheless, the potential uses of these polymers are intriguing, especially since preliminary evidence has been obtained that hydrolysis to glucose, phosphate, and ammonia takes place slowly in aqueous media. Mixed-substituent glucosyl polymers appear to have the greatest biomedical potential since the use of a second, less hindered, side group allows the steric hindrance and deprotection problems to be minimized (37). 

In line with a second novel synthetic principle, the authors further developed the repetitive Diels-Alder procedure, in which monomers containing cyclopentadienone (dienophile) units were reacted with protected/deprotected ethynylene functions (see [31]). In this way, they generated a novel class of highly arylated phenylene dendrimers 46, starting from a 3,3, 5,5 -tetraethynyl-substituted biphenyl core [60]. 

This modular methology involves the repetition of directed protection/cyclo-addition/deprotection steps, and allows for the synthesis of monodisperse dendritic oligophenylenes of the first (46a, 22 benzene rings) and second (46b, 62 benzene rings) generation [60]. Within the synthetic sequence, the authors made use of the different reactivities of protected and deprotected ethynylene functions within the key cycloadditon step. 

A second convergent synthesis of haliclamine A (64) was achieved in a stepwise sequence from cyclopropyl(thiophen-2-yl)methanone (76) (Scheme 7) [37]. The protected thiophene 77 was condensed with formyl-piperidine to give 78, suitable for a Wittig olefination with 79. After desulfurization of the product 80, the deprotected alcohol 82 was subjected to homoallylic rearrangement using MesSiBr in the presence of ZnBr2. The re-... 

The Stille reaction has been successfully applied to a number of macrocyclic ring closures.207 In a synthesis of amphidinolide A, the two major fragments were coupled via a selective Stille reaction, presumably governed by steric factors. After deprotection the ring was closed by coupling the second vinyl stannane group with an allylic acetate.208... 

Initially, 50 was converted into the benzoxazinone 51 by reaction with phosgene in the presence of triethylamine and 51 was isolated in 95% yield upon crystallization from methanol. Deprotection of the pMB group from 51 was accomplished with ceric ammonium nitrate (CAN) in aqueous acetonitrile. Efavirenz was isolated in 76% yield after crystallization from EtOAc-heptane (5 95), as shown in Scheme 1.19. There were two issues identified in this route. First, lequiv of ani-saldehyde was generated in this reaction, which could not be cleanly rejected from product 1 by simple crystallization to an acceptable level under the ICH guideline. Anisaldehyde was removed from the organic extract as a bisulfite adduct by washing with aqueous Na2S205 twice, prior to the crystallization of 1. Secondly,... 

Such biosyntheses were models for the Merrifield-synthesis [8] (Fig. 3), which culminated in the development of fully automated peptide synthesizers [9]. In a repeated reaction cycle a N-terminal protected amino acid, which is attached with its C-terminal end to an insoluble solid support, is deprotected, activated and lengthened by a second protected amino acid unit. The deprotect -ing and coupling steps can be repeated until the entire peptide is assembled. 

Completion of the total synthesis afforded only six further steps, including the installation of the second 2-aminopyrimidine ring via a second domino sequence. This process presumably involves a conjugate addition of guanidine (2-293) to the enone system of2-292, followed by a cyclizing condensation and subsequent aromatization. Under the basic conditions, the ethyl ester moiety is also cleaved and 2-294 is isolated in form of the free acid, in 89 % yield. Finally, decarboxylation and deprotection of the amino functionality yielded the desired natural product 2-295. 

A similar strategy served to carry out the last step of an asymmetric synthesis of the alkaloid (—)-cryptopleurine 12. Compound 331, prepared from the known chiral starting material (l )-( )-4-(tributylstannyl)but-3-en-2-ol, underwent cross-metathesis to 332 in the presence of Grubbs second-generation catalyst. Catalytic hydrogenation of the double bond in 332 with simultaneous N-deprotection, followed by acetate saponification and cyclization under Mitsunobu conditions, gave the piperidine derivative 333, which was transformed into (—)-cryptopleurine by reaction with formaldehyde in the presence of acid (Scheme 73) <2004JOC3144>. 

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