Final deprotection

The first syntheses of a-allenic a-amino acids [131,133] took advantage of Steg-lich s [134] protocol for the oxazole-Claisen rearrangement of unsaturated N-ben-zoylamino acid esters (Scheme 18.46). Thus, treatment of the propargylic ester 143 with triphenylphosphine and tetrachlormethane furnished the allenic oxazolone 144, which was converted into the amino acid derivative 145 by methanolysis. Stepwise deprotection finally led to the allenic DOPA analog 146, which shows a much higher decarboxylase-inhibiting activity than a-vinyl- and a-ethynyl-DOPA [133],... 

BUchi has used Mander s approach as a key step in his synthesis of a-sinensal (212 Scheme 50), and Corey has applied the ylidic 3,2-rearrangement to the efficient preparation of 3-cyclopentenones. Thus, base treatment of the sulfonium salt (213) first gave the rearranged product (215). Thermal vinylcyclo-propane ring expansion then produced the spiro compound (216). Deprotection finally gave the noncon-jugated cyclopentenone (217 Scheme 51). 

A C-nor derivative that retained the oxetane ring was formed by oxidation of 2 -protected diol with tetrapropyl-ammonium perruthenate (TPAP), which oxidized the C-6 hydroxyl group selectively to give an unstable 7-hydroxy-6-keto derivative. This derivative then underwent a retro-aldol reaction followed by an aldol reaction to give the C-nortaxol 4.2.2.4 unfortunately the deprotected final product 4.2.2.S was unstable and could not be completely characterized (779). 

In 2010, de Lera et al. synthesized the heterodimeric diketopiperazine (+)-pestalazine B (658) (416). With this material in hand, they were able to revise the earlier proposed structure 659 for the natural product. These investigators utilized a convergent synthesis strategy, starting with the condensation of L-trypto-phan methyl ester (616) and IV-Fmoc-o-phenylalanine (652), to give diketopiperazine derivative 653 after Fmoc-deprotection (Scheme 10.6). This was reacted with 3a-bromopyrrolidinoindoline 654 (417) to furnish the dimeric product 655. Boc-deprotection ( 656), coupling with iV-Fmoc-o-leucine ( 657), and Fmoc-deprotection finally led to compotmd 658 for which the spectroscopic data matched those of the natural product. 

Fig. 31. An acrylic terpolymer designed for chemically amplified resist applications. The properties each monomer contributes to the final polymeric stmcture are for MMA, PAG solubility, low shrinkage, adhesion and mechanical, strength for TBMA acid-cataly2ed deprotection and for MMA, aqueous...

The exocychc nitrogens on cytosine and the purine bases must be protected during the synthesis. The search is ongoing for protecting groups that are subject to fewer side reactions and that can be removed more easily in the final deprotection step (34). 

Robotic peptide synthesizers are now used to automatically repeat the coupling, washing, and deprotection steps with different amino acids. Each step occurs in high yield, and mechanical losses are minimized because the peptide intermediates are never removed from the insoluble polymer until the final step. Using this procedure, up to 25 to 30 mg of a peptide with 20 amino acids can be routinely prepared. 

The final step in DNA synthesis is deprotection by treatment with aqueous ammonia. Show the mechanisms by which deprotection occurs at the points indicated in the following structure ... 

The completion of the total synthesis only requires a few deprotection steps. It was gratifying to find that the final deprotections could be conducted smoothly and without compromising the newly introduced and potentially labile trisulfide residue. In particular, exposure of intermediate 101 to the action of HF pyridine results in the cleavage of all five triethylsilyl ethers, providing 102 in 90% yield (Scheme 23). Finally, hydrolytic cleavage of the ethylene ketal with aqueous para-toluenesulfonic acid in THF, followed by removal of the FMOC protecting group with diethylamine furnishes calicheamicin y (1) (see Scheme 24). Synthetic calicheami-cin y, produced in this manner, exhibited physical and spectroscopic properties identical to those of an authentic sample. 

Our strategy is based on the premise that the 31-membered ring and the conjugated triene array of the natural product could be fashioned simultaneously by a tandem inter-/intramolecular Stille coupling. Moreover, the mild conditions under which Stille couplings can be performed fueled hopes that the crucial stitching cycliza-tion could be conducted on a fully deprotected seco bis(vinyl iodide) (see 145, Schemes 40 and 54) the stitching cyclization would thus be the final operation in the synthesis. 

The final (3-glycosylation was carried out with fluoroglycoside 157 (R = Bz) to give, after deprotection, the desired natural compound [76c]. 

In 2004, Alterman et al. apphed their cyanation protocol to the synthesis of N-(t-butyl)-3-(4-cyanobenzyl)-5-isobutylthiophene-2-sulfonamide [61]. Deprotection of the sulfonamide followed by carbamate formation via reaction with butyl chloroformate finally gave the target compoimd for biological evaluation as a selective angiotensin 11 AT2 receptor agonist (Scheme 65). The cyano derivative, however, showed only a low affinity for the AT2 receptor (Ki value >10 p,M). 

Finally, we tried to deprotect the amide nitrogen of the obtained pyridi-nones upon reflirx in neat trifluoroacetic acid (TFA) for 18 h [ 116]. Products were isolated in 73% and 79% yield, respectively. In contrast, upon microwave irradiation at 120 °C for only 20 min, a (1 2) TFA/DCM mixture sufficed to deprotect the pyridinones (isolated yields 75% and 73% respectively). Surprisingly, deprotection with either refluxing neat TFA (18 h) or microwave irradiation in neat TFA with a catalytic amount of methanesulfonic acid (20 min) did not work for dihydrofuropyridinone. 

In the Fmoc protection approach, the acid-labile ferf-butyl groups are often used for side-chain protection. The base-labile Fmoc groups can be easily removed during a synthesis using piperidine (Fig. 4). The final global deprotection together with cleavage from the polymeric support is achieved with TFA. 

Isolated yield. A, CFjOF in CCI3F at — 60 to — 80° with or without CaO B, F2 in Ar (or N2—CCI3F) at — 78° B, F2 in N2—HjO at room temperature C, Xep2-BF3 OEt2 in ether, benzene, toluene, dichloromethane, or a mixture of some of them (0° to room temperature). Yield of the deprotected compound after hydrolysis. " 2,2-Difluoro compound, Estimated from the final 2-deoxy-2-fluoroglycose. 

To obtain this compound the key step consisted in the epimerization of the C-5 in compound 6. This was acomplished by triflation of the alcohol 6 and nucleophilic substitution of the triflate by a large excess of tetrabutylammonium acetate in dichloromethane. A controlled (4 °C, 3 h) basic methanolysis of the enol benzoate led to the keto-ester 11" whose hydroxyl functions at C-4 and C-6 were simultaneously deprotected under acidic conditions to furnish 12. Finally a Zemplen deprotection of the 5-acetoxy group led to 13 obtained in five steps and 11% overall yield from 6 (figure 4). 

Z-vinyl iodide was obtained by hydroboration and protonolysis of an iodoalkyne. The two major fragments were coupled by a Suzuki reaction at Steps H-l and H-2 between a vinylborane and vinyl iodide to form the C(ll)-C(12) bond. The macrocyclization was done by an aldol addition reaction at Step H-4. The enolate of the C(2) acetate adds to the C(3) aldehyde, creating the C(2)-C(3) bond and also establishing the configuration at C(3). The final steps involve selective deprotonation and oxidation at C(5), deprotection at C(3) and C(7), and epoxidation. 

The reduction of the isoxazoline ring after the cycloaddition was not successful with the usual reagents (see p. 532), but Sml2 accomplished the reaction. In contrast to the epoxidation used as the final step in most of the other epothilone A syntheses, the epoxide was introduced through a sulfite intermediate. Deprotection of C(15) leads to intramolecular displacement at the sulfite with formation of the epoxide (Steps E-3 and E-4). 

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