N-Fmoc deprotection

N -Fmoc serine benzyl ester 2, which could be prepared as shown or purchased commercially, was smoothly converted to the crystalHne O-methylthiomethyl (MTM) ether 3 in high yield via a Pummerer-Hke reaction using benzoyl peroxide and dimethyl sulfide in acetonitrile [39]. This common intermediate was used to synthesize both 5 and 8 [40]. Both Ogilvie [41] and Tsantrizos [42] had reported that I2 was an effective activator with similar MTM ether substrates. The H promoted nucleosidation reaction between O-MTM ether 3 and bis-silylated thymine 4 produced the nucleoamino acid 5 in 60% isolated yield (100% based on recovered 3). Hydrogenolytic deprotection of the benzyl ester with H2, Pd/C in MeOH gave the thymine-containing nucleoamino acid 6 in quantitative yield. 

The best results were achieved by employing N-(3-dimethylaminopropyl)-N -ethylcar-bodiimide hydrochloride (EDC) as coupling agent. After Fmoc deprotection with piperidine in N,N-dimethylformamide, additional diversity could be introduced by acylation of the liberated amine position. Finally, the acyl cyano phosphoranes could be efficiently cleaved by ozonolysis at -78 °C or by utilizing freshly distilled 3,3-dimethyloxirane at room temperature [65]. The released compounds constituted highly activated electrophiles, which could be further converted in situ with appropriate nucleophiles. 

The desired polymer-bound tryptophan was rapidly generated under microwave irradiation, employing a classical esterification protocol using N,N -dicydohexylcar-bodiimide (DCC) and a catalytic amount of N,N-dimethylaminopyridine (DMAP), followed by subsequent Fmoc deprotection (Scheme 7.68). Cyclocondensations with various carbonyl compounds were performed with catalytic amounts of p-toluene-... 

Houghten and co-workers[145] introduced a method for combinatorial synthesis of a per-alkylated peptide library using nonspecific N-alkylation. The peptides were synthesized by SMPS methodology 146 in combination with repetitive amide N-alkylation on the solid support after each coupling step. Peptides were synthesized on MBHA-PSty resin using Fmoc chemistry. After Fmoc deprotection the a-amino group was protected by Trt to prevent N -alkylation and to allow only amide alkylation. The on-resin amide alkylation was achieved by amide proton abstraction using LiOtBu in THF followed by nonfunctionalized alkyl and aryl halides in DMSO. 

Chen and co-workers at Procter and Gamble developed a traceless synthesis of 2,5-diketopiperazines [18b] by employing the universal Rink-isocyanide resin. The Ugi-4CR between the resin, aldehydes, amines, and N-Fmoc-protected a-amino acids afforded the resin-bound dipeptide derivatives 131 which were N-deprotected on treatment with piperidine in DMF. Cyclization by heating with 10% AcOH in DCE smoothly provided the desired diketopiperazines 132 in good yields (Scheme 2.47). 

Golebiowski et al. reported the solid-phase [92] and the solution-phase [93] syntheses of bycyclic diketopiperazines which were of great interest because their conformation was similar to the type-1 /i-turn motif. A Merrifield hydroxymethyl resin was esterified with a-N-Boc-fi-N-Fmoc-L-diaminopropionic acid and then mono-deprotected at the />-N with piperidine. Ugi-4CR of the resulting resin-bound amine gave the resin-bound adducts 168. Subsequent N-Boc deprotection and intramolecular N-alkylation afforded the ketopiperazines 169. The diketopiperazines 170 were formed via N-Boc amino acid coupling followed by N-Boc deprotection... 

The cyclative cleavage determined the SP synthetic scheme (Fig. 3.35) which supported commercially available 3.84 on hydroxymethyl PS resin, built the appropriate resin-bound cycloaddition substrate 3.93 via orthogonal N-deprotection and functionalization and led to the bicycle 3.94 this was to be coupled with 3.87, deprotected and decorated with 3.88, and cyclatively cleaved to 3.83 (Fig. 3.35). The choice of the two N-protecting groups is crucial for the success of the SP scheme the a-N-Boc on 3.84 was considered acceptable, being early removed in the SPS, but the P-N-Fmoc... 

The chemical reactivity of aliphatic hydroxy groups is reduced by acylation, but the resulting esters are reactive toward amino groups. Thus, under basic conditions, as commonly used for Fmoc deprotection, an intramolecular O N migration of the acyl residue can occur.b l This O N shift, which produces N-acylated derivatives (Scheme 3), is nearly irreversible and further elongation of the peptide is prevented. The same reaction can occur during acidolytic deprotection of final peptides with TFA via intermediate formation of the tri-fluoroacetyl ester of N-terminal hydroxy amino acids,... 

Although aspartimide formation can occur during base-catalyzed acylation in Boc-based chemistry, the reaction is more pronounced during Fmoc removal with piperidine.The reaction, shown in Scheme 6, is sequence dependent, but aspartimide formation can be up to 0.3% per N-terminal deprotection cycle when the required peptide contains -Asp-Gly-. When the resultant peptide is cleaved from the support the aspartimide ring may remain intact, but can also open to form the P-branched peptide. 

Recently, an environmentally benign phosphomolybdic acid supported on silica gel has been used for the chemoselective deprotection of TBS ethers in carbohydrate derivatives (O Scheme 53). The mild conditions are compatible with the presence of other protecting groups such as isopropylidene acetal, OTBDPS, OTHP, OAllyl, OBn, OAc, OBz, N-BOc, N-CBz, and N-Fmoc which are stable under the reaction conditions. Another advantage of this procedure is that the catalyst can be readily recovered and recycled [327]. 

The 3 -aminoacylated dinucleotides 66 have been prepared by reaction of N-FMOC amino acid fluorides with the p-cyanoethyl-protected dinucleotide. Deprotection with oximate removes all protecting groups without disturbing the aminoacyl linkage. ... 

The synthesis of these heterocycles was approached using two similar strategies. Fmoc-amino acid-derivatized Wang resins were N-deprotected (87) and coupled with either o-nitrobenzoic acid or N-Fmoc-anthranilic acid (88 and 89). Reduction of the nitro group with 2 m Sn( l, /DMF or Fmoc cleavage with piperidine/DMF, respectively, produced 90, which was cyclized with NaOtBu/THF at 60 °C. Extraction of the crude materials yielded 11 different l,4-benzodiazepine-2,5-diones 91 in yields of 45-80% with an average purity of 90% (Scheme 24) [39]. 

With the aim of preparing bicydic diketopiperazines as potential P-tum mim-etics [351], a-N-Boc-P-N-Fmoc-optically active diaminopropionic acids were attached to a standard Merrifield s hydroxymethyl resin under Mitsunobu conditions to afford [428]. Fmoc deprotection and subsequent Ugi reaction using, as the car-boxyhc component, optically active 2-bromoaIkyl adds (430), afforded the required intermediates (431). Further standard manipulations of these compounds, indud-ing a cydative deavage, gave rise to the desired bicydic peptidomimetics (432) (Scheme 88). 

Method A An appropriate N-Fmoc-protected amino add resin (100 mg, 0.06 mmol for the Sasrin-support-immobilized amines) was deprotected by treatment with 20% piperidine in DMF for 30 min. The resin was then filtered off, washed Hberally with DMF, MeOH, and CH2CI2, and dried under... 

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