Boc group, deprotection

An interesting variant of cationic-resin capture has recently been reported wherein a strongly acidic cation exchange resin mediated sequential amine deprotection and resin capture (Scheme 6).78 Protected aminoalco-hols were reacted with an excess of isocyanates to form /V-BOC-amine carbamates in solution phase. Methanol was subsequently added to quench excess isocyanates as the neutral methyl carbamate byproducts. Sulfonic acid resin 51 was then used to affect amine-BOC group deprotection and resin capture of the deprotected amines. Washing of the resin bed and release (ammonia/methanol) afforded purified amine carbamate products. 

In 2010, Luo and coworkers reported a practical and highly efficient route to the synthesis of pharmaceutically interesting quinoxalinones (Luo et al. 2010). The key step involves an intramolecular palladium-catalyzed A-arylation reaction (Buchwald-Hartwig amination Janey 2007 Appukkuttan and Van der Eycken 2008) under microwave irradiation. The precursors to the quinoxalinone core were easily prepared from D,L-proline 309d in accordance with the mixed anhydride protocol followed by Boc group deprotection (Scheme 2.57). 

HCl, Et20, 6 h, 83-88% yield.Acidic deprotection of the BOC group could not be achieved with complete selectivity in the presence of an MTM ester. The trityl and NFS (2-nitrophenylsulfenyl) groups were the preferred nitrogen protective groups. 

In a study of the deprotection of the MEM ethers of hydroxyproline and serine derivatives, it was found that the MEM group was stable to conditions that normally cleave the t-butyl and BOC groups [CF3COOH, CH2CI2, 1 1 (v v)]. The MEM group was also stable to 0.2 N HCl, but not stable to 2.0 N HCl or HBr-AcOH. ... 

Picolinamide 22 could be isolated in 87% yield by crystallization from aqueous i-PrOH, which also resulted in an ee upgrade from 92% to 99.3%. Deprotection of the N-Boc group was performed by dissolving 22 in 5 M aqueous HC1. It was found that the subsequent N-acetylation of the revealed amine could be performed in the same pot under Schotten-Baumann conditions by simply adding 10M aqueous NaOH and Ac20. After extraction with CH2C12, the organic phase was concentrated and used in the nitration step without any further purification. 

A functionalized piperidine system 204, on deprotection of the BOC group followed by treatment of the resulting amine with Me3Al, afforded a 4 1 mixture of trans- and cis- 4,6-disubstituted quinolizidines 205 and 206 (Scheme 39) <1999T15209>. 

Furthermore, multicomponent reactions can also be performed under fluorous-phase conditions, as shown for the Ugi four-component reaction [96], To improve the efficiency of a recently reported Ugi/de-Boc/cyclization strategy, Zhang and Tempest introduced a fluorous Boc group for amine protection and carried out the Ugi multicomponent condensation under microwave irradiation (Scheme 7.84). The desired fluorous condensation products were easily separated by fluorous solid-phase extraction (F-SPE) and deprotected by treatment with trifluoroacetic acid/tet-rahydrofuran under microwave irradiation. The resulting quinoxalinones were purified by a second F-SPE to furnish the products in excellent purity. This methodology was also applied in a benzimidazole synthesis, employing benzoic acid as a substrate. 

This approach may find application in peptide bond formation that would eliminate the use of irritating and corrosive chemicals such as trifluoroacetic acid and piperidine as has been demonstrated recently for the deprotection of N-boc groups (Scheme 6.7) a solvent-free deprotection of N-tert-butoxycarbonyl group occurs upon exposure to microwave irradiation in the presence of neutral alumina doped with aluminum chloride (Scheme 6.7) [41]. 

The irradiation of films prepared from 1% triphenylsulfonium salts in poly(4-t-butoxycarbonyloxystyrene) with lithographically useful doses of 254 nm light generates acid which is less than 0.1% of the t-BOC groups. The efficiency of the photochemistry is several times less than the efficiency of acid generation from triphenylsulfonium salts in solution. The catalytic chain is about 1000 for the t-BOC deprotection step at 100°C. This implies that catalyst diffusion during postbake is on the order of 50A... 

Next step is the construction of 8- and 15-membered ring systems by sequential RCM [7]. Tetracyclic alcohol 13 was converted to 14 by sequential oxidation and Peterson olefination followed by deprotection of the TMS group. After protection of the amine with a Boc group, the imide carbonyl group was... 

The synthesis of the remaining part of the molecule started from a condensation of protected Gly with the OHAsp derivative 98, and subsequently with protected Arg (102). In the resulting protected tripeptide the Boc group from the Arg residue was removed. Connection of the two building blocks between Gly and Arg was followed by ring closure between Ser and Gly. Deprotection yielded finally alterobactin (26) (83). 

Very recently, Mordini and coworkers" have overcome the problems associated with the long reaction times that are normally required for the synthesis of hydroxamic acids from esters by performing these transformations under MW irradiation. The protective groups are also well tolerated under these reaction conditions, though a partial deprotection of the feri-butoxycarbonyl (Boc) group was observed in the reaction with Boc-proline ester. Amidic bonds and ketals also survive without any detectable decomposition. All the reactions go to completion in about six minutes, except in the case of the conversion of Boc-protected phenylalanine methyl ester, which required longer reaction times (12 min). 

Initially, the Boc group was used for reversible a-amine protection and most side-chain functional groups were protected as benzyl derivatives, which are stable to Boc removal in HC1 or TFA. This Boc/Bzl strategy is still frequently used and is the method of choice in several laboratories. It has, however, been replaced in many laboratories by the base-labile Fmoc group, which allows weak acid deprotection of tert-butyl groups from the side chains. For short- and moderate-sized peptides both systems are effective. For protein synthesis, the relative merits have not yet been fully established. 

When solid-phase peptide synthesis was initially being developed, the question of whether or not a separate neutralization step is necessary was considered. Since it was known from the work of others that the chloride ion promotes racemization during the coupling step in classical peptide synthesis, and since we were deprotecting the Boc group with HC1, it seemed advisable to neutralize the hydrochloride by treatment with TEA and to remove chloride by filtration and washing. This short, additional step was simple and convenient and became the standard protocol. Subsequently, we became aware of three other reasons why neutralization was desirable (1) to avoid weak acid catalysis of piperazine-2,5-dione formation, 49 (2) to avoid acid-catalyzed formation of pyroglutamic acid (5-oxopyr-rolidine-2-carboxylic acid), 50 and (3) to avoid amidine formation between DCC and pro-tonated peptide-resin. The latter does not occur with the free amine. 

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