Deprotection amines

The choice of the acyl substituent X for Diels-Alder reactions of l-N-acylamino-l,3-butadicnes depends on the particular synthetic problem. The acyl substituent has a moderate effect on the cycloaddition reactivity of these dienes, and also determines what amine unmasking procedures are required. As a result of their stability and the variety of amine deprotection procedures available, " the diene carbamates are the components of choice in most cases. A particularly attractive aspect of the diene synthesis detailed here is the ability to tailor the amino-protecting group... 

Enantiopure N,N -hnked oligoureas were originally described in 1995 by Burgess and coworkers as novel peptide backbone mimetics [271, 272]. Several synthetic approaches have been reported, all of which involve sequential acylation and amine deprotection cycles using appropriately protected carbonyl synthons [83, 271, 272, 274, 286-288]. Although elongation can be performed in solution, most of the synthetic procedures are elaborated on solid supports starting from Rink s... 

In a recent patent, Hu et al. reported a similar procedure where the acceptor aldehyde contains aminoalkyl substituents in place of chloride. Subsequent to lactol oxidation and amine deprotection, these intermediates can directly undergo Paal-Knorr cyclization with the appropriate diketone to produce atorvastatin, thus avoiding the use of cyanide chemistry. 

More recently, Aitken and coworkers described a short and convergent formal total synthesis of cyclotheonamide C using a process that involves a Passerini reaction, amine deprotection, and an acyl migration (PADAM sequence. Scheme 22) [90]. The key linear pentapeptide 22e is obtained by a Passerini reaction of isocyanide a, Fmoc-amino aldehyde b, and Boc-dipeptide acid e followed by Fmoc removal and consequently 0,N-acyl migration [91]. The macrocyclization was achieved with TBTU and HOBt after Boc and fBu removal in good yield (52%) to furnish intermediate f. 

Scheme 22 Formal synthesis of cyclotheonamide C using the PAD AM-sequence (Passerini-3CR/ amine-deprotection/acyl-migration)...

It has also been found to be possible to effect the reductive fluoroolefination with the amine group protected as an anisidine derivative [71] (66) and thereby obviate the aforementioned amine deprotection-reprotection scheme (Scheme 24). 

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. 

V,/V -bis(acryIoyI)-l,3-diaminopropane. Amine deprotection after polymerization leads directly to the functionalized support. 

Amines can also be protected from unwanted acylation or from twofold alkylation by alkylation with a sterically demanding group that is amenable to selective removal after completion of the synthesis. The most commonly used groups for this purpose are triphenylmethyl derivatives. Amines are readily tritylated using trityl chloride in the presence of a tertiary amine. Deprotection is achieved by treatment with dilute... 

Derivatives to Amines (Deprotection of SMA) a. Hydrazinolysis of SMA Phthalimides and Formamidines... 

TIPS ether) A silyl ether of formula R -O-Sid-Prh commonly used to protect alcohol groups. Formed from an alcohol with TIPSC1 and a tertiary amine. Deprotected using aqueous fluoride salts, (p. 645)... 

The Fmoc group protection is common in solid-phase peptide synthesis. Fmoc is resistant to acidic conditions and easily deprotected by weak bases, particularly secondary amines. Deprotection occurs through base-catalyzed abstraction of the (3-proton of the protecting group with elimination leading to formation of dibenzofulvene (1.83) (Scheme 1.36). 

Kaiser et al. have reported a general entry for the selective synthesis of dimeric macrocycles like cyclostellettamines and for polymeric natural products [41]. It uses the Zincke reaction by which it is possible to control the number of units in a 3-alkylpyridinium polymer. As summarized in Fig. (33), the reaction of the free amine 89 with the Zincke salt 88 gives the dimer 90 (route b) which, after terminal amine deprotection and DNB functionalization at the A-pyridine centre, gives the cyclic dimer, as in the synthesis of cyclostellettamine B. Otherwise, compound 90 furnishes both the protected dimer 91 and the free linear dimer, which, refluxed together in butanol, give the linear tetramer (route c). By the same iterative sequence, the linear octamer was obtained from the tetramer, and from the latter the hexadecamer. 

The catalytic asymmetric synthesis of diarylmethylamines by a rhodium/phos phoramidite catalyzed addition of arylboronic adds to N,N dimethylsulfamoyl pro tected aldimines has been reported by de Vries and Feringa [118], The reaction produces very high yields and high enantioselectivities of the protected amine. Deprotection of the amine is achieved without any racemization upon heating the product in the microwave with 1,3 diaminopropane (Scheme 1.35). 

Secondary amides react selectively to yield esters and sulfilimines, which can then be converted into the corresponding amines. For example, amide 17 reacts with sulfurane 1 to furnish ester 19 and sulfilimine 18 which yields amine 21 upon reaction with either hydrochloric acid followed by base or hydrogen gas and catalytic palladium on carbon. Thus, this reaction can function both as an ester synthesis and an amine deprotection. Bulky secondary amides do not immediately undergo cleavage and instead yield imidates that, upon treatment with aqueous acid, furnish amines and esters. For example, combination of Martin s sulfurane (1) with amide 22 provides imidate 23 that can be easily converted into amine 25 and ester 24. Primary amides provide Af-acylsulfilimines, while tertiary amides are completely unreactive.7... 

Boc protection of the amine, complexation with hexacarbonylchromium, and then amine deprotection with neat formic acid provides (R)-( + )-halostachine(tricarbonyl)chromium(0) (57). Treatment of 57 with 3,4-dimethoxybenzyl bromide in dichloromethane affords in 36% yield (i )-( + )-tricarbonyl f -2-[3,4-dimethoxybenzyl(methyl)amino]-l-phenylethanol -chromium(O) (58), which undergoes a highly selective acid-promoted cyclization that proceeds with retention of configuration to yield, after decomplexation, optically pure (R)-(-h)-6,7-dimethoxy-2-methyl-4-phenyl-l,2,3,4-tetrahydroisoquinoline (59) in moderate yield (Scheme 11) [13]. 

Seebach and coworkers demonstrated that tetrahydroisoquinoline pivala-mides 75 containing a stereogenic center at the 3-position can be used in dias-tereoselective alkylations [66]. After dilithiation of the acid with 2 equivalents of f-BuLi, the resulting organolithium was quenched with alkyl halides, such as Mel and benzyl bromide, to afford products 76 in ca. 80% yield, Eq. (5). Oxidative decarboxylation followed by amine deprotection provided 77 with ers greater than 97 3. 

Construction of the Dolby model system began with epoxidation of cyclohexene 209 employing mCPBA in chloroform. The epoxide product was then subjected to a base-promoted cyclization via amide deprotonation and oxirane opening to provide benzamide 210 (Scheme 23). Hydroxyl oxidation using the Jones conditions next furnished cyclohexanone 211. A Fischer indole synthesis on this scaffold, followed by amine deprotection using sodium hydroxide, led to the desired l,3-(iminoethano)carbazole 83. While the yield of this route was low, it was the first example of a method to fashion the 2-azabicyclo[3.3.1]nonan-8-one system 211, and importantly demonstrated that indoHzation on such a scaffold was possible. 

In a reductive amination/deprotection/Davis-Beirut reaction process, o-nitrobenzaldehydes 147 and 4-(tritylthio)butan-l-amine 148 combined to form a pair of l,3-thiazepino-2H-indazoles 149. Subsequent S-oxidation gave the corresponding sulfones.The oxygen analog 150 was prepared by using 4-aminobutan-l-ol instead of 148 (14JOC6939). 

Another useful application of the resin involves amine deprotection reactions. PS-thiophenol ase can be used to remove the Fmoc protecting group and simultaneously capture the contaminating component (eq 4). ... 

A potentially useful synthetic extension in this area of research has been the Passerini reaction-amine deprotection-acyl migration (PADAM) sequence, first conceived as a tool for giving access to peptide-like structures [40] and mainly developed by Banfi, Riva, and coworkers [2a]. In this sense, PADAM sequence has been employed for the synthesis of interesting peptidomimetics since the resulting a-ketoamide scaffolds are useful for drug discovery [41] or in the synthesis of enzyme inhibitors [42], and this amplifies the scope of this valuable multicomponent process [43] (Fig. 8.4). 

In this context, and more recently, an interesting application of this methodology has been described by Faure, Aitken, and coworkers. Thus, they applied PADAM methodology (three-component Passerini reaction-amine deprotection-0,N-acyl migration) as key synthetic step of the linear pentapeptide intermediate in the formal total synthesis of cyclotheonamide C 54, a potent inhibitor of serine protease such as thrombin belonging to a family of cyclic pentapeptides with potential biological activities (Scheme 8.19) [47]. 

S. Fame, T. Hjehngaard, S. P. Roche, D. J. Aitken, Org. Lett. 2009, 11, 1167-1170. Passerini reaction-amine deprotection-acyl migration peptide assembly efficient formal synthesis of cyclotheonamide C. 

PADAM Passerini reaction-amine deprotection-acyl THBCs tetrahydro-p-carbohnes... 

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