Allyl amines deprotection

Hydroxylysine (328) was synthesized by chemoselective reaction of (Z)-4-acet-oxy-2-butenyl methyl carbonate (325) with two different nucleophiles first with At,(9-Boc-protected hydroxylamine (326) under neutral conditions and then with methyl (diphenylmethyleneamino)acetate (327) in the presence of BSA[202]. The primary allylic amine 331 is prepared by the highly selective monoallylation of 4,4 -dimethoxybenzhydrylamine (329). Deprotection of the allylated secondary amine 330 with 80% formic acid affords the primary ally-lamine 331. The reaction was applied to the total synthesis of gabaculine 332(203]. 

Allylic amination is important for the solid-phase organic synthesis.15 The solid-phase allylic aminations are devised into the G-N bond formation on solid support and the deprotection of allyl ethers. As a novel deprotection method, the palladium-catalyzed cyclization-cleavage strategy was reported by Brown et al. (Equation (4)).15a,15b The solid-phase synthesis of several pyrrolidines 70 was achieved by using palladium-catalyzed nucleophilic cleavage of allylic linkages of 69. 

Hydroboration of allylic amines.1 Hydroboration of primary and secondary allylic amines presents problems because amino groups interact with boron reagents. Hydroboration proceeds normally when the amino group is protected by trimethylsilyl groups, and deprotection can be effected by protonolysis in CH,OH. 

Allylic amines. The stabase adduct (1) of 2-chloroallylamine couples with Grignard reagents in the presence of NiCl2(dppp), dppp = (CfiH )2P(CH2),P(C6H5)2, to form, after deprotection, allylic amines. 

Palladium-catalyzed, Allylic Amination. Allylic substitution of mono-saccharidic hex-2-enopyranoside 4-acetates with secondary amines in the presence of tetrakis (triphenylphosphine)palladium(O) liad led to a large variety of 4-aminated 2-enosides, with retention of configuration (56-58). The method was applied to the disaccaridic enoside 1 to give, with benzylmethylamine or dibenzylamine, the 4-amino sugar derivatives g in yields of 92 and 67% (46). Studies concerning hydrox-ylation of t)ie double bond and subsequent deprotection are incomplete. 

Scheme 10.8 outlines the application of rhodium-catalyzed allyhc amination to the preparation of (il)-homophenylalanine (J )-38, a component of numerous biologically active agents [36]. The enantiospecific rhodium-catalyzed allylic amination of (l )-35 with the lithium anion of N-benzyl-2-nitrobenzenesulfonamide furmshed aUylamine (R)-36 in 87% yield (2° 1° = 55 1 >99% cee) [37]. The N-2-nitrobenzenesulfonamide was employed to facilitate its removal under mild reaction conditions. Hence, oxidative cleavage of the alkene (R)-36 followed by deprotection furnished the amino ester R)-37 [37, 38]. Hydrogenation of the hydrochloride salt of (l )-37 followed by acid-catalyzed hydrolysis of the ester afforded (i )-homophenylalanine (R)-3S in 97% overall yield. 

On the other hand, for allylic aminations very promising results have been realized with regard to regioselectivity, catalytic activity and substrate scope. However, further efforts are necessary to find nitrogen transfer reagents which allow convenient deprotection and isolation of the allylic amine. 

In most cases, the nature of the oftentimes messy side reactions attending oxidative deprotection of p-methoxybenzyl ethers is not elucidated but in a recent synthesis of an unusual constituent amino acid of the protein phosphatase inhibitor Motuporin, Bauer and Armstrong330 showed that treatment of the p-methoxybenzyl ether 177.1 [Scheme 4.177] with DDQ in the usual way afforded the product derived from oxidation of the allylic amine function to give the ketone... 

These amines can be deprotected under reduction conditions (Pd-C/R0H/HC02NH4 or Na/NH3). The allyl amines can be deprotected by oxidative cleavage with ozone (dimethyl-sulfide work up) or with KMn04 in acetone. 

Olefin isomerization catalyzed by ruthenium alkylidene complexes can be applied to the deprotection of allyl ethers, allyl amines, and synthesis of cyclic enol ethers by the sequential reaction of RCM and olefin isomerization. Treatment of 70 with allyl ether affords corresponding vinyl ether, which is subsequently converted into alcohol with an aqueous HCl solution (Eq. 12.37) [44]. In contrast, the allylic chain was substituted at the Cl position, and allyl ether 94 was converted to the corresponding homoallylic 95 (Eq. 12.38). The corresponding enamines were formed by the reaction of 70 with allylamines [44, 45]. Selective deprotection of the allylamines in the presence of allyl ethers by 69 has been observed (Eq. 12.39), which is comparable with the Jt-allyl palladium deallylation methodology. This selectivity was attributed to the ability of the lone pair of the nitrogen atom to conjugate with a new double bond of the enamine intermediate. 

The Cr-PILC catalyzed benzylic and allylic oxidations also provide a facile approach to the oxidative deprotection of allyl and benzyl ethers and amines. Treatment of allyl or benzyl ethers with one equivalent of tert-butyl hydroperoxide in the presence of Cr-PILC at room temperature resulted in the oxidative cleavage of the allyl- or benzyl-oxygen bond to give the alcohol but when two equivalents of tert-butyl hydroperoxide (TBHP) were used, the alcohol was oxidized further to the aldehyde or ketone (Eqn. 21.21).47 Oxidation of allyl amines resulted in the cleavage of the allyl-nitrogen bond to give the des-allyl amine.47 Benzyl amines, however, were oxidized to the benzamides (Eqn. 21.22).45... 

Allylic amines 54 have also been synthesised using the Mitosunobu protocol. Sen and Roach describe the formation of such amines from allylic alcohols 29 The phthaloyl group can be removed cleanly by hydrazine at room temperature, while for more bulky groups (e.g., nerol, famesol) phthaloyl cleavage was better effected with methylamine. Deprotection with methylamine was found to be exceptionally mild, and in substrates... 

A synthesis of Agelastatin A by Weinreb and co-workers featured the use of a 13 bis[2-(trimethylsilyl)ethylsuifonyl] sulfodiimide 137 2 as an enophile in a two-step allylic amination reaction [ heme 8.137]. The initial ene reaction produced a dipolar intermediate 1373 that underwent a [2,3] Sigmatropic shift to afford the SES-protected allylic amine derivative 137,4. Reductive cleavage of the N-S bond followed by cleavage of the Boc group with trifluoroacetic acid gave the sulfonamide 1373 in 50-60% overall yield. Final deprotection of the SES group with TBAF returned the desired amine 137,6 in 90% yield. 

A chiral ligand mediated approach to lithiation-substitutions of allylic amines has also been well developed. Weisenburger and Beak demonstrated that lithiation of doubly protected allylic amines 141 in the presence of the chiral ligand (-)-sparteine (5), and substitution with a variety of electrophiles provided highly enantioenriched enecarbamate products 142 (Scheme 44) [100]. The authors demonstrated that the intermediate organolithium could be viewed as either an aldehyde P-homoenolate or y-lithioamine synthetic equivalent by hydrolysis or reduction and deprotection of the enecarbamates, respectively. 

An iV-phenyl-allylamine has been arylated terminally using phosphine-free conditions and a heteroaryl iodide in the synthesis of an H+/K+-ATPase inhibitor (Figure 3.31) [91]. This class of inhibitors has attracted the interest of many medicinal chemistry groups due to the large sales of the blockbuster Losec/Prilosec (Omeprazole). In the cited case, the allylic amine moiety was added at a late stage of the synthesis and the primary amine was protected by Boc to prevent formation of 7r-allyl palladium complexes. The deprotection was then performed with trifluoroacetic acid. 

Initially, Pd-catalyzed deprotections were carried out under reductive conditions. The earliest examples of Pd-mediated allyl group deprotection employed formic acid, usually in conjunction with an amine base, at elevated temperature as a hydride source (Scheme 2). Later development of tri- -butyltin hydride as a hydride source has greatly facilitated the reductive deprotection of a wide variety of aUyl-based protecting groups, reacting almost instantaneously at ambient temperature. " Additional hydride sources for allyl group deprotection include phenyltrihydrosilane and several different borohydrides (Scheme Most recently, Guibe and Albericio have used amine-... 

The last class of nucleophiles used to scavenge the n-allylpalladium intermediate is that of sulfur nucleophiles. 2-Thiobenzoic acid has been used as a water-soluble scavenger of 7r-allylpalladium complexes in allyl carbamate deprotections. More recently, aryl sulfinic acids have been demonstrated to very effectively serve as nucleophiles in the Pd-mediated deprotection of allyl esters, carbamates, amines, and ethers. This reagent appears to afford substantially bettCT reactivity than most other classes of nucleophiles. 

The product (112) of D-xylose, allyl amine, and styrylboronic acid was then subjected to a protection/metathesis/dihydroxylation/deprotection/cyclization sequence that produced stereoisomerically pure (-F)-uniflorine A over a total of 11 steps. 

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