Allyl carbamates, deprotection

Since the initial studies of Tsuji and Trost, it has been known that Tr-allylpalladium complexes react irreversibly with active methylene compounds to form new carbon-carbon bonds. Applying this information, Kunz introduced dimedone and A,A-dimethylbarbi-turic acid (NDMBA) as nucleophiles in the Pd-catalyzed deprotection of allyl carbamates and carbonates. The presumed catalytic cycle for this process is shown in Scheme 4. Dimedone and NDMBA have also been employed as nucleophiles in the deprotection of aUyl esters. Dimethyl malonate has also been used occasionally in allyl carbamate deprotection, although it appears to be less reactive than the other carbon nucleophiles.f ... 

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. 

Following a first report by Kunz and WaldmannP l secondary amines such as diethylamine, piperidine, and in particular the less basic morpholineP l have been extensively used for the deprotection of allyl esters. As the allylammonium species formed in this process (Scheme 14) may also behave as an allyl donor towards palladium zerovalent complexes, the use of an excess of scavenger is highly recommended in order to totally displace the equilibrium towards deprotection. Secondary amines can also be used in the deprotection of allyl carbamates. Here again an excess of scavenger is necessary to avoid kineticaUy competitive allylation of the liberated amine. 

The enolate formed in this process then condenses irreversibly with the r -allylpalladium species. At the outset, dimedone and A,A-dimethylbarbituric acid had been more specifically devisedP for the deprotection of allyl carbamates in solution or in solid-phaseP chemistry in which case the enolate species also forms by proton transfer from the (3-dicarbonyl allyl scavenger to the liberated amine but since then it has also been used for the deprotection of allyl carboxylic esters (see Section 2.2.1.1.3).P 1... 

Due to the relative rapidity of the reactions and to the protonation of the free amine by the excess scavenger during the deprotection of allyl carbamates, the risk of formation of allylamine seems very limited and has not been reported. In the reactions with dimedone, a possible complication is the formation of substantial amounts of hydrolytically stable oxo-enamine by condensation with the liberated amine. For this reason, the use of N,N-di-methylbarbituric acid is probably a safer solution. 

N -Protection as allyl carbamate is used generally only for specific synthetic purposes where acid- or base-mediated deprotection procedures must be avoided or reduced to a minimal extent as in the case in the synthesis of glyco- and phosphopeptides (see Sections 6.3 and 6.5). Otherwise the orthogonality of this type of amino protection has been mainly exploited in side-chain protection to allow for selective chemistry such as selective acylations, e.g. cyclizations, to be performed on protected peptides in solution or in the resin-bound state (see Section 4.3.2.3.4). An additional interesting application of the Aloe group is the one-pot deprotection and acylation with carboxy components resistant to the paUadium(0)-catalyzed allyl cleavage by hydrostannolysis as reported in Section 4.3.2.3.4.P 1... 

Various water-insoluble substrates are deprotected smoothly in water using water-soluble ligand (TPPTS, II-l) in the presence of cyclodextrin [181]. Deprotection of allyl carbonates and carbamates can be carried out in MeCN/H20 using TPPTS as a ligand and Et2NH as the scavenger [182]. Chemoselective removal of allyl carbamate in a base-sensitive cephalosporin 478 was achieved with 1 % Pd(0)/TPPTS at room temperature to afford 479, and then the prenyl carboxylate... 

The prenyl (y,y-dimethylaUyl) ester was introduced as a more robust variant of the allyl ester.Experiments have shown that aUyl esters and allyl carbamates can be selectively deprotected in the presence of a prenyl ester,thereby permitting greater precision in the selectivity of deprotection of aUyl-based functionality. 

Pd(OAc)2, TPPTS, CH3CN, H2O, Et2NH, 30 min, 89-99% yield. Deprotection can be achieved in the presence of a prenyl or cinnamyl ester, but as the reaction times increase, these esters are also cleaved.Prenyl carbamates and allyl carbonates are cleaved similarly. 

This chemistry can be very powerful, since the amide product itself offers further possibilities for functionalisation by lithiation. The synthesis of the natural product ochratoxin A (section 9.1) illustrates this point. Two successive ortholithiations of carbamate 210 are used first to introduce one amide group and then a second, by anionic ortho-Fries rearrangement. The symmetrical diamide 211 can be allylated and then cyclised in acid, with concomitant hydrolysis of the second amide and deprotection of the phenol to yield a known intermediate... 

For the synthesis of the non-diene analogue 65, which bears a benzyl group in the terminal position (Scheme 17), 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) cleavage of the p-methoxybenzyl (PMB) ether at the C15-position did not proceed in the presence of the benzyl moiety (oxidation of the methylene in allylic-benzylic-position in C23-position). Therefore, we inverted the order of the first two steps (1) DDQ deprotection on 44 and (2) nickel-catalyzed cross-coupling reaction performed on a free primary alcohol in C15 position. After this minor modification, completion of the synthesis followed the established route Suzuki-Miyaura crosscoupling reaction between alkyl iodide 73 (via its trialkylboronate species) and vinyl iodide 60 to yield 74 selective carbamate installation and final deprotection to afford DDM analogue 65. 

Clearly the reaction of Scheme 63 can be used not only to deprotect amines but also for Pd(0)-catalyzed allylation of nucleophiles using carbamates as substrates, as proposed by J. Tsuji and co-workers " However, carbonates are preferred since amines liberated when working with carbamates are strongly nucleophilic and can react further. To avoid this side reaction Tsuji proposed the use of 7V,N -diisopropyl carbamates, which hberate the moderate nucleophile diisopropylamine. However, the side reaction is much less important with alcohols. 

The first total synthesis of the intricate Stemona alkaloid (+ /—)-isostemofoline (224) was reported by Kende and coworkers 81) starting from 1,2-hexanediol (225) which was straightforwardly converted to 227 (Scheme 22) 82). Reductive cycUzation with sodium hydrosulfite in refluxing aqueous ethanol, and protection of the unstable pyrrole as tert-butyl carbamate, afforded 228 in five steps with 12% overall )deld. The key bicyclic ketone 231 was assembled by [4 + 3] cycloaddition of pyrrole 228 and diazoester 229 promoted by rhodium octanoate dimer, followed by enol silane deprotection, exo-specific hydrogenation, and nucleophilic decarboxylation (47% overall yield). Sodium methoxide-catalyzed aldol condensation of ketone 231 and furfural provided the Q-j/i-unsaturated ketone 232 whose olefin configuration was established by nOe studies. Allylation of 232 provided a 2.4 1 mixture of ketone 234 and the corresponding allylic enol ether 233, which could be converted to the former via a stereoselective Claisen rearrangement. 

---