Hydrogenolytic debenzylation

As an alternative process, the nitrone (138 R Cl OCl Ph) yields a mixture of diastereoisomeric (benzyloxymethyl)phosphonic derivatives of which (141) is the main component acidolysis and hydrogenolytic debenzylation lead to phosphoserine (143), the (S) chirality of which was demonstrated by )(-ray analysis of the derivative (144). In a further variation, the di-tert-butyl... 

G Losse, H-U Stiehl, B Schwenger. Hydrogenolytic debenzylation of sulfur-containing peptides. Int J Pept Prot Res 19, 114, 1982. 

Primary benzenesufonamides have been notoriously difficult to protect. Theodore S. Widlanski of Indiana University has now found (Tetrahedron Lett. 2004,45, 8483) that while N-benzyl sulfonamides such as 1 are resistant to hydrogenolytic debenzylation, the easily-prepared Boc derivative 2 is smoothly debenzylated. Brief exposure of 3 to trifluoroacetic acid then gives the primary sulfonamide 4. 

The first enantioselective catalytic Strecker reaction of ketoimines to give chiral quaternary cyanohydrins was demonstrated by the Jacobsen group using 45b (Scheme 6.7) [41]. A series of substituted aryl and aliphatic N-benzyl methylketo-imines (48) reacted with HCN in the presence of 45b to provide essentially quantitative yields of the Strecker adducts in high optical purities (70-95% ee). The adducts were crystalline, and their recrystallization from hexanes increased their enantiopurities to >99.9% ee. The a-quaternary Strecker adducts (49) could be converted to a-quaternary a-amino acids through formamide protection of the secondary amine, followed by sequential hydrolysis of the nitrile and the formamide, followed by hydrogenolytic debenzylation. 

Subsequent exposure of geminal dibromide 62 to BU3S11H provided the desired ester 63 via a stereocontrolled cyclization-debromination tandem sequence. Finally, Barbier-Wieland degradation and hydrogenolytic debenzylation of ester 63 afforded 5a-carba-D-fructofuranose 64 in excellent yields. In a preliminary enzymological study, its 6-phosphate derivative showed to be an interesting substrate for the enzymes of the glycolysis pathway. 

The enantiomerically pure amines 82 and 84 are for example prepared by resolution of the racemic 8-benzyl-rfs-2,8-diazabicyclo[4.3.0]nonane 79 using natural R,R(+)-tartaric acid, whereupon the diastereomerically pure i ,i -tartrate of the R, /<-enantiomer is crystallized from dimethylformamide (DMF) and can be purified by recrystallization from methoxyethanol. The target S,S-enantiomer contained in the mother liquor is first converted into the free base, which is then, for the purpose of further purification, precipitated with S,S(-)-tartaric add to give the diastereomerically pure S,S-tartrate. The S,S-enantiomer 83 is then liberated with sodium hydroxide solution. The R,R-enantiomer 81 is obtained in the same way. Separation of the enantiomers can also be carried out with high optical yields in an aqueous/alcoholic solution [140]. The hydrogenolytic debenzylation of 81 and 83 produces the corresponding pure R,R- and, S, S —2,8-diazabicyclo[4.3,0]no-nanes 82 and 84 (Scheme 14.2) [129]. 

Losse et al. have demonstrated that the difficulty in the hydrogenolytic debenzylation of S-protected cysteine derivatives is due to the strong poisoning action of thiols that may be formed probably by a P elimination of the cysteine to give the dehydroalanine derivative.83 The overall reaction in the case of Z-Cys(Bzl)-OBzl may be formulated as in eq. 13.43. 

The first step of the total synthesis of 31 is the (7v )-proli nc-calal yzcd aldol reaction between 4 and 32, which gave the aldol adduct 33 with a good yield (69%) and nearly perfect stereocontrol (>96% de, >99% ee, Scheme 10). The same results were observed when the reaction was carried out on a 40-mmol scale yielding 5.22 g of 33 without a decrease of selectivity. The free hydroxyl group of 33 was quantitatively protected as MOM-ether. After hydrogenolytic debenzylation the aldehyde-ketone was obtained after Dess-Martin oxidation followed by a double Wittig reaction to provide the bisolefine 34 in 41% yield over 4 steps (Scheme 10). 

Since benzyl groups can be removed from N,N-dibenzylcyclopropylamines by catalytic hydrogenation over palladium catalysts, primary cyclopropylamines are accessible by this methodology. Thus, the theoretically interesting tricyclopropylamine [106,107] could be prepared from benzylcyclopropylformamide by a sequence of reductive cydopropanation of the formyl group, hydrogenolytic debenzylation, N-formylation, and repeated reductive cydopropanation [106,107]. 

Starling material was the silylprotected hydroxymethyl-cyclopentanone 8, readily available by a Lewis-acid promoted reaction (22) of 1-trimethylsilyloxyclyclopentene with formaldehyde-dibenzylacetal followed by hydrogenolytic debenzylation and protection (see scheme 3). 

The parallel, more convenient synthesis of KDO has been proposed by Schmidt and co-workers [94], Employing the ylide 92 and aldehyde 98 (protected with Bn group instead of TBS), the corresponding olefin was produced in 73% yield. Its transformation was simply achieved by hydrogenolytic debenzylation, proceeding with concomitant intramolecular cyclization, to furnish after treatment with diazomethane, the anomeric mixture a/p (2 1) of KDO methyl ester. 

The electrolytic oxidation of the sodium salt of (+ )-N-ethoxycarbonyl-Al-norarmepavine (46) led to the dimeric mixtures (47) and (48). The latter mixture was converted into a mixture of dauricine analogues (49) via O-benzylation, reduction with lithium aluminium hydride, and hydrogenolytic debenzylation. This transformation represents the first preparation of an analogue of a natural bis-benzylisoquinoline by oxidation of a phenolic monomeric benzylisoquinoline. Detailed studies on the mass-spectral cleavage patterns of bisbenzylisoquinolines have appeared. 

Vasella and Peer have developed a regioselective synthesis of the protected six-membered cyclic L-fucose-derived nitrone 157 in view of the synthesis of a-L-fucosidase inhibitors [70]. The nitrone 157 has been transformed into the indolizidines 160 and 161 via a cycloaddition to an acrylate (Fig. 37). The reaction proceeded regioselectively and led to a 60 40 mixture of the diastereomeric isoxazoHdines 158 (55%) and 159 (34%) by exclusively axial C - C bond formation. Reductive cleavage of the N - O bond of the isoxazoHdines 158 and 159, followed by reduction with BH3 in THF with subsequent hydrogenolytic debenzylation in MeOH/HCl, afforded the indoUzidines 160 and 161 as their hydrochlorides. 

Alkylation via enamine 18 and successive alkaline hydrolysis furnished 2-oxo-cyclohexylacelic acid derivative 19. Refluxing keto acid with benzylamine in orf/io-xylene and then in 87 % formic acid yielded unsaturated lactame 20. Catalytic hydrogenation of the C=C bond afforded trans,cis 21 as the sole stereoisomeric product. In the last steps, reduction of lactame by a complex hydride, hydrogenolytic debenzylation and the Pictet-Spengler reaction gave ( )-a-lycorane TM 9.4 in a moderate overall yield. 

Phenylsulfonyl)-3-phenyloxaziridine (1S6. Davis reagent. Figure 11.61) has been shown to react with sodium enolates of chiral carboximides of the Evans-Oppolzer type, providing a-hydroxyacyl derivatives with diastereoselectivities of 90-98% d. g 92,133 Subsequent titanium(IV) isopropoxide-mediated transesterification with benzyl alcohol and hydrogenolytic debenzylation releases the free a-hydroxy acids in enantiomerically pure form and in yields of 65-75%. This procedure was applied... 

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