Methoxybenzyl protective group, removal

The completion of the synthesis of the polyol glycoside subunit 7 requires construction of the fully substituted stereocenter at C-10 and a stereocontrolled dihydroxylation of the C3-C4 geminally-disub-stituted olefin (see Scheme 10). The action of methyllithium on Af-methoxy-Af-methylamide 50) furnishes a methyl ketone which is subsequently converted into intermediate 10 through oxidative removal of the /j-methoxybenzyl protecting group with DDQ. Intermediate 10 is produced in an overall yield of 83 % from 50) , and is a suitable substrate for an a-chelation-controlled carbonyl addition reaction.18 When intermediate 10 is exposed to three equivalents of... 

Reduction of benzylic oxygen functional groups with Raney nickel has occasionally been reported, but there are very few examples in the recent literature. Hydrogenolysis over W-2 Raney nickel has been used to selectively remove benzyl ether protection in the presence of a 4-methoxybenzyl protecting group (equation 30)." ... 

Benzyl ethers have been removed in the presence of 4-bromobenzoates without debromination using anhydrous ferric chloride in dichloromethane and TFA in dichloromethane has been used to effect removal of 0-4-methoxybenzyl protecting groups. ... 

Six protective groups for alcohols, which may be removed successively and selectively, have been listed by E.J. Corey (1972B). A hypothetical hexahydroxy compound with hydroxy groups 1 to 6 protected as (1) acetate, (2) 2,2,2-trichloroethyl carbonate, (3) benzyl ether, (4) dimethyl-t-butylsilyl ether, (5) 2-tetrahydropyranyl ether, and (6) methyl ether may be unmasked in that order by the reagents (1) KjCO, or NH, in CHjOH, (2) Zn in CHjOH or AcOH, (3) over Pd, (4) F", (5) wet acetic acid, and (6) BBrj. The groups may also be exposed to the same reagents in the order A 5, 2, 1, 3, 6. The (4-methoxyphenyl)methyl group (=MPM = p-methoxybenzyl, PMB) can be oxidized to a benzaldehyde derivative and thereby be removed at room temperature under neutral conditions (Y- Oikawa, 1982 R. Johansson, 1984 T. Fukuyama, 1985). 

FIGURE 8.7 Synthesis of a protected tripeptide containing a 2-hydroxy-4-methoxybenzyl-protected peptide bond.38 (A) Acylation of the carboxy-terminal residue, (B) removal of both protecting groups, (C) O-acylation of the benzyl-protector by the symmetrical anhydride of the amino-terminal residue, and (D) migration of the protected amino-terminal residue from the oxygen atom to the amino group of the dipeptide ester. 

An effective and mild electrocatalytic procedure for the deprotection of the 1,3-dithiane group of (68), giving the ketone (67), has been developed by using a small amount of tris(/ -tolyl)amine as a homogeneous electron-transfer catalyst (Scheme 26) [86]. The scope and limitations are discussed in detail [87]. The method can be applied also for oxidative removal of the 4-methoxybenzyl thioether protecting group from poly-cystinyl peptides [88]. 

Example 30 Bialy and Waldman in their synthesis of protein phosphates 2A inhibitor (4S, 5S, 6S, lOS, US, 12S) cytostatin have found that application of the fluorenylmethyl protecting group (Fm) allowed successful formation of the phosphate moiety [62]. Initial experiments with the methoxybenzyl group, successfully employed in the synthesis of fostriecin [63] failed. The 2-cyanoethyl protecting group was also not suitable because that one 2-cya-noethyl group could be removed without destroying the whole molecule (Examples 25 and 26). 

Deprotection of peptides. In a synthesis of bovine pancreatic ribonucleasc, the 33 protective groups required were removed by three treatments with l M TEMSA thioanisole at 0° for 60 minutes. The groups were Cbz, r-butyl, p-methoxybenzyl, and p-methoxybenzenesulfonyl. The final step involved air oxidation of the cysteine residues to disulfides mediated by glutathione.2... 

DDQ is a potent hydride abstractor with a great tendency to produce oxidations when an intermediate stable carbocation can be formed. That is why DDQ is able to remove p-methoxybenzyl (PMB),106 3,4-dime thoxyben-zyl (DMPM)106 and 2,4-dimethoxybenzyl (DMB)118 protecting groups under very mild conditions. 

The para-methoxybenzyl group belongs to a class of alcohol protecting groups that are stable to basic conditions but can be removed by oxidation. Here DDQ (2,3-dichloro-5,6-dicyano-l,4-benzoquinone) is used to yield the free primary alcohol 3. 

Methyl 1 -(/>-m ethoxy bcn/y I )tctra/olc-.S-carboxy late 371 under conditions of base catalysis reacted with substituted acetophenones giving diketones 372 and 373. On removing the protecting group (/>-methoxybenzyl, PMB) at position 1 of the tetrazole ring, the corresponding unsubstituted tetrazoles 374 and 375 were isolated (Scheme 42) <2004BML4915>. 

Later on, all the protecting groups will be removed the silyl groups with fluoride and the p-methoxybenzyl ether by oxidation with Ce(IV). In Ley s recently completed synthesis9 of azadirachtin 64 after 22 years of hard labour the key intermediate was 65. You will notice benzyl ethers, acetals and a silyl ether. This is a more modem, one might almost say minimalist, use of protection. In an ideal world no protecting groups would be necessary but in a real synthesis they will almost certainly be required as we shall see in the rest of the book. But our aim should be to keep them to a minimum. 

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