Benzyl group protection

Shaw and McDowellhave prepared imidazolone derivatives by cyclization of a-acylamino amides. In a variation of this reaction the azlactone (30) was gradually converted to the hydroxamic acid (31) by methanolic hydroxylamine. Sodium methoxide and hydroxylamine readily gave the acyclic hydroxamic acid (32) which could be cyclized to 31 by dilute acid. Benzyloxyurea has been used in the sjrnthesis of pyrimidine hydroxamic acids (33) by reaction with /S-diketones followed by catalytic hydrogenation of the benzyl group. Protection... 

Chemoselective catalytic hydrogenolysis (10 % Pd/C) of the glycosidic benzyl group of a 2-amino-2-deoxy-D-glucosederivative that carries another benzyl group protecting a 3-hydroxytetradecanoyl substituent at 0-3 has been applied in an efficient synthesis of lipid Y [215]. Benzyl ether is cleaved selectively in the presence of p-methoxy-benzyl ether by Raney nickel hydrogenolysis [216]. 

The benzyl group has been widely used for the protection of hydroxyl functions in carbohydrate and nucleotide chemistry (C.M. McCloskey, 1957 C.B. Reese, 1965 B.E. Griffin, 1966). A common benzylation procedure involves heating with neat benzyl chloride and strong bases. A milder procedure is the reaction in DMF solution at room temperatiue with the aid of silver oxide (E. Reinefeld, 1971). Benzyl ethers are not affected by hydroxides and are stable towards oxidants (e.g. periodate, lead tetraacetate), LiAIH, amd weak acids. They are, however, readily cleaved in neutral solution at room temperature by palladium-catalyzed bydrogenolysis (S. Tejima, 1963) or by sodium in liquid ammonia or alcohols (E.J. Rcist, 1964). 

A benzylidene acetal is a commonly used protective group for 1,2- and 1,3-diols. In the case of a 1,2,3-triol the 1,3-acetal is the preferred product. It has the advantage that it can be removed under neutral conditions by hydrogenolysis or by acid hydrolysis. Benzyl groups and isolated olefins have been hydrogenated in the presence of 1,3-benzylidene acetals. Benzylidene acetals of 1,2-diols are more susceptible to hydrogenolysis than are those of 1,3-diols. In fact, the former can be removed in the presence of the latter. A polymer-bound benzylidene acetal has also been prepared." ... 

Phosphinamides are stable to catalytic hydrogenation, used to cleave benzyl-derived protective groups, and to hydrazine. The rate of hydrolysis of phosphin-... 

KOH, H2O, reflux, 12 h, 64-92% yield. This group is more stable to n-BuLi than is the benzyl group when used to protect imidazoles. 

Show the steps involved in the synthesis of Ala-Leu from alanine and leucine using benzyloxycarbonyl and benzyl ester protecting groups and DCCI-promoted peptide bond formation. 

In carbohydrates in which benzyl groups are used extensively for protection, the stability of the benzyl groups toward electrophilic reagents is increased by the presence of electron-withdrawing groups in the ring." ... 

Phosphinamides are stable to catalytic hydrogenation, used to cleave benzyl-derived protective groups, and to hydrazine. The rate of hydrolysis of phosphinamides is a function of the steric and electronic factors around the phosphorus. This derivative has largely been used for the protection of amino acids and occurs few, if any, times in the general synthetic literature. 

While examining possible approaches to the sempervirine ring system Stevens found that when the pyridinium salt 238 was treated with acid a Pomeranz-Fritzch type eychzation occurred leading to 239. Without the protective influence of the benzyl group, attack at the indole nitrogen atom took place yielding 240. 

C—X) for the application at hand. Benzyl trans-l,3-butadiene-l-carbamate has the amino group protected with the benzyloxycar-bonyl group. The ability to remove this functionality by catalytic... 

In the Boc protection approach, benzyl groups are used to protect the reactive amino acid side-chain functionalities because they are more acid-stable than the Boc groups. Trifluoroacetic acid (TFA) is sufficient to remove the Boc groups while leaving the benzyl groups intact (Fig. 3). 

The benzyl group can serve as a hydroxy-protecting group if acidic conditions for ether cleavage cannot be tolerated. The benzyl C—O bond is cleaved by catalytic hydrogenolysis,176 or by electron-transfer reduction using sodium in liquid ammonia or... 

Methoxyphenyl (PMP) ethers find occasional use as hydroxy protecting groups. Unlike benzylic groups, they cannot be made directly from the alcohol. Instead, the phenoxy group must be introduced by a nucleophilic substitution.185 Mitsunobu conditions are frequently used.186 The PMP group can be cleaved by oxidation with CAN. 

As seen in the retro-synthetic Scheme 5.3, intermediate 15 is useful for both routes. The choice of benzyl protection group was made based on the robust stability of benzyl phenol ethers toward most reactions and several possible avenues to remove it, although it was reported from Medicinal Chemistry that benzyl group removal via hydrogenolysis posed challenges in this compound. The choice of iodide substitution was born out of the known high reactivity of iodides in the Ullmann-type coupling reaction with alcohols and the robust stability of aryl iodides in many other common reactions. 

The ketone 15 was eventually prepared by Grignard addition to Weinreb amide 21, as shown in Scheme 5.5. The Weinreb amide 21 was prepared from p-iodobenzoic acid (20). The phenol of readily available 3-hydroxybenzaldehyde (22) was first protected with a benzyl group, then the aldehyde was converted to chloride 24 via alcohol 23 under standard conditions. Preparation of the Grignard reagent 25 from chloride 24 was initially problematic. A large proportion of the homo-coupling side product 26 was observed in THF. The use of a 3 1 mixture of toluene THF as the reaction solvent suppressed this side reaction [7]. The iodoketone 15 was isolated as a crystalline solid and this sequence was scaled up to pilot plant scale to make around 50 kg of 15. 

---