Benzylidene, hydrogenolysis

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." ... 

Isopropylidene and benzylidene" groups have been used to protect simultaneously amide nitrogens and a neighboring hydroxyl. They can be removed by acid hydrolysis or hydrogenolysis (Pd-C, hydrazine, MeOH, 95% yield), respectively. 

We now tum our attention to the C21-C28 fragment 158. Our retrosynthetic analysis of 158 (see Scheme 42) identifies an expedient synthetic pathway that features the union of two chiral pool derived building blocks (161+162) through an Evans asymmetric aldol reaction. Aldehyde 162, the projected electrophile for the aldol reaction, can be crafted in enantiomerically pure form from commercially available 1,3,4,6-di-O-benzylidene-D-mannitol (183) (see Scheme 45). As anticipated, the two free hydroxyls in the latter substance are methylated smoothly upon exposure to several equivalents each of sodium hydride and methyl iodide. Tetraol 184 can then be revealed after hydrogenolysis of both benzylidene acetals. With four free hydroxyl groups, compound 184 could conceivably present differentiation problems nevertheless, it is possible to selectively protect the two primary hydroxyl groups in 184 in... 

Cyclic Acetals Benzyl ethers are obtained from benzylidene acetals on Ni but the product ethers are cleaved about as readily as the acetals.166 The hydrogenolysis of a p-bromobenzylidene derivative was achieved on 10% Pd/C in AcOEt and NaHC03.154... 

Similarly, a series of cyclophosphamides 143-145 were synthesized in good yields (78-87%) with very high diastereoselectivity by reacting alkyl 2-amino-4,6-0-benzylidene-2-deoxy-D-allopyranosides 140-142 with /V,/V-bis-(2-chlorocthyl) amidophosphoryl dichloride 138. Subsequent hydrogenolysis of cyclophosphamides 143-145 gave excellent yields (85-90%) of cyclophosphamides 146-148 which show higher hydrophilicity than their precursors (Scheme 41) [72],... 

Summarizing, it may be concluded that the ease of hydrogenolysis is (1) cyclic orthoester > isopropylidene acetal, cyclohexylidene acetal > benzylidene acetal > ethylidene acetal > methylene acetal, and (2) 5,6-O-linked and 3,5-O-linked > 1,2-0-linked acetals. 

Application of hydrogenolysis of benzylidene acetals to 2-amino-2-deoxy sugar derivatives was found to be possible.217 The reductive cleavage of benzyl 4,6-0-benzylidene-2-(benzyloxycarbonyl)amino-2-deoxy-a-D-glucopyranoside (209) gave, in a yield of 50%, a mixture of the 4-O-benzyl (210) and the 6-O-benzyl (211) derivatives. If the re-gioselectivity of this reaction, although notably inferior, was in ac-... 

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