Benzyloxymethyl group

T Brown, JH Jones, JD Richards. Further studies on the protection of histidine side chains in peptide synthesis use of the jr-benzyloxymethyl group. J Chem Soc Perkin Trans 1, 1553, 1982. 

Similarly, Takano et al. (79) reported the intramolecular, asymmetric cycloaddition of ylides derived from thermal decomposition of aziridines 255 with the stereoselectivity rationalized by the formation of a postulated nine-membered transition state 256 in which the benzyloxymethyl group was forced into an equatorial disposition. The resultant pyrrolidine 257 contained three new stereo-genic centers, each imposed with high control (Scheme 3.87). 

In an extension to this work, this group applied the protocol to the synthesis of (—)-mesembrine (258). The key ylide formation and cycloaddition sequence was performed in xylenes at 250 °C in a sealed tube, furnishing the desired pyrrolidine lactone 259 as a single isomer in excellent yield, and further chemical elaboration yielded the target compound 258. Again it can be postulated that the stereochemical outcome is due to the bulky benzyloxymethyl group lying in an equatorial environment in the transition state (Scheme 3.88). 

Chelation is probably also of importance since replacement of both of the benzyloxymethyl groups of 1 with butyl groups leads to a lower diastereoselectivity (d.r. 80 20) in the benzylation reaction6,17. 

The carbinyl nitrile acidifies the or-proton, which is deprotonated with LDA. The nucleophilic lithium salt is quenched with benzyloxymethyl bromide as electrophile to give 13 in 82 % yield. Again, the angular methyl group controls the facial selectivity the benzyloxymethyl group is introduced from the -face. 

Fig ( 18 ) A series of reactions are carried out for the conversion of dehydroabietic acid to ketone (155) to hydroxymethyiation, protection of aliphatic hydroxyl group, addition of an -benzyloxymethyl group and acid treatment provides (156) which is con verted to (158). The butenolide function is constructed by successive oxidation and debenzylation to yield (159) which is converted to triptolide (149) by conventional methods. 

The reaction proceeded with total stereoselectivity and high 1.2-asymmetric induction, due to the benzyloxymethyl group a to the double bond. The bicyclic system hindrance does not affect stereoselectivity since a 50 50 diastereomeric mixture is formed when the benzyloxymethyl group is absent. 

The benzyloxymethyl group has been used for the protection of the pyridazinone NH group. It is unaffected by a variety of acidic, basic, and reductive conditions and while removal by hydro-genolysis was erratic, the use of boron trichloride in DCM at — 78°C is effective <84JHC48l>. Ethyl (3-oxo-2,3-dihydropyridazin-2-yl)acetates react normally with ammonia and hydrazine to give the amides and hydrazides respectively <90CPB3009>. 

Taurospongin A (78) contains three chiral centers at C-3, C-7, and C-9. The relative stereochemistry of 1,3-diol at the C-7/C-9 position was revealed to be syn by applying Rychnovsky s C-acetonide analysis [51] for the acetonide (82 oc 19.9, 30.3, and 98.4) prepared fi-om 81. To elucidate the relative stereochemistry between C-3 and the C-7/C-9 position as well as the absolute stereochemistry of these three chiral centers, two possible diastereomers (83 and 84), which correspond to the acetonide derivative (82), were prepared as optically active forms as shown in Scheme 7. The methoxymelhyl (MOM) ether (86) derived from (/ )-3-hydroxy-3-methyl-5-pentanolide (85) was reduced with DIBAL to give a lactol, which was subjected to Wittig reaction with chloromethylenetriphenylphosphorane followed by protection with benzyloxymethyl group to yield a 2 1 mixture of the E/Z chlorovinyl... 

Benzyloxymethyl group (Bom), Ph-CH2-0-CH2-, an imidazole protection of histidine groups, often used in combination with N -Boc protection. Bom resists TFA, but is easily cleaved by HF or HBr/Ac/OH [T. Brown et al, J. Chem. Soc., Perkin Trans. I 1982, 1553]. 

Figure 5.10 Chiral diene ligand synthesized by Brown and Corey [39]. BOM benzyloxymethyl group.

The cyclitol derivatives (27) and (28) (see Chapter 18) were found to adopt in solution the "inverted" conformations shown, with the benzyloxymethyl groups axially disposed. ... 

Under the optimized conditions (Table 1, entry 11), the scope of this one-pot tetrahydro- S-carboline synthesis was explored using ethynylaniline derivative If and several aldehydes (Table 2). Reaction with aldehyde 2b or 2c containing a (trimethylsilyl)vinyl or benzyloxymethyl group afforded 6b and 6c in moderate yields (entries 1 and 2,48 and 55%, respectively), accompanied by the by-products 8b and 8c, respectively. In these reactions, a prolonged reaction time and elevated temperature were necessary for completion of the initial indole formation,... 

Y 92%) refluxed 3 hrs. in aq. tetrahydrofuran containing a catalytic amount of Triton B -> diethyl pyrrole-3,4-dicarboxylate (Y 92%). - The benzyloxymethyl group is stable to 4 Af HCl, refluxing acetic anhydride, refluxing aq-ethanolic 10%-KOH, and to dimethylcadmium, while the hydroxymethyl group is still fairly stable in aq. acid. H. J. Anderson and J. K. Groves, Tetrah. Let. 1971, 3165. 

The 5-ethyl HEPT analogues synthesized along these lines were evaluated for their anti-HIV-1 activity and the results are summarized in Table 12. 2,63 xhe activity of these compounds is uniformly much higher than that of the parent compound HEPT. Most of these compounds, such as 127,129,130-133, and 135, show a comparable EC50 to that of A2 T. The lowest EC50 value of 0.0022 pM was noted with 135 which was abbreviated as E-EBU-dM. In addition, these compounds are much less toxic than the reference compounds AZT and D4T, while 131-133 having a benzyloxymethyl group as an acyclic structure are rather cytotoxic. 

An alternate route which employed the substituted furan 63 in a Diels-Alder reaction with maleic anhydride (62) (25-27) was also explored (Scheme 3.11). The required reserpine C(21) carbon is now present in furan 63 as part of the benzyloxymethyl group. The adduct obtained from reaction of 62 with... 

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