PMB-protection

Taking Tomioka s pioneering work [8] as a precedent, we have screened 13-amino alcohols as chiral modifiers [9] in the nucleophilic addition of lithium 2-pyridinylacetylide 6 to the pMB protected ketimine 5. We were pleased to discover that when 5 was treated with a mixture prepared from 1.07 equiv each of quinine and 2-ethynylpyridine by addition of 2.13 equiv of n-BuLi in THF at -40 to -20 °C, the desired adduct 19 was obtained in 84% yield with maximum 64% ee. Soon after, we found selection of the nitrogen protective group had great influence on the outcome of the asymmetric addition and the ANM (9-anthranylmethyl)... 

Based on these reports, we started investigation of the asymmetric addition of acetylide to pMB protected 5, mainly in the presence of chiral P-amino alcohols. Many types of chiral amines were also screened (e.g., diamines, diethers), and it was soon found that addition of P-amino alkoxides effectively induced enantiose-lectivity on the addition. Since the best result was obtained with a stoichiometric amount of chiral amino alcohols, we focused our screen on readily available chiral P-amino alcohols and the results are summarized in Table 1.2. 

Table 1.2 Asymmetric addition of 2-pyridiylacetylide to pMB protected ketimine 5.

Obviously, there are two ways to prepare Efavirenz from the pMB protected chiral amino alcohol 50 (i) creation of the benzoxazinone first then removal of the pMB group or (ii) removal of the pMB first then formation of benzoxazinone. Preparation of the benzoxazinone was demonstrated by Medicinal Chemistry from the amino-alcohol with CDI. 

Here, we will discuss the reaction mechanism of the asymmetric lithium acetylide addition to pMB protected amino ketone 41. Then we will discuss some speculation about the asymmetric addition via the novel zinc acetylide addition. 

Reaction Mechanism for the Lithium Acetylide Addition to pMB Protected Amino Ketone 41... 

An example for the efficient formation of an electron-deficient double bond by RCM was disclosed by a Japanese group in a total synthesis of the macrosphelides A 295 and B 294 (Scheme 57). When PMB-protected compound 290 was examined as the metathesis substrate, the ring closure did not proceed at all in dichloromethane using catalysts B or G. When the reaction was carried out using equimolar amounts of catalyst G in refluxing 1,2-dichloroethane, the cyclized product 291 was obtained in 65% after 5 days. On the other hand, free allylic alcohol 292 reacted smoothly at RT leading to the desired macrocycle 293 in improved yield. 

Aldehyde 11 is first crolylaled with the ent-1 enantiomer of the reagent discussed above, leading to compound 34. Mild oxidation of the PMB protecting group with DDQ results in the p-methoxyphe-n>] protecting group, which corresponds to an acetal of anisalde-hyde.15, If>... 

Among the other reagents listed, activated Mn02 is specific for the oxidation of allylic and ben/ylie alcohols.22 KM11O4 is used for the oxidation of alkenes to diols.23 Ceriv(lV) ammonium nitrate (CAN) accomplishes oxidative cleavage of the PMB protecting group. 

Solution The PMB protecting group is cleaved with DDQ. Both free hydro-... 

As Fetizon s oxidation is carried out under neutral conditions, acid-and base-sensitive protecting groups resist its action. The oxidation-sensitive p-methoxybenzyl (PMB) protecting group resists the action of Fetizon s reagent.12... 

The synthesis of the /-hydroxy lactol ring starts with the cleavage of the PMB protecting group and the oxidation of the resulting hydroxy compound to the enone 22 (Figure 7) [20], Acid-induced removal of the isopropylidene group results in the spontaneous formation of... 

Access to derivatives with protecting groups other than benzyl was also desired. Tri-O-acetyl-D-glucal (13) was deacetylated and benzylated with p-methoxybenzyl chloride to give 14. Cleavage of the olefin in 14 gave formate aldehyde 15. Hydrolysis of the formate ester led to lactol 16 and Wittig olefination then furnished the PMB protected olefin alcohol Id (Scheme 3). 

The boron-aldol reaction of the p-methoxyben-zyl(PMB)-protected methylketone 16 proceeds with excellent 1,5-anti-selectivity (Scheme 4). In cases where the asymmetric induction is lower it may be improved by a double stereodifferential aldol reaction with chiral boron ligands [7]. The reason for this high stereoselectivity is currently unknown. Ab initio calculations suggest the involvement of twisted boat structures rather than chair transition structures [6]. 

Hirota and co-workers ° reported the selective removal of the benzyl (Bn) group with Pd-C-catalyzed hydrogenolysis of PMB protected phenols. The removal of the PMB group is inhibited by the presence of pyridine. 

The left part of the target molecule has now been made After deprotection of the PMB-protected alcohol with DDQ (72), the primary alcohol is oxidized to the aldehyde with the IBX reagent. Then, a Wittig reaction with PhsP CHCHs formed in situ transforms the carbonyl compound into a Z-configured alkene. At this stage, separation of the C-5-isomers is possible to obtain diastereopure 30. 

In the first step, carboxylic acid 25 is reduced with lithium aluminum hydride (LiAlH4). Then, the resulting primary alcohol is protected as TBS-ether and finally the PMB protecting group is removed as described before (see p. 261). 

An l-hydroxy-l,2-benziodoxol-3(17/)-one 1-oxide (IBX)-mediated process provides another efficient and stereoselective preparative route for the s)uithesis of amino sugars. For example, reaction of the D-glucal derivative 113 with p-methoxybenzene isocyanate in the presence of a catalytic amount of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) followed by treatment with IBX furnishes the cyclic carbonate 115, through urethane 114. Subsequent removal of the p-methoxybenzyl (PMB) protecting group by CAN affords the protected amino sugar 116 (O Scheme 56) [94]. 

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