PMB group

DDQ, CH3CN, H20. These conditions normally cleave the PMB group selectively in the presence of a TBDMS group. ... 

Ceric ammonium nitrate (CAN), CH3CN, H2O, it, 12 h, 96% yield. Benzylamides are not cleaved under these conditions. Some of the methods used to cleave the benzyl group should also be effective for cleavage of the PMB group. Ceric ammonium nitrate is also used to cleave the PMB group from a sulfonamide nitrogen. ... 

The next key step, the second dihydroxylation, was deferred until the lactone 82 had been formed from compound 80 (Scheme 20). This tactic would alleviate some of the steric hindrance around the C3-C4 double bond, and would create a cyclic molecule which was predicted to have a greater diastereofacial bias. The lactone can be made by first protecting the diol 80 as the acetonide 81 (88 % yield), followed by oxidative cleavage of the two PMB groups with DDQ (86% yield).43 Dihydroxylation of 82 with the standard Upjohn conditions17 furnishes, not unexpectedly, a quantitative yield of the triol 84 as a single diastereoisomer. The triol 84 is presumably fashioned from the initially formed triol 83 by a spontaneous translactonization (see Scheme 20), an event which proved to be a substantial piece of luck, as it simultaneously freed the C-8 hydroxyl from the lactone and protected the C-3 hydroxyl in the alcohol oxidation state. 

At the beginning of the project, we had studied the introduction of the pMB group to 4 as a nitrogen protecting group, as used in the Medicinal Chemistry route. There was a classical regioselectivity problem, O- versus N-alkylation. Under the Medicinal Chemistry conditions, the desired N-alkylated product 5 was mainly formed, but around 10-12% of the corresponding O-alkylated product 16 was also... 

Deprotection of the pMB group from 20 proceeded smoothly in TFA to provide the drug candidate 2. The isolation conditions of a suitable crystal form of 2 for development were optimized later since we had to change the protective group of the nitrogen of 4 for the subsequent asymmetric addition reaction. 

The effect of the nitrogen protective group in 37 was briefly studied and the results are summarized in Table 1.7. The pMB group provided a good selectivity. It is also noted that the reaction was sluggish and provided a lower enantiomeric excess (72%) if the nitrogen atom was not protected. 

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. 

Initially, 50 was converted into the benzoxazinone 51 by reaction with phosgene in the presence of triethylamine and 51 was isolated in 95% yield upon crystallization from methanol. Deprotection of the pMB group from 51 was accomplished with ceric ammonium nitrate (CAN) in aqueous acetonitrile. Efavirenz was isolated in 76% yield after crystallization from EtOAc-heptane (5 95), as shown in Scheme 1.19. There were two issues identified in this route. First, lequiv of ani-saldehyde was generated in this reaction, which could not be cleanly rejected from product 1 by simple crystallization to an acceptable level under the ICH guideline. Anisaldehyde was removed from the organic extract as a bisulfite adduct by washing with aqueous Na2S205 twice, prior to the crystallization of 1. Secondly,... 

Furthermore, several functionalities remained unaffected, namely the acid-labile TBDMS or PMB groups.118 Deprotection yields were in the range of 85-95% when methanol was used at room temperature as the solvent, whereas acetonitrile or dichloromethane led to very sluggish or nonexistent reactions, respectively. Cleavage of primary trityl ethers was also accomplished using the same conditions in a very rapid and effective fashion. The trityl pyranosides and furanosides assayed were selectively deprotected in 2-3 h and yields higher than 85% were achieved. This reaction was also more efficient when conducted in methanol, which acts as a nucleophile to trap the generated trityl cation. 

The synthesis of 3-H-oxazol-2-ones was described by Nam et al. [69]. The substituted benzoin 89 was formed from the coupling of 3,4,5-trimethoxy-benzaldehyde 18 with 3-nitro-4-methoxybenzaldehyde, Scheme 22. Reaction with PMB-isocyanate and subsequent cyclization gave the protected oxazolone derivative 90. The PMB group was removed by reflux in TFA and reduction of the nitro-group was performed using Zn to give the combretoxazolone-aniline 91. 

The secondary hydroxyl group of 206 is now protected with a PMB group. Reduction of the resulting diastereomeric mixture 207 gives the corresponding alcohol 208, which is then separated to give a single stereoisomer. A silyl ether... 

Diastereoselective reduction of the aldol 221/ can be achieved using AIH3 in toluene at —78°C. The corresponding ra-diol is preferentially formed. The diol can be protected with isopropylidene acetal to provide tricyclic compound 222. This can be converted to conformationally rigid C-l ketone 223 by deprotection of the PMB group and successive oxidation with PDC (Scheme 7-73). 

By how many carbon atoms has the distance from the boron atom to the PMB group changed ... 

While the known desymmetrization of divinylcarbinol by asymmetric Sharpless epoxidation worked well, introduction of the PMB group (which was chosen for its mild removal conditions) required the use of the unstable, non-commercially available PMB bromide (using the commercially available but less reactive PMB chloride, in presence of NaH, led to Payne rearrangement). 

The remaining steps for conversion to the fully functionalized cyclohexane found in fumagillol would consist in the precedented stereoselective formation of the spiroepoxide and the removal of the PMB group. Considering these steps as trivial, we turned our attention to the synthesis of fumagillol itself. Our synthetic plan now required the synthesis of the (R)-oxazolidinone 26 and its precursor trans-isogeranic acid 27 (Figure 4). 

A stereocontrolled synthesis of Z-vancosamine (72) was achieved by Nicolaou and co-workers starting from 168 via IBX-induced cyclization followed by CAN-mediated removal of PMB group and basic hydrolysis [130] (Scheme 38). 

The sulfonamide (30) undergoes a clean, uncatalysed deep-seated rearrangement to sulfone (31) via a ketenimine intermediate, a rearrangement in which both the / -toluenesulfonyl (Ts) and p-methoxybenzyl (PMB) groups sequentially migrate from the nitrogen atom on to a neighbouring carbon at the /3-position.51... 

Removal of the />-methoxybenzoyl (PMB) group in sulfamide (Equation 33) <20010L405>. 124 was effected with ceric ammonium nitrate... 

As shown in Scheme 29, the PSB group can be removed selectively in the presence of the PMB ether by peroxide oxidation, while the PMB group can be cleaved without affecting the PSB ether using 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ). 

Oxidative removal of the PMB group of the cyclopropane 987 followed by S-lactonization and Krapcho reaction furnishes tetrahydropyran-2-one 988, a key intermediate during the total synthesis of (+)-mycalamide A (Equation 385) <20060L875>. 

Catalytic hydrogenolysis or treatment with trifluoroacetic acid (TFA) in water and dichloromethane (DCM)13 will also remove a PMB group. This protecting group is, however, reasonably stable to cold aqueous acetic acid. 

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