Methoxymethyl deprotection

These amino acids were initially synthesized by asymmetric aminomethylation of optically pure (R)- and (S)-N-Acyl-4-phenyhnethyl)oxazolidin-2-ones 52 through TiCVenolates (Evans methodology [135]) with (benzoylamino)methylchloride or benzyl N-(methoxymethyl)carbamate [66, 97-99, 104]. Hydrolytic removal of the auxiliary yielded the N-protected (benzoyl or Z) amino acid 54. Deprotection afforded the free amino acid which was converted to the required Boc- or Fmoc-pro-tected derivatives (Scheme 2.7). 

Our retrosynthesis of (—)-kinamycin F (6) is shown in Scheme 3.20 [45]. It was envisioned that (—)-kinamycin F (6) could be prepared from the protected diazofluorene 114 by conversion of the ketone function of 114 to a trans-], 2-diol, followed by deprotection of the acetonide and methoxymethyl ether protecting groups. The diazofluorene 114 was envisioned to arise from diazo transfer to the hydroxyfulvene 115. The cyclopentadiene substructure of 115 was deconstructed by a two-step annulation sequence, to provide the bromoquinone 116 and the p-trimethylsilylmethyl unsaturated ketone 117. The latter two intermediates were prepared from juglone (118) and the silyl ether 119, respectively. 

N-alkylation and N-acylation of piperazine-2,5-diones are quite common and have been routinely employed in several synthetic sequences (see Section IV,C). Such operations have also been performed as measures for the temporary protection of the nitrogen during further synthetic maneuvers in other parts of the molecule. Three different alkyl groups have been employed as such protecting groups. Kishi has used the methoxymethyl group for N-protection (potassium r-butoxide, chloro-methyl methyl ether 0°C, 75% yield). Deprotection was achieved by cone. HCl-ethanol at reflux temperature (81T2045). 

Carbonylation 1,4-diazepines.1 A key step in the synthesis of the antitumor agents neothramycin A and B (3) is the Pd(0)-catalyzed carbonylation of 1, prepared by condensation of 2-bromo-4-methoxy-5-tosyloxyaniline with N,0-bistrifluoroac-etyl-4-hydroxyproline followed by deprotection and protection with methoxymethyl chloride. The reaction provides the 1,4-diazepine 2, which can be converted into a mixture of 3A and 3B. 

Very recently, a research group at the Sloan-Kettering Memorial Cancer Center reported a new approach to 5-deazaAP (80a), 5-deaza-5-methylAP (124) and 5-deaza-5-methylFA (126)[90, 91]. As an extension of their novel pyrimidine-to-pyridopyrimidine ring transformation [92] this strategy required four key steps - the pyrimidine-to-pyridopyrimidine ring transformation, removal of the 7-amino group, deprotection of the 1,3-A-methoxymethyl (MOM) substituents, and conversion of the resulting 2,4-dioxo derivative to the... 

Tetrahydropyranyl (THP) ethers, another species known to be unstable to acid, have similarly been reported to be cleaved by solutions of iodine in methanol.209 At room temperature, cleavage of the THP ethers was complete in 1.5 to 8 h. As with the previous example using iodine in methanol at lower than reflux temperature, TBDMS ethers were stable to these conditions. The ability to tune the reactivity of the iodine in methanol system by simply controlling the temperature is of value in selective deprotection. This is even more useful when fluorine, known to remove only silyl ethers,105 is exploited. Given that methoxymethyl ethers, essentially acetals, are known to be cleaved under acidic conditions, it seems likely they too should be subject to removal by solutions of iodine in methanol. Sundry examples of deprotections using iodine in methanol are presented in Table IV. 

An efficient asymmetric synthesis of the 3-substituted /3-sultams 163 has been reported. The key step of the synthesis is the Lewis acid-catalyzed aza-Michael addition of the enantiopure hydrazines (A)-l-amino-2-methoxy-methylpyrrolidine (SAMP) or CR,l ,l )-2-amino-3-methoxymethyl-2-azabicyclo[3.3.0]octane (RAMBO) to the alke-nylsulfonyl sulfonates 176. /3-Hydrazino sulfonates were obtained in good yield and excellent enantioselectivity. Cleavage of the sulfonates followed by chlorination resulted in the corresponding sulfonyl chlorides 177. The (A)-3-substituted /3-sultams 163 have been obtained in moderate to good yields and high enantioselectivity over two steps, an acidic N-deprotection followed by in situ cyclization promoted by triethylamine (Scheme 55) <2002TL5109, 2003S1856>. 

Next, pyralomicin 2c (38) was synthesized from 32 and 37 (16). The glucosyl donor 37 was prepared from benzyl a-D-glucopyranoside by methoxymethylation followed by hydrogenolysis. The stereoselective N-glycosylation of 37 with 32 was effectively accomplished by using Mitsunobu conditions to give 38, after acidic deprotection. This was identical in all respects with the natural product 38 (16). 

Reaction of racemic 1,2-diazocinone 2 with (S)-(—)-iV-(methoxymethyl)proline methyl ester, followed by crystallization from MeCN, gave the diastereomer (R,S,S)-(+)366-S <2004TA537>. The diazocinone 37a was subjected to epoxidation conditions (oxone, acetone, NaHCO() and subsequent deprotection of the Ar-carbobcnzyloxy moieties with Pd/C-H2 to give 38. 

Related oxidants that have been exploited to similar ends include l-(tert-butoxy)-l,2-benzoiodoxol-3(l//)-one292 and sodium bromate.293 Oxidation of benzyl ethers by l-(/erf-butoxy)-l,2-benzoiodoxol-3(l/f)-one followed by easy basic hydrolysis of the resultant benzoate ester provides a convenient alternative to the usual reductive deprotection. The reaction is carried out in the presence of alkali metal carbonates and the conditions are mild enough to be compatible with other hydroxyl protecting groups such as methoxymethyl, tetrahydropyranyl, TBS and acetate. 

An acyl chloride was used in the synthesis of the spermidine alkaloid cannabisativine (162) by Natsume and coworkers [92]. As shown in Scheme 53, the precursor 160 was hydrolyzed with Ba(OH)2 and the resulting amino acid was directly converted to acyl chloride HCl salt, a cold solution of which was added dropwise to a potassium carbonate suspension in acetonitrile to achieve the lactam closure. Deprotection of the methoxymethyl groups with acid afforded macrolactam 161 in 43% yield from 160. 

After deprotection of the methoxymethyl (MOM) ether under acidic conditions, alcohol 319 was deoxygenated through the Barton procedure to obtain the natural alkaloid (—)-pyrinodemin A (Scheme 72) <20030L2611>. 

Reaction of the monocyanoethyl-protected TTF 738 with cesium hydroxide in a mixture of methanol and DMF led to the deprotected thiolate, which was further alkylated with the bromobutyl-substituted MOM-triptycene 739 to give the MOM-TTF 740 in 89% yield (MOM = methoxymethyl). The MOM protecting group was removed quantitatively under acidic conditions and the resulting hydroquinone was oxidized to yield the TTF-quinone 741 in 54% yield (Scheme 109). The preparation of the pyrrolo-TTF derivatives 25 was accomplished in a similar way <1998JOC1198>. 

Sasai developed miceUe-derived polymer-supported catalysts for a variety of enantioselective reactions, including diethylzinc addition [18]. The surfactant monomer 20 having tetraethylene glycol chains formed micelles in water and, followed by copolymerization with styrene, gave the spherical polymer. A coupling reaction of the polymer with a BINOL derivative and deprotection of the methoxymethyl groups of the BINOL moiety afforded the desired chiral polymer 21, as shown in Scheme 3.5. The catalytic asymmetric ethylation of benzaldehyde was... 

With the basic skeleton of 47 and 48 in hand, we proceeded to incorporate the tethers (Scheme 13). The three-carbon tether was attached to the helicene unit by reacting the phenol of 53 with 3-bromo-l-propanol under basic conditions. Deprotection of the acetamide in 64 with KOH at reflux afforded the desired molecular rotary motor prototype 47 as a mixture of atropisomers. In an analogous way, the two-carbon tether was introduced by reaction of the phenol 53 with the methoxymethyl (MOM) ether of 2-bromoethanol. Deacetylation with KOH (—>66) and removal of the MOM group under acidic conditions led to the two-carbon tether molecular motor prototype 48, again as a mixture of three rotamers (Scheme 13). 

Ether cleavage. Silica gel on which oxalic acid is deposited hydrolyzes enol ethers. This reagent is useful for converting 3-methoxy-2,5(10)-diene steroids (Birch reduction products of A-aromatic steroids) into the corresponding 5(10)-en-3-ones. For the cleavage of other ethers in methanol, the silica-alumina gel (prepared by the sol-gel method) is very valuable. The ease of deprotection follows the order TMS > 1 -methyl-1 -methoxyethyl 1 -ethoxyethyl > THP methoxymethyl. 

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