Methyl ester protection

Applying only a few simple operations, the dibenzylaminocyclopropanes 133-R, prepared as described above from N,N-dibenzyl-a-benzyloxyacetamide in 33—48% yield (see Scheme 11.16 and Table 11.9), have been transformed into N-Boc-protected methyl esters of amino acids 138-R containing a cyclopropane moiety (Scheme 11.35) [109,110], Several such analogues of natural amino acids, also referred to as methanoamino acids, exhibit important biological activities [128],... 

The original Garner preparation3 of 5 involves the conversion of serine into the protected methyl ester 3 and controlled reduction of the latter by DIBAL. The reaction sequence employed for the preparation of 3 involves the protection of the amino acid as N-Boc derivative using di-tert-butyl dicarbonate, esterification with methyl iodide or diazomethane, and acetonization with 2,2-dimethoxypropane under acid catalysis. The N-Boc methyl serinate and the ester 3 require purification by vacuum distillation or chromatography. In a modification to this procedure reported by McKillop,2 the esterification reaction of serine is carried out first by methanol/acetyl chloride. The resulting ester is then converted into the N-Boc derivative 2 with di-tert-butyl dicarbonate and the latter transformed into 3 by acetonization. This procedure avoids... 

Protected methyl ester 76 (0.14 g, 0.38 mmol) was dissolved in a soln of MeOH saturated with ammonia. This mixture was stirred for 3 h at rt, at which time the MeOH was removed under reduced pressure. The resulting residue was chromatographed (silica gel column, EtOAc/hexane 5 2) to give 77 as a white solid yield 0.1 g (76%) mp 162-163 °C [a]D +143.4 (c 1.0, MeOH) FABMS mlz [M+H]+ 350. 

However, when the benzylidene protected methyl ester of (+)-tartaric acid 28 was used as a substrate, this methodology resulted in the unexpected formation of (+)-isoterrein (22) [36]. Scheme 13 shows this first, serendipitous synthesis of this compound. 

Farwick and Helmchen [28] prolonged the alkyl chain of chiral allylamines by a hydroformylation-(Wittig olefination) sequence (Scheme 5.139). Particular attention was paid to the choice of the JV-protective group. As expected in the Wittig olefination step, mainly the Z-configured olefins were formed. After selective removal of only one Af-protective group, the obtained Af-Boc protected methyl esters were converted via a diastereoselective aza-Michael reaction into the corresponding fi-proline derivatives. 

The successful separation of dipeptide diastereomers has been reported by Wieland and Bende (14), Taschner et al. (15), and Pravada et al. (16) either as the free peptides or as the N-protected methyl esters. Hubert and Dellacherie (5) separated diastereomeric p-nitrophenyl (Np) esters of N-protected di- and tripeptides starting from pure L-methionine and DL-alanine, they synthesized Np-S-L-Met-DL-Ala-O-Np and Np-S-L-Met-L-Met-DL-Ala-O-Np. The separation was achieved on silica gel F254 precoated (Merck) plates. TLC separation of diastereomeric dipeptides has been well documented by Arendt et al. (17) and Lepri et al. (18). 

The blocking and deblocking of carboxyl groups occurs by reactions similar to those described for hydroxyl and amino groups. The most important protected derivatives are /-butyl, benzyl, and methyl esters. These may be cleaved in this order by trifluoroacetic acid, hydrogenolysis, and strong acid or base (J.F.W. McOmie, 1973). 2,2,2-Trihaloethyl esters are cleaved electro-lytically (M.F. Semmelhack, 1972) or by zinc in acetic acid like the Tbeoc- and Tceoc-protected hydroxyl and amino groups. 

Carboxyl groups of ammo acids and peptides are normally protected as esters Methyl and ethyl esters are prepared by Fischer esterification Deprotection of methyl and ethyl esters is accomplished by hydrolysis m base Benzyl esters are a popular choice because they can also be removed by hydrogenolysis Thus a synthetic peptide protected at both... 

Subsequent dehydrohalogenation afforded exclusively the desired (Z)-olefin of the PGI2 methyl ester. Conversion to the sodium salt was achieved by treatment with sodium hydroxide. The sodium salt is crystalline and, when protected from atmospheric moisture and carbon dioxide, is indefinitely stable. A variation of this synthesis started with a C-5 acetylenic PGF derivative and used a mercury salt cataly2ed cyclization reaction (219). Although natural PGI has not been identified, the syntheses of both (6R)- and (65)-PGl2, [62777-90-6] and [62770-60-7], respectively, have been described, as has that of PGI3 (104,216). 

Nonfood Uses. Vegetable oils are utilized in a variety of nonedible applications, but only a few percent of the U.S. soybean oil production is used for such products (see Table 13). Soybean oil is converted into alkyd resins (qv) for protective coatings, plasticizers, dimer acids, surfactants (qv), printing inks, SoyDiesel fuel (methyl esters used to replace petroleum-based diesel fuel) and other products (76). 

Me3SiI, CH3CN, 25-50°, 100% yield. Selective removal of protective groups is possible with this reagent since a carbamate, =NCOOCMe3, is cleaved in 6 min at 25° an aryl benzyl ether is cleaved in 100% yield, with no formation of 3-benzyltyrosine, in 1 h at 50°, at which time a methyl ester begins to be cleaved. 

The Dim ester was developed for the protection of the carboxyl function during peptide synthesis. It is prepared by transesterification of amino acid methyl esters with 2-(hydroxymethyl)-l,3-dithiane and Al(/-PrO)3 (reflux, 4 h, 75°, 12 torr, 75% yield). It is removed by oxidation [H2O2, (NH4)2Mo04 pH 8, H2O, 60 min, 83% yield]. Since it must be removed by oxidation it is not compatible with.sulfur-containing amino acids such as cysteine and methionine. Its suitability for other, easily oxidized amino acids (e.g., tyrosine and tryptophan) must also be questioned. It is stable to CF3CO2H and HCl/ether. - ... 

Viprostol (81) also incorporates a hydroxy group moved to C-16 and protects this from facile metabolic oxidation by vinylation. It is a potent hypotensive and vasodilatory agent both orally and transdermally. The methyl ester moiety is rapidly hydrolyzed in skin and in the liver so it is essentially a prodrug. It is synthesized from protected E-iodo olefin 78 (compare with 75) by conversion to the mixed organocuprate and this added in a 1,4-sense to olefin 79 to produce protected intermediate 80. The synthesis of viprostol concludes by deblocking with acetic acid and then reesterification with diazomethane to give 81 [19]. 

The amino group of alanine is protected as the Boc derivative, and the carboxyl group of leucine is protected as the methyl ester. 

You will note that the oxygen atoms attached to carbons 5 and 12 in 43 reside in proximity to the C-9 ketone carbonyl. Under sufficiently acidic conditions, it is conceivable that removal of the triethylsilyl protecting groups would be attended by a thermodynamically controlled spiroketalization reaction.30 Indeed, after hydro-genolysis of the C-26 benzyl ether in 43, subjection of the organic residue to the action of para-toluenesulfonic acid in a mixture of methylene chloride, ether, and water accomplishes the desired processes outlined above and provides monensin methyl ester. Finally, saponification of the methyl ester with aqueous sodium hydroxide in methanol furnishes the sodium salt of (+)-monensin [(+)-1], Still s elegant synthesis of monensin is now complete.13... 

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