Boc-proline

FIGURE 7.32 Side reaction of aminolysis by proline at the carbonyl of the pynolidine-2,5-dione moiety of the succinimido ester of Boc-proline.117 R1 = tBu... 

Very recently, Mordini and coworkers" have overcome the problems associated with the long reaction times that are normally required for the synthesis of hydroxamic acids from esters by performing these transformations under MW irradiation. The protective groups are also well tolerated under these reaction conditions, though a partial deprotection of the feri-butoxycarbonyl (Boc) group was observed in the reaction with Boc-proline ester. Amidic bonds and ketals also survive without any detectable decomposition. All the reactions go to completion in about six minutes, except in the case of the conversion of Boc-protected phenylalanine methyl ester, which required longer reaction times (12 min). 

Starting from Boc-prolinal, double stereodifferentiation, where both substrate and reagent match, allows diastereoselective access to the homoallylic alcohol 3,4-syn-4,5-anti-48 in the synthesis of dolaproine (8) (Scheme 18) J81l... 

Z)-Crotylboration of Boc-prolinal with Chiral (Z)-Crotylboronate 47 Synthesis of fcrf-Butyl 2-(l-Hydroxy-2-methylbut-3-enyl)pyrroKdine-l-carboxylate (48) 81 ... 

The deprotection of t-Boc proline ester 2a is representative of the general procedure employed, tert-Butyl carbamate (0.217 g, 1.0 mmol) and aluminium chloride (0.134 g, 1.0 mmol) doped on a neutral alumina (1.0 g) were mixed thoroughly on a vortex mixer. The reaction mixture was placed in an alumina bath inside an unmodified household microwave oven (operating at frequency 2450 MHz) and irradiated for a period of 1 min. After completion of the reaction (monitored by TLC, EtOAc-hexane, 9 1 v/v), it was neutralized with aqueous sodium bicarbonate solution and the product was extracted into ethyl acetate (2x15 mL). The ethyl acetate layer was separated, dried over magnesium sulfate, filtered, and the crude product thus obtained was purified by column chromatography to afford pure methyl ester 2b in 88% yield. 

Figure 36 Lipase-catalyzed enantiomeric resolution of JV-Boc-proline 67. 81...

Kurokawa, M. Shindo, T. Suzuki, M. Nakajima, N. Ishihara, K. Sugai, T. Enzyme-catalyzed enantiomeric resolution of N-Boc-proline as the key-step in an expeditious route towards RAMP. Tetrahedron Asymmetry 2003, 14, 1323-1333. 

These observations imply that the Cu oxidant is little sensitive to the steric surroundings of the hydroxyl function. The scope of the reaction can be further extended to protected primary p-amino alcohols with equal efficiency. The oxidation of dibenzyl valinol (Entry 6), which contains a tertiary nitrogen atom, proceeds in excellent yield. Moreover, the involvement of a neutral medium is ideally demonstrated by the lack of racemization of both dibenzyl valinal and Boc-prolinal (Entries 6 and 7). Purification of this latter product, which was prepared on a gramm-scale, necessitated only a simple filtration (32). 

Hu S, Martinez C, Kline B, Yazbeck D, Tao J, Kucera D (2006) Efficient and scalable enzymatic process for the production of (2S)-4,4-difluoro-3,3-di-methyl-N-Boc-proline, a key intermediate in the synthesis of HIV protease inhibitors. Org Process Res Dev 10 650-654 Hu S, Kelly S, Lee S, Tao J, Elahive E (2006) Efficient chemoenzymatic synthesis of Pelitrexol via enzymatic differentiation of a remote stereocenter. Org Lett 8 1653-1655... 

Ohba and co-workers have demonstrated that A -protected a-amino esters are compatible with the Schollkopf oxazole synthesis cf., 38->39). In the case of ammo esters derived from natural amino acids (e.g., 38), the presence of an additional acidic N-H bond in the AABoc ester substrate necessitated the use of an added excess of metalated isocyanide (2.5 equiv was found to be optimal) to obtain maximal yields. Under optimized conditions, oxazoles (39) were obtained in good yield from iV-Boc glycine, alanine, and phenylalanine. Oxazole formation from iV-Boc serine (which possesses an additional acidic site in its hydroxylic side chain) proceeded in good yield (66%) using 3.5 equiv lithiated methyl isocyanide. Notably, no epimerization was detected in the reaction of N-Boc alanine methyl ester with lithiated methyl or ethyl isocyanide under these conditions. Minor epimerization was observed (91-92% ee product) with substrates that lacked a carbamate NH hydrogen e.g., A -Boc proline methyl ester), however. ... 

Difficulties in attachment and lower yields have been encountered with certain specific amino acids such as A -Boc-nitroarginine and N-Boc-proline. Difficulties in linking the first amino acids to the polymer support have also been observed in case of A -Boc-methionine and A -Boc-N -benzylhistidine. For methionine, the difficulty is due to the formation of suifonium derivatives. This was overcome by using methionine, as its sulfoxide, and then reducing the sulfoxide to its thioether by sodium iodide and acetyl chloride in DMF (Norris et aL, 1971). The two last-named amino acids can be linked without any difficulty to the hydroxymethyl polymers and the problem circumvented. 

Seven N-acyl-N -alkylamide derivatives of different amino acids were measured in CCI4 and CHCI3 using the spectral region 3600-3200 cm. The local conformation of the amide moiety was determined as well as the hydrogen bridge bonds using the VCD spectra. Other derivatives studied include N- -BOC-alanine and N- -BOC-proline (BOC = butoxy-carbonyl). 

Other examples of the solid-phase synthesis of various alkaloids have been reported. Hyacinthacine is a group of alkaloids that inhibit numerous glycosidase enzymes and are isolated from both Hyacinthoides non-scripta and Scilla campanulata. In 2009, a solid-phase synthesis of the fused pyrrolizidine core was reported by Eifler-Lima and colleagues (Scheme 3.12). L-Boc-Proline was used as the... 

Given the modest yield and the potential hazards associated with the fluorination reaction, an alternative sequence employing a Claisen rearrangement/iodolactamisation sequence starting from commercially available trifluoroacetaldehyde methyl hemiacetal was developed (Scheme 15.84). Classical chemical resolution provided (2S)-4,4-difluoro-3,3-dimethyl-AT-Boc-proline in >28% yield over 12 steps. 

Scheme 15.84 Modified synthesis of (2S)-4,4-difluoro-3,3-dimethyl-iV-Boc-proline...

McNulty, J. and Still, I.W.J. (1991) Diastereoselective Pictet-Spengler reactions of L-(boc)prolinal a biomimetic synthesis of eudistomins H and 1, and woodinine. Tetrahedron Lett. 32,4875-4878. 

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