Amino acids stereocenter

Other applications of this strategy include addition and trapping sequences with exo double bonds to install the a centers. This methodology has been applied to the formation of anri-aldol adducts as well as substituted a-amino acids. Stereocenters located in adjacent positions on the ring provide facial bias for selective hydrogen atom transfer. Equation (13.23) illustrates how this was applied towards the formation of a-amino acids [33]. 

Other methods of esterification that do not utilize a carbodi-imide coupling method have also been explored. For example, the stereoselective esterification of 20-(S)-camptothecin, a hindered 3 ° alcohol, with amino acid derivatives was accomplished with the use of scandium triflate (Sc(OTf)3) in high yields while retaining the integrity of the amino acid stereocenter (eq 9). ... 

Thus proper choice of substrates and conditions can produce useful products via the intermolecular PKR. For example, Pericas recently described the preparation of amino acid derivitives using the PKR, 58 to 59.Unfortunately, the amino acid stereocenter was too removed from the newly formed stereocenters to provide any asymmetric induction. The products were isolated as 1 1 mixtures of diastereomers that required chiral HPLC for separation. Despite the low yields observed in the PKR (18-47%),... 

Although these Boc derivatives underwent methylation with poor selectivity (compared to 3-amino-N-benzoyl butanoates [106] and Z-protected methyl 4-phen-yl-3-aminobutanoate [107]), epimers were succesfully separated by preparative HPLC or by flash chromatography. However, saponification of the methyl ester caused partial epimerization of the a-stereocenter and a two-step (epimerization free) procedure involving titanate-mediated transesterification to the corresponding benzyl esters and hydrogenation was used instead to recover the required Boc-y9 -amino acids in enantiomerically pure form [104, 105]. N-Boc-protected amino acids 19 and 20 for incorporation into water-soluble /9-peptides were pre-... 

The stereoselective total synthesis of (+)-epiquinamide 301 has been achieved starting from the amino acid L-allysine ethylene acetal, which was converted into piperidine 298 by standard protocols. Allylation of 297 via an. V-acyliminium ion gave 298, which underwent RCM to provide 299 and the quinolizidine 300, with the wrong stereochemistry at the C-l stereocenter. This was corrected by mesylation of the alcohol, followed by Sn2 reaction with sodium azide to give 301, which, upon saponification of the methyl ester and decarboxylation through the Barton procedure followed by reduction and N-acylation, gave the desired natural product (Scheme 66) <20050L4005>. 

Because of the tetrahedral stereocenter of the amino acid, three-point binding can occur with proper alignment for only one of the two enantiomers. 

A number of nonprotein amino acids with unsaturated side chains have been isolated. Many of these contain alkene side chains, but some alkyne side chains containing amino acids have also been identified. Nonprotein dehydroamino acids do not have an a-stereocenter these amino acids are still classified under this category. Dehydroamino acids are generally biosynthesized by the enzymatic elimination of a leaving group at the /3-carbon. For example, serine and threonine are enzymatically dehydrated to give dehydroalanine and dehydrobutyrine, respectively. A similar biosynthetic pathway is hypothesized for dehydroamino acids found in nonribosomal peptides, such as nodularins and microcystins. ... 

Figure 4 Retro-inversion of host defense peptides. Synthesis of RI peptides is achieved by substituting o-amino acids at all stereocenters within a peptide and reversal of peptide sequence (RI - R3 in the i-peptide and R3 RI in the Rl-peptide). By rotating the Rl-peptide at 180° it can be seen that the three-dimensional space occupied by the amino acid functional (R) groups is retained in comparison to the i-peptide although the peptide backbone has been reversed.

By employing A-acetamidoacrylates, rhodium-catalyzed 1,4-addition reactions can be applied to the enantioselective synthesis of a-amino acids. Unlike other typical 1,4-addition reactions, which install a stereogenic center at the p-position of the 1,4-adducts, this process deals with the formation of a stereocenter at the a-position, and thus the protonation (hydrolysis) step becomes an important step... 

A new stereocenter is formed when a synthon 143 with umpoled carbonyl reactivity (d reactivity) is introduced into aldehydes or imines. The enantioselective variant of this type of reaction was a longstanding problem in asymmetric synthesis. The very large majority of a-hetero-snbstitnted carbanions which serve as eqnivalents for synthons like 142 and 143 lead to racemic products with aldehydes or imines. However, enantiomerically pnre acylions and a-hydroxy carboxylic acids or aldehydes (144 and ent-144, respectively) as well as a-amino acids and aldehydes (145 and ent-145) are accessible either by nsing chiral d reagents or by reacting the components in the presence of chiral additives (Scheme 18). 

The stereochemistry of step polymerization is considered now. Bond formation during step polymerization almost never results in the formation of a stereocenter. For example, neither the ester nor the amide groups in polyesters and polyamides, respectively, possess stereocenters. Stereoregular polymers are possible when there is a chiral stereocenter in the monomer(s) [Oishi and Kawakami, 2000 Orgueira and Varela, 2001 Vanhaecht et al., 2001], An example would be the polymerization of (R) or (S)-H2NCHRCOOH. Naturally occurring polypeptides are stereoregular polymers formed from optically active a-amino acids. 

The method described here illustrates the transformation of optically active 2-chlorocarboxylic acids, which are readily available from 2-amino acids, via 2-chloroalkan-l-ols to alkyloxiranes with inversion of configuration at the stereocenter. Thus (R)-methyloxirane is prepared from (S)-alanine, (R)-isopropyloxirane from (S)-valine, (R)-isobutyloxirane from... 

Amino acids can be used as azomethine yhde precursors, although the stereo-genic center is by necessity lost and require reaction with chiral dipolarophiles to circumvent the problem of absence of stereocontrol. Harwood et al. (57) demonstrated that the chirality of the original amino acid could be preserved by derivatization to give back not only the original stereocenter, but further stereoinduction. 

Lanthionine is a dicarboxylic diamino acid possessing two stereocenters. However, because of the symmetry of the molecule there exist only three stereoisomers. Thus, with respect to lanthionine stereochemistry, one must differentiate between the 2/ ,6/ -lanthionine (L-lan-thionine), 25,65-lanthionine (D-lanthionine) and 25,67 -lanthionine (meso-lanthionine, d,l-lanthionine) (1) the latter is the naturally occurring stereoisomer of lanthionine isolated from lantibiotics. However, care must be taken when determining and assigning the stereochemistry of lanthionine residues present within peptide sequences. For naturally occurring lanthionine peptides the sulfide amino acid Lan within the peptide is no longer symmetrical and, in the majority of cases, it has been shown to be present as 25,67 -lan-thionine. 

The synthesis of jS-hydoxy-a-amino acids is important since these compounds are incorporated into the backbone of a wide range of antibiotics and cyclopeptides such as vancomycins. These highly functional compounds are also subject to dynamic kinetic resolution (DKR) processes, as the stereocenter already present in the substrate epimerizes under the reaction conditions and hence total conversions into single enantiomers are possible. These transformations can be iy -selective ° for N-protected derivatives as shown in Figure 1.27 when using a mthenium-BlNAP catalyzed system and anfi-selective when the jS-keto-a-amino acid hydrochloride salts are reduced by the iridium-MeOBlPHEP catalyst as shown in Figure 1.28. One drawback is that both these reductions use 100 atm hydrogen pressure. 

S)-leucine, and (S)-sec-butyl-(R)-oxirane from (2S,3S)-isoleucine, respectively. This useful three-step route complements the synthesis of (S)-alkyloxiranes from (S)-2-amino acids via (S)-2-hydroxy acids,4,5 with retention of configuration at the stereocenter. 

A less common approach to the synthesis of phosphinates is the reaction of electrophilic phosphonates with carbon nucleophiles such as Grignard reagents or lithium enolates. For example, the phosphinic acid analogue 71 of the amino acid statine was synthesized by displacement of tert-butyl lithioacetate on a 5-phenyl phosphonothioate 70 (Scheme 23)d104l The racemic diastereomers of the 5-phenyl phosphonothioate were obtained in pure form, and the displacement of the phenylsulfanyl moiety was found to be stereospecific, although the stereocenter at phosphorus would later be lost on hydrolysis of the ester. A similar displacement reaction has been described using the p h osp h on och I ori d ate.1711... 

Current methods for the hydrolysis of esters are fast, efficient, and sufficiently mild that they are compatible with the presence of a variety of other functional groups and/or stereocenters in the molecule. For example, protected amino acid esters are hydrolyzed quantitatively without racemization or deprotection by LiOH in aqueous THF. 

These results prompted them to attempt the stereoselective synthesis of the IV-phenylsulfonyl substituted spiro- (3-lactams 150, 151 (Scheme 36) from the N-(phenylmethyIe ne )be n ze nesulfonamide and the ketene valence tautomer of the bicyclic mesoionic compounds such as (2 S,4/ )-4-acetyloxy or benzoyloxy-IV-acyl-prolines 149 in the presence of acetic anhydride [109]. The presence of the stereocenter in position 4 of the cyclic amino acid 149 was found to be sufficient to ensure complete stereoselectivity on the spiranic C-4. 

Treatment of amino acid 156, imine and 2-chloro-l-methylpyridinium iodide (Mukaiyama s reagent) in the presence of triethylamine in refluxing dichloro-methane afforded spiro-(3-lactams 157,158. These were obtained as a 1.8 1 mixture of diastereoisomers and separated by column chromatography. The reaction of 159 and imine under the usual experimental conditions resulted in the formation of a single diastereoisomer 160. The absolute (3 S, 4 S, 7 -configuration was assigned on the basis of mechanistic considerations and XH NMR spectra. The presence of the stereocenter affords complete diastereoselectivity (only trans diastereoisomers 157, 158) and enantioselectivity (160). 

Quaternary stereocenters can be obtained with high selectivity with ot-amino acid amides as chiral auxiliaries, which were first converted with P-oxo esters to give enamines such as compounds 58. According to a combinatorial strategy, various enamino esters 58 were screened in Michael additions with MVK (41a) and several metal salts as catalysts. With FeCl3, however, the maximum stereoselectivity achieved was only 77% ee (with enamine 58a derived from L-isoleucine dimethylamide). Cu(0Ac)2H20 turned out be the optimal catalyst for this transformation. With L-valine diethylamide as chiral auxiliary in compound 58b, reaction proceeds with 86% yield and 98% ee after aqueous workup [79]. Importantly, this valuable method for the construction of quaternary stereocenters [80] under ambient conditions seems to be generally applicable to a number of Michael donors [81]. In all cases, the auxiliary can be quantitatively recovered after workup. 

Access to enantioenriched carbonyl compounds of high value which possess quaternary a-carbon stereocenters containing hetero-functionalities represents one of the most challenging tasks in phase-transfer-catalyzed asymmetric alkylation. In due course, Maruoka and coworkers devised the asymmetric alkylation of cyclic a-amino-P-keto esters 67 with C2-symmetric phase-transfer catalyst lh as a means of obtaining aza-cyclic amino acids with quaternary stereocenters (Scheme 5.32) [33]. 

The intramolecular alkylation of the enolate derived from phenylalanine derivatives 22a,b to form P-lactams 23a,b has also been achieved using Taddol as a chiral phase-transfer catalyst (Scheme 8.11) [23]. In this process, the stereocenter within enantiomerically pure starting material 22 is first destroyed and then regenerated, so that the Taddol acts as a chiral memory relay. Taddol was found to be superior to other phase-transfer catalysts (cinchona alkaloids, binol, etc.) in this reaction, and under optimal conditions (50 mol % Taddol in acetonitrile with BTPP as base), P-lactam 23b could be obtained with 82% et. The use of other amino acids was also studied, and the... 

However, they have not yet found many applications in asymmetric Ugi reactions [41-43], and this is probably due to the fact that diastereomeric excesses are often only moderate and strongly influenced by the structure of the side chain of the a-amino acid. A thorough study was carried out by Yamada et al. [42], who observed that the configuration of the newly generated stereocenter of the major diastereoisomer is always opposite to that of the amino ester. Representative examples are shown in Scheme 1.15. Although Yamada often also used chiral protected aminoacids as the carboxylic component, they were proved to have a negligible influence on the stereoselectivity. 

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