Chelation amino acid enolates

Kazmaier, U. Reactions of chelated amino acid ester enolates and their application to natural product synthesis. Bioorg. Chem. 1999, 201-206. 

Transition Metal-Catalyzed Allylie Alkylation. Chelated amino acid ester enolates were found to be suitable nucleophiles for palladium-catalyzed allylie alkylations (eq 25). They were conveniently prepared by deprotonation of a glycine derivative with LHMDS followed by transmetallation with zinc chloride. The palladium-catalyzed allylie alkylation then takes place in the presence of allyl carbonates to produce the desired anti amino acid derivative. ... 

Enolates of allyl esters of a-amino acids are also subject to chelation-controlled Claisen rearrangement.249... 

In addition to the asymmetric induction mentioned above, sultam 53 can also be used to prepare enantiomerically pure amino acids (Scheme 2-29 and Table 2-10).55 Me AI-mediated acylation of 53 with methyl A-[bis(methylthio)-methylene]glycinate 56 provided, after crystallization, glycinate 57, which can serve as a common precursor for various a-amino acids. In agreement with a kinetically controlled formation of chelated (Z)-enolates, alkylation happened from the SZ-face of the a-C, opposite to the lone pair electrons on the sultam nitrogen atom. High overall yield for both the free amino acid 58 and the... 

Further variations of the Claisen rearrangement protocol were also utilized for the synthesis of allenic amino acid derivatives. Whereas the Ireland-Claisen rearrangement led to unsatisfactory results [133b], a number of variously substituted a-allenic a-amino acids were prepared by Kazmaier [135] by chelate-controlled Claisen rearrangement of ester enolates (Scheme 18.47). For example, deprotonation of the propargylic ester 147 with 2 equiv. of lithium diisopropylamide and transmetallation with zinc chloride furnished the chelate complex 148, which underwent a highly syn-stereoselective rearrangement to the amino acid derivative 149. 

It has been shown that the Claisen rearrangement of lithium enolates of amino acid enynol esters allows the synthesis of very sensitive y, 5-unsaturated amino acids with conjugated enyne side chains.The chelate-enolate Claisen rearrangement has also been applied to the synthesis of unsaturated polyhydroxylated amino acids, polyhydroxylated piperidines, and unsaturated peptides. ... 

S,Sj-diastereoisomer was preferentially obtained when KOH was used as base. As an explanation for this stereodichotomic effect, it was proposed that liNR2 induces the formation of a N,0-chelated syn-enolate, and the reaction with KOH leads to an anti-enolate. The procedure also allowed a,a-disubstituted amino acids to be prepared. 

In 1997, the first truly catalytic enantioselective Mannich reactions of imines with silicon enolates using a novel zirconium catalyst was reported [9, 10]. To solve the above problems, various metal salts were first screened in achiral reactions of imines with silylated nucleophiles, and then, a chiral Lewis acid based on Zr(IV) was designed. On the other hand, as for the problem of the conformation of the imine-Lewis acid complex, utilization of a bidentate chelation was planned imines prepared from 2-aminophenol were used [(Eq. (1)]. This moiety was readily removed after reactions under oxidative conditions. Imines derived from heterocyclic aldehydes worked well in this reaction, and good to high yields and enantiomeric excesses were attained. As for aliphatic aldehydes, similarly high levels of enantiomeric excesses were also obtained by using the imines prepared from the aldehydes and 2-amino-3-methylphenol. The present Mannich reactions were applied to the synthesis of chiral (3-amino alcohols from a-alkoxy enolates and imines [11], and anti-cc-methyl-p-amino acid derivatives from propionate enolates and imines [12] via diastereo- and enantioselective processes [(Eq. (2)]. Moreover, this catalyst system can be utilized in Mannich reactions using hydrazone derivatives [13] [(Eq. (3)] as well as the aza-Diels-Alder reaction [14-16], Strecker reaction [17-19], allylation of imines [20], etc. 

Returning to the main theme in this section, another case where chelation to a metal centre controls reactions involving enolates is seen in complexes of amino acid derivatives. Amino acids are commonly found in metal complexes as the chelated anions in which the carboxylate oxygen and the amino group are co-ordinated to the metal. The co-ordinated amino acid anion could be in the keto (5.6) or enolate (5.7) form. 

An aromatic Claisen rearrangement has been used as a key step in a total synthesis of racemic heliannuols C and E.18 A formal synthesis of (-)-perhydrohistrionicotoxin has used Claisen rearrangement of an amino acid ester enolate as the key step, in which almost total chirality transfer was observed from (S, )-oct-3-en-2-ol in the sense predicted by a chair-shaped transition state with chelation control of enolate geometry.19 Treatment of 1-(cyclohex-l-enyl)-6-methoxy-2-propargylindanol derivatives with base... 

The use of a heteroatom a to the ester carbonyl group allows for the formation of a chelate with the metal counterion hence, the geometry of the ester enolate can be assured.336-338358359 This approach was used in the rearrangement of the glycine allylic esters 13 to y,8-unsaturated amino acids in good yields and excellent diastereoselectivity (Scheme 26.13).358 The enantioselectivity could be reversed by using quinidine instead of quinine. 

The diastereoselectivity for the reaction of 157, which possesses a 2-methyl-1,3-dioxolanyl group, with enolates generated from fert-butyl acetate was found to be highly dependent on the reaction conditions.89 For example, the lithium enolate gave (Ss,S)-158 (72% de) while the titanium enolate afforded (Ss,/ )-158 (92% de). A non-chelation-controlled transition state was used to explain the preferential formation of (Ss,S)-158 while a six-membered chairlike transition state containing a four-membered metallocycle and/or a seven-membered counterpart was proposed for the formation of the (Ss,R)-158. Treatment of (Ss,S)-158 with TFA gave P-amino acid 159 in 70% yield. 

A fast access to a-alkylated amino acids is also possible by the Claisen rearrangement of chelated enolates [20]. Esters of type 14 rearrange after treatment with base and chelation with a metal salt. The products 15 are obtained in good yields and with diastereoselectivities up to 99 % (Scheme 3). 

Better inductions by a vicinal amino acid were observed by Ojima and coworkers in the benzylation of chiral /3-lactam ester enolates (255, equation 67) °. Interestingly, the enolate formation occurred at an uncommonly high temperature (0°C) to form the thermodynamic Li-chelated enolate 256, which allowed a stereoselective attack of the electrophile, while the diastereoselectivity with the nonchelated kinetic enolate 259 was significantly lower. Subsequent hydrogenolytic cleavage of lactam 257 delivered S)-a-methylphenylalanine derivative 258 in nearly quantitative yield and high diastereoselectivity. 

Kazmaier, U. Synthesis of y,5-unsaturated amino acids via ester enolate Claisen rearrangement of chelated allylic esters. Amino Acids... 

Kazmaier, U. Application of the chelate-enolate Claisen rearrangement to the synthesis of y,5-unsaturated amino acids. Liebigs Ann. Chem. 

The six amino acids 63 were prepared individually, and mixed to give acids M-64 (see Scheme 13.15) [51]. Esterification of M-64, zinc-chelated ester enolate Claisen rearrangement of M-65, tert-butyl esterification, and removal of the Me3Si group yielded M-66. The alkynyl allenes M-67 were obtained by Af-propargylation. The allenic Pauson-Khand reaction of M-67 afforded three products (/ )-alkylidenecyclopentenone... 

Kazmaier, U., Synthesis of quaternary amino acids containing P.v- as well as 7,S-unsaturated side chains via chelate-enolate Claisen rearrangement. Tetrahedron Lett., 31, 5351, 1996. 

While the majority of examples of substrate control deal with cyclic sterocontrol, there are a few examples where diasteroselectivity is induced in an acylic system.27 A notable example of this was demonstrated during the synthesis of a fragment of tubulysin, by Wipf and co-workers.28 Utilizing a Davis reagent in their synthesis of an a-hydroxy-y-amino acid, the enolate of the y-amino acid derivative 42 was reacted with 1 to form the a-hydroxy derivative 43 as a single diastereomer in good yield. The stereoselective reaction has precedence in literature and likely involves a highly chelated dianionic species.29... 

Retention of geometry, perfect chirality transfer, and high reactivity have been observed by the reaction of the chelated Zn enolate of amino acid ester 53 even when PPhs was used [23]. In addition, the non-stabilized enolate 53 was found to be very reactive. Reaction of the allylic carbonates 54 and 56 with the enolate 53 gave 55 and 57 with perfect chirality transfer and high diastereoselectivity. The carbonates and the enolates are highly reactive and the reaction starts even at —78 °C. Lower selectivity was observed by the reaction of the corresponding allylic acetate. 

---