Amino acid derivatives asymmetric alkylation

A general approach towards the asymmetric synthesis of amino acid derived 4-alkyl-4-carboxy-2-azetidinones has been described [192], The (+)- or (-)-lO-(N, Af-dicyclohexylsulfamoyl)isobomeol was used as chiral auxiliary in the intramolecular cyclization of /V-(/>methoxybenzyI)-/V-chloroacetyl Phe and Ala derivatives for the stereocontrolled base-catalyzed construction of the (1-lactam ring (Scheme 85). 

A fi-keto-bis-a-amino acid derivative 267 is a common precursor in these syntheses (Scheme 57), obtained by asymmetric Schollkopf alkylation <1994TL4091>, by Claisen condensation of glutamic acid precursors <1997TL6483, 1998JOC5937>, or by hydrogenation of bis-a,/3-unsaturated amino acid derivatives <2001TL3159>. 

Belokon et al. (261) subsequently found that salen-Cu(II) complexes are effective catalysts for the asymmetric alkylation of amino acid derivatives. Excellent se-lectivities are observed with 1 mol% of 88b-Cu in toluene at ambient temperature, Eq. 225. Although no stereochemical model is advanced to account for the selec-tivities, these workers suggest the catalyst may be acting as a chiral phase-transfer agent. 

The utilization of a-amino acids and their derived 6-araino alcohols in asymmetric synthesis has been extensive. A number of procedures have been reported for the reduction of a variety of amino acid derivatives however, the direct reduction of a-am1no acids with borane has proven to be exceptionally convenient for laboratory-scale reactions. These reductions characteristically proceed in high yield with no perceptible racemization. The resulting p-amino alcohols can, in turn, be transformed into oxazolidinones, which have proven to be versatile chiral auxiliaries. Besides the highly diastereoselective aldol addition reactions, enolates of N-acyl oxazolidinones have been used in conjunction with asymmetric alkylations, halogenations, hydroxylations, acylations, and azide transfer processes, all of which proceed with excellent levels of stereoselectivity. 

As an extension of these studies on the use of sulfoximines in asymmetric reductions, BlNOL-derived phosphino sulfoximines of the 105 type were tested in both rhodium-catalyzed hydrogenations (yielding optically active diesters 104 or amino acid derivatives Scheme 2.1.1.35) and palladium-catalyzed allylic alkylations (not shown) in collaboration with Reetz and Gais [81, 82]. Here, enantioselectivities of up to >99 and 66% ee, respectively, were achieved. 

Whereas preparation of a-amino acid derivatives by asymmetric allylation of an acyclic iminoglycinate gave a modest enantioselectivity (62% ee) in an early investigation [189], the use of conformationally constrained nucleophiles in an analogous alkylation resulted in high selectivities (Scheme 8E.43) [190], With 2-cyclohexenyl acetate, the alkylation of azlactones occurred with good diastereomeric ratios as well as excellent enantioselectivities. This method provides very facile access to a variety of a-alkylamino acids, which are difficult to synthesize by other methods. When a series of azlactones were alkylated with a prochiral gem-diacetate, excellent enantioselectivities were uniformly obtained for both the major and minor diastereom-ers (Eq. 8E.20 and Table 8E.12). 

Other chiral PTC alkylations of active methylene compounds leading to amino acid derivatives have been reported [24] as have other alkylations [25]. Several reported asymmetric PTC alkylations have been disputed [26-29]. 

It is also important to note that the potential synthetic utility of the asymmetric alkylation protocol discussed in this section has been fruitfully demonstrated by its application to the stereoselective synthesis of various biologically adive natural products possessing unique a-amino acid derivatives as their structural components [27,28]. 

Cinchona alkaloids, of course, have occupied the central position in the design of chiral PTCs. By employing a simple chemical transformation of the tertiary amine ofthe natural cinchona alkaloids to the corresponding quaternary ammonium salts, using active halides (e.g., aryl-methyl halides), a basic series of PTCs can be readily prepared. Cinchona alkaloid-derived PTCs have proved their real value in many types of catalytic asymmetric synthesis, including a-alkylation of modified a-amino acids for the synthesis of higher-ordered a-amino acids [2], a-alkylation of... 

Besides the asymmetric alkylation of 1 for the synthesis of higher a-amino acid derivatives, the Park-Jew group applied their dimeric cinchona-PTCs to the... 

The vast synthetic utility of the asymmetric phase-transfer alkylation of glycine Schiff base 2 has been realized by its successful application to the synthesis of various useful amino acid derivatives and natural products. 

Metal-based asymmetric phase-transfer catalysts have mainly been used to catalyze two carbon-carbon bond-forming reactions (1) the asymmetric alkylation of amino acid-derived enolates and (2) Darzens condensations [5]. The alkylation ofprochiral glycine or alanine derivatives [3] is a popular and successful strategy for the preparation of acyclic a-amino acids and a-methyl-a-amino acids respectively (Scheme 8.1). In order to facilitate the generation of these enolates and to protect the amine substituent, an imine moiety is used to increase the acidity of the a-hydrogens, and therefore allow the use of relatively mild bases (such as metal hydroxides) to achieve the alkylation. In the case of a prochiral glycine-derived imine (Scheme 8.1 R3 = H), if monoalkylation is desired, the new chiral methine group... 

Catalyst screening experiments resulted in the discovery that copper(salen) complex 33 was a highly effective catalyst for the conversion of alanine derivative 16b into (f )-a-methyl phenylalanine 17 under the conditions shown in Scheme 8.16. The presence of just 1 mol% of catalyst 33 was sufficient to induce the formation of compound 17 with up to 92% ee and in >70% yield [33]. Allyl bromide, 1-chloromethylnaphthalene and ethyl iodide also reacted with substrate 16b to give the corresponding (H)-a-methyl a-amino acids in the presence of 2 mol % of complex 33 [34], Complex 33 also catalyzed the asymmetric mono-alkylation of glycine-derived substrate 34 by benzylic or allylic halides, to give (H)-a-amino acid derivatives 35 with 77-81% ee. and in greater than 90% yield, as shown in Scheme 8.17. 

Synthesis of Unnatural Amino Acid Derivatives by Asymmetric Alkylation... 

The power of this methodology lies in the ability to prepare unnatural amino acid derivatives by asymmetric alkylation of prochiral enolates. Several asymmetric alkylations of the alanine derivative 7, catalysed by the C2-symmetrical quaternary ammonium salt 6d, have been reported these reactions yield unnatural amino acids such as 8 in high enantiomeric excess (Scheme 2) [7]. The chiral salen complex 9 has also been shown to be an effective catalyst for the preparation of a,a-dialkyl a-amino acids [8, 9]. For example, benzylation of the Schiff base 10 gave the a-methyl phenylalanine derivative 11 in 92% ee (Scheme 3) [8]. Similar reactions have been catalysed by the TADDOL 12, and also give a,a-dialkyl a-amino acids in good enantiomeric excess [10]. 

Lygo has extended his asymmetric alkylation methodology to the synthesis of bis-a-amino acids (Scheme 4) [11], Bis-amino acids, such as meso-diaminopirnelic acid, dityrosine and isodityrosine, are found in nature and are thought to act as cross-linking agents which stabilise structural proteins in plants and bacteria. For example, asymmetric alkylation of the Schiff base 3 with the dibromide 13, catalysed by the quaternary ammonium salt le, gave the bis-amino acid derivative 14 in >95% ee. 

For example, N-(2-hydroxyphenyl)imines 9 (R = alkyl, aryl) together with chiral zirconium catalysts generated in situ from binaphthol derived ligands were used for the asymmetric synthesis of a-amino nitriles [17], the diastereo- and/or enantioselective synthesis of homoallylic amines [18], the enantioselective synthesis of simple //-amino acid derivatives [19], the diastereo- and enantioselective preparation of a-hydroxy-//-amino acid derivatives [20] or aminoalkyl butenolides (aminoalkylation of triisopropylsilyloxyfurans, a vinylogous variant of the Mannich reaction) [21]. A good example for the potential of the general approach is the diastereo- and enantioselective synthesis of (2R,3S)-3-phenylisoserine hydrochloride (10)... 

VH. MECHANISM OF MEMORY OF CHIRALITY IN ASYMMETRIC ALKYLATION OF a-AMINO ACID DERIVATIVES... 

The alkyl substituent of the asymmetric carbon of the D-enantiomer is syn to the R group of the L-diamide in either the C5 C7 or C7 C7 association. In general, all L-a-amino acid derivatives with an apolar R group, as well as D-y-amino acid derivatives, interact more strongly with the L-diamide than their antipode as a consequence, they elute last from the column. The main feature of these complexes is that the alkyl groups at the asymmetric carbons are in the syn position, yielding a more retained enantiomer than those in anti (Figure 22-7). 

One stoichiometric method that avoids the use of an expensive chiral auxiliary and allows for the use of nonpyrophoric bases is based on diketopiperazine chemistry. The use of this system as a chiral auxiliary is associated with a method that was developed for the preparation of the sweetener aspartame. At the same time, we were looking at the alkylation reactions of amino acid derivatives and dipeptides. These studies showed that high degrees of asymmetric induction were not simple, were limited to expensive moieties as the chiral units, and required the use of large amounts of lithium [25,26]. The cyclic system of the diketopiperazine has been used successfully by other investigators [27,28], and we also chose to exploit the face selectivity of this unit. L-Aspartic acid was chosen as the auxiliary unit because it is readily available and cheap. All of the studies were performed with sodium as the counterion because it is a more cost-effective metal at scale. Finally, we concentrated in the use of aldehydes rather than alkyl halides to allow for a general approach and so as not to limit the reaction to reactive alkyl halides. 

PEG-supported cinchona ammonium salts 54 were applied to the asymmetric alkylation of tert-butyl benzophenone Schiff base derivatives 52 [34]. The use of a water-soluble polymer support allowed the reaction to be conducted in a 1M KOH aqueous solution to give the a-amino acid derivatives 53 in high chemical yields (up to 98%). Ten different types of electrophile have been tested for the reaction, with the best enantioselectivity being obtained with o-chlorobenzylchloride (97% ee) (Scheme 3.15). 

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