Amino acids aldol reaction, chiral auxiliary

Since most often the selective formation of just one stereoisomer is desired, it is of great importance to develop highly selective methods. For example the second step, the aldol reaction, can be carried out in the presence of a chiral auxiliary—e.g. a chiral base—to yield a product with high enantiomeric excess. This has been demonstrated for example for the reaction of 2-methylcyclopenta-1,3-dione with methyl vinyl ketone in the presence of a chiral amine or a-amino acid. By using either enantiomer of the amino acid proline—i.e. (S)-(-)-proline or (/ )-(+)-proline—as chiral auxiliary, either enantiomer of the annulation product 7a-methyl-5,6,7,7a-tetrahydroindan-l,5-dione could be obtained with high enantiomeric excess. a-Substituted ketones, e.g. 2-methylcyclohexanone 9, usually add with the higher substituted a-carbon to the Michael acceptor ... 

Another chiral auxiliary for controlling the absolute stereochemistry in Mukaiyama aldol reactions of chiral silyl ketene acetals has been derived from TV-methyl ephedrine.18 This has been successfully applied to the enantioselec-tive synthesis of various natural products19 such as a-methyl-/ -hydroxy esters (ee 91-94%),18,20 a-methyl-/Miydroxy aldehydes (91% ee),21 a-hydrazino and a-amino acids (78-91% ee),22 a-methyl-d-oxoesters (72-75% ee),20b cis- and trans-l1-lactams (70-96% ee),23 and carbapenem antibiotics.24... 

The synthesis of the rare amino acid 3-hydroxy-4-methylproline (8)3 involves an aldol reaction of the oxazoiidinone 5 with methacrolein to provide the a-bromo-0-hydroxy adduct 6. Azide displacement and removal of the chiral auxiliary gives 7. On treatment with dicyclohexylborane, 7 undergoes hydroboration-cycloalkyl-ation to provide, after hydrolysis, the methyl ester hydrochloride (8) of (2S,3S,4S)-3-hydroxy-4-methylproline in >97% de. This cycloalkylation should be a useful route to cyclic amino acids as well as pyrrolidines. 

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. 

The amino acid derived chiral oxazolidinone 188 is a very commonly used auxiliary in Diels-Alder and aldol reactions. However, its use in diastereoselective 1,3-dipolar cycloadditions is less widespread. It has, however, been used with nitrile oxides, nitrones, and azomethine ylides. In reactions of 188 (R = Bn, R =Me, R = Me) with nitrile oxides, up to 92% de have been obtained when the reaction was performed in the presence of 1 equiv of MgBr2 (303). In the absence of a metal salt, much lower selectivities were obtained. The same observation was made for reactions of 188 (R = Bn, R = H, R = Me) with cyclic nitrones in an early study by Murahashi et al. (277). In the presence of Znl2, endo/exo selectivity of 89 11 and up to 92% de was observed, whereas in the absence of additives, low selectivities resulted. In more recent studies, it has been shown for 188 (R =/-Pr, R = H, R =Me) that, in the presence of catalytic amounts of Mgl2-phenanthroline (10%) (16) or Yb(OTf)3(20%) (304), the reaction with acyclic nitrones proceeded with high yields and stereoselectivity. Once again, the presence of the metal salt was crucial for the reaction no reaction was observed in their absence. Various derivatives of 188 were used in reactions with an unsubstituted azomethine ylide (305). This reaction proceeded in the absence of metal salts with up to 60% de. The presence of metal salts led to decomposition of the azomethine ylide. 

One of the early syntheses of orlistat (1) by Hoffmann-La Roche utilized the Mukaiyama aldol reaction as the key convergent step. Therefore, in the presence of TiCU, aldehyde 7 was condensed with ketene silyl acetal 8 containing a chiral auxiliary to assemble ester 9 as the major diastereomer in a 3 1 ratio. After removal of the amino alcohol chiral auxiliary via hydrolysis, the a-hydroxyl acid 10 was converted to P-lactone 11 through the intermediacy of the mixed anhydride. The benzyl ether on 11 was unmasked via hydrogenation and the (5)-7V-formylleucine side-chain was installed using the Mitsunobu conditions to fashion orlistat (1). 

A wide variety of chiral auxiliaries are available to prepare amino acids (Chapter 23). The most popular are oxazolidinones, a-amino acids, aminoindanol (Chapter 24), imidazolidones, and pseu-doephedrine.7 Oxazolidinones 5 have found widespread usage as chiral auxiliaries. A wide range of reactions is available and well documented7 and includes the following aldol alkylations ... 

Chiral acylthiazolidinethiones such as 26 can readily be prepared from commercially available amino acids in three steps12 (Scheme 2.2k). They have been employed as a synthetically useful auxiliary in diastereoselective aldol reactions.13 The magnesium-catalyzed aldol reaction of the thiazolidinethione 26.S with cin-namaldehyde afforded 27 as a major diastereomer in 87% yield. Interestingly, compound 27 is the opposite anti-aldol diastereomer to that seen with the oxa-zolidinone 23S. 

Chiral Auxiliary for Asymmetric Induction. Numerous derivatives of (—)-8-phenylmenthol have been utilized for asymmetric induction studies. These include inter- and intramolecular Diels-Alder reactions, dihydroxylations, and intramolecular ene reactions of a,p-unsaturated 8-phenylmenthol esters. These reactions usually proceed in moderate to good yield with high diastereofacial selectivity. a-Keto esters of 8-phenylmenthol (see 8-Phenylmenthyl Pyruvate) have been used for asymmetric addition to the keto group, as well as for asymmetric [2 -F 2] photoadditions and nucleophilic alkylation. Ene reactions of a-imino esters of 8-phenylmenthol with alkenes provide a direct route to a-amino acids of high optical purity. Vinyl and butadienyl ethers of 8-phenylmenthol have been prepared and the diastereofacial selectivity of nitrone and Diels-Alder cycloadditions, respectively, have been evaluated. a-Anions of 8-phenylmenthol esters also show significant diastereofacial selectivity in aldol condensations and enantiose-lective alkene formation by reaction of achiral ketones with 8-phenylmenthyl phosphonoacetate gives de up to 90%. ... 

The examples outlined in this chapter show that carbohydrates are efficient stereodifferentiating auxiliaries, which offer possibilities for stereochemical discrimination in a wide variety of chemical reactions. Interesting chiral products are accessible, including chiral carbo- and heterocycles, a- and 3-amino acid derivatives, 3-lactams, branched carbonyl compounds and amines. Owing to the immense material published since the time of the earlier review articles on carbohydrates in asymmetric synthesis [9,10], the examples discussed in this chapter necessarily focused on the use of carbohydrates as auxiliaries covalently linked to and cleavable from the substrate. Given the scope of this chapter, a discussion of other interesting asymmetric reactions has not been permitted — for example, reactions in which carbohydrate-derived Lewis acids, such as cyclopentadienyl titanium carbohydrate complexes, exhibit stereocontrol in aldol reactions [180]. Similarly, processes in which in situ glycosylation induces reactivity and stereodifferentiation — for example, in Mannich reactions of imines [181] — have also been excluded from this discussion. 

Diastereoselective radical allylations have been studied in many different contexts, and a plethora of information exists regarding stereocontrol in these reactions. Allylations have been performed using the traditional trapping and )9-elimination sequence occurring typically with allylstannanes as well as a stepwise atom transfer/ elimination sequence found to occur with allylsilanes. Stereochemistry is commonly controlled through the use of chiral auxiliaries or by 1,2-induction, and functionalized anh -aldol and amino acid products are available using this established methodology. 

Iron chiral auxiliary for asymmetric aldol reaction, Michael addition, p-amino acid and p-lactam synthesis. 

An important strategy for achieving substrate control is the use of chiral auxiliaries, which are structures incorporated into reactants for the purpose of influencing the stereochemistry. Two of the most widely used systems are oxazolidinones " derived from amino acids and sultams derived from camphorsulfonic acid. These groups are most often used as carboxylic acid amides. They can control facial stereoselectivity in reactions such as enolate alkylation, aldol addition, and Diels-Alder cycloadditions, among others. The substituents on the chiral auxiliary determine the preferred direction of approach. 

Aldol reaction with L-proline as catalyst has been extended to a-ketols thereby generating anti-diols. Transition state 48 is consistent with the results of aldol condensation catalyzed by Et2Zn-Ph,PS in the presence of a bisprolinol. a-Amino acid derived imi-dazolidinones serve as chiral auxiliaries in the same manner as the corresponding oxa-zolidinones. In employing 4-f-butylthiazolidin-2-thione, the presence of one or two equiv of a base leads to syn products of opposite enantiomeric series. 

Enantiomerically pure oxazolines and oxazolidinones have found widespread application in organic synthesis as chiral auxiliaries. They have been mainly used for the synthesis of enantiomerically pure amino acids but also as chiral auxiliaries to produce non-racemic enolates as pioneered by Evans.The reaction types proceeding with high stereocontrol include enolate alkylation, enolate oxidation, enolate halogenation, enolate amination, enolate acylation, aldol reaction and Diels-Alder reactions. 

The Cilag resolution of the pyridyl amino acid is described in Org. Process Res. Dev. 2001, 5, 23. For an informative comparison of different auxiliary and catalytic methods for the synthesis of a simple chiral carboxylic acid, see Org. Process Res. Dev. 2003, 7, 370. For a leading reference to the use of enzymes to reduce ketones, see the account of the Codexis work on montelukast in Org. Process Res. Dev. 2010, 14, 193. The spectacular synthesis of discodermolide by Novartis using a series of aldol reactions is described in Org. Process Res. Dev. 2004, 8, 92, 101 and 107. 

This reaction was first reported by Schollkopf in 1979. It is a synthesis of an unnatural nonproteinogenic amino acid from the lithiated enolate equivalent of a simple amino acid (e.g., glycine, alanine and valine), which involves the diastereoselective alkylation of the lithiated bis-lactim ether of an amino acid with an electrophile or an Aldol Reaction or Michael Addition to an o ,jS-unsaturated molecule and subsequent acidic hydrolysis. Therefore, the intermediate of the bis-lactim ether prepared from corresponding amino acids is generally referred to as the Schollkopf bis-lactim ether, " Schollkopf chiral auxiliary, Schollkopf reagent, or Schollkopf bis-lactim ether chiral auxiliary. Likewise, the Schollkopf bis-lactim ether mediated synthesis of chiral nonproteinogenic amino acid is known as the Schollkopf bis-lactim ether method, Schollkopf bis-lactim method, or Schollkopf methodology. In addition, the reaction between a lithiated Schollkopf bis-lactim ether and an electrophile is termed as the Schollkopf alkylation, while the addition of such lithiated intermediate to an Q ,j8-unsaturated compound is referred to as the Schollkopf-type addition. ... 

Since oxazolidines and oxazolidinones are fiindamental structural classes in organic chemistry (chiral auxiliaries) and in medicinal chemistry (e.g., Linezolid) and since they mask P-hydroxy-a-amino acids, which are widespread in various biologically active compounds and in natural products, the enantioselective synthesis of oxazolidinones is a challenging topic. Indeed, a new method for the direct synthesis of chiral 4-carboxyl oxazolidinones 168 by the catalytic asymmetric aldol reaction of isocyanato-malonate diesters 166 with aldehydes 167 in the presence of a thiourea catalyst (TUC) was developed. Since the resulting chiral 4-carboxy oxazolidinones are the equivalent of P-hydroxy-a-amino acids, this procedure... 

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