Reaction Strecker

The Strecker reaction starting from an aldehyde, ammonia and a cyanide source is an efficient method for the preparation of a-amino acids and their derivatives. A popular version for asymmetric purposes is based on the use of preformed imines and a subsequent nucleophilic addition of HCN or TMSCN in the presence of a chiral catalyst. An intense investigation of the asymmetric Strecker-type reaction has continued over many years, due to the importance of a-amino acid building blocks in medicinal chemistry. Interestingly, a number 

Among a wide variety of chiral organocatalysts that have been used in the asymmetric Mannich reaction, one of the most widely used remains proline itself, which generally provided excellent enantioselectivities for the Mannich products arisen from either three-component, one-pot reactions or reactions of preformed imines with aldol donors. While these reactions were mostly performed at a catalyst loading of 10mol %, Mannich reactions of enolisable aldehydes and ketones with imines catalysed by (i )-3-pyrrolidinecarboxylic 

In the area of the asymmetric organocatalytic Strecker reaction, a novel A,A -dioxide catalyst derived from BINOL and prolinamide was successfully applied at only 2 mol% of catalyst loading as an organocatalyst to the Strecker reaction of ketoimines with a fairly wide substrate scope, providing excellent enantioselectivities of up to 99% ee. In addition, a chiral thiourea catalyst was 

Chandler, M. Stadler, D. Kampen and B. List, Nature, 

Gomez-Bengoa, A. Linden, R. Lopez, I. Mugica-Mendiola, M. Oiarbide and C. Palomo, J. Am. Chem. Soc., 2008, 130, 7955-7966. 

Strecker reactions are among the most efficient methods of synthesis of a-amino nitriles, useful intermediates in the synthesis of amino acids [73] and nitrogen-containing heterocycles such as thiadiazoles, imidazoles, etc. [74]. Although classical Strecker reactions have some limitations, use of trimethylsilyl cyanide (TMSCN) as a source of cyano anion provides promising and safer routes to these compounds [73b,75]. TMSCN is, however, readily hydrolyzed in the presence of water, and it is necessary to perform the reactions under strictly anhydrous conditions. BusSnCN [76], on the other hand, is stable in water and a potential source of cyano anion, and it has been found that Strecker-type reactions of aldehydes, amines, and BuaSnCN proceed smoothly in the presence of a catalytic amoimt of Sc(OTf)3 in water [77]. No surfactant was needed in this reaction. The reaction was assumed to proceed via imine formation and successive cyanation (it was confirmed that imine formation was much faster than cyanohydrin ether formation under these reaction conditions) again the dehydration process (imine formation) proceeded smoothly in water. 

Several examples of the Strecker-type reaction were tested. For all the compounds investigated, including aromatic, aliphatic, heterocyclic, and aj3-unsaturated aldehydes, the reactions proceeded smoothly to afford the corresponding a-amino nitriles in high yield. The adducts, a-(A-benzhydryl)amino nitriles, were readily converted to a-amino acids [78], and Strecker-type reactions using other amines such as aniline and benzylamine also proceeded smoothly to afford the corresponding adducts in high yields. 

Even these proceeded in aqueous media [82]. Thus, naphthoquinone reacted with cyclopentadiene in THF-H2O (9 1) at room temperature to give the corresponding adduct in a 93 % yield endo/exo = 100 0) (Eq. 21). 

The Strecker reaction is a concise and direct method to synthesise both natural and unnatural optically active ot-amino acids. In the original report by Strecker, acetaldehyde, NH3 and HCN were added in a one-pot reaction. The HCN adds to the unstable imine, which was generated in situ. The intermediate was then hydrolysed to give the desired amino acid alanine. Variants of the Strecker reactions utilising preformed imine are often referred to as modified Strecker reactions.  

Although numerous organocatalytic asymmetric Strecker reactions have been reported, guanidine-catalysed asymmetric Strecker reactions are scarce. The works of Lipton and Corey and their coworkers are amongst these rare reports. However, the validity of the former has been questioned by Kunz and coworkers, who found no enantioselectivity, when the reactions of Lipton and coworkers were repeated by them.  

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Strecker reaction Strecker synthesis Strengthening agent Strength testing Strepavidin Strep, pyogenes Cruz Strep tase... 

In 1959 a new non-protein L-a-amino acid was isolated from the seeds of Acacia willardiana and later from other species of Acacia-, it proved to be l-/3-amino-/3-carboxyethyluracil (977) (59ZPC(316)164). The structure was confirmed by at least four syntheses in the next few years. The most important involves a Shaw synthesis (Section 2.13.3.1.2e) of the acetal (975) and hydrolysis to the aldyhyde (976) followed by a Strecker reaction (potassium cyanide, ammonia and ammonium chloride) to give DL-willardiine (977) after resolution, the L-isomer was identical with natural material (62JCS583). Although not unambiguous, a Principal Synthesis from the ureido acid (978) and ethyl formylacetate is the most direct route (64ZOB407). 

Other direct methods for the sulfonation of the higher fatty acids are by the use of sulfur trioxide vapor or by the use of chlorosulfonic acid. Indirect methods are also available for the preparation of a-sulfo fatty acids and their salts from an a-bromo fatty acid made by the Hell-Volhard-Zelinsky reaction. The bromo compound may be converted directly to the sodium salt of a sulfonic acid through the Strecker reaction or may be converted to the mercaptan and oxidized to the sulfonate. Sulfonation of the lower fatty acids has been studied by Backer and co-workers. ... 

A very efficient and universal method has been developed for the production of optically pue L- and D-amino adds. The prindple is based on the enantioselective hydrolysis of D,L-amino add amides. The stable D,L-amino add amides are effidently prepared under mild reaction conditions starting from simple raw materials (Figure A8.2). Thus reaction of an aldehyde with hydrogen cyanide in ammonia (Strecker reaction) gives rise to the formation of the amino nitrile. The aminonitrile is converted in a high yield to the D,L-amino add amide under alkaline conditions in the presence of a catalytic amount of acetone. The resolution step is accomplished with permeabilised whole cells of Pseudomonas putida ATCC 12633. A nearly 100% stereoselectivity in hydrolysing only the L-amino add amide is combined with a very broad substrate spedfidty. 

This contrary stereochemistry in the Bucherer - Bergs reaction of camphor has been attributed to steric hindrance of e.w-attack of the cyanide ion on the intermediate imine. Normally, equatorial approach of the cyanide ion is preferred, giving the axial (t>Mr/o)-amino nitrile by kinetic control. This isomer is trapped under Bucherer-Bergs conditions via urea and hydan-toin formation. In the Strecker reaction, thermodynamic control of the amino nitrile formation leads to an excess of the more stable compound with an equatorial (e.w)-amino and an axial (endo)-cyano (or carboxylic) function13-17. 

Although it is claimed that the Strecker reaction of 2 results in the exclusive formation of one isomer of 3 and that selective elimination of the minor isomer during isolation of the intermediate compound 4 is not possible, it is apparent that during the workup of the hydrolysis product 4, fractional precipitation or crystallization or other separation of the diastereomers may... 

The method is very useful for the synthesis of physiologically interesting a-mcthylamino acids, e.g., methyl dopa from the 3,4-dimethoxybenzyl derivative. The excellent stereoselection achieved in the process, however, is caused by the preferential crystallization of one pure diastereomerfrom the equilibrium mixture formed in the reversible Strecker reaction. Thus, the pure diastcrcomers with benzyl substituents, dissolved in chloroform or acetonitrile, give equilibrium mixtures of both diastereomers in a ratio of about 7 347. This effect has also been found for other s-methylamino nitriles of quite different structure49. If the amino nitrile (R1 = Bn) is synthesized in acetonitrile solution, the diastereomers do not crystallize while immediate hydrolysis indicates a ratio of the diastereomeric amino nitriles (S)I(R) of 86 1447. 

Stereoselective Strecker reactions with galactosylamine 1 can also be achieved with sodium cyanide and acetic acid in 2-propanol. The reactions, however, proceed slowly and with a lower stereoselectivity, giving diastereomeric ratios of the products between 3 1 and 7 1. The scope of the method can be extended to other glycosylamines, e.g., 2,3,4-tri-O-pivaloyl-a-D-arabinosyl-amine which allows the stereoselective synthesis of (A )-amino nitriles61,62. 

Interestingly, the diastereofacial selectivity can be reversed in the Strecker reaction of aldimines derived from galactosylamine 1 by simply changing the solvent. When the reaction of trimethylsilyl cyanide with the Schiff bases 2 catalyzed by zinc chloride, is carried out in chloroform instead of 2-propanol, there is a preferred formation of the (.S)-amino nitrile diastereomers63. 

The diastereodifferentiating effect of the galactosylamine template in these Strecker reactions is rationalized in terms of a preferred conformation 5 of the Schiff bases which is stabilized by a (7i-double bond into the carbohydrate ring. This conformation is supported by a strong NOE in the H-NMR spectrum between the anomeric and the iminc proton. 

The solid-phase synthesis of the 2(lff)-pyrazinone scaffold is based on a Strecker reaction of commercially available Wang amide linker with appropriate aldehyde and tetramethylsilyl (TMS) cyanide, followed by cyclization of a-aminonitrile with oxalyl chloride resulting in the resin linked pyrazinones. This approach allows a wide diversity at the C-6-position of pyrazinone scaffold (Scheme 35, Table 1). As it has been shown for the solution phase, the sensitive imidoyl chloride moiety can easily undergo an addition/elimination reaction with in situ-generated sodium methoxide affording the resin-linked... 

Hydantoinases belong to the E.C.3.5.2 group of cyclic amidases, which catalyze the hydrolysis of hydantoins [4,54]. As synthetic hydantoins are readily accessible by a variety of chemical syntheses, including Strecker reactions, enantioselective hydantoinase-catalyzed hydrolysis offers an attractive and general route to chiral amino acid derivatives. Moreover, hydantoins are easily racemized chemically or enzymatically by appropriate racemases, so that dynamic kinetic resolution with potential 100% conversion and complete enantioselectivity is theoretically possible. Indeed, a number of such cases using WT hydantoinases have been reported [54]. However, if asymmetric induction is poor or ifinversion ofenantioselectivity is desired, directed evolution can come to the rescue. Such a case has been reported, specifically in the production of i-methionine in a whole-cell system ( . coli) (Figure 2.13) [55]. 

Alkyl halides react with sulfite ion to form alkyl sulfonates, a reaction known as the Strecker reaction (20). "Organic Syntheses"... 

The Strecker reaction has been performed on the aldehyde 182 prepared from L-cysteine [86] (Scheme 28). The imine was formed in situ by treatment with benzylamine, then TMS cyanide was added to afford prevalently in almost quantitative yield the syn-diamine 183, which is the precursor of (-l-)-biotin 184. The syn selectivity was largely affected by the solvent, toluene being the solvent of choice. Since the aldehyde 182 is chemically and configurationally unstable, a preferred protocol for the synthesis of 183 involved the prehminary formation of the water-soluble bisulfite adduct 185 and the subsequent treatment with sodium cyanide. Although in this case the syn selectivity was lower, both diastereomers could be transformed to (-l-)-biotin. 

Even if organocatalysis is a common activation process in biological transformations, this concept has only recently been developed for chemical applications. During the last decade, achiral ureas and thioureas have been used in allylation reactions [146], the Bayhs-Hillman reaction [147] and the Claisen rearrangement [148]. Chiral organocatalysis can be achieved with optically active ureas and thioureas for asymmetric C - C bond-forming reactions such as the Strecker reaction (Sect. 5.1), Mannich reactions (Sect. 5.2), phosphorylation reactions (Sect. 5.3), Michael reactions (Sect. 5.4) and Diels-Alder cyclisations (Sect. 5.6). Finally, deprotonated chiral thioureas were used as chiral bases (Sect. 5.7). 

Similar organocatalytic species to those successfully used for the Strecker reaction were used for the asymmetric Mannich reaction. Catalyst structure/ enantioselectivity profiles for the asymmetric Strecker and Mannich reactions were compared by the Jacobsen group [160]. The efficient thiourea... 

Since the key thermal rearrangement was optimized, we turned our attention to earlier steps. The synthesis of amidoxime 7 was optimized from acetone cyanohydrin 4 (Scheme 6.6). The original Strecker reaction was carried out with ammonia... 

DOPA decarboxylase, should permit more efficient utilization of DOPA. A compound very closely related structurally to the substrate for the enzyme fulfills this function. Carbidopa 168 was designed for this purpose. Carbidopa s synthesis begins with a modified Strecker reaction using hydrazine and potassium cyanide on arylacetone 165 to give 166. This is then hydrolyzed with cold HC1 to give carboxamide 167. 

Officially, the history of MCRs dates back to the year 1850, with the introduction of the Strecker reaction (S-3CR) describing the formation of a-aminocyanides from ammonia, carbonyl compounds, and hydrogen cyanide [4]. In 1882, the reaction progressed to the Hantzsch synthesis (H-4CR) of 1,4-dihydropyridines by the reaction of amines, aldehydes, and 1,3-dicarbonyl compounds [5], Some 25 years later, in 1917, Robinson achieved the total synthesis of the alkaloid tropinone by using a three-component strategy based on Mannich-type reactions (M-3CR) [6]. In fact, this was the earliest application of MCRs in natural product synthesis [7]. 

The first MCR involving isocyanides (IMCR) was reported in 1921 with the Passerini reaction (P-3CR) [8], and over the years these reactions have become increasingly important and have been highlighted in several publications (for discussions, see below). Another older MCR which leads to (non-natural) a-amino acids is the Bucherer-Bergs reaction (BB-4CR), which was first reported in 1929 [9]. This type of transformation is closely related to the Strecker reaction, with C02 employed as a fourth component. 

Pyridine A-oxides have been utilized as asymmetric catalysts in the allylation of aldehydes <06JOC1458> and in the Strecker reaction <06T4071>. In the latter, the chiral A-oxides played a key role in the initial activation of the Si-C bond by coordinating an O atom to the Si atom of silyl cyanide and stabilizing the three-membered complex proposed by the... 

The addition of cyanide to imines, the Strecker reaction, constitutes an interesting strategy for the asymmetric synthesis of a-amino acid derivatives. Sigman and Jacobsen150 reported the first example of a metal-catalyzed enan-tioselective Strecker reaction using chiral salen Al(III) complexes 143 as the catalyst (see Scheme 2-59). 

Scheme 2-59. Chiral Al-salen-catalyzed Strecker reaction. 

Zr-Catalyzed Enantioselective Cyanide Additions to Imines (Strecker Reactions)... 

Starting from levulinic acid, it was possible to obtain 8a-substituted-4-phenyltetrahydro-l//-pyrrolo[2,l-c][l,4]oxa-zinc-1. />(7//)-dioncs 170 (Scheme 26) via Strecker reaction. Compound 171 was treated with 1 equiv of sodium hydroxide and the salt reacted with (f )-phenylglycinol to give a mixture of the Schiffs base 172 and the 1,3-oxazolidine 173 that was reacted with trimethylsilyl cyanide. Further treatment with HCl-saturated methanol afforded a mixture of 174 and 175. Heating at 200 °C in a sealed tube provided 170 as two separable isomers in 73% and 10% yields, respectively <1999TL5753>. 

To date, the most frequently used ligand for combinatorial approaches to catalyst development have been imine-type ligands. From a synthetic point of view this is logical, since imines are readily accessible from the reaction of aldehydes with primary or secondary amines. Since there are large numbers of aldehydes and amines that are commercially available the synthesis of a variety of imine ligands with different electronic and steric properties is easily achieved. Additionally, catalysts based on imine ligands are useful in a number of different catalytic processes. Libraries of imine ligands have been used in catalysts of the Strecker reaction, the aza-Diels-Alder reaction, diethylzinc addition, epoxidation, carbene insertions, and alkene polymerizations. 

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