Strecker adducts

Jacobsen and co-workers also described the highly enantioselective hydrocyanation of ketimines with the urea analogue. After recrystallisation of the corresponding Strecker adduct, formylation and hydrolysis, the N-benzyl R-methylphenylglycine, was obtained. The R-amino acid hydrochloride is obtained in 93% overall yield with > 99.9% ee on a gram scale [149]. 

In the presence of 42 (2mol% loading), aliphahc and aromafic N-allyl as well as N-benzyl aldimines were efficiently converted after 20 h at -70 °C in toluene to the respective Strecker adducts and subsequently trifluoroacetylated to obtain the products 1-10 in good to excellent yields (65-99%) and ee values J7-97%) (Scheme 6.41). It turned out that N-benzyl imines could be used as substrates without significant difference in comparison to analogous N-allyl imines (e.g., N-benzyl adduct 8 85% yield, 87% ee N-allyl adduct 9 88% yield, 86% ee Scheme 6.41). 

The synthehc utility and importance of the obtained Strecker adducts as precursors for access to enantiomerically pure a-amino acids was examplified for the... 

Scheme 6.44 Reaction sequence for the synthesis of enantiopure (/ )-tert-leucine hydrochloride starting from the pivalaldimine Strecker adduct obtained under catalysis with polymer-bound thiourea 41.

Figure 6.59 Structural modifications of glucosamine-derived urea catalysts screening in the formation of Strecker adduct 12 (Scheme 6.174).

A related process leads to the formation of the Strecker adducts 4 as diastereomeric mixtures from 3, hydrogen cyanide and the optically active amine in a reversible reaction75 ... 

R = aromatic 80-88% ee (8 examples) fiRJ-Strecker adduct R = aliphatic 63-84% ee (3 examples) ( SJ-Strecker adduct 80-99% yield... 

The first enantioselective catalytic Strecker reaction of ketoimines to give chiral quaternary cyanohydrins was demonstrated by the Jacobsen group using 45b (Scheme 6.7) [41]. A series of substituted aryl and aliphatic N-benzyl methylketo-imines (48) reacted with HCN in the presence of 45b to provide essentially quantitative yields of the Strecker adducts in high optical purities (70-95% ee). The adducts were crystalline, and their recrystallization from hexanes increased their enantiopurities to >99.9% ee. The a-quaternary Strecker adducts (49) could be converted to a-quaternary a-amino acids through formamide protection of the secondary amine, followed by sequential hydrolysis of the nitrile and the formamide, followed by hydrogenolytic debenzylation. 

The combination of MejSiCN and Yb(OTf)3 serves to convert aldehydes to trimethylsilyl ethers of cyanohydrins. Addition of amines to the system provides the Strecker adducts. ... 

The roots of the U-4CR lie in research reported long before its discovery in the early 1960s. The first multicomponent reaction (MCR) is credited to Laurent and Gerhardt who, in 1838, isolated an unexpected product from a reaction involving benzaldehyde, ammonia, and hydrogen cyanide. The resulting benzoyl azotide (1) presents the Schiff base of the Strecker adduct and benzaldehyde. Ironically, Strecker described such a reaction more than a decade later. In the years that followed, many variations of MCRs were reported, but it wasn t until 1921 that Passerini first utilized the isocyanide functionality and its unique reactivity in a MCR. It was this work that inspired Ugi and led to focused investigations of this reaction process. 

In the second case, a nonnatural amino acid of commercial value was synthesized in a Strecker reaction using a chiral amine to help induce chirality in the product. In this case, the authors were interested in the synthesis of 3-ethyl-L-norvaline. So, as shown in Scheme 12.33, a mixture of (5)-(-)-a-methylbenzylamine, potassium cyanide (KCN), and 2-ethylbutyraldehyde in dilute aqueous methanolic HCI was allowed to stir for several days at room temperature. During this time, the hydrochloride salt of the Strecker adduct precipitated and, under these conditions, the precipitate was found to be enriched in the levorotatory isomer (>30 1 by chromatographic separation of the diastereomers). Hydrolysis of the appropriate amino nitrile with cold concentrated sulfuric acid produced 3-ethyl-N -[(lS)-phenylethyl]-L-norvalinamide and debenzylation was accomplished by hydrogenation at lOOpsi of hydrogen (H2) over a 5% Pd/C catalyst. Finally, the amide was hydrolyzed in concentrated HCI to produce 3-ethyl-L-norvaline hydrochloride. 

More recently, Zhu and coworkers have employed the a-aminonitrile intermediate resulting of this process to generate in two steps polysubstituted 2-amino-5-cyanopyrroles 85 through a [4+1] cycloaddition of a,p-unsaturated imi-doyl cyanide (2-cyano-l-azadienes) with isocyanides, in combination with a previous in situ oxidation of the Strecker adduct (Schone 10.38) [108,109]. 

Following Snapper and Hoveyda s reports, Vilaivan and coworkers employed titanium complex of simple N-salicyl-P-amino alcohol (10 mol%) for catalytic asymmetric Strecker reaction of N-benzyl substituted imines with TMSCN, affording the Strecker adducts in excellent yields and up to >98% ee [229]. The presence of a protic additive is found to be essential to ensure good conversion and reaction rate (Scheme 14.97). 

For better enantiopurities with aliphatic substrates, structural elements crucial for a high stereoinduction were revised by library screening on a solid phase. It was found that the presence of a bulky substituent at both the amino acid and at the 3-position of the salicylimine moiety were key elements responsible for high enantioselectivity. By employing of a pivaloyl substituent at the 5-position of the salicylaldehyde moiety, 24 was found to be a superior catalyst for the Strecker reaction of aliphatic imines 23 (Scheme 30.5) [16]. By adaptation of solid-supported 24 to homogenous conditions, the thiourea was replaced with a urea moiety because of the more convenient synthesis. By applying the so-synthesized catalyst 25, Strecker adducts 26 were obtained in high ee s and yields. Transformation of 3,4-dihydroisoquinoline, a fixed (Z)-imine, into the Strecker adduct (in 88% yield ... 

Since there is great interest in compounds bearing quaternary stereocenters, soluble catalyst 25 was also applied to keto-imines in the presence of in situ generated HCN (Scheme 30.6) [17]. Whereas hydrocyanation adducts of N-allyl protected ketimines were prone to decompose via a retro-Strecker reaction, N-benzylated Strecker adducts 28 were obtained in mostly excellent yields and very high ee s. In general, acetophenone imines 27 were suitable substrates whereas aliphatic ketimines 27 showed a lowered optical purity. Although the benzyl protection group was necessary to obtain stable Strecker adducts 28, transformation of these adducts into amino acids was made more difficult. It could also be shown that... 

The scope of the Br0nsted acidic catalyst 88 could be extended to the hydrocya-nation of aromatic methyl keto-imines 90, but enantioselectivities of the formylated Strecker adducts 91 were in general lower (56-80% ee) but with good to high yields (69-95%) (Scheme 30.20) [48],... 

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