Asymmetric aldehyde formation

The catalysed reaction of aryl aldehydes with ammonia and chloroform (7.4.3) in the presence of chiral ephedrinium salts leads to the asymmetrically induced formation of a-amino acids. Yields are variable and with ca. 20-30% ee [49]. 

Bartlett PA, Johnson WS, Elliott JD (1983) Asymmetric synthesis via acetal templates. 3. On the stereochemistry observed in the cyclization of chiral acetals of polyolefinic aldehydes formation of optically active homoallylic alcohols. J Am Chem Soc 105 2088-2089... 

Cyanation of carbonyl compounds has one of the richest histories of any transformation in the field of asymmetric catalysis, and intensive research efforts have continued unabated since the editorial deadline for the first edition of Comprehensive Asymmetric Catalysis in 1998. This chapter will summarize all efforts in this area from 1998 to date, highlighting the most important catalytic systems from a synthetic and/or mechanistic standpoint. Significant advances in both the cyanation of aldehydes (formation of secondary cyanohydrins Section 28.2.1) and the cyanation of ketones (formation of tertiary cyanohydrins Section 28.2.2) will be addressed [1,2]. 

Asymmetric epoxide formation of enones and aldehydes 99MI23. 

The synthetic strategy is based on Yamaguchi macrolactonization, metal alkynylide addition at C17, Mukaiyama-aldol Prins reaction of vinyl ether 219 with aldehyde 218 forming 2,6-d5-tetrahydropyran, Hosomi-Sakurai reaction giving 2,6-tran5-tetrahydropyran, asymmetric center formation via Myers alkylation at C12 and Noyori reduction at C15 and C3 (Scheme 47). 

Historically, enzyme catalysis has played a highly prominent role, with the first enzyme-catalyzed asymmetric addition of HCN to aldehydes dating back to 1908 [167]. A wide range of both aromatic and aliphatic ketones are suitable substrates and produce cyanohydrins of high optical purity. The most readily available and hence most commonly employed enzyme for asymmetric cyanohydrin formation is (R)-hydroxynitrile lyase isolated from almonds. Recent cloning and over-expression techniques have also made a number of (S)-hydroxynitrile lyases available for organic synthesis [164, 165]. This was utilized in Griengl s synthesis of coriolic acid (255), a natural product that displays calcium ionophoric activity and acts as a prostacyclin mimic (Scheme 2.32) [168]. Thus, an (S)-hydroxynitrile lyase was cloned from rubber trees (Hevea brasiliensis), overexpressed in Pichia pastoris, and used to provide cyanohydrin 254 in 99 % ee. 

Alternatively, epoxides can be formed with concomitant formation of a C-C bond. Reactions between aldehydes and various carbon nucleophiles are an efficient route to epoxides, although the cis. trans selectivity can be problematic (see Section 9.1.4). Kinetic resolution (see Section 9.1.5.2) or dihydroxylation with sequential ring-closure to epoxides (see Section 9.1.1.3) can be employed when asymmetric epoxidation methods are unsatisfactory. 

Optically active Art-butyl 2-(4-methylphenylsulfinyl)propanoate only reacted with aldehydes in the presence of e//-butylmagnesium bromide as a base36. The asymmetric induction for the formation of the hydroxylic center was higher in the case of aliphatic aldehydes (75-80%) than in the case of benzaldehyde (33%). The diastereoselectivity regarding the tertiary center to sulfur was not determined. 

An excellent synthetic method for asymmetric C—C-bond formation which gives consistently high enantioselectivity has been developed using azaenolates based on chiral hydrazones. (S)-or (/ )-2-(methoxymethyl)-1 -pyrrolidinamine (SAMP or RAMP) are chiral hydrazines, easily prepared from proline, which on reaction with various aldehydes and ketones yield optically active hydrazones. After the asymmetric 1,4-addition to a Michael acceptor, the chiral auxiliary is removed by ozonolysis to restore the ketone or aldehyde functionality. The enolates are normally prepared by deprotonation with lithium diisopropylamide. 

Nair and co-workers have demonstrated NHC-catalysed formation of spirocyclic diketones 173 from a,P-unsaturated aldehydes 174 and snbstitnted dibenzylidine-cyclopentanones 175. Where chalcones and dibenzylidene cyclohexanones give only cyclopentene products (as a result of P-lactone formation then decarboxylation), cyclopentanones 175 give only the spirocychc diketone prodncts 173 [73]. Of particular note is the formation of an all-carbon quaternary centre and the excellent level of diastereoselectivity observed in the reaction. An asymmetric variant of this reaction has been demonstrated by Bode using chiral imidazolium salt 176, obtaining the desymmetrised product with good diastereo- and enantioselectivity, though in modest yield (Scheme 12.38) [74],... 

Asymmetric Allylation. One of the recent new developments on this subject is the asymmetric allylation reaction. It was found that native and trimethylated cyclodextrins (CDs) promote enantiose-lective allylation of 2-cyclohexenone and aldehydes using Zn dust and alkyl halides in 5 1 H2O-THF. Moderately optically active products with ee up to 50% were obtained.188 The results can be rationalized in terms of the formation of inclusion complexes between the substrates and the CDs and of their interaction with the surface of the metal. 

The first report on the reaction of D-pseudoephedrine 66 with phosphoryl chloride appeared as early as 1962 [49], More recently it was found that this condensation gave 2-chloro-l,3,2-oxazaphospholidine 2-oxides 67 as a single diastereomer which was subsequently esterified with racemic aldehyde cyanohydrins 68 without racemization at the phosphorus atom. The prepared diastereomeric esters 69 were used as substrates for the asymmetric synthesis of optically active cyanohydrins 72, which involves the intermediate formation of the tertiary esters 70, as shown in Scheme 22 [50],... 

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