Aldehyde asymmetric nucleophilic addition

CHIRAL CATALYST-INDUCED ALDEHYDE ALKYLATION ASYMMETRIC NUCLEOPHILIC ADDITION... 

MgBr2-mediated asymmetric nucleophilic addition of Grignard reagents and allyl-tributyltin to aldehydes bearing sugar-derived jS- or y-tetrahydropyranyloxy chiral auxiliaries designed to complex with MgBt2 has been achieved. ... 

A formal asymmetric nucleophilic addition to carbonyl compounds is achieved by Trost and his co-workers in the allylic alkylation of acylals of alkenals. An excellent enantioselectivity is observed in this alkylation. The starting acylals are easily prepared by the Lewis-acid catalyzed addition of acid anhydrides to aldehydes, by use of Trost s ligand 118 (Scheme 13), where various carbon-centered nucleophiles are available (Scheme l4),101,101a-10lc Asymmetric synthesis of some natural products is achieved according to this procedure. 

Dinaphtho[2, -d Y,2 7]-[l,3]dithiepins 58 are readily lithiated with -butyllithium at —78°C. Asymmetric nucleophilic addition of the anions to aldehydes afforded 59 with moderate to good diastereoselectivities (Scheme 7) <2002H(57)1487>. For a similar reaction, see <1991JOC4467>. 

Yoshida, T, Chika, J I, Takei, H, Asymmetric nucleophilic addition to (i- and y-alkoxy aldehydes using carbohydrate as a chiral auxiliary. Tetrahedron Lett., 39, 4305-4308, 1998. 

The first work about polymer-supported p-aminoalcohol used in the asymmetric nucleophilic addition to aldehydes was reported by Frechet [H3]. The best result (95/o ee) was obtained by using a polymeric catalyst derived N -dialkylated (-)-3-exo-... 

Chiral oxazolines developed by Albert I. Meyers and coworkers have been employed as activating groups and/or chiral auxiliaries in nucleophilic addition and substitution reactions that lead to the asymmetric construction of carbon-carbon bonds. For example, metalation of chiral oxazoline 1 followed by alkylation and hydrolysis affords enantioenriched carboxylic acid 2. Enantioenriched dihydronaphthalenes are produced via addition of alkyllithium reagents to 1-naphthyloxazoline 3 followed by alkylation of the resulting anion with an alkyl halide to give 4, which is subjected to reductive cleavage of the oxazoline moiety to yield aldehyde 5. Chiral oxazolines have also found numerous applications as ligands in asymmetric catalysis these applications have been recently reviewed, and are not discussed in this chapter. ... 

Nucleophilic addition of metal alkyls to carbonyl compounds in the presence of a chiral catalyst has been one of the most extensively explored reactions in asymmetric synthesis. Various chiral amino alcohols as well as diamines with C2 symmetry have been developed as excellent chiral ligands in the enantiose-lective catalytic alkylation of aldehydes with organozincs. Although dialkylzinc compounds are inert to ordinary carbonyl substrates, certain additives can be used to enhance their reactivity. Particularly noteworthy is the finding by Oguni and Omi103 that a small amount of (S)-leucinol catalyzes the reaction of diethylzinc to form (R)-l-phenyl-1 -propanol in 49% ee. This is a case where the... 

Most of the asymmetric aldol reactions discussed thus far deal with the nucleophilic addition of a chiral or achiral enolate onto a chiral or achiral aldehyde,... 

As a kind of nucleophilic addition reaction similar to the Grignard reaction, the Reformatsky reaction can afford useful ft-hydroxy esters from alkyl haloacetate, zinc, and aldehydes or ketones. Indeed, this reaction may complement the aldol reaction for asymmetric synthesis of //-hydroxy esters. 

For these and similar reactions recently a variety of Lewis acidic aluminium, rare earth metals, and titanium alkoxides have been applied. Alkoxides have the additional advantage that they can be made as enantiomers using asymmetric alcohols which opens the possibility of asymmetric catalysis. Examples of asymmetric alcohols are bis-naphtols, menthol, tartaric acid derivatives [28], Other reactions comprise activation of aldehydes towards a large number of nucleophiles, addition of nucleophiles to enones, ketones, etc. 

For purposes of illustration, consider the erythro selective reaction illustrated in eq. [69]. For aldehydes containing an adjacent asymmetric center (R, Rl = medium and large alkyl substituents), the bias for nucleophilic addition from a given diastereotopic face of the aldehyde is predicted empirically by Cram s rule (the open-chain... 

Remote steric effects have also been noted to play an unanticipated role in the sense of asymmetric induction. This is apparent from related condensations carried out on aldehydes 106 (26) and 107 (eqs. [76]-[78]) (26,92). Other examples illustrating the influence of remote structural perturbations on the carbonyl addition process have been observed in these laboratories. The addition of the lithio benzoxazole 110 to aldehyde 108 proceeded with good Cram diastereoface selection (95a), whereas the same nucleophilic addition to aldehyde 109 was stereorandom (95b). 

The asymmetric reactions discussed in this chapter may be divided into three different types of reaction, as (1) hydrometallation of olefins followed by the C—C bond formation, (2) two C C bond formations on a formally divalent carbon atom, and (3) nucleophilic addition of cyanide or isocyanide anion to a carbonyl or its analogs (Scheme 4.1). For reaction type 1, here described are hydrocarbonyla-tion represented by hydroformylation and hydrocyanation. As for type 2, Pauson-Khand reaction and olefin/CO copolymerization are mentioned. Several nucleophilic additions to aldehydes and imines (or iminiums) are described as type 3. 

The nucleophilic addition of organometallic reagents to imines provides an attractive route to amines [4]. Recendy, however, some completely different approaches to the synthesis of a-aryl amine were reported. Hayashi and Ishigeda-ni found a new catalytic system for the asymmetric addition of arylstannanes to imines derived from aromatic aldehydes (Scheme 11) [20]. 

In most cases chiral carbonyl compounds also afford low stereoselectivity. As for the related Passerini reaction, even the use of aldehydes that are known to give excellent asymmetric induction in the reaction with other kinds of C-nucleophiles, results in low or moderate diastereoisomeric ratios. For example, both norbornyl aldehyde 39 [47] and a-alkoxyaldehyde 40 [3, 48] gave drs lower than 2 1 (Scheme 1.16). The same happens with ortho-substituted chromium complex 41 [49], which usually leads to very high asymmetric induction in other nucleophilic additions. Finally, //-substituted aldehyde 42 [50] gave poor results as well. 

The Strecker reaction [1] starting from an aldehyde, ammonia, and a cyanide source is an efficient method for the preparation of a-amino acids. A popular version for asymmetric purposes is based on the use of preformed imines 1 and a subsequent nucleophilic addition of HCN or TMSCN in the presence of a chiral catalyst [2], Besides asymmetric cyanations catalyzed by metal-complexes [3], several methods based on the use of organocatalysts have been developed [4-14]. The general organocatalytic asymmetric hydrocyanation reaction for the synthesis of a-amino nitriles 2 is shown in Scheme 5.1. 

Triethoxysilyl acetylene (51) allows a new organocatalytic approach toward the introduction of the alkyne moiety via a nucleophilic addition to aromatic aldehydes, ketones, and aldimines, with EtOK as catalyst (10 mol%). Although a catalytic asymmetric version has not yet been developed, the application of a chiral auxiliary, in the case of imines 53 (Scheme 7.9), led to an impressively high dia-stereoselectivity (20 1) [54], unparalleled by other acetylenic organometallics. 

The reaction is thought to involve activated nucleophilic addition of the ketene to the aldehyde which is coordinated to the aluminum. TTie ketene is added as a gas by bubbling into a solution of the catalyst and aldehyde at -78 °C. Lower induction is observed if the aldehyde is added to a solution of the catalyst and ketene. One of the limitations of this catalyst system is that sub-stoichiometric amounts of the catalyst are not successful. With the 10 mol % of the catalyst less than 5 % yield of product was obtained. This limitation might be related to the observation that acylated phenols are observed as by-products in this reaction. The yields of the reaction are higher in dichloromethane but asymmetric induction decreases. The reaction in entry 2 of Table 5 was observed to occur in 90 % yield and in 20 % ee in dichloromethane. 

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