Catalytic asymmetric additions, aldehydes

In 1999, Shi el al. showed that a diphenylthiophosphoramide derived from (li ,2i )-l,2-diaminocyclohexane could be used as a ligand in the catalytic asymmetric addition of ZnEt2 to aldehydes in the presence of Ti(Oi-Pr)4, providing the corresponding alcohols in enantioselectivities of 40-50% ee (Scheme 3.20). Another class of new ligands such as the phenylthio-phosphoramide of (7 )-1,1 -binaphthyl-2,2 -diamine was developed by the same group, and further tested as a ligand in the same conditions (Scheme 3.20). ... 

Vinylsilane to copper transmetallation has entered the literature,93 93a,93b and a system suitable for catalytic asymmetric addition of vinylsilanes to aldehydes was developed (Scheme 24).94 A copper(l) fluoride or alkoxide is necessary to initiate transmetallation, and the work employs a copper(ll) fluoride salt as a pre-catalyst, presumably reduced in situ by excess phosphine ligand. The use of a bis-phosphine was found crucial for reactivity of the vinylcopper species, which ordinarily would not be regarded as good nucleophiles for addition to aldehydes. The highly tailored 5,5 -bis(di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino-4,4 -bis(benzodioxolyl) (DTBM-SEGPHOS) (see Scheme 24) was found to provide the best results, and the use of alkoxysilanes is required. Functional group tolerance has not been adequately addressed, but the method does appear encouraging as a way to activate vinylsilanes for use as nucleophiles. 

The addition of hydrogen cyanide to a carbonyl group results in the formation of an a-hydroxy nitrile, a so-called cyanohydrin (A, Scheme 6.1) [1]. Compounds of this type have in many instances served as intermediates in the synthesis of, e.g., a-hydroxy acids B, a-hydroxy aldehydes C, fS-amino alcohols D, or a-hydroxy ketones E (Scheme 6.1) [1], In all these secondary transformations of the cyanohydrins A, the stereocenter originally introduced by HCN addition is preserved. Consequently, the catalytic asymmetric addition of HCN to aldehydes and ketones is a synthetically very valuable transformation. Besides addition of HCN, this chapter also covers the addition of trimethylsilyl cyanide and cyanoformate to car-... 

Reagents of this type are suitable for performing catalytic asymmetric additions to aldehydes. For example, an enantiomerically pure Lewis acid is generated in situ from Ti(OiPr)4 and the enantiomerically pure bis(sulfonamide) C. It catalyzes the enantioselective addition of functionalized (or unfunctionalized) dialkylzinc compounds to widely variable aldehydes. There is no detailed, substantiated rationalization of the underlying addition mechanism in this case. 

A different method for the catalytic asymmetric addition of a dialkylzinc compound—Et2Zn and aromatic aldehydes have almost always been used—is shown in Figure 8.31. With regard to stereoselective synthesis, this method has an importance... 

Allylation of Aldehydes. Synthesis of enantiomerically pure allyl alcohols can be accomplished by catalytic asymmetric addition of divinylzinc to aldehydes using a camphorsulfonic acid-derived catalyst (eq 22). ... 

The tremendous success in the catalytic asymmetric addition of organozinc reagents to aldehydes spurred Itsuno and co-workers to examine the reactivity of diethylzinc with silyl imines in the presence of chiral amino alcohols and diols. Unfortunately, this type of azomethine function failed to react [23a]. The use of activated N-acyl- and iV-phosphinoylimines turned out to be crucial as evidenced by the following reports on the alkylation of these functions using di-... 

The search for a catalyst suitable to promote addition of the less reactive silyl enol ethers of ketones has identified a novel class of cationic transition metal complexes in two independent laboratories. The use of a chiral palladium(II) di-aquo complex in the catalytic asymmetric addition of silyl enol ethers to aldehydes (first demonstrated by Shibasaki, Sodeoka et al. [52a, 52b]) provided a clear precedent for their subsequent use with a-imino esters [53] (Scheme 27). Initial experiments focused on the reaction of various a-imino esters 82a-c with silyl enol ether 83 (1.5equiv) in the presence of the Pd diaquo complex 80a (10 mol %) in DMF. Extensive experimentation led to the formation of 84c in 67% ee, and also underscored the importance of suppressing the generation of tetrafluoroboric acid during the course of the reaction. 

Ishizaki and Hoshino prepared optically active secondary alkynyl alcohols (up to 95% e.e.) by the catalytic asymmetric addition of alkyl zinc reagents to both aromatic and aliphatic aldehydes. The chiral ligands studied were based on the pyridine scaffold. Of the three aryl substitutions studied, the a-napthyl derivative was found to be superior (Scheme 21.10). Mechanistically, it was proposed that (S)-l would react with dialkynyl zinc alkoxide A and ethyl zinc alkoxide B. Coordination of additional di-alkynyl zinc and alkynylethyl zinc with these alkoxides (A, B) would give C and D, respectively (Scheme 21.11). More bulky alkoxide (C) would have severe steric interactions with the alkynyl group and pyridine moiety, which might cause undesired conformational changes of the l-zinc complexes. Consequently, the enatioselectivity would be decreased. 

Langer, R, Schwink, L., Devasagayaraj, A., Chavant, P. Y. and Knochel, P. 1996. Preparation of functionalized dialkylzincs via a horon-zinc exchange Reactivity and catalytic asymmetric addition to aldehydes. J. Org. Chem. 61 8229-8243. 

Ostwald, R. et al.. Catalytic asymmetric addition of polyfunctional dialkylzincs to P-stannylated and P-silylated unsaturated aldehydes, J. Org. Chem., 59, 4143, 1994. 

Table 1 Catalytic asymmetric addition of Et2Zn to aldehydes using MITH as a ligand...

With the aim of improving the atom economy, Gau et al. also examined the catalytic asymmetric addition of reagents of type AlArEt2(THF) to aldehydes and ketones (cf. Sect. 3.1) [48]. These compounds are available through either... 

In comparison with the extensive developments in catalytic asymmetric additions to aldehydes and ketones (Chapters 2, 4, and 5), the corresponding catalytic enantioselective additions to imines are less well developed. The lower electrophilicity of the imine carbon in relation to carbonyls, together... 

L-valine. The application of these ligands to the asymmetric addition of ZnEt2 to aldehydes provided the corresponding products with excellent enan-tioselectivities as high as 99% ee in almost all cases and with a catalytic loading as little as 0.02 mol% of the ligand depicted in Scheme 3.9. 

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... 

TADDOL 104 and 126 afford 95-99% ee in the asymmetric addition of organozinc reagents to a variety of aldehydes. The best enantioselectivities are observed when a mixture of the chiral titanium TADDOL compound 127 and excess [Ti(OPr1)4] are employed (Scheme 2-49). The mechanism of the alkylzinc addition involves acceleration of the asymmetric catalytic process by the... 

Several other chiral Lewis acids have also been reported to effect asymmetric aldol reactions. Kruger and Carreira59 reported a catalytic aldol addition of silyl dienolate to a range of aldehydes in the presence of a bisphosphanyl-Cu(II) fluoride complex generated in situ from (iS )-Tol-BINAP, Cu(OTf)2, and (Bu4N)Ph3SiF2. Aromatic, heteroaromatic, and a,/ -unsaturated aldehydes provided the aldol adducts with up to 95% ee and 98% yield (Scheme 3-33). 

To enhance the efficiency of the cyanide addition, these workers subsequently reported a three-component asymmetric synthesis of amino nitriles that avoids the use of the previously mentioned undesirable stannane [74], Thus, as illustrated in Scheme 6.23, treatment of the requisite aniline and aldehyde with HCN (toxic but cheap and suitable for industrial use) at —45°C in the presence of 2.5 mol% 65 leads to the formation of 67 with 86 % ee and in 80 % yield. As was mentioned above in the context of catalytic asymmetric three-component alkylations of imines (see Scheme 6.18), the in situ procedure is particularly useful for the less stable aliphatic substrates (cf. 71—73, Scheme 6.23). The introduction of the o-Me group on the aniline is reported to lead to higher levels of asymmetric induction, perhaps because with the sterically less demanding aliphatic systems, the imine can exist as a mixture of interconverting cis and trans isomers. 

Lewis acids as water-stable catalysts have been developed. Metal salts, such as rare earth metal triflates, can be used in aldol reactions of aldehydes with silyl enolates in aqueous media. These salts can be recovered after the reactions and reused. Furthermore, surfactant-aided Lewis acid catalysis, which can be used for aldol reactions in water without using any organic solvents, has been also developed. These reaction systems have been applied successfully to catalytic asymmetric aldol reactions in aqueous media. In addition, the surfactant-aided Lewis acid catalysis for Mannich-type reactions in water has been disclosed. These investigations are expected to contribute to the decrease of the use of harmful organic solvents in chemical processes, leading to environmentally friendly green chemistry. 

For other catalytic asymmetric cyanosilylation of aldehydes, see C.-D. Hwang, D.-R, Hwang, B.-J. Uang, Enantioselective Addition of Trimethylsilyl Cyanide to Aldehydes Induced by a New Chiral TiflV) Complex, J. Org Chem 1998,63,6762-6763, and references tited therein. 

---