Carbonyl compounds stereoselective addition

Several papers are concerned with the threo-erythro stereoselectivity of the reaction of allylic organozinc reagents with carbonyl compounds. The addition (involving allylic rearrangement) of crotylzinc derivatives to various aldehydes occurs stereoselectively, and the relative amount of tAreo-alcohol increases with increasing steric demand of the group R tert-Bu, S4% f-Pr, 707o n-Bt, 46%) and in the sequence of metals Mg < Zn < Cd 3, 7). The temperature or the polarity of the solvent... 

Sato F, Kusakabe M, Kobayashi Y (1984) Highly diastereofacial selective addition of nucleophiles to 2-alkyl-3-trimethylsilylalk-3-enyl carbonyl compounds. Stereoselective preparation of P-methyl-homoallyl alcohols and p-hydroxy-a-methyl ketones. J Chem Soc Chem Common 1130-1132... 

Alcohols can be synthesized by the addition of carbanions to carbonyl compounds (W.C. Still, 1976) or epoxides. Both types of reactions often produce chiral centres, and stereoselectivity is an important aspect of these reactions. 

The Michael reaction is of central importance here. This reaction is a vinylogous aldol addition, and most facts, which have been discussed in section 1.10, also apply here the reaction is catalyzed by acids and by bases, and it may be made regioselective by the choice of appropriate enol derivatives. Stereoselectivity is also observed in reactions with cyclic educts. An important difference to the aldol addition is, that the Michael addition is usually less prone to sterical hindrance. This is evidenced by the two examples given below, in which cyclic 1,3-diketones add to o, -unsaturated carbonyl compounds (K. Hiroi, 1975 H, Smith, 1964). 

Synthetically useful stereoselective reductions have been possible with cyclic carbonyl compounds of rigid conformation. Reduction of substituted cyclohexanone and cyclopentan-one rings by hydrides of moderate activity, e.g. NaBH (J.-L. Luche, 1978), leads to alcohols via hydride addition to the less hindered side of the carbonyl group. Hydrides with bulky substituents 3IQ especially useful for such regio- and stereoselective reductions, e.g. lithium hydrotri-t-butoxyaluminate (C.H. Kuo, 1968) and lithium or potassium tri-sec-butylhydro-borates or hydrotri-sec-isoamylborates (=L-, K-, LS- and KS-Selectrides ) (H.C. Brown, 1972 B C.A. Brown, 1973 S. Krishnamurthy, 1976). 

The stereoselectivity of organometallic additions with carbonyl compounds fits into the general pattern for nucleophilic attack discussed in Chapter 3. With 4-r-butylcyclohex-anone, there is a preference for equatorial approach but the selectivity is low. Enhanced steric factors promote stereoselective addition. 

Analyze the factors which would determine stereoselectivity in the addition of organometallic compoimds to the following carbonyl compounds. Predict the major product. 

There has been recent interest in naphtho-fused dithiepines as chiral acyl anion equivalents, particularly since the starting dithiol 128 can be obtained in enan-tiomerically pure form (89TL2575). This is transformed using standard methods into the dithiepine 129, but showed only moderate diastereoselectivity in its addition to carbonyl compounds. On the other hand, as we have seen previously for other systems, formation of the 2-acyl compound 130 and reduction or addition of a Grignard reagent gave the products 131 with much better stereoselectivity (91JOC4467). 

H )-Euranones are useful building blocks in the synthesis of a variety of organic compounds. In addition, they often serve as valuable synthetic intermediates in the stereoselective construction of substituted y-butyrolactones via conjugated addition to the Q ,/3-unsaturated carbonyl moiety or catalytic hydrogenation of the double bond (88JOC1560). 

Me- SiCl also affects the stereoselectivity of 1,2-additions to carbonyl compounds [ 133]. Witli the aid of suitable activators, these mildly reactive reagents show selec-tivities unattainable by the conventional reagents, as ilustrated below for Me- SiCl-dependent Chemoselectivity fEq. 10.13) [134]. 

The stereochemical outcome of the Michael addition reaction with substituted starting materials depends on the geometry of the a ,/3-unsaturated carbonyl compound as well as the enolate geometry a stereoselective synthesis is possible. " Diastereoselectivity can be achieved if both reactants contain a stereogenic center. The relations are similar to the aldol reaction, and for... 

The stereoselectivity of an addition reaction is considerably lower when the reactions are conducted in polar solvents, complexing additives such as /V./V,A. A, -tetramethylethylenedi-arnine arc used, or when the stereogenic center carries a methoxy group instead of a hydroxy group. This behavior is explained as competition between the cyclic model and a dipolar model, proposed for carbonyl compounds bearing a polar substituent such as chlorine with a highly... 

Allyl anion synthons A and C, bearing one or two electronegative hetero-substituents in the y-position are widely used for the combination of the homoenolate (or / -enolate) moiety B or D with carbonyl compounds by means of allylmetal reagents 1 or 4, since hydrolysis of the addition products 2 or 5 leads to 4-hydroxy-substituted aldehydes or ketones 3, or carboxylic acids, respectively. At present, 1-hetero-substituted allylmetal reagents of type 1, rather than 4, offer the widest opportunity for the variation of the substitution pattern and for the control of the different levels of stereoselectivity. The resulting aldehydes of type 3 (R1 = H) are easily oxidized to form carboxylic acids 6 (or their derivatives). 

The addition of a vast number of mainly hetero-substituted allyllithium derivatives to carbonyl compounds has been studied, yet only a few examples proceeding with a preparatively useful level of stereoselectivity have been reported. As many methods were developed before the crucial role of the cation was realized, improvements are possible by simple metal exchange. Some reviews, which collect these reagents, arc cited in Section D.l.3.3.3.1.1. 

The complexation of achiral metal enolates by chiral additives, e.g., solvents or complexing agents could, in principle, lead to reagent-induced stereoselectivity. In an early investigation, the Reformatsky reaction of ethyl bromoacetate was performed in the presence of the bidentate ligand (—)-sparteine20. The enantioselectivity of this reaction varies over a wide range and depends on the carbonyl Compound, as shown with bcnzaldehyde and acetophenone. 

I.3.5.6.3. Stereoselective Addition to Enantiomerically Pure Carbonyl Compounds... 

Acyloins (a-hydroxy ketones) are formed enzymatically by a mechanism similar to the classical benzoin condensation. The enzymes that can catalyze reactions of this type arc thiamine dependent. In this sense, the cofactor thiamine pyrophosphate may be regarded as a natural- equivalent of the cyanide catalyst needed for the umpolung step in benzoin condensations. Thus, a suitable carbonyl compound (a -synthon) reacts with thiamine pyrophosphate to form an enzyme-substrate complex that subsequently cleaves to the corresponding a-carbanion (d1-synthon). The latter adds to a carbonyl group resulting in an a-hydroxy ketone after elimination of thiamine pyrophosphate. Stereoselectivity of the addition step (i.e., addition to the Stand Re-face of the carbonyl group, respectively) is achieved by adjustment of a preferred active center conformation. A detailed discussion of the mechanisms involved in thiamine-dependent enzymes, as well as a comparison of the structural similarities, is found in references 1 -4. 

Although considerable progress has been made in metal-catalyzed preparations of non-racemic cyanohydrins, the HNL-catalyzed reaction is still the most important method for the synthesis of chiral cyanohydrins, especially for large-scale reactions. The usefulness of HNLs as catalysts for the stereoselective addition of HCN to carbonyl compounds has increased substantially because (7 )-PaHNL... 

The Mukaiyama aldol reaction can provide access to a variety of (3-hydroxy carbonyl compounds and use of acetals as reactants can provide (3-alkoxy derivatives. The issues of stereoselectivity are the same as those in the aldol addition reaction, but the tendency toward acyclic rather than cyclic TSs reduces the influence of the E- or Z-configuration of the enolate equivalent on the stereoselectivity. 

In addition, Wu and Li recently have developed an efficient rhodium-catalyzed cascade hydrostannation/conjugate addition of terminal alkynes and unsaturated carbonyl compounds in water stereoselectively (Scheme 4.5).88... 

An efficient route for the synthesis of the Phe-Phe hydroxyethy-lene dipeptide isostere precursors utilized for the design of potential inhibitors of renin and HIV-protease was developed. The key step is the zinc-mediated stereoselective allylation of A-protected a-amino aldehydes in aqueous solution (Eq. 8.32).70 NaBF4/M (M = Zn or Sn) showed facilitating allylation of a variety of carbonyl compounds in water, and a-and y-addition products of crotylations could be alternatively obtained under the control of this novel mediator (Eq. 8.33).71... 

The stereoselective 1,4-addition of lithium diorganocuprates (R2CuLi) to unsaturated carbonyl acceptors is a valuable synthetic tool for creating a new C—C bond.181 As early as in 1972, House and Umen noted that the reactivity of diorganocuprates directly correlates with the reduction potentials of a series of a,/ -unsaturated carbonyl compounds.182 Moreover, the ESR detection of 9-fluorenone anion radical in the reaction with Me2CuLi, coupled with the observation of pinacols as byproducts in equation (40) provides the experimental evidence for an electron-transfer mechanism of the reaction between carbonyl acceptors and organocuprates.183... 

Haynes, R.K., Lam, W.W.-L., and Yeung, L.-L., Stereoselective preparation of functionalized tertiary P-chiral phosphine oxides by nucleophilic addition of lithiated tert-butylphenylphosphine oxide to carbonyl compounds, Tetrahedron Lett., 37, 4729, 1996. 

Darzens reaction, the reaction between a carbonyl compound and an a-halo ester in the presence of a base, consists of an initial aldol-type addition and a subsequent intramolecular Sn2 reaction, forming an epoxide as its final product. Its high stereoselectivity thus relies on the stereoselectivity of the nucleophilic addition of an a-halo ester onto the carbonyl substrate, which can be either an aldehyde or a ketone. 

Silyltitanation of 1,3-dienes with Cp2Ti(SiMe2Ph) selectively affords 4-silylated r 3-allyl-titanocenes, which can further react with carbonyl compounds, C02, or a proton source [26]. Hydrotitanation of acyclic and cyclic 1,3-dienes functionalized at C-2 with a silyloxy group has been achieved [27]. The complexes formed undergo highly stereoselective addition with aldehydes to produce, after basic work-up, anti diastereomeric (3-hydroxy enol silanes. These compounds have proved to be versatile building blocks for stereocontrolled polypropionate synthesis. Thus, the combination of allyltitanation and Mukayiama aldol or tandem aldol-Tishchenko reactions provides a short access to five- or six-carbon polypropionate stereosequences (Scheme 13.15) [28],... 

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