Aldol reaction steric hindrance

There also exists an acidregioselective condensation of the aldol type, namely the Mannich reaction (B. Reichert, 1959 H. Hellmann, 1960 see also p. 291f.). The condensation of secondary amines with aldehydes yields Immonium salts, which react with ketones to give 3-amino ketones (=Mannich bases). Ketones with two enolizable CHj-groupings may form 1,5-diamino-3-pentanones, but monosubstitution products can always be obtained in high yield. Unsymmetrical ketones react preferentially at the most highly substituted carbon atom. Sterical hindrance can reverse this regioselectivity. Thermal elimination of amines leads to the a,)3-unsaturated ketone. Another efficient pathway to vinyl ketones starts with the addition of terminal alkynes to immonium salts. On mercury(ll) catalyzed hydration the product is converted to the Mannich base (H. Smith, 1964). 

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). 

A syn-selective asymmetiic nih o-aldol reaction has been reported for structurally simple aldehydes using a new catalyst generated from 6,6-bis[(tiiethylsilyl)ethynyl]BINOL (g in Scheme 3.18). The syn selectivity in the nitro-aldol reaction can be explained by steric hindrance in the bicyclic transition state as can be seen in Newman projection. In the favored h ansition state, the catalyst acts as a Lewis acid and as a Lewis base at different sites. In conbast, the nonchelation-controlled transition state affords anti product with lower ee. This stereoselective nitro-aldol reaction has been applied to simple synthesis of t/ireo-dihydrosphingosine by the reduction of the nitro-aldol product with H2 and Pd-C (Eq. 3.79). 

In the reverse reaction, the addition anion reforms the carbonyi group by expeiiing the enoiate anion as ieaving group. This reverse aldol reaction is sufficientiy important in its own right, and we shaii meet exampies. Note that, as we saw with simpie aidehyde and ketone addition reactions, aidehydes are better eiectrophiies than ketones (see Section 7.1.1). This arises from the extra alkyl group in ketones, which provides a further inductive effect and extra steric hindrance. Accordingly, the aldol reaction is more favourable with aldehydes than with ketones. With ketones, it is absolutely essential to disturb the equilibrium in some way. 

A regioselective aldol condensation described by Biichi succeeds for sterical reasons (G. Biichi, 1968). If one treats the dialdehyde given below with acid, both possible enols are probably formed in a reversible reaction. Only compound A, however, is found as a product, since in B the interaction between the enol and ester groups which are in the same plane hinders the cyclization. Btlchi used acid catalysis instead of the usual base catalysis. This is often advisable, when sterical hindrance may be important. It works, because the addition of a proton or a Lewis acid to a carbonyl oxygen acidifies the neighbouring CH-bonds. 

The mechanism of the reaction is well-known. The first step is formation of a carbanion, followed by nucleophile addition to the carbonyl carbon atom halo-hydrin alcoholates are produced finally, ring-closure takes place by intramolecular substitution. The stereochemistry of the reaction is much disputed the reason why a unified viewpoint has not emerged is that the configuration of the end-product is influenced by the structure of the starting compound (including steric hindrance), the base employed, and solvation by the solvent, sometimes in an unclear manner. The stereochemical course of the reaction is controlled by the kinetic and thermodynamic factors in the second step the structure of the oxirane formed is decided by the reversibility of the aldolization and the reaction rate of the ring-closure. 

In general, the equilibrium in aldol condensations of ketones favors reactants rather than products. There is significant steric hindrance at both carbons with new bonds, so it is reasonable to conclude that this reaction of cyclohexanone would also favor reactants at equilibrium. 

Nakamura, Kuwajima and coworkers have recently shown that TBAF and TAS difluorotrimethylsili-conate-catalyzed reactions give identical sense and degree of stereoselection. As the stereoselectivity of the fluoride-catalyzed aldol reaction is independent of the countercation and of the type of silyl group,the open transition structures A (extended) and B (skew) have been proposed to account for the observed dependence of the symanti ratios on the steric hindrance of R , R and R (Figure 3). - ... 

The rearside attack model became equally important in the discussion of stereoselectivity in the aldol condensation. In 1981, Seebach and Golinski proposed a topological rule for aldol-like reactions which says that the H atom, the smaller substituent on the donor component, adopts an anti position with respect to the acceptor double bond C=A in the preferred transition state, cf. A and B in Scheme 6.28 [35]. This preference of A over B comes about as a result of the increases in steric hindrance when the donor substituent R2 is jammed against Rj and H of the acceptor in the non-perpendicular approach B. 

Stereoselectivity. See Asymmetric induction Axial/equatorial-, Cis/trans-, Enantio-, Endo/exo- or Erythro/threo-Selectivity Inversion Retention definition (e.e.), 107 footnote Steric hindrance, overcoming of in acylations, 145 in aldol type reactions, 55-56 in corrin synthesis, 261-262 in Diels-Alder cyclizations, 86 in Michael type additions, 90 in oiefinations Barton olefination, 34-35 McMurry olefination, 41 Peterson olefination, 33 in syntheses of ce-hydrdoxy ketones, 52 Steric strain, due to bridges (Bredt s rule) effect on enolization, 276, 277, 296, 299 effect on f3-lactam stability, 311-315 —, due to crowding, release of in chlorophyll synthesis, 258-259 in metc-cyclophane rearrangement, 38, 338 in dodecahedrane synthesis, 336-337 in prismane synthesis, 330 in tetrahedrane synthesis, 330 —, due to small angles, release of, 79-80, 330-333, 337... 

Retrosynthetically, spiroketal precursor 8 would be accessed via a diaster-eoselective aldol reaction between chiral aldehyde 9 and a-chiral (3-arylated methyl ketone 10 (Scheme 3). Aldehyde 9 would be readily accessible from commercially available ethyl (S)-hydroxybutyrate, while methyl ketone 10 would be constmcted by the Suzuki cross-coupling of trifluoroboratoamide 11 and rotationally symmetric aryl halides 12/13. The use of Br or I in place of Cl in halides 12/13 was intended to increase the reactivity of 12/13 toward oxidative insertion and overcome the steric hindrance imparted by the ortho-disubstituted aromatic framework. The required functionalization of the aromatic ring to install the phthalide motif was envisioned to be possible via iridium-catalyzed CH-borylation either before or after formation of the spiroketal core. Our group already had experience with this remarkable transformation in the context of naphthalene chemistry. 

Originally, formaldehyde was exclusively employed as the carbonyl component, but more recently, higher aldehydes and ketones have also been used. However, the usefulness of the latter compounds is limited by aldol-type condensations, Cannizzaro reactions, enamine formation, and steric hindrance. 

Pyridine bases have been foimd to catalyze the aldol reaction of o-glyceralde-hyde. Rate constants for reactions carried out with a series of catalysts in water at pH 7.0 and 30°C are shown in Table 7.10. (The observed reaction rates were divided by the molar concentration of improtonated base at the reaction pH in order to obtain the rate constants shown.) Determine whether the reaction is subject to general or specific base catalysis. Do the data suggest any role of steric hindrance in the catalysis of the reaction by pyridine bases ... 

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