Asymmetric steric requirements

In 2000, Woodward et al. reported that LiGaH4, in combination with the S/ 0-chelate, 2-hydroxy-2 -mercapto-1,1 -binaphthyl (MTBH2), formed an active catalyst for the asymmetric reduction of prochiral ketones with catecholborane as the hydride source (Scheme 10.65). The enantioface differentiation was on the basis of the steric requirements of the ketone substituents. Aryl w-alkyl ketones were reduced in enantioselectivities of 90-93% ee, whereas alkyl methyl ketones e.g. i-Pr, Cy, t-Bu) gave lower enantioselectivities of 60-72% ee. 

Pd complexes 9-12 were tested for their catalytic behavior in the asymmetric Heck reaction involving the phenylation of 2,3-dihydrofuran (Scheme 3). The results are summarized in Table 2. The two isomeric products of 2-phenyl-2,5-dihydrofuran are formed with varying yields from 80% to 0%. The obtained ee s are high. Complex 12 is shown to be catalytically inactive. The lack of catalysis in complex 12 is rationalized by differences in the steric requirements between the diphenylphosphinites 1-3 (cone angle >140°) and the more sterically hindered cyclohexyl-phosphinite 4 (cone angle >170°) and the resulting stereochemistry on the Pd center. The ligands in complex 12 adopt a... 

Some impressive levels of asymmetric induction were noted in the following examples (eq. [68], Table 30). From the cases studied, it is readily apparent that the steric requirements of the Rj Ugand at the resident asymmetric center in aldimine chelate 90 exerts a profound effect on the degree of asymmetric induction. Earher studies (80) offer a precedent for the suggestion that the aldolate complexes 93 and 94 are the penultimate precursors to the major and minor diastereomeric /3-lactams 91 and 92, respectively (Scheme 17). The pericyclic transition state 95 (M = TiL ) could well explain the sense of chirality transfer (82). 

Asymmetric hydroboration.1 This borane effects enantioselective hydroboration of rr. v-trisubstituted acyclic and cyclic olefins to provide, after oxidation, (R)-alcohols with optical purities of 60 78% ee. The steric requirements of 1 are less than those of diisopinocampheylborane(l, 262-263 4, 161), but greater than those of isopinocam-phcylborane (8,267). 

Tris[ (l S,2i )-6,6-dimethylbicylo[3.1.1]heptan-2-yl methyl]gallium reacts with ketones above room temperature, and optically active alcohols are obtained as main products (Scheme 145).438 LiGaH4, in combination with an S,0-chelate ligand, 2-hydroxy-2 -mercapto-l,T-binaphthyl (MTBH2), forms an active hydride catalyst for an asymmetric reduction of prochiral ketones with catecholborane. Enantiofacial differentiation is based on the steric requirement of the ketone substituents. Aryl//z-alkyl ketones are reduced in 90-93% ee and branched ketones RC(0)Me (e.g., R = Pr , oC6H11 Bu ) in 60-72% ee (Table 43).439 440... 

A hypothetical catalytic cycle for asymmetric hydroformylation reaction is shown in Fig. 9.13. The precatalyst Rh(acac)(P-P) reacts with H2 and CO to give the square planar catalytic intermediate 9.47. Alkene addition to 9.47 can lead to the formation of 9.48, 9.49, and 9.50. The steric requirements of the chelating ligand would have to be such that the formation of 9.50 is avoided. This is because alkene insertion into the Rh-H bond in this case would lead to the formation of the linear rather than the branched alkyl. Both 9.48 and 9.49, which differ in the coordination positions of the phosphorus atoms, can give 9.51, which has the desired branched alkyl ligand. 

Hypothesizing that primary amine catalysts, due to their reduced steric requirements, might be suitable for the activation of ketones, we studied various salts of a-amino acid esters. (For pioneering use of primary amine salts in asymmetric iminium catalysis involving aldehyde substrates, see Ishihara and Nakano 2005 Sakakura et al. 2006 for the use of preformed imines of a, 3-unsaturated aldehydes and amino acid esters in diastereoselective Michael additions, see Hashimot et al. 1977.) We have developed a new class of catalytic salts, in which both the cation and the anion are chiral. In particular, valine ester phosphate salt 35 proved to be an active catalyst for the transfer hydrogenation of a variety of a, 3-unsaturated ketones 36 with commercially available Hantzsch ester 11 to give saturated ketones 37 in excellent enantiose-lectivities (Scheme 28 Martin and List 2006). 

From this reaction and the reaction of 6 to give 7 (see Section 7.1.1.1.), it can be concluded that the steric requirements for azide transfer are modest, in fact even smaller than in analogous enolate methylation reactions2. It is worth comparing the low levels of internal asymmetric induction observed in the case of a cyclic amide enolate3 (see 2->-3->-4 in Section 7.1.1.). 

Asymmetric Hydroboration. Dilongifolylborane (Lgf2BH) is a chiral dialkylborane intermediate in steric requirement between the two widely investigated chiral organoboranes derived from a-pinene Monoisopinocampheylborane (IpcBH2) and Di-isopinocampheylborane (Ipc2BH). ... 

Asymmetric Hydroboration. The steric requirements of IpcBH2 are such that hydroboration of trans and trisubstituted alkenes proceeds with little or no displacement of a-pinene from the reagent, a phenomenon which is observed with the more hindered Diisopinocampheylborane (IpC2BH). Ipc2BH is most effective for the hydroboration of relatively unhindered cis alkenes,... 

Brown, H. C., Ramachandran, P. V. Selective reductions. 45. Asymmetric reduction of prochiral ketones by iso-2-methyl-, iso-2-ethyl-, and [iso-2-[2-(benzyloxy)ethyl]apopinocampheyl]-tert-butylchloroboranes. Evidence for a major influence of the steric requirements of the 2-substituent on the efficiency of asymmetric reduction. J. Org. Chem. 1989, 54,4504-4511. 

This work has allowed an empirical mnemonic to be proposed (cf. Scheme 3.4), which has later been refined. The mnemonic allows for the prediction of the reaction outcome and reactivity. Initially, the steric requirements of the system indicated that a hydrogen atom (i.e., a trisubstituted alkene is the best substrate) is necessary for a good asymmetric induction (Figure 3.2a) [84]. 

Figure 3.2 Steric requirements for the asymmetric dihydroxylation procedure as indicated by the...

The DlOP-rhodium(I) complex attached to organic polymers , e.g., polystyrene resin and poly(methyl vinyl alcohol), exhibits good catalytic activity as a chiral catalyst comparable to the corresponding homogeneous catalyst. In contrast, the rhodium(I) complexes anchored on inorganic supports display only a low efficiency . Studies show that the steric requirements for a match of the chiral ligand, a hydrosilane and a ketone are of definite importance in bringing about effective asymmetric induction. 

The selection of enantiotopic substrate faces during complexation or subsequent reactions can be affected by various factors. Besides the steric requirements of the substrate, the coordination number and geometry at the metal center, as well as the different relative conformations of substrate and ligands within the complex are important. This might be the reason for unexpected solvent and even temperature effects occasionally observed in asymmetric induction. 

The analogous five-coordinate olefin complexes show the presence of isomers because of an asymmetric environment above and below the equatorial plane. The isomer distribution depends on the steric requirement of the olefin substituent. In a number of fiuoroolefins, a direct through-space H-F coupling was observed (10). With allenes, Pt is coordinated to one of the double bonds, usually the less substituted one, and the uncoordinated double bond is probably bent backward by some 38°, by analogy with the bending found in PtP(C6H5)3(CH2=C=CH2) (11). 

The experimental confirmation to Corradini s model came, again, from C NMR analysis, in this case of the polymer chain ends. In fact, Zambelli and coworkers found that for highly isotactic-selective ZN catalysts, the enantioselectivity of 1,2 propene insertion into initial Ti-[ C-labeled]-aIkyl bonds is different from that of the subsequent ones. They observed no enantioselectivity for insertion into a Ti- CHs bond and only partial ( 80%) enantioselectivity for that into a Ti- CH2-CH3 bond, whereas the following propagation steps were almost completely enantioselective [37]. These findings highlighted the steric requirements for the asymmetric induction and proved, in particular, that for the onset of the stereocontrol the alkyl group bound to Ti needs to be a chain, i.e., consist of at least two C atoms and preferably more [6]. 

All the facts described here clearly indicate that the steric requirement for a match of the chiral ligand, a hydrosilane and a ketone is of definite importance in order to bring about an effective asymmetric induction. However, it is not understandable why the two catalysts, (BMPP)2Rh(SX l (8) and (DIOP)Rh(SX l (6), behave differently in activating monohydrosilanes. 

Brown and coworkers [1] have found that NB-Enantrane is effective only for the reduction of a,(3-acetylenic ketones. The reduction of other ketones is too slow to be of any practical use. The retarded rate is attributed to the steric bulk at the 2 position since no internal coordination has been detected by "B NMR (6 86 ppm) [2]. On the other hand, Alpine-Borane has proven to be versatile reagent for the asymmetric reduction of variety of ketones. Consequently, two reagents B-(iso-2-ethylapopinocampheyl)-9-borabicyclo[3.3.1]nonane (Eapine-Borane) and B-(iso-2- -propylapopinocampheyl)-9-BBN (Prapine-Borane) having increasing steric requirement at the 2 position, are prepared by the hydroboration [3] of 2-ethyl- and 2-n-propylapopinene. 

Next, consider a reaction between an atom and a diatomic molecule, A + BC. Reactions can differ also in their energetic requirements, but to focus attention on the steric requirements with the energetic effects being equal we take the barrier height Eq to be the same as in the previous reaction. To have minimal steric requirements let us take the transition state, ABC, to be bent. This choice allows A to approach BC within a cone. Because BC has an internal structure, the partition function for the reactants becomes Q = Q Q QvQ - The transition state is a bent triatomic. It has three vibrations, one of which is the reaction coordinate. (As we saw in Section 5.1, this is the asymmetric stretch vibration.) The bent transition state has three planes of rotation, = Q QIQ - Accordingly, for reasons that will become immediately apparent, we write k T) as... 

---