Cram’s rule, and

Cram s Rule and Related Views on Asymmetric Induction... 

Two examples of 1.2-asymmetric induction in the reduction of simple, i.e., nonheteroatom-sub-stituted ketones with dimethylphenylsilane and tris(diethylamino)sulfonium difluorotrimethyl-silicate have been reported4. The predominant stereoisomers are those predicted by Cram s rule, and the diastereomeric ratios suggest that this may be one of the better methods for achieving Cram (Felkin-Anh) selectivity in ketone reductions. 

The stereochemistry of organometallic additions in acyclic carbonyl compounds has also been examined. Additions of Grignard reagents to ketones and aldehydes was one of the reactions that led to the formulation of Cram s rule (see p. 179). Many ketones and aldehydes have subsequently been subjected to studies to determine the degree of stereoselectivity. Cram s rule is obeyed when no special complexing functional groups are present near the reaction site. One series of studies is summarized in Table 7.5. These data show consistent agreement with Cram s rule and the Felkin TS, as discussed in Section 2.4.I.2. 

The addition of methylmagnesium iodide to 2-phenylpropanal is stereoselective in producing twice as much syn-3-phenyl-2-butanol as the anti isomer (entry 5). The stereoselective formation of a particular configuration at a new stereogenic center in a reaction of a chiral reactant is called asymmetric induction. This particular case is one in which the stereochemistry can be predicted on the basis of an empirical correlation called Cram s rule. The structural and mechanistic basis of Cramls rule will be discussed in Chapter 3. 

We will discuss the structural and mechanistic basis of Cram s rule in Chapter 3. As would probably be expected, the influence of a stereogenic center on the diastereoselec-tivity of the reaction is diminished when the center is more remote from the reaction site. 

The more stable the LUMO, the stronger is the interaction with the HOMO of the approaching nucleophile. The observed (Cram s rule) stereoselectivity is then a combination of stereoelectronic effects ftiat establish a preference for a perpendicular substituent and a steric effect that establishes a preference for the nucleophile to approach from the direction occupied by the smallest substituent. 

Grignard reagents add to racemic AT-(2-phcnylpropylidene)alkylamine A-oxides 2 to afford hydroxylamines 3a and 3b in good yield (68-90%) but modest diastereoselectivity (d.r. 67 33 — 83 17)7. The major product 3a is the diastereomer predicted by Cram s rule. 1 shows the attack of the Grignard reagent according to the T elkin-Anh explanation of Cram s rule. 

There are other stereochemical aspects to the reduction of aldehydes and ketones. If there is a chiral center to the carbonyl group, even an achiral reducing agent can give more of one diastereomer than of the other. Such diastereoselective reductions have been carried out with considerable success. In most such cases Cram s rule (p. 147) is followed, but exceptions are known. ... 

Normally, the addition of C-nucleophiles to chiral a-alkoxyaldehydes in organic solvents is opposite to Cram s rule (Scheme 8.15). The anti-Cram selectivity has been rationalized on the basis of chelation control.142 The same anti preference was observed in the reactions of a-alkoxyaldehydes with allyl bromide/indium in water.143 However, for the allylation of a-hydroxyaldehydes with allyl bromide/indium, the syn isomer is the major product. The syn selectivity can be as high as 10 1 syn anti) in the reaction of arabinose. It is argued that in this case, the allylindium intermediate coordinates with both the hydroxy and the carbonyl function leading to the syn adduct. 

Almost 50 years ago, Cram outlined a rule (Cram s rule), which proved to be fruitful in understanding, predicting, and controlling diastereoselectivity induced by a remote stereocenter [258,259], Numerous examples of 1,2 induction have confirmed over the time the predictive character of this rule [260], Afterwards, other important contributions of Felkin and coworkers and Anh... 

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... 

In all the examples commented upon so far, we have dealt with reactions with internal diastereoselective induction. However, when a chiral centre is already present in one of the components [12] we must refer then to a relative diastereoselective induction, and Cram s rule [13] must be taken into account when the chiral centre is present at the a-position of the aldehyde (28). For instance, in the reaction shown in Scheme 9.7 of the four possible diastereomers only two are formed, the Cram-i yn-aldol 30a being the predominant diastereomer (see below 9.3.3). 

If stoichiometric quantities of the chiral auxiliary are used (i.e., if the chiral auxiliary is covalently bonded to the molecule bearing the prochiral centres) there are in principle three possible ways of achieving stereoselection in an aldol adduct i) condensation of a chiral aldehyde with an achiral enolate ii) condensation of an achiral aldehyde with a chiral enolate, and iii) condensation of two chiral components. Whereas Evans [14] adopted the second solution, Masamune studied the "double asymmetric induction" approach [22aj. In this context, the relevant work of Heathcock on "relative stereoselective induction" and the "Cram s rule problem" must be also considered [23]. The use of catalytic amounts of an external chiral auxiliary in order to create a local chiral environment, will not be considered here. 

Relative stereoselective induction and the "Cram s rule problem" "Double stereodifferentiation ". 

Optimizing the angles of attack strongly favours the stereochemistry predicted by Cram s rule compare the pairs of entries 1 and 2, 3 and 5, 6 and 7, 8 and 9. 

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