Cram-product

Methylmagnesium chloride has been added to various d-(4-substituted-phenyl) <5-oxo esters 15 (X = H, Cl 13, F, Cl, Br, OC11,) which provides the diastereomeric -lactones 1642. The electronic properties of the phenyl 4-substituent have no significant influence on the diastereoselectivity. Except for the 4-methoxyphenyl compound, which is unreactive even at 60 °C, a ratio of ca. 40 60 in favor of the anti-Cram product is observed at 60 "C in tetrahydrofuran as reaction solvent. Lowering the reaction temperature to 0 °C slightly increases the anti-Cram selectivity in the case of the 4-fluoro-, 4-chloro-, and 4-bromo-substituted compounds. On the other hand, a complete loss of reactivity is observed with the <5-phenyl- and <5-(4-methylphenyl)-substituted h-oxo esters. 

The diastereofacial selectivity of Lewis acid promoted reactions of allylsilancs with chiral aldehydes has been thoroughly investigated58. Aldehydes with alkyl substituted a-stereogenic centers react with a mild preference for the formation of Cram products, this preference being enhanced by the use of boron trifluoride-diethyl ether complex as catalyst58. 

As demonstrated, the organozinc reagent provides exclusively the Cram product, while the organomagnesium reagent shows poor diastereofacial selectivity in the addition to 1 and even reverses the selectivity in the addition to 4. 

Sometimes the Lewis acid that coordinates with the carbonyl oxygen is sufficiently bulky that it seriously influences the stereochemistry of attack. Sometimes these reaction products, which seem opposite of the expected Cram Rule analysis, are termed "anti-Cram" products. Compare the "normal" situation with the influence of a sterically bulky Lewis acid ... 

Additions of hydride donors to oc-chiral carbonyl compounds that bear only hydrocarbon groups or hydrogen at C-oc typically take place with the diastereoselectivities of Figure 10.14. One of the resulting diastereomers and the relative configuration of its stereocenters are referred to as the Cram product. The other diastereomer that results and its stereochemistry are referred to with the term anti-Cram product. 

Cram product Felkin-Anh product Cram chelate product... 

After Cram had discovered the selectivities now named after him, he proposed the transition state model for the formation of Cram chelate products that is still valid today. However, his explanation for the preferred formation of Cram products was different from current views. Cram assumed that the transition state for the addition of nucleophiles to a-alkylated carbonyl compounds was so early that he could model it with the carbonyl compound alone. His reasoning was that the preferred conformation of the free a-chiral carbonyl compound defines two sterically differently encumbered half-spaces on both sides of the plane of the C=0 double bond. The nucleophile was believed to approach from the less hindered half-space. 

Here, the Curtin-Hammett principle will be proven using the example of the reaction pair from Figure 10.17. The Cram product forms from a conformer C of the a-chiral aldehyde via the Cram transition state D with the rate constant k. The corresponding rate law is is shown in... 

Equation 10.11 for the rate of formation of the anti-Cram product is derived in a similar way ... 

By inserting Equation 8.9 into Equation 8.4, we finally obtain d[Cram product]... 

Yield of Cram product (nm I a.Cram Faanti-Cram... 

Yield of anti-Cram product Lmti-Cram... 

In the first reported example of asymmetric induction using organotitanium reagents, methyltitanium triisopropoxide 6 was reacted with 124 (0 °C/2 h, THF) 72). The ratio of Cram to anti-Cram product 125 126 turned out to be 88 12 (Table 6) which is higher than that observed for CH3MgX (66 34 = or CH3Li (65 35) 9S). 

As already shown in Section B.I, certain organotitanium reagents readily form isolable, octahedral 1 2 adducts with such donor molecules as THF, glyme, thio-ethers, amines and diamines1,19) (Equation 47). In case of methyltitanium trichloride 17, structural data show the methyl group to occupy the equatorial position 96). In order to test whether such molecules undergo stereoselective addition to aldehydes (Equation 47), we reacted 134, 135 and 136 (prepared from TMEDA, glyme and THF, respectively) with 2-phenylpropanal 12491. The 125 126 ratios of 80 20, 82 18 und 85 15 show that the Cram product is preferred in all cases... 

Of the large number of reducing agents, the most useful are DIBAH and lithium tri-i -butylborohydride. Regardless of the nature of R, DIBAH reduces 3 mainly to the alcohol 4 (the tzn/i-Cram product) in 60-80% de. Reduction with L-Selectride usually proceeds in the opposite sense and in aeeordanee with Cram s chelate rule, but high selectivity is observed only when R is a primary or tertiary alkyl group. 

Stereoselective catalysis in zeolites is still one of the ultimate goals in zeolite science. Earlier work in this field was summarized recently [4]. More recently, Mahrwald et al. [95] reported that the addition of aluminophosphate molecular sieves in the liquid phase alkylation of a-chiral benzaldehydes by butyllithium results in an increased proportion of the so-called Cram product in the diastereomeric mixture. It is argued that in this Grignard type reaction the adsorption of the reactants on the molecular sieves favors the attack at the sterically less hindered position of the molecule. This shape selectivity effect is even observed when the reactant is adsorbed at the outer crystal surface, as demonstrated for the case of the small-pore AIPO4-I7. 

Entries 1-4 in Table 3 illustrate the tendency for a Cram selective process in additions to aldehydes of type (4 equation 1). In contrast, when (4) is treated with the aluminum additive (1) prior to exposure to organometallics, the nucleophilic addition results in an anti-Cram product. The resulting facial selectivity may be most easily rationalized by considering transition state structure (6), which defmes the anti-Cram face of the aldehyde to be less hindered by virtue of precoordination of the aluminum reagent (1) to the less sterically demanding Cram face. For example, comparison of entries 2, 6 and 9 to the corresponding entries 5, 8 and 10 in Table 3 illustrates the dranuitic effect that the aluminum additive (1) has on the facial selectivity of the reaction. This approach to anti-Cram selectivity, however, does suffer... 

Crain s experiments using 2-phenylpiopanal with various traditional organometallic reagents have already been mentioned. - The same substrate was also subjected to several Ti and Zr complexes (equation 28),the results of which are summarized in Table 5. 2-Phenylbutanal, when treated with MeTi(OPi )3 in EtaO, affords preferentially the Cram product (87 13). Zri derivatives, like MeZr(OPri)3, follow the same tendency although in some cases the results are somewhat less appeal-... 

Less acidic than Ti and Zi chloroderivatives, MeTi(OPr )3 perfoims chelation-controlled addition to chiral alkoxy ketones as well as or better than organomagnesium compounds, but fails to chelate to aldehydes or hindered ketones. Should the formation of a cyclic chelation intermediate be forbidden, the reaction is subject to nonchelation control, according to Ae Felkin-Anh (or Comforth) model. Under these circumstances, the ratio of the diastereomeric products is inverted in favor of the anti-Cram product(s). In the case of benzil (83 Scheme 7) this can be accounted for by the unlikely formation of a cyclic intermediate such as (85), and thus the preferential intermediacy of the open chain intermediate (86) that leads to the threo compound (88). This view is substantiated by the fact that replacement of titanium with zirconium, which is characterized by longer M—O bonds, restores the possibility of having a cyclic intermediate and, as a consequence, leads to the erythro meso) compound (87) thus paralleling the action of Mg and Li complexes. 

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