Anti-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. 

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. 

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

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). 

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

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... 

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. 

MgBiyTHP Pericyclic/chelating with a-alkoxy aldehydes trans anti-Cram products with chelatable aldehydes, cis Cram products with nonchelatable aldehydes... 

Some examples of combined syn-anti and diastereofacial selectivity employing /V-n-propyl- and N-isopropyl-aldimines, derived from a-phenylpropionaldehyde, and crotyl-9-BBN, -magnesium and -zirconium reagents have been reported by Yamamoto et al. Cram selectivity, which is observed in the analogous reactions of these chiral imines with allyl organometallics (see Section 4.3.2.1.2i), is preserved as ratios of Cram anti-Cram products are consistently about 8 1. Anti selectivity is also observed but the ratios do not exceed 7 3. The weak anti selectivity parallels that observed in reactions of crotyl-9-BBN with branched a-alkylaldimines. Since syn-anti selectivity is influenced more by the a-substituent than by the A-substituent of the aldimine, more synthetically useful levels of combined syn-anti and diastereofacial selectivity might be expected in other series of a-substituted aldimines. 

This gives tlic anti-Cram" product... 

An efficient stereoselective reduction of 22-keto-23-acetylenic steroid to anti-Cram product 22-(R)-hydroxy-23-acetylenic steroid and Cram product 22-(S)- hydroxy-23-acetylenic steroid has been achieved using (R)-Alpine-Borane [(-i-)-a-pinene, 92% ee] (125 1, R-.S) and L-selectride (lithium tri-sec-butylboro-hydride) (1 11, R S), respectively [19] (Chart 26.7). (S)-Alpine-Borane (2 M in THE) prepared from (-)-a-pinene (92% ee) provides unexpectedly low 1 2.7, R S ratio due to the influence of the a-chiral center at C-20 of the steroid, and also the reduction is much slower than with (R)-Alpine-Borane. 

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