Bulky aluminum reagent

In fact, the highest anti-Cram selectivity reported to date (96% de) was observed with the MAT-mediated addition of methylmagnesium bromide to 2-(l-cyclohexenyl)propanal3 i 36. The stereochemical outcome of this addition reaction can be explained as follows on treatment of the carbonyl compound with the large aluminum reagent, the sterically least hindered complex 9 is formed. Subsequent addition of the nucleophile from the side opposite to the bulky aluminum reagent produces the anti-Cram diastereomer preferentially. 

Selective reduction of ketones.1 This reagent can be used to effect selective reduction of the more hindered of two ketones by DIBAH or dibromoalane. Thus treatment of a 1 1 mixture of two ketones with 1-2 equiv. of 1 results in preferential complexation of the less hindered ketone with 1 reduction of this mixture of free and complexed ketones results in preferential reduction of the free, originally more hindered, ketone. An electronic effect of substituents on a phenyl group can also play a role in the complexation. This method is not effective for discrimination between aldehydes and ketones, because MAD-complexes are easily reduced by hydrides. MAD can also serve as a protecting group for the more reactive carbonyl group of a diketone. The selectivity can be enhanced by use of a more bulky aluminum reagent such as methylaluminum bis(2-f-butyl-6-( 1,1-diethylpropyl)-4-methylphenoxide). 

Maruoka, K. Synthetic Utility of Bulky Aluminum Reagents as Lewis Acid Receptors. In Lewis Acid Reagents-, Yamamoto, H., Ed. Oxford University Press Oxford, 1999 pp 5-29. 

How can highly selective processes be developed using Lewis-acid reagents I would like to offer one typical example in this field of research—the chemistry of bulky aluminum reagents (Eqs 4 and 5) [10]. 

Benzaldehyde and the bulky aluminum reagent ATPH, for example, form a relatively stable complex which when exposed to an alkyllithium reagent from outside the system generates the cyclohexadiene derivative in high yield. The reaction proceeds not via the usual 1,2-addition pattern but through the unique 1,6-addition process, which is very difficult in the absence of such a bulky Lewis-acid catalyst (Eq. 6) [11]. 

The exceedingly bulky aluminum reagent aluminum tris(2,6-di-rert-butyl-4-methyl-phenoxide) (ATD) [140] was found to be superior to ATPH or MAD as a carbonyl protector in the alkylation of ynones [141]. Initial complexation of 3-octyn-2-one (13S) in toluene with ATD and subsequent addition of a hexane solution of BuLi at -78 °C generated 1,4 adduct 136 in 93 % yield together with a small amount of the 1,2 adduct (Sch. 103). 

Scheme 5 accounts for the observation in Eq. (206). At first, the bulky aluminum reagent occupies a less-hindered space of the substrate so that an incoming nucleophile should approach the ketone from its superficially more-hindered side (i.e., by axial attack). The change in selectivity here has been considered to arise from a steric control, rather than transmetallation of the Grignard reagent to an aluminumate complex before the addition. Other selective reactions based on the same notion have also been developed [451-453]. 

This seminal observation has recently been utilized by Yamamoto to develop an approach for the stereoselective and site selective addition of organometallics to carbonyl substrates. The approach makes use of the very bulky aluminum reagent (1), which is readily prepared in situ by exposure of trimethyl-aluminum to a toluene solution of 2,6-di-f-butyl-4-alkylphenols (molar ratio 1 2) at room temperature. 

It may be recalled that an opposite stereochemical result is obtained by employing the bulky aluminum reagents MAD and MAT. This observation has been explained by invoking out-of-plane complexation of the Lewis acid in a direction which would prevent equatorial attack (Figure 48). The X-ray crystal structure of methyl toluate complexed with a bulky aluminum Lewis acid is fully consistent with tius model7 However, it is worth mentioning that a six-membered transition state, perhaps involving [Me2( ArO)Al] Li, has not been considered as an alternative mechanism. 

Aldol reactions. Complexation of the carbonyl with the bulky aluminum reagent forces an enone to undergo aldol reaction at the y-position. 

Design, Preparation and Availability of Bulky Aluminum Reagent... 

Among a series of bulky aluminum reagents.. MAD and ATPH form coordination complexes with less hindered or more basic ketones preferentially, where MAD allows the activation of ketone carbonyls, whereas ATPH stabilizes, for subsequent nucleophilic alkylations (Scheme 2-20) (50]. These results are in contrast to the MAD-DIBAL reduction system in which MAD serves as an effective stabilizer for sterically less-hindered ketones (Scheme 2-21) [51],... 

Furthermore, saturated aldehydes are somewhat less basic than saturated ketones or esters, resulting in reversible complexation even with bulky aluminum reagents. However, whether the equilibrium [Lewis acid -i- base Lewis acid-base complex] is reversible or irreversible, the selective functionalization of more labile or sterically less-encumbered aldehydes is facile using bulky or mild Lewis acids. 

Examination of electronic and thermodynamic factors in the aforementioned conventional enolate formation revealed that steric factors were of fundamental importance in fhe reaction. One alternative is to complex a carbonyl compound with a bulky Lewis acid (Fig. 6.13). Bulky aluminum reagents usually form relatively stable 1 1 complexes irreversibly wifh carbonyl compounds. We first hypothesized that even in the presence of a strong base (LDA or LTMP), a steric environment applied in the aluminum-carbonyl complex would kinetically adjust site-selective deprotonation of carbonyl compounds which offer multiple sites for enohzation and kinetically stabilize fhe resulting bulky enolates by retarding the rate of proton transfer or other undesirable side reactions. These fundamental considerations found particular application in fhe formation and reaction of novel aluminum enolates. 

Obviously, the coordinated aldehyde is electronically activated but sterically deactivated with bulky aluminum reagents. The selective functionalization of more sterically hindered aldehydes was accomplished by the combined use of MAPH and alkyllithiums (RLi, where R = -Bu or Ph) [129]. In this system, MAPH acted as a carbonyl protector of a less hindered aldehyde such as 104, and therefore the carboanions reacted preferentially with more hindered carbonyl groups (Scheme 6.106). It should be noted that alkyllithium reagents could react with aldehydes in the absence of the aluminum reagent. 

Conjugate addition. Coordination of the very bulky aluminum reagent to the oxygen of a carbonyl disfavors attack of the latter by carbanions. 

Asymmetric Hetero-Diels Alder Reaction Catalyzed by Chiral Organoaluminum Reagent. Hetero-Diels-Alder reaction, an important organic transformation for the synthesis of a variety of heterocycles, was found to be catalyzed by the optically pure bulky aluminum reagent. ... 

For these, several chiral Lewis acid catalysts, which have the C-2 symmetry element, were designed and tested for various asymmetric syntheses, and in 1985 we reported a zinc reagent and in 1988 a bulky aluminum reagent (Scheme 8) [15, 16]. The zinc reagent was used for asymmetric cyclization of unsaturated aldehyde and the aluminum catalyst for asymmetric hetero-Diels-Alder reaction with Danishefsky diene. Both catalysts effectively discriminate the enantioface of aldehydes for reactions. 

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