Carbonyl compounds stereocontrol

TTie condensation of fluormated carbonyl compounds is a versatile approach to the stereo- and regioselective construction of specifically tluonnated materials It is possible to use fluormated reactants in vanous oxidation states and to utilize them either as the nucleophilic or electrophilic reaction partners Stereocontrol in those processes using the fluormated carbonyl compounds m a nucleophilic fashion has lagged behind the achievement of higher yields... 

The reactions of allylmetal reagents with carbonyl compounds and imines have been extensively investigated during the last two decades [1], These carbon—carbon bondforming reactions possess an important potential for controlling the stereochemistry in acyclic systems. Allylmetal reagents react with aldehydes and ketones to afford homo-allylic alcohols (Scheme 13.1), which are valuable synthetic intermediates. In particular, the reaction offers a complementary approach to the stereocontrolled aldol process, since the newly formed alkenes may be readily transformed into aldehydes and the operation repeated. 

Silyltitanation of 1,3-dienes with Cp2Ti(SiMe2Ph) selectively affords 4-silylated r 3-allyl-titanocenes, which can further react with carbonyl compounds, C02, or a proton source [26]. Hydrotitanation of acyclic and cyclic 1,3-dienes functionalized at C-2 with a silyloxy group has been achieved [27]. The complexes formed undergo highly stereoselective addition with aldehydes to produce, after basic work-up, anti diastereomeric (3-hydroxy enol silanes. These compounds have proved to be versatile building blocks for stereocontrolled polypropionate synthesis. Thus, the combination of allyltitanation and Mukayiama aldol or tandem aldol-Tishchenko reactions provides a short access to five- or six-carbon polypropionate stereosequences (Scheme 13.15) [28],... 

The sequences of spiroannulation-secobromination or, better, spiroannulation-secosulfenylation offer great versatility for geminal alkylation as summarized in Eq. 123. The fact that spiroannulation of carbonyl compounds proceeds with stereocontrol converts these transformations into stereocontrolled carbonyl group elaborations. 

Aldol reactions have also been used as a means of macrocychzation in total synthesis and were quite successful in some cases. However, over a broader spectrum of substrates, the results are unpredictable at best and yields and stereochemical outcome vary greatly. The predominant reasons are difficulties in selective enolate formation in multi-carbonyl compounds, competing and equilibrating retro-aldolizations—especially with polyketides, which often possess several aldol moieties—and intermolecular instead of intramolecular reaction preference. Whereas most of these drawbacks may be overcome, substrate-independent stereocontrol plays a crucial role. At least one new stereocenter is formed during a macroaldolization, and because of the folding constraints involved, its configuration cannot be adequately predicted. Therefore, this can be useful in special cases but with the current possibilities is not the method of choice for a general diversity-oriented synthesis. 

As previously noted (Scheme 1), prior to the explosion of interest in iminium ion catalysis as a platform for the activation of a,P-unsaturated carbonyl compounds in 2000, Yamaguchi [29-33] and Taguchi [34] showed that proline derived bi-func-tional catalysts could provide an effective platform for the ion-pair controlled conjugate addition of malonates and nitroalkanes to a, 3-unsaturated ketones with good levels of stereocontrol. 

The introduction of umpoled synthons 177 into aldehydes or prochiral ketones leads to the formation of a new stereogenic center. In contrast to the pendant of a-bromo-a-lithio alkenes, an efficient chiral a-lithiated vinyl ether has not been developed so far. Nevertheless, substantial diastereoselectivity is observed in the addition of lithiated vinyl ethers to several chiral carbonyl compounds, in particular cyclic ketones. In these cases, stereocontrol is exhibited by the chirality of the aldehyde or ketone in the sense of substrate-induced stereoselectivity. This is illustrated by the reaction of 1-methoxy-l-lithio ethene 56 with estrone methyl ether, which is attacked by the nucleophilic carbenoid exclusively from the a-face —the typical stereochemical outcome of the nucleophilic addition to H-ketosteroids . Representative examples of various acyclic and cyclic a-lithiated vinyl ethers, generated by deprotonation, and their reactions with electrophiles are given in Table 6. 

The class of ene reactions which involves a carbonyl compound as the enophile and what we refer to as the carbonyl-ene reaction [2c], constitutes a useful synthetic method for the stereocontrolled construction of carbon skeleton using either a stoichiometric or catalytic amount of various Lewis acids [3,4] (Scheme 8C.1). From the synthetic point of view, the carbonyl-ene reaction should—in principle—constitute a more-efficient alternative to the allylmetal carbonyl addition reaction, which has currently been one of the most useful methods for stereocontrol [5],... 

The reduction of double bond-containing functionalities, especially alkenes and carbonyl compounds, is an important methodology used in synthetic elaboration. In this section the stereocontrolled reduction of aldehydes, ketones and C=N-containing compounds and the catalytic hydrogenation of alkenes are covered, among other reductions. The emphasis here is placed on stereocontrolled reactions. 

In the past, Darzens methodology was primarily used for the synthesis of aldehydes and ketones, as a homologation reaction without any consideration of stereocontrol in the epoxide formation. For this sequence, saponification of the a,P-epoxy ester followed by decarboxylation gives the substituted carbonyl compound ... 

In general, the enantiomeric excess and the configuration of the optically active alcohols are strongly dependent on the structure of the starting carbonyl compound many examples of diastereo-selective reduction have also been reported. The reduction of an epoxy ketone is accompanied by a stereocontrolled epoxide hydrolytic opening to afford a racemic triol, diastereomerically pure (eq 4). ... 

The examples outlined in this chapter show that carbohydrates are efficient stereodifferentiating auxiliaries, which offer possibilities for stereochemical discrimination in a wide variety of chemical reactions. Interesting chiral products are accessible, including chiral carbo- and heterocycles, a- and 3-amino acid derivatives, 3-lactams, branched carbonyl compounds and amines. Owing to the immense material published since the time of the earlier review articles on carbohydrates in asymmetric synthesis [9,10], the examples discussed in this chapter necessarily focused on the use of carbohydrates as auxiliaries covalently linked to and cleavable from the substrate. Given the scope of this chapter, a discussion of other interesting asymmetric reactions has not been permitted — for example, reactions in which carbohydrate-derived Lewis acids, such as cyclopentadienyl titanium carbohydrate complexes, exhibit stereocontrol in aldol reactions [180]. Similarly, processes in which in situ glycosylation induces reactivity and stereodifferentiation — for example, in Mannich reactions of imines [181] — have also been excluded from this discussion. 

Stereocontrol in nucleophilic addition to carbonyl compounds 1.5.3.1.4 Addition to chiral alkoxycarbonyl compounds 1.53.1.5 Addition to a,p-unsaturated carbonyl compounds... 

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