Aldol reactions induced diastereoselectivity

Bis(oxazoline)-type complexes, which have been found useful for asymmetric aldol reactions, Diels-Alder, and hetero Diels-Alder reactions can also be used for inducing 1,3-dipolar reactions. Chiral nickel complex 180, which can be prepared by reacting equimolar amounts of Ni(C10)4 6H20 and the corresponding (J ,J )-4,6-dibenzofurandiyl-2,2 -bis(4-phenyloxazoline) (DBFOX/Ph) in dichloromethane, can be used for highly endo-selective and enantioselective asymmetric nitrone cycloaddition. The presence of 4 A molecular sieves is essential to attain high selectivities.88 In the absence of molecular sieves, both the diastereoselectivity and enantioselectivity will be lower. Representative results are shown in Scheme 5-55. 

There is an important difference between Horeau s and Heathcock s examples in that the aldol reaction generates two chirality elements in the bond-forming step. In principle, analysis of such a reaction requires evaluation of two aspects, i.e., the effect of double asymmetric induction on simple and induced diastereoselectivity. The aldol reaction is not particularly suited for this... 

Section A.5). Indeed, three enantiomeric pairs of 2-oxazolidinones have been commercially available since 1991. Enantiomerically pure 4-phenyl-2-oxazolidinone has likewise been prepared from / -aminobenzeneethanol (phenylglycinol)64. Base-catalyzed acylation of the enantiomerically pure 2-oxazolidinones with an appropriate acyl chloride gives the desired 3-acyl-2-oxazolidinones 3, 6 and 9 which have been used extensively in highly diastereoselective reactions of various types such as alkylations, aldol reactions (see Section D.l.3.4.2.4), hydrox-ylations (see Section D.4.1), aminations (see Section D.7.1) and Diels-Alder reactions (see Section D. 1.6.1.6) alkylation giving products with induced chirality in the a-position. 

Few chiral secondary amine organocatalysts have been applied to the asymmetric aldol reaction, in 2008. As an example, Maruoka and Kano have designed a binaphthyl-based amino acid, which was applied to induce the asymmetric aldolisation of both acyclic and cyclic ketones with both aliphatic and aromatic aldehydes performed in DMF. ° Remarkable results were obtained in general with enantioselectivities of up to 99% ee for either cyclic or acyclic ketones, which led to the <2 n-products (Scheme 2.41). Furthermore, these authors have used a closely related binapthyl-based amino sulfonamide to promote the cross-aldol reaction between aldehydes, which yielded the corresponding syn products in moderate to high yields (71-91%) and diastereoselectivities (72-90% de) combined with excellent enantioselectivities (94-99% ee). 

For Aldol and Related Reactions. The TMSI/(TMS)2NH combination can be used for the synthesis of polycyclic cyclobutane derivatives by tandem intramolecular Michael-aldol reaction. TMSI-induced diastereoselective synthesis of tetrahy-dropyranones by a tandem Knoevenagel-Michael reaction, has also been developed. More recently, the facile synthesis of a,a bis(substituted benzylidene)cycloalkanones has been reported, using TMSI (in situ generated) mediated cross-aldol condensations (eq 53). ... 

The principal aim in the development of the modern aldol reaction vas stereochemical control, a field that has been treated in a series of review articles [46, 48-60]. In stereochemical terminology, the topic is discussed in the terms of simple diastereoselectivity and induced stereoselectivity [61]. Except for relatively rare examples w hen is identical w ith R and R is identical w ith R, all aldol additions are stereogenic. If the carbonyl-active compound is either an aldehyde (except formaldehyde - R = H) or a pro-chiral ketone (R R ), addition of the enolate leads to formation of either... 

When, in reactions 1-3, the enolate does not have an a-substituent, e.g. 29 (R = H), induced stereoselectivity is highly desirable. In addition, the corresponding reaction of a-substituted enolates 29 (R H) should not only provide induced stereoselectivity but also simple diastereoselectivity. In this chapter we will not use induced diastereoselectivity as a subdivision applicable to reactions 1 and 2 and induced enantioselectivity for reaction 3 (leading to enantiomeric aldol products), because, irrespective of the stereochemical relationship of the products (diastereomers or enantiomers), the transition states leading to the different stereoisomeric compounds are always diastereotopic, even if the products are enantiomers (reaction 3). The term induced stereoselectivity , which includes the different variants 1-3, is therefore used here [57, 61]. 

In 1999 Holmes and coworkers reported preliminary results on the enantioselective synthesis of the Overman indohzidinone (—)-2369 by a route involving a diastereoselective intramolecular [3 + 2] cycloaddition of nitrones such as 2374. Full experimental details as well as the conversion of 2369 into (+)-aUopumihotoxin 323B (1714) were subsequently published. In this apphcation (Scheme 303), base-induced aldol reaction between 2369 and aldehyde (—)-2375, prepared in eight steps from (S)-3-bromo-2-methylpropanol, produced a mixture of diastereomers (—)-2376. Base-promoted dehydration of the trifluoroacetates gave rise to a single enone (- -)-2377, which was reduced stereoselectively with tetramethyl-ammonium tris(acetoxy)borohydride iyide supra) followed by mild deprotection of the benzyloxymethyl ether with lithium di-tefi-butylbiphenyl (LiDBB) to give the target alkaloid 1714. 

Aldol reaction of ketene silyl acetals with aldehydes (Mukaiyama aldol reaction) mediated by Li Lewis acid has been disclosed (Scheme 3.16) [42]. With 5.0 M LPDE the reaction proceeds smoothly (rt, 1 hour, >99%), although the reaction with 3 mol% of LPDE is less reactive (rt, 5 days, 86%). In the case of a substrate that induces chelation, the reaction is accelerated. Even in a condition with 3 mol% of LPDE, the reaction proceeded relatively smoothly (rt, 20 hours, 67%), and the high diastereoselectivity was gained (synjaniti = >9SI2) from the chelation. 

First reported in 1838, the aldol reaction has remained one of the most powerful tools for the formation of carbon-carbon bonds in organic chemistry. In order to induce diastereoselectivity in an aldol transformation, both enolate geometry and facial selectivity must be controlled. Oxazolidinone auxiliaries facilitate control over both of these parameters. By varying the Lewis aeid in oxazolidinone controlled aldol reaetions, both 1,2-syn and 1,2-anti stereoehemistries can be obtained. ... 

A stereoconvergent reaction without any correlation between the geometry of the enolate and simple diastereoselectivity occurs when fluoride ions are used to induce an aldol addition of enolsilanes to aldehydes. For example, both a 99 1 and a 9 91 mixture of the following (Z)/( )-enolsilane lead predominantly to the formation of the. un-adduct in a highly selective manner, when the addition is mediated by tris(diethylamino)sulfonium difluorotrimethylsili-conate27,28. 

Considerable effort has been devoted to finding Lewis acid or other catalysts that could induce high enantioselectivity in the Mukaiyama reaction. As with aldol addition reactions involving enolates, high diastereoselectivity and enantioselectivity requires involvement of a transition state with substantial facial selectivity with respect to the electrophilic reactant and a preferred orientation of the nucleophile. Scheme 2.4 shows some examples of enantioselective catalysts. 

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