Stereoselective aldol reaction using

Figure 10.19 Oxidative enzymatic generation of dihydroxyacetone phosphate in situ for stereoselective aldol reactions using DHAP aldolases (a), and extension by pH-controlled, integrated precursor preparation and product liberation (b).

Stereoselective Aldol Reactions Using Proline Organocatalysts... 

Stereoselective aldol reactions Using naturally derived compounds to ... 

Scheme 3-80. Stereoselective aldol reactions using enol tris(trimethylsilyl)silyl ethers followed by reactions with various nucleophiles.

Nagao and Fujita realized the highly stereoselective aldol reaction using a-nonsubstituted acyl compounds (Scheme 8.13), which in the Evans aldol reaction afforded the aldol adducts in moderate selectivity. The reaction between an aldehyde and acetylated thiazolidinethione 80 was promoted in the presence of Sn(ll) and the tertiary amine to give (3-hydroxyimide derivative 81. 

Evans and co-workers have established the boron-mediated stereoselective aldol reaction using chiral (3-alkoxyketones (Scheme 8.19). The boron enolate... 

The nib o-aldol reaction using l,l-diethoxy-2-nib oethane is useful for lengthening of the carbon chain of carbohydrates. The reaction of Eq. 3.86 proceeds in a stereoselective way (ds 75%) to give the syn-niho alcohol in 58% isolated yield.The product is converted into 2-amino-2-deoxyaldoses by reaction with Ha/Raney Ni. 

Reagents are available nowadays for acyl anions other than (4). Thus when Heathcock made the ketone (16), which he used in stereoselective aldol reactions, he needed a-hydroxy ketone (17), This required synthon (18) for which an acetylene is not a good choice as there are as yet no means of controlling the reglo-selectivity of hydration of (19). 

In the presence of zinc chloride, stereoselective aldol reactions can be carried out. The aldol reaction with the lithium enolate of /-butyl malonate and various a-alkoxy aldehydes gave anti-l,2-diols in high yields, and 2-trityloxypropanal yielded the syn-l,2-diol under the same conditions.633 Stoichiometric amounts of zinc chloride contribute to the formation of aminoni-tropyridines by direct amination of nitropyridines with methoxyamine under basic conditions.634 Zinc chloride can also be used as a radical initiator.635... 

Scheme 6.4 DERA-catalyzed stereoselective tandem aldol reaction, using chloroacetaldehyde and 2 equivalents of acetaldehyde, yielding (3R,5S)-6-chloro-2,4,6-trideoxyhexapyranoside (1).

Enzymatic synthesis relying on the use of aldolases offers several advantages. As opposed to chemical aldolization, aldolases usually catalyze a stereoselective aldol reaction under mild conditions there is no need for protection of functional groups and no cofactors are required. Moreover, whereas high specificity is reported for the donor substrate, broad flexibility toward the acceptor is generally observed. Finally, aldolases herein discussed do not use phosphorylated substrates, contrary to phosphoenolpyruvate-dependent aldolases involved in vivo in the biosynthetic pathway, such as KDO synthetase or DAHP synthetase [18,19]. 

Highly stereoselective aldol reactions of lithium ester enolates (LiCR1 R2CC>2R3) with (/0-2-(/ -tolylsulfiny I (cyclohexanone have been attributed to intermediacy of tricoordinate lithium species which involve the enolate and the sulfinyl and carbonyl oxygens of the substrates.43 The O-metallated /<-hydroxyalkanoatcs formed by aldol-type reaction of carbonyl compounds with enolates derived from esters of alkanoic acids undergo spontaneous intramolecular cyclization to /1-lactones if phenyl rather than alkyl esters are used the reaction has also been found to occur with other activated derivatives of carboxylic acids.44... 

Samarium(II) iodide mediates highly stereoselective aldol reactions of acylaziridines with aldehydes, typically accompanied by ring opening, producing useful /5-amino-/S -hydroxy derivatives.123... 

To achieve a stereoselective aldol reaction that does not depend on the structural type of the reacting carbonyl compounds, many efforts have been made to use boron enolates. Based on early studies by Mukaiyama et al.8a and Fenzl and K0ster,8b in 1979, Masamune and others reported a highly diastereoselective aldol reaction involving dialkylboron enolates (enol borinates)9... 

Oppolzer et al. completed an asymmetric synthesis of (-)-denticulatin A (48) by using a syn-aldol methodology as a key feature18 (Scheme 2.1r). The diethyl-boron enolate of N-propionyIbomanesultam (46-ent) obtained from diethylboron triflate and Hunig s base underwent a highly stereoselective aldol reaction with the mes o-dialdchydc 49 to furnish the lactols 50 in 74% yield as a 2 1 epimeric mixture. When the lactols 50 were treated with 1, 2-ethanedithiol in the presence... 

Dihydropyrones are valuable intermediates for the synthesis of a variety of substituted tetrahydropyran rings. Recently, stereoselective aldol reactions of p-chlorovinyl ketones using the dienol boronate derivative derived from chiral IpC2BOTf was utilized for enantioselective formation of dihydropyrones. No detectable racemization was reported on the cyclization step (eq 4). ... 

Mukaiyama and Kobayashi et al. have developed the use of Sn(OTf)2 in diastereose-lective and enantioselective aldol-type reactions [26,27]. Initially, the stereoselective aldol reactions were performed with a stoichiometric amount of Sn(OTf)2 [28], The reaction between 3-acylthiazolidine-2-thione and 3-phenylpropionaldehyde is a representative example of a diastereoselective syn-aldol synthesis (Eq. 17). 

In addition to enol silyl ethers, an optically active boryl enolate underwent the highly anri-stereoselective aldol reaction with a wide variety of aldehydes in the presence of TiCU (Eq. 34) [120]. The vinyl sulfides shown in Eq. (35) reacted with a,fi-unsaturated ketones via the 1,4-addition pathway in the presence of a titanium salt, but the reaction was followed by the cleavage of a carbon-carbon bond in the cycloalkane to give open chain products in a stereoselective manner [121]. The 1,2-type addition was observed, if the olefinie acetal was used instead of the corresponding carbonyl compound, as shown in Eq. (36) [121], The successive scission of the carbon-carbon bond took place analogously to give the same type of products as shown in Eq. (35). 

In accordance with this model one finds diastereoselectively anti products on reaction of aldehydes with ( )-allyl compounds, whereas allyl systems with the (Z)-configuration give mainly syn products and it is even possible to effect asymmetric induction. As the double bond of the product can be oxidatively cleaved to a CW3 group, the reaction can be regarded as a stereoselective aldol reaction, an aspect which explains the widespread interest in this type of reaction. With heterosubstituted allylic anions it is sometimes possible to effect predominantly y-attack with different electrophiles by the choice of the heteroatom.2 For instance it is well known that with sulfur substituents like —SR, —SOR or —SOjR the a-attack dominates, but doubly lithiated allenethiol possesses high y-reactivity and can be used as a homoenolate anion equivalent in reaction with electrophiles such as alkyl halides (Scheme 7). ... 

In a related manner, -keto imide 25 also functions as a versatile dipropionate reagent with three different stereoselective aldol reactions being reported by the Evans group (Scheme 9-9). Both syn aldol isomers, 26 and 27, are available from either the titanium or tin(II) enolates [14] and the anti adduct 28 can be accessed using the dicyclohexyl boron enolate [15], While a chiral auxiliary is present, it is the ketone a-stereocenter that controls the r-facial selectivity in these aldol reactions. 

---