Aldol condensation stereocenters

The addition of allenyl metal reagents to aldehydes affords homopropargylic alcohols with contiguous OH- and Me-substituted stereocenters, which serves as a complementary approach to the aldol condensation for polyketide synthesis. Marshall has developed this method extensively and this work is the subject of a more detailed review (cf. Chapter 9) [50]. The applications of this method to the synthesis of naturally occurring compounds have also been wide-ranging and a few are highlighted below. 

Scheme 2.6 provides an overall view of our strategy towards solving this problem. As depicted, our late generation synthesis embraces three key discoveries that were crucial to its success. We anticipated that the difficult Cl-Cll polypropionate domain could be assembled through a double stereodifferentiating aldol condensation of the C5-C6 Z-metalloenolate system B and chiral aldehyde C. Two potentially serious problems are apparent upon examination of this strategy. First was the condition that the aldol reaction must afford the requisite syn connectivity between the emerging stereocenters at C6-C7 (by uk addition) concomitant with the necessary anti relationship relative to the resident chirality at C8 (by Ik diastereoface addition). Secondly, it would be necessary to steer the required aldol condensation to C6 in preference to the more readily enolizable center at C2. 

The syntheses in Schemes 13.36 and 13.37 illustrate the use of chiral auxiliaries in enantioselective synthesis. Step A in Scheme 13.36 establishes the configuration at the carbon which becomes C-4 in the product. This is an enolate alkylation in which the steric effect of the oxazolinone substituents directs the approach of the alkylating group. Step C also uses the oxazolidinone structure. In this case, the enolborinate is formed and condensed with the aldehyde intermediate. This stereoselective aldol condensation establishes the configuration at C-2 and C-3. The configuration at the final stereocenter is established by the hydroboration in step D. The selectivity for the desired stereoisomer is 85 15. Stereoselectivity in the same sense has been observed for a number of other 2-methyl-alkenes in which the remainder of the alkene constitutes a relatively bulky 135... 

The intramolecular Michael reaction is also a powerful transformation. In the cyclizations reported by Tetsuaki Tanaka of Osaka University (J. Org. Chem. 2004, 69, 6335), the stereochemical outcome is controlled by the chirality of the sulfoxide. Remarkably, subsequent alkylation or aldol condensation leads to one or two additional off-ring stereocenters with high diastereocontrol. Note that the high stereoselectivity in the cyclization is only observed with the (Z)-unsaturated ester. 

Enantioselective Aldol Reactions. The use of 1 for generating two contiguous stereocenters via an asymmetric aldol condensation has also been investigated,but only with marginal success. For example, reaction of the lithium enolate derived from tert-butyl propionate with the /Y-lithio derivative of 1, followed by condensation with benzaldehyde, provided a mixture of anti and syn aldol products in poor-to-modest % ee (eq 8). 

In evaluating the aldol condensation as a method for building acyclic molecules containing many stereocenters, such as erythronolide-A, there are two types of diastereoselection which must be considered. The first is referred to as simple diastereo-... 

In the aldol condensation reported in reaction A in Fig. 7 only one of the four possible stereoisomeric aldehydes undergoes a completely anti stereoselective reaction with the indicated dialkylboron ketone enolate [35]. If the syn aldol is required, the use of the trichloroti-tanium enolate and of the C-3 epimeric aldehyde is necessary. These results show that two stereocenters of the same reagent can constitute a sort of internally matched or mismatched pair, and can operate synergically or antithetically in determining the steric course of a reaction. 

A.ii. Diastereoselection in the Aldol Condensation. In addition to the alkylation reaction, enolates react with other carbonyl compounds to give aldol or Claisen products, as discussed in previous sections. An aldol condensation with the enolate of 1-phenyl-1-propanone and benzaldehyde generates two new stereocenters and gives two racemic diastereomers (four stereoisomers). These two diastereomers are the racemic anti diastereomer (340 and 343) and the racemic syn diastereomer (341 and 342). Diastereoselectivity in this reaction is dependent on the reaction conditions and the enolate and aldehyde partners, and this section will explore the origins of that diastereoselection. 

The final example illustrates yet another use of the biomimetic approach. Figure 10.9shows a retro-synthetic analysis for Masamune s synthesis of deoxyerythronolide B (213). The biosynthetic building blocks of this and other macrolide antibiotics are known to be acetate and/or propionate units combined head-to-tail, as seen in 213. 7 xhe stereocenters in 213 are clearly shown in the acyclic (seco acid) form of the macrolide 215. The specific biopathway is not utilized but rather modified to include the basic building blocks, seven propionate units (bold lines in 213).Seco acid 215 was constructed by sequential aldol condensation reactions (sec. 9.4.A) of propionaldehyde units, as shown by the disconnections in Figure 10.9. Asymmetric... 

Addition of lithio alkene 636, a formaldehyde-anion equivalent ( CHO), to 808 at low temperature gives adduct 813 with a diastereomeric excess of 92%. Lithium—bromine exchange, desilation, ketalization, and ozonolysis furnishes aldehyde 814 (> 98% de). The last stereocenter is introduced by aldol condensation with R-HYTRA, thus giving 815 as a 91 9 mixture of isomers. Lactonization to 816 followed by reduction with disiamylborane gives 817, which is separated from the accompanying minor isomer by column chromatography. 

P. Kotame, B.-C. Hong, J.-H. Liao, Tetrahedron Lett. 2009, 50, 704—707. Enantioselective synthesis of the tetrahydro-6//-benzo[c]chromenes via domino Michael-aldol condensation control of five stereocenters in a quadruple-cascade organocatalytic multi-component reaction. 

The first clear attempt to address the stereochemical problem presented by the juvabiones was reported by Birch. The plan was to use enone 33 to desymmetrize the 4-substituted cyclohexanone intermediates encountered thus far. The vicinal stereocenters in enone 33 were to be derived from 34 via a retro-aldol condensation. As we will see, 34 was to be prepared via a Diels-Alder reaction, a reaction that frequently has been used to establish vicinal stereochemistry with a high degree of selectivity. 

The use of phosphoric acid ml-lGd for the catalysis of a tandem double F-C reaction gave rise to fluorene derivatives (up to 96% ee) by the reaction between indoles and 2-formylbiphenyl derivatives [74]. Vinyl indole derivatives combined with a,P-unsaturated aldehydes gave rise to functionalized tetrahydrocarbazoles with two or more stereocenters via an intermolecular triple cascade process by means of secondary amine 7a catalysis [75]. Catalyst 7a also promoted a quadruple F-C/Michael/Michael/aldol condensation reaction between indoles, acrolein, and aromatic nitroolefins (Scheme 35.19) [76]. This work provides a straightforward... 

The route employed to prepare indanone 51 involved the cycloaddition-hydrolysis-aldol sequence shown in Scheme 3.9. Accordingly, condensation of cyclopentenone 52 with ynamine 53 (84) afforded the bicyclic enamine 54 which was converted to indanones 51 and 55 by hydrolytic cyclobutane ring opening followed by intramolecular aldol condensation. Interestingly, treatment of 54 with aqueous formic acid yielded indanone 51 which has stereochemistry complementary to that at C(15) and C(20) in reserpine. In contrast, hydrolysis of this substance with aqueous hydrochloric acid afforded the trans-fused indanone 55. Subsequent to this work, the Ficini group found that esterification of 51 followed by photochemically induced addition of methanol afforded adduct 56 which has four of the reserpine stereocenters in place (23). While no further work on this problem has been reported, these preliminary investigations demonstrate a novel use of [2 -h 2] photocycloaddition chemistry in potential approaches to yohimbane alkaloid synthesis. 

The lithium enolate of (2/ ,4/ )-2,4-dimethylcyclohexanone has been condensed with an appropriate aldehyde to prepare several isomers of the antibiotic cycloheximide (equation 61). The major isomer results from reaction on the unsubstituted face of the cyclohexanone ring, and has the same relative stereochemistry at the two new stereocenters as the major isomer in Scheme 1. The second most abundant isomer is o a syn aldol, and results from attack on the more-substimted face of the dimethylcyclohexa-none. 

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