Anti-aldol-type adducts

Sibi et al. demonstrated for the first time that intermolecular radical addition to a,P-disubstituted substrates (12) followed by hydrogen atom transfer proceeded with high diastereo- and enantioselectivities (Scheme 4.6) [4]. In particular, a chiral bis(oxazoline)s-Mgl2 catalytic system was applied to the enantioselective and highly diastereoselective antijsyn = 99/1) synthesis of anti-aldol-type adducts (13). This is noteworthy because there have been few examples of highly selective methods for preparing anti aldol despite the array of solutions for the synthesis of syn aldol. The key to increasing the reactivity for a,P-disubstituted substrate (12) was N-H imide templates that relieve problems, and the promotion of Lewis acid catalysis via... 

The following examples show how open and closed transition states may be invoked by the choice of the reaction type. For instance, aldol-type addition normally proceeds via a closed transition state because the metal ion is shifted from the enolate oxygen to the carbonyl oxygen in an ene-like mechanism ( Zimmerman-Traxler transition state 9). The crucial interactions in the Zimmerman-Traxler transition state 16 are those between the 1,3-diaxially oriented substituents around the chair-like structure. R2 adopts the location shown, thus R3 avoids the 1,3-interaction and assumes an equatorial position. Therefore, the diastereomeric ratio depends mainly on the ( )/(Z) configuration of the enolate. Whereas (Z)-enolates 13 afford syn-config-urated enantiomers, 17 and 18, the corresponding ( )-enolates 14 lead to anti-configurated adducts 19 and 20 10. 

It should be noted that in the absence of the organocatalyst the E enolate affords mainly the syn adduct (syn/anti ratio 49 1, 92% yield, reaction temperature 0 °C [82, 84]) whereas in the presence of (S,S)-52 by dramatic reversal in diastereoselectivity the anti-aldol product anti-53 is preferentially formed (anti/syn ratio 50 1 anti 93% ee) [84], Other types of chiral phosphoramide, e.g. based on optically active 1,2-cyclohexyldiamine, had less satisfactory catalytic properties. 

In this case the trityl-protected lactaldehyde 882 is prepared from trityl lactate 463 by reduction of the ester with lithium aluminum hydride followed by oxidation under Swem conditions. An aldol-type addition of titanated furan produces a 6 1 mixture of anti and syn adducts from which the pure anti diastereomer 883 is isolated by column chromatography (55% yield, >95% de). Treatment of 883 with bromine in methanol followed by acidic hydrolysis gives the ulose 885. A 1,4-reduction to 886, acetylation to 887, and ozonolysis affords the unstable aldehyde 888, which is immediately coupled with 2,5,6-triamino-4-pyrimidinol (889) to afford 890 [237]. 

It is self-evident that the transition state hypotheses discussed above are exclusively relevant to kinetically controlled aldol additions. Although this type of reaction control is the rule when preformed enolates are used, one should be aware that the reversibility of aldol additions cannot be excluded a priori and in any instance. In aldol reactions of preformed enolates, reversibility becomes noticeable in equilibration of syn aldolates with anti aldolates rather than in an overall low yield as found in the traditional aldol reaction. Considering the chair conformations of the syn and the anti aldolates, the former seem to be thermodynamically less stable, because of the axial position of the a-substituent R. This situation is avoided in the anti adduct (Eq. 

Aldol condensation.1 These O-silyl enol derivatives of amides are available by hydrosilylation of a,P-unsaturated amides catalyzed by Wilkinson s catalyst. A typical reagent of this type, 1, reacts with aldehydes in the absence of a catalyst to form aldol adducts (2) with unusual anti-selectivity. This silyl aldol reaction can be ex-... 

The stereochemical outcome of the new FucA was indistinguishable compared to that obtained for the wild type. However, while the (J )-N-Cbz-aminoaldehydes yielded the anti(3i ,4i )-configured aldol adduct in high diastere-oselectivity (>2 98 syn iR,4-S)/anti(iR,4R) ratio), the (S) enantiomers depended on the aldehyde. In the extreme situation, R)-N-Chz prolinal derivatives ((J )-7a,b) gave exclusively the anti 3R,4-R) adduct whereas the S counterparts ((S)-7a,c,d) rendered the syn(3i ,4S) one. Protein molecular models were built to gain insight into the acceptor binding mode that led to this distinct stereochemical outcome [19]. 

R)-lOa) and rac-N-Cbz-2-(piperidin-4-yl)acetaldehyde ((rac)-lOb) as aldehyde acceptors (Scheme 16.4), which can be accessed from the commercially available alcohol precursors. fucA wild type as weU as FucA ", FucA , and mutants provided very low yields, and thus were not satisfactory from a preparative point of view. RhuA gave the best results using DHAP as donor (Scheme 16.4). The aldol addition of DHAP to (S)-N-Cbz-piperidin-2-carbaldehyde (S)-10a furnished the sy (3 R,4S)-configured aldol adduct, which is consistent with the results obtained with (S)-N-Cbz-proUnal derivatives [19]. On the other hand, its enantiomer (R)-10a furnished the (5R)-lla adduct as 2 3 syn(3R,4S)/anti(3R,4R) mixture. This was not observed in the case of the (R)-N-Cbz-proHnal, which exclusively provided the syn... 

The synthesis of iminocyclitols was also accomplished using aldol additions of the unphosphorylated analogs of DHAP, dihydroxyacetone (DHA). As mentioned before, RhuA ° and RhuA wild type/borate buffers proved their utility with examples reported in the literature [113, 128, 129]. High conversions, for example 90-99%, were accomplished with RhuA/borate buffer, which are comparable to those achieved under different optimized conditions using DHAP donors. Importantly, the full equivalence of the stereochemical outcome with the additions of DHAP indicated the unbiased orientation of DHA in the active site of RhuA catalyst. Remarkably, the additions of DHA-borate to (R)-N-Cbz-aminoaldehydes furnished exclusively the anti (3R,4R) configured adducts, whereas the (S)-N-Cbz-aminoaldehydes always yielded the syn (3R,4S) adducts. This high stereoselectivity toward the R enantiomers of N-Cbz-aminoaldehydes at 25 °C contrasted with the different syn/anti mixtures of aldol adduct obtained using DHAP [24]. 

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