Re-face selectivity

Furanones are a class of chiral dienophiles very reactive in thermal cycloadditions. For example, (5R)-5-(/-menthyloxy)-2-(5H)-furanone (28) underwent Diels Alder reaction with cyclopentadiene (21) with complete re-face-selectivity (Equation 2.10), affording a cycloadduct which was used as a key intermediate in the synthesis of dehydro aspidospermidine [27]. 

BINAPHOS] would favor the. ti-face selection by TS I and the re-face selection by TS II. This mixed result can explain the much lower enantioselectivities (<25% ee) observed when using Rh(R,R)-BINAPIIOS catalyst, that is a diastereomer of HRh(CO)[(R,S)-BINAPHOS ( )] ... 

The Cp(/f,f )-Ti[Crotyl] reagent is Si face selective and the Cp(,5,5)Ti[Crotyl] reagent is Re face selective. A clear drawback... 

Stereochemistry of the major products 61a-d was confirmed by the procedures of chemical conversion and X-ray analysis. The excellent re face selective alkylation into a presumed cyclic acylimine derived in situ from 60 was discussed and rationalized in terms of the most likely transition state, i.e., 63 (86JA4673). 

In 1978, Larcheveque and coworkers reported modest yields and diastereoselectivities in alkylations of enolates of (-)-ephedrine amides. However, two years later, Evans and Takacs and Sonnet and Heath reported simultaneously that amides derived from (S)-prolinol were much more suitable substrates for such reactions. Deprotonations of these amides with LDA in the THF gave (Z)-enolates (due to allylic strain that would be associated with ( )-enolate formation) and the stereochemical outcome of the alkylation step was rationalized by assuming that the reagent approached preferentially from the less-hindered Jt-face of a chelated species such as (133 Scheme 62). When the hydroxy group of the starting prolinol amide was protected by conversion into various ether derivatives, alkylations of the corresponding lithium enolates were re-face selective. Apparently, in these cases steric factors rather than chelation effects controlled the stereoselectivity of the alkylation. It is of interest to note that enolates such as (133) are attached primarily from the 5/-face by terminal epoxides. ... 

PH3 ligands were followed by force field calculations on the real system. In this manner, it was concluded that both transition states TS I and TS II show lower energies for re-face than si-face styrene insertion. An interesting issue of this work is that the RhH(CO) (i ,i )-BINAPHOS would result in si-face selection by TS I and re-face selection by TS II. This matches the experimental results that the Rh-(P,P)-BINAPHOS complex gives aldehydes in much lower ees than the Rh-(R,S)-BINAPHOS complex. Similarly, the enantioselectivity observed for (Z)-2-butene was nicely explained with the same model. 

The remarkable advantage of this C—C bond formation is that the reaction proceeds in a stereoselective manner. From the screening of microorganisms [71,74,80-81,86], two types of PDase that show complementary enantiofacial selectivity have been found. PDase from yeast (Saccharomyces) catalyzes the attack of TPP-thiazoUum intermediate on the si face of the aldehyde acceptor as shown in Eq. (23). In contrast, the enz)me from Zymo-monas mobilis shows re face selectivity to result in the opposite enantiomer of hydroxy... 

The hand-in-glove fit of a chiral substrate into a chiral receptor is relatively straightforward, but it s less obvious how a prochiral substrate can undergo a selective reaction. Take the reaction of ethanol with NAD+ catalyzed by yeast alcohol dehydrogenase. As we saw at the end of Section 9.13, the reaction occurs with exclusive removal of the pro-R hydrogen from ethanol and with addition only to the Re face of the NAD+ carbon. 

For oxathiane 1, lone pair selectivity is controlled by steric interactions of the gem-dimethyl group and an anomeric effect, which renders the equatorial lone pair less nucleophilic than the axial lone pair. Of the resulting ylide conformations, 25a will be strongly preferred and will react on the more open Re face, since the Si face is blocked by the gem-dimethyl group (Scheme 1.9) [3, 15]. 

In the case of sulfide 7 the bulky camphoryl moiety blocks one of the lone pairs on the sulfide, resulting in a single diastereomer upon alkylation. One of the conformations (29b) is rendered less favorable by non-bonded interactions such that conformation 29a is favored, resulting in the observed major isomer (Scheme 1.11). The face selectivity is also controlled by the camphoryl group, which blocks the Re face of the ylide. 

The high enantioselectivity observed was interpreted in terms of the face selectivity of the (Z)-enolate 59 (Scheme 1.20). The phenyl moiety is thought to stabilize the enolate through a n-n interaction and effectively shield its Re face such that the incoming ketone approaches preferentially from the Si face. 

Indeed, the combination of the aldehyde 1 with the (S)-enolate 2 delivers the diastereomers 3a and 3b in excellent selectivity (>100 1, matched pair ). On the other hand, a 1 30 ratio of 4 a/4 b is found in the corresponding reaction of the (2 )-enolate 2. Although the selectivity in the latter case ( mismatched pair ) is distinctly lower, the reliability of this chiral enolate 2 provides a degree of induced stereoselectivity which is sufficient for practical applications ( double diastereodifferentiation )29. The stereochemical outcome is largely determined by the chirality of the enolate in that the (S)-enolate 2 attacks the aldehyde almost exclusively from the Re-face whereas the (/ -enolate adds preferably to the Si-face of the carbonyl group in the aldehyde. 

Restrictions for the substrates of the transketolase-catalyzed reaction only arise from the stereochemical requirements of the enzyme. The acceptor aldehyde must be formaldehyde9,20, glycolaldehydel6,17 or a (R)-2-hydroxyaldehyde10,17. The donor ketose must exhibit a (3(7,4 R) configuration10. The enzyme selectively adds the hydroxyacetyl moiety to the Re-face of the acceptor aldehyde leading to a 3(7 configuration of the products. 

The asymmetric induction that has been observed in this reaction can be explained in terms of the model shown in Scheme 9. In the most stable conformation the appropriately positioned phenyl group shields selectively the Re,Re face of the chromadiene by 7r,7r-orbital overlap forcing the nucleophile to attack preferentially on the opposite side. 

Binaphthol-derived titanium complexes [64], prepared from chiral ligands 65 (Figure 3.13), also performed very well in the cycloadditions of conjugated aldehydes with cyclic and acyclic dienes. Judging from the absolute configurations of endo and exo adducts, this catalyst should cover the re-face of carbonyl on its u tz-coordination to s-trans a,/l-unsaturated aldehydes, and hence dienes should approach selectively from the si-face. 

The chiral catalyst 142 achieves selectivities through a double effect of intramolecular hydrogen binding interaction and attractive tt-tt donor-acceptor interactions in the transition state by a hydroxy aromatic group [88]. The exceptional results of some Diels-Alder reactions of cyclopentadiene with substituted acroleins catalyzed by (R)-142 are reported in Table 4.21. High enantio- and exo selectivity were always obtained. The coordination of a proton to the 2-hydroxyphenyl group with an oxygen of the adjacent B-0 bond in the nonhelical transition state should play an important role both in the exo-endo approach and in the si-re face differentiation of dienophile. 

The heterobimetallic asymmetric catalyst, Sm-Li-(/ )-BINOL, catalyzes the nitro-aldol reaction of ot,ot-difluoroaldehydes with nitromethane in a good enantioselective manner, as shown in Eq. 3.78. In general, catalytic asymmetric syntheses of fluorine containing compounds have been rather difficult. The S configuration of the nitro-aldol adduct of Eq. 3.78 shows that the nitronate reacts preferentially on the Si face of aldehydes in the presence of (R)-LLB. In general, (R)-LLB causes attack on the Re face. Thus, enantiotopic face selection for a,a-difluoroaldehydes is opposite to that for nonfluorinated aldehydes. The stereoselectivity for a,a-difluoroaldehydes is identical to that of (3-alkoxyaldehydes, as shown in Scheme 3.19, suggesting that the fluorine atoms at the a-position have a great influence on enantioface selection. 

The above interesting approach to the asymmetric allyltitanation reaction does, however, have a limitation. Thus, L-glucose is much more expensive that the D-form and, consequently, homoallylic alcohols of the opposite configuration cannot easily be obtained by this method. In an attempt to induce the opposite si face selectivity, other acetonide derivatives of monosaccharides from the xylose, idose, and allose series were tested [42b,42c], The enantiofacial discrimination was, however, much lower than that with DAGOH and both re and si face selective additions to aldehydes were observed. 

E. J. Corey, E-Y. Zhang, re and si-Face-Selective Nitroal-dol Reactions Catalyzed by a Rigid Chiral Quaternary Ammonium Salt A Highly Stereoselective Synthesis of the HIV Protease Inhibitor Amprenavir (Vertex 478) , Angew. Chern. Int. Ed 1999, 38,1931-1934. 

The utility of chiral oxazoline enolates in asymmetric synthesis has elegantly been demonstrated by Myers (106,120). The stereoselective aldol condensations of these enolates have been examined in a hmited number of cases (eq. [107]) (32,121). Assuming that the enolate formed has the geometry indicated in 164 (120b), the diastereoselection observed for both the aldol condensation and the previously reported alkylations favors electrophile attack on the Re face as indicated. In contrast, the unsubstituted enolate 163b exhibits significantly poorer diastereoface selection with a range of aldehydes (eq. [108]) (121). 

Having used their catalytic systems with dienolates derived from unsaturated esters, Denmark performed aldol reactions with the dioxanone-derived dienol ether described above in the context of Carreira s and Campagne s vinylogous aldol reactions (Scheme 21). Here, exclusively, the y product was formed with the nucleophile attacking from the Re face. For all three aldehydes, very good yields (83-92%) and selectivities (74-89% ee) were observed with only 0.01-0.05 mol% of the catalyst. 

Although the results are easily rationalised in the case of the a-alkylation (attack of the electrophile at the Re face, i.e., attack from the less hindered a face), in the aldol condensation it is somewhat more difficult to rationalise and several factors should be considered. According to Evans [14] one possible explanation for the diastereofacial selection observed for these chiral enolates is illustrated in Scheme 9.14. In the aldol reactions, the more basic carbonyl group of the aldehyde partner interacts with the chelated boron enolate 45 to give the "complex" A which may... 

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