Stereoselectivity syn-anti

The amines 3 reported by Morao and Cossio also constitute neutral dendritic catalysts without metal sites they consist of a simple amine core functionalised with Frechet dendrons (Fig. 6.44) [74]. Such amines can catalyse the nitroaldol or Henry reaction [75] between aromatic aldehydes and nitroalkanes. Whereas neither the yield nor the stereoselectivity (syn/anti 1 1) of the reaction of p-nitro-benzaldehyde with nitroethane was found to change on use of different generations of dendritic catalysts, a distinctly negative dendritic effect was observed in the reaction of benzaldehyde with 3-nitro-l-propanol. Catalysts 3 a and 3 b gave... 

Similarly, condensation of D-mannosamine, as well as D-mannose with methyl dimethyl[(3-bromopropen-2-yl)phosphate] [115], instead of ethyl (bromomethyl)acrylate, led to the corresponding Neu5Ac and phosphonate analogs with much higher stereoselectivity (syn/anti 20 1). 

Simple stereoselectivity (syn-.anti ratios) can be controlled in the Sn(OTf)2-mediated addition of the reagent to a-keto esters by varying the silyl ketene acetal geometry (eq 6). J... 

In ( )-[2-(l-propenyl)-l, 3-dithian-2-yl]lithium, no problem of EjZ selectivity arises. It is easily prepared by deprotonation of the allylic dithiane87,88 with butyllithium in THF, whereas deprotonation of the 2-propylidene-l, 3-dithiane requires the assistance of HMPA. The addition to saturated aldehydes proceeds with excellent y-regioseleetivity and anti selectivity88,89. As often observed in similar cases, aldehydes which bear an, p2-carbon atom adjacent to the carbonyl group give lower selectivities. The stereoselectivity decreases with ketones (2-bu-tanone y/a 84 16, antiisyn 77 23)88. The reaction with ethyl 2-oxopropanoate is merely nonstereoselective90, but addition of zinc chloride improved the syn/anti ratio to 96 4, leading to an efficient synthesis of ( )-crobarbatic acid. 

A more effective control of both simple diastereoselectivity and induced stereoselectivity is provided by the titanium enolate generated in situ by transmetalation of deprotonated 2,6-dimethylphenyl propanoate with chloro(cyclopentadienyl)bis(l,2 5,6-di-0-isopropylidene-a-D-glucofuranos-3-0-yl)titanium. Reaction of this titanium enolate with aldehydes yields predominantly the. yyw-adducts (syn/anti 89 11 to 97 3). The chemical yields of the adducts are 24 87% while the n-u-products have 93 to 98% ee62. 

The lithium enolate of the following (1 /C2.S )-2-phenyl-1-cyclohexylpropionate turns out to provide syn selectivity when reacted with benzaldehyde at —100 °C. However, the syn/anti ratio is only 86 14, and the induced stereoselectivity 92.5 7.522. 

Highly stereoselective formation of. syn-adducts (syn/anti. >95 < 5) results from the titanium(IV) chloride induced addition ofa-unsubsliluled enolsilanes, as well as of the a-dimethyl silylketene acetal, to 2-benzyloxypropanal3. 

Cyclic and open transition state models have been used to explain syn/anti stereoselectivity in these reactions1. The possible transition states (including boat B and chair C transition states) can be deduced from the E/Z geometry of the crotyl reagent and the imine. The postulated cyclic transition states for the preferred E geometry of the imine arc shown below. 

An excellent method for the diastereoselective synthesis of substituted amino acids is based on optically active bislactim ethers of cyclodipeptides as Michael donors (Schollkopf method, see Section 1.5.2.4.2.2.4.). Thus, the lithium enolates of bislactim ethers, from amino acids add in a 1,4-fashion to various a,/i-unsaturated esters with high diastereofacial selectivity (syn/anti ratios > 99.3 0.7-99.5 0.5). For example, the enolate of the lactim ether derivative 6, prepared from (S)-valine and glycine, adds in a highly stereoselective manner to methyl ( )-3-phenyl-propenoate a cis/trans ratio of 99.6 0.4 and a syn/anti ratio of 91 9, with respect to the two new stereogenic centers, in the product 7 are found105, los. 

The enolate of the 1,4-adduct, obtained after the stereoselective Michael addition step, as discussed in the previous sections, may be quenched in situ with various electrophiles. The fact that additional stereogenic centers may be formed via such tandem Michael addition/quench-ing procedures, giving products with high diastereoselectivity in many cases, extends the scope of these methods substantially. Furthermore these procedures occasionally offer the possibility of reversing the syn/anti diastereoselection. In the next sections pertinent examples of diastereoselective inter- and intramolecular quenching reactions will be discussed. 

Of perhaps greater use for organic synthesis was the observation that photo-driven reactions of alkoxycarbenes with unsubstituted optically active ene carbamates [65] produced aminocyclobutanones in fair yield with high dia-stereoselectivity (Table 12) [66]. In contrast, with a gem-disubstituted ene carbamate, the syn-anti selectivity was low but high asymmetric induction a to nitrogen was observed (Eq. 16). Trans-monosubstituted ene carbamates failed to react, as did a,/J-unsaturated chromium carbene complexes. 

If the carbanion has even a short lifetime, 6 and 7 will assume the most favorable conformation before the attack of W. This is of course the same for both, and when W attacks, the same product will result from each. This will be one of two possible diastereomers, so the reaction will be stereoselective but since the cis and trans isomers do not give rise to different isomers, it will not be stereospecific. Unfortunately, this prediction has not been tested on open-chain alkenes. Except for Michael-type substrates, the stereochemistry of nucleophilic addition to double bonds has been studied only in cyclic systems, where only the cis isomer exists. In these cases, the reaction has been shown to be stereoselective with syn addition reported in some cases and anti addition in others." When the reaction is performed on a Michael-type substrate, C=C—Z, the hydrogen does not arrive at the carbon directly but only through a tautomeric equilibrium. The product naturally assumes the most thermodynamically stable configuration, without relation to the direction of original attack of Y. In one such case (the addition of EtOD and of Me3CSD to tra -MeCH=CHCOOEt) predominant anti addition was found there is evidence that the stereoselectivity here results from the final protonation of the enolate, and not from the initial attack. For obvious reasons, additions to triple bonds cannot be stereospecific. As with electrophilic additions, nucleophilic additions to triple bonds are usually stereoselective and anti, though syn addition and nonstereoselective addition have also been reported. 

The stereoselectivity can be enhanced by addition of Ti(0-i-Pr)4. The active nucleophile under these conditions is expected to be an ate complex in which a much larger Ti(0- -Pr)4 group replaces Li+ as the Lewis acid.313 Under these conditions, the syn anti ratio is dependent on the stereochemistry of the enolate. 

It may be that (40) has some cyclic character as the overall addition of BH3 is found, in suitable cases, to be stereoselectively SYN. The first-formed RBH2 then reacts further with the alkene to yield the trialkylboron, R3B (38). H202 oxidation results in fission of the C—B bond to yield the alcohol (39), the net result being overall anti-Markownikov hydration that is often stereoselectively SYN yields are usually very good. 

Thus by suitable choice of reagent, the hydroxylation of alkenes can be made stereoselectively SYN or ANTI at will. 

For many catalytic cyclopropanations, the stereoselectivity describing the stereochemical relation between substituents at the carbenoid and those at the double bond is not very pronounced. EjZ or syn/anti ratios of ca. 1-3 in favor of the less congested isomer may be considered normal (for examples see Tables 6 and 7). The stereochemical outcome can be expected to be governed by the nature of the olefin, the diazo compound and the catalyst. 

Some care must be taken in drawing conclusions from the E/Z or syn/anti selectivity of a given catalyst/alkene combination. The intrinsic stereoselectivity may be altered in some cases by subsequent isomerizations initiated by the catalyst. For example, epimerization of disubstituted vinylcyclopropanes is effectively catalyzed by palladium compounds the cis - trans rearrangement of ethyl chrysanthemate or of chrysanthemic acid occurs already at room temperature in the presence of PdCl2 L2 (L = MeCN, EtCN, PhCN)96 Oxycyclopropane carboxylic esters undergo metal-... 

Diastereomer analysis on the unpurified aldol adduct 52b revealed that the total syn anti diastereoselection was 400 1 whereas enantioselective induction in the syn products was 660 1. On the other hand, Evans in some complementary studies also found that in the condensation of the chiral aldehyde 53 with an achiral enolate 56a only a slight preference was noted for the anti-Cram aldol diastereomer 58a (58a 57a = 64 36). In the analogous condensation of the chiral enolate 56b. however, the yn-stereoselection was approximately the same (57b 58b > 400 1) as that noted for enolate 49 but with the opposite sense of asymmetric induction (Scheme 9.17). Therefore, it can be concluded that enolate chirality transfer in these systems strongly dominates the condensation process with chiral aldehydes. 

In contrast to the solution photochemistry, irradiation of the crystals of le provided remarkably high diastereoselectivities in the formation of 2e. The temperature at which the reaction occurs is important in determining dia-stereoselectivity. At 15 °C, the de of syn-2e was 61 % and the ratio of syn/anti was 8.7, which was the reverse of that in the solution reaction (syn/anti=0.9). The solid-state photoreaction proceeded even at -78 °C, and with higher diastereo-selectivity. At low conversion (9%), only syn isomers (de=93%) were obtained, and 71% de was observed even at 90% conversion. 

To form the stereocenter at C-3 a direct reduction-alkynylation sequence was applied, that provided the diastereomeric homopropargylic alcohols 83 in a ratio of syn anti=76l2A, The major isomer syn-S3 was isolated in 55% yield. The key step of the synthesis was an intramolecular imidotitanium-al-kyne [2+2] cycloaddition/acyl cyanide condensation. With this sequence the pyrrolidine ring was formed and all the carbon atoms of the alkyl side chain were established in acrylonitrile 84. The reduction of the imine double bond proceeded stereoselectively and the nitrile group was removed reductively en route to the target compound. 

TABLE 4. Syn/anti stereoselectivity in the ene reaction of O2 with para substituted /S,/S-dimethylstyrenes... 

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