Syn diastereoselection

In 1963, Dauben and Berezin published the first systematic study of this syn directing effect (Scheme 3.15) [37]. They found that the cyclopropanation of 2-cyclohexen-l-ol 32 proceed in 63% yield to give the syn isomer 33 as the sole product. They observed the same high syn diastereoselectivity in a variety of cyclic allylic alcohols and methyl ethers. On the basis of these results, they reasonably conclude that there must be some type of coordinative interaction between the zinc carbenoid and the substrate. 

It is unlikely that a (8-chelate analogous to 2 is responsible for the very high syn diastereoselectivity which is observed with the chiral vinyllithium reagent (7 )-3 upon addition to (/t)-3-(benzyl oxy)butanal (Table 13)11 °. 

With respect to the nucleophilic addition of organocopper reagents, a sharp contrast between the rigid isopropylidene glyceraldehyde and its open-chained analog, 2,3-bis(benzyloxy)propanal. was observed (compare Tables 15 and 16). With the isopropylidene-protected aldehyde a high syn diastereoselectivity could only be obtained when tetrahydrofuran was used as reaction solvent, and the diastereoselectivity dropped considerably in diethyl ether. In contrast, the latter solvent allows excellent syn selectivities in additions to the dibenzyl-protected glyceraldehyde81. On the other hand, tetrahydrofuran yields better results than diethyl ether in the... 

For acyclic systems, the anti diastereoselectivity of the (i )-enolates is lower than the syn diastereoselectivity of comparable (Z)-enolates. For example, carboxylic acid esters, which form predominantly ( )-enolates, react with aldehydes with high anti selectivity only in those cases where bulky aromatic substituents are in the alcoholic part of the ester22 25. 

N,N-Dibenzyl (z -amino a-chloroketimines 202 can be prepared from the corresponding ketones, which in turn are available by the addition of chloromethyllithium to esters of natural cz-amino acids. Reduction of 202 with sodium cyanoborohydride directly afforded a-aminoalkyl-substituted aziridines 203 with high syn diastereoselectivity, which was only moderately affected by the size of the substituent [96] (Scheme 30). A complemen-... 

A comparison of the anti.syn diastereoselectivity of the lithium, dibutylboron, and (Cp)2Zr enolates of 3-methyl-2-hexanone with benzaldehyde has been reported.34d The order of stereoselectivity is Bu2B > (Cp)2Zr > Li. These results suggest that the reactions of the zirconium enolates proceed through a cyclic TS. 

Phenyl and phenylthio esters have proven to be advantageous in TiCl4-mediated additions, perhaps because they are slightly more acidic than the alkyl analogs. The reactions show syn diastereoselectivity, indicating that Z-enolates are formed.43... 

Entry 2 shows an E-enolate of a hindered ester reacting with an aldehyde having both an a-methyl and (3-methoxy group. The reaction shows a 13 1 preference for the Felkin approach product (3,4-syn) and is controlled by the steric effect of the a-methyl substituent. Another example of steric control with an ester enolate is found in a step in the synthesis of (-t-)-discodermolide.99 The E-enolate of a hindered aryl ester was generated using LiTMP and LiBr. Reaction through a Felkin TS resulted in syn diastereoselectivity for the hydroxy and ester groups at the new bond. 

Scheme 2.6 shows some examples of the use of chiral auxiliaries in the aldol and Mukaiyama reactions. The reaction in Entry 1 involves an achiral aldehyde and the chiral auxiliary is the only influence on the reaction diastereoselectivity, which is very high. The Z-boron enolate results in syn diastereoselectivity. Entry 2 has both an a-methyl and a (3-benzyloxy substituent in the aldehyde reactant. The 2,3-syn relationship arises from the Z-configuration of the enolate, and the 3,4-anti stereochemistry is determined by the stereocenters in the aldehyde. The product was isolated as an ester after methanolysis. Entry 3, which is very similar to Entry 2, was done on a 60-kg scale in a process development investigation for the potential antitumor agent (+)-discodermolide (see page 1244). 

With titanium enolates it was found that use of excess (3 equiv.) of the titanium reagent reversed facial selectivity of oxazolidinone enolates.140 This was attributed to generation of a chelated TS in the presence of the excess Lewis acid. The chelation rotates the oxazolidinone ring and reverses the facial preference, while retaining the Z-configuration syn diastereoselectivity. 

Crimmins and co-workers have developed (V-acyloxazolidinethiones as chiral auxiliaries. These reagents show excellent 2,3-syn diastereoselectivity and enantio-selectivity in additions to aldehydes. The titanium enolates are prepared using TiCl4, with (-)-sparteine being a particularly effective base.141... 

The reaction of an a-halo carbonyl compound with zinc, tin, or indium together with an aldehyde in water gave a direct cross-aldol reaction product (Eq. 8.90).226,227 A direct Reformatsky-type reaction occurred when an aromatic aldehyde reacted with an a-bromo ester in water mediated by zinc in low yields. Recently, it was found that such a reaction mediated by indium was successful and was promoted by son-ication (Eq. 8.91).228 The combination of BiCl3-Al,229 CdCl2-Sm,230 and Zn-Et3B-Eb0231 is also an effective mediator. Bismuth metal, upon activation by zinc fluoride, effected the crossed aldol reaction between a-bromo carbonyl compounds and aldehydes in aqueous media. The reaction was found to be regiospecific and syn-diastereoselective (Eq. 8.92).232... 

Table6 Highly syn-diastereoselective intermolecular Rh-catalyzed hydrogenative aldol coupling of vinyl ketones through the tri-2-furylphosphine effect3...

Scheme 4 syn-Diastereoselective intermolecular hydrogen-mediated aldol coupling employing cationic Rh catalysts ligated by tri-2-furylphosphine... 

The reaction is also applicable to a wide structural variety of 1,3-dienes, as demonstrated by the reaction of 2-furfural-p-anisidine imine (Table 9). All dienes react with the aldimine regioselectively at the diene termini bearing the highest electron densities and provide bis-homoallyl amines with excellent 1,3-syn diastereoselectivity. No C4-adducts are formed in these reactions. 

A change in the allyl hapticity (q3 to p1 slippage) leading to the less substituted titanium-carbon o bond accounts for the observed y-regioselectivity. The anti diastereoselectivity stems from a pseudo-equatorial orientation of the aldehyde group. The diastereoselectivity of the reaction can be reversed through the use of a more coordinating cosolvent such as HMPA (Scheme 13.7) [14]. This reversal of anti to syn diastereoselectivity can be rationalized in terms of an open transition state. 

Scheme 13.7. Reversal of anti to syn diastereoselectivity by using HMPA as a co-solvent.

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