Syn-product

When the aldol reaction is carried Wt under thermodynamic conditions, the product selectivity is often not as high as under kinetic conditions. All the regioisomeric and stereoisomeric enolates may participate as nucleophiles. The adducts can return to reactants, and so the difference in stability of the stereoisomeric anti and syn products will determine the product composition. 

For a ctiprale addition reaction to a diester derivative sudi as 88, it miglii be expected diai die ami addition product would be favored, since a pronounced allylic a " strain in diese substrates along "modided" Felfcin-Anb lines should favor transition state 52 fsee Fig. 6.1). However, experiments produced die opposite result, widi die syn product 89 being obtained as die major diastereomer (Sdieme 6.18) [36, 37]. 

The enantiomers are obtained as a racemic mixture if no asymmetric induction becomes effective. The ratio of diastereomers depends on structural features of the reactants as well as the reaction conditions as outlined in the following. By using properly substituted preformed enolates, the diastereoselectivity of the aldol reaction can be controlled. Such enolates can show E-ot Z-configuration at the carbon-carbon double bond. With Z-enolates 9, the syn products are formed preferentially, while fi-enolates 12 lead mainly to anti products. This stereochemical outcome can be rationalized to arise from the more favored transition state 10 and 13 respectively ... 

The stereoselectivity of Lewis acid promoted reactions between 2-butenylstannanes and aldehydes has been widely studied, and several very useful procedures for stereoselective synthesis have been developed. In particular syn-products are formed stereoselectively in reactions between trialkyl- and triaryl(2-butenyl)stannanes, and aldehydes induced by boron trifluoride-diethyl ether complex, irrespective of the stannane geometry66. 

With l-alkyl-3-alkoxyallylstannanes, effective asymmetric induction occurs to give (E)-syn-products consistent with an antiperiplanar, antarafacial S t process. The optical purity of the products parallels that of the stannane106. 

With (Z)-amide enolates and (Z)-thioamide enolates a strong preference for sm-adducts is also observed. In general, boron or zirconium (Z)-enolates of ketones and amides display a higher simple diastereoselectivity in favor of syn-products than the corresponding lithium or magnesium enolates6,7. 

The chlorotitanium enolate, generated by treatment of (S )-l-tm-butyldimethylsiloxy-l-cyclohexyl-2-butanone with titanium(iv) chloride and diisopropylethylamine, provides the syn-product upon reaction with benzaldehyde. The diastereoselectivity of 99 1 is defined as the ratio of the major isomer to the sum of all other isomers47bc. 

The addition of methyllithium to -alkoxy-a-(trimethylsilyl)-of/ unsaturated sulfones, 3-alkoxy-5-phenyl-l-phenylsulfonyl-l-(trimethylsilyl)-l-pentene and subsequent desilylation gives syn-products. The syn to anti diastereoselectivity is generally high and essentially independent of the nature of the y-alkoxy substituent8-13. 

More detailed stereochemical studies on the Diels-Alder reaction between cyclopen-tadiene and 2-phenylsulphinylacrylic acid 560 revealed that the formation of endo-syn products 561 is strongly favoured (75-80%) over that of the endo-anti forms661 (equation 359). 

The lithium enolates of a-alkoxy esters exhibit high stereoselectivity, which is consistent with involvement of a chelated enolate.374 39 The chelated ester enolate is approached by the aldehyde in such a manner that the aldehyde R group avoids being between the a-alkoxy and methyl groups in the ester enolate. A syn product is favored for most ester groups, but this shifts to anti with extremely bulky groups. 

Stereochemical Control by the Aldehyde. A chiral center in an aldehyde can influence the direction of approach by an enolate or other nucleophile. This facial selectivity is in addition to the simple syn, anti diastereoselectivity so that if either the aldehyde or enolate contains a stereocenter, four stereoisomers are possible. There are four possible chairlike TSs, of which two lead to syn product from the Z-enolate and two to anti product from the A-enolate. The two members of each pair differ in the facial approach to the aldehyde and give products of opposite configuration at both of the newly formed stereocenters. If the substituted aldehyde is racemic, the enantiomeric products will be formed, making a total of eight stereoisomers possible. 

If the substituents are nonpolar, such as an alkyl or aryl group, the control is exerted mainly by steric effects. In particular, for a-substituted aldehydes, the Felkin TS model can be taken as the starting point for analysis, in combination with the cyclic TS. (See Section 2.4.1.3, Part A to review the Felkin model.) The analysis and prediction of the direction of the preferred reaction depends on the same principles as for simple diastereoselectivity and are done by consideration of the attractive and repulsive interactions in the presumed TS. In the Felkin model for nucleophilic addition to carbonyl centers the larger a-substituent is aligned anti to the approaching enolate and yields the 3,4-syn product. If reaction occurs by an alternative approach, the stereochemistry is reversed, and this is called an anti-Felkin approach. 

E- and Z-silyl thioketene acetals give the 2,3-anti product. The 3,4-syn ratio is 50 1, and is consistent with the Felkin model. When this nucleophile reacts with 2-benzyloxypropanal (Entry 8), a chelation product results. The facial selectivity with respect to the methyl group is now reversed. Both isomers of the silyl thioketene acetal give mainly the 2,3-syn-3A-syn product. The ratio is higher than 30 1 for the Z-enolate but only 3 1 for the F-enolate. 

Entries 4 and 9 are closely related structures that illustrate the ability to control stereochemistry by choice of the Lewis acid. In Entry 4, the Lewis acid is BF3 and the (3-oxygen is protected as a f-butyldiphenylsilyl derivative. This leads to reaction through an open TS, and the reaction is under steric control, resulting in the 3,4-syn product. In Entry 9, the enolate is formed using di-n-butylboron triflate (1.2 equiv.), which permits the aldehyde to form a chelate. The chelated aldehyde then reacts via an open TS with respect to the silyl ketene acetal, and the 3,4-anti isomer dominates by more than 20 1. 

The stereoselectivity of this reaction also depends on the titanium reagent used to prepare the enolate.104 When the substituent is benzyloxy, the 2,2 -anti-2,3-syn product is preferred when ( -PrO)TiCl3 is used as the reagent, as would be expected for a chelated TS. However, when TiCl4 is used, the 2,2 -syn-2,2-syn product is formed. A detailed explanation for this observation has not been established, but it is expected that the benzyloxy derivative would still react through a chelated TS. The reversal on use of TiCl4 indicates that the identity of the titanium ligands is also an important factor. 

Tin(II) enolates having 3 -benzyloxy substituents are subject to chelation control. The enolate from 2-(benzyloxymethyl)-3-pentanone gave mainly 2,2 -syn-2,2>-syn product, a result that is consistent with a chelated TS.108... 

Camphor-derived sulfonamide can also permit control of enantioselectivity by use of additional Lewis acid. These chiral auxiliaries can be used under conditions in which either cyclic or noncyclic TSs are involved. This frequently allows control of the syn or anti stereoselectivity.143 The boron enolates give syn products, but inclusion of SnCl4 or TiCl4 gave excellent selectivity for anti products and high enantioselectivity for a range of aldehydes.145... 

The cyclic mechanism predicts that the addition reaction will be stereospecific with respect to the geometry of the double bond in the allylic group, and this has been demonstrated to be the case. The E- and Z-2-butenyl cyclic boronates 1 and 2 were synthesized and allowed to react with aldehydes. The F-boronate gave the carbinol with anti stereochemistry, whereas the Z-boronate resulted in the syn product.37... 

Conjugate addition to acyclic enones is subject to chelation control when TiCl4 is used as the Lewis acid. Thus, whereas the A-enone 12 gives syn product 13 via an acyclic TS, the Z-isomer 14 reacts through a chelated TS to give 15.133... 

Cyclic allylstannanes give syn products with high selectivity. 

The stereoselectivity of the P-carboethoxyallylic boronate derived from the endo-phenyl auxiliary A (p. 803) toward R- and. S -glyccraldchydc acetonide has been investigated. One enantiomer gives the anti product in 98 2 ratio, whereas the other favors the syn product by a 65 35 ratio. Based on the proposed transition structure for this boronate, determine which combination leads to the higher stereoselectivity and which to the lower. Propose the favored transition structure in each case. 

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