Diastereoselectivity acyclic systems

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. 

This isomerization was used in the heteroconjugate addition to the acyclic system. Therefore, the substituted olefin 72, in which the double bond is conjugated with both sulfone and silicon atoms, undergoes a diastereoselective addition of CHsLi. The resulting lithium alcoholate is quantitatively converted into the silyl ether dianion 73 and the addition of deuterium oxide afforded the functionalized product 74 in excellent yield (equation 16. 

Hoffmann has shown that diastereoselective bromine-lithium exchange may be achieved even in acyclic systems.118 Treatment of 138 with BuLi in the Trapp solvent mixture at -120 °C in the presence of acetone generates the epoxides 139 and 140 in a 94 6 ratio of diastereoisomers.119 120 The selectivity was found to depend on the organolithium used for the bromine-lithium exchange, and it must therefore be under kinetic control. 

Diastereoselective hydroxylation has also been observed at an alkenic center in an acyclic system that is guided by a sulfoxide group that is more remote than the homoallylic position. Alkenes (18 equation... 

Similar methodology can be used in acyclic systems for the diastereoselective, and sometimes dia-steteoselective (Scheme 18), foimation of 1,3-diols. Widi strnie substrates, the proptMtion of products arising from 6-endo-trig cyclization can be significant. 

Induced Diastereoselectivity 4.5.I.3.2.I. Acyclic Systems Substrate-Induced Diastereoselectivity... 

The development of reliable methods for the diastereoselective reduction of carbonyl compounds in a wide range of acyclic systems has been an area of explosive growth in recent years. This was prompted by the requirements of modem total synthesis in which redundant diastereoisomers are avoid, - together with enhanced theoretical understanding of stereoselectivity which allows rationalization of the results. 

The presence of a free alcohol is not essential as a similar enantiomeric excess is obtained with a rerr-biityl ether or dialkylamines [128], The chiral, thermodynamically favored benzylic organolithium compound 92Li, obtained after the carbometallation step, may react with a number of electrophiles in a highly diastereoselective manner with a fornial inversion of configuration [84, 85] as already described in Scheme 7-71. In all cases examined, the product is obtained in a diastereomeric ratio of >98 2 prior to purification and in 83% ee. Thus, two chiral centers in an acyclic system have been created in a singlepot operation. 

The oxy-Cope and anionic-oxy-Cope rearrangements involve highly ordered cyclic transition states, so the asymmetry is almost completely transferred from the substrate to the product. Most commonly in acyclic systems as in other [3,3]-sigmatroplc rearrangements, the transition states are chairlike and the substituents adopt a quasiequatorial position to minimize unfavorable steric interactions. In unsubstituted substrates the diastereoselection is low, tout the introduction of an alkyl substituent at C4 improves the diastereoselectivity. In (Z)-1-substituted alkenes there is preference for the oxyanionic bond to be pseudo-equatorial, whereas in ( )-1-substituted alkenes it tends to... 

The Felkin-Ahn and Cram models are best applied to acyclic systems. Problems arise when any of these models are used to predict the products generated by the reduction of cyclic ketones. These problems will be analyzed and new models for predicting diastereoselectivity in the reduction of cyclic molecules will be discussed in Section 4.7.C. 

Sulfoxide groups direct the dihydroxylation of a remote double bond in an acyclic system perhaps by prior complexation of the sulfoxide oxygen with osmium tetroxide (eqs 16 and 17). Chiral sulfoximine-directed diastereoselective osmylation of cy-cloalkenes has been used for the synthesis of optically pure di-hydroxycycloalkanones (eq 18). Nitro groups also direct the osmylation of certain cycloalkenes, resulting in dihydroxylation from the more hindered side of the ring. In contrast, without the nitro group the dihydroxylation proceeds from the less hindered side (eq 19). ... 

Three of many examples of directed hydrogenation are shown in Equations 15.15-15.17. Equation 15.15 shows the reduction of a homoaUylic alcohol, which was one of the substrates first used to demonstrate this effect. Equation 15.16 shows a more complex substrate in which the diastereoselective reduction by Crabtree s catalyst is directed by the amide function as part of tlie synthesis of pulmitoxins. Equation 15.17 shows that the addition of hydrogen can be directed to a hindered face of a bicyclic system. In this case, the cationic rhodium system qf Brown, as well as Crabtree s catalyst, led to hi selectivity. Many other reactions occur with high selectivity in the presence of Brown s cationic rhodium system. Diastereoselective additions to acyclic systems, along with a rationalization for the selectivity in these types of substrates, can be found in the review by Evans. ... 

Whereas cyclic allyhc alcohols of normal size can only yield (Z)acyclic allylic alcohols preferentially give ( )-isomers. Indeed, the Meerwein-Eschenmoser-Claisen rearrangement is an excellent method for the stereoselective formation of di- and trisubstituted (E)-double bonds in acyclic systems. The high diastereoselectivities observed (dr >95 5) can be explained by invoking a chair shaped transition state 35a or 36a (Scheme 7.15). This minimizes... 

This methodology was subsequently extended to the reaction with ketones, which allowed the diastereoselective preparation of adjacent quaternary aU-carbon stereogenic centers in an acyclic system [105]. In the case of ethoxyacetylene 360, the alkenylcopper derivatives 361 were formed quantitatively, followed by homologation with a zinc carbenoid and reaction of the resulting aUenylzinc intermediates with ketones (Scheme 10.124). 

DIASTEREOSELECTIVITY IN ACYCLIC SYSTEMS CRAM S RULE, FELKIN-AHN MODEL... 

We shall, of course, also cover directed selectivity in ether- and polyether synthesis, but we look at them not mainly as building blocks for very complicated molecules but rather as tools in stereoselective synthesis in general. Since selectivity, particularly diastereoselectivity, is very often unsatisfactory in acyclic systems, cyclic, conformational less mobile equivalents of the desired molecules could come to the rescue. 

The Kishi synthesis ot monensin teatures allylic conformational analysis to predict stereochemistry of hydroboratlon-oxidations in acyclic systems. The Still synthesis features acyclic diastereoselection in carbonyl addition reactions (chelation control and Felkin-Ahn control). 

If HMPA is included in the solvent, the Z-enolate predominates.236,238 DMPU also favors the Z-enolate. The switch to the Z-enolate with HMPA or DMPU is attributed to a looser, perhaps acyclic TS being favored as the result of strong solvation of the lithium ion. The steric factors favoring the -TS are therefore diminished.239 These general principles of solvent control of enolate stereochemistry are applicable to other systems.240 For example, by changing the conditions for silyl ketene acetal formation, the diastereomeric compounds 17a and 17b can be converted to the same product with high diastereoselectivity.241... 

The reaction of aryldiazoacetates with cyclohexene is a good example of the influence of steric effects on the chemistry of the donor/acceptor-substituted rhodium carbenoids. The Rh2(reaction with cyclohexene resulted in the formation of a mixture of the cyclopropane and the G-H insertion products. The enantios-electivity of the C-H insertion was high but the diastereoselectivity was very low (Equation (31)). 0 In contrast, the introduction of a silyl group on the cyclohexene, as in 15, totally blocked the cyclopropanation, and, furthermore, added sufficient size differentiation between the two substituents at the methylene site to make the reaction to form 16 proceed with high diastereoselectivity (Equation (32)).90 The allylic C-H insertion is applicable to a wide array of cyclic and acyclic substrates, and even systems capable of achieving high levels of kinetic resolution are known.90... 

Having established that pure enantiomer ( S,ZR)-77 was capable of undergoing remarkably regioselective and diastereoselective C-H activation, it followed that highly efficient enantiomeric differentiation of rac-77 could be accomplished.199 Hence, the Rh2(5Y-MEPY)4-catalyzed reaction of rac-77 effectively gave close to a 1 1 mixture of enantioenriched (lY)-78 (91% ee) and ( R)-79 (98% ee) (Equation (68)). Other equally spectacular examples of diastereo- and regiocontrol via chiral rhodium carboxamide catalysts in cyclic and acyclic diazoacetate systems have been reported.152 199 200 203-205... 

Facing the challenge of synthesizing the antibiotic erythromycin A la, Woodward s group took advantage of a cyclic system to achieve diastereofacial selectivity, the so-called cyclic approach.3 This approach was taken to deal with the common problem of low diastereoselectivity associated with acyclic substances. 

---