Anti Diastereoselectivity

As can be seen from the developments described above, the control of both relative and absolute acyclic stereochemistry in a variety of syn aldol reactions can now be achieved highly stereoselectively. Both boron and titanium enoiate-based syn aldol reactions have gained svidespread popularity and are frequently used in synthesis. Whereas anti-a-alkyl-/i-hydroxycarbonyl units are inherent to numerous bioactive natural products, there are relatively fesv effective synthetic processes that are convenient, operationally simple, and afford high diastereoselectivity for a svide range of aldehydes. Early examples of anti-selective aldol reactions, reported by Meyers in 1984, svere based upon oxazoline-derived boron enolates [60]. Several other methods based upon metal enolates other than titanium have subsequently been developed. In this chapter, ho vever, we vill focus on titanium enoiate-based methods. 

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The anti diastereoselectivity is improved to a 6 1 ratio by the addition of triethylborane to the reaction mixture83. NMR-spectroscopic investigations indicate that a boronate complex is the decisive intermediate84, since it can also be prepared by the addition of alkyllithium to the dialkyl(2-butenyl)borane (path ). 

Surprisingly, the titanated (Z)-carbamates also add to aldehydes with anti diastereoselectivity, although the level of selection is occasionally decreased compared with the (ZsT-substrate16-51. 

Allylic titanates having an electrofugal leaving group, e.g., trimethylsilyl68 75 - 77, at the 3-position are powerful reagents for the highly stereoselective synthesis of 1-hetero-substituted 3-alkadienes. For the carbonyl addition of the appropriate titanated allyl sulfides ( ) or carbamates ( and ), reliable y-selectivity and anti diastereoselectivity are reported. The... 

Both reagents 7 and 9 are also excellently suited for the introduction of 3-substituted allyl residues. Both high simple anti) diastereoselectivity and enantioselectivity are observed, irrespective of the configuration of the double bond in the allylmagnesium, -potassium, or -lithium reagent used for the in situ preparation 11,35 36. 

Following the general rules (Section 1.3.3.1.2.), the racemic ( )-2-butenyl derivative 1 exhibits good anti diastereoselectivity on reaction with benzaldehyde2. This is explained as passing through a six-membered chair-like transition state. 

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. 

Lithium and zinc tert-butyl phenylmethyl sulfoxide (1) and A-phenyl imines 2, in which the substituent R is alkenyl or aryl, react at —78 °C over 2 hours with high anti diastereoselection (d.r. >98.5 1.5)6. Shorter reaction times result in poorer yields, due to incomplete reaction. In contrast, the reaction of the sulfoxide anion with benzaldehyde is complete after 5 seconds, but shows poor diastereoselection. When the substituent R1 or R2 of the imine 2 is aliphatic, the substrates exhibit poor chemical reactivity and diastereoselection. The high anti diastereoselection suggests that if a chelated cyclic transition state is involved (E configuration of the imine), then the boat transition state 4 is favored over its chair counterpart 5. 

In a modified procedure, these additions lead to / ,y- and ) <5-unsaturated amino acid derivatives with cis/trans selectivity >99 1 and syn/anti diastereoselectivity >99 1 (see Section I.5.2.4.2.2.4.)108. 

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. 

When the cyclic enone is unsubstituted, but the resulting enolate is quenched with an electrophile under conditions of kinetic control the irons adduct is formed exclusively303. Particularly successful is the sequential Michael addition/enolate alkylation in diastereoselective routes to frans-a,/j-difunctionalized cycloalkanones and lactones304-308. The key steps in the synthesis of methyl ( + )-jasmonate (3)309-310 (syn/anti diastereoselection) and (-)-khushimone (4) (syn/anti and induced diastereoselection) illustrate this sequence311 (see also Section D. 1.1.1.3.). 

The Lewis acid mediated addition of allylic tin reagents to nitroalkenes has been reported. The condensation reaction of tributyl[(Z)-2-butenyl]tin(IV) with (E)-(2-nitroethenyl)benzene or (L)-l-nitropropene catalyzed by titanium(IV) chloride proceeded with modest anti diastereoselectivity. Poorer diastereoselection resulted when diethyl ether aluminum trichloride complex was employed as the Lewis acid 18. 

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. 

The boron enolates derived from (5)-4-silylated 2,2-dimethyl-l,3-dioxan-5-one undergo anti diastereoselective aldol reactions which provide access to protected oxopolyols of high stereochemical integrity <96SYN1095>. 

Enantiopure 3-phenyl-2-cyanoazetidines (S)-238 and (K)-238, which are epimeric at C2, are prepared in high yields from (K)-phenylglycinol. A one-pot sequence, including addition of organohthium or allyhnagne-sium bromide to the cyano group and in situ reduction of the resulting imine with sodium borohydride, allowed for the preparation of 2-(l-aminoalkyl)azetidines, which were then protected as N-Boc derivatives (R,S)-239 and (S,it)-239 [112] (Scheme 36). Complete anti diastereoselectivity (dr more than 95 5 by NMR) was observed in both cases. The same sequence... 

In the discussion of the stereochemistry of aldol and Mukaiyama reactions, the most important factors in determining the syn or anti diastereoselectivity were identified as the nature of the TS (cyclic, open, or chelated) and the configuration (E or Z) of the enolate. If either the aldehyde or enolate is chiral, an additional factor enters the picture. The aldehyde or enolate then has two nonidentical faces and the stereochemical outcome will depend on facial selectivity. In principle, this applies to any stereocenter in the molecule, but the strongest and most studied effects are those of a- and (3-substituents. If the aldehyde is chiral, particularly when the stereogenic center is adjacent to the carbonyl group, the competition between the two diastereotopic faces of the carbonyl group determines the stereochemical outcome of the reaction. 

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. 

The diastereoselectivity observed in simple systems led to investigation of enantiomerically pure aldehydes. It was found that the E- and Z-2-butenylboronates both exhibit high syn-anti diastereoselectivity with chiral a-substituted aldehydes. However, only the Z-isomer also exhibited high selectivity toward the diastereotopic faces of the aldehyde.38... 

Fig. 12.6. Conformational factors affecting syn and anti diastereoselectivity in Sharpless epoxidation. If substituent R4 > H, A1,3 strain favors the syn product. If R4 = H, the preferred transition structure leads to anti product. Reproduced from/. Org. Chem., 67, 1427 (2002), by permission of the American Chemical Society.

In the hydrogenation of cyclic / -keto esters (ketones substituted with an al-koxycarbonyl moiety), Ru(II)-binap reduced a racemic substrate in DCM with high anti-diastereoselectivity to give a 99 1 mixture of the trans-hydroxy ester (92% ee) and the ds-hydroxy ester (92% ee), quantitatively [Eq. (18)] [119, 120]. 

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. 

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. 

Domino processes can also be performed on open-chain compounds. MacMillan and co-workers demonstrated this with their own imidazolidinone catalysts. Conjugate addition of a nucleophilic heterocycle 231 to the a,(i-unsaturated enal 230 followed by a-chlorination of the resulting enamine led to the syn products 234 in very high enantioselectivities and good sytv.anti diastereoselectivities (Scheme 38) [347]. Similar domino sequences, but with different nucleophile-electrophile partners, were also reported independently by Jprgensen [348]. 

Scheme 6.169 Screening reaction to identify (R,R)-configured guanidine-thiourea 186 as matching catalyst for the anti-diastereoselective and enantioselective Henry reaction of (S)-a-amino aldehydes with nitromethane.

High anti-diastereoselectivity (95 5 dr) and enantioselectivity of the major isomer (99% ee) were obtained when utilizing the combination of (R,R)-catalyst and (S)-aldehyde. This stereochemical outcome (Scheme 6.169) was explained in terms of the Cram rule proposed transition-state model. The substituent on the aldehyde would be located in an onti-relationship to the nitronate. As the largest subshtuent (RJ should be in an anti position to the carbonyl group of the carbonyl substrate, the combination of (R,R)-catalyst 186 and (S)-substrate (TS 1) was favored rather than that of (S,S)-catalyst 183 and (S)-substrate (TS 2) because of the steric repulsion between Rs (smallest substituent) and nitronate (Scheme 6.170). 

Scheme 6.170 Suggested transitions states for the anti-diastereoselective Henry (nitroaldol) reaction promoted by (R,R)-catalyst 186 (TS 1) and its (S,S)-isomer 183 (TS 2) to demonstrate the match/mismatch relationship between guanidine-thiourea catalyst and (S)-a-aldehyde.

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