Anh -Felkin selectivity

I.3.4.3.1. Cram-Felkin-Anh Selective Additions of Achiral Enolates to Chiral Aldehydes... 

Scheme 25 Anti-Felkin-Anh selectivity in the reductive aldol reaction of a-alkoxy and a-aminoaldehydes...

Fig. 10.15. Examples and structural requirements for the occurrence of Felkin-Anh selective (top) or chelation-con-trolled (bottom) additions of hydride donors to a-chiral carbonyl compounds. EWG, electron-withdrawing group.

In order for the Cram chelate product to predominate after the addition of a hydride donor to a chiral carbonyl compound, which contains a heteroatom in the a-position, this heteroatom and part of the reagent must he able to form a five-membered ring chelate. If this is not possible, one observes Felkin-Anh selectivity (provided one observes selectivity at all). This has the following interesting consequences for synthesis. 

Fig. 11.11. Wittig-Horner synthesis of stereouniform alkenes via ketophosphine oxide B. The reaction proceeds via its Felkin-Anh-selective or chelate-controlled reduction to form the syn-configured hydroxyphosphine oxides D and the anti-configured hydroxyphosphine oxides E. D and E continue to react—after deprotonation with KO-tert-Bu—via a syn-elimination to give the trans- and cis-alkene, respectively. R1 in the formula A-C corresponds to a primary (prim-alkyl) or a secondary alkyl residue (sec-altyl).

The diastereoselectivities of addition of organometallic compounds to ketones and aldehydes are often quite poor (2 1), and there are numerous cases in which anti-Felkin-Anh selectivity is observed, but the rule is widely invoked anyway. 

If the E-al kcnc is required, reduction of the ketones 127, prepared by acylation of 119 or by oxidation of mixtures of isomers of 122, with NaBH4 in alcoholic solution gives anti-122 selectively. Stereospecific elimination then gives exclusively -126. The reduction is controlled by Felkin-Anh selectivity (see chapter 21). 

The syn selectivity is controlled by the double bond geometry of the trans enolate 272 whereas the more remote aspects of the stereocontrol are controlled by the molecules themselves. Just a note at this point we normally associate trans enolates with anti aldol products -the product observed is called syn only because of the way it is drawn, there is nothing unusual here 275. The chiral centres in the enolate 272 are too remote to be effective and it is those in the aldehyde 273 that control the more remote aspects of stereochemistry. If we want to explain this selectivity, we need to have a reason for why one diastereotopic face of the aldehyde is attacked and not the other. As might be expected, the aldehyde reacts with Felkin-Anh selectivity as described earlier in this chapter. 

These tri(alkoxy)titanium enolates, which have low Lewis acidity, are known to react chemoselective-ly with an aldehyde group in the presence of a ketone (equation 4). Other uses described by Reetz et al. include the diastereofacially selective additions of ketone and ester enolates to chiral a-alkoxy aldehydes with nonchelation control. - For example, aldol addition of the tri(isopropoxy)titanium enolate of pro-piophenone to the aldehyde (24) leads to only the two syn diastereomers, with the nonchelation adduct (25) favored (equation 5) i.e. Felkin-Anh selectivity is operating. In the case of aldol addition of t-butyl propionate to the same aldehyde (equation 6), highest stereoselectivity for the isomer (26) is obtained using the tri(diethylamino)titanium enolate. Very high levels of nonchelation stereoselectivity can also be obtained in the aldol addition to chiral a-siloxy or a-benzyloxy ketones if a titanium enolate of low Lewis acidity is employed, as in equation (7). ... 

Alternative methods for both the chelation-controlled and the Felkin Anh selective reduction of a-oxygenated ketones are described in Section D.2.3.4. (silane reductions). 

Two examples of 1.2-asymmetric induction in the reduction of simple, i.e., nonheteroatom-sub-stituted ketones with dimethylphenylsilane and tris(diethylamino)sulfonium difluorotrimethyl-silicate have been reported4. The predominant stereoisomers are those predicted by Cram s rule, and the diastereomeric ratios suggest that this may be one of the better methods for achieving Cram (Felkin-Anh) selectivity in ketone reductions. 

Figure 5.7. Analysis of possible transition structures for the aldol addition in Scheme 5.26 (a) The observed topicity (b) boat transition structure postulated by Masamune [127] (c) gauche pentane interaction that destabilizes the Cram (or Felkin-Anh) selectivity of the aldehyde (d) anti-Cram (anti Felkin-Anh) addition via a chelated chair [123].

The synthesis of the C29-C43 EF segment 479 is summarized in Scheme 68. Methylation of 467 under Prater s conditions stereoselectively afforded 2,3-anti compound 468 (dr = 5-8 1). After TES protection followed by thioester reduction, aldol reaction of the resulting aldehyde with thioketene acetal afforded a-alcohol 469 under Felkin-Anh selectivity. TES deprotection and silver-mediated lactonization followed by TES protection and lactone reduction gave lactol 470. Dehydration, debenzylation, and oxidation furnished aldehyde 471, which was transformed to benzotriazolyl amide 472. 

Addition of vinyllithium reagent 636 to 632 occurs largely from the re side (Felkin—Anh selectivity) to give the anti diastereomer 637 (85% de) [193]. Lithium—bromine exchange at — 78 °C followed by protonation affords 638 in 89% yield with complete retention of olefin geometry. Ozonolysis of 638 followed by lithium aluminum hydride reduction of the intermediate aldehyde furnishes protected triol 639 in 78% yield. 

The chromium(II)-mediated addition (Hiyama reaction) of chiral allylic bromide 835 to lactaldehyde 831 proceeds with high Felkin—Anh selectivity to furnish exclusively adduct 836 [230]. In addition to the Felkin model, the high stereoselectivity is also explained by the effect of matched pairing of the two reaction partners. If the corresponding R-enantiomer of THP-lactaldehyde 831 is employed ( mismatched pair ), a mixture of three diastereomers (3 1 1) is produced. The THP group of 836 can be removed in the presence of the TBPS protecting group by treatment with PPTS in methanol (54% yield). 

The organolithium compound LiCH20M0M can be prepared by tin-lithium exchange from the corresponding stannane with butyllithium. The stannane is prepared from formaldehyde by addition of BusSnLi followed by 0-protection. The major product from addition of the 2-phenylpropanal is shown below. Addition takes place with the expected Felkin-Anh selectivity (see Scheme 1.91) to give predominantly the syn diastereomer. See W. C. Still, J. Am. Chem. Soc., 100 (1978), 1481 G. A. Molander and A. M. EstevezBraun, Bull. Soc. Chem. Fr., 134 (1997), 275. 

Mulzer J, Kattner L, Strecker AR, Schroder C, Buschmann J, Lehmann C, Luger P (1991) Highly Felkin-Anh selective Hiyama additions of chiral allylic bromides to aldehydes. Application to the first synthesis of nephromopsinic acid and its enantiomer. J Am Chem Soc 113 4218-4229... 

Hashimoto T, Ito J, Nishiyama H. Felkin-Anh selectivity in Rh(bisoxazolinylphenyl)-catalyzed reductive aldol coupling reaction asymmetric synthesis of stereotriads. Tetrahedron 2008 64 9408-9412. 

Numerous examples of additions to carbonyl compounds incorporating a stereogenic center at Ca exist that yield products with impressive diastereo-selectivity, in accordance with the Felkin-Anh transition state model (Scheme 2.2) [51]. In a demonstration of the importance of the metal counterion, Reetz found that nucleophilic addition of organometallic species to (R)-2-phenylpropanal (19) occurs with Felkin-Anh selectivity. The diastereo-selectivity was much more pronounced when organotitanium reagents were... 

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