Evans asymmetric alkylation

IS,3S,7R)- methyl-a- hiniachalene 4 Sandlly [Lutzornya iongipalpis) Ms Intramolecular DieJs-Alder reaction catalyzed by EJ AICI and Evans asymmetric alkylation [180] [I8IJ... 

RUjr- himachalene Jp Flea beetle s Evans asymmetric alkylation 1191]... 

Why was our stereochemical conclusion opposite to that of Bartelt s To answer this question, I synthesized (RH/r-himachalene (84) by employing Evans asymmetric alkylation as the key step (Figure 4.25).49 The steric course of the Evans asymmetric process (A->-B) is well established and unambiguous. When the specific rotation of my synthetic (RH/r-himachalene (84) was measured, I immediately found the reason why Bartelt made a mistake. The hydrocarbon 84 was levorotatory in chloroform, but dextrorotatory in hexane. Although Sukh Dev used chloroform in his rotation measurement, Bartelt did not care about the solvent and used hexane, without knowing the fact that a different solvent may change the sign of rotation. 

A recently new designed Wang resin supported Evans chiral auxiliary (52) has been shown to perform Evans asymmetric alkylation on solid support (Scheme 12.19) [34, 35], Preparation of the auxiliary started with coupling of Fmoc-piperidine-4-carboxylic acid to Wang resin. Subsequent removal of the Fmoc protection was followed by coupling to N-protected (2J ,3S)-3-amino-2-hydroxy-4-phenylbutanoic acid. After deprotection, the amino-alcohol moiety was converted into the oxazolidinone auxiliary 52 using carbonyldiimidazole (CDI). 

The Evans asymmetric alkylation [127] and aldol reactions were also effectively applied to the synthesis of the C10-C19 top segment 230 (Scheme 33). The starting chiral unit 223 was synthesized via the Evans asymmetric alkylation of 218a. The subsequent Evans aldol reaction of 223 with 224 followed by trans-amidation yielded 2,3-sy -diol derivative 225 with complete stereoselectivity. Addition of alkyl lithium 226 to the Weinreb amide 225 produced ketone 227, which was stereoselectively reduced and methylated to give dimethyl ether 228. The standard functional group manipulation afforded thioacetal 229, which was converted into phosphine oxide 230. 

The synthesis of the C1-C15 AB spiroketal 457 is described in Scheme 65. The synthesis of the C8-C15 fragment 453 started with allyl TMS 450, prepared by Evans asymmetric alkylation. Addition of 450 to aldehyde 451 with SnCl4 stereo-selectively afforded a-alcohol 452, which was converted into methyl ketone 453 through a sequence of four steps involving Mitsunobu inversion. The synthesis of... 

Synthesis of the C12-C21 Quinone Precursor Portion using Evans Asymmetric Alkylation 45... 

R)-ar hiinachalene -cp Flea beetle S Evans asymmetric alkylation imi]... 

The 1,5-anti-aldol reaction was performed with chiral boron enolate of 325 and aldehyde 327, prepared by Evans asymmetric alkylation, cross metathesis, and Wittig homologation (Scheme 72), to afford 324 with a 96 4 diastereoselectivity. Stereoselective reduction of C9-ketone provided the 5y -l,3-diol, which was exposed to catalytic f-BuOK to give 2,6-cis-tetrahyderopyran 333 via an intramolecular Michael reaction. Finally, methyl etherification, deprotection, hydrolysis of ester, and Yamaguchi macrolac-tonization yielded the leucascandrolide macrolide 201 (Scheme 73). 

Imide Systems. Imide compounds 22 and 23, or Evans reagents, derived from the corresponding oxazolidines are chiral auxiliaries for effective asymmetric alkylation or aldol condensation and have been widely used in the synthesis of a variety of substances. 

Among chiral auxiliaries, l,3-oxazolidine-2-thiones (OZTs) have attracted important interest thanks to there various applications in different synthetic transformations. These simple structures, directly related to the well-documented Evans oxazolidinones, have been explored in asymmetric Diels-Alder reactions and asymmetric alkylations (7V-enoyl derivatives), but mainly in condensation of their 7V-acyl derivatives on aldehydes. Those have shown interesting characteristics in anti-selective aldol reactions or combined asymmetric addition. Normally, the use of chiral auxiliaries which can accomplish chirality transfer with a predictable stereochemistry on new generated stereogenic centers, are indispensable in asymmetric synthesis. The use of OZTs as chiral copula has proven efficient and especially useful for a large number of stereoselective reactions. In addition, OZT heterocycles are helpful synthons that can be specifically functionalized. 

Reviews on stoichiometric asymmetric syntheses M. M. Midland, Reductions with Chiral Boron Reagents, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 2, Academic Press, New York, 1983 E. R. Grandbois, S. I. Howard, and J. D. Morrison, Reductions with Chiral Modifications of Lithium Aluminum Hydride, in J. D. Morrison, ed.. Asymmetric Synthesis, Vol. 2, Chap. 3, Academic Press, New York, 1983 Y. Inouye, J. Oda, and N. Baba, Reductions with Chiral Dihydropyridine Reagents, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 4, Academic Press, New York, 1983 T. Oishi and T. Nakata, Acc. Chem. Res., 17, 338 (1984) G. Solladie, Addition of Chiral Nucleophiles to Aldehydes and Ketones, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 6, Academic Press, New York, 1983 D. A. Evans, Stereoselective Alkylation Reactions of Chiral Metal Enolates, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 1, Academic Press, New York, 1984. C. H. Heathcock, The Aldol Addition Reaction, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 2, Academic Press, New York, 1984 K. A. Lutomski and A. I. Meyers, Asymmetric Synthesis via Chiral Oxazolines, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 

D. A. Evans, Stereoselective Alkylation Reactions of Chiral Metal Enolates, in Asymmetric Synthesis -Stereodifferentiating Reactions, Part B (J. D. Morrison, Ed.), Vol. 3, 1, AP, New York, 1984. 

D. A. Evans, Stereoselective Alkylation Reactions of Chiral Metal Enolates, in Asymmetric Syn-... 

In order to maximize the diastereoselectivity observed for an auxiliary, it would appear reasonable that the stereo controlling functional group is in a position in space as close as possible to the newly forming stereogenic centre. Chiral imide auxiliaries such as Evans N-acyloxazolidinones (1.43) are used for asymmetric alkylation and asymmetric aldol condensation (Scheme 1.10). 

Evans, D. A., Ennis, M. D., Mathre, D. J. Asymmetric alkylation reactions of chiral imide enolates. A practical approach to the enantioselective synthesis of a-substituted carboxylic acid derivatives. J. Am. Chem. Soc. 1982, 104, 1737-1739. 

Application of asymmetric alkylation with Evans auxiliaries Aldol Reactions with Evans Oxazolidinones The syn aldol reaction with boron enolates... 

Application of asymmetric alkylation with Evans auxiliaries... 

A group of compounds that protect cartilage from enzymatic degradation Asymmetric alkylation of Evans s chiral enolates Asymmetric synthesis from an enantiomerically enriched hydroxy-acid Part V - Conformational Control and Resolution Kinetic or Not ... 

It is generally true that restrictions on conformational mobility minimize the number of competing transition states and simplify analysis of the factors that affect selectivity. Chelation of a metal by a heteroatom often provides such restriction and also often places the stereocenter of a chiral auxiliary in close proximity to the a-carbon of an enolate. This proximity often results in very high levels of asymmetric induction. A number of auxiliaries have been developed for the asymmetric alkylation of carboxylic acid derivatives using chelate-enforced intraannular asymmetric induction. The first practical method for asymmetric alkylation of carboxylic acid derivitives utilized oxazolines and was developed by the Meyers group in the 1970 s (Scheme 3.16a), whose efforts established the importance and potential for chelation-induced rigidity in asymmetric induction (reviews [77-79]). In 1980, Sonnet [80] and Evans [81,82] independently reported that the dianions of prolinol amides afford more highly selective asymmetric alkylations (Scheme 3.16b). 

Scheme 3.17. Evans s asymmetric alkylation of oxazolidinone imides [83].

The final fragment is a simple chiral carboxylic acid, so we need a method for its asymmetric synthesis. The most obvious choice is probably an asymmetric alkylation using Evans oxazolidinone auxiliary formation of the appropriate derivative of hexanoic acid is simple, and the enolate will be alkylated diastereoselectively by methyl iodide. You would probably take this approach if you need to make a few grams for initial studies. 

Atrasentan (58, Scheme 2.9), a potent and selective endothelin receptor antagonist developed by Abbott Laboratories (Abbott Park, IL), contains a substituted pyrroh-dine core that was initially accessed in optically pure form via a late-stage classic resolution." A more recent synthesis of atrasentan employs an Evans oxazolidinone in an asymmetric alkylation reaction to introduce the C3 stereocenter on the pyrrolidine ring. To this end, the mixed anhydride 53 was coupled with the L-valine-derived oxazolidinone 54... 

The first report of the use of N-acyl oxazolidinones in asymmetric alkylation was by Evans et al. in 1982. The reactions described were found to proceed with high levels of diastereoselectivity and with very good yields (Table 7.2). The primary factor in determining the stereochemical course of the reaction is the geometry of the enolate intermediate. Studies have shown the level of /Z-enolate control transfers directly to the level of diastereoselectivity of the alkylated product. Conveniently, it has also been established that the use of bulky bases (e.g., EDA and NaHMDS) for the deprotonation of A-acyl oxazolidinones strongly favors formation of the Z-(0)-enolate. Another factor influencing the stereochemical course of the reaction is the nature of the auxiliary itself. In particular, the ability of the... 

This highly convergent synthesis amply demonstrates the utility of Evans s asymmetric aldol and alkylation methodology for the synthesis of polypropionate-derived natural products. By virtue of the molecular complexity and pronounced lability of cytovaricin, this synthesis ranks among the most outstanding synthetic achievements in the macrolide field. 

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