Evans’ alkylation preparation

In addition, under the help of a chiral auxiliary group, the generated enolate can also react with electrophiles to form of-alkylated ketones," and this specific reaction is called Evans alkylation " (such as in the case for the preparation of discodermolide ). 

An allylic sulfenate, like 199, is known to be in equilibrium with allylic sulfoxide, like 196, although its concentration is usually low . Various allylic sulfoxides can be prepared by treatment of allylic alcohols with arenesulfenyl chlorides . Evans and coworkers prepared various allylic alcohols by treating the corresponding allylic sulfoxides with trimethyl phosphite. For example, the carbanion from a cycloalkenyl sulfoxide 201 was readily alkylated at the a-position by treatment with alkyl halide. The resulting alkylated derivative 202 was then treated with trimethyl phosphite and 3-substituted cycloalkenol was obtained. Alkylation of acyclic allylic sulfoxide 204 gave... 

The application of Evans imides in the preparation of various alkyl acids or the corresponding derivatives can be depicted as in Scheme 2—1829 ... 

The chiral boron enolates generated from /V-acyl oxazolidones such as 7 and 8 (which were named Evans auxiliaries and have been extensively used in the a-alkylation reactions discussed in Chapter 2) have proved to be among the most popular boron enolates due to the ease of their preparation, removal, and recycling and to their excellent stereoselectivity.8... 

Due to these limitations Evans et al. focussed on the exploration of imide-derived enolates (165). They expected these systems to react stereoselective in carbon-carbon bond formation and that the derived imides might be readily hydrolized or reduced under the mild conditions required for the construction of complex products, One of the two chiral 2-oxazolidones (175) chosen for study by Evans et al.179) is derived from (S)-valine and was readily prepared from this inexpensive commercially available a-amino acid having an optical purity exceeding 99 %. The preparation of the related imide-derived enolate (165) is shown in the next scheme. Alkylation reactions employing (175) resulted in excellent diastereoface selection, as summarized in Table 4 179). 

Although the racemization of the a-carbon can now be considered a potential problem, the synthesis of 32-peptides has been achieved in the same way as seen for 33-peptides. As the 32-amino acids cannot be prepared from the analogous a-amino acids, Seebach and co-workers 5,7 opted to use Evans oxazolidinone chemistry to produce enantiomerically pure 32-amino acids. Alkylation of 3-acyloxazolidin-2-ones 17 with A-(chloromethyl)benzamide yielded the products 18 with diastereomeric ratios between 93 7 and 99 1 (Scheme 8). Removal of the chiral auxiliary (Li0H/H202) and debenzoylation (refluxing acid) was followed by ion-exchange chromatography to yield the free 32-amino acids 20 which were converted by standard means into Boc 21 or benzyl ester 22 derivatives for peptide synthesis. 

Fig, 9.34, Apparatus used for the preparation and sampling of Grignard reagents for NMR spectroscopy. The apparatus was evacuated through J2 and the Mg baked. Excess ether and alkyl halide were distilled onto the metal, and the apparatus was sealed off at S3. Upon warming to 0°C and shaking, a rapid reaction occurred. The apparatus was evacuated at Jj, the break-seal B was broken, and ether and excess alkyl halide were removed. Fresh dry ether and the letramethyl silane standard were distilled in, the apparatus was sealed off at S, and a small portion of the solution was filtered through the frit F into the NMR tube, which was sealed off at S2. (Adapted from D. F. Evans and J. P. Mahler, / Chem. Soc.t 1962, 5125.)... 

Chiral glycine enolate synthons have been employed in diastereoselective alkylation reactions [15]. A complementary approach to the synthesis of a-amino acids is the electrophilic amination of chiral enolates developed by Evans [16]. Lithium enolates derived from A-acyloxazolidinones 38, reacted readily with DTBAD to produce the hydrazide adducts 39 in excellent yields and diastereoselectivities (Scheme 18). Carboximides 38 were obtained by A-acylation of (S)-4-(phenylmethyl)-2-oxazoli-dinone and the lithium-Z-enolates of 38 were generated at -78 °C in THF under inert atmosphere using a freshly prepared solution of lithium diisopropylamide (LDA, 1.05 equiv.) [17]. 

In the course of the preparation of maytansinoid model compoimds Goodwin et al. [116] used the regioselective a-alkylation of an allylic sulfide attached to an imidazole imit (one member of the G family depicted in Scheme 44), as already proposed by Evans [106] (Scheme 47). Metalation of 174 led to an allylic lithium compound with the metal chelated by the imidazole unit. This compound readily reacted with iodide 175 dehvering exclu-... 

As an extension of their chiral aldol and alkylation technology, Evans and cowotkers have reported a variety of methods for cleaving and replacing Ae chiral oxazolidinone auxiliary once chain construction has been completed. Included in this methodology was the direct transformation of a chiral imide to an lV-methoxy-/V-methylamide through the use of aluminum amides (prepared in situ). ° This reaction has been shown to be rather general for complex substrates (Scheme 2). ... 

The succinate core can be prepared by alkylation of a simple carboxylic acid (74a or b) with a bromoacetate using the Evans oxazolidinone chiral auxiliary derived from phenylalanine (chapter 27). The branched alkyl group must be present in the substrate for alkylation and the second acid group added in the alkylation so that there is no competition between two carbonyl groups during enolate formation. After hydrolysis (91% yield) the alkylated succinic acid 77 has >95% ee. Notice that the two acid groups are differentiated by this procedure.10... 

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 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... 

Evans and Takacs prepared several chiral auxiliaries derived from amino alcohols such as valinol or prolinol. Prolinol amides such as 473 preferentially form the (Z)-enolate (474) over the ( )-enolate (475). Alkylation proceeds with chelation control and good diastereoselectivity (from the si face) to give the alkylated products 476 and 477, favoring 476 as shown in Table 9.14.23 L20 enolate (474) is preferred over... 

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). 

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