Evans’ chiral oxazolidinone

The first enantioselective synthesis of pregabalin (2) was developed by Yuen and co-workers at Pfizer using Evans chiral oxazolidinone chemistry (Yuen et al., 1994). 

In a related contribution O Brien described the AA on styrenes and converted the amino alcohols into enantiopure diamines by using a reaction strategy similar to Janda s [83], Further synthetic applications of the AA include a new access to Evans chiral oxazolidinones [84], the enantioselective synthesis of a-amino ketones from silyl enol ethers [85], the stereoselective synthesis of cyclohexyl norstatine [86], and a route towards amino cyclitols by aminohydroxy-lation of dienylsilanes [87]. 

In search for control of absolute stereochemistry, the reaction of thio-chalcones was investigated with unsaturated amides bearing an Evans chiral oxazolidinone [223] and dimenthyl fumarate [224, 225]. For the first time with thiocarbonyl compounds, the efficiency of Lewis acid addition was demonstrated, and reactions could be conducted at room temperature. With EtAlCl2 (Table 4, entry 2) or A1C13 (entry 3), levels of induction up to 92% were attained for the endo isomer. Yb(OTf)3 in DMSO also caused the acceleration of the reaction with chiral acrylamides with p-facial selectivity [226]. This group has also reported [227] an intramolecular hetero Diels-Alder reaction with divinyl thioketones and the double bond of an allyloxy group (Table 4, entry 4). 

The scope and diastereoselectivity of reactions with various electrophiles are shown below. The only weak point is the poor diastereoselectivity in aldol reactions with aldehydes. These methods have been widely used as they are robust and reliable. Nevertheless the methods we have so far described for chiral enolates are less significant than the Evans chiral oxazolidinones in the next section. 

Recently, in a related approach by Evans, chiral oxazolidinones derived from (lR,25)-norephedrine and (5)-phenylalanine were employed to prepare novel, chiral sulfinyl transfer reagents (15) and (16), respectively [26]. 

The seminal work in the area of organometallic peptides with catalytic activity was carried out by Gilbertson et al. from the 1990s. This group synthesized diphenyl- and (dicylohexylphosphino)serine (Pps and Cps) according to the Evans chiral oxazolidinone chemistry route (Figure 10.18) [91,92]. These amino... 

Azide Transfer to Enolates. Evans chiral oxazolidinone auxiliaries continue to be widely used in the azide transfer to enolates because high stereoselectivity can be achieved (eqs 21, 22, and 233 ). 

Jamison synthesis of amphidinolide T1 started with the preparation of alkyne 201 via a diastereoselective propar-gylation using Evans chiral oxazolidinone auxihary and 3-bromo-l-phenyl-l-propyne [112] followed by the reduction of the diamide and protection of the resulting primary alcohol as a (er(-butyldimethylsilylether (Scheme 2.85). The latter was then engaged in the first transition metal-catalyzed reductive coupling in the presence of chiral epoxide 204 to... 

S)-4-isopropyl-2-oxazolidinone, 82% Scheme 2-19. Synthesis of Evans chiral auxiliary 25. 

Asymmetric aldol condensation of aldehyde and chiral acyl oxazolidinone, the Evans chiral auxiliary. 

James R. Gage and David A. Evans 83 DIASTEREOSELECTIVE ALDOL CONDENSATION USING A CHIRAL OXAZOLIDINONE AUXILIARY (2S, 3S )-3-HYDR0XY-3-PHENYL-2-METHYLPROPANOIC ACID... 

The initial work on the asymmetric [4-1-2] cycloaddition reactions of A -sulfinyl compounds and dienes was performed with chiral titanium catalysts, but low ee s were observed <2002TA2407, 2001TA2937, 2000TL3743>. A great improvement in the enantioselectivity for the reaction of AT-sulfinyl dienophiles 249 or 250 and acyclic diene 251 or 1,3-cyclohexadiene 252 was observed in the processes involving catalysis with Cu(ll) and Zn(ii) complexes of Evans bis(oxazolidinone) (BOX) ligands 253 and 254 <2004JOC7198> (Scheme 34). While the preparation of enantio-merically enriched hetero-Diels-Alder adduct 255 requires a stoichometric amount of chiral Lewis acid complex, a catalytic asymmetric synthesis of 44 is achieved upon the addition of TMSOTf. 

It has been demonstrated that optically active oxetanes can be formed from oxazolidinone 92, a crotonic acid moiety functionalized with Evans chiral auxiliary (Scheme 18) <1997JOC5048>. In this two-step aldol-cyclization sequence, the use of 92 in a deconjugative aldol reaction, with boron enolates and ethanal, led to formation of the syn-aldol 93. This product was then converted to the corresponding oxetanes, 94a and 94b, via a cyclization with iodine and sodium hydrogencarbonate. This reaction sequence was explored with other aldehydes to yield optically active oxetanes in similar yields. Unlike previous experiments using the methyl ester of crotonic acid, in an analogous reaction sequence rather than the oxazolidinone, there was no competing THF formation. 

Another type of substitution reaction is increasing in popularity—the use of an allylic substrate, such as an allyl acetate where the nucleophile is introduced with stereochemical control in the presence of a palladium catalyst and a chiral ligand. Reactions where a chiral anion, be it derived from a chiral heteroatom group, such as a sulfoxide, or an auxiliary, such as Evans s oxazolidinones, are not included in this chapter because the alkyl halide is usually relatively simple and the stereochemical selectivity is derived from the system itself. 

The first example of a chiral-auxiliary-induced [2+2] cycloaddition between 02 and oxazolidinone-functionalized enecarbamates, which proceeds with complete diastereoselectivity as a result of steric repulsions, has been reported to afford 57 <02JACS8814>. The optically active enecarbamates bearing Evans chiral auxiliary were photooxygenated at -35 °C with 5,10,15,20-tetrakis(pentafluorophenyl)porphine (TPFPP) as sensitizer and an 800 W sodium lamp as light source. The dioxetanes 57 were obtained exclusively, but they readily decomposed at room temperature to the expected carbonyl products because of their thermally labile nature. The absolute configuration of the dioxetanes 57 was established by reduction to the corresponding diols with L-methionine. 

Chiral auxiliaries can be used in plenty of other reactions, and one of the most common types is the alkylation of enolates. Evans s oxazolidinone auxiliaries are particularly appropriate here because they are readily turned into enolizable carboxylic acid derivatives. 

An alternative to the Evans chiral auxiliary described in the chapter is this oxazolidinone, made from natural phenylalanine. What strategy is used for this synthesis and why are die conditions and mechanism of the reactions important ... 

In a broad program of using chiral oxazolidinones in asymmetric synthesis,100 Evans s group published a paper in 1992 on the synthesis and utilization of fV-sulfinyl oxazolidinones as new sulfinylating agent.87 Two chiral auxiliaries were used in the study oxazolidinones derived from (4R, 5S)-norephedrine 74101 and (45)-phenylalanine 75.102 The corresponding fV-sulfinyl oxazolidinones 77 and 78 were obtained either by sulfmylation of the metallated oxazolidinone or by oxidation of the derived N-sulfenamides (Table 15). 

Chiral oxazolidinone auxiliaries based on D-glucose were used for aldol reactions by Koell et al. [160]. The highest select vities were observed with auxiliaries equipped with the pivaloyl protecting group. The pivaloylated oxazolidinone 228 was transformed into the boron enolate according to the procedure of Evans [161] and subsequently reacted with aliphatic and aromatic aldehydes. The best results were obtained with isobutyric aldehyde (Scheme 10.77). The syn-dldo 229 was formed in 16-fold excess over the a/i Z-diastereomer and with an acceptable yield of 59%. The authors explain the stereoselectivity by a chair-like transition state according to Zimmermann-Traxler. The electrophile approaches at the less hindered r -face of the (Z)-configured enolate double bond. For A -phenacetyl substituents, an inversed stereoselectivity was observed as described above for these oxazolidinone auxiliaries. 

Evans and coworkers have developed chiral oxazolidinone auxiliaries such as 10 and 11 that are easily obtainable from (5)-vanilol or from (liS, 2R)-norephedrine. As well as the excellent selectivities obtained in aldol reactions, ease of attachment and removal of these auxiliaries has made this method widely popular. The auxiliary may be recovered and reused after cleavage from the aldol product. 

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). ... 

We have introduced you to this chiral auxiliary before any other because it is more commonly used than any other. It is a member of the oxazolidinone (the name of the heterocyclic ring) family of auxiliaries developed by David Evans at Harvard University, and is easily and cheaply made from the amino acid (S)-valine. Not only is it cheaply made it can also be recycled. The last step of the route above, transesterification with benzyl alcohol, regenerates the auxiliary ready for re-use. synthesis of Evans s oxazolidinone chiral auxiliary from (S)-valine NH2 NH2... 

If you have got the idea by now that parallel kinetic resolutions are a complicated business then the next example will show just how simply they can be achieved. Eames set about using different (pseudo-enantiomeric) Evans auxiliaries to resolve an ester.34 However, the auxiliaries are nothing of the sort in this reaction. On each side of the reaction, an enantiomerically pure oxazolidinone is reacted with a racemic ester 63 which is to be resolved. A crucial foundation to the work was to establish which chiral oxazolidinones show good selectivity. This was done with racemic oxazo-lidinones and racemic substrate. Using racemic oxazolidinone exposes the diastereoselectivity of the reaction without the complication of the concentration of the substrate enantiomers varying as the reaction proceeds. It also mimics the environment of the parallel kinetic resolution itself. 

The oxazoline 184 provides an attractive approach to lactacystin as it is a protected form of 3-hydroxyleucine. The other half of the molecule was made in the LeukoSite synthesis by a very different method the alkylation of an Evans chiral auxiliary. This was chosen partly because they wished to vary the alkyl group on the pyrrolidone ring and we use the propyl compound as example. The phenylalanine derived oxazolidinone 193 (chapter 27) was acylated and then the titanium enolate of 194 was alkylated to give 195 with very high selectivity and the chiral auxiliary removed to give the simple acid 196. 

Evans s oxazolidinones 1.116 and 1.117 are a class of chiral auxiliaries that has been widely applied [160, 167, 261, 411]. Deprotonation of 7/-acyl-l,3-oxa-zolidin-2-ones 5 30 and 5.31 smoothly gives chelated Z-enolates, which then suffer alkylation between -78 and -30°C on their least hindered face [167, 1036]. After hydrolysis, the corresponding enantiomeric acids are obtained according to the auxiliary that was used (Figure 5.21). Due to the low reactivity of lithium enolates, sodium analogs are preferred in some cases [411, 862, 1036], This methodology has been applied to the synthesis of chiral a-arylpropionic acid anti-inflammatory drugs [1037, 1038], natural products [1039, 1040], and a-substituted optically active 3-lactams en route to nonracemic a,a-disubstituted aminoacids [136,1041]. 

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). 

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