Oxazolidinone acrylate

Asymmetric Diels-Alder reaction of 2-azadienes with acrylates using Cu(OTf)2 as a Lewis acid has been reported (Sch. 53) [99]. The reaction gives the exo product (244) with high enantioselectivity. Copper Lewis acid-mediated Diels-Alder reactions of thiabutadienes with oxazolidinone acrylate 196 have also been reported [100]. 

Highly diastereoselective allylations were also achieved in a slightly different manner through radical addition to chiral oxazolidinone acrylate and trapping with allylstannane [25]. In reactions with a,yS-unsaturated substrates, the Lewis acid... 

Moreno-Manas and coworkers have employed a Cu(SbF6)2/Adam-BOX (245) complex in an oxazolidinone acrylate (244) Diels-Alder cycloaddition (Scheme 17.54) [75]. The isolated yield of cycloadduct (246) is low relative to other Cu(II)/bisoxazoline complexes, but the diastereo- and enantioselectivity remains high. 

Enantioselective aza-Diels-Alder reactions utilizing 2-azadienes as the heterodiene have been reported by Jnoff and Ghosez (Scheme 17.66) [95]. Cycloadditions of 2-azadienes (294) with oxazolidinone acrylates (244) or (253) catalyzed by Cu(OTf)2/t-Bu-BOX (13) give exo products (295) in good yields and excellent enantioselectivities. 

The TiX2-TADD0Late-catalyzed 1,3-dipolar q cloaddition reactions were extended to include an acrylate derivative [66]. In the absence of a catalyst, the reaction between nitrones 1 and acryloyl oxazolidinone 19b proceeded to give a mixture all eight regio-and stereoisomers (Scheme 6.23). However, application of in this case only 10 mol% of Ti(OTs)2-TADDOLate 23d as catalyst for the reaction of various nitrones 1 with alkene 19b, led to complete regioselectivity and high endo selectivity in the reaction and the endo products 21 were obtained with 48-70% ee (Scheme 6.23) [66]. 

No single examples have been reported so far for the catalyzed asymmetric diazoalkane cydoadditions. Based on the kinetic data on the relative reaction rates observed by Huisgen in the competitive diazomethane cydoadditions between 1-alkene and acrylic ester (Scheme 7.32), it is found that diazomethane is most nu-deophilic of all the 1,3-dipoles examined (kaciyiate/fci-aikene = 250000) [78]. Accordingly, the cydoadditions of diazoalkanes to electron-defident alkenes must be most efficient when catalyzed by a Lewis acid catalyst. The author s group has become aware of this possibility and started to study the catalyzed enantioselective diazoalkane cydoadditions of 3-(2-alkenoyl)-2-oxazolidinones. 

The oxazoline ring acts as an electron-withdrawing group for a substituent at the 2-position. Thus, the ot-protons of a 2-alkyloxazoline exhibit some acidity and can be abstracted by a base. A 2-alkenyloxazoline can be viewed as a masked acrylic acid derivative and is capable of undergoing Michael addition and Diels-Alder reactions. These reactions can often be carried out stereoselectively using a chiral oxazoline. Other types of chiral auxilliaries, most notably oxazolidinones, are also very effective for these types of applications. However, they are outside the scope of this chapter. The discussion in this section will focus on the new developments with oxazolines. 

With Tartrate-Derived Chiral 1,4-Diol/Ti Complexes A catalytic asymmetric Diels-Alder reaction is promoted by the use of a chiral titanium catalyst prepared in situ from (Pr O TiC and a tartrate-derived (2.R,3.R)-l,l>4,4-tetraphenyl-2,3-0-(l-phenylethylidene)-l,2,3,4-butanetetrol. This chiral titanium catalyst, developed by Narasaka, has been successfully executed with oxazolidinone derivatives of 3-borylpropenoic acids as P-hydroxy acrylic acid equivalents [40] (Eq. 8A.21). The resulting chiral adduct can be utilized for the first asymmetric total synthesis of a highly oxygenated sesquiterpene, (-i-)-Paniculide. 

In three-component allyltin-mediated processes, if the alkenes contain a chiral auxiliary, the allylation step proceeds with a high degree of stereocontrol [35]. In an example in Scheme 6.20, an acrylated oxazolidinone having a chiral substituent in the ring is employed as the alkene portion. Magnesium bromide is used as a Lewis acid to fix the acrylate moiety [36]. Allylation takes place diastereoselectively so as to avoid the face in which the bulky diphenylmethyl group is located. 

Enantioselective Diels-Alder catalyst.3 The aluminum reagent 2, prepared by reaction of (CH3)3A1 with the N,N-ditriflate of (S,S)-1, is an effective catalyst for asymmetric Diels-Alder reactions of acrylates with dienes. Particularly high enan-tioselectivity obtains in the reaction of 3-acrylyl-l,3-oxazolidinone-2 with cyclopen-tadiene. In this case, the endo-exo ratio is >50 1, and the optical yield is 90%. The stereoselectivity probably results from binding of the catalyst to the acrylyl carbon group. 

Merck has used the L-phenylalanine-derived Evans oxazolidinone to make matrix metalloproteinase inhibitors such as 45 (Scheme 23.14) (see also Chapter 2).62 The mixed anhydride of 4-butyric acid was reacted with the lithium anion of the oxazolidinone. This was enolized with the standard titanium reagents. An enantioselective Michael addition was then carried out by the addition of t-butyl acrylate at low temperature. The auxiliary was removed with LiOH/peroxides to give the acid, which was further derivatized over multiple steps to yield the desired drug. 

Narasaka has demonstrated that TADDOL-Ti dichloride prepared from TADDOL and Cl2Ti(OPr )2 in the presence of MS 4A acts as an efficient catalyst in asymmetric catalytic Diels-Alder reactions with oxazolidinone derivatives of acrylates, a results in extremely high enantioselectivity (Sch. 45) [112]. Narasaka reported an intramolecular version of the Diels-Alder reaction, the product of which can be transformed into key intermediates for the syntheses of dihydrocompactin and dihydromevinolin (Sch. 46) [113]. Seebach and Chapuis/Jurczak [114] independently reported asymmetric Diels-Alder reactions promoted by chiral TADDOL- and 3,3 -diphenyl BINOL-derived titanium alkoxides. Other types of chiral diol ligands were also explored by Hermann [115] and Oh [116]. 

Some thermally forbidden [2 + 2]-cycloaddition reactions can be promoted by Lewis acids1-6. With chirally modified Lewis acids, the opportunity for application in asymmetric synthesis of chiral cyclobutanes arises (for a detailed description of these methods see Sections D.l. 6.1.3.. D.l. 61.4. and references 7, 28-30). Thus, a chiral titanium reagent, generated in situ from dichloro(diisopropoxy)titanium and a chiral diol 3, derived from tartaric acid, catalyzes the [2 + 2]-cycloaddition reaction of 2-oxazolidinone derivatives of a,/ -unsalurated acids 1 and the ketene thioacetal 2 in the presence of molecular sieves 4 A with up to 96 % yield and 98% ee. Fumaric acid substrates give higher yields and enantiomeric excesses than acrylic acid derivatives8. Michael additions are almost completely suppressed under these reaction... 

Applications of chirally modified titanium Lewis acids have been reported most cases use various acetal diols derived from tartrate as the chiral auxiliary26 33,31 90. Various methods of catalyst preparation are known, as well as the use of different types of dienes (open-chained, cyclopentadiene) and dienophiles (acroleins, acrylates, crotonates, fumarates and amides derived from oxazolidinone), including intramolecular cycloaddition30. Addition of 4 A molecular sieves can improve asymmetric induction31,34 (as observed with the Sharpless epoxidation, loc. cit 31 in ref 6) and shows remarkable solvent effects on enantioselectivity. This method has been applied to the asymmetric Diels-Alder cycloaddition of cyclopentadiene and open-chain dienes to acrylamides28, 35. 

In the past Lewis acid-catalyzed [4+2] cycloaddition reactions of chiral alkyl acrylates have been systematically studied. Chiral auxiliaries derived from camphor, menthol and amino acids or from carbohydrates have been developed. Stereochemical and theoretical aspects of these chiral inductors have been intensively reviewed (see. Chapter 6). Asymmetric Diels-Alder reactions of chiral acrylamides derived from Ca-symmetrical secondary amines lead selectively to the cycloadducts in the presence of Lewis acids such as AICI3. In reactions of chiral auxiliaries derived from (iS)-proline and (iS)-prolinol excellent endo/exo selectivities and diastereoselectivities were obtained in the presence of catalytic amounts of Et2AlCl or TiCL. Cycloadducts of chiral crotonoyl derivatives derived from oxazolidinones 62, sultam 63 or for example (S)-lactate IS were obtained with high selectivities in the presence of Lewis acids such as Et2AICl. 

Phenoxyethyl acrylate Piperonyl acetone C11H13CIO3 MCPB C11H13NO4 Acetyltyrosine Bendiocarb Oxazolidinone C11H14CINO Propachlor C11H14N2... 

Yamazaki et al. employed the Evans oxazolidinone enolate in diastereoselective Michael additions to /I-CF3 acrylates to afford intermediate allyl silyl ketene acetals [8]. The products were isolated as ca. 2 1 mixtures of pentenoic acids and Michael addition adducts (Scheme 4.59). The rearrangement of the silyl ketene acetal was catalyzed by PdCl2(CH3CN)2. The rearrangement apparently occurred via the Z-silyl ketene acetal and exhibited high 1,2-asymmetric induction. Aspects of stereochemical control and Pd catalysis have been discussed previously (cf Scheme 4.25). 

Narasaka reported that TADDOL-TiCl2 was able to catalyze asymmetric DA reaction of cyclopentadiene with oxazolidinone derivatives of acrylates in the presence of 4A MS [148]. A remarkable solvent effect on the enantioselectivity was observed, and high enantioselectivity was attained using mesitylene as the solvent. Cycloadditions to oxazolidinone derivatives of acrylates were also efficiently catalyzed by dendritic or polymer-supported TADDOL-Ti catalysts [149]. From the structural determination of the 3-(( )-3-cinnamoyl)-l,3-oxazolidin-2-one adduct, it can be deduced that the transition state involves binding of the dienophile to the titanium catalyst via the N-acyl-oxazolidinone [19a] (Scheme 14.59). The diastereo-and enantioselectivity of this type of catalyst are thus probably owing to both electronic and steric effects from TADDOL ligand. 

The use of radical translocation to generate cyclic radicals which can then add intramolecularly in a stereoselective manner to give addition products has been reported. The diastereoselective addition at C(4) of 1,3-oxazolidinones was examined using this approach. Thus, 1,5-hydrogen translocation from the aryl radical generated from (51) gives the C(4) radical, which can undergo radical addition to acrylate to furnish a 3 1 mixture of diastereomers (52). ... 

Related Reagents. Acrylonitrile boron trifluoride etherate ceric(rV) ammonium nitrate 2,3-dichloro-5,6-dicyano-/7-benzo-quinone drrhodium(II) tetrakis[methyl 4(/J)-2-oxazolidinone-4-carboxylate] drrhodium(II) tetrakis[(5)-Ai-phthaloyl-r-leucinate] DMSO epichlorohydrin lithium aluminum hydride methyl acrylate methyl lithium methyl triflate tetrabuty-lammonium fluoride trimethylsilyl chloride rhodium(II) tetraacetate. 

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