Acyl oxazolidinones

Some enantiomerically pure substituted 2-oxazolidinones are excellent as chiral auxiliaries. From the pioneering studies 2 conducted in the early 1980 s of the uses of such auxiliaries has emerged what is perhaps the most widely used method today for the preparation of enantiomerically highly enriched a-alkylalkanoic acids, alcohols and aldehydes, that is, the alkylation of enolates from chiral 3-acylated 2-oxazolidinones followed by auxiliary removal2 59. The early work has been reviewed60-62. These enantiomerically pure cyclic imide auxiliaries have been used not only for alkylations but also in a plethora of a-functionalization reactions, such as diastereoselective aldol, a-hydroxylation, a-amination and Diels-Alder reactions and these are discussed elsewhere in this volume. 

Section A.5). Indeed, three enantiomeric pairs of 2-oxazolidinones have been commercially available since 1991. Enantiomerically pure 4-phenyl-2-oxazolidinone has likewise been prepared from / -aminobenzeneethanol (phenylglycinol)64. Base-catalyzed acylation of the enantiomerically pure 2-oxazolidinones with an appropriate acyl chloride gives the desired 3-acyl-2-oxazolidinones 3, 6 and 9 which have been used extensively in highly diastereoselective reactions of various types such as alkylations, aldol reactions (see Section D.l.3.4.2.4), hydrox-ylations (see Section D.4.1), aminations (see Section D.7.1) and Diels-Alder reactions (see Section D. 1.6.1.6) alkylation giving products with induced chirality in the a-position. 

Chiral 4-Substitutcd and 4,5-Disubstituted 3-Acyl-2-oxazolidinones 11 General Acylation Procedure4,611,23,24 26 31-53. 

The 3-acyl-2-oxazolidinones are readily deprotonated by strong, sterically hindered amide bases in dry telrahydrofuran at low temperature to afford the. vyn-enolates. Alkylation then provides products with induced chirality in the a-position of the amide with good to excellent di as tereo selectivities. 

In the alkylation reactions of the chiral 3-acyl-2-oxazolidinones, deprotonation to the lithium or sodium enolate is by treatment with lithium diisopropylamide or lithium or sodium hexamethyldisilazanide in tetrahydrofuran at low temperature (usually — 78 °C). The haloalka-ne, usually in excess, is then added to the enolate solution at low temperature (usually — 78 °C) for the sodium enolates and at higher temperatures (between —78 and 0CC) for the lithium enolates. When small, less sterically demanding halides, such as iodomethane, are used the sodium enolate is usually preferred 2 24 and in these cases up to five equivalents2,6- 24,26,27 of the halide are necessary in order to obtain good yields of the alkylation products. Conventional extractive workup provides the crude product as a diastereomeric mixture (d.r. usually > 90 10) which is relatively easy to separate by silica gel chromatography and/or by recrystallization (for crystalline products). Thus, it is possible to obtain one diastereomer in very high diastereomeric purity. 

Enolates or etiolate equivalents from chiral 3-acyl-2-oxazolidinones have also been subjected to electrophiles from various organometallic reagents (see Table n)36-39-44... 

A camphor-based 3-acyl-2-oxazolidinone has also been used for diastereoselective alkylations66. The A-acylated auxiliary 18 is prepared in three steps from 7,7-dimethyl-2-oxobicy-clo[2.2.1]heptane-l-carboxylic acid (ketopinic acid, 17)67. Deprotonation by lithium diiso-propylamide in tetrahydrofuran at — 78 °C and subsequent alkylation with activated halides [(bromo- or (iodomethyl)benzene, 3-bromo- or 3-iodopropene] furnished moderate to good yields of alkylation products in high diastereomeric ratios (>97 3 by H NMR). With added hexamethylphosphoric triamide the alkylation yields are increased and bromoalkanes also give satisfactory yields. The diastereomeric ratios are, however, much lower (d.r. 70 30 to 85 15)67. 

As noted, direct acid- or base-catalyzed hydrolysis of the acyl C-N bond in the chiral alkylated 3-acyl-2-oxazolidinones is usually not practical. This is because it is often very slow and/or results in undesired side reactions such as cleavage of the oxazolidinone ring (there are, however, useful exceptions6 31-41). 

Since the alkylation products are usually crystalline, purification by recrystallization provides the pure diastereomers prior to cleavage. Hydride reduction of these purified alkylation products furnishes chiral, nonracemic alcohols 7 with moderate to high ee. Although not yet demonstrated, saponification of the alkylation products should be possible and would not occur in the ring, thereby providing an advantage over the corresponding 3-acyl-2-oxazolidinones (see Section 1.1.1.3.34.2.1.)6. 

As with the acyl oxazolidinone auxiliaries, each of these systems permits hydrolytic removal and recovery of the chiral auxiliary. 

The substituents direct the approach of the aldehyde. The acyl oxazolidinones can be solvolyzed in water or alcohols to give the enantiomeric (3-hydroxy acid or ester. Alternatively, they can be reduced to aldehydes or alcohols. 

Conditions for arylation of enolate equivalents have also been developed. In the presence of ZnF2, silyl enol ethers, silyl ketene acetals, and similar compounds react. For example, the TMS derivatives of /V-acyl oxazolidinones can be arylated. 

Seebach and Brenner have found that titanium enolates of acyl-oxazolidinones are added to aliphatic and aromatic nitroalkenes in high diastereoselectivity and in good yield. The effect of bases on diastereoselectivity is shown in Eq. 4.59. Hydrogenation of the nitro products yields y-lactams, which can be transformed into y-amino acids. The configuration of the products is assigned by comparison with literature data or X-ray crystal-structure analysis. 

Evans succeeded in oxidizing A-acyl oxazolidinone enolate 143 or 145 using oxaziridine 141 as the oxidant (Scheme 4-55).110 Representative results are summarized in Table 4-19. 

Immobilization of TADDOL-derivatives to silica and treatment with various tita-nium(IV) salts furnished a catalytic system (38) which was utilized in [2-1-3] cycloadditions of diphenylnitrone and acylated oxazolidinone to yield oxazolines (Scheme 4.23) [65]. It is noteworthy that the ligand X has an impact on the outcome of this cycloaddition. While the dichloro catalyst affords the exo-adduct in good yield and with a high stereoselectivity, the corresponding tosyloxy catalyst preferentially affords the endo-cycloadduct. The efficiency of the process is comparable to those obtained with the analogous soluble catalysts. The catalyst, however, had to be recycled prior to each experiment. 

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

The utilization of a-amino acids and their derived 6-araino alcohols in asymmetric synthesis has been extensive. A number of procedures have been reported for the reduction of a variety of amino acid derivatives however, the direct reduction of a-am1no acids with borane has proven to be exceptionally convenient for laboratory-scale reactions. These reductions characteristically proceed in high yield with no perceptible racemization. The resulting p-amino alcohols can, in turn, be transformed into oxazolidinones, which have proven to be versatile chiral auxiliaries. Besides the highly diastereoselective aldol addition reactions, enolates of N-acyl oxazolidinones have been used in conjunction with asymmetric alkylations, halogenations, hydroxylations, acylations, and azide transfer processes, all of which proceed with excellent levels of stereoselectivity. 

A method for enantioselective synthesis of carboxylic acid derivatives is based on alkylation of the enolates of /V-acyl oxazolidinones.59 The lithium enolates have the structures shown because of the tendency for the metal cation to form a chelate. 

The oxazolinone substituents R then direct the approach of the aldehyde. Because of the differing steric encumbrance provided by 1 and 3, the products have the opposite configuration at the new stereogenic sites. The acyl oxazolidinones are easily solvolyzed... 

TABLE 9.29. ENANTIOSELECTIVE FREE RADICAL CONJUGATE ADDITIONS TO a,p-UNSATURATED N-ACYL OXAZOLIDINONES... 

TABLE 9.14 DIELS-ALDER REACTIONS OE A-ACYL OXAZOLIDINONES, 553 TABLE 9.15 DIELS-ALDER REACTIONS WITH VARIOUS DIENOPHILES, 553 TABLE 9.16 ENANTIOSELECTIVE ENE REACTIONS OF ETHYL GLYOXYLATE, 556... 

The enantioselective amination of iV-acyl oxazolidinones has been studied as part of a general approach to the synthesis of arylglycines. In this case, the enolization is initiated by a chiral magnesium bis(sulfonamide) complex. The oxazolidinone imide enolates are generated using catalytic conditions (10 mol% of magnesium complex) and treated in situ with BocN=NBoc to provide the corresponding hydrazide. 20 mol% of iV-methyl-p-toluensulfonamide are added to accelerate the reaction (equation 117). 

Using a similar concept, a square-planar bis(imine)/Cu(OTf)2 complex has been developed, and it has been shown that the 2,6-dichlorophenyl-substituted bis(imine) ligand is, in general, the most effective for the asym metric Diels-Alder reaction of N-acyl oxazolidinones (83-94% ee) [31] (Eq. 16),... 

Narasaka s chiral titanium catalyst, prepared from (Pr 0)2TiCl2 and a tartrate-derived (2R,3R)-l,l,4,4-tetraphenyl-2,3-0-(l-phenylethylidene)-l,2,3,4-butanetetrol, is utilized for the asymmetric [2+2] cycloaddition of A-acyl oxazolidinones to 1,2-propadienyl sulfides possessing a-substituents, which afford methylenecyclobutane derivatives with high enantiomeric purity. These chiral adducts are readily transformed to seven- and eight-membered carbocycles with chiral side chains by the ring-cleavage reaction and subsequent cationic cyclization of the chiral cyclobutane derivative [68] (Eq. 8A.44). 

Oxidative homo-coupling of enolates from acyl oxazolidinones to give the corresponding dimers can be achieved in the presence of oxidants. Titanium and ytterbium enolates of 252 were coupled in the presence of a chiral diol or chiral bisoxazoline in the presence of ferrocenium cation 254 (Scheme 63) [166]. The amount of the meso dimer varied with the chiral ligand with a maximum of 5 1. TADDOL 172 performed best providing a 76% ee for the meso product. Ytterbium enolate gave a low ee of 34% with the same ligand. 

Scheme 14 The alkylation of N-acyl oxazolidinone 43 to afford diastereomers 47 and 48 investigated under continuous flow at —100 °C.

The direct transmetallation of alkenyl, acyl, and alkylzirconocenes to a copper catalyst and subsequent conjugate addition is also possible without a detour via another metal like zinc. For example, Wipf and Takahashi182 reported the highly diastereoselective 1,4-addition of in situ-prepared alkylzirconocenes (e.g., 246) to chiral N-acyl oxazolidinone 245 and similar substrates in the presence of BF3 OEt2 and catalytic amount of CuBr-SMe2, giving adducts of the type 247 with moderate to good yield (Equation (13)). 

Representative procedure. To a solution of Sml2 in THF (2.2 mmol) at —78 °C was added a mixture of the aldehyde (1.0 mmol) and acylated oxazolidinone (1.0 mmol) in THF dropwise over 5 min. The resulting solution was then stirred at —78°C for 30 min, during which time the reaction mixture decolourised. The solution was then quenched with 0.1 M HC1 and the aqueous layer extracted with Et20. The organic layers were washed with sodium thiosulfate and brine, dried (MgS04) and concentrated in vacuo. The crude product was purified by preparative TLC (ethyl acetate-hexane as eluent). 

An asymmetric synthesis of the aminocyclopentitol has been achieved from an acylated oxazolidinone (Scheme 38).110 Thus, the acylated oxazolidinone 295 was subjected to boron triflate-catalyzed condensation with 3-butenal to yield the syn aldol product 297 in 63% yield. Similarly, the A-acyloxazoI idineth ione 296 delivered the aldol adduct 298 in 75% yield when enolized with TiCl4-(—)-sparteine and then... 

This coupling procedure with the thioesters proved sensitive to the substitution pattern of both the amino acid and alkene. In contrast, coupling reactions with the M-acyl oxazolidinone derivatives such as 22 proved to be much more effective (Scheme 14) [20]. Mechanistic studies suggested that an alternative pathway was operating in these cases, where reduction of the al-... 

Scheme 14 Alternative acyl-like radical addition reactions with N-acyl oxazolidinone derivatives of amino acids...

Di-n-butylboryl Trifluoromethanesulfomte with a tertiary amine also provides the (Z)-enolates of chiral acyl oxazolidinones in >100 1 selectivity for use in subsequent aldol additions With Triethylamine, Diisopropylethylamine (Hunig s base), or 2,6-Lutidine the order of addition is of no consequence to enolization." Triethylamine has traditionally seen the greatest utilization in these reactions based upon cost considerations however, with certain sensitive aldehyde substrates, lutidine provides milder reaction conditions." ... 

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