A-Acyloxazolidinone Enolates

Excellent stereoselectivity is attained with the optically active boron enolate 7, prepared from the corresponding A-acyloxazolidinone (see Appendix) and diethylboron trifluoromethanesul-fonate177. The reaction presumably proceeds via a transition state similar to 5. 

Enantioselective enolate alkylation can be done using chiral auxiliaries. (See Section 2.6 of Part A to review the role of chiral auxiliaries in control of reaction stereochemistry.) The most frequently used are the A-acyloxazolidinones.89 The 4-isopropyl and 4-benzyl derivatives, which can be obtained from valine and phenylalanine, respectively, and the c -4-methyl-5-phenyl derivatives are readily available. Another useful auxiliary is the 4-phenyl derivative.90... 

Among the most useful carbonyl derivatives are (V-acyloxazolidinones, and as we shall see in Section 2.3.4, they provide facial selectivity in aldol addition reactions. l,3-Thiazoline-2-thiones constitute another useful type of chiral auxiliary, and they can be used in conjunction with Bu2B03SCF3,44 Sn(03SCF3)2,45 or TiCl446 for generation of enolates. The stereoselectivity of the reactions is consistent with formation of a Z-enolate and reaction through a cyclic TS. 

Among the early attempts of amination of lithium and copper enolates were those which involved formation of a-A-(Boc)- or A-(Alloc)amino-substituted carboxylic esters, A-acyloxazolidinones and diethyl phosphonates (Scheme 33) ° . a-Lithum or a-copper derivatives of these enolates were aminated using A-lithium derivatives of A-Alloc O-(mesitylenesulfonyl)hydroxylamine 3j, NHBocOTos 31 and NHAllocOTos 3m. 

Perhaps the most useful part of the reported synthesis is the facile preparation of (—)-pyrimidoblamic acid (12 Scheme 3). A key to this synthesis is the preparation of the fully substituted pyrimidine 8. This was done by a one-pot inverse electron demand Diels-Alder reaction between the symmetrical triazine 7 and prop-1-ene-1,1-diamine hydrochloride, followed by loss of ammonia, tautomerization, and loss of ethyl cyanoformate through a retro-Diels-Alder reaction. Selective low-temperature reduction of the more electrophilic C2 ester using sodium borohydride afforded 9, the aldehyde derivative of which was condensed with 7V -Boc-protected (3-aminoalaninamide to give the imine 10. Addition of the optically active A-acyloxazolidinone as its stannous Z-enolate provided almost exclusively the desired anti-addition product 11, which was converted into (—)-pyrimidoblamic acid (12). Importantly, this synthesis confirmed Umezawa s assignment of absolute configuration at the benzylic center. 

The stereoselective synthesis of /(-branched a-halocarboxylic acids containing two newly formed chiral centres (155) has been accomplished by a reaction consisting of 1,4-addition of dialkylaluminium chlorides to a,/(-unsaturated A -acyloxazolidinones (154) followed by quenching the intermediate aluminium enolate with /V-halosuccini-mides. The most efficient stereo-control was achieved with oxazolidines derived from glucosamine (154). Although /(-branched aliphatic a-halo carboxylic acids were synthesized stereo selectively, the highest stereoselectivity was observed for (3-aryl substrates.112... 

The diastereoselective alkylation of /V-acyloxazolidinones enolates was examined first. Lithium enolates of 107 were reacted with a variety of alkyl halides, and alkylation products were formed with excellent diastereoselectivities (94-99% de). Hydrolysis gave optically pure carboxylic acids, and the chiral auxiliary was recovered for reuse almost quantitatively.105-106 Highly diastereoselective bromination was also achieved by reaction of the boron enolate of 107 with /V-bromosuccinimide (NBS) (98% de). Optically pure amino acids could be accessed by simple synthetic transformations (Scheme 24.26).106... 

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]. 

The Evans-aldol method using a boron enolate derived from chiral iV-acyloxazolidinone reacted with aldehydes to give syn-aldols via attack exclusively on the re face of the double bond of the enolate (Equation (177)). Unexpected and unusual si face attack was resulted in the reaction with fluorine-containing carbonyl compounds such as trifluoro acetaldehyde (Equation (178)).680 681... 

Enolization of A-Acyloxazolidinones. Various methods have been developed to effect the enolization of chiral N-... 

It has also been reported that 4-substituted-5,5-dimethyloxazoIidin-2-ones can be prepared as illustrated in eq 3. Initially, stereoselective condensation of an N-acyloxazolidinone enolate with acetone affords a functionalized acyl fragment, which is then hydrolyzed to the carboxylic acid. Reaction of the hydroxy acid with DPPA at elevated temperatures yields the target via formation of the acyl azide, Curtius rearrangement and trapping of the isocyanate intermediate by the hydroxyl group (eq 3). 

As an extension of the elegant applications of chiral A -acyloxazolidinones to asymmetric aldolizations and enolate alkylations, Diels-Alder reactions of the unsaturated derivatives (351) and (355) were first described in 1984 (Scheme 86, Table 19). ... 

A -Acyl-oxazolidinones are, therefore, readily available to us. The use of this class of compounds for the preparation of unnatural amino acids has been well documented [5]. Di-ZerZ-butyl azodicarboxylate (DEAD) (3) reacts readily with the lithium enolates of A-acyloxazolidinones to provide hydrazides 4 in excellent yield and high diastereomeric ratio (Scheme 8) these adducts, 4, can be converted to amino acids [14,15]. 

Some progress has been made in performing asymmetric variations of this chemistry. Addition of the anion of sulfoximine ester (272) to achiral (cycloheptadienyl)iron cation complex (271, L = P(OPh)3), followed by desulfurization, affords enantiomerically enriched (273, 50% ee) (Scheme 77). In a similar manner, addition of the enolate derived from a chiral A/-acyloxazolidinone (274) to achiral (cyclohexadienyl)iron cation complex (275) and subsequent auxiliary removal affords (276, 70% ee). 

Two approaches have been studied to access non-racemic products a chiral nucleophile and a chiral auxiliary. In an approach based on Pearson s earUer work with dienyliron and dienemolybdenum complexes [79],Miles used a chiral enolate derived from AT-acyloxazolidinones in a reaction with a prochiral Mn(arene)(CO)3+ complex to give a 3.5 1 mixture of chiral q -dienylmanganese... 

Ultimately, a set of conditions which utilizes 1 equiv of tita-nium(IV) chloride, 1 equiv of (—)-sparteine, and 1 equiv of A/-methylpyrrolidinone as a ligand for the metal center was developed to avoid the need for greater than 1 equiv of (—)-sparteine (eq 12). These enolization conditions are also effective for A acyloxazolidinones and A -acylthiazolidinethiones. ... 

Although this methodology is not successful with acyclic carboxylic acid derivatives (e.g. Weinreb amides, A-acyloxazolidinones, carboxylic esters or thioesters), it is possible to reach this kind of valuable enantiomerically enriched products by a simple oxidation with commercial bleach from the corresponding ketone (Scheme 29, top). If the ketone possesses a substituent prone to oxidation, an alternative procedure, involving the formation of a silyl enol ether (which does not need isolation/purification), can be followed instead (Scheme 29, bottom). 

Stereochemical Control Through Reaction Conditions. In the early 1990s it was found that the stereochemistry of reactions of boron enolates of N-acyloxazolidinones can be altered by using a Lewis acid complex of the aldehyde or an excess of the Lewis acid. These reactions are considered to take place through an open TS, with the stereoselectivity dependent on the steric demands of the Lewis acid. With various aldehydes, TiCl4 gave a syn isomer, whereas the reaction was... 

Silyl enol ethers have also been used as a trap for electrophilic radicals derived from a-haloesters [36] or perfluoroalkyl iodides [32]. They afford the a-alkylated ketones after acidic treatment of the intermediate silyl enol ethers (Scheme 19, Eq. 19a). Similarly, silyl ketene acetals are converted into o -pcriluoroalkyl esters upon treatment with per fluoro alkyl iodides [32, 47]. The Et3B/02-mediated diastereoselective trifluoromethylation [48,49] (Eq. 19b) and (ethoxycarbonyl)difluoromethylation [50,51] of lithium eno-lates derived from N-acyloxazolidinones have also been achieved. More recently, Mikami [52] succeeded in the trifluoromethylation of ketone enolates... 

Although iV-acyloxazolidinones 88 and iV-acylthiazolidinethiones 90 lead to an anti aldol, the respective products 89 and 91 present a different anti configuration. Consequently, the corresponding derived magnesium enolates exhibit the opposite face selection in these reactions. On the basis of previous results involving enolates of various metal complexes such as boron, titanium, lithium or sodium enolates, the (Z)-metal enolate... 

Dialkylboron trifluoromethanesulfonates (triflates) are particularly useful reagents for the preparation of boron enolates from carbonyl compounds, including ketones, thioesters and acyloxazolidinones.4 Recently, the combination of dicylohexylboron trifluoromethanesulfonate and triethylamine was found to effect the enolization of carboxylic esters.5 The boron-mediated asymmetric aldol reaction of carboxylic esters is particularly useful for the construction of anti (3-hydroxy-a-methyl carbonyl units.6 The present procedure is a slight modification of that reported by Brown, et al.2... 

In conclusion, the animation of enolates of N-acyloxazolidinones with dibenzyl or di-r-butylazodicarboxylates presented the following properties (i) diastereomeric excesses in the range 80-98% (ii) good chemical yields (iii) efficient route to both chiral a-hydrazino and a-amino acid derivatives and (iv) non-destructive removal of the chiral oxazolidinone auxiliaries. 

Anions generated from tertiary amides preferentially assumed the Z-configura-tion. Reaction of MA-dimethylamides with 1 equiv. of LDA at -78 °C followed by addition of 1.5 equiv. of di(-)-isobomyl azodicarboxylate 97c gave in each case a 1 1 ratio of diastereomers (/ )-99 and (S)-99 (Table 3.10, entries 7 and 8). Double diastereoselection was tested with chiral enolates enantiomerically pure /V-acyloxazolidinone (S)-100 and its enantiomer (/ )-100 were aminated at -78 °C with 97c (Scheme 47). 

Evans and co-workers have reported successful diazo transfer from p-nitrobenzenesulfonyl azide (PNBSA) to the enolate derivatives of an N-acyloxazolidinone and a benzyl ester (a) Evans, D. A. Britton, T. C. Ellman, J. A. Dorow, R. L. J. Am. Chem. Soc. 1990, 112, 4011. However, we have not been able to achieve efficient diazo transfer to ketone enolates employing these conditions. For example, exposure of the lithium enolate of acetophenone to 1.2 equiv of PNBSA in THF at -TS C for 15 min gave a-diazoacetophenone in only 21% yield. 

Coixjugate Addition Reactions. a,3-Unsaturated N-acyloxazolidinones have been implemented as Michael acceptors, inducing chirality in the same sense as in enolate alkylation reactions. Chiral a,3-unsaturated imides undergo 1,4-addition when treated with diethylaluminum chloride (eq 55). Photochemical initiation is required for the analogous reaction with Dimethylaluminum Chloride. ... 

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