Oxazolidine enolates

Upon warming, these oxazolinyl-stabilized lithiooxiranes undergo an electrocyclic a-ring opening to give a-oxo-2-oxazolines after hydrolysis (Scheme 87). However, all attempts to quench the presumed oxazolidine enolate intermediates through reaction with electrophiles failed. 

Apparently, cyclization involves the formation of open-chain intermediates 342, 343, further closing up to imidazolidines 344 and oxazolidines 345 which eliminate the secondary amine, thus leading to imidazolines 346 and oxazolines 347. The latter exist in the solution exclusively in the enolic forms 348, 349 which are stabilized by conjugation and intramolecular hydrogen bonds. 

The related serine derived (4S)-4-methoxycarbonyl-3-(l-oxopropyl)-2-thiono-l,3-oxazolidine 11, and the cysteine derived (4A)-4-methoxycarbonyl-3-(l-oxobntyl)-2-thiono-1,3-thiazolidine 13, also serve as efficient chiral auxiliaries in boron- and tin(II)-mediated aldol condensations98. Thus, conversion of 11 into the boron or tin enolate, followed by reaction with 2-methylpropanal affords predominantly one adduct. Subsequent methanolysis and chromatographic purification delivers the syu-methyl ester in 98% ee. 

An entry to. yyrt-2-methoxy-3-hydroxycarboxylic acids is also opened using similar methodology. Thus the norephedrine derived (4/ ,5S)-3-(2-methoxy-l-oxoethyl)-4-methyl-5-phenyl-1,3-oxazolidine-2-one 23105a, as well as the phenylalanine derived (4S)-4-benzyl-3-(2-methoxy-l-oxoethyl)-l,3-oxazolidin-2-one 25105b, can be added to aldehydes via the boron enolates to give, after oxidative workup, the adducts in a stereoselective manner (d.r. 96 4, main product/sum of all others). Subsequent methanolysis affords the methyl esters. 

However, addition of the corresponding oc-unsubstituted enolate, derived from (4S)-3-acetyl-4-isopropyl-1,3-oxazolidin-2-one (3), under similar conditions delivers a 52 48 mixture of dia-slcreomers6 93. 

Rather surprisingly, the lithium enolate derived from the 2-oxo-l,3-oxazolidine 5 is distinctly more selective, and gives the diastereomeric adducts in the ratio of 87 13 when reacted with benzaldehyde. 

Use of the valine derived (4S )-3-acetyl-4-isopropyl-1,3-oxazolidine (8)92, the C2-symmetric reagents (2.5,55)-l-acetyl-2,5-bissubstituted pyrrolidine 994, or the doubly deprotonated acetyl urea /V-acetyl- V..V -bis[(.S)-l-phcnylethyl]urea (10), also does not lead to sufficient induced stereoselectivity combined with acceptable chemical yield. When the acetyl urea enolate is reacted with aliphatic and aromatic aldehydes, the diastereomeric adducts (ratios ranging from 1 1 to 3 1) may be separated by column chromatography to give ultimately both enantiomers of the 3-hydroxy acids in 99% ee110. 

Similar high /(-methyl selectivities are reported for divalent tin enolates of oxazolidine and thiazolidine derivatives1093. 

N-MorphoIinoearbonyI-aniIino)-2-phenyI-acetaldehyd (Enol-Form) liefert mit Lithiumaianat unter Ab-spaltung der Morpholinocarbonyl-Oruppe und C=C-Reduktion 2-Anilino-2-phenyl-dlhanol, mit Natriumboranat wird dagegen 2-Oxo-3,4-diphenyl-1,3-oxazolidin (55%, d.Th.) gebildet4 ... 

These examples and those in Scheme 2.6 illustrate the key variables that determine the stereochemical outcome of aldol addition reactions using chiral auxiliaries. The first element that has to be taken into account is the configuration of the ring system that is used to establish steric differentiation. Then the nature of the TS, whether it is acyclic, cyclic, or chelated must be considered. Generally for boron enolates, reaction proceeds through a cyclic but nonchelated TS. With boron enolates, excess Lewis acid can favor an acyclic TS by coordination with the carbonyl electrophile. Titanium enolates appear to be somewhat variable but can be shifted to chelated TSs by use of excess reagent and by auxiliaries such as oxazolidine-2-thiones that enhance the tendency to chelation. Ultimately, all of the factors play a role in determining which TS is favored. 

Chiral enolates of l,3-dioxalan-4-ones, methyl l,3-oxazolidine-4-carboxylates, and 1,3-imi-dazolidine-4-ones derived from chiral natural sources such as (S )-proline, (Sj-serine, and (S )-threonine are added to nitroalkenes in high diastereoselectivity (Scheme 4.12).77... 

Tejedor and coworkers have utilized a combination of two domino processes for a microwave-promoted synthesis of tetrasubstituted pyrroles [344]. The protocol combines two coupled domino processes the triethylamine-catalyzed synthesis of enol-protected propargylic alcohols and their sequential transformation into pyrroles through a spontaneous rearrangement from 1,3-oxazolidines (Scheme 6.183). Overall, these two linked and coupled domino processes build up two carbon-carbon bonds, two carbon-nitrogen bonds, and an aromatic ring in a regioselective and efficient manner. The tetrasubstituted pyrroles could be directly synthesized from the enol-protected propargylic alcohols and the primary amines by microwave irradia-... 

Very similar transformations have been reported by using titanium enolates of chiral thiazolidine-2-thiones or oxazolidine-2-ones in combination with various in r// -generated acyclic or cyclic iV-acyliminium ions as electrophiles.110-112... 

Table 2-5 summarizes the results of the asymmetric alkylation (Scheme 2-17) of the lithium enolates derived from 22 or 23.28 When chiral auxiliary 22 or 23 is involved in the alkylation reactions, the substituent at C-4 of the oxazolidine ring determines the stereoselectivity and therefore controls the stereogenic outcome of the alkylation reaction. 

Enol ethers 268a-c reacted with N-tosy]-4-vinylidene-l,3-oxazolidin-2-ones to give bicyclic tetrahydropyridine derivatives 269a-c (Table 12.12). Methyl /Tmcthoxyacry-late afforded 269c without formation of the [2 + 2] adduct. 

In studies not yet published (66), the A/-acyl-oxazolidine-2-one 62 has been found to exhibit exceptionally high levels of (Z)-enolization stereoselection with either amide bases (LDA, THF, -78°C) or boryl triflates [(n-C4H9)2BOTf, CH2CI2, -78°C] in the presence of diiso-propylethylamine (DPEA). Upon aldol condensation, the enolates 63a and 63b afford the aldolates 64 (Scheme 11), which react readily with nucleophiles at the carbonyl function (Table 22). As discussed earlier, the large preference for (Z)-enolate formation in this system can be attributed to allylic strain considerations (37)... 

The reactivity of lithium enolates has been explored in a theoretical study of the isomers of C2H30Li, such as the lithium enolate, the acyl lithium, and the a-lithio enol. Imides containing a chiral 2-oxazolidine have been employed for enantioselective protonation of prochiral enolates.A degree of kinetic control of the product E/Z-enolate ratio has been reported for the lithiation of 3,3-diphenylpropiomesitylene, using lithium amides/alkyls. " °... 

The fluorination of enolates of ketone, amide, or hydrazone bearing a chiral auxiliary (SAMP, Evans oxazolidine) with nonchiral fluorination reagent (A-fluoro sulfonimides, A-fluoropyridine) occurs with excellent diastereoselectivities. ... 

Using the same principle as that described for l,3-dioxolan-4-ones, it is possible to a-alkylate 2-amino acids without racemization76,78. An A. O-acetal is formed from an (7 )-amino acid 1, e.g., with trimethylacetaldehyde (R2 = -Bu) the l,3-oxazolidin-5-ones 2 and 3 are furnished with a defined diastereoselectivity, which is the first stage in the process of self-reproduction of chirality 82. Formation of the enolate 4 from 2 and attack of an electrophile in the second step gives the product 6 with retention of configuration in the a-position, and 7 with inversion of configuration, again with a defined diastereoselectivity. Hydrolysis yields the a-alkylated amino acids 10 and 11. 

The enantioselective synthesis of a-amino acids is an important goal in preparative organic chemistry89. The use of l,3-oxazolidin-5-ones for this purpose has already been shown. A number of examples utilizing six-membered heterocycles exist whereby the basic idea remains the same i.e., the nonracemic enolate is attacked preferentially from the less hindered side because of a built-in auxiliary bias which can be removed in the alkylation step in order to liberate the nonracemic a-amino acid90. 

The diastereoselectivity is reversed in the alkylation of the enolate derived from the structurally very similar bicyclic lactam, tetrahydro-3-phenyl-l//.577-pyrrolof 1,2-c]oxazol-5-one (3). Thus, the major diastereomer 4 produced has the tram relationship between the newly introduced substituent in the pyrrolidine ring and the fused oxazolidine ring residue11,12. Only active electrophiles such as iodomethane, 3-halopropenes or (halomethyl)benzenes react11,12. Base-catalyzed equilibration of the product obtained by reaction with 3-bromocyclohexene gives a 50 50 mixture of the cis- and rra s-diastereomers11. 

Enol ethers react with 1,3-oxazolidines in DMSO in the presence of Lewis acids to give 7-alkoxyhexahydro-l,4-oxazepines (76LA1792,1783). 

Masked chiral a-hetero substituted carboxylic acid enolates have also shown utility in dia-stereoselective additions to nitroalkenes. For example, derivatives of a-hydroxycarboxylic acids, e.g. l,3-dioxolan-4-ones (187) a-amino acids, e.g. 1,3-imidazolidin-4-ones (188) and a-amino-fi-hydroxy-carboxylic acids, e.g. methyl 1,3-oxazolidin-4-carboxylates (189) and methyl l,3-oxazolin-4-carboxy-lates (190), have been employed.1S0a Further, diastereoselective additions of chiral (3-hydroxyesters (191), via the enediolates, to nitroalkenes (40) afford predominant anr/ -P-hydroxyesters (192 Scheme... 

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... 

We tried the boron enolates of 3-acetyl-, 3-propionyl-, and 3-butyryl-4-benzyl-oxazolidin-2-one prepared either from BBN-triflate or freshly prepared Bu2OTf under usual reaction conditions. 

Tetrasubstituted pyrroles could be obtained by skeletal rearrangement of 1,3-oxazolidines, a reaction that is substantially accelerated by microwave irradiation. Dielectric heating of a 1,3-oxazolidine 7, absorbed on silica gel (1 g silica gel/mmol) for 5 min in a household MW oven (900 W power) cleanly afforded the 1,2,3,4-tetrasubstituted pyrrole 8 in 78% yield, thus reducing the reaction time from hours to minutes (Scheme 5) [24], 1,3-Oxazolidines are accessible in one-pot, two-step, solvent-free domino processes (see also Sect. 2.6). The first domino process, a multi-component reaction (MCR) between 2 equivalents of alkyl propiolate and 1 equivalent of aldehyde furnished enol ethers 9 (Scheme 5). Subsequent microwave-accelerated solvent-free reactions of enol ethers 9 with primary amines on silica support afforded intermediate 1,3-oxazolidines, which in situ rearranged to the tetrasubstituted pyrroles (2nd domino process). Performed in a one-pot format, these... 

Polysubstituted 1,3-oxazolidines were prepared in a one-pot diversity oriented four-component reaction (4-MCR), comprising two linked domino processes. Thus, domino synthesis of enol ethers 9 was followed by a sequential amine addition-cyclization sequence [74]. While strong microwave irradiation (900 W) of silica-gel absorbed conjugated alkynoates 9 and amines afforded tetrasubstituted pyrroles (via the skeletal rearrangement of 1,3-oxazolidines, see Sect. 2.1 and Scheme 5) [24], the use of milder microwave conditions (160 W power, 90 min) furnished 1,3-oxazolidines. Under these mild conditions the 1,3-oxazolidines did not rearrange to pyrroles and with respect to diastereoselectivity, the 1,3-oxazolidines were obtained as mixtures of syn/anti isomers. Overall, the formation of one C-C bond, one C-0 bond, two C - N bonds and a ring in this MCR required less than 3 hours and utilized simple and commercially available reagents (Scheme 26). 

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