Oxazolidinone aldol reactions

Reaction progress kinetic analysis offers a reliable alternative method to assess the stability of the active catalyst concentration, again based on our concept of excess [e]. In contrast to our different excess experiments described above, now we carry out a set of experiments at the same value of excess [ej. We consider again the proline-mediated aldol reaction shown in Scheme 50.1. Under reaction conditions, the proline catalyst can undergo side reactions with aldehydes to form inactive cyclic species called oxazolidinones, effectively decreasing the active catalyst concentration. It has recently been shown that addition of small amounts of water to the reaction mixture can eliminate this catalyst deactivation. Reaction progress kinetic analysis of experiments carried out at the same excess [e] can be used to confirm the deactivation of proline in the absence of added water as well to demonstrate that the proline concentration remains constant when water is present. 

Stereochemical Control Through Chiral Auxiliaries. Another approach to control of stereochemistry is installation of a chiral auxiliary, which can achieve a high degree of facial selectivity.124 A very useful method for enantioselective aldol reactions is based on the oxazolidinones 10,11, and 12. These compounds are available in enantiomerically pure form and can be used to obtain either enantiomer of the desired product. 

Ring D inversion seems to be a crucial step in biogenetic transformations of protoberberines to related alkaloids such as rhoeadine, retroprotoberberine, spirobenzylisoquinoline, and indenobenzazepine alkaloids. 8,14-Cyclober-bin-13-ol 478 derived from berberine (15) was successively treated with ethyl chloroformate, silver nitrate, and pyridinium dichromate (PDC) in dimethyl-formamide to give the keto oxazolidinone 479 (Scheme 98). Heating of 479 with 10% aqueous sodium hydroxide in ethanol effected hydrolysis, retro-aldol reaction, cyclization, and dehydration to provide successfully the... 

Among chiral auxiliaries, l,3-oxazolidine-2-thiones (OZTs) have attracted important interest thanks to there various applications in different synthetic transformations. These simple structures, directly related to the well-documented Evans oxazolidinones, have been explored in asymmetric Diels-Alder reactions and asymmetric alkylations (7V-enoyl derivatives), but mainly in condensation of their 7V-acyl derivatives on aldehydes. Those have shown interesting characteristics in anti-selective aldol reactions or combined asymmetric addition. Normally, the use of chiral auxiliaries which can accomplish chirality transfer with a predictable stereochemistry on new generated stereogenic centers, are indispensable in asymmetric synthesis. The use of OZTs as chiral copula has proven efficient and especially useful for a large number of stereoselective reactions. In addition, OZT heterocycles are helpful synthons that can be specifically functionalized. 

Novel aldol-type reactions under Cinchona-deriwed chiral thiourea catalysis was reported by Wang et al. [78]. In their report, a novel cascade Michael-aldol reaction was presented. The reaction involves a tandem reaction catalyzed via hydrogen-bonding with as little as 1 mol% catalyst loading to generate a product with three stereogenic centers (Scheme 28). hi the reaction of 2-mercaptobenzaldehyde 128 and a,P-unsatnrated oxazolidinone 129, the desired benzothiopyran 130 was formed smoothly in high yield and excellent stereoselectivity. 

The preceding reactions illustrate control of stereochemistry by aldehyde substituents. Substantial effort has also been devoted to use of chiral auxiliaries and chiral catalysts to effect enantioselective aldol reactions.71 72 Avery useful approach for enantioselective aldol condensations has been based on the oxazolidinones 1-3, which are readily available in enantiomerically pure form. 

Conversion of 2 to the highly crystalline oxazolidinone 3 with phosgene has been described by Thornton who has employed this substance as a chiral auxiliary in asymmetric aldol reactions of its N-propionyl derivative. Kelly has also used an oxazoline derived from 3 as a chiral auxiliary in asymmetric alkylation of a glycolate enolate. Oxazolidinone 3 has also been prepared from 2 with diethyl carbonate in the presence of potassium carbonate. The conversion of 2 to the oxazolidinone 3 is accomplished using triphosgene in this procedure because of the high toxicity of phosgene. 

The amino acid derived chiral oxazolidinone 188 is a very commonly used auxiliary in Diels-Alder and aldol reactions. However, its use in diastereoselective 1,3-dipolar cycloadditions is less widespread. It has, however, been used with nitrile oxides, nitrones, and azomethine ylides. In reactions of 188 (R = Bn, R =Me, R = Me) with nitrile oxides, up to 92% de have been obtained when the reaction was performed in the presence of 1 equiv of MgBr2 (303). In the absence of a metal salt, much lower selectivities were obtained. The same observation was made for reactions of 188 (R = Bn, R = H, R = Me) with cyclic nitrones in an early study by Murahashi et al. (277). In the presence of Znl2, endo/exo selectivity of 89 11 and up to 92% de was observed, whereas in the absence of additives, low selectivities resulted. In more recent studies, it has been shown for 188 (R =/-Pr, R = H, R =Me) that, in the presence of catalytic amounts of Mgl2-phenanthroline (10%) (16) or Yb(OTf)3(20%) (304), the reaction with acyclic nitrones proceeded with high yields and stereoselectivity. Once again, the presence of the metal salt was crucial for the reaction no reaction was observed in their absence. Various derivatives of 188 were used in reactions with an unsubstituted azomethine ylide (305). This reaction proceeded in the absence of metal salts with up to 60% de. The presence of metal salts led to decomposition of the azomethine ylide. 

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. 

The oxazolidinones have been used as chiral auxiharies for enolate alkylation and aldol reactions in enantioselective and total syntheses The interest in these substrates is largely known for iyw-diastereoselective aldol reactions with chlorotitanium or diaUcylboron oxazilidinone enolates (equation 114). 

Hence, if the proline-catalyzed aldol reaction between acetone and 4-nitrobenzal-dehyde in DM SO is carried out using 5 mol% proline, decarboxylation occurs and [3 + 2] cycloaddition between the resulting ylide and benzaldehyde gives a 1,3-oxazolidinone as the maj or side product [98]. Therefore, it is important that if catalyst loadings are to be reduced, either the carboxylic acid should be unable to decarbox-ylate (e.g. Appendix 7.B, Entries 12 [97, 98], 35 [99]) or else must be replaced by an isostere [101, 102] (e.g. Appendix 7.B, Entries 7 [103, 104], 8-10 [105], 11 [106], 28 [107]). Alternatively, the relative rate of the aldol reaction can be increased in order to minimize the concentration of iminium ion in solution and remove it from equilibrium before decarboxylation can take place. 

The approach for the enantioselective aldol reaction based on oxazolidinones like 22 and 23 is called Evans asymmetric aldol reaction.14 Conversion of an oxazolidinone amide into the corresponding lithium or boron enolates yields the Z-stereoisomers exclusively. Reaction of the Z-enolate 24 and the carbonyl compound 6 proceeds via the cyclic transition state 25, in which the oxazolidinone carbonyl oxygen and both ring oxygens have an anti conformation because of dipole interactions. The back of the enolate is shielded by the benzyl group thus the aldehyde forms the six-membered transition state 25 by approaching from the front with the larger carbonyl substituent in pseudoequatorial position. The... 

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. 

In 1992 Ghosh and co-workers provided the first example of the utility of rigid cis-1 -amino-2-indanol-derived oxazolidinone 36 as the chiral auxiliary in the asymmetric. vv//-aldol reaction.60-61 Aldol condensation of the boron enolate of 37 with various aldehydes proceeded with complete diastereofacial selectivity. Effective removal and recovery of the chiral auxiliary was carried out under mild hydrolysis conditions (Scheme 24.6). As both enantiomers of the chiral auxiliary were readily available, both enantiomers of the. yyn-aldol could be prepared with equal asymmetric induction. 

Ghosh et al. reported that the chiral oxazolidinone 87, derived from (1S,2R)-cis-l-amino-2-indanol (86), underwent a highly diastereoselective. vyn-aldol reaction with a variety of aldehydes30 (Scheme 2.1cc). Reaction of the indanolamine 86 with disuccinyl carbonate in acetonitrile gave the oxazolidinone 87, which was deprotonated with -BuLi and reacted with propionyl chloride to provide the N-propionyl derivative 88. Reaction of 88 with n-BioBOTf and... 

Sharma, A. Sunoj, R. Enamine versus oxazolidinone What controls stereoselectivity in proline-catalyzed asymmetric aldol reactions , Angew. Chem. Int. Ed. 2010, 49, 6373-6377. 

Hexafluoroacetone has also demonstrated unusual reactivity when condensed with the boron cnolatc of an optically active oxazolidinone or the boron enolate of the sultam derived from camphorsulfonic acid s to give products 3 and 4, respectively. The absolute stereochemistry of the products 3 and 4 is the opposite of that formed on addition to nonfluorinated ketones and aldehydes. This change was attributed to the involvement of an open transition state in the aldol reaction, a consequence of the diminished basicity of fluorinated carbonyl oxygens. 

The aldol reaction illustrated in eq 2 has been applied to the targeted synthesis of a number of complex molecules including Tylosin, Hapalosin, the antibiotic Sinefungin, and the HIV protease Saquinavir inhibitor. Oxazolidinone-type chiral auxiliaries derived from 1 have also been employed for the control of Diels-Alder reactions of attached acryloyl or crotonyl groups. ... 

A second entry to dicarbonyl substrates utilizes the aldol reaction to establish the a-methyl center prior to oxidation of the p-hydroxyl moiety. Commonly, this oxidation is performed using the Sulfur Trioxide-Pyridine complex, which results in <1% epimerization of the methyl-bearing center (eq 34). Interestingly, this procedure procures the opposite methyl stereochemistry from that obtained through enolate acylation of the same enantiomer of oxazolidinone. 

P-Ketoimide Aldol Reactions. As has been demonstrated, chiral oxazolidinones provide a gateway into asymmetric p-... 

As above (eq 1), a major drawback of this reagent is the lack of a readily available enantiomer. There are many alternative methods for the enantioselective propionate aldol reaction. The most versatile chirally modified propionate enolates or equivalents are N-propionyl-2-oxazolidinones, a-siloxy ketones, boron enolates with chiral ligands, as well as tin enolates. Especially rewarding are new chiral Lewis acids for the asymmetric Mukaiyama reaction of 0-silyl ketene acetals. Most of these reactions afford s yw-aldols good methods for the anri-isomers have only become available recently. ... 

Precursor of Useful Chiral Ligands. OPEN is widely used for the preparation of chiral ligands. Organometallic compounds with these ligands act as useful reagents or catalysts in asymmetric induction reactions such as dihydroxylation of olefins, transfer hydrogenation of ketones and imines, Diels-Alder and aldol reactions, desymmetrization of meso-diols to produce chiral oxazolidinones, epoxidation of simple olefins, benzylic hydroxylation, and borohydride reduction of ketones, imines, and a,p-unsaturated carboxylates. ... 

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. 

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