From 2-Oxazolidinones

I4 Boron enolates derived from oxazolidinone 3 arc reported to give either syn- or imp-adducts depending on the amounl of boryl Inflate and base employed, the character of the base, and the structure of the aldehyde see H. Danda, M. M. Hansen. C. H. Heathcock, J. Org. Chem. 55,173... 

The three-component reaction between isatin 432a, a-aminoacids 433 (proline and thioproline) and dipolarophiles in methanol/water medium was carried out by heating at 90 °C to afford the pyrrolidine-2-spiro-3 -(2-oxindoles) 51. The first step of the reaction is the formation of oxazlidinones 448. Loss of carbon dioxide from oxazolidinone proceeds via a stereospecific 1,3-cycloreversion to produce the formation of oxazolidinones almost exclusively with /razw-stereoselectivity. This /f-azomethine ylide undergo 1,3-dipolar cycloaddition with dipolarophiles to yield the pyrrohdinc-2-r/ V -3-(2-oxindolcs) 51. (Scheme 101) <2004EJ0413>. 

Palladium-catalyzed (PdCl2(PPh3)2) decarboxylative carbonylation reactions for the formation of lactams are known to proceed under carbon monoxide at a pressure of 60 atmospheres. The scheme below highlights a new procedure utilizing a different Pd catalyst, where the formation of lactams 171 from oxazolidinones 172 takes place at atmospheric pressure <06S227>. 

Asymmetric Diels-Alder reactions. Unlike methyl crotonate, which is a weak dienophile, chiral (E)-crotonyl oxazolidinones when activated by a dialkylaluminum chloride (1 equiv.) are highly reactive and diastereoselective dienophiles. For this purpose, the unsaturated imides formed from oxazolidinones (Xp) derived from (S)-phenylalanol show consistently higher diastereoselectivity than those derived from (S)-valinol or (IS, 2R)-norephedrine. The effect of the phenyl group is attributed in part at least to an electronic interaction of the aromatic ring. The reactions of the unsaturated imide 1 shown in equation (I) are typical of reactions of unsaturated N-acyloxazolidinones with cyclic and acyclic dienes. All the Diels-Alder reactions show almost complete endo-selectivity and high diastereoselectivity. Oxazolidinones are useful chiral auxiliaries for intramolecular Diels-Alder... 

The reactivity of 2/7-azirines 91 and 93 as 1,3-dipolarophiles towards (3-lactam based azomethine ylides derived from oxazolidinones 90 has been investigated [77]. The reaction of 3-(4-methoxyphenyl)-2//-azirine 91 with oxazolidinone 90 did not afford the expected cycloadduct. However, compound 92 was isolated as the... 

Formation of a 3-amino azetidinone and its N-Boc protected form from oxazolidinone precursors shows that various reactions can be performed with good yields (67-95%) without affecting the 7V-[bis(trimethylsilyl)methyl] group... 

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. 

The amides are derived from oxazolidinones and yield "Z"-enolates with high stereoselectivity. The alkylating agent reacts in both cases from the side that is opposite to the side of the substituent highlighted in red. Alkaline hydrolysis accelerated by hydrogen peroxide proceeds with retention of configuration and yields enantiomerically pure a-alky-lated carboxylic acids X t and X 2 are the chiral amide groups. 

The reactivity of 2H-azirines as 1,3-dipolarophiles towards (5-lactam-based azomethine ylides derived from oxazolidinones has been evaluated <02JCS(P1)2014>, providing cycloadducts 37, which incorporate the novel 2,6-diazatricyclo[4.2.0.02 4]octan-7-one ring system. 

The synthesis of penams 6 from oxazolidinones 4 via the carboxylated azomethine ylide intermediates 5 is outlined in Scheme 5 . 

Chiral dioxiranes continue to be examined for the synthesis of enantioenriched epoxides. An interesting report details the use of a dioxirane derived from oxazolidinone 7 for the... 

Scheme 65 Addition/allylation of enoates derived from oxazolidinones...

Sasikala et al. [16] used NMR, MS, and FTIR to characterize ezetimibe as s)mthesized from oxazolidinone. Moreover, and NMR assays were used to determine impurity-I in samples of ezetimibe. According to the results obtained, NMR spectral data of impurity-I have additional NMR bands at 2.74 and 9.82 ppm. The signal at 9.82 ppm was not observed on ezetimibe and was assigned to the -NH group. Further analysis confirmed that impurity-I has an extra -CH2 group at 38.61 ppm when compared to ezetimibe. To confirm the difference between impurity-I and ezetimibe, a correlation study and a... 

Oxazolone itself can be easily obtained from oxazolidinone through electrochemical reduction as described in CHEC-II(1996). A similar sequence was utilized in the synthesis of indole-substituted 2(3//)-oxazolone 244 (Scheme 71) <1997CPB733>. Electrochemical oxidation of 2-oxazolidinone in methanol gave a 4-methoxy oxazolidinone 241, which reacted with an organomagnesium indole reagent 242 in the presence of BF3-Et20, followed by... 

Another synthesis started from oxazolidinone 96 in reaction with selenoketones. Thermolysis of 100 with selenoketoncs gave the corresponding racemic selenopenams 23 in moderate yields (25-37%) in one step (Equation 30) <2001J(P1)1897, 2000T5579>. 

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. 

The enolates of other carbonyl compounds can be used in mixed aldol condensations. Extensive use has been made of the enolates of esters, thioesters, and amides. Of particular importance are several modified amides, such as those derived from oxazolidinones, that can be used as chiral auxiliaries. The methods for formation of these enolates are similar to those for ketones. Lithium, boron, tin, and titanium derivatives have all been used. Because of their usefulness in aldol additions and other synthetic methods (see especially Section 6.4.2.3, Part B), there has been a good deal of interest in the factors that control the stereoselectivity of enolate formation from esters. For simple esters such as ethyl propanoate, the E-enolate is preferred under kinetic conditions using a strong base such as EDA in THE solution. Inclusion of a... 

The use of chiral ketenes and imines has been examined, whereby the latter proved to be less efficient regarding cis/trans and face selectivity. The ketenes are generated in situ by treatment of acyl chlorides with triethylamine at -78°C. A -Acetyl chlorides are for instance appropriate precursor molecules. C/s-i3-lactams are accessible diastereoselectively by intermolecular reactions of chiral ketenes derived from oxazolidinones with imines. In general, the cleavage of these compounds is achieved with Li/NHs under recovery of the chiral auxiliaries. 

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. 

Other systems different from oxazolidinones have been successfully applied as ligand of Cu(I) salts for this transformation. The use of QUINAP (L in Scheme 11.15), combined with CuBr gave excellent results in the total synthesis of (S)-(-l-)-coniine, a highly toxic alkaloid inducing curare-type paralysis, in 45% overall yield and 90%... 

The scope of the method has been carefully evaluated. For highlighting the synthetic potential, an asymmetric synthesis of the naturally occurring lactone (—)-bursehernin is shown in Scheme 4.108 that requires only three steps and yields the natural product in 41% yield as a single diastereomer and enantiomer, starting from oxazolidinone 517 and ester 516. The key coupling step gives the product... 

A special problem arises in the preparation of secondary amines. These compounds are highly nucleophilic, and alkylation of an amine with alkyl halides cannot be expected to stop at any specifle stage. Secondary amides, however, can be monoalkylated and lydrolyzed or be reduced to secondary amines (p. 11 If.). In the elegant synthesis of phenyl- phrine an intermediate -hydroxy isocyanate (from a hydrazide and nitrous acid) cyclizes to pve an oxazolidinone which is monomethylated. Treatment with strong acid cleaves the cyclic irethan. 

D. s-Aaetyl-2(3B)-oxaaolone. The crude mixture of 3-acety1 4- and 5-chloro-2-oxazolidinone from Step C is placed in a 2-L, three-necked flask equipped with a thermometer, sealed mechanical stirrer, and gas discharge tube. The material is heated to 120°C with stirring, and the temperature is then slowly increased to 150 C and held there until the evolution of gas ceases (Note 10). The cooled, black reaction mixture is distilled at 20 nm. The fractions boiling up to 150°C are collected and redistilled through a 50-cm X 3-cm Vigreux column fitted with a variable take-off head. There is obtained 140-172 g (55-68%) of product, bp 108-112°C (24 mm), which solidifies, rap 35-37°C (Note 11). 

The data from the separation of the enantiomers of 4-phenyl-2-oxazolidinone [14] gave an expression for the retention volume of the two enantiomers, which are reiterated as follows. 

Scott and Beesley [2] measured the corrected retention volumes of the enantiomers of 4-benzyl-2-oxazolidinone employing hexane/ethanol mixtures as the mobile phase and correlated the corrected retention volume of each isomer to the reciprocal of the volume fraction of ethanol. The results they obtained at 25°C are shown in Figure 8. It is seen that the correlation is excellent and was equally so for four other temperatures that were examined. From the same experiments carried out at different absolute temperatures (T) and at different volume fractions of ethanol (c), the effect of temperature and mobile composition was identified using the equation for the free energy of distribution and the reciprocal relationship between the solvent composition and retention. 

---