1.2- Oxazine chiral

Another chiral auxiliary used in diastereoselective addition reactions is the 1,3-oxazine derivative 4a which shows a close structural resemblance to the 1,3-oxathiane 16 (vide supra). However, in contrast to the oxathiane, 4a cannot be readily acylatcd in the 2-position. Therefore, the benzoyl derivative 4b was prepared by condensing amino alcohol 3 with phenylglyoxal. 

N-Acylnitroso compounds 4 are generated in situ by periodate oxidation of hydroxamic acids 3 and react with 1,3-dienes (e.g. butadiene) to give 1,2-oxazines 5 (Scheme 6.3). The periodate oxidation of 4-O-protected homo-chiral hydroxamic acid 6 occurs in water in heterogeneous phase at 0°C, and the N-acylnitroso compound 7 that is generated immediately cyclizes to cis and tranx-l,2-oxazinolactams (Scheme 6.4) [17a, b]. When the cycloaddition is carried out in CHCI3 solution, the reaction is poorly diastereo-selective. In water, a considerable enhancement in favor of the trans adduct is observed. 

High diastereoselectivity occurs in the addition of lithiated methoxyallene to chiral cyclic nitrones. The hydroxylamines obtained can be easily transformed into derivatives of 1,2-oxazine hydroxylamine, which are products of a novel [3 + 3] cyclization reaction (Scheme 2.182) (646, 647). 

The hexahydro-l//-pyrrolo[2,l-f][l,4]oxazin-l-one 82 (obtained by radical cyclization see Section 11.11.7.3) was transformed into the proline derivative 83 by hydrogenation in the presence of the Pearlman s catalyst and a stoichiometric amount of trifluoroacetic acid (TFA) (Scheme 10). This reaction led with high yield to the disub-stituted proline 83 in an enantiomerically pure form <2003SL1058>. In an analogous approach, the chiral (4/ ,7/ ,8aA)-methyl 6,6-dimethyl-l-oxo-4-phenylhexahydro-l//-pyrrolo[2,l-r-][l,4]oxazine-7-carboxylate 84 was hydrogenated on Pd(OH)2 in the presence of TFA to give enantiomerically pure 5,5-dimethylproline derivatives 85 <2001SL1836> (Scheme 10). 

A series of analogous py rrolo[ 2,1 -c [ 1,4]oxazine-8-carboxy latcs 188 and 189 (Scheme 28) were obtained by cycloaddition of azomethine ylide 187 with dipolarophiles. The ylide was formed by /(-toluene sulfonic acid-mediated reaction of the benzotriazolyl chiral morpholinone 186, which can be considered as a stable crystalline azomethine ylide precursor <2001SL1841>. This procedure was applied also to morpholinone 190 that generated ylide 191 by reaction with... 

Pyrrolo[l,2- ][l,2]oxazines are a class of compounds with very few references regarding synthesis and reactivity. An interesting preparation has been described by intramolecular cyclization of IV-hydroxy pyrrolidines carrying a methoxyallene substituent at C-2 (242, Scheme 32). These compounds were obtained by addition of a lithiated allene to chiral cyclic nitrones 241. Cyclization occurred spontaneously after some days at relatively high dilution (0.05 M). Compounds 243 (obtained with excellent diastereoselectivity) can be submitted to further elaboration of the double bond or to hydrogenolysis of the N-O bond to form chiral pyrrolidine derivatives (Section 11.11.6.1) <2003EJ01153>. 

The substrate-controlled diastereoselective addition of lithiated alkoxyallenes to chiral nitrones such as 123, 125 and 126 (Scheme 8.32) furnish allenylhydroxyl-amines as unstable products, which immediately cydize to give enantiopure mono-orbicyclic 1,2-oxazines (Eqs 8.25 and 8.26) [72, 76]. Starting with (R)-glyceraldehyde-derived nitrone 123, cydization products 124 were formed with excellent syn selectivity in tetrahydrofuran as solvent, whereas precomplexation of nitrone 123 with... 

Cadogan and coworkers160 developed a fructose-derived l,3-oxazin-2-one chiral auxiliary which they applied in the Diels-Alder reactions of its iV-enoyl derivatives 246 with cyclopentadiene using diethylaluminum chloride as the Lewis acid catalyst. The reactions afforded mixtures of endo 247 and exo 248 (equation 68). The catalyst binds to the chiral dienophile in a bidentate fashion (co-ordination to both carbonyl groups). As a consequence, the dienophile is constrained to a rigid conformation which accounts for the almost complete diastereofacial selectivities observed. 

Substituted amino naphthols were synthesized with reactions of 1-naphthols and the appropriate aldehydes. Some new 2,4-disubstituted-3,4-dihydro-2/f-naphth [i,2-e][i,i]oxazines that are expected to show biological activities were obtained by the ring-closure reactions with these aminonaphthols and various aldehydes. In addition, substituted-1,3-amino-hydroxy compounds, 2, can be used in chiral ligands synthesis. 

In their closed forms, spiropyran, spiro-oxazine, and some naphthopyrans are chiral about the sp carbon atom that joins their orthogonal or out-of-plane ring... 

With the increasing demand for chiral nonracemic compounds, stereoselective methods for the synthesis of 1,3-oxazine derivatives and applications of enantiopure 1,3-oxazines in asymmetric transformations have gained in importance in the past decade, as reflected by the increasing trend in the number of publications on this topic, and accordingly by the share of this topic in the present compilation. The limited size of this survey and the scope of this chapter do not allow a discussion here of the applications of 1,3-oxazines in polymer chemistry and the synthesis and properties of 1,3-benzoxazine-containing hetero-calixarenes. 

The flexible, semi-flexible, or anancomeric behavior of tetrahydro-l,3-oxazines 83 spiro-connected to cyclohexane was studied by NMR spectroscopy. The possible stereoisomers were deduced by taking into account the special chirality of the heterocycle and the spiro skeleton <2000M975>. 

Chiral nonracemic bidentate 2-[o-(diphenylphosphino)phenyl]-5,6-dihydro-4//-l,3-oxazine derivatives proved to be effective P,N-ligands in Pd-catalyzed asymmetric transformations. When used in the Pd-catalyzed allylic alkylations of 1,3-diphenylallyl acetate with dimethyl malonate, phosphino-oxazines 147 and 148 and the... 

The asymmetric alcoholytic ring opening of 4-substituted-2-phenyl-4,5-dihydro-l,3-oxazin-6-ones proved to be a efficient method for the preparation of enatiomerically pure /3-amino acid derivatives <2005AGE7466>. Treatment of 2,4-diphenyl-4,5-dihydro-l,3-oxazin-6-one 208 in the presence of the bifunctional chiral thiourea catalyst 211 resulted in formation of an enantiomerically enriched mixture of the unchanged oxazinone (iJ)-208 and allyl (4)-3-benzoyl-amino-3-phenylpropanoate 209. The resolved material (iJ)-208 and the product 209 could easily be separated by a selective hydrolytic procedure that converted oxazinone (iJ)-208 quantitatively into the insoluble iV-benzoyl /3-amino acid 210 (Scheme 37). 

Almost complete retention of chirality was achieved in the alkylations of l-propionyl-l,4-dihydro-2//-3,1-benz-oxazines 242 bearing a stereogenic center in the substituent at position 2 (TBDPS = /< rt-butyldiphenylsilyl, KHMDS = potassium hexamethyldisilazide). The alkylations took place with high de s (70-92%) in favor of isomers 243, isolated after chromatographic separation. The allyl-substituted compound 243 (R = allyl) was reduced with LAH to yield the enantiopure (R)-3-methylpent-4-en-l-ol 244 and the N-unsubstituted 3,1-benzoxazine 245 as a 5 1 diastereomeric mixture (Scheme 45) <2000JOC6540>. 

The A -acyl derivatives of 4-substituted-3,4,5,6-tetrahydro-27/-l,3-oxazin-2-ones proved to behave as effective chiral auxiliaries in asymmetric enolate alkylations and aldol reactions, the stereoselectivities of which were found to be higher for 4-isopropyl than for 4-phenyl derivatives <2006OBC2753>. The transformations of 4-isopropyl-6,6-dimethyl-3-propa-noyl-3,4,5,6-tetrahydro-2/7-l,3-oxazin-2-one 251 to 252 or 253 proceeded with excellent diastereoselectivities (Scheme 47). 6,6-Dimethyl substitution within the oxazine ring facilitated exclusive exocyclic cleavage upon hydrolysis of the C-alkylated and the aldol products 252 and 253, to furnish a-substituted carboxylic acids 254 or a-methyl-/ -hydroxycarboxylic acids 256. 

The D-fructose-derived, chiral, nonracemic l,3-oxazin-2-one derivative 260 exerted smooth stereocontrol, resulting in high levels of asymmetric induction and good chemical yields in various synthetic transformations. The chiral fragments 256 and 261 formed in the aldol or a-bromination reactions of the A -propionyl derivative 257 could easily be removed from the parent auxiliary by mild hydrolysis (Scheme 48). The Diels-Alder cyloadditions of the A -acryloyl and A -cinnamoyl derivatives of 260 were also characterized by excellent diasterofacial selectivity <1998T9765>. 

Chiral nonracemic l-aryl-2-aminopropane-l,3-diols were converted to 2-trichloromethyl-5,6-dihydro-4/7-l,3-oxazine derivatives with complete diastereoselectivity via the corresponding bistrichloroacetimidate intermediates. In this transformation, one trichloroacetimidate participated as a leaving group, and the other as a nucleophile <20070L247>. 

Oxazine 115 with a 2-hemiacetal racemizes in ethyl acetate solution at above 50 °C but the racemic mixture can be resolved by chiral stationary phase chromatography <2005W040140>, or crystallization using (-)-(/ ,iJ)-di- -toluoyl-tartaric acid (DTTA) <2005W040141> as shown in Scheme 2. 

Suitably protected chiral tetrahydro-l,4-oxazin-2-ones can be deprotonated at the 3-position and the resulting enolates alkylated to give, after oxazine hydrolysis, a-amino acids. The advantage of the method shown in Scheme 13 using compound 170 to give 163 is that it can be used in the synthesis of a-quaternary amino acids <1999EJ01967>. 

The magnesium ion-mediated nitrone cycloaddition methodology can be successfully applied to the asymmetric reactions of a chiral cyclic nitrone of the lactone type (Scheme 11.51) (169). Although (/ )-2(/f)-oxo-5-phenyl-5,6-dihydro-1,4-oxazine A-oxide is an ( )-nitrone, all of its reactions are highly diastereose-lective, producing isoxazolidine 5-alcohol cycloadducts. The chelated transition... 

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