Imides diastereoselective

Industrial Synthetic Improvements. One significant modification of the Stembach process is the result of work by Sumitomo chemists in 1975, in which the optical resolution—reduction sequence is replaced with a more efficient asymmetric conversion of the meso-cyc. 02Lcid (13) to the optically pure i7-lactone (17) (Fig. 3) (25). The cycloacid is reacted with the optically active dihydroxyamine [2964-48-9] (23) to quantitatively yield the chiral imide [85317-83-5] (24). Diastereoselective reduction of the pro-R-carbonyl using sodium borohydride affords the optically pure hydroxyamide [85317-84-6] (25) after recrystaUization. Acid hydrolysis of the amide then yields the desired i7-lactone (17). A similar approach uses chiral alcohols to form diastereomic half-esters stereoselectivity. These are reduced and direedy converted to i7-lactone (26). In both approaches, the desired diastereomeric half-amide or half-ester is formed in excess, thus avoiding the cosdy resolution step required in the Stembach synthesis. 

In an effort to identify a more stereoselective route to dihydroagarofuran (15), trimethylsilylated alkyne 17 was utilized as a substrate for radical cyclization (Scheme 2). Treatment of 17 with a catalytic amount of AIBN and tri-n-butyltin hydride (1.25 equiv) furnishes a mixture of stereoisomeric vinyl silanes 18 (72% combined yield) along with an uncyclized reduction product (13% yield). The production of stereoisomeric vinyl silanes in this cyclization is inconsequential because both are converted to the same alkene 19 upon protodesiiyiation. Finally, a diastereoselective di-imide reduction of the double bond in 19 furnishes dihydroagaro-... 

Chiral amide and imide enolates are amongst the most effective reagents providing. yv -3-hy-droxycarboxylic acids in both high simple diastereoselectivity and induced stereoselectivity, e.g., the amides 1 and 2, and especially, the imides 3 and 4 (derived from (S(-valine and (l/ ,2S)-norephedrine, respectively)93 and the C2-symmetric amide 594 are highly effective systems ... 

The same auxiliary at nitrogen is used in the diastereoselective reduction of a series of bicyclic imides with sodium bis(2-methoxyethoxy)aluminum hydride or sodium diethylalu-minum hydride at — 78 "C, proceeding in 85-97% yield45 with d.r. values >75 25. 

Unsubstituted imides, with a single stereogcnic center appended to nitrogen, are stereoselective-ly reduced with lithium triethylborohydride at — 78 C with diastereoselectivities up to 100% in the case of severe steric crowding (Ar = 2,6-dichlorophenyl) (see Appendix)46. 

The original medicinal chemistry synthesis of ether 18 involved reaction of alcohol 10 with racemic imidate 17 in the presence of a catalytic amount of TfOH and furnished an approximately 1.1 1 mixture of 18 19 (Scheme 7.3) [1], We thought it worthwhile to reinvestigate this reaction with chiral imidate 67 in an effort to explore the diastereoselectivity of the etherification. 

Indium-mediated allylation reactions of a-keto imides derived from Oppolzer s sultam proceeded in aqueous THF in good yields and excellent diastereoselectivity (Eq. 11.43).74 The indium-mediated allylation of the Oppolzer camphorsultam derivatives of glyoxylic oxime ether... 

TABLE 2-5. Diastereoselective Alkylation Reaction of the Lithium Enolates Derived from Imides 22 and 23... 

Diastereoselective aldol reactions The boryl enolates of chiral crotonate imides (1) and (2) react with aldehydes to form adducts (3) and (4), respectively, with high diastereoselectivity and complete a-regioselectivity. The method of choice for reductive cleavage of the adducts is formulated for 3 hydrolysis can also be effected with LiOH and H202. 

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 success of bis(oxazoline)-copper(II) catalyzed Diels-Alder reactions involving acryloylimides as dienophiles has been extended to the Michael reaction, Eqs. 204 and 205. The observed enantiofacial discrimination in the Diels-Alder reactions was expected to translate well to Michael reactions involving enolsilanes as nucleophiles. Indeed, fumarate-derived imides afford Michael adducts of enolsilanes in high enantioselectivity (240). Diastereoselectivity in these reactions may be regulated by judicious choice of thioester and enolsilane geometry to provide either diastereomer in high selectivity (>99 1 syn or 95 5 anti). 

This radical cyclization strategy was utilized for the synthesis of the smaller fragment silyl ether 54 as well (Scheme 8). Evans aldol reaction of the boron eno-late derived from ent-32 with aldehyde 33, samarium(III)-mediated imide methyl ester conversion, and protecting group exchange led to tosylate 51. Elaboration of 51 to ketone 53 was achieved under the conditions used for construction of the second tetrahydrofuran moiety of 49 from 46. A highly diastereoselective reduc-... 

The stereochemistry of the addition can be controlled through the attachment of a chiral auxiliary or using asymmetric catalysis. Addition of 0-benzylhydroxylamine to unsaturated imide 51 (equation 33) bearing a chiral auxiliary was found to proceed with high diastereoselectivity at the a-position". ... 

A different approach to enantiotopic group differentiation in bicyclic anhydrides consists of their two-step conversion, first with (/ )-2-amino-2-phcnylethanol to chiral imides 3, then by diastereoselective reduction with sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) to the corresponding chiral hydroxy lactames 4, which may be converted to the corresponding lactones 5 via reduction with sodium borohydride and cyclization of the hydroxyalkyl amides 101 The overall yield is good and the enantioselectivity ranges from moderate to good. Absolute configurations of the lactones are based on chemical correlation. 

Some enantiomerically pure substituted 2-oxazolidinones are excellent as chiral auxiliaries. From the pioneering studies 2 conducted in the early 1980 s of the uses of such auxiliaries has emerged what is perhaps the most widely used method today for the preparation of enantiomerically highly enriched a-alkylalkanoic acids, alcohols and aldehydes, that is, the alkylation of enolates from chiral 3-acylated 2-oxazolidinones followed by auxiliary removal2 59. The early work has been reviewed60-62. These enantiomerically pure cyclic imide auxiliaries have been used not only for alkylations but also in a plethora of a-functionalization reactions, such as diastereoselective aldol, a-hydroxylation, a-amination and Diels-Alder reactions and these are discussed elsewhere in this volume. 

Stable A-phosphino- and A-phosphonio-nitrilimincs undergo 3 + 2-cycloaddition with electron-poor and electron-rich dipolarophiles, respectively, to produce substituted pyrazolines.101 The first diastereoselective 3 + 2-cycloaddition between bis(trityl)ni-trilimine and an acrylate, (R)-a-(acryloxy)-/f, /J-dimcthyl- y-butyrolactonc, has been reported.102 The 1,3-dipolar cycloaddition of A, A -diarylbisnitrilc imides with cinnamonitriles produces exclusively 5, 5 -dicyano-4, 4, 5, 5/-tetrahydro[3, 3 -di- l //-pyrazoles] which yield the corresponding 3,3 -di-l//-pyrazoles on thermal aromatization.103... 

Asymmetric aikyiation of imide etiolates.1 The sodium enolates of 3 and 7 are alkylated with marked but opposite diastereoselectivity by alkyl halides. The selectivity is improved by an increase in the size of the electrophile, with methylation being the least stereoselective process. The asymmetric induction results from formation of (Z)-enolates (chelation) with the diastereoselectivity determined by the chirality of the C4-substituent on the oxazolidone ring (equations I and II). The products can be hydrolyzed to the free carboxylic acids or reduced by LiAlH4 to the corresponding primary alcohols and the unreduced oxazolidone (1 or 2). 

Reduction of a chiral imide (2).1 Highly selective reduction is possible for the chiral protected ci s-dihydroxytartarimide 2 with this reagent (equation I). Lithium aluminum hydride shows only slight diastereoselectivity (22%), and use of SMEAH provides 3 in about 64% de. However, tetramethylammonium triacetyxyborohydride... 

The electrophilic introduction of azide with chiral imide enolates has also been used to prepare a-amino acids with high diastereoselection (Scheme 2.6). The reaction can be performed with... 

Diastereoselective acylation of the imide enolates of 107 proceeded smoothly, and the corresponding P-keto carboximides were obtained in good yield and excellent >96% de. The acylated products could be converted to P-hydroxy carboximides in high syn anti selectivity (96 4 in the... 

Stereoselective rearrangement reactions can involve sugar-linked functionalities. An example of this type is the Overman rearrangement of allylic trichloracetimidates formed from a D-glucofuranose derivative 20 [36]. This methods affords (L)-a-ami-no acids 25 from (Z)-allylic imidate 23 and (R)-a-amino acids 25 from ( )-imidates 23 with a diastereoselectivity of about 16 1. The oxidative cleavage of compound 24 with Ru04 yields the a-amino acid 25, (Scheme 15). 

Diastereoselective allylation of ct-keto imides derived from Oppolzer s sultam has been realized in aqueous THF (Equation (20)).181... 

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