Diastereoselective synthesis imides

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. 

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. 

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-... 

Imide enolates derived from (5)-valinol and (15,2/f)-norephe-drine and obtained by either LDA or Sodium Hexamethyldisi-lazide deprotonation (eq 24) exhibit complementary and highly diastereoselective alkylation properties. Mild and nondestructive removal of the chiral auxiliary to yield carboxylic acids, esters, or alcohols contributes to the significance of this protocol in small-and large-scale synthesis. ... 

Chiral oxazolidinones are the most popular auxiharies in the field of asymmetric synthesis. Chen and Sibi [76] employed this auxiliary for the domino asymmetric C-C/C-C single bond formation under convenient radical conditions (Scheme 5.51). During the reaction, the radical intermediates 240 was coordinated onto the Lewis acid Yb(OTf)3 at —78°C to form the desired s-cis conformation. Upon the treatment of this intermediate 240 by 2-methylallyl stannane, the product 241 was generated with a diastereoselectivity of >20 1. Similar radical conditions using a bromooxazolidinone imide source also resulted in allylated products with excellent diastereoselectivity (>50 1) and yield (>90%) even at room temperature. 

The most general protocol (eq 10) has therefore been based on potassium hexamethyldisilazide (KHMDS) as the base addition of trisyl azide at —78 °C and then acetic acid at the same temperature. Excellent levels of diastereoselectivity are ohsCTved with most substrates and the method has been used widely in the enantioselective synthesis of a-amino acids from chiral iniides. Chemoselective azidation of an imide enolate in the presence of an ester function has been demonstrated (eq 11). The product distribution is nevertheless finely balanced, as discovered with the respective dimethyl and dihenzyl ethers of the 3,5-substituted phenylacetyl imide (3) (eq 12). ... 

In the synthesis of ionomycin published in 1990, the Evans group provided a convincing acid test of their auxiharies in several alkylation and aldol addition steps. Just one of those, the preparation of the alcohol 72, that was required as C-13 to C-16 fragment of ionomycin, may serve as an Ulustrative example, shown in Scheme 4.13. The hthium enolate of imide 48 was alkylated with cinnamyl bromide in a highly diastereoselective manner. The a-branched imide 71 thus obtained was reduced to the alcohol 72 that, after conversion into the primary iodide 15 (Scheme 4.3), served as electrophile in Evans prolinol procedure for chain elongation en route to ionomycin [12b]. 

Sibi et al. demonstrated for the first time that intermolecular radical addition to a,P-disubstituted substrates (12) followed by hydrogen atom transfer proceeded with high diastereo- and enantioselectivities (Scheme 4.6) [4]. In particular, a chiral bis(oxazoline)s-Mgl2 catalytic system was applied to the enantioselective and highly diastereoselective antijsyn = 99/1) synthesis of anti-aldol-type adducts (13). This is noteworthy because there have been few examples of highly selective methods for preparing anti aldol despite the array of solutions for the synthesis of syn aldol. The key to increasing the reactivity for a,P-disubstituted substrate (12) was N-H imide templates that relieve problems, and the promotion of Lewis acid catalysis via... 

So far only one example for the successful use of acetals in diastereoselective a-functionalization of chiral isotopically labeled imides has been published. Though this reaction was performed with carbon-13 material, there is little doubt that it is also applicable in carbon-14 synthesis. The titanium enolate prepared from (45)-4-benzyl-3-[(2R)-2-[ C, H3]methylpropionyl]-l,3-oxazolidin-2-one (111) reacted with trioxane to afford the corresponding a-hydroxymethyl derivative 112 in 83% yield and >96%... 

The synthesis of e.p. a-[ " C ]amino acids through diastereoselective homologation of protected acyclic or cyclic homochiral glycine building blocks (Figure 11.62) by alkylation of their enolates is a valuable alternative to the electrophilic a-amination of chiral a-unsubstimted imide enolates ". ... 

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