Diastereoselectivity protonation

The initial nitronate anion intermediates formed from the addition of trimethylaluminum to nitroalkenes having a /i-phenylthio substituent, however, undergo a highly diastereoselective protonation to give awn -products19. 

The cis/trans ratio of 1,4-disubstituted cyclohexanes formed from activated cyclohexenes at a Hg cathode depends on the solvent and proton source and shows a low diastereoselectivity. Protonation of the first formed radical anion is kinetically... 

Racemic a-amino acid esters have been converted to single enantiomers by condensing them with 2-hydroxypinan-3-one (91), and then diastereoselectively protonating the resultant chiral Schiff base. ... 

Potassium enolates derived from the chiral Schiff bases obtained by reaction of racemic a-amino esters with 2-hydroxypinan-3-one undergo diastereoselective protonation, as evidenced by release of optically active a-amino esters on subsequent cleavage of the imine (Scheme 5). ... 

The proposed catalytic cycle for this reaction begins with the initial attack of the in situ generated thiazolylidene carbene on the epoxyaldehyde followed by intramolecular proton transfer (Scheme 28, XXXII-XXXIII). Isomerization occurs to open the epoxide forming XXXIV which undergoes a second proton transfer forming XXXV. Diastereoselective protonation provides activated carboxylate intermediate XXXVI. Nucleophilic attack of the activated carboxylate regenerates the catalyst and provides the desired P-hydroxy ester. 

Intramolecular hydroamination of cyclohexa-2,5-dienes has afforded the corresponding bicyclic allylic amines with high selectivity (Scheme 13).80 The reaction does not proceed through a direct hydroamination of one of the diastereotopic alkenes but more likely involves a diastereoselective protonation of a pentadienyl anion, followed by addition of a lithium amide across the double bond of the resulting 1,3-diene and a highly regioselective protonation of the final allylic anion. 

The mechanism does not proceed through a direct hydroamination of one of the diastereotopic alkenes, but involves a series of very selective processes including a deprotonation of (22), diastereoselective protonation of (26), intramolecular addition of lithium amide (27) to the 1,3-diene moiety, and final regioselective protonation of the allyl anion (28), all mediated by a substoichiometric amount of n-BuLi. 

The extended cyclic enolate derived from a simple pyrrol-3-en-2-one (butenolac-tam) has been deuterated at the 5-position with very high diastereoselectivity if the (g) nitrogen atom carries a a-methyl-p-methoxybenzyl group (de > 99 l).27 A similar diastereoselective protonation has been observed in a pyrrol-3-en-2-one formed by dearomatizing cyclization of a pyrrole. 

Diastereoselective protonation of arylmethylketenes. Merck chemists1 have described a conversion of (R,S)-2-arylpropionic acids (1) into the optically active forms. Thus 1 is converted into the corresponding arylmethylketene (2). Addition of a chiral alcohol can give optically active a-hydroxy esters 3 (and the acids). Of a... 

Very recently, Rovis examined the intramolecular Stetter reaction with a,/ -disubstituted acceptors 38 (Scheme 9.11) [42]. The key challenge is to secure a diastereoselective proton transfer onto the enolate intermediate. HMDS (from the KHMDS base) was shown to cause a deterioration in diastereoselectivity, but this problem was overcome by using the free carbene catalyst - that is, HMDS was removed in high vacuum prior to the reaction. Using the free carbene catalyst 39, the desired chromanone 40 could be obtained in excellent yield (94%),... 

Davies used Sml2 and D20 to carry out a highly diastereoselective conjugate reduction of benzylidene diketopiperazine templates en route to (2S3R)-dideuteriophenylalanine.57 The new stereocentres arise from diastereoselective protonation of a Sm(III) enolate and the protonation of a stereodefined organosamarium intermediate (Scheme 4.46).58... 

For weak acids, the proton is directly transferred from the acid to the substrate in a reagent-controlled manner and, in order to increase the selectivity, extremely shielded 2 -substituted m-terphenyls have been developed as concave protonating reagents inspired by the geometry of enzymes. Thus, the diastereoselective protonation by a series of substituted phenols of endocyclic keto enolates, obtained by the stereocontrolled 1,4-addition of lithiocuprates onto substituted cyclohexenones, was reported by Krause and coworkers354 355 and applied to the synthesis of racemic methyl dihydroepijasmonate356. 

SCHEME 70. Lithium relay in the diastereoselective protonation of (ff)-phenylglycmol-derived... 

The photolysis of chiral amino carbene complexes of type 31 [14] in the presence of alcohols leads diastereoselectively to products of type 32 and thus opens an efficient access to a wide range of natural and non-natural amino acid derivatives in optically active form [15]. These reactions proceed via the intermediates 33 and 34, the products being formed by highly diastereoselective protonation of 34 (Scheme 9). 

Nonalkylated 3,4-dehydroprolines 914 were obtained in 76-81% yields by diastereoselective protonation of an enolate resulting from Birch reduction of the A -BOC-pyrrole-2-carboxamide 913 (Equation 223) <1999T12309>. The reaction was quenched by addition of solid ammonium chloride after a reaction time of 1 h. The results using lithium and sodium are similar but the reaction with potassium failed. Remarkably, asymmetric protonation is more selective (de 88-90%) than methylation (de 50%). The selectivity decreases with increasing temperature (de 82% at —30°C). The diastereoselectivity of the reaction was detected by HPLC. 

Diastereoselective protonation of enolates has been extensively documented Conversion of a diastereoisomeric mixture of carbonyl-containing compounds into a single diastereoisomer through deprotonation (enolate formation) and re-protonation is well... 

Diastereoselective protonation under kinetic control is a useful strategy for allowing access to particular diastereoisomeric carbonyl derivatives. For example, deprotonation of y-lactone 116 with excess LiHMDS in THF at —78°C, and quenching the resulting lithium enolate with saturated aqueous solution of sodium sulfate, gave the diastereoiso-mericaUy pure y-lactone 116 (equation 27). The diastereoselective protonation of the intermediate hthium enolate with H2O must occur on its less hindered face, controlled by the y-benzyloxymethyl substituent of the y-lactone residue to give the required 116. ... 

The fi-kcto ester trans-140 undergoes deprotonation by Lewis base NaH, followed by reduction with AIH3 to an intermediate aluminum enolate (141), which on subsequent protonation with f-BuOH yields the /3-hydroxy ketone cis-142 in good yield and configurational purity (equation 37) . Diastereoselective protonation to the cis product allows both the 2-(hydroxymethyl) and the 4-methyl groups to be in axial positions for minimal steric interaction. 

Remote stereocentres have been shown to influence the facial preference for the diastereoselective protonation of enolates. Deprotonation of an equimolar diastereoisomeric mixture of 5-lactams (a-S, N-R)-143 and (a-R, N-R)-143 with -BuLi, followed by the... 

Schafer, A., Schafer, B. Diastereoselective protonation after the Birch reduction of pyrroles. Tetrahedron 1999, 55, 12309-12312. 

The nucleophilic addition on substituted ketenes is a well-known method to generate a prochiral enolate that can be further protonated by a chiral source of proton. Metallic nucleophiles are used under anhydrous conditions therefore, the optically pure source of proton must be added then (often in a stoichiometric amount) to control the protonation. In the case of a protic nucleophile, an alcohol, a thiol, or an amine, the chiral inductor is usually present at the beginning of the reaction since it also catalyzes the addition of the heteroatomic nucleophile before mediating the enantioselective protonation (Scheme 7.5). The use of a chiral tertiary amine as catalyst generates a zwitterionic intermediate B by nucleophilic addition on ketene A, followed by a rapid diastereoselective protonation of the enolate to acylammonium C, and then the release of the catalyst via its substitution by the nucleophile ends this reaction sequence. 

Pracejus also studied the tandem nucleophilic addition/diastereoselective protonation of optically pure (S)-phenylethylamine on phenylmethylketene [11], With the aim of synthesizing amino acids and their derivatives, Calmes and coworkers reinvestigated the reaction of prochiral ketenes (generated in situ from acid chorides in the presence of a tertiary amine) with (R)-pantolactonc, an a-hydroxylactone [12], The authors have shown that the diastereoselectivity is dependent on the base used. Particularly, triethylamine and quinuclidine afforded complementary results and the diasteromeric ratios observed with quinuclidine suggest that the high stereoselections could be observed in nucleophilic additions to prochiral ketenes in the presence of cinchona alkaloids. 

The aforementioned catalytic process was further apphed to diastereoselec-tive protonation of a chiral enolate of (-)-menthone (Scheme 6) [52]. When the lithium enolate 49 was quenched with BHT at -78 °C, an 86 14 mixture of transproduct 50 and cfs-product 51 was obtained. Reaction of the enolate 49 with (S)-imide 31 (0.1 equiv), which was derived from (S)-l-cyclohexylethylamine, followed by slow addition of BHT (1 equiv) at the same reaction temperature furnished a higher frans-selectivity (50 51=95 5). The enantiomer of (S,S)-imide 30 showed a similar level of frans-selectivity, while ds-isomer 51 was produced as a major product (50 51=31 69) in reaction with (S,S)-imide 30. This is an example of diastereoselective protonation in which a new stereogenic center is formed under the influence of a chiral proton source rather than of the asymmetric carbon of the enolate 49. 

---