Diastereoselectivity proton transfer

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%),... 

A possible mechanism for the reaction is nucleophihc addition of the catalyst to the ketene carbonyl followed by diastereoselective proton transfer from the aldehyde to the ketenyl zwitterion, similar to that shown in Eqn (4.108). 

Alonso et al. (2005) described anion-radical proton abstraction from prochiral organic acids. If the anion radicals were formed from homochiral predecessors, asymmetric deprotonation can be reached. However, low reactivity of the anion radical is required Slow proton transfer, that is, high activation energy of the reaction discriminates well between diastereoselective transition states. 

The observed diastereoselectivity of the protonation event may be explained by Model C (Scheme 13). In Model C, an intermolecnlar proton transfer wonld yield the minor diastereomer. Alternatively, the proton transfer may be intramolecnlar and occnr from the more sterically hindered face of the enolate, providing D. 

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. 

The high diastereoselectivity in the addition of i-PrOH, t-BuOH and EtOH (at low concentration) suggests that E Z photoisomerization of (E)- or (Z)-16 does not occur in solution at room temperature or that the trapping of (E)- or (Z)-16 by alcohols proceeds faster than the E Z isomerization. In addition, the results show that proton transfer in the intermediate adduct formed by the disilenes and alcohols occurs much faster than rotation around the Si—Si bond. However, in the reaction with ethanol, an appreciable amount of the anti addition product was formed. Thus, the diastereoselectivity remarkably depended on the concentration of ethanol. 

More recently, Apeloig and Nakash have studied diastereoselectivity in the reaction of (E)-5 with p-methoxyphenol53. In both benzene and THF, the stereochemistry of the products was independent of the phenol concentration. The syn/anti ratios of the addition products were 90 10 in benzene and 20 80 in THF. They have suggested that intramolecular proton transfer after rotation of the Si—Si bond of the phenol-coordinated intermediate is responsible for the formation of the anti-addition rather than intermolecular proton transfer. This must be a special case due to much slower (by a factor of 109-1012) rates of addition of phenol to (E)-5. Since phenolic oxygen is definitely less basic than alkyl alcoholic oxygen, coordination of oxygen in the zwitterionic intermediate in the reaction of (E)-5 with phenol must be loose and hence the intermediates should have much chance of rotation around the Si—Si bond. 

A limiting factor is also the stereoselectivity. As the substituents a to the keto group are prone to racemization using strong Lewis or Bn /nstedt acids due to equilibria involving proton transfer, the diastereoselectivity is often low ... 

The reaction of lithiated (+)-(5)-2f with racemic 2-alkylcyclohexanones gave three diastereomeric products, 60 and 61 the latter product was obtained as a mixture of diastereoisomers. The preference for the formation of 60 was rationalized as occurring via the favored boat transition state 62. The reaction of lithiated 48 with cyclohexanone proceeded with high diastereoselectivity (94 6) but the yield was low (60%) and starting materials were always recovered, probably as a result of a competing proton transfer reaction between the two reactants. The stereochemical assignment of the major (63a) and minor diastereoisomers (63b) from this reaction was based on their respective SMe chemical shifts and by analogy with the reaction of 2f with aldehydes.49... 

In the same vein, Schmalz has proposed a facile construction of the colchicine skeleton by a rhodium-catalyzed cyclization/cycloaddition cascade [56]. A TMS group has to be introduced on the alkyne moiety of 66 in order to avoid participation of the relatively acidic alkynyl hydrogen atom in undesired proton transfers. The resulting 6,7,7 of 67a and 67b architecture was assembled in a remarkably diastereoselective manner (14 1) and in satisfactory yield (Scheme 30). 

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. 

The amination of 2-alkenylphenols occurred efficiently compared to 2-allylphenols and -naph-thols69. The mechanism involves a proton exchange equilibrium between the phenolic and amino functions and the photoinduced proton transfer (PPT) from the ammonium ion to the alkenyl group, followed by attack of the amine on the intermediate benzylic carbocation. No photoamination of O-methylated and O-acetylated phenols occurred at all. As a single example of diastereoselective amination, the amine 6 was produced from 5 with good yield and diastereoselectivity, although the configuration was not determined. 

Significant progress has been made towards the understanding of proton delivery 152,165 Diastereomeric silyl ethenyl ethers 145 and 148 decompose on addition of TBAF and AcOH into the corresponding enols 146 and 149, which yield with AcOH two complementary bicyclic ketones (147 and 150, respectively), in different degrees of diastereomeric purity (equations 40 and 41). Two different proton transfer processes take place Bicyclic ketone 147 is formed by external delivery of a proton to 146 on its less hindered face (equation 40) the complementary ketone 150 is formed by protonation of 149 on its more hindered face (equation 41), invoking internal proton dehvery from the intermediate pyridinium acetate 151. For a more sterically demanding and weaker acid, such as phenol, the diastereoselectivity increased for 147 but reversed for 150. ... 

The preceding reactions dealt with the use of chiral auxiliaries linked to the electrophilic arene partner. The entering nucleophile can also serve as a chiral controller in diastereoselective SjjAr reactions. This approach was successfully employed for the arylation of enolates derived from amino acids. To illustrate the potential of the method, two examples have been selected. Arylation of Schollkopf s bislactim ether 75 with aryne 77 as electrophilic arylation reagent was demonstrated by Barrett to provide substitution product 81 with good yield (Scheme 8.18) [62, 63]. Aryne 77 arises from the orf/jo-lithiation of 76 between the methoxy and the chlorine atom followed by elimination of LiCl. Nucleophilic attack of 77 by the lithiated species 78 occurs by the opposite face to that carrying the i-Pr substituent. Inter- or intramolecnlar proton transfer at the a-face of the newly formed carbanion 79 affords the anionic species 80. Subsequent diastereoselective reprotonation with the bulky weak acid 2,6-di-f-butyl-4-methyl-phenol (BHT) at the less hindered face provides the syn product 81. Hydrolysis and N-Boc protection give the unnatural arylated amino acid 82. The proposed mechanism is supported by a deuterium-labeling experiment. Unnatural arylated amino acids have found application as intermediates for the construction of pharmaceutically important products such as peptidomi-metics, enzyme inhibitors, etc. [64, 65]. 

As shown in Fig. 8, the Ni2-lb complex was applicable to broad range of catalytic asymmetric reactions under simple proton transfer conditions [19-30]. As donors in direct Mannich-type reactions, not only a-nitroacetates, but also malonates, p-keto esters [22], p-keto phosphonates [23], and a-ketoaniUdes [24] gave excellent enantioselectivity and diastereoselectivity. It is noteworthy that the Ni2-lb complex also promoted vinylogous direct catalytic asymmetric Mannich-type reaction of an a,p-unsaturated y-butyrolactam, giving synthetically versatile functionalized a,p-unsaturated y-butyrolactam in 99% ee [25]. Because the Ni2-lb... 

The nitroaldol (Henry) reaction provides 1,2-nitro alkanols under atom-economical proton transfer conditions, which allows for easy access to highly versatile 1,2-amino alcohols (Scheme 6) [31]. A number of catalytic systems have been devised to render this useful C-C bond-forming reaction asymmetric however, diastereoselectivity remained a longstanding problem, in particular for a ri-selective reactions [14, 32, 33]. syw-Selective reaction can be achieved by a monometalhc catalytic system as shown in Fig. 9a, where both an aldehyde and a nitronate coordinate to the metal center to give syn product due to steric repulsion [34—36]. To make the reaction proceed in fluft-selective manner, different strategy in catalyst design is required [37, 38]. Simultaneous activation of both the aldehyde and the nitronate in an anti-paraUel fashion can afford the anti-1,2-nitro alkanols preferentially (Fig. 9b). To attain the a ri-paraUel transition state, a heterobimetalhc catalyst offers a suitable... 

First, the carboxylic acid group is moved farther to the third position and an additional trans methyl group is introduced at the fifth position. While the later substituent would steer the enamine conformation to an s-trans arrangement, the carboxyhc acid can still participate in effective proton transfer as shown in Figure 17.15b. The relative energies of transition states indicated 95 5 anti syn diastere-oselectivity and about 98% enanhomeric excess for the (2S,3R)-Mannich product. Subsequent experimental verification of these predictions yielded near quantitative agreements for the extent of both enanho- and diastereoselectivities in favor of onti-Mannich product. 

For the reaction with a stabilized phosphoniutn ylide, the betaine intermediate undergoes proton transfer and even extrudes a sulfonamide group to give a vinyl phosphonium salt that can be trapped with water, a stabilized phosphonium yUde [223], or nitromethane (solvent) [225]. These findings suggest that the conversion of the betaine to the azaphosphetane is much slower than the interconversion between the two betaine diastereomers (Scheme 49). Thus, the Z/E ratio for the alkene product does not correspond to the diastereoselectivity for the initial imine/ ylide addition. Instead, the Z/E selectivity is decided by the different rates for the transformation of the two betaine diastereomers into their corresponding azaphosphetanes. 

More recently this form of cyclopropanol formation was found to occur with P-(p-aminophenyl)pro-piophenones, in which the aniline electron donor promotes a p-proton transfer and 1,3-biradical formation. - This study was particularly interesting in that phosphorescence of the intermediate exciplex was detected. Various structural modifications led to interesting diastereoselectivity in the products. 

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