Reversal of stereochemistry

Stereoselective epoxidation can be realized through either substrate-controlled (e.g. 35 —> 36) or reagent-controlled approaches. A classic example is the epoxidation of 4-t-butylcyclohexanone. When sulfonium ylide 2 was utilized, the more reactive ylide irreversibly attacked the carbonyl from the axial direction to offer predominantly epoxide 37. When the less reactive sulfoxonium ylide 1 was used, the nucleophilic addition to the carbonyl was reversible, giving rise to the thermodynamically more stable, equatorially coupled betaine, which subsequently eliminated to deliver epoxide 38. Thus, stereoselective epoxidation was achieved from different mechanistic pathways taken by different sulfur ylides. In another case, reaction of aldehyde 38 with sulfonium ylide 2 only gave moderate stereoselectivity (41 40 = 1.5/1), whereas employment of sulfoxonium ylide 1 led to a ratio of 41 40 = 13/1. The best stereoselectivity was accomplished using aminosulfoxonium ylide 25, leading to a ratio of 41 40 = 30/1. For ketone 42, a complete reversal of stereochemistry was observed when it was treated with sulfoxonium ylide 1 and sulfonium ylide 2, respectively. ... 

The templates used in these reactions have a significant impact on the reaction outcome and in determining product enantioselectivity. Sibi et al. also showed that changing the oxazolidinone template as in 119 to a 3,5-dimethylpyrazole in 131 resulted in a reversal of stereochemistry using the same chiral Lewis acid (Scheme 34) [91]. Additions in the presence of stoichiometric amounts of zinc triflate and ligand 19 gave good yields and moderate selectivities of 132. These acylated pyrazoles 131 form 5-membered... 

It is noteworthy that the strain introduced by substituents at the carbon atoms C3-C4 can have a dramatic effect on the stereochemical outcome of the thiadiazole reduction (Equations (4) and (5)). In these cases, Na/EtOH will also reduce the 1,2,5-thiadiazole but with a reversal of stereochemistry (trara-diamine predominates) <91JHC55, 91JHC289>. 

Ghosh and co-workers have also demonstrated that the Cu(II)-bis(oxazoline) complexes of conformationally constrained inda-box ligands 9a and ent-9a are excellent catalysts for the enantioselective Diels-Alder reaction. Using copper(II) trrflate as the metal source, the reaction resulted in selectivities up to >99 1 endo/ exo ratio with endo ee up to 99% (2R isomer), as shown in Table 9.10 (Fig. 9.24). Of particular interest, Cu(II)-phe-box ligand 6-derived catalyst complex exhibited considerably lower enantioselectivity (30%)." Furthermore, they have shown that the use of Mg(II) as the chelating metal resulted in a reversal of stereochemistry [up to 98 2 endo/exo and 61% endo ee for the (25) isomer]. Davies also showed that the use of copper(II) triflate with his stmcturally related inda-box ligands 9b and 34a led to similar selectivities. 

Among bicyclic cyclohex-2-enones, the formation of tricyclo[4.4.2.01,6]dodecane-2,7-dione from bicyclo[4.4.0]dec-l(6)-ene-2,7-dione and ethene proceeds in 95% yield,101 and that of 8-mcthyl-tricyclo[6.4.0.01,4]dodecan-5-ones from 6-methylbicyclo[4.4.0]dec-l(2)-en-3-one and ethene in 77% yield,102 respectively. Steroids containing cyclohex-2-enone subunits,103 e.g. 17/ -acetoxy-5a-androst-1 -en-3-one,104 often afford /raw-fused cycloadducts with alkenes. When such reactions are performed on silica gel, complete reversal of stereochemistry to that observed in solution can occur.105... 

Surface adsorption can also influence observed stereochemistry in a profound way. In enone photocycloadditions on silica gel and on alumina, the reaction which normally occurs from the less hindered alpha face is shifted toward the more hindered beta face, Eq. (9) Adsorption thus apparently disfavors conformational inversion in the intermediate biradical, as is required for formation of trans-fused products. The magnitude of the effect is sufficient to be synthetically useful the above reaction represents a complete reversal of stereochemistry from that observed in methanolic solution... 

Takahashi et al. also reported a route to muconin. Their synthesis adopted Keinan et al. s strategy to construct the stereochemistries by Sharpless AD and AE upon multiple olefin containing fatty acid (Scheme 10-35). The di-olefin 214 was subject to Sharpless AD conditions and then treated with acid, yielding a THP-containing diol. This diol was further protected as acetonide 215. The reversion of stereochemistry of alcohol 215 was achieved by Dess-Marlin oxidation and Zn(BH4)2 reduction. Williamson etherification of tosylate 216 and epoxide formation afforded tri-ring intermediate 217. Opening with acetylene, 217 was converted into the terminal alkyne 218, which was coupled with vinyl iodide to finally give muconin. 

Sibi, M. P Liu, M. Reversal of Stereochemistry in Enantioselective Transformations. Can They be Planned or are They Just Accidental Curr. Org. Chem. 2001,5,719-755. 

Stereochemistry is also affected in a significant way by surface adsorption. When enone photocycloadditions are allowed to occur as adsorbates on silica gel or alumina, larger fractions of reaction product derived from attack on the more hindered P face are observed. Thus, surface adsorption apparently influences conformational inversion, enhancing the formation of /ra s-fused products. This effect is synthetically useful, for sometimes a complete reversal of stereochemistry is observed compared with that seen in methanolic solution. 

Photochemical Reactions. The addition of allene to a steroidal enone on AI2O3 revealed a reversal of stereochemistry to that observed in solution [41] (Scheme 13). 

Warren has used a variation of his phosphine oxide-based olefination method to synthesise single isomers (E or Z) of unsaturated carboxylic acids.23 a-Diphenylphosphinoyl ketones (32) are reduced by sodium borohydride to give diastereomeric mixtures of the corresponding alcohols (33) and (34). These alcohols can be converted to the lactones (35) and (36) which can be separated and individually converted stereospecifically into (Z)-(37) and (E)-(38) alkenes by base treatment (Scheme 6). In many cases it is possible to reduce p-ketophosphine oxides (39) and enones (41) stereoselectively to the ery/Aro-alcohols (40) and (42), respectively, using sodium borohydride in the presence of cerium chloride (Scheme 7).24 An earlier report that reduction in the presence of cerium salts did not cause reversal of stereochemistry compared to reduction with borohydride alone appears to be true only of the compounds studied in that report. The carbanions of 3-hydroxypropylphosphine oxides (43) have been reported to undergo O- to C-acyl transfer to give the p-ketoalkylphosphine oxides... 

A similar reversal of stereochemistry [22] was achieved with the TDP-4-keto-6-deoxyhexose reductase gene from S. nogalater, snogC, which caused the 4 -ketoreductase mutant S. galilaeus H039 to produce an aklavinone glycoside with 4 -epi-2-deoxyfucose glycosylation (Scheme 10). 

Basavaiah et al. successfully reduced various MBH acetates with LiAlH4. The treatment of methyl a-methylene-p-acetoxyalkanoates with LAH-EtOH (1 1) gave exclusively (2 )-2-methylalk-2-en-l-ols 358, while similar reaction of ot-methylene-p-acetoxyalkanenitriles with LAH-EtOH led to remarkable reversal of stereochemistry of product, giving (2Z)-2-methylalk-2-enenitriles 359 (Scheme 3.159). The efficiency of this methodology was amply demonstrated by the synthesis of ( )-nuciferol (360) and a precursor (361) of (Z)-nuciferol (Scheme 3.159). ... 

A Striking illustration of the relationship between orbital symmetry considerations and the outcome of photochemical reactions can be found in the stereochemistry of electrocyclic reactions. In Chapter 10, the distinction between the conrotat-ory and disrotatory modes of reaction as a function of the number of electrons in the system was described. Orbital symmetry considerations predict, and it has been verified experimentally, that photochemical electrocyclic reactions show a reversal of stereochemistry ... 

Transition-state factors which may account for the reversal of stereochemistry of diethylzinc addition to aldehydes caused by alteration of the backbone substituent Y (from Ph to Bu) of L-serine-derived ligands have been discussed (Scheme 7). ... 

If the MAD reagent is used, reversal of stereochemistry is almost complete, changing from a 24 76 ratio to a 99 1 ratio in favor of equatorial alcohol 8 (Scheme 3.3). 

Another structurally modified guanidine, catalyst 57, was reported by Ishikawa et al. [36] for asymmetric Michael additions of glycine imines to acrylates under neat conditions. The high conversion and selectivity was attributed to the relative configuration of the three chiral centers of the catalyst in the absence of any solvent interactions. A reversal of stereochemistry may be achieved when the chiral center... 

Danda H, Hansen MH, Heathcock CH. Reversal of stereochemistry in the aldol reactions of a chiral boron enolate. J. Org. Chem. 1990 55(1) 173-181. 

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