Aldol phase-transfer-catalysts

Enantioselective aldol reactions also can be used to create arrays of stereogenic centers. Two elegant ot-amino anion approaches have recently been published. Fujie Tanaka and Carlos F. Barbas III of the Scripps Institute, La Jolla, have shown (Org. Lett. 2004,6,3541) that L-proline catalyzes the addition of the aldehyde 6 to other aldehydes with high enantio- and diastereocontroJ. Keiji Maruoka of Kyoto University has developed (J. Am. Chem. Soc. 2004,126,9685) a chiral phase transfer catalyst that mediates the addition of the ester 9 to aldehydes, again with high enantio- and diastcrcocontrol. 

ALDOL CONDENSATION, CATALYSTS Bis(p-methoxypheny])telluroxide. Phase-transfer catalysts. Zinc chloride. 

Recently, Castle and coworkers introduced C3-alkyny]-substituted chiral quaternary ammonium salt of type 41, and evaluated its ability as a chiral phase-transfer catalyst in the aldol reaction between 1 and hydrocinnamaldehyde using BTTP as a base, in which a high level of enantioselectivity (91% ee) was observed for syn-22 (Scheme 2.19) [41],... 

Whilst simple alkylations of enolates and Michael additions have been successfully catalyzed by phase-transfer catalysts, aldol-type processes have proved more problematic. This difficulty is due largely o the reversible nature of the aldol reaction, resulting in the formation of a thermodynamically more stable aldol product rather than the kinetically favored product. However, by trapping the initial aldol product as soon as it is formed, asymmetric aldol-type reactions can be carried out under phase-transfer catalysis. This is the basis of the Darzens condensation (Scheme 8.2), in which the phase-transfer catalyst first induces the deprotonation of an a-halo... 

Very recently, Belokon and North have extended the use of square planar metal-salen complexes as asymmetric phase-transfer catalysts to the Darzens condensation. These authors first studied the uncatalyzed addition of amides 43a-c to aldehydes under heterogeneous (solid base in organic solvent) reaction conditions, as shown in Scheme 8.19 [47]. It was found that the relative configuration of the epoxyamides 44a,b could be controlled by choice of the appropriate leaving group within substrate 43a-c, base and solvent. Thus, the use of chloro-amide 43a with sodium hydroxide in DCM gave predominantly or exclusively the trans-epoxide 44a this was consistent with the reaction proceeding via a thermodynamically controlled aldol condensation... 

Aldol reactions using a quaternary chinchona alkaloid-based ammonium salt as orga-nocatalyst Several quaternary ammonium salts derived from cinchona alkaloids have proven to be excellent organocatalysts for asymmetric nucleophilic substitutions, Michael reactions and other syntheses. As described in more detail in, e.g., Chapters 3 and 4, those salts act as chiral phase-transfer catalysts. It is, therefore, not surprising that catalysts of type 31 have been also applied in the asymmetric aldol reaction [65, 66], The aldol reactions were performed with the aromatic enolate 30a and benzaldehyde in the presence of ammonium fluoride salts derived from cinchonidine and cinchonine, respectively, as a phase-transfer catalyst (10 mol%). For example, in the presence of the cinchonine-derived catalyst 31 the desired product (S)-32a was formed in 65% yield (Scheme 6.16). The enantioselectivity, however, was low (39% ee) [65],... 

In this system, the chiral phase transfer catalyst (PTC) is able to recognize one aldolate selectively. There is an equilibrium between syn- and anti-aldolates via retro-aldol addition, and the formation of a stable, chelated lithium salt blocks the non-catalyzed subsequent reaction from yielding the epoxide product ... 

Another control experiment was done to determine the importance of water in this oxidative cleavage reaction. Water was found to be a necessary reagent for the reaction to occur since no p-hydroxybenzaldehyde was obtained when the sodium salt of chlorostilbene 5b was heated in neat nitrobenzene with or without solid sodium hydroxide and a crown ether phase transfer catalyst. Another set of controls was done to evaluate the formation of p-hydroxybenzaldehyde by a nonoxidative reaction, such as the loss of X-PI1-CH2 in a retrograde-type Aldol reaction. No p-hydroxybenzaldehyde was formed when the chlorostilbene 5b was heated at 155 °C for 5 hours in the presence of 2N NaOH but without the presence of nitrobenzene and atmospheric oxygen. Finally, in all of the above control experiments, no oxidized cleavage products were observed from the nonphenolic side of the alcohols 4 or stilbenes 5 (Dershem, S. M., et al., Holzforschung, in press). 

Ooi and Maruoka developed an efficient phase transfer catalyst (46a-e), which consisted of chiral N-spiro ammonium salts with binaphthalene skeleton. 3,3 -(3,4,5-Trifluorophenyl)ammonium salt (46e) provided a perfect stereoselection in benzylation of benzophenone Schiffbase of glycine terf-butyl ester (47) (Scheme 5.13, Table 5.5) [19]. The perfect stereoselective alkylation is applicable for a variety of alkyl bromides in the presence of 1 mol% of the catalyst (46e). Not only monoalkylation but also the consecutive double alkylation of 49 was successful to give 50 in excellent enantioselectivities (Scheme 5.14) [20]. The protocol is useful for the enantioselective aldol reaction of 47 with aldehyde (51) [21] and a-imino ester [22], in which catalysts (46f) and (46g) were effective (Scheme 5.15) [23]. 

Another approach to the synthesis of p hydroxy-a-amino acids is by aldol reaction of imines derived from amino adds. The benzophenone imine of glycine (7.102) undergoes highly enantioselective aldol addition with a range of aliphatic aldehydes, including (7.71) xmder phase-transfer conditions in the presence of the bromide salt of phase-transfer catalyst (7.103). A similar transformation is catalysed, in low to moderate ee, by the bimetallic catalysts developed by Shibasaki and CO workers. ... 

Shimizu. S. Shirakawa. S. Suzuki, T. Sasaki, Y. Water-soluble calixarenes as new inverse phase-transfer catalysts. Their application to aldol-type condensation and Michael addition reaction in water. Tetrahedron 2001. 57, 6169-6173. 

The construction of polyheterocycHc spirotetrahydrothio derivatives via a sulfa-Michael/aldol cascade reaction appeared in the literature in the year 2014 (14TL6335).The authors were attraaed to tetrahydrothiophenes due to their ability to serve as building blocks in many pharmaceutical agents and natural products. Previously, methods for preparing tetrahydrothiophenes lacked generality and efficiency. These workers were able to prepare titled compounds by the reaction of various chalcones with 1,4-dithane-2,5-diol under mild conditions. A few examples are shown below.The latter reaction showed excellent diasteroselectivity in the presence of a chiral phase transfer catalyst. 

The reaction of a glycine Schiff base (159) with aldehydes can be catalyzed by cinchona-derived salts, though the stereoselectivity is rather low [171]. Maruoka reported that this reaction proceeded well with a C2-symmetric chiral quarternary ammonium salt (160) as a phase-transfer catalyst [172]. The reaction generated tz fi -(3-hydroxy-a-aminoacids with reasonable yields and stereoselectivities (Scheme 3.28). Further modifications of the catalyst structure led to a salt which provided predominantly jy -aldols [173]. 

The combinational use of inorganic base and chiral phase-transfer catalyst provides an efficient process for the synthesis of -hydroxyl-a-amino acids via the aldol reaction (260-262). A representative and successful example was reported by Maruoka and co-workers (319) that a highly efficient direct asymmetric aldol reaction of a glycinate Schiff base with aliphatic aldehydes has been achieved under mild organic/aqueous biphasic conditions with excellent stereochemical control activity (Scheme 67) (96 99% ee). 

The spiro-type phase-transfer catalyst (188, Ar = H) possessing a C2-symmetry axis provides a single type of asymmetric environment in contrast, a newly designed spiro-type phase-transfer catalyst (188, Ar H) has two different asymmetric environments. The substituents of the binaphthyl subunits affect enantioselectiv-ity, and the 3,5-bis[3,5-bis(trifluoromethyl)phenyl]phenyl group is the best substituent of those evaluated in the anti-selective aldol reactions of glycine SchifF base 186 with aldehydes (35) (Scheme 28.21) [94]. Similarly, simpMed chiral phase-transfer catalyst 189 bearing the 3,5-bis[3,5bis(trifluoromethyl)phenyl] phenyl substituent, which is prepared in a combinatorial approach from the readily available (S)-l,l -binaphthyl-2,2 -dicarboxylic acid, effectively catalyzes syn-selective aldol reactions [95]. 

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