Cinchona alkaloid squaramide

Dai L, Wang S, Chen F. A bifunctional cinchona alkaloid-squaramide catalyst for the highly enantioselective addition of thiols to trans-chalcones. Adv. Synth. Catal. 2010 352 2137-2141. 

The cinchona alkaloid-derived thioureas (237a,b) and their squaramide counterparts (238a,b) have been employed to catalyse the Michael addition of a-alkyl and of-phenylselenenyl ketones R CH(X)COR (X=alkyl, SePh) and the corresponding... 

In 2012, Maikov and coworkers reported a similar strategy for the synthesis of spirocyclopropanes bearing two quaternary centers. In this approach, 2-chloroacetoacetates (49) reacted with 17c via a Michael/a-alkylation domino reaction (Scheme 10.16) [22]. The reaction was catalyzed by bifunctional Brpnsted Acid-Lewis base X. The final spirocyclopropanes 50 were obtained under optimized conditions in good yields and excellent diastereo and enantioselectivities. A similar approach was developed by the same research group using 3-chlorooxindoles (51) instead of 2-chloroacetoacetates [23]. This time, the catalyst was a bifiinctional squaramide-tertiary amine XI derived from cinchona alkaloids, rendering the final spirocyclopropanes 52 in good yields and excellent enantioselectivities. 

In 2003, Rawal reported the use of TADDOLs 177 as chiral H-bonding catalysts to facilitate highly enantioselec-tive hetero-Diels-Alder reactions between dienes 181 and different aldehydes 86 (Scheme 6.29A) [82], and also BINOL-based catalysts 178 were found to facilitate this reaction with excellent selectivities [83]. TADDOLs were also successfully used as organocatalysts for other asymmetric transformations like Mukaiyama aldol reactions, nitroso aldol reactions, or Strecker reactions to mention a few examples only [84]. In addition, also BINOL derivatives have been employed as efficient chiral H-bonding activators as exemplified in the Morita-Baylis-Hilhnan reaction of enone 184 with different carbaldehydes 86 [85]. The use of chiral squaramides for asymmetric reactions dates back to 2005 when Xie et al. first used camphor-derived squaric amino alcohols as ligands in borane reductions [86]. The first truly organocatalytic application was described by Rawal et al. in 2008 who found that minute amounts of the bifunctional cinchona alkaloid-based squaramide 180 are... 

Cinchona Alkaloid Derivatives with a Sulfonamide, Urea, Thiourea, Squaramide, or Guanidine Function... 

The concept of bifunctional catalysis as advanced for the natural cinchona alkaloids and cuprei(di)nes has resulted in the design and synthesis of a range of new cinchona derivatives. The major part of these novel organocatalysts are urea and thiourea cinchona derivatives together with cinchona alkaloids modified with, for example, a sulfonamide, squaramide, or guanidine group (Figure 6.8). 

Rawal and coworkers prepared a squaramide derivative of cinchonine (30) and proved this cinchona alkaloid analog to be an efficient catalyst for the conjugate addition of 2,4-pentadione to P-nitrostyrene [59] (Scheme 6.39). With sub-shtuted 2,4-pentadiones, the diastereoselectivity was low, except for the methyl ester of 2-oxocyclopentanecarboxylic acid, which gave rise to a raho of 50 1 for the diastereoisomers. 

A Study by Xu and coworkers examined a series of cinchona alkaloid derivatives with a benzyl or 1-phenylethyl group at the second nitrogen atom of the squaramide moiety [91]. The catalyst with 1-phenylethyl group and a C6 methoxy group (32) gave the highest yield and enantioselectivity for the conjugate addition of 4-hydroxycoumarins to a-keto esters (Scheme 6.42). 

Squaramide-based dimeric cinchona alkaloid organocatalysts have also been described [92] and shown to be highly suitable for the dynamic kinetic resolution of racemic azlactones (Scheme 6.43). The dimeric squaramide derivatives were free from self-association, as indicated by the observation that the enantioselectivity was not influenced to any significant extent by the concentration of the dimeric squaramide, in contrast to the monomeric species that showed a decline in ee upon an increase in concentration. 

Kim and coworkers have developed a binaphthyl-modified chiral squaramide (20) bearing both central and axial chiralities [89]. The Michael addition of anthrone to nitroalkenes catalyzed by squaramide 20 afforded the products in high yield and good enantioselectivity (Scheme 10.17). Notably, the reaction at lower temperature (0 °C) resulted in a reduced enantioselectivily. This transformation has also been shown to be catalyzed by cinchona alkaloid and thiourea derivatives [90-92]. 

Addition of CH2(CN)2 to -substituted 2-enoylpyridines RCH=CHCO(2-Py), catalysed by the cinchona alkaloid-based bifunctional ureas, such as (345) (10mol%), has been reported to proceed with <97% ee in m-xylene at room temperature. Squaramide (346) proved to be even more efficient for the addition of the same nucleophile to enones R CH=CHCOR, which required only 0.5 mol% catalyst loading to attain <96% ee (in CHCI3 at room temperature), ... 

Malonates, malononitrile, and anthranone, can be added to -nitroalkenes RCH=CHN02 (R = alkyl, Ar) in the presence of the original Takemoto s thiourea organocatalyst (421) (5 mol%) in liquid CO2 (100 bar, room temperature) with 67-89% ee The same reaction, with an extended portfolio of substrates, catalysed by 0 the cinchona alkaloid-based squaramides (lmol%) in CH2CI2 at 15 C exhibited <96% ee ... 

Improved catalytic activity can be expected if the hydroxyl group of the cinchona alkaloids is replaced with a better hydrogen bond donor group. The most popular variants of this type are the thiourea and the squaramide groups (Fig. 6.2). Before... 

The extension of the thiourea-tertiary amine concept to the cinchona alkaloids was reported by several groups independently in 2005. The general usefulness of cinchona alkaloids as bifunctional catalysts was recognized by several groups even before this date [9]. The focus herein is on (thio)urea and squaramide catalysts since they are prototypes of more efficient catalysts. The Chen and the Dixon groups screened cinchonine and cinchonidine-derived thiourea catalysts for conjugate... 

In a model reaction, Deng et al. reached enantioselectivities up to 99% with (DHQD)2PYR at —60 °C inferior results were obtained at room temperature. Natural alkaloids showed usable enantioselectivities with chalcones as substrates, " and more recently, excellent enantioselectivities (61-99%) have been reported using Cinchona squaramide-type catalysts, also with acrylates. Enantioselectivities of CiracAoraa-sulfonamides were low compared to the Cinchona-AetweA ureas (see Chapter 19). Nitro-olefins turned out to be slightly more demanding substrates, both for natural alkaloids and their squaramides. ... 

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