Chiral triazolium syntheses

Scheme 14.2 Knight and Leeper s chiral triazolium syntheses.

NHC-catalysed homoenolate generation has been applied by Bode and Struble in the formal synthesis of the natural product salinosporamide A [77], The key step in the synthesis is a late-stage NHC-catalysed intramolecular lactonisation step of intermediate 186. When this reaction was attempted with an achiral triazolium-derived NHC, a 4 1 diastereomeric ratio of products was obtained in preference for the undesired product 189. In order to circumvent this, chiral triazolium salt 187 was employed, giving an approximately 1 1 mixture of desired undesired diastereoisomers (Scheme 12.41). 

Catalytic enantioselective crossed aldehyde-ketone benzoin cyclizations of ketoaldehydes, such as 13, readily obtained from an aryl nitrile oxide and a 1,3-diketone, were studied in order to perform the synthesis of complex molecules. Significant asymmetric induction was observed with chiral triazolium salts such as 14, in the presence of DBU as base, leading to compound 15 in high yield and with 99% ee in favor of the R enantiomer <06AG(E)3492>. 

In the context of our work in the area of chiral nucleophilic carbenes and their utility in organic synthesis, we have developed a conceptually distinct approach to catalyzed acylation using a-haloaldehydes as acylation precursors. The use of a chiral triazolium salt in the presence of base allows an enantioselective desymme-trization of meio-hydrobenzoin to proceed in 83% ee and good yield ... 

The triazol-5-ylidene 12 was found to be a powerful catalyst for the conversion of formaldehyde to glycolaldehyde in a formoin reaction [25.] The concept of triazolium salt catalysis appeared to show promise, and consequently our research group undertook the synthesis of a variety of chiral triazolium salts for the asymmetric benzoin reaction [26]. However, the ce-values and catalytic activities shifted widely with slight structural changes in the substitution pattern of the triazolium system. The most active catalyst 15 (Fig. 9.4) afforded benzoin (6, Ar = Ph) in its (R -configuration with 75% ee and a satisfactory yield of 66%. 

With the enantioselective intramolecular benzoin reaction established as a synthetic tool, and in combination with our efforts in the synthesis of bioactive natural products bearing a quaternary a-hydroxy ketone unit (Davis and Weismiller 1990 Heller and Tamm 1981), such as the 4-chromanone derivative (S)-eucomol (Bohler and Tamm 1967 Crouch et al. 1999), a catalytic asymmetric synthesis of various 3-hydroxy-4-chromanones brought about by the chiral triazolium salts 127, 123b and 102 as pre-catalysts was investigated (Enders et al. 2006d). The sterically different pre-catalysts were chosen in order to adjust the catalyst system to the steric and electronic properties of the substrates 128. A screening of the reaction conditions indicated 10 mol% of the... 

You and co-workers successfully developed a series of novel chiral triazolium salts based on the readily available camphor scaffold in 2008. These catalysts are capable of rendering excellent enantioseleetivity in the intramolecular Stetter reaction (up to 97% yield, 97% ee). A later report from the same group delivered the synthesis of chiral NHCs from (lR,2R)-(+)-diphenyl ethylenediamine. With 10 mol% of the catalyst, the intramolecular Stetter reaction was realized in excellent yields with up to 97% ee. These newly developed catalysts from camphor and (lR,2R)-(+)-diphenyl ethylenediamine accumulate in the toolkit of NHCs. 

In 2005, Rovis et al. reported the synthesis of a-chloroesters from a,a-dichloroaldehydes using chiral triazolium salt F5 as the precatalyst. A variety of dichloroaldehydes worked well for the reaction and afforded the desired esters 134 in good yields and enantioselectivities. (Scheme 20.57). 

Recently, the group reported the synthesis of a-fluoroamides from a-fluoroenals using chiral triazolium salt F9 as the catalyst.Subjecting a... 

It is worth noting, however, that the rise of enantioselective benzoin and Stetter reactions were one of the forerunners of the new generation of NHC-catalyzed processes that have been reported since 2004. These studies, particularly the work of Knight and keeper on chiral triazolium salts for benzoin and Stetter reactions, formed the basis for the design and synthesis of the now widely used chiral NHCs (Scheme 14.2). These designs were elegantly extended by Enders and by Rovis for the development of catalytic enantioselective benzoin condensations, intramolecular Stetter reactions, and the wide variety of enantioselective NHC-catalyzed transformations detailed below. 

Extension of this work to the diastereoselective synthesis of y-lactams from N-sulfonyl aldimines [93] and ketimines [94] was subsequently reported. Scheldt and coworkers disclosed an enantioselective version (up to 98% ee) from reactive hydrazones in the initial demonstration of cooperative NHC/Lewis acid catalysis using a bulky, chiral triazolium salt and catalytic Mg(OBu )2 [95]. Rovis and coworkers synthesized y-lactams 109 enantioselectively using a chiral N-C Fs triazolium salt (Scheme 18.19). A weak carboxylate base was sufficient to partially deprotonate the precatalyst 108 in situ, and the carboxylic acid formed could activate the N-Ar imine acceptor 107 via protonation [lib]. In all these cases, a fine balance must exist between sufficient electrophilicity vis-a-vis the competing enal and reversible addition of the carbene to the imine/hydrazone/iminium or to the Lewis acid. 

Enders has been a key pioneer in the use of nucleophilic carbenes in asymmetric synthesis [49]. In particular, in 1996 he disclosed the first catalytic asymmetric Stetter reaction (Equation 53) [190]. A key discovery that opened up new avenues for further explorations in this field was the identification of chiral triazolium salts as nucleophilic carbene catalysts (cf. 259) [49]. As an example, treatment of 258 with 20 mol % of 259 gave ketoester 260 in 69% yield and 62% ee [190]. 

Precatalyst 19 was built up from cheap L-pyroglutamic acid (21) in a short and easy synthesis sequence involving a one-pot variant developed by Rovis et al. to form the triazolium core (Scheme 9.4) [36]. The synthesis of 20 started from a-tetralone (22), which was stereo selectively converted to the polycyclic y-lactam 23 with inexpensive (R)-phenylglycinol as chiral source. After cleavage of the auxiliary, the one-pot-procedure that had already been used before yielded the triazolium salt 20 (Scheme 9.5). 

Kerr MS, Read de Alaniz J, Rovis T (2005) An efficient synthesis of achiral and chiral 1,2,4-triazolium salts bench stable precursors for N-heterocyclic carbenes. J Org Chem 70 5725-5728... 

Kantchev EAB, O Brien CJ, Organ MG (2007) Palladium complexes of A-heterocyclic carbenes as catalysts for cross-coupling reactions - a synthetic chemist s perspective. Angew Chem Int Ed 46 2768-2813 Kerr MS, Rovis T (2004) Enantio selective synthesis of quaternary stereocenters via a catalytic asymmetric Stetter reaction. J Am Chem Soc 126 8876-8877 Kerr MS, Read de Alaniz J, Rovis T (2002) A highly enantio selective catalytic intramolecular Stetter reaction. J Am Chem Soc 124 10298-1029 Kerr MS, Read de Alaniz J, Rovis T (2005) An efficient synthesis of achiral and chiral 1,2,4-triazolium salts bench stable precursors for A-heterocyclic carbenes. J Org Chem 70 5725-5728... 

In 2012, Sun and co-workers documented an enantioseleetive synthesis of P,y-unsaturated a-fluoro esters catalyzed by NHC. Chiral NHC prepared in situ by the reaction of the corresponding triazolium chloride with sodium... 

The first asymmetric intramolecular process was described by Enders in 1996, who used triazolium salt 143 in the synthesis of chiral chroman-4-one derivatives. Moderate yields (22-73%) and enantioselectivities of up to 74% were obtained (Scheme 1.35) [48]. 

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