Quinidines aldol reaction

Later, the scope of this methodology was successfully extended to the intramolecular version by List and coworkers [14]. By employing 9-amino-9-deoxyepiquinine 24 as a catalyst (20 mol%) and an acid cocatalyst (AcOH, 60 mol%), 5-substituted-3-methyl-2-cydohexene-l-ones (26) were obtained with high enantioselectivity (up to 94% ee) from the diketones 25 via the intramolecular aldol reaction (Scheme 8.8). The chiral enones 26 are valuable synthetic building blocks for the synthesis of many biologically important compounds (e.g., HIV-1 protease-inhibitive didemnaketals). The pseudoenantiomeric quinidine analogue 23 of 24 also provided the opposite... 

Keywords aldol reaction, ball mill, proline, quinidine... 

Enolates, generated by Michael addition reactions of a,p-unsaturated esters or ketones, can add to aldehydes. If the Michael addition is carried out with a tertiary amine (or phosphine) then this is referred to as the Baylis-Hillman reaction. Typically, an amine such as l,4-diazabicyclo[2.2.2]octane (DABCO) is used. After the aldol reaction, the tertiary amine is eliminated and it can therefore be used as a catalyst (1.61). The reaction is somewhat slow (requiring several days), but rates may be enhanced with other amines such as quinuclidine or quinidine derivatives, the latter effecting asymmetric reaction with high levels of selectivity. ... 

The mechanism of enamine catalysis has been established the enamine is the active form of nucleophile. Other modes of activation are less developed and are limited to a certain group of donors and acceptors. Quinidine was found to catalyze the reaction of hydroxyacetone with aldehydes to yield the desired 5y -aldols with moderate diastereoselectivity and low enantioselectivity [169]. This represents the first example of a tertiary amine catalyzing the direct aldol reaction. Even (3, y-unsaturated a-keto ester 154 was successfidly coupled with protected hydroxyacetone 51 in the presence of 20 mol% of 9-amino-9-deoxy-cpi-cinchonine 155 and a small amount of TEA (Scheme 3.27). 

The first organocatalyzed enolate-mediated aldol reaction of active carbonyl derivatives with unactivated ketones was reported by Zhao and co-workers [170]. In this methodology, a ketone is deprotonated by the tertiary amine in the quinidine thiourea catalyst backbone and the enolate associates closely with the catalyst through ionic interactions. This method of activation can be used in cases where... 

Very recently, an intramolecular cycloaldolization was employed successfully early in the synthesis of quinine (2) and quinidine (3) (97). Hatakeyama etal. used a (S)-12 catalyzed aldol reaction followed by in situ reduction of the aldol product with NaBBLj to obtain the diastereomers 99 and 100 in good yield and enantios-electivity (dr = 1 2). Followed by protection of the primary alcohol and oxidation of the secondary one, intermediate 101 with the desired configuration could easily be obtained. The intermediate 101 was then transformed into either 2 or the pseudoenantiomeric 3 by known methods (Scheme 23) (97). 

S)-proline-catalyzed reaction is not sufficient therefore, a large number of (S)-proline-derived secondary amine catalysts have been developed. Primary amine catalysts derived from natural amino acids and cinchona alkaloids have also emerged as highly versatile and powerful catalysts [25]. For example, in the intramolecular 6-endo aldol reaction of diketone 43, quinine-derived primary amine 44 in acetic acid affords the cyclic ketone (S)-46 in 94% yield with 90% ee (Scheme 28.3) (S)-prohne gives the cycUzation product in low yield with moderate ee. In addition, the pseudo-enantiomeric quinidine-derived primary amine 45 deUvers the opposite product, the (R)-enantiomer 46, with similar yield and enantioselectivity [26]. 

Aldol reactions of unachvated ketones (164) with isahns (165) are catalyzed by the quinidine-thiourea bifunctional catalyst 166 through an ammonium enolate... 

Quinine 84 and quinidine 85 are well-known medicinally important alkaloids as well as mother structures for organocatalysts. Hatakeyama and co-workers reported on organocatalytic asymmetric synthesis of a key intermediate for these alkaloids. They performed the intramolecular direct aldol reaction of bis aldehyde 79 in the presence of L-proline 57. After reduction of the ketone, syn-diol 80 and anti-diol 81 were obtained with high enantiose-lectivity (Scheme 27.14). The mixture was converted into the common intermediate 83 for quinine 84 and quinidine 85 via ketone 82. Quinine 84 and quinidine 85 were... 

Mechanistic studies have discounted the possibility that cycloadduct 70 arises from a tandem Michael-aldolization pathway [ 140]. Stereospecificity is observed using fumaronitrile trans double bond) or maleonitrile cis double bond) as di-enophiles, indicating either a concerted reaction or a rapid second step (aldol) relative to internal bond rotation. Upon treatment with triethylamine in methanol, ring opening to the formal Michael adduct, a thermodynamic sink, is observed this Michael adduct was not formed in the enantioselective catalytic reaction. Further, the Michael adduct was not converted to cycloadduct 70 upon treatment with quinidine in chloroform in fact, access to 70 from the Michael product could be achieved only under fairly special conditions. 

An important contribution elucidating the potential of primary amines derived from Cinchona alkaloids has been the aldol cyclodehydration of achiral 4-substituted-2,6-heptanediones to enantiomerically enriched 5-substituted-3-methyl-2-cyclohexene-l-ones, presented by List and coworkers in 2008 (Scheme 14.26). Both 9-deo>y-9-amino-epr-quinine (QNA) and its pseudoenantiomeric, quinidine-derived amine QDA, in combination with acetic acid as cocatalyst, proved to be efficient and highly enantio-selective catalysts for this transformation, giving both enantiomers of 5-substituted-3-methyl-2-cyclohexene-l-ones with very good results. The authors observed that proline and the catalytic antibody 38C2 delivered poor enantioselectivity in this reaction. Furthermore, the synthetic utility of the reaction was exemplified by the first asymmetric synthesis of both... 

Subsequently, Romo et al. studied an intramolecular nucleophile (O-acetyl quinidine, O-Ac-QD) catalysed aldol-lactonisation (NCAL) process of achiral acid-aldehydes (R = R ) promoted by a modified Mukaiyama reagent (Scheme 15.10) and EtsN, providing p-oxoketenes in situ, leading to a variety of novel p-lactone-fused bicyclic systems. This process was then extended to keto-acid substrates and more recently to racemic substrates (R t R ) demonstrating the utility of the Cinchona alkaloid catalysts O-TMS quinidine (O-TMS-QD) and O-TMS quinine (O-TMS-Q), in doubly diastereoseleetive NCAL reactions. ... 

Recent investigations by Nelson have led to the development of this reaction into a general approach to optically active /1-lactones (Equation 15) [127]. The O-TMS-protected quinidine 185 proved optimal in this regard, in combination with LiC104 as an efficient Lewis acidic cocatalyst. Nelson has accentuated the fact that /1-lactones such as 186 (>99% ee) can be conveniently transformed into anti-a-substituted-/l-hydroxy carboxyl derivatives. Consequently, the approach provides convenient access to 2-anti aldol products and polyketide fragments, the synthesis of which may not be readily accessible through the implementation of standard carbonyl addition chemistry (see Chapter 4). 

---