Proline-Catalyzed Aldol Additions

Recent developments in this area have considerably expanded the scope of the process to include a wide range of ketone and aldehyde components [98-100). Direct proline-catalyzed cross-coupling aldol reactions from ketones (Equation 16) [98] and aldehydes (Equation 17) [101] have been reported. Moreover, domino processes are possible thus, the proline-catalyzed aldol addition reaction of acetaldehyde proceeds through a double aldol addition and elimination to give useful building blocks for asymmetric synthesis (Equation 18) [100], As with any catalytic process, these processes are in essence multivariable problems, consisting of multiple steps and reactive intermediates, the reactivities and stabilities of which are finely balanced. 

The selectivity observed with hydroxyacetone (206) in proline-catalyzed aldol additions is particularly remarkable, as the scope includes a wide range of aldehydes to furnish a,/i-ketone diols such as 207 under mild conditions (Equation 19) [102]. The addition reactions of protected derivatives of a-hydrox) aldehydes as nucleophile coupling partners and aldehyde electrophiles in proline-catalyzed aldol reactions have recently been used to provide access to fragments that can be converted into a variety of carbohydrates [103). 

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A DFT study found a corresponding TS to be the lowest energy.167 This study also points to the importance of the solvent, DMSO, in stabilizing the charge buildup that occurs. A further computational study analyzed the stereoselectivity of the proline-catalyzed aldol addition reactions of cyclohexanone with acetaldehyde, isobu-tyraldehyde, and benzaldehyde on the basis of a similar TS.168 Another study, which explored the role of proline in intramolecular aldol reactions, is discussed in the next section.169... 

The TS proposed for these proline-catalyzed reactions is very similar to that for the proline-catalyzed aldol addition (see p. 132). In the case of imines, however, the aldehyde substituent is directed toward the enamine double bond because of the dominant steric effect of the (V-aryl substituent. This leads to formation of syn isomers, whereas the aldol reaction leads to anti isomers. This is the TS found to be the most stable by B3LYP/6-31G computations.199 The proton transfer is essentially complete at the TS. As with the aldol addition TS, the enamine is oriented anti to the proline carboxy group in the most stable TS. 

General Procedure for the Proline-catalyzed Aldol Addition Reactions [16c]... 

The proline-catalyzed aldol addition of acetone (1) to isatin 143 affords desired product 144 within 4 days in quantitative yield but with very low enantiomeric excess [158]. Other simple proline derivatives gave disappointing results. However, di- and pseudopeptides 145-147 generate useful levels of selectivity (Chart 3.19) [89b, 159, 160]. 

The large number of research programs aimed at the syntheses of steroids produced a phenomenal wealth of reaction methods for organic synthesis. The development of the asymmetric proline-catalyzed Robinson annulation reaction for the preparation of the Wieland-Miescher ketone (36, Equation 3) in the early 1970s [41] is noteworthy and marks an important milestone for catalysis by small organic molecules. Asymmetric amine-catalyzed aldol reactions represent an additional variant of the stereoselective aldol addition reaction. The mechanism of the proline-catalyzed aldol addition reaction has been the subject of extensive debate, but the general consensus, based on recent mechanistic studies and quantum mechanical calculations, supports the notion of the involvement of a single amino acid molecule in the transition state structure (39, Scheme 4.4) [42]. 

Visual models, additional information and exercises on Proline-Catalyzed Aldol Reactions can be found in the Digital Resource available at Springer.com/carey-sundberg. 

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. 

The Kotsuki group investigated the effect of high-pressure conditions on the direct proline-catalyzed aldol reaction [79a], a process which, interestingly, does not require use of DMSO as co-solvent. Use of high-pressure conditions led to suppression of the formation of undesired dehydrated by-product and enhancement of the yield. Study of the substrate range with a range of aldehydes and ketones revealed that enantioselectivity was usually comparable with that obtained from experiments at atmospheric pressure. Additionally, proline catalyzed aldol reactions in ionic liquids, preferably l-butyl-3-methylimidazolium hexafluorophosphate, have been successfully carried out [79b,c]. 

The concept of the proline-catalyzed aldol reaction has been recently extended by List et al. towards the synthesis of aldol products with two stereogenic centers [9]. The desired anti-diols 4 have been obtained in a regio-, diastereo- and enantioselective step starting from achiral compounds. Impressive diastero- and enantioselectivities were observed, with a dia-stereomeric ratio up to dr > 20 1 and ee-values of up to >99% ee (Scheme 2, reaction 2). In addition, the reaction leads to a high regioselectivity of >20 1. 

In the (S)-proline-catalyzed aldol reactions, the addition of a small amount of water did not affect the stereoselectivities [6]. However, a large amount of water often resulted in products with low enantiomeric excess water molecules interrupt the hydrogen bonds and ionic interactions critical for the transition states that lead to the high stereocontrol. For example, in the (S)-proline-catalyzed aldol reaction of acetone and 4-nitrobenzaldehyde in DMSO, the addition of 10% (v/v) water to the reaction mixture reduced the ee-value from 76% (no water) to 30% [6]. Note that the addition of a small amount of water into (S)-proline-catalyzed reactions often accelerates the reaction rate, and the addition of water should be investigated when optimizing these reactions [61]. 

List B, Lerner RA, Barbas CF 3rd (2000) Proline-catalyzed direct asymmetric aldol reactions. J Am Chem Soc 122 2395-2396 List B, Pojarliev P, Martin HJ (2001) Efficient proline-catalyzed Michael additions of unmodified ketones to nitro olefins. Org Lett 3 2423-2425 List B, Pojarliev P, Biller WT, Martin HJ (2002) The proline-catalyzed direct asymmetric three-component Mannich reaction scope, optimization, and application to the highly enantioselective synthesis of 1,2-amino alcohols. J Am Chem Soc 124 827-833... 

Computational studies suggest that the mechanism of the proline catalyzed aldol cyclization is best described by the nucleophilic addition of the neutral enamine to the carbonyl group together with hydrogen transfer from the proline carboxylic acid moiety to the developing alkoxide. A metal-free partial Zimmerman-Traxler-type transition state involving a chair-like arrangement of enamine and carbonyl atoms and the participation of only one proline molecule has been established [118,119]. On the basis of density functional theory (DFT) calculations Cordova and co-workers [120,121] have studied the primary amino acid intermolecular aldol reaction mechanism. They demonstrated that only one amino acid molecule is involved in the... 

Chirality amplification in the proline-catalyzed a-aminoxylation of aldehydes was uncovered and analyzed by Blackmond and co-workers in 2004 [29]. These researchers found that, contrary to what happens in proline-catalyzed aldol reactions, when the reaction was carried out with non-enantiopure proline, the enantiomeric excess of the product was higher than that expected from a linear relationship, and this enantiomeric excess rose over the course of the reaction. These results were rationalized by assuming an autoinductive behavior of the a-aminoxylation product, which formed a new catalytic species via enamine formation with proline, with the additional hypothesis of a matched interaction of L-Pro with the (/ )-enantiomer of the product (Scheme 2.3). 

Despite the high catalyst loading, the rate of the proline-catalyzed aldol reaction is very low. However, regardless of an aromatic aldehyde, the reaction time can be significantly shortened via microwave irradiation [16]. The addition of either acidic or basic co-catalysts slows down the reaction. Water has a beneficial effect on the reactivity [17]. On the other hand, extensive studies by Armstrong and Blackmond have revealed that water slows down the rate of the reaction but at the same time decreases the amount of side reactions [18]. In some cases, when the reaction was run using a chiral additive co-catalyst and a large excess of water, increased... 

The proline-catalyzed aldol reaction of cyclohexanone (57) with 4-nitrobenzal-dehyde (2a) in DMSO affords the desired aldol anti-SSa with good yield but rather low stereoselectivity (Scheme 3.15) [14]. However, the addition of water led to an increase both in the yield and enantioselectivity, though the reaction rate remained [17]. 

Aldol additions of acetone (1) as a nucleophile to ketones without a-acidic protons are feasible. The proline-catalyzed aldol reaction between acetone (1) and 1-aryl-2,2,2-trifluoroethanone (128) led to tertiary alcohol 129 in good yield but with low stereoselectivity [146]. A proline-derived sulfonamide 130 performs much better (Table 3.10, entry 2). Kokotos prepared a prolinamide-thiourea catalyst 131, which under optimum conditions can be used in 2 mol%, even at 0°C (entry 3) [ 147], With proline, the reaction was completed within hours, while more stereoselective catalysts 130 and 131 required 2 days. So far, these are the catalysts of choice for this tran ormation [146-148]. 

Scheme 16.3 FucA " -catalyzed aldol additions reactions of DHAP to C-a branched substituted N-Cbz-aminoaldehydes (4d-e) as well as to the conformation-ally restrained (R)- and (S)-N-Cbz-prolinal...

In addition to studying alternative catalysts, researchers have also investigated new reaction conditions for proline-catalyzed aldolizations. It has, for example, been found that the commonly used DMSO could be replaced vith the room temperature ionic liquids [bmim][PF6] (174) or [emim][OTf ] (175) vith comparable yields and selectivity (Scheme 4.38) [136-138]. 

What is the role of water under these conditions It has been suggested that water suppresses the formation of proHne-oxazoUdinone, which has been considered to be a parasitic species [11]. Then, the role of water is to prevent deactivation rather than to promote activity. Studies, carried out on the proUne-catalyzed reaction between acetone and 2-chlorobenzaldehyde allow one to hypothesize a conflicting role of water. Water increases the total catalyst concentration due to suppression of unproductive species and decreases the relative concentration of productive intermediates by shifting the iminium ion back to proline [12]. Addition of water suppresses formation of both on- and ofF-cyde iminium ions 1 and 2 by Le Chatelier s principle (Scheme 24.2a). The net effect of added water on the globally observed rate will depend on the relative concentrations of iminium ions 1 and 2, which may be different for different aldehydes and can be a function of substrate concentrations and rate and equilibrium constants. Seebach and Eschen-moser have raised doubts about the fact that oxazoUdinones are unproductive and parasitic species in proline-catalyzed aldol reactions [13]. The small excess of water will potentially facilitate proton-transfer in the transition state (Scheme 24.2b), which both lowers the LUMO of the incoming electrophile as well as directs the enantioselectivity of the newly formed stereocenters. 

Polypropionate fragment 24 is obtained upon desulfurization (Raney nickel) of the corresponding thiane. It is interesting to note that addition of nucleophile to aldehyde ( )-21 shows exclusive Felkin diastereoface selectivity. One can assume that the transition state of the aforementioned transformation equals that predicted for proline-catalyzed aldol reactions between cyclohexanone... 

Lewis-Acid Catalyzed. Recently, various Lewis acids have been examined as catalyst for the aldol reaction. In the presence of complexes of zinc with aminoesters or aminoalcohols, the dehydration can be avoided and the aldol addition becomes essentially quantitative (Eq. 8.97).245 A microporous coordination polymer obtained by treating anthracene- is (resorcinol) with La(0/Pr)3 possesses catalytic activity for ketone enolization and aldol reactions in pure water at neutral pH.246 The La network is stable against hydrolysis and maintains microporosity and reversible substrate binding that mimicked an enzyme. Zn complexes of proline, lysine, and arginine were found to be efficient catalysts for the aldol addition of p-nitrobenzaldehyde and acetone in an aqueous medium to give quantitative yields and the enantiomeric excesses were up to 56% with 5 mol% of the catalysts at room temperature.247... 

The best chemical and optical yields in the above reactions are obtained by using (S)- or (R)-proline. Some 19-norsteroids are prepared on an industrial scale from products of intramolecular aldol additions catalyzed by (S)-proline 68). 

The key observation was that L-proline would catalyze the addition of a-hetero aldehydes to a-branched aldehydes such as 2 to give the aldol product 3 with high cnantio- and diastereocontrol. Even more exciting, in the absence of other acceptors the a-hetero aldehydes dimerize with high relative and absolute stereocontrol. Both alkoxy and silyloxy aldehydes worked efficiently. 

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