Enantioselective proline-catalyzed

Extensions of the proline-catalyzed aldol reaction Recently interesting extensions of the enantioselective proline-catalyzed aldol reaction have been reported. An enan-tioselective proline-catalyzed self-aldolization of acetaldehyde was observed by Barbas and co-workers (Scheme 6.21) [77]. Starting from acetaldehyde, the valuable building block 5 -h ydroxy-( 2E)-hexcnal, (S)-43, was obtained as a product with up to 90% ee, although the yield did not exceed 13%, irrespective of the reaction conditions. This reaction requires a small amount catalyst only (ca. 2.5 mol%). 

Enamine-mediated aldolizations offer much better prospects for a stereo-controlled process. The famous enantioselective proline-catalyzed triketone cyclization to the Wieland-Miescher ketone 43 [56], as well as the chemistry of type I aldolase enzymes [57],provide ample precedents for stereo- and enantioselective enamine-mediated reactions. 

In 2009, List and coworkers reported a highly diastereo and enantioselective proline-catalyzed double Mannich reaction of acetaldehyde with A-Boc imines [3], The treatment of 1 equiv of acetaldehyde with 3 equiv of A-Boc imine derived from benzaldehyde in the presence of 20 mol% of L-Pro produced the double Mannich adduct 2 in quantitative yield and with exceptionally high diastereo and enantiose-lectivities (dr > 99 1, ee > 99%) (Scheme 12.2). The reaction was performed with a variety of A-Boc imines, namely aromatic and heteroaromatic substituted imines, and furnished the products in excellent yields (76-99%) and with similar stereoselectivities (dr > 99 1, ee > 99%). Even the unstable isovaleraldehyde-derived A-Boc imine gave the double Mannich adduct stereoselectively, albeit with a moderate yield (30%). 

The detailed mechanism of this enantioselective transformation remains under investigation.178 It is known that the acidic carboxylic group is crucial, and the cyclization is believed to occur via the enamine derived from the catalyst and the exocyclic ketone. A computational study suggested that the proton transfer occurs through a TS very similar to that described for the proline-catalyzed aldol reaction (see page 132).179... 

Typical starting materials, catalysts, and products of the enamine-catalyzed aldol reaction are summarized in Scheme 17. In proline-catalyzed aldol reactions, enantioselectivities are good to excellent with selected cyclic ketones, such as cyclohexanone and 4-thianone, but generally lower with acetone. Hindered aldehyde acceptors, such as isobutyraldehyde and pivalaldehyde, afford high enantioselectivities even with acetone. In general, the reactions are anti selective, but there are aheady a number of examples of syn selective enamine aldol processes [200, 201] (Schemes 17 and 18, see below). However, syn selective aldol reactions are still rare, especially with cychc ketones. 

The amine-catalyzed Mannich reaction has also been a subject of special reviews [243, 244]. In general, yields and enantioselectivities of proline-catalyzed Mannich reactions are very high. Initially, the reactions were restricted to imines bearing an aromatic A-substituent, such as the p-methoxyphenyl (PMP) group. This restriction considerably limited the usefulness of the protocol, because relatively... 

Rh2(S-TBSP)4 8 and Rh2(S-DOSP)4 9 (Tab. 14.3) [40, 45]. A very unusual feature of the prolinate-catalyzed cyclopropanations is that the reactions proceed with much higher asymmetric induction when hydrocarbon solvents are used instead of dichloromethane [40, 45]. Room-temperature cyclopropanations of styrene with Rh2(S-TBSP) or Rli2(S-D0SP)4 typically occur with 90-92% enantioselectivity, while the Rh2(S-DOSP)4-cata-lyzed reaction at -78°C occurs in 98% enantiomeric excess (Tab. 14.3) [40]. The rhodium prolinate catalysts are very easy to handle, being stable to air, heat, and moisture although it has been reported that the enantioselectivity can decrease if the cyclopropanation is conducted in wet solvents [46]. 

Fluoral hydrate and hemiacetals are industrial products. They are stable liquids that are easy to handle, and they react as fluoral itself in many reactions. Thus, in the presence of Lewis acids, they react in Friedel-Crafts reactions. They also react very well with organometallics (indium and zinc derivatives) and with silyl enol ethers.Proline-catalyzed direct asymmetric aldol reaction of fluoral ethyl hemiac-etal with ketones produced jS-hydroxy-jS-trifluoromethylated ketones with good to excellent diastereo- (up to 96% de) and enantioselectivities. With imine reagents, the reaction proceeds without Lewis acid activation. The use of chiral imines affords the corresponding 8-hydroxy ketones with a 60-80% de (Figure 2.49). ° ... 

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. 

It is true that highly enantioselective reactions are possible with proline in the asymmetric a-amination of aldehydes by azodicarboxylates and in a-oxidation with nitrosobenzene. However, good rather than excellent yields and enantioselectivities are more common in intermolecular Michael and aldol reactions. Moreover, the high catalyst loadings required for proline-catalyzed aldol reactions (up to 30%), and low TOFs (from hours to days to achieve a good conversion, even at a high catalyst... 

List gave the first examples of the proline-catalyzed direct asymmetric three-component Mannich reactions of ketones, aldehydes, and amines (Scheme 14) [35], This was the first organocatalytic asymmetric Mannich reaction. These reactions do not require enolate equivalents or preformed imine equivalent. Both a-substituted and a-unsubstituted aldehydes gave the corresponding p-amino ketones 40 in good to excellent yield and with enantiomeric excesses up to 91%. The aldol addition and condensation products were observed as side products in this reaction. The application of their reaction to the highly enantioselective synthesis of 1,2-amino alcohols was also presented [36]. A plausible mechanism of the proline-catalyzed three-component Mannich reaction is shown in Fig. 2. The ketone reacts with proline to give an enamine 41. In a second pre-equilib-... 

It was reported that proline catalyzed the direct catalytic asymmetric Mannich reactions of hydroxyacetone, aldehydes, and aniline derivatives [(Eq. (10)] [40-44]. Not only aromatic aldehydes but also aliphatic aldehydes worked well in this reaction, and good to excellent enantioselectivity and moderate to excellent yields were observed. Mannich reactions of glyoxylate imines with aldehydes or ketones were also successfully performed [45,46]. 

An important feature of this reaction is that in contrast to most other catalytic asymmetric Mannich reactions, a-unbranched aldehydes are efficient electrophiles in the proline-catalyzed reaction. In addition, with hydroxy acetone as a donor, the corresponding syn-l, 2-aminoalcohols are furnished with high chemo-, regio-, diastereo-, and enantioselectivities. The produced ketones 14 can be further converted to 4-substituted 2-oxazolidinones 17 and /i-aminoalcohol derivatives 18 in a straightforward manner via Baeyer-Villiger oxidation (Scheme 9.4) [5]. 

Surprisingly, the catalytic potential of proline (1) in asymmetric aldol reactions was not explored further until recently. List et al. reported pioneering studies in 2000 on intermolecular aldol reactions [14, 15]. For example, acetone can be added to a variety of aldehydes, affording the corresponding aldols in excellent yields and enantiomeric purity. The example of iso-butyraldehyde as acceptor is shown in Scheme 1.4. In this example, the product aldol 13 was obtained in 97% isolated yield and with 96% ee [14, 15]. The remarkable chemo- and enantioselectivity observed by List et al. triggered massive further research activity in proline-catalyzed aldol, Mannich, Michael, and related reactions. In the same year, MacMillan et al. reported that the phenylalanine-derived secondary amine 5 catalyzes the Diels-Alder reaction of a,/>-un saturated aldehydes with enantioselectivity up to 94% (Scheme 1.4) [16]. This initial report by MacMillan et al. was followed by numerous further applications of the catalyst 5 and related secondary amines. 

Cheap and readily available L-proline has been used numerous times for the intermediate and reversible generation of chiral iminium ions from a,/ -unsaturated carbonyl compounds. For example, Yamaguchi et al. reported in 1993 that the rubidium salt of L-proline catalyzes the addition of di-iso-propyl malonate to the acyclic Michael acceptors 40a-c (Scheme 4.13), with enantiomeric excesses as high as 77% [22], With 2-cycloheptenone and 2-cyclohexenone as substrates ca 90% yield and ee of 59% and 49% were obtained. Later the enantioselectivity of this process was increased to a maximum of 88% ee in the addition of di-tert-butyl malonate to the E-pentenone 40a in the presence of 20 mol% Rb-L-prolinate and 20 mol% CsF [23], Taguchi and Kawara employed the L-proline-derived ammonium salts 41a and... 

Yamaguchi et al. also showed that Rb-L-prolinate catalyzes enantioselective addition of nitroalkanes to several acyclic and cyclic enones [25, 26]. For acyclic enone acceptors the best result, i.e. 74% yield and 68% ee of the S product, was achieved in the addition of 2-nitropropane to -3-penten-2-one (40a, Scheme 4.13) [25]. Screening of several proline derivatives and cyclic amino acids of other ring size resulted in the identification of the O-TBDMS-derivative of 4-hydroxyproline as the best catalyst for addition of nitrocyclohexane to cycloheptenone. In this particular reaction 74% yield and 86% ee were achieved [26]. 

Extension of this reaction toward a one-pot asymmetric Mannich-hydrocyanation reaction sequence was also reported by the Barbas group [29]. In this one-pot two-step process proline-catalyzed asymmetric Mannich reaction of unmodified aldehydes with the a-imino glyoxylate was performed first, then diastereoselective in situ cyanation. The resulting /i-cyanohydroxymethyl a-amino acids were obtained with high enantioselectivity (93-99% ee) [29]. Another one-pot two-step reaction developed by Barbas et al. is the Mannich-allylation reaction in which the proline-catalyzed Mannich reaction is combined with an indium-promoted allylation [30], This one-pot synthesis was conducted in aqueous media and is the first example of a direct organocatalytic Mannich reaction in aqueous media [28, 30]. 

The concept The possibility of using a simple organic molecule from the chiral pool to act like an enzyme for the catalytic intermolecular aldol reaction has recently been reported by the List and Barbas groups [69-71]. L-proline, (S)-37, was chosen as the simple unmodified catalytic molecule from the chiral pool . The proline-catalyzed reaction of acetone with an aldehyde, 36, at room temperature resulted in the formation of the desired aldol products 38 in satisfactory to very good yields and with enantioselectivity up to >99% ee (Scheme 6.18) [69, 70a],... 

The substrate range scope and limitations Promising prospects for synthetic applications of the proline-catalyzed aldol reaction in the future were opened up by experimental studies of the range of substrates by the List [69, 70a, 73] and Barbas [71] groups. The reaction proceeds well when aromatic aldehydes are used as starting materials - enantioselectivity is 60 to 77% ee and yields are up to 94% (Scheme 6.19) [69, 70], The direct L-proline-catalyzed aldol reaction proceeds very efficiently when isobutyraldehyde is used as substrate - the product, (R)-38d, has been obtained in very good yield (97%) and with high enantioselectivity (96% ee). 

Another interesting extension of the proline-catalyzed aldol reaction was recently reported by the Jorgensen group (Scheme 6.22), who used keto malonates as acceptors and a-substituted acetone derivatives as donors [78]. In contrast with the classic proline-catalyzed reaction discussed above, in this reaction the stereogenic center is formed at the nucleophilic carbon atom of the donor. The resulting products of type 46 are formed in good yields, from 88% to 94%, and with enantioselectivity between 84 and 90% ee (Scheme 6.22). The reactions were performed with a catalytic amount of 50 mol% [78],... 

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 reactions also led to high regioselectivity (> 20 1). For alkylated aldehydes unbranched in the a-position, however, low diastereoselectivity (d.r. 1.7 1) and yields of 38% were obtained, although enantioselectivity remained excellent (> 97% ee). Use of aromatic substrates resulted in a d.r. of 1 1 to 1.5 1 only, and the enantioselectivity was in the range 67 to 80% ee [93]. Some representative examples of the L-proline-catalyzed aldol reaction with hydroxyacetone are given in Scheme 6.35. 

Mechanism and transition states The basic principles of the proline-catalyzed direct aldol reaction are summarized in Section 6.2.1.1 [93, 94a], The preferred diastereo- and enantioselectivity were explained in terms of the potential transition states for the aldol reaction using hydroxyacetone shown in Scheme 6.38 [93], Thus, re-facial attack of the aldehyde at the si face of hydroxyacetone leads to the... 

A detailed study of the reaction mechanism based on quantum mechanical calculations was reported very recently by Houk and List et al. [96]. In this connection, the ratio of the four stereoisomeric products in the proline-catalyzed dia-stereo- and enantioselective aldol reaction was predicted and excellent agreement... 

This reaction is particularly suitable for the preparation of the Wieland-Miescher ketone 96, a very useful building block for construction of a broad variety of biologically active compounds such as steroids, terpenoids, and taxol. On the basis of the proline-catalyzed approach described above Barbas et al. recently reported an optimized procedure for formation of the chiral Wieland-Miescher ketone, 96 [105]. It has been shown that this synthesis (which comprises three reactions) can be performed as a one-pot synthesis. The desired product is obtained in 49% yield with enantioselectivity of 76% ee (Scheme 6.43). Here L-proline functions as an efficient catalyst for all three reaction steps (Michael-addition, cydiza-tion, dehydration). It is also worth noting that although many other amino adds and derivatives thereof were tested as potential alternative catalysts, L-proline had the best catalytic properties for synthesis of 96. This result emphasizes the superior catalytic properties of proline reported after previous comparative studies by the Hajos group [100, 101]. 

In conclusion, there have been many reports of the high synthetic potential of the intramolecular aldol reaction in the enantioselective construction of cyclic enones. In particular the proline-catalyzed desymmetrization of triketones has been widely used for formation of optically active bicyclic systems which are versatile building blocks for steroids and other biologically active compounds. 

It should be added that improved formation of products of type 126 was achieved by choosing a different reaction strategy [133], A typical proline-catalyzed aldol reaction (starting from aldehydes as donors and compounds 125 as acceptors), followed by conversion of the C=0 functionality of the aldol adduct into a nitrone group by condensation with a hydroxylamine component led to products of type 126 in good yield and with high enantioselectivity (up to 96% ee) [133],... 

Extension of this proline-catalyzed a-amination to the use of aldehydes as starting materials has been described independently by the Jorgensen and List groups [6, 7]. The principle of the reaction and some representative examples are shown in Scheme 7.4. The practicability is high - comparable with that of the analogous reaction with ketones described above. For example, in the presence of 5 mol% L-proline as catalyst propanal reacts with azodicarboxylate 3a at room temperature in dichloromethane with formation of the a-aminated product 5a in 87% yield and with 91% ee [7]. Good yields and high enantioselectivity can be also obtained by use of other types of solvent, e.g. toluene and acetonitrile. The products of type 5 were isolated simply by addition of water, extraction with ether, and subsequent evaporation. 

The List group synthesized a broad variety of N-protected amino alcohols 6 by proline-catalyzed a-amination of aldehydes (Scheme 7.5) [6], Under optimized conditions, the desired products of type 6 were obtained in high yields (93-99%) and with excellent enantioselectivity (up to >95% ee). Acetonitrile was found to be the preferred solvent and a catalytic amount (10 mol%) of proline was used. 

This a-aminooxylation has subsequently been successfully extended to the use of ketones as donors [12]. For example, use of cyclohexanone as donor led to (R)-12a in 79% yield and with an excellent enantioselectivity of >99% ee (Scheme 7.12) [12a]. Very recently, the Cordova group reported further examples of this proline-catalyzed a-aminooxylation [13]. In addition, this method has been successfully applied in the synthesis of corresponding chiral 1,2-diols after subsequent derivatiza-tion [13]. Furthermore, computational studies of transition states were carried out [13b],... 

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. 

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