Prolines aldehyde donors

Barbas et al. [113] have published the asymmetric synthesis of spiro-p-lactams 171 (Scheme 39) using proline-catalyzed Mannich reaction with branched aldehyde donors. The Mannich reactions of a,a-disubstituted aldehydes 168 with... 

The mechanism of proline-catalyzed Mannich reactions is depicted in Scheme 5. The ketone or aldehyde donor reacts with proline to give an enamine. Next, the preformed or in-situ-generated imine reacts with the enamine to give, after hydrolysis, the enantiomerically enriched Mannich adduct the catalytic cycle can then be repeated. 

S)-Proline-catalyzed aldehyde donor reactions were first studied in Michael [21] and Mannich reactions (see below), and later in self-aldol and in cross-aldol reactions. (S)-Proline-catalyzed self-aldol and cross-aldol reactions of aldehydes are listed in Table 2.6 [22-24]. In self-aldol reactions, the reactant aldehyde serves as both the aldol donor and the acceptor whereas in cross-aldol reactions, the donor aldehyde and acceptor aldehyde are different. 

Aldol and Mannich-Type Reactions 27 Table 2.6 (S)-Proline-catalyzed cross-aldol reactions of aldehyde donors.3)... 

For the aldol reactions of aldehyde donors using (S)-proline or diamine (S)-8-CF3C02H, the major products and the proposed most suitable transition state that explains the stereochemistries of the products are also shown in Scheme 2.12 [8, 29a]. 

Scheme 2.12 The proposed most suitable transition states of the (S)-proline-catalyzed and diamine 8-CF3C02H-catalyzed aldol reactions of aldehyde donors [29b].

Table 2.10 (S)-Proline-catalyzed Mannich-type reactions of aldehyde donors and /N/-PMP-protected glyoxylate imine [71 a,b].

The (S)-proline-catalyzed Mannich reactions of aldehyde donors and N-PMP-protected imines of fluorinated aldehyde, such as CF3CHO, C2F5CHO, and PI1CF2CHO, were also used for the expedient synthesis of fluorinated aminoalco-hols [81]. 

Table 2.14 (S)-Proline-catalyzed three-component Mannich reactions of aldehyde donors [71b, 82].

General Procedures for (S)-Proline-Catalyzed Cross-Aldol Reactions of Aldehyde Donors (p. 28)... 

The cross-aldol reaction between enolisable aldehydes (donor aldehydes) and nonenolisable aldehydes (acceptor aldehydes) is known to be catalysed by L-proline and the related amine catalysts, giving antz -aldol adducts. For instance, the cross-aldol reaction of propanal with 4-nitrobenzaldehyde gave the corresponding anti-dXdoX adduct with excellent diastereo- and enantioselectivity (Scheme 17.4). ° The reaction catalysed by an amino sulfonamide (5 )-3, on the other hand, gave the unusual q n-aldol product as the major diastereomer. ... 

In 2003, Barbas and coworkers described a one-pot synthesis of functionalized P-aminoalcohols from aldehydes, acetone, and dibenzyl azodicarboxylate [2], This enzyme-like direct asymmetric assembly process was catalyzed with 20 mol% of L-proline (l-Pto) and provided the optically active products 1. This was the first example of an assembly reaction that used directly both an aldehyde and a ketone as donors in a single vessel. The success of the assembly reaction can be attributed to the higher reactivity of aldehydes over ketones in the L-Pro-catalyzed a-amination. The reaction of propionaldehyde, acetone, and dibenzyl azodicarboxylate in acetonitrile produced the expected aminoalcohol 1 in 85% yield (Scheme 12.1). The two diastereomers were obtained with an anti/syn ratio of 54 46 and with an enantioselectivity of >99% for the anti product. The authors explored the scope of the assembly reaction using various aldehydic donors, and this transformation was applied to the expedient synthesis of a potent renin inhibitor. 

Proline catalyzed aldolreactions with aldehyde donors. 

A different type of catalysis is observed using proline as a catalyst.166 Proline promotes addition of acetone to aromatic aldehydes with 65-77% enantioselectivity. It has been suggested that the carboxylic acid functions as an intramolecular proton donor and promotes reaction through an enamine intermediate. 

Organic-Base Catalyzed. Asymmetric direct aldol reactions have received considerable attention recently (Eq. 8.98).251 Direct asymmetric catalytic aldol reactions have been successfully performed using aldehydes and unmodified ketones together with chiral cyclic secondary amines as catalysts.252 L-proline and 5,5-dimethylthiazolidinium-4-carboxylate (DMTC) were found to be the most powerful amino acid catalysts for the reaction of both acyclic and cyclic ketones as aldol donors with aromatic and aliphatic aldehydes to afford the corresponding... 

The first asymmetric enamine-catalyzed Mannich reactions were described by List in 2000 [208]. Paralleling the development of the enamine-catalyzed aldol reactions, the first asymmetric Mannich reactions were catalyzed by proline, and a range of cyclic and acyclic aliphatic ketones were used as donors (Schemes 24 and 25). In contrast to the aldol reaction, however, most Mannich reactions are syn selective. This is presumably due to the larger size of the imine acceptor, forcing the imine and the enamine to approach each other in a different manner than is possible with aldehyde acceptors (Scheme 23). 

Since the initial studies, the substrate scope has expanded to include heteroatom-substituted ketones [208-216], cyclic ketones [217] and aldehydes [211, 218-226] as donors, and formaldehyde-derived imines [218, 227-232] as well as glyoxylate-derived imines [96, 220, 233-237] as acceptors. In addition, several alternative catalysts to proline have been pursued [238-242]. 

Enamine nucleophiles react readily with soft conjugated electrophiles, such as a, 3-unsaturated carbonyl, nitro, and sulfonyl compounds [20-22], Both aldehydes and ketones can be used as donors (Schemes 27 and 28). These Michael-type reactions are highly useful for the construction of carbon skeletons and often the yields are very high. The problem, however, is the enantioselectivity of the process. Unlike the aldol and Mannich reactions, where even simple proline catalyst can effectively direct the addition to the C = O or C = N bond by its carboxylic acid moiety, in conjugate additions the charge develops further away from the catalyst (Scheme 26) ... 

Another possible mechanism for the racemization of amino acid esters involves the in situ, transient, formation of Schiff s bases by reaction of the amine group of an amino acid ester with an aldehyde. Using this approach, DKR of the methyl esters of proline 5 and pipecolic acid 6 was achieved using lipase A from C. ant-arclica as the enantioselective hydrolytic enzyme and acetaldehyde as the racemiz-ing agent (Scheme 2.4). Interestingly, the acetaldehyde was released in situ from vinyl butanoate, which acted as the acyl donor, in the presence of triethylamine. The use of other reaction additives was also investigated. Yields of up to 97% and up to 97% e.e. were obtained [6]. 

Important extensions of proline catalysis in direct aldol reactions were also reported. Pioneering work by List and co-workers demonstrated that hydroxy-acetone (24) effectively serves as a donor substrate to afford anfi-l,2-diol 25 with excellent enantioselectivity (Scheme 11) [24]. The method represents the first catalytic asymmetric synthesis of anf/-l,2-diols and complements the asymmetric dihydroxylation developed by Sharpless and other researchers (described in Chap. 20). Barbas utilized proline to catalyze asymmetric self-aldoli-zation of acetaldehyde [25]. Jorgensen reported the cross aldol reaction of aldehydes and activated ketones like diethyl ketomalonate, in which the aldehyde... 

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]. 

The formation of covalent substrate-catalyst adducts might occur, e.g., by single-step Lewis-acid-Lewis-base interaction or by multi-step reactions such as the formation of enamines from aldehydes and secondary amines. The catalysis of aldol reactions by formation of the donor enamine is a striking example of common mechanisms in enzymatic catalysis and organocatalysis - in class-I aldolases lysine provides the catalytically active amine group whereas typical organocatalysts for this purpose are secondary amines, the most simple being proline (Scheme 2.2). 

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],... 

The capability of L-proline - as a simple amino acid from the chiral pool - to act like an enzyme has been shown by List, Lemer und Barbas III [4] for one of the most important organic asymmetric transformations, namely the catalytic aldol reaction [5]. In addition, all the above-mentioned requirements have been fulfilled. In the described experiments the conversion of acetone with an aldehyde resulted in the formation of the desired aldol products in satisfying to very good yields and with enantioselectivities of up to 96% ee (Scheme 1) [4], It is noteworthy that, in a similar manner to enzymatic conversions with aldolases of type I or II, a direct asymmetric aldol reaction was achieved when using L-proline as a catalyst. Accordingly the use of enol derivatives of the ketone component is not necessary, that is, ketones (acting as donors) can be used directly without previous modification [6]. So far, most of the asymmetric catalytic aldol reactions with synthetic catalysts require the utilization of enol derivatives [5]. The first direct catalytic asymmetric aldol reaction in the presence of a chiral heterobimetallic catalyst has recently been reported by the Shibasaki group [7]. 

To a mixture of anhydrous dimethyl sulfoxide (4 mL) and ketone donor (1 mL) was added the corresponding aldehyde (0.5 mmol) followed by L-proline (20-30mol%) and the resulting mixture was stirred at room temperature for 4—72 h. The reaction mixture was treated with saturated ammonium chloride solution, the layers were separated, and the aqueous layer was extracted several times with ethyl acetate, dried with anhydrous MgS04, and evaporated. The pure aldol products were obtained by flash column chromatography (silica gel, mixture of hexanes and ethyl acetate). 

Significant for cross-aldol reactions, when an aldehyde was mixed with (S)-proline in a reaction solvent, the dimer (the self-aldol product) was the predominant initial product. Formation of the trimer typically requires extended reaction time (as described above). Thus, it is possible to perform controlled cross-aldol reactions, wherein the donor aldehyde and the acceptor aldehyde are different. In order to obtain a cross-aldol product in good yield, it was often required that the donor aldehyde be slowly added into the mixture of the acceptor aldehyde and (S)-proline in a solvent to prevent the formation of the self-aldol product of the donor aldehyde. The outcome of these reactions depends on the aldehydes used for the reactions. Slow addition conditions can sometimes be avoided through the use of excess equivalents of donor or acceptor aldehyde - that is, the use of 5-10 equiv. of acceptor aldehyde or donor aldehyde. In general, aldehydes that easily form self-aldol products cannot be used as the acceptor aldehydes in... 

Conditions Entry 2 A solution of donor aldehyde (2.0 mmol, 2 equiv.) in DMF (500 pL) was added slowly over 2.5 h to a stirring mixture of acceptor aldehyde (1.0 mmol, 1 equiv.) and (S)-proline (0.10 mmol,... 

S)-Proline-catalyzed cross-aldol reaction of aldehydes followed by Mukaiyama aldol reaction sequence was used for the synthesis of prelactone B [27]. The products of the aldol reactions of O-protected a-oxyaldehydes are protected carbohydrates, and were also transformed to highly enantiomerically enriched hexose derivatives, again through a second Mukaiyama aldol reaction (Scheme 2.5) [28]. The products of the aldol reactions of N-protected a-aminoaldehyde donor were easily converted to the corresponding highly enantiomerically enriched /Miydroxy-a-amino acids and their derivatives (Scheme 2.6) [24]. (For experimental details see Chapter 14.1.1). 

S)-Proline has been used to catalyze Mannich-type reactions of enolizable carbonyl donors. Reactions of unmodified aldehydes and N-p-methoxyphenyl (PMP)-protected glyoxylate imine in the presence of a catalytic amount of (S)-proline at room temperature afforded enantiomerically enriched / -aminoaldehydes, as... 

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