Aldol Reactions of Aldehyde Donors

Self-aldolization of acetaldehyde provided one-step enantioselective syntheses of (5R)- and (5S)-Hydroxy-(2E)-hexenal using either (R) or (S)-proline as catalysts of the homologation of three acetaldehyde units ee-values of up to 90% were obtained [25]. Using this methodology, a series of triketides was prepared by slow addition of propionaldehyde into acceptor aldehyde and (S)-proline in DMF, and the isolated lactols were converted to the corresponding d-lactones [26]. The product enantiomeric purity was typically moderate because of the isomerization 

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, 

Conditions Diamine 8 (0.05 mmol, 0.1 equiv), CF3C02H (0.05 mmol, 0.1 equiv), donor aldehyde (1.0 mmol, 2 equiv), acceptor aldehyde (0.5 mmol, 1 equiv), DMSO (0.5 mL). Entries 1 and 2, 12 h entry 3, 

---

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].

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

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... 

The phase-transfer-catalyzed enantioselective direct aldol reactions of glycine donor with aldehyde acceptors provide an ideal method for the simultaneous construction of the primary structure and stereochemical integrity of P-hydroxy-a-amino acids, which are extremely important chiral units. In the first report from the Miller s group, N-benzyldnchorudinium chloride (4a) was employed as a catalyst for the reaction of 1 with heptanal, and the corresponding aldol product 21 was obtained in 74% yield, though the diastereo- and enantioselectivities were unfortunately not satisfactory (Scheme 2.18) [40]. 

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. 

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). 

General Procedure for O-tert-Butyl-L-Threonine Catalyzed Cross-Aldol Reactions of Ketone Donors and Aldehyde Acceptors [2] (p. 23)... 

Aldolase antibodies 38C2 and 33F12 are able to catalyze both the aldol addition and the retro-aldol reaction [99]. These catalysts have been employed to carry out the kinetic resolution of /3-hydroxyketones [100] and have been found to catalyze the asymmetric aldol reactions of 23 donors (ketones) and 16 acceptors (aldehydes) [101]. A highly efficient enantioselective... 

As shown in Scheme 8.2, chiral P-hydroxy-a-amino adds can be obtained by the Mukaiyama-type aldol reaction of aldehydes with glycine-derived enol silyl ethers using cinchona-based quaternary ammonium salts. In 2004, Castle and coworkers [9] found that dnchona-based quaternary ammonium salts such as 13 are also able to catalyze the dired aldol readion of aldehydes with the glydne donor 14 in the presence of a phosphazene base such as BTTP (t-butyliminotri(pyrrolidino)phos-... 

In this cross-aldol reaction, formation of the enamine intermediate of an a-chloroaldehyde would be inhibited or significantly slowed down due to steric repulsion, and the formed enamine intermediate of a donor aldehyde reacts predominantly with the electronically activated a-chloroaldehyde (Scheme 17.7). The homo-aldol reaction of the donor aldehyde is suppressed probably due to the moderate nucleophilicity of (S)-4. 

The aldol reaction of aldehydes with ketones where an aldehyde acts as a donor was developed by Jprgensen and co-workers [125], In the presence of L-proline,... 

Here the hapten (Scheme 2) is a 13-diketone, which incorporates structural features of both reactants - ketone donor and aldehyde acceptor (see below, Scheme 3) - in the aldol reaction of interest. In favorable cases the hapten reacts with the primary amino-group of a lysine residue in the complementary-determining region of an antibody to form a Schiffbase 5, which readily tautomerises to the more stable vinylogous amide 6. 

Aldol reactions using phosphoramides as organocatalysts The organic base-catalyzed asymmetric intermolecular aldol reaction with ketone-derived donors can be successfully applied to the construction of aldol products with two stereogenic centers [82-86]. Trichlorosilyl enolates of type 51 have been used as nucleophiles. Such enolates are strongly activated ketone derivatives and react spontaneously with several aldehydes at —80 °C. A first important result was that in the aldol reaction of 51 catalytic amounts of HMPA led to acceleration of the rate of reaction. After screening several optically active phosphoramides as catalysts in a model reaction the aldol product anti-53 was obtained with a diastereomeric... 

Table 2.7 Diamine 8-CF3C02H-catalyzed aldol reactions of a,a-disubstituted aldehyde donors to afford hydroxyaldehydes with a quaternary carbon atom [29].

In the case of the 9-catalyzed aldol reactions of ketones and aldehyde donors that have a high affinity for water (e.g., chloral, trifluoroacetaldehyde, aqueous formaldehyde or the corresponding hydrates of the aldehydes), the addition of 100-500 mol% water to the reaction mixture accelerated the reaction rate and afforded the products with higher enantiomeric excess (Scheme 2.13) [16]. The presence of a catalytic amount of water (20 or 50 mol%) or no addition of water... 

The phase-transfer-catalyzed enantioselective direct aldol reactions of a glycine donor with aldehyde acceptors provide an ideal method for the simultaneous con-... 

The enzyme DERA, 2-deoxyribose-5-phosphate aldolase (EC 4.1.2.4), is unique among the aldolases in that the donor is an aldehyde. In vivo it catalyzes the reversible aldol reaction of acetaldehyde and D-glyceraldehyde 3-phosphate, forming 2-deoxyribose 5-phosphate, with an equilibrium lying in the synthetic direction (Scheme 5.41). DERA, the only well-characterized member of this type I aldolase, has been isolated from both animal tissue and microorganisms.67... 

A ternary chelate of TiCU, sparteine and the A-acetyl derivative of the tricyclic thiazoli-dinethione 74 acts as a chiral donor in aldol reaction with aldehydes. The tryptophan-derived oxazaborolidinone 75 is serviceable in completing the vinylogous Mukaiyama aldol reaction to furnish chiral products. ... 

A high enantioselectivity is found in the aldol reaction of silylketene acetal derived from ethyl l,3-dithiolane-2-carboxylate with aldehydes, which is promoted by the oxaza-borolidinone 16. The products are readily desulfurized with the stereogenic center intact. With trichlorosilyl enolates as donors and a chiral phosphoric triamide 17 as catalyst, asymmetric aldol reactions with aldehydes are realized at low temperatures. ... 

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. ... 

Hydroxy ketones can be synthesized via the pyrrolidine sulfonamide- and prolinamide-catalyzed direct aldol reaction of methyl-aryl ketones with aromatic aldehydes [51]. Modest enantioselectivities were obtained for all donors and acceptors studied. Yields are strongly affected by the nature of the substrates (Chart 3.2). These ketones react also with acetals and hemiacetals of ttichloro- or trifluoroacetaldehyde in the presence of prohne-derived tetrazol to provide the desired aldols [28c, 52]. 

---