Acetaldehydes aldol reaction donors

The simplest possible aldehyde donor, acetaldehyde, can also be used as the donor Very recently, Hayashi and coworkers discovered how to use acetaldehyde in crossed-aldol reactions - the trick is to use diarylprohnol as the catalyst and to optimize the reaction conditions carefully to prevent oligomerization of acetaldehyde. However, so far the acetaldehyde aldol reactions appear to be limited to aromatic aldehyde acceptors [205],... 

Aldolases catalyze asymmetric aldol reactions via either Schiff base formation (type I aldolase) or activation by Zn2+ (type II aldolase) (Figure 1.16). The most common natural donors of aldoalses are dihydroxyacetone phosphate (DHAP), pyruvate/phosphoenolpyruvate (PEP), acetaldehyde and glycine (Figure 1.17) [71], When acetaldehyde is used as the donor, 2-deoxyribose-5-phosphate aldolases (DERAs) are able to catalyze a sequential aldol reaction to form 2,4-didexoyhexoses [72,73]. Aldolases have been used to synthesize a variety of carbohydrates and derivatives, such as azasugars, cyclitols and densely functionalized chiral linear or cyclic molecules [74,75]. 

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... 

It is worthy of note that - similarly to the proline catalyzed aldol reaction - the Mannich reaction can also be extended to an enantio- and diastereoselective process in which two stereogenic centers are formed in one step, although using non-chiral starting materials (Scheme 5.16) [22, 23, 26, 27, 28]. In these reactions substituted acetone or acetaldehyde derivatives, rather than acetone, serve as donor. In contrast with the anti diastereoselectivity observed for the aldol reaction (Section 6.2.1.2), the proline-catalyzed Mannich reaction furnishes products with syn diastereoselectivity [23]. A proline-derived catalyst, which led to the formation of anti Mannich products has, however, been found by the Barbas group [29]. 

In nature, most aldolases are rooted in the sugar metabolic cycle and accept highly functionalized substrates for the aldol reaction. Nevertheless, the scope of enzymatic aldol reactions is limited, since aldolases strictly distinguish between the acceptor and the donor, yielding almost exclusively one product, and is furthermore restricted to only a few different possible natural donors. According to the donor molecules, aldolases are grouped in dihydroxyacetone phosphate-, phosphoenolpyruvate- or pyruvate-, acetaldehyde-, and glycine-dependent aldolases [41]. 

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... 

In DERA reactions, where acetaldehyde is the donor, products are also themselves aldehydes. In certain cases a second aldol reaction will proceed until a product has been formed that can cyclize to a stable hemiacetal.71 For example, when a-substituted aldehydes were used, containing functionality that could not cyclize to a hemiacetal after the first aldol reaction, these products reacted with a second molecule of acetaldehyde to form 2,4-dideoxyhexoses, which then cyclized to a hemiacetal, preventing further reaction. Oxidation of these materials to the corresponding lactone, provided a rapid entry to the mevinic acids and compactins (Scheme 5.43). Similar sequential aldol reactions have been studied, where two enzyme systems have been employed72 (Scheme 5.44). The synthesis of 5-deoxy ketoses with three substitutents in the axial position was accomplished by the application of DERA and RAMA in one-pot (Scheme 5.44). The long reaction time required for the formation of these thermodynamically less stable products, results in some breakdown of the normally observed stereoselectivity of the DERA and FDP aldolases. In a two-pot procedure, DERA and NeuAc aldolase have... 

It is the only known member of the group of acetaldehyde-dependent aldolases. In vivo, DERA catalyzes the reversible aldol reaction of acetaldehyde and G3P. The donor substrate specificity of this enzyme is not as strict as with the other aldolases. 

Aldehyde donors were also employed successfully in the syntheses of convolutamydines E (77) and B (78) (80-82). The strategy was the same as depicted for the synthesis of (/ )- and (5)-convolutamydine A (32) (Scheme 9), but using acetaldehyde (79) instead of acetone (13) as the nucleophile in the cross-aldol reaction with dibromo-isatm 33 (Scheme 19). Nakamura et al. utilized catalyst 37, followed by a NaBH3CN-mediated reduction to obtain (/ )-convolutamydine E (77) in excellent yield and enantioselectivity. Chlorination of 77 then gave (l )-convolutamydine B (78) (Scheme 19) (80, 81). 

An elegant method for sequential aldol reactions performed in a one-pot reaction has been discovered for 2-deoxyribose-5-phosphate aldolase (Scheme 2.195) [1439]. When a (substituted) aldehyde was used as acceptor, condensation of acetaldehyde (as donor) led to the corresponding 3-hydroxy aldehyde as intermediate product. The latter, however, can undergo a second aldol reaction with another acetaldehyde donor, forming a P,8-dihydroxy aldehyde. At this stage, this aldol... 

In the enzymatic aldol reaction, the role of the donor and acceptor is strictly determined by the specificity of the enzyme and only raie coupling product can be obtained. In contrast, the possible product range is more complex in acyloin and benzoin reactions If only a single aldehyde species is used as substrate, only one product can be obtained via homocoupling however, a pair of regioisomeric a-hydroxyketones can be obtained via heterocoupling, when two different aldehydes are used, the ratio of which is determined by the choice of substrates (e.g., benzoyl formate vs. benzaldehyde, pyruvate vs. acetaldehyde), and the specificites of enzymes, respectively (Scheme 2.198). 

The commercially available acetaldehyde (34) serves as a donor for aldol reactions, but undesirable side products are generally formed because of its very high degree of reactivity. In 2002, the (S)-proline catalyzed self-aldol reaction of this acetaldehyde was reported the reaction yielded over-reacting (-F)-(5S)-hydroxy-(2 )-hexenal with 57 to 90% ee [21]. The synthetically challenging i-hydroxy a-unsubstituted... 

Acetaldehyde 34, which is the simplest of all enolizable carbonyl compounds but highly reactive as an electrophile, is an inexpensive and versatile two-carbon nucleophile in enamine-based Mannich reactions. Mannich reactions of acetaldehyde as a donor with aryl or alkyl substituted N-Boc-imines 90 are effectively catalyzed by (S) -proline (13) in moderate yield but excellent enantioselectivity (Table 28.6, entries 1 and 2) [47]. Chemical yields are improved up to 87% when N-benzoyl (Bz)-imine is employed in the presence of diaryl prolinol silyl ether 85 with p-nitrobenzoic acid (entry 3) [48]. To suppress side reactions, such as self-aldol reactions, the moderate nucleophilicity of the axially chiral amino sulfonamide 23 is particularly useful for this type of Mannich reaction these conditions give the corresponding adducts 91 in good yield and excellent stereoselectivity (entries 4 and 5) [49]. 

When acetaldehyde is used as the donor, the products from the DERA-catalyzed reaction are aldehydes, capable of being acceptor substrates for a second aldol condensation (Fig. 14.1-31)[1871. For example, when a-substituted acetaldehydes were employed as substrates, products of the first aldol condensation could not cyclize to a hemiacetal, and the products reacted with a second molecule of acetaldehyde to form 2,4-dideoxyhexoses. These products could then cyclize to stable... 

In addition to ketones, aldehydes can also be used as aldol donors in pro-line-catalyzed reactions [144]. Barbas et al. found that treating acetaldehyde solutions tvith proline provided aldehyde 185, an aldol trimer of acetaldehyde, in 84% ee and 4% yield (Scheme 4.42, Eq. (1)) [145, 146]. As shotvn by Jorgensen et al., other simple a-unbranched aldehydes can also be used as donors in proline-catalyzed cross aldolization tvith activated non-enolizable ketone acceptors to give aldols 188 in high enantioselectivity and yield (Scheme 4.42, Eq. (2)) [147]. 

When acetaldehyde is used as the only substrate, the initial aldol product can serve again as a suitable acceptor for sequential addition of a second donor molecule to give (3R,5R)-2,4,6-trideoxyhexose 133 (Figure 5.60) [282, 283]. Cyclization to stable hemiacetals masks the free aldehyde and thus effectively precludes formation of higher-order adducts. When the first acceptor is an a-substituted acetaldehyde, related aldol products from tv ofold donor additions can be prepared that are structurally related to mevino-lactone. Combination of a RibA-catalyzed initial addition to other aldolases such as FruA or NeuA in a consecutive addition reaction has also been studied for synthesis of non-natural sugars [277, 282]. 

The 2-deoxy-D-ribose 5-phosphate aldolase (RibA EC 4.1.2.4) is a class I enzyme that catalyzes in vivo the addition of acetaldehyde (85) to D-glyceraldehyde 3-phosphate (15), Hence, it is a unique aldolase in that it uses two aldehydic substrates both as the aldol donor and acceptor components. RibA from E. coli been cloned [146] and overexpressed. The equilibrium constant for synthesis of 2 X 10 M does not strongly favor synthesis [43]. Interestingly, the enzyme s relaxed acceptor specificity allows for substitution of both cosubstrates, albeit at strongly reduced (<1% of rates propionaldehyde 77, acetone 83, or fluoroacetone 84 (Fig. 28) can replace 85 as the donor [147,148], and a number of aldehydes up to a chain length of four nonhydrogen atoms are tolerated as acceptors. However, reactions that lead to thermodynamically unfavorable products may proceed nonstereospecifically at the reaction center [149]. 

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