Aldol reaction with azodicarboxylate

Azodicarboxylates are attractive aminating reagents, since a-aminocarbonyl compounds are not only useful building blocks in organic synthesis, but also essential tools for biological studies.33 Hence, the development of general and efficient methods for the preparation of these compounds is an important issue in organic synthesis. 

The allylation reaction of carbonyl compounds is a classical but excellent method for constructing highly functionalized organic molecules. More recently, allylation 

Although many catalysts have been developed for these reactions, most of them are Lewis acid catalysts that are typically sensitive to moisture. The silver catalysts we mentioned above might become a preferable choice since silver catalysts can be used in water and many silver salts are commercially available and inexpensive. The chemistry of silver catalysts in this context can be expected to expand significantly in the future. 

Mahrwald, R., ed., Modern Aldol Reactions, Wiley-VCH, Weinheim, 2004, Vols.l, 2. 

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In 2003, a proline-catalyzed enamine-enamine activation sequence was used to develop a three-component reaction leading to functionalized P-amino alcohols 35 [29, 30]. The reaction used both ketones (specifically, acetone) and aldehydes 33 as donors, together with azodicarboxylate 34 (Scheme 42.9) [30]. The first step is the pro line-catalyzed amination of aldehydes [31], leading to intermediate 36, which represents the electrophiUc substrate for the subsequent aldol reaction with acetone. Both intermolecular steps proceed under enamine catalysis by proline 1. A key factor in the high level of chemoselectivity observed was the much higher reactivity of aldehyde over ketone in the proline-catalyzed a-amination reaction, which selectively forms 36. 

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... 

Synthesis of (-I-) calanolide A (Scheme 8-11) was achieved by enzyme catalyzed resolution of the aldol products ( )-53. Compound 7 with acetaldehyde by aldol reaction in the presence of LDA/TiCU stereoselectively produced a mixmre of ( )-53 and ( )-54 (94% yield), the ratio of which was 96 4. ( )-53 was then resolved by lipase AK-catalyzed acylation reaction in the presence of tert-butyl methyl ether and vinyl acetate at 40 °C to obtain 41% yield of (+)-55 and 54% yield of the acetate (—)-56. Mitsunobu cyclization of (+)-55 in the presence of tri-phenylphosphine and dielthyl azodicarboxylate afforded 63% yield of (-l-)-43 with 94% ee as determined by chiral HPLC. Luche reaction on (+)-43 with CeCla 7H2O and triphenyl phosphine oxide and NaBH4 in the presence of ethanol at 30 °C gave the crude product. It was purified by column chromatography on silica gel to give 78% yield of a mixture containing 90% of (+)-calanolide A and 10% (+)-calanohde B, which were further separated by HPLC. 

A more complex process was the multicomponent reaction [9u, 21] between acetone (3a), benzyl azodicarboxylate (6) and enolizable aldehydes 5 (Scheme 4.2) [22] catalyzed by substoichiometric amounts of (S)-proline (1). The higher reactivity of the aldehydes over acetone (about 100-fold) towards the azodicarboxylate, led to the formation of an a-amino aldehyde derivative which was the electrophilic partner for the fnrther aldol reaction. The low diastereomeric ratio (ca. 1 1) of the products 7 was attributed to the easy and fast racemization of the initial formed a-amino aldehyde, compare to its reaction with acetone. Notwithstanding, this strategy has been used in the synthesis of a rennin inhibitor. 

List [86] and Jorgensen [87] have recently independently described a novel application of L-proline (107) for catalysis of enantioselective hydrazidation of aldehydes [88]. For example, when aldehyde 106 is allowed to react with di-tert-butyl azodicarboxylate (95) in the presence of 10 mol% 107, adduct 108 is isolated in > 90% yield and 93% ee (Scheme 10.18) [87]. The product hydra-zides can be transformed into protected amino acid derivatives through a sequence that involves oxidation of the aldehyde to the corresponding carboxylic acid, esterification, deprotection, and N-N bond cleavage with Raney-Ni [86, 87]. The observed selectivity has been attributed to the intervention of transition state 111 [86]. This structure incorporates a hydrogen bond between proline s carboxyl group and the azodicarboxylate as a key organizing feature. The transition state structure has parallels to that proposed for the proline-cata-lyzed aldol addition reactions and is supported by quantum mechanical studies by Houk [89]. 

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