Aldol reactions approach

Murayama, K., Tanabe, T Ishikawa, Y Nakamura, K., and Nishiyama, S. (2009) A synthetic study on gymnastatins F and Q the tandem Michael and aldol reaction approach. Tetrahedron Lett., 50, 3191-3194. 

Bernard A, A M CapeUi, A Comotti, C Gannari, J M Goodman and I Paterson 1990. Transltion-St Modeling of the Aldol Reaction of Boron Enolates A Force Field Approach. Journal of Orga Chemistry 55 3576-3581. 

Several approaches based on nitro-aldol for the synthesis of amino sugars have been reported Alumina-catalyzed reaction of methyl 3- nitropropanoate with O-benzyl-o-lactaldehyde gives the o-ribo-nitro-aldol fanti, and isomeri in 63% yield, which is converted into L-dannosamine fsee Secdon 3 3 Jager and coworkers have reported a short synthesis of L-acosamine based on the stereoselective nitro-aldol reaction of 2-O-benzyl-L-lactaldehyde with 3-nitropropanal dimethyl acetal as shovm in Scheme 3 10 The stereoselecdve nitro-aldol reacdon is carried ont by the silyl nitronate approach as discussed in Secdon 3 3... 

Another approach involved encapsulation of a bulky guanidine, N,N,N-tricyclohexyl-guanidine, in the super-cages of hydrophobic zeolite Y (Sercheli et ai, 1997). The resulting ship-in-a-bottle guanidine catalysed the aldol reaction of benzaldehyde with acetone to give 4-phenyl-4-hydroxybutan-2-one. 

Scheme 2.2 illustrates several examples of the Mukaiyama aldol reaction. Entries 1 to 3 are cases of addition reactions with silyl enol ethers as the nucleophile and TiCl4 as the Lewis acid. Entry 2 demonstrates steric approach control with respect to the silyl enol ether, but in this case the relative configuration of the hydroxyl group was not assigned. Entry 4 shows a fully substituted silyl enol ether. The favored product places the larger C(2) substituent syn to the hydroxy group. Entry 5 uses a silyl ketene thioacetal. This reaction proceeds through an open TS and favors the anti product. 

Stereochemical Control Through Chiral Auxiliaries. Another approach to control of stereochemistry is installation of a chiral auxiliary, which can achieve a high degree of facial selectivity.124 A very useful method for enantioselective aldol reactions is based on the oxazolidinones 10,11, and 12. These compounds are available in enantiomerically pure form and can be used to obtain either enantiomer of the desired product. 

Another attractive domino approach starts with an aldol reaction of preformed enol ethers and carbonyl compounds as the first step. Rychnovsky and coworkers have found that unsaturated enol ethers such as 2-237 react with different aldehydes 2-238 in the presence of TiBr4. The process consists of an aldol and a Prins-type reaction to give 4-bromotetrahydropyrans 2-239 in good yields, and allows the formation of two new C-C-bonds, one ring and three new stereogenic centers (Scheme 2.56) [131]. In the reaction, only two diastereomers out of eight possible isomers were formed whereby the intermediate carbocation is quenched with a bromide. 

This approach was used for the total synthesis of the macrolide leucascandrolide A (2-245) starting from the building blocks 2-242 and 2-243 [133]. The transformation led to 2-244 in 78% yield as a 5.5 1 mixture of the C-9-epimers (Scheme 2.58). The observed unusual high facial selectivity in the aldol reaction can apparently be traced back to the stereogenic center in 3-position of the aldehyde 2-242. 

A fourfold anionic sequence which is not initiated by a Michael but an aldol reaction has been reported by the group of Suginome and Ito (Scheme 2.129) [295]. In this approach, the borylallylsilane 2-573 reacts selectively in the presence of TiCl4 with two different aldehydes which are added sequentially to the reaction mixture. First, a Lewis acid-mediated allylation of the aldehyde with 2-573 takes place to form a homoallylic alcohol which reacts with the second aldehyde under formation of the oxenium ion 2-574. The sequence is terminated by a Prins-type cyclization of 2-574 and an intramolecular Friedel-Crafts alkylation of the intermediate 2-575 with formation of the fraws-1,2-be rizoxadeca lines 2-576 as single diastereomers. 

Johnson has developed two linear approaches to synthesize the C-nor-D-homosteroid skeleton (Scheme 2.2). In his first approach [21], tetralone 19, obtained from reduction of 2,5-dimethoxynaphthalene, was used as the source of the C,D-rings. The B- and A-rings were constructed by sequential Robinson annulations (19 —> 20 —> 21). The Cl 1,12 olefin was then introduced to provide 22. Ozonolysis of 22 followed by an aldol reaction of the resulting dialdehyde gave 23. Subsequent deformylation and deoxygenation afforded the cyclopamine skeleton 24. 

Using a similar C12,C 13 disconnection approach, Schinzer et al. also achieved a total synthesis of epothilone A (4) [16]. The key step involved a highly selective aldol reaction between ketone 27 and aldehyde 10 to afford exclusively alcohol 28 with the correct C6,C7 stereochemistry (Scheme 6). Further elaboration led to triene 29, which underwent RCM using ruthenium initiator 3 in dichloromethane at 25°C, to afford macrocyles 30 in high yield (94%). Although no selectivity was observed (Z E=1 1), deprotection and epoxidation of the desired Z-isomer (30a) completed the total synthesis [16]. 

Thus far, most of the stereoselective approaches to aldol reactions mentioned have depended on substrate-based asymmetric induction by employing chiral... 

Deoxyerythronolide B (28), produced by blocked mutants of Streptomyces erythreus, is a common biosynthetic precursor leading to erythromycins. A different route to this compound was developed with aldol methodology.5 In this approach, all the crucial C C bond formations involved in the construction of the carbon framework are exclusively aldol reactions. 

The aldol reaction is one of the most important reactions in synthetic organic chemistry. Many traditional ionic routes are currently available for diastereo- and enantioselective aldol reaction [97-99]. In contrast to highly basic ionic processes, development of radical methods for preparation of aldols using neutral conditions is attractive [100-102]. With the exception of intramolecular cyclization reactions, radical approaches towards aldol products remain largely unexplored [103-109]. 

Our second approach involved condensation of the lithium enolate of acetate 32 with aldehyde 28. In the event, the aldol reaction afforded an 85 % yield of a ca. 5 1 mixture of C3 epimers with the desired diastereomer (35) comprising the major product. 

Three tactical approaches were surveyed in the evolution of our program. As outlined in Scheme 2.7, initially the aldol reaction (Path A) was performed direcdy between aldehyde 63 and the dianion derived from tricarbonyl 58. In this way, it was indeed possible to generate the Z-lithium enolate of 58 as shown in Scheme 2.7 which underwent successful aldol condensation. However, the resultant C7 P-hydroxyl functionality tended to cyclize to the C3 carbonyl group, thereby affording a rather unmanageable mixture of hydroxy ketone 59a and lactol 59b products. Lac-tol formation could be reversed following treatment of the crude aldol product under the conditions shown (Scheme 2.7) however, under these conditions an inseparable 4 1 mixture of diastereomeric products, 60 (a or b) 61 (a or b) [30], was obtained. This avenue was further impeded when it became apparent that neither the acetate nor TES groups were compatible with the remainder of the synthesis. 

Scheme 1.57). Although the natural donor aldehyde is D-2-deoxyribose-5-phosphate, non-phosphorylated donor aldehydes are also tolerated and the enzyme displays some flexibility towards both donor and acceptor. Importantly, as both donor and acceptor substrates are aldehydes, the enzyme can perform sequential aldol reactions allowing the preparation of a key lactol intermediate to the atorvastatin side chain in a single step. Following substantial modification, this approach is now operated on an industrial scale to... 

This dual behaviour must allow control of the configuration at the a carbon atom in an aldol reaction, provided that one can control whether or not the metal is chelated at the time the aldol condensation occurs. Thornton and Nerz-Stormes [35] reported an approach to this problem by using titanium enolates to obtain "non-Evans" 5jn-aldols. On the other hand, Heathcock and his associated found that aldehydes react with chelated boron enolates 100b to afford the anh-aldols 102 or the "non-Evans" i yn-aldols 103 depending upon the reaction conditions (Scheme 9.32). 

For the mixed aldol reaction to be of value in synthetic work, it is necessary to restrict the number of combinations. This can be accomplished as follows. First, if one of the materials has no a-hydrogens, then it cannot produce an enoiate anion, and so cannot function as the nucleophile. Second, in aldehyde plus ketone combinations, the aldehyde is going to be a better electrophile, so reacts preferentially in this role. A simple example of this approach is the reaction of benzaldehyde with acetone under basic conditions. Such reactions are synthetically important as a means of increasing chemical complexity by forming new carbon-carbon bonds. 

An alternative approach to mixed aldol reactions, and the one usually preferred, is to carry out a two-stage process, forming the enolate anion first using a strong base like EDA (see Section 10.2). The first step is essentially irreversible, and the electrophile is then added in the second step. An aldol reaction between butan-2-one and acetaldehyde exemplifies this approach. Note also that the large base EDA selectively removes a proton from the least-hindered position, again restricting possible combinations (see Section 10.2). 

Alternatively, and much more satisfactory from a synthetic point of view, it is possible to carry out a two-stage process, forming the enolate anion first. We also saw this approach with a mixed aldol reaction (see Section 10.3). Thus, ethyl acetate could be converted into its enolate anion by reaction with the strong base EDA in a reaction that is essentially irreversible (see Section 10.2). 

Marhwald reported that ligand exchange of Ti(rac-BINOLate)(Of-Bu)2 with optically active a-hydroxy acids presents an unexpected and novel approach to enantio-selective direct aldol reactions of aldehydes and ketones (Scheme 12.19). The aldol products have been isolated with a high degree of syn diastereoselectivity. High enantioselectivities have been observed when using simple optically pure a-hydroxy acids. 

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