Aldol methodology

Scheme 6a presents the synthesis of fragment 15. Intermediate 15 harbors two vicinal stereogenic centers, and is assembled in a very straightforward manner through the use of asymmetric aldol methodology. Treatment of the boron enolate derived from 21 with 3-[(p-methoxybenzyl)oxy]propanal (22) affords crystalline syn aldol adduct 34 in 87 % yield as a single diastereomer. Transamination to the A-methoxy-A-methylamide,20 followed by silylation of the secondary hydroxyl group at C-19 with triethylsilyl chloride, provides intermediate 15 in 91 % yield. 

The classical aldol addition, which is usually run in protic solvents, is reversible. Most modern aldol methodologies, however, rely on highly reactive preformed metal enolates, whereby proton donors are rigorously excluded. As a consequence, the majority of recent stereoselective aldol additions are performed under kinetic control. Despite this, reversibility and, as a consequence, an equilibration of yrn-aldolates to a t/-aldolates by retro-aldol addition, should not be excluded a priori. 

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. 

Oppolzer has designed two approaches to modhephene, both of which are based on the high level of stereochemical control attainable in intramolecular thermal ene reactions. In the first (Scheme XCIV), a, jJ-unsaturated ketone 793 is obtained by aldol methodology and heated at 250 °C in toluene to produce 794 A methyl group and double bond are next introduced in standard fashion prior to arrival at the final sesquiterpene stage. 

S. Masamune, T. Kaiho, and D. S. Garvey, Aldol methodology Synthesis of versatile intermediates. 3-Hydroxy-2-vinylcarbonyl compounds, J. Am. Chem. Soc. 704 5521 (1982). 

A. S. Franklin, I. Paterson, Recent Developments in Asymmetric Aldol Methodology, Contemporary Organic Synthesis 1994, 1, 317. 

Oppolzer et al. completed an asymmetric synthesis of (-)-denticulatin A (48) by using a syn-aldol methodology as a key feature18 (Scheme 2.1r). The diethyl-boron enolate of N-propionyIbomanesultam (46-ent) obtained from diethylboron triflate and Hunig s base underwent a highly stereoselective aldol reaction with the mes o-dialdchydc 49 to furnish the lactols 50 in 74% yield as a 2 1 epimeric mixture. When the lactols 50 were treated with 1, 2-ethanedithiol in the presence... 

Masamune s norephedrine-based anti -aldol methodology was again employed successfully in the total synthesis of the antitumor macrolide natural product rhizoxin D (17)7 (Scheme 2.2g). The synthesis began with an anti-aldol addition of boron enolate of 3-ent to the aldehyde 18. The addition proceeded with... 

Heathcock, C H, Montgomery, S H, A cyclic stereoselection. 28. Use of stereoselective aldol methodology in the total synthesis of cladinose. Tetrahedron Lett., 26, 1001-1004, 1985. 

Another example of this methodology has appeared recently from Masamune and coworkers in connection with a total synthesis of bryostatin (equation 67). The salient point here is the demonstrated utility of the thiol ester, prepared directly through stereoselective boron enolate aldol condensation. Notice Aat no further activation or removal of a chiral auxiliary is necessary for this transformation, unlike other related aldol methodology. 

Franklin, A. S., Paterson, I. Recent developments in asymmetric aldol methodology. Contemp. Org. Synth. 1994,1, 317-338. 

In addition to the acetate aldol problem, stereoselective aldol additions of substituted enolates to yield 1,2-anti- or f/treo-selective adducts has remained as a persistent gap in asymmetric aldol methodology. A number of innovative solutions have been documented recently that provide ready access to such products. The different successful approaches to anri-selective propionate aldol adducts stem from the design of novel auxiliaries coupled to the study of metal and base effects on the reaction stereochemistry. The newest class of auxiliaries are derived from A-arylsulfonyl amides prepared from readily available optically active vicinal amino alcohols, such as cw-l-aminoindan-2-ol and norephedrine. 

The pioneering discovery by Mukaiyama in 1974 of the Lewis acid mediated aldol addition reaction of enol silanes and aldehydes paved the way for subsequent explosive development of this innovative method for C-C bond formation. One of the central features of the Mukaiyama aldol process is that the typical enol silane is un-reactive at ambient temperatures with typical aldehydes. This reactivity profile allows exquisite control of the reaction stereoselectivity by various Lewis acids additionally, it has led to the advances in catalytic, enantioselective aldol methodology. Recent observations involving novel enol silanes, such as enoxy silacyclobutanes and O-si-lyl M(9-ketene acetals have expanded the scope of this process and provided additional insight into the mechanistic manifolds available to this versatile reaction. 

In the study of catalytic, dienolate addition reactions, the use of stannyl prope-nal 50 as a substrate in aldol methodology has been introduced (Scheme 8-4). The adduct 51 produced from the process is isolated in 92% ee and, importantly, serves as a useful building block for subsequent synthetic elaboration. It is amenable for further manipulations such as Stille cross-coupling reactions to give a diverse family of protected acetoacetate adducts 52. 

Many of the previously mentioned auxiliaries do not lead to high selectivity with unsubstituted enolates. In this case, the use of Nagao s acetate aldol methodology is frequently applied [30]. For example, in a recent synthesis of pate-amine A, two such aldol reactions of 46 were used, both of which proceeded with >95%ds (Scheme 9-15) [31]. 

Aplyronine A. Aplyronine A (155) was isolated in 1993 from a Japanese sea hare and is an unusual 24-membered macrolide displaying potent antitumor activity (Scheme 9-47). The three stereotetrads within the molecule, C7-C10, C23-C26 and C29-C32, make it an attractive target to demonstrate aldol methodology. To date, the only total synthesis was completed by Yamada et al., which served to... 

This methodology was combined with established. yn-selective aldol methodology in the formation of trisubstituted butyrolactone natural products, (-)-roccella-... 

Over the past decade the enantio- and diastereo-selective aldol methodology has been developed mainly with the purpose of synthesizing polyketide-type natural products such as macrolides and iono-phore antibiotics. These natural products have the basic structural units that result from propionate and acetate addition a-methyl-P-hydroxycarbonyl (27a-d) and (3-hydroxycarbonyl (28a and 28b). Discussions on the construction of these units will be followed by comments on the stereoselective assembly... 

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