Natural products asymmetric aldol reactions

The development of enantioselective aldol reactions has been widely studied in conjunction with the synthesis of natural products. Highly enantioselective aldol reactions have been achieved by employing chiral enolates of ethyl ketones and propionic acid derivatives.(1) On the other hand, achieving high asymmetric induction in the asymmetric aldol reaction of methyl ketones is still a problem.(2)... 

Whilst simple alkylations of enolates and Michael additions have been successfully catalyzed by phase-transfer catalysts, aldol-type processes have proved more problematic. This difficulty is due largely o the reversible nature of the aldol reaction, resulting in the formation of a thermodynamically more stable aldol product rather than the kinetically favored product. However, by trapping the initial aldol product as soon as it is formed, asymmetric aldol-type reactions can be carried out under phase-transfer catalysis. This is the basis of the Darzens condensation (Scheme 8.2), in which the phase-transfer catalyst first induces the deprotonation of an a-halo... 

The norephedrine-derived Masamune asymmetric aldol reaction was utilized in the total synthesis of (+)-testudinariol A (12), a triterpene marine natural product that possesses a highly functionalized cyclopentanol framework with four contiguous stereocenters appended to a central 3-alkylidene tetrahydropyran6 (Scheme 2.2f). The norephedrine-derived ester 13 was enolized with dicyclo-hexylboron triflate and triethylamine in dichloromethane and then treated with 3-benzyloxypropanal to afford the aldol adduct (14) as a 97 3 mixture of anti/syn diastereomers in 72% yield. Diastereoselectivity within the anti -manifold was 90 10. Protection of alcohol as the methoxyethoxymethyl (MEM) ether followed by conversion of the ester to an aldehyde by LiAlELt reduction and subsequent Swem oxidation gave the aldehyde 16 in 64% yield over three steps. 

The stereoselectivities seem to be kinetically controlled. In fact, the ee of the aldol product was constant during the course of the reaction. Thus, we have succeeded in performing the first catalytic asymmetric aldol reaction between aldehydes and unmodified ketones by using heterobimetallic or heteropolymetallic catalysts. Several reactions have already been synthetically useful especially for tertiary aldehydes, leading to the catalytic asymmetric synthesis of key intermediates en route to natural products [63]. Further studies are currently in progress. 

Evans synthesis of bryostatin 2 (113) also relied upon asymmetric aldol reactions for the introduction of most of the 11 stereocenters [58], At different points, the synthesis used control from an auxiliary, a chiral Lewis acid, chiral ligands on the enolate metal and substrate control from a chiral aldehyde. Indeed, this represents the current state of the art in the aldol construction of complex polyketide natural products. 

Rutamydns. Rutamycins A (137) and B (138) are 26-membered macrolide antibiotics isolated from Streptomyces cultures (Scheme 9-43). They are closely related to the oligomycin family of natural products and more distantly to the 22-membered cytovaricin. Each of these macrocycles consists of a highly functionalized spiroacetal unit bridged by a polypropionate-derived chain. In the rutamycins, the asymmetric aldol reaction could be envisaged to play a key role in assembling the spiroacetal portion and the C4-C]4 polypropionate sector with various strategic disconnections possible. 

The development of catalytic asymmetric aldol reactions is being extensively studied [20]. Further progress in this field will expand the impact of these reactions on the total synthesis of natural products. 

You saw in Chapter 33 that it is possible to use aldol reactions to create two new chiral centres in a single step, and that the relative stereochemistry of the two chiral centres depends in many cases on the geometry of the enolate used to do the aldol reaction. The power of an asymmetric aldol reaction is easy to see it creates two new chiral centres with control over their absolute stereochemistry, and also constructs a new C—C bond. What is more, the products of aldol reactions are very common features in a huge number of natural products known as polyketides—as you will see in the next chapter, polyketides are made by living things using a series of successive enzyme-controlled aldol reactions. 

Since oxazolidines and oxazolidinones are fiindamental structural classes in organic chemistry (chiral auxiliaries) and in medicinal chemistry (e.g., Linezolid) and since they mask P-hydroxy-a-amino acids, which are widespread in various biologically active compounds and in natural products, the enantioselective synthesis of oxazolidinones is a challenging topic. Indeed, a new method for the direct synthesis of chiral 4-carboxyl oxazolidinones 168 by the catalytic asymmetric aldol reaction of isocyanato-malonate diesters 166 with aldehydes 167 in the presence of a thiourea catalyst (TUC) was developed. Since the resulting chiral 4-carboxy oxazolidinones are the equivalent of P-hydroxy-a-amino acids, this procedure... 

RCM was used to form the seven-membered ring of sundiversifolide 8.232 (Scheme 8.63). The substrate 8.229 was assembled by an asymmetric aldol reaction and cyclized using the Grubbs second-generation catalyst. Reduction of the enone 8.230 formed allowed lactone formation by Claisen rearrangement, iodocy-clization and deiodination. Further steps lead to the natural product 8.232. 

The catalytic version of this type of reaction was realized by using acetoacetate derived O-silyl dienolate as nucleophiles in the presence of Carreira s catalyst, giving acetoacetate y-adducts in high yields and enantiomeric excesses [119] (Scheme 14.42). The products are ubiquitous structural subunits in biologically active natural products such as the polyene macrolide antibiotic and medicinally important HMG-CoA reductase inhibitors. This aldol addition can also be catalyzed by BINOL-Ti complex in the presence of 4A MS with moderate to good enantioselectivity [120]. The same catalyst system was also efficient in the asymmetric aldol reaction between the aldehydes and Chan s diene [ 1,3-bis-(trimethylsilyloxy)-l-methoxy-buta-1,3-diene] and other related silyl enol ethers [121, 122] (Scheme 14.43) or the functionalized silyl enol ether such as 2-(trimethylsilyloxy)furan with good to excellent enantioselectivities [123]. 

ASYMMETRIC ALDOL REACTIONS IN THE TOTAL SYNTHESES OF NATURAL PRODUCTS... 

In this chapter, typical types of asymmetric aldol reactions and their applications to syntheses of natural products are discussed. The main point of the aldol reaction is how to achieve high stereoselectivity. Because an aldol reaction includes two steps, production of an enolate and its nucleophilic addition to an aldehyde, it is necessary to form an enolate stereoselectively ( or Z) and set a rigid transition state in the addition reaction to realize a stereoselective... 

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