Evans synthesis

J. R. Rasmussen, C. J. Slinger, R. J. Kordish, and D. D. Newman-Evans, Synthesis of deoxy sugars. Deoxygenation by treatment with AV -thiocarbonyldiimidazole/tri-n-butylstannane, J. Org. Chem., 46 (1981) 4843-4846. 

Fig. 13.43. Evans synthesis of enantiomerically pure a-alkylated carboxylic acids.

The alkylations of the oxazolidinone-containing amide enolate of Figure 13.43 occur with diastereoselectivities of 93 7 and > 99 1, respectively. The hydrogen peroxide-accelerated alkaline hydrolysis of these compounds occurs with complete retention of the previously established configuration at the a-stereocenter. To date, the Evans synthesis offers the most versatile access to enantiomerically pure a-alkylated carboxylic acids. 

Fig. 10.38. Evans synthesis of enantiomerically pure a-alkylated carboxylic acids. The amides are derived from oxazolidinones and yield Z -enolates with high stereoselectivity. The alkylating agent attacks in both cases from the side that is opposite to the side of the substituent highlighted in red.

Kochetkov and coworkers synthesized erythronolides A (20) and B (21) via a different route [26,27,28]. There have been many reports on the syntheses of erythromycin. Among them, four examples are the Yonemitsu synthesis of erythronolide A (20) [29,30], featuring an extremely efficient macrocyclization (the modified Yamaguchi method) Martin s synthesis of erythromycin B (19) [31,32] Evans synthesis of 6-deoxyerythronolide B [33,34], featuring the aldol-based assemblage of each synthetic segment and the Carreira synthesis of erythronolide A (20), featuring the Mg-mediated cycloadditions of nitrile oxides [35]. 

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. 

In the Evans synthesis of the polypropionate region (Scheme 9-45), the boron-mediated anti aldol reaction of -ketoimide ent-25 with a-chiral aldehyde 145 afforded 146 with 97% ds in what is expected to be a matched addition. Adduct 146 was then converted into aldehyde 147 in readiness for union with the C -Cs ketone. This coupling was achieved using the titanium-mediated syn aldol reaction of enolate 148 leading to the formation of 149 with 97% ds. 

Both these syntheses of oleandolide relied upon substrate-controlled aldol reactions of dipropionate reagents (5)-18 and ent-25. Substrate control is also evident in the way both groups incorporated the exocyclic epoxide with greater than 95% ds. While we chose to use macrocyclic control for this transformation, the Evans synthesis used acyclic stereocontrol and the directing influence of a nearby hydroxyl group. 

A simple example is the oxidation of an alkene to a carboxylic acid 93 in Evans synthesis of cytovaricin. The alkene had been put in by allylation and the optically active unsaturated alcohol 90 was first protected 91 and then subjected to hydroboration and oxidation. Protection before the second alcohol appeared prevented impossible chemoselectivity problems.14... 

A useful source of terminal alkynes are 1,1-dibromoalkenes such as 24. When this was treated with n-butyl-lithium in THF at -78°C, alkyne 25 was formed in 83% yield.3 This example was taken from Evans synthesis of (+)-miyakolide. Dibromides such as 24 can be formed from aldehydes or ketones via a variation of the Wittig olefination reaction (see sec. 8.8.A). 

Scheme 28. Evans synthesis of A-ring building block 62.

Scheme 29. Evans synthesis of B-ring building block 60.

Scheme 30. Evans synthesis of C-ring building block 63.

Scheme 31. Evans synthesis of D-ring building block 58.

Y. Tian, G. Wang, F. Li, and D. G. Evans, Synthesis and thermo-optical stability of o-methyl red-intercalated Ni-Fe layered double hydroxide material. Materials Letters, 61 (2007), 1662-6. 

Total syhthesis oah serve as a template tor reaction development. It we look back this was the case tor this synthesis ahd the Evans synthesis (ahd several that will follow). Asymmetric syhthesis is also worth considerihg at the point. All of the preceeding syntheses afforded racemic material. At what poiht could you ihtroduoe asymmetry ihto each of these syntheses Which strategies would be most amenable to asymmetric synthesis Of course this problem has been addressed (not necessarily within the context of the strategies we have seen thus far) and we will now turn to this issue. 

Let s look at another alkaloid whose structure screams Mannich reaction for an endgame. Luciduline is one member of the Lycopodium family of alkaloids. This is a large family of natural products. A few structures are shown here (50-54). Luciduline (55) is a )8-aminoketone. This is precisely the difunctional relationship that results from the Mannich reaction. Thus, a strategy that passes through 56 en route to 55 seems likely to succeed. Aminoketone 56 is a 1,5-difunctional compound and, in principle, should be available using normal carbonyl chemistry. We will see an example of this later, but the first synthesis of luciduline approached 56 from 1,6-difunctional intermediate 57. One versatile method for the preparation of 1,6-dicarbonyl compounds is the oxy-Cope rearrangement. We saw this in the Evans synthesis of juvabione (Chapter 5) and indeed, this is the methodology used by Evans and Scott in their synthesis of luciduline (58 57). 

This synthesis of calcimycin was one of the first total syntheses of an ionophore. It was preceeded by syntheses of nonactin (Gerlach and Schmidt), followed shortly by syntheses of lasalocid A (X537A) (Ireland), and then by the landmark syntheses of monensin (2) developed by Kishi and Still. The Evans synthesis illustrates the importance of symmetry in synthesis design, and documented observations that were clearly useful to those that followed. The synthesis suffered somewhat from stereocontrol, particularly... 

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