Aldehydes amide boron enolates

Table 8. Aldol Reaction of the Amide Boron Enolates CF3CF=C[0B (C4H9)2]N(C2Hs)2 with Aldehydes [9]...

A key step in the synthesis of the spiroketal subunit is the convergent union of intermediates 8 and 9 through an Evans asymmetric aldol reaction (see Scheme 2). Coupling of aldehyde 9 with the boron enolate derived from imide 8 through an asymmetric aldol condensation is followed by transamination with an excess of aluminum amide reagent to afford intermediate 38 in an overall yield of 85 % (see Scheme 7). During the course of the asymmetric aldol condensation... 

Note also the stereochemistry. In some cases, two new stereogenic centers are formed. The hydroxyl group and any C(2) substituent on the enolate can be in a syn or anti relationship. For many aldol addition reactions, the stereochemical outcome of the reaction can be predicted and analyzed on the basis of the detailed mechanism of the reaction. Entry 1 is a mixed ketone-aldehyde aldol addition carried out by kinetic formation of the less-substituted ketone enolate. Entries 2 to 4 are similar reactions but with more highly substituted reactants. Entries 5 and 6 involve boron enolates, which are discussed in Section 2.1.2.2. Entry 7 shows the formation of a boron enolate of an amide reactions of this type are considered in Section 2.1.3. Entries 8 to 10 show titanium, tin, and zirconium enolates and are discussed in Section 2.1.2.3. 

The C(9)-C(14) segment VI was prepared by Steps D-l to D-3. The formation of the vinyl iodide in Step D-3 was difficult and proceeded in only 25-30% yield. The C(15)-C(21) segment VII was synthesized from the common intermediate 17 by Steps E-l to E-6. A DDQ oxidation led to formation of a 1,3-dioxane ring in Step E-l. The A-methoxy amide was converted to an aldehyde by LiAlH4 reduction and the chain was extended to include C(14) and C(15) using a boron enolate of an oxazo-lidinone chiral auxiliary. After reductive removal of the chiral auxiliary, the primary alcohol group was converted to a primary iodide. The overall yield for these steps was about 25%. 

Reagent control This involves the addition of a chiral enolate or allyl metal reagent to an achiral aldehyde. Chiral enolates are most commonly formed through the incorporation of chiral auxiliaries in the form of esters, acyl amides (oxazolines), imides (oxazolidinones) or boron enolates. Chiral allyl metal reagents are also typically joined with chiral ligands. 

The approach for the enantioselective aldol reaction based on oxazolidinones like 22 and 23 is called Evans asymmetric aldol reaction.14 Conversion of an oxazolidinone amide into the corresponding lithium or boron enolates yields the Z-stereoisomers exclusively. Reaction of the Z-enolate 24 and the carbonyl compound 6 proceeds via the cyclic transition state 25, in which the oxazolidinone carbonyl oxygen and both ring oxygens have an anti conformation because of dipole interactions. The back of the enolate is shielded by the benzyl group thus the aldehyde forms the six-membered transition state 25 by approaching from the front with the larger carbonyl substituent in pseudoequatorial position. The... 

Paquette et al. start with the bis-vinylogation of the same compound 29 [14], by Wittig-Horner reaction, reduction, and oxidation (Scheme 5). For the formation of the C17-C16 bond, the onti-aldol 41 (ds not reported) is obtained by treatment of the aldehyde 39 with the (Z)-boron enolate 40, bearing a dithioketal moiety that is later to be the C51-C54 side chain. 3-Hydroxy-assisted, diastereoselective reduction of the keto group at C15 gives 41, which is converted into intermediate 42 in five more steps. The dethioketalization of 41 is achieved with phenyliodine(m) bis(trifluoroacetate) [16], As in Nicolaou s synthesis, the N12-C13 amide bond is formed first, followed by a low-yielding (21%, even at a concentration of 1 him) macrolactonization to 3. Table 1 summarizes the benchmark data of the two total syntheses of sanglifehrin A (1). 

In the total synthesis of (+)-trienomycins A and F, Smith et al. used an Evans aldol reaction technology to construct a 1,3-diol functional group8 (Scheme 2.1i). Asymmetric aldol reaction of the boron enolate of 14 with methacrolein afforded exclusively the desired xyn-diastereomer (17) in high yield. Silylation, hydrolysis using the lithium hydroperoxide protocol, preparation of Weinreb amide mediated by carbonyldiimidazole (CDI), and DIBAL-H reduction cleanly gave the aldehyde 18. Allylboration via the Brown protocol9 (see Chapter 3) then yielded a 12.5 1 mixture of diastereomers, which was purified to provide the alcohol desired (19) in 88% yield. Desilylation and acetonide formation furnished the diene 20, which contained a C9-C14 subunit of the TBS ether of (+)-trienomycinol. 

Silyl enol ethers react with aldehydes in the presence of chiral boranes or other additives " to give aldols with good asymmetric induction (see the Mukaiyama aldol reaction in 16-35). Chiral boron enolates have been used. Since both new stereogenic centers are formed enantioselectively, this kind of process is called double asymmetric synthesis Where both the enolate derivative and substrate were achiral, carrying out the reaction in the presence of an optically active boron compound ° or a diamine coordinated with a tin compound ° gives the aldol product with excellent enantioselectivity for one stereoisomer. Formation of the magnesium enolate anion of a chiral amide, adds to aldehydes to give the alcohol enantioselectively. 

The synthesis of three fragments 278, 282, and 285 for the C21-C42 bottom segment is summarized in Scheme 41. The Eschenmoser-Claisen rearrangement of amido acetal of 276, which was prepared via 2-bromocyclohexenone by Corey s asymmetric reduction, afforded amide 277. Functional group manipulation including chain elongation provided Evans-type amide 278. The Evans aldol reaction of boron enolate of 279 with aldehyde 280 stereoselectively afforded 281, which was converted into aldehyde 282 through a sequence of seven steps... 

Thermodynamic control. Note that it is also possible for the aldolate adduct to revert to aldehyde and enolate, and equilibration to the thermodynamic product may afford a different diastereomer (the anti aldolate is often the more stable). The tendency for aldolates to undergo the retro aldol addition increases with the acidity of the enolate amides < esters < ketones (the more stable enolates are more likely to fragment), and with the steric bulk of the substituents (bulky substituents tend to destabilize the aldolate and promote fragmentation). On the other hand, a highly chelating metal stabilizes the aldolate and retards fragmentation. The slowest equilibration is with boron aldolates, and increases in the series lithium < sodium < potassium, and (with alkali metal enolates) also increases in the presence of crown ethers. ... 

The aldol reaction is not restricted to the use of ketone enolates and indeed some of the most important examples in this area use carboxylic esters or amides. Proton abstraction with EDA (or other strong base) at low temperature to give the enolate and addition of the aldehyde or ketone gives a -hydroxyester or p-hydroxyamide product. Likewise the boron or other metal enolates of esters provide alternative methods to effect the aldol reaction. 

A large variety of propionic acid esters and higher homologs having a chiral alcohol moiety have been used in additions to aldehydes [56, 57]. It turned out, however, that the lithium enolates result in only moderate simple diastereoselectivity and induced stereoselectivity, in contrast with the corresponding boron, titanium, tin, or zirconium enolates and silyl ketene acetals, with which stereoselectivity is excellent. The same feature has been observed in enolates derived from chiral amides and oxazolidinones, as... 

Combination of achiral enolates vith achiral aldehydes mediated by chiral ligands at the enolate counter-ion opens another route to non-racemic aldol adducts. Again, this concept has been extremely fruitful for boron, tin, titanium, zirconium and other metal enolates. It has, ho vever not been applied very frequently to alkaline and earth alkaline metals. The main, inherent, dra vback in the use of these metals is that the reaction of the corresponding enolate, vhich is not complexed by the chiral ligand, competes vith that of the complexed enolate. Because the former reaction path vay inevitably leads to formation of the racemic product, the chiral ligand must be applied in at least stoichiometric amounts. Thus, any catalytic variant is excluded per se. Among the few approaches based on lithium enolates, early vork revealed that the aldol addition of a variety of lithium enolates in the presence of (S,S)-l,4-(bisdimethylamino)-2,3-dimethoxy butane or (S,S)-1,2,3,4-tetramethoxybutane provides only moderate induced stereoselectivity, typical ee values being 20% [177]. Chelation of the ketone enolate 104 by the chiral lithium amide 103 is more efficient - the j5-hydroxyl ketone syn-105 is obtained in 68% ee and no anti adduct is formed (Eq. (47)) [178]. 

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