Hydrazone enolates alkylation

In this latter structure, roughly depicted as (154), there are two different lithium atoms as well as two different anion residues. In one of the residues a lithium is -coordinated and in the other residue the lithium is T) -coordinated. Hie possible origins of the selectivity of the alkylations of the metallated hydiazones are discussed relative to this structure. Hie lithiated hydrazone enolate (155) prepared from (S)-(-)-l-amino-2-(methoxymethyl)pyrrolidine (SAMP) hydrazone of 2-acetylnaphthalene (156) yields the monomeric bis-THF-solvated species (157) as ruby red crystals. Hiis is one of the few examples of the crystallization of a resolved enolate substrate. ... 

The SAMP/RAMP Method As early as 1976, azaenolates derived from A,A-dialkyl hydrazones were studied as an alternative to direct ketone and aldehyde enolate alkylations. These species were found to exhibit higher reactivity toward electrophiles, as well as better regioselectivity for C-alkylation than their parent carbonyl compounds. A,A-diaIkyl hydrazones are stable and are relatively easy to prepare, making them appealing from a practical point of view in comparison with imines and enamines, which can be difficult to form quantitatively and are hydrolytically unstable. Given these desirable attributes, Enders undertook the development of chiral nonrace-mic A,A-diaIkyl hydrazine auxiliaries for the asymmetric a-alkylation of ketones. The result of his efforts were (5)-and (R)-l-amino-2-methoxypyrrohdine hydrazine (1 and 2, respectively), now commonly known as the SAMP and RAMP auxiliaries, respectively (Figure 7.1). Over the years, the SAMP/RAMP method has come to be considered the state-of-the-art approach to asymmetric ketone... 

Carbons adjacent to a Z group (as defined on p. 548) can be nitrosated with nitrous acid or alkyl nitrites. The initial product is the C-nitroso compound, but these are stable only when there is no tautomerizable hydrogen. When there is, the product is the more stable oxime. The situation is analogous to that with azo compounds and hydrazones (12-7). The mechanism is similar to that in 12-7 R—H —> R + N=0 — R—N=0. The attacking species is either NO or a carrier of it. When the substrate is a simple ketone, the mechanism goes through the enol (as in halogenation 12-4) ... 

Simple 1,2,4-triazole derivatives played a key role in both the synthesis of functionalized triazoles and in asymmetric synthesis. l-(a-Aminomethyl)-1,2,4-triazoles 4 could be converted into 5 by treatment with enol ethers <96SC357>. The novel C2-symmetric triazole-containing chiral auxiliary (S,S)-4-amino-3,5-bis(l-hydroxyethyl)-l,2,4-triazole, SAT, (6) was prepared firmn (S)-lactic acid and hydrazine hydrate <96TA1621>. This chiral auxiliary was employed to mediate the diastereoselective 1,2-addition of Grignard reagents to the C=N bond of hydrazones. The diastereoselective-alkylation of enolates derived from ethyl ester 7 was mediated by a related auxiliary <96TA1631>. 

Chapter 2 provided a general introduction to the a-alkylation of carbonyl compounds, as well as the enantioselective nucleophilic addition on carbonyl compounds. Chiral auxiliary aided a-alkylation of a carbonyl group can provide high enantioselectivity for most substrates, and the hydrazone method can provide routes to a large variety of a-substituted carbonyl compounds. While a-alkylation of carbonyl compounds involves the reaction of an enolate, the well known aldol reaction also involves enolates. 

Since ketone R)-16 was prepared in a non-selective way when an achiral imino enolate was alkylated, it was considered whether alkylation of chiral enolates, such as that of oxazoline 18, with benzyl bromide 14, would provide stereoselective access to the corresponding alkylation product 19 with R-configuration at C(8) (Scheme 4). Indeed, alkylation of 18 with 14 gave the biaryl 19 and its diastereoisomer almost quantitatively, in a 14 1 ratio. However, reductive hydrolysis using the sequence 1. MeOTf, 2. NaBH4, and 3. H30", afforded hydroxy aldehyde 20 in 25% yield at best. Furthermore, partial epimerization at C(8) occurred (dr 7.7 1). An alternative route, using chiral hydrazones, was even less successful. 

The SAMP-hydrazone derived from 2,2-dimethyl-l,3-dioxan-5-one is used as a chiral 1,3-di-hydroxy-2-propanone enolate equivalent and transformed to the corresponding 4-alkyl derivatives in good yield and high enantiomeric purity (89 to >95% ee, see Table 2)15. 

Reaction of phthalic anhydride (70-1) with the ylide from ethyl triphenylphos-phoniumacetate leads to the condensation product (70-2), which in effect consists of a cyclic enol anhydride. Treatment of this product with hydrazine leads to the hydrazone-hydrazide (70-3). Alkylation of the anion from removal of the hydrazide proton with the substituted benzyl bromide (70-4) affords the alkylation product (70-5). Saponification then leads to the aldose reductase inhibitor ponalrestat (70-6) [79]. 

A diird strategy for controlling enolate formation is to convert the carbonyl group to a jV,jV-dimediylhydrazone. The hydrazone is less reactive than die carbonyl group, and removal of an a proton by a strong base takes place at the least hindered a position. Alkylation followed by hydrolysis gives back carbonyl product that is die same as die result of kinetic control of enolate... 

The aldimine of Figure 13.34 is a chiral and enantiomerically pure aldehydrazone C. This hydrazone is obtained by condensation of the aldehyde to be alkylated, and an enantiomerically pure hydrazine A, the S-proline derivative iS-aminoprolinol methyl ether (SAMP). The hydrazone C derived from aldehyde A is called the SAMP hydrazone, and the entire reaction sequence of Figure 13.34 is the Enders SAMP alkylation. The reaction of the aldehydrazone C with LDA results in the chemoselective formation of an azaenolate D, as in the case of the analogous aldimine A of Figure 13.33. The C=C double bond of the azaenolate D is fraws-configured. This selectivity is reminiscent of the -preference in the deprotonation of sterically unhindered aliphatic ketones to ketone enolates and, in fact, the origin is the same both deprotonations occur via six-membered ring transition states with chair conformations. The transition state structure with the least steric interactions is preferred in both cases. It is the one that features the C atom in the /3-position of the C,H acid in the pseudo-equatorial orientation. 

Michael addition of trialkylstannyllithium to cyclohexenone SAMP- or RAMP-hydrazone gives 3-stannyl derivatives with de values of 42-44%, while subsequent alkylation of the enolate formed affords trans-products with de values >96%. The hydrazones obtained are subjected to ozonolysis to give 3-stannylcyclohexanones trans-1 with ee values up to 96%17. 

Now the benzyl ether can be deprotected, and the hydroxyl group substituted for iodide via its tosylate. This iodide is an alkylating agent, and is used for two successive alkylations of a hydrazone s aza-enolate. 

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