Acyl anion precursors

Intramolecular asymmetric Stetter reactions enjoy a range of acceptable Michael acceptors and acyl anion precursors. These reactions can utilize aromatic, heteroaromatic, and aliphatic aldehydes with a tethered a,p-unsaturated ester, ketone, thioester, malonate, nitrile, or Weinreb amide. In this part, we will give a brief summary about asymmetric intramolecular Stetter reactions and selected recent results in this area (Scheme 7.17). 

We employed our previous conditimis using 20 mol% of a thiazolium salt with DBU in THF as a platform to identify suitable acceptors with pymvic acid as the acyl anion precursor. After a brief survey, 2-acyl IV-methyl imidazole [86, 87] was... 

Cyclic thioacetals are masked acyl anion precursors... 

The acyl anion chemistry of acylzirconocene chlorides has also been applied to the stereoselective preparation of ( )-a,(3-unsaturated selenoesters and telluroesters (Scheme 5.35) [38]. Although no carbon—carbon bond was formed, this reaction reflects the synthetic interest in ( )-a,(3-unsaturated selenoesters and telluroesters, which are well-known precursors of acyl radicals and acyl anions, respectively. 

The proposed catalytic cycle is shown in Scheme 35 and begins with the imida-zolylidene carbene adding to the enal. Proton transfer provides acyl anion equivalent XLVII, which may be drawn as its homoenolate resonance form XLVIII. Addition of the homoenolate to aldehyde followed by tautomerization affords L the precursor for lactonization and regeneration of the carbene. 

In 2008, the same group employed chiral dicarboxylic acid (R)-5 (5 mol%, R = 4- Bu-2,6-Me2-CgHj) as the catalyst in the asymmetric addition of aldehyde N,N-dialkylhydrazones 81 to aromatic iV-Boc-imines 11 in the presence of 4 A molecular sieves to provide a-amino hydrazones 176, valuable precursors of a-amino ketones, in good yields with excellent enantioselectivities (35-89%, 84-99% ee) (Scheme 74) [93], Aldehyde hydrazones are known as a class of acyl anion equivalents due to their aza-enamine structure. Their application in the field of asymmetric catalysis has been limited to the use of formaldehyde hydrazones (Scheme 30). Remarkably, the dicarboxylic acid-catalyzed method applied not only to formaldehyde hydrazone 81a (R = H) but also allowed for the use of various aryl-aldehyde hydrazones 81b (R = Ar) under shghtly modified conditions. Prior to this... 

Benzodithioles 285 (R1 = H) and 7,8-dimethyl-l,5-dihydro-2,4-benzodithiepins286 (R = H) have been used as precursors of formyl and acyl anion derivatives. The lithiation of compounds 285 takes place at —30 °C with n-BuLi and these anions are stable for long periods of time at this temperature454. They react with alkyl iodides, carbonyl compounds and epoxides, the addition to cyclohex-2-enone taking place at the carbonyl group. The deprotection has also been carried out with mercury(II) oxide and BF3 OEt2-... 

Acylate anions can be made by nucleophilic attacks of lithium alkyls on metal carbonyls, for example, W(CO)6 + LiR - Li[(C0)5WC(0)R]. They are precursors of alkylidenes which will be discussed shortly. 

OL-MethoxyvinyUithium. Details are available for deprotonation of methyl vinyl ether by r-butyllithium to provide a-methoxyvinyllithium (a), a useful acyl anion equivalent. Thus a reacts with ClSilCHj), to provide I-(methoxyvinyl)trimethylsilane (1), a useful precursor to acetotrimethylsilane (2). 

Even acyl groups may be transferred from Zr to Al, as in equation (48) this generates an acylalumin-um or acyl anion equivalent (45). Its acyl anion chemistry appears limited, however only protonolysis to the aldehyde was achieved in good yield, and that could have been done directly with the acylzirco-nium precursor. ... 

The addition of lithium and Grignard reagents to isocyanides which do not contain a-hydrogens proceeds by an a-addition to produce a metalloaldimine (7, an acyl anion equivalent). The lithium aldimines are versatile reagents which can be used as precursors for the preparation of aldehydes, ketones, a-hy-droxy ketones, a-keto acids, a- and 3-hydroxy acids, silyl ketones and a-amino acids (Scheme 5). - ... 

Silylated cyanohydrins have found considerable utility in the regioselective protection of p-qui-nones, as intermediates for the preparation of 3-amino alcohols and as precursors to acyl anion equivalents. Such compounds are typicdly prepared in high yield by either thermal or Lewis acid catalyzed addition of TMS-CN across the carbonyl group. This cyanosilylation has a variety of disadvantages and modified one-pot cyanosilylation procedures have been reported. - The carbonyl group can be regenerated by treatment with acid, silver fluoride or triethylaluminum hydrofluoride followed by base. ... 

Trimethylsiloxy cyanohydrins (9) derived from an a,3-unsaturatied aldehyde form ambident anions (9a) on deprotonation. The latter can react with electrophiles at the a-position as an acyl anion equivalent (at -78 C) or at the -y-position as a homoenolate equivalent (at 0 C). The lithium salt of (9) reacts exclusively at the a-position with aldehydes and ketones. The initial kinetic product (10) formed at -78 C undergoes an intramolecular 1,4-silyl rearrangement at higher temperature to give (11). Thus the initial kinetic product is trapped and only products resulting from a-attack are observed (see Scheme 11). The a-hydroxyenones (12), -y-lactones (13) and a-trimethylsiloxyenones (11) formed are useful precursors to cyclopentenones and the overall reaction sequence constitutes a three-carbon annelation procedure. 

In 2006, Scheidt and coworkers [44] reported the first enantioselective direct nucleophilic addition ofthe silylated thiazolium salt 148, a precursor of the equivalent acyl anion, to nitroalkene 149 in the presence of tetramethylammonium fluoride (TMAF) and stoichiometric amounts of quinine-based thiourea 81b, producing the chiral [3-nitroketone 150 in 67% yield and with 74% ee (Scheme 9.51). The acyl anion equivalent 152 can be generated by the desilylation of 148 with TMAF, followed by the 1,2-H shift of the resulting alkoxide 151. The observed asymmetric induction indicates that there is a strong interaction between the thiourea and the nitroalkene during the carbonyl anion addition step. 

Ipso anion precursor. Nucleophilic homologation of the reagent generates products that readily submit a PhS unit to another nucleophile (e.g., 5ec-BuLi). The resulting lithio compounds are acyl anion or methylene anion equivalents. 

B.ii. Acyl Anion Equivalents. The most common umpolung equivalent is that for acyl anion 339, and dithianes 344 are the most common reagent used for this purpose. Dithiane 344 is prepared from an aldehyde, but ketones are also precursors (sec. 7.3.B.ii). Removal of the hydrogen adjacent to the sulfur requires a base such as n-butyllithium and the product is a-lithiodithiane (345). The acidity of this hydrogen is largely... 

The usual a.d-disconnection on (47) is not very productive as it suggests a 1,7-dicarbonyl precursor (49), but the strategically preferable ring-chain disconnection is good providing we have a reagent for acyl anion (SO). We have already met the synthesis of (47) using acetylide ion as the acyl anion equivalent (Chapter 16). 

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