Nucleophilic acyl equivalents

Sulfur compounds are useful as nucleophilic acyl equivalents. The most common reagents of this type are 1,3-dithianes, which on lithiation provide a nucleophilic acyl equivalent. In dithianes an umpolung is achieved on the basis of the carbanion-stabilizing ability of the sulfur substituents. The lithio derivative is a reactive nucleophile toward alkyl halides and carbonyl compounds. 11... 

This procedure is an excellent method to prepare 1,4-dicarbonyl compounds 163 (Scheme 7.48) and, using triethylamine, has been extended to include other activated double bonds.Thus, the starting a-amino acids can be considered as nucleophilic acyl equivalents. Representative examples of 5(47/)-oxazolones prepared via Michael additions are shown in Table 7.18 (Fig. 7.20). 

A general synthesis of cyanoethyl ketones, in which a-amino-acids function as nucleophilic acyl equivalents, is outlined in Scheme 1... 

Homoenolate equivalents (d reagents) are less conunon than nucleophilic acyl equivalents. The uses of 1-trimethylsilylallyl alcohols as effective homoenolate equivalents have been discussed. y-Alkylation of the trimethylsilyloxy-stabil-ized allylic anion formed by Brook rearrangement leads to the (isolable) tri-methylsilylenol ether (18) (Scheme 16). y-Alkylation of the functionalized ally-loxy-carbanion (19) has been reported. ... 

Amidrazones are new precursors of a-lithioenamines, which act as nucleophilic acyl equivalents (Scheme 8). The method appears to be limited to precursors derived from acids bearing an a- methylene group. 

A third term which has become useful for the discussion of synthetic analysis and planning is synthon. This term refers to a structural unit which has the potential for some specific synthetic operation. Again using the example above, we are searching for a group which would serve as a nucleophilic acyl synthon that is, some structural entity that would correspond to the addition of a nucleophilic acyl equivalent to an electrophilic carbon-carbon double bond. 

Sulfur compounds have also proven useful as the basis for nucleophilic acyl equivalents. The first reagent to find general use was 1,3-dithiane, which on lithiation provides the nucleophilic acyl group masked as a thioketal. The lithium derivative is reactive toward alkyl halides and carbonyl compounds." Closely... 

The cyclobutane ring was then cleaved by hydrolysis of the enamine and ring opening of the resulting (3-diketone. The relative configuration of the chiral centers is unaffected by subsequent transformations, so the overall sequence is stereoselective. Another key step in this synthesis is Step D, which corresponds to the transformation 10-IIa => 10-la in the retrosynthesis. A protected cyanohydrin was used as a nucleophilic acyl anion equivalent in this step. The final steps of the synthesis in Scheme 13.11 employed the C(2) carbonyl group to introduce the carboxy group and the C(l)-C(2) double bond. 

In Step C a dithiane anion was used as a nucleophilic acyl anion equivalent to introduce the C(10)-C(13) isobutyl group. 

The benzoin reaction dates back to 1832 when Wohler and Liebig reported that cyanide catalyzes the formation of benzoin 6 from benzaldehyde 5, a seminal example in which the normal mode of polarity of a functional group was reversed (Eq. 1) [26], This reversal of polarity, subsequently termed Umpolung [27], effectively changes an electrophilic aldehyde into a nucleophilic acyl anion equivalent. 

Breslow and co-workers elucidated the currently accepted mechanism of the benzoin reaction in 1958 using thiamin 8. The mechanism is closely related to Lapworth s mechanism for cyanide anion catalyzed benzoin reaction (Scheme 2) [28, 29], The carbene, formed in situ by deprotonation of the corresponding thiazolium salt, undergoes nucleophilic addition to the aldehyde. A subsequent proton transfer generates a nucleophilic acyl anion equivalent known as the Breslow intermediate IX. Subsequent attack of the acyl anion equivalent into another molecule of aldehyde generates a new carbon - carbon bond XI. A proton transfer forms tetrahedral intermediate XII, allowing for collapse to produce the a-hydroxy ketone accompanied by liberation of the active catalyst. As with the cyanide catalyzed benzoin reaction, the thiazolylidene catalyzed benzoin reaction is reversible [30]. 

The equivalence 13a = 13b (synthons and reagents for nucleophilic haloalkyla-tion) which was demonstrated by our experiments is very similar to the well-known equivalence 13c = iJtf (synthons and reagents for nucleophilic acylation) drown by... 

The widespread use of compounds derived from the 1,3-dithiane carbanion or its homologues as acyl anion equivalents (for applications see Section 4.2.1.1) followed the pioneering works of Corey and Seebach on nucleophilic acylation (for reviews, see [43] and [44]). 

The use of masked acyl anion equivalents in a synthetic protocol requires additional steps to unmask the carbonyl unit. Sometimes the deprotection procedures are incompatible with sensitive compounds thus, a direct nucleophilic acylation protocol is desirable. While C-nucleophilic carbonyl groups do not... 

A sequence in which a carbonyl group has been masked as a sulfur derivative, alkylated with an electrophile, and then revealed again is a nucleophilic acylation. These nucleophilic equivalents of carbonyl compounds are known as acyl anion equivalents. In the retrosynthetic terms of Chapter 50 they are d1 reagents corresponding to the acyl anion synthon. 

Reductive nucleophilic acylation. The reagent 1 condenses with aldehydes and ketones to give products (2) of carbonyl addition, which do not undergo syn-elimination of —OSi(CH3)3 in situ. However, treatment of 2 with KH in THF affords enol ethers (3) in excellent yields. The latter products are readily converted into aldehydes (4) on hydrol) is with 90% aqueous formic acid ( 90% yield, equation I). The adducts (2) are desilylated to 5 with CsF in DMSO (equation II). In this case, 1 functions as an equivalent of the —CH2OCH3 anion. 

Lithiated SMP formamides and thioformamides have been used as acylanion equivalents (d synthons) in the synthesis of enan-tiomerically pure a-hydroxy ketones and vicinal diols. Metalated SMP aminonitriles have been used in nucleophilic acylation reactions to give a-hydroxy ketones. ... 

The mechanism of the benzoin condensation, as depicted in Scheme 1, suggested that anions derived from a protected aldehyde cyanohydrin should function as nucleophilic acylating reagents. The use of protected cyanohydrins as carbanion equivalents has been studied by Stork and by Hunig and has found wide applicability in chemical synthesis. Such species may serve as either acyl anion equivalents or homoenolate anions. ... 

The ABC ring system of the carbocyclic skeleton of variecolin, a sesterterpenoid natural product was accomplished by G.A. Molander and co-workers. In their approach, they utilized two samarium diiodide mediated processes. First, a primary alkyl iodide was reacted with a ketone substrate in the presence of two equivalents of samarium diiodide and catalytic nickel(ll) iodide under samarium Grignard conditions. Subsequent oxidation and lactone formation provided the chlorolactone substrate. As alkyl chlorides are less reactive than alkyl bromides and iodides, the second samarium diiodide mediated process, an intramolecular nucleophilic acyl substitution, required visible light irradiation. 

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