Weinreb amides acylation with

A retrosynthetic analysis of fragment 152 can be completed through cleavage of the C16-C17 bond in enone 155, the projected precursor of epoxide 152. This retrosynthetic maneuver furnishes intermediates 156 and 157 as potential building blocks. In the forward sense, acylation of a vinyl metal species derived from 156 with Weinreb amide 157 could accomplish the construction of enone 155. Iodide 153, on the other hand, can be traced retrosynthetically to the commercially available, optically active building block methyl (S)-(+)-3-hydroxy-2-methyIpropionate (154). 

The preparation of 3-vinylpyrroles was investigated utilizing the Horner-Wads worth-Emmons reaction with 3-formyl-lV-tosylpyrrole <06S1494>. The intramolecular acylation of pyrrole-2-Weinreb amides provided access to novel indolizinone derivatives <06T6182>. The amidation of pyrrole-2-carbonyl chloride was utilized as a key step in the preparation of pyrrole-oxazole analogue 90 of the insecticide Pirate <06S1975>. 

The mechanism of acylation of lithium phenylacetylide with a Weinreb amide has been investigated (Scheme 10).71 Dimeric lithium acetylide has reacted via a mono-solvated monomer-based transition structure. The robust tetrahedral intermediate (12) forms sequentially a C(l) 2 2 mixed tetramer with the excess lithium acetylide and a 1 3 (alkoxide-rich) mixed tetramer. The stabilities of the mixed tetramers are consistent with a pronounced autoinhibition. 

The organolithium species is generated by reaction of 4 with 2 eq. of tBuLi at -78 °C in ether. Acylation with M-methoxy-A-methylamide (Weinreb amide)15 5 forms the intermediate complex 22. 

Fig. 6.44. Chemoselective acylation of an organometallic compound C with the Weinreb amide D of Figure 6.21 a general approach to ketones.

Figure 6.50 displays acylations of C nucleophiles with NMe(OMe) derivatives of carbonic instead of carboxylic acids. The discussion of acylation reactions with NMe(OMe) derivatives of carboxylic acids ( Weinreb amides ) in Figures 6.42 and 6.44 revealed that the NMe(OMe) group has two effects first, it increases the reactivity and second, it is responsible for the occurrence of clean acylations. Against this background we will leave you to your own studies of a picture without words, namely Figure 6.50. Convince yourself that the approaches A —4 C, D —> C and E —> C to Weinreb amides outlined in this figure work and find out why alternative ketone syntheses D —> H and E —> H are also possible ...

Fig. 6.50. Acylation of organometallic compounds with various Weinreb amides (A, D and E) of carbonic acid.

The Weinreb amide syntheses in Figure 6.50 proceeding via the stable tetrahedral intermediates B and F are chemoselective SN reactions at the carboxyl carbon atom of carbon acid derivatives that are based on strategy 1 of the chemistry of carboxylic acid derivatives outlined in Figure 6.41. Strategy 2 of the chemistry of carboxylic acid derivatives in Figure 6.41 also has a counterpart in carbon acid derivatives, as is demonstrated by a chemoselective acylation of an organolithium compound with chloroformic acid methyl ester in this chapter s final example ... 

Fig. 13.64. Acylation of a bis(ketone enolate) with one equivalent of a Weinreb amide.

V-acyl aziridines therefore behave like Weinreb amides (see p. 300), and stabilization of the tetrahedral intermediate by chelation may also play a role. Esters, of course, typically react twice with organolithiums to give tertiary alcohols. 

The first noncarbohydrate-based asymmetric synthesis of kedarosamine uses the A,0-protected D-threonine 166. It is first converted into the corresponding Weinreb amide via the acyl chloride. Subsequent coupling with the allyl Grignard reagent provides 167. The nonchelation controlled reduction of ketone 167 with NaBH4 is syn selective, whereas 1,2-chelation controlled reduction... 

A/-acyl aziridines therefore behave iike Weinreb amides (see p. 000), and stabiiization of the tetrahedrai intermediate byoheiation mayaiso piay a roie. Esters, of course, typicaiiy react twice with organoiithiums to give tertiary aicohois. 

The most popular method these days for the acylation of Grignard or organolithium reagents is the Weinreb amide (also discussed in chapter 8). Acylation of vinyl Grignard with the complex intermediate 60 was part of a synthesis of ( )-fumagillolB 62. 

The intramolecular acylation of the vinyl lithium derivative of 63, prepared by exchange of iodine with lithium (chapter 8) with the Weinreb amide on the side chain gives the five-membered heterocyclic ring in 64, an intermediate on the way to (-)-brunsvigine 65, an alkaloid of the montanine group.14... 

To confirm our formal total synthesis of (-)-agelastatin A, we went on to reproduce the A-acylation reaction that was performed by Weinreb on ( )-77 with acid chloride 18. It proceeded in 80% yield, but required a slow syringe pump addition of the acid chloride in CFI2CI2 to amide (-)-77 and DMAP for success. As previously, the spectra of (-)-76 matched those reported by Weinreb and coworkers for their racemic version of the same intermediate. 

A number of recently described routes take rather different approaches to the synthesis of quinolines and isoquinolines, for example ozonolyses of indenes, as shown below provides homophthalaldehydes which are at exactly the right oxidation level for aromatic pyridine ring closure with ammonia. Another method for the generation of equivalent species depends on the side-chain lithiation of ortho-methylaraldehyde cyclohexylamine imines, then acylation with a Weinreb amide. 

S )-(+)-4-Phenyloxazolidinone (28) was acylated with crotonoyl chloride to give crotonamide 29 (Scheme 5). Diastereoselective Hosomi-Sakurai allylation of 29 with allyltrimethylsilane in the presence of TiCLi afforded compound 30 in a sufficient yield with a diastereomeric ratio of ca. 8 1. Next, the direct conversion of the oxazolidinone 30 into the Weinreb amide 31 was achieved using A,(9-dimethyl-hydroxylamine. 

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). 

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