Amides retrosynthetic analysis

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 initial retrosynthetic analysis of 1 resulted in the cleavage of the two amide bonds and a C-N bond leading to the four components oxadiazole carbonyl chloride 2, methyl iodide, 4-fluorobenzylamine (4-FBA) and the densely functionalized hydroxypyrimidinone 3 (Scheme 6.1). These synthetic disconnections were reasonable and should be applicable for long term route development. 

Much of the recent work on the use of anodic amide oxidation reactions has focused on the utility of these reactions for functionalizing amino acids and for synthesizing peptide mimetics [13]. For example, in work related to the cyclization strategy outlined in Scheme 3, the anodic amide oxidation reaction has been used to construct a pair of angiotensin-converting enzyme inhibitors [14]. The retrosynthetic analysis for this route is outlined in Scheme 4. In this work, the anodic oxidation reaction was used to functionalize either a proline or a pipercolic add derivative and then the resulting methoxylated amide used to construct the bicyclic core of the desired inhibitor. A similar approach has recently been utilized to construct 6,5-bicyclic lactam building blocks for... 

Primary amides may be produced by a Beckmann rearrangement both from E or Z oximes which are commonly obtained from the corresponding carbonyl compound (aldehyde). Retrosynthetic analysis follows equation 98. 

Retrosynthetic analysis reduces the 1,3,5-triazine system by cycloreversion to three HCN or nitrile molecules. Alternatively, bond fission at the C=N units suggests amides and their... 

Now that you ve seen the principle of retrosynthetic analysis at work, you should be able to suggest a reasonable disconnection of the compound in the margin, known as daminozide. You probably spotted immediately that daminozide is again an amide, so the best disconnection is the C-N bond, which could take us back to acyl chloride and dimethyUiydrazine. This time we ve written C-N amide above the retrosynthetic arrow as a reminder of why we ve made the disconnection and we advise you to follow this practice. 

Use retrosynthetic analysis to propose effective single-step and multistep syntheses of compounds with amines as intermediates or products, protecting the amine as an amide if necessary. 

The retrosynthetic analysis is outlined in Scheme 22. The amide was introduced by the Curtius rearrangement, and the macrolide 117 was formed by Horner-Emmons macrocyclization at the C2-C3 bond. The C17-C18 bond was constructed by the ring-opening of epoxide 118. 119 was formed via the Kocienski-Julia olefination at the C8-C9 bond. The cis-2,6-disubstituted tetrahydropyran in 120 was constructed by the Petasis-Ferrier rearrangement. The C4-C5 (Z)-trisubstituted alkene in 121 was formed by carbomet-allation to an alkyne. 

The retrosynthetic analysis (see Chapter 25) of a peptide is easy because polypeptides are chains of amino acids coupled together. Each of the peptide (amide) bonds is disconnected to give a collection of individual amino acids. The synthesis is not trivial, however, because the amino acids must be coupled together in the correct sequence N- to C-terminus, the primary structure. To do this requires a strategy, which is outlined in Figru-e 27.5. 

There are three key mles to be followed in retrosynthetic analysis disconnection should follow the correct mechanism, allow maximal simplification of the TM and lead to available starting materials. The fexofenadine molecule can be maximally simplified by discormections made at critical bonds (Scheme 10.3). These are disconnections at the CH2-aryl bond (a) and an alternative disconnection of the CH2-CH2Ar bond (b). In addition, disconnection of the N-CH2 bond, after FGI of the amine to an amide group, represents another possibility (c), which can be completed to create a pathway to the sila-bioisostere of fexofenadine, as described in Sect. 10.4.3. 

Two synthons C and D are the result of an alternative disconnection b of the CH2-CH2Ar bond. Finally, retrosynthetic analysis c suggests two functional group interconversions followed by disconnection of the amide N-CO bond, affording synthons E and F. This analysis has been used in the synthesis of the sila-bioisostere of fexofenadine (49), as described in Sect. 10.4.3. 

The key structural feature of BIRT-377 (1) is the A-aryl-substituted-hydantoin bearing a quaternary stereogenic center. In our retrosynthetic analysis, the hydantoin ring can be synthesized by cyclization of the corresponding acyclic a-substituted amino acid amide (9), which could be derived from (Z>) or (L)-alanine. 

Moving ahead with this analysis, the retrosynthetic sword next cut the D-ring diketopiperazine ring of 6 (see Scheme 1) at the indicated amide linkage to reveal 7 as a protected amino acid precursor. Although the selection of a methyl ester and a 9-fluorenylmethyl carbamate (Fmoc) group to protect these new functionalities... 

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