Amines retrosynthetic analysis

Each of the unsaturated cyclic amines shown below has been synthesized by reaction of an amino-substituted allylic silane under iminium ion cyclization conditions (CH2=0, TFA). By retrosynthetic analysis, identify the appropriate precursor for each cyclization. Suggest a method of synthesis of each of the required amines. 

Retrosynthetic analysis of the carbazomycins C (263) and D (264) based on the iron-mediated construction of the carbazole framework leads to tricarbonyl [3-methoxy-(l-5-ri)-cyclohexadienyl]iron hexafluorophosphate (779) and the aryl-amines 780a and 780b (see Scheme 5.84) as synthetic precursors (611). The arylamines 780a and 780b have been used previously as precursors for the total syntheses of carbazomycin A (260) and B (261) (see Schemes 5.86, 5.87 and 5.88). 

In continuation of our investigations on asymmetric nucleophilic acylations with lithiated a-aminonitriles [40], we envisaged the asymmetric synthesis of 3-substituted 5-amino-4-oxo esters A, bearing both a-amino ketone and 5-amino ester functionalities (Scheme 1.1.14) [41]. Since a-amino ketones are precursors of chiral p-amino alcohols [42, 43] and chiral amines [43], their asymmetric synthesis has the potential to provide valuable intermediates for the synthesis of biologically active compounds, including peptidomimetics [44]. The retrosynthetic analysis of A leads to the a-aminoacyl carbanion B and p-ester carbocation... 

A retrosynthetic analysis for a target molecule of either a primary or secondary amine is therefore a two-stage process first an FGI to reveal an imine, and then a disconnection to ammonia (or primary amine) and the carbonyl compound. 

In a reaction which is mechanistically related to the Skraup reaction an a,/ -unsaturated carbonyl compound, generated by way of an acid-catalysed aldol condensation, reacts with a primary aromatic amine in the presence of acid to yield a quinoline derivative (Doebner-Miller reaction). For example, when aniline is heated with paraldehyde (which depolymerises to acetaldehyde during the reaction) in the presence of hydrochloric acid the final product is 2-methyl-quinoline (101) (quinaldine, Expt 8.40). Retrosynthetic analysis for the 1,2-dihydroquinoline reveals crotonaldedhyde as the unsaturated carbonyl component which is in turn formed from acetaldehyde (see Section 5.18.2, p. 799). 

Retrosynthetic analysis of the oxazolidinone pharmacophore 1 shown in Fig. 3 revealed that the oxazolidinone aminomethyl group could serve as an attachment site to the solid support during the elaboration of a suitably substituted scaffold. We envisioned amine scaffold 2 could be readily coupled to a resin-bound aldehyde. Attachment of two points of diversity via derivatization of the solid-supported secondary amine 3 with a variety... 

You should now be able to suggest a plausible analysis of the secondary amine terodilin. This is the structure write down a retrosynthetic analysis and suggested synthesis before looking at the actual synthesis below. 

Our retrosynthetic analysis of the desired sphingoids relies on the previously developed diastereo- and enantioselective (S)-proline-cata-lyzed aldol reaction of the readily available dioxanone (4). In a second step, the amino group should be installed by reductive amination (Scheme 6) (Enders et al. 2006a). 

The retrosynthetic analysis dictated a heptasaccharide 251, with all free hydroxyls in the final product henzylated, and the three sites of phosphorylation all differentially protected, so that aU three can he manipulated separately for maximal flexibility. The free amine of glucosamine is protected as an azide, which can be taken through multiple transformations and will only be unmasked at the end of the s)uithesis (O Scheme 37). The heptasaccharide is in turn put... 

Polycyclic amine alkaloids (3-alkylpiperidine alkaloids) containing a complex skeleton with several macrocyclic rings have been isolated from marine sponges. They include manzamines, sarains, haliclamine A and ingenamines. Their structures, synthesis and biochemical aspects have been recently reviewed [35]. Our focus, therefore, is on the biogenetic origin of the bis-pyridinium macrocycle and on the role of precursors in their biosynthesis, as summarized in the retrosynthetic analysis for manzamines demonstrated schematically in Fig.(23). 

Our first approach to 1 is based on a retrosynthetic analysis depicted in Fig (8). The crucial step to construct the cw-fused bicyclic ring skeleton of 1 is the intramolecular allylic amination of a cw-allylic carbonate 25. The paUadium-catalyzed allylation takes place with retention of the configuration [76] and requires the c/s-isomer 25 for the ring closure. Compound 25 may be derived from keto acid 24 through a sequence of reactions including esterification, O-methoxycarbonylation, removal of the Boc and benzylidene groups, dehydrative cyclization, reductive alkylation and ureido formation. The last five transformations are to be conducted in a successive manner, i.e., without isolation of the intermediates. The 4-carboxybutyl chain of 1 may be installed by the reaction of O-trimethylsilyl (TMS) cyanohydrin 23 with a di-Grignard... 

The retrosynthetic analysis outlined in scheme 1 suggested that the reaction of the amine (2) with a readily available arylisocyanate (3) would be the key step in the preparation of the target molecules (1). 

Euchrestifoline (159) was isolated from the leaves of the Chinese medicinal plant M. euchrestifolia by Wu and co-workers [179]. The structurally related compound girinimbine (168) was obtained and characterized first by Chakraborty and co-workers from the stem bark of M. koenigii [180]. Retrosynthetic analysis of the tetracyclic ring system leads to bromobenzene (160) and 2,2,8-trimethyl-2/7-chromen-5-amine (161) as appropriate starting materials for application of our methodology (Scheme 35). The keto function was thought to be introduced via a regioselective Wacker oxidation of the chromene moiety. Compound 161... 

Chida et al. used this strategy for the total synthesis of murrastifoline A [204, 205]) and ( )-murrayazoline [( )-206] [206]. In addition to the double Buchwald-Hartwig amination generating the carbazole framework, two further palladium(0)-catalyzed couplings have been applied to construct the hexacyclic skeleton of ( )-murrayazoline [( )-206], an 0-arylation and a Suzuki-Miyaura coupling. Retrosynthetic analysis of ( )-murrayazoline [( )-206] led to 2-bromo-phenylboronic acid, the arylamine 211, and the monoprotected cyclohexane-1,4-dione 212 as precursors (Scheme 49). 

The development of a silver-mediated Diels-Alder reaction to construct the pentacyclic intermediate 77a in which the two methylene groups were positioned trans to each other paved the way for the asymmetric total synthesis of (+)-perophoramidine. In our retrosynthetic analysis (Scheme 26), we planned to synthesize (+)-perophoramidine via late-stage regioselective N1 -methylation of the hexacycUc intermediate 100. We planned to constmct the B-ring in 100 via intramolecular amination of the imidate functional group in 101, which could be readily synthesized fi-om 77a via a series of functional group transformations. 

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. 

Scheme 15.4 Retrosynthetic analysis with the r2.31-Meisenheimer rearrangement. Scheme 15.5 Synthesis of amine IV-oxides from tertiary amines.

Following is a retrosynthetic analysis for a synthesis of diazepam. Note that the formation of compound B involves a Friedel-Crafts acylation. In this reaction, it is necessary to protect the 2° amine by prior treatment with acetic anhydride. The acetyl-protecting group is then removed by treatment with aqueous NaOH followed by careful acidification with HCl. 

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