Cyclohexenyl amine

The main synthetic challenge in a synthesis of -acarbose is the attachment of the polyhydroxylated cyclohexene unit, by a nitrogen atom, to the 6"-deoxy trisaccharide. If one accepts that molecular ammonia is not likely to be the ideal reagent to link the cyclohexene and trisaccharide units together, then one also realizes that only two approaches are left either a trisaccharide amine may be attached to a cyclohexene unit or, conversely, a cyclohexenyl amine may be joined to a trisaccharide. 

We now turned our attention to the second approach, the alkylation of a cyclohexenyl amine by some trisaccharide derivative. The logical choice of amine was the 1-epivalienamine derivative 81, a molecule that was readily available through various literature procedures. We chose to utilize the excellent synthesis described by Panza et al. to produce multi-gram amounts of the amine 81 [56]. 

Asymmetric induction may also derive from chirality in the amine part of the enamine. The reaction of the enamine (S)-l-(l-cyclohexenyl)-2-(methoxymethyl)pyrrolidine with ( )-(2-ni-troethenyl)arenes gives, after hydrolysis, a single diastereomeric product in >90% ee30. 

In a total synthesis of inhibitors of this kind, the following methods have so far been employed successfully (a) reaction of a cyclohexenyl halide with an amine, (b) coupling of an amine with an epoxide, and (c) condensation of an amine with ketone and reduction of the resulting Schiff base (reductive alkylation of an amino sugar). 

Samuel Danishefsky of Columbia University has also described (J. Am. Chem. Soc. 2005, 127, 8298) a total synthesis of 1, starting from the pyroglutamate derivative 10. Conjugate addition followed by alkylation established the lactam framework. Intramolecular cyclization of 12 gave 13, establishing the aminated quaternary center. The oxygenated quaternary center was then constructed by phenylselenyl-mediatcd cyclization of 14. The end game of this synthesis used the already-established cyclohexenyl zinc addition, which worked as well with 16 as it had with 7. 

Loss of stereospecificity, however, has also been reported in the addition of amines. The use of homogeneous Pd° catalysts in the addition of dimethylamine to a cyclohexenyl acetate led to substantial stereochemical scrambling (equation 186). Employment of polymer-bound Pd° catalysts, however, gave complete stereospecificity via ligand addition.398 The epimerization noted in this reaction is apparently due to acetate attack at the metal center, which is prohibited by steric congestion of the metal in the polymer matrix (equation 187).398... 

The synthesis started with an Ugi four-component condensation involving protected glutamic acid 242, aldehyde 243, methylamine and cyclohexenyl isocyanide 244. The resulting dipeptide product 245 was first hydrolyzed to acid 246, which was then coupled with amine 247. Further derivatizations of the resulting tripeptide 248 afforded the desired natural product. 

In the simplest picture of optimum resonance-derived stabilization, the two carbons of the double bond, the amine nitrogen and all five atoms affixed to these three enamine atoms lie in a common plane. Much the same demand for planarity exists for the exocyclic isopropylide-necycloalkanes. For these hydrocarbons, one finds the rearrangement of 1-isopropylcyclohexene to isopropylidenecyclohexane is exothermic by 3.1 0.6 kJ mol-1 but that of 1-isopropylcyclo-pentene to isopropylidenecyclopentane is exothermic by 4.3 0.3 kJ mol -1 [D. B. Bigley and R. W. May, J. Chem. Soc. (B), 1761 (1970)]. If one ignores error bars, the 3.1 - (-4.3) s 7 kJ mol -1 net destabilization for the exocyclic double bond in the cyclopentene vs cyclohexene hydrocarbon case is essentially identical to the 51 — 45 6 kJ mol -1 for the cyclopentenyl and cyclohexenyl enamines. 

Sulfonium Dimethyl-(2-morpholino-1-cyclohexenyl)- (fluorsulfonat) Ell, 468 (R2 —NR2 4 En — amin)... 

Neat A-(l -methyl-4-pentenyl)hydroxylamine underwent facile cyclization to the corresponding Y-hydroxypyrrolidine 1 on wanning briefly to 50- 60 °C, via a radical chain reaction involving the nitroxide radical. A-(l-Methyl-5-hexenyl)hydroxylamine cyclized to give A-hydroxypipe-ridine 2 only in refluxing xylene under high dilution conditions, this is necessary to avoid formation of byproducts. The cyclization was facilitated by the presence of a-methyl substituents in the hydroxylamine. Transannular cyclization of A-[(3-cyclohexenyl)methyl]hydroxylamine was not successful. Since the isolation of pure samples of the water-soluble and easily oxidized hydroxylamines was not a satisfactory procedure, the crude reaction mixtures were subjected to reduction with a zinc/acetic acid/acetic anhydride system to isolate acetylated cyclic amines. 

Semmler-Wolff reaction. Rearrangement of ,(i-iinsaturatcd cyclohexenyl ketoximes into aromatic amines under acidic conditions. 

A number of other aryl-cyclic amine functionalities were examined as replacements for the 1,2,3,6-tetrahydro-4-phenylpiperidine of 36 (Table 6). Thiophene analogue 41 was found to have somewhat weaker DA D2 receptor affinity. In the 1,4-cyclohexenyl series 2-pyridylpiperazine attached to the phenyl cyclohexene produced potent compounds. The 1,5-cyclohexenyl analogue 42 having a 2-pyridylpiperazine group was also an interesting compound. However, the parent tetrahydropyridine 36 caused greater decreases in DA synthesis than piperazine 42. Replacement of the 2-pyridyl group with phenyl (43) or 2-pyrimidyl (44) resulted in compounds with decreased receptor affinity and in vivo activity. 

Concurrently with the studies in the aryl-cyclohexenyl systems, we undertook the study of amide functionality in the 4-position of the cyclohexyl ring. Benzamides such as sulpiride comprise a well-known class of DA antagonists. But when applied in a somewhat different context, benzamide functionality attached via the cyclohexyl tether to an aryl amine led to DA partial agonists. A series of analogues probed the importance of distance and stereochemistry between the pyridinyl piperazine and the benzamide functionalities and some analogues were found to have potent activity as DA autoreceptor agonists.77... 

Alkylation (R" = alkyl or substituted alkyl) is most satisfactorily accomplished with active halogen compounds such as allyl, benzyl, and propargyl halides, but a-halo ketones, esters, and nitriles can also be used.467,474 Treating l-(l-cyclohexenyl)pyrrolidine with allyl bromide in the presence of /V-ethyl-dicyclohexylamine as base leads to introduction of two allyl groups, i.e., formation of 2,6-diallylcyclohexanone.475 Arylation can be effected by, for example, l-chloro-2,4-dinitrobenzene (R" = 2,4-dinitrophenyl).476 A-Isobutyl-fl-butylamine477 and pyrrolidine478 have been recommended as amine components for C-alkylation by simple alkyl halides such as ethyl and methyl iodides. The following two examples are illustrative ... 

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