Iminium ions stereochemistry

The stereoselective addition of the titanium enolate of A-acetyl-4-phenyl-l,3-thiazolidine-2-thione 153 to the cyclic A-acyl iminium ion 154 is utilized in the synthesis of (-)-stemoamide, a tricyclic alkaloid <06JOC3287>. The iminium ion addition product 155 undergoes magnesium bromide-catalyzed awtz-aldol reaction with cinnamaldehyde 156 to give adduct 157, which possesses the required stereochemistry of all chiral centers for the synthesis of (-)-stemoamide. 

Now the stereochemistry. Assume the thermodynamically more stable iminium ion forms (Me groups cis). The Cope rearrangement occurs from a chair conformation. This puts the Ph, H2, and HI 1 all pointing up both before and after the rearrangement. Assuming the Mannich reaction occurs without a change in conformation (a reasonable assumption, considering the proximity of the nucleophilic and electrophilic centers), the Ph, H2, and HI 1 should all be cis in the product. 

Iminium ion-vinylsilane cyclizations closely related to the one described here have been used to prepare indolizidine alkaloids of the pumiliotoxin A and elaeokanine families, indole alkaloids, amaryllidaceae alkaloids, and the antibiotic (+)-streptazolin. The ability of the silicon substituent to control the position, and in some cases stereochemistry, of the unsaturation in the product heterocycle was a key feature of each of these syntheses. 

It is initially puzzling that it is not necessary to hydrolyse the acetal before the Mannich reaction. Under the acidic conditions, the acetal is in equilibrium with the end ether and this is reactive enough to combine with the very electrophilic iminium ion 102. The stereochemistry of the product is determined in this cyclisation step and simply ensures that the two five-membered rings are cis fused. 

This methodology was employed for the synthesis of the reported structure of the alkaloid jamtine (02OL715, 02JOC929). The key sulfoxide intermediate 307 was heated with CSA to produce several tricyclic products (98% yield) as a mixture (5 2 1 1) of diastereomers in which 308 predominated (Scheme 57). The stereochemistry of 308 was secured by X-ray crystallographic analysis and is consistent with a Nazarov-type conrotatory 47i-electrocyclization followed by attack of the nucleophilically disposed aromatic ring from the least hindered side of the intermediate iminium ion. Reaction of a-ethylthio amide 308 with NaH effected an intramolecular alkylation to provide tetracycle 309. 

The adduct 121 was presumed to arise from a cycloaddition reaction between the iminium ion 120 and its 1,6-dihyropyridine tautomer. Adduct 121 has the same regiochemistry and relative stereochemistry as the naturally occurring ingenamine alkaloids. 

A related example involving a more complex substrate is found in Rapoport and Luly s formal synthesis of the 7-methoxymitosene (24). Again, decarbonylation of an a-tertiary amino acid chloride is employed to generate the iminium ion. The indoline acetal (23) produced in this way is essentially one diastereomer however, its stereochemistry was not established (Scheme 13). 

When the pre-existing stereocenter is adjacent to the iminium ion carbon atom, Pictet-Spengler cyclization most commonly occurs from the face opposite the substituent, as in the conversion of (42) to (43) (Scheme 20). A related example is the cyclization of the disubstituted A -tetrahydropyridine (44), which was treated with hydrogen chloride gas in anhydrous methanol to produce three of the four possible diastereomeric products in the indicated abundances (Scheme 21). The relative stereochemistry at C-1 is set by protonation of the enamine, while that at C-12b is determined in the cyclization step. The authors argue that protonation is kinetically controlled and occurs preferentially from the... 

Working with dehydroquinase isolated from E. coli 83-2, Butler et al. [119] demonstrated that the reaction was catalyzed via iminium ion formation, in a manner analogous with the model system shown in Scheme 19. They demonstrated that the enzyme was inhibited in the presence of both substrate and sodium borohydride. The inhibited enzyme did not regain activity upon dialysis. The enzymatic SYN elimination is contrasted with the non-enzymatic, base-catalyzed, trans-eUmination found in aqueous solution, in which the pro-S proton is stereo-selectively removed (Scheme 20). The stereochemistry of proton abstraction in the non-enzymatic case arises from the pro-S proton being in an axial position such that... 

Although this review concerns those reactions catalyzed by iminium ion formation, it is important to note that there are enzymatic reactions that could logically be catalyzed by iminium ion formation but which are not. Yeast aldolase, for example, is the best known case [26] (see Ch. 6). This enzyme is metal ion dependent, does not demonstrate the loss activity in the presence of both substrate and borohydride, and is sensitive to inhibition by EDTA. The reaction catalyzed by this enzyme is identical to that catalyzed by the imine-forming enzyme, and even has evolved to exhibit the same retention stereochemistry. Another example is A -3-oxosteroid reductase which is responsible for the NADPH-dependent reduction of the enone double bond to the corresponding dihydrosteroid [124]. Even though iminium ion formation would increase the reactivity of this substrate toward the -hydride addition, a demonstrated lack of the required oxygen exchange proves that this does not occur. 

Reduction of (140a) and (140b) separately with H2/PdCl2 in ethanol afforded the epimeric pyr-rolizines (143a) and (143b) (Equation (14)) the stereochemistry at C-5 is presumably due to a face-selective reduction of an intermediate cyclic iminium ion <89JCS(P1)2415>. 

Sequential Iminium-Enamine Catalysis. Directed Electrostatic Activation. A comparison of the standard catalytic cycles for enamine activation (Scheme 2.1) and for iminium ion activation (Scheme 2.12) show that iminium catalysis proceeds, after the addition of the nucleophile, via an ( )-enamine. In the presence of a suitable electrophile, this enamine gives rise to an iminium ion that after hydrolysis can give rise to an a,p-diftmctionalyzed carbonyl (Scheme 2.13) [85]. Scheme 2.13 also shows that when using a chiral 2-substituted pyrrohdine or an imidazolidinone as the catalyst, the sequential apphcation of the steric model for Michael addition to iminium ions (Figure 2.15) and of the steric model for electrophilic attack to enamines (Figure 2.IB) predicts the absolute stereochemistry of the major isomer obtained in the reaction. 

Reversal of the stereochemistry of the Michael addition to PhCH=CHCH=0 has been observed for the MacMillan-type catalysts (257) and (258), which can be rationalized either by yn-addition with respect to the benzylic substituent of an ( )-iminium ion intermediate or by anti-addition to the corresponding (Z)-iminium ion. The issue has not yet been resolved. ... 

The influence of the stereochemistry of branched aUylsilanes on addition to carbonyl compounds is displayed in the next example, which contains an enan-tioselective construction of 9-azabicyclo[3.3.1]nonene via iminium ion initiated cychzation of aUylsilanes (Scheme 3.41) [66]. 

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