Iminium ions Pictet-Spengler cyclization

We used this method as the key sequence in the synthesis of ( )-lycopodine (78). The intramolecular isomiinchnone cycloadduct 81 was envisaged as the precursor of the key Stork intermediate 79 (via 80) [42]. The heart of our synthetic plan was the formation of the latter intermediate by a Pictet-Spengler cyclization of the N-acyliminium ion derived from 81. Central to this strategy was the expectation that the bicyclic iminium ion originating from 81 would exist in a chair-like conformation [42,43]. Cyclization of the aromatic ring onto the iminium ion center should take place readily from the axial position. The readily available heptenoic acid 82 would serve as the precursor for the a-dia-zoimide, the direct progenitor of the isomiinchnone dipole. This extension of the tandem cycloaddition-cationic 1-cyclization protocol to the formal synthesis of ( )-lycopodine (78) is outlined below. 

Since its discovery the Pictet-Spengler cyclization has formed the basis of numerous syntheses of alkaloids containing aromatic subunits. This high-yielding reaction involves, in its broadest sense, nucleophilic attack on an iminium ion by the Tr-electrons of a tethered aromatic moiety. In the classical reaction a substituted P-phenethylamine is condensed with an aldehyde under acidic conditions to produce a te-trahydroisoquinoline (Scheme 16). A useful variant of the Pictet-Spengler reaction, which provides tetr ydro-(3-carbolines and their derivatives, involves the condensation of a tryptamine derivative and an aldehyde (Scheme 16). Whether nucleophilic attack on the resulting iminium ion occurs initially at the a- or -indole carbon is a topic of current debate and, indeed, there is evidence to suggest that the mechanistic pathway could be substrate dependent. ... 

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... 

In 2009, Klausen and Jacobsen disclosed another activation pathway, in which the thiourea catalyst enhances the acidity of a relatively weak Brpnsted acid catalyst, and applied this to an enantioselective version of the Pictet-Spengler cyclization [149]. This increase on the acidity of the Br0nsted acid allows the protonation of the imine substrate and to the formation of an iminium ion with a chiral counterion, which is stereoselectively attacked by a nucleophile (Scheme 2.28). 

In the case of A -homoveratryl-2-azanorbonene, heterocycloreversion gives rise to a 61% yield of homoveratrylamine (103) along with 18% of the Pictet-Spengler cyclization product 102 derived from internal trapping of iminium ion 101 ... 

The formation of an iminium ion as 2-530 is also proposed by Heaney and coworkers in the synthesis of a tetrahydro- 3-carboline 2-531 (Scheme 2.120) [282]. Herein, heating a solution of tryptamine (2-526) and the acetal 2-527 in the presence of 10 mol% of Sc(OTf)3 gives in the first step the N, O-acetal 2-528, which then leads to the lactam 2-529 and further to the iminium ion 2-530 by elimination of methanol. The last step is a well-known Pictet-Spengler type cyclization to give the final product 2-531 in 91% yield. 

Another useful variation is the Pictet-Spengler isoquinoline synthesis, also known as the Pictet-Spengler reaction. The reactive intermediate is an iminium ion 49 rather than an oxygen-stabilized cation, but attack at the electrophilic carbon of the C=N unit (see 16-31) leads to an isoquinoline derivative. When a p-aryla-mine reacts with an aldehyde, the product is an iminium salt, which cyclizes with an aromatic ring to complete the reaction and generate a tetrahydroisoquinoline." ° A variety of aldehydes can be used, and substitution on the aromatic ring leads to many derivatives. When the reaction is done in the presence of a chiral thiourea catalyst, good enantioselectivity was observed." ... 

Iminium ion cycUzations such as the Pictet-Spengler reaction have been widely used in alkaloid chemistry to create a carbon-carbon bond between the carbon a to the basic nitrogen and an aromatic ring. The requisite iminium ions in these reactions are often readily available via the modified Polonov-ski reaction. Although two steps, IV-oxide formation and reaction with trifluoroacetic anhydride, are involved, this approach is often preferable to the reaction of a tertiary amine with mercury(II) acetate, in which it is necessary to destroy the amine-mercury complex at the end of the reaction. In this way the secoheteroyohimbinoidiV-oxide (34) was cyclized selectively to uammigine (35 equation 12). Using mercuiy(II) acetate a nearly equal mixture of (35) and its C-3 P-H epimer tetrahydroalstonine is obtained. 

The use of a-cyanoamines in place of their less stable iminium ion precursors often results in high product yields in the Pictet-Spengler and other ring closure reactions. Thus, the Polonovski-derived a-cyanoamine (39a) cyclized to (40) in 84% yield, whereas reaction of the tertiary amine (39b) with mercury(n) acetate was unsuccessful (equation 13). The conversion of unstable S,6-dihydropyridinium salts (41), obtained by reaction of tetrahydropyridine IV-oxides with trifluoroacetic anhydride, into the stable, synthetically versatile tetrahydropyridine-2-carbonitiile (42) is another area in which use of this methodology has met with particular success (equation 14). ... 

The Pictet-Spengler reaction is an important reaction involving condensation of an unsubstituted or substituted tryptamine 145 with an aldehyde RiCHO, usually in the presence of a Bronsted acid to afford an iminium ion 146 which undergoes intramolecular cyclization to afford biologically important tetrahydro- 3-carboline (147). Although the cyclization affords the C-2 adduct, the initial F-C product is the spirocyclic C-3 adduct, which... 

Cyclization of iminium ions onto arenes were first described by Pictet and Spengler in 1911, with the formation of tetrahydroisoquinoline 152 (Equation 10) [125]. This versatile transformation has been widely used in the diastereoselective synthesis of polycyclic aromatic alkaloids of biological interest, in particular of tetrahydro-/5-carbolines 154 (Equation 11) [126]. A few selected examples that highlight stereoselective Pictet-Spengler reactions are discussed below [9, 103, 127]. 

In the first catalytic, enantioselective version of the Pictet-Spengler reaction, Jacobsen utilized the chiral thiourea derivative 171 as catalyst (Equation 12) [132], Such thioureas have emerged as a versatile class of chiral promoters and have proven to be of general utility in a number of enantioselective transformations [40], A particularly interesting feature of this study is the fact that in situ acetylation of the intermediary aldimine leads to an N-acyl iminium ion as the reactive species that subsequently undergoes cyclization. A priori, the more basic imine resulting from condensation of aldehyde 170 with tryptamine 169 would have been expected to be more likely than the N-acyl iminium ion to interact with catalyst 171. Nonetheless, the latter species was responsive to the H-donor catalyst, leading to N-acetylated tetrahydro-/ -carboline 172 in 81 % yield and 93 % ee [132],... 

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