Alkaloid syntheses nitrogen nucleophiles

The opening of activated cyclopropanes with nitrogen nucleophiles has been widely applied to the synthesis of pynolizidine and pyrroline alkaloids by Danishefsky this subject has been reviewed. A number of pyrroline annulations have been based on this principle, illustrated in equation (35a). > Similar opening can be accomplished with halides, cuprates, and sulfur or selenium nucleophiles. ... 

The application of chiral sulfoxides to the asymmetric synthesis of biologically active compounds has recently been reviewed [3]. Conjugate addition to chiral vinyl sulfoxides has been used by several research groups to achieve the enantioselective synthesis of natural products. For example, intramolecular asymmetric conjugate addition of a nitrogen nucleophile to a chiral vinyl sulfoxide (Scheme 3) was studied by Pyne and applied to the enantioselective synthesis of (-R)-carnegine and other alkaloid systems (Scheme 3) [10]. 

C.ii.c. Cyclizations Involving Nitrogen Nucleophiles. Heterocyclization catalyzed by palladium complexes has also been applied in nitrogen series for the synthesis of several alkaloids such as ( )-alchomeine, ( )-isoalchomeine, a- or y-lycorane, ( )-heUotridane, ( )-cephalotaxine, and (-)-anatoxin-a (Scheme 33). 

Predictably, vobparicine originates from attack of the strongly nucleophilic C-22 of 66 on C-3 of 314. In fact, when a mixture of vobasinol and excess apparicine was refluxed for 2 hr in 1.5% methanolic HC1 under nitrogen, vobparicine was formed, identical in all respects with the natural product. Vobparicine was considered to be a genuine alkaloid because the conditions for its synthesis were not achieved during isolation procedure. 

The focus of this review is to discuss the role of Cinchona alkaloids as Brpnsted bases in organocatalytic asymmetric reactions. Cinchona alkaloids are Lewis basic when the quinuclidine nitrogen initiates a nucleophilic attack to the substrate in asymmetric reactions such as the Baylis-Hillman (Fig. 3), P-lactone synthesis, asymmetric a-halogenation, alkylations, carbocyanation of ketones, and Diels-Alder reactions 30-39] (Fig. 4). 

Preliminary mechanistic studies show no polymerization of the unsaturated aldehydes under Cinchona alkaloid catalysis, thereby indicating that the chiral tertiary amine catalyst does not act as a nucleophilic promoter, similar to Baylis-Hilhnan type reactions (Scheme 1). Rather, the quinuclidine nitrogen acts in a Brpnsted basic deprotonation-activation of various cychc and acyclic 1,3-dicarbonyl donors. The conjugate addition of the 1,3-dicarbonyl donors to a,(3-unsaturated aldehydes generated substrates with aU-carbon quaternary centers in excellent yields and stereoselectivities (Scheme 2) Utility of these aU-carbon quaternary adducts was demonstrated in the seven-step synthesis of (H-)-tanikolide 14, an antifungal metabolite. 

Azirines can be synthesised, enantioselectively if required using a natural alkaloid as base, from the O-tosyl derivatives of the oximes of 1,3-keto esters in this synthesis the carbon is the nucleophilic centre and it is the nitrogen which is attacked with departure of tosylate. ... 

Heteroatom nucleophiles were described less often. Ye and coworkers published a phospha-Michael addition catalysed by prolinol silyl ether catalyst. Another method for constructing a new C-N bond is the aza-Michael addition, that is the addition of nitrogen-based nucleophiles to a,(3-unsaturated aldehydes. Several groups published these type of reactions using diatylprolinol silyl ether as catalyst. " Fustero and coworkers used this reaction as a key step in the synthesis of biologically active chiral heterocycles. Recently, the authors showed the synthesis of quinolizidine alkaloids, such as (-l-)-myrtine, (-)-lupine and (-l-)-epiquinamide. Vicario applied 5-mercaptotetrazoles as nucleophiles towards a range of unsaturated aldehydes. The reaction proceeded via the iminium activation. The... 

The second set of examples involves the use of thionium ions as electrophiles in inter- and intramolecular processes to obtain a-substituted sulfides (see 24 25, Scheme 20.7T which is the most common type of Pummerer reaction. Applications of this classical Pummerer rearrangement are exemplified in the synthesis of trans-solamin, the synthesis of indolizidine alkaloids, and the synthesis of the CDE ring of erinacine E. The first exanple fScheme 20.10 uses Pummerer chemistry in the generation of a thionium ion, which reacts in an intermolecular tin-mediated ene reaction the second one fScheme 20.11 uses Pummerer chemistry to introduce a nitrogen-containing heterocycle by intramolecular addition to form the coniceine core and the third example fScheme 20.12 is an intramolecular silicon-induced Pummerer reaction with oxygenated nucleophiles applied to the synthesis of a precursor of erinacine. Details of these Pummerer-based strategies are discussed below. 

Additionally, Scheme 20.11 shows the versatility of Pummerer products. Under classical Pummerer conditions, heterocyclic conpounds behave as good nucleophiles, including for the production of tertiary bicyclic lactams 44. Kuhakarn et used a silicon-induced Pummerer reaction (this activation method will be explained in more detail later in this section) to generate the thionium intermediate, which was intramolecularly trapped by the lactamic nitrogen. Even when a mixture of S-stereoisomers was used, the reaction proved to be diastereoselective, and the lactam sulfide 44 was obtained as 5 1 mixture of trans cis products. Subsequent transformations led to the synthesis of a variety of bicyclic alkaloids 45-48 starting from the same sulfide lactam intermediate 44. 

A further extension of the Pd-catalyzed intramolecular 1,4-oxidation was the use of amide, whose amino functionality had the ability of making a twofold nucleophilic attack. The use of nitrogen as nucleophile led to pyrrolizidine and indolizidine derivatives. This strategy was applied for the synthesis of another alkaloid, ( )-heliotridanef (Scheme 36). Pd-catalyzed reaction of dieneamide, obtained from the known ester 167, in THF employing CUCI2/O2 as the oxidant afforded the azabicyclic product 168 in 85% yield. The mechanism of this tandem cyclization involved a TT-allylpalladium... 

Moving away from ketones to other prochiral nucleophiles has also been an important goal in our group. We choose to explore lactam-derived substrates in part because we envisioned that the products formed would be useful intermediates in the synthesis of various alkaloids and because we would be able to modulate the electronics and sterics of the lactam enolate by attaching different groups at nitrogen with the aim of optimizing the enantioselectivity of the allylic alkylation. In the event, we chose to initially test tosyl-protected lactam allyl ester 29 and Boc-protected lactam aUyl ester 30 with two Pd PHOX catalysts in several solvents (Scheme 18). 

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