Alkaloids are an important class of natural products that are widely distributed in nature and produced by a large variety of organisms. They have a wide spectrum of biological activity and for many years were used in folk medicine. These days, alkaloids also have numerous applications in medicine as therapeutic agents. The importance of these natural products in inspiring drug discovery programs is proven and, therefore, their continued synthesis is of significant interest. The condensation discovered by Pictet and Spengler is the most important method for the synthesis of alkaloid scaffolds. The power of this synthetic method has been convincingly proven in the construction of stereochemically and structurally complex alkaloids.
The purpose of this section is to take a look at the latest advances in the stereoselective PictetSpengler reaction. It is believed by the author that by doing so, it will help to put this work in a general synthetic perspective given the critical role that this reaction plays in the correct construction of the initial stereocenters. To that end, it was found that the excellent contributions by Lorenz and Van Linn (Lorenz, M.; Van Linn, M. L.; Cook, J. M. Current Organic Synthesis 2010, 7, 189-223) in Milwaukee and that by Stöckigt and Waldmann (Stockigt, J.; Antonchick, A. P.; Wu, F-R.; Waldmann, H. Angew Chem. Int.
Ed. 2011, 50, 8538-8564) as key in order to quickly get access to some of the advances in
the stereoselective applications of the PictetSpengler reaction up to 2011 and part of their work is worth mentioning here. The PictetSpengler reaction had been extensively reviewed by many before.210
Scheme 140
The reaction was first discovered in 1911 when phenethylamine with methylal were condensed to produce the tetrahydroisoquinoline (736).211a Tatsui in 1928, executed the first examples with indoles, when he utilized this reaction with indole bases to form 1- methyl-1,2,3,4-tetrahydro-β-carboline (737) from tryptamine and acetaldehyde (Scheme 140).211b
The PictetSpengler reaction involves the cyclization of electron-rich aryl or heteroaryl groups onto imine or iminium ion electrophiles and has long been a standard method for the construction of both tetrahydro-β-carboline and tetrahydroisoquinoline systems. The proposed mechanism of Jackson et al. is illustrated in Schemes (141, 142).212,213
Scheme 142
6.1) Diastereospecific PictetSpengler Reactions via Internal Asymmetric Induction
Advances in the asymmetric PictetSpengler reaction originated from the need to form the 1,2,3,4-tetrahydro-β-carboline system in stereospecific fashion. The stereochemical direction of the reaction can be understood through the steric influence that substituents at the 1, 2, and 3 positions, as well as the functionality on the indole nitrogen, have on the course of the reaction (Figure 15).
Figure 15. Tetra-substituted carboline system
In an effort to synthesize biologically important indole alkaloids in a diastereospecific fashion, the asymmetric PictetSpengler reaction was developed.214 The PictetSpengler cyclization in nonacidic aprotic media was first reported by Sandrin et al.215 The cis and
trans isomers of the PictetSpengler cyclization were isolated from the condensation of tryptophan methyl ester with benzaldehyde using a DeanStark trap to remove the water formed in the process. Ungemach demonstrated later that Nb-benzyl tryptophan methyl ester could cyclize in a stereospecific fashion by making use of this modified Pictet Spengler reaction in the total synthesis of indole alkaloids.216 When the aldehyde sub- strate carried a bulky substituent, 100% trans diastereoselectivity was observed. A breakthrough in the enantiospecific preparation of the key azabicyclo[3.3.1]nonane (tetracyclic ketone) template was realized by Zhang (Scheme 143) when the optically pure D-Na-methyl-Nb-benzyl tryptophan methyl ester (738) was employed as the substrate.217 Under the nonacidic aprotic conditions (refluxing benzene/DeanStark trap), the D-Na-methyl-Nb-benzyl tryptophan methyl ester reacted with methyl 3-formyl-
propionate to provide a diastereomeric mixture of trans and cis tetrahydro--carbolines in a ratio of 72:28, respectively.
Scheme 143
Zhang also showed that when the cis isomer was heated in 1% HCl in methanol, complete conversion into the trans isomer was observed (Scheme 143), while the trans isomer remained intact under the same conditions. The trans diastereomer was then elaborated further and eventually it was converted into the indole alkaloid alstonerine.218 This represented the first enantiospecific synthesis of an indole alkaloid employing the asymmetric PictetSpengler reaction. The reaction conditions of this PictetSpengler cyclization were later modified to gain better entry into the desired trans diastere- omer.138,55b,219
In order to evaluate the effects of kinetic or thermodynamic control on the Pictet– Spengler reaction, a series of experiments have been carried out. In regard to the
mechanism of the condensation itself, two possible pathways were proposed earlier by Jackson et al. (Schemes 141, 142). Attack at C-3 to form the spiroindolenine intermediate (VIII, Scheme 142) was demonstrated by Nakagawa et al., when a tetracyclic product was observed from the cyclization of tryptamines functionalized with nitrone moieties with cysteinals under conditions of a Pictet–Spengler condensation.220 Jackson et al., Cook et al., Williams et al., and many others have also presented evidence in support of attack at the C-3 position; however, direct attack at the C-2 position could not be completely ruled out.212,213,221This was especially important when the C-2 position of the indole double bond was activated by a ring-A substituent(s) such as a 6-methoxy function. Under nonacidic aprotic conditions, various tryptophan derivatives were condensed with methyl 3-formyl-propionate to give a mixture of the trans and cis tetrahydro--carbolines in an approximate ratio of 72:28 in favor of the trans diastereomer (Table 1). The only exception arose from the cyclization of 6-methoxy Na-H tryptophan ethyl ester (741c) and methyl 3-formyl-propionate (Table 1, entry 3). This process provided 95% trans diastereoselectivity from analysis of the 1H and 13C NMR spectra of the crude reaction mixture.222
It is believed that the product distribution of this condensation under nonacidic aprotic conditions was obtained under kinetic control.214,223 The attack from the face opposite of the ester function (anti spiroindolenine, Scheme 144) would be kinetically more favorable than the attack on the iminium ion from the same side of the ester function (syn spiroindolenine). In addition, calculation of the energy difference between the two different spiroindolenine intermediates indicated the anti spiroindolenine (746a) was energetically more favorable than the syn counterpart (746b) by about 2.1 kcal/mol.223