Pictet natural products synthesis

The Pictet-Spengler reaction has mainly been investigated as a potential source of polycyclic heterocycles for combinatorial apphcations or in natural product synthesis [149]. Tryptophan or differently substituted tryptamines are the preferred substrates in a cyclocondensation that involves also aldehydes or activated ketones in the presence of an acid catalyst. Several versions of microwave-assisted Pictet-Spengler reactions have been reported in the hter-ature. Microwave irradiation allowed the use of mild Lewis acid catalysts such as Sc(OTf)3 in the reaction of tryptophan methyl esters 234 with different substituted aldehydes (aliphatic or aromatic) [150]. Under these conditions the reaction was carried out in a one-pot process without initial formation of the imine (Scheme 86). 

Czerwinski, K. M., Cook, J. M. Stereochemical control of the Pictet-Spengler reaction in the synthesis of natural products. Advances in Heterocyclic Natural Product Synthesis 1996, 3, 217-277. 

A l,2,3,4-tetrahydro-/ -carboline, which consists of a tricyclic indole, is an attractive drug template due to its potential antioxidative activity [1-7], Carboline derivatives are also useful as intermediates for natural product synthesis [8-23]. Because construction of tetrahydro-jS-carbolines is mostly dependent on the Pictet-Spengler [8-17] and related reactions [18-23], development of alternative synthetic methodologies is extremely important to ensure diversity-oriented synthesis. For other representative synthetic routes, see [24—31]. 

I will next move to reseipine. One reason is that, in all approaches to this alkaloid, the final reaction used to assemble the pentacyclic skeleton is formally a Mannich-type reaction (a Bischler-Napieralski reaction or a Pictet-Spengler reaction). hi2 more honest reason is that this alkaloid is a classical target in natural product synthesis that has retained the interest of synthetic organic chemists for more than a half-century, including myself As we will see, there are some good lessons to be learned from approaches to this alkaloid. 

Scheme 35.28 The Pictet-Spengler reaction and natural products synthesis.

The Pictet-Spengler condensation has been of vital importance in the synthesis of numerous P-carboline and isoquinoline compounds in addition to its use in the formation of alkaloid natural products of complex structure. A tandem retro-aldol and Pictet-Spengler sequence was utilized in a concise and enantioselective synthesis of 18-pseudoyohimbone. Amine 49 cyclized under acidic conditions to give the condensation product 50 in good yield. Deprotection of the ketone produced the indole alkaloid 51. 

The opiate alkaloid, papaverine, from Papaver somniferum is an anti-spasmodic, vasodilator, and smooth muscle relaxant. Its total synthesis has been studied since Pictet and Gams early work in 1909 and has since been followed up by various industrial syntheses up till the early 1950s using important industrial commodities as vanillin, acetovanillone, veratraldehyde (methylvanillin), and homoveratric acid as starting materials (see Figure 4.50). Table 4.23 summarizes the results of the five synthetic plans for this natural product. All are convergent... 

However, the following are examples of direct electrophilic alkylation of imidazole. A two-step synthesis of marine natural product ageladine A 271 started from the commercially available histamine 269 and the pyrrole-2-carbox-aldehyde 268. The entire skeleton of the alkaloid was built in one step via a Pictet-Spengler type condensation. The reaction was accelerated by Lewis acid scandium triflate, although the reaction did proceed without a catalyst but at a slower pace (Scheme 68) <20060L4083>. 

Lebrun and coworkers reported a convenient synthesis to a range of phenanthroindo- and quinolizidine natural products [62]. In this approach, the alkaloids (+)-antofine [( )-3] (n-1) and (+)-cryptopleurine [(+)-5] (n=2), were synthesized by Pictet-Spengler cyclization of 72 [2-arylmethyl-piperidine (n=2) and -pyrrolindine (n=l)], Scheme (7). The intermediate compounds were obtained by sequential iV-deprotection-reduction of the parent enecarbamates 71, which were obtained from Homer reaction of phosphorylated carbamates 70 with the appropriate aldehyde (69). 

This methodology was expanded to the synthesis of (-)-amabiline (145)(/42c). Namely, 2-aza-allylstannane 189 (derived from 25,35-0-isopropylidene-y-butyrolactone) was exposed to butyllithium in THF at -78"C to provide 3a-(3,4-methylenedioxy)phenylhexahydroindoline (190) along with a diastereomer in 74% yield (a 5 1 mixture of two diastereo-mers). The Pictet-Spengler cyclization of 190, followed by acid treatment, afforded (-)-amabiline (145), confirming the absolute stereochemistry of the natural product (Scheme 17). 

Diketopiperazine formation has long been described as a side reaction in peptide synthesis. It occurs after deprotection or neutralization of the oc-amino group at the dipeptide stage and reduces the overall yield of the synthesis. However, diketopiperazine structures have also been found in natural products with therapeutic properties and hence they have been used as a scaffolds to design new potential drugs [38, 91, 92]. A typical example would be the synthesis of indolyl diketopiperazine alkaloids. Access to these compounds may be achieved by Pictet-Spengler reaction of L-tryptophan bound to hydroxymethylpolystyrene resin with aldehydes. Fmoc amino acids were then coupled and final Fmoc deprotection resulted in cyclative release to yield alkaloids in 50-99% yields (Figure 15.9) [93, 94],... 

Saframycin belongs to a family of complex polycyclic alkaloids endowed with spectacular antiproliferative activity. The successful demonstration that analogues of the natural product are clinically effective for the treatment of solid tumors has stimulated intense efforts towards the total synthesis and medicinal chemistry of these alkaloids. Myers and Lanman adapted their solution phase synthesis of saframycin to a ten-step solid phase synthesis, leading to the preparation of 16 analogues [40]. The key steps are two Pictet-Spengler reactions, which are used... 

The racemic laudanosine (7g) syntheses were referred to earlier in The Alkaloids (Vol. XII, p. 348). From the racemic mixture it is difficult to obtain (S)-(+)-laudanosine which is widely distributed in nature. The synthesis of its unnatural (R )-form (in poor yields) has been reported (asymmetric reduction of 3,4-dihydropapaverine with lithium butyl-(hydro)dipinan-3a-y borate) (363). Recently, a description of the biogenetic synthesis of these two forms from methyl-L-(+)-3,4-dihy-droxyphenylalaninate hydrochloride by condensation with sodium 3-(3,4-dimethoxyphenyl)glycinate at pH 4 and 35° was given. Thus, a dia-stereoisomeric mixture of the Pictet-Spengler products 11a and lib (ratio... 

Despite their great structural variety, isoquinoline alkaloids were, for a long time, considered as a vast, but biosynthetically uniform family of natural products, the common key step of their biogenesis always being the Mannich-type condensation of phenylethylamines with aldehydes or a-ketoacids (7). The preparative imitation of this reaction principle, the Pictet-Spengler-type isoquinoline synthesis (2), has been the basis for countless biomimetic alkaloid syntheses (5). 

With all five rings of manzamine A now formed, 57 was then converted into ircinal A (17) in just two steps full reduction of the ester to a primary alcohol foUowed by Dess—Martin oxidation. As such, the first total synthesis of this secondary metabolite was complete. Finally, following the procedure of Kobayashi and co-workers, 17 was then transformed into manzamine A (1) in 50% overall yield upon Pictet—Spengler cyclization with tryptamine (16) in the presence of TFA to afford the natural product manzamine D (58), followed by DDQ-mediated oxidation. This elegant sequence provided synthetic manzamine A (1) in a total of 31 linear steps, with just 17 of these operations occurring after the union of building blocks 27 and 28. 

The Pummerer rearrangement has been employed in tandem with other reactions to enable complex transformations to be carried out efficiently and in a one-pot manner. Studies of these have been reported mainly by Padwa who has utilized such transformations in the syntheses of natural products. A particularly intriguing cascade sequence involving the Pummerer rearrangement was employed in the synthesis of the alkaloid jamtine, 57. " Padwa et al. synthesized the bromo-enamide 55 in a 4 1 (Z/ ) mixture of isomers. Treatment of the isomeric mixture with camphorsulfonic acid caused the the sulfoxide to undergo a Pummerer/Mannich ion cyclization, which was then followed by a spontaneous Pictet-Spengler reaction to furnish the isoquinoline core. Although a 5 2 1 1 mixture of diastereoisomers was obtained, the desired diastereoisomer 56 was formed preferentially. This was attributed to a 4 r-Nazarov-type conrotatory electrocyclisation which controls the direction of closure from the a-acylthionium ion intermediate. 

The final natural product that will be discussed herein to demonstrate the applicability of asymmetric organocatalysis to assemble the monoterpenoid part of indole alkaloids is (H-)-yohimbine (282) (Scheme 6.46). Yohimbine is a well-known monoterpenoid indole alkaloid that has been isolated from several natural sources and for which the first total synthesis dates back to the 1950s [140]. Two organocatalytic total syntheses of this important natural product have been reported recently by the groups of Jacobsen and Hiemstra [141,142], Jacobsen s synthesis of 282 commenced with the thiourea 170a-catalyzed acyl-Pictet-Spengler reaction between tryptamine 283 and the protected hydroxyaldehyde... 

Lee S, Park SB. Solid-phase parallel synthesis of natural product-like diaza-biidged heterocycles through Pictet-Spengler intramolecular cyclization. J. Comb. Chem. 2006 8 50-57. 

Nicotine is an another very popular pyrrolidine ring-containing natural product, and it was isolated for the first time firom the dried leaves of tobacco plants Nicotiana rus-tica and N. tabacum, in 1828. After the first synthesis of this alkaloid by Pictet and Rotschy in 1904, the synthesis of nicotine and its analogs became attractive field in organic synthesis. In 1999, Crooks and co-workers synthesized (5)-nornicotine 211 using C—N alkylative cyclization as the key step (Scheme 40.42). 2-Hydroxy-3-pinanone keti-mine 207 obtained from 2-hydroxy-3-pinanone 206,... 

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