Alkaloids natural synthesis

In spite of the diverse nature of alkaloid structures, two structural units, i.e. fused pyrrolidine and piperidine rings in different oxidation states, appear as rather common denominators. We therefore chose to give several examples for four types of synthetic reactions which have frequently been used in alkaloid total synthesis and which provide generally useful routes to polycyclic compounds with five- or six-membered rings containing one nitrogen atom. These are ... 

The Bischler-Napieralski reaction involves the cyclization of phenethyl amides 1 in the presence of dehydrating agents such as P2O5 or POCI3 to afford 3,4-dihydroisoquinoline products 2. This reaction is one of the most commonly employed and versatile methods for the synthesis of the isoquinoline ring system, which is found in a large number of alkaloid natural products. The Bischler-Napieralski reaction is also frequently used for the conversion of N-acyl tryptamine derivatives 3 into p-carbolines 4 (eq 2). 

The Bischler-Napieralski reaction is one of the most widely used methods for the construction of dihydro- and tetrahydroisoquinoline units in the synthesis of alkaloid natural products. A few representative examples of the Bischler-Napieralski reaction in complex alkaloid syntheses are shown below. 

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. 

Baxendale, I.R., Deeley, J., Griffiths-Jones, C.M., Ley, S.V., Saaby, S., Tranmer, G.K. (2006) A Flow Process for the Multi-Step Synthesis of the Alkaloid Natural Product Oxomaritidine A New Paradigm for Molecular Assembly. Chemical Communications, 2566-2568. 

Sequential pyrrolidine and hydantoin ring-forming reactions via intramolecular [2+3] cycloaddition have been applied to the stereoselective solid-phase synthesis of conformationally constrained tricyclic triazacyclopenta [C]pentalene scaffold 43 < 1999JOC8342>. These novel compounds 43 share the structural complexity characteristic of certain alkaloid natural products, angular triquinanes. The retrosynthetic analysis is shown in Scheme 87. 

Baxendale IR, Deeley J, Griffiths-Jones CM, Ley SV, Saaby S, Tranmer GK (2006) A flow process for the multi-step synthesis of the alkaloid natural product oxomaritidine a new paradigm for molecular assembly. Chem Commun, p 2566-2568... 

Luciduline, as an example of an alkaloid whose synthesis -either in its racemic form or as the natural optically pure dextrorotatory enantiomer-, has been accomplished by different research groups following essentially two different strategies. One of the strategies involves the disconnection of the 1,3-C bifunctional... 

Keywords Alkaloids Natural products Photochemistry Terpenes Total synthesis... 

Recent advances in the Stevens rearrangement of ammonium ylides have been reviewed in terms of application to the synthesis of alkaloid natural products.147... 

Since the first publication, amine-catalyzed Diels-Alder reactions of a,/ -unsaturated aldehydes have been investigated in much detail [15, 26-33]. Catalyst immobilization studies on solid support [26, 27], as well as in ionic liquids [29], have shown advantages for amine recycling, while partially maintaining good levels of asymmetric induction [34]. The use of this reaction in total synthesis has allowed the rapid preparation of (+)-hapalindole Q, a tricyclic alkaloid natural product containing four contiguous stereocenters (Scheme 3.2) [28]. 

The highly diastereoselective intramolecular aza-Cope-Mannich reaction was used in the total synthesis of (i)-pancracine (11), an alkaloid natural product5... 

Synthesis of alkaloid natural products - epimaritidine and epibatadine... 

Scheme 7, Synthesis of the alkaloid natural product ( )-epimaritidine...

The closure of a bond between positions 12 and 19, presumably involved in the natural synthesis of aspidospermine-type alkaloids from quebrachamine, has been shown (18) to occur during the zinc dust distillation of the latter when a compound IX was isolated whose mass spectrum was exactly comparable with that of the indolenine VII, except for the 30-unit shift in the indole-containing fragments (Table V). Substance IX has subsequently been found in nature (Section II, E). 

The cyclopropylimine ynoline rearrangement (equation 68) has been exploited by Stevens in alkaloid syntheses. - Wenkert s cyclopropylcarbinyl rearrangement (equation 69) served extremely well in the design of 1,4-dicarbonyl synthons or 3,-y-unsaturated carbonyl compounds which then were expressed in numerous syntheses of terpenoid and alkaloid natural products. Donor-acceptor concepts continue to be express in the applicability of these rearrangements to organic synthesis. 

The Denmark laboratory has developed an elegant tandem [4 + 2]/[3 + 2]-cyclo-addition strategy for the synthesis of a variety of alkaloid natural products (96CR137). Nitroethylene (166) readily undergoes a Lewis acid promoted cycloaddition with vinyl ethers that contain a chiral auxiliary group to give nitronates 168... 

Mannich-type cyclizations of vinylsilanes have found considerable application in the area of alkaloid total synthesis. Cyclizations that occur in the exocyclic mode with respect to the vinylsilane nucleophile have been widely employed to assemble 3-alkylidenepiperidine substructures with high stereocontrol. Overman and coworkers have made extensive use of the acid-promoted conversion of bicyclic oxazolidines to alkylideneindolizidines in their total syntheses of pumiliotoxin A alkaloids (Scheme 36). - " - An illustration of the mild nature of iminium ion-vinylsilane cyclizations is provided in the conversion of (101) to (102), the penultimate precursor of (-i-)-pumiliotoxin A. This conversion was accomplished in 71% yield by heating (101) at 80 C in a methanolic pyridine-pyridinium tosylate buffer (pH 4.5). More strongly acidic conditions had to be avoided since they led to competitive solvolysis of the allylic benzyl ether functionality of the pumiliotoxin A side chain. To the limits of detection by high... 

Recent Advances In The Stevens Rearrangement Of Ammonium Ylides. Application To The Synthesis Of Alkaloid Natural Products Vanecko, J.A. Wan, H. West, F.G. Tetrahedron 2006, 62, 1043. 

Merging chemical synthesis and biosynthesis as a strategy of the total synthesis of natural products and natural product libraries 12AG(E)4012. Palladium-mediated total synthesis ofbioactive natural products 13S1271. Recent contributions from the asymmetric aza-Michael reaction to alkaloids total synthesis 13NPR1211. 

Overman and coworkers have extensively developed the utility of asymmetric Mizoroki-Heck reactions for constructing quaternary carbon stereocentres through various alkaloid total synthesis endeavours. A particular focus of these studies has been the catalytic asymmetric synthesis of enantioenriched 3,3-disubstituted oxindoles, because oxindoles of this type are versatile precursors of many natural alkaloids, hi an early, unanticipated discovery, it was found that either enantiomer of spirocychc oxindole 103 could be formed with moderate selectivity using a single enantiomer of a chiral diphosphine ligand (Scheme 16.24) [13]. Specifically, the use of Ag3P04 as an HI scavenger in the cyclization of 102 produced (S)-103 in 71% ee, whereas use of the amine base PMP under otherwise identical reaction conditions yielded (7 )-103 in 66% ee. 

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