Alkaloids total synthesis

Yoda, H. Recent Advances in the Synthesis of Naturally Occuring Polyhydroxy-lated Alkaloids Current Organic Chemistry 2002, d, 223-243. Casiraghi, G. Zanardi, F. Rassu, G. Pinna, L. Recent Advances in the Stereoselective Synthesis of Hydroxylated Pyrrolizidines. A Review Org. Prep. Procedures Int. 1996, 28, 641-682. Stevens, R. V. General Methods of Alkaloids Synthesis Acc. Chem. Res. 1977, 10, 193-198. Stevens, R. V. Alkaloid Synthesis Total Synth. Nat. Prod. 1977, 3, 439-554. 

The intramolecular cycloaddition reaction of enamides has been exploited in alkaloid synthesis (81JOC3763). One successful application is provided by the total synthesis of the fused indolizidine 5 from 4 as a 1 1 mixture of epimers in 43% total yield 5 is a key intermediate in aspidosperma alkaloid synthesis (79JA3294). 

The thermal reaction of the compound (318) may be chosen as an example to show the usefulness of the benzocyclobutene — o-xylylene rearrangement in alkaloid synthesis U1). On heating (318) at 120 °C, an intermediate product (319) was formed, which cyclized to give the compound (320). This method formulated the key step in the total synthesis of the alkaloid chelidonine (321) ni). 

A series of papers have been published by Lounasmaa et al. (122-128) on the synthesis of different alkaloid-like indolo[2,3-a]quinolizidine derivatives by means of reduction and subsequent cyclization of A-[2-(indol-3-yl)ethyl]piridi-nium salts, developed as a general method for indole alkaloid synthesis by Wenkert and co-workers (129, 130). Aimed at the total synthesis of vallesiachotamine (9), valuable model studies were reported (131-133). Reduction of pyridinium salts 183 and 184 with sodium dithionite and subsequent acid-induced cyclization represents a convenient method for preparing val-lesiachotamine-type derivatives 185 and 186, respectively. 

The A2-piperideines are capable of behaving as dehydrosecodine analogs in alkaloid synthesis. One of the first successful applications of this approach is provided by the total synthesis of the aspidosperma alkaloid minovine (234 Scheme 41) (73JA7146). 

In summary, the cycloaddition reactions of 1,2-dihydropyridines have proven to be very useful in the total synthesis of natural products. The primary reasons for their utility are that they have electron-rich reactive 7r-systems, they contain a heterocyclic nitrogen atom for alkaloid synthesis, and the stereochemistry is controlled in their cycloaddition reactions. 

Tohma H, Harayama Y, Hashizume M, Iwata M, Egi M, Kita Y (2002) Synthetic Studies on the Sulfur-Cross-Linked Core of Antitumor Marine Alkaloid, Discorhabdins Total Synthesis of Discorhabdin A. Angew Chem hit Ed 41 348... 

Kokas OJ, Banwell MG, Willis AC (2008) Chemoenzymatic Approaches to the Montanine Alkaloids A Total Synthesis of (+)-Nangustine. Tetrahedron 64 6444... 

A total of more than 20 total syntheses have been described which aim to generate the most important members of the morphinan-type alkaloids, morphine and codeine. These long-standing efforts in alkaloid synthesis have been primarily due to the exceptional pharmacological importance of both compounds, as the most efficacious therapies for pain and cough, respectively. 

Many of the alkaloids from Veratrum, Zygadenus and related genera are based on the cevane structure 1. The chemistry of the Veratrum alkaloids has been reviewed from time to time both in this treatise (1-3) and elsewhere (4-6). The most recent of these articles was published in 1973, and many new compounds have been discovered since then. Recent years have seen the announcement of many X-ray crystal structure determinations on these stereochemically complex alkaloids. A total synthesis has been reported for only one of the natural products, namely, verticine (7). The work that lead to this notable achievement has been reviewed (8). The pharmacology of both the alkaloids (9-12) and their synthetic derivatives (13) has been reviewed, although not since 1977. This chapter takes a different approach from previous reviews. The chemical reactions used for structure determination and modification are first summarized, but the main part of the chapter is a series of tables which include all the known cevane derivatives, both old and new. This is intended as a reference source for future workers in the field. The literature has been covered to the end of Volume 113 of Chemical Abstracts (1990). 

Pandey, G., Murugan, A., and Balakrishnan, M. (2002) A new strategy towards the total synthesis of phenanfhridone alkaloids synthesis of... 

For the synthesis of pandoline (284) and 20-epi-pandoline (285), the epoxy-aldehyde (286) was condensed with the indolo-azepine (278) (Scheme 40) the result was an equimolecular mixture of the two alkaloids, in total yield of 64%, based on (278). In accordance with earlier observations, pandoline and 20-epi-pandoline can be reduced to the velbanamine derivatives (287) and (288), which can be isomerized to the C-16 epimers (289) and (290). These compounds contain, respectively, the complete structure and stereochemistry of the non-vindoline component of the oncolytic alkaloids leurosidine and vinblastine. 

Total synthesis of protoberberine alkaloids via the route involving enamide photocyclization consists of nonoxidative photocyclization of the 2-aroyl-l-methylene-3,4-dihydroisoquinolines and the subsequent metal-hydride reduction of the photocyclized lactams. This simple combination of reactions for alkaloid synthesis provides one of the most convenient synthetic routes to this group of popular alkaloids. 

Martin SF, Li W (1989) General Methods for Alkaloid Synthesis via Intramolecular Diels-Alder Reactions. A Concise Formal Total Synthesis of ( )-Dendrobine. J Org Chem 54 268... 

Lee CH, Westling M, Livinghouse T, Williams AC (1992) Acybiitrilium Ion Initiated Heteroannulations in Alkaloid Synthesis. An Efficient, Stereocontrolled, Total Synthesis of Orchidaceae Alkaloid ( )-Dendrobine. J Am Chem Soc 114 4089... 

Solanidine-type steroid alkaloids, synthesis and reactions 88MI6I. Streptonigrin, total syntheses of 84MI30. 

Indole alkaloids, synthesis and biosynthesis of 87H(25)617. Yohimbine, total synthesis of 90YGK206. 

The advantages of Robinson s concept was confirmed in numerous total syntheses of alkaloids. One of the most illustrative examples is served by Stevens synthesis of the tricyclic compound coccinelline 45 (Scheme 3.10), the pheromone of the ladybug (ladybird). As was acknowledged in Stevens review article, in less time than it took to write this paragraph, we had developed on paper an attractive approach that relies on one of the oldest reactions known in alkaloid synthesis, namely the classical Robinson-Schopf condensation . This approach involved the retrosynthetic transformation of 45 into the ketopiper-idine derivative 46, which is amenable to disconnection in accordance with the same logic as used by Robinson in the analysis of tropinone. 

Simple, neutral electron-rich imines are generally not useful dienophiles unless q>propriately reactive dienes are used. Thus it is possible to effect cycloadditions of neutral imines with some electron-deficient dienes. - In a series of p rs, Langlois and coworkers have described Diels-Alder reactions of cyclic imines and methyl 2,4-pentadienoate to afford adducts used in alkaloid synthesis. For example, the cycloadditicMi shown in equation (IS) was used in a total synthesis of the indole alkaloid vincamine (45). 

Liu, X., Cook, J. M. General Approach for the Synthesis of Sarpagine/Macroline Indole Alkaloids. Enantiospecific Total Synthesis of the Indole Alkaloid Trinervine. Org. Lett. 2001, 3,4023-4026. 

Since the monumental accomplishments of Woodward s total syntheses of strychnine in 1954 [I] and rcserpinc in 1958 (2], the arsenal of synthetic methods in indole alkaloid synthesis has greatly expanded. In the same time period, the use of palladium chemistry in organic syntheses has also witnessed tremcndou- growth with an ever-expanding repc loire of synthetic methods and their applications to total synthesis. The use of palladium chemistry for the synthesis of indole alkaloids has been explored, and several examples have been included in recent reviews [3-6]. This account attempts to present a comprehensive collection of total syntheses of naturally occurring indole alkaloids where palladium chemistry plays a central role in the syntheses. 

Another advantage of lead compounds is their ability to tolerate a variety of functional groups. This is noticeable from their usefulness in modern syntheses of complex natural products, one of the main subjects of this chapter. In early studies, for example, Pb(OAc)4 found particular application in alkaloid synthesis [28]. Donnelly and Finet have focused on the compact array of aromatic rings found in several members of the flavonoid family [29] by use of organolead species. A review of this new approach to arylation reactions with aryllead compounds can also be found in the total synthesis of natural products [30]. 

The material is presented in a similar order to that used in last year s report1" on this group of alkaloids, but this year bis-indole alkaloids are included in this section. Within each sub-section the order is (i) mention of full reports which contain material already reviewed, (ii) isolation of known alkaloids from different plants, (iii) new physical measurements on known alkaloids or systems, (iv) new chemistry of known alkaloids or systems, (v) new structures, together with supporting chemical and physical evidence, (vi) synthesis of model systems, (vii) partial synthesis of alkaloids, (viii) total synthesis of alkaloids. 

The third total synthesis of strychnine (1), so far the only enantioselective route to the natural product, was accomplished by Overman et al. [10] The key to their approach to 1 is the sequential cationic aza-Cope rearran-gement/Mannich cyclization, which is frequently employed with success in alkaloid synthesis. With the synthesis of akuammicine rac-19 the authors proved that this strategy offers an efficient route to the strychnos alkaloids. [8g]... 

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