Applications to Alkaloid Synthesis

Since only two of the four possible addition products (9) were formed, one may surmise that SKT was not responsible for the low selectivity. The minor isomer was the I (thieo) addition product. The reasons lor the loss of selectivity arc not known, but undoubtedly involve very subtle differences in Grignard structure, possibly caused by the lithium cnrboxylaic and the two mellioxy substituents, although neither of these components on their own caused a loss of selectivity U f. Table 5.2, entry 2 and Table 5.3, entry I). 

SCHEME 5.8. Seebach s synthesis of [- )eorluntine using a cliiral tcirahydroisoquinoline cduei 145.  

SCHEME 5.9. Generality l tlte c.unplini-iiciiscd ow.oltnc dtirai atisili.ny. U.49 and analysis nl the enamiomet ratio by chiral stationary phase Hl I.C 54  

SC IIKMK 5.10. Synthetic iargeis and rcirosyniliciic analysis tor phllialnle isni iiiiHiiiiies using ihe euin[ linr-oxa/olinc ehirul auxiliary 1.12.-lfi.671. 

She then developed a successful approach using the valine-derived oxii/nlinc auxiliary t.V-4-iso-propyloxa/oline Table 5.5. entries 5 X) 46.67. Later. Pingsheng /.hang opiimi/cd the process with a better auxiliary as indicated by the examples in 

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The photocyclization reaction of acrylanilide to 3,4-dihydroquinolinone was first reported in 1971, and its application to alkaloid synthesis has long been studied [44], Although stereo- and enantio-control are important in this reaction, no such attempt has been reported, except one enantioselective photocyclization of 1-(methylacryl)-A-methylanilide (85) in benzene-ether containing (i )-bis(/>tolu-oyl)tartaric acid to give ( )-3-methyl-A-methyl-3,4-dihydroquinolinone (87) of 12-16% ee [45],... 

Taking particular consideration of the application to alkaloid synthesis, enamides are divided into four groups depending on the nature of the... 

Applications to alkaloid synthesis are exemplified by the construction of the morphinan ring system (I) and synthesis of the oxocrinine analog (II). 

The synthesis of /8-chloro-a-cyanoenamines from JV-l-(2,2-dichloroalky-lidene)amines has been described/ " and the geminal acylation-alkylation of regiospecifically generated metalloenamines/ and applications to alkaloid synthesis/ have been reported. 

This methodology has the potential to be generally applicable to the synthesis of various alkaloids that have a bridgehead nitrogen via the intramolecular aza-Diels-Alder reaction (Eq. 12.43).108... 

Buchwald parlayed the powerful Buchwald-Hartwig aryl amination technology [439-447] into a simple and versatile indoline synthesis [448-452], For example, indole 368, which has been employed in total syntheses of the marine alkaloids makaluvamine C and damirones A and B, was readily forged via the Pd-mediated cyclization shown below [448], This intramolecular amination is applicable to the synthesis of -substituted optically active indolines [450], and o-bromobenzylic bromides can be utilized in this methodology, as illustrated for the preparation of 369 [451]. Furthermore, this Pd-catalyzed amination reaction has been applied to the synthesis of arylhydrazones, which are substrates for the Fischer indole synthesis [453,454],... 

Intramolecular bicyclization of tosylamide with alkynyliodonium salt (see Scheme 31), developed by Feldman and co-workers (95JA7544), is also applicable to the synthesis of A-tosylpiperidine derivatives related to polycyclic alkaloids (Eq. 40). Examples leading to seven-membered rings have also been reported. 

A review which describes recent developments of the aza-Wittig rearrangement and its application in alkaloid synthesis has appeared.212 The aza-[2,3]-Wittig rearrangement (157) (158) has been shown to be accelerated by the incorporation of certain... 

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

The amidoalkylation is conveniently applicable to the synthesis of alkaloid type compounds. Some examples are shown below. 

Interestingly, the anodic oxidation of N-methoxycarbonylpiperidine derivatives 41 in AcOH affords 2,3-diacethoxylated products 42. This reaction is conveniently applicable to the synthesis of Conium alkaloids such as pseudoconhydrine 28). 

This substitution method has been extended to an annelation reaction which is applicable to the synthesis of berbine (berberine) type alkaloids 55. 

Pearson, W.H. and Stoy, P. (2003) Cydoadditions of nonstabilized 2-azaallyllithiums (2-azaallyl anions) and azomethine ylides with alkenes [3 +2] cydoaddition approaches to pyrrolidines and application to alkaloid total synthesis. Synlett, 903—921. 

The structural diversity and pharmacological activity associated with this class of alkaloids have stimulated synthetic activity by numerous groups[23]. However, the route which can be applicable to the synthesis of both cis- and /raws-fused ring systems has been reported only to a limited extent[24]. Moreover, no methodology for the divergent synthesis of the 2,8a-c/s and -trans substituted ring system has been reported to date. 

Trost s synthesis138 of desethylibogamine (233) illustrates the application of a new approach to alkaloid synthesis, in which the two vital cyclization processes involve catalysis by palladium complexes protection of the nitrogen by formation of an amide, so often necessary in conventional syntheses, is here unnecessary. The first of the cyclization processes, (234)—>(235), results in a very neat formation of the isoquinuclidine ring system via a palladium-catalysed SN2 cyclization of the tryptamine derivative (234) (Scheme 24). 

Hydrastine has been prepared by the hydrogenolysis of the 1-phenyl-l/f-5-tetrazolyl ether of (—)-a-narcotoline,154 and in the racemic form by the reductive cyclization of the quaternary salt of the keto-acid (53) that is obtained from oxidoberberine (51) as described above.133 The lactone (80), prepared by the dye-sensitized photo-oxidation of oxidonorcoralyne followed by reduction with sodium borohydride and from 6 -acetylpapaveraldine by oxidation with hypo-bromite followed by reduction, has been TV-methylated and reduced with sodium borohydride to an isomer of cordrastine.133 Cordrastine itself has been synthesized by the electrolytic reduction of a mixture of the iminium salt (81) and bromomeconine (82), a process that has been shown to be of general applicability to the synthesis of alkaloids of this group.155... 

The first observation was N— C acyl migration on irradiation of N-acylenamines (4-10). However, when A-benzoylenamines were irradiated, a new photocyclization reaction was discovered (9,10), and since has been developed for use as a synthetic tool with general applicability to the synthesis of various alkaloids. As a result, it is now firmly established as enamide photocyclization. 

Started in the late 1960s, studies on enamide photocyclization and its application to the synthesis of alkaloids have been successfully accumulated and have achieved a number of total syntheses of various types of isoquinoline and indole alkaloids and related heterocyclic compounds (11). 

The phenanthridine skeleton is synthesized by photocyclization of the enamides prepared from cyclohexanonimines and benzoyl chlorides (17,18). The benzo[c]phenanthridine skeletons are formed from the enamides prepared from 2-tetralonimines and benzoyl chlorides (19,20). More conveniently, the skeletons of protoberberine alkaloids are readily synthesized from the enamides prepared by simple acylation of 1 -methyl-3,4-dihy-droisoquinolines with benzoyl chlorides (21-24). This berbine synthesis is one of the most typical examples of the application of enamide photocyclization to alkaloid synthesis and can be further extended to the facile synthesis of the skeletons of the yohimbine group of indole alkaloids (25,26). 

In this chapter, we first summarize more or less basic works on the synthesis of the common and basic skeletons of various types of natural alkaloids, aiming at their application to total synthesis, and also those works that seem applicable to the above syntheses, and then collected works on total syntheses of alkaloids via the route involving enamide cyclization. 

Crinane. A stereoselective synthesis of ( )-crinane was reported as the first application of nonoxidative photocyclization of an enamide to alkaloid synthesis (79,80). Acylation of the benzylimine of 2-allylcyclohexanone with piperonyloyl chloride gave a mixture of two isomeric enamides, 47 and 48, which were converted to the homogeneous enamide 48 by simple heating or irradiation with a high-pressure mercury lamp. Irradiation of the... 

Pedro Molina Buendla was born in Totana (Murcia), Spain, in 1945. He received his Ph.D. in organic chemistry at the University of Murcia in 1973. After a postdoctoral stay at the University of East Anglia (UK) with Professor A. R. Katritzky (1975-77), he joined the University of Murcia where he became full professor in 1982. His interests focus on the development of iminophos-phorane-bassed synthetic methods and their applications to the synthesis of marine alkaloids, nitrogen-substituted metallocenes, and chemosensors. 

Martin SF, Li W (1991) Applications of Intramolecular Diels-Alder Reactions to Alkaloid Synthesis. A Formal Total Synthesis of ( )-Dendrobine. J Org Chem 56 642... 

Shishido. K., Hiroya, K.. Fukumoto, K., and Kametani, T., Highly efficient constniction of the 7-axabicyclo[3.3.l non-2-cnc system. An application to the. synthesis of the AEF ring system of the aconitine-type diterpcnc alkaloids, J. Chem. Res. Synop., 100,1989 Chem. Abstr.. 112.21174, 1990. 

Kouznetsov VV (2009) Recent synthetic developments in a powerful imino Diels-Alder reaction (Povarov reaction) application to the synthesis of V-polyheterocycles and related alkaloids. Tetrahedron 65 2721-2750... 

Oxosilicine (163), a new alkaloid of a Malagasy plant, Hazunta silicicola Pichon, has an a-acylindole structure related to 20-epiervatamine. Although details of the isolation are still not available, the synthesis of (163) has already been announced (Scheme 19) this constitutes the first total synthesis of an alkaloid of the dihydrovobasine-ervatamine group. The major feature of the route adopted is that the acylindole linkage is formed at the outset, and the bond to C-7 (indole jS -position) formed much later. This route may well be applicable to the synthesis of other 2-acylindole alkaloids. 

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