Synthesis of the Alkaloids

There have been more than 10 syntheses of physostigmine (1) and 

Improved syntheses based on classical routes such as the Fischer indolization route and the oxindole alkylation route have also been reported. The former could provide substantial amounts of the racemic alkaloids, while the latter made possible the practical production of both the natural and the unnatural enantiomers of the alkaloids with the development of a highly efficient method for resolving the racemic intermediate. The latter may be particularly interesting from the pharma- 

The photochemical valence isomerization of 1,2-dihydronaphthalenes to l,la,2,6b-tetrahydrocycloprop[Z ]indenes (e.g., 30 31) is well estab- 

3-dipolar intermediate and internal cycloaddition toward the nonac-tivated double bond in a single operation. 

The aminoolefin (82) obtained from the acetanilide 80 in a three-step sequence of reactions was converted to the formamide 83 in 88% yield by sequential formylation and methylation. Treatment of 83 with methyl trifluoromethanesulfonate followed by trimethylsilylmethylamine gave the formamidine 84 in 77% yield. Methylation of 84 with methyl trifluo-romethanesulfonate, followed by exposure of the resulting salt (24) to tetra-zi-butylammonium fluoride brought about a facile generation of the 

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Aldehyde 198 served as a key intermediate in a synthesis of the alkaloid ajmaline. The. Mannich aminomethylation transform triggers disconnection of two bonds in 198 to form dialdehyde 199, which by connective transform application can be converted to cyclopentene 200.58,59 The reduction in functional group reactivity and in structural complexity are both apparent by comparison of 198 and 200. 

The validity of this formula for ricinine was established by the same authors synthesis of the alkaloid from 4-chIoroquinoline (I). The... 

A number of other syntheses of coniine have been effected, of which that of Diels and Alder is of special interest. The initial adduct of pyridine and methyl acetylenedicarboxylate, viz., tetraraethylquinolizine-1 2 3 4-tetracarboxylate (IX) on oxidation with dilute nitric acid is converted into methyl indolizinetricarboxylate (X). This, on hydrolysis and decarboxylation, furnishes indolizine, the octahydro-derivative (XI) of which, also known as octahydropyrrocoline, is converted by the cyanogen bromide method (as applied by Winterfeld and Holschneider to lupinane, p. 123) successively into the broraocyanoamide (XII), cyanoaraide (XIII) and dZ-coniine (XIV). A synthesis of the alkaloid, starting from indolizine (pyrrocoline) is described by Ochiai and Tsuda. ... 

B. HCl, m.p. 242-3°). The methiodide, m.p. 104-7°, of this, on treatment with potassium hydroxide in methyl aleohol, yielded 5 6-pimethoxy-8-vinylphenanthrene, m.p. 86-7°, along with dimethyl-de-iV-methylnorroemerine, oil, [aju + 13-55° (EtOH) the methiodide, m.p. 278°, of this, on like treatment also yielded 5 6-dimethoxy-8-vinyl-phenanthrene, whose identity was established by its oxidation by permanganate to 5 6-dimethoxyphenanthrene-8-earboxylie aeid. Rcemerine is, therefore, 5 6-methylenedioxy-iV-methylaporphine, and this eon-stitution has been confirmed by Marion and Grassie s synthesis of the alkaloid. 

On treatment of N-methylpapaverine, formed by the lithium aluminum hydride reduction of papaverine methiodide with phosphoric acid, N-methylpavine is formed which is identical with the racemic alkaloid argemonine. This reaction was used for the synthesis of the alkaloid (-h)-coreximine (268) (174) and similar compounds containing the proto-berberine grouping in the molecule (269,270). 

In synthesis of the alkaloid tjipanazole E (19b), the required symmetric dichloro-indolo[2,3-fl]carbazole 20a was obtained in a two-step procedure starting fi-om 4-chlorophenylhydrazine hydrochloride and 1,2-cyclohexanedione employing a Fischer indolization. Subsequent attachment of an acetyl-protected glucopyranosyl moiety to one of the nitrogens, followed by cleavage of the protective groups with ammonia in methanol, produced the desired natural product (91X7739). 

Indolo[3,2-fl]pyrrolo[3,4-c]carbazoles 120 have been obtained in one step from indole and the corresponding maleimides in acetic acid, with coformation of the Michael adducts 121 (Scheme 15). This reactitai required careful temperature control in order to obtain the desired product ratios. An alternative independent synthesis of compounds 120 could also be accompKshed from 2,3 -biindolyl (115) andsuitable maleimides in hot acetic acid (99T2363). The system 120 where R = H has also been reported as a minor product during studies toward a synthesis of the alkaloid arcyriaflavin A (95TL2689). 

RCM of a dienyne was also a key step in Mori s recent total synthesis of the alkaloid erythrocarine (447) [183]. The tetracyclic framework of447 was elaborated in the penultimate step, by exposing the hydrochloride of metathesis precursor 445 (1 1 diastereomeric mixture at the carbinol center) to first-generation catalyst A. The tandem process occurred smoothly within 18 h at room temperature leading to tetracycles 446 (1 1 mixture) in quantitative yield. Deprotection of the a-acetoxy isomer 446a led to 447 (Scheme 88). 

Bicyclic compounds of structure (4) are needed for the synthesis of the alkaloid dendrobine. What is the starting material for a Diels-Alder synthesis of (4) Stereochemistry is obviously vital here. 

Figure 4.60 shows a synthesis map for various starting materials for the synthesis of the alkaloid reserpine. Metrics for 10 plans are summarized in Table 4.27. The Liao and Stork plans are the best performers overall, however the Pearlman plan has the highest atom... 

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. 

Ley, S.V., Schucht, O., Thomas, A.W., Murray, P.J. (1999) Synthesis of the Alkaloids ( )-Oxomaritidine and ( )-Epimaritidine Using an Orchestrated Multi-Step Sequence of Polymer Supported Reagents. Journal of the Chemical Society Perkin Transactions I, 1251-1252. 

The first few steps in a synthesis of the alkaloid conessine produce 9B, starting from 9A. Suggest a sequence of reactions for effecting this conversion. 

The product of the reaction in Entry 8 was used in the synthesis of the alkaloid pseudotropine. The proper stereochemical orientation of the hydroxy group is determined by the structure of the oxazoline ring formed in the cycloaddition. Entry 9 portrays the early stages of synthesis of the biologically important molecule biotin. The reaction in Entry 10 was used to establish the carbocyclic skeleton and stereochemistry of a group of toxic indolizidine alkaloids found in dart poisons from frogs. Entry 11 involves generation of a nitrile oxide. Three other stereoisomers are possible. The observed isomer corresponds to approach from the less hindered convex face of the molecule. 

Scheme 10.12 gives some examples of enantioselective cyclopropanations. Entry 1 uses the W.s-/-butyloxazoline (BOX) catalyst. The catalytic cyclopropanation in Entry 2 achieves both stereo- and enantioselectivity. The electronic effect of the catalysts (see p. 926) directs the alkoxy-substituted ring trans to the ester substituent (87 13 ratio), and very high enantioselectivity was observed. Entry 3 also used the /-butyl -BOX catalyst. The product was used in an enantioselective synthesis of the alkaloid quebrachamine. Entry 4 is an example of enantioselective methylene transfer using the tartrate-derived dioxaborolane catalyst (see p. 920). Entry 5 used the Rh2[5(X)-MePY]4... 

Another very new radical/radical domino procedure was used in the total synthesis of the alkaloid lennoxamine by Ishibashi and coworkers. Here, a 7-endo cycliza-tion/homolytic aromatic substitution reaction cascade led to the target compound in 41% yield [75]. 

Officially, the history of MCRs dates back to the year 1850, with the introduction of the Strecker reaction (S-3CR) describing the formation of a-aminocyanides from ammonia, carbonyl compounds, and hydrogen cyanide [4]. In 1882, the reaction progressed to the Hantzsch synthesis (H-4CR) of 1,4-dihydropyridines by the reaction of amines, aldehydes, and 1,3-dicarbonyl compounds [5], Some 25 years later, in 1917, Robinson achieved the total synthesis of the alkaloid tropinone by using a three-component strategy based on Mannich-type reactions (M-3CR) [6]. In fact, this was the earliest application of MCRs in natural product synthesis [7]. 

A similar strategy served to carry out the last step of an asymmetric synthesis of the alkaloid (—)-cryptopleurine 12. Compound 331, prepared from the known chiral starting material (l )-( )-4-(tributylstannyl)but-3-en-2-ol, underwent cross-metathesis to 332 in the presence of Grubbs second-generation catalyst. Catalytic hydrogenation of the double bond in 332 with simultaneous N-deprotection, followed by acetate saponification and cyclization under Mitsunobu conditions, gave the piperidine derivative 333, which was transformed into (—)-cryptopleurine by reaction with formaldehyde in the presence of acid (Scheme 73) <2004JOC3144>. 

A recent formal synthesis of the alkaloid (—)-mitralactonine relied on a reaction that allowed the simultaneous creation of three new bonds, two of them a and one ft with respect to the quinolizine nitrogen. As shown in Scheme 112, treatment of triptamine with chiral aldehyde 480 in the presence of acid directly gave a mixture of diastereo-meric indoloquinolizidines 481 and 482 through a mechanism involving a Pictet-Spengler cyclization and a N-alkylation reaction <2007SL79>. 

So far only a few examples of the uses of organosilicon compounds in cross-couplings have been published. Noteworthy is the smooth reaction with a sterically hindered substrate (87).295 The synthesis of the alkaloid nitidine included a cross-coupling step using an alkenylsilane (88),296 while the syntheses of some antitumor agents involved the alkenylation of unprotected iodouracyls using alkenyl-silicon species.297... 

Allenes behave as somehow special olefins in such photocycloadditions 476a,b,477) Additions of enones to allene have been used as key step in the synthesis of the alkaloids annotinine 478a) (4.65) and chasmanine (4.66) 478b). 

Pseudopelletierine has been obtained from the bark of the pomegranate tree (Punica granatum L.).2-5 The synthesis of the alkaloid from glutaraldehyde, methylamine, and calcium acetonedicarboxylate was first achieved by Menzies and Robinson.6 The synthetic method subsequently was improved by Schopf and Lehmann,7 and others.8 9 The condensation of a dialdehyde with an amine and acetonedicar-boxylic acid to form a heterobicyclic compound (an alkaloid or alkaloid analog, usually employing mild or so-called physiological conditions) is sometimes referred to as a Robinson-Schopf synthesis. 

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... 

Ley SV, Baxendale IR (2002b) New tools and concepts for modern organic synthesis. Nat Rev Drug Disc 1 573-586 Ley S V, Massi A (2000) J Comb Chem Polymer supported reagents in synthesis preparation of bicyclo[2.2.2]octane derivatives via tandem michael addition reactions and subsequent combinatorial decoration. 2 104—107 Ley SV, Schucht O, Thomas AW, Murray PJ (1999) Synthesis of the alkaloids ( )-oxomaritidine and ( )-epimaritidine using an orchestrated multi-step sequence of polymer supported reagents. J Chem Soc Perkin Trans 1 1251— 1252... 

A copper-catalyzed one-pot three-component atom-economical C-H functionalization process was used to form enantioenriched propargylamines. This protocol was also employed for the synthesis of the alkaloid (A)-(+)-coniine (Equation (196)).159 159a... 

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). 

Somei adapted this chemistry to syntheses of (+)-norchanoclavine-I, ( )-chanoclavine-I, ( )-isochanoclavine-I, ( )-agroclavine, and related indoles [243-245, 248]. Extension of this Heck reaction to 7-iodoindoline and 2-methyl-3-buten-2-ol led to a synthesis of the alkaloid annonidine A [247]. In contrast to the uneventful Heck chemistry of allylic alcohols with 4-haloindoles, reaction of thallated indole 186 with 2-methyl-4-trimethylsilyl-3-butyn-2-ol affords an unusual l-oxa-2-sila-3-cyclopentene indole product [249]. Hegedus was also an early pioneer in exploring Heck reactions of haloindoles [250-252], Thus, reaction of 4-bromo-l-(4-toluenesulfonyl)indole (11) under Heck conditions affords 4-substituted indoles 222 [250], Murakami described the same reaction with ethyl acrylate [83], and 2-iodo-5-(and 7-) azaindoles undergo a Heck reaction with methyl acrylate [19]. 

The synthesis of the alkaloid (—)-dendroprimine is obtained via a piperidine derivative obtained through a one-pot azaelectrocyclization protocol <20060L3813>. A new synthesis of ( )-tashiromine is also reported <2006JOC704>. 

This reaction was used to effect a polyolefin cyclization in a synthesis of the alkaloid yohimbone (3).2 Thus reaction of the trifluoroacetate of 1 with HCHO provides a 63% yield of 2, which was converted into 3 by a six-step sequence (10% overall yield). 

Such lanthanide catalysts were also used in hydroamination/cyclization strategies for the synthesis of the alkaloid (+)-xenovenine. This reaction of enantiomerically pure 147 leading to 148 via two C-N bond formations was used in a late step of the synthesis after a hydrogenation, the natural product was isolated (Scheme 15.46) [100]. 

The first step in the total synthesis of the alkaloid ( )-ipalbidine 104 was the reaction of the diene 103 with A1-pyrrol ine (equation 60)53. The proportions of threo- and m // TO-dihydro- -pyridones, 106 and 107, respectively, produced in the diethylaluminium chloride-catalyzed reactions of the a-benzyloxyimines 105 (R = n-CsHn, i-Pr or i-Bu) with the diene 86 (equation 61), depend on the nature of R and the amount of imine used54. 

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