Synthesis of the Skeleton

In general 3-benzylidenechroman-4-ones are prepared by condensation of chroman-4-ones with aromatic aldehydes (72). Strong alkaline (55) or acidic (75) conditions can be applied only if eventual sensitive substituents are suitably protected. Using dry hydrogen chloride in acetic acid Boehler and Tamm synthesized 5,7-di-O-methyleucomin (33) from 5,7-dimethoxychroman-4-one and anisaldehyde (9). Later Krishna-MURTY et al. (45) observed the simultaneous formation of a C-6 or C-8 a-chlorobenzylated product (34) in this reaction. Starting from O-benzoylated compounds 5,7-di-O-benzoyleucomin (35) and 4, 5,7-tri-0-benzoyl-4 -demethyleucomin (36) are easily prepared by this method using diethyl ether and ethyl acetate as solvents respectively (45). The unprotected phenolic compounds can be condensed successfully in boiling acetic anhydride (23, 24). The relatively low yield of 5,7-di-O- 

Ravish and Kirkiacharian (60) reported on a new and effective condensation procedure which employs a mixture of acetic acid and piperidine as solvents. This combination is known to possess mild acid as well as base-catalytic properties. 

In a different approach dihydrochalcones have been transformed to 3-benzyl-4-chromones. Treatment of (37) with ethyl formate and sodium led to (38) which on hydrogenation and selective demethylation yielded racemic 4 -0-methyl-3,9-dihydropunctatin (18) (25). A modified method 

Other possible intermediates are 3-benzyl-4-hydroxycoumarins. Starting from the parent compound (41) the reaction to 3-benzyl-4-chromone (42) is achieved in moderate yield by reduction with diborane, followed by oxidation with sodium bichromate in aqueous sulfuric acid 42). 

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Chemoselective C-alkylation of the highly acidic and enolic triacetic acid lactone 104 (pAl, = 4.94) and tetronic acid (pA, = 3.76) is possible by use of DBU[68]. No 0-alkylation takes place. The same compound 105 is obtained by the regioslective allylation of copper-protected methyl 3,5-dioxohexano-ate[69]. It is known that base-catalyzed alkylation of nitro compounds affords 0-alkylation products, and the smooth Pd-catalyzed C-allylation of nitroalkanes[38.39], nitroacetate[70], and phenylstilfonylnitromethane[71] is possible. Chemoselective C-allylation of nitroethane (106) or the nitroacetate 107 has been applied to the synthesis of the skeleton of the ergoline alkaloid 108[70]. 

Some older examples of this type of process include the studies of Marko on the synthesis of pseudomonic acid C analogues [118], the preparation ofindanones by Snider [119], and synthesis of the skeleton of the sesquiterpenes khusiman and zi-zaen by Wenkert and Giguere and their coworkers [120, 121]. 

The use of vinylallenes as the diene component in Diels-Alder reactions is very common, thus resulting in their ubiquitous use in natural product synthesis. A vinylal-lene has even been proposed by Schreiber and Kiessling [10] as a biogenetic intermediate in the synthesis of the skeleton of esperamicin A (32 —> 33). Their synthetic approach to esperamicin A (34) was modeled after this biogenetic proposal in which a Type II intramolecular Diels-Alder cycloaddition was used to gain access to the highly unsaturated bicyclic core of 34 (Scheme 19.8) [10]. 

A twofold intramolecular Heck reaction has been employed as a key step for the synthesis of the skeleton of the natural product (—)-chimonanthine 58 (Scheme 19). The synthetically most challenging structural features of this bispyrro-loindoline alkaloid are its two adjacent quaternary centers. They were both built up by intramolecular double-bond carbopalladations, which stereoselectively produced the pentacycle 57 from the f72-symmetrical bis[A-(2-iodophenyl)-cyclohexane-1,2-dicarboxamide 55 via the intermediate 56. The key intermediate 57 was thus obtained as a single enantiomer in 90% yield. 

Although the anodic generation of a cation in a-position to nigrogen in aliphatic amines is not difficult, this type of reaction is not always useful to the synthesis of alkaloidal compounds, since the cation is not stable and a simple dealkylation is the usual follow-up reaction. N-monomethyl and N,N-dimethylanilines are, however, useful starting materials for the synthesis of the skeleton of tetrahydroquinoline. The anodic methoxylation of N,N-dimethylaniline 20 takes place at the methyl group, and an iminium ion intermediate 22 is easily generated by treatment of the methoxylat-ed product 21 with Lewis add. This intermediate can be trapped in situ with a variety of nucleophiles such as electron-rich olefins yielding tetrahydroquinolines 23 16). 

Tetracyclization. The Heathcock group1 has described a remarkably short and efficient synthesis of the skeleton of Daphniphyllum alkaloids (2) by reaction of the dialdehyde 1 with gaseous ammonia and then dissolution in acetic acid at 70°. The yield is 77%, based on the diol precursor to 1. The azadiene a and the imine b have both been isolated and identified. The conversion of a to b is an intramolecular Diels-Alder type reaction. The tetracyclization may well be involved in the biosynthesis of alkaloids such as Daphnilactone A (3). 

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). 

The use of enamide photocyclization in the synthesis of Amaryllidaceae alkaloids has remained a basic study and so far limited only to the synthesis of the skeletons of lycorine and crinine, as well as intermediates in the total synthesis of haemanthidine and nortazettine, and some of the degradation products of these alkaloids. 

Yamamoto K, Kawasaki I, Kaneko T (1970) Synthesis of the Skeleton of Dendrobine. Tetrahedron Lett 11 4859... 

The efficiency of this method is impressively proved by the synthesis of the skeleton of shikimic and chinic acid starting from an open chain sugar derivative and the synthesis of optically active cyclopent-anediol synthetic building blocks from tartaric acid. ... 

Synthesis of the skeleton of the morphine molecule by mammalian liver Weitz, Charles J. Faull, Kym F. Goldstein, Avram... 

Heathcock s synthesis of the strange polycyclic terpene copaene (16) illustrates this approach well. Copaene was made from ketone (17) by a series of relatively trivial reactions it is the synthesis of the skeleton (17) which is interesting. The central four-mem bered ring contains all the common atoms ( in 17) but disconnection of any two bonds, e.g. by a 2 + 2 approach to give (18), gives a difficult ten-membered ring. 

The synthesis of the skeleton of these two monoterpenic alkaloids and the control of the relative stereochemistry at C4, CS, and C6 was aehieved using a Wolff rearrangement followed by a photoreductive cyclization of unsaturated Af-alkyl-2-oxo-cyclopentane carboxamides of type D (Scheme 40). 

Fujimoto, H., and O. Tanaka Synthesis of the Skeleton of Dammarane Type Triterpene. Chem. Pharm. Bull. (Japan) 18, 1440 (1970). 

The acetate (238) has also been used for the synthesis of the skeleton... 

Amide Formation. The synthesis of an amide can be accomplished by initial reaction of an acid with PhsP-CCU and then reaction of the intermediate with 2 equiv of the appropriate amine. A tertiary amine, such as Diisopropylethylamine, can be employed as the HCl scavenger in cases where one would not want to waste any of a potentially valuable amine.This method has been used in the construction of an amide in the synthesis of the skeleton of the lycorine alkaloids (eq 29). ... 

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