Erythrinane derivatives

Several c/s-erythrinan derivatives have been synthesized in Mondon s laboratories 17 e.g., the cycloerythrinane (16a) was obtained by heating the bromo-compound (15) with potassium hydroxide in diethylene glycol at 180 °C. On hydrolysis, it yielded the keto-amide (16b), which afforded the amide (16c) and the amine (16d) via the unsaturated amide (17). Bromination of the ketone... 

Another approach to the erythrinan skeleton has been developed (Scheme 3).11 The hexahydro-indolone (23), readily available from indoline (21) via the imino-enol ether (22), underwent cyclization [in very low yield (4%)] on treatment with phosphorus oxychloride to give the erythrinan derivative (24). Uncyclized compound (25) was identified as a by-product (16%) in this reaction. This latter compound was formed in 47% yield, with no product (24), when the cyclization was attempted in chloroform solution. Extensive variation of reaction conditions failed to give reasonable yields of the required compound (24). 

Only in tw o cases has an erythrinane derivative of trans geometry been reported ... 

A more efficient asymmetric approach to the erythrinane core has been achieved by utilizing a bicyclic lactam template of Meyers. In the present case condensation of racemic cyclohexanoylacetic acid (64) with the chiral benzylaminoethanol 63 stereoselectively gives the required tricyclic lactam 65, which on treatment with titanium tetrachloride has been cyclized - via the A-acyliminium intermediate 66 - to the desired erythrinane derivative 67 with 98% yield. Finally, the hydroxymethyl auxiliary group at the 10-position has been readily removed by an established three-step procedure affording the chiral (—)-3-demethoxy-tetrahydroerysotramidine (68) (61) (Scheme 7). 

Reactions of 3- and 4-piperidone-derived enamines with a dienester gave intermediates which could be dehydrogenated to tetrahydroquinolines and tetrahydroisoquinolines (678). The methyl vinyl ketone annelation of pyrrolines was extended to an erythrinan synthesis (679). Perhydrophenan-threnones were obtained from 1-acetylcyclohexene and pyrrolidinocyclo-hexene (680) or alternatively from Birch reduction and cyclization of a 2-pyridyl ethyl ketone intermediate, which was formed by alkylation of an enamine with a 2-vinylpyridine (681). 

During the course of attempts to synthesize unsaturated derivatives of erythrinane Mondon and Menz (2) found an unexpected ring closure of VIII to form a seven-membered ring. The product (IX) could readily be converted to apoerysopine as shown in Fig. 2. Several of the intermediates in the conversion of VIII to IX could be isolated using milder conditions. 

Two minor by-products formed in the phosphoric acid catalyzed cyclization of LXI have different carbon skeletons than the main products. One is the hydroxylactam LXV, shown to arise by acid-catalyzed rearrangement of LXIII. In acid solution it exists as the colored imonium ion LXVI 33). The second by-product is LXVII. Its formation is explained by the generation of two different cations from LXII in acid, one leading to the erythrinane skeleton (LXIV), the other to the isomeric apo skeleton of LXVII. Bromination of LXI with X-bromosuccinimide afforded the bromo derivative VIII, whose cyclization led almost exclusively to the apo skeleton and a synthesis of apoerysopine (see Fig. 2). 

When these approaches proved unsuccessful, a total synthesis of erysotrine was finally achieved beginning with the oxalyl derivative (LIT) of 4-methoxycyclohexanone. The synthetic scheme has so far been reported only in preliminary communications 27, 36). The condensation with -(3,4-dimethoxyphenyl)-ethylamine leading to the tetracyclic erythrinane skeleton and the further conversion to LV have been discussed in Section III, C (Fig. 8) the remainder of the synthesis is outlined in Fig. 10. 

The most attractive detailed hypotheses (Fig. 11) suggest the formation of the erythrinane skeleton by oxidation of LXXXVIII, a symmetrical intermediate derived from two molecules of tyrosine or dihydroxyphenylalanine. The two additional bonds necessary might be formed in either order. In one hypothesis (1, 57) oxidation of one aromatic ring to the o-quinone (LXXXIX) is followed by nucleophilic addition of the amino group and further oxidation to XC (or the related o-quinone). This sequence is exactly analogous to the in vitro oxidation of dihydroxyphenylalanine itself to the quinone dopachrome (3S). Nucleophilic or radical addition of the second phenolic ring to the quinoid system would complete the spiro skeleton of XCI. 

An interesting conversion of an erythrinan (9) into a -erythroidine derivative (12) has been reported (Scheme 1). Birch reduction of (9) followed by hydrolysis gave a good yield of the conjugated enone (10), which upon successive treatment with benzaldehyde, ozone, hydrogen peroxide, and diazomethane provided the... 

In the late 1960s ring C-homologues of erythrinane alkaloids have been anticipated firom the biosynthetic pathway of certain alkaloids, which are known to be generated from 1-phenethyl-isoquinoline derivatives as precursors (75, 16). Only a short time later such compounds named homoerythrinanes, homoerythrina alkaloids, or schelhammeranes indeed have been found in the plant kingdom 17) (parent compound 2, Fig. 1). 

A new diastereoselective route to aromatic cw-erythrinanes represents the combined intramolecular Strecker and Bruylants reactions of the phenethyl-cyclohexanylethylamines 88 (Scheme 11). Deprotection of the carbonyl function and addition of potassium cyanide causes the Strecker reaction to give the angularly substituted hydroindole derivatives 89 in nearly quantitative yields. Then the Bruylants reaction is... 

In a new attractive B/C(a) route the required N-disubstituted amine derivatives, e.g. the metalated carboxamides 169, have been generated in situ, reacting at first the primary phenethylamins 52 or 167 with trimethylaluminum followed by the enolacetates of cyclohexanoyl carboxylic acids 168. The intermediates 169 eliminate acetic acid affording the Ai-acyliminium ions (170), which cyclize to the desired erythrinanes 68 and 96. Due to the typical H NMR shift of 14-H given (5 = 6.93 ppm (31)) the products should possess the B/C cw-configura-... 

Furthermore, sulfur containing compounds, especially a-S-function-alized acetamide derivatives are suitable precursors to assemble the erythrinane framework via a combined radical/acyliminium ion cyclization. Thus, treatment of the xanthate 178 (Scheme 31) with lauroyl peroxide causes B ring generation via the radicals 179 and 180. After further oxidation of the latter forming the acyliminium ion 181, cat-alytical amounts of p-toluenesulfonic acid induces the ring closure to the aromatic unit furnishing 15,16-dimethoxy-2,8-dioxoeiythrinane (175) in 82% yield (96). 

Finally, there is also only a single report descrihing the sequential formation of the rings A, B, and C of the erythrinane framework in one step. Starting from the complex homoveratrylimide derivative 191 this triple cascade process involves - apart from the initial Pummerer reaction 191 —1192 - the Diels-Alder reaction 192 —> 193 as well as the final acyliminium ion cyclization 194 —1195 providing the erythrinane 195 in 83% yield. This in turn could be converted to ( )-erysotramidine (73) by a sequence already reported (76) (Scheme 34). The requisite educt 191 has been smoothly prepared through six steps in 45% overall yield (80). 

In contrast, the erythrinane synthesis based on the above mentioned cycloadditions of 1,3-butadienes to pyrrole derivatives is fully applicable to that of the ring C-homologue alkaloids. Thus, the phenylhydroindol 100b prepared by [2 - - 2] cycloaddition according to Scheme 13 cyclizes to yield the 2,8-dioxohomoerythrinane 205, which then has been transformed via the 1,7-cyclointermediate 206 to 2,7-dihydrohomoerysotrine (207) (110) (Scheme 37). 

Barton DHR, Cohen T (1957) In Festschrift Dr A Stoll, Birkhauser, Basel, p 117 Barton DHR, Kirby GW, Taylor JB, Thomas GM (1963) Phenol oxidation and biosynthesis, part VI. The biogenesis of amaryllidaceae alkaloids. J Chem Soc 4545—4558 Barton DHR, Hesse RH, Kirby GW (1965) Phenol oxidation and biosynthesis, part VIII. Investigations on the biosynthesis of berberine and protopine. J Chem Soc 6379-6389 Barton DHR, Bracho RD, Potter CJ, Widdowson DA (1974) Phenol oxidation and biosynthesis, part XXIV. Origin of chirality in the erythrinan system and derivation of the lactone rings of a- and ]3-erythroidine. J Chem Soc Perkin Trans 1 2278-2283 Basmadjian GP, Paul AG (1971) The isolation of an O-methyltransferase from peyote and its role in the biosynthesis of mescaline. Uoydia 34 91-93 Basmadjian GP, Hussain SF, Paul AG (1978) Biosynthetic relationships between phenethylamine and tetrahydroisoquinoline alkaloids in peyote. Lloydia 41 375-380 Battersby AR, Binks R, Francis RJ, McCaldin DJ, Ramuz H (1964) Alkaloid biosynthesis, part IV. 1-Benzylisoquinolines as precursors of thebaine, codeine and morphine. J Chem Soc 3600-3610... 

---