Alkaloid Aspidosperma

Synthesis The final stages are very similar to Review Problem 20 (frames 212-3). TM 249 is an intermediate in Stork s synthesis of Aspidosperma alkaloids. Stork s method was actually a variation on the one we have proposed ( J. Amer. Chem. Soc., 1963, 85, 2872) ... 

Snyder has conducted similar chemistry but with the goal of generating carbon skeletons for the total synthesis of alkaloids. Using indole 84 as a dienophile, the canthine alkaloid skeleton 85 was produced. Access to aspidosperma alkaloids was obtained when 86 was transformed into 87. 

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). 

Likewise, treatment of sulfoxide 1254 with Me3CSi(Me)20Tf 987/NEt3 induces rearrangement via 1255 to give 30% of the aspidosperma alkaloid 1256 and 25% starting material 1254 [51] (Scheme 8.20). 

Scheme 3.62. Domino radical hydrogen abstraction-cyclization procedure in the synthesis towards Aspidosperma alkaloids.

Indolin-3-yl)ethyl]aminomethylenemalonates (27) were treated with a 3 2 mixture of acetic anhydride and acetic acid at reflux for 72 hr to give aspidosperma alkaloids (1418) in 45-92% yields, as a mixture of epimers (Scheme 56) (77H1699, 77MI3 78CC943 79MI1). 

Since in the synthesis of heterocyclic compounds the ring closure usually involves the formation of the carbon-heteroatom bond, in the retrosynthetic analysis the first bond to be disconnected is the carbon-heteroatom bond (Cf. heuristic principle HP-8), either directly or after the pertinent (FGI or FGA) functional group manipulation. For instance, compound 17 -which is the starting material for Stork s synthesis of Aspidosperma alkaloids [30]- may be disconnected as shown in Scheme 6.11. 

The versatile cyclohexa-1,4-diene 32a has served as an intermediate for synthesis of (—)-eburnamonine 81 and the Aspidosperma alkaloid (—)-aspidospermidine 84 (Scheme 18).3s Butyrolactone carboxylic acids 78 and 82 were prepared from 32 by modification of the methodology outlined in Scheme 7. The key Pictet-Spengler-type cyclization of 79 under conditions of kinetic control gave an 18 1 mixture of 80 and its C(3) (3-epimer in 93% yield. Subsequent hydroboration... 

Almost nothing is known about the biosynthetic pathway between a Corynanthe intermediate and the first Aspidosperma alkaloid tabersonine (38) and, indeed, the first Iboga alkaloid catharanthine (4). Thus, the focus of further work has been the intermediates involved in the pathway... 

It is interesting to note that while vindoline and catharanthine are abundant in Catharan-thus roseus (L.) G. Don, a carbomethoxycleavamine (the initially presumed biogenetic precursor of the binary alkaloids), could not be detected or isolated. This suggested to Atta-ur-Rahman (45) that the VLB-type alkaloids are formed by union of Iboga and Aspidosperma alkaloids, an idea reinforced by biochemical studies (46-49). 

In more recent work, Chiu and co-workers [167, 168] have reported an intramolecular 1,3-dipolar cycloaddition approach toward the pseudolaric acids 85, in which the di-polarophile is an unactivated 1,1-disubstituted alkene. Hence, treatment of the diazo ketone 86 with catalytic Rh2(OAc)4 furnished a mixture of tricyclic products 87 and 88 in nearly equal proportions (Scheme 19.13). The synthesis of 2-pyridones [169] and their application to the ipalbidine core [170] has been described. The pentacyclic skeleton of the aspidosperma alkaloids was prepared via the cycloaddition of a push-pull carbonyl ylide [171]. The dehydrovindorosine alkaloids 89 have also been investigated, in which the a-diazo-/ -ketoester 90 undergoes a facile cycloaddition to furnish 91 in... 

L-tyrosine Tyrosine-derived alkaloids Indole alkaloids Quinoline alkaloids /3-carboline alkaloids Pyrroloindole alkaloids Ergot alkaloids Iboga alkaloids Corynanthe alkaloids Aspidosperma alkaloids Protoalkaloids Terpenoid indole alkaloids True alkaloids... 

Aspidosperma alkaloids These alkaloids have an aspidosperma-type nucleus. The a and are the same as in corynanthe type. Catharantine is the P4 from cathenamine (Figure 68). 

Muthusamy et al. (89) approached the formation of decahydrobenzocarbazoles 191 utilizing an indolic five-membered olefin 190 as the dipolarophile in reaction with a carbonyl yhde derived from 189. This intermolecular approach is strategically similar to an intramolecular approach to aspidosperma alkaloids developed by Padwa (Scheme 4.47). 

Padwa and co-workers (60,106,107) have been highly active in using carbonyl ylides for the synthesis of a number of bioactive alkaloids (Scheme 4.51). In an approach to the aspidosperma alkaloids, a push-pull carbonyl ylide was used to generate a bicyclic ylide containing a tethered indole moiety. This strategy ultimately allowed for the synthesis of the dehydrovindorosin skeleton (108). Starting from a quaternary substimted piperidone (200), elaboration of the 3-carboxylic acid provided p-ketoester amide 201. Addition of the indole tethered side chain provided a very rapid and efficient method to generate the cycloaddition precursor 203. 

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). 

A closer analogy to dehydrosecodine (228) has been developed using A2-piperideines (e.g. 236). These compounds are not isolated but are produced by the fragmentation of salt (235). This elegant method is illustrated in Scheme 42 by the synthesis of racemic pandoline (237) and its C2o epimer. This reaction has provided an efficient route to a number of aspidosperma alkaloids (80JOC3259). 

---