Porantherine, synthesis

Poly (vinyl pyrrol idones) polymerization, 1, 271 Polyviologens synthesis, 1, 286 Pomeranz-Fritsch synthesis isoqutnolines, 2, 428 6, 218 Pongapin synthesis, 4, 710 Poranthericine, 4, 494 ( )-Porantherine synthesis, 2, 377 Porphin, 4, 386 structure, 4, 378 Porphin, mcso-aryltri-p-tolyl-synthesis, 4, 230 Porphin, mcso-tetraalkyl-synthesis, 4, 230 Porphin, mcso-tetraaryl-synthesis, 4, 230 Porphin, mcso-tetraferrocenyl-synthesis, 4, 230 Porphin, meso-tetraphenyl-synthesis, 7, 767 Porphobilinogen biosynthesis, 1, 100... 

Observe too that, on its right, there is a window with a " 1" in a box. The synthesis tree will appear in this window as we generate it. In the upper part of this window you can read "Synt. tree of Porantherine". 

Process automatically the structure of the alkaloid porantherine, first with the "default-order" of disconnections and then giving priority to "consonant" over "rings" disconnections. In the latter case you should "Save" only the intermediate precursors leading to the same synthetic sequence and the same starting material (A) used in Corey s synthesis, which was actually found by LHASA (see ref. 19, Chapter 12). 

The addition of acid to Az-piperideine results in an iminium ion that readily reacts with nucleophilic species. This reaction has been particularly useful for the formation of carbon-carbon bonds in alkaloid total synthesis. For example, key steps in the total synthesis of ( )-porantherine (equation 36) (74JA6517), coccinelidine (equation 37) (77H(7)685) and eburnamonine (equation 38) (65JA1580) were acid-catalyzed ring closures between A2-piperideine derivatives and ends. Even the weakly nucleophilic carbon-carbon double bond can participate in this type of reaction (80JA5955), as has been demonstrated by a recent total synthesis of a morphinan derivative (Scheme 13). 

Systematic bond disconnection of porantherine [151] with recognition of the double bond-carbonyl equivalence for synthesis generated a synthetic pathway which is based on two intramolecular Mannich reactions. The symmetrical nature of the amino diketone precursor identified by the retrosynthetic analysis facilitates its preparation and subsequent transformations. Moreover, all the hetero atoms (donors) are separated by odd-numbered carbon chains and such arrangements are most amenable to normal modes of assembly. 

By protecting sensitive functional groups like ketones it becomes possible to make reagents that would otherwise be unstable. In a synthesis of the natural product porantherine, a compound based on this structure was needed. 

Nevertheless, where this procedure is applicable it can lead to elegant solutions to difficult synthetic problems. An example of the power of the method is found in Corey s "network analysis" of longi-foline.9 More recently,10 a synthesis of porantherine grew out of the logic-centered analysis summarized below ... 

A remarkably successful total synthesis of the tetracyclic alkaloid ( )-porantherine (60) by Corey and Balanson (Scheme 5) was planned by means of... 

Intramolecular enamine formation between an aldehyde or ketone and the nitrogen atom of a piperidine ring can serve as the key step in the preparation of quinolizidine derivatives. For example, the ketal (184), prepared by double addition of the lithio derivative (183) to 6-methoxy-2,3,4,5-tetrahydropyridine, can be easily cyclized to the quinolizidine derivative (185) by double acid-catalyzed deprotection, cyclization, and dehydration (Scheme 31). These reactions constitute the first steps of a stereocontrolled total synthesis of the alkaloid ( )-porantherine <87JA4940>. 

Porantherin (1) is an alkaloid from the Australian plant Poranthera corymbosa and possesses an interesting tetracyclic skeleton of the 9b-azaphenalene type [167]. In an instructive biomimetic synthesis of 1 developed by Corey [168] the key intermediate (X) was subjected to the following reactions (a) and (b) leading via A to B, which was further transformed to the target molecule 1 ... 

By protecting sensitive functional groups like ketones it becomes possible to make reagents that would otherwise be unstable. In a synthesis of the natural product porantherine, a compound based on the structure in the margin was needed. As it s a symmetrical secondary alcohol (see p. 216), a good way to make it is to add a Grignard reagent twice to ethyl formate. 

The total synthesis of the alkaloid porantherine 114 represented a tour-de-force in the Mannich reaction. Exposure of 108 to acid tmmasks the ketals which triggered the initial Mannich reaction to afford 109. This intermediate was labile under these reaction conditions and underwent a second Mannich reaction to generate 110. Elaboration of this compound provided access to 111, the precursor to Mannich base 113 via the intermediacy of 112. Reduction and dehydration then gave 114. 

The next stage of the synthesis called for conversion of the terminal olefin to an aldehyde. This was accomplished using a Johnson-Lemieux oxidation. The resulting ketoaldehyde was then converted to fr-ketal 15. Basic hydrolysis of the formamide provided 16 and hydrolysis of the acetals afforded a mixture of diastereometic enaminoketones 17. An acid-promoted intramolecular Mannich reaction gave 2. Presumably epimerization of the ketone allowed both diastereomers of 17 to follow the path to 2. Reduction of ketone 2 with sodium borohydride provided an alcohol, which underwent formal dehydration upon treatment with thionyl chloride and pyridine, to give porantherine (1) as a racemic mixture. 

Porantherine is one member of a family of structurally (and presumably biosynthetically) related alkaloids shown here. One might imagine that a late step in the synthesis (or biosynthesis) of alkaloids 19-21 could also involve capture of an iminium ion by an appropriate nucleophile (to construct the bonds marked a ). Even porantherilidine (18) contains the 1,3-difiinctional relationship needed to develop a synthetic strategy that takes advantage of the Mannich reaction. 

A related approach to porantherine was reported by the Stevens group about 10 years after publication of the Corey synthesis. The Stevens synthesis emphasized the notion that the stereoelectronic requirement for addition of a nucleophile to an imine (or iminium ion) was development of an anti-periplanar relationship between the nucleophile and the developing lone pair on nitrogen. This notion also leads to the disconnection of 2 —> 3 —> 22, and iminium ion 22 was to be prepared by oxidation of piperidine 23. Thus, the major difference between the Stevens and Corey approaches is the choice of a surrogate for the aldehyde required for generation of iminum ion 3. In the forward direction, the lithium reagent derived from 26 was treated with iminoether 27 to provide 28. Hydroysis of 28 gave enamine 29. 

As in the Corey synthesis, an intramolecular Mannich reaction converted 29 to 31. Mercuric acetate oxidation of 31 to the corresponding iminium ion, followed by basification, gave enaminoketone 32. This intermediate does not have the proper stereochemistry for an intramolecular Mannich reaction, but under acidic conditions, epimerization is followed by cyclization to provide 2. The synthesis of porantherine (1) was completed using a Bamford-Stevens reaction to introduce the olefin. ... 

The synthesis of porantherine vividly illustrates the application of antithetic (retrosynthetic) analysis in developing synthetic routes to complex molecules. Systematic bond disconnection suggests structures A-F (or their equivalents) as key intermediates and also provides the overall plan of synthesis. 

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