Isostrychnine synthesis

The structural homology between intermediate 4 and isostrych-nine I (3) is obvious intermediates 3 and 4 are simply allylic isomers and the synthetic problem is now reduced to isomerizing the latter substance into the former. Treatment of 4 with hydrogen bromide in acetic acid at 120°C results in the formation of a mixture of isomeric allylic bromides which is subsequently transformed into isostrychnine I (3) with boiling aqueous sulfuric acid. Following precedent established in 194810 and through the processes outlined in Scheme 8a, isostrychnine I (3) is converted smoothly to strychnine (1) upon treatment with potassium hydroxide in ethanol. Woodward s landmark total synthesis of strychnine (1) is now complete. 

Following the application of a Heck cyclization to a concise synthesis of the Strychnos alkaloid dehydrotubifoline [287, 288], and earlier model studies [289], Rawal employed a similar strategy to achieve a remarkably efficient synthesis of strychnine [290]. Thus, pentacycle 277 is smoothly cyclized and deprotected to isostrychnine (278) in 71% overall yield — an appropriate finale to this section ... 

As in Rawal s synthesis (Scheme 20), deprotection of the silyl ether 51 under acidic conditions provided isostrychnine (2) in almost quantitative yield (Scheme 29). The synthetic material was identical with the natural compound in its and I3C NMR spectra and by TLC. 

An elegant and efficient stereocontrolled total synthesis of strychnine has been achieved by applying intramolecular Diels Alder and Heck reations as key reactions [47]. An unusual exo-Diels-Alder reaction of 102 afforded 103, which was converted to the vinyl iodide 104. The Heck reaction of 104 using Pd(OAc)2 gave the hexacyclic strychnan system 105 smoothly in 74% yield. Hydrolysis of 105 afforded isostrychnine, which was isomerized to strychnine (106) under basic conditions. 

CH2, and the N lactam carbonyl intact. Unbelievable Vigorous acid treatment finally caused an allyl rearrangement and gave isostrychnine (CCXXXV). Since this had already been converted into strychnine (see Section II, B, 2), the total synthesis was complete. 

Finally, in Rawafs total synthesis of ( )-strychnine, Heck cyclization of vinyl iodide 68 was employed to access the hexacyclic Strychnos alkaloid skeleton and deliver ( -) isostrychnine (69) in 74% yield [25J. Rearrangement in this case would not have been expected since the intermediate formed upon 6-exo closure would contain a particularly unstable tertiary C—Pd bond. The success of the transformation of 68 to 69 in spite of this potential obstacle is noteworthy. 

The four new total syntheses demonstrate that some of the difficulties in the synthesis of strychnine, such as the diastereoselective constmction of the double bond at C20, can now be solved elegantly, but that others like the isostrychnine - strychnine conversion remain unsolved. Thus it can be expected that the search for improved solutions for the... 

An efficient synthesis of the alkaloid strychnine makes good use of an intramolecular Heck reaction. Oxidative addition of palladium(O) into the alkenyl iodide 212 and cyclization onto the cyclohexene gave, after p-hydride elimination and silyl deprotection, isostrychnine 213 (1.214). isomerization of the new alkene to give the enone and cyclization of the alcohol onto the enone gives strychnine. 

Total syntheses of the complex molecule of strychnine have been carried out by several groups applying intramolecular HR as key reactions. The first elegant Pd-based total synthesis of stryclmine (237) has been achieved by Rawal. An intramolecular Diels-Alder reaction and HR were key reactions. The Pd-catalyzed cyclization of the pentacyclic lactam 238 under Jeffery s conditions gave isostrychnine 239 in 74% yield. Conversion of 239 to 237 is known [106]. 

Another recent and outstanding achievement of Canesi s group is their version of a synthesis of rac-isostrychnine in only nine steps starting from the readily available phenol 166, which was first converted into the phenohc amide 167 (Fig. 42) [106]. This compound was subjected to a DIB-mediated methoxylative phenol dearomatization to afford the para-quinol ether 168, the amide function of which was then engaged in an intramolecular aza-Michael addition (Mito its cyclohexa-2,5-dienone moiety to forge the fused bicyclic system 169 en route to isostrychnine, which was obtained after six additional steps (Fig. 42) [106]. Canesi s group also reported several elegant applications of the phenol dearomatization-induced processes of their own invention in natural product synthesis, such as in... 

The carbon patterns of the products (Chart 3.1) of the drastic degradation of strychnine can all be discerned in the parent molecule but cannot by themselves be used to deduce a unique formula. That the A and B rings were six and five membered respectively was reconfirmed over the years often at the cost of considerable labour. One such case concerned dinitrostrychol-carboxylic acid, one of the nitric acid oxidation products of strychnine. It was first obtained about the turn of the century and after considerable work in the late twenties was found in the early thirties to be 5,7-dinitroindole-2-carboxylic acid. Actually the structure of strychnine would probably have been realized much earlier than it was if any one of a number of degradations had been persevered with in a systematic way. The constitution arrived at by the chemical methods rests on the properties of the functionalities in their special environments and their interlocking reactions. The advent of commercial recording infrared and ultraviolet machines played an important part in the latter phase of this work. A synthesis of the alcohol, isostrychnine I (strychnine with its cyclic ether opened at dotted line and A double bond) has confirmed these conclusions as has the determination of the structure and absolute stereochemistry by the X-ray crystallographic method. 

AB ABCE ABCDE - ABCDEF W-G aldehyde (-)-Strychnine] (27) After his racemic synthesis of strychnine (26), Kuehne also achieved an enantioselective synthesis of (—)-strychnine (Scheme 9). To avoid the low yield conversion of isostrychnine to strychnine, the second approach was directed to the W-G aldehyde. Starting from L-tryptophan methyl ester (86), the cyclization precursor 87 was prepared in seven steps in a similar way as in the previous racemic synthesis. The domino condensation-electrocyclization reaction of 87 with dienal 88 proceeded with quite high diastereoselectivity (>95% de) [AB ABCE, C7 quaternary center] (85). After conversion of the tetracyclic compound 89 to tosylate 92, removal of the benzyl group resulted in the clean formation of the D ring [ABCE ABCDE ]. Unlike in the first synthesis, introduction of the hydroxyethylidene side chain by a Horner-Wadsworth-Emmons reaction of ketone 93 proceeded with high stereoselectivity (E Z = 17 1). Einally, the E isomer 94E was converted to (-)-strychnine via the W-G aldehyde (50). 

Pd-catalyzed reactions have been used quite often in the syntheses of natural products (120). Indeed, in Mori s total synthesis of (—)-strychnine, all cyclizations for the synthesis of (+)-isostrychnine were performed using Pd-catalyzed reactions, including the first enantioselective allylic substitution (121-124) (Scheme 12). The strategy used for this synthesis was previously developed by this group for the synthesis of (—)-tubifoline (124). 

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