Total synthesis strychnine

Strychnine (1), an alkaloid, was introduced into European medical practice in the early sixteenth century after being used as a rat poison (see Alkaloids). As of 1996, it was stiU used as a rodenticide. The total synthesis of this complex molecule is known (3,4). 

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. 

Kaburagi, Y, Tokuyama, H., Fukuyama, T. (2004) Total Synthesis of (—)-Strychnine. Journal of the American Chemical Society, 126, 10246-10247. 

Scheme 7.20. Zn-mediated domino reduction/biscyclization process in the total synthesis of (-)-strychnine (7-76).

Bonjoch and coworkers have developed a general synthetic entry to strychnos alkaloids of the curan type via a common 3a-(2-nitrophenyl)hexahydroindole-4-one intermediate. Total synthesis of (-)-strychnine is presented in Scheme 9.5.20 The first step is based on the SNAr reaction of o-iodonitrobenzene with 1,3-cyclohexanone. 

Examples of such an approach are found in the synthesis of strychnine [22] and morphine [23], labours which have been said to bear resemblance to Sysiphus s torment [24], since they involve linear sequences of more than 25 steps. However, the most illustrative example is found, perhaps, in the synthesis of penicillin (10 ). in the course of which the penicilloic acid derivative JJL was synthesised, though through a laborious and lenghty route. Because this intermediate was easily available from natural penicillin, it was convenient to resort to such a method of degradation in order to make it available in sufficient quantities for studying the last step -that requires the formation of a P-lactam- and thus accomplishing successfully the total synthesis [25]. 

CATALYTIC ASYMMETRIC TOTAL SYNTHESIS OF (-)-STRYCHNINE AND FOSTRIECIN... 

We describe herein our recent achievement of total syntheses of (-)-strychnine and fostriecin. The key stereocenters were constructed using catalytic asymmetric reactions developed in our group. Catalytic asymmetric reactions that can produce versatile chiral building blocks with high practicality should ensure further efficient total synthesis of complex molecules in future. 

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. 

The alio series of the pumiliotoxin A class have an additional hydroxyl group that has been placed at C-7 on the indolizidine ring, without assignment of configuration. Three members of the alio series have been assigned the tentative structures (7), (8), and (9).3 Pumiliotoxins A and B are relatively toxic, and comparable in potency to strychnine. Pumiliotoxin B has a potent cardiotonic and myotonic activity.3 An enantioselective total synthesis of pumiliotoxin A alkaloids from L-proline has already been announced.4... 

Fused carbazoles related to pyrido[4,3-6]carbazole alkaloids were prepared by a Diels-Alder route, and a 3-aza bioisostere of the antitumor alkaloid olivacine was synthesized <02CPB1479>. Indoloid [3.3]cyclophane 40a gave the pentacyclic indoloid 41a upon heating <02OL127>. This led to a concise formal total synthesis of ( )-strychnine in 12 facile steps from tryptamine when a similar transannular inverse-electron-demand Diels-Alder reaction of indoloid [3.3]cyclophane 40b gave 41b <02AG(E)3261>. 

The final stage was reached when Woodward and his collaborators announced the total synthesis of strychnine, a truly great achievement (see Section IV) (39). 

The total synthesis was achieved in 1954 by Woodward and his collaborators (156). Before this, various unsuccessful attempts had been made to make a start toward a synthesis of strychnine (179, 180, 181, 182,) but these are now of little interest, with the exception of Robinson s idea (182) to emulate the postulated biosynthesis by attempting to synthesize the dialdehyde CCXVI, which then might be induced to cyclize by a combination of Mannich and aldol type condensations to the Wieland-Gumlich aldehyde (LV) the synthesis of CCXVI unfortunately was not realized. Much more recently, however, this idea has been used by van Tamelen et al. (184), who successfully synthesized the dialdehyde CCXVII and converted it in aqueous acetic acid-sodium... 

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. 

Among the wide variety of unsaturated functionalities which participate in the cobalt-mediated [2+2+2] cycloaddition that has proved to be a powerful tool for the assembly of complex polycyclic molecules are a number of aromatic heterocyclic double bonds, such as those in pyrrole and indole <20000L2479, 2001JA9324 and references therein>. Indoles, including those substituted at C-3, can be cyclized, both intra- and intermolecularly, with a wide variety of alkynes to yield functionalized products in moderate to good yields. A stereoselective cobalt-mediated [2+2+2] cycloaddition reaction between the W(pent-2-en-4-ynoyl)indole moiety of tryptamine derivative 1093 (R = (CH2)2NHAc) and acetylene has been employed for the formal total synthesis of strychnine 1097, the most famous Strychnos alkaloid and a commonly used rodenticide and animal stimulant (Scheme 213). 

Similarly, in a total synthesis of strychnine, the optical resolution was carried out by separation of the sulfinyl lactam diastere-omers (7) and (8), which were obtained from the heptacyclic indole alkaloid precursor (6) this was first transformed with (/ )-(+)-p-tolylsulfinylacetic acid into the corresponding sulfinyl amide and then converted to the diastereomeric lactams (7) and (8) by an intramolecular conjugate addition (eq 3). ... 

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. 

In the laboratory of S.F. Martin, a biomimetic approach toward the total synthesis of ( )-strychnine was developed by using tandem vinylogous Mannich addition and HDA reaction to construct the pentacyclic heteroyohimboid core of the natural product.The commercially available 4,9-dihydro-3/-/-P-carboline was first converted to the corresponding A/-acylium ion and then reacted with 1-trimethylsilyloxybutadiene in a vinyiogous Mannich reaction. The resulting cycloaddition precursor readily underwent the expected HDA reaction in 85% yield. 

Enantioselective total syntheses based on asymmetric catalysis including total synthesis of strychnine, asymmetric epoxidation of a,/l-unsaturated acid derivatives, and ring opening of oxiranes 04CPB1031. 

In 2002, Bodwell and Li reported an elegant and efficient total synthesis of strychnine based on an intramolecular inverse-electron-demand Diels-Alder reaction that involves a pyridazine as diene. The required cyclophane 91 was built up via hydroboration of A-[2-(l-allyl-l/7-indol-3-yl)ethyl]-6-iodopyridazin-3-amine (90) followed by an intramolecular sp —sp coupling reaction [55]. 

Since the monumental accomplishments of Woodward s total syntheses of strychnine in 1954 [I] and rcserpinc in 1958 (2], the arsenal of synthetic methods in indole alkaloid synthesis has greatly expanded. In the same time period, the use of palladium chemistry in organic syntheses has also witnessed tremcndou- growth with an ever-expanding repc loire of synthetic methods and their applications to total synthesis. The use of palladium chemistry for the synthesis of indole alkaloids has been explored, and several examples have been included in recent reviews [3-6]. This account attempts to present a comprehensive collection of total syntheses of naturally occurring indole alkaloids where palladium chemistry plays a central role in the syntheses. 

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