Strychnine structural elucidation

Scheme 4.2 Strychnine is readily accessed via isostrychnine or the Wieland-Gumlich aldehyde using chemistry discovered during structural elucidation/degradation studies...

The complex structures of alkaloids, along with their biological activity and relative ease of isolation, have kept the interest of organic chemists over the years. They have provided enormously challenging structure elucidation problems. For example, although strychnine was first isolated in 1818, its complete structure was not determined until 1946. (R. Robinson was awarded the 1947 Nobel Prize in chemistry for the determination of the structure of strychnine and other alkaloids as well as synthetic work in this area.) Of course, soon after this, synthetic chemists accepted the challenge of preparing this complicated compound in the laboratory. The first synthesis, reported by... 

NMR has become a standard tool for structure determination and, in particular, for these of Strychnos alkaloids. The last general article in this field was authored by J. Sapi and G. Massiot in 1994 [65] and described the advances in spectroscopic methods applied to these molecules. More recently, strychnine (1) has even been used to illustrate newly introduced experiments [66]. We comment, here, on their advantages and sum up the principles of usual 2D experiments in Fig. (1) and Fig. (2) (COSY Correlation SpectroscopY, TOCSY TOtal Correlation SpectroscopY, NOESY Nuclear Overhauser Enhancement SpectroscopY, ROESY Rotating frame Overhauser Enhancement SpectroscopY, HMQC Heteronuclear Multiple Quantum Coherrence, HMBC Heteronuclear Multiple Bond Correlation). This section updates two areas of research in the field new H and 13C NMR experiments with gradient selection or/and selective pulses, 15N NMR, and microspectroscopy. To take these data into account, another section comments on the structure elucidation of new compounds isolated from Strychnos. It covers the literature from 1994 to early 2000. 

The first alkaloids were already isolated in the early 19th century (e.g., morphine, strychnine). Although the methods for identification and structure elucidation have changed a great deal, the methods of isolation used in the last century are still widely used. Originally, pure chemistry, like derivati-zation and degradation, was used to unravel the often complex structures of alkaloids. The structure elucidation of a well-known alkaloid, such as, for example, strychnine, took almost 140 years after its first isolation by Pelletier and Caventou in 1818. 

The applicability of the HSQC experiment in natural product structure elucidation studies remains to be evaluated. To the best of our knowledge, no natural product structure elucidation studies have been reported using HSQC rather than HMQC to establish direct proton-carbon chemical shift correlations. This will undoubtedly change in time. A modification of the HSQC experiment, inverted direct response HSQC-TOCSY, has, however, been reported using strychnine as a model compound (Domke 1991). In the case of congested proton spectra, there may be advantages inherent to the use of HSQC instead of HMQC. 

The progress in NMR hardware to support the structure elucidation of limited quantity samples allowed to exploit the ADEQUATE experiment to a greater extent [2,93,94]. The advantage of the ADEQUATE pulse sequence originates from C-C magnetization step transfers that allow to specifically differentiate between Jch and Jch bonds which is not possible from HMBC-based experiments. It also includes connectivity information to non-protonated carbon atoms. Thus, multiplicity-edited H-C HSQC and 1,1-ADEQUATE experiments were co-processed to yield a C—C correlation plot [28]. The map was diagonally symmetric in case of adjacent Jcc-coupled protonated carbons and asymmetric in case of Jcc between protonated and quaternary carbons. It was emphasized that the latter responses were observed at the C shift of the protonated carbon in the FI direction and the correlation at the C shift of the quaternary carbon in the F2 dimension, cf. exemplarily for the methylene Cl 1 and the carbonyl CIO in Fig. 5.12. The well-known compound strychnine served as proof-of-principle for the HSQC-1,1-ADEQUATE. 

Hence, a multiplicity-edited H-C HSQC and a H—N HMBC were UIC transformed into a C—N correlation, referred to as C-N HSQC-HMBC [42]. This otherwise inaccessible —spectrum of a few milligrammes of strychnine was constructed after a total recording time of less than 4 h for both component spectra. The spectral representation was predicted to be of interest for the structure elucidation of pharmaceutical actives, agrochemicals and alkaloids due to their elevated nitrogen content. 

Acetate (+)-29 was also the key precursor in the synthesis of (-)-strychnine.t First isolated in 1818 from Strychnos ignatii, strychnine was among the first plant alkaloids obtained in pure form. The structural elucidation was reported in 1946, and by now four total syntheses including two racemic ones have been described. The sequence described... 

Strychnine (126, Scheme 11.19), first isolated in 1818 [112], is the most famous member of the Strychnos alkaloids. It possesses a unique complex polycyclic structure, which has served to inspire organic chemists ever since its structural elucidation in 1946 [113]. After Woodward s landmark synthesis of strychnine in 1954 [114], almost 40 years were to pass before this daunting structure was the subject of a second total synthesis by Mag-... 

Using either of the methods just described in successive steps allows the identification of progressively larger fragments of the chemical structure of the molecule being studied or elucidated. In the case of strychnine, 1, shown... 

Woodward then moved across town in Cambridge to devote a year of postgraduate study at Harvard University. At the end of that year, he accepted an appointment to the Harvard chemistry faculty, a post he held for most of the rest of his life. One of his great interests at Harvard was the synthesis of large, complex molecules, the first of which was quinine in 1944. He followed that work with the elucidation of other molecular structures and the development of synthetic methods for each. Included among these molecules were penicillin (1945), patulin (1948), cholesterol and cortisone (1951), oxytetracycline (1952), strychnine (1954), lysergic acid (1954), reserpine (1956), chlorophyll (1960), colchicine (1963), cephalosporin C (1965), and vitamin (1971). 

Strychnine and brucine have been the subject of a very large number of degradative researches, nearly all of them before the advent of modern spectroscopic techniques, and the elucidation of their structure represents one of the major achievements of classical organic chemistry. The... 

Geissoschizoline [= pereirine (106)] is an indoline derivative with a Strychnos carbon keleton. The complete structure was elucidated by partial synthesis from (—)-akuammicine (117) the latter on reduction with zinc and acid forms 2/ ,16jS-dihydroakuammicine which on lithium aluminium hydride reduction followed by catalytic hydrogenation gives geissoschizoline (106). The base can also be obtained by degradation of the strychnine derivative (1IS). " ... 

X-ray analysis. In the pantheon of methods employed to elucidate structures, single-crystal Z-ray analysis reigns supreme. It deserves every chemist s respect for it unites speed, completeness, and dependability. Using a modem diffractometer for measurements and a computer for calculations, this method unequivocally establishes within a few days or weeks the composition and solid-state conformation of a small molecule. By contrast, 150 years separated the discovery of the notorious alkaloid poison strychnine and the confirmation of its complex structure by synthesis, which in 1947 culminated a half-century s chemical research. 

Securinine (1), the parent alkaloid of this astonishing family, was isolated by Murav eva and Ban kovskii from Securinega suffrutkosa (Pall.) Rehder during their work on the plants of Russian Far East. Its molecular ftirmula was estabhshed as CisHjsNOa. In addition, Soviet researchers determined the presence of a lactone moiety and extended conjugation by IR and UV spectroscopy. Further analysis of the structural information predicted the absence of N-methyl, O-methyl, hydroxyl, methylenedioxy, or ketone groups. Despite its unknown structure, 1 was approved for medical use in the USSR as a substitute of imported strychnine (see Section 8.1). The patents on its isolation, its dihydro and tetrahydro derivative, and various quaternary salts followed. Later, the structure of securinine (1) was simultaneously elucidated... 

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