When was morphine structure first elucidated?
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Introduction
Total structure elucidation of complex natural products has become more straightforward over the past several decades. Contributing factors for unambiguous structure elucidationstem from further advances in the newly developed NMR probes, novel MS technology including ultra-high-resolution MS (HRMS) and tandem MS (MS/MS), and the application of synchrotrons for X-ray structure analysis. Classical structure elucidationprior to the development of these techniques (around 1960) was quite challenging, and required tremendous effort and time even for small organic molecules (MW < 500). The structures shown in Figure 1 are classical natural products which illustrate the difficulty of structure elucidation without the techniques mentioned above. Structure elucidation of morphine (C17H19NO3), which is perhaps the first secondary metabolite isolated in pure form, took almost 150 years (isolation: 1806, two-dimensional (2D) structure: 1923, three-dimensional (3D) structure: 1952).1 The puffer fish toxin, tetrodotoxin (C11H17N3O8), required more than 50 years for its structure to be fully elucidated (isolation: 1907, 3D structure: 1964).2 Compared to these two examples, the structure elucidationof the antibiotic penicillin G (C16H18N2O4S) was relatively fast, but still needed more than 15 years (discovery: 1929, isolation: 1941, 3D structure: 1945).3 Although it had been suggested that penicillin possessed a β-lactam core, the total structure of penicillin G was directly determined by the application of X-ray structural analysis.4 The structural motifs of these molecules continue to intrigue chemists, notably the fascinating ring systems.
Modern structure elucidation using one of, or a combination of, the abovementioned analytical techniques has enabled chemists to investigate large and complex biomolecules (MW > 1000). Some outstanding total structure analysis utilizing limited samples in the past 15 years for marine-derived macromolecules are shown in Figure 2: (1) polyether toxin, maitotoxin (C164H256O68S2Na2), (discovery: 1979,52D structure: 1993,6 3D structure: 19967,8), (2) polyketide, amphidinol 3 (C70H118O23), (3D structure: 1999,9structure revision: 200810), lipopolysaccharide, axinelloside A (C137H219O117S19Na19), (3D structure: 200511) and (3) polypeptide, polytheonamide A (C219H376N60O72S), (2D structure: 1994,12 3D structure plus structure revision13). However, it is also true that incorrectly assigned structures for small biomolecules continue to appear in the literature. This issue was emphasized in a recent review, which suggested that more than 300 errors in proposed structures were disclosed from 1990 to early 2004.14 It is important to learn and analyze the outstanding structure elucidationexamples mentioned above. However, considering the number of recently revised structures and stereochemical reassignments, it is more practical and significant to study why structure elucidation goes wrong. This chapter discusses a subset of misassigned molecules derived from marine sources and is composed of incorrect 2D and 3D structures. It should be mentioned that the object of this chapter is not to criticize the structure misassignments based on the original works, but to provide clues to avoid the pitfalls for future structure elucidation works.
Total structure elucidation of complex natural products has become more straightforward over the past several decades. Contributing factors for unambiguous structure elucidationstem from further advances in the newly developed NMR probes, novel MS technology including ultra-high-resolution MS (HRMS) and tandem MS (MS/MS), and the application of synchrotrons for X-ray structure analysis. Classical structure elucidationprior to the development of these techniques (around 1960) was quite challenging, and required tremendous effort and time even for small organic molecules (MW < 500). The structures shown in Figure 1 are classical natural products which illustrate the difficulty of structure elucidation without the techniques mentioned above. Structure elucidation of morphine (C17H19NO3), which is perhaps the first secondary metabolite isolated in pure form, took almost 150 years (isolation: 1806, two-dimensional (2D) structure: 1923, three-dimensional (3D) structure: 1952).1 The puffer fish toxin, tetrodotoxin (C11H17N3O8), required more than 50 years for its structure to be fully elucidated (isolation: 1907, 3D structure: 1964).2 Compared to these two examples, the structure elucidationof the antibiotic penicillin G (C16H18N2O4S) was relatively fast, but still needed more than 15 years (discovery: 1929, isolation: 1941, 3D structure: 1945).3 Although it had been suggested that penicillin possessed a β-lactam core, the total structure of penicillin G was directly determined by the application of X-ray structural analysis.4 The structural motifs of these molecules continue to intrigue chemists, notably the fascinating ring systems.
Modern structure elucidation using one of, or a combination of, the abovementioned analytical techniques has enabled chemists to investigate large and complex biomolecules (MW > 1000). Some outstanding total structure analysis utilizing limited samples in the past 15 years for marine-derived macromolecules are shown in Figure 2: (1) polyether toxin, maitotoxin (C164H256O68S2Na2), (discovery: 1979,52D structure: 1993,6 3D structure: 19967,8), (2) polyketide, amphidinol 3 (C70H118O23), (3D structure: 1999,9structure revision: 200810), lipopolysaccharide, axinelloside A (C137H219O117S19Na19), (3D structure: 200511) and (3) polypeptide, polytheonamide A (C219H376N60O72S), (2D structure: 1994,12 3D structure plus structure revision13). However, it is also true that incorrectly assigned structures for small biomolecules continue to appear in the literature. This issue was emphasized in a recent review, which suggested that more than 300 errors in proposed structures were disclosed from 1990 to early 2004.14 It is important to learn and analyze the outstanding structure elucidationexamples mentioned above. However, considering the number of recently revised structures and stereochemical reassignments, it is more practical and significant to study why structure elucidation goes wrong. This chapter discusses a subset of misassigned molecules derived from marine sources and is composed of incorrect 2D and 3D structures. It should be mentioned that the object of this chapter is not to criticize the structure misassignments based on the original works, but to provide clues to avoid the pitfalls for future structure elucidation works.
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