In natural product structure

Logan, T.M. Murali, N. Wang, G. Jolivet, C. Application of a high resolution superconducting NMR probe in natural product structure determination. Magn. Reson. Chem. 

Ultimately, the definitive structure elucidation of unknown molecules is most often accomplished via NMR. NMR has traditionally been performed on the purified natural product isolated using bioassay-guided fractionation. With the advent of hyphenated techniques such as LC/NMR, these data can now be obtained prior to purification [130,131]. LC/NMR can prove useful even in the dereplication phase, particularly when LC/UV/MS data are insufficient for unambiguous peak identification. LC/NMR has played an important role in natural products structure elucidation, where several related compounds (factors) are often encountered in a single sample. For example, isobaric or isomeric mixtures that may prove difficult or impossible to differentiate by MS, can often be readily distinguished by NMR. Several thorough reviews of LC/NMR in natural products discovery and phytochemical analysis have recently appeared [132,133]. 

N.m.r. spectroscopy is the latest important general technique in natural product structural elucidation work and is on the verge of becoming routinely used. As part of broad and systematic studies, Wenkert and his students have examined the n.m.r. spectrum of piperine (27) and found that differentiation between the chemical shifts of the aromatic C-6 and olefinic a and y carbons as well as olefinic and <5 carbons was still not possible.However, it was found that the Eu(dpm)3 shift reagent is as useful in n.m.r. as in H n.m.r. spectroscopy... 

In an interesting departure from the otherwise exclusive applications of the D-HMBC experiment in natural product structure elucidation that have been cited above, Carbajo etal. used the D-HMBC experiment in a study of alkenylcarbyne- and alkenylvinylidene-tungsten complexes. Using both H- - W and inverse detection methods, the authors demonstrated an approxi-... 

The increase in sensitivity afforded by the proton-detected HMBC experiment revolutionized structure elucidation studies. The utilization of HMBC data in the characterization of alkaloid structures has been reviewed [70] and is also treated in a more general review of the application of inverse-detected methods in natural products structure elucidation [71]. Other applications of the experiment are quite... 

Clearly the development and dissemination of two-dimensional NMR techniques has had a profound impact in natural products structure elucidation. Some techniques, COSY and variants of the C-detected heteronuclear chemical shift correlation (variously referred to as HETCOR, HC-COSY, etc.) experiment, have been widely used by the natural products chemistry community. Inverse-detected heteronuclear shift correlation techniques are becoming recognized as a powerful adjunct to the COSY experiment and a replacement for their less sensitive and, in some cases, less versatile C-detected predecessor experiments (Martin and Crouch 1991). 

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. 

Syn elimination provides a means of determining stereochemical relationships in natural product structure elucidation. Barton, D. H. R. /. Chem. Soc. 1949, 2174. 

THPs, six-membered ring lactones, or 6,6-spiroketals are common units encountered in natural product structures. As RCM is a versatile and che-moselective reaction, aU these heterocycles can be constmcted by using this reaction. In general, the formation of the C3—C4 bond is preferred to construction of the C2—C3 bond, which is more problematic (2006H705). Even if the RCM can be realized under mild conditions, and has also an excellent functional group tolerance, the main drawback of this reaction is that the stereochemistry of the substituents has to be controlled prior to the RCM (Scheme 25). 

Diol cleavage played an important role in natural product structure analysis in the days before instrumental analysis. Understandably, the importance of periodic acid oxidations has diminished somewhat in modern organic chemistry. 

The next molecule we will consider is lasonolide A (1). Lasonolide A provides a modern example of synthesis playing a role in natural product structure determination. There are other examples for sure, but I have selected this one because of a personal interest in the problem, and because it also is a polyolefin that will let us continue our discussion of diastereoselective olefin synthesis. 

Weinreb, S.M. (2003) Lepadiformine a case study of the value of total synthesis in natural product structure elucidation. Acc. Chem. Res., 36, 59-65. 

Many classes of natural product possess heterocyclic components (e.g. alkaloids, carbohydrates). However, their structures are often complex, and although structure-based names derived by using the principles outlined in the foregoing sections can be devised, such names tend to be impossibly cumbersome. Furthermore, the properties of complex natural product structures are often closely bound up with their stereochemistry, and for a molecule containing a number of asymmetric elements the specification of a particular stereoisomer by using the fundamental descriptors (R/S, EjZ) is a job few chemists relish. 

The asymmetric addition of organolithium reagents to arylox azolines has been used to construct highly complex polycyclic terpene structures found in natural products. For example, the asymmetric addition of vinyllithium to chiral naphthyloxazoline 3 followed by treatment of the resulting anionic intermediate with iodoethyl dioxolane 61... 

The cycloaromatization of enediynes, having a structure like 1, proceeds via formation of a benzenoid 1,4-diradical 2, and is commonly called the Bergman cyclization. It is a relatively recent reaction that has gained importance especially during the last decade. The unusual structural element of enediynes as 1 has been found in natural products (such as calicheamicine and esperamicine) which show a remarkable biological activity... 

Methods for the synthesis of pyrroles are of importance, since the pyrrole unit is found in natural products widespread in nature. For example a pyrrole unit is the building block of the porphyrin skeleton, which in turn is the essential structural subunit of chlorophyll and hemoglobin. 

A highlight in the application of RCM methodology in natural product synthesis is Hirama s total synthesis of ciguatoxin CTX3C (183) [90], including the more recent improved protective group strategy, as depicted in Scheme 34 [90b]. The structure of 183 spans more than 3 nm and is characterized by 12 six- to nine-membered trans-fused cyclic ethers and a spiroannulated terminal tetra-... 

Spiroketals based upon such structures as l,7-dioxaspiro[5.5]undecane (18), occur frequently in natural products. Accordingly, an extensive amount of literature relates to the isolation and total synthesis of this type of compound. This literature was reviewed104 in 1989. The authors of Ref. 104 listed three factors that influence conformational preferences in these systems. They are (7) steric influences, (2) anomeric and related effects, and (3) intramolecular hydrogen bonding and other chelation effects. 

This chapter deals with single crystal x-ray diffraction as a tool to study marine natural product structures. A brief introduction to the technique is given, and the structure determination of PbTX-1 (brevetoxin A), the most potent of the neurotoxic shellfish poisons produced by Ptychodiscus brevis in the Gulf of Mexico, is presented as an example. The absolute configuration of the brevetoxins is established via the single crystal x-ray diffraction analysis of a chiral 1,2-dioxolane derivative of PbTX-2 (brevetoxin B). 

With the chemical structure of PbTX-1 finally known and coordinates for the molecule available from the dimethyl acetal structure, we wanted to return to the natural product crystal structure. From the similarities in unit cells, we assumed that the structures were nearly isomorphous. Structures that are isomorphous are crystallographically similar in all respects, except where they differ chemically. The difference between the derivative structure in space group C2 and the natural product structure in P2. (a subgroup of C2) was that the C-centering translational symmetry was obeyed by most, but not all atoms in the natural product crystal. We proceeded from the beginning with direct methods, using the known orientation of the PbTX-1 dimethyl acetal skeleton (assuming isomorphism) to estimate phase... 

It is my opinion that this approach has considerable merit, provided that the questions posed in the problems are wisely selected, as indeed they are in this text. The authors themselves are well versed in natural-product chemistry, an area that presents a wide array of small molecule structural problems. They are therefore concerned that the reader reach the practical goal of applying the full power of NMR spectroscopy to problems of this type. To this end they have selected problems that address methods for solving structures as well as those that pertain to basic theory. The authors have wisely made a point of treating the more widely used ID and 2D experiments in considerable detail. Nevertheless, they also introduce the reader to many of the less common techniques. 

Verdier, L., Sakhaii, P., Zweekstetter, M., Griesinger, C. Measurement of long range H,C couplings in natural products in orienting media a tool for structure elucidation of natural products. /. Magn. Reson. 2003, 163, 353-359. 

---