Stereochemical problems

In the reaction of a substituted ylide (r CH—PPh ) with an aldehyde R CHO, a stereochemical problem arises. Much work has been carried out in order to achieve control of either cis- or rrans-alkene formation. This work has been reviewed several times with always changing viewpoints (A. Maercker, 1965 L.D. Bergelson, 1964 M. Schlosser, 1970 H. Best-mann, 1979). 

Many stereoselective reactions have been most thoroughly studied with steroid examples because the rigidity of the steroid nucleus prevents conformational changes and because enormous experience with analytical procedures has been gathered with this particular class of natural products (J. Fried, 1972). The name steroids (stereos (gr.) = solid, rigid) has indeed been selected very well, if one considers stereochemical problems. We shall now briefly point to some other interesting, more steroid-specific reactions. 

Ring contraction of 2-thiocephems has also been examined as a route to penems. Desulfurization of (82, n = 0) using triphenylphosphine gave mixtures of 5(R)- and 5(5)-penems (121). The stereochemical problem was neatiy overcome by regioselective oxidation to the thiosulfonate (82, n = 2) which underwent stereospecific thermal extmsion of sulfur dioxide (122) to give the S(R)-penem (83). 

The data available on the stereochemistry of reduction of steroidal ketones have been obtained largely in the course of synthetic work, rather than in studies devoted specifically to stereochemical problems. As discussed in an earlier section, the proportion of epimers depends on the steric environment of the ketone, the reagent, the solvent and the temperature. These factors will be discussed below. 

In section V-A it has been pointed out that catalytic reduction of conjugated enones is usually a good method for the preparation of p- or y-labeled ketones. To overcome certain stereochemical problems, however, it is occasionally necessary to use the lithium-ammonia reduction. In this case deuteration takes place at the / -carbon and generally leads to the thermodynamically more stable product (see chapter 1). 

In 1952, it was reported that a constituent of excretions from female American cockroaches of the species Periplaneta ameri-cana is an extraordinarily potent sex pheromone.1 Early attempts to isolate and characterize the active compounds were hampered because individual cockroaches store only minute amounts of the pheromone ( 1 pg), and a full 25 years elapsed before Persoons et al. reported the isolation of two extremely active compounds, periplanones A and B.2 The latter substance is present in larger relative measure and its germacranoid structure (1, without stereochemistry) was tentatively assigned on the basis of spectroscopic data. Thus, in 1976, the constitution of periplanone B was known but there remained a stereochemical problem of a rather serious nature. Roughly three years intervened between the report of the gross structure of periplanone B and the first total synthesis of this substance by W. C. Still at Columbia.3... 

Aove Advanced Example Lactone (25) was needed in the synthesis of pcderamldc, an inhibitor of protein synthesis found in a beetle. Disconnection of the lactone reveals two stereochemical problems a c-ir, double bond is required and two adjacent chiral centres ( in 26) must be set up correctly. 

The second reason is related to the misconception that proton dipolar relaxation-rates for the average molecule are far too complicated for practical use in stereochemical problems. This belief has been encouraged, perhaps, by the formidable, density-matrix calculations " commonly used by physicists and physical chemists for a rigorous interpretation of relaxation phenomena in multispin systems. However, proton-relaxation experiments reported by Freeman, Hill, Hall, and their coworkers " have demonstrated that pessimism regarding the interpretation of proton relaxation-rates may be unjustified. Valuable information of considerable importance for the carbohydrate chemist may be derived for the average molecule of interest from a simple treatment of relaxation rates. 

On direct comparison of stephanaberrine (26) and metaphanine (2) (75), close similarity of the H-NMR and mass spectra was observed. The stereochemical problem of the ethylamine linkage was resolved by the fact that the optical activity of 26, [a]D —47.5°, agrees with that of 2, [a]D —41.4° (72). Thus, structures 18 and 26 were proposed for prostephanaberrine and stephanaberrine, respectively (72). 

NOE Nuclear Overhauser experiment. Experiment designed to capitalise on the above. Such experiments (and related techniques, e.g., NOESY, etc.) are extremely useful for solving stereochemical problems by spatially relating groups or atoms to each other. 

Intermolecular cyclopropanation of olefins poses two stereochemical problems enantioface selection and diastereoselection (trans-cis selection). In general, for stereochemical reasons, the formation of /ra ,v-cyclopropane is kinetically more favored than that of cis-cyclopropane, and the asymmetric cyclopropanation so far developed is mostly /ram-selective, except for a few examples. Copper, rhodium, ruthenium, and cobalt complexes have mainly been used as the catalysts for asymmetric intermolecular cyclopropanation. 

As exponents of catalytic antibodies have become more confident of the power of abzymes, their attention has turned from reactions of moderate to good feasibility to more demanding processes. Their work has on the one hand tackled more adventurous stereochemical problems and on the other hand is attempting to catalyse reactions whose spontaneous rates are very slow indeed. Examples of both of these areas are discussed in this section. 

In addition to a review of the recent developments in the preparation of chiral amino compounds, developments concerning the interpretation of their ORD and CD in the visible and ultraviolet spectral regions will be reviewed, together with the emerging impact of vibrational (infrared) optical activity (VOA) observations, including vibrational circular dichroism (VCD) and Raman optical activity (ROA) measurements23, on important stereochemical problems concerning chiral amino compounds. 

The interdependence of chemical constitution and the spatial arrangement of atoms in molecules suggests the simultaneous treatment of constitutional and stereochemical problems. Traditional separation of these latter aspects is more than likely due to the fact that the concepts and methodology of the two chemical disciplines differ enough to justify individual approaches. 

There are some very interesting questions of stereospecificity posed by the structure and mode of operation of multienzyme complexes. Reed and Cox 35> have summarized available information on the pyruvate and a-ketoglutarate dehydrogenase complexes, and the fatty add synthetase. The mechanism of synthesis of the peptide antibiotics likewise presents interesting stereochemical problems 36>. 

In principle, mass spectrometry is not suitable to differentiate enantiomers. However, mass spectrometry is able to distinguish between diastereomers and has been applied to stereochemical problems in different areas of chemistry. In the field of chiral cluster chemistry, mass spectrometry, sometimes in combination with chiral chromatography, has been extensively applied to studies of proton- and metal-bound clusters, self-recognition processes, cyclodextrin and crown ethers inclusion complexes, carbohydrate complexes, and others. Several excellent reviews on this topic are nowadays available. A survey of the most relevant examples will be given in this section. Most of the studies was based on ion abundance analysis, often coupled with MIKE and CID ion fragmentation on MS " and FT-ICR mass spectrometric instruments, using Cl, MALDI, FAB, and ESI, and atmospheric pressure ionization (API) methods. 

Liedtke, R.J. Djerassi, C. Mass Spectrometry in Structural and Stereochemical Problems. CLXXXIII. A Study of the Electron Impact Induced Fragmentation of Aliphatic Aldehydes. J. Am. Chem. Soc. 1969,97,6814-6821. 

Williams, D.H. Budzikiewicz, H. Pelah, Z. Djerassi, C. Mass Spectroscopy and Its Application to Structural and Stereochemical Problems. XLIV. Fragmentation Behavior of Monocychc Ketones. Monatsh. Chem. 1964,95,166-177. 

Duffield AM, Beugelmans R, Budzikiewicz H, Lightner DA, Williams DH and Djerassi C (1965) Mass spectrometry in structural and stereochemical problems. LXIII. Hydrogen rearrangements induced by electron impact on N-n-butyl- and N-n-pentylpyrroles. J Am Chem Soc 87, 805-810. 

ZJE isomerization of the alkene bond in A -enecarboxyIic acids occurs during Kolbe electrolysis because the intermediate radical reacts reversibly with this function to form a cyclopropane [92], This process leads to a partial loss of stereochemistry in the synthesis of long chain alkenes [93]. However, it does not present stereochemical problems during the synthesis of cycloalkenes such as chaul-moogric acid [94]. 

The polymerization of enantiomerically pure monomers presents no relevant stereochemical problems when the asymmetric carbon atom is not involved in the reaction and no new centers of stereoisomerism are formed. This is the case, for example, in polycondensation of chiral diacids with diamines (274) and in ring-opening polymerization of substituted lactams (275) and A -carboxyanhy-drides of a-amino acids (276). Interest here lies mainly in the properties of the polymer. Accidental racemization may sometimes occur but is not necessarily related to the mechanism of polymerization. 

At the synthetic level, stereochemical problems are far from being exhausted. A common research target today is that of the so-called tailor-made polymers, that is, polymers suited to specific uses electronic (semi- and superconductors). 

Due to the difficulties in interpretation and the sensitivity of vibrations in the fingerprint and skeletal regions to structural alterations, the application of ROA to stereochemical problems remains limited. However, the recent advances in experimental techniques and theoretical descriptions are promoting increased research activity in ROA. Especially in aqueous solution, where VCD signals are obscured by the solvent and in low frequency regions, in which VCD spectra are not yet available, Raman optical activity remains a promising tool for stereochemical investigations. 

As noted eailier, the dynamic sensitivity of VCD carries it beyond the Bom-Oppenheimer approximation (17, 18). Even though non-Bom-Oppenheimer calculations have recently been initiated (116-119), the use of molecular orbital methods to describe these vibrationally induced currents is lagging behind the measurement and interpretation of VCD based on such currents. Nevertheless, the empirical basis that is now emerging for understanding VCD intensities based on chirally oriented oscillators and induced currents makes possible the immediate application of this methodology to stereochemical problems of widespread interest. 

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