Absolute stereochemistry, determination

Isolated yields. Enantiomeric excesses of the allylated product were determined by chiral HPLC analysis. Absolute stereochemistry determined to be (JR) by CD spectrum of 2-methyl-2-propyl-4-methoxyindanone. 

Branch at C-4. - The novel branched-sugar 11, named caryophyllose has been isolated from the lipopolysaccharide of the bacterium Pseudomonas caryophylli and its relative and absolute stereochemistry determined. ... 

In the case of thienamycin (Fig. lb) the absolute stereochemistry at C-5 was unambiguously deterrnined from the ene-lactam (16). The resultant (R)-aspartic acid (17) demonstrated that the absolute stereochemistry at C-5 of thienamycin is (R), corresponding to that found in the C-5 position of both penicillins and cephalosporins. Confirmation of the stereochemical assignments in both thienamycin (2) and the olivanic acid MM 13902 (3, n = 0) has been confirmed by x-ray crystallography (19,21,22). The stmctural determination of the nonsulfated derivatives from S. olivaceus (23), PS-5 (5) (5), the carpetimycins (6), and the asparenomycins (7) followed a similar pattern. 

The desilylacetylated qrcloadducts, produced from the reactions of trimethylsilyl-diazomethane with 3-crotonoyl-2-oxazolidinone or 3-crotonoyl-4,4-dimethyl-2-oxa-zolidinone, were transformed to methyl traws-l-acetyl-4-methyl-l-pyrazoline-5-car-boxylate through the reactions with dimethoxymagnesium at -20 °C. When the optical rotations and chiral HPLC data were compared between these two esters, it was found that these two products had opposite absolute stereochemistry (Scheme 7.39). The absolute configuration was identified on the basis of the X-ray-determined structure of the major diastereomer of cycloadduct derived from the reaction of trimethylsilyldiazomethane to (S)-3-crotonoyl-4-methyl-2-oxazolidi-none. 

The polyene macrolide filipin was isolated in 1955 from the cell culture filtrates of Sterptomyces filipinensis, and was later shown to be a mixture of four components [36]. Although too toxic for therapeutic use, the filipin complex has found widespread use as a histochemical stain for cholesterol and has even been used to quantitate cholesterol in cell membranes [37]. The flat structure of filipin III, the major component of the filipin complex, was assigned from a series of degradation studies [38]. Rychnovsky completed the structure determination by elucidating the relative and absolute stereochemistry [39]. The total synthesis plan for filipin III relied heavily on the cyanohydrin acetonide methodology discussed above. 

Schroder, H. Netscher, T. Determination of the absolute stereochemistry of vitamin E derived oxa-spiro compounds by NMR spectroscopy. Magrt. Resort. Chem. 2001, 39, 701-708. 

This oxidation method was applied to determination of the absolute stereochemistry of berberastine (HO) and thalidastine (111). (+)-Tetra-hydrojatrorrhizine (112) was converted to 5a- and 5/J-hydroxyl derivatives 113 and 114 in a 2 1 ratio (Scheme 24). The major product 113 was dehydrogenated to give rise to the dextrorotatory quaternary protoberberine 115. Thus, 110 and 111, being dextrorotatory, should have the same absolute configuration as that of 115 (77). 

Figure 1.1 Schematic diagram explaining the Cahn-Ingold-Prelog convention for determining the absolute stereochemistry of a chiral molecule.

The structure of (+)-phomactin A was determined using both NMR and crystallographic methods (Fig. 8.1). Although the crystal structure is of low quality, it clearly revealed the unusual ABCD-tetracyclic topology as well as the absolute stereochemistry. Subsequently, nine additional phomactins were isolated from various fungal sources with many of them displaying anti-PAF activity [3-5] B [3], B1 [3], B2 [3], C [3] (or Sch 47918 [6]), D [3], E [4], F [4], G [4], and finally, H [5] (Fig. 8.2). 

The configurational differences between 104 and 105 with the partial cis-fused junctions and those of the all trans-fused 95 and 101 (and related compounds) were pointed out [22] and resolved [62] with the determination of the absolute stereochemistry of diisocyanoadociane (95) (vide supra). Selective conversion to, and preparation of, an appropriate formamido-(p-bromobenzamide) derivative for X-ray determination [62], coupled with total synthesis [63], support the lR,2f ,3aS,5S,6/ ,8S,8aS, lOaS, lObS, lOcS absolute configuration. 

The absolute stereochemistries for both compounds were determined by CD analysis of the p-bromobenzoate derivatives. Two other eicosanoids were also isolated from whole animals [198], The trihydroxylated oxylipin 8jR,11S,12R-trihydroxyeicosa-5Z,9 ,14Z,17Z-tetraenoic acid (trioxilin A4,150) was detected in, or isolated from, five starfish species P. miniata, Dermasterias imbricata, Pycnopodia helianthoides, Culcita novaeguinea, and Nardoa tubercolata. Its structure was determined by H and 13C NMR and FAB-MS analyses of the natural product and of an acetonide derivative. The co6 analog of this compound (151) was isolated only from P. helianthoides. The relative stereochemistry in these metabolites (150, 151) was established from a comparison of NMR shifts with malyngic acid, a trihydroxylated C18 compound isolated from Lyngbya majuscula, while the absolute stereochemistry was proposed on the basis of the earlier isolation of 8R-HETE from P. miniata. 

The relative and absolute stereochemistry of antimitotic macrolide archazolid A and B, originally isolated in the early nineties, has been determined on the basis of extensive high-field NMR studies, molecular modelling and chemical derivatization <06OL4751>. The proposed structures have yet to be confirmed by total synthesis. 

Related catalytic enantioselective processes Although great progress has been achieved in the area of metal-catalyzed hydrogenation reactions [124], examples of catalytic asymmetric hydrogenations of tetrasubstituted alkenes are rare. One other example, reported by Pfaltz and co-workers, is depicted in Eq. 6.26 (81 % ee, absolute stereochemistry of the product not determined) [125],... 

Few structures have been solved for this kind of compound. A crystal structure of (2-R,5R,2 R,5 R)-bi(2,2 - / -butyl-1,1 -aza-3,3 -oxabicyclo[3.3.0] octan-4,4 -one prepared from the diastereoselective dimerization of the pivaloyl oxa-zolidin-5-one derivative of proline has been obtained for the determination of the absolute stereochemistry of the C-a atoms of compound 265. 

Andrus et al. (109) proposed a stereochemical rationale for the observed selec-tivities in this reaction. The model is based on the Beckwith modification (97) of the Kochi mechanism, suggesting that the stereochemistry-determining event is the ally lie transposition from Cu(III) allyl benzoate intermediates 152 and 153, Fig. 13. Andrus suggests that the key Cu(III) intermediate assumes a distorted square-planar geometry. Steric interactions are decreased between the ligand substituent and the cyclohexenyl group in Complex 152 as opposed to Complex 153 leading to the observed absolute stereochemistry. 

Chelation of the nitrone to a square-planar metal center predicts the wrong absolute stereochemistry, as determined for the exo adduct. Jprgerisen proposes that a trigonal bipyramidal metal geometry may be operative, involving chelation of the nitrone, the ligand and vinyl ether in the transition state, 403 in Fig. 32. Alternately, a tetrahedral geometry may also account for the observed sense of induction. The absolute stereochemistry of the endo adduct was not determined. 

The prefix (RS) is used to denote a racemic modification. For example, (RS)-Sec butyl chloride. The symbols R and S are applied to compounds whose absolute stereochemistry has been determined. However, while applying the nomenclature to projection formulae of compounds containing several asymmetric centres Cahn, Ingold. Pielog procedures are supplemented by the following conversion rule. 

The absolute stereochemistry for 150 (entries 2 and 3) was determined by hydrolysis and conversion to known compounds. Assuming a tetrahedral or cis octahedral geometry for the magnesium [110], the product stereochemistry is consistent with si face radical addition to an s-cis conformer of the substrate. This is the same sense of selectivity as that obtained with oxazo-lidinone crotonates or cinnamates suggesting that the rotamer geometry of the differentially substituted enoates is the same. The need for stoichiometric amount of the chiral Lewis acid to obtain high selectivity with 148 in contrast to successful catalytic reactions with crotonates is most likely a reflection of the additional donor atom present in the substrate. 

A 2 1 (- )-90-LAH reagent was employed in the asymmetric synthesis of a cij-diol (91) by reduction of c/j-2-acetoxy-6-phenylcyclohexanone (99,100). Diol 91 is of interest as the tetrahydro derivative of a metabolite obtained from the microbial oxidation of biphenyl. Diol 91 was obtained in 46% e.e. as determined by NMR in the presence of a chiral shift reagent. It was shown to have the absolute stereochemistry (lS,2/ )-dihydroxy-3(S)-phenylcyclohexane by oxidation to ( + )-2-(S)-phenyladipic acid of known absolute stereochemistry. 

Cathodic cyclization reactions have supphed and continue to provide a fertile territory for the development and exploration of new reactions and the determination of reaction mechanism. Two areas that appear to merit additional exploration include the application of existing methodology to the synthesis of natural products, and, more significantly, a systematic assessment of the factors associated with the control of both relative and absolute stereochemistry. Until there is a solid foundation to which the non-electrochemist can confidently turn in evaluating the prospects for stereochemical control, it seems somewhat unlikely that electrochemically-based methods will see widespread use in organic synthesis. Fortunately, this comment can be viewed as a challenge and as a problem simply awaiting creative solution. 

Ondansetron (17) is a racemic compound not easy to resolve by chemical means because the carbonyl function is poorly reactive so it is difficult to form chiral derivatives. However, a resolution was achieved by the classical method of forming diastereomeric salts with an optically active acid and then separating the salts by recrystallisation. A number of acids were tried, but only the salts prepared from (-f)- and (—)-di-p-toluoyltartaric acid could be separated in this way. Each isomer was obtained in greater than 95 %ee. The absolute stereochemistry of the isomer from the (-E)-acid was determined by X-ray crystallography (Williams, D., personal communication) and shown to possess the 5-configuration (18). 

An a-substituted system (Entry 28) has also been epoxidised in good yield and with moderate stereoselectivity. Although the absolute stereochemistry of the resulting epoxide has yet to be determined, this is the first example of such an enone undergoing asymmetric epoxidation using polyamino acid catalysis. 

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