Camphane, analysis

Norvasc , Pfizer s entry into the crowded CCB market, was launched in 1990. Like most of the more recently launched compounds, this drug also has two different ester substituents and thus is sold as a mixture of isomers. Initial work on the analysis of the two possible isomers suggested that the R isomer 22 was more potent than the corresponding S isomer 23 this suggested that amlodipine differed in this respect from other dihydropyridine CCBs in which the S isomer is usually the more active (Gold-mann and Stoltefuss, 1991). A more recent preparation of the (—)-(15)-camphanic derivatives of amlodipine and the subsequent X-ray of its derivatives clearly showed that it is the S derivative that is more active (Arrowsmith et ak, 1986 Goldmann et al., 1992). 

Oxabicyclo[6.3.2]trideca-l(ll),8,12-trienes (3,6-hexanooxepine) [15, R = CH2OH]83 was resolved via the diastereomeric esters with (lS ,4iR)-camphanic acid. X-ray analysis of one of the esters was used for configurational assignment (see p 447). 

The diastereomeric esters that resulted from rat-8a with (—)-camphanic acid were separated, and an X-ray analysis established the configuration of one of the esters. This compound was then converted via 8b into D3-trishomocubane (—)-9159. 

The absolute configuration of the product has been proved by X-ray analysis of the corresponding camphanic ester.2 3... 

Yields, melting points, and specific rotations of nitrodiol monoacetates which were prepared by procedure C described above by using PLE-powder2 instead of purified enzyme. Entries 1 and 3 in Table 1 refer to runs following the above procedure, for all other cases the self made crude PLE-powder was used. The configuration and the sense of chirality of the products of entries 1,3 and 4 were determined by x-ray crystal structure analysis of the camphanic esters, those of the other are inferred by analogy and by NMR comparison. The open chain compounds (entries 1 and 2) were obtained using TES buffer at pH 6.5... 

Figure 6.14 Examples of the application of normal-phase, radio-HPLC to the analysis of de novo biosynthetic pathways in bark beetles (Scolytidae). Derivatization of 14C-labeled ipsenol from Ips paraconfusus (A, B) and 14C-labeled ipsdienol from Ips pini (C, D) leads to expected retention time shifts of radioactivity for each compound and derivative. Derivatization of /. paraconfusus ipsenol with (2/= )-(+)-a-methoxy-a-(trifluoromethyl) phenylacetic acid (MTPA) leads to the formation of only one diastereomer [(4S)-(-)-ipsenoyl-(2 P )-2 -methoxy-2 -phenyl-2 - (trifluoromethyl) phenylacetate] indicating the de novo biosynthesis of highly pure (4S)-(-)-ipsenol (B) Derivatization of I. pini ipsdienol with (1 S)-(-)-camphanic acid leads to the formation of both diastereomers [(4R)- -)- and (4S)-(+)-ipsdienyl-(TS)-camphanates] indicating the de novo biosynthesis of approximately 90 percent-(4/ )-(-)-ipsdienol (D). Figures adapted from Seybold et al. (1995b).

In the case of the halogenated alcohols 14 and 15, their diastereomeric CSDP esters were obtained as fine crystals, which were unsuitable for X-ray crystallography, so the enantiopure alcohol recovered (—)-14 was converted to camphanate ester, the absolute configuration of which was determined by X-ray crystallography as R (entry 4). Alcohol ( )-15 was treated in the same way, but its caphanate ester was not suitable for X-ray analysis (entry 5). The absolute configuration of ( )-15 was determined as R by comparison of its CD spectrum with that of (P)-(-)-14. 

Full details of the previously reported (Vol. 6, p. 73) synthesis of the seco-illudane sequiterpenoid hypacrone (346) have been published. An interesting feature of the synthetic route is the use of a directed crossed aldol condensation between the diketone (344) and the trimethylsilyl enol-ether (343) to produce the trans-isomer (345) of hypacrone (346). The absolute configuration of fomannosin (347) has finally been established by X-ray analysis of the camphanate ester derivative (348). Full details of the biosynthesis of fomannosin (347) from [l,2- C2]acetate (c/. Vol. 7, pp. 82, 196) have been published. The labelling pattern and couplings in fomannosin (347) are consistent with a biosyn-... 

Both alcohols were treated with 1 (S)-(-)-camphanic chloride in the presence of DMAP in pyridine to afford a mixture of diatereoisomers, which were separated by HPLC. In the case of alcohol 4, diastereoi somers 13 and 14 were obtained and these were then treated with KOH/MeOH to yield optically active alcohols, (+)-4 and (-)-4. Jones reagent was then used to oxidise these and afforded the ketones, (-)-ll and (+)-ll, respectively. The CD spectrum of (-)-ll showed a negative Cotton effect, and that of (+)-ll a positive. Using the Octant rule, the absolute configurations were assigned as shown in Scheme 3 (7). These results were confirmed by the X-ray analysis of ester 14 (8). The alcohol 12 afforded the ketones (-)-ll and (+)-ll through 15, 16 and 12. The absolute configurations of 15,16 and 12 were determined as shown in Scheme 3. 

Separation and Assay. Procedures for the separation, purification, and assay of carotenoids and retinoids by h.p.l.c., g.c., and g.c.-m.s. are given in an extensive article." Another, general, review includes information on the h.p.l.c. separation of retinoids.A particularly useful method has been developed for resolution and analysis of some carotenoid optical isomers.For example, (3R,3 R)-, (3S,3 S)-, and (3/ ,3 5)-astaxanthin were converted into the diastereomeric (-)-camphanic acid diesters, which were separated by h.p.l.c. This procedure has been used to analyse the isomeric composition of a natural astaxanthin sample. An h.p.l.c. procedure for separation of a-, P-, and y-carotenes (173)—(175) and lycopene (176) has been described." Several papers describe methods for the h.p.l.c. separation and purification of various retinal and retinol isomers and derivatives.A procedure for the preparative t.l.c. of oxidation products of retinyl acetate has been described,and a competitive protein-binding radioassay for retinoic has been reported. 

A typical example of this internal reference method is shown in Figure 55.5, where alcohol (—)-6 has a bromine atom but no single crystals suitable for X-ray diffraction analysis were obtained. Therefore, alcohol ( )-6 was esterified with (15)-(—)-camphanic acid 5 (CXR), yielding ester 7 as single crystals. From the X-ray stereostructure of ester 7, the AC of (—)-6 was unambiguously determined to heR. 

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