Hemi-synthesis

Roblot et al. (63) were the first to report the hemi-synthesis of a natural acetogenin of Annonaceae. They have shown that treatment of a natural precursor, diepomuricanin-A 121, by NaOH followed by acetylation with Ac20-pyridine afforded solamin diacetate 155 in 60 % yield. Unfortunately the composition of the expected diastereomeric mixture was not discussed. Indeed opening of the bis-epoxide system at either C-15 or C-20 would lead to two different compounds 155 and 156 with the same relative configuration but of opposite absolute configuration across the THF ring (Fig. 23). 

Tam et al. (14) have reported the hemi-synthesis of reticulatacin 154 from dieporeticanin 157, but by treatment with 70 % perchloric acid. Here again, two compounds 154 and 158 were expected with identical relative configuration, but with opposite absolute configuration across the THF ring, because of the opening arising either at C-17 or C-22 (Fig. 25). 

Tam et al. also reported the hemi-synthesis of trieponeticanin 159 (14) and its bisepimer (at C-23/24), by treatment with m-CPBA of a natural precursor, dieporeticenin 160 (Fig. 26). 

Corrossolone 161 was isolated from Annona muricata (48). Gromek et al. (9) reported its hemi-synthesis as an diastereomeric mixture at C-15/16/19/20, starting from corepoxylone 5, after treatment with 70 % perchloric acid in acetone. Indeed it has been shown by HPLC that two products, 161 and 162, were obtained, having identical spectroscopic data ( H NMR, 13C NMR, MS). These two compounds arise from the opening of the oxiranes at either C-15 or at C-20 position (Fig. 27). 

Isodeacetyl uvaricin 163 was isolated from Uvaria narum in 1991 (75), and more recently from Annona bullata and re-named 4-deoxy asimicin (76) In 1993, Sahpaz et al. (77) reported the hemi-synthesis of 163, starting from tripoxyrollin 164, which after treatment with perchloric acid (9) as already described in section 5.2., led to a complex mixture from which isodeacetyl uvaricin 163 could be characterized as well as other minor unnatural acetogenins (Fig. 28). 

Interest in die synthesis of enantiomerically pure compounds is also significant since both enantiomers of the same product often show distinctly different biological activities. In recent decades an enormous effort has been focused on the development of new methods for the stereoselective synthesis of natural products. These methods include a number of approaches for achieving enantioselective transformations of achiral substrates by using chiral auxiliaries, chiral reagents, or chiral catalysts [3]. However, from the range of different synthetic approaches available, the most useful for the synthesis of enantiomerically pure sesquiterpenes is still the hemi-synthesis from readily available natural sesquiterpenes. 

Bang, L., G. Ourisson, and P. Teisseire, 1975. Hydroxylation of patchoulol by rabbits. Hemi-synthesis of nor-patchoulenol, the odour carrier of patchouli oil. Tetrahedron 16 2211-2214. 

Stoddart and his coworkers have reported syntheses of the trans-syn-trans and the trans-anti-trans isomers of dicyclohexano-18-crown-6 The synthesis of these two compounds from trans-l,2-cyclohexanediol was accomplished in two stages. First, the diols were temporarily linked on one side by formation of the formal, and this was treated with diethylene glycol ditosylate and sodium hydride to form the hemi-crown formal. Removal of the formal protecting group, followed by a second cychzation completed the synthesis. The synthesis of the trans-anti-trans compound is illustrated below m Eq (3 12) and the structures of the five possible stereoisomers are shown as structures 1—5. 

In another variant of such reactions, the hemi-acetal 104, generated in situ by reaction of the corresponding allylic alcohol with acetaldehyde, undergoes cyclization in the presence of HgClOAc to afford the mercurated acetal 105.128 Under these conditions, the reaction leads to the jy -product with a high selectivity (dr > 10 1 Scheme 14). The same strategy has been applied iteratively for the stereoselective synthesis of natural products containing 1,3,5,7,9-pentaether chains.129... 

Scheme 37 Three-component synthesis and reactivity of hemi-ketal tetrahydrochromene derivatives...

Diols were converted to lactols by TPAP/NMO/PMS/CHjCN [352] or TPAP/NMO/ PMS/CH Clj-CHjCN [353] oxidation of a keto hemi-ketal by TPAP/NMO/PMS/ CH Cl in an avermectin synthesis yielded a lactol, via an intermediate retro-aldol [354], The 1,4-diols in Fig. 2.19 (R=C3H, Ph) produced lactones with TPAP/ NMO/PMS/CHjClj as did the 1,5-diol HO(CH3) C(OH)C5H, [46]. 

For the synthesis of CIO carba derivatives, a better leaving gronp than hydroxyl is nsnally preferred. The anomeric finoride , bromide, acetate, benzoate and phenyl-snlphonyl gronps have all been nsed and some of the chemistry that has been achieved is shown in Scheme 25. AllylsUanes tend to provide /S-confignred prodncts by axial attack on the oxoninm ion species (Scheme 25C) whereas larger nncleophiles snch as electron-rich aromatics add by attack on the a face (Scheme 25D). For nitrogen nncleophiles, Haynes and CO workers have employed the CIO anomeric bromide intermediate that gives the ClO-a hemi-aminal prodncts (Scheme 25E), some of which exhibit remarkable stability (Chart 1) . ... 

Cysteine proteases play key roles in the pathogenesis of a variety of disease states including osteoporosis [49], muscular dystrophy [50] and several CNS-related disorders [51]. A 100-member library of a-ketoamides 50 was generated via a two-step one-pot synthesis, in which the initial condensation was followed by a pyridinium dichromate (PDC) oxidation (Scheme 11.9). Yields were respectable, ranging from 53 to 75%. Note that a-ketoamides are potential reversible inhibitors with the ability to form hemi-thioacetals with the active thiol of cysteine residues. 

Corrphycenes and their metal complexes undergo four distinct one-electron redox steps, two are reduction steps and two are oxidation steps. A comparison with porphyrins and porphycenes indicates that the first reduction potentials of the free base and of metallo-corrphycenes are between those of porphycene 38, the easiest to reduce molecules, and those of porphyrins 2. The oxidation potentials of corrphycenes and porphyrins, however, are quite similar (00IC2850). The synthesis of hemi-porphycene 70 (Scheme 33) has been achieved (05ACI3047) from corrole 8 (R=C6H5). 

Fig. 12.4 Synthesis of the library of mixed hemi-salen titanium complexes, (a) Parallel synthesis MeOH, reflux, 12 h, >95% (b) pooled synthesis n-BuLi, -60°C to 20°C, 4 h (1 equiv.) TiCI4, -60°C to 20°C, 16 h (0.5 equiv.), >90%.

In addition to the preparation of a- and /3-hydrastine described above from the betaine (64), another conversion of a tetrahydroberberine into hydrastine has been reported. Acetylophiocarpine, on treatment with ethyl chloroformate, gives the acetoxy-derivative of (88), which can be hydrolysed to the hydroxymethyl compound and then oxidized to the aldehyde by pyridinium perchlorate. Hydrolysis of the acetoxyl group afforded the hemi-acetal (93 R = H), conversion of which into the mixed acetal (93 R = Et) protected the aldehyde system during reduction of N—C02Et to NMe by lithium aluminium hydride. Hydrolysis of the acetal, followed by oxidation, then gave a-hydrastine, and a similar sequence of reactions starting from O-acetyl-13-epi-ophiocarpine afforded / -hydrastine.119 Methods of synthesis of alkaloids of this group have been reviewed.120... 

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