Previous Synthetic Work

The C2o-diterpene alkaloids have long served as classic targets within the field of natural product synthesis [14], Total syntheses of four C2o-diterpene alkaloids have thus far been reported atisine [15], veatchine [16], garryine [17], and napelline [18]. In spite of this progress, synthetic efforts toward the hetisine alkaloids have been relatively sparse. Prior to our work in the area, these efforts include one total synthesis and five synthetic studies. 

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Synthetic work on the mesembrane group will no doubt be further stimulated by reports on their central nervous system activity and somewhat surprising biosynthesis. An interesting asymmetric synthesis of unnatural (+ )-mesembrine (38) has been announced (Scheme 4). The key intermediate (35), prepared in nine steps from 1,2-dimethoxybenzene, was treated with L-proline pyrrolidide (36) under conditions typical for the preparation of enamines. The product was not isolated but subjected to reaction with methyl vinyl ketone followed by acid treatment to give the cyclohexenone (37) in 38 % overall yield. The last step in the synthesis [(37) — (38)] was based on previous synthetic work on mesembrine alkaloids. The synthetic (+ )-mesembrine (38) was shown to exhibit a positive Cotton effect and thus an antipodal relationship to natural (— )-mesembrine. The mesembrine analogues (40 = H or OMe, = H, Me, or CHjPh) have... 

The original objective of the synthetic work was the preparation of basic derivatives of the 3,1,4-benzoxadiazepine system (2) for animal testing. The basic ring system had been reported previously in the literature as the dehydration products of 2-acylaminobenzophenone oximes (1). Repetition of the work quickly cast doubt on the earlier structural assignment. Both the chemistry of the products and their spectral data suggested that the products were in fact quinazoline-3-oxides (3). ... 

An alternative to chemical synthesis is to use human CYP enzymes to generate the desired human drug metabolites. Various means of making human P450s have been used, all with certain drawbacks [81]. The most common source is pooled HLMs, which has been described in detail previously, but these microsomal preparations contain a mixture of many different enzymes, and their cost, batch-to-batch variability in activity and restrictions on availability can limit the usefulness of HLMs for preparative synthetic work. These limitations can become particularly acute when the required amount of a pure metabolite exceeds 5-10 mg. 

Probably the most important recent advance in the chemistry of dibenzothiophene has been the adoption of NMR techniques for structural determination. This will eliminate much of the tedious synthetic work which was previously needed to establish the structure of new derivatives. 

Closely related to the synthetic work reported in the previous section is the incorporation (131) of a 2,5-anhydro-3,4Hdi-0-methyl-D-mannitol residue (Figure 15) into the 18-crown-6 derivative d-91. Other derivatives of D-mannitol that have been built into crown ether receptors include l,4 3,6-dianhydro-D-maiuiitol (132), l,3 4,6-di-0-methylene-D-marmitol (13 134), and 1,3 4,6-di-O-benzylidene-D-mannitol (134). Examples of chiral crown compounds containing these residues include dd-92, dd-93, d-94, and d-95. Although not derived from carbohydrates—but rather (135) from the terpene, (-t-)-pulegone—... 

This chapter represents an update to the previous two editions, published in 19771 and 19892, and covers the literature of the period 1989-1994 with some references to 1995 papers. It deals mainly with electrophilic additions across the C=C, C=Si and Si=Si bonds and includes both theoretical (ab initio calculations, orbital approach, molecular modelling etc.) and experimental aspects. Particular attention is paid to mechanistic studies, facial selectivity and neighbouring group participation. Synthetic utilization of electrophilic addition is discussed only if including substantial mechanistic insight purely synthetic work is not covered. Aside from the classical reactions, such as hydration, bromination etc., newly included material comprises aziridination (Section VI), attack at C=C bond by an electron-deficient carbon (Section VII) and those electrophilic reactions which utilize a transition or non-transition metal as the electrophile (Section VIII). 

Since the synthesis of glycolipids involves the synthesis of both the lipid and the oligosaccharide portions, we shall also discuss that part of the recorded lipid synthetic work which has involved the use of carbohydrates. In fact, some of the first-recorded applications of carbohydrate molecules as chiral templates are to be found in the lipid field particularly with the use of 1,2 5,6-di-O-isopropylidene-D-mannitol [33] as a precursor of chiral glycerol derivatives for the synthesis of phospholipids and glycolipids based on glycerol and with the use of glucosamine derivatives for the synthesis of phytosphingosines [34] and since this area has not previously been reviewed, it will be treated with a more historical perspective. 

Some of the earlier synthetic work in the vinblastine area, previously reported in brief, has now been published in detail. This includes syntheses of 16 -desmethoxycarbonyl-20 -deoxy-16 -ept-vinblastine,107a Catharine, and vinami-dine,120 and Potier has summarized the work which culminated in the synthesis of vinblastine.121... 

Advances in petroleum characterization at the molecular structure level by GC-MS methods renewed interest in OSC. Within the past few years, at least one-thousand new and novel OSC that previously were not known to be present in petroleum and bitumens have been reported. Tentative molecular structures inferred from GC-MS and other techniques have been confirmed in many cases by synthesis of authentic reference-compounds. The difficult and time-consuming synthetic work has been crucial in validating many of the novel structures. Another key finding has been that immature bitumens and crude oils (samples that have not received significant thermal stress) differ markedly from the previously known OSC in that they have carbon-skeletons resembling ubiquitous biomarker hydrocarbons (e.g., n-alkanes, isoprenoid alkanes, steranes, and hopanes). This similarity, of course, suggests that the hydrocarbons and OSC have common biogenic precursors. 

Asymmetric syntheses directed toward construction of enantiomers of the western and southern corn root-worm pheromones are described. A brief review of the subject of asymmetric synthesis as it is related to the synthesis of insect sex pheromones is presented. The laboratory s previous research with chiral pheromones is summarized (Japanese beetle, white peach scale, and lesser tea tortrix) before detailing synthetic work on the pheromones of the aforementioned rootworm species. Throughout the course of the synthetic effort, cholesteric stationary phases for GLC have found use. Their superior ability to separate crucial diastereomeric intermediates for synthesis is detailed. 

Ban s synthetic work has been taken a stage further this year with the first total synthesis of aspidofractinine (207) (Scheme 28). The closely related alchohol (208), synthesized previously, could not be converted into aspidofractinine hence, an alternative synthesis was devised from the important intermediate (209), in which the sixth ring was introduced via a Diels-Alder addition of nitroethylene, which was highly regio- and stereo-selective, to the diene (210). 

A facile synthetic route to a-santalol (105) from the previously known aldehyde (106) has been reported by Corey et a/. in which a stereospecific modified Wittig reaction [(i) ethylidenetriphenylphosphorane, (ii) n-butyl-lithium, and (iii) paraformaldehyde] yielded the desired cis-isomer. Erman and co-workers, in a continuation of their synthetic work on the santalols, have reported the preparation of -santalol (107) from 3-methylnorcamphor. The route also provided a sample of the tmns-isomer which had previously been considered to be the natural isomer. The use of a borate ester as a protecting group for a hydroxy-function facilitated the synthesis of dihydro- -santalol (108) as outlined in Scheme 3. (These borate esters are stable to anhydrous acid or base but are readily hydrolysed in aqueous media.)... 

Synthetic work has utilized, in the main, the base-catalyzed eliminations noted previously,1 and a series of compounds having the general structure 40 have now been synthesized as outlined in Table II. 

In continuation of extensive synthetic work on alkaloids, Schopf and coworkers have prepared meso-l,3-di-(2-piperidyl)propan-2-one and shown that it is identical with anaferine (15), previously isolated from Withania somnifera.20 Condensation of 2,3,4,5-tetrahydropyridine with acetonedicarboxylic acid at pH 11.5 gives a mixture of the meso- and racemic forms of (15). Their configurations were established by reduction to stereoisomeric mixtures of alcohols. An interesting reaction [(15) —>(16)] was observed when anaferine was distilled at high vacuum. The preparation of (17), a compound related to the piperidine alkaloid anaferine, using a well-travelled reaction sequence, has been reported.21... 

The order of reactivity agrees with previous studies—TMEDA being by far the most reactive of the readily available tertiary diamines. [Sparteine appears to be the most activating of the tertiary diamines investigated (I, 10)]. Recent reports by Langer and others indicate that increased activation is expected from the methyl tertiary polyamines containing more than two basic nitrogens, all separated by two carbons (II). Preparative and synthetic work centered on TMEDA and TED (DABCO) because of their economic practicality. 

The characterization of the degradation products 31, 32, and 100, facilitated by the previous synthetic and degradative work on securinine, fully describes the relative configuration of the three centers of chirality (C-2, C-7, and C-9) in allosecurinine (96). In addition, it may be seen that one of these, lactam-carbinol C (31) (mp 258-260° [a] -I- 45.3° in EtOH IR (KBr) 3289 and 1634 cm" ), corresponds fully in physical constants to the hexahydroallosecurinine obtained by Satoda 14) and Parello 16) and their co-workers (Table II). Interestingly, Horii... 

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