Synthetic Efforts

Another aspect of the progress toward the development of a camptothecin drug candidate concerns the study of proper formulations, such as liposomes [22], and the finding of innovative drug delivery systems [23]. 

On the other hand, a total synthesis offers the possibility of substitutions and structural modifications that depend only on the manageability of the synthetic scheme, so enlarging the diversity of the target compounds, and is free from the constraints indicated above. However, an asymmetric synthesis is required, with several steps, and so far most of the total syntheses appear too expensive. Actually, the two drugs currently in clinical practice and most of the candidates presently (2006) in an advanced stage of development are produced by semisynthesis. 

The accessibility of position 9 becomes much higher when an activating group, such as an OH, is present in position 10. Although 10-hydroxycamptothecin (8) is available in small amounts from the plant material, two efficient preparations of this compound were developed, via catalytic reduction of CPT in acid medium to a tetrahydroquinoline, followed by selective oxidation with lead tetraacetate [8], or phenyliodonium diacetate [27], or via a photochemical rearrangement of camptothe- 

The early syntheses have been revietved by Schultz [38] and Hutchinson [39]. Other reviews, more medicinally oriented, have appeared [40]. One of the most recent and detailed, covering work from 1990 onward, is that of Du [41]. 

As it is not possible to review here the large number of different syntheses of C PT, we will only attempt to call the attention of the reader to some particular or relevant, in our biased view, aspects of the large portfolio of synthetic approaches to camptothecins. 

---

Cyclobutadiene escaped chemical charactenzation for more than 100 years Despite numerous attempts all synthetic efforts met with failure It became apparent not only that cyclobutadiene was not aromatic but that it was exceedingly unstable Beginning m the 1950s a variety of novel techniques succeeded m generating cyclobutadiene as a transient reactive intermediate... 

The additive approach to compatibilization is limited by the fact that there is a lack of economically viable routes for the synthesis of suitable block and graft copolymers for each system of interest. The compatihilizer market is often too specific and too small to justify a special synthetic effort. 

The first reported assignment of the PPS stmcture to reaction products prepared from benzene and sulfur in the presence of aluminum chloride was made by Genvresse in 1897 (8). These products were oligomeric and contained too much sulfur to be pure PPS. Genvresse isolated thianthrene and an amorphous, insoluble material that melted at 295°C. These early synthetic efforts have been reviewed (9—11). 

Despite the progress made in the stereoselective synthesis of (R)-pantothenic acid since the mid-1980s, the commercial chemical synthesis still involves resolution of racemic pantolactone. Recent (ca 1997) synthetic efforts have been directed toward developing a method for enantioselective synthesis of (R)-pantolactone by either chemical or microbial reduction of ketopantolactone. Microbial reduction of ketopantolactone is a promising area for future research. 

In the course of synthetic efforts aimed at obtaining 6j5-fluoro steroids, Kirk and Petrow treated a 3)5-acetoxy-6-raethyl-5a,6a-epoxide with boron trifluoride etherate and unexpectedly obtained a fluorine-free acetoxy ketone." Later transformations established that the product was the A-homo-B-norsteroid (104). 

The most recent synthetic efforts in this area have focused on the preparation of mono- and diformyl-substituted indolo[3,2-l)]carbazoles 202 and 203, which are potent aryl hydrocarbon receptor (AHR) ligands (cf. Section V,C). 

Although the preparation of the quite complex selector modules prior to the synthesis of the library represented a rather significant synthetic effort, this study showed clearly the potential of combinatorial chemistry in the early development stage of a chiral separation medium and demonstrated a novel approach to rapid screening that might be amenable to full automation in the future. 

The interest in azacyclooctatetraenes is mainly due to their structural similarity to cycloocta-tetraene.1 3 Most synthetic efforts have concentrated on a comparison of the unusual chemical and physical properties of cyclooctatetraene with its aza analogs. Besides studies concerning the aromaticity, the primary focus of much work has concerned the stability of the eight-membered ring and its valence isomerization. 

Synthetic efforts in Woodward s33 and Johnson s311 laboratories were directed at the same time towards a [3 + 2]-McDonald strategy to make sapphyrins readily available. This approach was then used by others to synthesize different sapphyrins.le 15a,b 16,17... 

The novel marine natural product laulimalide (65), a metabolite of various sponges, has received attention as a potential antitumor agent due to its taxol-like ability to stabilize microtubules. There has been considerable synthetic effort toward 65, culminating within not more than 2 years in as many as ten... 

Due to the prevalence and diversity of indole alkaloids and the limitations of space, no attempt will be made to describe all of the synthetic efforts in this area. However, noteworthy synthetic achievements include a synthesis of gelsemine <96JA7426>, (+)-duocarmycin by... 

New synthetic methods are the lifeblood of organic chemistry. Synthetic efforts toward natural products often provide the impetus for the development of novel methodology. Reactive synthons derived from 1,3-dioxanes have proven to be valuable intermediates for both syn- and anfz-1,3-diols found in many complex natural products. Coupling reactions at the 4-position of 1,3-dioxanes exploit anomeric effects to generate syu-1,3-diols (cyanohydrin acetonides), autz-1,3-diols (4-acetoxy-1,3-dioxanes), and either syn- or azztz-1,3-diols (4-lithio-1,3-dioxanes). In the future, as biologically active polyol-containing natural products continue to be discovered, the methods described above should see much use. 

The advantage of iterative strategies is based on the specific preparation of well defined structures and structurally perfect spacers of nanometer scale. This stepwise approach yields monodisperse material in contrast to other statistical routes. The use of the same reactants and the conversion of the same functional groups facilitates the synthetic effort compared with non-iterative methods. 

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. 

In nearly two decades, challenging structured of phomactins coupled with the interesting biological activity has elicited an impressive amount of synthetic efforts [16-18]. (+)-Phomactin D was first synthesized by Yamada in 1996 [19], and Wulff [20] reported the synthesis of ( )-phomactin B2 in 2007. However, (+)-phomactin A has been the most popular target because of its unique topology. To date, two monumental total syntheses have been accomplished Pattenden s [21] racemic synthesis and Halcomb s [22] asymmetric synthesis in 2002 and 2003, respectively. Both syntheses are beautifully done but also mimicked Yamada s synthesis of D, thereby underscoring the remarkable influence of Yamada s earlier work on the phomactin chemistry. Upon completing their synthesis of ( )-phomactin A, Pattenden [23] completed ( )-phomactin G via a modified route used for A. 

For an excellent review on synthetic efforts toward phomactins, see Goldring WPD, Pattenden G (2006) Acc Chem Res 39 354... 

However, soon afterward the original authors [137] as well as one other group, simultaneously revised the structures of punaglandins 3 (97) and 4 (98) based on synthesis of all possible stereoisomers [138]. These synthetic efforts not only established that the stereochemistry at Cl2 was opposite to that proposed, they also defined the complete absolute stereochemistry in punaglan-... 

Several of the synthetic efforts outlined in Section II were motivated partially by the necessity of increasing the processability of polyanhydrides. Solubilities of the 20 80 copolymers of P(CPP SA) and P(FAD SA) are compared by Domb and Maniar (1993). They reported improved solubility of the later over former in several organic solvents including (in order of decreasing solubility) THF, 2-butanone, 4-methyl-2-pentanone, acetone, and ethyl acetate. 

---