The Wender Synthesis

The Wender synthesis was reported in two communcations in 1997 435, 436), but the full papers have yet to appear. The synthesis is linear of the form A- AB- ABC- ABCD, but it is very different from the formally similar Holton approach. 

The synthesis depends on some key rearrangement chemistry of verbenone (14.4.1), the oxidation product of the abundant natural product pinene. Verbenone provided 10 of the 20 carbons of the baccatin III ring system and also its chirality. Verbenone (14.4.1) was converted to the chrysanthenone derivative 14.4.3 by photorearrangement of 

and 14.4.3 was then converted to the tricyclic intermediate 14.4.8. Oxidative cleavage of 14.4.8 then gave the AB synthon 14.4.9 in good yield. 

The C-ring of baccatin III was elaborated through the C-3 position, which was used as a base on which to build aldehyde side chain of 14.4.16. Aldol cyclization and protection then gave 14.4.17, which was converted to baccatin III (14.4.23) or 10-deacetylbaccatin III (14.4.22) by the reactions shown. The overall synthesis, at 37 steps from verbenone, is claimed to be the shortest reported synthesis of taxol. 

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There are numerous other syntheses of indoles, and a modern example is the Wender synthesis. Here a 2-bromo-iV-(trifluoroacetyl)aniline in THF is deprotonated by butyllithium and then, in the same pot, reacted with fert-butyllithium to effect halogen-metal exchange to give the dilithiated derivative. To this intermediate is added an a-bromo ketone. A carbon-carbon bond is established first between the reactants, and then cyclization occurs to form a hydroxyindoline. Finally, dehydration generates the indole (Scheme 7.16). 

Wender, P. Miller, B.L. (1993) Toward the Ideal Synthesis Connectivity Analysis and Multibond-Forming Processes. In Organic Synthesis Theory and Applications, Vol. 2 (ed. T. Hudlicky), pp. 27-65. JAl Press, Greenwich, CT. 

PA Wender, DJ Mitchell, K Pattabiraman, ET Pelkey, L Steinman, JB Rothbard. The design, synthesis, and evaluation of molecules that enable or enhance cellular uptake Peptoid molecular transporters. Proc Natl Acad Sci USA 97 13003-13008, 2000. 

The [4+ 4]-cycloaddition reaction of tethered bis-dienes has been used by Wender and co-workers in total synthesis as exemplified in syntheses of ( )-salsolene oxide and (-l-)-asteriscanolide (Scheme 28). In the synthesis of ( )-salsolene oxide, a nickel(0)-catalyst cleanly effects the cycloaddition of the two conjugated dienes in compound 93 to afford the bicyclo[5.3.1]undecadiene in a good yield and with moderate selectivity.99 The first synthesis of (-l-)-asteriscanolide was accomplished in only 13 steps. The key [4+ 4]-cycloaddition reaction efficiently set the requisite eight-membered ring of (-l-)-asteriscanolide in good yield and with excellent diastereoselectivity.100 The diastereoselective [4 + 4]-cycloaddition has also been applied to the synthesis of the core ring system found in several sesterterpenes such as the ophiobolins (Scheme 28).101... 

In Holton s and Wender s work, the total synthesis was achieved by sequentially forming the AB ring through the fragmentation of epoxy alcohols derived from (—)-camphor and a-pinene. Nicolau s, Danishefsky s, and Kuwa-jima s total syntheses involved B ring closure connecting the A and C rings, whereas in Mukaiyama s synthesis, the aldol reaction was extensively applied to construct the polycyclic system. 

Wender et al. s [5 + 2] metal-catalyzed annulation strategy has also been applied to the total synthesis of (+)-aphanamol I (154) [34]. The scope of this method was expanded by using a tetrasubstituted allene that resulted in the stereoselective formation of an angular methyl group. The reaction of allene 149 with 0.5 mol% of rhodium biscarbonyl choride dimer afforded the fused bicyclic product 152 in 93% yield with complete exo/endo and diastereoselectivity (Scheme 19.28). The stereoselectivity of this process was attributed to a preference for formation of the cis-fused metallo-... 

Wender PA, Handy ST, Wright DL (1997) Towards the ideal synthesis. Chem Ind 765-768 14. Zhu JP (2003) Recent developments in the isonitrile-based multicomponent synthesis of heterocycles. Eur J Org Chem 1133-1144... 

Finally, in a very recent disclosure, Lee et al. (165) approached the total synthesis of arteminolide using a [5 + 2] cycloaddition strategy with an oxidopyrylium ion. Despite its long history of use, Lee was the first to utilize an allene moiety both in an intra- and an intermolecular cycloaddition with oxidopyrylium ions. By utilizing a pyrone cycloaddition precursor (294) similar to those used in the Wender phorbol synthesis, Lee was able to synthesize various ring sizes and... 

Overall MCRs are a big step towards the ideal synthesis, which, according to Wender et al. can be measured by parameters such as the step count, overall yield, selectivity, cost, scale, resource requirements, waste stream, development time, execution time and personnel [8], The discovery of novel IMCRs are explained and several conceptually different approaches towards this goal, with an emphasis on our recent contributions in this area are shown. 

These intramolecular meta-addition processes were utilized in the key steps for the total synthesis of a-cedrene [245], isocomene [246], hirsutene [247], coriolin [248], silphinene [249], rudmollin [250], laurenene [251], and fenestranes [252-254], which were synthesized by Wender s and Keese s groups (Scheme 58). 

Wender PA, Howbert JJ, Dore TM. The total synthesis of (+/—)-a-cedrene. In Mattay J, Griesbeck AG, eds. Photochemical Key Steps in Organic Synthesis. Weinheim VCH, 1994 181-185. 

Wender PA, Handy ST, Wright DL (1997) Towards the ideal synthesis. Chem Ind 765 767-769... 

Wender and co-workers have continued their elegant use of the meta photocycloaddition of ethylenes to arenes as the key step in the synthesis of several naturally occurring compounds. The major product from irradiation of benzene and vinyl acetate is the 1-endo acetate of (36), and using this as the starting material, the total synthesis of the ant defensive secretion, isoiridomyrmecin (50), has been accomplished in seven further steps." There... 

A structurally novel cancer therapeutic agent, (-)-laulimalide, was isolated from Pacific marine sponges in trace amounts, and it was shown to promote abnormal tubulin polymerization. P.A. Wender et al. applied the modified Seyfert-Gilbert homologation on a complex substrate in the endgame of the total synthesis to obtain the desired terminal alkyne""... 

E S S CONTENTS Preface, Tomas Hudlicky. Modern Synthetic Design Symmetry, Simplicity, Efficiency and Art, Tomas Hudlicky and Michael Natchus. Toward the Ideal Synthesis Connectivity Analysis, Paul Wender and Benjamin L. Miller. Application of Graph Theory to Synthesis Planning Complexity, Reflexivity and Vulnerability, Steven H. Bertz and Toby J. Sommer. Asymmetric Reactions Promoted by Titanium Reagents, Koichi Narasaka and Nobuharu Iwasawa. The Use of Arene Cis-diols in Synthesis, Stephen M. Brown... 

Wender s construction of the A/B ring system [8a] in principle resembles the Holton synthesis, but makes use of the 4/6 precursor... 

The more convergent routes of Nicolaou et al. and Danishefsky et al. with B ring closure from a tethered A-C precursor are clearly the least efficient with respect to total yield (about 0.01 % starting from commercially available materials) if directly compared to the other two routes. Additionally the Nicolaou route needs enantiomer separation or a -presumably less favorable - asymmetric synthesis, whereas the Danishefsky route addresses absolute stereochemistry but involves more steps. Holton s synthesis shows quite good yields throughout with a total one of approximately 0,1 %, but has less room for improvements and is based on a not readily available starting material. The best synthesis in all respects to date is the one of Wender and coworkers, which is about 1-2 orders of magnitudes better in total yield (ca. 0.8%),... 

The second new synthesis of 7-methoxymitosene (3) was published by Wender and Cooper [34]. Based on a novel triazole photolysis, it affords the product in 8.3% yield after 12 steps. It is more efficient than the original synthesis of 3, but it requires more steps than the synthesis reported by Luly and Rapoport in 1984. As illustrated in Scheme 12, it began with 2,6-dimethoxytol-uene (91), which was converted into azido derivative 92 by the sequence of nitration, catalytic reduction, diazotization, and treatment with sodium azide. Dimroth condensation of 92 with ethyl 6-triisopropylsiloxy-3-oxohexanoate in... 

The Wender group has investigated the (5 + 2) cycloaddition for quite some time and made seminal contributions to this important reaction. The group has also made fundamental contributions to higher order cycloadditions, thus opening up possibilities for the synthesis of natural products containing medium-sized rings. The first example leads toward the phorbol diterpenes... 

The next synthesis by Wender (Scheme 11.22) [29] is method-oriented. It demonstrates a metal-mediated 4 + 4 -cycloaddition to generate the eight-membered carbocycle. This renders the synthetie sequenee short, allowing the preparation of the cyclization precursor to use traditional steps of open-chain synthesis. Note that all branches are generated by bond-formation. 

Scheme 6. The mechanism of oxidopyrylium formation (a) and its application (b) to the total synthesis of phorboi (2). (Wender, 1989)i ...

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