Endiandric acid synthesis

We planned to test the RCDA reaction on the known diol 4 (an intermediate in Nicolaou s endiandric acid synthesis) or a derivative thereof (Scheme 3). These model compounds have substituents at the relevant positions on the cyclobutane ring. However, unlike the pre-kingianin isomeric pairs, which have the potential to afford eight racemic endo Diels-Alder products. 

Although the above-mentioned electrocyclization reactions were well studied prior to the discovery of the endiandric acids, their utilization in the total synthesis of complex molecules had not been demonstrated. The endiandric acids, therefore, offered an irresistible opportunity to explore the utility of electrocyclization reactions in synthesis. The successful studies disclosed below demonstrate that these reactions can provide concise solutions to the challenge presented by complex polycyclic frameworks. 

Stepwise, Stereocontrolled Total Synthesis of Endiandric Acids A-D (and E-G)... 

Although the biosynthetic cascade hypothesis predicts the co-occurrence of endiandric acids D (4) and A (1) in nature, the former compound was not isolated until after its total synthesis was completed in the laboratory (see Scheme 6). Our journey to endiandric acid D (4) commences with the desilylation of key intermediate 22 to give alcohol 31 in 95% yield. The endo side chain is then converted to a methyl ester by hydrolysis of the nitrile to the corresponding acid with basic hydrogen peroxide, followed by esterification with diazomethane to afford intermediate 32 in 92% overall yield. The exo side chain is then constructed by sequential bromination, cyanide displacement, ester hydrolysis (33), reduction, and olefination (4) in a straight-... 

The biogenetic scheme for endiandric acids also predicts the plausible existence in nature of endiandric acids E (5), F (6), and G (7). Even though they are still undiscovered, their synthesis has been achieved (Scheme 6). For endiandric acids E and F, key intermediate 24 is converted, by conventional means, to aldehyde 35 via intermediate 34. Oxidation of 35 with silver oxide in the presence of sodium hydroxide results in the formation of endiandric acid E (5) in 90 % yield, whereas elaboration of the exo side chain by standard olefination (85 % yield) and alkaline hydrolysis (90 % yield) furnishes endiandric acid F (6). The construction of the remaining compound, endiandric acid G (7), commences with the methyl ester of endiandric acid D (36) and proceeds by partial reduction to the corresponding aldehyde, followed by olefination and hydrolysis with aqueous base as shown in Scheme 6. 

Through a display of a series of electrocyclization reactions, the Nicolaou group demonstrated the biomimetic , one-step synthesis of the endiandric acids involving the cascade of reactions proposed by Black. The polyunsaturated compounds 37 and 38 (Scheme 7) were designed for their relative stability and potential to serve as... 

Industrial synthesis of vitamin A (Hoffman-La-Roche) goes through partial hydrogenation of an enyne (equation 161)277. A number of syntheses of pheromones, where the reduction of an enyne to a diene is the key step, have been devised. A few selected examples are given in Table 29278. During the total synthesis of endiandric acids, Nico-laou employed hydrogenation of a polyenyne intermediate with a Lindlar catalyst to generate an intermediate which underwent symmetry-allowed cyclizations to result in the natural product (equation 162)279. 

During the biomimetic total synthesis of endiandric acids A-G by K.C. Nicolaou and co-workers, the key polyunsaturated precursor was assembled via the Giaser coupiing of two different terminal alkynes. " One of the alkynes was used in excess so the yield of the heterocoupled diyne could be maximized. In a solvent mixture of pyridine methanol (1 1), the two reactant alkynes were treated with Cu(OAc)2 at 25 °C to provide the desired diyne in 70% yield. 

Nicolaou, K. C., Petasis, N. A., Uenishi, J., Zipkin, R. E. The endiandric acid cascade. Electrocyclizations in organic synthesis. 2. Stepwise, stereocontrolled total synthesis of endiandric acids C-G. J. Am. Chem. Soc. 1982, 104, 5557-5558. 

Various eupomatenoids, e.g., (184), have been prepared by a simple procedure involving a one-pot quarternization and intramolecular Wittig reaction as the key step (Scheme 24). In a series of papers investigating the synthesis of the endiandric acids both Wittig and phosphonate olefinations have been used. o... 

The synthesis of lanosterol (140) from epoxide 139 has an Lfo, =+4. The key multiple ring-closure step 141+142- [143] in Johnson s synthesis of progesterone has also an Lfoj =+4 (Lfor for [143]- 144 would depend on the by-products). Next, we see the three steps 145+146- 147- [148]- 149 in Vollhardts synthesis of estrone with Lfor is +3, -1, +2 respectively for the overall transformatiom L r =+3-l+2=+4. The next two transformations, ISO- 151 in Nicolaou s biomimetic synthesis of endiandric acid A, and Negishi s palladium-catalyzed tetracyclization 152- 153 are also characterized by Lfor =+4. Trost s one-step polyclization... 

Draw the structure of the product from the following reaction (formed during a synthesis of one of the endiandric acids by K. C. Nicolaou) ... 

Reduction-triggered pericyclic reaction has been used for the biomimetic total synthesis of endiandric acids A-G [72]. Endiandric acids are polycychc natural products isolated from the Australian plant Endiandra introrsa and exist naturally as a racemic mixture which is found to have very high antibacterial effect [73]. In 1980, Black and coworkers [74] proposed a hypothesis that these polycyclic systems are formed in nature by a series of electrocycUzation reactions. On the basis of this hypothesis, Nicolaou et al. [72c] in 1982 reported an excellent domino reduction/electrocyclization process for the synthesis of endiandric acid A 127 (Scheme 9.25). Selective hydrogenation using a Lindlar catalyst of diacetylenic diol 123 afforded the bicyclic diol 126. The reaction presumably proceeds via polyene 124, which then undergoes a spontaneous 8 [i-electrocyclization to give 125. It follows a second 6n-electrocyclization to afford bicyclic 126, which is further converted to endiandric acid A 127. 

Scheme 9.25 Synthesis of endiandric acid A by domino reduction/double electrocyclization.

The first chapter provides an informative introduction to this area of biomimetic natural product synthesis, in particular focusing on the role of electrocyclisation reaction cascades, from K.C. Nicolaou s seminal synthesis of the endiandric acids, to the more recent research carried out on the tridachiahydropyrones and related sacoglossan metabolites. The thesis then sets out to explore the hypothesis that these secondary metabolites function as photo-protective membrane antioxidants, shielding the producing organisms from the damaging effects of UV radiation. 

The earliest example of a biomimetic electrocyclisation cascade sequence in natural product synthesis is in Nicolaou s syntheses of the endiandric acids, isolated by Black in the early 1980s [15]. To explain the racemic nature of these natural products, Black proposed that they are formed spontaneously from achiral polyene precursors through non-enzymatically assisted electrocyclisation and cycloaddition cascades. In 1982 Nicolaou reported the synthesis of the methyl esters of all endiandric acids A-G in a one-operation cascade approach from linear polyene precursors [16]. The synthesis of endiandric acids A, D and E methyl esters (32, 30 and 31 respectively) is outlined below (Scheme 1.5). 

Scheme 1.5 Nicolaou s biomimetic synthesis of the endiandric acid methyl esters. Reagents and conditions a H2, Pd/BaSOa, quinoline b PhMe, 100 °C...

A new synthesis of (l/J)-frfl/i5-chrysanthemic ester has appeared along with routes to its known chiral precursors. A remarkable illustration of the use of electrocyclizations in the synthesis of endiandric acids is reported which has important biosynthetic consequences. Other notable synthetic achievements this year include ( )-pisiferic acid, (+)-zizanoic acid, ( )-lysergic acid, and chorismic acid. ... 

In an impressive piece of work, Nicolaou et al. have worked out a total synthesis for the acids, where the strategy relies on a unique series of Wood-ward-Hoffman-controlled electrocyclic reactions. Thus, Lindlar hydrogenation of the diene-diyne (136), for example, led to (139) via (137) and (138) (139) was then converted into (140). Intramolecular Diels-Alder cycli2ation of (140) then gave (141), which is a precursor to endiandric acid A (142). Furthermore, based... 

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