Natural product synthesis 3 + 2 cyclizations

The cyclization to form very congested quaternary carbon centers involving the intramolecular insertion of di-, tri-, and tetrasubstituted alkenes is particularly useful for natural products synthesis[l36-138], In the total synthesis of gelsemine, the cyclization of 166 has been carried out, in which very severe steric hindrance is e.xpected. Interestingly, one stereoisomer 167... 

Buchwald has developed a route to indolines by the Pd-catalyzed intramolecular amination of aryl halides <96T7525> and applied this method to the synthesis of natural products. Thus, cyclization of tetrahydroquinoline 70 provided 71 which was elaborated to a key intermediate in syntheses of damirones A and B and makuluvamine <96JA1028>. 

Harring, S. R. Livinghouse, T. Sulfenium ion promoted polyene cyclizations in natural product synthesis. An efficient biomimetic-like synthesis of ( )-nimbidiol. Tetrahedron Lett. 1989, 30, 1499-1502. 

The Heck reaction, a palladium-catalyzed vinylic substitution, is conducted with olefins and organohalides or pseudohalides are frequently used as reactants [15, 16], One of the strengths of the method is that it enables the direct monofunctionalization of a vinylic carbon, which is difficult to achieve by other means. Numerous elegant transformations based on Heck chemistry have been developed in natural and non-natural product synthesis. Intermolecular reactions with cyclic and acyclic al-kenes, and intramolecular cyclization procedures, have led to the assembly of a variety of complex and sterically congested molecules. 

A relatively recent application to natural product synthesis stems from efforts to synthesize a sesquiterpene called 1-sterpurene 7 [17]. This substance is thought to be the causative agent of the so-called silver leaf disease that affects certain species of shrubs and trees. The strategy focuses on three key steps (a) electrochemical cyclization of the bis unsaturated ester 11 to produce the five-membered ring of 10, (b) a Ruhlman-modified acyloin condensation to... 

The first natural product synthesis that utilized the Stetter reaction was reported by Stetter and Kuhhnann in 1975 as an approach to aT-jasmone and dihydrojas-mone (Scheme 21) [93]. Thiazolium pre-catalyst 74 was effective in catalyti-cally generating the acyl anion equivalent with aldehydes 144 and 145, then adding to 3-buten-2-one 146 in good yield. Cyclization followed by dehydration gives cii-jasmone and dihydrojasmone in 62 and 69% yield, respectively, over two steps. Similarly, Galopin coupled 3-buten-2-one and isovaleraldehyde in the synthesis of ( )-rran5-sabinene hydrate [94]. 

In another early application to natural product synthesis, Fleming and coworkers utilized this approach in the efficient formation of the gelsemine model (47) from 45 according to Scheme 8. The cyclization step to form the spiro-oxindole (46) proceeded in 85% yield and provided a means of generating the spiro-fused quaternary carbon without the need for carbenium ion or carbanion chemistry. 

This strategy has already been found useful in natural product synthesis. In the course of a synthesis of V-ATPase inhibitor oximidine HI, John Porco of Boston University has described (Angew. Chem. Ini. Ed. 2004,43, 3601) the cyclization of 7 to 8. In the absence of the pententyl director, the initial complexation of the Ru catalyst was with the 1,3-diene, leading to allylidene complex and so effectively killing the catalyst. In this case, the Hoveyda catalyst 8 provided a cleaner product than G2 did. 

The product of this synthesis is an especially useful, highly functionalized hydroazulene that is not available commercially. We have used it as a synthetic precursor to homoazulene,5 and to a variety of homoazulene derivatives,6 bridged homotropylium cations,7 and azulene quinones.8 It could undoubtedly serve as a precursor to numerous natural products. The cyclization reaction tolerates electron-donating substituents3 9 but not halogens10 on the aromatic ring. 

The Heck reaction of 1,3 -diene systems via 7r-allylpalladium is also useful. This cyclization, which forms very congested quaternary carbon centers involving the intramolecular insertion of di-, tri- and tetrasubstituted alkenes, is particularly useful for natural products synthesis. In the synthesis of morphine, bis-cyclization of the octahydroisoquninoline precursor 112 by the intramolecular Heck reaction proceeded using palladium trifluoroacetate and 1,2,2,6,6-pentamethylpiperidine (PMP). The insertion of the diene system forms the 7i-allylpalladium intermediate 113, which attacks the phenol intramolecularly to form the benzofuran ring 114. Based on this method, the elegant total syntheses of (—)- and (+)-dihydrocodeinone, and (—)- and (+)-morphine (115) have been achieved [50],... 

This rearrangement-cyclization cascade was applied to natural products synthesis. For example, DDQ oxidation of the appropriate dihydro-3 (27T)-furanone enol acetates (Table 3.5, entries 1 and 7) afforded bullatenone and the antitumor agent geiparvarin in a very rapid route (Fig. 3.1).69 70... 

Fig. 67 Vitamin Bi2-catalyzed radical cyclizations in natural product synthesis...

Stoichiometric palladium-mediated cyclization was used in natural product synthesis by Boger a number of years ago, as was noted in the introduction. More recently, an intramolecular palladium-catalyzed amination of a heteroaromatic halide has been used as a step in the synthesis of an a-carboline natural product analog [146]. As discussed above, the diphenylhydrazone arylation can also be used for nitrogen heterocycle synthesis [140]. 

The formation of /3-hydroxyselenides through the reaction of a selenium-stabilized carbanion with carbonyl compounds has been extensively used also in the context of natural product synthesis. The phenylselenoalkyllithium compound 115 was reacted with aldehyde 116 to afford /3-hydroxyselenide 117. In a radical cyclization cascade the tricyclic molecule 118 was generated in good yields and subsequent transformations led to the synthesis of pentalenene 119 (Scheme 28).1 9 Also other natural products like zizaene and khusimone have been synthesized via a similar route.200... 

In conjunction with work in natural products synthesis, the controlled installation of stereocenters alpha to indole C2 remains of significant interest. In their approach to Clausena alkaloids, e.g., (-)-(5R, 6S)-balasubramide, Wang and co-workers employed an intramolecular 8-CMc/o-epoxide-arene cyclization for installation of a C2-C3 8-membered lactam moiety with excellent enantioselectivity <07OL1387>. The Chen group has reported a diastereoselective reaction between 2-lithioindoles and chiral A -terf-but ane sulfinyl... 

Sufficient information about the reaction has been gathered to allow fairly accurate predictions of yield as well as of stereo- and regioselectivity.176177 The reaction proceeds via the formation of hexacarbonylalkyne-dicobalt complexes and is remarkably tolerant of functional groups in both the alkyne and the alkene. The intramolecular Pauson-Khand reaction is an effective way of preparing bi- and polycyclic systems, and the cyclization of 1,6-heptenyne derivatives to give bicyclo[3.3.0]oct-l-en-3-ones has been the most popular application of the Pauson-Khand reaction in natural product synthesis [Eq. (17)]. 

Although most of the work with Rh-mediated intramolecular C-H insertion has focussed on five-membered ring construction, the first application to natural product synthesis, by Cane, involved establishment of a six-membered ring. Thus, on exposure to Rh2(OAc>4, diazoketone 2 was cyclized to the tricyclic lactone 3 [2. This product had previously been transformed by Paquette into pentalenolactone E (4) [3]. 

The high point in the development to date of Rh-mediated C-H insertion has been the design by Doyle of enantiomerically pure Rh(II) complexes that direct the absolute sense of the cy-clization of a-diazo acetates. The applicability of such cyclizations to natural product synthesis has been demonstrated by Doyle with the con-... 

As the factors governing regio-, chemo-, dia-stereo- and enantioselectivity come to be better understood, the Rh-mediated cyclization of an a-diazocarbonyl derivative will come to be a powerful tool for natural product synthesis. 

Overman and Pennington have developed a versatile methodology for stereoselective tetrahydrofuran synthesis based on pinacol terminated Prins cyclizations. The general reaction is outlined in Scheme 63. A review on the strategic use of these cascade reactions in natural product synthesis has been published <2003JOC7143>. 

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