Nickel natural product synthesis

The nickel-mediated [4 -i- 4] cycloaddition strategy has also provided a concise and stereocontroUed route into the sequiterpene lactone (+)-asteiiscanolide (128). The basic features of this approach are outlined in Scheme 17. The critical [4 + 4] cycloaddition st occurred under standard conditions to give the key intermediate in 67% yield. Clearly, the intramolecular version of the nickel-catalyzed diene cy-clodimerization has been established as a powerful and highly-selective protocol for the synthesis of cyclooctane ring systems and should find extensive qjplication to natural product synthesis. 

In a natural product synthesis aza bicyclic compound 11 was hydrogenated over Raney nickel in excellent yield. As expected, hydrogenation occurs from the less hindered side to give 12 as the sole product39. 

Asymmetric Buchner reactions using chiral auxiliary have also been undertaken. The diazoketo substrate 126 for the chiral tethered Buchner reaction is prepared from optically pure (2/ ,4/f)-2,4-pentanediol in three steps the Mitsunobu reaction with 3,5-dimethylphenol, esterification with diketene, and diazo formation/deacetylation. Treatment of 126 with rhodium(II) acetate results in a quantitative yield of 127 with more than 99% ee. This compound is reduced with lithium aluminium hydride, and the resulting diol 128 undergoes epoxidation and concurrent acetal formation to give 129 as a single diastereomer. Hydrogenation of 129 with Raney nickel proceeds stereoselectively to yield saturated diol 130, which is converted to aldehyde 132 via acid hydrolysis followed by oxidation. Compound 132 is a versatile intermediate for natural product synthesis. 

Whilst the literature on nickel-catalyzed C—H activation is considerably less extensive than for, say, palladium or iridium, there has been a marked increase in the rate of publication since ca. 2005. Much of the earlier work is summarized in a small number of excellent reviews. - Recent examples of the use of nickel-catalyzed activation in natural product synthesis are summarized in a recent review by Yamaguchi et al. ... 

Applications of Palladium and Nickel Complexes in Natural Product Synthesis... 

Nickel halides and nickel complexes resulting from oxidative addition can also give rise to subsequent replacement and insertion reactions. Replacement reactions have been described mainly with arylnickel halide complexes (examples 23, 29, and 31, Table III). Carbanionic species replace halide ions and can undergo coupling or insertion reactions. An example of application of a carbanionic reaction to the synthesis of a natural product is the coupling step between an aromatic iodo-derivative and an active methylene group to form cephalotaxinone (example 23, Table III). 

Nozaki-Hiyama-Kishi (NHK) reactions215,216 are well known and often employed as a useful method for the synthesis of natural products by coupling of allyl, alkenyl, alkynyl, and aryl halides or triflates with aldehydes. The organochromium reagents are prepared from the corresponding halides or triflates and chromium(ll) chloride, and are employed in polar aprotic solvents (THF, DMF, DMSO, etc.). Subsequently, it was found that nickel salts exhibited a significant catalytic effect on the formation of the C-Cr bond217,218 (Equation (19)). 

While transition metal-catalyzed hydroboration is a well-established reaction, the same cannot be said for the transition metal-catalyzed hydroalumination. The synthetic utility of this reaction is only just beginning to emerge. Lautens has led the way in the use of hydroaluminations as the key step in the total synthesis of complex natural products. The synthesis of the anti-depressant sertraline130 involved the formation of the tetrahydronaphthalene core, and this is best achieved using the nickel-catalyzed hydroalumination of oxabicyclic alkenes (Table 16). 

The method for forming cycloolefins from bis-allylic halides and nickel carbonyl was first reported by Corey and coworkers [135] and has been appli to the synthesis of several macrocycUc natural products [136]. The 14-membered diter-pene cembrene (225) was synthesized by Dauben et al. [136b], for example. As... 

Before the modem era of organotransition metal reactivity, it was observed that nickel carbonyl reacted with 2-methallyl chloride in methanol to give methyl 3-methyl-3-butenoate and 2,5-dimethyl-1,5-hexadiene as a by-product. In THF at 25 °C, the diene was the exclusive product. This mild formation of a carbon carbon bond, and the interest in the synthesis of terpene-based natural products led to efforts to test the scope and limitations of the process. An obvious pathway involves stepwise oxidative addition of each aUyl unit followed by Reductive Elimination. As discussed below, the key intermediates (left vague in Scheme 48) are likely to involve Ni -Ni couples. 

Nickel-catalyzed cyclization of 1,3-dienes with a tethered carbonyl group and its application to synthesis of natural products 01YGK576. 

---