Reductive cyclization cascade

Scheme 1.4 Epoxide opening/reductive cyclization cascade.

Mukai and co-workers used a reduction/cyclization cascade to prepare (-)-nakadomarin, a manzamine-related alkaloid with cytotoxic activity, inhibitor activity against cyclin-dependent kinase 4 (CDK-4), and anti-fungal and antibacterial activity. Treatment of the tetracyclic precursor with DIBAL-H followed by reaction with HCl led to the desired pentacyclic system in 41% yield. 

Strategic exploitation of the molecular shape of lactone 309 was next utilized to install the desired stereogenicity at all positions on tricychc compound 311, a key intermediate targeted as the substrate for a reductive cyclization cascade. The quaternary center at the lactone a-position was first addressed. Deprotonation with hthium diisopropylamide in THF and addition of 1-cyanobenzotriazole (BtCN) yielded an a-cyanolactone, which was then alkylated from the convex face of the molecule employing ethyl iodide in a mixture of warm acetonitrile and potassium carbonate to furnish lactone 310. The scaffold curvature was then exploited to epoxidize stereoselec-tively the double bond from the convex face to provide oxirane 311 following a Prilezhaev oxidation protocol. 

The palladium-catalyzed cyclization reaction was used in the syntheses of several natural products such as siccanin [86], streptazolin [87], and ceratopi-canol (through a diyne, diene cascade) [80]. The production of the streptazolin precursor 149 through reductive cyclization of 150 is illustrative of the complexity that the reaction can provide (Eq. 29) [87]. 

One of the earliest radical cyclization cascades initiated by addition of S-centered radicals to alkynes was reported in 1987 by Broka and Reichert (Scheme 2.25). Thiophenyl radicals, PhS, which were generated under radical chain conditions, undergo addition to the terminal end of the C = C triple bond in enyne 138. The resulting vinyl radical 141 can undergo cychzation in both 6-endo (preferred) and 5-exo fashion, and reduction of the radical intermediates 142 and 143 leads to the final observed products 139 and 140, respectively. 

A diastereoselective formal addition of a 7ra i-2-(phenylthio)vmyl moiety to a-hydroxyhydrazones through a radical pathway is shown in Scheme 2.29. To overcome the lack of a viable intermolecular vinyl radical addition to C=N double bonds, not to mention a reaction proceeding with stereocontrol, this procedure employs a temporary silicon tether, which is used to hold the alkyne unit in place so that the vinyl radical addition could proceed intramolecularly. Thus, intermolecular addition of PhS" to the alkyne moiety in the chiral alkyne 161 leads to vinyl radical 163, which cyclizes in a 5-exo fashion, according to the Beckwith-Houk predictions, to give aminyl radical 164 with an a 7z-arrangement between the ether and the amino group. Radical reduction and removal of the silicon tether without prior isolation of the end product of the radical cyclization cascade, 165, yields the a-amino alcohol 162. This strategy, which could also be applied to the diastereoselective synthesis of polyhydroxylated amines (not shown), can be considered as synthetic equivalent of an acetaldehyde Mannich reaction with acyclic stereocontrol. 

Recent advances in the cyclizations catalyzed by transition metals and their complexes are reviewed. The catalytic cyclizations discussed here include various carbocyclizations, for example, cycloisomerization, cycloaddition, reductive cyclization, and so on cascade carbocyclizations, for example, cyclotrimerization, silylcarbocyclization, and Heck reaction carbonylative carbocyclizations cyclohy-drocarbonylations intramolecular hydrosilylations intramolecular silylformyla-tions and aldol cyclizations. These reactions serve as efficient and useful methods for the syntheses of a variety of heterocycles and carbocycles that are important... 

Wu and co-workers presented an efficient domino reaction for the rapid synthesis of 5-phenyl-[l,2,3]triazolo[l,5-c]quinazolines derivatives (80) from simple and readily available (E)-l-bromo-2-(2-nitrovinyl)benzenes 79, aldehydes, and sodium azide (Scheme 7.56) [124]. This reaction cascade comprised [3 + 2] cycloaddition, copper-catalyzed SnAt, reduction, cyclization, and oxidation. It is noteworthy that sodium azide is used as a dual nitrogen source in the construction of these fascinating fused A-heterocycles. 

It is worth mentioning that some precursors easily catalyze the reductive carbonylation of alkynes from the C0/H20 couple. Here, the main role of water is to furnish hydrogen through the water-gas-shift reaction, as evidenced by the co-production of CO2. In the presence of Pd /KI terminal alkynes have been selectively converted into furan-2-(5H)-ones or anhydrides when a high concentration in CO2 is maintained. Two CO building blocks are incorporated and the cascade reactions that occur on palladium result in a cyclization together with the formation of an oxygen-carbon bond [37,38]. Two examples are shown in Scheme 4. 

The consecutive reduction and cyclization of O-benzoyl protected 5-0-methylhexose 0-(terf-butyldiphenylsilyl)oxime (104) with dimethylphenylsilane in trifluoroacetic acid afforded a iV-hydroxypyrrolidine (105) ring system in good yield (equation 44). The mechanism involves a cascade of neighboring group participation steps involving the 0-benzoyl protecting groups " ". ... 

Rhodium carbonyl complexes also catalyze the cascade cyclization/hydrosilylation of 6-dodecene-l,l 1-diynes to form silylated tethered 2,2 -dimethylenebicyclopentanes. For example, reaction of ( )-85 with dimethylphenylsilane catalyzed by Rh(acac)(CO)2 in toluene at 50 °G under GO (1 atm) gave 86a in 55% yield as a single diastereomer (Equation (56)). Rhodium-catalyzed caseade cyclization/hydrosilylation of enediynes was stereospecific, and reaction of (Z)-85 under the conditions noted above gave 86b in 50% yield as a single diastereomer (Equation (57)). Rhodium(i)-catalyzed cascade cyclization/hydrosilylation of 6-dodecene-1,11-diynes was proposed to occur via silyl-metallation of one of the terminal G=G bonds of the enediyne with a silyl-Rh(iii) hydride complex, followed by two sequential intramolecular carbometallations and G-H reductive elimination. ... 

The enantioselective synthesis of the C(18)-C(25) segment of lasanolide A 324 can be achieved via an oxonia-Cope-Prins cascade cyclization of a-acetoxy ether 325. The in situ reduction of the oxocarbenium ion intermediate 326 with Bu3SnH prevents the formation of a tetrahydropyran 4-one side product (Scheme 81) <20050L1589>. 

Some mechanistic aspects of the above cascade reaction deserve comment. Thus, after the intermolecular addition of the nucleophilic acyl radical to the alkene, the electrophilic radical adduct A, instead of undergoing reduction, reacts intramolecularly at the indole 3-position (formally a 5-endo cyclization) to give a new stabilized captodative radical B, which is oxidized to the fully aromatic system. (For a discussion of this oxidative step, see Section 1.5.)... 

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