The intermolecular Pauson-Khand reaction

Five membered carbocycles are important building blocks for many biologically active molecules. Moreover, substituted cyclopentenones (e.g. cyclopentenone prostaglandins) exhibit characteristic biological activity. The efficiency and atom economy of the Pauson-Khand reaction render this process potentially one of the most attractive methods for the synthesis of such compounds. Although it was discovered in its intermolecular form, the scope of the intermolecular Pauson-Khand reaction has always been limited by the poor reactivity and selectivity of the alkene component. The past decade, especially the last three years, has seen concerted efforts to broaden the scope of this reaction. In this overview, we provide a comprehensive and critical coverage of the intermolecular Pauson-Khand reaction based on the reactivity characteristics of different classes of alkenes and a rationalization of successes and misfortunes in this area.     

Gold catalysis: phenol synthesis in the presence of functional groups

The effect of different substituents, such as bromo, chloromethyl, hydroxymethyl, formyl, acetyl, carboxy, and acylated hydroxymethyl and ammonium groups, on the furan ring of substrates in gold-catalyzed phenol synthesis has been investigated. The furan ring was also replaced by different heterocycles, such as pyrroles, thiophenes, oxazoles, and a 2,4-dimethoxyphenyl group; gold catalysis then delivered no phenols, but occasionally other products were obtained. [Ru(3)(CO)(12)] also catalyzed the conversion of 1 at a low rate, [Os(3)(CO)(12)] failed as a catalyst, and with [Co(2)(CO)(8)] the alkyne complex 19 can be obtained, it does not lead to any phenol but reacts with norbornene to give the product of a Pauson-Khand reaction. Efforts to prepare vinylidene complexes of 1 provided the only evidence for these species; in the presence of a phosphane ligand with ruthenium an interesting deoxygenation to 22 was observed. The phenol 2 c was converted to the allyl ether, a building block for para-Claisen rearrangements, and to the aryl triflate, a building block for cross-coupling reactions.     

Rhodium-catalyzed asymmetric aqueous Pauson-Khand-type reaction

An interesting rhodium-catalyzed asymmetric aqueous Pauson-Khand-type reaction was developed. A chiral atropisomeric dipyridyldiphosphane ligand was found to be highly effective in this system. This operationally simple protocol allows both catalyst and reactants to be handled under air without precautions. Various enynes were transformed to the corresponding bicyclic cyclopentenones in good yield and enantiomeric excess (up to 95 % ee). A study of the electronic effects of the enyne substrates revealed a correlation between the electronic properties of the substrates and the ee value obtained in the product of the Pauson-Khand-type reaction. A linear free-energy relationship was observed from a Hammett study.     

Two birds with one metallic stone: single-pot catalysis of fundamentally different transformations

Advances in metal catalysis have revolutionized organic synthesis, with the scope of metal-catalyzed reactions now covering nearly all areas of carbon-carbon, carbon-hydrogen, and carbon-heteroatom bond formation. For years, the goal was to develop catalysts that were highly selective for a single transformation. However, a promising current area of research is the use of a single catalyst to mediate more than one transformation in a selective manner. Whereas much early work was focused on using a catalyst for several similar transformations, recent investigations have shown that it is also possible to employ a single catalyst for several very different transformations in a single reaction sequence. This Minireview focuses on methods in which the mechanisms of the transformations are fundamentally very different.     

Vinyl sulfoxides as stereochemical controllers in intermolecular Pauson-Khand reactions: applications to the enantioselective synthesis of natural cyclopentanoids

The use of sulfoxides as chiral auxiliaries in asymmetric intermolecular Pauson-Khand reactions is described. After screening a wide variety of substituents on the sulfur atom in alpha,beta-unsaturated sulfoxides, the readily available o-(N,N-dimethylamino)phenyl vinyl sulfoxide (1 i) has proved to be highly reactive with substituted terminal alkynes under N-oxide-promoted conditions (CH3CN, 0 degrees C). In addition, these Pauson-Khand reactions occurred with complete regioselectivity and very high diastereoselectivity (de=86->96 %, (S,R(S)) diastereomer). Experimental studies suggest that the high reactivity exhibited by the vinyl sulfoxide 1 i relies on the ability of the amine group to act as a soft ligand on the alkyne dicobalt complex prior to the generation of the cobaltacycle intermediate. On the other hand, both theoretical and experimental studies show that the high stereoselectivity of the process is due to the easy thermodynamic epimerization at the C5 center in the resulting 5-sulfinyl-2-cyclopentenone adducts. When it is taken into account that the known asymmetric intermolecular Pauson-Khand reactions are limited to the use of highly reactive bicyclic alkenes, mainly norbornene and norbornadiene, this novel procedure constitutes the first asymmetric version with unstrained acyclic alkenes. As a demonstration of the synthetic interest of this sulfoxide-based methodology in the enantioselective preparation of stereochemically complex cyclopentanoids, we have developed very short and efficient syntheses of the antibiotic (-)-pentenomycin I and the (-)-aminocyclopentitol moiety of a hopane triterpenoid.     

Transition-metal-mediated synthesis of novel carbocyclic nucleoside analogues with antitumoral activity

A diversity-oriented, enantioselective synthesis of new (monoprotected) carbocyclic nucleoside analogues (CNAs) with the nucleobase attached to a 3-hydroxymethyl-4-trialkylsilyloxymethylcyclopent-2-en-1-yl scaffold was developed. As a key intermediate, racemic (5SR,8RS)-8-allyloxy-2-trimethylsilyl-7-oxa-bicyclo[3.3.0]-oct-1-en-3-one was prepared from 1,1-diallyloxy-3-trimethylsilyl-2-propyne in a cobalt-mediated Pauson-Khand reaction. The enantiomerically pure material was obtained through efficient kinetic resolution (selectivity factor s >/= 40 at -78 degrees C) by means of an oxazaborolidine-catalyzed borane reduction (CBS reduction) with catecholborane. The absolute configuration of the resolved products was determined by CD spectroscopy, Mosher ester analysis, and chemical correlation. Subsequent steps involve diastereoselective ketone reduction and fully regio- and diastereoselective introduction of the nucleobase through Pd(0)-catalyzed allylic substitution. The generality of the method was demonstrated by preparation of CNAs in both enantiomeric series with all five natural nucleobases, as well as 5-bromouracil, 5-fluorouracil, and 6-chloropurine. Screening of the various compounds in a cytotoxicity assay with BJAB and ALL tumor cell lines revealed that some of the compounds possess pronounced antitumoral properties (LD50 values down to 9 microM, as determined by lactate dehydrogenase release after 48 h). By measuring DNA fragmentation, it could be shown that the activity results from induction of apoptosis.     

Catalyst precursors for the catalytic Pauson-Khand reaction

Dicobalt hexacarbonyl complexes of enynes serve as Co₂(CO)₈ surrogates for the intramolecular Pauson-Khand cycloaddition. Enynes with polar functional groups allow for easy separation of the catalyst cyclopentenone by-product (acid or base wash, silica gel plug column) from the desired cyclopentenone.     

Three characteristic reactions of alkynes with metal compounds in organic synthesis

Alkynes have two sets of mutually orthogonal π‐bonds that are different from the π‐bonds of alkenes. These π‐bonds are able to bond with transition metal compounds. Alkynes easily bond with the various kinds of compounds having a π‐bond such as carbon monoxide, alkenes, other alkynes and nitriles in the presence of the transition metal compounds. The most representative reaction of alkynes is called the Pauson–Khand reaction. The Pauson–Khand reactions include the cyclization of alkynes with alkenes and carbon monoxide in the presence of cobalt carbonyls. Similar Pauson–Khand reactions also proceed in the presence of other transition metal compounds. These reactions are the first type of characteristic reaction of alkynes. Other various kinds of cyclizations with alkynes also proceed in the presence of the transition metal compounds. These reactions are the second type of characteristic reaction of alkynes. These include cyclooligomerizations and cycloadditions. The cyclooligomerizations include mainly cyclotrimerizations and cyclotetramerizations, and the cycloadditions are [2 + 2], [2 + 2 + 1], [2 + 2 + 2], [3 + 2], [4 + 2], etc., type cycloadditions. Alkynes are fairly reactive because of the high s character of their σ‐bonds. Therefore, simple coupling reactions with alkynes also proceed besides the cyclizations. The coupling reactions are the third type of characteristic reactions of alkynes in the presence of, mainly, the transition metal compounds. These reactions include carbonylations, dioxycarbonylations, Sonogashira reactions, coupling reactions with aldehydes, ketones, alkynes, alkenes and allyl compounds. Copyright © 2008 John Wiley & Sons, Ltd.     

Asymmetric total synthesis of a pentacyclic lycopodium alkaloid: huperzine-q

Right on Q: The first asymmetric total synthesis of (-)-huperzine-Q, which possesses six stereogenic centers and a spiroaminal moiety, has been achieved in 19 steps and 16.4?% overall yield. This synthesis involved a novel stereoselective Pauson-Khand reaction, a vinyl Claisen rearrangement, and a biomimetic spiroaminal formation. TBDPS=tert-butyldiphenylsilyl.