Carbocyclizations enantioselectivities

Extracts from Clavularia viridis and also many other coral species convert arachidonic acid to the prostanoidpreclavulone-A via 8-( f )-hydroperoxy-5,ll,14( Z), QfEj-eicosatetraenoic acid. The carbocyclization is considered to occur from allene oxide and oxidopentadienyl cation intermediates. An enantioselective total synthesis of preclavulone-A was developed to assist the biosynthetic research. 

In contrast to the synthesis of carbocyclic rings, the Cope rearrangement has been used sparsely for generating azepinones. Recently, the enantioselectivity of the conversion of 2-aza-divinylcyclopropane 286 has been investigated. The synthesis started from the optically active cyclopropanecarboxylic acid (90% ee), which had been converted into the isocyanate 286 by initial azidation to 285 and a consecutive Curtius rearrangement. Furthermore, the conditions of the iso-... 

With the advent of enantioselective zirconocene-catalyzed alkene carbomagnesiation,27 27a 27c 28 28a chirally modified zirconocenes soon were applied to asymmetric reductive diene carbocyclization.2 a c As demonstrated by the reductive cyclization of 5a,29 highly enantioselective cyclization is enabled through the use Brintzinger s chiral, mszz-zirconocene.30 30a (For the preparation and resolution of chiral tf .szz-zirconocene 6, see Refs 30,30a.) However, moderate diastereoselectivities and yields are generally observed (Scheme 5). 

Hydrosilylation of 1,6-dienes accompanied by cyclization giving a five-membered ring system is emerging as a potential route to the synthesis of functionalized carbocycles.81,81a,81b 82 As its asymmetric version, diallylmalonates 86 were treated with trialkylsilane in the presence of a cationic palladium catalyst 88, which is coordinated with a chiral pyridine-oxazoline ligand. As the cyclization-hydrosilylation products, //ww-disubstituted cyclopentanes 87 were obtained with high diastereoselectivity (>95%), whose enantioselectivity ranged between 87% and 90% (Scheme 25).83 83a... 

Under a pressure (20 bar) of carbon monoxide, carbonylative silylcarbocyclization of enyne 92 was examined in the presence of a cationic rhodium-BINAP catalyst (Scheme 31).86 Although the enantioselectivity is low, the five-membered carbocycle functionalized with an alkenylsilane moiety and a formyl group was obtained with high selectivity. 

The chemistry described in this review article demonstrates the impressive positive influence that catalytic RCM has had on our research in connection to the development of other catalytic and enantioselective C-C bond forming reactions. There is no doubt that in the absence of pioneering work by Schrock and Grubbs, the Zr-catalyzed alkylation and kinetic resolution would be of less utility in synthesis. The number of unsaturated heterocyclic and carbocyclic substrates available for Zr-catalyzed asymmetric carbomagnesation would be far more limited without catalytic RCM. 

Enantioselective hydrogenation of 1,6-enynes using chirally modified cationic rhodium precatalysts enables enantioselective reductive cyclization to afford alky-lidene-substituted carbocycles and heterocycles [27 b, 41, 42]. Good to excellent yields and exceptional levels of asymmetric induction are observed across a structurally diverse set of substrates. For systems that embody 1,2-disubstituted alkenes, competitive /9-hydride elimination en route to products of cycloisomerization is observed. However, related enone-containing substrates cannot engage in /9-hydride elimination, and undergo reductive cyclization in good yield (Table 22.12). 

Keyword Carbocycles a Cascade Reactions a Cycloadditions a Combinatorial Chemistry a Domino Reactions a Enantioselective Transformations a Ene Reactions a Eieterocydes a Natural products a Preservation of Resources and Environment a Sigmatropic Rearrangements a Tandem Reactions a Transition Metal-Catalyzed Transformations... 

A method for highly efficient asymmetric cyclopropanation with control of both relative and absolute stereochemistry uses vinyldiazomethanes and inexpensive a-hydroxy esters as chiral auxiliaries263. This method was also applied for stereoselective preparation of dihydroazulenes. A further improvement of this approach involves an enantioselective construction of seven-membered carbocycles (540) by incorporating an initial asymmetric cyclopropanation step into the tandem cyclopropanation-Cope rearrangement process using rhodium(II)-(5 )-N-[p-(tert-butyl)phenylsulfonyl]prolinate [RhjtS — TBSP)4] 539 as a chiral catalyst (equation 212)264. 

Miscellaneous Iminium Catalyzed Transformations The enantioselective construction of three-membered hetero- or carbocyclic ring systems is an important objective for practitioners of chemical synthesis in academic and industrial settings. To date, important advances have been made in the iminium activation realm, which enable asymmetric entry to a-formyl cyclopropanes and epoxides. In terms of cyclopropane synthesis, a new class of iminium catalyst has been introduced, providing the enantioselective stepwise [2 + 1] union of sulfonium ylides and ot,p-unsaturated aldehydes.As shown in Scheme 11.6a, the zwitterionic hydro-indoline-derived catalyst (19) enables both iminium geometry control and directed electrostatic activation of sulfonium ylides in proximity to the incipient iminium reaction partner. This combination of geometric and stereoelectronic effects has been proposed as being essential for enantio- and diastereocontrol in forming two of the three cyclopropyl bonds. 

Morken and co-workers have reported the highly enantioselective version of this reaction, albeit with low efficacy in the aldol-type coupling [8d, e]. Unfortunately, we obtain low enantioselectivity ee 2-4%) using chiral rhodium complexes under our reaction conditions. An intramolecular adaptation has led to new opportunities in cobalt-catalyzed carbocyclizations, wherein the use of PhSiHs was essential for smooth ring formation (Eq. 4) [9]. The identical products were also formed by a combination of [Rh(COD)2]OTf/(p-CE3Ph)3P and molecular hydrogen [10]. 

Tab. 11.11 Representative examples of rhodium(l)-catalyzed enantioselective [4-tl] carbocyclization.

The optimum result in terms of enantioselectivity was obtained with the vinylallene bearing an ester group, 63 e, wherein the carbocyclization proceeds at lower temperature to afford remarkably improved selectivity (Scheme 11.20). 

Recent advances in the rhodium-catalyzed [4-1-2] reactions have led to the development of the first highly regioselective intermolecular cyclization, providing access to new classes of carbocycles with both activated and unactivated substrates. The chemo- and stereoselective carbocyclizations of tethered diene-allene derivatives afford new classes of 5,6- and 6,6-bicyclic systems. Additionally, examination of a wide range of factors that influence both diastereo- and enantioselectivity has provided a significant advance in the understanding of catalyst requirements across these systems. 

A number of workers have described the synthesis and cycloaddition reactions of oxazoline nitrone dipoles, (e.g., 361 and 362, Scheme 1.80) (413 17). A homochiral oxazoline nitrone derived from camphor has been used to great effect by Langlois and co-workers (418,419), from which they have prepared a number of natural targets through enantioselective cycloaddition reactions, including the antiviral carbocyclic nucleoside analogue (+)-carbovir (48) (Fig. 1.1, Section 1.3). 

Another way to approach the enantioselective construction of carbocycles is to start with a readily-available carbohydrate. Gloria Rassu of the Insituto di Chimica Biomolecolare del CNR, Sassari, and Giovanni Casiraghi of the University di Parma report (J. Org. Chem. 68 5881, 2003) that the lactone 8 undergoes smooth aldol condensation to give the highly-substituted, and... 

While enantioselective transition metal catalysis continues to be important, several useful all-organic catalysts have been developed over the past few years. Tomislav Rovis of Colorado Stale University has reported (J. Am. Chem. Soc. 2004, /26, 8876) that the triazolium salt 5 catalyzes the enantioselective Stetter-type cyclization of 4 to 6. The cyclization also works well for the enantioselective construction of azacyclic, thiacyclic and carbocyclic rings. 

The push toward enaotiomerically-pure carbocyclic intermediates has led to the development of new methods for the enantiodifferentiation of inexpensive prochiral cyclic starting materials. For instance, Robert H. Morris of the University of Toronto recently reported (Organic Lett. 2005, 7, 1757) that a family of enantiomerically-pure Ru complexes originally developed for asymmetric transfer hydrogenation also mediate the enantioselective addition of malonatc to cyclohexenone. 

Unlike carbocyclic and oxygen-containing heterocyclic systems, catalytic enantioselective synthesis of eight-membered ring amines proceeds efficiently and with excellent enantioselectivity. These catalytic ARCM reactions can be carried out in the absence of solvent as well. Representative data regarding cat-... 

Scheme 15. Enantioselective synthesis of carbocyclic tertiary ethers and spirocycles through Mo-catalyzed asymmetric olefin metathesis...

A process related to those shown in Scheme 14 involves the asymmetric Mo-catalyzed conversion of tertiary carbocyclic cyclopentenyl ethers to the corre-sponsing cyclohexenyl ethers with enantioselectivity (e.g., 67—>69, Scheme 15) [25]. A remarkable and unusual attribute of this class of transformations is that significantly higher levels of enantioselectivity are observed when ten substrate equivalents of THF are used as an additive. As an example, 69 (Scheme 15) is formed in only 58% ee in the absence of THF (<5% conversion is observed when THF is used as solvent). As also shown in Scheme 15 (70—471), enantioenriched spirocycles may be accessed easily by a similar approach in this case, no additive effect is observed. 

Problem 1 focuses on reagents for the synthesis of carbocyclic systems. Problems 2-4 address selectivity issues associated with carbocyclic systems. The syntheses of TMs in Problems 5 and 6 require the selection of specific reagents to achieve chemo-, stereo-, or enantioselective cyclizations. 

During our further studies of ketone catalysts, ketone 16 was found to be highly enantioselective for a number of acyclic and cyclic d.s-olefins (Table 10.6).73-74 It is important to note that the epoxidation is stereospecific with no isomerization observed in the epoxidation of acyclic systems. Ketone 16 also provides encouragingly high ee s for certain terminal olefins, particularly styrenes.74-75 In general, ketones 1 and 16 have complementary substrate scopes. In our subsequent study of the conformational and electronic effects of ketone catalysts on epoxidation, ketone 17, a carbocyclic analog of 16, was found to be highly enantioselective for various styrenes (Table 10.7).76... 

The Diels-Alder reaction is a valuable transformation for the construction of complex carbocycles, and represents arguably one of the most powerful approaches in organic chemistry. In particular, catalytic enantioselective variants have received unprecedented attention [22], representing an appealing starting point for the development of MacMillan s concept of iminium catalysis. 

A modification of this system was also used in intramolecular MBH reactions (also called as aldol cycloisomerization) [71, 74]. In this reaction, optically active pipecolinic acid 61 was found to be a better co-catalyst than proline, and allowed ee-values of up to 80% to be obtained, without a peptide catalyst. The inter-molecular aldol dimerization, which is an important competing side-reaction of the basic amine-mediated intramolecular MBH reaction, was efficiently suppressed in a THF H20 (3 1) mixture at room temperature, allowing the formation of six-membered carbocycles (Scheme 5.14). The enantioselectivity of the reaction could be improved via a kinetic resolution quench by adding acetic anhydride as an acylating agent to the reaction mixture and a peptide-based asymmetric catalyst such as 64 that mediates a subsequent asymmetric acylation reaction. The non-acylated product 65 was recovered in 50% isolated yield with ee >98%. 

A total enantioselective synthesis of antiviral carbocyclic oxetanocins 289 and 290 was also completed by the Ichikawa group by utilizing a... 

Crimmins, M.T. New Developments in Enantioselective Synthesis of Cyclopentyl Carbocyclic Nucleosides. 1998 [2d]... 

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