Enantioselective construction

The synthetic problem is now reduced to the enantioselective construction of the two sectors of cytovaricin, intermediates 6 and 7, and it was anticipated that this objective could be achieved through the application of asymmetric aldol, alkylation, and epoxi-... 

In a synthesis of (-i-)-asteltoxin, Cha applied the Suzuki-Tsuchihashi rearrangement to silyloxy epoxide 184 for the enantioselective construction of the unusual... 

Mermerian AH, Fu GC (2005) Catalytic enantioselective construction of all-carbon quaternary stereocenters synthesis and mechanistic studies of the C-acylation of silyl ketene acetals. J Am Chem Soc 127 5604—5607... 

Ruble JC, Fu GC (1998) Enantioselective construction of quaternary stereocenters rearrangements of 0-acylated azlactones catalyzed by a planar-chiral derivative of 4-(pyrrolidino) pyridine. J Am Chem Soc 120 11532-11533... 

We became interested in a disconnection between the pyrrolidine and the aryl group (Approach D) as the most convergent method for enantioselective construction of 12 [10]. Although (-)-sparteine mediated enantioselective lithiation of N-Boc pyrrolidine 19 is well established by Beak [11], arylation of the resulting chiral... 

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. 

The Yamauchi group used two pentoses, D-xylose (59) [49] and L-arabinose (58) [50], for the enantioselective construction of olivil-type lignans (Scheme 16). Depending on the pentose employed (58 or 59), they have de-... 

Catalytic asymmetric desymmetrization as a field is still growing, with new applications appearing weekly. It is evident that advances in this subfield have kept in step with advances in catalysis as a whole. Some spectacular successes have been reported in recent years, and this strategy has been applied to many new reactions. Willis mentions in conclusion to his 1999 review of this field that desymmetrization reactions involving catalytic enantioselective construction of C—C bonds are... 

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. 

A major advancement for the subfield of enamine catalysis was achieved with the identification of aldehydes as useful donors for similar Mannich reactions.In particular, the addition of mono- or disubstituted aldehydes to ketoi-mines or aldimines, respectively, represents an elegant and highly efficient approach to the enantioselective construction of quaternary a-amino acids (Scheme 11A one-pot, three-component variant of the aldehyde Mannich reaction has also been recently disclosed (Scheme i 296-300... 

The enantioselective construction of quaternary carbon centers is invariably a challenging goal41. The double alkylation of a nonracemic jS-hydroxy ester is a useful preparative method from a collection of procedures which are used to reach this objective. In Table 3 the results from the preparation of quaternary centers by this method are shown. 

As most pharmaceuticals are heterocyclic, there is continuing interest in methods for the direct enantioselective construction of heterocycles. Greg Fu of reports (J. Am. Chem. Soc. 125 10778, 2003) that the addition of the dipole 1 to alkynes is catalyzed by Cul, and that in the presence of the planar-chiral ligand 2 the reaction proceeds in high enantiomeric excess. The is maintained with aryl-substituted alkynes, and is higher when there are alkyl substituents on the heterocyclic ring of 1. 

Many methods have been developed for the enantioselective synthesis of unnatural a-amino acids. Jeff Johnston of Indiana University reports (J. Am. Chem. Soc. 125 163,2003) coupling the asymmetric alkylation of O Donnell with intramolecular radical cyclization, leading to what appears to be a general method for the enantioselective construction of indolines. 

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. 

Because the stereocontrolled construction of cyclic ethers has been difficult and expensive, the use of cyclic ethers as pharmaceuticals has not been fully explored. With the development of powerful new methods for the diastereoselective and enantioselective construction of cyclic ethers, this situation is changing. The best of the recently developed methods for stereocontrolled cyclic ether construction are highlighted here. 

Stereocontrolled syntheses of macrolides and macrolactams are well developed. Much remains to be done toward the efficient enantioselective construction of five and suc-membered cyclic ethers and amines. Four recent natural product syntheses illustrate the current state of the art. 

Enantioselective Construction of Oxygenated and Halogenated Secondary Stereocenters... 

The enantioselective construction of aminated stereogenic centers is a central task both for pharmaceutical production and for alkaloid synthesis. 

EnantiomericaUly-pure carbacyclic rings arc important components both of physiologically-active natural products and of important pharmaceuticals. Often it is most effective to control the absolute configuration of the ring as it is formed. Recent developments in the enantioselective construction of carbacyclic rings will be covered next week and the week after. The focus this week is on the asymmetric transformation of preformed prochiral rings. 

Although many methods have been developed for enantioselective carbon-carbon construction, not all of these are robust and scalable. A promising recent addition has been the development of protocols for the enantioselective construction of allylic carbon-carbon bonds. 

One of the severest challenges of asymmetric synthesis is the direct enantioselective construction of quaternary stereogenic centers. Brian Pagenkopof of the University of Texas has reported (Chem. Communications 2003 2592) that alkynyl aluminum reagents will open a trisubstituted epoxide such as 10 at the more substituted center, with inversion of absolute configuration. As the epoxide 10 is available in high from 9 by the method of Yian Shi of Colorado State (J. Am. Chem. Soc. 119 11224, 1997), this opens a direct route to quaternary cyclic stereogenic centers. 

The first-developed method for the enantioselective construction of secondary aminated stereocenters, by Knowles, was the hydrogenation of enamides such as II. In the context of a synthesis of BILN 2061 15, an antiviral protease inhibitor, Anne-Marie Faucher of Boehringer-Ingeiheim, Laval has shown (Organic Lett. 2004, 6, 2901) that such hydrogenations can be effected even in the presence of a terminal vinyl group. The product 12 was carried on to 15 over several steps, including the Ru (Hoyveda) cyclization of 13 to 14. 

We have put forward (J. Am. Client. Soc. 2004, /26, 13900) an alternative approach to the enantioselective construction of cyclic quaternary centers. Addition of phenylacetylene to cyclopentanone followed by dehydration and Shi epoxidation gave the epoxide 10. Opening of the epoxide with allylmagnesium chloride proceeded with inversion, to give II. The alcohol 11 can also be carried on to bicyclic products, exemplified by the sulfone 12. 

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