Erick M. Carreira

Chiral Olefins as Steering Ligands in Asymmetric Catalysis

Metal-catalyzed asymmetric processes offer one of the most straightforward ways to introduce stereogenic centers. Hence, the development of novel chiral ligands that can effectively induce asymmetry in reactions is crucial in modern organic synthesis. While many established chiral ligands bind to a metal through heteroatoms, structures that coordinate to metals through carbon atoms have received little attention so far. Here, we highlight the increasing number of such chiral chelating olefin ligands as well as their application in a variety of metal-catalyzed transformations.

Enantio- and Diastereodivergent Dual Catalysis: α-Allylation of Branched Aldehydes

Independent Chiral Catalysts Synthetic catalysts can be prepared in their mirror-image form and thereby furnish the mirror-image (enantiomer) of the reaction product. In practice, however, this versatility is largely limited to products featuring a single stereocenter that accounts for the dissymmetry. Krautwald et al. (p. 1065; see the Perspective by Schindler and Jacobsen) now report a pair of chiral catalysts—an iridium complex and an amine—that operate in concert to facilitate carbon-carbon bond formation, while retaining independent stereoselectivity toward their respective sides of the bond. Two catalysts independently set the chiral sense of adjacent stereocenters in a carbon–carbon bond-forming reaction. [Also see Perspective by Schindler and Jacobsen] An important challenge in asymmetric synthesis is the development of fully stereodivergent strategies to access the full complement of stereoisomers of products bearing multiple stereocenters. In the ideal case, where four products are possible, applying distinct catalysts to the same set of starting materials under identical conditions would in a single step afford any given stereoisomer. Herein, we describe the realization of this concept in a fully stereodivergent dual-catalytic synthesis of γ,δ-unsaturated aldehydes bearing vicinal quaternary/tertiary stereogenic centers. The reaction is enabled by chiral iridium and amine catalysts, which activate the allylic alcohol and aldehyde substrates, respectively. Each catalyst exerts high local stereocontrol irrespective of the others inherent preference.

Arynes and Cyclohexyne in Natural Product Synthesis

This Minireview highlights recent advances in the field of aryne and cyclohexyne chemistry that have allowed the extraordinary reactivity of these entities to be harnessed during the course of natural product syntheses. The syntheses presented rely on the use of these reactive species in chemoselective transformations and follow unprecedented synthetic strategies that are inspiring for the practitioners of synthetic organic chemistry.

Oxetanes in Drug Discovery: Structural and Synthetic Insights

An oxetane can trigger profound changes in aqueous solubility, lipophilicity, metabolic stability, and conformational preference when replacing commonly employed functionalities such as gem-dimethyl or carbonyl groups. The magnitude of these changes depends on the structural context. Thus, by substitution of a gem-dimethyl group with an oxetane, aqueous solubility may increase by a factor of 4 to more than 4000 while reducing the rate of metabolic degradation in most cases. The incorporation of an oxetane into an aliphatic chain can cause conformational changes favoring synclinal rather than antiplanar arrangements of the chain. Additionally spirocyclic oxetanes (e.g., 2-oxa-6-aza-spiro[3.3]heptane) bear remarkable analogies to commonly used fragments in drug discovery, such as morpholine, and are even able to supplant the latter in its solubilizing ability. A rich chemistry of oxetan-3-one and derived Michael acceptors provide venues for the preparation of a broad variety of novel oxetanes not previously documented, thus providing the foundation for their broad use in chemistry and drug discovery.

Oxetanes as Versatile Elements in Drug Discovery and Synthesis

Sizable resources, both financial and human, are invested each year in the development of new pharmaceutical agents. However, despite improved techniques, the new compounds often encounter difficulties in satisfying and overcoming the numerous physicochemical and many pharmacological constraints and hurdles. Oxetanes have been shown to improve key properties when grafted onto molecular scaffolds. Of particular interest are oxetanes that are substituted only in the 3-position, since such units remain achiral and their introduction into a molecular scaffold does not create a new stereocenter. This Minireview gives an overview of the recent advances made in the preparation and use of 3-substituted oxetanes. It also includes a discussion of the site-dependent modifications of various physicochemical and biochemical properties that result from the incorporation of the oxetane unit in molecular architectures.

Stereodivergent α-Allylation of Linear Aldehydes with Dual Iridium and Amine Catalysis

We describe the fully stereodivergent, dual catalytic α-allylation of linear aldehydes. The reaction proceeds via direct iridium-catalyzed substitution of racemic allylic alcohols with enamines generated in situ. The use of an Ir(P,olefin) complex and a diarylsilyl prolinol ether as catalysts in the presence of dimethylhydrogen phosphate as the promoter proved to be crucial for achieving high enantio- and diastereoselectivity (>99% ee, up to >20:1 dr). The utility of the method is demonstrated in a concise enantioselective synthesis of the antidepressant (-)-paroxetine.

Iridium-catalyzed enantioselective allylic vinylation

The first example of Ir-catalyzed asymmetric substitution reaction with vinyl trifluoroborates is described. The direct reaction between branched, racemic allylic alcohols and potassium alkenyltrifluoroborates proceeded with high site selectivity and excellent enantioselectivity (up to 99%) mediated by an Ir-(P,olefin) complex. This method allows rapid access to various 1,4-dienes or trienes including the biologically active natural products (-)-nyasol and (-)-hinokiresinol.

Iridium-Catalyzed Enantioselective Polyene Cyclization

A highly enantioselective polycyclization method has been developed using the combination of Lewis acid activation with iridium-catalyzed allylic substitution. This strategy relies on direct use of branched, racemic allylic alcohols and furnishes a diverse and unique set of carbo- and heteropolycyclic ring systems in good yields and ≥99% ee.

Total synthesis of a chlorosulpholipid cytotoxin associated with seafood poisoning.

Each year, there are many cases of seafood poisoning in humans worldwide. Among the various toxins isolated that contribute to these poisonings, the chlorosulpholipids are particularly intriguing because of their structural and stereochemical complexity. The mechanism of biological activity remains unknown and, although chlorosulpholipids are associated with membranes in the organisms from which they are isolated, little is understood about their role within biological membranes. The lack of availability of the natural products has impaired more in-depth biochemical studies. So far, none of the chlorosulpholipids have been obtained from total synthesis, and efficient routes to their synthesis would be desirable for the preparation of material for pharmacological characterization and proper evaluation of the risk to human health. Despite the notable advances in the science of organic synthesis, reliable methods for stereoselective construction of polychlorinated acyclic substrates are lacking, although some preliminary investigations have appeared. Here we report the synthesis of a chlorosulpholipid cytotoxin, leading to confirmation of the proposed structure and the discovery of unanticipated reactivity of polychlorinated hydrocarbons. The concise synthetic approach should enable the preparation of material in sufficient quantities to facilitate biological studies.

Enantioselective Cobalt‐Catalyzed Preparation of Trifluoromethyl‐Substituted Cyclopropanes

There is scarcity of approaches for the enantioselective generation of trifluoromethyl-substituted cyclopropanes. We have been interested in the discovery and identification of catalysts that are compatible with conditions necessary to generate reactive intermediates in situ in order to access new building blocks for drug discovery. Towards that aim, we have documented reaction processes involving diazotization of 2,2,2-trifluoroethylamine in the presence of Fe-porphyrin or [{Rh(esp)}2] (esp=a,a,a’,a’-tetramethyl-1,3-benzenedipropionate) catalysts as ways of accessing trifluoromethylsubstituted cyclopropanes and cyclopropenes, respectively. The generation of the reactive intermediate and concomitant cyclopropanation in water comprise a tandem sequence that avoids preparation, purification, and handling of the diazoalkane. Herein, we report an enantioselective cobaltcatalyzed process that furnishes trifluoromethyl-substituted cyclopropanes in high ee, d.r. and yield [Eq. (1)]. The reaction proceeds smoothly in aqueous media with the alkene as limiting reagent and in situ generation of the reactive F3CCHN2 from 2,2,2-trifluoroethylamine hydrochloride. [7,8]