P. Andrew Evans

Intermolecular Rhodium-Catalyzed [3+2+2] Carbocyclization of Alkenylidenecyclopropanes with Activated Alkynes: Regio- and Diastereoselective Construction of cis-Fused Bicycloheptadienes

Polycyclic structures that contain seven-membered carbocycles constitute important structural motifs that are ubiquitous in several classes of bioactive natural products. We have developed the first regio- and diastereoselective intermolecular rhodium-catalyzed [3+2+2] carbocyclization of carbon- and heteroatom-tethered alkenylidenecyclopropanes with mono- and disubstituted alkynes for the construction of cis-fused bicycloheptadienes. This study delineates some of the critical features for controlling regioselectivity in this process and demonstrates that E-alkenes can be incorporated in a stereospecific manner to afford products with up to three new stereogenic centers. The latter feature is particularly significant given that related carbocyclization reactions are often limited in this respect.

A central strategy for converting natural products into fluorescent probes

A Central Strategy for Converting Natural Products into Fluorescent Probes Matthew D. Alexander, Michael D. Burkart, Michael S. Leonard, Padma Portonovo, Bo Liang, Xiaobin Ding, Madeleine M. Joulli!, Brian M. Gulledge, James B. Aggen, A. Richard Chamberlin, Joel Sandler, William Fenical, Jian Cui, Santosh J. Gharpure, Alexei Polosukhin, Hai-Ren Zhang, P. Andrew Evans, Adam D. Richardson, Mary Kay Harper, Chris M. Ireland, Binh G. Vong, Thomas P. Brady, Emmanuel A. Theodorakis, and James J. La Clair*

Regioselective and Enantiospecific Rhodium-Catalyzed Allylic Amination with N-(Arylsulfonyl)anilines

[reaction: see text]. The regioselective and enantiospecific rhodium-catalyzed allylic amination of secondary allylic carbonates 1 with N-(arylsulfonyl)anilines provides a convenient process for the construction of arylamines 2. This method, in conjunction with ring-closing metathesis and radical cyclization reactions, allows the direct construction of biologically relevant pharmacophores as exemplified by the construction of dihydroquinoline and dihydrobenzo[b]indoline derivatives.

Regioselective rhodium-catalyzed allylic alkylation with a modified Wilkinson's catalyst

Abstract Treatment of the secondary and tertiary allylic carbonates 1 with the sodium salt of dimethyl malonate and a amount of Wilkinsons catalyst modified with a triorganophosphite, furnished the tertiary and quaternary carbon stereogenic centers 2 in high yield with excellent regioselectivity.

Enantioselective Total Synthesis of the Nonisoprenoid Sesquiterpene (−)‐Kumausallene

An acyl radical cyclization to form the bicyclic core of (-)-kumausallene (1) was the key feature in the 14-step, enantioselective synthesis. This work demonstrates that the bromoallene unit is robust enough to withstand multiple synthetic operations and provides the unambiguous assignment of the absolute configuration of the bromoallene.

Stereoselective rhodium-catalyzed [3 + 2 + 1] carbocyclization of alkenylidenecyclopropanes with carbon monoxide: theoretical evidence for a trimethylenemethane metallacycle intermediate.

The theoretically inspired development of a Rh-catalyzed [3 + 2 + 1] carbocyclization of carbon- and heteroatom-tethered alkenylidenecyclopropanes (ACPs) with CO for the stereoselective construction of cis-fused bicyclohexenones is described. This study demonstrates that the ring opening of alkylidenecyclopropane proceeds through a Rh(III)-trimethylenemethane complex, which undergoes rate-determining carbometalation through a transition state that accurately predicts the stereochemical outcome for this process. The experimental studies demonstrate the validity of this approach and include the first highly enantioselective reaction involving an ACP to highlight further the synthetic utility of this transformation.

Diastereoselective Rhodium-Catalyzed Ene-Cycloisomerization Reactions of Alkenylidenecyclopropanes: Total Synthesis of (−)-α-Kainic Acid

The rhodium-catalyzed ene-cycloisomerization of alkenylidenecyclopropanes provides an atom-economical approach to five-membered carbo- and heterocycles that contain two new stereogenic centers. A key and striking feature of this protocol is that the alkene geometry does not impact the efficiency and diastereocontrol, which provides excellent synthetic versatility. For instance, (E)- and (Z)-allylic alcohols furnish the corresponding aldehydes with similar efficiency and selectivity. This process facilitates the construction of a key intermediate in an eight-step total synthesis of (-)-α-kainic acid.

Diastereoselective construction of syn-1,3-dioxanes via a bismuth-mediated two-component hemiacetal/oxa-conjugate addition reaction.

The bismuth-mediated two-component hemiacetal/oxa-conjugate addition of δ-trialkylsilyloxy and δ-hydroxy α,β-unsaturated aldehydes and ketones with alkyl aldehydes provides the syn-1,3-dioxanes in a highly efficient and stereoselective manner. The key advantages of this protocol are its operational simplicity and its ability to directly access electron-withdrawing groups without recourse to oxidation state adjustments.

ENANTIOSELECTIVE ALLYLIC SUBSTITUTION USING A NOVEL (PHOSPHINO-1,3-OXAZINE)PALLADIUM CATALYST

Abstract Treatment of 1,3-diphenyl-2-propenyl acetate 1 with the sodium salt of dimethyl malonate and the palladium complex of the phosphino-1,3-oxazine ligand cis-3a gave the allylic substitution product 2 in 99% yield and 95% enantiomeric excess.

Regiodivergent Ligand‐Controlled Rhodium‐Catalyzed [(2+2)+2] Carbocyclization Reactions with Alkyl Substituted Methyl Propiolates

The importance of transition metal-catalyzed reactions may be attributed, at least in part, to the manner in which they can control the formation of a specific product using ancillary ligands on the metal center. In this context, metal-catalyzed [2+2+2] carbocyclization reactions present a formidable challenge with respect to controlling chemo-, regio-, and various aspects of stereoselectivity. A fundamental objective in this area is the ability to predict and control the outcome of a specific transformation without recourse to extensive experimentation. In a program directed towards the development and understanding of this type of transformation, we described the first regioand enantioselective rhodium-catalyzed [(2+2)+2] carbocyclization of 1,6-enynes 1 with aryl substituted methyl propiolates 2 for the construction of bicyclohexa-1,3-dienes 3 (Scheme 1). As a consequence of this study, we were intrigued by the factors that control regioselectivity and whether the ancillary ligands could be modified to switch the regioselective outcome to provide selective access to both regioisomers. Herein, we now describe the regiodivergent rhodiumcatalyzed [(2+2)+2] carbocyclization of 1,6-enynes 1 with alkyl substituted methyl propiolates 2 for the construction of the bicyclohexa-1,3-dienes 3 and 4 (Scheme 1). Furthermore, these studies provide another example of the detrimental role that silver salts have on selectivity in a metalcatalyzed reaction, which has important implications for development and rationalization of related higher-order carbocyclization reactions. Table 1 outlines the preliminary studies to probe the feasibility of the regiodivergent carbocyclization reaction. Treatment of the 1,6-enyne 1a (X=NTs) and methyl 2-