Joshua D. Sieber

Catalytic asymmetric allylic alkylation employing heteroatom nucleophiles: a powerful method for C–X bond formation

Metal catalyzed asymmetric allylic alkylation (AAA) reactions have been an extensively studied and fruitful area of research in organic chemistry. The use of heteroatom-centered nucleophiles in this reaction is a powerful method for asymmetric C–X (X = heteroatom) bond formation. This perspective summarizes developments and applications of metal catalyzed AAA reactions employing heteroatom nucleophiles.

The Palladium Catalyzed Asymmetric Addition of Oxindoles and Allenes: An Atom-Economical Versatile Method for the Construction of Chiral Indole Alkaloids

The Pd-catalyzed asymmetric allylic alkylation (AAA) is one of the most useful and versatile methods for asymmetric synthesis known in organometallic chemistry. Development of this reaction over the past 30 years has typically relied on the use of an allylic electrophile bearing an appropriate leaving group to access the reactive Pd(π-allyl) intermediate that goes on to the desired coupling product after attack by the nucleophile present in the reaction. Our group has been interested in developing alternative approaches to access the reactive Pd(π-allyl) intermediate that does not require the use of an activated electrophile, which ultimately generates a stoichiometric byproduct in the reaction that is derived from the leftover leaving group. Along these lines, we have demonstrated that allenes can be used to generate the reactive Pd(π-allyl) intermediate in the presence of an acid cocatalyst, and this system is compatible with nucleophiles to allow for formation of formal AAA products by Pd-catalyzed additions to allenes. This article describes our work regarding the use of oxindoles as carbon-based nucleophiles in a Pd-catalyzed asymmetric addition of oxindoles to allenes (Pd-catalyzed hydrocarbonation of allenes). By using the chiral standard Trost ligand (L1) and 3-aryloxindoles as nucleophiles, this hydrocarbonation reaction provides products with two vicinal stereocenters, with one being quaternary, in excellent chemo-, regio-, diastereo-, and enantioselectivities in high chemical yields.

Efficient asymmetric synthesis of P-chiral phosphine oxides via properly designed and activated benzoxazaphosphinine-2-oxide agents.

A general, efficient, and highly diastereoselective method for the synthesis of structurally and sterically diverse P-chiral phosphine oxides was developed. The method relies on sequential nucleophilic substitution on the versatile chiral phosphinyl transfer agent 1,3,2-benzoxazaphosphinine-2-oxide, which features enhanced and differentiated P-N and P-O bond reactivity toward nucleophiles. The reactivities of both bonds are fine-tuned to allow cleavage to occur even with sterically hindered nucleophiles under mild conditions.

Asymmetric Total Synthesis of Soraphen A: a Flexible Alkyne Strategy

The alkyne functional group can be a valuable handle for organic synthesis since the alkyne can function both as a nucleophile or as an electrophile when activated with an appropriate metal catalyst. Herein, we exploit this dual nature of the alkyne moiety for the concise total synthesis of the natural product soraphen A.

Efficient Asymmetric Synthesis of Structurally Diverse P-Stereogenic Phosphinamides for Catalyst Design†

The use of chiral phosphinamides is relatively unexplored because of the lack of a general method for the synthesis. Reported herein is the development of a general, efficient, and highly enantioselective method for the synthesis of structurally diverse P-stereogenic phosphinamides. The method relies on nucleophilic substitution of a chiral phosphinate derived from the versatile chiral phosphinyl transfer agent 1,3,2-benzoxazaphosphinine-2-oxide. These chiral phosphinamides were utilized for the first synthesis of readily tunable P-stereogenic Lewis base organocatalysts, which were used successfully for highly enantioselective catalysis.

Rh-catalyzed reagent-free ring expansion of cyclobutenones and benzocyclobutenones

A reagent-free Rh-catalyzed ring-expansion reaction via C–C cleavage of cyclobutenones and benzocyclobutenones is reported.

Development of new P-chiral P,π-dihydrobenzooxaphosphole hybrid ligands for asymmetric catalysis.

A new family of P-chiral P,π-hybrid ligands was prepared from the dihydrobenzooxaphosphole core. These new ligands were demonstrated to be both sterically and electronically tunable at the substituents on the phosphorus atom and the π-system of the ligand. Application of these new ligands to the catalytic asymmetric addition of boronic acids to imine electrophiles was shown to proceed with high levels of enantioinduction.

Design and Synthesis of Chiral Oxathiozinone Scaffolds: Efficient Synthesis of Hindered Enantiopure Sulfinamides and Sulfinyl Ketimines

Chiral-sulfinamide-mediated (1; see Scheme 1) chemistry has become one of the most employed approaches for the synthesis of compounds containing chiral amine functionalities. Moreover, their utility has been extended to being used as chiral ligands for many catalytic asymmetric transformations. Although the potential of chiral sulfinamides has long been recognized, only a few methods have been developed for their synthesis. Among the prominent works are the method reported by Davis et al. for the synthesis of p-toluenesulfinamide (pTSA) from Anderson s reagent, the method reported by Ellman and co-workers for the synthesis of tert-butanesulfinamide (tBSA) from tert-butyl tert-butanethiosulfinate, and others. However, these methods cannot meet the demand for accessing sulfinamides with diverse structures, which are required to fine-tune stereoselectivities in asymmetric synthesis. To meet this need, soon after the report from the group of Ellman, we designed and developed a versatile cyclic-oxathiozolidinone-based chiral sulfinyltransfer agents which provide access to a range of sulfinamides with diverse structures (Scheme 1). The success of this method hinged on the recognition that the reactivity of the cyclic oxathiozolidinone 2 could be activated by an electron-withdrawing substituent on the nitrogen atom (3), thus allowing for the facile cleavage of the S N bond to provide the desired sulfinate intermediate 4. However the reaction conditions required for the cleavage of the S O bond in 4 to liberate the desired sulfinamides relied heavily on the steric bulk of the R substituent. While the S O bond could be readily cleaved with LHMDS at 0 8C to room temperature to generate some sulfinamides, in the case of hindered substrates [e.g. R = tBu or triisopropylphenyl (TIPP)], the use of excess NH2Li/NH3 (Li/NH3) was required to incorporate the amino group. Currently, NH2Li/NH3 is prepared in situ by portionwise addition of a large excess of solid Li metal to anhydrous NH3 at reaction temperatures of less than 70 8C. These reaction conditions, in addition to the safe handling and disposal of waste generated by using NH2Li/NH3, have limited our ability to produce these important sulfinamides on large scale. Therefore, the efficient and practical synthesis of sterically hindered sulfinamides remained an unsolved problem in the field. Considering that the steric environment provided by the bulky alkyl (e.g. tBu) or aryl (e.g. TIPP) substituents of the sulfinamides is critical for obtaining high stereoselectivities, 7] it was highly desirable to develop a more practical and cost-effective process for their synthesis by replacing NH2Li/ Scheme 1. Approaches for the synthesis of sulfinamides. Ts = 4toluenesulfonamide.

Ligand-Enabled Pd(II)-Catalyzed Bromination and Iodination of C(sp3)–H Bonds

We herein report the palladium(II)-catalyzed bromination and iodination of a variety of α-hydrogen-containing carboxylic acid and amino acid-derived amides. These reactions are exclusively enabled by quinoline-type ligands. The halogenated products obtained in this reaction are highly versatile and rapidly undergo further diversification. Further, we report the first example of a free carboxylic acid-directed Pd(II)-catalyzed C(sp3)-H bromination, enabled by quinoline ligands.

Rh-catalysed asymmetric conjugate addition of boronic acids to nitroalkenes employing a P-chiral P,π-hybrid ligand

A Rh-catalysed asymmetric conjugate addition of aryl boronic acids to β-substituted nitroalkenes was developed employing a P-chiral P-alkene hybrid bidentate ligand with enantioselectivities of up to 94:6 er. DFT modelling of the transition state for the addition reaction was consistent with our previous model for stereocontrol employing this family of chiral ligands. Application of the β-chiral nitroalkanes was demonstrated in the intramolecular Buchwald–Hartwig amination and aminocarbonylation to provide 5- and 6-membered chiral heterocycles.