Background Moxetumomab pasudotox is a recombinant CD22-targeting immunotoxin. Here, we present the long-term follow-up analysis of the pivotal, multicenter, open-label trial (NCT01829711) of moxetumomab pasudotox in patients with relapsed/refractory (R/R) hairy cell leukemia (HCL). Methods Eligible patients had received ≥ 2 prior systemic therapies, including ≥ 2 purine nucleoside analogs (PNAs), or ≥ 1 PNA followed by rituximab or a BRAF inhibitor. Patients received 40 µg/kg moxetumomab pasudotox intravenously on Days 1, 3, and 5 of each 28-day cycle for up to six cycles. Disease response and minimal residual disease (MRD) status were determined by blinded independent central review. The primary endpoint was durable complete response (CR), defined as achieving CR with hematologic remission (HR, blood counts for CR) lasting > 180 days. Results Eighty adult patients were treated with moxetumomab pasudotox and 63% completed six cycles. Patients had received a median of three lines of prior systemic therapy; 49% were PNA-refractory, and 38% were unfit for PNA retreatment. At a median follow-up of 24.6 months, the durable CR rate (CR with HR > 180 days) was 36% (29 patients; 95% confidence interval: 26–48%); CR with HR ≥ 360 days was 33%, and overall CR was 41%. Twenty-seven complete responders (82%) were MRD-negative (34% of all patients). CR lasting ≥ 60 months was 61%, and the median progression-free survival without the loss of HR was 71.7 months. Hemolytic uremic and capillary leak syndromes were each reported in ≤ 10% of patients, and ≤ 5% had grade 3–4 events; these events were generally reversible. No treatment-related deaths were reported. Conclusions Moxetumomab pasudotox resulted in a high rate of durable responses and MRD negativity in heavily pre-treated patients with HCL, with a manageable safety profile. Thus, it represents a new and viable treatment option for patients with R/R HCL, who currently lack adequate therapy. Trial registration ClinicalTrials.gov identifier: NCT01829711; first submitted: April 9, 2013. https://clinicaltrials.gov/ct2/show/NCT01829711

An efficient synthesis of cyclic carbonates from epoxides and CO 2 under mild reaction conditions was achieved via the use of a newly designed bifunctional quaternary phosphonium iodide catalyst. The importance of the bifunctional design of the catalysts was clearly demonstrated in the present work by control experiments. Furthermore, a chiral version of the bifunctional phosphonium salt could be applied to a kinetic resolution of this reaction.Carbon dioxide (CO 2 ) is recognized as an unfavorable industrial waste due to its greenhouse effect, and the reduction of CO 2 emissions has become integral to the creation of a sustainable society.1 From a different point of view, however, CO 2 is also recognized as an ideal C1 source for chemical synthesis because it is inexpensive, abundant, and nontoxic. In this context, the development of chemical transformations to useful compounds via the use of CO 2 as a reactant has become a hot topic in the field of green sustainable chemistry. 2 Among these transformations, the synthesis of cyclic carbonates 2 from epoxides 1 and CO 2 has been the most extensively studied due to their high utility in industrial processes. 3Although a wide variety of metal catalysts and organocatalysts such as quaternary onium salts have been developed to promote this reaction, high temperature (>100 °C) and pressure (>10 atm) are often required to produce the products 2 in satisfactory yields. 4 Therefore, the development of catalysts that can be effective for this reaction under mild conditions continues to be highly desired. To achieve this desirable task, we became interested in the design of new bifunctional quaternary onium salt catalysts possessing a phenolic hydroxy group when a binary catalyst system with onium salts and phenols was reported to have effectively promoted the reaction under relatively mild conditions (Scheme 1). 5,6 Herein, we report the development of effective bifunctional quaternary phosphonium salts 7 for the synthesis of cyclic carbonates 2 with epoxides 1 under atmospheric CO 2 pressure, mild temperature (60 °C), and low catalyst loading (1 mol %). The utility of a bifunctional design for the catalyst in this reaction was clearly demonstrated in the present work. Furthermore, a chiral version of the bifunctional organocatalyst was also developed, and we applied the chiral catalyst to a kinetic resolution in this reaction. 9Scheme 1 Synthesis of cyclic carbonates 2 under mild reaction conditions.To achieve an efficient synthesis of cyclic carbonates 2 under mild reaction conditions, we designed bifunctional quaternary phosphonium bromides 3 possessing a phenolic hydroxy group. The phosphonium salts 3 with a biphenyl backbone were readily prepared via the reaction with triphenylphosphine and corresponding arylmethyl bromides. There was a concern that the distance between the phosphonium salt moiety and the hydroxy group on catalyst 3 could affect the catalytic activity, and therefore, we prepared regioisomers: o-3, m-3, and p-3 (Scheme 2). The structure of the phosph...

Although the hydrogen-bonding ability of the α-hydrogens on tetraalkylammonium salts is often discussed in the chemistry of phase-transfer catalysts, the catalysis that utilizes the hydrogenbond donor properties of tetraalkylammonium salts remains unknown. In the present work, we demonstrated hydrogen-bonding catalysis with newly designed tetraalkylammonium salt catalysts in Mannich-type reactions. Both the structure and the hydrogenbonding ability of the new ammonium salts were investigated via Xray diffraction analysis and NMR titration studies.Tetraalkylammonium salts are recognized as representative organocatalysts, [1] and are often used as phase-transfer catalysts for the activation of anionic nucleophiles through the formation of an ion pair with an ammonium cation. [2] Although the structures of tetraalkylammonium salts are commonly expressed as 1a shown in Figure 1, the actual ionic structures are discussed differently. [3][4][5] The positive charge of ammonium salts delocalized on the α-hydrogen atoms, which are known to interact with an anionic counterion through hydrogen bonding, as shown in 1A. Reetz proved the delocalization of the positive charge in tetraalkylammonium salts by X-ray crystal analysis of tetrabutylammonium salts such as tetrabutylammonium enolate and phenoxide. [3] Furthermore, DFT calculations support the delocalized structures of ammonium salts, which include chiral ammonium salts. [4,5] The interaction between α-hydrogens on the chiral tetraalkylammonium salt catalyst and the enolate oxygen was thought to be important in the transition-state model of asymmetric phase-transfer reactions. [5] However, despite the interesting hydrogen-bonding ability of the α-hydrogens on tetraalkylammonium salts, the catalysis that could utilize such properties is, to the best of our knowledge, still unknown. Herein, we report a new dimension of tetraalkylammonium salt as a hydrogen-bonding catalyst that utilizes the characteristic properties of the α-hydrogens on the catalyst. [6] Figure 1. Structures of tetraalkylammonium salt.To realize the efficient hydrogen-bonding catalysis of a tetraalkylammonium salt, we designed a new tetraalkylammonium salt, 2, which was readily prepared via the methylation of a commercially available 2,6-piperidinecarboxylate, 3 (Scheme 1). The ammonium salt 2 possesses carboxylate groups at the α-carbon, which enhance the hydrogen-bonding ability of the α-hydrogens. Furthermore, the six-membered structure of the piperidine backbone fixes the acidic α-hydrogens to a position that is appropriate for bidentate binding to an anionic group. [7] Scheme 1. Design and synthesis of a new tetraalkylammonium salt for use as a hydrogen-bonding catalyst.To obtain structural information of newly prepared tetraalkylammonium salts 2, we performed an X-ray diffraction COMMUNICATIONanalysis of ammonium iodide 2a (Figure 2). [8] The crystal structure of 2a provided important structural information. As expected, the hydrogen-bonding interactions between the α-hydrogens and the...

The development of chiral quaternary phosphonium salt catalysts for environmentally benign asymmetric phase-transfer reactions is summarized.

Axially, planar, and helical chiral compounds are indispensable building blocks in modern organic synthesis. A wide variety of chiral ligands and catalysts were designed based on these chiral scaffolds, and these chiral ligands and catalysts were used for various catalytic asymmetric transformations to produce important chiral compounds in an optically enriched form. Furthermore, these chiral skeletons are found in the structure of biologically active natural products. Thus, the development of efficient enantioselective methods for the synthesis of these chiral compounds is an important task in the field of organic chemistry. In the last few years, organocatalyzed approaches, which are one of the most reliable catalytic asymmetric methods, became a hot topic. This Focus Review summarizes asymmetric organocatalytic methods for the synthesis of axially, planar, and helical chiral compounds as useful chiral building blocks.