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Acute myeloid leukemia (AML) is the most common leukemia in adult patients, with a 5-year survival rate of less than 30 percent. Therefore, more effective therapeutic strategies are required to prolong the survival of AML patients. Importantly, anti-apoptotic proteins, especially B-cell lymphoma 2 (Bcl-2), overexpression in AML is associated with uncontrolled growth as well as chemoresistance. Unsurprisingly, Bruton’s tyrosine kinase (BTK) overexpresses in AML and associated with poor prognosis and chemoresistance. The FDA-approved BTK inhibitor, ibrutinib, has been successful in treating other hematologic malignancies, but a proportion of patients relapse mainly because of acquired mutations at Cys481Ser (C481S) in the kinase domain of BTK. If we are to develop effective BTK-based therapeutic regimens, it is critical that we account for these likely mutations and avoid agents that target the kinase domain. To develop a more selective and effective BTK inhibitor, we modified our first-generation BTK inhibitor to avoid the C481S mutation in the BTK kinase domain. This advance allowed us to develop a second-generation BTK inhibitor, KS151, that shows in vitro potency against C481S mutants. Because BTK and Bcl-2 are critical in chemoresistance and poor prognosis, combination therapy targeting BTK and Bcl-2 is a more viable option for AML patients to achieve better therapeutic outcomes. We propose the combination of KS151 with venetoclax (ABT-199) or ABT-737 in resistant AML cells. We employed a panel of three AML cell lines: Kusami-1, U937, and THP-1. Remarkably, KS151 was able to induce AML cell death with an average IC50 of 4 μM. Furthermore, KS151 showed a significant increase in both venetoclax and ABT-737 efficacy against AML cells. Western blot analysis demonstrated that Kusami-1 cells have the highest expression of both BTK and Bcl-2 proteins. Taken further, flow cytometry (Annexin V staining) demonstrated that KS151 combined with inhibition of Bcl-2 by venetoclax synergistically induced apoptosis (approximately 95%) of Kusami-1 cells. Collectively, the combination therapy showed promising and synergistic in vitro anti-leukemic activity against AML cell lines and represents a new viable treatment for AML patients. Future studies will apply the combination strategies in AML-resistant cell lines and include assessment in patient samples and in vivo studies. Citation Format: Nicole K. Schmalbach, Omar S. Al-Odat, Weam Othman Elbezanti, Gabriella Yao, Daniel A. Guirguis, Krishne Gowda, Shantu G Amin, Tulin Budak-Alpdogan, Subash C. Jonnalagadda, Manoj K. Pandey. Development of a novel BTK inhibitor against resistant acute myeloid leukemia [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A01.

Recent advancements in multiple myeloma (MM) therapy have not changed the fact that it is incurable, and all patients experience relapse or become refractory. Thus, more effective treatments are needed to prolong the survival of MM patients. Anti-apoptotic myeloid cell leukemia 1 (Mcl-1) overexpression is correlated with poor prognosis and drug resistance in MM. Nonetheless, there is a lack of effective Mcl-1 inhibitors. To address this unmet clinical need, we developed KS18, a Mcl-1 inhibitor. We generated respective resistant cells to investigate whether KS18 may overcome acquired resistance against various available drugs in the clinic including bortezomib, venetoclax, and ABT-737. KS18 was effective against all MM cells with IC50 values ranging between 1.5 to 2.5µM. KS18 showed significant Mcl-1 inhibition in various MM cells including resistant cells. Importantly, KS18 re-sensitizes resistant cells to bortezomib and other chemotherapeutic drugs. Moreover, KS18 was able to enhance the anti-myeloma activity of venetoclax and ABT-737 treatments toward bortezomib-resistant cells. These results indicate that KS18 possesses the potential to overcome resistance by targeting Mcl-1. Our future studies in patient samples and in vivo model are proposed for further preclinical assessment of this exciting molecule. Citation Format: Omar S. Al Odat, Krishne Gowda, Shantu G. Amin, Tulin Budak- Alpdogan, Subash C. Jonnalagadda, Manoj K. Pandey. Mcl-1 inhibitor KS18 overcomes bortezomib, venetoclax, and ABT-737 resistance in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1748.

Discovery and development of novel anti-cancer drugs are expensive and time consuming. Systems biology approaches have revealed that a drug being developed for a non-cancer indication can hit other targets as well, which play critical roles in cancer progression. Since drugs for non-cancer indications would have already gone through the preclinical and partial or full clinical development, repurposing such drugs for hematological malignancies would cost much less, and drastically reduce the development time, which is evident in case of thalidomide. Here, we have reviewed some of the drugs for their potential to repurpose for treating the hematological malignancies. We have also enlisted resources that can be helpful in drug repurposing.

Purpose Nucleic acid-based therapies are a promising therapeutic tool. The major obstacle in their clinical translation is their efficient delivery to the desired tissue. We developed a novel nanosized delivery system composed of conjugates of α-tocopherol, polyethyleneimine, and polyethylene glycol (TPP) to deliver nucleic acids. Methods We synthesized a panel of TPP molecules using different molecular weights of PEG and PEI and analyzed with various analytical approaches. The optimized version of TPP (TPP111 - the 1:1:1 molecular ratio) was self-assembled in water to produce nanostructures and then evaluated in diversified in vitro and in vivo studies. Results Through a panel of synthesized molecules, TPP111 conjugate components self-assembled in water, forming globular shaped nanostructures of ~90 nm, with high nucleic acid entrapment efficiency. The polymer had low cytotoxicity in vitro and protected nucleic acids from nucleases. Using a luciferase-expressing plasmid, TPP111-plasmid nano-complexes were rapidly up-taken by cancer cells in vitro and induced strong transfection, comparable to PEI. Colocalization of the nano-complexes and endosomes/lysosomes suggested an endosome-mediated uptake. Using a subcutaneous tumor model, intravenously injected nano-complexes preferentially accumulated to the tumor area over 24 h. Conclusion These results indicate that we successfully synthesized the TPP111 nanocarrier system, which can deliver nucleic acids in vitro and in vivo and merits further evaluation.

Multiple myeloma (MM) is a deadly malignancy of the blood, characterized by the uncontrolled proliferation of plasma cells. MM is challenging to diagnose and treat, accounting for approximately 12% of hematologic malignancies. The overexpression of anti-apoptotic proteins, particularly Myeloid cell leukemia 1 (Mcl-1), play a significant role in the pathogenesis of MM. The overexpression of Mcl-1 is associated with acquired resistance and poor prognosis. Thus, inhibition of the Mcl-1 protein is an attractive therapeutic strategy against myeloma cells. We synthesized and developed a novel Mcl-1 inhibitor, KS18. The preclinical testing of this novel agent is investigated in MM cell lines. Through docking studies, we predicted that KS18 interacts with Mcl-1. KS18 down-regulates the expression of Mcl-1 in MM cells in a dose- and time-dependent manner. Suppression of Mcl-1 expression by KS18 correlated with activation of caspases, PARP- cleavage, and apoptosis. However, this molecule had no effect on the expression of Bcl-2 and Bcl-xL proteins. Importantly, KS18 markedly enhances the efficacies of Venetoclax and ABT-737 in MM cells. Our results propose that targeting Mcl-1 by KS18 may represent a new viable strategy for MM treatment. Citation Format: Omar S. Al-Odat, Rahul S. Tripathi, Sandeep K. Srivastava, Krishne Gowda, Shantu G. Amin, Tulin Budak-Alpdogan, Subash C. Jonnalagadda, Manoj K. Pandey. A novel Mcl-1 inhibitor induces cells death in a caspase-dependent manner and increases the efficacies of Venetoclax and ABT-737 in multiple myeloma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3952.

Novel N-phenylindazole based diarylureas have been designed, synthesized and evaluated as potential anticancer agents. In vitro cell viability studies of these derivatives illustrate good potency with IC50 values in the range of 0.4–50 μM in several cancer cell lines including murine metastatic breast cancer 4T1, murine glioblastoma GL261, human triple negative breast cancer MDA-MB-231, human pancreatic cancer MIAPaCa-2, and human colorectal cancer cell line WiDr. The ester group in the lead compound 8i was modified to incorporate amino-amides to increase solubility and stability while retaining biological activity. Further in vitro studies reveal that lead candidates inhibit tube length in HUVEC cells. In vivo systemic toxicity studies indicate that these candidate compounds are well tolerated in mice without any significant side effects. Anticancer efficacy studies in WiDr tumor xenograft and 4T1 tumor syngraft models demonstrate that the lead candidate 11 exhibits significant antitumor properties as a single agent in these tumor models.

Arylphosphonium-benzoxaborole conjugates have been synthesized as potential mitochondria targeting anticancer agents. The synthesized compounds have been tested for their effects on cell viability in various solid tumor cell lines including breast cancer 4T1 and MCF-7, pancreatic cancer MIAPaCa-2 and colorectal adenocarcinoma WiDr. Compound 6c is designated as a lead compound for further studies due to its enhanced effects on cell viability in the above-mentioned cell lines. Seahorse Xfe96 based metabolic assays reveal that the lead candidate 6c inhibits mitochondrial respiration in 4T1 and WiDr cell lines as evidenced by the reduction of mitochondrial ATP production and increase in proton leak. Epiflourescent microscopy experiments also illustrate that 6c causes significant mitochondrial fragmentation in 4T1 and WiDr cells, morphologically consistent with programmed cell death. Our current studies illustrate that arylphosphonium-benzoxaborole conjugates have potential to be further developed as anticancer agents.

Benzoboroxoles are cyclic boronic acids and they have gained significant attention amongst the organic and medicinal chemistry community in recent years with the approval of benzoboroxole based drugs such as tavaborole for onychomycosis and crisaborole for atopic dermatitis. There have been numerous other benzoboroxole-based compounds identified that exhibit excellent biological activity against wide variety of diseases. Much of the recent literature describes the preparation of functionalized benzoboroxoles and their applications in organic synthesis, materials, and medicinal chemistry. This review outlines the various methods reported for the synthesis of this class of compounds along with few recent applications of benzoboroxoles in medicinal chemistry.

Human telomeric DNA G-quadruplex has been identified as a good therapeutic target in cancer treatment. G-quadruplex-specific ligands that stabilize the G-quadruplex have great potential to be developed as anticancer agents. Two crystal structures (an apo form of parallel stranded human telomeric G-quadruplex and its holo form in complex with BRACO19, a potent G-quadruplex ligand) have been solved, yet the binding mechanism and pathway remain elusive. In this study, we simulated the binding of a free BRACO19 molecule to the apo form of the G-quadruplex using the latest AMBER DNA (OL15) and ligand (GAFF2) force fields. Three binding modes have been identified: top stacking, bottom intercalation, and groove binding. Bottom intercalation (51% of the population) resembles the bottom binding pose in the complex crystal structure very well. The groove binding mode is less stable than the bottom binding mode and is likely to be an intermediate state leading to the bottom binding mode. A flip-insertion mechanism was observed in the bottom intercalation mode, during which flipping of the bases outward makes space for ligand insertion, after which the bases flip back to increase the stability of the complex. In addition to reproducing the base-flipping behavior for some loop residues upon ligand binding, the direct alignment type of the ATAT-tetrad was observed in our simulations for the first time. These successes provide initial support for using this combination of the OL15 and GAFF2 force fields to study quadruplex-ligand interactions.

Multiple myeloma (MM), a clonal plasma cell disorder, disrupts the bones’ hematopoiesis and microenvironment homeostasis and ability to mediate an immune response against malignant clones. Despite prominent survival improvement with newer treatment modalities since the 2000s, MM is still considered a non-curable disease. Patients experience disease recurrence episodes with clonal evolution, and with each relapse disease comes back with a more aggressive phenotype. Bruton’s Tyrosine Kinase (BTK) has been a major target for B cell clonal disorders and its role in clonal plasma cell disorders is under active investigation. BTK is a cytosolic kinase which plays a major role in the immune system and its related malignancies. The BTK pathway has been shown to provide survival for malignant clone and multiple myeloma stem cells (MMSCs). BTK also regulates the malignant clones’ interaction with the bone marrow microenvironment. Hence, BTK inhibition is a promising therapeutic strategy for MM patients. In this review, the role of BTK and its signal transduction pathways are outlined in the context of MM.

Triple Negative Breast Cancer (TNBC), the most aggressive subtype of breast cancer, is characterized by the absence of hormone receptors usually targeted by hormone therapies like Tamoxifen. Because therapy success and survival rates for TNBC lag far behind other breast cancer subtypes, there is significant interest in developing novel anti-TNBC agents that can target TNBC specifically, with minimal effects on non-malignant tissue. To this aim, our study describes the anti-TNBC effect of strictinin, an ellagitanin previously isolated from Myrothamnus flabellifolius. Using various in silico and molecular techniques, we characterized the mechanism of action of strictinin in TNBC. Our results suggest strictinin interacts strongly with Receptor Tyrosine Kinase Orphan like 1 (ROR1). ROR1 is an oncofetal receptor highly expressed during development but not in normal adult tissue. It is highly expressed in several human malignancies however, owing to its numerous pro-tumor functions. Via its interaction and inhibition of ROR1, strictinin reduced AKT phosphorylation on ser-473, inhibiting downstream phosphorylation and inhibition of GSK3β. The reduction in AKT phosphorylation also correlated with decreased cell survival and activation of the caspase-mediated intrinsic apoptotic cascade. Strictinin treatment also repressed cell migration and invasion in a beta-catenin independent manner, presumably via the reactivated GSK3s’s repressing effect on microtubule polymerization and focal adhesion turnover. This could be of potential therapeutic interest considering heightened interest in ROR1 and other receptor tyrosine kinases as targets for development of anti-cancer agents. Further studies are needed to validate these findings in other ROR1-expressing malignancies but also in more systemic models of TNBC. Our findings do however underline the potential of strictinin and other ROR1-targeting agents as therapeutic tools to reduce TNBC proliferation, survival and motility.

Several derivatives of aminobenzoboroxole have been prepared starting from 2-boronobenzaldehyde. All of these derivatives have been evaluated for their anti-mycobacterial activity on Mycobacterium smegmatis and cytotoxicity on breast cancer cell line MCF7. Based on these studies, all the tested molecules have been found to be generally non-toxic and benzoboroxoles with unsubstituted (primary) amines have been found to exhibit good anti-mycobacterial activity. Some of the key compounds have been evaluated for their anti-tubercular activity on Mycobacterium tuberculosis H37Rv using 7H9 and GAST media. 7-Bromo-6-aminobenzoboroxole 4 has been identified as the lead candidate compound for further development.

Several aminobenzoboroxole derivatives have been prepared starting from o-boronobenzaldehyde employing reductive amination protocol. The corresponding aminobenzoboroxole derivatives have been further functionalized as N-nitrosoaminobenzoboroxoles as well as N-benzoboroxolylureas. These derivatives have been evaluated for their anti-cancer activity on human pancreatic cancer MIAPaCa-2 and human breast cancer MDA-MB-231 cell lines. 2015 Elsevier Ltd. All rights reserved.

5-Hydroxymethyl-2-furfural (HMF) is considered an important platform chemical among other intermediates derived from biomass. In this study, we have used mesoporous zirconium phosphate as a catalyst for the conversion of sugars into HMF. The catalyst was synthesized using a hydrothermal method and was characterized using powder XRD, FT-IR spectroscopy and FESEM. The as-prepared catalyst showed porous structure and a very high surface area. Mesoporous zirconium phosphate exhibited excellent catalytic activity for the formation of HMF, from fructose, glucose and sucrose. The effect of various factors such as reaction time, temperature and reaction systems on formation of HMF has been investigated.

Furan-2,5-dicarboxylic acid (FDCA) is a potential platform chemical in polymer industry for manufacturing polyester, polyamides and polyurethanes. Here, we introduced Li2CoMn3O8 as an efficient catalyst for the selective oxidation of 5-hydroxymethyl-2-furfural (HMF) to FDCA with 80% isolated yield in a gram scale reaction. The nanocrystalline spinel Li2CoMn3O8 catalyst was synthesized by gel pyrolysis method using urea and citric acid as complexing agent. The catalyst was characterized using PXRD, BET, ICP-MS and TEM. The catalyst is cheap and easy to prepare. The use of naturally abundant oxygen as oxidant results to high isolated product yield making this procedure scalable.

Triterpenes are widely found amongst various natural sources and are derived from squalene or related 30-carbon acyclic congeners. Medicinal plants are an excellent source of pharmaceutical agents, and the renewability of these resources renders further significance and importance to the discovery and development of drugs from natural products. Betulin, betulinic acid, and other analogous triterpenoids related to the lupane, oleanane, and ursane families are secondary plant metabolites that are most commonly found in fruit peels, leaves, and stem bark. Betulin and betulinic acid are lupane-type natural products isolated from the bark of yellow and white birch trees. Betulin occurs in > 200 types of plant species with the highest percentage of the natural product of up to 10%–25% composing the outer part of certain types of birch bark. These birch trees are native to North America and several parts of Europe. Betulin is remarkably abundant in nature, which makes it an excellent raw material for the synthesis of the biologically active compounds. This review will cover the latest developments in the design, synthesis, characterization, and medicinal applications of betulin and betulinic acid derivatives, specifically in the areas of cancer and aids.

Alkylation of α-amino acid derived iminoesters with Baylis-Hillman (BH) reaction template based allyl bromides/allyl acetates followed by acidic hydrolysis furnished α-methylene-β-substituted-pyroglutamates and α-alkylidene pyroglutamates respectively. Application of these methodologies has been demonstrated in the synthesis of fused [3.2.0]-γ-lactam-β-lactones. Further, substrate controlled stereoselective alkylation of L-threonine derived oxazoles with BH reaction based allyl bromides and acetates yielded optically pure α-methylene-β-substituted pyroglutamates, and α-alkylidene pyroglutamates. These methodologies have been applied in the preparation of chiral [3.2.0] heterobicyclic pyroglutamates containing hydroxyethyl side chain. All the synthesized pyroglutamates have been evaluated for their anti-cancer and enzyme proteasome inhibition activity.

A novel methodology for the efficient synthesis of [2.2.1] heterobicyclic pyroglutamates has been described. The key synthetic steps involve alkylation of amino acid-derived iminoesters with Baylis-Hillman bromide, RhCl3-catalyzed exocyclic olefin isomerization, diastereoselective dihydroxylation, and regioselective lactonization. All the compounds were evaluated for their cytotoxicity using multiple myeloma cancer cell lines RPMI 8226.

Several novel benzoxaborole derivatives were synthesized starting from 2-formylphenylboronic acid utilizing Baylis–Hillman reaction, Barbier allylation, Passerini reaction, and aldol reaction protocols as the key step. All the synthesized benzoxaboroles have been evaluated for their antibacterial, antifungal, and anticancer activities.

A concise protocol for the synthesis of α-methylene-β-hydroxy-γ-carboxy-γ-lactams has been described via alkylation of amino acid derived iminoesters with α-bromomethylmethacrylate, followed by allylic hydroxylation. All the synthesized compounds have been evaluated for their cytotoxicity on multiple myeloma cancer cell lines.

Novel stereoselective synthesis of α-methylene-β-substituted pyroglutamates, and α-alkylidene-pyroglutamates has been achieved via substrate controlled asymmetric alkylation of l -threonine derived oxazole with Baylis–Hillman reaction based allyl bromides and acetates, respectively. The synthesized compounds were evaluated for their proteasome inhibition and cytotoxicity on multiple myeloma cells.

An exceptionally short procedure for the synthesis of heterobicyclic pyroglutamates (V) applies an alkylation of amino acid-derived iminoesters (I) with Baylis-Hillman bromide, rhodium-catalyzed exocyclic olefin isomerization, diastereoselective dihydroxylation, and regioselective lactonization as the key steps.

Benzoxaborole derivatives are prepared from formylphenylboronic acid derivatives (I) utilizing Baylis-Hillman reaction [cf.

Herein we describe a brief account of betulin and betulinic acid: two natural products isolated from birch bark, their chemical modifications and further biological/medicinal applications.

Alkylation of α-amino acid derived iminoesters with Baylis-Hillman (BH) reaction template based allyl bromides/allyl acetates followed by acidic hydrolysis furnished α-methylene-β-substituted-pyroglutamates and α-alkylidene pyroglutamates respectively. Application of these methodologies has been demonstrated in the synthesis of fused [3.2.0]-γ-lactam-β-lactones. Further, substrate controlled stereoselective alkylation of L-threonine derived oxazoles with BH reaction based allyl bromides and acetates yielded optically pure α-methylene-β-substituted pyroglutamates, and α-alkylidene pyroglutamates. These methodologies have been applied in the preparation of chiral [3.2.0] heterobicyclic pyroglutamates containing hydroxyethyl side chain. All the synthesized pyroglutamates have been evaluated for their anti-cancer and enzyme proteasome inhibition activity.

Novel stereoselective synthesis of α-methylene-β-substituted pyroglutamates, and α-alkylidene-pyroglutamates has been achieved via substrate controlled asymmetric alkylation of l -threonine derived oxazole with Baylis–Hillman reaction based allyl bromides and acetates, respectively. The synthesized compounds were evaluated for their proteasome inhibition and cytotoxicity on multiple myeloma cells.

A series of pyroglutamates (III), (VIII), and (X) is readily prepared by reaction of iminoesters (I) with corresponding Baylis—Hillman derivatives followed by acidic cleavage of imines and a subsequent lactamization.

Alkylation of amino-acid derived iminoesters with Baylis–Hillman (BH) template based allyl bromides furnished α-methylene-β-substituted-pyroglutamates, while the corresponding alkylation with BH derived allylic acetates provided α-alkylidene-pyroglutamates. These methodologies have been applied in the synthesis of fused [3.2.0]-γ-lactam-β-lactones.

2-Formylphenylboronic acids upon reaction with activated olefins such as acrylates, methyl vinyl ketone, and acrylonitrile, etc. provide functionalized benzoboroxoles. The corresponding homologated benzoboroxoles were synthesized via the reaction of 2-formylphenylboronic acids with α-bromomethylacrylates.

An efficient methodology for the preparation of α-hydroxyamides via boric acid-mediated addition of isonitriles onto aldehydes has been developed. The reaction of isonitriles with α-boronobenzaldehyde takes place under intramolecular catalysis conditions to provide functionalized benzoxaboroles.

Novel α-carboranyl-α-acyloxy-amides were prepared as potential BNCT agents utilizing three component Passerini reaction. Preliminary cytotoxicity of the representative compounds on two brain tumor cell lines (U-87 and A-172) showed no effect on cell viability; an essential requirement for utility as potential BNCT agents.

[112571-25-2] InChI = 1S/C24H41BO/c1-15-19-11-17(23(19,3)4)13-21(15)25(9-8-10-26-7)22-14-18-12-20(16(22)2)24(18,5)6/h8,10,15-22H,9,11-14H2,1-7H3/b10-8-/t15-,16-,17+,18+,19-,20-,21?,22?/m1/s1 InChIKey = REIADFKXVYZJJI-AATYWXFTSA-N [112482-55-0] C24H41BO (MW 356.39) InChI = 1S/C24H41BO/c1-15-19-11-17(23(19,3)4)13-21(15)25(9-8-10-26-7)22-14-18-12-20(16(22)2)24(18,5)6/h8,10,15-22H,9,11-14H2,1-7H3/b10-8-/t15-,16-,17+,18+,19-,20-,21?,22?/m1/s1 InChIKey = REIADFKXVYZJJI-AATYWXFTSA-N (monofunctional alkoxyallylborating agent used for the reaction with aldehydes and imines to provide the α-alkoxyhomoallylic alcohols and amines, respectively, in a highly stereoselective fashion) Alternative Names: B-γ-Alkoxydiisopinocampheylborane. Analysis of Reagent Purity: 11B NMR (δ ∼80.0, s). Form Supplied in: not available commercially. Handling, Storage, and Precaution: prepared under inert nitrogen/argon atmosphere and used in situ. Physical Data: unstable at higher temperature and undergoes scrambling of the double bond. Preparative Methods: this reagent is prepared and used in situ and the typical procedure involves the lithiation of allylic ether 2 with sec-BuLi at −78 °C to form the (Z)-allylic anion 31 that upon reaction with Ipc2BOMe 4 provides an ‘ate’ complex 5. Addition of a strong Lewis acid (BF3·Et2O) to the ‘ate’ complex 5 releases the reagent (B)-(Z)-(γ)-alkoxyallyldiisopinocampheylborane 1 that is used in situ without isolation (eq 1).2 (1) Purification: none (air and moisture sensitive and unstable at higher temperatures, hence prepared and used in situ). Solubility: soluble in ether, THF, CH2Cl2, and other organic solvents.