Classical protocols for carbonyl allylation, propargylation and vinylation typically rely upon the use of preformed allyl metal, allenyl metal and vinyl metal reagents, respectively, mandating stoichiometric generation of metallic byproducts. Through transfer hydrogenative C-C coupling, carbonyl addition may be achieved from the aldehyde or alcohol oxidation level in the absence of stoichiometric organometallic reagents or metallic reductants. Here, we review transfer hydrogenative methods for carbonyl addition, which encompass the first cataltyic protocols enabling direct C–H functionalization of alcohols.

We report byproduct-free carbonyl reverse prenylation, crotylation, and allylation from the alcohol oxidation state via alcohol−allene hydrogen autotransfer. Specifically, exposure of alcohols 1a−6a to 1,1-dimethylallene, methylallene, and allene in the presence of [Ir(cod)(BIPHEP)]BARF (5−7.5 mol %) delivers reverse prenylation products 1c−6c, crotylation products 1d−3d, and allylation product 1e. Similarly, under the conditions of transfer hydrogenation employing isopropanol as terminal reductant, aldehydes 1b−6b are converted to the very same adducts 1c−6c, 1d−3d, and 1e. Isotopic labeling studies corroborate a mechanism involving hydrogen donation from the reactant alcohol or sacrificial alcohol (i-PrOH). The ability to achieve carbonyl addition directly from the alcohol oxidation level circumvents the redox manipulations so often required to convert alcohols to aldehydes. Further, through hydrogen autotransfer, there resides the potential to develop myriad byproduct-free carbonyl additions wherein alcohols and π-unsaturated compounds are exploited as coupling partners.

Under the conditions of ruthenium catalyzed transfer hydrogenation, 2-butyne couples to benzylic and aliphatic alcohols 1a–1i to furnish allylic alcohols 2a–2i, constituting a direct C-H vinylation of alcohols employing alkynes as vinyl donors. Under related transfer hydrogenation conditions employing formic acid as terminal reductant, 2-butyne couples to aldehydes 4a, 4b, and 4e to furnish identical products of carbonyl vinylation 2a, 2b, and 2e. Thus, carbonyl vinylation is achieved from the alcohol or the aldehyde oxidation level in the absence of any stoichiometric metallic reagents. Nonsymmetric alkynes 6a–6c couple efficiently to aldehyde 4b to provide allylic alcohols 2m–2o as single regioisomers. Acetylenic aldehyde 7a engages in efficient intramolecular coupling to deliver cyclic allylic alcohol 8a.

Under hydrogen auto-transfer conditions employing a catalyst derived from [Ir(cod)Cl] 2 and BIPHEP, 1,3-cyclohexadiene (CHD) couples to benzylic alcohols 1a-9a to furnish carbonyl addition products 1c-9c, which appear as single diastereomers with variable quantities of regioisomeric adducts 1d-9d. Under related transfer hydrogenation conditions employing isopropanol as terminal reductant, identical carbonyl adducts 1c-9c are obtained from the aldehyde oxidation level. Isotopic labeling studies corroborate a mechanism involving hydrogen donation from the reactant alcohol or sacrificial alcohol (i-PrOH).As part of a broad program aimed at the development of methods for byproduct-free carbonyl and imine addition, 1,2 we recently reported that carbonyl allylation may be achieved by simply hydrogenating allenes in the presence of aldehydes. 2h Though effective for reverse prenylation, attempted crotylations and allylations using gaseous hydrogen as the terminal reductant suffered from over-reduction of the olefinic adduct. To address this limitation, allene-aldehyde reductive coupling was performed under the conditions of mkrische@mail.utexas.edu . Supporting Information Available. Experimental procedures and spectral data for all new compounds ( 1 H NMR, 13 C NMR, IR, HRMS). This material is available free of charge via the internet at http://pubs.acs.org. transfer hydrogenation using isopropanol as the terminal reductant. 2i In the course of these studies, it was found that carbonyl allylation could be achieved directly from the alcohol oxidation level by way of allene-alcohol transfer hydrogenation, 2i constituting a novel variant of hydrogen auto-transfer processes wherein hydrogen exchange between reactants is used to generate nucleophile-electrophile pairs (Scheme 1). 2i, 3,4,5,6,7 Through hydrogen auto-transfer, there exists the potential to develop a broad new family of byproduct-free catalytic C-C bond formations wherein alcohols and diverse π-unsaturated compounds are exploited as coupling partners. Motivated by this prospect, diene-aldehyde hydrogen auto-transfer was explored. Catalytic diene-aldehyde reductive coupling has been accomplished in both intra-and intermolecular settings. 8,9,10 Recently, the first examples of asymmetric diene-aldehyde intermolecular coupling were reported.9k,l Here, we disclose that 1,3-cyclohexadiene and aromatic alcohols 1a-9a engage in C-C coupling under the conditions of iridium catalyzed hydrogen auto-transfer. Additionally, we report the coupling of 1,3-cyclohexadiene to an analogous set of aldehydes 1b-9b under related transfer hydrogenation conditions employing isopropanol as the terminal reductant. NIH Public AccessInitial studies focused upon the coupling of benzyl alcohol 1a to 1,3-cyclohexadiene (CHD) under the conditions of iridium catalysis. It was found that a catalyst derived from commercially available [Ir(cod)Cl] 2 and BIPHEP delivers homoallylic alcohol 1c as a mixture of diastereomers, along with significant amounts of the regioisomeric product 1...

Over the past half century, numerous protocols for carbonyl propargylation using allenylmetal reagents have been developed.[1] Allenic Grignard reagents were used by Prévost et al.[2a] in carbonyl additions to furnish mixtures of β-acetylenic and α-allenic carbinols, which led to them to coin the term "propargylic transposition." [2a,b] Subsequent studies by Chodkiewicz and co-workers[2c] demonstrated relative stereocontrol in such additions. Shortly thereafter, Lequam and Guillerm[2d] reported that isolable allenic stannanes provide products of carbonyl propargylation upon exposure to chloral. Later, Mukaiyama and Harada[2e] demonstrated that stannanes generated in situ from propargyl iodides and stannous chloride reacted with aldehydes to provide mixtures of β-acetylenic and α-allenic carbinols. Related propargylations employing allenylboron reagents were first reported by Favre and Gaudemar,[2f] and propargylations employing allenylsilicon reagents were first reported by Danheiser and Carini.[2g] Asymmetric variants followed (Scheme 1). Allenylboron reagents chirally modified at the boron center engage in asymmetric propargylation, as was first reported by Yamamoto and coworkers[2h] and Corey et al.[2i] Allenylstannanes chirally modified at the tin center also induce asymmetric carbonyl propargylation, as was first reported by Minowa and Mukaiyama.[2j] Axially chiral allenylstannanes, allenylsilanes, and allenylboron reagents propargylate aldehydes enantiospecifically, as was first described by Marshall et al.,[2k,l] and Hayashi and coworkers,[2m] respectively. Finally, asymmetric aldehyde propargylation using allenylmetal reagents may be catalyzed by chiral Lewis acids or chiral Lewis bases, as was first reported by Keck et al.,[2n] and Denmark and Wynn,[2o] respectively.Here, we report a new approach to carbonyl propargylation based on ruthenium-catalyzed C-C bond-forming transfer hydrogenation. [3][4][5] Specifically, upon exposure of 1,3-enynes 1a-1g to alcohols 2a-2o in the presence of [RuHCl(CO)(PPh 3 ) 3 ]/dppf (dppf =1,1′-bis (diphenylphosphino)ferrocene), hydrogen shuffling between reactants occurs to generate nucleophile-electrophile pairs that regioselectively combine to furnish products of carbonyl

Dedicated to Professor Barry M. Trost on the occasion of his 70th birthday.Trisubstituted allylic alcohols [1,2] are ubiquitous in natural products and are readily converted into diverse chiral building blocks by enantioselective epoxidation, [2a,b] cyclopropanation, [2a,c] hydrogenation, [2a,d] and allylic substitution. [2a,e] Among methods for the regio-and stereoselective synthesis of trisubstituted primary allylic alcohols, alkyne hydrometalation or carbometalation mediated by stoichiometric organometallic reagents has found broad use. [3][4][5][6][7] For example, in seminal studies by Corey et al. (1967), [4c] the regio-and stereoselective hydroalumination of propargyl alcohols was used to construct vinyl iodides, which were converted into trisubstituted allylic alcohols upon exposure to lithium dialkyl cuprates. Similarly, alkyne hydromagnesiation and carbomagnesiation with Grignard reagents delivered trisubstituted allylic alcohols regio-and stereoselectively. [6,7] Although alkyne functionalization through hydrometalation and carbometalation remains at the forefront of research, [3][4][5][6][7] the development of equivalent transformations that avoid stoichiometric metal reagents is clearly desirable. Conversely, whereas related nickel-catalyzed alkyne-carbonyl reductive couplings can be highly regioselective, such processes require terminal reductants that are metallic, pyrophoric, or highly mass intensive (e.g. ZnR 2 , BEt 3 , HSiR 3 ; Scheme 1), [8][9][10] although nickel-catalyzed alcoholmediated alkyne-enone couplings were recently disclosed. [11] Hence, the discovery of alkyne-carbonyl (or alkyneimine) reductive couplings under hydrogenation conditions is significant. [12,13] More recently, an alkyne-carbonyl reductive coupling by ruthenium-catalyzed transfer hydrogenation was developed; however, regioselectivity in such processes remains largely unexplored. [14,15] Herein, we report the regio-and stereoselective synthesis of trisubstituted primary allylic alcohols from alkynes in the absence of stoichiometric metallic reagents. In this reaction, paraformaldehyde is used as a C 1 feedstock and, more remarkably, as a reductant under conditions of transfer hydrogenation with nickel and ruthenium catalysts, which exhibit complementary regioselectivity (Scheme 2).In response to the lack of efficient methods for diene hydroformylation, [16] we recently developed a process for diene hydrohydroxymethylation under the conditions of ruthenium-catalyzed transfer hydrogenation using paraformaldehyde as a C1 feedstock; [17] paraformaldehyde was itself prepared from synthesis gas (via methanol). As the development of efficient catalysts for alkyne hydroformylation remains an unmet challenge, [18] we undertook the current investigation into alkyne-paraformaldehyde reductive coupling. Initial studies focused on the reductive coupling of 1-phenylpropyne (1 a) with paraformaldehyde. We explored the nickel-catalyzed reductive coupling of 1 a with paraformaldehyde in the absence of a reducing agent. [8][9][10] Re...

Under the conditions of ruthenium catalyzed transfer hydrogenation, 2-butyne couples to alcohols 1a–1j to deliver α,β-unsaturated ketones 3a–3j in good to excellent isolated yields with complete E-stereoselectivity. Under identical conditions, aldehydes 2a–2j couple to 2-butyne to provide an identical set of α,β-unsaturated ketones 3a–3j in good to excellent isolated yields with complete E-stereoselectivity. Nonsymmetric alkyne 4a couples to alcohol 1d or aldehyde 2d in good yield to deliver enone 3k as a 5:1 mixture of regioisomers. Thus, intermolecular alkyne hydroacylation is achieved from the alcohol or aldehyde oxidation level. In earlier studies employing the same ruthenium catalyst under slightly different conditions, alkynes were coupled to carbonyl partners from the alcohol or aldehyde oxidation level to furnish allylic alcohols. Therefore, under the conditions of C-C bond forming transfer hydrogenation, all oxidation levels of substrate (alcohol or aldehyde) and product (allylic alcohol or α,β-unsaturated ketone) are accessible.

Protein arginine methyltransferase 5 (PRMT5) overexpression in hematologic and solid tumors methylates arginine residues on cellular proteins involved in important cancer functions including cell-cycle regulation, mRNA splicing, cell differentiation, cell signaling, and apoptosis. PRMT5 methyltransferase function has been linked with high rates of tumor cell proliferation and decreased overall survival, and PRMT5 inhibitors are currently being explored as an approach for targeting cancer-specific dependencies due to PRMT5 catalytic function. Here, we describe the discovery of potent and selective S-adenosylmethionine (SAM) competitive PRMT5 inhibitors, with in vitro and in vivo characterization of clinical candidate PF-06939999. Acquired resistance mechanisms were explored through the development of drug resistant cell lines. Our data highlight compound-specific resistance mutations in the PRMT5 enzyme that demonstrate structural constraints in the cofactor binding site that prevent emergence of complete resistance to SAM site inhibitors. PRMT5 inhibition by PF-06939999 treatment reduced proliferation of non–small cell lung cancer (NSCLC) cells, with dose-dependent decreases in symmetric dimethyl arginine (SDMA) levels and changes in alternative splicing of numerous pre-mRNAs. Drug sensitivity to PF-06939999 in NSCLC cells associates with cancer pathways including MYC, cell cycle and spliceosome, and with mutations in splicing factors such as RBM10. Translation of efficacy in mouse tumor xenograft models with splicing mutations provides rationale for therapeutic use of PF-06939999 in the treatment of splicing dysregulated NSCLC.