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UC Irvine UC Irvine Previously Published Works Title Enantioselective semireduction of allenes. Permalink https://escholarship.org/uc/item/2t77t56v Journal Nature communications, 8(1) ISSN 2041-1723 Authors Chen, Zhiwei Dong, Vy M Publication Date 2017-10-04 DOI 10.1038/s41467-017-00793-0 License https://creativecommons.org/licenses/by/4.0/ 4.0 Peer reviewed eScholarship.org Powered by the California Digital Library University of California ARTICLE DOI: 10.1038/s41467-017-00793-0 OPEN Enantioselective semireduction of allenes Zhiwei Chen1 & Vy M. Dong1 Rh-hydride catalysis solves a synthetic challenge by affording the enantioselective reduction of allenes, thereby yielding access to motifs commonly used in medicinal chemistry. A designer Josiphos ligand promotes the generation of chiral benzylic isomers, when combined with a Hantzsch ester as the reductant. This semireduction proceeds chemoselectively in the presence of other functional groups, which are typically reduced using conventional hydro- genations. Isotopic labelling studies support a mechanism where the hydride is delivered to the branched position of a Rh-allyl intermediate. 1 Department of Chemistry, University of California, Irvine, 4403 Natural Sciences 1, Irvine, CA 92697, USA. Correspondence and requests for materials should be addressed to V.M.D. (email: [email protected]) NATURE COMMUNICATIONS | 8: 784 | DOI: 10.1038/s41467-017-00793-0 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-017-00793-0 – n nature, chemo- and stereocontrolled reduction of unsatu- source8 14 (Fig. 1a). As allenes are readily accessible15, a method Irated bonds are catalysed by enzymes and mediated to access these motifs through a semireduction of allenes would by cofactors such as nicotinamide adenine dinucleotide avoid the pre-installation of a suitable leaving group. Allenes are phosphate (NAD(P)H)1. Inspired by this cofactor, chemists have challenging functional groups for reduction because of problems used Hantzsch esters as mild reagents to solve various challenges with in asymmetric reductions2. It occurred to us that this cofactor chemo-, regio-, and stereoselectivity. Both π-bonds can be mimic could be combined with Rh-hydride catalysis to enable a reduced to the corresponding alkane (Fig. 1b), or one π-bond can valuable strategy for reducing allenes to generate benzylic motifs, be reduced to afford one or a mixture of alkene isomers (Fig. 1c). which are traditionally made by an allylic substitution between an Before studies in the regioselective semireduction of allenes have – allylic electrophile and an organometallic reagent3 7 or a hydride shown that the less substituted π-bond is typically reduced to H R1 a 1 Cu or Pd R 2 R LG 2 or R LG Allylic alkylation 2 ++ R or reduction R1–M H– R1 Complete reduction b Me R2 Less substituted R1 1 Semireduction R c R2 Me R2 More Hydride 1 1 d substituted Rh–H R Rh nucleophile R 2 R2 R Fig. 1 Challenges in the selective reduction of allenes. a Traditional methods to access chiral allylic motifs. b Complete reduction affords alkanes. c Existing allene semireductions favour formation of the internal alkene. d Proposed strategy for regio- and enantioselective semireduction to afford the complementary terminal alkene [Rh(COD)CI]2 DPEphos Ph (PhO) P(O)(OH) Ph Ph 2 + Me Ar Reductant Ar Ar CH2CI2, 30 °C, 18 h 1a 2a 3a (E & Z) Ar = 4-MeOC6H4 Entry Reductant Yield (%) 2a:3a 1 HCO2H 62 50:50 2 HCO2NH4 63 67:33 HCO H/ 3 2 48 0:100 1,8-bis(dimethylamino)naphthalenea b 4 NaBH4 Trace ND 5 HSiMe(OEt)2 28 50:50 EtO2C CO2Et 6 87 88:12 Me N Me H 5a Fig. 2 Evaluation of reductants. Reaction conditions: 1a (0.050 mmol), reductant (0.10 mmol), [Rh(COD)Cl]2 (4 mol%), DPEphos (8 mol%), (PhO)2P(O) 1 (OH) (8 mol%), CH2Cl2 (0.1 mL), 30 °C, 18 h. Yields and regioselectivities were determined by H NMR analysis of the unpurified reaction mixture using a b dimethyl terephthalate as an internal standard. HCO2H (0.11 mmol), 1,8-bis(dimethylamino)naphthalene (0.060 mmol). ND, not determined 2 NATURE COMMUNICATIONS | 8: 784 | DOI: 10.1038/s41467-017-00793-0 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | DOI: 10.1038/s41467-017-00793-0 ARTICLE Ph Ph Ar + Ar 1a [Rh(COD)CI]2/L + (PhO)2P(O)(OH) 2a EtO2C CO2Et CH2CI2, 30 °C, 18 h Ph Ph Ar = 4-OMeC6H4 Me + Me N Me Ar Ar H 3a (E & Z) 4a (E & Z) 5a Me Me O PPh2 Me PPh2 P Me PPh PPh Ph P 2 Me O 2 2 Fe Me Me L1 (R )-BINAP L2 (R,R )-DIOP L3 1:3:2 2a:3a:4a 5:2:1 2a:3a:4a 20:1: 1 2a:3a:4a 11% 2a 37% 2a 69% 2a OMe Me Me tBu tBu P Me Ar P t 2 Fe Bu P PAr 2 Me Fe Me MeO Me tBu L3 Ar = Ph L5a Ar = Ph 20:1:1 2a:3a:4a >20:1:1 2a:3a:4a 69% 2a, 61:39 er 27% 2a, 83:17 er a a L4 Ar = 3,5-(CF3)2C6H3 L6 Ar = 3,5-(CF3)2C6H3 >20:1:1 2a:3a:4a >20:1:1 2a:3a:4a 67% 2a, 67:33 er 85% 2a, 95:5 er Fig. 3 Evaluation of chiral ligands. Reaction conditions: 1a (0.10 mmol), 5a (0.20 mmol), [Rh(COD)Cl]2 (4 mol%), L (8 mol%), (PhO)2P(O)(OH) (8 mol%), 1 CH2Cl2 (0.2 mL), 30 °C, 18 h. Yields and product ratios were determined by H NMR analysis of the unpurified reaction mixture using dimethyl a terephthalate as an internal standard. Enantioselectivities (er’s) were determined by chiral SFC analysis. Using [Rh(COD)Cl]2 (2 mol%), L (4 mol%), (PhO)2P(O)(OH) (4 mol%), CH2Cl2 (0.1 mL) – afford the achiral internal alkene16 18. Existing methods chiral benzylic motifs. Using a designed Josiphos ligand and a that reduce the more substituted π-bond are limited to Hantzsch ester reductant, various allenes are reduced to the monosubstituted and symmetrical allenes, which give rise to corresponding chiral terminal alkenes with high selectivities. achiral terminal alkenes19, 20. The generation of electrophilic metal-allyl species from allenes using iridium- and rhodium-hydrides is an emerging strategy in Results allene hydrofunctionalisation21, 22. These intermediates can Reaction development. To test our hypothesis (Fig. 1d), we chose undergo allylic substitution with various nucleophiles to afford 1-methoxy-4-(3-phenylpenta-3,4-dien-1-yl)benzene (1a) as the branched allylated products. We envisioned that a Rh-hydride model substrate for semireduction in the presence of [Rh(COD) catalyst would transform an allene to an electrophilic Rh-allyl Cl]2, (PhO)2P(O)(OH), and DPEphos (Fig. 2). Through a survey intermediate, which can then be trapped with a hydride of achiral bidentate phosphine ligands, we found DPEphos to be – nucleophile23 26. Given that allenes are known to isomerise to the most promising scaffold for suppressing diene formation, dienes in the presence of transition metal-hydrides27, we recog- in the presence of various reductants. Tsuji and Mandai8 nise that a key challenge would be identifying a catalyst that demonstrated that formic acid and formates are competent promotes semireduction over isomerisation. reductants in the reduction of allylic carbonates. However, Herein, we demonstrate an asymmetric semireduction of these reagents led to semireductions with little to no regiocontrol allenes enabled by Rh-hydride catalysis as a complementary (50:50 to 67:33 2a:3a, Fig. 2, entries 1 and 2). Hayashi and approach to allylic alkylation and allylic reduction to generate Kawabata showed that a combination of formic acid and an NATURE COMMUNICATIONS | 8: 784 | DOI: 10.1038/s41467-017-00793-0 | www.nature.com/naturecommunications 3 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-017-00793-0 EtO2C CO Et [Rh(COD)CI] (2 mol%) R1 2 2 1 Josiphos L6 (4 mol%) R + 2 R Me N Me (PhO)2P(O)(OH) (4 mol%) R2 H CH2CI2, 30 °C, 18 h 15a 2, >20:1:1 Me OBn Me Me = R2 2 R R2 MeO R2 R2 2b 2c 75%, 88:12 er 88%, 96:4 er 2d 2e 92%, 95:5 er 85%, 97:3 er CF3 CI Br TsN 2 2 2 2 R R R R2 R 2f 2g 2h 2i 2j 92%, 93:7 er 90%, 94:6 er 87%, 95:5 er 91%, 94:6 er 70%, 94:6 er Me S Ph Ph Ph Me R2 2 2n 2o R 99%, 93:7 er 60%, 92:8 er 2 2k 2l R 92%, 94:6 er 81%, 93:7 er 2m 78%, 95:5 er OMe Ph O Ph O RO NC R = H 2q, 61%, 96:4 er 2sa R = OTIPS 2r, 96%, 95:5 er 2p 67%, 89:11 er 99%, 94:6 er Fig. 4 Enantioselective semireduction of allenes. Reaction conditions: 1 (0.20 mmol), 5a (0.40 mmol), [Rh(COD)Cl]2 (2 mol%), L6 (4 mol%), (PhO)2P(O) 1 (OH) (4 mol%), CH2Cl2 (0.2 mL), 30 °C, 18 h. Isolated yields. Product ratios were determined by H NMR analysis of the unpurified reaction mixture. Enantioselectivities (er’s) were determined by chiral SFC analysis. aReaction performed with 1,2-dichloroethane at 60 °C amine base, such as 1,8-bis(dimethylamino)naphthalene, reduced ligand L3 was employed. Josiphos ligand L4, where one – allylic carbonates and esters9 12. In our system, this combination phosphine is more electron-deficient, afforded an increase in suppressed semireduction of the more substituted π-bond (Fig. 2, the reaction rate, so the catalyst loading can be reduced two-fold.
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  • Olefination of Ketenes for the Enantioselective Synthesis Of

    Olefination of Ketenes for the Enantioselective Synthesis Of

    Tetrahedron 63 (2007) 8046–8053 Olefination of ketenes for the enantioselective synthesis of allenes via an ylide route Chuan-Ying Li,a Ben-Hu Zhu,b Long-Wu Ye,a Qing Jing,a Xiu-Li Sun,a Yong Tanga,* and Qi Shenb,* aState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China bSchool of Chemistry and Chemical Engineering, Suzhou University, Suzhou 215123, China Received 5 February 2007; revised 14 May 2007; accepted 15 May 2007 Available online 18 May 2007 Abstract—Pseudo-C2-symmetric chiral phosphorus ylide is designed and synthesized for the enantioselective preparation of allenic esters, amides, ketone, and nitrile. Up to 92% ee is achieved. Ó 2007 Elsevier Ltd. All rights reserved. 1. Introduction phosphorus ylide bearing 10-phenylsulfonylisoborneol re- acted with methylketene to give penta-2,3-dienoic ester In recent years, optically active allenes have been used as with excellent diastereoselectivity.7e versatile chiral building blocks in organic synthesis due to their high reactivity and the unique ability that they can In a previous study on ylide chemistry in organic synthesis,8 transfer the axial chirality to final products efficiently.1 In we were interested in developing asymmetric ylide-medi- addition, allenes are important subunits in a variety of natu- ated synthesis of optically active allenes and communicated ral products and biologically active compounds.2 Thus, the that newly designed chiral phosphorus ylides could react development of synthetic methodology for enantiomerically with ketenes to afford enantiomerically enriched allenic es- enriched allenes is of great interest and several strategies ters.9 Recently, we modified the chiral ylides and found that have been developed.