Copper-Catalyzed Conjugate Addition Research Articles

Direct Catalytic Enantioselective Conjugate Addition of α-Substituted Benzyl Nitriles to Alkyl Acrylates.

The first enantioselective copper-catalyzed conjugate addition of α-substituted benzyl nitriles to alkyl acrylates is described. This protocol allows the direct and 100% atom-economic generation of a nitrile-containing quaternary stereogenic center in a highly enantioselective manner. The practical application of our methodology was demonstrated through the concise formal synthesis of (-)-aphanorphine.

Copper-catalyzed conjugate addition of allene-derived nucleophiles to alkenyl-substituted carboxamides

Catalytic Michael addition reaction represents a fundamental importance in organic synthetic chemistry. Whereas corresponding conversions toward intrinsically low reactive enamide remains an ongoing challenging. We herein report a copper-catalyzed conjugate addition of allenes to β-substituted alkenyl amides, one of the most challenging Michael acceptors. The present method utilizes readily available allenes as the latent carbon-based nucleophiles and simple, common β-substituted alkenyl amides as starting materials, unlike previous methods that usually preinstall an activating group to improve the reactivity of amide or uses highly reactive stoichiometric quantities of organometallics. Hence, this approach shows good functional group compatibility and can be implemented under mild reaction conditions with excellent level of chemo- and regioselectivities.

Copper-Catalyzed Conjugate Additions to Isocyanoalkenes.

A copper iodide-Pyox complex catalyzes the first conjugate addition of diverse sulfur, nitrogen, and carbon nucleophiles to isocyanoalkenes. The anionic addition generates metalated isocyanoalkanes capable of SNi displacements, providing a rapid route to a series of functionalized, cyclic isocyanoalkanes. The Cu(I)I-Pyox complex efficiently catalyzes a first-in-class conjugate addition affording a range of complex, functionalized isocyanoalkanes that are otherwise challenging to synthesize while laying a foundation for catalytic reactions that maintain the isocyanide group.

Copper-Catalyzed Conjugate Addition of Carbonyls as Carbanion Equivalent via Hydrazones

Copper-catalyzed conjugate addition is a classic method for forming new carbon-carbon bonds. However, copper has never showed catalytic activity for umpolung carbanions in hydrazone chemistry. Herein, we report a facile conjugate addition of hydrazone catalyzed by readily available copper complexes at room temperature. The employment of mesitylcopper(I) and electron-rich phosphine bidentate ligand is a key factor affecting reactivity. The reaction allows various aromatic hydrazones to react with diverse conjugated compounds to produce 1,4-adducts in yields of about 20 to 99%.

Asymmetric copper-catalyzed conjugate additions of organometallic reagents in the syntheses of natural compounds and pharmaceuticals.

Access to enantiopure complex molecular structures is crucial for the development of new drugs as well as agents used in crop-protection. In this regard, numerous asymmetric methods have been established. Copper-catalyzed 1,4-additions of organometallic reagents are robust C-C bond formation strategies applicable in a wide range of circumstances. This review analyses the syntheses of natural products and pharmaceutical agents, which rely on the application of asymmetric Cu-catalyzed conjugate additions of various organometallic reagents. A wide range of available organometallics, e.g. dialkylzinc, trialkylaluminum, Grignard, and organozirconium, can now be used in conjugate additions to address various synthetic challenges present in targeted natural compounds. Furthermore, efficient catalysts allow high levels of stereofidelity over a diverse array of starting Michael acceptors.

Copper-catalyzed conjugate addition of in situ formed alkyl boranes to α,β-unsaturated ketones

Conjugate addition of in situ formed organometallic reagents to α,β-unsaturated carbonyl compounds provides an efficient way to generate new C–C bonds. We show optimization of the copper-catalyzed conjugate addition of alkylboranes, which were formed directly in the reaction mixture by hydroboration of alkenes. We have improved the reaction conditions by employing “greener”, less hygroscopic, and higher boiling solvent, 2-methyltetrahydrofuran. We have also broadened the scope of the reaction. Furthermore, chiral ferrocenyl carbene ligands were assessed in the enantioselective version of the transformation with medium enantioselectivity 67:33 e.r.

Access to Functionalized Quaternary Stereocenters via the Copper-Catalyzed Conjugate Addition of Monoorganozinc Bromide Reagents Enabled by N,N-Dimethylacetamide

Monoorganozinc reagents, readily obtained from alkyl bromides, display excellent reactivity with β,β-disubstituted enones and TMSCl in the presence of Cu(I) and Cu(II) salts to synthesize a variety of cyclic functionalized β-quaternary ketones in 38-99% yields and 9:1-20:1 diastereoselectivities. The conjugate addition features a pronounced improvement in DMA using monoorganozinc bromide reagents. A simple one-pot protocol that harnesses in situ generated monoorganozinc reagents delivers comparable product yields.

Total Synthesis of (±)-Prostratin

•Concise total synthesis of prostratin, a complex anti-HIV and anti-tumor agent•Modular synthesis of a polycyclic molecule with potentials in peripheral variations•Stereocontrolled construction of highly functionalized cyclohexane from phenol•Acid- and solvent-controlled stereoselective photochemical cyclopropane synthesis Natural molecules have been continuously offering drug leads for treatment of human diseases. However, searching for the optimal drugs can be often challenging because of the complexity of structural modifications. In this regard, efficient and flexible chemical synthesis routes to the relevant molecules can provide unparalleled opportunities. Prostratin and its structural relatives are complex plant-derived molecules that have shown diverse potential as drug candidates. Prostratin itself is a promising lead for developing a long-sought-after cure for human immunodeficiency virus (HIV) infection and an anti-cancer drug. In this work, we report a short and modular synthetic route to prostratin from very simple chemicals. Because of its high efficiency and flexibility, this route enables full structural optimization of the molecule and also provides a chemical foundation for exploring its derivatives' potential as medical agents. Prostratin, a highly complex diterpene natural product, is a pre-clinical candidate in developing a cure for HIV-1 infection and also a potent and selective inhibitor of several tumors. Despite nearly 40 years of progress, prostratin and related natural products still present formidable challenges for synthetic chemists. Here, we report a total synthesis of (±)-prostratin that proceeds in 23 steps from cyclopentadiene. The synthetic strategy includes rapid assembly of the tricyclic core and highly controlled establishment of the densely functionalized C ring, featuring an array of stereoselective transformations including alkoxide-guided 1,4-additions and cyclopropane formation. This work should enable further explorations of chemical and biological spaces based on prostratin and related natural products. Prostratin, a highly complex diterpene natural product, is a pre-clinical candidate in developing a cure for HIV-1 infection and also a potent and selective inhibitor of several tumors. Despite nearly 40 years of progress, prostratin and related natural products still present formidable challenges for synthetic chemists. Here, we report a total synthesis of (±)-prostratin that proceeds in 23 steps from cyclopentadiene. The synthetic strategy includes rapid assembly of the tricyclic core and highly controlled establishment of the densely functionalized C ring, featuring an array of stereoselective transformations including alkoxide-guided 1,4-additions and cyclopropane formation. This work should enable further explorations of chemical and biological spaces based on prostratin and related natural products. Tiglianes and daphnanes are two biogenetically correlated large families of diterpenoids isolated from plants such as Euphorbiaceae and Thymelaeaceae.1Liao S.-G. Chen H.-D. Yue J.-M. Plant orthoesters.Chem. Rev. 2009; 109: 1092-1140Crossref PubMed Scopus (159) Google Scholar, 2Wang H.-B. Wang X.-Y. Liu L.-P. Qin G.-W. Kang T.-G. Tigliane diterpenoids from the Euphorbiaceae and Thymelaeaceae families.Chem. Rev. 2015; 115: 2975-3011Crossref PubMed Scopus (130) Google Scholar Structurally, they are highly oxidized compact polycyclic compounds as shown by the representative members in Figure 1. These molecules share a densely substituted [5,7,6] tricyclic core that features C4,C10 and C8,C9 double trans configurations at ring junctions and multiple contiguous stereocenters including three tertiary alcohols. Prostratin (1), phorbol (2), and phorbol 12-myristate 13-acetate (PMA, 3), belonging to tigliane diterpenes, have an additional gem-dimethyl substituted cyclopropane ring. Degradation of phorbol (2) under acidic conditions produces crotophobolone (4), the simplest daphnane, by opening the cyclopropane ring. In contrast, however, most daphnane diterpenes present themselves with a caged orthoester substructure as exemplified by resiniferatoxin (RTX, 5). Many members within these two families have exhibited significant biological functions including anti-cancer,3Mackay H.J. Twelves C.J. Targeting the protein kinase C family: are we there yet?.Nat. Rev. Cancer. 2007; 7: 554-562Crossref PubMed Scopus (321) Google Scholar anti-viral,4Kaur P. Chu J.J.H. Chikungunya virus: an update on antiviral development and challenges.Drug Discov. Today. 2013; 18: 969-983Crossref PubMed Scopus (81) Google Scholar immunomodulatory properties.5Isakov N. Altman A. Regulation of immune system cell functions by protein kinase C.Front. Immunol. 2013; 4: 384Crossref PubMed Scopus (18) Google Scholar Phorbol (2) and PMA (3) are potent tumor promoters through activation of protein kinase C (PKC) and have been long used as biomedical tools. RTX (5) is currently in phase I trial for treatment of severe pain associated with advanced cancer. Among these members, prostratin (1) is unique because it does not show tumor-promoting related toxicity, rather behaving as a promising anti-HIV and anti-cancer agent. The current clinically used antiretroviral therapy (ART) for HIV infection can only control the levels of plasma viremia but cannot affect the latently infected cells that will lead to rebound. Therefore, an agent that can effectively reactivate viral replication in latently infected cells is highly desirable because it may provide the first cure for HIV infection when used as an adjuvant with ART.6Gulakowski J. McMahon J.B. Buckheit R.W. Gustafson K.R. Boyd M.R. A non-tumor-promoting phorbol ester, against human immunodeficiency virus (HIV).Antivir. Res. 1997; 33: 87-97Crossref PubMed Scopus (91) Google Scholar, 7Gustafson J.K.R. Cardellina J.H. McMahon J.B. Gulakowski R.J. Ishitoya J. Szallasi Z. Lewin N.E. Blumberg P.M. Weislow O.S. A nonpromoting phorbol from the Samoan medicinal plant Homalanthus nutans inhibits cell killing by HIV-1.J. Med. Chem. 1992; 35: 1978-1986Crossref PubMed Scopus (188) Google Scholar Prostratin (1) represents such a role through activation of protein kinase C (PKC) and is currently in pre-clinical tests. Moreover, recent studies have shown that prostratin (1) selectively suppressed the K-Ras-mediated human pancreatic and papilloma tumor initiation and growth in mouse models.8Wang M.-T. Holderfield M. Galeas J. Delrosario R. To M.D. Balmain A. McCormick F. K-Ras promotes tumorigenicity through suppression of non-canonical Wnt signaling.Cell. 2015; 163: 1237-1251Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar It was also proposed that prostratin (1) alone or administered with other anti-cancer agents is effective in differentiation therapy of acute myeloid leukemia.9Shen X. Xiong G.-L. Jing Y. Xiao H. Cui Y. Zhang Y.-F. Shan Y.-J. Xing S. Yang M. 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Pioneering work from the Wender group culminated in the first total synthesis of phorbol (2) in 52 steps by employing an elegant intramolecular oxidopyrylium-alkene [5 + 2] cycloaddition in 1989.49Wender P.A. Lee H.Y. Wilhelm R.S. Williams P.D. Studies on tumor promoters. 7. The synthesis of a potentially general precursor of the tiglianes, daphnanes, and ingenanes.J. Am. Chem. Soc. 1989; 111: 8954-8957Crossref Scopus (144) Google Scholar, 50Wender P.A. Kogen H. Lee H.Y. Munger J.D. Wilhelm R.S. Williams P.D. Studies on tumor promoters. 8. The synthesis of phorbol.J. Am. Chem. Soc. 1989; 111: 8957-8958Crossref Scopus (151) Google Scholar Using this type of reaction they also accomplished a formal asymmetric synthesis of 2 in 1997.51Wender P.A. Rice K.D. Schnute M.E. The first formal asymmetric synthesis of phorbol.J. Am. Chem. 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In 2015, the first total synthesis of crotophorbolone (4) was disclosed by the Inoue group (33 steps).55Asaba T. Katoh Y. Urabe D. Inoue M. Total synthesis of crotophorbolone.Angew. Chem. Int. Ed. 2015; 54: 14457-14461Crossref PubMed Scopus (56) Google Scholar An alkoxy bridgehead radical reaction was used to forge the key C9–C10 bond. Furthermore, the first total synthesis of resiniferatoxin (5) was achieved by the Wender group in 1997 (44 steps).56Wender P.A. Jesudason C.D. Nakahira H. Tamura N. Tebbe A.L. Ueno Y. The first synthesis of a daphnane diterpene: the enantiocontrolled total synthesis of (+)-resiniferatoxin.J. Am. Chem. Soc. 1997; 119: 12976-12977Crossref Google Scholar Very recently, the Inoue group has also reported a total synthesis of 5 by employing well-designed tandem radical reactions (41 steps).57Hashimoto S. Katoh S. Kato T. Urabe D. Inoue M. Total synthesis of resiniferatoxin enabled by radical-mediated three-component coupling and 7-endo cyclization.J. Am. Chem. Soc. 2017; 139: 16420-16429Crossref PubMed Scopus (68) Google Scholar Despite its close relevance to anti-HIV and anti-cancer research and development, a total synthesis of prostratin (1) has not been reported. In 2008, Wender and co-workers described an elegant preparation of 1 in four steps from crotophorbolone (4) or in five steps from phorbol (2).58Wender P.A. Kee J.-M. Warrington J.M. Practical synthesis of prostratin, DPP, and their analogs, adjuvant leads against latent HIV.Science. 2008; 320: 649-652Crossref PubMed Scopus (166) Google Scholar Using the semi-synthetic approach, they prepared a series of prostratin analogs with modification at C13 and found that the single-site mutation already had dramatic effects on expression of latent HIV; some analogs exhibited up to 100-fold increase in activity compared with 1.59Beans E.J. Fournogerakis D. Gauntlett C. Heumann L.V. Kramer R. Marsden M.D. Murray D. Chun T.-W. Zack J.A. Wender P.A. Highly potent, synthetically accessible prostratin analogs induce latent HIV expression in vitro and ex vivo.Proc. Natl. Acad. Sci. U S A. 2013; 110: 11698-11703Crossref PubMed Scopus (115) Google Scholar Therefore, it would be of great value to access a broad spectrum of prostratin analogs and fully investigate the structure-activity relationship in order to find optimal drug candidates. This would then in turn require a flexible and efficient de novo synthetic strategy. To meet this need, herein we wish to report a total synthesis of (±)-prostratin (1) that is concise and highly modular. There are two important facts in the chemistry and biology of tigliane and daphnane natural products. The [5,7,6] tricyclic core and the five contiguous stereocenters (C4, C8–C10, and C11) are ubiquitous; the oxidation state and substituents, particularly on the C ring, have great effects on biological activities. Therefore, our synthetic plan was designed to rapidly and controllably assemble the core structure while at the same time to maximize the possibilities of peripheral modifications. As shown in the retrosynthetic analysis of prostratin (1) (Figure 2), whereas the B ring should be formed by ring-closing olefin metathesis reaction from diene 6, the A-ring and C-ring skeletons were to be introduced directly from diol 10 and Grignard reagent 11 at the early stage.60Tong G. Liu Z. Li P. Stereocontrolled construction of the tricyclic framework of tiglianes and daphnanes by an oxidative dearomatization approach.Org. Lett. 2014; 16: 2288-2291Crossref PubMed Scopus (30) Google Scholar Diol 10 was known to be readily available in either racemic or enantiopure form in three or four steps from simple commercially available chemicals.61An G.-i. Rhee H. 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Chem. 1996; 61: 4192-4193Crossref PubMed Scopus (172) Google Scholar The densely functionalized C ring, arguably the most challenging part, would be established from the phenol moiety in 9 by a regio- and stereocontrolled functionalization sequence including oxidative dearomatization (9 to 8), hydroxyl group-guided sequential 1,4-additions, 2-propenyl cross-coupling (8 to 7), and cyclopropanation (7 to 6). We commenced the synthesis from 10 in racemic form, which was prepared in more than 50 g scale in three steps from cyclopentadiene61An G.-i. Rhee H. A facile synthesis of cis-4-amino-2-cyclopentene-1-methanol, a key intermediate for the synthesis of carbocyclic nucleosides.Nucleosides Nucleotides Nucleic Acids. 2002; 21: 65-72Crossref PubMed Scopus (16) Google Scholar (Figure 3). The strategically selected stereocenters in 10 laid the foundation for all later stereoselective steps. Protection of the two hydroxyl groups in 10 with standard acetonide group followed by one-pot epoxidation with m-CPBA furnished the epoxide (see SI-1 in the Supplemental Information; Figures S1 and S2) as a single diastereomer in 75% yield. Copper(I) iodide-catalyzed epoxide opening reaction of the above intermediate with 4-methoxyphenylmagnesium bromide (11) delivered alcohol 12 (Figures S3 and S4) in 77% yield again as the only stereoisomer. Treatment of 12 with tert-butyldimethyl chlorosilane to cover the C4 hydroxyl group followed by demethylation using lithium diphenylphosphide64Ireland R.E. Walba D.M. Demethylation of methyl aryl ethers: 4-ethoxy-3-hydroxybenzaldehyde.Org. Synth. 1977; 56: 44-48Crossref Google Scholar cleanly unveiled phenol 9 (Figures S5 and S6) in 95% yield over two steps. Consequently, 9 could be prepared in decagrams in a short sequence, setting the stage for the planned controlled manipulation of the C ring. Oxidative dearomatization of phenol 9 using singlet oxygen according to our previously reported conditions using tetraphenylporphyrin (TPP) as the sensitizer in oxygen gas-bubbled chloroform led to only low yield (35%) even after 48 hr of visible light irradiation (sodium lamp).60Tong G. Liu Z. Li P. Stereocontrolled construction of the tricyclic framework of tiglianes and daphnanes by an oxidative dearomatization approach.Org. Lett. 2014; 16: 2288-2291Crossref PubMed Scopus (30) Google Scholar, 65Matsuura T. Omura K. Nakashima R. Photo-induced reaction. II. The photo-sensitized oxidation of hindered phenols.Bull. Chem. Soc. Jpn. 1965; 38: 1358-1362Crossref Google Scholar After extensive optimization, we found that the use of rose bengal as the sensitizer and methanol/chloroform (1:1 v/v) mixed solvents could significantly improve the conversion and the desired cyclohexadienone 8 (Figures S7 and S8) was isolated in 85% yield. Different from standard protocols for this type of reaction, no reductant was needed in this case since the expected intermediate peroxy quinol was directly decomposed to quinol 8. In principle, a single nucleophilic addition to 8 could take place at the diastereotopic C8 and C11 positions (1,4-addition) or at C13 (1,2-addition), generating six possible regio- and/or diastereoisomers. Stimulated by the ligand assisted nucleophilic addition (LANA) method by Liotta and co-workers,66Solomon M. Jamison W.C.L. McCormick M. Liotta D. Cherry D.A. Mills J.E. Shah R.D. Rodgers J.D. Maryanoff C.A. Ligand-assisted nucleophilic additions. Control of site and face attack of nucleophiles on 4-oxido enones.J. Am. Chem. Soc. 1988; 110: 3702-3704Crossref Scopus (73) Google Scholar we first treated 8 with lithium hexamethyldisilazide (LiHMDS) to deprotonate the newly generated C9-hydroxyl group and then added methylmagnesium chloride to achieve the alkoxide-guided face selective 1,4-addition. Two separable diastereomers (∼1:1 ratio, 73%) were isolated after silica gel column chromatography.67Attempts in copper-catalyzed conjugate addition reactions of the hydroxyl-protected substrates were unsuccessful most likely because of the γ-steric hindrance and the proneness to rearomatization. Single-crystal X-ray diffraction analysis confirmed the cis configuration of the desired diastereomer 13 (Figures S9 and S10; Table S9) and its 9,11-epimer (see SI-2 in the Supplemental Information; Figures S11 and S12; Table S10). To install the C15–C17 side chain, Johnson iodination (iodine/pyridine) of 13 led to an α-iodoenone (see SI-3 in the Supplemental Information; Figures S13 and S14) in 85% yield, which then underwent palladium-catalyzed Suzuki-Miyaura coupling with 2-isopropenyl boronic acid pinacol ester, providing the cross-conjugated dienone 14 (Figures S15 and S16) in excellent yield (93%). Next, we attempted to introduce a vinyl group at C8 again employing the LANA method with vinyl Grignard reagent. However, only 14 was recovered, likely due to the high steric hindrance around C8 (see Table S7 for more details). Inspired by Yamamoto's work in super bulky Lewis acids,68Maruoka K. Shimada I. Imoto H. Yamamoto H. Conjugate addition of reactive carbanions to α,β-unsaturated ketones in the presence of ATPH.Synlett. 1994; 1994: 519-520Crossref Scopus (49) Google Scholar we reasoned that a suitable bulky Lewis acid might block C13 site by coordination with the carbonyl oxygen while at the same time activate the C8 site. Indeed, when 2 equiv of aluminum tris(2,6-diphenylphenoxide) (ATPH) were added before addition of vinylmagnesium chloride (5 equiv) to a solution of 14 in toluene, exclusive 1,4-addition was observed. With concomitant double bond migration, the α,β-unsaturated enone 7 (Figures S17 and S18) could thus be obtained in 81% yield. The configuration was again unambiguously confirmed by X-ray diffraction analysis of a single crystal of 7 (Table S11). Attempts in copper-catalyzed conjugate addition reactions of the hydroxyl-protected substrates were unsuccessful most likely because of the γ-steric hindrance and the proneness to rearomatization. Next, we tested formation of the gem-dimethyl cyclopropane D ring through photochemical nitrogen extrusion of a cyclic diazene (Figure 4).58Wender P.A. Kee J.-M. Warrington J.M. Practical synthesis of prostratin, DPP, and their analogs, adjuvant leads against latent HIV.Science. 2008; 320: 649-652Crossref PubMed Scopus (166) Google Scholar, 69Freeman J.P. A synthesis of cyclopropyl acetates.J. Org. Chem. 1964; 29: 1379-1382Crossref Scopus (41) Google Scholar Simple treatment of 7 with hydrazine hydrate in ethanol formed a pyrazoline intermediate (Intcis, observed with nuclear magnetic resonance [NMR]) that could be oxidized using lead(IV) acetate to diazene 15 (Figures S19 and S20) after removal of the silyl group. However, the key configuration of 15 was identified by coupling constant (3JH8–H14 = 8.3 Hz) and X-ray diffraction of a single crystal to be 8,14,13-cis,cis (Table S12). Denitrogenative cyclopropanation of 15 under UV irradiation (254 nm) and successive one-pot oxidation generated 16 (Figures S21 and S22) as single isomer but with wrong configuration of the cyclopropane as evidenced by X-ray crystallography (Table S13). This result indicated the challenge in building the desired C14 stereocenter in pyrazoline formation and its necessity in following cyclopropanation, since no epimerization at C14 was observed. Notably, in Wender's semi-synthesis work from crotophorbolone (4), C14 center was preset.58Wender P.A. Kee J.-M. Warrington J.M. Practical synthesis of prostratin, DPP, and their analogs, adjuvant leads a

Enantioselective copper-catalyzed conjugate additions of in situ generated organozirconium reagents to N-heterocyclic Michael acceptors

Stereoselective conjugate additions of organometallic reagents provide access to many useful chiral compounds. In this work, we have studied the enantioselective Cu-catalyzed conjugate addition of organozirconium reagents, which were generated in situ by hydrozirconation of alkenes. We show that N-heterocyclic Michael acceptors, represented by unsaturated lactams and 2,3-dihydropyridin-4(1H)-ones can be useful substrates for Cu-catalyzed conjugate additions of organozirconium reagents. Phosphorus ligands screening identified Feringa's phosphoramidite as the most active and enantioselective ligand for this transformation, which afforded corresponding conjugate addition products with an enantiomeric purity of up to 92:8 e.r. The absolute configuration of one of the conjugate addition products was established by comparison of DFT calculated and experimental electronic CD spectra. The study also showed that mildly reactive organozirconium reagents combined with relatively unreactive Michael acceptors afford typically conjugate addition products in medium yields. DFT calculations of LUMO maps also supported non-reactivity of heterocyclic Michael acceptors. LUMO maps showed decreasing electrophilicity at the β-carbon due to donor substituents present near unsaturated carbonyl scaffold.

Copper-Catalyzed Asymmetric Conjugate Addition of Alkylzirconium Reagents

Copper-Catalyzed Asymmetric Conjugate Addition of Alkylzirconium Reagents

Lewis Acid Enabled Copper-Catalyzed Asymmetric Synthesis of Chiral β-Substituted Amides.

Here we report that readily available silyl- and boron-based Lewis acids in combination with chiral copper catalysts are able to overcome the reactivity issues of unactivated enamides, known as the least reactive carboxylic acid derivatives, toward alkylation with organomagnesium reagents. Allowing unequaled chemo-reactivity and stereocontrol in catalytic asymmetric conjugate addition to enamides, the method is distinguished by its unprecedented reaction scope, allowing even the most challenging and synthetically important methylations to be accomplished with good yields and excellent enantioselectivities. This catalytic protocol tolerates a broad temperature range (−78 °C to ambient) and scale up (10 g), while the chiral catalyst can be reused without affecting overall efficiency. Mechanistic studies revealed the fate of the Lewis acid in each elementary step of the copper-catalyzed conjugate addition of Grignard reagents to enamides, allowing us to identify the most likely catalytic cycle of the reaction.

Electrophilic Trapping of Zirconium Enolates Obtained by Copper-Catalyzed Addition of In Situ Generated Organozirconium Reagents

Building complex structures from simple starting materials is important for effective organic synthesis. In this context, domino reactions comprising hydrozirconation of alkenes, their subsequent utilization in a copper-catalyzed conjugate addition to enones, followed by electrophilic trapping of the formed zirconium enolates with activated alkene and carbocations are described. Reactivity of metal enolates was studied by DFT calculations.

Enantioselective synthesis of chiral acylsilanes by copper/HZNU-Phos-catalyzed asymmetric conjugate addition of diethyzinc to α,β-unsaturated acylsilanes

The catalytic asymmetric copper-catalyzed conjugate addition of diethylzinc reagent to α,β-unsaturated acylsilanes was found to proceed smoothly in moderate to good yields and enantioselectivities (up to 85% ee) in the presence of the multifunctional HZNU-Phos.

ChemInform Abstract: Copper‐Catalyzed Asymmetric Conjugate Addition of Dimethylzinc to Acyl‐N‐methylimidazole Michael Acceptors: Scope, Limitations and Iterative Reactions.

AbstractThe copper catalyzed enantioselective addition of dimethylzinc to α,β‐unsaturated ketones having a heterocyclic moiety on the other side is investigated in the presence of a chiral bidentate hydroxyalkyl‐NHC ligand.

Strategies for the Synthesis of Deoxypropionates

Deoxypropionates constitute an important class of polyketide natural products. The biological properties of deoxypropionates are diverse and synthetic strategies toward their preparation are equally manifold. This short review presents some recent developments on the synthesis of deoxypropionate units involving, besides iterative and non-iterative routes, other methods such as stereoselective Mukaiyama reactions or lithiation–borylation–protodeboronation sequences. 1 Introduction 2 Biosynthesis of Deoxypropionates 3 Iterative Synthetic Methods 3.1 Conjugate Addition of Cuprates 3.2 Copper-Catalyzed Conjugate Additions 3.3 Copper-Mediated Allylic Substitution 3.4 Myers Alkylation 3.5 Zirconium-Catalyzed Carboalumination 3.6 Homologation of Boronates with Organolithiums 4 Non-Iterative Methods 4.1 Enzymatic Desymmetrization 4.2 Ex Chiral Pool Synthesis from Wax Esters 4.3 Ex Chiral Pool Synthesis from the Roche Ester 4.4 Sequential [3,3]-Sigmatropic Rearrangement and Catalytic Hydrogenation 5 Miscellaneous Methods 6 Conclusion

Copper-Catalyzed Enantioselective Conjugate Addition to α,β-Unsaturated Aldehydes with Various Organometallic Reagents

β-Substituted aldehydes constitute a very important class of compounds found in nature. Synthesis of this motif can be envisioned by C–C bond formation on enals. For this purpose, we report herein the development of enantioselective copper-catalyzed conjugate addition of various organometallic reagents to α,β-unsaturated aldehydes with (R)-H8BINAP, (R)-TolBINAP, and (R)-SEGPHOS as chiral ligands. Three sets of conditions were successfully developed and several enals were used. Reactivity and regio- and enantioselectivities were strongly dependent on reaction conditions and substrates. Good to excellent regio- and enantioselectivities were obtained with zinc reagents R2Zn and aluminum reagents R3Al. However, the asymmetric conjugate addition of Grignard reagents afforded only moderate to good regio- and enantioselectivities.

Palladium(II)-Catalyzed Cross-Dehydrogenative Coupling (CDC) of N-Phthaloyl Dehydroalanine Esters with Simple Arenes: Stereoselective Synthesis of Z-Dehydrophenylalanine Derivatives.

Pd(II)-catalyzed cross-dehydrogenative coupling (CDC) of methyl N-phthaloyl dehydroalanine esters with simple aromatic hydrocarbons is reported. The reaction, which involves the cleavage of two sp(2) C-H bonds followed by C-C bond formation, stereoselectively generates highly valuable Z-dehydrophenylalanine skeletons in a practical, versatile, and atom economical manner. In addition, a perfluorinated product was expediently converted into important nonproteinogenic amino acid building blocks through copper-catalyzed conjugate additions of boron, silicon, and hydride moieties.

Scalable Route to Chiral Phosphoramidites

The chiral copper-catalyzed conjugate addition is a well-developed methodology to create asymmetric C-C bonds. Many efforts have been dedicated to design efficient systems and identifying highly efficient ligands. Among the most proficient ligands, the ones possessing a bis-phenol or a bis-naphthol moiety are the most prominent. Herein we describe a scalable convenient route that can afford phosphoramidites in excellent yield.<br />Please find "Figure 1. General structure and application of phosphoramidites" in PDF format.

Copper-Catalyzed Asymmetric Conjugate Addition

Copper-Catalyzed Asymmetric Conjugate Addition

ChemInform Abstract: Copper‐Catalyzed Stereoselective Conjugate Addition of Alkylboranes to Alkynoates.

A copper-catalyzed conjugate addition of alkylboron compounds (alkyl-9-BBN, prepared by hydroboration of alkenes with 9-BBN-H) to alkynoates to form β-disubstituted acrylates is reported. The addition occurred in a formal syn-hydroalkylation mode. The syn stereoselectivity was excellent regardless of the substrate structure. A variety of functional groups were compatible with the conjugate addition.