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Published in final edited form as: ACS Catal. 2022 Jun 23;12(14):8164–8174. doi: 10.1021/acscatal.2c02444

Enantioselective Metal-Catalyzed Reductive Coupling of Alkynes with Carbonyl Compounds and Imines: Convergent Construction of Allylic Alcohols and Amines

Eliezer Ortiz 1, Jonathan Shezaf 1, Yu-Hsiang Chang 1, Michael J Krische 1,*
PMCID: PMC10112658  NIHMSID: NIHMS1841659  PMID: 37082110

Abstract

The use of alkynes as vinylmetal pronucleophiles in intermolecular enantioselective metal-catalyzed carbonyl and imine reductive couplings to form allylic alcohols and amines is surveyed. Related hydrogen auto-transfer processes, wherein alcohols or amines serve dually as reductants and carbonyl or imine proelectrophiles, also are cataloged, as are applications in target-oriented synthesis. These processes represent an emerging alternative to the use of stoichiometric vinylmetal reagents or Nozaki-Hiyama-Kishi (NHK) reactions in carbonyl and imine alkenylation.

Keywords: Alkyne, Reductive Coupling, Enantioselective, Allylic Alcohol, Allylic Amine, Hydrogen Transfer

Graphical Abstract

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1. Introduction to Alkyne-Mediated C═X (X = O, NR) Vinylation

Catalytic enantioselective additions of vinyl anions to carbonyl compounds and imines to form allylic alcohols and allylic amines represent an important subset of carbonyl addition reactions.1,2 Among methods of this type, Noyori-type vinylzinc additions3,4 and Nozaki-Hiyama-Kishi reactions5 of vinyl halide pronucleophiles are utilized most frequently. The vinylic reactants utilized in these processes invariably derive from alkynes. Hence, over the past two decades substantial effort has been devoted to the development of direct enantioselective metal-catalyzed reductive couplings of alkynes to carbonyl compounds and imines and, more recently, related hydrogen auto-transfer protocols (Figure 1).6,7,8

Figure 1.

Figure 1.

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Strategies for catalytic enantioselective vinylation of carbonyl compounds and imines.

Here, intermolecular enantioselective metal-catalyzed reductive couplings of alkynes with carbonyl compounds and imines to form allylic alcohols and allylic amines, respectively, are surveyed. Corresponding enantioselective reductive cyclizations of acetylenic carbonyl compounds and imines are not covered.9,10 Discussion is limited to processes that result in C─H and C─C bond formation via formal addition of H2 across the alkyne pronucleophile and C═X (X = O, NR) π-bond. Hence, multicomponent intermolecular alkylative6a,7d,11 alkyne-C═X (X = O, NR) reductive couplings are not covered (nor are related alkylative/arylative12 or borylative/silylative13 cyclization processes). Finally, metal-catalyzed reductive couplings of alkynes with carbon dioxide are beyond the scope of this monograph.14 Content is organized on the basis of alkyne structure (1,3-enynes and 1,3-diynes vs alkyl-and aryl-substituted alkynes) and then on the basis of metal catalyst.

2. 1,3-Enyne and 1,3-Diyne-C═X (X = O, NR) Reductive Coupling

2.1. Rhodium

Hydrogenation of 1,3-enynes or 1,3-diynes in the presence of activated aldehydes or ketones using cationic rhodium catalysts modified by chiral chelating bis(phosphine) ligands promotes reductive coupling to form enantiomerically enriched secondary and tertiary allylic alcohols as single regioisomers with complete control of alkene geometry (Scheme 1).15 Remarkably, although cationic rhodium complexes are widely utilized as catalysts for alkene hydrogenation,16 competing hydrogenation of π-unsaturated products is not observed. This stems from the fact that the reactants are more π-acidic than the products and, consequently, are better ligands for the low-valent rhodium catalyst. Therefore, upon full consumption of the carbonyl partner, excess enyne reactant binds the catalyst to suppress product hydrogenation. Hence, beyond the reductive coupling of enynes with pyruvates (Scheme 1A),15a glyoxalates (Scheme 1C),15d or certain heterocyclic aldehydes or ketones (Scheme 1B),15c 1,3-diyne-glyoxalate reductive coupling15b can be achieved without further reaction (over-reduction or coupling) of the 1,3-enyne-containing products (Scheme 1D).

Scheme 1.

Scheme 1.

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Enantioselective rhodium-catalyzed reductive coupling of 1,3-enynes or 1,3-diynes with activated aldehydes or ketones mediated by hydrogen.

The indicated mechanism for rhodium-catalyzed reductive coupling of conjugated alkynes with activated carbonyl compounds mediated by hydrogen is supported by isotopic labelling15a and computational studies (Scheme 2).17 The square planar cationic rhodium complex I has two vacant coordination sites, which enables the binding of both enyne and carbonyl compound and, in turn, their oxidative coupling to form an oxarhodacyclopentene. Direct σ-bond metathesis of the oxarhodacyclopentene and hydrogen, which occurs by way of the 4-centered transition structure II, can be slow. Brønsted acid co-catalysts, typically carboxylic acids, are often required to enhance rate and conversion via protonolytic cleavage of the oxarhodacyclopentene by way of the 6-centered transition structure III. σ-Bond metathesis of the resulting rhodium carboxylate with hydrogen can now occur more rapidly through the 6-centered transition structure IV.18 Reductive elimination releases the product of reductive coupling and regenerates low-valent rhodium to close the catalytic cycle.

Scheme 2.

Scheme 2.

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Mechanism for rhodium-catalyzed reductive coupling of conjugated alkynes with activated carbonyl compounds mediated by hydrogen.

Related rhodium-catalyzed reductive couplings of conjugated enynes or diynes with activated imines mediated by hydrogen occur under essentially identical conditions, but in the absence of Brønsted acid co-catalysts (Scheme 3).19 Whereas ethyl (N-tert-butanesulfinyl)iminoacetate provides optimal levels of asymmetric induction for enyne pronucleophiles, ethyl (N-2,4,6-triisopropylbenzenesulfinyl)iminoacetate is required for diyne pronucleophiles. Both enynes and diynes undergo C─C coupling with complete levels of regioselectivity. Although these reactions are not enantioselective, this chiral auxiliary-based method provides access to chiral nonracemic allylic amines in the form of nonproteogenic amino acid esters.

Scheme 3.

Scheme 3.

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Diastereoselective rhodium-catalyzed reductive coupling of 1,3-enynes or 1,3-diynes with ethyl (N-tert-butanesulfinyl)iminoacetate mediated by hydrogen.

The exceptional functional group tolerance and stereoselectivity of these rhodium-catalyzed hydrogen-mediated alkyne-carbonyl reductive couplings is demonstrated by their application to the total synthesis of bryostatin 7 and preparation of related seco-B-ring analogs (Scheme 4).20 The bryostatins are a family of structurally complex marine macrolides that bind the C1 domain of protein kinase C (PKC) isozymes, antagonizing most biological responses of the phorbol esters, classic PKC activators that are generally tumor promoting. To construct the bryostatin C-ring and simplified congeners, hydrogen-mediated reductive coupling of the indicated glyoxals and 1,3-enynes was conducted using a cationic rhodium catalyst modified by (R)-tol-BINAP. This process forges the C20-C21 bond with complete control of regioselectivity and alkene geometry, as well as good levels of catalyst-directed diastereoselectivity vis-à-vis control of the C20 carbinol stereochemistry.

Scheme 4.

Scheme 4.

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Synthesis of bryostatin 7 and selected seco-B-ring analogs via asymmetric rhodium-catalyzed reductive coupling of 1,3-enynes with glyoxals mediated by hydrogen.

2.2. Nickel

Like their rhodium-catalyzed counterparts,14,19,20 enantioselective nickel-catalyzed carbonyl reductive couplings of conjugated enynes occur with complete control of regioselectivity and alkene geometry to furnish dienyl allylic alcohols (Scheme 5).21 These processes are applicable to aldehydes (Scheme 5B) and, quite remarkably, unactivated ketones (Scheme 5A). However, triethylborane, a pyrophoric liquid, is required as terminal reductant and modest yields and enantioselectivities are observed upon use of the indicated monodentate P-chiral ferrocenyl phosphine ligand. Nevertheless, these data support the prospect of developing highly enantioselective reductive couplings of enynes with unactivated ketones, which would represent a significant achievement.

Scheme 5.

Scheme 5.

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Enantioselective nickel-catalyzed reductive coupling of 1,3-enynes with aldehydes or ketones mediated by triethylborane.

3. Nonconjugated and Aryl Alkyne-C═X (X = O, NR) Reductive Coupling

3.1. Rhodium

Hydrogenation of acetylene, an abundant feedstock (>10 x 106 tons/yr),22 in the presence of carbonyl compounds (Scheme 6A) or imines (Scheme 6B) provides products of reductive C─C coupling in the form of (Z)-dienyl allylic alcohols and amines, respectively.23a,b Here, a cationic rhodium complex with the BAr4F counterion, tetrakis[3,5-bis(CF3)phenyl]borate, was employed as catalyst. Using enantiomeric rhodium catalysts ligated by (R)- and (S)-MeO-BIPHEP, L-glyceraldehyde acetonide is converted to the indicated diastereomeric adducts with good levels of catalyst-directed asymmetric induction and, therefrom, all eight L-hexoses (Scheme 6A).23c As corroborated by deuterium labelling and ESI mass spectrometric analyses, these processes occur via oxidative coupling of acetylene to furnish a rhodacyclopentadiene followed by insertion of the C═X (X = O, NSO2Ar) π-bond (Scheme 6C).23d Carboxylic acid co-catalyzed hydrogenolysis of the resulting oxa/aza-rhodacycloheptadiene releases the product and returns rhodium to its low valent form. This method was applied to the total syntheses of (+)-trienomycins A and F (not shown).23e

Scheme 6.

Scheme 6.

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Enantioselective and diastereoselective rhodium-catalyzed reductive coupling of acetylene with carbonyl compounds or imines mediated by hydrogen.

3.2. Iridium

Cationic iridium complexes modified by chiral chelating bis(phosphine) ligands catalyze enantioselective reductive couplings of alkyl-substituted alkynes with imines mediated by hydrogen (Scheme 7).24 These reactions proceed via stereoselective alkyne-C═NSO2Ar oxidative coupling to form the indicated aza-iridacyclopentene that suffers carboxylic acid co-catalyzed hydrogenolysis to release the allylic amine. In reactions of non-symmetric alkynes, there exists a pronounced preference for placement of the larger alkyne substituent distal to the sterically demanding metal center to promote high levels of contrasteric regioselectivity in the C─C bond forming event.

Scheme 7.

Scheme 7.

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Enantioselective iridium-catalyzed reductive coupling of nonconjugated alkynes with N-arylsulfonyl aldimines mediated by hydrogen.

3.3. Ruthenium

Pursuant to the development of non-asymmetric processes,25a enantioselective ruthenium-catalyzed carbonyl vinylations via hydrogen auto-transfer recently were disclosed (Scheme 8).25b Using an iodide-bound ruthenium-JOSIPHOS catalyst and 2-butyne as the vinyl donor, structurally diverse primary alcohols are converted to the corresponding chiral allylic alcohols with excellent levels of enantioselectivity and complete control of alkene geometry. Deuterium labelling experiments corroborate a catalytic cycle in which alcohol dehydrogenation forms an aldehyde and a ruthenium hydride, which upon alkyne hydrometallation delivers a nucleophilic vinylruthenium species that participates in carbonyl addition. Beyond interactions with the chiral ligand, the absolute stereochemical course of vinylation is influenced by formyl CH···I[Ru] and CH···O≡C[Ru] hydrogen bonding26,27 and iodide-dependent stereogenicity of the ruthenium center.28

Scheme 8.

Scheme 8.

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Enantioselective and diastereoselective ruthenium-catalyzed reductive coupling of 2-butyne with aldehydes via hydrogen auto-transfer from alcohol reactants.

3.4. Cobalt

Cobalt catalysts modified by (S,S)-BDPP promote the Hantzsch ester-mediated reductive coupling of alkynes with aldehydes upon irradiation with visible light in the presence of an organic photoredox catalyst (Scheme 9).29 Although irradiation and use of a mass-intensive reductant (the Hantzsch ester) are required, nonsymmetric alkynes undergo C─C coupling to furnish the allylic alcohols with excellent control of regio- and enantioselectivity. A key feature of the reaction mechanism involves photo-mediated electron transfer from Hantzsch ester to 4-CzlPN. The resulting anion radical of 4-CzlPN affects reduction of cobalt(II) to cobalt(I), which promotes alkyne-carbonyl oxidative coupling. The authors posit that formal hydrogenolysis of the cobalt(III) oxametallacyclopentene occurs through successive protonation-electron transfer-protonation events to releases product and regenerate cobalt(II).

Scheme 9.

Scheme 9.

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Enantioselective and diastereoselective cobalt-catalyzed reductive coupling of alkynes with aldehydes mediated by Hantzsch ester.

3.5. Nickel

In 2003, Jamison reported enantioselective nickel-catalyzed alkyne-aldehyde reductive couplings mediated by triethylborane (Scheme 10A).30a Using a zero-valent nickel catalyst modified by (+)-(neomenthyl)diphenylphosphino, (+)-NMDPP, aryl-substituted alkynes and α-branched aldehydes are transformed to highly enantiomerically enriched trisubstituted allylic alcohols with complete control of regioselectivity and alkene geometry. In parallel studies by Montgomery, chiral NHC-modified nickel-catalysts were developed for enantioselective alkyne-aldehyde reductive couplings mediated by silane.30b,d Initial work led to the design of the ligand NHC-I, for which the N-aryl moieties are geared conformationally with respect to the 1,2-diphenylethylenediamine-containing tetrahydroimidazole core to induce an element of axial chirality (Scheme 10B).30b However, in subsequent studies, the less complex ligand NHC-II was found to be superior. Upon use of NHC-II in combination with tert-butyldimethylsilane as reductant, the reductive coupling products are formed as their TBS ethers with good control of regio- and enantioselectivity (Scheme 10C).30d Finally, as demonstrated in work by the Scheidt laboratory, nickel catalysts modified by the planar chiral ferrocene-containing NHC ligand, NHC-III, are also effective in enantioselective silane-mediated alkyne-aldehyde reductive coupling (Scheme 10D).30c Several total syntheses of complex secondary metabolites were accomplished using stereoselective nickel-catalyzed alkyne-carbonyl reductive couplings (Scheme 11).31 These applications in target-oriented synthesis involve reductive cyclizations and, with one exception, exploit substrate-directed asymmetric induction using achiral nickel catalysts, thus falling outside the purview of this monograph. Nevertheless, selected target structures are indicated for the benefit of the interested reader.

Scheme 10.

Scheme 10.

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Enantioselective nickel-catalyzed reductive coupling of alkynes with aldehydes mediated by boranes or silanes.

Scheme 11.

Scheme 11.

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Natural products prepared via nickel-catalyzed alkyne-carbonyl reductive coupling.

Redox-neutral alkyne-aldehyde couplings were achieved by the Shi laboratory using alcohol reactants under the conditions of nickel-catalyzed hydrogen auto-transfer (Scheme 12A).32a Optimal results were obtained using symmetric alkynes in combination with a nickel catalyst modified by the chiral N-heterocyclic carbene ligand, (R,R,R,R)-SIPE, developed by the authors’ group. Triphenyl phosphite was required as secondary ligand to inhibit isomerization of the alkene-containing products. Related redox-neutral alkyne-imine couplings from amine reactants are especially challenging due to the endothermic nature of amine dehydrogenation. Despite this challenge, the Shi laboratory identified conditions for such nickel-catalyzed hydrogen auto-transfer processes.32b,c Specifically, using a nickel-catalyst modified by the indicated P-chiral monodentate phosphine ligand, amines bearing a mesitylene-2-sulfonyl (Mts) protecting group engage in redox-neutral C─C coupling with aryl-substituted alkynes to furnish the corresponding allylic sulfonamides with good levels of regio- and enantioselectivity (Scheme 12B). These reactions proceed by way of an aza-nickelacyclopentene, which upon transfer hydrogenolysis from the amine reactant releases product and nickel(0) along with the requisite imine to close the catalytic cycle (not shown).

Scheme 12.

Scheme 12.

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Enantioselective nickel-catalyzed reductive coupling of alkynes with aldehydes or aldimines via hydrogen auto-transfer from alcohol or amine reactants, respectively.

4. Conclusion and Outlook

From the inception of organic chemistry as a discrete field of research to modern day drug discovery, carbonyl and imine addition mediated by premetalated reagents continues to serve as one of the foremost methods for C─C bond formation.33 However, the organometallic reagents typically used in such processes pose issues of safety, selectivity, cost and waste. Metal-catalyzed carbonyl reductive coupling has emerged as an alternative to stoichiometric organometallic reagents in an ever-increasing array of carbonyl addition reactions. As demonstrated by the transformations described herein, metal-catalyzed alkyne-carbonyl/imine reductive couplings and related hydrogen auto-transfer reactions of alcohol and amine proelectrophiles may serve as alternatives to classical carbonyl and imine alkenylations; the Noyori-type vinylzinc additions3,4 and Nozaki-Hiyama-Kishi reactions5 of vinyl halide pronucleophiles. Although considerable progress has been made, numerous unmet challenges remain. For example, catalysts capable of promoting highly enantioselective alkenylations from terminal alkyne pronucleophiles remain highly underrepresented and, in the case of hydrogen auto-transfer reactions, are entirely unknown. It is the authors’ hope the present state-of-the art summary will expedite progress toward this and other challenges in this growing area of research.

ACKNOWLEDGMENTS

The Robert A. Welch Foundation (F-0038) and the NIH-NIGMS (RO1-GM069445) are acknowledged for financial support.

Footnotes

The authors declare no competing financial interest.

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