Simple, Chemoselective Hydrogenation with Thermodynamic Stereocontrol (2024)

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Abstract

Hydrogenation of alkenes isamong the cardinal reactions available to synthetic chemists. Appliedretrosynthetically, this transform adds points of unsaturation tocarbon skeletons, which can be used to dissect complex bond networksinto simple fragments.¹ However, a long-standingchallenge in complex molecule synthesis is hydrogenation of alkenesto a thermodynamically favored configuration² when steric constraints of the substrate favor hydrogenation toa nonthermodynamic (kinetic) alkane product (see 1→cis-2, Figure ​Figure1a).1a). Dissolvingmetal reduction provides a means to achieve thermodynamic controland can reduce conjugated³ or electron-pooralkenes⁴ at low temperature (see 1→trans-2), but requiresambient or elevated temperature to reduce electron-neutral alkenes.⁵ These latter substrates are therefore seldomemployed because chemoselectivity is unsatisfactory: most other functionalgroups are reduced preferentially to electron-neutral alkenes. Thisproblem is especially evident in chemical syntheses of terpenoid secondarymetabolites, which include the FDA approved steroid, taxoid, artemisinin,and ingenoid classes. Thus, many terpenes that contain equatorialmethyl groups, for instance 3–5,have proven difficult to access, since hydrogenation of the correspondingexomethylene using standard methods yields either the wrong epimeror an equimolar mixture of two epimers (Figure ​(Figure11b).⁶⁻⁸ The origin of the poor chemoselectivity associated with dissolvingmetal reduction is the low reduction potential of electron neutralalkenes (E_red < –3 V,Pb cathode),⁹ which form high-energy radicalanions (6→7, Figure ​Figure1c)1c) prior to protonation to lower energy tertiary radicals(8) and further reduction, protonation to alkanes (9). We thought that circumvention of radical anion 7 via direct hydrogen atom transfer (HAT)¹⁰ might increase chemoselectivity but lead to the same stereochemicalpreferences as dissolving metal reduction. Here we show that manganeseand cobalt catalysts can effect this stepwise radical hydrogenationof electron-neutral alkenes and exhibit the same stereochemical preferencesas dissolving metals but spare a variety of reactive functional groupsthat are normally reduced.

As a representative model system for the terpenesshown in Figure ​Figure1b1b and as a starting pointto probe the concept andconsequences of HAT hydrogenation, we chose 4-tert-butylmethylenecyclohexane 10, since extensive dataon its hydrogenation are available (Table 1).^11,12 Whereas hydrogenation of 10 with Wilkinson’s¹² or Adam’scatalyst¹³ delivers primarily 12 (cis), bearing an axial methyl, and diimide reductiongives a 1:1 mixture,¹⁴ dissolving metalreduction instead provides high selectivity for 11 (95:5).¹⁵ It seemed reasonable that hydrogenation viaa tertiary carbon radical might lead to high selectivity for an equatorialmethyl group, since methyl-substituted cyclohexyl radicals are knownto trap tributyltin deuteride with high axial selectivity for C–Dbond formation, owing to the nonplanar ground state¹⁶ and transition state pyramidalization of tertiary radicals.¹⁷ We considered the redox hydration conditionsof Mukaiyama¹⁸ as a good starting pointfor an iterative HAT hydrogenation of alkenes since tertiary radicalsare readily generated from electron-neutral alkenes, and the cobaltor manganese catalysts¹⁹ are inexpensiveand air-stable. However, the oxidizing conditions required for thistransformation appeared to be an ostensible barrier to implementationof a reductive reaction.²⁰ Even so, Carreirademonstrated that tert-butyl hydroperoxide can serveas a replacement activator and/or reoxidant in the context of cobalt-catalyzedhydroazidation¹⁹ and hydrocyanation ofalkenes.²¹ Similarly, we found that ifTBHP is added in stoichiometric quantities to a mixture of alkene 10, phenylsilane, and a manganese catalyst in the absenceof heteroatom radical traps, the reaction rapidly produces 12 (trans) with high selectivity, albeit in poor yield.Higher conversion to hydrogenated products is highly ligand and solventdependent; the dipivaloyl-methane (dpm) ligand and isopropanol solventwere found to be optimal.²² Most appealingly,the experimental procedure is simple, conversion occurs usually within1 h, and no hydrogen atmosphere is required. Nonanhydrous conditionsare tolerated, however excess water does inhibit conversion (10 equiv= 5 M water in i-PrOH, 33% conversion at 1 h; see Supporting Information (SI) for an optimizationtable and corresponding observations). Co(dpm)₂ inducesequally high levels of stereoselectivity and also allows nonpolarsolvents and hydrophobic substrates to be used (vide infra), however Mn(dpm)₃-catalyzed reactions are generallyhigher yielding.

As illustrated by Table 2a, trans-selective hydrogenation of cyclohexenes is difficultto achieveby standard methods. For instance 13a and b afford poor stereoselectivity using Pd/C catalysis, and only marginallybetter ratios using Crabtree’s catalyst, due to the poor directivityafforded by sterically encumbered substituents.²³ However, using HAT hydrogenation, where directivity isirrelevant, trans-substitution with high stereoselectivityis favored in both cases.

As a result, diversely substitutedcyclohexenes now can be hydrogenatedto the thermodynamically preferred trans-isomers(Table 2b) in the absence of any directinggroups.^23b Remarkably, chloro- and bromoalkenes,which generally do not tolerate dissolving metal conditions and arechallenging substrates even with standard hydrogenation methods, areefficiently reduced to equatorial halo-cyclohexanes 15 and 16. Electron-releasing siloxy (enolsilane) andacetamide (enamide) groups are also efficiently reduced to the trans-isomers 17 and 18, illustratingthe electronic flexibility of the method.

As suggested by substrates 15–18, the functional group compatibility of ourmethod is significantlybetter than dissolving metal reduction and a fuller scope is illustratedby Table 3. For instance, not only alcohols(19) but also their corresponding alkyliodides (20) are viable substrates for this transformation. Selectivityagainst the reduction of aromatic rings is excellent, and thereforecarboxybenzyl (Cbz) groups (21) are spared from reduction,as are phenyl ethers (22), aryl chlorides and fluorides(23), aryl bromides (24), and aryl iodides(25), although some deiodination was observed by GCMS(∼5%). Trifluoromethyl ethers (26), electron-richarenes (27), phenyl thioethers (28), trifluoromethylarenes(29), and heterocycles like imidazole 30 are all well tolerated, although some rate decrease is observedwith this last entry, likely due to equilibrium coordination/deactivationof the catalyst.

Weinreb amides, which suffer N–O bond cleavageunder dissolvingmetal conditions,²⁴ do not react competitivelywith the reduction of trisubstituted alkenes (32, Table 4). Thioesters undergo facile reduction to aldehydesusing tributylstannyl radical reduction (Bu₃SnH, AIBN)or palladium catalysis (Pd/C, Et₃SiH),²⁵ but using our method, saturated thioester 33 is produced and no aldehyde or alcohol is observed. When the alkeneis allylic to a potentially labile C-heteroatom bond, simple to complexheterocycles (34–36) are toleratedand no scission of the allylic bond is observed, which might argueagainst the intermediacy of a carbon–metal bond.^18,19 No Minisci addition products were observed using these substrates.Interestingly, β-ionone can be selectively reduced at the α,β-positions(37),^20b in contrast to theselectivity observed using Mukaiyama’s hydration.²⁰ Unsaturated thiols, aldehydes, and allylic alcohols(38–40) are also chemoselectivelyreduced; the thiol is oxidized in situ to the disulfidewhich can be cleaved on workup.

Polycyclic systems can alsobe predictably hydrogenated to thethermodynamically stable diastereomer in preference to the normallyobserved kinetic stereochemistry (Scheme 1).For instance, Δ^9,10-octalin (41) ispreferentially hydrogenated with iridium catalysis to cis-decalin (42a) via syn-hydrogenation of the alkene.²⁶ However, using HAT hydrogenation, a formal anti-additionof hydrogen is observed to produce the lower-energy trans-decalin (42b) with nearly the same selectivity as dissolvingmetal conditions.⁵ Similarly, 1,2-dimethylcyclohexene (43) is hydrogenated to the cis-stereoisomer 44a using iridium catalysis,²⁷ whereas our method produces trans-1,2-dimethylcyclohexane (44b), albeit with lower selectivity.Nevertheless, this stereochemical dichotomy between existing hydrogenationmethods and the title reaction can be most vividly illustrated usingproblems already encountered in terpene syntheses. For example, enroute to the putative structure of a sesquiterpene isolated from Cistus creticus, Katerinopoulos could not directly accessa targeted trans-decalone framework since hydrogenationof their intermediate ketone 45 using heterogeneous catalysisproduced cis-decalone 46a with highselectivity.²⁸ In contrast, HAT hydrogenationcan directly access this thermodynamically preferred but kineticallydisfavored configuration (46b). Additionally, the terpene-derivedpetroleum biomarker drimane (48b) could not be directlyaccessed via hydrogenation of drimene 47, since use ofAdam’s catalyst delivers the kinetically favored axial methylsubstituent in 48a, and a four-step work-around was devisedinstead.²⁹ In contrast, our method directlyyields drimane (48b), which bears the thermodynamicallyfavored equatorial methyl.

An unusual aspect of this hydrogenation is its general disregardfor alkene substitution or electronic patterning (Scheme 2a). Unlike dissolving metal reduction, which exhibitsprofound rate acceleration when the alkene is conjugated to an electronacceptor,⁵ various substitution patternsare readily reduced by our HAT method with little influence by directlyattached functionality (see SI for competitionexperiments). These minor effects of electron-modulating groups mayindicate a direct hydrogen atom transfer to generate a carbon-centeredradical,^30b rather than the intermediacyof a carbon–metal bond en route to carbon–metal bondhom*olysis, as often proposed.^18,19,22 Based on competition experiments, some trends are observed: increasedsubstitution decreases the rate of consumption; electron-withdrawinggroups have a minor accelerating effect on reaction rate; and electron-donatinggroups are weakly deactivating. Consequently, simple reductive cyclizationsof polyenes are possible (Scheme 2b).³⁰ For instance, diene 49 is readilycyclized to cyclopentane 50, which bears vicinal all-carbonquaternary centers, highlighting the ability of carbon-centered radicalsto overcome severe steric clash via early transition states.³¹ This preliminary example paves the way for ageneral approach to reductive mono- and polycyclizations of unconjugatedpolyenes and a “traceless” approach to fully saturatedmolecules like terpenes.³²

The demonstrated utility of this new method for the thermodynamichydrogenation of alkenes illustrates its potential to solve currentand future problems in complex molecule synthesis, especially thereduction of halogenated alkenes (see Table 2b).³³ Given the frequency with which hydrogenationsare employed and their breadth of applications in chemistry, a newtool is advantageous. We expect that the experimental ease, broadscope, and orthogonal stereoselectivity of HAT hydrogenation willlead to its extensive use.

Acknowledgments

Financial supportfor this work was provided by the NIH (GM104180),the NSF GRFP (K.K.W.; DGE-1346837), and the Italian Ministry for Educationand Research (fellowship to A.O.). We thank Professors Dale L. Boger,Phil S. Baran, and Donna G. Blackmond for helpful conversations. Weare grateful to the Scripps Research Institute, Eli Lilly, BoehringerIngelheim, Amgen, and the Baxter Foundation for additional financialsupport.

Funding Statement

National Institutes of Health, United States

Supporting Information Available

Experimental procedures andspectroscopic data. This material is available free of charge viathe Internet at http://pubs.acs.org.

Author Present Address

^† Department of Chemistry, Tohoku University, 6-3 Aoba-ku, Sendai,980-8578, Japan.

Author Contributions

^‡ Theseauthors contributed equally.

Notes

Theauthors declare nocompeting financial interest.

Supplementary Material

References