Science. Author manuscript; available in PMC 2018 Aug 25.
Published in final edited form as:
Science. 2017 Aug 25; 357(6353): 779–781.
PMCID: PMC5649382
NIHMSID: NIHMS909711
PMID: 28839069
Matthias Bender,* Ben W. H. Turnbull,* Brett R. Ambler,* and Michael J. Krische†
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- Supplementary Materials
Abstract
Current catalytic processes involving C-C bond activation rely on π-unsaturated coupling partners. Exploiting the concept of transfer hydrogenative coupling, we report here a ruthenium(0)-catalyzed cycloaddition of benzocyclobutenones that functionalizes two adjacent saturated diol C-H bonds. These regio- and diastereoselective processes enable convergent construction of type II polyketide substructures.
Metal-catalyzed C-C bond activation emerged as a discrete field of chemical research (1–4) with reports on the oxidative addition of low valent metal complexes to strained carbocycles to form isolable metallacycles. For example, Halpern described the reaction of cubane and quadricyclane, respectively, with [Rh(CO)2Cl]2 to form rhodacycles (5, 6). The oxidative additions of a platinum(0) complex to diphenylcyclopropenone and benzocyclobutene dione, respectively, to form 4- and 5-membered platinacycles were documented soon thereafter (7, 8). The utility of metallacycles obtained through C-C bond oxidative addition vis-à-vis π-bond insertion was demonstrated in stoichiometric alkyne-cyclobutene cycloadditions by Liebeskind (9, 10), who later showed such reactions can be catalyzed by nickel(0) (11). Access to related rhodium-catalyzed cycloadditions was accelerated by Murakami’s 1994 report on the hydrogenolysis of acyl C-C bonds (12, 13), along with inter- and intramolecular rhodium-catalyzed ketone-mediated olefin carboacylations reported by Jun (14, 15) and Murakami (16, 17), respectively.
Metal-catalyzed cycloadditions based on the insertion of π-unsaturated reactants into activated C-C bonds now represent a broad area of research (1–4). Intermolecular cycloadditions of cyclobutanone derivatives, which are catalyzed by nickel (11, 18–23) rhodium (24, 25) and ruthenium (24, 26) complexes, comprise a growing subset of these transformations. To our knowledge, the formal insertion of saturated C-H bonds into C-C σ-bonds has not been documented. Here, using the concept of C-C bond forming transfer hydrogenation (27–29) we now report reactions of this type. Specifically, under the conditions of ruthenium(0) catalysis, benzocyclobutenones react with 1,2-diols to form cycloadducts wherein each vicinal carbinol C-H bond of the 1,2-diol is functionalized to become a C-C bond. The present method provides a convergent means of assembling type II polyketides bearing bridgehead diol motifs (Fig 1).
Fig 1
Ruthenium-catalyzed cyclobutenone-diol [4+2]cycloaddition via C-C bond activation – a gateway to type II polyketide natural products.
We have found that ruthenacycles arising via diene-carbonyl oxidative coupling promote dehydrogenation of α-hydroxy esters and 1,2-diols to form vicinal dicarbonyl species, enabling a wide range of formal alcohol C-H functionalizations (28–34). We posited that ruthenacycles obtained upon C-C bond oxidative addition would display similar reactivity. To explore this possibility, benzocyclobutenone 1a was exposed to racemic trans-cyclohexane 1,2-diol 2b in the presence of the catalyst generated in situ from Ru3(CO)12 and various phosphine ligands (1 M in toluene) at 110 °C for 24 h. This initial screen revealed that the ruthenium(0) catalyst modified by bis(diphenylphosphino)propane (dppp), which is anticipated to be a discrete, mono-nuclear complex (35), provides the product of cycloaddition 3a in 22% isolated yield with complete syn-diastereoselectivity as determined by 1H NMR analysis (>20:1 dr). The structure of 3a was corroborated by single crystal x-ray diffraction analysis. Upon increasing reaction temperature (150 °C, xylene solvent), cycloadduct 3a was obtained in 88% yield.
These conditions were applied to the reaction of benzocyclobutenones 1a–1j with racemic trans-cyclohexane 1,2-diol 2b (Table 1). The cycloadducts 3a–3j were isolated in excellent yields. As demonstrated by the formation of 3d, benzocyclobutenones bearing benzylic substitution delivered products in which three contiguous stereocenters formed in selective fashion. Dione 1e was converted to cycloadduct 3e, which embodies the dihydroxy-quinone motif found in numerous type II polyketides (Fig 1). The formation of 3g and 3h establish tolerance of halide functional groups, which is important vis-à-vis subsequent elaboration. For example, ortho-chloro-cycloadduct 3g was converted to the corresponding dimethylamino-containing product 4 through nucleophilic aromatic substitution (Fig 2, eq. 1). Alternatively, Suzuki coupling of 3g delivered the pyrimidine-modified compound 5 (Fig 2, eq. 2).
Fig 2
Elaboration of cycloadduct 3g (eq. 1,2) and redox independent cycloaddition from the diol, ketol or dione oxidation levels (eq. 3–5).
Table 1
Ruthenium(0)-catalyzed cycloaddition of benzocyclobutenones 1a–1j with diol 2b. Reported yields refer to material isolated by silica gel chromatography. Products 3a–3j are racemic. See Supporting Information for further experimental details.
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*130 °C.
Diverse diols 2a–2i engaged in the cycloaddition initiated by C-C bond activation (Table 2). Beyond the reaction of symmetric saturated cyclic diols 2a–2c, we found that non-symmetric diols reacted with high regioselectivity. For example, the cycloadducts 3m–3s were formed as single regioisomers as determined by 1H NMR analysis (>20:1 rr). The congested “bay-region” ortho-methoxy-substituent found in cycloadduct 3o and 3p is a pervasive structural feature among angucycline natural products (36), such as arenimycin and collinone (Fig 1). Fusion to an aromatic ring is not required to induce regiocontrol. As illustrated by the formation of 3q–3s, alkyl substituents adjacent to the diol enforced complete regioselectivity. Notably, the latter cycloadducts 3r and 3s, which were derived from enantiomerically pure starting materials, did not suffer erosion of enantiomeric enrichment in the course of cycloaddition.
Table 2
Ruthenium(0)-catalyzed cycloaddition of benzocyclobutenone 1a or 1d with diols 2a–2i. Reported yields refer to material isolated by silica gel chromatography. Products 3a, 3k–3q are racemic. Products 3r and 3s are enantiomerically enriched. See Supporting Information for further experimental details.
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*Reaction conducted from ketol oxidation level.
†130 °C.
The present diol cycloadditions appear to be oxidative processes wherein benzocyclobutenone (50 mol%) accepts two equivalents of hydrogen (Tables 1 and and2).2). This assertion was corroborated by the isolation of the ring-opened hydrogenolysis product (2-methoxy-6-methylphenyl)methanol in cycloadditions of cyclobutanone 1a (Fig 2, eq. 3). As illustrated by the reaction of cyclobutanone 1a with diol 2b (Fig 2, eq. 3), α-ketol dehydro-2b (Fig 2, eq. 4) and dione didehydro-2b (Fig 2, eq. 5) to form 3a, cycloaddition is possible in oxidative, redox-neutral and reductive modes, respectively. In the latter case, 2-propanol (300 mol%) served as terminal reductant. The use of equimolar quantities of reactant in the redox-neutral reaction (Fig 2, eq. 4) establishes the practicality of applying this methodology to the union of complex fragments.
We posit a general mechanism for the ruthenium-catalyzed cycloaddition (Fig 3). Oxidative addition of a discrete, mono-metallic ruthenium catalyst (35) to benzocyclobutenone 1a provides the ruthena-indanone I (37), which upon successive addition of the C-Ru bonds to 1,2-dione, didehydro-2b, provides the ruthenium(II) diolate complex III by way of the benzylruthenium alkoxide II. Related additions of ruthenacyclopentadienes to vicinal dicarbonyl compounds have been documented (34). Transfer hydrogenolysis of the ruthenium(II) diolate is accomplished through protonolysis by diol 2b or ketol dehydro-2b to deliver the ruthenium(II) alkoxide IV, which suffers β-hydride elimination to furnish the ruthenium hydride V. Finally, O-H reductive elimination releases the cycloadduct 3a. The latter steps of this catalytic mechanism find precedent in Ru3(CO)12-catalyzed ketone transfer hydrogenations mediated by 2-propanol (38).
Fig 3
Proposed catalytic mechanism for ruthenium catalyzed benzocyclobutenone-diol cycloaddition.
Using the ruthenium precatalyst (CF3CO2)Ru(CO)(PPh3)2•MeOH in combination with the chiral chelating phosphine ligand (R)-SEGPHOS under otherwise standard conditions provided cycloadduct 3a with promising levels of enantiomeric enrichment (51% ee). We anticipate that, together with recent insights into the structural and physical features of small-molecule antibiotics vis-à-vis gram-negative activity (39), this convergent cycloaddition methodology should accelerate progress toward synthetic type II polyketide drugs.
Supplementary Material
Supporting Information
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Acknowledgments
The Robert A. Welch Foundation (F-0038) and the NIH-NIGMS (RO1-GM093905) are acknowledged for financial support. The Deutsche Forschungsgemeinschaft (DFG) is acknowledged for postdoctoral fellowship support (MB). Metrical parameters for compounds 3a, 3d, 3e, 3n, and 3q are available free of charge from the Cambridge Crystallographic Data Centre under reference numbers CCDC- 1562339, 1562342, 1562341, 1562338, and 1562340 respectively.
Footnotes
SUPPLEMENTARY MATERIALS
Materials and Methods
Figures S1 to S5
Tables S1 to S5
References (40–51)
NMR Spectra
References and Notes
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