Ruthenium-catalyzed insertion of adjacent diol carbon atoms into C-C bonds: Entry to type II polyketides

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Science  25 Aug 2017:
Vol. 357, Issue 6353, pp. 779-781
DOI: 10.1126/science.aao0453

Slicing through both C-C and C-H bonds

A variety of catalysts can cleave the strained bonds in four-membered carbon rings and then link the ends to a reactive partner. Bender et al. found that after prying the ring open, a double-duty ruthenium catalyst could forge bonds to a traditionally unreactive partner. They used the reaction to couple cyclobutenones to adjacent saturated carbon centers in diols. This approach efficiently yielded a motif common in polyketide natural products. The reaction proceeds through dehydrogenation and is also amenable to coupling the opened rings to ketol or dione reagents.

Science, this issue p. 779


Current catalytic processes involving carbon-carbon bond activation rely on π-unsaturated coupling partners. Exploiting the concept of transfer hydrogenative coupling, we report a ruthenium(0)-catalyzed cycloaddition of benzocyclobutenones that functionalizes two adjacent saturated diol carbon-hydrogen 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 (14) 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, respectively, to form four- and five-membered platinacycles were documented soon thereafter (7, 8). The utility of metallacycles obtained through C-C bond oxidative addition with regard to π-bond insertion was demonstrated in stoichiometric alkyne-cyclobutene cycloadditions by Liebeskind (9, 10), who later showed that 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 (14). Intermolecular cycloadditions of cyclobutanone derivatives, which are catalyzed by nickel (11, 1823), rhodium (24, 25), and ruthenium (24, 26) complexes, constitute 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 (2729), we report reactions of this type. Specifically, under 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. This 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 (2834). We posited that ruthenacycles obtained upon C-C bond oxidative addition would display similar reactivity. To explore this possibility, we exposed benzocyclobutenone 1a 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 hours. This initial screen revealed that the ruthenium(0) catalyst modified by bis(diphenylphosphino)propane (dppp)—which is anticipated to be a discrete, mononuclear complex (35)—provides the product of cycloaddition 3a in 22% isolated yield with complete syn-diastereoselectivity, as determined by 1H nuclear magnetic resonance (NMR) analysis [>20:1 diastereomeric ratio (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 1a1j with racemic trans-cyclohexane 1,2-diol 2b (Table 1). The cycloadducts 3a3j were isolated in excellent yields. As demonstrated by the formation of 3d, benzocyclobutenones bearing benzylic substitution delivered products in which three contiguous stereocenters are formed in a selective fashion. Dione 1e was converted to cycloadduct 3e, which embodies the dihydroxyquinone motif found in numerous type II polyketides (Fig. 1). The formation of 3g and 3h establishes tolerance of halide functional groups, which is an important prerequisite for 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).

Table 1 Ruthenium(0)-catalyzed cycloaddition of benzocyclobutenones 1a–1j with diol 2b.

Reported yields refer to material isolated by silica gel chromatography. Products 3a3j are racemic. See supplementary materials for experimental details. *130°C.

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Fig. 2 Elaboration of cycloadduct 3g (Eqs. 1 and 2) and redox-independent cycloaddition from the diol, ketol, or dione oxidation levels (Eqs. 3 to 5).

Cy, cyclohexyl; dba, dibenzylideneacetone; ArHet, heteroaryl.

Diverse diols 2a2i were found to engage in the cycloaddition initiated by C-C bond activation (Table 2). Beyond the reaction of symmetric saturated cyclic diols 2a2c, we found that nonsymmetric diols reacted with high regioselectivity. For example, the cycloadducts 3m3s were formed as single regioisomers as determined by 1H NMR analysis (>20:1 regioisomeric ratio). The congested “bay-region” ortho-methoxy-substituent found in cycloadducts 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 3q3s, 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 and 3k3q are racemic. Products 3r and 3s are enantiomerically enriched. See supplementary materials for experimental details. *Reaction conducted from ketol oxidation level. †130°C.

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The present diol cycloadditions appear to be oxidative processes wherein benzocyclobutenone (50 mol %) accepts two equivalents of hydrogen (Tables 1 and 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 cycloaddition (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, monometallic 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). Oxidative addition to form ruthenaindanone I may occur directly or through an ortho-ketene methide formed upon cycloreversion of 1a. Mechanisms for C-C bond activation involving oxidative coupling of 1a and didehydro-2b to form a dioxaruthenacycle followed by β-carbon elimination cannot be excluded.

Fig. 3 Proposed catalytic mechanism for ruthenium-catalyzed benzocyclobutenone-diol cycloaddition.

Using the ruthenium precatalyst (CF3CO2)2Ru(CO)(PPh3)2•MeOH (Ph, phenyl; Me, methyl) in combination with the chiral chelating phosphine ligand (R)-SEGPHOS ([4(R)-(4,4′-bi-1,3-benzodioxole)-5,5′-diyl]bis[diphenylphosphine]) under otherwise standard conditions provided cycloadduct 3a with promising levels of enantiomeric enrichment (51% enantiomeric excess). We anticipate that, together with recent insights into the structural and physical features of small-molecule antibiotics with respect to their activity against Gram-negative bacteria (39), this convergent cycloaddition methodology should accelerate progress toward synthetic type II polyketide drugs.

Supplementary Materials

Materials and Methods

Figs. S1 to S5

Tables S1 to S5

NMR Spectra

References (4051)

References and Notes

Acknowledgments: Supported by a Deutsche Forschungsgemeinschaft postdoctoral fellowship (M.B.), Robert A. Welch Foundation grant F-0038, and National Institute of General Medical Sciences grant RO1-GM093905. 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.
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