Abstract
Under the conditions of nickel(0) catalysis, enantiomerically enriched vinyl-dioxanones engage boroxines or B2(pin)2 in stereospecific cross-coupling to form diverse tetrasubstituted cyclopropanes bearing all-carbon quaternary stereocenters. The collective data corroborate a mechanism involving nickel(0)-mediated benzylic oxidative addition with inversion of stereochemistry followed by reversible olefin insertion to form a (cyclopropylcarbinyl)nickel complex, which upon reductive elimination releases the cyclopropane.
Graphical abstract
Cyclopropanes appear as substructures across diverse secondary metabolites1 and are frequently found in commercial medicines, agrochemicals and fragrances.2 Hence, the development of methods for cyclopropane formation represents a persistent challenge in chemical research.3 Among the most effective methods for the preparation of enantiomerically enriched cyclopropanes is the reaction of olefins with metal carbenoids.3 Here, we report a strategy for the asymmetric synthesis of cyclopropanes under the conditions of metal catalyzed cross-coupling. Specifically, nickel(0) catalysts4,5 react with enantiomerically enriched 4-aryl-5-vinyl-1,3-dioxanones to form (cyclopropylcarbinyl)nickel(II) species, which, in the presence of organoboron reagents or B2(pin)2deliver cyclopropanes in a stereospecific manner. Thus, the enantioselective synthesis of tetra-substituted cyclopropanes bearing all-carbon quaternary stereocenters is achieved (Scheme 1).
Scheme 1.
Synthesis of enantiomerically enriched cyclopropanes from vinyl-dioxanones by way of transient (cyclopropylcarbinyl)nickel species.
In connection with ongoing investigations into the formation of C-C bonds via hydrogenation and transfer hydrogenation,6 we recently reported an iridium catalyzed coupling of primary alcohols with isoprene oxide to form products of tert-(hydroxy)-prenylation – a byproduct-free transformation that occurs with exceptional control of anti-diastereo- and enantioselectivity.7 It was posited that cyclic carbonates derived from these reaction products should be predisposed toward cyclopropane formation under cross-coupling conditions, as geminal substitution of the neopentyl glycol precludes competing β-hydride elimination of the σ-benzylmetal intermediate and should conformationally bias the system toward olefin insertion8 via Thorpe-Ingold effect.9 However, the facility of conventional benzylic cross-coupling rendered the feasibility of the proposed cyclopropane formation uncertain.10
In an initial experiment, vinyl-dioxanone 1a was exposed to the catalyst derived from Ni(cod)2 (10 mol%) and PCy3 (20 mol%) in the presence of tri(p-tolyl)boroxine 2a and K3PO4 (200 mol%) in toluene (0.1 M) at 60 °C. To our delight, cyclopropane 3a was formed in 36% yield as a single diastereomer. Conversion was found to be sensitive to concentration and temperature. At 45 °C under otherwise identical conditions, a 53% yield of cyclopropane 3a was obtained. Using the nickel catalyst modified by PCy2Ph (20 mol%), cyclopropane 3a was obtained in 77% yield. Finally, at slightly higher concentration (toluene, 0.2 M), an 85% yield of cyclopropane 3a was achieved (eq. 1). Stereospecificity was corroborated by chiral stationary phase HPLC analysis of cyclopropane 3a. Relative stereochemistry of cyclopropane 3a was confirmed by single crystal X-ray diffraction analysis. p-Tolylboronic acid also delivers cyclopropane 3a (eq. 1), but in slightly lower yield. Application of these optimal conditions to unsubstituted methyl carbonate model-1a did not result in cyclopropane formation; rather, the indicated product obtained through β-hydride elimination of the σ-benzyl intermediate was formed (eq. 2). Cyclic carbonate 1a reacted more efficiently than related acyclic carbonates, suggesting the internal alkoxide generated upon ionization-decarboxylation facilitates group transfer from boron to nickel through an internal boron ate-complex.
 |
(eq. 1) |
 |
(eq. 2) |
Optimal conditions utilizing tri(p-tolyl)boroxine 2a were applied to a structurally diverse set of enantiomerically enriched vinyl-dioxanones 1a–1i (Table 1). Vinyl dioxanones bearing a variety of substituted aromatic (1a–1d) and heteroaromatic (1e–1i) rings were converted to cyclopropanes 3a–3i in good yield with complete levels of diastereoselectivity. Relative stereochemistry was assigned in analogy to that determined for 3a. Although the preexisting non-epimerizable quaternary stereocenter serves as an “internal standard,” stereospecificity was spot-checked for compounds 3a, 3b, 3d and 3h. Notably, unlike prior work involving nickel catalyzed benzylic substitution, extended aromatic systems are not required.11 Standard conditions also were applied to the coupling of vinyl-dioxanones 1a and 1h with boroxines 2b–2d, which incorporate p-CF3-phenyl, p-methoxyphenyl and (E)-styryl moieties, respectively (Table 2). The resulting cyclopropanes 3j–3o were formed in good yield in a completely stereoselective fashion. The coupling of vinyl-dioxanones 1a, 1b, 1d, 1h and 1f with B2(pin)2 under standard conditions delivers the cyclopropylcarbinyl boronates 3p–3t in good yield with complete stereocontrol (Table 3).12 To briefly illustrate the utility of coupling products, the neopentyl alcohol 3a was subjected to Jones oxidation to provide the cyclopropyl carboxylic acid 4a in good yield (eq. 3). Additionally, the cyclopropylcarbinyl alcohol 3h was exposed to Mitsunobu conditions in the presence of phthalimide to furnish 4b in excellent yield (eq. 4).
 |
(eq. 3) |
 |
(eq. 4) |
Table 1.
Stereospecific nickel-catalyzed cross coupling of vinyl-dioxanones 1a–1i with tri(p-tolyl)boroxine 2a to form cyclopropanes 3a–3i.a
|
Yields of material isolated by silica gel chromatography. All reactions were conducted using enantiomerically enriched starting materials. See Supporting Information for further experimental details.
Table 2.
Stereospecific nickel-catalyzed cross coupling of vinyl-dioxanones 1a or 1h with boroxines 2b–2d to form cyclopropanes 3j–3o.a
|
Yields of material isolated by silica gel chromatography. All reactions were conducted using enantiomerically enriched starting materials. See Supporting Information for further experimental details.
Table 3.
Stereospecific nickel-catalyzed cross coupling of vinyl-dioxanones 1a, 1b, 1d, 1h and 1f with B2(pin)2 to form cyclopropanes 3p–3t.a
|
Yields of material isolated by silica gel chromatography. All reactions were conducted using enantiomerically enriched starting materials. See Supporting Information for further experimental details.
A general mechanism for stereospecific cyclopropane formation under the conditions of nickel catalyzed cross-coupling has been proposed (Scheme 2). Stereospecific oxidative addition of a nickel(0) species to the benzylic C-O bond occurs with inversion to furnish the indicated σ-benzylnickel(II) complex.10 Decarboxylation and transmetalation delivers the indicated alkene complex, which upon reversible migratory insertion8 provides a (cyclopropylcarbinyl)nickel(II) complex. Regardless of the kinetic diastereoselectivity of olefin insertion, reductive elimination occurs exclusively from a single stereoisomer of the (cyclopropylcarbinyl)nickel(II) species to release the cyclopropane and regenerate the zero-valent nickel catalyst.
Scheme 2.
General catalytic mechanism. Haptomeric equilibria are excluded for clarity.
In summary, we report a new method for the preparation of enantiomerically enriched cyclopropanes via stereospecific nickel catalyzed cross-coupling of vinyl-dioxanones with boroxines or B2(pin)2. The collective data are consistent with a catalytic mechanism involving nickel(0)-mediated benzylic oxidative addition with inversion of stereochemistry followed by reversible olefin insertion to form a (cyclopropyl-carbinyl)nickel complex, which upon reductive elimination delivers the cyclopropane. The novel reactivity embodied by this process should serve as the basis for the syntheses of diverse enantiomerically enriched cyclopropanes.
Supplementary Material
Acknowledgments
The Robert A. Welch Foundation (F-0038) and the NIH-NIGMS (RO1-GM069445) are acknowledged for partial support of this research.
Footnotes
Supporting Information Available: Experimental procedures and spectral data. HPLC traces corresponding to racemic and enantiomerically enriched samples. Single crystal X-ray diffraction data for 3a. This material is available free of charge via the internet at http://pubs.acs.org.
The authors declare no competing financial interest.
References
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