Letter pubs.acs.org/OrgLett
Tandem Hydroalumination/Cu-Catalyzed Asymmetric Vinyl Metalation as a New Access to Enantioenriched Vinylcyclopropane Derivatives Daniel S. Müller,† Veronika Werner,† Sema Akyol,‡ Hans-Günther Schmalz,‡ and Ilan Marek*,† †
The Mallat Family Laboratory of Organic Chemistry, Schulich Faculty of Chemistry and Lise Meitner-Minerva Center for Computational Quantum Chemistry, Technion-Israel Institute of Technology, Technion City, Haifa 32000, Israel ‡ University of Cologne, Department of Chemistry, Greinstrasse 4, 50939 Koeln, Germany S Supporting Information *
ABSTRACT: Herein, we report the first enantio- and diastereoselective addition of stereodefined vinyl organometallic reagents to cyclopropenes. The operationally simple tandem hydroalumination and copper-catalyzed vinylmetalation allows for the unique access of a diverse set of enantioenriched vinylcyclopropane derivatives.
V
inylcyclopropanes (VCPs) are reactive entities, wellknown to participate in various rearrangements such as the renowned divinylcylopropane−cycloheptadiene or vinylcyclopropane−cyclopentene rearrangement. 1 Furthermore, the reactivity of vinylcyclopropanes has also been extensively exploited in transition-metal catalysis to access molecular structures of high complexity.2 Importantly, VCPs are also found in natural products, insecticides, drugs, and other biologically active compounds such as carenes, sesquicarenes, sirenines, dictyopterenes, pyrethrine, and ambrutucin.3 Among the few nonauxiliary based methods that exist to access enantiomerically enriched VCPs,4 the most straightforward approach would be the asymmetric metal-catalyzed decomposition of vinyldiazoacetates, but it proceeds efficiently mainly for terminal alkenes.5 The complementary strategy, namely the metal-catalyzed reaction of diazoesters with dienes, is highly enantioselective, but is usually restricted to symmetric or cyclic dienes.6 Other enantioselective methods such as the Simmons− Smith reaction on dienol7 or Michael-initiated ring closure have also been reported.8 Recently, our group has described the copper catalyzed carbozincation and carbomagnesiation of cyclopropenes to afford highly enantioenriched and diastereoisomerically pure polysubstituted cyclopropanes (see i, Figure 1).9 We anticipated that a related process using easily accessible vinyl Grignard reagents would offer a facile and short access to vinyl-substituted cyclopropanes, but in contrast to our expectations, early scouting studies showed that the addition reaction of 1-(E)-hexenylmagnesium bromide led to a complete racemic mixture with all chiral ligands and copper salts tested. Although much less common than the addition of other organometallic species, the catalytic enantioselective addition of vinylaluminum species to various Michael acceptors have recently emerged as a direct access to vinylated products.10 We were therefore intrigued by the possibility of performing the asymmetric copper-catalyzed vinyl alumination reactions of cyclopropene derivatives as a new approach to diastereo- and enantiomerically enriched VCPs (see ii, Figure 1). Our model © 2017 American Chemical Society
Figure 1. Vinylcyclopropanes through carbometalation reactions on cyclopropenes.
experiment consisted in the hydroalumination reaction of 5chloropentyne followed by the addition of a catalytic amount of copper salt and chiral ligand in Et2O at 0 °C (Figure 2). However, the copper-catalyzed vinylalumination reaction was revealed to be much more challenging than expected, as no traces of VCPs were observed after hydrolysis but rather the formation of higher molecular weight materials (see i, with (R)H8-BINAP L2 as representative chiral ligand, Figure 2).11 Importantly, we found that the addition of Et2Zn was crucial to promote clean vinylmetalation of cyclopropenes12 (see ii, Received: June 1, 2017 Published: July 25, 2017 3970
DOI: 10.1021/acs.orglett.7b01661 Org. Lett. 2017, 19, 3970−3973
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Figure 2. Et2Zn, a crucial additive for successful carbometalation of cyclopropenes. GC: gas chromatography.
Figure 2; see Supporting Information (SI) for a full list of MXn tested). The addition of 1.0−1.5 equiv of Et2Zn to the 1.2 equiv of vinylaluminum species afforded the best results. Less equivalents of Et2Zn resulted in a drop in yield whereas more than 1.5 equiv of Et2Zn led to a significant increase in either the transfer of an ethyl or isobutyl group to the cyclopropene (see ii, with the same (R)-H8-BINAP L2 as the representative chiral ligand, Figure 2).13 With the optimized conditions in hand, the screening of several chiral phosphorus based ligands and copper salts was carried out (Figure 3) to finally identify either (R)-DTBMSEGPHOS (L8) or SchmalzPhos (L9),14 with copper(I)thiophene-2-carboxylate (CuTC) as the copper salt, as the most efficient catalysts to provide the expected VCPs in outstanding diastereoselectivities and good enantioselectivities (entries 8 and 10, Figure 3; see SI for a complete table of all the ligands evaluated) but still with minor formation of A and B resulting from the transfer of 2−10% of ethyl and 2−9% of iBu groups, respectively. In general, bulky ligands as well as polar solvents favor alkyl transfer products whereas solvents with low coordinating abilities and phosphorus ligands with small steric bulk favor the vinyl-transfer product (Figure 3; see SI for additional information). In contrast to the previously reported enantioselective copper-catalyzed carbozincation and carbomagnesiation where Cu(CH3CN)4PF6 was the best source of copper salt, the highest percentage of vinyl transfer possessing the best diastereo- and enantiomeric ratios was observed with CuTC (compare entries 8 and 9 with entries 11 and 12; Figure 3).9a,b It should be noted that this particular vinylmetalation reaction must address several major difficulties for an efficient catalytic system, as it requires not only efficiency to avoid the formation of dimers and higher molecular weight materials but also selectivity for the transfer of only the vinyl moiety while inducing high diastereo- and enantioselectivities. Opting for the best combination for all these requirements (Figure 3, entries 8 and 10), we set out to investigate the scope of the nucleophilic component of the reaction (Part a, Figure 4). We found that the diastereoisomeric ratios are consistently very high for all vinylmetalations tested and, in all cases, the nucleophile is introduced syn to the methyl group. Enantiomeric ratios are in
Figure 3. Optimization of the Cu-Catalyzed enantioselective vinylalumination with cyclopropene 1a. Reactions were run on a 0.25 mmol scale. If not otherwise noted, full conversion was observed. aAll reactions contain ∼50% of hydrocarbon solvents originating from DIBAL-H and cyclopropene solutions. bEstimated by GC or GC-MS analysis. cDetermined by chiral GC. dThe opposite enantiomer was observed with L9. eNo conversion observed. f No addition of Et2Zn, ∼30% conversion; 0% product formation. CuTC = copper(I) thiophene-2-carboxylate. ND = not determined.
the range of 85:15 except for the 1-octenyl product 2d that reaches 89:11. We were particularly delighted to introduce the vinylcyclopropane nucleophile to furnish the bis-cyclopropane 2g with excellent diastereoisomeric and good enantiomeric ratios albeit in lower yield. The carbometalation with βstyrenylaluminum was particularly pleasing, as the hydroalumination of phenyl acetylene usually leads to approximately 25% of Ph−CC−Al(iBu)2 which typically hampers copper catalysis.15 However, in this particular case, the reaction has to be performed in the presence of (R)-BINAP as the chiral ligand to produce 2h in good yield and enantiomeric ratio. Chlorosubstituted as well as sterically more demanding vinylaluminum reagents were successfully incorporated, albeit the latter with lower enantioselectivity and a higher ratio of alkyl transfer 3971
DOI: 10.1021/acs.orglett.7b01661 Org. Lett. 2017, 19, 3970−3973
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cyclopropanes in natural products, drugs, and insecticides, we were intrigued if whether our developed enantioselective vinylmetalation procedure would also proceed for the simple dimethylcyclopropene substrate.16 Indeed, the desired product 2o was obtained in good enantioselectivity demonstrating the capacity of the chiral catalyst to differentiate the enantiotopic faces of small substrates. Finally, the corresponding metalated VCPs can be further functionalized (Figure 5). The configuration of the cyclo-
Figure 4. Scope of the Cu-catalyzed enantioselective vinylalumination of cyclopropenes. Reactions were conducted on 0.5 mmol scale material. Enantioselectivity was determined by chiral HPLC. Diastereoselectivity was determined by GC or 1H NMR analysis. Alkyl transfer was estimated by GC. aLow yield due to difficult separation from A and B. bCompound 2h decomposes during GC analysis; therefore, no alkyl transfer of the crude reaction could be determined. cYield determined for inseparable mixture of 2j and sideproducts A and B. dLow yield due to volatility of the product; percentage of A and B could not be determined due to the high volatility of these products. ND = not determined.
Figure 5. Miscellaneous reactions.
propane after deuterolysis confirmed the expected cis-adition of the organometallic species during the carbometalation reaction (2p),17 and transmetalation to copper allowed an allylic substitution reaction to proceed and afford tetrasubstituted cyclopropane 2q. Further postfunctionalization can also be easily achieved. For instance, cross-metathesis using Grubbs’ second generation catalyst efficiently produced 2r and oxidative cleavage following Jin’s procedure18 yielded known aldehyde 2s, which confirmed the absolute configuration.19 In summary, we have successfully developed a new general procedure for the challenging enantioselective tandem hydroalumination−vinylmetalation reaction employing commercially available (R)-DTBM-SEGPHOS L8 or SchmalzPhos ligand L9. These procedures are suitable for a wide range of vinyl nucleophiles and cyclopropene substrates, allowing the synthesis of the important vinylcyclopropane motif.
(products 2a, 2i, and 2j). We were delighted to confirm that SchmalzPhos ligand L9 combines also all the desired attributes (selectivity for the ligand transfer, diastereo- and enantioselectivities) and is comparable to ligand L8 in most of the cases, surpassing all other chiral ligands (Figure 4, ent-2a, ent-2d, ent2g) albeit in lower enantiomeric ratio for a slightly bulkier vinylaluminum derivative such as ent-2g. Subsequently, several cyclopropenes were subjected to the optimized reaction conditions (Part b, Figure 4). Cyclopropenes with electronwithdrawing (1k) and -donating groups (1l) afforded the desired product with consistent levels of enantioselectivity. Rigid scaffolds on the cyclopropene substrate led to slightly higher levels of alkyl transfer (2m) whereas a less encumbered substrate (2n) gave very low levels of alkyl transfer as a mixture of two diastereomers. Unexpectedly, product 2n was obtained as the opposite diastereoisomer of trans-2n when ligand L9 was used. Due to the importance of geminal dimethyl-substituted
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01661. Experimental procedures and characterization data for all products, including 1H and 13C NMR spectra (PDF) 3972
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Alexakis, A. Chem. - Eur. J. 2013, 19, 15226. (d) Cottet, P.; Müller, D. S.; Alexakis, A. Org. Lett. 2013, 15, 828. (e) Müller, D. S.; Alexakis, A. Org. Lett. 2012, 14, 1842. (f) Müller, D. S.; Tissot, M.; Alexakis, A. Org. Lett. 2011, 13, 3040. (g) May, T. L.; Dabrowski, J. A.; Hoveyda, A. H. J. Am. Chem. Soc. 2011, 133, 736. (h) Müller, D.; Hawner, C.; Tissot, M.; Palais, L.; Alexakis, A. Synlett 2010, 2010, 1694. (11) Aluminium etherates (e.g., L. Et3Al−Et2O) are known to catalyze the dimerization and oligomerization of cyclopropenes: (a) Binger, P.; Schäfer, H. Tetrahedron Lett. 1975, 16, 4673. (b) Richey, H. G.; Smith, M. A. Organometallics 2007, 26, 609. (12) Yoshikai, N.; Nakamura, E. Chem. Rev. 2012, 112, 2339. (13) At this point we can only speculate about the role of diethyl zinc in the complex reaction mixture containing three metals (Al, Zn, Cu). Transmetalation from aluminum to zinc comparable to the B/Zn exchange might be one explanation, but Et2Zn can also be seen as a Lewis acid thus activating the cyclopropene. (14) Dindaroğlu, M.; Falk, A.; Schmalz, H.-G. Synthesis 2013, 45, 527. (15) (a) Gao, F.; Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132, 10961. (b) Acetylides are nontransferable ligands in Cu-chemistry. See: Corey, E. J.; Beames, D. J. J. Am. Chem. Soc. 1972, 94, 7210. (16) (a) Duran-Pena, M. J.; Ares, J. M. B.; Hanson, J. R.; Collado, I. G.; Hernandez-Galan, R. Nat. Prod. Rep. 2015, 32, 1236. (b) DuranPena, M. J.; Ares, J. M. B.; Collado, I. G.; Hernandez-Galan, R. Nat. Prod. Rep. 2014, 31, 940. (17) Hutton, H. M.; Schaefer, T. Can. J. Chem. 1963, 41, 684. (18) Yu, W. S.; Mei, Y.; Kang, Y.; Hua, Z. M.; Jin, Z. D. Org. Lett. 2004, 6, 3217. (19) Sherrill, W. M.; Rubin, M. J. Am. Chem. Soc. 2008, 130, 13804.
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Hans-Günther Schmalz: 0000-0003-0489-1827 Ilan Marek: 0000-0001-9154-2320 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This research was supported by the European Research Council under the European Community’s Seventh Framework Program (ERC Grant Agreement No. 338912) and by the Israel Science Foundation administrated by the Israel Academy of Sciences and Humanities (140/12). I.M. is holder of the Sir Michael and Lady Sobell Academic Chair.
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REFERENCES
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