Xiang-Phos-Catalyzed Asymmetric Intramolecular Cyclopropanation

Letter pubs.acs.org/OrgLett

Cite This: Org. Lett. 2018, 20, 7049−7052

Gold(I)/Xiang-Phos-Catalyzed Asymmetric Intramolecular Cyclopropanation of Indenes and Trisubstituted Alkenes Pei-Chao Zhang,† Yidong Wang,† Zhan-Ming Zhang,† and Junliang Zhang*,†,‡ †

Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, P. R. China ‡ Department of Chemistry, Fudan University, 2005 Songhu Road, Shanghai 2000438, P. R. China

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S Supporting Information *

ABSTRACT: The first intramolecular enantioselective cyclopropanation of indenes and trisubstituted alkenes was accomplished by using new chiral phosphine X5 derived gold(I) complexes. This reaction is a straightforward, efficient method for constructing [5−3−6] fused-ring compounds with two vicinal all-carbon quaternary stereogenic centers, a core structure shared by numerous pharmacological products, and bioactive compounds. The salient features of this transformation include high enantioselectivity (up to >98% ee), excellent yield (>97%), and nice functional group tolerance.

F

Scheme 1. Asymmetric Intramolecular Cyclopropanation of Olefins for Constructing [5−3−6] Fused-Ring Systems

used-ring molecules containing vicinal all-carbon quaternary stereocenters are particularly important, and they exhibit a variety of biological and pharmacological activities, due to their unique structural features and tendency to tightly bind to target molecules.1 However, the construction of such a structural motif, especially bearing multiple vicinal all-carbon quaternary stereocenters, remains a significant challenge in a single-step operation. Transition-metal-catalyzed intramolecular asymmetric cyclopropanation (ACP) of olefins is one of the most powerful and straightforward synthetic tools for constructing fused-ring systems from simple linear substrates.2 Cyclopropanation represents a typical cycloisomerization of 1,6-enyne, which provides an efficient approach to ring-fused compounds. Recently, Toste3a reported the gold(I)-catalyzed stereoselective olefin cyclopropanation. Zhu and Zhou3b reported the first copper- or iron-catalyzed intramolecular ACP of indole for constructing a [5−3−6] fused-ring system (Scheme 1b). Indole-to-indene core change led to the the large difference in the reactivity and stability (Scheme 1a).4 However, the method for building polycyclic systems with indene skeletons remains unexplored so far. The fused [5−3−6] ring system bearing one or two vicinal all-carbon quaternary stereocenters is a subunit frequently found in pharmaceuticals and agrochemicals.5 Intramolecular cyclopropanation of the 1,6-enynes is one of the most efficient approaches to construct bicyclo[4.1.0]heptene derivatives.6,7 Despite much progress that has been made, the development of a highly enantioselective version still poses a considerable challenge, and only a few examples have been reported so far.8 © 2018 American Chemical Society

We herein report the first gold-catalyzed ACP of indenes using alkynes as gold(I) carbene precursors, which provides a reliable strategy for the efficient construction of a valuable [5−3−6] Received: September 19, 2018 Published: October 29, 2018 7049

DOI: 10.1021/acs.orglett.8b02999 Org. Lett. 2018, 20, 7049−7052

Letter

Organic Letters Table 1. Screening Reaction Conditionsa

fused-ring system with indene skeletons featuring three continuous stereocenters including two vicinal all-carbon quaternary stereocenters in a highly stereoselective manner (Scheme 1c). Indene-derived 1,6-enyne 1aa was easily prepared by the Mitsunobu reaction from the corresponding (1H-inden-3yl)methanol and propargylamine. A series of commercially available chiral ligands such as (S)-BINAP, (R)-MOP, (R)DM-SEGPhos, BIPHEP, binol-derived phosphoramidite, and our recently developed chiral Ming-Phos,9a,b,c,e PC-Phos,9f,g and Xiang-Phos9d (Figure 1) were investigated for the gold-

entry

ligand

additive

solvent

yield [%]

ee [%]b

1 2 3 4 5 6 7 8c 9d 10 11 12e 13f 14g 15c,d 16i

(S,Rs)-X1 (S,Rs)-X2 (S,Rs)-X3 (R,Rs)-X4 (R,Rs)-X5 (R,Rs)-X6 (R,Rs)-X5 (R,Rs)-X5 (R,Rs)-X5 (R,Rs)-X5 (R,Rs)-X5 (R,Rs)-X5 (R,Rs)-X5 (R,Rs)-X5 (R,Rs)-X5 (R,Rs)-X5

AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgNTf2 AgOTf NaBArF NaBArF NaBArF NaBArF NaBArF NaBArF NaBArF NaBArF

DCM DCM DCM DCM DCM DCM DCM DCM DCM toluene CF3Ph 4-F-CF3Ph 4-F-CF3Ph 4-F-CF3Ph 4-F-CF3Ph 4-F-CF3Ph

>90 >90 >90 >90 >90 >90 >90 (82) >90 >90 >90 >90 >90 >90 (99) >90

−35 −13 11 63 67 −45 46 37 66 77 80 81 82 83 91 88

a

Unless otherwise noted, all reactions were carried out with 0.1 mmol of 1a and 5 mol % of catalyst ([Au]/Xiang-Phos) in 2.0 mL of solvent at rt for 0.5−12 h. bDetermined by HPLC analysis. cIsolated yield. d NaBArF: sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate. e0 °C. f−10 °C. g−15 °C. h10 mol % of NaBArF, 6.0 mL of solvent at −15 °C. i10 mol % of NaBArF, 6.0 mL of solvent at −20 °C.

Figure 1. Screening chiral ligands.

catalyzed intramolecular ACP of 1aa (for more details, see Supporting Information (SI), Scheme S1). The new (R,Rs)X4−X6 were prepared from the corresponding (Rs)-3 with the corresponding aryl lithium instead of the previous alkyl magnesium (Scheme 2). The structure and absolute

electron-withdrawing groups on the para- and meta-positions of the phenyl ring (R2) were compatible, and the desired products 2aa−2ar were isolated in 98−99% yields with 90− 96% ee’s. Gratifyingly, the 1-naphthyl, 2-naphthyl, and 2thienyl derived 1as−1au also worked well, delivering the desired products 2as−2av in 98−99% yields with 89−94% ee’s. Moreover, benzoindene and the 4,7-dimethyl-substituted indene-derived substrates 1av−1ax could also work well, furnishing the desired product 2av−2ax with 99% yield with 93−98% ee’s. When the R2 is an ortho-substituted phenyl group 1ay or methyl group 1az, the desired products 2ay in 98% yield, 67% ee, and 2az were isolated in 98% yield but with only 62% ee, indicating further ligand modification is necessary. For the substrate with terminal alkyne 1ba (R2 = H), the reaction is messy. Inspired by the above success, we next turned our attention to examine the scope and limitation of the reaction by extending the indene moiety of 1,6-enynes to other alkenes (Scheme 4). Gratifyingly, a substrate bearing acyclic trisubstituted olefin 4 was also highly reactive, allowing for an ACP reaction under the standard reaction conditions to give the desired bicyclic product 4a in 99% yield with 97% ee. 1,6-Enynes 5−9 with 5−8 cycloalkene moieties also worked smoothly, delivering the corresponding 5a−9a in excellent yields with 85−90% ee’s. It is noteworthy that the yne-diene 7 was also comptible to selectively produced the desired tricyclic product 7a in 99% yield, with 89% ee. O-tethered 1,6-enyne 10 also worked well under the standard reaction conditions, to give the desired bicyclic product 10a in 98% yield but with only 24% ee, indicating the tether moiety affects the enantioselectivity significantly. Boc was used, which is another easily removable protecting group, and the desired bicyclic product 11a was obtained in 98% yield with 96% ee.

Scheme 2. Concise Synthetic Approach to (R,Rs)-X4−6 and Gold Complexes

configuration of the gold complex X5−AuCl were established by single-crystal X-ray diffraction analysis. To our delight, this gold complex treated with AgSbF6 could deliver 2aa as a single diastereomer in high yield with 67% ee (Table 1, entry 5). Subsequently, the effect of the counterion was investigated (Table 1, entries 6−9). With the use of sodium tetrakis[3,5bis(trifluoromethyl) phenyl]borate (BArF−) as additive, the desired product 2aa was obtained in 99% yield with 66% ee at room temperature for 2 h. The solvent screening showed that the benzene solvent was favorable to the reaction, and 4-FPhCF3 proved to be the best solvent (Table 1, entries 10−12 and SI). Finally, running the reaction at lower temperature (−15 °C) with the use of 10 mol % of NaBArF led to a significant improvement in enantioselectivity, thus affording (−)-2aa in 99% isolated yield with 91% ee. The structure and absolute configuration of (S,R,R)-2aa were determined by single-crystal X-ray diffraction analysis. With the optimal reaction conditions in hand, we next examined the scope of the reaction by variation of the 1,6enyne 1 (Scheme 3). First, the R2 substituent effect at the alkyne moiety was studied. Not only electron-donating but also 7050

DOI: 10.1021/acs.orglett.8b02999 Org. Lett. 2018, 20, 7049−7052

Letter

Organic Letters

afford 1.1 g of 2aa in 99% yield with 89% ee under the optimal conditions (Scheme 5). The selective oxidative cleavage of the

Scheme 3. Gold(I)-Catalyzed Intramolecular ACP of Indene-Derived 1,6-Enyne 1

Scheme 5. Synthetic Transformations of 2aa

double bond of 2aa with ozone led to the highly functionalized cyclopropane 12 in 91% yield with 89% ee. It is interesting to find that the selective epoxidation of the double bond of 2aa with m-CPBA delivered the unstable N-tosylamide 13, which would quickly convert into 12 in 95% yield with 89% ee. Moreover, the allylation of 2aa by treatment with allyltrimethylsilane in the presence of trifluoroacetic acid delivered the allylation product 14 in 96% yield with 92% ee and 9:1 dr. In summary, we have demonstrated for the first time intramolecular ACP of 1,6-enynes under the catalysis of X5/ gold complexes. Chiral [5−3−6] fused-ring compounds with two vicinal all-carbon quaternary stereogenic centers were prepared in high yields (98−99%) with excellent enantioselectivities (up to >98% ee) under mild reaction conditions. This method provides an efficient, reliable, and atom-economic strategy for the excellent diastereo- and enantioselectivity construction of valuable highly chiral [5−3−6] fused-ring compounds featuring two vicinal all-carbon quaternary stereogenic centers. Moreover, the broad substrate scope, easy scaleup, and the easily made ligand in the large scale make this reaction quite practical and highly attractive. Further studies including synthetic application of this efficient transformation and the employment of the chiral catalyst to other reactions are currently in progress.

Scheme 4. Gold(I)-Catalyzed Intramolecular ACP of 1,6Enynes 4−11

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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.8b02999. Experimental procedures, 1H and 13C NMR spectra, and HPLC data for all new products (PDF) Accession Codes

CCDC 1859820−1859821 and 1868217 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/ cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

To display the synthetic utility of the present methodologies, the reaction of 1aa proceeded smoothly on a gram scale to

*E-mail: [email protected]. 7051

DOI: 10.1021/acs.orglett.8b02999 Org. Lett. 2018, 20, 7049−7052

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Organic Letters ORCID

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Junliang Zhang: 0000-0002-4636-2846 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge the funding support of the NSFC (21425205, 21672067), the 973 Program (2015CB856600), and the Program of Eastern Scholar at Shanghai Institutions of Higher Learning.

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DOI: 10.1021/acs.orglett.8b02999 Org. Lett. 2018, 20, 7049−7052