Enantio- and Diastereoselective Cyclopropanation of β,γ-Unsaturated

Letter pubs.acs.org/OrgLett

Enantio- and Diastereoselective Cyclopropanation of β,γUnsaturated α‑Ketoester by a Chiral Phosphate/Indium(III) Complex Xingren Zhong,†,‡ Jian Lv,*,†,‡,§ and Sanzhong Luo*,†,‡,§ †

Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China ‡ University of Chinese Academy of Sciences, Beijing 100049, China § Collaborative Innovation Center of Chemical and Engineering (Tianjin), Tianjin 300071, China S Supporting Information *

ABSTRACT: We report herein an enantioselective cyclopropanation of β,γ-unsaturated α-ketoesters with diazoesters by the complexes of InBr3 and chiral calcium phosphate. The reaction proceeds via a Michael addition−cyclization pathway to afford highly functionalized chiral cyclopropanes with excellent enantioselectivities (up to >99% ee) as a single diastereoisomer. Scheme 1. Lewis Acid Catalyzed Asymmetric Reactions of αDiazo Esters

C

hiral cyclopropanes are versatile structure moieties in many bioactive natural products.1 In the past decade, much effort has been devoted to developing synthetic strategies for preparing highly functionalized chiral cyclopropane derivatives.2 In this regard, asymmetric cyclopropanation with diazo reagents represents a powerful approach for both electron-deficient and electron-rich alkenes. The reactions generally preceded via metal carbenoid3−5 or metalloradical intermediates.6 In addition, Lewis acid catalyzed Michael addition-cyclization of electron-deficient olefins via chiral sulfonium and ammonium ylides has appeared as a complementary yet appealing strategy for cyclopropanation reaction.7 Recently, Maruoka8a and Ryu8b,c have reported chiral Lewis acid catalyzed asymmetric cyclopropanation of α- or α,βsubstituted acroleins with diazoacetates, respectively (Scheme 1A). However, this reaction is limited to only acroleins and their derivatives. Asymmetric cyclopropanation with diazo-type ylides remains largely unexplored. The major challenge comes from the strong tendency of diazo ylides to undergo 1,2addition instead of 1,4-conjugate addition for cyclopropanation process. In fact, homologation via 1,2-diazo esters addition to carbonyl is known.9 Feng has reported elegant examples on those asymmetric homologation reaction of α-ketoesters by using chiral Yttrium triflate complex (Scheme 1B).9b In a way overriding the homologation process, we herein report an unprecedented enantioselective cyclopropanation reaction of β,γ-unsaturated α-ketoesters with a series of diazoacetates by a chiral Indium phosphate complex (Scheme 1C). Recently, we have developed pentafluorobenzene appended chiral phosphoric acids as effective ligands for asymmetric Lewis acid catalysis.10 In this binary acid catalysis, chiral phosphoric acids may play additional roles as protonic catalyst and balancing anion besides serving as oxygen-centered ligand.10a,11 In our further explorations along this line, we have found that Indium-pentafluorophosphate binary acid © 2017 American Chemical Society

complex could effectively promote a chemo- and stereoselective diazo-ylides cyclopropanation reaction (Scheme 1C). Our studies started with a model reaction of β,γ-unsaturated α-ketoester 2a with tert-butyl benzyldiazoacetate 3a by Lewis acids and 1a at room temperature. While no reaction was observed when transition-metal salts such as Ag(I), Au(I), Cu(II), Zn(II) and Fe(III) were used, a binary acid InBr3/1a led to cyclopropane 4a as a single stereoisomer with moderate yield and low enantioselectivity (Table 1, entry 1). At the same Received: May 25, 2017 Published: June 7, 2017 3331

DOI: 10.1021/acs.orglett.7b01577 Org. Lett. 2017, 19, 3331−3334

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Organic Letters

whereas others resulted in either lower activities or poor enantioselectivities. Under the optimized conditions, the formation of 1,2-adduct was largely suppressed. In control experiments, we found that the reaction did not proceed with Ca[1e]2 only (Table 1, entry 16). In addition, InBr3 alone turned out to be not an active catalyst for the reaction in the absence of chiral phosphoric acid 1e or the calcium salt Ca[1e]2 (10% yield, Table 1, entry 15). These results highlight the synergistic combinations of phosphoric acid/phosphate salt with Indium Lewis acid. With the optimal reaction conditions established, the scope of an asymmetric binary Lewis acid catalyzed enantioselective cyclopropanation was next explored with InBr3/Ca[1e]2 in 1,2dichloroethane (DCE) at room temperature. The results are presented in Scheme 2. Different ester groups on both diazoesters and ketoesters part were tolerated to give the cyclopropane adducts with excellent enantioselectivity (Scheme 2, 4a−d,o−r). When both ester moieties were tert-butyl ester, no reaction was observed, pinpointing the steric tolerance for

Table 1. Optimization Studies for Asymmetric Cyclopropanation of β,γ-Unsaturated α-Ketoester 2a with tert-Butyl Benzyldiazoacetate 3aa

entry

ligand

solvent

yieldb (%)

eec (%)

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

1a 1b 1c 1d 1e 1f 1g 1h Ca[1e]2 Ca[1e]2 Ca[1e]2 Ca[1e]2 Ca[1e]2 Ca[1e]2 none Ca[1e]2 only

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 cyclohexane toluene CHCl3 DCE DCE DCE DCE

45 48 38 49 50 NR 39 42 59 53 46 16 70 57 10 NR

18 36 22 65 98  16 12 99 44 91 50 99 97

Scheme 2. Asymmetric Cyclopropanation of β,γ-Unsaturated α-Ketoester 2 with α-Diazoacetate 3a

a

General conditions: 2a (0.10 mmol), 3a (0.2 mmol), 1 (10 mol %), InBr3 (5 mol %), and 4 Å MS (5 mg) at room temperature in solvent (0.5 mL) for 30 min. bDetermined by 1H NMR analysis with an internal standard, 1,3,5-trimethyloxylbenzene. cThe enantioselectivities were determined by chiral HPLC. dCa[1e]2 (5 mol %). eCa[1e]2 (2.5 mol %). fNo InBr3. NR = no reaction. DCE = 1,2-dichloroethane.

time, a 15% yield of the 1,2-homologation adduct of αketoester 3a was also isolated. With Lewis acid InBr3, we next set out to further improve the enantioselectivity by examining different free phosphoric acids. The phosphoric acid 1b bearing a remote pentafluorophenyl group, as an effective ligand in other Lewis acid catalysis,10c,e only gave 4a in 48% yield and 36% ee (Table 1, entry 2). Moreover, steric tuning, widely applied in the catalysis with phosphoric acids,12,13 worked against us. The reaction did not occur at all with the bulky triisopropyl phosphoric acid 1f (Table 1, entry 6). On the other hand, electronic effect of the side aromatic moiety seemed to significantly impact the stereoselectivity (Table 1, entries 3−8). In particular, the fluoro effect, widely observed in Lewis acid/ phosphoric acid binary catalysis,10c,e was found to dramatically benefit the enantioselective control. A steady increase of the enantioselectivity was noticed by increasing the number of fluoro substituent (Table 1, entries 3−5). Following this trend, the optimal pentafluorophenyl substitute on the 3,3′- positions of chiral BINOL-derived phosphoric acid was found to give the cyclopropane adduct 4a with excellent enantioselectivity (98% ee) in moderate yield (50%, Table 1, entry 5). The use of a calcium salt Ca[1e]2 instead of the free acid increased the yield to 59% with 99% ee (Table 1, entry 9). The reaction was then further optimized with the binary complex InBr3/Ca[1e]2 (1:1) at room temperature in terms of solvent (Table 1, entries 9− 14). The best result was obtained in DCE (Table 1, entry 13)

a General conditions: 2 (0.20 mmol), 3 (0.40 mmol), Ca[1e]2 (5 mol %), InBr3 (5 mol %), and 4 Å MS (10 mg) at room temperature in DCE (1.0 mL) for 30 min.

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DOI: 10.1021/acs.orglett.7b01577 Org. Lett. 2017, 19, 3331−3334

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Organic Letters the reaction (4e). A number of β,γ-unsaturated α-ketoesters 2 were examined, and aromatic ketoesters bearing either an electron-withdrawing group or electron-donating group can be equally applied with comparable activity and uniformly high enantioselectivity as single diastereoisomers (Scheme 2, 4f− h,j−n). Heterocycle, e.g., thiophene, can also be incorporated to deliver the cyclopropane adduct 4s in 67% yield and with >99% ee. Unfortunately, aliphatic ketoester worked poorly in the reaction to give rather low yield and enantioselectivity (Scheme 2, 4i). The scope of the diazoesters was examined. The reactions worked well with aliphatic diazoesters, and alkyl groups such as 4-bromobenzyl (4t,u), methyl (4j−s), ethyl (4v), and n-hexyl (4w) could all be well tolerated to deliver the desired cyclopropanes with moderate to good yields and all in >99% ee (Scheme 2, 4t−x). In particular, the reaction with allylic diazoester also proceeded smoothly to give the expected cyclopropane 4x in 60% yield and >99% ee. Aromatic diazoester has also been attempted in the reaction, resulting in surprisingly no reaction at all (4y, Scheme 2). It was noted that in most cases the 1,2-adducts were detected by NMR in 99% ee) (Scheme 2). The absolute configuration was assigned on the basis of the structure of 4u, which was confirmed unambiguously by an X-ray crystallographic study.14 Treatment of 4u with NaBH3CN in CH3OH led to the reduction of the CO bond, providing methyl α-hydroxy ester 5 as a single diastereoisomer in 91% yield and with >99% ee (Scheme 3B). Based on the determined absolute configuration of (1R,2R,3S)-4u (Figure S1 and Scheme 3) and our experimental results, a tentative transition state is proposed to account for the stereoselectivity (Figure 1A). α-Ketoester is bidentately activated by the cationic indium complex,15 setting the stage for diazo ylide addition. Provided with a dramatic stereoelectronic effect (Table 1, entries 3−8), a weak π-interaction (e.g., anion−π interaction)16 was invoked to direct a facial attack of diazo ylide onto activated β,γ-unsaturated α-ketoester, and a back attack then cyclized to form (1R,2R,3S)-cyclopropane with loss of nitrogen. The calculated quadrupole moments Qzz of the 3,3′-aromatic group were found to correlate linearly with

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Sanzhong Luo: 0000-0001-8714-4047 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the Natural Science Foundation of China (21390400, 21521002, and 21472193) and the Chinese Academy of Sciences for financial support. S.L. is supported by the National 3333

DOI: 10.1021/acs.orglett.7b01577 Org. Lett. 2017, 19, 3331−3334

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