DOI: 10.1002/chem.201406189
Communication
& Synthetic Methods
Highly Enantioselective Catalytic Asymmetric [2+2] Cycloadditions of Cyclic a-Alkylidene b-Oxo Imides with Ynamides Kazuaki Enomoto, Harufumi Oyama, and Masahisa Nakada*[a] Abstract: Highly enantioselective catalytic asymmetric [2+2] cycloadditions of cyclic a-alkylidene b-oxo imides with ynamides are described. The high reactivity of the cyclic a-alkylidene b-oxo imide allows the [2+2] cycloadditions of a hindered substrate with unreactive ynamides at low temperature. The X-ray crystallographic analysis of the product suggests that the enantioselectivity of the [2+2] cycloaddition can be well explained by the chelate model comprising the intramolecular hydrogen bond, wherein the cyclic a-alkylidene b-oxo imide coordinates with CuII through the two imide carbonyls. The imide group in the product can be transformed to amide, nitrile, and ester groups; moreover, it is removable.
Scheme 1. Proposed reaction mechanism of Ficini reaction.
successful example of which was reported by Hsung and coworkers.[7] Ynamides are stabilized by an electron-withdrawing group such as a carbonyl/sulfonyl group attached to the nitrogen atom; thereby, the reactivity of ynamides is less than that of enamines, and a catalyst is required for the successful formal [2+2] cycloaddition. Hsung’s studies elicited the asymmetric catalysis in the [2+2] cycloaddition of enones with ynamides. However, to our knowledge, the enantioselective variant has been limited to the work of Mezzetti and co-workers.[8] Catalytic asymmetric [2+2] cycloaddition with ynamides is difficult because the enantiosite discrimination of the reacting double bond of the electrophile is insufficient, even when cyclic unsaturated b-keto esters are used. The first carbon– carbon bond formation is expected to occur at the electrophilic position of the enone, which is located far from the bisoxazoline substituent, resulting in low enantioselectivity. Indeed, Mezzetti reported successful [2+2] cycloadditions of ynamides using a chiral ruthenium complex.[8c] However, the choice of substrate was limited to the b-keto ester of cyclopentenone and heating was required to remove the product from the catalyst, indicating the difficulty in the catalytic asymmetric [2+2] cycloadditions. We recently reported [4+2] cycloadditions and Hosomi–Sakurai reactions of cyclic a-alkylidene b-oxo imides.[9] Both the reactions proceeded in high yields and enantioselectivities. For example, the [4+2] cycloaddition of imide 1 a in the presence of a catalytic amount of bisoxazoline–Cu(OTf)2 afforded the product in an excellent yield and enantioselectivity. a-Alkylidene b-oxo imides are interesting compounds because the acidic imide hydrogen can form an intramolecular hydrogen bond (complex A, Figure 1), which was suggested by X-ray crystallographic analysis and NMR studies,[9] leading to a rigid conformation. Therefore, the two imide carbonyls act as a bidentate ligand to form a chelate. Thus, complex A would result in the clear differentiation of the two enantiotopic faces of the reacting double bond, due to its proximity to the
Four-membered carbocyclic compounds are important because they have been used as synthetic intermediates that allow the formation of new bonds and stereogenic centers through the ring-opening reaction[1] and, moreover, they can be found as a part of the structures of bioactive natural products.[2] Consequently, great effort has been put into developing efficient methods for the preparation of cyclobutanes. The preparation of four-membered carbocyclic rings largely depends on photochemical [2+2] cycloadditions because concerted thermal [2+2] cycloadditions are symmetrically forbidden in the usual suprafacial process.[3] However, stepwise formal [2+2] cycloadditions that afford four-membered carbocyclic compounds have been reported and, among them, the Ficini reaction, a stepwise thermal [2+2] cycloaddition of an ynamine with an enone to form aminocyclobutenes (Scheme 1), has drawn the attention of synthetic chemists because of its versatility and the utility of the product.[4] However, the synthetic application of the Ficini reaction has been limited, probably because of practical problems in the preparation, handling, and storage of reactive ynamines.[5] To improve the applicability of the Ficini reaction, [2+2] cycloadditions of enones with ynamides[5, 6] were studied, the first [a] K. Enomoto, H. Oyama, Prof. Dr. M. Nakada Department of Chemistry and Biochemistry School of Advanced Science and Engineering, Waseda University 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555 (Japan) Fax: (+ 81) 3-5286-3240 Home page: http://www.chem.waseda.ac.jp/nakada/ E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201406189. Chem. Eur. J. 2014, 20, 1 – 6
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Communication Table 1. Effect of varying bisoxazoline ligands (L1–L5) on catalytic asymmetric [2+2] cycloaddition of 1 a with 2 a.[a]
Figure 1. Proposed structures of complexes A and B.
bisoxazoline substituent. However, in complex B, which is a square-planar complex[10] formed by the cyclic a-alkylidene b-oxo ester and a bisoxazoline-CuII catalyst, the reacting double bond lies on the pseudo-C2 axis, cutting through the Cu atom and the bisoxazoline ligand to be located far from the bisoxazoline substituent, resulting in low enantioselectivity. We studied the applicability of cyclic a-alkylidene b-oxo imides to the formal [2+2] cycloaddition and herein report the highly enantioselective catalytic asymmetric [2+2] cycloadditions of cyclic a-alkylidene b-oxo imides with ynamides. Hsung and co-workers used a catalytic amount of CuCl2 and AgSbF6 for the [2+2] cycloadditions of ynamides, which proceeded to completion below 0 8C and within 1 h.[7] The catalytic activity of the bisoxazoline-ligated cationic CuII salt decreases because the bisoxazoline ligand is basic and bulky, and ynamides are unreactive.[11] However, the [2+2] cycloaddition of aalkylidene b-oxo imides with ynamides was expected to proceed because a-alkylidene b-oxo imides, on account of the two electron-withdrawing groups attached, are highly reactive. Moreover, the NH bond is acidified upon coordination and thus activates the enone system. Therefore, we investigated the reaction of a-alkylidene boxo imide 1 a with ynamide 2 a[12] (Table 1). Because the use of the bisoxazoline ligand and CuII salt was effective in the [4+2] cycloadditions of 1 a, the reaction of 1 a with 2 a was carried out using L1–Cu(OTf)2 (20 mol %; Table 1, entry 1) and, at 0 8C, was completed after 9 h to afford 3 aa in 65 % yield with 88 % ee. Interestingly, this reaction also afforded the [4+2] cycloadduct 4 aa in 18 % yield with 99 % ee, similar to the products obtained by Evans and co-workers. in the Mukaiyama–Michael reaction.[13] The reaction of 1 a with 2 a was also carried out using bisoxazoline ligands L2–L4 alongside Cu(OTf)2 (Table 1, entries 2–4), but the yield, ee, and ratio of 3 aa/4 aa were almost unchanged. However, the reaction of 1 a with 2 a using Ishihara’s ligand L5[14] proceeded to completion within 20 minutes to afford ent-3 aa in 92 % yield with 91 % ee, without forming ent-4 aa (Table 1, entry 5). The high 3 aa selectivity on using ligand L5 could be explained by the fact that the two amide substituents of L5 coordinate with the CuII catalyst at the apical position,[14] which causes steric strain between the apical amide group and 2 a in the transition state of the [4+2] cycloaddition with 2 a. Finally, the reaction using 10 mol % of L5–Cu(OTf)2 at 60 8C afforded ent-3 aa in 97 % yield with 96 % ee (Table 1, entry 6). Compound ent-3 aa was highly crystalline and suitable for Xray crystallographic analysis.[15] The crystal structure of ent-3 aa &
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Entry 1 2 3 4 5 6[f]
Ligand L1 L2 L3 L4 L5 L5
Time [h] 9 9 9 9 20 min 10
3 aa Yield [%][b] 65 67 66 67 92 97
3 aa ee [%][c]
4 aa Yield [%][b]
88 87 90 83 91[e] 96[e]
18[d] 19 19 15 0 0
[a] Reaction conditions: 1 a (1.0 equiv), 2 a (1.5 equiv), Ligand–Cu(OTf)2 (20 mol %), MS 4 , CH2Cl2, 0 8C; [b] yield of isolated product; [c] determined by HPLC analysis using a chiral stationary phase; [d] 99 % ee; [e] ent3 aa. [f] 10 mol % of catalyst was used at 60 8C.
Figure 2. X-ray crystal structure of ent-3 aa. Thermal ellipsoids are set at 50 % probability.
(Figure 2) indicates that complex A in Figure 1 rationally explains the sense of induction; the reaction occurs at the lesshindered enantioface of 1 a in complex A. Next, the reaction of 1 a was investigated with various derivatives of ynamide 2 a (2 b–e, Table 2). The result of the reaction with 2 a at 0 8C is shown in Table 2, entry 1, for comparison. The reaction of 1 a with 2 b (R3 = Me) required 5 h to afford ent-3 ab in 80 % yield with 86 % ee (Table 2, entry 2). The reactions with 2 c and d were slow, probably owing to the steric 2
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Communication 0 8C, to afford ent-3 bb in 45 % yield and the ee was slightly decreased (83 % ee) when compared with that for the reaction of 2 b with 1 a (86 % ee; Table 2, entry 2). The reaction of 1 c, an imide of cyclopentenone, with 2 a proceeded at 60 8C to afford ent-3 ca in 58 % yield with 86 % ee (Table 3, entry 3). The low yield was attributed to the formation of unidentified products derived from 1 c. The reaction of 1 c with 2 b was unexpectedly fast, affording ent-3 cb in 93 % yield with 88 % ee in only 9 hours (Table 3, entry 4). The relatively low ee of ent-3 ca, compared with that of ent-3 ba, was attributed to the fact that the intramolecular imide hydrogen bond was weakened in the imide of cyclopentenone. Indeed, the imide NH signal of 1 c was detected at d = 10.13 ppm, upfield of those for 1 a (d = 10.71 ppm) and 1 b (d = 10.90 ppm), which indicates that the hydrogen bond of 1 c was weakened. The formal [2+2] cycloaddition of imide 1 d, which comprises an all-carbon quaternary center vicinal to the reacting double bond, was then examined (Table 4). The reaction of 1 d was expected to be slow owing to the steric hindrance;
Table 2. Catalytic asymmetric [2+2] cycloadditions of 1 a with 2 a–e using L5–Cu(OTf)2.[a]
Entry 1 2 3 4 5
R3 H (2 a) Me (2 b) c-Hexyl (2 c) Ph (2 d) CO2Me (2 e)
Time [h]
Yield [%][b]
ee [%][c]
1 5 72 72 24
91 (ent-3 aa) 80 (ent-3 ab) 74 (ent-3 ac) 15 (ent-3 ad) –[d]
89 86 10 35 –
[a] Reaction conditions: 1 a (1.0 equiv), 2 a-e (1.5 equiv), L5-Cu(OTf)2 (10 mol %), MS 4 , CH2Cl2, 0 8C; [b] yield of isolated product; [c] determined by HPLC analysis using a chiral stationary phase; [d] No reaction.
hindrance of substituents at the alkyne terminal. The reactions of 1 a with 2 c (R3 = cyclohexyl) and 2 d (R3 = Ph) took 72 h to afford ent-3 ac (74 %, 10 % ee; Table 2, entry 3) and ent-3 ad (15 %, 35 % ee; Table 2, entry 4), respectively. The decreased yields and ee values are clearly attributed to the steric effect of the substituents at the alkyne terminal. No reaction occurred in the case of 2 e (R3 = CO2Me; Table 2, entry 5). The results summarized in Table 2 indicate that 2 a (R3 = H) and 2 b (R3 = Me) are synthetically useful. Hence, the [2+2] cycloaddition of other cyclic a-alkylidene b-oxo imides, 1 b and 1 c, were investigated using 2 a and 2 b (Table 3). The reaction of 1 b, an imide of cyclohexenone, with ynamide 2 a was carried out and ent-3 ba was formed at 40 8C in 73 % yield with 96 % ee (Table 3, entry 1). The ee in this reaction was almost the same as that for the reaction of 1 a with 2 a at 60 8C (Table 1, entry 6). The reaction of 1 b with less reactive 2 b proceeded sluggishly (Table 3, entry 2), taking 24 h, even at
Table 4. Catalytic asymmetric [2+2] cycloadditions of 1 d with 2 a and 2 b.
Entry Products Conditions 1
Table 3. Catalytic asymmetric [2+2] cycloadditions of 1 b and 1 c with 2 a and 2 b.[a]
Time Yield [%][a] ee [h] [%][b]
ent-3 da L5–Cu(OTf)2 (10 mol %), MS 4 , 48 CH2Cl2, 0 8C
2
3 da
L4–Cu(BF4)2 (10 mol %), MS 4 , 15 CH2Cl2, 20 8C
3
3 da
L4–Cu(BF4)2 (10 mol %), CH2Cl2, 20 8C
4
3 da
5
3 db
7
L4–Cu(BF4)2 (10 mol %), CH2Cl2/ 3 toluene = 1/5, 20 8C L4–Cu(SbF6)2 (10 mol %), CH2Cl2/ 22 toluene = 1/5, 0 8C
30 (at 53 % conv) 73 (at 63 % conv) 78 (at 91 % conv) quant. quant.
57
93
96
99 99
[a] Yield of isolated product; [b] determined by HPLC analysis using a chiral stationary phase.
Entry 1 2 3 4
Product
Temp [8C]
ent-3 ba ent-3 bb ent-3 ca ent-3 cb
40 0 60 40
Time [h]
Yield [%][c]
ee [%][b]
15 24 13 9
73 45 58 93
96 83 86 88
indeed, the reaction using L5–Cu(OTf)2 (10 mol %) with 2 a (3.0 equiv) proceeded slowly even at 0 8C, taking 48 h, to afford ent-3 da in 30 % yield (at 53 % conversion) with 57 % ee (Table 4, entry 1). Because the best yield, conversion, and ee in the [4+2] cycloaddition of 1 d was attained on using L4– Cu(BF4)2, the [2+2] cycloaddition of 1 d with 2 a was examined using 10 mol % of L4–Cu(BF4)2 at 20 8C. This reaction afforded 3 da after 15 h, in 73 % yield (at 63 % conversion; 37 % of starting material was recovered) with 93 % ee (Table 4, entry 2). The
[a] Reaction conditions: 1 b or 1 c (1.0 equiv), 2 a or 2 b (1.5 equiv), L5– Cu(OTf)2 (10 mol %), MS 4 , CH2Cl2 ; [b] yield of isolated product; [c] determined by HPLC analysis using a chiral stationary phase.
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Communication ee was significantly higher than for the previous reaction. The same ligand effect was not observed in the reaction with 1 a (Table 1). Hence, it is possible that the geminal dimethyl group in 1 d disturbed the transition state of the reaction when L5– Cu(OTf)2 was used. Interestingly, although other reactions resulted in inferior yield and enantioselectivity in the absence of MS 4 , the reaction of 1 d with 2 a using L4–Cu(BF4)2 in the absence of MS 4 proceeded faster, taking 7 h, and afforded 3 da in 78 % yield (at 91 % conversion) with 96 % ee (Table 4, entry 3). Finally, using a mixed solvent (1:5 CH2Cl2/toluene) increased the yield and ee of 3 da to quantitative and 99 %, respectively (Table 4, entry 4). For the reaction of 1 d and 2 b, the more catalytically active L4–Cu(SbF6)2[16] was used to accelerate the reaction owing to the low reactivity of 2 b. In this case, 3 db was quantitatively formed with 99 % ee at 0 8C (Table 4, entry 5). As described above, the [2+2] cycloaddition of the imide with an unreactive ynamide proceeds when the reacting double bond is located at the position vicinal to an all-carbon quaternary center. A ring system, like that in 3 da, comprising a geminal dimethyl group adjacent to consecutive stereogenic centers comprising an all-carbon quaternary stereogenic center is found in the structure of various terpenes (e.g., entkaurane diterpenoids). Hence, the developed catalytic asymmetric [2+2] cycloaddition could be useful for enantioselective natural product synthesis. Transformation of the imide group in the products is important for applying the developed [2+2] cycloaddition to natural product synthesis.[17] Consequently, transformation of the imide group in 3 da was investigated (Scheme 2). The reaction of 3 da using MeMgBr in MeOH[18] afforded amide 4 a in 94 % yield, which was further transformed to nitrile 4 b using trifluroacetic anhydride (TFAA) in 89 % yield. The transformation of 3 da to ester 4 c was low-yielding (27 %) owing to the preferential formation of 4 a. However, imide 3 da’, which was
formed in 98 % yield with 99 % ee using the same reaction conditions as those in Table 4, entry 4, was transformed to ester 4 c in 68 % yield on treatment with MeONa in MeOH, though formation of 4 a was not completely suppressed. Moreover, the treatment of 3 da’ with LiOH in aqueous THF resulted in the removal of the imide group to afford 4 d in 80 % yield. The transformations in Scheme 2 could make the developed catalytic asymmetric [2+2] cycloaddition useful for natural product synthesis. In summary, the highly enantioselective catalytic asymmetric [2+2] cycloaddition of cyclic a-alkylidene b-oxo imide with ynamide has been developed. The high reactivity of the cyclic a-alkylidene b-oxo imide allowed the reaction of a hindered substrate with unreactive ynamides at low temperature. X-ray crystallographic analysis of the [2+2] cycloaddition product suggested that the enantioselectivity of the [2+2] cycloaddition can be well explained by the chelate model comprising the intramolecular hydrogen bond, wherein the cyclic a-alkylidene b-oxo imide, which coordinates with CuII through two imide carbonyl groups. The imide group in the product was successfully transformed into amide, nitrile, and ester groups. Moreover, it was removable. Application of the developed catalytic asymmetric [2+2] cycloaddition to natural product synthesis is now underway in our laboratory.
Acknowledgements This work was financially supported in part by the Grant-in-Aid for Scientific Research B (25293003), by MEXT, and by a Waseda University Grant for Special Research Projects. Keywords: asymmetric catalysis enantioselectivity · imides · ynamides
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[1] For reviews, see: a) E. Lee-Ruff, G. Mladenova, Chem. Rev. 2003, 103, 1449; b) J. C. Namyslo, D. E. Kaufmann, Chem. Rev. 2003, 103, 1485. [2] V. M. Dembitsky, J. Nat. Med. 2007, 62, 1. [3] a) R. Hoffmann, R. B. Woodward, J. Am. Chem. Soc. 1965, 87, 2046; b) R. B. Woodward, R. Hoffmann, Angew. Chem. Int. Ed. Engl. 1969, 8, 781; Angew. Chem. 1969, 81, 797. [4] a) J. Ficini, A. Krief, Tetrahedron Lett. 1969, 10, 1431; b) J. Ficini, A. M. Touzin, Tetrahedron Lett. 1972, 13, 2093; c) J. Ficini, A. M. Touzin, Tetrahedron Lett. 1974, 15, 1447; d) J. Ficini, Tetrahedron 1976, 32, 1449; e) J. Ficini, S. Falou, J. d’Angelo, Tetrahedron Lett. 1977, 18, 1931; f) J. Ficini, A. Krief, A. Guingant, D. Desmaele, Tetrahedron Lett. 1981, 22, 725; g) J. Ficini, A. Guingant, J. d’Angelo, G. Stork, Tetrahedron Lett. 1983, 24, 907; h) J. Ficini, D. Desmaele, A. M. Touzin, Tetrahedron Lett. 1983, 24, 1025. [5] For a review, see: C. A. Zificsak, J. A. Mulder, R. P. Hsung, C. Rameshkumar, L.-L. Wei, Tetrahedron 2001, 57, 7575. [6] For recent reviews, see: a) G. Evano, A. Coste, K. Jouvin, Angew. Chem. Int. Ed. 2010, 49, 2840; Angew. Chem. 2010, 122, 2902; b) K. A. DeKorver, H. Li, A. G. Lohse, R. Hayashi, Z. Lu, Y. Zhang, R. P. Hsung, Chem. Rev. 2010, 110, 5064; c) T. Lu, R. P. Hsung, ARKIVOC (Gainesville, FL, U.S.) 2014, 1, 127; d) X.-N. Wang, H.-S. Yeom, L.-C. Fang, S. He, Z.-X. Ma, B. L. Kedrowski, R. P. Hsung, Acc. Chem. Res. 2014, 47, 560. [7] H. Li, R. P. Hsung, K. A. DeKorver, Y. Wei, Org. Lett. 2010, 12, 3780. [8] a) C. Schotes, A. Mezzetti, J. Am. Chem. Soc. 2010, 132, 3652; b) C. Schotes, A. Mezzetti, Chimia 2011, 65, 231; c) C. Schotes, A. Mezzetti, Angew. Chem. Int. Ed. 2011, 50, 3072; Angew. Chem. 2011, 123, 3128; d) C. Schotes, A. Mezzetti, J. Org. Chem. 2011, 76, 5862; e) C. Schotes, R.
Scheme 2. Transformations of [2+2] cycloaddition products.
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[9] [10]
[11] [12] [13] [14]
[15] CCDC-1033309 (ent-3 aa) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif. [16] D. A. Evans, J. A. Murry, P. van Matt, R. D. Norcross, S. J. Miller, Angew. Chem. Int. Ed. Engl. 1995, 34, 798; Angew. Chem. 1995, 107, 864. [17] Reported transformations of imides: a) J. K. Myers, E. N. Jacobsen, J. Am. Chem. Soc. 1999, 121, 8959; b) G. M. Sammis, E. N. Jacobsen, J. Am. Chem. Soc. 2003, 125, 4442; c) M. S. Taylor, E. N. Jacobsen, J. Am. Chem. Soc. 2003, 125, 11204. [18] D. A. Evans, M. M. Morrissey, R. L. Dorow, J. Am. Chem. Soc. 1985, 107, 4346.
Bigler, A. Mezzetti, Synthesis 2012, 44, 513; f) C. Schotes, M. Althaus, R. Aardoom, A. Mezzetti, J. Am. Chem. Soc. 2012, 134, 1331. K. Orimoto, H. Oyama, Y. Namera, T. Niwa, M. Nakada, Org. Lett. 2013, 15, 768. The bisoxazoline-CuII complex may have a distorted square-planar geometry. See: a) D. A. Evans, S. J. Miller, T. Lectka, J. Am. Chem. Soc. 1993, 115, 6460; b) D. A. Evans, S. J. Miller, T. Lectka, P. von Matt, J. Am. Chem. Soc. 1999, 121, 7559. The [2+2] cycloaddition of ynamides with cyclic isoimidium salts: Y. Yuan, L. Bai, J. Nan, J. Liu, X. Luan, Org. Lett. 2014, 16, 4316. Y.-P. Wang, R. L. Danheiser, Tetrahedron Lett. 2011, 52, 2111. D. A. Evans, K. A. Scheidt, J. N. Johnston, M. C. Willis, J. Am. Chem. Soc. 2001, 123, 4480. A. Sakakura, R. Kondo, Y. Matsumura, M. Akakura, K. Ishihara, J. Am. Chem. Soc. 2009, 131, 17762.
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Received: November 23, 2014 Published online on && &&, 0000
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COMMUNICATION & Synthetic Methods K. Enomoto, H. Oyama, M. Nakada* && – && Highly Enantioselective Catalytic Asymmetric [2+2] Cycloadditions of Cyclic a-Alkylidene b-Oxo Imides with Ynamides
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Cyclobutiful: The high reactivity of the cyclic a-alkylidene b-oxo imide allows the [2+2] cycloadditions of a hindered substrate with unreactive ynamides at
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low temperature. The imide group in the product can be transformed into amide, nitrile, or ester groups. Moreover, it is removable.
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& Synthetic Methods
Highly Enantioselective Catalytic Asymmetric [2+2] Cycloadditions of Cyclic a-Alkylidene b-Oxo Imides with Ynamides Kazuaki Enomoto, Harufumi Oyama, and Masahisa Nakada*[a] Abstract: Highly enantioselective catalytic asymmetric [2+2] cycloadditions of cyclic a-alkylidene b-oxo imides with ynamides are described. The high reactivity of the cyclic a-alkylidene b-oxo imide allows the [2+2] cycloadditions of a hindered substrate with unreactive ynamides at low temperature. The X-ray crystallographic analysis of the product suggests that the enantioselectivity of the [2+2] cycloaddition can be well explained by the chelate model comprising the intramolecular hydrogen bond, wherein the cyclic a-alkylidene b-oxo imide coordinates with CuII through the two imide carbonyls. The imide group in the product can be transformed to amide, nitrile, and ester groups; moreover, it is removable.
Scheme 1. Proposed reaction mechanism of Ficini reaction.
successful example of which was reported by Hsung and coworkers.[7] Ynamides are stabilized by an electron-withdrawing group such as a carbonyl/sulfonyl group attached to the nitrogen atom; thereby, the reactivity of ynamides is less than that of enamines, and a catalyst is required for the successful formal [2+2] cycloaddition. Hsung’s studies elicited the asymmetric catalysis in the [2+2] cycloaddition of enones with ynamides. However, to our knowledge, the enantioselective variant has been limited to the work of Mezzetti and co-workers.[8] Catalytic asymmetric [2+2] cycloaddition with ynamides is difficult because the enantiosite discrimination of the reacting double bond of the electrophile is insufficient, even when cyclic unsaturated b-keto esters are used. The first carbon– carbon bond formation is expected to occur at the electrophilic position of the enone, which is located far from the bisoxazoline substituent, resulting in low enantioselectivity. Indeed, Mezzetti reported successful [2+2] cycloadditions of ynamides using a chiral ruthenium complex.[8c] However, the choice of substrate was limited to the b-keto ester of cyclopentenone and heating was required to remove the product from the catalyst, indicating the difficulty in the catalytic asymmetric [2+2] cycloadditions. We recently reported [4+2] cycloadditions and Hosomi–Sakurai reactions of cyclic a-alkylidene b-oxo imides.[9] Both the reactions proceeded in high yields and enantioselectivities. For example, the [4+2] cycloaddition of imide 1 a in the presence of a catalytic amount of bisoxazoline–Cu(OTf)2 afforded the product in an excellent yield and enantioselectivity. a-Alkylidene b-oxo imides are interesting compounds because the acidic imide hydrogen can form an intramolecular hydrogen bond (complex A, Figure 1), which was suggested by X-ray crystallographic analysis and NMR studies,[9] leading to a rigid conformation. Therefore, the two imide carbonyls act as a bidentate ligand to form a chelate. Thus, complex A would result in the clear differentiation of the two enantiotopic faces of the reacting double bond, due to its proximity to the
Four-membered carbocyclic compounds are important because they have been used as synthetic intermediates that allow the formation of new bonds and stereogenic centers through the ring-opening reaction[1] and, moreover, they can be found as a part of the structures of bioactive natural products.[2] Consequently, great effort has been put into developing efficient methods for the preparation of cyclobutanes. The preparation of four-membered carbocyclic rings largely depends on photochemical [2+2] cycloadditions because concerted thermal [2+2] cycloadditions are symmetrically forbidden in the usual suprafacial process.[3] However, stepwise formal [2+2] cycloadditions that afford four-membered carbocyclic compounds have been reported and, among them, the Ficini reaction, a stepwise thermal [2+2] cycloaddition of an ynamine with an enone to form aminocyclobutenes (Scheme 1), has drawn the attention of synthetic chemists because of its versatility and the utility of the product.[4] However, the synthetic application of the Ficini reaction has been limited, probably because of practical problems in the preparation, handling, and storage of reactive ynamines.[5] To improve the applicability of the Ficini reaction, [2+2] cycloadditions of enones with ynamides[5, 6] were studied, the first [a] K. Enomoto, H. Oyama, Prof. Dr. M. Nakada Department of Chemistry and Biochemistry School of Advanced Science and Engineering, Waseda University 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555 (Japan) Fax: (+ 81) 3-5286-3240 Home page: http://www.chem.waseda.ac.jp/nakada/ E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201406189. Chem. Eur. J. 2014, 20, 1 – 6
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Communication Table 1. Effect of varying bisoxazoline ligands (L1–L5) on catalytic asymmetric [2+2] cycloaddition of 1 a with 2 a.[a]
Figure 1. Proposed structures of complexes A and B.
bisoxazoline substituent. However, in complex B, which is a square-planar complex[10] formed by the cyclic a-alkylidene b-oxo ester and a bisoxazoline-CuII catalyst, the reacting double bond lies on the pseudo-C2 axis, cutting through the Cu atom and the bisoxazoline ligand to be located far from the bisoxazoline substituent, resulting in low enantioselectivity. We studied the applicability of cyclic a-alkylidene b-oxo imides to the formal [2+2] cycloaddition and herein report the highly enantioselective catalytic asymmetric [2+2] cycloadditions of cyclic a-alkylidene b-oxo imides with ynamides. Hsung and co-workers used a catalytic amount of CuCl2 and AgSbF6 for the [2+2] cycloadditions of ynamides, which proceeded to completion below 0 8C and within 1 h.[7] The catalytic activity of the bisoxazoline-ligated cationic CuII salt decreases because the bisoxazoline ligand is basic and bulky, and ynamides are unreactive.[11] However, the [2+2] cycloaddition of aalkylidene b-oxo imides with ynamides was expected to proceed because a-alkylidene b-oxo imides, on account of the two electron-withdrawing groups attached, are highly reactive. Moreover, the NH bond is acidified upon coordination and thus activates the enone system. Therefore, we investigated the reaction of a-alkylidene boxo imide 1 a with ynamide 2 a[12] (Table 1). Because the use of the bisoxazoline ligand and CuII salt was effective in the [4+2] cycloadditions of 1 a, the reaction of 1 a with 2 a was carried out using L1–Cu(OTf)2 (20 mol %; Table 1, entry 1) and, at 0 8C, was completed after 9 h to afford 3 aa in 65 % yield with 88 % ee. Interestingly, this reaction also afforded the [4+2] cycloadduct 4 aa in 18 % yield with 99 % ee, similar to the products obtained by Evans and co-workers. in the Mukaiyama–Michael reaction.[13] The reaction of 1 a with 2 a was also carried out using bisoxazoline ligands L2–L4 alongside Cu(OTf)2 (Table 1, entries 2–4), but the yield, ee, and ratio of 3 aa/4 aa were almost unchanged. However, the reaction of 1 a with 2 a using Ishihara’s ligand L5[14] proceeded to completion within 20 minutes to afford ent-3 aa in 92 % yield with 91 % ee, without forming ent-4 aa (Table 1, entry 5). The high 3 aa selectivity on using ligand L5 could be explained by the fact that the two amide substituents of L5 coordinate with the CuII catalyst at the apical position,[14] which causes steric strain between the apical amide group and 2 a in the transition state of the [4+2] cycloaddition with 2 a. Finally, the reaction using 10 mol % of L5–Cu(OTf)2 at 60 8C afforded ent-3 aa in 97 % yield with 96 % ee (Table 1, entry 6). Compound ent-3 aa was highly crystalline and suitable for Xray crystallographic analysis.[15] The crystal structure of ent-3 aa &
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Entry 1 2 3 4 5 6[f]
Ligand L1 L2 L3 L4 L5 L5
Time [h] 9 9 9 9 20 min 10
3 aa Yield [%][b] 65 67 66 67 92 97
3 aa ee [%][c]
4 aa Yield [%][b]
88 87 90 83 91[e] 96[e]
18[d] 19 19 15 0 0
[a] Reaction conditions: 1 a (1.0 equiv), 2 a (1.5 equiv), Ligand–Cu(OTf)2 (20 mol %), MS 4 , CH2Cl2, 0 8C; [b] yield of isolated product; [c] determined by HPLC analysis using a chiral stationary phase; [d] 99 % ee; [e] ent3 aa. [f] 10 mol % of catalyst was used at 60 8C.
Figure 2. X-ray crystal structure of ent-3 aa. Thermal ellipsoids are set at 50 % probability.
(Figure 2) indicates that complex A in Figure 1 rationally explains the sense of induction; the reaction occurs at the lesshindered enantioface of 1 a in complex A. Next, the reaction of 1 a was investigated with various derivatives of ynamide 2 a (2 b–e, Table 2). The result of the reaction with 2 a at 0 8C is shown in Table 2, entry 1, for comparison. The reaction of 1 a with 2 b (R3 = Me) required 5 h to afford ent-3 ab in 80 % yield with 86 % ee (Table 2, entry 2). The reactions with 2 c and d were slow, probably owing to the steric 2
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Communication 0 8C, to afford ent-3 bb in 45 % yield and the ee was slightly decreased (83 % ee) when compared with that for the reaction of 2 b with 1 a (86 % ee; Table 2, entry 2). The reaction of 1 c, an imide of cyclopentenone, with 2 a proceeded at 60 8C to afford ent-3 ca in 58 % yield with 86 % ee (Table 3, entry 3). The low yield was attributed to the formation of unidentified products derived from 1 c. The reaction of 1 c with 2 b was unexpectedly fast, affording ent-3 cb in 93 % yield with 88 % ee in only 9 hours (Table 3, entry 4). The relatively low ee of ent-3 ca, compared with that of ent-3 ba, was attributed to the fact that the intramolecular imide hydrogen bond was weakened in the imide of cyclopentenone. Indeed, the imide NH signal of 1 c was detected at d = 10.13 ppm, upfield of those for 1 a (d = 10.71 ppm) and 1 b (d = 10.90 ppm), which indicates that the hydrogen bond of 1 c was weakened. The formal [2+2] cycloaddition of imide 1 d, which comprises an all-carbon quaternary center vicinal to the reacting double bond, was then examined (Table 4). The reaction of 1 d was expected to be slow owing to the steric hindrance;
Table 2. Catalytic asymmetric [2+2] cycloadditions of 1 a with 2 a–e using L5–Cu(OTf)2.[a]
Entry 1 2 3 4 5
R3 H (2 a) Me (2 b) c-Hexyl (2 c) Ph (2 d) CO2Me (2 e)
Time [h]
Yield [%][b]
ee [%][c]
1 5 72 72 24
91 (ent-3 aa) 80 (ent-3 ab) 74 (ent-3 ac) 15 (ent-3 ad) –[d]
89 86 10 35 –
[a] Reaction conditions: 1 a (1.0 equiv), 2 a-e (1.5 equiv), L5-Cu(OTf)2 (10 mol %), MS 4 , CH2Cl2, 0 8C; [b] yield of isolated product; [c] determined by HPLC analysis using a chiral stationary phase; [d] No reaction.
hindrance of substituents at the alkyne terminal. The reactions of 1 a with 2 c (R3 = cyclohexyl) and 2 d (R3 = Ph) took 72 h to afford ent-3 ac (74 %, 10 % ee; Table 2, entry 3) and ent-3 ad (15 %, 35 % ee; Table 2, entry 4), respectively. The decreased yields and ee values are clearly attributed to the steric effect of the substituents at the alkyne terminal. No reaction occurred in the case of 2 e (R3 = CO2Me; Table 2, entry 5). The results summarized in Table 2 indicate that 2 a (R3 = H) and 2 b (R3 = Me) are synthetically useful. Hence, the [2+2] cycloaddition of other cyclic a-alkylidene b-oxo imides, 1 b and 1 c, were investigated using 2 a and 2 b (Table 3). The reaction of 1 b, an imide of cyclohexenone, with ynamide 2 a was carried out and ent-3 ba was formed at 40 8C in 73 % yield with 96 % ee (Table 3, entry 1). The ee in this reaction was almost the same as that for the reaction of 1 a with 2 a at 60 8C (Table 1, entry 6). The reaction of 1 b with less reactive 2 b proceeded sluggishly (Table 3, entry 2), taking 24 h, even at
Table 4. Catalytic asymmetric [2+2] cycloadditions of 1 d with 2 a and 2 b.
Entry Products Conditions 1
Table 3. Catalytic asymmetric [2+2] cycloadditions of 1 b and 1 c with 2 a and 2 b.[a]
Time Yield [%][a] ee [h] [%][b]
ent-3 da L5–Cu(OTf)2 (10 mol %), MS 4 , 48 CH2Cl2, 0 8C
2
3 da
L4–Cu(BF4)2 (10 mol %), MS 4 , 15 CH2Cl2, 20 8C
3
3 da
L4–Cu(BF4)2 (10 mol %), CH2Cl2, 20 8C
4
3 da
5
3 db
7
L4–Cu(BF4)2 (10 mol %), CH2Cl2/ 3 toluene = 1/5, 20 8C L4–Cu(SbF6)2 (10 mol %), CH2Cl2/ 22 toluene = 1/5, 0 8C
30 (at 53 % conv) 73 (at 63 % conv) 78 (at 91 % conv) quant. quant.
57
93
96
99 99
[a] Yield of isolated product; [b] determined by HPLC analysis using a chiral stationary phase.
Entry 1 2 3 4
Product
Temp [8C]
ent-3 ba ent-3 bb ent-3 ca ent-3 cb
40 0 60 40
Time [h]
Yield [%][c]
ee [%][b]
15 24 13 9
73 45 58 93
96 83 86 88
indeed, the reaction using L5–Cu(OTf)2 (10 mol %) with 2 a (3.0 equiv) proceeded slowly even at 0 8C, taking 48 h, to afford ent-3 da in 30 % yield (at 53 % conversion) with 57 % ee (Table 4, entry 1). Because the best yield, conversion, and ee in the [4+2] cycloaddition of 1 d was attained on using L4– Cu(BF4)2, the [2+2] cycloaddition of 1 d with 2 a was examined using 10 mol % of L4–Cu(BF4)2 at 20 8C. This reaction afforded 3 da after 15 h, in 73 % yield (at 63 % conversion; 37 % of starting material was recovered) with 93 % ee (Table 4, entry 2). The
[a] Reaction conditions: 1 b or 1 c (1.0 equiv), 2 a or 2 b (1.5 equiv), L5– Cu(OTf)2 (10 mol %), MS 4 , CH2Cl2 ; [b] yield of isolated product; [c] determined by HPLC analysis using a chiral stationary phase.
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Communication ee was significantly higher than for the previous reaction. The same ligand effect was not observed in the reaction with 1 a (Table 1). Hence, it is possible that the geminal dimethyl group in 1 d disturbed the transition state of the reaction when L5– Cu(OTf)2 was used. Interestingly, although other reactions resulted in inferior yield and enantioselectivity in the absence of MS 4 , the reaction of 1 d with 2 a using L4–Cu(BF4)2 in the absence of MS 4 proceeded faster, taking 7 h, and afforded 3 da in 78 % yield (at 91 % conversion) with 96 % ee (Table 4, entry 3). Finally, using a mixed solvent (1:5 CH2Cl2/toluene) increased the yield and ee of 3 da to quantitative and 99 %, respectively (Table 4, entry 4). For the reaction of 1 d and 2 b, the more catalytically active L4–Cu(SbF6)2[16] was used to accelerate the reaction owing to the low reactivity of 2 b. In this case, 3 db was quantitatively formed with 99 % ee at 0 8C (Table 4, entry 5). As described above, the [2+2] cycloaddition of the imide with an unreactive ynamide proceeds when the reacting double bond is located at the position vicinal to an all-carbon quaternary center. A ring system, like that in 3 da, comprising a geminal dimethyl group adjacent to consecutive stereogenic centers comprising an all-carbon quaternary stereogenic center is found in the structure of various terpenes (e.g., entkaurane diterpenoids). Hence, the developed catalytic asymmetric [2+2] cycloaddition could be useful for enantioselective natural product synthesis. Transformation of the imide group in the products is important for applying the developed [2+2] cycloaddition to natural product synthesis.[17] Consequently, transformation of the imide group in 3 da was investigated (Scheme 2). The reaction of 3 da using MeMgBr in MeOH[18] afforded amide 4 a in 94 % yield, which was further transformed to nitrile 4 b using trifluroacetic anhydride (TFAA) in 89 % yield. The transformation of 3 da to ester 4 c was low-yielding (27 %) owing to the preferential formation of 4 a. However, imide 3 da’, which was
formed in 98 % yield with 99 % ee using the same reaction conditions as those in Table 4, entry 4, was transformed to ester 4 c in 68 % yield on treatment with MeONa in MeOH, though formation of 4 a was not completely suppressed. Moreover, the treatment of 3 da’ with LiOH in aqueous THF resulted in the removal of the imide group to afford 4 d in 80 % yield. The transformations in Scheme 2 could make the developed catalytic asymmetric [2+2] cycloaddition useful for natural product synthesis. In summary, the highly enantioselective catalytic asymmetric [2+2] cycloaddition of cyclic a-alkylidene b-oxo imide with ynamide has been developed. The high reactivity of the cyclic a-alkylidene b-oxo imide allowed the reaction of a hindered substrate with unreactive ynamides at low temperature. X-ray crystallographic analysis of the [2+2] cycloaddition product suggested that the enantioselectivity of the [2+2] cycloaddition can be well explained by the chelate model comprising the intramolecular hydrogen bond, wherein the cyclic a-alkylidene b-oxo imide, which coordinates with CuII through two imide carbonyl groups. The imide group in the product was successfully transformed into amide, nitrile, and ester groups. Moreover, it was removable. Application of the developed catalytic asymmetric [2+2] cycloaddition to natural product synthesis is now underway in our laboratory.
Acknowledgements This work was financially supported in part by the Grant-in-Aid for Scientific Research B (25293003), by MEXT, and by a Waseda University Grant for Special Research Projects. Keywords: asymmetric catalysis enantioselectivity · imides · ynamides
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cycloadditions
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[1] For reviews, see: a) E. Lee-Ruff, G. Mladenova, Chem. Rev. 2003, 103, 1449; b) J. C. Namyslo, D. E. Kaufmann, Chem. Rev. 2003, 103, 1485. [2] V. M. Dembitsky, J. Nat. Med. 2007, 62, 1. [3] a) R. Hoffmann, R. B. Woodward, J. Am. Chem. Soc. 1965, 87, 2046; b) R. B. Woodward, R. Hoffmann, Angew. Chem. Int. Ed. Engl. 1969, 8, 781; Angew. Chem. 1969, 81, 797. [4] a) J. Ficini, A. Krief, Tetrahedron Lett. 1969, 10, 1431; b) J. Ficini, A. M. Touzin, Tetrahedron Lett. 1972, 13, 2093; c) J. Ficini, A. M. Touzin, Tetrahedron Lett. 1974, 15, 1447; d) J. Ficini, Tetrahedron 1976, 32, 1449; e) J. Ficini, S. Falou, J. d’Angelo, Tetrahedron Lett. 1977, 18, 1931; f) J. Ficini, A. Krief, A. Guingant, D. Desmaele, Tetrahedron Lett. 1981, 22, 725; g) J. Ficini, A. Guingant, J. d’Angelo, G. Stork, Tetrahedron Lett. 1983, 24, 907; h) J. Ficini, D. Desmaele, A. M. Touzin, Tetrahedron Lett. 1983, 24, 1025. [5] For a review, see: C. A. Zificsak, J. A. Mulder, R. P. Hsung, C. Rameshkumar, L.-L. Wei, Tetrahedron 2001, 57, 7575. [6] For recent reviews, see: a) G. Evano, A. Coste, K. Jouvin, Angew. Chem. Int. Ed. 2010, 49, 2840; Angew. Chem. 2010, 122, 2902; b) K. A. DeKorver, H. Li, A. G. Lohse, R. Hayashi, Z. Lu, Y. Zhang, R. P. Hsung, Chem. Rev. 2010, 110, 5064; c) T. Lu, R. P. Hsung, ARKIVOC (Gainesville, FL, U.S.) 2014, 1, 127; d) X.-N. Wang, H.-S. Yeom, L.-C. Fang, S. He, Z.-X. Ma, B. L. Kedrowski, R. P. Hsung, Acc. Chem. Res. 2014, 47, 560. [7] H. Li, R. P. Hsung, K. A. DeKorver, Y. Wei, Org. Lett. 2010, 12, 3780. [8] a) C. Schotes, A. Mezzetti, J. Am. Chem. Soc. 2010, 132, 3652; b) C. Schotes, A. Mezzetti, Chimia 2011, 65, 231; c) C. Schotes, A. Mezzetti, Angew. Chem. Int. Ed. 2011, 50, 3072; Angew. Chem. 2011, 123, 3128; d) C. Schotes, A. Mezzetti, J. Org. Chem. 2011, 76, 5862; e) C. Schotes, R.
Scheme 2. Transformations of [2+2] cycloaddition products.
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Communication
[9] [10]
[11] [12] [13] [14]
[15] CCDC-1033309 (ent-3 aa) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif. [16] D. A. Evans, J. A. Murry, P. van Matt, R. D. Norcross, S. J. Miller, Angew. Chem. Int. Ed. Engl. 1995, 34, 798; Angew. Chem. 1995, 107, 864. [17] Reported transformations of imides: a) J. K. Myers, E. N. Jacobsen, J. Am. Chem. Soc. 1999, 121, 8959; b) G. M. Sammis, E. N. Jacobsen, J. Am. Chem. Soc. 2003, 125, 4442; c) M. S. Taylor, E. N. Jacobsen, J. Am. Chem. Soc. 2003, 125, 11204. [18] D. A. Evans, M. M. Morrissey, R. L. Dorow, J. Am. Chem. Soc. 1985, 107, 4346.
Bigler, A. Mezzetti, Synthesis 2012, 44, 513; f) C. Schotes, M. Althaus, R. Aardoom, A. Mezzetti, J. Am. Chem. Soc. 2012, 134, 1331. K. Orimoto, H. Oyama, Y. Namera, T. Niwa, M. Nakada, Org. Lett. 2013, 15, 768. The bisoxazoline-CuII complex may have a distorted square-planar geometry. See: a) D. A. Evans, S. J. Miller, T. Lectka, J. Am. Chem. Soc. 1993, 115, 6460; b) D. A. Evans, S. J. Miller, T. Lectka, P. von Matt, J. Am. Chem. Soc. 1999, 121, 7559. The [2+2] cycloaddition of ynamides with cyclic isoimidium salts: Y. Yuan, L. Bai, J. Nan, J. Liu, X. Luan, Org. Lett. 2014, 16, 4316. Y.-P. Wang, R. L. Danheiser, Tetrahedron Lett. 2011, 52, 2111. D. A. Evans, K. A. Scheidt, J. N. Johnston, M. C. Willis, J. Am. Chem. Soc. 2001, 123, 4480. A. Sakakura, R. Kondo, Y. Matsumura, M. Akakura, K. Ishihara, J. Am. Chem. Soc. 2009, 131, 17762.
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Received: November 23, 2014 Published online on && &&, 0000
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Communication
COMMUNICATION & Synthetic Methods K. Enomoto, H. Oyama, M. Nakada* && – && Highly Enantioselective Catalytic Asymmetric [2+2] Cycloadditions of Cyclic a-Alkylidene b-Oxo Imides with Ynamides
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Cyclobutiful: The high reactivity of the cyclic a-alkylidene b-oxo imide allows the [2+2] cycloadditions of a hindered substrate with unreactive ynamides at
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low temperature. The imide group in the product can be transformed into amide, nitrile, or ester groups. Moreover, it is removable.
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