Qing
Gu
and
Shu-Li
You
*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai, 200032, China. E-mail: slyou@sioc.ac.cn; Fax: (+86) 21-5492-5087
First published on 19th May 2011
Desymmetrization of cyclohexadienones via aza-Michael reaction catalyzed by cinchonine derived thiourea has been realized to afford a series of highly enantioenriched pyrrolidine and morpholine derivatives in excellent yields and ees. With this newly established methodology, asymmetric total synthesis of (-)-Mesembrine in high enantiomeric excess (98% ee) was accomplished.
Development of efficient methods for the synthesis of chiral nitrogen-containing heterocyclic compounds is in great demand because of their frequent appearance in natural products and biologically interesting compounds (Scheme 1).8 Among the methods developed, the asymmetric catalytic aza-Michael reaction has become a simple and useful tool for the preparation of these compounds. Since the first example was introduced by Jørgensen in 1996,9 several asymmetric catalytic systems have been developed for this reaction.10 Despite the fact that highly enantioselective aza-Michael reactions have been known with either chiral amines11 or bifunctional thioureas12 as the catalysts, to our knowledge, the dearomatization/desymmetrization process via asymmetric aza-Michael reaction has not been reported yet (Scheme 2). As part of our ongoing program on asymmetric dearomatization reactions, herein we report the desymmetrization via asymmetric aza-Michael reaction catalyzed by cinchonine derived thiourea and their application in the total synthesis of (-)-Mesembrine.
Scheme 1 Natural products possessing a chiral pyrrolidine and piperidine moiety. |
Scheme 2 Dearomatization/desymmetrization process via asymmetric aza-Michael reaction. |
We began our investigation by testing the intramolecular aza-Michael reaction of 3a as the substrate with chiral phosphoric acid 1a as the catalyst. The aza-Michael addition proceeded in complete conversion but the cyclization product 4a was obtained with only moderate enantioselectivity (71% ee, Table 1, entry 1). We then screened cinchona alkaloid derived thioureas 1b–g, well-known as bifunctional catalysts,6b, 13 and sulfonamide 1h. With 5 mol% of thioureas (1b–g) in CH2Cl2 at room temperature, gratifyingly, all reactions proceeded smoothly to give the desired product 4a with yields from 89 to 95% and ee values from 92 to 97% (Table 1, entries 2–7). Thiourea 1b bearing 3,5-(CF3)2C6H3 derived from cinchonine proved to be the most efficient catalyst, affording 4a in 95% yield and 97% ee. Sulfonamide 1h bearing a monodentate hydrogen bond donor was found to be completely ineffective (Table 1, entry 8). Both cinchonine and quinine alone afforded product in moderate yields and ees (24% yield, 29% ee and 75% yield, 29% ee, Table 1, entries 9 and 10, respectively). The results indicate the importance of double hydrogen bonding interactions. Varying solvents disclosed that CH2Cl2 was the optimal one. Further screening of other reaction parameters including substrate concentration, reaction temperature and catalyst loading did not improve the results (for details, see the ESI†).
Entry | Catalyst 1 (Ar, X) | Time (h) | Yield (%)b | ee (%)c |
---|---|---|---|---|
a Reaction conditions: 5 mol% of catalyst, 0.1 mol L−13a in CH2Cl2 at room temperature. b Isolated yields. c Determined by HPLC analysis (chiralpak AD-H). d Conversion determined by 1H NMR. | ||||
1 | 1a | 20 | 99 d | 71 |
2 | 1b (3,5-(CF3)2C6H3, S) | 12 | 94 | 97 |
3 | 1c (C6H5, S) | 60 | 89 | 93 |
4 | 1d (4-FC6H4, S) | 36 | 95 | 95 |
5 | 1e (4-CF3C6H4, S) | 24 | 95 | 95 |
6 | 1f (3,5-(CF3)2C6H3, O) | 20 | 94 | 94 |
7 | 1g (3,5-(CF3)2C6H3, S) | 12 | 95 | 92 |
8 | 1h | 6 days | NR | ND |
9 | cinchonine | 24 | 24d | 29 |
10 | quinine | 24 | 75 | 29 |
With the optimized conditions in hand, the reaction scope for the synthesis of pyrrolidine derivatives was investigated. The results are summarized in Table 2. As seen from the results, the nitrogen protecting groups have great effect on both reactivity and enantioselectivity (Table 2, entries 1–4). Acidic N–H14 was required for the reactivity since it could be easily deprotonated by the tertiary amine of the bifunctional catalyst 1b. When Ts was used as a protecting group, the best yield and enantioselectivity were obtained (94% yield and 97% ee, Table 2, entry 1). To our great delight, regardless of the substituent R in the 4-position of cyclohexadienones, all the asymmetric aza-Michael reaction proceeded smoothly to afford pyrrolidine derivatives with excellent enantioselectivities (89–99% ees, Table 2, entries 5–11). The substrate 3j, bearing an acetamide substituent, gave the best ee (99% ee, Table 2, entry 10). In addition, substrate 3k, with a bulky aromatic group, also gave the cyclization product in 91% yield and 97% ee (Table 2, entry 11). The ee values of product 4a were invariable during the reaction by examining the ee at different conversions. When racemic 4a was subjected to the optimal conditions with 5 mol% of 1b, the product 4a was recovered as a racemic compound. These two experiments suggest that the aza-Michael addition reaction is not reversible under our conditions. The one-pot dearomatization/desymmetrization process was also explored for the synthesis of 4e. After the dearomatization reaction (N-(4-hydroxyphenethyl)-4-methylbenzenesulfonamide with PhI(OAc)2 in MeOH), the solvent was removed and then the residue was treated with 5 mol% of 1b in CH2Cl2. The product 4e was obtained in 28% overall yield and 95% ee.
Entry | 3: R, Pg | Time (h) | Yield (%)b | ee (%)c |
---|---|---|---|---|
a Reaction conditions: 5 mol% of 1b, 0.1 mol L−13 in CH2Cl2. b Isolated yields. c Determined by HPLC analysis. d 10 mol% of 1b. | ||||
1 | 3a: OH, p-Ts | 12 | 94 | 97 |
2 | 3b: OH, Ms | 72 | 26 | 80 |
3 | 3c: OH, p-Ns | 60 | 75 | 87 |
4 | 3d: OH, Boc | 72 | NR | ND |
5 | 3e: OMe, Ts | 10 | 83 | 94 |
6 | 3f: OEt, Ts | 24 | 89 | 90 |
7d | 3g: O(CH2)2OH, Ts | 15 | 88 | 89 |
8 | 3h: O(CH2)3OH, Ts | 36 | 80 | 97 |
9 | 3i: OAc, Ts | 48 | 75 | 89 |
10 | 3j: NHAc, Ts | 24 | 70 | 99 |
11 | 3k: 3,4-(MeO)2C6H3, Ts | 10 | 91 | 97 |
For substrate 6a, readily prepared from 4-phenyl phenol, the desired product was obtained in a low yield (20%) but with high ee (97%) under the above reaction conditions. After further optimizing the reaction conditions (for details, see the ESI†), the aza-Michael adduct 7a was obtained in excellent yield and ee when the reaction was carried with 20 mol% of 1b in CH2Cl2 at 40 °C. As summarized in Table 3, the reaction was general for substrates 6 bearing different aromatic groups at the 4-position. The substrates 6a–g, containing either an electron-donating group or an electron-withdrawing group on the phenyl ring, all led to their desired cyclization products in 76–97% yields and 93–98% ees (Table 3, entries 1–7). The alkyl group in the 4-position of cyclohexadienones can also be well tolerated and the bulkiness of the group has great influence on the reactivity (Table 3, entries 8–11). The reactivity was significantly decreased when sterically more hindered group was introduced (Me, 96% yield; Et, 97% yield; i-Pr, 73% yield; t-Bu, NR). In the case of substrates 6h–j, excellent ees were obtained for the cyclization products.
Entry | 6: R | Time (h) | Yield (%)b | ee (%)c |
---|---|---|---|---|
a Reaction conditions: 20 mol% of 1b, 0.5 mol L−16 in CH2Cl2 at 40 °C. b Isolated yields. c Determined by HPLC analysis. | ||||
1 | 6a: C6H5 | 72 | 82 | 97 |
2 | 6b: 2-MeC6H4 | 84 | 76 | 95 |
3 | 6c: 3-MeC6H4 | 84 | 79 | 98 |
4 | 6d: 4-MeC6H4 | 72 | 96 | 96 |
5 | 6e: 4-FC6H4 | 72 | 97 | 98 |
6 | 6f: 4-ClC6H4 | 72 | 96 | 96 |
7 | 6g: 4-BrC6H4 | 72 | 84 | 93 |
8 | 6h: Me | 60 | 96 | 97 |
9 | 6i: Et | 72 | 97 | 97 |
10 | 6j: i-Pr | 96 | 73 | 96 |
11 | 6k: t-Bu | 96 | NR | ND |
The multifunctionalized products obtained here could undergo versatile transformations. As shown in Scheme 3, product 4g bearing another nucleophilic moiety can undergo oxo-Michael addition in the presence of catalytic amount of p-TsOH affording a spiro-tricyclic compound 8. Hydrogenation of 4a afforded ketone 10 in 95% yield. In both cases, the products were obtained without loss of the optical purity. To determine the absolute configuration of the products, crystals of enantiopure 9 (>99% ee after recrystallization, Scheme 3) derived from 4a were obtained and single crystal X-ray analysis revealed the configuration to be (3aS, 7aS) (see the ESI†).
Scheme 3 Derivatization of the aza-Michael adducts. |
(-)-Mesembrine,15 isolated as the major alkaloid component of Sceletium tortuosum, has been found to have potent serotonin re-uptake inhibitor activity.16 Due to its interesting biological activity, (-)-Mesembrine has received extensive synthetic studies during the past several decades.17 The main challenge in the synthesis of (-)-Mesembrine is the installation of sterically congested chiral arylated quaternary carbon center. Although remarkable progress has been made for its enantioselective total syntheses, most of them employed chiral auxiliaries strategy17b–n rather than asymmetric catalysis.17o–t As a further demonstration of the utility of our newly developed desymmetrization process via intramolecular aza-Michael reaction, a concise total synthesis of (-)-Mesembrine was developed as shown in Scheme 4. The product 4k was hydrogenated under 1 atm H2 at room temperature to afford saturated ketone 14 in 91% yield. Subjecting ketone 14 to NaBH4 in CH3OH, followed by removal of the tosyl group using sodium naphthalenide, N-methylation,18 and Jones oxidation, led to (-)-Mesembrine in 35% yield over four steps with 98% ee. The synthetic (-)-Mesembrine has spectral characteristics identical to those reported in the literatures.
Scheme 4 Total synthesis of (-)-Mesembrine. |
In summary, we have developed cinchonine-derived thiourea catalyzed desymmetrization of cyclohexadienones via asymmetric aza-Michael reaction, affording a series of highly enantioenriched pyrrolidine and morpholine derivatives in excellent yields and ees. In addition, the utility of this method has been demonstrated in the total synthesis of (-)-Mesembrine. The application of the current methods in the total syntheses of other natural products is currently underway in our lab.
Footnote |
† Electronic supplementary information (ESI) available: Experimental procedures and analysis data for new compounds, CIF file of 9. CCDC reference number 805906. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c1sc00083g |
This journal is © The Royal Society of Chemistry 2011 |