b State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
(-)-Swainsonine (Fig. 1) is an indolizidine alkaloid that is also classified as an azasugar (imino sugar) [1]due to the presence of three hydroxyl groups in the molecule. After its first isolation in 1973 from the fungus Rhizoctomia leguminicola [2a],it has also been extracted from diverse fungi and numerous species of flowering plants [2b,1a]. As an azasugar,(-)-swainsonine exhibits lysosomal a-mannosidase and mannosidase II inhibitory properties. Although the pharmacological properties of this product have not been fully investigated,it has been tested as a treatment for cancer [3],HIV,and immunological disorders [1,4a]. The important biological properties of swainsonine have attracted the interest of many synthetic and medicinal chemists. Numerous methods have been developed for the stereoselective synthesis of swainsonine and its diastereomers [4, 5, 6, 7]. In connection with a general program on the development of efficient and general methodologies for the synthesis of N-containing bioactive compounds and alkaloids [8], we became interested in the stereoselective synthesis of (-)- swainsonine,and have recently reported the synthesis of two diastereomers of (-)-swainsonine [9]. We now report a short formal stereoselective synthesis of (-)-swainsonine.
A survey of literature revealed that among the many approaches to swainsonine [4, 5, 6, 7],the unsaturated indolizidine derivatives 2 [5],3 [6a],and 4 [6b]proved to be reliable advanced intermediates for the synthesis of swainsonine (Scheme 1). Since indolizidine 2 is a silica gel sensitive compound [5d],we chose the unsaturated indolizidine 3 as our target in view of developing a short formal stereoselective synthesis of (-)-swainsonine.
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| Scheme 1.Typical synthetic approaches to (-)-swainsonine based on the unsaturated indolizidines 2-4. | |
To a solution of anhydrous zinc chloride (1.0 mol/L in diethyl ether,3.6 mL. 3.6 μmol) in dichloromethane (0.5 mL) was added dropwise an Et2O solution of vinylmagnesium bromide (1.0 mol/L in diethyl ether,6.0 mL,6.0 μmol). The mixture was stirred at room temperature under nitrogen for 30 min. A solution of a diastereomeric mixture of sulfone 8 (1.16 g,3.01 μmol) in anhydrous dichloromethane (8 mL) was added and the mixture was stirred at room temperature for 14-16 h. The reaction was quenched with a saturated aqueous NH4Cl and the resulting mixture was extracted with dichloromethane (3×25 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: EtOAc/ PE = 1/4) to give an inseparable diastereomeric mixture of trans-7 and cis-7 as a colorless oil (612 mg,combined yield: 75%,trans/ cis = 6/1). IR (film,cm-1): νmax 2925,1723,1652,1457,1403,1358, 1266,1076,922,730,698; 1HNMR(400 MHz,CDCl3): δ(data of the major diastereomer read from the spectrum of the diastereomeric mixture) 1.96 (dt,2H,J = 8.8,4.4 Hz),2.35 (dt,1H,J = 18.0,4.4 Hz), 2.65 (dt,1H,J = 18.0,9.6 Hz),3.18 (dd,1H,J = 15.6,7.2 Hz),3.65 (dd,1H,J = 5.6,2.8 Hz),4.11 (d,1H,J = 5.6 Hz),4.56 (d,1H, J = 12.8 Hz),4.60 (d,1H,J = 12.8 Hz),4.77 (dt,1H,J = 15.6,2.0 Hz), 5.11-5.29 (m,4H),5.61-5.79 (m,1H),7.26-7.35 (m,5H); 13C NMR (100 MHz,CDCl3): δ 21.4,27.1,47.1,62.2,70.3,73.9,116.9,118.2, 127.4 (2C),127.7,128.4 (2C),132.9,135.8,138.0,169.6; HRESIMS calcd. for [C17H21NNaO2]+ (M+Na+): 294.1465; found: 294.1470.
A solution of a diastereomeric mixture of 6-vinylpiperidin-2- one 7 (116.7 mg,0.43 μmol) in degassed CH2Cl2 (8 mL) containing Grubbs second generation catalyst 10 (36 mg,0.043 μmol) was stirred for 12 h at refluxing. The solution was concentrated and the resulting residue was purified by flash chromatography on silica gel (eluent: EtOAc/PE = 1/3) to give trans-6 (83 mg,yield: 80%) and cis-6 (14 mg,yield: 13%).
trans-6: colorless oil. [α]D20 -110.1 (c 0.33,CHCl3); IR (film, cm-1): νmax 2925,2847,1648,1611,1441,1407,1096,1063,740, 698; 1H NMR (400 MHz,CDCl3): d 1.78-1.88 (m,1H),2.17-2.23 (m, 1H),2.40 (dt,1H,J = 17.6,8.0 Hz),2.62 (ddd,1H,17.6,8.0,4.8 Hz), 3.41 (ddd,1H,J = 14.4,9.2,5.6 Hz),4.04 (d,1H,J = 16.0 Hz),4.27- 4.28 (m,1H),4.44 (dt,1H,J = 16.0,2.2 Hz),4.52 (d,1H,J = 11.6 Hz), 4.68 (d,1H,J = 11.6 Hz),5.88-5.93 (m,1 H),6.01-6.05 (m,1H), 7.28-7.38 (m,5H); 13C NMR (100 MHz,CDCl3): d 26.4,29.7,52.9, 67.4,71.3,77.1,126.9,127.7 (2C),127.9,128.3,128.5 (2C),137.9, 168.7; HRESIMS calcd. for [C15H17NNaO2]+ (M+Na+): 266.11515; found: 266.11514.
cis-6: colorless oil. [α]D20 -8.5 (c 0.8,CHCl3) {[α]D20 -8.4 (c 1.31, CHCl3) [14]}; 1HNMR(400 MHz,CDCl3): d 1.77-1.98 (m,1H),2.09- 2.26 (m,1H),2.44-2.57 (m,2H),3.93-3.98 (m,1H),4.05 (d,1H, J = 16.0 Hz),4.39-4.45 (m,1H),4.49 (d,1H,J = 12.4 Hz),4.59 (dt, 1H,J = 16.0,2.4 Hz),4.60 (d,1H,J = 12.4 Hz),5.76-5.81 (m,1H), 5.93-5.98 (m,1H),7.25-7.36 (m,5H); 13C NMR (100 MHz,CDCl3): d 24.8,27.0,53.0,68.0,70.5,70.7,127.0,127.3,127.4 (2C),127.7, 128.4 (2C),138.3,169.1; HRESIMS calcd. for [C15H17NNaO2]+ (M+Na+): 266.11515; found: 266.11515.
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| Fig. 1.The structure of (-)-swainsonine (1). | |
To an ice-cooled,stirred solution of indolizidinone trans-6 (25.9 mg,0.11 μmol) in THF (2 mL) was added LiAlH4 (20.0 mg, 0.53 μmol),and the mixture was stirred at room temperature for 4 h. The reaction was quenched with a saturated aqueous NaHCO3 at 0℃. The resulting slurry was filtered through a celite pad and washed with EtOAc (5 mL). The filtrate was extracted with EtOAc (3× 5 mL),and the combined organic extracts were dried over anhydrous Na2SO4,filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (EtOAc/PE = 1/1) to give compound 3 (22 mg,yield: 89%) as a colorless oil: [α]D20 -115 (c 1.0,CHCl3) {[α]D20 -115 (c 3.85, CHCl3) [6a]}; IR (film,cm-1): νmax 3058,3029,2925,2851,2772, 2751,1635,1494,1449,1192,1088,889,731,694; 1H NMR (400 MHz,CDCl3): δ 1.14-1.32 (m,1H),1.52-1.74 (m,2H),2.20 (ddd,1H,J = 11.7,7.1,3.9 Hz),2.43 (dt,1H,J = 11.4,3.2 Hz),2.94 (dd,1H,J = 11.4,3.6 Hz),2.97-3.04 (m,1H),3.23-3.32 (m,2H),3.63 (d,1H,J = 13.2 Hz),4.54 (d,1H,J = 12.0 Hz),4.66 (d,1H,J = 12.0 Hz), 5.89 (ddd,1H,J = 6.0,4.0,2.0 Hz),6.14 (dd,1H,J = 6.0,0.8 Hz), 7.20-7.36 (m,5H); 13C NMR (100 MHz,CDCl3): δ 24.2,30.4,48.9, 57.7,71.0,72.1,78.5,127.5,127.6 (2C),128.4 (2C),128.8,131.4, 138.9; HRESIMS calcd. for [C15H20NO]+ (M+H+): 230.1539; found:230.1540.
Our retrosynthetic analysis of indolizidine 3 is outlined in Scheme 2. The essential of this analysis resides on the use of (R)- benzyloxyglutarimide (5),a versatile chiral building block developed from our laboratory as a source of chirality for (-)- swainsonine [10]. Indolizidine 3 can be derived from indolizidinone 6. The pyrroline moiety in indolizidinone 6 is accessible by the RCM reaction from diene 7 [11],and one vinyl group in 7 can be introduced by the Ley’s sulfone-based chemistry [12].
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| Scheme 2.Retrosynthetic analysis of indolizidine 3. | |
The synthesis commenced with the regio- and diastereoselective reduction [10a]of the known chiral building block (R)- benzyloxyglutarimide 5 [10b](NaBH4,THF,-30℃,10 min),which produced the hemiaminal 9 as a diastereomeric mixture (dr = 11:1) in a combined yield of 82% (Scheme 3). The major diastereomer was tentatively assigned as cis in light of our previous results on a similar system [10b]. Without separation,the diastereomeric mixture [13, 14]of 9 was treated with phenylsulfinic acid and CaCl2 [12a]in CH2Cl2 at r.t. for 2 h to give the sulfone 8 in a yield of 86%. Although sulfone 8 was obtained as an inseparable diastereomeric mixture,the diastereomeric mixture can be used in the next step without separation. The subsequent reaction is considered to pass through an N-acyliminium intermediate [10, 13],either diastereomer could give the same N-acyliminium ion. On standing at -20℃ for two weeks,the minor diastereomer in the diastereomeric mixture was epimerized gradually and completely to give the trans-diastereomer. This is in accordance with the phenomenon we observed previously on the corresponding 5-phenylsulfonyl-pyrrolidin-2-one homologue [12b]. Reaction of the diastereomeric mixture of 6-phenylsulfonyllactam 8 with organozinc reagent,generated in situ from vinylmagnesium bromide and a 1.0 mol/L solution of anhydrous ZnCl2 in diethyl ether [12b],at r.t. for 14-16 h yielded 6- vinyllactam 7 in 75% yield as an inseparable 6:1 diastereomeric mixture (determined by 1H NMR). The stereochemistry of the major diastereomer was tentatively deduced as trans based on our previous results with the pyrrolidinone homologous [12b,12d], which was confirmed by converting the diastereomeric mixture 7 into the known compounds cis-6 [14]and 3 [6a],respectively.
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| Scheme 3.Formal stereoselective synthesis of (-)-swainsonine (1). | |
We next investigated the RCM reaction [8b,11]. Treatment of the diastereomeric mixture of diene 7 with Grubbs second generation catalyst [15]10 in CH2Cl2 at reflux produced the desired unsaturated indolizidinones trans-6 and cis-6 (ratio = 6:1) in a combined yield of 93%. The physical and spectral data of cis-6 match those reported {[α]D20 -8.5 (c 0.8,CHCl3); [α]D20 -8.4 (c 1.31, CHCl3) [15]}. Reduction of indolizidinone trans-6 with LiAlH4 in THF provided the known unsaturated (8R,8aS)-indolizidine (3) in an 89% yield. The physical and spectral (1H NMR and 13C NMR) data of the synthetic indolizidine 3 are in agreement with those reported {[α]D20 -115 (c 1.0,CHCl3); [α]D20 -115 (c 3.85,CHCl3)} [6a]. Thus,the stereochemistry assigned for trans-6 and cis-6 was further confirmed. Since the unsaturated indolizidine (8R,8aS)-3 has been converted by Pyne and co-workers in four steps into (-)- swainsonine (1) [6a],our synthesis thus constitutes a short formal stereoselective synthesis of this alkaloid.
In summary,we have developed a five-step synthesis of the unsaturated indolizidine (8R,8aS)-3,and thus accomplished a short formal stereoselective synthesis of (-)-swainsonine (1). Through this work,we have demonstrated that a combination of the versatile building block (R)-5 with the Ley’s-sulfone chemistry and the RCM reaction constitutes a powerful method for a rapid access to the highly functionalized 8-oxygenated indolizidin-5-one 6, which may be used as a versatile intermediate for the stereoselective synthesis of other hydroxylated indolizidine alkaloids.
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