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Enantioselective access to (−)-indolizidines 167B, 209D, 239AB, 195B and (−)-monomorine from a common chiral synthon
Tetrahedron 68 (2012) 145e151
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Enantioselective access to ()-indolizidines 167B, 209D, 239AB, 195B and ()-monomorine from a common chiral synthon Chada Raji Reddy *, Bellamkonda Latha, Nagavaram Narsimha Rao Organic Chemistry Division-I, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history: Received 18 July 2011 Received in revised form 20 October 2011 Accepted 22 October 2011 Available online 29 October 2011
An enantioselective access to ()-indolizidine alkaloids 167B, 209D, 239AB, 195B and ()-monomorine from a new chiral synthon is described. The use of (S)-3-(Cbz-amino)-4-(tert-butyldimethylsilyloxy) butanal, obtained from L-aspartic acid, has provided efficient access of the indolizidine frame work through a HornereWadswortheEmmons reaction and reductive cyclization as the key steps. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Indolizidine alkaloid Chiral synthon HornereWadswortheEmmons reaction Reductive cyclization
1. Introduction The synthesis of indolizidine alkaloids has stimulated considerable efforts due to the frequent presence of indolizidine ring system in naturally occurring bio-active molecules.1 Of particular interest are 5-substituted and 3,5-disubstituted indolizidines due to their biological activities.2 Although numerous enantioselective syntheses are known for these indolizidines,3 the development of new strategies using a common chiral synthon having distinct absolute stereochemistry and functional attributes for structural elaboration is of interest. In continuation of our work on the synthesis of bio-active molecules,4 we wish to report an expedient general strategy toward the synthesis of ()-indolizidines 167B,5 209D,6 239AB,7 195B3b,8 and ()-monomorine9 (Fig. 1) using a new chiral synthon,10 derived from L-aspartic acid. We hypothesized that (S)-3-(Cbz-amino)-4-(tert-butyldimethylsilyloxy)butanal (7) would be a suitable chiral synthon having an aldehyde functionality for accessing 5-substituted and 3,5-disubstituted indolizidines via a HornereWadswortheEmmons (HWE) reaction followed by reductive cyclization as the key steps (Scheme 1). The desired stereocenters in indolizidine scaffold can be created as follows: (i) C-5 stereocenter from the chirality of the synthon (ii) the C-9 configuration through reductive amination (iii) the C-3 chirality via proline-catalyzed a-hydroxylation. Further, the choice of benzyloxy carbonyl (Cbz) protection would allow its
* Corresponding author. Tel.: þ91 040 27191885; fax: þ91 040 27160512; e-mail address: [email protected] (C.R. Reddy). 0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2011.10.076
Fig. 1. Structures of ()-indolizidines 167B, 209D, 239AB, 195B and ()-monomorine.
removal during the reductive cyclization step and the tert-butyldimethyl silyl (TBS) group was expected to be stable throughout the sequence of reactions and can then be removed after the construction of indolizidine frame work for further structural elaboration.
2. Results and discussion In order to verify the hypothesis, initially chiral synthon 7 was prepared from a known ester 6, obtained in four steps from Laspartic acid.11 Reduction of compound 6 using DIBAL-H delivered the requisite aldehyde 7 in 90% yield. The aldehyde was prepared
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Scheme 1. Proposed strategy for ()-indolizidines 167B, 209D, 239AB, 195B and ()-monomorine.
on a several-gram scale without any difficulty and found to be stable at rt for several months (Scheme 2).
Scheme 3. Formal total synthesis of ()-indolizidine 167B and 209D.
Scheme 2. Synthesis of chiral synthon 7.
Having the desired new chiral synthon in hand, next the construction of indolizidine ring was studied with the syntheses of ()-indolizidine 167B and 209D in mind. The other subunit needed for HWE olefination, 5-hydroxy-2-oxo-pentylphosphonic acid dimethyl ester (9),12 was easily prepared from g-butyrolactone (8) in one-step.13 Now, the chiral synthon 7 was subjected to HWE olefination with b-keto phosphonate 9 to afford the key enone 10 in 89% yield, a precursor for reductive cyclization. Exposure of 10 to 10% Pd/CeH2 (gas) in EtOH provided piperidine 11 in 90% yield. This hydrogenation reaction involves four transformations in single step: (a) olefin reduction, (b) Cbz-removal, (c) intramolecular cyclic imine formation, and (d) stereoselective reduction of the imine to give piperidine 11 exclusively as cis-isomer. The formation of cis-11 was confirmed at later stage (converting alcohol 13 to known acetyl derivative)5f by NOE experiments.14 Further, to achieve the indolizidine scaffold, compound 11 was treated with Et3N/ MsCl at 0 C under which the free hydroxyl group was mesylated followed by in situ cyclization furnishing the indolizidine 12 in 92% yield. TBS deprotection of 12 using 0.1 M HCl in EtOH provided compound 13 in 85% yield, which has previously been converted to ()-indolizidine 167B and 209D in a known two step sequence (Scheme 3).5f After the above success, we decided to apply a similar strategy for the synthesis of 3,5-disubstituted indolizidine alkaloids, ()-indolizidine 239AB, 195B and ()-monomorine from chiral synthon 7. Following the retrosynthetic approach depicted in Scheme 1, the desired phosphonate partner for the HWE reaction was accessed from n-hexanal 14. Compound 14 was subjected to asymmetric a-aminoxylation (PhNO/D-proline/DMSO) followed by HWE reaction with ethyl 2-(diethoxyphosphoryl)acetate (DBU/LiCl/ CH3CN) in one-pot to obtain g-aminoxy a,b-unsaturated ester, which was subsequently exposed to hydrogenation conditions (10% Pd/CeH2 in EtOAc) to provide 3-hydroxy ethyl octanoate 15 (94% ee)15 in 62% yield (over three operations).16a The reaction of 15 with
dimethyl methylphosphonate in the presence of n-BuLi in THF afforded the b-keto phosphonate 16 in 63% yield.12 Phosphonate 16 was used for the HWE olefination with chiral synthon 7 to provide enone 17 in 87% yield. The concomitant one-pot hydrogenationecyclization reaction (H2/PdeC, rt) of 17 gave 2,6disubstituted piperidine 18 in 83% yield. Compound 18 underwent a second cyclization in the presence of Et3N/MsCl followed by TBS deprotection to afford 3,5-disubstituted indolizidine 19 in 78% yield (over two steps) with excellent stereoselectivity (Scheme 4).
Scheme 4. Synthesis of 3,5-disubstituted indolizidine 19.
The key indolizidine subunit 19 was further utilized to complete the synthesis of ()-indolizidine 239AB and 195B. Thus, alcohol 19 was oxidized to the corresponding aldehyde using ParikheDoering conditions, which upon exposure to (ethoxycarbonylmethylene) triphenyl phosphorane gave the a,b-unsaturated ester 20 in 74% yield over two steps. Saturation of olefin 20 under atmospheric pressure of H2 in the presence of 10% Pd/C and subsequent reduction of the ester using LiAlH4 in THF completed the total syn7 thesis of ()-indolizidine 239AB (½a30 D 92, c 0.4, MeOH) (3) in 85%
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yield (Scheme 5). Similarly, compound 19 was subjected to a two step sequence of transformations involving (i) conversion of alcohol 19 to chloride 21 (ii) reduction of chloro methyl to methyl 3b,8 group, to obtain ()-indolizidine 195B (½a27 D 61, c 0.5, MeOH) (4) in 64% yield (over two steps) (Scheme 6).
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using a stable and scalable new chiral synthon, obtained from Laspartic acid. The formal synthesis of ()-indolizidine 167B, 209D and total synthesis of ()-indolizidine 239AB, 195B and ()-monomorine have been successfully accomplished in good yield. Further, applications of this strategy using a new chiral synthon in the synthesis of indolizidine as well as piperidine alkaloids are currently underway. 4. Experimental section 4.1. General 1
Scheme 5. Synthesis of ()-indolizidine 239AB (3).
Scheme 6. Synthesis of ()-indolizidine 195B (4).
With the efficient routes established for enantioselective synthesis of ()-indolizidine 167B, 209D, 239AB, and 195B from a common chiral synthon, the stereoselective synthesis of unnatural ()-monomorine, C3-epimer of ()-indolizidine 195B, was also pursued. The desired g-hydroxy ester 15a was obtained from n-hexanal 14 using L-proline (94% ee).16b,17 The ester 15a was then 9 converted to ()-monomorine 5 (½a28 D 30.5, c 0.9, n-hexane) following the same sequence of reactions carried out for ()-indolizidine 195B (4) (Scheme 7).
Scheme 7. Synthesis of ()-monomorine (5).
3. Conclusion In summary, an efficient and general route for the stereoselective synthesis of indolizidine alkaloids has been developed
H NMR and 13C NMR spectra were recorded in CDCl3 solvent on 300 MHz or 75 MHz spectrometer at ambient temperature. Chemical shifts d are given in parts per million, coupling constant J are in hertz. The chemical shifts are reported in ppm on scale downfield from TMS as internal standard and signal patterns are indicated as follows: s, singlet; d, doublet; dd, doublet of doublet, t, triplet; td, triplet of doublets; m, multiplet; br, broad peak. FTIR spectra were recorded as KBr thin films or neat. Optical rotations were measured on digital polarimeter using a 1 mL cell with a 1 dm path length. For low (MS) and High (HRMS) resolution, m/z ratios are reported as values in atomic mass units. All the reagents and solvents were reagent grade and used without further purification unless specified otherwise. Technical grade ethyl acetate and petroleum ether used for column chromatography were distilled prior to use. Tetrahydrofuran (THF) when used as solvent for the reactions was freshly distilled from sodium benzophenone ketyl and the solvents acetonitrile and dichloromethane prior to use were dried using CaH2. Column chromatography was carried out using silica gel (60e120 mesh and 100e200 mesh) or neutral Al2O3 packed in glass columns. All the reactions were performed under an atmosphere of nitrogen in flame-dried or oven-dried glassware with magnetic stirring. 4.1.1. (S)-Benzyl 1-(tert-butyldimethylsilyloxy)-4-oxobutan-2ylcarbamate (7). To a mixture of 6 (2.0 g, 5.25 mmol) in anhydrous toluene (20 mL), DIBAL-H (7.8 mL, 1 M in toluene, 7.8 mmol) was added slowly at 78 C under N2. The mixture was stirred at 78 C for 10 min. After completion of the reaction (monitored by TLC) the mixture was quenched with aqueous saturated sodium potassium tartrate (20 mL), diluted with ethyl acetate (20 mL), stirred for 3 h at rt by which time two layers formed. The organic layers were separated and the aqueous layer was extracted with ethyl acetate (230 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexanes/EtOAc 7:3) to afford pure 7 (1.65 g, 90%) as a white solid. Rf (30% EtOAc/hexanes) 0.6; mp: 58e60 C; ½a27 D 10.3 (c 1.0, CHCl3); IR (KBr): vmax 3442, 2928, 2855, 2738, 1723, 1253, 1512, 1064, 837 cm1; 1H NMR (300 MHz, CDCl3) d 9.75 (s, 1H, HCO), 7.38e7.25 (m, 5H, Ph), 5.17 (br d, J¼7.9 Hz, 1H, HN), 5.06 (s, 2H, CH2ePh), 4.20e4.06 (br m, 1H, HCeN), 3.74e3.60 (m, 2H, CH2eOSi), 2.73e2.63 (br m, 2H, CH2eCO), 0.89 (s, 9H, tBu-Si), 0.04 (s, 6H, Si(CH3)2); 13C NMR (75 MHz, CDCl3): d 200.6, 155.7, 136.2, 128.5 (2C), 128.1, 128.0 (2C), 66.8, 64.3, 48.2, 45.4, 25.8 (3C), 18.2, -5.6 (2C); MS (ESI): m/z 352 (MþH)þ; HRMS (ESI): (m/z) calcd for C18H30NO4Si [MþH]þ, 352.1939; found 352.1940. 4.1.2. Dimethyl 5-hydroxy-2-oxopentylphosphonate (9)13. n-Butyl lithium (14 mL, 2.5 M in hexanes, 35 mmol) was added to a solution of dimethyl methylphosphonate (4.7 g, 38.3 mmol) in tetrahydrofuran (60 mL) at 78 C. The mixture was stirred for 1 h and the gbutyrolactone 8 (1 g, 11.6 mmol) in tetrahydrofuran (10 mL) was added drop wise. After 1 h, water (20 mL) was added, slowly
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warmed to rt and the mixture poured into dichloromethane (100 mL). The aqueous layer was extracted with dichloromethane (320 mL). The combined organic extracts were washed with water (40 mL), dried over Na2SO4, and concentrated under reduced pressure. Flash column chromatography of the residue using hexane/ethyl acetate/methanol (10:2:1) as eluent gave the b-keto phosphonate 9 (1.9 g, 80%), as a colorless oil, which present as the mixture of ketoelactol form. Rf (10% MeOH/CH2Cl2) 0.5.
1 H NMR (300 MHz, CDCl3): d 3.78 (dd, J¼5.2, 9.8 Hz, 1H, CH2eOSi), 3.38 (dd, J¼6.7, 9.8 Hz, 1H, CH2eOSi), 3.19 (td, J¼2.2, 9.0 Hz, 1H, HeqeC(3)), 2.10e1.99 (m, 2H, HaxeC(3), H-C(5)) 1.91e1.55 (m, 7H, CeCH2eC, including HeC(9)), 1.46e0.99 (m, 4H, CeCH2eC), 0.89 (s, 9H, tBu-Si), 0.04 (s, 6H, Si(CH3)2); 13C NMR (75 MHz, CDCl3): d 66.8, 65.3, 65.0, 51.9, 30.9, 29.9, 29.0, 25.9 (3C), 24.2, 20.8, 18.2, 5.4 (2C); MS (ESI): m/z 270 (MþH)þ; HRMS (ESI): (m/z) calcd for C15H32NOSi [MþH]þ, 270.2253; found 270.2258.
4.1.3. (S,E)-Benzyl 1-(tert-butyldimethylsilyloxy)-9-hydroxy-6oxonon-4-en-2-ylcarbamate (10). To a solution of keto phosphonate 9 (1.08 g, 5.17 mmol) in THF (50 mL) was added Ba(OH)2$8H2O (3.5 g, 20.6 mmol) under N2 and stirred for 45 min at rt. The reaction mixture was cooled to 0 C, added aldehyde 7 (1.6 g, 4.7 mmol) in 20 mL of THF/H2O (40:1) slowly and mixture was allowed to warm to rt and stirring continued for 4 h. The reaction mixture was diluted with CH2Cl2 (50 mL), organic layer was washed with aqueous saturated NaHCO3 (50 mL), brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, hexanes/EtOAc 1:1) afforded enone 10 (1.8 g, 89%) as a colorless oil. Rf (50% EtOAc/hexanes) 0.3; ½a23 D 8.43 (c 1.6, CHCl3); IR (KBr): vmax 3441, 3332, 2931, 2859, 1699, 1531, 1251, 838 cm1; 1H NMR (300 MHz, CDCl3): d 7.40e7.27 (m, 5H, Ph), 6.90e6.95 (m, 1H, CH2eCH]C), 6.12 (d, J¼15.8 Hz, 1H, C]CHeCO), 5.14e5.01 (m, 3H, CH2ePh, eNH), 3.94e3.79 (br m, 1H, CHeN), 3.69e3.56 (m, 4H, CH2eOSi, CH2eOH), 2.70e2.60 (br t, J¼6.7 Hz, 2H, COeCH2), 2.52e2.40 (m, 2H, CH2eC]C), 1.84 (m, 2H, CH2eCH2eCH2), 0.89 (s, 9H, tBu-Si), 0.05 (s, 6H, Si(CH3)2); 13C NMR (75 MHz, CDCl3): d 200.6, 155.9, 143.4, 136.3, 132.5, 128.5 (2C), 128.1, 128.0 (2C), 66.7, 64.3, 62.0, 51.5, 36.4, 35.1, 26.9, 25.8 (3C), 18.2, -5.5 (2C); MS (ESI): m/z 458 (MþNa)þ; HRMS (ESI): (m/z) calcd for C23H37NO5SiNa [MþNa]þ, 458.2338; found 458.2342.
4.1.6. ((5S,8aR)-Octahydroindolizin-5-yl)methanol (13). To the compound 12 (930 mg, 3.4 mmol) was added 0.1 M concd HCl (17.2 mL) in ethanol and stirred for 4 h at rt. After the completion of reaction (monitored by TLC) ethanol was evaporated to dryness under reduced pressure and added 5% HCl (10 mL). The aqueous layer was washed with diethyl ether (310 mL) and then basified with 2 N NaOH solution. The aqueous layer was extracted with diethyl ether (215 mL), dried over Na2SO4, and evaporated the solvent at <20 C under reduced pressure to furnish the desired compound 13 (445 mg, 85%) as yellow oil. Rf (10% MeOH/CH2Cl2) 0.1; ½a23 D 13.2 (c 1.1, CHCl3); IR (KBr): vmax 3364, 2927, 2861, 1726, 1459, 1280, 1055, 745 cm1; 1H NMR (300 MHz, CDCl3): d 3.72 (dd, J¼3.9, 10.7 Hz, 1H, CH2eOH), 3.43 (dd, J¼2.2, 10.7 Hz, 1H, CH2eOH), 3.21 (td, J¼2.0, 8.6 Hz, 1H, HeqeC(3)), 2.66e2.51 (br s, 1H, OH), 2.12e2.00 (m, 2H, HaxeC(3), HeC(5)), 2.00e1.52 (m, 6H, CeCH2eC, including HeC(9)), 1.47e1.07 (m, 5H, CeCH2eC); 13C NMR (75 MHz, CDCl3): d 68.0, 64.6, 64.1, 51.1, 30.3, 30.1, 27.9, 24.1, 20.4; MS (ESI): m/z 156 (MþH)þ; HRMS (ESI): (m/z) calcd for C9H18NO [MþH]þ, 156.1388; found 156.1382.
4.1.4. 3-((2R,6S)-6-((tert-Butyldimethylsilyloxy)methyl) piperidin-2yl)propan-1-ol (11). 10% Pd on C (5 mol %) was added to a degassed solution of the carbamate 10 (1.8 g, 4.18 mmol) in EtOH (0.5 M) and the heterogeneous mixture was stirred for 12 h under hydrogen atmosphere at rt. After filtration over Celite, the solvent was evaporated under reduced pressure and the crude product was purified by flash chromatography (silica gel, EtOAc) to obtain 11 (1.0 g, 90%). Rf (10% MeOH/CH2Cl2) 0.5; ½a23 D þ0.39 (c 1.2, CHCl3); IR (KBr): vmax 3620, 2931, 2858, 2362, 1693, 1516, 839 cm1; 1H NMR (300 MHz, CDCl3): d 3.91e3.70 (br s, 1H, OH), 3.59e3.40 (m, 4H, CH2eOSi, CH2eOH), 2.70e2.53 (m, 2H, CHeNH, CHeNH), 1.89e1.78 (m, 1H, CeCH2eC), 1.78e1.44 (m, 6H, CeCH2eC), 1.44e1.01 (m, 3H, CeCH2eC), 0.88 (s, 9H, tBu-Si), 0.04 (s, 6H, Si(CH3)2); 13C NMR (75 MHz, CDCl3): d 67.0, 62.5, 58.0, 56.1, 35.5, 31.7, 29.6, 27.7, 25.8 (3C), 24.1, 18.2, 5.4 (2C); MS (ESI): m/z 288 (MþH)þ; HRMS (ESI): (m/z) calcd for C15H34NO2Si [MþH]þ, 288.2358; found 288.2347. 4.1.5. (5S,8aR)-5-((tert-Butyldimethylsilyloxy)methyl) octahydroindolizine (12). To a solution of 11 (1.0 g, 3.76 mmol) in dichloromethane (30 mL) at 20 C were added Et3N (2.41 g, 3.4 mL, 23.9 mmol) and MsCl (0.45 mL, 5.64 mmol) in dichloromethane (10 mL) successively. The reaction mixture was continued to stir at 0 C for 3 h and quenched by adding water (20 mL), the layers were separated and aqueous layer was extracted with dichloromethane (230 mL). The dichloromethane extracts were washed with 1 M HCl (20 mL), water (20 mL), aqueous saturated NaHCO3 (20 mL), brine (20 mL), dried over Na2SO4, and evaporated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, hexanes/EtOAc 7:3) to obtain compound 12 (0.93 g, 92%). Rf (100% EtOAc) 0.4; ½a23 D 42.6 (c 1.4, CHCl3); IR (KBr): vmax 2929, 2857, 1464, 1253, 1102, 837, 775 cm1;
4.1.7. (S)-Ethyl 4-hydroxyoctanoate (15)16a. To a solution of hexanal (1.2 g, 8.67 mmol) and nitroso benzene (0.93 g, 8.67 mmol) in anhydrous DMSO (20 mL) was added D-proline (0.4 g, 3.5 mmol) at 20 C. The mixture was vigorously stirred for 25 min under nitrogen atmosphere. The reaction mixture was cooled to 0 C and was quickly added a premixed and cooled (0 C) solution of triethylphosphonoacetate (5.2 mL, 26.1 mmol), DBU (3.9 mL, 26.1 mmol), and LiCl (1.1 g, 26.1 mmol) in CH3CN (20 mL) at 0 C. The resulting mixture was allowed to warm to rt over 1 h, and quenched by addition of ice pieces. The acetonitrile was evaporated under reduced pressure. The reaction mixture then poured into water (60 mL) and was extracted with Et2O (550 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over Na2SO4, and concentrated in vacuo to give crude product, which was directly subjected to hydrogenation. To the crude product was added 10% Pd on C (5 mol %) in ethyl acetate (0.5 M) and the heterogeneous mixture was stirred for 12 h under hydrogen atmosphere at rt. The mixture was filtered through a pad of Celite and evaporated the solvent in vacuo. The crude product was then purified by using flash column chromatography (silica gel, hexanes/EtOAc 9.5:0.5) to obtain g-hydroxy ester 15 as a colorless liquid (1.0 g, 62%). Rf (20% EtOAc/hexanes) 0.3; ½a27 D 1.2 (c 2.24, CHCl3); 1H NMR (300 MHz, CDCl3): d 4.12 (q, J¼7.5 Hz, 2H, OCH2), 3.62e3.52 (m, 1H, OCH), 2.41 (t, J¼7.5 Hz, 2H, CH2eCO), 1.99e1.57 (m, 3H, CH2eCH2eCO, CHeOH), 1.50e1.21 (m, 6H, CeCH2eC), 1.26 (t, J¼7.5 Hz, 3H, OCH2eCH3), 0.95e0.86 (m, 3H, CH3eCH2); 13C NMR (75 MHz, CDCl3): d 174.0, 70.8, 60.1, 36.9, 31.8, 30.4, 27.5, 22.3, 13.8, 13.7. 4.1.8. (S)-Dimethyl 5-hydroxy-2-oxononylphosphonate (16). n-Butyl lithium (9 mL, 2.5 M in hexane, 23 mmol) was added to a solution of dimethyl methylphosphonate (3.0 g, 25 mmol) in tetrahydrofuran (50 mL) at 78 C. The mixture was stirred for 1 h and the hydroxy ester 15 (1.4 g, 7.5 mmol) in tetrahydrofuran (10 mL) was added drop wise. After 1 h, water (10 mL) was added, slowly warmed to rt and the mixture poured into dichloromethane (100 mL). The aqueous layer was extracted with dichloromethane (320 mL). The
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combined organic extracts were washed with water (30 mL), dried over Na2SO4, and concentrated under reduced pressure. Flash column chromatography of the residue using hexanes/ethyl acetate/ methanol (10:2:1) as eluent gave the b-keto phosphonate 16 (1.2 g, 63%), as a yellow oil, which present as the mixture of ketoelactol form. Rf (100% EtOAc/hexanes) 0.4. 4.1.9. Benzyl (2S,9S,E)-1-(tert-butyldimethylsilyloxy)-9-hydroxy-6oxotridec-4-en-2-ylcarbamate (17). The reaction was carried out according to the representative procedure described for the preparation of compound 10. Aldehyde 7 (2 g, 5.69 mmol) was treated with b-keto phosphonate 16 (1.6 g, 6.2 mmol), to obtain 17 (2.4 g) in 87% yield as colorless oil. Rf (20% EtOAc/hexanes) 0.32; ½a27 D 6.9 (c 1.0, CHCl3); IR (KBr): vmax 3441, 3332, 2932, 1697, 1531, 1252, 838, 777 cm1; 1H NMR (300 MHz, CDCl3): d 7.40e7.28 (m, 5H, Ph), 6.91e6.76 (m, 1H, CH2eCH]C), 6.14 (d, J¼16.0 Hz, 1H, C]CHeCO), 5.09 (s, 2H, CH2ePh), 5.02 (br d, J¼8.8 Hz, 1H, NH), 3.92e3.79 (br m, 1H, CHeNH), 3.63 (br d, J¼2.8 Hz, 2H, CH2eOSi), 3.67e3.51 (m, 1H, CHeOH), 2.69 (t, J¼6.9 Hz, 2H, COeCH2), 2.54e2.41 (m, 2H, CH2eC]C), 1.89e1.57 (br m, 4H, CeCH2eC), 1.51e1.39 (m, 2H, CeCH2eC), 1.39e1.27 (m, 2H, CeCH2eC), 0.95e0.85 (m, 3H, CH2eCH3), 0.89 (s, 9H, tBu-Si), 0.05 (s, 6H, Si(CH3)2); 13C NMR (75 MHz, CDCl3): d 200.9, 155.9, 143.2, 136.3, 132.5, 128.5 (2C), 128.1, 128.0 (2C), 71.3, 66.8, 64.2, 51.5, 37.4, 36.2, 35.1, 31.3, 27.8, 25.8 (3C), 22.7, 18.2, 14.0, 5.5 (2C); MS (ESI): m/z 514 (MþNa)þ; HRMS (ESI): (m/z) calcd for C27H45NO5SiNa [MþNa]þ, 514.2964; found 514.2983. 4.1.10. (S)-1-((2R,6S)-6-((tert-Butyldimethylsilyloxy)methyl) piperidin-2-yl) heptan-3-ol (18). Preparation of compound 18 from compound 17 (2.4 g, 4.94 mmol) was accomplished following the procedure used for compound 11 in 83% yield (1.4 g) as colorless oil. Rf (5% MeOH/CH2Cl2) 0.5; ½a28 D þ0.06 (c 1.0, CHCl3); IR (KBr): vmax 2927, 2857, 1649, 1460, 1255, 1092, 836 cm1; 1H NMR (300 MHz, CDCl3): d 4.32e4.19 (br s, 1H, NH), 3.63 (dd, J¼10.0, 3.9 Hz, 1H, CH2eOSi), 3.54e3.46 (m, 1H, CHeOH), 3.50 (dd, J¼9.8, 6.9 Hz, 1H, CH2eOSi), 2.81e2.69 (m, 2H, CHeNH, CHeNH), 1.92e1.09 (m, 16H, CeCH2eC), 0.93e0.86 (m, 12H, CH2eCH3, tBu-Si), 0.07 (s, 6H, Si(CH3)2); 13C NMR (75 MHz, CDCl3): d 71.3, 66.4, 58.1, 55.7, 37.4, 33.3, 32.9, 30.3, 28.1, 27.2, 25.9 (2C), 23.9, 22.8, 18.3, 14.1, 5.4 (2C); MS (ESI): m/z 344 (MþH)þ; HRMS (ESI): (m/z) calcd for C19H42NO2Si [MþH]þ, 344.2984; found 344.2977. 4.1.11. ((3R,5S,8aR)-3-Butyl-octahydroindolizin-5-yl)methanol (19). The reaction was carried out using the procedure described for the preparation of compound 12 starting from 18 (1.4 g, 4 mmol) to obtain TBS protected bicyclic compound. The crude TBS ether product underwent deprotection of TBS group as described for the compound 13 to provide compound 19 (0.68 g, 78% over two steps) as colorless oil. Rf (10% MeOH/CH2Cl2) 0.1; ½a29 D 34.3 (c 0.5, CHCl3); IR (KBr): vmax 3355, 2927, 2861, 1649, 1458, 1052 cm1; 1H NMR (300 MHz, CDCl3): d 3.78 (dd, J¼11.3, 3.7 Hz, 1H, CH2eOH), 3.50 (dd, J¼11.3, 2.2 Hz, 1H, CH2eOH), 3.36 (br t, J¼8.3 Hz, 1H, HeC(3)), 2.79e2.66 (m, 1H, HeC(5)), 2.66e2.51 (m, 1H, HeC(9)), 2.04e1.88 (m, 1H, CeCH2eC), 1.88e1.77 (m, 1H, CeCH2eC), 1.71e1.62 (m, 1H, CeCH2eC), 1.60e1.41 (m, 2H, CeCH2eC), 1.39e1.02 (m, 11H, CeCH2eC), 0.91 (t, J¼6.8 Hz, 3H, CH2eCH3); 13C NMR (75 MHz, CDCl3): d 63.2, 59.1, 58.6, 57.1, 31.3, 29.5, 28.8, 27.8, 26.4, 25.9, 23.9, 22.9, 14.1; MS (ESI): m/z 212 (MþH)þ; HRMS (ESI): (m/z) calcd for C13H26NO [MþH]þ, 212.2014; found 212.2021. 4.1.12. (E)-Ethyl 3-((3R,5S,8aR)-3-butyl-octahydroindolizin-5-yl)acrylate (20). To the compound 19 (0.25 g, 1.18 mmol) in dichloromethane (2 mL), Et3N (2 mL, 14.1 mmol), and DMSO (2 mL, 28.2 mmol) was added SO3$Py (0.93 g, 5.9 mmol) at 0 C, stirred for 1 h at 0 C and slowly warmed to rt. Continued stirring for another
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30 min at rt, added (ethoxycarbonylmethylene)triphenyl phosphorane (0.5 g, 1.53 mmol) to the reaction mixture at 0 C and stirred at rt for 5 h. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (215 mL). The combined organic layers were washed with brine (10 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and crude was purified by column chromatography (silica gel, hexanes/ EtOAc 8:2) to get 20 (0.24 g, 74%) as colorless oil. Rf (100% EtOAc) 0.57; ½a26 D 46.6 (c 1.4, CHCl3); IR (KBr): vmax 2957, 2924, 2854, 1731, 1639, 1464, 1285, 1074, 721 cm1; 1H NMR (300 MHz, CDCl3): d 6.89 (dd, J¼15.8, 9.0 Hz, 1H, C]CHeCH), 5.91 (d, J¼15.8 Hz, 1H, COeCH]C), 4.18 (q, J¼7.5 Hz, 2H, CH2eCH3), 3.25e3.09 (m, 2H, HeC(3), HeC(5)), 2.49e2.33 (m, 1H, HeC(9)), 2.4e1.73 (m, 4H, CeCH2eC), 1.68e1.51 (m, 1H, CeCH2eC), 1.51e1.35 (m, 2H, CeCH2eC), 1.36e1.10 (m, 8H, CeCH2eC), 1.30 (t, J¼7.5 Hz, 3H, OCH2eCH3), 1.11e0.93 (m, 1H, CeCH2eC), 0.87 (t, J¼6.8 Hz, 3H, CH2eCH3); 13C NMR (75 MHz, CDCl3): d 166.6, 151.1, 120.9, 60.2, 59.7, 59.1, 58.1, 32.6, 31.8, 29.8, 28.7, 26.3, 25.5, 24.1, 22.8, 14.2, 14.0; MS (ESI): m/z 280 (MþH)þ; HRMS (ESI): (m/z) calcd for C17H30NO2 [MþH]þ, 280.2276; found 280.2288. 4.1.13. ()-Indolizidine 239AB (3). To a solution of compound 20 (240 mg, 0.86 mmol) in ethyl acetate (4 mL), 10% PdeC (5 mol %) was added and stirred for 12 h under hydrogen atmosphere. The mixture was filtered through a plug of Celite, washed with diethyl ether (10 mL), and concentrated at <20 C under reduced pressure to give saturated ester as yellow oil (228 mg, 95%), which was used for the next step without further purification. The above compound (228 mg, 0.81 mmol) in THF (2 mL) was added to a suspension of LiAlH4 (62 mg, 1.63 mmol) in THF (5 mL) at 0 C, warmed to rt slowly and continued stirring for 1 h at rt. After the completion of reaction (monitored by TLC), the mixture was cooled to 0 C, quenched slowly by adding few drops of 10% aqueous NaOH solution. The reaction mixture was stirred for 2 h and filtered through a small pad of Celite, washed with diethyl ether (10 mL), dried over Na2SO4, and concentrated under reduced pressure at <20 C. The residue was purified by column chromatography (neutral alumina, hexanes/diethyl ether 9:1) to get 3 (164 mg, 85%) as pale yellow oil. Rf (5% MeOH/EtOAc) 0.1; ½a30 D 92 (c 0.4, MeOH); IR (KBr): vmax 3459, 2924, 2852, 1639, 1463, 1378, 697 cm1; 1H NMR (300 MHz, CDCl3): d 3.63e3.53 (m, 1H, CH2eOH), 3.52e3.39 (m, 1H, CH2eOH), 3.35e3.26 (m, 1H, HeC(3)), 2.64e2.55 (m, 1H, HeC(5)), 2.49e2.39 (m, 1H, HeC(9)), 1.99e1.41 (m, 9H, CeCH2eC), 1.39e0.98 (m, 12H, CeCH2eC), 0.90 (t, J¼5.8 Hz, 3H, CH2eCH3); 13C NMR (75 MHz, CDCl3): d 62.6, 60.3, 58.9, 56.3, 30.3, 29.7, 29.6, 29.0, 28.5, 28.4, 27.8, 25.7, 23.9, 22.7, 14.0; MS (ESI): m/z 240 (MþH)þ; HRMS (ESI): (m/z) calcd for C15H31NO [MþH]þ, 240.2322; found 240.2329. 4.1.14. (3R,5S,8aR)-3-Butyl-5-(chloromethyl)-octahydroindolizine (21). To the compound 19 (0.25 g, 1.18 mmol) in THF (5 mL) was added SOCl2 (0.12 mL, 1.77 mmol) at 0 C under nitrogen atmosphere. The reaction mixture was allowed to rt and heated for 20 min at 50 C. The mixture was cooled to 0 C and quenched with saturated aqueous NH4Cl (5 mL) and extracted with diethyl ether (210 mL). The organic layer was dried over Na2SO4 and concentrated at <20 C under reduced pressure. The residue was purified by flash column chromatography (silica gel, hexanes/EtOAc 8:2) to get the compound 21 (0.21 g, 78%) as a colorless oil. Rf (30% EtOAc/ hexanes) 0.43; ½a26 D 47.2 (c 0.5, CHCl3); IR (KBr): vmax 2952, 2854, 1644, 1463, 1379, 1274, 1083, 739 cm1; 1H NMR (300 MHz, CDCl3): d 3.64 (dd, J¼3.0, 10.5 Hz, 1H, CH2eCl), 3.34 (dd, J¼7.5, 10.5 Hz, 1H, CH2eCl), 3.21 (br t, J¼9.1 Hz, 1H, HeC(3)), 2.74e2.65 (m, 1H, HeC(5)), 2.48e2.37 (m, 1H, HeC(9)), 1.99e1.73 (m, 4H, CeCH2eC), 1.52e1.00 (m, 12H, CeCH2eC), 0.91 (t, J¼6.8 Hz, 3H, CH2eCH3); 13C NMR (75 MHz, CDCl3): d 59.0, 58.5, 57.5, 47.1, 31.8, 29.7, 29.6, 28.9,
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26.5, 25.2, 24.0, 22.9, 14.1; MS (ESI): m/z 230 (MþH)þ; HRMS (ESI): (m/z) calcd for C13H25ClN [MþH]þ, 230.1670; found 230.1671. 4.1.15. ()-Indolizidine 195B (4). Compound 21 (200 mg, 0.87 mmol) in dry THF (2 mL) was added to the suspension of LiAlH4 (70 mg, 1.84 mmol) in THF (3 mL) at 0 C, allowed to rt and it was refluxed for 12 h. After the completion of reaction (monitored by TLC), the mixture was cooled to 0 C, quenched with aqueous 10% NaOH, stirred for 2 h and filtered through a pad of Celite, washed with diethyl ether (10 mL). The organic solvent was evaporated under reduced pressure at <20 C and the residue was purified by flash column chromatography (neutral alumina, hexanes/diethyl ether 9:1) to get compound 4 as a pale yellow oil (139 mg, 82%). Rf (50% MeOH/CH2Cl2) 0.1; ½a27 D 61 (c 0.5, MeOH); IR (KBr): vmax 2956, 2923, 2852, 1637, 1463, 1377, 1248, 772 cm1; 1 H NMR (300 MHz, CDCl3): d 3.24 (br t, J¼7.9 Hz, 1H, HeC(3)), 2.57e2.44 (m, 1H, HeC(5)), 2.43e2.31 (m, 1H, HeC(9)), 1.94e1.65 (m, 4H, CeCH2eC), 1.62e1.15 (m, 12H, CeCH2eC), 1.08 (d, J¼6.2 Hz, 3H, CHeCH3), 0.90 (t, J¼6.9 Hz, 3H, CH2eCH3); 13C NMR (75 MHz, CDCl3): d 60.0, 59.3, 53.2, 33.2, 30.8, 29.6, 29.2, 28.7, 25.9, 24.2, 22.8, 19.5, 14.1; MS (ESI): m/z 196 (MþH)þ; HRMS (ESI): (m/z) calcd for C13H26N [MþH]þ, 196.2065; found 196.2058. 4.1.16. (R)-Ethyl 4-hydroxyoctanoate (15a)16b. Preparation of compound 15a (ent-15) from compound 14 (2 g, 19.9 mmol) was accomplished following the procedure used for compound 15 (by using L-proline, 40 mol %) in 61% yield (2.2 g) as colorless oil. ½a27 D þ1.0 (c 2.24, CHCl3); 1H NMR (300 MHz, CDCl3): d 4.12 (q, J¼7.5 Hz, 2H, OCH2), 3.62e3.52 (m, 1H, OCH), 2.41 (t, J¼7.5 Hz, 2H, CH2eCO), 1.99e1.57 (m, 3H, CH2eCH2eCO, CHeOH), 1.50e1.21 (m, 6H, CeCH2eC), 1.26 (t, J¼7.5 Hz, 3H, OCH2eCH3), 0.95e0.86 (m, 3H, CH3eCH2); 13C NMR (75 MHz, CDCl3): d 174.0, 70.8, 60.1, 36.9, 31.8, 30.4, 27.5, 22.3, 13.8, 13.7. 4.1.17. (R)-Dimethyl 5-hydroxy-2-oxononylphosphonate (16a). The reaction was carried out according to the representative procedure described for the preparation of compound 16. (R)-Hydroxy ester 15a (2 g, 10.6 mmol) was treated with (dimethoxyphosphoryl) methanide (3 equiv) to obtain 16a (ent-16) as a pale yellow oil (1.8 g, 65%), which present as the mixture of ketoelactol form. 4.1.18. Benzyl (2S,9R,E)-1-(tert-butyldimethylsilyloxy)-9-hydroxy-6oxotridec-4-en-2-ylcarbamate (22). The reaction was carried out according to the representative procedure described for the preparation of compound 10. Aldehyde 7 (1 g, 2.87 mmol) was treated with b-keto phosphonate 16a (840 mg, 3.15mmol), to obtain 22 (1.2 g) in 86% yield as colorless oil. Rf (20% EtOAc/hexanes) 0.32. 1 ½a24 D 13.5 (c 1.1, CHCl3); H NMR (300 MHz, CDCl3): d 7.42e7.27 (m, 5H, Ph), 6.91e6.71 (m, 1H, CH2eCH]C), 6.13 (d, J¼15.8 Hz, 1H, C] CHeCO), 5.22e4.98 (m, 3H, CH2ePh, NH), 3.97e3.78 (br m, 1H, CHeNH), 3.74e3.48 (br m, 3H, CH2eOSi, CHeOH), 2.76e2.60 (m, 2H, COeCH2), 2.56e2.36 (m, 2H, CH2eC]C), 1.89e1.58 (m, 3H, CeCH2eC), 1.50e1.19 (m, 5H, CeCH2eC), 0.88 (s, 12H, tBu-Si), 0.04 (s, 6H, Si(CH3)2); 13C NMR (75 MHz, CDCl3): d 200.9, 155.8, 143.3, 136.3, 132.6, 128.5 (2C), 128.2, 128.1, 128.0, 71.2, 66.7, 64.2, 51.5, 37.3, 35.2, 35.1, 31.3, 27.8, 25.8 (3C), 22.7, 18.2, 14.0, 5.5 (2C); MS (ESI): m/z 514 (MþNa)þ; HRMS (ESI): (m/z) calcd for C27H45NO5SiNa [MþNa]þ, 514.2959; found 514.2993.
2.59e2.46 (m, 1H, CHeNH),1.93e1.81 (br d, J¼13.6 Hz, 1H, CHeOH), 1.72e1.04 (br m, 16H, CeCH2eC), 0.90 (s, 12H, tBu-Si), 0.06 (s, 6H, Si(CH3)2); 13C NMR (75 MHz, CDCl3): d 71.6, 67.1, 58.4, 57.8, 37.3, 34.8, 33.6, 31.8, 27.9, 26.7, 25.8 (3C), 23.7, 22.6, 18.2, 13.9, 5.5, 5.4; MS (ESI): m/z 344 (MþH)þ; HRMS (ESI): (m/z) calcd for C19H42NO2Si [MþH]þ, 344.2979; found 344.3000. 4.1.20. ((3S,5S,8aR)-3-Butyl-octahydroindolizin-5-yl) methanol (24). Compound 23 (700 mg, 2 mmol) was transformed to compound 24 (337 mg) according to the representative procedure described for the preparation of compound 19 in 78% yield as colorless 1 oil. Rf (10% MeOH/CH2Cl2) 0.1. ½a26 D þ6.75 (c 1.5, CH2Cl2); H NMR (300 MHz, CDCl3): d 3.73 (dd, J¼11.3, 4.5 Hz, 1H, CH2eOH), 3.50 (dd, J¼11.3, 3.0 Hz, 1H, CH2eOH), 2.56 (br t, J¼9.0 Hz, 1H, HeC(3)), 2.29e2.18 (m, 1H, HeC(5)), 2.18e2.06 (m, 1H, HeC(9)), 1.91e1.54 (m, 6H, CeCH2eC), 1.49e1.15 (m, 10H, CeCH2eC), 0.89 (t, J¼6.7 Hz, 3H, CH2eCH3); 13C NMR (75 MHz, CDCl3): d 67.4, 65.9, 65.1, 62.9, 38.3, 30.4, 29.9, 29.6, 29.5, 29.3, 24.4, 22.9, 14.2; MS (ESI): m/z 212 (MþH)þ; HRMS (ESI): (m/z) calcd for C13H26NO [MþH]þ, 212.2009; found 212.2024. 4.1.21. (3S,5S,8aR)-3-Butyl-5-(chloromethyl)octahydroindolizine (25). The reaction was carried out according to the representative procedure described for the preparation of compound 21. Compound 24 (300 mg, 1.42 mmol) was treated with SOCl2 (0.15 mL, 2.1 mmol) to obtain 25 (244 mg, 75%) as pale yellow color oil. Rf 1 (30% EtOAc/hexanes) 0.45; ½a27 D 24.1 (c 1.4, CHCl3); H NMR (300 MHz, CDCl3): d 3.66 (d, J¼10.3 Hz, 1H, CH2eCl), 3.41 (dd, J¼10.3, 7.5 Hz, 1H, CH2eCl), 2.50e2.33 (m, 1H, HeC(3)), 2.74e2.65 (m, 1H, HeC(5)), 2.23e2.06 (m, 1H, HeC(9)), 1.99e1.58 (m, 4H, CeCH2eC), 1.57e1.12 (m, 12H, CeCH2eC), 0.90 (t, J¼6.9 Hz, 3H, CH2eCH3); 13C NMR (75 MHz, CDCl3): d 67.4, 65.4, 62.2, 48.6, 39.3, 30.7, 29.9, 29.7, 29.5, 29.1, 24.2, 22.8, 14.0; MS (ESI): m/z 230 (MþH)þ; HRMS (ESI): (m/z) calcd for C13H25ClN [MþH]þ, 230.1670; found 230.1687. 4.1.22. ()-Monomorine (5). Compound 25 (100 mg, 0.43 mmol) was treated with LiAlH4 (35 mg, 0.92 mmol) as described in the procedure for the preparation of compound 4 to obtain ()-monomorine 5 (65 mg, 80%). Rf (50% MeOH/CH2Cl2) 0.1; ½a28 D 30.5 (c 0.9, n-hexane); IR (KBr): vmax 2925, 2860, 1733, 1516, 1458, 1271, 1066 cm1; 1H NMR (300 MHz, CDCl3): d 2.47 (br t, J¼9.4 Hz, 1H, HeC(3)), 2.29e2.15 (m, 1H, HeC(5)), 2.13e1.99 (m,1H, HeC(9)), 1.91e1.49 (br m, 6H, CeCH2eC), 1.49e1.15 (br m, 10H, CeCH2eC), 1.13 (d, J¼6.4 Hz, 3H, CHeCH3), 0.89 (t, J¼6.9 Hz, 3H, CH2eCH3); 13C NMR (75 MHz, CDCl3): d 67.1, 62.9, 60.2, 39.6, 35.8, 30.8, 30.3, 29.7, 29.4, 24.8, 22.9, 22.8, 14.1; MS (ESI): m/z 196 (MþH)þ; HRMS (ESI): (m/z) calcd for C13H26N [MþH]þ, 196.2065; found 196.2067. Acknowledgements B.L. and N.N.R. thank Council of Scientific and Industrial Research (CSIR), New Delhi for research fellowships. The authors are thankful to the reviewers for their valuable suggestions in improving the quality of the manuscript. Supplementary data 1
4.1.19. (R)-1-((2R,6S)-6-((tert-Butyldimethylsilyloxy)methyl) piperidin-2-yl)heptan-3-ol (23). Compound 22 (1.2 g, 2.46 mmol) on hydrogenation according to procedure described for preparation of compound 11 yields 23 (700 mg, 83%) as colorless oil. Rf (5% MeOH/ 1 CH2Cl2) 0.5; ½a26 D 5.61 (c 1.6, CHCl3); H NMR (300 MHz, CDCl3): d 3.59 (dd, J¼9.8, 3.7 Hz, 1H, CH2eOSi), 3.51 (dd, J¼9.8, 6.0 Hz, 1H, CH2eOSi), 3.53e3.42 (m, 1H, CHeOH), 2.69e2.59 (m, 1H, CHeNH),
H and 13C NMR spectra for all the new compounds. Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.tet.2011.10.076. References and notes 1. (a) Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68, 1556e1575; (b) Jones, T. H.; Voegtle, H. L.; Miras, H. M.; Weatherford, R. G.; Spande, T. F.;
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9.
10.
Garraffo, H. M.; Daly, J. W.; Davidson, D. W.; Snelling, R. R. J. Nat. Prod. 2007, 70, 160e168; (c) Michael, J. P. Nat. Prod. Rep. 2007, 24, 191e222; (d) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139e165; (e) Huang, P.-Q. In Asymmetric Synthesis of Nitrogen Heterocycles; Royer, J., Ed.; Wiley: Weinheim, 2009. (a) Daly, J. W.; Brown, G. B.; Mensahdwumah, M.; Myers, C. W. Toxicon 1978, 16, 163e188; (b) Erspamer, V.; Melchiorri, P. Trends Pharmacol. Sci. 1980, 1, 391e395; (c) Daly, J. W.; Spande, T. F. Alkaloids: Chem. Biol. Perspect. 1986, 4, 1e274; (d) Elbein, A. D.; Molyneux, R. J. Alkaloids 1987, 5, Chapter 1; (e) Daly, J. W.; Myers, C. W.; Whittaker, N. Toxicon 1987, 25, 1023e1095. (a) Holmes, A. B.; Smith, A. L.; Williams, S. F.; Hughes, L. R.; Lidert, Z.; Swithenbank, C. J. Org. Chem. 1991, 56, 1393e1405; (b) Machinaga, N.; Kibayashi, C. J. Org. Chem. 1992, 57, 5178e5189; (c) Kiddle, J. J.; Green, D. L. C.; Thompson, C. M. Tetrahedron 1995, 51, 2851e2864; (d) Celimene, C.; Dhimane, H.; Saboureau, A.; Lhommet, G. Tetrahedron: Asymmetry 1996, 7, 1585e1588; (e) Chenevert, R.; Ziarani, G. M.; Dasser, M. Heterocycles 1999, 51, 593e598; (f) Back, T. G.; Nakajima, K. Org. Lett. 1999, 1, 261e263; (g) Back, T. G.; Nakajima, K. J. Org. Chem. 2000, 65, 4543e4552; (h) Amat, M.; Llor, N.; Hidalgo, J.; Escolano, C.; Bosch, J. J. Org. Chem. 2003, 68, 1919e1928; (i) Varga, T. R.; Nemes, P.; Mucsi, Z.; Scheiber, P. Tetrahedron Lett. 2007, 48, 1159e1161; (j) Barbe, G.; Pelletier, G.; Charette, A. B. Org. Lett. 2009, 11, 3398e3401. (a) Reddy, C. R.; Rao, N. N. Tetrahedron Lett. 2009, 50, 2478e2480; (b) Chandrasekhar, S.; Murali, R. V. N. S.; Reddy, C. R. Tetrahedron Lett. 2009, 50, 5686e5688; (c) Reddy, C. R.; Rao, N. N.; Srikanth, B. Eur. J. Org. Chem. 2010, 345e351. Representative references for synthesis of ()-167B: (a) Polniaszek, R. P.; Belmont, S. E. J. Org. Chem. 1990, 55, 4688e4693; (b) Lee, E.; Li, K. S.; Lim, J. Tetrahedron Lett. 1996, 37, 1445e1446; (c) Carbonnel, S.; Troin, Y. Heterocycles 2002, 57, 1807e1830; (d) Zaminer, J.; Stapper, C.; Blechert, S. Tetrahedron Lett. 2002, 43, 6739e6741; (e) Corvo, M. C.; Pereira, M. M. A. Tetrahedron Lett. 2002, 43, 455e458; (f) Reddy, P. G.; Baskaran, S. J. Org. Chem. 2004, 69, 3093e3101; (g) Roa, L. F.; Gnecco, D.; Galindo, A.; Teran, J. L. Tetrahedron: Asymmetry 2004, 15, 3393e3395; (h) Guazzelli, G.; Lazzaroni, R.; Settambolo, R. Synthesis 2005, 3119e3123; (i) Sun, Z.; Yu, S.; Ding, Z.; Ma, D. J. Am. Chem. Soc. 2007, 129, 9300e9301; (j) Stead, D.; Obrien, P.; Sanderson, A. Org. Lett. 2008, 10, 1409e1412; (k) Kapat, A.; Nyfeler, E.; Giuffredi, G. T.; Renaud, P. J. Am. Chem. Soc. 2009, 131, 17746e17747; (l) Gracia, S.; Jerpan, R.; Pellet-Rostaing, S.; Popowycz, F.; Lemaire, M. Tetrahedron Lett. 2010, 51, 6290e6293. Representative references for synthesis of ()-209D: (a) Takahata, H.; Kubota, M.; Ihara, K.; Okamoto, N.; Momose, T.; Azer, N.; Eldefrawi, A. T.; Eldefrawi, M. E. Tetrahedron: Asymmetry 1998, 9, 3289e3301; (b) Yamazaki, N.; Ito, T.; Kibayashi, C. Org. Lett. 2000, 2, 465e467; (c) Kim, G.; Lee, E. J. Tetrahedron: Asymmetry 2001, 12, 2073e2076; (d) Kim, G.; Jung, S.; Kim, W. Org. Lett. 2001, 3, 2985e2987; (e) Patil, N. T.; Pahadi, N. K.; Yamamoto, Y. Tetrahedron Lett. 2005, 46, 2101e2103; (f) Yu, R. T.; Lee, E. E.; Malik, G.; Rovis, T. Angew. Chem., Int. Ed. 2009, 48, 2379e2382; (g) Liu, H.; Su, D.; Cheng, G.; Xu, J.; Wang, X.; Hu, Y. Org. Biomol. Chem. 2010, 8, 1899e1904. For isolation of ()-239AB see: (a) Skrinjar, M.; Wistrand, L. G. Tetrahedron Lett. 1990, 31, 1775e1778 For synthesis of ()-239AB see: (b) Thanh, G. V.; Celerier, J.-P.; Lhommet, G. Tetrahedron: Asymmetry 1996, 7, 2211e2212; (c) Celimene, C.; Dhimane, H.; Lhommet, G. Tetrahedron 1998, 54, 10457e10468; (d) Dhimane, H.; Vanucci-Bacque, C.; Hamon, L.; Lhommet, G. Eur. J. Org. Chem. 1998, 9, 1955e1963. For isolation of ()-195B see: (a) Edwards, M. W.; Daly, J. W. J. Nat. Prod. 1988, 51, 1188e1197 Representative references for synthesis of ()-195B: (b) Angle, S. R.; Kim, M. J. Org. Chem. 2007, 72, 8791e8796; (c) Davis, F. A.; Zhang, J.; Wu, Y. Tetrahedron Lett. 2011, 52, 2054e2057. Representative references for synthesis of ()-monomorine: (a) Royer, J.; Husson, H. P. J. Org. Chem. 1985, 50, 670e673; (b) Jefford, C. W.; Sienkiewicz, K.; Thornton, S. R. Tetrahedron Lett. 1994, 35, 4759e4762; (c) Zhang, S. H.; Xu, L.; Miao, L.; Shu, H.; Trudell, M. L. J. Org. Chem. 2007, 72, 3133e3136; (d) Pattenden, L. S.; Adams, H.; Smith, S. A.; Harrity, J. P. A. Tetrahedron 2008, 64, 2951e2961; (e) Toyooka, N.; Zhou, D. J.; Nemoto, H. J. Org. Chem. 2008, 73, 4575e4577. The similar aldehyde with different protecting groups is little explored. For references see: (a) Ofuna, Y.; Hori, K. Jpn. Kokai Tokkyo Koho, JP 63063673 A 19880322, 1988. (b) Acharya, H. P.; Clive, D. L. J. J. Org. Chem. 2010, 75, 5223e5233; (c) Alvaro, G.; Amantini, D.; Castiglioni, E.; Fabio, R. D.; Pavone, F. PCT Int. Appl. WO 2010063662 A1 2010610, 2010.
151
11. Andres, J. M.; Munoz, E. M.; Pedrosa, R.; Perez-Encabo, A. Eur. J. Org. Chem. 2003, 3387e3397. 12. Compounds 9 and 16 exist as a mixture of keto and lactol forms, which was confirmed by 1H NMR.
O P O O
O
O R OH
OH P O O O
R = H, 9 R = n-Bu, 16 R
13. Folker, L. Ger. Offen. DE2711010, 1978. 14. NOE experiment has been carried out on known acetyl derivative of alcohol 13 and key NOE enhancements are shown below.
15. To determine the enantiomeric excess of (S)-ethyl 4-hydroxyoctanoate 15 by chiral HPLC, it was converted to p-nitro benzoate derivative under DCC/DMAP reaction conditions using p-nitrobenzoic acid. Chiral HPLC: Chiralcel OD-H column (2504.6 mm, 5 m), isopropanol/hexanes¼7:93, flow rate 1.0 mL/min, l 210 nm. Retention time (min): 7.32 (major) and 7.96 (minor); ee 94%; Rf (20% 1 EtOAc/hexanes) 0.55; ½a20 D þ12.3 (c 0.6, CHCl3); H NMR (300 MHz, CDCl3): d 8. 29 (d, J¼8.7 Hz, 2H, CH(Ar)), 8.20 (d, J¼8.7 Hz, 2H, CH(Ar)), 5.23e5.17 (m, 1H, OeCH), 4.14e4.02 (m, 2H, OCH2eCH3), 2.39 (t, J¼7.6 Hz, 2H, CH2eCO), 2.15e1. 97 (m, 2H, CH2eCH2eCO), 1.81e1.62 (m, 2H, CH2eCHeO), 1.44e1.27 (m, 4H, CeCH2eC), 1.21 (t, J¼7.6 Hz, 3H, OCH2eCH3), 0.89 (t, J¼7.6 Hz, 3H, CH3eCH2); 13 C NMR (75 MHz, CDCl3): d 172.8, 164.2, 150.5, 135.7, 130.6, 123.5, 75.4, 60.5, 33.7, 30.3, 29.1, 27.3, 22.4, 14.1, 13.8.
16. (a) Kondekar, N. B.; Kumar, P. Org. Lett. 2009, 11, 2611e2614; (b) Jha, V.; Kondekar, N. B.; Kumar, P. Org. Lett. 2010, 12, 2762e2765. 17. The enantiomeric excess of (R)-ethyl 4-hydroxyoctanoate 15a was determined by converting it to p-nitro benzoate derivative under DCC/DMAP reaction conditions using p-nitrobenzoic acid. Chiral HPLC: Chiralcel OD-H column (2504.6 mm, 5 m), isopropanol/hexanes¼7:93, flow rate 1.0 mL/min, l 210 nm. Retention time (min): 7.39 (minor) and 8.00 (major); ee 94%; Rf (20% EtOAc/ hexanes) 0.55; ½a20 D 12.9 (c 0.6, CHCl3).
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Enantioselective access to ()-indolizidines 167B, 209D, 239AB, 195B and ()-monomorine from a common chiral synthon Chada Raji Reddy *, Bellamkonda Latha, Nagavaram Narsimha Rao Organic Chemistry Division-I, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history: Received 18 July 2011 Received in revised form 20 October 2011 Accepted 22 October 2011 Available online 29 October 2011
An enantioselective access to ()-indolizidine alkaloids 167B, 209D, 239AB, 195B and ()-monomorine from a new chiral synthon is described. The use of (S)-3-(Cbz-amino)-4-(tert-butyldimethylsilyloxy) butanal, obtained from L-aspartic acid, has provided efficient access of the indolizidine frame work through a HornereWadswortheEmmons reaction and reductive cyclization as the key steps. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Indolizidine alkaloid Chiral synthon HornereWadswortheEmmons reaction Reductive cyclization
1. Introduction The synthesis of indolizidine alkaloids has stimulated considerable efforts due to the frequent presence of indolizidine ring system in naturally occurring bio-active molecules.1 Of particular interest are 5-substituted and 3,5-disubstituted indolizidines due to their biological activities.2 Although numerous enantioselective syntheses are known for these indolizidines,3 the development of new strategies using a common chiral synthon having distinct absolute stereochemistry and functional attributes for structural elaboration is of interest. In continuation of our work on the synthesis of bio-active molecules,4 we wish to report an expedient general strategy toward the synthesis of ()-indolizidines 167B,5 209D,6 239AB,7 195B3b,8 and ()-monomorine9 (Fig. 1) using a new chiral synthon,10 derived from L-aspartic acid. We hypothesized that (S)-3-(Cbz-amino)-4-(tert-butyldimethylsilyloxy)butanal (7) would be a suitable chiral synthon having an aldehyde functionality for accessing 5-substituted and 3,5-disubstituted indolizidines via a HornereWadswortheEmmons (HWE) reaction followed by reductive cyclization as the key steps (Scheme 1). The desired stereocenters in indolizidine scaffold can be created as follows: (i) C-5 stereocenter from the chirality of the synthon (ii) the C-9 configuration through reductive amination (iii) the C-3 chirality via proline-catalyzed a-hydroxylation. Further, the choice of benzyloxy carbonyl (Cbz) protection would allow its
* Corresponding author. Tel.: þ91 040 27191885; fax: þ91 040 27160512; e-mail address: [email protected] (C.R. Reddy). 0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2011.10.076
Fig. 1. Structures of ()-indolizidines 167B, 209D, 239AB, 195B and ()-monomorine.
removal during the reductive cyclization step and the tert-butyldimethyl silyl (TBS) group was expected to be stable throughout the sequence of reactions and can then be removed after the construction of indolizidine frame work for further structural elaboration.
2. Results and discussion In order to verify the hypothesis, initially chiral synthon 7 was prepared from a known ester 6, obtained in four steps from Laspartic acid.11 Reduction of compound 6 using DIBAL-H delivered the requisite aldehyde 7 in 90% yield. The aldehyde was prepared
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Scheme 1. Proposed strategy for ()-indolizidines 167B, 209D, 239AB, 195B and ()-monomorine.
on a several-gram scale without any difficulty and found to be stable at rt for several months (Scheme 2).
Scheme 3. Formal total synthesis of ()-indolizidine 167B and 209D.
Scheme 2. Synthesis of chiral synthon 7.
Having the desired new chiral synthon in hand, next the construction of indolizidine ring was studied with the syntheses of ()-indolizidine 167B and 209D in mind. The other subunit needed for HWE olefination, 5-hydroxy-2-oxo-pentylphosphonic acid dimethyl ester (9),12 was easily prepared from g-butyrolactone (8) in one-step.13 Now, the chiral synthon 7 was subjected to HWE olefination with b-keto phosphonate 9 to afford the key enone 10 in 89% yield, a precursor for reductive cyclization. Exposure of 10 to 10% Pd/CeH2 (gas) in EtOH provided piperidine 11 in 90% yield. This hydrogenation reaction involves four transformations in single step: (a) olefin reduction, (b) Cbz-removal, (c) intramolecular cyclic imine formation, and (d) stereoselective reduction of the imine to give piperidine 11 exclusively as cis-isomer. The formation of cis-11 was confirmed at later stage (converting alcohol 13 to known acetyl derivative)5f by NOE experiments.14 Further, to achieve the indolizidine scaffold, compound 11 was treated with Et3N/ MsCl at 0 C under which the free hydroxyl group was mesylated followed by in situ cyclization furnishing the indolizidine 12 in 92% yield. TBS deprotection of 12 using 0.1 M HCl in EtOH provided compound 13 in 85% yield, which has previously been converted to ()-indolizidine 167B and 209D in a known two step sequence (Scheme 3).5f After the above success, we decided to apply a similar strategy for the synthesis of 3,5-disubstituted indolizidine alkaloids, ()-indolizidine 239AB, 195B and ()-monomorine from chiral synthon 7. Following the retrosynthetic approach depicted in Scheme 1, the desired phosphonate partner for the HWE reaction was accessed from n-hexanal 14. Compound 14 was subjected to asymmetric a-aminoxylation (PhNO/D-proline/DMSO) followed by HWE reaction with ethyl 2-(diethoxyphosphoryl)acetate (DBU/LiCl/ CH3CN) in one-pot to obtain g-aminoxy a,b-unsaturated ester, which was subsequently exposed to hydrogenation conditions (10% Pd/CeH2 in EtOAc) to provide 3-hydroxy ethyl octanoate 15 (94% ee)15 in 62% yield (over three operations).16a The reaction of 15 with
dimethyl methylphosphonate in the presence of n-BuLi in THF afforded the b-keto phosphonate 16 in 63% yield.12 Phosphonate 16 was used for the HWE olefination with chiral synthon 7 to provide enone 17 in 87% yield. The concomitant one-pot hydrogenationecyclization reaction (H2/PdeC, rt) of 17 gave 2,6disubstituted piperidine 18 in 83% yield. Compound 18 underwent a second cyclization in the presence of Et3N/MsCl followed by TBS deprotection to afford 3,5-disubstituted indolizidine 19 in 78% yield (over two steps) with excellent stereoselectivity (Scheme 4).
Scheme 4. Synthesis of 3,5-disubstituted indolizidine 19.
The key indolizidine subunit 19 was further utilized to complete the synthesis of ()-indolizidine 239AB and 195B. Thus, alcohol 19 was oxidized to the corresponding aldehyde using ParikheDoering conditions, which upon exposure to (ethoxycarbonylmethylene) triphenyl phosphorane gave the a,b-unsaturated ester 20 in 74% yield over two steps. Saturation of olefin 20 under atmospheric pressure of H2 in the presence of 10% Pd/C and subsequent reduction of the ester using LiAlH4 in THF completed the total syn7 thesis of ()-indolizidine 239AB (½a30 D 92, c 0.4, MeOH) (3) in 85%
C.R. Reddy et al. / Tetrahedron 68 (2012) 145e151
yield (Scheme 5). Similarly, compound 19 was subjected to a two step sequence of transformations involving (i) conversion of alcohol 19 to chloride 21 (ii) reduction of chloro methyl to methyl 3b,8 group, to obtain ()-indolizidine 195B (½a27 D 61, c 0.5, MeOH) (4) in 64% yield (over two steps) (Scheme 6).
147
using a stable and scalable new chiral synthon, obtained from Laspartic acid. The formal synthesis of ()-indolizidine 167B, 209D and total synthesis of ()-indolizidine 239AB, 195B and ()-monomorine have been successfully accomplished in good yield. Further, applications of this strategy using a new chiral synthon in the synthesis of indolizidine as well as piperidine alkaloids are currently underway. 4. Experimental section 4.1. General 1
Scheme 5. Synthesis of ()-indolizidine 239AB (3).
Scheme 6. Synthesis of ()-indolizidine 195B (4).
With the efficient routes established for enantioselective synthesis of ()-indolizidine 167B, 209D, 239AB, and 195B from a common chiral synthon, the stereoselective synthesis of unnatural ()-monomorine, C3-epimer of ()-indolizidine 195B, was also pursued. The desired g-hydroxy ester 15a was obtained from n-hexanal 14 using L-proline (94% ee).16b,17 The ester 15a was then 9 converted to ()-monomorine 5 (½a28 D 30.5, c 0.9, n-hexane) following the same sequence of reactions carried out for ()-indolizidine 195B (4) (Scheme 7).
Scheme 7. Synthesis of ()-monomorine (5).
3. Conclusion In summary, an efficient and general route for the stereoselective synthesis of indolizidine alkaloids has been developed
H NMR and 13C NMR spectra were recorded in CDCl3 solvent on 300 MHz or 75 MHz spectrometer at ambient temperature. Chemical shifts d are given in parts per million, coupling constant J are in hertz. The chemical shifts are reported in ppm on scale downfield from TMS as internal standard and signal patterns are indicated as follows: s, singlet; d, doublet; dd, doublet of doublet, t, triplet; td, triplet of doublets; m, multiplet; br, broad peak. FTIR spectra were recorded as KBr thin films or neat. Optical rotations were measured on digital polarimeter using a 1 mL cell with a 1 dm path length. For low (MS) and High (HRMS) resolution, m/z ratios are reported as values in atomic mass units. All the reagents and solvents were reagent grade and used without further purification unless specified otherwise. Technical grade ethyl acetate and petroleum ether used for column chromatography were distilled prior to use. Tetrahydrofuran (THF) when used as solvent for the reactions was freshly distilled from sodium benzophenone ketyl and the solvents acetonitrile and dichloromethane prior to use were dried using CaH2. Column chromatography was carried out using silica gel (60e120 mesh and 100e200 mesh) or neutral Al2O3 packed in glass columns. All the reactions were performed under an atmosphere of nitrogen in flame-dried or oven-dried glassware with magnetic stirring. 4.1.1. (S)-Benzyl 1-(tert-butyldimethylsilyloxy)-4-oxobutan-2ylcarbamate (7). To a mixture of 6 (2.0 g, 5.25 mmol) in anhydrous toluene (20 mL), DIBAL-H (7.8 mL, 1 M in toluene, 7.8 mmol) was added slowly at 78 C under N2. The mixture was stirred at 78 C for 10 min. After completion of the reaction (monitored by TLC) the mixture was quenched with aqueous saturated sodium potassium tartrate (20 mL), diluted with ethyl acetate (20 mL), stirred for 3 h at rt by which time two layers formed. The organic layers were separated and the aqueous layer was extracted with ethyl acetate (230 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexanes/EtOAc 7:3) to afford pure 7 (1.65 g, 90%) as a white solid. Rf (30% EtOAc/hexanes) 0.6; mp: 58e60 C; ½a27 D 10.3 (c 1.0, CHCl3); IR (KBr): vmax 3442, 2928, 2855, 2738, 1723, 1253, 1512, 1064, 837 cm1; 1H NMR (300 MHz, CDCl3) d 9.75 (s, 1H, HCO), 7.38e7.25 (m, 5H, Ph), 5.17 (br d, J¼7.9 Hz, 1H, HN), 5.06 (s, 2H, CH2ePh), 4.20e4.06 (br m, 1H, HCeN), 3.74e3.60 (m, 2H, CH2eOSi), 2.73e2.63 (br m, 2H, CH2eCO), 0.89 (s, 9H, tBu-Si), 0.04 (s, 6H, Si(CH3)2); 13C NMR (75 MHz, CDCl3): d 200.6, 155.7, 136.2, 128.5 (2C), 128.1, 128.0 (2C), 66.8, 64.3, 48.2, 45.4, 25.8 (3C), 18.2, -5.6 (2C); MS (ESI): m/z 352 (MþH)þ; HRMS (ESI): (m/z) calcd for C18H30NO4Si [MþH]þ, 352.1939; found 352.1940. 4.1.2. Dimethyl 5-hydroxy-2-oxopentylphosphonate (9)13. n-Butyl lithium (14 mL, 2.5 M in hexanes, 35 mmol) was added to a solution of dimethyl methylphosphonate (4.7 g, 38.3 mmol) in tetrahydrofuran (60 mL) at 78 C. The mixture was stirred for 1 h and the gbutyrolactone 8 (1 g, 11.6 mmol) in tetrahydrofuran (10 mL) was added drop wise. After 1 h, water (20 mL) was added, slowly
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warmed to rt and the mixture poured into dichloromethane (100 mL). The aqueous layer was extracted with dichloromethane (320 mL). The combined organic extracts were washed with water (40 mL), dried over Na2SO4, and concentrated under reduced pressure. Flash column chromatography of the residue using hexane/ethyl acetate/methanol (10:2:1) as eluent gave the b-keto phosphonate 9 (1.9 g, 80%), as a colorless oil, which present as the mixture of ketoelactol form. Rf (10% MeOH/CH2Cl2) 0.5.
1 H NMR (300 MHz, CDCl3): d 3.78 (dd, J¼5.2, 9.8 Hz, 1H, CH2eOSi), 3.38 (dd, J¼6.7, 9.8 Hz, 1H, CH2eOSi), 3.19 (td, J¼2.2, 9.0 Hz, 1H, HeqeC(3)), 2.10e1.99 (m, 2H, HaxeC(3), H-C(5)) 1.91e1.55 (m, 7H, CeCH2eC, including HeC(9)), 1.46e0.99 (m, 4H, CeCH2eC), 0.89 (s, 9H, tBu-Si), 0.04 (s, 6H, Si(CH3)2); 13C NMR (75 MHz, CDCl3): d 66.8, 65.3, 65.0, 51.9, 30.9, 29.9, 29.0, 25.9 (3C), 24.2, 20.8, 18.2, 5.4 (2C); MS (ESI): m/z 270 (MþH)þ; HRMS (ESI): (m/z) calcd for C15H32NOSi [MþH]þ, 270.2253; found 270.2258.
4.1.3. (S,E)-Benzyl 1-(tert-butyldimethylsilyloxy)-9-hydroxy-6oxonon-4-en-2-ylcarbamate (10). To a solution of keto phosphonate 9 (1.08 g, 5.17 mmol) in THF (50 mL) was added Ba(OH)2$8H2O (3.5 g, 20.6 mmol) under N2 and stirred for 45 min at rt. The reaction mixture was cooled to 0 C, added aldehyde 7 (1.6 g, 4.7 mmol) in 20 mL of THF/H2O (40:1) slowly and mixture was allowed to warm to rt and stirring continued for 4 h. The reaction mixture was diluted with CH2Cl2 (50 mL), organic layer was washed with aqueous saturated NaHCO3 (50 mL), brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, hexanes/EtOAc 1:1) afforded enone 10 (1.8 g, 89%) as a colorless oil. Rf (50% EtOAc/hexanes) 0.3; ½a23 D 8.43 (c 1.6, CHCl3); IR (KBr): vmax 3441, 3332, 2931, 2859, 1699, 1531, 1251, 838 cm1; 1H NMR (300 MHz, CDCl3): d 7.40e7.27 (m, 5H, Ph), 6.90e6.95 (m, 1H, CH2eCH]C), 6.12 (d, J¼15.8 Hz, 1H, C]CHeCO), 5.14e5.01 (m, 3H, CH2ePh, eNH), 3.94e3.79 (br m, 1H, CHeN), 3.69e3.56 (m, 4H, CH2eOSi, CH2eOH), 2.70e2.60 (br t, J¼6.7 Hz, 2H, COeCH2), 2.52e2.40 (m, 2H, CH2eC]C), 1.84 (m, 2H, CH2eCH2eCH2), 0.89 (s, 9H, tBu-Si), 0.05 (s, 6H, Si(CH3)2); 13C NMR (75 MHz, CDCl3): d 200.6, 155.9, 143.4, 136.3, 132.5, 128.5 (2C), 128.1, 128.0 (2C), 66.7, 64.3, 62.0, 51.5, 36.4, 35.1, 26.9, 25.8 (3C), 18.2, -5.5 (2C); MS (ESI): m/z 458 (MþNa)þ; HRMS (ESI): (m/z) calcd for C23H37NO5SiNa [MþNa]þ, 458.2338; found 458.2342.
4.1.6. ((5S,8aR)-Octahydroindolizin-5-yl)methanol (13). To the compound 12 (930 mg, 3.4 mmol) was added 0.1 M concd HCl (17.2 mL) in ethanol and stirred for 4 h at rt. After the completion of reaction (monitored by TLC) ethanol was evaporated to dryness under reduced pressure and added 5% HCl (10 mL). The aqueous layer was washed with diethyl ether (310 mL) and then basified with 2 N NaOH solution. The aqueous layer was extracted with diethyl ether (215 mL), dried over Na2SO4, and evaporated the solvent at <20 C under reduced pressure to furnish the desired compound 13 (445 mg, 85%) as yellow oil. Rf (10% MeOH/CH2Cl2) 0.1; ½a23 D 13.2 (c 1.1, CHCl3); IR (KBr): vmax 3364, 2927, 2861, 1726, 1459, 1280, 1055, 745 cm1; 1H NMR (300 MHz, CDCl3): d 3.72 (dd, J¼3.9, 10.7 Hz, 1H, CH2eOH), 3.43 (dd, J¼2.2, 10.7 Hz, 1H, CH2eOH), 3.21 (td, J¼2.0, 8.6 Hz, 1H, HeqeC(3)), 2.66e2.51 (br s, 1H, OH), 2.12e2.00 (m, 2H, HaxeC(3), HeC(5)), 2.00e1.52 (m, 6H, CeCH2eC, including HeC(9)), 1.47e1.07 (m, 5H, CeCH2eC); 13C NMR (75 MHz, CDCl3): d 68.0, 64.6, 64.1, 51.1, 30.3, 30.1, 27.9, 24.1, 20.4; MS (ESI): m/z 156 (MþH)þ; HRMS (ESI): (m/z) calcd for C9H18NO [MþH]þ, 156.1388; found 156.1382.
4.1.4. 3-((2R,6S)-6-((tert-Butyldimethylsilyloxy)methyl) piperidin-2yl)propan-1-ol (11). 10% Pd on C (5 mol %) was added to a degassed solution of the carbamate 10 (1.8 g, 4.18 mmol) in EtOH (0.5 M) and the heterogeneous mixture was stirred for 12 h under hydrogen atmosphere at rt. After filtration over Celite, the solvent was evaporated under reduced pressure and the crude product was purified by flash chromatography (silica gel, EtOAc) to obtain 11 (1.0 g, 90%). Rf (10% MeOH/CH2Cl2) 0.5; ½a23 D þ0.39 (c 1.2, CHCl3); IR (KBr): vmax 3620, 2931, 2858, 2362, 1693, 1516, 839 cm1; 1H NMR (300 MHz, CDCl3): d 3.91e3.70 (br s, 1H, OH), 3.59e3.40 (m, 4H, CH2eOSi, CH2eOH), 2.70e2.53 (m, 2H, CHeNH, CHeNH), 1.89e1.78 (m, 1H, CeCH2eC), 1.78e1.44 (m, 6H, CeCH2eC), 1.44e1.01 (m, 3H, CeCH2eC), 0.88 (s, 9H, tBu-Si), 0.04 (s, 6H, Si(CH3)2); 13C NMR (75 MHz, CDCl3): d 67.0, 62.5, 58.0, 56.1, 35.5, 31.7, 29.6, 27.7, 25.8 (3C), 24.1, 18.2, 5.4 (2C); MS (ESI): m/z 288 (MþH)þ; HRMS (ESI): (m/z) calcd for C15H34NO2Si [MþH]þ, 288.2358; found 288.2347. 4.1.5. (5S,8aR)-5-((tert-Butyldimethylsilyloxy)methyl) octahydroindolizine (12). To a solution of 11 (1.0 g, 3.76 mmol) in dichloromethane (30 mL) at 20 C were added Et3N (2.41 g, 3.4 mL, 23.9 mmol) and MsCl (0.45 mL, 5.64 mmol) in dichloromethane (10 mL) successively. The reaction mixture was continued to stir at 0 C for 3 h and quenched by adding water (20 mL), the layers were separated and aqueous layer was extracted with dichloromethane (230 mL). The dichloromethane extracts were washed with 1 M HCl (20 mL), water (20 mL), aqueous saturated NaHCO3 (20 mL), brine (20 mL), dried over Na2SO4, and evaporated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, hexanes/EtOAc 7:3) to obtain compound 12 (0.93 g, 92%). Rf (100% EtOAc) 0.4; ½a23 D 42.6 (c 1.4, CHCl3); IR (KBr): vmax 2929, 2857, 1464, 1253, 1102, 837, 775 cm1;
4.1.7. (S)-Ethyl 4-hydroxyoctanoate (15)16a. To a solution of hexanal (1.2 g, 8.67 mmol) and nitroso benzene (0.93 g, 8.67 mmol) in anhydrous DMSO (20 mL) was added D-proline (0.4 g, 3.5 mmol) at 20 C. The mixture was vigorously stirred for 25 min under nitrogen atmosphere. The reaction mixture was cooled to 0 C and was quickly added a premixed and cooled (0 C) solution of triethylphosphonoacetate (5.2 mL, 26.1 mmol), DBU (3.9 mL, 26.1 mmol), and LiCl (1.1 g, 26.1 mmol) in CH3CN (20 mL) at 0 C. The resulting mixture was allowed to warm to rt over 1 h, and quenched by addition of ice pieces. The acetonitrile was evaporated under reduced pressure. The reaction mixture then poured into water (60 mL) and was extracted with Et2O (550 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over Na2SO4, and concentrated in vacuo to give crude product, which was directly subjected to hydrogenation. To the crude product was added 10% Pd on C (5 mol %) in ethyl acetate (0.5 M) and the heterogeneous mixture was stirred for 12 h under hydrogen atmosphere at rt. The mixture was filtered through a pad of Celite and evaporated the solvent in vacuo. The crude product was then purified by using flash column chromatography (silica gel, hexanes/EtOAc 9.5:0.5) to obtain g-hydroxy ester 15 as a colorless liquid (1.0 g, 62%). Rf (20% EtOAc/hexanes) 0.3; ½a27 D 1.2 (c 2.24, CHCl3); 1H NMR (300 MHz, CDCl3): d 4.12 (q, J¼7.5 Hz, 2H, OCH2), 3.62e3.52 (m, 1H, OCH), 2.41 (t, J¼7.5 Hz, 2H, CH2eCO), 1.99e1.57 (m, 3H, CH2eCH2eCO, CHeOH), 1.50e1.21 (m, 6H, CeCH2eC), 1.26 (t, J¼7.5 Hz, 3H, OCH2eCH3), 0.95e0.86 (m, 3H, CH3eCH2); 13C NMR (75 MHz, CDCl3): d 174.0, 70.8, 60.1, 36.9, 31.8, 30.4, 27.5, 22.3, 13.8, 13.7. 4.1.8. (S)-Dimethyl 5-hydroxy-2-oxononylphosphonate (16). n-Butyl lithium (9 mL, 2.5 M in hexane, 23 mmol) was added to a solution of dimethyl methylphosphonate (3.0 g, 25 mmol) in tetrahydrofuran (50 mL) at 78 C. The mixture was stirred for 1 h and the hydroxy ester 15 (1.4 g, 7.5 mmol) in tetrahydrofuran (10 mL) was added drop wise. After 1 h, water (10 mL) was added, slowly warmed to rt and the mixture poured into dichloromethane (100 mL). The aqueous layer was extracted with dichloromethane (320 mL). The
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combined organic extracts were washed with water (30 mL), dried over Na2SO4, and concentrated under reduced pressure. Flash column chromatography of the residue using hexanes/ethyl acetate/ methanol (10:2:1) as eluent gave the b-keto phosphonate 16 (1.2 g, 63%), as a yellow oil, which present as the mixture of ketoelactol form. Rf (100% EtOAc/hexanes) 0.4. 4.1.9. Benzyl (2S,9S,E)-1-(tert-butyldimethylsilyloxy)-9-hydroxy-6oxotridec-4-en-2-ylcarbamate (17). The reaction was carried out according to the representative procedure described for the preparation of compound 10. Aldehyde 7 (2 g, 5.69 mmol) was treated with b-keto phosphonate 16 (1.6 g, 6.2 mmol), to obtain 17 (2.4 g) in 87% yield as colorless oil. Rf (20% EtOAc/hexanes) 0.32; ½a27 D 6.9 (c 1.0, CHCl3); IR (KBr): vmax 3441, 3332, 2932, 1697, 1531, 1252, 838, 777 cm1; 1H NMR (300 MHz, CDCl3): d 7.40e7.28 (m, 5H, Ph), 6.91e6.76 (m, 1H, CH2eCH]C), 6.14 (d, J¼16.0 Hz, 1H, C]CHeCO), 5.09 (s, 2H, CH2ePh), 5.02 (br d, J¼8.8 Hz, 1H, NH), 3.92e3.79 (br m, 1H, CHeNH), 3.63 (br d, J¼2.8 Hz, 2H, CH2eOSi), 3.67e3.51 (m, 1H, CHeOH), 2.69 (t, J¼6.9 Hz, 2H, COeCH2), 2.54e2.41 (m, 2H, CH2eC]C), 1.89e1.57 (br m, 4H, CeCH2eC), 1.51e1.39 (m, 2H, CeCH2eC), 1.39e1.27 (m, 2H, CeCH2eC), 0.95e0.85 (m, 3H, CH2eCH3), 0.89 (s, 9H, tBu-Si), 0.05 (s, 6H, Si(CH3)2); 13C NMR (75 MHz, CDCl3): d 200.9, 155.9, 143.2, 136.3, 132.5, 128.5 (2C), 128.1, 128.0 (2C), 71.3, 66.8, 64.2, 51.5, 37.4, 36.2, 35.1, 31.3, 27.8, 25.8 (3C), 22.7, 18.2, 14.0, 5.5 (2C); MS (ESI): m/z 514 (MþNa)þ; HRMS (ESI): (m/z) calcd for C27H45NO5SiNa [MþNa]þ, 514.2964; found 514.2983. 4.1.10. (S)-1-((2R,6S)-6-((tert-Butyldimethylsilyloxy)methyl) piperidin-2-yl) heptan-3-ol (18). Preparation of compound 18 from compound 17 (2.4 g, 4.94 mmol) was accomplished following the procedure used for compound 11 in 83% yield (1.4 g) as colorless oil. Rf (5% MeOH/CH2Cl2) 0.5; ½a28 D þ0.06 (c 1.0, CHCl3); IR (KBr): vmax 2927, 2857, 1649, 1460, 1255, 1092, 836 cm1; 1H NMR (300 MHz, CDCl3): d 4.32e4.19 (br s, 1H, NH), 3.63 (dd, J¼10.0, 3.9 Hz, 1H, CH2eOSi), 3.54e3.46 (m, 1H, CHeOH), 3.50 (dd, J¼9.8, 6.9 Hz, 1H, CH2eOSi), 2.81e2.69 (m, 2H, CHeNH, CHeNH), 1.92e1.09 (m, 16H, CeCH2eC), 0.93e0.86 (m, 12H, CH2eCH3, tBu-Si), 0.07 (s, 6H, Si(CH3)2); 13C NMR (75 MHz, CDCl3): d 71.3, 66.4, 58.1, 55.7, 37.4, 33.3, 32.9, 30.3, 28.1, 27.2, 25.9 (2C), 23.9, 22.8, 18.3, 14.1, 5.4 (2C); MS (ESI): m/z 344 (MþH)þ; HRMS (ESI): (m/z) calcd for C19H42NO2Si [MþH]þ, 344.2984; found 344.2977. 4.1.11. ((3R,5S,8aR)-3-Butyl-octahydroindolizin-5-yl)methanol (19). The reaction was carried out using the procedure described for the preparation of compound 12 starting from 18 (1.4 g, 4 mmol) to obtain TBS protected bicyclic compound. The crude TBS ether product underwent deprotection of TBS group as described for the compound 13 to provide compound 19 (0.68 g, 78% over two steps) as colorless oil. Rf (10% MeOH/CH2Cl2) 0.1; ½a29 D 34.3 (c 0.5, CHCl3); IR (KBr): vmax 3355, 2927, 2861, 1649, 1458, 1052 cm1; 1H NMR (300 MHz, CDCl3): d 3.78 (dd, J¼11.3, 3.7 Hz, 1H, CH2eOH), 3.50 (dd, J¼11.3, 2.2 Hz, 1H, CH2eOH), 3.36 (br t, J¼8.3 Hz, 1H, HeC(3)), 2.79e2.66 (m, 1H, HeC(5)), 2.66e2.51 (m, 1H, HeC(9)), 2.04e1.88 (m, 1H, CeCH2eC), 1.88e1.77 (m, 1H, CeCH2eC), 1.71e1.62 (m, 1H, CeCH2eC), 1.60e1.41 (m, 2H, CeCH2eC), 1.39e1.02 (m, 11H, CeCH2eC), 0.91 (t, J¼6.8 Hz, 3H, CH2eCH3); 13C NMR (75 MHz, CDCl3): d 63.2, 59.1, 58.6, 57.1, 31.3, 29.5, 28.8, 27.8, 26.4, 25.9, 23.9, 22.9, 14.1; MS (ESI): m/z 212 (MþH)þ; HRMS (ESI): (m/z) calcd for C13H26NO [MþH]þ, 212.2014; found 212.2021. 4.1.12. (E)-Ethyl 3-((3R,5S,8aR)-3-butyl-octahydroindolizin-5-yl)acrylate (20). To the compound 19 (0.25 g, 1.18 mmol) in dichloromethane (2 mL), Et3N (2 mL, 14.1 mmol), and DMSO (2 mL, 28.2 mmol) was added SO3$Py (0.93 g, 5.9 mmol) at 0 C, stirred for 1 h at 0 C and slowly warmed to rt. Continued stirring for another
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30 min at rt, added (ethoxycarbonylmethylene)triphenyl phosphorane (0.5 g, 1.53 mmol) to the reaction mixture at 0 C and stirred at rt for 5 h. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (215 mL). The combined organic layers were washed with brine (10 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and crude was purified by column chromatography (silica gel, hexanes/ EtOAc 8:2) to get 20 (0.24 g, 74%) as colorless oil. Rf (100% EtOAc) 0.57; ½a26 D 46.6 (c 1.4, CHCl3); IR (KBr): vmax 2957, 2924, 2854, 1731, 1639, 1464, 1285, 1074, 721 cm1; 1H NMR (300 MHz, CDCl3): d 6.89 (dd, J¼15.8, 9.0 Hz, 1H, C]CHeCH), 5.91 (d, J¼15.8 Hz, 1H, COeCH]C), 4.18 (q, J¼7.5 Hz, 2H, CH2eCH3), 3.25e3.09 (m, 2H, HeC(3), HeC(5)), 2.49e2.33 (m, 1H, HeC(9)), 2.4e1.73 (m, 4H, CeCH2eC), 1.68e1.51 (m, 1H, CeCH2eC), 1.51e1.35 (m, 2H, CeCH2eC), 1.36e1.10 (m, 8H, CeCH2eC), 1.30 (t, J¼7.5 Hz, 3H, OCH2eCH3), 1.11e0.93 (m, 1H, CeCH2eC), 0.87 (t, J¼6.8 Hz, 3H, CH2eCH3); 13C NMR (75 MHz, CDCl3): d 166.6, 151.1, 120.9, 60.2, 59.7, 59.1, 58.1, 32.6, 31.8, 29.8, 28.7, 26.3, 25.5, 24.1, 22.8, 14.2, 14.0; MS (ESI): m/z 280 (MþH)þ; HRMS (ESI): (m/z) calcd for C17H30NO2 [MþH]þ, 280.2276; found 280.2288. 4.1.13. ()-Indolizidine 239AB (3). To a solution of compound 20 (240 mg, 0.86 mmol) in ethyl acetate (4 mL), 10% PdeC (5 mol %) was added and stirred for 12 h under hydrogen atmosphere. The mixture was filtered through a plug of Celite, washed with diethyl ether (10 mL), and concentrated at <20 C under reduced pressure to give saturated ester as yellow oil (228 mg, 95%), which was used for the next step without further purification. The above compound (228 mg, 0.81 mmol) in THF (2 mL) was added to a suspension of LiAlH4 (62 mg, 1.63 mmol) in THF (5 mL) at 0 C, warmed to rt slowly and continued stirring for 1 h at rt. After the completion of reaction (monitored by TLC), the mixture was cooled to 0 C, quenched slowly by adding few drops of 10% aqueous NaOH solution. The reaction mixture was stirred for 2 h and filtered through a small pad of Celite, washed with diethyl ether (10 mL), dried over Na2SO4, and concentrated under reduced pressure at <20 C. The residue was purified by column chromatography (neutral alumina, hexanes/diethyl ether 9:1) to get 3 (164 mg, 85%) as pale yellow oil. Rf (5% MeOH/EtOAc) 0.1; ½a30 D 92 (c 0.4, MeOH); IR (KBr): vmax 3459, 2924, 2852, 1639, 1463, 1378, 697 cm1; 1H NMR (300 MHz, CDCl3): d 3.63e3.53 (m, 1H, CH2eOH), 3.52e3.39 (m, 1H, CH2eOH), 3.35e3.26 (m, 1H, HeC(3)), 2.64e2.55 (m, 1H, HeC(5)), 2.49e2.39 (m, 1H, HeC(9)), 1.99e1.41 (m, 9H, CeCH2eC), 1.39e0.98 (m, 12H, CeCH2eC), 0.90 (t, J¼5.8 Hz, 3H, CH2eCH3); 13C NMR (75 MHz, CDCl3): d 62.6, 60.3, 58.9, 56.3, 30.3, 29.7, 29.6, 29.0, 28.5, 28.4, 27.8, 25.7, 23.9, 22.7, 14.0; MS (ESI): m/z 240 (MþH)þ; HRMS (ESI): (m/z) calcd for C15H31NO [MþH]þ, 240.2322; found 240.2329. 4.1.14. (3R,5S,8aR)-3-Butyl-5-(chloromethyl)-octahydroindolizine (21). To the compound 19 (0.25 g, 1.18 mmol) in THF (5 mL) was added SOCl2 (0.12 mL, 1.77 mmol) at 0 C under nitrogen atmosphere. The reaction mixture was allowed to rt and heated for 20 min at 50 C. The mixture was cooled to 0 C and quenched with saturated aqueous NH4Cl (5 mL) and extracted with diethyl ether (210 mL). The organic layer was dried over Na2SO4 and concentrated at <20 C under reduced pressure. The residue was purified by flash column chromatography (silica gel, hexanes/EtOAc 8:2) to get the compound 21 (0.21 g, 78%) as a colorless oil. Rf (30% EtOAc/ hexanes) 0.43; ½a26 D 47.2 (c 0.5, CHCl3); IR (KBr): vmax 2952, 2854, 1644, 1463, 1379, 1274, 1083, 739 cm1; 1H NMR (300 MHz, CDCl3): d 3.64 (dd, J¼3.0, 10.5 Hz, 1H, CH2eCl), 3.34 (dd, J¼7.5, 10.5 Hz, 1H, CH2eCl), 3.21 (br t, J¼9.1 Hz, 1H, HeC(3)), 2.74e2.65 (m, 1H, HeC(5)), 2.48e2.37 (m, 1H, HeC(9)), 1.99e1.73 (m, 4H, CeCH2eC), 1.52e1.00 (m, 12H, CeCH2eC), 0.91 (t, J¼6.8 Hz, 3H, CH2eCH3); 13C NMR (75 MHz, CDCl3): d 59.0, 58.5, 57.5, 47.1, 31.8, 29.7, 29.6, 28.9,
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26.5, 25.2, 24.0, 22.9, 14.1; MS (ESI): m/z 230 (MþH)þ; HRMS (ESI): (m/z) calcd for C13H25ClN [MþH]þ, 230.1670; found 230.1671. 4.1.15. ()-Indolizidine 195B (4). Compound 21 (200 mg, 0.87 mmol) in dry THF (2 mL) was added to the suspension of LiAlH4 (70 mg, 1.84 mmol) in THF (3 mL) at 0 C, allowed to rt and it was refluxed for 12 h. After the completion of reaction (monitored by TLC), the mixture was cooled to 0 C, quenched with aqueous 10% NaOH, stirred for 2 h and filtered through a pad of Celite, washed with diethyl ether (10 mL). The organic solvent was evaporated under reduced pressure at <20 C and the residue was purified by flash column chromatography (neutral alumina, hexanes/diethyl ether 9:1) to get compound 4 as a pale yellow oil (139 mg, 82%). Rf (50% MeOH/CH2Cl2) 0.1; ½a27 D 61 (c 0.5, MeOH); IR (KBr): vmax 2956, 2923, 2852, 1637, 1463, 1377, 1248, 772 cm1; 1 H NMR (300 MHz, CDCl3): d 3.24 (br t, J¼7.9 Hz, 1H, HeC(3)), 2.57e2.44 (m, 1H, HeC(5)), 2.43e2.31 (m, 1H, HeC(9)), 1.94e1.65 (m, 4H, CeCH2eC), 1.62e1.15 (m, 12H, CeCH2eC), 1.08 (d, J¼6.2 Hz, 3H, CHeCH3), 0.90 (t, J¼6.9 Hz, 3H, CH2eCH3); 13C NMR (75 MHz, CDCl3): d 60.0, 59.3, 53.2, 33.2, 30.8, 29.6, 29.2, 28.7, 25.9, 24.2, 22.8, 19.5, 14.1; MS (ESI): m/z 196 (MþH)þ; HRMS (ESI): (m/z) calcd for C13H26N [MþH]þ, 196.2065; found 196.2058. 4.1.16. (R)-Ethyl 4-hydroxyoctanoate (15a)16b. Preparation of compound 15a (ent-15) from compound 14 (2 g, 19.9 mmol) was accomplished following the procedure used for compound 15 (by using L-proline, 40 mol %) in 61% yield (2.2 g) as colorless oil. ½a27 D þ1.0 (c 2.24, CHCl3); 1H NMR (300 MHz, CDCl3): d 4.12 (q, J¼7.5 Hz, 2H, OCH2), 3.62e3.52 (m, 1H, OCH), 2.41 (t, J¼7.5 Hz, 2H, CH2eCO), 1.99e1.57 (m, 3H, CH2eCH2eCO, CHeOH), 1.50e1.21 (m, 6H, CeCH2eC), 1.26 (t, J¼7.5 Hz, 3H, OCH2eCH3), 0.95e0.86 (m, 3H, CH3eCH2); 13C NMR (75 MHz, CDCl3): d 174.0, 70.8, 60.1, 36.9, 31.8, 30.4, 27.5, 22.3, 13.8, 13.7. 4.1.17. (R)-Dimethyl 5-hydroxy-2-oxononylphosphonate (16a). The reaction was carried out according to the representative procedure described for the preparation of compound 16. (R)-Hydroxy ester 15a (2 g, 10.6 mmol) was treated with (dimethoxyphosphoryl) methanide (3 equiv) to obtain 16a (ent-16) as a pale yellow oil (1.8 g, 65%), which present as the mixture of ketoelactol form. 4.1.18. Benzyl (2S,9R,E)-1-(tert-butyldimethylsilyloxy)-9-hydroxy-6oxotridec-4-en-2-ylcarbamate (22). The reaction was carried out according to the representative procedure described for the preparation of compound 10. Aldehyde 7 (1 g, 2.87 mmol) was treated with b-keto phosphonate 16a (840 mg, 3.15mmol), to obtain 22 (1.2 g) in 86% yield as colorless oil. Rf (20% EtOAc/hexanes) 0.32. 1 ½a24 D 13.5 (c 1.1, CHCl3); H NMR (300 MHz, CDCl3): d 7.42e7.27 (m, 5H, Ph), 6.91e6.71 (m, 1H, CH2eCH]C), 6.13 (d, J¼15.8 Hz, 1H, C] CHeCO), 5.22e4.98 (m, 3H, CH2ePh, NH), 3.97e3.78 (br m, 1H, CHeNH), 3.74e3.48 (br m, 3H, CH2eOSi, CHeOH), 2.76e2.60 (m, 2H, COeCH2), 2.56e2.36 (m, 2H, CH2eC]C), 1.89e1.58 (m, 3H, CeCH2eC), 1.50e1.19 (m, 5H, CeCH2eC), 0.88 (s, 12H, tBu-Si), 0.04 (s, 6H, Si(CH3)2); 13C NMR (75 MHz, CDCl3): d 200.9, 155.8, 143.3, 136.3, 132.6, 128.5 (2C), 128.2, 128.1, 128.0, 71.2, 66.7, 64.2, 51.5, 37.3, 35.2, 35.1, 31.3, 27.8, 25.8 (3C), 22.7, 18.2, 14.0, 5.5 (2C); MS (ESI): m/z 514 (MþNa)þ; HRMS (ESI): (m/z) calcd for C27H45NO5SiNa [MþNa]þ, 514.2959; found 514.2993.
2.59e2.46 (m, 1H, CHeNH),1.93e1.81 (br d, J¼13.6 Hz, 1H, CHeOH), 1.72e1.04 (br m, 16H, CeCH2eC), 0.90 (s, 12H, tBu-Si), 0.06 (s, 6H, Si(CH3)2); 13C NMR (75 MHz, CDCl3): d 71.6, 67.1, 58.4, 57.8, 37.3, 34.8, 33.6, 31.8, 27.9, 26.7, 25.8 (3C), 23.7, 22.6, 18.2, 13.9, 5.5, 5.4; MS (ESI): m/z 344 (MþH)þ; HRMS (ESI): (m/z) calcd for C19H42NO2Si [MþH]þ, 344.2979; found 344.3000. 4.1.20. ((3S,5S,8aR)-3-Butyl-octahydroindolizin-5-yl) methanol (24). Compound 23 (700 mg, 2 mmol) was transformed to compound 24 (337 mg) according to the representative procedure described for the preparation of compound 19 in 78% yield as colorless 1 oil. Rf (10% MeOH/CH2Cl2) 0.1. ½a26 D þ6.75 (c 1.5, CH2Cl2); H NMR (300 MHz, CDCl3): d 3.73 (dd, J¼11.3, 4.5 Hz, 1H, CH2eOH), 3.50 (dd, J¼11.3, 3.0 Hz, 1H, CH2eOH), 2.56 (br t, J¼9.0 Hz, 1H, HeC(3)), 2.29e2.18 (m, 1H, HeC(5)), 2.18e2.06 (m, 1H, HeC(9)), 1.91e1.54 (m, 6H, CeCH2eC), 1.49e1.15 (m, 10H, CeCH2eC), 0.89 (t, J¼6.7 Hz, 3H, CH2eCH3); 13C NMR (75 MHz, CDCl3): d 67.4, 65.9, 65.1, 62.9, 38.3, 30.4, 29.9, 29.6, 29.5, 29.3, 24.4, 22.9, 14.2; MS (ESI): m/z 212 (MþH)þ; HRMS (ESI): (m/z) calcd for C13H26NO [MþH]þ, 212.2009; found 212.2024. 4.1.21. (3S,5S,8aR)-3-Butyl-5-(chloromethyl)octahydroindolizine (25). The reaction was carried out according to the representative procedure described for the preparation of compound 21. Compound 24 (300 mg, 1.42 mmol) was treated with SOCl2 (0.15 mL, 2.1 mmol) to obtain 25 (244 mg, 75%) as pale yellow color oil. Rf 1 (30% EtOAc/hexanes) 0.45; ½a27 D 24.1 (c 1.4, CHCl3); H NMR (300 MHz, CDCl3): d 3.66 (d, J¼10.3 Hz, 1H, CH2eCl), 3.41 (dd, J¼10.3, 7.5 Hz, 1H, CH2eCl), 2.50e2.33 (m, 1H, HeC(3)), 2.74e2.65 (m, 1H, HeC(5)), 2.23e2.06 (m, 1H, HeC(9)), 1.99e1.58 (m, 4H, CeCH2eC), 1.57e1.12 (m, 12H, CeCH2eC), 0.90 (t, J¼6.9 Hz, 3H, CH2eCH3); 13C NMR (75 MHz, CDCl3): d 67.4, 65.4, 62.2, 48.6, 39.3, 30.7, 29.9, 29.7, 29.5, 29.1, 24.2, 22.8, 14.0; MS (ESI): m/z 230 (MþH)þ; HRMS (ESI): (m/z) calcd for C13H25ClN [MþH]þ, 230.1670; found 230.1687. 4.1.22. ()-Monomorine (5). Compound 25 (100 mg, 0.43 mmol) was treated with LiAlH4 (35 mg, 0.92 mmol) as described in the procedure for the preparation of compound 4 to obtain ()-monomorine 5 (65 mg, 80%). Rf (50% MeOH/CH2Cl2) 0.1; ½a28 D 30.5 (c 0.9, n-hexane); IR (KBr): vmax 2925, 2860, 1733, 1516, 1458, 1271, 1066 cm1; 1H NMR (300 MHz, CDCl3): d 2.47 (br t, J¼9.4 Hz, 1H, HeC(3)), 2.29e2.15 (m, 1H, HeC(5)), 2.13e1.99 (m,1H, HeC(9)), 1.91e1.49 (br m, 6H, CeCH2eC), 1.49e1.15 (br m, 10H, CeCH2eC), 1.13 (d, J¼6.4 Hz, 3H, CHeCH3), 0.89 (t, J¼6.9 Hz, 3H, CH2eCH3); 13C NMR (75 MHz, CDCl3): d 67.1, 62.9, 60.2, 39.6, 35.8, 30.8, 30.3, 29.7, 29.4, 24.8, 22.9, 22.8, 14.1; MS (ESI): m/z 196 (MþH)þ; HRMS (ESI): (m/z) calcd for C13H26N [MþH]þ, 196.2065; found 196.2067. Acknowledgements B.L. and N.N.R. thank Council of Scientific and Industrial Research (CSIR), New Delhi for research fellowships. The authors are thankful to the reviewers for their valuable suggestions in improving the quality of the manuscript. Supplementary data 1
4.1.19. (R)-1-((2R,6S)-6-((tert-Butyldimethylsilyloxy)methyl) piperidin-2-yl)heptan-3-ol (23). Compound 22 (1.2 g, 2.46 mmol) on hydrogenation according to procedure described for preparation of compound 11 yields 23 (700 mg, 83%) as colorless oil. Rf (5% MeOH/ 1 CH2Cl2) 0.5; ½a26 D 5.61 (c 1.6, CHCl3); H NMR (300 MHz, CDCl3): d 3.59 (dd, J¼9.8, 3.7 Hz, 1H, CH2eOSi), 3.51 (dd, J¼9.8, 6.0 Hz, 1H, CH2eOSi), 3.53e3.42 (m, 1H, CHeOH), 2.69e2.59 (m, 1H, CHeNH),
H and 13C NMR spectra for all the new compounds. Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.tet.2011.10.076. References and notes 1. (a) Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68, 1556e1575; (b) Jones, T. H.; Voegtle, H. L.; Miras, H. M.; Weatherford, R. G.; Spande, T. F.;
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2.
3.
4.
5.
6.
7.
8.
9.
10.
Garraffo, H. M.; Daly, J. W.; Davidson, D. W.; Snelling, R. R. J. Nat. Prod. 2007, 70, 160e168; (c) Michael, J. P. Nat. Prod. Rep. 2007, 24, 191e222; (d) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139e165; (e) Huang, P.-Q. In Asymmetric Synthesis of Nitrogen Heterocycles; Royer, J., Ed.; Wiley: Weinheim, 2009. (a) Daly, J. W.; Brown, G. B.; Mensahdwumah, M.; Myers, C. W. Toxicon 1978, 16, 163e188; (b) Erspamer, V.; Melchiorri, P. Trends Pharmacol. Sci. 1980, 1, 391e395; (c) Daly, J. W.; Spande, T. F. Alkaloids: Chem. Biol. Perspect. 1986, 4, 1e274; (d) Elbein, A. D.; Molyneux, R. J. Alkaloids 1987, 5, Chapter 1; (e) Daly, J. W.; Myers, C. W.; Whittaker, N. Toxicon 1987, 25, 1023e1095. (a) Holmes, A. B.; Smith, A. L.; Williams, S. F.; Hughes, L. R.; Lidert, Z.; Swithenbank, C. J. Org. Chem. 1991, 56, 1393e1405; (b) Machinaga, N.; Kibayashi, C. J. Org. Chem. 1992, 57, 5178e5189; (c) Kiddle, J. J.; Green, D. L. C.; Thompson, C. M. Tetrahedron 1995, 51, 2851e2864; (d) Celimene, C.; Dhimane, H.; Saboureau, A.; Lhommet, G. Tetrahedron: Asymmetry 1996, 7, 1585e1588; (e) Chenevert, R.; Ziarani, G. M.; Dasser, M. Heterocycles 1999, 51, 593e598; (f) Back, T. G.; Nakajima, K. Org. Lett. 1999, 1, 261e263; (g) Back, T. G.; Nakajima, K. J. Org. Chem. 2000, 65, 4543e4552; (h) Amat, M.; Llor, N.; Hidalgo, J.; Escolano, C.; Bosch, J. J. Org. Chem. 2003, 68, 1919e1928; (i) Varga, T. R.; Nemes, P.; Mucsi, Z.; Scheiber, P. Tetrahedron Lett. 2007, 48, 1159e1161; (j) Barbe, G.; Pelletier, G.; Charette, A. B. Org. Lett. 2009, 11, 3398e3401. (a) Reddy, C. R.; Rao, N. N. Tetrahedron Lett. 2009, 50, 2478e2480; (b) Chandrasekhar, S.; Murali, R. V. N. S.; Reddy, C. R. Tetrahedron Lett. 2009, 50, 5686e5688; (c) Reddy, C. R.; Rao, N. N.; Srikanth, B. Eur. J. Org. Chem. 2010, 345e351. Representative references for synthesis of ()-167B: (a) Polniaszek, R. P.; Belmont, S. E. J. Org. Chem. 1990, 55, 4688e4693; (b) Lee, E.; Li, K. S.; Lim, J. Tetrahedron Lett. 1996, 37, 1445e1446; (c) Carbonnel, S.; Troin, Y. Heterocycles 2002, 57, 1807e1830; (d) Zaminer, J.; Stapper, C.; Blechert, S. Tetrahedron Lett. 2002, 43, 6739e6741; (e) Corvo, M. C.; Pereira, M. M. A. Tetrahedron Lett. 2002, 43, 455e458; (f) Reddy, P. G.; Baskaran, S. J. Org. Chem. 2004, 69, 3093e3101; (g) Roa, L. F.; Gnecco, D.; Galindo, A.; Teran, J. L. Tetrahedron: Asymmetry 2004, 15, 3393e3395; (h) Guazzelli, G.; Lazzaroni, R.; Settambolo, R. Synthesis 2005, 3119e3123; (i) Sun, Z.; Yu, S.; Ding, Z.; Ma, D. J. Am. Chem. Soc. 2007, 129, 9300e9301; (j) Stead, D.; Obrien, P.; Sanderson, A. Org. Lett. 2008, 10, 1409e1412; (k) Kapat, A.; Nyfeler, E.; Giuffredi, G. T.; Renaud, P. J. Am. Chem. Soc. 2009, 131, 17746e17747; (l) Gracia, S.; Jerpan, R.; Pellet-Rostaing, S.; Popowycz, F.; Lemaire, M. Tetrahedron Lett. 2010, 51, 6290e6293. Representative references for synthesis of ()-209D: (a) Takahata, H.; Kubota, M.; Ihara, K.; Okamoto, N.; Momose, T.; Azer, N.; Eldefrawi, A. T.; Eldefrawi, M. E. Tetrahedron: Asymmetry 1998, 9, 3289e3301; (b) Yamazaki, N.; Ito, T.; Kibayashi, C. Org. Lett. 2000, 2, 465e467; (c) Kim, G.; Lee, E. J. Tetrahedron: Asymmetry 2001, 12, 2073e2076; (d) Kim, G.; Jung, S.; Kim, W. Org. Lett. 2001, 3, 2985e2987; (e) Patil, N. T.; Pahadi, N. K.; Yamamoto, Y. Tetrahedron Lett. 2005, 46, 2101e2103; (f) Yu, R. T.; Lee, E. E.; Malik, G.; Rovis, T. Angew. Chem., Int. Ed. 2009, 48, 2379e2382; (g) Liu, H.; Su, D.; Cheng, G.; Xu, J.; Wang, X.; Hu, Y. Org. Biomol. Chem. 2010, 8, 1899e1904. For isolation of ()-239AB see: (a) Skrinjar, M.; Wistrand, L. G. Tetrahedron Lett. 1990, 31, 1775e1778 For synthesis of ()-239AB see: (b) Thanh, G. V.; Celerier, J.-P.; Lhommet, G. Tetrahedron: Asymmetry 1996, 7, 2211e2212; (c) Celimene, C.; Dhimane, H.; Lhommet, G. Tetrahedron 1998, 54, 10457e10468; (d) Dhimane, H.; Vanucci-Bacque, C.; Hamon, L.; Lhommet, G. Eur. J. Org. Chem. 1998, 9, 1955e1963. For isolation of ()-195B see: (a) Edwards, M. W.; Daly, J. W. J. Nat. Prod. 1988, 51, 1188e1197 Representative references for synthesis of ()-195B: (b) Angle, S. R.; Kim, M. J. Org. Chem. 2007, 72, 8791e8796; (c) Davis, F. A.; Zhang, J.; Wu, Y. Tetrahedron Lett. 2011, 52, 2054e2057. Representative references for synthesis of ()-monomorine: (a) Royer, J.; Husson, H. P. J. Org. Chem. 1985, 50, 670e673; (b) Jefford, C. W.; Sienkiewicz, K.; Thornton, S. R. Tetrahedron Lett. 1994, 35, 4759e4762; (c) Zhang, S. H.; Xu, L.; Miao, L.; Shu, H.; Trudell, M. L. J. Org. Chem. 2007, 72, 3133e3136; (d) Pattenden, L. S.; Adams, H.; Smith, S. A.; Harrity, J. P. A. Tetrahedron 2008, 64, 2951e2961; (e) Toyooka, N.; Zhou, D. J.; Nemoto, H. J. Org. Chem. 2008, 73, 4575e4577. The similar aldehyde with different protecting groups is little explored. For references see: (a) Ofuna, Y.; Hori, K. Jpn. Kokai Tokkyo Koho, JP 63063673 A 19880322, 1988. (b) Acharya, H. P.; Clive, D. L. J. J. Org. Chem. 2010, 75, 5223e5233; (c) Alvaro, G.; Amantini, D.; Castiglioni, E.; Fabio, R. D.; Pavone, F. PCT Int. Appl. WO 2010063662 A1 2010610, 2010.
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11. Andres, J. M.; Munoz, E. M.; Pedrosa, R.; Perez-Encabo, A. Eur. J. Org. Chem. 2003, 3387e3397. 12. Compounds 9 and 16 exist as a mixture of keto and lactol forms, which was confirmed by 1H NMR.
O P O O
O
O R OH
OH P O O O
R = H, 9 R = n-Bu, 16 R
13. Folker, L. Ger. Offen. DE2711010, 1978. 14. NOE experiment has been carried out on known acetyl derivative of alcohol 13 and key NOE enhancements are shown below.
15. To determine the enantiomeric excess of (S)-ethyl 4-hydroxyoctanoate 15 by chiral HPLC, it was converted to p-nitro benzoate derivative under DCC/DMAP reaction conditions using p-nitrobenzoic acid. Chiral HPLC: Chiralcel OD-H column (2504.6 mm, 5 m), isopropanol/hexanes¼7:93, flow rate 1.0 mL/min, l 210 nm. Retention time (min): 7.32 (major) and 7.96 (minor); ee 94%; Rf (20% 1 EtOAc/hexanes) 0.55; ½a20 D þ12.3 (c 0.6, CHCl3); H NMR (300 MHz, CDCl3): d 8. 29 (d, J¼8.7 Hz, 2H, CH(Ar)), 8.20 (d, J¼8.7 Hz, 2H, CH(Ar)), 5.23e5.17 (m, 1H, OeCH), 4.14e4.02 (m, 2H, OCH2eCH3), 2.39 (t, J¼7.6 Hz, 2H, CH2eCO), 2.15e1. 97 (m, 2H, CH2eCH2eCO), 1.81e1.62 (m, 2H, CH2eCHeO), 1.44e1.27 (m, 4H, CeCH2eC), 1.21 (t, J¼7.6 Hz, 3H, OCH2eCH3), 0.89 (t, J¼7.6 Hz, 3H, CH3eCH2); 13 C NMR (75 MHz, CDCl3): d 172.8, 164.2, 150.5, 135.7, 130.6, 123.5, 75.4, 60.5, 33.7, 30.3, 29.1, 27.3, 22.4, 14.1, 13.8.
16. (a) Kondekar, N. B.; Kumar, P. Org. Lett. 2009, 11, 2611e2614; (b) Jha, V.; Kondekar, N. B.; Kumar, P. Org. Lett. 2010, 12, 2762e2765. 17. The enantiomeric excess of (R)-ethyl 4-hydroxyoctanoate 15a was determined by converting it to p-nitro benzoate derivative under DCC/DMAP reaction conditions using p-nitrobenzoic acid. Chiral HPLC: Chiralcel OD-H column (2504.6 mm, 5 m), isopropanol/hexanes¼7:93, flow rate 1.0 mL/min, l 210 nm. Retention time (min): 7.39 (minor) and 8.00 (major); ee 94%; Rf (20% EtOAc/ hexanes) 0.55; ½a20 D 12.9 (c 0.6, CHCl3).