Hindawi Publishing Corporation Organic Chemistry International Volume 2014, Article ID 982716, 7 pages http://dx.doi.org/10.1155/2014/982716 Research Article Stereoselective Synthesis of (+)--Conhydrine from R-(+)-Glyceraldehyde Nageshwar Rao Penumati and Nagaiah Kommu Fine Chemicals Laboratory, Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500607, India Correspondence should be addressed to Nagaiah Kommu; [email protected] Received 22 August 2014; Revised 27 September 2014; Accepted 27 September 2014; Published 20 October 2014 Academic Editor: Ashraf Aly Shehata Copyright © 2014 N. R. Penumati and N. Kommu. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Stereoselective synthesis of (+)--Conhydrine was accomplished from protected (R)-(+)-glyceraldehyde, a familiar carbohydrate predecessor. Our synthetic strategy featured the following two key reactions. One is Zn-mediated stereoselective aza-Barbier reaction of imine 6 with allyl bromide to afford chiral homoallylic amine 7, and the other is ring-closing metathesis. 1. Introduction In view of the interesting biological and structural prop- erties, especially the nitrogen containing alkaloids makes (+)- Exploiting natural products to ascertain a lead has always -Conhydrine 1 as an attractive and challenging synthetic tar- been important technique in drug discovery. Nature pro- get. As mentioned above (+)--Conhydrine 1 was synthesized vides a rich source of bioactive compounds with significant from various synthetic routes which involve a large number biological activity and has therefore received considerable of steps to obtain the target molecule. Thus development attention from the synthetic organic communities. The major of new methods for the synthesis of (+)--Conhydrine 1 class of biologically active molecules containing substituted constitutes an area of current interest. Herein, an efficient piperidines has been widely present in the nature. The efforts synthesis of (+)--Conhydrine 1 has been designed starting to find a short and high yielding synthetic route for this from 2,3-isopropylidene-R-(+)-Glyceraldehyde, by means of class of natural products were always a contemporary interest. Zn-mediated stereoselective Barbier allylation as a key step, Some of the hydroxylated piperidine alkaloids are reported to which was developed previously for the synthesis of different be highly toxic and have drawn significant attention through natural products in our laboratory [19–22]. To the best of our their biological activity [1–3]. knowledge synthesis of (+)--Conhydrine via aza-Barbier Conhydrineisoneoftheclassesofalkaloidswhichwere zinc allylation was not reported so far. isolated by Wertheim from the poisonous plant, Conium maculatum L[4], in 1856. A highly fatal toxin causing 2. Materials and Methods paralysis of the skeletal musculature, 2-(1-hydroxyalkyl)- piperidine is a recurrent unit in many alkaloids such as All reagents were purchased from Aldrich (Sigma-Aldrich, Homopumiliotoxin 223 G 2,Slaframine3,andCastanosper- Bangalore, India). All reactions were monitored by TLC, mine 4 (Figure 1).Sincethepioneeringstudiesonthe performed on silica gel glass plates containing 60 F-254. synthesis of (+)--Conhydrine 1 by Galinovasky and Mulley Column chromatography was performed with Merck 60– [5], various methods have been reported normally based on 120 mesh silica gel. IR spectra were recorded on a Perkin- 1 auxiliarysupportedorchiralpoolapproach[6–18]. Elmer RX-1 FT-IR system. H NMR spectra were recorded on 2 Organic Chemistry International OH HO -OCH), 3.80 (d, J =6.0Hz,1H,HofOCH2), 3.71 (d, J = H 6.8 Hz, 1H, H of OCH2), 3.61 (d, J=5.9 Hz, 1H, allylic NCH2), 3.55 (q, J=8.1 Hz, 1H, allylic NCH2), 2.70 (q, J =5.9 Hz, 1H homoallylic NCH), 2.35 (q, J =7.3Hz,2H,allylicCH2), 1.43 HN N 13 (s, 6H, 2xCH3); C NMR (75 MHz, CDCl3): 137.0, 134.9, 117.7, (+)--Conhydrine 1 Homopumiliotoxin 223 G 2 115.6, 108.6, 77.6, 66.6, 57.9, 50.3, 35.0, 25.3, 25.2; IR (neat): 3404, 3068, 3028, 2926, 2855, 2801, 1640, 1494, 1417, 1368, OAc OH OH −1 H H 1250,1069,1029,994cm ;ESIMS:m/z = 212 (M+H); HRMS HO (ESI): m/z calculated for C12H22NO2 (M+H) 212.1650, found 212.1652. N N H2N HO 2.2. tert-Butyl-allyl((S)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl) (−) Slaframine 3 (−) Castanospermine 4 but-3-enyl) Carbamate (8). To a stirred solution of amine 7a (12.7 g, 60 mmol) in 100 mL dry DCM were added triethy- Figure 1: Some important piperidine, quinolizidine and indolizi- lamine (12.12 g, 120 mmol) and catalytic amount of DMAP dine alkaloids. (1 mol %). The reaction mixture was allowed to stir for 30 min ∘ at 0 C. A solution of Boc2O(14.4g,66mmol)in50mL dry DCM was added. The solution was allowed to warm to 13 Bruker-300 MHz spectrometer; CNMR(75MHz)spectra room temperature, stirred for 5 h. The reaction mixture was were recorded on Bruker-Avance spectrometer. Chemical partitioned between water and EtOAc. The combined organic shifts () are reported in parts per million (ppm) downfield layer was washed with brine, dried over anhydrous sodium from internal TMS standard. Peaks are labeled as singlet (s), sulfate, and evaporated. The residue was purified by column doublet (d), triplet (t), quartet (q), and multiplet (m). ESI chromatography (hexane/EtOAc, 9.5 : 0.5) to afford the pure 8 spectra recorded on Micro mass, Quattro LC using ESI+ Boc-protected amine (14.7 g, 79%) as pale yellowish oil. Rf = [] 27 1 software with a capillary voltage of 3.98 kV and ESI mode 0.57 (1 : 9 EtOAc and hexane). D =+21.9(c 1, CHCl3); H positive ion trap detector. Optical rotations were measured NMR(300MHz,CDCl3): 5.90–5.63 (m, 2H, 2xCH of olefin), on Horiba-SEPA-300 digital polarimeter. 5.17–4.99 (m, 4H, 2xCH2 of olefin), 4.14 (q, J =7.8Hz,1H, -OCH), 3.97–3.92 (m, 1H, homoallylic NCH), 3.83 (d, J = 2.1. (S)-N-Allyl-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)but-3-en- 5.9 Hz, 1H, H of OCH2), 3.69 (d, J =6.5Hz,1H,HofOCH2), 1-amine (7). To a stirred solution of glyceraldehyde 5 (13 g, 3.62 (d, J =5.9Hz,1H,allylicNCH2), 3.56 (q, J =8.0Hz, 100 mmol) in dry ether (150 mL) was added anhydrous 1H, allylic NCH2), 2.49–2.46 (m, 1H, allylic CH2), 2.40–2.32 (m, 1H, allylic CH2), 1.47 (s, 3H, -CH3), 1.43 (s, 6H, 2xCH3), magnesium sulfate (20 g). The mixture was cooled in an ice 13 bath and allyl amine (5.75 g, 101 mmol) was added dropwise 1.40 (s, 3H, -CH3), 1.31 (s, 3H, -CH3); C NMR (75 MHz, under nitrogen atmosphere. After stirring for 3 h, the reac- CDCl3): 154.0, 136.4, 135.0, 117.2, 116.8, 109.5, 80.8, 77.4, 66.6, 34.2, 28.2, 26.8; IR (neat): 3078, 2981, 2933, 2693, 1644, 1455, tion mixture was filtered and concentrated under reduced −1 6 1399, 1368, 1312, 1251, 1156, 1066, 994 cm ;ESIMS(m/z): pressure to obtain imine (14 g, 82%) as colorless oil. The + 6 334 (M+Na) ; HRMS (ESI): m/z calculated for C17H29NO4 obtained imine was further used in the next step without + purification. (M+Na) 334.1994, found. 334.2008. To a stirred suspension of activated zinc (10.8 g, 166 mmol) in 100 mL of dry THF was added solution of 2.3. tert-Butyl-allyl-(2S,3S)-1,2-dihydroxyhex-5-en-3-ylcarba- imine 6 (14 g, 83 mmol) in 50 mL of dry THF under nitrogen mate (9). To a stirred solution of Boc–protected amine ∘ atmosphere at 0 C. After 15 min, allyl bromide (19.9 g, 8a (12.44 g, 40 mmol) in MeOH (75 mL), PTSA (0.688 g, ∘ 0.166 mol) was added dropwise over 15 min at 0 Cand 0.4 mmol) was added at room temperature and stirred reaction mixture was stirred for 10 h. After completion for 12 h under nitrogen atmosphere to completion of the of the reaction (monitored by TLC), the reaction was reaction. The reaction mixture was quenched with aqueous quenched with saturated aqueous ammonium chloride saturated NaHCO3 (10 mL) solution, concentrated under ∘ solution (20 mL) at 0 C over 15 min. After being stirred reduced pressure. The crude was partitioned between EtOAc for 1 h, the mixture was filtered through celite pad. The and water. The organic layer was washed with brine and filtrate was concentrated under reduced pressure. The dried over anhydrous Na2SO4.Thesolutionwasconcentrated crude product was partitioned between water and ethyl under reduced pressure and residue was subjected to column acetate. The combined organic layer was washed with brine, chromatography (hexane/EtOAc, 7 : 3) to afford diol 9 (9.5 g, dried over anhydrous Na2SO4, and concentrated under 88%) as yellowish oil. Rf = 0.45 (1 : 1 EtOAc and hexane). reduced pressure. The residue was purified by column [] 27 1 D =+1.9(c 1, CHCl3); H NMR (300 MHz, CDCl3): chromatography (hexane/EtOAc, 2 : 8) to afford the pure 5.91–5.71 (m, 2H, 2xCH of olefin), 5.30–5.14 (m, 4H, 2xCH2 7a compound amine (14 g, 80%) as colorless oil. Rf =0.12 of olefin), 4.16 (q, J = 8.1 Hz, 1H, -OCH), 3.94–3.88 (m, 1H, [] 27 1 (9 : 1 EtOAc and hexane) D =+18.7(c 1, CHCl3); H homoallylic NCH), 3.78 (d, J =7.9Hz,1H,HofOCH2), 3.68 NMR(300MHz,CDCl3): 5.79–5.65 (m, 2H, 2xCH of olefin), (d, J =7.5Hz,1H,HofOCH2), 3.57 (d, J = 5.0 Hz, 1H, allylic 5.17–4.93 (m, 4H, 2xCH2 of olefin), 4.10 (q, J =7.5Hz,1H, NCH2), 3.47 (q, J =8.5Hz,1H,allylicNCH2), 2.43 (d, J = Organic Chemistry International 3 3.0 Hz, 1H, allylic CH2), 2.34 (dd, J = 4.5, 5.3 Hz, 1H, allylic 1H, allylic NCH2), 3.53 (d, J =4.8Hz,1H,allylicNCH2), 2.60– CH2), 1.47 (s, 3H, -CH3), 1.40 (s, 3H, -CH3), 1.31 (s, 3H, - 2.51 (m, 1H, allylic CH2), 2.38–2.30 (m, 1H, allylic CH2), 1.42 13 CH3); C NMR (75 MHz, CDCl3): 153.5, 135.4, 134.9, 117.3, (s, 9H, t-butyl), 1.26–1.22 (m, 2H, CH2), 0.94 (t, J =7.8Hz, 13 116.5, 80.5, 73.4, 64.0, 58.2, 33.5, 28.2; IR (neat): 3412, 3078, 3 3 −1 3H, CH ); C NMR (75 MHz, CDCl ): 154.0, 135.8, 135.0, 2976,2928,1667,1456,1407,1366,1330,1250,1179,996cm ; + 116.9, 116.5, 79.9, 51.3, 30.7, 28.2, 27.0, 10.4; IR (neat): 3386, ESI MS (m/z): 272 (M+H) ; HRMS (ESI): m/z calculated for 3077, 2966, 2925, 2856, 1668, 1456, 1414, 1368, 1254, 1166, + −1 + C14H26NO4 (M+H) 272.1861, found 272.1874.