# Stereoselective Synthesis of (+)-α-Conhydrine from R-(+)-Glyceraldehyde

Authors: Nageshwar Rao Penumati; Nagaiah Kommu
Journal: Organic Chemistry International
 (2014)

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## Abstract

Stereoselective synthesis of (+)-α-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.


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## Body

## 1. Introduction

Exploiting natural products to ascertain a lead has always been important technique in drug discovery. Nature provides a rich source of bioactive compounds with significant biological activity and has therefore received considerable attention from the synthetic organic communities. The major class of biologically active molecules containing substituted piperidines has been widely present in the nature. The efforts to find a short and high yielding synthetic route for this class of natural products were always a contemporary interest. Some of the hydroxylated piperidine alkaloids are reported to be highly toxic and have drawn significant attention through their biological activity [1–3].Conhydrine is one of the classes of alkaloids which were isolated by Wertheim from the poisonous plant,Conium maculatumL [4], in 1856. A highly fatal toxin causing paralysis of the skeletal musculature, 2-(1-hydroxyalkyl)-piperidine is a recurrent unit in many alkaloids such as Homopumiliotoxin 223 G2, Slaframine 3, and Castanospermine 4 (Figure 1). Since the pioneering studies on the synthesis of (+)-α-Conhydrine1by Galinovasky and Mulley [5], various methods have been reported normally based on auxiliary supported or chiral pool approach [6–18].Figure 1
Some important piperidine, quinolizidine and indolizidine alkaloids.In view of the interesting biological and structural properties, especially the nitrogen containing alkaloids makes (+)-α-Conhydrine1 as an attractive and challenging synthetic target. As mentioned above (+)-α-Conhydrine1 was synthesized from various synthetic routes which involve a large number of steps to obtain the target molecule. Thus development of new methods for the synthesis of (+)-α-Conhydrine1 constitutes an area of current interest. Herein, an efficient synthesis of (+)-α-Conhydrine1 has been designed starting from 2,3-isopropylidene-R-(+)-Glyceraldehyde, by means of Zn-mediated stereoselective Barbier allylation as a key step, which was developed previously for the synthesis of different natural products in our laboratory [19–22]. To the best of our knowledge synthesis of (+)-α-Conhydrinevia aza-Barbier zinc allylation was not reported so far.


## 2. Materials and Methods

All reagents were purchased from Aldrich (Sigma-Aldrich, Bangalore, India). All reactions were monitored by TLC, performed on silica gel glass plates containing 60 F-254. Column chromatography was performed with Merck 60–120 mesh silica gel. IR spectra were recorded on a Perkin-Elmer RX-1 FT-IR system.1H NMR spectra were recorded on Bruker-300 MHz spectrometer; 13C NMR (75 MHz) spectra were recorded on Bruker-Avance spectrometer. Chemical shifts (δ) are reported in parts per million (ppm) downfield from internal TMS standard. Peaks are labeled as singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m). ESI spectra recorded on Micro mass, Quattro LC using ESI+ software with a capillary voltage of 3.98 kV and ESI mode positive ion trap detector. Optical rotations were measured on Horiba-SEPA-300 digital polarimeter.


### 2.1. (S)-N-Allyl-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)but-3-en-1-amine(7)

To a stirred solution of glyceraldehyde5 (13 g, 100 mmol) in dry ether (150 mL) was added anhydrous magnesium sulfate (20 g). The mixture was cooled in an ice bath and allyl amine (5.75 g, 101 mmol) was added dropwise under nitrogen atmosphere. After stirring for 3 h, the reaction mixture was filtered and concentrated under reduced pressure to obtain imine6 (14 g, 82%) as colorless oil. The obtained imine6was further used in the next step without purification.To a stirred suspension of activated zinc (10.8 g, 166 mmol) in 100 mL of dry THF was added solution of imine6 (14 g, 83 mmol) in 50 mL of dry THF under nitrogen atmosphere at 0°C. After 15 min, allyl bromide (19.9 g, 0.166 mol) was added dropwise over 15 min at 0°C and reaction mixture was stirred for 10 h. After completion of the reaction (monitored by TLC), the reaction was quenched with saturated aqueous ammonium chloride solution (20 mL) at 0°C over 15 min. After being stirred for 1 h, the mixture was filtered through celite pad. The filtrate was concentrated under reduced pressure. The crude product was partitioned between water and ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane/EtOAc, 2 : 8) to afford the pure compound amine7a (14 g, 80%) as colorless oil.R
f = 0.12 (9 : 1 EtOAc and hexane) [
α
]
D
27 = +18.7 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3): 5.79–5.65 (m, 2H, 2xCH of olefin), 5.17–4.93 (m, 4H, 2xCH2 of olefin), 4.10 (q,J = 7.5 Hz, 1H, -OCH), 3.80 (d,J = 6.0 Hz, 1H, H of OCH2), 3.71 (d,J= 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 = 7.3 Hz, 2H, allylic CH2), 1.43 (s, 6H, 2xCH3); 13C NMR (75 MHz, CDCl3): 137.0, 134.9, 117.7, 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, 1250, 1069, 1029, 994 cm−1; ESI MS:m/z = 212 (M+H); HRMS (ESI):m/z calculated for C12H22NO2 (M+H) 212.1650, found 212.1652.


### 2.2. tert-Butyl-allyl((S)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)but-3-enyl) Carbamate(8)

To a stirred solution of amine7a (12.7 g, 60 mmol) in 100 mL dry DCM were added triethylamine (12.12 g, 120 mmol) and catalytic amount of DMAP (1 mol %). The reaction mixture was allowed to stir for 30 min at 0°C. A solution of Boc2O (14.4 g, 66 mmol) in 50 mL dry DCM was added. The solution was allowed to warm to room temperature, stirred for 5 h. The reaction mixture was partitioned between water and EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by column chromatography (hexane/EtOAc, 9.5 : 0.5) to afford the pure Boc-protected amine8 (14.7 g, 79%) as pale yellowish oil.R
f = 0.57 (1 : 9 EtOAc and hexane). [
α
]
D
27 = +21.9 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3): 5.90–5.63 (m, 2H, 2xCH of olefin), 5.17–4.99 (m, 4H, 2xCH2 of olefin), 4.14 (q,J = 7.8 Hz, 1H, -OCH), 3.97–3.92 (m, 1H, homoallylic NCH), 3.83 (d,J = 5.9 Hz, 1H, H of OCH2), 3.69 (d,J = 6.5 Hz, 1H, H of OCH2), 3.62 (d,J = 5.9 Hz, 1H, allylic NCH2), 3.56 (q,J = 8.0 Hz, 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), 1.40 (s, 3H, -CH3), 1.31 (s, 3H, -CH3); 13C NMR (75 MHz, 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, 1399, 1368, 1312, 1251, 1156, 1066, 994 cm−1; ESI MS (m/z): 334 (M+Na)+; HRMS (ESI):m/z calculated for C17H29NO4 (M+Na)+ 334.1994, found. 334.2008.


### 2.3. tert-Butyl-allyl-(2S,3S)-1,2-dihydroxyhex-5-en-3-ylcarbamate(9)

To a stirred solution of Boc–protected amine8a (12.44 g, 40 mmol) in MeOH (75 mL), PTSA (0.688 g, 0.4 mmol) was added at room temperature and stirred for 12 h under nitrogen atmosphere to completion of the reaction. The reaction mixture was quenched with aqueous saturated NaHCO3 (10 mL) solution, concentrated under reduced pressure. The crude was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solution was concentrated under reduced pressure and residue was subjected to column chromatography (hexane/EtOAc, 7 : 3) to afford diol9(9.5 g, 88%) as yellowish oil.R
f = 0.45 (1 : 1 EtOAc and hexane). [
α
]
D
27 = +1.9 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3): 5.91–5.71 (m, 2H, 2xCH of olefin), 5.30–5.14 (m, 4H, 2xCH2 of olefin), 4.16 (q,J = 8.1 Hz, 1H, -OCH), 3.94–3.88 (m, 1H, homoallylic NCH), 3.78 (d,J = 7.9 Hz, 1H, H of OCH2), 3.68 (d,J = 7.5 Hz, 1H, H of OCH2), 3.57 (d,J = 5.0 Hz, 1H, allylic NCH2), 3.47 (q,J = 8.5 Hz, 1H, allylic NCH2), 2.43 (d,J = 3.0 Hz, 1H, allylic CH2), 2.34 (dd,J = 4.5, 5.3 Hz, 1H, allylic CH2), 1.47 (s, 3H, -CH3), 1.40 (s, 3H, -CH3), 1.31 (s, 3H, -CH3); 13C NMR (75 MHz, CDCl3): 153.5, 135.4, 134.9, 117.3, 116.5, 80.5, 73.4, 64.0, 58.2, 33.5, 28.2; IR (neat): 3412, 3078, 2976, 2928, 1667, 1456, 1407, 1366, 1330, 1250, 1179, 996 cm−1; ESI MS (m/z): 272 (M+H)+; HRMS (ESI):m/z calculated for C14H26NO4 (M+H)+ 272.1861, found 272.1874.


### 2.4. (2S,3S)-3-(Allyl(tert-butoxycarbonyl)amino)-2-hydroxyhex-5-enyl 4-Methylbenzenesulfonate(10)

To a stirred clear solution of Diol9 (8.13 g, 30 mmol), Bu2SnO (0.05 mol %), and triethylamine (6.06 g, 60 mmol) in 80 mL dry DCM was added TsCl (5.715 g, 30 mmol) in one portion under nitrogen atmosphere at 0°C and reaction mixture was stirred for 5 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (hexane/EtOAc, 8 : 2) to afford monotosylated product10 (8.16 g, 64%) as pale yellowish oil.R
f = 0.55 (1 : 1 EtOAc and hexane). [
α
]
D
27 = −7.8 (c1, CHCl3); 1H NMR (300 MHz, CDCl3): 7.75 (d,J = 7.5 Hz, 2H, Ar-H), 7.34 (d,J = 8.3 Hz, 2H, Ar-H), 5.91–5.60 (m, 2H, 2xCH of olefin), 5.21–5.02 (m, 4H, 2xCH2 of olefin), 4.21–3.90 (m, 3H, -OCH, OCH2), 3.88–3.72 (m, 1H, homoallylic NCH), 3.61 (d,J = 6.1 Hz, 1H, allylic NCH2), 3.56 (q,J = 7.8 Hz, 1H, allylic NCH2), 2.48–2.42 (m, 5H, allylic CH2, Ar-Me), 1.42 (s, 9H,t-butyl); 13C NMR (75 MHz, CDCl3): 154.5, 145.1, 140.5, 134.1, 132.9, 131.1, 129.9, 128.9, 128.0, 127.0, 125.9, 120.5, 118.5, 117.6, 70.2, 68.6, 57.2, 48.8, 32.0, 29.6; IR (neat): 3375, 3077, 2978, 2928, 1666, 1599, 1457, 1406, 1363, 1252, 1178, 1098, 978 cm−1; ESI MS (m/z): 426 (M+H)+; HRMS (ESI):m/z calculated for C21H32NO6S (M+H)+ 426.1950, found 426.1962.


### 2.5. tert-Butyl-allyl((4S,5R)-5-hydroxyhept-1-en-4-yl)carbamate(11)

To a solution of monotosylated compound10 (6.375 g, 15 mmol) in 50 mL methanol was added anhydrous K2CO3 (2.07 g, 15 mmol) at 0°C, stirred for 1 h. After completion of the reaction, K2CO3 was filtered off and the filtrate was concentratedin vacuo. The crude was diluted with EtOAc and washed with water and brine, dried over anhydrous Na2SO4. The solution was concentrated under reduced pressure to afford desired epoxide (3.415 g, 90%). The formed epoxide was used without purification.To a solution of epoxide (3.415 g, 13.5 mmol) in 15 mL dry THF was added MeMgI (4.48 g, 27 mmol) in 25 mL dry THF under nitrogen atmosphere at 0°C. The resulting reaction mixture was allowed to stir for 2 h at the same temperature. Then the reaction was quenched with aqueous NH4Cl (5 mL) at 0°C and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solvent was evaporatedin vacuo and the residue was subjected to column chromatography (hexane/EtOAc, 8 : 2) to afford 2° alcohol11(2.76 g, 76%) as colorless oil.R
f = 0.38 (3 : 7 EtOAc and hexane). [
α
]
D
27 = −1.5 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3): 5.86–5.67 (m, 2H, 2xCH of olefin), 5.28–5.10 (m, 4H, 2xCH2 of olefin), 3.96–3.88 (m, 1H, OCH), 3.77 (q,J = 8.9 Hz, 1H, homoallylic NCH), 3.64 (d,J = 7.9 Hz, 1H, allylic NCH2), 3.53 (d,J = 4.8 Hz, 1H, allylic NCH2), 2.60–2.51 (m, 1H, allylic CH2), 2.38–2.30 (m, 1H, allylic CH2), 1.42 (s, 9H,t-butyl), 1.26–1.22 (m, 2H, CH2), 0.94 (t,J = 7.8 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3): 154.0, 135.8, 135.0, 116.9, 116.5, 79.9, 51.3, 30.7, 28.2, 27.0, 10.4; IR (neat): 3386, 3077, 2966, 2925, 2856, 1668, 1456, 1414, 1368, 1254, 1166, 1095, 919 cm−1; ESI MS (m/z): 292 (M+Na)+; HRMS (ESI):m/z calculated for C15H27NO3 (M+Na)+ 292.1888, found 292.1888.


### 2.6. (S)-tert-Butyl-6-((R)-1-hydroxypropyl)-5,6-dihydropyridine-1(2H)-carboxylate(12)

To a stirred solution of diene12 (1.9 g, 7 mmol) in 50 mL dry DCM was added Grubb’s 1st generation catalyst (0.3 g, 0.35 mmol) and the resulting purple-colored solution mixture was stirred at room temperature for 8 h. After completion of the reaction, the brown-colored solution was concentrated and subjected to column chromatography (hexane/EtOAc, 8 : 2) to afford the tetrahydropyridine12 (1.5 g, 89%) as yellowish oil.R
f = 0.30 (3 : 7 EtOAc and hexane). [
α
]
D
27 = +3.2 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3): 5.88–5.59 (m, 2H, olefinic), 4.33–4.07 (m, 3H, allylic NCH2, OCH), 3.60–3.55 (m, 1H, homoallylic NCH), 2.40–2.35 (m, 2H, allylic CH2), 1.42 (s, 9H,t-butyl), 1.26 (m, 2H, CH2), 0.95 (t,J = 8.0 Hz, 3H, -CH3); 13C NMR (75 M Hz, CDCl3): 154.2, 123.3, 122.4, 79.8, 72.2, 52.6, 41.3, 28.4, 26.7, 25.6, 10.0; IR (neat): 3445, 2969, 2926, 1685, 1414, 1365, 1307, 1249, 1171, 1113, 1051, 966 cm−1; ESI MS (m/z): 264 (M+Na)+; HRMS (ESI):m/z calculated for C13H23NO3 (M+Na)+ 264.1575, found 264.1584.


### 2.7. (S)-tert-Butyl-2-((R)-1-hydroxypropyl)piperidine-1-carboxylate(13)

To a stirred solution of tetrahydropyridine12 (1.2 g, 5 mmol) in 6 mL methanol was added 10% Pd on activated charcoal (0.5 g). The mixture was stirred for 10 h under hydrogen atmosphere. The reaction mass was filtered on celite pad and washed with MeOH. The filtrate was concentrated under reduced pressure and the crude was purified by column chromatography (hexane/EtOAc, 9 : 1) to afford pure piperidine13(1.1 g, 90%) as colorless oil.R
f = 0.45 (2 : 8 EtOAc and hexane). [
α
]
D
27 = −9.4 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3): 4.31–4.05 (br, 1H, -OH), 3.83–3.78 (m, 1H, OCH), 3.64–3.58 (m, 2H, NCH2), 3.40–3.34 (m, 1H, NCH), 1.61–1.52 (m, 6H, 3xCH2, aliphatic), 1.43 (s, 9H,t-butyl), 1.25–1.21 (m, 2H, CH2), 0.95 (t,J =8.0 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3): 155.2, 79.8, 70.8, 55.3, 40.3, 29.7, 28.4, 26.5, 25.6, 25.2, 24.5, 10.0; IR (neat): 3443, 2963, 2874, 1677, 1462, 1414, 1366, 1250, 1160, 976 cm−1; ESI MS (m/z): 266 (M+Na)+; HRMS (ESIMS):m/z calculated for C13H25NO3Na (M+Na)+ 266.1732, found 266.1742.


### 2.8.  (+)-α-Conhydrine (1)

To a solution of piperidine13 (0.243 g, 1 mmol) in 2.5 mL Dry DCM was added dropwise solution of TFA (0.72 g, 5 mmol) in 5 mL dry DCM at 0°C. The resulting reaction mixture was stirred under nitrogen atmosphere for 4 h at 0°C and then treated with saturated NaHCO3 (20 mL) until it has become alkaline and then extracted with DCM (2 × 5 mL). The combined organic layers were washed with water and brine, dried, and evaporated under reduced pressure to afford crude product. The crude product was purified by column chromatography (chloroform/methanol, 8 : 2) over silica gel to furnish (+)-α-Conhydrine1 (90 mg, 64%) as colorless solid.R
f = 0.12 (9 : 1 chloroform and methanol). [
α
]
D
27 = +8.8 (c 1, EtOH); 1H NMR (300 MHz, CDCl3): 3.80–3.72 (m, 1H, OCH), 3.04–2.77 (m, 3H, NCH2, NCH), 2.1–2.0 (br, 1H, -NH), 1.60–1.20 (m, 8H, 3xCH2-ring, CH2-ethyl), 1.0–0.8 (m, 3H, CH3); 13C NMR (75 MHz, CDCl3): 71.5, 60.8, 49.9, 29.6, 25.5, 22.3, 21.2, 10.3; IR (neat): 3409, 2923, 2856, 1659, 1458, 1375, 1259, 1093, 797 cm−1; ESI MS (m/z): 144 (M+H)+; HRMS (ESI):m/z calculated for C8H18NO (M+H)+ 144.1388, found 144.1395.


## 2.1. (S)-N-Allyl-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)but-3-en-1-amine(7)

To a stirred solution of glyceraldehyde5 (13 g, 100 mmol) in dry ether (150 mL) was added anhydrous magnesium sulfate (20 g). The mixture was cooled in an ice bath and allyl amine (5.75 g, 101 mmol) was added dropwise under nitrogen atmosphere. After stirring for 3 h, the reaction mixture was filtered and concentrated under reduced pressure to obtain imine6 (14 g, 82%) as colorless oil. The obtained imine6was further used in the next step without purification.To a stirred suspension of activated zinc (10.8 g, 166 mmol) in 100 mL of dry THF was added solution of imine6 (14 g, 83 mmol) in 50 mL of dry THF under nitrogen atmosphere at 0°C. After 15 min, allyl bromide (19.9 g, 0.166 mol) was added dropwise over 15 min at 0°C and reaction mixture was stirred for 10 h. After completion of the reaction (monitored by TLC), the reaction was quenched with saturated aqueous ammonium chloride solution (20 mL) at 0°C over 15 min. After being stirred for 1 h, the mixture was filtered through celite pad. The filtrate was concentrated under reduced pressure. The crude product was partitioned between water and ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane/EtOAc, 2 : 8) to afford the pure compound amine7a (14 g, 80%) as colorless oil.R
f = 0.12 (9 : 1 EtOAc and hexane) [
α
]
D
27 = +18.7 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3): 5.79–5.65 (m, 2H, 2xCH of olefin), 5.17–4.93 (m, 4H, 2xCH2 of olefin), 4.10 (q,J = 7.5 Hz, 1H, -OCH), 3.80 (d,J = 6.0 Hz, 1H, H of OCH2), 3.71 (d,J= 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 = 7.3 Hz, 2H, allylic CH2), 1.43 (s, 6H, 2xCH3); 13C NMR (75 MHz, CDCl3): 137.0, 134.9, 117.7, 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, 1250, 1069, 1029, 994 cm−1; ESI MS:m/z = 212 (M+H); HRMS (ESI):m/z calculated for C12H22NO2 (M+H) 212.1650, found 212.1652.


## 2.2. tert-Butyl-allyl((S)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)but-3-enyl) Carbamate(8)

To a stirred solution of amine7a (12.7 g, 60 mmol) in 100 mL dry DCM were added triethylamine (12.12 g, 120 mmol) and catalytic amount of DMAP (1 mol %). The reaction mixture was allowed to stir for 30 min at 0°C. A solution of Boc2O (14.4 g, 66 mmol) in 50 mL dry DCM was added. The solution was allowed to warm to room temperature, stirred for 5 h. The reaction mixture was partitioned between water and EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by column chromatography (hexane/EtOAc, 9.5 : 0.5) to afford the pure Boc-protected amine8 (14.7 g, 79%) as pale yellowish oil.R
f = 0.57 (1 : 9 EtOAc and hexane). [
α
]
D
27 = +21.9 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3): 5.90–5.63 (m, 2H, 2xCH of olefin), 5.17–4.99 (m, 4H, 2xCH2 of olefin), 4.14 (q,J = 7.8 Hz, 1H, -OCH), 3.97–3.92 (m, 1H, homoallylic NCH), 3.83 (d,J = 5.9 Hz, 1H, H of OCH2), 3.69 (d,J = 6.5 Hz, 1H, H of OCH2), 3.62 (d,J = 5.9 Hz, 1H, allylic NCH2), 3.56 (q,J = 8.0 Hz, 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), 1.40 (s, 3H, -CH3), 1.31 (s, 3H, -CH3); 13C NMR (75 MHz, 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, 1399, 1368, 1312, 1251, 1156, 1066, 994 cm−1; ESI MS (m/z): 334 (M+Na)+; HRMS (ESI):m/z calculated for C17H29NO4 (M+Na)+ 334.1994, found. 334.2008.


## 2.3. tert-Butyl-allyl-(2S,3S)-1,2-dihydroxyhex-5-en-3-ylcarbamate(9)

To a stirred solution of Boc–protected amine8a (12.44 g, 40 mmol) in MeOH (75 mL), PTSA (0.688 g, 0.4 mmol) was added at room temperature and stirred for 12 h under nitrogen atmosphere to completion of the reaction. The reaction mixture was quenched with aqueous saturated NaHCO3 (10 mL) solution, concentrated under reduced pressure. The crude was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solution was concentrated under reduced pressure and residue was subjected to column chromatography (hexane/EtOAc, 7 : 3) to afford diol9(9.5 g, 88%) as yellowish oil.R
f = 0.45 (1 : 1 EtOAc and hexane). [
α
]
D
27 = +1.9 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3): 5.91–5.71 (m, 2H, 2xCH of olefin), 5.30–5.14 (m, 4H, 2xCH2 of olefin), 4.16 (q,J = 8.1 Hz, 1H, -OCH), 3.94–3.88 (m, 1H, homoallylic NCH), 3.78 (d,J = 7.9 Hz, 1H, H of OCH2), 3.68 (d,J = 7.5 Hz, 1H, H of OCH2), 3.57 (d,J = 5.0 Hz, 1H, allylic NCH2), 3.47 (q,J = 8.5 Hz, 1H, allylic NCH2), 2.43 (d,J = 3.0 Hz, 1H, allylic CH2), 2.34 (dd,J = 4.5, 5.3 Hz, 1H, allylic CH2), 1.47 (s, 3H, -CH3), 1.40 (s, 3H, -CH3), 1.31 (s, 3H, -CH3); 13C NMR (75 MHz, CDCl3): 153.5, 135.4, 134.9, 117.3, 116.5, 80.5, 73.4, 64.0, 58.2, 33.5, 28.2; IR (neat): 3412, 3078, 2976, 2928, 1667, 1456, 1407, 1366, 1330, 1250, 1179, 996 cm−1; ESI MS (m/z): 272 (M+H)+; HRMS (ESI):m/z calculated for C14H26NO4 (M+H)+ 272.1861, found 272.1874.


## 2.4. (2S,3S)-3-(Allyl(tert-butoxycarbonyl)amino)-2-hydroxyhex-5-enyl 4-Methylbenzenesulfonate(10)

To a stirred clear solution of Diol9 (8.13 g, 30 mmol), Bu2SnO (0.05 mol %), and triethylamine (6.06 g, 60 mmol) in 80 mL dry DCM was added TsCl (5.715 g, 30 mmol) in one portion under nitrogen atmosphere at 0°C and reaction mixture was stirred for 5 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (hexane/EtOAc, 8 : 2) to afford monotosylated product10 (8.16 g, 64%) as pale yellowish oil.R
f = 0.55 (1 : 1 EtOAc and hexane). [
α
]
D
27 = −7.8 (c1, CHCl3); 1H NMR (300 MHz, CDCl3): 7.75 (d,J = 7.5 Hz, 2H, Ar-H), 7.34 (d,J = 8.3 Hz, 2H, Ar-H), 5.91–5.60 (m, 2H, 2xCH of olefin), 5.21–5.02 (m, 4H, 2xCH2 of olefin), 4.21–3.90 (m, 3H, -OCH, OCH2), 3.88–3.72 (m, 1H, homoallylic NCH), 3.61 (d,J = 6.1 Hz, 1H, allylic NCH2), 3.56 (q,J = 7.8 Hz, 1H, allylic NCH2), 2.48–2.42 (m, 5H, allylic CH2, Ar-Me), 1.42 (s, 9H,t-butyl); 13C NMR (75 MHz, CDCl3): 154.5, 145.1, 140.5, 134.1, 132.9, 131.1, 129.9, 128.9, 128.0, 127.0, 125.9, 120.5, 118.5, 117.6, 70.2, 68.6, 57.2, 48.8, 32.0, 29.6; IR (neat): 3375, 3077, 2978, 2928, 1666, 1599, 1457, 1406, 1363, 1252, 1178, 1098, 978 cm−1; ESI MS (m/z): 426 (M+H)+; HRMS (ESI):m/z calculated for C21H32NO6S (M+H)+ 426.1950, found 426.1962.


## 2.5. tert-Butyl-allyl((4S,5R)-5-hydroxyhept-1-en-4-yl)carbamate(11)

To a solution of monotosylated compound10 (6.375 g, 15 mmol) in 50 mL methanol was added anhydrous K2CO3 (2.07 g, 15 mmol) at 0°C, stirred for 1 h. After completion of the reaction, K2CO3 was filtered off and the filtrate was concentratedin vacuo. The crude was diluted with EtOAc and washed with water and brine, dried over anhydrous Na2SO4. The solution was concentrated under reduced pressure to afford desired epoxide (3.415 g, 90%). The formed epoxide was used without purification.To a solution of epoxide (3.415 g, 13.5 mmol) in 15 mL dry THF was added MeMgI (4.48 g, 27 mmol) in 25 mL dry THF under nitrogen atmosphere at 0°C. The resulting reaction mixture was allowed to stir for 2 h at the same temperature. Then the reaction was quenched with aqueous NH4Cl (5 mL) at 0°C and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solvent was evaporatedin vacuo and the residue was subjected to column chromatography (hexane/EtOAc, 8 : 2) to afford 2° alcohol11(2.76 g, 76%) as colorless oil.R
f = 0.38 (3 : 7 EtOAc and hexane). [
α
]
D
27 = −1.5 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3): 5.86–5.67 (m, 2H, 2xCH of olefin), 5.28–5.10 (m, 4H, 2xCH2 of olefin), 3.96–3.88 (m, 1H, OCH), 3.77 (q,J = 8.9 Hz, 1H, homoallylic NCH), 3.64 (d,J = 7.9 Hz, 1H, allylic NCH2), 3.53 (d,J = 4.8 Hz, 1H, allylic NCH2), 2.60–2.51 (m, 1H, allylic CH2), 2.38–2.30 (m, 1H, allylic CH2), 1.42 (s, 9H,t-butyl), 1.26–1.22 (m, 2H, CH2), 0.94 (t,J = 7.8 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3): 154.0, 135.8, 135.0, 116.9, 116.5, 79.9, 51.3, 30.7, 28.2, 27.0, 10.4; IR (neat): 3386, 3077, 2966, 2925, 2856, 1668, 1456, 1414, 1368, 1254, 1166, 1095, 919 cm−1; ESI MS (m/z): 292 (M+Na)+; HRMS (ESI):m/z calculated for C15H27NO3 (M+Na)+ 292.1888, found 292.1888.


## 2.6. (S)-tert-Butyl-6-((R)-1-hydroxypropyl)-5,6-dihydropyridine-1(2H)-carboxylate(12)

To a stirred solution of diene12 (1.9 g, 7 mmol) in 50 mL dry DCM was added Grubb’s 1st generation catalyst (0.3 g, 0.35 mmol) and the resulting purple-colored solution mixture was stirred at room temperature for 8 h. After completion of the reaction, the brown-colored solution was concentrated and subjected to column chromatography (hexane/EtOAc, 8 : 2) to afford the tetrahydropyridine12 (1.5 g, 89%) as yellowish oil.R
f = 0.30 (3 : 7 EtOAc and hexane). [
α
]
D
27 = +3.2 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3): 5.88–5.59 (m, 2H, olefinic), 4.33–4.07 (m, 3H, allylic NCH2, OCH), 3.60–3.55 (m, 1H, homoallylic NCH), 2.40–2.35 (m, 2H, allylic CH2), 1.42 (s, 9H,t-butyl), 1.26 (m, 2H, CH2), 0.95 (t,J = 8.0 Hz, 3H, -CH3); 13C NMR (75 M Hz, CDCl3): 154.2, 123.3, 122.4, 79.8, 72.2, 52.6, 41.3, 28.4, 26.7, 25.6, 10.0; IR (neat): 3445, 2969, 2926, 1685, 1414, 1365, 1307, 1249, 1171, 1113, 1051, 966 cm−1; ESI MS (m/z): 264 (M+Na)+; HRMS (ESI):m/z calculated for C13H23NO3 (M+Na)+ 264.1575, found 264.1584.


## 2.7. (S)-tert-Butyl-2-((R)-1-hydroxypropyl)piperidine-1-carboxylate(13)

To a stirred solution of tetrahydropyridine12 (1.2 g, 5 mmol) in 6 mL methanol was added 10% Pd on activated charcoal (0.5 g). The mixture was stirred for 10 h under hydrogen atmosphere. The reaction mass was filtered on celite pad and washed with MeOH. The filtrate was concentrated under reduced pressure and the crude was purified by column chromatography (hexane/EtOAc, 9 : 1) to afford pure piperidine13(1.1 g, 90%) as colorless oil.R
f = 0.45 (2 : 8 EtOAc and hexane). [
α
]
D
27 = −9.4 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3): 4.31–4.05 (br, 1H, -OH), 3.83–3.78 (m, 1H, OCH), 3.64–3.58 (m, 2H, NCH2), 3.40–3.34 (m, 1H, NCH), 1.61–1.52 (m, 6H, 3xCH2, aliphatic), 1.43 (s, 9H,t-butyl), 1.25–1.21 (m, 2H, CH2), 0.95 (t,J =8.0 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3): 155.2, 79.8, 70.8, 55.3, 40.3, 29.7, 28.4, 26.5, 25.6, 25.2, 24.5, 10.0; IR (neat): 3443, 2963, 2874, 1677, 1462, 1414, 1366, 1250, 1160, 976 cm−1; ESI MS (m/z): 266 (M+Na)+; HRMS (ESIMS):m/z calculated for C13H25NO3Na (M+Na)+ 266.1732, found 266.1742.


## 2.8.  (+)-α-Conhydrine (1)

To a solution of piperidine13 (0.243 g, 1 mmol) in 2.5 mL Dry DCM was added dropwise solution of TFA (0.72 g, 5 mmol) in 5 mL dry DCM at 0°C. The resulting reaction mixture was stirred under nitrogen atmosphere for 4 h at 0°C and then treated with saturated NaHCO3 (20 mL) until it has become alkaline and then extracted with DCM (2 × 5 mL). The combined organic layers were washed with water and brine, dried, and evaporated under reduced pressure to afford crude product. The crude product was purified by column chromatography (chloroform/methanol, 8 : 2) over silica gel to furnish (+)-α-Conhydrine1 (90 mg, 64%) as colorless solid.R
f = 0.12 (9 : 1 chloroform and methanol). [
α
]
D
27 = +8.8 (c 1, EtOH); 1H NMR (300 MHz, CDCl3): 3.80–3.72 (m, 1H, OCH), 3.04–2.77 (m, 3H, NCH2, NCH), 2.1–2.0 (br, 1H, -NH), 1.60–1.20 (m, 8H, 3xCH2-ring, CH2-ethyl), 1.0–0.8 (m, 3H, CH3); 13C NMR (75 MHz, CDCl3): 71.5, 60.8, 49.9, 29.6, 25.5, 22.3, 21.2, 10.3; IR (neat): 3409, 2923, 2856, 1659, 1458, 1375, 1259, 1093, 797 cm−1; ESI MS (m/z): 144 (M+H)+; HRMS (ESI):m/z calculated for C8H18NO (M+H)+ 144.1388, found 144.1395.


## 3. Results and Discussion

A retrosynthetic analysis for (+)-α-Conhydrine1 based on chiron approach with diastereoselective Barbier allylic addition as the prominent strategy is pictorially presented in Scheme 1. We envisioned that the synthesis of (+)-α-Conhydrine could be achieved by employing stereoselective allylation and ring closing metathesis as key strategy to create this root as more feasible and simple. As illustrated in Scheme 1, we decided to prepare (+)-α-Conhydrine by intercepting olefinic intermediate12 that we envisaged would be made available from ring closing metathesis of diene11, which was successively obtained from the imine6by diastereoselective aza-Barbier zinc allylation. Subsequently this imine6 could be easily attained from condensation ofR-(+)-Glyceraldehyde5 and allyl amine (Scheme 1).Scheme 1
Retrosynthetic analysis of (+)-α-Conhydrine1.The synthesis of title compound initiates from a well-known carbohydrate precursor (R)-2,3-isopropylidene glyceraldehyde5, which can be easily prepared from commercially available D-mannitol [23–26]. As depicted in Scheme 2, condensation of allylamine with glyceraldehyde5 gave imine6, which was then further converted to secondary amine7 by zinc mediated Barbier allylation [13, 27–32] protocol with good diastereoselectivity (anti/syn = 9 : 1) in 80% yield.Scheme 2
Reagent and conditions: (a) CH2=CHCH2NH2, Et2O, anhyd.MgSO4, 0°C to rt, 3 h, 82%; (b) CH2=CHCH2Br, Zn, THF, aq.NH4Cl, 0°C to rt, 10 h, 80%.The ratio of diastereomers was determined by gas chromatography. The diastereoselectivity [32–34] of this reaction can be explained by Felkin-Anh model (Figure 2), the carbon nucleophile preferentially approach from the less hindered side (i.e., from the side of H), thus resulting in the formation antidiastereomer predominantly. However, thesyn- andanti-relative configuration of stereogenic centre was unambiguously established based on 1H NMR, in which proton at newly formed stereocentre ofanti-isomer7a appeared atδ 2.70 (q,J =5.9 Hz, 1H) whereassyn- isomer7b is atδ2.62 (q,J = 6.5 Hz, 1H). These values were in good agreement with earlier reports [34].Figure 2
Felkin-Anh model for antistereoselectivity.The major diastereomer7a upon treatment with Boc-anhydride and TEA in DCM using catalytic amount of DMAP at 0°C to rt produced carbamate8with 79% yield. The acetonide deprotection of carbamate8wasachieved successfully by using catalytic amount of PTSA in methanol at room temperature for 12 h which gave desired diol9 in 88% yield. The primary hydroxyl group of glycol9 was regioselectively monotosylated [35–37] by using TsCl and Et3N in the presence of dibutyltinoxide at 0°C to rt in DCM to afford sulfonate10in 64% yield. Sulfonate10was treated with K2CO3 followed by methyl magnesium iodide in dry THF at 0°C which affords dienol11via the formation of epoxide and regioselective ring opening; formation of epoxide was confirmed by its FT-IR spectrum which showed disappearance of absorption band at 3375 cm−1 (–OH stretching). Upon ring-closing metathesis [38–40] of dienol11in the presence of Grubb’s 1st generation catalyst (5 mol %) in CH2Cl2 at room temperature delivered tetrahydropyridine12in 89% yield. Catalytic hydrogenation of tetrahydropyridine12 in presence of 10% Pd/C in MeOH at room temperature afforded piperidine13with 90% yield. Boc-deprotection of piperidine13 with TFA in DCM accomplished desired compound1(Scheme 3). The physical and spectroscopic data of title compound1were in excellent agreement with the earlier report.Scheme 3
Reagent and conditions: (a) Boc2O, Et3N, DMAP, DCM, 0°C to rt, 5 h, 79%; (b) PTSA, MeOH, rt, 12 h, 88%; (c) TsCl, Bu2SnO, Et3N, DCM, 0°C to rt, 5 h, 64%; (d) (i) K2CO3, MeOH, 0°C, 1 h, 90%; (ii) MeMgI, THF, 0°C, 2 h, 76%; (e) Grubbs’ catalyst I gen., DCM, rt, 8 h, 89%; (f) 10% Pd/C, H2, MeOH, rt, 10 h, 90%; (g) TFA, DCM, 0°C to rt, 4 h, 64%.


## 4. Conclusions

In conclusion, we achieved a stereoselective total synthesis of (+)-α-Conhydrine from a common carbohydrate precursor, (R)-2,3-isopropylidene glyceraldehyde. The prominent steps involved are zinc mediated Aza-Barbier allylation and construction of piperidine ring by RCM. Further investigations towards other 2-(α-hydroxyl alkyl) piperidine analogues and indolizidines by introduction of various alkenyl substituents in the Barbier allylation are in progress.



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*Source: 982716-2014-10-20.xml*