Synthesis of (R)-Coniine and (S)-Coinicine via Organocatalytic α-Aminoxyl­ation of an Aldehyde

Abstract

A short and efficient synthesis of the indolizidine alkaloid (S)-coinicine has been achieved using organocatalytic sequential α-aminoxylation and Horner-Wadsworth-Emmons olefination of an aldehyde catalyzed by l-proline. Similarly, a common organocatalytic α-aminoxylation route has been developed for the asymmetric synthesis of both (R)-coniine and (S)-coinicine.

Substituted piperidines and ring-fused piperidines such as indolizidines are among the most ubiquitous heterocyclic building blocks in both natural products and synthetic compounds with important biological activities (Figure  [¹] ). [¹] [²] The interest in the piperidine and indolizidine alkaloids, which display a wide array of structural diversity, is well displayed by the wealth of published material detailing their sources and biological activities. [³] (R)-Coniine (1) and (S)-coinicine (2), the simplest members of the piperidine and indolizidine alkaloids, respectively, have attracted a great deal of interest from chemists as representative targets, resulting in numerous successful asymmetric syntheses of these molecules. [4]

During the last decade it has been established that small organic molecules can be highly selective and efficient catalysts, and the area of organocatalysis has emerged as a promising strategy and as an alternative to expensive protein catalysis and toxic metal catalysis, [5] thus becoming a fundamental tool in the catalysis toolbox available for asymmetric synthesis. [6] Proline in the recent past has been defined as a ‘universal catalyst’ because of its utility in different reactions providing rapid, catalytic, atom-­economical access to enantiomerically pure products. [7] Similarly, organocatalytic tandem processes are providing an efficient means to construct complex target molecules in an environmentally friendly and rapid way from simple and readily available precursors, while minimizing yield, time and energy losses. [8]

In continuation of our interest in organocatalysis [9] and asymmetric synthesis of piperidine and indolizidine alkaloids, [¹0] we wish to report α-aminoxylation and sequential α-aminoxylation and Horner-Wadsworth-Emmons (HWE) olefination approaches for the synthesis of (R)-­coniine and (S)-coinicine.

Our synthetic approach for the synthesis of (R)-coniine (1) and (S)-coinicine (2) via α-aminoxylation was envisioned through the retrosynthetic routes shown in Scheme  [¹] . Azide 12, which was thought to be a common intermediate for the synthesis of both compounds, could be easily obtained from epoxide 9 which, in turn, could be prepared from the diol derivative 7 obtained by α-aminoxylation of the corresponding aldehyde 6.

Thus, the synthesis began with the aldehyde 6 [¹¹] which on α-aminoxylation catalyzed by l-proline and in situ reduction with sodium borohydride gave the O-amino-substituted diol 7 in 71% yield and 95% ee [¹²] (Scheme  [²] ). This O-amino-substituted diol 7 was then subjected to reductive hydrogenation conditions using palladium-on-carbon to afford the diol 8 in 85% yield. Compound 8 on selective monotosylation using p-toluenesulfonyl chloride with catalytic dibutyltin oxide, followed by base treatment, furnished the epoxide 9 in 79% yield (over two steps). Regioselective opening of epoxide 9 with lithium acetylide afforded homopropargyl alcohol 10 in 82% yield, which on partial reduction using hydrogen with Lindlar catalyst gave the homoallylic alcohol 11 in 90% yield. The free hydroxy group was then converted into an azido group following a two-step process of mesylation using methanesulfonyl chloride and triethylamine, and subsequent sodium azide treatment, to afford the azide 12 in 68% yield (over two steps). Compound 12 was used as a common precursor for the synthesis of (R)-coniine (1) and (S)-coinicine (2).

For the synthesis of (R)-coniine (1), double bond reduction of 12 along with in situ conversion of azide into free amine and tert-butyl carbamate protection of the resulting amine was achieved in one step using hydrogen with palladium-on-carbon and (Boc)₂O. Subsequent p-methoxybenzyl (PMB) deprotection using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) afforded the free hydroxy compound 13 in 80% yield (over two steps). The free hydroxy group of 13 was converted into its methanesulfonyl ester using methanesulfonyl chloride and triethyl-amine in 85% yield. Subsequent base treatment of 14 using sodium hydride furnished Boc-protected (R)-coniine in good yield. Finally, the hydrochloride salt of (R)-coniine (1) {[α]_D ^²5 -8.64 (c 0.25, EtOH); Lit. [4i] [α]_D ^²5 -7.3 (c 0.33, EtOH)} was easily obtained by Boc deprotection using methanolic hydrochloric acid. The physical and spectroscopic data of 1 were in full agreement with the literature data.

Similarly, for the synthesis of (S)-coinicine (2), the azide 12 was converted into amine using triphenylphosphane under Staudinger reaction conditions, which was followed by in situ protection of the free amine as its benzyl carbamate under basic conditions to afford compound 15 in 90% yield (Scheme  [³] ). Olefin 15 was further subjected to a hydroboration-oxidation reaction using borane-dimethyl-sulfide complex and then hydrogen peroxide to afford the corresponding alcohol which, on subsequent PMB deprotection using DDQ, gave the diol 16 in 74% yield. Both free hydroxy groups of diol 16 were then mesylated using methanesulfonyl chloride to provide dimesyl compound 17 in 84% yield. Finally, benzyl carbamate deprotection and concomitant cyclization under hydrogenation conditions using palladium hydroxide furnished (S)-coinicine (2) {[α]_D ^²5 +9.5 (c 1.1, EtOH); Lit. [4q] [α]_D ^²5 +10.2 (c 1.76, EtOH)} in excellent yield. The physical and spectroscopic data of 2 were in full agreement with the literature data. [4q]

We have recently developed a new methodology for enantiopure syn/anti-1,3-polyols in an iterative manner using γ-hydroxy esters as a substrate by a proline-catalyzed sequential α-aminoxylation and HWE olefination reaction of aldehydes. [9] As an extension of our research interest in the area of organocatalysis and in order to reduce the overall number of steps for the synthesis of (S)-coinicine (2), a different route via sequential α-aminoxylation and HWE olefination of aldehyde 6 was envisioned, as shown in the retrosynthetic analysis in Scheme  [4] .

As illustrated in Scheme  [5] , the sequential α-aminoxylation and HWE olefination of aldehyde 6 and subsequent reduction of the resulting O-amino-substituted allylic alcohol furnished the γ-hydroxy ester 18 in 65% yield and 95% ee. [¹³] The free hydroxy group of 18 was reacted with methanesulfonyl chloride, which was followed by treatment with sodium azide, to furnish the azido ester 19 in 71% yield (over two steps). In situ conversion of azide 19 into Boc-protected amine 20 was achieved in one step in excellent yield using hydrogen with palladium-on-carbon and (Boc)₂O. The ester 20 on DIBAL-H reduction gave the alcohol 21 in 87% yield which, on subsequent PMB deprotection using DDQ, afforded diol 22 in 78% yield. Treatment of diol 22 with methanesulfonyl chloride gave dimesyl compound. Finally, Boc deprotection using acid treatment (methanolic HCl) followed by reaction with excess sodium hydride afforded the target molecule (S)-coinicine (2). The physical and spectroscopic data of 2 were in accord with those described in the literature. [4q]

In conclusion, proline-catalyzed α-aminoxylation and ­sequential α-aminoxylation and Horner-Wadsworth-­Emmons olefination approaches have been successfully applied to the synthesis of (R)-coniine and (S)-coinicine. The present method is easily amenable for the synthesis of a variety of piperidine and indolizidine alkaloids. Currently, studies in this direction are in progress.

All reactions were carried out under inert atmosphere, unless otherwise mentioned, following standard syringe septa techniques. Solvents were dried and purified by conventional methods prior to use. The progress of all reactions was monitored by TLC using glass plates precoated with silica gel 60 F254 to a thickness of 0.25 mm (Merck). Column chromatography was performed on silica gel (60 and 230 mesh) using EtOAc and petroleum ether (PE) as the eluents. Optical rotations were measured with a JASCO DIP-360 digital polarimeter at 25 ˚C. IR spectra were recorded on a Perkin-Elmer FT-IR spectrophotometer. ^¹H and ^¹³C NMR spectra were recorded in CDCl₃ on Bruker AC 200, AV 400 and DRX 500 spectrometers (^¹H at 200 or 500 MHz; ^¹³C at 50, 100 or 125 MHz) with TMS as internal standard. ESI-MS were obtained using an Applied Biosystems API QSTAR mass spectrometer.

( R )-6-(4-Methoxybenzyloxy)-2-(phenylaminooxy)hexan-1-ol (7)

To a stirred soln of 6-(4-methoxybenzyloxy)hexanal (6; 1.00 g, 4.24 mmol) and nitrosobenzene (0.379 g, 3.53 mmol) in DMSO (9 mL) was added l-proline (0.097 g, 0.84 mmol, 20 mol%) in one portion at 25 ˚C. After 1 h, the temperature was lowered to 0 ˚C, which was followed by dilution of the mixture with anhyd MeOH (10 mL) and careful addition of excess NaBH₄ (0.643 g, 17.0 mmol). The reaction was quenched after 10 min by pouring the mixture into a vigorously stirred, biphasic solution of Et₂O and aq 1 M HCl. The organic layer was separated, and the aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic phases were dried (Na₂SO₄), concentrated and purified by column chromatography over silica gel (EtOAc-PE, 4:6) to give pure aminooxy alcohol 7; yield: 1.03 g (71%).

[α]_D ^²5 +1.14 (c 1.8, CHCl₃).

IR (CHCl₃): 3028, 2979, 2358, 1600, 1494, 1454, 1029 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 1.44-1.68 (m, 8 H), 3.44-3.52 (m, 3 H), 3.63-3.69 (m, 1 H), 3.83 (s, 3 H), 3.93-4.00 (m, 1 H), 4.46 (s, 2 H), 6.88-6.93 (m, 2 H), 6.98-7.04 (m, 2 H), 7.22-7.38 (m, 5 H).

^¹³C NMR (50 MHz, CDCl₃): δ = 22.4, 29.6, 29.7, 55.2, 65.0, 69.7, 72.5, 83.8, 113.7, 114.7, 122.3, 122.8, 128.9, 129.2, 130.5, 148.4, 159.1.

Anal. Calcd for C₂₀H₂₇NO₄: C, 69.54; H, 7.88; N, 4.05. Found: C, 69.67; H, 7.71; N, 4.17.

( R )-6-(4-Methoxybenzyloxy)hexane-1,2-diol (8)

The aminooxy alcohol 7 (1.00 g, 2.89 mmol) was dissolved in EtOAc (10 mL); to the solution was added 10% Pd/C (0.050 g) and the mixture was stirred in a H₂ atmosphere (1 atm, balloon pressure) for 12 h. After completion of the reaction (monitored by TLC), the mixture was filtered through a Celite^® pad, the filtrate was concentrated and the crude product was purified by silica gel chromatography (EtOAc-PE, 4:6) to give pure diol 8; yield: 0.625 g (85%).

[α]_D ^²5 +0.84 (c 0.5, CHCl₃).

IR (CHCl₃): 3412, 3018, 2938, 1612, 1513, 1248, 1215 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 1.33-1.56 (m, 6 H), 2.81 (br s, 2 H), 3.27-3.40 (m, 3 H), 3.49-3.56 (m, 1 H), 3.59-3.63 (m, 1 H), 3.72 (s, 3 H), 4.35 (s, 2 H), 6.80 (d, J = 8.7 Hz, 2 H), 7.18 (d, J = 8.7 Hz, 2 H).

^¹³C NMR (50 MHz, CDCl₃): δ = 22.1, 29.5, 32.7, 55.2, 66.5, 69.8, 72.0, 72.4, 113.7, 129.2, 130.4, 159.1.

Anal. Calcd for C₁₄H₂₂O₄: C, 66.12; H, 8.72. Found: C, 66.02; H, 8.84.

( R )-2-[4-(4-Methoxybenzyloxy)butyl]oxirane (9)

To a soln of diol 8 (0.21 g, 0.825 mmol) in anhyd CH₂Cl₂ (5 mL) was added dibutyltin oxide (0.004 g, 0.016 mmol), followed by the addition of TsCl (0.157 g, 0.825 mmol) and Et₃N (0.115 mL, 0.83 mmol), and the mixture was stirred at r.t. under N₂. After completion of the reaction (15 min, monitored by TLC), it was quenched by the addition of H₂O. The solution was extracted with CH₂Cl₂ (3 × 10 mL), and the combined organic phases were washed with H₂O (20 mL), dried (Na₂SO₄) and concentrated.

To this crude mixture in MeOH (10 mL) at 0 ˚C was added K₂CO₃ (0.215 g, 1.56 mmol) and the resulting mixture was stirred for 1 h at that temperature. After completion of the reaction (as indicated by TLC), it was quenched by the addition of ice pieces and MeOH, and the mixture was concentrated on a rotatory evaporator. The concentrated mixture was then extracted with EtOAc (3 × 20 mL), and the combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated. Column chromatography (PE-EtOAc, 9:1) gave the epoxide 9 as a colorless liquid; yield: 0.15 g (79%).

[α]_D ^²5 +4.18 (c 1.00, CHCl₃).

IR (CHCl₃): 2934, 2858, 1615, 1586, 1513, 1463, 1248 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 1.52-1.67 (m, 6 H), 2.45-2.49 (m, 1 H), 2.73-2.77 (m, 1 H), 2.87-2.94 (m, 1 H), 3.46 (t, J = 6.3 Hz, 2 H), 3.81 (s, 3 H), 4.44 (s, 2 H), 6.88 (d, J = 8.7 Hz, 2 H), 7.27 (d, J = 8.7 Hz, 2 H).

^¹³C NMR (125 MHz, CDCl₃): δ = 22.6, 29.4, 32.2, 46.9, 52.1, 55.1, 69.7, 72.5, 113.7, 129.1, 130.6, 159.1.

Anal. Calcd for C₁₄H₂₀O₃: C, 71.16; H, 8.53. Found: C, 71.04; H, 8.65.

( R )-8-(4-Methoxybenzyloxy)oct-1-yn-4-ol (10)

To a soln of epoxide 9 (0.5 g, 2.11 mmol) in DMSO (2 mL) at 0 ˚C was added lithium acetylide-ethylenediamine complex (0.292 g, 3.16 mmol) in one portion. The mixture was stirred at 0 ˚C for 30 min and at r.t. for 12 h. The excess reagent was quenched with 0.3 N H₂SO₄, the mixture was extracted with Et₂O (3 × 20 mL), and the extracts were washed with H₂O (2 × 20 mL) and brine, dried (Na₂SO₄) and concentrated. The residue was purified by silica gel chromatography (PE-EtOAc, 9:1) to afford homopropargyl alcohol 10 as a colorless liquid; yield: 0.455 g (82%).

[α]_D ^²5 +1.07 (c 1.02, CHCl₃).

IR (CHCl₃): 3438, 2937, 2250, 1608, 1463, 1249 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 1.43-1.68 (m, 6 H), 1.79 (br s, 1 H), 2.06 (t, J = 2.6 Hz, 1 H), 2.33-2.42 (m, 2 H), 3.46 (t, J = 6.3 Hz, 2 H), 3.71-3.74 (m, 1 H), 3.81 (s, 3 H), 4.44 (s, 2 H), 6.88 (d, J = 8.7 Hz, 2 H), 7.27 (d, J = 8.7 Hz, 2 H).

^¹³C NMR (125 MHz, CDCl₃): δ = 22.3, 27.3, 29.5, 35.9, 55.3, 69.8, 70.8, 72.6, 80.9, 113.8, 129.2, 130.6, 131.5, 159.1.

Anal. Calcd for C₁₆H₂₂O₃: C, 73.25; H, 8.45. Found: C, 73.38; H, 8.31.

( R )-8-(4-Methoxybenzyloxy)oct-1-en-4-ol (11)

To a soln of homopropargyl alcohol 10 (1.0 g, 3.81 mmol) in EtOAc (10 mL) was added Lindlar catalyst (0.08 g). The mixture was stirred for 0.5 h under a balloon of H₂ at r.t. and was then filtered through a Celite^® pad. The filtrate was concentrated and the residue was purified by silica gel column chromatography (PE-EtOAc, 9:1) to give homoallylic alcohol 11 as a pale yellow oil; yield: 0.90 g (90%).

[α]_D ^²5 +3.60 (c 1.35, CHCl₃).

IR (CHCl₃): 3464, 2983, 1614, 1587, 1514, 1447, 1098 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 1.32-1.43 (m, 5 H), 1.52-1.59 (m, 2 H), 2.01-2.24 (m, 2 H), 3.37 (t, J = 2.6 Hz, 2 H), 3.48-3.61 (m, 1 H), 3.72 (s, 3 H), 4.35 (s, 2 H), 5.00-5.02 (m, 1 H), 5.06-5.10 (m, 1 H), 5.64-6.85 (m, 1 H), 6.78 (d, J = 8.7 Hz, 2 H), 7.18 (d, J = 8.7 Hz, 2 H).

^¹³C NMR (50 MHz, CDCl₃): δ = 22.1, 29.4, 36.2, 41.7, 54.8, 69.7, 70.3, 70.9, 72.2, 113.5, 117.3, 129.0, 134.8, 158.8.

Anal. Calcd for C₁₆H₂₄O₃: C, 72.69; H, 9.15. Found: C, 72.80; H, 9.29.

( S )-1-[(5-Azidooct-7-enyloxy)methyl]-4-methoxybenzene (12)

To an ice-cold, stirred soln of homoallylic alcohol 11 (1.0 g, 3.78 mmol) and Et₃N (0.948 mL, 6.8 mmol) in anhyd CH₂Cl₂ (75 mL) was added dropwise MsCl (0.322 mL, 4.16 mmol) over 15 min. The resulting mixture was allowed to warm to r.t. and was stirred for 2 h. After dilution with CH₂Cl₂ (100 mL), the solution was washed with H₂O (3 × 50 mL) and brine, dried (Na₂SO₄) and concentrated to give the crude mesylated product. This was used for the next step without further purification.

To a soln of the mesylated product in anhyd DMF (15 mL) was added portionwise NaN₃ (1.47 g, 22.69 mmol) and the resulting suspension was stirred at 45 ˚C for 24 h. After cooling the orange solution to r.t., Et₂O (50 mL) and H₂O (50 mL) were added and the aqueous layer was extracted with Et₂O (3 × 40 mL). The combined organic layers were dried (Na₂SO₄) and the solvent was removed under reduced pressure. Purification of the crude product by silica gel column chromatography (PE) gave azide 12 as a yellowish liquid; yield: 0.744 g (68%).

[α]_D ^²5 -21.41 (c 1.25, CHCl₃).

IR (CHCl₃): 2931, 2104, 1607, 1512, 1465, 1258 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 1.48-1.66 (m, 6 H), 2.27-2.34 (m, 2 H), 3.31-3.36 (m, 1 H), 3.46 (t, J = 6.2 Hz, 2 H), 3.81 (s, 3 H), 4.44 (s, 2 H), 5.10-5.12 (m, 1 H), 5.15-5.21 (m, 1 H), 5.72-5.92 (m, 1 H), 6.89 (d, J = 8.7 Hz, 2 H), 7.27 (d, J = 8.7 Hz, 2 H).

^¹³C NMR (125 MHz, CDCl₃): δ = 22.8, 29.4, 33.7, 38.7, 55.2, 62.2, 69.7, 72.5, 113.7, 118.0, 129.2, 130.6, 133.9, 159.1.

Anal. Calcd for C₁₆H₂₃N₃O₂: C, 66.41; H, 8.01; N, 14.52. Found: C, 66.56; H, 8.17; N, 14.65.

tert -Butyl ( R )-8-Hydroxyoctan-4-ylcarbamate (13)

To a soln of azide 12 (0.8 g, 2.76 mmol) in EtOAc (8 mL) was added 10% Pd/C (0.05 g) and (Boc)₂O (0.7 mL, 3.04 mmol). The resulting solution was stirred under H₂ atmosphere at r.t. for 12 h until disappearance of the azide (as monitored by TLC). The mixture was filtered through a Celite^® pad to remove the catalyst and the filtrate was concentrated under reduced pressure.

To a crude soln of the ester (0.960 g, 2.61 mmol) in CH₂Cl₂ (9.5 mL) and H₂O (0.5 mL) was added DDQ (0.655 g, 2.88 mmol), and the mixture was stirred at r.t. for 30 min. After completion of the reaction (monitored by TLC), it was quenched by the addition of ice-cooled aq NaHCO₃ soln and the mixture was extracted with CH₂Cl₂ (3 × 20 mL). The combined organic fractions were washed with sat. NaHCO₃ soln (15 mL) followed by brine, then dried (Na₂SO₄) and concentrated. Silica gel column chromatography of the crude product (PE-EtOAc, 8:2) gave alcohol 13 as an oily liquid; yield: 0.542 g (80%).

[α]_D ^²5 +4.32 (c 1.72, CHCl₃).

IR (CHCl₃): 3464, 2984, 1740, 1518, 1478, 1465, 1243 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 0.88-0.99 (m, 3 H), 1.25-1.35 (m, 4 H), 1.43 (s, 9 H), 1.52-1.79 (m, 4 H), 1.94-2.04 (m, 2 H), 2.26-2.44 (m, 1 H), 3.63 (t, J = 6.4 Hz, 2 H), 4.30 (t, J = 6.7 Hz, 1 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 13.7, 14.0, 19.1, 22.0, 27.4, 28.4, 30.5, 32.5, 35.4, 38.0, 62.7, 65.5, 167.7.

Anal. Calcd for C₁₃H₂₇NO₃: C, 63.64; H, 11.09; N, 5.71. Found: C, 63.80; H, 11.21; N, 5.58.

( R )-5-( tert -Butoxycarbonylamino)octyl Methanesulfonate (14)

To an ice-cold, stirred soln of alcohol 13 (0.3 g, 1.22 mmol) and Et₃N (0.306 mL, 2.2 mmol) in anhyd CH₂Cl₂ (7 mL) was added dropwise MsCl (0.104 mL, 1.34 mmol) over 15 min. The resulting mixture was allowed to warm to r.t. and was stirred for 2 h. After dilution with CH₂Cl₂ (15 mL), the solution was washed with H₂O (3 × 25 mL) and brine, dried (Na₂SO₄) and concentrated. Silica gel column chromatography of the crude mesylated product (PE-EtOAc, 8:2) gave mesyl ester 14 as an oily liquid; yield: 0.336 g (85%).

[α]_D ^²5 +2.80 (c 1.16, CHCl₃).

IR (CHCl₃): 2985, 1742, 1242, 1047 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 0.90 (t, J = 6.7 Hz, 3 H), 1.32-1.43 (m, 18 H), 1.68-1.85 (m, 2 H), 3.00 (s, 3 H), 3.53 (br s, 1 H), 4.22 (t, J = 6.5 Hz, 2 H).

^¹³C NMR (50 MHz, CDCl₃): δ = 13.8, 18.9, 21.7, 28.2, 28.8, 34.8, 37.1, 37.6, 49.9, 69.9, 78.7, 155.7.

Anal. Calcd for C₁₄H₂₉NO₅S: C, 51.99; H, 9.04; N, 4.33; S, 9.91. Found: C, 52.11; H, 9.11; N, 4.21; S, 9.81.

( R )-2-Propylpiperidine [( R )-Coniine, 1]

To a soln of mesyl ester 14 (0.1 g, 0.309 mmol) in DMF at 0 ˚C was added NaH (60% dispersion in oil, 0.008 g). The reaction was allowed to stir at r.t. On completion of the reaction (3 h, as indicated by TLC), it was quenched by the addition of ice pieces. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with H₂O (20 mL) and brine, then dried (Na₂SO₄). Silica gel column chromatography (EtOAc-PE, 9:1) furnished the Boc-protected product as a colorless liquid.

To this product (0.05 g, 0.22 mmol) in anhyd CH₂Cl₂ (2 mL) was added methanolic HCl (2 mL) in a catalytic amount. The mixture was stirred at r.t. for 2 h, then sat. aq NaHCO₃ (30 mL) was added and the mixture was extracted with CH₂Cl₂ (3 × 5 mL). The combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated. The crude product was purified by silica gel column chromatography (MeOH-CH₂Cl₂, 1:10) to give 1 as a solid compound; yield: 0.032 g (90%). The physical and spectroscopic data of 1 were in full agreement with the literature data.

[α]_D ^²5 -8.64 (c 0.25, EtOH) {Lit. [4i] [α]_D ^²5 -7.3 (c 0.33, EtOH)}.

IR (CHCl₃): 3020, 2962, 1215 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 0.96 (t, J = 7.0 Hz, 3 H), 1.46 (br s, 4 H), 1.93 (br s, 5 H), 2.85-2.92 (m, 2 H), 3.45-3.50 (m, 1 H), 9.14-9.39 (m, 2 H).

^¹³C NMR (125 MHz, CDCl₃): δ = 13.8, 18.7, 22.3, 22.4, 28.2, 35.4, 45.0, 57.3.

ESI-MS: m/z = 128.2709 [M + H⁺].

Benzyl ( S )-8-(4-Methoxybenzyloxy)oct-1-en-4-ylcarbamate (15)

To a soln of azide 12 (2.0 g, 6.91 mmol) in THF (30 mL) and H₂O (4.5 mL) was added Ph₃P (2.71 g, 10.36 mmol) and the mixture was stirred at r.t. for 12 h. The mixture was concentrated, then 1,4-dioxane (25 mL), H₂O (25 mL) and Na₂CO₃ (1.6 g, 15.20 mmol) were added, and this mixture was stirred for another 10 min at 0 ˚C. To this ice-cold solution, CbzCl (1.28 mL, 8.98 mmol) was added and the mixture was allowed to warm to r.t. and was stirred overnight. On completion of the reaction, the solvent was evaporated under reduced pressure and the residue was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with H₂O (50 mL) and brine, dried (Na₂SO₄) and concentrated. Silica gel column chromatography of the crude product (PE-EtOAc, 19:1) gave olefin 15 as a colorless liquid; yield: 2.47 g (90%).

[α]_D ^²5 -5.22 (c 1.8, CHCl₃).

IR (CHCl₃): 3438, 2928, 1716, 1510, 1215 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 1.43-1.53 (m, 4 H), 1.54-1.64 (m, 2 H), 1.94 (br s, 1 H), 2.21-2.30 (m, 1 H), 3.46 (t, J = 6.3 Hz, 2 H), 3.65-3.74 (m, 1 H), 3.83 (s, 3 H), 4.45 (s, 2 H), 4.53-4.65 (m, 1 H), 5.06-5.12 (m, 4 H), 5.69-5.89 (m, 1 H), 6.91 (d, J = 8.7 Hz, 2 H), 7.30 (d, J = 8.7 Hz, 2 H), 7.35-7.41 (m, 5 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 22.5, 29.4, 34.2, 39.3, 50.5, 55.1, 69.6, 72.3, 113.6, 117.6, 127.8, 128.3, 129.1, 130.5, 134.1, 136.6, 155.9, 159.0.

Anal. Calcd for C₂₄H₃₁NO₄: C, 72.52; H, 7.86; N, 3.52. Found: C, 72.39; H, 7.98; N, 3.61.

Benzyl ( S )-1-Hydroxy-8-(4-methoxybenzyloxy)octan-4-ylcarbamate

To a soln of olefin 15 (0.54 g, 1.36 mmol) in anhyd THF (10 mL) at 0 ˚C under argon atmosphere was added 2 M BH₃˙SMe₂ in THF (0.103 g, 0.68 mL, 1.36 mmol) and the mixture was allowed to warm to r.t. and was stirred for 3 h. The reaction flask was cooled to 0 ˚C and then a soln of NaOH (0.108 g, 2.72 mmol) in EtOH-H₂O (2:1, 10 mL), followed by a 30% w/v soln of H₂O₂ in H₂O (0.5 mL, 4.08 mmol), were added dropwise over 15 min. The mixture was then stirred at r.t. for 6 h. The product was taken up in EtOAc (20 mL) and the aqueous layer was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with H₂O (30 mL) and brine, dried (Na₂SO₄) and concentrated to give the crude alcohol product, benzyl (S)-1-hydroxy-8-(4-methoxybenzyloxy)octan-4-ylcarbamate, which was used in the next step without purification; yield: 0.485 g (86%).

IR (CHCl₃): 3318, 2922, 1685, 1540, 1463, 1216 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 1.42-1.46 (m, 4 H), 1.54-1.60 (m, 6 H), 1.90 (br s, 2 H), 3.42 (t, J = 6.3 Hz, 2 H), 3.64 (t, J = 5.5 Hz, 3 H), 3.80 (s, 3 H), 4.42 (s, 2 H), 5.09 (s, 2 H), 6.89 (d, J = 8.7 Hz, 2 H), 7.27 (d, J = 8.7 Hz, 2 H), 7.33-7.36 (m, 5 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 22.4, 28.6, 29.4, 31.6, 35.0, 50.9, 55.1, 62.2, 66.4, 69.7, 72.3, 113.6, 127.8, 128.3, 129.2, 130.4, 136.5, 156.3, 159.0.

ESI-MS: m/z = 438.2811 [M + Na⁺].

Benzyl ( S )-1,8-Dihydroxyoctan-4-ylcarbamate (16)

To a soln of benzyl (S)-1-hydroxy-8-(4-methoxybenzyloxy)octan-4-ylcarbamate (0.23 g, 0.55 mmol) in CH₂Cl₂ (9.5 mL) and H₂O (0.5 mL) was added DDQ (0.15 g, 0.663 mmol), and the mixture was stirred at r.t. for 30 min. After completion of the reaction (monitored by TLC), the mixture was extracted with EtOAc (3 × 20 mL). The combined organic fractions were washed with sat. NaHCO₃ soln (2 × 25 mL) followed by brine, then dried (Na₂SO₄) and concentrated. Silica gel column chromatography of the crude product (PE-EtOAc, 6:4) gave diol 16 as an oily liquid; yield: 0.14 g (86%).

[α]_D ^²5 +2.53 (c 0.32, CHCl₃).

IR (CHCl₃): 3300, 2858, 1740, 1603, 1495, 1454, 1256 cm^-¹.

^¹H NMR (400 MHz, CDCl₃): δ = 1.39-1.59 (m, 10 H), 2.58 (br s, 2 H), 3.57-3.63 (m, 4 H), 3.81-3.85 (m, 1 H), 4.77-4.85 (br s, 1 H), 5.08 (s, 2 H), 7.34 (m, 5 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 22.0, 28.7, 31.8, 32.3, 35.2, 51.0, 62.3, 62.4, 66.3, 128.0, 128.1, 128.5, 136.6, 156.6.

ESI-MS: m/z = 296.2657 [M + H⁺], 318.2326 [M + Na⁺].

Anal. Calcd for C₁₆H₂₅NO₄: C, 65.06; H, 8.53; N, 4.74. Found: C, 65.19; H, 8.41; N, 4.88.

( S )-4-(Benzyloxycarbonylamino)octane-1,8-diyl Dimethanesulfonate (17)

To an ice-cold, stirred soln of diol 16 (0.5 g, 1.69 mmol) and Et₃N (0.943 mL, 6.8 mmol) in anhyd CH₂Cl₂ (10 mL) was added dropwise MsCl (0.314 mL, 4.06 mmol) over 15 min. The resulting mixture was allowed to warm to r.t. and was stirred for 2 h. After dilution with CH₂Cl₂ (25 mL), the solution was washed with H₂O (3 × 15 mL) and brine, dried (Na₂SO₄) and concentrated. Silica gel column chromatography of the crude mesylated product (PE-EtOAc, 7:3) gave dimesyl compound 17 as an oily liquid; yield: 0.64 g (84%).

[α]_D ^²5 +0.82 (c 1.0, CHCl₃).

IR (CHCl₃): 3022, 1710, 1512, 1217 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 1.39-1.54 (m, 5 H), 1.67-1.86 (m, 5 H), 2.77-2.89 (m, 1 H), 2.99 (s, 6 H), 4.10-4.27 (m, 4 H), 4.60-4.70 (m, 1 H), 5.09 (s, 2 H), 7.35 (m, 5 H).

^¹³C NMR (50 MHz, CDCl₃): δ = 21.8, 25.7, 28.7, 31.5, 34.9, 37.3, 50.4, 66.7, 69.6, 128.0, 128.2, 128.5, 136.4, 156.2.

Anal. Calcd for C₁₈H₂₉NO₈S₂: C, 47.88; H, 6.47; N, 3.10; S, 14.20. Found: C, 47.98; H, 6.31; N, 3.17; S, 14.04.

( S )-Octahydroindolizine [( S )-Coinicine, 2]

To the dimesyl compound 17 (0.05 g, 0.11 mmol) in EtOAc (5 mL) was added Pd(OH)₂ (0.015 g) and the mixture was stirred under hydrogenation conditions for 12 h, until disappearance of the dimesyl compound (as monitored by TLC). The mixture was filtered through a Celite^® pad to remove the catalyst and the filtrate was concentrated under reduced pressure. Silica gel column chromatography (MeOH-CH₂Cl₂, 1:10) gave 2 as a solid compound; yield: 0.011 g (80%). The physical and spectroscopic data of 2 were in full agreement with the literature data.

[α]_D ^²5 +9.5 (c 1.1, EtOH) {Lit. [4q] [α]_D ^²5 +10.2 (c 1.76, EtOH)}.

IR (CHCl₃): 2952, 2920, 1461, 1454, 1320, 1255, 1096 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 1.12-1.87 (m, 11 H), 1.95 (dt, J = 3.6, 11.2 Hz, 1 H), 2.07 (q, J = 9.0 Hz, 1 H), 3.02-3.12 (m, 2 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 20.5, 24.5, 25.4, 30.4, 31.0, 53.0, 54.2, 64.3.

Ethyl ( R )-4-Hydroxy-8-(4-methoxybenzyloxy)octanoate (18)

To a soln of 6-(4-methoxybenzyloxy)hexanal (6; 2.0 g, 8.57 mmol) and nitrosobenzene (0.92 g, 8.57 mmol) in anhyd DMSO (18 mL) was added l-proline (0.395 g, 3.42 mmol) at 20 ˚C. The mixture was vigorously stirred for 25 min under argon (the color of the reaction mixture changed from green to yellow during this time), then cooled to 0 ˚C. Thereafter, a premixed and cooled (0 ˚C) soln of triethyl phosphonoacetate (5.12 mL, 25.7 mmol), DBU (3.83 mL, 25.7 mmol) and LiCl (1.09 g, 25.7 mmol) in MeCN (18 mL) was added quickly (1-2 min) at 0 ˚C. The resulting mixture was allowed to warm to r.t. over 1 h, and the reaction was quenched by the addition of ice pieces. The MeCN was evaporated under reduced pressure. The remaining mixture was then poured into H₂O (50 mL) and the resulting mixture was extracted with Et₂O (5 × 100 mL). The combined organic layers were washed with H₂O (300 mL) and brine, dried (Na₂SO₄) and concentrated under reduced pressure to give crude product which was directly subjected to the next step without purification.

To the crude O-amino-substituted allylic alcohol in EtOAc (25 mL) was added 10% Pd/C (cat.) under hydrogenation conditions and the mixture was stirred overnight. On completion of the reaction (until ^¹H NMR analysis of the crude mixture indicated complete conversion), the mixture was filtered through a Celite^® pad and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (PE-EtOAc, 85:15) to give γ-hydroxy ester 18 as a colorless liquid; yield: 1.78 g (65%).

[α]_D ^²5 +1.81 (c 1.16, CHCl₃).

IR (CHCl₃): 3452, 2928, 1731, 1613, 1586, 1462, 1248 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 1.29 (t, J = 7.0 Hz, 3 H), 1.37-1.51 (m, 4 H), 1.54-1.78 (m, 4 H), 2.33-2.56 (m, 2 H), 3.48 (t, J = 6.3 Hz, 2 H), 3.62-3.69 (m, 1 H), 3.84 (s, 3 H), 4.18 (q, J = 7.0 Hz, 2 H), 4.46 (s, 2 H), 6.91 (d, J = 8.7 Hz, 2 H), 7.29 (d, J = 8.7 Hz, 2 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 14.0, 22.1, 29.4, 30.6, 32.0, 37.0, 55.0, 60.3, 69.8, 70.7, 72.4, 113.6, 129.1, 130.4, 158.9, 174.6.

ESI-MS: m/z = 325.3509 [M + H⁺], 347.3415 [M + Na⁺], 363.3388 [M + K⁺].

Anal. Calcd for C₁₈H₂₈O₅: C, 66.64; H, 8.70. Found: C, 66.52; H, 8.86.

Ethyl ( S )-4-Azido-8-(4-methoxybenzyloxy)octanoate (19)

To an ice-cold, stirred soln of alcohol 18 (1.0 g, 3.08 mmol) and Et₃N (0.86 mL, 6.16 mmol) in anhyd CH₂Cl₂ (10 mL) was added dropwise MsCl (0.266 mL, 3.44 mmol) over 15 min. The resulting mixture was allowed to warm to r.t. and was stirred for 2 h. After dilution with CH₂Cl₂ (15 mL), the solution was washed with H₂O (3 × 50 mL) and brine, dried (Na₂SO₄) and concentrated to give the crude mesylated product. This was used for the next step without further purification.

To a soln of the mesylated product in anhyd DMF (10 mL) was added portionwise NaN₃ (1.20 g, 18.5 mmol) and the resulting suspension was stirred at 45 ˚C for 24 h. After cooling the orange solution to r.t., Et₂O (25 mL) and H₂O (25 mL) were added and the aqueous layer was extracted with Et₂O (3 × 20 mL). The combined organic layers were dried (Na₂SO₄) and the solvent was removed under reduced pressure. Silica gel column chromatography of the crude product (PE-EtOAc, 95:5) gave azide 19 as a yellowish liquid; yield: 0.764 g (71%).

[α]_D ^²5 +10.37 (c 1.54, CHCl₃).

IR (CHCl₃): 2937, 2099, 1732, 1613, 1586, 1247 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 1.29 (t, J = 7.2 Hz, 3 H), 1.55-1.81 (m, 8 H), 2.39-2.49 (m, 2 H), 3.29-3.38 (m, 1 H), 3.48 (t, J = 6.0 Hz, 2 H), 3.83 (s, 3 H), 4.19 (q, J = 7.2 Hz, 2 H), 4.46 (s, 2 H), 6.91 (d, J = 8.7 Hz, 2 H), 7.29 (d, J = 8.7 Hz, 2 H).

^¹³C NMR (50 MHz, CDCl₃): δ = 14.0, 22.7, 29.3, 30.7, 34.0, 55.1, 60.4, 62.0, 69.5, 72.4, 113.6, 129.1, 130.4, 159.0, 172.8.

ESI-MS: m/z = 372.3995 [M + Na⁺], 388.1639 [M + K⁺].

Anal. Calcd for C₁₈H₂₇N₃O₄: C, 61.87; H, 7.79; N, 12.03. Found: C, 61.65; H, 7.63; N, 12.17.

Ethyl ( S )-4-( tert -Butoxycarbonylamino)-8-(4-methoxybenzyl-oxy)octanoate (20)

To a soln of azide 19 (0.14 g, 0.40 mmol) in EtOAc (2 mL) was added 10% Pd/C (cat.) and (Boc)₂O (0.101 mL, 0.44 mmol). The resulting solution was stirred under H₂ atmosphere at r.t. for 12 h until disappearance of the azide (as monitored by TLC). The mixture was filtered through a Celite^® pad to remove the catalyst and the filtrate was concentrated under reduced pressure. Silica gel column chromatography of the crude product (PE-EtOAc, 8:2) gave Boc-protected amine 20 as a colorless liquid; yield: 0.154 g (91%).

[α]_D ^²5 -1.37 (c 1.6, CHCl₃).

IR (CHCl₃): 2978, 1743, 1716, 1612, 1514, 1247, 1097 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 1.29 (t, J = 7.6 Hz, 3 H), 1.47 (s, 9 H), 1.49-1.52 (m, 2 H), 1.58-1.69 (m, 4 H), 1.81-1.95 (m, 2 H), 2.39 (t, J = 7.6 Hz, 2 H), 3.43-3.49 (m, 2 H), 3.55-3.60 (m, 1 H), 3.84 (s, 3 H), 4.16 (q, J = 7.2 Hz, 2 H), 4.45 (s, 2 H), 6.91 (d, J = 9.0 Hz, 2 H), 7.29 (d, J = 9.0 Hz, 2 H).

^¹³C NMR (50 MHz, CDCl₃): δ = 14.0, 22.4, 28.2, 29.4, 30.3, 30.9, 35.4, 50.2, 55.0, 60.2, 69.6, 72.3, 78.8, 113.6, 129.1, 130.5, 155.6, 158.9, 173.5.

ESI-MS: m/z = 446.335 [M + Na⁺].

Anal. Calcd for C₂₃H₃₇NO₆: C, 65.22; H, 8.81; N, 3.31. Found: C, 65.29; H, 8.69; N, 3.24.

tert -Butyl ( S )-1-Hydroxy-8-(4-methoxybenzyloxy)octan-4-ylcarbamate (21)

To a soln of ester 20 (1.0 g, 2.36 mmol) in CH₂Cl₂ (10 mL) was added 2.27 M DIBAL-H in toluene (2.52 mL, 5.72 mmol) at 0 ˚C under argon atmosphere. The mixture was stirred at this temperature for 1 h, then sat. aq tartaric acid (4 mL) was added. The resulting mixture was stirred for 15 min and the organic layer was separated. The aqueous phase was extracted with CH₂Cl₂ (3 × 10 mL), and the combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure to give crude product which, on silica gel column chromatography (PE-EtOAc, 8:2), gave alcohol 21 as a colorless liquid; yield: 0.783 g (87%).

[α]_D ^²5 -0.99 (c 1.8, CHCl₃).

IR (CHCl₃): 3308, 2922, 1741, 1685, 1554, 1453, 1216 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 1.29-1.40 (m, 4 H), 1.47 (s, 9 H), 1.54-1.66 (m, 8 H), 3.46 (t, J = 6.3 Hz, 2 H), 3.59-3.71 (m, 3 H), 3.84 (s, 3 H), 4.45 (s, 2 H), 6.91 (d, J = 8.6 Hz, 2 H), 7.30 (d, J = 8.6 Hz, 2 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 22.5, 28.3, 28.8, 29.5, 32.0, 35.3, 50.3, 55.2, 62.5, 69.8, 72.4, 79.0, 113.7, 129.2, 130.6, 155.9, 159.0.

ESI-MS: m/z = 404.561 [M + Na⁺].

Anal. Calcd for C₂₁H₃₅NO₅: C, 66.11; H, 9.25; N, 3.67. Found: C, 66.25; H, 9.14; N, 3.81.

tert -Butyl ( S )-1,8-Dihydroxyoctan-4-ylcarbamate (22)

To a soln of alcohol 21 (0.1 g, 0.262 mmol) in CH₂Cl₂ (9.5 mL) and H₂O (0.5 mL) was added DDQ (0.065 g, 0.288 mmol), and the mixture was stirred at r.t. for 30 min. After completion of the reaction (monitored by TLC), the mixture was extracted with EtOAc (3 × 20 mL). The combined organic fractions were washed with sat. NaHCO₃ soln (25 mL) followed by brine, then dried (Na₂SO₄) and concentrated. Silica gel column chromatography of the crude product (PE-EtOAc, 4:6) gave diol 22 as an oily liquid; yield: 0.053 g (78%).

[α]_D ^²5 -1.96 (c 0.8, CHCl₃).

IR (CHCl₃): 3310, 3081, 2850, 1740, 1216, 1035 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 1.20-1.31 (m, 4 H), 1.42 (s, 9 H), 1.50-1.58 (m, 6 H), 2.74 (br s, 2 H), 3.58-3.63 (m, 4 H), 4.52-4.56 (m, 1 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 22.0, 28.4, 28.8, 29.6, 32.0, 32.4, 35.3, 40.8, 50.2, 62.4, 155.8.

ESI-MS: m/z = 284.368 [M + Na⁺].

Anal. Calcd for C₁₃H₂₇NO₄: C, 59.74; H, 10.41; N, 5.36. Found: C, 59.87; H, 10.32; N, 5.48.

( S )-Octahydroindolizine [( S )-Coinicine, 2]

To an ice-cold, stirred soln of diol 22 (0.5 g, 1.91 mmol) and Et₃N (1.06 mL, 7.65 mmol) in anhyd CH₂Cl₂ (7 mL) was added dropwise MsCl (0.36 mL, 4.6 mmol) over 15 min. The resulting mixture was allowed to warm to r.t. and was stirred for 2 h. After dilution with CH₂Cl₂ (25 mL), the solution was washed with H₂O (3 × 15 mL) and brine, dried (Na₂SO₄) and concentrated to give the crude di­mesylated product as an oily liquid.

To the crude dimesylated product (0.10 g, 0.24 mmol) in anhyd CH₂Cl₂ (2 mL) was added methanolic HCl (2 mL) in a catalytic amount. The mixture was stirred at r.t. for 2 h and was then concentrated on a rotatory evaporator to remove CH₂Cl₂ and MeOH. To this crude reaction mixture was then added DMF (2 mL) and NaH (60% dispersion in oil, 0.04 g) at 0 ˚C and the mixture was stirred overnight. On completion of the reaction, it was quenched by the addition of ice pieces, and the mixture was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were washed with H₂O (2 × 15 mL) and brine, then dried (Na₂SO₄). Silica gel column chromatography (MeOH-CH₂Cl₂, 1:10) furnished (S)-octahydroindolizine (2) as a solid compound; yield: 0.02 g (67%). The physical and spectroscopic data of 2 were in full agreement with the literature data. [4q]

Acknowledgment

N.B.K. thanks CSIR, New Delhi for the award of a research fellowship. Financial support in the form of a research grant (Grant No. SR/S1/OC-40/2003) from DST, New Delhi is gratefully ­acknowledged.

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The enantiomeric excess (95% ee) was calculated using Mosher analysis by converting alcohol 8 into the monobenzylated alcohol 23 (Figure  [²] ) and then derivatizing alcohol 23 as its Mosher ester.

The enantiomeric excess of 18 (95% ee) was calculated using Mosher analysis by derivatizing alcohol 18 as its Mosher ester.

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The enantiomeric excess (95% ee) was calculated using Mosher analysis by converting alcohol 8 into the monobenzylated alcohol 23 (Figure  [²] ) and then derivatizing alcohol 23 as its Mosher ester.

The enantiomeric excess of 18 (95% ee) was calculated using Mosher analysis by derivatizing alcohol 18 as its Mosher ester.