Organocatalytic stereoselective approach to the total synthesis of (−)-halosaline

Abstract

A practical and efficient organocatalytic approach to the synthesis of substituted piperidine alkaloids in high enantio- and diastereomeric excess was achieved using proline-catalyzed sequential α-aminoxylation/α-amination reaction and HWE olefination reaction of an aldehyde.

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Introduction

Naturally occurring alkaloids containing multifunctionalized piperidine rings are found abundantly in nature and many of them exhibit a wide range of biological and pharmacological activity.^1,2 These include piperidine ring containing oxygenated side chains such as halosaline, epi-halosaline, etc. and fused piperidines with bicyclic rings such as elaeokanine A, elaeokanine C etc. or tricyclic ring such as tetraponerine T-4 (Fig 1). (−)-Halosaline 1, a 2-(2-hydroxy substituted)-piperidine was isolated from Haloxylon salicornicum.³ (−)-8-Epi-halosaline 2, a diastereomer of (−)-halosaline, was isolated from Andrachne aspera spreng,⁴ a small perennial under shrub commonly found in Karachi. Tetraponerine T-4 3 was isolated from the venom of a New Guinean ant Tetraponera sp.⁵ Elaeocarpus alkaloids elaeokanine A 4 and C 5 were isolated from Ekaeocarous kaniensis Schltr.,⁶ a large rain-forest tree found in New Guinea.

Fig. 1 Substituted piperidine alkaloids.

There are several literature reports on the synthesis of (−)-halosaline.⁷ The most recent publication by Yadav et al.^7a describes its synthesis via Prins cyclization followed by reductive ring opening reaction. While Radha Krishna et al.^7b used an iterative asymmetric allylation/RCM strategy, Posner et al.^7d have utilized a cyclopentanone ring-expansion based functionalized strategy. In another report, Lesma et al.^7e employed ruthenium catalyzed ring-opening/ring-closing metathesis strategy, whereas Takahata et al.^7g used an iterative asymmetric dihydroxylation strategy to arrive at target molecule.

In recent years, there has been growing interest in the use of small organic molecules to catalyze organic reactions. As a result, the area of organocatalysis has emerged as a promising strategy and as an alternative to enzyme catalysis and metal catalysis,⁸ thus becoming a fundamental tool in the catalysis toolbox available for asymmetric synthesis.⁹ Proline in the recent past has been defined as ‘universal catalyst’ because of its utility in different reactions providing rapid access to enantiomerically pure products.¹⁰ Similarly organocatalytic tandem reactions are characterized by high efficiencies and are in a way biomimetic. They often proceed with excellent stereocontrol and are environmentally friendly.¹¹

Recently, we have developed¹² an efficient approach to the asymmetric synthesis of 1,3-amino alcohols using sequential α-aminoxylation^13a,b/α-amination^13c,d and HWE olefination reaction catalyzed by proline. In continuation of our interest in organocatalysis¹⁴ and asymmetric synthesis of substituted piperidine alkaloids,¹⁵ we further became interested to extrapolate the above knowledge to develop a general flexible approach to chiral 2-substituted piperidines. Herein we report our successful endeavours to devise a simple route towards synthesis of (−)-halosaline, employing sequential α-aminoxylation/α-amination reaction and HWE olefination of an aldehyde catalyzed by proline.

Results and discussion

Our synthetic approach for (−)-halosaline was envisioned via the retrosynthetic route shown in the Scheme 1. (−)-Halosaline 1 was thought to be synthesized from cyclic aminoalcohol 6. The piperidine ring in cyclic aminoalcohol 6 could be constructed by the allylation and ring closing metathesis of homoallylic amine 7, which could be synthesized from 1,3-aminoalcohol 8 using standard protocol. Compound 8 could be obtained from γ-hydroxy ester 9 by α-amination which in turn could be easily obtained by the sequential α-aminoxylation and HWE olefination of the corresponding aldehyde 10.

Scheme 1 Retrosynthetic route to (−)-halosaline.

Thus as shown in Scheme 2, synthesis started from the commercially available valeraldehyde 10 which on sequential α-aminoxylation using nitroso benzene as oxygen source and L-proline as catalyst and subsequent Horner–Wadsworth–Emmons (HWE) olefination using ylide generated from triethyl phosphonoacetate followed by hydrogenation using catalytic amount of Pd/C furnished the γ-hydroxy esters 9¹⁶ in 78% yield and 94% ee.¹⁷ The free hydroxy group of γ-hydroxy ester 9 was protected as TBS ether using TBSCl in DMF to furnish compound 11 in 95% yield. The DIBAL-H reduction of ester 11 at −78 °C furnished the corresponding aldehyde which was then subjected to α-amination using commercially available dibenzyl azodicarboxylate (DBAD) as a nitrogen source and D-proline as a catalyst to furnish the α-amino aldehyde, which on in situ trapping by triethyl phosphonoacetate (HWE olefination) in presence of DBU furnished the anti-1,3-amino alcohol 8 in 71% yield and 98 : 2 diastereomeric ratio as determined from HPLC analysis.¹⁷ The absolute and relative configuration of amino alcohol 8 is based on L- or D-proline used in the reaction and analogous to those as reported by us in our earlier studies.¹² The N–N-bond of diastereomerically pure 1,3-anti-aminoalcohol 8 was easily cleaved with concomitant reduction of double bond under hydrogenation conditions using freshly prepared RANEY®-Ni at 60 psi to give free amine, which was subsequently converted into its Boc derivative using Boc₂O to furnish ester 12 in 79% yield. Compound 12 was reduced using LiBH₄ to give alcohol 13 which was subsequently converted to its iodo derivative 14 using Appel reaction conditions. Dehydrohalogenation¹⁸ of 14 was attempted using n-BuLi but to our disappointment we could get only the cyclic aminoalcohol 15 instead of the expected compound 7. The formation of 15 was confirmed using ¹H NMR spectrum and HRMS.

Scheme 2 Attempted synthesis of homoallylic amine.

By analyzing the result, we concluded that due to presence of NH proton, nucleophilic displacement was the predominant reaction instead of dehydrohalogenation leading to exclusive formation of 15. Therefore, further attempts were made to functionalize the amine group of compound 12. For this purpose, compound 12 was treated with Boc₂O in presence of catalytic DMAP, but to our disappointment once again we obtained cyclic amide 17 as the only product instead of di-boc compound 16 (Scheme 3).

Scheme 3 Attempted functionalization of amino ester compound.

We then switched over to a different strategy to construct the piperidine ring, via one carbon homologation and further cyclization of alcohol 13. Towards this end, the free hydroxy group of 13 was converted into its toluenesulfonate derivative which on subsequent treatment with NaCN in dry DMF at 100 °C furnished the cyano compound 18 in 85% yield. Compound 18 was subjected to reduction using DIBAL-H at −78 °C followed by acid hydrolysis to give the aldehyde which on subsequent treatment with NaBH₃CN afforded the cyclized product 19, along with small amount of open chain product 20 (Scheme 4). The formation of compound 19 was confirmed by ¹H NMR spectrum and HRMS. We have used both the products 19 and 20 for the synthesis of the target molecule (−)-halosaline.

Scheme 4 Revised synthetic strategy and completion of synthesis of (−)-halosaline.

Towards this end, compound 19 was subjected to the double bond reduction under hydrogenation conditions using 10% Pd–C in EtOAc to give piperidine 21 which on global deprotection of both the TBS and Boc groups with TFA afforded the target compound (−)-halosaline 1 (Scheme 4). The physical and spectroscopic data of compound 1 matched with reported data in literature {solid. Mp 80–82 °C [ref. 7b 82 °C], [α]²⁵_D: −18.9 (c 0.9, EtOH) [ref. 3 [α]²⁵_D: −19.5 (c 0.6, EtOH)]}.

Similarly, the open chain compound 20 obtained as the minor product, was also converted into (−)-halosaline 1 by two-step process. As shown in the Scheme 4, compound 20 was first converted into its p-toluene sulfonate derivative. Subsequent global deprotection of both the TBS and Boc groups with TFA followed by nucleophilic displacement of tosylate with the resultant amine in the presence of diisopropylethyl amine afforded (−)-halosaline 1 in 79% yield.

Conclusions

In conclusion, a stereoselective synthesis of (−)-halosaline was accomplished using proline-catalyzed sequential α-aminoxylation/α-amination reaction and HWE olefination reaction of an aldehyde as the key step. The strategy used is amenable to both the syn- and anti-1,3-aminoalcohols with a high degree of enantio- and diastereoselectivities. The syn- and anti-configuration of the 1,3-amino-alcohol moiety can be manipulated simply by changing the proline in the α-aminoxylation/α-amination step. The synthetic strategy described here has significant potential for stereochemical variations and gives further access to other stereoisomers as well as various other substituted piperidine alkaloids.

Experimental section

Ethyl (R)-4-hydroxyheptanoate (9)

To a solution of valeraldehyde 10 (2.0 g, 23.2 mmol) and nitroso benzene (0.83 g, 7.74 mmol) in anhydrous CH₃CN (50 mL) was added L-proline (0.27 g, 2.32 mmol) at 0 °C. The mixture was vigorously stirred for 24 h under argon (the color of the reaction changed from green to orange red during this time) at 0 °C. Thereafter, A premixed and cooled (0 °C) solution of triethylphosphonoacetate (9.25 mL, 46.4 mmol), DBU (6.95 mL, 46.4 mmol) and LiCl (1.969 g, 46.4 mmol) in CH₃CN (40 mL) was added quickly (1–2 min) at 0 °C. The resulting mixture was allowed to warm to room temperature over 1 h, and quenched by addition of ice pieces. The acetonitrile was evaporated under vacuum. This reaction mixture was then poured into water (100 mL) and extracted with Et₂O (5 × 100 mL). The combined organic layers were washed with water, brine, dried (Na₂SO₄) and concentrated in vacuo to give crude product which was directly subjected to next step without purification. To the crude allylic alcohol in ethyl acetate was added Pd–C (10%) under hydrogenation conditions at 4 atm and the reaction mixture was allowed to stir overnight. On completion of reaction (until ¹H NMR analysis of the crude mixture indicated complete conversion), the mixture was filtered through a pad of celite and concentrated in vacuo to give γ-hydroxy ester 9. The crude product was then purified by using silica gel flash column chromatography using pet ether : EtOAc (85 : 15) as eluent to give (R)-ethyl 4-hydroxyheptanoate 9 as a colorless liquid (1.05 g, Yield 78%, based on nitrosobenzene). [α]²⁵_D: +11.66 (c 2.4, CHCl₃) IR (CHCl₃, cm⁻¹): ν_max 3430, 2934, 1719, 1466, 1177. ¹H NMR (200 MHz, CDCl₃): δ 0.91–0.96 (m, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.38–1.49 (m, 3H), 1.61–2.05 (m, 4H), 2.46 (t, J = 7.2 Hz, 2H), 3.58–3.78 (m, 1H), 4.14 (q, J = 7.1 Hz, 2H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ 13.9, 18.7, 30.7, 32.1, 39.6, 60.4, 70.8, 174.3 ppm. MS (ESI): m/z 197.1862 (M + Na)⁺. HRMS: 197.1173 (M + Na)⁺ calcd 197.1148.

Ethyl (R)-4-((tert-butyldimethylsilyl)oxy)heptanoate (11)

To an ice-cold stirred solution of 9 (1.0 g, 5.75 mmol) in DMF (12 mL) were added imidazole (0.452 g, 6.64 mmol) and TBSCl (1.00 g, 6.64 mmol) at room temperature. The resulting mixture was stirred for 6 h at 0 °C before H₂O (20 mL) was added. The aqueous layer was extracted with diethyl ether (3 × 25 mL). The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. Silica gel column chromatography (petroleum ether : ethyl acetate: 99 : 1) of the crude product gave ethyl (R)-4-((tert-butyldimethylsilyl)oxy)-heptanoate 11 as a colorless liquid (1.57 g, yield 95%). [α]²⁵_D: −7.98 (c 1.34, CHCl₃). IR (CHCl₃, cm⁻¹): ν^max 2958, 1727, 1463, 1256, 908. ¹H NMR (400 MHz, CDCl₃): δ 0.04 (s, 6H), 0.87–0.93 (m, 3H), 0.89 (s, 9H), 1.26 (t, J = 7.1 Hz, 3H), 1.29–1.46 (m, 4H), 1.63–1.83 (m, 2H), 2.36 (t, J = 7.8 Hz, 2H), 3.68–3.73 (m, 1H), 4.12 (q, J = 7.1 Hz, 2H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ −4.6, −4.5, 14.2, 18.0, 18.4, 25.8, 25.9, 31.7, 39.3, 60.2, 70.9, 173.9 ppm. MS (ESI): m/z 311.3840 (M + Na)⁺. Analysis for C₁₅H₃₂O₃Si: calcd C, 62.45; H, 11.18; found: C, 62.64; H, 11.12%.

Dibenzyl 1-((4S,6R,E)-6-((tert-butyldimethylsilyl)oxy)-1-ethoxy-1-oxonon-2-en-4-yl)hydrazine-1,2-dicarboxylate (8)

To a solution of ethyl ester 11 (1.0 g, 3.5 mmol) in CH₂Cl₂ (10 mL), was added DIBAL-H (1.7 mL 2.25 M solution in toluene, 3.85 mmol) at −78 °C under argon atmosphere. The reaction was stirred at this temperature for 40 min. Then solution of tartaric acid (5 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 × 15 mL), the combined organic layers were dried (Na₂SO₄), filtered and evaporated under reduced pressure to give aldehyde as a colorless liquid, which was directly used in the next step without further purification.

To a cooled solution of dibenzylazodicarboxylate (DBAD) (1.02 g, 2.9 mmol) and D-proline (0.038 g, 0.28 mmol) in CH₃CN (40 mL) at 0 °C was added above aldehyde (1.0 g, 3.5 mmol) and the mixture was stirred for 2 h at 0 °C and further for 1 h at 10 °C. This was followed by addition of lithium chloride (0.22 g, 4.3 mmol), triethyl phosphonoacetate (1.02 mL, 4.3 mmol) and DBU (0.5 mL, 2.9 mmol) in that sequence and the whole mixture was stirred at 5 °C for 45 min. It was then quenched with aq. ammonium chloride solution (15 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine, dried over anhyd. Na₂SO₄ and concentrated under reduced pressure to give crude product (diastereomeric ratio/98 : 2). Silica gel column chromatography (petroleum ether : ethyl acetate: 90 : 10) of the crude product gave dibenzyl 1-((4S,6R,E)-6-((tert-butyldimethylsilyl)oxy)-1-ethoxy-1-oxonon-2-en-4-yl)hydrazine-1,2-dicarboxylate 8 as a colorless syrupy liquid (1.52 g, yield 71%, based on DBAD). [α]²⁵_D: −1.56 (c 0.5, CHCl₃). IR (CHCl₃, cm⁻¹): ν^max 3428, 2950, 1717, 1652, 1399, 1084. ¹H NMR (200 MHz, CDCl₃): δ 0.02 (s, 6H), 0.84 (m, 12H), 1.24–1.31 (m, 5H), 1.40–1.53 (m, 2H), 1.72–1.81 (m, 1H), 1.89–2.02 (m, 1H), 3.58–3.90 (m, 1H), 4.17 (q, J = 7.0 Hz, 2H), 4.84–5.25 (m, 5H), 5.92 (d, J = 17.5 Hz, 1H), 6.51 (m, 1H), 6.85 (dd, J = 6.4, 15.1 Hz, 1H), 7.31 (m, 10H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ −4.9, −4.4, 14.0, 14.2, 17.9, 25.8, 39.4, 60.4, 67.5, 68.1, 121.9, 122.7, 127.9, 128.1, 128.3, 135.6, 146.0, 155.5, 156.3, 166.2 ppm. MS (ESI): m/z 635.5057 (M + Na)⁺, 651.5379 (M + K)⁺. HRMS: 635.3116 (M + Na)⁺ calcd 635.3123.

Diastereomeric ratio was determined by HPLC analysis; 98 : 2 dr.

UV detector: Merck-HITACHI L-7400 series

Column: Grace Denali RP-18, Flow rate: 1.0 mL min⁻¹, MeOH : H₂O = 97 : 3; t_R for (anti)-isomer = 6.90 min and t_R for (syn)-isomer = 6.31 min.

Ethyl (4R,6R)-4-((tert-butoxycarbonyl)amino)-6-((tert-butyldimethylsilyl)oxy)nonanoate (12)

The solution of dibenzyl 1-((4S,6R,E)-6-((tert-butyldimethylsilyl)oxy)-1-ethoxy-1-oxonon-2-en-4-yl)hydrazine-1,2-dicarboxylate 8 (2.0 g, 3.3 mmol) in MeOH (12 mL) and acetic acid (8 drops) was treated with RANEY® nickel (4.0 g, excess) under H₂ (70 psig) atmosphere for 24 h. The reaction mixture was then filtered over celite and concentrated to give crude free amino alcohol which was further treated with triethylamine (0.93 mL, 6.7 mmol) and Boc anhydride (1.2 mL, 5.1 mmol) in dry DCM (4 mL) for 2 h. Ice pieces were added to the reaction mixture and organic layer was separated. The aqueous layer was extracted with diethyl ether (3 × 5 mL). The combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated under reduced pressure to give crude N-Boc derivative. Silica gel column chromatography (petroleum ether : ethyl acetate: 85 : 15) of the crude product gave ethyl (R)-4-((tert-butoxycarbonyl)amino)-8-((tert-butyldimethylsilyl)oxy)octanoate 12 as a viscous liquid (1.11 g, 79%). [α]²⁵_D: −10.37 (c 1.1, CHCl₃). IR (CHCl₃, cm⁻¹): ν^max 3382, 2956, 1722, 1703, 1173. ¹H NMR (200 MHz, CDCl₃): δ 0.06 (s, 3H), 0.07 (s, 3H), 0.90 (m, 12H), 1.25 (t, J = 7.0 Hz, 3H), 1.31–1.35 (m, 2H), 1.43 (s, 9H), 1.47–1.60 (m, 4H), 1.76–1.86 (m, 2H), 2.35 (t, J = 7.5 Hz, 2H), 3.59–3.87 (m, 2H), 4.12 (q, J = 7.0 Hz, 2H), 4.92–4.95 (m, 1H) ppm. ¹³C NMR (50 MHz, CDCl₃): −4.7, −4.3, 14.2, 17.9, 18.2, 25.9, 28.3, 30.9, 39.4, 40.7, 47.8, 60.3, 69.7, 78.7, 155.6, 173.6 MS(ESI): m/z 454.21 (M + Na)⁺. Analysis for C₂₂H₄₅NO₅Si: calcd C, 61.21; H, 10.51; N, 3.24; found: C, 61.29; H, 10.44; N, 3.29%.

tert-Butyl ((4R,6R)-6-((tert-butyldimethylsilyl)oxy)-1-hydroxynonan-4-yl)carbamate (13)

To a stirred suspension of LiBH₄ (0.60 g, 2.2 mmol) in dry THF (1 mL) was added a solution of 12 (0.60 g, 1.4 mmol) in THF (5 mL) at 0 °C and the mixture was stirred at room temperature for 3 h. After being cooled to ambient temperature, the mixture was quenched with ice pieces and extracted with CH₂Cl₂ (3 × 5 mL). The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. Silica gel column chromatography (petroleum ether : ethyl acetate: 65 : 35) of the crude product gave tert-butyl ((4R,6R)-6-((tert-butyldimethylsilyl)oxy)-1-hydroxynonan-4-yl)carbamate 13 as a colorless liquid (0.51 g, 96%). [α]²⁵_D: −8.29 (c 0.9, CHCl₃). IR (CHCl₃, cm⁻¹): ν^max 3525, 3365, 2929, 1691, 1100. ¹H NMR (200 MHz, CDCl₃): δ 0.06 (s, 3H), 0.08 (s, 3H), 0.90 (m, 12H), 1.20–1.38 (m, 4H), 1.43 (s, 9H), 1.54–1.66 (m, 6H), 3.60–3.91 (m, 4H), 5.12 (brs, 1H) ppm. ¹³C NMR (50 MHz, CDCl₃): −4.8, −4.4, 14.2, 17.9, 18.2, 25.9, 28.3, 28.6, 32.1, 39.9, 40.3, 47.6, 62.3, 69.7, 78.8, 155.9 ppm. MS(ESI): m/z 412.20 (M + Na)⁺. HRMS: 390.3032 (M + H)⁺ calcd 390.3034.

tert-Butyl ((4R,6R)-6-((tert-butyldimethylsilyl)oxy)-1-cyanononan-4-yl)carbamate (18)

To an ice-cold stirred solution of 13 (0.50 g, 1.33 mmol) and triethylamine (0.27 mL, 1.99 mmol) in anhydrous CH₂Cl₂ (8 mL) was added dropwise toluenesulfonyl chloride (0.5 mL, 2.66 mmol) over 15 min. The resulting mixture was allowed to warm up to room temperature and stirred for 6 h. After diluting with 10 mL CH₂Cl₂, the solution was washed with (3 × 15 mL) brine, dried over Na₂SO₄ and concentrated to give the crude tosylated product which was subjected to next reaction without purification.

To a solution of tosyl ester in DMF was added NaCN (0.13 g, 2.66 mmol) and was stirred at 115 °C for 10 h. After the consumption of starting material the reaction mixture was poured into H₂O and extracted with ether (25 mL), The organic phase was washed with H₂O and brine (15 mL), dried (NaSO₄) and concentrated in vacuo. Silica gel column chromatography of the crude product using (petroleum ether : ethyl acetate 90 : 10) gave tert-butyl ((4R,6R)-6-((tert-butyldimethylsilyl)oxy)-1-cyanononan-4-yl)carbamate 18 as yellow syrupy liquid. (0.44 g, 85%). [α]²⁵_D: −18.34 (c 1.4, CHCl₃), IR (CHCl₃, cm⁻¹): ν^max 3369, 2957, 2931, 2247, 1704, 1505, 1253, 1056. ¹H NMR (200 MHz, CDCl₃): δ 0.07 (s, 3H), 0.08 (s, 3H), 0.90 (m, 12H), 1.19–1.35 (m, 4H), 1.43 (s, 9H), 1.56–1.74 (m, 6H), 2.41 (t, J = 6.7 Hz, 2H), 3.59–3.89 (m, 2H), 5.04 (brs, 1H) ppm. ¹³C NMR (50 MHz, CDCl₃): −4.9, −4.4, 14.9, 16.8, 17.8, 18.0, 21.8, 25.7, 28.2, 29.5, 34.9, 39.3, 46.9, 69.4, 78.6, 119.5, 155.6 ppm. MS(ESI): m/z 421.20 (M + Na)⁺ HRMS: 421.2856 (M + Na)⁺, calcd 421.2857.

tert-Butyl (R)-2-((R)-2-((tert-butyldimethylsilyl)oxy)pentyl)-3,4-dihydropyridine-1(2H)-carboxylate (19)

To a solution of 18 (0.250 g, 0.65 mmol) in CH₂Cl₂ (10 mL), was added DIBAL-H (0.715 mL 1 M solution in toluene, 0.71 mmol) at −78 °C under argon atmosphere. The reaction was stirred at this temperature for 2 h. Then saturated solution of ammonium chloride (0.8 mL) was added. The resulting mixture was warmed to ambient temperature and was then diluted with 0.2 M aqueous HCl (0.67 mL) followed by EtOAc and organic layer was separated. The aqueous phase was extracted with CH₂Cl₂ (3 × 10 mL), the combined organic layers were dried (Na₂SO₄), filtered and evaporated under reduced pressure to give aldehyde, which was directly used in the next step without further purification.

To the cooled solution of anhydrous THF and a drop of MeOH was added NaBH₃CN (0.098 g, 2.6 mmol) over 20 min followed by addition of aldehyde derived from 18. The reaction mixture was allowed to warm to room temperature and was stirred for 8 h. After being cooled to ambient temperature, the mixture was quenched with ice pieces and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure to give crude product. The crude product was then purified by silica gel flash column chromatography using (pet ether : EtOAc: 19 : 1) to give 19 (0.216 g, 90%) as a yellow oil. Continued chromatography with pet ether : EtOAc/4 : 1 provided 20 (0.026 g, 5%) as a colorless liquid. [α]²⁵_D: +42.97 (c 0.6, CHCl₃) IR (CHCl₃, cm⁻¹): ν^max 2929, 2857, 1702, 1649, 1254 ¹H NMR (500 MHz, CDCl₃): spectra showed 1 : 1 mixture of amide rotamers δ 0.06 (s, 6H), 0.88 (m, 12H), 1.26–1.44 (m, 4H), 1.48 (s, 9H), 1.53–1.63 (m, 2H), 1.69–1.73 (m, 1H), 1.80–1.82 (m, 1H), 1.94–1.98 (m, 1H), 2.06–2.12 (m, 1H), 3.70–3.79 (m, 1H), 4.07–4.15 (m, 0.5H), 4.30–4.33 (m, 0.5H), 4.77–4.88 (m, 1H), 6.65 (d, J = 7.3 Hz, 0.5H), 6.79 (d, J = 7.4 Hz, 0.5H) ppm.¹³C NMR (125 MHz, CDCl₃): −4.5, −4.4, 14.3, 18.0, 23.9, 24.5, 25.9, 28.3, 30.3, 38.3, 38.5, 39.0, 39.3, 47.6, 48.8, 69.9, 80.3, 80.5, 104.5, 104.8, 124.0, 124.4, 151.9, 152.3 ppm. MS(ESI): m/z 406.24 (M + Na)⁺ HRMS: 384.2929 (M + H)⁺ calcd 384.2928.

tert-Butyl ((5R,7R)-7-((tert-butyldimethylsilyl)oxy)-1-hydroxydecan-5-yl)carbamate (20)

[α]²⁵_D: −18.47 (c 1.0, CHCl₃) IR (CHCl₃, cm⁻¹): ν^max 3365, 2930, 1692, 1366, 1100. ¹H NMR (200 MHz, CDCl₃): δ 0.06 (s, 3H), 0.08 (s, 3H), 0.90 (m, 12H), 1.29–1.35 (m, 4H), 1.43 (s, 9H), 1.47–1.57 (m, 4H), 1.58–1.68 (m, 2H), 1.76–1.88 (m, 2H), 3.58–3.73 (m, 3H), 3.78–3.91 (m, 1H), 5.02 (brs, 1H) ppm. ¹³C NMR (50 MHz, CDCl₃): −4.7, −4.3, 14.3, 17.9, 18.3, 21.8, 25.9, 28.4, 29.7, 32.5, 35.5, 39.5, 47.6, 62.7, 69.8, 78.7, 155.8 ppm. MS(ESI): m/z 426.26 (M + Na)⁺

tert-Butyl (R)-2-((R)-2-((tert-butyldimethylsilyl)oxy)pentyl)piperidine-1-carboxylate (21)

To the solution of 19 (0.1 g, 0.27 mmol) in ethyl acetate was added Pd–C (10%) under hydrogenation conditions. The reaction mixture was allowed to stir overnight. On completion of reaction, (until ¹H NMR analysis of the crude mixture indicated complete conversion), the mixture was filtered through a pad of celite and concentrated in vacuo to give 21 as a colorless liquid (0.098 g, 98%). [α]²⁵_D: +23.91 (c 1.05, CHCl₃) IR (CHCl₃, cm⁻¹): ν^max 2931, 2858, 1693, 1416, 1253, 1167. ¹H NMR (200 MHz, CDCl₃): δ 0.05 (s, 3H), 0.07 (s, 3H), 0.89 (m, 12H), 1.26–1.41 (m, 4H), 1.46 (s, 9H), 1.57–1.62 (m, 6H), 1.70–1.83 (m, 2H), 2.69–2.82 (m. 1H), 3.59–3.71 (m, 1H), 3.91–3.97 (m, 1H), 4.11–4.35 (m, 1H) ppm. ¹³C NMR (50 MHz, CDCl₃): spectra showed amide rotamers −4.5, −4.4, 14.0, 14.3, 18.0, 18.3, 19.0, 19.2, 25.6, 25.9, 28.4, 28.5, 29.7, 30.3, 37.8, 39.3, 48.5, 70.8, 79.1, 154.9 ppm. MS(ESI): m/z 408.18 (M + Na)⁺ HRMS: 386.3085 (M + H)⁺ calcd 386.3085.

(−)-Halosaline (1)

To the solution of 21 (0.1 g, 0.27 mmol) in dry CH₂Cl₂ (1 mL) was added TFA (0.075 mL, 0.78 mmol) at 0 °C and reaction mixture was allowed to stir at rt for 2 h. Then solvent was evaporated and neutralized with sat. NaHCO₃ and extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure to give crude product. Silica gel column chromatography of the crude product using (MeOH/CH₂Cl₂/NH₄OH: 8/95/2) gave (−)-halosaline 1 (0.042 g, 92%) as a solid compound. Mp 80–82 °C, [α]: −18.9 (c 0.9, EtOH) [lit.³ [α]²⁵_D: −19.5 (c 0.6, EtOH); IR (CHCl₃, cm⁻¹): ν^max 3445, 3373, 2928, 1399, 1125. ¹H NMR (200 MHz, CDCl₃): δ 0.90 (t, J = 7.1 Hz, 3H), 1.25–1.95 (m, 12H), 2.84 (dt, J = 4.5, 12.1 Hz, 1H), 3.19–3.34 (m, 1H), 3.41 (d, J = 12.7 Hz, 1H), 3.87–4.00 (m, 1H) ppm. ¹³C NMR (50 MHz, CDCl₃): 13.8, 18.7, 22.1, 22.6, 28.6, 39.2, 39.4, 45.0, 55.0, 66.8 ppm. MS(ESI): m/z 194.06 (M + Na)⁺ HRMS: 172.1696 (M + H)⁺ calcd 172.1696.

tert-Butyl (R)-2-((R)-2-((tert-butyldimethylsilyl)oxy)pentyl)-5-oxopyrrolidine-1-carboxylate (17)

To an ice-cold stirred solution of 12 (0.060 g, 0.15 mmol) and triethylamine (0.03 mL, 0.2 mmol) in anhydrous CH₃CN (2 mL) was added dropwise Boc anhydride (0.05 mL, 0.2 mmol) and DMAP (catalytic) at 0 °C. The resulting mixture was allowed to warm up to room temperature and stirred for 6 h. Ice pieces were added to the reaction mixture and organic layer was separated. The aqueous layer was extracted with diethyl ether (3 × 5 mL). The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure to give crude N-Boc derivative. Silica gel column chromatography (petroleum ether : ethyl acetate: 9 : 1) of the crude product gave 17 as a colorless liquid (0.075 g, 92%). [α]²⁵_D: +17.34 (c 1.7, CHCl₃). IR (CHCl₃, cm⁻¹): ν^max 3019, 1777, 1728, 1215. ¹H NMR (400 MHz, CDCl₃): δ 0.06 (s, 6H), 0.89 (m, 12H), 1.31–1.47 (m, 4H), 1.53 (s, 9H), 1.60–1.67 (m, 1H), 1.85–2.11 (m, 3H), 2.38–2.45 (m, 1H), 2.52–2.62 (m, 1H), 3.74–3.80 (m, 1H), 4.04–4.09 (m, 1H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ −4.5, 14.2, 18.1, 23.9, 25.8, 28.0, 31.1, 39.9, 40.7, 57.1, 70.9, 82.7, 149.7, 174.4 ppm. MS (ESI): m/z 408.20 (M + Na)⁺. HRMS: 408.2541 (M + H)⁺ calcd 408.2541.

tert-Butyl (R)-2-((R)-2-hydroxypentyl)pyrrolidine-1-carboxylate (15)

To a cooled (0 °C), stirred solution of Ph₃P (0.35 g, 1.46 mmol) in THF–MeCN (1 : 1, 5 mL) were added imidazole (0.10 g, 1.45 mmol) and I₂ (0.34 g, 1.46 mmol). The mixture was stirred for 2 h and then a solution of alcohol 13 (0.50 g, 1.33 mmol) in THF (10 mL) was added at 0 °C. The mixture was stirred for 2 h, then diluted with 10% aq Na₂S₂O₃ (6 mL) and extracted with EtOAc (2 × 6 mL). The combined organic layer was dried (Na₂SO₄) and concentrated under reduced pressure and then used without purification for the next step.

To the crude iodo compound dissolved in THF (5 mL) was added n-BuLi (0.4 mL, 2.66 mmol) and the mixture was stirred at r.t. for 1 h. Then, the mixture was poured into aq. NH₄Cl and the organic layer was separated. The aqueous layer was extracted with Et₂O (3 × 20 mL) and the combined organic layer was washed with brine (2 × 10 mL), dried (Na₂SO₄) and concentrated. Purification of the crude product by silica gel column chromatography (petroleum ether : ethyl acetate: 9 : 1) afforded 15 as a colorless liquid (0.26 g, 76%). [α]²⁵_D: +21.56 (c 1.7, CHCl₃). IR (CHCl₃, cm⁻¹): ν^max 3419, 2928, 1690, 1415, 1163. ¹H NMR (400 MHz, CDCl₃): δ 0.88 (t, J = 7.1 Hz, 3H), 1.24–1.37 (m, 5H), 1.44 (s, 9H), 1.51–1.60 (m, 2H), 1.83–2.00 (m, 3H), 3.28–3.35 (m, 2H), 3.39–3.49 (m, 1H), 4.11–4.21 (m, 1H), 4.94 (m, 1H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ 14.0, 19.1, 23.5, 28.3, 31.1, 38.9, 43.9, 46.4, 53.6, 67.0, 79.7, 156.6 ppm. MS (ESI): m/z 280.20 (M + Na)⁺. HRMS: 280.1878 (M + Na)⁺ calcd 280.1883.

Acknowledgements

V. J. thanks UGC New Delhi for fellowship. We thank Ms. S. Kunte for HPLC analysis. The authors thank CSIR, New Delhi for financial support as part of XII Five Year Plan under title ORIGIN (CSC0108).

Notes and references

1. (a) T. H. Jones and M. S. Blum, in Alkaloids: Chemical and Biological Perspectives, ed. S. W. Pelletier, Wiley, New York, NY, 1983, vol. 1, ch. 2, pp. 33–84; (b) G. B. Fodor and B. Colasanti, in Alkaloids: Chemical and Biological Perspectives, ed. S. W. Pelletier, Wiley: New York, NY, 1985, vol. 3, ch. 1, pp. 1–90; (c) M. J. Schneider, in Alkaloids: Chemical and Biological Perspectives, ed. S.W. Pelletier, Wiley, New York, NY, 1996, vol. 10, ch. 3, pp. 155–315; (d) G. M. Strunz and J. A. Findlay, in The Alkaloids, ed. A. Brossi, Academic, London, UK, 1985, vol. 26, ch. 3, pp. 89–183; (e) A. Numata and I. Ibuka, in The Alkaloids, ed. A. Brossi, Academic, New York, NY, 1987, vol. 31, pp. 193–315,; (f) R. S. Angle and J. G. Breitenbucher, in Studies in Natural Products Chemistry. Stereoselective Synthesis (Part J), ed. Atta-ur-Rahman, Elsevier, Amsterdam, The Netherlands, 1995, vol. 16, pp. 453–502.
2. D. O'Hagen, Nat. Prod. Rep., 1997, 14, 637.
3. (a) K. H. Michel, F. Sandberg, F. Haglid and T. Norin, Acta Pharm. Suec., 1967, 4, 97; (b) K. H. Michel, F. Sandberg, F. Haglid, T. Norin, R. P. K. Chan and J. Cymerman Craig, Acta Chem. Scand., 1969, 23, 3479.
4. (a) V. U. Ahmad and M. A. Nasir, Heterocycles, 1986, 24, 2841; (b) V. U. Ahmad and M. A. Nasir, Phytochemistry, 1987, 26, 585; (c) S. Mill and C. Hootele, J. Nat. Prod., 2000, 63, 762.
5. (a) P. Merlin, J. C. Braekman, D. Daloze and J. M. Pasteels, J. Chem. Ecol., 1988, 14, 517; (b) J. C. Braekman, D. Daloze, J. M. Pasteels, P. Vanhecke, J. P. Declercq, V. Sinnwell and W. Z. Franke, Naturforsch., 1987, 42, 627.
6. N. K. Hart, S. R. Johns and J. A. Lamberton, Aust. J. Chem., 1972, 25, 817.
7. (a) J. S. Yadav, Y. J. Reddy, P. A. Reddy and B. V. Subba Reddy, Org. Lett., 2013, 15, 546; (b) P. Radha Krishna, B. K. Reddy and P. Srinivas, Tetrahedron, 2012, 68, 841; (c) A. Bisai and V. K. Singh, Tetrahedron Lett., 2007, 48, 1907; (d) W. A. Maio, S. Sinishtaj and G. H. Posner, Org. Lett., 2007, 9, 2673; (e) G. Lesma, S. Crippa, B. Danieli, D. Passarella, A. Sacchetti, A. Silvani and A. Virdis, Tetrahedron, 2004, 60, 6437; (f) T. Kochi, T. P. Tang and J. A. Ellmann, J. Am. Chem. Soc., 2003, 125, 11276; (g) H. Takahata, M. Kubota and N. Ikota, J. Org. Chem., 1999, 64, 8594; (h) R. Stragies and S. Blechert, Tetrahedron, 1999, 55, 8179; (i) H. Takahata, M. Kubota and T. Momose, Tetrahedron Lett., 1997, 38, 3451.
8. (a) P. I. Dalko, Enantioselective Organocatalysis: Reactions and Experimental Procedures, Wiley-VCH, Weinheim, 2007; (b) A. Dondoni and A. Massi, Angew. Chem., Int. Ed., 2008, 47, 4638.
9. D. W. C. MacMillan, Nature, 2008, 455, 304.
10. (a) B. List, R. A. Lerner and C. F. Barbas III, J. Am. Chem. Soc., 2000, 122, 2395; (b) K. Sakthivel, W. Notz, T. Bui and C. F. Barbas III, J. Am. Chem. Soc., 2001, 123, 5260; (c) For a review of proline-catalyzed asymmetric reactions, see: B. List, Tetrahedron, 2002, 58, 5573; (d) P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2004, 43, 5138; (e) B. List, Chem. Commun., 2006, 819; (f) For α-functionalization reviews, see: J. Franzen, M. Marigo, D. Fielenbach, T. C. Wabnitz, A. Kjærsgaard and K. A. Jørgensen, J. Am. Chem. Soc., 2005, 127, 18296; (g) G. Guillena and D. J. Ramon, Tetrahedron: Asymmetry, 2006, 17, 1465; (h) For a comprehensive review on α-aminoxylation, see: P. Merino and T. Tejero, Angew. Chem., Int. Ed., 2004, 43, 2995 , and references cited therein.
11. (a) T. Bui and C. F. Barbas III, Tetrahedron Lett., 2000, 41, 6951 ; For reviews on organocatalytic tandem reactions, see: ; (b) W. Notz, F. Tanaka and C. F. Barbas III, Acc. Chem. Res., 2004, 37, 580; (c) D. Enders, C. Grondal and M. R. M. Hüttl, Angew. Chem., Int. Ed., 2007, 46, 1570; (d) X. Yu and W. Wang, Org. Biomol. Chem., 2008, 6, 2037; (e) A. M. Walji and D. W. C. MacMillan, Synlett, 2007, 1477; (f) M. Lu, D. Zhu, Y. Lu, Y. Hou, B. Tan and G. Zhong, Angew. Chem., Int. Ed., 2008, 47, 10187.
12. V. Jha, N. B. Kondekar and P. Kumar, Org. Lett., 2010, 12, 2762.
13. (a) G. Zhong, Angew. Chem., Int. Ed., 2003, 42, 4247; (b) P. J. Chua, B. Tan and G. Zhong, Green Chem., 2009, 11, 543; (c) B. List, J. Am. Chem. Soc., 2002, 124, 5656; (d) S. P. Kotkar, V. B. Chavan and A. Sudalai, Org. Lett., 2007, 9, 1001.
14. (a) N. Dwivedi and P. Kumar, Acc. Chem. Res., 2013, 46, 289; (b) S. V. Kauloorkar, V. Jha and P. Kumar, RSC Adv., 2013, 3, 18288; (c) P. Kumar, V. Jha and R. G. Gonnade, J. Org. Chem., 2013 DOI:10.1021/jo401722e.
15. (a) S. K. Pandey, M. Pandey and P. Kumar, Tetrahedron Lett., 2008, 49, 3297; (b) S. K. Pandey and P. Kumar, Tetrahedron Lett., 2005, 46, 4091; (c) P. Kumar and M. S. Bodas, J. Org. Chem., 1999, 70, 360.
16. L. Thijs, P. P. Waanders, E. H. M. Stokkingreef and B. Zwanenburg, Recl. Trav. Chim. Pays-Bas, 1986, 105, 332.
17. The enantiomeric excess was determined using chiral GC analysis whereas diastereomeric ratio was determined using HPLC analysis (see ESI†). In order to determine the chiral purity of (R)-ethyl 4-hydroxyoctanoate 9, it was converted into lactone 22 on treatement with p-TSA in methanol.
    Chiral GC using Cyclodextrin TA column (70 kPa pressure, 140 °C isotherm for 35 min, major enantiomer 19.9 min, minor enantiomer 20.6 min). The racemic standard was prepared in the same way with racemic γ-hydroxy ester, ee 94%.
18. M. Nomura, S. Shuto, M. Tanaka, T. Sasaki, S. Mori, S. Shigeta and A. Matsuda, J. Med. Chem., 1999, 42, 2901.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra44700f

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