Total synthesis of a piperidine alkaloid, microcosamine A

Abstract

The first asymmetric total synthesis of a new natural piperidine alkaloid, microcosamine A, has been accomplished from D-serine and D-methyl lactate as chiral pool starting materials. Key features of the strategy include the utility of Horner–Wadsworth–Emmons reaction, Luche reduction, intramolecular carbamate N-alkylation to form the piperidine framework and Julia–Kocienski olefination to install the triene side-chain.

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Introduction

2-Methyl-3-hydroxy-6-alkylated piperidines constitute an important class of natural alkaloids due to their interesting biological and pharmacological properties (anaesthetic, analgesic, antitumor, antibiotic, CNS stimulating biological properties, antihypertensive and antifungal activities etc.).^1–6 These molecules possess different stereochemical patterns and C6 side chains with either saturated or unsaturated alkyl groups. To date three types of 2-methyl-3-hydroxy natural piperidines having different unsaturated side chains at C6 carbon, such as corydendramines A & B (1a, 1b),⁴ microgrewiapine A (1c)⁵ and microcosamines A & B (2a, 2b)⁶ have been isolated (Fig. 1). However, there is no synthesis reported for any of these molecules. The interesting structural feature of these molecules is the presence of a chiral hydroxy group at the C3-position of the piperidine ring with trans stereochemistry with respect to the C2 and C6 carbons, which is a rare substructure in piperidine alkaloids. Structurally, these compounds possess a polar head group with hydroxyl and amine functionalities and a hydrophobic aliphatic tail, which can be considered as cyclic analogues of the lipid sphingosine membrane.⁷ The above observations combined with our interest in the synthesis of alkaloids⁸ have driven us for the synthesis of microcosamine A (2a).

Fig. 1 Structures of corydendramines A & B, microgrewiapine A and microcosamines A & B.

Microcosamine A (2a), was first isolated by Lin and co-workers in 2008, from the chloroform extraction of the leaves of Microcos paniculata along with microcosamine B (2b) and found their insecticidal activity against the larvae of Culex quinquefasciatus with LC₅₀ values of 5.2 and 17.0 μg mL⁻¹, respectively.⁶Microcos paniculata, a large shrub or a small tree that grows in South and Southeast Asian countries, is found to be a rich source of bio-active compounds and several parts such as roots, stem bark, leaves and fruits are being used traditionally to treat diarrhea and fever, as herbal tea to treat cold, enteritis, and skin rashes and as insecticides.⁹ There is a good number of 2,3,6-trisubstituted piperidine alkaloids which have been isolated from this species.¹⁰ Later, in 2013, 2a was again isolated from the same plant along with some other piperidine alkaloids by Kinghorn et al. and examined for their effects on neuronal nicotinic acetylcholine receptors (nAChRs).⁵ Microcosamine A (2a) exhibited approximately 53.7% and 59% of hα3β4 and hα3β2 nAChR activity, respectively. Herein, we present the first total synthesis of microcosamine A (2a).

Results and discussion

Scheme 1 outlines the retrosynthetic strategy of 2a. We planned the installation of the triene-side chain at the C6 position of hydroxy piperidine ring 4 by using 3via oxidation followed by Julia–Kocienski olefination.¹¹ Synthesis of the sulfone fragment 3 was achieved from 1-octyne (8) by using a known conjugated alcohol 5.¹² The construction of piperidine 4 was designed through the intramolecular carbamate N-alkylation of its precursor which could be obtained from N,O-protected D-serine ester 6 and β-keto phosphonate 7 using Horner–Wadsworth–Emmons (HWE) olefination¹³ as the key reaction. Ester 6 and phosphonate 7 in turn could be prepared from the chiral starting materials, D-serine (9) and D-methyl lactate (10), respectively. The C2 and C6 stereochemistry is expected to arise from 9 and C3-hydroxyl stereochemistry envisaged from 10 using diastereoselective Luche reduction¹⁴ of keto functionality.

Scheme 1 Retrosynthetic analysis of 2a.

The ester intermediate 6 was prepared in three steps from D-serine (9) following the reported procedure.¹⁵ The desired β-keto phosphonate 7 was also smoothly obtained in two steps from D-methyl lactate (10) using a literature protocol.¹⁶ The synthesis of the piperidine fragment is outlined in Scheme 2. Initially, the ester 6 was subjected to DIBAL-H reduction to aldehyde followed by HWE olefination with β-keto phosphonate 7 under Ba(OH)₂·8H₂O in THF/H₂O conditions to afford the enone 11 in 87% yield, a precursor for diastereoselective Luche reduction. Exposure of 11 to NaBH₄ in MeOH in the presence of CeCl₃·H₂O at −78 °C provided the allylic alcohol 12 along with its minor diastereomer in 85% yield [dr >9 : 1, based on the diastereomers 17 & 17a, separated in the cyclization step]. At this stage, we were unable to separate these diastereomers either by column or by HPLC (in ¹H NMR spectra, the signals were not separated to verify the diastereomeric ratio) and hence, were moved for further transformations as a mixture. Thus, the hydroxyl group of 12 was protected as methoxy methyl (MOM) ether 13 using MOMCl/diisopropylethyl amine in CH₂Cl₂ (89%). To obtain a free secondary hydroxyl group, a two-step protecting group manipulation was chosen. Deprotection of both the tert-butyldimethyl silyl groups of 13 under HF (40% in water) in CH₃CN followed by selective protection of the resulting primary hydroxyl group as a TBS ether produced the required alcohol 14 in 81% yield over two steps. After the oxidation of alcohol 14 to the corresponding ketone 14-I, the attempt to form the piperidine ring 14-II through hydrogenation was unsuccessful.¹⁷

Scheme 2 Synthesis of 4 from 6 and 7.

Thus, an alternative sequence was followed. The hydrogenation reaction of 14 using 10% Pd/C in EtOH involves the olefin reduction as well as Cbz-deprotection to free amine, which was subsequently treated with di-tert-butyl-dicarbonate (Boc₂O)/Et₃N to obtain Boc-protected amino alcohol 15 in 88% yield. Treatment of 15 with methanesulfonyl chloride in the presence of triethyl amine in CH₂Cl₂ gave the mesylate 16 in 85% yield. Compound 16 was successfully converted into 2,3,6-trisubstituted piperidine via intramolecular carbamate N-alkylation (SN reaction) using potassium tert-butoxide in THF (88%).¹⁸ At this point, the diastereomers formed during the Luche reduction of 11 were separated by column chromatography (dr 92 : 8). The major isomer 17 was found to be the desired one and the minor isomer 17a was undesired, which were characterized by 2D COSY and NOESY experiments.¹⁹ The nOe cross correlations between H8(Me)/H7(H7′), H2/H9 and H3/H8(Me) for 17 (Fig. 2) support the desired diastereomer. In the case of 17a the nOe cross correlations observed between H8(Me)/H7(H7′), H7/H9, H8/H9, and H2/H3 support the undesired diastereomer (Fig. 2). Next, the TBS group of 17 was deprotected using HF (40% in water) in CH₃CN to give the piperidinol 4 in 80% yield.

Fig. 2 The characteristic nOe cross correlations of compounds 17 and 17a.

The sulfone 3 required for Julia olefination was synthesised from dienol 5, obtained from 1-octyne (8).¹² The Mitsunobu reaction²⁰ of the alcohol 5 with 1-phenyl-1H-tetrazole-5-thiol to thio-tetrazole 18 (95% yield) followed by ammonium molybdate catalyzed oxidation²¹ using hydrogen peroxide in EtOH provided the sulfone 3 in 82% yield (Scheme 3).

Scheme 3 Synthesis of sulfone 3.

The stage was set for the conversion of 4 to microcosamine A (2a) by connecting the side chain (Scheme 4). Accordingly, the alcohol 4 was oxidized with IBX (2-iodoxybenzoic acid) to the corresponding aldehyde followed by Julia–Kocienski olefination with the trienyl sulfone 3 by treating with KHDMS in the presence of 18-crown-6 in DME provided the trienyl-piperidine 19 exclusively as the Z-isomer in 72% yield over two steps.²² Removal of MOM and Boc groups was accomplished in one step by the treatment of 19 with 3 N HCl in MeOH to give the desired microcosamine A (2a) in 78% yield.

Scheme 4 Synthesis of 2a from 4.

The spectral data (¹H, ¹³C NMR and mass) of our synthetic microcosamine A (2a) were in full agreement with those reported for the natural product (see Table S1 in the ESI†). The specific rotation of synthetic 2a {[α]²⁰_D: +5.6 (c 1.00, CH₃OH)} was also comparable to the natural product {[α]²⁰_D: +4.0 (c 1.00, CH₃OH)}. These results confirm the structure and absolute configuration of the natural product 2a.

Conclusions

In summary, the first asymmetric total synthesis of a natural piperidine alkaloid, microcosamine A, was accomplished using commercially available D-serine, D-methyl lactate (for piperidine unit) and 1-octyne (for triene-side chain) as starting materials. The key features of the strategy are the successful utilization of HWE-olefination and intramolecular carbamate N-cyclization for piperidine ring construction and Julia–Kocienski olefination for the installation of the side chain in the natural product synthesis. The approach is handy for the synthesis of other natural products and their analogues having different side chains.

Experimental

General

Melting points were determined on a POLMON melting point apparatus and are uncorrected. NMR spectra were recorded in CDCl₃ on 300 MHz, 400 MHz or 500 MHz spectrometers at ambient temperature. Chemical shifts δ were denoted with reference to TMS or solvent residual (CDCl₃: δ 7.26 ppm for ¹H and 77.0 ppm for ¹³C) peaks given in ppm (parts per million) and coupling constants J are measured in Hz (hertz). FTIR spectra were recorded on a Perkin-Elmer 683 infrared spectrophotometer in KBr or as neat. Optical rotations were measured on an Anton Paar MLP 200 modular circular digital polarimeter by using a 2 mL cell with a path length of 1 dm with MeOH or CHCl₃ as the solvent. Low-resolution MS were collected on an Agilent Technologies LC-MSD trap SL spectrometer in positive ion mode. Technical-grade EtOAc and hexanes used for column chromatography were distilled before use. All the reagents and solvents were of reagent grade and used without further purification unless otherwise stated. THF, when used as a solvent for reactions, was freshly distilled from a sodium benzophenone ketyl radical. Progress of the reactions was monitored by thin-layer chromatography using silica plates (UV₂₅₄, glass backed; Merck KGaA) and the spots were visualized under UV-light and/or after charring with ninhydrin or potassium permanganate or β-naphthol stain solutions. Column chromatography was performed over silica gel (60–120 mesh) or on alumina (aluminium oxide activated, neutral, 150 mesh) packed in glass columns, eluted with gradients of petroleum ether and ethyl acetate. Column fractions were concentrated under reduced pressure at temperatures not more than 40 °C. All the reactions were performed under N₂ in oven dried glassware with magnetic stirring.

Benzyl (6S,10R,E)-2,2,3,3,10,12,12,13,13-nonamethyl-9-oxo-4,11-dioxa-3,12-disilatetradec-7-en-6-ylcarbamate (11). Methyl N-((benzyloxy)carbonyl)-O-(tert-butyldimethylsilyl)-D-serinate¹⁵6 (2.2 g, 5.99 mmol) was taken in a round bottomed flask and added anhydrous toluene (20 mL). The mixture was cooled to −78 °C before adding DIBAL-H (25% w/v in toluene, 5.1 mL, 7.18 mmol) dropwise under N₂ and stirred at the same temperature for 10 min. The mixture was quenched with aqueous saturated sodium potassium tartrate (20 mL), diluted with DCM (20 mL), and stirred for 3 h at rt for the separation of two layers. The organic layers were separated and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The aldehyde was used for the next step without further purification.

To a stirred solution of (R)-dimethyl (3-((tert-butyldimethylsilyl)oxy)-2-oxobutyl)phosphonate¹⁶7 (2.2 g, 7.19 mmol) in THF (30 mL), was added Ba(OH)₂·8H₂O (2.8 g, 8.99 mmol) at rt and stirred vigorously for 45 min. The reaction mixture was cooled to 0 °C before adding the above crude aldehyde in 15 mL of THF/H₂O (20 : 1) and the mixture was allowed to warm to rt. After completion of the reaction (4 h), the reaction mixture was diluted with EtOAc (30 mL), the organic layer was washed with water (30 mL), and brine (30 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography (neutral alumina, hexanes/EtOAc 9 : 1) to afford enone 11 (2.7 g, 87%) as a colorless oil. R_f = 0.4 (petroleum ether : EtOAc = 9 : 1); [α]²⁰_D = +9.5 (c 1.50, CHCl₃); IR (neat): ν_max 3446, 2954, 2931, 2858, 1705, 1631, 1255, 1116, 837 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.41–7.28 (m, 5H, Ph), 6.93 (dd, J = 15.8, 4.7 Hz, 1H, CH=CH), 6.73 (d, J = 15.8 Hz, 1H, CH=CH), 5.22–5.06 (m, 3H, CH₂–Ph, –NH), 4.52–4.43 (br m, 1H, CH–N), 4.25 (q, J = 13.6, 6.8 Hz, 1H, CH–CH₃), 3.76 (d, J = 3.7 Hz, 2H, CH₂–O), 1.29 (d, J = 6.8 Hz, 3H, CH–CH₃), 0.90 (s, 9H, ^tBu-Si), 0.85 (s, 9H, ^tBu-Si), 0.06 (s, 3H, Si(CH₃)₂), 0.05 (s, 3H, Si(CH₃)₂), 0.03 (s, 3H, Si(CH₃)₂), 0.02 (s, 3H, Si(CH₃)₂); ¹³C NMR (100 MHz, CDCl₃): δ 201.0, 155.7, 145.2, 136.3, 128.5, 128.1, 128.0, 124.2, 74.3, 66.9, 64.6, 53.7, 25.7, 25.7, 20.8, 18.2, 18.0, −4.8, −4.9, −5.5, −5.5; MS (ESI): m/z 544 (M + Na)⁺; HRMS (ESI): m/z calcd for C₂₇H₄₇NO₅Si₂Na (M + Na)⁺, 544.2885; found 544.2890.

Benzyl (6S,9R,10R,E)-9-hydroxy-2,2,3,3,10,12,12,13,13-nonamethyl-4,11-dioxa-3,12-disilatetradec-7-en-6-ylcarbamate (12). To a stirred solution of 11 (2.5 g, 4.79 mmol) in MeOH (30 mL) was added CeCl₃·7H₂O (3.5 g, 9.59 mmol) and was allowed to stir for 45 min at room temperature. It was cooled to −78 °C and NaBH₄ (265 mg, 7.18 mmol) was added portion wise for over 10 min and stirred for an additional 1 h at the same temperature. After completion of the reaction (10 min), it was quenched by addition of ice pieces/ice cold water (2 mL) at −78 °C and slowly allowed to warm to room temperature. After stirring at room temperature for further 30 min, it was poured into water (20 mL) and extracted with diethyl ether (3 × 25 mL). Combined organic layers were washed with brine (20 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by column chromatography (neutral alumina, hexanes/EtOAc 8 : 2) to furnish 12 (2.1 g, 85%) as a colorless oil. R_f = 0.2 (petroleum ether : EtOAc = 9 : 1); [α]²⁰_D = −6.6 (c 1.10, CHCl₃); IR (neat): ν_max 3446, 2953, 2930, 1714, 1253, 773 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.41–7.28 (m, 5H, Ph), 5.79 (dd, J = 15.6, 5.7 Hz, 1H, CH=CH), 5.65 (dd, J = 15.6, 5.9 Hz, 1H, CH=CH), 5.15–5.04 (m, 1H, –NH), 5.11 (s, 2H, CH₂–Ph), 4.32–4.20 (br m, 1H, CH–N), 3.84–3.76 (m, 1H, CH–OH), 3.72 (dd, J = 10.1, 4.1 Hz, 1H, CH₂–OTBS), 3.67–3.58 (m, 2H, CH₂–OTBS, CH–OTBS), 1.10 (d, J = 5.8 Hz, 3H, CH₃), 0.91 (s, 9H, ^tBu-Si), 0.89 (s, 9H, ^tBu-Si), 0.09 (s, 3H, Si(CH₃)₂), 0.08 (s, 3H, Si(CH₃)₂), 0.05 (s, 6H, Si(CH₃)₂); ¹³C NMR (125 MHz, CDCl₃): δ 155.7, 136.5, 131.2, 130.9, 130.4, 128.4, 128.0, 76.5, 71.9, 66.6, 65.2, 53.7, 25.7, 25.8, 19.8, 18.2, 17.9, −4.2, −4.8, −5.4; MS (ESI): m/z 524 (M + H)⁺; HRMS (ESI): m/z calcd for C₂₇H₅₀NO₅Si₂ (M + H)⁺, 524.3222; found 524.3228.

Benzyl (6S,9R,10R,E)-9-(methoxymethoxy)-2,2,3,3,10,12,12,13,13-nonamethyl-4,11-dioxa-3,12-disilatetradec-7-en-6-ylcarbamate (13). To compound 12 (2 g, 3.82 mmol) in dry dichloromethane (40 mL) was added iPr₂EtN (1.98 mL, 11.47 mmol) and methoxymethyl chloride (MOMCl) (0.92 mL, 11.47 mmol) at 0 °C. The solution was stirred at rt for 12 h and quenched by the addition of saturated aqueous NaHCO₃ solution (30 mL). The aqueous layer was separated and extracted with DCM (2 × 25 mL). The combined organic layers were dried over Na₂SO₄ and volatiles were removed under reduced pressure. The crude product was purified by column chromatography (neutral alumina, hexanes/EtOAc 9 : 1) to obtain compound 13 as a colourless liquid (1.9 g, 89%). R_f = 0.4 (petroleum ether : EtOAc = 9 : 1); [α]²⁰_D = −15.4 (c 1.00, CHCl₃); IR (neat): ν_max 3446, 2954, 2857, 1725, 1254, 1106, 836 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.43–7.27 (m, 5H, Ph), 5.71 (dd, J = 15.8, 5.6 Hz, 1H, CH=CH), 5.57 (dd, J = 15.7, 6.9 Hz, 1H, CH=CH), 5.16–5.03 (m, 3H, CH₂–Ph, –NH), 4.64 (A of AB q, J = 6.5 Hz, 1H, OCH₂O), 4.57 (B of AB q, J = 6.6 Hz, 1H, OCH₂O), 4.35–4.21 (m, 1H, CH–N), 3.89 (t, J = 6.4 Hz, 1H, CHOMOM), 3.85–3.76 (m, 1H, CH–OTBS), 3.70 (dd, J = 10.0, 4.3 Hz, 1H, CH₂–OTBS), 3.64 (dd, J = 9.6, 3.5 Hz, 1H, CH₂–OTBS), 3.34 (s, 3H, OCH₃), 1.06 (d, J = 6.1 Hz, 3H, CH₃), 0.89 (s, 9H, ^tBu-Si), 0.87 (s, 9H, ^tBu-Si), 0.06 (s, 6H, Si(CH₃)₂), 0.03 (s, 3H, Si(CH₃)₂), 0.03 (s, 3H, Si(CH₃)₂). ¹³C NMR (100 MHz, CDCl₃): δ 155.7, 136.5, 131.8, 128.5, 128.4, 128.0, 94.4, 80.3, 70.4, 66.6, 65.2, 55.3, 53.7, 25.8, 25.8, 19.4, 18.2, 18.1, −4.6, −4.7, −5.5, −5.5; MS (ESI): m/z 590 (M + Na)⁺; HRMS (ESI): m/z calcd for C₂₉H₅₃NO₆Si₂Na (M+ Na)⁺, 590.3303; found 590.3304.

Benzyl (5R,8S,E)-5-((R)-1-hydroxyethyl)-11,11,12,12-tetramethyl-2,4,10-trioxa-11-silatridec-6-en-8-ylcarbamate (14). To a stirred solution of 13 (1.9 g, 3.35 mmol) in CH₃CN (20 mL) at 0 °C was added HF (40% in water, 0.29 mL, 6.70 mmol) dropwise and allowed to warm to rt over 30 min. After completion of the reaction, saturated aqueous NaHCO₃ (20 mL) was added dropwise and the aqueous layer was extracted with EtOAc (2 × 25 mL). The combined organic extracts were washed with brine (20 mL), dried over Na₂SO₄ and evaporated under reduced pressure. To the residue in DCM (30 mL) was added imidazole (296 mg, 4.35 mmol) and t-BuMe₂SiCl (502 mg, 3.35 mmol) at 0 °C and warmed to rt. The reaction mixture was diluted with water (20 mL) at the point where all the starting materials were consumed and extracted with DCM (2 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na₂SO₄ and evaporated. Flash chromatography of the residue over neutral alumina (hexanes/EtOAc 7 : 3) gave 14 (1.23 g, 81%) as a colorless oil. R_f = 0.3 (petroleum ether : EtOAc = 7 : 3); [α]²⁰_D = −46.2 (c 1.70, CHCl₃); IR (neat): ν_max 3445, 3332, 2953, 2931, 1716, 1255, 1102, 838 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.39–7.30 (m, 5H, Ph), 5.75 (dd, J = 15.7, 5.5 Hz, 1H, CH=CH), 5.49 (dd, J = 15.6, 8.0 Hz, 1H, CH=CH), 5.11 (s, 2H, CH₂–Ph), 4.70 (d, J = 6.1 Hz, 1H, OCH₂O), 4.55 (d, J = 6.4 Hz, 1H, OCH₂O), 4.28 (m, 1H, CH–N), 3.79 (t, J = 7.6 Hz, 1H, CHOMOM), 3.74–3.62 (m, 3H, CH₂–OTBS, CH–OH), 3.38 (s, 3H, OCH₃), 2.03 (br s, 1H, OH), 1.12 (d, J = 6.0 Hz, 3H, CH₃), 0.88 (s, 9H, ^tBu-Si), 0.04 (s, 3H, Si(CH₃)₂), 0.04 (s, 3H, Si(CH₃)₂). ¹³C NMR (100 MHz, CDCl₃) δ 155.7, 136.4, 134.0, 128.5, 128.1, 93.9, 81.7, 69.5, 66.7, 65.0, 55.6, 53.7, 25.8, 18.4, 18.2, −5.5, −5.5; MS (ESI): m/z 476 (M + Na)⁺; HRMS (ESI): m/z calcd for C₂₃H₃₉NO₆SiNa (M + Na)⁺, 476.2438; found 476.2445.

Benzyl ((5R,8S,E)-5-acetyl-11,11,12,12-tetramethyl-2,4,10-trioxa-11-silatridec-6-en-8-yl)carbamate (14-I). 2-Iodoxybenzoic acid (IBX) (185 mg, 0.66 mmol) was taken in a round bottomed flask, added DMSO (0.5 mL) and stirred at rt under a nitrogen atmosphere for 10 min to obtain a clear solution. To the clear solution, at the same temperature, was added compound 14 (200 mg, 0.44 mmol) in EtOAc (2 mL) dropwise. The reaction mixture was heated to 70 °C and stirred for 30 min. After completion of the reaction, the mixture was diluted with EtOAc (10 mL). The precipitate was filtered and washed with EtOAc (10 mL). The filtrate was washed with aqueous saturated NaHCO₃ solution (15 mL), and brine (15 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (neutral alumina, hexanes/EtOAc 8 : 2) to yield ketone 14-I as the product (175 mg, 88%). R_f = 0.7 (petroleum ether : EtOAc = 7 : 3); [α]²⁰_D = −28.8 (c 1.57, CHCl₃); IR (neat): ν_max 3441, 2940, 1716, 766 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.38–7.29 (m, 5H, Ph), 5.91 (dd, J = 15.6, 5.5 Hz, 1H,CH=CH), 5.61 (dd, J = 15.6, 6.6 Hz, 1H, CH=CH), 5.15–5.07 (m, 1H, –NH), 5.09 (s, 2H, CH₂–Ph), 4.68 (d, J = 6.4 Hz, 1H, OCH₂O), 4.61 (d, J = 6.6 Hz, 1H, OCH₂O), 4.52 (d, J = 6.6 Hz, 1H, CHOMOM), 4.34–4.26 (br m, 1H, CH–N), 3.70 (dd, J = 10.0, 4.3 Hz, 1H, CH₂–OTBS), 3.65 (d, J = 7.2 Hz, 1H, CH₂–OTBS), 3.35 (s, 3H, OCH₃), 2.15 (s, 3H, COCH₃), 0.86 (s, 9H, ^tBu-Si), 0.03 (s, 3H, Si(CH₃)₂), 0.02 (s, 3H, Si(CH₃)₂); ¹³C NMR (125 MHz, CDCl₃) δ 206.1, 155.7, 136.3, 133.9, 128.4, 128.1, 125.7, 94.7, 82.0, 66.8, 64.9, 55.8, 53.6, 25.7, 18.2, −5.5; MS (ESI): m/z 452 (M + H)⁺; HRMS (ESI): m/z calcd for C₂₃H₃₇NO₆SiNa (M+ Na)⁺, 474.2282; found 474.2286.

tert-Butyl (5R,8S)-5-((R)-1-hydroxyethyl)-11,11,12,12-tetramethyl-2,4,10-trioxa-11-silatridecan-8-ylcarbamate (15). 10% Pd on C (5 mol%) was added to a degassed solution of compound 14 (1.0 g, 2.20 mmol) in EtOH (0.5 M) and the heterogeneous mixture was stirred for 12 h under a hydrogen atmosphere at rt. The reaction mixture was filtered over celite, and the volatiles removed under reduced pressure. To the residue and triethyl amine (0.62 ml, 4.41 mmol) in THF (20 ml), di-tert-butyl-dicarbonate (Boc₂O) (0.5 mL, 2.20 mmol) was added at 0 °C. The reaction mixture was warmed to rt and stirred for 4 h. The reaction mixture was diluted with water after the completion of the reaction and extracted with EtOAc (2 × 20 mL). The combined organic layer was washed with brine (20 mL), dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography of the residue over neutral alumina (hexanes/EtOAc 7 : 3) gave 15 (817 mg, 88%) as a colorless oil. R_f = 0.5 (petroleum ether : EtOAc = 7 : 3); [α]²⁰_D = −19.5 (c 1.00, CHCl₃); IR (neat): ν_max 3451, 2955, 2932, 1709, 1103, 838 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 4.71–4.66 (m, 2H, OCH₂O), 3.71–3.63 (m, 1H, CH–OH), 3.59–3.52 (m, 2H, CH₂–OTBS), 3.40 (s, 3H, OCH₃), 3.29–3.22 (m, 1H, CH–N), 3.05–3.14 (m, 1H, CHOMOM), 1.70–1.57 (m, 2H, CH₂–CH₂), 1.50–1.38 (m, 11H, ^tBu in Boc, CH₂–CH₂), 1.13 (d, J = 6.4 Hz, 3H, CH₃), 0.87 (s, 9H, ^tBu-Si), 0.03 (s, 6H, Si(CH₃)₂). ¹³C NMR (100 MHz, CDCl₃) δ 155.5, 97.4, 85.4, 79.0, 69.1, 64.6, 55.7, 52.0, 28.3, 27.7, 27.1, 25.8, 18.8, 18.2, −5.4; MS (ESI): m/z 444 (M + Na)⁺; HRMS (ESI): m/z calcd for C₂₀H₄₄NO₆Si (M + H)⁺, 422.2751; found 422.2761.

(2R,3R,6S)-6-(tert-Butoxycarbonylamino)-7-(tert-butyldi-methylsilyloxy)-3-(methoxymethoxy)heptan-2-yl methanesulfonate (16). To a stirred solution of compound 13 (1.0 g, 2.37 mmol), and triethyl amine (0.66 mL, 4.75 mmol) in dichloromethane (20 mL) at 0 °C, was added methane sulfonyl chloride (0.27 mL, 3.56 mmol) dropwise. The mixture was allowed to warm to rt and stirred for a further 1 hour. After completion of the reaction, it was diluted with water (20 mL) and the aqueous layer was extracted with DCM (2 × 15 mL). The combined organic layer was washed with brine (20 mL), and dried over Na₂SO₄. Volatiles were removed under reduced pressure and the residue was purified by flash column chromatography (neutral alumina, hexanes/EtOAc 7 : 3) to yield pale yellow oil 16 as the product (1 g, 85%). R_f = 0.6 (petroleum ether : EtOAc = 7 : 3); [α]²⁰_D = −6.9 (c 1.20, CHCl₃); IR (neat): ν_max 3392, 2933, 1712, 1361, 1176, 837 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 4.87–4.59 (m, 3H, OCH₂O, CHOMs), 3.69–3.49 (m, 4H, CH₂–OTBS, CH–N, CHOMOM), 3.39 (s, 3H, OCH₃), 3.02 (s, 3H, CH₃ in Ms), 1.80–1.60 (m, 2H, CH₂–CH₂), 1.56–1.47 (m, 2H, CH₂–CH₂), 1.47–1.38 (m, 12H, tBu in Boc, CH₃), 0.88 (s, 9H, tBu-Si), 0.04 (s, 6H, Si(CH₃)₂). ¹³C NMR (100 MHz, CDCl₃) δ 155.6, 96.9, 79.6, 79.2, 79.1, 64.8, 55.9, 51.9, 38.4, 28.3, 26.9, 26.6, 25.8, 18.2, 16.8, −5.4; MS (ESI): m/z 522 (M + Na)⁺; HRMS (ESI): m/z calcd for C₂₁H₄₅NO₈SSiNa (M + Na)⁺, 522.2527; found 522.2560.

(2S,3R,6S)-tert-Butyl 6-((tert-butyldimethylsilyloxy)methyl)-3-(methoxymethoxy)-2-methylpiperidine-1-carboxylate (17). The mesylated compound 16 (650 mg, 1.30 mmol) was dissolved in dry THF (20 mL) under a nitrogen atmosphere and added potassium tert-butoxide (1.16 g, 10.4 mmol) dropwise as a solution in dry THF (10 mL). The reaction was stirred at rt for 2 h then quenched with water (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (1 × 20 mL), dried over Na₂SO₄, filtered and concentrated. The residue was purified by flash column chromatography (neutral alumina, 2% EtOAc in hexanes) to give 17 (425 mg, 81%) and 17a (37 mg, 7%) as a separable mixture (92 : 8) of diastereomers. R_f = 0.4 (petroleum ether : EtOAc = 9 : 1); 17: [α]²⁰_D = −8.7 (c 0.90, CHCl₃); IR (neat): ν_max 2954, 2932, 1691, 1367, 1099, 838 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 4.70–4.61 (m, 2H, OCH₂O), 4.25 (q, J = 6.8 Hz, 1H, 2-CH–N), 4.17–4.06 (m, 1H, 6-CH–N), 3.61–3.50 (m, 2H, CH₂–OTBS, CHOMOM), 3.46 (dd, J = 9.3, 4.7 Hz, 1H, CH₂–OTBS), 3.36 (s, 3H, OCH₃), 1.97–1.56 (m, 4H, CH₂–CH₂), 1.45 (s, 9H, ^tBu in Boc), 1.07 (d, J = 7.1 Hz, 3H, CH₃), 0.89 (s, 9H, tBu-Si), 0.06 (s, 3H, Si(CH₃)₂), 0.05 (s, 3H, Si(CH₃)₂). ¹³C NMR (100 MHz, CDCl₃) δ 155.4, 94.7, 79.3, 73.5, 63.1, 55.3, 51.2, 50.0, 28.4, 25.8, 19.6, 19.3, 18.2, 17.3, −5.2, −5.4; MS (ESI): m/z 426 (M + Na)⁺; HRMS (ESI): m/z calcd for C₂₀H₄₂NO₅Si (M + H)⁺, 404.2827; found 404.2858.

17a: [α]²⁰_D = −26.2 (c 1.01, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 4.62 (q, J = 7.0 Hz, 2H, OCH₂O), 4.11 (qd, J = 7.0, 3.1 Hz, 1H, 2-CH–N), 3.87 (t, J = 9.5 Hz, 1H, CH₂–OTBS), 3.75 (dd, J = 9.6, 4.2 Hz, 1H, CH₂–OTBS), 3.69–3.55 (m, 2H, 6-CH–N, CHOMOM), 3.34 (s, 3H, OCH₃), 2.00–1.83 (m, 2H, CH₂–CH₂), 1.81–1.69 (m, 2H, CH₂–CH₂), 1.44 (s, 9H, tBu in Boc), 1.22 (d, J = 7.1 Hz, 3H, CH₃), 0.88 (s, 9H, ^tBu-Si), 0.04 (s, 6H, Si(CH₃)₂). ¹³C NMR (75 MHz, CDCl₃) δ 155.7, 94.5, 79.2, 73.9, 62.9, 55.3, 53.3, 51.3, 28.4, 25.9, 22.9, 20.2, 18.2, 17.9, −5.2, −5.3.

(2S,3R,6S)-tert-Butyl 6-(hydroxymethyl)-3-(methoxy-methoxy)-2-methylpiperidine-1-carboxylate (4). HF (40% in water, 0.04 mL, 0.99 mmol) was added to a stirred solution of 17 (400 mg, 0.99 mmol) in CH₃CN (10 mL) at 0 °C. The reaction mixture was allowed to warm to rt slowly over 30 min and added saturated aqueous NaHCO₃ (10 mL) dropwise. The reaction mixture was extracted with EtOAc (2 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography of the residue over neutral alumina (hexanes/EtOAc 1 : 1) gave 4 (229 mg, 80%) as a colorless oil. R_f = 0.2 (petroleum ether : EtOAc = 6 : 4); [α]²⁰_D = −5.4 (c 1.10, CHCl₃); IR (neat): ν_max 3444, 2973, 2936, 1667, 1686, 1369, 1042 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 4.67 (s, 2H, OCH₂O), 4.29 (q, J = 6.9 Hz, 2H, CH–N), 3.68–3.52 (m, 3H, CH₂–OH, CHOMOM), 3.37 (s, 3H, OCH₃), 2.06–1.94 (m, 1H, CH₂–CH₂), 1.84–1.49 (m, 3H, CH₂–CH₂), 1.46 (s, 9H, tBu in Boc), 1.15 (d, J = 7.2 Hz, 3H, CH₃). ¹³C NMR (75 MHz, CDCl₃) δ 156.9, 94.9, 80.0, 73.5, 65.6, 55.4, 51.1, 50.5, 28.4, 19.7, 19.5, 18.4; MS (ESI): m/z 312 (M + Na)⁺; HRMS (ESI): m/z calcd for C₁₄H₂₇NO₅Na (M + Na)⁺, 312.1781; found 312.1808.

5-((2E,4E)-Nona-2,4-dien-1-ylthio)-1-phenyl-1H-tetrazole (18). To a solution of (2E,4E)-nona-2,4-dien-1-ol¹²5 (500 mg, 3.57 mmol) in THF (30 mL) was added PPh₃ (1.12 g, 4.28 mmol) and 1-phenyl-1H-tetrazole-5-thiol (762 mg, 4.28 mmol). The reaction mixture was cooled to 0 °C, and DIAD (0.9 mL, 4.64 mmol) was slowly added and stirred at room temperature for 1 h. After completion of the reaction, solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (silica gel, hexanes/EtOAc 9 : 1) to give 18 (1.01 g, 94%) as a colorless oil. R_f = 0.4 (petroleum ether : EtOAc = 9 : 1); ¹H NMR (300 MHz, CDCl₃) δ 7.68–7.43 (m, 5H, Ar), 6.31 (dd, J = 15.0, 10.4 Hz, 1H, 3-CH), 5.97 (dd, J = 15.2, 10.4 Hz, 1H, 4-CH), 5.81–5.55 (m, 2H, 2-CH, 5-CH), 4.06 (d, J = 7.6 Hz, 2H, 1-CH₂), 2.05 (q, J = 6.7 Hz, 2H, 6-CH₂), 1.43–1.20 (m, 4H, CH₂–CH₂), 0.87 (t, J = 7.0 Hz, 3H, –CH₃); ¹³C NMR (75 MHz, CDCl₃) δ 153.8, 137.0, 135.8, 133.6, 130.0, 129.6, 128.7, 123.7, 122.8, 35.7, 32.2, 31.1, 22.1, 13.8; MS (ESI): m/z 323 (M + Na)⁺; HRMS (ESI): m/z calcd for C₁₆H₂₁N₄S (M + H)⁺, 301.1481; found 301.1482.

5-((2E,4E)-Nona-2,4-dien-1-ylsulfonyl)-1-phenyl-1H-tetrazole (3). To the solid (NH₄)₆Mo₇O₂₄·4H₂O (1.03 g, 0.834 mmol) in a round bottomed flask at 0 °C was added aq. H₂O₂ (30% w/w, 4 mL) and stirred for 15 min at 0 °C before it was added to a solution of 18 (0.5 g, 1.66 mmol) in EtOH (17 mL) at 0 °C. The mixture was allowed to warm up to room temperature and stirred overnight. After completion of the reaction, it was diluted with water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with saturated aqueous Na₂S₂O₃ (20 mL), and brine (20 mL), dried over Na₂SO₄ and concentrated under reduced pressure. Flash column chromatography of the residue (silica gel, hexanes/EtOAc 9 : 1) gave 3 (453 mg, 82%) as a colorless oil. R_f = 0.4 (petroleum ether : EtOAc = 9 : 1); IR (neat): ν_max 2958, 2930, 2871, 1723, 1498, 1349, 1153, 763 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.69–7.50 (m, 5H, Ar), 6.35 (dd, J = 15.2, 10.5 Hz, 1H, 3-CH), 6.01 (dd, J = 15.2, 10.5 Hz, 1H, 4-CH), 5.86–5.78 (m, 1H, 2-CH), 5.48 (dt, J = 15.3, 7.6 Hz, 1H, 5-CH), 4.41 (d, J = 7.6 Hz, 2H, 1-CH₂), 2.09 (q, J = 7.0 Hz, 2H, 6-CH₂), 1.40–1.24 (m, 4H, CH₂–CH₂), 0.89 (t, J = 7.2 Hz, 3H, –CH₃); ¹³C NMR (125 MHz, CDCl₃) δ 153.0, 142.4, 139.9, 132.9, 131.3, 129.5, 128.3, 125.2, 111.8, 60.0, 32.2, 30.9, 22.1, 13.8; MS (ESI): m/z 355 (M + Na)⁺; HRMS (ESI): m/z calcd for C₁₆H₂₁N₄O₂S (M + H)⁺, 333.1380; found 333.1404.

(2S,3R,6S)-tert-Butyl 6-((1E,3E,5E)-deca-1,3,5-trienyl)-3-(methoxymethoxy)-2-methylpiperidine-1-carboxylate (19). A round bottomed flask charged with 2-iodoxybenzoic acid (IBX) (116 mg, 0.41 mmol), and DMSO (0.2 mL) was stirred under a nitrogen atmosphere for 10 min at rt to obtain a clear solution. To this solution was then added compound 4 (60 mg, 0.20 mmol) in EtOAc (1 mL) dropwise at room temperature. The reaction mixture was heated to 70 °C and stirred for 30 min. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with EtOAc (5 mL). The precipitate was filtered and washed with EtOAc (5 mL). The filtrate was washed with aqueous saturated NaHCO₃ solution (10 mL), and brine (10 mL), dried over Na₂SO₄ and concentrated under reduced pressure to obtain aldehyde which was used for the next step without further purification.

To a solution of sulfone 3 (82 mg, 0.24 mmol) and 18-crown-6 (64 mg, 0.24 mmol) in dry DME (5 mL) was added dropwise KHMDS (1 M in THF, 0.2 mL, 0.2 mmol) at −78 °C under a nitrogen atmosphere. After being stirred for 30 min, a solution of the above prepared aldehyde in dry DME (3 mL) was added slowly to the reaction mixture and stirred for 2 h at −78 °C before warming to rt and stirred overnight. The reaction mixture was poured into aqueous saturated NH₄Cl solution (5 mL) and extracted with ethyl acetate (2 × 5 mL). The combined organic layer was washed with brine (5 mL), dried over Na₂SO₄, and the solvent was removed under reduced pressure. Flash chromatography of the crude over neutral alumina (5% EtOAc in hexanes) gave 19 (58 mg, 72%) as a colorless oil. R_f = 0.3 (petroleum ether : EtOAc = 9 : 1); [α]²⁰_D = −18.6 (c = 1.30, CHCl₃); IR (neat): ν_max 2930, 1688, 1365, 1038 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 6.20–5.98 (m, 4H, =CH–CH=CH–CH=), 5.76–5.62 (m, 2H, –CH₂–CH=, =CH–CHN), 4.77 (br t, J = 5.1 Hz, 1H, 6-CH–N), 4.66 (q, J = 7.0 Hz, 2H, OCH₂O), 4.31 (q, J = 7.0 Hz, 1H, 2-CH–N), 3.64–3.55 (m, 1H, CHOMOM), 3.36 (s, 3H, OCH₃), 2.19–2.00 (m, 2H, =CH–CH₂), 1.90–1.54 (m, 3H, CH₂–CH₂), 1.45 (s, 9H, ^tBu in Boc), 1.50–1.22 (m, 5H, CH₂–CH₂), 1.11 (d, J = 7.2 Hz, 3H, CH–CH₃), 0.88 (t, J = 7.0 Hz, 3H, CH₂–CH₃). ¹³C NMR (75 MHz, CDCl₃) δ 155.4, 135.4, 134.7, 132.5, 130.3, 130.1, 130.1, 94.7, 79.4, 73.3, 55.3, 50.5, 50.4, 32.4, 31.4, 28.4, 22.1, 21.6, 19.8, 19.3, 13.8; MS (ESI): m/z 416 (M + Na)⁺; HRMS (ESI): m/z calcd for C₂₃H₄₀NO₄ (M + H)⁺, 394.2952; found 394.2976.

Microcosamine A (2a). To compound 19 (100 mg, 2.18 mmol) was added 3 N HCl in methanol (2 mL) and stirred for 12 h at rt. After completion of the reaction, methanol was evaporated to dryness under reduced pressure and 6 N HCl (5 mL) was added. The aqueous layer was washed with diethyl ether (2 × 10 mL), basified with 2 N NaOH solution and extracted with diethyl ether (3 × 15 mL), dried over Na₂SO₄ and concentrated under reduced pressure to furnish the desired compound 2a (49 mg, 78%) as a pale yellow solid. Mp: 107–109 °C; R_f = 0.2 (EtOAc : MeOH = 95 : 5); [α]²⁰_D = +5.6 (c 1.00, CH₃OH); IR (neat): ν_max 3445, 2924, 2854, 1660, 1127, 473 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 6.22–6.11 (m, 2H, =CH–CH=CH–CH=), 6.11–5.98 (m, 2H, =CH–CH=CH–CH=), 5.73–5.66 (m, 1H, –CH₂–CH=), 5.60 (dd, J = 15.2, 7.1 Hz, 1H, =CH–CHN), 3.23–3.14 (m, 2H, 6-CH–N, CHOH), 2.57–2.50 (m, 1H, 2-CH–N), 2.25 (br s, 1H, OH), 2.11–2.04 (m, 3H, =CH–CH₂, CH₂–CH₂), 1.77–1.71 (m, 1H, CH₂–CH₂), 1.40–1.28 (m, 6H, CH₂–CH₂), 1.20 (d, J = 6.1 Hz, 3H, CH–CH₃), 0.89 (t, J = 7.1 Hz, 3H, CH₂–CH₃); ¹³C NMR (125 MHz, CDCl₃) δ 135.6, 135.0, 132.9, 130.4, 130.1, 129.8, 73.6, 58.6, 58.3, 33.9, 32.4, 31.9, 31.4, 22.2, 18.9, 13.9; MS (ESI): m/z 250 (M + H)⁺; HRMS (ESI): m/z calcd for C₁₆H₂₈NO (M + H)⁺, 250.2165; found 250.2180.

Acknowledgements

The authors thank the Council of Scientific and Industrial Research (CSIR)-New Delhi for the award of research fellowship to BL and KW, and for financial support as part of XII-five year plan project under title ORIGIN (CSC-0108).

Notes and references

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17. Oxidation of compound 14 under IBX conditions smoothly gave ketone 14-I in 88% yield. Further, hydrogenation of compound 14-I in the presence of H₂/Pd–C (10 wt%) in EtOH gave the complex mixture of diastereomeric products 14-II along with the starting material.
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19. The 2D COSY and NOESY spectra of compounds 17 and 17a are included in the ESI.†.
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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ob02085a

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