Total Synthesis of (–)-Invictolide

Abstract

A convergent approach to the total synthesis of (–)-invictolide, a component of the queen recognition pheromone of Solenopsis­ invicta, is described. Key steps involve the desymmetrization of a bicyclic olefin with Brown’s chiral hydroboration, C–C bond formation, 1,3-syn reduction, and oxidative lactonization of a 1,3,5-triol with TEMPO/PhI(OAc)₂.

Invictolide (1) is a component of the queen recognition pheromone of the red fire ant, Solenopsis invicta. Invictolide, exhibits pheromone activity in both the laevorotatory and racemic forms in surrogate queen field tests.[ ¹ ] (–)-Invictolide [(–)-1] is isolated from the red fire ant queen, Solenopsis invicta Buren (Figure [1]).[ ^2a ] Its relative stereochemistry was proposed by Rocca et al.[ ^2b ] and its absolute stereochemistry was established by Mori’s group[ ³ ] to have the (3R,5R,6S,1′R)-configuration. The significant stereochemistry and the fascinating biosynthetic pathways involving δ-lactone compounds have driven many groups to attempt the synthesis of invictolide and several synthetic approaches have been reported.[ ⁴ ] In fact, ongoing research studies at our group on the synthesis of polyketide natural products exploring a desymmetrization strategy[ ⁶ ] has given impetus to attempt the synthesis of invictolide in a hitherto unreported approach. The present work depicts a radically different, novel strategy for total synthesis of (–)-invictolide [(–)-1] and efforts are mainly centered on the construction of a Prelog–Djerassi-type lactone unit as a key intermediate.[ ⁵ ]

Accordingly, the envisaged retrosynthetic strategy for (–)-invictolide [(–)-1] is shown in Scheme [1]. (–)-Invictolide [(–)-1] can be prepared by short sequential manipulations of triol 19 embedded with all the required stereocenters, which in turn can be generated from bicyclic lactone 8 via triol 9. Bicyclic lactone 8 could be obtained from bicyclic olefin 4 [ ^6f ] as shown in Scheme [2].

The synthesis commenced with precursor 4, the compound synthesized in our group and utilized for the synthesis of several natural products. The desymmetrization approach is explored to create five stereogenic centers at once.[ ⁶ ] The bicyclic olefin 4 was subjected to the key desymmetrization reaction using the enantioselective hydroboration reaction of Brown et al.[ ⁷ ] [(–)-Ipc₂BH, THF, 0 °C, NaOH, H₂O₂] to afford the required alcohol 5 with 97% ee in 95% yield. Alcohol 5 was converted into the bicyclic lactone 7 in 97% yield by pyridinium chlorochromate oxidation followed by Baeyer–Villiger oxidation (MCPBA, NaHCO₃, CH₂Cl₂). The thus-formed bicyclic lactone 7 was then subjected to enolization using lithium diisopropylamide in tetrahydrofuran at –78 °C followed by treatment with iodomethane to furnish the methylated lactone 8 as a single diastereomer in 99% yield. Reductive cleavage of bicyclic lactone 8 with lithium aluminum hydride in tetrahydrofuran at room temperature furnished triol 9 in 97% yield, which is the key intermediate in the desymmetrization strategy with five stereogenic centers as shown in Scheme [3].[ ⁶ ]

The 1,3-diol functionality of triol 9 is protected by using 2,2-dimethoxypropane and a catalytic amount of 10-camphorsulfonic acid to give acetonide compound 10 followed by protection of the free hydroxy group as benzyl ether 11 using sodium hydride, benzyl bromide, and a catalytic amount of tetrabutylammonium iodide in 93% yield. Deprotection of the acetonide group using catalytic 10-camphorsulfonic acid in methanol afforded diol 12 in 96% yield. Selective protection of the primary hydroxy group with tosyl chloride, triethylamine, and catalytic dibutyltin oxide gave tosylate 13 in 92% yield. Protection of the secondary hydroxy group as its tert-butyldimethylsilyl ether with tert-butyldimethylsilyl triflate and 2,6-lutidine in dichloromethane afforded 14 in 94% yield.[ ⁸ ] The C–C bond formation occurred by treating 14 with ethylmagnesium bromide in tetrahydrofuran with copper(I) bromide–dimethyl sulfide complex to provide 15 in 83% yield.[ ⁹ ] Deprotection of the silyl ether with 4-toluenesulfonic acid in methanol provided 16 in 92% yield.

Inversion of the configuration of the secondary hydroxy group in the intermediate 16 was achieved by an oxidation–reduction strategy. Thus, oxidation of 16 with Dess–Martin periodinane in dichloromethane yielded ketone 17 in 96% yield, followed by reduction of 17 with diisobutylaluminum hydride in dichloromethane at –78 °C to afford exclusively alcohol 18 in 94% yield, as a result of 1,3-syn reduction.[ ¹⁰ ] Deprotection of the benzyl ethers of compound 18 was achieved using lithium/naphthalene in anhydrous tetrahydrofuran at –20 °C to yield the triol 19 in 93% yield.[ ¹¹ ] The resulting triol is subjected to oxidative lactonization in the presence of (diacetoxyiodo)benzene/ 2,2,6,6-tetramethylpiperdin-1-oxyl to obtain Prelog–Djerassi-type lactone 20 in 83% yield.[ ¹² ] Epimerization of lactone 20 at C3 was carried out by mesylation, elimination with DBU, followed by catalytic reduction with 10% palladium on carbon to provide (–)-invictolide [(–)-1] and its 3-epimer in the ratio of 3:1. Pure (–)-invictolide [(–)-1] was separated from its 3-epimer by crystallization from n-hexane at –78 °C. The spectroscopic data (¹H and ¹³C NMR) and specific rotation of the synthetic (–)-invictolide [(–)-1] is in good agreement with those of the reported data.[ ³ ]

In conclusion total synthesis of (–)-invictolide is presented with an overall yield of 23%. The stereogenic centers are all obtained through a desymmetrization strategy and 1,3-syn reduction.

All reactions were conducted under N₂ in anhydrous solvents such as CH₂Cl₂, THF, EtOAc, and Et₂O. Preparative chromatographic separations were performed on silica gel (35–75 μm); reactions were monitored by TLC analysis using silica plates with fluorescent indicator (254 nm) and visualized with a UV lamp, anisaldehyde or β-naphthol soln or alkaline KMnO₄ soln. All commercially available reagents were purchased and were typically used as supplied.

Optical rotations were measured at r.t. (25 °C) on CHCl₃ solns with a polarimeter using a 2-mL capacity cell with a 100-mm path length. Infrared spectra were recorded using a thin film between NaCl plates or as a solid embedded in a KBr disc. ¹H (300 MHz) and ¹³C NMR (75 MHz) spectra were recorded in Fourier transform mode on a Bruker UXNMR FT-300 MHz (Avance). Spectra were obtained on CDCl₃ solns in 5-mm diameter tubes, and signals are reported relative to the residual signals of CHCl₃ (δ_H = 7.25 or δ_C = 77.0).

7-(Benzyloxy)-6,8-dimethyl-2,9-dioxabicyclo[3.3.1]nonan-3-one (7)

To a stirred soln of NaHCO₃ (13.56 g, 161 mmol) and ketone 6 (14 g, 53.8 mmol) in CH₂Cl₂ (150 mL) was added anhyd MCPBA (18.57 g, 107 mmol) at 0 °C. The mixture was stirred for 10 h at r.t. After completion of the reaction, the mixture was diluted with CH₂Cl₂ (100 mL) and quenched with sat. NaHCO₃ soln (50 mL) at 0 °C. The organic layer was separated and washed with sodium metabisulfite soln (50 mL) followed by brine (50 mL). The organic layer was dried (anhyd Na₂SO₄) and the solvent was removed in vacuo. The residue was purified by column chromatography to afford pure 7 as a pale-yellow liquid; yield: 14 g (97%); R_f = 0.5 (30% EtOAc–hexane); [α]_D ²⁵ –46.5 (c 2.0, CHCl₃).

IR (neat): 2963, 2882, 1742, 1225, 1064, 970 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.95 (d, J = 7.5 Hz, 3 H), 1.15 (d, J = 7.5 Hz, 3 H), 2.01–2.11 (m, 1 H), 2.20–2.30 (m, 1 H), 2.71–2.73 (m, 2 H), 3.58–3.60 (m, 1 H), 4.06–4.12 (m, 1 H), 4.48–4.52 (m, 1 H), 4.65–4.69 (m, 1 H), 5.43–5.44 (d, J = 2.3 Hz, 1 H), 7.23–7.36 (m, 5 H).

¹³C NMR (75 MHz, CDCl₃): δ = 13.1, 13.7, 31.0, 37.5, 39.6, 70.1, 76.7, 79.3, 99.8, 127.4, 128.2, 137.6, 166.2.

LC-MS: m/z = 299 [M + Na]⁺.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₆H₂₀O₄Na: 219.1250; found: 299.1253.

(4S)-7-(Benzyloxy)-4,6,8-trimethyl-2,9-dioxabicyclo[3.3.1]nonan-3-one (8)

LDA [prepared by the addition of 1.6 M BuLi in hexane (52 mL, 82 mmol) to a cooled soln of i-Pr₂NH (10.5 g, 15 mmol) at –10 °C in THF (100 mL)] was added to a soln of lactone 7 (14.3 g, 52 mmol) in THF (50 mL) at –78 °C. The lithium enolate thus generated was alkylated with MeI (6.5 mL, 103.5 mmol) after 1 h. Stirring was continued for a further 2 h and the reaction was quenched with sat. NH₄Cl (100 mL). The mixture was extracted with EtOAc (3 × 100 mL), the solvent was evaporated, and the residue was purified by column chromatography to afford pure 8 as a pale-yellow liquid; yield: 15 g (99%); R_f = 0.4 (30% EtOAc–hexane); [α]_D ²⁵ –54.7 (c 3.0, CHCl₃).

IR (neat): 2970, 2937, 2881, 1742, 1457, 1392, 1210, 1073, 977, 739 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.96 (d, J = 8.0 Hz, 3 H), 1.16 (d, J = 8.0 Hz, 3 H), 1.42 (d, J = 5.0 Hz, 3 H), 2.06–2.08 (m, 1 H), 2.24–2.26 (m, 1 H), 2.76–2.81 (m, 1 H), 3.57–3.60 (m, 1 H), 3.69–3.71 (m, 1 H), 4.49–4.70 (m, 2 H), 5.43 (s, 1 H), 7.27–7.34 (m, 5 H).

¹³C NMR (75 MHz, CDCl₃): δ = 13.1, 13.5, 20.4, 35.8, 37.6, 39.7, 76.6, 77.4, 79.2, 100.0, 127.4, 128.1, 137.7, 170.5.

LC-MS: m/z = 313 [M + Na]⁺.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₇H₂₂O₄Na: 313.1407; found: 313.1410.

(2R,3R,4S,5R,6R)-5-(Benzyloxy)-2,4,6-trimethylheptane-1,3,7-triol (9)

To an ice-cooled suspension of LiAlH₄ (5.7 g, 150 mmol) in THF (100 mL) was added a soln of lactone 8 (14.5 g, 50 mmol) in THF (50 mL) under a N₂ atmosphere. The mixture was stirred for 5 h at r.t. After completion of the reaction, the mixture was quenched with H₂O (6 mL) and 5 M NaOH (6 mL) and H₂O (18 mL), and the thus-formed precipitate was filtered through a Celite pad using EtOAc. The filtrate was dried (anhyd Na₂SO₄), the solvent was evaporated, and the residue was purified by column chromatography to afford pure 9 as a pale-yellow liquid; yield: 14.5 g (97%); R_f = 0.1 (50% EtOAc–hexane); [α]_D ²⁵ +0.26 (c 1.0, CHCl₃).

IR (neat): 3403, 3032, 2967, 1458, 1061 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.69 (d, J = 7.1 Hz, 3 H), 0.94 (d, J = 7.1 Hz, 3 H), 1.10 (d, J = 7.1 Hz, 3 H), 1.81–1.86 (m, 2 H), 2.25 (m, 1 H), 3.48–3.50 (dd, J = 2.0 Hz, 6.1 Hz, 1 H), 3.55–3.62 (m, 2 H), 3.63–3.66 (dd, J = 5.0, 6.1 Hz, 1 H), 3.70–3.72 (m, 1 H), 3.82 (d, J = 10.0 Hz, 1 H), 4.61–4.66 (q, J = 11.0, 5.1 Hz, 2 H), 7.25–7.32 (m, 5 H).

¹³C NMR (75 MHz, CDCl₃): δ = 11.5, 13.2, 14.6, 35.5, 37.2, 37.8, 65.1, 69.0, 76.4, 88.4, 127.8, 128.1, 128.6, 137.4.

LC-MS: m/z = 319 [M + Na]⁺.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₇H₂₈O₄Na: 319.1885; found: 319.1901.

(2R,3R,4R)-3-(Benzyloxy)-2-methyl-4-[(4R,5R)-2,2,5-trimethyl-1,3-dioxan-4-yl]pentan-1-ol (10)

To a stirred soln of triol 9 (11 g, 37 mmol) in anhyd CH₂Cl₂ (100 mL) was added 2,2-dimethoxypropane (9.12 mL, 74.3 mmol) and CSA (1.5 g); the mixture was stirred at r.t. for 5 h. The mixture was quenched with solid NaHCO₃ (2 g) and it was filtered through a small Celite pad. Solvent was evaporated in vacuo and the residue was purified by column chromatography to afford pure 10 as a colorless solid; yield: 11.2 g (89%); R_f = 0.3 (30% EtOAc–hexane); [α]_D ²⁵ –40.0 (c 1.0, CHCl₃).

IR (neat): 3480, 2964, 2929, 2879, 1458, 1382, 1198, 1060, 1033 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.72 (d, J = 6.8 Hz, 3 H), 0.87 (d, J = 6.8 Hz, 3 H), 1.22 (d, J = 6.8 Hz, 3 H), 1.36 (s, 3 H), 1.37 (s, 3 H), 1.83–2.06 (m, 3 H), 2.92 (br s, OH), 3.46–3.54 (m, 3 H), 3.66–3.72 (m, 1 H), 3.88–3.92 (m, 2 H), 4.6–4.71 (q, J = 10.5, 11.3 Hz, 2 H), 7.27–7.37 (m, 5 H).

¹³C NMR (75 MHz, CDCl₃): δ = 9.8, 12.4, 16.3, 19.4, 29.8, 30.2, 36.0, 37.4, 64.2, 66.1, 73.3, 75.4, 85.5, 97.9, 126.9, 127.5, 128.4, 138.3.

LC-MS: m/z = 359 [M + Na]⁺.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₀H₃₂O₄Na: 359.2198; found: 359.2210.

(4R,5R)-4-[(2R,3R,4R)-3,5-Bis(benzyloxy)-4-methylpentan-2-yl]-2,2,5-trimethyl-1,3-dioxane (11)

To an ice-cooled suspension of NaH (2 g, 83.3 mmol, 60% in mineral oil) in anhyd THF (100 mL) was added a soln of alcohol 10 (11.1 g, 33 mmol) in THF (50 mL) under a N₂ atmosphere. After stirring for 10 min, BnBr (5.89 mL, 49.5 mmol) in THF (10 mL) was added slowly; TBAI (cat.) was then added at the same temperature. The resulting mixture was heated to reflux for 3 h. After completion of the reaction, it was cooled to 0 °C and the excess hydride was quenched with sat. NH₄Cl soln (25 mL). The mixture was extracted with EtOAc (3 × 60 mL), and the combined extracts were washed with brine (50 mL), dried (anhyd Na₂SO₄), and evaporated. The residue was purified by column chromatography to afford pure 11 as a pale-yellow liquid; yield: 13.1 g (93%); R_f = 0.8 (30% EtOAc­–hexane); [α]_D ²⁵ –35.6 (c 1.0, CHCl₃).

IR (neat): 3060, 3031, 2965, 1602, 1457, 1382, 1198, 1101, 735 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.64 (d, J = 6.7 Hz, 3 H), 0.86 (d, J = 6.7 Hz, 3 H), 1.12 (d, J = 7.5 Hz, 3 H), 1.35 (s, 3 H), 1.37 (s, 3 H), 1.78–1.96 (m, 2 H), 2.14–2.21 (m, 1 H), 3.34–3.51 (m, 3 H), 3.62–3.70 (m, 2 H), 3.84–3.88 (m, 1 H), 4.43–4.51 (m, 2 H), 4.56–4.65 (q, J = 11.3, 5.2 Hz, 2 H), 7.22–7.31 (m, 10 H).

¹³C NMR (75 MHz, CDCl₃): δ = 11.6, 13.3, 14.9, 26.5, 34.7, 36.7, 37.2, 69.1, 72.1, 73.1, 76.0, 76.8, 87.2, 127.3, 127.5, 127.6, 127.9, 128.3, 128.5, 137.7, 138.3.

LC-MS: m/z = 449 [M + Na]⁺.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₇H₃₈O₄Na: 449.2667; found: 449.2667.

(2R,3R,4S,5R,6R)-5,7-Bis(benzyloxy)-2,4,6-trimethylheptane-1,3-diol (12)

Compound 11 (13 g, 30.5 mmol) was dissolved in MeOH (100 mL), CSA (cat.) was added and the mixture was stirred at r.t. for 3 h. After completion of the reaction, it was quenched with solid NaHCO₃ (2 g). The solvent was evaporated, and the residue was purified by column chromatography to afford pure 12 as a pale-yellow liquid; yield: 11.3 g (96%); R_f = 0.2 (30% EtOAc–hexane); [α]_D ²⁵ +22.0 (c 0.5, CHCl₃).

IR (neat): 3441, 3060, 3032, 2968, 1457, 1091, 738, 699 cm^–1 _.

¹H NMR (300 MHz, CDCl₃): δ = 0.75 (d, J = 6.9 Hz, 3 H), 1.04 (d, J = 6.9 Hz, 3 H), 1.16 (d, J = 6.9 Hz, 3 H), 1.86–1.93 (m, 2 H), 2.13–2.20 (m, 1 H), 3.52–3.74 (m, 4 H), 3.88 (d, J = 9.6 Hz, 1 H), 4.14 (s, 1 H), 4.54–4.66 (m, 4 H), 7.26–7.37 (m, 10 H).

¹³C NMR (75 MHz, CDCl₃): δ = 11.7, 13.3, 14.9, 34.7, 36.8, 37.3, 69.1, 72.2, 73.2, 76.1, 76.8, 87.3, 127.6, 127.6, 127.7, 127.9, 128.3, 128.5, 137.8, 138.4.

LC-MS: m/z = 409 [M + Na]⁺.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₄H₃₄O₄Na : 409.2354; found: 409.2366.

(2R,3R,4S,5R,6R)-5,7-Bis(benzyloxy)-3-hydroxy-2,4,6-trimethylheptyl 4-Methylbenzenesulfonate (13)

To a stirred soln of 12 (11 g, 28.5 mmol) in anhyd CH₂Cl₂ (100 mL) was added Et₃N (8.72 mL, 62 mmol) and Bu₂SnO (cat.), the mixture was stirred for 15 min, and then cooled to 0 °C; TsCl (8.86 g, 47 mmol) was added and the mixture was stirred overnight. After completion of the reaction, H₂O (50 mL) was added and the mixture was extracted with CH₂Cl₂ (3 × 80 mL). The combined extracts were dried (Na₂SO₄), the solvent was evaporated in vacuo, and the residue was purified by column chromatography to afford pure 13 as a pale-yellow liquid; yield: 14.3 g (92%); R_f = 0.5 (20% EtOAc–hexane); [α]_D ²⁵ +18.43 (c 1.0, CHCl₃).

IR (neat): 3482, 3032, 2970, 1599, 1457, 1358, 1176, 1081, 963 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.84 (d, J = 6.9 Hz, 3 H), 0.96 (d, J = 6.9 Hz, 3 H), 1.00 (d, J = 7.9 Hz, 3 H), 1.83–1.85 (m, 2 H), 2.01–2.05 (m, 1 H), 2.37 (s, 3 H), 3.45–3.48 (dd, J = 3.0, 5.9 Hz, 1 H), 3.50–3.53 (dd, J = 2.0, 8.8 Hz, 1 H), 3.56–3.59 (m, 2 H), 3.97–4.01 (m, 1 H), 4.07–4.10 (dd, J = 2.9, 5.9 Hz, 1 H), 4.45–4.55 (m, 4 H), 7.17 (d, J = 7.9 Hz, 2 H), 7.24–7.31 (m, 10 H), 7.74 (d, J = 7.9 Hz, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 11.5, 13.4, 15.3, 21.9, 34.2, 36.5, 37.0, 70.8, 72.4, 73.5, 73.6, 76.4, 87.3, 127.9, 128.0, 128.1, 128.2, 128.3, 128.7, 128.8, 130.0, 133.4, 138.1.

LC-MS: m/z = 563 [M + Na]⁺.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₁H₄₀O₆NaS: 563.2432; found: 563.2437.

(2R,3R,4S,5R,6R)-5,7-Bis(benzyloxy)-3-(tert-butyldimethylsil­oxy)-2,4,6-trimethylheptyl 4-Methylbenzenesulfonate (14)

To a stirred soln of 13 (13.2 g, 24.4 mmol) in anhyd CH₂Cl₂ (130 mL) was added 2,6-lutidine (5.6 mL, 48.8 mmol), the mixture was cooled to 0 °C and TBSOTf (8.4 mL, 36.6 mmol) was added. The mixture was stirred at r.t. for 1 h. After completion of the reaction, H₂O (50 mL) was added and the mixture was extracted with CH₂Cl₂ (3 × 75 mL). The combined extracts were dried (Na₂SO₄) and evaporated and the residue was purified by column chromatography to afford pure 14 as a pale-yellow liquid; yield: 15.1 g (94%); R_f = 0.6 (10% EtOAc–hexane); [α]_D ²⁵ +16.1 (c 0.5, CHCl₃).

IR (neat): 3060, 3032, 2958, 1600, 1458, 1364, 1178, 1095, 967, 836 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.12 (s, 3 H), 0.19 (s, 3 H), 0.98 (d, J = 4.5 Hz, 3 H), 1.0 (s, 9 H), 1.02–1.05 (d, J = 6.8 Hz, 3 H), 1.28 (d, J = 6.8 Hz, 3 H), 1.98–2.16 (m, 2 H), 2.29–2.34 (m, 1 H), 2.6 (s, 3 H), 3.46–3.50 (dd, J = 3.7, 5.3 Hz, 1 H), 3.55–3.6 (t, J = 9.1, 7.5 Hz, 1 H), 3.75–3.79 (m, 1 H), 3.95–4.01 (m, 2 H), 4.28–4.32 (m, 1 H), 4.61–4.83 (m, 4 H), 7.45–7.52 (m, 12 H), 7.90–7.92 (d, J = 8.3 Hz, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = –4.2, –3.2, 12.1, 14.4, 16.0, 18.6, 25.7, 26.1, 35.7, 39.0, 39.4, 72.2, 72.9, 73.1, 73.7, 74.0, 84.5, 127.2, 127.4, 127.5, 127.7, 127.7, 127.9, 128.3, 128.5, 129.7, 138.7, 138.9, 144.5.

LC-MS: m/z = 677 [M + Na]⁺.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₇H₅₄O₆SSiNa: 677.1724; found: 677.1723.

[(2R,3R,4R,5R,6R)-1,3-Bis(benzyloxy)-2,4,6-trimethylnonan-5-yloxy]-tert-butyldimethylsilane (15)

To a stirred soln of CuBr·Me₂S (12.6 g, 87 mmol) in anhyd THF (130 mL) was added 1 M EtMgBr in THF (150 mL), the mixture was stirred for 1 h; it was then cooled to –20 °C and 14 (15 g, 29.2 mmol) dissolved in anhyd THF (50 mL) was added and the mixture was for 5 h at r.t. After completion of the reaction, it was quenched with sat. NH₄Cl soln (100 mL) and extracted with EtOAc (3 × 100 mL). The combined extracts were dried (Na₂SO₄) and the solvent was evaporated. The residue was purified by column chromatography to afford pure 15 as a pale-yellow liquid; yield: 9.8 g (83%); R_f  = 0.5 (10% EtOAc­–hexane); [α]_D ²⁵ +3.83 (c 0.5, CHCl₃).

IR (neat): 3065, 3031, 2957, 1459, 1252, 1068, 835 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.03 (s, 3 H), 0.04 (s, 3 H), 0.80–0.85 (m, 6 H), 0.87 (d, J = 2.3 Hz, 3 H), 0.91 (s, 9 H), 1.12 (d, J = 7.6 Hz, 3 H), 1.25–1.40 (m, 4 H), 1.47–1.61 (m, 1 H), 1.83–1.95 (m, 1 H), 2.07–2.22 (m, 1 H), 3.22–3.28 (dd, J = 3.0, 5.3 Hz, 1 H), 3.34–3.42 (m, 1 H), 3.58–3.64 (m, 1 H), 3.79–3.82 (m, 1 H), 4.46 (s, 2 H), 4.53–4.66 (m, 2 H), 7.20–7.32 (m, 10 H).

¹³C NMR (75 MHz, CDCl₃): δ = –3.7, 12.3, 14.3, 15.7, 16.5, 20.7, 26.1, 35.0, 35.7, 38.0, 39.6, 72.3, 73.0, 74.3, 75.3, 85.2, 127.2, 127.3, 127.4, 128.1, 128.2, 138.8, 139.1.

LC-MS: m/z = 535 [M + Na]⁺.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₂H₅₂O₃NaSi: 535.35855; found: 535.35779.

(2R,3R,4S,5R,6R)-1,3-Bis(benzyloxy)-2,4,6-trimethylnonan-5-ol (16)

To a stirred soln of 15 (9.7 g, 18.9 mmol) in MeOH (100 mL) was added PTSA at 0 °C; the mixture was stirred at r.t. for 2 h. After completion of the reaction, it was quenched with solid NaHCO₃ (3 g), the solvent was evaporated, and the residue was purified by column chromatography to afford pure 16 as a pale-yellow liquid; yield: 6.9 g (92%); R_f = 0.4 (10% EtOAc–hexane); [α]_D ²⁵ +40.1 (c 0.5, CHCl₃).

IR (neat): 3501, 3064, 3031, 2961, 1456, 1074, 736 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.68 (d, J = 6.0 Hz, 3 H), 0.79 (t, J = 7.0 Hz, 3 H), 0.92 (d, J = 6.0 Hz, 3 H), 0.98–0.99 (d, J = 7.0 Hz, 3 H), 1.09–1.17 (m, 2 H), 1.31–1.38 (m, 2 H), 1.42–1.47 (m, 1 H), 1.62–1.68 (m, 1 H), 1.83–1.87 (m, 1 H), 2.02–2.07 (br s, OH), 3.41–3.48 (m, 3 H), 3.56–3.59 (m, 1 H), 4.40–4.43 (m, 4 H), 7.14–7.25 (m, 10 H).

¹³C NMR (75 MHz, CDCl₃): δ = 11.3, 14.4, 14.9, 15.0, 19.8, 34.3, 35.1, 35.7, 36.7, 72.2, 73.0, 74.2, 76.0, 87.2, 127.5, 127.6, 127.7, 128.2, 128.3, 137.8, 138.4.

LC-MS: m/z = 421 [M + Na]⁺.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₆H₃₈O₃Na: 421.2709; found: 421.2712.

(2R,3R,4R,6R)-1,3-Bis(benzyloxy)-2,4,6-trimethylnonan-5-one (17)

To a soln of 16 (3 g, 7.53 mmol) in CH₂Cl₂ (40 mL) at 0 °C was added NaHCO₃ (1.89 g, 22.5 mmol) and then Dess–Martin periodinane (4.79 g, 11.3 mmol) and the mixture was stirred at r.t. for 1 h. After completion of the reaction, hexane (50 mL) was added. A white precipitate separated, it was filtered, and the filtrate was concentrated under reduced pressure to a viscous oil, which was purified by column chromatography to afford pure 17 as a colorless oil; yield: 2.87 g (96%); R_f = 0.8 (10% EtOAc–hexane); [α]_D ²⁵ –28.63 (c 0.5, CHCl₃).

IR (neat): 3065, 3032, 2963, 1713, 1455, 1090, 735 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.78–0.83 (t, J = 7.5, 6.7 Hz, 3 H), 0.86 (d, J = 6.8 Hz, 3 H), 0.93 (d, J = 6.8 Hz, 3 H), 1.03 (d, J = 6.8 Hz, 3 H), 1.14–1.22 (m, 2 H), 1.53–1.60 (m, 2 H), 2.05–2.12 (m, 1 H), 2.49–2.56 (m, 1 H), 3.03–3.13 (m, 1 H), 3.30–3.35 (m, 1 H), 3.60–3.66 (m, 2 H), 4.33–4.44 (m, 4 H), 7.14–7.29 (m, 10 H).

¹³C NMR (75 MHz, CDCl₃): δ = 14.0, 14.1, 15.1, 16.0, 20.4, 34.3, 35.6, 46.9, 47.4, 71.7, 73.0, 74.8, 84.4, 127.2, 127.3, 127.4, 128.0, 128.2, 138.5, 138.7, 217.3.

LC-MS: m/z = 419 [M + Na]⁺.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₆H₃₆O₃Na: 419.2551; found: 419.2556.

(2R,3R,4S,5S,6R)-1,3-Bis(benzyloxy)-2,4,6-trimethylnonan-5-ol (18)

To a stirred soln of ketone 17 (2.87 g) in anhyd CH₂Cl₂ (7.24 mmol), was added DIBAL-H (15.6 mL, 26 mmol) dropwise at –78 °C. The reaction was stirred at this temperature for 1 h while monitoring the progress of the reaction. After the reaction was complete, the mixture was quenched by the addition of MeOH at –78 °C and the mixture was allowed to reach r.t. The solvent was evaporated under vacuum and the residue was treated with sat. sodium potassium tartrate soln (40 mL). The residue dissolved in the aqueous layer and the product was extracted with CH₂Cl₂ (3 × 50 mL). The combined organic layers were washed with brine (50 mL) and then dried (Na₂SO₄). The solvent was evaporated and the residue was purified by column chromatography to afford pure 18 as a pale-yellow liquid; yield: 2.7 g (94%); R_f = 0.4 (10% EtOAc–hexane); [α]_D ²⁵ –6.3 (c 0.5, CHCl₃).

IR (neat): 3499, 3064, 3031, 2925, 1454, 1069, 698 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.82 (d, J = 3.0 Hz, 3 H), 0.84 (d, J = 3.0 Hz, 3 H), 0.89–0.91 (t, J = 6.9 Hz, 3 H), 1.11 (d, J = 7.9 Hz, 3 H), 1.25–1.41 (m, 4 H), 1.56–1.60 (m, 1 H), 1.93–1.98 (m, 1 H), 2.18–2.23 (m, 1 H), 3.42–3.47 (m, 2 H), 3.51–3.57 (m, 1 H), 3.60–3.63 (m, 1 H), 4.45–4.53 (m, 2 H), 4.60–4.65 (m, 2 H), 7.26–7.34 (m, 10 H).

¹³C NMR (75 MHz, CDCl₃): δ = 12.0, 14.3, 15.4, 15.7, 20.6, 34.3, 36.8, 37.6, 38.5, 72.3, 73.0, 74.7, 76.4, 88.0, 127.4, 127.5, 127.7, 128.2, 128.3, 138.0, 138.6.

LC-MS: m/z = 421 [M + Na]⁺.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₆H₃₈O₃Na: 421.2709; found: 421.2713.

(2R,3R,4S,5S,6R)-2,4,6-Trimethylnonane-1,3,5-triol (19)

To a stirred soln of naphthalene powder (17.36 g, 135.6 mmol) in anhyd THF (30 mL) was added Li metal (0.5 g, 67.7 mmol). The mixture was stirred for 3 h at r.t. then cooled to –20 °C and 18 (2.7 g, 6.78 mmol) in anhyd THF (10 mL) was added. After stirring the mixture for 2 h at –20 °C, it was quenched with sat. aq NH₄Cl soln (20 mL), extracted with Et₂O (3 × 20 mL) and dried (Na₂SO₄). The solvent was evaporated, and the residue was purified by column chromatography to afford pure 19 colorless oil; yield: 1.37 g (93%); R_f = 0.1 (40% EtOAc–hexane); [α]_D ²⁵ –4.37 (c 1.0, CHCl₃).

IR (neat): 3334, 2961, 1455, 976 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.74 (d, J = 6.0 Hz, 3 H), 0.84 (d, J = 7.0 Hz, 3 H), 0.87–0.90 (t, J = 7.0 Hz, 3 H), 1.14 (d, J = 7.0 Hz, 3 H), 1.21–1.35 (m, 4 H), 1.66–1.70 (m, 1 H), 1.82–1.89 (m, 2 H), 3.34 (br s, OH), 3.45 (br s, OH), 3.55–3.61 (m, 3 H), 3.95 (d, J = 11.0 Hz, 1 H), 4.98 (br s, OH).

¹³C NMR (75 MHz, CDCl₃): δ = 11.8, 13.4, 14.2, 15.3, 20.4, 34.5, 35.4, 36.3, 38.7, 64.6, 80.0, 83.1.

LC-MS: m/z = 241 [M + Na]⁺.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₂H₂₆O₃Na: 241.1781; found: 241.1774.

(3S,4S,5R,6R)-4-Hydroxy-3,5-dimethyl-6-[(R)-pentan-2-yl]-2H-tetrahydropyran-2-one (20)

To a stirred soln of triol 19 (1.37 g, 6.28 mmol) in anhyd CH₂Cl₂ (20 mL) was added PhI(OAc)₂ (7 g, 22 mmol) and TEMPO (0.2 g, 1.28 mmol) at r.t. The mixture was stirred at r.t. for 3 h. After completion of the reaction, sat. Na₂S₂O₃ soln (20 mL) and Et₂O (20 mL) were added. The organic layer was washed with sat. NaHCO₃ (15 mL) and H₂O (15 mL), and dried (Na₂SO₄). The solvent was evaporated, and the residue was purified by column chromatography to afford pure 20 as a colorless solid; yield: 1.1 g (83%); R_f = 0.4 (30% EtOAc­–hexane); [α]_D ²⁵ –24.36 (c 1.0, CHCl₃).

IR (neat): 3445, 2963, 1714, 1461, 1211, 977 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.85–0.88 (t, J = 7.0, 5.0 Hz, 3 H), 0.89–0.90 (d, J = 7.0 Hz, 3 H), 1.02–1.03 (d, J = 7.0 Hz, 3 H), 1.28 (d, J = 8.0 Hz, 3 H), 1.32–1.43 (m, 2 H), 1.47–1.54 (m, 1 H), 1.61–1.65 (m, 1 H), 1.91–1.97 (m, 1 H), 2.19–2.36 (m, 1 H), 2.43–2.48 (m, 1 H), 3.82 (s, 1 H), 4.36 (d, J = 10.0 Hz, 1 H).

¹³C NMR (75 MHz, CDCl₃): δ = 12.3, 12.8, 14.2, 20.5, 33.6, 35.9, 36.0, 42.5, 72.9, 83.1, 96.1, 174.0.

LC-MS: m/z = 237 [M + Na]⁺.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₂H₂₂O₃Na: 237.1463; found: 237.1461.

(5R,6S)-3,5-Dimethyl-6-[(R)-pentan-2-yl]-5,6-dihydro-2H-pyran-2-one (21)

To a stirred soln of 20 (1 g, 4.67 mmol) in anhyd CH₂Cl₂ (10 mL) was added Et₃N (3.6 mL, 25 mmol) and MsCl (1 mL, 10 mmol) at 0 °C; the mixture was stirred at r.t. for 1 h. H₂O (10 mL) was added and the mixture was extracted with CH₂Cl₂ (3 × 20 mL). The combined extracts were dried (Na₂SO₄) and the solvent was evaporated in vacuo.

DBU (2 mL, 14.5 mmol) was added to the crude product dissolved in anhyd THF (10 mL) at r.t. The mixture was stirred at r.t. for 2 h and then it was diluted with H₂O (50 mL) and extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried (Na₂SO₄), and evaporated to give crude α,β-unsaturated lactone, which was purified by column chromatography to afford pure 19 as a colorless liquid; yield: 0.81 g (88%); R_f = 0.3 (10% EtOAc–hexane); [α]_D ²⁵ –26.81 (c 1.0, CHCl₃).

IR (neat): 2961, 1722, 1715, 1456, 1138 cm^–1 _.

¹H NMR (300 MHz, CDCl₃): δ = 0.86–0.91 (t, J = 6.8 Hz, 3 H), 0.92 (d, J = 6.8 Hz, 3 H), 1.03 (d, J = 7.5 Hz, 3 H), 1.23–1.51 (m, 4 H), 1.71–1.73 (dd, J = 1.5, 5.3 Hz, 1 H), 1.88 (s, 3 H), 2.54–2.64 (m, 1 H), 3.93–3.97 (dd, J = 2.3, 8.3 Hz, 1 H), 6.32 (s, 1 H).

¹³C NMR (75 MHz, CDCl₃): δ = 13.1, 14.0, 16.1, 16.8, 20.3, 30.9, 33.3, 35.5, 86.0, 127.0, 146.4, 166.3.

LC-MS: m/z = 219 [M + Na]⁺.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₂H₂₀O₂Na: 219.1354; found: 219.1355.

(3R,5R,6S)-3,5-Dimethyl-6-[(R)-pentan-2-yl]-2H-tetrahydropyran-2-one [(–)-Invictolide, (–)-1]

To a stirred soln of 21 (0.1 g, 0.5 mmol) in EtOAc (10 mL), was added 10% Pd/C (cat.) and the mixture was stirred under H₂ atmosphere for 6 h. Then, the mixture was filtered through a small Celite pad and concentrated in vacuo. The crude residue thus obtained was a mixture of (–)-invictolide and its 3-epimer (3:1). The pure isomer 1 could be separated by crystallization (n-hexane at –78 °C). The resulting spectral data, specific rotation are in good agreement with the reported data.[ ³ ] Colorless oil; yield: 75 mg (80%); R_f = 0.5 (10% EtOAc–hexane); [α]_D ²⁵ –93.06 (c 1.0, CHCl₃) [Lit.³ [α] _d –101 (c 0.45, CHCl₃)].

IR (neat): 2963, 1741, 1460, 1193 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.86–0.96 (m, 6 H), 0.97 (d, J = 6.8 Hz, 3 H), 1.20 (d, J = 6.8 Hz, 3 H), 1.30–1.48 (m, 5 H), 1.62–1.74 (t, J = 8.3 Hz, 2 H), 1.84–2.04 (m, 1 H), 2.54–2.67 (m, 1 H), 3.86 (dd, J = 2.3, 9.8 Hz, 1 H).

¹³C NMR (75 MHz, CDCl₃): δ = 12.2, 14.0, 16.4, 17.5, 20.3, 28.3, 32.4, 33.5, 35.2, 36.0, 85.6, 176.7.

LC-MS: m/z = 221 [M + Na]⁺.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₂H₂₂O₂Na: 221.1512; found: 221.1512.

Acknowledgement

K. A. Lakshmi and N. M. Reddy thank UGC and CSIR, New Delhi, respectively, for research fellowships.

• References

• 1 Toshio H, Shin-ichi Y, Fumihiro I, Miho K. Tetrahedron 1996; 52: 12177
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• 2a Rocca JR, Tumlinson JH, Glancy BM, Lofgren CS. Tetrahedron Lett. 1983; 24: 1889
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• 2b Rocca JR, Tumlinson JH, Glancy BM, Lofgren CS. Tetrahedron Lett. 1983; 24: 1893
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For the synthesis of racemic invictolide:
• 4a Hoye TR, Peck DR, Thrumper PK. J. Am. Chem. Soc. 1981; 103: 5618
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• 4b Hoye TR, Peck DR, Swanson TA. J. Am. Chem. Soc. 1984; 106: 2738
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• 4d Yamamoto Y, Taniguchi K, Maruyama K. J. Chem. Soc., Chem. Commun. 1985; 1429

For the synthesis of optically active invictolide:
• 4e Ziegler FE, Stirchak EP, Wester RT. Tetrahedron Lett. 1986; 27: 1229
  CrossrefSearch in Google Scholar
• 4f Mori K, Senda S. Agric. Biol. Chem. 1987; 51: 1379
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• 5a Djerassi C, Zderic JA. J. Am. Chem. Soc. 1956; 78: 6390
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• 5b Martin SF, Guinn DE. Synthesis 1991; 245
  Thieme Connect
• 6a Yadav JS, SrinivasRao C, Chandrasekhar S, Ramarao AV. Tetrahedron Lett. 1995; 36: 7717
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• 6b Yadav JS, Abraham S, MuralidharReddy M, Sabitha G, Ravisankar A, Kunwar AC. Tetrahedron Lett. 2001; 42: 4713
  CrossrefSearch in Google Scholar
• 6c Yadav JS, Ahmed MM. Tetrahedron Lett. 2002; 43: 7147
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• 6d Yadav JS, Srinivas R, Sathaiah K. Tetrahedron Lett. 2006; 47: 1603
  CrossrefSearch in Google Scholar
• 6e Yadav JS, Rajender V, Gangadhararao Y. Org. Lett. 2010; 12: 348
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• 6f Yadav JS, Hossain SS, Madhu M, Mohapatra DK. J. Org. Chem. 2009; 74: 8822
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• 6g Yadav JS, Rajender V. Eur. J. Org. Chem. 2010; 2148
• 7a Brown HC, Varaprasad JV. N. J. Am. Chem. Soc. 1986; 108: 2049
  CrossrefSearch in Google Scholar
• 7b Brown HC, Desai MC, Yadav PK. J. Org. Chem. 1982; 47: 5065
  CrossrefSearch in Google Scholar
• 8 Chakraborty TK, Das S. Tetrahedron Lett. 2001; 42: 3387
  CrossrefSearch in Google Scholar
• 9a Chandrasekhar S, Pavankumarreddy G, Sathish K. Tetrahedron Lett. 2009; 50: 6851
  CrossrefSearch in Google Scholar
• 9b Mori K. Tetrahedron 1981; 37: 1341
  CrossrefSearch in Google Scholar
• 10a Yadav JS, Pratap TV, Rajender V. J. Org. Chem. 2007; 72: 5882
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• 10b Evans DA. J. Org. Chem. 1990; 55: 5190
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• 11 Liu HJ, Yip J. Tetrahedron Lett. 1997; 38: 2253
  CrossrefSearch in Google Scholar
• 12 Hansen TM, Florence GJ, Lugo-Mas P, Chen J, Abrams JN, Forsyth CJ. Tetrahedron Lett. 2003; 44: 57
  CrossrefSearch in Google Scholar

• References

• 1 Toshio H, Shin-ichi Y, Fumihiro I, Miho K. Tetrahedron 1996; 52: 12177
  CrossrefSearch in Google Scholar
• 2a Rocca JR, Tumlinson JH, Glancy BM, Lofgren CS. Tetrahedron Lett. 1983; 24: 1889
  CrossrefSearch in Google Scholar
• 2b Rocca JR, Tumlinson JH, Glancy BM, Lofgren CS. Tetrahedron Lett. 1983; 24: 1893
  CrossrefSearch in Google Scholar
• 3 Mori K, Nakazono Y. Tetrahedron 1986; 42: 6459
  CrossrefSearch in Google Scholar

For the synthesis of racemic invictolide:
• 4a Hoye TR, Peck DR, Thrumper PK. J. Am. Chem. Soc. 1981; 103: 5618
  CrossrefSearch in Google Scholar
• 4b Hoye TR, Peck DR, Swanson TA. J. Am. Chem. Soc. 1984; 106: 2738
  CrossrefSearch in Google Scholar
• 4c Schreiber SL, Wang Z. J. Am. Chem. Soc. 1985; 107: 5303
  CrossrefSearch in Google Scholar
• 4d Yamamoto Y, Taniguchi K, Maruyama K. J. Chem. Soc., Chem. Commun. 1985; 1429

For the synthesis of optically active invictolide:
• 4e Ziegler FE, Stirchak EP, Wester RT. Tetrahedron Lett. 1986; 27: 1229
  CrossrefSearch in Google Scholar
• 4f Mori K, Senda S. Agric. Biol. Chem. 1987; 51: 1379
  CrossrefSearch in Google Scholar
• 4g Wakamatsu T, Nishikimi Y, Kikuiri H, Nakamura H, Ban Y. Heterocycles 1987; 26: 1761
  CrossrefSearch in Google Scholar
• 4h Hoffman RW, Ditrich K, Koster G, Sturmer R. Chem. Ber. 1989; 122: 1783
  CrossrefSearch in Google Scholar
• 5a Djerassi C, Zderic JA. J. Am. Chem. Soc. 1956; 78: 6390
  CrossrefSearch in Google Scholar
• 5b Martin SF, Guinn DE. Synthesis 1991; 245
  Thieme Connect
• 6a Yadav JS, SrinivasRao C, Chandrasekhar S, Ramarao AV. Tetrahedron Lett. 1995; 36: 7717
  CrossrefSearch in Google Scholar
• 6b Yadav JS, Abraham S, MuralidharReddy M, Sabitha G, Ravisankar A, Kunwar AC. Tetrahedron Lett. 2001; 42: 4713
  CrossrefSearch in Google Scholar
• 6c Yadav JS, Ahmed MM. Tetrahedron Lett. 2002; 43: 7147
  CrossrefSearch in Google Scholar
• 6d Yadav JS, Srinivas R, Sathaiah K. Tetrahedron Lett. 2006; 47: 1603
  CrossrefSearch in Google Scholar
• 6e Yadav JS, Rajender V, Gangadhararao Y. Org. Lett. 2010; 12: 348
  CrossrefSearch in Google Scholar
• 6f Yadav JS, Hossain SS, Madhu M, Mohapatra DK. J. Org. Chem. 2009; 74: 8822
  CrossrefSearch in Google Scholar
• 6g Yadav JS, Rajender V. Eur. J. Org. Chem. 2010; 2148
• 7a Brown HC, Varaprasad JV. N. J. Am. Chem. Soc. 1986; 108: 2049
  CrossrefSearch in Google Scholar
• 7b Brown HC, Desai MC, Yadav PK. J. Org. Chem. 1982; 47: 5065
  CrossrefSearch in Google Scholar
• 8 Chakraborty TK, Das S. Tetrahedron Lett. 2001; 42: 3387
  CrossrefSearch in Google Scholar
• 9a Chandrasekhar S, Pavankumarreddy G, Sathish K. Tetrahedron Lett. 2009; 50: 6851
  CrossrefSearch in Google Scholar
• 9b Mori K. Tetrahedron 1981; 37: 1341
  CrossrefSearch in Google Scholar
• 10a Yadav JS, Pratap TV, Rajender V. J. Org. Chem. 2007; 72: 5882
  CrossrefPubMedSearch in Google Scholar
• 10b Evans DA. J. Org. Chem. 1990; 55: 5190
  CrossrefSearch in Google Scholar
• 11 Liu HJ, Yip J. Tetrahedron Lett. 1997; 38: 2253
  CrossrefSearch in Google Scholar
• 12 Hansen TM, Florence GJ, Lugo-Mas P, Chen J, Abrams JN, Forsyth CJ. Tetrahedron Lett. 2003; 44: 57
  CrossrefSearch in Google Scholar