Studies on the Synthesis of Reidispongiolide A: Stereoselective Synthesis of the C(22)-C(36) Fragment

Abstract

A highly stereoselective synthesis of the C(22)-C(36) fragment 2 of reidispongiolide A is described. This synthesis features the highly stereoselective mismatched double asymmetric crotylboration reaction of the aldehyde derived from 5 and the new chiral reagent (S)-(E)-7 that provides 12 with >15:1 d.r. Subsequent coupling of the derived vinyl iodide 3 with aldehyde 16 provided allylic alcohol 17, that was elaborated by three steps into the targeted reidispongiolide fragment 2.

1. Introduction

The reidispongiolides and sphinxolides are structurally related, biologically active families of marine natural products isolated from the New Caledonian sponges Reidispongia coerulea and Neosiphonia superstes.^1–4 According to previous research, these compounds inhibit actin filament assembly assembling and induce F-actin depolymerization.⁵ These compounds also have the ability to circumvent multi-drug resistance mediated by P-glycoprotein in cell-based assays.⁵ Reidispongiolide A, the most active member of reidispongiolide family, exhibits potent cytotoxicity against various human cancer cell lines (IC₅₀ 0.01 to 0.16 μg/ml).³

The relative configuration of the C(7), C(10–15), C(24–28) and C(32–33) subunits of sphinxolide B were first assigned by J-based NMR methods.⁶ The relative and absolute stereochemistry of the C(17–22)⁷, C(22–35)⁸ and C(5–16)⁹ subunits of reidispongiolide A were assigned via asymmetric synthesis. The absolute configuration of this family of natural products was determined from the actin-bound X-ray crystal structure of reidispongiolide A.¹⁰

The structure complexity and biological properties of reidispongiolide A have stimulated interest in its synthesis. The total synthesis of reidispongiolide A was reported by Paterson and co-workers in 2007.^11,9,12 More recently, Suenaga and co-workers reported the synthesis of the C(11–22) and C(23–35) fragments of 1.¹³ Because recent research suggests that the C(24)–C(36) side chain plays a very important role in the binding of the reisipongiolides to the actin target,^14,15 we have focused our current efforts on this segment of the natural product.

We report here a highly stereoselective synthesis of the reidispongiolide A C(22)–C(36) subunit 2 that proceeds along the general outline of the retrosynthetic analysis that is presented in Scheme 1. The synthetic target 2 possesses seven stereocenters, including the C(26)–C(28) anti-anti stereotriad that represents a historically difficult challenge for synthesis via asymmetric aldol or crotylmetalation reactions,¹⁶ as this bond construction is stereochemically mismatched. However, synthesis of the anti, anti stereotriad with exceptional stereochemical control is now possible by virtue of the remarkable enantioselectivity of the new α-stannyl crotylborane 7 that is accessible via enantioselective hydroboration of racemic allene 8 with diisopinocampheylborane [(Ipc)₂BH].^17,18 Thus, by application of this new crotylboration technology we anticipated that vinyl iodide intermediate 3 could be assembled via α-stannylcrotylboration of the aldehyde deriving from 5 with the chiral reagent (S)-(E)-7. Similarly, we anticipated that vinyl iodide fragment 4 would be accessible via α-stannylallylboration of the aldehyde deriving from 6 with the a-stannylallylborane (R)-9 that is readily accessible via the hydroboration of allenylstannane 10 with [(^lIpc)₂BH].¹⁹

Scheme 1.

Retrosynthetic Analysis of 2

2. Results and Discussion

The synthesis of fragment 3 (Scheme 2) starts from the primary alcohol 6 which is prepared in two steps from commercially available precuresors.²⁰ Alcohol 6 was oxidized to the corresponding aldehyde using a Swern procedure²¹ and then the aldehyde was treated with the diisopropyl (R,R)-tartrate (E)-crotylboronate reagent²² to give the known homoallylic alcohol 11 in 88% yield with 14:1 diastereoselectivity.²³ Protection of the hydroxyl group of 11 as a TBS ether followed by PMB ether deprotection with DDQ²⁴ provided primary alcohol 5 in 69% yield over the two steps. Alcohol 5 was then oxidized to the corresponding aldehyde and then added to a solution of α-stannylcrotylborane (S)-(E)-7 that was generated, as previously described, via the hydroboration of racemic allene 8 with (^dIpc)₂BH.¹⁷ This reaction proceeded overnight at ambient temperature and provided the vinylstannane product 12, with the requisite anti-anti stereochemistry at C(26–28), in 66% yield with >15:1 d.r. The stereochemistry of 12 was assigned by analogy to related mismatched double asymmetric reactions described elsewhere.¹⁸ Treatment of 12 with I₂ in Et₂O effected tin-iodine exchange and afforded vinyl iodide 13 in 73% yield. O-Methylation of the hindered hydroxyl group of 13 proved challenging. Attempted use of NaH and MeI for this step caused partial migration of the TBS unit between two hydroxyl groups, while use of Me₃OBF₄ and Proton Sponge® led to partial deprotection of TBS ether. Fortunately, use of MeOTf and 2,6-di-^tbutylpyridine resulted in a very clean reaction that provided 3 in 85% yield.²⁵

Scheme 2.

Synthesis of Vinyl Iodide 3

Alcohol 6 also served as the starting material for synthesis of vinyl iodide fragment 4. The aldehyde generated by Swern oxidation of 6 was added to a −78 °C solution the α-stannylallylborane reagent (R)-9, generated by the hydroboration of allenylstannane 10 with (^lIpc)₂BH as previously described,¹⁹ to give 14 in 67% yield and with >50:1 d.r. The (R)-stereochemistry of the hydroxyl group of 14 was assigned by using the Mosher ester method. Treatment of 14 with I₂ followed by alcohol O-methylation gave vinyl iodide 4 in 80% yield. Deprotection of PMB ether of 4 gave the primary alcohol 15 in 76% yield, which was then oxidized under Dess-Martin oxidation²⁶ conditions to give aldehyde 16. Aldehyde 16 is not stable for long-term storage and was usually freshly prepared before immediately before use in subsequent chemistry.

Treatment of vinyl iodide 3 with t-BuLi at −78 °C generated the corresponding the vinyllithium intermediate which was then treated with aldehyde 16, also at − 78 °C. This reaction gave alcohol 17 in 50% yield as a ca. 2: 1 mixture of diastereomers (Scheme 4). This mixture was of no consequence, as both alcohols smoothly were oxidized in the next step upon treatment with the Dess-Martin periodinane reagent. The resulting enone was then treated with Stryker’s copper hydride reagent²⁷ to give ketone 18 in 60% yield from 17. It was anticipated that 18 would be a suitable substrate for introduction of the N-methylformamide unit, by application of Porco’s procedure.^28–31 While this proved to be the case, a small amount of epimerization occurred at C(32) in the conversion of 18 to 2 owing to the basicity of these reaction conditions. Unfortunately, the epimerization at C(32) could not be avoided, and the best result that we obtained was a 13:1 mixture of 2 and its (C32)-eipmer.

Scheme 4.

Initial Studies on the Coupling of Vinyl Iodide 3 and Aldehyde 16

Fortunately, this epimerization process could be avoided by introducing the N-methyl formamide unit prior to oxidation of the C(31)-alcohols (Scheme 5). Thus, the N-methyl formamide was introduced at the stage of alcohol 17 to give 19 in 72% yield.^30,31 Subsequent oxidation of 19 with the Dess-Martin periodinane reagent, followed by reduction of the enone using Stryker’s copper hydride reagent afforded 2 in 50% over the final two steps. The ¹H NMR spectrum of 2 showed no evidence of epimerization of the C32 stereocenter.

Scheme 5.

Completion of the Synthesis of 2

3. Conclusion

In summary, we have developed a highly stereoselective synthesis of C(22)-C(36) fragment 2 of reidispongiolide A that features the highly stereoselective mismatched double asymmetric crotylboration reaction of the aldehyde derived from 5 and the new chiral reagent (S)-(E)-7 that provides 12 with >15:1 d.r. Subsequent coupling of the derived vinyl iodide 3 with aldehyde 16 provided allylic alcohol 17, that was elaborated by three steps into the targeted reidispongiolide fragment 2. This work sets the stage for further studies on the chemistry and biology of reidispongiolide A, that will be reported in due course.

4. Experimental

General Experimental Details

All reaction solvents were purified before use. Tetrahydrofuran, dichloromethane, diethyl ether, and toluene were purified by passing through a solvent column composed of activated A-1 alumina. Unless indicated otherwise, all reactions were conducted under an atmosphere of argon using flame-dried or oven-dried (170 °C) glassware. 4A molecular sieves were activated under high vacuum with at 180 °C for 12 h and re-activated through flame-drying immediately prior to use.

Proton nuclear magnetic resonance (¹H NMR) spectra were recorded on commercial instruments at 400 or 500 MHz. Carbon-13 nuclear magnetic resonance (¹³C NMR) spectra were recorded at 100 MHz. The proton signal for residual non-deuterated solvent (δ 7.26 for CHCl₃) was used as an internal reference for ¹H NMR spectra. For ¹³C NMR spectra, chemical shifts are reported relative to the δ 77.16 resonance of CHCl₃. Coupling constants are reported in Hz. Infrared (IR) spectra were recorded as films on an FTIR instrument. Mass spectra were recorded on a commercial spectrometer. Optical rotations were measured on a polarimeter using a 10-cm, 1-mL quartz cell.

(2S,3S,4S)-1-((4-methoxybenzyl)oxy)-2,4-dimethylhex-5-en-3-ol (11)

A solution of the oxalyl chloride (1 mL, 11.4 mmol) in dry CH₂Cl₂ (20 mL) was added DMSO (1.86 mL, 26 mmol) dropwise at −78°C. This mixture was stirred for 15 min, then a solution of alcohol 6 (2.10 g, 10 mmol) in CH₂Cl₂ (10 mL) was added dropwise. The reaction mixture was stirred at −78°C for 30 min. Diisopropylethylamine (9.2 mL, 52.8 mmol) was then added and the mixture was allowed to warm to room temperature. The mixture was diluted with Et₂O (100 mL). The organic phase was separated and washed with 1N HCl, sat aq NaHCO₃ solution and brine, and then dried over MgSO₄. Filtration and concentration of this solution under reduced pressure provided the aldehyde as colorless oil, which was used immediately in the next step without further purification.

A 1.0 M solution of diisopropyl (R,R)-tartrate (E)-crotylboronate in toluene (20 mL, 20 mmol) was added to a slurry of powdered 4Å molecular sieves (0.4 g) in toluene (10 mL) at ambient temperature. The mixture was stirred for 20 min, then was cooled to −78°C and a solution of the aldehyde in toluene (10 mL) was added dropwise. After being stirred for 8 h at −78°C, the reaction mixture was quenched by 1 M NaOH (40 mL). The resulting two-phase mixture was stirred vigorously for 30 min, and extracted with Et₂O (3 × 50 mL). The combined organic layers were washed with brine, dried over MgSO₄, and concentrated. Purification of the crude product by column chromatography (4:1 hexanes-EtOAc) provided the known alcohol 11 (2.32 g, 88% for two steps) as colorless oil.²³

(2S,3S,4S)-3-((tert-butyldimethylsilyl)oxy)-2,4-dimethylhex-5-en-1-ol (5)

A solution of the alcohol 11 (1.79 g, 6.8 mmol) and 2,6-lutidine (1.6 mL, 13.6 mmol) in CH₂Cl₂ (60 mL) at −78 °C was treated with TBSOTf (1.85 mL, 10.2 mmol). The reaction mixture was stirred for 1 h and warmed to 0 °C over 30 min. The reaction was quenched by addition of saturated aqueous NaHCO₃ (30 mL). The resulting mixture was extracted with CH₂Cl₂ (3 × 30 mL). The combined organic layers were washed with brine, dried over MgSO₄ and concentrated. Purification of the crude product by column chromatography (9:1 hexanes-EtOAc) provided the known TBS ether (2.29 g, 89%) as a colorless oil.²³

To a 0 °C stirred CH₂Cl₂ solution (40 mL) of the above TBS ether (2.29 g, 6.06 mmol) was added a small amount of pH 7 buffer (5% relative to CH₂Cl₂) followed by DDQ (1.66 g, 7.3 mmol). The resulting mixture was stirred at 0°C for 30 min, then was allowed to warm to room temperature and stirred for another 30 min. The mixture was then diluted with saturated aqueous NaHCO₃ (50 mL) and was extracted with CH₂Cl₂ (3 × 50 mL). The combined organic layers were treated with NaBH₄ (500 mg, 12.5 mmol) and then washed with saturated aqueous NaHCO_3, and brine. The extracts were dried over MgSO₄, filtered and concentrated. Purification of the crude product by column chromatography (4:1 hexanes-EtOAc) provided the known alcohol 5 (1.23 g, 78%) as a colorless oil.³²

(3S,4S,5S,6S,7S,E)-6-((tert-butyldimethylsilyl)oxy)-3,5,7-trimethyl-1-(tributylstannyl)nona-1,8-dien-4-ol (12)

To a solution of oxalyl chloride (0.19 mL, 2.32 mmol) in dry CH₂Cl₂ (10 mL) was added DMSO (0.36 mL, 5.1 mmol) dropwise at −78°C. This mixture was stirred for 15 min, then a solution of alcohol 5 (500 mg, 1.93 mmol) in CH₂Cl₂ (3 mL) was added dropwise and the reaction left at −78°C for 30 min. Diisopropylethylamine (1.77 mL, 10.2 mmol) was then added and the mixture was allowed to warm to room temperature. Et₂O (50 mL) was added to dilute the mixture. The organic layer was separated and washed with 1N HCl, saturated aqueous NaHCO₃ and brine, and then dried over MgSO₄. After being filtered, this solution was concentrated under vacuum to give the aldehyde as colorless oil, which was used immediately in the next step without further purification.

Generation of α-stannylcrotylborane (S)-(E)-7 was performed as follows.¹⁷ Finely powdered (^dIpc)₂BH (1.05, 3.86 mmol) was weighed into a round bottom flask containing a stir bar in a glove box. Et₂O (10 mL) was added to the flask and the mixture was cooled to 0 °C. Racemic allenylstannane 8 (1.33 g, 3.86 mmol) was added dropwise. This mixture was stirred for 5 h at 0 °C, during which time the solid (^dIpc)₂BH dissolved to leave a colorless solution of the reagent, (S)-(E)-7.

A solution of the aldehyde (theoretically 1.93 mmol) in 3 mL of Et₂O was added at 0 °C dropwise to the freshly prepared solution of (S)-(E)-7. The mixture was allowed to warm to room temperature and stirred overnight at room temperature. The reaction mixture was then cooled to 0 °C, then saturated aqueous NaHCO₃ (6 mL) was added followed by slow addition of 30% H₂O₂ (3 mL). This mixture was stirred vigorously for 4 h at room temperature. After separation, the aqueous layer was extracted with Et₂O (3 × 20 mL). The combined organic layers were dried over MgSO₄ filtered and concentrated. Purification of the crude product by column chromatography (silica gel neutralized with 1% Et₃N in hexanes; 50:1 hexanes-Et₂O) providing alcohol 8 (766 mg, 66% yield over 2 steps) as a colorless oil: [α]_D= −5.2°(c=1.03, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 6.06 – 5.97 (m, 2H), 5.91 (d, J = 19.2 Hz, 1H), 5.01 (m, 2H), 3.75 (dd, J = 4.1, 2.9 Hz, 1H), 3.62 (dt, J = 10.0, 2.6 Hz, 1H), 3.33 (s, 1H), 2.52 – 2.44 (m, 1H), 2.33 – 2.25 (m, 1H), 1.77 (ddd, J = 10.0, 7.1, 2.8 Hz, 1H), 1.53 – 1.42 (m, 6H), 1.36 – 1.24 (m, 6H), 1.09 (d, J = 7.0 Hz, 3H), 1.03 (d, J = 7.0 Hz, 3H), 0.94 – 0.83 (m, 25H), 0.80 (d, J = 7.0 Hz, 3H), 0.10 (s, 3H), 0.07 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 149.7, 141.7, 128.8, 114.5, 80.2, 76.5, 44.9, 41.4, 41.0, 29.3, 27.4, 26.2, 19.6, 18.3, 18.1, 13.9, 12.9, 9.6, −3.9, −4.3.. IR (neat) 3503, 2957, 2927, 1641, 1596, 1464, 1252 cm⁻¹; HRMS m/z for C₃₀H₆₂O₂SiSnH [M+H]⁺ calcd 603.3619, found 603.3645.

(3S,4S,5S,6S,7S,E)-6-((tert-butyldimethylsilyl)oxy)-1-iodo-3,5,7-trimethylnona-1,8-dien-4-ol (13)

To a solution of vinylstannane 12 (766 mg, 1.27 mmol) in Et₂O (20 mL) was added iodine (381 mg, 1.5 mmol) at room temperature. After being stirred for 1 h, the reaction was diluted with saturated aqueous Na₂S₂O₃. The organic layer was separated and the aqueous layer was extracted with Et₂O (3 × 20 mL). The combined organic layers were treated with KF/Celite (700 mg per mmol of 12). This solution was stirred vigorously for at least 2 h and then filtered through Celite. Purification of the crude product by column chromatography (9:1 hexanes-Et₂O) provided the vinyl iodide 13 (406 mg, 73%) as a colorless oil: [α]_D= −17.6°(c=0.98, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 6.63 (dd, J = 14.6, 9.4 Hz, 1H), 6.07 – 5.97 (m, 2H), 5.09 – 4.98 (m, 2H), 4.01 (s, 1H), 3.70 (t, J = 3.5 Hz, 1H), 3.67 (dt, J = 10.3, 2.0 Hz, 1H), 2.56 – 2.47 (m, 1H), 2.33 – 2.24 (m, 1H), 1.85 – 1.75 (m, 1H), 1.10 (d, J = 7.0 Hz, 3H), 1.05 (d, J = 7.0 Hz, 3H), 0.93 (s, 9H), 0.79 (d, J = 7.1 Hz, 3H), 0.13 (s, 3H), 0.08 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 147.8, 141.2, 114.7, 81.4, 76.4, 74.7, 43.9, 41.2, 40.3, 26.1, 20.3, 18.3, 17.7, 13.7, −3.9, −4.5. IR (neat) 3480, 2959, 2930, 1640, 1602, 1463, 1254 cm⁻¹; HRMS m/z for C₁₈H₃₅O₂SiIH [M+H]⁺ calcd 439.1529 found 439.1525.

tert-butyl(((3S,4S,5S,6S,7S,E)-9-iodo-6-methoxy-3,5,7-trimethylnona-1,8-dien-4-yl)oxy)dimethylsilane (3)

To a stirred solution of freshly distilled MeOTf (0.52 mL, 4.7 mmol) in 2,6-di-tert-butylpyridine (2.06 mL, 9 mmol) was added alcohol 13 (110 mg, 0.25 mmol) in CHCl₃ (6 mL). The reaction mixture was then heated to reflux for 15 h. The reaction mixture was then cooled to room temperature and NH₄OH (2 mL, aqueous) was added. The resulting mixture was stirred for 2h at room temperature and then was poured into 30 mL of water. Once the organic layer separated, the aqueous layer was extracted with CH₂Cl₂ (3 × 10 mL) and the combined organic layers was washed with 1N HCl, brine, dried over MgSO₄ and concentrated. Purification of the crude product by column chromatography (100:1 hexanes-EtOAc) provided the vinyl iodide 3 (96 mg, 81%) as a colorless oil: [α]_D= −6.8°(c=1.04, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 6.58 (dd, J = 14.6, 8.6 Hz, 1H), 6.00 (dd, J = 14.6, 0.9 Hz, 1H), 5.88 – 5.78 (m, 1H), 5.05 – 4.98 (m, 2H), 3.82 (dd, J = 4.5, 2.4 Hz, 1H), 3.44 (s, 3H), 2.90 (dd, J = 8.6, 2.8 Hz, 1H), 2.51 – 2.41 (m, 1H), 2.34 – 2.23 (m, 1H), 1.74 – 1.65 (m, 1H), 1.10 (d, J = 7.0 Hz, 3H), 1.01 (d, J = 7.0 Hz, 3H), 0.91 (s, 9H), 0.77 (d, J = 7.0 Hz, 3H), 0.08 (s, 3H), 0.08 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 148.3, 141.5, 114.5, 87.2, 74.9, 74.8, 60.8, 44.8, 42.9, 39.3, 26.3, 18.7, 18.2, 16.7, 11.9, −3.4, −3.5. IR (neat) 2959, 2929, 1640, 1602, 1462, 1252, 1093 cm⁻¹; HRMS m/z for C₁₉H₃₇O₂SiIH [M+H]⁺ calcd 453.1686 found 453.1693.

(2S,3R,E)-1-((4-methoxybenzyl)oxy)-2-methyl-6-(tributylstannyl)hex-5-en-3-ol (14)

To a −78 °C solution of oxalyl chloride (0.25 mL, 2.85 mmol) in dry CH₂Cl₂ (10 mL) was added DMSO (0.47 mL, 6.5 mmol) dropwise. The mixture was stirred for 15 min, then a solution of alcohol 6 (525 mg, 2.5 mmol) in CH₂Cl₂ (3 mL) was added dropwise. The reaction mixture was left at −78°C for 30 min. Diisopropylethylamine (2.3 mL, 13.2 mmol) was then added and the mixture was allowed to warm to room temperature. Et₂O (50 mL) was added and the organic layer was washed with 1N HCl, saturated aqueous NaHCO₃ and brine and dried over MgSO₄. The solution was filtered and then concentration under vacuum to provide the crude aldehyde as colorless oil, which was used immediately in the next step without further purification.

Generation of α-stannylallylborane (R)-9 was performed following the literature procedure.¹⁹ Finely powdered (^lIpc)₂BH (950 mg, 3.5 mmol) was weighed into a round bottom flask containing a stir bar in a glove box. Toluene (10 mL) was added to the flask and the mixture was cooled to −40 °C. Allenylstannane 10 (1.65 g, 5 mmol) was added dropwise. This mixture was allowed to warm to −20 °C over 5 h, during which time the solid (^lIpc)₂BH dissolved to leave a colorless solution of the reagent (R)-9.

A −78 °C solution of the aldehyde (theoretically 2.5 mmol) in 3 mL toluene was added dropwise to the freshly prepared solution of α-stannylallylborane (R)-9 in toluene. The mixture was stirred overnight at −78 °C. The reaction was then allowed to warm to 0 °C. To this mixture was added saturated aqueous NaHCO₃ (6 mL) followed by slow addition of 30% H₂O₂ (3 mL). This mixture was stirred vigorously for 4 h at room temperature. After separation of the two phases, the aqueous layer was extracted with Et₂O (3 × 20 mL). The combined organic layers were dried over MgSO₄ and concentrated. Purification of the crude product by column chromatography (silica gel neutralized with 1% Et₃N in hexanes; 85:15 hexanes-Et₂O) provided alcohol 14 (900 mg, 67% yield over two steps) as a colorless oil: [α]_D= +2.2°(c=1.15, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.27 – 7.23 (m, 2H), 6.91 – 6.84 (m, 2H), 6.10 – 5.96 (m, 2H), 4.45 (s, 2H), 3.80 (s, 3H), 3.63 – 3.56 (m, 1H), 3.55 (dd, J = 9.2, 4.7 Hz, 1H), 3.47 (dd, J = 9.2, 6.7 Hz, 1H), 3.08 (d, J = 3.5 Hz, 1H), 2.48 – 2.40 (m, 1H), 2.30 – 2.21 (m, 1H), 1.92 – 1.81 (m, 1H), 1.53 – 1.44 (m, 6H), 1.33 – 1.26 (m, 6H), 0.92 – 0.85 (m, 18H). ¹³C NMR (101 MHz, CDCl₃) δ 151.4, 145.7, 131.6, 130.3, 129.4, 114.0, 74.8, 74.4, 73.2, 55.4, 43.8, 38.0, 29.3, 27.4, 14.0, 13.9, 9.6. IR (neat) 3479, 2924, 1613, 1512, 1247 cm⁻¹; HRMS m/z for C₂₇H₄₈O₃SnH [M+H]⁺ calcd 541.2704 found 541.2711.

1-((((2S,3R,E)-6-iodo-3-methoxy-2-methylhex-5-en-1-yl)oxy)methyl)-4-methoxybenzene (4)

To a solution of vinylstannane 14 (900 mg, 1.67 mmol) in Et₂O (30 mL) was added iodine (460 mg, 1.8 mmol) at room temperature. The mixture was stirred for 1 h, then saturated aqueous Na₂S₂O₃ was added to reduce remaining iodine. The organic phase was separated and the aqueous phase was extracted with Et₂O (3 × 30 mL). The combined organic layers were treated with KF/Celite (700 mg per mmol of 14). This mixture was stirred vigorously for at least 2 h and then filtered through Celite. Purification of the crude product by column chromatography (4:1 hexanes-EtOAc) provided the vinyl iodide product (618 mg, 1.64 mmol) as a colorless oil.

To a mixture of the above vinyl iodide (618 mg, 1.64 mmol) and MeI (1.05 mL, 16.4 mmol) in DMF (10 mL) was added 60% NaH in mineral oil (140 mg, 3.5 mmol). The reaction was stirred overnight at room temperature. The mixture wasp poured into 50 mL water, then the aqueous layer was separated and extracted with CH₂Cl₂ (3 × 30 mL). The combined organic layers were washed with brine, dried over MgSO₄ and concentrated. Purification of the crude product by column chromatography (4:1 hexanes-EtOAc) provided the product 4 (524 mg, 80% yield over two steps) as a colorless oil: [α]_D= −28.6° (c=1.07, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.26 – 7.22 (m, 2H), 6.92 – 6.84 (m, 2H), 6.56 (dt, J = 14.6, 7.4 Hz, 1H), 6.04 (dt, J = 14.4, 1.3 Hz, 1H), 4.42 (s, 2H), 3.81 (s, 3H), 3.38 (qd, J = 9.1, 5.8 Hz, 2H), 3.32 (s, 3H), 3.24 – 3.18 (m, 1H), 2.26 (dddd, J = 14.8, 7.1, 4.2, 1.4 Hz, 1H), 2.20 – 2.11 (m, 1H), 2.07 – 1.96 (m, 1H), 0.90 (d, J = 7.0 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 159.3, 143.2, 130.8, 129.3, 113.9, 81.3, 76.7, 72.9, 72.0, 57.8, 55.4, 36.7, 36.4, 13.1. IR (neat) 2904, 1612, 1512, 1244, 1086 cm⁻¹; HRMS m/z for C₁₆H₂₃O₃INa [M+Na]⁺ calcd 413.0590 found 413.0592.

(2S,3R,E)-6-iodo-3-methoxy-2-methylhex-5-en-1-ol (15)

To a stirred 0° C solution of 4 (548 mg, 1.41 mmol) in CH₂Cl₂ (5 mL) containing a small amount of pH 7 buffer (5% relative to CH₂Cl₂) was added DDQ (522 g, 2.3 mmol). The mixture was stirred at 0°C for 30 min, then was allowed to warm to room temperature and stirred for another 30 min. Saturated aqueous NaHCO₃ (20 mL) was added, then the mixture was extracted with CH₂Cl₂ (3 × 20 mL). The combined organic layers were washed with saturated aqueous NaHCO_3, brine, dried over MgSO₄, and concentrated. Purification of the crude product by column chromatography provided the primary alcohol 15 (290 mg, 76%) as a colorless oil: [α]_D= −41.4° (c=1.15, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 6.55 (ddd, J = 14.7, 8.1, 6.8 Hz, 1H), 6.12 (dt, J = 14.4, 1.4 Hz, 1H), 3.67 – 3.54 (m, 2H), 3.39 (s, 3H), 3.19 (dt, J = 7.4, 4.9 Hz, 1H), 2.75 (dd, J = 7.0, 4.3 Hz, 1H), 2.44 (dddd, J = 15.1, 6.5, 4.8, 1.5 Hz, 1H), 2.30 – 2.21 (m, 1H), 1.89 – 1.80 (m, 1H), 0.91 – 0.86 (m, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 141.9, 85.1, 77.0, 66.9, 57.8, 38.0, 36.9, 13.9. IR (neat) 3405, 2928, 1606, 1083 cm⁻¹; HRMS m/z for C₈H₁₅O₂IH [M+H]⁺ calcd 271.0195 found 271.0204.

(1E,4R,5S,7E,9S,10S,11S,12S,13S)-12-((tert-butyldimethylsilyl)oxy)-1-iodo-4,10-dimethoxy-5,9,11,13-tetramethylpentadeca-1,7,14-trien-6-ol (17)

To a solution of Dess Martin periodinane (154 mg, 0.35 mmol) in CH₂Cl₂ (5 mL) was added alcohol 15 (81 mg, 0.3 mmol) in CH₂Cl₂ (3 mL). Once the reaction was complete (TLC monitoring), Et₂O (10 mL), saturated aqueous NaHCO₃ (5 mL) and Na₂S₂O₃ (1 mL) were added. The organic layer was separated and aqueous layer was extracted with Et₂O (3 × 10 mL). The combined organic layers were washed with brine, dried over MgSO₄ and concentrated. The crude aldehyde 16 was used immediately without purification in the next step.

t-BuLi (0.4 mmol, 0.25 mL, 1.6 M in pentane) was added dropwise to a −78 °C solution of vinyl iodide 3 (91 mg, 0.2 mmol) in THF (2 mL). The mixture was stirred for 30 min, then a solution of aldehyde 16 (prepared from 0.3 mmol of alcohol 15) in THF (1 mL) was added dropwise. The mixture was stirred at −78°C for additional 1.5 h, then the reaction mixture was allowed to warm to 0°C. Saturated aqueous NH₄Cl solution was then added to terminate the reaction. The organic layer was separated and aqueous layer was extracted with Et₂O (3 × 10 mL). The combined organic layers were dried over MgSO₄, filtered and concentrated. Purification of the crude product by column chromatography (9:1 hexanes-EtOAc) provided the alcohol 17 (58 mg, 50%) as a colorless oil, as a mixture of two isomers (2:1 ratio). This mixture was carried to next step without separation. ¹H NMR (400 MHz, CDCl₃) δ 6.63 – 6.48 (1H), 6.16 – 6.05 (1H), 5.90 – 5.59 (2H), 5.48 – 5.33 (1H), 5.03 – 4.92 (2H), 4.26 (1H), 3.86 (1H), 3.51 – 3.43 (3H), 3.39 – 3.33 (3H), 3.30 – 3.22 (1H), 2.91 (2H), 2.52 – 2.37 (2H), 2.33 – 2.17 (2H), 1.86 – 1.74 (1H), 1.74 – 1.64 (1H), 1.15 – 1.09 (3H), 1.01 – 0.96 (m, 3H), 0.90 (9H), 0.88 – 0.82 (m, 3H), 0.79 – 0.73 (m, 3H), 0.11 – 0.07 (m, 6H).

(4R,5R,9S,10S,11S,12S,13S,E)-12-((tert-butyldimethylsilyl)oxy)-1-iodo-4,10-dimethoxy-5,9,11,13-tetramethylpentadeca-1,14-dien-6-one (18)

To a solution of Dess–Martin periodinane (44 mg, 0.1 mmol) in CH₂Cl₂ (1 mL) was added alcohol 17 (46 mg, 0.078 mmol) in CH₂Cl₂ (1 mL). Once the reaction was complete (TLC monitoring), Et₂O (5 mL), saturated aqueous NaHCO₃ (2 mL) and Na₂S₂O₃ (0.5 mL) were added. The organic layer was separated and the aqueous layer was extracted with Et₂O (3 × 10 mL). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated to give crude product ketone (42 mg). This crude product was used directly in the next step without purification.

To a solution of Stryker’s copper hydride reagent ([PPh₃CuH]₆; 78mg, 0.04 mmol) in 2 mL of degassed toluene was added the above enone as a solution in toluene (1 mL, degassed) and 1 drop of water via syringe. The mixture was stirred overnight at room temperature, then was diluted with 20 mL of CH₂Cl₂. The combined organic layers were washed with saturated aqueous NH₄Cl solution, brine, dried over MgSO₄ and concentrated. Purification of the crude product by column chromatography (9:1 hexanes-EtOAc) provided the ketone 18 (28 mg, 60% over two steps) as a colorless oil: [α]_D= −30.7° (c=1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 6.56 (ddd, J = 14.7, 8.4, 6.5 Hz, 1H), 6.12 (dt, J = 14.5, 1.3 Hz, 1H), 5.92 – 5.79 (m, 1H), 5.06 – 4.96 (m, 2H), 3.84 (dd, J = 4.5, 2.1 Hz, 1H), 3.45 – 3.41 (m, 4H), 3.27 (s, 3H), 2.88 (dd, J = 8.3, 3.3 Hz, 1H), 2.76 – 2.67 (m, 1H), 2.55 (ddd, J = 17.5, 9.2, 5.3 Hz, 1H), 2.49 – 2.37 (m, 2H), 2.34 – 2.26 (m, 1H), 2.19 – 2.08 (m, 1H), 1.83 – 1.69 (m, 2H), 1.65 (ddd, J = 13.5, 6.8, 3.4 Hz, 1H), 1.44 – 1.33 (m, 1H), 1.01 (d, J = 7.0 Hz, 3H), 0.97 (d, J = 6.9 Hz, 3H), 0.96 (d, J = 7.0 Hz, 3H), 0.91 (s, 9H), 0.81 (d, J = 7.0 Hz, 3H), 0.09 (s, 2H), 0.08 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 213.6, 141.8, 141.7, 114.3, 88.8, 81.5, 77.1, 75.0, 60.9, 57.9, 49.1, 45.0, 41.6, 38.9, 36.4, 34.5, 26.3, 24.2, 18.7, 17.7, 16.7, 12.8, 12.3, −3.4, −3.5. IR (neat) 2959, 2931, 1716, 1462, 1253, 1095 cm⁻¹; HRMS m/z for C₂₇H₅₁O₄SiIH [M+H]⁺ calcd 595.2680 found 595.2678.

N-((4R,5R,9S,10S,11S,12S,13S,E)-12-((tert-butyldimethylsilyl)oxy)-4,10-dimethoxy-5,9,11,13-tetramethyl-6-oxopentadeca-1,14-dien-1-yl)-N-methylformamide (2)

N-Methyl formamide (0.1 mL), Cs₂CO₃ (26 mg, 0.08 mmol), CuTC (9 mg, 0.045 mmol), and 1,10-phenanthroline (16 mg, 0.09 mmol) were placed in a flame-dried 10 mL Schlenk tube with a stir bar. Vinyl iodide 18 (27 mg, 0.045mmol) in 1 mL of anhydrous DMA was added and the system was degassed under vacuum until gas evolution ceased. The mixture was heated to 45°C for 18 h. The reaction mixture was then diluted with Et₂O and pH 7 buffer. The organic layer was separated and the aqueous layer was extracted with Et₂O. The combined organic layers was washed with brine, dried over MgSO₄, filtered and concentrated. Purification of the crude product by column chromatography (1:1 hexanes-EtOAc) provided the product 2 (12 mg, 50%, 75% based on recovered starting material) as a colorless oil. The product contains two amide rotamers at room temperature, and was a 12:1 mixture of epimers at C(32): [α]_D= −25.1° (c=0.75, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 8.28 – 8.06 (1H, 8.28 (s, 0.7H), 8.06 (s, 0.3H)), 7.18 – 6.51 (1H, 7.18 (d, J = 14.6 Hz, 0.3H), 6.51 (d, J = 14.0 Hz, 0.7H)), 5.94 – 5.76 (m, 1H), 5.17 – 4.95 (m, 3H), 3.84 (dd, J = 4.4, 2.0 Hz, 1H), 3.49 – 3.39 (m, 4H), 3.29 – 3.28 (3H, 3.29 (s, 2H), 3.28 (s, 1H)), 3.06 – 3.03 (3H, 3.06 (s, 1H), 3.03 (s, 2H)), 2.88 (dd, J = 8.3, 3.1 Hz, 1H), 2.78 – 2.67 (m, 1H), 2.60 – 2.39 (m, 3H), 2.35 – 2.25 (m, 1H), 2.22 – 2.08 (m, 1H), 1.83 – 1.70 (m, 2H), 1.70 – 1.62 (m, 1H), 1.37 (m, 1H), 0.98 (m, 9H), 0.91 (s, 9H), 0.81 (d, J = 7.0 Hz, 3H), 0.08 (s, 3H), 0.08 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 213.8, 162.3(160.9), 141.8, 130.5(126.5), 114.3, 105.7(107.3), 88.8, 82.5, 75.0, 60.9, 57.9(57.7), 49.0(49.2), 45.0, 41.5(41.3), 38.9, 34.5, 30.6(30.5), 27.7(33.2), 26.3, 24.2, 18.7, 17.8(17.7), 16.7, 12.8(13.0), 12.3, −3.4, −3.5. IR (neat) 2958, 2930, 1696, 1659, 1462, 1252, 1078 cm⁻¹; HRMS m/z for C₂₉H₅₅O₅SiH [M+H]⁺ calcd 526.3928 found 526.3925.

N-((1E,4R,5S,7E,9S,10S,11S,12S,13S)-12-((tert-butyldimethylsilyl)oxy)-6-hydroxy-4,10-dimethoxy-5,9,11,13-tetramethylpentadeca-1,7,14-trien-1-yl)-N-methylformamide (19)

N-Methyl formamide (0.2 mL), Cs₂CO₃ (49 mg, 0.15 mmol), CuTC (19 mg, 0.1 mmol), 1,10-phenanthroline (36 mg, 0.2 mmol) were placed in a flame-dried 10 mL Schlenk tube with a stir bar. A solution of vinyl iodide 17 (58 mg, 0.098 mmol) in 1 mL of anhydrous DMA was added and the system was degassed under vacuum until gas evolution ceased. The mixture was heated to 45°C for 18 h. The reaction was then diluted with Et₂O and pH 7 buffer. The organic layer was separated and the aqueous layer was extracted with Et₂O. The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated. Purification of the crude product by column chromatography (1:4 hexanes-EtOAc) provided the product 19 (37 mg, 72%) as a colorless oil. This compound contains two isomers (alcohol epimers, deriving from 17) and there are two rotamers for each isomer. The product was used directly in the next step. ¹H NMR (400 MHz, CDCl₃) δ 8.33 – 8.01 (1H), 7.21 – 6.45 (1H), 5.90 – 5.59 (2H), 5.50 – 5.32 (1H), 5.19 – 4.91 (3H), 4.29 (s, 1H), 3.86 (1H), 3.49 – 3.44 (3H), 3.41 – 3.37 (3H), 3.31 – 3.22 (1H), 3.07 – 3.00 (3H), 3.00 – 2.81 (2H), 2.55 – 2.39 (2H), 2.33 – 2.17 (2H), 1.88 – 1.78 (1H), 1.73 – 1.65 (1H), 1.12 (3H), 1.02 – 0.95 (3H), 0.93 – 0.88 (9H), 0.88 – 0.81 (3H), 0.80 – 0.74 (3H), 0.10 – 0.04 (6H).

N-((4R,5R,9S,10S,11S,12S,13S,E)-12-((tert-butyldimethylsilyl)oxy)-4,10-dimethoxy-5,9,11,13-tetramethyl-6-oxopentadeca-1,14-dien-1-yl)-N-methylformamide (2)

To a solution of Dess–Martin periodinane (44 mg, 0.1 mmol) in CH₂Cl₂ (1 mL) was added alcohol 19 (37 mg, 0.07 mmol) in CH₂Cl₂ (1 mL). Once the reaction was complete (TLC monitoring), Et₂O (5 mL), saturated aqueous NaHCO₃ (2 mL) and Na₂S₂O₃ (0.5 mL) were added. The organic layer was separated and the aqueous layer was extracted with Et₂O (3 × 5 mL). The combined organic layers were washed with brine, dried over MgSO₄ and concentrated to give crude product ketone (36 mg) that was used directly in the next step without purification.

To a solution of Stryker’s copper hydride reagent ([PPh₃CuH]₆; 69 mg, 0.035 mmol) in 2 mL of degassed toluene was added a solution of the above ketone in toluene (1 mL, degassed) and 1 drop of water via syringe. This mixture was stirred overnight at room temperature, then was diluted with 20 mL of CH₂Cl₂. The organic layer was washed with saturated aqueous NH₄Cl solution, and brine, then dried over MgSO₄, filtered and concentrated. Purification of the crude product by column chromatography (1:1 hexanes-EtOAc) provided product 2 (18 mg, 50% over 2 steps) as a colorless oil. This material was showed no evidence of C(32) epimerization, but was a mixture of formamide rotamers. Otherwise, the spectroscopic properties of this material was the same as described above.

Figure 1.

Structures of selected members of the reidispongiolide-sphinxolide natural products

Scheme 3.

Synthesis of Vinyl Iodide 4 and Elaboration to Aldehyde 16