Formal Synthesis of the Bryostatin Northern Hemisphere: Asymmetric Synthesis of the B Ring and C1-C9 Fragment

Abstract

A formal synthesis of the top half fragment of bryostatin 11 has been developed. Stereoselective construction of the B ring was achieved by using a ring-closing metathesis reaction in conjunction with asymmetric glycolate alkylation. Furthermore, the C1-C9 fragment was synthesized by Brown allylation, chelation-controlled aldol condensation, and Saksena-Evans reduction to construct all stereogenic centers.

Key words

bryostatin 11 - asymmetric glycolate alkylation - ring-closing metathesis

References and Notes

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1

Current address: K. Nakagawa-Goto, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

6

For current information, see: http://clinicaltrials.gov.

17

N -Acyloxazolidinone 13 A round-bottom flask was charged with NaH (60% on mineral oil, 1.52 g, 39.3 mmol) and washed with hexanes to remove the mineral oil. The NaH was then dissolved in THF (15 mL) and cooled to 0 ˚C. Allylic alcohol 11 (2.27 g, 12.6 mmol) in THF (10 mL) was added and stirred at r.t. for 10 min. The mixture was cooled to 0 ˚C, and bromoacetic acid (1.84 g, 13.5 mmol) in THF (5 mL) was added dropwise via an addition funnel over 10 min with evolution of hydrogen gas. The reaction mixture was warmed to r.t. and stirred overnight. The cloudy reaction mixture was quenched slowly with H₂O at 0 ˚C. The organic layer was separated. The aqueous layer was adjusted to pH 4 with 1 N HCl aq solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to obtain the crude glycolic acid (2.8 g) as an orange oil, which was dissolved in dry Et₂O (40 mL). Et₃N (2.0 mL, 14.4 mmol) was added slowly, and the mixture was cooled to -78 ˚C. Pivaloyl chloride (1.6 mL, 13.0 mmol) was added dropwisee. After 5 min, the mixture was warmed to 0 ˚C, where it was stirred for 1 h and subsequently recooled to -78 ˚C. In a separate flask, (S)-(+)-4-iso-propyloxazolidin-2-one (1.70 g, 13.1 mmol) was dissolved in THF (20 mL) and cooled to -78 ˚C. n-BuLi (1.3 M in hexanes, 11.5 mL, 14.9 mmol) was added dropwise via syringe, and the mixture was stirred for 10 min. The lithiated oxazolidinone 12 was added via cannula to the mixed anhydride, and the reaction was stirred for an additional 10 min before being warmed to 0 ˚C, where stirring continued for 3 h. The reaction was quenched by the addition of H₂O and extracted twice with EtOAc. The combined organic layers were washed with brine and dried over Na₂SO₄. Concentration in vacuo and purification by flash chroma-tography gave acyl oxazolidinone 13 (1.98 g, 45% from 11) as a colorless oil: ^¹H NMR (400 MHz, CDCl₃): δ = 7.39-7.30 (m, 3 H), 7.30-7.24 (m, 2 H), 5.85-5.74 (m, 1 H), 5.39-5.26 (m, 2 H), 4.78 (AB, J = 17.9 Hz, 2 H), 4.73 (AB, J = 11.5 Hz, 2 H), 4.59 (s, 2 H), 4.40-4.33 (m, 1 H), 4.24-4.18 (m, 2 H), 4.18-4.10 (m, 1 H), 3.67 (dd, J = 10.2, 6.6 Hz, 1 H), 3.58 (dd, J = 10.2, 4.2 Hz, 1 H), 2.48-2.37 (m, 1 H), 0.90 (d, J = 7.0 Hz, 3 H) 0.85 (d, J = 7.0 Hz, 3 H). HRMS: m/z calcd for C₁₉H₂₅NO₅Na [M⁺ + Na]: 370.1625; found: 370.1607.

18

Diene 6 Into a flask equipped with an addition funnel was added sodium bis(trimethylsilyl)amide (0.75 M in toluene, 15 mL, 11.3 mmol). THF (30 mL) was added, and the solution was cooled to -78 ˚C. Acyl oxazolidinone 13 (2.42 g, 7.0 mmol) in THF (10 mL) was added dropwise via an addition funnel. After stirring for 30 min at -78 ˚C, allyl iodide 14 (5.05 g, 22.1 mmol) in THF (10 mL) was added via syringe. After 10 min, the reaction was warmed to -45 ˚C and stirred at that temperature for 1 h. The reaction was quenched by the addition of sat. NH₄Cl and warmed to r.t. The aqueous
layer was extracted twice with 50% EtOAc-hexanes. The combined organic layers were washed with brine and dried over Na₂SO₄. Concentration in vacuo and purification by flash chromatography provided diene 6 (2.29 g, 74%) as a colorless oil. ^¹H NMR (400MHz, CDCl₃): δ = 7.40-7.22 (m, 5 H), 5.83-5.71 (m, 1 H), 5.57-5.50 (m, 1 H), 5.37 (d, J = 17.2 Hz, 1 H), 5.22 (d, J = 10.5 Hz, 1 H), 4.96-4.90 (m, 2 H), 4.54-4.43 (m, 2 H), 4.28-4.07 (m, 3 H), 3.97 (dd, J = 9.0, 3.1 Hz, 1 H), 3.64-3.50 (m, 3 H), 3.41 (s, 3 H), 2.66 (dd, J = 14.2, 3.8 Hz, 1 H), 2.46 (dd, J = 14.2, 8.5 Hz, 1 H), 2.34-2.21 (m, 1 H), 0.83 (d, J = 6.9 Hz, 3 H), 0.80 (d, J = 6.9 Hz, 3 H). ^¹³C NMR (400 MHz, CDCl₃): δ = 172.8, 156.5, 153.7, 138.7, 128.6, 128.5, 127.7, 127.6, 127.0, 118.0, 93.9, 87.7, 81.2, 75.8, 74.5, 72.9, 63.6, 58.3, 56.3, 39.2, 28.3, 18.0, 14.8. [α]_D ^²³ +68.9 (c 3.14, CH₂Cl₂). HRMS: m/z calcd for C₂₄H₃₃NO₇Na [M⁺ + Na]: 470.2155; found: 470.2192.

20

Pyrane 16 Into a flask equipped with a reflux condenser was added diene 6 (2.09 g, 4.68 mmol) in CH₂Cl₂ (1 L). Argon was bubbled through the stirring solution for 1 h. The solution was heated to reflux and Grubbs second-generation catalyst (0.411 g, 0.49 mmol) was added in one portion. The reaction was refluxed for 24 h and cooled to r.t. The air was bubbled into the reaction mixture and stirred for 3 h at r.t. Concentration in vacuo and purification by flash chroma-tography provided pyrane 16 (1.72 g, 88%) as a colorless oil: ^¹H NMR (400 MHz, CDCl₃): δ = 7.36-7.34 (m, 3 H), 7.30-7.26 (m, 2 H), 5.30 (dd, J = 10.7, 3.9 Hz, 1 H), 4.98 (d, J = 6.2 Hz, 1 H), 4.91 (d, J = 6.2 Hz, 1 H), 4.90-4.88 (m, 1 H), 4.62 (d, J = 12.1 Hz, 1 H), 4.57 (d, J = 12.1 Hz, 1 H), 4.56-4.50 (m, 1 H), 4.50-4.44 (m, 1 H), 4.32 (t, J = 9.2 Hz, 1 H), 4.23 (dd, J = 9.2, 2.9 Hz, 1 H), 3.60 (dd, J = 10.2, 6.5 Hz, 1 H), 3.48 (dd, J = 10.2, 4.8 Hz, 1 H), 3.42 (s, 3 H), 2.57-2.47 (m, 1 H), 2.45-2.32 (m, 2 H), 0.92 (d, J = 7.0 Hz, 3 H), 0.88 (d, J = 7.0 Hz, 3 H). HRMS: m/z calcd for C₂₂H₂₉NO₇Na [M⁺ + Na]: 442.1842; found: 442.1860.

21

Acetal 17
Pyrane 16 (61.2 mg, 0.15 mmol) was dissolved in THF (1.2 mL) and MeOH (0.4 mL). Methylorthoformate (0.25 mL, 2.29 mmol), PPTS (2.1 mg, 0.01 mmol), and PTSA (1.9 mg, 0.01 mmol) were added to the mixture, which was then refluxed for 1 h. The reaction mixture was quenched with sat. NaHCO₃ and extracted with EtOAc. The organic layer was washed with brine and dried over Na₂SO₄. Concentration in vacuo and purification by flash chromatography provided acetal 17 (51.5 mg, 82%) as a colorless oil: ^¹H NMR (400 MHz, CDCl₃): δ = 7.38-7.30 (m, 3 H), 7.30-7.26 (m, 2 H), 5.22 (dd, J = 11.7, 2.2 Hz, 1 H), 4.60 (d, J = 10.2 Hz, 1 H), 4.56 (d, J = 10.2 Hz, 1 H), 4.50-4.44 (m, 1 H), 4.31 (t, J = 8.7 Hz, 1 H), 4.23 (dd, J = 9.2, 3.1 Hz, 1 H), 3.92-3.85 (m 1 H), 3.60 (dd, J = 10.3, 5.9 Hz, 1 H), 3.50 (dd, J = 10.3, 4.5 Hz, 1 H), 3.29 (s, 3 H), 3.23 (s, 3 H), 2.40-2.30 (m, 2 H), 2.60-1.98 (m, 1 H), 1.62-1.54 (m, 1 H), 1.45 (t, J = 12.5 Hz, 1 H), 0.91 (d, J = 7.0 Hz, 3 H), 0.87 (d, J = 7.0 Hz, 3 H). HRMS: m/z calcd for C₂₂H₃₁NO₇Na [M⁺ + Na]: 444.1998; found: 444.2040.

22

Olefin 19
To a solution of 17 (1.23 g, 2.92 mmol) in Et₂O (15 mL) and MeOH (1.0 mL), lithium borohydride (2 M solution in THF, 7.0 mL, 14.0 mmol) was added at 0 ˚C. The reaction mixture was stirred for 1 h and then quenched with 3 N NaOH aq. The reaction mixture was allowed to warm to r.t. The organic layer was separated, and the organic layer was washed with 3 N NaOH aq. The combined aqueous layers were re-extracted with Et₂O. The combined organic layers were washed with brine and dried over Na₂SO₄. Concentration in vacuo and purification by flash chroma-tography provided 891.2 mg of alcohol 18 including the removed oxazolidinone (the ratio was 3:2 calcd from ^¹H NMR). It was found that the alcohol could be carried on without further purification. Into a flask equipped with a low-temperature thermometer was added CH₂Cl₂ (3.0 mL) and oxalyl chloride (2.0 M in CH₂Cl₂, 3.0 mL, 6.0 mmol). After cooling to -78 ˚C, DMSO (0.85 mL, 12.0 mmol) in CH₂Cl₂ (1.0 mL) was added dropwise via syringe. After stirring for 10 min, the resulting primary alcohol in CH₂Cl₂ (3.0 mL) was added dropwise via syringe. After stirring for 15 min, Et₃N (2.1 mL, 15.1 mmol) was added slowly via syringe. The cooling bath was removed after 20 min, and the reaction was allowed to warm to 0 ˚C. The reaction mixture was quenched with H₂O. The organic layer was separated and washed with H₂O. The combined aqueous layers were re-extracted with CH₂Cl₂. The combined organic layers were washed with brine, and dried over Na₂SO₄. Concentration in vacuo and purification by flash chromatography provided 660.1 mg of aldehyde as colorless oil, which was a mixture with the cleaved oxazolidinone (the ratio was 21:10 calcd from ^¹H NMR) and used in the next reaction without further purification.
To a solution of Ph₃PCH₃Br (2.49 g, 7.0 mmol) in toluene (15.0 mL), KOt-Bu (520.0 mg, 4.6 mmol) in THF (3.0 mL) was added, and the mixture was stirred at r.t. for 1.5 h. To the resulting yellow suspension, aldehyde (660.1 mg) in toluene (7.0 mL) was added, and the mixture was stirred at r.t. overnight. The reaction was quenched by the addition of sat. NH₄Cl and warmed to r.t. The aqueous layer was extracted with EtOAc. The organic layer was washed with brine and dried over Na₂SO₄. Concentration in vacuo and purification by flash chromatography provided 498.9 mg (60%, 3 steps yields from 17) of olefin 19 as colorless oil: Colorless oil. [α]_D ^²³ +1.09 (c 1.83, CH₂Cl₂). IR (film): ν_max = 2938, 2861, 2828, 2361, 2339, 1458, 1358, 1314, 1075, 1049, 924, 737, 698 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.36-7.31 (4 H, m, ArH), 7.30-7.25 (1 H, m, ArH), 5.88 (1 H, ddd, J = 5.7, 10.5, 16.8 Hz, CH₂=CH), 5.27 (1 H, d, J = 16.8 Hz, CHH=CH), 5.12 (1 H, d, J = 10.5 Hz, CHH=CH), 4.56 (2 H, s, CH₂Ph), 4.06-4.00 (1 H, m, 6-H), 3.82-3.74 (1 H, m, 2-H), 3.56 (1 H, dd, J = 5.6, 10.2 Hz, CH₂OBn), 3.48 (1 H, dd, J = 4.6, 10.2 Hz, CH₂OBn), 3.22 (3 H, s, OCH₃), 3.19 (3 H, s, OCH₃), 2.06-1.96 (2 H, m, 3- and 5-H_eq), 1.38 (2 H, dd, J = 11.9, 12.3 Hz, 3- and 5-H_ax). ^¹³C NMR (400 MHz, CDCl₃): δ = 138.5, 128.6, 127.9, 127.8, 115.6, 99.0, 75.2, 73.7, 73.6, 73.1, 47.9, 47.6, 38.7, 35.4. HRMS: m/z calcd for C₁₇H₂₄O₄Na [M⁺ + Na]: 315.1572; found: 315.1580.

24

PMB Ether 21 To a solution of 4-ICr₂B-allyl in Et₂O (ca. 270 mmol), aldehyde 20 (8.25 g, 43.0 mmol), in Et₂O (15.0 mL) was added slowly via additional funnel at -78 ˚C. After stirring for 2 h, the mixture was allowed to warm to r.t. Then aq NaOH (3 M, 60 mL) was added carefully, followed by H₂O₂ (30% aq, 30 mL). The biphasic mixture was refluxed without condenser to evaporate Et₂O, and THF (60 mL) was added. The mixture was refluxed overnight, then diluted with H₂O and the phases separated. The aqueous layer was back extracted with Et₂O. The combined organic layers were washed with brine and dried over Na₂SO₄. Concentration in vacuo and purification by flash chromatography provided allylic alcohol (9.0 g) including a small amount of 4-ICr-OH. The resulting alcohol (9.0 g) in THF (10.0 mL) was added to a suspension of KH (30% in mineral oil, 7.96 g, 59.7 mmol) in THF (50.0 mL) at 0 ˚C. After stirring at r.t. for 15 min, the mixture was cooled to 0 ˚C. PMBCl (11.0 mL, 80.9 mmol) was added, and the mixture was stirred at r.t. overnight. The mixture was quenched with H₂O and extracted with EtOAc (3×). The combined organic layers were washed with brine and dried over Na₂SO₄. Concentration in vacuo and purification by flash chromatography provided PMB ether 21 (10.07 g, 70%, 2 steps yield from 20) as a colorless oil. ^¹H NMR (400 MHz, CDCl₃): δ = 7.36-7.30 (m, 4 H), 7.30-7.25 (m, 1 H), 7.22 (d, J = 8.5 Hz, 2 H), 6.84 (d, J = 8.5 Hz, 2 H), 6.02-5.89 (m, 1 H), 5.14-5.06 (m, 1 H), 5.05-5.00 (m, 1 H), 4.55 (d, J = 10.7 Hz, 1 H), 4.49 (d, J = 12.3 Hz, 1 H), 4.45 (d, J = 12.3 Hz, 1 H), 4.39 (d, J = 10.7 Hz, 1 H), 3.79 (s, 3 H), 3.47 (dd, J = 8.6, 3.5 Hz, 1 H), 3.39 (d, J = 8.6 Hz, 1 H), 3.14 (d, J = 8.6 Hz, 1 H), 2.38-2.20 (m, 2 H), 0.95 (s, 3 H), 0.94 (s, 3 H). ^¹³C NMR (400 MHz, CDCl₃): δ = 159.2, 139.1, 137.6, 131.7, 129.3, 128.5, 127.7, 127.6, 116.2, 113.8, 83.1, 77.61, 74.0, 73.3, 55.4, 40.2, 35.7, 22.3, 20.8. [α]_D ^²³ +15.57 (c 4.74, CH₂Cl₂). HRMS: m/z calcd for C₂₃H₃₀O₃Na [M⁺ + Na]: 377.2087; found: 377.2081.

26

Hydroxy Ketone 24
To a solution of (i-Pr)₂NH (1.5 mL, 10.7 mmol) in THF (3.0 mL), n-BuLi (1.4 M in hexane, 7.4 mL, 10.7 mmol) was added dropwise at -30 ˚C. After stirring for 10 min, the mixture was cooled to -78 ˚C, and a solution of 23 (3.54 g, 10.9 mmol) in THF (5.0 mL) was added slowly. The mixture was stirred for 2 h, and a solution of aldehyde 22 (1.74 g, 4.9 mmol) in THF (5.0 mL) was added slowly. After stirring for 15 min, the mixture was treated according to Vandewalle’s procedure to provide hydroxy ketone 24 (2.33 g, 70%) as a colorless oil. ^¹H NMR (400 MHz, CDCl₃): δ = 7.68-7.60 (m, 4 H), 7.30-7.25 (m, 11 H), 7.23 (d, J = 8.6 Hz, 2 H), 6.83 (d, J = 8.6 Hz, 2 H), 4.62 (d, J = 10.9 Hz, 1 H), 4.56 (d, J = 10.9 Hz, 1 H), 4.51 (d, J = 12.1 Hz, 1 H), 4.46 (d, J = 12.1 Hz, 1 H), 4.29-4.20 (m, 1 H), 3.92 (t, J = 6.1 Hz, 2 H), 3.81-3.75 (m, 1 H), 3.77 (s, 3 H), 3.40 (d, J = 8.7 Hz, 1 H), 3.16 (d, J = 8.7 Hz, 1 H), 2.63-2.56 (m, 4 H), 1.66-1.56 (m, 1 H), 1.52-1.40 (m, 1 H), 1.03 (s, 9 H), 0.95 (s, 3 H), 0.94 (s, 3 H). ^¹³C NMR (400 MHz, CDCl₃): δ = 211.2, 159.2, 138.9, 135.7, 133.5, 131.6, 130.0, 129.5, 128.5, 127.9, 127.7, 127.6, 113.9, 79.4, 74.8, 73.3, 64.9, 59.6, 55.5, 50.9, 46.3, 40.0, 37.6, 31.1, 27.0, 22.4, 20.8, 19.3. [α]_D ^²³ -3.63 (c 3.55, CH₂Cl₂). HRMS: m/z calcd for C₄₂H₅₄O₆SiNa [M⁺ + Na]: 705.3587; found: 705.3588.

29

Acetonide 25
A suspension of Me₂NHB(OAc)₃ (1.68 g, 6.39 mmol) in MeCN (5.0 mL) and AcOH (5.0 mL) was stirred at r.t. for 30 min under argon. The mixture was cooled to -45 ˚C, and hydroxy ketone 24 (773.7 mg, 1.14 mmol) in MeCN (5.0 mL) solution was then added. After stirring at -45 ˚C for 24 h, the mixture was quenched with 10% Rochelle’s salts and extracted with CH₂Cl₂ (3×). The combined organic layers were washed with brine and dried over Na₂SO₄. Concentration in vacuo and purification by flash chroma-tography afforded diol (760.8 mg, 98%, anti/syn = 7.6:1 mixture). To a solution of diol (614.0 mg, 0.9 mmol) in THF (5.0 mL), 2,2-dimethoxypropane (5.0 mL, excess) and PPTS (25.9 mg, 0.1 mmol) were added. After stirring at r.t. overnight, the mixture was quenched with sat. NaHCO₃. The whole was extracted with EtOAc (3×). The combined organic layers were washed with brine and dried over Na₂SO₄. Concentration in vacuo and purification by flash chromatography provided acetonide 25 (626.4 mg, 96%) as a colorless oil. Further purification by flash chromatography (CH₂Cl₂-hexane-Et₂O = 4:1:0.2 then 35% EtOAc-hexane) afforded anti-acetonide (553.6 mg) and syn-acetonide (72.8 mg) as a colorless oil. ^¹H NMR (400 MHz, CDCl₃): δ = 7.69-7.63 (m, 4 H), 7.44-7.30 (m, 10 H), 7.30-7.24 (m, 1 H), 7.21 (d, J = 8.6 Hz, 2 H), 6.84 (d, J = 8.6 Hz, 2 H), 4.60-4.43 (m, 4 H), 4.15-4.02 (m, 2 H), 3.84-3.75 (m, 1 H), 3.79 (s, 3 H), 3.63-3.64 (m, 2 H), 3.38 (d, J = 8.6 Hz, 1 H), 3.16 (d, J = 8.6 Hz, 1 H), 1.79-1.50 (m, 4 H), 1.45-1.30 (m, 2 H), 1.38 (s, 3 H), 1.37 (s, 3 H), 1.04 (s, 9 H), 0.95 (s, 6 H). ^¹³C NMR (400 MHz, CDCl₃): δ = 159.2, 139.1, 135.8, 135.8, 134.2, 134.1, 131.8, 131.1, 129.8, 129.0, 128.5, 127.8, 127.8, 127.7, 127.6, 113.9, 100.36, 79.6, 77.6, 74.5, 73.3, 63.9, 63.5, 60.3, 55.5, 40.1, 39.3, 39.1, 38.9, 38.4, 30.6, 29.9, 29.1, 27.1, 25.8, 25.5, 23.9, 23.2, 22.3, 21.0, 19.4, 14.3, 11.2. [α]_D ^²³ -3.82 (c 2.49, CH₂Cl₂). HRMS: m/z calcd for C₄₅H₆₀O₆SiNa [M⁺ + Na]: 747.4051; found: 747.4016.

31

Similar coupling was successfully performed by Hale, see ref. 12b.