Conclusion

Progress Toward the Total Synthesis of Zoanthenol

Scheme 11. Endgame for zoanthenol

III. Conclusion

With the goal of establishing a synthetic route to enantiopure caprolactam (–)-33, three routes to the key δ-lactone of type 44 were explored. Our initial plan to derive the desired lactone from the chiral pool was soon abandoned due to preliminary synthetic difficulties. A more modern method utilizing glycidol as the starting material was explored, resulting in successful delivery of the racemic caprolactam 33. Ultimately, enantiopure δ-lactone (–)-37 was obtained by means of a highly diastereoselective and

16

enantioselective hetero-Diels-Alder cyclization. Key features of the subsequent synthesis include a highly diastereoselective cuprate addition and a protecting group strategy for the masking of the reactive amino alcohol moiety. The enantiopure caprolactam (–)-33 generated by the detailed method is expected to be a competent electrophile for coupling with the appropriate nucleophile of alkynyl-tricycle 32. After fragment coupling, only a few synthetic transformations are expected to complete the total synthesis of zoanthenol 1.

Materials and Methods

Unless stated otherwise, reactions were conducted in flame-dried glassware using anhydrous solvents (either freshly distilled or passed through activated alumina columns).

All reactions were conducted under an inert atmosphere of dry nitrogen or argon, unless otherwise stated. All commercially obtained reagents were used as received. When required, commercial reagents were purified following the guidelines of Perrin and Armarego.¹⁹ Reaction temperatures were controlled using an IKAmag temperature modulator. Thin-layer chromatography (TLC) was conducted with E. Merck silica gel 60 F254 pre-coated plates (0.25 mm) and visualized using a combination of UV, anisaldehyde, ceric ammonium molybdate, and potassium permanganate staining. ICN silica gel (particle size 0.032–0.063 mm) was used for flash chromatography using the method described by Still.²⁰

1H NMR spectra were recorded on a Varian Mercury 300 (at 300 MHz), a Varian Inova 500 (at 500 MHz), and are reported relative to residual protio solvent signals.

Data for ¹H NMR spectra are reported as follows: chemical shift (δ ppm), multiplicity (s

= singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant (Hz), and integration. ¹³C NMR spectra were recorded on a Varian Mercury 300 (at 75 MHz) and are reported relative to residual protio solvent signals. Data for ¹³C NMR spectra are reported in terms of chemical shift. IR spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer and are reported in frequency of absorption (cm^-1). Optical rotations were measured with a Jasco P-1010 polarimeter (Na lamp, 589 nm). HPLC analysis was performed on a Hewlet-Packard 1100 Series HPLC (UV detector at 245 nm) equipped

18

with the following Chiralcel columns: OD-H (25 cm), OD guard (5 cm), AD (25 cm), OJ (25 cm) and OB-H (25 cm). High resolution mass spectra were obtained from the California Institute of Technology Mass Spectral Facility.

Preparative Procedures

O O

OTBS

Me₂CuLi Et₂O, O °C

O O

OTBS

84% yield 64

37

β-Me, δ-Lactone (64). MeLi (1.3 M in ether, 5.8 mL, 7.56 mmol) was added to a stirring slurry of CuI (714 mg, 3.89 mmol) in diethyl ether cooled to –78 °C. The vessel was warmed to 0 °C for 15 min, then cooled again to –78 °C. A solution of the α,β- unsaturated lactone 37 (471 mg, 1.95 mmol) in diethyl ether (4 mL) was then carefully added along the cooled inner walls of the reaction flask. After 1 h, the reaction mixture was quenched by the slow addition of saturated aq ammonium chloride (15 mL) at –78

°C. The reaction flask was gradually warmed to ambient temperature for 30 min, then diluted with ether (30 mL). The biphasic mixture was transferred to a separatory funnel and shaken vigorously to dissolve solids. The organic layer was washed with saturated aq ammonium chloride (2 x 20 mL), then brine (1 x 10 mL), dried over magnesium sulfate and concentrated. The resulting material was purified by flash chromatography over silica gel (25% EtOAc:hexane eluent) to yield δ-lactone 64 (422 mg, 84% yield, R_F= 0.20 in 25%

EtOAc:hexane) as a clear oil: ¹H NMR (300 MHz, CDCl₃) δ 4.47-4.40 (m, 1H), 3.70- 3.73 (m, 2H), 2.55 (dd, J=16.3, 5.1 Hz, 1H), 2.18-2.29 (m, 1H), 2.12 (dd, J=16.4, 8.9 Hz, 1H), 1.90-1.99 (m, 1H), 1.52-1.60 (m, 1H), 1.05 (d, J=6.6 Hz, 3H), 0.87 (s, 9H), 0.06 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 171.7, 77.8, 65.1, 38.1, 31.7, 26.2, 24.1, 21.4, 18.6,

201.0950; [α]D20 -25.027° (c=1, CDCl3).

O O

OH

65

Dowex 50X8-100

MeOH 96% yield O

O

OTBS

64

Alcohol 65. The lactone (100 mg, 0.39 mmol) was dissolved in methanol (5.0

mL) and added to a reaction flask equipped with Dowex 50X8-100 cation exchange resin (1.0 g). The mixture was stirred at ambient temperature for 3 h, then filtered. The resin was washed with methanol (2 x 5 mL) and the combined organics were concentrated. The crude material was dried overnight under high vacuum to yield the alcohol 65 (53 mg, 96%

yield, RF= 0.18 in 80% EtOAc:hexane) as a clear oil: ¹H NMR (300 MHz, CDCl3) δ 4.47-4.52 (m, 1H), 3.75 (dd, J=12.3, 3.6 Hz, 1H), 3.66 (dd, J=12.1, 5.8 Hz, 1H), 2.69 (br s, 1H), 2.53-2.58 (m, 1H), 2.13-2.23 (m, 2H), 1.88-1.97 (m, 1H), 1.49-1.57 (m, 1H), 1.08 (d, J=6.0 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 172.3, 78.2, 65.1, 37.8, 31.1, 24.3, 21.4; IR (neat) 1722.4 cm^-1; HRMS (FAB⁺) m/z calc'd for [C7H12O3]⁺: 144.0786, found 144.0787; [α]D20 -162.147° (c=1, CDCl3).

O O

OH 65

phthalamide, PPh₃ DEAD, THF

86% yield

O O

N O O

57

Phthalimide (57). To a stirred solution of alcohol 65 (1.48 g, 10.28 mmol) in tetrahydrofuran (30 mL) was added triphenyl phosphine (2.83 g 10.79 mmol), then

20

phthalimide (1.59 g, 10.76 mmol). Once all reagents had dissolved, the reaction mixture was cooled to 0 °C and DEAD (1.707 mL, 10.79 mmol) was added dropwise to the stirred solution. The reaction flask was then warmed to 30 °C for 12 h, then concentrated. The concentrated reaction mixture was flashed over silica (4:1 hexanes/EtOAc eluent). The resulting solid was recrystalized from dichloromethane to provide phthalimide 57 (2.42 g, 86% yield, R_F= 0.16 in 40% EtOAc:hexane) as a white solid: m.p. 118-120 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.82-7.88 (m, 2H), 7.71-7.76 (m, 2H), 4.74-4.83 (m, 1H), 4.04 (dd, J=15.0, 8.3 Hz, 1H), 3.78 (dd, J=15.0, 5.5 Hz, 1H), 2.63 (dd, J=16.6, 5.4 Hz, 1H), 2.28 (m, 1H), 2.16 (dd, J=16.5, 9.1 Hz, 1H), 1.86 (m, 1H), 1.66 (m, 1H), 1.09 (d, J=6.9 Hz, 3H); ¹³C NMR (300 MHz, CDCl3) δ 170.9, 168.1, 134.4, 132.0, 123.7, 74.1, 41.9, 37.9, 32.8, 24.0, 21.5; IR (neat) 1773.9, 1715.8 cm^-1; HRMS (FAB⁺) m/z calc'd for [C₁₅H₁₆NO₄]⁺: 274.1079, found 274.1076; [α]_D²⁰ - 68.6255° (c=1, CDCl3).

O O

N O O

N N

OMe

O OTBS

O 1. Me(MeO)NH•HCl O

Me3Al, DCM, -5 °C 2. TBSOTf, 2,6-lut.

DCM, 0 °C 72% yield, 2 steps

57 58

Weinreb Amide (58). Trimethylaluminum (2.0 M in toluene, 10.32 mL, 20.64 mmol) was slowly added to a stirred solution of N,O-dimethylhydroxylamine hydrochloride (2.01 g, 16.80 mmol) in dichloromethane (40 mL) cooled to -10 °C The solution was stirred for 20 min before the dropwise addition of the Mitusunobu adduct 57 (2.26 g, 8.23 mmol) in dichloromethane (10 mL). The reaction temperature was maintained at -10 °C for 30 min before the addition of saturated sodium bicarbonate (20

reaction mixture was diluted with dichloromethane (30 mL) and brine (20 mL) to dissipate emulsions during extraction. The crude was transferred to a separatory funnel and the organic layer was separated. The aqueous layer was extracted with dichloromethane (2 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL), then dried and concentrated to a volume of 10 mL over a rotovap pot temperature of 15 °C.

The crude amide was diluted with dichloromethane (20 mL) and cooled to 0 °C.

To the cooled, stirred solution was added TBSOTf (3.79 mL, 16.51 mmol) followed by 2,6-lutidine (1.442 mL, 12.38 mmol). The solution was maintained at 0 °C for 20 min, then quenched by addition of saturated ammonium chloride (20 mL). The biphasic mixture was allowed to warm to room temperature while stirring vigorously, then transferred to a separatory funnel. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2 x 20 mL). The combined organics were washed with saturated sodium bicarbonate solution (1 x 15 mL) and water (1 x 15 mL), then dried over magnesium sulfate and concentrated. The resulting crude product was flashed over silica gel (20% EtOAc:hexanes eluent) to provide Weinreb amide 58 (2.58g, 72% yield, R_F= 0.30 in 40% EtOAc:hexane) as an oil: ¹H NMR (300 MHz, CDCl₃)δ 7.82 (dd, J=5.4, 3.1 Hz, 2H), 7.70 (dd, J=5.6, 2.9 Hz, 2H), 4.05-4.14 (m, 1H), 3.68-3.78 (m, 2H),

3.65 (s, 3H), 3.14 (s, 3H), 2.38-2.45 (m, 1H), 2.18-2.29 (m, 1H), 1.51-1.60 (m, 1H), 1.38- 1.47 (m, 1H), 1.03 (d, J=6.3 Hz, 3H), 0.76 (s, 9H), -0.01 (s, 3H), -0.20 (s, 3H); ^{1 3}C NMR (300 MHz, CDCl₃) δ 168.5, 134.1, 132.3, 123.3, 68.3, 61.5, 44.0, 43.7, 39.7, 32.3, 26.9, 26.0, 20.8, 18.1, -4.3, -4.4; IR (neat) 3473.5, 2955.4, 2857.3, 1774.2, 1714.5, 1660.3

22

cm^-1; HRMS m/z calc'd for [C_{2 3}H_{3 7}N₂O₅Si]⁺: 449.2472, found 449.2470; [α]_D^{2 0} -29.7°

(c=1, CDCl₃).

OTBS

O O

N N

OMe O

HN O

TBSO H2NNH2•H2O

EtOH/ H₂O 81% yield

58 59