Spiroleucettadine

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Strategies, Setbacks and Successes in the Synthesis of (-)-Spiroleucettadine Richard A Lamb, Nigel T. Lucas, Guillaume Lessene, and Bill Corey Hawkins J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01404 • Publication Date (Web): 13 Jul 2018 Downloaded from http://pubs.acs.org on July 14, 2018

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The Journal of Organic Chemistry

Strategies, Setbacks and Successes in the Synthesis of (−)-Spiroleucettadine Richard A. Lamb,a Nigel, T. Lucas,a Guillaume Lessene*,b,c and Bill C. Hawkins*,a a

Department of Chemistry, University of Otago, PO Box 56, Dunedin, New Zealand

b

The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, 3052, Australia c

Department of Medical Biology and Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville 3050, Australia [email protected] [email protected]

Graphical Abstract

1 ACS Paragon Plus Environment

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Abstract Various strategies toward the synthesis of the marine natural product (-)-spiroleucettadine are described. In the original strategy, a biomimetic inspired oxidation of a 2-imidazoline scaffold uncovered unexpected reactivity, where benzylic oxidation followed by a BaeyerVilliger was observed. The second generation approach examined oxidative dearomatization of the phenol ring system first, where a competing spirocyclization process was uncovered. Efforts to forge the scaffold via a carbocation mediated benzyl migration were unsuccessful. Highlights of the successful synthesis include two consecutive hypervalent iodine reactions: the first formed the spirocyclic centre and the second facilitated installation of an acetate group at the C-5 position to allow for subsequent introduction of the methyl amine side chain. Introduction Marine natural products continue to be an invaluable source of biologically active and structurally fascinating compounds. Among these is spiroleucettadine which was isolated from the Leucetta sea sponge in 2004.1 The discovery of spiroleucettadine was met with international interest as it exhibited a novel structure featuring a highly strained 5,5-transfused 2-amino imidazole-oxolane core that was seemingly able to sustain an unusual orthoamide type functional group. Very few natural products contain 5,5-trans-fused bicyclic ring systems as opposed to the more common cis-isomer, however some examples have been reported, the most famous being palau’amine.2-6 Additionally, spiroleucettadine was also shown to possess moderate anti-bacterial activity (minimum inhibitory activity MIC 250 °C. 1H NMR (400 MHz, CDCl3) δ: 7.44-7.13 (m, 10H), 7.08 (d, J= 9 Hz, 1H), 6.91 (d,

J= 9 Hz, 1H), 5.05 (s, 2H), 3.82 (s, 2H), 3.69 (s, 2H), 2.98 (s, 3H).

13

C NMR (100 MHz,

CDCl3) δ: 157.6, 154.4, 137.9, 137.0, 130.6, 129.5, 128.7, 128.6, 127.9, 127.4, 126.7, 117.4, 117.1, 115.0, 70.0, 29.7, 29.2. νmax (ATR-IR) cm-1 3061, 2920, 1709, 1609. HRMS-ESI: calcd. C25H24N2NaO2 [M + Na+]: 407.1730, found 407.1698.

tert-Butyl (1-(4-(benzyloxy)phenyl)-4-(4-methoxyphenyl)-3-oxobutan-2-yl)carbamate (16) 4-methoxybenzyl ketone 16 was prepared using general procedure 1 from the known Weinreb amide 1413 (3.00 g, 7.23 mmol) in THF using a 0.33 M solution paramethoxybenzyl magnesium chloride (44 mL, 14.5 mmol). The title compound was obtained as a white solid (2.30 g, 67%). [α]25D = +18.6 (c = 1.93, CHCl3). M.P. 103-104°C. 1H NMR (400 MHz, CDCl3) δ: 7.44-7.29 (m, 5H), 7.02 (m, 4H), 6.90 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 5.08 (d, J = 7.7 Hz, 1H), 5.04 (s, 2H), 4.58 (m, 1H), 3.79 (s, 3H), 3.62 (ABq, ∆δAB = 25.6 Hz, J = 16.4 Hz), 2.95 (m, 2H), 1.43 (s, 9H).

13

C NMR (100 MHz, CDCl3) δ:

207.2, 158.8, 157.9, 155.3, 137.1, 130.7, 130.4, 128.7, 128.5, 128.1, 127.6, 125.2, 115.1, 114.2, 80.0, 70.1, 59.6, 55.4, 47.2, 37.2, 28.4. νmax (ATR-IR) cm-1 3351, 2980, 1718, 1613, 1512. HRMS-ESI: calcd. C29H33NNaO5 [M + Na+]: 498.2251, found 498.2251.

5-(4-Benzyloxybenzyl)-4-(4-methoxybenzyl)-3-methyl-imidazol-2-one (19) 23 ACS Paragon Plus Environment


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The primary amine HCl salt was prepared from benzyl ketone 16 (1.35 g, 2.83 mmol) using to general procedure 5: white solid (1.16 g, 74%). [α]25D = + 61.2 (c = 1.03, MeOH). M.P. 130-131°C. 1H NMR (400 MHz, CDCl3) δ: 8.35 (br s, 3H),7.46-7.31 (m, 5H), 7.23 (d, J = 8.6 Hz, 2H), 7.23 (m, 4H), 6.87 (d, J = 8.7 Hz, 2H), 5.10 (s, 3H), 4.40 (t, J = 6.4 Hz, 1H), 3.87 and 3.69 (ABq, J =17.3 Hz, 2H), 3.73 (s, 3H), 3.15 and 3.08 (two dd, J =14.3, 6.9 Hz, 2H). 13

C NMR (100 MHz, CDCl3) δ: 204.3, 158.2, 157.6, 137.6, 130.8, 130.7, 128.4, 127.9, 127.7,

126.7, 125.1, 115.0, 113.8, 69.2, 58.5, 55.1, 45.5, 39.2, 34.3. νmax (ATR-IR) cm-1 3361, 2864, 1724, 1612,1511. HRMS-ESI: calcd. C24H26NO3 [M - Cl-]: 376.1907, found 376.1917. To a solution of the above amine salt (854 mg, 2.08 mmol) and N-methyl carbamoylimidazole (520 mg, 4.16 mmol) in THF was added trimethylamine (0.58 ml, 4.16 mmol).22 The solution was stirred at room temperature for 18 h before being concentrated and subjected to silica gel column chromatography to afford the title compound as a white solid (299 mg, 33%). M.P. > 250°C. 1H NMR (400 MHz, CDCl3) δ: 7.43-7.31 (m, 5H), 7.20 (d, J = 7.7 Hz, 2H), 6.97 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 6.97 Hz, 2H), 6.83 (d, J = 7.7 Hz, 2H), 5.87 (br s, 1H), 5.03 (s, 2H), 3.85 (s, 2H), 3.79 (s, 5H), 3.06 (s, 3H).

13

C NMR (100 MHz,

CDCl3) δ: 158.8, 157.9, 137.1, 129.7, 129.0, 128.7, 128.3, 128.1, 127.6, 121.0, 119.9, 115.4, 114.5, 70.0, 55.47, 29.52, 28.5, 28.2. νmax (ATR-IR) cm-1 3033, 2833, 1676, 1609, 1509. HRMS-ESI: calcd. C26H26N2NaO3 [M + Na+]: 437.1836, found 437.1833.

tert-Butyl 4-benzyl-5-(4-(benzyloxy)benzyl)-3-methyl-2-oxo-imidazolone-1-carboxylate (20) Compound 20 was prepared according to general procedure 2 from compound 18 (92 mg, 0.226 mmol). The title compound was obtained as light brown oil (88 mg, 76%). 1H NMR (400 MHz, CDCl3) δ: 7.42-7.21 (m, 12H), 7.13 (d, J = 7 Hz, 2H), 7.02 (d, J = 8 Hz, 2H), 6.87 (d, J = 8 Hz, 2H), 5.04 (s, 2H), 4.06 (s, 2H), 3.82 (s, 2H), 2.99 (s, 3H), 1.38 (s, 9H). 13C NMR (100 MHz, CDCl3) δ: 157.3, 151.9, 148.5, 137.1, 136.8, 131.2, 128.9, 128.9, 128.6, 128.6, 128.0, 127.95, 127.5, 127.1 120.8, 116.4, 114.9, 84.1, 70.1, 29.3, 29.1, 27.74, 27.7. νmax (ATR-IR) cm-1 3061, 1771, 1720, 1508. HRMS-ESI: calcd. C30H32N2NaO4 [M + Na+]: 507.2254, found 507.2232.

tert-Butyl

5-(4-(benzyloxy)benzyl)-4-(4-methoxybenzyl)-3-methyl-2-oxo-imidazolone-1-

carboxylate (21)


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Compound 21 was prepared according to general procedure 2 from compound 19 (266 mg, 0.642 mmol). The title compound was obtained as a light brown oil (248 mg, 72%). 1H NMR (400 MHz, CDCl3) δ: 7.42-7.30 (m, 5H), 7.03 (d, J = 8.9 Hz, 2H), 7.01 (d, J = 8.9 Hz, 2H), 6.86 (d, J = 8.9 Hz, 2H), 6.81 (d, J = 8.9 Hz, 2H), 5.03 (s, 2H), 4.05 (s, 2H), 3.77 (s, 3H), 3.75 (s, 2H), 1.37 (s, 9H). 13C NMR (100 MHz, CDCl3) δ: 158.6, 157.3, 151.9, 148.3, 137.1, 131.3, 128.9, 128.87, 128.6, 128.0, 127.4, 121.2, 116.2, 115.0, 114.3, 84.0, 70.1, 55.4, 29.3, 28.2, 27.7. νmax (ATR-IR) cm-1 2980, 1770, 1658, 1454. HRMS-ESI: calcd. C31H34N2NaO5 [M + Na+]: 537.2360, found 537.2364.

tert-Butyl 4-benzyl-5-(4-hydroxybenzyl)-3-methyl-2-oxo-imidazole-1-carboxylate (22) Compound 22 was prepared according to general procedure 6 starting from compound 20 (26 mg, 0.0513 mmol). The title compound was obtained as a colourless foam (19 mg, 90%). 1H NMR (400 MHz, CDCl3) δ: 7.32-7.17 (m, 3H), 7.11 (d, J =7.22, 2H), 6.93 (s, 1H), 6.91 (d, J = 8.5 Hz, 2H), 6.74 (d, J = 8.5 Hz, 2H), 4.04 (s, 2H), 3.81 (s, 2H), 2.99 (s, 3H), 1.34 (s, 9H). 13

C NMR (100 MHz, CDCl3) δ: 155.0, 152.2, 148.2, 136.7, 130.1, 129.0, 128.8, 127.1, 121.0,

116.9, 115.5, 84.5, 29.3, 29.1, 27.9, 27.7. νmax (ATR-IR) cm-1 3266, 2980, 1766, 1694, 1594. HRMS-ESI: calcd. C23H26N2NaO4 [M + Na+]: 417.1785; found 417.1759.

tert-Butyl

5-(4-hydroxybenzyl)-4-(4-methoxybenzyl)-3-methyl-2-oxo-2,3-imidazole-1-

carboxylate (23) Phenol 23 was prepared according to general procedure 6 from compound 21 (10 mg, 0.0186 mmol) scale in MeOH. The title compound was obtained as a white film (7 mg, 87%). 1H NMR (400 MHz, CDCl3) δ: 7.02 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 6.74 (d, J = 8.7 Hz, 2H), 4.04 (s, 2H), 3.77 (s, 3H), 3.72 (s, 2H), 2.99 (s, 3H), 1.34 (s, 9H). 13C NMR (100 MHz, CDCl3) δ: 158.7, 155.1, 152.2, 148.4, 130.7, 130.0, 129.7, 129.0, 128.7, 128.6, 121.3, 116.7, 115.5, 114.4, 84.6, 55.4, 29.3, 28.3, 27.9, 27.8, 27.7. νmax (ATR-IR) cm-1 3277, 2980, 1768, 1697, 1594. HRMS-ESI: calcd. C24H28N2NaO5 [M + Na+]: 447.1890, found 447.1903.



tert-Butyl

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5-(4-(benzyloxy)benzyl)-5-hydroxy-3-methyl-2,4-dioxoimidazolidine-1-

carboxylate (25) and tert-butyl 4-benzoyl-5-(4-(benzyloxy)benzyl)-4,5-dihydroxy-3-methyl2-oxoimidazolidine-1-carboxylate (26) To a solution of 20 (100 mg, 0.206 mmol) in acetone (2 mL) was added mCPBA (55% with 41% water and 4% m-Cl-benzoic acid) (64 mg, 0.206 mmol) at 0°C. The reaction was stirred for 1h, and was quenched with sat. NaHCO3(aq). The mixture was partitioned between EtOAc (5 mL) and water (5 mL) and the aqueous layer was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over MgSO4 and concentrated

in vacuo. The crude NMR showed starting material still present in the mixture. The crude mixture was taken up in acetone (2 mL) to which was added mCPBA (55% with 41% water and 4% m-Cl-benzoic acid) (172 mg, 0.618 mmol) at 0 °C and the reaction was stirred for 3h and quenched with sat. NaHCO3(aq). The mixture was partitioned between EtOAc (5 mL) and water (5 mL) and the aqueous layer was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over MgSO4 and concentrated in vacuo. Column chromatography yielded 25 (14 mg, 15%) and 26 (9 mg, 8%) as colourless oils. 25: 1H NMR (400 MHz, CDCl3) δ: 7.42-7.30 (m, 5H), 6.96 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 5.01 (ABq, ∆δAB = 7.1 Hz, JAB = 11.6 Hz, 2H), 3.59 and 3.40 (ABq, J = 13.6 Hz, 2H), 2.79 (s, 3H), 1.63 (s, 9H).13C NMR (100 MHz, CDCl3) δ: 169.4, 158.5, 150.6, 149.7, 136.9, 130.5, 128.7, 128.2, 127.7, 125.1, 115.3, 88.9, 85.4, 70.1, 41.2, 28.3, 24.7. νmax (ATR-IR) cm-1 3415, 2852, 1810, 1740, 1611, 1511. HRMS-ESI: calcd. C23H26N2NaO6 [M + Na+]: 449.1683; found 449.1649. 26: 1H NMR (400 MHz, CDCl3) δ: 7.45-7.30 (m, 10H), 7.20 (d, J = 7.6 Hz, 2H), 6.95 (d, J = 7.6 Hz, 2H), 5.06 (s, 2H), 4.22 (s, 1H), 4.24 and 3.85 (ABq, J = 17.1 Hz, 2H), 3.95 (s, 1H), 2.65 (s, 3H), 1.65 (s, 9H). 13C NMR (100 MHz, CDCl3) δ: 205.3, 158.2, 153.0, 150.2, 138.4, 137.1, 133.7, 131.8, 131.0, 130.8, 130.3, 130.0, 129.9, 129.5, 128.73, 128.68, 128.7, 128.4, 128.1, 127.9, 127.6, 126.1, 115.1, 93.1, 91.0, 70.2, 44.3, 28.0, 26.4. νmax (ATR-IR) cm-1 3392, 2980, 2324, 1725, 1610, 1511. HRMS-ESI: calcd. for C30H32N2NaO7 [M + Na+] 555.2107; found 555.2129.


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tert-Butyl

(E)-4-benzylidene-5-(4-(benzyloxy)benzyl)-5-hydroxy-3-methyl-2-

oxoimidazolidine-1-carboxylate

(24a)

and

tert-butyl

(Z)-4-benzylidene-5-(4-

(benzyloxy)benzyl)-5-hydroxy-3-methyl-2-oxoimidazolidine-1-carboxylate (24b) To a solution of 20 (60 mg, 0.111 mmol) in wet acetone (1.1 mL) was added Davis oxaziridine (29 mg, 0.111 mmol) and the reaction was monitored by TLC analysis. Upon consumption of the starting material, the mixture was concentrated in vacuo and the title

compounds 24a:24b were isolated as a 1:1.3 mixture (23 mg, 40%). 1H NMR are reported separately,

13

C NMR, IR and HRMS are reported as a mixture due to isomerization.

Individual yields not reported due to difficulty separating the compounds using column chromatography. 24a: 1H NMR (400 MHz, CDCl3) δ: 7.78 (d, J = 7.6 Hz, 2H), 7.43-7.25 (m, 8H), 6.84 (d, J = 8.8 Hz, 2H), 6.77 (d, J = 8.8 Hz), 5.82 (s, 1H), 5.09 (s, 1H), 4.99 (s, 2H), 3.47 and 3.23 (ABq,

J = 13.5 Hz, 2H), 2.83 (s, 3H), 1.62 (s, 9H). 24b: 1H NMR (400 MHz, CDCl3) δ: 7.41-7.21 (m, 8H), 7.17 (d, J = 7.1 Hz, 2H), 7.07 (d, J = 8.2 Hz, 2H), 6.86 (d, J = 8.2 Hz, 2H), 6.03 (s, 1H), 5.01 (ABq, ∆δAB = 9.17 Hz, JAB = 11.6 Hz, 2H), 6.63 (s, 1H), 3.75 and 3.12 (ABq, J = 14.0 Hz, 2H), 2.37 (s, 3H), 1.63 (s, 9H). 24a/b (mixture):

13

C NMR (100 MHz, CDCl3) δ: 158.1, 157.9, 151.5, 151.1, 151.0, 151.0,

138.2, 137.3, 137.0, 136.92, 136.9, 134.6, 134.4, 130.7, 130.4, 129.6, 129.4, 128.5, 127.8, 127.5, 126.9, 126.81, 126.8, 126.5, 114.7, 114.6, 104.8, 102.3, 90.1, 89.6, 84.2, 69.9, 45.4, 39.6, 30.6, 28.2, 26.6. νmax (ATR-IR) cm-1 3399, 3063, 2979, 1747, 1599. HRMS-ESI: calcd. for C30H32N2NaO5 [M + Na+]: 523.2203; found 523.2229.

1'-(4-Methoxybenzyl)-2'-methyl-2',8'-dihydro-3'H,5'H-spiro[cyclohexane-1,7'-imidazo[1,5c][1,3]oxazine]-2,5-diene-3',4,5'-trione (29) To a solution of 23 (54 mg, 0.121 mmol) in wet 2,2,2-trifluoroethanol (1.20 mL) was added PIDA (39 mg, 0.121 mmol) and the solution immediately turned black. The reaction was monitored by TLC and upon consumption of starting material, was quenched with NaS2O3 (1 M). The mixture was partitioned between EtOAc (5 mL) and H2O (5 mL) and the aqueous layer was extracted with EtOAc (3 × 3 mL). The combined organic layers were washed with brine (5 mL), dried over MgSO4 and concentrated in vacuo. The title compound was obtained as a brown oil following column chromatography using EtOAc as eluent (16 mg, 34%). 1H 27 ACS Paragon Plus Environment


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NMR (400 MHz, CDCl3) δ: 7.01 (d, J = 8.7Hz, 2H), 6.87 (d, J = 10.2 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 6.32 (d, J = 10.2 Hz, 2H), 3.78 (s, 3H), 3.68 (2H), 3.07 (s, 3H), 2.88 (s, 2H). 13C NMR (100 MHz, CDCl3) δ: 183.5, 159.3, 150.2, 143.6, 143.2, 136.7, 130.4, 129.2, 126.9, 121.1, 114.7, 108.4, 76.5, 55.5, 29.7, 28.8, 27.8. νmax (ATR-IR) cm-1 2933, 1786, 1674, 1611, 1511. HRMS-ESI: calcd. for C20H18N2NaO5 [M + Na+]: 389.1113, found 389.1108.

4-(4-(Benzyloxy)benzyl)-5-(4-methoxybenzyl)-1,3-dimethyl-imidazol-2-one (31) To a solution of imidazolone 19 (149 mg 0.340 mmol) and iodomethane (57 µL, 0.902 mmol) in THF (6.8 mL) at 0°C was added NaH 60% dispersion in mineral oil (14 mg, 0.340 mmol). The reaction was monitored by TLC analysis and upon completion was quenched with sat. NH4Cl(aq). The mixture was partitioned between EtOAc (10 mL) and H2O (10 mL) and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4 and concentrated in vacuo. The title

compound was obtained as a colourless oil following purification by column chromatography using EtOAc as eluent (106 mg, 69%). 1H NMR (400 MHz, CDCl3) δ: 7.44-7.28 (m, 5H), 7.04 (d, J = 8.0 Hz, 4H), 6.90 (d, J = 8.7 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 5.03 (s, 2H), 3.79 (s, 7H), 3.04 (s, 6H).

13

C NMR (100 MHz, CDCl3) δ: 158.4, 157.7, 153.8, 137.0, 130.6,

130.2, 129.9, 128.7, 128.1, 127.5, 117.7, 115.4, 115.2, 114.2, 80.2, 55.4, 28.4, 27.9. νmax (ATR-IR) cm-1 2908, 1673, 1582. HRMS-ESI: calcd. for C27H29N2O3 [M + H+]: 429.2173; found 429.2154.

4-(4-Hydroxybenzyl)-5-(4-methoxybenzyl)-1,3-dimethyl-imidazol-2-one (32) Compound 32 was prepared according to general procedure 6 starting from 31 (106 mg, 0.247 mmol). The title compound was obtained as a colourless oil (63 mg, 76%). 1H NMR (400 MHz, CDCl3) δ: 8.50 (s, 1H), 7.01 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 6.80 (d,

J = 8.4 Hz, 2H), 6.72 (d, J = 8.4 Hz, 2H), 3.78 (s, 2H), 3.77 (s, 5H), 3.05 (s, 3H), 3.05 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 158.5, 156.1, 153.7, 129.7, 129.0, 128.8, 128.2, 118.4, 114.3, 55.4, 28.4, 28.1. νmax (ATR-IR) cm-1 3171, 2834, 1642. HRMS-ESI: calcd. for C20H22N2NaO3 [M + Na+]: 361.1532; found 361.1513.


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5-(4-(Benzyloxy)benzyl)-3-methylimidazolidine-2,4-dione (39) Et3N (1.73 mL, 12.4 mmol) was added to a suspension of HCl salt of 38 (3.32 g, 10.3 mmol) in THF (35 mL), followed by N-methylcarbamoyl imidazole (1.551 g, 12.4 mmol) and the reaction was heated to reflux overnight. The solution was cooled to room temperature, and partitioned between H2O (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (3 × 50 mL) and the combined organic phases were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. The crude residue was dissolved in EtOH (50 mL) and Na (284 mg, 12.4 mmol) was added to the solution and a white precipitate appeared. Upon consumption of starting material as determined by TLC, the reaction was concentrated in vacuo. The crude residue was taken up in EtOAc/isopropanol (4:1) (100 mL) and washed with H2O (50 mL). The aqueous layer was extracted with EtOAc/isopropanol (4:1) (3 × 50 mL) and the combined organic phases were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. The crude product was washed with cold EtOH and used without further purification. The title compound was obtained as a white crystalline solid (2.84 g, 74 % over two steps). M.P. 166-167 °C 1H NMR (400 MHz, CDCl3) δ: 7.43-7.31 (m, 5H), 7.11 (d, J = 8.7 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 5.47 (s, 1H), 5.05 (s, 2H), 4.19 (dd, J = 8.9, 3.7), 3.23 (AMXdd, J = 14.0 Hz, 3.7 Hz, 1H) and 2.77 (AMXdd, J = 14 Hz, 9 Hz, 1H), 2.97 (s, 3H).

13

C NMR (100 MHz, CDCl3) δ: 173.4,

158.0, 157.4, 136.8, 130.3, 128.6, 128.0, 127.4, 127.4, 151.1, 70.0, 59.6, 37.0, 24.4. νmax (ATR-IR) cm-1 3316, 2924, 1774, 1708, 1600, 1511. HRMS-ESI: calcd. C18H18N2NaO3 [M + Na+]: 333.1210, found 333.1180.

tert-Butyl 5-(4-(benzyloxy)benzyl)-3-methyl-2,4-dioxoimidazolidine-1-carboxylate (40) To a solution of 39 (200 mg, 0.665 mmol) in THF (2 mL) was added Boc2O (168 mg, 0.774 mmol) followed by DMAP (8 mg, 0.0664 mmol). Upon consumption of starting material as indicated by TLC analysis, the reaction was diluted with EtOAc (6 mL) and quenched with sat NH4Cl(aq) and partitioned between EtOAc (5 mL) and water (5 mL). The aqueous layer was extracted with EtOAc (3 × 5 mL) and the combined organic layers were washed with brine (10 mL), dried over MgSO4 and concentrated in vacuo. The title compound was obtained as a white crystalline solid that was used without further purification (233 mg, 86%). M.P. 114-116°C 1H NMR (400 MHz, CDCl3) δ: 7.42-7.30 (m, 5H), 6.95 (d, J = 8.6 29 ACS Paragon Plus Environment


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Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 5.01 (ABq, ∆δAB = 5.0 Hz, JAB = 12.2 Hz, 2H), 4.60 (dd, J = 5.3 Hz, 2.5 Hz, 1H), 3.41 (AMXdd, J = 14.1 Hz, 5.5 Hz, 1H), 3.24 (AMXdd, J = 14.1 Hz, 2.5 Hz, 1H), 2.78 (s, 3H), 1.61 (s, 9H). 13C NMR (100 MHz, CDCl3) δ: 170.7, 158.3, 152.2, 148.7, 137.0, 130.7, 128.7, 128.1, 127.7, 125.6, 115.1, 84.4, 70.1, 60.7, 34.5, 28.2, 24.8. νmax (ATR-IR) cm-1 2978, 1814, 1727, 1610, 1582, 1511. HRMS-ESI: calcd. C23H26N2NaO5 [M + Na+]: 433.1734, found 433.1707.

tert-Butyl 5-(4-(benzyloxy)benzyl)-5-(4-methoxybenzyl)-3-methyl-2,4-dioxoimidazolidine1-carboxylate (41) A solution of 40 (1.90 g, 4.39 mmol) in THF (44 mL) and HMPA (5 mL) was cooled to −78 °C and a solution of LiHMDS (4.40 mL, 1M, 4.40 mmol) was added dropwise. The solution was stirred for 15 mins at which point a solution of 4-methoxybenzyl chloride (750 mg, 4.40 mmol) in THF (4.40 mL) was added dropwise. The reaction was slowly warmed to 0 °C and following consumption of starting material was quenched with sat. NH4Cl(aq) and partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (3 × 50 mL) and the combined organic layers were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. The title compound was obtained following column chromatography using EtOAc/40:60 petroleum ether as eluent as a colourless oil (1.58 g, 65%). 1H NMR (400 MHz, CDCl3) δ: 7.42-7.28 (m, 5H), 6.99 (d, J = 8.4 Hz, 4H), 6.82 (d, J = 8.8 Hz, 2H), 6.74 (d, J = 8.8 Hz, 2H), 4.99 (ABq, ∆δAB = 6.6 Hz, JAB = 11.7 Hz, 2H), 3.75 (s, 3H), 3.58 and 3.26 (ABq, J = 13.9 Hz, 4H), 2.56 (s, 3H), 1.66 (s, 9H). 13C NMR (100 MHz, CDCl3) δ: 173.4, 159.0, 158.3, 152.0, 149.5, 137.0, 130.51, 130.5, 128.7, 128.1, 127.7, 126.7, 126.4, 115.0, 114.0, 84.1, 72.9, 70.0, 55.2, 39.5, 28.3, 24.5. νmax (ATR-IR) cm-1 3354, 3034, 1795, 1651, 1611, 1510. HRMS-ESI: calcd. for C31H34N2NaO6 [M + Na+]: 553.2309; found 553.2294

5-(4-Hydroxybenzyl)-5-(4-methoxybenzyl)-3-methylimidazolidine-2,4-dione (42) The Intermediate TFA salt was prepared according to general procedure 3 starting from compound 41 (3.14, 5.93 mmol) and the title compound was isolated as a white solid which was taken forward with no further purification (2.40 g, 94%). M.P. 179-180 °C. 1H NMR (400 MHz, CDCl3) δ: 7.43-7.29 (m, 5H), 7.04 (d, J = 8.6 Hz, 4H), 6.87 (d, J = 8.7 Hz, 2H), 30 ACS Paragon Plus Environment

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6.79 (d, J = 8.7 Hz, 2H), 6.03 (s, 1H), 5.01 (s, 2H), 3.76 (s, 3H), 3.13 and 2.86 (ABq J = 13.9 Hz, 4H), 2.60 (s, 3H).

13

C NMR (100 MHz, CDCl3) δ: 175.6, 159.0, 158.2, 156.8, 137.0,

131.2, 128.7, 128.1, 127.6, 126.5, 126.2, 114.9, 114.0, 70.0, 67.4, 55.3, 41.7, 24.2. νmax (ATR-IR) cm-1 3285, 2947, 1769, 1703, 1609, 1582. HRMS-ESI: calcd. C26H26N2NaO4 [M + Na+]: 453.1785; found 453.1821. To the TFA salt above (50 mg, 0.116 mmol) in MeOH, was treated under general procedure 6 for benzyl ether removal to afford the title compound as a white solid (39 mg, 98%). M.P. 236-237 °C. 1H NMR (400 MHz, (CD3)2CO) δ: 7.13 (s, 1H), 7.09 (d, J = 8.7 Hz, 2H), 7.00 (d, J = 8.6 Hz, 2H), 6.78 (d, J = 8.7 Hz, 2H), 6.78 (d, J = 8.7 Hz, 2H), 6.69 (d, J = 8.6 Hz, 2H), 3.73 (s, 3H), 3.14 and 2.88 (ABq, J = 11.2, 2H), 3.11 and 2.91 (ABq, J = 11.2, 2H), 2.40 (s, 3H). 13C NMR (100 MHz, (CD3)2CO) δ: 176.0, 159.6, 157.3, 156.4, 132.0, 128.0, 126.6, 115.6, 114.2, 110.9, 68.3, 55.3, 42.6, 42.4, 23.8. νmax (ATR-IR) cm-1 3249, 2922, 1752, 1692, 1613, 1511. HRMS-ESI: calcd. for C19H21N2O4 [M + H+]: 341.1496; found 341.1484.

5-Hydroxy-4-(4-hydroxybenzyl)-4-(4-methoxybenzyl)-1-methylimidazolidin-2-one (43) To a solution of hydantoin 42 (25 mg, 0.0173 mmol) in toluene (3.66 mL) was added DIBAL-H (1.0 M) (52 µL, 0.052 mmol, 3 equiv) at 0°C and the reaction was monitored by TLC analysis. Following consumption of the starting material, the reaction was quenched with sat. NH4Cl(aq) and diluted with Rochelle’s salt (5 mL) and EtOAc (5 mL). When the Al complexes were dissolved the aqueous layer was extracted with EtOAc (3 × 5 mL) and the combined organic layers were washed with brine (10 mL), dried over MgSO4 and concentrated in vacuo to yield the title compound as a white semi solid and 1:1 mixture of diastereoisomers (1.6 mg, 25%). 1H NMR (400 MHz, (CD3)2CO) δ: 8.28 (s, 0.5H), 8.25 (s, 0.5H), 7.29 (d, J = 8.4, 1H), 7.19 (d, J = 8.2, 1H), 7.09 (d, J = 8.2, 1H), 6.99 (d, J = 8.4, 1H), 6.87 (d, J = 8.3, 1H), 6.77 (app t, J = 7.9, 2H), 6.67 (d, J = 8.2, 1H), 5.43 (m, 1H), 5.09 (t, J = 7.6 Hz, 1H), 4.92 (dd, J = 7.9, 2.2 Hz, 1H), 3.78 (s, 1.5 H), 3.72 (s, 1.5H), 2.99 (s, 1H), 2.96 (s, 1H), 2.64 (m, 2H), 2.38 (s, 1.5H), 2.36 (s, 1.5H).

13

C NMR (100 MHz, (CD3)2CO) δ:

158.4, 156.0, 155.99, 131.7, 131.1, 131.0, 129.5, 128.5, 128.2, 127.0, 114.9, 114.8, 114.7, 113.4, 113.3, 113.1, 86.1, 61.2, 59.6, 54.5, 54.4, 42.2, 42.1, 39.5, 25.8. νmax (ATR-IR) cm-1 3326, 2926, 1674, 1612. HRMS-ESI: calcd. for C19H22N2NaO4 [M + Na+]: 365.1472; found 365.1469.



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6a'-(4-Methoxybenzyl)-3'-methyl-3',3a',6',6a'-tetrahydrospiro[cyclohexane-1,5'-furo[2,3d]imidazole]-2,5-diene-2',4(1'H)-dione (34) and 4-(4-methoxybenzyl)-1-methyl-2,9-dioxo1,3-diazaspiro[5.5]undeca-7,10-diene-4-carbaldehyde (44) To a solution of hemi-aminal 43 (9 mg, 0.0246 mmol) in MeCN (0.25 mL) was added PIDA (8 mg, 0.0246 mmol) and the reaction was momnitored by TLC analysis. The reaction was quenched with Na2S2O3 and partitioned between EtOAc (5 mL) and H2O (5 mL). The aqueous layer was extracted with EtOAc (3 × 5 mL) and the combined organic layers were washed with brine (5 mL), dried over MgSO4 and concentrated in vacuo. The title compounds 44 and 34 were obtained as an inseparable mixture in a 4:1 ratio, respectively, following purification by column chromatography (7 mg, 86%). 44: 1H NMR (400 MHz, (CD3)2CO) δ: 9.80 (s, 1H), 7.21 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 6.71 (dd, J = 10.0, 3.2 Hz, 1H), 6.56 (dd, J = 10.2, 3.3 Hz, 1H), 6.29 (s, 1H), 6.11 (m , 2H), 3.68 (s, 3H), 2.92 and 2.79 (ABq, J = 13.9 Hz, 2H), 2.62 (s, 3H), 2.29 and 2.13 (ABq, J = 14.1 Hz, 2H).

13

C NMR (100 MHz, (CD3)2CO) δ: 203.72, 184.2, 160.0, 155.6,

152.3, 150.0, 132.8, 130.2, 126.2, 114.7, 64.2, 57.9, 55.5, 41.4, 37.7, 30.4. HRMS-ESI: calcd. for C19H20N2NaO4 [M + Na+]: 363.1315; found 363.1313. 34: 1H NMR (400 MHz, CDCl3) δ: 7.27 (d, J = 8.7 Hz, 2H), 6.85 (dd, J = 10.1, 2.1 Hz, 1H), 6.78 (d, J = 8.7 Hz, 2H), 6.73 (obscured, 1H), 5.99 (dd, J = 10.1, 2.1 Hz, 1H), 5.92 (dd, J = 10.3, 2.0 Hz, 1H), 5.48 (s, 1H), 3.77 (s, 3H), 3.10 and 2.99 (ABq, J = 13.8 Hz, 2H), 2.65 (s, 3H), 2.57 and 2.24 (ABq, J = 13.7 Hz, 2H).

13

C NMR (100 MHz, CDCl3) δ: 185.1, 159.7,

159.0, 151.5, 150.3, 144.1, 132.2, 128.9, 128.7, 127.3, 98.1, 79.9, 68.1, 55.4, 49.5, 43.6, 27.6. νmax (ATR-IR) cm-1 3305, 2929, 1730, 1667, 1612, 1512. HRMS-ESI: calcd. for C19H20N2NaO4 [M + Na+]: 363.1315; found 363.1313.

5-Benzyl-4-(4-(benzyloxy)benzyl)-5-hydroxy-1-methylimidazolidin-2-one (46) Compound 46 was prepared according to general procedure 1 starting from compound 39 (652 mg, 1.96 mmol) and the title compound was obtained as a white solid (566 mg, 61%). MP: 154-156 °C. 1H NMR (400 MHz, (CD3)2SO) δ: 7.42-7.16 (m, 8H), (6.99, app. d, J = 8.8 Hz, 4H), 6.89 (d, J = 8.33 Hz, 2H), 6.24 (s, 1H), 5.90 (s, 1H), 5.05 (s, 1H), 3.38 (t, J = 6.6


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Hz, 1H), 2.91 and 2.67 (ABq, J = 13.9 Hz, 2H), 2.67 (s, 3H), 2.52 and 2.42 (two dd, J = 13.8, 5.8 Hz, 4H).

13

C NMR (100 MHz, (CD3)2SO) δ: 159.9, 156.7, 137.2, 136.3, 130.9, 130.3,

130.27, 128.4, 128.0, 127.7, 127.6, 114.6, 89.9, 69.1, 57.1, 42.2, 34.9, 24.3. νmax (ATR-IR) cm-1 3360, 3035, 2860, 1701, 1512. HRMS calcd. for C25H26N2NaO3 [M + Na+] 425.1836; found 425.1836.

tert-Butyl

2-benzyl-5-(4-(benzyloxy)benzyl)-2-hydroxy-3-methyl-4-oxoimidazolidine-1-

carboxylate (47) Compound 40 (109 mg, 0.256 mmol) was subjected to general procedure 1 using 1 equiv. of BnMgCl to afford the title compound as a white solid (62 mg, 47%). 1H NMR is complicated by a mixture of rotamers. 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.42-7.17 (m, 8H), 7.04-6.94 (m, 4H), 6.93-6.81 (m, 2H), 5.03 (s, 0.5H), 5.00 (s, 1.5H), 3.09 (dd, J = 13.8, 5.5, 1H), 3.86 (m, 1.2H), 3.63 (m, 1.2H), 3.43 (m, 0.77H) 3.00, 2.97 and 2.94 (3s, 2H) ,2.75 and 2.71 (two s, 3H).

13

C NMR (100 MHz, CDCl3) δ 168.5, 158.1, 151.6, 137.1, 136.7, 134.5,

134.2, 131.0, 130.6, 130.3, 129.5, 129.2, 128.8, 128.7, 128.5, 128.2, 128.1, 127.5, 127.3, 99.5, 99.0, 85.7, 82.0, 81.6, 70.1, 70.05, 60.9, 60.8, 39.3, 38.3, 35.1, 33.7, 28.6, 28.6, 28.0, 24.7. νmax (ATR-IR) cm-1 3516, 2977, 1757, 1698, 1609, 1509. HRMS calcd. for C30H34N2NaO5 [M + Na+]: 525.2360; found 525.2376.

Diethyl 1-(4-(4-(benzyloxy)benzyl)-3-(tert-butoxycarbonyl)-1-methyl-2,5-dioxoimidazolidin4-yl)hydrazine-1,2-dicarboxylate (50) To a solution of Boc-protected hydantoin 40 (340 mg, 0.828 mmol) in anhydrous THF (5 mL) was added LiHMDS (0.994 mL, 0.994 mmol) dropwise at -78°C. The mixture was stirred at -78 °C for 15 minutes. A solution of DEAD (155 µL, 3.988 mmol) in THF (1 mL) was added to the solution dropwise at -78°C and the mixture was stirred for a further 15 minutes at the same temperature. Following this, the solution was allowed to slowly warm to room temperature and quenched with sat. NH4Cl(aq). The resulting mixture was partitioned between H2O (15 mL) and EtOAc (15 mL) and the aqueous layer was further extracted with EtOAc (3 × 15 mL). The combined organic phases were washed with brine (15 mL), dried over MgSO4 and concentrated in vacuo. Column chromatography using EtOAc/40:60 petroleum ether as eluent yielded the title compound as a colourless oil (260 mg, 53%). 1H 33 ACS Paragon Plus Environment


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NMR (400 MHz, CDCl313C NMR (100 MHz, CDCl3) δ: 7.41-7.29 (m, 5H), 6.94 (m, 2H), 6.84 (d, J = 8.7 Hz), 5.01 (ABq, ∆δAB = 11.9 Hz, JAB = 11.6 Hz, 2H), 4.33-4.14 (m, 4H), 3.72 (app. t, J = 14.2 Hz, 1H), 3.14 and 3.03 (m, 1H), 2.70 (s, 3H), 1.60 (s, 9H), 1.39-1.18 (m, 6H). 13

C spectrum is complicated by a mixture of rotamers 13C NMR (100 MHz, CDCl3) δ:168.2,

167.8, 158.5, 155.7, 155.1, 154.3, 150.6, 150.5, 150.2, 150.0, 136.7, 131.1, 128.5, 128.0, 127.5, 123.6, 123.5, 114.9, 114.6, 84.9, 84.8, 80.3, 69.9, 63.5, 62.4, 62.2, 36.8, 36.4, 28.1, 28.0, 24.5, 14.5, 14.2. νmax (ATR-IR) cm-1 3345, 2981, 1804, 1722, 1609, 1511. HRMS-ESI: calcd. C29H36N4NaO9 [M + Na+]: 607.2374, found 607.2353.

tert-Butyl

5-azido-5-(4-(benzyloxy)benzyl)-3-methyl-2,4-dioxoimidazolidine-1-carboxylate

(51) To a solution of Boc-protected hydantoin 40 (1.32 g, 3.32 mmol) in anhydrous THF (15 mL) was added LiHMDS (4.00 mL, 3.99 mmol) dropwise at -78°C. The mixture was stirred at 78°C for 15 minutes. A solution of 4-acetamidobenzenesulfonyl azide (957 mg, 3.99 mmol) in THF (10 mL) was added to the solution dropwise at -78°C and the mixture was stirred for a further 15 minutes at the same temperature. Following this, the solution was allowed to slowly warm to room temperature and quenched with sat. NH4Cl(aq). The resulting mixture was partitioned between H2O (45 mL) and EtOAc (45 mL) and the aqueous layer was further extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. Column chromatography using EtOAc/40:60 petroleum ether as eluent yielded the title compound as a white crystalline solid (1.13 g, 82%). M.P. 100-101°C. 1H NMR (400 MHz, CDCl3) δ: 7.43-7.30 (m, 5H), 7.00 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 5.02 (s, 2H), 3.88 and 3.44 (ABq, J = 13.3 Hz, 2H), 2.80 (s, 3H), 1.65 (s, 9H). 13C NMR (100 MHz, CDCl3) δ: 168.3, 158.7, 150.6, 148.4, 136.7, 130.7, 128.7, 128.1, 127.6, 123.7, 115.3, 85.5, 79.5, 70.0, 37.0, 28.2, 25.0. νmax (ATR-IR) cm1

3034, 2980, 1823, 1741, 1582, 1510. HRMS-ESI: calcd. C23H25N5NaO5 [M + Na+]:

474.1748; found 474.1711.

tert-Butyl 5-amino-5-(4-(benzyloxy)benzyl)-3-methyl-2,4-dioxoimidazolidine-1-carboxylate (52) 34 ACS Paragon Plus Environment

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To a solution of azide 51 (1.13 g, 2.51 mmol) in MeOH (11 mL) was added Pd(en)/C 5% (113 mg, 10% wt) and the suspension was stirred under a hydrogen atmosphere until TLC analysis showed the consumption of starting material. The mixture filtered through a plug of celite and the filtrate was concentrated in vacuo to yield the title compound as a white solid, which was used without further purification (991 mg, 92%). M.P. 127-128°C. 1H NMR (400 MHz, CDCl3) δ: 7.42-7.30 (m, 5H), 6.95 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 5.00 (ABq, ∆δAB = 8.4 Hz, JAB = 11.8 Hz, 2H), 3.55 and 3.26 (ABq, J = 13.6 Hz, 2H), 2.76 (s, 3H), 2.64 (br s, 2H), 1.62 (s, 9H). 13C NMR (100 MHz, CDCl3) δ: 171.7, 158.4, 150.9, 149.2, 136.8, 130.4, 128.7, 128.1, 127.6, 126.0, 115.1, 84.6, 78.3, 67.0, 42.5, 28.3, 24.7. νmax (ATRIR) cm-1 3390, 3323, 2979, 2933, 1811, 1730, 1610, 1582, 1511, 1453, 1369, 1320, 1278, 1244, 1176, 1152, 1111, 1070, 1018, 910, 843, 821, 786, 753, 733, 696, 622, 572. HRMSESI: calcd. C23H27N3NaO5 [M + Na+]: 448.1843, found 448.1830.

Benzyl

(4-(4-(benzyloxy)benzyl)-1-methyl-2,5-dioxoimidazolidin-4-yl)(methyl)carbamate

(53) To a mixture of primary amine 52 (50 mg, 0.118 mmol) and Na2CO3 (34 mg, 0.323 mmol) in THF/H2O (1:1) (1 mL) was added benzyl chloroformate (17 µL, 0.118 mmol) at 0°C. The reaction was monitored by TLC and upon consumption of starting material was quenched with sat. NH4Cl(aq). The resulting mixture was extracted with EtOAc (3 × 5 mL) and the combined organic layers were washed with brine (5 mL), dried over MgSO4 and concentrated

in vacuo. Column chromatography using EtOAc/40:60 petroleum ether as eluent yielded the cbz-protected amine as a white crystalline solid (51 mg, 77%). M.P. 150 °C. 1H NMR (400 MHz, CDCl3) δ: 7.42-7.28 (m, 10H), 6.98 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 5.86 (br s, 1H), 5.06 (m, 4H), 3.55 and 3.25 (ABq, J = 13.2 Hz, 2H), 2.82 (s, 3H), 1.57 (s, 9H). 13

C NMR (100 MHz, CDCl3) δ: 169.2, 158.6, 154.1, 151.0, 148.9, 136.7, 135.5, 128.6, 128.4,

128.1, 127.5, 123.7, 115.0, 84.5, 75.6, 69.9, 67.5, 39.5, 28.1, 24.7, 24.7. νmax (ATR-IR) cm-1 3351, 3033, 2979, 2932, 2360, 2255, 1804, 1726, 1611, 1582, 1509, 1453, 1394, 1350, 1320, 1243, 1194, 1177, 1150, 1055, 1025, 990, 910, 844, 784, 770, 732, 696, 570. HRMS-ESI: calcd. C31H33N3NaO7 [M + Na+]: 582.2211, found 582.2181 To a stirred solution of the cbz-protected amine (42 mg, 0.0721 mmol) and iodomethane (13 µL, 0.216 mmol) in DMF (0.710 mL) at 0 °C was added NaH 60% dispersion in mineral oil (3 mg, 0.0721 mmol). The reaction was monitored by TLC analysis and upon completion was 35 ACS Paragon Plus Environment


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quenched with sat. NH4Cl(aq). The mixture was partitioned between EtOAc (3 mL) and H2O (3 mL) and the aqueous layer was extracted with EtOAc (3 × 3mL). The combined organic layers were washed with brine (5 mL), dried over MgSO4 and concentrated in vacuo. The NMethyl-Cbz analog was obtained as a colourless oil following purification by column chromatography using EtOAc as eluent (36 mg, 84%). 1H NMR (400 MHz, CDCl3) δ: 7.437.26 (m, 10H), 6.99 (d, J = 7.6 Hz, 2H), 6.86 (d, J = 7.6 Hz, 2H), 5.06 (m, 4H), 3.86 and 3.12 (ABq, J = 12.6 Hz, 2H) 3.29 (s, 3H), 2.67 (s, 3H), 1.60 (s, 9H). 13C NMR (100 MHz, CDCl3) δ: 170.6, 158.6, 155.4, 151.3, 149.4, 136.8, 135.9, 131.1, 128.7, 128.3, 128.1, 127.8, 127.6, 123.9, 84.2, 79.2, 70.1, 68.0, 37.7, 31.9, 28.3, 24.5. νmax (ATR-IR) cm-1 3243, 3075, 2975, 2929, 1685, 1542, 1456. HRMS-ESI: calcd. for C32H35N3NaO7 [M + Na+]: 596.2367; found 596.2316. Compound 53 was prepared by treatment of the above N-Methyl-Cbz analog (104 mg, 0.174 mmol) to general procedure 3 and the title compound was obtained as a colourless semi-solid (59 mg, 72%). 1H NMR (400 MHz, CDCl3) δ: 7.39-7.24 (m, 10H), 7.08 (d, J = 8.8 Hz, 2H), 6.9 (d, J = 8.8 Hz, 2H), 5.12 (m, 2H), 4.99 (m, 2H), 3.34 and 3.20 (ABq, J = 13.0 Hz, 2H), 3.14 (s, 3H), 2.52 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 171.4, 158.4, 156.5, 156.0, 136.9, 135.6, 131.7, 131.4, 128.74, 128.7, 128.5, 128.4, 115.3, 114.8, 76.8, 70.0, 68.3, 40.2, 31.5, 24.1. νmax (ATR-IR) cm-1 3272, 3064, 2940, 1782, 1701, 1610, 1510. HRMS-ESI: calcd. for C27H28N3O5 [M + H+]: 474.2023; found 474.2047.

5-(4-(Benzyloxy)benzyl)-5-(dimethylamino)-3-methylimidazolidine-2,4-dione (54) Primary amine 52 (200 mg, 0.470 mmol) was dissolved in DMF (2 mL), to which was added K2CO3 (195 mg, 1.411 mmol) and MeI (88 µL, 1.411 mmol). The reaction mixture was heated to 40°C and stirred overnight. Following a polar solvent work-up, the Ndimethylamine analog was purified using column chromatography using EtOAc//40:60 petroleum ether as eluent and obtained as a white semi-solid (213 mg, 100%). 1H NMR (400 MHz, CDCl3) δ: 7.41-7.28 (m, 5H), 7.01 (d, J = 8.7 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 4.99 (ABq, ∆δAB = 9.3 Hz, JAB = 11.6 Hz, 2H), 3.83 and 3.21 (ABq, J = 13.1 Hz, 2H), 2.68 (s, 3H), 2.51 (s, 6H), 1.62 (s, 9H). 13C NMR (100 MHz, CDCl3) δ: 171.8, 158.3, 151.6, 149.7, 136.8, 130.9, 128.6, 128.0, 127.6, 125.8, 114.9, 86.7, 84.0, 69.9, 39.1, 37.8, 28.2, 24.3. νmax


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(ATR-IR) cm-1 3670, 2980, 1803, 1726, 1610, 1510. HRMS-ESI: calcd. C25H31N3NaO5 [M + Na+]: 476.2156; found 476.2145. Treatment of the above N-dimethylamine analog (188 mg, 0.395 mmol) to general procedure 3 provided the title compound as a white solid (120 mg, 86%). M.P. 233-234 °C. 1H NMR (400 MHz, CDCl3) δ: 7.40-7.27 (m, 5H), 7.08 (d, J = 8.6 Hz, 2H), 6.94 (s, 1H) 6.86 (d, J = 8.6 Hz, 2H), 5.00 (s, 2H), 3.25 and 3.09 (ABq, J = 13.5 Hz, 2H), 2.65 (s, 3H), 2.41 (s, 6H). 13

C NMR (100 MHz, CDCl3) δ: 173.4, 158.2, 157.2, 136.9, 131.4, 128.7, 128.1, 127.6, 114.8,

82.5, 70.0, 40.7, 39.0. νmax (ATR-IR) cm-1 3320, 2966, 2787, 1773, 1701, 1618, 1514. HRMS-ESI: calcd. C20H24N3O3 [M + H+]: 354.1818; found 354.1812.

(-)-des-Methylamino-spiroleucettadine (55) To a solution of N-methylcarbamoyl imidazole (704 mg, 5.63 mmol) and Et3N (785 µL, 5.63 mmol) in THF (6 mL) was added the TFA salt 57 (749 mg, 1.88 mmol) in THF (21 mL) dropwise over 20 min and the resulting solution was stirred at room temperature overnight. The mixture was partitioned between EtOAc (60 mL) and H2O (30 mL) and the aqueous layer extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4 and concentrated in vacuo. The crude residue was taken up in 2,2,2-trifluoroethanol (10 mL) and cooled to 0°C. PIDA (604 mg, 1.88 mmol) was added and the solution was stirred at 0°C for 15 min. The reaction was quenched with Na2S2O3 (1M) and partitioned between EtOAc (20 mL) and H2O (10 mL). The aqueous layer extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4 and concentrated in vacuo. Colum chromatography using EtOAc as eluent followed by recrystallization from EtOAc yielded the title compound as a white crystalline solid (105 mg, 17%, over two steps). [α]24D = -37.3 (c = 0.533, MeOH). M.P. 122-123°C 1H NMR (400 MHz, CDCl3) δ: 7.19 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.5 Hz, 2H), 6.84 (dd, J = 10.3, 3.0 Hz, 1H), 6.34 (dd, J = 10.1, 3.0 Hz, 1H), 6.12 (dd, J = 10.1, 3 Hz, 1H), 6.09 (br s, 1H), 6.06 (dd, J = 10.1, 3.0 Hz, 1H), 4.24 (dd, J = 6.5, 1.5 Hz, 1H), 3.82 (s, 3H), 3.36 and 2.84 (abq, J = 14.1, 2H), 2.93 (s, 3H), 1.83 (d, J = 13.8 Hz, 1H), 1.45 (dd, J = 13.8, 6.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 185.0, 159.5, 159.1, 149.2, 148.8, 131.8, 129.0, 127.3, 126.1, 113.9, 102.7, 79.7, 58.3, 55.4, 44.8, 41.1, 25.1. νmax (ATR-IR) cm-1 3277, 2956, 1670, 1513. HRMS-ESI: calcd. for C19H20N2NaO4 [M + Na+]: 363.1315; found 363.1342



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(-)-des-Methylamino-5-acetoxy-spiroleucettadine (58) To a solution of the spiro compound 55 (39 mg, 0.115 mmol) in fluorobenzene (4 mL) was added Dess-Martin periodinane (98 mg, 0.230 mmol) and the solution was heated to 60°C. The reaction was monitored by TLC analysis and upon consumption of starting material was cooled to room temperature. The reaction was quenched with solid NaHCO3 and filtered through a plug of silica and purified by column chromatography to yield the title compound as a colourless foam (34 mg, 75%). [α]25D = +37.8 (c = 1.083, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 7.31 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 6.87 (m, 1H), 6.14 (br s, 1H), 6.05 (m, 3H), 3.83 (s, 3H), 3.35 and 3.14 (abq, J = 14.5 Hz, 2H), 2.92 (s, 3H), 2.81 and 1.87 (abq, J = 13.6, 2H), 2.21 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 184.7, 170.2, 160.0, 156.6, 148.1, 147.4, 133.1, 129.3, 127.9, 126.3, 113.5, 102.0, 95.1, 78.1, 55.4, 47.8, 38.2, 25.6, 21.6. νmax (ATR-IR) cm-1 3260, 2960, 1716, 1632, 1513. HRMS-ESI: calcd. for C21H22N2NaO6 [M + Na+]: 421.1370; found 421.1377.

(-)-Spiroleucettadine (2) The OAc substituted spiro 58 (13 mg, 0.0327 mmol) compound was dissolved in THF (2 mL), to which was added methylamine hydrochloride (22.1 mg, 0.327 mmol) and Et3N (45 µL, 0.327 mmol) and the reaction was monitored by TLC analysis. Upon consumption of starting material the mixture was diluted with EtOAc (5 mL) and washed with distilled H2O (5 mL), brine (5 mL), dried over MgSO4 and concentrated in vacuo. Column chromatography using EtOAc/MeOH as eluent yielded the spiroleucettatadine as a colourless semi-solid (11 mg, 91%). [α]25D = -2.6 (c = 0.25, MeOH). 1H NMR (500 MHz, MeOH-d4) δ: 7.45 (d, J = 8.6 Hz, 2H), 6.99 (dd, J = 10.5, 2.2 Hz, 1H), 6.88 (d, J = 8.5 Hz, 2H), 6.01 (app. d, J = 10.8 Hz, 1H), 5.93 (dd, J = 10.1, 2.3 Hz, 1H), 5.92 (dd, J = 10.1, 2.3 Hz, 1H), 3.80 (s, 3H), 3.21 and 3.17 (abq, J = 14.5 Hz, 2H), 2.79 (s, 3H), 2.40 (s, 3H), 2.22 and 2.07 (abq, J = 13.2 Hz, 2H). 13

C NMR (100 MHz, MeOH-d4) δ: 186.9, 161.2, 160.2, 152.5, 151.5, 134.2, 129.0, 128.4,

127.4, 114.2, 104.0, 84.0, 78.6, 55.7, 49.0, 38.6, 29.0, 26.2. νmax (ATR-IR) cm-1 3293, 2928, 2809, 1699, 1610, 1511. HRMS-ESI: calcd. for C20H23N3NaO4 [M + Na+]: 392.1581;found 392.1592.

Crystallography. A crystal of 47 was attached with Paratone N oil to a CryoLoop supported in a copper mounting pin, then quenched in a cold nitrogen stream. Data were collected at 38 ACS Paragon Plus Environment

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100 K using Cu-Kα radiation (micro-source, mirror monochromated) using an Agilent SuperNova diffractometer with Atlas detector. The data processing was undertaken within the CrysAlisPro software;25 combined Gaussian and multiscan scaling absorption corrections were applied to the data.25 The structures were solved by direct methods with SHELXS-2014, and extended and refined with SHELXL-2014.26,27 The non-hydrogen atoms were modelled with anisotropic displacement parameters and a riding atom model with group displacement parameters used for the hydrogen atoms. The asymmetric unit contains two molecules for the main compound related by a pseudo-translation along the b-axis. CCDC 1838716 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via https://www.ccdc.cam.ac.uk. Crystal data for 47: C30H34N2O5, M = 502.59, colorless plate, 0.36 × 0.23 × 0.03 mm3, triclinic, a = 9.1299(2) Å, b = 13.1630(3) Å, c = 23.1982(4) Å, α = 97.047(2)°,

β = 91.529(2)°, γ = 101.080(2)°, V = 2711.63(10) Å3, space group P-1 (#2), Z = 4, µ(Cu-Kα) = 0.676 mm–1, 2θmax = 149.81°, 2θfull = 134° (99.9% complete), 45735 reflections measured, 10848 independent reflections (Rint = 0.0605). The final R1(F) = 0.0486 (I > 2σ(I)); 0.0576 (all data). The final wR2(F2) = 0.1232 (I > 2σ(I)); 0.1320 (all data). GoF = 1.025.

Supporting Information NMR spectra of all new compounds and an ORTEP diagram of 47 (PDF). Crystallographic data for the X-ray crystal structure of 47 (CIF).

Acknowledgements The authors thank the University of Otago for funding and Dr Eng Tan for helpful discussions. Support for this research from the NHMRC (fellowship for G.L. GNT1117089), the Australian Cancer Research Foundation, the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS is gratefully acknowledged.

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Spiroleucettadine

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