Synthetic Studies on Cyclocitrinol: Construction of the ABC Ring System Based on Epoxy–Nitrile Cyclization

Kazuto Sato; Keiji Tanino

doi:10.1055/a-1334-6100

Synlett, Table of Contents

Synlett 2021; 32(07): 674-678
DOI: 10.1055/a-1334-6100

letter

Synthetic Studies on Cyclocitrinol: Construction of the ABC Ring System Based on Epoxy–Nitrile Cyclization

Authors

Kazuto Sato

^aGraduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo 060-0810, Japan
Keiji Tanino ∗

^bDepartment of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan

Abstract

All articles of this category

Abstract

The stereoselective synthesis of a model compound containing the ABC ring system of cyclocitrinol was accomplished. After connecting a C ring allyltitanium segment with an A ring bicyclo[4.1.0]heptanone segment, the seven-membered B ring moiety was constructed by an intramolecular cyclization reaction of an epoxy nitrile. The enone moiety was introduced through an oxidative decyanation reaction, and the bicyclo[4.4.1]undecane skeleton with the highly strained olefin moiety was formed through a ring-opening reaction of the bicyclo[4.1.0]heptane substructure.

Key words

natural product - total synthesis - allyl titanocene - epoxy nitrile - cyclization reaction - cyclopropane ring opening - cyclocitrinol

Full Text

References

References and Notes
1 Kozlovsky AG, Zhelifonova VP, Ozerskaya SM, Vinokurova NG, Adanin VM, Gräfe U. Pharmazie 2000; 55: 470
2 Amagata T, Amagata A, Tenney K, Valeriote FA, Lobkovsky E, Clardy J, Crews P. Org. Lett. 2003; 5: 4393

3a do Rosário Marinho AM, Rodrigues-Filho E, Ferreira AG, Santos LS. J. Braz. Chem. Soc. 2005; 16: 1342
3b Du L, Zhu T, Fang Y, Gu Q, Zhu W. J. Nat. Prod. 2008; 71: 1343
3c Ying YM, Zheng Z.-Z, Zhang L.-W, Shan W.-G, Wang J.-W, Zhan Z.-J. Helv. Chim. Acta 2014; 97: 95
3d Zhou Z.-F, Yang X.-H, Liu H.-L, Gu Y.-C, Ye B.-P, Guo Y.-W. Helv. Chim. Acta 2014; 97: 1564
3e Xia M.-W, Cui C.-B, Li C.-W, Wu C.-J. Mar. Drugs 2014; 12: 1545
3f Lin S, Chen K.-Y, Fu P, Ye J, Su Y.-Q, Yang X.-W, Zhang Z.-X, Shan L, Li H.-L, Shen Y.-H, Liu R.-H, Xua X.-K, Zhang W.-D. Magn. Reson. Chem. 2015; 53: 223
3g Yu F.-X, Li Z, Chen Y, Yang Y.-H, Li G.-H, Zhao P.-J. Fitoterapia 2017; 117: 41

4a Plummer CW, Soheili A, Leighton JL. Org. Lett. 2012; 14: 2462
4b Plummer CW, Wei CS, Yozwiak CE, Soheili A, Smithback SO, Leighton JL. J. Am. Chem. Soc. 2014; 136: 9878 ; corrigendum: J. Am. Chem. Soc. 2015, 137, 13722

5a Mei G, Liu X, Qiao C, Chen W, Li C.-C. Angew. Chem. Int. Ed. 2015; 54: 1754
5b Liu J, Wu J, Fan J.-H, Yan X, Mei G, Li C.-C. J. Am. Chem. Soc. 2018; 140: 5365

6 El Sheikh S, Meier zu Greffen A, Lex J, Neudoerfl J.-M, Schmalz H.-G. Synlett 2007; 1881

7a Wang Y, Ju W, Tian W, Gui J. J. Am. Chem. Soc. 2018; 140: 9413
7b Wang Y, Ju W, Tian H, Sun S, Li X, Tian W, Gui J. J. Am. Chem. Soc. 2019; 141: 5021

8 Stork G, Cama LD, Coulson DR. J. Am. Chem. Soc. 1974; 7: 5268
9 Hanada R, Mitachi K, Tanino K. Tetrahedron Lett. 2014; 55: 1097
10 Tanino K, Takahashi M, Tomata Y, Tokura H, Uehara T, Narabu T, Miyashita M. Nat. Chem. 2011; 3: 484
11 Voigtritter K, Chorai S, Lipshutz BH. J. Org. Chem. 2011; 76: 4697
12 Corey EJ, Chaykovsky M. J. Am. Chem. Soc. 1965; 87: 1353

13a Takeda T, Miura I, Horikawa Y, Fujiwara T. Tetrahedron Lett. 1995; 36: 1495
13b Yatsumonji Y, Nishimura T, Tsubouchi A, Noguchi K, Takeda T. Chem. Eur. J. 2009; 15: 2680
13c Takeda T, Nishimura T, Yatsumonji Y, Noguchi K, Tsubouchi A. Chem. Eur. J. 2010; 16: 4729
13d Takeda T, Wasa H, Tsubouchi A. Tetrahedron Lett. 2011; 52: 4575
13e Takeda T, Yamamoto M, Yoshida S, Tsubouchi A. Angew. Chem. Int. Ed. 2012; 51: 7263
13f Takeda T, Nishimura T, Yoshida S, Saiki F, Tajima Y, Tsubouchi A. Org. Lett. 2012; 14: 2042
13g Takeda T, Yoshida S, Nishimura T, Tsubouchi A. Tetrahedron Lett. 2012; 53: 3930
13h Takeda T, Amarume S, Sekioka I, Tsubouchi A. Org Lett. 2015; 17: 1150
13i Takeda T, Tateishi K, Tsubouchi A. Tetrahedron Lett. 2015; 56: 4016

14 Kasatkin A, Nakagawa T, Okamoto S, Sato F. J. Am. Chem. Soc. 1995; 117: 3881
15 When epoxide 8 was prepared through methylation of allyl alcohol 9 followed by epoxidation with mCPBA, a 1:1 mixture of epimers was formed. The result suggested that coordination of the hydroxy group of 9 with the vanadium catalyst is essential for the stereoselective epoxidation, while the conformational analysis of 9 has not yet explored.
16 Nicolaou KC, Harrison ST. Angew. Chem. Int. Ed. 2006; 45: 3256
17 The ORTEP drawing of compound 7 by X-ray crystallographic analysis is shown in Figure 3. The CIF file of 7 is provided as Supporting Information.
18 Selikson SJ, Watt DS. J. Org. Chem. 1975; 40: 267

For selected examples on the cyclopropylcarbinyl rearrangement, see:

19a Gassman PG, Steppel RN, Armour EA. Tetrahedron Lett. 1973; 35: 3287
19b Anderson GD, Powers TJ, Djerassi C, Fayos J, Clardy J. J. Am. Chem. Soc. 1975; 97: 388
19c Marshall JA, Ellison RH. J. Org. Chem. 1975; 14: 2070
19d Marshall JA, Ellison RH. J. Am. Chem. Soc. 1976; 98: 4312
19e Thielemann W, Schäfer HJ, Kotila S. Tetrahedron 1995; 51: 12027
19f Cossy J, BouzBouz S, Laghgar M, Tabyaoui B. Tetrahedron Lett. 2002; 43: 823
19g Moriarty R, Albinescu D. J. Org. Chem. 2005; 70: 7624

20 The stereochemistry of cyclopropane ring-opening product was determined by NOE experiment of 24 converted from 20. Transformation of 24 into 5 was also achieved in three steps as follows, indicating that the configuration of compound 5 corresponds to that of the ABC ring system of natural product (Scheme 5).
21 Synthesis of Compound 6 (Coupling Reaction of Ketone 10) To a cooled (–78 °C) suspension of Cp₂TiCl₂ (1.50 g, 6.0 mmol) in THF (8.0 mL) was added n-BuLi (2.67 M in hexane, 4.5 mL, 12.0 mmol). After being stirred for 1 h, a THF solution (1.0 mL) of S3 (490 mg, 2.4 mmol, see the Supporting Information) was added, and stirring was continued for 10 min at the same temperature and then at 0 °C for 1 h. After cooling to –78 °C, ketone 10 (300 mg, 2.0 mmol) in THF (1.0 mL) was added. After being stirred for 1 h, a 1 M aqueous NaOH solution was added, and the mixture was filtered through a pad of Celite. The insoluble materials were washed with EtOAc, and the filtrate was separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 75:15) to afford 9 as a yellow oil (370 mg, 1.5 mmol, 75%, single isomer). IR (neat): ν = 2926, 2853, 2360, 2341, 1638, 1447, 1420, 1386, 1113, 1059, 995, 984, 953, 891 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 4.90 (1 H, s), 4.83 (1 H, s), 2.33 (1 H, dd, J = 9.0, 6.0 Hz), 2.26 (1 H, q, J = 6.5 Hz), 2.21 (1 H, t, J = 4.6 Hz), 2.11 (1 H, dd, J = 12.6, 4.0 Hz), 2.04 (2 H, d, J = 5.2 Hz), 1.87 (1 H, d, J = 10.3 Hz), 1.82–1.74 (3 H, m), 1.53–1.40 (4 H, m), 1.31–1.23 (4 H, m), 0.55 (2 H, dt, J = 17.9, 6.3 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 149.33, 118.37, 108.47, 71.97, 56.65, 38.97, 38.11, 29.41, 29.00, 28.94, 26.15, 24.38, 21.12, 13.79, 5.83. HRMS (FI): m/z calcd for C₁₆H₂₃NO [M]⁺: 245.1780; found: 245.1773. Synthesis of Compound 7 (Cyclization Reaction of Epoxy Nitrile) To a cooled (–78 °C) solution of LTMP, which was freshly prepared from tetramethylpiperidine (250 μL, 1.45 mmol) in THF (6.3 mL) and n-BuLi (2.67 M in hexane, 540 μL, 1.45 mmol), was added a solution of 8 (200 mg, 0.727 mmol) in THF (1.0 mL). After being stirred for 30 min, the reaction mixture was slowly warmed up to room temperature. After being stirred for 1 h, the reaction was quenched with a saturated aqueous NH₄Cl solution. The mixture was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 75:15) to afford 7 as a white solid (146 mg, 0.531 mmol, single isomer); mp 207–209 °C. IR (neat): ν = 3381, 2960, 2939, 2919, 2872, 2359, 2225, 1496, 1296, 1237, 1061, 1036, 1004, 978 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 3.39 (1 H, dd, J = 10.9, 7.4 Hz), 3.17 (3 H, s), 2.36 (1 H, dd, J = 14.0, 12.3 Hz), 2.12–2.08 (2 H, m), 2.01 (2 H, t, J = 14.9 Hz), 1.90 (1 H, q, J = 4.4 Hz), 1.83 (1 H, dd, 12.0, 6.3 Hz) 1.75–1.66 (2 H, m), 1.58 (2 H, m), 1.47 (1 H, s), 1.41 (1 H, dt, J = 14.1, 3.9 Hz), 1.33–1.22 (4 H, m), 1.17 (1 H, dd, J = 15.2, 8.9 Hz), 1.03 (1 H, td, J = 8.9, 4.6 Hz), 0.85 (1 H, d, J = 14.3 Hz), 0.29 (1 H, q, J = 5.5 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 124.41, 74.74, 72.16, 50.72, 47.09, 46.26, 36.05, 34.52, 31.38, 30.97, 27.75, 25.69, 23.90, 23.39, 18.87, 13.91, 12.66. HRMS (FI): m/z calcd for C₁₇H₂₅NO₂ [M]⁺: 275.1885; found: 275.1884. Synthesis of Compound 5 (Cleavage of the Cyclopropane Moiety Followed by Saponification) To a cooled (0 °C) mixture of 6 (40 mg, 0.162 mmol) and AcOH (200 μL) in CH₂Cl₂ (400 μL) was added BF₃·OEt₂ (2.0 μL, 0.016 mmol). The reaction mixture was warmed up to room temperature and was stirred for 1 h. After cooling to 0 °C, a saturated aqueous NaHCO₃ solution was added, and the mixture was separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 9:1) to afford 23 as a yellow oil (34 mg, 0.123 mmol, 76%). IR (CHCl₃): ν = 2931, 2856, 2365, 2342, 1656, 1617, 1460, 1437, 1363, 1326, 1162, 1108, 1085, 1020, 970, 888, 867, 850, 751 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 5.76 (1 H, s), 5.61 (1 H, t, J = 7.4 Hz), 4.52–4.48 (1 H, m), 2.87–2.80 (2 H, m), 2.74 (1 H, d, J = 5.2 Hz), 2.65 (1 H, q, J = 6.7 Hz), 2.54–2.43 (2 H, m), 2.33–2.29 (2 H, m), 2.18 (1 H, dd, J = 14.9, 12.6 Hz), 2.01 (3 H, s), 1.91–1.77 (3 H, m), 1.80 (1 H, td, J = 12.2, 4.4 Hz), 1.73 (1 H, d, J = 12.6 Hz), 1.43 (2 H, dtd, J = 47.7, 15.3, 8.6 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 204.20, 169.97, 156.94, 146.84, 125.82, 121.11, 67.48, 53.75, 48.32, 37.62, 37.36, 32.65, 31.13, 27.32, 27.15, 25.22, 21.38. HRMS (FI): m/z calcd for C₁₇H₂₂O₃ [M]⁺: 274.1569; found: 274.1572. A mixture of 23 (33 mg, 0.123 mmol) and K₂CO₃ (50 mg, 0.362 mmol) in MeOH (500 μL) was stirred at room temperature for 3 h. To this was added EtOAc and brine. The mixture was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 2:1) to afford 5 as a white solid (27.0 mg, 0.118 mmol, 96%); mp 114–117 °C. IR (neat): ν = 3298 (br), 2927, 2853, 2366, 2358, 2342, 1655, 1614, 1031 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 5.75 (1 H, s), 5.57 (1 H, t, J = 7.4 Hz), 3.50 (1 H, t, J = 11.2 Hz), 2.86 (2 H, m), 2.71 (1 H, t, J = 6.0 Hz), 2.64 (1 H, q, J = 6.7 Hz), 2.49 (2 H, dt, J = 17.2, 8.3 Hz), 2.33–2.16 (3 H, m), 1.88 (2 H, t, J = 16.3 Hz), 1.70 (2 H, m), 1.50–1.37 (2 H, m). ¹³C NMR (125 MHz, CDCl₃): δ = 205.01, 157.10, 146.37, 125.82, 121.62, 64.68, 53.84, 48.58, 41.71, 37.34, 35.66, 31.11, 27.31, 27.30, 25.23. HRMS (FD): m/z calcd for C₁₅H₂₀O₂ [M]⁺: 232.1463; found: 232.1458.

Supplementary Material