Synthetic Studies on Huperzine R: Construction of the 1-Azabi­cyclo[5.4.3]tetradec-6-ene Core

Abstract

Synthetic studies on huperzine R are described. The 1-azabicyclo[5.4.3]tetradec-6-ene core was constructed by elimination of an ammonium salt formed at a position β to a carbonyl group.

Key words

alkaloids - ammonium salts - lactams - asymmetric synthesis - polycycles

• References

• 1 Tan C.-H, Chen G.-F, Ma X.-Q, Jiang S.-H, Zhu D.-Y. J. Nat. Prod. 2002; 65: 1021

For reviews of Lycopodium alkaloids, see:
• 2a MacLean DB. Alkaloids (San Diego, CA, U. S.) 1968; 10: 305
• 2b MacLean DB. Alkaloids (San Diego, CA, U. S.) 1973; 14: 48
• 2c MacLean DB. Alkaloids (San Diego, CA, U. S.) 1985; 26: 241
• 2d Ayer WA, Trifonov LS. Alkaloids (San Diego, CA, U. S.) 1994; 45: 233
• 2e Ma X, Gang DR. Nat. Prod. Rep. 2004; 21: 752
• 2f Kobayashi J, Morita H. Alkaloids (San Diego, CA, U. S.) 2005; 61: 1
• 2g Hirasawa Y, Kobayashi J, Morita H. Heterocycles 2009; 77: 679
• 2h Kitajima M, Takayama H. Top. Curr. Chem. 2012; 309: 1
• 2i Siengalewicz P, Mulzer J, Rinner U. Alkaloids (San Diego, CA, U. S.) 2013; 72: 1
• 2j Murphy RA, Sarpong R. Chem. Eur. J. 2013; 20: 42
• 2k Zeng C, Zhao J, Zhao G. Tetrahedron 2015; 71: 64

A biogenic route to the related alkaloid phlegmariurine A has been proposed; see:
• 3a Takayama H, Katakawa K, Kitajima M, Yamaguchi K, Aimi N. Tetrahedron Lett. 2002; 43: 8307
• 3b Nakayama A, Kogure N, Kitajima M, Takayama H. Org. Lett. 2009; 11: 5554
• 4 Cahn RS, Ingold C, Prelog V. Angew. Chem. Int. Ed. 1966; 5: 385
• 5 We envisioned that the transformation of the tertiary amine into an amide might be effected by a Polonovski reaction of the corresponding N-oxide.
• 6 Chiyoda K, Shimokawa J, Fukuyama T. Angew. Chem. Int. Ed. 2012; 51: 2505
• 7 Kitaori K, Mikami M, Furukawa Y, Yoshimoto H, Otera J. Synlett 1998; 499
• 8 Ok T, Jeon A, Lee J, Lim JH, Hong CS, Lee H.-S. J. Org. Chem. 2007; 72: 7390
• 9 Shibuya M, Tomizawa M, Suzuki I, Iwabuchi Y. J. Am. Chem. Soc. 2006; 128: 8412
• 10 (5S,6S,9R)-6-Allyl-9-{4-[tert-butyl(diphenyl)silyl]butyl}-7-oxa-1-azaspiro[4.4]nonane-2,8-dione (14a) and (5S,6R,9R)-6-Allyl-9-{4-[tert-butyl(diphenyl)silyl]butyl}-7-oxa-1-azaspiro[4.4]nonane-2,8-dione (14b) A stirred solution of spiro lactone 12 (4.2 g, 9.0 mmol) in CH₂Cl₂ (90 mL) was treated by dropwise addition of a 1.0 M solution of DIBAL-H in CH₂Cl₂ (27.0 mL, 27.0 mmol) at –78 °C, and the mixture was stirred for 30 min at –78 °C. The reaction was then quenched with MeOH, the mixture was warmed to 0 °C. After quenching the reaction with a 30% aqueous solution of potassium sodium tartrate, the mixture was warmed to r.t. The solution was partitioned between CH₂Cl₂ and H₂O, and the aqueous phase was extracted with CH₂Cl₂ (4 ×). The organic extracts were combined, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue containing the hemiacetal was used in the next step without further purification. A stirred solution of the hemiacetal (9.0 mmol) in THF (90 mL) was treated by dropwise addition of a 2.0 M solution of allylmagnesium chloride in THF (45 mL, 90 mmol) at r.t., and the mixture was stirred for 24 h at r.t. The mixture was then cooled to 0 °C and the reaction was quenched with sat. aq NH₄Cl at 0 °C. The solution was partitioned between CH₂Cl₂ and H₂O, and the aqueous phase was extracted with CH₂Cl₂ (4 ×). The organic extracts were combined, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue containing the diol was used in the next step without further purification. A stirred mixture of the diol (9.0 mmol) and AZADO (274 mg, 1.8 mmol) in MeCN (90 mL) and aqueous phosphate buffer (10 mL, pH 6.8) was treated with PhI(OAc)₂ (8.7 g, 27 mmol) at 0 °C, and the mixture was stirred for 3 h. The reaction was quenched with sat. aq Na₂S₂O₃, and the solution was partitioned between EtOAc and H₂O. The aqueous phase was extracted EtOAc (2 ×), and the combined organic extracts were washed with brine, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by medium-pressure liquid chromatography (silica gel, EtOAc–hexane) to give 14a as a white solid [yield: 1.4 g (2.8 mmol, 31%); 3 steps] and 14b as a clear oil [yield: 2.2 g (4.4 mmol, 50%), 3 steps]. 14a: ¹H NMR (400 MHz, CDCl₃): δ = 7.65 (dd, J = 7.8, 0.9 Hz, 4 H), 7.43–7.35 (m, 6 H), 7.30 (br s, 1 H), 5.82 (dddd, J = 17.0, 9.8, 7.5, 6.0 Hz, 1 H), 5.20 (dd, J = 17.0, 0.9 Hz, 1 H), 5.14 (dd, J = 9.8, 0.9 Hz, 1 H), 4.19 (dd, J = 8.5, 5.3 Hz, 1 H), 3.67 (t, J = 6.2 Hz, 2 H), 2.56–2.27 (m, 6 H), 2.14–2.08 (m, 2 H), 1.78–1.67 (m, 2 H), 1.62–1.40 (m, 3 H), 1.04 (s, 9 H). mp 106.0–106.3 °C. 14b: ¹H NMR (400 MHz, CDCl₃): δ = 7.64 (d, J = 7.2 Hz, 4 H), 7.43–7.35 (m, 6 H), 5.85–5.75 (m, 1 H), 5.67 (br s, 1 H), 5.20 (d, J = 17.6 Hz, 1 H), 5.19 (d, J = 9.2 Hz, 1 H), 4.32 (dd, J = 8.4, 4.8 Hz, 1 H), 3.66 (t, J = 6.0 Hz, 2 H), 2.46–2.34 (m, 8 H), 2.02–1.96 (m, 1 H), 1.78–1.70 (m, 1 H), 1.65–1.40 (m, 3 H), 1.03 (s, 9 H)

The stereochemistries of the isomers were determined by NOESY experiments on 23a and 23b (Figure 3), obtained from 14a and 14b, respectively, by a three-step conversion:
• 11a BH₃·THF, THF, 0 °C (37% from 14a, 42% from 14b);
• 11b Cp₂ZrHCl, THF, –20 °C;
• 11c NaBH₄, MeOH, 0 °C, [68% for 23a, 47% for 23b (2 steps)].
• 12 Schedler DJ. A, Li J, Ganem B. J. Org. Chem. 1996; 61: 4115
• 13 3-[(3S,3aS,11aR)-1-Oxooctahydro-4H-furo[3,4-b]pyrrolo[1,2-a]azepin-3-yl]propyl Methanesulfonate (19a) A stirred solution of 18a (80 mg, 0.22 mmol) in MeOH (2 mL) was treated with AcCl (155 μL, 2.2 mmol) at 0 °C and the mixture was stirred for 15 min at 0 °C. The reaction was quenched with sat. aq NaHCO₃, and the solution was partitioned between EtOAc and H₂O. The aqueous phase was extracted with EtOAc (2 ×), and the organic extracts were combined, washed with brine, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue containing the alcohol product was used in the next step without further purification. A stirred solution of the residue and TMEDA (97 μL, 0.66 mmol) in CH₂Cl₂ (1 mL) was treated with MsCl (34 μL, 0.44 mmol) at –78 °C. The mixture was stirred for 10 min at –78 °C then warmed to 0 °C and stirred for a further 20 min. The reaction was quenched with sat. aq NaHCO₃, and the solution was partitioned between EtOAc and H₂O. The aqueous phase was extracted with EtOAc, and the organic extracts were combined, washed with brine, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue containing mesylate 19a was used in the next step without further purification.
• 14 (3S)-5,6,8,9,10,11-Hexahydro-3H-3,7-propanofuro[3,4-e]-azecin-1(4H)-one (21a) Mesylate 19a (0.22 mmol) was dissolved in MeOH (1 mL) at r.t. and the mixture was stirred at 40 °C for 50 min. i-Pr₂NEt (115 μL, 0.66 mmol) was added at 40 °C, and the mixture was stirred for 30 min then cooled to r.t. The reaction was quenched with sat. aq NaHCO₃, and the solution was partitioned between EtOAc and H₂O. The aqueous phase was extracted with EtOAc (2 ×), and the organic extracts were combined, washed with brine, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (Merck HPTLC silica gel 60 NH₂ F₂₅₄S, 33% EtOAc–hexane) to give a white solid; yield: 26 mg (0.11 mmol, 51%; 3 steps); mp 149.0–149.1 °C. IR (neat): 2923, 2850, 2793, 1727, 1658, 1446, 1108, 1034, 990 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 4.86 (br s, 1 H), 2.74 (td, J = 12.7, 3.6 Hz, 1 H), 2.61 (td, J = 13.6, 4.4 Hz, 1 H), 2.53–2.47 (m, 2 H), 2.27 (dt, J = 14.7, 3.0 Hz, 1 H), 2.25–1.75 (m, 7 H), 1.72–1.65 (m, 2 H), 1.56–1.45 (m, 3 H), 1.28–1.23 (m, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 174.9 (C), 165.1 (C), 125.3 (C), 81.4 (CH), 57.2 (CH₂), 56.9 (CH₂), 50.4 (CH₂), 32.1 (CH₂), 30.3 (CH₂), 29.0 (CH₂), 27.2 (CH₂), 26.0 (CH₂), 24.6 (CH₂), 20.0 (CH₂). HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₄H₂₂NO₂: 236.1649; found: 236.1651.