Synlett 2015; 26(15): 2131-2134
DOI: 10.1055/s-0034-1380425
letter
© Georg Thieme Verlag Stuttgart · New York

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

Hiroshi Kumazaki
a   Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
,
Rie Nakajima
a   Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
,
Yuka Bessho
a   Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
,
Satoshi Yokoshima*
b   Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan   Email: fukuyama@ps.nagoya-u.ac.jp
,
Tohru Fukuyama*
b   Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan   Email: fukuyama@ps.nagoya-u.ac.jp
› Author Affiliations
Further Information

Publication History

Received: 11 April 2015

Accepted after revision: 13 May 2015

Publication Date:
11 August 2015 (online)


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.

Supporting Information

 
  • References

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      A biogenic route to the related alkaloid phlegmariurine A has been proposed; see:
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  • 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.
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  • 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.