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One-Pot Synthesis of MK-9; 2-methyl-3-((2E,6E,10E,14E,18E,22E,26E,30E)-3,7,11,15,19,23,27,31,35- nonamethylhexatriaconta-2,6,10,14,18,22,26,30,34-nonaen-1-yl)naphthalene-1,4-dione (Vitamin K2 variant: MK-9)

SyntheticPage 944
Submitted Jan 09, 2021, published Feb 10, 2021
Satyanarayana Battula (satyamssd@gmail.com), Nanaji Yerramsetti (naniorg@gmail.com), Nitin Patel (nitin@aether.co.in)
A contribution from Satyam's Group


			Reaction Scheme: One-Pot Synthesis of MK-9

Chemicals Used

1. Solanesol (Sigma-Aldrich) >90%, S8754

2. Diels-Alder adduct of menadione

3. Ghosez reagent (Sigma-Aldrich) 96%, 498270

4. tBuOK (Sigma-Aldrich) 98%, 156671

5. Toluene (Rankem), directly used without drying

6. 8-Crown-6 (Sigma-Aldrich) 99%, 186651

7. AcOH (Sigma-Aldrich) >99%, A6283

8. Bu3MeNBr (Sigma-Aldrich) >98%, 70444

9. Ethyl acetate (SD Fine Chemicals Ltd), directly used without drying

10. Hexane (SD Fine Chemicals Ltd), directly used without drying

Procedure

Ghosez reagent (1-Chloro-N,N,2-trimethyl-1-propenylamine; 0.146 mL, 1.1 mmol) was added dropwise over 20 min to a solution of solanesol (631.1 mg, 1.0 mmol) in toluene (30 mL) at 15 °C under inert (N2) environment. Then the reaction mixture was stirred at 15 °C with the help of Julabo chiller for 6 h, and after halogenation of solanesol, Diels-Alder adduct 4a-methyl-1,4,4a,9a-tetrahydro-1,4-methanoanthracene-9,10-dione (290.0 mg, 1.01 mmol), t-BuOK (123.2 mg, 1.1 mmol) and 18-crown-6 (13.2 mg, 0.05 mmol) were added to reaction mixture at 0 °C for 6 h. After 6 h, acetic acid followed by tributylmethylammonium bromide (14.0 mg, 0.05 mmol) was added to the reaction mixture at 120 °C. Stirring was continued further at the same 120 ºC until completion of the reaction. The reaction status was monitored continually by TLC, after its completion ethyl acetate was added to the reaction mixture followed by water. The aqueous layer was extracted with EtOAc (3 × 15.0 mL). The combined organic extract was washed with H2O (3 × 15.0 mL) and brine (20.0 mL) and dried over Na2SO4. The solvent was removed under reduced pressure to give crude product which was purified by flash column chromatography on silica gel (# 230-400 mesh) using ethyl acetate in petroleum ether to afford the pure products MK-9 (610 mg, 0.77 mmol, 77%) as a yellow solid. 

Author's Comments

  • Ghosez reagent is used here to generate efficiently solanesyl chloride from solanesol.
  • Using less efficient leaving group/ more efficient nucleophile (Cl) in the solanesyl chloride makes it more prominent reaction and causes low possibilities of side reactions.
  • Solanesyl chloride coupled with Diels-Alder adduct of menadione followed by the elimination of cyclopentadiene to produce MK-9. 
  • The menaquinone MK-9 in this procedure was obtained as an exclusive diastereomer with significant yield (77%, 99.9% purity by chiral HPLC).

Data

1H NMR (400 MHz, CDCl3): δ (ppm) 8.89−8.39 (m, 2H), 7.64−7.98 (m, 2H), 5.22−4.98 (m, 9H), 3.36 (d, J = 7.2 Hz, 2H), 2.80 (s, 3H), 2.18−1.88 (m, 37H), 1.78 (s, 3H), 1.66 (s, 3H), 1.60-1.48 (m, 19H).

m.p.: 50.8 - 61.6 °C.


Lead Reference

N. Yerramsetti, L. Dampanaboina, V. Mendu, and S. Battula, Synergistic Factors Ensue High Expediency in the Synthesis of Menaquinone [K2] Analogue MK-6: Application to Access an Efficient One-Pot Protocol to MK-9. Tetrahedron, 2020, 76, 131696.

(https://doi.org/10.1016/j.tet.2020.131696)

Other References

  • A. Rüttimann, Recent Advances in the Synthesis of K-Vitamins. Chimia 1986, 40, 290–306.
  • A. Baj, P. Walejko, A. Kutner, L. Kaczmarek, J. W. Morzycki, S. Witkowski, Org. Process Res. Dev, 2016, 20, 1026-1033.(https://doi.org/10.1021/acs.oprd.6b00037)
  • F. Munyemana, I. George, A. Devos, A. Colens, E. Badarau, A. -M. Frisque-Hesbain, A. Loudet, E. Differding, J.-M. Damien, J. Remion, J. V. Uytbergen, L. Ghosez, Tetrahedron 2016, 72, 420-430. (https://doi.org/10.1016/j.tet.2015.11.060)

Supplementary Information

Data File.docx

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Get structure file (.cdx, .sk2, .mol)

Keywords: alcohols, alkyl/alkenyl/aryl halides, nucleophilic, substitution, terpenoid, thermal, Vitamin K2

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