Convenient, scalable synthesis of 2-methyl-3-(3′,3′-carboxymethylpropyl)-1,4-naphthoquinone, the principal vitamin K urinary metabolite

Article abstract of DOI:10.1016/j.tetlet.2016.11.043

The ultimate metabolite of vitamin K, 2-methyl-3-(3′,3′-carboxymethylpropyl)-1,4-naphthoquinone (1), has been shown to be biologically active and may be used as a measure of vitamin K levels in the body. We report a facile, five-step synthesis of 1 that requires only two isolated intermediates and a single chromatographic purification, and provides the title product in 26% overall yield. The structure of one of the intermediates was confirmed by X-ray crystallography.

Full text of DOI:10.1016/j.tetlet.2016.11.043

Accepted Manuscript
Convenient, scalable synthesis of 2-methyl-3-(3’,3’-carboxymethylpropyl)-1,4-
naphthoquinone, the principal vitamin K urinary metabolite
Erik S. Goebel, George Barany
PII:
S0040-4039(16)31511-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.11.043
TETL 48329
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 September 2016
2 November 2016
8 November 2016
Please cite this article as: Goebel, E.S., Barany, G., Convenient, scalable synthesis of 2-methyl-3-(3’,3’-
carboxymethylpropyl)-1,4-naphthoquinone, the principal vitamin K urinary metabolite, Tetrahedron Letters (2016),
doi: http://dx.doi.org/10.1016/j.tetlet.2016.11.043
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Convenient, scalable synthesis of 2-methyl-3-(3’,3’-carboxymethylpropyl)-1,4-
naphthoquinone, the principal vitamin K urinary metabolite
Erik S. Goebel a,b,* and George Baranyb
aOcchem Labs, 1000 Westgate Drive, Saint Paul, MN 55114, USA
bDepartment of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, MN 55455, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The ultimate metabolite of vitamin K, 2-methyl-3-(3’,3’-carboxymethylpropyl)-1,4-
naphthoquinone (1), has been shown to be biologically active and may be used as a measure of
vitamin K levels in the body. We report a facile, five-step synthesis of 1 that requires only two
isolated intermediates and a single chromatographic purification, and provides the title product
in 26% overall yield. The structure of one of the intermediates was confirmed by X-ray
crystallography.
Available online
Keywords:
Vitamin K
©2016 Elsevier Ltd. All rights reserved.
Metabolite
Total Synthesis
Natural Product
Naphthoquinone
1

1. Introduction
Vitamin K1 refers to a family of molecules based upon the 2-methyl-1,4-naphthoquinone
moiety2, with variability of the side-chain at the 3-position. This family is divided into the plant-
derived phylloquinone (vitamin K1), having a phytyl side-chain, and the menadiones (vitamin
K2), which have isoprenoid side-chains of varying lengths. In humans, vitamin K is essential for
3
blood coagulation and bone health, as well as further functions.4 The title compound (1 in
Scheme 1) is a human metabolite formed from vitamin K, and has been shown to be biologically
active.5,6,7
This paper reports a convenient and scalable synthesis of 1 that uses only inexpensive reagents
and catalysts. Literature routes to 1 entail long synthetic routes,8 complex product mixtures, and
relatively poor overall yields.9 After our studies were underway, Teitelbaum and coworkers10
reported the most straightforward route to date for synthesis of 1, but their method still requires
an expensive starting material and catalyst; their overall yield was 6% encompassing five steps,
including one particularly low-yielding (17%) step.
2. Results and Discussion
The present synthesis begins with Michael addition of diethyl methyl malonate (2) onto benzyl
acrylate (3). The reaction is run neat in the presence of catalytic NaOH, and gives product 4
quickly (5 min at rt). The NaOH is removed by simple filtration through a plug of silica, using
EtOAc as eluent, to provide a solution of 4 that is used directly in the next reaction, i.e.,
hydrogenolysis utilizing a low loading of Pd/C catalyst (0.5 mol % Pd) under 1 atm of H2. Thus,
free acid 5 is obtained in 99% yield, over two steps, on a multi-gram scale, without the need for
purification. Radical coupling between 5 and menadione is accomplished by an adaptation of the
Kochi-Anderson reaction,11,12,13 with pure product 6 obtained readily after workup by simple
trituration. The malonate ester moiety of 6 is then saponified to produce the diacid species as an
2

intermediate. While continued application of heat provides the decarboxylation product 1
directly, we find that treatment with N,N’-carbonyldiimidazole (CDI) is a milder way (fewer side
products) to effect decarboxylation.14 Upon completion of all chemical steps, the single
chromatographic purification of the entire route is accomplished on silica gel, providing pure 1
in an overall yield of 26%.
Scheme 1. Synthesis of vitamin K metabolite (1).
3

Note that the structure of intermediate 6 was confirmed by x-ray crystallography (Figure
1). Bond lengths and angles were within expected ranges.
3. Conclusion
This synthesis of vitamin K metabolite 1 uses only inexpensive starting materials and reagents,
and avoids protecting groups. The synthesis is readily scalable, and can be conducted with no
special precautions to exclude air. Upon completion of all synthetic steps, only one
chromatographic purification step is required. Due to its simplicity and robust nature, we expect
this approach to become the primary method to produce 1, along with numerous analogous
compounds.
Figure 1. Crystal structure of 2-methyl-3-(3',3'-dicarboxybutyl)-1,4-naphthoquinone diethyl ester (6). For
clarity, hydrogens are not shown.
4. Acknowledgments
The authors would like to acknowledge the CHEM5755 (X-Ray Crystallography) course
and the University of Minnesota for providing the crystal structure determination for compound
4

6. We acknowledge helpful discussions with both Dr. Victor G. Young, Jr. and Mr. Christopher
Roberts. This work was supported by Occhem Labs, LLC and the Barany Research Fund.
5. Supplementary data
Supplementary data (synthetic procedures, analytical data, and NMR spectra) associated with
this article can be found, in the online version, at: Crystallographic data (excluding structure
factors) for the structures in this paper have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication no. CCDC 1503070. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK,
(fax: +44-(0)1223-336033 or e-mail:deposit@ccdc.cam.ac.Uk).
1 Suttie, J. W.; Cadenas, E.; Packer, L.; Vitamin K in Health and Disease; CRC Press, 2009.
2 Mal, D.; Ghosh, K.; Jana, S. Org. Lett. 2015, 17, 5800.
3 Vermeer, C.; Gijsbers, B. L. M. G.; Crackin, A. M.; Groenen-Van Dooren, M. C. L.; Knapen, M. H. J. J. Nutr.
1996, 126, 1187S.
4 Cockayne, S.; Adamson, J.; Lanham-New, S.; Shearer, M. J.; Gilbody, S.; Torgerson, D. J. Arch. Intern. Med.
2006, 166, 1256.
5 Mc Burney, A.; Shearer, M. J.; Barkhan,, P. Biochem. Med. 1980, 24, 250.
6 Soper, R. J.; Oguz, C.; Emery, R.; Pitsillides, A. A.; Hodges, S. J. Mol. Nutr. Food Res. 2014, 58, 1658.
7 Shearer, M. J.; Bach, A.; Kohlmeier, M. J. Nutr. 1996, 126, 1181S.
8 Fujii, S.; Shimizu, A.; Takeda, N.; Oguchi, K.; Katsurai, T. Shirakawa, H.; Komai, M.; Kagechika, H. Bioorg.
Med. Chem. 2015, 23, 2344.
9 Watanabe, M.; Kawada, M..; Nishikawa, M.; Imada, I.; Morimoto, H. Chem. Pharm. Bull. 1974, 22, 556.
10 Teitelbaum, A. M.; Scian, M.; Nelson, W. L.; Rettie, A. E. Synthesis 2015, 47, 944.
11 Naturale, G.; Lamblin, M.; Commandeur, C.; Felpin, F.-X.; Dessolin, J. Eur. J. Org. Chem. 2012, 2012, 5774.
12 Deblander, J.; Van Aeken, S.; Jacobs, J.; De Kimpe, N.; Abbaspour Tehrani, K.; Eur. J. Org. Chem. 2009, 2009,
4882
13 Mal, D.; Ray, S. Eur. J. Org. Chem. 2008, 2008, 3014.
14 Lafrance, D.; Bowles, P.; Leeman, K.; Rafka, R. Org. Lett. 2011, 13, 2322.
5

Graphical abstract

Highlights
• all steps air-tolerant
• two isolated intermediates
• single chromatographic step
• 26% overall yield