An improved synthesis of the "miracle nutrient" coenzyme Q 10

Article abstract of DOI:10.1021/ol051329y

(Chemical Equation Presented) A new route to the key coupling partner, chloromethylated CoQ₀ (1), allows for direct formation of CoQ ₁₀ (3) via nickel-catalyzed cross-coupling with the side chain in the form of an in situ-derived vin

Full text of DOI:10.1021/ol051329y

ORGANIC
LETTERS
2005
Vol. 7, No. 19
4095-4097
An Improved Synthesis of the
“Miracle Nutrient” Coenzyme Q10
Bruce H. Lipshutz,*,† Asher Lower,† Volker Berl,‡ Karin Schein,‡ and
Frank Wetterich‡
Department of Chemistry and Biochemistry, UniVersity of California-Santa Barbara,
Santa Barbara, California 93106, and BASF AG, GV-B9,
67056 Ludwigshafen, Germany
lipshutz@chem.ucsb.edu
Received June 8, 2005
ABSTRACT
A new route to the key coupling partner, chloromethylated CoQ0 (1), allows for direct formation of CoQ10 (3) via nickel-catalyzed cross-
coupling with the side chain in the form of an in situ-derived vinyl alane (2).
Coenzyme Q10 (also known as ubiquinone; CoQ10, 3) is a
vital human nutrient responsible for shuttling electrons
through the respiratory chain. CoQ10 is used, in reduced form,
by all cells as an antioxidant, quenching free radicals and
thereby fighting the aging process. The extent of CoQ10 in
tissue has been linked to energy levels, and the benefits for
cardiac patients are especially well documented.1 With the
demand for CoQ10 as a dietary supplement already exceeding
worldwide supply, there is considerable incentive to find an
efficient synthetic route for its preparation. Herein we
describe an improved synthesis of key coupling partners
chloromethylquinone 1 and vinylalane 2. As previously
described,2 these reactive species combine under nickel
catalysis to generate ubiquinones directly.
toluene 5, the most expensive ingredient in our CoQ10
synthesis is solanesol 6, notwithstanding its status as a waste
product of tobacco.5 Isolation of this 45-carbon allylic alcohol
in both quantity and in high (>90%) purity is challenging
and can be costly depending upon the method of purifica-
tion.6 Thus, an ideal synthesis would seek to minimize the
extent to which intermediates based on solanesol are
manipulated en route to CoQ10.
In proceeding through intermediate 7, two additional
operations are required to arrive at the natural product: (1)
treatment with n-BuLi to effect detosylation and (2) autoxi-
dation mediated by catalytic amounts of racemic Jacobsen’s
Co(salen) complex.7 Although the yields are quite high, we
Our prior sequence2 (Scheme 1) relies on the nickel-
mediated coupling3,4 of 2 with readily available benzylic
chloride 4. Since 4 derives from inexpensive trimethoxy-
(3) (a) Lipshutz, B. H.; Mollard, P. M.; Pfeiffer, S. S.; Chrisman, W. J.
Am. Chem. Soc. 2002, 124, 14282. (b) Lipshutz, B. H.; Frieman, B.; Pfeiffer,
S. S. Synthesis 2002, 14, 2110.
(4) For more information regarding carboalumination/benzylic couplings,
see: Negishi, E. I.; Matsushita, H.; Okukado, N. Tetrahedron Lett. 1981,
22, 2715. Negishi, E. I. Handbook of Organopalladium Chemistry for
Organic Synthesis; John Wiley and Sons: Hoboken, NJ, 2002.
(5) (a) Rowland, R. L.; Latimer, P. H.; Giles, J. A. J. Am. Chem. Soc.
1956, 78, 4680. (b) Sheen, S. J.; davis, D. L.; DeJong, D. W.; Chaolin, S.
F. J. Agric. Food Chem. 1978, 26, 259.
(6) (a) Rao, V. C. N.; Chakraborty, M. K. Res. Ind. 1979, 24, 83. (b)
Yasumatsu, N.; Eda, M.; Tsujino, Y.; Noguchi, M. Agric. Biol. Chem. 1976,
40, 1757.
(7) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen,
K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc.
2002, 124, 1307.
† University of California-Santa Barbara.
‡ BASF AG.
(1) (a) Lenaz, G. Coenzyme Q. Biochemistry, Bioenergetics, and Clinical
Applications of Ubiquinone; Wiley-Interscience: New York, 1985. (b)
Trumpower, B. L. Function of Ubiquinones in Energy ConserVing Systems;
Academic Press: New York, 1982. (c) Thomson, R. H. Naturally Occurring
Quinones, 3rd ed.; Academic Press: New York, 1987. (d) Bliznakov, G.
G.; Hunt, G. L. The Miracle Nutrient Coenzyme Q10; Bantom Books: New
York, 1987.
(2) Lipshutz, B. H.; Bulow, G.; Fernandez-Lazaro, F.; Kim, S.-K.; Lowe,
R.; Mollard, P. M.; Stevens, K. L. J. Am. Chem. Soc. 1999, 121, 11664.
10.1021/ol051329y CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/18/2005

Scheme 1. Previous Synthesis of CoQ10 Proceeding through Tosylate 7
sought to devise a strategy that would provide CoQ10 in a
single coupling reaction. To realize this goal, efficient entry
to coupling partner 1 is needed such that the Ni-catalyzed
cross-coupling reaction serves as the final step. This concept
was developed for the syntheses of CoQ3-8 and recently
applied by Negishi to CoQ10.9
Standard Vilsmeier formylation of aromatic 5 followed
3a,10
by regioselective demethylation with AlCl3
proceeded
smoothly to afford phenol 11 in 94% yield over two steps
(Scheme 4). Reduction of the newly inserted aldehyde
8
The existing sequence to quinone 1 (Scheme 2) is less
than ideal in that it starts with far more expensive CoQ0 (9)
Scheme 4. Synthesis of Solanesylalkyne 8
Scheme 2. Previous Synthesis of 1 Starting from CoQ0
and requires four steps to install the chloromethyl functional-
ity, including a final modest-yielding reoxidation from a
protected hydroquinone 10 employing (NH4)2Ce(NO3)6.3 We
now describe a new and concise series of reactions beginning
with inexpensive trimethoxytoluene 5 that very efficiently
leads to chloromethylated para-quinone 1 (Scheme 3).
functionality using 0.26 equiv of NaBH4 in MeOH led to
benzylic alcohol intermediate 12 in 95% yield. We were
pleased to discover that phenolic oxidation can now be
carried out under the influence of the less expensive parent
Co(salen) complex to produce 13 in 91% yield. The final
step in this sequence employs a modified Vilsmeier chlorina-
tion to convert quinone alcohol 13 to the corresponding
chloride coupling partner 1 (five steps, 76% overall yield).
Although quinone 1 can be readily converted to CoQ10
by existing technology,7,8 we endeavored to improve the
three-step process leading from solanesol to alkyne 8, the
48-carbon precursor to vinyl alane 2 (Scheme 4). Thus,
solanesyl chloride 14 could be made by preformation of the
Vilsmeier salt (0.66 equiv of PCl3, 0.66 equiv of DMF neat)
to which was then added THF followed by substrate 6,
Scheme 3. New Route to 1 Based on Trimethoxytoluene 5
(8) (a) Lipshutz, B. H.; Kim, S.-K.; Mollard, P.; Stevens, K. L.
Tetrahedron 1998, 54, 1241. (b) Lipshutz, B. H.; Bulow, G.; Lowe, R. F.;
Stevens, K. L. J. Am. Chem. Soc. 1996, 118, 5512.
(9) Negishi, E.-i.; Liou, S.-Y.; Xu, C.; Huo, S. Org. Lett. 2002, 4, 261.
(10) Paul, E. G.; Wang, P. S.-C. J. Org. Chem. 1979, 44, 2307.
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Org. Lett., Vol. 7, No. 19, 2005

controlled amount of n-BuLi, afforded the desired terminal
alkyne 8 directly without observable byproduct formation
(cf. Scheme 4). This modification not only increases alkyne
purity but also shortens the sequence by one step (i.e., no
desilylation of 15 to 8 is required). Moreover, the alkylation
can be run at 0 °C to room temperature rather than the far
lower temperatures (-78 to -20 °C) used previously.3a
In summary, several major improvements have been made
in the synthesis of the nutraceutical coenzyme Q10. A new
sequence has been developed leading to the substituted para-
quinone headgroup 1, thereby reducing the extent of ma-
nipulation of the (relatively costly) side-chain and eliminating
two synthetic steps late in the synthesis. In addition, a
shortened route to the side-chain precursor, alkyne 8, has
been realized. Taken together, these advances significantly
enhance opportunities for potential industrial scale-up of this
essential vitaminlike compound.
Scheme 5. Competing Processes in the Alkylation of Lithiated
Trimethylsilylpropyne
thereby minimizing both reagents and avoiding the use of
DMF as a solvent. Prior formation of the salt, followed by
use of an alternative solvent, appears to be, to the best of
our knowledge, an unprecedented procedure.
While displacement of allylic chloride 14 with lithiated
trimethylsilylpropyne leads to protected alkyne 15 in 87%
yield,3 the remaining mass is composed of products of E2
elimination and, to a lesser degree, SN2′ addition (Scheme
5). The similar nature of the byproducts to the alkyne makes
separation difficult. Remarkably, use of dilithiopropyne,11
generated in situ by bubbling propyne gas through a
Acknowledgment. Financial support provided by the
BASF is gratefully acknowledged. We appreciate comments
and suggestions by Dr. Keith Drouet (Cambridge Major
Labs).
Supporting Information Available: Experimental pro-
cedures and characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(11) Pereira, A. R.; Cabezas, J. A. J. Org. Chem. 2005, 70, 2594.
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