A short, highly efficient synthesis of coenzyme Q10

Article abstract of DOI:10.1021/ja021015v

The most efficient synthesis reported to date of ubiquinone (CoQ₁₀) is described. A sequence consisting of six operations is involved which leads to crystalline material in an overall yield of >64%. Copyright

Full text of DOI:10.1021/ja021015v

Published on Web 11/09/2002
A Short, Highly Efficient Synthesis of Coenzyme Q10
Bruce H. Lipshutz,* Paul Mollard, Steven S. Pfeiffer, and Will Chrisman
Department of Chemistry and Biochemistry, UniVersity of California, Santa Barbara, California 93106
Received July 25, 2002
Scheme 1. Retrosynthetic Analysis of CoQ10
Open any textbook on basic biochemistry and there is likely to
be considerable discussion devoted to the essential roles played by
coenzyme Q10.1 Its presence in virtually every cell in the human
body accounts for its alternative name: ubiquinone. With close to
three decades of biomedical science to its credit, the combination
of a polar headgroup attached to a 50 carbon tail is a remarkable
construct of evolution. Oftentimes referred to as the “miracle
nutrient”,2 CoQ10 plays a vital role in maintaining human health
and vigor. Its involvement in mitochondrial processes such as
respiration, cellular production of ATP, maintenance of heart muscle
strength, quenching of free radicals in the battle against aging, and
enhancement of the immune system are only a few of its many
virtues.3 Although much of society is unaware of the importance
of ubiquinone, chemists on the other hand have devoted consider-
able effort in attempting to devise economically viable routes to
this nutraceutical,4 as well as its lower homologues.5 In this report,
we describe our ongoing work in this field which has led to a very
short and highly efficient synthesis of CoQ10.
Attachment of the two subsections of the target, that is, a polar
quinone or aromatic precursor, and a (49 carbon) lipophilic
hydrocarbon side chain, was anticipated to occur via a nickel(0)-
catalyzed cross-coupling involving in-situ-derived vinyl alane 1
(Scheme 1), as previously developed for related couplings.6 Starting
with solanesol (3), isolated in quantity from tobacco leaves,7
acetylene 2 could be prepared as illustrated in Scheme 2. Thus,
conversion of 3 to the corresponding chloride 4 (96%) is best done
using PCl3 in DMF, which gives rise to material of excellent quality
simply upon workup. Treatment of 4 with lithiated TMS-propyne
(1.2 equiv)8 in THF gives intermediate 5 in 87% isolated yield.
Exposure of 5 to warm sodium ethoxide in ethanol (or 95% EtOH)
led essentially quantitatively to terminal alkyne 2.
Scheme 2. Preparation of Alkyne 2
The quinone section of CoQ10 was initially planned starting with
the readily available and inexpensive crystalline benzaldehyde
derivative 6,9 because selective demethylation with AlCl3 is known10
and could be effected in high yield (94%; Scheme 3). After
tosylation (98%), the resulting crystalline aldehyde 7 was smoothly
converted in one pot to an ideal coupling partner, the derived
benzylic chloride 8 (95%; mp 110-110.5 °C). Given the inexpen-
sive nature of both 6 and 7, and the newly developed process for
direct conversion of 7 to 8, this benzylic chloride is now offered
in quantity.9
Scheme 3. Generation of Coupling Partner 8
With 2 available in three steps and 8 provided commercially,
the coupling could be carried out using nickel catalysis in standard
fashion (Scheme 4).6 Initial Negishi carboalumination11 of 2 led to
intermediate 1. Exposure of 1 (1.3 equiv) to 3 mol percent Ni(0)
and halide 8 (1 equiv) provided the CoQ skeleton 9. This oily
product could then be detosylated using 2 equiv of n-BuLi at 0 °C,
thereby generating free phenol 10 as a stable crystalline solid (92%;
mp 49-50.5 °C). Oxidation of 10 using catalytic amounts of
Jacobsen’s12 Co(salen) complex13 under an oxygen atmosphere at
ambient temperature14 afforded yellow-orange, all-E, CoQ10 in 94%
isolated yield.
* To whom correspondence should be addressed. E-mail: lipshutz@chem.ucsb.edu.
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J. AM. CHEM. SOC. 2002, 124, 14282-14283
10.1021/ja021015v CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4. Cross-Coupling and Final Conversion to CoQ10
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In summary, a novel route to CoQ10 has been realized, which
calls for six total operations (3 f 4 f 5 f 2 f 9 f 10 f CoQ10)
to arrive at ubiquinone in 64% overall yield, which constitutes the
most efficient synthesis reported to date.4,15 Synthetic CoQ10 was
identical to authentic material in all respects.16 Particularly note-
worthy is the fact that by virtue of the synthetic sequence outlined
herein, typical impurities such as the corresponding cis-isomer and
CoQ9, oftentimes found in CoQ10 which is produced industrially
almost entirely by fermentation,17 are completely averted.
(7) Kanazawa, M.; Takahashi, T. In Biochemical and Clinical Aspects of
Coenzyme Q10; Yamamura, Y., Folkers, K., Ito, Y., Eds.; Elsevier:
Amsterdam, 1981; Vol. III, p 31. Rowland, R. L.; Latimer, P. H.; Giles,
J. A. J. Am. Chem. Soc. 1956, 78, 4680. Solanesol was provided to us by
Bommidala Brothers of Guntur (India), imported via Sarchem Labs
(Navesink, NJ).
Acknowledgment. Financial support provided by the ACS
(Cope Scholar award to B.H.L.), the NSF (CHE 97 34813), and
Boehringer-Ingelheim in the form of a graduate student fellowship
(to S.S.P.) is warmly acknowledged. We are indebted to Dr. Sam
Kumar (Sarchem Labs) for supplying solanesol, Mr. Raj Chopra
(Tishcon Corp.) for providing authentic samples of CoQ10, and Mr.
Jack Etheridge (Organic Technologies) for a generous sample of
TMS-propyne used in this work.
(8) Corey, E. J.; Ruecker, C. Tetrahedron Lett. 1982, 23, 719. TMS-propyne
was supplied to us by Organic Technologies.
(9) Other organic intermediates were provided by Sarchem Labs (NJ).
(10) Paul, E. G.; Wang, P. S.-C. J. Org. Chem. 1979, 44, 2307. Aquila, v. H.
Liebigs Ann. Chem. 1969, 721, 220.
(11) Negishi, E. Acc. Chem. Res. 1987, 20, 65. Negishi, E.; Van Horn, E. E.;
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Chem. 1981, 53, 2333. Van Horn, D. E.; Negishi, E. J. Am Chem. Soc.
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(12) 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. Nonracemic material was used for convenience; it is com-
mercially available from Strem Chemicals. See also http://www.rhodi-
achirex.com.
Note Added in Proof: Results from a recently completed
study by the NIH on the beneficial effects of CoQ10 on those
who suffer from Parkinson’s disease have been disclosed; see
www.msnbc.com/news/821158.asp?0si)-.
(13) The simpler, achiral Co(salen) complex works well, although the isolated
yield was 84%, the remaining mass corresponding to ubiquinol. Thus,
the limited lifetime of this catalyst relative to the Jacobsen analogue
Supporting Information Available: Experimental procedures and
spectroscopic data for all intermediates (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
appears to be responsible for the incomplete oxidation of 10 to CoQ10
.
Bazendale, I. R.; Lee, A.-L.; Ley, S. V. Synlett 2001, 9, 1482. Kraus, G.
A.; Choudhury, P. K. Tetrahedron Lett. 2001, 42, 6649. Van Dort, H.
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