A novel route to coenzyme Q(n)

Full text of DOI:10.1021/ja961285b

5512
J. Am. Chem. Soc. 1996, 118, 5512-5513
Scheme 1
A Novel Route to Coenzyme Qn
Bruce H. Lipshutz,* Gerd Bulow, Richard F. Lowe, and
Kirk L. Stevens
Department of Chemistry, UniVersity of California
Santa Barbara, California 93106-9510
ReceiVed April 18, 1996
Scheme 2
Scheme 3
The ubiquinones, also commonly called coenzyme Qn (n )
1-12), constitute essential cellular components of many life
forms. In humans, CoQ10 is the predominant member of this
class of polyprenoidal natural products and is well-known to
function primarily as a redox carrier in the respiratory chain.1
Several approaches to the ubiquinones have been developed over
the past 3-4 decades, attesting to their importance. Recent
contributions2 have invoked such varied approaches as Lewis
acid-induced prenoidal stannane additions to quinones,2a reitera-
tive Pd(0)-catalyzed couplings of doubly activated prenoidal
chains with allylic carbonates bearing the required aromatic
nucleus in protected form,2b and a Diels-Alder, retro Diels-
Alder route to arrive at the quinone oxidation state directly.2c,d
Nonetheless, all are lengthy, linear rather than convergent, and/
or inefficient. Moreover, problems in controlling double bond
stereochemistry using, e.g., a copper(I)-catalyzed allylic Grig-
nard-allylic halide coupling can lead to complicated mixtures
of geometrical isomers that are difficult to separate given the
hydrocarbon nature of the side chains.3 An alternative discon-
nection that relies on the well-known4 maintenance of olefin
geometry in group 10 coupling reactions was envisioned,
potentially involving a vinyl organometallic and a benzylic
halide (Scheme 1). We now report that such couplings, using
the appropriate reaction partners and based on unprecedented
Ni(0) catalysis, are quite general and can be used to directly
afford known precursors5 to various CoQn, as well as related
systems such as found with vitamins K1 and K2.
Scheme 4
vinylalane 5 and 5 mol % Ni(0) afforded CoQ4 precursor 6,
again in high isolated yield (87%), in minutes at room
temperature. EVen lesser amounts of catalyst, as low as 0.5
mol %, are equally effectiVe.10 Only traces of product were
observed using Pd(0) under identical conditions, while refluxing
the reaction mixture for 12 h returned no starting material and
only 68% of 6 (Scheme 3).
Initially, it was anticipated that Pd(0)-catalyzed cross-coupling
of a vinylalane (2, LnM ) Me2Al) with benzylic electrophile 1
would result in the desired C-C bond, notwithstanding the
existence of but a single (partial) report on such a carboalumin-
ation-benzylic coupling process.6 Studies using model vinyl-
alane 37 and p-fluorobenzyl chloride in the presence of 5 mol
% Pd(PPh3)4 gave coupling product 4 in 67% yield after 12 h
at room temperature. By contrast, switching to cataytic Ni(0)8
afforded 92% of 4 in <15 min (Scheme 2). More relevant to
the CoQn issue, and a far more challenging coupling, is the case
of chloride 1, X ) Cl.9 Treatment of this halide with the C19
Extension of this approach to the protected hydroquinone
precursors of CoQ3 (8) and CoQ5 (9) could also be accomplished
under similar conditions (Scheme 4). Acetylenic chains (7)
employed were constructed from commercially available prenoi-
dal alcohols or halides. Likewise, precursors to vitamins11 K1
(8) Ni(0) has been generated in this study Via two methods. (1) Treatment
of Ni(acac)2 in THF with DIBAL-H in the presence of 4 equiv of PPh3,
cf.: Negishi, E. I.; King, A. O.; Okukado, N. J. Org. Chem. 1977, 42, 1821.
(2) Treatment of NiCl2(PPh3)2 with 2 equiv of n-BuLi in the presence of 2
equiv of PPh3, cf. the preparation of Pd(PPh3)4 Via reduction of Pd(PPh3)2-
Cl2 with n-BuLi in the presence of 2 equiv of PPh3: Negishi, E.; Takahashi,
T.; Akiyoshi, K. J. Chem. Soc., Chem. Commun. 1986, 1338.
(9) Prepared by chloromethylation of the corresponding aromatic, cf.:
Shunk, C. H.; Wolf, D. E.; McPherson, J. F.; Linn, B. O.; Folkers, K. J.
Am. Chem. Soc. 1960, 82, 5914.
(10) Preliminary studies with catalyst levels as low as 0.5 mol % Ni(0)
at ambient temperatures have led to equally efficient couplings, e.g., en
route to CoQ4 precursor 6. As with simpler systems, Pd(0) was ineffective
under these conditions.
* Fax: 805-893-8265. E-mail: lipshutz@sbmm1.ucsb.edu.
(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 occuring
quinones, 3rd ed.; Academic Press: New York, 1987. (d) Bliznakov, E.
G.; Hunt, G. L. The Miracle Nutrient Coenzyme Q10; Bantom Books: New
York, 1987.
(2) (a) Naruta, Y. J. Org. Chem. 1980, 45, 4097. (b) Eren, D.; Keinan,
E. J. Am. Chem. Soc. 1988, 110, 4356 and references therein. (c) Van Lient,
W. B. S.; Steggerda, W. F.; Esmeijer, R.; Lugtenburg, J. Rec. TraV. Chim.
Pays-Bays 1994, 113, 153. (d) Ru¨ttimann, A.; Lorenz, P. HelV. Chim. Acta
1990, 73, 790. (e) Terao, S.; Kato, K.; Shiraishi, M.; Morimoto, H. J. Chem.
Soc., Perkin Trans. 1 1978, 1101.
(3) Yanagisawa, A.; Nomura, N.; Noritake, Y.; Yamamoto, H. Synthesis
1991, 1130.
(4) Hegedus, L. S. Transition Metals in the Synthesis of Complex Organic
Molecules; University Science Books: Mill Valley, CA, 1994.
(5) Oxidation of protected hydroquinone precursors leads directly to the
corresponding CoQn.2
(6) Negishi, E. I.; Matsushita, H.; Okukado, N. Tetrahedron Lett. 1981,
22, 2715.
(7) Van Horn, D. E.; Negishi, E. J. Am. Chem. Soc. 1978, 100, 2252.
Negishi, E.; Van Horn, D. E.; Yoshida, T. J. Am. Chem. Soc. 1985, 107,
6639. Matsushita, H.; Negishi, E. Org. Synth. 1984, 63, 31. Negishi, E.
Pure Appl. Chem. 1981, 53, 2333.
(11) (a) Tso, H-H.; Chen, Y-J. J. Chem. Res. 1995, 104. (b) Kozhevnikov,
I. V.; Kulikov, S. M.; Chukaeva, N. G.; Kirsanov, A. T.; Letunova, A. B.;
Blinova, V. I. React. Kinet. Catal. Lett. 1992, 47, 59. (c) Schmid, R.;
Antoulas, S.; Ru¨ttimann, A.; Schmid, M.; Vecchi, M.; Weiser, H. HelV.
Chim. Acta 1990, 73, 1276. (d) Review: Ru¨ttimann, A. Chimia 1986, 40,
290 and references therein. Masaki, Y.; Hashimoto, K.; Kaji, K. Chem.
Pharm. Bull. 1984, 10, 3959. (e) Godschalx, J. P.; Stille, J. K. Tetrahedron
Lett. 1983, 24, 1905. (f) Do¨tz, K. H.; Pruskil, I. J. Organomet. Chem. 1981,
209, C4. (g) Chenard, B. L.; Manning, M. J.; Raynolds, P. W.; Swenton, J.
S. J. Org. Chem. 1980, 45, 378.
S0002-7863(96)01285-1 CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 23, 1996 5513
Scheme 5
In conclusion, a conceptually unique strategy has been
uncovered for preparing CoQn and vitamin K precursors
involving vinylalanes and benzylic chlorides. The rapidity and
efficiency of the process derives from catalysis Via inexpensive
Ni(0), rather than Pd(0). The potential here for the former
catalyst to mediate cross-couplings of this type was not only
previously unappreciated but, in fact, unknown. Further
developments which rely on a novel linchpin approach toward
precursors of the higher, extremely expensive homologues of
14
those prepared herein (i.e., CoQ6-9
)
are in progress and will
be reported in due course.
Table 1. Ni(0)-Catalyzed Reactions of Vinylalanes with Benzylic
Acknowledgment. Financial support provided by the National
Institutes of Health (GM 40287) and NATO (postdoctoral fellowship
to G.B.) is warmly acknowledged, with thanks.
Chloridesa
Supporting Information Available: Spectral data for all precursors
to CoQ3-5, vitamins K1 and K2(20), and new compounds in Table 1 (29
pages). This material is contained in many libraries on microfiche,
immediately follows this article in the microfilm version of the journal,
can be ordered from the ACS, and can be downloaded from the Internet;
see any current masthead page for ordering information and Internet
access instructions.
JA961285B
(13) A general procedure for the preparation of 6 is as follows. Carbo-
alumination: To a 10 mL round-bottom Schlenk flask (equipped with a
medium ground glass filter frit) was added zirconocene dichloride (73 mg,
0.25 mmol) under an argon atmosphere. A solution of trimethylaluminum
(0.75 mL, 2.0 M in hexane, 1.5 mmol) was added at 0 °C and stirred under
reduced pressure until the hexane was removed. 1,2-Dichloroethane was
added (1.0 mL), and the solution was allowed to stir and warm to room
temperature over 30 min. To this solution was added alkyne 7 (n ) 4, 244
mg, 1.0 mmol), and the mixture was stirred at 0 °C for 30 min, after which
carboalumination was complete, as determined by GC. The dichloroethane
was pumped off in Vacuo, and freshly distilled hexane (2 mL) was added,
which was then also removed in Vacuo. Additional hexane (5 mL) was
then added to the flask to precipitate the zirconium salts. The hexane layer
was removed by carefully decanting and filtering through the frit, with great
care taken to avoid contamination by the zirconium salts. The leftover salts
were not washed. The orange hexane solution was concentrated under
reduced pressure and dissolved in THF (2.0 mL). Nickel-catalyzed
coupling: To a 5 mL round-bottom flask were added bis(triphenylphos-
phine)nickel(II) chloride (Aldrich, 22 mg, 0.033 mmol) and triphenylphos-
phine (18 mg, 0.067 mmol) under an argon atmosphere at room temperature.
THF (1.0 mL) was added, followed by n-butyllithium (0.136 mL, 0.49 M
in hexane, 0.067 mmol). The deep red solution was allowed to stir for 30
min, at which time benzyl chloride 1 (174 mg, 0.67 mmol) was added, and
the subsequent dark blue solution was stirred for an additional 5 min. The
solution containing the nickel catalyst was then transferred Via cannula to
the vinylalane at room temperature, and the cross-coupling reaction followed
by GC analysis. When the reaction was complete (<15 min in this case),
the solution was diluted with diethyl ether (10 mL) and quenched at 0 °C
by carefully adding 1.0 M HCl dropwise (3 mL). The mixture was allowed
to stir for an additional 5 min and then extracted with diethyl ether. The
combined organic layers were dried (Na2SO4/MgSO4) and concentrated in
Vacuo. Silica gel column chromatography of the residue (petroleum ether)
afforded 6 (0.281 g, 87%) as a viscous, clear oil: Rf ) 0.10 (2% acetone/
pentane); IR (neat) 2931, 2856, 1470, 1454, 1446, 1417, 1406, 1350, 1107,
1068, 1041 cm-1; 1H NMR (500 MHz, CDCl3) δ 5.09-5.02 (m, 4H), 3.89
(s, 3H), 3.88 (s, 3H), 3.77 (s, 3H), 3.77 (s, 3H), 3.31 (d, J ) 6.5 Hz, 2H),
2.12 (s, 3H), 2.08-1.92 (m, 12H), 1.75 (s, 3H), 1.66 (s, 3H), 1.58 (s, 3H),
1.57 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 147.85, 147.67, 144.92, 144.67,
135.05, 134.96, 134.84, 131.17, 129.23, 125.34, 124.40, 124.22, 124.13,
122.87, 61.17, 61.04, 60.61, 39.70, 26.76, 26.62, 25.78, 25.64, 17.64, 16.20,
15.96, 11.67; HREIMS calcd for C31H48O4 M+ 484.3553, found 484.3548.
(14) According to the 1995 edition of the Sigma catalog, CoQ6 is listed
at $571.30/50 mg (or $11,426/g), while CoQ9 is $376.30/10 mg (or $37,630/
g).
a All reactions were run using 5 mol % Ni(0), unless specified
otherwise. b Fully characterized by IR, NMR, MS, and HRMS data.
c Isolated, chromatographically purified materials. d Run using 10 mol
% Ni(0).
(11; racemic)12 and K2(20) (12; CoQ4 side chain) could be
efficiently prepared using this protocol (Scheme 5).
The generality of this new coupling sequence for realizing
allylated aromatics not related to the ubiquinones has also been
investigated, using a variety of benzylic chlorides and vinylic
alanes (Table 1).13 Clearly, both electron-rich and electron-
poor aromatics participate with equal facility. Importantly, there
is reason to believe that good functional group compatibility is
maintained (e.g., entry 6).
(12) Alkyne preparation: Addition of 1-(triisopropylsilyl)propynyllithium
to in situ generated iodide (from 3,7,11-trimethyldodecanol; Wiley Organ-
ics), followed by tetrabutylammonium fluoride deprotection and column
chromatography (pentane), afforded the alkyne in 67% overall yield. Educt
10 is a known precursor, cf.: Adams, R.; Geissman, T. A.; Baker, B. R.;
Teeter, H. M. J. Org. Chem. 1940, 63, 528.