Synthetic studies on coenzyme Q10: Part 2 - A efficient and improved synthesis of coenzyme Q10 via the C5 + C 45 approach

Article abstract of DOI:10.1002/hlca.200690130

An improved route to coenzyme Q₁₀ (1) starting from commercially available coenzyme Q₁ is described. The key steps in this synthesis are the SeO₂-mediated oxidation of the protected isoprenylhydroquinone 3 into the (E)-allyl alcohol 5 without the formation of undesired stereoisomer and the one-pot reductive elimination of the phenylsulfonyl and dibenzyl groups in 7 by using naphthalenyllithium.

Full text of DOI:10.1002/hlca.200690130

Helvetica Chimica Acta – Vol. 89 (2006)
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Synthetic Studies on Coenzyme Q10
Part 21)
An Efficient and Improved Synthesis of Coenzyme Q10 via the C5 +C45 Approach
by Hui-FangDai , Fen-Er Chen*, and Xiong-Jie Yu
Department of Chemistry, Fudan University, Shanghai, 200433, P. R. China
(fax: +86-21-65642021; e-mail: rfchen@fudan.edu.cn)
An improved route to coenzyme Q10 (1) starting from commercially available coenzyme Q1 is descri-
bed. The key steps in this synthesis are the SeO2-mediated oxidation of the protected isoprenylhydroqui-
none 3 into the (E)-allyl alcohol 5 without the formation of undesired stereoisomer and the one-pot
reductive elimination of the phenylsulfonyl and dibenzyl groups in 7 by using naphthalenyllithium.
Introduction. – There is considerable interest in the chemical synthesis of coenzyme
Q10 (1) due to its unusual structure and biological significance [2] and commercial
importance. Although various synthetic routes [3] to 1 have been developed to date,
the synthetic strategy implying a terminally functionalized protected isoprenylhydro-
quinone as a key intermediate seems to be one of the most attractive approach. Our
recently proposed route based on (2E)-4-[3,4-dimethoxy-2,5-bis(methoxymethoxy)-6-
methyl]-2-methylbut-2-en-1-ol allowed us to develop a convenient and highly stereose-
lective process for 1 starting from coenzyme Q0 (=2,3-dimethoxy-5-methyl-1,4-benzo-
quinone) [1]. However, in this process, one important issue became apparent: an
incomplete H/Li exchange of the protected hydroquinone was observed2). The overall
yield of the thus prepared terminally functionalized protected isoprenylhydroquinone
was compromised by this inefficient metalation procedure. The metalation step turned
out to be a bottleneck, hampering the scale-up trials. Thus, the development of an effi-
cient and highly regio- and stereoselective preparation of 1 is still in demand.
The SeO2-mediated terminal oxidation of an isopropylidene moiety to an allyl alco-
hol is an important strategy towards the formation of an (E)-allyl alcohol under regio-
1
)
)
For part 1, see [1].
2
Only 65% of 1,4-bis(methoxymethoxy)-2,3-dimethoxy-5-methylbenzene was lithiated by BuLi in the
presence of N,N,N’,N’-tetramethylethane-1,2-diamine (TMEDA).
© 2006 Verlag Helvetica Chimica Acta AG, Zürich

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Helvetica Chimica Acta – Vol. 89 (2006)
and stereochemical control in the synthesis of natural products [4]. Herein we describe
a practical synthesis of 1 starting from commercially available coenzyme Q1 (=2,3-
dimethoxy-5-methyl-6-(3-methylbut-2-enyl)cyclohexa-2,5-diene-1,4-dione) via SeO2-
mediated oxidation of protected isoprenylhydroquinone 3 into the (E)-allyl alcohol 5
(Scheme).
Results and Discussion. – Coenzyme Q1 was prepared in 90% yield from commer-
cially available coenzyme Q0 according to our previously reported procedure [5].
Scheme
a) Na2S2O4, H2O, MeOH, r.t., 3 h. b) BnBr, KOH, Bu4
ACHTREUNG
EtOH, reflux, 1 h, then NaBH4, MeOH; 65.0%. d) CBr4, -C6
A
ACHTREUNG
t
tolyl sulfone, BuOK, THF/DMF 9 :1, ꢀ408, 3 h; 85.3%. f) Naphthalenyllithium, THF, ꢀ788, 2 h;
77.0%; 38% (from coenzyme Q1).

Helvetica Chimica Acta – Vol. 89 (2006)
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Reduction of coenzyme Q1 with 40% aqueous Na2S2O4 solution in MeOH, followed by
phase-transfer-catalyzed benzylation of the resulting hydroquinone 2 with benzyl bro-
mide in the presence of a catalytic amount of Bu4NBr and of KOH in acetone under
G
reflux for 3 h furnished the bis(benzyloxy) derivative 3 in 96% yield.
Next, we turned our attention to the efficient stereoselective conversion of 3 into
the (E)-allyl alcohol 5. Thus, allylic oxidation of 3 with SeO2 in EtOH under reflux
for 2.5 h gave a mixture of 5 and (E)-butenal 4 in the approximate ratio 90 :10 (by
HPLC and GC/MS of the crude product). Without separation, the crude mixture 5/4
was directly reduced with NaBH4 in MeOH at room temperature for 30 min to lead
to the (E)-allyl alcohol 5 in a yield of 65% and (E)/(Z) ratio of 98 :2 (by HPLC).
The (E)-configuration of 5 was established by NOESY experiments: NOEs were
found between the signals of MeꢀC(2) and the CH2(4) protons. Bromination of 5
with CBr4 and polymer-supported triphenylphosphine in CH2Cl2 at 08 affored the
(E)-allyl bromide 6 in a 95.3% yield. It is worthy to note that the polymer-supported
phosphine oxide formed in the reaction can be reduced to the original phosphine with-
out much loss of activity by trichlorosilane according to the method of Regen and Lee
[6].
The coupling of solanesyl p-tolyl sulfone (=4-{[(2E,6E,10E,14E,18E,22E,26E,30E)-
U
hexatriaconta-2,6,10,14,18,22,26,30,34-nonaenyl]sulfonyl}-4-methylbenzene) with 6 in
the presence of potassium tBuOK in THF/DMF (9 :1) at ꢀ408 provided the desired sul-
fone 7 in 85% yield. The transformation of 7 into 1 was achieved in 77% overall yield
via a two-step procedure comprising a one-pot reductive cleavage of the benzyl and
arylsulfonyl groups in 7 by treatment with freshly prepared naphthalenyllithium and
the air-oxidation of the resulting hydroquinone in hexane at room temperature.
Conclusions. – An effective and convergent process for the preparation of the (E)-
allyl alcohol 5 via SeO2-mediated chain-terminal oxidation resulted in a stereoselective
synthesis of coenzyme Q10 (1) in 38% overall yield starting from commercially available
coenzyme Q1. This method should prove applicable to the synthesis of not only coen-
zyme Qn (n=2–12) but also of many other natural products possessing a polyprenyl
moiety.
Experimental Part
General. Reagents and chemicals were obtained from commercial suppliers and used without further
purification. THF was distilled from Na/benzophenone under N2. DMF was freshly distilled from CaH2.
Petroleum ether for column chromatography (CC) had a b.p. of 30–608. Solanesyl p-tolyl sulfone was
prepared according to [7]. TLC: Aluminium-backed silica gel 60 F254 plates. Anal. reversed-phase
HPLC: Shimadzu-LC-10AT liquid chromatograph with Spd-10A-UV-VIS detector; Supelco-C18
150×4.6 column; mobile phase MeOH/H2O 3 :1, flow rate 1.0 ml/min; detection by UV absorbance at
270 nm. M.p.: WRS-1-B digital melting point apparatus; uncorrected. IR Spectra: Nicolet-FT-IR 360
spectrophotometer; in cmꢀ1 1H-NMR Spectra: Bruker-DMX-500 and Jeol-ECA-400 spectrometer;
.
chemical shifts d in ppm rel. to internal Me4Si, coupling constants J in Hz. Mass spectra: HP-5989A spec-
G
trometer.
1,4-Bis(benzyloxy)-2,3-dimethoxy-5-methyl-6-(3-methylbut-2-enyl)benzene (3). To a stirred soln. of
coenzyme Q1 (7.6 g, 30 mmol) in MeOH (25 ml) was added dropwise a 40% aq. Na2S2O4 soln. until
the red color of the soln. disappeared. The mixture was stirred at r.t. for 3 h. The aq. layer was extracted

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Helvetica Chimica Acta – Vol. 89 (2006)
with 1,2-dichloroethane (3×20 ml) and the combined org. layer washed with ice-water (3×20 ml), dried
(Na2SO4), and evaporated. The crude hydroquinone 2 was added to a stirred a suspension of KOH (3.67
g, 65.5 mmol) and Bu4NBr (0.1 g) under N2, maintaining the temp. at or below 208. Benzyl bromide (11.1
A
g, 65.5 mmol) was then added dropwise within 20 min under vigorous stirring, and the mixture was stirred
for 3 h under reflux. After cooling to r.t., H2O (100 ml) was added, the resulting mixture extracted with
Et2O (3×40 ml), the combined org. layer washed with brine (2×100 ml), dried (MgSO4), and evaporated,
A
and the crude product purified by CC (SiO2, petroleum ether): pure 3 (12.36 g, 94%). Colorless oil. 1H-
NMR (500 MHz, CDCl3): 1.57 (br. s, Me); 1.66 (s, Me); 2.11 (s, Me); 3.38 (d, J=7.3, CH2); 3.94 (s, 2
MeO); 4.94 (s, 2 CH2O); 5.43 (t, J=7.3, CH=C); 7.26–7.41 (m, 2 Ph). EI-MS: 432 (M+), 249, 219, 91.
(2E)-4-[2,5-Bis(benzyloxy)-3,4-dimethoxy-6-methylphenyl]-2-methylbut-2-en-1-ol (5). To a stirred
suspension of SeO2 (5.5 g, 46 mmol) in EtOH (100 ml) was added 3 (10 g, 23 mmol ) at r.t. The reaction
mixture was stirred under reflux for 2 h and filtered. The solvent was evaporated, the residue extracted
with Et2O (3×40 ml), and the combined org. layer washed with brine (2×100 ml), dried (MgSO4), and
G
evaporated. A soln. of NaBH4 (0.7 g, 18.4 mmol) in MeOH (150 ml) was added to the residue, and the
mixture was stirred for 30 min at 08. Sat. aq. NH4Cl soln. was added dropwise, and the aq. layer was
extracted with Et2O. The combined org. layer was washed with sat. aq. NaCl soln. (3×40 ml) and H2O
G
(3×25 ml), dried (MgSO4), evaporated and the crude product purified by CC (SiO2; petroleum ether/
1
AcOEt 8 :1): pure 5 (6.70 g, 65%). Colorless oil. IR (film): 3410, 2932, 1640, 1455, 1104, 1030, 698. H-
NMR (500 MHz, CDCl3): 1.63 (s, OH); 1.71 (s, Me); 2.30 (s, Me); 3.32 (d, J=8, CH2); 3.95 (s, 2
MeO); 3.97 (s, CH2); 5.16 (d, J=15.5, 2 CH2); 5.83 (t, J=7, CH=); 7.15–7.23 (m, 2 Ph). EI-MS: 448
(M+), 431, 363, 265, 249, 91.
1,4-Bis(benzyloxy)-2-[(2E)-4-bromo-3-methylbut-2-enyl]-5,6-dimethoxy-3-methylbenzene (6). To a
soln. of 5 (1.12 g, 2.5 mmol) in CH2Cl2 (10 ml) at 08, successively CBr4 (1.08 g, 3.25 mmol) and poly-
mer-supported triphenylphosphine (1.25 g, 3.75 mmol) was added. The suspension was stirred at 08 for
4 h and then filtered. The solvent was evaporated and the excess of CBr4 removed in vacuo: pure 6
(1.22 g, 95.3%). Colorless oil. 1H-NMR (500 MHz, CDCl3): 1.72 (s, Me); 2.10 (s, Me); 3.35 (d, J=8,
CH2); 3.94 (s, CH2); 3.95 (s, 2 MeO); 5.02 (t, J=15, 2 CH2); 5.83 (t, J=7, CH); 7.33–7.43 (m, 2 Ph).
EI-MS: 512 (M+), 431, 340, 249, 91.
1,4-Bis(benzyloxy)-2-{(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decame-
thyl-5-[(4-methylphenyl)sulfonyl]tetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl}-5,6-dimethoxy-3-meth-
ylbenzene (7). To a stirred soln. of 6 (5.11 g, 10 mmol) and solanesyl p-tolyl sulfone (6.03 g, 8 mmol) in
THF/DMF 9 :1 (100 ml) was added tBuOK (1.58 g, 14 mmol ), at ꢀ408 under N2. Stirring was continued
at ꢀ408 for 1.5 h, and further at 208 for 1 h. The mixture was poured into sat. aq. NH4Cl soln. (150 ml)
and extracted with Et2O (3×40 ml), the combined org. layer washed with 1M aq. HCl soln. (3×25 ml) and
E
H2O (3×25 ml), dried (Na2SO4), and evaporated, and the crude product purified by CC (SiO2, petroleum
ether/AcOEt 8 :1): pure 7 (8.08 g, 85.3%). Colorless oil. 1H-NMR (500 MHz, CDCl3): 1.51(s, MeC); 1.68
(s, 8 MeC); 1.67, 1.73 (2s, 2 Me); 1.85–2.16 (m, 8 CH2CH2); 2.70 (d, J=6.5, CH2); 3.20 (s, CH2); 3.40–3.55
(m, CH); 3.91 (s, 2 MeO); 4.83 (d, J=10.1, CH2); 4.89 (s, CH2); 5.0 (s, C=CH); 5.10 (s, 2 CH2O, 9 C=
CH); 7.28 (d, J=8.2, Ph); 7.70 (d, J=8.2, Ph). MALDI-MS: 1207.8 ([M+Na]+, C79
N
N
Coenzyme Q10 (=2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-Decame-
thyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3-methylcyclohexa-2,5-diene-1,4-
dione; 1): A freshly prepared soln. of 1M naphthalenyllithium in THF (10 mmol, 10 ml) was added drop-
wise to a soln. of 7 (1.18 g, 1 mmol) in THF at ꢀ788. The mixture was stirred for 2 h at ꢀ788 before being
warmed up to 08, quenched with sat. aq. NH4Cl soln. (20 ml) and extracted with Et2O (3 ml). The com-
E
bined org. layer was washed with sat.aq. NaCl soln. (2×15 ml) and H2O (2×15 ml), dried (Na2SO4), and
evaporated and the crude product purified by CC (SiO2, hexane/THF 9 :1). The obtained orange solid
was recrystallized from EtOH at 08: pure 1 (0.67 mg, 77%). Orange crystals. M.p. 48.3–498 ([3d]: m.p.
1
48–498). Purity ꢁ98.5% (by HPLC). H- NMR (500 MHz, CDCl3): 1.57, 1.59 (2s, 9 MeC=C); 1.69 (s,
MeC=C); 1.72 (s, MeC=C); 2.03 (s, arom. Me); 1.98–2.11 (m, 9 (CH2)2CH=); 3.18 (d, J=6.9, CH2);
G
3.96 , 4.01 (2s, 2 MeO); 4.90 (t, J=7.3, CH); 5.02–5.14 (m, 9 C=CH). MALDI-MS: 885.6 ([M+Na]+,
C59H90O4
Na+).
A
N
ACHTREUNG

Helvetica Chimica Acta – Vol. 89 (2006)
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Received February 17, 2006