The Friedel-Crafts allylation of a prenyl group stabilized by a sulfone moiety: Expeditious syntheses of ubiquinones and menaquinones

Article abstract of DOI:10.1021/jo0350155

An efficient synthetic method for the protected p-hydroquinone compounds 4 containing the C₅ trans allylic sulfone moiety has been developed by the direct Friedel-Crafts allylation of the protected dihydroquinone 2 with 4-chloro-2-methyl-1-phenylsulfonyl-2-butene (7a) or 4-hydroxy-2-methyl-1-phenylsulfonyl-2-butene (7b). Expeditious total syntheses of coenzyme Q-10 and vitamin K₂₍₂₀₎ have been demonstrated from these valuable key compounds 4a and 4b.

Full text of DOI:10.1021/jo0350155

SCHEME 1. Discon n ection Ap p r oa ch es to
Isop r en oid Na tu r a l P r od u cts Con ta in in g a
p-Qu in on e Hea d Gr ou p
Th e F r ied el-Cr a fts Allyla tion of a P r en yl
Gr ou p Sta bilized by a Su lfon e Moiety:
Exp ed itiou s Syn th eses of Ubiqu in on es a n d
Men a qu in on es
J ae-Hong Min, J un-Sup Lee, J ae-Deuk Yang, and
Sangho Koo*
Department of Chemistry, Myong J i University, Yongin,
Kyunggi-Do, 449-728, Korea
sangkoo@mju.ac.kr
Received J uly 14, 2003
Abstr a ct: An efficient synthetic method for the protected
p-hydroquinone compounds 4 containing the C5 trans allylic
sulfone moiety has been developed by the direct Friedel-
Crafts allylation of the protected dihydroquinone 2 with
4-chloro-2-methyl-1-phenylsulfonyl-2-butene (7a ) or 4-hy-
droxy-2-methyl-1-phenylsulfonyl-2-butene (7b). Expeditious
total syntheses of coenzyme Q-10 and vitamin K2(20) have
been demonstrated from these valuable key compounds 4a
and 4b.
intrinsic instability problems of polypreniol or the cor-
responding halide under acidic condition has not been
overcome. Coupling of the protected p-hydroquinone 4
containing the C5 allylic sulfone moiety and the polypre-
nyl chain 5 (X ) halogen) by the J ulia sulfone protocol6
(approach 2, Scheme 1), originally delineated by Terao
for coenzyme Q-10 synthesis,7 was an excellent method
in that not only a high yield of the coupling product was
Isoprenoid natural products containing a p-quinone
head group play important roles in biological processes
of higher plants and animals. Ubiquinones ubiquitously
exist in mitochondria of every cell to participate in the
electron transport process for respiration, thus producing
energy for living organisms.1 Coenzyme Q-10 (1a ), the
ubiquinone of humans, also has a treatment effect on
heart-related disease.2 Menaquinones, known as vitamin
K2 (1b), promote normal clotting of the blood.
There have been extensive synthetic efforts for these
indispensable natural products,3 where the key issue was
the coupling method of the quinone core and the poly-
prenyl side chain. Coupling of the p-hydroquinone 2 (P
) H) and the polyprenyl chain 3 (X ) OH or halogen) by
the Friedel-Crafts reaction (approach 1, Scheme 1) was
a straightforward method,4 which, however, suffered from
low yields especially due to cyclization within the poly-
prenyl side chain and cyclization of the coupling product
to form chromanol. Some modifications of this method
have appeared,5 but the stereoselectivity at 2∆ and the
2
obtained, but also the E-configuration at ∆ as well as at
the other double bonds was retained, which would
provide better biological activities. The more attractive
point of the above method is that solanesol, C45 all-E-
polyprenyl alcohol, that is readily obtained by extraction
from the leaves of tobacco or potato can be directly
utilized in the synthesis of coenzyme Q-10. The potential
of this approach then relied on the efficient preparation
of compound 4.
The first preparation of 4 (P ) benzyl, R ) OCH3) by
Terao7 from 2,3-dimethoxy-5-methyl-1,4-benzoquinone
(coenzyme Q-0) was lengthy and thus industrially inap-
plicable. A better procedure has been proposed by Fujita8
that made use of 4-chloro-2-methyl-1-phenylsulfonyl-2-
butene (7a ) (Scheme 2). 2,3-Dimethoxy-5-methyl-1,4-
hydroquinone 2 (P ) H, R ) OCH3), which was obtained
by reduction of coenzyme Q-0, was brominated at the
unsubstituted ring carbon. Protection of the hydro-
quinone as 2-methoxyethoxymethyl (MEM) ether to give
6 (P ) MEM, R ) OCH3) was followed by the Grignard
(1) (a) Thomson, R. H. Naturally Occurring Quinones; Academic
Press: New York, 1971. (b) Mitchell, P.; Moyle, J . Coenzyme Q; Lenaz,
G., Ed.; Wiely: Chichester, UK, 1985.
(2) Lenaz, G. Coenzyme Q, Biochemistry, Bioenergetics and Clinical
Applications of Ubiquinone; Wiley-Interscience: New York, 1982.
(3) (a) Lipshutz, B. H.; Kim, S.-K.; Mollard, P.; Stevens, K. L.
Tetrahedron 1998, 1241. (b) Lipshutz, B. H.; Bulow, G.; Fernandez-
Lazaro, F.; Kim, S.-K.; Lowe, R.; Mollard, P.; Stevens, K. L. J . Am.
Chem. Soc. 1999, 121, 11664. (c) Lipshutz, B. H.; Mollard, P.; Pfeiffer,
S. S.; Chrisman, W. J . Am. Chem. Soc. 2002, 124, 14282. (d) van Liemt,
W. B. S.; Steggerda, W. F.; Esmeijer, R.; Lugtenburg, J . Recl. Trav.
Chim. Pays-Bas 1994, 113, 153. (e) Inoue, S.; Yamaguchi, R.; Saito,
K.; Sato, K. Bull. Chem. Soc. J pn. 1974, 47, 3098. (f) Garc´ıas, X.;
Ballester, P.; Capo´, M.; Saa´, J . M. J . Org. Chem. 1994, 59, 5093. (g)
Sato, K.; Inoue, S.; Saito, K. J . Chem. Soc., Perkin Trans. 1 1973, 2289.
(h) Snyder, C. D.; Rapoport, H. J . Am. Chem. Soc. 1974, 96, 8046 (i)
Naruta, Y. J . Org. Chem. 1980, 45, 4097.
(5) (a) Hirschmann, R.; Miller, R.; Wendler, N. L. J . Am. Chem. Soc.
1954, 76, 4592. (b) Araki, S.; Manabe, S.; Butsugan, Y. Chem. Lett.
1982, 797.
(6) (a) J ulia, M.; Arnould, D. Bull. Soc. Chim. Fr. 1973, 743. (b) J ulia,
M.; Arnould, D. Bull. Soc. Chim. Fr. 1973, 746.
(7) Terao, S.; Kato, K.; Shiraishi, M.; Morimoto, H. J . Org. Chem.
1979, 44, 868.
(4) (a) Isler, O.; Ru¨egg, R.; Chopard-dit-J ean, L.; Winterstein, A.;
Wiss, O. Helv. Chim. Acta 1958, 41, 786. (b) Isler, O.; Doebel, K. Helv.
Chim. Acta 1954, 37, 225.
(8) (a) Fujita, Y.; Ishiguro, M.; Onishi, T.; Nishida, T. Synthesis 1981,
469. (b) Fujita, Y.; Ishiguro, M.; Onishi, T.; Nishida, T. Bull. Chem.
Soc. J pn. 1982, 55, 1325.
10.1021/jo0350155 CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/09/2003
J . Org. Chem. 2003, 68, 7925-7927
7925

TABLE 1. Th e F r ied el-Cr a fts Allyla tion of
SCHEME 2. P r ep a r a tion of th e P r otected
p-Hyd r oqu in on e 4 Con ta in in g th e P r en yl Un it
w ith a P h en ylsu lfon yl Gr ou p
Tetr a m eth oxytolu en e (2a ) w ith 7a or 7b
entry C5 sulfone Lewis acid (equiv) condition % of 4a (E/Z)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7b
7b
7b
7b
7b
7b
MgBr2 (1.2)
AlEt3 (1.2)
TiCl4 (1.2)
FeCl3 (1.2)
AlCl3 (1.2)
BF3‚OEt2 (1.2)
ZnBr2 (1.2)
ZnCl2 (0.1)
ZnCl2 (0.3)
ZnCl2 (1.2)
ZnCl2 (1.2)
SnCl4 (0.3)
SnCl4 (1.2)
AlCl3 (1.2)
BF3‚OEt2 (1.2)
ZnCl2 (1.2)
ZnCl2 (1.2)
SnCl4 (1.2)
ZnBr2 (1.2)
Aa
Aa
Aa
Aa
Aa
Aa
Aa
Bc
Bc
Cd
Aa
Bc
Aa
Aa
Aa
Cd
Aa
Aa
Aa
0 (-)
0 (-)
-b (-)
-b (-)
20 (E)
20 (E)
30 (5:1)
44 (10:1)
62 (10:1)
56 (10:1)
69 (10:1)
68 (3:1)
92 (3:1)
42 (E)
58 (10:1)
30 (10:1)
68 (10:1)
84 (3:1)
89 (10:1)
reagent generation. Copper-mediated coupling of the
Grignard reagent and 7a then produced 4 (P ) MEM, R
) OCH3). This multistep sequence from rather expensive
coenzyme Q-0, however, still needs improvement for
industrial application. It was envisioned based on the
stability of the white-crystalline C5 chloroallylic sulfone
7a that 7a might be used in the Friedel-Crafts reaction
with the protected p-hydroquinone 2 to directly produce
compound 4. Furthermore, tetramethoxytoluene (2a ),
which can be economically prepared from a readily
available precursor without going through the coenzyme
Q-0,9 might be an ideal electron-rich substrate for the
Friedel-Crafts reaction.
(E)-4-Chloro-2-methyl-1-phenylsulfonyl-2-butene (7a )
has been reported to be prepared from the copper-
catalyzed addition of benzenesulfonyl chloride to isoprene
at the reflux temperature of acetonitrile for 2 h in 42%
yield.10 We were able to improve the yield of this reaction
up to 90% by lowering the temperature to 60 °C and
extending the time to 15 h. (E)-4-Hydroxy-2-methyl-1-
phenylsulfonyl-2-butene (7b) was then prepared from 7a
by trivial transformations: substitution of chloride by
acetate followed by hydrolysis of the acetate.11 The
Friedel-Crafts allylation of tetramethoxytoluene (2a )
with 7a or 7b (eq 1) has been thoroughly studied under
various Lewis acidic conditions, and the results are
summarized in Table 1.
a
b
Condition A: 1,2-dichloroethane at 80 °C for 8 h. Decompo-
sition of the starting materials was observed. c Condition B: 1,2-
dichloroethane at 80 °C for 12 h. Condition C: CH2Cl2 at 40 °C
for 24 h.
d
AlEt3 were no good in activating 7a for the coupling
reaction; on the other hand, extensive decomposition of
the starting materials was observed in the cases with
TiCl4 and FeCl3. A similar trend of each Lewis acid for
7a and 7b in providing the yield and E/ Z ratio of the
coupling product 4a was noticed. Overall, better yields
were obtained with allylic alcohol 7b than allylic chloride
7a as an electrophile, and zinc(II) halide consistently
produced high yields of 4a , where the E/ Z ratio of 10:1
was maintained. It is also noteworthy that an appreciable
amount of the Z-isomer of the coupling product 4a was
obtained for the SnCl4 case, even though a good yield was
obtained. The E/ Z ratio of the coupling product 4a was
kinetically determined, and the ratio at 20% conversion
was mostly maintained throughout the entire reaction.
The pure E-isomer of the coupling product 4a was fully
recovered without isomerization to the Z-isomer under
the above standard reaction condition with ZnCl2. The
best condition (89%, E/ Z ) 10:1) was observed when 2a
and 7b were coupled under the above standard condi-
tion with ZnBr2. The Friedel-Crafts allylation of 1,4-
dimethoxy-2-methylnaphthalene (2b)12 with 7a or 7b (eq
2) under various Lewis acids also has been studied for
The standard condition of the Friedel-Crafts allylation
with 1.2 equiv of Lewis acid in 1,2-dichloroethane at 80
°C for 8 h (condition A in Table 1) was established
according to our preliminary study, where a little conver-
sion to 4a was observed at 40 °C in CH2Cl2 with use of a
stoichiometric amount of Lewis acid (condition C in Table
1). The reaction also proceeded at 80 °C with a less than
stoichiometric amount (0.1∼0.3 equiv) of Lewis acids
(condition B in Table 1); however, it required longer
reaction times to produce lower yields of 4a . MgBr2 and
vitamin K synthesis. The above standard reaction condi-
tion (1.2 equiv of Lewis acid in 1,2-dichloroethane at 80
°C for 8 h) has been used, and the results are summarized
in Table 2.
A much different result was obtained for the Friedel-
Crafts allylation of the less electron-rich naphthalene
(9) Keinan, E.; Eren, D. J . Org. Chem. 1987, 52, 3872.
(10) Truce, W. E.; Goralski, C. T.; Christensen, L. W.; Bavry, R. H.
J . Org. Chem. 1970, 35, 4217.
(11) Olson, G. L.; Cheung, H.-C.; Morgan, K. D.; Neukom, C.; Saucy,
G. J . Org. Chem. 1976, 41, 3287.
(12) Tuyen, N. V.; Kesteleyn, B.; De Kimpe, N. Tetrahedron 2002,
58, 121.
7926 J . Org. Chem., Vol. 68, No. 20, 2003

TABLE 2. Th e F r ied el-Cr a fts Allyla tion of
1,4-Dim eth oxy-2-m eth yln a p h th a len e (2b) w ith 7a or 7b
SCHEME 3. Tota l Syn th eses of Coen zym e Q-10
(1a ) a n d Vita m in K2(20) (1b) fr om 4a a n d 4ba
a
entry
C5 sulfone
Lewis acid
% of 4b (E/Z)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
7a
7a
7a
7a
7a
7a
7a
7a
7a
7b
7b
7b
7b
7b
7b
7b
BF3‚OEt2
MgBr2
TiCl4
FeCl3
Et2AlCl
SnCl4
ZnBr2
ZnCl2
AlCl3
AlCl3
ZnCl2
Et2AlCl
SnCl4
FeCl3
ZnBr2
BF3‚OEt2
0 (-)
0 (-)
-b (-)
55 (4:1)
56 (7:1)
56 (E)
60 (7:1)
67 (7:1)
72 (E)
0 (-)
0 (-)
0 (-)
-b (-)
22 (E)
40 (7:1)
41 (5:1)
a
b
1.2 equiv of Lewis acid was used. Decomposition of the
starting materials was observed.
derivative 2b, where the yields of the coupling product
4b were generally better for the allylic chloride 7a than
those for the allylic alcohol 7b. Furthermore, different
trends of each Lewis acid for 7a and 7b in providing the
yield and E/ Z ratio of the coupling product 4b were
noticed. MgBr2 and TiCl4 were no good as an activator
for the coupling reaction. Zinc(II) halide generally pro-
duced decent yields of the coupling product 4b, where
the E/ Z ratio of 7:1 was maintained. The best condition
(72%, E only) was observed when 2b and 7a were coupled
under the above standard condition with AlCl3. The
success of the above Friedel-Crafts allylations is pre-
sumably due to the presence of the rigid sulfone moiety
in the prenyl compounds 7a and 7b, which prevents a
further cyclization to form chromanol even in the reaction
with trimethylhydroquinone. It has been reported that
the chromanol product was exclusively obtained for the
Friedel-Crafts reaction of trimethylhydroquinone with
the tertiary allylic alcohol containing a flexible sulfide
group.13
With the key compounds 4a and 4b in our hands, we
then attempted the total syntheses of coenzyme Q-10 (1a )
and vitamin K2(20) (1b) (Scheme 3). The J ulia-type
coupling reaction of 4a and solanesyl bromide 5 (X ) Br,
n ) 9), prepared from solanesol by reaction with PBr3,
produced compound 8a containing all the required carbon
atoms for coenzyme Q-10. Several conditions can be used
in the coupling reaction such as t-BuOK/THF-DMF/-20
°C or n-BuLi/THF/-78 °C. Two consecutive functional
group transformations from 8a would provide coenzyme
Q-10. Among the various hydrodesulfonation conditions
reported, the Pd(dppe)Cl2-catalyzed substitution reaction
by LiEt3BH was the best.14 Any other conditions with Li
or Na(Hg) invariably produced an appreciable amount
of the side products derived from the CdC bond migra-
tion at 2∆ or indiscriminating demethylations of the
methoxy groups at the aromatic ring. The final oxidation
with CAN (ammonium cerium(IV) nitrate)15 gave rise to
a
Reagents: (a) 4a , n-BuLi in THF at -78 °C then 5 (X ) Br, n
) 9), 90% for 8a , or 4b and 5 (X ) Br, n ) 3), t-BuOK in THF at
-20 °C, 95% for 8b; (b) Pd(dppe)Cl2 (0.05 equiv), LiEt3BH in THF,
77% for 9a , 91% for 9b; (c) CAN in MeCN/CH2Cl2/H2O, 61% for
1a , 72% for 1b.
coenzyme Q-10 (1a ) in 42% overall yield from 4a .
Likewise, vitamin K2(20) (1b) was synthesized from 4b by
the J ulia-type coupling reaction with farnesyl bromide 5
(X ) Br, n ) 3), hydrodesulfonation (LiEt3BH catalyzed
by Pd(dppe)Cl2), followed by CAN oxidation in 62%
overall yield.
In conclusion, we have developed an efficient synthetic
method for the key compound 4 by direct Friedel-Crafts
allylation of the protected p-hydroquinone 2 with 4-chloro-
2-methyl-1-phenylsulfonyl-2-butene (7a ) or 4-hydroxy-2-
methyl-1-phenylsulfonyl-2-butene (7b). The success of
this approach is presumably due to the stabilization
provided by a phenylsulfonyl group in 7a or 7b under
the conditions with Lewis acids. Furthermore, the E-
configuration of the CdC bond was mostly retained in 4
after the Friedel-Crafts reaction. Expeditious total
syntheses of coenzyme Q-10 (1a ) and vitamin K2(20) (1b)
were demonstrated from 4a and 4b, respectively. This
approach can be generally applied to the syntheses of
various isoprenoid natural products containing a p-
quinone head group.
Ack n ow led gm en t. This work was supported by the
RRC program of MOST and KOSEF. We also acknowl-
edge helpful suggestions from Dr. Gary D. Allred
(Frontier Scientific, Inc., Utah).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures, characterization data, and H NMR spectra of 8a and
8b. This material is available free of charge via the Internet
at http://pubs.acs.org.
1
(13) Akkerman, J . M.; De Koning, H.; Huisman, H. O. J . Chem. Soc.,
Perkin Trans. 1 1979, 2124.
J O0350155
(14) Mohri, M.; Kinoshita, H.; Inomata, K.; Kotake, H. Chem. Lett.
1985, 451.
(15) Syper, L.; Kloc, K.; Młochowski, J . Tetrahedron 1980, 36, 123.
J . Org. Chem, Vol. 68, No. 20, 2003 7927