Improved synthesis of vitamin K1

Article abstract of DOI:10.1081/SCC-120016320

With (E/Z)-isomeric phytyl halides as side-chain materials, vitamin K₁ is synthesized via a Diels-Alder reaction to activate the free bridgehead hydrogen of 3 for the alkylation and a retro-Diels-Alder reaction to eliminate cyclopentadiene from 2 in a high yield, in which the configuration of the double bond in the phytyl side-chain is retained.

Full text of DOI:10.1081/SCC-120016320

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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 5, pp. 763–772, 2003
Improved Synthesis of Vitamin K1
1
1
Ya-Fei Ji,1, Zhi-Min Zong, Xian-Yong Wei,
*
Guang-Zhong Tu,2 Li Xu,2 and Lin-Tao He2
1School of Chemistry Engineering, China University of
Mining and Technology, Xuzhou, Jiangsu, P.R. China
2Analytical Center, Beijing Institute of Microchemistry,
Beijing, P.R. China
ABSTRACT
With (E/Z )-isomeric phytyl halides as side-chain materials,
vitamin K1 is synthesized via a Diels–Alder reaction to activate the
free bridgehead hydrogen of 3 for the alkylation and a retro-Diels–
Alder reaction to eliminate cyclopentadiene from 2 in a high yield, in
which the configuration of the double bond in the phytyl side-chain is
retained.
Vitamin K1 (1) is the blood-clotting vitamin and it is important as an
obligatory cofactor for the enzyme which carboxylates selected glutamate
*Correspondence: Ya-Fei Ji, School of Chemistry Engineering, China
University of Mining and Technology, Xuzhou 221008, Jiangsu, P.R. China;
E-mail: jyf@imm.ac.cn.
763
DOI: 10.1081/SCC-120016320
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764
Ji et al.
residues in the proteins of the blood coagulation cascade. The detailed
review on 1 has already been given by Ruttimann for its history, biolog-
ical activity, and synthetic advances.[1] The mechanism of action of 1 has
been investigated by Dowd et al.[2] Though the synthesis of all four
stereoisomers of (E )-vitamin K1, i.e., (20E, 70R, 110R)-1, (20E, 70R,
110S )-1, (20E, 70S, 110S )-1, and (20E, 70S, 110R)-1 and the determination
of their biopotencies have been achieved,[3] a geometrical stereoselective
synthesis of (E )-vitamin K1 received increasing attention during the last
decade for the practical inactivity of (Z )-vitamin K1.[4–7]
In search for alternative procedures, we devoted our attention to the
strategy that in the vitamin K series a Diels–Alder approach for the
alkylation had successfully been employed where the non-acidic olefinic
hydrogen is activated for enolization by intermediate formation of a
cyclopentadiene–menadione cycloadduct (3).[1] After alkylation of 3,
the cyclopentadiene adduct (2) is readily decomposed to release
cyclopentadiene in a retro-Diels–Alder reaction (Sch. 1). In terms of
this principle, the stereochemistry in the side-chain can be retained
fromphytyl halide ( 5) to 1 by virtue of the basic conditions of alkylation.
In particular, this methodology can meet the prerequisites for economical
geometrical stereoselective synthesis of 1,[1] and may be extended to other
stereoselective syntheses of vitamin K derivatives and coenzyme Q
derivatives.[1,4,5,8] Therefore, it is very necessary for this method to be
improved to satisfy efficient and practical manufacture of 1 for the future.
In the present report, we describe certain syntheses of 1 for exploring to
Scheme 1.

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Improved Synthesis of Vitamin K1
765
make the E/Z-ratio>79.0:21.0 accord with the request of pharmaco-
poeia[9] utilizing isophytol or natural phytol as starting material via
(E/Z )-isomeric 5 to prepare 1. A milder and more efficient technique
should be developed for a practical process.
In our investigations, with isophytol as the precursor, the E/Z-
ratio ¼ 80.5:19.5 phytyl chloride was prepared by hydrochloric acid as
chlorinating agent but only the E/Z-ratio ¼ 75.5:24.5 phytyl bromide
was prepared using hydrobromic acid as brominating agent, and besides,
the E/Z-ratio ¼ 70.0:30.0 phytyl bromide was synthesized using
phosphorus tribromide as brominating agent. On the other hand, with
phytol as the precursor, the E/Z-ratio ¼ 90:10–85:15 phytyl bromides
can be produced using phosphorus tribromide as brominating agent. In
these preparations of (E/Z )-isomeric 5, we suggest that a mechanism
concerning allylic cation rearrangement results in (E/Z )-5 in favor of the
(E )-isomer under the acidic conditions (Sch. 2). In contrast with that, the
alkylation of 3 results in full retention of the stereochemistry of double
bond in the side-chain under the basic conditions and it implies that the
mechanism of nucleophilic substitution with carbon anion (6) as
nucleophilic agent should be considered without a rearrangement of allylic
cation resulting from 5 (Sch. 3). The spectroscopic data determined by
500 MHz NMR other than 5a by 300 MHz NMR for the stereochemistry
at phytyl chain are listed in Table 1.
The endo-configuration and the steric compression of the angular
methyl group indicated for 3 were confirmed by a single-crystal X-ray
analysis.[10] These analytic results can also expect that the steric compres-
sion of the cis-arrangement of the phytyl group with respect to the angu-
lar methyl group in 2 is the structural reason why the diketone 2 is
extremely thermally unstable.[1] In order to understand and demonstrate
their thermal instability and steric effect, detailed thermal studies have
Scheme 2.

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766
Ji et al.
Scheme 3.
Table 1. Stereochemistry at phytyl chain.
X
ꢀ
trans-CH3
ꢀ
cis-CH3
ꢀ
trans-CH2
ꢀcis-CH2
CH2OHa
CH2Cl
CH2Br
1.66
1.78
1.72
1.74
1.86
1.77
—
—
—
—
2.01
2.10
1.78
1.68
—
—
aIn natural phytol E-isomer>97% determined by 500 MHz NMR.
been carried out. The thermogravimetry-differential scanning calorimetry
(TG-DSC) analyses for 2 and 3 revealed that the decomposition of 2,
even at roomtemperature, is easier than that of 3.[10]
The steric effect similarly exists in Diels–Alder reactions of
1,4-naphthoquinones with cyclopentadiene. For example, at room
temperature in the presence of conventional catalyst like Lewis acid,
1,4-naphthoquinone reacts with cyclopentadiene for only 2 h to result
in their adduct in 94% isolated yield,[4] but it takes more than 48 h for
the reaction of 2-methyl-1,4-naphthoquinones with cyclopentadiene to
achieve their cycloadditions in ca. 90% isolated yields.[5,11] Singh et al.
reported that the micelle catalyzed Diels–Alder reaction of cyclic dienes
with various quinone in aqueous media were remarkably faster and gave

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Improved Synthesis of Vitamin K1
767
better yields of the adducts compared with the conventional reaction.[12]
We performed herein a cycloaddition of menadione with cyclopentadiene
in acetic acid catalyzed by dodecyltrimethylammonium bromide to give 3
in 93.2% isolated yield only requiring 3–5 h at roomtemperature,
confirming again the unusual ability of micelles to enhance the rate of
Diels–Alder reaction.
We found that the remarkable excess of potassium tert-butanolate
(ca. 5.0–6.0 equiv.) was necessary for accomplishing a highly yield of
alkylation of 3 to produce 2. If appropriate excess of potassium tert-
butanolate (ca. 1.0–2.0 equiv.) was introduced, the alkylation of 3
would possibly lead to a failing result. Desimoni et al. indicated that
the nature of the solvent effect was the same in both Diels–Alder and
retro-Diels–Alder reaction, and that the rate constant of the retro-Diels–
Alder reaction of 3 was the largest in acetic acid by contrast with in
different solvents thereof.[13] Furthermore, we reported that the cyclore-
version of 2 in acetic acid, which reacted at 90ꢀC catalyzed by
dodecyltrimethylammonium bromide to give 1 and cyclopentadiene
quantitatively, was easier than that of 2 in toluene.[4,5,11] Apparently,
the low temperature and the short time of the cycloreversion of 2 are
favorable for the quality and refining of 1. As such, these works to
improve the preparation of 1 will intensify the understanding on its
mechanism and technique for practical application.
EXPERIMENTAL
All reactions were monitored by TLC and the spots were visualized
with iodine vapor. Column chromatography was performed on domestic
silica gel (particle size 120–200 mesh). Melting points were determined by
capillary method without correction. Elemental analyses were performed
on a PE240-C element analysis instrument. Ultraviolet spectra were
recorded on a Shimadzu UV-240 spectrometer. Infrared spectra were
measured on a Nicolet Magna FTIR-560 spectrometer as neat films.
Proton NMR spectra were recorded on a Bruker AVANCE DRX-500
spectrometer using CDCl3 as solvent and the solvent peak (7.260 ppm)
was used as reference, unless otherwise noted. Chemical shifts were
expressed in parts per million (ꢀ, ppm). Mass spectra were recorded on
a VG-12-250 low-resolution quadrupole spectrometer and m/z values
were given with relative intensities in parentheses. With a flow of
1 mL/min (n-hexane/n-amyl alcohol 2000:1.5), HPLC was performed on

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768
Ji et al.
a HP 1050 chromatograph using an Alltech HPLC column (hypersil silica
5 mm, 250 mm  4.6 mm) and a UV monitor by 254 nm.[9]
Synthesis of Phytyl Chloride 5a
A mixture of 300 mL of 37% aqueous hydrochloric acid (excess) and
2 g of dodecyltrimethylammonium bromide were placed in a 3-necked
round-bottomed flash equipped with a mechanical stirrer, and the solu-
tion was cooled to À20ꢀC. To this 100.0 g (0.338 mol) of isophytol were
added and the resultant mixture was stirred vigorously for more than 20 h
at À20ꢀC. The oil layer was separated and the acid layer was extracted
with benzene twice (150 mL Â 2). The benzene extract was added to the
solid oil layer, the combined liquids were washed with water twice
(150 mL Â 2), and the washed organic layer was dried over anhydrous
calciumchloride. The organic layer was filtered and the solvent was
removed by rotary evaporation. Thus, 84.3 g (79.3%) of 5a was obtained
1
as a colorless oil (80.5%-trans by NMR). H NMR (300 MHz, TMS as
the internal standard in CDCl3): ꢀ ¼ 0.94 (d, 12H, J ¼ 7 Hz, 4CH3), 1.31
(m, 19H, CH and CH2), 1.78 (d, 3H, J ¼ 1 Hz, trans-CH3), 1.86 (d, 3H,
J ¼ 1 Hz, cis-CH3), 2.05 (t, 2H, J ¼ 8 Hz, CH2 at C4), 4.05 (d, 2H,
J ¼ 8.5 Hz, CH2 at C1), 5.46 (t, 1H, J ¼ 2 Hz, ¼CH at C2).
Synthesis of Phytyl Bromide 5b
Following above procedure, isophytol (100.0 g, 0.338 mol) was
treated with 300 mL of 48% aqueous hydrobromic acid (excess) to give
93.0 g (76.7%) of 5b as a light yellow oil (75.5%-trans by NMR).
1H NMR: ꢀ ¼ 0.85 (s, 6H, 2CH3), 0.87 (s, 6H, 2CH3), 1.01–1.42 (br. m,
17H, CH and CH2), 1.52 (m, 2H, CH2 at C5), 1.72 (s, 3H, J ¼ 1 Hz,
trans-CH3), 1.77 (s, 3H, J ¼ 1 Hz, cis-CH3), 2.01 (t, 2H, J ¼ 8 Hz,
trans-CH2 at C4), 2.10 (t, 2H, J ¼ 8 Hz, cis-CH2 at C4), 4.02 (d, 2H,
J ¼ 8.5 Hz, CH2 at C1), 5.53 (t, 1H, J ¼ 2 Hz, ¼CH at C2).
Synthesis of Phytyl Bromide 5c
Following the procedure of Isler et al.,[14] 9.0 g (0.030 mol) of
isophytol was treated with 9.0 g (0.033 mol) of phosphorus tribromide
at 0–5ꢀC for 6 h to yield 8.2 g (75.2%) of 5c as a light yellow oil
1
(70.0%-trans by NMR). H NMR spectra are in accordance with 5b.

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Improved Synthesis of Vitamin K1
Synthesis of Phytyl Bromide 5d
769
Following the procedure of Davisson et al.,[15] 9.0 g (0.030 mol) of
natural phytol was treated with 9.0 g (0.033 mol) of phosphorus tribro-
mide at 0–5ꢀC for 6 h to yield 8.0 g (73.6%) of 5d as a light yellow oil
1
(86.6%-trans by NMR). H NMR spectra are in accordance with 5b.
Synthesis of the Cyclopentadiene–Menadione Adduct 3
A mixture of 17.2 g (0.10 mol) of menadione and 1 g of dodecyl-
trimethylammonium bromide in 100 mL of acetic acid were placed in a
flask. To this 23.0 mL (0.28 mol) of freshly cracked cyclopentadiene were
then added and the resultant mixture was stirred at room temperature for
5 h. The solvent and the diene excess were evaporated with a rotary
evaporator at 50ꢀC. The residue was recrystallized frommethanol. The
crystals were filtered off and dried at 40ꢀC for 5 h in vacuumto give 22.2 g
(93.2%) of 3 as a white solid, m.p. 97–98ꢀC (Lit. 98ꢀC).[12] UV
(methanol): ꢁmax ¼ 224, 257 nm; IR (KBr): ꢂ ¼ 2950, 1670, 1590 cmÀ1
;
1H NMR: ꢀ ¼ 1.54 (s, 3H, CH3), 1.73 (ABq, J ¼ 9.5 Hz, 2H, bridge
CH2), 3.04 (d, J ¼ 4.1 Hz, ring junction CH ), 3.20 (s, 1H, CH ), 3.55
(m, 1H, CH ), 5.89 (dd, J1 ¼ 2.9 Hz, J2 ¼ 2.7 Hz, 1H, olefinic ¼CH ),
6.08 (dd, J1 ¼ 2.9 Hz, J2 ¼ 2.7 Hz, 1H, olefinic ¼CH ), 7.68 (m, 2H,
aromatic H ), 8.02 (m, 2H, aromatic H ). Anal. for C16H14O2, calcd.
(%) C 80.00, H 5.83; found C 79.81, H 5.92.
Synthesis of Vitamin K1 1
A mixture of 12.3 g (0.110 mol) of freshly prepared potassium tert-
butanolate and 100 mL of tetrahydrofuran were placed under argon in a
flask equipped with a magnetic stirrer, a reflux condenser, and argon
gasification. After cooling the mixture to À3ꢀC, 5.0 g (0.021 mol) of 3
were added. The red solution obtained was stirred at À3 to 0ꢀC for
30 min to dissolve 3. A solution of ca. 0.24 mol (1.15 equiv.) of phytyl
halide 5a–d in 25 mL of tetrahydrofuran was then added dropwise during
ca 30 min, respectively, followed by stirring at 0ꢀC for additional 1 h.
Thereupon, 1 N HCl was added until acidity, then the resultant yellow
solution was concentrated with a rotary evaporator and extracted with
toluene twice (100 mL Â 2). The organic extracts were washed with satu-
rated sodiumchloride solution, dried over anhydrous sodiumsulfate,
filtered and concentrated under reduced pressure.

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Improved Synthesis of Vitamin K1
771
The above-obtained yellow oil 2 was dissolved in acetic acid
(ca. 30 mL) in the presence of dodecyltrimethylammonium bromide
(ca. 0.2 g) and heated at 90ꢀC under argon in the dark for 15 min. The
mixture was then cooled and concentrated with a rotary evaporator.
This residue was purified by column chromatography on silica gel with
n-hexane/diethyl ether (20:1) as eluent, thereby obtaining (E/Z )-isomeric
1 as a yellow oil in 80–91% yields (Table 2). UV (hexane): ꢁmax ¼ 243, 249,
261, 270, 327 nm; IR (film): ꢂ ¼ 2940, 2920, 2850, 1660, 1620, 1598,
1
718 cmÀ1; H NMR: ꢀ ¼ 0.81 (d, 3H, J ¼ 6.5 Hz, CHCH3), 0.82 (d, 3H,
J ¼ 6.5 Hz, CHCH3), 0.86 (d, 6H, J ¼ 6.5 Hz, CHCH3), 0.97–1.45 (m,
17H, CH and CH2), 1.52 (m, 2H, CH2 at C50), 1.68 (s, 3H, cis-CH3
at C30), 1.78 (s, 3H, trans-CH3 at C30), 1.94 (t, 2H, J ¼ 9 Hz, CH2 at C40),
2.19 (s, 3H, ring CH3), 3.37 (d, 2H, J ¼ 7 Hz, CH2 at C10), 5.00 (t, 1H,
J ¼ 7 Hz, ¼CH at C20), 7.69 (m, 2H, aromatic H ), 8.08 (m, 2H, aromatic
H ); EIMS m/z ¼ 450 (Mþ, 100), 435 (6), 224 (26), 197 (18), 185 (20%).
Anal. for C31H46O2, calcd. (%) C 82.61, H 10.29; found C 82.44, H 10.37.
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Received in Japan November 6, 2001