Note: Descriptions are shown in the official language in which they were submitted.
5702-145F
This invention relates to an intermediate for use in the synthesis
of optically active alpha-tocopherol.
The present application is divided from applica,nts copending
Canadian application Serial INo. 396522 :Filed on February 18, 1982 ~ihich
related to a process for preparino an optically active alpha-tocopherol of
the formula
CH3
HO ~ ' ~ ICH3 lCH3
3 ~ ~A-(cH2cH2cH)(CH2C~2CH2CH ~ CH3
CP.3
wherein A is ~ ~ CH -or ~ /JCH~-
CH~3 2CH3
which comprises effecting cyclization of an optically active compound of che
formula
CH
CH3 1 3
~ G -~CH2CH2CH2CH)3 CH
H3C ~
CH3
OH OH
wherein G is -C- or -C-
CH3 CH3
to obtain said optically active alpha-tocophero], wherein the cyclization
reagent is d-camphor sulphonic acid in an inert solvent.
- 1 - 3~-P `'~
,~
9~
The compound d-alpha-tocopherol is the principal compound present
in natural vitamin E sources. At present, d-alpha-tocopherol and other
tocopherol derivatives are used in pharmaceuticals, foods and animal feeds.
Because d-alpha-tocopherol must generally be extracted from
natural sources, such as vegetable oils, it is not suitable for industrial
mass production. The content of d-alpha-tocopherol in vegetable oils is
very small, and it is essential to purify d-alpha-tocopherol by separating it
from beta, gamma and delta tocopherol isomers.
Several attennpts to synthesize optically active alpha-tocopherol
have been reported; for instance, see H. Mayler and 0. Isler et al, Helv.
Chim. Acta. _, 650 ~1963); J. W. Scott, W. M. Cort, H. Harley, F. T.
Bizzarro, D. R. Panish and G. Saucy, J. Amer. Chem. Soc. 51, 200 (1974);
ibid 52, 174 (1975); Helv.Chim. Acta. 59, 290 ~1976); K. K. Chan, and N.
Cohen et al, J. Org. Chem. 41, 3497, 3512 (1976); ibid 43, 3435 (1978).
None of these methods are suitable for industrial mass production.
Known methods, including those cited above, require an optical
resolution step, and this causes a serious reduction of the yield of about
30 to 40%. The present inventors have conducted research in order to
achieve a method of synthesis that does not require an optical resolution
step.
According to the present invention, there is now proviled a process
for preparing an optically active compound of the formula IX
CH3 cl~l3
R20 ~ ~ ~ E t C1l2CH2CH2CH ~ CH3
Il C / ~ OR3
CH3
~;~3~3~,4'7
\ ~CH3 \ ~C~-13
wherein E is C or ~C , and
R10 R10
Rl, R2 and R3 are protecting groups for hydroxyl functions which comprises
catalytically hydrogenating the double bond in the aliphatic chain of a com-
pound of formula VIII
C11 C11
R2 ~ ~f~ /E~cl-l2c~l2cll2c~l}~cH3
~13C~ 3
C113
~ CH3 \ ~CH3
wherein E is ~C or ~C , and
R10 Rl~
Rl, R2 and R3 are protecting groups for hydroxyl functions. The novel inter-
mediate of formula IX represents one of a number of steps involved in the
formation of optically active alpha-tocopherol from phytol.
The present invention further provides the step of converting the
compound of formula IX to a compound of formula X
CH3 CH3
~ \ ~ ~ Q -(cH2cH2cH2cH ~ C1-13
C113
ORl O~Rl
wherein Q is -C- or -C-
C~13 CH3
and Rl is a protecting group for a hydroxyl function by removal of all of the
protecting groups Rl, R2 and R3 following by oxidation.
- 2a -
~L~3~ 7
The present invention, together with that of aforementioned
parent application Serial No. 396,522 and copending divisional applications
'1~ Serial Nos. ~ , G '~ 7 and ~ ~ Ç , will now be described in more
detail.
~ ~3964'7
HO /~\~ C1i3 CH3 C~3
H3C ~V~\J\ ( I )
CH3 natural
phytol
HO'/ ~3
H3C ( I I )
HO '/--\ ~CH3 CH~, C-~3 C~3
HO~ = (III)
HO~ ~3
R I ( I V )
OHC
~ C113 - 3 CH3 CH3
O~ \~ (V) .
R1 CH3
OR2
¦ 3 r
OF~3
~ 3~ 6~ ~
OH
R~O ~ I~CH3 ( - 3
H3C OR3 ~ ~ (VII)
CH3 ORI CH3 CH3 CH3
H3C~ ~ (VIII)
CH3
C~ OR~ CH3 CH3 CH3
H3C ~ (IX)
CH3
CH3 ~ CH3 CH3 CH3
( X )
H3C ~ o CH3 CH3
CH3
HO ~ CH3 .CH3 CH3
C ~ O ~ H (XI)
C~!3 CH~ 3
d-~-tocopherol [(2R, 4'R,
8'R)-~-tocopherolJ
123~64~
In the structural representations of the compounds given
throug]lout this application, Rl~ R2, R3 and R~, which are the same or
different, indicate protecting groups of the hydroxyl function, and X
indicates halogen. A wedge-shaped line ( ~) indicates a substituent whicl
protrudes out of the plane of the paper towards the reader, that is,
the particular substituent is above the overall plane of the molecule. A
broken line (-= ) indicates a substituent which protrudes out of the plane
of the paper in tlle direction away from the reader, tha-t is, the particular
substituent is below the overall plane of the molecule. A wavy line (~ )
indicates a mixture of two compounds, each of which has the substituent,
but wherein the substituent is above the plane for one compound and below
the plane for the other.
A detailed description of one embodiment of this invention is as
follows.
The compound of formula I (natural phytol) is converted to the
compound of formula II or II' ~see below) by enantio selective oxidation.
This oxidation is carried out with natural phytol (I), diethyl tartrate,
titanium tetraisopropoxide and t-butyl hydroperoxide, in a halogenated
hydrocarbon solvent, such as di-chloromethane, trichloroethane, etc., at
a temperature in the range of -70C to 30C. In carrying out this reaction,
any tartrate ester can be utilized. Preferred tartrate esters include
dimethyl tartrate and diethyl tartrate. If D-~-)- diethyl tartrate is
utilized, then the compound of the formula II will
~2~ 7
be produeed. If the L-(+)- diethyl tartrate is
utilized, then the compound of the formula (II') given
below will be produeed.
HO ~ 0 C~3 CH3 CH3
H3C ~ ( II )
The eompound of the formula (II') is ultimately con-
verted to an optieally active alpha-tocopherol
eompound, namely, (2S, 4'R, 8'R) alpha-tocopherol in
the manner illustrated above.
In aceordanee with this invention, the term
"optieally active alpha-tocopherol" relates both
to eompounds of (2R, 4'R, 8'R)-alpha-tocopherol and
(2S, 4'R, 8'R)-alpha-tocopherol. The process for
synthesizing (2S, 4'R, 8'R) alpha-tocopherol starting
from the compound of the formula (II') is as follows.
--7--
H 0/--¦¦ C~~3 C ~13 ~ H3
H3C/= (I)
C~3 natural
phy to 1
'' CH~ C H3~ CH3
H 3C / ~/ \~\/\~, \/\~ ( I I ' )
CH3
HO~--~CH3 U3 C~i3 CH3
H O ~ ( I I I ' )
H O "'I H3 C U3 C H3 CH3
iL23~7
OHC
CH3 CH3 CH3 C~J3
O ~\~\CH3 (V' )
OR2
OR3
CH3 H
R20~ CH3 CH3 CH3 CH3
H3C~OR3 ~ ~ ( VI I )
CH3 R1
~1~3 ~ Rl b ~3 C H3 CU3
H3C ~ f ~ (VIII
CCHH33 ORI 1 C~3 CH3 CH3
H~C ~CH~ ( IX
CH3
:ELZ39~7
C~3 ~ ~ C~3 C~13 CH3
H~C ~ ~ H3
CH3
Cl 13
HO~ ~ C~,3 CH3 1~3
H3~oJ~ "I/V\ = (XI ' )
C~3 CH3
(2S, 4'R, 8'R)-cl-tocopherol
`` i~3g~
--10--
The compound of formula (II) or (II') is con-
verted to the compound of formula (III) or (III') by
reductive cleavage of the epoxide. Among the con-
ventional reducing agents usable in this reaction
lithium aluminum hydride is preferred. In carrying
out this reaction, an ether solvent, such as diethyl
ether, tetrahydrofuran, etc., is used. The reaction
temperature is not critical, but generally this re-
action is carried out at a temperature in the range of
from about -10C to about 40C.
The compound of formula (lII) or (III') is
converted to the compound of formula (V) or (V') via
the compound of formula (IV) or (IV'). First the
3-hydroxyl group is protected wi~h a protecting group
Rl, and then the 1-hydroxyl group is oxidized to form
the aldehyde of formula ~V) or (V'). In carrying out
the formation of the compound of formula (IV) or
(IV'), both the primary alcohol is protected, and the
tertiary alcohol is protected. Then the protecting
group of the primary a]cohol is removed to afford the
compound of formula (IV) or (IV').
The compound of formula (IV) or (IV') is con-
verted to the compound of formula (V) or (V') by oxi-
dation. The entire reaction sequence is as il-
lustrated below, first for the case of starting com-
pound (III) and then for the case of starting compound
(III').
~2~9~
HO---l CH CH3 CH3 CH3
HO~ ` (III)
1~40 ~1 3
H0 ( I I I-a )
R40 C H3
Rl~ (III-b)
H0 , I ~3 C113
C ~3
~ 2~9~4~7
OHC
CH3 CH3 C11
~1~ (V)
HO~ CH3 ~H3 CH3 C~3
H0 G~ ( I I I ' )
c~3
R4U /--1 H3 3 CH~ c~3
HO ~ H3 ( I I I ' -a )
~4~`~1 H3 C~3 CH3 CH3
~/~ (III '-b)
~3~6~7
-13-
HO ~ CH3
R~ (IV' )
OHC\
1~CH3 3 CH3 CH3
C~3
~23~
-14-
The compou~d of formula (III) or (III') is
converted to the compound of formula (III-a) or (III'-a)
by protecting the primary alcohol with a protecting
group which will react only with the primary alcohol.
Any conventional protecting group reacting only with
a primary alcohol can be utilized. Therefore, in the
above structures, R4 denotes a protecting group
that reacts only with a primary alcohol. Among the
protecting group reactants, ester derivatives such
as acetyl chloride, propionyl chloride, butyroyl
chloride and pivaloyl chloride are preferred. In
using these carboxylic acid chlorides, the reaction
conditions are not critical and the reaction is
carried out in an amine solvent, such as pyridine,
trimethylamine or triethylamine, at a temperature of
from about 0C to about 70C.
The compound of formula (III-a) or (III'-a) is
converted to the compound of formula (III-b) or (III'-b)
by protecting the tertiary alcohol. Any protecting
group reactants that react with a tertiary alcohol
can be utilized. Therefore, in the structures shown
above, Rl represents a protecting group that reacts
only with a tertiary alcohol. Conventional protect-
ing groups usable in the invention include alkyl,
aryl, alkoxyalkyl and aralkyl groups. The preferred
group for use in this reaction is methoxymethylene.
In carrying out this reaction, a methoxymethylene
halide, such as methoxymethylene chloride or methoxy-
methylene bromide, can be used,in a solvent of di-
chloromethane, dichloroethane, diethyl ether, or thelike.
The compound of formula (IlI-b) or (III'-b) is
converted to the compound of formula (IV) or (IV') by
~L~3~
-15-
removing the protecting group in position 1. Any
conventional method for reacting only with the pro-
tecting group in position 1 can be utilized. Among
the conventional methods of saponification that can
be used to remove the protecting group, basic
hydrolysis reactions utilizing potassium hydroxide,
sodium hydroxide, sodium carbonate, etc. can be used.
In carrying out this reaction, the use of lithium
aluminum hydride in an ether solvent is preferred,
usable ethers including diethyl ether, tetrahydro-
furan, and the like.
The cornpound of foxmula (IV) or (IV') is con-
verted to the compound of formula (V) or (V') by
oxidation of the primary alcohol to an aldehyde.
In carrying out this reaction, chromic acid reagents,
such as pyridinium chlorochromate (PCC) or Collins
reagent (chromic anhydride-pyridine) can be utilized
in a dichloromethane, dichloroethane or trichloro-
ethane solvent,at a temperature of from about 0C to
about 40C.
The compound of formula (V) or (V') is con-
verted to the compound of formula (VII) or (VII')
by reaction with the compound of formula (VI). In the
compound of formula (VI), X designates a halogen
atom, such as chlorine, bromine and iodine. The corn-
pound of formula (VI) designates 1,4-protected
2-halo-3,5,6-trimethyl-1,4-hydroquinone. R2 and R3
are the same as for Rl in the compound of formula
(III-b) or (III'-b).
In carrying out this reaction, alkyl, aryl,
alkoxyalkyl and aralkyl protecting groups can be used
as R2 and R3. Among these, the preferred protecting
group is methoxymethylene. The compound (VI) formed
1~396~
-16-
thereby is 2-halo-3,5,6-trimethyl 1,4-hydroquinone
dimethoxymethyl ether.
The compound of formula (V) or (V') is converted
to the compound of formula (VII) or (VII') by a
Grignard reac-tion. In carrying out this reaction, the
preferred solvents are ethers, such as diethyl ether,
tetrahydrofuran, dioxane, etc. In carrying out the
reaction, temperatures of from about 0C to about
50~C are generally utilized.
The compound of formula (Vl) is prepared as
follows. 3,5,6-trimethyl-1,4-benzoquinone is con~
verted to compound (VI) first by treatment with halo-
gen, followed by reduction to afford a halogenated
hydroquinone. The hydroxyl groups are then pro-
tected with methoxymethylene groups. The structure
is illustrated in the case below wherein X designates
bromide and R2 and R3 designate methoxymethylene
groups.
.. . .
, _ _ _ . , .... . . , . , _ .. .... , . _ . ___ ._ .. _ .... ..
3~
--17--
O O
H 3 C / ` CH ( 1 3 H 3 C i~l~ ` 3 r
(i) (ii)
f/--OCH3
1) N a B H4 H3C~ 3
E t O H I
> I
2) E t ON a , ~ J~
CH30CI12Cl H3C ~/ Br
~_ OCH3
( iii )
~;~3~6~7
-18-
The compound of formula (VII) or (VII') is
converted to the compound of formula (VIII) or (VIII')
by dehydration. Any conventional dehydration method
can be used for this purpose. Such conventional
methods include chlorination by thionyl chloride to
afford a chlorinat~d compound followed b~ dehydro-
chlorination with diazabicycloundecene (DBU) or
diazabicyclononene (DBN). Any conventional inert
solvent, such as diethyl ether, tetrahydrofuran,
benzene or toluene, can be used for the chlorination.
III carrying out this reaction, the temperature is not
critical. Generally temperatures of from about 0C
to about 50C are utilized. In carrying out the
dehydrochlorination, inert solvents, such as dimethyl
sulfoxide, benzene and toluene are used.
The compound of formula (VIII) or (VIII') is
converted to the compound of formula (IX) or (IX')
by catalytic hydrogenation of the double bond on the
aliphatic chain. Any conventional catalyst, such as
palladium-charcoal, Raney nickel, platinum oxide,
rhodium-aluminum, etc., can be used. In carrying
out this reaction, temperatures of from about 0C to
about 80C and solvents of ethanol, methanol, propanol,
acetic acid, benzene, toluene, diethyl ether, etc.,
are utilized.
The compound of formula IX or IX' is converted to the
compound of formula X or X' by removal of all of the protecting
groups Rl, R2 and R3, followed by oxidation. The compound of
formula X or X' can be prepared from the compound of formula
IX or IX' via the compound of formula IX-a or IX'-a.
:1~3~ Eii4~
-19-
CU3 ORl cH3 CH3 C~3
O ~
~3C~o CU~3 CH3
CH3 (IX-a~
CH3 ~1 CH3 CH3 CH3
o
H3CJq~o C1~3 CH3
CH3 ( IX ' -a )
3~
-20-
The compound of formula (IX-a) or (IX'-a) can
be isolated,but such a step is not essential.
Any conventional method of removing the protect-
ing groups can be utilized to form the compounds of
formulas (X) and (X'). Among the preferred methods
for removing the protectin~ groups are treatment with
acetic acid, hydrochloric acid-methanol, sulfuric acid-
methanol or palladium-charcoal in a hydrogen atmos-
phere. Any conventional method of converting hydro-
quinone to quinone can then be utilized to completethe reaction. Preferred oxidizing reagents include
lead dioxide, silver oxide, hydrogen peroxide, Fremy's
salt, etc.
The compound of formula (X) or (X~) is converted
to the compound of formula (XI) or (XI') by acidic
cyclization to provide optically active alpha-
tocopherol. Among the acids,d-carnphor sulfonic acid
is preferred. In carrylng out this reaction, an inert
solvent, such as methanol, ethanol, propanol, acetic
acid and diethyl ether, is used,a-t a temperature of
from about 0C to about 90C,to provide optically
active (2R, 4'R, 8'R) alpha-tocopherol. In carrying
out this reaction, the procedure described in O. Isler
et al,Helv. Chim. Acta., 50, 1168 (1967) can also be
utilized.
(2R, 4'R, 8'R) alpha-tocopherol synthesized ac-
cording to the invention was fully characterized
physically and chemically by comparison with naturally
occurring d-alpha-tocopherol. For instance, the [~]D
value of acetate of (2R,4'R, 8'R) alpha-tocopherol
synthesized according to the invention, and the oxida-
tion product produced by treatment of (2R, 4'R, 8'R)
alpha-tocopherol with potassium ferricyanide absolutely
3~64~7
-21-
correspond with the results obtained using authentic
natural tocopherol.
The following intermediates in this invention are
novel compounds: (II), (II ' ), (III), (III ' ), (IV),
(IV' ), (V), (V' ), (VII), (VII ' ), (VIII), (VIII ' ),
(IX), (IX'), (III-a), (III'-a), (III-b~, (III'-b),
(IX-a) and (IX'-a).
The present invention is of great value because
optical resolution is not absolutely necessary in order
to produce optically active alpha-tocopherol by the
process of the invention.
The following examples are illustrative of the
invention, but the invention is not limited thereto.
EXAMPLE 1
Synthesis of (2S, 3S)-epoxy-(3S, 7R, llR)-3,7,11,
15-tetramethylhexadecane-1-ol (formula II')
A solution of 11.4 y (40 mM) of titanium tetraiso-
propoxide and 8.24 g (40 mM) of L-(+)-diethyl
tartrate in 400 ml of dry dichloromethane was stirred
at -20C to - 30C in a nitrogen atmosphere. After
stirring for 10 min., 12 g (40 mM) of natural phytol
in 30 ml of dry dichloromethane was added and then
a dichloroethane solution co~taining 80 mM of t-butyl
hydroperoxide was added. The reaction was monitored
by thin layer chromatography (tlc). (CHC13 - benzene
solvent).
After stirring for 2 hours at -20C to 30C,
100 ml of 10~ tartric acid solution was added and the
drying bath was then removed. The organic layer was
separated and washed with water. The dried organic
solution was concentrated under water aspirator pres-
sure to give 12.4 g of a colorless oil. This crude
~3g6~7
-2~-
product was dissolved in 300 ml of diethyl ether and
120 ml of 1 N sodium hydroxide solution was added with
ice cooling.
After stirring for 30 min., the organic layer was
separated, washed with water and dried over magnesium
sulfate. This diethyl ether solution was concentrated
under water aspirator pressure to give 12.2 g of a
colorless liquid. This crude material was chromato-
graphed on 200 g of 60 to 80 mesh silica gel. Elution
with n-hexane-ethyl acetate gave 11.7 g of the pure
title compound (yield: 91.3~).
[~lD = ~4-4 (c 3.63 ETOH). Anal. Calcd.for
C20H40O2 = ~,76.86%; H, 12.906.Found : C,77.14%;
H, 12.75%.IR v cm - 3,400. NMR (CDC13) ~: -
0.87 (d, 6H, J=6 Hz) 1.30 (s, 3H) 2.20 (m, lH)
2.97 (d-d, lH) 3.48 - 4.00 (m, 2H). MS m/e
= 294.
EX~MPLE 2
Synthesis of (2R, 3R)-epoxy-(3R, 7R, llR)-3, 7,
11, 15 - tetramethylhexadecane-l-ol (formula II)
5.7 g (20 mM) of titanium tetraisopropoxide, 4.2 g
(20 mM) of D-(-)- diethyl tartrate 7 6 g (20 mM) of
natural phytol and 40 mM of t-butyl hydroperoxide were
reacted in the same manner as in Example 1 to afford
5.6 g of the title compound (yield: 89.7%).
[~]D5 = + 4 3 (c 2.8 ETOH)
IR, NMR, Mass spectra were completely identical
with the spectra obtained in Example 1.
EXAMPLE 3
Synthesis of (3S, 7R, llR) - 3, 7, 11, 15 - tetra-
methylhexadecane-1,3-diol (formula III')
~2;~4~
To a solution of 0.75 g (20 mM) of lithil~ aluminum
hydride in 100 ml of TE3F was added 20 ml of a THF solu-
tion containing 6.24 g (20 mM~ of (2S, 3S)-epoxy-(3S,
7R, llR) - 3, 7, 11, 15 - tetramethylhexadecane-l-ol
over a period of 30 min.
After stirring ~or 2 hours at 5C, the reaction
mixture was treated in the usual manner to give 6.1 g
of title compound (yield: 100%).
20 42 2
Found: C, 76.10%; H, 13.57%. IR ~ cm = 3400.
N~R (CDC13) ~ : 0.86 (d, 6H , J=6 Hz), 1.24
(s, 3E~) 2.40 (b-s, lH), 2.84 (b-s, lH) 3.65 -
4.00 (m, 2H) MS m/e : 296
EXAMPLE 4
Synthesis of (3R, 7R, llR) - 3, 7, 11, 15 - tetra-
methylhexadecane-1,3-diol (formula III)
1.52 g ~40 ïnM) of lithium aluminum hydride and 2.48
g (40 mM) of (2R, 3R)-epoxy-~3S, 7R, llR)-3, 7, 11, 15-
tetramethylhexadecane-l-ol were reacted in the same
manner as in Example 3 to give 2.3 g (yield: 100%) of
the title compound.
IR, NMR and Mass spectra were completely
identical with the spectra obtained in
Example 3.
EXAMPLE 5
Synthesis of (3S, 7R, llR) - 3, 7, 11, 15 -tetra-
methyl-3-methoxymethyleneoxy-hexadecane-1-ol (formula IV')
(i)
~ a solution of 6.3 g (20 mM) of (3S, 7R, llR)-3,
7, 11, 15 - tetramethylhexadecane-1,3-diol in 50 ml of
pyridine was added 2.9 g of (24 mM) of pivaloyl ch]oride
at 0C
.~L2,39fia~7
-24-
After stirring for 1 hour, the reaction mixture
was poured into 200 ml of 5~ HCL solution. The organic
layer was washed with water, then dried to give 7.7 g
of crude material.
(ii)
To the solution of 7.7 g of pivaloyl ester in 100
ml of dry dichloromethane,2.9 g (24 mM) of N,N-dimethyl
aniline was added followed by addition of 1.9 g (24 mM)
of methoxymethyl chloride.
After stirring for 4 hours at ambient temperature,
the reaction mixture was poured into 100 ml of 5% HCL
solution. Work-up with diethyl ether in the usual
manner gave 8.2 g of colorless oil.
This material was chromatographed on 150 g of
60 to 80 mesh silica gel. Elution with n-hexane and
ethyl acetate afforded 8.0 g of the pure title compound
(yield: 95%).
[~]D = + 2.13 (c 6.34 ETOH). Anal. Calcd.for
C27H54O4; C,73.25%; H, 12.30 %,Found
C, 73.86%; E~, 12.45%; IR v cm = 1745.NMR
(CDC13) ~ : 0.86 (d, 6H, J=6 Hz) 1.20 (s, 9H),
1.24 (s, 3H), 1.85 (t, 2H , J=7Hz), 3.37 (s, 3H),
4.16 (t, 2H, J=7Hz), 4.70 (s, 2H). MS m/e = 442.
(iii )
The solution of 8.0 g of the above compound pro- _
duced in (ii) in 20 ml of diethyl ether was added to
a solution of 1.0 g of lithium aluminum hydride in 50
ml of die-thyl ether at 0C.
After stirring for 1 hour, the reaction mixture
was chilled with an ice bath. Work-up with water and
15% NaoH solution in the usual manner gave 6.5 g of the
title compound (yield: 95%).
~ 3~3647
[~]D =+1.8 (c 7.50 ETOH)
22 4G 3
H~12.93~; Found: C,73.36%; H, 13.28%.
IR v cm = 3,450.NMR (CDC13) ~ : 0.86
(d, 61~,J-6Hz), 1.28 (s, 3H), 2.80 (t, lH
, J = 5Hz), 3.28 (s, 3H), 3.78 (q7 2H,
J = SHz), 4.72 (s, 2~
MS m/e = 358, 340, 327.
EXP~LE 6
Synthesis of (3R, 7R, llR) - 3, 7, 11, 15 -
tetramethyl-3-methoxyrnethleneoxyhexadecane-1-ol
(formula IV)
6.3 g (20 mM)-of (3R, 7R, llR) - 3, 7, 11, 15 -
tetramethylhexadecane-1,3-diol was -treated in the same
manner as in Example 5, (i), (ii) and (iii), to give
6.4 g (yield: 89.3%) of the title compound.
L~]D = - 1.8 (c 3.59 ETOH)
IR, NMR and Mass spectra were completely identical
with the spectra obtained in Example S.
EXAMPLE 7
Synthesis of (3S, 7R, llR) - 3, 7, 11, lS -
tetramethyl-3-methoxymethyleneoxyhexadecane-1-al
(formula V')
To a solution of 3.6 g (10 mM) of (3S, 7R, llR) -
3, 7, 11, lS - tetramethyl-3-methoxymethyleneoxy-
hexadecane-l-ol in 50 ml of dichloromethane was added
6.4 g (30 mM) of PCC in small portions. The reaction
was monitored by tlc.
After stirring for several hours at room tempera-
ture, 50 ml of diethyl ether was added to the reaction
mixture and filtered through 50 g of Florisil. The
resulting filtrate was evaporated to afford 3.7 g of
yellow oil. This crude material was chromatographed
* a trade mark
~l23~7
on ;'0 g of 60 to 80 mesh silica gel. Elution with
n-hexane and diethyl ether afforded 3.1 g of the color-
less title compound (yield: 87.1~)
[C~]D = + 6.66 ( c 2.1 ETOil)
Anal. Calcd.for C22H44O3 : C, 74.10~; H, 12.44~;
Found: C.73.89~; ~3. 12.73%, IR v cm 1 = 1730.
NMR (CDC13) ~ : 0.86 (d, 6H), 1.32 (S7 3H),
2.52 (t7 2H), 3.36 (s, 3H), 4.72 (s, 2H),
9.80 - 9.97 (m, lH). MS m/e -- 356.
EXAMPLE 8
Synthesis of (3R, 7R, llR) - 3, 7, 11, 15 -
tetramethyl-3-methoxymethyleneoxyhexadecane-1-al
(formula V)
5.4 g (15 mM) of (3R, 7R, llR) - 3, 7, 11, 15 -
tetramethyl-3-methoxymethyleneoxy hexadecane-l-ol and
9.6 g (45 mM) of PCC were reacted in the same manner
as in Example 7 to give 4.8 g (yield: 89.7~) of the
title compound
[~]25 = _ 6.45 (c 2.17 ETOH)
IR, NMR and Mass spectra were completely identical
with the spectra obtained in Example 7.
EXAMPLE 9
Synthesis of 2-[(3'S, 7'R, ll'R) - 3', 7', 11',
15' - tetramethyl-3'-methoxymethyleneoxy-1'-hydroxy
hexadecanyl] - 3, 5, 6 - trimethyl-l, 4-hydroquinone
dimethoxymethyl ether (formula VII')
To a solution of 0.24 g (10 mM) of magnesium in
20 ml of dry THF was added 1 or 2 drops of ethylene-
dibromide for activation of the magnesium. To this
30 solution was added 3.19 g (10 mM) of 2-bromo-3, 5, 6-
trimethyl-1,4-hydroquinone dimethoxymethyl ether in 10
ml of dry THF. After the addition was finished, the
reaction mixture was refluxed for 2 hours.
:~239~47
-27-
To this Grignard reagent was aclded 15 ml of dry
THF solution containing 2.85 g (8 mM) of (3S, 7R, llR)-
3, 7, 11, 15 - tetramethyl-3-methoxymethyleneoxy hexa-
decane-l-al. After stirring for 1 hour at reflux, the
reaction mixture was poured in~o 100 ml of saturated
NEI4Cl solution.
Work--up with diethyl ether in the usual manner gave
5.5 g of pale yellow oil.
This crude material was chromatographed on 100 g
of 60 to 80 mesh silica gel. Elution with n-hexane and
diethyl ether afforded 3.8 g of the colorless title
compound (yield: 79.7%).
[a]D = -4.58 (c 2.4 ETOH)
Anal. Calcd.for C35H64O7 : C, 70.43%; H, 10.81%,
Found: C, 70.30%; H, 11.01%; IR v cm = 3500.
NMR (CDC13) ~ : 0.86 (d, 6H , J = 7Hz),
2.18 (s, 3EI), 2.20 (s, 3E~), 2.42 (d, 3H, J =
2 Hz), 3.40 (s, 3~1), 3.63 (s, 6H), 3.76 - 3.96
(m, lH),4.75 (d, 2H,J = 2 Hz), 4.86 (s, 2H), 4.96
(s, 2H), 5.28 ~ 5.57 (m, lH).MS m/e=596.
EXAMPLE 10
Synthesis of 2 - [(3'R, 7'R, ll'R) - 3', 7', 11',
15'- tetramethyl-3'-methoxymethyleneoxy-l' hydroxy
hexadecanyl] -3, 5, 6-trimethyl-1,4-hydroquinone
dimethoxymethyl ether (formula VII)
0.12 g (5 mM) of magnesium, 1.6 g (5 m~) of 2-
bromo-3, 5, 6-trimethyl-1,4-hydroquinone dimethoxymethyl
ether and 1.4 g (4 mM) of (3R, 7R, llR) - 3, 7, 11, 15 -
tetramethyl-3-me-thoxymethyleneoxyhexadecane-1-al were
reacted according to Example 9 to give 1.8 g (yield:
75.6%) of the colorless title compound.
3~
-28-
[ ]25= + 5 87 (c 5.14 ETOH)
IR, NMR and Mass spectra were completely identical
with the spectra obtained in Example 9.
EXAMPLE 11
Synthesis of 2-[(3'S, 7'R, ll'R) - 3', 7', 11', 15'
- tetramethyl-3l-methoxymethyleneoxy-ll-hexadecenylJ
-3, 5, 6-trimethyl-1,4-hydroquinone dimethoxymethyl
ether (forrnula VIII')
To a solution of 1.8 g (3 m~l) of 2-[(3'S, 7'R,
ll'R)-3', 7', 11', 15' - tetramethyl-3'-rmethoxymethylene-
oxy-l'-hydroxy hexadecanyl] - 3,5,6-trimethyl -1, 4-
hydroquinone dirnethoxymethyl ether in 50 ml of ether
were added successively 3 ml of pyridine and 1.0 g
(8.4 mM) of thionyl chloride at 0C.
After stirring for 30 min., the reaction mixture
was poured into 50 rnl of 5% HCl solution. Work-up
with diethyl ether in the usual manner gave 1.9 g of
crude product material.
The product did not S}IOW hydroxyl absorption in
its IR spectrum.
1.9 g. of this crude material were dissolved in
30 ml of dry DMSO, and then treated with 2 g of DBN
at 100C.
After stirring for 30 min., the reaction mixture
was poured into 100 ml of ice water. Work-up with
diethyl ether in the usual manner gave 1.8 g of pale
yellow oil. This material was chromatographed on 50
g of silica gel. Elution with n-hexane and ether af-
forded 1.5 g of the colorless title compound (yield:
86.4%)
[~]D = ~ 10.08~ (c 7.8 ETOH)
35 62 6
H, 10.80~, Found: C, 72.98~; H, 11.07%.
- :123'~6~7
-29-
NMR (CDC13) ~ : 0.87 (d, 6H , J - 7 Hz),
1.44 (s, 3H), 2.23 (s, 6H) 2.27 (s, 3H),
3.40 (s, 311) 3.57 (s, 3H),3.63 (s, 3H),
4.75 (q, 2H, J= 6Hz), 4.85 (s, 2H~, 4.90
(s, 2H), 5.90 (d, lH, J=17 Hz), 6.52 (d, lH,
J = 17 Hz). MS m/e = 578.
EXAMPLE 12
Synthesis of 2-[(3'R, 7'R, ll'R) - 3', 7', 11',
15'-tetramethyl-3'-methoxymethyleneoxy-1'-hexadecenyl]
-3, 5, 6-trimethyl-1,4-hydroquinone dimethoxymethyl
ether (formula VIII)
1.2 g (2 m~l) of 2-[(3'R, 7'R, ll'R)-3', 7', 11',
15'-tetramethyl-3'-methoxymethyleneoxy-1'-hydroxy
hexadecanyl]-3, 5, 6-trimethyl-1,4-hydroquinone di-
methoxymethyl ether, 0.67 g (5.6 mM) of thionyl
chloride and 1.3 g of DBN were reacted according to
Example 11 to give 0.9 g (yield: 77.8%) of the title
compound.
[~]D = + 11.81 (c 2.07 ETOH)
IR, NMR and Mass spectra were completely identical
with the spectra obtained in Example 11.
EXAMPLE 13
Synthesis of 2-[(3'S, 7'R, ll'R) - 3', 7', 11', 15'
- tetramethyl-3'-methoxymethyleneoxy hexadecanyl~ - 3, 5,
6 - trimethyl-1,4-hydroquinone dimethoxyme-thyl ether -~
(formula (IX')
1.5 g (2.6 n~l) of 2-[(3'S, 7'R, ll'R) - 3', 7',
11', 15' - tetramethyl-3'-methoxymethyleneoxy-1'-hexa-
decenyl]-3, 5, 6-trimethyl-1, 4-hydroquinone dimethoxy-
methyl ether was dissolved in 50 ml of ethanol contain-
ing 500 mg of 5% palladium-charcoal. The resulting
mix-ture was vigorously stirred under a hydrogen pressure
il~3~4~
-30-
of one atmosphere at room temperature.
After stirring for 2 hours, the reaction mixture
was filtered. The filtrate was concentrated under
aspirator pressure to give 1.45 g of the colorless
title compound (yield: 100~)
[~]D = -4.58 (c 3.5 ETOH)
. . C35H60O6 : C, 72.87~;H,
10.48~;Found: C, 73.15%;H, 10.65%. NMR
(CDC13) ~ : 0.87 (d, 6~, J=6Hz), 2.20 (s, 6H),
2.25 (s, 3H), 2.52 - 2.84 (m, 2H), 3.40 (s, 3H),
3.62 (s, 6H), 4.76 (s, 2H), 4.88 (s, 2H) 4.89
(s, 2H). MS m/e = 576
EXAMPLE 14
Synthesis of 2-[(3'P~, 7'R, ll'R) - 3', 7', 11',
15' - tetramethyl-3'-methoxymethyleneoxy hexadecanyl]
- 3, 5, 6 - trimethyl - 1,4 - hydroquinone dimethoxy-
methyl ether (formula IX)
1.06 g (2 m~l) of 2-[(3'R, 7'R, ll'R) - 3', 7',
11', 15' - tetramethyl-3'-methoxymethyleneoxy-1'-
hexadecenyl] -3, 5, 6-trimethyl-1, 4-hydroquinone
dimethoxymethyl ether and 0.3 g of 5% palladium-
charcoal were reacted according to Example 13 to give
1.04 g of the colorless title compound.
[ ]25 = + 5 02 ( c 4.8 ETOH)
IR~, NMR and Mass spectra were completely
identical with the spectra obtained in Example
13.
EX~MPLE 15
Synthesis of 2-[(3'S, 7'R, ll'R) - 3', 7', 11',
15'-tetramethyl-3'-hydroxyhexadecanyl] -3, 5, 6-
trimethyl-1,4-benzoquinone, also called (alpha-(3'S)
-tocopheryl quinone) (formula X')
:3~239~7
(i)
To a solution of 1.45 g (2.5 I~M) of 2-~(3'S, 7'R,
ll'R) -3', 7', 11', 15' - tetramethyl-3'-methoxy-
methyleneoxy hexadecanyl] - 3, 5, 6 - trimethyl - 1,4 -
hydroquinone dimethoY.ymethyl ether in 20 ml of THF
was added 20 ml of ln~ HCl solution. After stirring
for 1 hour at roorn temperature, the reaction mixture
was diluted with 50 ml of water. This solution was
extracted with diethyl ether twice. To the combined
ether solutions was added 2 g of lead dioxide at room
temperature.
After stirring for 1 hour, the reaction mixture
was filtered and the filtrate was concentrated under
water aspirator pressure to give 1.4 g of pale yellow .
oil. This material was chromatographed on 30 g of
silica gel. Elution with n-hexane and ether afforded
1.1 g Iyield: 89.6%~ of pale yellow alpha-(3'S)-
methoxymethyl tocopheryl quinone.
[~]25 = _ 3.27 (c 1.69 ETOH)
Anal.Calcd. for C31H54O4 : C, 75.87%, H,
11.09~, Found: C, 76.18%; H, 11.36~. IR
v cm = 1640. N~R (CDC13) ~ : 0.87 (d, 6H
, J = 6 Hz), 2.02 (st 6H), 2.04 (s, 3H), 2.36
- 2.62 (m, 2~1), 3.40 (s, 3H), 4.75 (s, 2H).
MS m/e = 429.
(ii)
To a solution of 1.1 g (2~2 I~M) of alpha-(3'S)-
methoxymethyl tocopheryl quinone in 30 ml of methanol
was added 20 ml of 10~ HCl solution.
After stirring for 5 hours at room temperature,
50 ml of water was added. This solution was extracted
with 50 ml of diethyl ether twice. The combined ether
solutions were concentrated under wa-ter aspirator
~2;39~47
pressure to give 7.7 g of pale red oil.
This material was chromatographed on 25 g of
silica gel. Elution with n-hexane and diethyl ether
afforded 0.9 g (yield: 89%) of the pale red title
compound.
[ ]25 = + 1 08 (c 10.6 EIOH)
29 50 3 , 7 .97~1 H, 11. 8%.
Found: C, 78.15%; H, 11.41%; IR v cm
3450, 1640. NMR (CDC13) ~ : 0.87 (d, 6H, J =
7 Hz), 1.24 (s, 3H), 2.0G (s, 6H), 2.03 (s, 3H),
2.4a - 2.70 (m, 2H). MS m/e = 428.
E ~AMP LE 16
Synthesis o. 2-[(3'R, 7'R, ll'R) - 3', 7', 11', 15'
- tetramethyl-3'-hydroxy hexadecanyl] -3, 5, 6 -
trimethyl-1,4-benzoquinone, also called (alpha-(3'R)
-tocopheryl quinone) (formula X)
(i)
1 g (1.7 mM) of 2-~(3'R, 7'R, ll'R) - 3', 7', 11',
15' - tetramethyl-3'-methoxymethyleneoxy hexadecanyl]
-3, 5, 6 - trimethyl-l, 4 - hydroquinone dimethoxy-
methyl ether, 15 ml of 10~ HCl solution and 1.5 g
of lead dioxide were reacted according to Example 15(i)
to give 0.75 g (yield: 89.9%) of pale yellow alpha-
(3'R)-methoxymethyl tocopheryl quinone.
[ ]25 = + 3 8 (c 4.39 ETOH)
IR, NMR and Mass spectra were completely identical
with the spectra obtained in Example 15.
(ii)
0.75 g (1.5 mM) of alpha-(3'Rj-methoxymethyl
tocopheryl quinone and 15 ml of 10% HCl solution
were reacted according to Example ]5 (ii) to give
0.6 g (yield: 89.5~) of thepale redtitle compound.
~3~6~
-33~
[~]D5 = -1.01 (c 18.8 ETOH)
IR, NMR and Mass spectra were completely identi-
cal with the spectra obtained in Example 15.
EXAMPLE 17
Synthesis of (2S, ~'R, 8'R) - alpha-tocopherol
(formula XI')
1 g (4 mM) of d-camphor sulfonic acid was added
to a solution of 0.9 g (2 mM) of 2-[(3'S, 7'R, ll'R)
-3', 7', 11', 15' - tetramethyl-3'-hydroxy hexadecanyl]
-3, 5, 6 - trimethyl-1,4-benzoquinone in 20 ml of meth-
anol. After stirring for 15 min. at room temperature,
the mixture was poured into 50 ml of ice water.
Work-up in the usual manner (extraction with diethyl
ether 2 times, and drying over magnesium sulfate)
afforded 0.85 g of pale yellow oil.
This material was chromatographed on 30 g of
silica gel. Elution with n-hexane and diethyl ether
afforded 0.8 g (yield: 93%) of colorless title com-
pound.
[~]25 = + 0.85 (c 1.15, benzene)
K3Fe(CN)6 oxidation product:
[~]D = ~ 29.6 (c 1.70, isooctane)
This (2S, 4'R, 8'R)-alpha-toCopheryl quinone was ~.
acetylated with acetic anhydride and pyridine to give
(2S, 4'R, 8'R)-alpha-tocopheryl acetate in quantitative
yield.
[~]D = -2.25 (c 1.1 ETOH)
EXAMPLE 18
Synthesis of (2R, 4'R, 8'R) - alpha-tocopherol
(formula XI)
123964~
-34-
0.65 g (2.6 mM) of d-camphor sulfonic acid and
0.6 g (1.3 mM) of 2-[(3'R, 7'R, ll'R) - 3', 7', 11', 15'
- tetramethyl-3'-hydroxy hexadecanyl] - 3,5,6 - tri-
methyl - 1,4 - benzoquinorle were reacted according to
Example 17 to give 0.52 g of the colorless title
compound (yield: 90.3~)
[~]D = ~ 2.76 (c 1.07, benzene)
UV ~ max = 292 nm; ~ c1% = 69.7
K3Fe(CN)6 oxidation product:
[~]D = + 29.8 (c 1.05 isooctane)
Acetate (formed according to Example 17):
[ ]25=+ 3 49o (c 1.1 ETOH)
