Chemistry of Vitamin E

OTTO ISLER, PETER SCHUDEL, HANS MAYER, JOSEF WURSCH,

A N D RUDOLF RUEGG

Ilesenrrh Laboratories, It’. HoJ.rnanwLa Roche & Co., Ltd., Hasle, Switzerland
P a ye
I . Introductiori.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38!1
11. Synt,heses of a-Tocopherol... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
A . ?‘oi.al Syntheses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 592
R . Partial Syntheses from M e t h y l t m o l s . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395
111. Synthesis of t.he a-Tocopherol Metabolite.. . . . . . . . . . . . . . . . . . . . . . . . 395
IV. Syntheses of Methyltocols... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397
A . Syntheses of I)iniethylt,ocols.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398
€3. Syntheses of Monomethyltocols.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398
\J. Syrit!lietic Interrnetiiat,es and Transformations of a-Tocopherol. . . . . . . . . 398
A . Triniethylphytylhydroquinoncs as Synthetic Intermediates.. . . . . . . . . 398
I3. Inversion of Configuration a t C-2 of d-a-Tocopherol. . . . . . . . . . . . . . . . . 400
C. a-Tocopherol and 3,4-l>ehydro-a-tocopherolfrom Trimethylphytyl-
benzoyuinone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400
V I . Related Compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404
I‘II. Concluding R e m a r k s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404
Iteferences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404

I. INTRODUCTION
Vitamin I3 occurs in vegetable oils and acts as a biological antioxidant.
It is distributed throughout the tissues of animals and man, and its defici-
rncy causes a variety of syndromes in the animal organism.
a-Tocopherol, thc most activc vitamin E factor known to occur in nature,
is :t 6-hydroxychroman derivative with methyl groups in positions 2, 5 , 7,
and 8 arid a C l d i p h a t i c sidr chain attached to C-2 (Fig. 1). The side
chain, together with the c:irbon atoms 2 , :3, and 4 and the methyl group a t
C-2 of the vhroman moiety, represents the carbon skeleton of phytol.
a-Tocopherol possesscs thrcc dissimilar centers of asymmetry, which are
located at (3-2, C-4’, and C-8’ (l‘ig. l), according to the numbering system
proposcd by Icarrer et al. (1939).
Natural phytol contains two asymmetric centers (C-7 and C - l l ) , the
absolute configurations of which have been determined by Burrell et al.
(1959) and Crabbe et al. (1959) to be 71%and 11R (Fig. 1). [We use the
specification of asymmetric configuration proposed by Cahn, Ingold, and
l’relog (1 956) in this review.] It seems likely and has iisually been assumed
389
390 ISLER, SCHUDEL, MAYER, WURSCH, AND RUEGG

in the literature that the absolute configurations a t C-4’ and C-8’ of natural
d-a-tocopherol correspond to those of the centers C-7 and C-11 of natural
phytol. Nothing is known about the absolute configuration of the asym-
metric center C-2 of d-a-tocopherol, but work with a view to its determina-
tion is in progress.
Simon et al. (1956a,b) shomcd that a-tocopherol is metabolized into the
two quinoncs listed in Fig. 1. These mctabolites, found in the urine of

4‘ Vitamin E (a-Tocopherol)

a - Toc op her o 1 Met a bol it e s

OH COOH
0

HoH2cL...r3
jH?d H
I\...
H
Natural Phytol

7R 11R .=Optically active center

VIG. 1. Structural relationship of a-tocopherol, t h e a-tocophcrol melabolites,

and phytol.

humans ingesting large quantities of a-tocopherol, are devoid of the two

asymmetric centers 4’ and 8’ of the “phytyl” side chain. They can be
formally derived from a-tocopherol by oxidative cleavage of the chromari
ring and the :3‘ ,-t’-(*arhon-carl>onbond.
Investigations in our laboratories have shown that the configurations of
the asymmetric. centers C-4’ and C-8’ of thc a-tocopherol side chain h a w ,
within the limits of error, no effect on vitamin 3; activity (antisterility test).
a-l‘ocopherols with different configurations a t C-2, however, show within
limits of error the difference of biological activity specified in the Na-
tional Formulary (1960).
Except 5-methyltocol (Bacharach and Green, 1961) and tocol [%methyl-
2-(3’ ,8’,12’-trimethyltridccyl)-6-chromanol], all the lower homologs of
a-tocopherol hearing only one or two methyl groups on the aromatic nu-
 CHEMISTRY OF VITAMIN E 39 1

cleus have been found in nature. Their main sources are the vegetable oils
listed in Table I.
The purpose of this paper is to give a brief survey on syntheses and
chemical transformations of vitamin E. Special emphasis will be laid on
methods suitable for labeling of the tocopherols. Except for a-, p-, y-, and
&tocopherol, the tocol nomenclature proposed by Karrer and Fritzsche
(1938) will be used throughout this review.

TABLE I
TOCOPHEROLS SIDECHAIN
WITII SATURATED

R1

Name Main occurrence

a -Tocopherol Wheal germ
0 -Tocopherol Wheat germ
F -Tocopherol Maize
5,7- Dimethyltocol Rice
d - Tocopherol Soy bean
7 - Methyltocol Rice
5 - Methyltocol Synthetic
Tocol synthetic

11. SYNTHESES
OF CY-TOCOPHEROL

A synthesis of a vitamin E active product has been first achieved in the

laboratories of F. Hoffmann-La Roche & Co., Ltd. in Basle, by condensa-
tion of trimethylhydroquinone and 1 ,3-dibromophytane derived from
phytol. The first total synthesis of (2RS : 4’R : 8’R)-a-tocopherol was
described by Karrcr ct al. (1938a,b), who condensed trimethylhydro-
quinone with phytyl bromide. This synthesis, later performed in a different
manner by Smith et al. (1938), Karrer and Ringier (1939), and Smith and
Ungnade (1939), could be modified, replacing phytyl bromide by natural
phytol (Karrer and Isler, 1938;Bergel et al., 1938a, 193%; Smith et al., 1939;
Fieser et al., 1940) or by isophytol (Karrer and Isler, 1941).
Thc earlier synthetic work in the vitamin E field has been reviewed by
Karrer (1939), John (1939), Todd (1939), Karrer and Bergcl (1939), Smith
:m ISLER, SCHUDEL, MAYER, WUKSCH, ANT) RUEGG

(1940), and Isler (1942). Latcr on, the conversion of dimethyl- and mono-
methyltocols, such as, e.g., p-, y-, and &tocopherol into a-tocopherol was
described.
SYNTHESES
A. TOTAL
The tcchnical syntheses are bascd on the condensation of phytol or
isophytol with trimethylhydroquinone, which can be prcparcd from 3,s-
dimcthylphcnol by the Mannich reaction followed by a series of obvious
steps. We prcparcd radioactive C14-labcledtrimcthylhydroqiiinone (specific
activity: 11.8 pc/mg), as shown in Fig. 2 .
Further condensation with natural phytol, e.g., in the presence of zinc
chloride (Fig. :3) gave (2RS :4’R :8’R)-a-tocopherol (specific activity of the
acetate : 3.85 pc/mg). Wit,h isophytol synthesized from acetone, totally
racemic a-tocopherol (spccific activity of the acetate: 4.3 pclmg) was oh-

tuincd. Another labeling with CI4 or tritium might be achieved as indicated

in Fig. 3.
I n 1942 two further methods for preparing a-tocopherol wcrc published
(Fig. 4). The essential step in the synthesis developed by John and Pini
(1942) was the Grignard reaction of the aromatic ketone (I) with hexahy-
drofarnesylmethylmagncsium bromide (11). After several further steps,
totally racemic a-tocopherol was obtained. Smith and Miller (1942) used
the Cls-ketone (IV), prepared by ozonolysis of natural phytol and thc
aromatic Grignard compound (111) to gct finally (2RS :4’R: 8’R)-a-toco-
pherol.
The total synthesis of natural d-a-tocopherol could have been achieved,
had the separation of the synthetic epimerir mixture of (2R:4’R:8’R)- and
(2S:4’R:8’R)-a-tocophcrolbccn carried out; this on the assumption that
the absolute configurations of t,he asymmetric ccntcrs C-7 and C-11 of
natural phytol arc identical with the corresponding ccntcrs in natural
d-a-tocophcrol.
liarrer ~t al. (10:381), 1944) ciidcavorcd to separatc the rpimcric mixturc
of (2RS:4’R :8’It)-a-tocophcrol by means of thc :~-bromocamphorsiilfonic
acid rsters. Repc%ition of this work in our lahoratmies, with thc :3-bromo-d-
camphor-10-sulfonic acid esters also gave no separation. I n order to havc
 CHEMISTRY OF VITAMIN E 393
L
b
4-
C
V
II I1
0.
f
YI
.-
D
394 ISLER, SCHUDEL, MAYER, WURSCH, AND RUEGG
/
0
U I I
ff
/f
-‘
+
 CHEMISTRY OF VITAMIN E 395

the two epimeric a-tocopherols (2R:4’R: 8%) and (2s:4’R: 8’R) at hand,
we therefore devised the following synthesis :
Trimethylhydroquinone was converted in four steps (Fig. 5) into the
aromatic ketone (V) which was transformed to the ethynylchroman (VI).
Catalytic hydrogenation to the vinylchroman (VII) and ozonolysis yielded
the formylchroman (VIII). Condensation with the Cl&riphenylphospho-
nium salt (IX) derived from hexahydrofarnesol under the conditions of the
Wittig reaction followed by hydrogenation and hydrolysis gave totally
racemic a-tocopherol. The phosphonium salt (IX) can be prepared as well
by degradation of natural phytol according to Crabbe et al. (1959). Resolu-
tion of one of the three chroman derivatives VI, VII, or VIII into their
optical antipodes is in progress. Condensation of either one of the optical
isomers of the aldehyde (VIII) with the phosphonium bromide (IX) derived
from natural phytol will give the two epimeric a-tocopherols mentioned.
The labeling indicated in Fig. 5 may thereby be introduced into the toco-
pherol molecule. [Specific activity of 1’,2’-H3-(2RS:4’RS:8’RS)-a-toco-
pherol acetate:356 pclmg].
B. PARTIAL SYNTHESES FROM METHYLTOCOLS

Several patents (Weisler, 1950, 1952, 1953; Weisler and Chechak, 1949;
Green and Marcinkiewicz, 1960) describe the conversion of mixed natural
methyltocols into a-tocopherol under a variety of’ experimental conditions.
In general the procedures follow known synthetic methods of aromatic
chemistry to introduce methyl substituents into the free positions of an
aromatic ring, as, e.g., chloromethylation, formylation, hydroxyalkylation
or the Mannich reaction, each followed by reduction.
I n order to prepare CI4-labeled d-a-tocopherol we started from natural
d-y-tocopherol (Fig. 6) and introduced the C14-methyl group into the 5-
position by use of the Mannich reaction. Condensation of d-y-tocopherol
with radioactive paraformaldehyde in the presence of diethylamine fol-
lowed by catalytic reduction gave d-a-tocopherol. This was acetylated to
methyl-C14-labeledd-a-tocopherol acetate (specific activity 1.7 pclmg; Fig.
6).
111. SYNTHESIS
OF THE WTOCOPHEROL METABOLITE
Experiments performed by Corwin and Schwarz (1960) gave evidence
that the a-tocopherol metabolite (X) (Fig. 7) exerts tocopherol-like activity
in the respiratory decline test. In order to mabe some material available for
further biological testing, the tritium-labeled y-lactone (X) was synthe-
sized following the lines given by Weichet et al. (1959) :
The ethynyl-y-lactone (XI), prepared from levulinic acid as indicated in
Fig. 7, was partially tritiated to give the labeled vinyl-y-lactone (XII).
396 ISLER, SCHTIDEL, MAYER, WURSCH, AND HUEGG
.i
k
0
2U
9
0
X I
$1
X
*2
C
-Pu
;$
0
F
N
n
->
8 Y
U
 CHEMISTRY OF VITAMIN E 397

Condensation with trimethylhydroquinone in the presence of BF,, ZnCL

and acetic anhydride yielded the chroman derivative (XIII).Subsequent
acid hydrolysis and oxidation under acid conditions gave the desired
racemic y-lactone (X) (specific activity of 164 pc/mg).
*

2)Pd/H2

3)AczO

FIG.F. d-a-Tocopherol acetate froin d-7-tocopherol.

poss~blelabeling: Experimentally labeled:

Tritium}

V I G . 7 . Synthesis of t h e a-tocopherol metabolite.

or’ METHYLTOCOLS
IV. SYNTHESES
The syntheses of the six possible dimcthyl- and monomethyltocols follow
in gcneral the lines described with a-tocopherol. Difficulties, however, arise
from the fact that two or threc aromatic positions in the dimethyl- or mono-
methylquinols, respectively, are free to react with phytol or isophytol.
The relative potencies of the different tocopherols (Harris et al., 1944;
Joffe and Harris, 1943) in various biological tests have recently been sum-
marized (Bunyan et al., 1961). Comparison of the data shows thsit the
dimethyl- or monomethyltocols havc a much lower vitamin E activity than
a-tocopherol.
398 ISLER, SCHUDEL, MAYER, WURSCH, AND RUEGG

A. SYNTHESES
OF DIMETHYLTOCOLS

A lower homolog of a-tocopherol, 5,7-dimcthyltocol, was synthesized by

Bergel et al. (1938b) through reaction of m-xyloquinol with phytol and
ZnC12. Rarrer and liritxsche (1938) showed that condensat,ion of o- or p-
xyloquinol with phytyl bromide gave complex mixtures and therefore con-
densed the xyloquinols with phytol in ariliydrous formic acid. Jacob et ul.
(1939) prepared p- and y-tocopherol by letting o- and p-xyloqninol mono-
benaoates react with phytol or phyt)yl bromide and ZnC12, followed by
alkaline ester hydrolysis. In our experiments (Fig. 8) totdly racemic y-toco-
pherol and 5 ,7-dimethyltoool were easily obtained by condensation of the
corresponding xylohydroquinones with isophytol in formic acid followed by
acid hydrolysis. p-Xyloquinol mononretate, however, w ~ i sthe starting
material of choicr to synthesizc totally racemic @-tocopherol.

FIG.8. Syntheses of dimethyltocols.

B. SYNTHESES OF MONOMETI-IYLTOCOLS

In the syntheses of monomethyltocols additional difficulties arise since

mixtures of different isomeric monomcthyltocols may be formed. Reaction
of toluquinol with phytol was first carried out by Karrer and Fritmche
(1939), who obtainrd a mixture of 5-, 7-, arid 8-methyltocols in the ratio of
1:2: 1 (Marcinkicwica et ul., 1959). Jacob et al. (1940) achieved the synthc-
sis of (2ttS:4%:8’R)-6-tocophcrol (8-mcthyltorol) frce from othcr mcthyl-
kxols by condensation of pure toluquirrol 4-monobcnzotttr: with phytol and
%nC&followed by alkdinc hydrolysis (Fig. 9). Another prcpartition of
&tocopherol WAS reported by Green ct al. (1959b). The Hame team synthc-
sized (2RS:4’R:8’lt)-5-methyltocol (McHale et al., 1959) and (2RS:4‘1t:
8’R)-7-metjhyltocol (McHnle et al., 1958) by uriambigiious routes similar to
the one devised by Smith and Miller (1942) for a-tocopherol (Fig. 9).
V. SYKTHETIC AND TRANSFORMATIONS
INTERMEDIATES OF TOCOPHEROL

AS SYNTHETIC
A. TRIMETHYLPHYTYLHYDROQUINONES INTERMEDIATES
The prcpuration of a-tocopherol consists in condensing trimethylhydro-
quinone with phytol or isophytol (Fig. 3 ) . Undcr specified experimental
 CHEMISTRY OF VITAMIN E 399
L
u
c
C
U
u,
L
0
I
+

01 +

w
I
0 $$
0=s
I
u
,
400 ISLER, SCHIJDEL, MAYEH, WURSCH, AND RUEGG

conditions it becomes possible to isolate the hydroyuinonc intermediate

(XIV; Fig. lo), which c&n be transformed either to a-tocopherol by acid
treatment or to trimethylphytylbcneoyuinone by silver oxide oxidation.
The interesting feature of the intermediate (XIV) or of the corresponding
benzoyuinonc is the configuration of the isolated double bond. A homoge-
neous condensation product with trans configuration (H:CH3 = trans) is
obtained when natural phytol, which contains a trans double bond (Burrell
ct al., 19?9), is used as starting material. Isophytol, however, gives a mix-
t,iire of cis and trans isomers containing predominantly the trans isomer, as
determined by nuclear magnetic resonance studies of the trimcthylphytyl-
hmzoquinone obtained.
B. INVEllSION OF CONFIGURATION A T c-2 O F d-a-'rOCOPHEROL

d-a-Tocopherol has a 3 6 % higher vitamin E activity than dl-a-toco-

pherol (National Formulary, 1960). As the configuration of carbon atom 2
seems to be responsible for the differenre in activity observed, a-tocopherol
with inverted configuration a t C-2 in rcspec t to natural d-a-tocopherol
should show a biological activity of 64 %, of the a-tocophrrol synthesized
from natural phytol. This could actually be confirmed in the hemolysis
test by extrapolation of thc values of vitamin E activity of the two following
a-tocopherol samples: ( I ) natural a-tocopherol with dextrorotatory cori-
figuration a t C-2 and (2) a mixture of a-tocopherol epimers, containing
25 '% with dcxtrorotatory and 75 % with levorotatory configuration a t (3-2.
The preparation of the sample (2) was achieved as follows: d-a-Toc.o-
pherol was oxidized with ferric chloride (Roheson and Nclari, 1961) to givc
a-tocophcrylquinone (Fig. I 1). Mechanistic considerations suggested that
the chroman ring opens to tocopherylquinone with retention of configura-
tion a t C-2 and that recyclixation of the corresponding hydroquinone could
then occur with partial inversion. In agreement with theory, a-tocopherol
with 75% inverted and 25% retained configuration a t C-2 was obtained.
The composition of the mixture of cpimeric a-tocopherols prepared was
determined by the rotatory powcr of the potassium ferricyanide oxidation
product (Nelan and Robeson, 1962), whcrcby it was ascertained that the
contribution of the asymmetric centers 4' and 8' of the sidc chain to the
rotatory power of the potassium ferricyanide oxidation product is negligible.
Rccrystallization of the p-phenylazobcnzoate to constant, optical rotation,
followed by saponification and chromatography, yielded a-tocopherol with
inverted, unnatural r*onfigurationat C-2.
c. a-TOC'OPHlCltOT~AND :<, 4 - I ) E l I Y ~ l t o - ~ - ' l ' O ~ ~ I ~ H FROM
~ l ~ O LTIUMETHYL-
I'HYTYLUEN ZOQUINONE

Totally racemic 3,4-dehydro-a-tocophcrol(Karrer et al., 1940) is a

vitamin E active compound. We prepared it from trimethyphytylhenzo-
 CHEMISTRY OF VITAMIN E 401
LK
+
402 ISLER, SCHUDEL, MAYER, WURSCH, AND RUEGG
M
a
El
m
 CHEMISTRY OF VITAMIN E 403

quinone by adsorption on aluminum oxide, in analogy to the procedure de-

scribed by Links (1960) (Fig. 12). The chromene structure was proved by
ultraviolet and nuclear magnetic resonance spectroscopy and by catalytic
hydrogenation to a-tocopherol.

TABLE I1

H:2w;
RELATEDCOMPOUNDS
Occurrence
C1-Tocopherol:Rl = R 2 = R 3 = C H 3

E -Tocopherol R1 = R J = C H ~ , R Z = H ] { Wheat

R3

0: -Tocopherol isoprenologues:

n = 0-9 1 n
{ Synthetic

R 2 = R3:OCHji R1=CH3 Livers

Ubichromenols.
n = 6-9 Kidneys

Solanachromene:
R * = R 3 = CH3iRl.H
{ Tobacco
n: 8

n=5 - 9 :Man,Yeast,Rats
-
n =O 4:Synthetic
n = B :Leaves
n i2.9 :Sy nthelic

{ ~=0,12,3,8:5ynthetic

ITocopherylquinones: n = 0,3,5 }
OH n
{ Synthetic

A reaction of special interest found in our laboratories is the reductive

cyclization of trimethylphytylbenzoquinone into a-tocopherol by means of
a series of acidic reagents, e.g., boron trifluoride in petroleum ether (Fig. 12).
This transformation which probably involves a hydride transfer reaction,
ran also he achieved with a-tocophcrylquinone (Issidorides, 1951) and
404 ISLER, SCHUDEL, MAYER, WURSCH, AND RUEGG

therefore might suggest a possible mode of action of a-tocopherol or related

compounds in the living cell.
VI. RELATEDCOMPOUNDS
The well-known series of natural tocopherols consists of methylnted
t ocols derived from phytol. Rccently Green et al. (1959a, 1960) showed the
existence of n second, closely related series of natural tocopherols containing
an unsaturated (trimcthyltrideca-3,7,ll-trienyl) side chain, as represented
by t- and {,-tocopherol (Table 11). Further chromanols, chromenols, and
benzoquinones which may play a role together with or similar to that of
vitamin E in the living cell are also listed in Table 11.
VII. CONCLUDING REMARKS
This paper showed the prefcrred routes to specific labelings of vitamin E
and has indicated t,he chemical research that, is necessary for getting a final
st>ereochemicalinsight into tlhe tocopherol molecules. Similar investigat,ions
on rclatcd nat,ural chromnnols and ohromenols might help to eliicidate
their mutual biogenetic relationship. Furthermore, the reported chemical
interconversions of trimethylphytylbenzoquinone into either a-tocopherol
or 3,4-dehydro-a-tocopherol(Fig. 12) may indicate some biological inter-
relations which might also be common to the related natmal quinones,
chromanols, and chromenols listcd in Table 11.
REFERENCES
Bacharach, A. L . , arid Green, J . 1961. Ghem. & I n d . (London), p. 2135.
Bergel, F., Jucob, A . , Todd, A . R., arid Work, T. S. 1938a. Nature, 142,36.
Bergel, F., Copping, A . M . , Jacob, A . , Todd, A. R . , and Work, T. S. 193%. J. Chenc.
S O C . ,pp. 1382-1384.
Bunyan, J . , McHale, D . , Green, J., and Marcinkiewicz, 8. 1961. Brit. J . Nutrition
16, 253-257.
13urrel1, J. W. K . , Jackman, 1,. M., and Weedon, B . C. L. 1959. Pro/*.Chem. Soc.,
pp. 2K-264.
Chhn R . S., Ingoltl, C . K.,arid l’rcloy, V . 1956. Esperientia 12, 81-84.
Corwirr, 1 2 . M . , and Schwara, K . 1960. N u t w e 186, 1048-1049.
(:rnhhe, P., Iljerassi, C . , Eisenbraun, E.J . , and Liu, H. 1959. t’roc. G h ~ n rSocs.,
. pp.
264-265.
Picser, I,. F . , Tishler, M . , and Wendler, N . 1,. 1940. J . A m . Cheni. SOP.62.2861-2866.
(.ireen, J . , and Marcinkiewicx, R. %. 1960. British Paldent,827, 391.
Grccn, J., McHale, TI.,Marcinkiewicz, S.,Mamalis, P., and W:Ltt, 1’. It. 1059s. J .
Chem. SOC., pp. 3362-3373.
Green, J., McHale, D . , Marnalis, P., and Marcinkiewica, S.1959b. J . Chevr. S O P . ,
pp. 3374-3376.
Green, J., Mnmnlis, P., Marcinkiewica, S., and McHale, D. 1960. Chem. & Ind.
(London), pp. 73-74.
Harris, 1’. I,., Jenaen, J . I,., Joffe, M., and Mason, K . E . 1944. J . B i d . Chern. 166,
491-498.
Isler, 0.1942. M itt. nalurforsch. Ges. Schaffhausen, pp. 321-338.
IHsidorides, A., 1951. J . Am. C‘hcrn. SOC.73, 5146-5148.
 CHEMISTRY OF VITAMIN E 405

Jacob, A,, Steiger, M., Todd, A . It., and Work, T . S. 1939. J . Chem. S O C . pp., 542-
545.
Jacob, A., Sutcliffe, F. K., and Todd, A. R. 1940. J . Chem. SOC., pp. 327-332.
Joffe, M., and Harris, P. L. 1943. J. A m . Chem. SOC.65,925-927.
John, W. 1939. Angeu,. Chem. 62,413-419.
John, W., and Pini, H. 1942.2. physiol. Chem. 273,225-234.
Karrer, P., 1939. Helv. Chirn. Acta22,334-350.
K:trrer, P., and Bergel, F. 1939. I n “Vitamin E. A Symposium Held under t h e Aus-
pices of the Food Group (Nutrition Panel) of t h e Society of Chemical
Industry,” pp. 9-13. W. Heffer & Soils, Cambridge, England.
Karrer, P., and Fritzsche, H.1938. Helv. Chini. Acta 21, 1234-1240.
Karrer, P., and Fritzsche, H. 1939. Helv. C h i m . Acta 22, 260-263.
Karrer, P., and Tsler, 0. 1938. U. 9.Patent, 2,411,967.
Karrer, P . , and Isler, 0. 1941. U. 8. Patent 2,411,969.
Karrer, P., and Ringier, B. H. 1939. Helv. Chim. Acta 22, 610-616.
Karrer, P., Fritzsche, H., Ringier, B. H., and Salomon, H. 1938a. HeZv. Chim. Acta
21, 520-525.
Knrrer, P., Fritzsche, H . , Ringier, B. H., and Salomon, H. 1938b. Helv. Chim. Acta
21, 820-828.
Karrer, P., Koenig, H., Ringier, H. H., and Salomon, H. 1939. Helv. Chim. A d a 22,
1139-1145.
Karrer, P., Legler, R . G . , and Schwab, G . 1940. Helv. Chim. Acta 23, 1132-1137.
Karrer, P., Kugler, A , , and Simon, €I. 1944. Helv. (’him. Acla 27, 1006-1009.
Links, J. 19130. Biocham. et Biophys. Acta 38, 193-194.
McHale, D., Mamalis, P., Green, J., and Marcinkiewicz, S.1958. J . Chem. Soc., pp.
1800-1603.
McHale, l)., Mamalis, P., Marcinkiewicz, S., and Green, J. 1959. J . Chcm. S o c . , pp.
3358-3362.
Marcinkiewicz, S.,McHale, D., Mamalis, P., and Green, J. 1959. J . Chem. Sac.., pp.
3377-3378.
National Formulary, 11th ed. 1960. Mack Printing Co., Easton, Pennsylvania.
Nelan, D. It., and Robeson, C. D. 1962. Nature 193,477.
Robeson, C. D., and Nelan, D. R. 1961. Swiss Patent 356,754.
Simon, E. J., Gross, C. S., and Milhorat, A. T. 1956a. J. B i d . Chem. 221,797-805.
Simon, E. J., Eisengart, A . , Sundheim, L., andMilhorat, A. T. 1956b. J. BioZ. Chem.
221, 807-817.
Smith, L. I. 1940. Chem. Revs. 27,287-329.
Smith, L. I., andMiller, H. C. 1942. J . A m . Chem. SOC.64,440-445.
Smith, L. I., and Ungnade, H. E. 1939. J . Org. Chem. 4,298-304.
Smith, L. I., Ungnade, H. E., and Prichard, W. W. 1938. Science 88,37-38.
Smith, L. I., Ungnade, H. E., Stevens, J . R . , and Christman, C. C. 1939. J . A m .
Chem. S O C .61, 2615-2618.
Todd, A. R. 1939. I n “Vitamin E . A. Symposium Held under t h e Auspices of t h e
Food Group (Nutrition Panel) of t h e Society of Chemical Industry,” pp. 3-8.
W. Heffer & Sons, Cambridge, England.
Weichet, J., Bl&ha, L., and Kak46, B. 1959. Collection Czechoslov. Chem. Communs.
24, 1689-1694.
Weisler, L. 1950. U. S. P a t e n t 2,519,863.
Weisler, L. 1952. U. S. P a t e n t 2,592, 628.
Weisler, L. 1953. U. 8 . P a t e n t 2,640,058.
Weisler, L., and Chechak, J. 1949. U. S. Patent 2,486,542.