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Palladium-Catalyzed Enantioselective Domino Reaction for the Efficient Synthesis of Vitamin E.

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Angewandte
Chemie
Domino Reactions
Palladium-Catalyzed Enantioselective Domino
Reaction for the Efficient Synthesis of
Vitamin E**
Lutz F. Tietze,* Konrad M. Sommer, Julia Zinngrebe,
and Florian Stecker
Dedicated to Professor Hiriyakkanavar Ila
on the occasion of her 60th birthday
Vitamin E is one of the fat-soluble vitamins and a collective
term for all tocopherols and tocotrienols. The vitamin E
family consists of eight natural compounds which, depending
upon the degree of methylation of their aromatic ring, are
specified as a, b, g and d. All possess a chroman framework
with a stereogenic center at C2 with R configuration
(examples: a-tocopherol: 1, a-tocotrienol: 2).[1] Natural
a-tocopherol (1) with the R configuration at all stereogenic centers has the most pronounced biological activity.
Vitamin E acts as an antioxidant and is considered an
essential protective factor against lipid peroxidation; in
particular, it protects polyunsaturated fatty acids essential
for animal and human metabolism by capturing highly
reactive free radicals formed in the body as by-products of
normal oxidative metabolism and which cause irreversible
destruction of cell membranes.[2]
Industrially a-tocopherol (1) is produced on a large scale
by the acid-catalyzed reaction of trimethylhydroquinone (3)
with all-rac-isophytol (4; see Scheme 1), whereby a mixture of
eight stereoisomers is formed. However, in this reaction
compounds with an S configuration in the chroman framework and thus of far lower antioxidant action are also
formed.[3] Thus, from the point of view of industry there is
considerable interest in the development of a process for the
efficient enantioselective construction of a-tocopherol (1);
this applies especially to the stereoselective formation of the
stereogenic center on the chroman ring, if possible with the
concomitant introduction of the side chain.
There are already a number of enantioselective synthetic
methods for 1, which are not suitable, however, for industrial
use.[4] Here we describe a new enantioselective palladiumcatalyzed method[5] which allows not only the formation of
the chiral chroman framework[6] with an enantioselectivity of
96 % ee but also the simultaneous introduction of part of the
side chain of vitamin E within the context of a domino
reaction.[7] . This sequence comprises an enantioselective
Wacker oxidation[8] and a subsequent Heck reaction
(Scheme 1).[9]
The substrate for the domino reaction, alkene 5, was
obtained in an overall yield of 60 % from trimethylhydroquinone (3) in a few steps by acid-catalyzed condensation with
methyl vinyl ketone and reaction with the Lombardo
reagent.[10] The reaction of 5 with methyl acrylate in dichloro-
[*] Prof. Dr. L. F. Tietze, Dr. K. M. Sommer, Dipl.-Chem. J. Zinngrebe,
Dipl.-Chem. F. Stecker
Institut fr Organische und Biomolekulare Chemie
Georg-August-Universitt Gttingen
Tammannstrasse 2, 37077 Gttingen (Germany)
Fax: (+ 49) 551-39-9476
E-mail: ltietze@gwdg.de
[**] This research was supported by the Deutsche Forschungsgemeinschaft (SFB 416) and the Fonds der Chemischen Industrie. We
thank Roche Vitamins (now DSM Vitamins) for reference samples
and Symrise for (R)-citronellol.
Angew. Chem. Int. Ed. 2005, 44, 257 –259
Scheme 1. Top: Industrial production of racemic a-tocopherol (1) by the reaction
of trimethylhydroquinone (3) with all-rac-isophytol (4). Bottom: Domino reaction
for the preparation of 7 with BOXAX ligands 6 a–c. Bn = Benzyl.
DOI: 10.1002/anie.200461629
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
257
Communications
methane in the presence of catalytic amounts of Pd(TFA)2
(TFA = trifluoroacetate), the chiral ligand (S,S)-iPr-BOXAX
6 a,[11] and p-benzoquinone afforded the desired chroman 7 a
with 96 % ee in 84 % yield;[12] comparably good selectivities
were obtained with (S,S)-Bn-BOXAX (6 b). The selectivity
was significantly lower with the use of 6 c as ligand which was
obtained from (L)-tleucine; similar effects have already been
observed in other catalytic processes.[13] The domino reaction
was also carried out with methyl vinyl ketone to provide 7 b;
however, in this case the yield and the selectivity (84 % ee)
were lower. The reaction with simple alkenes such as 3methyl-1-pentene failed to yield the desired product.
We assume that in the first step of the domino reaction 5
coordinates enantiofacially through its double bond to the
chiral catalyst generated from Pd(TFA)2 and the enantiomerically pure 6. The resulting intermediate 8 reacts further by
oxypalladation to give 9 with formation of the chroman
framework and construction of the stereogenic center
(Scheme 2). The palladium species can then form the
intermediate 10 in a subsequent Heck reaction with acrylate
or methyl vinyl ketone, which leads to the final product 7 and
Pd0 in a b-hydride elimination. It is necessary for the catalytic
Scheme 2. Mechanism of the palladium-catalyzed domino reaction of 5.
cycle that Pd0 is reoxidized to Pd2+; this is achieved by the
addition of p-benzoquinone, which does not interfere with the
course of the reaction.
Numerous possibilities are plausible for the further
conversion of 7 a or 7 b to a-tocopherol (1). Thus the
unsaturated ester 7 a was converted into the respective diol
by dihydroxylation[14] with AD-mix-b. Subsequent oxidative
cleavage with sodium periodate afforded aldehyde 11 a, which
can be converted into a-tocopherol (1) in a few steps by
known methods.[15] Direct cleavage of 7 a by ozonolysis to give
258
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
11 a was not successful. We reduced aldehyde 11 a to alcohol
11 b so that the absolute configuration of the stereogenic
center in 7 a could be determined by comparison of the data
with known values.[16] Alternatively we prepared vitamin E
from ketone 7 b by reaction with the vinyl iodide 13 readily
obtained from (R)-citronellal (12) followed by subsequent
dehydration and hydrogenation.
The enantioselective domino reaction described here
facilitates the efficient and stereoselective construction of
the chroman framework of vitamin E with concomitant
introduction of part of the side chain in high yield with very
good ee values.
Received: August 12, 2004
Published Online: November 26, 2004
.
Keywords: asymmetric catalysis · domino reactions ·
Heck reactions · palladium · vitamins · Wacker oxidation
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Angewandte
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A mixture of palladium trifluoroacetate (7.1 mg, 0.0214 mmol,
0.1 equiv) and (S,S)-iPr-BOXAX 6 a (40.7 mg, 0.0856 mmol,
0.4 equiv) in CH2Cl2 (0.1 mL, degassed) was stirred for 30 min at
room temperature, then treated with p-benzoquinone (93.1 mg,
0.855 mmol, 4.0 equiv), and stirred for a further 10 min. A
solution of 5 (50 mg, 0.214 mmol, 1.0 equiv) and methyl acrylate
(91.9 mg, 1.07 mmol, 5.0 equiv) in CH2Cl2 (0.20 mL, degassed)
was added to the suspension, and the mixture was stirred at room
temperature for 3.5 d (TLC control). At the end of the reaction
the mixture was treated with 1n HCl (5 mL) and the aqueous
phase extracted with Et2O (3 5 mL). The combined organic
phases were washed with 1n NaOH solution (3 5 mL) and
dried over MgSO4, and the solvent was removed under reduced
pressure. The crude product was purified by column chromatography (n-pentane/diethyl ether). Chroman 7 a (57 mg,
0.181 mmol, 84 %) was obtained as a clear oil. The enantiomeric
excess was determined by HPLC on a chiral phase (ODChiracel, hexane/isopropanol) and gave a value of 96 % ee. The
absolute configuration was determined by conversion into the
alcohol 11 b and comparison of the optical rotation with known
literature values.[16] 1H NMR (300 MHz, CDCl3): d = 1.23 (s, 3 H,
2’-CH3), 1.77 (dd, 1 H, J = 7.1, 14.2 Hz, 3’-Ha), 1.85 (dd, 1 H, J =
7.1, 14.1 Hz, 3’-Hb), 2.09, 2.14, 2.19 (3 s, 9 H, 5’-CH3, 7’-CH3, 8’CH3), 2.45 (ddd, 1 H, J = 1.2, 8.2, 14.1 Hz, 4-Ha), 2.53 (ddd, 1 H,
J = 1.2, 8.2, 14.1 Hz, 4-Hb), 2.60 (t, 2 H, J = 7.1 Hz, 4’-H2), 3.63 (s,
3 H, 6’-OCH3), 3.74 (s, 3 H, 1-OCH3), 5.88 (dt, 1 H, J = 1.2,
15.9 Hz, 2-H), 7.05 ppm (dt, 1 H, J = 7.8, 15.9 Hz, 3-H); 13CNMR (50.3 MHz, CDCl3): d = 11.66, 11.76, 12.52 (5’-CH3, 7’CH3, 8’-CH3), 20.43 (C4’), 24.38 (2’-CH3), 31.20 (C4), 42.31 (C3’),
51.44 (1’-OCH3), 60.36 (6’-OCH3), 74.22 (C2’), 117.1 (C4a’),
123.1 (C8’), 123.8 (C2), 125.8 (C7’), 128.1 (C5’), 144.7 (C3), 147.1
(C8a’), 149.7 (C6’), 166.7 ppm (C1); [a]20
D = + 15.4 (c = 0.52,
CHCl3); IR (KBr): ñ = 2977 cm 1 (CH), 2936, 1725 (C=O); UV
(CH3CN): lmax (lge): 202.5 nm (5.609), 287.0 (1.558); MS (70 eV,
EI): m/z (%) = 179 (30), 219 (60), 318 (100) [M]+. C19H26O4
(318.41): calcd: 318.1831; found: 318.1831 (HRMS).
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(S)-( )-6-benzyloxy-2,5,7,8-tetramethylchroman-2-ethanol: S.
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Lett. 1990, 31, 3619 – 3622: [a]20
D =
Angew. Chem. Int. Ed. 2005, 44, 257 –259
www.angewandte.org
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
259
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efficiency, synthesis, vitamins, domino, reaction, palladium, enantioselectivity, catalyzed
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