Total synthesis of (2RS)-α-tocopherol through Ni-catalyzed 1,4-addition to a chromenone intermediate

Article abstract of DOI:10.1002/ejoc.201402240

A novel strategy for the total synthesis of α-tocopherol ("vitamin E") was elaborated on the basis of the conjugate addition of AlMe₃ (as a methyl anion equivalent) to a 2-substituted chromenone. Starting from trimethylhydroquinone and (R,R)-he

Full text of DOI:10.1002/ejoc.201402240

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402240
Total Synthesis of (2RS)-α-Tocopherol through Ni-Catalyzed 1,4-Addition to a
Chromenone Intermediate
Andreas Ole Termath,[a] Janna Velder,[a] René T. Stemmler,[b] Thomas Netscher,[b]
Werner Bonrath,[b] and Hans-Günther Schmalz*[a]
Keywords: Natural products / Oxygen heterocycles / Conjugate addition / Nickel / Radicals
A novel strategy for the total synthesis of α-tocopherol (“vita-
min E”) was elaborated on the basis of the conjugate ad-
dition of AlMe3 (as a methyl anion equivalent) to a 2-substi-
tuted chromenone. Starting from trimethylhydroquinone and
(R,R)-hexahydrofarnesol, the required chromenone substrate
was efficiently prepared in a short sequence exploiting a
TiCl4-mediated Fries rearrangement and a KOtBu-induced
Baker–Venkatamaran rearrangement. The envisioned key
step, which sets up the quaternary center at C2, was per-
formed in virtually quantitative yield through Ni-catalyzed
conjugate addition of AlMe3. However, this transformation,
which likely proceeds through a radical mechanism, could
not be rendered stereoselective by means of chiral ligands.
Nevertheless, the elaborated synthesis of (2RS,4ЈR,8ЈR)-α-
tocopherol (2-ambo-α-tocopherol) is efficient and challenges
the future development of suitable protocols for the asym-
metric 1,4-addition.
ence of a chiral ligand.[8] We herein disclose the results of a
study, which so far has culminated in the elaboration of an
efficient synthesis of 2-ambo-α-tocopherol [(2RS)-1].
Introduction
Vitamin E is an essential food ingredient of high eco-
nomical value owing to its biological activity and antioxi-
dant properties.[1] The commercially most important form
is (all-rac)-α-tocopherol (all-rac-1), which is produced on a
scale of Ͼ35000 tyear–1 and mainly applied in animal nu-
trition.[2] Although the eight individual stereoisomers of
this equimolar mixture exhibit qualitatively the same bio-
logical activity, the (R,R,R)-1 is the only naturally occurring
compound that also shows the highest bioactivity.[3] As the
growing demand of this single-isomer product cannot be
satisfied through natural sources, the development of scal-
able and stereoselective syntheses of 1 represents an impor-
tant research goal.[4] Whereas the stereocenters of the side
chain can be established with an impressive level of
stereocontrol through asymmetric hydrogenation,[5] the (R)-
selective generation of the quaternary stereocenter at C2
still remains a tough challenge.[6]
Results and Discussion
In our retrosynthetic analysis (Scheme 1), ketone 2 serves
as a pretarget molecule, which results from conjugate ad-
dition of a methyl-metal reagent to chromenone 3. This in-
termediate in turn could be assembled from ortho-hydroxy
acetophenone derivative 4 and acid 5. Aromatic building
block 4 is derived from commercially available trimethyl-
hydroquinone (6, TMHQ) through regioselective O-methyl-
ation and C-acetylation (possibly through Fries rearrange-
ment).[9] Side-chain building block 5 could be prepared un-
der C2 chain elongation from hexahydrofarnesol (7). For
the protection of the phenol function, we selected a methyl
ether because of its stability and because of the availability
of an efficient deprotection protocol for O-methyltoco-
pherol.[10]
The preparation of acetophenone building block 4
(Scheme 2) required the differentiation of the two OH
groups of 6, which was achieved by pivaloylation.[11] The
remaining phenol function of 8 was then methylated (NaH,
Me2SO4) before alkaline ester hydrolysis and subsequent
acetylation of the phenol intermediate (AcCl, pyridine) af-
forded acetate 9 (85% overall from 6 on a 100 scale). An
In continuation of our recent work in the field of enan-
tioselective 1,4-addition,[7] we devised a new approach
towards vitamin E in which the methyl group at C2 is
introduced through metal-catalyzed 1,4-addition to a
chromenone precursor. We reasoned that this key step
could possibly be conducted stereoselectively in the pres-
[a] Department of Chemistry, University of Cologne,
Greinstrasse 4, 50939 Köln, Germany
E-mail: schmalz@uni-koeln.de
www.schmalz.uni-koeln.de
initial attempt to perform the Fries rearrangement of 9 by
[12]
[b] DSM Nutritional Products, Research and Development,
P. O. Box 2676, 4002 Basel, Switzerland
using BF3·OEt2
failed, because of concomitant cleavage
of the methyl ether. However, after screening various Lewis
acids and conditions we succeeded in effectively achieving
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402240.
Eur. J. Org. Chem. 2014, 3337–3340
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3337

H.-G. Schmalz et al.
SHORT COMMUNICATION
Scheme 3. Synthesis of side-chain building block 5; DMP = Dess–
Martin periodinane.
ment),[16] which was then dehydrated under acidic condi-
tions (AcCl, MeOH) to give chromenone 3 in high overall
yield.
Scheme 1. Retrosynthetic analysis of α-tocopherol (1) by using 1,4-
addition to generate the quaternary C2 center.
the desired transformation by using TiCl4 in refluxing
CH2Cl2 over 3 d. The sequence shown in Scheme 2 offers
reliable access to acetophenone 4 on a multigram scale.
Scheme 4. Assembly of key intermediate 3 from building blocks 4
and 5; DCC = N,NЈЈ-dicyclohexylcarbodiimide, DMAP = 4-(di-
methylamino)pyridine.
Scheme 2. Preparation of aromatic building block 4.
With chromenone 3 in hand, we next turned our atten-
tion to the key 1,4-addition. Initial attempts to react 3 with
The synthesis of side-chain building block 5 (Scheme 3) MeMgBr or Me3Al in the presence of different CuI catalysts
started with Dess–Martin oxidation[13] of (R,R)-hexahy- failed completely.[17] However, the reaction of 3 with Me3Al
drofarnesol (7)[14] followed by immediate olefination of al- in the presence of NiII salts[18] afforded the desired product
dehyde 10 by using the Wittig reagent obtained from benzyl (Scheme 5). Under the optimized conditions (using 5 equiv.
bromoacetate. Hydrogenation of resulting enoate 11 (H2, of Me3Al in the presence of 15 mol-% of NiCl2·glyme), 4-
Pd/C, EtOH) then proceeded smoothly under additional oxo-α-tocopheryl methyl ether (2) was obtained in virtually
hydrogenolytic ester cleavage to afford 5 in high overall quantitative yield as a 1:1 mixture of diastereomers.
yield (96% over three steps).
Hydrogenolytic removal of the benzylic keto functionality
The assembly of key intermediate 3 (Scheme 4) was initi- (H2, Pd/C) then afforded α-tocopheryl methyl ether (14).
ated by connecting building blocks 4 and 5 by ester forma- The final deprotection of the aryl methyl ether is known to
tion under Steglich conditions.[15] Treatment of a THF solu- proceed with BF3·SMe2/AlCl3 according to Woggon et al.,
tion of resulting ester 12 with KOtBu as a base smoothly which furnished 2-ambo-α-tocopherol (2-ambo-1) in high
afforded hemiacetal 13 (Baker–Venkatamaran rearrange- yield.[6d,10]
3338
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3337–3340

Total Synthesis of (2RS)-α-Tocopherol
Scheme 6. Attempted Ni-catalyzed 1,4-addition of Me3Al to cy-
clopropyl-substituted chromanone 15.
to the proposed (highly stabilized) radical intermediate B,
to which the methyl group is then delivered in a fast radical-
transfer reaction. This C–C bond-forming step is not ex-
pected to proceed stereoselectively under the influence of
(rather remote) chiral ligands at the nickel center. Resulting
enolate intermediate C, which should be configurationally
stable (see above), is then converted into the chromanone
product during aqueous workup.
Scheme 5. Completion of the synthesis of 2-ambo-1.
Having completed the total synthesis of 2-ambo-α-toc-
opherol (2-ambo-1), we next investigated the possibility to
perform the key 1,4-addition stereoselectively in the pres-
ence of a chiral Ni complex. However, despite extensive ex-
perimentation this goal could not be achieved. Besides chi-
ral ferrocenyl ligands (Taniaphos, Mandyphos, and Jos-
iphos),[19] we tested different phosphoramidites,[20] modular
phosphine–phosphites,[21] box ligands,[22] as well as chiral
amines and amino alcohols. However, we never observed
any significant degree of asymmetric induction (Ͻ2%de ac-
cording to HPLC analysis). Epimerization of the product
at C2 under the reaction conditions could be excluded by
means of a reference sample obtained through HPLC sepa-
ration of the diastereomers of (2RS)-2. However, the pres-
ence of the Ni catalyst was required for the 1,4-addition to
proceed. The complete lack of asymmetric induction sug-
gested that the stereodefining C–C bond-forming step did
not take place in the expected fashion (i.e., by reductive
elimination from the chirally ligated Ni center). To probe
whether the reaction possibly proceeded through a radical
mechanism, we synthesized cyclopropyl-substituted sub-
strate 15[23] and subjected it to the established conditions
(Scheme 6). Noteworthy, we did not observe the formation
of 1,4-addition product 16 in this case. Instead, a complex
Scheme 7. Proposed mechanistic pathway (only the core structure
of substrate 3 is shown for clarity). SET = single-electron transfer.
Conclusions
In conclusion, we devised a new strategy for the synthesis
of tocopherols and elaborated an efficient total synthesis of
2-ambo-α-tocopherol (2-ambo-1) proceeding with an overall
yield of Ͼ60% over nine steps starting from (R,R)-hexa-
hydrofarnesol (7). As a key step, we exploited a high-yield-
ing Ni-catalyzed 1,4-addition of AlMe3 to a chromenone
substrate as a novel option to build up the quaternary cen-
ter at C2. Noteworthy, this reaction could not be rendered
stereoselective by means of chiral ligands, probably because
of the radical nature of the C–C bond-forming step. This
failure might be an important lesson also to other research-
ers working in the field of low-valent Ni catalysis and chal-
lenges future methodology development. In any case, the
facile formation of radical intermediates by single-electron
reduction of 2-substituted chromenones must be taken into
account in any future attempts to exploit an asymmetric
1,4-addition strategy in the synthesis of vitamin E or related
natural products.
1
mixture was formed that showed olefinic signals in the H
NMR spectrum.
The above-mentioned experiment suggested that the Ni-
catalyzed 1,4-addition of AlMe3 to the chromenone sub-
strates indeed proceeded via a (delocalized) radical interme-
diate. A possible mechanism is shown in Scheme 7. As an
excess amount of AlMe3 is required, we assume that the
reaction starts with the formation of 4-oxybenzopyrylium
species A,[24] which accepts an electron from a low-valent
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details and copies of the 1H NMR and 13C
methyl nickel complex (single-electron transfer). This leads NMR spectra of all relevant compounds.
Eur. J. Org. Chem. 2014, 3337–3340
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3339

H.-G. Schmalz et al.
SHORT COMMUNICATION
[9] a) K. Fries, G. Finck, Ber. Dtsch. Chem. Ges. 1908, 41, 4271–
4284; b) K. Fries, W. Pfaffendorf, Ber. Dtsch. Chem. Ges. 1910,
43, 212–219.
Acknowledgments
[10] J. Chapelat, U. Hengartner, A. Chougnet, K. Liu, P. Huebbe,
G. Rimbach, W.-D. Woggon, ChemBioChem 2011, 12, 118–24.
[11] a) T. Yoshioka, T. Fujita, T. Kanai, Y. Aizawa, T. Kurumada,
K. Hasegawa, H. Horikoshi, J. Med. Chem. 1989, 32, 421–428;
b) S. Menichetti, R. Amorati, M. G. Bartolozzi, G. F. Pedulli,
A. Salvini, C. Viglianisi, Eur. J. Org. Chem. 2010, 2218–2225.
[12] N. Cohen, R. J. Lopresti, T. H. Williams, J. Org. Chem. 1978,
43, 3723–3726.
The authors thank Andreas Adler, University of Cologne, for
HPLC measurements.
[1]
For reviews, see: a) M. L. Colombo, Molecules 2010, 15, 2103–
13; b) T. Netscher, in: Vitamins & Hormones (Ed.: G. Litwack)
Academic Press, 2007, vol. 76, pp 155–202, and references cited
therein.
[13] D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277–
[2]
[3]
7287.
W. Bonrath, M. Eggersdorfer, T. Netscher, Catal. Today 2007,
121, 45–57.
[14] For the synthesis of (R,R)-7 [93.45% (3R,7R); 5.81% (3R,7S);
0.75% (3S,7R); Ͻ0.1% (3S,7S)] see ref.[5a,5c]
a) W. P. Weiss, J. S. Hogan, D. J. Wyatt, Dairy Sci. Abstr. 2009,
92, 720–731; b) S. K. Jensen, C. Lauridsen, Vitamins & Hor-
mones (Ed.: G. Litwack), Elsevier, Amsterdam, 2007, vol. 76,
p. 81–308; c) J. K. Lodge, J. Plant Physiol. 2005, 162, 790–796;
d) P. P. Hoppe, G. Krennrich, Eur. J. Nutr. 2000, 39, 183–193;
e) K. E. Ferslew, R. V. Acuff, E. A. Daigneault, T. W. Woolley,
P. E. Stanton, J. Clin. Pharmacol. 1993, 33, 84–88; f) B. J. Wei-
mann, H. Weiser, Am. J. Clin. Nutr. 1991, 53, 1056S–1060S; g)
H. Weiser, M. Vecchi, Int. J. Vitam. Nutr. Res. 1982, 52, 351–
370; h) H. Weiser, M. Vecchi, Int. J. Vitam. Nutr. Res. Suppl.
1981, 51, 100–113.
[15] B. Neises, W. Steglich, Angew. Chem. Int. Ed. Engl. 1978, 17,
522–524; Angew. Chem. 1978, 90, 556–557.
[16] a) H. S. Mahal, K. Venkataraman, J. Chem. Soc. 1934, 1767–
1769; b) W. Baker, J. Chem. Soc. 1933, 1381–1389.
[17] a) P. D. Clarke, A. O. Fitton, H. Suschitzky, T. W. Wallace,
H. A. Dowlatshahi, J. L. Suschitzky, Tetrahedron Lett. 1986,
27, 91–94; b) S. T. Saengchantara, T. W. Wallace, Tetrahedron
1990, 46, 3029–3036.
[18] a) E. C. Ashby, G. Heinsohn, J. Org. Chem. 1974, 39, 3297–
3299; b) E. A. Jeffery, A. Meisters, T. Mole, J. Organomet.
Chem. 1974, 74, 365–371; c) L. Bagnell, E. Jeffery, A. Meisters,
T. Mole, Aust. J. Chem. 1975, 28, 801–815; d) C. M. Schmeck,
H. W. Bischoff, V. V. Li, K. W. Lustig, M. E. Thutewohl, A. H.
Vakalopoulos, O. W. Weber, U.S. Patent 0306197 A1, 2009.
[19] a) A. Togni, Angew. Chem. Int. Ed. Engl. 1996, 35, 1475;
Angew. Chem. 1996, 108, 1581–1583; b) T. Ireland, G.
Grossheimann, C. Wieser-Jeunesse, P. Knochel, Angew. Chem.
Int. Ed. 1999, 38, 3212; Angew. Chem. 1999, 111, 3397–3400;
c) B. L. Feringa, R. Badorrey, D. Pena, S. R. Harutyunyan,
A. J. Minnaard, Proc. Natl. Acad. Sci. USA 2004, 101, 5834–
5838; d) F. López, S. R. Harutyunyan, A. J. Minnaard, B. L.
Feringa, J. Am. Chem. Soc. 2004, 126, 12784–12785.
[20] a) A. Alexakis, D. Polet, C. Benhaim, S. Rosset, Tetrahedron:
Asymmetry 2004, 15, 2199–2203; b) M. d’Augustin, L. Palais,
A. Alexakis, Angew. Chem. Int. Ed. 2005, 44, 1376–1378; An-
gew. Chem. 2005, 117, 1400–1402; c) M. Vuagnoux-d’Augustin,
A. Alexakis, Chem. Eur. J. 2007, 13, 9647–9662.
[4]
W. Bonrath, T. Netscher, Appl. Catal. A 2005, 280, 55–73.
[5] a) A. Wang, B. Wüstenberg, A. Pfaltz, Angew. Chem. Int. Ed.
2008, 47, 2298–2300; Angew. Chem. 2008, 120, 2330–2332; b)
S. Bell, B. Wüstenberg, S. Kaiser, F. Menges, T. Netscher, A.
Pfaltz, Science 2006, 311, 642–644; c) T. Netscher, M. Scalone,
R. Schmid, Asymmetric Catalysis on Industrial Scale (Eds.: H.-
U. Blaser, E. Schmidt), Wiley-VCH, Weinheim, Germany,
2004, p. 71–89.
[6] a) U. Hengartner, A. Chougnet, K. Liu, W.-D. Woggon, Chem.
Eur. J. 2010, 16, 1306–1311; b) G. Hernandez-Torres, A. Ur-
bano, M. C. Carreno, F. O. Colobert, Org. Lett. 2009, 11,
4930–4933; c) J. Chapelat, A. Chougnet, W.-D. Woggon, Eur.
J. Org. Chem. 2009, 2069–2076; d) K. Liu, A. Chougnet, W.-
D. Woggon, Angew. Chem. Int. Ed. 2008, 47, 5827–5829; An-
gew. Chem. 2008, 120, 5911–5913; e) J. Chapelat, A. Buss, A.
Chougnet, W.-D. Woggon, Org. Lett. 2008, 10, 5123–5126; f)
C. Rein, P. Demel, R. A. Outten, T. Netscher, B. Breit, Angew.
Chem. Int. Ed. 2007, 46, 8670–8673; Angew. Chem. 2007, 119,
8824–8827; g) L. F. Tietze, F. Stecker, J. Zinngrebe, K. M. Som-
mer, Chem. Eur. J. 2006, 12, 8770–8776.
[7] a) T. Robert, J. Velder, H.-G. Schmalz, Angew. Chem. Int. Ed.
2008, 47, 7718–7721; Angew. Chem. 2008, 120, 7832–7835; b)
Q. Naeemi, T. Robert, D. P. Kranz, J. Velder, H.-G. Schmalz,
Tetrahedron: Asymmetry 2011, 22, 887–892.
[8] a) S. R. Harutyunyan, T. den Hartog, K. Geurts, A. J. Min-
naard, B. L. Feringa, Chem. Rev. 2008, 108, 2824–2852; b) M.
Vuagnoux-d’Augustin, A. Alexakis, Chem. Eur. J. 2007, 13,
9647–9662.
[21] J. Velder, T. Robert, I. Weidner, J.-M. Neudörfl, J. Lex, H.-
G. Schmalz, Adv. Synth. Catal. 2008, 350, 1309–1315 (see also
ref.[7]).
[22] a) M. Schinnerl, M. Seitz, A. Kaiser, O. Reiser, Org. Lett. 2001,
3, 4259–4262; b) Y.-S. Kwak, E. J. Corey, Org. Lett. 2004, 6,
3385–3388.
[23] Compound 15 was prepared from 4 and cyclopropanecarbonyl
chloride in analogy to the synthesis of 3.
[24] Treatment of a related chromenone with an unbranched n-
C15H31 side chain in [D8]THF with Me3Al (3 equiv.) led to a
downfield shift of the olefinic 1H NMR signal (H3) by
0.5 ppm. This supports structure A.
Received: March 10, 2014
Published Online: April 17, 2014
3340
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3337–3340