Stereocontrolled generation of the (2R) chroman core of vitamin E: Total synthesis of (2R,4'RS,8'RS)-α-tocopherol

Article abstract of DOI:10.1021/ol9020783

(2R,4'RS,8'RS)-α-Tocopherol (1) was prepared using, as the two key steps, a novel diastereoselective TiCl4-promoted (S)-sulfoxide-directed allylation of ketal 2 with allyl trimethyl silane 3 to efficiently generate the challenging (2R) stereocenter of the

Full text of DOI:10.1021/ol9020783

ORGANIC
LETTERS
2009
Vol. 11, No. 21
4930-4933
Stereocontrolled Generation of the (2R)
Chroman Core of Vitamin E: Total
Synthesis of (2R,4′RS,8′RS)-r-Tocopherol
Gloria Herna´ndez-Torres,† Antonio Urbano,*,† M. Carmen Carren˜o,*,† and
Franc¸oise Colobert*,‡
Departamento de Qu´ımica Orga´nica (C-I), UniVersidad Auto´noma de Madrid,
Cantoblanco, 28049 Madrid, Spain, and Laboratoire de Ste´re´ochimie associe´ au
CNRS, UMR 7509 UniVersite´ de Strasbourg, ECPM 25 rue Becquerel, 67087
Strasbourg Cedex 2, France
antonio.urbano@uam.es; carmen.carrenno@uam.es; francoise.colobert@unistra.fr
Received September 8, 2009
ABSTRACT
(2R,4′RS,8′RS)-r-Tocopherol (1) was prepared using, as the two key steps, a novel diastereoselective TiCl4-promoted (S)-sulfoxide-directed
allylation of ketal 2 with allyl trimethyl silane 3 to efficiently generate the challenging (2R) stereocenter of the chroman moiety and a cross-
metathesis reaction with olefin 4 to efficiently join the lipophilic alkyl chain present in the final target.
(R,R,R)-R-Tocopherol (1) is the biologically most active
member of the vitamin E family as a natural lipophilic
antioxidant and radical scavenger.1 In particular, 1 protects
polyunsaturated fatty acids, other components of the cell
membrane, and low-density lipoproteins (LDL) by capturing
highly reactive free radicals formed in the body as byproduct
of natural oxidative metabolism.2,3
Tocopherols possess a shikimate-derived aromatic moiety
and a terpenoid side chain leading to a 6-chromanol
framework with a (R) stereogenic center at C-2 and two (R)
stereocenters at the saturated chain (Figure 1). Industrially,
R-tocopherol is produced on a large scale as a mixture of
all eight possible stereoisomers, (all-rac)-1.4 Recent studies
have shown that (2S)-configured tocopherols have no anti-
oxidant effect in biological systems because they are not
accepted as substrates by the R-tocopherol transfer protein
(TTP), which is responsible for the transport of vitamin E
into the tissue.5 On the other hand, the configuration of the
stereogenic centers in the side chain appears to have no
influence on the antioxidant effect.5 As a result, (all-rac)-1
exhibits a maximum of 50% of the biological activity of
(R,R,R)-1. Therefore, there is considerable interest in devel-
(3) (a) Netscher, T. In Lipid Synthesis and Manufacture; Gunstone, F. P.,
Ed.; Academic Press: Sheffield, U.K., 1999; pp 250-267. (b) Kreimayer,
J.; Schmidt, M. Pharm. Ztg. 1998, 143, 823–828. (c) Acuff, R. V.;
Dunworth, R. G.; Webb, L. W.; Lane, J. R. Am. J. Clin. Nutr. 1998, 67,
459–464. (d) Kiyose, C.; Maramatsu, R.; Kameyama, Y.; Ueda, T.; Igarashi,
O. Am. J. Clin. Nutr. 1997, 65, 785–789. (e) Ullmans Encyclopedia of
Industrial Chemistry; Elvers, B., Ed.; Wiley-VCH: Weinheim, 1996; Vol.
A27, pp 478-488. (f) Ingold, K. U.; Burton, G. W.; Foster, D. O.; Hughes,
L.; Lindsay, D. A.; Webb, A. Lipids 1987, 22, 163–172. (g) Cheng, S. C.;
Burton, G. W.; Ingold, K. U.; Foster, D. O. Lipids 1987, 22, 469–473.
(4) Bonrath, W.; Netscher, T. Appl. Catal., A 2005, 280, 55–73.
(5) (a) Hoppe, P. P.; Krennrich, G. Eur. J. Nutr. 2000, 39, 183–193. (b)
Blatt, D. H.; Pryor, W. A.; Mata, J. E.; Rodriguez-Proteau, R. J. Nutr.
Biochem. 2004, 15, 380–395.
† Universidad Auto´noma de Madrid.
‡ Universite´ de Strasbourg.
(1) Vitamin E-A ComprehensiVe Treatise; Machlin, L. J.; Ed.; Marcel
Dekker: New York, 1980.
(2) (a) Vatessary, G. T.; Smith, W. E.; Quach, H. T. Lipids 1989, 24,
1043–1047. (b) Jacobson, H. N. Free Radical Biol. Med. 1987, 3, 209–
213. (c) Burton, G. W.; Joyce, A.; Ingold, K. U. Arch. Biochem. Biophys.
1983, 221, 281–290. (d) Burton, G. W.; Joyce, A.; Ingold, K. U. Lancet
1982, 2, 327. (e) Packer, J. E.; Slater, T. F.; Willson, R. L. Nature 1979,
278, 737–738. (f) Simon, E. J.; Cross, C. S.; Milhorat, A. T. J. Biol. Chem.
1956, 221, 797–805
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10.1021/ol9020783 CCC: $40.75
Published on Web 09/30/2009
 2009 American Chemical Society

oping processes for the enantioselective synthesis of vitamin
E with special attention to the construction of the (R)
stereogenic center at C-2, which is the more challenging task.
Scheme 1. Retrosynthesis towards (2R,4′RS,8′RS)-R-Tocopherol (1)
Figure 1. Structure of (R,R,R)-R-tocopherol (1).
Concerning the overall synthetic strategy, the three major
problems of the total synthesis of (R,R,R)-1 are the formation
of the chiral chroman ring,6 the introduction of the two chiral
centers in the aliphatic side chain, and the coupling of
chroman and side chain building blocks.7a General routes
have used classical optical resolutions, biocatalysis, chiral-
pool starting materials, the application of chiral auxiliaries,
and asymmetric catalysis.7
Among the many types of transition-metal-catalyzed
carbon-carbon bond-forming reactions, olefin metathesis has
attracted widespread attention from the synthetic community
in recent years and has become a powerful tool for organic
chemists.8 Nevertheless, to the best of our knowledge, the
only example described in the literature for the olefin cross-
metathesis (CM) reaction applied to the synthesis of vitamin
E intermediates has been recently reported by Netscher et
al.9
Herein, we describe a short synthesis of (2R,4′RS,8′RS)-
R-tocopherol (1) using a novel diastereoselective (S)-sul-
foxide-directed10 allylation to generate the challenging (R)
stereogenic center at C-2 of the chroman unit and a cross-
metathesis reaction to join the alkyl chain present in the final
target.
intermediate such as 2, after desulfinylation, double bond
reduction, and OTBDMS deprotection. The assembly of the
full carbon skeleton of 2 would be possible after a cross-
metathesis reaction between allyl sulfinyl chroman 3 and
olefin 4, which in turn could be available from (E,E)-farnesol
after simple transformations. Compound 3, showing the
correct absolute configuration at the C-2 stereogenic center,
would be formed by a diastereoselective sulfoxide-directed
allylation of ketal 5, which could be obtained from 3,4-
dihydrocoumarin 6.
The stereoselective synthesis of the chroman moiety of
R-tocopherol (1), (S,SS)-3, is depicted in Scheme 2 and
started with known OTBS-protected 3,4-dihydrocoumarin
6,11 which was submitted to reaction with the LDA-generated
lithium anion of (S)-methyl p-tolyl sulfoxide12 to afford
sulfinyl chromanol 7, in 73% yield. After ketalization of 7
[CH(OMe)3, p-TsOH, 87%], the resulting 2-methoxy-3,4-
dihydro-benzopyran 5, obtained as mixture of stereoisomers
at C-2, was submitted to the key step formation of the C-2
stereogenic center of the chroman unit through a sulfoxide-
directed Lewis acid promoted nucleophilic substitution
reaction.13 After trying several nucleophiles (Me3Al,
Me3SiCH2CHdCH2), Lewis acids (TBDMSOTf, TiCl4,
ZrCl4), and experimental conditions, we found that the best
results, in terms of diastereoselectivity and yield, were
achieved from reaction of 5 with allyl trimethyl silane (3
As can be seen in the retrosynthetic Scheme 1,
(2R,4′RS,8′RS)-1 could be obtained from an advanced
(6) (a) Knight, D. W.; Qing, X. Tetrahedron Lett. 2009, 50, 3534–3537,
recent review. (b) Shen, H. C Tetrahedron 2009, 65, 3931–3952.
(7) Reviews: (a) Netscher, T. In Vitamins and Hormones; Litwack, G.,
Ed.; Elsevier: San Diego, 2007; Vol. 76, pp 155-202.(b) Netscher, T.;
Scalone, M.; Schmid, R. In Asymmetric Catalysis on an Industrial Scale;
Blaser, H. U., Schmidt, E., Eds.; Wiley-VCH: Weinheim, 2004; p 71. (c)
Woggon, W.-D. Angew. Chem., Int. Ed. 1999, 38, 2715–2716. (d) Netscher,
T. Chimia 1996, 50, 563–567. Recent references: (e) Chapelat, J.; Chougnet,
A.; Woggon, W.-D. Eur. J. Org. Chem. 2009, 2069–2076. (f) Liu, K.;
Chougnet, A.; Woggon, W.-D. Angew. Chem., Int. Ed. 2008, 47, 5827–
5829. (g) Chapelat, J.; Buss, A.; Chougnet, A.; Woggon, W.-D. Org. Lett.
2008, 10, 5123–5126. (h) Rein, Ch.; Demel, P.; Outten, R. A.; Netscher,
T.; Breit, B. Angew. Chem., Int. Ed. 2007, 46, 8670–8673. (i) Tietze, L. F.;
Stecker, F.; Zinngrebe, J.; Sommer, K. M. Chem.sEur. J. 2006, 12, 8770–
8776. (j) Gru¨tter, Ch.; Alonso, E.; Chougnet, A.; Woggon, W.-D. Angew.
Chem., Int. Ed. 2006, 45, 1126–1130. (k) Tietze, L. F.; Sommer, K. M.;
Zinngrebe, J.; Stecker, F. Angew. Chem., Int. Ed. 2005, 44, 257–259.
(8) Recent reviews:(a) Gradillas, A.; Pe´rez-Castells, J. Angew. Chem.,
Int. Ed. 2006, 45, 6086–6101. (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah,
D. Angew. Chem., Int. Ed. 2005, 44, 4490–4527. (c) Grubbs, R. H.
Tetrahedron 2004, 60, 7117–7140. (d) Connon, S. J.; Blechert, S. Angew.
Chem., Int. Ed. 2003, 42, 1900–1923.
(11) Compound 6 was prepared in two steps (see Supporting Informa-
tion) from commercially available trimethyl hydroquinone following a
modification of a previously described procedure:Harada, T.; Hayashiya,
T.; Wada, I.; Iwa-ake, N.; Oku, A. J. Am. Chem. Soc. 1987, 109, 527–532.
(12) Solladie´, G.; Hutt, J.; Girardin, A. Synthesis 1987, 173–175.
(13) Cohen, N.; Schaer, B.; Saucy, G.; Borer, R.; Todaro, L.; Chiu, A.-
M. J. Org. Chem. 1989, 54, 3282–3292.
(9) (a) Netscher, T.; Malaise´, G.; Bonrath, W.; Breuninger, M. Catal.
Today 2007, 121, 71–75. (b) Malaise´, G.; Bonrath, W.; Breuninger, M.;
Netscher, T. HelV. Chim. Acta 2006, 89, 797–812. (c) Netscher, T. Curr.
Top. Med. Chem. 2005, 5, 1579–1585.
(10) Recent review: Carren˜o, M. C.; Herna´ndez-Torres, G.; Ribagorda,
M.; Urbano, A. Chem. Commun. 2009, DOI 10.1039/b908043k.
Org. Lett., Vol. 11, No. 21, 2009
4931

OH free derivative (S,SS)-10 (TBAF, THF, 0 °C, 5 min,
100%), suitable crystals were collected for X-ray analysis15
(Scheme 3).
Scheme 2. Diastereoselective Synthesis of Chroman (S,SS)-3
Scheme 4. Synthesis of Olefin (all-rac)-4 from (E,E)-Farnesol
equiv) in the presence of TiCl4 (1.2 equiv) in CH2Cl2 at -78
°C. Under these conditions, a difficult to separate 81:19 mix-
ture of (S,SS)-3 and the corresponding epimer at C-2 was
obtained. Fortunately, when the reaction mixture was allowed
to warm to rt, a mixture of allyl sulfinyl chroman (S,SS)-3
and thioether (R)-914 was obtained, from which (S,SS)-3
could be isolated in a remarkable 73% yield. The stereose-
lective (S)-sulfoxide-directed addition of the allylsilane to
the upper face of oxocarbenium intermediate 8, formed after
the TiCl4-promoted elimination of the methoxy group present
in the starting material 5, explains the formation of (S,SS)-
3.
With the appropriately substituted (2S)-chroman moiety
in hand, we turned our attention to the synthesis of the
lipophilic alkyl chain present in the final target. Very recently,
Pfaltz et al.16 have reported an enantioselective hydrogenation
protocol to efficiently transform (E,E)-farnesol into (R,R)-
hexahydrofarnesol (11), with 91% yield and 99% ee (Scheme
4), which could serve us as starting material for the synthesis
of natural (R,R,R)-R-tocopherol via (R,R)-4. Nevertheless,
taking into account that the necessary chiral catalyst is not
commercially available, we decided to validate our initially
proposed CM strategy by using a racemic analogue. Thus,
(E,E)-farnesol was fully hydrogenated (H2, Pd/C, EtOH, rt,
21 h, 93%)17 into hexahydrofarnesol (all-rac)-11, which was
converted into iodide (all-rac)-12, by treatment with iodine
in the presence of imidazole and triphenyl phosphine
(Et2O-CH3CN, 0 °C to rt, 1.5 h), with 83% yield. Finally,
dehydroiodination of 12 with potassium tert-butoxide fur-
nished olefin (all-rac)-4, in 84% yield (Scheme 4). Thus,
we could prepare the alkyl chain of (2R,4′RS,8′RS)-R-
tocopherol (1), (all-rac)-4, in only three steps from com-
mercially available (E,E)-farnesol, with 65% overall yield.
Having efficiently synthesized the two main fragments of
(2R,4′RS,8′RS)-R-tocopherol (1), sulfinyl chroman 3, and
alkyl chain 4, we undertook their coupling using a cross-
metathesis approach (Scheme 5). After trying several ex-
perimental conditions, we found that the best yield was
Thus, we have performed the stereoselective synthesis of
the chroman fragment of (2R,4′RS,8′RS)-R-tocopherol (1),
(S,SS)-3, in only three steps from known starting material
6, with 49% overall yield.
Scheme 3
.
Synthesis and X-ray ORTEP of Sulfinyl Chroman
(S,SS)-10
achieved by heating, under microwave irradiation,18
a
mixture of allyl chroman (S,SS)-3 and 2.9 equiv of olefin
(15) CCDC 730815 for (S,SS)-10 contains the supplementary crystal-
lographic data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
The absolute configuration of the newly created stereo-
genic center at C-2 of chroman (S,SS)-3 could not be
determined at this stage, but after transformation into the
(16) Wang, A.; Wu¨stenberg, B.; Pfaltz, A. Angew. Chem., Int. Ed. 2008,
47, 2298–2300.
(14) (R)-9 was shown to proceed from the reduction of a small
percentage of the sulfoxide epimer at C-2 of (S,SS)-3, probably produced
by the presence of the Lewis acid TiCl4.
(17) Bennett, Ch. J.; Caldwell, S. T.; McPhail, D. B.; Morrice, P. C.;
Duthie, G. G.; Hartley, R. C. Bioorg. Med. Chem. 2004, 12, 2079–2098.
(18) Coquerel, Y.; Rodriguez, J. Eur. J. Org. Chem. 2008, 1125–1132.
4932
Org. Lett., Vol. 11, No. 21, 2009

[H2, Pd (C), MeOH, rt, overnight, 87%], and OTBS depro-
tection (TBAF, THF, 0 °C, 5 min, 91%), with >99% ee.21
In conclusion, we have reported a new, short and efficient
total synthesis of (2R,4′RS,8′RS)-R-tocopherol (1) in only
seven steps for the longest linear sequence and 10 total steps,
starting from a known 3,4-dihydrocoumarin and com-
mercially available (E,E)-farnesol, with 24.4% overall yield.
The two key features of our synthetic approach were a novel
homochiral sulfoxide-directed ionic allylation of a 2-chro-
manol derivative to create the challenging stereogenic center
at C-2, and a cross -metathesis reaction to efficiently couple
the lipophilic alkyl chain present in the final target. To the
best of our knowledge, the described synthesis is one of the
shortest procedures reported to date for the preparation of a
(2R)-configured tocopherol. Moreover, our methodology
represents a new access to natural (R,R,R)-R-tocopherol by
combining with the enantioselective hydrogenation protocol
reported by Pfaltz.
Scheme 5. Completion of Synthesis of
(2R,4′RS,8′RS)-R-Tocopherol (1)
Acknowledgment. We thank MICINN of Spain (Grant
CTQ2008-04691) and Ministe`re de la Recherche and CNRS
for financial support.
Supporting Information Available: Experimental pro-
cedures, characterization data, and NMR spectra for all
compounds, and X-ray data in CIF format for (S,SS)-10. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(all-rac)-4 in the presence of 20 mol % of the commercially
available modified second-generation Grubbs-Hoveyda ru-
thenium catalyst 13. Under these conditions, compound
(S,SS)-2, bearing the full carbon skeleton of R-tocopherol
(1), was isolated in 55% yield, after chromatographic
purification (63% yield based on recovered starting materi-
al).19 To the best of our knowledge, this is the first example
described in the literature for a successful cross-metathesis
OL9020783
(20) For an unsuccessful attempt, see:(a) Michrowska, A.; Bieniek, M.;
Kim, M.; Klajn, R.; Grela, K. Tetrahedron 2003, 59, 4525–4531. For a
few examples of ring-closing metathesis chemistry applied to sulfoxides,
see: (b) Bates, D. K.; Li, X.; Jog, P. V. J. Org. Chem. 2004, 69, 2750–
2754. (c) Cachoux, F.; Ibrahim-Ouali, M.; Santelli, M. Synlett 2002, 1987–
1990. (d) Liras, S.; Davoren, J. E.; Bordner, J. Org. Lett. 2001, 3, 703–
706.
reaction of
a
sulfoxide-containing olefin.20 Finally,
(2R,4′RS,8′RS)-1 could be obtained from 3 after desulfiny-
lation (Raney Ni, EtOH, rt, 1 h, 89%), double bond reduction
(21) The optical purity was determined by HPLC allowing separation
of the C-2 diastereoisomers [Daicel Chiralpack IB, 1% i-PrOH in hexane,
1.0 mL/min, 254 nm, t(2R,4′RS,8′RS) ) 12.2 min, t(2S,4′RS,8′RS) ) 13.4 min].
(19) When the same reaction was performed in absence of microwave
irradiation, compound 2 was isolated pure in 48% yield.
Org. Lett., Vol. 11, No. 21, 2009
4933