Enantioselective total synthesis of the natural γ -tocopherol metabolite (S)-γ-CEHC (S)-LLU-α

Article abstract of DOI:10.1021/ol9027804

[Chemical equation presented] The asymmetric synthesis of the natural: -tocopherol metabolite (S)-; -CEHC (1) Is described In 10 steps and 18.4% overall yield starting from 2,3-dimethylhydroquinone. The key step Is a stereoselective TiCl₄-mediated homochiral sulfoxide-directed allylation of ketal (SS) 3 to efficiently generate the challenging C-2 stereogenic carbon of chroman (SS,S)-2 with the correct absolute configuration.

Full text of DOI:10.1021/ol9027804

ORGANIC
LETTERS
2010
Vol. 12, No. 3
580-583
Enantioselective Total Synthesis of the
Natural γ-Tocopherol Metabolite
(S)-γ-CEHC [(S)-LLU-r]
Mercedes Lecea,†,‡ Gloria Herna´ndez-Torres,† Antonio Urbano,*,†
M. Carmen Carren˜o,*,† and Franc¸oise Colobert*,‡
Departamento de Qu´ımica Orga´nica (Mo´dulo 01), UniVersidad Auto´noma de Madrid,
c/Francisco Tomas y Valiente 7, 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
Received December 2, 2009
ABSTRACT
The asymmetric synthesis of the natural γ-tocopherol metabolite (S)-γ-CEHC (1) is described in 10 steps and 18.4% overall yield starting from
2,3-dimethylhydroquinone. The key step is a stereoselective TiCl4-mediated homochiral sulfoxide-directed allylation of ketal (SS)-3 to efficiently
generate the challenging C-2 stereogenic carbon of chroman (SS,S)-2 with the correct absolute configuration.
(2S)-2,7,8-Trimethyl-2-(2′-carboxyethyl)-6-hydroxychro-
man, (S)-γ-CEHC (1), was originally discovered as an
endogenous natriuretic factor in patients suffering from
uremia and named (S)-LLU-R by Wechter et al. in 1995.1
The structure of this compound was determined by spectro-
scopic analysis2 and proven by a racemic synthesis from 2,3-
dimethylhydroquinone.2,3 The absolute stereochemistry at
C-2 was secured by X-ray analysis of an enantiopure amide
and the resolution of the enantiomers was accomplished by
chiral HPLC.3 (S)-γ-CEHC was later found to be a major
metabolite of (2R)-γ-tocopherol,4 a component of the vitamin
E family, and recent studies showed that (2R)-γ-tocotrienol
is also metabolized to 1 in rats5 and humans.6
The study of racemic γ-CEHC (1) in vitro in various model
oxidative reactions has shown that, by its high antioxidant
properties, it is comparable with R-tocopherol, ascorbic acid,
and Trolox, a cardioprotective short-chain tocopherol analogue.7
On the other hand, short-chain hydrophilic analogues of
tocopherols, such as 1, are water-soluble metabolites of Vitamin
E possessing unique properties distinguishing them from the
† Universidad Auto´noma de Madrid.
(4) Murray, E. D., Jr.; Wechter, W. J.; Kantoci, D.; Wang, W.-H.; Pharm,
T.; Quiggle, D. D.; Gibson, K. M.; Leipold, D.; Anner, B. M. J. Pharm.
Exp. Ther. 1997, 282, 657–662.
‡ UMR 7509 Universite´ de Strasbourg.
(1) Murray, E. D., Jr.; Kantoci, D.; DeWind, S. A.; Bigornia, A. E.;
D’Amico, D. C.; King, J. G., Jr.; Pham, T.; Levine, B. H.; Jung, M. E.;
Wechter, W. J. Life Sci. 1995, 57, 2145–2161.
(5) Hattori, A.; Fukushima, T.; Yoshimura, H.; Abe, K.; Imai, K. Biol.
Pharm. Bull. 2000, 23, 1395–1397.
(2) Wechter, W. L.; Kantoci, D.; Murray, E. D., Jr.; D’Amico, D. C.;
Jung, M. E.; Wang, W.-H. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 6002–
6007.
(6) Lodge, J. K.; Ridington, J.; Leonard, S.; Vaule, H.; Traber, M. G.
Lipids 2001, 36, 43–48.
(7) (a) Yoshida, Y.; Niki, E. Biofactors 2002, 16, 93–103. (b) Betancor-
Fernandez, A.; Sies, H.; Stahl, W.; Polidori, M. C. Free Radical Res. 2002,
36, 915–921.
(3) Kantoci, D.; Wechter, W. J.; Murray, E. D., Jr.; Dewind, S. A.;
Borchardt, D.; Khan, S. I. J. Pharm. Exp. Ther. 1997, 282, 648–656
.
10.1021/ol9027804  2010 American Chemical Society
Published on Web 01/06/2010

initial liposoluble tocopherols.8 They exhibit antiinflammatory
and natriuretic action, being endogenous ligands.9 Unlike other
diuretics, γ-CEHC selectively promotes the excretion of sodium
ions without affecting the potassium ions.1,4,10 Furthermore, 1
has been shown to inhibit the generation of prostaglandin
E2, an important mediator synthesized during inflammation
via the cyclooxygenase-2-catalyzed oxidation of arachidonic
acid.11 Thus, (S)-γ-CEHC is expected to be a useful
therapeutic agent.
Scheme 1. Retrosynthesis Toward (S)-γ-CEHC (1)
These multiple biological activities make (S)-γ-CEHC (1)
an attractive target for total synthesis. To achieve this goal, the
main challenge and non-well-resolved task is the efficient
generation of the C-2 stereogenic center at the chroman unit.12
Besides several racemic approaches,2,3,13 the only total syn-
thesis of the natural (S)-enantiomer of γ-CEHC (1), reported
in 1999 by Jung et al., was accomplished in 13 steps and
18% overall yield, starting from geraniol.14 The key steps
were a Sharpless asymmetric epoxidation of geraniol to
generate the required stereogenic center, a Gassman-Sato
process to join the alkyl chain to the phenolic moiety, and
the cyclization of a triol with acid to give the corresponding
chroman with retention of configuration at the tertiary alcohol
center.
We have recently developed an enantioselective access to
C-2-substituted chromans using the cyclization/nucleophilic
substitution of several 2-(p-tolylsulfinylmethyl)-2-chromanols.15
Herein, we describe a new and shorter enantioselective total
synthesis of (S)-γ-CEHC (1) using, as the key step, a diaste-
reoselective homochiral sulfoxide-directed16 allylation to ef-
ficiently generate the challenging (S) stereogenic center at C-2
of the chroman moiety present in the final target.
The retrosynthetic analysis of (S)-γ-CEHC (1) is depicted in
Scheme 1. As can be seen, (S)-1 could be obtained from an
advanced intermediate such as (SS,S)-2, after desulfinylation,
double bond transformation, and OTBS deprotection. Com-
pound 2, showing the correct absolute configuration at the C-2
stereogenic center, would be formed after a Lewis acid-
promoted diastereoselective (S)-sulfoxide-directed allylation of
ketal intermediate (SS)-3, which could be obtained from 3,4-
dihydrocoumarin 5 and (SS)-methyl p-tolyl sulfoxide (4).
Finally, lactone 5 could be easily accessible from commercially
available starting materials such as 2,3-dimethylhydroquinone
(6) and acrylic acid (7).
One of the methods used to synthesize 3,4-dihydrocoumarins
is the Friedel-Crafts alkylation of phenols with an excess of
acrylic acid in the presence of the ion-exchange resin Amberlyst
15 as acid catalyst.17 Thus, the hitherto unknown dihydrocou-
marin derivative 9 could be synthesized from commercially
available reagents 2,3-dimethyl-1,4-hydroquinone (6) and acrylic
acid (7) under these conditions (Scheme 2). Nevertheless, in
our hands, the formation of 9 was always accompanied with
variable amounts of dicoumarin 8, which could not be avoided.
After several trials, we found the best conditions to minimize
the undesired presence of 8, by carrying out the reaction
between 6 (1 equiv) and 7 (1.05 equiv) and an excess of
Amberlyst in refluxing toluene for 2 days. From the crude
reaction mixture formed under these conditions, the dicoumarin
8 was precipitated with EtOAc (10% yield). The mother liquors
were later concentrated and purified by flash column chroma-
tography to obtain a 65% yield of 3,4-dihydrocoumarin 9.
Then, the phenolic OH group of 9 was protected as its silyl
ether (TBSOTf, 2,6-lutidine, CH2Cl2, 12 h, 100%) and the
resulting OTBS-protected lactone 5 was submitted to reaction
with the Li anion of (SS)-methyl p-tolyl sulfoxide (4)18 (LDA,
THF, -78 °C, 1 h) furnishing sulfinyl lactol (SS)-10, in 75%
yield. After methylation of lactol (SS)-10 [TMSOTf, MgSO4,
CH2Cl2, MeOH, 0 °C to rt, 3 h, 85%),19 the resulting
2-methoxy-3,4-dihydrobenzopyran (SS)-3, obtained as a 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 allylation
reaction.20 After trying different Lewis acids (TiCl4, ZrCl4) and
experimental conditions, we found that the best results, in terms
(8) Review: Odinokov, V. N.; Spivak, A. Y.; Knyshenko, O. V. Russ.
J. Bioorg. Chem. 2007, 33, 359–375.
(9) Hensley, K.; Benaksas, E. J.; Bolli, R.; Comp, R.; Grammas, P.;
Hamdheydari, L.; Mou, S.; Pye, Q. N.; Stoddard, M. F.; Wallis, G.;
Williamson, K. S.; West, M.; Wechter, W. J.; Floyd, R. A. Free Radical
Biol. Med. 2004, 36, 1–15.
(10) (a) Appenroth, D.; Karge, E.; Kieaˆling, G.; Wecther, W. J.;
Winnefeld, K.; Fleck, C. Toxicol. Lett. 2001, 122, 255–265. (b) Takata, J.;
Hidaka, R.; Yamasaki, A.; Hattori, A.; Fukushima, T.; Tanabe, M.;
Matsunaga, K.; Karube, Y.; Imai, K. J. Lipid Res. 2002, 43, 2196–2204
.
(11) (a) Jiang, Q.; Elson-Schwab, I.; Courtemanche, C.; Ames, B. N.
Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 11494–11499. (b) Grammas, P.;
Hamdheydari, L.; Benaksas, E. J.; Mou, S.; Pye, Q. N.; Wechter, W. J.;
Floyd, R. A.; Stewart, C.; Hensley, K. Res. Commun. 2004, 319, 1047–
1052.
(12) Review: Shen, H. C. Tetrahedron 2009, 65, 3931–3952.
(13) Sachdeva, R.; Thomas, B.; Wang, X.; Ma, J.; Jones, K. H.; Hatcher,
P. G.; Cornwell, D. G. Chem. Res. Toxicol. 2005, 18, 1018–1025
.
(17) (a) Hoefnagel, A. J.; Gunnewegh, E. A.; Downing, R. S.; Van
Bekkum, H. J. Chem. Soc., Chem. Commun. 1995, 225–226. (b) Graham,
S. R.; Murphy, J. A.; Kennedy, A. R. J. Chem. Soc., Perkin Trans. 1 1999,
21, 3071–3073. (c) Posakony, J.; Hirao, M.; Stevens, S.; Simon, J. A.;
Bedalov, A. J. Med. Chem. 2004, 47, 2635–2644.
(14) Jung, M. E.; MacDougall, J. M. Tetrahedron Lett. 1999, 40, 6339–
6342.
(15) (a) Herna´ndez-Torres, G.; Urbano, A.; Carren˜o, M. C.; Colobert,
F. Org. Lett. 2009, 11, 4930–4933. (b) Carren˜o, M. C.; Herna´ndez-Torres,
G.; Urbano, A.; Colobert, F. Eur. J. Org. Chem. 2008, 2035–2038.
(16) Review: Carren˜o, M. C.; Herna´ndez-Torres, G.; Ribagorda, M.;
Urbano, A. Chem. Commun. 2009, 6129–6144.
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57, 4297–4309.
Org. Lett., Vol. 12, No. 3, 2010
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Scheme 2
.
Stereoselective Synthesis of Chroman (SS,S)-2 En
Route to (S)-γ-CEHC (1)
Scheme 3
.
Synthesis and X-ray ORTEP of Sulfinyl Chroman
(SS,S)-12
shown in Scheme 4. First, the reaction of the allyl moiety of 2
with 9-BBN (0 °C to rt, 2 d) followed by treatment with H2O2
and NaOH (rt, 3 h) gave rise to the corresponding sulfinyl
alcohol (SS)-13, which, without further purification, was
submitted to desulfinylation with Raney Ni (EtOH, rt, overnight)
furnishing the 1-hydroxypropyl chroman (S)-14 with 87% yield
for the two last steps. Then, we tried to perform the direct
oxidation of the primary OH of (S)-14 into the corresponding
carboxylic acid present in the final target. In our hands, this
one-pot oxidation using different protocols23 [(t-BuOOH, 5%
mol CuCl, CH3CN, rt),23a (0.03 equiv of RuCl3, NaIO4, H2O/
CH3CN/CCl4, rt),23b (TPAP, NMO, CH3CN/H2O, rt),23c (2.5%
mol NiCl2, NaOCl aq, CH2Cl2, rt),23d (CrO3, H5IO6, CH3CN/
Scheme 4. Completion of the Synthesis of (S)-γ-CEHC (1)
of diastereoselectivity and yield, were achieved from reaction
of (SS)-3 with allyl trimethyl silane (3 equiv) in the presence
of TiCl4 (1.4 equiv) at -78 °C in CH2Cl2. Under these
conditions, a 15:85 mixture21 of allyl sulfinyl chroman epimers
at C-2, (SS,R)-11 and (SS,S)-2, was obtained after stereoselective
(S)-sulfoxide-directed addition of the allyl group of the reagent
to the upper face of oxocarbenium intermediate (SS)-A, formed
after the TiCl4-promoted elimination of the methoxy group
present in the starting material (SS)-3. Both diastereoisomers
(SS,R)-11 and (SS,S)-2 could be separated after flash chroma-
tography, being isolated in 12% and 67% yield, respectively
(Scheme 2).
The (S) absolute configuration of the newly created
stereogenic center at C-2 of chroman (SS,S)-2 could not be
determined at this stage but, after transformation into the
corresponding free-OH derivative (SS,S)-12 (TBAF, THF,
0 °C, 15 min, 100%), suitable crystals were collected for
X-ray analysis22 (Scheme 3).
With allyl sulfinyl chroman (SS,S)-2 in hand, we undertook
the final steps toward the total synthesis of (S)-γ-CEHC (1), as
H2O, rt)]23e afforded complex reaction mixtures containing the
desired carboxylic acid, the aldehyde intermediate, and/or
degradation products. Thus, we decided to perform this oxida-
(20) Cohen, N.; Schaer, B.; Saucy, G.; Borer, R.; Todaro, L.; Chiu, A.-
M. J. Org. Chem. 1989, 54, 3282–3292.
(21) When the reaction was carried out with the OAc-protected analogue
of (SS)-3, we observed a 37:63 diastereoisomeric ratio, indicating a
remarkable effect of the remote protecting group in the selectivity of the
process.
(23) (a) Mannam, S.; Sekar, G. Tetrahedron Lett. 2008, 49, 2457–2460.
(b) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org.
Chem. 1981, 46, 3936–3938. (c) Ley, S. V.; Norman, J.; Griffith, W. P.;
Marsden, S. P. Synthesis 1994, 639–666. (d) Grill, J. M.; Ogle, J. W.; Miller,
S. A. J. Org. Chem. 2006, 71, 9291–9296. (e) Zhao, M.; Li, J.; Song, Z.;
Desmond, R.; Tschaen, D. M.; Grabowski, E. J. J.; Reider, P. J. Tetrahedron
Lett. 1998, 39, 5323–5326.
(22) CCDC-742661 for (SS,S)-12 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.
582
Org. Lett., Vol. 12, No. 3, 2010

tion process in two steps. First, the treatment of alcohol (S)-14
with SO3·Py in the presence of Et3N (DMSO-CH2Cl2, 0 °C to
rt, 2 h) gave rise to the aldehyde intermediate (S)-15, which,
without further purification, was transformed into the corre-
sponding carboxylic acid (S)-16 after NaClO2 oxidation
(NaH2PO4, 2-methyl-2-butene, t-BuOH-H2O, 0 °C, 10 min),24
in 76% yield for the two last steps. Finally, desilylation of
compound (S)-16 with TBAF (THF, 0 °C, 15 min) took place
in quantitative yield to afford (S)-γ-CEHC (1) {[R]20D +5.5 (c
1.43, MeOH); lit3 [R]20D +5.1 (c 1.27, MeOH)}, showing >99%
enantiomeric excess.25 All physical and spectroscopic data of
synthetic 1 were identical with those reported for the natural
metabolite.2,3
In conclusion, we have successfully achieved a new,
short, and highly stereoselective total synthesis of the
natural γ-tocopherol metabolite (S)-γ-CEHC [(S)-LLU-
R], in 10 steps and 18.4% overall yield, using an
enantiopure (S)-sulfoxide-directed nucleophilic allylation
of a sulfinyl ketal intermediate as the key step to efficiently
generate the challenging stereogenic center at C-2 of the
chroman moiety.
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, NMR spectra, and X-ray data
(CIF) for (SS,S)-12. This material is available free of charge
via the Internet at http://pubs.acs.org.
(24) Kraus, G. A.; Roth, B. J. Org. Chem. 1980, 45, 4825–4830.
(25) The optical purity was determined by chiral HPLC (Daicel
Chiralpack IA, 9.5% i-PrOH and 0.5% AcOH in hexane, 1 mL min-1, 25
°C, 254 nm): tR(2R) ) 23.5 min and tR(2S) ) 28.8 min.
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