A short and convenient chemical route to optically pure 2-methyl chromanmethanols. Total asymmetric synthesis of β-, γ-, and δ-tocotrienols

Article abstract of DOI:10.1021/jo0705418

(Chemical Equation Presented) With use of inexpensive commercially available raw materials, chromanmethanol precursors to the natural β-, γ-, and δ-tocotrienols have been prepared in high yield. Enzymatic resolution afforded chiral chromanmethanols in high enantiomeric excess. Subsequent attachment of the farnesyl side chain was high yielding, thus allowing the preparation of asymmetric β-, γ-, and δ-tocotrienols in one final step wherein simultaneous deprotection of the phenol and removal of the sulfone group occurs. This chemistry provides the first synthesis of natural-series β-tocotrienol.

Full text of DOI:10.1021/jo0705418

A Short and Convenient Chemical Route to Optically Pure 2-Methyl
Chromanmethanols. Total Asymmetric Synthesis of â-, γ-, and
δ-Tocotrienols
Elias A. Couladouros,*,†,‡ Vassilios I. Moutsos,‡ Maria Lampropoulou,‡ James L. Little, and
John A. Hyatt*,§,
Chemistry Laboratories, Agricultural UniVersity of Athens, Iera Odos 75, GR 118 55 Athens, Greece,
Natural Product Synthesis and Bioorganic Chemistry Laboratory, Institute of Physical Chemistry, NCSR
“Demokritos”, P.O. Box 60228, GR 153 10 Ag. ParaskeVi, Greece, Yasoo Health, Inc., 2109 West Market
Street, Johnson City, Tennessee 37602, and Department of Chemistry, East Tennessee State UniVersity,
Box 70695, Johnson City, Tennessee 37614
ecoula@chem.demokritos.gr; hyatt@etsu.edu
ReceiVed March 15, 2007
With use of inexpensive commercially available raw materials, chromanmethanol precursors to the natural
â-, γ-, and δ-tocotrienols have been prepared in high yield. Enzymatic resolution afforded chiral
chromanmethanols in high enantiomeric excess. Subsequent attachment of the farnesyl side chain was
high yielding, thus allowing the preparation of asymmetric â-, γ-, and δ-tocotrienols in one final step
wherein simultaneous deprotection of the phenol and removal of the sulfone group occurs. This chemistry
provides the first synthesis of natural-series â-tocotrienol.
Introduction
and asymmetric synthesis.12-24 However, in spite of the high
efficiency of both Trost’s14-19 and Tietze’s methods22,24 for
Chromans and chromens have attracted the interest of many
synthetic groups due to their occurrence in many biologically
important compounds.1 Among them, 2-methyl derivatives,
including trolox, MDL-73404, and the natural products clusi-
foliol, daurichromenic acid, cordiachromene, and Vitamin E
components consist of a particularly interesting subgroup.
From a synthetic point of view, setting the chirality at position
2 is the major issue. This has been addressed so far in several
ways, including kinetic resolution,2,3 enzymatic resolution,4-11
(6) Kalaritis, P.; Regenye, R. W.; Partridge, J. J.; Coffen, D. L. J. Org.
Chem. 1990, 55, 812-815.
(7) Hyatt, J. A.; Skelton, C. Tetrahedron: Asymmetry 1997, 8, 523-
526.
(8) Mizuguchi, E.; Suzuki, T.; Achiwa, K. Synlett 1996, 743-744.
(9) Mizuguchi, E.; Suzuki, T.; Achiwa, K. Synlett 1994, 929-930.
(10) Mizuguchi, E.; Takemoto, M.; Achiwa, K. Tetrahedron: Asymmetry
1993, 4, 1961-1964.
(11) Chenevert, R.; Courchesne, G. Tetrahedron Lett. 2002, 43, 7971-
7973.
(12) Goujon, J. Y.; Duval, A.; Kirschleger, B. J. Chem. Soc., Perkin
Trans 1 2002, 496-499.
† Agricultural University of Athens.
‡ Institute of Physical Chemistry.
(13) Bouzbouz, S.; Goujon, J. Y.; Deplanne, J.; Kirschleger, B. Eur. J.
Org. Chem. 2000, 3223-3228.
§ Yasoo Health, Inc.
East Tennessee State University.
(1) Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao, G.-Q.;
Barluenga, S.; Mitchell, H. J. J. Am. Chem. Soc. 2000, 122, 9939-9953
and references cited therein.
(2) Scott, J. W.; Cort, W. M.; Harley, H.; Parrish, D. R.; Saucy, G. J.
Am. Oil Chem. Soc. 1974, 51, 200-203.
(3) Shitara, H.; Aoki, Y.; Hirose, T.; Nohira, H. Bull. Chem. Soc. Jpn.
2000, 73, 259-265.
(4) Sugai, T.; Watanabe, N.; Ohta, H. Tetrahedron: Asymmetry 1991, 2,
371-376.
(5) Goujon, J. Y.; Zammattio, F.; Kirschleger, B. Tetrahedron: Asymmetry
2000, 11, 2409-2420.
(14) Trost, B. M.; Shen, H. C.; Dong, L.; Surivet, J. P.; Sylvain, C. J.
Am. Chem. Soc. 2004, 126, 11966-11983.
(15) Trost, B. M.; Asakawa, N. Synthesis 1999, 1491-1494.
(16) Trost, B. M.; Shen, H. C.; Surivet, J. P. Angew. Chem., Int. Ed.
2003, 42, 3943-3947.
(17) Trost, B. M.; Shen, H. C.; Dong, L.; Surivet, J. P. J. Am. Chem.
Soc. 2003, 125, 9276-9277.
(18) Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 2003, 125, 7482-
7483.
(19) Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 2002, 124, 2528-
2533.
(20) Sakito, Y.; Suzukamo, G. Tetrahedron Lett. 1982, 23, 4953-4954.
10.1021/jo0705418 CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/09/2007
J. Org. Chem. 2007, 72, 6735-6741
6735

Couladouros et al.
FIGURE 1. Typical chromanes and tocols.
SCHEME 1. Retrosynthetic Analysis for Tocotrienolsa
synthesizing optically pure 2-methylchroman derivatives, the
pioneering work of the Hoffman-La Roche25 group and a recent
chemoenzymatic synthesis26 remain the only completed total
asymmetric syntheses of any tocotrienols reported so far.11,25-33
We would like to report a new convenient chemical route
toward chiral chromanols 4 via Trolox type esters 3 (Scheme
1), which may serve as key intermediates for the synthesis of
members of the 2-methylchroman family. Our method is
potentially scalable and fulfills the following requirements: (a)
high availability of relatively inexpensive raw materials, (b)
“fast-and-cheap-arrival” to a chiral chroman key intermediate,
(21) Labrosse, J. R.; Poncet, C.; Lhoste, P.; Sinou, D. Tetrahedron:
Asymmetry 1999, 10, 1069-1078.
(22) Tietze, L. F.; Sommer, K. M.; Zinngrebe, J.; Stecker, F. Angew.
Chem., Int. Ed. 2004, 43, 2-4.
(23) Jung, M. E.; MacDougall, J. M. Tetrahedron Lett. 1999, 40, 6339-
6342.
(24) Tietze, L. F.; Stecker, F.; Zinngrebe, J.; Sommer, K. M. Chem. Eur.
J. 2006, 12, 8770-8776.
a a, b, c, and d refer to R-, â-, γ-, and δ-tocotrienols, respectively.
(25) Scott, J. W.; Bizzarro, F. T.; Parrish, D. R.; Saucy, G. HelV. Chim.
Acta 1976, 59, 290-306.
(26) Chenevert, R.; Courchesne, G. Bioorg. Med. Chem. 2006, 14, 5389-
5396.
(c) short synthetic scheme for its transformation to the target
molecule, and (d) avoidance of significant isomerization during
chemical manipulations. As an application, we report herein the
first total synthesis of natural-series â-tocotrienol, as well as
the synthesis of γ- and δ-tocotrienols.
(27) Pearce, B. C.; Parker, R. A.; Deason, M. E.; Dischino, D. D.;
Gillespie, E.; Qureshi, A. A.; Wright, J. J. K.; Volk, K. J. Med. Chem.
1994, 37, 526-541.
(28) McHale, D.; Green, J.; Marcinkiewicz, S.; Feeney, J.; Sutcliffe, L.
H. J. Chem. Soc. 1963, 784-791.
(29) Schudel, P.; Mayer, H.; Metzger, J.; Rueegg, R.; Isler, O. HelV.
Chim. Acta 1963, 46, 2517-2526.
Results and Discussion
(30) Kajiwara, M.; Sakamoto, O.; Ohta, S. Heterocycles 1980, 14, 1995-
1998.
(31) Pearce, B. C.; Parker, R. A.; Deason, M. E.; Qureshi, A. A.; Wright,
J. J. K. J. Med. Chem. 1992, 35, 3595-3606.
(32) Urano, S.; Nakano, S. I.; Matsuo, M. Chem. Pharm. Bull. 1983,
31, 4341-4345.
According to Scheme 1, an efficient disconnection for the
formation of tocotrienols would have led to commercially
available farnesol and trolox-type esters 3. Simple conversion
to the respective sulfone (1) and triflate (2) derivatives and
(33) Zheng, A.; Shan, D.; Wang, B. J. Org. Chem. 1999, 64, 156-161.
6736 J. Org. Chem., Vol. 72, No. 18, 2007

Synthesis of â-, γ-, and δ-Tocotrienols
SCHEME 2. Synthesis of Chromanmethanols
SCHEME 3. Resolution of Chromanmethanolsa
a 38-40% total yield, 95.9-97.5% ee after two cycles.
subsequent coupling under alkaline conditions followed by
radical desulfonylation would furnish the targeted tocotrienols.
Chiral 4 could in turn be derived from its racemates by applying
a scalable enzymatic resolution protocol previously established
by Hyatt et al.7 Though there are several approaches toward
(()-3 or (()-4, we decided to try Nohira’s protocol,3 which
has been applied only on unsubstituted hydroquinones. The
advantage of this approach, if successful, would be the formation
of (()-3 in one step, employing only commercially available
chemicals. The required hydroquinones 5 are commercially
available or can be easily and quantitatively derived by reduction
of the appropriate cheaper quinones 6 with sodium dithionite33
(Scheme 2).
â, γ, and δ series gave similar results; therefore a range of yields
is stated instead of exact numbers per case throughout this
article.
The crucial condensation of substituted phenols 8 was then
attempted. To our delight, condensation of all phenols with
formaldehyde and methyl methacrylate under buffered condi-
tions gave the chroman esters 9 in substantially higher yields
than the reported one for the unsubstituted phenol (80-82% vs
30-32%).3 All attempts to perform the above reaction on
unprotected substrate (5b) gave significantly lower yields.
Finally, esters 9 were converted quantitatively to the desired
(()-4 alcohols upon simultaneous reduction of the ester group
and the benzoyl group.
Our synthesis commences with the acylation of 5 with
benzoyl chloride, which afforded a 1:4 mixture of di- and
monoprotected substrates. However, the dibenzoate byproducts
7 could be selectively hydrolyzed to monobenzoates 8 with use
of sodium perborate34 (the MeOH/MeONa protocol was less
selective). Thus, 8 was derived in 70-78% total yield based
on 5. It should be noted that all chemical manipulations in the
The resolution of racemic alcohols 4 was accomplished
following the reported protocol for 4a (R1 ) R2 ) Me) as
depicted in Scheme 3.7,35 In a single run the resolution proceeded
in 40-45% conversion and 70-87% ee. By repeating the same
protocol once more, alcohol 4(S) was obtained in high enan-
tiomeric excess (95.9-97.5% ee) and 38-40% conversion based
on racemic 4.
(34) Bandgar, B. P.; Uppalla, L. S.; Sadavarte, V. S.; Patil, S. V. New J.
Chem. 2002, 26, 1273-1276.
(35) Bovara, R.; Carrea, G.; Ferrara, L.; Riva, S. Tetrahedron: Asymmetry
1991, 2, 931-938.
J. Org. Chem, Vol. 72, No. 18, 2007 6737

Couladouros et al.
SCHEME 4. Completion of the Total Synthesis of Tocotrienols b, c, and d
TABLE 1. Comparison of the Optical Rotation between Reported
(ref 31) and Synthetic Tocotrienols
While the optical purity of the resolved alcohols was
confirmed by chiral column HPLC, the depicted absolute
configuration was initially assumed based on analogy to reported
data for the R-series7 and had to be confirmed upon completion
of the synthesis. In the event, the enzymatic resolution of 4b
had proceeded in the opposite sense to that of 4c and 4d, and
provided the heretofore unknown ent-â-tocotrienol. Thus it was
necessary to repeat the synthesis of â-tocotrienol by using the
opposite enantiomer of 4b in order to obtain the natural-series
final product (vide infra).
Having accomplished the synthesis of the chiral chroman-
methanols 4(S)b,c,d in enantiomerically pure form, the prepara-
tions of the appropriate key intermediates 2b,c,d and 1 were
easy tasks. Indeed, selective benzylation of the phenol followed
by sulfonylation of the primary hydroxyl group led to triflates
2b,c,d. Farnesyl sulfone 1 was produced from commercially
available farnesol via farnesyl bromide in high overall yield,11
as shown in Scheme 4:
literature
synthetic
â-tocotrienol
13b
-1.1, c 2.7, CHCl3 -0.9, c 0.16, CHCl3
+1.0, c 03.0, CHCl3
-5.2, c 1.0, CHCl3 -5.7, c 0.59, CHCl3
-2.2, c 1.0, CHCl3 -1.3, c 0.38, CHCl3
ent-â-tocotrienol ent-13b
γ-tocotrienol
δ-tocotrienol
13c
13d
dependent on the substitution of the aromatic ring. The final
results are summarized in Table 1. The synthetic tocotrienols
had NMR spectra identical with those of natural-source material
in all cases.
Experimental Section
General Procedure for the Preparation of 2,5-Dimethylhy-
droquinone Monobenzoate 8b, 2,3-Dimethylhydroquinone
Monobenzoate 8c, and 20-Methylhydroquinone-4-monobenzoate
8d. A solution of benzoyl chloride (14.5 mmol) in benzene (40
mL) was added dropwise to a solution of hydroquinone 5b, 5c, or
5d (14.5 mmol) in pyridine (10 mL) and benzene (20 mL) at 0 °C
for 1 h. The reaction mixture was washed with a saturated aqueous
solution of CuSO4 (4 × 20 mL). The aqueous layer was extracted
with EtOAc (3 × 30 mL) and the combined organic phases were
washed with brine (3 × 20 mL), dried over Na2SO4, and
concentrated under reduced pressure. The residue thus obtained was
purified by flash column chromatography (10% EtOAc in hexanes)
to yield the monoprotected hydroquinone 8b, 8c, or 8d, along with
the diesters 7b, 7c, or 7d, respectively.
Triflates 2b,c,d coupled smoothly with the anion of sulfone
1 to afford coupled intermediates 12b,c,d (Scheme 4). Extensive
experimentation on the deprotection of the phenol and the
removal of the sulfone group was carried out on 12b. We first
used a dissolving-metal reduction method employing Li/
naphthalene at -20 °C,36 whereupon an inseparable mixture of
â-tocotrienol together with double bond migration and/or cis-
trans isomerization byproducts was obtained. In contrast, the
Li/MeNH2 reducing system at -78 °C gave much more
promising results.37 Simultaneous desulfonylation and deben-
zylation occurred and â-, γ-, and δ-tocotrienols were obtained
as colorless liquids. In most runs isomerization was less than
2,5-Dimethylhydroquinone dibenzoate 7b: Rf 0.65 (30%
1
EtOAc in hexanes). H NMR (CDCl3, 250 MHz) δ 8.22 (4 H, d,
J ) 7.3 Hz), 7.67-7.62 (2 H, m), 7.55-7.49 (4 H, m), 7.06 (2 H,
br s), 2.21 (6 H, s). 13C NMR (CDCl3, 62.5 MHz) δ 184.9, 146.9,
133.6, 130.2, 129.4, 129.0, 128.6, 124.3, 16.0. IR (neat) ν 3036,
2926, 1738.
1
5-8%, observed by H NMR spectra.
The optical rotations of our synthetic tocotrienols were
compared to those of authentic samples or literature reports.
Surprisingly, all were comparable except 13b, indicating that,
only in this case, the enzymatic kinetic resolution gave opposite
results. To confirm this hypothesis, the enantiomeric alcohol
4b was transformed to the related tocotrienol, following the same
reaction sequence. The measured optical rotation was this time
in agreement with that of an authentic sample of â-tocotrienol
confirming that the enzymatic resolution of alcohols 4 was
2,3-Dimethylhydroquinone dibenzoate 7c: Rf 0.80 (30%
1
AcOEt in hexanes). H NMR (CDCl3, 250 MHz) δ 8.16 (3 H, d,
J ) 7.1 Hz), 8.07 (1H, d, J ) 7.1 Hz), 7.60-7.51 (2 H, m), 7.45-
7.38 (5 H, m), 6.99 (1 H, s), 2.09 (6 H, s). 13C NMR (CDCl3, 62.5
MHz) δ 184.5, 164.7, 147.0, 137.0, 134.3, 133.4, 130.5, 130.3,
130.0, 129.2, 128.7, 128.5, 128.2, 128.1, 12.7. IR (neat) ν 3048,
2925, 1743.
Methylhydroquinone dibenzoate7d: Rf 0.62 (30% EtOAc in
hexanes). 1H NMR (CDCl3, 500 MHz) δ 8.27 (4 H, m), 7.68 (2 H,
m), 7.56 (4 H, m), 7.02 (3 H, m), 2.31 (3 H, s). 13C NMR (CDCl3,
125 MHz) δ 165.0, 164.7, 148.4, 147.0, 133.6, 133.5, 131.7, 130.1,
129.5, 129.3, 128.6, 128.5, 124.0, 122.8, 120.0, 16.4. IR (neat) ν
3042, 2923, 1735.
(36) Liu, H. J.; Yip, J.; Shia, K. Tetrahedron Lett. 1997, 38, 2253-
2256.
(37) Truce, W. E.; Tate, D. P.; Burdge, D. N. J. Am. Chem. Soc. 1960,
82, 2872-2876.
6738 J. Org. Chem., Vol. 72, No. 18, 2007

Synthesis of â-, γ-, and δ-Tocotrienols
General Procedure for the Preparation of Monoprotected
Hydroquinones 8b, 8c, and 8d from Diprotected Hydroquinones
7b, 7c, and 7d. Compounds 7b, 7c, or 7d (6.4 mmol) and sodium
perborate tetrahydrate (13 mmol) were stirred in methanol (10 mL)
at 40 °C for 6 h. After completion of the reaction NaBO3 was
filtered off and washed with EtOAc (3 × 10 mL). The solvent was
removed under reduced pressure and the crude products were
purified by flash column chromatography (10% EtOAc in hexanes)
to yield compounds 8b, 8c, or 8d, respectively.
1600, 1476, 1451, 1267, 1228, 1110, 1067, 1026, 719. HRMS calcd
for C20H20O5 340.1311, found 340.1326.
General Procedure for the Preparation of 2,5,8-Trimethyl-
6-hydroxychroman-2-methanol 4b, 2,7,8-Trimethyl-6-hydroxy-
chroman-2-methanol 4c, and 2,8-Dimethyl-6-hydroxychroman-
2-methanol 4d. To a stirred solution of 9b, 9c, or 9d (10.7 mmol)
in Et2O (10 mL) was added LAH (21 mmol) at 0 °C. When the
reaction was completed, 1 N HCl was added dropwise and the
mixture was stirred for 15 min. The reaction mixture was poured
into water, neutralized with NaHCO3, and extracted with EtOAc
(3 × 30 mL). The combined organic layers were washed with brine
(3 × 20 mL), dried over Na2SO4, and concentrated under reduced
pressure. The residue thus obtained was purified by flash column
chromatography (20% EtOAc in hexanes) to yield 4b, 4c, or 4d,
respectively.
1
8b: Yield 70%. Rf 0.75 (30% EtOAc in hexanes). H NMR
(CDCl3, 250 MHz) δ 8.00 (2 H, m), 7.47-7.39 (1 H, m), 7.33-
7.26 (2 H, m), 6.63 (1 H, s), 6.33 (1 H, s), 5.28-5.00 (1 H, br s),
1.96 (3 H, s), 1.89 (3 H, s). 13C NMR (CDCl3, 62.5 MHz) δ 165.9,
151.7, 142.4, 133.6, 130.2, 129.4, 128.6, 128.2, 123.7, 122.7, 117.2,
109.6, 15.8, 15.4. IR (neat) ν 3437, 1716.
1
8c: Yield 73%. Rf 0.63 (30% EtOAc in hexanes). H NMR
1
4b: Yield 98%. Rf 0.58 (50% EtOAc in hexanes). H NMR
(CDCl3, 250 MHz) δ 8.20 (2 H, m), 7.64-7.58 (1 H, m), 7.52-
7.46 (2 H, m), 6.79 (1 H, d, J ) 8.7 Hz), 6.59 (1 H, d, J ) 8.7
Hz), 4.89 (1 H, br s), 2.1 (3 H, s), 2.08 (3 H, s). 13C NMR (CDCl3,
62.5 MHz) δ 171.1, 165.7, 151.4, 142.8, 133.8, 133.5, 130.2, 129.5,
129.2, 128.6, 128.6, 128.5, 124.2, 120.1, 119.4, 113.0, 13.1, 13.0,
12.1. IR (neat) ν 3441, 1710.
(CDCl3, 250 MHz) δ 6.46 (1 H, s), 4.56 (0.5 H, br s (OH)), 3.59
(2.5 H, ABq, J ) 11.4 Hz, ∆ν ) 15.9 Hz, also OH br s), 2.67-
2.60 (2 H, m), 2.07 (6 H, br s), 2.03-1.91 (1 H, m), 1.75-1.65 (1
H, m), 1.19 (3H, s). 13C NMR (CDCl3, 62.5 MHz) δ 146.2, 144.9,
123.7, 120.2, 115.4, 109.4, 74.8, 69.1, 27.6, 20.3, 20.2, 15.8, 10.9.
IR (neat) ν 3747, 3311, 2933, 1705, 1463, 1230. HRMS calcd for
C13H18O3 222.1256, found 222.1250.
1
8d: Yield 72%. Rf 0.50 (30% EtOAc in hexanes). H NMR
(CDCl3, 250 MHz) δ 8.21 (2 H, d, J ) 7.1 Hz), 7.64 (1 H, m),
7.51 (2 H, m), 6.98-6.81 (2 H, m), 6.69 (1 H, d, J ) 8.6 Hz), 5.48
(1 H, br s), 2.22 (3 H, s). 13C NMR (CDCl3, 62.5 MHz) δ 166.2,
151.8, 143.8, 133.6, 130.1, 128.6, 128.5, 125.4, 123.6, 119.6, 115.6,
15.9. IR (neat) ν 3445, 1712.
4c: Yield 99%. Rf 0.58 (50% EtOAc in hxanes). 1H NMR
(CDCl3, 250 MHz) δ 6.35 (1 H, s), 4.99 (1 H, br s), 3.60 (2 H,
ABq, J ) 11.3 Hz, ∆ν ) 16.4 Hz), 2.80-2.56 (2 H, m), 2.11 (3 H,
s), 2.06 (3H, s), 2.01-1.89 (1 H, m), 1.68-1.58 (1 H, m), 1.21
(3H, s). 13C NMR (CDCl3, 62.5 MHz) δ 146.9, 145.0, 128.2, 125.5,
121.8, 118.1, 112.3, 69.1, 29.5, 27.9, 21.9, 20.7, 12.0. IR (neat) ν
3745, 3290, 2930, 1715, 1453, 1210. HRMS calcd for C13H18O3
222.1256, found 222.1254.
General Procedure for the Preparation of Methyl 2,5,8-
Trimethyl-6-benzoyloxychroman-2-carboxylate 9b, Methyl 2,7,8-
Trimethyl-6-benzoyloxychroman-2-carboxylate 9c, and Methyl
2,8-Dimethyl-6-benzoyloxychroman-2-carboxylate 9d. Hydro-
quinone monobenzoyl ester 8b, 8c, or 8d (13.2 mmol) was added
to a mixture of methyl methacrylate (64.5 mmol) and paraforma-
dehyde (421 mg). The reaction mixture was stirred at 0 °C and
dibutylamine (1.6 mmol) and acetic acid (6.6 mmol) were added.
Then, the reaction mixture was refluxed for 23 h. The resulting
mixture was then poured into a saturated aqueous solution of
NaHCO3 and extracted with EtOAc (3 × 10 mL). The combined
organic phases were washed with water (10 mL) and brine (3 ×
10 mL), dried over Na2SO4, and concentrated under reduced
pressure. The residue thus obtained was purified by flash column
chromatography (10% EtOAc in hexanes) to yield 9b, 9c, or 9d,
respectively, as white amorphous solid.
1
4d: Yield 99%. Rf 0.48 (50% EtOAc in hexanes). H NMR
(CDCl3, 250 MHz) δ 6.49 (1 H, s), 6.41 (1 H, s), 3.62 (2 H, ABq,
J ) 11.4 Hz, ∆ν ) 16.1 Hz), 2.73 (2 H, m), 2.12 (3 H, s), 1.99 (1
H, m), 1.67 (1 H, m), 1.24 (3 H, s). 13C NMR (CDCl3, 62.5 MHz)
δ 148.2, 145.3, 127.3, 123.0, 115.8, 112.6, 76.1, 69.4, 27.7, 22.0,
20.7, 16.1. IR (neat) ν 3737, 3350, 2923, 1708, 1465, 1280. HRMS
calcd for C12H16O3 208.1099, found 208.1112.
Immobilization of Lipase PS-30. Lipase PS-30 (3 g) and
Hyflosupercell (10 g) were added to a buffered solution (10 mL)
of Na2HPO4 (117.12 mg) and KH2PO4 (81.66 mg) in distilled water
(30 mL, pH 7) and the mixture was shaken vigorously then dried
under high vacuum for 24 h.
General Procedure for the Resolution of the Racemic Chro-
mandiols 4b, 4c, and 4d (First Cycle). A mixture of compound
4a, 4b, or 4c (2 g), hyflosupercell-supported PS-30 lipase (1.3 g),
succinic anhydride (1.2 g), and tert-butyl methyl ether (33 mL)
was stirred at room temperature for 5 h, at which time TLC analysis
indicated formation of equal amounts of a polar product and
unreacted alcohol. The mixture was diluted with ethyl acetate and
acetone, filtered through a pad of Celite, and extracted 5 times with
5% aq sodium bicarbonate. After separation of the two phases, the
aqueous layer was carefully acidified with 1 N aq HCl and extracted
with ethyl acetate. The solution was dried and the solvent evaporated
to give crude succinate 10b, 10c, or 10d as white amorphous solids,
which were used without further purification (yields of crude acids
were 55-65%).
The acid 10b, 10c, or 10d (1.4 mmol) was dissolved in methanol
(8 mL) and THF (8 mL). An aqueous solution of 3 N LiOH (150
µL) was added at 0 °C and the mixture was stirred for 20 min.
When the reaction was completed, it was poured into a saturated
aqueous solution of ammonium chloride (10 mL) and then extracted
with EtOAc (3 × 10 mL). The combined organic phases were
washed with brine (3 × 10 mL), dried over Na2SO4, and
concentrated under reduced pressure. The residue thus obtained was
purified by flash column chromatography (30% EtOAc in hexanes)
to yield enriched diols 4(S)b, 4(S)c, or 4(S)d, respectively, as white
amorphous solids (yields 90-95%, ee 70-87% (hplc)).
1
9b: Yield 82%. Rf 0.55 (20% EtOAc in hexanes). H NMR
(CDCl3, 250 MHz) δ 8.11 (2 H, d, J ) 7.7 Hz), 7.59-7.48 (1 H,
m), 7.46-7.37 (2 H, m), 6.71 (1 H, s), 3.60 (3 H, s), 2.64-2.32 (2
H, m), 2.14 (3 H, s), 1.90 (3 H, s), 1.88-1.73 (2 H, m), 1.53 (3 H,
s). 13C NMR (CDCl3, 62.5 MHz) δ 174.1, 165.4, 149.6, 142.0,
133.4, 130.1, 129.7, 128.5, 125.6, 124.6, 121.5, 119.8, 77.2, 52.4,
30.1, 25.4, 20.9, 15.9, 11.9. IR (KBr) ν 2934, 1757, 1732, 1601,
1479, 1450, 1268, 1230, 1102, 1066, 1024, 713. HRMS calcd for
C21H22O5 354.1467; found 354.1439.
1
9c: Yield 80%. Rf 0.46 (20% EtOAc in hexanes). H NMR
(CDCl3, 250 MHz) δ 8.20-8.16 (2 H, m), 7.63-7.56 (1 H, m),
7.51-7.44 (2 H, m), 6.65 (1 H, s), 3.68 (3 H, s), 2.70-2.64 (2 H,
m), 2.41-2.32 (1 H, m), 2.20 (3 H, s), 2.07 (3H, s), 1.92-1.79 (1
H, s), 1.62 (3 H, s). 13C NMR (CDCl3, 62.5 MHz) δ 174.0, 165.5,
149.2, 142.4, 133.4, 130.1, 129.7, 128.5, 125.9, 118.9, 118.1, 78.0,
52.4, 30.2, 29.6, 28.4, 25.5, 12.8, 12.0. IR (KBr) ν 2927, 1740,
1476, 1450, 1233, 1188, 1102, 1027, 893, 712. HRMS calcd for
C21H22O5: 354.1467; found 354.1473.
1
9d: Yield 82%. Rf 0.61 (20% EtOAc in hexanes). H NMR
(CDCl3, 500 MHz) δ 8.19 (2 H, d, J ) 7.7 Hz), 7.64 (1 H, m),
7.51 (2 H, m), 6.85 (1 H, d, J ) 2.2 Hz), 6.74 (1 H, d, J ) 2.2
Hz), 3.73 (3 H, s), 2.73 (2 H, m), 2.42 (1 H, m), 2.28 (3 H, s), 1.91
(1 H, m), 1.66 (3 H, s). 13C NMR (CDCl3, 125 MHz) δ 174.1,
165.7, 149.5, 143.5, 133.4, 130.1, 128.5, 127.4, 121.6, 120.8, 119.1,
78.2, 52.5, 30.3, 25.5, 22.8, 16.1. IR (KBr) ν 2936, 1758, 1738,
J. Org. Chem, Vol. 72, No. 18, 2007 6739

Couladouros et al.
General Procedure for the Resolution of the Enriched
Chromandiols 4(S)b, 4(S)c, and 4(S)d (Second Cycle). The
enriched diols 4(S)b, 4(S)c, or 4(S)d were subjected to the same
protocol as before. The final yields after the two enzymic resolutions
are listed below (maximium theoretical yield ) 50%). All resolved
compounds had spectroscopic data identical with those of the
respective racemic diols.
Na2SO4, and concentrated under reduced pressure. The residue thus
obtained was purified by flash column chromatography (20%
EtOAc in hexanes) to yield 2b, 2c, or 2d, respectively, as white
amorphous solids.
2b: Yield 96%. Rf 0.66 (20% EtOAc in hexanes). [R]20D -0.23
(c 0.51 in CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.47-7.30 (5 H,
m), 6.68 (1 H, s), 4.99 (2 H, s), 4.47 (2.4 H, ABq, J ) 10.1 Hz, ∆ν
) 18.8 Hz), 2.70 (2.2 H, t, J ) 6.9 Hz), 2.15 (6.6 H, br s), 2.03-
1.96 (1 H, m), 1.89-1.83 (1 H, m), 1.37 (3 H, s). 13C NMR (125
MHz, CDCl3) δ 150.2, 144.8, 137.9, 128.4, 127.7, 127.3, 123.9,
122.9, 119.5, 117.4, 114.0, 79.6, 71.3, 29.7, 27.9, 21.1, 19.9, 16.0,
11.2. IR (KBr) ν 2936, 1482, 1413, 1245, 1235, 1210, 1151, 962.
HRMS calcd for C21H23F3O5S 444.1218, found 444.1249.
2c: Yield 95%. Rf 0.72 (30% EtOAc in hexanes). [R]20D +0.70
(c 0.52 in CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.46-7.25 (5 H,
m), 6.49 (1 H, s), 4.97 (2 H, s), 4.44 (2 H, ABq, J ) 10.2 Hz, ∆ν
) 15.4 Hz), 2.76 (2 H, ABq, J ) 8.4 Hz, ∆ν ) 15.6 Hz), 2.18 (3
H, s), 2.11 (3 H, s), 2.00-1.80 (1 H, m), 1.78-1.70 (1 H, m), 1.37
(3 H, s). 13C NMR (125 MHz, CDCl3) δ 150.6, 144.5, 137.8, 128.4,
127.7, 127.1, 126.4, 125.5, 121.1, 116.5, 116.1, 109.8, 109.5, 79.6,
73.4, 70.8, 46.5, 29.7, 27.8, 21.7, 21.3. 12.1, 11.8. IR (KBr) ν 3744,
2925, 1542, 1459, 1207, 945. HRMS calcd for C21H23F3O5S
444.1218, found 444.1239.
4(S)b: Yield 38%. [R]20D -2.44 (c 0.41 in CHCl3). HRMS calcd
for C13H18O3 222.1256, found 222.1257.
4(S)c: Yield 40%. [R]20D +6.3 (c 0.98 in CHCl3). HRMS calcd
for C13H18O3 222.1256, found 222.1264.
4(S)d: Yield 38%. [R]20 +3.8 (c 0.7 in CHCl3). HRMS calcd
D
for C12H16O3 208.1099, found 208.1103.
(It must be noted that the compound characterized above as 4-
(S)b was found, after completion of the tocotrienol synthesis, to
actually be the enantiomeric 4(R)b substance. Recovery of the
opposite enantiomer from the enzymatic kinetic resolution gave
the true (S) enantiomer, which afforded natural-series â-tocotrienol
upon completion of the synthesis.)
General Procedure for the Preparation of 2,5,8-Trimethyl-
6-benzyloxychroman-2-methanol 11b, 2,7,8-Trimethyl-6-ben-
zyloxychroman-2-methanol 11c, and 2,8-Dimethyl-6-benzylox-
ychroman-2-methanol 11d. To a stirred solution of compound
4(S)b, 4(S)c, or 4(S)d (1.8 mmol) in DMF (2 mL) were added
benzyl bromide (2.68 mmol) and K2CO3 (2.68 mmol) at room
temperature. When the reaction was completed (12 h), it was
neutralized with water and 1 N HCl. It was extracted EtOAc (3 ×
10 mL) and the combined organic phases were washed with brine
(3 × 10 mL), dried over Na2SO4, and concentrated under reduced
pressure. The residue thus obtained was purified by flash column
chromatography (10% EtOAc in hexanes) to yield 11b, 11c, or
11d, respectively.
2d: Yield 95%. Rf 0.50 (20% EtOAc in hexanes). [R]20D +1.96
(c 0.97 in CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.51-7.32 (5 H,
m), 6.72 (1 H, s), 6.57 (1 H, s), 5.01 (2 H, s), 4.49 (2 H, ABq, J )
10.2 Hz, ∆ν ) 18.8 Hz), 2.90-2.73 (2 H, m), 2.19 (3 H, br s),
2.04-1.96 (1 H, m), 1.88-1.81 (1 H, m), 1.41 (3 H, s). 13C NMR
(125 MHz, CDCl3) δ 152.2, 144.8, 137.4, 128.5, 127.8, 127.7,
127.4, 120.0, 116.3, 112.1, 79.5, 73.6, 70.5, 27.8, 21.8, 21.3, 16.0.
IR (KBr) ν 2929, 2852, 1604, 1484, 1414, 1250, 1216, 1146, 975,
950, 623. Compound 2d was unstable and repeatedly failed to give
correct elemental analysis or HRMS. However, compounds 12d
and 13d, prepared sequentially from 2d, gave satisfactory analytical
data.
11b: Yield 72%. Rf 0.38 (20% EtOAc in hexanes). [R]20D -0.87
(c 0.46 in CHCl3). 1H NMR (CDCl3, 500 MHz) δ 7.48-7.26 (4.3
H, m), 6.69 (1 H, s), 5.00 (2 H, s), 3.65 (2.4 H, ABq, J ) 11.1 Hz,
∆ν ) 19.5 Hz), 2.72-2.66 (2 H, m), 2.18 (6 H, br s), 2.07-2.00
(1 H, m), 1.79-1.76 (1 H, m), 1.26 (3 H, s). 13C NMR (CDCl3,
125 MHz) δ 149.7, 145.5, 137.9, 128.4, 127.6, 127.2, 123.3, 122.9,
120.5, 113.7, 75.1, 71.2, 69.3, 27.6, 20.4, 20.2, 16.2, 11.2. IR (KBr)
ν 3300, 2940, 1705, 1440, 1160. HRMS calcd for C20H24O3
312.1725, found 312.1720.
General Procedure for the Preparation of 2′-Phenylsulfonyl-
â-tocotrienyl Benzyl Ether 12b, 2-Phenylsulfonyl-γ-tocotrienyl
Benzyl Ether 12c, and 2-Phenylsulfonyl-δ-tocotrienyl Benzyl
Ether 12d. n-Butyllithium (1.6 M in hexanes, 1.2 mmol) was added
dropwise to a stirred solution of all-trans-farnesyl benzyl sulfone
111 (0.9 mmol) and HMPA (504 µL) in THF (3 mL) at -78 °C.
The orange-colored anion was stirred for 45 min at -78 °C. Then
a mixture of compound 2b, 2c, or 2d (1.1 mmol) in THF (350 µL)
was added and the mixture was slowly warmed to room temperature
over a period of 2 h. The reaction mixture was then poured into a
saturated solution of ammonium chloride (5 mL) and 1 N HCl (1
mL) was added. The mixture was then extracted with EtOAc (3 ×
10 mL) and the combined organic phases were washed with brine
(3 × 10 mL), dried over Na2SO4, and concentrated under reduced
pressure. The residue thus obtained was purified by flash column
chromatography (10% acetone in hexanes) to yield 12b, 12c, or
12d, respectively, as light yellow oil.
11c: Yield 71%. Rf 0.42 (30% EtOAc in hexanes). [R]20D +0.81
(c 0.37 in CHCl3). 1H NMR (CDCl3, 500 MHz) δ 7.56-7.27 (5 H,
m), 6.53 (1 H, s), 4.99 (2 H, s), 3.64 (2 H, ABq, J ) 11.2 Hz, ∆ν
) 25.2 Hz), 2.86-2.80 (1 H, m), 2.75-2.69 (1H, m), 2.21 (3 H,
s), 2.14 (3H. s), 2.04-1.89 (1 H, m), 1.72-1.67 (1 H, m), 1.26 (6
H, d, J ) 4.5 Hz). 13C NMR (CDCl3, 125 MHz) δ 164.3, 160.7,
150.3, 145.4, 137.9, 128.4, 127.6, 127.2, 126.9, 125.9, 125.1, 118.8,
117.5, 110.2, 109.5, 74.5, 70.9, 69.4, 68.3, 66.6, 29.7, 29.2, 29.0,
28.0, 27.8, 22.2, 20.7, 12.3, 12.0. IR (KBr) ν 3350, 2950, 1718,-
1260. HRMS calcd for C20H24O3 312.1725, found 312.1720.
11d: Yield 73%. Rf 0.54 (30% EtOAc in hexanes). [R]20D +2.5
(c 0.7 in CHCl3). 1H NMR (CDCl3, 250 MHz) δ 7.48-7.27 (5 H,
m), 6.67 (1 H, d, J ) 2.5 Hz), 6.55 (1 H, d, J ) 2.5 Hz), 4.98 (2
H, s), 3.62 (2 H, ABq, J ) 11.3 Hz, ∆ν ) 16.2 Hz), 2.92-2.64 (2
H, m), 2.15 (3 H, br s), 2.07-1.92 (1 H, m), 1.75-1.62 (1 H, m),
1.25 (3 H, s). 13C NMR (CDCl3, 62.5 MHz) δ 151.8, 145.6, 137.5,
128.5, 127.8, 127.4, 127.2, 121.0, 115.9, 112.2, 76.1, 70.5, 69.5,
27.7, 22.2, 20.7, 16.2. IR (KBr) ν 3320, 2935, 1708,1220. HRMS
calcd for C19H22O3 298.1569, found 298.1559.
General Procedure for the Preparation of 2,5,8-Trimethyl-
6-benzyloxychroman-2-methanol Triflate 2b, 2,7,8-Trimethyl-
6-benzyloxychroman-2-methanol Triflate 2c, and 2,8-Dimethyl-
6-benzyloxychroman-2-methanol Triflate 2d. To a stirred solution
of compound 11b, 11c, or 11d (1.3 mmol) in pyridine (2 mL) was
added Tf2O (1.3 mmol) at 0 °C and the mixture was stirred for 2
h. The reaction was quenched with 1 N HCl (2 mL) then extracted
with EtOAc (3 × 10 mL). The combined organic phases were
washed with water (10 mL) and brine (2 × 10 mL), dried over
12b: Yield 62%. Rf 0.48 (20% EtOAc in hexanes). [R]20D -28.30
1
(c 1.29 in CHCl3). H NMR (CDCl3, 500 MHz) δ 7.86 + 7.79 (2
H, d, J ) 7.7 Hz), 7.67-7.30 (8 H, m), 6.63 + 6.62 (1 H, s),
5.19-4.95 (5 H, m), 4.17 + 4.10 (1 H, t, J ) 10.2 Hz), 2.67-2.50
(2 H, m), 2.18-1.55 (30 H, m), 1.32-1.16 (3 H, m). 13C NMR
(CDCl3, 125 MHz) δ 149.5, 149.4, 145.5, 145.3, 144.6, 144.0,
137.9, 137.7, 137.6, 135.4, 135.3, 133.2, 133.0, 131.1, 129.3, 128.8,
128.5, 128.4, 128.3, 128.2, 127.5, 127.4, 127.1, 124.1, 123.4, 123.4,
123.2, 122.8, 122.7, 119.8, 119.7, 118.9, 118.8, 113.7, 113.6, 73.7,
73.4, 71.2, 71.1, 61.4, 61.0, 39.7, 39.6, 39.5, 37.2, 37.1, 32.1, 31.7,
26.5, 25.9, 25.8, 25.5, 24.0, 23.9, 20.5, 20.3, 17.5, 16.5, 16.4, 16.0,
15.8, 14.0, 11.1, 11.0. IR (neat) ν 3075, 2921, 2852, 1588, 1486,
1308, 1235, 1090, 1030, 842. HRMS calcd for C41H56NO4S [M +
NH4]+ 658.3930, found 658.3910.
12c: Yield 63%. Rf 0.44 (20% EtOAc in hexanes). [R]20D +27.87
1
(c 0.94 in CHCl3). H NMR (CDCl3, 500 MHz) δ 7.87 + 7.81 (2
H, d, J ) 7.5 Hz), 7.65-7.34 (8 H, m), 6.50 + 6.45 (1 H, s),
6740 J. Org. Chem., Vol. 72, No. 18, 2007

Synthesis of â-, γ-, and δ-Tocotrienols
5.20-4.99 (5 H, m), 4.19 + 4.11 (1 H, t, J ) 9.5 Hz), 2.74-2.58
(2 H, m), 2.20-1.62 (30 H, m), 1.32-1.17 (3 H, m). 13C NMR
(CDCl3, 125 MHz) δ150.1, 150.1, 145.0, 144.7, 144.1, 137.9, 137.7,
137.5, 135.5, 135.5, 133.3, 133.1, 131.3, 129.4, 128.9, 128.6, 128.5,
128.3, 128.2, 127.5, 127.5, 127.1, 125.8, 125.5, 124.8, 124.8, 124.1,
123.4, 123.4, 118.9, 118.8, 116.8, 116.8, 110.0, 110.0. IR (neat) ν
2972, 2923, 2857, 2362, 1484, 1447, 1426, 1382, 1302, 1230, 1145,
1100, 1085, 742, 691. HRMS calcd for C41H56NO4S [M + NH4]+
658.3930, found 658.3890.
5.17-5.00 (3 H, m), 4.15 (1 H, br s), 2.58 (2 H, t, J ) 6.7 Hz),
2.13-1.94 (18 H, m), 1.78 (2 H, m), 1.65 (3 H, s), 1.56 (9 H, br
s), 1.22 (3 H, s). 13C NMR (CDCl3, 145.9, 139.9, 135.0, 134.9,
131.2, 124.4, 124.4, 124.2, 123.4, 120.3, 119.2, 115.4, 74.2, 39.7,
39.6, 39.4, 31.5, 26. 8, 26.6, 25.7, 23.7, 22.2, 20.8, 17.7, 16.0, 15.9,
15.8, 10.9. IR (neat) ν 3370, 2945, 2935, 1616, 1450, 1233, 1110.
HRMS calcd for C28H42O2 410.3185, found 410.3196.
13c: Yield 73%. Rf 0.20 (10% acetone in hexanes). [R]20D -5.7
1
(c 0.59 in CHCl3). H NMR (CDCl3, 500 MHz) δ 7.38 (1 H, s),
12d: Yield 60%. Rf 0.40 (20% EtOAc in hexanes). [R]20D +20.70
6.39 (1H, s), 5.17-5.11 (3 H, m), 4.34 (1 H, s), 2.69 (2 H, t, J )
6.3 Hz), 2.19-1.97 (18 H, m), 1.83-1.72 (2 H, m), 1.70 (3 H, s),
1.62 (3 H, s), 1.61 (3H, s), 1.28 (3 H, s). 13C NMR (CDCl3), 146.2,
145.6, 145.5, 139.9, 131.2, 128.3, 125.7, 124.4, 124.3, 124.1, 121.6,
118.2, 112.7, 75.2, 39.8, 39.6, 31.4, 26.7. 26.6, 25.6, 24.3, 24.0,
22.2, 22.2, 17.6, 15.9, 15.8.11.8. IR (neat) ν 2966, 2972, 2854,
1446, 1374, 1227, 1087, 937, 849, 743. HRMS calcd for C28H42O2
410.3185, found 410.3207.
1
(c 0.99 in CHCl3). H NMR (CDCl3, 500 MHz) δ 7.87 + 7.82 (2
H, d, J ) 7.2 Hz), 7.67-7.31 (8 H, m), 6.70-6.48 (2 H, m), 5.21-
4.96 (5 H, m), 4.18 + 4.09 (1 H, t, J ) 10.1 Hz), 2.78-2.54 (2 H,
m), 2.19-1.57 (27 H, m), 1.32-1.14 (3 H, m). 13C NMR (CDCl3,
62.5 MHz) δ 151.7, 151.6, 144.7, 144.1, 137.7, 137.6, 137.5, 135.6,
135.5, 133.3, 133.2, 131.3, 129.4, 129.0, 128.6, 128.6, 128.4, 128.3,
127.7, 127.4, 127.1, 126.8, 124.2, 123.4, 123.4, 120.3, 118.9, 118.9,
115.9, 115.8, 112.1, 112.0, 74.7, 74.5, 73.1, 70.4, 61.5, 61.0, 50.1,
39.8, 39.7, 39.6, 37.5, 37.2, 32.1, 31.7, 29.6, 28.0, 26.6, 26.0, 25.9,
25.6, 25.3, 24.2, 24.1, 22.4, 22.2, 21.9, 21.8, 21.3, 17.6, 16.5, 16.4,
16.2, 15.9, 13.4. IR (neat) ν 2972, 2921, 2853, 1603, 1480, 1450,
1304, 1224, 1147, 1086, 1058, 741, 696, 596. HRMS calcd for
C40H54NO4S [M + NH4]+ 644.3774, found 644.3710.
13d: Yield 75%. Rf 0.12 (10% acetone in hexanes). [R]20D -1.32
1
(c 0.38 in CHCl3). H NMR (CDCl3, 500 MHz) δ 6.49 (1 H, d, J
) 2.1 Hz), 6.40 (1 H, d, J ) 2.1 Hz), 5.19-5.07 (3 H, m), 4.20 (1
H, br s), 2.71 (2 H, m), 2.15 (3 H, s), 2.11-1.95 (15 H, m), 1.86-
1.72 (2 H, m), 1.70 (3 H, s), 1.62 (9 H, br s), 1.28 (3 H, s). IR
(neat) ν 3389, 2965, 2932, 2856, 1606, 1473, 1378, 1259, 1221,
1098, 798. HRMS calcd for C27H40O2 396.3028, found 396.3042.
General Procedure for the Preparation of â-Tocotrienol 13b,
γ-Tocotrienol 13c, and δ-Tocotrienol 13d. Li (1.15 mmol) was
added to a stirred solution of the sulfone 12b, 12c, or 12d (0.28
mmol) in Et2O (1.5 mL) and liquid MeNH2 (1.5 mL) at -78 °C.
The mixture was colored deep blue and changed to red as the
reaction proceeded. After being stirred at -78 °C for 45 min, the
reaction was quenched by the dropwise addition of MeOH until
the color disappeared. The reaction mixture was allowed to warm
at ambient temperature and stirred overnight to evaporate the amine.
Then it was poured into a saturated solution of ammonium chloride
(10 mL) and extracted with EtOAc (3 × 15 mL). The combined
organic phases were washed with brine (2 × 10 mL), dried over
Na2SO4, and concentrated under reduced pressure. The residue thus
obtained was purified by flash column chromatography (10%
acetone in hexanes) to yield 13b, 13c, or 13d, respectively, as
colorless oils.
Acknowledgment. This work was supported in part by a
joint Greek-Cypriot research and technology program co-funded
by the Greek Secretariat for Research and Technology of the
Greek Ministry of Development and the European Community.
We would also like to thank Eastman Chemical Co. for
analytical assistance.
Supporting Information Available: General experimental
methods, HPLC traces for resolution of 4b, and 1H and 13C NMR
spectra of compounds 2, 4, 7, 8, 9, 11, 12, and 13 for b, c, and d
series. This material is available free of charge via the Internet at
http://pubs.acs.org.
13b: Yield 72%. Rf 0.20 (10% acetone in hexanes). [R]20D -0.90
1
(c 0.16 in CHCl3). H NMR (CDCl3, 500 MHz) δ 6.45 (1 H, s),
JO0705418
J. Org. Chem, Vol. 72, No. 18, 2007 6741