Biomimetic chromanol cyclisation: A common route to a-tocotrienol and α-tocopherol

Article abstract of DOI:10.1002/ejoc.200900019

A common synthetic route to a-tocotrienol and a-tocopherol has been accomplished by a biomimetic cyclisation that yields the chromanol ring. The chirality at C2 of the chro- manol was induced by a covalently attached chiral dipeptide. Its terminal Asp participates in the enantioface-selective pro-tonation of the double bond of the a-tocotrienol precursor. a-Tocotrienol was diastereoselectively hydrogenated to a-tocopherol.

Full text of DOI:10.1002/ejoc.200900019

FULL PAPER
DOI: 10.1002/ejoc.200900019
Biomimetic Chromanol Cyclisation: A Common Route to α-Tocotrienol and
α-Tocopherol
Julien Chapelat,[a] Antoinette Chougnet,[a] and Wolf-D. Woggon*[a]
Keywords: Biomimetic synthesis / Chromanols / Vitamins / Cyclization / Peptides
A common synthetic route to α-tocotrienol and α-tocopherol
has been accomplished by a biomimetic cyclisation that
yields the chromanol ring. The chirality at C2 of the chro-
manol was induced by a covalently attached chiral dipeptide.
tonation of the double bond of the α-tocotrienol precursor.
α-Tocotrienol was diastereoselectively hydrogenated to
α-tocopherol.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Its terminal Asp participates in the enantioface-selective pro- Germany, 2009)
In view of the weak acidity of the amino acids in the
Introduction
active site of the protein it was suggested[4] that substrates
such as 9 bind to the enzyme in a high-energy conformation
(Scheme 1), in which both the phenol and proton source
are within binding distance of the double bond.
Vitamin E comprises naturally occurring tocopherols 1–
4 and tocotrienols 5–8 (Figure 1). The discovery of the en-
zyme tocopherol cyclase from Cyanobacteria[1] and investi-
gations of its substrate specificity[2] and reaction mecha-
nism[3] revealed that (i) the enzyme enables cyclisation of
hydroquinone precursors with a phytyl side-chain (see 9)
and unsaturated side-chains to give 2 and 6, respectively,
with the same efficiency and (ii) the 42 kD protein operates
by Si protonation of the double bond and concomitant Re
attack of the phenol (Scheme 1).
This insight led to a biomimetic synthesis of α-toco-
pherol (1) by using a large protecting group R and a dipep-
tide as steric constraints to generate a suitable conformation
of the hydroquinone and to provide a proton source[4] (10;
Scheme 2). We wish to report herein a similar approach to
diastereomerically enriched α-tocotrienol (5) and α-toco-
pherol (1) in a convergent fashion.
Results and Discussion
The synthesis of the precursor
D-11 was designed by
analogy to the preparation of 10[4] (Scheme 3). The chiral
unit could be attached to the aromatic ring of 13 by a Man-
nich coupling reaction with the proline derivative 12 and
was further derivatised by using a classical peptide synthe-
sis.
Finally, 13 could be obtained by aromatic substitution of
the bis(protected) hydroquinone 14 with (all-E)-geranylger-
anyl bromide (15) generated from 2,3-dimethylhydro-
quinone (16) and geranylgeraniol (17), respectively.
Synthesis of Precursor
The synthesis of
D
-11
D
-11 started from the commercially
available 2,3-dimethylhydroquinone (16), which was pro-
tected stepwise as the tetrahydropyranyl (THP) and triiso-
propylsilyl (TIPS) ethers to afford 14 in 42% overall yield
(Scheme 4). By analogy to the synthesis reported by Klinge
and Demuth,[5] (all-E)-farnesylacetone was converted into
its unsaturated ester homologue by a Horner–Wadsworth–
Emmons reaction and subsequently reduced by using
Figure 1. Structures of vitamin E compounds.
[a] Department of Chemistry, University of Basel,
St. Johanns-Ring 19, 4056 Basel, Switzerland
Fax: +41-61-267-1113
E-mail: wolf-d.woggon@unibas.ch
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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J. Chapelat, A. Chougnet, W.-D. Woggon
FULL PAPER
Scheme 1. Reaction mechanism of tocopherol cyclase.
Scheme 2. Biomimetic approach to α-tocopherol (1).
by the coordination of the lithium cation to the THP oxy-
gen atom. Owing to the difficulties involved in separating
19 and 14 the crude product 19 was treated with TBAF in
THF to afford 13 in 71% from 14.
Scheme 4. Synthesis of 20.
From our previous work[4] with the phytylhydroquinone
derivative 10, it is known that cyclisation to the chromanol
yields the (R) chirality at C2 only if the -Pro–-Asp pep-
tide is employed as a chiral auxiliary. Consequently, the
same strategy was used in this case and Mannich coupling
of 13 with N-methylene--proline was pursued. The re-
Scheme 3. Retrosynthetic approach to compound D-11.
DIBAL-H to furnish (all-E)-geranylgeraniol (17). The cor- sulting prolinylphenol 20 was treated with trimethylsilyldi-
responding bromide 15 was directly coupled with the bis- azomethane to yield the ester 21 to prevent intramolecular
(protected) hydroquinone 14 to afford 19. The regioselectiv- side-reactions during the following step (Scheme 5). Treat-
ity of the substitution adjacent to the THP group is directed ment of 21 with (–)-camphanoyl chloride furnished the es-
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Biomimetic Chromanol Cyclisation
Scheme 5. Synthesis of precursor D-11 and its biomimetic cyclisation.
ter 22 carrying a bulky substituent R (see 10) adjacent to THF (20:1) did not afford the desired product in sufficient
the chiral auxiliary, which is required to force the final di- quantity. The von Braun reaction[8] seemed to be a promis-
peptide into a conformation that is close to the C8 double ing method and has been reported to be unreactive towards
bond. Note that the chirality of the camphanoyl group is olefins. However, the original reaction conditions using cy-
not significant to the diastereoselectivity of the cyclisation; anogen bromide failed; 25 was recovered unchanged. Fi-
however, this group facilitates the separation of diastereo- nally, the use of chloroformate[9] gave satisfactory results,
isomers in consecutive steps.
and treatment of 25 with an excess of 2,2,2-trichlorethyl
Hydrolysis of the prolinyl methyl ester proved to be diffi- chloroformate afforded the corresponding benzyl chloride
cult but was finally accomplished by using LiI under a con- 26 in 80% yield (Scheme 6). In contrast, reactions with ben-
stant flow of N2 to eliminate the MeI formed, driving the zyl and allyl chloroformates were sluggish.
reaction to completion. It was observed that the THP group
was partially cleaved under these conditions; its hydrolysis
was completed to afford 23 in 83% from 22. Coupling of
23 with the TFA salt of Fm-protected -aspartate yielded
24, which was finally deprotected to give the geranylgeran-
ylphenol D-11 ready for cyclisation (Scheme 5).
Cyclisation of
D-11
Treatment of
D-11 with 2 equiv. of pTsOH·H2O at 25 °C
for 48 h led to the desired chromanol ring as the major
product together with unreacted starting material. Proton-
ation of the side-chain double bonds must be a minor path-
way as we could not isolate any tricyclic product arising
from a cascade cyclisation, as described by Yamamoto and
co-workers.[6] To facilitate isolation and purification, diester
25 was prepared directly from the crude mixture by using
trimethylsilyldiazomethane. The selectivity of the cycli-
sation was determined at a later stage, as the separation of
the C2 diastereoisomers was not possible for 25.
Scheme 6. Cleavage of the chiral auxiliary – synthesis of α-tocotri-
enol (5).
Treatment of 26 with LiAlH4 led to the simultaneous re-
duction of the benzyl chloride and the (–)-camphanate es-
ter, yielding (2R)-α-tocotrienol (5) in 92% yield and 65%
ee.[10] This value corresponds to the diastereoisomeric ex-
cess observed in the reaction depicted in Scheme 2.[4]
Removal of Chiral Auxiliary – Synthesis of α-Tocotrienol
(5)
Asymmetric Hydrogenation – Synthesis of α-Tocopherol (1)
The synthesis of α-tocotrienol (5) requires the removal of
Recently, Pfaltz and co-workers reported the use of the
the chiral auxiliary. Reductive hydrogenation of the ben- chiral iridium catalyst 28 for the asymmetric hydrogenation
zylamine unit is not compatible with substrate 25 due to of isolated olefins.[11] A remarkable example of this investi-
the presence of double bonds in the side-chain. Several al- gation was the hydrogenation of (2R)-γ-tocotrienyl acetate
ternatives were envisaged, such as the Birch reduction,[7] but (27), which afforded (2R,4ЈR,8ЈR)-γ-tocopheryl acetate (29)
treatment of 25 with a mixture of Li (1% Na) in EtNH2/ in more than 98% de (Scheme 7).
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J. Chapelat, A. Chougnet, W.-D. Woggon
FULL PAPER
(S,R,R)-α-tocopherol (1) in an (R)/(S) ratio of up to Ͼ99:1
at C4Ј and C8Ј. These results confirm the influence of the
peptide configuration on the cyclisation and demonstrate
the high selectivity of the iridium catalyst 28, which is inde-
pendent of the configuration at C2[11] and tolerates an ad-
ditional methyl group on the aromatic ring.
Conclusions
The diastereofacial protonation of the isolated double
bond of a geranylgeranylhydroquinone derivative has been
accomplished with a proline–aspartate dipeptide attached
to the aromatic ring. Addition of the phenol to the proton-
ated double bond furnished the chromanol system of α-toc-
otrienol. A chiral iridium complex was then used to catalyse
the hydrogenation of the double bonds of α-tocotrienol to
give α-tocopherol with excellent diastereoselectivity. This
procedure allows for the biomimetic synthesis of two im-
portant members of the vitamin E family by a common
route.
Scheme 7. Asymmetric hydrogenation of γ-tocotrienyl acetate
(27).[11]
Iridium catalyst 28 was therefore employed in the cata-
lytic hydrogenation of enantiomerically enriched α-tocotri-
enyl acetate (30), derived from 5 (Scheme 8). Hydrogenation
proceeded smoothly to afford α-tocopheryl acetate (31),
which was subsequently reduced to α-tocopherol (1).
Experimental Section
The ratio of the eight possible stereoisomers was deter- General Remarks: Unless stated otherwise, reactions were per-
formed in flame-dried glassware under a positive pressure of argon.
Chemicals and solvents were purchased from commercial suppliers
and purified by standard techniques whenever necessary. For thin-
mined by a combination of HPLC analysis of 1 and GC
analysis of α-tocopheryl methyl ether (32) developed by
Walther and Netscher.[12] An excellent (R)/(S) ratio of up
to Ͼ99:1 at C4Ј and C8Ј in favour of the (R) configuration
was observed.
The synthetic route depicted in Scheme 5 was also pur-
sued with -Pro–-Asp as the chiral auxiliary. Precursor L-
layer chromatography (TLC), silica gel plates (Merck AG 60F254
)
were used and compounds were visualised by irradiation with UV
light and/or by treatment with a solution of phosphomolybdic acid,
cerium(IV) sulfate and concd. H2SO4 in water (2:4:40:160, wt/wt)
followed by heating. Flash chromatography was performed by
using Merck silica gel 60 (particle size 0.040–0.063 mm). 1H and
13C NMR spectra were recorded with a Bruker DPX NMR (400
11 was obtained in similar yields, and its cyclisation gave
predominantly the (2S)-configured α-tocotrienol (5; 73%
ee). Subsequent acetylation and hydrogenation afforded and 500 MHz) spectrometer at 25 °C. Chemical shifts δ are given
Scheme 8. Asymmetric hydrogenation of α-tocotrienyl acetate (30).
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Biomimetic Chromanol Cyclisation
in ppm relative to tetramethylsilane (TMS), and the coupling con-
stants J are given in Hz. The spectra were recorded in CDCl3 as
solvent (δ = 7.26 ppm for 1H, δ = 77.2 ppm for 13C). HPLC was
carried out by using an LC-20AB pump, an SPD-M20A detector
and an SIL-20A autosampler (Shimadzu) with Chiracel OD-H
column. Microanalyses were performed with a Perkin-Elmer 240
Analyser. IR spectra recorded with a Shimadzu FTIR-8400S
spectrometer.
123.3, 124.5, 124.8, 131.7, 135.4, 136.6, 160.2, 167.3 ppm. GC [Op-
tima-5 PhMe Si column, 25 mϫ0.2 mm, 0.35 µm; split injector
(1:20), injector temp. 250 °C; FID detector, detector temp. 270 °C,
carrier gas: H2, 20 psi; 100–270 °C (6 °C/min), 39 min]: t(Z,E,E,E)
=
26.6 min, t(E,E,E,E) = 27.4 min, (E)/(Z) Ͼ 99:1. DIBAL-H (0.7–1.3 
in hexane, 10.0 mL) was added dropwise to a solution of the (all-
E)-geranylgeranoyl ethyl ester (1.67 g, 5.25 mmol) in Et2O (20 mL)
at 0 °C and the reaction mixture was further stirred at 25 °C for
2 h. The reaction was quenched by the addition of H2O at 0 °C,
the mixture extracted with EtOAc, and the organic phase was
washed with H2O, dried with Na2SO4, and the solvents were evapo-
rated to dryness. The residue was passed through a pad of SiO2
(EtOAc) to afford (all-E)-geranylgeraniol (17; 1.1 g, 72%) as a
slightly yellow oil. The spectral data were identical to those pre-
viously reported.[13] Selected data: 1H NMR (400 MHz, CDCl3,
25 °C): δ = 1.60 (s, 9 H, CH3C=C), 1.68 (s, 6 H, CH3C=C), 1.90–
2.15 (m, 12 H, CH2), 4.15 (t, J = 6.1 Hz, 2 H, CH2OH), 5.03–5.15
(m, 3 H, CH=C), 5.42 (m, 1 H, C=CHCH2OH) ppm.
Mono-THPO-hydroquinone 18:[4] 2,3-Dihydropyran (16.7 mL,
183.1 mmol) was added to a solution of 2,3-dimethylhydroquinone
(16; 23.0 g, 166.5 mmol) in THF (150 mL) at –5 °C, followed by p-
tosylOH·H2O (285.2 mg, 1.50 mmol), and the mixture was stirred
at 25 °C for 5 h. The reaction was quenched with saturated
NaHCO3 and the mixture extracted with TBME (3ϫ). The com-
bined organic phases were washed with H2O and then brine (2ϫ),
dried with Na2SO4, concentrated to dryness, and the residue was
purified by column chromatography on SiO2 (hexane/EtOAc,
83:17) to afford 18 (18.6 g, 50%) as a light-orange solid. M.p. 92–
94 °C. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.60–1.70 (m, 3 H,
CH2-THP), 1.85–1.95 (m, 2 H, CH2-THP), 1.95–2.05 (m, 1 H,
CH2-THP), 2.17 (s, 3 H, 2/3-CH3), 2.20 (s, 3 H, 2/3-CH3), 3.62–
3.65 (m, 1 H, CH2-THP), 3.90–3.98 (m, 1 H, CH2-THP), 4.42 (s,
1 H, OH), 5.24 (t, J = 3.3 Hz, 1 H, CH-THP), 6.56 (d, J = 8.7 Hz,
1 H, HAr), 6.84 (d, J = 8.7 Hz, 1 H, HAr) ppm.
Monoprotected Hydroquinone 13: TMEDA (1.7 mL, 11.4 mmol)
and 14 (4.3 g, 11.4 mmol) in Et2O (10 mL) were added to a solution
of nBuLi (1.6  in hexane, 7.4 mL, 11.8 mmol) in Et2O (40 mL) at
0 °C. The mixture was stirred at 0 °C for 3 h and then cooled to
–20 °C. CuBr (530 mg, 3.6 mmol) was added followed by geranyl-
geranyl bromide (15;[14] 3.2 g, 9.11 mmol) in Et2O (10 mL), and the
mixture was stirred at 25 °C for 6 h. The reaction was quenched
with saturated NaHCO3 and the mixture extracted with TBME
(3ϫ). The combined organic phases were dried with Na2SO4, con-
centrated to dryness, and the residue was purified by column
chromatography on SiO2 (hexane/CH2Cl2, 75:25) to afford a mix-
ture of 19 and 14 (5.33 g). TBAF (1  in THF, 10.5 mL, 10.5 mmol)
was added to the mixture of 19 and 14 (5.33 g) in THF (70 mL),
and the mixture was stirred at 25 °C for 1 h. The reaction was
quenched with saturated NaHCO3 and the mixture extracted with
TBME (3ϫ). The combined organic phases were dried with
Na2SO4, concentrated to dryness, and the residue was purified by
column chromatography on SiO2 (CH2Cl2) to afford 13 (3.20 g,
THPO-TIPSO-hydroquinone 14:[4] NaH (60% on mineral oil,
517.0 mg, 13.0 mmol) was added to a solution of 18 (2.63 g,
11.8 mmol) in THF (150 mL) at 0 °C, and the mixture was stirred
for 10 min. Triisopropylsilyl chloride (3.0 mL, 14.2 mmol) was
added dropwise at 0 °C and the mixture further stirred at 25 °C for
3 h. The reaction was quenched with saturated NaHCO3 and the
mixture extracted with TBME (3ϫ). The combined organic phases
were dried with Na2SO4, concentrated to dryness, and the residue
was purified by column chromatography on SiO2 (hexane/EtOAc,
97:3) to afford 14 (3.77 g, 84%) as a white solid. M.p. 34–35 °C.
1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.10 (d, J = 6.5 Hz, 18
H, CH3-TIPS), 1.21–1.33 (m, 3 H, CH-TIPS), 1.60–1.70 (m, 3 H,
CH2-THP), 1.84–1.95 (m, 2 H, CH2-THP), 1.95–2.05 (m, 1 H,
CH2-THP), 2.17 (s, 3 H, 2/3-CH3), 2.18 (s, 3 H, 2/3-CH3), 3.57–
3.62 (m, 1 H, CH2-THP), 3.91–4.00 (m, 1 H, CH2-THP), 5.23 (t,
J = 3.3 Hz, 1 H, CH-THP), 6.57 (d, J = 8.8 Hz, 1 H, HAr), 6.79 (d,
J = 8.8 Hz, 1 H, HAr) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ
= 13.0, 13.4, 18.5, 19.6, 25.8, 31.2, 62.6, 97.9, 115.0, 115.4, 127.8,
128.3, 149.1, 149.5 ppm. C22H38O3Si (378.62): calcd. C 69.79, H
1
71% over two steps) as a slightly yellow oil. H NMR (400 MHz,
CDCl3, 25 °C): δ = 1.48–1.63 (m, 12 H, 3Ј/4Ј-H, 9/13/17-CH3),
1.66–1.70 (dd, J = 5.7, 1.0 Hz, 6 H, 21-CH3), 1.77–1.87 (m, 1 H,
5Ј-H), 1.90–2.02 (m, 6 H, 14/18/3Ј/4Ј-H), 2.02–2.16 (m, 6 H, 10/11/
15/19-H), 2.12 (s, 3 H, 2-CH3), 2.21 (s, 3 H, 3-CH3), 3.36 (d, J =
7.3 Hz, 2 H, 7-H), 3.40–3.47 (m, 1 H, 2Ј-H), 4.00–4.19 (m, 1 H, 2Ј-
H), 4.49 (s, 1 H, OH), 4.61–4.69 (m, 1 H, 1Ј-H), 5.05–5.17 (m, 3
H, 12/16/20-H), 5.29 (t, J = 6.9 Hz, 1 H, 8-H), 6.44 (s, 1 H, 6-H)
ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 11.9, 12.2, 14.0,
15.9, 16.0, 16.1, 17.6, 21.1, 25.1, 25.6, 26.5, 26.7, 28.4, 31.2, 39.6,
39.7, 65.1, 103.7, 112.9, 120.8, 122.8, 124.1, 124.3, 131.2, 132.7,
134.9, 136.1, 147.8, 149.6 ppm. MS (ESI, MeOH): m/z = 571.4 [M +
10.12; found C 70.00, H 10.12. IR (KBr): νmax = 2942, 2866, 1540,
˜
1477, 1384, 1247, 1091, 1038, 923, 883 cm–1. UV (CH2Cl2): λmax
=
238, 286 nm.
(all-E)-Geranylgeraniol (17): Triethyl phosphonoacetate (2 mL,
10.0 mmol) was slowly added to a suspension of NaH (60% in
mineral oil, 430 mg, 10.8 mmol) in THF (25 mL) and the mixture
was stirred at 25 °C for 1 h. Farnesylacetone (1.86 g, 7.1 mmol) in
THF (3 mL) was then added and the mixture further stirred for
16 h. The reaction was quenched with cold saturated brine, the mix-
ture extracted with EtOAc, and the organic phase was washed with
H2O, dried with Na2SO4, and the solvents were evaporated to dry-
ness. The residue was purified by column chromatography on SiO2
(hexane/Et2O, 95:5) to afford (all-E)-geranylgeranoyl ethyl ester
(1.48 g, 66%) as a colourless oil. 1H NMR (400 MHz, CDCl3,
25 °C): δ = 1.27 (t, J = 7.1 Hz, 3 H, Et), 1.60 (s, 9 H, CH3C=C),
Na]+. IR (neat): ν
= 3401, 2922, 2852, 1442, 1379, 1200, 1074,
˜
max
1034, 954, 910, 833, 651 cm–1. UV (MeOH): λmax = 209, 285 nm.
D-ProOH Derivative 20: A solution of -proline (4.6 g, 39.9 mmol)
in formaldehyde (35% aq., 3.3 mL, 41.9 mmol) was stirred at 40 °C
under a flow of N2 for 15 min. The viscous white solid was dis-
solved in MeOH (15 mL), and 13 (959.7 mg, 1.94 mmol) was added
in MeOH (7 mL). The mixture was stirred at 40 °C for 17 h and
then cooled to 25 °C. The reaction was quenched with saturated
NaHCO3 and the mixture extracted with CH2Cl2 (3ϫ). The com-
bined organic phases were dried with Na2SO4, concentrated to dry-
ness, and the residue was purified by column chromatography on
1.68 (s, 3 H, CH3C=C), 1.90–2.20 (m, 15 H, CH3C=C, CH2), 4.14 SiO2 (CH2Cl2/MeOH, 90:10) to afford 20 (989 mg, 82%) as a pink
1
(q, J = 7.2 Hz, 2 H, Et), 5.02–5.12 (m, 3 H, CH=C), 5.66 (s, 3 H,
oil. H NMR (400 MHz, CDCl3, 25 °C): δ = 1.45–1.63 (m, 12 H,
3Ј/4Ј-H, 9/13/17/21-CH3), 1.67 (s, 3 H, 9/13/17/21-CH3), 1.71–1.84
C=CHCOOEt) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
14.7, 16.4, 18.1, 19.2, 26.1, 26.4, 27.0, 27.2, 40.1, 41.4, 59.8, 116.0, (m, 1 H, 5Ј-H), 1.75 (s, 3 H, 9/13/17/21-CH3), 1.84–2.00 (m, 8 H,
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14/18/3Ј/4Ј/4ЈЈ-H), 2.00–2.10 (m, 6 H, 10/11/15/19-H), 2.11–2.31
(m, 7 H, 2/3-CH3, 3ЈЈ-H), 2.30–2.44 (m, 1 H, 3ЈЈ-H), 2.73–2.82 (m,
1 H, 5ЈЈ-H), 3.25–3.52 (m, 3.5 H, 7/2Ј/5ЈЈ-H), 3.52–3.57 (m, 0.5 H,
7-H), 3.72–3.80 (m, 1 H, 6ЈЈ-H), 3.83–4.03 (m, 2 H, 2Ј/1ЈЈ-H), 4.35–
4.42 (m, 1 H, 1ЈЈ-H), 4.55–4.62 (m, 1 H, 1Ј-H), 5.00–5.16 (m, 4 H,
8/12/16/20-H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 12.9,
14.4, 14.5, 15.9, 16.0, 16.5, 17.6, 21.2, 23.5, 25.0, 25.6, 26.5, 26.7,
31.2, 39.6, 65.2, 65.4, 103.9, 123.7, 123.8, 124.0, 124.3, 131.2, 134.9,
1232, 1166, 1063, 1033, 632, 534 cm–1. UV (MeOH): λmax = 208,
270 nm.
(–)-CamphanoylO-/HO-D-ProOH Derivative 23: LiI (3.3 g,
24.6 mmol) was added to a solution of 22 (733.0 mg, 0.90 mmol)
in EtOAc (7 mL). The solution was stirred at 60 °C under a flow
of N2 (addition of EtOAc, ca. 3 mL/h) for 8 h, and then the reac-
tion was quenched with saturated NaHCO3 and the mixture ex-
tracted with CH2Cl2 (3ϫ). The combined organic phases were
dried with Na2SO4, concentrated to dryness, and the residue was
filtered through a pad of SiO2 (CH2Cl2/MeOH, 99:1) to afford a
crude oil (574.8 mg), which was used directly without further puri-
fication. The crude material was dissolved in THF (60 mL), and 1
 HClaq. (30 mL) was added. The mixture was stirred for 1 h at
25 °C. The reaction was quenched with saturated NaHCO3 and the
mixture extracted with CH2Cl2 (3ϫ). The combined organic phases
were dried with Na2SO4, concentrated to dryness, and the residue
was purified by column chromatography on SiO2 (CH2Cl2/MeOH,
99:1) to afford 23 (531.4 mg, 83% over two steps) as a slightly yel-
135.0, 135.3, 147.4 ppm. MS (ESI, MeOH): m/z
[M + H]+, 644.5 [M + Na]+. C39H59NO5 (621.90): calcd. C 75.32,
H 9.56, N 2.25; found C 74.84, H 9.29, N 2.18. IR (neat): ν
= 622.8
=
˜
max
2920, 2851, 1619, 1450, 1377, 1251, 1202, 1074, 1033, 907, 645,
587 cm–1. UV (MeOH): λmax = 207, 290 nm.
D-ProOMe Derivative 21: Trimethylsilyldiazomethane (2  in hex-
ane, 8.1 mL, 16.29 mmol) was added dropwise to a solution of 20
(779.6 g, 1.25 mmol) in MeOH (50 mL) at 25 °C. The mixture was
stirred for 2 h, the reaction quenched with saturated NaHCO3 and
the mixture extracted with CH2Cl2 (3ϫ). The combined organic
phases were dried with Na2SO4, concentrated to dryness, and the
residue was purified by column chromatography on SiO2 (CH2Cl2/
MeOH, 99.5:0.5) to afford 21 (677.4 mg, 85%) as a slightly yellow
1
low oil. H NMR (400 MHz, CDCl3, 25 °C): δ = 1.11–1.21 (m, 9
H, 5ЈЈ/7ЈЈ-CH3), 1.54–1.63 (m, 9 H, 9/13/17/21-CH3), 1.67 (s, 3 H,
9/13/17/21-CH3), 1.73–1.89 (m, 5 H, 9/13/17/21-CH3, 4ЈЈ-H), 1.91–
2.01 (m, 6 H, 14/18/4Ј-H), 2.01–2.13 (m, 11 H, 2-CH3, 10/11/15/19-
H), 2.17 (s, 3 H, 3-CH3), 2.21–2.33 (m, 2 H, 3Ј/3ЈЈ-H), 2.50–2.62
(m, 1 H, 3ЈЈ-H), 2.75–3.02 (m, 1 H, 5Ј-H), 3.35–3.42 (m, 1 H, 5Ј-
H), 3.42–3.61 (m, 2 H, 7-H), 3.62–3.75 (m, 1 H, 2Ј-H), 3.75–4.07
(m, 2 H, 1Ј-H), 5.00–5.20 (m, 4 H, 8/12/16/20-H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 9.6, 12.5, 13.7, 15.9, 16.0, 16.4, 16.7,
17.1, 17.6, 24.3, 25.5, 25.6, 26.2, 26.3, 26.5, 26.7, 28.6, 29.6, 31.1,
39.5, 39.6, 54.8, 90.1, 90.7, 120.5, 123.3, 124.1, 124.3, 128.1, 131.1,
134.9, 135.7, 140.2, 151.8, 165.9, 177.5 ppm. MS (ESI, MeOH):
m/z = 718.6 [M + H]+, 740.5 [M + Na]+, 756.3 [M + K]+.
C44H63NO7 (717.98): calcd. C 73.61, H 8.84, N 1.95; found C
1
oil. H NMR (400 MHz, CDCl3, 25 °C): δ = 1.45–1.64 (m, 12 H,
3Ј/4Ј-H, 9/13/17/21-CH3), 1.67 (s, 3 H, 9/13/17/21-CH3), 1.74 (s, 3
H, 9/13/17/21-CH3), 1.76–1.89 (m, 2 H, 5Ј-H), 1.89–2.00 (m, 8 H,
14/18/4Ј/3ЈЈ/4ЈЈ-H), 2.01–2.10 (m, 6 H, 10/11/15/19-H), 2.16 (s, 3 H,
2-CH3), 2.17–2.26 (m, 4 H, 3-CH3, 3ЈЈ-H), 2.34 (m, 1 H, 4ЈЈ-H),
3.04 (m, 1 H, 4ЈЈ-H), 3.24–3.34 (m, 2 H, 7-H), 3.36–3.55 (m, 2 H,
2Ј/2ЈЈ-H), 3.61 (dd, J = 13.4, 8.5 Hz, 1 H, 1ЈЈ-H), 3.74 (s, 3 H,
CH3O), 3.93 (dd, J = 13.4, 10.83 Hz, 1 H, 1ЈЈ-H), 3.98–4.05 (m, 1
H, 2Ј-H), 4.61 (d, J = 8.0 Hz, 1 H, 1Ј-H), 4.97–5.15 (m, 4 H, 8/12/
16/20-H), 10.68 (s, 1 H, OH) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 11.9, 14.1, 15.9, 16.5, 17.6, 21.3, 23.2, 25.1, 25.6, 25.7,
25.9, 26.6, 26.7, 29.5, 31.2, 39.6, 52.1, 52.5, 52.9, 53.2, 65.1, 65.2,
65.5, 65.7, 104.0, 104.1, 117.8, 117.9, 122.2, 124.0, 124.3, 129.9,
131.2, 134.3, 134.8, 134.9, 135.0, 146.4, 152.4, 173.8 ppm. MS (ESI,
MeOH): m/z = 636.6 [M + H]+, 658.4 [M + Na]+. C40H61NO5
(635.93): calcd. C 75.55, H 9.67, N 2.20; found C 75.38, H 9.42, N
72.55, H 8.86, N 1.80. IR (neat): ν
= 3537, 2916, 2853, 1794,
˜
max
1755, 1635, 1448, 1381, 1311, 1240, 1161, 1090, 1034, 845,
735 cm–1. UV (MeOH): λmax = 205, 288 nm.
(–)-CamphanoylO-/HO-D-Pro-D-Asp(Fm)2 Derivative 24: A solu-
tion of 23 (506.0 mg, 0.705 mmol) and HCTU (1.1 g, 2.61 mmol)
in CH2Cl2 (20 mL) was stirred at 25 °C for 0.5 h. Then -Asp(Fm)2·
2.03. IR (neat): ν
= 2919, 2850, 1741, 1438, 1377, 1250, 1203,
˜
max
1076, 1033 cm–1. UV (MeOH): λmax = 224, 289 nm.
(–)-CamphanoylO-/THPO-
(432 mg, 3.54 mmol) followed by (–)-camphanoyl chloride (831 mg, added, and the mixture was stirred at 25 °C for 5 h. The reaction
D-ProOMe Derivative 22: DMAP TFA (850.0 mg, 1.41 mmol) and DIEA (730 µL, 4.23 mmol) were
3.84 mmol) were added to a solution of 21 (642.6 mg, 1.01 mmol)
in CH2Cl2 (40 mL) at 25 °C. The mixture was stirred for 3 h, the
reaction quenched with saturated NaHCO3 and the mixture ex-
tracted with CH2Cl2 (3ϫ). The combined organic phases were
dried with Na2SO4, concentrated to dryness, and the residue was
purified by column chromatography on SiO2 (CH2Cl2/MeOH,
99:1) to afford 22 (769.0 mg, 93%) as a slightly yellow oil. 1H NMR
was quenched with saturated NH4Cl and the mixture extracted
with CH2Cl2 (3ϫ). The combined organic phases were dried with
Na2SO4, concentrated to dryness, and the residue was purified by
column chromatography on SiO2 (CH2Cl2/MeOH, 95:5) to afford
24 (512.4 mg, 62%) as a colourless oil. 1H NMR (500 MHz,
CDCl3, 25 °C): δ = 1.07–1.22 (m, 9 H, 5ЈЈ/7ЈЈ-CH3), 1.49–1.62 (m,
9 H, 9/13/17/21-CH3), 1.67 (s, 3 H, 9/13/17/21-CH3), 1.69–1.86 (m,
(400 MHz, CDCl3, 25 °C): δ = 1.10–1.22 (m, 9 H, 5ЈЈЈ/7ЈЈЈ-CH3), 5 H, 9/13/17/21-CH3, 4ЈЈ-H), 1.86–2.34 (m, 23 H, 2/3-CH3, 10/11/
1.46–1.63 (m, 12 H, 3Ј/4Ј-H, 9/13/17/21-CH3), 1.67 (s, 3 H, 9/13/ 14/15/18/19/3Ј/4Ј/3ЈЈ-H), 2.35–2.70 (m, 3 H, 5Ј/3ЈЈ-H), 2.70–2.98 (m,
17/21-CH3), 1.69–1.87 (m, 7 H, 9/13/17/21-CH3, 5Ј/3ЈЈ/4ЈЈЈ-H), 2 H, 10Ј-H), 3.02–3.84 (m, 6 H, 7/1Ј/2Ј-H), 4.09–4.20 (m, 2 H, 12Ј-
1.88–2.00 (m, 9 H, 11/14/15/18/19/4Ј/5Ј/4ЈЈ-H), 2.00–2.12 (m, 11 H,
H), 4.25–4.55 (m, 4 H, 11Ј-H), 4.75–4.90 (m, 1 H, 8Ј-H), 4.93–5.15
2-CH3, 10/11/15/19/3ЈЈ/4ЈЈЈ-H), 2.18–2.33 (m, 4 H, 3-CH3, 3ЈЈЈ-H), (m, 4 H, 8/12/16/20-H), 5.21 (s, 1 H, OH), 7.19–7.43 (m, 7 H, Fm-
2.36–2.70 (m, 2 H, 5ЈЈ/3ЈЈЈ-H), 2.72–3.00 (m, 1 H, 5ЈЈ-H), 3.12–3.17
(m, 0.5 H, 2ЈЈ-H), 3.24–3.54 (m, 4.5 H, 7/2Ј/1ЈЈ/2ЈЈ/7ЈЈ-H), 3.54–
3.95 (m, 4 H, 7/1ЈЈ/7ЈЈ-H), 3.96–4.06 (m, 1 H, 2Ј-H), 4.71 (d, J =
5.8 Hz, 1 H, 1Ј-H), 4.97–5.13 (m, 4 H, 8/12/16/20-H) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 9.63, 13.7, 14.5, 15.9, 16.5,
17.0, 17.6, 21.1, 25.0, 25.6, 26.6, 26.7, 28.9, 31.2, 31.4, 39.6, 54.8,
64.4, 65.1, 90.9, 103.9, 124.1, 124.3, 126.6, 131.1, 134.8 ppm. MS
(ESI, MeOH): m/z = 816.6 [M + H]+, 838.5 [M + Na]+. C50H73NO8
(816.13): calcd. C 73.59, H 9.02, N 1.72; found C 72.82, H 8.72, N
HAr), 7.46–7.60 (m, 4 H, Fm-HAr), 7.64–7.79 (m, 4 H, Fm-HAr)
ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ = 9.6, 12.2, 13.5, 15.9,
16.0, 16.2, 16.8, 16.9, 17.6, 25.5, 25.6, 26.2, 26.5, 26.7, 28.8, 35.8,
39.5, 39.6, 46.5, 51.3, 54.7, 66.8, 70.5, 119.9, 121.1, 123.3, 124.1,
124.3, 124.9, 127.0, 127.2, 127.7, 131.1, 134.8, 135.7, 141.1, 143.4,
143.5, 151.2, 170.8 ppm. MS (ESI, MeOH): m/z
= 1190.7
[M + H]+, 1212.3 [M + Na]+, 1227.8 [M + K]+. C76H88N2O10
(1189.54): calcd. C 76.74, H 7.46, N 2.36; found C 76.12, H 7.51,
N 2.22. IR (neat): νmax = 3365, 2966, 2914, 1792, 1738, 1668, 1506,
˜
1.65. IR (neat): ν
= 2921, 2852, 1795, 1748, 1448, 1377, 1261, 1448, 1263, 1227, 1163, 1092, 1047, 739 cm–1.
˜
max
2074
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 2069–2076

Biomimetic Chromanol Cyclisation
(–)-CamphanoylO-/HO- -Pro- -Asp(OH)2 Derivative
(2.5 mL) was added to a solution of 24 (153.6 mg, 0.129 mmol) in
CH2Cl2 (10 mL), and the mixture was stirred at 25 °C for 2 h. The
solvents were removed in vacuo, and the crude product was dis-
solved in CH2Cl2 and extracted with KHSO4 (100 mg in 5 mL
H2O). The aqueous phase was washed with CH2Cl2 (3ϫ), and the
combined organic phases were dried with Na2SO4, concentrated to
dryness, and the residue was purified by column chromatography
D
D
D-11: Et2NH
centrated to dryness and purified by column chromatography on
SiO2 (CH2Cl2) to afford 26 as a colourless oil. (10.9 mg, 80%). H
1
NMR (400 MHz, CDCl3, 25 °C): δ = 1.14–1.29 (m, 9 H, 5ЈЈ/7ЈЈ-
CH3), 1.50–1.72 (m, 18 H, 2/4Ј/8Ј/12Ј-CH3, 1Ј/4ЈЈ-H), 1.72–1.91 (m,
4 H, 3/5Ј/9Ј-H), 1.89–2.16 (m, 15 H, 7/8-CH3, 2Ј/5Ј/6Ј/9Ј/10Ј/4ЈЈ-
H), 2.25–2.34 (m, 1 H, 3ЈЈ-H), 2.55–2.70 (m, 1 H, 3ЈЈ-H), 2.77–2.85
(m, 2 H, 4-H), 4.36–4.67 (m, 2 H, CH2Cl), 5.05–5.17 (m, 3 H, 3Ј/
7Ј/11Ј-H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 9.6, 12.2,
13.2, 15.8, 15.9, 16.8, 17.6, 19.1, 22.0, 25.6, 26.5, 26.6, 28.9, 29.2,
on SiO2 (CH2Cl2/MeOH, 75:25) to afford D-11 (42.9 mg, 40%) as
1
a colourless oil. H NMR (600 MHz, DMSO, 25 °C): δ = 0.96 (s, 30.6, 31.4, 37.8, 39.6, 54.3, 54.9, 75.3, 91.1, 117.9, 123.9, 124.0,
3 H, 5ЈЈ/7ЈЈ-CH3), 1.00 (s, 3 H, 5ЈЈ/7ЈЈ-CH3), 1.06–1.15 (s, 3 H, 5ЈЈ/ 124.3, 127.4, 131.2, 134.9, 135.3, 150.0, 166.0, 177.9 ppm. MS (ESI,
7ЈЈ-CH3), 1.44–1.51 (m, 9 H, 9/13/17/21-CH3), 1.51–1.73 (m, 8 H, MeOH): m/z = 661.5 [M + Na]+, 675.3 [M + HCl]+.
9/13/17/21-CH3, 3Ј/4Ј/4ЈЈ-H), 1.78–2.00 (m, 16 H, 3-CH3, 10/11/14/
α-Tocotrienol (5): LiAlH4 (1  in THF, 0.150 mmol) was added to
a solution of 26 (38.1 mg, 59.8 µmol) in THF (2.5 mL), and the
mixture was heated at reflux for 18 h. The reaction was quenched
with H2O/1  HCl and the mixture extracted with Et2O (3ϫ). The
combined organic phases were dried with Na2SO4, concentrated to
dryness and purified by column chromatography on SiO2 (CH2Cl2)
to afford 5 as a colourless oil (23.4 mg, 92%). The spectral data
were identical to those of an original sample. Selected data: 1H
NMR (500 MHz, CDCl3, 25 °C): δ = 1.26 (s, 3 H, 2-CH3), 1.57–
1.70 (m, 14 H, 1Ј-H, 4Ј/8Ј/12Ј-CH3), 1.75–1.87 (m, 2 H, 3-H), 1.90–
2.20 (m, 19 H, 5/7/8-CH3, 2Ј/5Ј/6Ј/9Ј/10Ј-H), 2.61 (t, J = 6.8 Hz, 2
H, 4-H), 4.20 (s, 1 H, OH), 5.05–5.18 (m, 3 H, 3Ј/7Ј/11Ј-H) ppm.
15/18/19/3Ј/4Ј-H), 2.00–2.33 (m, 6 H, 2-CH3, 3ЈЈ/4ЈЈ-H), 2.33–2.45
(m, 1 H, 5Ј-H), 2.46–2.62 (m, 1 H, 5Ј-H), 2.62–2.78 (m, 0.2 H, 8Ј-
H), 2.93–3.63 (m, 7 H, 7/1Ј/2Ј/5Ј/10Ј-H), 3.69–4.17 (m, 0.8 H, 8Ј-
H), 4.87–5.12 (m, 4 H, 8/12/16/20-H), 7.44–7.84 (m, 1 H, NH),
7.98–8.68 (m, 2 H, OH) ppm. 13C NMR (125 MHz, DMSO, from
2D exp. HMQC/HMBC, 25 °C): δ = 9.1, 12.7, 13.0, 15.4, 16.2,
16.3, 17.2, 23.6, 25.1, 25.8, 26.2, 27.9, 30.8, 38.8, 39.1, 47.6, 49.9,
52.8, 53.9, 54.4, 55.3, 64.2, 66.4, 90.7, 123.7, 124.7, 125.6, 127.5,
130.6, 134.3, 140.7, 150.9, 177.8 ppm. MS (ESI, MeOH): m/z =
834.0 [M + H]+, 856.0 [M + Na]+, 877.9 [M + 2Na]+, 832.0 [M –
H]–. IR (neat): ν
= 3353, 2968, 2918, 1795, 1751, 1595, 1423,
˜
max
1416, 1238, 1163, 1091, 1048, 930 cm–1. UV (MeOH): λmax = 240,
284 nm.
α-Tocotrienyl Acetate (30): Acetic anhydride (400 µL) was added to
a solution of α-tocotrienol (5; 23.4 mg, 55.0 µmol) in pyridine
(2 mL), and the mixture was stirred at 25 °C for 4 h. The reaction
was quenched with 1  HCl and the mixture extracted with CH2Cl2
(3ϫ). The combined organic phases were dried with Na2SO4, con-
centrated to dryness and purified by column chromatography on
SiO2 (CH2Cl2) to afford 30 as a colourless oil (25.7 mg, Ͼ99%).
1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.26 (s, 3 H, 2-CH3), 1.57–
1.70 (m, 14 H, 1Ј-H, 4Ј/8Ј/12Ј-CH3), 1.75–1.87 (m, 2 H, 3-H), 1.92–
2.18 (m, 19 H, 5/7/8-CH3, 2Ј/5Ј/6Ј/9Ј/10Ј-H), 2.33 [s, 3 H, CH3(CO)-
O], 2.60 (t, J = 6.6 Hz, 2 H, 4-H), 5.05–5.22 (m, 3 H, 3Ј/7Ј/11Ј-H)
ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 11.7, 12.0, 12.8,
15.8, 15.9, 17.6, 20.5, 22.1, 25.6, 26.5, 26.7, 39.6, 74.7, 91.1, 117.2,
123.0, 124.1, 124.3, 126.6, 131.2, 134.9, 135.0, 140.4, 149.3,
169.6 ppm. MS (ESI, MeOH): m/z = 489.6 [M + Na]+, 505.4 [M
+ K]+.
(–)-Camphanoyl-
TosylOH·H2O (16.3 mg, 85.7 µmol) in ACN (2 mL) was added to
a solution of -11 (34.0 mg, 40.82 µmol) in CH2Cl2 (35 mL), and
D-Pro-D-Asp(OMe)2 Cyclised Derivative 25: p-
D
the mixture was stirred at 25 °C for 48 h. The reaction was
quenched with saturated NaHCO3 and the mixture extracted with
CH2Cl2 (3ϫ). The combined organic phases were dried with
Na2SO4, concentrated to dryness, and the crude oil was dried under
high vacuum. The residue was then dissolved in MeOH/CH2Cl2
(4:1, 2.5 mL), and trimethyldiazomethane (2  in hexane, 0.6 mL,
1.2 mmol) was added. The mixture was stirred at 25 °C for 1 h, and
the reaction was quenched with saturated NaHCO3 and the mix-
ture extracted with CH2Cl2 (3ϫ). The combined organic phases
were dried with Na2SO4, concentrated to dryness and purified by
column chromatography on SiO2 (CH2Cl2/MeOH, 98.5:1.5) to af-
ford 25 (15.2 mg, 41% over two steps) as a colourless oil. 1H NMR
(500 MHz, CDCl3, 25 °C): δ = 1.10–1.32 (m, 9 H, 5ЈЈЈ/7ЈЈЈ-CH3),
1.49–1.89 (m, 23 H, 2/4Ј/8Ј/12Ј-CH3, 3/1Ј/3ЈЈ/4ЈЈ/4ЈЈЈ-H), 1.89–2.31
(m, 19 H, 7/8-CH3, 2Ј/5Ј/6Ј/9Ј/10Ј/3ЈЈ/3ЈЈЈ/4ЈЈЈ-H), 2.35–3.42 (m, 9
H, 4/2ЈЈ/5ЈЈ/10Ј/3ЈЈЈ/4ЈЈЈ-H), 3.53–3.89 (m, 8 H, COOCH3, 1ЈЈ-H),
4.53–4.99 (m, 1 H, 8ЈЈ-H), 5.00–5.23 (m, 3 H, 3Ј/7Ј/11Ј-H), 7.68–
8.17 (m, 1 H, NH) ppm. 13C NMR (125 MHz, CDCl3, from 2D
exp. HMQC/HMBC, 25 °C): δ = 9.6, 12.2, 13.5, 17.0, 17.3, 21.3,
23.0, 25.5, 25.7, 28.7, 28.9, 30.8, 35.3, 39.4, 39.7, 52.2, 53.9, 55.2,
59.5, 61.4, 63.1, 64.6, 69.3, 74.2, 75.4, 77.2, 77.4, 85.7, 89.3, 90.8,
92.6, 124.3, 131.2, 134.9, 141.2, 143.2, 171.4, 178.1 ppm. MS (ESI,
α-Tocopherol (1): The iridium catalyst 28 (0.55 µmol) was added to
a solution of 30 (25.7 mg, 55.0 µmol) in CH2Cl2 (0.5 mL), and the
mixture was stirred at 25 °C under 50 bar of H2 for 3 h. The solvent
was removed in vacuo, and hexane (1 mL) was added. The solids
were filtered off (0.45 µm filter) and washed with hexane. The sol-
vent was removed in vacuo, and the crude colourless oil was used
directly in the next step. The crude oil was dissolved in THF
(1 mL), and LiAlH4 (1  in THF, 0.38 mmol) was added. The mix-
ture was stirred at 25 °C for 2 h. The reaction was quenched with
H2O and the mixture extracted with Et2O (3ϫ). The combined
organic phases were dried with Na2SO4 and concentrated to dry-
ness to afford α-tocopherol as a colourless oil (21.3 mg, 90%). The
crude material was used without further purification. The spectral
data were identical to those of an original sample. Selected data:
1H NMR (400 MHz, CDCl3, 25 °C): δ = 0.80–0.91 (m, 12 H, 4Ј/
8Ј/12Ј-CH3), 0.97–1.57 (m, 24 H, 2-CH3, 1Ј/2Ј/3Ј/4Ј/5Ј/6Ј/7Ј/8Ј/9Ј/
10Ј/11Ј/12Ј-H), 1.70–1.83 (m, 2 H, 3-H), 2.11 (s, 6 H, 5/7/8-CH3),
2.16 (s, 3 H, 5/7/8-CH3), 2.60 (t, J = 6.9 Hz, 2 H, 4-H), 4.19 (s, 1
H, OH) ppm. HPLC (Chiracel OD-H, 0.5% EtOH in n-hexane,
MeOH): m/z = 861.8 [M + H]+, 883.7 [M + Na]+. IR (neat): ν
˜
max
= 3365, 2921, 2853, 1794, 1739, 1674, 1502, 1436, 1376, 1225, 1163,
1092, 1044 cm–1. C50H72N2O10 (861.13): calcd. C 69.74, H 8.43, N
3.25; found C 69.23, H 8.36, N 3.15. Determination of the dia-
stereoisomeric excess by HPLC analysis was not possible at this
stage, peaks were not properly resolved.
Benzyl Chloride 26: 2,2,2-Trichlorethyl chloroformate (135.2 mg,
0.64 mmol) was added to a solution of 25 (18.4 mg, 21.4 µmol) in
benzene (2 mL). The solution was heated at reflux for 24 h, and
the mixture was then cooled to 25 °C. The reaction was quenched
with saturated NaHCO3 and the mixture extracted with CH2Cl2
(3ϫ). The combined organic phases were dried with Na2SO4, con-
1 mL/min, 25 °C, 220 nm): t(2R,4ЈRS,8ЈRS)
t(2S,4ЈRS,8ЈRS) = 9.0 min (16.7%).
= 7.9 min (79.8%),
Eur. J. Org. Chem. 2009, 2069–2076
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2075

J. Chapelat, A. Chougnet, W.-D. Woggon
FULL PAPER
α-Tocopheryl Methyl Ether (32): To a suspension of NaH (60% in
mineral oil, 2.9 mg, 74.0 µmol) in DMF (0.5 mL) at 0 °C was added
a solution of 1 (21.3 mg, 49.5 µmol) in DMF (1 mL). The mixture
was stirred at 0 °C for 30 min, and MeI (7 µL, 59.0 µmol) was
added. The solution was warmed to 25 °C and stirred for 3 h. The
reaction was quenched with a saturated NaHCO3 solution and the
mixture extracted with CH2Cl2 (3ϫ). The combined organic phases
were dried with Na2SO4, concentrated to dryness, and the residue
was purified by column chromatography on SiO2 (hexane/EtOAc,
9:1) to afford 32 as a colourless oil (18.9 mg, 86%). The spectral
data were identical to those previously reported.[15] Selected data:
1H NMR (500 MHz, CDCl3, 25 °C): δ = 0.85 (d, J = 6.6 Hz, 3 H,
4Ј/8Ј-CH3), 0.86 (d, J = 6.6 Hz, 3 H, 4Ј/8Ј-CH3), 0.87 (d, J =
6.6 Hz, 6 H, 12Ј-CH3), 0.90–1.19 (m, 7 H, 2Ј/3Ј/5Ј/6Ј/7Ј/9Ј/10Ј-H),
1.23 (s, 3 H, 2-CH3), 1.19–1.47 (m, 13 H, 1Ј/2Ј/3Ј/4Ј/5Ј/6Ј/7Ј/8Ј/9Ј/
10Ј/11Ј-H), 1.48–1.53 (m, 1 H, 12Ј-H), 1.70–1.83 (m, 2 H, 3-H),
2.09 (s, 3 H, 5-CH3), 2.14 (s, 3 H, 8-CH3), 2.18 (s, 3 H, 7-CH3),
2.58 (t, J = 6.8 Hz, 2 H, 4-H), 3.63 (s, 3 H, CH3O) ppm. GC [CP-
Sil-88 column, 50 mϫ0.25 mm, 0.25 µm; split injector (1:30), injec-
tor temp. 280 °C; FID detector, detector temp. 250 °C, carrier gas:
H2, 90 kPa; 170 °C, 140 min]: t(R,R,S/S,S,R) = 136.9 min (1.29%),
t(R,R,R/S,S,S) = 138.9 min (80.4%), t(R,S,R/S,R,S) = 140.7 min (1.29%),
t(R,S,S/S,R,R) = 144.9 min (17.0%); (R,R,R) = 80.4%, (S,R,R) =
17.0%, (R,S,S) ≈ 0%, (S,S,S) ≈ 0%, (R,R,S) = 1.06%, (R,S,R) =
1.06%, (S,S,R) = 0.23%, (S,R,S) = 0.23%.
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analysis that allows separation of the C2 diastereoisomers [Chi-
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Compound 15 was formed in situ by treating geranylgeraniol
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to the formation of phytyl bromide, see ref.[4]).
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Acknowledgments
We thank the Swiss National Science Foundation for financial sup-
port and Dr. T. Netscher (DSM) for a generous sample of farnesyl-
acetone. We also thank Mr. W. Kirsch at the Department of Chem-
istry, University of Basel, for the microanalyses.
Received: January 9, 2009
Published Online: March 10, 2009
2076
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Eur. J. Org. Chem. 2009, 2069–2076