Enantioselective palladium-catalyzed total synthesis of vitamin E by employing a domino Wacker-Heck reaction

Article abstract of DOI:10.1002/chem.200600849

An enantioselective total synthesis of vitamin E in which a novel palladium-catalyzed domino reaction was employed as the key step is described. This reaction allows the formation of the chiral chroman framework and the concurrent introduction of part of the side chain of vitamin E. The sequence comprises an enantioselective Wacker cyclization and a subsequent Heck reaction. Accordingly, reaction of alkenylphenol 12 with methyl vinyl ketone (13) in the presence of catalytic amounts of Pd(OTFA)₂ (TFA = trifluoroacetate), the enantiopure ligand (S,S)-Bn-BOXAX (8b; Bn = benzyl, BOXAX = 2,2′-bis(oxazolyl)-1,1′-binaphthyl, and p-benzoquinone (9) as an oxidant gives access to chiral chroman 10 with an enantioselectivity of 97% ee in 84% yield. Chroman 10 is then converted into 24 by an aldol condensation reaction with (3R)-3,7-dimethyloctanal (11). Subsequent 1,2-addition of methyllithium, elimination of water, and hydrogenation yields vitamin E.

Full text of DOI:10.1002/chem.200600849

DOI: 10.1002/chem.200600849
Enantioselective Palladium-Catalyzed Total Synthesis of Vitamin E by
Employing a Domino Wacker–Heck Reaction
Lutz F. Tietze,* Florian Stecker, Julia Zinngrebe, and Konrad M. Sommer[a]
Dedicated to Professor Gyula Schneider on the occasion of his 75th birthday
Abstract: An enantioselective total
synthesis of vitamin E in which a novel
palladium-catalyzed domino reaction
was employed as the key step is de-
alkenylphenol 12 with methyl vinyl
ketone (13) in the presence of catalytic
naphthyl, and p-benzoquinone (9) as
an oxidant gives access to chiral chro-
man 10 with an enantioselectivity of
97% ee in 84% yield. Chroman 10 is
then converted into 24 by an aldol con-
densation reaction with (3R)-3,7-di-
amounts of Pd(OTFA)2 (TFA = tri-
R
fluoroacetate), the enantiopure ligand
(S,S)-Bn-BOXAX (8b; Bn = benzyl,
A
G
tion of the chiral chroman framework
and the concurrent introduction of part
of the side chain of vitamin E. The se-
quence comprises an enantioselective
Wacker cyclization and a subsequent
Heck reaction. Accordingly, reaction of
BOXAX
=
2,2’-bis(oxazolyl)-1,1’-bi-
A
A
N
dition of methyllithium, elimination of
water, and hydrogenation yields vita-
min E.
Keywords: asymmetric catalysis
·
domino reactions · Heck reactions ·
palladium · vitamins
Introduction
Vitamin E is one of the fat-soluble vitamins and a collective
term for all tocopherols and tocotrienols. The vitamin E
family consists of eight naturally occurring compounds
which, depending upon the degree of methylation on their
aromatic ring, are specified as a-, b-, g- and d-tocopherol
and -tocotrienol, respectively. All are derivatives of 6-chro-
manol with a stereogenic center at C-2. The tocopherols
have a saturated 16-carbon side chain with two stereogenic
centers, whereas the tocotrienols have an unsaturated 16-
carbon side chain with two E-configured double bonds (for
example, a-tocopherol (1), a-tocotrienol (2)).[1] a-Tocopher-
ol (1), which has the R configuration at all stereogenic cen-
ters, has the most pronounced biological activity. It acts as
an antioxidant and is considered to be an essential protec-
tive factor against lipid peroxidation. In particular, 1 pro-
tects polyunsaturated fatty acids, other components of the
cell membrane, and low-density lipoproteins (LDL) by cap-
turing highly reactive free radicals formed in the body as by-
products of normal oxidative metabolism.[2,3]
a-Tocopherol (rac-1) is produced industrially on a large
scale, by means of an acid-catalyzed reaction of trimethylhy-
droquinone (3) with all-rac-isophytol (4), as a mixture of all
eight possible stereoisomers (Scheme 1).[4]
[a] Prof. Dr. L. F. Tietze, Dipl.-Chem. F. Stecker,
Dipl.-Chem. J. Zinngrebe, Dr. K. M. Sommer
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Gçttingen
Tammannstrasse 2, 37077 Gçttingen (Germany)
Fax : (+49)551-39-9476
Scheme 1. Industrially used synthesis of racemic a-tocopherol (all-rac-1)
by reaction of trimethylhydroquinone (3) with all-rac-isophytol (4).
E-mail: ltietze@gwdg.de
8770
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FULL PAPER
Recent studies have shown that 2S-configured tocopherols
have no antioxidant effect in biological systems because
they are not accepted as substrates by the a-tocopherol
transfer protein (TTP), which is responsible for the trans-
port of vitamin E into the tissue. On the other hand, the
configuration of the stereogenic centers in the side chain ap-
pears to have no influence on the antioxidant effect.[5] As a
result, rac-1 exhibits a maximum of 50% of the biological
activity of (R,R,R)-1. Therefore, there is considerable inter-
est in the development of an efficient process for the enan-
tioselective synthesis of vitamin E with special attention to
the configuration of stereogenic center C-2.
zation of the stereogenic center at C-2. We therefore fo-
cused on a new intermediate, 10, which contains a benzyl
protecting group that can be removed under milder condi-
tions, and a methyl carbonyl moiety that can be used direct-
ly in an aldol reaction. Thus, retrosynthetic analysis of 1
gives intermediate 10 and (3R)-3,7-dimethyloctanal (11)
(Scheme 3). Further disassembly of 10 gives the hydroqui-
Several enantioselective approaches to the synthesis of 1
based on resolution of the products, the use of enantiopure
natural building blocks, auxiliary-controlled reactions, and
asymmetric oxidations have been described.[6] In addition, a
palladium-catalyzed asymmetric allylic alkylation reaction
to construct the chiral chroman framework has been em-
ployed.[6a,b,d] We have developed asymmetric syntheses of
the chiral chroman moiety by using a selective allylation of
an alkyl methyl ketone and a Sharpless dihydroxylation as
key steps.[6c,e,g–k] However, all these methods are not effi-
cient enough for an industrial approach. Following these re-
sults, we have recently shown that the chiral chroman
moiety in vitamin E can be prepared in a much more effi-
cient way, with concurrent introduction of a part of the side
chain, by using a novel enantioselective domino Wacker–
Heck process (Scheme 2).[7–9] Thus, reaction of 5 with
Scheme 3. Retrosynthetic analysis of a-tocopherol (1).
none derivative 12, which in turn can be prepared from tri-
methylhydroquinone (3) and methyl vinyl ketone (13). As
previously outlined, we envisioned the introduction of ste-
reogenic center C-2 into 1 by the catalytic enantioselective
domino Wacker–Heck reaction of 12, whereas stereogenic
center C-8’ originates from (R)-citronellol (14).
Alkenyl phenol 12 was prepared by using a multistep re-
action sequence (Scheme 4). First, trimethylhydroquinone
(3) was reacted with methyl vinyl ketone (13) in the pres-
ence of trimethyl orthoformate to give 15, which was benzyl-
Scheme 2. Synthesis of chiral chroman 7. Reagents and conditions:
A
N
3.5 d.
methyl acrylate (6), in the presence of catalytic amounts of
Pd
(OTFA)2 and the enantiopure ligand BOXAX[10] (8a),
G
led to the formation of 7 with an enantioselectivity of
96% ee in 84% yield. Here, we present the total synthesis
of a-tocopherol (1) that was achieved by using the newly de-
veloped enantioselective domino Wacker–Heck reaction.
Results and Discussion
Scheme 4. Synthesis of alkene 12. Reagents and conditions: a) 13,
A
N
Preparation of a-tocopherol (1) using 7 did not seem appro-
priate because the acidic conditions required for cleavage of
the methyl ether moiety in 7 might lead to a partial isomeri-
24 h, 97%; c) HCl, acetone, 808C, 88%; d) Ac2O, pyridine, RT, 20 h,
then 708C, 4 h, 94%; e) TiCl4/Zn/CH2Br2, CH2Cl2, RT, 2 h, 88%;
f) NaOMe, MeOH, RT, 3 h, 88%.
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L. F. Tietze et al.
A
We aimed to introduce the missing part of the side chain
of a-tocopherol (1) that contains one stereogenic center by
using (R)-citronellal. (R)-Citronellol (14), commercially
available in a higher enantiomeric excess than (R)-citronel-
lal, was employed as the substrate, which was then oxidized
to (R)-citronellal. However, the aldol condensation of 10
with (R)-citronellal was not satisfying as a result of the for-
mation of a byproduct from an intramolecular Prins reaction
of (R)-citronellal. Therefore, for the coupling reaction with
10, we used (3R)-3,7-dimethyloctanal (11), which was ob-
tained from 14 by hydrogenation of the double bond fol-
lowed by a Swern oxidation, with an overall yield of 92%.
For the aldol reaction, 10 was transformed into the corre-
sponding boron enolate by using cHex2BCl to give product
22 in an excellent yield of 90% (Scheme 7).[13] Unfortunate-
ly, 22 was not an ideal substrate for subsequent transforma-
tions. We therefore repeated the sequence by using chroman
23 containing a saturated side chain (Scheme 8).
quently, the acetal moiety in 16 was cleaved with hydro-
chloric acid to afford 17. Exploiting the keto–enol tautomer-
ism of 17, phenyl ester 18 was prepared in 94% yield by
using acetic anhydride dissolved in pyridine. Ultimately, for-
mation of the double bond using the Lombardo reagent,[12]
followed by ZemplØn saponification afforded desired sub-
strate 12 in six steps with an overall 56% yield based on 3.
The domino reaction of benzyl-protected phenol 12 and
methyl vinyl ketone (13) dissolved in dichloromethane in
the presence of catalytic amounts of Pd(OTFA)2, the chiral
ligand (S,S)-Bn-BOXAX (8b), and p-benzoquinone (9) as a
reoxidant afforded key intermediate 10 with 97% ee in 84%
yield (Scheme 5).
Scheme 5. Synthesis of chiral chroman 10. Reagents and conditions:
A
N
We assume that as the first step of the domino Wacker–
Heck reaction, the chiral catalyst generated from Pd-
(OTFA)2 and the enantiomerically pure ligand (S,S)-Bn-
Scheme 7. Synthesis of 22. Reagents and conditions: a) iPr2EtN,
cHex2BCl, Et2O, ꢀ788C, 1h, then 11, ꢀ788C, 3 h, 90%.
ACHTREUNG
BOXAX (8b), coordinates enantiofacially to the aliphatic
double bond in 12 (Scheme 6). Oxypalladation provides the
Scheme 6. Proposed mechanism for the domino Wacker–Heck reaction.
Scheme 8. Synthesis of 1. Reagents and conditions: a) PtO2·H2O, H2,
EtOAc, RT, 30 min, 86%; b) iPr2EtN, cHex2BCl, Et2O, ꢀ788C, 1h, then
11, ꢀ788C, 3 h; c) cat. p-TsOH, toluene, 608C, 30 min, 82% over two
steps; d) MeLi, THF, ꢀ788C, 1h; e) cat. p-TsOH, toluene, 608C, 30 min,
76% over two steps; f) Pd/C, H2 (2 bar), EtOAc, RT, 30 min, 90%.
enantioselective formation of palladated chroman 20 with
the correct absolute configuration at C-2 relative to 1. Be-
cause b-hydride elimination is not possible, an intermolecu-
lar reaction with methyl vinyl ketone (13) to form 21 occurs,
which can now undergo b-hydride elimination to yield 10.
To perform this reaction catalytically, Pd0 must be reoxi-
dized to Pdii. To date, the best reagent for this reoxidation
has been p-benzoquinone (9) because it does not interfere
with the course of the reaction. Replacement of 9 by O2/
CuCl was unsuccessful because under these conditions oxi-
dation of substrate 12 to give a p-benzoquinone derivative
occurred.
Saturated ketone 23 could easily be prepared from 10 by
using PtO2·H2O/H2. Formation of the boron enolate of 23,
using iPr2NEt and cHex2BCl at ꢀ788C followed by an aldol
reaction with 11, proceeded smoothly to give the corre-
sponding aldol adduct, which was treated with catalytic
amounts of p-toluenesulfonic acid (p-TsOH) dissolved in
toluene to afford 24 in 82% yield over two steps. The last
8772
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Enantioselective Domino Wacker–Heck Reaction
FULL PAPER
254 mmol) in methanol (120 mL). Stirring was continued for 2 d at room
temperature, the mixture was then diluted with Et2O (500 mL), washed
with brine, and dried over Na2SO4. The solvent was evaporated under re-
duced pressure and the residue recrystallized from methanol to yield 15
as colorless needles (44.2 g, 94%). M.p. 1568C; 1H NMR (200 MHz,
CDCl3): d=4.33 (s, 1H; OH), 3.18 (s, 3H; OCH 3), 2.67–2.48 (m, 2H; 4-
H2), 2.16 (s, 6H; 5-CH3, 7-CH3), 2.12 (s, 3H; 8-CH3), 1.84–1.72 (m, 2H;
3-H2), 1.52 ppm (s, 3H; 2-CH3); 13C NMR (50.3 MHz, CDCl3): d=145.4,
143.7 (C-6, C-8a), 122.1, 121.1, 118.7, 118.4 (C-4a, C-5, C-7, C-8), 97.2 (C-
2), 48.8 (OCH3), 31.9 (C-3), 23.1 (2-CH3), 19.9 (C-4), 12.2, 11.6, 11.2 ppm
(5-CH3, 7-CH3, 8-CH3); IR (KBr): n˜? =3452, 2986, 2946, 2882, 2836, 1638,
1546 cmꢀ1; UV (CH3CN): lmax (lge)=291(3.484), 919 nm (4.658); MS
(70 eV, EI): m/z (%): 236 (46) [M+], 221(3) [ M+ꢀCH3], 205 (38) [M+
ꢀOCH3], 189 (13) [M+ꢀC2H7O], 164 (100) [M+ꢀC4H8O]; HRMS: m/z
calcd for C14H20O3: 236.1412; found: 236.1412.
three transformations for the synthesis of 1 included a 1,2-
addition of methyllithium to the carbonyl moiety in 24 to
give the corresponding tertiary alcohol, which was trans-
formed into diene 25 in 76% over two steps by means of an
acid-catalyzed elimination using p-TsOH. The final step was
hydrogenation of the diene moiety in 25 with simultaneous
deprotection of the benzylated phenolic hydroxyl group
using hydrogen in the presence of catalytic amounts of Pd/
C. In this reaction (2R,4’R,8’R)-a-tocopherol (1) was formed
together with its (4’S)-epimer, as expected, in almost a 1:1
mixture in 90% total yield. To date, we have been unable to
perform a stereoselective hydrogenation of the butadiene
moiety in 25, but Pfaltz and co-workers have recently dem-
onstrated that trisubstituted alkenes can be hydrogenated
with high enantioselectivity by using a new iridium-based
catalyst.[14] However, it has been shown that the configura-
tion of the stereogenic centers in the side chain have no in-
fluence on the bioactivity of vitamin E[5] so the diastereo-
meric mixture we have prepared should have the same anti-
oxidant effect as the natural product.
6-Benzyloxy-2-methoxy-2,5,7,8-tetramethylchroman (16): Benzyl chloride
(31.5 g, 176 mmol) was added to a suspension of chromanol 15 (20.8 g,
88.0 mmol) and K2CO3 (26.7 g, 193 mmol) in degassed acetone (100 mL)
and the mixture was stirred for 24 h at room temperature. After addition
of water (500 mL), the mixture was extracted with Et2O (3”200 mL) and
the combined organic layers were washed with brine and dried over
Na2SO4. Concentration under reduced pressure and column chromatogra-
phy on silica gel (n-pentane/Et2O 10:1) provided acetal 16 as a colorless
1
oil (27.9 g, 97%). H NMR (300 MHz, CDCl3): d=7.53–7.30 (m, 5H; Ar-
H), 4.69 (s, 2H; CH2Ph), 3.23 (s, 3H; OCH3), 2.74–2.51(m, 2H; 4-H 2),
2.22, 2.17–2.15 (3”s, 9H; 5-CH3, 7-CH3, 8-CH3), 1.88–1.76 (m, 2H; 3-H2),
1.55 ppm (s, 3H; 2-CH3); 13C NMR (50.3 MHz, CDCl3): d=148.9 (C-6),
146.1 (C-8a), 137.9 (C-1’), 128.4 (C-3’, C-5’), 127.8 (C-4’), 127.7 (C-2’, C-
6’), 127.6, 125.9, 122.6, 118.8 (C-4a, C-5, C-7, C-8), 97.3 (C-2), 74.6
(CH2Ph), 48.9 (OCH3), 31.8 (C-3), 23.1 (2-CH3), 19.9 (C-4), 12.8, 11.9,
11.6 ppm (5-CH3, 7-CH3, 8-CH3); IR (film): n˜ =3030, 2988, 2937, 1606,
1497, 1377 cm1; UV (CH3CN): lmax (lge)=283 (0.967), 201nm (2.987);
MS (70 eV, EI): m/z (%): 326 (20) [M+], 295 (16) [M+ꢀOCH3], 235
(100) [M+ꢀBn], 91(45) [Bn +]; HRMS: m/z calcd for C21H26O3:
326.1882; found: 326.1882.
Conclusion
In conclusion, we have developed a new total synthesis of
vitamin
E by using a novel enantioselective domino
Wacker–Heck process as the key reaction step. This reaction
not only allows the formation of the chroman framework
with the necessary R configuration at stereogenic center C-2
with 97% ee, but also the introduction of a part of the side
6-Benzyloxy-2,5,7,8-tetramethylchroman-2-ol (17): 0.1n aqueous HCl
(30 mL) was added to a solution of acetal 16 (22.3 g, 68.4 mmol) in ace-
tone (120 mL) and then the solvent was distilled off at 808C. After addi-
tion of acetone (80 mL), the process was repeated. The residue was dis-
solved in Et2O (200 mL), and the obtained solution washed with water
(150 mL), 2n aqueous HCl (100 mL), brine, and dried over Na2SO4. Re-
moval of the solvent under reduced pressure and recrystallization from
Et2O afforded chromanol 17 as colorless needles (18.2 g, 88%). M.p.
1098C; 1H NMR (300 MHz, CDCl3): d=7.53–7.30 (m, 5H; Ar-H), 4.69
(s, 2H; CH2Ph), 2.78–2.58 (m, 2H; 4-H2), 2.49 (s, 1H; OH), 2.20, 2.19,
2.12 (3”s, 9H; 5-CH3, 7-CH3, 8-CH3), 1.90–1.79 (m, 2H; 3-H2), 1.65 ppm
(s, 3H; 2-CH3); 13C NMR (75.5 MHz, CDCl3): d=148.9, 148.8 (C-6, C-
8a), 137.8 (C-1’), 128.4 (C-3’, C-5’), 127.8 (C-4’), 127.7 (C-2’, C-6’), 128.3,
126.0, 124.0, 117.8 (C-4a, C-5, C-7, C-8), 95.4 (C-2), 74.7 (CH2Ph), 31.4
(C-3), 28.7 (2-CH3), 20.00 (C-4), 12.4, 12.0, 11.9 ppm (5-CH3, 7-CH3, 8-
chain in 84% yield. Condensation with (3R)-3,7-di
yloctanal (11) followed by reaction with methyllithium com-
pleted the synthesis.
A
ACHTREUNG
Experimental Section
General: All reactions were performed under argon in flame-dried flasks.
All solvents were dried and distilled prior to use by means of usual labo-
ratory methods. All reagents obtained from commercial sources were
used without further purification. Thin-layer chromatography (TLC) was
performed on precoated silica gel SIL G/UV254 plates (Macherey-Nagel
GmbH & Co. KG), and silica gel 60 (0.032–0.063 mm, Merck) was used
for column chromatography. Phosphomolybdic acid dissolved in metha-
nol (PMA) or vanillin dissolved in methanolic sulfuric acid were used as
staining reagents for TLC analysis. UV spectra were recorded, using
CH3CN or MeOH as solvents, on a Perkin–Elmer Lambda 2 spectrome-
ter. IR spectra were recorded as KBr pellets or as films on a Bruker IFS
25 spectrometer. 1H and 13C NMR spectra were recorded with Mercury-
200, VXR-200, Unity-300, Inova-500, Unity Inova-600 (Varian), or AMX
300 (Bruker) spectrometers. Chemical shifts are reported in ppm using
tetramethylsilane (TMS) as the internal standard. Multiplicities of
13C NMR peaks were determined with the attached proton test (APT)
pulse sequence. Mass spectra were measured on a Finnigan MAT 95,
TSQ 7000 or LCQ instrument. Elemental analysis was carried out by
members of the Mikroanalytisches Labor, Institut für Organische und
CH3); IR (film): n˜ =3379, 3034, 1496 cmꢀ1
.
Acetic acid 4-benzyloxy-2,3,5-trimethyl-6-(3-oxobutyl)phenyl ester (18a):
A solution of chromanol 17 (21.3 g, 68.2 mmol) dissolved in pyridine
(114 mL) was treated with acetic anhydride (19.8 mL, 210 mmol) and the
resulting solution was stirred for 20 h at room temperature and then for
4 h at 708C. The solvent was removed and the resulting residue recrystal-
lized from ethanol to yield ketone 18a as a colorless solid (22.7 g, 94%).
M.p. 838C; 1H NMR (300 MHz, CDCl3): d=7.51–7.32 (m, 5H; Ar-H),
4.72 (s, 2H; CH2Ph), 2.84–2.50 (m, 4H; 1’’-H2, 2’’-H2), 2.34 (s, 3H; 2’-H3),
2.23, 2.22, 2.15 (3”s, 9H; 2-CH3, 3-CH3, 5-CH3), 2.02 ppm (s, 3H; 4’’-H3);
13C NMR (75.5 MHz, CDCl3): d=208.0 (C-3’’), 169.8 (C-1’), 153.4 (C-4),
144.0 (C-1), 137.5 (C-1’’’), 129.9 (C-6), 129.0 (C-5), 128.5 (C-3’’’, C-5’’’),
128.0 (C-4’’’), 127.7 (C-3), 127.6 (C-2’’’, C-6’’’), 127.5 (C-2), 74.3 (CH2Ph),
42.8 (C-2’’), 29.9 (C-4’’), 21.6 (C-1’’), 20.6 (C-2’), 13.2, 13.1, 12.4 ppm (2-
CH3, 3-CH3, 5-CH3); IR (film): n˜ =2982, 2950, 2832, 1750, 1216 cmꢀ1; UV
(CH3CN): lmax (lge)=314 (3.364), 264 (4.047), 200 nm (4.463); MS
(70 eV, EI): m/z (%): 354 (10) [M+], 263 (20) [M+ꢀBn], 221(100) [ M+
ꢀBnꢀAc]; HRMS: m/z calcd for C21H26O4: 354.1831; found: 354.1831.
A
2-Methoxy-2,5,7,8-tetramethylchroman-6-ol (15): Concentrated sulfuric
acid (0.5 mL) and methyl vinyl ketone (29.5 g, 400 mmol) were added
dropwise to a stirring, degassed and ice-cooled solution of trimethyl-p-hy-
droquinone (3) (30.4 g, 200 mmol) and trimethyl orthoformate (27.0 g,
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L. F. Tietze et al.
Acetic acid 4-benzyloxy-2,3,5-trimethyl-6-(3-methylbut-3-enyl)phenyl
ester (18b): Ketone 18a (6.86 g, 19.5 mmol) was added portionwise to an
ice cooled solution of the Lombardo reagent[12] (174 mL, 58.0 mmol) dis-
solved in CH2Cl2 (70 mL). The resulting suspension was then stirred for
2 h at room temperature before saturated aqueous NaHCO3 (400 mL)
was added. The precipitate was filtered over Celite and washed with
CH2Cl2 (3”500 mL). Water (1000 mL) was added to the filtrate and the
mixture was extracted with CH2Cl2 (3”100 mL). The combined organic
layers were dried over Na2SO4 and concentrated under reduced pressure.
Column chromatography on silica gel (n-pentane/Et2O 9:1) afforded
128.4 (C-3’’, C-5’’), 128.3 (C-7’), 127.8 (C-4’’), 127.7 (C-2’’, C-6’’), 126.1
(C-5’), 123.0 (C-8’), 117.1 (C-4a’), 74.7 (CH2Ph), 74.2 (C-2’), 42.5 (C-5),
31.4 (C-3’), 26.8 (C-1), 24.4 (2’-CH3), 20.5 (C-4’), 11.8, 11.9, 12.8 ppm (5’-
CH3, 7’-CH3, 8’-CH3); IR (film): n˜ =2927, 1674, 1455, 1253, 1088,
984.9 cmꢀ1; UV (CH3CN): lmax (lge)=202.5 (4.749), 280.0 nm (3.374),
286.0 (3.380); MS (70 eV, EI): m/z (%): 378.3 (22) [M+], 287.2 (100) [M+
ꢀBn]; HRMS: m/z calcd for C25H30O3: 378.2195; found: 378.2195.
(2S)-5-(6-Benzyloxy-2,5,7,8,-tetramethylchroman-2-yl)pentan-2-one (23):
PtO2·H2O (19.5 mg, 0.08 mmol, 4 mol% Pt) was added to a solution of
enone 10 (725 mg, 1.92 mmol) dissolved in EtOAc (20 mL). The mixture
was stirred for 30 min under 1atm of hydrogen at room temperature and
then filtered over Celite (rinsing with EtOAc). The filtrate was concen-
trated under reduced pressure and the crude material was purified by
flash chromatography on silica gel (n-pentane/EtOAc 20:1) to give 23 as
a colorless oil (624 mg, 86%). 1H NMR (300 MHz, CDCl3): d=7.56–7.28
(m, 5H; Ar-H), 4.69 (s, 2H; CH2Ph), 2.60 (t, J=6.8 Hz, 2H; 4’-H2), 2.46
(dt, J=7.1, 4.1 Hz, 2H; 3-H2), 2.22, 2.17, 2.15 (3”s, 9H; 5’-CH3, 7’-CH3,
8’-CH3), 2.11 (s, 3H; 1-H3), 1.93–1.65 (m, 4H; 3’-H2, 4-H2), 1.65–1.47 (m,
2H; 5-H2), 1.27 ppm (s, 3H; 2’-CH3); 13C NMR (50.3 MHz, CDCl3): d=
208.9 (C-2), 148.1 (C-8a’), 147.6 (C-6’), 137.9 (C-1’’), 128.4 (C-3’’, C-5’’),
128.0 (C-7’), 127.7 (C-4’’), 127.6 (C-2’’, C-6’’), 126.0 (C-5’), 122.8 (C-8’),
117.4 (C-4a’), 74.6 (CH2Ph), 74.5 (C-2’), 43.9 (C-5), 38.9 (C-3), 31.2 (C-
3’), 29.8 (C-1), 23.7 (2’-CH3), 20.5 (C-4’), 18.0 (C-4), 12.8, 11.9, 11.8 ppm
(5’-CH3, 7’-CH3, 8’-CH3); IR (film): n˜ =2926, 1716, 1455, 1373, 1255,
1088, 735.4, 698.3 cmꢀ1; UV (CH3CN): lmax (lge)=204.0 (4.747), 287.5 nm
(3.367); MS (70 eV, EI): m/z (%): 378.3 (22) [M+], 287.2 (100) [M+
ꢀBn)]; HRMS: m/z calcd for C25H32O3: 380.5198; found: 380.5198.
alkene 18b as
a
colorless solid (6.00 g, 88%). 1H NMR (300 MHz,
CDCl3): d=7.50–7.31(m, 5H; Ar-H), 4.74 (s, 2H; 4 ’’-H2), 4.73 (s, 2H;
CH2Ph), 2.80–2.40 (m, 2H; 1’’-H2), 2.34 (s, 3H; 2’-H3), 2.20–1.90 (m, 2H;
2’’-H2), 2.27, 2.24, 2.00 (3”s, 9H; 2-CH3, 3-CH3, 5-CH3), 1.79 ppm (s, 3H;
3’’-CH3); 13C NMR (50.3 MHz, CDCl3): d=169.6 (C-1’), 153.3 (C-4),
145.8 (C-3’’), 144.0 (C-1), 137.6 (C-1’’’), 130.9 (C-6), 128.5 (C-3, C-2),
128.4 (C-3’’’, C-5’’’), 127.9 (C-4’’’), 127.7 (C-2’’’, C-6’’’), 127.4 (C-5), 109.9
(C-4’’), 74.3 (CH2Ph), 37.4 (C-2’’), 26.9 (C-1’’), 22.4 (3’’-CH3), 20.6 (C-2’),
13.2, 13.1, 12.3 ppm (2-CH3, 3-CH3, 5-CH3); IR (KBr): n˜ =3485, 3074,
2967, 1750, 1647, 1454, 1209, 1010 cmꢀ1; UV (CH3CN): lmax (lge)=268
(0.080), 200 nm (5.916); MS (70 eV, EI): m/z (%): 352 (40) [M+], 310
(20) [M+ꢀAc], 219 (100) [M+ꢀBnꢀAc]; HRMS: m/z calcd for
C23H28O3: 352.2038; found: 352.2083; elemental analysis calcd (%) for
C23H28O3 (352.40): C 77.32, H 7.65; found: C 78.38, H 8.01.
4-Benzyloxy-2,3,5-trimethyl-6-(3-methylbut-3-enyl)phenol (12):
A 5.4m
NaOMe solution (0.53 mL, 1.71 mmol) was added dropwise to a solution
of acetic ester 18b (6.00 g, 17.1 mmol) dissolved in methanol (150 mL).
The mixture was stirred for 3 h at room temperature and after consump-
tion of the starting material, the pH was adjusted to pH 7 by careful addi-
tion of Amberliteꢁ IR-120. The solvent was removed under reduced pres-
sure and the crude product purified by using column chromatography on
silica gel (PE/Et2O 99:1!90:10) to yield 12 as a colorless solid (4.69 g,
(2’R,8R)-1-(6-Benzyloxy-2,5,7,8-tetramethylchroman-2-yl)-8,12-dimethyl-
5-tridecen-4-one (24): iPr2NEt (339 mg, 2.61mmol) and cHex2BCl (2 mL
of an 1m solution in hexane, 196 mmol) were added dropwise at ꢀ788C
to a solution of methyl ketone 23 (497 mg, 1.31 mmol) dissolved in Et2O
(15 mL). The resulting white heterogeneous mixture was stirred for
30 min at ꢀ788C followed by slow addition of a solution of aldehyde 11
(419 mg, 2.61 mmol) dissolved in Et2O (25 mL) over 15 min. The mixture
was then stirred for 3 h at ꢀ788C before pH 7 buffer/MeOH (v/v 1:6) so-
1
88%). H NMR (300 MHz, CDCl3): d=7.53–7.30 (m, 5H; Ar-H), 4.80 (s,
2H; 4’-H2), 4.69 (s, 2H; CH2Ph), 4.50 (brs, 1H; OH), 2.80–2.72 (m, 2H;
1’-H2), 2.20–2.10 (m, 2H; 2’-H2), 2.25, 2.23, 2.15, (3”s, 9H; 3”Ar-CH3),
1.81 ppm (s, 3H; 3’-CH3); 13C NMR (50.3 MHz, CDCl3): d=149.2 (C-4),
147.9 (C-1), 146.3 (C-3’), 137.8 (C-1’’), 128.5 (C-3’’, C-5’’), 127.9 (C-4’’),
127.7 (C-2’’, C-6’’), 127.1 (C-2, C-6), 124.9 (C-3), 120.4 (C-5), 110.1 (C-4’),
74.6 (CH2Ph), 37.1(C-2 ’), 26.0 (C-1’), 22.7 (3’-CH3), 13.0, 12.3, 12.2 ppm
(2-CH3, 3-CH3, 5-CH3); IR (KBr): n˜ =3438, 3065, 2967, 2915, 2873, 1646,
A
and 30% H2O2/MeOH (v/v 1:2) solution (5 mL) was added. The ice bath
was removed and the reaction was stirred at room temperature for 1h.
The solution was diluted with Et2O (10 mL) and the combined organic
layers were washed with saturated aqueous NaHCO3, brine, and dried
over MgSO4. The solvent was removed under reduced pressure and the
crude product purified by using flash chromatography (n-pentane/EtOAc
20:1). p-Toluenesulfonic acid (45.1mg, 0.237 mmol) was added to a solu-
tion of the latter aldol product (635 mg, 1.18 mmol) dissolved in toluene
(10 mL). The resulting mixture was stirred at 608C for 30 min. Triethyla-
mine (24 mg, 0.240 mmol) and Et2O (10 mL) were added to the mixture
and the organic phase was washed with H2O (10 mL). The aqueous phase
was extracted with Et2O (3”5 mL) and the combined organic phases
were washed with saturated aqueous NaHCO3, brine, and dried over
MgSO4. The solvent was removed under reduced pressure and the crude
product purified by flash chromatography on silica gel (n-pentane/EtOAc
4:1) to give 24 as a colorless oil (560 mg, 82% over two steps). 1H NMR
(300 MHz, CDCl3): d=7.60–7.30 (m, 5H; Ar-H), 6.95–6.74 (m, 1H; 6-H),
6.10 (d, J=15.8 Hz, 1H; 5-H), 4.72 (s, 2H; CH2Ph), 2.74–2.48 (m, 4H; 1-
H2, 4’-H2), 2.24, 2.19, 2.12 (3”s, 9H; 5’-CH3, 7’-CH3, 8’-CH3), 2.31–1.99
(m, 2H; 3-H2), 1.92–1.72 (m, 4H; 3’-H2, 2-H2), 1.72–1.46 (m, 4H; 7-H2, 8-
H, 12-H), 1.29 (s, 3H; 2’-CH3), 1.38–1.06 (m, 8H; 1-H2, 9-H2, 10-H2, 1 1 -
H2), 0.89 (d, J=6.6 Hz, 3H; 8-CH3), 0.88 ppm (d, 6H; J=6.5 Hz, 6H; 12-
CH3, 13-H3); 13C NMR (75.5 MHz, CDCl3): d=200.4 (C-4), 148.2 (C-8a’),
147.7 (C-6’), 146.3 (C-6), 138.0 (C-1’’), 131.3 (C-5), 128.4 (C-3’’, C-5’’),
127.9 (C-7’), 127.7 (C-4’’), 127.6 (C-2’’, C-6’’), 126.0 (C-5’), 122.8 (C-8’),
117.5 (C-4a’), 74.6 (CH2Ph), 74.6 (C-2’), 40.3 (C-1), 39.9 (C-3), 39.1 (C-7),
39.1 (C-11), 36.9 (C-9), 32.6 (C-8), 31.2 (C-3’), 27.9 (C-12), 24.7 (C-10),
23.8 (2’-CH3), 22.6 (C-13), 22.5 (12-CH3), 20.6 (C-4’), 19.6 (8-CH3), 18.4
(C-2), 12.8, 12.0, 11.8 ppm (5’-CH3, 7’-CH3, 8’-CH3); IR (Film): n˜ =2926,
1673, 1455, 1373, 1255, 1088, 733.6 cmꢀ1; UV (CH3CN): lmax (lge)=204.0
(4.803), 282.0 nm (3.380), 287.5 (3.424); HRMS: m/z calcd for C35H52O4:
536.7850; found: 536.7850.
1455, 1375, 1329, 1262, 1156, 1087, 1069, 988, 886, 696 cmꢀ1
; UV
(CH3CN): lmax (lge)=191.0 (5.371), 201.0 (5.229), 284.5 nm (1.398), MS
(70 eV, EI): m/z (%): 310.3 (20) [M+], 219 (100), [M+ꢀBn]; HRMS: m/z
calcd for C21H26O2: 310.4299; found: 310.4299.
(2S)-5-(6-Benzyloxy-2,5,7,8,-tetramethylchroman-2-yl)-3-penten-2-one
(10): A mixture of palladium trifluoroacetate (6.4 mg, 19.8 mmol) and
(S,S)-Bn-BOXAX 8b (44.6 mg, 77.9 mmol) dissolved in CH2Cl2 (0.1mL,
degassed) was stirred for 30 min at room temperature, then treated with
p-benzoquinone (9, 84.9 mg, 0.785 mmol), and stirred for
a further
10 min. A solution of 12 (60.4 mg, 0.195 mmol) and methyl vinyl ketone
(13, 90.4 mg, 0.975 mmol) dissolved in CH2Cl2 (0.10 mL, degassed) was
added and the mixture was stirred at room temperature for 3 d (TLC
control). After consumption of the starting material, the mixture was
treated with 1n HCl (5 mL) and the aqueous phase extracted with Et2O
(3”10 mL). The combined organic phases were washed with 1 n NaOH
solution (3”5 mL), dried over MgSO4, and the solvent was removed
under reduced pressure. The crude product was purified by column chro-
matography (n-pentane/EtOAc 20:1) and chroman 10 was obtained as a
colorless oil (62 mg, 0.165 mmol, 84%, 97% ee). The enantiomeric excess
was determined by using HPLC on chiral stationary phase.[15] HPLC
(OD Chiracel): wavelength 210 nm, flow 0.8 mLminꢀ1, eluent: hexane/
isopropanol 97:3; tR =19.09 min ((ꢀ)-10); tR =28.31min (( +)-10); ee=
97%; 1H NMR (300 MHz, CDCl3): d=7.53–7.30 (m, 5H; Ar-H), 6.90
(ddd, J=16.0, 16.0, 7.9 Hz, 1H; 4-H), 6.11 (d, J=16.0 Hz, 1H; 3-H), 4.69
(s, 2H; CH2Ph), 2.62 (t, J=6.9 Hz, 2H; 4’-H2), 2.57 (dd, J=14.1, 8.0 Hz,
1H; 5-Hb), 2.51(dd, J=14.1, 7.4 Hz, 1H; 5-Ha), 2.27 (s, 3H; 1-H3), 2.23,
2.17, 2.11 (3”s, 9H; 5’-CH3, 7’-CH3, 8’-CH3), 1.83 (t, J=6.9 Hz, 2H; 3’-
H2), 1.29 ppm (s, 3H; 2’-CH3); 13C NMR (50.3 MHz, CDCl3): d=198.3
(C-2), 148.5 (C-8a’), 147.2 (C-6’), 143.6 (C-4), 137.8 (C-1’’), 134.0 (C-3),
8774
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 8770 – 8776

Enantioselective Domino Wacker–Heck Reaction
FULL PAPER
ACHTREUNG
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1047; b) H. N. Jacobson, Free Radical Biol. Med. 1987, 3, 209–213;
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1982, 2, 327; e) J. E. Packer, T. F. Slater, R. L. Willson, Nature 1979,
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Chem. 1956, 221, 797–805.
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b) R. V. Acuff, R. G. Dunworth, L. W. Webb, J. R. Lane, Am. J.
Clin. Nutr. 1998, 67, 459–464; c) C. Kiyose, R. Maramatsu, Y. Ka-
meyama, T. Ueda, O. Igarashi, Am. J. Clin. Nutr. 1997, 65, 785–789;
d) Ullmans Encyclopedia of Industrial Chemistry, Vol. A27 (Ed.: B.
Elvers), Wiley-VCH, Weinheim, 1996, pp. 478–488; e) K. U. Ingold,
G. W. Burton, D. O. Foster, L. Hughes, D. A. Lindsay, A. Webb,
Lipids 1987, 22, 163–172; f) S. C. Cheng, G. W. Burton, K. U.
Ingold, D. O. Foster, Lipids 1987, 22, 469–473.
[4] W. Bonrath, T. Netscher, Appl. Catal. A 2005, 280, 55–73.
[5] a) http://www.cognis.com/veris/FactSheets/VERISFS_vitaminE_Ger-
man.pdf; b) P. P. Hoppe, G. Krennrich, Eur. J. Nutr. 2000, 39, 183–
193; c) D. H. Blatt, W. A. Pryor, J. E. Mata, R. Rodriguez-Proteau,
J. Nutr. Biochem. 2004, 15, 380–395.
[6] For some additional enantioselective approaches, see: a) B. M. Trost,
H. C. Shen, L. Dong, J.-P. Surivet, C. Sylvain, J. Am. Chem. Soc.
2004, 126, 11966–11983; b) B. M. Trost, N. Asakawa, Synthesis
1999, 1491–1494, and references therein; c) L. F. Tietze, J. Gçrlitzer,
A. Schuffenhauer, M. Hübner, Eur. J. Org. Chem. 1999, 1075–1080,
and references therein; d) B. M. Trost, F. D. Toste, J. Am. Chem.
Soc. 1998, 120, 9074–9075; e) L. F. Tietze, J. Gçrlitzer, Synthesis
1998, 873–878; f) J. A. Hyatt, C. Skelton, Tetrahedron: Asymmetry
1997, 8, 523–526; g) L. F. Tietze, J. Gçrlitzer, Liebigs Ann./Recl.
1997, 2221–2225; h) L. F. Tietze, J. Gçrlitzer, Synlett 1997, 1049–
1050; i) L. F. Tietze, J. Gçrlitzer, Synthesis 1997, 877–885; j) L. F.
Tietze, J. Gçrlitzer, Synlett 1996, 11, 1041–1042; k) L. F. Tietze, K.
Schiemann, C. Wegner, J. Am. Chem. Soc. 1995, 117, 5851–5852;
l) H. Mayer, P. Schudel, R. Rüegg, O. Isler, Helv. Chim. Acta 1963,
46, 650–671.
[7] L. F. Tietze, K. M. Sommer, J. Zinngrebe, F. Stecker, Angew. Chem.
2005, 117, 262–264; Angew. Chem. Int. Ed. 2005, 44, 257–259.
[8] a) L. F. Tietze, G. Brasche, K. Gericke, Domino Reactions in Organ-
ic Synthesis, Wiley-VCH, Weinheim, 2006; b) L. F. Tietze, H. Ila,
H. P. Bell, Chem. Rev. 2004, 104, 3453–3516; c) L. F. Tietze, A.
Modi, Med. Res. Rev. 2000, 20, 304–322; d) L. F. Tietze, F. Haunert
in Stimulating Concepts in Chemistry (Eds.: F. Vçgtle, J. F. Stoddart,
M. Shibasaki), Wiley-VCH, Weinheim, 2000, pp. 39–64; e) L. F.
Tietze, M. E. Lieb, Curr. Opin. Chem. Biol. 1998, 2, 363–371; f) L. F.
Tietze, Chem. Rev. 1996, 96, 115–136; g) L. F. Tietze, U. Beifuss,
Angew. Chem. 1993, 105, 137–170; Angew. Chem. Int. Ed. Engl.
1993, 32, 131–163.
ACHTREUNG
in Et2O (10 mL) at ꢀ788C under argon and MeLi (1.6m solution in Et2O,
1mL, 1.6 mmol) was added dropwise. The resulting mixture was stirred
at this temperature for 1h, quenched with ice water (5 mL), and then al-
lowed to warm to room temperature. The layers were separated and the
aqueous phase was extracted with Et2O (3”10 mL). The combined or-
ganic extracts were washed with brine (10 mL) and dried over Na2SO4.
The solvent was removed under reduced pressure and the residue was re-
dissolved in toluene (10 mL). p-Toluenesulfonic acid (50.1mg,
0.260 mmol) was added and the resulting mixture was stirred at 608C for
30 min. After addition of triethylamine (26 mg, 0.260 mmol) and Et2O
(10 mL), the organic phase was washed with H2O (10 mL). The aqueous
phase was extracted with Et2O (3”5 mL), the combined organic extracts
were washed with saturated aqueous NaHCO3 (10 mL), brine (10 mL),
and dried over MgSO4. The solvent was removed under reduced pressure
and the crude product purified by using flash chromatography on silica
gel (n-pentane/EtOAc 50:1) to give 25 as colorless oil (532 mg, 76% over
two steps). 1H NMR (300 MHz, CDCl3): d=7.55–7.29 (m, 5H; Ar-H),
6.45–5.03 (m, 3H; 3-H, 5-H, 6-H), 4.69 (s, 2H; CH2Ph), 2.63–2.53 (m,
2H; 4’-H2), 2.22, 2.16, 2.10 (3”s, 9H; 5’-CH3, 7’-CH3, 8’-CH3), 1.72 (s,
3H; 4-CH3), 2.47–1.40 (m, 10H; 3’-H2, 1 -H, 2-H2, 7-H2, 8-H, 12-H), 1.27,
2
1.24 (s, 3H; 2’-CH3), 0.85 (d, J=6.4 Hz, 6H; 12-CH3, 13-H3), 1.38–
0.80 ppm (m, 9H; 8-CH3, 9-H2, 10-H2, 11-H2); 13C NMR (75.5 MHz,
CDCl3): d=148.1 (C-8a’), 147.8 (C-6’), 138.7 (C-6), 138.0 (C-1’’), 136.2
(C-4), 135.7 (C-5), 128.4 (C-3’’, C-5’’), 128.0 (C-7’), 127.7 (C-4’’), 127.6 (C-
2’’, C-6’’), 126.3 (C-5’), 126.0 (C-3), 122.9 (C-8’), 117.5 (C-4a’), 74.7
(CH2Ph), 74.6 (C-2’), 40.4, 40.1(C-2, C-7), 39.4 (C-1), 39.1(C-11), 36.87
(C-9), 31.4 (C-3’), 27.9 (C-12), 24.8 (2’-CH3), 22.6 (C-10), 22.6 (C-13, 12-
CH3), 20.7 (C-8), 20.6 (C-4’), 19.6 (8-CH3), 12.8 (7’-CH3), 12.3 (4-CH3),
12.00 (8’-CH3), 11.84, 11.82 ppm (5’-CH3); IR (Film): n˜ =2925, 1455,
1373, 1255, 1088, 732.5 cmꢀ1; UV (CH3CN): lmax (lge)=204.0 (4.803),
282.0 nm (3.380), 287.5 (3.424); HRMS: m/z calcd for C36H52O2:
516.7969; found: 516.7969.
(2R,4’RS,8’R)-a-Tocopherol (1): Palladium on charcoal (24 mg, 10
mol%) was added to
a degassed solution of diene 25 (97.0 mg,
0.188 mmol) dissolved in EtOAc (10 mL) and the reaction mixture was
shaken for 30 min at room temperature under an atmosphere of hydro-
gen (2 bar). The solution was filtered over Celite, washed with EtOAc,
and the filtrate was concentrated under reduced pressure. The crude ma-
terial was purified by using flash chromatography on silica gel (n-pen-
tane/EtOAc 20:1) to give 1 as a yellow oil as a 1:1 mixture together with
(2R,4’S,8’R)-a-tocopherol (73.1mg, 90%). 1H NMR (300 MHz, CDCl3):
d=4.16 (s, 1H; OH), 2.59 (t, J=6.9 Hz, 2H; 4-H2), 2.14, 2.09 (2”s, 9H;
5-CH3, 7-CH3, 8-CH3), 1.80 (dt, J=13.5, 6.9 Hz, 1H; 3-Hb), 1.74 (dt, J=
13.4, 6.9 Hz, 1H; 3-Ha), 1.21 (s, 3H; 2-CH3), 1.65–1.00 (m, 21H; 1’-H2, 2’-
H2, 3’-H2, 4’-H, 5’-H2, 6’-H2, 7’-H2, 8’-H, 9’-H2, 1 0’-H2, 1 1’-H2, 1 2’-H), 0.85
(d, J=6.5 Hz, 6H; 12’-CH3, 13-H3), 0.85 (d, J=6.4 Hz, 3H; 8’-CH3),
0.83 ppm (d, J=6.4 Hz, 3H; 4’-CH3); 13C NMR (150 MHz, CDCl3): d=
146.3 (C-8a), 145.9 (C-6), 122.9 (C-8), 122.4 (C-7), 120.4 (C-5), 117.0 (C-
4a), 74.79, 74.78 (C-2), 40.4 (C-1’), 40.3, 40.0 (C-11’), 38.32, 38.18 (C-3’),
38.17 (C-9’), 38.12, 38.11 (C-5’), 38.05, 38.04, 38.03 (C-7’), 33.46, 33.45 (C-
8’), 33.36, 33.35 (C-4’), 32.43, 32.37 (C-3), 28.6 (C-12’), 25.49, 25.48 (C-
10’), 25.06, 25.04 (C-6’), 24.13, 24.12, (2-CH3), 22.98, 22.89(12’-CH3, C-
13), 21.7, 21.6 (C-2’), 21.3 (C-4), 20.1 (8’-CH3), 20.0 (4’-CH3), 12.2 (7-
CH3), 12.0 (8-CH3), 11.8 ppm (5-CH3); IR (KBr): n˜ =2926, 1456, 1378,
[9] a) A. B. Dounay, L. E. Overman, Chem. Rev. 2003, 103, 2945–2964;
b) I. P. Beletskaya, A. V. Cheprakov, Chem. Rev. 2000, 100, 3009–
3066; c) A. de Meijere, E. F. Meyer in Metal-Catalyzed Cross-Cou-
pling Reactions (Eds.: F. Diederich, P. J. Stang), Wiley-VCH, Wein-
heim, 1998; d) M. Beller, T. H. Riermeir, G. Stark in Transition
Metals for Organic Synthesis (Eds.: M. Beller, C. Bolm), Wiley-
VCH, Weinheim, 1998.
1259, 1086 cmꢀ1
; UV (CH3CN): lmax (lge)=201.5 (4.653), 293.5 nm
(3.532); MS (70 eV, EI): m/z (%): 429.4 (10) [M+], 205.2 (100) [M+
ꢀC16H33]; HRMS: m/z calcd for C29H80O2: 430.7220; found: 430.7220.
[10] a) H. Hocke, Y. Uozumi, Synlett 2002, 2049–2053; b) T. Furutani,
M. Hatsuda, R. Imashiro, M. Seki, Tetrahedron: Asymmetry 1999,
10, 4763–4768; c) F. Dubois, M. Gingras, Tetrahedron Lett. 1998, 39,
5039–5040; d) Y. Uozumi, K. Kato, T. Hayashi, J. Am. Chem. Soc.
1997, 119, 5063–5064; e) M. B. Andrus, D. Asgari, J. A. Sclafani, J.
Org. Chem. 1997, 62, 9365–9368; f) Y. Uozumi, H. Kyota, E. Kishi,
K. Kitayama, T. Hayashi, Tetrahedron: Asymmetry 1996, 7, 1603–
1606; g) T. D. Nelson, A. I. Meyers, J. Org. Chem. 1994, 59, 2655–
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Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft (SFB
416) and the Fonds der Chemischen Industrie. We thank DSM-Vitamins
for reference samples and Symrise for supplying (R)-citronellol. F.S.
thanks the Deutsche Bundesstiftung Umwelt (DBU) for a Ph.D. scholar-
ship.
Chem. Eur. J. 2006, 12, 8770 – 8776
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8775

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Received: June 16, 2006
Published online: September 25, 2006
8776
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 8770 – 8776