Preparation of chiral building blocks for a highly convergent vitamin E synthesis. Systematic investigations on the enantioselectivity of the sharpless bishydroxylation

Article abstract of DOI:10.1055/s-1998-2076

The enantioselective bishydroxylation of protected 2-methylprop-2-enol 15 and 3-methylbut-3-en-1-ol 16 to give the corresponding diols 18 and 19, respectively, which can be transformed into building blocks for the synthesis of natural vitamin E, is described. It is shown that the enantioselectivity of the bishydroxylation reaction clearly depends on the type of protecting group and its distance from the alkene moiety, with 96% ee for 16a and 16f as the best and 8% ee for 15d as the lowest result.

Full text of DOI:10.1055/s-1998-2076

June 1998
SYNTHESIS
873
Preparation of Chiral Building Blocks for a Highly Convergent Vitamin E Synthesis.
Systematic Investigations on the Enantioselectivity of the Sharpless Bishydroxylation
Lutz F. Tietze,* Jochen Görlitzer
Institut für Organische Chemie, Georg-August-Universität, Tammannstrasse 2, D-37077 Göttingen, Germany
Fax +49(551)399476; E-mail: ltietze@gwdg.de
Received 15 August 1997; revised 4 November 1997
Dedicated to Professor C. Djerassi on the occasion of his 75th birthday
Benzylation of 10 gave the ether 1117 which was bishy-
Abstract: The enantioselective bishydroxylation of protected 2-
methylprop-2-enol 15 and 3-methylbut-3-en-1-ol 16 to give the
corresponding diols 18 and 19, respectively, which can be trans-
yield and a low 41% ee.17 Further transformations of 12
formed into building blocks for the synthesis of natural vitamin E,
is described. It is shown that the enantioselectivity of the bishy-
droxylated in the usual manner to give 1216 in 79% overall
according to a known protocol afforded 13.3
droxylation reaction clearly depends on the type of protecting
group and its distance from the alkene moiety, with 96% ee for
16a and 16f as the best and 8% ee for 15d as the lowest result.
Key words: vitamin E, protecting groups, arylation, bishydrox-
ylation, palladium
The enantioselective generation of the stereogenic center
C-2 in the chromane moiety of vitamin E (a-tocopherol)
1 with a tertiary ether group is a crucial step in the synthe-
sis of enantiopure vitamin E.1 Synthetic approaches aimed
at this goal have been based on optical resolution,2 the use
of enantiopure natural substrates,3 auxiliary controlled re-
actions,4 and asymmetric oxidations.5–8 In addition, a se-
lective allylation of an alkyl methyl ketone has been used
by us.6 In this paper we describe a convergent enantiose-
lective synthesis of the known enantiopure vitamin E pre-
cursor 93 using the Sharpless bishydroxylation9 of 3 and
16a–f to give 7 after deprotection and transformation into
the iodide, which was coupled with the iodoarene 8. In ad-
dition, the building block 13, which has also already been
used in the synthesis of vitamin E3, was prepared from 11
and 15. For the bishydroxylation reaction the influence of
the type of protecting group used in 3, 11, 15 and 16 on
the enantioselectivity was investigated.
a: NaH, BnBr, TBAI, THF. b: AD-Mix-a[(DHQ)2PHAL], t-BuOH,
H2O. c: MIPE, PPTS, CH2Cl2, 83%. d: Pd/C, 3 atm H2, EtOAc, 77%.
e: I2, PPh3, imidazole, MeCN, Et2O, 81%. f: Zn/Cu, Pd(PPh3)2Cl2,
DMF, benzene, 44%.
Scheme 1
Since the bishydroxylation of both 3 and 11 containing the
benzyl protecting group showed unsatisfactory enantiose-
lectivities, we investigated the influence of the protecting
group in correlation to the distance between the double
bond and the ether moiety. In this way we were able to im-
prove the enantioselectivity of the bishydroxylation up to
96% ee. For our investigations we used the phenyl, and the
2-, 3-, and 4-methoxyphenyl groups, as well as two 4-
methoxyphenyl groups with alkyl substituents in the ortho
position. The phenyl protecting groups derived from the
phenols 14a,c,d,e can be readily cleaved off by oxidative
methods, as shown for 22. For the synthesis of the protect-
ed allyl alcohols 15 and the homoallyl alcohols 16 the cor-
responding alcohols 10 and 2, respectively, were treated
with diisopropyl azodicarboxylate in the presence of
triphenylphosphane and the phenol 14 in a Mitsunobu-
The iodoarene 8 for the coupling reaction with the iodide
7 was prepared according to known procedures8, 10 and the
second iodide 7 was obtained in 5 steps starting from the
commercially available alcohol 2 (Scheme 1): benzyla-
tion of 2 to give 311 and subsequent bishydroxylation un-
der standard conditions (AD-Mix-a[(DHQ)2PHAL], t-
BuOH, H2O, 4°C, 24 h) afforded the monoprotected triol
4
14 in good yield but only moderate enantioselectivity (ee
= 53%). Acetalization with MIPE (methyl isopropenyl
ether) under PPTS catalysis and reductive cleavage of the
benzyl ether followed by an Appel-type reaction12 gave
the iodide 713 via 514 and 614 in 43% overall yield based
on 2. Coupling of iodide 7 and the iodoarene 8 was
achieved under palladium catalysis using the method of
Yoshida.15

874
Papers
SYNTHESIS
type reaction according to Fukuyama (Scheme 2).18 Com- Independent from the distance of the alkene moiety from
pound 15 could also be obtained in good yields by alkyla- the protecting group, the ethers 15a and 16a with the 4-
tion of the phenol 14 with methallyl chloride 17 (Table 1). methoxyphenyl group gave the highest enantioselectivi-
ties. The ee values decrease significantly with the migra-
tion of the methoxy group from the para (15a, 16a) to the
meta (15b, 16b) and to the ortho position (15c, 16c). The
bishydroxylation of the phenyl ether 15f without a substit-
uent showed a lower selectivity compared to 15a. Howev-
er, as already mentioned, the enantioselectivity of the
reaction of 16f, with ee = 96%, was as good as that of 16a.
The 4-methoxyphenyl ethers containing an alkyl group in
the ortho position, as 15d,e and 16d,e are again Iess suit-
able substrates for the bishydroxylation. This is especially
true for the ethers 15d,e.
Scheme 3. Ar: a–f as in Scheme 2
Table 2. Synthesis of the Monoprotected Triols 18a–f and 19a–f from
the Ethers 15a–f and 16a–f
a: diisopropyl azodicarboxylate, PPh3, CH2Cl2, 3 h, r.t. b: methallyl
chloride (1.5 equiv), acetone, K2CO3, NaI, 18 h, reflux.
Product
n
Substrate
Yield (%)
ee (%)
18a24
18b24
18c24
18d
1
1
1
1
1
1
2
2
2
2
2
2
15a
15b
15c
15d
15e
15f
16a
16b
16c
16d
16e
16f
95
91
91
79
94
84
93
94
93
94
92
86
90
85
24
8
14
77
96
86
80
77
92
96
Scheme 2
Table 1. Synthesis of the Aryl Ethers 15 and 16
18e25
18f24
19a23
19b
Product
n
ArOH 14
Method
Yield (%)
15a19
15b
1
1
1
1
1
1
2
2
2
2
2
2
a
b
c
d
e
f
a
b
c
d
e
f
a
b
b
a
b
b
a
a
a
a
a
a
93
86
83
89
82
87
86
89
91
91
83
79
19c
19d
19e
19f
15c20
15d
15e
15f20
16a
16b
16c
16d
We assume that the difference in the enantioselectivities
found for 15 and 16 depends on the conformation of the side
chain.Thisisunderlinedbyourresultsfromthebishydroxy-
lationof206 and21.7 Thereactionof20withthearylmoiety
separated by two methylene groups as in 15 gave a very low
enantioselectivity (ee = 28%), whereas the enyne 21 with its
slim alkyne moiety seems to fit very well into the enzyme-
like pocket of the catalyst (ee = 84%). Nevertheless thissub-
strate is not as good as the homoallyl ethers 16a and 16f.
Recently Corey23, 26 has pointed out that in substrates con-
tainingthreeatomsbetweenthealkeneandthearomaticring,
the side chain adopts a suitable conformation in the pocket of
the catalyst with little steric interaction, as shown by MM2
calculations. The decrease in the enantioselectivity of the
bishydroxylation using the substrates with an ortho substitu-
ent at an aryl moiety is also in accordance with published re-
sults.17, 27 The aryl ether 19a can easily be transformed into
enantiopure6byacetalizationwithMIPEunderPPTScatal-
ysistogive22followedbyoxidativecleavageofthe4-meth-
oxyphenyl group using cerium ammonium nitrate (CAN) to
afford 6 in 91% yield (Scheme 4).
16e
16f21
Bishydroxylation of 15a–f and 16a–f under standard con-
ditions (AD-Mix-a[(DHQ)2PHAL], t-BuOH, H2O, 4°C,
24 h) gave the monoprotected triols 18a–f and 19a–f in
good yields partly with excellent enantioselectivities (Ta-
ble 2). The enantiopurity of these compounds was deter-
mined by 1H and 19F NMR spectroscopy after conversion
into the corresponding Mosher esters.22 The following
general results were obtained (Scheme 3): for the aryl
ethers of 2-methylprop-2-enol 15 a dramatic difference in
the enantioselectivity of the bishydroxylation depending
on the aryl moiety is observed. For the aryl ethers 16 ob-
tained from 3-methylbut-3-en-1-ol (2) the difference is
much less pronounced and the enantioselectivities are
generally higher showing an ee = 96% for the 4-methoxy-
phenyl and the phenyl ether, 16a23 and 16f, respectively.

June 1998
SYNTHESIS
875
3-Benzyloxy-2-methylpropene (11): reaction of 10 according to Typi-
cal Procedure 1; yield 86%; colorless oil; bp 85°C/10 mbar.
1H NMR (200 MHz, CDCl3): d = 1.78 (s, 3H), 3.94 (s, 2H), 4.50 (s,
2H), 4.93 (s, 1H), 5.02 (s, 1H), 7.23–7.38 (m, 5H).
(S)-4-Benzyloxy-2-methylbutane-1,2-dio1 (4);TypicalProcedure 2:
AD-Mix-a[(DHQ)2PHAL] (1.4 g) was dissolved in t-BuOH/water
(10 mL 1:1) and cooled to 4°C. Compound 3 (192 mg, 1.00 mmol)
was added and the solution was stirred at this temperature for 24 h.
The solution was treated with Na2SO3 (1.5 g), stirred for 1 h at r.t. and
extracted with CH2Cl2 (1 ´ 15 mL, 3 ´ 10 mL). The combined organic
layers were dried (Na2SO4) and concentrated. The crude product was
purified by column chromatography (EtOAc/petroleum ether 1:1);
yield: 210 mg (92%); colorless oil; [a]D20 +3.5 (c = 2.2, CH2Cl2) [ent-
4 lit.14 [a]D20 +9.5 (c = 4.0, CHCl3)].
1H NMR (300 MHz, CDCl3, D2O-exchange): d = 1.18 (s, 3H), 1.71
(ddd, J = 15.0, 7.0, 4.5 Hz, 1H), 1.98 (ddd, J = 15.0, 7.0, 4.5 Hz, 1 H),
3.36 (d, J = 12.0 Hz, 1H), 3.46 (d, J = 12.0 Hz, 1H), 3.62–3.72 (m,
1H), 3.74–3.83 (m, 1H), 4.56 (s, 2H), 7.23–7.40 (m, 5H).
PMP = 4-methoxyphenyl. a: MIPE, PPTS, CH2Cl2, 93%. b: CAN,
MeCN, H2O, 91%.
Scheme 4
(R)-3-Benzyloxy-2-methylpropane-1,2-diol (12): reaction of 11 ac-
cording to Typical Procedure 2; yield: 92%; colorless oil; [a]D20 –3.4
(c = 2.0, CHCl3) [lit.16 [a]D20 –6.3 (c = 0.87, CH2Cl2)].
In conclusion we have shown that the nature of the aryl
group in the ethers 15 and 16, obtained from the methyl-
substituted allyl and homoallyl alcohols 10 and 2, re-
spectively, has a strong influence on the enantioselectiv-
ity of the bishydroxylation. This influence, however, is
much more pronounced for 15 compared to 16 in which
the ether group is one methylene group farther away
from the alkene moiety. By far the best results were
achieved with the 4-methoxyphenyl and phenyl ethers;
thus, the monoprotected triols 19a and 19f were obtained
in excellent yields and 96% ee. Since 19a can easily be
transformed into the vitamin E precursor 6, the bishy-
droxylation of the readily available ether 16a allows a
new, effective and highly enantioselective access to
enantiopure vitamin E.
1H NMR (300 MHz, CDCl3): d = 1.14 (s, 3H), 2.34 (mc, 1H), 2.79 (s,
1H), 3.45 (d, J = 10.0 Hz, 1H), 3.48 (dd, J = 12.0, 5.0 Hz, 1H), 3.52
(d, J = 10.0 Hz, 1H), 3.65 (dd, J = 12.0, 5.0 Hz, 1H), 4.56 (s, 2H),
7.23–7.41 (m, 5H).
(S)-4-(2-Benzyloxyethyl)-2,2,4-trimethyl-1,3-dioxolane (5); Typi-
cal Procedure 3:
To a solution of 4 (269 mg, 1.28 mmol) in CH2Cl2 (6 mL) was added
methyl isopropenyl ether (0.26 mL, 2.80 mmol) and PPTS (50 mg,
0.20 mmol) and the solution was stirred at r.t. for 4 h. The mixture was
diluted with Et2O (20 mL) and the organic layer was washed with wa-
ter and brine, dried (Na2SO4) and concentrated. The crude product
was purified by column chromatography (EtOAc/petroleum ether
1:8); yield: 267 mg (83%); colorless oil.
1H NMR (200 MHz, CDCl3): d = 1.28 (s, 3H), 1.36 (s, 3H), 1.38 (s,
3H), 1.93 (t, J = 7.0 Hz, 2H), 3.52 (m, 2H), 3.72 (d, J = 8.0 Hz, 1H),
3.92 (d, J = 8.0 Hz, 1H), 4.59 (s, 2H), 7.23–7.41 (m, 5H).
All reactions were carried out where appropriate in an inert atmo-
1
sphere. H NMR and 13C NMR spectra: Varian XL-200, VXR-200,
(S)-4-(2-Hydroxyethyl)-2,2,4-trimethyl-1,3-dioxolane (6):
To a solution of 5 (834 mg, 3.30 mmol) in EtOAc (10 mL) was added
Pd/C (80 mg, 10%) and the solution was stirred under an atmosphere
of H2 (3 atm) at r.t. for 20 h. After filtration from the catalyst and
evaporation of the solvent the crude alcohol was purified by column
chromatography (EtOAc/petroleum ether 1:2) and distillation; yield:
406 mg (77%); colorless oil; bp 85°C/0.1 mbar (lit.14 60–70°C/
0.1 Torr).
Bruker AMX-300. IR: Bruker IFS-25. MS and HMRS: MAT 95. El-
emental analyses: Analytical laboratory of the University of Göttin-
gen. Column chromatography: Macherey, Nagel & Co. Kieselgel 60
(0.063–0.200 mm). Analytical TLC: Macherey, Nagel & Co (SIL G/
UV254). Solvents (distilled from): Et2O (KOH or Na/benzophenone),
petroleum ether 40–80°C (KOH), EtOAc (CaH2), THF (LiAlH4).
Satisfactory elemental analyses (C, H ± 0.4%) or correct HRMS were
obtained for all new compounds.
1H NMR (200 MHz, CDCl3): d = 1.34 (s, 3H), 1.42 (s, 6H), 1.65–1.81
(m, 1H), 1.85–2.01 (m, 1H), 2.75 (s br, 1H), 3.71–3.96 (m, 4H).
4-Benzyloxy-2-methylbut-1-ene (3); Typica1 Procedure 1 for the
Benzylation of Alcohols:
To a suspension of NaH (820 mg, 20.5 mmol, 60% suspension in min-
eral oil) in THF (8 mL) was added 2 (2.00 mL, 20.0 mmol) in THF
(8 mL) dropwise at r.t. After the evolution of gas had ceased BnBr
(2.37 mL, 20.0 mmol) in THF (8 mL) and TBAI (200 mg, 0.54 mmol)
were added and the solution was stirred for 4 h at 40°C. Water was
added and the mixture was extracted with Et2O (2 ´ 100 mL) and the
combined organic layers were washed with water and brine, dried
(Na2SO4) and concentrated. The crude product was purified by distil-
lation; yield: 91% ; colorless oil; bp 100°C/8 mbar (lit.11 120 °C/
16 Torr).
(S)-4-(2-Iodoethyl)-2,2,4-trimethyl-1,3-dioxolane (7):
To a solution of imidazole (129 mg, 1.90 mmol), PPh3 (471 mg,
1.79 mmol) and 6 (160 mg, 1.00 mmol) in a mixture of Et2O (4 mL)
and MeCN (0.75 mL) was added at 0°C I2 (507 mg, 2.00 mmol) and
the solution was stirred 5 h in the dark at r.t. Water (2.0 mL) was add-
ed, the organic layer was washed with 5% Na2S2O3 (2 mL) and dried
(Na2SO4). After evaporation of the solvent the residue was subjected
to column chromatography (EtOAc/petroleum ether 1:8); yield:
216 mg (81%); colorless oil.
1H NMR (200 MHz, CDCl3): d = 1.27 (s, 3H), 1.38 (s, 6H), 2.06–2.35
(m, 1H), 3.09–3.30 (m, 2H), 3.71 (d, J = 9.0 Hz, 1H), 3.83 (d, J =
9.0 Hz, 1H).
1H NMR (200 MHz, CDCl3): d = 1.75 (s, 3H), 2.36 (t, J = 7.0 Hz, 2H),
3.60 (t, J = 7.0 Hz, 2H), 4.52 (s, 2H), 4.74 (s, 1H), 4.80 (s, 1H), 7.23–
7.39 (m, 5H).

876
Papers
SYNTHESIS
(S)-4-[2-(2,5-Dimethoxy-3,4,6-trimethylphenyl)ethyl]-2,2,4-tri-
methyl-1,3-dioxolane (9):
3-(2-Methoxyphenoxy)-2-methylpropene (15c): reaction of phenol
14c according to Typical Procedure 5; yield: 83%; colorless oil; bp
103°C/7 mbar.
To a solution of 7 (405 mg, 1.50 mmol) in a mixture of DMF (0.2 mL)
and benzene (3 mL) was added zinc/copper couple (150 mg,
2.30 mmol) and stirring was continued for 1 h at r.t. and 3 h at 60°C.
Then 8 (306 mg, 1.00 mmol) and Pd(PPh3)2Cl2 (14 mg, 0.02 mmol)
were added and the solution was stirred for 1 h at 60°C. The mixture
was diluted with Et2O (20 mL) and the organic layer was washed with
water and brine, dried (Na2SO4) and concentrated. The crude product
was purified by column chromatography (EtOAc/petroleum ether
1:11); yield: 139 mg (44%); colorless oil; [a]D20 +4.4 (c = 2.2, CHCl3)
[lit.4 [a]D20 +4.5 (c = 2.2, CHCl3)].
1H NMR (200 MHz, CDCl3): d = 1.85 (s, 3H), 3.89 (s, 3H), 4.53 (s,
2H), 4.99 (s, 1H), 5.09 (s, 1H), 6.91 (s, 4H).
2-Methyl-3-phenoxypropene (15f): reaction of phenol 14f according
to Typical Procedure 5; yield: 87%; colorless oil.
1H NMR (200 MHz, CDCl3): d = 1.83 (s, 3H), 4.43 (s, 2H), 4.98 (s,
1H), 5.09 (s, 1H), 6.95 (t, J = 8.0 Hz, 3H), 7.29 (t, J = 8.0 Hz, 2H).
4-(4-Methoxyphenoxy)-2-methylbut-1-ene (16a): reaction of 2 ac-
cording to Typical Procedure 4; yield: 86%; colorless oil.
1H NMR (200 MHz, CDCl3): d = 1.81 (s, 3H), 2.49 (t, J = 7.0 Hz, 2H),
3.88 (s, 3H), 4.05 (t, J = 7.0 Hz, 2H), 4.81 (s, 1H), 4.85 (s, 1H), 6.85
(s, 4H).
1H NMR (300 MHz, CDCl3): d = 1.40 (s, 1H), 1.44 (s, 3H), 1.46 (s,
3H), 1.65 (dt, J = 14.0, 7.0 Hz, 1H), 1.78 (dt, J = 14.0, 7.0 Hz, 1H),
2.18 (s, 6H), 2.23 (s, 3H), 2.69 (mc, 2H), 3.65 (s, 3H), 3.69 (s, 3H),
3.78 (d, J = 9.0 Hz, 1H), 3.89 (d, J = 9.0 Hz, 1H).
3-(4-Methoxyphenoxy)-2-methylpropene (15a); Typica1 Proce-
dure 4:
4-(3-Methoxyphenoxy)-2-methylbut-1-ene (16b): reaction of 2 ac-
cording to Typical Procedure 4; yield: 89%; colorless oil.
1H NMR (200 MHz, CDCl3): d = 1.82 (s, 3H), 2.50 (t, J = 7.0 Hz, 2H),
3.79 (s, 3H), 4.07 (t, J = 7.0 Hz, 2H), 4.81 (s, 1H), 4.86 (s, 1H), 6.48–
6.53 (m, 3H), 7.17 (t, J = 8.0 Hz, 1H).
To an ice-cold solution of 10 (0.85 mL, 10.0 mmol), PPh3 (3.6 g,
13.7 mmol) and 4-methoxyphenol 14a (3.85 g, 31.0 mmol) was add-
ed diisopropyl azodicarboxylate (2.71 mL, 13.7 mmol) and the solu-
tion was stirred for 3 h at r.t. The solvent was evaporated and the
residue purified by column chromatography (petroleum ether/t-
BuOMe 20:1); yield: 1.66 g (93%); colorless oil.
13C NMR (50 MHz, CDCl3): d = 22.8, 37.2, 55.1, 66.4, 101.0, 106.2,
106.7, 112.0, 129.8, 142.1, 160.1, 160.8.
IR (film): n = 1650 cm–1 (C=C).
1H NMR (200 MHz, CDCl3): d = 1.83 (s, 3H), 3.79 (s, 3H), 4.39 (s,
2H), 4.99 (s, 1H), 5.08 (s, 1H), 6.85 (s, 4H).
MS (70 eV, EI): m/z (%) = 192 (55, M+), 124 (100).
Anal.: C12H16O2 (192.1): calcd. C: 74.97, H: 8.39; found C: 75.14, H:
8.47.
3-(2-tert-Butyl-4-methoxyphenoxy)-2-methylpropene (15d): reaction
of 10 according to Typical Procedure 4; yield: 89%; colorless oil; bp
103°C/0.5 mbar.
4-(2-Methoxyphenoxy)-2-methylbut-1-ene (16c): reaction of 2 ac-
cording to Typical Procedure 4; yield: 91%; colorless oil; bp 100°C/
3 mbar.
1H NMR (200 MHz, CDCl3): d = 1.33 (s, 9H), 1.81 (s, 3H), 3.69 (s,
3H), 4.33 (s, 2H), 4.91 (s, 1H), 5.15 (s, 1H), 6.59 (dd, J = 9.0, 3.0 Hz,
1H), 6.73 (d, J = 9.0 Hz, 1H), 6.84 (d, J = 3.0 Hz, 1H).
13C NMR (50 MHz, CDCl3): d = 19.8, 29.7, 34.9, 55.5, 72.3, 109.7,
112.9, 114.3, 112.1, 139.7, 141.3, 151.8, 153.2.
1H NMR (200 MHz, CDCl3): d = 1.82 (s, 3H), 2.57 (t, J = 7.0 Hz, 2H),
3.87 (s, 3H), 4.13 (t, J = 7.0 Hz, 2H), 4.81 (s, 1H), 4.83 (s, 1H), 6.92
(s, 4H).
13C NMR (50 MHz, CDCl3): d = 22.9, 37.2, 55.9, 67.6, 112.0, 113.4,
120.8, 121.1, 142.1, 148.3, 149.5.
IR (film): n = 1658 (C=C), 1378 cm–1 (t-Bu).
MS (70 eV, EI): m/z (%) = 234.4 (51), 180 (100), 165 (93).
Anal.: C15H22O2 (234.1): calcd. C: 76.90, H: 9.46; found C: 76.96, H:
9.53.
IR (film): n = 1648 (C–C), 1504 cm–1 (arom. C=C).
MS (70 eV, EI): m/z (%) = 192 (47, M+), 124 (100).
HRMS : C12H16O2 (192.1): calcd. 192.1150; found 192.1150.
4-(2-tert-Butyl-4-methoxyphenoxy)-2-methylbut-1-ene (16d): reac-
tion of 2 according to Typical Procedure 4; yield: 91%; colorless oil;
bp 107°C/0.4 mbar.
3-(4-Methoxy-2-propylphenoxy)-2-methylpropene (15e); Typical
Procedure 5 for the b-Methallylation of Phenols:
To a solution of phenol 14e (4.99 g, 30.0 mmol) and K2CO3 (4.56 g,
33.0 mmol) in acetone (30 mL) were added b-methallyl chloride
(4.41 mL, 45.0 mmol) and NaI (320 mg, 2.00 mmol) and the mixture
was heated for 18–24 h to reflux. The solution was cooled and diluted
with t-BuOMe (100 mL) and water (400 mL). The organic layer was
extracted with 2 N NaOH (2 ´ 100 mL), washed with brine and dried
(Na2SO4). After evaporation of the solvent the residue was purified
by distillation; yield: 5.42 g (82%); colorless oil; bp 107°C/2 mbar.
1H NMR (200 MHz, CDCl3): d = 0.96 (t, J = 7.0 Hz, 3H), 1.63 (tq, J
= 7.0, 7.0 Hz, 2H), 1.84 (s, 3H), 2.60 (t, J – 7.0 Hz, 2H), 3.77 (s, 3H),
4.96 (s, 1H), 5.10 (s, 1H), 6.65–6.74 (m, 3H).
1H NMR (200 MHz, CDCl3): d = 1.36 (s, 9H), 1.80 (s, 3H), 2.55 (t, J
= 7.0 Hz, 2H), 3.77 (s, 3H), 4.05 (t, J = 7.0 Hz, 2H), 4.84 (s, 2H), 6.66
(dd, J = 9.0, 3.0 Hz, 1H), 6.79 (d, J = 9.0 Hz, 1H), 6.85 (d, J = 3.0 Hz,
1H).
13C NMR (50 MHz, CDCl3): d = 22.5, 29.7, 34.9, 37.7, 55.5, 66.5,
109.6, 112.2, 114.3, 112.2, 139.6, 142.1, 152.0, 153.1.
IR (film): n = 1652 (C=C), 1360 cm–1 (t-Bu).
MS (70 eV, EI): m/z (%) = 248 (79, M+), 180 (100), 165 (93).
Anal.: C16H24O2 (248.1): calcd. C: 77.46, H: 9.75 ; found C: 77.23, H:
9.53.
13C NMR (50 MHz, CDCl3): d = 14.1, 19.5, 23.1, 32.6, 55.5, 72.2,
110.5, 112.4, 116.3, 111.8, 132.7, 141.4, 150.8, 153.4.
4-(4-Methoxy-2-propylphenoxy)-2-methylbut-1-ene (16e): reaction of
2 according to Typical Procedure 4; yield: 83%; colorless oil; bp
102°C/1.5 mbar.
IR (film): n = 1658 (C=C), 1500 (arom. C=C), 1062 cm–1 (OCH3).
MS (70 eV, EI): m/z (%) = 220 (100, M+), 165 (47), 137 (26).
Anal.: C14H20O2 (220.1): calcd. C: 76.31, H: 9.16; found C: 76.39, H:
9.37.
1H NMR (200 MHz, CDCl3): d = 0.94 (t, J = 7.0 Hz, 3H), 1.60 (tq, J
= 7.0, 7.0 Hz, 2H), 1.81 (s, 3H), 2.44–2.61 (m, 4H), 3.76 (s, 3H), 4.01
(t, J = 7.0 Hz, 2H), 4.80 (s, 1H), 4.82 (s, 1H), 6.6l–6.80 (m, 3H).
13C NMR (50 MHz, CDCl3): d = 14.0, 22.5, 23.1, 32.4, 37.5, 55.3,
66.9, 110.4, 112.0, 116.2, 116.8, 132.5, 142.3, 150.9, 153.3.
IR (film): n = 1650 (C=C), 1500 (arom. C=C), 1078 cm–1 (OCH3).
MS (70 eV, EI): m/z (%) = 234 (37, M+), 166 (100), 137 (42).
Anal.: C15H22O2 (234.1): calcd. C: 76.78, H: 9.47; found C: 77.04, H:
9.52.
3-(3-Methoxyphenoxy)-2-methylpropene (15b): reaction of phenol
14b according to Typical Procedure 5; yield: 86%; colorless oil; bp
105 °C/7 mbar.
1H NMR (200 MHz, CDCl3): d = 1.84 (s, 3H), 3.80 (s, 3H), 4.48 (s,
2H), 5.00 (s, 1H), 5.11 (s, 1H), 6.47–58 (m, 3H), 7.18 (t, J = 8.0 Hz,
lH).

June 1998
SYNTHESIS
877
2-Methyl-4-phenoxybut-1-ene (16f): reaction of 2 according to Typi- (S)-4-(3-Methoxyphenoxy)-2-methylbutane-1,2-diol (19b): reaction
cal Procedure 4; yield: 79%; colorless oil; bp 82°C/6 mbar.
1H NMR (200 MHz, CDCl3): d = 1.81 (s, 3H), 2.51 (t, J = 7.0 Hz, 2H),
4.08 (t, J = 7.0 Hz, 2H), 4.80 (s, 1H), 4.83 (s, 1H), 6.95 (t, J = 8.0 Hz,
3H), 7.29 (t, J = 8.0 Hz, 2H).
of 16b according to Typical Procedure 2; yield: 94%; colorless oil;
[a]D20 +5.7 (c = 1.0, CH2Cl2).
1H NMR (300 MHz, CDCl3): d = 1.26 (s, 3H), 1.96 (ddd, J = 15.0,
6.0, 3.5 Hz, 1H), 2.15 (ddd, J = 15.0, 8.0, 4.5 Hz, 1H), 3.62–3.81 (m,
2H), 3.80 (s, 3H), 4.07–4.29 (m, 2H), 6.45–6.59 (m, 3H), 7.20 (t, J =
8.0 Hz, 1H).
(R)-3-(4-Methoxyphenoxy)-2-methylpropane-1,2-diol (18a): reaction
of 15a according to Typical Procedure 2; yield: 95%; white solid;
[a]D20 –0.4 (c = 2.0, CHCl3).
13C NMR (50 MHz, CDCl3): d = 23.7, 37.2, 55.1, 64.3, 69.8, 72.3,
100.9, 106.5, 106.6, 129.8, 159.4, 160.7.
IR (film): n = 3404 (OH), 1602 cm–1 (arom. C=C).
MS (70 eV, EI): m/z (%) = 226 (15, M+), 124 (100).
Anal.: C12H18O4 (226.1): calcd. C: 63.70, H: 8.02; found C: 63.95, H:
7.93.
1H NMR (300 MHz, CDCl3): d = 1.28 (s, 3H), 2.15 (t, J = 6.5 Hz, 1H),
2.79 (s, 1H), 3.58 (dd, J = 12.0, 6.5 Hz, 1H), 3.74 (dd, J = 12.0,
6.5 Hz, 1H), 3.78 (s, 3H), 3.86 (d, J = 9.0 Hz, 1H), 3.94 (d, J = 9.0 Hz,
1H), 6.96 (s, 4H).
(S)-4-(2-Methoxyphenoxy)-2-methylbutane-1,2-diol (19c): reaction
of 16c according to Typical Procedure 2; yield: 93%; colorless oil;
[a]D20 +10.7 (c = 1.0, CH2Cl2).
(R)-3-(3-Methoxyphenoxy)-2-methylpropane-1,2-diol (18b): reaction
of 15b according to Typical Procedure 2; yield: 91%; white solid;
[a]D20 0.0 (c = 1.0, CH2Cl2).
1H NMR (300 MHz, CDCl3): d = 1.24 (s, 3H), 1.96 (ddd, J = 15.0,
6.5, 3.5 Hz, 1H), 2.15 (ddd, J = 15.0, 8.0, 4.0 Hz, 1H), 3.46 (d, J =
12.0 Hz, 1H), 3.54 (d, J = 12.0 Hz, 1H), 3.86 (s, 3H), 4.10–4.26 (m,
2H), 6.85–6.99 (m, 4H).
1H NMR (300 MHz, CDCl3): d = 1.22 (s, 3H), 3.51 (d, J = 11.0 Hz,
lH), 3.66 (d, J = 11.0 Hz, 1H), 3.70 (s, 3H), 3.82 (d, J = 9.0 Hz, 1H),
3.89 (d, J = 9.0 Hz, 1H), 6.39–6.51 (m, 3H), 7.18 (t, J = 8.0 Hz, 1H).
13C NMR (50 MHz, CDCl3): d = 24.1, 37.5, 55.6, 65.4, 69.8, 72.9,
111.2, 112.3, 120.8, 121.4, 148.3, 149.5.
(R)-3-(2-Methoxyphenoxy)-2-methylpropane-1,2-diol (18c): reaction
of 15c according to Typical Procedure 2; yield: 91%; white solid;
[a]D20 –2.0 (c = 1.0, CH2Cl2).
IR (film): n = 3380 (OH), 1506 cm–1 (arom. C=C).
MS (70 eV, EI): m/z (%) = 226 (23, M+), 124 (100).
Anal.: C12H18O4 (226.1): calcd C: 63.70, H: 8.02; found C: 63.73, H:
7.90.
1H NMR (300 MHz, CDCl3): d = 1.22 (s, 3H), 3.59 (d, J = 12.0 Hz,
1H), 3.74 (d, J = 12.0 Hz, 1H), 3.85 (s, 3H), 3.94 (d, J = 9.0 Hz, 1H),
4.02 (d, J = 9.0 Hz, 1H), 6.85–7.04 (m, 4H).
(S)-4-(2-tert-Butyl-4-methoxyphenoxy)-2-methylbutane-1,2-diol
(19d): reaction of 16d according to Typical Procedure 2; yield: 94%;
white solid; mp 61°C (hexane/t-BuOMe); [a]D20 +3.6 (c = 2.0,
CHCl3).
(R)-3-(2-tert-Butyl-4-methoxyphenoxy)-2-methylpropane-1,2-diol (18d):
reaction of 15d according to Typical Procedure 2; yield: 79%; white sol-
id; mp 63°C (hexane/t-BuOMe); [a]D20 –0.5 (c = 2.0, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.36 (s, 3H), 1.39 (s, 9H), 2.07 (t, J
= 6.0 Hz, 1H), 2.50 (s, 1H), 3.63 (dd, J = 12.0, 6.0 Hz, 1H), 3.76 (s,
3H), 3.77 (dd, J = 12.0, 6.0 Hz, 1H), 3.89 (d, J = 10.0 Hz, 1H), 3.93
(d, J = 10.0 Hz, 1H), 6.68 (dd, J = 9.0, 3.0 Hz, 1H), 6.85 (d, J = 9.0 Hz,
1H), 6.91 (d, J = 3.0 Hz, 1H).
1H NMR (300 MHz, CDCl3, D2O-exchange): d = 1.30 (s, 3H), 1.37
(s, 9H), 1.92–2.04 (m, 1H), 2.11–2.23 (m, 1H), 3.48 (d, J = 7.0 Hz,
1H), 3.57 (d, J = 7.0 Hz, 1H), 3.77 (s, 3H), 4.06–4.25 (m, 2H), 6.68
(dd, J = 8.0, 3.0 Hz, 1H), 6.86–6.91 (m, 2H).
13C NMR (50 MHz, CDCl3): d = 23.8, 29.8, 34.8, 37.9, 55.5, 65.2,
69.9, 72.2, 109.9, 113.7, 114.3, 139.7, 151.8, 153.3.
IR (KBr): n = 3328 (OH), 1502 (arom. C=C), 1360 cm–1 (t-Bu).
MS (70 eV, EI): m/z (%) = 282 (34, M+), 180 (100), 165 (45).
Anal.: C16H26O4 (282.1): calcd. C: 68.04, H: 9.29; found C: 68.06, H:
9.22.
13C NMR (50 MHz, CDCl3): d = 22.0, 29.9, 34.8, 55.5, 67.4, 72.5,
72.6, 109.8, 112.9, 114.4, 139.4, 151.4, 153.4.
IR (KBr): n = 3402 (OH), 1586 (arom. C=C), 1362 cm–1 (t-Bu).
MS (70 eV, EI): m/z (%) = 268 (67, M+), 180 (100), 165 (91).
Anal.: C15H24O4 (268.1): calcd. C: 67.20, H: 8.95; found C: 67.14, H:
9.08.
(R)-3-(4-Methoxy-2-propylphenoxy)-2-methylpropane-1,2-diol
(18e): reaction of 15e according to Typical Procedure 2; yield: 94%;
colorless oil; [a]D20 0.0 (c = 1.0, CH2Cl2).
(S)-4-(4-Methoxy-2-propylphenoxy)-2-methylbutane-1,2-diol (19e):
reaction of 16e according to Typical Procedure 2; yield: 92%; color-
less oil; [a]D20 +6.3 (c = 1.0, CH2Cl2).
1H NMR (200 MHz, CDCl3): d = 0.96 (t, J = 7.0 Hz, 3H), 1.30 (s, 3H),
1.64 (tq, J = 7.0, 7.0 Hz, 2H), 2.12 (t, J = 6.0 Hz, 1H), 2.57 (t, J =
7.0 Hz, 2H), 2.65 (s, 1H), 3.58 (dd, J = 12.0, 6.0 Hz, 1H), 3.76 (dd, J
= 12.0, 6.0 Hz, 1H), 3.77 (s, 3H), 3.81 (d, J = 10.0 Hz, 1H), 3.87 (d,
J = 10.0 Hz, 1H), 6.63–6.84 (m, 3H).
1H NMR (200 MHz, CDCl3): d = 0.96 (t, J = 7.0 Hz, 3H), 1.28 (s, 3H),
1.48–1.72 (m, 2H), 1.84–2.24 (m, 2H), 2.28 (t, J = 7.0 Hz, 1H), 2.54
(t, J = 7.0 Hz, 2H), 2.95 (s, 1H), 3.45–3.66 (m, 2H), 3.77 (s, 3H),
4.04–4.30 (m, 2H), 6.68 (dd, J = 3.0, 8.5 Hz, 1H), 6.72 (d, J = 3.0 Hz,
1H), 6.81 (d, J = 8.5 Hz, 1H).
13C NMR (50 MHz, CDCl3): d = 14.1, 23.8, 23.1, 32.4, 37.6, 55.6,
65.3, 69.9, 72.5, 110.7, 112.4, 116.3, 132.3, 150.6, 153.6.
IR (film): n = 3402 (OH), 1500 cm–1 (arom. C=C).
(R)-2-Methyl-3-phenoxypropane-1,2-diol (18f): reaction of 15f ac-
cording to Typical Procedure 2; yield: 84%; white solid; [a]D20 –0.7 (c
= 1.0, CH2Cl2).
MS (DCI, NH3): m/z (%) = 554 (100, [2·M + NH4+]), 286 (58, [M +
NH4+]), 268 (23, M+).
1H NMR (200 MHz, CDCl3): d = 1.30 (s, 3H), 2.07 (t, J = 6.0 Hz, 1H),
2.67 (s, 1H), 3.58 (dd, J = 11.0, 6.5 Hz, 1H), 3.74 (dd, J = 11.0,
6.5 Hz, 1H), 3.91 (d, J = 9.0 Hz, 1H), 4.03 (d, J = 9.0 Hz, 1H), 6.81–
7.02 (m, 3H), 7.26 (t, J = 8.0 Hz, 2H).
HRMS: C15H24O4 (268.1): calcd. 268.1675; found 268.1675.
(S)-2-Methyl-4-phenoxybutane-1,2-diol (19f): reaction of 16f accord-
ing to Typical Procedure 2; yield: 86%; white solid; mp 54°C (cyclo-
hexane/t-BuOMe); [a]D20 +7.0 (c = 1.0, CH2Cl2).
(S)-4-(4-Methoxyphenoxy)-2-methylbutane-1,2-diol (19a): reaction
of 16a according to Typical Procedure 2; yield: 93%; white solid;
[a]D20 +6.3 (c = 2.0, CHCl3).
1H NMR (200 MHz, CDCl3): d = 1.26 (s, 3H), 1.86–2.01 (m, 1H),
2.06–2.22 (m, 1H), 3.47 (d, J = 11.0 Hz, 1H), 3.55 (d, J = 11.0 Hz,
1H), 4.08–4.19 (m, 2H), 6.87 (m, 3H), 7.25 (t, J = 8.0 Hz, 2H).
13C NMR (50 MHz, CDCl3): d = 24.0, 37.4, 64.5, 70.0, 72.4, 114.5,
121.2, 129.5, 158.1.
1H NMR (200 MHz, CDCl3): d = 1.26 (s, 3H), 1.91 (ddd, J = 15.0,
6.0, 4.5 Hz, 1H), 2.11 (ddd, J = 15.0, 6.0, 4.5 Hz, 1H), 3.47 (d, J =
10.0 Hz, 1H), 3.56 (d, J = 10.0 Hz, 1H), 3.77 (s, 3H), 4.02–4.25 (m,
2H), 6.84 (s, 4H).
IR (KBr): n = 3354 (OH), 1502 cm–1 (arom. C=C).

878
Papers
SYNTHESIS
MS (70 eV, EI): m/z (%) = 196 (13, M+), 165 (21), 94 (100).
Anal.: C11H16O3 (196.1): calcd. C: 67.31, H: 8.22; found C: 67.48, H:
8.22.
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(S)-4-[2-(4-Methoxyphenoxy)ethyl]-2,2,4-trimethyl-1,3-diox-
olane (22):
Reaction of 19a according to Typical Procedure 3; yield: 93%; color-
less oil; [a]D20 –5.0 (c = 1.0, CH2Cl2).
1H NMR (300 MHz, C6D6): d = 1.16 (s, 3H), 1.36 (s, 3H), 1.40 (s,
3H), 1.91 (t, J = 7.0 Hz, 2H), 3.35 (s, 3H), 3.55 (d, J = 8.0 Hz, 1H),
3.76 (d, J = 8.0 Hz, 1H), 3.80–3.96 (m, 2H).
13C NMR (50 MHz, C6D6): d = 25.15, 27.25, 27.51, 39.35, 55.22,
64.94, 74.61, 79.95, 109.1, 115.0, 115.6, 153.5, 154.4.
IR (film): n = 1510 (arom. C=C), 1376 cm–1 [C(CH3)2].
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