Synthesis of chiral acetals by asymmetric selenenylations

Article abstract of DOI:10.1080/10426500902930167

Asymmetric selenenylations of (E)-ethoxystyrene are described leading to chiral acetals. An efficient synthesis of such compounds including the determination of their absolute configuration is described.

Full text of DOI:10.1080/10426500902930167

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Phosphorus, Sulfur, and Silicon
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Synthesis of Chiral Acetals by
Asymmetric Selenenylations
Lars Uehlin a & Thomas Wirth a
a School of Chemistry , Cardiff University , Cardiff,
UK
Published online: 06 Jun 2009.
To cite this article: Lars Uehlin & Thomas Wirth (2009) Synthesis of Chiral Acetals
by Asymmetric Selenenylations, Phosphorus, Sulfur, and Silicon and the Related
Elements, 184:6, 1374-1385, DOI: 10.1080/10426500902930167
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Phosphorus, Sulfur, and Silicon, 184:1374–1385, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902930167
Synthesis of Chiral Acetals by Asymmetric
Selenenylations
Lars Uehlin and Thomas Wirth
School of Chemistry, Cardiff University, Cardiff, UK
Asymmetric selenenylations of (E)-ethoxystyrene are described leading to chiral
acetals. An efficient synthesis of such compounds including the determination of
their absolute configuration is described.
Keywords Acetals; selenium electrophiles; stereoselective synthesis
INTRODUCTION
For several decades now, selenium reagents have attracted growing
interest for their applications in organic synthesis.1−4 The use of enan-
tiomerically pure selenium electrophiles for the functionalization of
double bonds has received particular attention, as a broad range of
compounds is accessible using this methodology.5
The addition of selenium electrophiles to enol ethers of type 1 leads
to the formation of seleniranium cations with the higher positive charge
located at the carbon atom next to the oxygen, due to resonance stabi-
lization. Nucleophilic attack by an alcohol will then form the acetal 2.
This protocol has been known for a long time and is a well established
method for glycosylation in carbohydrate chemistry.6 If the ether moi-
ety is different from the attacking alcohol, a new stereogenic center
will be formed. Cleavage of the selenium functionality will then yield
an enantiomerically enriched acetal 3, with the acetal carbon as the
only stereocenter in the molecule (Scheme 1).
Received 19 December 2007; accepted 13 January 2008.
Dedicated to Professor Marian Mikolꢀajczyk, CBMiM PAN in Lꢀ o´dz´, Poland, on the
occasion of his 70th birthday.
We are thankful for the high-resolution mass spectrometric data obtained from the
EPSRC National Mass Spectrometry Service Centre, Swansea, UK. We thank the Swiss
National Science Foundation (SNF) for support.
Address correspondence to Thomas Wirth, School of Chemistry, Cardiff University,
Cardiff CF10 3AT, UK. E-mail: wirth@cf.ac.uk
1374

Synthesis of Chiral Acetals
1375
SCHEME 1
The use of chiral selenium electrophiles in such a reaction sequence
will consequently allow the formation of enantiomerically enriched ac-
etals. Although several of these compounds have already been isolated
from biological systems, their optical purities and absolute configura-
tions were not established. Only one route to this class of molecules has
been reported.7
RESULTS AND DISCUSSION
The unsaturated compound (E)-ethoxystyrene 4 was applied due to its
structural similarity to styrene and because of the better reactivity of
(E)-alkenes compared to the corresponding (Z)-derivatives. Compound
4 was prepared in one step from phenyl acetaldehyde, sodium amide,
and diethylsulfate, although a separation of the (E)- and (Z)-isomers
was necessary.8 The subsequent reaction with the selenium electrophile
5 at –100◦C yielded the addition product 6 in 87% yield with a diastere-
1
omeric excess of 80%, determined by analysis of the H and 13C NMR
spectra. Radical cleavage of the carbon–selenium bond using triph-
enyltin hydride and AIBN gave the acetal 7 with 62% ee (Scheme 2).
This observation was in agreement with the literature, where a loss of
optical purity by the removal of the selenium function was observed.7
SCHEME 2
The optical purity of 7 was determined by GC using a chiral col-
umn and compared to the racemate, which was obtained by transac-
etalization from phenylacetaldehyde dimethylacetal and ethanol with
hydrochloric acid.9 To obtain a higher selectivity in the methoxysele-
nenylation reaction, a C2-symmetrical reagent was developed that was
able to coordinate to the selenium from two directions and therefore

1376
L. Uehlin and T. Wirth
have a higher influence on the direction from which the electrophilic
attack will occur. Although structurally related compounds have al-
ready been described in literature,10,11 their long-winded and arduous
synthesis recommended the design of a new approach.
Oxidation of the two methyl groups of 2-bromoxylene 8 was achieved
with chromium trioxide to give 2-bromoisophthalaldehyde 9.12 This
was subjected to an asymmetric diethylzinc addition using 1 mol%
of the nitrogen-containing diselenide 10 as a catalyst, leading to
the chiral diol 11.13,14 Protecting the hydroxy functionalities as the
methoxymethyl ether (MOM) derivatives with chloromethyl methyl
ether gave 19% of the mono- (12) and 76% of the dimethoxylated
compound 13 (Scheme 3). Both compounds could be transferred into
their corresponding mixed oxo-seleno acetals by halogen-metal ex-
change with t-BuLi and subsequent addition of the dimethoxymethyl
diselenide.15 Applying the selenenyl triflate 5d generated from 15 for
the methoxyselenenylation of (E)-ethoxystyrene showed a somewhat
decreased yield of 63%, but no other diastereomer in the NMR spec-
tra. Therefore the diastereomeric excess was assumed to be higher
than 95%. The selenium function was removed by radical cleavage,
and the enantiomeric excess of the acetal 7 was determined to be 86%
(Table I).
SCHEME 3
The last step was the determination of the absolute configuration
of the acetal 7. To determine the configuration at the stereogenic cen-
ter of 7, (E)-ethoxystyrene 4 was methoxyselenenylated, using elec-
trophile 5a. The obtained asymmetric acetal 6a was hydrolyzed with
aqueous trifluoroacetic acid to the corresponding aldehyde, which was

Synthesis of Chiral Acetals
1377
TABLE I Methoxyselenenylation of (E)-Ethoxystyrene
Selenium electrophile
6 Yield
6 de
7 ee
5a
5b
5c
76%
54%
n.d.a
87%
80%
62%
n.d.a
n.d.a
46% (70% yield)
5d
63%
> 95%
86%
aNot determined.
subsequently reduced to the alcohol 16 using sodium borohydride. The
diastereomeric excess of 16 was found to be 54% according to the opti-
cal rotation, although the deviation was relatively high, due to a small
amount of substance. The absolute configuration was assigned by com-
parison of the optical rotation with compound 16, which had been ob-
tained by selenolate opening of styrene epoxide. The nucleophilic open-
ing of (S)-styrene oxide 17 by enantiomerically pure selenolate 18 leads
to two different products, depending upon which carbon atom of the
epoxide function will be attacked (Scheme 4). The opening at the ben-
zylic carbon leads to the β-phenylethanol derivative 16.16
As an interesting result, the investigations showed that the attack of
the selenium electrophile occurs from the si-face of (E)-ethoxystyrene,
whereas for (E)-methylstyrene, the attack occurs from the re-face. This
result was in accordance with ab initio calculations. Thus, the changed
electronic situation due to the introduction of the ethoxy moiety must be
assumed to have a very strong influence on the selectivity. Furthermore,

1378
L. Uehlin and T. Wirth
SCHEME 4
it was possible to separate the diastereomers of 6a by preparative TLC.
To avoid hydrolysis of the acetal, it was necessary to treat the plates
with triethylamine in order to eliminate acidic residues. This protocol
is therefore promising to be a versatile route to obtain chiral acetals of
type 7 also in enantiomerically pure form.
EXPERIMENTAL
1H and 13C NMR experiments were carried out on a Varian Gemini 300
and on a Bruker 400-DPX spectrometer. IR measurements were taken
using a Perkin-Elmer 1600FTIR spectrometer as a liquid film. Low
resolution mass spectrometry was carried out using a Varian Saturn
2 GC-MS. Flash chromatography was carried out using Fisher Silica
Gel (35–70 mesh). Preparative thin layer chromatography was carried
out using Merck silica gel 60 F254 on glass plates. All solvents used
were dried and purified by standard methods. Reactions requiring the
exclusion of air were carried out under an atmosphere of argon in oven-
dried glassware.
Addition of Selenium Electrophiles to Styrene (GP1): General
Procedure
The diselenide (0.1 mmol) or methoxymethylselenide (0.2 mmol) was
dissolved in dry diethyl ether (4 mL) under argon, cooled to 0◦C, and
treated with bromine (0.11 mmol, 0.11 mL of a 1 M solution in car-
bon tetrachloride). After 10 min, a solution of silver triflate (72 mg,
0.28 mmol) in methanol (0.1 mL) was added and stirred for 10 min at
–78◦C. The reaction mixture was cooled to –100◦C and treated with
styrene (0.4 mmol, 0.046 mL). After stirring for 3–4 hours at –100◦C,
sym-collidine (0.3 mmol, 0.04 mL) was added followed by water (4 mL).
After extraction of the reaction mixture with tert.-butyl methyl ether
(3 × 10 mL), drying of the combined organic phases with magnesium

Synthesis of Chiral Acetals
1379
sulfate, and removal of the solvent under reduced pressure, the residue
was purified by flash chromatography on silica gel yielding the addi-
tion products as colorless oils. Enrichment of diastereomers by flash
chromatography was excluded by comparison with the diastereomeric
excess of the crude reaction mixtures. Spectroscopic data are given only
for the major diastereomers.
Synthesis of Methoxymethyl Selenides from Bromo
Precursors (GP2): General Procedure
The bromo precursor (2.0 mmol) was dissolved in dry THF (20 mL)
under argon, cooled to –78◦C, and treated slowly with tert-butyllithium
(6.0 mmol, 1.6 M in hexane) (in case of a phenol functionality 8.0
mmol). After warming up and stirring for 30 min at room tempera-
ture (2 h, in case of a phenol moiety), dimethoxymethyl diselenide15
(0.55 g, 2.2 mmol) was added. The mixture was allowed to warm up to
room temperature and stirred for an additional 3 h, then hydrochloric
acid (20 mL, 1 M) was added. After extraction of the resulting mix-
ture with tert-butyl methyl ether (3 × 25 mL) and drying of the com-
bined organic phases with magnesium sulfate, powdered potassium
hydroxide (0.1 g, 1.8 mmol) was added. The solvent was removed un-
der vacuum and the residue purified by flash chromatography on silica
gel.
(E)-Ethoxystyrene (4)
Preparation from phenylacetaldehyde, sodium amide, and diethyl
sulfate. Separation from the (Z)-isomer was achieved by MPLC with
hexane/tert-butyl methyl ether 300:1. Yield: 60%. Spectroscopic data
see literature.8
5a: Generated from (S,S)-Bis-[2-(1-hydroxypropyl)phenyl] dise-
lenide.17
5b: Generated from (S,S)-Bis-[2-(1-methoxymethoxypropyl)phenyl]
diselenide.18
5c: Generated from mesoporous silica-supported (S)-3-(1-metho-
xymethoxyethyl)-4-methoxymethylselanylphenol.19
5d: Generated from 15.
(S)-1-{[(S)-2-Ethoxy-2-methoxy-(R)-1-phenyl-
ethylselenyl]-phenyl}-propanol (6a)
Synthesized according to GP1. Purification by preparative TLC
(plates pretreated with triethylamine) with tert-butyl methyl ether/
pentane/triethylamine 10:40:2. Yield: 76%; colorless oil; de = 54%;

1380
L. Uehlin and T. Wirth
[α]2D5 = 99.1 (c = 1.12, CHCl3); H NMR (400 MHz, CDCl3): δ = 0.77
(t, J = 7.4 Hz, 3H, CH3), 1.16 (t, J = 7.1 Hz, 3H, CH3), 1.46 (s, 1H, OH),
1.62 (m, 2H, CH2), 3.21 (s, 3H, OCH3), 3.52 (dq, J = 9.3 Hz, J = 7.1 Hz,
1H, OCHHCH3), 3.74 (dq, J = 9.3 Hz, J = 7.1 Hz, 1H, OCHHCH3), 4.34
(d, J = 5.8 Hz, 1H, CHSe), 4.73 (t, J = 5.1 Hz, 1H, CHOH), 4.88 (d, J =
5.9 Hz, 1H, OCHO), 7.00–7.28 (m, 6H, arom-H), 7.19 (dt, J = 6.5 Hz, J =
1.0 Hz, 1H, arom-H), 7.25 (dd, J = 7.8 Hz, J = 2.4 Hz, 1H, arom-H), 7.49
(dd, J = 7.0 Hz, J = 1.0 Hz, 1H, arom-H); 13C NMR (100.4 MHz, CDCl3):
δ = 10.3 (q, CH3), 15,0 (q, CH3), 30.9 (t, CH2), 52.4 (t, OCH2), 54.1 (q,
OCH3), 63.0 (d, CHSe), 74.5 (d, ArCHOH), 105.4 (d, OCHO), 126.4 (d),
127.1 (d), 127.6 (d), 128.0 (d), 128.6 (s), 128.7 (d), 128.8 (d), 137,5 (d),
139.1 (s), 148.2 (s). IR (NaCl): 2928, 2850, 1601, 1454, 1213, 1158, 1125,
1101, 1033, 921, 700 cm–1; MS (70 eV, EI): m/z(%): 495 (6) [M]+, 476 (9),
447 (32), 401 (100), 369 (71), 339 (22), 299 (21), 269 (11), 237 (30), 135
(54), 121 (8), 101 (14); HRMS for C20H26O3Se: Calcd. 394.1047, Found
394.1058.
1
(S)-1-{[(S)-2-Ethoxy-2-methoxy-(R)-1-phenyl-
ethylselenyl]-phenyl}-propyl Methoxymethyl Ether (6b)
Synthesized according to GP1. Purification by preparative TLC
(plates pretreated with triethylamine) with tert-butyl methyl
ether/pentane/triethylamine 10:100:2. Yield: 87%; colorless oil; de =
80%; [α]2D5 = 42.5 (c = 1.48, CHCl3); H NMR (300 MHz, CDCl3): δ =
1
0.89 (t, J = 7.4 Hz, 3H, CH2CH3), 1.13 (t, J = 7.1 Hz, 3H, CH2CH3),
1.58 (m, 2H, CH2CH3), 3.20 (s, 3H, OCH3), 3.30 (s, 3H, OCH3), 3.50 (dq,
J = 4.9 Hz, J = 2.1 Hz, 1H, OCHHCH3), 3.68 (dq, J = 4.9 Hz, J = 2.0
Hz, 1H, OCHHCH3), 4.14 (d, J = 6.5 Hz, 1H, OCHHO), 4.31 (d, J =
6.5 Hz, 1H, OCHHO), 4.48 (d, J = 5.8 Hz, 1H, CHSe), 4.83 (d, J = 5.9
Hz, 1H, OCHO), 4.93 (dd, J = 7.6 Hz, J = 5.1 Hz, 1H, PhCH), 6.95 (t,
J = 7.5 Hz, 1H, arom-H), 7.00–7.18 (m, 6H, arom-H), 7.27 (dd, J = 7.7
Hz, J = 1.6 Hz, 1H, arom-H), 7.35 (d, J = 7.7 Hz, 1H, arom-H); 13C
NMR (75 MHz, CDCl3): δ = 10.9 (q,CH3), 15,5 (q, CH3), 31.6 (t, CH2),
52.0 (t, OCH2), 54.4(q, OCH3), 56.0 (q, OCH3), 63.4 (d, CHSe), 78.8 (d,
ArCHO), 94.8 (d, OCHO), 106.1 (d, OCHO), 126.3 (d), 126.9 (d), 127.1
(d), 127.9 (d), 128.0 (d), 128.1 (d), 128.8 (d), 129.1 (s), 136,3 (d), 138.6
(s), 145.4 (s); IR (NaCl): n = 3059, 3029, 2934, 2888, 1586, 1496, 1458,
1374, 1259, 1195, 1158, 1107, 1032, 919, 832, 757, 702 cm−1; MS (CI):
m/z(%): 407 (18), 375 (6), 345 (8), 317 (7), 278 (8), 216 (6), 198 (30), 166
(11), 149 (48), 136 (26), 120 (100), 108 (9), 89 (52), 52 (28); HRMS for
C22H30O4Se: Calcd. 438.1309, Found 438.1312.

Synthesis of Chiral Acetals
1381
(S,S)-1,3-Bis-(1-methoxymethoxy-propyl)-2-[(S)-2-ethoxy-
2-methoxy-(R)-1-phenyl-ethylselenyl]-benzene (6d)
Synthesized from 15 according to GP1. Purification by preparative
TLC (plates pretreated with triethylamine to eliminate acidic residues
in the silica) with tert-butyl methyl ether/pentane/triethylamine
10:80:1. Yield: 63%; colorless oil; de > 95% (1H NMR showed no other
diastereomer); [α]2D5 = –64.8 (c = 1.00, CHCl3); 1H NMR (400 MHz,
CDCl3): δ = 0.98 (t, J = 7.2 Hz, 6H, CH3), 1.09 (t, J = 7.1 Hz, 3H, CH3),
1.54–1.73 (m, 4H, CH2), 3.20 (s, 3H, OCH3), 3.24 (s, 6H, OCH3), 3.45
(dq, J = 5.0 Hz, J = 2.0 Hz, 1H, OCHHCH3), 3.62 (dq, J = 4.9 Hz, J =
2.1 Hz, 1H, OCHHCH3), 4.09 (d, J = 6.4 Hz, 2H, OCHHO), 4.15 (d,
J = 6.2 Hz, 1H, CHSe), 4.26 (d, J = 6.4 Hz, 2OCHHO), 4.77 (d, J = 6.2
Hz, 1H, OCHO), 5.10 (dd, J = 8.8 Hz, J = 3.2 Hz, 2H, PhCH), 7.06–
7.13 (m, 5H, arom-H), 7.23–7.30 (m, 3H, arom-H); 13C NMR (100 MHz,
CDCl3): δ = 11.6 (q, CH3), 15,4 (q, CH3), 31.9 (t, CH2), 52.8 (t, OCH2),
54.6 (q, OCH3), 56.0 (q, OCH3), 63.7 (d, CHSe), 79.9 (d, ArCHO), 95.2
(d, OCHO), 106.0 (d, OCHO), 126.3 (d), 126.3 (d), 127.6 (d), 128.6 (d),
129.1 (d), 128.0(d), 129.6 (s), 139.3 (s), 147.9 (s).
rac-2-Ethoxy-2-methoxy-ethyl)-benzene (7)
To phenylacetaldehyde dimethyl acetal (166 mg, 1.0 mmol), ethanol
(92 mg, 2.0 mmol) and hydrochloric acid (20 mL, 1 M in diethyl ether)
were added. The mixture was stirred for 8 h, then quenched with tri-
ethylamine (50 mL). Purification by MPLC with petroleum ether/tert-
butyl methyl ether/triethyl amine 94:5:1 gave the product in 65% yield,
as well 15% of diethyl acetal and 13% of the starting material. Spectro-
scopic data according to the literature.9 Separation of the enantiomers
by GC. Column: Macherey-Nagel, Hydrodex-β-3P, 50 m × 0.25 mm, 20
psi, 115◦C, 60 min, then heating 10◦C/min to 200◦C. Rf (S): 65.7 min,
Rf (R): 66.1 min.
2-Bromobenzene-1,3-dicarbaldehyde (9)12
Chromium trioxide (9.9 g, 96 mmol) was dissolved in ice-cooled acetic
anhydride (30 mL). At 0◦C a mixture of 2,6 dimethylbromobenzene (3.0
g, 16 mmol), acetic anhydride (30 mL), and conc. sulphuric acid (8.1
mL) was added dropwise. The mixture was allowed to warm up to 15◦C,
stirred for 2 h, then poured on 240 g ice and left for 12 h. Extraction with
dichloromethane (3 × 25 mL), washing with aqueous potassium carbon-
ate and water (each 50 mL), and evaporation of the solvent in vacuo
yielded the tetraacetate as a brown solid. This was dissolved in dioxane
(25 mL) and refluxed with conc. hydrochloric acid (6 mL) for 4 h. The
mixture was concentrated in vacuo to 10% of the original volume, and

1382
L. Uehlin and T. Wirth
the residue was washed with water. Filtration of the residue (dissolved
in 50 mL dichloromethane) through basic alumina and purification by
flash chromatography on silica with dichloromethane yielded the prod-
1
uct in 48% as colorless needles. H NMR (300 MHz, CDCl3): δ = 7.55
(t, J = 12.0, 1H, arom-H), 8.15 (d, J = 12.0 Hz, 2H, arom-H), 10.43 (s,
2H, CHO).
(S,S)-2,6-Bis(1-hydroxypropyl)bromobenzene (11)20
Diethylzinc (0.31 g, 2.5 mmol) was added to a solution of the dis-
elenide 1014 (20 µmol) in toluene (10 mL) at 0◦C. After stirring for
10 min, compound 9 (1.0 mmol) was added dropwise and the solution
stirred for 15 h. After quenching with hydrochloric acid (5 mL, 1 M) and
water (40 mL), the mixture was allowed to warm up. Extraction with
tert-butyl methyl ether (3 × 25 mL) and evaporation of the solvent in
vacuo gave the crude product, which, if necessary, was purified by flash
chromatography on silica. Purification by recrystallization from ethyl
25
1
acetate. Yield 43%; mp 148.5◦C; [α]D = –101.2 (c = 1.01, CHCl3); H
NMR (300 MHz, CDCl3): δ = 1.02 (t, J = 7.9 Hz, 6H, CH3), 1.63–1.73
(m, 2H, CH2), 1.80–1.89 (m, 2H, CH2),1.93 (d, J = 3.6 Hz, 2H, OH), 5.11
(dt, J = 8.2 Hz, J = 4.2 Hz, 1H, OCHHCH3), 7.38 (t, J = 7.7 Hz, 1H,
arom-H), 7.48 (d, J = 7.7 Hz, 1H, arom-H); 13C NMR (75 MHz, CDCl3):
δ = 10.6 (q, CH3), 31.0 (t, CH2), 74.5 (d, ArCHO), 122.1 (s), 126.5 (d),
127.8 (d), 144.4 (s); IR (NaCl): 3288 (br), 3045, 2968, 1463, 1420, 1354,
1126, 1065, 1018, 985, 779, 735, 692 cm–1; MS (70 eV, EI): m/z(%): 255
(33) [M-H2O]+, 237 (100), 211 (52), 193 (12), 175 (12), 158 (10), 135 (29),
128 (11), 121 (10), 79 (98), 75 (21), 60 (5).
(S,S)-2-(1-Methoxymethoxy-propyl)-6-(1-hydroxypropyl)-
bromobenzene (12)
Obtained as a by-product in the synthesis of 13 in 19% yield. Colour-
less oil; [α]2D5 = –129.1 (c = 2.02, CHCl3); H NMR (300 MHz, CDCl3):
1
δ = 0.98 (d, J = 7.4 Hz, 3H, CH3), 1.02 (d, J = 7.4 Hz, 3H, CH3), 1.61–
1.85 (m, 4H, CH2), 3.34 (s, 3H, OCH3), 4.50 (d, J = 6.5 Hz, 1H, OCHHO),
4.77 (d, J = 6.4 Hz, 1H, OCHHO), 5.02 (dd, J = 8.8 Hz, J = 3.2 Hz, 1H,
PhCH), 5.08 (dd, J = 8.4 Hz, J = 3.1 Hz, 1H, PhCH), 7.21–7.39 (m,
3H, arom-H); IR (NaCl): n = 2935, 2884, 1463, 1423, 1342, 1294, 1215,
1159, 1107, 1031, 992, 923, 796, 731 cm–1; MS (70 eV, EI): m/z(%): 287
(15), 257 (11), 225 (61), 199 (20), 171 (5), 118 (9), 91 (8), 77 (14), 45 (100);
HRMS for C14H25BrNO3[M+NH4]: Calcd. 334.1018, Found 334.1023.

Synthesis of Chiral Acetals
1383
(S,S)-2,6-Bis-(1-methoxymethoxy-propyl)-bromobenzene (13)
The alcohol 11 was dissolved in ethyl diisopropyl amine (15 equiv.),
and the solution was cooled down to 0◦C. Chloromethyl methyl ether (4
eq) was added, and the mixture was allowed to warm up. Stirring was
continued for 12 h and then quenched with conc. aqueous ammonia (5
equiv.). The solvents were evaporated, and the residue was extracted
with dichloromethane. Yield: 76%, colorless oil. [α]2D5 = –259.6 (c = 1.0,
CHCl3); 1H NMR (300 MHz, CDCl3): δ = 1.01 (t, J = 7.4 Hz, 6H, CH3),
1.61–1.85 (m, 4H, CH2), 3.39 (s, 6H, OCH3), 4.50 (d, J = 6.7 Hz, 2H,
OCHHO), 4.58 (d, J = 6.7 Hz, 2H, OCHHO), 5.03 (dd, J = 7.9 Hz,
J = 3.4 Hz, 2H, PhCH), 7.30–7.39 (m, 3H, arom-H); 13C NMR (75 MHz,
CDCl3): δ = 10.3 (q, CH3), 29.9 (t, CH2), 55.7 (q, OCH3), 78.2 (d, ArCHO),
94.7 (d, OCHO), 123.5 (s), 126.7 (d), 127.3 (d), 142.0 (s); IR (NaCl):
2933, 2882, 1463, 1341, 1215, 1159, 1125, 1106, 1030, 921, 796, 731
cm−1; MS (70 eV, EI): m/z(%): 331 (9), 301 (10), 272 (8), 227 (32), 211
(5), 197 (8), 169 (5), 131 (5), 118 (7), 91 (7), 77 (5), 45 (100); HRMS for
C16H29BrNO4[M+NH4]: Calcd. 378.1280, Found 378.1278.
(S,S)-1-[3-(1-Methoxymethoxy-propyl)-
2-methoxymethylselanyl-phenyl]-propan-1-ol (14)
Synthesized from 12 according to GP2. Purification by MPLC with
tert-butyl methyl ether/pentane 1:10. Yield: 74%; pale yellow oil; [α]D25
=
1
–266.2 (c = 0.9, CHCl3); H NMR (300 MHz, CDCl3): δ = 0.98 (t, J =
7.4 Hz, 3H, CH3), 1.03 (t, J = 7.3 Hz, 6H, CH3), 1.65–1.90 (m, 4H, CH2),
2.74 (d, J = 3.6 Hz, 1H, OH), 3.34 (s, 3H, OCH3), 3.43 (s, 3H, OCH3),
4.46 (d, J = 6.7 Hz, 1H, OCHHO), 4.52 (d, J = 6.7 Hz, 1H, OCHHO),
4.92 (d, J = 9.3 Hz, 1H, SeCHH), 5.01 (d, J = 9.3 Hz, 1H, SeCHH),
5.31–5.40 (m, 2H, PhCH), 7.37–7.47 (m, 3H, arom-H); 13C NMR (75
MHz, CDCl3): δ = 10.7 (q, CH3), 10.8 (q, CH3), 30.5 (t, CH2), 31.0 (t,
CH2), 55.5 (q, OCH3), 57.6 (q, OCH3), 75.0 (d, ArCHO), 76,0 (t, SeCH2),
79.2 (d, ArCHO), 94.4 (d, OCHO), 125.8 (d), 126.4 (d), 129.0 (s), 129.6
(d), 147.1 (s) 148.7 (s); IR (NaCl): 2932, 2880, 1729, 1463, 1288, 1213,
1159, 1125, 1100, 1032, 922, 798 cm–1; MS (70 eV, CI): m/z(%): 362 (1)
[M]+, 345 (27), 307 (6), 301 (31), 269 (10), 239 (100), 117 (27); HRMS
for C16H26O4Se: Calcd. 362.0996, Found 362.0991.
(S,S)-1,3-Bis-(1-methoxymethoxy-propyl)-
2-methoxymethylselanyl-benzene (15)
Synthesized from 13 according to GP2. Purification by MPLC with
tert-butyl methyl ether/pentane 1:10. Yield: 78%; pale yellow oil; [α]D25
–209.2 (c = 1.46, CHCl3); H NMR (300 MHz, CDCl3): δ = 1.04 (t, J =
7.3 Hz, 6H, CH3), 1.70–1.75 (m, 4H, CH2), 3.35 (s, 6H, OCH3), 3.41 (s,
=
1

1384
L. Uehlin and T. Wirth
3H, OCH3), 4.47 (d, J = 6.7 Hz, 2H, OCHHO), 4.53 (d, J = 6.7 Hz, 2H,
OCHHO), 4.95 (d, J = 8.9 Hz, 1H, SeCHHO), 5.08 (d, J = 8.9 Hz, 1H,
SeCHHO), 5.03 (t, J = 6.3 Hz, 2H, PhCH), 7.37–7.45 (m, 3H, arom-
H); 13C NMR (75 MHz, CDCl3): δ = 10.9 (q, CH3), 31.2 (t, CH2), 55.2
(q, OCH3), 57.7 (q, OCH3), 76,2 (t, SeCH2), 79.2 (d, ArCHO), 94.5 (d,
OCHO), 126.2 (d), 128.4 (s), 129.3 (d), 147.1 (s); IR (NaCl): n = 2932,
2883, 2820, 1455, 1269, 1214, 1181, 1158, 1125, 1087, 1032, 924, 801
cm–1; MS (70 eV, EI): m/z(%): 406 (1) [M]+, 330 (6), 300 (6), 225 (5),
238 (61), 223 (18), 209 (29), 15 (15), 183 (7), 156 (6), 129 (12), 115 (22),
102 (5), 91 (14), 84 (8), 57 (41), 45 (100); HRMS for C18H30O5Se: Calcd.
406.158, Found 406.1257.
(S)-1-({[(R)-(2-Hydroxy-1-phenyl)ethyl]seleno}phenyl)propanol
(18)
Compound 6a (20 mg, 0.05 mmol) was dissolved in chloroform (5
mL), trifluoroacetic acid (1 mL) and water (1 mL) were added, and the
mixture was stirred for 2 h. The aqueous layer was discarded, and the
chloroform was removed in vacuo. The remaining oil was dissolved in
dry ethanol (5 mL), and sodium borohydride (2.0 mg, 0.05 mmol) was
added at 0◦C. The mixture was allowed to warm up to room temperature
and was stirred for 1 h. The solvent was removed in vacuo, and the
remaining oil was purified by preparative TLC with tert-butyl methyl
ether/petroleum ether 1:2. Yield: 29%; colorless oil; [α]2D5 = –15.2 (c =
0.25, CHCl3). From this optical rotation a diastereomeric ratio of 77:23
(S,R):(S,S) (54% de) was calculated. (Values for the enantiomerically
pure compounds (S,R)-18: [α]2D5 = –64.6; (S,S)-18: [α]2D5 = +150.8.)16 1
H
NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 7.4 Hz, 3H, CH3), 1.50–1.72
(m, 2H, CH2), 1.95 (s (br), 1H, OH), 2.40 (s (br), 1H, OH), 3.95 (d, J =
6.9 Hz, 1H, CHHCOH), 4.35 (t, J = 7.0 Hz, 1H, CHSe), 4.92 (t,J = 6.5
Hz, 1H, CHOH), 7.10-7.32 (m, 6H, arom-H), 7.36 (td,J = 7.4 Hz, J = 1.2
Hz, 1H, arom-H), 7.47 (dd,J = 7.8 Hz, J = 1.6 Hz, 1H, arom-H), 7.60
(dd,J = 7.7 Hz, J = 1.4 Hz, 1H, arom-H).
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