Synthesis of enantioenriched substituted tetrahydrofurans and tetrahydropyrans via iron-mediated chirality transfer and ring closure

Article abstract of DOI:10.1055/s-2000-8732

The synthesis of optically active, functionalized tetrahydrofurans and tetrahydropyrans via Fe(CO)₄-mediated cycloetherification has been accomplished. The ring closure reaction proceeds with chirality transfer and under retention of the configuration at the allylic carbon center.

Full text of DOI:10.1055/s-2000-8732

2092
PAPER
Synthesis of Enantioenriched Substituted Tetrahydrofurans and
Tetrahydropyrans via Iron-Mediated Chirality Transfer and Ring Closure
Dieter Enders,* Duy Nguyen
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Professor-Pirlet-Straße 1, D-52074 Aachen, Germany
Fax +49(241)8888127; E-mail: Enders@RWTH-Aachen.de
Received 16 August 2000; revised 23 August 2000
OH
Abstract: The synthesis of optically active, functionalized tetrahy-
a, b
CH2
TBSO
TBSO
drofurans and tetrahydropyrans via Fe(CO)4-mediated cycloetheri-
fication has been accomplished. The ring closure reaction proceeds
with chirality transfer and under retention of the configuration at the
allylic carbon center.
OH
n
n
3, n=1, 60 %
4, n=2, 68 %
1, n=1
2, n=2
c
Key words: cyclic ethers, allylic substitution, iron tetracarbonyl
complexes, chirality transfer, enzymatic kinetic resolution, ring clo-
sure
OAc
OAc
e, f
CH2
CH2
CH2
TBSO
TBSO
TBSO
TBSO
Acc
n
n
(S)-5, n=1, 41 %
(S)-6, n=2, 38 %
(S)-7, n=1, Acc = CO2Me, 65 %
(S)-8, n=1, Acc = SO2Ph, 64 %
(S)-9, n=2, Acc = SO2Ph, 72 %
The abundant occurrence of tetrahydrofuran and tetrahy-
dropyran rings as crucial structural features in many natu-
ral products sustains a strong effort to develop methods
for their synthesis.1,2 As part of our program employing
cationic (h3-allyl)tetracarbonyliron complexes in organic
synthesis3,4 we wish to report our preliminary results on
Fe(CO)4-mediated cycloetherification providing a novel
route towards optically active, functionalized tetrahydro-
furans and tetrahydropyrans.
Starting from the monoprotected diols 1 and 25 the racem-
ic allylic alcohols 3 and 4 were obtained by Dess-Martin
oxidation to the corresponding aldehyde6 and subsequent
Grignard addition. Enzymatic kinetic resolution with li-
pase PS “Amano”7 afforded the enantioenriched (S)-ace-
tates 5 and 6 as well as the (R)-alcohols 3 and 4.8 The
alcohol (R)-4 was acylated under standard conditions9 and
both acetate enantiomers 6 were separately subjected to
ozonolysis.10 Subsequent Horner-Wadsworth-Emmons
olefination11 afforded the suitably functionalized precur-
sors 7-10 with yields ranging from 64-72% (Scheme 1).
OH
n
(R)-4, n=2, 48 %
d
OAc
OAc
e, f
TBSO
Acc
n
n
(R)-10, n=2, Acc = CO2Me, 64 %
(R)-6, n=2, 85 %
Reagents and conditions: a) Dess-Martin periodinane/CH2Cl2, r.t.;
b) vinylmagnesium bromide/Et2O, 0 °C to r.t.; c) Lipase PS “Ama-
no”/i-Pr2O/vinyl acetate, 40 °C, 72 h; d) Ac2O/Et3N/DMAP/CH2Cl2,
r.t.; e) O3, CH2Cl2/MeOH (5:1), NaHCO3, –78 °C, Me2S, then r.t.; f)
LiBr/(EtO)2P(O)CH2Acc/Et3N/MeCN, r.t.
Scheme 1
The Fe(CO)4-mediated, C-O connective ring closure re-
action is a one-pot consecutive procedure, typically em-
ploying 1.3 equivalents of Fe2(CO)9 and 2.4-2.6
equivalents of HBF4◊OEt2 for the formation of the cationic
(h3-allyl)tetracarbonyliron complex and 8.0-9.0 equiva-
lents ceric ammonium nitrate (CAN) for the oxidative de-
complexation (Scheme 2). The results are summarized in
Table 1, indicating that individual cyclization conditions
are required for each system. The ring size, the electron-
withdrawing properties of the acceptor, as well as the sol-
vent polarity and the temperature are the parameters that
influence the racemization process.12
OAc
n
a, b, c
TBSO
*
Acc
*
Acc
n
O
7-10
11, n=2, Acc = SO2Ph
12, n=1, Acc = SO2Ph
13, n=2, Acc = CO2Me
14, n=1, Acc = CO2Me
Reagents and conditions: a) Fe2(CO)9 (1.3 equiv)/CO/cyclohexane,
r.t., 24 h; b) see Table 1; c) CAN (8.0-9.0 equiv)/aq NH4Cl, r.t.
Scheme 2
The optimum conditions for the formation of 11 with 44%
overall yield are indicated in Entry 1, Table 1. We also in-
vestigated the influence of the temperature and solvent.
Elevated temperature (Entry 2) and increased solvent po-
larity (Entry 3) lead to considerable racemization. The
conditions indicated in Entry 1, however, could not be
employed for the formation of 12 (Entry 4). Addition of a
base such as K2CO3 limited racemization (Entry 5). Re-
Synthesis 2000, No. 14, 2092–2098 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Enantioenriched Substituted Tetrahydrofurans and Tetrahydropyrans
2093
Table 1 Cyclization Conditions for the Functionalized Cyclic Ethers 11-14
Entry
Substrate ee (%)a Conditions
Product
11
Yield (%) ee (%)b
1
2
3
4
5
(S)-9
(S)-9
(S)-9
(S)-8
(S)-8
93
85
85
99
99
Et2O, 2.6 equiv HBF4◊OEt2 at –10°C, 60 min, then 45 min at 0°C
Et2O, 2.4 equiv HBF4◊OEt2, 100 min at r.t.
44
45
49
50
30
93
77
14
64
87
11
CH2Cl2, 2.4 equiv HBF4◊OEt2 at –10°C, 60 min, then 45 min at 0°C
Et2O, 2.4 equiv HBF4◊OEt2 at –10°C, 60 min, then 60 min at 0°C
11
12
Et2O, 2.4 equiv HBF4◊OEt2 at –10°C, 60 min, 2.4 equiv K2CO3,
then 60 min at 0°C
12
6
7
(S)-8
(S)-8
99
97
Et2O, 2.4 equiv HBF4◊OEt2 at –10°C, 30 min, 5 equiv Cs2CO3,
then 60 min at –10°C
12
12
31
44
90
95
Et2O/CH2Cl2 (4:1), 2.4 equiv HBF4◊OEt2 at –23°C, 30 min, 5 equiv
Cs2CO3, then 50 min at –10°C
8
9
(R)-10
(R)-10
85
90
Et2O, 2.4 equiv HBF4◊OEt2 at –10°C, 70 min, then 50 min at 0°C
13
13
32
42
76
89
Et2O, 2.5 equiv HBF4◊OEt2 at –23°C, 50 min, 5 equiv K2CO3,
then 45 min at r.t.
10
(S)-7
96
Et2O/CH2Cl2 (4:1), 2.4 equiv HBF4◊OEt2 at –40°C, 90 min, 5 equiv
K2CO3, 30 min at –10°C
14
30
93
a Determined by HPLC.
b Determined by GC.
OH
ducing the reaction time before addition of the base and
using Cs2CO3 instead of K2CO3 (Entry 6) slightly im-
proved the enantiomeric excess, but racemization still oc-
curred. We concluded that -10 °C was still too high, and
therefore the reaction should be performed at a lower tem-
perature. However, to ensure that the reaction also pro-
ceeds with acceptable rate at lower temperatures the
polarity of the solvent was increased. Consequently, the
cyclization reaction was performed at -23 °C in Et2O/
CH2Cl2 (4:1) to give 12 with 44% overall yield without ra-
cemization (Entry 7). Entry 8 demonstrates the influence
of the electron-withdrawing properties of the acceptor on
racemization. The conditions employed for the formation
of sulfone 11 (Entry 1) lead to racemization (Entry 8),
whereas complete chirality transfer was observed when
carrying out the reaction at -23 °C in Et2O and with
K2CO3 to give 13 in 42% yield (entry 9). The formation of
14 with 30% yield proceeded without racemization at
-40 °C in Et2O/CH2Cl2 (4:1) and with K2CO3 (Entry 10).
a, b
CH2
H3C
H3C
CO2Et
70 %
OTBS
16
OTBS
15
c
OAc
OAc
d, e
CH2
H3C
H3C
Acc
OTBS
OTBS
19, Acc = SO2Ph, 58 %, > 96 % de
20, Acc = CO2Me, 59 %, > 96 % de
17, 38 %, > 96 % de
+
OH
CH2
H3C
OTBS
18, 43 %, 90 % de
Reagents and conditions: a) DIBAL/Et2O, –80 °C; b) vinylmagnesi-
um bromide/THF, 0 °C to r.t.; c) Lipase PS “Amano”/vinyl acetate/
i-Pr2O, 40 °C, 72 h; d) O3/CH2Cl2/MeOH (5:1)/NaHCO3, –78 °C,
Me2S, then r.t.; e) LiBr/(EtO)2P(O)CH2Acc/Et3N/MeCN, r.t.
It was not possible to establish the stereochemistry of the
cyclized products at this point. We envisaged that the
presence of an additional stereogenic center would allow
the determination of the relative stereochemistry (by NOE
experiments) and therefore the nature of the cyclization.
Furthermore, it would also allow an extension of the
methodology to the synthesis of 2,5-disubstituted tetrahy-
drofurans. The synthesis of the precursors is outlined in
Scheme 3.
Scheme 3
1:1 epimeric mixture of the allylic alcohol 16 in 70%
yield, which was subjected to the enzymatic kinetic reso-
lution giving analogously acetate 17 and alcohol 18. Ozo-
nolysis and subsequent olefination of the acetate 17
afforded the sulfone 19 and the ester 20 in 58 and 59%
yield, respectively.
Compound 15 could be obtained in 61% yield from TBS-
protected (S)-ethyl lactate in three steps with no loss of
enantiomeric purity (ee >96%).13 DIBAL reduction to the
aldehyde and subsequent Grignard addition14 afforded a
Synthesis 2000, No. 14, 2092–2098 ISSN 0039-7881 © Thieme Stuttgart · New York

2094
D. Enders, D. Nguyen
PAPER
thesis of more highly functionalized tetrahydrofurans and
tetrahydropyrans is under investigation in our laborato-
ries.
OAc
a, b, c
H3C
Acc
H3C
Acc
O
OTBS
20, 21
22, Acc = SO2Ph
23, Acc = CO2Me
All reagents were of commercial quality used from freshly opened
containers. Lipase PS “Amano” was obtained from Amano, Düssel-
dorf (activity: not less than 30000 units/g, test method: JIS method,
pH 7). Solvents were dried and purified by conventional methods.
Column chromatography: Merck silica gel 60, particle size 0.040-
0.063 mm (230-400 mesh). Analytical TLC: silica gel 60 F254
plates, Merck, Darmstadt. Microanalyses: Heraeus CHN-O-Rapid
element analyzer. Optical rotation values: Perkin Elmer P 241 pola-
rimeter, solvents used were of Merck UVASOL-quality. IR spectra:
Perkin-Elmer FT/IR 1750 and 1720 X. Mass spectra: Varian MAT
Reagents and conditions: a) Fe2(CO)9 (1.3-2.0 equiv)/CO/cyclohex-
ane, r.t., 24 h; b) see Table 2; c) CAN (8.0-9.0 equiv)/aq NH4Cl, r.t.
Scheme 4
The conditions employed for the formation of the func-
tionalized tetrahydrofurans 12 and 14 were also applica-
ble to the cyclization of 19 and 20 (Scheme 4, Table 2).
1
212 (EI 70 eV, CI 100 eV), HRMS: Finnigan MAT 95. H NMR
Compound 21 was obtained in 36% (19% recovered start- (300, 400 MHz), 13C NMR (75, 100 MHz): Varian VXR 300, Gem-
ini 300 or Varian Inova 400 (TMS as internal standard). Melting
points: Büchi 510, uncorrected. Unless otherwise noted, all the re-
actions were performed in oven-dried glassware under an argon at-
mosphere.
ing material) and 22 in 30% (31% recovered starting ma-
terial) yield. Due to signal overlap in the crude NMR the
determination of the diastereomeric excess by 13C NMR
was only possible after column chromatography.
Oxidation with Dess-Martin Periodinane (DMP) and Subse-
quent Grignard Addition; General Procedure
H
H
SO2Ph
To a stirred solution of alcohol (1.0 equiv) in CH2Cl2 (20 mL/mmol
alcohol) at r.t. was added DMP (Dess-Martin's periodinane)
(1.3 equiv). The solvent was removed in vacuo after the reaction
was complete. The residue was taken up in Et2O (80 mL) and then
washed with 1:1 aq 10% Na2S2O3 and aq sat. NaHCO3 solutions
(30 mL/mmol DMP). The aqueous layer was extracted with Et2O
(3 î 80 mL). The combined organic extracts were washed with H2O
and brine, dried (MgSO4) and concentrated in vacuo. The crude al-
dehyde was used without further purification. To a stirred solution
of vinylmagnesium bromide (1.3 equiv) in Et2O (3 mL/mmol vinyl-
magnesium bromide) at 0 °C was added slowly a solution of the
crude aldehyde in Et2O (1 mL/mmol aldehyde). The mixture was
then stirred at r.t. and quenched with aq sat NH4Cl solution (50 mL).
The aqueous layer was extracted with Et2O (3 î 25 mL). The com-
bined extracts were dried (MgSO4) and concentrated in vacuo. The
residue was purified by column chromatography.
H3C
O
H
21
NOE experiment of 21 indicated the cis relative stere-
ochemistry. Consequently, the absolute configuration at
the allylic carbon center could be assigned as (S) demon-
strating that the cyclization proceeded with overall reten-
tion of stereochemistry. Based on the assumption of a
uniform cyclization mechanism the stereochemistry at the
allylic carbon center could be assigned as (S) for 11, 12,
14 and as (R) for 13.
(rac)-6-{[1-(tert-Butyl)-1,1-dimethylsilyl]oxy}hex-1-en-3-ol (3)
Following the general procedure, 1 (3.0 g, 14.7 mmol), DMP
(11.24 g, 17.61 mmol), CH2Cl2 (300 mL), vinylmagnesium bromide
(1 M solution in THF, 18 mL, 18 mmol) and Et2O (90 mL) were
used. Purification by chromatography (SiO2, Et2O/pentane,
1:5Æ1:3) afforded 3 (2.01 g, 60%) as a pale yellow oil. The analyt-
ical data were consistent with those reported in the literature.15
In conclusion, an Fe(CO)4-mediated cycloetherification
has been developed. Optically active substituted tetrahy-
drofurans and tetrahydropyrans were obtained in moder-
ate overall yields. The reaction proceeds with chirality
transfer and net retention of the configuration at the allylic
carbon center. Extension of this methodology to the syn-
(rac)-7-{[1-(tert-Butyl)-1,1-dimethylsilyl]oxy}hept-1-en-3-ol (4)
Following the general procedure, 2 (3.58 g, 16.4 mmol), DMP
(12.6 g, 19.67 mmol), CH2Cl2 (350 mL), vinylmagnesium bromide
(1M solution in THF, 20 mL, 20 mmol) and Et2O (100 mL) were
used. Purification by chromatography (SiO2, Et2O/pentane,
1:5Æ1:3) afforded 4 (2.72 g, 68%) as a pale yellow oil. The analyt-
ical data were consistent with those reported in the literature.16
Table 2 Cyclization Conditions for the Disubstituted Tetrahydro-
furans 21 and 22
Substrate Conditions
(de %)a
Product Yield
(de %)a (%)
(3R/S,6S)-6-{1-[tert-Butyl)-1,1-dimethylsilyl]oxy}hept-1-en-3-ol
(16)
19 (87)
1.3 equiv Fe2(CO)9, Et2O/CH2Cl2
21 (85) 36
22 (93) 30
(4:1), 2.5 equiv HBF4◊OEt2 at –23°C,
30 min, 5 equiv Cs2CO3, then 50 min
at –10 °C
To a stirred solution of 15 (1.52 g, 5.8 mmol) in Et2O (60 mL) at
-90 °C was added slowly DIBAL (1 M solution in toluene, 7 mL,
7 mmol). The mixture was then stirred for 3 h at -80 °C and
quenched with aq sat. NH4Cl solution (30 mL). The reaction mix-
ture was allowed to warm to r.t. Solid NH4Cl was added until a slur-
ry was formed. The mixture was filtered through a pad of silica gel
and concentrated in vacuo. The residue was partitioned between
Et2O (30 mL) and brine (30 mL) and the aqueous layer was extract-
ed with Et2O (3 î 15 mL). The combined organic extracts were
20 (>96) 2.0 equiv Fe2(CO)9, Et2O/CH2Cl2
(4:1), 2.5 equiv HBF4◊OEt2 at –40 °C,
80 min, 5 equiv K2CO3, 30 min
at –10 °C
a Determined by 13C NMR, after column chromatography.
Synthesis 2000, No. 14, 2092–2098 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Enantioenriched Substituted Tetrahydrofurans and Tetrahydropyrans
2095
dried (MgSO4) and concentrated in vacuo. The crude aldehyde was
dissolved in THF (40 mL) and cooled to 0 °C. Vinylmagnesium
bromide (1 M solution in THF, 9 mL, 9 mmol) was slowly added.
The mixture was stirred at r.t. (TLC control) and quenched with aq
sat. NH4Cl solution (20 mL). After the workup as given in the
general procedure, purification of the residue by chromatography
(SiO2, Et2O/pentane: 1:5) afforded 16 (0.993 g, 70%) as a pale
yellow oil. This 1:1 mixture of epimers was directly subjected to the
kinetic resolution without characterization.
CH3CHO), 5.14-5.26 (m, 3 H, CH2CHO, CH=CH2), 5.70-5.82 (m,
1 H, CH=CH2).
13C NMR (75 MHz, CDCl3): d = -4.8, -4.4 [Si(CH3)2], 18.1
[SiC(CH3)3], 21.2 (COCH3), 23.8 (CH3CHO), 25.9 [SiC(CH3)3],
30.4, 34.9 (CH2CH2), 68.2 (CH3CHO), 74.9 (CH2CHO), 116.6
(CH=CH2), 136.6 (CH=CH2), 170.3 (COCH3).
GC/MS (EI, 70 eV): m/z (%) = 117 (40), 95 (100), 75 (23), 73 (15),
67 (15).
IR (capillary): n = 2956, 2930, 2857, 1743, 1238, 1022, 836, 775
cm-1.
Enzymatic Kinetic Resolution with Lipase PS “Amano”; Gen-
eral Procedure
Anal. calcd for C15H30O3Si: C, 62.88; H, 10.55. Found: C, 63.21; H,
10.70.
To a stirred solution of allylic alcohol (1.0 equiv) and vinyl acetate
(2.0-2.5 equiv) in i-Pr2O (25 mL/mmol alcohol) was added Lipase
PS “Amano” (260 mg/mmol alcohol). The mixture was stirred for
72 h at 40 °C. The enzyme was removed by filtration and the filtrate
was concentrated. The residue was purified by chromatography
(SiO2, Et2O/pentane, 1:5).
(1R)-1-(4-{[1-(tert-Butyl)-1,1-dimethylsilyl]oxy}butyl)prop-2-
enyl Acetate [(R)-6]
To a stirred solution of (R)-4 (688 mg, 2.8 mmol), DMAP (43 mg,
0.3 mmol) and Et3N (1.31 mL, 9.4 mmol) in CH2Cl2 (30 mL) at r.t.
(TLC control) was added Ac2O (0.74 mL, 7.8 mmol). The reaction
was quenched with H2O (20 mL) and the aqueous layer was extract-
ed with Et2O (3 î 15 mL). The combined organic extracts were
dried (MgSO4) and concentrated in vacuo. Purification of the resi-
due by chromatography (SiO2, Et2O/pentane, 1:8 then 1:5) gave
(R)-6 (682 mg, 85%); [a]D24 +4.9 (c = 0.53, CHCl3). The analytical
data were consistent with those reported for the enantiomer (S)-6.
(1S)-1-(3-{[1-(tert-Butyl)-1,1-dimethylsilyl]oxy}propyl)prop-2-
enyl Acetate [(S)-5]
Following the general procedure, (S)-5 (0.527 g, 41%) was obtained
as an oil from 3 (1.088 g, 4.72 mmol); [a]D24 -6.1 (c = 1.28,
CHCl3).
1H NMR (300 MHz, CDCl3): d = 0.04 [s, 6 H, Si(CH3)2], 0.89 [s, 9
H, SiC(CH3)3], 1.50-1.71 (m, 4 H, CH2CH2), 2.06 (s, 3 H, COCH3),
3.62 (t, 2 H, J = 6.4 Hz, CH2OSi), 5.14-5.28 (m, 3 H, CHO,
CH=CH2), 5.72-5.84 (m, 1 H, CH=CH2).
13C NMR (75 MHz, CDCl3): d = -5.3 [Si(CH3)2], 18.2 [SiC(CH3)3],
21.2 (COCH3), 25.9 [SiC(CH3)3], 28.3, 30.6 (CH2CH2), 62.7
(CH2OSi). 74.6 (CHO), 116.5 (CH=CH2), 136.5 (CH=CH2), 170.4
(COCH3).
Ozonlysis and Subsequent Horner-Wadsworth-Emmons Ole-
fination; General Procedure
A mixture of allylic acetate (1.0 equiv) and NaHCO3 (10 equiv) in
CH2Cl2/MeOH (5:1) (60 mL) at -78 °C was subjected to ozonolysis
until a blue color was visible. Oxygen or argon was bubbled through
the reaction mixture until the disappearance of the blue colour was
observed. Me2S (2.0-3.0 equiv) was added and the mixture was al-
lowed to warm to r.t. The mixture was filtered and concentrated in
vacuo. The residue was used in the next step without further purifi-
cation. LiBr (2.0-2.5 equiv) and phosphonate (1.5-1.7 equiv) were
dissolved in MeCN (10 mL/mmol aldehyde). After 15 min Et3N
(1.7-2.0 equiv) was added. The crude aldehyde was added after a
further 15 min and the mixture was stirred at r.t. (TLC control). The
mixture was diluted with aq sat NH4Cl solution (15 mL) and Et2O
(10 mL). The aqueous layer was extracted with Et2O (3 ¥ 15 mL).
The combined extracts were dried (MgSO4) and concentrated. Puri-
fication of the residue by chromatography gave the product.
MS (CI, isobutane): m/z (%) = 273 (MH+, 38), 214 (17), 213 (100).
IR (CHCl3): = 2955, 2930, 2858, 1743, 1472, 1463, 1434, 1372,
1240, 1100, 1021, 836, 777 cm-1.
Anal. calcd for C14H28O3Si: C, 61.72; H, 10.36. Found: C, 61.74; H,
10.42.
(1S)-1-(4-{[1-(tert-Butyl)-1,1-dimethylsilyl]oxy}butyl)prop-2-
enyl Acetate [(S)-6]
Following the general procedure, (S)-6 (0.563 g, 37%) was obtained
as a pale yellow oil from 4 (1.295 g, 5.3 mmol); [a]D24 -5.6 (c = 1.2,
CHCl3).
1H NMR (300 MHz, CDCl3): d = 0.00 [s, 6 H, Si(CH3)2], 0.85 [s, 9
H, SiC(CH3)3], 1.28-1.65 (m, 6 H, CH2CH2CH2), 2.02 (s, 3 H,
COCH3), 3.56 (t, 2 H, J = 6.3 Hz, CH2OSi), 5.10-5.24 (m, 3 H,
CH2CHO, CH=CH2), 5.66-5.80 (m, 1 H, CH=CH2).
13C NMR (75 MHz, CDCl3): d = -4.7 [Si(CH3)2], 18.9 [SiC(CH3)3],
21.8 (COCH3), 22.0 (CH2CH2CH2), 26.5 [SiC(CH3)3], 33.0, 34.5
(CH2CHO, CH2CH2OSi), 63.4 (CH2OSi), 75.3 (CHO), 117.2
(CH=CH2), 137.1 (CH=CH2), 170.9 (COCH3).
Methyl (2E,4S)-4-(Acetyloxy)-7-{[1-(tert-butyl)-1,1-dimethylsi-
lyl]oxy}hept-2-enoate [(S)-7]
Following the general procedure, (S)-7 (297 mg, 65%) was obtained
from (S)-5 (375 mg, 1.4 mmol) as an oil after chromatography
(SiO2, Et2O/pentane, 1:7 then 1:5); [a]D22 -10.4 (c = 1.18, CHCl3);
90% ee [HPLC: (S,S)-Whelk-01 (4 î 250) mm, 30 °C, 54 bar, cy-
clohexane/i-PrOH (99:1), Flow 0.5 mL/min, Rt 10.93, 14.99 min].
1H NMR (300 MHz, CDCl3): d = 0.00 [s, 6 H, Si(CH3)2], 0.85 [s, 9
H, SiC(CH3)3], 1.48-1.78 (m, 4 H, CH2CH2), 2.06 (s, 3 H,
CO2CH3), 3.57 (t, 2 H, J = 6.4 Hz, CH2OSi), 3.70 (s, 3 H, CO2CH3),
5.38-5.42 (m, 1 H, CHO), 5.90 (dd, 1 H, J = 15.8, 1.7 Hz,
MS (CI, isobutane): m/z (%) = 288 (20), 287 (MH+, 100), 227 (35),
95 (57).
IR (capillary): n = 2952, 2931, 2858, 1742, 1472, 1462, 1241, 1101,
CH=CHCO2CH3), 6.81 (dd,
CH=CHCO2CH3).
1
H, J = 15.8, 5.0 Hz,
837, 776 cm-1.
13C NMR (75 MHz, CDCl3): d = -5.3 [Si(CH3)2], 18.4 [SiC(CH3)3],
21.1 (COCH3), 26.0 [SiC(CH3)3], 28.2, 30.3 (CH2CH2), 51.8
(CO2CH3), 62.5 (CH2OSi), 72.3 (CHO), 121.3 (CH=CHCO2CH3),
145.7 (CH=CHCO2CH3), 166.5 (CO2CH3), 170.1 (COCH3).
MS (CI, isobutane): m/z (%) = 332 (14), 331 (MH+,67), 274 (19),
273 (100), 272 (40), 271 (90), 75 (21).
Anal. calcd for C15H30O3Si: C, 62.88; H, 10.55. Found: C, 62.83; H,
10.90.
(1S)-1-((3S)-3-{1-[tert-Butyl)-1,1-dimethylsilyl]oxy}butyl)prop-
enyl Acetate (17)
Following the general procedure, 17 (0.446 g, 38%) was obtained
as an oil from 16 (0.993 g, 4.1 mmol); [a]D25 +6.1 (c = 1.29, CHCl3).
1H NMR (300 MHz, CDCl3): d = 0.05 [s, 6 H, Si(CH3)2], 0.88 [s, 9
H, SiC(CH3)3], 1.12 (d, 3 H, J = 6.0 Hz, CH3CHO), 1.38-1.75 (m,
4 H, CH2CH2), 2.06 (s, 3 H, COCH3), 3.76-3.82 (m, 1 H,
IR (capillary): n = 2954, 2932, 2858, 1731, 1463, 1437, 1234, 1205,
1172, 1099, 837, 778 cm-1.
Synthesis 2000, No. 14, 2092–2098 ISSN 0039-7881 © Thieme Stuttgart · New York

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D. Enders, D. Nguyen
PAPER
Anal. calcd for C16H30O5Si: C, 58.15; H, 9.15. Found: C, 57.78; H,
9.26.
13C NMR (75 MHz, CDCl3): d = -5.4 [Si(CH3)2], 18.3 [SiC(CH3)3],
20.9 (COCH3), 25.9 [SiC(CH3)3], 27.9, 30.2 (CH2CH2), 62.2
(CH2OSi), 71.3 (CHO), 127.7, 129.3, 130.8 (ArC), 133.6
(CH=CHS), 139.9 (ArC), 143.6 (CH=CHS), 169.7 (COCH3).
Methyl (2E,4R)-4-(Acetyloxy)-8-{[1-(tert-butyl)-1,1-dimethylsi-
lyl] oxy}oct-2-enoate [(R)-10]
Following the general procedure, (R)-10 (343 mg, 64%) was ob-
tained from (R)-6 (462 mg, 1.6 mmol) as an oil after chromatogra-
phy (SiO2, Et2O/pentane, 1:7 then 1:5); [a]D25 +10.4 (c = 0.24,
CHCl3); 97% ee [HPLC: (S,S)-Whelk-01 (4 î 250 mm), 30 °C, 56
bar, cyclohexane/i-PrOH (99:1), Flow 0.5 mL/min, Rt 11.16, 14.47
min].
1H NMR (300 MHz, CDCl3): d = 0.00 [s, 6 H, Si(CH3)2], 0.85 [s, 9
H, SiC(CH3)3], 1.35-1.68 (m, 6 H, CH2CH2CH2), 2.05 (s, 3 H,
COCH3), 3.56 (dd, 2 H, J = 6.3, 6.0 Hz, CH2OSi), 3.70 (s, 3 H,
CO2CH3), 5.33-5.39 (m, 1 H, CH2CHO), 5.90 (dd, 1 H, J = 15.7,
1.7 Hz, CH=CHCO2CH3), 6.80 (dd, 1 H, J = 15.7, 5.5 Hz,
CH=CHCO2CH3).
13C NMR (75 MHz, CDCl3): d = -5.2 [Si(CH3)2], 18.4 [SiC(CH3)3],
21.1 (COCH3), 21.4 (CH2CH2CH2), 26.0 [SiC(CH3)3], 32.4, 33.6
(CH2CH2OSi, CH2CHO), 51.8 (CO2CH3), 62.8 (CH2OSi), 72.5
(CHO), 121.2 (CH=CHCO2CH3), 145.8 (CH=CHCO2CH3), 166.5
(CO2CH3), 170.2 (COCH3).
IR (CHCl3): n = 2955, 2930, 2857, 1745, 1448, 1321, 1309, 1233,
1150, 1088, 836, 777, 755, 688 cm-1.
HRMS: m/z calcd. for C16H23O5SSi (M+- C4H9): 355.1035. Found:
355.1035.
(1S,2E)-1-(4-{[1-(tert-Butyl)-1,1-dimethylsilyl]oxy}butyl)-3-
(phenylsulfonyl)prop-2-enyl Acetate [(S)-9]
Following the general procedure, (S)-9 (688 mg, 72%) was obtained
from (S)-6 (645 mg, 2.25 mmol) as an oil after chromatography
(SiO2, Et2O/pentane, 1:4 then 1:2); [a]D20 -4.9 (c = 0.51, CHCl3),
85% ee [HPLC: Chiralcel OD 2 (4.6 î 250 mm), 30 °C, 36 bar, cy-
clohexane/i-PrOH (95:5), Flow 0.5 mL/min, Rt 11.52, 13.74 min).
1H NMR (300 MHz, CDCl3): d = 0.04 [s, 6 H, Si(CH3)2], 0.85 [s, 9
H, SiC(CH3)3], 1.30-1.72 (m, 6 H, CH2CH2CH2), 2.03 (s, 3 H,
COCH3), 3.55 (dd, 2 H, J = 6.4, 6.0 Hz, CH2OSi), 5.42-5.46 (m, 1
H, CH2CHO), 6.42 (dd, 1 H, J = 15.1, 1.7 Hz, CH=CHS), 6.89 (dd,
1 H, J = 15.1, 4.4 Hz, CH=CHS), 7.52-7.64 (m, 3 H, ArH), 7.82-
7.88 (m, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = -5.2 [Si(CH3)2], 18.4 [SiC(CH3)3],
21.0 (COCH3), 21.36 (CH2CH2CH2), 26.0 [SiC(CH3)3], 32.3, 33.5
(CH2CH2OSi, CH2CHO), 62.7 (CH2OSi), 71.5 (CHO), 127.8,
129.5, 130.8 (ArC), 133.7 (CH=CHS), 140.1 (ArC), 143.7
(CH=CHS), 169.9 (COCH3).
MS (CI, isobutane): m/z (%) = 346 (20), 345 (MH+, 100), 287 (96),
285 (39), 113 (13),112 (18).
IR (CHCl3): n = 2952, 2929, 2857, 1731, 1471, 1462, 1437, 1236,
1101, 837; 776, 760 cm-1.
Anal. calcd for C17H32O5Si: C, 59.26; H, 9.36. Found: C, 59.15; H,
9.83.
IR (CHCl3): n = 1745, 1321, 1309, 1234, 1150, 1088, 836, 777 cm-
1
.
Methyl (2E,4S,7S)-4-(Acetyloxy)-7-{[1-(tert-butyl)-1,1-dimeth-
ylsilyl]oxy}oct-2-enoate (20)
Following the general procedure, 20 (260 mg, 59%) was obtained
from 17 (366 mg, 1.275 mmol) as an oil after chromatography
(SiO2, Et2O/pentane, 1:7 then 1:5); [a]D20 0.0 (c = 0.68, CHCl3);
96% de (13C NMR, after chromatography).
1H NMR (300 MHz, CDCl3): d = 0.04, 0.05 [2 s, 6 H, Si(CH3)2],
0.88 [s, 9 H, SiC(CH3)3], 1.12 (d, 3 H, J = 6.0 Hz, CH3CHO), 1.40-
1.85 (m, 4 H, CH2CH2), 2.09 (s, 3 H, COCH3), 3.74 (s, 3 H,
CO2CH3), 3.76-3.82 (m, 1 H, CH3CHO), 5.37-5.43 (m, 1 H,
CH2CHO), 5.94 (dd, 1 H, J = 15.7, 1.4 Hz, CH=CHCO2CH3), 6.85
(dd, 1 H, J = 15.7, 5.2 Hz, CH=CHCO2CH3).
13C NMR (75 MHz, CDCl3): d = -4.8, -4.4 [Si(CH3)2], 18.1
8SiC(CH3], 21.0 (COCH3), 23.7 (CH3CHO), 25.9 [SiC(CH3)3],
29.9, 34.6 (CH2CH2), 51.7 (CO2CH3), 68.0 (CH3CHO), 72.5
(CH2CHO), 121.2 (CH=CHCO2CH3), 145.7 (CH=CHCO2CH3),
166.4 (CO2CH3), 170.0 (COCH3).
HRMS: m/z calcd for C17H25O5SSi (M+ - C4H9): 369.1192. Found:
369.1194.
(1S,2E)-1-((3S)-3-{[1-(tert-Butyl)-1,1-dimethylsilyl]oxy}butyl)-
3-(phenylsulfonyl)prop-2-enyl Acetate (19)
Following the general procedure, 19 (148 mg, 58%) was obtained
from 17 (172 mg, 0.60 mmol) as an oil after chromatography (SiO2,
Et2O/pentane, 1:2); [a]D20 +4.8 (c = 0.46, CHCl3); ≥96% de (13C
NMR, after chromatography).
1H NMR (300 MHz, CDCl3): d = 0.25, 0.39 [2 s, 6 H, Si(CH3)2],
0.87 [s, 9 H, SíC(CH3)3], 1.12 (d, 3 H, J = 6.1 Hz, CH3CHO), 1.42-
1.88 (m, 4 H, CH2CH2), 2.06 (s, 3 H, COCH3), 3.75-3.80 (m, 1 H,
CH3CHO), 5.43-5.49 (m, 1 H, CH2CHO), 6.46 (dd, 1 H, J = 15.1,
1.7 Hz, CH=CHS), 6.92 (dd, 1 H, J = 15.1, 4.7 Hz, CH=CHS),
7.52-7.68 (m, 3 H, ArH), 7.86-7.90 (m, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = -4.8, -4.4 [Si(CH3)2], 18.1
[SiC(CH3], 20.9 (COCH3), 23.6 (CH3CHO), 25.8 [SiC(CH3)3],
29.7, 34.4 (CH2CH2), 67.8 (CH3CHO), 71.4 (CH2CHO), 127.7,
129.4, 130.8 (ArC), 133.58 (CH=CHS), 140.0 (ArC), 143.6
(CH=CHS), 170.0 (COCH3).
IR (capillary): n = 2955, 2930, 2857, 1732, 1463, 1437, 1374, 1276,
1233, 1172, 1142, 1050, 1077, 837, 776 cm-1.
HRMS: m/z calcd for C13H23O5Si (M+ - C4H9): 287.1314. Found:
287.1313.
MS (CI, isobutane): m/z (%) = 428 (27), 427 (MH+, 100), 367 (11).
(1S,2E)-1-(3-{[1-(tert-Butyl)-1,1-dimethylsilyl]oxy}propyl)-3-
(phenylsulfonyl)prop-2-enyl Acetate [(S)-8]
IR (capillary): n = 2956, 2930, 1746, 1322, 1232, 1150, 1087, 1050,
836 cm-1.
Following the general procedure, (S)-8 (476 mg, 63%) was obtained
from (S)-5 (502 mg, 1.8 mmol) as an oil after chromatography
(SiO2, Et2O/pentane, 1:4 then 1:2); [a]D22 -3.7 (c = 1.01, CHCl3),
97% ee [HPLC: (S,S)-Whelk-01 (4 î 250) mm, 30 °C, 56 bar, cy-
clohexane/i-PrOH, 98:2, Flow: 0.5 mL/min, Rt: 37.3, 50.4 min].
1H NMR (300 MHz, CDCl3): d = 0.04 [s, 6 H, Si(CH3)2), 0.88 [s, 9
H, SiC(CH3)3], 1.47-1.82 (m, 4 H, CH2CH2), 2.07 (s, 3 H,
CO2CH3), 3.60 (t, 2 H, J = 6.1 Hz, CH2OSi), 5.50-5.54 (m, 1 H,
CHO), 6.46 (dd, 1 H, J = 15.1, 1.6 Hz, CH=CHS), 6.93 (dd, 1 H,
J = 15.1, 4.4 Hz, CH=CHS), 7.52-7.67 (m, 3 H, ArH), 7.86-7.88
(m, 2 H, ArH).
Anal. calcd for C21H34O5SSi: C, 59.12; H, 8.03. Found: C, 58.94; H,
7.94.
Fe(CO)4-Mediated Ring Closure; General Procedure
The complexation and cyclization reactions were performed under
the exclusion of light, air and moisture. Fe2(CO)9 and the byproduct
Fe(CO)5 are highly toxic. All work was carried out in a well venti-
lated hood. All glassware was treated with concd HNO3 before re-
use.
Complexation: To a vigorously stirred solution of Fe2(CO)9 (1.3
equiv) in cyclohexane was added the subtrate (1.0 equiv). The reac-
tion mixture was saturated with CO (CO-balloon) and stirred for 24
Synthesis 2000, No. 14, 2092–2098 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Enantioenriched Substituted Tetrahydrofurans and Tetrahydropyrans
2097
h at r.t. under a CO atmosphere. After the removal of the solvent,
the residue was used without further purification.
(E)-2-[(2S,5S)-5-Methyltetrahydro-2-furanyl]ethenyl Phenyl
Sulfone (21)
Following the general procedure and the cyclization conditions de-
scribed for (S)-12: 19 (137 mg, 0.32 mmol), Fe2(CO)9 (152 mg, 0.42
mmol), cyclohexane (35 mL), HBF4◊OEt2 (0.11 mL, 0.81 mmol),
Et2O/CH2Cl2 (4:1, 25 mL), Cs2CO3 (0.533 g, 1.63 mmol) and CAN
(1.93 g, 3.5 mmol) were used. Purification by chromatography
(Et2O/pentane, 1:2 then Et2O) gave 21 (29 mg, 36%) as an oil;
[a]D24 +15.5 (c = 1.38, CHCl3, de ≥96%); 85% de (13C NMR).
1H NMR (300 MHz, CDCl3): d = 1.24 (d, 3 H, J = 6.0 Hz,
CH3CHO), 1.44-1.52 (m, 1 H, CHHCHCH3), 1.75-1.80 (m, 1 H,
CHHCHO), 1.95-2.06 (m, 1 H, CHHCHCH3), 2.14-2.24 (m, 1 H,
CHHCHO), 4.02-4.12 (m, 1 H, CH3CHO), 4.52-4.58 (m, 1 H,
CH2CHO), 6.58 (dd,1 H, J = 14.8, 1.7 Hz, CH=CHS), 7.00 (dd, 1
H, J = 14.8, 3.8 Hz, CH=CHS), 7.50-7.66 (m, 3 H, ArH), 7.87-
7.91 (m, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 21.4 (CH3CHO), 31.7, 32.6
(CH2CH2), 77.0, 77.1 (CH3CHO, CH2CHO, CDCl3), 128.0, 129.3,
129.6 (ArC), 133.7 (CH=CHS), 140.7 (ArC), 147.3 (CH=CHS).
GC-MS (CI, isobutane): m/z (%) = 254 (15), 253 (MH+, 100).
IR (CHCl3): n = 1318, 1308, 1282, 1147, 1086, 689 cm-1.
Cyclization: See the descriptions of the compounds below.
Decomplexation: A solution of CAN (8.0-9.0 equiv) in aq sat.
NH4Cl solution (20-30 mL) was added to the reaction mixture
above, which was vigorously stirred for 12-24 h at r.t. (additional
CAN was added when required). The aqueous phase was extracted
with Et2O (3 î 20 mL). The combined extracts were washed with
H2O (20 mL) and brine (20 mL), dried (MgSO4) and concentrated
in vacuo. Purification of the residue by chromatography afforded
the cyclic ethers.
(2S)-2-[(E)-2-(Phenylsulfonyl)ethenyl)tetrahydro-2H-pyran
[(S)-11]
Following the general procedure, (S)-9 (60 mg, 0.14 mmol),
Fe2(CO)9 (67 mg, 0.18 mmol) and cyclohexane (25 mL) were used.
The residue was taken up in Et2O (20 mL) and cooled to -10 °C.
HBF4◊OEt2 (0.05 mL, 0.37 mmol) was added and the mixture was
stirred for 60 min at this temperature, then for 45 min at 0 °C. CAN
(0.702 g, 1.28 mmol) was used for decomplexation. Purification by
chromatography (SiO2, Et2O/pentane, 1:2) gave (S)-11 (15.6 mg,
44%) as an oil; [a]D23 -7.4 (c = 0.74, CHCl3); 93% ee (GC: Lipodex
E, 140-190 °C, rate 1.0 °C/min, then 45 min at 190 °C, Rt 58.70,
59.73 min).
1H NMR (300 MHz, CDCl3): d = 1.24-1.96 (m, 6 H, CH2CH2CH2),
3.43-3.47 (m, 1 H, CHHO), 3.95-4.05 (m, 2 H, CHO, CHHO),
6.56 (dd, 1 H J = 14.8, 1.9 Hz, CH=CHS), 6.93 (dd, 1 H, J = 14.8,
3.3 Hz, CH=CHS), 7.50-7.64 (m, 3 H, ArH), 7.87-7.90 (m, 2 H,
ArH).
Anal. calcd for C13H16O3S: C, 61.88; H, 6.39. Found: C, 61.63; H,
6.76.
Methyl (E)-3-[(2R)Tetrahydro-2H-2-pyranyl]prop-2-enoate
[(R)-13]
Following the general procedure, (R)-10 (67 mg, 0.19 mmol),
Fe2(CO)9 (92 mg, 0.25 mmol) and cyclohexane (25 mL) were used.
The residue was taken up in Et2O (20 mL) and cooled to -23 °C.
HBF4◊OEt2 (0.065 mL, 0.48 mmol) was added and the mixture was
stirred for 45 min at -23 °C. After the addition of K2CO3 (136 mg,
0.97 mmol) the reaction mixture was stirred for 50 min at r.t. CAN
(854 mg, 1.56 mmol) was used for the decomplexation. Purification
by chromatography (SiO2, Et2O/pentane, 1:7 then 1:5) gave (R)-13
(13.8 mg, 42%) as an oil;17 [a]D20 +19.3 (c = 0.37, CHCl3), 89% ee
[GC: Lipodex E, 80-100 °C, rate 1.0 °C/min, 100-190 °C, rate
3.0 °C/min, then 10 min at 190 °C, Rt 21.72, 22.40 min]. The ana-
lytical data were consistent with those reported in the literature.19
13C NMR (75 MHz, CDCl3): d = 23.3, 25.4, 31.1 (CH2CH2CH2),
68.4 (CH2O), 75.3 (CHO), 127.7, 129.2, 129.2 (ArC), 133.3
(CH=CHS), 140.1 (ArC), 145.8 (CH=CHS).
IR (CHCl3): n = 1318, 1308, 1147, 1100, 1085, 755, 689, 573, 551
cm-1.
HRMS: m/z calcd. for C12H16O3S (M+): 252.0820. Found:
252.0818.
(2S)-2-[(E)-2-(Phenylsulfonyl)ethenyl)tetrahydrofuran [(S)-12]
Following the general procedure, (S)-8 (162 mg, 0.39 mmol),
Fe2(CO)9 (185 mg, 0.51 mmol) and cyclohexane (35 mL) were
used. The residue was taken up in Et2O/CH2Cl2 (4:1, 25 mL) and
cooled to -23 °C. HBF4◊OEt2 (0.13 mL, 0.96 mmol) was added and
the mixture was stirred for 30 min at this temperature. After the ad-
dition of Cs2CO3 (0.65 g, 2.0 mmol), the mixture was stirred for
50 min at -10 °C. CAN (1.93 g, 3.5 mmol) was used for decom-
plexation. Purification by chromatography (SiO2, Et2O/pentane,
1:2) gave (S)-12 (41 mg, 44%) as a colourless solid. A small quan-
tity was recrystallized (Et2O/pentane) to give fine needles; mp 79-
80 °C; [a]D23 +13.3 (c = 1.88, CHCl3); 95% ee (GC: Lipodex E,
140-190 °C, rate 2.0 °C/min, then 35 min at 190 °C, Rt 34.32,
35.71 min).
1H NMR (300 MHz, CDCl3): d = 1.67-1.78 (m, 1 H, CHHCHO),
1.88-1.97 (m, 2 H, CH2CH2O), 2.12-2.23 (m, 1 H, CHHCHO),
3.80-3.95 (m, 2 H, CH2O), 4.57-4.63 (m, 1 H, CHO), 6.56 (dd, 1
H, J = 14.8, 1.7 Hz, CH=CHS), 6.97 (dd, 1 H, J = 14.8, 3.9 Hz
CH=CHS), 7.50-7.65 (m, 3 H, ArH), 7.87-7.91 (m, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 25.4, 31.4 (CH2CH2), 68.8
(CH2O), 76.7 (CHO), 127.7, 129.4, 129.7 (ArC), 133.4
(CH = CHS), 140.4 (ArC), 146.4 (CH = CHS).
Methyl (E)-3-[(2S)Tetrahydro-2-furanyl]prop-2-enoate [(S)-
14]
Following the general procedure, (S)-7 (105 mg, 0.32 mmol),
Fe2(CO)9 (172 mg, 0.47 mmol) and cyclohexane (25 mL) were
used. The residue was taken up in Et2O/CH2Cl2 (4:1, 25 mL) and
cooled to -40 °C. HBF4◊OEt2 (0.105 mL, 0.77 mmol) was added
and the mixture was stirred for 90 min at -40 °C. After the addition
of K2CO3 (230 mg, 1.58 mmol) the reaction mixture was stirred for
30 min at -10 °C. CAN (1.38 g, 2.52 mmol) was used for the de-
complexation. Purification by chromatography (SiO2, Et2O/pen-
tane, 1:5) gave (S)-14 (15.2 mg, 30%) as an oil;18 [a]D25 -2.3
(c = 0.44, CHCl3); 93% ee (GC: Lipodex E, 40 min at 50 °C, 50-
60 °C, rate: 1.0 °C/min, 60-80 °C, rate 2.0 °C/min, 80-190 °C,
rate 3.0 °C/min, then 10 min at 190 °C, Rt 72.89, 73.34 min). The
analytical data were consistent with those reported in the litera-
ture.19
Methyl (E)-3-[(2S,5S)-5-Methyltetrahydro-2-furanyl]prop-2-
enoate (22)
Following the general procedure and the cyclization conditions de-
scribed for (S)-14, 20 (133 mg, 0.38 mmol), Fe2CO9 (281 mg,
0.77 mmol), cyclohexane (35 mL), HBF4◊OEt2 (0.13 mL, 0.96
mmol), Et2O/CH2Cl2 (4:1, 25 mL) and CAN (1.89 g, 3.45 mmol)
were used. Purification by chromatography (SiO2, Et2O/pentane,
1:5) gave 22 (20 mg, 30%) as an oil; [a]D25 +1.4 (c = 0.65, CHCl3),
93% de (13C NMR, after chromatography).
IR (KBr): n = 2922, 2879, 2852, 1307, 1284, 1148, 1085, 1021,
981, 726, 536 cm-1.
HRMS: m/z calcd. for C12H14O3S (M+): 238.0663. Found:
238.0661.
1H NMR (300 MHz, CDCl3): d = 1.28 (d, 3 H, J = 6.1 Hz,
CH3CHO), 1.46-1.56 (m, 1 H, CHHCHCH3), 1.70-1.80 (m, 1 H,
Synthesis 2000, No. 14, 2092–2098 ISSN 0039-7881 © Thieme Stuttgart · New York

2098
D. Enders, D. Nguyen
PAPER
CHHCHO), 1.95-2.06 (m, 1 H, CHHCHCH3), 2.09-2.20 (m, 1 H,
CHHCHO), 3.74 (CO2CH3), 4.02-4.14 (m, 1 H, CH3CHO), 4.47-
4.54 (m, 1 H, CH2CHO), 6.05 (dd, 1 H, J = 15.7, 1.7 Hz,
(6) Schreiber, S. L.; Meyer, S. D.; J. Org. Chem. 1994, 59, 7549.
(7) (a) Johnson, C. R.; Golebiowski, A.; Steensma, D. H. J. Am.
Chem. Soc. 1992, 114, 9414.
CH=CHCO2CH3), 6.95 (dd,
CH=CHCO2CH3).
1
H, J = 15.7, 4.9 Hz,
(b) Takahada, H.; Uchida, Y.; Momore, T. Tetrahedron Lett.
1992, 33, 3331.
(c) Takagi, Y.; Teramoto, J.; Kihara, H.; Itoh, T.; Tsukube, H.;
Tetrahedron Lett. 1996, 37, 4991.
(d) Itoh, T.; Sakabe, K.; Kudo, K.; Zagatti, P.; Renou, M.
Tetrahedron Lett. 1998, 39, 4071.
13C NMR (75 MHz, CDCl3): d = 21.2 (CH3CHO), 31.7, 32.5
(CH2CH2), 51.6 (CO2CH3), 76.5 (CH3CHO), 77.6 (CH2CHO),
119.8 (CH=CHCO2CH3), 149.3 (CH=CHCO2CH3), 167.1
(COCH3).
(8) (a) The absolute configuration was determined by comparison
of the optical rotation value of the benzoate of homologous
(R)-3 (n = 3) ([a]D25 -11.7 (c = 1.215, CHCl3), ([a]D25 -14.0
(c = 1.2, CHCl3)8b), which was obtained analogously after
kinetic resolution with Lipase PS “Amano”. The
stereochemical assignment of 4, 5, and 6 is based on the same
enantiopreference of the enzyme for structurally similar
substrates in the kinetic resolution; also see: Kazlaukas, R. J.;
Weissfloch A. N. E.; Rappaport A. T.; Cuccia, L. A. J. Org.
Chem. 1991, 56, 2656.
IR (capillary): n = 2971, 1726, 1437, 1300, 1270, 1197, 1167, 1075
cm-1.
HRMS: m/z calcd. for C9H13O3 (M+ - H): 169.0864. Found:
169.0864.
Acknowledgement
This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie. We wish to thank Degussa
AG, BASF AG and Bayer AG for the donation of chemicals. D.N.
thanks Amano, Düsseldorf, for the generous gift of enzyme and Dr.
J. Runsink for the recording and interpretation of the NOE experi-
ments.
(b) Martin, V. S.; Ode, J. M.; Palazón, J. M.; Soler, M. A.
Tetrahedron: Asymmetry 1992, 3, 573.
(9) Nicolaou, K. C.; Hummel, C. W.; Nakada, M.; Shibayama, K.;
Pitsinos, E. N.; Saimoto, H.; Mitzuno, Y.; Baldenius, K.-U.;
Smith, A. L. J. Am. Chem. Soc. 1993, 115, 7625.
(10) Schreiber, S. L.; Claus, R. E.; Reagan, J. Tetrahedron Lett.
1982, 23, 3867.
(11) (a) Rathke, M. W.; Nowak, M. J. Org. Chem. 1985, 50, 2624.
(b) Roush, W. E.; Masamume, S.; Sakai, T.; Essenfeld, A. P.;
Davis, J. T.; Choy, W., Blanchette, M. A. Tetrahedron Lett.
1984, 21, 2183.
(12) For the proposed mechanism rationalizing the racemization of
the related (h4-diene)Fe(CO)3 system, see: Grée, D.; Grée, R.;
Lowinger, T. B.; Martelli, J.; Negri, J. T.; Paquette, L. A. J.
Am. Chem. Soc. 1992, 114, 8841.
(13) Suh, Y-G.; Jung, J-K.; Suh, B-C.; Lee, Y-C.; Kim, S-A.
Tetrahedron Lett. 1998, 39, 5377. The ee was determined after
reduction to the corresponding alcohol and esterification with
Mosher´s acid chloride.
References
(1) Natural Products Index in Heterocycles 1999, 51, 3103.
(2) For recent reviews, see:
(a) Faul, M. M.; Huff, B. E. Chem. Rev. 2000, 100, 2407.
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(b) Enders, D; Jandeleit, B. Synthesis 1994, 1327.
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(17) 13 was obtained with yields ranging from 27-42%.
(18) 14 was obtained with yields ranging from 18-30%.
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Article Identifier:
1437-210X,E;2000,0,14,2092,2098,ftx,en;Z08200SS.pdf
Synthesis 2000, No. 14, 2092–2098 ISSN 0039-7881 © Thieme Stuttgart · New York