Synthesis, enzymic resolution and enantiomeric enhancement of bis(hydroxymethyl)[7]thiaheterohelicenes

Article abstract of DOI:10.1039/a707196e

Racemic bis(hydroxymethyl)[7]thiaheterohelicene 9 has been prepared in eight steps (33% overall yield) from 2-(hydroxymethyl)benzo[1,2-b:4,3-b′]dithiophene 1. Lipase (Pseudomonas cepacia)-catalyzed transesterification of diol 9 by vinyl acetate in dichloromethane produces optically stable (P)-bis(hydroxymethyl)[7]thiaheterohelicene [(P)-9] with 98% ee along with the corresponding monoacetate [(M)-10] and the diacetate [(M)-11]. Hydrolysis of acetates (M)-10 and (M)-11 by aq. NaOH gives (M)-9 in 77% and 94% ee, respectively. In contrast, the enzymic resolution of diol 9 with Candida antarctica afforded diol (M)-9 in 92% ee. Column chromatography of optically enriched helicenediol 9 on silica gel shows an enantiomeric enhancement. A possible cause of the phenomenon is discussed.

Full text of DOI:10.1039/a707196e

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Synthesis, enzymic resolution and enantiomeric enhancement of
bis(hydroxymethyl)[7]thiaheterohelicenes
Kazuhiko Tanaka,* Hideji Osuga, Hitomi Suzuki, Yuka Shogase and
Yoshinori Kitahara
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-01,
Japan
Racemic bis(hydroxymethyl)[7]thiaheterohelicene 9 has been prepared in eight steps (33% overall yield)
from 2-(hydroxymethyl)benzo[1,2-b:4,3-bЈ]dithiophene 1. Lipase (Pseudomonas cepacia)-catalyzed
transesterification of diol 9 by vinyl acetate in dichloromethane produces optically stable
(P)-bis(hydroxymethyl)[7]thiaheterohelicene [(P)-9] with 98% ee along with the corresponding
monoacetate [(M)-10] and the diacetate [(M)-11]. Hydrolysis of acetates (M)-10 and (M)-11 by aq. NaOH
gives (M)-9 in 77% and 94% ee, respectively. In contrast, the enzymic resolution of diol 9 with Candida
antarctica afforded diol (M)-9 in 92% ee. Column chromatography of optically enriched helicenediol 9 on
silica gel shows an enantiomeric enhancement. A possible cause of the phenomenon is discussed.
KOBut in EtOH–tetrahydrofuran (THF) afforded the 1,2-
Introduction
diarylethylene 7 in 89% yield. Photocyclization of the olefine 7
was carried out using propylene oxide as HI-trapping reagent,13
Helicenes containing more than six benzene rings ([6]carbo-
helicenes) or seven aromatic heterocycles such as thiophenes
([7]heterohelicenes) are very stable toward acids, bases and rela-
tively high temperatures because of their rigid helical frame-
works. For this reason, chiral functionalized helicenes are
promising candidates for chiral ligands and auxiliaries in
asymmetric syntheses.1 The syntheses of optically active
helicenes, however, requires repeated recrystallizations of the
diastereomeric charge-transfer complex derived from racemic
helicenes and optically active reagents like 2-(2,4,5,7-tetranitro-
fluoren-9-ylideneaminooxy)propionic acid,2,3 crystal selection
of conglomerates,4–7 recrystallization from chiral solvent,8 or
separation by high-performance liquid chromatography
(HPLC) using a chiral column.9,10
and
gave
2,13-bis(triisopropylsiloxymethyl)[7]thiahetero-
helicene 8 in 66% yield. Finally, desilylation of compound 8
by tetrabutylammonium fluoride (TBAF)14 in THF gave the
desired racemic 2,13-bis(hydroxymethyl)dithieno[3,2-e:3Ј,2Ј-
eЈ]benzo[1,2-b:4,3-bЈ]bis[1]benzothiophene 9 in 90% yield.
Initial attempts to resolve the racemic helicenediol 9 by using
(R,R)-(ϩ)-2,3-dimethoxy-N,N,NЈ,NЈ-tetramethylsuccinamide15
or brucine16 were unsuccessful. However, lipase-catalyzed
transesterification was found to be most effective for the kinetic
resolution of our helical molecule.11 Among lipases such as
those from Pseudomonas cepacia (PCL), Ps. sp. (AK), Rizomu-
cor miehei (LZ), Candida antarctica (CAL) and Ps. aeruginosa
(LPL) investigated under various conditions, high enantioselec-
tivities were observed with CAL and PCL in dichloromethane.
The reaction was terminated after 25–79% conversion by filtra-
tion off of the immobilized enzyme. Column chromatography
of the reaction mixture gave unchanged helicenediol 9, mono-
acetate 10 and diacetate 11 (Scheme 2). The product proportions
of compounds 9, 10 and 11 and the enantiomeric excess (ee) of
diol 9 were determined by HPLC. These results are summarized
in Table 1. The enantioselectivity of diol 9 was indicated by
enantiomeric ratio, E.17,18 It is noteworthy that with CAL, the
E-value was 20.6 in the absence of molecular sieves 4 Å, but the
enantioselectivity significantly decreased to 7.9 with increasing
amounts of molecular sieves 4 Å. In contrast, the highest
enantioselectivity (E 26.6) was obtained with PCL in the pres-
ence of molecular sieves 4 Å. By use of the optimized procedure
described above, the optical resolution of helicenediol 9 was
carried out on both 100-mg and 1-g scales. Thus the trans-
esterification of diol (PM)-9 (101.2 mg) with PCL gave (P)-9 in
98% ee (44.7 mg, 45% yield) along with acetate (M)-10 (37%
yield) and diacetate (M)-11 (13% yield). Hydrolysis of acetates
(M)-10 and (M)-11 by aq. sodium hydroxide in methanol gave
diol (M)-9 in 77% ee and 94% ee, respectively (Scheme 3). The
reaction of diol (PM)-9 (1.003 g) with CAL gave (M)-9 in 92%
ee (437 mg, 44% yield) together with the corresponding mono-
acetate (P)-10 in 53% yield and the diacetate (P)-11 in 3% yield.
Hydrolysis of acetates (P)-10 and (P)-11 gave diol (P)-9 in 67%
ee and 89% ee, respectively.
We have recently reported the synthesis and enzymic reso-
lution of racemic 2,13-bis(hydroxymethyl)dithieno[3,2-e:3Ј,2Ј-
eЈ]benzo[1,2-b:4,3-bЈ]bis[1]benzothiophene
[(PM)-helicene-
diol].11 We now report a full account of the synthesis of the
optically active helicenediols and the first enantiomeric
enhancement of the partially resolved helical molecules by col-
umn chromatography on an achiral phase.
Results and discussion
Synthesis
Our starting material for the synthesis of (PM)-helicenediol
was 2-(hydroxymethyl)benzo[1,2-b:4,3-bЈ]dithiophene 1, the
hydroxy group of which was converted into the silyl ether 2
(95%) using triisopropylsilyl triflate12 and 2,6-dimethylpyridine
(2,6-lutidine) in dichloromethane (Scheme 1). Treatment of
compound 2 with BuLi at Ϫ78 ЊC afforded the 5-lithio species
exclusively, which was trapped with dimethylformamide
(DMF) to give aldehyde 3 in 94% yield. Phosphonium salt 6
was prepared from the aldehyde in three steps. Thus, reduction
of aldehyde 3 was achieved by NaBH4 at room temp. to give 2-
(hydroxymethyl)-7-(triisopropylsiloxymethyl)benzodithiophene
4 in 97% yield. Chlorination of the hydroxy group of alcohol 4
and subsequent treatment of the chloride 5 with triphenyl-
phosphine in refluxing benzene gave the corresponding phos-
phonium salt 6 in 72% overall yield. The Wittig reaction of
aldehyde 3 and phosphonium salt 6 in the presence of
The optically active helicenediol 9 was stable under these
J. Chem. Soc., Perkin Trans. 1, 1998
935

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HOH2C
Pri3SiOH2C
a
S
S
S
S
S
S
1
2
S
S
b
HOH2C
CH2OH
(PM)-9
Pri3SiOH2C
CHO
Pseudomonas cepacia
Candida antarctica
S
S
CH2Cl2
molecular sieves 4 Å
vinyl acetate
CH2Cl2
vinyl acetate
28–29 °C, 9.5 h
c
3
room temp., 25 h
Pri3SiOH2C
R
S
S
S
S
S
S
4 R = CH2OH
d
e
S
S
5 R = CH2Cl
S
S
+
CH2OH
6 R = CH2PPh3 Cl –
HOH2C
HOH2C
CH2OH
(P)-9
(M)-9
3
+
6
+
+
f
S
S
S
S
CH2OSiPri3
Pri3SiOH2C
S
S
S
AcOH2C
S
S
S
S
S
CH2OH
AcOH2C
CH2OH
(P)-10
7
(M)-10
g
+
+
ROH2C
S
CH2OR
S
S
S
S
S
S
AcOH2C
(M)-11
S
S
S
S
S
CH2OAc
AcOH2C
CH2OAc
(P)-11
8 R = SiPri3
9 R = H
h
Scheme 2
Scheme 1 Reagents and conditions: a, Pri3SiOTf, 2,6-lutidine, CH2Cl2,
0 ЊC; b, BuLi, TMEDA, DMF, THF, Ϫ78 ЊC; c, NaBH4, EtOH–THF,
room temp.; d, SOCl2, pyridine, benzene, 0 ЊC; e, Ph3P, benzene, reflux;
f, KOBut, EtOH–THF, 0 ЊC; g, hν, I2, propylene oxide, benzene, room
temp.; h, TBAF, THF, 0 ЊC
column chromatography on silica gel with hexane–ethyl acetate
(3:1) as eluent, the depletion of ee (69%) occurred in the first
fraction, and the enhancement of ee (89%) was observed in
the last fraction (Fig. 1). In order to check the reproducibility
of this enhancement, the chromatographic separation of the
(P)-enantiomer with 92% ee was carried out under the same
reaction conditions as those described for (M)-9. The highest
ee (95% ee) was again obtained in the last fraction and the
depletion (90% ee) was observed in the first fraction. However,
no appreciable enantiomeric enhancement was observed in the
cases of (M)- and (P)-helicenediols with less than 50% ee.
These results are summarized in Table 2.
reaction conditions. No racemization was indicated even in
refluxing toluene or xylene (commercial mixture) for 100 h, but
a slow racemization was observed when the diol was heated at
160 ЊC in mesitylene. The racemization rate constant (kr) of
(M)-9 was calculated to be 2.71 × 10Ϫ7 (sϪ1) at 160 ЊC, which is
1/4.8-times slower than that for 2-methyl[7]thiaheterohelicene
and 1/7.7-times slower than for the unsubstituted analogue.19
Enantiomeric enhancement
The observed enantiomeric enrichment can be explained by
assuming diastereomeric associations between two enantiomers
by intermolecular hydrogen bonding. If heterochiral-associ-
ation (PM- and MP-dimers) is favoured over homochiral-
association (PP- and MM-dimers), (P)- or (M)-enantiomers
would preferentially interact with the stationary phase (SiO2)
via hydrogen bonds. Such a situation would lead to a differ-
ence in chromatographic mobilities, whereby the more mobile
Although it is very rare, ee increases when a chiral compound is
isolated by chromatography on an achiral phase. This pheno-
menon is referred to as enantiomeric enhancement or enantio-
meric enrichment.20–28
We report here the first example of enantiomeric enhance-
ment by chromatographic separation of helical molecules on an
achiral phase. Thus when (M)-9 of 82% ee was purified by
936
J. Chem. Soc., Perkin Trans. 1, 1998

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Table 1 Lipase-catalyzed transesterification of racemic helicenediol 9 in organic solventsa
Enzyme
(mg)
MS 4 Å
(mg)
Time
(t/h)
Ee (%)
Convn.
(%)b
Solvent
P-9:M-9:10:11
of 9b
E-value
AK (5)
benzene ϩ CH2Cl2
isopropenyl acetate
THF
20
50
20
30
30
50
0
24
25
24
1
24
0.5
3
7
8
7
5
14
14
14
1
18
24
8
44:15:36:5
42:19:34:5
17:40:42:2
10:40:42:8
13:41:43:2
18:41:39:2
17:47:35:0.6
0.7:40:56:3
4:42:53:2
0.3:25.5:69.5:4.7
47:29:23:1
46:21:31:2
47:17:35:2
45:1.8:46:8
16:6:65:13
31:19:45:6
37:23:37:3
45:21:31:4
49
38
40
60
52
39
47
97
83
98
24
37
47
92
45
24
23
36
41
39
44
50
45
41
36
59
55
74
24
33
37
54
78
51
40
35
9.3
5.6
4.5
7.2
7.4
AK (10)
CAL (5)
CAL (5)
CAL (5)
CAL (5)
CAL (5)
CAL (5)
CAL (5)
CAL (5)
PCL (5)
PCL (30)
PCL (30)
PCL (30)
LZ (5)
Pri2O ϩ CH2Cl2
AcOEt
benzene ϩ CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
benzene ϩ CH2Cl2
CH2Cl2
CH2Cl2
5.2
17.7
20.6
13.2
7.9
0
20
40
50
0
10
20
20
30
20
50
9.3
10.1
14.3
26.6
1.8
2.0
2.5
CH2Cl2
benzene ϩ CH2Cl2
isopropenyl acetate
benzene ϩ CH2Cl2
isopropenyl acetate
LZ (5)
LPL (5)
LPL (50)
7.1
a Racemic helicenediol (2 mg) and 40 µl of vinyl acetate in 2 cm3 of solvent at 30 ЊC. b Determined by HPLC using Sumichiral OA2000 (100:1,
1,2-dichloroethane–ethanol).
S
S
S
S
MeOH
NaOH
S
S
S
S
CH2OH
CH2OH
HOH2C
AcOH2C
(M)-9 (77% ee)
(M)-10
S
S
MeOH
NaOH
Fig. 1 Chromatography of (M)-helicenediol of 82.0% ee
(M)-9 (94% ee)
S
(5:1) as a mobile phase. Under these conditions, no enhance-
ment was observed because intermolecular hydrogen bonding
between heterochiral dimers was interrupted by ethanol mol-
ecules. Recrystallization of racemic helicenediol 9 from ethanol
yielded the crystalline inclusion complex as supported by X-ray
crystallography,11 where the host molecules of same helicity
are aligned in a stacking column along the crystallographic b
direction by intermolecular hydrogen bonds. These results indi-
cate that the association between ethanol molecules and enan-
tiomers is preferred over the heterochiral-association. We also
found that recrystallization of diol (P)-9 of 69% ee from
hexane–ethyl acetate (3:1) gave racemic crystals of diol 9, but
the ee of the filtrate increased to 97%. This means that hetero-
chiral association of helicenediols is favoured over the homo-
chiral association.
S
CH2OAc
AcOH2C
(M)-11
S
S
S
S
MeOH
NaOH
S
S
S
S
HOH2C
CH2OH
AcOH2C
(P)-10
CH2OH
(P)-9 (67% ee)
S
S
MeOH
NaOH
Conclusions
(P)-9 (89% ee)
We have prepared racemic bis(hydroxymethyl)[7]heterohelicene
9 in eight steps from readily available 2-(hydroxymethyl)-
benzodithiophene. The overall yield of diol 9 from compound
1 was 33%. The enzymic resolution of the racemate gave either
(P)- or (M)-helicenediols in 95–98% ee. A single crystallization
of the helicenediols leads to essentially 100% ee. The first enan-
tiomeric enhancement of helical molecules in the chromato-
graphic separation can be explained by assuming heterochiral
association to be more favourable than homochiral association
in an achiral stationary phase.
S
S
AcOH2C
CH2OAc
(P)-11
Scheme 3
heterochiral dimers would elute faster than the less mobile
enantiomers, with the enantiomeric enrichment being observed
at the end of the elution in our case. These phenomena are
very similar to the self-amplification observed by Charles and
Gil-Av.21
Experimental
In order to confirm the hypothesis, we used hexane–ethanol
Mps were determined on a Yanagimoto hotstage apparatus and
J. Chem. Soc., Perkin Trans. 1, 1998
937

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Table 2 Enantiomeric enhancement of helicenediols 9
bined organic phases were washed with brine, dried over
anhydrous magnesium sulfate and concentrated. The crude
product was purified by silica gel column chromatography
(10:1, hexane–ethyl acetate) to give aldehyde 3 (18.73 g, 94%)
as a light orange solid (Found: C, 62.39; H, 7.00. C21H28-
O2S2Si requires C, 62.33; H, 6.97%); mp 56–57 ЊC; δH(CDCl3)
1.1–1.22 (21 H, m, 3 × Me2CH), 5.16 (2 H, d, J 1.1, CH2), 7.56
(1 H, d, J 1.1, 8-H), 7.74 (1 H, d, J 8.7) and 7.89 (1 H, d, J 8.8)
(together 4- and 5-H), 8.30 (1 H, s, 1-H) and 10.14 (1 H, s,
ee (%) of
sample
ee (%) of
first fraction
ee (%) of
last fraction
Helicenediol
(M)-9
(M)-9
(P)-9
(P)-9
(P)-9
(P)-9
(P)-9
66
82
92
67
50
42
20
55
69
90
64
50
42
20
77
89
95
72
50
42
20
CHO); νmax(KBr)/cmϪ1 2942, 2863, 1676 (C᎐O), 1055, 882,
᎐
787, 658 and 490.
are not corrected. IR spectra were recorded on a SHIMADZU
FT IR DR8000/8100 infrared spectrometer. NMR spectra were
obtained with a Varian Gemini 200 (200 MHz) spectrometer for
samples in CDCl3 solution with tetramethylsilane as internal
standard, and J-values are given in Hz. Fast-atom bombard-
ment mass spectra (FAB-MS) were recorded on a JEOL-JMS
HS110 mass spectrometer. Optical rotations were measured in 1
dm path length cells of 10 cm3 volume on a JASCO Model
2-(Hydroxymethyl)-7-(triisopropylsiloxymethyl)benzo-
[1,2-b:4,3-bЈ]dithiophene 4
To a stirred solution of aldehyde 3 (15.04 g, 37.17 mmol) in a
mixture of ethanol (72 cm3) and THF (58 cm3) was added
sodium borohydride (4.22 g, 111.50 mmol) at 0 ЊC. The
resulting yellow solution was stirred for 2 h at room temp.
Diethyl ether (100 cm3) was added and then saturated aq.
citric acid was added to decompose remaining sodium boro-
hydride. The reaction mixture was diluted with water and
extracted with diethyl ether. The combined organic phases
were washed with brine, dried over anhydrous magnesium
sulfate, and concentrated. The crude product was recrystal-
lized from hexane to give the title alcohol 4 (13.65 g, 90%) as
a solid. From the filtrate, which was concentrated, and then
chromatographed on silica gel (3:1, hexane–ethyl acetate),
title compound 4 was obtained (0.98 g, 7%). The total yield
DIP181 polarimeter; [α]D-values are given in 10Ϫ1 deg cm2 gϪ1
.
THF was distilled under argon from sodium benzophenone
ketyl immediately before use. Dichloromethane and benzene
were distilled from calcium hydride and stored over molecular
sieves 4 Å. Dichloromethane for lipase-catalyzed transesterifi-
cation was distilled from calcium hydride after being washed by
water and was dried over anhydrous calcium chloride, and
stored over molecular sieves 4 Å. All photocyclizations were
accomplished in an ice–water-cooled Pyrex photoreactor using
a 200 W or 400 W high-pressure mercury lamp. Silica gel
(Wakogel C-200) of the size 100–200 mesh was used for column
chromatography. HPLC analysis was carried out with an
Hitachi instrument equipped with UV detector L4000, using
Sumichiral OA2000 or OA2000I.
of compound
4 was 97% (Found: C, 61.97; H, 7.57.
C21H30O2S2Si requires C, 62.02; H, 7.44%); mp 97–99 ЊC;
δH(CDCl3) 1.08–1.30 (21 H, m, 3 × Me2CH), 1.96 (1 H, t, J
6.0, OH), 5.00 (2 H, d, J 6.0, CH2OSi), 5.13 (2 H, d, J 1.1,
CH2O), 7.46 (1 H, q, J 1.1, 8-H), 7.54 (1 H, q, J 0.74, 1-H) and
7.68 (1 H, d, J 8.6) and 7.74 (1 H, d, J 8.6) (together 4- and
5-H).
2-(Triisopropylsiloxymethyl)benzo[1,2-b:4,3-bЈ]dithiophene 2
To a stirred solution of 2-(hydroxymethyl)benzo[1,2-b:4,3-bЈ]-
dithiophene 1 (7.56 g, 34.31 mmol) in dichloromethane (115 cm3)
were added 2,6-lutidine (9.19 g, 85.78 mmol) and triisopro-
pylsilyl triflate (11.04 g, 36.03 mmol) at 0 ЊC under argon. The
ice-bath was removed and the solution was stirred at room
temp. for 4 h. The reaction was quenched by 5% hydrochloric
acid (400 cm3) and the organic layer was separated. The aque-
ous layer was extracted with dichloromethane. The combined
organic phases were washed with brine, dried over anhydrous
magnesium sulfate, and concentrated. The crude product was
crystallized from hexane to give siloxane 2 (11.51 g, 89%) as an
off-white solid. The filtrate was concentrated and chromato-
graphed on silica gel (hexane) to give more siloxane 2 (0.78 g,
6%) as a solid. The total yield of title compound 2 was 95%
(Found: C, 63.80; H, 7.50. C20H28OS2Si requires C, 63.78; H,
7.49%); mp 50–51 ЊC; δH(CDCl3) 1.08–1.29 (21 H, m,
3 × Me2CH), 5.13 (2 H, d, J 1.1, CH2), 7.51 (1 H, t, J 1.0, 1-H),
7.51 (1 H, d, J 5.3, 8-H), 7.64 (1 H, d, J 5.5, 7-H) and 7.72 (1 H,
d, J 9.3) and 7.77 (1 H, d, J 8.1) (together 4- and 5-H);
νmax(KBr)/cmϪ1 2959, 2940 and 2863.
2-(Chloromethyl)-7-(triisopropylsiloxymethyl)benzo-
[1,2-b:4,3-bЈ]dithiophene 5
To a stirred solution of alcohol 4 (18.09 g, 44.48 mmol) in
benzene (250 cm3) were added pyridine (3.69 g, 46.70 mmol)
and thionyl dichloride (5.57 g, 46.70 mmol) at 0 ЊC under
argon. The reaction mixture was allowed to warm to room
temp. and was stirred overnight. The reaction mixture was then
diluted with benzene and the solution was poured into water.
The organic layer was separated and the aqueous layer was
extracted with benzene. The combined organic phases were
washed with brine, dried over anhydrous magnesium sulfate,
and concentrated to give the crude chloride 5 as a yellow-brown
oil. Since chloride 5 was unstable at room temp. it was used for
the next step without purification; δH(CDCl3) 1.00–1.28 (21 H,
m, 3 × Me2CH), 4.94 (2 H, d, J 0.73, CH2Cl), 5.13 (2 H, d, J 1.1,
CH2O), 7.46 (1 H, d, J 1.1, 8-H), 7.61 (1 H, d, J 0.7, 1-H) and
7.67 (1 H, d, J 8.7) and 7.75 (1 H, d, J 9.0) (together 4- and
5-H).
({7-(Triisopropylsiloxymethyl)benzo[1,2-b:4,3-bЈ]dithiophenyl-
2-yl}methyl)triphenylphosphonium chloride 6
2-Formyl-7-(triisopropylsiloxymethyl)benzo[1,2-b:4,3-bЈ]-
dithiophene 3
A solution of the above chloride 5 and triphenylphosphine
(17.50 g, 66.72 mmol) in benzene (100 cm3) was heated under
reflux for 20 h. Benzene was removed by evaporation and the
residue was washed with diethyl ether to give the salt 6 (18.19
g, 59%) as an off-white solid. From the filtrate, which was
concentrated, and refluxed in dry toluene for 6 h, more salt 6
was isolated (4.00 g, 13%). The total yield of the salt 6 was
72%. An analytical sample was obtained by silica gel column
chromatography (10:1, dichloromethane–methanol); mp 159–
161 ЊC; δH(CDCl3) 1.08–1.29 (21 H, m, 3 × Me2CH), 5.07
(2 H, d, J 1.1, CH2O), 6.09 (2 H, d, J 14.2, CH2P) and 7.37–7.89
(19 H, m, 19 × ArH); νmax(KBr)/cmϪ1 2944, 2867, 1439, 1132
and 507.
To a stirred solution of compound 2 (18.45 g, 48.99 mmol) in
THF (240 cm3) were added N,N,NЈ,NЈ-tetramethylethyl-
enediamine (TMEDA) (14.42 g, 124.0 mmol) and BuLi (37.2
cm3 of 1.58  solution in hexane) at Ϫ78 ЊC under argon and
this mixture was stirred for 5 h. To the resulting green solu-
tion was added a solution of DMF (7.16 g, 97.94 mmol) in
THF (9.5 cm3) at Ϫ78 ЊC. The reaction mixture was allowed
to warm to room temp. during 16 h. The reaction was
quenched by saturated aq. ammonium chloride and 5%
hydrochloric acid. The organic layer was separated and the
aqueous layer was extracted with dichloromethane. The com-
938
J. Chem. Soc., Perkin Trans. 1, 1998

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2-(Triisopropylsiloxymethyl)-7-({7-(triisopropylsiloxymethyl)-
benzo[1,2-b:4,3-bЈ]dithiophenyl-2-yl}ethenyl)benzo-
[1,2-b:4,3-bЈ]dithiophene 7
(2.0 cm3, 21.7 mmol), and the mixture was stirred at 30 ЊC. The
reaction was terminated close to the 50% esterification point
(ca. 25 h) by filtration off of lipase. Evaporation of the mixture
followed by silica gel chromatography gave diol (P)-9 (44 mg,
44%) in 98% ee {[α]D ϩ1973 (c 0.055 in CHCl3)} along with
acetate (M)-10 (41 mg, 37%) and diacetate (M)-11 (15 mg,
13%). Hydrolysis of acetate (M)-10 in methanol (10 cm3) with
0.1  aq. sodium hydroxide gave diol (M)-9 (36 mg) in 77% ee.
In a similar way, hydrolysis of diacetate (M)-11 led to diol (M)-
9 (12 mg) in 94% ee.
The aldehyde 3 (10.71 g, 26.46 mmol) and the phosphonium
salt 6 (18.19 g, 26.46 mmol) were dissolved to a mixture of
THF (90 cm3) and ethanol (380 cm3). To the solution was added
a solution of potassium tert-butoxide (4.45 g, 39.69 mmol) in
ethanol (80 cm3) at room temp. The resulting yellow suspension
was stirred for 16 h. The reaction was quenched by water and
10% hydrochloric acid, and the precipitates were removed
by filtration. The residue was washed with ethanol and then
with hexane, and dried in vacuo to give the coupling product 7 as
a yellow powder (17.69 g, 86%) (Found: C, 64.82; H, 7.42.
C42H56O2S4Si2 requires C, 64.90; H, 7.26%); mp 197–199 ЊC;
δH(CDCl3) 1.09–1.29 (42 H, m, 6 × Me2CH), 5.14 (4 H, d, J 1.1.
2 × CH ), 7.30 (2 H, s, 2 × CH᎐), 7.48 (2 H, d, J 1.1, 2 × 1-H),
(M)-(؊)-2,13-Bis(hydroxymethyl)dithieno[3,2-e:3Ј,2Ј-eЈ]-
benzo[1,2-b:4,3-bЈ]bis[1]benzothiophene (M)-9
To a solution of racemate (PM)-9 (1.00 g, 0.217 mmol) in
dichloromethane (800 cm3) were added CAL (2.50 g, 70 units
mgϪ1, Novo) and vinyl acetate (20.0 cm3, 217 mmol), and the
mixture was stirred at 30 ЊC. The reaction was terminated close
to the 50% esterification point (9.5 h) by filtration off of lipase.
Evaporation of the mixture followed by silica gel chroma-
tography gave diol (M)-9 (440 mg, 44%) in 92% ee {[α]D Ϫ1965
(c 0.050 in CHCl3)} along with acetate (P)-10 (578 mg, 53%)
and diacetate (P)-11 (34 mg, 3%). Hydrolysis of acetate (P)-10
gave diol (P)-9 in 67% ee, and diacetate (P)-11 gave diol (P)-9 in
89% ee.
᎐
2
7.61 (2 H, s, 2 × 8-H) and 7.66 (2 H, d, J 9.0) and 7.74 (2 H, d, J
9.0) (together 2 × 4-, 2 × 5-H); νmax(KBr)/cmϪ1 2942, 2865 and
995.
2,13-Bis(triisopropylsiloxymethyl)dithieno[3,2-e:3Ј,2Ј-eЈ]-
benzo[1,2-b:4,3-bЈ]bis[1]benzothiophene 8
The olefin 7 (2.00 g, 2.57 mmol) was dissolved in benzene (1.7
dm3), and argon gas was bubbled into the solution for 30 min
before photo-irradiation. The photoreactor was cooled to 10 ЊC
by an ice–water-bath. Iodine (1.44 g, 5.65 mmol) and propylene
oxide (36.0 cm3, 51.45 mol) were added and then the solution
was irradiated for 10 h under argon. The reaction mixture was
washed successively with aq. sodium thiosulfate and aq. sodium
hydrogen carbonate. The organic layer was separated and the
aqueous layer was extracted with benzene. The combined
organic phases were washed with brine, dried over anhydrous
sodium sulfate, and concentrated. These procedures were
repeated four times. The combined crude product obtained
from 2.00 g × 5 of substrate 7 (12.87 mmol) was purified by
silica gel column chromatography (100:1, hexane–ethyl acetate)
to give title heptacycle 8 (6.58 g, 66%) as a pale yellow solid
(Found: C, 65.43; H, 7.07. C42H54O2S4Si2 requires C, 65.06; H,
7.02%); mp 164–167 ЊC; δH(CDCl3) 0.93–1.13 (42 H, m,
6 × Me2CH), 4.53 (2 H, dd, J 1.1 and 13.4, CH2), 4.60 (2 H, dd,
J 1.1 and 13.5, CH2), 6.56 (2 H, t, J 1.1, 1- and 14-H), 7.88 (2 H,
d, J 8.6) and 7.97 (2 H, d, J 9.0) (together 4-, 5-, 10- and 11-H)
and 7.99 (2 H, s, 7- and 8-H); νmax(KBr)/cmϪ1 2942, 2865, 1134,
1092, 1067 and 735.
Thermal racemization of compound 9
(M)-Helicenediol 9 (5 mg) of 95% ee was dissolved in 20 cm3 of
mesitylene, then the solution was heated under argon. Every
24 h, 0.4 cm3 of the reaction was withdrawn via a syringe as a
sample for HPLC analysis.
Enantiomeric enhancement
Chromatography was carried out on a column packed with
silica gel (18 mm diameter, 20 cm height) by elution with
hexane–ethyl acetate (3:1). A dichloromethane solution of
helicenediol 9 was chromatographed and fractions of 20 cm3
volume were collected in test tubes. The ees were determined by
HPLC by using methyl m-hydroxybenzoate as an internal
standard.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific
Research and by Grants-in-Aid for Scientific Research on
Priority Areas from the Ministry of Education, Science, Sports
and Culture. H. O. thanks JSPS for fellowships (Nos. 6-3089
and 9-2575).
2,13-Bis(hydroxymethyl)dithieno[3,2-e:3Ј,2Ј-eЈ]benzo[1,2-b:4,3-
bЈ]bis[1]benzothiophene 9
To a solution of compound 8 (6.68 g, 8.62 mmol) in THF (150
cm3) was added a solution of TBAF (18.1 cm3 of 1  solution in
THF) at 0 ЊC. The solution was stirred at 0 ЊC for 4 h and at
room temp. for 2 h. The reaction was quenched by brine, and
ethyl acetate was added to separate the organic layer. The aque-
ous layer was extracted with ethyl acetate. The combined
organic phases were washed, dried over anhydrous magnesium
sulfate, and concentrated. The crude product was purified by
silica gel column chromatography (2:1, hexane–ethyl acetate)
and recrystallized from ethanol to give title diol 9 (3.95 g, 90%)
as a yellow solid [Found: C, 61.46; H, 3.76. C26H20O3S4
(9 ϩ C2H5OH) requires: C, 61.39; H, 3.96%]; mp 179–181 ЊC;
δH(CDCl3) 1.24 (3 H, t, J 8.0, Me of ethanol), 1.72 (2 H, m,
OH), 3.73 (2 H, q, J 8.0, CH2 of ethanol), 4.27 (2 H, d, J 12.8,
CH2), 4.46 (2 H, d, J 12.8, CH2), 6.59 (2 H, s, 1- and 14-H), 7.97–
8.02 (4 H, d, J 8.0, 4-, 5-, 10- and 11-H) and 8.06 (2 H, s, 7- and
8-H).
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Paper 7/07196E
Received 6th October 1997
Accepted 25th November 1997
940
J. Chem. Soc., Perkin Trans. 1, 1998