Synthesis and absolute configuration of (1S,8S)-as-hydrindacene-1,8-diol as determined by the circular dichroism exciton chirality method

Article abstract of DOI:10.1016/j.tetlet.2004.11.028

2,3,6,7-Tetrahydro-as-indacene-1,8-dione 4 was prepared in 4 steps starting from 2-methyl-furan by modification of a literature procedure. Appliance of Noyori's asymmetric transfer hydrogenation, resulted in (1S,8S)-1,2,3,6,7,8- hexahydro-as-indacene-1,8-

Full text of DOI:10.1016/j.tetlet.2004.11.028

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 75–78
Synthesis and absolute configuration of (1S,8S)-as-hydrindacene-
1,8-diol as determined by the circular dichroism exciton
chirality method
Koen Vandyck, Bavo Matthys and Johan Van der Eycken*
Laboratory for Organic and Bio-organic Synthesis, Department of Organic Chemistry, Ghent University,
Krijgslaan 281 (S4), B-9000 Gent, Belgium
Received 6 September 2004; revised 4 November 2004; accepted 5 November 2004
Abstract—2,3,6,7-Tetrahydro-as-indacene-1,8-dione 4 was prepared in 4 steps starting from 2-methyl-furan by modification of a
literature procedure. Appliance of Noyoriꢀs asymmetric transfer hydrogenation, resulted in (1S,8S)-1,2,3,6,7,8-hexahydro-
as-indacene-1,8-diol 5 in high yield (81%) and excellent enantioselectivity (>99% ee) or (8S)-8-hydroxy-3,6,7,8-tetrahydro-2H-
as-indacen-1-one 6 in moderate yield (58%) and equally high enantioselectivity (98.5% ee), depending on the conditions. The
asymmetric reduction was expected to yield the (S)-alcohols using the (S,S)-Ts-DPEN ligand, which was confirmed by the appliance
of the exciton chirality method on the corresponding bis(p-dimethylamino)benzoate 7.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The use of enantiomerically pure indane derivatives as
chiral auxiliary or ligand has been extensively described
in literature,1 whereas reports of chiral ligands based on
1,2,3,6,7,8-hexahydro-as-indacene (Scheme 1, frame) are
scarse.2 Nevertheless, rigid 1,8-disubstituted as-hydrin-
dacenes can become the cornerstone of an interesting
new ligand architecture. In order to investigate the
applicability of such structures in asymmetric synthesis,
we needed to have facile access to as-hydrindacene-1,8-
dione 43 in multigram quantities. The intermediate
[2.2](2.5)furanophane 3 was readily obtained using a
procedure described for the synthesis of the structurally
analogous [2.2]paracyclophane.4 (Scheme 1).
Starting from the methylated Mannich adduct 1, which
was obtained on a 500g scale in two easy steps from
commercial 2-methyl-furan,5 anion exchange using
Ag2O resulted in the intermediate ammonium hydroxide
2. Subsequently, without isolation, 2 was dimerized to
the furanocyclophane 3 on a 70g scale while removing
water in a Dean–Stark apparatus in the presence of
a polymerization inhibitor. Further transformation of
Scheme 1. Reagents, conditions and yields: (a) HNMe2ÆHCl, 37% H2CO, 35ꢁC, 1.5h then reflux 2h, 85%; (b) MeI, EtOH, 0ꢁC, 97%; (c) Ag2O, H2O,
rt, 2h; (d) phenothiazine, toluene, Dean–Stark, reflux, 7h, 71%; (e) (i) m-CPBA, CH2Cl2, ꢀ30ꢁC, 1.5h then Na2S2O3 (aq) and rt for 5h; (ii) Na2CO3,
MeOH, rt, 1.5h, 88%.
Keywords: Chiral ligands; As-hydrindacene-1,8-diol; Circular dichroism; Exciton chirality method.
*
Corresponding author. Tel.: +32 9 264 44 80; fax: +32 9 264 49 98; e-mail: johan.vandereycken@ugent.be
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.028

76
K. Vandyck et al. / Tetrahedron Letters 46 (2005) 75–78
furanocyclophane 3 was accomplished by oxidizing a
furan moiety employing m-CPBA, after which an in situ
Diels–Alder reaction and dehydration with Na2CO3 in
MeOH resulted in the desired 2,3,6,7-tetrahydro-as-
indacene-1,8-dione 4.6 On a 20g scale this proved to
be a more practical approach than the photooxidation
as reported in the original procedure.3
The CD exciton chirality method is very powerful for
the determination of the absolute stereochemistry of chi-
ral organic compounds.11 In order to confirm the abso-
lute stereochemistry of diol (+)-5, bis(p-Me2N)-benzoate
7 and its O-acetyl-mono(p-Me2N)benzoate 9 (Scheme 3)
were synthesized. Both 7 (e = 55,700) and 9 (e = 28,200)
exhibit strong p–p*-absorption at kmax = 311nm (Fig.
1). In contrast to the case of UV-spectra, a striking dif-
In order to obtain the C2-symmetrical diol 5, we submit-
ted diketone 4 to Noyoriꢀs asymmetric transfer hydroge-
nation conditions,7 applying an in situ prepared catalyst
(A) derived from commercial (1S,2S)-(+)-N-p-tosyl-1,2-
diphenylethylenediamine and [RuCl2(g6-cymene)]2 in a
5:2 formic acid–triethylamine mixture. This resulted in
mono-hydrogenated keto-alcohol (+)-6 or bis-hydroge-
nated diol (+)-5, depending on reaction time, tempera-
ture and catalyst loading (Scheme 2).
In this way, using 3% in situ generated catalyst A, diol
(+)-5 was obtained in high yield (81%) and excellent
enantioselectivity (>99% ee) after 4 days at room tem-
perature. In contrast, using only 1% of catalyst, mono-
hydrogenated keto-alcohol (+)-6 could be isolated in
58% yield and 98.5% ee after 54h at room temperature.
Repeating the latter reaction at 60ꢁC resulted in a dra-
matic increase of the reaction rate, allowing isolation
of (+)-6 in similar yield and enantiomeric excess after
only 3h. Finally, reduction at 60ꢁC for 24h with 3%
catalyst gave (+)-5 in 73% yield and >99% ee.8,9
Scheme 3. Reagents, conditions and yields: (a) p-Me2N-benzoylchlo-
ride, THF, DMAP, 60ꢁC, 24h; 57% of 7 and 38% of 8; (b) Ac2O,
DMAP, pyridine, rt, 1h; 72%.
100
80
The absolute configuration obtained in the asymmetric
reduction was predicted to be S, by analogy with the
reduction of indanone to (S)-indanol using the same cat-
alyst and given the fact that the enantiofacial differenti-
ation occurs via a p–CH interaction of a metal saturated
species and the aromatic ketone.10
60
40
20
0
-20
6
4
2
0
Scheme 2. Reagents, conditions and yields: in situ preparation of
catalyst A: [RuCl2(g6-cymene)]2, (S,S)-Ts-DPEN, NEt3, (0.5:1.05:2),
DMF, 80ꢁC, 1h; (a) HCOOH/NEt3 (molar ratio 5:2) and DMF (1:2),
3mol% A, 96h, rt, 81% (>99% ee) or 24h, 60ꢁC, 73% (>99% ee);
(b) HCOOH/NEt3 (molar ratio 5:2) and DMF (1:2), 1mol% A, 54h,
rt, 58% (ꢁ98.5% ee) or 3h, 60ꢁC, 58% (ꢁ98.5% ee).
240
260
280
300
320
340
360
λ (nm)
Figure 1. UV (bottom) and CD (top) spectra of bis(p-Me2N-benzoate)
7 (bold black line) and p-Me2N-benzoyl-acetyl derivative 9 (thin gray
line) in CH3CN.

K. Vandyck et al. / Tetrahedron Letters 46 (2005) 75–78
77
4. Winberg, H. E.; Fawcett, F. S. Org. Synth. Coll. 1973, 5,
883–885.
5. (a) Eliel, E. L.; Peckham, P. E. J. Am. Chem. Soc. 1950,
72, 1209–1211; (b) Holdren, R. F.; Hixon, R. M. J. Am.
Chem. Soc. 1946, 68, 1198–1201.
6. Experimental procedure for the synthesis of 4: Furano-
cyclophane 3 (20.0g; 0.106mol) was dissolved in 500mL
CHCl3 and cooled to ꢀ30ꢁC. m-CPBA (20.1g; 0.116mol;
ꢁ90% purity) was added, followed by two more portions
(2 · 0.6g; 2 · 3.48mmol), respectively, after 30 and 60min.
The mixture was stirred for 30min more at ꢀ30ꢁC and
then quenched with 0.1M aqueous Na2S2O3. After
warming to room temperature, stirring was continued
for 5h. The white heterogenous mixture was poured into
250mL aqueous NaHCO3 (satd) and extracted with
CHCl3 (2 · 250mL). The combined organic fractions were
washed with 150mL NaHCO3 and the volatiles were
removed in vacuo, resulting in 21.1g crude mixture. The
white solid was dissolved in 800mL MeOH and 200mL
aqueous Na2CO3 (satd) was added. After 1.5h the
reaction mixture was poured into H2O (1L) and extracted
with CHCl3 (3 · 1L) After drying over anhydrous MgSO4,
filtration and removal of the solvent in vacuo, the solid
residue was redissolved and filtered over 100mL silicagel
using CHCl3/EtOAc 6:4 as eluent. Evaporation of the
volatiles in vacuo resulted in 18.2g crude mixture.
Recrystallization from MeOH gave 17.4g (0.0934mol;
88%) 4 as a pale yellow solid. Selected data for 4: mp 211–
212ꢁC (lit. 208–209);3 dH (500MHz; CDCl3): 2.70–2.75
(4H, m,), 3.15–3.20 (4H, m), 7.65 (2H, s); dC (125MHz;
CDCl3): 26.2 (CH2), 36.8 (CH2), 132.3 (CH), 134.6 (C),
156.3 (C), 203.5 (C) ppm.
Figure 2. The positive chirality constituted by the two benzoate
moieties, resulting in a positive first and a negative second Cotton
effect.
ference is observed between CD spectra of monobenzo-
ate 9 and di-benzoate 7. Monobenzoate 9 shows a weak
positive Cotton effect (De = 4.7) in the region of the
absorption maximum kmax = 311nm. In contrast, the
CD spectrum of 7 shows a strong exciton split CD Cot-
ton effect centred at 305nm: a positive first extremum at
320nm (De = 86) and a negative second extremum at
292nm (De = ꢀ26). The large difference between the cir-
cular dichroism of 7 and 9 can therefore only be attrib-
uted to the chiral exciton coupling of the two identical
p-Me2N-benzoate chromophores.11 The positive ampli-
tude (A = 112) indicates a clockwise screw sense between
the two benzoate moieties (Fig. 2).12 The absolute
configuration is therefore assigned as (1S,8S)-5 and
(8S)-6. Transformation of (+)-5 and (+)-6 into chiral
N- and P-ligands, and their application in asymmetric
catalysis is under current investigation and will be
published in due course. As enantiomeric (1R,2R)-(ꢀ)-
N-p-tosyl-1,2-diphenylethylenediamine is commercially
available as well, our approach also constitutes a synthe-
sis of (ꢀ)-5 and (ꢀ)-6, and hence will allow access to
both enantiomeric series of all derived N- and P-ligands.
7. Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521–2522.
20
8. Selected data for (+)-5: mp 155.5–156.5ꢁC; ½aꢂD +70.5 (c
1.09, CHCl3); dH (500MHz, CDCl3): 1.91 (2H, dddd [app.
dq], J = 8.4, 9.3, 9.3, 12.5Hz), 2.56 (2H, dddd, J = 2.0, 7.1,
7.5, 12.5 Hz), 2.77 (2H, ddd, J = 7.5, 9.3, 15.0Hz), 2.94
(2H, ddd, J = 2.0, 9.3, 15.0Hz), 5.47 (2H, dd [app. t],
J = 7.1, 8.4Hz), 7.10 (2H, s); dC (125MHz; CDCl3): 29.7
(CH2), 35.9 (CH2), 75.6 (CH), 124.5 (CH), 140.7 (C), 141.1
(C) ppm; HPLC: Chiralcel OD-H column, solvent:
n-hexane/EtOH (97:3), flow rate = 1mL/min, T =
35ꢁC, retention times: (1S,8S)-5 = 14.2min, (1R,8R)-5 =
16.1min.
20
Selected data for (+)-6: mp 108–110ꢁC; ½aꢂD +94.4 (c 1.01,
Acknowledgements
CHCl3); dH (500MHz; CDCl3): 2.03 (1H, dddd [app. dq],
J = 8.2, 9.5, 9.5, 13.0Hz), 2.61 (dddd, 1H, J = 1.8, 7.8, 8.0,
13.0Hz), 2.69–2.80 (2H, m), 2.87 (1H, ddd, J = 8.0, 9.5,
15.9Hz), 3.04 (1H, ddd, J = 1.8, 9.5, 15.9Hz), 3.14–3.23
(2H, m), 5.58 (1H, dd, J = 7.8, 8.2Hz), 7.34 (1H, d,
J = 7.8Hz), 7.44 (1H, d, J = 7.8Hz); dC (125MHz;
CDCl3): 26.6 (CH2), 30.3 (CH2), 33.9 (CH2), 36.5 (CH2),
75.3 (CH), 126.0 (CH), 131.7 (CH), 133.5 (C), 142.2 (C),
144.8 (C), 154.9 (C), 210.3 (C) ppm; HPLC: Chiralcel
OD-H column, solvent: n-hexane/EtOH (98:2), flow
Thanks are addressed to Professor M. Rosseneu and Dr.
B. Vanloo (Ghent University) for permitting the use of
their CD spectrometer and the kind assistance. K.V.
is a Research Assistant of the Fund for Scientific
Research—Flanders, Belgium, (F.W.O.—Vlaanderen).
References and notes
rate=1mL/min, T = 35ꢁC,
6 = 11.5min, (8R)-6 = 12.8min.
retention
times = (8S)-
1. Ghosh, A. K.; Fidanze, S.; Senanayake, C. H. Synthesis
1998, 937–961, and references cited therein.
9. Together with (+)-5, ꢁ5% (+)-6 and ꢁ2% meso-diol were
isolated applying 3% catalyst at rt; using 1% catalyst at rt
or 60ꢁC, 25–30% of a mixture of diols was isolated
together with (+)-6. With 3% catalyst at 60ꢁC for 24h,
18% (+)-6 and 6% meso-diol were obtained as byproducts.
Selected data for meso-diol: mp 109ꢁC (lit. 111.0–
111.8ꢁC)3; dH (500MHz; CDCl3): 2.01 (2H, dddd,
J = 4.9, 6.5, 9.0, 13.6Hz), 2.50 (2H, dddd, J = 4.7, 7.3,
8.8, 13.6Hz), 2.83 (2H, ddd, J = 6.5, 8.8, 15.6Hz), 3.08
(2H, ddd, J = 4.7, 9.0, 15.6Hz), 5.46 (2H, dd, J = 4.9,
7.3Hz), 7.14 (2H, s); dC (125MHz; CDCl3): 30.3 (CH2),
2. For a chiral as-indacene catechol derivative: Kelly, T. R.;
Chandrakumar, N. S.; Saha, J. K. J. Org. Chem. 1989, 54,
980–983; For an as-indacene-bridged bis(a-amino acid):
Hoven, G. B.; Efskind, J.; Romming, C.; Undheim, K. J.
Org. Chem. 2002, 67, 2459–2463; For the use of similar
verbenone dimers: Paquette, L. A.; Zhou, R. J. Org.
Chem. 1999, 64, 7924–7929.
3. Katz, T. J.; Balogh, V.; Schulman, J. M. J. Am. Chem.
Soc. 1968, 90, 734–739.

78
K. Vandyck et al. / Tetrahedron Letters 46 (2005) 75–78
34.7 (CH2), 75.7 (CH), 124.9 (CH), 141.3 (C), 142.0 (C)
ppm.
K.; Woody, R. W. Circular Dichroism: Principles and
Applications; Wiley-VCH: New-York, 2000.
10. Noyori, R.; Yamakawa, M.; Hashiguchi, S. J. Org. Chem.
2001, 66, 7931–7944.
11. (a) Harada, N.; Nakanishi, K. Circular Dichroic Spectros-
copy—Exciton Coupling in Organic Stereochemistry;
Oxford University: Oxford, 1983; (b) Berova, N.; Nakanishi,
12. Due to the irreversible nature of the transfer hydrogen-
ation in a 5:2 HCOOH/NEt3 mixture, the absolute
configuration of (8S)-6 can be related to (1S,8S)-5. This
was confirmed by the reduction of (8S)-6 into a mixture of
meso- and (1S,8S)-5 (3:1) with NaBH4 in MeOH.