Asymmetric synthesis of (7aS)-7a-methyl-4,5,7,7a-tetrahydro-1H-indene-2,6- dione and useful derivatives thereof

Article abstract of DOI:10.3390/11090707

The enantioselective synthesis of the title compound, using Meyers' bicyclic lactam methodology, is described. This compound and a few of its derivatives are useful intermediates in natural product synthesis.

Full text of DOI:10.3390/11090707

Molecules 2006, 11, 707-713
molecules
ISSN 1420-3049
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Full Paper
Asymmetric Synthesis of (7aS)-7a-Methyl-4,5,7,7a-tetrahydro-
1H-indene-2,6-dione and Useful Derivatives Thereof
Samuël Demin, Dirk Van Haver and Pierre J. De Clercq*
Ghent University, Department of Organic Chemistry, Laboratory for Organic Synthesis, Krijgslaan
281 (S4), B-9000 Gent, Belgium
* Author to whom correspondence should be addressed: E-mail: pierre.declercq@UGent.be
Received: 7 September 2006; in revised form: 14 September 2006 / Accepted: 14 September 2006 /
Published: 18 September 2006
Abstract: The enantioselective synthesis of the title compound, using Meyers' bicyclic
lactam methodology, is described. This compound and a few of its derivatives are useful
intermediates in natural product synthesis.
Keywords: Asymmetric synthesis, Meyers' bicyclic lactam template, hydrindenones.
Introduction
In the context of the development of structural analogs of calcitriol, the hormonally active
metabolite of vitamin D3 [1], we required the cis-fused perhydrindanone 7 (Scheme 1) [2]. We herein
describe in detail the enantioselective synthesis of the potentially useful dione 5 and its further
conversion to 7.
Results and Discussion
The synthesis of 7, a cis-fused angularly substituted perhydrindane dione, in which one of the
carbonyl groups is protected as cyclic ketal, involves two phases. First Meyers' methodology for the
enantioselective synthesis of hydrindenones is applied in the preparation of 5 [3]. In a second phase,
the cyclohexanone carbonyl group of 5 is protected as an ethylene ketal and the cis-fusion in 7 is
obtained by stereoselective catalytic hydrogenation of 6.

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708
Meyers' approach for the asymmetric synthesis of angularly substituted hydrinden-2-ones proceeds
in 3 stages: (i) the asymmetric introduction of the quaternary center using a chiral bicyclic lactam such
as 1; (ii) the reductive intramolecular alkylation in which the 1,4-diketone is generated; (iii) the
intramolecular aldolisation of the latter to the hydrinden-2-one. We chose to introduce the second
carbonyl group in 5 via oxidative cleavage of the exocyclic double bond in 4. Following Meyers'
methodology the latter is obtained from diastereomer 2a.
To stereoselectively obtain the correct configuration at the 6-position in 2a, the methyl group and
the unsaturated side chain need to be introduced sequentially and in that precise order. Indeed, the
prior introduction of the unsaturated side chain could eventually lead to the formation of spirocyclic
derivatives [4]. On the other hand, the preferred endo-alkylation of Meyers' bicyclic lactam template
has been well documented [5]. Hence, enantiomerically pure (+)-1 was required as starting material [6].
Scheme 1. Synthetic pathway to tetrahydro-1H-inden-2,6-dione 5 and derivatives.
Br
Br
8
1
O
O
O
a, b
6
+
N
N
Br
N
Br
3
O
O
O
c, d
(+)-1
2a
2b
O
O
h
e
f
g
O
O
O
O
O
O
3
4
5
6
O
O
O
7
H
(a) (i) LDA, THF, –78 °C; (ii) MeI, –78 °C, 2 h (96%); (b) (i) LDA, DMPU, THF, –78 °C;
(ii) 8, –78 °C; 3 h (84%); (c) t-BuLi, KH, THF, –78 °C, 45 min; (d) n-Bu4NH2PO4, EtOH,
75 °C, 12 h (68% from 2a); (e) KOH, EtOH, rt, 16 h (89%); (f) O3, CH2Cl2, –78 °C (73%); (g)
HO(CH2)2OH, TsOH, toluene, reflux, 2 h (92%); (h) H2, Pd/C, EtOAc, rt, 2.5 h (100%).
The methylation of 1 led to a 9:1 diastereomeric mixture, which was not separated. After further
deprotonation with LDA (DMPU, THF) and alkylation with the known dibromide 8 [7], a 7:3 mixture
of 2a and 2b was obtained, which was separated by chromatography. The preferred formation of the
1
endo-isomer 2a was proven by H-NMR nOe signal-enhancement studies establishing the relative
positions of the Me groups and H atoms indicated in Figure 1. The major isomer 2a was subjected to

Molecules 2006, 11
709
Meyers' protocol (KH, t-BuLi) yielding diketone 3. Basic treatment (KOH, EtOH) led to hydrinden-2-
one 4. Selective cleavage of the exocyclic double bond in 4 (ozone, Me2S) gave diketone 5 in which
the saturated carbonyl group was further protected to afford the ketal 6. Finally, catalytic
hydrogenation of the latter occurred exclusively from the convex side of the bicyclic molecule leading
1
to the cis-fused perhydrindanone 7, the structure of which was confirmed by H-NMR structural
analysis: upon irradiation of the angular Me group a clear nOe enhancement of the signal of the
bridgehead hydrogen was observed, confirming the cis-fusion of the hydrindane (Figure 1).
Figure 1. 1H-NMR nOe signal-enhancement studies of 2a and 7.
H
CH3
7a
H
CH3
O
CH3
7
3a
O
N
H
3
6
O
R
H
O
2a
7
O
Conclusions
Angularly substituted perhydrindanones are useful intermediates in synthesis. The asymmetric
synthesis of 7, in which an additional carbonyl group in protected ketal form is present (overall yield
33%), following a sequence of 7 steps starting from commercially available (+)-1 provides a useful
example of the general applicability of Meyers' methodology.
Experimental
General
Tetrahydrofuran (THF) was distilled from benzophenone ketyl. Dichloromethane (DCM) was
distilled from CaH2. Toluene was distilled from sodium. TLC were run on glass plates precoated with
silica gel (Merck, 60F-254). Column chromatography was performed on silica gel (Merck, 230-400
1
mesh). IR spectra were recorded on a Perkin–Elmer series 1600 FT-IR spectrometer. H-NMR and
13C-NMR spectra were recorded on a Bruker AM-500 spectrometer. Hydrogen chemical shifts δ are
reported in ppm relative to CDCl (7.26 ppm) as an internal reference. J values are given in Hz.
3
Carbon chemical shifts δ are reported in ppm relative to CDCl (77.16 ppm) as an internal reference.
3
Mass spectra (EI) were recorded on a Hewlett–Packard 5898A spectrometer at 70 eV.
(3S,6S,7aR)-6-[2-(2-Bromoethyl)-3-methylbut-2-en-1-yl]-3-isopropyl-6,7a-dimethyltetrahydro-
pyrrolo[2,1-b][1,3]oxazol-5(6H)-one ((+)-2a) [8]
To i-Pr2NLi (LDA, 2 M solution in THF; 110 mL, 0.22 mol) was added dry THF (1100 mL) and
the solution was cooled to –78 °C. (3S,7aR)-3-Isopropyl-7a-methyltetrahydropyrrolo[2,1-b][1,3]-
oxazol-5(6H)-one ((+)-1; 20 g, 0.11 mol) was added dropwise and the mixture was stirred for 30 min.
MeI (46.74 g, 20.5 mL, 0.33 mol) was then added dropwise, the reaction mixture was stirred for 2 h
and then allowed to warm to rt. An aqueous saturated NH4Cl solution (50 mL) was added and the

Molecules 2006, 11
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mixture was stirred for 1 h. H2O was added, the aqueous layer was extracted with Et2O (3×), the
combined organic layers were dried over anhydrous MgSO4 and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel (isooctane/EtOAc, 7:3) to afford a
9:1 mixture of the (6R/6S)-diastereomers of the methylated bicyclic lactam (20.8 g, 96%).
To LDA (2 M solution in THF; 7.5 mL, 20 mmol) was added dry THF (100 mL) and the solution
was cooled to –78 °C. 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU; 11 mL) was
added and the mixture was stirred for 10 min. The above mixture of methylated bicyclic lactams (2.0 g,
10.1 mmol) in dry THF (10 mL) was added dropwise and the reaction mixture was stirred for 2 h.
5-Bromo-3-(bromomethyl)-2-methylpent-2-ene (8; 5.12 g, 20 mmol) in dry THF (10 mL) was then
added dropwise and stirring was continued for 1 h. An aqueous saturated NH4Cl solution (20 mL) was
added and the mixture was allowed to warm to rt. H2O was added, the aqueous layer was extracted
with Et2O, the combined organic layers were dried over anhydrous MgSO4 and concentrated under
reduced pressure. The obtained 7:3 mixture of isomers of the dialkylated bicyclic lactam (3.1 g, 84%)
was separated by column chromatography on silica gel (isooctane/ EtOAc, 7:3) to give the major (6S)-
isomer (+)-2a as a solid: mp 45 °C; Rf (isooctane/EtOAc, 95:5) 0.22; [α]Drt +106.5 (c 1.15, CHCl3); IR
(KBr pellet) ν 2963, 2871, 1708, 1463, 1376, 1381, 1298, 1252, 1218, 1176, 1130, 1037, 1006), 967,
903, 842, 808, 771, 684, 650 cm–1; 1H-NMR (500 MHz, CDCl3) δ 4.18 (1 H, dd, J = 8.8, 8.8 Hz), 3.77
(1 H, dd, J = 7.9, 7.9 Hz), 3.59–3.54 (1 H, m), 3.39–3.34 (1 H, m), 3.28–3.22 (1 H, m), 2.39 (2 H, s),
2.68–2.62 (1 H, m), 2.29–2.23 (1 H, m), 2.24 (1 H, d, J = 13.5 Hz), 1.88 (1 H, d, J = 13.3 Hz), 1.71 (3
H, s), 1.66–1.63 (1 H, m), 1.63 (3 H, s), 1.50 (3 H, s), 1.29 (3 H, s), 1.04 (3 H, d, J = 6.6 Hz), 0.88 (3 H,
13
d, J = 6.6 Hz) ppm; C-NMR/DEPT (50 MHz, CDCl3) δ 183.7 (C), 132.9 (C ), 126.8 (C), 96.8 (C),
70.6 (CH2), 61.6 (CH), 48.3 (C), 45.5 (CH2), 38.2 (CH2), 35.6 (CH2), 34.2 (CH), 30.9 (CH2), 27.5
(CH3), 25.8 (CH3), 21.4 (CH3), 20.7 (CH3), 20.6 (CH3), 18.9 (CH3) ppm; MS m/z (%) 372 (M+, 17),
359 (17), 358 (88), 357 (20), 356 (88), 341 (14), 331 (11), 330 (60), 328 (100), 326 (46), 310 (7), 300
(21). Anal. Calcd for C18H30BrNO2: C, 58.10; H, 8.06; N, 3.76. Found: C, 57.95; H, 8.25, N, 3.70.
(2S)-2-Methyl-4-(1-methylethylidene)-2-(2-oxopropyl)cyclohexanone ((+)-3)
To a solution of dialkylated bicyclic lactam (+)-2a (1.0 g, 2.7 mmol) in dry THF (54 mL) were
added t-BuLi (1.7 M solution in pentane; 3.32 mL, 5.6 mmol) and KH (0.324 g, 8.1 mmol) at –78 °C
and the reaction mixture was stirred for 45 min. H2O (20 mL) was added and the mixture was allowed
to warm to rt under stirring for 20 min. The solution was concentrated under reduced pressure to 1/3 of
its volume and EtOH (20 mL) was added to obtain a homogeneous solution. A 1 M n-Bu4NH2PO4
solution (26.5 mL, 0.081 mmol) was added and the mixture was refluxed for 12 h. After cooling, H2O
was added, the aqueous layer was extracted with Et2O (2×), the combined organic layers were dried
over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by column
chromatography on silica gel (isooctane/EtOAc, 8:2) to give diketone (+)-3 (0.388 g, 68%): Rf
rt
(isooctane/EtOAc, 8:2) 0.33; [α]D +20.5 (c 1.10, CHCl3); IR (KBr film) ν 2963, 2921, 1710, 1456,
1
1360, 1167, 1104 cm–1; H-NMR (500 MHz, CDCl3) δ 2.98 (1 H, AB, J = 17.7 Hz), 2.69–2.63 (2 H,
m), 2.56–2.47 (2 H, m), 2.49 (1 H, AB, J = 17.7 Hz), 2.44–2.38 (1 H, m), 2.34 (1 H, d, J = 14.1 Hz),
13
2.10 (3 H, s), 1.71 (3 H, s), 1.70 (3 H, s), 1.03 (3 H, s) ppm; C-NMR/APT (125 MHz, CDCl3) δ
206.9 (C), 206.9 (C), 126.1 (C), 125.3 (C), 52.2 (CH2), 47.0 (C), 38.6 (CH2), 38.6 (CH2), 30.7 (CH3),
27.2 (CH2), 24.1 (CH3), 20.4 (CH3), 20.3 (CH3); MS m/z (%) 208 (M+, 1), 150 (49), 135 (34), 107 (43),

Molecules 2006, 11
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93 (21), 79 (26), 67 (21), 43 (100).
(7aS)-7a-Methyl-6-(1-methylethylidene)-1,4,5,6,7,7a-hexahydro-2H-inden-2-one ((+)-4)
To a solution of diketone (+)-3 (2.5 g, 12 mmol) in EtOH (12 mL) was added KOH (0.64 g, 12
mmol) and the reaction mixture was stirred at rt for 16 h. H2O was added and the aqueous layer was
extracted with Et2O (3×). The combined organic layers were washed with a saturated NaCl solution,
dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel (isooctane/EtOAc, 9:1) to give enone (+)-4 (2.0 g, 89%) as
yellow crystals: mp 84 °C; Rf (isooctane/EtOAc, 8:2) 0.37; [α]Drt +53.15 (c 0.75, CHCl3); IR (KBr film)
1
ν 2956, 2916, 2860, 2358, 1709, 1620, 1437, 1409, 1372, 1274, 1220, 1171, 840, 750, 670 cm–1; H-
NMR (500 MHz, CDCl3) δ 5.79 (1 H, d, J = 1.6 Hz), 2.96 (1 H, m), 2.89 (1 H, dd, J = 13.0, 2.3 Hz),
2.72 (1 H, ddd, J = 13.6, 4.6, 2.3 Hz), 2.36 (1 H, ddd, J = 13.5, 13.5, 6.3 Hz), 2.33 (1 H, AB, J = 18.4
Hz), 2.28 (1 H, AB, J = 18.4 Hz), 1.82–1.75 (2 H, m), 1.77 (3 H, s), 1.72 (3 H, s), 1.13 (3H, s) ppm;
13C-NMR/APT (125 MHz, CDCl3) δ 208.2 (C), 188.0 (C), 126.8 (C), 126.2 (C), 126.0 (CH), 51.1
(CH2), 45.2 (C), 43.9 (CH2), 30.6 (CH2), 28.9 (CH2), 24.2 (CH3), 20.5 (CH3), 20.4 (CH3) ppm; MS m/z
(%) 190 (M+, 100), 175 (32), 162 (10), 147 (76), 133 (15), 119 (57), 105 (44), 91 (47), 79 (38), 55 (28),
41 (45).
(7aS)-7a-Methyl-4,5,7,7a-tetrahydro-1H-indene-2,6-dione ((–)-5)
O3 was bubbled through a solution of alkene (+)-4 (0.48 g, 2.5 mmol) in DCM (126 mL) at –78 °C
for 8 min. Me2S (0.3 mL, 3.4 mmol) was added, the reaction mixture was allowed to warm to 0 °C,
stirred for 1 h and then allowed to warm to rt. The solvent was evaporated and the residue was purified
by column chromatography on silica gel (Et2O/isooctane, 9:1) to give ketone (–)-5 (0.298 g, 73%): Rf
(Et2O/isooctane, 9:1) 0.23; [α]Drt –62.0 (c 1.10, CHCl3); IR (KBr film) ν 3070, 2953, 1710, 1678, 1622,
1
1432, 1337, 1296, 1198, 1090, 1070, 902 cm–1; H-NMR (500 MHz, CDCl3) δ 6.02 (1 H, d, J = 1.7
Hz), 3.06 (1 H, ddd, J = 14.6, 7.5, 1.4 Hz), 2.83 (1 H, dddd, J = 14.6, 13.1, 6.7, 1.7 Hz), 2.67–2.61 (2
H, m), 2.52–2.44 (2 H, m), 2.43 (1 H, AB, J = 18.6 Hz), 2.39 (1 H, AB, J = 18.6 Hz), 1.25 (3 H, s)
ppm; 13C-NMR/APT (125 MHz, CDCl3) δ 207.2 (C), 206.4 (C), 181.2 (C), 128.3 (C), 54.2 CH2), 51.2
(CH2), 45.4 CH), 40.0 (CH2), 26.09 (CH2), 25.5 (CH3) ppm; MS m/z (%) 164 (M+, 86), 149 (18), 136
(14), 121 (39), 107 (44), 93 (56), 79 (100), 55 (25), 53 (30).
(3a'S)-3a'-Methyl-3a',4',6',7'-tetrahydrospiro[1,3-dioxolane-2,5'-inden]-2'(3'H)-one ((+)-6)
To a solution of ketone (–)-5 (0.77 g, 4.7 mmol) in dry toluene (47 mL) were added
HOCH2CH2OH (0.3 g, 0.27 mL, 4.7 mmol) and TsOH (90 mg, 0.47 mmol). The reaction mixture was
refluxed for 2 h with azeotropic removal of the generated H2O (Dean–Stark). The solution was allowed
to cool, concentrated under reduced pressure and an aqueous saturated NaHCO3 solution (10 mL) was
added. The aqueous layer was extracted with Et2O (3 × 20 mL), the combined organic layers were
dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel (Et2O/isooctane, 9:1) to give ketal (+)-6 (0.9 g, 92%) as white-
yellow crystals: mp 72 °C; Rf (Et2O/isooctane, 9:1) 0.46; [α]Drt +6.28 (c 1.03, CHCl3); IR (KBr pellet)

Molecules 2006, 11
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ν 2989, 2965, 2925, 1707, 1621, 1448, 1363, 1290, 1262, 1181, 1105, 1069, 1010, 952, 934, 907), 866,
844, 716 cm–1; 1H-NMR (500 MHz, CDCl3) δ 5.83 (1 H, s), 4.05–4.00 (2 H, m), 3.92 (2 H, t, J = 6.09
Hz), 2.69 (2 H, dd, J = 8.8, 3.2 Hz), 2.31 (1 H, AB, J = 18.3 Hz), 2.24 (1 H, AB, J = 18.3 Hz), 2.07–
2.00 (2 H, m), 1.70–1.62 (2 H, m), 1.37 (3 H, s) ppm; 13C-NMR/APT (125 MHz, CDCl3) δ 185.97 (C),
126.8 (CH), 107.9 (C), 107.9 (C), 64.9 (CH2), 64.0 (CH2), 53.3 (CH2), 47.3 (CH2), 43.5 (C), 35.7
(CH2), 26.3 (CH3), 25.2 (CH2) ppm; MS m/z (%) 208 (M+, 26), 193 (34), 152 (13), 121 (13), 107 (26),
86 (100), 79 (35), 55 (18), 53 (21). Anal. Calcd for C12H16O3: C, 69.21; H, 7.74. Found: C, 68.86; H,
7.95.
(3a'S,7a'R)-3a'-Methylhexahydrospiro[1,3-dioxolane-2,5'-inden]-2'(3'H)-one ((+)-7)
To a solution of enone (+)-6 (1.0 g, 4.8 mmol) in EtOAc (96 mL) was added Pd/C (10%; 0.5 g, 0.48
mmol) and the reaction mixture was shaken under 4 bar H2 pressure (Parr apparatus) at rt for 2.5 h.
The mixture was filtered through Celite® and the solvent was evaporated under reduced pressure to
rt
afford saturated ketone (+)-7 (1.0 g, 100%): Rf (isooctane/EtOAc, 9:1) 0.09; [α]D +43.4 (c 1.5,
CHCl3); IR (KBr film) ν 2931, 2884, 2250, 1736, 1453, 1407, 1364, 1256, 1211, 1145, 1098, 1068,
1018, 994, 911, 732, 648, 608 cm–1; 1H NMR (500 MHz, CDCl3) δ 3.93–3.90 (4 H, m), 2.73 (1 H, AB,
J = 18.4 Hz), 2.47 (1 H, dd, J = 18.8, 7.7 Hz), 2.04 (1 H, dd, J = 18.8, 4.2 Hz), 1.95–1.93 (1 H, m),
1.87 (1 H, AB, J = 18.4 Hz), 1.85–1.80 (1 H, m), 1.71–1.66 (2 H, m), 1.59–1.48 (3 H, m), 1.12 (3 H, s)
13
ppm; C NMR/APT (125 MHz, CDCl3) δ 219.4 (C), 108.4 (C), 64.2 (CH2), 63.9 (CH2), 49.9 (CH2),
43.0 (CH2), 42.0 (CH2), 40.8 (CH), 39.7 (CH2), 32.0 (C), 28.8 (CH3), 26.0 (CH2) ppm; MS m/z (%)
210 (M+, 3), 153 (9), 126 (28), 99 (100), 86 (30), 55 (18), 42 (15).
Acknowledgements
Financial assistance of the FWO-Vlaanderen (projects G.0150.02 and G.0036.00) is gratefully
acknowledged. S. D. thanks the IWT for a scholarship.
References and Notes
1. (a) Proceedings of the 12th Workshop on Vitamin D; Bouillon, R.; Norman, A. W.; Pasqualini, J.
R.; Eds.; J. Steroid Biochem. Mol. Biol. 2004, 89–90, 1–633, and the previous 11 volumes in this
series; (b) Vitamin D; Feldman, D.; Glorieux, F. H.; Pike, J. W., Eds.; Academic Press: San Diego,
1997.
2. Demin, S.; Van Haver, D.; Vandewalle, M.; De Clercq, P. J.; Bouillon, R.; Verstuyf, A. Bioorg.
Med. Chem. Lett. 2004, 14, 3885–3888.
3. Snyder, L.; Meyers, A. I. J. Org. Chem. 1993, 58, 7507–7515.
4. Stork, G.; Danheiser, R. L.; Ganem, B. J. Am. Chem. Soc. 1973, 95, 3414–3415.
5. (a) Meyers, A. I.; Seefeld, M. A.; Lefker, B. A.; Blake, J. F.; Williard, P. G. J. Am. Chem. Soc.
1998, 120, 7429–7438. (b) Meyers, A. I.; Seefeld, M. A.; Lefker, B. A. J. Org. Chem. 1996, 61,
5712–5713.
6. The enantiomeric purity of commercial (+)-1, purchased from Aldrich, was established by chiral
GC (0.25-µm SUPELCO β-DEX 120 column, 30 m × 0.25 mm, 120 °C). Comparison with

Molecules 2006, 11
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racemic (±)-1, prepared from DL-valinol and levulinic acid according to Meyers, showed virtually
100% ee. See: Meyers, A. I.; Lefker, B. A. Tetrahedron 1987, 43, 5663–5676.
7. (a) Posner, G. H.; Hamill, T. G. J. Org. Chem. 1988, 53, 6031–6035; (b) Paquette, L. A.;
Charumilind, P.; Kravetz, T. M.; Böhm, M. C.; Gleiter, R. J. Am. Chem. Soc. 1983, 105, 3126–
3135.
8. The ACD/I-Lab Web service (ACD/IUPAC Name Free 8.05) was used to generate the chemical
names of compounds 1–8.
Sample Availability: No samples available.
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