Conformationally Constrained α2 Antagonists: The Bicyclo[3.1.0]hexane Approach
FULL PAPER
maintained at –15 °C, was added dropwise MeLi (60 mL,
0.096 mol, 1.6 m in Et2O). The suspension was stirred at –15 °C for
4 h and at 0 °C for 3 h. Saturated aqueous NH4Cl solution (50 mL)
was added, and the mixture was extracted twice with EtOAc. The
combined organic layers were washed with brine, dried, filtered,
and concentrated under reduced pressure. The residue was purified
by silica gel chromatography eluting with cyclohex/CH2Cl2 (1:1) to
give 20a (3.55 g, 64%) as a pale yellow oil: C12H12O: 172.22; Rf 0.3
ane/EtOH (9:1), 100 mL/min; UV, 220 nm. Enantiomeric excess
was determined with an analytical HPLC Chiralpack® AD column
(Daicel) eluting with cyclohexane/EtOH (9:1), 1 mL/min; UV,
220 nm. Compound (+)-1a: fumaric acid salt, crystallized from
EtOH/EtOAc, white solid: m.p. 152–154 °C. [α]2D5 = +108.5 (c, 0.32,
MeOH); tR 7.6 min; 99.8% ee. C17H16N2O4 (312.31): calcd. C
65.37, H 5.16, N 8.97; found C 65.12, H 5.27, N 8.83; chemical
purity (HPLC): 99.9%. Compound (–)-1a: fumaric acid salt, crys-
tallized from EtOH/EtOAc, white solid: 152.154 °C. [α]2D5 = –106.2
(c, 0.35, MeOH); tR 11.2 min; 99% ee. C17H16N2O4 (312.31): calcd.
C 65.37, H 5.16, N 8.97; found C 65.10, H 5.32, N, 8.84; chemical
cyclohex/EtOAc (9:1). IR (neat): ν = 1686 cm–1. 1H NMR (CDCl ):
˜
3
δ = 0.8 (t, 1 H, J = 4.4 Hz), 2.03 (dd, 1 H, J = 4.4 Hz, 8.4 Hz),
2.14 (s, 3 H), 3.01 (m, 1 H), 3.05 (d, 1 H, J = 17.2 Hz), 3.76 (d, 1
H, J = 17.2 Hz), 7.13–7.29 (m, 4 H) ppm. 13C NMR (CDCl3): δ = purity (HPLC): 99.6%.
25.83, 26.91, 35.01, 36.82, 39.69, 123.13, 125.59, 126.18, 126.35,
4-(1,1-Dimethyl-1a,6-dihydro-1H-cyclopropa[a]indene-6a-yl)-1H-imid-
141.05, 143.58, 206.61 ppm. MS (APCI) 173.1 [M + H]+.
azole (1h): To a suspension of tBuOK (0.30 g, 0.0026 mol) in anhy-
drous DME (3 mL), maintained at –40 °C, was added dropwise a
solution of tosylmethyl isocyanide (TosMIC) (0.37 g, 0.0019 mol)
in DME (3 mL). At –40 °C was then added 26h (0.35 g, 0.0019 mol)
in DME (3 mL). After 1 h at –40 °C, the cold mixture was poured
into ice-water, acidified with acetic acid, and then extracted twice
with EtOAc. The combined organic layers were washed with brine,
dried (MgSO4), filtered, and the solvents were evaporated to dry-
ness. The residue was taken up in DME (2 mL), then TEA (1.3 mL,
0.0093 mol) and POCl3 (0.2 mL, 0.002 mol) were added at –15 °C.
The mixture was stirred at 0 °C for 1 h, then quenched by addition
of ice-water. The mixture was extracted by CH2Cl2, washed with
brine, dried, filtered, and evaporated under reduced pressure. The
residue was treated with a methanolic ammonia solution (7 mL,
4 n) and heated at 45 °C overnight. The volatiles were evaporated
off, the residue was taken up in HCl (1 n), and the aqueous layer
was washed with EtOAc and made basic (concentrated NaOH),
and then extracted with EtOAc. After evaporation of the solvent,
the residue was purified by silica gel chromatography eluting with
CH2Cl2/MeOH (95:5) to give 1h (0.10 g, 24%) as an orange oil:
Rf 0.40 CH2Cl2/MeOH (95:5). The product was crystallized as its
fumaric acid salt from EtOH/EtOAc to yield a pale yellow solid:
1a,6-Dihydro-1H-cyclopropa[a]indene-6a-α-bromomethyl
Ketone
(21a): To a solution of diisopropylamine (0.84 mL, 0.006 mol) and
anhydrous THF (10 mL) cooled in an ice bath, was added dropwise
nBuLi (2.4 mL, 0.006 mol, 2.5 m in THF). After 10 min, the solu-
tion was cooled to –70 °C. Then 20a (0.87 g, 0.005 mol) in THF
(2 mL) was added, and stirring was maintained for 1 h. A solution
of chlorotrimethylsilane (1.71 mL, 0.0135 mol), triethyl amine
(0.45 mL, 0.00325 mol), and THF (8 mL) was added, and the mix-
ture was stirred for 2 h at –70 °C. NaHCO3 (0.30 g, 0.0035 mol)
was added, followed by aqueous NaHCO3 (50 mL, 5%). The mix-
ture was diluted with Et2O, the organic layer was washed with
brine, dried (MgSO4), and filtered. The volatiles were removed in
vacuo to give a pale yellow oil (1.30 g) which was taken up in anhy-
drous THF (12 mL) and cooled to –70 °C. To this solution were
added successively NaHCO3 (0.50 g, 0.006 mol) and N-bromosuc-
cinimide (0.89 g, 0.005 mol). The mixture was stirred at –70 °C for
3.5 h and at room temperature overnight. The suspension was
poured into aqueous NaHCO3 and extracted twice with EtOAc.
The combined organic layers were washed with brine, dried
(MgSO4), filtered, and the solvent was evaporated off. The residue
was purified by silica gel chromatography eluting with cyclohex/
EtOAc (95:5) to give 21a (0.86 g, 67%) as a pale yellow oil:
1
mp: 110–112 °C; chemical purity (HPLC): 97.7%. H NMR ([D6]
C H BrO: 251.13; R 0.35 cyclohex/EtOAc (9:1). IR (neat): ν =
˜
DMSO): δ = 0. 69 (s, 3 H), 0.99 (s, 3 H), 2.61 (s, 1 H), 3.05 (d, 1
H, J = 17.6 Hz), 3.18 (s, 1 H, J = 17.6 Hz), 6.61 (s, 2 H), 6.83 (s,
1 H), 7.09 (m, 3 H), 7.26 (d, 1 H), 7.58 (d, 1 H) ppm. 13C NMR
([D6]DMSO): δ = 14.82, 23.03, 26.40, 33.64, 38.63, 118.03, 123.58,
123.99, 125.44, 125.90, 134.02, 134.17, 142.61, 143.72, 166.09 ppm.
C19H20N2O4 (340.37): calcd. C 67.04, H 5.92, N 8.23; found C
66.70, H 6.03, N 8.28. MS (ESI) 224.8 [M + H]+.
12 11
f
1685 cm–1. H NMR (CDCl3): δ = 0.91 (t, 1 H, J = 4.4 Hz), 2.13
(dd, 1 H, J = 4.4 Hz, 8.4 Hz), 3.14 (m, 1 H), 3.23 (d, 1 H, J =
17.2 Hz), 3.74 (d, 1 H, J = 17.2 Hz), 3.98 (d, 1 H, J = 12 Hz), 4.05
(d, 1 H, J = 12 Hz), 7.14–7.30 (m, 4 H) ppm.
1
4-(1a,6-Dihydro-1H-cyclopropa[a]indene-6a-yl)-1H-imidazole (1a):
A suspension of 21a (0.85 g, 0.0034 mol), formamidine acetate
(0.52 g, 0.005 mol), and liquid ammonia (15 mL) in anhydrous
Et2O (15 mL) was heated overnight at 60 °C. Water was added to
the cooled reaction mixture, which was then washed with EtOAc.
The organic layer was extracted twice with HCl (1 n), then the com-
bined aqueous layers were made basic (concentrated NaOH) and
extracted with EtOAc. The residue was purified by neutral alumina
chromatography eluting with CH2Cl2/MeOH (95:5) to give 1a
(0.30 g, 38%) as a yellow oil: Rf 0.31 CH2Cl2/MeOH/NH4OH
(90:9:1). The product was crystallized as its fumaric acid salt from
EtOH/Et2O to give a white solid (0.25 g): m.p. 150–152 °C; chemi-
cal purity (HPLC): 98.3%. 1H NMR ([D6]DMSO): δ = 0.5 (t, 1 H,
J = 4 Hz, 8 Hz), 1.71 (dd, 1 H, J = 4 Hz, 8 Hz), 2.53 (m, 1 H), 3.18
(d, 1 H, J = 17.2 Hz), 3.49 (d, 1 H, J = 17.2 Hz), 6.62 (s, 2 H),
6.99 (s, 1 H), 7.10 (m, 2 H), 7.20 (m, 1 H), 7.28 (m, 1 H), 7.65 (s,
1 H) ppm. 13C NMR ([D6]DMSO): δ = 23.61, 25.65, 32.80, 38.74,
122.85, 125.09, 125.29, 125.79, 133.94, 134.65, 141.29, 146.09,
165.96 ppm. C17H16N2O4 (312.31): calcd. C 65.37, H 5.16, N 8.97;
found C 65.05, H 5.19, N 8.85. MS (APCI) 197.0 [M + H]+.
Supporting Information Available: Experimental and/or analytical
data for compounds 1b,d,f,g, 2c,d,f,g,h, 6b-f, 7b-f, 9b,c,f,h, 15c-h,
17a,c,e, 19, 20b,d, 21b,d, 22g, 23, 25f-h, 26f,h, 28, 29, and esters of
type 3 bearing a motif (+)-menthol or (R)-pantolactone (see also
the footnote on the first page of this article).
Acknowledgments
We thank Dr. Jean-Paul Ribet, Mr. P. Zalavari for analytical sup-
port and Dr. I. Rauly-Lestienne for in vitro screening. Mr. Luc
Petitpas’ assistance for bibliographic searches was also very much
appreciated.
[1] A. M. Lands, A. Arnold, J. P. McAuliff, F. P. Luduena, T. G.
Brown, Jr., Nature 1967, 214, 597–598. Another β receptor sub-
type (i.e., β3) has been cloned more recently: L. J. Emorine, S.
Marullo, M.-M. Briend-Sutren, G. Patey, K. Tate, C. Delavier-
Klutchko, A. D. Strosberg, Science 1989, 245, 1118–1121. It
seems predominantly located in adipose tissues; V. A. Skeb-
erdis, Medicina (Kaunas) 2004, 40, 407–413.
Compounds (+) and (–)-1a: The separation was made by preparative
HPLC with a Chiralpack® AD column (Daicel) eluting with hex-
Eur. J. Org. Chem. 2005, 3360–3369
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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