Regiospecific synthesis of a bridgehead-functionalized bicyclo[2.2.2]octenone

Article abstract of DOI:10.1016/S0040-4039(02)01065-1

Three independent strategies are tested toward the synthesis of the protected 1-aminobicyclo[2.2.2]octene ketodiester 1. One of these three is found to be completely regioselective. It proceeds by Diels-Alder addition of dimethyl acetylenedicarboxylate to

Full text of DOI:10.1016/S0040-4039(02)01065-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5237–5239
Regiospecific synthesis of a bridgehead-functionalized
bicyclo[2.2.2]octenone
Andrew S. Kende,a,* Jiong Lana and Dorit Aradb
aDepartment of Chemistry, University of Rochester, Rochester, NY 14627-0216, USA
bDrug Design Department, eXegenics Inc., Dallas, TX 75235, USA
Received 22 May 2002; accepted 4 June 2002
Abstract—Three independent strategies are tested toward the synthesis of the protected 1-aminobicyclo[2.2.2]octene ketodiester 1.
One of these three is found to be completely regioselective. It proceeds by Diels–Alder addition of dimethyl acetylenedicarboxylate
to the silyl enol ether of 3-benzyloxycarbonyl-2-cyclohexenone, followed by a chemoselective Curtius rearrangement. © 2002
Elsevier Science Ltd. All rights reserved.
carbinols in this system.7 Starting from 1,3-cyclohex-
Bicyclo[2.2.2]octanes bearing a free or protected NH2
anedione, we prepared the vinylogous urea 2.8 The
group at the bridgehead have served as scaffolds for
antiviral agents,1,2 as inhibitors of phenylethanolamine
N-methyl transferase3 and as ligands for the
phencyclidine4 and dopamine5 receptors. In contrast,
the literature on analogous bicyclo[2.2.2]octenes is
sparse,6 and highly functionalized ring derivatives
appear to be unknown. We now report a comparison of
three synthetic strategies directed toward the protected
amino ketone diester 1 in this series.
latter was converted to an O,N-bis-silyl derivative, for-
mulated as 3. This was subjected to Diels–Alder reac-
tion with dimethyl acetylenedicarboxylate to yield an
adduct, expected to yield on mild acid hydrolysis the
bridgehead carbamate 4.
To our surprise, hydrolysis of the initial Diels–Alder
adduct gave a product ketone devoid of nitrogen,
namely the bridgehead hydroxy ketone 5 previously
prepared by Wolinsky.7 It thus became clear that the
diene initially assigned structure 3 was in fact the
regioisomer 3%, and that the isolation of 5 as the final
product had proceeded by the parallel Diels–Alder
sequence picture below. Thus, enolization of 2 had
followed the pathway noted by Bryson and Gammill,
involving enolization at C(4) of the cyclohexenone
system.9
Our initial approach to 1 attempted to parallel earlier
work by Wolinsky and Login toward bridgehead
Keywords: Diels–Alder reaction; enols and derivatives; Curtius rearrangement; bicyclooctenones; regiospecificity.
* Corresponding author. Fax: 585-506-0205; e-mail: kende@chem.rochester.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01065-1

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Scheme 1. Reagents and conditions: (a) i. 40°C, 2 days, ii. CH3I, CH2Cl2, iii. DBU, CH2Cl2, 67%; (b) dimethyl acetylenedicarboxyl-
ate, N,N-dimethylaniline, 80°C, 69%; (c) i. catecholborane, 2 mol% Rh(PPh3)3Cl, THF, then H2O2, Buffer pH 7.0, ii. DMSO,
(COCl)2, Et3N, CH2Cl2, −78ꢀ−60°C, 55%; (d) i. 30% CF3CO2H, CH2Cl2, ii. (COCl)2, DMF, CH2Cl2, iii. NaN3, acetone/H2O
(3:1), iv. t-butanol, reflux, 63%.
Scheme 2. Reagents and conditions: (a) see Ref. 14; (b) TBSOTf, Et3N, CH2Cl2, 0°C; (c) dimethyl acetylenedicarboxylate, 80°C,
66% from 10; (d) 1 M TBAF, THF, 91%; (e) Raney-Ni, ethanol, (f) i. (COCl)2, DMF, CH2Cl2, ii. NaN3, acetone/H2O (3:1), iii.
t-butanol, reflux, 55% from 13.
To overcome this problem, we sought to introduce the
of 13 over Raney-Ni chemoselectively produced the
bicyclooctene acid 14. Curtius rearrangement by the
sequence described above gave the protected aminoke-
tone 1 in 55% yield from 13. The last route comprises
an efficient sequence to this highly functionalized bicy-
clo[2.2.2]octene system (Scheme 2).16
bridgehead nitrogen by Curtius rearrangement.6 Diels–
Alder
addition
of
1-(N,N-dimethylamino)-1,3-
butadiene10 to t-butyl acrylate gave adducts which
upon Hoffman elimination gave in 67% yield the diene
ester 6.11 Reaction of this ester with excess dimethyl
acetylenedicarboxylate in the presence of 5 mol%
Me2NPh gave 69% of the bicyclo[2.2.2]octadiene tri-
ester 7, accompanied by ca. 10% of the retro-Diels–
Alder product 8.12 Hydroboration of diene 7 with B2H6
gave no selectivity. However, reaction with catecholbo-
rane and Rh(PPh3)3Cl as catalyst13 proceeded with
moderate regioselectivity to yield, after neutral H2O2
workup and Swern oxidation, a 55% yield of the ketone
9. Trifluoroacetic acid cleavage of the t-butyl ester, then
successive conversion of the carboxyl group to acid
chloride and then acyl azide, followed by overnight
reflux in t-BuOH gave the desired target 1 in 63% yield
from 9 (Scheme 1).16
References
1. Whitney, J. G.; Gregory, W. A.; Kauer, J. C.; Roland, J.
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Finally, a completely regioselective third approach to
the protected aminoketone 1 was achieved starting
from 2-cyclohexenone. Conversion of the latter to the
3-benzyloxycarbonyl derivative 10 by
a
known
procedure14 was followed by treatment of 10 with
TBSOTf and Et3N to give the diene ester 11.15 Diels–
Alder reaction of 11 with dimethyl acetylenedicarboxyl-
ate gave adduct 12 which on hydrolysis produced
ketone 13 in 60% overall yield from 11. Hydrogenation
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8. Ovenden, S. P. B.; Capon, R. J. J. Org. Chem. 1999, 64,
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5239
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16. Selected spectroscopic data; 7: colorless oil; 1H NMR
(CDCl3, 400 MHz): l 1.52 (s, 9H), 1.55–1.70 (m, 3H),
1.81–1.88 (m, 1H), 3.76 (s, 3H), 3.86 (s, 3H), 4.18–4.23
(m, 1H), 6.47 (dd, J=6.1, 7.4 Hz, 1H), 6.57 (dd, J=1.6,
7.4 Hz, 1H) ppm; 13C NMR (CDCl3, 100 MHz): l 24.9,
27.8 (3×C), 30.2, 37.9, 51.97, 52.00, 55.3, 81.8, 133.1,
134.0, 137.8, 146.0, 164.1, 166.7, 170.7 ppm; anal. calcd
for C17H22O6: C, 63.34; H, 6.88. Found: C, 63.22; H,
1
6.84%; 9: mp 144–145°C; H NMR (CDCl3, 400 MHz): l
1.52 (s, 9H), 1.80–1.90 (m, 1H), 1.95–2.05 (m, 3H), 2.38
(d, J=18.7 Hz, 1H), 2.48 (dd, J=2.5, 18.7 Hz, 1H), 3.79
(s, 3H), 3.79–3.82 (m, 1H), 3.84 (s, 3H) ppm; 13C NMR
(CDCl3, 100 MHz): l 22.1, 27.6 (3×C), 29.0, 41.4, 48.7,
51.5, 52.2, 52.4, 82.5, 130.8, 146.6, 163.1, 166.0, 170.0,
206.6 ppm; anal. calcd for C17H22O7: C, 60.35; H, 6.55.
1
Found: C, 60.14; H, 6.46%; 1: mp 152–153°C; H NMR
(CDCl3, 400 MHz): l 1.34 (s, 9H), 1.67–1.73 (m, 1H),
1.86–1.96 (m, 3H), 2.26 (d, J=18.4 Hz, 1H), 2.92 (dd,
J=2.8, 18.4 Hz, 1H), 3.61–3.65 (m, 1H), 3.68 (s, 3H),
3.70 (s, 3H), 5.08 (brs. 1H) ppm; 13C NMR (CDCl3, 100
MHz): l 21.6, 28.0 (3×C), 30.1, 43.5, 48.1, 52.2, 52.4,
57.5, 79.9, 130.0, 147.8, 154.4, 163.3, 165.4, 205.7 ppm;
anal. calcd for C17H23NO7: C, 57.78; H, 6.56; N, 3.96.
Found: C, 57.88; H, 6.32; N, 3.91%.