Novel bridged bicyclic α-amino acid esters and key derivatives from quincorine and quincoridine

Article abstract of DOI:10.1021/ol990981o

(matrix presented). Oxidation of Quincorine (QCI) and Quincoridine (QCD) has been investigated, giving bicyclic α-amino acids and dicarboxylic acid derivatives, which are epimerically and also enantiomerically pure. Acidic Cr(VI)-mediated oxidation (Jones oxidation) has been optimized with respect to reaction conduct and work up (addition of ethylenediamine).

Full text of DOI:10.1021/ol990981o

ORGANIC
LETTERS
1999
Vol. 1, No. 10
1607-1610
Novel Bridged Bicyclic r-Amino Acid
Esters and Key Derivatives from
Quincorine and Quincoridine
Olaf Schrake, Volker S. Rahn, Jens Frackenpohl, Wilfried M. Braje, and
H. Martin R. Hoffmann*
Department of Organic Chemistry, UniVersity of HannoVer, Schneiderberg 1B,
D-30167 HannoVer, Germany
hoffmann@mbox.oci.uni-hannoVer.de
Received August 24, 1999
ABSTRACT
Oxidation of Quincorine (QCI) and Quincoridine (QCD) has been investigated, giving bicyclic r-amino acids and dicarboxylic acid derivatives,
which are epimerically and also enantiomerically pure. Acidic Cr(VI)-mediated oxidation (Jones oxidation) has been optimized with respect to
reaction conduct and work up (addition of ethylenediamine).
Monosubstituted quinuclidines play an important role in
medicinal chemistry as the quinuclidine nucleus has been
found to be a good mimic for the quaternary nitrogen in
acetylcholine. However, unlike acetylcholine, the unpro-
tonated form is able to cross the blood-brain barrier.1
Quinuclidine derivatives are able to block 5-HT3 and NK1
receptors2 and to act as squalene synthase inhibitors.3
Quincorine (QCI, 1) and pseudoenantiomeric Quincoridine
(QCD, 5) are homochiral 1,2-amino alcohols containing four
stereogenic centers each, including the chiral 1S-configured
bridgehead nitrogen.4,5 The quinuclidine derivatives described
herein represent a novel class of seminatural, conformation-
ally constrained amino acid esters and dicarboxylic esters,
which are also bicyclic. In contrast to the traditional
quinuclidines frequently used in pharmacology, the QCI- and
QCD-based title compounds contain two side chains at C2
and C5. These side chains have now been further chemo-
differentiated6 without recourse to protecting groups.
Results and Discussion. Oxidation of 1,2-amino alcohols
to R-amino acids is well-known to be difficult and remains
a challenging task especially if the basic amino nitrogen is
not masked or protected.7 To our knowledge, a readily
accessible route to quinuclidine-2-carboxylic acids has not
been described in the literature. A few de novo syntheses
and semisynthetic routes provide the desired target molecules
(acids, esters, aldehydes, etc.) only in poor yields and as
epimeric mixtures.8 During studies on the oxidative func-
tionalization of carbon C9 of QCI 1 and of QCD 5 we have
(1) (a) Wadsworth, H. J.; Jenkins, S. M.; Orlek, B. S.; Cassidy, F.; Clark,
M. S. G.; Brown, F.; Riley, G. J.; Graves, D.; Hawkins, J.; Naylor, C. B.
J. Med. Chem. 1992, 35, 1280. (b) Baker, R.; Street, L. J.; Reeve, A. J.;
Saunders, J. J. Chem. Soc., Chem. Commun. 1991, 760.
(2) (a) Snider, R. M.; Constantine, J. W.; Lowe, J. A.; Longo, K. P.;
Lebel, W. S.; Woody, H. A.; Drozda, S. E.; Hess, H.-J. Science 1991, 251,
435. (b) Lowe, J. A.; Ewing, F. E.; Snider, R. M.; Longo, K. P.; Constantine,
J. W.; Lebel, W. S.; Woody, H. A.; Bordner, J. Bioorg. Med. Chem. Lett.
1994, 4, 839.
(3) (a) Brown, G. R.; Foubister, A. J.; Freeman, S.; McTaggart, F.;
Mirrlees, D. J.; Reed, A. C.; Smith, G. J.; Taylor, M. J.; Thomason, D. A.;
Whittamore, P. R. O. Bioorg. Med. Chem. Lett. 1997, 7, 597. (b) Brown,
G. R.; Clarke, D. S.; Foubister, A. J.; Freeman, S.; Harrison, P. J.; Johnson,
M. C.; Mallion, K. B.; McCormick, J.; McTaggart, F.; Reid, A. C.; Smith,
G. J.; Taylor, M. J. J. Med. Chem. 1996, 39, 2971.
(4) QCI and QCD are derived from the Cinchona alkaloids quinine and
quinidine. They are commercially available from Aldrich.
(5) Hoffmann, H. M. R.; Plessner, T.; von Riesen, C. Synlett 1996, 690.
(6) (a) Schrake, O.; Braje, W. M.; Hoffmann, H. M. R.; Wartchow, R.
Tetrahedron: Asymmetry 1998, 9, 3715. (b) Wartchow, R.; Schrake, O.;
Braje, W. M.; Hoffmann, H. M. R. Z. Kristallogr. NCS 1999, 214, 285.
(7) Little information on the oxidation of hydroxymethyl-quinuclidine
is available in the literature. See, however: Prelog, V.; Cerkovnikov, E.
Liebigs Ann. 1940, 545, 229, 262.
10.1021/ol990981o CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/11/1999

found Jones oxidation combined with subsequent esterifi-
cation to be the only suitable method (Scheme 1, Table 1).
unstable. Therefore, further investigations toward a stepwise
oxidation were abandoned in favor of the direct route.
To optimize the Jones oxidation, we carried out the
reaction under a variety of conditions (Table 2). Slow and
Scheme 1. Oxidation of 1 and 5a
Table 2. Optimized Oxidation of 1 to 2
J ones
esterificationa
in situ
yield
(%)
entry
1
oxidation
[mol/L]
0.28
workupb
pH 5
catal. J ones;
14 d, rt
0
24
H5IO6
2
3
4
3 d, rt; Ba(OH)2, 3 d, rt
0.28
0.24
0.24
pH 5, eda
pH 5, eda
0
25
CuSO4
5 d, rt,
ultrasound
5 d, rt,
ultrasound
0
2 d, rt
2 d, rt
KOH, pH 9,
eda
9c
5
6
7
8
9
12 h, rt, eda
7 d, rt
14 d, rt, eda
7 d, rt
0.40
0.24
0.24
pH 5, eda
pH 5, eda
pH 5, eda
17d
26c
28c
14 d, rt
14 d, rt
3 d, reflux
3 d, reflux
3 d, reflux
3 d, reflux
0.125 pH 8, eda, 7 d 54c
0.10
pH 8, eda, 5 d 60c
a MeOH, HCl (catal.). b With NaHCO3 (saturated aqueous) unless
otherwise stated. c Epimerically pure. d Mixture (1:1) of epimers at C2; eda
) ethylenediamine.
careful addition of Jones reagent was crucial for obtaining
the epimerically pure R-amino acid esters 2 and 6. The
formation of the carboxylic acid is assumed to proceed via
a stable chromium chelate, which precludes epimerization
at carbon C2. However, this chelate is believed to make
aqueous workup also more difficult. Addition of ethylene-
diamine during workup facilitates isolation of the desired
product, whereas the presence of ethylenediamine in the
preceding oxidation reaction led to complete epimerization
at carbon C2 and reduced the yield to 17% (entry 5).21
Intermolecular hydrogen bonding of the 1,2-amino alcohol
is believed to be another reason for the sluggish and
incomplete oxidation process. To minimize intermolecular
hydrogen-bond formation the molarity of the solution was
decreased. Refluxing22 the reaction mixture and also refluxing
on subsequent esterification improved the yield of epimeri-
cally and enantiomerically pure R-amino acid ester 2 to
60%.23
a Reagents and conditions: (a) (i) KMnO4, H2SO4, H2O, 0 °C
f room temperature; (ii) MeOH, catal. HCl, room temperature;
(b) (i) see Table 2; (ii) MeOH, catal. HCl, reflux.
All other standard oxidation methods failed to give the
desired compounds. In some cases N-oxides (entries 2 and
5) and aldol-like coupling products (entries 9 and 10) were
obtained. The aldehyde itself proved to be extremely
Table 1. Oxidation at C9 at 1 and 5
entry
reagent
target
result
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
â-hydride acceptors9
HOTMCa,10
aldehyde
aldehyde
aldehyde
aldehyde
aldehyde
aldehyde
aldehyde
aldehyde
aldehyde
-
(8) (a) Ch’ang-pai, C.; Evstigneeva, R. P.; Preobrazhenskii, N. Z. Obshch.
Khim. 1960, 30, 495. (b) Grethe, G.; Lee, H. L.; Mitt, T.; Uskokovic, M.
R. J. Am. Chem. Soc. 1978, 100, 581.
(9) (a) Woodward, R. B.; Wendler, N. L.; Brutschy, F. J. J. Am. Chem.
Soc. 1945, 67, 1425. (b) Marco´, I. E.; Giles, P. R.; Tsukazaki, M.; Brown,
S. M.; Urch, C. J. Science 1996, 274, 2044.
(10) (a) Fatiadi, A. J. Synthesis 1987, 85. (b) Firouzabadi, H.; Mot-
tghinejad, E.; Seddighi, M. Synthesis 1989, 378. (c) Sala, T.; Sargent, M.
V. J. Chem. Soc., Chem. Commun. 1978, 253. (d) Ley, S. V.; Norman, J.;
Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639. (e) Urch, C. J.; Brown,
S. M.; Marco´, I. E.; Giles, R. R.; Tuskazaki, M. PCT Int. Appl. WO 9851654
A1.
(11) (a) Yoshimura, J.; Sato, K.; Hashimoto, H. Chem Lett. 1977, 1327.
(b) Kametani, T.; Kanaya, N.; Hino, H.; Huang, S.-P.; Ihara, M. J. Chem.
Soc., Perkin Trans. 1 1981, 3168. (c) Petersen, J. S.; Fels, G.; Rapoport,
H. J. Am. Chem. Soc. 1984, 106, 4539. (d) Kornblum, N.; Powers, J. W.;
Anderson, G. J.; Jones, W. J.; Larson, H. O.; Levand, O.; Weaver, W. M.
J. Am. Chem. Soc. 1957, 79, 6562. (e) Kornblum, N.; Jones, W. J.; Anderson,
G. J. J. Am. Chem. Soc. 1959, 81, 4113.
-/N-oxide
-/18%
-
N-oxide
-
-
-
DMSO methods11
PDC-DCM12
TEMPO13
Dess-Martin14
DDQ15
16
Activated MnO2
Ag2CO3/Celite17
aldol-like products
Ag2O/Ag2CO3/Celite18
acid in situ aldol-like products
mod. Kornblum/NaOCl acid in situ complex products
19
KMnO4
acid
acid
acid
acid
3,c 53%d
-
Cr reagents20
PDC-DMF12
J ones oxidationb
-
2,c 60%d
a Highly oxidized transition metal compounds. b See Table 2. c Diastereo-
merically pure. d After esterification.
(12) Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 399.
(13) Ma, Z.; Bobbitt, J. M. J. Org. Chem. 1991, 56, 6110.
1608
Org. Lett., Vol. 1, No. 10, 1999

To our surprise, KMnO4-mediated oxidation cleaved the
vinylic side chain of 1 and 5 in the presence of the
unprotected primary C9 alcohol function.27 The configuration
at carbon C5 was preserved and isolation of the ꢀ-hydroxy
monoesters 3 and 7 was possible upon esterification. The
1,6-dicarboxylic acid esters 4 and 8 were formed as side
products in changing yield (10-20%). In general, the
Scheme 2. Synthesis of N-Methoxy-N-methylamidesa
(14) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(15) Paterson, I.; Cowden, C. J.; Rahn, V. S.; Woodrow, M. D. Synlett
1998, 915.
(16) Wie, X.; Taylor, R. J. K. Tetrahedron Lett. 1998, 39, 3815.
(17) (a) Fe´tizon, M. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; Wiley: Chichester, UK, 1995; Vol. 6, p 4448. (b)
McKillop, A.; Young, D. W. Synthesis 1979, 401.
(18) Grethe, G.; Lee, H. L.; Mitt, T.; Uskokovic, M. R. J. Am. Chem.
Soc. 1978, 100, 581.
(19) Forst, C.; Bo¨hringer, C. Chem. Ber. 1882, 15, 1659.
(20) (a) Collins, J. C.; Hess, W. W.; Frank, F. J. Tetrahedron Lett. 1968,
3363. (b) Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 2647.
(21) Bidentate chromium complexes of quinine and quinidine are known,
see: Tsangaris, J. M.; Baxevanidis, G. T. Z. Naturforsch. 1974, 29b, 532.
(22) High-temperature favors epimerization. We believe the chelated
chromium prevents epimerization from taking place.
1
(23) The configuration at C2 and C5 can easily be deduced by H and
13C NMR, especially NOESY [cross-peak for H2 and H3-endo in QCI
(none) and QCD (present)]. All compounds of Scheme 1 are also epimers.
Epimeric purity has been determined by 13C NMR and GC.
(24) Zhao, M.; Li, J.; Song, Z.; Desmond, R.; Tschaen, D. M.; Grabowski,
E. J. J.; Reider, P. J. Tetrahedron Lett. 1998, 39, 5323.
(25) Goutarel, R.; Janot, M.-M.; Prelog, V.; Taylor, W. I. HelV. Chim.
Acta 1950, 23, 150.
(26) (a) Nahm, S. Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815. (b)
Shimizu, T.; Osako, K.; Nakata, T. Tetrahedron Lett. 1997, 38, 2685. (c)
Review: Mentzel, M.; Hoffmann, H. M. R. J. Prakt. Chem. 1997, 339,
517.
a Reagents and conditions: (a) MeNHOMe‚HCl, Me2AlCl, DCM,
0 °C f room temperature; yield up to 87% (b) (i) TBDMSCl, Et3N,
DMAP, DCM, room temperature; (ii) MeNHOMe‚HCl, Me2AlCl,
DCM, 0 °C f room temperature; yield over 2 steps 57%; (c) (i)
TBDPSCl, Et3N, DMAP, DCM, room temperature; (ii) MeNHOMe‚
HCl, Me2AlCl, DCM, 0 °C f room temperature; yield over 2 steps
62%.
(27) Selected Experimental Procedures and Spectroscopic Data.
General Procedure for the Synthesis of C9 Esters. A solution of
Quincorine 1 or Quincoridine 5 (1 equiv) in acetone was cooled to 0 °C
and treated dropwise with Jones reagent (2.67 M solution, 3.6 equiv). The
mixture was refluxed for 3 days, followed by addition of 2-propanol at
room temperature and stirred for 30 min. The solvent was removed and
the residue was dried for 3 days in vacuo. The solid was dissolved in
absolute MeOH under argon at room temperature, catalytic amounts of
hydrochloric acid (concentrated) were added, and the reaction mixture was
refluxed for 3 days. Two-thirds of the solvent was removed. The solution
was cooled to 0 °C, and the pH was adjusted to 7-8 by adding NaHCO3
(saturated aqueous), and then ethylenediamine was added dropwise within
15 min. Thereafter Et2O was added for liquid-liquid extraction over 2 days.
The organic layer was dried (MgSO4), the solvent was evaporated in vacuo,
and the crude product was purified by column chromatography (EtOAc/
MeOH 10:1) to provide the desired esters as pale yellow oils. (1S,2S,4S,5R)-
5-Vinyl-1-azabicyclo[2.2.2]octane-2-carboxylic Acid Methyl Ester (2).
Quincorine 1 (840 mg, 5.00 mmol, 1.0 equiv) was allowed to react according
to the general procedure to yield C9 ester 2 (60%, 586 mg, 3.00 mmol):
IR (CHCl3) ν 2952, 2870, 1734, 1637, 1456, 1437, 1372, 1264, 1230, 1081,
hydroxymethyl side chain of both QCI and QCD is very
unreactive toward oxidation even when using powerful
HOTMCs (Table 1, entry 2).
Because of their utility in organic synthesis, Weinreb
amides26 were prepared, including bis-(Weinreb amide) 11.
These amides were formed in good yield (Scheme 2) and
5-carboxylic Acid Methyl Ester (3) and (1S,2S,4S,5R)-1-Azabicyclo-
[2.2.2]octane-2,5-dicarboxylic Acid Dimethyl Ester (4). Quincorine sulfate
(7.93 g, 30.0 mmol, 1.0 equiv) was allowed to react according to the general
procedure to yield C10 ester 3 (53%, 3.16 g, 15.9 mmol) as the main product
and C9, C10 diester 4 (16%, 1.087 g, 4.79 mmol) as a side product. Data
for 3: IR (CHCl3) ν 3434, 2999, 2952, 2878, 1728, 1456, 1437, 1371,
1333, 1236, 1198, 1178, 1138, 1100, 1050, 1017, 983 cm-1; 1H NMR (400
MHz, CDCl3) δ 3.72-3.68 (m, 1H, H-9), 3.69 (s, 3H, OMe), 3.62 (dd, 1H,
J 11.5 and 10.4 Hz, H-9), 3.44-3.36 (m, 2H, H-2, H-6), 3.02-2.92 (m,
2H, H-7, H-7), 2.87 (dd, 1H, J 13.3 and 8.9 Hz, H-6), 2.57-2.51 (m, 1H,
H-5), 2.23-2.19 (m, 1H, H-4), 1.70-1.64 (m, 2H, H-3, H-8), 1.57-1.49
(m, 1H, H-8), 1.10-1.03 (m, 1H, H-3); 13C NMR (100 MHz, CDCl3) δ
174.54 (C, C-10), 62.02 (CH2, C-9), 57.47 (CH, C-2), 51.93 (CH3, C-11),
48.76 (CH2, C-6), 42.94 (CH2, C-7), 41.20 (CH, C-5), 25.89 (CH2, C-3),
25.18 (CH, C-4), 24.64 (CH2, C-8); MS m/z 199 (M+, 71.00), 197 (22.27),
182 (36.77), 168 (100.00), 158 (64.92), 140 (75.08), 126 (18.40), 112
(25.66), 96 (17.63), 82 (65.44); HRMS calcd. for C10H17NO3 199.1208,
found 199.1208. Data for 4: IR (CHCl3) ν 3434, 2951, 2878, 1776, 1731,
1462, 1410, 1372, 1292, 1230, 1151, 1136, 1119, 1086, 1027, 996, 834
cm-1;1H NMR (400 MHz, CDCl3) δ 3.77 (s, 3H, OMe), 3.69 (s, 3H, OMe),
3.53-3.45 (m, 1H, H-2), 3.36 (ddd, 1H, J 14.5, 7.5, and 2.4 Hz, H-6),
3.05-2.97 (m, 2H, H-7, H-7), 2.91-2.82 (m, 1H, H-6), 2.54-2.48 (m,
1H, H-5), 2.30-2.26 (m, 1H, H-4), 2.02-1.96 (m, 1H, H-3), 1.79-1.71
(m, 1H, H-8), 1.65-1.59 (m, 2H, H-8, H-3); 13C NMR (100 MHz, CDCl3)
δ 174.44 (C, C-10), 173.03 (C, C-9), 58.08 (CH, C-2), 52.24 (CH3, C-11),
51.81 (CH3, C-12), 48.34 (CH2, C-6), 46.01 (CH2, C-7), 40.86 (CH, C-5),
25.82 (CH2, C-3), 25.02 (CH, C-4), 24.94 (CH2, C-8); MS m/z 227 (M+,
44.95), 212 (22.55), 196 (16.75), 186 (2.84), 168 (100.00), 155 (10.13),
140 (53.19), 126 (3.99), 113 (13.81), 100 (14.87), 82 (47.16); HRMS calcd
for C11H17NO4 227.1157, found 227.1157.
1
1036, 993, 909, 834 cm-1; H NMR (400 MHz, CDCl3) δ 5.89 (ddd, 1H,
J 17.8, 10.5 and 7.3 Hz, H-10), 5.10-5.04 (m, 2H, H-11), 3.76 (s, 3H,
OMe), 3.56-3.49 (m, 1H, H-2), 3.19 (dd, 1H, J 14.4 and 10.0 Hz, H-6),
2.95-2.85 (m, 1H, H-7), 2.83-2.70 (m, 2H, H-6, H-7), 2.35-2.26 (m,
1H, H-5), 2.01-1.92 (m, 1H, H-4), 1.86-1.78 (m, 2H, H-8), 1.66-1.46
(m, 2H, H-3); 13C NMR (100 MHz, CDCl3) δ 173.36 (C, C-9), 141.36
(CH, C-10), 114.63 (CH2, C-11), 58.72 (CH3, OMe), 55.00 (CH2, C-6),
52.23 (CH, C-2), 43.09 (CH2, C-7), 39.30 (CH2, C-5), 27.23 (CH2, C-8),
27.10 (CH, C-4), 23.77 (CH2, C-3); MS m/z 195 (M+, 15.02), 180 (4.77),
154 (2.92), 137 (11.98), 136 (100.00), 122 (2.57), 108 (5.47), 100 (5.86),
95 (4.59), 81 (12.45), 77 (3.28), 67 (5.01); HRMS calcd for C11H17N1O2
195.1259, found 195.1259. General Procedure for the Synthesis of C10
Esters. A solution of KMnO4 (2.05 equiv) in H2O was slowly added to a
vigorously stirred solution of the corresponding â-amino alcohol sulfate
(1.0 equiv) in 2 N H2SO4 at 0 °C under argon. After beeing stirred at room
temperature for 5 h, the reaction mixture was concentrated and dried under
reduced pressure. The residue was dissolved in absolute MeOH, concentrated
HCl (catal.) was added, and the reaction mixture was stirred at room
temperature for 5 days. After neutralization with saturated aqueous NaHCO3,
the aqueous layer was extracted (CH2Cl2). The organic layer was dried,
the solvent was evaporated, and the crude product was purified by column
chromatography (EtOAc/MeOH 6:1) to afford the C10 ester including C9,
C10 diesters. (1S,2S,4S,5R)-2-(Hydroxymethyl)-1-azabicyclo[2.2.2]octane-
Org. Lett., Vol. 1, No. 10, 1999
1609

widen the scope of application of 1 and 5 toward the
synthesis of pharmacologically important and interesting
compounds with additional heterocyclic and aromatic ring
systems.
(glutamic acid) and like the other azabicyclics (Scheme 1)
of interest in medicinal chemistry and combinatorial chem-
istry.
Conclusion. Although there are potentially many methods
for the difficult oxidation of protected and unprotected 1,2-
amino alcohols the acidic Cr(VI)-mediated procedure has
proven to be the only feasible oxidation method for the
demanding 2-(hydroxymethyl)-5-vinylquinuclidine system.
Moreover, after optimization all desired products were
isolated in epimerically pure form and also enantiopure. The
various reactions are all one-pot methods. Due to their low
molecular weight, their compact and rigid [2.2.2]azabicyclic
structure, and their chemodifferentiated sidearms, the new
azabicyclic carboxylic acids and dicarboxylic acids are
versatile homochiral building blocks for organic synthesis.
The 2-amino hexanedioic esters 4 and 8 are one-carbon
homologues and mimics of 2-amino pentanedioic acid
Acknowledgment. We thank the Graduiertenfo¨rderung
(O.S.), the Fonds der Chemischen Industrie (J.F.) and the
Friedrich-Naumann-Stiftung (W.M.B.) for Ph.D. scholarships
and Ulrike Eggert for her help. The support by the Deutsche
Forschungsgesellschaft (“Chemische und Technische Grund-
lagen der Naturstofftransformation”, Graduiertenkolleg) is
also gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and complete spectroscopic data for key compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL990981O
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Org. Lett., Vol. 1, No. 10, 1999