Synthesis of 10,11-didehydro- and 10,11-dihydro-quincorine and of the quincoridine analogs: Functionalized and enantiopure 1-azabicyclo[2.2.2]- octanes with four stereogenic centers

Article abstract of DOI:10.1016/S0957-4166(98)00364-4

The convenient synthesis of 10,11-didehydro-QCI (2) and of 10,11- didehydro-QCD (4) as well as 10,11-dihydro-QCI (5) and 10,11-dihydro-QCD (6) is described. Conversion of the olefinic double bond of Quincorine 1 and Quincoridine 3 into the corresponding alkynes 2 and 4 involves twofold dehydrobromination, and an important application of the solid KOH/aliquat 336 system in the key step. The structure of didehydro-QCI (2) has been elucidated by X-ray crystal diffraction. The new alkynes 2 and 4 are more polar and more basic than QCI and QCD, respectively.

Full text of DOI:10.1016/S0957-4166(98)00364-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3717–3722
Synthesis of 10,11-didehydro- and 10,11-dihydro-Quincorine and
of the Quincoridine analogs: functionalized and enantiopure
1
-azabicyclo[2.2.2]-octanes with four stereogenic centers
Olaf Schrake, Wilfried Braje, H. M. R. Hoffmann and R. Wartchow b
a
a
a,∗
a
Department of Organic Chemistry, University of Hannover, Schneiderberg 1B, Germany
b
Department of Inorganic Chemistry, University of Hannover, Callinstr. 9, D-30167 Hannover, Germany
Received 4 September 1998; accepted 9 September 1998
Abstract
The convenient synthesis of 10,11-didehydro-QCI (2) and of 10,11-didehydro-QCD (4) as well as 10,11-
®
dihydro-QCI (5) and 10,11-dihydro-QCD (6) is described. Conversion of the olefinic double bond of Quincorine
1
and Quincoridine® 3 into the corresponding alkynes 2 and 4 involves twofold dehydrobromination, and an
important application of the solid KOH/aliquat 336 system in the key step. The structure of didehydro-QCI (2)
has been elucidated by X-ray crystal diffraction. The new alkynes 2 and 4 are more polar and more basic than QCI
and QCD, respectively. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
®
®
Quincorine 1 and Quincoridine 3 are two new scalemic β-amino alcohols containing four stereo-
genic centers each, including the N-chiral 1S-configurated bridgehead. Because of their compact azabi-
cyclic structure and their low molecular weight, both 1 and 3 are of general interest and use.1 We now
report the preparation of the four derived title compounds.
,2
2. Results and discussion
The acetylenes 2 and 4 were prepared via a bromination–double dehydrobromination sequence. This
was accomplished by isolating the intermediate vinylic bromides (method a) and by a simple one-pot
procedure (method b).
∗
Corresponding author. Fax: +(0)511-762 3011; e-mail: hoffmann@mbox.uni-hannover.de
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00364-4

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O. Schrake et al. / Tetrahedron: Asymmetry 9 (1998) 3717–3722
QCI 1 and QCD 3 were brominated rapidly by addition of bromine in solvent tetrachloromethane.
The resulting precipitate then underwent self-induced mono-dehydrobromination giving a mixture of
the corresponding vinylic bromides. This first dehydrobromination was caused by the basicity of the
bridgehead nitrogen. Subsequent addition of triethylamine shortened the reaction time. The second
dehydrobromination to the corresponding alkynes was more demanding, as expected. Orientating initial
t
experiments with different bases such as KOBu were not satisfactory. Use of the highly lipophilic
methyltrioctylammonium chloride (aliquat 336) in catalytic amount together with 2 equiv. of solid KOH
simplified the procedure and alkyne formation was feasible under mild conditions, with best overall
3
results. The two step sequence (method a), which included a purification of the vinylic bromides,
provided overall yields of 78%, whereas the simple one-pot reaction (method b) without purification
of intermediates gave a slightly lower yield of 68% (Scheme 1).
Scheme 1.
We also prepared the related dihydro-derivatives of QCI and QCD in order to evaluate the properties of
the alkynes. The hydrogenation was advantageously carried out homogenously with Wilkinson’s catalyst
to afford dihydro-QCI (5) and dihydro-QCD (6) in high yields (Scheme 2).
4
QCI 1 and QCD 3 and their respective dihydro analogs 5 and 6 are highly viscous liquids at room
temperature. We were pleased to find that the new alkynes 2 (mp 67°C) and 4 (mp 44°C) could readily
be isolated as crystalline solids. On TLC the parent QCI 1 and QCD 3 are less polar than the four title
5
6
compounds (R -values). Thus the remote C5-substituent has a significant impact not only on melting
f
points, but also on chemical properties, i.e. basicity. It is assumed that the distortion of the azabicyclic
cage affects the basicity of the bridgehead nitrogen. By comparison, the distortion of the azabicyclic cage
7
in the alkynes of QCI 2 and QCD 4 is less than in dihydroquinine and dihydroquinidine. The structure
of 10,11-didehydroquincorine 2 was corroborated by X-ray crystal diffraction (see Experimental).

O. Schrake et al. / Tetrahedron: Asymmetry 9 (1998) 3717–3722
3719
Scheme 2.
3. Conclusion
®
®
We have described four new members of the Quincorine and Quincoridine family, including 2 and 4.
In view of the high synthetic flexibility of alkynes, the scope of these attractive chiral building blocks and
chiral auxiliaries has been widened. To our knowledge the solid KOH/aliquat 336 system has previously
3
been used for the preparation of simple alkynes. We have shown that the conversion of functionalized
alkenes into alkynes works well and utilizes inexpensive reagents. It is therefore the procedure of choice.
4. Experimental section
Melting points were determined on a Büchi apparatus and are uncorrected. Infrared spectra were
1
13
recorded on a Perkin–Elmer 1710 infrared spectrometer. H NMR and C NMR spectra were recorded
on a Bruker AM 400 spectrometer in deuterated chloroform unless otherwise stated, with tetramethylsi-
lane as internal standard. Mass spectra were recorded on a Finnigan MAT 312 (70 eV) or a VG Autospec
spectrometer at rt unless otherwise stated. Microanalyses were performed in the Department of Organic
Chemistry of the University of Hannover. Preparative column chromatography was performed on J. T.
Baker silica gel (particle size 30–60 µm). Analytical TLC was carried out on aluminum-backed 0.2 mm
silica gel 60 F254 plates (E. Merck). R -values were determined by using MTBE:methanol (20 ml, 5:1)
f
and conc. NH (0.2 ml). THF was distilled over sodium and benzophenone before use. CH Cl (DCM)
3
2
2
was distilled over CaH before use. CCl and CHCl were distilled before use.
2
4
3

3720
O. Schrake et al. / Tetrahedron: Asymmetry 9 (1998) 3717–3722
4.1. (1S,2S,4S,5R)-2-Hydroxymethyl, 5-ethynyl-[2.2.2]-1-azabicyclooctane 2 and (1S,2R,4S,5R)-
2-hydroxymethyl, 5-ethynyl-[2.2.2]-1-azabicyclooctane 4
4.1.1. Method a
QCI 1 and QCD 3, respectively (2.0 g, 12.0 mmol) were dissolved in dry CCl (15 ml). Bromine (1.1
4
ml, 21.5 mmol) was added neat at 0°C. The reaction mixture was stirred for 1 h. After work-up (CHCl3
and Na S O solution) the resulting yellow solid was dissolved in CHCl (25 ml). Et N (3.1 ml, 24
2
2
3
3
3
mmol) was added and the mixture was then stirred for 4 h at rt. Work-up (CHCl and sat. NaHCO ) and
3
3
column chromatography (MTBE:methanol=5:1) furnished the yellowish vinylic bromides in 98% yield
(2.80 g, 11.8 mmol).
The vinylic bromides (200 mg, 0.81 mmol) were dissolved under argon in THF (10 ml), followed
by addition of KOH (116 mg, 2.0 mmol) and aliquat 336 (0.73 ml, 0.16 mmol). The reaction mixture
was then heated at reflux for 20 h. Work-up (CHCl and sat. NaHCO ) and column chromatography
3
3
(MTBE:methanol=5:1) furnished the alkynes 2 and 4 in 78% overall yield (105 mg, 0.64 mmol).
4.1.2. Method b
QCI 1 and QCD 3, respectively (2.0 g, 12.0 mmol) were dissolved in dry CCl (15 ml). Bromine
4
(1.1 ml, 21.5 mmol) was added neat at 0°C. The reaction mixture was stirred for 1 h. After removal
of the solvent at reduced pressure the yellow solid was dissolved in CHCl (25 ml). Et N (3.1 ml, 24
3
3
mmol) was added and the mixture was then stirred for 4 h at rt. After work-up (CHCl and sat. NaHCO )
3
3
the crude vinylic bromides (200 mg, 0.81 mmol) were dissolved under argon in THF (10 ml), followed
by addition of KOH (116 mg, 2.0 mmol) and aliquat 336 (0.73 ml, 0.16 mmol). The reaction mixture
was then heated at reflux for 20 h. Work-up (CHCl and sat. NaHCO ) and column chromatography
3
3
(MTBE:methanol=5:1) furnished the alkynes 2 and 4 in 68% overall yield (1.35 g, 8.2 mmol).
Data for 2. Solid, mp 67°C, [α] 35 (c 1.005; CHCl ). IR (CHCl ) ν 3304 (s), 3000 (m), 2940 (s),
D
3
3
2
1
868 (m), 1620 (w), 1452 (m), 1412 (m), 1376 (w), 1336 (m), 1324 (m), 1300 (w), 1264 (m), 1228 (m),
−1 1
164 (w), 1132 (w), 1100 (w), 1020 (m), 996 (m), 960 (m), 936 (w), 864 (w) cm ; H NMR (400 MHz)
δ 3.51 (dd, 1H, J=10 Hz, J=7.4 Hz, H-9), 3.45 (dd, 1H, J=8 Hz, J=5 Hz, H-9), 3.26 (dd, 1H, J=13.2 Hz,
J=9.8 Hz, H-6), 3.15–3.05 (m, 1H, H-2), 2.62–2.52 (ddd, J=10.7 Hz, J=4.8 Hz, J=2 Hz, H-3), 2.58–2.52
(
(
(
m, 1H, H-5), 2.14–2.05 (m, 1H, H-3), 2.11 (d, 1H, J=2.5 Hz, H-11), 1.96–1.90 (m, 1H, H-4), 1.55–1.35
m, 2H, H-8, H-8), 0.87–0.80 (m, 1H, H-3); 13C NMR (100 MHz) δ 87.75 (C-10), 68.74 (C-11), 62.77
C-9), 57.0 (C-2), 56.73 (C-6), 39.65 (C-7), 27.76 (C-5), 26.50 (C-4), 26.29 (C-8), 24.81 (C-3); MS
+
m/z 165 (M , 19.46), 148 (6.53), 136 (6.63), 135 (12.09), 134 (100.00), 126 (15.83), 124 (10.18), 120
(4.09), 106 (19.17), 96 (6.64), 91 (7.98), 82 (17.09), 77 (21.37), 72 (22.39), 67 (5.86); HRMS calcd for
C H NO: 165.1154, found 165.1142. X-Ray crystal structure, see Scheme 3.
10
15
Data for 4. Solid, mp 44°C, [α] 92 (c 1.005; CHCl ); mp 67°C. IR (cap. film) ν 3288 (s), 2940 (s),
D
3
2
1
1
872 (s), 2108 (w), 1648 (w), 1452 (m), 1412 (m), 1388 (m), 1324 (m), 1256 (w), 1200 (w), 1136 (w),
−1 1
096 (m), 1072 (m), 1036 (s), 908 (m), 628 (s) cm ; H NMR (400 MHz) δ 4.49 (s, 1H, OH), 3.64 (dd,
H, J=11.7 Hz, J=10.3 Hz, H-9), 3.49 (dd, 1H, J=11.7 Hz, J=5.2 Hz, H-9), 3.11–2.84 (m, 5H, H-7, H-7,
H-6, H-6, H-2), 2.60–2.52 (m, 1H, H-5), 2.12 (d, 1H, J=2.4 Hz, H-11), 1.95 (m, 1H, H-3), 1.72–1.64 (m,
1
3
1
6
2
1
H, H-4), 1.63–1.53 (m, 2H, H-8, H-8), 1.51–1.43 (m, 1H, H-3); C NMR (100 MHz) δ 88.68 (C-10),
9.76 (C-11), 62.03 (C-9), 57.83 (C-2), 48.45 (C-6), 47.76 (C-7), 28.08 (C-5), 27.32 (C-4), 25.32 (C-8),
4.02 (C-3); MS m/z 165 (M , 19.46), 148 (6.46), 135 (12.41), 134 (100.00), 132 (2.83), 126 (12.57),
24 (9.75), 120 (3.73), 108 (6.86), 106 (18.2), 94 (6.44), 91 (8.58), 84 (11.61), 82 (18.71), 80 (9.86), 79
+
(
16.27), 77 (21.72), 72 (24.53); HRMS calcd for C H NO: 165.1154, found 165.1155.
10 15

O. Schrake et al. / Tetrahedron: Asymmetry 9 (1998) 3717–3722
3721
Scheme 3. 7,8
4
2
.2. (1S,2S,4S,5R)-2-Hydroxymethyl, 5-ethyl-[2.2.2]-1-azabicyclooctane 5 and (1S,2R,4S,5R)-
-hydroxymethyl, 5-ethyl-[2.2.2]-1-azabicyclooctane 6
QCI 1 and QCD 3, respectively (2.5 g, 15 mmol) and Rh(PPh ) Cl (250 mg, 10 wt%) were dissolved
3
3
in a 1:1 mixture of ethanol:toluene (40 ml) and stirred under an H atmosphere for 3 days. Work-up
2
(CHCl and sat. NaHCO ) and column chromatography (MTBE:methanol=5:1) furnished dihydro-QCI
3 3
(5) and dihydro-QCD (6) with yields in the range 97% (2.46 g, 14.55 mmol).
Data for 5. Oil, [α] 11 (c 0.1, CHCl ). IR (CHCl ) ν 3332 (b), 2964 (s), 2880 (w), 1600 (m), 1461
D
3
3
−1 1
(
m), 1384 (m), 1340 (m), 1236 (m), 1120 (w), 1072 (m), 612 (m), 544 (m), 512 (m) cm ; H NMR (400
MHz) δ 4.24 (s, 1H, OH), 3.48 (dd, 1H, J =11.6 Hz, J =10.3 Hz, H-9), 3.39 (dd, 1H, J =11.6 Hz, J =4.8
2
3
2
3
Hz, H-9), 3.15 (dd, 1H, J=13.4 Hz, J=9.6 Hz, H-2), 3.02–2.36 (m, 4H, H-7, H-7, H-6, H-6), 1.81–1.67
m, 2H, H-5, H-4), 1.53–1.43 (m, 3H, H-8, H-8, H-3), 1.38 (q, 2H, J=7.2 Hz, H-10, H-10), 0.89 (t, 3H,
(
13
J=7.2 Hz, H-11), 0.79–0.72 (m, 1H, H-3); C NMR (100 MHz) δ 62.97 (C-9), 57.45 (C-2), 57.10 (C-6),
0.26 (C-7), 37.58 (C-5), 28.44 (C-8), 27.58 (C-10), 24.90 (C-4), 24.31 C-3), 12.13 (C-11); MS m/z 169
4
+
(
(
M , 52.76), 152 (34.70), 138 (100.00), 126 (22.11), 121 (5.55), 110 (32.27), 105 (5.61), 97 (19.49), 91
8.76), 82 (47.94)), 79 (10.00) 77 (7.83), 72 (46.13), 67 (17.74).
Data for 6. Oil, [α] 147 (c 1.005; CHCl ). IR (CHCl ) ν 3356 (b), 2932 (s), 2868 (s), 1664 (m), 1460
D
3
3
−1 1
(
m), 1376 (m), 1320 (m), 1200 (w), 1148 (w), 1076 (m), 1040 (s), 932 (m), 908 (m), 860 (m) cm ; H

3722
O. Schrake et al. / Tetrahedron: Asymmetry 9 (1998) 3717–3722
NMR (400 MHz) δ 4.43 (s, 1H, OH, 3.50 (dd, 1H, J =11.4 Hz, J =10 Hz, H-9), 3.38 (dd, 1H, J =11.4
2
3
2
Hz, J =4.6 Hz, H-9), 2.94–2.80 (m, 4H, H-7, H-7, H-6, H-2), 2.43 (ddd, 1H, J =14.8 Hz, J=7.8 Hz,
3
2
J=3 Hz, H-6), 1.69–1.60 (m, 2H, H-5, H-4), 1.59–1.50 (m, 1H, H-8), 1.48–1.39 (m, 2H, H-8, H-3), 1.31
(
q, 2H, J=7.4 Hz, H-10, H-10), 1.15–1.06 (m, 1H, H-3), 0.86 (t, 3H, J=7.4 Hz, H-11); 13C NMR (100
MHz) δ 62.13 (C-9), 57.74 (C-2), 48.93 (C-6), 48.30 (C-7), 37.50 (C-5), 27.61 (C-8), 25.74 (C-4), 25.49
+
(
C-10), 23.61 (C-3), 11.92 (C-11); MS m/z 169 (M , 53.57), 152 (29.55), 138 (100.00), 128 (15.56), 122
(3.05), 110 (32.75), 101 (3.22), 96 (8.28), 86 (7.06), 82 (39.01), 77 (3.35), 72 (36.73).
Acknowledgements
We thank Buchler GmbH-Chininfabrik Braunschweig for a generous gift of QCI and QCD, the
Graduiertenförderung for a Ph.D. scholarship (O.S.), the Friedrich Naumann Stiftung for a Ph.D schol-
arship (W.B.) and Jens Holzgrefe for his help.
References
1. Hoffmann, H. M. R.; Plessner, T.; von Riesen, C. Synlett 1996, 690. QCI and QCD are available from Buchler GmbH,
Harxbütteler Str. 3, D-38110 Braunschweig, fax: +(0)5307-931-31.
2
3
4
. Hoffmann, H. M. R.; Schrake, O. Tetrahedron: Asymmetry 1998, 9, 1051.
. Dehmlow, E. V.; Lissel, M. Tetrahedron 1981, 37, 1653.
. QCI solidifies on prolonged cooling below 0°C and melts at room temperature (23–26°C). C. von Riesen, personal
communication.
5
6
7
f
. R -values for QCI/QCD: 0.24; 10,11-dihydro-QCI/QCD: 0.18; 10,11-didehydro-QCI/QCD: 0.16.
. Wynberg, H.; Smaardijk, A J. Org. Chem. 1987, 52, 135.
. (a) Dijkstra, G. D. H.; Kellogg, R. M.; Wynberg, H.; Svendsen, J. S.; Marko, I.; Sharpless, K. B. J. Am. Chem. Soc. 1989,
111, 8069. (b) Norrby, P.; Kolb, H. C.; Sharpless, K. B. J. Am. Chem. Soc. 1994, 116, 8470.
8
. The angles given in the left hand column correspond to those on the right, but are numbered according to different
conventions (IUPAC for 1-azabicyclo[2.2.2]octanes and traditional nomenclature for cinchona alkaloids). Detailed X-ray
diffraction data will be submitted to Z. Krist-NCS.