COMMUNICATIONS
1H; H-11cis), 4.25 (d, J 9.7 Hz, 1H; H-2), 3.94 (s, 3H; H-11'), 3.73 ± 3.64
(m, 1H; H-3), 3.35 (dd, J 6.7, 14.7 Hz, 1H; H-7endo), 3.23 ± 3.05 (m, 6H;
H-12, H-8endo, H-8exo, H-7exo), 2.56 ± 2.48 (m, 1H; H-6), 2.32 ± 2.25 (m, 1H;
H-4exo), 2.09 ± 2.05 (m, 1H; H-5), 1.95 ± 1.86 (m, 1H; H-9exo), 1.80 ± 1.71 (m,
1H; H-9endo), 1.43 ± 1.34 (m, 1H; H-4endo); 13C NMR (100 MHz, CDCl3):
d 157.67 (C, C-6'), 149.11 (C, C-4'), 147.68 (CH, C-2'), 144.69 (C, C-10'),
141.20 (CH, C-10), 131.55 (CH, C-8'), 128.65 (C, C-9'), 121.62 (CH, C-7'),
117.69 (CH, C-3'), 114.15 (CH2, C-11), 101.35 (CH, C-5'), 98.86 (CH, C-2),
55.44 (CH3, C-11'), 54.38 (CH3, C-12), 46.48 (CH2, C-8), 45.04 (CH2, C-7),
40.74 (CH, C-3), 39.66 (CH, C-6), 37.48 (CH2, C-4), 33.01 (CH2, C-9), 32.57
(CH, C-5); IR (CHCl3): nÄ 2934 (s), 2875 (w), 1621 (m), 1510 (m), 1473
(m), 1433 (w), 1237 (m), 1074 (s), 1034 (w), 843 (m) cm 1; MS (608C): m/z
(%): 339 (9.6) [M 1], 338 (36.7) [M ], 323 (100.0), 307 (11.1), 264 (3.9),
224 (3.8), 214 (3.8), 196 (5.4), 186 (9.3), 169 (9.0), 153 (10.6), 138 (17.8), 122
(60.6), 105 (69.8), 84 (70.7) 77 (45.2); HRMS: C21H26N2O2 requires
338.1994; found: 338.1993. Crystal structure analysis:[16] C21H26N2O2,
Mr 338.45, monoclinic, space group P21 (No. 4), a 7.877(1), b
7.246(1), c 16.359(2) , a 90, b 101.59(2), g 908, V 914.7(2) 3,
Z 2, 1calcd 1.229 g cm 3, F(000) 364, crystal size 0.41 Â 0.74 Â 0.48 mm,
T 300 K, m(MoKa) 0.8 cm 1. Data collection as for 2c, 2q range 5.2 ±
47.98, data set h, k, l 8:8, 8:8, 18:17, total data 3158, unique data 2409,
More than half a century has passed since the hetero-
cinchona bases were first isolated and introduced into the
literature. We have fully elucidated the structure of the the
hetero-cinchona bases 7 and 8 and have revised supposedly
established results. Since the constitution and conformation of
the hetero-cinchona bases have now been clarified and
corrected, earlier mechanistic interpretations[6, 8, 10a,b] of the
hetero-cinchona rearrangement must also be abandoned.
Experimental Section
The numbering of the alkaloids follows the conventional nomenclature of
Rabe.[15] The hetero-cinchona bases are numbered according to the
IUPAC-Autonom. Quinine and quinidine (>99% purity) were obtained
from Chininfabrik Buchler GmbH, Braunschweig, Germany.
Crystal structure analysis of 2c:[16] C20H23BrN2O, Mr 387.32, orthorhom-
bic, space group P212121 (No. 19), a 8.507(1), b 9.056(1), c
23.646(2) , a 90, b 90, g 908, V 1821.7(3) 3, Z 4, 1calcd
1.412 g cm 3, F(000) 800, crystal size 0.48 Â 1.7 Â 0.41 mm, T 300 K,
m(MoKa) 22.7 cm 1. Data collection: diffractometer Stoe IPDS (Imaging
Plate), graphite-monochromated MoKa radiation (fine-focus sealed tube,
l 0.71073 ), 2V range 4.8 ± 48.18, data set h,k,l 9:9, 10:10, 26:26,
observed data 1678 with I > 2s(I), Rint 0.029. Structure solution and
3
refinement as for 2c, max./min. residual electron density 0.11/ 0.09 e
,
R(F 1) 0.0307 based on 1678 reflections with Fo > 4s(Fo), wR2 0.0591,
wR2 based on F 2 of 2409 reflections, Flack parameter 0.3(15).
total data 9746, unique data 2811, observed data 2202 with I > 2s(I), Rint
0.055. Structure solution by SHELXS-86 and refinement by SHELXL-93,
hydrogen atoms in geometrically calculated positions, max./min. residual
electron density 0.30/ 0.24 e 3, R(F 1) 0.0304 based on 2202 reflec-
tions with Fo > 4s(Fo), wR2 0.0416, wR2 based on F 2 of 2811 reflections,
Flack parameter 0.01(1).
Received: March 5, 1998 [Z13110IE]
German version: Angew. Chem. 1999, 111, 2698 ± 2701
Keywords: alkaloids ´ nitrogen heterocycles ´ rearrange-
ments ´ stereoelectronic control ´ structure elucidation
General procedure for preparation of 7 and 8: Freshly prepared silver
benzoate (150 mg, 0.65 mmol) was added to a solution of 2b (200 mg,
0.58 mmol) in MeOH (5 mL). and the mixture was refluxed for 5 d. An
aqueous solition of NaHCO3 was added and the organic phase extracted
(CHCl3). Column chromatography on silica gel (EtOAc/MeOH 10/1)
afforded 7 (144 mg, 73%), as a colorless solid. Compound 8 was prepared
from 5 by the same procedure.
[1] H. C. Kolb, M. S. VanNieuwenhze, K. B. Sharpless, Chem. Rev. 1994,
94, 2483.
[2] W. Braje, J. Frackenpohl, P. Langer, H. M. R. Hoffmann, Tetrahedron
1998, 54, 3495; b) P. Langer, J. Frackenpohl, H. M. R. Hoffmann, J.
Chem. Soc. Perkin Trans. 1 1998, 801; c) H. M. R. Hoffmann, O.
Schrake, Tetrahedron Asymmetry 1998, 9, 1051; d) O. Schrake, W.
Braje, H. M. R. Hoffmann, R. Wartchow, Tetrahedron Asymmetry
1998, 9, 3715; e) C. von Riesen, P. G. Jones, H. M. R. Hoffmann,
Chem. Eur. J. 1996, 2, 673; f) C. von Riesen, H. M. R. Hoffmann,
Chem. Eur. J. 1996, 2, 680; g) H. M. R. Hoffmann, T. Plessner, C.
von Riesen, Synlett 1996, 690.
7: 1H NMR (400 MHz, CDCl3): d 8.72 (d, J 4.5 Hz, 1H; H-2'), 8.01 (d,
J 9.2 Hz, 1H; H-8'), 7.41 (d, J 2.6 Hz, 1H; H-5'), 7.36 (dd, J 2.6,
9.2 Hz, 1H; H-7'), 7.23 (d, J 4.8 Hz, 1H; H-3'), 5.89 (ddd, J 6.8, 10.5,
17.2 Hz, 1H; H-10), 5.11 (ddd, J 1.5, 1.5, 5.9 Hz, 1H; H-11cis), 5.07 (ddd,
J 1.5, 1.5, 12.5 Hz, 1H; H-11trans), 4.19 ± 4.13 (m, 1H; H-2), 3.95 (s, 3H;
H-11'), 3.74 ± 3.64 (m, 1H; H-3), 3.54 (dd, J 9.4, 14.7 Hz, 1H; H-7exo),
3.40 ± 3.31 (m, 1H; H-8endo), 3.12 (s, 3H; H-12), 2.91 (ddd, J 2.0, 7.8,
10.2 Hz, 1H; H-7endo), 2.78 (ddd, J 4.8, 8.8, 15.1 Hz, 1H; H-8exo), 2.52 ±
2.44 (m, 1H; H-6), 2.09 (brs, 1H; H-5), 2.03 ± 1.93 (m, 1H; H-9endo), 1.88 ±
1.72 (m, 3H; H-4endo, H-4exo, H-9exo); 13C NMR (100 MHz, CDCl3): d
157.51 (C, C-6'), 148.60 (C, C-4'), 147.71 (CH, C-2'), 144.68 (C, C-10'), 141.10
(CH, C-10), 131.65 (CH, C-8'), 128.50 (C, C-9'), 120.83 (CH, C-7'), 118.00
(CH, C-3'), 114.75 (CH2, C-11), 102.13 (CH, C-5'), 101.34 (CH, C-2), 55.40
(CH3, C-11'), 54.74 (CH3, C-12), 52.27 (CH2, C-7), 43.64 (CH, C-6), 41.60
(CH, C-3), 37.96 (CH2, C-8), 32.54 (CH, C-5), 31.11 (CH2, C-4), 27.96 (CH2,
C-9); IR (CHCl3): nÄ 2935 (s), 2870 (m), 1621 (m), 1589 (w), 1510 (s), 1473
(m), 1432 (m), 1255 (m), 1230 (m), 1176 (w), 1075 (s), 1034 (m) cm 1; MS
[3] Apparently, 9-chloroquinine 3 has been the only example that shows
coalescence in the NMR spectrum: G. D. H. Dijkstra, R. M. Kellogg,
H. Wynberg, J. Org. Chem. 1990, 55, 6121.
[4] a) G. D. H. Dijkstra, R. M. Kellogg, H. Wynberg, J. S. Svendsen, I.
Marko, K. B. Sharpless, J. Am. Chem. Soc. 1989, 111, 8069; b) G. D. H.
Dijkstra, R. M. Kellogg, H. Wynberg, J. Org. Chem. 1990, 55, 6121.
[5] The close analogy between the conformation found in the solid state
and in solution indicates that intramolecular forces predominate in
determining the overall conformation of cinchona alkaloids, rather
than solid-state or solvent interactions: F. I. Carroll, P. Abraham, K.
Gaetano, S. W. Mascarella, R. A. Wohl, J. Lind, K. Petzoldt, J. Chem.
Soc. Perkin Trans 1 1991, 3017.
(1308C): m/z (%): 339 (6.6) [M 1], 338 (31.2) [M ], 323 (100.0), 307 (7.4),
296 (1.5), 264 (1.3), 250 (1.1), 210 (1.8), 196 (2.1), 186 (3.8), 168 (4.5), 137
(10.2); HRMS: C21H26N2O2 requires 338.1994; found: 338.1994. Crystal
structure analysis:[16] C21H26N2O2, Mr 338.45, orthorhombic, space group
P212121 (No. 19), a 8.398(1), b 9.038(1), c 24.936(2) , a 90, b 90,
g 908, V 1892.7(3) 3, Z 4, 1calcd 1.188 g cm 3, F(000) 728, crystal
size 0.74 Â 0.41 Â 0.37 mm, T 300 K, m(MoKa) 0.8 cm 1. Data collection
as for 2c, 2V range 4.7 ± 48.08, data set h,k,l 9:9; 10:8; 28:28, total
data 9067, unique data 2912, observed data 1743 with I > 2s(I), Rint 0.041.
Structure solution and refinement as for 2c, max./min. residual electron
density 0.17/ 0.13 e 3, R(F1) 0.0340 based on 1743 reflections with
Fo > 4s(Fo), wR2 0.0638, wR2 based on F 2 of 2912 reflections, Flack
parameter 0.07(148).
[6] P. Rabe, Justus Liebigs Ann. Chem. 1949, 561, 132.
[7] a) P. Rabe, A. Hochstätter, Justus Liebigs Ann. Chem. 1934, 514, 61;
b) P. Rabe, Chem. Ber. 1941, 74, 225.
[8] R. B. Turner, R. B. Woodward in The Chemistry of Cinchona
Alkaloids, Vol. III (Eds.: R. H. F. Manske, H. L. Holmes), Academic
Press, New York, pp. 1 ± 63, 1953; in particular pp. 17 ± 18, structures
75, 76.
[9] a) R. B. Woodward, W. E. Doering, J. Am. Chem. Soc. 1944, 66, 849;
b) R. B. Woodward, W. E. Doering, J. Am. Chem. Soc. 1945, 67, 860.
[10] a) E. W. Warnhoff, Molecular Rearrangements, Vol. 2, (Ed.: P.
de Mayo), Wiley, New York, 1964, pp. 877 ± 879; b) W. Solomon,
Chemistry of the Alkaloids, (Ed.: S. W. Pelletier), Van Nostrand
Reinhold, New York, 1970, pp. 327 ± 330; see also: c) V. Braschler,
C. A. Grob, A. Kaiser, Helv. Chim. Acta 1963, 2646; d) G. R. Pettit,
S. K. Gupta, J. Chem. Soc. C 1968, 1208; p. 1209, footnote, structure I;
1
8: H NMR (400 MHz, CDCl3): d 8.71 (d, J 4.8 Hz, 1H; H-2'), 7.99 (d,
J 9.0 Hz, 1H; H-8'), 7.34 (dd, J 2.5, 9.0 Hz, 1H; H-7'), 7.31 (d, J
2.5 Hz, 1H; H-5'), 7.21 (d, J 4.8 Hz, 1H; H-3'), 6.12 (ddd, J 5.4, 10.9,
16.1 Hz, 1H; H-10), 5.28 (d, J 17.6, 1H; H-11trans), 5.22 (d, J 10.7 Hz,
2542
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Angew. Chem. Int. Ed. 1999, 38, No. 17