Preparation of enantiopure 1-azabicyclo[3.2.2]nonanes Functionalized at carbon C3, from cinchonine and cinchonidine. Stereoselective solvolysis and an easily enolizable ketone

Article abstract of DOI:10.1021/jo026890d

Solvolysis of C9 mesylated cinchonidine 1-OMs and cinchonine 2-OMs in solvent MeOH, EtOH, and CF₃CH₂OH affords ring-expanded 1-azabicyclo[3.2.2]nonanes oxygenated at carbon C3 ("second Cinchona rearrangement"). The newly introduced s

Full text of DOI:10.1021/jo026890d

SCHEME 1. P r ep a r a tion of C9 Mesyla tes of
Cin ch on id in e a n d Cin ch on in ea
P r ep a r a tion of En a n tiop u r e
1-Aza bicyclo[3.2.2]n on a n es F u n ction a lized
a t Ca r bon C3, fr om Cin ch on in e a n d
Cin ch on id in e. Ster eoselective Solvolysis
a n d a n Ea sily En oliza ble Keton e
Stefanie Ro¨per,† M. Heiko Franz,†
Rudolf Wartchow,‡ and H. Martin R. Hoffmann*,†
Department of Organic Chemistry, University of Hannover,
Schneiderberg 1B, D-30167 Hannover, Germany, and
Department of Inorganic Chemistry, University of Hannover,
Callinstrasse 9, D-30167 Hannover, Germany
hoffmann@mbox.oci.uni-hannover.de
Received December 20, 2002
Abstr a ct: Solvolysis of C9 mesylated cinchonidine 1-OMs
and cinchonine 2-OMs in solvent MeOH, EtOH, and
CF3CH2OH affords ring-expanded 1-azabicyclo[3.2.2]nonanes
oxygenated at carbon C3 (“second Cinchona rearrange-
ment”). The newly introduced substituents at C3 and the
neighboring quinolyl group Q′ at C2 adopt quasiequatorial
positions. The derived 1-azabicyclo[3.2.2]nonan-3-ones 5 and
6 are easily equilibrated. On contact with MeOD uptake of
deuterium takes place at room temperature.
a
Reagents and conditions: (i) MsCl, NEt3, THF, rt, 3-16 h.
the product cations giving the benzoyloxy derivatives
3-OBz and 4-OBz. Sodium benzoate also buffers meth-
anesulfonic acid, which is liberated on solvolysis (NaOBz
+ MsOH f NaOMs + HOBz). On changing the solvent
to methanol (ET(30) ) 55.5) the reaction proceeded with
an increase of 1-azabicyclo[3.2.2]nonane products 4-OMe
and 4-OBz (55% vs 31% in ethanol).
In even more polar 2,2,2-trifluoroethanol (ET(30) )
59.5) solvolysis was most selective. The only cage ex-
panded product was benzoyloxy derivative 3-OBz. The
cage-expanded trifluoroethyl ether 3-OCH2CF 3 was not
detected, unlike ethyl ether 3-OEt and methyl ether
3-OMe obtained in EtOH and MeOH, respectively
(Scheme 2). Unrearranged benzoic esters 1-OBz and
2-OBz may be recycled.
The structure of the new [3.2.2]azabicyclics was es-
tablished by NMR spectroscopy, including NOE experi-
ments, and corroborated by single-crystal X-ray analysis
(Supporting Information). Ring-expanded 3-X and 4-X
were formed with complete inversion of configuration at
C3 (previously C8) resulting in a quasiequatorial ar-
rangement of substituents at C3 and C2. Unrearranged
solvolysis products 1-OEt, 1-OMe, 1-OBz, and also
1-OCH2CF 3 were formed with clean retention of config-
uration at C9. Similarly, pseudoenantiomeric products
2-X were formed with complete retention under these
conditions.6
Cinchona alkaloids are indispensable auxiliaries in
enantioselective reactions such as the AD reaction.1 A
further important application of quaternized Cinchona
salts is in asymmetric phase transfer reactions.2
In contrast to these many applications the general
chemistry of Cinchona alkaloids has been studied much
less over the years.3 We report the preparation of
enantiopure 1-azabicyclo[3.2.2]nonanes oxygenated at C3
from so-called cinch bases cinchonine and cinchonidine
and ancillary reactions.
Mesylation at C9 under standard conditions afforded
the O-mesylated derivatives 1-OMs and 2-OMs in excel-
lent yield. Heating of the pseudo-enantiomeric4 mesylates
1-OMs and 2-OMs in ethanol (solvent polarity index,
ET(30) ) 51.9)5 at reflux provided the new cage expanded
azabicyclics 3-OEt and 4-OEt, respectively, as major
products. Addition of NaOBz is helpful for intercepting
† Department of Organic Chemistry, University of Hannover.
‡ Department of Inorganic Chemistry, University of Hannover.
(1) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483. (b) Sharpless, K. B. Angew. Chem., Int. Ed. 2002,
41, 2024.
(2) (a) O’Donnell, M. J . Asymmetric Phase Transfer Reactions. In
Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley: New York, 1993.
(b) Corey, E. J .; Xu, F.; Noe, M. C. J . Am. Chem. Soc. 1997, 119, 12414.
(c) Corey, E. J .; Zhang, F.-Y. Angew. Chem., Int. Ed. 1999, 38, 1931.
(d) Nelson, A. Angew. Chem., Int. Ed. 1999, 38, 1583. (e) Lygo, B.;
Wainwright, P. G. Tetrahedron Lett. 1998, 39, 1599. (f) Arai, S.; Shirai,
Y.; Ishida, T.; Shioiri, T. Tetrahedron 1999, 55, 6375.
(3) The solvolysis of C9 halogenated quinine and quinidine has been
studied in the last century before the advent of modern spectroscopic
and separation techniques: (a) Rabe, P. Liebigs Ann. Chem. 1949, 561,
132-158. (b) Rabe, P. Chem. Ber. 1941, 74, 725-728.
(4) Replacement of the vinyl group by hydrogen creates enantiomers.
The term pseudo-enantiomer is used routinely for related pairs of
Cinchona alkaloids, e.g. quinine and quinidine.
(6) The solvolysis of C9 mesylated quinine and quinidine (6′-R )
OMe instead of 6′-R ) H) was faster than that of 1-OMs and 2-OMs
(4-12 h vs 3-4 d for the cinch bases). Cage expansion was less
developed (9% for quinine and 36% for quinidine in MeOH). In
methanol the products with intact [2.2.2]azabicyclic cage were formed
with epimerization at C9 (C9-nat:C9-epi ∼ 1:1). For C9 carbocations
derived from quinine and quinidine an open classical cation rather than
a nitrogen-bridged species becomes more favorable because of extended
conjugation with the 6′-OMe donor ii T iii.
(5) Reichardt, C. Solvent Effects in Organic Chemistry, 2nd ed.;
VCH: Weinheim, Germany, 1988.
10.1021/jo026890d CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/21/2003
4944
J . Org. Chem. 2003, 68, 4944-4946

SCHEME 2. Ca ge Exp a n sion a n d Ster eor eten tive
Solvolysis of C9 Mesyla tes of Cin ch on in e a n d
Cin ch on id in ea
SCHEME 4. Ta u tom er s of Keton es 5 a n d 6
SCHEME 5. P ostu la ted Mech a n ism : Solvolysis of
2-OMs via Aza br id ged Ca tion ia
a
Key: (i) EtOH, rf; (ii) EtOH, NaOBz, rf; (iii) MeOH, NaOBz,
rf; (iv) CF3CH2OH, NaOBz, rf.
SCHEME 3. Sw er n Oxid a tion a
a
Key: ‘a’ and ‘b’ indicate trajectories of attack by external
nucleophile.
derived from pseudoenantiomeric cinchonine was oxi-
dized. Again, an epimeric mixture of R-amino ketones (5:6
2:1) was obtained, indicating substantially complete
equilibration of 5 and 6. On contact with MeOD freshly
prepared ketones 5 and 6 smoothly took up deuterium
at C2, exchange being complete after 2 days at room tem-
perature. A number of factors clearly facilitate enolization
and tautomerization of ketones 5 and 6, including
extended conjugation (Scheme 4).
We formulate stereochemistry and product type via
intermediate i to account for 100% inversion (trajectory
‘a’) and 100% retention (trajectory ‘b’) (Scheme 5). Cation
i is a nitrogen-bridged species. In general, the extent of
bridging depends on conformation, electron demand at
carbon C9 (Q′ versus Q), solvent ionizing power, and
pH.11,12
a
Reagents and conditions: (i) CH2Cl2, DMSO, (COCl)2, NEt3,
-78 °C-rt, 90%.
Swern oxidation of the â-amino alcohol7 3-OH afforded
not only the expected azabicyclic R-amino ketone8 5, but
also its epimer 6 (ratio 5:6 2:1).9
As a test of the extent of kinetic10 versus thermo-
dynamic control of the oxidation procedure, alcohol 4-OH
(7) Illustrative route to â-amino alcohol 4-OH: To a solution of
4-OBz in MeOH/H2O (5:1) was added Ba(OH)2‚8H2O. The reaction
mixture was stirred for 16 h. After workup with H2O and extraction
with CH2Cl2 the crude product was purified by column chromatography
to furnish 4-OH (82%).
(8) The synthesis of parent 1-azabicyclo[3.2.2]nonan-3-one (iv) has
very recently been put forward as InnoCentive Challenge 260715,
$70 000 USD. See www.innocentive.com.
In conclusion a variety of cage expanded and enantio-
pure 1-azabicyclo[3.2.2]nonanes are accessible, both
as R-amino ethers by the “first Cinchona rearrange-
ment”13 and now also as â-amino ethers and their
derivatives by
a second Cinchona rearrangement.
(11) The structure of the nitrogen-bridged intermediate remains
open to discussion. While we prefer a flat-topped σ-bridged species, a
referee has suggested that the limiting case of the highly electrophilic,
parent model cation (Q′ ) H and vinyl group replaced by H) in the gas
phase can be described as a conventional aziridinium ion (B3LYP/6-
31G* calculations).
(9) The ratio of 5:6 was determined by 1H NMR and NOESY.
(10) Review of kinetic enantioselective protonation of enolates: Fehr,
C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2566. See also: (b)
Zimmerman, H. E.; Wang, P. Org. Lett. 2002, 4, 2593.
J . Org. Chem, Vol. 68, No. 12, 2003 4945

These new substances and their derivatives are of
interest as ligands in asymmetric syntheses and in
pharmacology.
Ack n ow led gm en t. We thank Amy Stockwell for
experimental contributions, Dr. Edgar Hofer for NMR
measurements, Ulrike Eggert and Lars Ole Haustedt
for their help, Buchler GmbH Braunschweig for Cin-
chona bases, and the Fonds der Chemischen Industrie
for continued support of our work.
(12) Cf. also reviews on structural studies of the 2-norbornyl
cation: (a) Olah, G. A.; Prakash, G. K. S.; Saunders, M. Acc. Chem.
Res. 1983, 16, 440. (b) Methoden der Organischen Chemie, Houben-
Weyl; Hanack, M., Ed.; Thieme: Stuttgart, Germany, 1990; Vol. E19c.
(c) Saunders, M.; J ime´nez-Vazquez, H. A. Chem. Rev. 1991, 91, 375.
(d) X-ray crystal structures: Laube, T. Acc. Chem. Res. 1995, 28, 339.
(e) Carey, F. A.; Sundberg, R. J . Advanced Organic Chemistry, 3rd ed.;
Plenum Press: New York, 1993.
(13) (a) Ro¨per, S.; Wartchow, R.; Hoffmann, H. M. R. Org. Lett. 2002,
4, 3179. (b) Ro¨per, S.; Frackenpohl, J .; Schrake, O.; Wartchow, R.;
Hoffmann, H. M. R. Org. Lett. 2000, 2, 1661. (c) Braje, W. M.;
Wartchow, R.; Hoffmann, H. M. R. Angew. Chem., Int. Ed. 1999, 38,
2540.
Su ppor tin g In for m ation Available: Experimental prepa-
rations and spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org. Crystal-
lographic data of 4-OBz (CCDC-188973) can be obtained
free of charge on application to CCDC (e-mail: deposit@
ccdc.cam.ac.uk).
J O026890D
4946 J . Org. Chem., Vol. 68, No. 12, 2003