Oxazatricyclic noradamantanes: Stereocontrolled synthesis of functionalized scopolines, related cage molecules, and drug leads

Article abstract of DOI:10.1021/ol048603t

(Chemical Equation Presented) Scopolines 4 and the noradamantane scaffold are accessible from 8-oxabicyclo[3.2.1]oct-6-en-3-ones such as 6 by a concise route involving introduction of an axial amino nitrogen at C3, epoxidation, and cyclization. The result

Full text of DOI:10.1021/ol048603t

ORGANIC
LETTERS
2004
Vol. 6, No. 23
4155-4158
Oxazatricyclic Noradamantanes:
Stereocontrolled Synthesis of
Functionalized Scopolines, Related Cage
Molecules, and Drug Leads
Mar´ıa Vidal Pascual,† Steffen Proemmel,† Winfried Beil,‡ Rudolf Wartchow,§ and
H. M. R. Hoffmann*,†
Department of Organic Chemistry, UniVersity of HannoVer, D-30167 HannoVer,
Department of Pharmacology, Medical UniVersity, D-30625 HannoVer, and
Department of Inorganic Chemistry, UniVersity of HannoVer, D-30167 HannoVer
hoffmann@mbox.oci.uni-hannoVer.de
Received July 20, 2004
ABSTRACT
Scopolines 4 and the noradamantane scaffold are accessible from 8-oxabicyclo[3.2.1]oct-6-en-3-ones such as 6 by a concise route involving
introduction of an axial amino nitrogen at C3, epoxidation, and cyclization. The resulting cage molecules are versatile drug leads.
Tropane alkaloids occur in plants of the family Solanaceae
and show a diverse pharmacological profile. They are used
medicinally, e.g., as anticholinergics, competing with acet-
ylcholine for the muscarinic receptor site of the parasym-
pathetic nervous system.1 Bicyclic tropane alkaloids have
been studied intensively as cocaine receptor antagonists.2
Scopoline 3 (oscine) isolated from Datura spp. (Angels’
trumpets) is a naturally occurring tricyclic tropane alkaloid
formed from scopolamine 1 (hyoscine), a strong cerebral
sedative.3 The use of these broadly applicable alkaloids dates
back at least as far as 3000 BC: Native Americans and
ancient Hindus smoked selected alkaloidal plants during
ritualistic ceremonies. The problem of defining their utility
as a medicinal agent is complicated by the fact that the plant
produces a large number of closely related alkaloids, and
those present in larger relative quantity are not necessarily
those with the more interesting medicinal properties.
Scopoline 3 occurs only in small amounts in nature.
Pharmacological studies of scopoline derivatives have indi-
cated analgesic activity,4 surface anesthetic activity,5 and
antispasmodic, antisecretory, anti-Parkinson, and tranquil-
izing effects (travel sickness).6 The biosynthetic route to
scopoline 3 implicates epoxy alcohol scopine 2. Under achiral
conditions this meso-configured intermediate is desymme-
trized to (()-3 (Scheme 1).7
A useful route to tropane alkaloids is the [4 + 3]
cycloaddition of pyrroles to oxyallyls,8 reported several years
ago: oxyallyls are typically generated from R,R’-dibromo
ketones with NaI/Cu,8a Fe2(CO)9,8b or Et2Zn.8c It occurred
to us that scopoline can be regarded as a dihetero analogue
† Department of Organic Chemistry, University of Hannover.
‡ Department of Pharmacology, Medical University of Hannover.
§ Department of Inorganic Chemistry, University of Hannover.
(1) Derwick, P. M. Medicinal Natural Products; Wiley: Chichester, UK,
1998; Chapter 6.
(4) Waters, J. A.; Creveling, C. R.; Witkop, B. J. Med. Chem. 1974, 17,
(2) Reviews: (a) Singh, S. Chem. ReV. 2000, 100, 925. (b) Fodor, G. In
Rodd’s Chemistry of Carbon Compounds, 2nd ed.; Sainsbury, M., Ed.;
Elsevier: Amsterdam, 1997; Vol. 4, pp 4251-4276.
(3) (a) Heusner, A. Chem. Ber. 1954, 87, 1063. (b) Fodor, G.; Kovacs,
O. J. Chem. Soc. 1953, 2341. (c) Stereochemistry and configuration of
scopolamine: Fodor, G. Tetrahedron 1957, 1, 86.
488.
(5) Zeile, K.; Heusner, A. Chem. Ber. 1957, 90, 2800-2809.
(6) Zaugg, H. E. U.S. Patent 2,927,925, 1960; Chem. Abstr. 1960, 54,
14293.
(7) Enzymatic resolution of (()-scopoline: Cramer, N.; Laschat, S.; Baro,
A. Synlett 2003, 2178.
10.1021/ol048603t CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/12/2004

to reductive amination.12a Only the axial amines 9a,b were
obtained. Best results were achieved with NaBH3CN in the
presence of dry NH4OAc (Table 1, entries 2 and 3).
Scheme 1. Biosynthetic Route to Scopoline 3
12b
Experiments with NaBH(OAc)3 were not successful.
Table 1. Stereocontrolled Reductive Amination of Oxabicyclic
Ketones 7a,b
of noradamantane. Removal of any one of the six methylene
groups in adamantane generates a zero-bridge between two
of the four bridgeheads. Simultaneously the high Td sym-
metry (24 symmetry operations) of adamantane is lowered
to C2V (4 symmetry operations). Site-selective introduction
of oxygen and nitrogen into the noradamantane scaffold
provides the asymmetric scopoline framework (arbitrary
absolute configuration) (Scheme 2).
yield
entry
R
R′
conditions
product [%]
1
2
3
4
8a
8a
H
H
H
H
NH4OAc, NaBH(OAc)3,
MeOH, rt, 2-3 d
NH4OAc, NaBH3CN,
MeOH, rt, 2-3 d
NH4OAc, NaBH3CN,
MeOH, rt, 2-3 d
9a
nr
55
90
40
H
9a
Scheme 2. Gedanken Experiment Linking Adamantane and
8b Me
9bR
9bâ
Scopoline
8b Me PhCH(Me) PhCH(Me)NH2, NaBH3CN,
MeOH, 5N HCl in
MeOH, rt, 2-3d
Protection of the basic nitrogen in 9a,b as N-Boc deriva-
tives and epoxidation proceeded smoothly, giving the cy-
clization precursors 10a,b. Cyclization to 2-oxa-6-azatricyclo-
[3.3.1.03,7]nonanes 11 and 12 was tried under a variety of
conditions. Grignard reagents such as tert-butylmagnesium
chloride gave the desired oxazatricyclics 11 and 12 in good
to high yield (Table 2). The bulky Grignard reagent appears
to function first as a base and then as a Lewis acid, activating
Accordingly, scopoline and many derivatives should be
accessible in nonobvious fashion by delayed introduction of
amino nitrogen, starting from 8-oxabicyclo[3.2.1]oct-6-en-
3-ones 6 (Scheme 3).9 Epoxidation and cyclization involving
nitrogen as internal nucleophile were envisioned to yield the
oxazatricyclic noradamantane scaffold 4.10
Table 2. Cycloisomerization of Tricyclic Amino Epoxides to
Functionalized Scopolinesa
Scheme 3. Retrosynthesis of Functionalized
2-Oxa-6-azatricyclo[3.3.1.03,7]nonanes 4a
a Only one enantiomer shown for clarity.
yield
[%]
entry
R
R′
conditions
products
11a, 12a
We started from 2R-benzyloxy bicyclics 8a,b that are
available from 7 on a multigram scale11 and submitted them
1
2
3
4
5
6
10a
H
Bn tBuMgCl, THF,
0 °C to rt, 2 h
60
(8) (a) Fierz, G.; Chidgey, R.; Hoffmann, H. M. R. Angew. Chem., Int.
Ed. Engl. 1974, 13, 410. (b) Hayakawa, Y.; Baba, Y.; Makino, S.; Noyori,
R. J. Am. Chem. Soc. 1978, 100, 1786. (c) Mann, J.; Barbosa, L.-C. J.
Chem. Soc., Perkin Trans. 1 1992, 787. See, however: Hodgson, D. M.;
Paruch, E. Tetrahedron 2004, 60, 5185. The classical Robinson tropinone
synthesis proceeds with umpolung of reactivity from three-carbon and four-
carbon building blocks. See: Robinson, R. J. Chem. Soc. 1917, 762.
(9) Hartung, I. V.; Hoffmann, H. M. R. Angew. Chem., Int. Ed. 2004,
43, 1934.
(10) Compare also synthesis of epibatidine: Fletcher, S. R.; Baker, R.;
Chambers, M. S.; Herbert, R. R.; Hobbs, S. C.; Thomas, S. R.; Verrier, H.
M.; Watt, A. P.; Ball, R. G. J. Org. Chem. 1994, 59, 1771.
(11) Experimental procedure submitted to Org. Synth., available on e-mail
request from the corresponding author.
10a
10b
10b
10b
H
Bn PrMgCl, THF,
0 °C to rt, 4 h
11a, 12a
61
75
68
77
70
Me Bn PrMgCl, THF,
0 °C to rt, 4 h
Me Bn PrMgCl, THF,
0 °C to rt, 65 h
Me Bn tBuMgCl, THF,
0 °C to rt, 2 h
11b, 12b
11b, 12b
11b, 12b
10-OH Me
H
tBuMgCl, THF,
11-OH, 12-OH
0 °C to rt, 2 h
4156
Org. Lett., Vol. 6, No. 23, 2004

Scheme 4. Functionalized Scopoline Synthesis Exemplified
the epoxide. The relative orientation of functional groups in
carbon C7, irrespective of possible obviating factors such
as the orientation and precise nature of the nucleophile under
the experimental conditions.
the major product 11 and the more “cocaine-like” structure
of minor product 12 are noteworthy and generate further
interesting stereochemical issues. For example, in 12 the
oxygen at C2 is axial with respect to the piperidine and
equatorial with respect to the tetrahydropyran segment.
The X-ray crystal structure of 10a shows that the amino
nitrogen is not equidistant from epoxide carbon C6 and C7.
Rather the distance N-C7 is shorter (3.06 Å) than N-C6
(3.12 Å) (Figure 1). Internal attack of amino nitrogen results
Debenzylation of 10b and treatment of the resulting
N-Boc-protected epoxy amino alcohol 10-OH with tert-
butylmagnesium chloride gave the hydroxylated scopoline
skeleton 11-OH (Scheme 4) rather than dioxatricyclic
dictyoxetane skeleton 14, which is another cage molecule
and drug lead.13 Again a regiopreference (3:2) of ring closure
of precursor 10-OH to form major diol 11-OH and minor
diol 12-OH was observed (Scheme 4).
2-Oxa-6-azatricyclo[3.3.1.03,7]nonanes 11a,b were easily
oxidized to crystalline ketones 13a,b. Diol 11-OH afforded
keto alcohol 13-OH by site-selective Swern oxidation of the
more accessible hydroxy group. Reductive amination of keto
alcohol 13-OH and the introduction of NH-Cbz-protected
alanine gave the weakly antitumor active peptide 11-NH-
AlaCbz.
The oxaza tricycles 10, 11, and 13 were tested for
biological activity, derivative 13a being most active toward
carcinoma type HMO 2 (gastric carcinoma), HEP G2 (hepatic
carcinoma), and MCF 7 (mamma carcinoma) (Table 3). To
our knowledge, this is the first time that antitumor activity
has been observed for this class of compounds.
Figure 1. Truncated X-ray structure of 10a. All hydrogen atoms
are omitted.
in oxazatricyclics 11 and 12 in the ratio of 3:2, indicating
preferred nucleophilic attack of the more proximate epoxide
(13) (a) Reinecke, J.; Hoffmann, H. M. R. Chem. Eur. J. 1995, 1, 368.
(b) Wittenberg, J.; Beil, W.; Hoffmann, H. M. R. Tetrahedron Lett. 1998,
39, 8259. (c) Proemmel, S.; Hoffmann, H. M. R.; Beil, W. Tetrahedron
2002, 58, 6199.
(12) (a) Baxter, E. W.; Reitz, A. B. Org. React. 2002, 59, 1. (b) Abdel-
Magid, A. F.; Garson, K. G.; Harris, B. D.; Maryanoff, C. A., Shaw, R. D.
J. Org. Chem. 1996, 61, 3849.
Org. Lett., Vol. 6, No. 23, 2004
4157

iliary [cf. 6, R ) (R)- or (S)-CH(Me)Ph]16 instead of the
O-benzyl group (6, R ) PhCH2) allows stereocontrol of up
to four stereocenters and then seven in all. Hence our work
also constitutes a formal total synthesis of enantiopure
oxazatricyclic noradamantanes, scopolines, and related cage
molecules, which do not occur in the natural series. (iv)
Tuning of lipophilicity/hydrophilicity along the Lipinski
rules17 of drug design is feasible.
Table 3. Antitumor Activity for 13a (in µg/mL)14
HMO2
HEP G2
MCF 7
Finally, the growing potential of [4 + 3] cycloadducts and
the wide applicability of 8-oxabicyclo[3.2.1]oct-6-en-3-ones9
are underscored.
GI50
TGI
LC50
0.17
0.26
0.42
0.16
0.25
1.8
0.38
0.42
4.4
Acknowledgment. We thank the Deutsche Forschungs-
gemeinschaft, the Volkswagen Foundation, and the Fonds
der Chemischen Industrie for support.
In assessing the scope and utility of our protocol for the
construction of noradamantanes and related small-molecule
NCEs,15 the following points should be borne in mind: (i)
Diversity connecting points for combinatorial studies can be
installed at all peripheral carbon atoms of the densely
functionalized noradamantane skeleton, including the four
bridgehead carbons. These four sites are often the most
difficult to functionalize by traditional methodology. (ii)
Heteroatom combinations other than O and N are feasible.
Mono-hetero noradamantanes are accessible from cyclopen-
tadiene [4 + 3] cycloadducts. (iii) The resolution of racemic
cage molecules can be notoriously difficult. Our asymmetric
cycloaddition utilizing the enantiopure R-methylbenzyl aux-
Supporting Information Available: Preparation of (()-
2-benzyloxy-8-oxabicyclo[3.2.1]oct-6-en-3-one 8a and also
8b (see ref 11), spectroscopic data of nine tricyclics and
bicyclics, and supplementary crystallographic data for four
tricycles (see ref 18). This material is available free of charge
via the Internet at http://pubs.acs.org.
OL048603T
(16) Stark, C. B. W.; Eggert, U.; Hoffmann, H. M. R. Angew. Chem.,
Int. Ed. 1998, 37, 1266. Pierau, S.; Hoffmann, H. M. R. Synlett 1999, 213.
Stark, C. B. W.; Pierau, S.; Wartchow, R.; Hoffmann, H. M. R. Chem.
Eur. J. 2000, 6, 684. Beck, H.; Stark, C. B. W.; Hoffmann, H. M. R. Org.
Lett. 2000, 2, 883.
(14) GI50 ) concentration causing 50% growth inhibition; TGI )
concentration causing 100% growth inhibition; LC50 ) concentration
causing 50% reduction of the cells present.
(15) New Chemical Entity; see: Rouhi, A. M. Chem. Eng. News 2003,
Oct 13, 77, 93, 104.
(17) Lipinski, C. A. Drug DiscoVery Today 2003, 8, 12.
(18) CCDC 240296 (10a), CCDC 240294 (11b), CCDC 240297 (11-
OH), and CCDC 240295 (13a) can be obtained from the Cambridge
Crystallographic Data Centre, deposit@ccdc.cam.ac.uk.
4158
Org. Lett., Vol. 6, No. 23, 2004