A practical synthesis of (±)-α-isosparteine from a tetraoxobispidine core

Article abstract of DOI:10.1021/ol0519184

(Chemical Equation Presented) The title alkaloid was synthesized in racemic form from 3,7-diallyl-2,4,6,8-tetraoxo-3,7-diazabicyclo[3.3.1]nonane (7) by a regioselective diallylation reaction followed by double ring-closing olefin metathesis and exhaustive reduction. Tetraoxobispidine 7 was itself prepared in three simple operations from dimethyl malonate. The entire sequence to α-isosparteine was conducted on a multigram scale and proceeded without recourse to chromatography.

Full text of DOI:10.1021/ol0519184

ORGANIC
LETTERS
2
005
Vol. 7, No. 21
721-4724
A Practical Synthesis of
4
(
±
)-
r
-Isosparteine from a
†
Tetraoxobispidine Core
Paul R. Blakemore,*,‡ Colin Kilner, Neil R. Norcross, and Peter C. Astles
§
§
|
Department of Chemistry, Oregon State UniVersity, CorVallis, Oregon 97331-4003,
School of Chemistry, UniVersity of Leeds, Leeds, West Yorkshire LS2 9JT, U.K., and
Eli Lilly & Co. Ltd., Lilly Research Centre, Erl Wood Manor, Windlesham,
Surrey GU20 6PH, U.K.
paul.blakemore@science.oregonstate.edu
Received August 9, 2005
ABSTRACT
The title alkaloid was synthesized in racemic form from 3,7-diallyl-2,4,6,8-tetraoxo-3,7-diazabicyclo[3.3.1]nonane (7) by a regioselective diallylation
reaction followed by double ring-closing olefin metathesis and exhaustive reduction. Tetraoxobispidine 7 was itself prepared in three simple
operations from dimethyl malonate. The entire sequence to
to chromatography.
r-isosparteine was conducted on a multigram scale and proceeded without recourse
The sparteine subgroup of lupine alkaloids are 3,11-
system and display exo-exo and endo-endo bridgehead
hydrogen atom configurations, respectively.
3,8 11,16
diazatetracyclo[7.7.1.0. 0 ]heptadecanes which exhibit a
1
,2
range of useful biological and physical properties. Three
relative stereochemical configurations for this tetracycle are
geometrically possible, and each diastereomeric form is
3
naturally occurring (Figure 1). The eponymous sparteine
group alkaloid (2), abundant as its levorotatory enantiomorph
4
in a number of common papilionaceous plants, is distin-
guished by an asymmetrical exo-endo arrangement of
bridgehead hydrogen atoms at C6 and C11 (sparteine
numbering). R-Isosparteine (1)5 and â-isosparteine (3)
6
2
represent the two C -symmetric forms of the parent ring
†
Dedicated to Professor Emeritus James D. White on the occasion of
his 70th birthday.
‡
Oregon State University.
University of Leeds.
Eli Lilly & Co. Ltd.
§
|
(1) Reviews: (a) Michael, J. P. Nat. Prod. Rep. 2003, 20, 458. (b)
Ohmiya, S.; Saito, K.; Murakoshi, I. In The Alkaloids; Cordell, G. A., Ed.;
Academic Press: New York, 1995; Vol. 47, p 1. See also earlier reviews
in the same series.
(2) Biological activity: (a) Schmeller, T.; Wink, M. In Alkaloids:
Biochemistry, Ecology, and Medicinal Applications; Roberts, M. F., Wink,
M., Eds.; Plenum Press: New York, 1998; p 435. (b) Seeger, R.; Neumann,
H. G. Inst. Pharmakol. Toxikol. 1992, 132, 1577.
Figure 1. Six stereoisomers of 3,11-diazatetracyclo[7.7.1.0. 011,16]-
heptadecane (1-3) and tetraoxobispidines 4.
3,8
(3) Leonard, N. J. In The Alkaloids; Manske, R. H. F., Ed.; Academic
Press: New York, 1960; Vol. 7, p 253.
1
0.1021/ol0519184 CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/13/2005

(-)-Sparteine (l-2), which is commercially available, and
standing the plethora of known racemic routes to 1-3, two
(
-)-R-isosparteine (l-1), conveniently obtained from l-2 by
enantioselective syntheses of sparteine itself have now been
reported. Arguably, neither of these asymmetric approaches
is simple enough in its execution or of sufficient brevity to
compete effectively with resolution based protocols to (+)-
sparteine (d-2) and (+)-R-isosparteine (d-1).
7
17
isomerization, have found widespread use as chiral ligands
in asymmetric synthesis.8 At present, all enantioselective
methods based on these diamines are inherently limited due
to the lack of a readily available source of sparteine bases
in dextrorotatory form.1
A practical stereocontrolled entry to all six stereoiso-
mers of the characteristic sparteine skeleton is a desira-
ble goal and would extend the versatility of existing
asymmetric methods which rely on these intriguing com-
pounds. Numerous racemic syntheses of the sparteine bases
-10
1,12
Pursuant of an efficient and unified strategy for the
stereocontolled elaboration of all members of the sparteine
group, we identified C2V-symmetric tetraoxobispidines 4 as
pivotal synthons for this purpose. Bisimides 4 provide the
central sparteine BC-ring bispidine system in a form
amenable for the regio- and stereocontrolled annulation of
rings A and D. Furthermore, the enantioselective desymme-
13-15
have appeared,
ficient16 and no obvious methods exist to render enantiose-
lective the routes which are genuinely practical. Notwith-
but few of these approaches are ef-
18
trization of prochiral imides has been well demonstrated,
and we felt confident that suitable dissymmetric reagents
would be available to effectively discriminate between pairs
of enantiotopic carbonyl groups within 4 when required.
Herein, we report our initial forays in this area and describe
(4) (-)-Sparteine (lupinidine), a cardiac stimulant easily extracted from
the weed Scotch broom (Cytisus scoparius), was first isolated in 1851 by
Stenhouse and its structure correctly elucidated 82 years later by Clemo
and Raper; see: Clemo, G. R.; Raper, R. J. Chem. Soc. 1933, 644.
an annulation strategy based on ring-closing olefin metathesis
(5) (-)-R-Isosparteine (genisteine) was first obtained semi-synthetically
19
(
RCM) to convert allyl-substituted tetraoxobispidine 7 to
from (-)-sparteine but later found naturally occurring in Lupinus caudatus,
see: Marion, L.; Turcotte, F.; Ouellet, J. Can. J. Chem. 1951, 22, 29.
(()-R-isosparteine (dl-1).
(6) (-)-â-Isosparteine has also been known as l-spartalupine and pusilline
Our new approach to the sparteine alkaloids required an
efficient synthesis of tetraoxobispidines 4. Tetraoxobispidines
and occurs in a variety of Lupinus species; see: Greenhalgh, R.; Marion,
L. Can. J. Chem. 1956, 34, 456.
(
7) (a) For isomerization with AlCl3, see: Galinovsky, F.; Knoth, P.;
substituted on the methylene bridge are a well-known class
of compounds, commonly referred to as “Guareschi imides”
Fischer, W. Monatsh. Chem. 1955, 86, 1014. (b) For isomerization by
oxidation/reduction, see: Okamoto, Y.; Suzuki, K.; Kitayama, T.; Yuki,
H.; Kageyama, H.; Miki, K.; Tanaka, N.; Kasai, N. J. Am. Chem. Soc. 1982,
20
in regard to their usual manner of construction via Guareschi
1
04, 4618.
8) For a review of sparteine/alkyllithium reagent pairs in synthesis,
see: Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 2282.
9) Recent representative synthetic applications of (-)-sparteine: (a)
Vrancken, E.; Alexakis, A.; Mangeney, P. Eur. J. Org. Chem. 2005, 1354.
b) Caupene, C.; Boudou, C.; Perrio, S.; Metzner, P, J. Org. Chem. 2005,
21,22
condensation.
By contrast, tetraoxobispidines unsubsti-
(
tuted on the methylene bridge are scarcely known; indeed,
(
only the parent compound (6) has appeared in an isolated
23
report by Guthzeit. Since it proved impossible to prepare
(
7
2
6 by Guareschi condensation, or by a related tactic,24 we
0, 2812. (c) Kocienski, P. J.; Christopher, J. A.; Bell, R.; Otto, B. Synthesis
005, 75. (d) Martinez, M. M.; Hoppe, D. Org. Lett. 2004, 6, 3743. (e)
Bagdanoff, J. T.; Stoltz, B. M. Angew. Chem., Int. Ed. 2004, 43, 353. (f)
Metallinos, C.; Szillat, H.; Taylor, N. J.; Snieckus, V. AdV. Synth. Catal.
003, 345, 370. (g) Shintani, R.; Fu, G. C. Angew. Chem., Int. Ed. 2002,
1, 1057
(
elected to reexamine Guthzeit’s long neglected synthesis of
6
from tetraamide 5.
2
4
Compound 5 was prepared by way of the Knoevenagel
condensation adduct formed from dimethyl malonate and
10) Recent representative synthetic applications of (-)-R-isosparteine:
2
5
(
a) Allen, B. D.; Cintrat, J.-C.; Faucher, N.; Berthault, P.; Rousseau, B.;
paraformaldehyde. This tetraester was not isolated but
treated directly with concentrated aqueous ammonia to afford
O’Leary, D. J. J. Am. Chem. Soc. 2005, 127, 412. (b) Hodgson, D. M.;
Galano, J.-M.; Christlieb, M. Tetrahedron 2003, 59, 9719. (c) Muller, P.;
Patrice, N.; Bernardinelli, G. Eur. J. Org. Chem. 2001, 21, 4137. (d)
Hodgson, D. M.; Cameron, I. D.; Christlieb, M.; Green, R.; Lee, G. P.;
Robinson, L. A. J. Chem. Soc., Perkin Trans. 1 2001, 18, 2161.
(17) The following enantioselective syntheses by Aub e´ and O’Brien could
each be used in principle to prepare either (+)- or (-)-sparteine: (a) Smith,
B. T.; Wendt, J. A.; Aub e´ , J. Org. Lett. 2002, 4, 2577. (b) Hermet, J.-P. R.;
McGrath, M. J.; O’Brien, P.; Porter, D. W.; Gilday, J. Chem. Commun.
2004, 1830.
(
11) O’Brien has introduced a (+)-sparteine surrogate derived from (-)-
cytisine which goes some way to addressing this issue, see: (a) Dearden,
M. J.; Firkin, C. R.; Hermet, J.-P. R.; O’Brien, P. J. Am. Chem. Soc. 2002,
1
2
24, 11870. (b) Dearden, M. J.; McGrath, M. J.; O’Brien, P. J. Org. Chem.
004, 69, 5789.
(18) Speckamp and Hiemstra have made seminal contributions in this
area; see: Ostendorf, M.; Romagnoli, R.; Pereiro, I. C.; Roos, E. C.;
Moolenaar, M. J.; Speckamp, W. N.; Hiemstra, H. Tetrahedron: Asymmetry
1997, 8, 1773.
(12) (+)-Sparteine has been obtained from natural (()-lupanine by
resolution followed by reduction, see: Ebner, T.; Eichelbaum, M.; Fischer,
P.; Meese, C. O. Arch. Pharm. (Weinheim) 1989, 322, 399.
(19) Review: Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(20) By tetraoxobispidine we imply 2,4,6,8-tetraoxo-3,7-diazabicyclo-
[3.3.1]nonane. A substructure search of Scifinder Scholar retrieved 188
examples of this ring system mono- or disubstituted at position 9.
(21) The Guareschi condensation is a Knoevenagel-type three-component
coupling reaction between a cyanoacetate, a carbonyl compound and
ammonia; the initially generated R,R’-dicyanoglutarimides cyclize to
tetraoxobispidines upon treatment with sulfuric acid; see: (a) Guareschi, I.
Gazz. Chim. Ital. 1919, 49, 126. (b) Kon, G. A. R.; Thorpe, J. F. J. Chem.
Soc. 1919, 686. (c) Vogel, A. I. J. Chem. Soc. 1934, 1758.
(22) Guareschi imides have been used as precursors to bispidines having
antiarrhythmic properties; see: Sch o¨ n, U.; Antel, J.; Br u¨ ckner, R.;
Messinger, J. J. Med. Chem. 1998, 41, 318.
(
13) Syntheses of (()-sparteine: (a) Leonard, N. J.; Beyler, R. E. J. Am.
Chem. Soc. 1948, 70, 2298. (b) Leonard, N. J.; Beyler, R. E. J. Am. Chem.
Soc. 1950, 72, 1316. (c) Clemo, G. R.; Raper, R.; Short, W. S. J. Chem.
Soc. 1949, 663. (d) van Tamelen, E. E.; Foltz, R. L. J. Am. Chem. Soc.
1
1
969, 91, 7372. (e) Bohlmann, F.; M u¨ ller, H.-J.; Schumann Chem. Ber.
973, 106, 3026. (f) Takatsu, N.; Noguchi, M.; Ohmiya, S.; Otomasu, H.
Chem. Pharm. Bull. 1987, 35, 4990. (g) Wanner, M. J.; Koomen, G.-J. J.
Org. Chem. 1996, 61, 5581. (h) Butler, T.; Fleming, I.; Gonsior, S.; Kim,
B.-H.; Sung, A.-Y.; Woo, H.-G. Org. Biomol. Chem. 2005, 3, 1557.
(
14) Syntheses of (()-R-isosparteine: (a) Sorm, F.; Keil, B. Collect.
Czech. Chem. Commun. 1948, 13, 544. (b) Tsuda, K.; Sato, T. Chem. Pharm.
Bull. 1954, 2, 190. (c) Oinuma, H.; Dan, S.; Kakisawa, H. J. Chem. Soc.,
Perkin Trans. 1 1990, 2593. See also ref 13b.
(23) Guthzeit, J. J. Prakt. Chem. 1902, 2, 11.
(
15) Syntheses of (()-â-isosparteine: Carmack, M.; Douglas, B.; Martin,
E. W.; Suss, H. J. Am. Chem. Soc. 1955, 77, 4435. See also refs 14b and
3 g.
16) Notable exceptions include the very first synthesis of sparteine and
(24) Acidic hydrolysis of 1,1,3,3-tetracyanopropane failed to produce
bisimide 6. For the preparation of 1,1,3,3-tetracyanopropane, see: Bell, R.
A.; Brown, B. E.; Duarte, M.; Howard-Lock, H. E.; Lock, C. J. L. Can. J.
Chem. 1987, 65, 261.
1
(
R-isosparteine by Leonard and Beyler (two steps, ref 13ab) and the elegant
three-step approach to R-isosparteine by Kakisawa et al (ref 14c).
(25) Gogoll, A.; Johansson, C.; Ax e´ n, A.; Grennberg, H. Chem. Eur. J.
2001, 7, 396.
4722
Org. Lett., Vol. 7, No. 21, 2005

hexanes. An X-ray crystallographic analysis of 7 provided
unequivocal proof of structure and indicated the well-
distinguished exo and endo faces of this bicyclo[3.3.1]nonane
system (Figure 2).
Scheme 1. Synthesis of N,N′-Diallyltetraoxobispidine 7
Figure 2. ORTEP diagram for 7. 50% probability ellipsoids are
plotted for non-hydrogen atoms.
a precipitate of the amide product 5 (Scheme 1). Following
filtration, subsequent drying of the material afforded a 56%
yield of 5 from over one mole of paraformaldehyde as
limiting reagent. The easy isolation of 5 in pure form by
simple filtration set the trend for the entire synthesis of dl-1
as it turned out that not a single compound en route to this
initial target required chromatographic purification (vide
infra). Guthzeit’s preparation of 6 called for pyrrolysis of 5
Our plan next called for the nucleophilic introduction of
two further allyl moieties with the intention of forging the
A and D rings of dl-1 via double RCM. Allyl bromide was
again used as the carbon source, but this time converted to
allylmagnesium bromide in diethyl ether to effect the desired
reactivity umpolung (Scheme 2). Rapid addition of an excess
23
at reduced pressure. In our hands, brief heating of 5 at 250
C and 20-50 mmHg (water aspirator) resulted in melting
°
with vigorous gas evolution. Upon cessation of bubbling,
the resinous dark brown pyrrolyte was allowed to cool and
subsequent trituration and recrystallization from ethanol
permitted quantities of 6 to be isolated in low yield (4-
Scheme 2. Synthesis of (()-R-Isosparteine (dl-1) from 7
6%). Notwithstanding the poor efficiency of this transforma-
tion, it proved impossible to execute reliably from any more
than single gram quantities of 5, either in conventional
apparatus or in a microwave reactor. Reasoning that some
sort of activation of 5 might allow for a less torturous
conversion to 6, we investigated a modification of the
Guthzeit condensation process in acidic media. After some
experimentation, it was discovered that methanesulfonic acid
served this purpose very well, presumably by facilitating the
generation of acylium cations from 5 while also sequestering
liberated ammonia. In the event, heating a mechanically
stirred paste composed of finely ground 5 and methane-
sulfonic acid, resulted in dissolution followed by copious
gas evolution. After cooling, bisimide 6 was isolated in 23%
yield by simple trituration of the pale oily residue with
methanol followed by washing of the resulting solid with
water. The modest yield for this transformation was offset
by its operational simplicity, its reproducibility over a range
of scales (near identical yields at 5, 100, and 300 mmol)
and the extreme ease of product isolation.
With the establishment of a robust and convenient tet-
raoxobispidine synthesis, our approach to R-isosparteine
continued uneventfully by electrophilic alkylation of both
nitrogen-atoms of 6 with allyl bromide. Owing to the
insolubility of bisimide 6 in most organic solvents, the
allylation reaction was conducted in DMF. Following a
standard workup procedure, crystalline N,N′-diallyltetraoxo-
bispidine 7 was obtained in pure form by trituration with
of the Grignard reagent to 7 in chilled THF solvent resulted
in a remarkably regioselective diallylation reaction and
afforded a tetraene compound (8) which was adjudged to
be C
2
-symmetric on the basis of NMR analysis.26 No other
isomers were evident in the crude product mixture and
recrystallization from hexanes gave 8 in 77% yield. Double
(26) Whether the hydroxyl groups in 8 are both exo or both endo has
not been determined; however, we presume that they are configurated endo
as illustrated based on steric considerations.
Org. Lett., Vol. 7, No. 21, 2005
4723

RCM of the tetraene 8 was sluggish, requiring over 24 h
and the portionwise addition of 4 mol % of Grubbs’ first-
generation ruthenium alkylidene catalyst,27 but eventually
delivered sparteine derivative 9 in an acceptable yield on a
ceed beyond intermediate 9 due to the poor solubility of this
rigid tetracycle in 1,2-dichloroethane.
Finally, (()-R-isosparteine (dl-1) was generated from 10
by exhaustive reduction with borane tetrahydrofuran com-
plex. The free-base of dl-1 was isolated as a hydrate which
readily crystallized from an alkaline solution during workup.
The identity of our synthetic material was confirmed by
comparison to literature data reported for dl-131 and l-1.
The stereochemical outcome of the concluding step in our
synthesis was anticipated on the basis that acyl iminium ions
generated by formal loss of hydroxide from 10 would suffer
2
8
10 mmol scale. The tetracyclic product precipitated as it
was formed and was isolated directly by filtration of the
reaction mixture. Interestingly, while NMR spectral analysis
suggested that this material had retained the C -symmetry
2
32
of its parent, X-ray analysis indicated otherwise, and revealed
an asymmetric configuration for 9 in the solid state (Figure
2
9
3).
3
3
exo attack from exogenous hydride species.
In summary, a racemic synthesis of R-isosparteine (dl-1)
from an easily prepared tetraoxobispidine derivative 7 has
been demonstrated. The alkaloid was ultimately fabricated
from three inexpensive carbon sources (dimethyl malonate,
paraformaldehyde, and allyl bromide) by a short sequence
of simple synthetic operations, none of which required a
chromatographic purification stage. Efforts to access sparteine
and â-isosparteine along similar lines are in progress,34 as
are studies directed at the enantiocontrolled desymmetrization
of tetraoxobispidines for the purpose of rendering these novel
alkaloid syntheses enantioselective.
We predict that tetraoxobispidines 4 will find further
applications as versatile synthons for the preparation of other
valuable target molecules containing bispidine nuclei.
Figure 3. ORTEP diagram for 9. 50% probability ellipsoids are
plotted for non-hydrogen atoms.
Acknowledgment. Oregon State University, the Univer-
sity of Leeds, and Eli Lilly & Co. Ltd. are thanked for
financial support. N.R.N. thanks the University of Leeds for
a Henry Ellison scholarship and Eli Lilly & Co. Ltd. for a
CASE award.
Hydrogenation of diene 9 in aqueous methanol resulted
in saturation of its olefinic moieties and gave the expected
product (10) in high yield. In this case, NMR analysis clearly
indicated an asymmetric anomeric configuration for the
bishemiaminal which was isolated as a single isomer by
trituration. An attempt to fashion 10 more directly from 8
by tandem olefin metathesis/hydrogenation30 failed to pro-
Supporting Information Available: Experimental pro-
1
cedures, characterization data, and H NMR spectra for all
compounds. CIF files for 7 and 9. This material is available
free of charge via the Internet at http://pubs.acs.org.
(
27) Schwab, P. E.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
18, 100.
28) It is worth noting that tetracycle 9 could potentially be generated
OL0519184
1
(
(30) Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2001,
123, 11312.
in enantioenriched form by kinetic resolution of 8 using a chiral metathesis
catalyst. For an example of enantioselective olefin metathesis, see: van
Veldhuizen, J. J.; Garber, S. B.; Kingsbury, J. S.; Hoveyda, A. H. J. Am.
Chem. Soc. 2002, 124, 4954.
(31) dl-1: mp 74-75 °C (H2O) [lit.1 mp 76-79 °C]. dl-1‚C6H3N3O7
4c
13b
(monopicrate salt): mp 124-125 °C (EtOH) [lit. mp 132.5-133.5 °C
(EtOH)].
(
29) The 13C NMR spectrum (75 MHz) for 9 collected in DMSO-d6 at
(32) 13C NMR data for dl-1 prepared from 7 were essentially identical
to those reported for l-1 by Galasso et al.; see: Galasso, V.; Asaro, F.;
Berti, F.; Kovac, B.; Habus, I.; Sacchetti, A. Chem. Phys. 2003, 294, 155.
(33) Harrison and O’Brien have observed that related bispidine-type acyl
iminium ions experience nucleophilic attack exclusively from their open
exo faces; see: Harrison, J. R.; O’Brien, P. Tetrahedron Lett. 2000, 41,
6167.
ambient temperature showed eight peaks, as expected for a symmetric
structure. The H NMR spectrum for 9 (300 MHz, DMSO-d6) was broad,
but also suggestive of C2-symmetry (see the Supporting Information). The
apparent discrepancy between solution- and solid-state structures for 9 is
explicable by a number of arguments. Either a symmetric anomer of 9
equilibrates to the asymmetric form only upon crystallization or the two
1
(
indistinguishable) asymmetric forms for 9 are in rapid dynamic equilibrium
(34) Strategic reversal in allylation and reduction of 7 leads in principle
to â-isosparteine stereochemistry. Isomerization of â-isosparteine to sparteine
is known; see ref 15.
in solution. A third possibility, that NMR is a poor indicator of molecular
symmetry for this molecule, seems less likely.
4724
Org. Lett., Vol. 7, No. 21, 2005