Concise asymmetric synthesis of (-)-sparteine

Article abstract of DOI:10.1039/b406632d

A six-step asymmetric synthesis of natural (-)-sparteine from ethyl 7-iodohept-2-enoate is reported, involving a connective Michael addition of an amino ester-derived enolate to an α,β-unsaturated amino ester.

Full text of DOI:10.1039/b406632d

Concise asymmetric synthesis of (2)-sparteine†
Jean-Paul R. Hermet,a Matthew J. McGrath,a Peter O’Brien,*a David W. Portera and John Gildayb
a Department of Chemistry, University of York, Heslington, York, UK YO10 5DD.
E-mail: paob1@york.ac.uk; Fax: +44 (0)1904 432516; Tel: +44 (0)1904 432535
b AstraZeneca, Process R & D, Avlon Works, Severn Road, Hallen, Bristol, UK BS10 7ZE
Received (in Cambridge, UK) 5th May 2004, Accepted 2nd June 2004
First published as an Advance Article on the web 21st July 2004
A six-step asymmetric synthesis of natural (2)-sparteine from
ethyl 7-iodohept-2-enoate is reported, involving a connective
Michael addition of an amino ester-derived enolate to an a,b-
unsaturated amino ester.
which we imagined would be prepared from bicyclic amino ester 3.
Amino ester 3 is a 1,5-dicarbonyl compound which would be
constructed from the union of the enolate of amino ester (R)-4 with
Michael acceptor 5 (itself prepared from amino ester (S)-4). An
important design feature in this route to (2)-sparteine 1 was the
anticipated stereocontrol in the Michael reaction. Alkylations of
enolates of cyclic b-amino esters 4 (R = Boc8 and R = a-
methylbenzyl9) are known to give the required Ca–Cb relative
stereochemistry (syn stereochemistry of Ca and Cb hydrogens as
drawn—see 3) and enolate reaction with an a,b-unsaturated ester
was expected to proceed with similar Ca–Cb stereocontrol.
Furthermore, stereoselective protonation of the Michael adduct
enolate should proceed under analogous stereocontrol to furnish the
desired Cc–Cd stereochemistry (anti stereochemistry of Cc and Cd
hydrogens—see 3). At the outset, we imagined preparing b-amino
esters (R)- and (S)-4 (R = a-methylbenzyl) using our previously
published three-step route from ethyl 7-chlorohept-2-enoate, based
on Davies-style lithium amide conjugate addition.10 However, in
the end, we developed a stereoselective version of a reaction
introduced by Bunce et al.11 in which ethyl 7-iodohept-2-enoate 6
was converted into b-amino ester 4 (R = a-methylbenzyl) in one
step.
(2)-Sparteine 1, a cardiovascular agent,1 is the most well-known of
the naturally occurring lupin alkaloids2 due to its widespread use as
a chiral ligand in asymmetric synthesis.3 Following on from our
recent work on the synthesis of sparteine analogues4 (culminating
in the introduction of a (+)-sparteine surrogate5), we became
intrigued by (2)-sparteine as a target molecule in its own right. In
particular, we envisaged developing a general, concise and
connective methodology for the preparation of lupin alkaloids; the
total asymmetric synthesis of (2)-sparteine was seen as a
challenging test-bed of the new methodology. The route should also
be adaptable to the synthesis of new “designer” sparteine analogues
for use as chiral ligands.
The three-step synthesis of Michael acceptor 10 is shown in
Scheme 2. First of all, reaction of known12 ethyl 7-iodohept-
2-enoate 6 with (R)-a-methylbenzylamine (EtOH, Et3N, reflux, 16
h) gave cyclic b-amino esters 7 and 8 directly, presumably via
substitution and subsequent intramolecular conjugate addition of
the amine (as proposed by Bunce et al. for the benzylamine
reaction11). The stereochemistry of 7 and 8 was assigned as shown
since we had previously prepared ent-8 via a different route.10
Although seven different approaches to racemic sparteine (albeit
with little or no control of relative stereochemistry) have been
described over the last fifty years,6 only one asymmetric synthesis
is known. In 2002, Aubé and co-workers reported an elegant
synthetic sequence that delivered (+)-sparteine in an efficient,
15-step route.7 Herein, we report a new approach to the lupin
alkaloids: natural (2)-sparteine 1 was prepared in just six steps
from ethyl 7-iodohept-2-enoate. The key feature of the route is a
connective, Michael reaction between an amino ester-derived
enolate and an a,b-unsaturated amino ester.
1
Although the stereocontrol in this reaction ( ~ 2 : 1 from the H
NMR spectrum of the crude product) was moderate,13 amino esters
7 and 8 were readily separable by column chromatography and this
allowed us to easily progress gram quantities of the major product
7 (45% isolated yield) for our synthetic endeavours. Attempts to
improve the yield of 7 via acid- or base-mediated epimerisation of
8 have so far proved fruitless. Nonetheless, cyclic amino esters such
as 7 are well established synthetic building blocks8,9 and the one-
Our retrosynthetic analysis of (2)-sparteine 1 is shown in
Scheme 1. The direct precursor to (2)-1 is tetracyclic bislactam 2
Scheme 1 Retrosynthetic analysis of (2)-sparteine 1.
Scheme 2 Reagents and conditions: (i) (R)-a-methylbenzylamine, Et3N,
EtOH, reflux, 16 h. (ii) (a) 1.5 equiv. LHMDS, THF, 278 °C, 1 h; (b)
EtOCH2Cl, 278 °C ? rt over 4 h; (c) rt, 12 h. (iii) 1.2 equiv. KOtBu, THF,
278 °C, 8.5 h.
† Electronic supplementary information (ESI) available: full experimental
procedures/data for 7, 8, ent-7, ent-8, 9, 10, 2 and (2)-1. See http://
www.rsc.org/suppdata/cc/b4/b406632d/
1830
C h e m . C o m m u n . , 2 0 0 4 , 1 8 3 0 – 1 8 3 1
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

step direct asymmetric synthesis of amino ester 7 could prove to be
a useful methodology for alkaloid natural product synthesis.
Next, amino ester 7 was alkylated using LHMDS and EtOCH2Cl
to give a 94% yield of adduct 9. Adduct 9 was obtained as a single
diastereomer and, although of no consequence to the present work
(as this stereochemical feature would subsequently be removed),
the stereochemistry was assigned by analogy with other alkylations
of ent-7 reported by Lhommet et al.9 Elimination of ethoxide from
9 using a procedure slightly modified from that reported by Sworin
and Lin14 (KOtBu, THF, 278 °C) then gave Michael acceptor 10
(65% yield) (Scheme 2).
For the key Michael reaction, we proposed to combine the
enolate of amino ester ent-7 (prepared in 46% yield from (S)-a-
methylbenzylamine and iodo ester 6 according to the method
described above) with a,b-unsaturated amino ester 10. Surpris-
ingly, we were unable to find many examples of the Michael
addition of monoester-derived enolates to a,b-unsaturated es-
ters.15–18 Adaptation of two of these protocols15,16 led to a
successful reaction with our system (Scheme 3).
We thank Astra-Zeneca for funding (J.-P. R. H.), the EPSRC and
GlaxoSmithKline for an industrial CASE award (D. W. P.) and the
EPSRC for postdoctoral support (M. J. M).
Notes and references
1 R. Seeger and H. G. Neumann, Inst. Pharmakol. Toxikol., 1992, 132,
1577.
2 J. P. Michael, Nat. Prod. Rep., 2003, 20, 458.
3 For a review, see: D. Hoppe and T. Hense, Angew. Chem., Int. Ed. Engl.,
1997, 36, 2282.
4 J. R. Harrison, P. O’Brien, D. W. Porter and N. M. Smith, J. Chem. Soc.,
Perkin Trans. 1, 1999, 3623; J. R. Harrison and P. O’Brien, Tetrahedron
Lett., 2000, 41, 6167.
5 M. J. Dearden, C. R. Firkin, J.-P. R. Hermet and P. O’Brien, J. Am.
Chem. Soc., 2002, 124, 11870.
6 G. R. Clemo, R. Raper and W. S. Short, J. Chem. Soc., 1949, 663; N. J.
Leonard and R. E. Beyler, J. Am. Chem. Soc., 1950, 72, 1316; E. F. L.
J. Anet, G. K. Hughes and E. Ritchie, Aust. J. Sci. Res., 1950, 3A, 635;
E. E. van Tamelen and R. Foltz, J. Am. Chem. Soc., 1969, 91, 7272; F.
Bohlmann, H.-J. Müller and D. Schumann, Chem. Ber., 1973, 106,
3026; N. Takatsu, M. Noguchi, S. Ohmiya and H. Otomasu, Chem.
Pharm. Bull., 1987, 35, 4990; M. J. Wanner and G.-J. Koomen, J. Org.
Chem., 1996, 61, 5581.
7 B. T. Smith, J. A. Wendt and J. Aubé, Org. Lett., 2002, 4, 2577.
8 C. Morley, D. W. Knight and A. C. Share, J. Chem. Soc., Perkin Trans.
1, 1994, 2903.
9 S. Ledoux, J.-P. Célérier and G. Lhommet, Tetrahedron Lett., 1999, 40,
9019; S. Ledoux, E. Marchalant, J.-P. Célérier and G. Lhommet,
Tetrahedron Lett., 2001, 42, 5397.
10 P. O’Brien, D. W. Porter and N. M. Smith, Synlett, 2000, 1336. For a
related route, see: A. M. Chippindale, S. G. Davies, K. Iwamoto, R. M.
Parkin, C. A. P. Smethurst, A. D. Smith and H. Rodriguez-Solla,
Tetrahedron, 2003, 59, 3253.
11 R. A. Bunce, C. J. Peeples and P. B. Jones, J. Org. Chem., 1992, 57,
1727.
Amino ester ent-7 was deprotonated using LDA and the resulting
enolate was allowed to react with Michael acceptor 10 at 278 °C ?
230 °C for 8.5 hours in total before quenching with 1 M HCl(aq) at
0 °C.16 After work-up and purification by column chromatography,
we isolated an inseparable mixture ( ~ 3 : 2) of adduct 3 and amino
ester ent-7. From close inspection of the 1H and 13C NMR spectra
of this mixture, adduct 3 appears to be generated as a single
diastereomer (stereochemistry assigned based on our earlier
analysis of the expected stereocontrol19 and on subsequent
conversion into (2)-sparteine 1). As it was not possible to obtain a
pure sample of 3, all of the ~ 3 : 2 mixture of 3 and ent-7 was
2
subjected to transfer hydrogenation (Pd(OH)2/C, NH4+HCO2
,
EtOH, reflux, 14 h). Under these conditions, hydrogenolysis of the
a-methylbenzyl groups followed by cyclisation occurred to give
bislactam 2 (single diastereomer) in 36% yield over the two steps
from ent-7 (isolated by crystallisation from Et2O). Finally, lithium
aluminium hydride reduction of bislactam 2 gave (2)-sparteine 1
{[a]D 218.1 (c 1.3 in EtOH); [a]D 218.0 (c 1.3 in EtOH) recorded
for an authentic sample} in 88% yield after distillation, identical by
1H and 13C NMR spectroscopy to an authentic sample (Scheme
3).
In summary, a concise, six-step asymmetric synthesis of
(2)-sparteine has been completed. This methodology represents a
new approach to the lupin alkaloid family and could be adapted to
complete total syntheses of other lupin alkaloids (e.g. lupanine and
multiflorine2). Of note, our chiral auxiliary-based approach is also
suitable for the synthesis of (+)-sparteine and for the synthesis of
either enantiomer of novel sparteine analogues (for evaluation as
chiral ligands for asymmetric synthesis).
12 Ethyl 7-iodohept-2-enoate 6 was prepared in 82% yield over three steps
from 5-chloropentanol. See: R. W. Hoffmann, T. Sander and A. Hense,
Liebigs Ann. Chem., 1993, 771; M. P. Cooke and R. K. Widener, J. Org.
Chem., 1989, 52, 1381; ref. 11.
13 The 2 : 1 stereoselectivity observed in the conversion of iodo ester 6 into
amino esters 7 and 8 can be rationalised in the following way. Based on
the original work of Bunce et al. (see ref. 11), it is reasonable to assume
that intermolecular SN2 substitution of the iodide precedes the
cyclisation and hence, two competing transition states for cyclisation
can be constructed: A ? 7 and B ? 8. In both A and B, the a-
methylbenzyl substituent is arranged so that the hydrogen occupies the
most sterically hindered “inside” position. The major product 7 arises
from transition state A in which the larger phenyl group minimises its
steric clash with the axial hydrogen on C*. We briefly investigated the
use of other chiral amines but were unable to improve on the 2 : 1
stereoselectivity.
14 M. Sworin and K.-C. Lin, J. Am. Chem. Soc., 1989, 111, 1815.
15 M. Yamaguchi, M. Tsukamoto and I. Hirao, Chem. Lett., 1984, 375.
16 I. T. Barnish, M. Corless, P. J. Dunn, D. Ellis, P. W. Finn, J. D.
Hardstone and K. James, Tetrahedron Lett., 1993, 34, 1323; P. J. Dunn,
M. L. Highes, P. M. Searle and A. S. Wood, Org. Process Res. Dev.,
2003, 7, 244.
17 D.-P. Jang, J.-W. Chang and B.-J. Uang, Org. Lett., 2001, 3, 983.
18 For a related intramolecular Michael addition, see: J. G. Urones, N. M.
Garrido, D. Díez, S. H. Dominguez and S. G. Davies, Tetrahedron:
Asymmetry, 1997, 8, 2683.
19 In a model study, enolate 11 added to ent-10 to give 83% of a ~ 9 : 1
diastereomeric mixture of Michael adducts (major assigned as 12 based
on the relative stereocontrol in the (2)-sparteine synthesis).
Scheme 3 Reagents and conditions: (i) (a) 1.05 equiv. LDA, THF, 278 °C
for 20 min, 0 °C for 5 min then to 278 °C for 30 min; (b) 1.0 equiv. Michael
acceptor 10; (c) 278 °C ? 230 °C over 5.5 h then 230 °C for 3 h; (d) 1
M HCl(aq); (ii) (a) Pd(OH)2/C, NH4+HCO22, EtOH, reflux, 14 h; (b)
crystallise from Et2O; (iii) LiAlH4, THF, reflux, 16 h.
C h e m . C o m m u n . , 2 0 0 4 , 1 8 3 0 – 1 8 3 1
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