A Two-Directional Synthesis of (+)-β-Isosparteine

Article abstract of DOI:10.1021/acs.orglett.7b01475

A two-directional synthesis of (+)-β-isosparteine is described in five steps from glutaric acid, where the entire carbon and nitrogen backbone of the alkaloid, possessing the requisite relative and absolute stereochemistry at its four stereogenic centers, is assembled using a double imino-aldol reaction.

Full text of DOI:10.1021/acs.orglett.7b01475

Letter
pubs.acs.org/OrgLett
A Two-Directional Synthesis of (+)-β-Isosparteine
Firas M. Al-Saffar and Richard C. D. Brown*
Department of Chemistry, University of Southampton, Southampton, Hampshire SO17 1BJ, U.K.
S
* Supporting Information
ABSTRACT: A two-directional synthesis of (+)-β-isosparteine is
described in five steps from glutaric acid, where the entire carbon
and nitrogen backbone of the alkaloid, possessing the requisite
relative and absolute stereochemistry at its four stereogenic
centers, is assembled using a double imino-aldol reaction.
parteine alkaloids represent a subset of a larger group of
quinolizidine-containing alkaloids known as lupinus or
lupin alkaloids due to their widespread occurrence as secondary
metabolites in lupins.1 Both enantiomeric forms of sparteine
((−)-1 and (+)-1) are present in nature,2 as are the less
abundant C2 symmetrical diastereoisomers (−)-α- and (−)-β-
isosparteine (3 and 2, respectively, Figure 1).3 The enantiomers
ble diastereoisomeric sparteine alkaloids 1−3 may also be
considered to possess “syn” or “anti” relationships between
adjacent stereogenic centers based upon their synthetic origin
from amino-aldols (Figures 1 and 2). For example, C6/C7 and
S
Figure 2. Two-directional synthesis approach to (+)-β-isosparteine.
C9/C11 have “syn” and “anti” relationships in sparteine, while
the relative relationships are both “syn” in (+)-β-isosparteine
((+)-2). Here we show how a two-directional, syn-selective,
double imino-aldol reaction can be applied to achieve a short
synthesis of (+)-β-isosparteine.
Previous studies from our laboratory involving imino-aldol
reactions of tert-butanesulfinimines showed that lithium
enolates of phenyl esters underwent addition to alkyl- and
alkenyl-substituted tert-butanesulfinimines with good to ex-
cellent diastereoselectivity.13 Furthermore, these imino-aldol
reactions tolerated a reasonable variety of functionalization in
both ester and sulfinimine substrates. Our starting point for the
current work was to explore whether this methodology could
be used in a two-directional approach to the C2-symmetrical
tetracyclic lupin alkaloid (+)-β-isosparteine. Deprotonation of
diphenyl glutarate (7) with 2.2 equiv of LDA in THF at −78
°C (Scheme 1), followed by treatment with 2 equiv of tert-
butanesulfinimine 8, yielded the anticipated double imino-aldol
9, isolated in diastereoisomerically pure form in 30% yield, and
containing the entire skeleton of (+)-β-isosparteine with the
requisite relative and absolute stereochemistry. Other reaction
components included a cyclized single syn imino aldol 10
(16%), and an unseparated mixture of cyclized and uncyclized
minor double imino aldol stereoisomers. Further details and
stereochemical assignments for the minor components can be
found in the Supporting Information.
Figure 1. Structures of sparteine stereoisomers and simple
quinolizidine alkaloids.
of sparteine are valued by organic chemists for a diversity of
applications as chiral diamines in asymmetric synthesis,4
although supply issues have stimulated interest in the
development of surrogates.4e,5 Reported bioactivity is also
dominated by the more available stereoisomer,1d and
(−)-sparteine even found clinical applications, for example as
an oxytocic agent,6,7 although its FDA approved drug status was
withdrawn due to safety concerns. Comparatively less is known
about the more scarce C2 symmetrical isomers in terms of
either pharmacology8 or synthetic applications as ligands.4f,9
There have been racemic total syntheses of α- and β-
isosparteine, and enantiomerically enriched α- and β-stereo-
isomers have been obtained from synthetic conversions of
other sparteine alkaloids.10−12
We have shown that simple quinolizidine alkaloids, such as
epilupinine 3, possessing a “syn” relationship are conveniently
accessible using syn-selective imino-aldol reactions wherein
control of absolute stereochemistry is enabled through use of
tert-butanesulfinyl auxiliaries.13−16 Stereochemically, the possi-
Received: May 16, 2017
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.7b01475
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(+)-10,17-dioxo-β-isosparteine ((+)-12) was formed in 81%
yield as a crystalline solid. Single crystal X-ray analysis allowed
confirmation of the structure 12.
Scheme 1. Double Imino−aldol Reaction of Diphenyl
Glutarate Giving the Acyclic Carbon Skeleton of (+)-β-
Isosparteine
The natural product, (+)-β-isosparteine, was obtained in high
yield following LiAlH4 reduction of bis lactam (+)-12. It was
also possible to obtain (+)-β-isosparteine directly from 11, by
LiAlH4 reduction, although the isolation of pure product was
complicated by the presence of byproducts arising from
reduction of the chloroalkyl groups. Hence, the two-step
protocol was favored, providing the synthetic (+)-β-isospar-
teine with physical and spectroscopic data in good agreement
with reported values.
In conclusion, we have reported a short synthesis of the C2-
symmetrical alkaloids (+)-10,17-dioxo-β-isosparteine and β-
isosparteine over four and five steps, respectively, from glutaric
acid. The carbon framework with all four stereogenic centers
was created in a single reaction step through implementation of
a two-directional double imino-aldol reaction of diphenyl
glutarate with tert-butanesulfinimine 8.
Stereochemical assignment of double imino-aldol 9 was
confirmed by X-ray structure determination of an intermediate
later in the synthesis (Figure 3), and ultimately through its
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01475.
Figure 3. X-ray structure of (+)-10,17-dioxo-β-isosparteine ((+)-12).
Crystallographic data (CIF, CIF, CIF, CIF)
Experimental details and procedures; compound charac-
terization data; stereochemical assignment; X-ray struc-
tural data for 10, (+)-12, SI1, SI5; and copies of 1H and
13C NMR spectra for all new compounds (PDF)
Scheme 2. Total Syntheses of (+)-10,17-Dioxo-β-
isosparteine and (+)-β-Isosparteine
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: rcb1@soton.ac.uk.
ORCID
Richard C. D. Brown: 0000-0003-0156-7087
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge financial support from EPSRC (EP/
K039466/1) and the Iraqi Ministry for Higher Education and
Scientific Research (sponsorship of F.M.A.-S.)
conversion to (+)-β-isosparteine (Scheme 2). The structure of
lactam 10 was confirmed directly using X-ray crystallography,
and the configuration of the newly formed stereogenic centers
in both compounds is consistent with a six-centered chairlike
transition state model.13,15b Thus far we have not been able to
improve upon the yield of the double imino-aldol 9, although
the conditions could be biased to produce N-sulfinyl δ-lactam
10 in 51% yield when the bis enolate of 7 was reacted with a
reduced quantity of imine 8 (0.8 equiv).
In view of the fact that the complete acyclic carbon skeleton
of (+)-β-isosparteine had been created in a single reaction,
along with all of its stereochemical complexity, we considered
the somewhat modest yield of 9 satisfactory for progression
with the total synthesis. In fact, only three steps were required
to access (+)-β-isosparteine from 9 (Scheme 2). Cleavage of
the tert-butanesulfinyl groups from double imino-aldol 9 and
cyclization were effected using molecular iodine followed by
neutralization with bicarbonate to give the enantiomerically
enriched 2,6-dioxobispidine 11. Under basic conditions, and in
the presence of tertabutylammonium bromide (TBAB),
REFERENCES
■
(1) For the most recent in a series of reviews of indolizidine and
quinolizidine alkaloids: (a) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139.
General background: (b) Boshin, G.; Resta, D. Alkaloids derived from
lysine: Quinolizidine (a focus on lupin alkaloids). In Natural Products,
Phytochemistry, Botany and Metabolism of Alkaloids, Phenolics and
́
Terpenes, 2nd ed.; Ramawat, K. G., Merillon, J.-M., Eds.; Springer:
Heidelberg, Germany, 2013; pp 381−403. (c) Ohmiya, S.; Saito, K.;
Murakoshi, I. Lupine Alkaloids. In The Alkaloids: Chemistry and
Pharmacology; Cordell, G. A., Ed.; Academic Press: New York, 1995;
Vol. 47, pp 1−114. (d) Kinghorn, A. D.; Balandrin, M. F.
Quinolizidine Alkaloids of the Leguminosae: Structural Types,
Analysis, Chemotaxonomy and Biological Activities. In Alkaloids:
Chemical and Biological Perspectives; Pelletier, S. W., Ed.; John Wiley &
Sons: New York, 1984; Vol. 2, pp 105−148.
(2) For selected papers describing isolation of sparteine enan-
tioisomers: (−)-Sparteine: (a) Stenhouse, J. Ann. 1851, 78, 1.
(b) Marion, L.; Turcotte, F.; Ouellet, J. Can. J. Chem. 1951, 29, 22.
B
DOI: 10.1021/acs.orglett.7b01475
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(+) Sparteine: (c) Orechoff, A.; Rabinowitch, M.; Konowalowa, R. Ber.
Dtsch. Chem. Ges. B 1933, 66, 621. Structure elucidation of (−)
sparteine: (d) Clemo, G. R.; Raper, R. J. Chem. Soc. 1933, 644.
Absolute configuration: (e) Okuda, S.; Kataoka, H.; Tsuda, K. Chem.
Pharm. Bull. 1965, 13, 491.
(3) Isolation of (−)-α-isosparteine: See ref 2b and (a) Keller, W. J.;
Meyer, B. N.; McLaughlin, J. L. J. Pharm. Sci. 1983, 72, 563. Isolation
of pusilline ((−)-β-isosparteine): (b) Marion, L.; Fenton, S. W. J. Org.
Chem. 1948, 13, 780. (c) Greenhalgh, R.; Marion, L. Can. J. Chem.
1956, 34, 456. Isolation of l-spartalupine ((−)-β-isosparteine):
(d) Carmack, M.; Douglas, B.; Martin, E. W.; Suss, H. J. Am. Chem.
Soc. 1955, 77, 4435.
(4) For selected articles describing applications of sparteine in
synthesis: (a) Chuzel, O.; Riant, O. Top. Organomet. Chem. 2005, 15,
59. (b) Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan,
S. Acc. Chem. Res. 1996, 29, 552. (c) Hoppe, D.; Hense, T. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2282. (d) Boczon, W. Heterocycles 1992,
33, 1101. (e) Mitchell, E. A.; Peschiulli, A.; Lefevre, N.; Meerpoel, L.;
Maes, B. U. W. Chem. - Eur. J. 2012, 18, 10092. (f) Breuning, M.;
Steiner, M. Synthesis 2008, 2008, 2841. (g) Rouden, J.; Lasne, M. C.;
Blanchet, J.; Baudoux, J. Chem. Rev. 2014, 114, 712.
(5) (a) Dearden, M. J.; Firkin, C. R.; Hermet, J. P. R.; O’Brien, P. J.
Am. Chem. Soc. 2002, 124, 11870. (b) Hermet, J. P. R.; Porter, D. W.;
Dearden, M. J.; Harrison, J. R.; Koplin, T.; O’Brien, P.; Parmene, J.;
Tyurin, V.; Whitwood, A. C.; Gilday, J.; Smith, N. M. Org. Biomol.
Chem. 2003, 1, 3977. (c) Phuan, P. W.; Ianni, J. C.; Kozlowski, M. C. J.
Am. Chem. Soc. 2004, 126, 15473. (d) O’Brien, P. Chem. Commun.
2008, 655.
(12) Syntheses of sparteine. Enantioselective: (a) Smith, B. T.;
Wendt, J. A.; Aube, 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. Diastereoselective: Reference 10b and (c) Bohlmann, F.;
Muller, H. J.; Schumann, D. Chem. Ber. 1973, 106, 3026. (d) Buttler,
T.; Fleming, I.; Gonsior, S.; Kim, B. H.; Sung, A. Y.; Woo, H. G. Org.
Biomol. Chem. 2005, 3, 1557. Mixtures of stereoisomers: Reference
10e−10g.
(13) (a) Watkin, S. V.; Camp, N. P.; Brown, R. C. D. Org. Lett. 2013,
15, 4596. (b) Cutter, A. C.; Miller, I. R.; Keily, J. F.; Bellingham, R. K.;
Light, M. E.; Brown, R. C. D. Org. Lett. 2011, 13, 3988.
(14) For a related approach to quinolizidines employing an auxiliary
derived enolate: Nagao, Y.; Dai, W. M.; Ochiai, M.; Tsukagoshi, S.;
Fujita, E. J. Org. Chem. 1990, 55, 1148.
(15) For selected examples of imino−aldol reactions of sulfinimines,
see: (a) Davis, F. A.; Reddy, R. T.; Reddy, R. E. J. Org. Chem. 1992, 57,
6387. (b) Tang, T. P.; Ellman, J. A. J. Org. Chem. 2002, 67, 7819.
(c) Wen, S.; Carey, K. L.; Nakao, Y.; Fusetani, N.; Packham, G.;
Ganesan, A. Org. Lett. 2007, 9, 1105. (d) Davis, F. A.; Song, M. Org.
Lett. 2007, 9, 2413.
(16) For reviews of sulfinimines in synthesis: (a) Zhou, P.; Chen, B.
C.; Davis, F. A. Tetrahedron 2004, 60, 8003. (b) Morton, D.;
Stockman, R. A. Tetrahedron 2006, 62, 8869. (c) Ferreira, F.; Botuha,
C.; Chemla, F.; Perez-Luna, A. Chem. Soc. Rev. 2009, 38, 1162.
(d) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110,
3600. (e) Edupuganti, R.; Davis, F. A. Org. Biomol. Chem. 2012, 10,
5021.
(6) Munsick, R. A. Am. J. Obstet. Gynecol. 1965, 93, 442.
(7) Traditional herbal remedies composed of the dried flowers of
Broom contain (−)-sparteine as the major bioactive alkaloid
component. Barnes, J.; Anderson, L. A.; Phillipson, J. D.; Broom
Herbal Medicines, 3rd ed.; Pharmaceutical Press: London, U.K., 2007;
pp 98−99.
(8) (a) Kim, I. C.; Balandrin, M. F.; Kinghorn, A. D. J. Agric. Food
Chem. 1982, 30, 796. (b) Lisevitskaya, L. I.; Bandyukova, V. A.;
Shinkarenko, A. L. Biol. Nauki. 1972, 11, 50.
(9) (a) Trend, R. M.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130,
15957. (b) Hodgson, D. M.; Galano, J. M.; Christlieb, M. Tetrahedron
2003, 59, 9719. (c) Muller, P.; Nury, P.; Bernardinelli, G. Eur. J. Org.
Chem. 2001, 2001, 4137. X-ray structure of Cu(II) complex with
(−)-β-isosparteine: (d) Childers, L. S.; Folting, K.; Merritt, L. L.;
Streib, W. E. Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem.
1975, 31, 924. X-ray structure of Cu(II) complex with (−)-α-
isosparteine: (e) Kim, B. J.; Lee, Y. M.; Kim, E. H.; Kang, S. K.; Choi,
S. N. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2002, 58, M361−
M362.
(10) Diastereocontrolled syntheses of ( )-β-isosparteine: (a) Blake-
more, P. R.; Norcross, N. R.; Warriner, S. L.; Astles, P. C. Heterocycles
2006, 70, 609. (b) Norcross, N. R.; Melbardis, J. P.; Solera, M. F.;
Sephton, M. A.; Kilner, C.; Zakharov, L. N.; Astles, P. C.; Warriner, S.
L.; Blakemore, P. R. J. Org. Chem. 2008, 73, 7939. Stereocontrolled
syntheses of ( )-α-isosparteine: Reference 10b and (c) Blakemore, P.
R.; Kilner, C.; Norcross, N. R.; Astles, P. C. Org. Lett. 2005, 7, 4721.
(d) Oinuma, H.; Dan, S.; Kakisawa, H. J. Chem. Soc., Perkin Trans. 1
1990, 2593. For examples of syntheses where mixtures of α- and/or β-
stereoisomers were obtained, see ref 3d and (e) Wanner, M. J.;
Koomen, G. J. J. Org. Chem. 1996, 61, 5581. (f) Leonard, N. J.; Beyler,
R. E. J. Am. Chem. Soc. 1950, 72, 1316. (g) Sorm, F.; Keil, B. Collect.
Czech. Chem. Commun. 1948, 13, 544.
(11) For examples of interconversions of α- and/or β-isosparteines
with other sparteine alkaloids: References 2b, 3c, 9a, 10f, and
(a) Winterfeld, K.; Rauch, C. Arch. Pharm. 1934, 272, 273.
(b) Cockburn, W. F.; Marion, L. Can. J. Chem. 1951, 29, 13.
(c) Moore, B. P.; Marion, L. Can. J. Chem. 1953, 31, 187.
(d) Galinovsky, F.; Knoth, P.; Fischer, W. Monatsh. Chem. 1955, 86,
1014. (e) Winterfeld, K.; Bange, H.; Lalvani, K. S. Ann. Chem. 1966,
698, 230.
C
DOI: 10.1021/acs.orglett.7b01475
Org. Lett. XXXX, XXX, XXX−XXX