Total syntheses of (-) epilupinine and (-)-tashiromine using imino-aldol reactions

Article abstract of DOI:10.1021/ol2015048

Short routes to enantiomerically pure indolizidine and quinolizidine alkaloids have been developed using imino-aldol reactions of enolates derived from phenyl 5-chlorovalerate. High levels of syn selectivity (dr ～13-16:1) were obtained using lithium enolates of phenyl esters in combination with tert-butylsulfinyl imines. The imino-aldol adducts were deprotected and cyclized to afford (-)-epilupinine ((-)-2) and (-)-tashiromine ((-)-1) in two further steps.

Full text of DOI:10.1021/ol2015048

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3988–3991
Total Syntheses of (ꢀ)
Epilupinine and (ꢀ)-Tashiromine
Using Imino-Aldol Reactions
Amanda C. Cutter,† Iain R. Miller,† John F. Keily,‡
Richard K. Bellingham,§ Mark E. Light,† and Richard C. D. Brown*,†
The School of Chemistry, The University of Southampton, Highfield, Southampton
SO17 1BJ, U.K., Prosidion Ltd., Transport Way, Cowley, Oxford OX4 6LT, U.K., and
Chemical Development, GlaxoSmithKline Pharmaceuticals, The Old Powder Mills,
Leigh, Tonbridge, Kent TN11 9AN, U.K.
rcb1@soton.ac.uk
Received June 3, 2011
ABSTRACT
Short routes to enantiomerically pure indolizidine and quinolizidine alkaloids have been developed using imino-aldol reactions of enolates
derived from phenyl 5-chlorovalerate. High levels of syn selectivity (dr ∼13ꢀ16:1) were obtained using lithium enolates of phenyl esters in
combination with tert-butylsulfinyl imines. The imino-aldol adducts were deprotected and cyclized to afford (ꢀ)-epilupinine ((ꢀ)-2) and (ꢀ)-
tashiromine ((ꢀ)-1) in two further steps.
(þ)-Tashiromine ((þ)-1) and (þ)-epilupinine ((þ)-2) are
5-hydroxymethylated indolizidine and quinolizidine alka-
loids respectively,1 possessing common relative and abso-
lute stereochemistry at C5 and C6 of their bicyclic ring
systems. (þ)-Tashiromine was first isolated in 1990 from
Maackia Tashoroi,2 whereas epilupinine has been known
for considerably longer. (þ)-Epilupinine was reported as a
product of the epimerzation of (þ)-lupinine,3 but it exists
naturally as a secondary metabolite in various members of
the lupin family.4 (þ)-Epilupinine has been shown to
exhibit in vitro inhibitory activity against Leukaemia
P-388 (LD50 = 28 μg/mL) and lymphocytic Leukaemia
L1210 (LD50 = 28 μg/mL) cells.5 Both natural products
(5) Hua, D. H.; Miao, S. W.; Bravo, A. A.; Takemoto, D. J. Synthesis
1991, 970–974.
† The University of Southampton.
(6) For selected asymmetric total syntheses of epilupinine: (a) Nagao,
Y.; Dai, W.-M.; Ochiai, M.; Tsukagoshi, S.; Fugita, E. J. Org. Chem.
1990, 55, 1148–1156. (b) West, F. G.; Naidu, B. N. J. Am. Chem. Soc.
1994, 116, 8420–8421. (c) Naidu, B. N.; West, F. G. Tetrahedron 1997,
53, 16565–16574. (d) Mangeney, P.; Hamon, L.; Rassou, S.; Urbain, N.;
Alexakis, A. Tetrahedron 1998, 54, 10349–10362. (e) Ma, S.; Ni, B.
Chem.;Eur. J. 2004, 10, 3286–3300. (f) Ahari, M.; Perez, A.; Menant,
C.; Vasse, J.-L.; Szymoniak, J. Org. Lett. 2008, 10, 2473–2376. (g) Su,
D. Y.; Wang, X. Y.; Shao, C. W.; Xu, J. M.; Zhu, R.; Hu, Y. F. J. Org.
Chem. 2011, 76, 188–194.
‡ Prosidion Ltd.
§ GlaxoSmithKline Pharmaceuticals.
(1) For the most recent in a series of reviews dealing with indolizidine,
and quinolizidine alkaloids: (a) Michael, J. P. Nat. Prod. Rep. 2008, 25,
139–165. For lupin alkaloids: (b) Ohmiya, S.; Saito, K.; Murakoshi, I.
In The Alkaloids: Chemistry and Pharmacology; Geoffrey, A. C., Ed.;
Academic Press: 1995; pp 1ꢀ114. (c) Saito, K.; Murakoshi, I. In Studies in
Natural Products Chemistry, Vol. 15: Structure and Chemistry, Part C;
Atta-ur-Rahman, Ed.; Elsevier Science B. V.: Amsterdam, Netherlands,
1995; pp 519ꢀ549.
(7) For selected asymmetric total syntheses of tashiromine, see ref 6a
and: (a) Gage, J. L.; Branchaud, B. P. Tetrahedron Lett. 1997, 38, 7007–
7010. (b) David, O.; Blot, J.; Bellec, C.; Fargeau-Bellassoued, M.-C.;
(2) Ohmiya, S.; Kubo, H.; Otomasu, H.; Saito, K.; Murakoshi, I.
Heterocycles 1990, 30, 537–542.
(3) For the epimerization of lupinine to epilupinine: (a) Winterfeld,
K.; Holschneider, F. W. Chem. Ber. 1931, 64, 137–150. (b) Sparatore, A.;
Tasso, B.; Boido, V.; Sparatore, F. Helv. Chim. Acta 2005, 88, 245–251.
(4) (a) White, E. P. N. Z. J . Sci. Technol., Sect. B 1951, 33, 50–54. (b)
Beck, A. B.; Goldspink, B. H.; Knox, J. R. J. Nat. Prod. 1979, 42, 385–
398.
ꢀ ꢀ
Haviari, G.; Celerier, J.-P.; Lhommet, G.; Gramain, J.-C.; Gardette, D.
J. Org. Chem. 1999, 64, 3122–3131. (c) Banwell, M.; Beck, D. A. S.;
Smith, J. A. Org. Biomol. Chem. 2004, 2, 157–159. (d) Dieter, R. K.;
Chen, N.; Watson, R. T. Tetrahedron 2005, 61, 3221–3230. (e) Conrad,
J. C.; Kong, J.; Laforteza, B. N.; MacMillan, D. W. C. J. Am. Chem. Soc.
2009, 131, 11640–11641.
r
10.1021/ol2015048
Published on Web 07/11/2011
2011 American Chemical Society

have been the focus of considerable synthetic attention and
have been prepared by total synthesis in racemic and
enantiomerically enriched form.5ꢀ9
Table 1. Influence of Ester Structure and Reaction Conditions
on the Stereoselectivity of the Imino-Aldol Reaction
Scheme 1. Imino-Aldol Approach to (ꢀ)-Tashiromine and (ꢀ)-
Epilupinine
As part of studies toward quinolizidine and indolizidine
containing natural products, we were attracted to an
approach centered on imino-aldol reactions of tert-buta-
nesulfinyl imines to correctly establish the required con-
figurations at C5 and C6 (Scheme 1).10,11 By incorporating
chloroalkyl chains into the reacting enolate and imine,
N-deprotection of the imino-aldol product would result in
direct double cyclization to produce the required indolizi-
dine and quinolizidine systems.12
drc
entry
R
conditionsa
yield (%)b
(10:11:12:13)
1
2
3
4
Me
Me
Ph
Ph
A
B
A
B
43
56
56
78
7:2:1:ꢀ
9:1:ꢀ:ꢀ
9:1:ꢀ:ꢀ
16:1:ꢀ:ꢀ
a Conditions A: (i) LDA, 6 or 9, THF, ꢀ78 °C; (ii) TiCl(OiPr)3; (iii)
imine 3. Conditions B: (i) LDA, 6 or 9, THF, ꢀ78 °C; (ii) imine 3.
b Combined yield of the indicated mixture of diastereomers isolated by
column chromatography. c dr estimated by integration of crude 1H
NMR for 10:11:12:13 respectively. “ꢀ” indicates that the isomer was
not observed in the crude 1H NMR spectra.
Scheme 2. Synthesis of Sulfinyl Imines
observed stereoisomers were identified as syn-adducts 10a,
12a (isolated as a mixture), and anti-aduct 11a respectively,
by elaboration to known compounds.14 In comparison to
propionate imino-aldol reactions, which are often highly
diastereoselective, modest levels of stereoselectivity have
been noted previously for imino-aldol reactions of methyl
and para-methoxybenzyl esters of functionalized straight-
chain carboxylic acids.10b,15,16
The diastereoselectivity and product distribution was
influenced significantly with respect to the choice of ester
The (S)-tert-butanesulfinyl imines3 and 4 were prepared
from the corresponding chloroalkyl esters 5 and 6 in two
steps (Scheme 2).13 Initial imino-aldol reaction between
titanium enolates derived from commercially available
methyl 5-chlorovalerate (6) and imine 3 gave a modest
level of diastereocontrol (entry 1, Table 1: dr = 7:2:1). The
(10) (a) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev.
2010, 110, 3600–3740. (b) Tang, T. P.; Ellman, J. A. J. Org. Chem. 2002,
67, 7819–7832.
(11) For examples of imino-aldol reactions of aryl N-sulfinyl imines:
(a) Davis, F. A.; Song, M. Org. Lett. 2007, 9, 2413–2416. (b) Davis, F. A.;
Edupuganti, R. Org. Lett. 2010, 12, 848–851.
(12) For some sequences involving additions of organometallic spe-
cies to tert-butylsulfinyl imines followed by cyclization: (a) Voituriez, A.;
(8) For selected examples of syntheses of racemic epilupinine: van
Tamelen, E. E.; Foltz, R. L. J. Am. Chem. Soc. 1969, 91, 7372–7377. (b)
Yamada, Y.; Hatano, K.; Matsui, M. Agr. Biol. Chem. 1971, 35, 285–
286. (c) Okita, M.; Wakanatsu, T.; Ban, Y. Heterocycles 1983, 20, 129–
129. (d) Beckwith, A. L. J.; Westwood, S. W. Tetrahedron 1989, 45,
5269–5282. (e) Molander, G. A.; Nichols, P. J. J. Org. Chem. 1996, 61,
6040–6043. (f) Amorde, S. M.; Jewett, I. T.; Martin, S. F. Tetrahedron
2009, 65, 3222–3231. (g) Airiau, E.; Chemin, C.; Girard, N.; Lonzi, G.;
Mann, A.; Petricci, E.; Salvadori, J.; Taddei, M. Synthesis 2010, 2901–
2914.
(9) For selected syntheses of racemic tashiromine, see ref 8d,8f and:
(a) Pandey, G.; Lakshmaiah, G. Tetrahedron Lett. 1993, 34, 4861–4864.
(b) Kim, S.-H.; Kim, S.-I.; Lai, S.; Cha, J. K. J. Org. Chem. 1999, 64,
6771–6775. (c) Bates, R. W.; Boonsombat, J. J. Chem. Soc., Perkin
Trans. 1 2001, 654–656. (d) McElhinney, A. D.; Marsden, S. P. Synlett
2005, 2528–2530.
ꢀ
Ferreira, F.; Perez-Luna, A.; Chemla, F. Org. Lett. 2007, 9, 4705–4708.
(b) Reddy, L. R.; Prashad, M. Chem. Commun. 2010, 46, 222–224. For
an example using p-tolylsulfinyl imines:(c) Ruano, J. L. G.; Aleman, J.;
Cid, M. B. Synthesis 2006, 687–691.
(13) An unusual sulfonamide byproduct, t-BuSNHSO2t-Bu, was
isolated after prolonged reaction times for the formation of sulfinyl
imines. The structure was confirmed by X-ray crystallography. For the
formation of a similar compound, see: Drabowicz, J. Heteroat. Chem.
2002, 13, 437–442.
(14) Conversion of the syn adducts 10a and 12a to tashiromine and
the anti adduct 11a to 5-epitashiromine is described in the Supporting
Information.
(15) Thomas, E. J.; Vickers, C. F. Tetrahedron: Asymmetry 2009, 20,
970–979.
Org. Lett., Vol. 13, No. 15, 2011
3989

Scheme 3. Synthesis of (ꢀ)-Epilupinine and (ꢀ)-Tashiromine
Figure 1. X-ray structure of the major imino-aldol product 10b.
a dr = 16:1 with 11b (1H NMR). bdr = 13:1 with 17 (1H NMR).
and the enolization conditions. The lithium enolate of the
methyl ester 6, generated using LDA in THF, gave an
enhanced selectivity for 10a (entry 2). However, the phenyl
ester 917 afforded the highest levels of selectivity in the
imino-aldol reaction with sulfinyl imine 3, and most
effectively when the lithium enolate was employed
(entries 3 and 4). Significantly, the minor syn-diastereoi-
somer 12b was not observed, and separation of the syn and
anti diastereomers 10b and 11b was possible by either
column chromatography or crystallization. Furthermore,
the stereochemistry of 10b was determined using X-ray
diffraction (Figure 1).
to the synthesis of the indolizidine and quinolizidine
alkaloids (Scheme 3). The syn imino-aldol product 10b
contained the entire framework of (ꢀ)-tashiromine ((ꢀ)-1),
and the correctly established stereochemistry. Removal of
the N-sulfinyl protecting group using HCl in dioxane
afforded the primary amine, which underwent the key
double cyclization under basic conditions to give the
indolizidine 15. Finally, ester reduction was carried out
using LiAlH4 to produce a mixture of phenol and (ꢀ)-
tashiromine ((ꢀ)-1). Ion exchange chromatography gave
(ꢀ)-tashiromine, which exhibited physical and spectro-
scopic characteristics consistent with those reported for
the authentic material,19 with the exception that our
material was obtained as a low melting solid.
Scheme 4. Synthesis of (þ)-Lupinine: Confirmation of Stereo-
chemistry of Minor Imino-Aldol Stereoisomer
Figure 2. Proposed transition state model to account for the
observed diastereocontrol in the imino-aldol reaction.
The formation of the major observed stereoisomer is
consistent with the closed transition state model presented
by Ellman for the imino-aldol reactions of E-enolates of
propionate esters with tert-butylsulfinyl imines (Figure 2).10
Although, we were not able to trap the enolate derived from 9,
enolization of phenyl propionate with LDA in THF has been
reported to give predominantly the E-silyl ketene acetal.18
Having achieved high levels of diastereoselectivity in the
imino-aldol reactions of phenyl ester 9, attention returned
Similarly, chemoselective reaction of the lithium enolate
derived from phenyl ester 9 with the homologous sulfinyl
imine 4 secured the β-amino ester precursor 14 in 70%
yield (14:17, dr = 13:1 by 1H NMR). Subjecting pure 14 to
the deprotectionꢀdouble cyclizationꢀreduction sequence
described above afforded (ꢀ)-epilupinine ((ꢀ)-2, Scheme 3),
which also gave physical and spectroscopic data that were
consistent with reported values.18 The the minor amino-aldol
product 17 was converted to (þ)-lupinine ((þ)-19), thereby
providing confirmation of its relative and absolute stereo-
chemistry (Scheme 4).19,20
(16) For an example of a prionate imino-aldol reaction with a
functionalized tert-butylsulfinyl imine: Wen, S. J.; Carey, K. L.; Nakao,
Y.; Fusetani, N.; Packham, G.; Ganesan, A. Org. Lett. 2007, 9, 1105–
1108.
(17) The phenyl ester was obtained in one step from commercial
5-chloropentanoyl chloride.
(18) (a) Ishihara, K.; Maruyama, T.; Mouri, M.; Gao, Q. Z.; Furuta,
K.; Yamamoto, H. Bull. Chem. Soc. Jpn. 1993, 66, 3483–3491. (b)
Denmark, S. E.; Beutner, G. L.; Wynn, T.; Eastgate, M. D. J. Am.
Chem. Soc. 2005, 127, 3774–3789.
(19) Physical and spectroscopic data for (ꢀ)-tashiromine, (ꢀ)-epilu-
pinine, and (þ)-lupinine are provided in the Supporting Information.
3990
Org. Lett., Vol. 13, No. 15, 2011

In summary, lithium enolates derived from chloroalk-
anoic acid phenyl esters have been shown to undergo
highly chemoselective and syn selective imino-aldol reac-
tions with chloroalkyl sulfinyl imines, and the resulting
adducts have been elaborated to yield indolizidine and
quinolizidine systems. Six-step total syntheses of (ꢀ)-ta-
shiromine ((ꢀ)-1) and (ꢀ)-epilupinine ((ꢀ)-2) were rea-
lized in 12% and 15% overall yields respectively.
Acknowledgment. We thank EPSRC, GlaxoSmithKline,
and Prosidion Ltd. for studentship funding (I.R.M. and
A.C.C.). R.C.D.B. also acknowledges the Royal Society
for a University Research Fellowship.
Supporting Information Available. Experimental pro-
cedures, characterization data, copies of 1H and 13C
NMR spectra for all new compounds, X-ray crystallo-
graphic data for 10b, 14, and t-BuSNHSO2t-Bu. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(20) Davis and Xu have recently reported that anti imino aldol products
can be obtained by diastereoselective alkylation of acetate imino-aldol
adducts: Davis, F. A.; Xu, P. J. Org. Chem. 2011, 76, 3329–3337.
Org. Lett., Vol. 13, No. 15, 2011
3991