A general organocatalytic approach toward the enantioselective total synthesis of indolizidine based alkaloids

Article abstract of DOI:10.1021/ol302871u

Four indolizidine based alkaloids (IBAs) have been synthesized in a highly enantioselective, straightforward, and flexible manner. As a key step our previously developed Bronsted acid catalyzed vinylogous Mannich reaction was employed which easily afforded gram amounts of an optically pure central intermediate which can be converted into a wide range of diversely substituted IBAs.

Full text of DOI:10.1021/ol302871u

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
A General Organocatalytic Approach
toward the Enantioselective Total
Synthesis of Indolizidine Based Alkaloids
Falko Abels, Chris Lindemann, Eva Koch, and Christoph Schneider*
€
Institut fu€r Organische Chemie, Universitat Leipzig, Johannisallee 29, 04103 Leipzig
schneider@chemie.uni-leipzig.de
Received October 19, 2012
ABSTRACT
Four indolizidine based alkaloids (IBAs) have been synthesized in a highly enantioselective, straightforward, and flexible manner. As a key step
our previously developed Brønsted acid catalyzed vinylogous Mannich reaction was employed which easily afforded gram amounts of an optically
pure central intermediate which can be converted into a wide range of diversely substituted IBAs.
Lipid soluble indolizidine based alkaloids (IBAs) are
commonly found in amphibian skin and display a wide
range of biological activities. Among them significant
inhibitory effects are observed on nicotinic acetylcholine
receptors,1 which make them promising candidates, e.g.,
for control of Alzheimer’s disease, schizophrenia, epilepsy,
and Parkinson’s disease.2,3 The structuraldiversityof IBAs
is quite broad, as over 240 different members of this natural
product class have been isolated thus far, which only differ
in their substitution pattern and in the relative configura-
tion of the substituents.4 In particular, 5-mono-, 3,5-di-,
and 5,8-disubstituted indolizidines represent a large por-
tion of this group with over 100 members (Scheme 1). The
relative configuration of some IBAs has been established
whereas their absolute configuration remains largely un-
known. Thus, IBAs depicted in Scheme 1 are drawn in a
convenient manner as described by Daly and co-workers5
but do not necessarily represent the correct absolute con-
figuration. In several cases all stereoisomers have been
isolated. Only microgram amounts of IBAs are typically
available from natural sources, and therefore they have
often been characterized merely by vapor-phase FT-IR
and mass spectrometry.6 In addition, due to this low
availability, some structures have not yet been confirmed
to be of natural origin (e.g., 1 and 2). For further structure
elucidation/validation and biological testing, a straightfor-
ward and flexible synthetic access toward sufficient quan-
tities of optically pure material is highly desirable.
Accordingly, a wide range of different strategies toward
IBAs have been developed which have been reviewed
extensively on a regular basis since 1984.7
However, most of the reported procedures employ
ex-chiral-pool strategies starting from amino acids and
(1) (a) Daly, J. W.; Spande, T. F. Alkaloids: Chemical and Biological
Perspectives: Amphibian Alkaloids: Chemistry, Pharmacology, and Biol-
ogy; AWiley-Interscience Publication: New York, 1986. (b) Aronstam, R. S.;
Daly, J. W.; Spande, T. F.; Narayanan, T. K.; Albuquerque, E. X. Neurochem.
Res. 1986, 11, 1227–40. (c) Takahata, H.; Kubota, M.; Ihara, K.;
Okamoto, N.; Momose, T.; Azer, N.; Eldefrawi, A. T.; Eldefrawi,
M. E. Tetrahedron: Asymmetry 1998, 9, 3289–3301.
(2) (a) Tan, R.; Zhang, G.; Song, Y.; Cui, J.; Wang, W. Curvularia for
manufacture of indolizidine alkaloid as acetylcholinesterase inhibitor
for control of Alzheimer’s disease. CN102329735A. (b) Toyooka, N.
Yakugaku Kenkyu no Shinpo 2007, 23, 41–50.
(5) Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68,
1556–1575.
(6) Saporito, R. A.; Norton, R. A.; Andriamaharavo, N. R.; Garraffo,
H. M.; Spande, T. F. J. Chem. Ecol. 2011, 37, 213–218.
(3) Zhou, D.; Toyooka, N.; Nemoto, H.; Yamaguchi, K.; Tsuneki,
H.; Wada, T.; Sasaoka, T.; Sakai, H.; Tezuka, Y.; Kadota, S.; Jones,
T. H.; Garraffo, H. M.; Spande, T. F.; Daly, J. W. Heterocycles 2009, 79,
565–571.
(4) Saporito, R. A.; Spande, T. F.; Garraffo, H. M.; Donnelly, M. A.
Heterocycles 2009, 79, 277–297.
(7) (a) Grundon, M. F. Nat. Prod. Rep. 1984, 1, 349–353. (b)
Grundon, M. F. Nat. Prod. Rep. 1985, 2, 235–243. (c) Grundon, M. F.
Nat. Prod. Rep. 1987, 4, 415–422. (d) Grundon, M. F. Nat. Prod. Rep.
1989, 6, 523–536. (e) Michael, J. P. Nat. Prod. Rep. 1994, 11, 639–657and
the following years within this journal until 2008 (ref 7f). (f) Michael,
J. P. Nat. Prod. Rep. 2008, 25, 139–165.
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10.1021/ol302871u
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et al. or the R-aminoxylation19 of aldehydes by the Kumar
group also lead to some IBAs. Most of these strategies,
however, are limited to specific substitution patterns
within the indolizidine core and, in addition, typically
require further functional group manipulations to assem-
ble the bicyclic framework.
Scheme 1. Access toward Differently Substituted IBAs from a
Versatile, Central Building Block
Recently, we have documented the Brønsted acid cata-
lyzed, enantioselective vinylogous MukaiyamaꢀMannich
reaction (VMMR) of acyclic silyl dienolates 9a and 9b to
furnish δ-amino-R,β-unsaturated esters 10 in good yields
and excellent enantio- and diastereoselectivities.20
Scheme 2. Brønsted Acid Catalyzed, Enantioselective, Vinylo-
gous Mannich Reaction with Aliphatic Imines
their derivatives which are directly incorporated into the
final products.8 Alternatively, chiral auxiliary-based stra-
tegies (e.g., with SAMP/RAMP,9 carbohydrates,10 ami-
no alcohols,11 or N-sulfinylimines12) have been developed
and provide optically active IBAs with excellent diastereo-
selectivity.13 An elegant three-component linchpin coupling
of 2-silyl-1,3-dithianes with an optically pure epoxide and
aziridine has been developed toward indolizidine 223AB.14
Very few catalytic enantioselective approaches based upon
the asymmetric Sharpless dihydroxylation,15 the iridium-
catalyzed allylic amination,16 or the asymmetric Heck17
reaction are known. Organocatalytic procedures such as the
proline-catalyzed asymmetric R-amination/Hornerꢀ
WadsworthꢀEmmons olefination approach18 by Kalkote
Whereas our initially disclosed protocol21 was best
suited for aromatic and heteroaromatic aldimines, we have
recently been able to extend this reaction to aliphatic
aldimines 8 by a slight modification of the reaction condi-
tions (Scheme 2). Functional groups such as ester moieties,
halogen atoms, and alkynes were readily tolerated in this
process. The use of the γ-methyl substituted dienolate 9b
furnished the corresponding vinylogous Mannich prod-
ucts carrying a second stereogenic center with good anti-
diastereoselectivity as well. We report herein a generally
applicable, flexible, catalytic, and enantioselective syn-
thetic access to gram amounts of optically pure IBAs
with the VMMR as the key step. In addition, this
strategy at the same time provides the opportunity for
a late-stage incorporation of substituents at various
positions within the indolizidine core from a versatile
central building block.
(8) Selected recent papers: (a) Reddy, C. R.; Latha, B.; Rao, N. N.
Tetrahedron 2012, 68, 145–151. (b) Liu, X.-K.; Zheng, X.; Ruan, Y.-P.;
Ma, J.; Huang, P.-Q. Org. Biomol. Chem. 2012, 10, 1275–1284. (c)
Settambolo, R. Heterocycles 2009, 79, 219–228.
(9) (a) Enders, D.; Thiebes, C. Synlett 2000, 1745–1748. (b) Lebrun,
S.; Couture, A.; Deniau, E.; Grandclaudon, P. Synthesis 2008, 2771–
2775.
(10) Stoye, A.; Quandt, G.; Brunnhofer, B.; Kapatsina, E.; Baron, J.;
Fischer, A.; Weymann, M.; Kunz, H. Angew. Chem., Int. Ed. 2009, 48,
2228–2230.
(11) Kobayashi, T.; Hasegawa, F. ; Hirose, Y.; Tanaka, K.; Mori, H.;
Katsumura, S. J. Org. Chem. 2012, 77, 1812–1832.
(12) Davis, F. A.; Yang, B. J. Am. Chem. Soc. 2005, 127, 8398–8407.
(13) Some novel, yet diastereoselective approaches toward indolizi-
dines: (a) Yang, D.; Micalizio, G. C. J. Am. Chem. Soc. 2009, 131,
17548–18549. (b) Lapointe, G.; Schenk, K.; Renaud Chem.;Eur. J.
2011, 17, 3207–3212. (c) Jiang, T.; Livinghouse, T.; Lovick, H. M. Chem.
Commun. 2011, 47, 12861–12863. (d) Pronin, S. V.; Tabor, M. G.;
Jansen, D. J.; Shenvi, R. A. J. Am. Chem. Soc. 2012, 134, 2012–2015.
(14) Kim, D.-S.; Smith, A. B. J. Org. Chem. 2006, 71, 2547–2557.
(15) (a) Takahata, H.; Kubota, M.; Takahashi, S.; Momose, T.
Tetrahedron: Asymmetry 1996, 7, 3047–3054. (b) Toyooka, N.; Zhou,
D.; Nemoto, H., Garraffo, H. M.; Spande, T. F.; Daly, J. W. Beilstein J.
Org. Chem. 2007, 3, Nos. 29 and 30.
We envisioned an ester-substituted imine as a suitable
reaction partner for the VMMR under the consideration
thatitshould readily undergoa subsequent cyclization into
the corresponding γ-lactam. This transformation would
not only form the five-membered ring and set the first
bridgehead stereogenic center but also provide a function-
alized carbon chain required for the assembly of the
bicyclic framework at the same time. To put these plans
€
(16) Gartner, M.; Wihofen, R.; Helmchen, G. Chem.;Eur. J. 2011,
17, 7605–7622.
(17) (a) Nukui, S.; Sodeoka, M.; Shibasaki, M. Tetrahedron Lett.
1993, 34, 4965–4968. (b) Nukui, S.; Sodeoka, M.; Sasai, H.; Shibasaki,
M. J. Org. Chem. 1995, 60, 398–404.
(19) Kondekar, N. B.; Kumar, P. Synthesis 2010, 3105–3112.
(20) Abels, F.; Schneider, C. Synthesis 2011, 4050–4058.
(21) (a) Sickert, M.; Abels, F.; Lang, M.; Sieler, J.; Birkemeyer, C.;
Schneider, C. Chem.;Eur. J. 2010, 16, 2806–2818. (b) Sickert, M.;
Schneider, C. Angew. Chem., Int. Ed. 2008, 47, 3631–3634. (c) Giera,
D. S.; Sickert, M.; Schneider, C. Org. Lett. 2008, 10, 4259–4262.
(18) Panchgalle, S. P.; Bidwai, H. B.; Chavan, S. P.; Kalkote, U. R.
Tetrahedron: Asymmetry 2010, 21, 2399–2401.
B
Org. Lett., Vol. XX, No. XX, XXXX

into practice, we treated bifunctional aldehyde 11, para-
anisidine, and vinylketene silyl-O,O-acetal 9a with cata-
lytic amounts of the TRIP phosphoric acid22 (TRIP-cat.)
for only 10 min at ꢀ55 °C which yielded the corresponding
vinylogous Mannich product with 99% ee. Without
further isolation the reaction mixture was subsequently
stirred in acetic acid under reflux for 1 h which eventually
affordedthe desiredlactam 12a in 80% yield over two steps
on a laboratory scale (Scheme 3).
Scheme 4. Synthesis of Chiral Lactam 12b
yield of 68% using the 3,30-bismesityl-substituted BINOL-
phosphoric acid (Mes-cat.) as the Brønsted acid catalyst
which proved superior over the TRIP-cat. in this particular
case. 12b was subsequently recrystallized to give a single
diastereomer with >99% ee (Scheme 4, for the X-ray
structure of 12b, please see the SI). With multigram
amounts of optically pure lactams 12a and 12b in hand,
conversion into the target IBAs was undertaken. Com-
pound 12a was first transformed into the saturated
Boc-protected lactam 13a via a high-yielding three-step
sequence and further elaborated in two distinct ways
depending upon the substitution pattern of the final
product (Scheme 5).
For 3-unsubstituted indolizidines, a chemoselective re-
duction of the imide via the hemiaminal furnished Boc
protected pyrrolidine 14 in excellent yield24 which was further
converted into indolizidinone 16 through a deprotectionꢀ
cyclization protocol in a quantitative yield.25 In order to
access 3-substituted indolizidines, Grignard addition on
13a and subsequent reduction of the in situ generated
N-acyl iminium ion, using a combination of trispentafluor-
ophenyl borane and triphenylsilane, occurred with com-
plete cis-diastereoselectivity, to deliver pyrrolidine 15
which was converted into indolizidinone 17 in a very good
yield over the two steps.26
Scheme 3. Synthesis of Chiral Lactam 12a
The scale-up of this process was easily possible simply by
prolonging the reaction time to 16 h which furnished 12a
in 86% yield over two steps and with a slightly decreased
enantioselectivity of 96% ee.
For the 8-substituted indolizidines, lactam 12b was
employed as the starting material, which was first trans-
formed into the imide 13b and subsequently fully reduced,
deprotected, and cyclized to furnish 8-methyl substituted
indolizidinone 18 in 71% overall yield (Scheme 6).
The 5-substituent could now easily be installed via
organometallic addition to indolizidinones 16ꢀ18 and
subsequent diastereoselective iminium ion reduction.27
Following this protocol, (þ)-indolizidine 167B (2), (þ)-
monomorine (3), and indolizidine 167A (4), differing in
their substitution at C3, C5, and C8, were obtained from
their respective precursors as their TFA-salts in excellent
yields as single stereoisomers (Scheme 7).28
Figure 1. X-ray structure of 12a. Elipsoid level at 50%; H-atoms
are ommited for clarity except H4.
The optical purity of lactam 12a was further enhanced to
>99%eethrougha single recrystallization from abiphasic
toluene/hexane solution which also provided material
suitable for X-ray crystallography thereby proving its
absolute configuration23 (Figure 1; for further informa-
tion, please see the SI).
The vinylogous Mannich reaction could also be em-
ployed advantageously to introduce a second stereogenic
center at the 8-position of the indolizidine ring with good
diastereoselectivity when the γ-methyl-substituted dieno-
late 9b was used as the starting material.
(24) Pedregal, C.; Ezquerra, J. Tetrahedron Lett. 1994, 35, 2053–
2056.
(25) Bertrand, M. B.; Neukom, J. D.; Wolfe, J. P. J. Org. Chem. 2008,
73, 8851–8860.
(26) (a) Lin, G.-J.; Huang, P.-Q. Org. Biomol. Chem. 2009, 7, 4491–
4495. (b) Massey, A. G.; Park, A. J. J. Organomet. Chem. 1964, 2, 245–
250.
The vinylogous Mannich product 12b was obtained with
very good diastereo- and enantioselectivity and an overall
(27) Pinho, V. D.; Burtoloso, A. C. B. Tetrahedron Lett. 2012, 53,
876–878.
(28) Deslongchamps, P. Organic Chemistry Series; Pergamon Press:
Oxford, U.K., 1983.
(22) (a) Adair, G.; Mukherjee, S.; List, B. Aldrichimica Acta 2008, 41,
31–39. (b) Klussmann, M.; Ratjen, L.; Hoffmann, S.; Wakchaure, V.;
Goddard, R.; List, B. Synlett 2010, 2189–2192.
(23) Flack, H. D. Acta Crystallogr. 1983, 39, 876ꢀ881; CCDC
905605.
(29) Danishefsky, S.;Webb, R. R., II. Tetrahedron Lett. 1983, 24, 11–14.
Org. Lett., Vol. XX, No. XX, XXXX
C

nonvolatile TFA salts. (þ)-Coniceine (1) was obtained
after complete reduction of 16 using lithium aluminum
hydride.29
Scheme 5. Elaboration in Two Distinct Ways
Scheme 7. Syntheses of Various IBAs 1ꢀ4
In conclusion, we have established a novel, catalytic,
enantioselective, and at the same time highly flexible
synthetic access toward differently substituted IBAs 1ꢀ4
using our previously developed Brønsted acid catalyzed
vinylogous Mannich reaction (VMMR). Both key inter-
mediates 12a and 12b were formed on a large scale in good
overall yields with excellent enantioselectivity, which was
further enhanced through a single recrystallization to
>99% ee. Further manipulations gave rise to (S)-con-
iceine and indolizidines 167A, 167B, and 195B as their
TFA-salts in optically pure form, documenting the versa-
tility of this approach. Hence, this strategy could conceiv-
ably be used to synthesize an even broader variety of
naturally and non-naturally occurring IBAs using a par-
allel synthesis format. Further studies in this direction are
currently ongoing in our laboratories.
Acknowledgment. We are grateful to the Deutsche
Forschungsgemeinschaft and the Evonik-Stiftung (graduate
fellowship to F.A.) for the generous financial support of
this work. The donation of chemicals from Evonik,
Chemetall, and BASF is gratefully acknowledged. We
would like to thank J. Sieler for providing X-ray crystallo-
graphic data for compounds 12a and 12b.
Scheme 6. Synthesis 8-Methyl-indolizidinone 18
Supporting Information Available. Experimental pro-
cedures, characterization data, and NMR spectra for all
new compounds, and CIF data for compounds 12a and
12b. This material is available free of charge via the
Internet at http://pubs.acs.org.
The yields of this final transformation exceed those
reported in the literature quite significantly and are most
likely due to the facile and quantitative isolation of the
The authors declare no competing financial interest.
D
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