A chemoenzymatic total synthesis of the Amaryllidaceae alkaloid narseronine

Article abstract of DOI:10.1016/j.tetlet.2011.06.050

A 15-step and fully stereocontrolled total synthesis of the title alkaloid 1 has been accomplished using the enantiomerically pure and enzymatically- derived cis-1,2-dihydrocatechol 2 as starting material. The final and pivotal step involved the intramole

Full text of DOI:10.1016/j.tetlet.2011.06.050

Tetrahedron Letters 52 (2011) 4526–4528
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Tetrahedron Letters
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A chemoenzymatic total synthesis of the Amaryllidaceae alkaloid narseronine
⇑
Brett D. Schwartz, Martin G. Banwell , Ian A. Cade
Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra ACT 0200, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
A 15-step and fully stereocontrolled total synthesis of the title alkaloid 1 has been accomplished using the
enantiomerically pure and enzymatically-derived cis-1,2-dihydrocatechol 2 as starting material. The final
and pivotal step involved the intramolecular hetero-Michael addition of secondary amine 16 to a teth-
ered enone moiety followed by trapping of the resulting enolate through its reaction with an adjacent
ester residue.
Received 18 May 2011
Accepted 10 June 2011
Available online 18 July 2011
Keywords:
Alkaloid
Ó 2011 Elsevier Ltd. All rights reserved.
Chemoenzymatic
Michael addition
Narseronine
Natural product synthesis
In 2010 Bastida and colleagues reported1 the isolation of the
alkaloid narseronine (1) from the flowering plant Narcissus serotinus
L. which grows in dry coastal regions of many parts of the Mediter-
ranean.1 The illustrated structure, including relative stereochemis-
with m-chloroperbenzoic acid (m-CPBA). The resulting and previ-
ously reported6 epoxide 4 (95%), which was obtained in a com-
pletely regio- and diastereo-selective manner, was then treated
with the acetonitrile anion and thereby affording the c-hydroxyni-
try, was proposed on the basis of the derived 1- and 2-D 1H and 13
C
trile 54,7 (96%) as the only isolable product of reaction. Subjection
of the latter compound to a Barton–McCombie deoxygenation
reaction8 provided, via the intermediate xanthate ester 6 (94%),
the desired methylene-containing derivative 7 (82% from 5). Suzu-
ki–Miyaura cross-coupling9 of compound 7 with the readily avail-
able boronate ester 84,7 then gave the arylated cyclohexene 94,7
(75%), a key intermediate associated with our recently reported7
synthesis of a lycorine degradation product.
NMR, UV, infra-red, and mass spectral data.1,2 As such, the com-
pound appears to be a member of the masanane- or lycorenine-type
subclass of Amaryllidaceae alkaloids and one that possesses an
unsaturated d-lactone residue as a notable feature. No biological
evaluation of the title compound appears to have been undertaken.
However, other compounds within the subclass and other natural
products possessing related structures display various interesting
biological effects, including antifungal, antitumour, and apopto-
sis-inducing activities.3 Accordingly, we sought to develop an enan-
tioselective total synthesis of narseronine in order to obtain
material for biological evaluation and to confirm the assigned struc-
ture. Herein we report the first total synthesis of the title alkaloid.
The opening stages of our synthesis of compound 1 (Scheme 1)
involve the same sequence of reactions as employed during the
course of assembling the framework originally (and erroneously)
assigned to the alkaloid nobilisitine A.4 Details are re-iterated here
so as to provide the reader with a self-contained overview of the
entirety of the present synthesis. Thus, as with our previous work,4
the starting material used was cis-1,2-dihydrocatechol 2, an enan-
tiomerically pure compound available in large quantity via the
whole-cell biotransformation of bromobenzene.5 This diol 2 was
converted, under standard conditions, into the well known6 aceto-
nide 3 (93%) that was then subjected to electrophilic epoxidation
The nitrile moiety within compound 9 was reduced to the cor-
responding primary amine 10 in a completely chemoselective
manner using dihydrogen in the presence of Raney-cobalt.10 Reac-
tion of the latter compound with Alloc-Cl in the presence of pyri-
dine gave carbamate 11 (88% from 9) that could be N-methylated
by treating it with lithium hexamethyldisilazide (LiHMDS) and
methyl iodide. Compound 12 was thereby obtained in 98% yield.
The conversion of compound 12 into target 1 was carried out
using the reaction sequence shown in Scheme 2. So, treatment of
acetonide/lactone 12 with aqueous acetic acid resulted in cleavage
of the acetonide unit but the subsequent and desired lactonization
⇑
Corresponding author. Tel.: +61 2 6125 8202; fax: +61 2 6125 8114.
E-mail address: mgb@rsc.anu.edu.au (M.G. Banwell).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.050

B. D. Schwartz et al. / Tetrahedron Letters 52 (2011) 4526–4528
4527
Scheme 2.
a 10-fold excess of dimedone to trap the intermediate
plex it was possible to eliminate almost completely the formation
p
-allyl com-
Scheme 1.
of this by-product.
process proved sluggish. Accordingly, the crude hydrolysis product
was treated with LiHMDS and the target compound 13 was thereby
obtained in 77% yield. Irvine–Purdie methylation11 of alcohol 13
gave the corresponding ether/lactone (72%) that was immediately
subjected to saponification with sodium hydroxide and thus form-
ing, after acidic work-up, hydroxy acid 14 (68% from 13) that was
rather prone to relactonization. Upon subjecting compound 14 to
Swern oxidation conditions the allylic alcohol was converted into
the corresponding enone and the free carboxylic acid was trans-
formed into the methylthiomethyl ester12 such that compound
15 (48%) was obtained together with quantities of the precursor
lactone O-methyl ether (29%).
In the final step of the reaction sequence, carbamate 15 was
treated with (Ph3P)4Pd and an excess of dimedone.13 As a result
the target compound narseronine (1) was obtained in 82% yield.
Presumably compound 1 is formed through the secondary amine
16 (arising from deprotection of carbamate 15) engaging in a spon-
taneous intramolecular hetero-Michael addition to the pendant
enone moiety with the resulting enolate then undergoing an inter-
molecular acylation reaction involving the adjacent ester group.
Accompanying target 1 were variable but small amounts of the
chromatographically separable allyl amine 17 that presumably
All of the spectral data derived from lactone 1 were in complete
accord with the assigned structure but final confirmation of this
followed from a single-crystal X-ray analysis.14 The ORTEP arising
from this analysis is shown in Figure 1.
A comparison of the 1H and 13C NMR spectral data derived from
lactone 1 with those reported1 for narseronine is presented in Ta-
ble 1. This strongly suggests that the two compounds are the same
in terms of structure and relative stereochemistry. The infra-red
and mass spectral data obtained on the synthetically-derived
material also matched those reported for the natural product.
Unfortunately, the specific rotation of the natural product has
not been reported so it is not possible to comment on the absolute
configuration of this alkaloid.15
arises through attack of secondary amine 16 on the
p-allyl palla-
dium complex arising from deprotection of carbamate 15. By using

4528
B. D. Schwartz et al. / Tetrahedron Letters 52 (2011) 4526–4528
Table 1
Comparison of the 13C and 1H NMR data recorded for synthetically-derived narseronine and the natural product
13C NMR data (dC)
1H NMR data (dH)
Synthetic 1a
Narseronineb
Synthetic 1c
Narseronined
161.5
153.5
152.3
148.1
135.1
116.3
111.5
107.6
103.1
102.2
74.8
161.5
153.8
152.9
148.4
135.1
116.4
110.9
107.9
103.3
102.4
75.0
7.68, s, 1H
7.28, s, 1H
7.66, s, 1H
7.29, s, 1H
6.13, d, J = 1.2 Hz, 1H
6.11, d, J = 1.2 Hz, 1H
4.22, t, J = 6.0 Hz, 1H
3.91, d, J = 7.0 Hz, 1He
3.57, s, 3H
6.12, d, J = 1.2 Hz, 1H
6.10, d, J = 1.2 Hz, 1H
4.22, t, J = 6.1 Hz, 1H
3.94, d, J = 6.4 Hz, 1H
3.57, s, 3H
3.05, dt, J = 11.0 and 7.6 Hz, 1H
2.81, m, 1H
2.64, m, 1H
3.07, dt, J = 11.0 and 7.6 Hz, 1H
2.78, m, 1He
2.63, m, 1He
2.43, s, 3H
2.41, s, 3H
61.9
58.0
54.1
61.7
58.3
54.3
2.23–2.10, complex m, 2H
2.03, dt, J = 13.0 and 6.0 Hz, 1H
1.89, ddd, J = 13.0, 8.0 and 4.4 Hz, 1H
2.22–2.13, m, 2H
2.01, dt, J = 13.5 and 5.5 Hz, 1H
1.90, ddd, J = 12.6, 8.3 and 4.2 Hz, 1H
42.1
41.8
34.7
35.1
31.2
31.4
29.3
29.6
a
b
c
Data recorded in CDCl3 at 100 MHz.
Data obtained from spectrum provided by Professor Bastida and recorded in CDCl3 at 125 MHz.
Data recorded in CDCl3 at 400 MHz.
Data obtained from Ref. 1 and recorded in CDCl3 at 500 MHz.
The chemical shift of this resonance varied somewhat from run-to-run.
d
e
References and notes
1. Pigni, N. B.; Berkov, S.; Elamrani, A.; Benaissa, M.; Viladomat, F.; Codina, C.;
Bastida, J. Molecules 2010, 15, 7083.
2. Narseronine also appears to have been isolated from a sample of Narcissus
serotinus L. collected in Greece but its structure was incorrectly assigned. See:
Vrondeli, A.; Kefalas, P.; Kokkalou, E. Pharmazie 2005, 60, 559.
3. See, for example: (a) Evidente, A.; Andolfi, A.; Abou-Donia, A. H.; Touema, S. M.;
Hammoda, H. M.; Shawky, E.; Motta, A. Phytochemistry 2004, 65, 2113; (b) Liu,
J.; Hu, W.-X.; He, L.-F.; Ye, M.; Li, Y. FEBS Lett. 2004, 578, 245; (c) Liu, X.-s.; Jiang,
J.; Jiao, X.-y.; Wu, Y.-e.; Lin, J.-h.; Cai, Y.-m. Cancer Lett. 2009, 274, 16; (d)
McNulty, J.; Nair, J. J.; Bastida, J.; Pandey, S.; Griffin, C. Phytochemistry 2009, 70,
913; (e) Lamoral-Theys, D.; Andolfi, A.; Van Goietsenoven, G.; Cimmino, A.; Le
Calvé, B.; Wauthoz, N.; Mégalizzi, V.; Bruyère, C.; Dubois, J.; Mathieu, V.;
Kornienko, A.; Kiss, R.; Evidente, A. J. Med. Chem. 2009, 52, 6244; (f) Evidente,
A.; Kornienko, A. Phytochem. Rev. 2009, 8, 449; (g) Van Goietsenoven, G.;
Andolfi, A.; Lallemand, B.; Cimmino, A.; Lamoral-Theys, D.; Gras, T.; Abou-
Donia, A.; Dubois, J.; Lefranc, F.; Mathieu, V.; Kornienko, A.; Kiss, R.; Evidente, A.
J. Nat. Prod. 2010, 73, 1223; (h) Hayden, R. E.; Pratt, G.; Drayson, M. T.; Bunce, C.
M. Haematologica 2010, 95, 1889; (i) Feng, T.; Wang, Y.-Y.; Su, J.; Li, Y.;
Cai, X.-H.; Luo, X.-D. Helv. Chim. Acta 2011, 94, 178.
4. Schwartz, B. D.; Jones, M. T.; Banwell, M. G.; Cade, I. A. Org. Lett. 2010, 12, 5210.
5. For reviews on methods for generating compounds such as 2 by microbial
dihydroxylation of the corresponding aromatics, as well as the synthetic
applications of these metabolites, see: (a) Hudlicky, T.; Gonzalez, D.; Gibson, D.
T. Aldrichim. Acta 1999, 32, 35; (b) Banwell, M. G.; Edwards, A. J.; Harfoot, G. J.;
Jolliffe, K. A.; McLeod, M. D.; McRae, K. J.; Stewart, S. G.; Vögtle, M. Pure Appl.
Chem. 2003, 75, 223; (c) Johnson, R. A. Org. React. 2004, 63, 117; (d) Hudlicky,
T.; Reed, J. W. Synlett 2009, 685; (e) Banwell, M. G.; Lehmann, A. L.; Menon, R.
S.; Willis, A. C. Pure Appl. Chem. 2011, 83, 411.
Figure 1. ORTEP derived from the single-crystal X-ray analysis of compound 1.
Displacement ellipsoids are drawn at the 50% probability level. Hydrogen atoms are
shown as spheres of arbitrary radius.
6. Hudlicky, T.; Price, J. D.; Rulin, F.; Tsunoda, T. J. Am. Chem. Soc. 1990, 112, 9439.
7. Jones, M. T.; Schwartz, B. D.; Willis, A. C.; Banwell, M. G. Org. Lett. 2009, 11,
3506.
Acknowledgements
8. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574.
9. Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513.
10. For related reduction processes employing Raney-cobalt see: (a) Janey, J. M.;
Orella, C. J.; Njolito, E.; Baxter, J. M.; Rosen, J. D.; Palucki, M.; Sidler, R. R.; Li, W.;
Kowal, J. J.; Davies, I. W. J. Org. Chem. 2008, 73, 3212; (b) Ref. 7; (c) Ref. 4.
11. Purdie, T.; Irvine, J. C. J. Chem. Soc., Trans. 1903, 83, 1021.
12. For related conversions see: (a) Jadhav, S. B.; Ghosh, U. Tetrahedron Lett. 2007,
48, 2485; (b) Ragan, J. A.; Ide, N. D.; Cai, W.; Cawley, J. J.; Colon-Cruz, R.; Kumar,
R.; Peng, Z.; Vanderplas, B. C. Org. Process Res. Dev. 2010, 14, 1402.
13. Kunz, H.; Unverzagt, C. Angew. Chem., Int. Ed. 1984, 23, 436.
14. X-ray crystal data for compound 1 can be found in the Supplementary data.
Crystallographic data (excluding structure factors) for compound 1 have been
deposited with the Cambridge Crystallographic Data Centre (CCDC no.
822115). Copies of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44-(0)1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk).
We thank the Institute of Advanced Studies and the Australian
Research Council for financial support. Professor Jaume Bastida
(University of Barcelona) is thanked for providing copies of the
1H and 13C NMR spectra recorded on naturally-derived
narseronine.
Supplementary data
Supplementary data (experimental procedures and product
characterization for compounds 13, 13 O-methyl ether, 14, 15,
and 1 as well as the X-ray crystallographic data for compound 1)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2011.06.050.
15. The specific rotation recorded for synthetically-derived material was À25.4
(c 1.6, CDCl3).