A facile approach to the synthesis of securinega alkaloids: stereoselective total synthesis of (-)-allonorsecurinine

Article abstract of DOI:10.1016/j.tetlet.2012.08.088

A concise stereoselective total synthesis of alkaloid (-)-allonorsecurinine is described utilizing classical reactions such as Grignard, Aldol and Horner-Wittig reactions as the key steps.

Full text of DOI:10.1016/j.tetlet.2012.08.088

Tetrahedron Letters 53 (2012) 5926–5928
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Tetrahedron Letters
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A facile approach to the synthesis of securinega alkaloids: stereoselective
total synthesis of (ꢀ)-allonorsecurinine
⇑
Alugubelli Sathish Reddy, Pabbaraja Srihari
Division of Natural Products Chemistry, GCL 1st floor, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise stereoselective total synthesis of alkaloid (ꢀ)-allonorsecurinine is described utilizing classical
reactions such as Grignard, Aldol and Horner–Wittig reactions as the key steps.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 23 July 2012
Revised 21 August 2012
Accepted 23 August 2012
Available online 30 August 2012
Keywords:
Alkaloid
Aldol reaction
Grignard
Horner–Wittig
Bromination
The securinega alkaloids isolated from plants of the Euphorbia-
ceae family have attracted significant interest from the synthetic
chemistry community and biologist because of their complex ring
systems and important biological activities exhibited by them.1
Historically, many of the plants that produce these alkaloids have
been used in traditional folk medicine.2 Though securinine, the first
alkaloid from this class was found to be a specific GABA receptor
antagonist and displayed significant in vivo CNS activity,3 further
exploration of this class of compounds led to the identification of
molecules exhibiting potent biological properties such as antima-
larial,4 antibiotic,5 antifungal,6 antipyretic,7 diuretic,8 and in the
treatment of hepatic disorders.9 Structurally, many of the mole-
cules from this class have a common bridged tetracyclic ring sys-
tem which forms a major back bone skeleton and based on the
size of the heterocycle (ring A), they are classified into two main
groups securinine (wherein a six-membered heterocycle, piperi-
dine is present) and norsecurinine group (wherein a five-mem-
bered heterocycle, pyrrolidine is present). Owing to the unique
structural feature (Fig. 1) and significant biological properties of
these compounds, several synthetic efforts have been made and
are well precedented in the literature.10,11
the classical synthetic approach utilizing Grignard reaction, Aldol
reaction and a Horner–Wittig reaction as the key steps for the total
synthesis of (ꢀ)-allonorsecurinine
Initially, our intent was to elaborate the commercially available
L-proline into a bicyclic compound 11 with A & C rings followed by
the extension of the C ring to form the CD ring 10 with appropriate
stereogenicity. Finally, the pyrrolidine ring A and bicyclic CD ring
can be bridged together using an intramolecular nucleophilic
substitution reaction to form the B ring affording the tetracyclic
framework of norsecurinine (Scheme 1). The strategy can be poten-
tially extended to the synthesis of securinines by starting with an
appropriate enantiopure pipecolinic acid.
Our synthesis began with Boc protection of secondary amine
L
-proline with di-tert-butyl dicarbonate13 to get carbamate 14
O
O
O
O
O
O
O
H
O
H
H
H
D
A
B
N
N
N
N
C
In continuation of our efforts on studies towards the total syn-
thesis of lactone containing natural products12 and as part of an
academic exercise, we have initiated a programme to develop a
general strategy for these complex and biologically interesting lac-
tone containing alkaloids. We herein describe a strategy involving
1 Securinine
4 Viroallosecurinine
3 Virosecurinine
2 Allosecurinine
O
OH
O
H
O
O
H
3
H O
H
O
4
5
O
9
D
A
2
N
O
N
12
N
B
8
N
13
14
C
O
7
15
7 Secuamamine
5 (-) Norsecurinine 6 (-) Allonorsecurinine
8 Phyllantidine
⇑
Corresponding author. Tel.: +91 4027191815; fax: +91 4027160512.
E-mail address: srihari@iict.res.in (P. Srihari).
Figure 1. Structures of a few securinega alkaloids.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.088

A. Sathish Reddy, P. Srihari / Tetrahedron Letters 53 (2012) 5926–5928
5927
O
magnesium bromide (prepared by 2-bromo-1-propene and mag-
nesium) gave the mixture of diastereomers 13 and 13a in 95:5 ra-
tio.15 Though, we could not establish the stereochemistry of the
products based on NOE studies at this stage, later it was confirmed
that the major product has 2S,9S configuration based on the final
product synthesized (vide infra). The major diastereomer 13 was
subjected to ozonolysis to get the crude dicarbonyl compound 12
which was directly treated with KOH in the presence of triton-B
to yield the aldol product enone 11 (C ring formation) in 55%
over-all yield.16 Utilizing the free tertiary alcohol adjacent to car-
bonyl functionality in 11, we proceeded further for the construc-
tion of the D ring. The tertiary alcohol 11 was coupled with
phosphonate derived acetic acid 17 employing standard DCC cou-
pling protocol17 to get the ester 18 and was then subjected to the
Horner–Wittig reaction18 with NaH to yield the product butenolide
10 (D ring) affording product with bridged CD ring skeleton. The
spectral data of this compound was found to be identical to that
of the reported structure.10f With the three rings in the skeleton
(A and BC), next was to complete the synthesis of the tetracyclic
core by bridging the A ring with the C ring to form the B ring.
Accordingly, we proceeded with allylic bromination of the product
10 with NBS in the presence of benzoyl peroxide to yield the cor-
responding bromide 9. The compound 9 upon TFA mediated Boc
deprotection followed by base (K2CO3) induced nucleophilic sub-
stitution reaction10f produced the B ring affording the tetracyclic
core 6 thus accomplishing the total synthesis of (ꢀ)-allonorsecur-
inine 6 (Scheme 2). The spectral data of our compound were iden-
tical with those of the reported data10f (1H and 13C NMR) with a
variation in the optical rotation.19
O
O
O
H
B
O
O
D
A
N
C
H
H
N
n
N
n
n
Br
9
Boc
Boc
10
2 when n=2
6
when n=1
O
HO
N
HO
H
OH
H
n
H
N
n
Boc
N
O
n
Boc
H
13
L-Proline when n=1
11
Pipecolinic acid when n=2
Securinine analogues when n=2
Norsecurinine analogues when n=1
Scheme 1. General retrosynthetic strategy for securinine and norsecurinine
analogues.
H
OH
O
H
OH
O
(Boc)2O
H
N
O
O
CDI, CH2Cl2
O
Aq NaHCO3
19 h, 95%
N
H
N
N
Boc
14
N
Boc
15
H.HCl
20 h, 90%
H
O
HO
Br
In conclusion, the total synthesis of (ꢀ)-allonorsecurinine has
been accomplished. The adopted strategy is very facile and paves
the way for the synthesis of other natural and unnatural securinine
and norsecurinine analogues by starting with the appropriate chi-
ral proline or pipecolinic acids involving a similar set of reaction
sequences. Further application of this strategy towards the synthe-
sis of other analogues is currently being investigated.
Br
13a
Mg, THF
12 h, 85%
+
N
H
Mg, THF
8 h, 84%
N
Boc
Boc
16
13
O
HO
O
O3, TPP, CH2Cl2
KOH, Triton-B, 4-6 h,
H
-78 C, 30 min.
°
THF: H2O: Et2O, reflux
55% over two steps
N
Boc
O
P
12
Acknowledgments
OEt
OEt
O
O
HO
O
O
P
A.S.R. thanks the CSIR, New Delhi for financial assistance. P.S.
acknowledges the Council of Scientific & Industrial Research (CSIR),
New Delhi for financial support under the project (MLP-10a).
OEt
OEt
O
O
HO
NaH, THF
17
H
N
H
DCC, CH2Cl2
reflux, 3 h, 75%
N
Boc
0 °C - rt
30 min. 55%
Boc
11
Supplementary data
18
O
O
Supplementary data (Experimental details and analytical data)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2012.08.088.
O
O
NBS,CCl4, reflux
1) TFA, CH2Cl2
2) K2CO3, 65%
benzoylperoxide
90 min. 75%
H
H
N
N
References and notes
Br
Boc
Boc
9
10
O
1. (a) For reviews on Securinega alkaloids, see. Snieckus, V.; The Securinega
Alkaloids In The Alkaloids:The Alkaloids Manske; R. H. F.; Academic Press: New
York, 1973; Vol. 14, pp 425–503; (b) Buetler, J. A.; Brubaker, A. N. Drugs Fut.
1987, 12, 957–976; (c) Bayon, P.; Busque, F. M.; Figueredo Targets Hetercocyclic
System 2005, 9, 281–310.
O
H
HO
N
H
N
2. (a) Nakano, T.; Terao, S.; Lees, K. H.; Saeki, Y.; Durham, L. J. J. Org. Chem. 1966,
31, 2274–2279; (b) Horii, Z.; Imanishi, T.; Yamauchi, M.; Hanaoka, M.; Parello,
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3. Beutler, J. A.; Karbon, E. W.; Brubaker, A. N.; Malik, R.; Curtis, D. R.; Enna, S. J.
Brain Res. 1985, 330, 135–140.
Boc
13a
6
Scheme 2. Synthesis of (ꢀ)-allonorsecurinine.
4. Weenen, H.; Nkunya, M. H. H.; Bray, D. H.; Mwasumbi, L. B.; Kinabo, L. S.;
Kilimali, V. A.; Wijnberg, J. B. Planta Med. 1990, 56, 371–373.
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Ethnopharmacol. 1990, 28, 129–133.
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Mycobiology 2005, 33, 97–103.
which was converted to the corresponding Weinreb amide 15 with
N,O-dimethylhydroxylamine hydrochloride using 1,10-carbonyl
diimidazole (CDI).14 Weinreb amide 15 was subjected to Grignard
reaction with homoallyl magnesium bromide (generated in situ
with homoallyl bromide and magnesium) to yield ketone 16. Ke-
tone 16 when subjected to Grignard reaction with the isopropenyl
7. Serra, R. M. An. Univ. Santo Domingo. 1944, 8, 295–297.
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5928
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13. Huy, P.; Neudorfl, J. M.; Schmalz, H. G. Org. Lett. 2011, 13, 216–219.
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503–508.
15. The diastereomeric ratio was calculated based on the isolated yields after
column chromatography. Based on the stereochemistry of final product, we
believe that Grignard reaction might have proceeded by facial selectivity that
is, si face attack.
16. (a) Nicolaou, K. C.; Tria, G. S.; Edmonds, D. J. Angew. Chem., Int. Ed. 2008, 47,
1780–1783; (b) Yadav, J. S.; Tirupataiah, B.; Srihari, P. Tetrahedron 2010, 66,
2005–2009. The reaction worked well when Triton-B was utilized as a catalyst.
17. Clive, D. L. J.; Huang, X. Tetrahedron 2002, 58, 10243–10250.
18. (a) Horner, L.; Hoffmann, H.; Wippel, H. G. Chem. Ber. 1958, 91, 61–63; (b)
Wordswoth, W. S.; Emmons, W. D., Jr. J. Am. Chem. Soc. 1961, 83, 1733–1738;
(c) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405–4408.
10. For review on total synthesis of Securinega alkaloids see (a) Weinreb, S. M. Nat.
Prod. Rep. 2009, 26, 758–775; For other publications of securinines (b) Satoda,
I.; Murayama, M.; Tauji, J.; Yoahii, E. Tetrahedron Lett. 1962, 3, 1199–1206; (c)
Honda, T.; Namiki, H.; Kudoh, M.; Watanbe, N.; Nagase, H.; Mizutani, H.
Tetrahedron Lett. 2000, 41, 5927–5930; (d) Liras, S.; Davoren, J.; Bordner, J. Org.
lett. 2001, 3, 703–706; (e) Honda, T.; Namiki, H.; Watanbe, M.; Mizutani, H.
Tetrahedron Lett. 2004, 45, 5211–5213; (f) Honda, T.; Namiki, H.; Kaneda, K.;
Mizutani, H. Org. lett. 2004, 6, 87–89; (g) Alibes, R.; Ballbe, M.; Busque, F.;
March, P.; Elias, L.; Figuredo, M.; Font, J. Org. Lett. 2004, 6, 1813–1816; (h)
Bardaji, G. G.; Canto, M.; Alibes, R.; Bayon, P.; Busque, F.; March, D. D.;
Figueredo, M.; Font, J. J. Org. Chem. 2008, 73, 7657–7662; (i) Leduc, A. B.; Kerr,
M. A. Angew. Chem. 2008, 47, 7945–7948; (j) Dhudshia, B.; Cooper, B. F. T.;
Macdonald, C. L. B.; Thadani, A. N. Chem. Commmun. 2009, 45, 463–465; (k)
Gonzalez-Galvez, D.; Garcia-Garcia, E.; Alibes, R.; Bayon, P.; March, P.;
Figueredo, M.; Font, J. J. Org. Chem. 2009, 74, 6199–6211.
11. Other syntheses for norsecurinines (a) Jacobi, P. A.; Blum, C. A.; Desimome, R.
W.; Udodong, U. E. S. Tetrahedron Lett. 1989, 30, 7173–7176; (b) Han, G.;
Laporte, M. G.; Folmer, J. J.; Werner, K. M.; Weinreb, S. M. J. Org. Chem. 2000, 65,
6293–6306; (c) Alibes, R.; Bayon, P.; March, P. D.; Figueredo, M.; Font, J.;
Garcia-Garcia, E.; Gonzalez-Galvez, D. Org. Lett. 2005, 7, 5107–5109; (d)
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8059–8072; (f) Han, G.; Laporte, M. G.; Folmer, J. J.; Werner, K. M.; Weinreb, S.
M. Angew. Chem., Int. Ed. 2000, 39, 237–240; (g) Carson, C. A.; Kerr, M. Angew.
Chem. 2006, 118, 6710–6713; (h) Liu, P.; Hong, S.; Weinreb, S. M. J. Am. Chem.
Soc. 2008, 130, 7562–7756.
19. Selective analytical data; Allonorsecurinine 6: ½a D25
ꢁ
ꢀ40.0 (c 0.53, EtOH); lit.10f
½
a 2D5
ꢁ
ꢀ441.3 (c 0.3, EtOH). 1H NMR (500 MHz, CDCl3): d 6.83 (dd, J = 9.0, 6.0 Hz,
1 H), 6.73 (dd, J = 9.0, 0.7 Hz, 1H), 5.80 (s, 1H), 4.18 (t, J = 7.0 Hz, 1H), 4.04 (t,
J = 5.0 Hz, 1H), 2.98–2.89 (m, 2H), 2.88–2.80 (m, 1H), 2.05 (d, J = 10.0 Hz, 1H),
1.92–1.85 (m, 1H), 1.83–1.76 (m, 1H) 1.72–1.65 (m, 1H), 1.31–1.23 (m, 1H)
ppm. 13C NMR (75 MHz, CDCl3): d 172.0, 166.5, 147.8, 124.2, 110.3, 90.5, 68.8,
57.6, 49.1, 46.6, 27.7, 25.3; 10: ½a D20
ꢁ
ꢀ151.9 (c 0.7, CHCl3); Lit.10f a 2D5
½ ꢁ ꢀ166.8 (c
0.56, CHCl3). IR (NEAT): 2927, 2856, 1753, 1695, 1650, 1452, 1390, 1249, 1166,
1104, 1027, 922, 852, 764, 648 cmꢀ1 1H NMR (300 MHz, CDCl3): d 6.57 (d,
.
J = 9.8 Hz, 1H), 6.22 (dt, J = 9.8, 3.8 Hz, 1H), 5.57 (s, 1 H), 4.31 (dd, J = 5.7, 1.5 Hz,
1H), 3.53–3.46 (m, 1H), 3.27–3.17 (m, 1H), 2.50–2.37 (m, 3H), 2.18–1.73 (m,
5H), 1.38 (s, 9H) ppm. 13C NMR (75 MHz, CDCl3): d 172.8, 166.1, 154.8, 135.3,
122.6, 109.8, 87.5, 79.3, 58.1, 47.1, 30.1, 26.2, 24.4, 24.3. MS (ESI): m/z 328
[M+Na]+. HRMS (ESI): m/z calculated for C17H23O4NNa 328.15193, found 328.
12. (a) Srihari, P.; Mahankali, B.; Rajendra Prasad, K. Tetrahedron Lett. 2012, 53, 56–
58; (b) Srihari, P.; Satyanarayana, K.; Ganganna, B.; Yadav, J. S. J. Org. Chem.
2011, 76, 1922–1925; (c) Yadav, J. S.; Mandal, S. S.; Reddy, J. S. S.; Srihari, P.
Tetrahedron 2011, 67, 4620–4627; (d) Srihari, P.; Maheswar Rao, G.; Srinivasa
Rao, R.; Yadav, J. S. Synthesis 2010, 2407–2412; (e) Srihari, P.; Kumaraswamy,
B.; Shankar, P.; Ravishashidhar, V.; Yadav, J. S. Tetrahedron Lett. 2010, 51, 6174–
6176; (f) Srihari, P.; Kumaraswamy, B.; Bunia, D. C.; Yadav, J. S. Tetrahedron Lett.
2010, 51, 2903–2905; (g) Srihari, P.; Kumaraswamy, B.; Maheswar Rao, G.;
Yadav, J. S. Terahedron: Asymmetry 2010, 21, 106–111.
15195; 11: ½a 2D0
ꢁ
ꢀ85.4 (c 0.68, CHCl3). IR (KBr): 3413, 2977, 2932, 1685, 1407,
1361, 1252, 1092, 981, 879, 654, 568 cmꢀ1
.
1H NMR (500 MHz, CDCl3): d
6.89–6.81(m, 1H) 6.17 (d, J = 9.5 Hz, 1H), 4.36 (d, J = 4.0 Hz, 1H), 4.16 (s, 1H),
3.54–3.46 (m, 1H), 3.26–3.21 (m, 1H), 2.50-2.37 (m, 2H), 2.20–2.15 (m, 1H),
2.07–1.91 (m, 4H), 1.74–1.67 (m, 1H), 1.38 (s, 9H) ppm. 13C NMR (75 MHz,
CDCl3): d 200.1, 155.2, 147.0, 128.5, 79.4, 77.4, 59.6, 47.5, 32.5, 28.1, 26.1, 24.7,
24.1 ppm. MS (ESI): m/z 304 [M+Na]+. HRMS (ESI): m/z calculated for C15
H23O4NNa 304.15193, found 304.15188.