Total synthesis of the tetracyclic lupin alkaloid (+)-allomatrine

Article abstract of DOI:10.1021/ol402198n

(+)-Allomatrine (1) has been synthesized using an imino-aldol reaction and N-acyliminium cyclization as key steps. Strategically, use of the tert-butylsulfinimine derivative of (E)-4-(trimethylsilyl)but-2-enal enabled the staged formation of three C-C bon

Full text of DOI:10.1021/ol402198n

ORGANIC
LETTERS
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Vol. XX, No. XX
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Total Synthesis of the Tetracyclic Lupin
Alkaloid (þ)-Allomatrine
Samuel V. Watkin,† Nicholas P. Camp,‡ and Richard C. D. Brown*,†
Department of Chemistry, The University of Southampton, Highfield, Southampton
SO17 1BJ, U.K., and Eli Lilly Research Centre U.K., Erl Wood Manor,
Windlesham GU20 6PH, U.K.
rcb1@soton.ac.uk
Received August 2, 2013
ABSTRACT
(þ)-Allomatrine (1) has been synthesized using an imino-aldol reaction and N-acyliminium cyclization as key steps. Strategically, use of the
tert-butylsulfinimine derivative of (E)-4-(trimethylsilyl)but-2-enal enabled the staged formation of three CꢀC bonds, a CꢀN bond, and the four
stereogenic centers within the target.
(þ)-Allomatrine (1) is a tetracyclic lupin alkaloid of the
matrine structural class (Figure 1) first reported in 1952 as
a product of chemical epimerization of (þ)-matrine (2)
at C6.1ꢀ3 While (þ)-matrine (2) was obtained from the
root bark of Sophora flavescens by Nagai as early as 1889,4
(þ)-allomatrine has only recently been reported as a
chemicalcomponent from the Sophora species.5 Curiously,
Orechoff isolated an alkaloid, (ꢀ)-leontine (3),6 from
Leontice eversmanni Bge. in the 1930s that was later shown
to be the enantiomer of (þ)-allomatrine (1).7 Matrine (2)
and its related alkaloids exhibit a variety of interesting
biological activities such as anticancer, promotion of hair
growth, and antiviral activity.5b,8 Notably, (þ)-allomatrine
(1) mediates antinociception in mice through selective
activity at the κ-opioid receptor while being structurally
distinct from known pharmacological agents.9
Three total syntheses of racemic matrine have been
accomplished with varying levels of diastereocontrol,10ꢀ12
and a mixture enriched in (()-allomatrine ((()-leontine) was
obtained by Mandell and co-workers from Pd-catalyzed
† The University of Southampton.
‡ Eli Lilly Research Centre U.K.
(1) Isomerization of (þ)-matrine to (þ)-allomatrine: Ochiai, E.;
Okuda, S.; Minato, H. Yakugaku Zasshi. 1952, 72, 781–784.
(2) Structural and stereochemical elucidation: (a) Bohlmann, F.;
Weise, W.; Rahtz, D.; Arndt, C. Chem. Ber. 1958, 91, 2176–2189. (b)
Tsuda, K.; Mishima, H. J. Org. Chem. 1958, 23, 1179–1183. X-ray
structure: (c) Ibragimov, B. T.; Tishenko, G. N.; Kushmuradov, Y. K.;
Aripov, T. F.; Sadikov, A. S. Khim. Prir. Soedin. 1979, 416–417.
Absolute stereochemistry (inferred from 11R configuration in
(þ)-matrine): (d) Okuda, S.; Yoshimoto, M.; Tsuda, K.; Utzugi, N.
Chem. Pharm. Bull. 1966, 14, 314–318.
(3) For a review of lupin alkaloids, see: (a) Ohmiya, S.; Saito, K.;
Murakoshi, I. In The Alkaloids: Chemistry and Pharmacology; Cordell,
G. A., Ed.; Academic Press: New York, 1995; Vol. 47, pp 1ꢀ114. For the
most recent in a series of reviews of quinolizidine alkaloids, see:
(b) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139–165.
(6) Orechoff, A.; Konowalowa, R. Arch. Pharm. 1932, 270, 329–334.
(7) Rulko, F.; Proskurnina, N. F. Zh. Obshch. Khim. 1961, 31, 308–
313.
(8) For examples, see: (a) Ma, L. D.; Wen, S. H.; Zhan, Y.; He, Y. J.;
Uu, X. S.; Jiang, J. K. Planta Med. 2008, 74, 245–251. (b) Roh, S.-S.;
Kim, C. D.; Lee, M.-H.; Hwang, S.-L.; Rang, M.-J.; Yoon, Y.-K. Derm.
Sci. 2002, 30, 43–49. (c) Gao, L. M.; Han, Y. X.; Wang, Y. P.; Li, Y. H.;
Shan, Y. Q.; Li, X.; Peng, Z. G.; Bi, C. W.; Zhang, T. A.; Du, N. N.;
Jiang, J. D.; Song, D. Q. J. Med. Chem. 2011, 54, 869–876.
(9) Higashiyama, K.; Takeuchi, Y.; Yamauchi, T.; Imai, S.; Kamei,
J.; Yajima, Y.; Narita, M.; Suzuki, T. Biol. Pharm. Bull. 2005, 28, 845–
848.
(10) Mandell, L.; Singh, K. P.; Gresham, J. T.; Freeman, W. J. J. Am.
Chem. Soc. 1965, 87, 5234–5236.
(11) Chen, J.; Browne, L. J.; Gonnela, N. C. J. Chem. Soc., Chem.
Commun. 1986, 905–907.
(12) Boiteau, L.; Boivin, J.; Liard, A.; Quiclet-Sire, B.; Zard, S. Z.
Angew. Chem., Int. Ed. 1998, 37, 1128–1131.
(4) Nagai, N. Yakugaku Zasshi 1889, 9, 54–87.
(5) Allomatrine is described as a natural product in previous pub-
lications; however, these papers give reference to isomerized matrine or
personal communications. For isolation of (þ)-allomatrine Sophora
species, see: (a) Xiao, P.; Li, J.; Kubo, H.; Saito, K.; Murakoshi, I.;
Ohmiya, S. Chem. Pharm. Bull. 1996, 44, 1951–1953. (b) Ding, P.-L.;
Liao, Z.-X.; Huang, H.; Zhou, P.; Chen, D.-F. Bioorg. Med. Chem. Lett.
2006, 16, 1231–1235. (c) Liu, X.-J.; Cao, M.-A.; Li, W.-H.; Shen, C.-S.;
Yan, S.-Q.; Yuan, C.-S. Fitoterapia 2010, 81, 524–527.
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10.1021/ol402198n
XXXX American Chemical Society

isomerization of synthetic (()-matrine.10 Okuda et al.
also reported a semisynthesis of (þ)-allomatrine from
octadehydromatrine,13 which required optical resolution of
an intermediate. We are not aware of any stereocontrolled
total syntheses of allomatrine, although Zard and co-
workers obtained a tetracyclic intermediate with the required
relative stereochemistry as a minor diastereoisomer during
their total synthesis of (()-matrine using a xanthate-
mediated radical cascade approach.12
Closure of the final B ring of the tetracycle would then
proceed by using RCM.19 The key allylsilane functionality
could be introduced through an imino-aldol reaction of the
enolate obtained from phenyl 5-chloropentanoate and the
tert-butylsulfinimine of (E)-4-(trimethylsilyl)but-2-enal,14
where the ester group would later provide suitable
functionality to append the C/D ring precursor to the
N-acyliminium ion.
Scheme 2. Imino-aldol Reaction and Subsequent Synthesis of
N-Allylated Piperidine 10
Figure 1. Tetracyclic alkaloids of the matrine family.
As a prelude to the enantiocontrolled synthesis of tetra-
cyclic lupin alkaloids containing a quinolizidine core, we
recently described a short stereoselective synthesis of
epilupinine14 using an imino-aldol reaction of a tert-
butylsulfinimine as the key step.15,16 The high level of syn
diastereoselectivity attained by using the imino-aldol was
considered to provide an excellent platform for a stereo-
controlled synthesis of other quinolizidine-containing
lupin alkaloids.3 Here we describe a stereocontrolled
synthesis of (þ)-allomatrine (1) using an imino-aldol reac-
tion and N-acyliminium ion cyclization as key steps.
Scheme 1. Synthetic Plan for (þ)-Allomatrine (1)
First, a convenient access to sulfinimine 7 was achieved
in 77% yield over two steps through formation of the tert-
butylsufinimine 6 of acrolein followed by cross-metathesis
with allyltrimethylsilane (Scheme 2).20 The alternative
order of steps gave inferior yields and the inconvenience
of a rathervolatile and sensitive aldehyde intermediate. The
lithium enolate of phenyl 5-chlorovalerate (8) underwent
(17) For reviews of N-acyliminium ion chemistry, see: (a) Speckamp,
W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817–3856. (b) Marson,
C. M. ARKIVOC 2001, (i), 1–16. (c) Maryanoff, B. E.; Zhang, H. C.;
Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem. Rev. 2004, 104, 1431–
1628. (d) Gonzalez-Lopez, M.; Shaw, J. T. Chem. Rev. 2009, 109, 164–
189. (e) Yazici, A.; Pyne, S. G. Synthesis 2009, 513–541.
Analysis of the tetracyclic framework of allomatrine (1)
suggested that the C7ꢀC11 bond could be formed through
addition of an N-acyliminium ion to a sufficiently reactive
pendant alkene, such as an allylsilane (Scheme 1).17,18
(18) For early examples of allylsilane addition to N-acyliminium
ions. Intermolecular: (a) Hart, D. J.; Tsai, Y. M. Tetrahedron Lett.
1981, 22, 1567–1570. (b) Kraus, G. A.; Neuenschwander, K. J. Chem.
Soc., Chem. Commun. 1982, 134–135. (c) Aratani, M.; Sawada, K.;
Hashimoto, M. Tetrahedron Lett. 1982, 23, 3921–3924. Intramolecular:
(d) Hiemstra, H.; Sno, M. H. A. M.; Vijin, R. J.; Speckamp, W. N.
J. Org. Chem. 1985, 50, 4014–4020. For further examples, see ref 17.
(19) van den Broek, S. A. M. W.; Meeuwissen, S. A.; van Delft, F. L.;
Rutjes, F. P. J. T. In Metathesis in Natural Product Synthesis: Strategies,
Substrates and Catalysts; Cossy, J., Arseniyadis, S., Meyer, C., Eds.;
WileyꢀVCH Verlag: Weinheim, 2010; pp 45ꢀ85.
(13) Okuda, S.; Yoshimoto, M.; Tsuda, K. Chem. Pharm. Bull. 1966,
14, 275–279.
(14) Cutter, A. C.; Miller, I. R.; Keily, J. F.; Bellingham, R. K.; Light,
M. E.; Brown, R. C. D. Org. Lett. 2011, 13, 3988–3991.
(15) For examples of imino-aldol reactions of sulfinimines, see: (a)
Tang, T. P.; Ellman, J. A. J. Org. Chem. 2002, 67, 7819–7832. (b) Davis,
F. A.; Reddy, R. T.; Reddy, R. E. J. Org. Chem. 1992, 57, 6387–6389.
(c) Davis, F. A.; Song, M. Org. Lett. 2007, 9, 2413–2416.
(16) For reviews of sulfinimines in synthesis, see: (a) Zhou, P.; Chen,
B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003–8030. (b) Morton, D.;
Stockman, R. A. Tetrahedron 2006, 62, 8869–8905. (c) Robak, M. T.;
Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600–3740.
(20) (a) Raghavan, S.; Krishnaiah, V.; Sridhar, B. J. Org. Chem.
2010, 75, 498–501. (b) BouzBouz, S.; De Lemos, E.; Cossy, J. Adv. Synth.
Catal. 2002, 344, 627–630.
B
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addition to sulfinimine 7 with near-perfect diastereoselec-
tivity (only one diastereoisomer was observed by 1H NMR);
a single syn adduct 5 was isolated in 75% yield.21 The
stereochemical assignment was confirmed in subsequent
derivatives (see below) and is consistent with a cyclic chair-
like transition-state model previously described.14,15 This
highly functionalized imino-aldol 5 was subjected to a one-
pot deprotection, cyclization, and allylation sequence fur-
nishing the alkylated piperidine 9in 81% yield over the three
steps. A single equivalent of HCl in dioxane was employed
in the deprotection of the sulfinyl group, with preservation
of the allylsilane functionality. Subsequent LiAlH4 reduc-
tion of the phenyl ester yielded primary alcohol 10, in
preparation for attachment of the C/D-ring precursor.
In the first approach to closing the C-ring, the primary
alcohol 10 was coupled with glutarimide under Mitsunobu
conditions to secure the bicyclic derivative 11 in 75% yield
(Scheme 3). The N-acyliminium precursor, aminal 12, was
accessed by reduction of glutarimide 11 with NaBH4/HCl
at ꢀ15 °C.22 Although this reduction proved to be capri-
cious, it allowed the cyclization to be explored. Pleasingly,
treatment of 12 with TfOH afforded the desired tricyclic
diene 13 in 74% yield as a predominant diastereoisomer.
The stereochemical course of the cyclization can be ac-
counted for by a kinetically controlled reaction proceeding
through a trans-decalin chairlike arrangement in the
transition state (Figure 2).18d Spectroscopic evidence to
support the stereochemical assignment of tricyclic diene 13
came from 1H NMR analysis and was later corroborated
with X-ray structural data for the tetracycle 16 formed
after successful RCM (see below).
Scheme 3. N-Acyliminium Cyclization and Total Synthesis of
(þ)-Allomatrine (1)
Attempts to improve the efficiency of the reduction of
glutarimide 11 under a variety of conditions met with
limited success, typicallyyieldingN-acyliminium precursor
12 with low conversion or as a complex mixture.23 There-
fore, 5,5-dimethoxypentanamide derivative 15 was targeted
as an alternative cyclization precursor (Scheme 3).24
The required primary amine 14 was obtained by conver-
sion of the alcohol 10 to the azide followed by azide reduc-
tion using LiAlH4. 5,5-Dimethoxypentanoic acid25 was
then coupled with primary amine 14 in 69% yield using
the cyclic triphosphate coupling reagent T3P (propylphos-
phonic anhydride). Treatment of acetal 15 with an excess of
BF3 OEt2 initiated a sequence of reactions culminating in
3
N-acyliminium ion formation and ring-closure to produce
tricylic diene 13 in 84% yield, effectively doubling the
overall yield for the transformation of 10 to diene 13.
Figure 2. Proposed chairlike TS arrangement in the N-acyliminium
cyclization reaction.
(21) We have observed improved diastereoselectivities for phenyl
esters compared to the corresponding methyl esters in imino-aldol
reactions with tert-butylsulfinimines (see ref 14).
The total synthesis of (þ)-allomatrine (1) was completed
by inducing RCM of the diene 13 by exposure to the
HoveydaꢀGrubbs II (HG II) catalyst in CH2Cl2, followed
by hydrogenation of 8,9-dehydroallomatrine (16) over
Pd/C. Gratifyingly, 8,9-dehydroallomatrine (16) afforded
crystals suitable for structural determination by X-ray
(22) Hubert, J. C.; Wijnberg, J. B. P. A.; Speckamp, W. N. Tetra-
hedron 1975, 31, 1437–1441.
ꢀ
(23) (a) Judd, W. R.; Ban, S.; Aube, J. J. Am. Chem. Soc. 2006, 128,
13736–13741. (b) Hande, S. M.; Nakajima, M.; Kamisaki, H.; Tsukano,
C.; Takemoto, Y. Org. Lett. 2011, 13, 1828–1831.
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4665–4673. (b) Hart, D. J.; Leroy, V. Tetrahedron 1995, 51, 5757–5770.
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1833–1836.
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Chen, J.; Chen, J.; Xie, Y.; Zhang, H. Angew. Chem., Int. Ed. 2012, 51,
1024–1027.
(26) Light, M. E.; Watkin, S. V.; Brown, R. C. D. Private commu-
nication to C.S.D. 2013, CCDC 948924.
Org. Lett., Vol. XX, No. XX, XXXX
C

In conclusion, a highly diastereoselective synthesis of
(þ)-allomatrine has been described (13% overall yield,
13 steps) involving an imino-aldol reaction and an intra-
molecular addition of an allylsilane to an N-acyliminium
as key steps. The introduction of the tert-butylsulfinimine
derivative of (E)-4-(trimethylsilyl)but-2-enal (7) is note-
worthy as this functional group-rich fragment is ultimately
responsible for the staged formation of 3 CꢀC bonds,
a CꢀN bond, and the four stereogenic centers within
the natural product and may be applied in the synthesis
of other polycyclic amines.
Acknowledgment. We acknowledge Eli Lilly, EPSRC,
and the European Regional Development Fund (ERDF,
ISCE-Chem, INTERREG IVa program 4061) for
support.
Figure 3. X-ray structure of 8,9-dehydroallomatrine (16).
diffraction (Figure 3),26 thus confirming the stereochemical
assignment of the product 13 from the N-acyliminium
cyclization. In addition, spectroscopic and physical data
for synthetic (þ)-allomatrine (1) were consistent with those
previously reported.1,27
Supporting Information Available. Experimental pro-
1
cedures, characterization data, and copies of H NMR
and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(27) (a) Bohlmann, F.; Zeisberg, R. Chem. Ber. 1975, 108, 1043–1051.
(b) Galasso, V.; Asaro, F.; Berti, F.; Pergolese, B.; Kovac, B.; Pichierri,
F. Chem. Phys. 2006, 330, 457–468. (c) Okuda, S.; Yoshimoto, M.;
Tsuda, K. Chem. Pharm. Bull. 1966, 14, 275–279. (d) Bohlmann, F.;
Schumann, D. Tetrahedron Lett. 1965, 2435–2440.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX