Total synthesis of (±)-maistemonine and (±)-stemonamide

Article abstract of DOI:10.1039/c0cc02612c

The first total synthesis of polycyclic Stemona alkaloid maistemonine has been achieved. The efficient approach features a stereoselective intramolecular Schmidt reaction, a ketone-ester condensation, and a Reformatsky reaction. Additionally, another Stemona alkaloid stemonamide was divergently synthesized from a common intermediate.

Full text of DOI:10.1039/c0cc02612c

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Total synthesis of (Æ)-maistemonine and (Æ)-stemonamidew
Zhi-Hua Chen, Yong-Qiang Zhang, Zhi-Min Chen, Yong-Qiang Tu* and Fu-Min Zhang*
Received 16th July 2010, Accepted 12th November 2010
DOI: 10.1039/c0cc02612c
The first total synthesis of polycyclic Stemona alkaloid maiste-
monine has been achieved. The efficient approach features a
stereoselective intramolecular Schmidt reaction, a ketone–ester
condensation, and a Reformatsky reaction. Additionally, another
Stemona alkaloid stemonamide was divergently synthesized from
a common intermediate.
synthesis of maistemonine (1e) with more intricate skeleton
has not been reported to date.
Maistemonine with a relatively complex polycyclic structure
consists of a tetracyclic nucleus and an a-methyl-g-butyrolactone
moiety annexed to C-3 as a side-chain, and contains five
stereogenic carbons including two contiguous hetero-quaternary
centers. Its challenging molecular architecture and potential
biological activities prompted us to develop an efficient and
economical synthesis based on rational synthetic design.
Herein, we report the first synthetic strategy that leads back to
a readily available compound to the pentacyclic alkaloid,
(Æ)-maistemonine (1e).
The traditional Chinese and Japanese medicine Stemona has
long been used for the treatment of respiratory diseases, such
as pertussis and tuberculosis, and also used as vermifuges and
insecticides.1 So far, more than 80 alkaloids have been isolated
from the Stemona plants, and Pilli et al. have classified them
into eight groups according to their structural features,2
A retrosynthetic analysis of 1e is shown in Scheme 1. We
envisioned that the right-side butyrolactone unit E of 1e could be
forged through a Reformatsky-type reaction. The spirolactone
ring D at C-12 might be established by the Dieckmann
condensation or ketone–ester condensation. Construction of
the enone ring C from 4 would involve sequential oxidation,
reduction and aldol cyclization. A particularly appealing entry to
wherein
a family of stemonamine group including six
Stemona alkaloids (1a–1f) is characterized by the inclusion of
a spirolactone ring at C-12 of the basic azatricyclic 7,5,5-ring
system (Fig. 1). Among them, maistemonine (1e) was isolated
from the roots of Stemona mairei as one of the structurally
complex major components by Xu and co-workers in 1991,3
and has been shown to display significant antitussive activity.4
In the past decade, a number of ingenious synthetic efforts
towards (Æ)-stemonamine (1a),5c,e,f (Æ)-isostemonamine
(1b),5e (Æ)-stemonamide (1c),5a,b,d,e and (Æ)-isostemonamide
(1d)5a,b,d,e have been reported, including the first total synthesis
of (Æ)-stemonamine (1a) by our group. However, total
bicycle
4
was conceived via
a
highly stereoselective
intramolecular Schmidt reaction of precursor 5 which could be
derived from the known aldehyde 65f in three steps.
The convenient preparation of the key precursor 3 is
outlined in Scheme 2. Selective Grignard addition of
ethynylmagnesium chloride to the known tricarbonyl
compound 6, followed by the mesylation, resulted in the
formation of the ketone mesylate 7. The mesylate group in 7
was subsequently substituted by NaN3 to give the secondary
azide 5. With 5 in hand, the key intramolecular Schmidt
Fig. 1 Six alkaloids of the stemonamine group.
State Key Laboratory of Applied Organic Chemistry & Department
of Chemistry, Lanzhou University, Lanzhou 730000, P. R. China.
E-mail: tuyq@lzu.edu.cn; Fax: +86 931-8915557
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization of all new compounds including X-ray
data for compounds 2 and 1e. CCDC 782618–782619. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c0cc02612c
Scheme 1 Retrosynthetic analysis of (Æ)-maistemonine.
c
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D based on a ketone–ester condensation11 was designed
(path b). As depicted in Scheme 4, reaction of ketone 3 with
LHMDS and propanal efficiently provided b-hydroxy ketone 9
as a single diastereoisomer. Oxidation using Dess–Martin
periodinane12 afforded the desired b-dicarbonyl compound.
To introduce the contiguous spirocyclic quaternary center, the
nonpurified b-dicarbonyl compound was initially treated with
Davis’ reagent, resulting in the unexpected rearrangement
product.13 Gratifyingly, reaction of the crude b-dicarbonyl
i
compound with 10 mol% CeCl3Á7H2O in PrOH under an
atmosphere of oxygen14 furnished a-hydroxylation adduct 10
accompanied by its epimer in the ratio of 8 : 1, which were
readily separated by column chromatography. The desired
major isomer was converted to carbonate 11 by treatment
with ethyl chloroformate in CH2Cl2 at room temperature.
With the vital intermediate in hand, the unique
intramolecular ketone–ester condensation to access the
spirolactone D was attempted. After extensive investigation,
it was found that treatment of 11 with KHMDS in THF at À78
Scheme 2
reaction6 of secondary azide was then investigated. To our
delight, the desired amide 4 was obtained by using Lewis acid
TiCl4 in a stereoselective form.7 The remarkable stereoselectivity
might be understood by considering the unfavored steric
hindrance between 2-methylenebutyl and alkynyl moieties in
the transition state.8 The introduction of the alkynyl group was
elaborate for the convenient establishment of ring E and also
made it possible to obtain stemonamide (1c) in the later stage.
Ozonolysis and subsequent Lindlar reduction9 produced the
corresponding terminal olefin, which was subjected to aldol
condensation without purification with K2CO3 in MeOH to
provide the crucial tricyclic product 3 in 23% overall yield from
6. It should be noted that the use of stronger bases such as
tBuOK was not suitable for this cyclization in which a reto-aza-
Michael process might account for the observed epimerization
at C-2 of 3.10
to 10 1C for
5 h, followed by O-methylation with
diazomethane, provided tetracyclic skeleton 2 in good yield.
Its relative stereochemistry was confirmed by X-ray
crystallography.15 Indeed, exposure of 11 to other bases
t
(LDA, LHMDS, NaHMDS, or BuOK) only resulted in the
substrate decomposition, and the selection of less bulky ethoxy
as leaving group is crucial in this ring closure reaction.16 This
method provides a novel approach for the construction of
similarly unsaturated spirolactone skeleton.5a,c,d
With the tetracyclic core of maistemonine completed, the
final challenge was stereoselective establishment of ring E. By
comparing the relative configurations of 2 and 1e, we found the
inconsistency of the C-3 stereochemistry. After accessing
aldehyde 15 by oxidative cleavage of 2 (Scheme 5), we
investigated the epimerization of C-3 via the enolization/
protonation sequence from a-face. A variety of bases and
proton sources were attempted, however, no desired
epimerization product was observed.
The next steps of the synthesis required the construction of
ring D. According to our previous study in the total synthesis
of (Æ)-stemonamine (1a), the spirolactone D might be
established by the Dieckmann condensation5c in path a
(Scheme 3). A series of bases with the combination of
various solvents were carefully examined for the cyclization
of 14, however no expected ring closure product was obtained.
Therefore, an alternative strategy for the construction of ring
As an alternative synthetic approach to 1e (Scheme 6), we
explored the reduction of the lactam carbonyl without
touching double bond and other carbonyls in 2. Pleasingly,
after extensive experimentation, the desired tertiary amine 12
was obtained by means of O-methylation and reductive
removal of lactam carbonyl in a chemoselective reduction
manner. Oxidative cleavage of the terminal vinyl moiety in
12 with K2OsO4–NaIO4 provided the requisite aldehyde 13 in
64% yield. Notably, a slow C-3 epimerization of 13 in CDCl3
at room temperature was observed during the NMR analysis,
and a one pot protocol of epimerization and construction of
ring E was conceived. To our delight, treatment of 13 with
ethyl bromomethylacrylate and zinc in THF,17 followed by
Scheme 3 Two designed strategies for construction of ring D.
Scheme 4
Scheme 5
c
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Chem., 1978, 42, 457–463; (c) Y. Ye, G.-W. Qin and R.-S. Xu,
Phytochemistry, 1994, 37, 1205–1213.
2 For recent reviews, see: (a) R. A. Pilli and M. C. F. de Oliverira,
Nat. Prod. Rep., 2000, 17, 117–127; (b) R. A. Pilli, G. B. Rosso and
M. C. F. de Oliverira, in The Alkaloids, ed. G. A. Cordell, Elsevier,
New York, 2005, vol. 62, pp. 77–173; (c) H. Greger, Planta Med.,
2006, 72, 99–113.
3 (a) W. Lin, Y. Ye and R.-S. Xu, Youji Huaxue, 1991, 11, 500–503;
(b) Y. Ye, G.-W. Qin and R.-S. Xu, J. Nat. Prod., 1994, 57,
665–669.
4 X.-Z. Yang, J.-Y. Zhu, C.-P. Tang, C.-Q. Ke, G. Lin, T.-Y. Cheng,
J. A. Rudd and Y. Ye, Planta Med., 2009, 75, 174–177.
5 (a) A. S. Kende, J. I. M. Hernando and J. B. J. Milbank, Org. Lett.,
2001, 3, 2505–2508; (b) A. S. Kende, M. J. I. Hernando and J. B.
J. Milbank, Tetrahedron, 2002, 58, 61–74; (c) Y.-M. Zhao,
P.-M. Gu, Y.-Q. Tu, C.-A. Fan and Q.-W. Zhang, Org. Lett.,
2008, 10, 1763–1766; (d) T. Taniguchi, G. Tanabe, O. Muraoka and
H. Ishibashi, Org. Lett., 2008, 10, 197–199; (e) T. Taniguchi and
H. Ishibashi, Tetrahedron, 2008, 64, 8773–8779; (f) Y.-M. Zhao,
P.-M. Gu, H.-J. Zhang, Q.-W. Zhang, C.-A. Fan, Y.-Q. Tu and
F.-M. Zhang, J. Org. Chem., 2009, 74, 3211–3213.
Scheme 6
subsequent hydrogenation of the exo-double bond of the
resulting unstable a-methylen-g-lactone intermediate in the
presence of Pd/C under atmospheric pressure, produced
(Æ)-maistemonine (1e) stereoselectively.18 Its NMR spectra
were in all aspects identical with the spectra of natural
product. The relative configuration of 1e was unambiguously
established by the later X-ray analysis.15
6 For the intramolecular Schmidt reaction, see: (a) J. Aube
G. L. Milligan, J. Am. Chem. Soc., 1991, 113, 8965–8966;
(b) G. L. Milligan, C. J. Mossman and J. Aube, J. Am. Chem.
Soc., 1995, 117, 10449–10459.
7 The intramolecular Schmidt reaction was used by Aube
synthesis of the stenine alkaloids featuring a 7,6,5-tricyclic core,
see: (a) J. E. Golden and J. Aube, Angew. Chem., Int. Ed., 2002, 41,
4316–4318; (b) Y. Zeng and J. Aube, J. Am. Chem. Soc., 2005, 127,
15712–15713; (c) K. J. Frankowski, J. E. Golden, Y. Zeng and
J. Aube, J. Am. Chem. Soc., 2008, 130, 6018–6024.
´
and
´
´
et al. in the
´
´
Interestingly, another Stemona alkaloid (Æ)-stemonamide
(1c) was obtained in 83% yield from 12 in the oxidative
cleavage reaction by increasing the amount of NaIO4,
elevating the reaction temperature and prolonging the
reaction time (Scheme 6). Spectral data of 1c were in
agreement with the authentic data of stemonamide.3b Thus,
we have accomplished a new route to stemonamide.5a,d
In summary, the first total synthesis of (Æ)-maistemonine
(1e) was achieved in 19 steps with an overall yield of 5% from
known compound 6. Key transformations include a highly
stereoselective intramolecular Schmidt reaction of secondary
azide to form the central perhydroazaazulene ring system, a
new protocol for the construction of the spirolactone ring
through a ketone–ester condensation, and a sequence of
Reformatsky reaction and hydrogenation involving
epimerization of C-3 to introduce the vicinal butyrolactone
moiety. Besides, (Æ)-stemonamide (1c) was divergently
synthesized from intermediate 12 in the later stage. It is
noteworthy that the synthetic strategy described here is a
step economy process and no extra protecting-group
manipulations were required in the current total synthesis.
This work was supported by the NSFC (Nos. 20621091,
20672048, 20732002, and 20972059) and ‘‘111’’ program of
MOE. We also thank Prof. W. Lin (Peking University) and
Prof. Y. Ye (Shanghai Institute of Materia Medica) for
providing us the NMR spectra and the sample of
maistemonine.
´
8 Proposed process for the stereoselective Schmidt reaction.
9 H. Lindlar and R. Dubuis, Org. Synth., 1966, 46, 89–91.
10 Diastereoisomers (ca. 5 : 1) were obtained by using tBuOK in this
cyclization.
11 V. H. Wallingford, A. H. Homeyer and D. M. Jones, J. Am. Chem.
Soc., 1941, 63, 2252–2254.
12 D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155–4156.
13 F. A. Davis, H. Liu, B.-C. Chen and P. Zhou, Tetrahedron, 1998,
54, 10481–10492.
14 (a) J. Christoffers and T. Werner, Synlett, 2002, 119–121;
(b) J. Christoffers, T. Werner, S. Unger and W. Frey, Eur. J. Org.
Chem., 2003, 425–431.
15 See ESIw.
16 Exposure of analogous substrate with tert-butoxy as leaving group
could not give ring closure product under the same condition. It
was assumed that the bulky tert-butoxy group retarded the
ketone–ester condensation.
17 (a) A. P. Rauter, J. Figueiredo, M. Ismael, T. Canda, J. Font and
M. Figueredo, Tetrahedron: Asymmetry, 2001, 12, 1131–1146;
´ ´ ´
(b) F. Sanchez-Izquierdo, P. Blanco, F. Busque, R. Alibes, P. de
March, M. Figueredo, J. Font and T. Parella, Org. Lett., 2007, 9,
1769–1772.
18 It was assumed that simple epimerization of the aldehyde
a-stereocenter or a retro-Mannich and Mannich process (see
ref. 5e) might account for the epimerization of the stereogenic
center C-3 (or C-4 and C-12) in the epimerization/Reformatsky
reaction.
Notes and references
1 (a) H. Iizuka, H. Irie, N. Masaki, K. Osaki and S. Ueno, J. Chem.
Soc., Chem. Commun., 1973, 125–126; (b) K. Sakata, K. Aoki,
C.-F. Chang, A. Sakurai, S. Tamura and S. Murakoshi, Agric. Biol.
c
1838 Chem. Commun., 2011, 47, 1836–1838
This journal is The Royal Society of Chemistry 2011