Diastereoselective synthesis of allosecurinine and viroallosecurinine from menisdaurilide

Article abstract of DOI:10.1021/jo801470u

(Chemical Equation Presented) A new and versatile synthetic route to Securinega alkaloids is reported. The first synthesis of allosecurinine has been accomplished in seven steps and 40% yield, starting from (+)-menisdaurilide, using a vinylogous Mannich reaction as the key transformation. Similarly, viroallosecurinine has been synthesized from (-)-menisdaurilide.

Full text of DOI:10.1021/jo801470u

Diastereoselective Synthesis of Allosecurinine and Viroallosecurinine
from Menisdaurilide
Gisela G. Bardaj´ı, Mariona Canto´, Ramo´n Alibe´s, Pau Bayo´n, Fe´lix Busque´,*
Pedro de March,* Marta Figueredo, and Josep Font
Departament de Qu´ımica, UniVersitat Auto`noma de Barcelona, 08193 Bellaterra, Spain
felix.busque@uab.es; pere.demarch@uab.es
ReceiVed July 4, 2008
A new and versatile synthetic route to Securinega alkaloids is reported. The first synthesis of allosecurinine
has been accomplished in seven steps and 40% yield, starting from (+)-menisdaurilide, using a vinylogous
Mannich reaction as the key transformation. Similarly, viroallosecurinine has been synthesized from
(-)-menisdaurilide.
The Securinega alkaloids include a large number of polycyclic
compounds elaborated mainly by plants of the genus Securinega
and Phyllanthus belonging to the Euphorbiaceae family.1 Some
of these alkaloids exhibit several pharmacological activities,
including diuretic, hepatic protection, antimicrobial, antibacterial,
and GABAA receptor antagonism, among others.2 The most
representative examples of these alkaloids are securinine 1, first
isolated in 1956,3 its epimer at C-2, allosecurinine 2, their
corresponding enantiomers, virosecurinine and viroallosecuri-
nine, respectively, and (-)-norsecurinine 3 (Figure 1). Most
Securinega alkaloids present a tetracyclic structure, enclosing
a benzofuranone subunit (rings C and D) and either a piperidine
FIGURE 1. Representative examples of Securinega alkaloids and other
natural products.
or pyrrolidine ring (ring A), with the size of this last ring
characterizing the securinine- and norsecurinine-type subgroups,
respectively.
fashion,4 whereas the rings C and D (ArC2 subunit) come from
tyrosine,4b,5 which is in turn biosynthesized from shikimic acid.
In 1978 Parry proposed a biosynthesis of Securinega alkaloids
consistent with the former experiments (Scheme 1, path a).5
According to his proposal, tyrosine would be initially trans-
formed into bicyclic intermediate 8, where rings A and C are
already present. The route would continue with an intramolecular
1,4-addition to close ring D, furnishing the tricyclic precursor
9, and the subsequent reduction of the carbonyl group would
The biosynthesis of Securinega alkaloids received particular
attention in the 1970s (Scheme 1). On the basis of experiments
performed with labeled precursors, it was established that the
piperidine ring A of securinine is derived from a C5N subunit
(∆1-piperidine 7), formed from lysine in a nonsymmetrical
(1) Snieckus, V. In The Alkaloids; Manske, R. H. F., Ed.; Academic Press:
New York, 1973;Vol. 14, pp 425-503.
(2) (a) Rognan, D.; Boulanger, T.; Hoffmann, R.; Vercauteren, D. P.; Andre,
J.-M.; Durant, F.; Wermuth, C.-G. J. Med. Chem. 1992, 35, 1969–1977. (b)
Han, G.; LaPorte, M. G.; Folmer, J. J.; Werner, K. M.; Weinreb, S. M. J. Org.
Chem. 2000, 65, 6293–6306, and references therein. (c) Bayo´n, P.; Busque´, F.;
Figueredo, M. Targets Heterocycl. Syst. 2005, 9, 281–310, and references therein.
(3) Murev’eva, V. L.; Ban’kovskii, A. I. Dokl. Akad. Nauk. SSSR 1956, 110,
998–1000.
(4) (a) Golebiewski, W. M.; Horsewood, P.; Spencer, I. D. J. Chem. Soc.,
Chem. Commun. 1976, 217–218. (b) Sankawa, U.; Ebizuka, Y.; Yamasaki, K.
Phytochemistry 1977, 16, 561–563.
(5) Parry, R. J. Bioorg. Chem. 1978, 7, 277–288.
10.1021/jo801470u CCC: $40.75
Published on Web 09/10/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7657–7662 7657

Bardají et al.
SCHEME 1. Putative Biosynthesis of Securinine: Path a,
Parry’s Proposal; Path b, Alternative Route
SCHEME 2. Retrosynthetic Analysis
diastereoselective synthesis of both antipodes of menisdaurilide,
starting from p-benzoquinone and using (R,R)-hydrobenzoin as
a chiral auxiliary.14
With our biosynthetic considerations about Securinega alka-
loids in mind, we envisaged a novel stereoselective synthesis
of these alkaloids starting from menisdaurilide (Scheme 2). The
key step of this new approach would be a vinylogous Mannich
reaction15 to connect the benzofuranone fragment 11 (rings C
and D), closely related to menisdaurilide, with the C5N or C4N
subunit (ring A), generating two of the three stereogenic centers
present in the targets. Both antipodes of menisdaurilide 4 would
be synthesized according to our reported procedure.14
Among the 14 publications describing total syntheses of
Securinega alkaloids,2b,12,13,16 only that reported by Liras et
al.16g made use of a vinylogous Mannich reaction involving a
C5N electrophilic synthon, but the nucleophilic partner was not
related with any possible biogenetic precursor.
generate the intermediate 10. Finally, an intramolecular nucleo-
philic substitution would afford the tetracyclic structure.
In 1984, the isomeric bicyclic lactones menisdaurilide (-)-4
and its epimer, aquilegiolide (-)-5 (Figure 1), were isolated
for the first time from Aquilegia atrata.6 Both epimers have
been isolated from other plants of the genus Phyllanthus7-9 and
Securinega.10 This last work reports for the first time the
simultaneous extraction of the bicyclic lactones 4 and 5 and
several Securinega alkaloids, among them securinine, from the
same plant. Studies about the biosynthesis of menisdaurilide or
aquilegiolide have not been reported, although a plausible
biosynthetic route for the related compound rengyolone 6 from
shikimic acid has been proposed.11
The structural similarity of 4 and 5, matching rings C and D
of the aforementioned Securinega alkaloids, the reported isola-
tion of all these natural products from plants of the same genus
Phyllanthus and Securinega, along with the recently discovered
common natural source, led us to consider the possibility that
the benzofuranones 4 and/or 5 could be intermediates in the
biosynthesis of the alkaloids. According to this alternative
biosynthetic route (Scheme 1, path b), the formation of the
benzofuranone skeleton (rings C and D of the alkaloids) would
precede the coupling with the C5N subunit (ring A of the
alkaloids) to afford the amino alcohol 10. This route would be
equally consistent with the labeling experiments described.4,5
In the past decade, we have been working in the synthesis of
Securinega alkaloids and have already described a diastereo-
selective synthesis of securinine and (-)-allonorsecurinine based
on materials from chiral pool12 and an enantioselective prepara-
tion of (-)-norsecurinine13 based on the use of asymmetric
catalysis. Our group has also developed a highly efficient
Herein we present a new diastereoselective synthesis of the
two Securinega alkaloids allosecurinine 2, and its enantiomer,
viroallosecurinine, through a straightforward sequence based
upon the retrosynthetic analysis outlined in Scheme 2.
Results and Discussion
We initiated our studies starting from the benzofuranone ketal
12(Scheme3),accessibleina45%yieldfromp-benzoquinone,14,17
and used as an advanced intermediate in our previously
mentioned synthesis of (+)-menisdaurilide (+)-4.14 The ketal
would serve both as a chiral directing group for the vinylogous
Mannich reaction and as a carbonyl protecting group. The
compound 1318 was selected as the C5N synthon.
Thus, the (7a)-epimeric mixture of 12 was treated with
triethylamine and triisopropylsilyl triflate (TIPSOTf) to furnish
the corresponding silyloxyfuran 14. The vinylogous Mannich
reaction between 14 and the piperidinium ion generated in situ
from 13 was accomplished using 1 equiv of TIPSOTf as Lewis
(13) Alibe´s, R.; Bayo´n, P.; de March, P.; Figueredo, M.; Font, J.; Garc´ıa-
Garc´ıa, E.; Gonza´lez-Ga´lvez, D. Org. Lett. 2005, 7, 5107–5109.
(14) Busque´, F.; Canto´, M.; de March, P.; Figueredo, M.; Font, J.; Rodr´ıguez,
S. Tetrahedron: Asymmetry 2003, 14, 2021–2032.
(15) (a) Bur, S. K.; Martin, S. F. Org. Lett. 2000, 2, 3445–3447. (b) Martin,
S. F. Acc. Chem. Res. 2002, 35, 895–904.
(16) (a) Horii, Z.; Hanaoka, M.; Yamawaki, Y.; Tamura, Y.; Saito, S.;
Shigematsu, N.; Kotera, K.; Yoshikawa, H.; Sato, Y.; Nakai, H.; Sugimoto, N.
Tetrahedron 1967, 23, 1165–1174. (b) Heathcock, C. H.; von Geldern, T. W.
Heterocycles 1987, 25, 75–78. (c) Jacobi, P. A.; Blum, C. A.; DeSimone, R. W.;
Udodong, U. E. S. J. Am. Chem. Soc. 1991, 113, 5384–5392. (d) Xi, F. D.;
Liang, X. T. Acta Pharm. Sin. 1992, 27, 349–352. (e) Magnus, P.; Rodr´ıguez-
Lo´pez, J.; Mulholland, K.; Matthews, I. J. Am. Chem. Soc. 1992, 114, 382–383.
(f) Magnus, P.; Rodr´ıguez-Lo´pez, J.; Mulholland, K.; Matthews, I. Tetrahedron
1993, 49, 8059–8072. (g) Liras, S.; Davoren, J. E.; Bordner, J. Org. Lett. 2001,
3, 703–706. (h) Honda, T.; Namiki, H.; Kudoh, M.; Nagase, H.; Mizutani, H.
Heterocycles 2003, 59, 169–187. (i) Honda, T.; Namiki, H.; Kaneda, K.;
Mizutani, H. Org. Lett. 2004, 6, 87–89. (j) Honda, T.; Namiki, H.; Watanabe,
M.; Mizutani, H. Tetrahedron Lett. 2004, 45, 5211–5213. (k) Magnus, P.; Padilla,
A. I. Org. Lett. 2006, 8, 3569–3571.
(6) Guerriero, A.; Pietra, F. Phytochemistry 1984, 23, 2394–2396.
(7) Bachman, T. L.; Ghia, F.; Torssell, K. B. G. Phytochemistry 1993, 33,
189–191.
(8) Kuster, R. M.; Mors, W. B.; Wagner, H. Biochem. Syst. Ecol. 1997, 25,
675–675.
(9) Youkwan, J.; Srisomphot, P.; Sutthivaiyakit, S. J. Nat. Prod. 2005, 68,
1006–1009.
(10) Wang, Y.; Li, Q.; Ye, W.-C.; Ip, F.; Ip, N.; Zhao, S.-X. Zhongguo
Tianran Yaowu 2006, 4, 260–263; Chem. Abstr. 2006, 146, 518050.
(11) Endo, K.; Seya, K.; Hikino, H. Tetrahedron 1989, 45, 3673–3682.
(12) Alibe´s, R.; Ballbe´, M.; Busque´, F.; de March, P.; Elias, L.; Figueredo,
M.; Font, J. Org. Lett. 2004, 6, 1813–1816.
(17) de March, P.; Escoda, M.; Figueredo, M.; Font, J.; Alvarez-Larena, A.;
Piniella, J. F. J. Org. Chem. 1995, 60, 3895–3897.
(18) Dieter, R. K.; Shama, R. R. J. Org. Chem. 1996, 61, 4180–4184.
7658 J. Org. Chem. Vol. 73, No. 19, 2008

DiastereoselectiVe Synthesis of Allosecurinine and Viroallosecurinine
SCHEME 3. Diastereoselective Synthesis of Allosecurinine,
First Approach
FIGURE 2. Preferred transition states for the vinylogous Mannich
reactions.
19
Ketone 16 was reduced with NaBH4 in presence of CeCl3
to furnish, essentially, a 1:1 mixture of the corresponding
diastereomeric alcohols in 58% yield, along with several
degradation products with phenolic structure. The ca. 1:1
mixture of alcohols was sequentially treated with PBr3 to afford
the corresponding allylic bromides and aqueous K2CO3 solution
to yield, in 75% yield for the two steps, a sample of the final
alkaloid, pure enough to be identified as allosecurinine according
SCHEME 4. Diastereoselective Synthesis of Allosecurinine
1
to its H NMR data and negative value of its specific rotation.
Following this experimental methodology, both intermediate
bromide derivatives proved to be reactive enough in the final
cyclization step to give the target alkaloid, despite the fact that
every diastereomer is expected to react through a different
mechanism and with distinct reaction rates.16j
The lack of orthogonality of the protecting groups, along with
the instability of the intermediate ketone 16, were two major
problems encountered across the above synthetic route. The
tactical modification to overcome these problems was starting
the synthesis from menisdaurilide 4 itself (Scheme 4).
Thus, the hydroxyl group of (+)-4 was protected as the tert-
butyldiphenylsilyl ether affording compound (-)-17 in 89%
yield (Scheme 4). This compound was treated with TIPSOTf
and TEA at 0 °C to furnish the corresponding silyloxyfuran,
which without further purification was used to react with the
piperidinium ion generated in situ from 13, under the vinylogous
Mannich reaction conditions. Thus, the condensation reaction
was accomplished using 1 equiv of n-Bu2BOTf as Lewis acid
in diethyl ether at -78 °C, giving a mixture of only two (among
the four possible) diastereomeric products in a ca. 4:1 ratio and
almost quantitative yield. Remarkably, these two isomers proved
to be easily separable by standard flash chromatography,
allowing the isolation of the major isomer (-)-18 in 76% yield
acid in CH2Cl2 at -78 °C, affording in 77% yield an inseparable
mixture of only two (among the four possible) diastereomeric
condensation products 15 in a ca. 5:1 ratio (Scheme 3),
1
according to its H NMR spectrum, which shows two sets of
signals due to the presence of the two diastereomers. Moreover,
for the major diastereomer, two signals corresponding to two
rotamers, in a proportion of ca. 4:1, are observed for some
protons. This assignment was corroborated with variable tem-
perature 1H NMR experiments and NOESY experiments, where
exchange signals between absorptions of the same proton but
corresponding to different rotamers were observed. The absolute
configuration of the major isomer was later established as
(2S,7a′S) by chemical correlation (vide infra).
1
(Scheme 4). The H NMR spectrum of (-)-18 shows two sets
of signals, due to the presence of two rotamers, in a proportion
of 6:1. This assignment was corroborated with variable tem-
1
perature H NMR and NOESY experiments, where exchange
signals between absorptions of the same proton but correspond-
ing to different rotamers were observed. This behavior, to a
lesser extent, can be guessed too in the 13C NMR spectrum.
The absolute configuration of (-)-18 was unambiguously
established as (2S,7a′S) by chemical correlation (vide infra) with
the natural alkaloid allosecurinine 2. The stereochemical
outcome of the reaction is also consistent with the preferential
formation of a threo adduct, according to Martin studies,15 and
the facial selectivity of the furan, now induced by the silyloxy-
ether substituent (Figure 2b).
The stereochemical outcome of the reaction is consistent with
the preferential formation of a threo adduct, through a “Diels-
Alder”-like transition state, according to Martin studies,15 and
the facial selectivity of the furan induced by the bulky ketal
moiety (Figure 2a).
To complete the remaining steps leading to allosecurinine
outlined in Scheme 3, the 5:1 mixture of isomers 15 was used,
although only the main isomer is depicted. Thus, the selective
hydrolysis of the ketal group of 15 was tried under different
experimental conditions but could not be achieved, since
concomitant deprotection of Boc group was always observed.
As the best result, by treating 15 with trifluoroacetic acid (TFA),
the unstable aminoketone 16 could be isolated in 58% yield.
Removal of the silyl protecting group in (-)-18 using
Et3N·3HF reagent led efficiently (90% yield) to the alcohol (-)-
19. Again, the 1H NMR spectrum of this compound shows two
(19) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454–5459.
J. Org. Chem. Vol. 73, No. 19, 2008 7659

Bardají et al.
(400 MHz, CDCl3): δ 7.75-7.60 (m, 4H, H-ar), 7.53-7.33 (m,
6H, H-ar), 6.46 (dd, J ) 10.0, 2.4 Hz, 1H: H-4), 6.21 (d, J ) 10.0
Hz, 1H, H-5), 5.75 (br s, 1H, H-3), 4.63 (ddd, J ) 13.4, 4.9, 1.7
Hz, 1H, H-7a), 4.55-4.51 (m, 1H, H-6), 2.67 (ddd, J ) 11.1, 5.2,
4.8 Hz, 1H, H-7eq), 1.79 (ddd, J ) 13.4, 11.0, 10.3 Hz, 1H, H-7’ax),
1.09 (s, 9H, C(CH3)3). 13C NMR (100 MHz, CDCl3): δ 173.3, 163.1,
144.4, 135.9, 133.1, 130.2, 128.0, 119.5, 111.2, 78.0, 68.2, 40.2,
26.9, 19.2. IR (ATR, cm-1): ν 2949, 2859, 1736 (CdO st.), 1639,
1426, 1324, 1020, 702. Anal. Calcd for C24H26O3Si: C, 73.81; H,
6.71. Found: C, 73.66; H, 6.83. HRMS (ESI+) m/z: calcd for
C24H26O3SiNa 413.1543 (MNa+); found 413.1550. [R]D -61.2 (c
2.0, CHCl3). Mp 109-110 °C (n-pentane/ether).
(6S,7aR)-6-(tert-Butyldiphenylsilanyloxy)-7,7a-dihydrobenzo-
furan-2(6H)-one (17). The same experimental procedure previously
described for the preparation of (-)-17 was followed, starting with
(350 mg, 2.300 mmol) of (-)-menisdaurilide, 4, and yielding (+)-
17 (819 mg, 2.10 mmol, 91% yield) as a white solid. [R]D +57.0
(c 1.8, CHCl3). Mp 109-110 °C (n-pentane/ether).
sets of signals due to the presence of two rotamers; in this case,
the proportion between rotamers is 83:17. This assignment was
corroborated, as in previous cases, with variable temperature
1H NMR and NOESY experiments. Sequential mesylation of
alcohol (-)-19 with MsCl and TEA, removal of the carbamate
group using TFA, and then treatment of the reaction mixture
with aqueous K2CO3 solution afforded the alkaloid allosecuri-
nine 2 in 69% overall yield for the three last steps, without
isolation of any of the involved intermediates. The optical
rotation of the synthetic material {[R]D -1092 (c 1.0, EtOH)}
is in agreement with the previously reported values {lit. -1082
(EtOH),20 -1004 (MeOH),21 -1082 (EtOH),22 -114023}.
Hence, the first synthesis of allosecurinine 2 has been completed,
in a seven-step sequence and 42% overall yield, starting from
(+)-menisdaurilide (+)-4. Considering our previous synthesis
of (+)-4,14 starting from p-benzoquinone and using (R,R)-
hydrobenzoin as a chiral auxiliary, the synthesis of allosecurinine
2 has been accomplished in 14 steps and 4.4% overall yield.
The same synthetic sequence depicted in Scheme 4 was also
performed starting from (-)-menisdaurilide (-)-4, giving access
to the alkaloid viroallosecurinine in 38% overall yield from (-)-
4, 3.8% from p-benzoquinone, {[R]D +1068 (c 1.2, EtOH), [lit.
+1084.6 (EtOH),24 +1200 (EtOH),25 +990 (EtOH),26 +1113
(EtOH)16j]}.
(2S,7aS,4′′R,5′′R)-tert-Butyl-2-{4′,5′-diphenyl-2-oxo-7,7a-dihy-
drospiro-[benzofuro-6(2H),2′-[1,3]dioxolan-7a-yl]}piperidine-1-
carboxylate (15). To a solution of an isomeric mixture of 1214
(301 mg, 0.87 mmol) in dry CH2Cl2 (15 mL) under argon
atmosphere and cooled to 0 °C, triethylamine (350 µL, 2.51 mmol)
was added, and the reaction mixture was stirred for 45 min at 0
°C. Then, TIPSOTf (255 µL, 0.95 mmol) was added, and the
reaction mixture was allowed to stir overnight at room temperature.
The reaction mixture was concentrated in vacuo to afford an oil
that was purified by flash chromatography with n-hexane/AcOEt
(9:1) to yield (4′R,5′R)-4′,5′-diphenyl-2-(triisopropyl)sililoxyspiro[ben-
zofuro-6(7H),2′-[1,3]dioxolan] 14 (427 mg, 0.85 mmol, 98%) as a
colorless oil. 1H NMR (250 MHz, CDCl3): δ 7.40-7.28 (6H, H-ar),
7.27-7.10 (4H, H-ar), 6.45 (d, J ) 9.7 Hz, 1H, H-4), 5.80 (d, J )
9.7 Hz, 1H, H-5), 5.11 (s, 1H, H-3), 4.83 (s, 2H, H-4′, H-5′), 3.46
(d, J ) 18.3 Hz, 1H, H-7), 3.33 (d, J ) 18.3 Hz, 1H, H-7),
1.40-1.15 (m, 3H, 3CH(CH3)2), 1.15-1.00 (m, 18H, 3CH(CH3)2).
13C NMR (62.5 MHz, CDCl3) δ (ppm): 156.4, 138.3, 136.2, 136.1,
128.4, 126.8, 126.7, 123.8, 123.0, 115.6, 108.5, 85.5, 84.8, 82.1,
36.0, 17.7, 12.3. EM (ESI+) m/z: 525 (M+ + 23, 100). To a solution
of 14 (556 mg, 1.11 mmol) in dry CH2Cl2 (20 mL) was added
another solution of tert-butyl-2-hydroxipiperidine-1-carboxylate
1318 (228 mg, 1.13 mmol) in dry CH2Cl2 (13 mL), and the solution
was cooled to -78 °C. Then, TIPSOTf (305 µL, 1.14 mmol) was
added dropwise during 5 min, and the mixture was allowed to stir
45 min at -78 °C. The mixture was quenched with NaHCO3
saturated solution (30 mL) and allowed to warm to room temper-
ature. Phases were separated, and the aqueous phase was extracted
with CH2Cl2 (2 × 30 mL). The combined organic layers were dried
(MgSO4) and concentrated in vacuo to afford an oil. This crude
material was purified by flash chromatography with n-hexane/
AcOEt (8:1 to 4:1) to yield a colorless oil identified as a inseparable
5:1 mixture of 15 and another related isomer (572 mg, 1.08 mmol,
97%). 1H NMR (400 MHz, CDCl3): δ 7.40-7.25 (6H, H-ar),
7.23-7.13 (4H, H-ar), 6.78 (d, J ) 10.0 Hz) + 6.73 (d, J ) 10.0
Hz) (1H, H-4′), 6.31 (d, J ) 10.0 Hz) + 6.20 (d, J ) 10.0 Hz)
(1H, H-5′), 5.91 (s) + 5.79 (s) + 5.78 (s) (1H, H-3′), 4.88 (d, J )
8.8 Hz) + 4.84 (d, J ) 8.8 Hz) + 4.77 (d, J ) 8.8 Hz) + 4.74 (d,
J ) 8.8 Hz) (2H, H-4′′, H-5′′), 4.67 (t, J ) 5.9 Hz) + 4.61 (t, J )
6.2 Hz) + 4.55 (t, J ) 6.2 Hz) (1H, H-2), 4.05 (dd, J ) 13.3 Hz,
J ) 5.6 Hz) + 3.84 (dd, J ) 13.3 Hz, J ) 5.6 Hz) (1H, H-6),
3.10-2.87 (m, 1H, H-6), 3.11 (d, J ) 13.8 Hz) + 3.03 (d, J )
12.6 Hz) (1H, H-7′), 2.29 (d, J ) 13.8 Hz) + 2.23 (d, J ) 13.5
Hz) + 2.22 (d, J ) 13.5 Hz) (1H, H-7′), 2.00 (m, 1H, H-3), 1.80
(m, 2H), 1.58-1.15 (m, 3H), 1.40 (s) + 1.37 (s) + 1.35 (s) (9H,
OC(CH3)3). 13C NMR (100 MHz, CDCl3) δ (ppm): 172.2, 165.0,
155.6, 135.2, 133.8, 128.5, 126.5, 124.0, 112.6, 105.6, 90.0, 85.5,
85.4, 79.4, 53.6, 42.0, 40.8, 28.2, 23.7, 23.3, 18.6. IR (ATR, cm-1):
ν 2928, 2860, 1756 (CdO st), 1684 (CdO st), 1644, 1451, 1365,
1276, 1123, 757. EM (ESI+) m/z: 568 (M+ + 23, 100).
Conclusions
In summary, a new diastereoselective synthesis of two
Securinega alkaloids has been developed, using a vinylogous
Mannich reaction as the key transformation. The first synthesis
of allosecurinine has been accomplished, in seven steps and
around 40% yield, starting from (+)-menisdaurilide (+)-4.
Similarly, viroallosecurinine has been synthesized, in seven steps
and 38% yield, from (-)-menisdaurilide (-)-4. The reported
procedure is susceptible to be extended to the synthesis of
norsecurinine-type alkaloids.
Experimental Section
General experimental details are provided in Supporting Informa-
tion.
(6R,7aS)-6-(tert-Butyldiphenylsilanyloxi)-7,7a-dihydrobenzo-
furan-2(6H)-one (17). To a solution of (+)-menisdaurilide 4 (270
mg, 1.75 mmol), imidazole (369 mg, 5.42 mmol) and DMAP (21
mg, 0.17 mmol) in anhydrous dichloromethane (18 mL), tert-
butylchlorodiphenylsilane (490 µL, 1.85 mmol) was added drop-
wise, and the mixture was allowed to stir overnight at room
temperature. The mixture was quenched with NH4Cl (15 mL),
extracted with dichloromethane (3 × 25 mL,) and dried (MgSO4).
After concentration in vacuo the crude was purified by flash
chromatography with n-hexane/AcOEt (10:1 to 1:2) affording (-)-
1
17 (605 mg, 1.55 mmol, 89% yield) as a white solid. H NMR
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7660 J. Org. Chem. Vol. 73, No. 19, 2008

DiastereoselectiVe Synthesis of Allosecurinine and Viroallosecurinine
(2S,6′R,7a′S)-tert-Butyl-2-(6-(tert-butyldiphenylsilanyloxy)-2-
oxo-7,7a-dihydro-2H-benzofuran-7a-yl)piperidine-1-carboxy-
late (18) and Its Isomer (18m). To a solution of (-)-17 (500 mg,
1.28 mmol) in dry ethyl ether (13 mL) under argon atmosphere
and cooled to 0 °C, triethylamine (360 µL, 2.57 mmol) was added,
and the reaction mixture was stirred for 45 min at 0 °C. TIPSOTf
(410 µL, 1.48 mmol) was added, and the reaction mixture was
allowed to stir overnight at room temperature. To the reaction
mixture, another solution of tert-butyl-2-hydroxipiperidine-1-car-
boxylate 13 (580 mg, 2.88 mmol) in dry ethyl ether (13 mL) was
added, and the solution was cooled to -78 °C. Then, n-Bu2BOTf
(1000 µL, 1.0 mmol) was added dropwise during 5 min, and the
mixture was allowed to stir for 5 min at -78 °C. The mixture was
quenched with NH4Cl (30 mL) and allowed to warm to room
temperature. The aqueous phase was extracted with ether (2 × 30
mL), and the combined organic layers were dried (MgSO4) and
concentrated in vacuo to afford a mixture of the two diastereomeric
condensation products (-)-18 and (+)-18m in a ca. 4:1 ratio. This
crude material was purified by flash chromatography with n-hexane/
AcOEt (10:1 to 5:1) to yield (-)-18 (562 mg, 0.98 mmol, 76%) as
a colorless oil and (+)-18m (123 mg, 0.21 mmol, 17%) as a white
wax. (-)-18. 1H NMR (400 MHz, CDCl3): (ca. 86% major
conformer) δ 7.79-7.56 (4H, H-ar), 7.54-7.33 (6H, H-ar), 6.52
(dd, J ) 10.0, 2.1 Hz, 1H, H-4′), 6.25 (d, J ) 10.1 Hz, 1H, H-5′),
5.64 (s, 1H, H-3′), 4.39 (m, 1H, H-6′), 3.82 (t, J ) 5.9 Hz, 1H,
H-2), 3.73 (dd, J ) 13.8, 5.5 Hz, 1H, H-6), 2.90 (dt, J ) 13.4, 5.4
Hz, 1H, H-6), 2.36 (dd, J ) 12.4, 5.3 Hz, 1H, H-7′), 1.80 (dd, J )
12.2, 10.4 Hz, 1H, H-7′), 1.63-0.66 (m, 6H, 2H-3/2H-4/2H-5),
1.30 (s, 9H, OC(CH3)3), 1.06 (s, 9H, C(CH3)3); (ca. 14% minor
conformer, observable signals) δ 6.48 (dd, J ) 10.1, 2.1 Hz, 1H,
H-4′), 6.17 (d, J ) 10.1 Hz, 1H, H-5′), 5.74 (s, 1H, H-3′), 4.33 (m,
1H, H-6′), 3.96 (dd, J ) 13.8, 5.5 Hz, 1H, H-6), 2.83 (dt, J )
13.1, 4.3 Hz, 1H, H-6). 13C NMR (100 MHz, CDCl3) δ (ppm):
172.5, 166.1, 155.6, 139.9, 136.0, 136.0, 133.4, 133.0, 130.2, 128.1,
128.1, 121.8, 111.1, 89.7, 79.8, 67.2, 52.4, 41.6, 40.9, 28.3, 27.0,
23.7, 23.3, 19.2, 18.6. IR (ATR, cm-1): ν 2932, 2857, 1751 (CdO
st), 1684 (CdO st), 1405, 1365, 846, 752. HRMS (ESI+) m/z: calcd
for C34H43NO5SiNa 596.2803 (MNa+); found 596.2804. [R]D -93.9
(2S,6′R,7a′S)-tert-Butyl-2-(6-hydroxy-2-oxo-7,7a-dihydro-2H-
benzofuran-7a-yl)piperidin-1-carboxylate (19). To a solution of
(-)-18 (495 mg, 0.86 mmol) in dry THF (25 mL) under nitrogen
atmosphere, Et3N·3HF (2.9 mL, 17.44 mmol) was added, and the
reaction mixture was refluxed for 3.5 h. The reaction mixture was
quenched with NH4Cl (20 mL), the phases were separated, and the
aqueous phase was extracted with CH2Cl2 (3 × 30 mL). The
combined organic extracts were dried (MgSO4) and concentrated
in vacuo to afford an oil that was purified by flash chromatography
with n-hexane/AcOEt (2:1 to 1:1), yielding (-)-19 (260 mg, 0.775
mmol, 90%) as a colorless oil. 1H NMR (400 MHz, CDCl3): (83%
major conformer) δ 6.57 (dd, J ) 10.0 Hz, J ) 2.0 Hz, 1H, H-4′),
6.20 (d, J ) 10.0 Hz, 1H, H-5′), 5.70 (s, 1H, H-3′), 4.54 (br s, 1H,
H-6′), 4.20 (t, J ) 6.0 Hz, 1H, H-2), 3.84 (dd, J ) 14.1, 5.3 Hz,
1H, H-6eq), 3.02 (ddd, J ) 13.5, 12.3, 4.9 Hz, 1H, H-6ax), 2.90
(dd, J ) 12.4, 5.5 Hz, 1H, H-7’eq), 2.28 (br, J ) 5.8 Hz, 1H,
-OH), 2.03 (m, 1H, H-3), 1.94-1.41 (m, 5H, 1H-3/2H-4/2H-5),
1.72 (dd, J ) 12.3, 10.7 Hz, 1H, H-7’ax), 1.36 (s) (9H, C(CH3)3);
(17% minor conformer, observable signals) δ 5.70 (s, 1H, H-3′),
4.14 (t, J ) 5.4 Hz, 1H, H-2), 4.05 (dd, J ) 13.9, 5.2 Hz, 1H,
H-6eq). 13C NMR (100 MHz, CDCl3) δ (ppm): 172.6, 166.0, 155.8,
139.01, 122.5, 111.6, 89.8, 80.0, 65.9, 52.6, 41.4, 41.1, 28.3, 24.1,
23.9, 18.9. IR (ATR, cm-1): ν 3418 (OH st), 2938, 2871, 1737
(CdO st), 1670 (CdO st), 1641, 1405, 1280, 849, 749. HRMS
(ESI+) m/z: calcd for C18H25NO5Na 358.1625 (MNa+); found
358.1620. [R]D -71.9 (c 2.3, CHCl3).
(2R,6′S,7a′R)-tert-Butyl-2-(6-hydroxy-2-oxo-7,7a-dihydro-2H-
benzofuran-7a-yl)piperidin-1-carboxylate (19). The same ex-
perimental procedure previously described for the preparation of
(-)-19 was followed, starting with 488 mg (0.85 mmol) of (+)-18
and yielding (+)-19 (247 mg, 0.74 mmol, 87%) as a colorless oil.
[R]D +72.3 (c 2.8, CHCl3).
Allosecurinine. To a solution of (-)-19 (90 mg, 0.268 mmol)
in dry CH2Cl2, under nitrogen atmosphere at 0 °C, Et3N (94 µL,
0.671 mmol) was added. After 10 min, MsCl (31 µL, 0.399 mmol)
was added, and the reaction mixture was allowed to stir at 0 °C for
30 min. The mixture was quenched with NH4Cl (5 mL) and
extracted with CH2Cl2 (3 × 10 mL). The combined organic extracts
were dried (MgSO4) and concentrated in vacuo, affording an oil
identified as the corresponding mesylate derivative. The previous
crude material was dissolved in CH2Cl2, and TFA (83 µL, 1.067
mmol) was added. The mixture was allowed to stir for 3 h at room
temperature and concentrated under reduced pressure. The resulting
crude material was dissolved in THF (3 mL) and aqueous K2CO3
saturated solution (1 mL). The mixture was allowed to stir for 30
min at room temperature, diluted with brine (4 mL), and extracted
with CH2Cl2 (3 × 10 mL). The combined organic phases were
washed with brine (10 mL), dried (MgSO4), and concentrated in
vacuo. The crude material was purified by flash chromatography
using a flash chromatographic system with a basic alumina presealed
column and n-hexane/AcOEt (8:1 to 1:1) as eluent, yielding
allosecurinine, 2 (40.5 mg, 0.186 mmol, 69%) as a yellowish solid.
Mp: 126-127 °C (ethyl ether) {lit. 136-138 °C,20 137-138 °C,21
1
(c 2.3, CHCl3). (+)-18m. H NMR (400 MHz, CDCl3): (ca. 64%
major conformer) δ 7.86-7.57 (m, 4H, H-ar), 7.57-7.31 (m, 6H,
H-ar), 6.43 (d, J ) 9.9 Hz, 1H, H-4′), 5.65 (dd, J ) 9.8, 4.4 Hz,
1H, H-5′), 5.59 (s, 1H, H-3′), 4.76 (t, J ) 6.8 Hz, 1H, H-2), 4.56
(t, J ) 4.6 Hz, 1H, H-6′), 4.07 (t, J ) 6.7 Hz, 1H, H-6), 3.21-2.87
(m, 1H, H-6), 2.59 (d, J ) 14.1 Hz, 1H, H-7′), 2.12-0.80 (m)
(6H, 2H-3, 2H-4, 2H-5), 1.74 (dd, J ) 14.2, 5.4 Hz, 1H, H-7′),
1.40 (s) (9H, OC(CH3)3), 1.07 (s) (9H, C(CH3)3); (ca. 36% minor
conformer, observable signals) δ 6.38 (d, J ) 9.9 Hz, 1H, H-4′),
5.71 (s, 1H, H-3′), 5.53 (dd, J ) 9.6, 4.4 Hz, 1H, H-5′), 4.85 (t, J
) 5.9 Hz, 1H, H-2), 4.62 (t, J ) 4.3 Hz, 1H, H-6′), 3.87 (dt, J )
13.2, 3.6 Hz, 1H, H-6). 13C NMR (100 MHz, CDCl3) δ (ppm):
173.0 + 172.2 (C-2′), 166.1 + 164.7 (C-3a’), 156.1 + 155.7 (N-
CO), 136.2 + 136.1 + 135.9 + 135.8 + 133.5 + 133.3 + 133.1
+ 130.3 + 130.1 + 128.1 + 128.0 (C-ar), 135.2 + 134.2 (C-5′),
122.8 + 122.6 (C-4′), 113.5 + 111.7 (C-3′), 88.9 (C-7a′), 80.2 +
79.3 (OC(CH3)3), 66.1 (C-6′), 54.8 (C-2), 40.7 + 40.0 (C-6), 37.9
+ 37.5 (C-7′), 28.9 + 28.7 + 28.4 (OC(CH3)3), 27.2 (C(CH3)3),
24.5 + 23.7 + 23.3 + 22.3 (C-3, C-5), 19.1/18.9 (C-4), 19.3
(C(CH3)3). IR (ATR, cm-1): ν 2931, 2858, 1751 (CdO st), 1686
(CdO st), 1401, 1364, 1148, 911, 751. HRMS (ESI+) m/z: calcd
for C34H43NO5SiNa 596.2803 (MNa+, 100); found 596.2815. [R]D
+126.7 (c 0.9, CHCl3).
23
136-138 °C,22 128 °C (ether) }. H NMR (600 MHz, CD2Cl2):
δ 6.82 (dd, J ) 9.1, 5.3 Hz, 1H, H-15), 6.63 (dd, J ) 9.1, 0.9 Hz,
1H, H-14), 5.68 (s, 1H, H-12), 3.85 (t, J ) 4.9 Hz, 1H, H-7), 3.60
(dd, J ) 13.1, 3.5 Hz, 1H, H-2), 2.81-2.68 (m, 2H, 2H-6), 2.61
(dd, J ) 9.6, 4.4 Hz, 1H, H-8), 1.89 (d, J ) 9.7 Hz, 1H: H-8),
1.73-1.56 (m, 3H: 2H-5, H-4), 1.46-1.33 (m, 1H, H-4), 1.33-1.24
(m, 1H, H-3eq), 1.15 (qd, J ) 13.1, 6.0 Hz, 1H: H-3ax). 13C NMR
(150 MHz, CD2Cl2): δ 172.1, 167.4, 148.7, 122.1, 108.3, 91.4, 60.5,
58.5, 43.4, 42.4, 22.1, 20.9, 18.5. IR (ATR, cm-1): ν 2936, 2855,
1742 (CdO st), 1623, 1454, 1250, 1053, 961, 690. HRMS (ESI+)
m/z: calcd for C13H15NO2H 218.1176 (MH+); found 218.1180. [R]D
-1092 (c 1.0, EtOH) {lit. [R]D -1082 (EtOH),20 [R]D -1004
(MeOH),21 [R]D -1082 (EtOH),22 [R]D -114023}.
1
(2R,6′S,7a′R)-tert-Butyl-2-(6-(tert-butyldiphenylsilanyloxy)-2-
oxo-7,7a-dihydro-2H-benzofuran-7a-yl)piperidine-1-carboxy-
late (18 and 18m). The same experimental procedure previously
described for the preparation of (-)-18 and (+)-18m was followed,
starting with 500 mg (1,280 mmol) of (+)-17 and affording (+)-
18 (529 mg, 0.922 mmol, 72%) as a colorless oil and (-)-18m
(149 mg, 0.260 mmol, 20%) as a white wax. (+)-18: [R]D +86.3
(c 2.1, CHCl3). (-)-18m: [R]D -138.6 (c 1.8, CHCl3).
Viroallosecurinine. The same experimental procedure previously
described for the preparation of allosecurinine, 2, was followed,
starting with 110 mg (0.328 mmol) of (+)-19 and affording
J. Org. Chem. Vol. 73, No. 19, 2008 7661

Bardají et al.
viroallosecurinine (48 mg, 0.221 mmol, 67%) as a yellowish solid.
Mp: 138-139 °C (n-hexane/acetone) {lit. 133-134 °C (ligroine),25
135-136 °C,26 145-147 °C (n-hexane/acetone)16j}. [R]D +1068
(c 1.2, EtOH) {[R]D +1084.6 (EtOH),24 [R]D +1200 (EtOH),25 [R]D
+990 (c 0.98, EtOH),26 [R]D +1113 (c 1.0, EtOH)16j}.
and FSE for a predoctoral grant. We also acknowledge MCYT-
ERDF for a Ramo´n y Cajal contract (F.B.).
Supporting Information Available: General experimental
1
data. Copies of H and 13C NMR spectra of all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We acknowledge financial support from
DGI (project CTQ2004-2539). G.G.B. and M.C. thank DURSI
JO801470U
7662 J. Org. Chem. Vol. 73, No. 19, 2008