Tungsten-Promoted Hetero-Pauson-Khand Cycloaddition: Application to the Total Synthesis of (-)-Allosecurinine

Article abstract of DOI:10.1055/s-0037-1612063

Herein, we report a concise enantioselective synthesis of (-)-allosecurinine, a tetracyclic Securinega alkaloid featuring an α,β-unsaturated γ-lactone moiety. Starting from inexpensive and readily available trans - l -hydroxyproline, our strategy entails a rare late-stage [2+2+1]-hetero-Pauson-Khand cycloaddition between a ketone and an alkyne as the key complexity-generating step to rapidly install the CD-ring system. The reported W(CO) ₆ -promoted intramolecular cyclization provides the first example of a tungsten-mediated hetero-Pauson-Khand reaction. This approach to the strained bicyclic CD motif present in allosecurinine provides some insights into the boundaries of this potentially powerful methodology that might be further extended to other butenolide-containing natural products.

Full text of DOI:10.1055/s-0037-1612063

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–F
paper
A
en
E. Chirkin et al.
Paper
Synthesis
Tungsten-Promoted Hetero-Pauson–Khand Cycloaddition:
Application to the Total Synthesis of (–)-Allosecurinine
Egor Chirkin1
O
hetero-
Pauson–Khand
cyclization
O
Chouaha Bouzidi
H
N
OTBS
O
H
Peterson olefination
oxidation
OTBS
H
N
H
O
François-Hugues Porée*
0
0
0
0-0
0
0
3-3
3
4
4-
5
2
6
0
N
BocN
Laboratoire de Pharmacognosie UMR CNRS 8638, Faculté de
Pharmacie, Université Paris Descartes, 4 Avenue de l’Obser-
vatoire, 75006 Paris, France
CO2Me
CO2Me
(–)-allosecurinine
CO, W(CO)6
toluene/DMF, heat
francois-hugues.poree@parisdescartes.fr
12%
Received: 06.12.2018
Accepted after revision: 17.12.2018
Published online: 18.02.2019
first identified as a GABAA antagonist and used as a CNS
agent.6 Securinine (1) was shown to promote the differenti-
ation of HL60 leukemic cells in vitro and demonstrated an in
vivo activity in mouse xenograft experiments.7 These bio-
logical activities make securinine (1) and its congeners a
compelling starting point for the development of a medici-
nal chemistry program. Furthermore, systematic structure–
activity relationship (SAR) studies have not yet been report-
ed for this alkaloid family, and only a very limited set of
analogues produced by semisynthetic modifications is
available.8 In addition to antileukemic activity, norse-
curinine (2) and its analogues were reported to inhibit my-
eloperoxidase, an enzyme involved in immune inflammato-
ry disorder.9 The naturally occurring oligomers of norse-
curinine (2) were also shown to exhibit anti-HIV activity.10
DOI: 10.1055/s-0037-1612063; Art ID: ss-2018-t0703-op
Abstract Herein, we report a concise enantioselective synthesis of (–)-
allosecurinine, a tetracyclic Securinega alkaloid featuring an α,β-unsat-
urated γ-lactone moiety. Starting from inexpensive and readily available
trans-L-hydroxyproline, our strategy entails a rare late-stage [2+2+1]-
hetero-Pauson–Khand cycloaddition between a ketone and an alkyne
as the key complexity-generating step to rapidly install the CD-ring sys-
tem. The reported W(CO)6-promoted intramolecular cyclization pro-
vides the first example of a tungsten-mediated hetero-Pauson–Khand
reaction. This approach to the strained bicyclic CD motif present in
allosecurinine provides some insights into the boundaries of this poten-
tially powerful methodology that might be further extended to other
butenolide-containing natural products.
Key words alkaloids, total synthesis, tungsten, cyclization, natural
products
O
O
O
O
O
O
11
12
13
O
O
3
6
9
2
Securinega alkaloids constitute a unique class of plant-
derived alkaloids isolated from Securinega (= Flueggea),
Phyllanthus, Margaritaria, and Breynia genera, of the
Phyllanthaceae family.2 Since the isolation of the first con-
gener securinine (1), interest in this series culminated in
the isolation of 80 compounds. Characteristic of this group
is the occurrence of a compact tetracyclic backbone divided
into four subgroups: securinane, neosecurinane, norsecuri-
nane, and neonorsecurinane (Figure 1). In addition to this
feature, it should be noted that almost all the stereoisomer
combinations are naturally occurring, as recently reported
by Yue for the neosecurinane group.3 Therefore, these alka-
loids represent appealing targets for total synthesis, and
several original routes have been developed.4 In addition,
this series represents a good example of the helpful assis-
tance of total synthesis to support the biogenesis hypothe-
sis.5 Besides, these alkaloids display promising biological
activities. Securinine (1), the most abundant derivative, was
4
5
14
15
8
N1
N
N
N
7
securinane
neosecurinane
norsecurinane
O
neonorsecurinane
O
O
O
O
H
O
D
H
N
H
A
B
C
N
N
securinine (1)
norsecurinine (2)
allosecurinine (3)
Figure 1 Structural diversity of Securinega alkaloids
Within this context, a concise and flexible synthetic ac-
cess to Securinega alkaloids is of general interest. The
daunting construction of the critical butenolide-containing
CD moiety gave rise in the past years to very creative syn-
thetic solutions; however, most of them consisted of
lengthy reaction sequences and thus did not lend them-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F

B
E. Chirkin et al.
Paper
Synthesis
selves for the preparation of analogues for SAR studies.5a,11
We recently proposed an efficient entry to this series with
the use of a hetero-Pauson–Khand (HPK) strategy to con-
struct the BCD core of the securinane/neosecurinane
groups on a model compound.12 Herein, we report our ef-
forts to implement this cyclocarbonylation reaction to the
synthesis of the securinane skeleton through the total syn-
thesis of allosecurinine (3), the C2-epimer of securinine (1).
At the onset of our investigations, we faced the chal-
lenge to prove the overall viability of the HPK strategy to-
ward the securinega alkaloids. To the best of our knowl-
edge, the only attempt to implement the HPK strategy in
this alkaloid family has been made by the group of Rovis in
their efforts toward secu’amamine A.13 However, this at-
tempt met with failure, since the prepared highly function-
alized substrate did not undergo the planned HPK cycload-
dition. The advances made over the last few years in the
HPK methodology led to the introduction of novel, more
powerful transition-metal catalysts and promoters. This
consideration prompted us to reinvestigate the application
of the HPK strategy to the synthesis of securinega alkaloids.
Of note, success in the application of an oxa-hetero-Pau-
son–Khand reaction (oxa-HPK)14 would provide a well-suit-
ed and elegant synthetic solution, enabling the collective
synthesis of securinega alkaloids and, importantly, de-
signed analogues thereof. Based on our initial report on the
construction of the BCD core of the securinane / norsecuri-
nane core, we decided to investigate the capacity of other
metal–carbonyl promoters to trigger the critical oxa-HPK
event. One of our goals is to develop a simple procedure us-
ing an easy-to-handle metal complex. For this reason, we
reported an all-together procedure, which was successfully
applied by Tao et al.14a During the course of our investiga-
tions of other metal–carbonyl-containing complexes,
W(CO)6 was identified as a promising candidate for this re-
action (Table 1).
Table 1 Construction of the BCD Core Using the W(CO)6 Complexa
O
O
O
CO (1 atm), W(CO)6
toluene/DMF, 140 °C
BocN
[2+2+1]
BocN
5
4
Entry
Time (h)
Yield (%)b
1
0.5
1
30
29
12
2c
3d
2
a Reaction conditions: 4 (0.33 mmol, 1 equiv), CO (initially 1 atm;
pressure not assessed during reaction), W(CO)6 (2.5 equiv), toluene/DMF
(1:0.6 ratio; 1.2 mL/0.7 mL), 140 °C, sealed vial
b Isolated yields.
c W(CO)6 (1.1 equiv) was used.
d The reaction was carried out under argon.
under pressure. Nevertheless, these results constitute the
first example of the use of the W(CO)6 complex in the HPK
reaction. With this encouraging result in hand, we next
turned our efforts to illustrate the application of this proce-
dure to the synthesis of allosecurinine (3).
We focused on the securinane skeleton by investigating
allosecurinine (3). The retrosynthetic plan is depicted in
Scheme 1. The key HPK cyclization was envisaged as the last
step of the synthesis of the bicyclic compound 6 featuring
both a ketone and a Z-enyne function. Installation of the Z-
enyne moiety could be envisaged to occur via a stereoselec-
tive olefination reaction following either a modified Julia–
Kocienski or a Peterson approach on the in situ generated
aldehyde derived from ester 7. After removal of the TBS pro-
tecting group, oxidation of the secondary alcohol would
give access to the corresponding ketone. Indolizidine 7 cor-
responding to the AB motif of the securinane skeleton could
be prepared from bis-allyl compound 8 via an efficient
RCM/hydrogenation sequence. The latter could derive from
known oxo compound 9 after introduction of an allyl chain
at the C2 and the nitrogen positions. To resume, the pro-
posed strategy consists of the elaboration of the A ring from
a B ring precursor and further one-step construction of the
CD motif.
The W(CO)6 complex is a white, air-stable, and easy-to-
handle solid. Using our procedure, we were delighted to ob-
serve the cyclization in only 30 minutes in 30% yield (Table
1, entry 1). This result was very encouraging, even though
the yield was moderate. Interestingly, the same result was
obtained with a charge of 1.1 equivalents of promoter after
one hour (entry 2). Also, the reaction proceeded without a
CO atmosphere in a low yield (12%, entry 3). At this stage,
we were not able to improve this yield, and further investi-
gations should be carried out, in particular on the use of CO
O
RCM /
hydrogenation
sequence
OTBS
OTBS
O
OTBS
H
N
HPK
cyclization
allyl chain
introduction
O
O
H
N
H
N
H
N
olefination
H
BocN
CO2Me
CO2Me
CO2Me
allosecurinine (3)
6
7
8
9
Scheme 1 Retrosynthetic analysis
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F

C
E. Chirkin et al.
Paper
Synthesis
During synthesis, compound 9 was prepared on a multi-
gram scale from commercial L-OH proline 10 according to
known procedures (Scheme 2).15 According to Thadani, par-
tial reduction of the C4-carbonyl by LiBEt3H, followed by
Ac2O trapping furnished a mixture of acetates, which was
treated with allyltrimethylsilane in the presence of BF3·OEt2
to yield an inseparable mixture of diastereomeric allyl com-
pounds in overall good yields (85%).15b Boc removal by
action of trifluoroacetic acid enabled separation of the dia-
stereomers on silica gel, furnishing the 4R-compound 11 as
the major one (60% over 3 steps, dr 4:1). Surprisingly, this
result contrasted with the report of Thadani, giving the 4S-
stereoisomer 12 as the major one.15b However, in our case,
the observed stereochemistry is in favor of a steric control
of the OTBS group during the attack of the in situ generated
iminium by the allyltrimethylsilane agent and corresponds
to the allosecurinine series.16 The next sequence of the syn-
thesis consisted of the construction of ring A. For this pur-
pose, an allyl chain was introduced on the nitrogen atom to
give the bis-allyl derivative 8 (90% yield), which was
engaged in a Grubbs-II-catalyzed RCM cyclization reaction
followed by Pd/C hydrogenation to furnish indolizidine 7 in
76% yield over the two steps.17 Of note, during the meta-
thesis event some epimerization at the C2-position was ob-
served. At this stage, installation of the Z-enyne motif was
considered. The Julia–Kocienski procedure which was suc-
cessfully applied in the model study12 gave disappointing
results with the aldehyde derived from ester 7. The yields
were low, not constant, and purification of the reaction
product from the residual sulfone proved to be difficult.
Conversely, Peterson olefination in the presence of alkyne
13 offered an interesting alternative.18 The overall yield and
reproducibility were better and the expected Z-compound
14 was isolated in 52% yield. Then, the silyl groups were re-
moved by action of TBAF at 0 °C and direct purification by
chromatography without workup allowed isolation of alco-
hol 15 in 60% yield. Of note, the compound is very polar on
normal-phase silica gel. Finally, a Swern oxidation was car-
ried out to furnish ketone 6, the precursor of the HPK
cyclization. As previously reported, we followed the ‘all to-
gether’ procedure by mixing the substrate and the W(CO)6
complex in a toluene/DMF mixture under a CO atmosphere
at 140 °C for 0.5 h. To our delight, allosecurinine (3) was
isolated after chromatography, albeit in low yield (12%).19
When the Mo(CO)6 complex was used as promotor, the
same result was obtained (14%). However, this result
demonstrates the viability of this strategy to access the
securinane skeleton and its analogues. Efforts will next be
on extending the scope of this cyclocarbonylation, in partic-
ular with regard to the impact of CO pressure on the out-
come of the reaction.
In summary, our efforts to develop a concise synthetic
route to the securinane skeleton of the Securinega alkaloids
via a hetero-Pauson–Khand cyclocarbonylation and its ap-
plication in the synthesis of allosecurinine (3) are reported.
Despite a low yield, the present work demonstrates the use-
fulness of this reaction in total synthesis, in particular the
capacity to generate a high degree of structural complexity.
We identified hexacarbonyltungsten [W(CO)6] as an un-
precedented promoter of this annulation. Importantly, the
reaction conditions did not require the use of air-unstable,
1) LiBEt3H, THF, –78 °C, then
Ac2O, Et3N, DMAP, CH2Cl2
2) Allyl-TMS, BF3•OEt2
Et2O, –78 °C
OH
OTBS
OTBS
OTBS
O
ref. 15
2
+
HN
BocN
HN
HN
3) TFA, CH2Cl2,
separation (chromatograpy)
CO2H
CO2Me
CO2Me
CO2Me
11
12
9
trans-OH proline (10)
60% (3 steps) dr 4:1
major
minor
allosecurinine series
securinine series
1) DIBAL-H, toluene, –78 °C
2) nBuLi, THF, –78 °C to r.t.
Br
OTBS
OTBS
OTBS
H
H
N
H
1) Grubbs II, CH2Cl2, heat
2) H2, Pd/C, EtOAc
TIPS
TIPS
13
Et3N, DMF
TIPS
11
N
N
76% (2 steps)
52% (2 steps)
90%
CO2Me
CO2Me
8
7
14
O
OH
O
O
H
H
N
H
(COCl)2, DMSO, Et3N
CH2Cl2, –78 °C
CO, W(CO)6
H
H
TBAF, THF, 0 °C
60%
toluene/DMF, heat
N
N
90%
12%
allosecurinine (3)
15
6
Scheme 2 Synthesis of allosecurinine (3)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F

D
E. Chirkin et al.
Paper
Synthesis
preformed metal-containing complexes. Further theoretical
and experimental work is needed to improve the overall
yield and scope of this reaction.
1H NMR (400 MHz, CDCl3): δ = 5.85–5.76 (m, 1 H), 5.13–5.05 (m, 2 H),
3.93 (t, J = 13.0 Hz, 1 H), 3.88 (q, J = 5.4 Hz, 1 H), 3.71 (s, 3 H), 2.98–
2.94 (m, 1 H), 2.35–2.28 (m, 1 H), 2.16–1.97 (m, 3 H), 0.86 (s, 9 H),
0.03 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 175.0, 135.2, 117.2, 76.0, 68.1, 57.9,
52.0, 38.8, 38.2, 25.8, 17.9, –4.5.
The analytical data matched well with those in the literature.15
All reactions were carried out under argon or nitrogen atmosphere
with anhydrous solvents under anhydrous conditions, unless other-
wise stated. Commercially available reagents were used without fur-
ther purification, unless otherwise stated. Isolated yields are given,
unless otherwise noted. NMR spectra were recorded on Bruker AC300
(300 MHz) and Bruker Avance III HD (400 MHz) instruments and pro-
cessed with TopSpin Bruker software. NMR spectra were calibrated
using the residual peaks of deuterated solvents as internal reference
(CDCl3: 1H, 7.26; 13C 77.0 ppm). IR spectra were recorded on a Perkin
Elmer 60 FT-IR instrument; only selected absorbances are reported.
High-resolution mass spectra were recorded in the UMR 8638 MS
core facility using a Waters ZQ 2000 ESI spectrometer. Optical rota-
tions were measured using a Perkin Elmer 314 polarimeter and con-
centration are reported in mg/mL.
Methyl (2S,4R,5S)-1,5-Diallyl-4-(tert-butyldimethylsiloxy)pyrroli-
dine-2-carboxylate (8)
To a solution of 11 (2.37 g, 7.89 mmol) in DMF (25 mL) at r.t. was add-
ed Et3N (2.66 mL, 19.75 mmol, 2.5 equiv) and freshly distilled allyl
bromide (0.98 mL, 11.83 mmol, 1.5 equiv). The resulting mixture was
stirred for 16 h at r.t. Et2O was then added and the organic layer was
washed with sat. aq NaHCO3. The layers were separated and the aque-
ous phase was extracted with Et2O (2 × 50 mL). The combined organic
extracts were dried over MgSO4, filtered, and concentrated in vacuo.
The crude material was purified by chromatography (silica gel, cyclo-
hexane/EtOAc 9:1).
Yield: 2.41 g (7.10 mmol, 90%); [α]D20 –255 (c 2.5, CHCl3).
Methyl (2S,4R,5S)-5-Allyl-4-(tert-butyldimethylsiloxy)pyrrolidine-
2-carboxylate (11)
1H NMR (400 MHz, CDCl3): δ = 5.86–5.76 (m, 2 H), 5.11–4.95 (m, 4 H),
3.96–3.92 (m, 1 H), 3.62 (s, OCH3), 3.60–3.54 (m, 1 H), 3.35–3.23 (m, 2
H), 2.69–2.66 (m, 1 H), 2.26–2.19 (m, 1 H), 2.10–2.03 (m, 1 H), 2.00–
1.93 (m, 1 H), 1.87–1.82 (m, 1 H), 0.82 (S, 9 H), –0.01 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 175.0, 135.8, 135.0, 117.4, 116.5, 74.6,
71.4, 63.7, 57.0, 51.7, 38.4, 38.0, 25.8, 17.8, –4.6.
HRMS (ESI): m/z [M + Na]+ calcd for C18H33NO3SiNa: 362.2127; found:
362.2139.
The analytical data matched well with those in the literature.15
Step 1: Superhydride Reduction and Acetate Formation: To a solution of
oxo compound 915 (6.07 g, 16.2 mmol) in anhyd THF (30 mL) at –78 °C
was added 1 M LiBEt3H in THF (17 mL, 17.01 mmol, 1.05 equiv) over 5
min. The reaction mixture was stirred for 1 h at –78 °C, and then
quenched with sat. aq NaHCO3 (15 mL). H2O2 (2 drops) was added and
the resulting mixture was allowed to warm to r.t. All the volatiles
were removed in vacuo. CH2Cl2 (30 mL) was added, followed by brine.
After separation, the organic layer was dried over MgSO4 and concen-
trated in vacuo. The pale yellow oil was dissolved in CH2Cl2 (50 mL)
and Et3N (3.3 mL, 24.3 mmol, 1.5 equiv), Ac2O (2.3 mL, 24.3 mmol, 1.5
equiv), and cat. DMAP were successively added. The mixture was
stirred at r.t. overnight. Sat. aq NaHCO3 was added. The layers were
separated and the aqueous layer was extracted with CH2Cl2. The com-
bined organic layers were dried over MgSO4, filtered, and concentrat-
ed in vacuo. The residue was filtered through a pad of silica (cyclo-
hexane/EtOAc 8:2) to afford the corresponding acetates (6.75 g),
which were used without further purification in the next step.
Methyl (1R,3S,8aS)-1-(tert-Butyldimethylsiloxy)octahydroindol-
izine-3-carboxylate (7)
Step 1: RCM Cyclization: A round-bottom flask equipped with a con-
denser was charged with the Grubbs II catalyst (119 mg, 0.14 mmol,
0.05 equiv) and purged (3×) with an argon/vacuum cycle. Then, a
solution of the above bis-allylpyrrolidine-2-carboxylate 8 (951 mg,
2.8 mmol) in anhyd CH2Cl2 (35 mL) was added and the red solution
was refluxed for 4 h. A second charge of Grubbs II catalyst (50 mg)
was added and reflux was maintained for an additional 4 h (total 8 h).
The reaction mixture was cooled to r.t. and the solvent was removed
in vacuo. The crude material was purified by flash chromatography
(silica gel, cyclohexane/EtOAc 9:1 to 8:2); this afforded the corre-
sponding indolizine.
Step 2: Allyltrimethylsilane Addition: To a solution of the acetates (6.75
g) in anhyd Et2O (100 mL) at –78 °C was added BF3·OEt2 (2.5 mL, 20.2
mmol, 1.25 equiv) and allyltrimethylsilane (11.8 mL, 72.9 mmol, 4.5
equiv). The reaction mixture was stirred for 15 min at –78 °C and
then allowed to warm to r.t. over 1 h, after which it was stirred a fur-
ther 2 h at r.t. Sat. aq NaHCO3 was added. The layers were separated
and the aqueous layer was extracted with Et2O. The combined organic
layers were dried over MgSO4, filtered and concentrated in vacuo. The
residue was filtered through a pad of silica (cyclohexane/EtOAc 9:1)
to afford the corresponding allyl compounds as a pale yellow oil (5.5
g, 85%). This material was used without further purification in the
next step.
20
Yield: 698 mg (2.24 mmol, 80%); yellowish oil; [α]D –129 (c 5,
CHCl3).
IR (film): 2952, 2856, 1747, 1251, 1129, 1092, 834, 774 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 5.73–5.70 (m, 1 H), 5.64–5.60 (m, 1 H),
3.96–3.91 (m, 1 H), 3.71 (s, 3 H, OCH3), 3.60–3.55 (m, 1 H), 3.23 (dd,
J = 7.7 Hz, 9.5 Hz, 1 H), 2.82–2.77 (m, 1 H), 2.33–2.25 (m, 3 H), 2.14–
2.09 (m, 1 H), 1.95–1.88 (m, 1 H), 0.86 (s, 9 H), 0.03 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 173.2, 124.7, 124.5, 75.8, 66.3, 65.4,
52.3, 52.0, 36.8, 30.2, 25.8, 18.0, –4.7.
Step 3: Boc Removal: To a solution of the allyl compounds (5.5 g, 13.8
mmol) in CH2Cl2 (100 mL) at 0 °C was slowly added TFA (10.5 mL, 138
mmol, 10 equiv). The reaction mixture was stirred at r.t. for 10 h. Sat.
aq NaHCO3 was carefully and slowly added at 0 °C. The layers were
separated and the aqueous phase was extracted with CH2Cl2 (2 × 50
mL). The combined organic extracts were dried over MgSO4, filtered,
and concentrated in vacuo. The residue was subjected to chromatog-
raphy (silica gel, cyclohexane/EtOAc) to afford 11.
HRMS (ESI): m/z [M + Na]+ calcd for C16H29NO3SiNa: 334.1814; found:
334.1811.
Step 2: Hydrogenation: A round-bottom flask was charged with a
solution of the above indolizine (1.403 g, 4.5 mmol) in EtOAc (50 mL)
and purged with H2. Then, Pd/C (Degussa-type, reference E105CA/W;
Yield: 2.92. g (9.72 mmol, 70%; 60% from 9); yellow oil.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F

E
E. Chirkin et al.
Paper
Synthesis
48 mg, 0.45 mmol, 10 mol%) was added and the resulting suspension
was stirred overnight under a H2 atmosphere. The mixture was
filtered through a pad of silica and concentrated in vacuo to afford 7.
(1R,3S,8aS,Z)-3-(But-1-en-3-ynyl)octahydroindolizin-1-ol (15)
To a solution of 14 (150 mg, 0.324 mmol) in anhyd THF (5 mL) at 0 °C
under argon was added via syringe a solution of TBAF (178 mg, 0.682
mmol, 2.1 equiv) in anhyd THF (3 mL). The resulting solution was
stirred at 0 °C for 3.5 h. Then the solvent was removed in vacuo and
the crude material was subjected to flash chromatography (silica gel,
cyclohexane/EtOAC 8:2 to 2:8).
20
Yield: 1.34 g (4.27 mmol, 95%); clean yellowish oil; [α]D –90 (c 14,
CHCl3).
IR (film): 2930, 2855, 1752, 1255, 1196, 1088, 835, 775 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 3.87 (q, J = 7.5 Hz, 1 H), 3.68 (s, 3 H),
3.12 (dd, J = 7.5 Hz, 9.4 Hz, 2 H), 2.21–2.14 (m, 1 H), 1.96–1.74 (m, 5
H), 1.58–1.49 (m, 2 H), 1.34–1.23 (m, 1 H), 1.22–1.10 (m, 1 H), 0.84 (s,
9 H), 0.00 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 173.4, 74.9, 70.5, 64.8, 52.5, 51.8, 36.8,
28.5, 25.8, 25.0, 23.8, 18.0, –4.7.
Yield: 37 mg (0.194 mmol, 60%); white solid; [α]D20 –63 (c 1.1, CHCl3).
IR (film): 3295, 2934, 2853, 1652, 1441, 1258, 1139 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 5.86 (dd, J = 10.6 Hz, 8.9 Hz, 1 H), 5.57
(d, J = 10.6 Hz, 1 H), 3.97–3.92 (m, 1 H), 3.56 (q, J = 8.5 Hz, 1 H), 3.08
(dd, J = 0.9 Hz, 2.4 Hz, 1 H), 3.00–2.98 (m, 1 H), 2.78 (br s, 1 H), 2.00–
1.75 (m, 7 H), 1.63 (d, J = 12.7 Hz, 1 H), 1.29–1.18 (m, 2 H).
HRMS (ESI): m/z [M + Na]+ calcd for C16H31NO3SiNa: 336.1967; found:
336.1971.
13C NMR (100 MHz, CDCl3): δ = 145.8, 110.9, 82.3, 79.9, 74.9, 71.8,
62.8, 51.5, 39.0, 28.8, 25.0 23.9.
(1R,3S,8aS,Z)-1-(tert-Butyldimethylsiloxy)-3-[4-(triisopropylsi-
HRMS (ESI): m/z [M + H]+ calcd for C12H18NO: 192.1388; found:
lyl)but-1-en-3-ynyl]octahydroindolizine (14)
192.1381.
Step 1: DIBAL-H Reduction: To a solution of 7 (204 mg, 0.65 mmol) in
anhyd toluene (10 mL) at –78 °C was added 1.1 M DIBAL-H in THF (1.2
mL, 1.3 mmol, 2 equiv) over a period of 5 min. After 2 h at –78 °C,
anhyd EtOH (4 mL) was added and the reaction mixture was allowed
to warm to –20 °C. A 1 M solution of potassium sodium tartrate in
H2O (6.5 mL, 10 equiv) was added and the biphasic solution was vig-
orously stirred for 1 h while warming to r.t. The layers were separated
and the aqueous phase was extracted with Et2O (3 × 25 mL). The com-
bined organic extracts were dried over MgSO4, filtered, and concen-
trated in vacuo to afford the corresponding aldehyde as a pale, yellow
oil; it was used without further purification in the olefination step.
(3S,8aS,Z)-3-(But-1-en-3-ynyl)hexahydroindolizin-1(5H)-one (6)
An oven-dried Schlenk tube equipped with a stirring bar and an argon
inlet was charged with a solution of oxalyl chloride (48 μL, 0.564
mmol, 1.2 equiv) in CH2Cl2 (2 mL) and cooled at –78 °C. A solution of
DMSO (83 μL, 1.175 mmol, 2.5 equiv) in CH2Cl2 (2 mL) was added and
the resulting mixture was stirred for 10 min. Then, a solution of alco-
hol 15 (90 mg, 0.47 mmol) in CH2Cl2 (2 mL) was slowly added and the
solution was stirred for 1 h at –78 °C prior to the addition of Et3N
(320 μL, 2.35 mmol, 5 equiv). After 15 min, the reaction mixture was
allowed to warm to r.t. over a period of 30 min. Upon completion (TLC
monitoring), the reaction was quenched by addition of brine (10 mL).
The layers were separated and the aqueous phase was extracted with
EtOAc (2 × 20 mL). The combined organic extracts were dried over
MgSO4, filtered, and concentrated in vacuo. Flash chromatography
(silica gel, cyclohexane/EtOAc 8:2 to 7:3 + 1% Et3N) afforded 6.
Step 2: Peterson Olefination: An oven-dried Schlenk tube equipped
with a magnetic stirring bar and an argon inlet was charged with 1,3-
bis(triisopropylsilyl)prop-1-yne 13 (337 mg, 0.957 mmol, 1.5 equiv)
in anhyd THF (3.5 mL) and cooled to –20 °C. A 1.6 M solution of nBuLi
in hexanes (0.6 mL, 0.957 mmol, 1.5 equiv) was added dropwise and
the resulting yellow solution was stirred for 20 min at –20 °C and
then cooled to –78 °C. A solution of the above prepared aldehyde in
THF (5 mL) was added dropwise. The resulting mixture was stirred for
2 h at –78 °C and was then warmed to r.t. over 6 h. The reaction was
quenched by the addition of H2O (20 mL). The layers were separated
and the aqueous phase was extracted with Et2O (2 × 30 mL). The com-
bined organic layers were dried over MgSO4, filtered, and concentrat-
ed in vacuo. The residue was purified by flash chromatography (silica
gel, cyclohexane/EtOAc 10:0 to 8:2) to afford the corresponding Z-
diene.
20
Yield: 80 mg (0.423 mmol, 90%); amorphous white solid; [α]D –65
(c 5, CHCl3).
IR (film): 3288, 2937, 2857, 1733, 1583, 1439, 1099, 760 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 5.93 (t, J = 9.9 Hz, 1 H), 5.70 (dd, J = 9.9
Hz, 1.7 Hz, 1 H), 3.72 (q, J = 8.7 Hz, 1 H), 3.18–3.14 (m, 1 H), 3.14 (s, 1
H), 2.55 (dd, J = 18.3 Hz, 6.4 Hz, 1 H), 2.29–2.24 (m, 1 H), 2.14–2.05
(m, 2 H), 2.03–1.97 (m, 1 H), 1.89–1.83 (m, 1 H), 1.71–1.58 (m, 2 H),
1.52–1.45 (m, 1 H), 1.30–1.23 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 212.4, 144.2, 112.2, 83.0, 79.5, 70.0,
Yield: 156 mg (0.0.338 mmol, 52% over the two steps); oil; [α]D20 –46
(c 1.5, CHCl3).
60.4, 51.6, 42.0, 25.5, 25.2, 23.8.
HRMS (ESI): m/z [M + H]+ calcd for C12H16NO: 190.1232; found:
IR (film): 2936, 2864, 1463, 1257, 1143, 1071, 836, 775 cm–1
.
190.1311.
1H NMR (400 MHz, CDCl3): δ = 5.82 (t, J = 10.6 Hz, 1 H), 5.61 (d, J =
10.6 Hz, 1 H), 3.91–3.83 (m, 1 H), 3.64–3.57 (m, 1 H), 3.03–2.97 (m, 1
H), 1.97–1.87 (m, 3 H), 1.84–1.79 (m, 2 H), 1.62–1.56 (m, 2 H), 1.45–
1.39 (m, 1 H), 1.23–1.17 (m, 2 H), 1.08 (s, 21 H), 0.88 (s, 9 H), 0.04 (s, 6
H).
13C NMR (100 MHz, CDCl3): δ = 145.7, 111.6, 103.2, 96.1, 75.8, 71.0,
62.9, 51.7, 39.3, 29.0, 25.8, 25.3, 23.9, 18.7, 18.1, 11.3, –4.6.
Allosecurinine (3)
An oven-dried vial equipped with a stirring bar was charged with
W(CO)6 (303 mg, 0.862 mmol, 2.5 equiv) and sealed with a crimp cap.
The vial was evacuated and flushed with CO (3×). Then, a solution of 6
(65 mg, 0.354 mmol) in toluene/DMF (1.5 mL/0.9 mL) was added via
syringe. The resulting mixture was stirred for 0.5 h at 140 °C and then
cooled to r.t. The content of the vial was transferred into a round-bot-
tom flask and concentrated in vacuo. The resulting black residue was
subjected to flash chromatography (silica gel, toluene/EtOAc, 95:5 to
85:15 +1% Et3N) to afford allosecurinine/phyllochrysine (3).
HRMS (ESI): m/z [M + H]+ calcd for C27H52NOSi2: 462.3587; found:
462.3591.
Yield: 9 mg (0.041 mmol, 12%); yellow solid; [α]D20 –1033 (c 2, EtOH).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F

F
E. Chirkin et al.
Paper
Synthesis
The analytical data were identical to those reported in the litera-
ture.19
(7) (a) Rana, S.; Gupta, K.; Gomez, J.; Matsuyama, S.; Chakrabarti,
A.; Agarwal, M. L.; Agarwal, A.; Agarwal, M. K.; Wald, D. N.
FASEB J. 2010, 24, 2126. (b) Gupta, K.; Chakrabarti, A.; Rana, S.;
Ramdeo, R.; Roth, B. L.; Agarwal, M. L.; Tse, W.; Agarwal, M. K.;
Wald, D. N. PloS One 2011, 6, e21203. (c) Li, M.; Han, S.; Zhang,
G.; Wang, Y.; Ji, Z. Pharmazie 2014, 69, 217. (d) Chen, C. R.; Xia,
X. H.; Yao, S. Y.; Zhang, Q.; Wang, Y.; Ji, Z. Pharmazie 2012, 67,
351.
(8) (a) Perez, M.; Ayad, T.; Maillos, P.; Poughon, V.; Fahy, J.;
Ratovelomanana-Vidal, V. Eur. J. Med. Chem. 2016, 109, 287.
(b) Klochkov, S. G.; Afanas’eva, S. V.; Grigor’ev, V. V. Chem. Nat.
Compd. 2008, 44, 197.
1H NMR (400 MHz, CDCl3): δ = 6.80 (dd, J = 5.2 Hz, 8.8 Hz, 1 H), 6.64
(d, J = 9.2 Hz, 1 H), 5.72 (s, 1 H), 3.90 (t, J = 4.6 Hz, 1 H), 3.65 (dd, J = 3.2
Hz, 13.4 Hz, 1 H), 2.76–2.73 (m, 2 H), 2.68 (dd, J = 4.2 Hz, 9.6 Hz, 1 H),
1.91 (d, J = 9.8 Hz, 1 H), 1.72–1.64 (m, 3 H), 1.47–1.32 (m, 2 H), 1.19–
1.08 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 172.6, 167.4, 148.5, 122.7, 109.0, 91.6,
60.7, 58.8, 43.6, 42.6, 22.1, 21.0, 18.4.
HRMS (ESI): m/z [M + Na]+ calcd for C13H15NO2Na: 240.1000; found:
240.1001.
(9) Gundluru, M. K.; Agarwal, M.; Xia, Z.; Karan, G.; Wald, D. N.
Patent WO2015051276 A1, 2015.
(10) (a) Zhang, H.; Zhu, K. K.; Han, Y. S.; Luo, C.; Wainberg, M. A.;
Yue, J. M. Org. Lett. 2015, 17, 6274. (b) Zhang, H.; Zhang, C. R.;
Han, Y. S.; Wainberg, M. A.; Yue, J. M. RSC Adv. 2015, 5, 107045.
(11) For selected recent syntheses of securinega alkaloids, see:
(a) Jeon, S.; Han, S. J. Am. Chem. Soc. 2017, 139, 6302. (b) Han, H.;
Smith, A. B. III. Org. Lett. 2015, 17, 4232. (c) Ma, N.; Yao, Y.; Zhao,
B. X.; Wang, Y.; Ye, W. C.; Jiang, S. Chem. Commun. 2014, 50,
9284. (d) ElSohly, A. M.; Wespe, D. A.; Poore, T. J.; Snyder, S. A.
Angew. Chem. Int. Ed. 2013, 52, 5789. (e) Chen, J. H.; Levine, S. R.;
Buergler, J. F.; McMahon, T. C.; Medeiros, M. R.; Wood, J. L. Org.
Lett. 2012, 14, 4531. (f) Leduc, A. B.; Kerr, M. A. Angew. Chem. Int.
Ed. 2008, 47, 7945.
(12) Chirkin, E.; Michel, S.; Porée, F.-H. J. Org. Chem. 2015, 80, 6525.
(13) Friedman, R. K. Ph.D. Thesis; Colorado State University: USA,
2010.
(14) For recent use of oxa-HPK in total synthesis, see: (a) Tao, C.;
Zhang, J.; Chen, X.; Wang, H.; Li, Y.; Cheng, B.; Zhai, H. Org. Lett.
2017, 19, 1056. (b) Lu, H. H.; Martinez, M. D.; Shenvi, R. A. Nat.
Chem. 2015, 7, 604. (c) Chen, J.; Gao, P.; Yu, F.; Yang, Y.; Zhu, S.;
Zhai, H. Angew. Chem. Int. Ed. 2012, 51, 5897.
Acknowledgment
Université Paris Descartes and CNRS are gratefully acknowledged for
their financial support. P. Leproux (UMR CNRS 8638, Université Paris
Descartes) is acknowledged for her technical assistance (mass spec-
trometry). F.H.P. thanks E. P. Santos (Antoine Béclère Hospital) for her
technical assistance during the preparation of the manuscript.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1612063.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
References
(1) Present address: CEA IBiTec-S/SCBM, CEA Saclay, Labex LERMIT,
91191 Gif-sur-Yvette, France.
(2) (a) Wehlauch, R.; Gademann, K. Asian J. Org. Chem. 2017, 6,
1146. (b) Chirkin, E.; Atkatlian, W.; Porée, F.-H. The Securinega
Alkaloids, In The Alkaloids, Vol. 74; Knölker, H.-J., Ed.; Academic
Press: New York, 2015, 1–120. (c) Snieckus, V. The Securinega
Alkaloids, In The Alkaloids, Vol. 14; Manske, R. H. F., Ed.; Aca-
demic Press: New York, 1973, 425–506.
(15) (a) Zhang, X.; Schmitt, A. C.; Jiang, W. Tetrahedron Lett. 2001, 42,
5335. (b) Dhudshia, B.; Cooper, B. F. T.; Macdonald, C. L. B.;
Thadani, A. N. Chem. Commun. 2009, 463.
(16) The spectroscopic data of 11 correspond to those in ref. 15. For
the initial report on the preparation of 11 in a stereoselective
manner and via a different strategy (both enantiomers), see:
Katoh, M.; Matsune, R.; Honda, T. Heterocycles 2006, 67, 189.
(17) Katoh, M.; Mizutani, H.; Honda, T. Heterocycles 2006, 69, 193.
(18) (a) Denmark, S. E.; Yang, S. M. J. Am. Chem. Soc. 2004, 126,
12432. (b) Corey, E. J.; Rucker, C. Tetrahedron Lett. 1982, 23, 719.
(19) The data for the synthetic sample were identical to those
reported in the literature; see: Levant, P. D.; Beutler, J. A. Tetra-
hedron 1987, 43, 2915.
(3) Zhang, H.; Zhu, K.-K.; Gao, X.-H.; Yue, J.-M. Tetrahedron 2017,
73, 4692.
(4) Weinreb, S. M. Nat. Prod. Rep. 2009, 26, 758; see also ref. 1.
(5) (a) Wei, H.; Qiao, C.; Liu, G.; Yang, Z.; Li, C. C. Angew. Chem. Int.
Ed. 2013, 52, 620. (b) Wehlauch, R.; Grendelmeier, S. M.;
Miyatake-Ondozabal, H.; Sandtorv, A. H.; Scherer, M.;
Gademann, K. Org. Lett. 2017, 19, 548.
(6) Beutler, J. A.; Karbon, E. W.; Brubaker, A. N.; Malik, R.; Curtis, D.
R.; Enna, S. J. Brain Res. 1985, 330, 135.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F