Asymmetric total synthesis of (+)-virosine A via sequential nucleophilic cyclizations onto an activated formamide

Article abstract of DOI:10.1021/jo202651t

The first synthesis of tetracyclic alkaloid virosine A is reported. The natural alkaloid was prepared in only 13 steps, in an enantioenriched form. The azabicyclo[2.2.2]octane core was efficiently assembled using a key Vilsmeier-Haack and Mannich cyclizations sequence performed in one pot.

Full text of DOI:10.1021/jo202651t

Article
pubs.acs.org/joc
Asymmetric Total Synthesis of (+)-Virosine A via Sequential
Nucleophilic Cyclizations onto an Activated Formamide
Guillaume Belanger,* Marianne Dupuis, and Robin Larouche-Gauthier
́
́ ́ ́ ́
Departement de Chimie, Universite de Sherbrooke, 2500 boulevard Universite, Sherbrooke, Quebec J1K 2R1, Canada
S
* Supporting Information
ABSTRACT: The first synthesis of tetracyclic alkaloid virosine A
is reported. The natural alkaloid was prepared in only 13 steps, in
an enantioenriched form. The azabicyclo[2.2.2]octane core was
efficiently assembled using a key Vilsmeier−Haack and Mannich
cyclizations sequence performed in one pot.
analogies with more abundant members of this family such as
viroallosecurinine (3), an azabicyclo[3.2.1]octane core was
initially proposed by the authors (see structures 4 and 5 for
securinol B and A, respectively). In 1991, Arbain and Sargent
revised the structure of securinol A (2) to an azabicyclo[2.2.2]-
octane core skeleton based on X-ray analysis of its hydro-
bromide salt. Because it was known that both securinol A and B
lead to viroallosecurinine (3) upon treatment of their respective
mesylate with collidine,6 presumably through the same
aziridinium ion 6,4 Arbain and Sargent therefore proposed
the revised structure 1 for securinol B even though they had not
isolated the latter. When Ye and co-workers reported the
isolation of a new alkaloid in the same family in 2008, even
though the structure 1 they elucidated matched the one
proposed for securinol B, in the absence of sufficient
characterization data on securinol B they legitimately proposed
another name, virosine A.3 No synthesis of this interesting and
rather unusual polycyclic alkaloid is reported to date.
INTRODUCTION
■
Virosine A is a tetracyclic alkaloid from the Securinega family.
These alkaloids are isolated from several species of the
Euphorbiaceae plant family1 and are known to act on the
central nervous system as γ-aminobutyric acid (GABA)
receptor antagonists.2 Visorine A (1) was isolated by Ye and
co-workers in 2008.3 The structure elucidation is essentially
based on 1D and 2D NMR data (Figure 1).
RESULTS AND DISCUSSION
■
We planned to make use of a cascade of Vilsmeier−Haack and
Mannich cyclizations as the key step to assemble the
azabicyclo[2.2.2]octane core of the natural product.7 Scheme
1 shows our retrosynthetic analysis of virosine A (1). The latter
could be derived from intermediate 7, which in turn could be
obtained upon chemoselective amide activation of formamide
8, generating two rings and two of the four stereocenters of
virosine A. Intermediate 8 would be obtained after functional
group manipulation on amine 9 and enolization of the
butenolide ring. The latter would be the product of an
intramolecular olefination. Finally, azido-alcohol 10 would be
prepared by desymmetrization of meso-epoxide 11 and
functionalization of the alkene moiety.
Figure 1. Representative Securinega alkaloids.
Intriguingly, the structure of visorine A is exactly the same as
was proposed for securinol B by Arbain and Sargent in 1991.4
In fact, securinol B and its epimer, securinol A, were both
initially isolated from Securinega suffriticosa by Tamura and
Iwamoto in 1965.5 While securinol A was fully characterized,
data about securinol B only allowed the authors to suggest that
securinol B was a stereoisomer of securinol A. Based on
Received: December 22, 2011
Published: March 5, 2012
© 2012 American Chemical Society
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possibility to generate directly the butenolide in the key step
and a suitable nucleophilicity.9 In a second generation approach
(Scheme 3), the furyl was installed from intermediate 13
Scheme 1. Retrosynthetic Analysis of Virosine A
Scheme 3. Second Generation Approach towards
( )-Virosine A
We already have disclosed our approach to the core of
virosine A (securinol B) (Scheme 2).8 In this first generation
Scheme 2. First Generation Approach towards the Core of
( )-Virosine A
common to the first generation approach. After a Staudinger
type reduction of the azide, amine 168 was alkylated with a
homopropargylic tosylate. The steric hindrance generated by
the adjacent OTIPS group prevented the bis-alkylation of the
amine, which is often problematic with less congested primary
amines. Rubottom oxidation of enol ether 17 in the presence of
bromoacetic acid then afforded bromoacetate 18 as a single
diastereomer and regioisomer. The butenolide ring was
installed by aid of an Arbuzov reaction with triethylphosphite
and a subsequent intramolecular Horner−Wadsworth−Em-
mons olefination. Formylation of amine 20 with N-
formylbenzotriazole10 followed by enolization of the butenolide
21 produced the key step precursor 8. Even though the furyl
group could be successfully installed this way, this route was
not optimal since three steps (from 17 to 20) showed
reproducibility issues (cf. yield ranges).
Hence, we developed a third generation approach, which
turned out to be much more efficient and reliable. To access
virosine A in a non-racemic form, the synthesis started with the
desymmetrization of epoxide 11 using Jacobsen’s conditions to
afford enantioenriched azido-alcohol 22 in a 94:6 enantiomeric
ratio (Scheme 4),11 which compares to literature.12 Compound
22 was submitted to a hydroxy-directed epoxidation followed
by protection of the resulting alcohol as a silyl ether. Instead of
opening epoxide 12 with bromoacetic acid followed by an
Arbuzov reaction (as we did in the second generation approach,
Scheme 3), the epoxide 12 was rather opened with diethyl
phosphonoacetic acid, and the desired phosphonoester 10 was
approach, we demonstrated the viability of the key Vilsmeier−
Haack/Mannich cyclizations to generate a tricyclic product 15
in a racemic form. Only 11 steps were required to access this
advanced intermediate. Unfortunately, all attempts to install the
butenolide ring of virosine A from 15 failed.
From these initial results, it became clear that a butenolide
precursor needed to be installed prior to the key biscyclization.
Hence, the furyl group was elected because it offers both the
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Scheme 4. Third Generation Approach: Total Synthesis of (+)-Virosine A
generated in one step (Scheme 4). Again, only one
diastereomer and regioisomer for the opening of epoxide 12
was observed, for the reason explained in Scheme 5: the
cleanly monoalkylated (no dialkylation observed) and then
formylated. Enolization of butenolide 21 generated the key step
precursor 8, now in 10 steps from 11 instead of 14 steps as in
the second generation approach.
Upon activation of formamide 8 with triflic anhydride (1.5
equiv) in the presence of 2,6-di-tert-butyl-4-methylpyridine (3
equiv) as the base, the Vilsmeier−Haack cyclization of the furyl
proceeded smoothly at rt over 20 min, and the addition of a
bromide salt (10 equiv) triggered a Mannich cyclization of the
alkyne. The optimized14 one-pot Vilsmeier−Haack and
Mannich cyclizations generated amine 7 containing the
tetracyclic core of the natural product in 58% yield, in a
separable 5:1 mixture with epimeric adduct 27. The stereo-
chemical assignment of compound 7 was done by NOESY
experiments that showed correlations for protons indicated in
Figure 2. Treatment of vinylic bromide 7 with Pd/C and
Scheme 5. Diastereoselectivity in Epoxide 12 Opening
opening through Route a leads to a twist-boat-like transition
state, higher in energy than the chair-like transition state for the
opening following Route b (preferred). Oxidation of the
resulting alcohol 10 using Dess−Martin periodinane furnished
the corresponding ketone 24 in high yield (Scheme 4). Then,
intramolecular Horner−Wadsworth−Emmons olefination pro-
moted by t-BuOK gave butenolide 25 in 60% yield, along with
11% of product 26 that suffered N3 elimination from 25.13 The
azide was reduced via a catalytic hydrogenation, and the
resulting amine 9 was initially formylated. However, all
attempts to alkylate the resulting formamide failed, presumably
due to steric hindrance engendered by the adjacent OTIPS.
Taking advantage of this steric encumbrance, substrate 9 was
Figure 2. NOESY interactions for compound (+)-7.
hydrogen resulted in a fast hydrogenolysis of the C−Br bond,
followed by reduction of the resulting disubstituted alkene
(Scheme 4). No hydrogenation of the butenolide trisubstituted
alkene was observed. It should be noted that the latter alkene is
quite hindered on both faces, by the OTIPS (top face) and the
piperidine ring (bottom face). Deprotection of the TIPS ether
finally afforded virosine A. The characterization of the synthetic
material matched that for the isolated natural product.3
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( + ) - ( 1 S , 2 R , 8 S , 1 5 S ) - 7 - A z a - 4 - b r o m o - 1 3 - o x a - 1 5 -
(triisopropylsilyloxy)tetracyclo[6.5.2.0.2,701,10]pentadeca-3,10-
dien-12-one (7) and (+)-(1S,2S,8S,15S)-7-Aza-4-bromo-13-oxa-
15-(triisopropylsi-lyloxy)tetracyclo[6.5.2.0.2,701,10]pentadeca-
3,10-dien-12-one (27). Triflic anhydride (15 μL, 0.087 mmol) was
added to a solution of formamide 8 (30 mg, 0.058 mmol) and 2,6-di-
tert-butyl-4-methylpyridine16 (36 mg, 0.17 mmol) in CDCl3 (5.8 mL)
at 0 °C. The reaction mixture was stirred at rt for 20 min.
Tetrabutylphosphonium bromide (197 mg, 0.577 mmol) and MeCN
(5.8 mL) were added, and the mixture was stirred at 70 °C for 15 h.
Saturated aq Na2CO3 was added, and then the layers were separated.
The aqueous phase was extracted with EtOAc. The combined organic
phases were washed with brine, dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The crude material was
purified by flash chromatography (silica gel saturated with Et3N, 0% to
15% EtOAc in hexanes) to give 7 (13 mg, 48%) and 27 (2.8 mg, 10%).
CONCLUSION
■
In summary, we demonstrated the use of one-pot Vilsmeier−
Haack and Mannich cyclizations as an efficient synthetic
strategy for the construction of complex polycyclic alkaloids.
This strategy was applied to the first total synthesis of virosine
A, prepared in an enantioenriched form in only 13 steps and
3.4% overall yield. We therefore corroborate the absolute
configuration deducted by Ye3 for virosine A. Even though the
revised structure proposed by Arbain and Sargent4 for securinol
B is exactly the same as for virosine A, the absence of spectral
data for the former do not allow us to conclude that they are
indeed the same natural product.
EXPERIMENTAL SECTION
■
Data for 7: beige solid, mp 82−84 °C; [α]20 +33.0 (c 0.54,
D
General Information. All reactions requiring anhydrous con-
ditions were conducted in flame-dried glassware under a dry nitrogen
or argon atmosphere. THF was distilled from Na and benzophenone
under nitrogen immediately prior to use. Acetonitrile, dichloro-
methane, benzene, toluene, diisopropylethylamine, and triethylamine
were distilled from CaH2 under nitrogen immediately prior to use.
Methanol was distilled over 4 Å molecular sieves. Triflic anhydride and
CDCl3 were distilled over a small amount of phosphorus pentoxide
(P2O5) under nitrogen immediately prior to use. Azidotrimethylsilane
and tert-butyldimethylsilyl trifluoromethanesulfonate were distilled
under nitrogen immediately prior to use. p-Toluenesulfonyl chloride
was recrystallized in benzene prior to use. All other required fine
chemicals were used directly without purification. Thin layer
chromatography (TLC) was conducted with precoated 60 Å 250
μm silica gel plates with F-254 indicator and visualized using a
combination of UV and anisaldehyde, ceric ammonium molybdate,
iodine on silica, or potassium permanganate staining. Flash column
chtomatography was performed using silica gel (230−400 mesh).
Melting points are uncorrected. Optical rotations were measured at rt
in a 1.0 dm cell (c in g cm−3). IR spectra were recorded with a FTIR
CHCl3);15 IR (film) ν 2937, 2866, 1788, 1769, 1653, 1465, 1140,
1053, 877 cm−1; 1H NMR (300 MHz, CDCl3) δ 5.85, (br. s, 1H), 5.75
(br. s, 1H), 4.33 (dd, J = 8.0, 4.9 Hz, 1H), 3.99−3.94 (m, 1H), 3.31−
3.16 (m, 2H), 3.10 (dd, J = 14.3, 5.4 Hz, 1H), 2.99−2.93 (m, 1H),
2.76 (dd, J = 12.9, 8.5 Hz, 1H), 2.68−2.48 (m, 2H), 2.32−2.21 (m,
1H), 1.50 (d, J = 13.1 Hz, 1H), 1.13−0.96 (m, 21H); 13C NMR (100
MHz, CDCl3) δ 173.4 (s), 172.3 (s), 127.6 (d), 122.7 (s), 112.0 (d),
84.8 (s), 67.3 (d), 59.2 (d), 58.8 (d), 49.7 (t), 42.5 (t), 34.1 (t), 27.2
(t), 18.1 (q), 12.1 (d); MS (ESI) m/z (rel %) 470 and 468 [M+]
(100), 414 (10), 227 (10), 196 (10); HRMS (ESI) calcd for
C22H34BrNO3Si [M+] 468.1570, found 468.1571.
Data for 27: oily solid. [α]20D +16.7 (c 0.29, CHCl3);15 IR (film) ν
2945, 2926, 2866, 1776, 1758, 1653, 1465, 1128, 1053, 881, 840 cm−1;
1H NMR (300 MHz, CDCl3) δ 6.28 (br. s, 1H), 5.75 (br. s, 1H),
4.27−4.18 (m, 1H), 3.55 (br. s, 1H), 3.29−3.10 (m, 2H), 3.04 (dd, J =
14.6, 4.9 Hz, 1H), 2.99−2.94 (m, 1H), 2.92−2.81 (m, 1H), 2.69 (dd, J
= 13.0, 9.4 Hz, 1H), 2.57−2.42 (m, 1H), 2.42−2.31 (m, 1H), 1.37−
1.29 (m, 1H), 1.12−0.96 (m, 21H); 13C NMR (100 MHz, CDCl3) δ
175.3 (s), 173.5 (s), 128.8 (d), 122.3 (s), 111.5 (d), 84.6 (s), 67.1 (d),
61.4 (d), 61.1 (d), 49.1 (t), 36.7 (t), 35.1 (t), 29.0 (t), 18.2 (q), 12.2
(d); MS (ESI) m/z (rel %) 490 [M+ + Na] (95), 446 (30), 393 (15),
349 (20), 301 (25), 289 (20), 202 (15); HRMS (ESI) calcd for
C22H34BrNNaO3Si [M+ + Na] 490.1389, found 490.1389.
1
instrument by applying substrates as thin films onto a KBr plate. H
and 13C NMR spectra were recorded on 300 MHz and/or 400 MHz
spectrometers. All chemical shifts are referenced to residual non-
deutarated solvent. Data for proton spectra are reported as follows:
chemical shift (multiplicity [singlet (s), doublet (d), triplet (t), quartet
(q), quintet (quint), and multiplet (m)], coupling constants [Hz],
integration). Carbon spectra were recorded with complete proton
decoupling and the chemical shifts are reported in ppm.
(+)-N-(But-3-ynyl)-N-((5S,6S)-4,5,6,7-tetrahydro-2-(tert-bu-
tyldimethylsilyloxy)-6-(triisopropylsilyloxy)benzofuran-5-yl)-
formamide (8). To a solution of butenolide 21 (19 mg, 0.047 mmol)
and Et3N (34 μL, 0.24 mmol) in DCM (0.5 mL) at 0 °C was added
tert-butyldimethylsilyl trifluoromethanesulfonate (28 μL, 0.12 mmol).
Saturated aq Na2CO3 was immediately added. The usual workup
(DCM) and purification (silica gel saturated with Et3N, 30% EtOAc in
hexanes) gave 8 (20 mg, 82%) as a colorless oil: [α]20D +34.8 (c 0.85,
CHCl3);15 IR (film) ν 3316, 2945, 2892, 2866, 1683, 1597, 1462,
1271, 1256, 1095, 885, 844 cm−1; 1H NMR (300 MHz, CDCl3,
mixture of rotamers) δ 8.19 (s) and 8.14 (s) (1H, rotamers), 4.92 (s)
and 4.89 (s) (1H, rotamers), 4.87−4.77 (m) and 4.23−4.13 (m) (1H,
rotamers), 3.69−3.33 (m, 2H), 3.33−3.19 (m, 1H), 3.02 (td, J = 16.1,
5.7 Hz, 1H), 2.76−2.34 (m, 5H), 2.06 (t, J = 2.5 Hz) and 2.01 (t, J =
2.5 Hz) (1H, rotamers), 1.08−1.03 (m, 21H), 0.98−0.94 (m, 9H),
0.24−0.20 (m, 6H); 13C NMR (100 MHz, CDCl3, mixture of
rotamers) δ 163.9 (d), 163.7 (d), 156.7 (s), 156.3 (s), 135.5 (s), 135.1
(s), 116.0 (s), 115.2 (s), 84.0 (d), 83.8 (d), 81.6 (s), 80.5 (s), 71.4 (d),
70.1 (d), 69.2 (d), 68.1 (d), 61.5 (d), 60.6 (d), 49.2 (t), 42.1 (t), 33.4
(t), 32.8 (t), 26.5 (t), 25.6 (q), 24.1 (t), 20.4 (t), 18.6 (t), 18.3 (q),
18.2 (s), 13.0 (d), 12.9 (d), −4.8 (q); MS (EI) m/z (rel %) 519 [M+]
(40), 476 [M+ − C3H7] (35), 422 (50), 248 (80), 224 (100), 210
(15), 73 (55); HRMS (EI) calcd for C28H49NO4Si2 [M+] 519.3200,
found 519.3193.
Usual Reaction Workup and Purification. After addition of the
indicated aqueous solution, layers were separated. The aqueous phase
was extracted with the indicated solvent and washed with the indicated
aqueous solution. The combined organic phases were dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pressure
using a rotary evaporator. The crude material was purified by flash
chromatography using silica gel with the indicated eluent.
(+)-Virosine A (1). To a solution of 28 (4.0 mg, 0.010 mmol) in
THF (0.2 mL) at 0 °C was added tetrabutylammonium fluoride (1.0
M in THF, 11 μL, 0.011 mmol). The reaction mixture was stirred at rt
for 20 min. Aqueous NaOH (1 N) and EtOAc were added, and layers
were separated. The aqueous phase was extracted with EtOAc. The
combined organic phases were dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The crude material was
purified by flash chromatography (silica gel, 85% EtOAc in hexanes) to
give virosine A (1) (1.5 mg, 63%) as an oily solid. [α]20D +22.8 (c 0.35,
1,4-dioxane);15 IR (film) ν 3394 (br), 2926, 2851, 1755, 1728, 1653,
1597, 1454, 1143 cm−1; 1H NMR (300 MHz, CDCl3) δ 5.71 (s, 1H),
4.43−4.34 (m, 1H), 3.02−2.86 (m, 3H), 2.85−2.66 (m, 4H), 1.87−
1.76 (m, 1H), 1.74−1.51 (m, 4H), 1.46 (dd, J = 12.4, 5.0 Hz, 1H),
1.38−1.26 (m, 1H), 0.86 (qd, J = 11.8, 4.0 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 174.1 (s), 173.9 (s), 111.8 (d), 84.5 (s), 65.5 (d), 65.3
(d), 59.1 (d), 52.9 (t), 41.1 (t), 29.6 (t), 26.8 (t), 25.8 (t), 24.2 (t);
MS (EI) m/z (rel %) 235 [M+] (60), 191 (100), 163 (15), 149 (20),
140 (45), 110 (55), 84 (30); HRMS (EI) calcd for C13H17NO3 [M+]
235.1208, found 235.1210.
(+)-(5S,6S,7aS)-5-Amino-5,6,7,7a-tetrahydro-6-
(triisopropylsilyloxy)benzofuran-2(4H)-one (9). To a solution of
azide 25 (754 mg, 2.14 mmol) in EtOAc (20 mL) at rt was added
palladium on carbon (10 wt %, 223 mg). The reaction mixture was
stirred for 2 h at rt under hydrogen atmosphere. The solution was
filtered on Celite (EtOAc washings). The solvent was evaporated
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under reduced pressure, and the usual purification (10% MeOH in
NaHCO3 and EtOAc were added. The usual workup (EtOAc, brine)
and purification (silica gel saturated with Et3N, 5% EtOAc in hexanes)
gave 17 (2.02 g, 88%) as a colorless oil: IR (film) ν 3314, 2933, 2869,
1676, 1464, 1252, 1194, 1098, 886, 839, 780, 680 cm−1; 1H NMR (300
MHz, CDCl3) δ 4.72−4.66 (m, 1H), 3.80 (td, J = 8.1, 5.3 Hz, 1H),
2.91−2.64 (m, 3H), 2.43−2.28 (m, 4H), 2.16−2.02 (m, 2H), 2.00−
1.86 (m, 1H), 1.09−1.04 (m, 21H), 0.91 (s, 9H), 0.12 (s, 6H); 13C
NMR (75.5 MHz, CDCl3) δ 148.2 (s), 100.7 (d), 82.6 (s), 71.4 (d),
69.6 (d), 58.8 (d), 45.8 (t), 34.8 (t), 31.8 (t), 25.8 (q), 19.8 (t), 18.3
(q), 18.1 (s), 12.7 (d), −4.4 (q); MS (EI) m/z (rel %) 451 [M+] (15),
408 [M+ − C3H7] (30), 371 (30), 278 (100), 256 (70), 210 (25);
HRMS (EI) calcd for C25H49NO2Si2 [M+] 451.3302, found 451.3304.
rac-(1S,4S,5S)-4-(But-3-ynylamino)-5-(triisopropylsilyloxy)-
2-oxocyclohexyl Bromoacetate (18). Bromoacetic acid (3.50 g,
25.5 mmol) was added to a solution of m-chloroperbenzoic acid (77%,
372 mg, 1.66 mmol) in DCM (3.5 mL) at −25 °C. A solution of
amine 17 (500 mg, 1.11 mmol) in DCM (3 mL) was added over 1 h,
and the solution was stirred for 30 min at −25 °C. Saturated aq
Na2SO3 was added, and the mixture was stirred for 30 min at rt.
Aqueous NaOH (1 N) was added. The usual workup (DCM) and
purification (20% EtOAc in hexanes) gave 18 (single diastereomer,
383 mg, 73%) as a yellowish oil: IR (film) ν 3752, 3734, 2944, 2869,
2335, 1734, 1650, 1562, 1504, 1465, 1275, 1107 cm−1; 1H NMR (300
MHz, CDCl3) δ 5.55 (dd, J = 12.2, 6.9 Hz, 1H), 4.23−4.17 (m, 1H),
3.96 (s, 2H), 3.33−3.27 (m, 1H), 3.08 (dd, J = 13.8, 4.0 Hz, 1H),
2.84−2.64 (m, 2H), 2.46−2.23 (m, 6H), 1.22−1.00 (m, 21H); 13C
NMR (75.5 MHz, CDCl3) δ 203.0 (s), 166.4 (s), 81.9 (s), 74.8 (d),
70.2 (d), 69.2 (d), 61.6 (d), 45.4 (t), 41.2 (t), 35.5 (t), 25.9 (t), 19.6
(t), 18.2 (q), 12.3 (d); MS (EI) m/z (rel %) 432 and 430 [M+ −
C3H7] (20), 317 (70), 278 (100), 253 (25), 241 (35), 223 (20), 131
(20); HRMS (EI) calcd for C18H29BrNO4Si [M+ − C3H7] 430.1049,
found 430.1054.
EtOAc) gave 9 (573 mg, 82%) as a white solid: mp 61−64 °C; [α]20
D
+57.7 (c 0.80, CHCl3);15 IR (CHCl3) ν 3686, 3623, 3023, 2971, 2870,
1750, 1522, 1428, 1215, 1035, 930 cm−1; 1H NMR (300 MHz,
CDCl3) δ 5.87 (s, 1H), 5.08 (dd, J = 11.0, 6.4 Hz, 1H), 4.09−4.00 (m,
1H), 3.42−3.36 (m, 1H), 3.02 (dd, J = 13.8, 4.4 Hz, 1H), 2.61 (d, J =
13.8 Hz, 1H), 2.57−2.47 (m, 1H), 1.76−1.65 (m, 1H), 1.55 (s, 2H),
1.18−1.01 (m, 21H); 13C NMR (100 MHz, CDCl3) δ 173.4 (s), 169.4
(s), 115.6 (d), 79.2 (d), 71.9 (d), 53.6 (d), 36.1 (t), 31.9 (t), 18.2 (q),
12.3 (d); MS (EI) m/z (rel %) 308 (5), 282 [M+ − C3H7] (100), 184
(2), 130 (10), 102 (5); HRMS (EI) calcd for C14H24NO3Si [M+ −
C3H7] 282.1525, found 282.1527.
(+)-(1S,2S,4S,5S)-4-Azido-2-hydroxy-5-(triisopropylsilyloxy)-
cyclohexyl (diethylphosphono)acetate (10). To a solution of
epoxide 12 (2.42 g, 7.77 mmol) in THF (78 mL) was added
diethylphosphonoacetic acid (25.0 mL, 155 mmol). The solution was
stirred for 15 h at 70 °C. The reaction mixture was concentrated under
reduced pressure, and the residue was dissolved in EtOAc and washed
three times with saturated aq NaHCO3. The usual workup (EtOAc,
H2O) and purification (50% EtOAc in hexanes) gave 10 (2.60 g, 66%)
as a colorless oil: [α]20 +38.5 (c 1.11, CHCl3);15 IR (film) ν 3377,
D
2944, 2869, 2109, 1734, 1646, 1557, 1465, 1390, 1266, 1120 cm−1; 1H
NMR (300 MHz, CDCl3) δ 5.11 (ddd, J = 11.5, 9.1, 4.6 Hz, 1H), 4.40
(s, 1H), 4.23−4.10 (m, 4H), 4.05−3.99 (m, 1H), 3.93−3.82 (m, 1H),
3.82−3.77 (m, 1H), 3.12−2.81 (m, 2H), 2.16−1.97 (m, 3H), 1.84−
1.72 (m, 1H), 1.35 (dd, J = 13.2, 6.9 Hz, 6H), 1.18−0.98 (m, 21H);
13C NMR (75.5 MHz, CDCl3) δ 165.2 (d, J
P = 5.5 Hz), 75.9 (d),
13C−31
13C−31
P
13C−31
P
69.4 (d), 67.7 (d), 63.3 (td, J
= 5.8 Hz), 62.8 (td, J
= 6.3
13C−31
Hz), 62.0 (d), 35.0 (td, J
P = 130.6 Hz), 32.7 (t), 30.8 (t), 17.9 (q),
P = 4.9 Hz), 12.1 (d); MS (EI) m/z (rel %) 464 [M+ −
13C−31
16.3 (qd, J
C3H7] (60), 309 (5), 281 (5), 240 (100), 222 (65), 179 (30), 123
(30); HRMS (EI) calcd for C18H35N3O7PSi [M+ − C3H7] 464.1982,
found 464.1993.
rac-(1S,4S,5S)-4-(But-3-ynylamino)-5-(triisopropylsilyloxy)-
2-oxocyclohexyl (Diethylphosphono)acetate (19). To a solution
of bromide 18 (252 mg, 0.531 mmol) in toluene (11 mL) was added
triethylphosphite (1.4 mL, 8.0 mmol) at rt. The reaction mixture was
stirred for 3 h at reflux. Solvent and excess triethylphosphite were
evaporated under reduced pressure. The usual purification (50% to
85% EtOAc in hexanes) gave 19 (253 mg, 90%) as a colorless oil: IR
(film) ν 3297, 2945, 2870, 1754, 1735, 1638, 1465, 1391, 1267, 1106,
1053, 1024, 971, 881 cm−1; 1H NMR (300 MHz, CDCl3) δ 5.54 (dd, J
= 12.2, 6.8 Hz, 1H), 4.26−4.12 (m, 5H), 3.33−3.26 (m, 1H), 3.18−
2.98 (m, 3H), 2.83−2.64 (m, 2H), 2.46−2.22 (m, 6H), 1.34 (td, J =
7.1, 1.2 Hz, 6H), 1.21−1.01 (m, 21H); 13C NMR (75.5 MHz, CDCl3)
(+)-((1R,3S,4S,6S)-4-Azido-7-oxabicyclo[4.1.0]heptan-3-
yloxy)triisopropylsilane (12). Sodium hydride (60% in mineral oil,
1.88 g, 47.1 mmol) was added to a solution of alcohol 23 (6.09 g, 39.3
mmol) in THF (250 mL) at 0 °C. The resulting mixture was stirred at
rt for 1.5 h, TIPSCl was added at 0 °C, and the reaction mixture was
stirred at rt for 18 h. Water was added carefully, and the reaction
mixture was concentrated under reduced pressure. The usual workup
(EtOAc, brine) and purification (2% to 10% EtOAc in hexanes) gave
12 (11.2 g, 93%) as a light brown oil: [α]20D +11.1 (c 1.24, CHCl3);15
1
IR (film) ν 2940, 2105, 1465, 1256, 1110, 818, 681 cm−1; H NMR
(300 MHz, CDCl3) δ 3.64 (td, J = 10.0, 7.0 Hz, 1H), 3.40 (ddd, J =
11.0, 10.0, 5.0 Hz, 1H), 3.17 (dt, J = 4.0, 2.0 Hz, 1H), 3.08 (dd, J = 5.0,
4.0 Hz, 1H), 2.50 (ddd, J = 15.0, 5.0, 2.0 Hz, 1H), 2.40 (ddd, J = 15.0,
7.0, 5.0 Hz, 1H), 1.98 (dd, J = 15.0, 10.0 Hz, 1H), 1.67 (ddd, J = 15.0,
11.0, 2.0 Hz, 1H), 1.15−0.99 (m, 21H); 13C NMR (75.5 MHz,
CDCl3) δ 71.2 (d), 61.4 (d), 52.3 (d), 50.5 (d), 34.1 (t), 30.4 (t), 18.0
(q), 12.7 (d); MS (CI) m/z (rel %) 312 [M+ + H] (100), 240 (20);
HRMS (CI) calcd for C15H30N3O2Si [M+ + H] 312.2107, found
312.2120.
But-3-ynyl p-Toluenesulfonate. To a solution of but-3-yn-1-ol
(1.20 mL, 15.8 mmol), triethylamine (2.70 mL, 19.0 mmol), and 4-
(dimethylamino)pyridine (39 mg, 0.32 mmol) in DCM (53 mL) at 0
°C was added p-toluenesulfonyl chloride (3.16 g, 16.6 mmol) in three
portions. The reaction mixture was brought to rt and stirred 15 h. Aq
NaOH (1 N, 30 mL) was added, and the mixture was vigorously
stirred for 15 min at rt. The usual workup (DCM, brine) gave but-3-
ynyl p-toluenesulfonate (3.46 g, 98%) as a yellowish oil. The product
obtained is in agreement with published spectra:17 1H NMR (300
MHz, CDCl3) δ 7.81 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H),
4.10 (t, J = 7.1 Hz, 2H), 2.56 (td, J = 7.1, 2.7 Hz, 2H), 2.46 (s, 3H),
1.97 (t, J = 2.7 Hz, 1H).
13C−31
P
δ 203.1 (s), 164.9 (d, J
69.2 (d), 63.7 (td, J
(d), 45.3 (t), 41.2 (t), 35.6 (t), 34.0 (td, J
= 4.4 Hz), 81.9 (s), 74.1 (d), 70.1 (d),
13C−31
P
13C−31
P
= 6.7 Hz), 61.7
= 3.9 Hz), 62.8 (td, J
13C−31
P = 134.8 Hz), 19.6 (t),
13C−31
18.2 (q), 16.4 (qd, J
= 5.2 Hz), 12.3 (d); MS (EI) m/z (rel %)
531 [M+] (10), 492 [M+P− C3H3] (20), 488 [M+ − C3H7] (50), 331
(40), 313 (60), 153 (100); HRMS (EI) calcd for C25H46NO7PSi [M+]
531.2781, found 531.2787.
rac-(5S,6S,7aS)-5-(But-3-ynylamino)-5,6,7,7a-tetrahydro-6-
(triisopropylsilyloxy)benzofuran-2(4H)-one (20). To a suspen-
sion of sodium hydride (60% dispersion in mineral oil, 7.7 mg, 0.19
mmol) in THF (0.6 mL) at −40 °C was added a solution of
phosphonate 19 (92.4 mg, 0.174 mmol) in THF (0.6 mL). The
reaction mixture was stirred for 2 h at −40 °C. Brine and Et2O were
added. The usual workup (Et2O, H2O) and purification (30% EtOAc
in hexanes) gave 20 (47.7 mg, 73%) as a white solid: mp 34−36 °C;
IR (CHCl3) ν 3690, 3626, 3308, 3023, 2975, 2870, 1746, 1525, 1424,
1
1215, 1042, 922, 788 cm−1; H NMR (300 MHz, CDCl3) δ 5.83 (s,
1H), 5.06 (dd, J = 11.2, 6.3 Hz, 1H), 4.20−4.13 (m, 1H), 3.15−3.09
(m, 1H), 2.98−2.87 (m, 1H), 2.86−2.67 (m, 3H), 2.56−2.45 (m, 1H),
2.38−2.29 (m, 2H), 2.00 (t, J = 2.5 Hz, 1H), 1.76−1.64 (m, 1H),
1.18−1.00 (m, 21H); 13C NMR (100 MHz, CDCl3) δ 173.5 (s), 169.7
(s), 115.1 (d), 82.1 (s), 79.1 (d), 70.2 (d), 69.8 (d), 59.5 (d), 45.9 (t),
36.5 (t), 29.0 (t), 19.9 (t), 18.2 (q), 12.3 (d); MS (EI) m/z (rel %)
377 [M+] (15), 338 [M+ − C3H3] (15), 334 [M+ − C3H7] (100), 280
(20), 73 (40); HRMS (EI) calcd for C21H35NO3Si [M+] 377.2386,
found 377.2382.
rac-N-(But-3-ynyl)-N-((1S,6S)-3-(tert-butyldimethylsilyloxy)-
6-(triisopropylsilyloxy)cyclohex-3-enylamine (17). A solution of
but-3-ynyl p-toluenesulfonate (2.27 g, 10.1 mmol) in MeCN (30 mL)
was added to a solution of amine 168 (2.02 g, 5.06 mmol) and N,N-
diisopropylethylamine (1.90 mL, 11.1 mmol) in MeCN (20 mL) at rt.
The reaction mixture was stirred for 15 h at 70 °C. Saturated aq
3219
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Article
(+)-N-(But-3-ynyl)-N-((5S,6S,7aS)-2,4,5,6,7,7a-hexahydro-6-
triisopropylsilyloxy-2-oxobenzofuran-5-yl)formamide (21).
Preparation from 20: To a solution of butenolide 20 (15.9 mg,
0.042 mmol) in THF (2.1 mL) was added N-formylbenzotriazole10
(49.6 mg, 0.34 mmol) at rt. The reaction mixture was stirred for 15 h
at rt and then concentrated under reduced pressure. DCM was added,
and the organic layer was washed twice with aq NaOH (1 N). The
usual workup (DCM, brine) and purification (30% EtOAc in hexanes)
gave 21 (11.8 mg, 69%) as a yellowish oil. Preparation from 9: A
solution of but-3-ynyl p-toluenesulfonate (2.38 g, 10.6 mmol) in
MeCN (9 mL) was added to a solution of amine 9 (574 mg, 1.76
mmol) and N,N-diisopropylethylamine (0.6 mL, 3.52 mmol) in
MeCN (9 mL) at rt. The reaction mixture was stirred for 60 h at 70
°C. Saturated aq NaHCO3 and EtOAc were added. After the usual
workup (EtOAc, brine), the residue was dissolved in THF (88 mL),
and N-formylbenzotriazole10 (2.07 g, 14.1 mmol) was added at rt. The
reaction mixture was stirred for 72 h at rt and then concentrated under
reduced pressure. DCM was added, and the organic layer was washed
twice with aq NaOH (1 N). The usual workup (DCM) and
purification (30% to 50% EtOAc in hexanes) gave 21 (524 mg, 73%)
1.98−1.89 (m, 1H); 13C NMR (75.5 MHz, CDCl3) δ 68.5 (d), 59.7
(d), 51.8 (d), 51.2 (d), 30.0 (t), 28.0 (t); MS (CI) m/z (rel %) 156
[M+ + H] (35), 113 (50), 98 (75), 82 (100); HRMS (CI) calcd for
C6H10N3O2 [M+ + H] 156.0773, found 156.0777.
(+)-(1S,4S,5S)-4-Azido-5-(triisopropylsilyloxy)-2-oxocyclo-
hexyl (Diethylphosphono)acetate (24). To a solution of
phosphonate 10 (1.40 g, 2.76 mmol) in DCM (15 mL) at 0 °C was
slowly added a solution of Dess−Martin periodinane20 (2.30 g, 5.52
mmol) in DCM (13 mL). The solution was stirred for 2 h at 0 °C and
1 h at rt. Saturated aq Na2S2O3 was added, and the mixture was
vigorously stirred for 1 h at rt. The usual workup (DCM, H2O) and
purification (50% EtOAc in hexanes) gave 24 (1.16 g, 85%) as a
colorless oil: [α]20 +8.98 (c 1.66, CHCl3);15 IR (film) ν 2948, 2869,
D
2114, 1743, 1650, 1557, 1456, 1270, 1116, 1027, 966, 882, 683 cm−1;
1H NMR (300 MHz, CDCl3) δ 5.56 (dd, J = 12.3, 6.9 Hz, 1H), 4.26−
4.09 (m, 6H), 3.18−2.98 (m, 3H), 2.64−2.56 (m, 1H), 2.37−2.18 (m,
2H), 1.34 (dt, J = 7.1, 1.8 Hz, 6H), 1.22−1.00 (m, 21H); 13C NMR
13C−31
(100 MHz, CDCl3) δ 200.1 (s), 164.5 (d, J
P = 5.8 Hz), 73.2 (d),
13C−31
P
13C−31
P
68.4 (d), 64.1 (d), 62.7 (td, J
= 6.3 Hz), 62.5 (td, J
= 6.3
13C−31
P
Hz), 39.7 (t), 35.0 (t), 33.7 (td, J
= 134.6 Hz), 17.8 (q), 16.2
as a yellowish oil: [α]20 +70.0 (c 1.12, CHCl3);15 IR (film) ν 3282
13C−31
13C−31
P = 6.2 Hz), 11.9 (d); MS (EI)
D
(qd, J
P = 6.2 Hz), 16.1 (qd, J
m/z (rel %) 462 [M+ − C3H7] (5), 419 (100), 281 (30), 235 (45),
179 (25), 151 (15), 123 (20); HRMS (EI) calcd for C18H33N3O7PSi
[M+ − C3H7] 462.1825, found 462.1810.
(br.), 2949, 2870, 1761, 1671, 1462, 1394, 1098, 1080, 1001, 900, 881
1
cm−1; H NMR (300 MHz, CDCl3, mixture of rotamers) δ 8.25 (s)
and 8.17 (s) (1H, rotamers), 5.92 (s, 1H), 5.23 (dd, J = 12.0, 6.0 Hz,
1H), 4.60−4.53 (m), 4.37 (br. s), 4.28 (br. s) and 4.03−3.96 (m) (2H,
rotamers), 3.76−3.64 (m), 3.44−3.35 (m), 3.28−3.10 (m), 3.02 (br. s)
and 2.97 (br. s) (4H, rotamers), 2.67−2.39 (m, 3H), 2.13 (t, J = 2.6
Hz) and 2.02 (t, J = 2.7 Hz) (1H, rotamers), 1.70−1.46 (m, 1H),
1.25−1.02 (m, 21H); 13C NMR (100 MHz, CDCl3, mixture of
rotamers) δ 172.7 (s), 172.2 (s), 169.5 (s), 168.2 (s), 164.4 (d), 161.8
(d), 114.8 (d), 114.3 (d), 81.2 (s), 78.6 (d), 78.1 (d), 72.6 (d), 70.5
(d), 69.5 (d), 68.6 (d), 60.4 (d), 54.6 (d), 43.7 (t), 43.6 (t), 35.9 (t),
34.3 (t), 28.0 (t), 25.9 (t), 22.2 (t), 18.1 (q), 17.7 (t), 12.1 (d); MS
(EI) m/z (rel %) 362 [M+ − C3H7] (100), 294 (5), 210 (5), 74 (20);
HRMS (EI) calcd for C19H28NO4Si [M+ − C3H7] 362.1787, found
362.1782.
(+)-(5S, 6S,7aS)-5-Azido-5, 6,7,7a-tetrahydro-6-
(triisopropylsilyloxy)benzofuran-2(4H)-one (25) and
(−)-(6S,7aS)-7,7a-Dihydro-6-(triisopropylsilyloxy)benzofuran-
2(6H)-one (26). To a solution of phosphonate 24 (1.99 g, 3.94
mmol) in THF (20 mL) at −78 °C was added over 2 h a solution of
potassium tert-butoxide (442 mg, 3.94 mmol) in THF (20 mL). The
reaction mixture was stirred for 3 h at −78 °C and then was allowed to
warm up to rt. Water was added. The usual workup (EtOAc, H2O)
and purification (10% to 20% EtOAc in hexanes) gave 25 (837 mg,
60%) along with 26 (132 mg, 11%) as white solids.
Data for 25: mp 86−89 °C; [α]20 +156.8 (c 1.35, CHCl3);15 IR
D
(CHCl3) ν 3023, 2948, 2869, 2109, 1752, 1650, 1540, 1222, 1014,
926, 785 cm−1; 1H NMR (300 MHz, CDCl3) δ 5.91 (s, 1H), 5.07 (dd,
J = 11.3, 6.5 Hz, 1H), 4.23−4.14 (m, 1H), 4.02−3.94 (m, 1H), 3.05−
2.88 (m, 2H), 2.59−2.47 (m, 1H), 1.77−1.65 (m, 1H), 1.19−0.97 (m,
21H); 13C NMR (100 MHz, CDCl3) δ 173.0 (s), 166.9 (s), 116.0 (d),
78.3 (d), 68.9 (d), 61.9 (d), 36.3 (t), 27.9 (t), 18.2 (q), 12.2 (d); MS
(EI) m/z (rel %) 308 [M+ − C3H7] (90), 280 (70), 236 (40), 225
(20), 184 (100), 142 (20), 131 (45), 115 (25), 103 (60); HRMS (EI)
calcd for C14H22N3O3Si [M+ − C3H7] 308.1430, found 308.1436.
(+)-(1S,6S)-6-Azidocyclohex-3-enol (22). Nitrogen was bubbled
in epoxide 11 (1.95 g, 20.3 mmol) for 10 min, and it was then brought
12,18
to −25 °C. (R,R)-SalenCrN3
(975 mg, 1.52 mmol) and
azidotrimethylsilane (2.80 mL, 21.3 mmol) were added, and the
reaction mixture was stirred at −25 °C for 5 days. The mixture was
filtered on a silica pad, eluting with a mixture of 15% EtOAc in
hexanes. The filtrate was concentrated under reduced pressure and
then diluted in methanol (70 mL). Aqueous 1 N HCl (5 drops) was
added. The resulting mixture was stirred 1 h at rt, concentrated under
reduced pressure, and then diluted in DCM. The organic phase was
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The usual purification (10% EtOAc in hexanes) gave
22 (2.47 g, 87%) as a yellowish oil: er 94:6 (GC, RT-BetaDexsp
column, 30 m × 0.25 mm × 0.25 μm); [α]20D +100.0 (c 1.25, CHCl3);
IR (film) ν 3402 (br), 3035, 2914, 2108, 1658, 1254, 1062, 667 cm−1;
1H NMR (300 MHz, CDCl3) δ 5.64−5.54 (m, 2H), 3.74 (tdd, J = 9.0,
Data for 26: mp 73−77 °C; [α]20 −182.7 (c 1.14, CHCl3);15 IR
D
(CHCl3) ν 3023, 2949, 2870, 2110, 1746, 1645, 1522, 1424, 1215,
1
1050, 926 cm−1; H NMR (300 MHz, CDCl3) δ 6.54 (d, J = 9.6 Hz,
1H), 6.28 (dd, J = 9.6, 5.1 Hz, 1H), 5.79 (s, 1H), 5.34 (ddd, J = 12.5,
4.9, 1.6 Hz, 1H), 4.72−4.63 (m, 1H), 2.64−2.55 (m, 1H), 1.75 (td, J =
12.5, 3.6 Hz, 1H), 1.18−0.94 (m, 21H); 13C NMR (100 MHz, CDCl3)
δ 173.5 (s), 163.2 (s), 138.4 (d), 121.0 (d), 112.1 (d), 76.8 (d), 65.2
(d), 38.4 (t), 18.1 (q), 12.3 (d); MS (EI) m/z (rel %) 308 [M+] (5),
300 (5), 265 [M+ − C3H7] (100), 223 (5), 184 (5), 131 (10), 103
(20); HRMS (EI) calcd for C14H21O3Si [M+ − C3H7] 265.1260, found
265.1266.
(+)-(1S,2R,8S,15S)-7-Aza-13-oxa-15-(triisopropylsilyloxy)-
tetracyclo[6.5.2.0.2,701,10]pentadec-10-en-12-one (28). To a
solution of bromide 7 (6.6 mg, 0.014 mmol) in EtOH (1.4 mL) at
rt was added palladium on carbon (10 wt.%, 0.15 mg). The reaction
mixture was stirred for 2 h at rt under hydrogen atmosphere. The
solution was filtered on Celite (EtOAc washings). The solvent was
evaporated under reduced pressure and the usual purification (15%
6.0, 3.0 Hz, 1H), 3.55 (dt, J = 9.0, 6.0 Hz, 1H), 2.59−2.47 (m, 2H),
2.26 (d, J = 3.0 Hz, 1H), 2.22−2.05 (m, 2H); 13C NMR (75.5 MHz,
CDCl3) δ 124.4 (d), 123.2 (d), 69.8 (d), 63.0 (d), 32.8 (t), 30.0 (t);
MS (EI) m/z (rel %) 139 [M+] (1), 94 (45), 83 (50), 55 (100);
HRMS (EI) calcd for C6H9N3O [M+] 139.0746, found 139.0748.
(+)-(1R,3S,4S,6S)-4-Azido-7-oxabicyclo[4.1.0]heptan-3-ol
(23). A solution of anhydrous tert-butyl hydroperoxide19 (2.30 M in
toluene, 41.8 mL, 96.1 mmol) was added over 5 min to a solution of
alkene 22 (6.08 g, 43.7 mmol) and Mo(CO)6 (0.58 g, 2.2 mmol) in
benzene (300 mL) at reflux. After 2 h at reflux, the reaction mixture
was cooled to 0 °C and quenched by carefully adding saturated aq
Na2S2O3. Water was added, and the usual workup (EtOAc, brine) and
purification (40% EtOAc in hexanes) gave 23 (5.90 g, 87%) as a white
solid: mp 59−61 °C; [α]20D +61.6 (c 1.02, CHCl3);15 IR (film) ν 3327
EtOAc in hexanes) gave 28 (4.0 mg, 73%) as a colorless oil: [α]20
D
+16.9 (c 0.40, CHCl3);15 IR (film) ν 2945, 2866, 1765, 1653, 1462,
1151, 1113, 1061, 1012, 881, 836 cm−1; 1H NMR (300 MHz, CDCl3)
δ 5.69 (br. s, 1H), 4.39−4.31 (m, 1H), 3.00 (d, J = 18.2 Hz, 1H),
2.94−2.82 (m, 2H), 2.81−2.61 (m, 4H), 1.86−1.75 (m, 1H), 1.62−
1.40 (m, 4H), 1.37−1.20 (m, 1H), 1.11−0.96 (m, 21H), 0.92−0.78
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 174.3 (s), 174.1 (s), 111.5
(d), 84.6 (s), 65.6 (d), 65.3 (d), 59.9 (d), 52.8 (t), 42.4 (t), 29.5 (t),
1
(br), 3012, 2924, 2118, 1436, 1256, 1065, 953, 714 cm−1; H NMR
(300 MHz, CDCl3) δ 3.63−3.54 (m, 2H), 3.27−3.24 (m, 1H), 3.22 (t,
J = 4.0 Hz, 1H), 2.59−2.58 (m, 1H), 2.54 (dd, J = 4.0, 1.0 Hz, 1H),
2.37 (ddd, J = 16.0, 5.5, 4.0 Hz, 1H), 2.06 (dd, J = 16.0, 7.0 Hz, 1H),
3220
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The Journal of Organic Chemistry
Article
26.7 (t), 25.8 (t), 24.1 (t), 18.1 (q), 12.1 (d); MS (EI) m/z (rel %)
391 [M+] (25), 348 [M+ − C3H7] (85), 218 (30), 191 (100), 163
(10), 110 (10); HRMS (EI) calcd for C22H37NO3Si [M+] 391.2543,
found 391.2536.
(14) Lowering the amount of triflic anhydride and/or tetrabutyl-
phosphonium bromide and/or base, using other solvents or solvent
mixtures, and increasing the reaction time or temperature for either
the Vilsmeier−Haack or the Mannich cyclizations all resulted in lower
yields, often as the result of extensive decomposition of the iminium
intermediate obtained after the Vilsmeier−Haack cyclization.
(15) The estimated enantiomeric ratio of this compound is 96:4
based on the enantiomeric ratio of compound (+)-22 from which it is
derived.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies H and 13C NMR spectra for all new compounds and
copy of NOESY spectrum for compound 7. This material is
available free of charge via the Internet at http://pubs.acs.org.
(16) (a) Anderson, A. G.; Stang, P. J. Org. Synth. 1981, 60, 34−39.
(b) Anderson, A. G.; Stang, P. J. J. Org. Chem. 1976, 41, 3034−3036.
(17) Deng, B.-L.; Hartman, T. L.; Buckheit, R. W.; Pannecouque, C.;
De Clercq, E.; Fanwick, P. E.; Cushman, M. J. Med. Chem. 2005, 48,
6140−6155.
AUTHOR INFORMATION
Corresponding Author
*E-mail: Guillaume.Belanger@USherbrooke.ca.
■
(18) Leighton, J. L.; Jacobsen, E. N. J. Org. Chem. 1996, 61, 389−390.
(19) Hill, G. J.; Rossiter, B. E.; Sharpless, K. B. J. Org. Chem. 1983,
48, 3607−3608.
Notes
(20) Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899−2899.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This research was supported by the Natural Science and
Engineering Research Council (NSERC) of Canada, the
■
́
Canadian Fund for Innovation (CFI), and the Universite de
Sherbrooke. NSERC doctoral fellowship to R.L.-G. and
NSERC masters fellowship to M.D. are also gratefully
acknowledged.
REFERENCES
■
(1) Snieckus, V. iIn The Alkaloids; Academic Press: New York, 1973;
Vol. 14, pp 425−506.
(2) Beutler, J. A.; Karbon, E. W.; Brubaker, A. N.; Malik, R.; Curtis,
D. R.; Enna, S. J. Brain Res. 1985, 330, 135−140.
(3) Wang, G.-C.; Wang, Y.; Li, Q.; Liang, J.-P.; Zhang, X.-Q.; Yao, X.-
S.; Ye, W.-C. Helv. Chim. Acta 2008, 91, 1124−1128 . It should be
noted that the structure of securinol A drawn in this article is
erroneous: to be consistent with data and discussion in this article, the
A ring should be a piperidine, not a pyrrolidine.
(4) Arbain, D.; Birkbeck, A. A.; Byrne, L. T.; Sargent, M. V.; Skelton,
B. W.; White, A. H. J. Chem. Soc., Perkin Trans. 1 1991, 1863−1869.
(5) (a) Horii, Z.; Ikeda, M.; Tamura, Y.; Saito, S.; Kotera, K.;
Iwamoto, T. Chem. Pharm. Bull. 1965, 13, 1307−1311. (b) The same
initially proposed structures for securinol A and B by Horii (ref 5a)
were mistakenly used again by Raj in 2008 ( Raj, D.; Łuczkiewicz, M.
Fitoterapia 2008, 79, 419−427 ), even though the structure had
already been corrected by Arbain and Sargent in 1991 (ref 4).
(6) Horii, Z.; Yamauchi, M.; Ikeda, M.; Momose, T. Chem. Pharm.
Bull. 1970, 18, 2009−2012.
(7) For the development of the Vilsmeier−Haack cyclization, see:
(a) Bel
Barabe,
Gauthier, R.; Men
71, 704−712. For the development of one-pot Vilsmeier−Haack and
Mannich cyclizations, see: (c) Belanger, G.; O’Brien, G.; Larouche-
Gauthier, R. Org. Lett. 2011, 13, 4268−4271.
(8) Larouche-Gauthier, R.; Belanger, G. Org. Lett. 2008, 10, 4501−
4504.
(9) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66−
77.
́
anger, G.; Larouche-Gauthier, R.; Men
́
ard, F.; Nantel, M.;
anger, G.; Larouche-
́
F. J. Org. Chem. 2006,
́
F. Org. Lett. 2005, 7, 4431−4434. (b) Bel
́
́
ard, F.; Nantel, M.; Barabe,
́
́
(10) (a) Katritzky, A. R.; Chang, H.-X.; Yang, B. Synthesis 1995,
503−505. (b) Pasqua, A. E.; Matheson, M.; Sewell, A. L.; Marquez, R.
Org. Process Res. Dev. 2011, 15, 467−470.
(11) The enantiomeric ratio was determined by gas chromatography.
See Experimental Section.
(12) Wu, M. H.; Jacobsen, E. N. Tetrahedron Lett. 1997, 38, 1693−
1696.
(13) Other bases (KHMDS, DIPEA, NaH), additives (LiCl, 18-
crown-6 ether), solvents (MeCN, PhMe), and temperatures (−40, 0
°C) were screened without yield improvement.
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