First total synthesis of the pyrrolizidine alkaloid amphorogynine C through intramolecular azide-olefin cycloaddition

Article abstract of DOI:10.1002/ejoc.201200384

The first total synthesis of the natural alkaloid amphorogynine C is reported (2.9 % overall yield in 20 steps). The key steps include a Claisen-Johnson rearrangement and an intramolecular azide-olefin cycloaddition, followed by a reduction of the resulting imine. The construction of the pyrrolizidine skeleton was achieved by an alkoxide-mediatedlactone ring opening and subsequent cyclization of a conveniently functionalized bicyclic amine. Finally, the proposed structure of amphorogynine C was confirmed by single-crystal X-ray diffraction analysis. The first synthesis of the representative pyrrolizidine alkaloid amphorogynine C is described. The key step includes an intramolecular azide-olefin cycloaddition reaction. The proposed structure of the natural product was confirmed by single-crystal X-ray diffraction analysis. Copyright

Full text of DOI:10.1002/ejoc.201200384

Job/Unit: O20384
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Date: 27-06-12 09:54:17
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FULL PAPER
DOI: 10.1002/ejoc.201200384
First Total Synthesis of the Pyrrolizidine Alkaloid Amphorogynine C through
Intramolecular Azide–Olefin Cycloaddition
Irene de Miguel,[a] Marina Velado,[a] Bernardo Herradón,[a] and Enrique Mann*[a]
Keywords: Total synthesis / Alkaloids / Cycloaddition / Natural products / Azides
The first total synthesis of the natural alkaloid amphorogyn-
ine C is reported (2.9% overall yield in 20 steps). The key
steps include a Claisen–Johnson rearrangement and an in-
tramolecular azide–olefin cycloaddition, followed by a re-
izidine skeleton was achieved by an alkoxide-mediated
lactone ring opening and subsequent cyclization of a conve-
niently functionalized bicyclic amine. Finally, the proposed
structure of amphorogynine C was confirmed by single-crys-
duction of the resulting imine. The construction of the pyrrol- tal X-ray diffraction analysis.
Introduction
Results and Discussion
In connection with our ongoing interest in the applica-
tion of 1,3-dipolar azide–olefin cycloadditions to the syn-
theses of nitrogen-containing heterocycles and natural alk-
aloids,[5] we prepared azidoalkene 5. When this compound
was heated at 140 °C in toluene (sealed tube), the corre-
sponding imine 6 was formed, with total epimerization oc-
curring at the C-3a position [Scheme 1 (top)]. A close in-
spection of the structure of compound 6 revealed that two
of the stereogenic centers already present in this molecule,
C-3a and C-6, have the same configuration as C-1 and C-6
of amphorogynine C (Figure 1). In addition, imine 6 al-
ready contains all of the carbon and nitrogen atoms (with
the exception of the methoxy group of the carboxylate func-
tionality) present in the bicyclic core of 3. With these con-
siderations in mind, the preparation of amphorogynine C
was approached according to the retrosynthetic correlation
summarized in Scheme 1 (bottom). The preparation of the
1-azabicyclo[3.3.0]octane I could be achieved by opening
the lactone and subsequent cyclization of a conveniently
functionalized derivative of bicyclic amine II. Intermediate
II would result from a stereoselective reduction of the imine
group, which would allow for the construction of the third
stereogenic center present in amphorogynine C and subse-
quent oxidation of the anomeric position of III. This key
intermediate might be secured by an intramolecular 1,3-di-
polar azide–olefin cycloaddition of azidoalkene IV. This de-
rivative of 3,6-dihydro-2H-pyran should be obtainable from
allylic alcohol V by employing a Claisen–Johnson re-
arrangement as the key step.
Because of their diverse structures and biological activi-
ties, pyrrolizidine alkaloids have attracted considerable syn-
thetic interest during the previous decades.[1] In 1998, four
new pyrrolizidine alkaloids were isolated by Païs and co-
workers from the New Caledonian plant Amphorogynine
spicata.[2] This class of compounds, named amphorogyin-
ines A, B, C, and D (1–4, Figure 1) are characterized by a
double substitution pattern at the C-1 and C-6 positions
of the bicyclic pyrrolizidine core. Prior to this work, two
syntheses of amphorogynine A (1)[3,4a] and one total syn-
thesis of amphorogynine D (4)[4b] were described. Herein,
we report the first synthesis of amphorogynine C (3).
Figure 1. Chemical structures of amphorogynines A–D.
The synthesis of the key imine 6 is outlined in Scheme 2.
The requisite starting material, allylic alcohol 8 was pre-
pared on a multigram scale in five steps from commercially
available 3,4,6-tri-O-acetyl-d-glucal (7) according to a
method previously reported by our group.[6] The Claisen–
Johnson rearrangement was accomplished by heating to re-
[a] Instituto de Química Orgánica General, CSIC,
Juan de la Cierva 3, 28006 Madrid, Spain
E-mail: mann@iqog.csic.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200384.
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I. de Miguel, M. Velado, B. Herradón, E. Mann
FULL PAPER
Scheme 1. Key transformation of azide 5 into imine 6 (top), and
retrosynthesis of amphorogynine C (3) (bottom).
flux compound 8 in trimethyl orthoacetate in the presence
of propanoic acid. This gave the corresponding γ,δ-unsatu-
rated ester 9 as the only product in excellent yield (85%).
Furthermore, the reaction took place in a completely stereo-
selective way, as is expected for such suprafacial allylic
rearrangements. The reduction of 9 with lithium borohyd-
ride (LiBH4) furnished alcohol 10 (90% yield), and that,
in turn, was treated with methanesulfonyl chloride in the
presence of triethylamine to give methanesulfonate 11 in
quantitative yield (96%). Compound 11 was converted into
5 by treatment with sodium azide (95% yield). With azido-
alkene 5 in hand, we focused our attention on its conversion
to the key intermediate 6. Under thermal conditions, azides
react with olefins through a 1,3-dipolar cycloaddition to
form 1,2,3-Δ2-triazolines[7] that – unlike their aromatic ana-
logues (1,2,3-triazoles) – are generally not isolable and
evolve after nitrogen loss to the corresponding imines.[8] In
particular, the intramolecular azide–olefin cycloaddition re-
action (IAOC) has found broad application in the syntheses
of complex molecules.[8,9] Upon heating of azidoalkene 5 at
140 °C in toluene (sealed tube), a readily separable mixture
of imine 6 (68% yield) and aziridine 13 (16% yield) was
obtained. As anticipated, because of the configurationally
labile nature of the enaminic C-3a position of 6, a total
epimerization took place at this center (see below). On the
other hand, such an epimerization was not observed in azir-
idine 13, because equilibration was not possible in this case.
The use of other solvents such as DMF (N,N-dimethyl-
formamide) and methanol or the employment of microwave
heating resulted in lower yields and more complex mixtures
of products. Furthermore, all attempts to decrease the
amount of aziridine 13 by modifying the temperature and
reaction times were unsuccessful, leading to similar ratios
but lower yields.
Scheme 2. Synthesis of key imine 6.
tert-butyl dicarbonate afforded intermediate 14 as a single
diastereomer. As expected, the reduction of the imine func-
tionality proceeded from the less hindered convex face of
bicycle 6. The relative syn stereochemistry between 3a-H,
7a-H, and 4-H was established with the aid of NOE experi-
ments. These assignments were ultimately confirmed by the
conversion of imine 6 into compound 16 through deprotec-
tion with TBAF (tetra-n-butylammonium fluoride), re-
duction of the resulting imino alcohol 15 with NaBH4, and
a subsequent reaction with 3,5-dinitrobenzoyl chloride (3,5-
DNBC) in the presence of Et3N. The structure and relative
stereochemistry of amide 16 was determined by single-crys-
tal X-ray diffraction analysis (Figure 2).[10]
As shown in Scheme 3, the reduction of imine 6 with
sodium borohydride (NaBH4) in the presence of methanol
and the in situ protection of the generated amine with di- Scheme 3. Synthesis of Boc-protected amine 14 and amide 16.
2
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Total Synthesis of the Pyrrolizidine Alkaloid Amphorogynine C
mer with an overall yield of 50% (3 steps). Finally, the eli-
mination of the benzyl group by catalytic hydrogenation
(H2, Pd/C) cleanly afforded amphorogynine C (3) in 75%
yield. The physical and spectroscopic data (1H and 13C
NMR) obtained for the synthetic material are in agreement
with those previously reported in the literature.[2,15]
Finally, slow concentration of a methanol solution of 3
afforded crystals suitable for X-ray diffraction analysis (Fig-
ure 3).[10] Because the synthetic route from tri-O-acetyl-d-
glucal is unambiguous with total stereocontrol, it confirms
the structure of amphorogynine C proposed by Païs and co-
workers[2].
Figure 2. X-ray structure of amide 16.
With the three stereocenters required for the synthesis of
the amphorogynine C skeleton already installed, we turned
our attention to the formation of the pyrrolizidine core.
Treatment of compound 14 with palladium chloride[11] in a
mixture of THF/H2O (9:1) afforded lactol 17 in moderate
yield (Scheme 4). The oxidation of 17 to the corresponding
bicyclic lactone 18 proved to be one of the most problem-
atic steps in the synthesis. Although PCC (pyridinium chlo-
rochromate), Dess–Martin periodinane, MnO2, and TPAP
(tetra-n-propylammonium perruthenate) were unsuccessful
in promoting the oxidation,[12] resulting in the recovery of
unaltered starting material, exposing 17 to Jones reagent[13]
and subsequent treatment of the crude material with TBAF
(see Exp. Sect.) provided 18 in a 55% combined yield. The
treatment of the alcohol 18 with carbon tetrabromide in the
presence of triphenylphosphane delivered the correspond-
ing bromide 19 (70% yield). After some experimentation,
we found that exposing compound 19 to trifluoroacetic acid
and subsequent treatment with freshly prepared sodium
methoxide afforded hydroxypyrrolizidine 20, which was im-
mediately esterified with the O-benzylated derivative of the
hydroferulic acid 21[14] to afford 22 as single diastereoiso-
Figure 3. X-ray structure of amphorogynine C (3).
Conclusions
The first total synthesis of natural amphorogynine C was
achieved. The key steps include an intramolecular 1,3-di-
polar cycloaddition of an azide onto an alkene and subse-
quent reduction of the resulting imine to the corresponding
amine. Finally, the proposed structure of amphorogynine C
was confirmed by single-crystal X-ray diffraction analysis.
Experimental Section
General Methods: When it was appropriate, the reactions were car-
ried out under argon, by using dry solvents and anhydrous condi-
tions, unless it was stated otherwise. Stainless steel syringes or can-
nulae were used to transfer air- and moisture-sensitive liquids. Dry
dichloromethane (DCM), tetrahydrofuran (THF), DMF, toluene,
and diethyl ether were obtained by passing the previously degassed
solvents through activated alumina columns. The reagents pur-
chased were of the highest commercial quality and used without
further purification, unless otherwise stated. Flash column
chromatography was performed by using silica gel (60 Å pore size,
40–63 μm, Merck) or deactivated alumina (Brockmann I, Sigma-
Aldrich). The reactions were monitored by thin layer chromatog-
raphy (TLC) on silica gel-coated plates (Merck 60 F254). Detection
was performed by using UV light and by charring the plate at ca.
150 °C, after dipping it into an aqueous solution of potassium per-
manganate (KMnO4), an ethanolic solution of phosphomolybdic
acid (PMA), or an ethanolic solution of ninhydrin. The yields refer
to chromatographically and spectroscopically (1H NMR) homo-
geneous material, unless otherwise stated. The NMR spectroscopic
data were recorded with Varian Unity-500, Inova-400, Mercury-
400, and Inova-300 instruments and are calibrated by using the
residual undeuterated solvent as an internal reference. The abbrevi-
Scheme 4. Completion of total synthesis.
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I. de Miguel, M. Velado, B. Herradón, E. Mann
FULL PAPER
ations used to explain multiplicities are s = singlet, d = doublet, t
= triplet, q = quartet, m = multiplet, br. = broad. High-resolution
mass spectra (HRMS) were recorded with an Agilent 6520-Accu-
rate-Mass LC/MS Q-TOF mass spectrometer. IR experiments were
recorded with a Perkin–Elmer Spectrum One FTIR spectrometer.
Optical rotations were performed with a Perkin–Elmer 241 MC
polarimeter.
4.05 (ddd, J = 12.9, 6.3, 1.6 Hz, 1 H), 3.75 (m, 2 H), 2.97 (s, 3 H),
2.31 (m, 1 H), 1.96 (td, J = 13.9, 6.9 Hz, 1 H), 1.83 (td, J = 13.9,
6.3 Hz, 1 H), 1.07 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 135.7, 134.3, 133.6, 129.8, 127.8, 127.4, 125.6, 117.6, 98.6, 69.6,
68.5, 67.5, 66.2, 37.6, 35.7, 33.0, 27.0, 19.4 ppm. FTIR (neat): ν =
˜
3072, 3032, 2931, 2858, 1736, 1647, 1589, 1473, 1428, 1359, 1176,
1114, 1030, 958, 823, 796, 742, 704 cm–1. HRMS (ESI): calcd. for
C28H38NaO6SSi [M + Na]+ 553.2051; found 553.2046.
Ester 9: A mixture of alcohol 8 (5.0 g, 11.8 mmol) and trimethyl
orthoacetate (22.1 mL, 118 mmol) was heated to 100 °C, and then
propionic acid (0.09 mL, 1.18 mmol) was added. The mixture was
stirred at 140 °C for 72 h. (The MeOH formed during the reaction
was eliminated periodically with a rotary evaporator.) The solvent
was evaporated, and the residual product was purified by flash
chromatography (silica gel, gradient from hexanes to hexanes/
EtOAc, 9:1). Ester 9 (4.82 g, 85%) was obtained as a colorless vis-
cous oil. [α]2D5 = +29.5 (c = 1.10, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.68 (m, 4 H), 7.41 (m, 6 H), 5.93 (dddd, J = 17.2,
10.4, 6.2, 5.2 Hz, 1 H), 5.79 (m, 2 H), 5.29 (ddd, J = 17.2, 1.7,
Azide 5: Mesylate 11 (800 mg, 1.51 mmol) was dissolved in anhy-
drous N,N-dimethylformamide (10 mL). Sodium azide (980 mg,
15.1 mmol) was added, and the mixture was heated at 60 °C for
2 h. Then, the solvent was removed in vacuo. The residue was dis-
solved in water, and the resulting solution was extracted with
EtOAc (3ϫ40 mL). The combined organic phases were dried with
MgSO4, filtered, and concentrated in vacuo. The crude residue was
purified by column chromatography (silica gel, gradient from hex-
anes to hexanes/EtOAc, 85:15) to yield 5 (691 mg, 96%) as a color-
less oil. [α]2D5 = +67.2 (c = 1.00, CHCl3). 1H NMR (300 MHz,
1.6 Hz, 1 H), 5.18 (ddd, J = 10.4, 1.7, 1.3 Hz, 1 H), 4.80 (s, 1 H), CDCl3): δ = 7.68 (m, 4 H), 7.40 (m, 6 H), 5.92 (dddd, J = 17.2,
4.26–4.20 (m, 2 H), 4.06 (ddd, J = 13.0, 6.2, 1.3 Hz, 1 H), 3.73 (m, 10.2, 6.3, 5.2 Hz, 1 H), 5.79 (m, 2 H), 5.28 (ddd, J = 17.2, 1.7,
2 H), 3.67 (s, 3 H), 2.60 (m, 1 H), 2.48 (dd, J = 16.1, 8.1 Hz, 1 H), 1.6 Hz, 1 H), 5.19 (ddd, J = 10.3, 1.7, 1.3 Hz, 1 H), 4.75 (s, 1 H),
2.36 (dd, J = 16.1, 6.6 Hz, 1 H), 1.07 (s, 9 H) ppm. 13C NMR
4.22 (m, 2 H), 4.05 (ddd, J = 12.8, 6.3, 1.3 Hz, 1 H), 3.73 (m, 2
(100 MHz, CDCl3): δ = 172.5, 135.8, 134.4, 133.6, 129.8, 127.8, H), 3.32 (m, 2 H), 2.23 (m, 1 H),1.71 (m, 2 H), 1.07 (s, 9 H) ppm.
127.0, 126.0, 117.4, 98.2, 69.5, 68.6, 66.3, 51.8, 37.8, 35.8, 27.0,
19.4 ppm. FTIR (neat): ν = 3072, 3048, 2931, 2858, 1739, 1647,
13C NMR (75 MHz, CDCl3): δ = 135.8, 134.4, 133.7, 129.8, 127.8,
127.0, 125.9, 117.5, 98.8, 69.5, 68.5, 66.4, 49.0, 36.7, 32.6, 27.0,
˜
1590, 1473, 1428, 1391, 1361, 1267, 1113, 1027, 933, 823, 794, 740, 19.4 ppm. FTIR (neat): ν = 3072, 3048, 2931, 2859, 2096, 1473,
˜
702 cm–1. HRMS (ESI): calcd. for C28H40NO5Si [M + NH4]+
498.2670; found 498.2668.
1462, 1428, 1362, 1261, 1187, 1114, 1033, 823, 702 cm–1. HRMS
(ESI): calcd. for C27H35N3NaO3Si [M + Na]+ 500.2340; found
500.2316.
Alcohol 10: Lithium borohydride (272 mg, 12.5 mmol) was added
to a solution of compound 9 (2.0 g, 4.16 mmol) in anhydrous THF
(10 mL) at 0 °C. Then, MeOH (1 mL) was added dropwise. The
mixture was stirred at 0 °C for 30 min and then at room tempera-
ture for another 4 h. The mixture was cooled again to 0 °C and
the reaction quenched by the addition of H2O. The MeOH was
evaporated, and the residue was extracted with EtOAc (3ϫ60 mL).
The combined organic layers were dried with MgSO4, filtered, and
concentrated in vacuo. The crude residue was purified by
chromatography (silica gel, gradient from hexanes to hexanes/
EtOAc, 8:2) to provided compound 10 (1.69 g, 90%) as a colorless
oil. [α]2D5 = +51.0 (c = 1.00, CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 7.69 (m, 4 H), 7.40 (m, 6 H), 5.94 (dddd, J = 17.2, 10.4, 6.2,
5.2 Hz, 1 H), 5.85 (m, 1 H), 5.75 (m, 1 H), 5.28 (ddd, J = 17.2, 1.6,
Imine 6: In a sealed tube, a solution of compound 5 (300 mg,
0.63 mmol) in toluene (10 mL) was heated at 140 °C for 24 h. The
mixture was cooled to room temperature, and the solvent was evap-
orated under reduced pressure. The residue was purified by column
chromatography (silica gel, gradient from CH2Cl2 to CH2Cl2/
MeOH, 3%) to afford the desired imine 6 (192 mg, 68%) as a pale
yellow, viscous oil and aziridine 13 (45 mg, 16%) as a dark yellow
oil. Data for compound 6: [α]2D5 = +110.5 (c = 0.88, CHCl3). 1H
NMR (500 MHz, CDCl3): δ = 7.69 (m, 4 H), 7.39 (m, 6 H), 5.86
(dddd, J = 17.2, 10.7, 5.9, 4.9 Hz, 1 H), 5.23 (ddd, J = 17.2, 1.7,
1.6 Hz, 1 H), 5.14 (ddd, J = 10.7, 1.7, 1.3 Hz, 1 H), 5.09 (d, J =
4.7 Hz, 1 H), 4.16 (ddd, J = 13.3, 4.9, 1.6 Hz, 1 H), 3.94 (m, 3 H),
3.79 (dd, J = 10.7, 5.6 Hz, 1 H), 3.72 (m, 2 H), 2.93 (m, 1 H), 2.65
1.5 Hz, 1 H), 5.19 (ddd, J = 10.4, 1.6, 0.9 Hz, 1 H), 4.88 (s, 1 H), (dd, J = 14.0, 2.9 Hz, 1 H), 2.30 (m, 1 H), 1.90 (m, 2 H), 1.06 (s,
4.23 (m, 2 H), 4.05 (ddd, J = 12.9, 6.3, 1.1 Hz, 1 H), 3.80–3.59 (m, 9 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 172.8, 135.7, 134.1,
4 H), 2.33 (m, 1 H), 2.19 (br. s, 1 H), 1.73 (m, 2 H), 1.07 (s, 9 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 135.8, 134.4, 133.6, 129.8,
127.8, 126.7, 126.0, 117.5, 99.5, 69.3, 68.5, 66.3, 59.9, 36.9, 35.9,
133.5, 129.8, 127.8, 116.9, 98.5, 69.2, 67.7, 66.7, 60.2, 51.6, 34.4,
26.9, 22.8, 19.4 ppm. FTIR (neat): ν = 3071, 3049, 2956, 2930,
˜
2859, 1663, 1472, 1462, 1428, 1362, 1287, 1136, 1113, 1031, 823,
703 cm–1. HRMS (ESI): calcd. for C27H36NO3Si [M + H]+
450.2459; found 450.2474. Data for aziridine 13: [α]2D5 = +29.9 (c =
0.97, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.72 (m, 4 H),
7.40 (m, 6 H), 5.93 (dddd, J = 17.2, 10.3, 6.2, 5.2 Hz, 1 H), 5.29
(dd, J = 17.2, 1.6 Hz, 1 H), 5.20 (dd, J = 10.3, 1.6 Hz, 1 H), 4.60
(s, 1 H), 4.34 (td, J = 6.2, 2.3 Hz, 1 H), 4.15 (ddt, J = 12.9, 5.2,
1.5 Hz, 1 H), 4.01–3.87 (m, 3 H), 3.05 (m, 1 H), 2.81 (m, 2 H), 2.41
(m, 2 H), 2.16 (m, 1 H), 1.81 (m, 1 H), 1.08 (s, 9 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 135.8, 134.3, 133.5, 129.8, 127.8, 117.6, 98.0,
67.9 (2 C), 64.9, 49.0, 40.2, 38.4, 37.1, 36.6, 26.9, 19.3 ppm. FTIR
27.0, 19.4 ppm. FTIR (neat): ν = 3072, 3048, 2931, 2859, 1473,
˜
1428, 1187, 1113, 1031, 823, 740, 703 cm–1. HRMS (ESI): calcd.
for C27H36NaO4Si [M + Na]+ 475.2275; found 475.2262.
Mesylate 11: Et3N (0.74 mL, 5.30 mmol) was added to a solution
of alcohol 10 (1.0 g, 2.21 mmol) in CH2Cl2 (30 mL) at 0 °C, fol-
lowed by the dropwise addition of MsCl (0.22 mL, 2.88 mmol) dis-
solved in CH2Cl2 (5 mL). The mixture was stirred at 0 °C for
30 min and then at room temperature for 2 h. The solvent was re-
moved by rotary evaporation, and the residue was purified by col-
umn chromatography (silica gel, gradient from hexanes to hexanes/
EtOAc, 8:2) to afford compound 11 (1.124 g, 96%) as a colorless
oil. [α]2D5 = +47.4 (c = 1.00, CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 7.69 (m, 4 H), 7.41 (m, 6 H), 5.93 (dddd, J = 17.2, 10.3, 6.3,
(neat): ν = 3071, 3049, 2956, 2931, 2858, 1472, 1463, 1428, 1391,
˜
1362, 1190, 1113, 1089, 1029, 999, 823, 740, 703 cm–1. HRMS
(ESI): calcd. for C27H36NO3Si [M + H]+ 450.2459; found 450.2478.
5.2 Hz, 1 H), 5.82 (m, 2 H), 5.29 (ddd, J = 17.2, 1.7, 1.6 Hz, 1 H), Boc-Protected Amine 14: To a solution of 6 (500 mg, 1.11 mmol)
5.20 (ddd, J = 10.3, 1.7, 1.3 Hz, 1 H), 4.78 (s, 1 H), 4.26 (m, 4 H), in MeOH (25 mL) at 0 °C was added NaBH4 (84 mg, 2.22 mmol).
4
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Total Synthesis of the Pyrrolizidine Alkaloid Amphorogynine C
After 30 min, the mixture was warmed to room temperature and (400 MHz, CDCl3): δ = 9.25 (t, J = 2.1 Hz, 1 H), 9.19 (d, J =
stirred for an additional 1 h. Then, a saturated solution of NH4Cl
(10 mL) was added, and the MeOH was removed under reduced
pressure. The resulting residue was diluted with aqueous NaOH
(1 n solution, 10 mL), and the mixture was thoroughly extracted
with CH2Cl2 (3ϫ40 mL). The combined organic phases were dried
with MgSO4, filtered, and concentrated in vacuo. The crude amine
was dissolved in CH2Cl2 (25 mL), and the resulting solution was
cooled to 0 °C. Et3N (0.23 mL, 1.66 mmol) and (Boc)2O (291 mg,
1.33 mmol) dissolved in CH2Cl2 (3 mL) were sequentially added.
The mixture was left at 0 °C for 30 min and then at room tempera-
ture for 12 h. The solvent was removed under reduced pressure,
and the crude oil was purified by column chromatography (silica
gel, gradient from hexanes to hexanes/EtOAc, 9:1) to yield 14
(521 mg, 85%) as a colorless oil. [α]2D5 = –3.9 (c = 0.93, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 7.69 (m, 4 H), 7.38 (m, 6 H), 5.89
(dddd, J = 17.2, 10.5, 5.3, 4.9 Hz, 1 H), 5.25 (d, J = 17.2 Hz, 1 H),
5.14 (ddd, J = 10.5, 1.6, 1.4 Hz, 1 H), 4.95 (d, J = 4.9 Hz, 1 H),
4.27 (m, 1 H), 3.96 (m, 3 H), 3.66 (m, 2 H), 3.52 (m, 1 H), 3.42
(m, 1 H), 2.48 (m, 1 H), 2.30 (m, 1 H), 2.12 (m, 1 H), 1.95 (m, 1
H), 1.79 (m, 1 H), 1.46 (s, 9 H), 1.05 (s, 9 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 155.1, 135.8, 134.8, 133.7, 129.8, 127.8,
116.4, 97.0, 68.5, 67.6, 66.8, 53.4, 47.5, 41.0, 28.0 (2 C), 27.4, 27.1,
2.1 Hz, 2 H), 9.12 (t, J = 2.1 Hz, 1 H), 8.76 (d, J = 2.1 Hz, 2 H),
6.01 (dddd, J = 17.1, 10.6, 5.6, 4.9 Hz, 1 H), 5.36 (ddd, J = 17.1,
1.7, 1.6 Hz, 1 H), 5.32 (dd, J = 10.6, 1.5 Hz, 1 H), 5.04 (d, J =
5.4 Hz, 1 H), 4.50 (d, J = 5.6 Hz, 2 H), 4.38 (m, 3 H), 4.07 (m, 2
H), 3.32 (t, J = 9.0 Hz, 1 H), 2.73 (m, 2 H), 2.04 (m, 1 H), 1.96
(m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.9, 162.4,
148.8, 148.6, 140.3 (2 C), 133.7, 129.6, 128.1, 122.7, 120.4, 117.7,
97.4, 68.7, 68.6, 62.1, 54.8, 52.3, 39.3, 27.0, 26.5 ppm. FTIR (KBr):
ν = 3100, 2922, 1733, 1631, 1543, 1463, 1404, 1345, 1281, 1171,
˜
1079, 1024, 921, 730, 721 cm–1. HRMS (ESI): calcd. for
C25H24N5O13 [M + H]+ 602.1365; found 602.1365.
Lactol 17: Compound 14 (500 mg, 0.91 mmol) was dissolved in
THF/H2O (9:1, 30 mL) at room temperature. Then, PdCl2 (160 mg,
0.91 mmol) was added. After 8 h, additional catalyst (0.2 equiv.)
was added, and, after 24 h, more catalyst (0.2 equiv.) was added.
After 36 h, the reaction mixture was filtered through a plug of Ce-
lite. The filtrate was diluted with water, and the resulting mixture
was extracted with Et2O (3ϫ50 mL). The combined organic layers
were dried with MgSO4, filtered, and concentrated in vacuo. The
residue was purified by column chromatography (silica gel, gradient
from hexanes to hexanes/EtOAc, 3:7) to afford the lactol 17
(354 mg, 76%) as a mixture of diastereomers (85:15). Data for
major diastereomer: [α]2D5 = –2.1 (c = 0.62, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.67 (m, 4 H), 7.39 (m, 6 H), 4.94 (d, J =
5.0 Hz, 1 H), 4.22 (m, 1 H), 4.08 (d, J = 17.4 Hz, 1 H), 3.97 (m, 1
H), 3.91 (m, 1 H), 3.54 (m, 2 H), 2.51 (m, 1 H), 2.33 (m, 1 H), 2.09
(m, 1 H), 2.06 (m, 1 H), 1.84 (m, 1 H), 1.45 (s, 9 H), 1.05 (s, 9 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 155.1, 135.8, 133.7, 129.9,
127.9, 98.0, 72.7, 68.1, 53.2, 47.4, 40.9, 28.8, 27.1 (2 C), 26.6, 24.9,
24.5, 19.4 ppm. FTIR (neat): ν = 3072, 3050, 2931, 2859, 1811,
˜
1757, 1694, 1474, 1456, 1428, 1393, 1366, 1262, 1211, 1172, 1113,
1034, 824, 741, 703, 613 cm–1. HRMS (ESI): calcd. for
C32H45NNaO5Si [M + Na]+ 574.2959; found 574.2975.
Imino Alcohol 15: Tetrabutylammonium fluoride trihydrate
(320 mg, 1.02 mmol) was added to a solution of 6 (230 mg,
0.051 mmol) in THF (10 mL). The mixture was stirred at room
temperature for 2 h. The solvent was evaporated, and the residual
oil was purified by flash chromatography (silica gel, gradient from
DCM to DCM/MeOH, 4%) to afford compound 15 (87 mg, 81%)
as a yellow oil. [α]2D5 = +229.3 (c = 1.60, CH3Cl3). 1H NMR
(300 MHz, CDCl3): δ = 5.84 (dddd, J = 17.2, 10.6, 5.9, 5.1 Hz, 1
H), 5.22 (ddd, J = 17.2, 1.7, 1.6 Hz, 1 H), 5.13 (ddd, J = 10.4, 1.6,
19.4 ppm. FTIR (neat): ν = 3072, 3050, 1733, 1694, 1474, 1455,
˜
1428, 1393, 1366, 1334, 1254, 1172, 1148, 1113, 1064, 824, 741,
704 cm–1. HRMS (ESI): calcd. for C29H40NO5Si [M
–
H]–
510.2681; found 510.2669. Data for minor diastereomer: [α]2D5
=
–62.0 (c = 0.95, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.67
(m, 4 H), 7.39 (m, 6 H), 4.69 (br. s, 1 H), 4.06 (m, 1 H), 3.99 (m,
1.5 Hz, 1 H), 5.08 (d, J = 4.6 Hz, 1 H), 4.14 (ddt, J = 13.3, 5.1, 1 H), 3.72–3.61 (m, 3 H), 3.59 (m, 1 H), 3.33 (ddd, J = 10.6, 8.6,
1.5 Hz, 1 H), 3.97–3.84 (m, 3 H), 3.75–3.58 (m, 3 H), 2.91 (m, 1 8.4 Hz, 1 H), 2.17 (m, 1 H), 1.84 (m, 2 H), 1.75 (m, 2 H), 1.46 (s,
H), 2.38 (dd, J = 13.9, 3.1 Hz, 1 H), 1.88 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 172.9, 133.9, 117.1, 98.8, 69.1, 67.9, 65.1,
9 H), 1.06 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 155.3,
135.8, 133.5, 129.8, 127.8, 95.3, 71.2, 66.9, 54.5, 46.4, 43.9, 28.6,
60.1, 51.6, 33.5, 22.8 ppm. FTIR (neat): ν = 3233, 2914, 2871, 1664,
28.7, 27.0, 26.4 (2 C), 19.4 ppm. FTIR (neat): ν = 3072, 3050, 1733,
˜
˜
1461, 1424, 1370, 1344, 1314, 1288, 1132, 1032, 979, 955, 820,
731 cm–1. HRMS (ESI): calcd. for C11H18NO3 [M + H]+ 212.1281;
found 212.1291.
1694, 1474, 1455, 1428, 1393, 1366, 1334, 1254, 1172, 1148, 1113,
1064, 824, 741, 704 cm–1. HRMS (ESI): calcd. for C29H42NO5Si
[M + H]+ 512.2827; found 512.2858.
Amide 16: Sodium borohydride (31 mg, 0.81 mmol) was added to a
solution of compound 15 (86 mg, 0.41 mmol) in absolute methanol
(5 mL) at 0 °C. After 45 min, the reaction was quenched with a
saturated NH4Cl solution, and the resulting mixture was concen-
trated under reduced pressure. The residue was diluted with aque-
ous NaOH (1 n solution, 5 mL), and the resulting solution was
thoroughly extracted with CH2Cl2 (3ϫ30 mL). The combined or-
ganic phases were dried with MgSO4, filtered, and concentrated in
vacuo. The crude material was dissolved in CH2Cl2 (10 mL), and
the solution was cooled to 0 °C. Et3N (0.23 mL, 1.63 mmol) and
3,5-dinitrobenzoyl chloride (281 mg, 1.22 mmol) were sequentially
added. After stirring at room temperature for 8 h, the reaction mix-
ture was quenched with a saturated NH4Cl solution, and the aque-
ous layer was extracted with CH2Cl2 (3ϫ10 mL). The combined
organic layers were washed with brine (10 mL), dried with MgSO4,
filtered, and concentrated in vacuo. The crude solid was purified
by chromatography (silica gel, gradient from hexanes to hexanes/
EtOAc, 6:4) to afford compound 16 (48 mg, 19%) as a yellow solid;
m.p. 193–195 °C. [α]2D5 = +0.09 (c = 1.40, CHCl3). 1H NMR
Lactone 18: Lactol 17 (180 mg, 0.35 mmol) was dissolved in acet-
one (10 mL), and some anhydrous magnesium sulfate was added.
Then, the solution was cooled to 0 °C, and freshly prepared Jones
reagent (2 mL) was added dropwise. After 30 min, the mixture was
warmed to room temperature over 1 h. Isopropyl alcohol (5 mL)
was then added to destroy the excess Jones reagent, and the mixture
was filtered through a small pad of Celite. The solvent was removed
in vacuo, and the crude residue was dissolved in a solution of
NaHCO3, and the resulting mixture was extracted with EtOAc
(3ϫ40 mL). The combined organic layers were dried with MgSO4,
filtered, and concentrated in vacuo. The crude oil was used in the
next step without further purification. Tetrabutylammonium fluo-
ride trihydrate (110 mg, 0.35 mmol) was added to a solution of the
crude lactone in THF (15 mL). The mixture was stirred at room
temperature for 2 h. The solvent was evaporated, and the residual
product was purified by flash chromatography (silica gel, gradient
from hexanes to hexanes/EtOAc, 2:8) to afford 18 (52 mg, 55%, 2
1
steps) as a colorless oil. [α]2D5 = –89.3 (c = 2.50, CHCl3). H NMR
(500 MHz, CDCl3): δ = 4.47 (m, 1 H), 4.21 (br. s, 1 H), 3.82 (d, J
Eur. J. Org. Chem. 0000, 0–0
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Pages: 8
I. de Miguel, M. Velado, B. Herradón, E. Mann
(3 mL). The mixture was stirred under H2 for 2 h. Upon comple-
FULL PAPER
= 11.3 Hz, 1 H), 3.68 (dd, J = 11.3, 4.9 Hz, 1 H), 3.52 (br. s, 1 H),
3.37 (dt, J = 11.1, 7.1 Hz, 1 H), 3.21 (m, 1 H), 2.33 (m, 1 H), 2.27 tion, the mixture was filtered through Celite by using several
(m, 1 H), 2.19 (m, 1 H), 1.97 (ddd, J = 14.7, 10.5, 4.2 Hz, 1 H), washes of EtOAc to ensure quantitative transfer. The solvent was
1.45 (s, 9 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 172.5, 154.5, removed under reduced pressure, and the crude residue was puri-
77.0, 64.7, 53.6, 46.4, 43.2, 29.6, 28.6 (2 C), 28.1 ppm. FTIR (neat):
ν = 3444, 2976, 2935, 2880, 1732, 1694, 1399, 1367, 1260, 1167,
fied by column chromatography (silica gel, gradient from CH2Cl2
to CH2Cl2/MeOH, 3%) to obtain amphorogynine C (3, 21 mg,
˜
1096, 1049, 856, 773 cm–1. HRMS (ESI): calcd. for C13H22NO5 [M 75%) as a white solid; m.p. 120 °C. [α]2D5 = –1.7 (c = 1.30, CHCl3).
+ H]+ 272.1492; found 272.1495.
1H NMR (400 MHz, CDCl3): δ = 6.80 (d, J = 8.0 Hz, 1 H), 6.68
(d, J = 1.9 Hz, 1 H) 6.65 (dd, J = 8.0, 1.9 Hz, 1 H), 5.34 (t, J =
4.6 Hz, 1 H), 4.03 (m, 1 H), 3.85 (s, 3 H), 3.69 (s, 3 H), 3.28 (d, J
= 11.8 Hz, 1 H), 3.19 (ddd, J = 8.2, 8.2, 8.2 Hz, 1 H), 3.13 (m, 1
H), 2.87 (m, 1 H), 2.85 (m, 2 H), 2.80 (m, 1 H), 2.58 (t, J = 8.5 Hz,
2 H), 2.12 (m, 1 H), 1.99 (m, 1 H), 1.90 (dd, J = 14.1, 6.9 Hz, 1
H), 1.68 (ddd, J = 14.1, 9.7, 5.1 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 173.5, 172.8, 146.7, 144.3, 132.3, 120.9,
114.6, 111.1, 76.3, 64.6, 60.4, 56.0, 53.8, 52.0, 46.7, 36.4, 34.4, 30.7,
Bromide 19: Lactone 18 (100 mg, 0.37 mmol) was dissolved in
CH2Cl2 (10 mL), and the solution was cooled to 0 °C. Carbon tet-
rabromide (184 mg, 0.56 mmol) and triphenylphosphane (147 mg,
0.56 mmol) were added, and the mixture was stirred at 0 °C for 1 h
and then at room temperature for 2 h. Upon completion, the sol-
vent was removed in vacuo, and the crude residue was purified
by column chromatography (silica gel, gradient from hexanes to
hexanes/EtOAc, 7:3) to obtain 19 (90 mg, 70%) as a white solid;
m.p. 90–92 °C. [α]2D5 = –96.1 (c = 0.71, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 4.55 (m, 1 H), 4.19 (br. s, 1 H), 3.52 (m, 3
H), 3.36 (dt, J = 11.2, 7.3 Hz, 1 H), 3.23 (m, 1 H), 2.59 (m, 1 H),
2.24 (m, 2 H), 1.93 (ddd, J = 14.7, 10.6, 4.0 Hz, 1 H), 1.47 (s, 9 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 171.5, 154.4, 74.8, 53.5,
27.3 ppm. FTIR (KBr): ν = 2952, 1732, 1597, 1516, 1452, 1436,
˜
1377, 1275, 1236, 1202, 1156, 1125, 1035, 754 cm–1. HRMS (ESI):
calcd. for C19H26NO6 [M + H]+ 364.1755; found 364.1765.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of all H and 13C NMR spectra.
46.4, 43.1, 33.4, 29.5, 28.6 (2 C), 28.0 ppm. FTIR (KBr): ν = 3449,
˜
2960, 2926, 2854, 2097, 1739, 1694, 1394, 1367, 1260, 1168, 1115,
1042 cm–1. HRMS (ESI): calcd. for C13H24N2O4Br [M + NH4]+
351.0903; found 351.0927.
Acknowledgments
We thank the Spanish Ministry of Economy and Competitivity
(Project CTQ2010-19295) for its financial support as well as for the
purchase of a QToF-HRMS instrument (Project CTQ2007-28978-
E). I. M. (JAE predoc fellowship) and E. M. (I3P contract) thank
the Spanish National Research Council (CSIC). We also thank
Jose Antonio Romero of Universidad Autónoma of Madrid for as-
sistance with the optical rotation measurements of amphorogyn-
ine C.
Compound 22: Bromide 19 (50 mg, 0.15 mmol) was dissolved in
CH2Cl2 (5 mL), and TFA (trifluoroacetic acid, 0.5 mL) was added
dropwise. The reaction mixture was stirred for 90 min, and then
the solvent was removed in vacuo. The crude amine was then dis-
solved in MeOH (5 mL), and freshly prepared NaOMe (solution
in methanol, 1 mL) was added. The reaction was stirred at room
temperature for 1 h, and the methanol was eliminated under re-
duced pressure. The crude residue was dissolved in HCl (5% solu-
tion), and the resulting mixture was extracted with diethyl ether
(1ϫ10 mL). The aqueous layer was basified with NaOH (1 n solu-
tion), and the resulting solution was extracted with CH2Cl2
(3ϫ30 mL). The combined organic layers were dried with MgSO4,
filtered, and concentrated in vacuo to obtain hydroxy ester 20 that
was used without further purification. To a solution of the crude
hydroxy ester in CH2Cl2 (4 mL), O-benzyl-protected hydroferulic
acid 21 (43 mg, 0.15 mmol), DMAP [4-(dimethylamino)pyridine,
0.24 mg, 0.002 mmol], and 1-ethyl-3-[3-(dimethylamino)propyl]-
carbodiimide (40 mg, 0.21 mmol) were sequentially added. The re-
action mixture was stirred at room temperature for 3 h and then
filtered through Celite. The filtrate was concentrated under reduced
pressure, and the residue was purified by column chromatography
(silica gel, gradient from CH2Cl2 to CH2Cl2/MeOH, 2%) to afford
22 (34 mg, 50%) as a white solid; m.p. 101–103 °C. [α]2D5 = –3.8 (c
[1] For reviews on the pyrrolizidine alkaloids, see: a) M. Dreger,
M. Stanislawska, A. Krajewska-Patan, S. Mielcarek, P. L. Mi-
kolajczak, W. Buchwald, Herba Pol. 2009, 55, 127–146; b) W.-
M. Dai, Y. Nagao, Heterocycles 1990, 30, 1231–1261; c) D. J.
Robins, Nat. Prod. Rep. 1989, 6, 221–230.
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Païs, J. Nat. Prod. 1998, 61, 1444–1446.
[3] H. Yoda, T. Egawa, K. Takabe, Tetrahedron Lett. 2003, 44,
1643–1646.
[4] a) C. Roche, P. Delair, A. E. Greene, Org. Lett. 2003, 5, 1741–
1744; b) C. Roche, K. Kadlecíková, A. Veyron, P. Delair, C.
Philouze, A. E. Greene, J. Org. Chem. 2005, 70, 8352–8363.
[5] I. de Miguel, B. Herradón, E. Mann, Adv. Synth. Catal. 2012,
354, 1731–1736.
[6] A. Montero, E. Mann, B. Herradón, Eur. J. Org. Chem. 2004,
1
3063–3073.
= 1.75, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.41 (m, 2 H),
[7] a) L. Wolff, Justus Liebigs Ann. Chem. 1912, 394, 23–59; b) R.
Huisgen, Angew. Chem. 1963, 75, 604–637; Angew. Chem. Int.
Ed. Engl. 1963, 2, 565–632.
7.33 (m, 2 H), 7.27 (m, 1 H), 6.77 (d, J = 8.0 Hz, 1 H), 6.73 (d, J
= 2.0 Hz, 1 H), 6.64 (m, 1 H), 5.33 (t, J = 5.0 Hz, 1 H), 5.10 (s, 2
H), 4.14 (m, 1 H), 3.84 (s, 3 H), 3.68 (s, 3 H), 3.36 (d, J = 12.1 Hz,
1 H), 3.26–3.17 (m, 2 H), 2.88–2.78 (m, 4 H), 2.60 (td, J = 8.0,
2.7 Hz, 2 H), 2.14 (m, 1 H), 2.05 (m, 1 H), 1.95 (dd, J = 14.2,
7.0 Hz, 1 H), 1.72 (ddd, J = 14.2, 10.0, 5.0 Hz, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 173.0, 172.6, 149.7, 146.6, 137.4,
133.7, 128.6, 127.8, 127.3, 120.1, 114.2, 112.3, 75.8, 71.2, 64.3, 59.9,
[8] a) S. Bräse, A. Friedrich, M. Gartner, T. Schröder, Top. Hetero-
cycl. Chem. 2008, 12, 45–115; b) V. Nair, T. D. Suja, Tetrahe-
dron 2007, 63, 12247–12275; c) C. K. Sha, A. K. Mohanakrish-
nan in Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products (Eds.: A.
Padwa, W. H. Pearson), Wiley, New York, 2002, pp. 623–629.
[9] For representative examples, see: a) B. W. Q. Hui, S. Chiba,
Org. Lett. 2009, 11, 729–732; b) Y. Zhou, P. V. Murphy, Org.
Lett. 2008, 10, 3777–3780; c) S. Kim, Y. M. Lee, J. Lee, T. Lee,
Y. Fu, Y. Song, J. Cho, D. Kim, J. Org. Chem. 2007, 72, 4886–
4891; d) Y. Konda-Yamada, K. Asano, T. Satou, S. Monma,
M. Sakayanagi, N. Satou, K. Takeda, Y. Harigaya, Chem.
Pharm. Bull. 2005, 53, 529–536; e) V. Santagada, E. Perissutti,
56.0, 53.4, 52.0, 46.4, 36.1, 34.2, 30.5, 27.3 ppm. FTIR (KBr): ν =
˜
3062, 3033, 2951, 2871, 1732, 1606, 1591, 1463, 1455, 1419, 1378,
1262, 1231, 1158, 1139, 1034, 853, 807, 736, 698 cm–1. HRMS
(ESI): calcd. for C26H32NO6 [M + H]+ 454.2224; found 454.2240.
Amphorogynine C (3): Activated Pd/C (10%, 4 mg) was added in a
single portion to a solution of 22 (35 mg, 0.077 mmol) in EtOAc
6
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Job/Unit: O20384
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Pages: 8
Total Synthesis of the Pyrrolizidine Alkaloid Amphorogynine C
F. Fiorino, B. Vivenzio, G. Caliendo, Tetrahedron Lett. 2001,
42, 2397–2400; f) W. H. Pearson, H. Suga, J. Org. Chem. 1998,
63, 9910–9918; g) J. M. Schkeryantz, W. H. Pearson, Tetrahe-
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Montgomery, J. K. Cha, J. Am. Chem. Soc. 1989, 111, 2580–
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[13] S. Valverde, B. Herradon, R. M. Rabanal, M. Martín-Lomas,
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LaVoie, Bioorg. Med. Chem. 2003, 11, 3795–3805.
[15] Because of the low absolute value of the optical rotation de-
scribed for amphorogynine C, we measured it at different wave-
lengths: [α]D = –1.7 (c = 1.3, CHCl3), [α]578 = –1.9 (c = 1.3,
CHCl3), [α]546 = –2.3 (c = 1.3, CHCl3), [α]465 = –1.8 (c = 1.3,
CHCl3), [α]365 = –27.1 (c = 1.3, CHCl3). These values are in
agreement with the negative sign for the optical rotation re-
ported for the natural compound.[2]
[10] CCDC-872920 (for 16) and -872921 (for 3) contain the supple-
mentary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[11] L. Ban, M. Mrksich, Angew. Chem. 2008, 120, 3444; Angew.
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[12] J.-E. Bäckvall (Ed.), Modern Oxidation Methods, Wiley-VCH,
Weinheim, 2004.
Received: March 27, 2012
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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I. de Miguel, M. Velado, B. Herradón, E. Mann
FULL PAPER
Pyrrolizidine Alkaloids
I. de Miguel, M. Velado, B. Herradón,
E. Mann* .......................................... 1–8
First Total Synthesis of the Pyrrolizidine
Alkaloid Amphorogynine C through Intra-
molecular Azide–Olefin Cycloaddition
The first synthesis of the representative
pyrrolizidine alkaloid amphorogynine C is
described. The key step includes an intra-
molecular azide–olefin cycloaddition reac-
tion. The proposed structure of the natural
product was confirmed by single-crystal X-
ray diffraction analysis.
Keywords: Total synthesis / Alkaloids /
Cycloaddition / Natural products / Azides
8
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