Total synthesis of unsaturated imine venom alkaloids of Costa Rican ant by way of Schmidt reaction via allyl/pentadienyl cations

Article abstract of DOI:10.1016/j.tet.2014.09.058

Total synthesis of α,β-, and α,β,γ,δ-unsaturated imine ant venom alkaloids is described. The labile two conjugated imine alkaloids were synthesized by late stage intramolecular Schmidt reaction via allyl and pentadienyl cation intermediates.

Full text of DOI:10.1016/j.tet.2014.09.058

Tetrahedron 70 (2014) 8600e8605
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Total synthesis of unsaturated imine venom alkaloids of Costa Rican
ant by way of Schmidt reaction via allyl/pentadienyl cations
*
Huan Zhang, Kyohei Hayashi, Hiroki Tanimoto , Tsumoru Morimoto,
Yasuhiro Nishiyama, Kiyomi Kakiuchi
Graduate Schlool of Materials Science, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama-cho, Ikoma, Nara 6300192, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 August 2014
Received in revised form 18 September 2014
Accepted 18 September 2014
Available online 28 September 2014
Total synthesis of a,b-, and a,b,g,d-unsaturated imine ant venom alkaloids is described. The labile two
conjugated imine alkaloids were synthesized by late stage intramolecular Schmidt reaction via allyl and
pentadienyl cation intermediates.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Total synthesis
Alkaloid
Organic azides
Unsaturated imines
Schmidt reaction
1. Introduction
a,b-Unsaturated imines (1-aza-1,3-butadienes, enimines) and
related compounds provide more useful synthetic efficiency than
general imines. For example, these compounds can work as Michael
acceptors, hetero-DielseAlder diene units, and dienophiles.1 Not
only for their usefulness in organic synthesis, had nature produced
bioactive molecules possessing
like chartellines, human -opioid receptor-affinitive grandisines,
and ant venoms (Fig. 1).2e4
Among natural products of
a,b-unsaturated imine structures
d
a,b-unsaturated imines, cyclic im-
ines 1 and 2 were isolated from venom of Costa Rican ant Mega-
lomyrmex foreli (Myrmicinae) along with other two saturated
compounds by Jones et al.4 The toxicity of
a
,
b
-unsaturated imine 1
against termites was reported to be stronger than -un-
saturated imine 2 and knock-down effect was not observed.
Despite the usefulness, interesting bioactivity and their simple
structures of -unsaturated imines, the preparation, especially
Fig. 1. Alkaloids containing a,b-unsaturated imine structures.
a,b,g,d
On the other hand, organic azides are important chemical sub-
stances possessing nucleophilic amido position and diazonium site
of strong leaving group. By using their intrinsic property, the
Schmidt reaction and [3þ2] cycloaddition to afford imines, have
been utilized in natural product synthesis.5e8 However, Schmidt
reaction with alcohols or olefins and azides gives corresponding
imines via aminodiazonium intermediates, and this requires strong
acids and the substrates are limited to benzyl alcohols and styrenes
to generate carbocations. Although simple olefins can also produce
imines with azide by way of [3þ2] cyclization, high temperatures
(>100 ꢀC) and long reaction times (from several hours to days) are
a,b
alkyl and cyclic enimines, is problematic due to the tendency to-
ward polymerizations and hydrolysis by strong reactivity. Simple
condensation of unsaturated carbonyls and amines, and some
elimination strategies have been developed, but their heating
conditions should be avoided for the reactivity of products.
* Corresponding author. Tel.: þ81 743 72 6085; fax: þ81 743 72 6089; e-mail
address: tanimoto@ms.naist.jp (H. Tanimoto).
http://dx.doi.org/10.1016/j.tet.2014.09.058
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

H. Zhang et al. / Tetrahedron 70 (2014) 8600e8605
8601
required. Moreover, direct transformation to ‘unsaturated’ imines
through these procedures is quite limited. For these reasons a more
efficient method is required.
and 2 could be synthesized through common strategy. Thus, both
pipeline rings of unsaturated cyclic imine moieties of 1 and 2 could
be constructed from azido compounds 3 and 4 by allyl/pentadienyl
cation-mediated Schmidt reactions we developed. Although it is
challenging that our key step to the unsaturated imine was set at
the last stage of synthesis, the demonstrated mild reaction condi-
tions (0 ꢀC in 10 min) would be expected to achieve the total syn-
thesis. To the best of our knowledge, no example of Schmidt
reaction with pentadienol compounds has been appeared. The cy-
clization precursors 3 and 4 were planned to be prepared from
Previously, we reported novel Schmidt-type reaction of allyl
alcohols and azides to produce cyclic unsaturated imines.9 Our
method can afford labile a,b-unsaturated imines under mild con-
ditions (0 ꢀCert) in a short period (mostly in 10 min) (Scheme 1,
Eq. 1).10 To demonstrate further efficiency of our method, we
envisioned that pentadienyl alcohols could lead desired
a,b,g,d-unsaturated cyclic imines via pentadienyl cations, which
seem to be lesser stable than the case of azido allyl alcohols (Eq. 2).
Herein, we describe the full detail of total synthesis of Costa Rican
common intermediate 5 by chain-elongation through Hor-
nereWadswortheEmmons reactions. Aldehyde 5 was thought to
synthesize by alkylation of commercially available valeraldehyde 6.
ant venom alkaloids of
a,b-unsaturated imine 1, and more unstable
a
,b
,g,
d-unsaturated imine 2 by way of allyl/pentadienyl cation-
Our synthetic route to ant venom alkaloid of a,b-unsaturated
mediated Schmidt reactions.
imine 1 was summarized in Scheme 3. First, allylation of valer-
aldehyde 6 followed by silylation of hydroxy group afforded 7,
which was subjected to hydroboration-oxidation to give primary
alcohol 8. Unexpectedly, oxidation of 8 with SO3$pyridine complex
did not proceed (Scheme 4). Dess-Martin oxidation gave desired
product 9, but the yield was slightly irreproducible. We finally
found that oxidation with trifluoroacetic anhydride (TFAA) could
produce aldehyde 9 in good yield with reproducibility.
HornereWadswortheEmmons reaction of obtained aldehyde 9
with phosphonate 10 gave enone 11 in good yield. Luche reduction
successfully afforded allyl alcohols as a diastereomeric mixture.11
Because the stereochemistry at allylic position would be
diminished at the stage of cyclizations, we did not separate the
diastereomers. The allylic hydroxy group of product was masked
with methoxymethyl group (MOM) followed by desilylation with
TBAF under heating conditions afforded secondary alcohol 12.
Mitsunobu azidation of 12 with diphenylphosphoryl azide suc-
cessfully generated key intermediate 13 for a,b-unsaturated imine
synthesis.12 Since we have confirmed that protected hydroxy
groups can be also applicable to the cyclization reactions,9 the
MOM-masked precursor 13 was treated with trimethylsilyl tri-
fluoromethanesulfonate (TMSOTf) in dichloromethane, and the
desired reaction mediated by allyl cation 14 was successfully
proceeded to afford ant venom of
a,b-unsaturated imine 1. The
Scheme 1. Intramolecular azide-allyl cation cyclization to produce
imines, and approach to a,b,g,d-unsaturated imines.
a,b-unsaturated
obtained -unsaturated imine 1 was slightly unstable against
a,b
silica gel purifications, the isolation yield was moderate. Alumina
column chromatography or silica gel with triethylamine-
containing elution was not effective for purification of 1.
Although optical rotation values of 1 or 2 were not mentioned in
the report, other spectroscopic characterization data of synthetic 1
were in accord with published values.4
2. Results and discussion
Retrosynthetic analyses of Costa Rican ant venoms are shown in
Scheme 2. We envisioned that two unsaturated imine alkaloids 1
We next turned our attention to the total synthesis of
a,b,g,d-unsaturated imine alkaloid 2 though pentadienyl cations
(Scheme 5). Starting from common compound alcohol 8, oxidation
with TFAA and DMSO followed by HornereWadswortheEmmons
reaction gave (E)-unsaturated ester 15 in good yield. Ester 15 was
reduced to alcohol, which easily formed dimeric ether under pu-
rification. Resulting alcohol was subjected to TFAA oxidation
without purification to afford aldehyde 16. Oxidation with man-
ganese dioxide was quite sluggish even in the presence of excess
oxidant. The crude 16 and phosphonate 17 was successfully coupled
to afford dienyl ketone 18 in 66% for three steps. The 1,2-reduction
of unstable 18 followed by MOM protection and desilylation gave
secondary alcohol 19 in 79% yield for three steps. Surprisingly,
although compounds 12 and 19 were quite similar, Mitsunobu
azidation of 19 under the same condition in Scheme 3 did not afford
desired azide 20, and the starting material was recovered. After
investigation of reaction conditions, benzene as a solvent could
afford 20 in 63% yield. In final step, the cyclization precursor 20 was
treated with TMSOTf in dichloromethane at 0 ꢀC. Pleasingly, the
reaction was successfully completed in 10 min to afford our desired
Scheme 2. Retrosynthesis of ant venom alkaloids.
compound, a,b,g,d-unsaturated imine alkaloid 2 via pentadienyl

8602
H. Zhang et al. / Tetrahedron 70 (2014) 8600e8605
Scheme 3. Synthesis of Costa Rican ant venom of a,b-unsaturated imine.
research of treatment, extraction, and purification methods, ant
venom 2 was successfully purified to afford 2 in 51% yield by ex-
traction with ether and silica gel purification with chloroform/ether
elution. The spectroscopic data for both synthetic and natural 2
were in good agreement with published values.
Scheme 4. Modification of oxidation conditions.
3. Conclusion
We accomplished total synthesis of labile Costa Rican ant venom
cation intermediate 21. The product was obtained in lower yield
with triflate equivalents TfOH (32%), and Tf2NH (37%). Catalytic
scandium triflate could not consume the starting material, and the
2 was yielded in 20% along with 30% of 20. Although our desired
alkaloid was successfully synthesized, 2 was less stable than
alkaloids possessing a,b-, and a,b,g,d-unsaturated imine structures.
The allyl/pentadienyl cation-mediated Schmidt reactions de-
veloped by our group were set as key reactions at the last stage of
syntheses. Our reactions successfully afforded unstable
a,b- and
a,b,g,d-unsaturated imine alkaloids. Our method could be applica-
a
,
b
-unsaturated imine 1, and was easily decomposed by alumina
ble to complex natural products containing conjugated imine
structures.
purification, heat, and concentrated conditions. After careful
Scheme 5. Synthesis of Costa Rican ant venom of a,b,g,d-unsaturated imine.

H. Zhang et al. / Tetrahedron 70 (2014) 8600e8605
8603
4. Experimental section
4.1. General
ether, and washed with water and brine. Then the collected organic
layer was dried over magnesium sulfate followed by concentration
in vacuo and silica gel column chromatography (ethyl acetate/
hexane¼1/200 to 1/100) to afford ethyl ester 15 (483.3 mg, 86%) as
a colorless oil.: Rf value 0.54 (ethyl acetate/hexane¼1/10); IR (NaCl,
1H and 13C NMR were recorded on a JEOL JNM-ECP500 spec-
trometer (500 MHz for 1H NMR, 125 MHz for 13C NMR). Chemical
neat) nmax 2956, 2931, 2858, 1724, 1655, 1256, 835, 774 cm-1 1H
;
shifts are reported as
solvent peak (CDCl3,
tetramethylsilane (
0 for 1H NMR). Abbreviations are following: s
d
values in ppm and calibrated by residual
NMR (500 MHz, CDCl3)
d
6.98 (dt, 1H, J¼15.5, 7.0 Hz), 5.81 (dt, 1H,
d
7.26 for 1H NMR, 77.00 for 13C NMR) or
d
J¼15.5, 2.0 Hz), 4.18 (q, 2H, J¼7.5 Hz), 3.67 (tt, 1H, J¼5.5, 5.5 Hz),
2.23 (m, 2H), 1.57 (m, 2H), 1.44 (m, 2H), 1.30e1.22 (m, 7H),
0.92e0.86 (m, 12H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (125 MHz,
d
(singlet), d (doublet), t (triplet), q (quartet), br (broad peak), m
(complex multiplet). Inflared spectra were measured on a JASCO FT/
IR-4200 spectrometer. Mass spectra were recorded on a double-
focusing mass spectrometer JEOL JMS-700 MStaion [EI (70 eV), CI,
FAB and ESI]. Flush column chromatography was performed by
MERCK Silica gel 60. The progress of reactions was monitored by
silica gel thin layer chromatography plates (MERCK TLC Silicagel 60
F254). Phosphomolybdic acid ethanol solution, ninhydrin-acetic
acid butanol solution and anisaldehyde-acetic acid-sulfuric acid
ethanol solution were used as TLC stain. All reagents were pur-
chased from SigmaeAldrich, Wako pure chemical industries, Ltd,
TCI (Tokyo Chemical Industry, Co. Ltd), Kanto Chemical Co. Inc., and
Nakalai Tesque. Used Dehydrated solventsdtetrahydrofuran,
dichloromethane and toluenedwere purchased from Kanto
Chemical, Wako pure chemical industries, Ltd, and Nakalai Tesque.
For the analytical data not described here, see previous report.9
CDCl3) d 166.7,149.5,121.1, 71.5, 60.1, 36.7, 35.1, 28.0, 27.4, 25.9, 22.8,
18.1, 14.3, 14.1, ꢁ4.4, ꢁ4.5; HRMS (ESI) calcd for C18H36O3SiNa
[MþNa]þ 351.2331, found 351.2332.
4.4. (E)-6-(tert-Butyldimethylsilyl)oxydec-2-enal (16)
To a stirred solution of ester 15 (1.68 g, 5.11 mmol) in toluene
(51 mL) was added diisobutylaluminum hydride (10.3 mL, 1.0 M in
toluene, 10.22 mmol) dropwise under nitrogen atmosphere at 0 ꢀC.
After 30 min, the reaction was quenched with ammonium chloride.
The mixture was diluted with ethyl acetate, and was washed with
water and brine. Then the collected organic layer was dried over
magnesium sulfate followed by concentration in vacuo to afford
crude allyl alcohol (1.35 g) as a colorless oil. The crude product was
used to the next step without further purification due to di-
merization under silica gel purification.
4.2. 4-((tert-Butyldimethylsilyl)oxy)octan-1-ol (8)
To a stirred solution of crude allyl alcohol (1.35 g) and dime-
thylsulfoxide (1.34 mL, 18.89 mmol) in THF (47 mL) was added
trifluoroacetic anhydride (0.985 mL, 7.08 mmol) under nitrogen
atmosphere at 0 ꢀC. After 30 min, triethylamine was added at the
same temperature. After 30 min, the reaction was quenched with
ammonium chloride. The mixture was diluted with ether, and was
washed with water and brine. Then the collected organic layer was
dried over magnesium sulfate followed by concentration in vacuo
to afford crude aldehyde 16 (1.5 g) as colorless oil. Then the crude
product was used to the next step without further purification.
When purified with column chromatography (ethyl acetate/
hexane¼1/50), aldehyde 16 was obtained in 99% yield in 2 steps as
a colorless oil.: Rf value 0.62 (ethyl acetate/hexane¼1/10); IR (NaCl,
To a solution of 2-methyl-2-butene (0.813 mL, 7.65 mmol) in
THF (12 mL) was added borane dimethylsulfide complex (0.27 mL,
3.70 mmol) at 0 ꢀC, and then the resulted solution was stirred at the
same temperature for 1 h. To this solution was added olefin 7
(0.299 g, 1.23 mmol) in THF (1þ1 mL rinse). The mixture was stirred
at 0 ꢀC for 3 h before treatment with saturated sodium bicarbonate
aqueous solution (2.4 mL) and 30% H2O2 solution (1.2 mL). Stirred at
room temperature for 1 h, the reaction mixture was extracted by
ethyl acetate, and the organic layer was washed with water and
brine. Then the collected organic layer was dried over magnesium
sulfate followed by silica gel column chromatography (ethyl ace-
tate/hexane¼1/10) to afford primary alcohol 8 (262.8 mg, 82%) as
a colorless oil: Rf value 0.34 (ethyl acetate/hexane¼1/4); IR (NaCl,
neat) nmax 3348, 2955, 2930, 2858, 1471, 1463, 1254, 1059 cm-1; 1H
neat) nmax 2955, 2930, 2858, 1696, 1254, 836, 774 cm-1
;
1H NMR
(500 MHz, CDCl3)
d
9.50 (d, 1H, J¼8.0 Hz), 6.88 (dt, 1H, J¼15.5,
6.5 Hz), 6.12 (ddt, 1H, J¼15.5, 8.0, 2.0 Hz), 3.70 (tt, 1H, J¼6.0, 6.0 Hz),
2.39 (m, 2H), 1.63 (m, 2H), 1.45 (m, 2H), 1.32e1.24 (m, 4H), 0.89 (t,
3H, J¼7.5 Hz), 0.88 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR
NMR (500 MHz, CDCl3)
d
3.71 (tt, 1H, J¼5.5, 5.5 Hz), 3.60 (m, 2H),
2.37 (br-s, 1H, OH), 1.61 (m, 2H), 1.55 (m, 2H), 1.46 (m, 2H), 1.31e1.15
(m, 4H), 0.89 (m, 3H), 0.88 (s, 9H), 0.05 (s, 6H); 13C NMR (125 MHz,
(125 MHz, CDCl3) d 194.2, 159.3, 132.7, 71.4, 36.7, 34.8, 28.5, 27.4,
CDCl3)
d
72.1, 63.1, 36.2, 33.3, 28.1, 27.7, 25.9, 22.8, 18.1, 14.1, ꢁ4.6;
25.8, 22.8, 18.1, 14.1, ꢁ4.4, ꢁ4.5; HRMS (CI) calcd for C16H33O2Si
HRMS (CI) calcd for C14H33O2Si [MþH]þ 261.2250, found 261.2250.
4.3. Ethyl (E)-((tert-butyldimethylsilyl)oxy)dec-2-enoate (15)
To a stirred solution of primary alcohol 8 (500 mg, 1.90 mmol)
[MþH]þ 285.2250, found 285.2251.
4.5. Dimethyl (2-oxopentyl)phosphonate (17)
To a stirred solution of n-butyllithium (1.62 M in hexane, 14 mL,
22.4 mmol) in THF (19 mL) under nitrogen atmosphere was added
dimethyl methylphosphonate (2 mL, 18.7 mmol) at ꢁ90 ꢀC. After
30 min, methyl butyrate (2.1 mL, 18.7 mmol) was added to the
mixture at the same temperature. The reaction mixture was grad-
ually warmed up to room temperature. After overnight reaction,
the mixture was diluted with ethyl acetate and was washed with
water and brine. The used aqueous layer was washed well with
ethyl acetate. Then the collected organic layer was dried over
magnesium sulfate followed by concentration in vacuo and silica
gel column chromatography (ethyl acetate/hexane¼1/1 to 2/1 to
4/1) to afford 17 (3.24 g, 89%) as a colorless oil.: Rf value 0.10
(ethyl acetate/hexane¼1/1); IR (NaCl, neat) nmax 3475, 2962,
and DMSO (550
fluoroacetic anhydride (396
m
L, 7.7 mmol) in THF (19 mL) was added tri-
m
L, 2.85 mmol) at 0 ꢀC. After 30 min,
triethylamine (1.0 mL, 7.7 mmol) was added to the mixture at 0 ꢀC,
and was stirred for 30 min the mixture was diluted with ether, and
washed with water and brine. Then the collected organic layer was
dried over magnesium sulfate followed by concentration in vacuo
to obtain crude materials of resulting aldehyde 9 (442 mg), which
was used in next reaction without purification.
To a stirred solution of triethyl phosphonoacetate (411
mL,
2.1 mmol) in THF (17 mL) was added sodium hydride (60% in oil,
88.3 mg, 2.22 mmol) at 0 ꢀC. After 45 min, crude aldehyde 9
(442 mg) was added to the mixture and the flask was rinsed with
THF. The reaction mixture was stirred at room temperature over-
night and was quenched with water. The mixture was diluted with
1714, 1256, 1032, 813 cm-1; 1H NMR (500 MHz, CDCl3)
JH-P¼10.5 Hz), 3.07 (d, 2H, JH-P¼23.0 Hz), 2.58 (t, 2H, J¼7.5 Hz), 1.60
d 3.77 (d, 6H,

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H. Zhang et al. / Tetrahedron 70 (2014) 8600e8605
(tq, 2H, J¼7.5, 7.5 Hz), 0.90 (t, 3H, J¼7.5 Hz); 13C NMR
was washed with saturated sodium bicarbonate aqueous solution
and brine. Then the collected organic layer was dried over mag-
nesium sulfate followed by concentration to afford crude MOM
protected alcohol 1800, which was used without purification. To
collect analytical data, crude material was purified with silica gel
column chromatography (ethyl acetate/hexane¼1/200) to give
product 1800 (63%) as a colorless oil.: Rf value 0.46 (ethyl acetate/
hexane¼1/10); IR (NaCl, neat) nmax 2956, 2930, 2878, 1464, 1254,
(125 MHz, CDCl3)
d
202.0 (d, JC-P¼6.0 Hz), 53.0 (d, JC-P¼6.0 Hz), 46.0,
41.2 (d, JC-P¼127.5 Hz), 16.8, 13.4; LRMS (EI) 194 (Mþ, 17%), 179 (26),
151 (100), 124 (69), 109 (53); HRMS (EI) calcd for C7H15O4P (Mþ)
194.0708, found 194.0709.
4.6. (5E,7E)-11-((tert-Butyldimethylsilyl)oxy)pentadeca-5,7-
dien-4-one (18)
1096, 835, 773 cm-1 1H NMR (500 MHz, CDCl3)
; d 6.14 (dd, 1H,
To a stirred solution of 1.5 g of crude aldehyde 16 in THF (47 mL)
was added sodium hydride (60% in oil, 339.0 mg, 8.48 mmol) at
0 ꢀC. After 15 min, prepared dimethyl (2-oxopentyl)phosphonate 17
(1.57 g, 7.06 mmol) was added to the mixture at 0 ꢀC, and the re-
action mixture was stirred at room temperature for 4 h. The re-
action was quenched with ammonium chloride, and the mixture
was diluted with ether. The extract was washed with water and
brine. Then the collected organic layer was dried over magnesium
sulfate followed by concentration in vacuo and silica gel column
chromatography (ethyl acetate/hexane¼1/50 to 1/30 to 25/1) to
afford ketone 18 (1.09 g, 66% for 3 steps from 1.68 g of ester 15) as
a colorless oil.: Rf value 0.44 (ethyl acetate/hexane¼1/10); IR (NaCl,
neat) nmax 2956, 2930, 2858, 1669, 1637, 1597, 1254, 1051, 1000, 835,
J¼15.5, 11.0 Hz), 6.02 (dd, 1H, J¼15.0, 11.0 Hz), 5.69 (dt, 1H, J¼15.0,
6.5 Hz), 5.37 (dd, 1H, J¼15.5, 8.0 Hz), 4.71 (d, 1H, J¼6.5 Hz), 4.50 (d,
1H, J¼6.5 Hz), 4.00 (dt, 1H, J¼8.0, 8.0 Hz), 3.64 (tt, 1H, J¼5.5, 5.5 Hz),
3.36 (s, 3H), 2.11 (m, 2H), 1.54e1.23 (m, 12H), 0.93e0.88 (m, 15H),
0.03 (s, 6H); 13C NMR (125 MHz, CDCl3)
d 135.4, 133.1, 130.8, 129.3,
93.3, 76.2, 71.8, 55.3, 37.9, 36.8, 36.4, 28.5, 27.4, 25.9, 22.9, 18.7, 18.1,
14.1, 14.0, ꢁ4.4, ꢁ4.5,; HRMS (ESI) calcd for C23H46O3SiNa [MþNa]þ
421.3114, found 421.3114.
4.9. (8E,10E)-12-(Methoxymethyl)oxy)pentadeca-8,10-dien-5-
ol (19)
To a stirred solution of crude MOM ether 1800 in THF (2 mL)
was added tetrabutylammonium fluoride (1.0 M in THF, 340 mL,
773 cm-1
;
1H NMR (500 MHz, CDCl3)
d
7.13 (ddd, 1H, J¼15.5, 6.5,
3.5 Hz), 6.19e6.17 (m, 2H), 6.08 (d, 1H, J¼15.5 Hz), 3.66 (tt, 1H,
J¼6.0, 6.0 Hz), 2.52 (t, 2H, J¼7.5 Hz), 2.22 (m, 2H), 1.64 (qt, 2H, J¼7.5,
7.5 Hz), 1.54 (m, 2H), 1.42 (m, 2H), 1.33e1.25 (m, 4H), 0.94 (t, 3H,
J¼7.5 Hz), 0.90e0.88 (m, 12H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR
0.340 mmol) at room temperature and the mixture was heated to
70 ꢀC. After 6 h, the mixture was diluted with ethyl acetate, and was
washed with saturated ammonium chloride aqueous solution
and brine. Then the collected organic layer was dried over mag-
nesium sulfate followed by concentration in vacuo and silica gel
column chromatography (ethyl acetate/hexane¼1/10 to 1/8) to af-
ford alcohol 19 (43.6 mg, 79% for 3 steps from 68.4 mg of ketone 18)
as a colorless oil.: Rf value 0.26 (ethyl acetate/hexane¼1/4);
IR (NaCl, neat) nmax 3413, 2956, 2930, 2872, 1466, 1154, 1095,
(125 MHz, CDCl3)
d 201.1, 145.6, 142.9, 128.8, 127.9, 71.6, 42.4, 36.7,
35.8, 29.0, 27.4, 25.9, 22.9, 18.1, 17.9, 14.1, 13.8, ꢁ4.4, ꢁ4.5; HRMS
(FAB) calcd for C21H41O2Si [MþH]þ 353.2876, found 353.2884.
4.7. (5E,7E)-11-((tert-Butyldimethylsilyl)oxy)pentadeca-5,7-
dien-4-ol (180)
1037 cm-1
;
1H NMR (500 MHz, CDCl3)
d
6.14 (dd, 1H, J¼15.0,
10.5 Hz), 6.06 (dd, 1H, J¼15.0, 10.5 Hz), 5.70 (dt, 1H, J¼15.0, 7.5 Hz),
5.38 (dd, 1H, J¼15.0, 8.0 Hz), 4.701 (d, 1H, J¼6.0 Hz), 4.699 (from
isomer, d, 1H, J¼6.0 Hz), 4.50 (d, 1H, J¼6.0 Hz), 4.00 (dt, 1H, J¼8.0,
7.5 Hz), 3.60 (br, 1H), 3.36 (s, 3H), 2.20 (m, 2H), 1.63e1.25 (m, 13H)
To a stirred solution of ketone 18 (68.4 mg, 0.194 mmol) in
methanol (2 mL) was added cerium chloride heptahydrate
(108.4 mg, 0.291 mmol) at room temperature. After 30 min, the
mixture was cooled down to 0 ꢀC and sodium borohydride (7.3 mg,
0.194 mmol) was added to the mixture. 10 minutes later, the re-
action was quenched with saturated ammonium chloride aqueous
solution. The mixture was diluted with ethyl acetate, and was
treated with saturated ammonium chloride aqueous solution and
brine. Then the collected organic layer was dried over magnesium
sulfate followed by concentration to afford crude alcohol, which
was used without purification. To collect analytical data, the crude
material was purified with silica gel column chromatography (ethyl
acetate/hexane¼1/80 to 1/50 to 1/40) to give alcohol 180 (63%) as
a colorless oil.: Rf value 0.25 (ethyl acetate/hexane¼1/10); IR (NaCl,
neat) nmax 3342, 2956, 2930, 2858, 1463, 1254, 1065, 986, 835,
0.90 (t, 6H, J¼7.5 Hz); 13C NMR (125 MHz, CDCl3)
d 134.76, 134.74
(from isomer), 132.9, 131.2, 129.8, 93.4, 76.2, 71.44, 71.43 (from
isomer), 55.3, 37.8, 37.2, 36.7, 28.91, 28.87 (from isomer), 27.8, 22.7,
18.7, 14.1, 14.0; HRMS (ESI) calcd for
307.2249, found 307.2250.
C
17H32O3Na [MþNa]þ
4.10. (5E,7E)-11-Azido-4-(methoxymethyloxy)pentadeca-5,7-
diene (20)
To a stirred solution of alcohol 19 (51.4 mg, 0.181 mmol) and
triphenylphosphine (142.2 mg, 0.542 mmol) in benzene (2 mL)
under nitrogen atmosphere was added diisopropyl azodicarbox-
713 cm-1; 1H NMR (500 MHz, CDCl3)
d
6.17 (dd, 1H, J¼15.0, 10.5 Hz),
ylate (106.4
mL, 0.542 mmol) dropwise at room temperature fol-
6.02 (dd, 1H, J¼15.0, 10.5 Hz), 5.70 (dt, 1H, J¼15.0, 6.5 Hz), 5.57 (dd,
1H, J¼15.0, 7.0 Hz), 4.12 (td, 1H, J¼7.0, 7.0 Hz), 3.64 (tt, 1H, J¼6.0,
6.0 Hz), 2.11 (m, 2H), 1.58e1.24 (m, 13H), 0.94e0.88 (m, 15H), 0.04
lowed by dropwise addition of diphenylphosphorylazide (103.0
mL,
0.542 mmol). After 1 h, the mixture was diluted with ethyl acetate,
and washed with water and brine. Then the collected organic layer
was dried over magnesium sulfate followed by silica gel column
chromatography twice (ethyl acetate/hexane¼1/50) to give azide
20 (35.4 mg, 63%) as a colorless oil.: Rf value 0.68 (ethyl acetate/
hexane¼1/4); IR (NaCl, neat) nmax 2957, 2932, 2873, 2097, 1466,
(s, 6H); 13C NMR (125 MHz, CDCl3)
d 135.4, 133.7, 130.9, 129.3, 72.6,
71.7, 39.4, 36.8, 36.4, 28.5, 27.4, 25.9, 22.9, 18.6, 18.1, 14.1, 14.0, ꢁ4.4,
ꢁ4.5; HRMS (FAB) calcd for C21H42O2SiNa [MþNa]þ 377.2852,
found 377.2843.
1037 cm-1
;
1H NMR (500 MHz, CDCl3)
d
6.14 (dd, 1H, J¼15.0,
4.8. (5E,7E)-11-((tert-Butyldimethylsilyl)oxy)-4-((methox-
10.0 Hz), 6.06 (dd, 1H, J¼15.0, 10.0 Hz), 5.65 (dt, 1H, J¼15.0, 6.5 Hz),
5.41 (dd, 1H, J¼15.0, 3.0 Hz), 4.704 (d, 1H, J¼6.5 Hz), 4.701 (isomer,
d, 1H, J¼6.5 Hz), 4.50 (d, 1H, J¼6.5 Hz), 3.37 (s, 3H), 3.25 (tt,
1H, J¼6.5, 6.5 Hz), 2.20 (m, 2H), 1.65e1.32 (m, 12H), 0.93e0.90 (m,
ymethyl)oxy)pentadeca-5,7-diene (1800)
To a stirred solution of crude alcohol 180 in dichloromethane
(2 mL) were added diisopropylethylamine (167
mL, 0.970 mmol),
6H); 13C NMR (125 MHz, CDCl3)
d 133.5, 132.7, 131.6, 130.3, 93.4,
chloromethyl methyl ether (59 L, 0.776 mmol) and tetrabuty-
lammonium iodide (72.7 mg, 0.194 mmol) at room temperature.
After 18 h, the reaction mixture was diluted with ethyl acetate, and
m
76.2, 62.4, 55.3, 37.8, 34.1, 33.8, 29.2, 28.2, 22.5, 18.7, 14.0 (2C);
HRMS (ESI) calcd for C17H31N3O2Na [MþNa]þ 332.2314, found
332.2306.

H. Zhang et al. / Tetrahedron 70 (2014) 8600e8605
8605
Manabe, Y.; Fukase, K. Synlett 2014, 1026e1030; (e) Hachiya, I.; Mizota, M.;
Shimizu, M. Heterocycles 2012, 85, 993e1016; (f) Duttwyler, S.; Lu, C.;
Rheingold, A. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2012, 134,
4064e4067; (g) Oberg, K. M.; Rovis, T. J. Am. Chem. Soc. 2011, 133, 4785e4787;
4.11. Costa Rican ant venom alkaloid of
imine (2)
a,b,g,d-unsaturated
€
(h) Marcoux, D.; Bindschadler, P.; Speed, A. W. H.; Chiu, A.; Pero, J. E.; Borg, G.
To a stirred solution of azide 20 (35.4 mg, 0.114 mmol) in
A.; Evans, D. A. Org. Lett. 2011, 13, 3758e3761; (i) Johannes, J. W.; Wenglowsky,
S.; Kishi, Y. Org. Lett. 2005, 7, 3997e4000; (j) Hong, B.-C.; Wu, J.-L.; Gupta, A. K.;
Hallur, M. S.; Liao, J.-H. Org. Lett. 2004, 6, 3453e3456; (k) Fletcher, M. D.; Hurst,
T. H.; Miles, T. J.; Moody, C. J. Tetrahedron 2006, 62, 5454e5463; (l) Kobayashi,
S.; Furuya, T.; Otani, T.; Saito, T. Tetrahedron 2008, 64, 9705e9716; (m) Chen,
W.-S.; Fowder, F. W.; Lupo, A. T., Jr. J. Am. Chem. Soc. 1981, 103, 2090e2091; (n)
Franc¸ ois, D.; Maden, A.; Murray, W. V. Org. Lett. 2004, 6, 1931e1934; (o) Boger,
D. L.; Corbett, W. L.; Curran, T. T.; Kasper, A. M. J. Am. Chem. Soc. 1991, 113,
1713e1729; (p) Schuster, E.; Hesse, C.; Schumann, D. Synlett 1991, 916e918.
2. (a) Anthoni, U.; Chevolot, L.; Larsen, C.; Nielsen, P. H.; Christophersen, C. J. Org.
Chem. 1987, 52, 4709e4712; (b) Baran, P. S.; Shenvi, R. A. J. Am. Chem. Soc. 2006,
128, 14028e14029.
dichloromethane (1.5 mL) under nitrogen atmosphere was added
trimethylsilyl trifluoromethanesulfonate (21.7
mL, 0.120 mmol)
dropwise at 0 ꢀC and stirred for 10 min. The reaction was quenched
with saturated sodium bicarbonate aqueous solution. The reaction
mixture was extracted with diethyl ether, and the organic layer was
washed with saturated sodium bicarbonate aqueous solution and
brine. Then the collected organic layer was dried over magnesium
sulfate followed by silica gel column chromatography (chloroform/
ether¼50:1) to give Costa Rican Ant Venom Alkaloid 2 (12.9 mg,
51%) as a colorless oil.: Rf value 0.13 (ethyl acetate/hexane¼10/1); IR
3. (a) Katavic, P. L.; Venables, D. A.; Forster, P. I.; Guymer, G.; Carroll, A. R. J. Nat.
Prod. 2006, 69, 1295e1299; (b) Cuthbertso, J. D.; Godgrey, A. A.; Taylor, R. J. K.
Org. Lett. 2011, 13, 3976e3979; (c) Cuthbertson, J. D.; Taylor, R. J. K. Angew. Chem.
, Int. Ed. 2013, 52, 1490e1493.
(NaCl, neat) nmax 2957, 2928, 2870,1620,1579,1456,1336, 989 cm-1
;
1H NMR (500 MHz, CDCl3)
d
6.57 (dd, 1H, J¼16.0, 10.0 Hz), 6.40 (d,
4. Jones, T. H.; DeVries, P. J.; Escoubas, P. J. Chem. Ecol. 1991, 17, 2507e2518.
5. (a) Tanimoto, H.; Kakiuchi, K. Nat. Prod. Commun. 2013, 8, 1021e1034; (b) Brase,
1H, J¼16.0 Hz), 6.18 (ddt, 1H, J¼15.0, 10.0, 1.5 Hz), 5.92 (dt, 1H,
J¼15.0, 7.0 Hz), 4.00 (m,1H), 2.73 (m,1H), 2.56 (m,1H), 2.12 (m, 2H),
1.75 (m, 1H), 1.46e1.35 (m, 9H), 0.93e0.89 (m, 6H); 13C NMR
€
S.; Banert, K. Organic Azides, Syntheses and Applications; John Wiley & Sons, Ltd.:
€
Chichester, U.K., 2010; (c) Chiba, S. Synlett 2012, 21e44; (d) Brase, S.; Gil, C.;
Knepper, K.; Zimmermann, V. Angew. Chem., Int. Ed. 2005, 44, 5188e5240; (e)
Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297e368.
6. Wrobleski, A.; Coombs, T. C.; Huh, C. W.; Li, S.-W.; Aube, J. Org. React. 2012, 78,
(125 MHz, CDCl3)
d 172.7, 139.9, 139.4, 130.0, 126.3, 72.6, 36.3, 34.9,
33.4, 28.9, 28.4, 22.8, 22.2, 14.0, 13.6; LRMS (EI) m/z 219 (Mþ, 58%),
ꢀ
190 (42), 176 (100), 162 (53), 120 (61); HRMS (EI) calcd for C15H25
(Mþ) 219.1987, found 219.1982.
N
1e320.
7. (a) Banerjee, A.; Kumar, P. S.; Baskaran, S. Chem. Commun. 2011, 12218e12220;
(b) Pearson, W. H.; Fang, W. K. J. Org. Chem. 2000, 65, 7158e7174; (c) Molina, P.;
Alc_antara, J.; Leonardo, L. Synlett 1995, 363e364; (d) Pearson, W. H.; Fang, W.
K. J. Org. Chem. 1995, 60, 4960e4961; (e) Pearson, W. H.; Walavalkar, R.;
Schkeryantz, J. M.; Fang, W. K.; Blickendorf, J. D. J. Am. Chem. Soc. 1993, 115,
10183e10194; (f) Pearson, W. H.; Fang, W. K.; Kampf, J. W. J. Org. Chem. 1994, 59,
2682e2684 For an SN2-type Schmidt reaction, see; (g) Kapat, A.; Nyfeler, E.;
Giuffredi, G. T.; Renaud, P. J. Am. Chem. Soc. 2009, 131, 17746e17747.
Acknowledgements
This work was partly supported by funding from NAIST for
young scientists working on photonanoscience. We acknowledge
Ms. Samia Hammouti of Universite Paul Sabatier for joining our
ꢀ
ꢀ
8. (a) de Miguel, E.; Valedo, M.; Herradon, B.; Mann, E. Eur. J. Org. Chem. 2012,
4347e4353; (b) Zhao, Y.-M.; Gu, P.; Tu, Y.-Q.; Zhang, H.-J.; Zhang, Q.-W.; Fan,
C.-A. J. Org. Chem. 2010, 75, 5289e5295; (c) Zhou, Y.; Murphy, P. V. Org. Lett.
2008, 10, 3777e3780; (d) Kim, S.; Lee, Y. M.; Lee, T.; Fu, Y.; Song, Y.; Cho, J.;
Kim, D. J. Org. Chem. 2007, 72, 4886e4891; (e) Schkeryantz, J.; Pearson, W. H.
Tetrahedron 1996, 52, 3107e3116; (f) Hudlicky, T.; Luna, J. H.; Price, J. D.; Rulin,
project as an exchange program student. We also thank Ms. Mika
Yamamura, Ms. Yuriko Nishiyama, Ms.Yoshiko Nishikawa (HRMS
measurement) of NAIST.
ꢀ
F. J. Org. Chem. 1990, 55, 4683e4687; (g) Reddy, D. S.; Judd, W. R.; Aube, J. Org.
Lett. 2003, 5, 3899e3902.
Supplementary data
9. Hayashi, K.; Tanimoto, H.; Zhang, H.; Morimoto, T.; Nishiyama, Y.; Kakiuchi, K.
Org. Lett. 2012, 14, 5728e5731.
1H and 13C NMR spectra related to this article can be found at
website. Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2014.09.058.
10. For recently developed organic azide reaction with propargyl cations, see: (a)
Zhang, H.; Tanimoto, H.; Morimoto, T.; Nishiyama, Y.; Kakiuchi, K. Org. Lett.
2013, 15, 5222e5225; (b) Huang, X.; Jiao, N. Org. Biomol. Chem. 2014, 12,
4324e4328; (c) Song, X.-R.; Song, B.; Qiu, Y.-F.; Han, Y.-P.; Qiu, Z.-H.; Hao, X.-H.;
Liu, X.-Y.; Liang, T.-M. J. Org. Chem. 2014, 79, 7616e7625.
11. Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454e5459.
12. (a) Mitsunobu, O. Synthesis 1981, 1e28; (b) Kumara Swamy, K. C.; Bhuva Kumar,
N. N.; Balaraman, E.; Pavan Kumar, K. V. P. Chem. Rev. 2009, 109, 2551e2651; (c)
Lal, B.; Pramanik, B.; Manhas, M. S.; Bose, A. K. Tetrahedron Lett. 1977, 18,
1977e1980.
References and notes
1. (a) Bunora, P.; Olse, J.-C.; Oh, T. Tetrahedron 2001, 57, 6099e6138; (b)
Groenendaal, B.; Ruijter, E.; Orru, V. A. Chem. Commun. 2008, 5474e5489; (c)
Tanaka, K.; Siwu, E. R. O.; Hirosaki, S.; Iwata, T.; Matsumoto, R.; Kitagawa, Y.;
Pradipta, A. R.; Okumura, M.; Fukase, K. Tetrahedron Lett. 2012, 53, 5899e5902;
(d) Tanaka, K.; Matsumoto, R.; Pradipta, A. R.; Kitagawa, Y.; Okumura, M.;