Efficient total synthesis of (+)-dihydropinidine, (-)-epidihydropinidine, and (-)-pinidinone

Article abstract of DOI:10.1021/np100852p

The 2,6-disubstituted piperidine alkaloids (+)-dihydropinidine (1), (-)-epidihydropinidine (2) (as HCl salts), and (-)-pinidinone (3) were efficiently synthesized from (S)-epichlorohydrin (7) as common substrate using regioselective Wacker-Tsuji oxidation of alkenylazides 10 and 14 as well as a highly diastereoselective reduction of cyclic imine 11 as key steps. The protecting group free total syntheses represent the up to date shortest routes with highest overall yields for all three naturally occurring alkaloids (1-3). The first single-crystal X-ray analysis of (-)-epidihydropinidine hydrochloride (2 · HCl) confirmed its proposed absolute configuration to be (2S,6S), corresponding to that of the isolated natural product.

Full text of DOI:10.1021/np100852p

ARTICLE
pubs.acs.org/jnp
Efficient Total Synthesis of (þ)-Dihydropinidine,
(ꢀ)-Epidihydropinidine, and (ꢀ)-Pinidinone
Miroslav Kavala,† Frantiꢀsek Mathia,† Jozef Koꢀzíꢀsek,‡ and Peter Szolcsꢁanyi*,†
†Department of Organic Chemistry and ‡Department of Physical Chemistry, Slovak University of Technology,
Radlinskꢁeho 9, SK-812 37 Bratislava, Slovakia
S Supporting Information
b
ABSTRACT: The 2,6-disubstituted piperidine alkaloids (þ)-dihy-
dropinidine (1), (ꢀ)-epidihydropinidine (2) (as HCl salts), and (ꢀ)-
pinidinone (3) were efficiently synthesized from (S)-epichlorohydrin
(7) as common substrate using regioselective WackerꢀTsuji oxida-
tion of alkenylazides 10 and 14 as well as a highly diastereoselective
reduction of cyclic imine 11 as key steps. The protecting group free
total syntheses represent the up to date shortest routes with highest
overall yields for all three naturally occurring alkaloids (1ꢀ3). The
first single-crystal X-ray analysis of (ꢀ)-epidihydropinidine hydro-
chloride (2 HCl) confirmed its proposed absolute configuration to
3
be (2S,6S), corresponding to that of the isolated natural product.
he alkaloids (þ)-dihydropinidine (1), (ꢀ)-epidihydropinidine
(2), and (ꢀ)-pinidinone (3) are naturally occurring defense
of either EtLi or EtMgCl in diethyl ether to furnish exclusively the
desired alkenol 8 (Table 1). On the other hand, the employment
of EtMgI led to the formation of undesired iodohydrin 9 with
only traces of 8 (Table 1), while the addition of EtMgBr gave
roughly an equimolar mixture of both the desired alkenol 8 and
the unwanted bromohydrin 10 (cf. ref 6).
Subsequent installation of an azido function was accomplished
either by direct SN2 displacement of the OH group in alkenol 8
under Mitsunobu conditions7 or via activation of 8 and the sub-
stitution of the mesylate 11, yielding the alkenylazide 12 as a key
substrate in overall yield 70% over five steps (Scheme 3). The
WackerꢀTsuji oxidation8 of alkenylazide 12 to azidoketone 4 was
devised as a key transformation of the whole synthetic sequence.9 In
order to obtain the highest level of regioselectivity (desired
ketone vs unwanted aldehyde), systematic reaction screening
was performed. The influence of the nature of the palladium(II)
salt, solvent system, (co)oxidant, and temperature was evaluated
(Table 2; see Supporting Information).
First, the composition of the aqueous solvent mixture was
scrutinized. Wet DMF10a and THF performed comparably well
in contrast to MeOH, acetone, and/or dioxane (Table 2). Interest-
ingly, drastic reduction of CuCl content from stoichiometric to
the catalytic amount under the O2 blanket led to much faster
reaction and slightly higher yield of ketone 4 (Table 2). On the
other hand, replacement of oxygen atmosphere with air caused a
significant yield drop of 4. Regarding the evaluation of catalyst
efficiency, PdCl2 clearly outperformed all other palladium(II)
salts used in the screening. The benzonitrile complex as well as
trifluoroacetate (Table 2) gave only low yields of ketone 4.
T
chemicals isolated from many Picea (spruce) and/or Pinus (pinus)
species1 and from various insects.2 Regarding the biological
activity, (ꢀ)-epidihydropinidine (2) was reported to have mod-
erate to high antifeedant activity1a against eastern spruce budworm.
Very recently, racemic dihydropinidine was practically used as an
effective antifeedant in latex-based coatings against pine weevil,
Hylobius abietis.3
While there are numerous known syntheses of (þ)-dihydro-
pinidine (1),4 only two preparations of (ꢀ)-epidihydropinidine
(2) have been published so far.4i,5 Similarly, we are aware of only
one synthesis4g of (ꢀ)-pinidinone (3). Due to the extensive use
of protecting groups, most of the published syntheses are relatively
lengthy and low-yielding. Some of them also suffer from low
levels of stereoselectivity in the chirality-generating steps.
Thus, we present the straightforward and protecting group
free total synthesis of alkaloids 1ꢀ3 starting from (S)-epichlo-
rohydrin (7). Our approach relied on the highly regioselective
WackerꢀTsuji oxidation of alkenylazides 12 and 16, leading
exclusively to methyl ketones 4 and 5, while both these substrates
are accessible from the enantiomerically pure epoxide 6 as a
common precursor (Scheme 1).
’ RESULTS AND DISCUSSION
The common starting material (S)-epichlorohydrin (7) was
efficiently transformed to the hemilabile and volatile6 epoxide 6.
In order to obtain the alkenol 8, the subsequent Cu(I)-catalyzed
ring-opening of 6 was scrutinized using different organometallic
nucleophiles (Scheme 2, and Table 1 in Supporting Information).
The best chemo- and regioselectivity was observed with the use
Received: November 23, 2010
Published: March 16, 2011
r
Copyright
2011 American Chemical Society and
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American Society of Pharmacognosy
|

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ARTICLE
Figure 1
Scheme 1. Retrosynthetic Analysis of Piperidine Alkaloids
1ꢀ3
Figure 2. ORTEP view of the crystal structure of (ꢀ)-epidihydropini-
dine hydrochloride (2 HCl).
3
the use of pure oxygen in dimethylacetamide as the solvent (entry
16, Table 2). Eventually, the best catalytic system11 operated
under copper-free conditions using 20 mol % of PdCl2 in a
solvent mixture of N-methyl-2-pyrrolidone/water (8/1 w/w)
under an atmospheric pressure of O2 as the sole oxidant at room
temperature, delivering the desired ketone 4 in 85% yield after
24 h (Table 2, entry 17).
The azidoketone 4 subsequently underwent intramolecular
Staudingerꢀaza-Wittig condensation12 to furnish the cyclic
imine 13 (Scheme 3). This was subsequently subjected to the
reaction screening of low-temperature CdN reduction in order
to obtain the highest diastereoselectivity favoring the formation
of the 2,6-trans-arrangement of substituents on the piperidine
ring (Table 3; see Supporting Information).
Scheme 2. Preparation of Alkenol 8a
The large excess (7 equiv each) of both hydride (LiAlH4) and
N-chelating Lewis acid (Me3Al) was crucial for the preferential
formation of 2 (entries 1ꢀ3, Table 3), as the reduction of molar
equivalents led to erosion of diastereoselectivity (entries 1ꢀ3 vs
entries 4, 5, Table 3). Moreover, the order of addition of reagents
was also important for achieving high selectivity (entry 3 vs
entries 1, 2, Table 3). Finally, omission of Me3Al from the
reaction mixture completely reversed the selectivity of reduction
of cyclic imine 13 (entries 6, 7 vs entries 1ꢀ5, Table 3). Our
observation is consistent with previously reported results and
points to the key role of Me3Al as chelating agent.13a,b Eventually,
the highly diastereoselective reduction of 13 using the Me3Al/
LiAlH4 system at ꢀ78 °C afforded the target piperidine alkaloid
(ꢀ)-epidihydropinidine (2) in acceptable 64% yield, with ex-
cellent 95% de. This eight-step synthesis with 34% overall yield
(from commercially available (S)-epichlorohydrine, 7) repre-
sents the most efficient access to (ꢀ)-epidihydropinidine (2) to
date. Moreover, the first single-crystal X-ray analysis of 2 (as HCl
salt) confirmed14 its proposed absolute configuration to be (2S,6S),
the same as that of the natural product (Figure 2). On the other
hand, azidoketone 4 was subjected to the one-pot three-step
sequence15 (azide reduction, amine condensation, and imine re-
duction) using the hydrogenation on Pearlman’s catalyst to afford
the naturally occurring alkaloid (þ)-dihydropinidine (1), as the
hydrochloride, in high yield. In this case, our approach required
only seven steps and gave 54% overall yield of 1 starting from 7
(Scheme 3).
a Conditions: (i) C4H7MgBr, cat. CuI, THF, ꢀ78 °C, 95%; (ii) NaOH,
Et2O, rt; (iii) EtMgCl, cat. CuI, Et2O, ꢀ78 °C, 95% (in 2 steps); (iv)
EtLi, cat. CuI, Et2O, ꢀ78 °C, 80% (in 2 steps).
Scheme 3. Optimized Synthesis of (þ)-Dihydropinidine
1 HCl and (ꢀ)-Epidihydropinidine 2 HCla
3
3
a Conditions: (i) MsCl, Et3N, DCM, 0 °C to rt, 92% (from 8); (ii) Ph3P,
DPPA, DIAD, THF, 0 °C, 80% (from 8); (iii) NaN3, DMF, ultrasound,
50 °C, 95% (from 11); (iv) O2, cat. PdCl2, NMP/H2O, rt, 85%; (v)
polymer-bound Ph3P, Et2O, sealed tube, reflux, 90%; (vi) H2, Pd-
(OH)2/C, MeOH, rt then HCl, 91%; (vii) Me3Al, LiAlH4, THF,
ꢀ78 °C, then HCl, 64%.
Moreover, the use of neither triphenylphospine nor the (ꢀ)-
sparteine complex10b led to the formation of 4. Interestingly,
employment of metallic palladium10c instead of Pd(II) salts deliv-
ered the desired product, albeit in only 21% yield. The alternative
oxidant10d K2S2O8 was even less effective. The significant improve-
ment in WackerꢀTsuji oxidation of alkenylazide 12 came with
An analogous strategy was applied for the synthesis of the third
target alkaloid, (ꢀ)-pinidinone (3) (Scheme 4). Thus, Cu(I)-
catalyzed chemo- and regioselective ring-opening16 of epoxide 6
with vinylmagnesium bromide furnished the dienol 14. Installa-
tion of the azido function was done either by direct SN2
displacement of the OH group in dienol 14 under the Mitsunobu
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Scheme 4. Optimized Synthesis of (ꢀ)-Pinidinone (3)a
the residual protic solvent was used as internal reference. The COSY
1
1
technique was used in assignment of Hꢀ H relationships and the
determination of relative configuration. The multiplicities of carbons
were assigned from a broadband decoupled analysis used in conjunc-
tion with APT. The HSQC technique was used throughout for the
13
assignment of the 1Hꢀ C relationships. High-resolution mass
spectra (HRMS) were recorded on a Q-Tof Premier hybrid mass
spectrometer using electron spray ionization (ESI). Liquid chroma-
tographyꢀmass spectrometry (LC-MS) analyses were performed on
an Agilent 1200 Series instrument equipped with a multimode MS
detector using the MM ESI/APCIþ ionization method (column:
Zorbax SB C-8 12.5 ꢁ 2.1 mm, particle size 5 μm, eluent: acetoni-
trile/water with 0.1% HCO2H, gradient 20ꢀ100% of CH3CN for
7 min, flow 1.5 mL/min).
(R)-Non-8-en-4-ol (8). Finely powdered NaOH (1.212 g, 30.30
mmol) was added to a solution of (S)-1-chlorohept-6-en-2-ol6 (1.501 g,
10.10 mmol) in dry Et2O (10 mL). The mixture was vigorously stirred at
rt for 4 h and filtered, and the solution was dried over activated 4 Å
molecular sieves. After filtration of solids, anhydrous CuI (384 mg, 2.02
mmol) was added under Ar, and the mixture was cooled to ꢀ78 °C.
After 5 min stirring a solution of ethylmagnesium chloride (2 M in Et2O,
20.2 mL, 20.20 mmol) was added dropwise over 20 min. After 4 h of
stirring, a saturated aqueous solution of NH4Cl (40 mL) and H2O
(40 mL) was added at ꢀ20 °C. The cooling bath was removed, and the
mixture was left to stir for 30 min and then extracted with Et2O (2 ꢁ
50 mL). Combined organic extracts were dried over anhydrous MgSO4,
filtered, and concentrated in vacuo (120 mbar, 25 °C). The resulting
yellowish oil was subjected to short-path distillation (8 mbar, 100ꢀ120 °C),
yielding pure alcohol 8 (1.36 g, 95%).
a Conditions: (i) vinylMgBr, cat. CuI, THF, ꢀ78 °C, 84%; (ii) MsCl,
Et3N, DCM, 0 °C to rt, 90% (crude); (iii) Ph3P, DPPA, DIAD, THF,
0 °C, 71%; (iv) NaN3, DMF, ultrasound, 50 °C, 95%; (v) O2, cat. PdCl2,
NMP/H2O, rt, 70%; (vi) H2, Pd(OH)2/C, MeOH, rt, 70%.
conditions7 or via activation of 14 and the substitution of the mesylate
15, yielding the dialkenylazide 16 as the key substrate in overall
yield 68% over five steps. By application of the previously optimized
WackerꢀTsuji transformation (entry 17, Table 3) the dialkeny-
lazide 16 was oxidized in good yield to the desired azidodiketone 5.
The latter was finally subjected to the one-pot three-step sequence
(azide reduction, amine condensation, and imine reduction)15 using
hydrogenation on Pearlman’s catalyst to afford the naturally
occurring alkaloid (ꢀ)-pinidinone (3) in high yield (Scheme 4).
Also in this case, our approach required only seven steps and gave
35% overall yield of 3 starting from 7.
Compound 8: colorless oil; [R]25 ꢀ1.97 (c 3.31, CH2Cl2); IR
D
(ATR) νmax 3344, 3078, 2957, 2929, 2871, 1641, 1458, 1124, 992,
908 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 5.80 (1H, dddd, J = 6.6, 6.7,
10.3, 17.1 Hz, H-8), 4.9ꢀ5.2 (2H, m, J = 10.3, 17.1 Hz, H-9), 3.6 (1H, m,
H-4), 2.05 (2H, m, H-7), 1.7 (1H, brs, exchangeable with D2O, OH),
1.3ꢀ1.6 (8H, m, H-2, H-3, H-5, H-6), 0.92 (3H, t, H-1); 13C NMR (75
MHz, CDCl3) 138.6 (CH, C-8), 114.4 (CH2, C-9), 71.4 (CH, C-4),
39.5 (CH3, C-5), 36.7 (CH2, C-3), 33.6 (CH2, C-7), 24.7 (CH2, C-6),
18.6 (CH2, C-2), 13.9 (CH3, C-1); LC-MS, m/z (M þ 1)þ 143; HRMS
m/z 142.1614 (calcd for C9H18O, 142.1358).
Commercially available (S)-epichlorohydrin (7) served as a com-
mon substrate for the efficient preparation of alkenyl azides 12
and/or 16. A novel application of highly regioselective copper-
free WackerꢀTsuji oxidation on 12 and/or 16 subsequently led
to the desired azidoketones 4 and/or 5 as key intermediates in
good yields. Final hydrogenation of 4 and/or 5 provided the
target piperidine alkaloids (þ)-dihydropinidine (1) (as HCl salt)
and/or (ꢀ)-pinidinone (3) in 54% and/or 33% overall yield over
seven steps. On the other hand, the cyclization of azidoketone 4
followed by highly diastereoselective reduction of imine 13
provided the target alkaloid (ꢀ)-epidihydropinidine (2), as the
hydrochloride, in 32% overall yield over seven steps. Our approach
features the protecting group free strategy and represents the
shortest total syntheses with highest overall yields for all three
naturally occurring alkaloids (1ꢀ3) to date. Finally, we have
performed the first single-crystal X-ray analysis of (ꢀ)-epidihy-
(S)-1-Iodohept-6-en-2-ol (9). Finely powdered NaOH (0.403 g,
10.1 mmol) was added to a solution of (S)-1-chlorohept-6-en-2-ol6
(0.500 g, 3.36 mmol) in dry Et2O (3.5 mL). The mixture was vigorously
stirred at rt for 4 h and filtered, and the solution dried over activated 4 Å
molecular sieves. After filtration of solids, anhydrous CuI (124 mg, 0.65
mmol) was added under Ar, and the mixture was cooled to ꢀ78 °C.
After 5 min stirring a solution of ethylmagnesium iodide (1.92 M in
Et2O, 3.5 mL, 6.72 mmol) was added dropwise over 20 min. After 4 h
stirring, a saturated aqueous solution of NH4Cl (20 mL) and H2O
(20 mL) was added at ꢀ20 °C. The cooling bath was removed, and the
mixture was stirred for 30 min and then extracted with Et2O (2 ꢁ
30 mL). Combined organic extracts were dried over anhydrous MgSO4,
filtered, and concentrated (120 mbar, 25 °C). The resulting yellowish oil
contained a mixture of iodohydrin 9 and alcohol 8 in a 26/1 ratio (based
on LC-MS analysis). An aliquot of the crude reaction mixture was
subjected to FLC (SiO2, EtOAc/toluene, 1/30) to obtain pure 9.
Compound 9: colorless oil; [R]20D ꢀ5.31 (c 1, MeOH); IR (ATR)
νmax 3356, 2931, 2858, 1639, 1456, 1435, 1414, 1180, 1076, 1053, 994,
910 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 5.79 (1H, ddt, J = 6.7, 10.2,
16.9 Hz, H-6), 4.9ꢀ5.1 (2H, m, H-7), 3.52 (1H, m, H-2), 3.30 (2H, ddd,
J = 5.2, 10.2, 17.0 Hz, H-1), 2.0ꢀ2.2 (3H, m, H-5, OH), 1.4ꢀ1.6 (4H, m,
H-3, H-4); 13C NMR (75 MHz, CDCl3) δ 138.4 (CH, C-6), 115.1
(CH2, C-7), 71.0 (CH, C-2), 36.1 (CH2, C-3), 33.6 (CH2, C-5), 25.0
(CH2, C-4), 16.7 (CH2, C-1); LC-MS tR 0.790 min, m/z (M þ 1) 241
(calcd for C7H13IO, 240.08).
dropinidine hydrochloride (2 HCl).
3
’ EXPERIMENTAL SECTION
General Experimental Procedures. All commercial reagents
were purchased from Alfa Aesar. All solvents were distilled before use:
diethyl ether, THF, and dioxane from Na/benzophenone, MeOH from
MeONa, and CH2Cl2 from P2O5. Thin-layer chromatography (TLC)
was performed on aluminum plates precoated with 0.2 mm silica gel 60
F254 (Merck). Flash column liquid chromatography (FLC) was per-
formed on silica gel [Kieselgel 60 (40ꢀ63 μm)]. Melting points were
determined on a B€uchi B-540 apparatus and are uncorrected. Optical
rotations were measured with a Perkin-Elmer 241 polarimeter with a
1.0 cm cell. Infrared (IR) spectra were recorded on a Nicolet 5700 FTIR
spectrometer as films on a diamond sampler (ATR). NMR spectra were
recorded on Varian VXR-300 (300 MHz) and Inova 600 (600 MHz)
spectrometers, respectively. Chemical shifts (δ) are quoted in ppm, and
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(S)-1-Bromohept-6-en-2-ol (10). Finely powdered NaOH (0.403
g, 10.1 mmol) was added to a solution of (S)-1-chlorohept-6-en-2-ol6
(0.500 g, 3.36 mmol) in dry Et2O (3.5 mL). The mixture was stirred at rt for
4 h and filtered, and the solution dried over activated 4 Å molecular sieves.
After filtration of solids, anhydrous CuI (124 mg, 0.65 mmol) was added
under Ar, and the mixture was cooled to ꢀ78 °C. After 5 min stirring a
solution of ethylmagnesium bromide (1.92 M in Et2O, 3.5 mL, 6.72 mmol)
was added dropwise over 20 min. After 4 h of stirring, a saturated aqueous
solution of NH4Cl (20 mL) and water (20 mL) was added at ꢀ20 °C. The
cooling bath was removed, and the mixture was left to stir for 30 min and
then extracted with Et2O (2 ꢁ 30 mL). Combined organic extracts were
dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The
residue contained bromohydrin 10 and alcohol 8 in a 1/1.2 ratio (based on
LC-MS analysis). An aliquot of the crude reaction mixture was subjected to
FLC (SiO2, ethyl acetate/toluene, 1/30) to obtain pure 10.
Compound 12: colorless oil; [R]25 þ1.37 (c 0.31, CH2Cl2); IR
D
(ATR) νmax 3078, 2958, 2934, 2872, 2095, 1641, 1458, 1442, 1273,
1250, 992, 911 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 5.83 (1H, dddd,
J = 6.7, 6.7, 10.3, 17.0 Hz, H-2), 5.00 (2H, dd, J = 10.3, 17.2 Hz, H-1), 3.24
(1H, m, H-6), 2.10 (2H, m, H-3), 1.30ꢀ1.54 (8H, m, H-4, H-5, H-7,
H-8), 0.94 (3H, t, H-9); 13C NMR (75 MHz, CDCl3) δ 138.2 (CH,
C-8), 114.8 (CH2, C-9), 62.7 (CH, C-4), 33.4 (CH2, C-7), 36.5, 33.7,
25.3, 13.3 (4 ꢁ CH2, C-2, C-3, C-5, C-6), 13.8 (CH3, C-1); HRMS m/z
167.1443 (calcd for C9H17N3, 167.1422).
(S)-6-Azidononan-2-one (4).PdCl2 (210 mg, 1.18 mmol, 0.2 equiv)
was added to the N-methylpyrrolidone/water (30 mL/3.5 mL) solvent
mixture, and the suspension was stirred under O2 atmosphere (balloon) until
PdCl2 had dissolved completely (approximately 1 h). Azide 12 (1.00 g, 5.99
mmol) was added, and the reaction mixture was stirred for 24 h at rt under O2
atmosphere while maintaining a slight gas pressure (approximately 1.25 bar).
Water (30 mL) and Et2O (30 mL) were added, and the mixture was stirred for
10 min. The aqueous layer was extracted with Et2O (2 ꢁ 20 mL), combined
organic phases were dried (Na2SO4), and the solvent was evaporated in vacuo.
The residue was purified by FLC (silica gel, Et2O) to give azidoketone 4
(0.930 g, 85%).
Compound 10: colorless oil; [R]25D ꢀ9.16 (c 1, MeOH); IR (ATR)
νmax 3362, 2930, 2860, 1640, 1457, 1435, 1421, 1224, 1082, 1055, 1027,
994, 911 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 5.80 (1H, ddt, J = 6.7,
10.2, 16.9 Hz, H-6), 4.9ꢀ5.1 (2H, m, H-7), 3.79 (1H, m, H-2), 3.46 (2H,
ddd, J = 5.2, 10.3, 17.4 Hz, H-1), 2.15 (1H, d, J = 5.1 Hz, exchangeable
with D2O, OH), 2.0ꢀ2.1 (2H, m, H-5), 1.4ꢀ1.7 (4H, m, H-3, H-4); 13
C
Compound 4: pale yellow oil; [R]25 þ3.19 (c 1.66, CH2Cl2); IR
D
NMR (75 MHz, CDCl3) 138.4 (CH, C-6), 115.1 (CH2, C-7), 71.1 (CH,
C-2), 40.7 (CH2, C-1), 34.6 (CH2, C-3), 33.6 (CH2, C-5), 25.0 (CH2,
C-4); LC-MS tR 0.537 min, m/z (Mþ þ 2) 195 (calcd for C7H13BrO,
193.08).
(ATR) νmax 2958, 2933, 2873, 2094, 1715, 1457, 1410, 1359, 1271,
1250, 1162, 745 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 3.34ꢀ3.16 (1H,
m, H-6), 2.47 (2H, t, H-3), 2.15 (3H, s, H-1), 1.60ꢀ1.76 (2H, m, H-4),
1.37ꢀ1.56 (6H, m, H-5, H-7, H-8), 0.94 (3H, t, H-9); 13C NMR (75
MHz, CDCl3) δ 208.4 (C, C-2), 62.6 (CH, C-6), 43.2 (CH2, C-3), 36.4,
33.7 (2 ꢁ CH2, C-5, C-7), 29.9 (CH3, C-1), 20.3 (CH2, C-4), 19.3
(CH2, C-8), 13.9 (CH3, C-9); HRMS m/z 183.1453 (calcd for
C9H17N3O, 183.1372).
(R)-Non-8-en-4-yl Methanesulfonate (11). A solution of 8
(1.300 g, 9.27 mmol) and triethylamine (1.031 g, 1.42 mL, 10.19 mmol)
in anhydrous CH2Cl2 (25 mL) was cooled to 0 °C, and methanesulfonyl
chloride (1.168 g, 0.79 mL, 10.19 mmol) was added dropwise over
5 min. The ice bath was removed, and the mixture was stirred for 2 h. The
mixture was diluted with CH2Cl2 (25 mL), washed with water (2 ꢁ
25 mL) and brine (20 mL), and dried over Na2SO4. Filtration,
evaporation of volatiles in vacuo, addition of Et2O (1 mL), and quick
filtration through short pad of silica gel (0.5 ꢁ 2 cm, eluting with Et2O)
afforded mesylate 11 (1.878 g, 92%).
(2R,6S)-2-Methyl-6-propylpiperidine Hydrochloride (1).
To a solution of azidoketone 4 (155 mg, 0.92 mmol) in anhydrous
MeOH (2 mL) was added 20% Pd(OH)2 on carbon (40 mg), and the
mixture was stirred at 25 °C under H2 atmosphere (balloon). After 2 h
the catalyst was removed by filtration, and a 1 M solution of HCl in Et2O
(1 mL) was added to the remaining solution. The solvent was removed
in vacuo, and remaining solid was washed with Et2O to give pure (þ)-
dihydropinidine hydrochloride 1 (146 mg, 91%).
Compound 11: pale yellow oil; [R]25D þ3.82 (c 2.21, CH2Cl2); IR
(ATR) νmax 2960, 2937, 2874, 1640, 1459, 1330, 1171, 897, 527 cmꢀ1
;
1H NMR (300 MHz, CDCl3) δ 5.79 (1H, dddd, J = 6.5, 6.6, 10.1, 17.1
Hz, H-8), 5.00 (2H, m, J = 10.0, 17.0 Hz, H-9), 4.78ꢀ4.67 (1H, m, H-4),
3.00 (3H, s, SO2CH3), 2.09 (2H, m, J = 6.7, 6.9, 7.1 Hz, H-7), 1.60ꢀ1.76
(4H, m, H-3, H-5), 1.38ꢀ1.6 (4H, m, H-2, H-6), 0.95 (3H, t, H-1); 13C
NMR (75 MHz, CDCl3) δ 138.0 (CH, C-8), 115.2 (CH2, C-9), 83.8
(CH, C-4), 38.9 (CH3, SO2CH3), 36.7, 34.8, 33.3 (3 ꢁ CH2, C-3, C-5,
C-7), 24.2, 18.3 (2 ꢁ CH2, C-2, C-6), 14.0 (CH3, C-1); HRMS m/z
220.0995 (calcd for C10H20O3S, 220.1133).
Compound 1: white solid; mp 226ꢀ228 °C; [R]25D þ14.47 (c 0.304,
96% EtOH), [(þ)-dihydropinidine: [R]20 þ14.2 (c 0.66, EtOH),4m
D
[R]20 þ12.4 (c 0.10, EtOH)4l]; IR (ATR) νmax 3392, 2935, 2865,
D
2835, 2805, 2744, 2719, 2543, 1460, 1448, 1380, 1013, 498, 488 cmꢀ1
;
1H NMR (300 MHz, CDCl3) δ 9.27ꢀ9.56, 9.18ꢀ8.89 (2H, 2m,
NþH2), 3.01ꢀ3.19, 2.85ꢀ3.00, (2H, 2m, H-2, H-6), 1.22ꢀ2.21 (10H,
m, H-3, H-4, H-5, H-7, H-8), 1.59 (3H, d, J = 6.2 Hz, H-1), 0.92 (3H, t,
J = 7.3 Hz, H-9); 13C NMR (75 MHz, CDCl3) δ 58.6, 54.7 (2 ꢁ CH,
C-2, C-6), 35.3, 30.9, 27.6, 23.0, 19.6 (5 ꢁ CH2, C-3, C-4, C-5, C-7,
C-8), 18.9 (CH3, C-1), 13.3 (CH3, C-9).
(R)-6-Azidonan-1-ene (12). From Alcohol 8. A solution of
alcohol 8 (0.910 g, 6.39 mmol) in anhydrous THF (50 mL) was cooled
to 0 °C, and triphenylphosphine (3.355 g, 12.80 mmol) was added at
once. After 5 min stirring DIAD (2.588 g, 2.52 mL, 12.80 mmol) and
subsequently DPPA (3.522 g, 2.76 mL, 12.80 mmol) were added, the ice
bath was removed, and the resulting mixture was stirred from 0 °C to rt
for 16 h. Volatiles were evaporated in vacuo, and the residue was subjected
to FLC (SiO2, hexane) to yield alkenyl azide 12 (0.854 g, 80%).
From Mesylate 11. To a solution of mesylate 11 (350 mg, 1.59 mmol)
in anhydrous dimethylacetamide (10 mL) was added anhydrous NaN3
(310 mg, 4.77 mmol) in one portion at rt. The resulting suspension was
sonicated in an ultrasonic bath for 3 h while the bath temperature
reached 60 °C. After cooling the mixture to rt, pentane (20 mL) and
water (15 mL) were added, and the aqueous layer was extracted with
pentane (2 ꢁ 15 mL). The combined organic layers were dried
(Na2SO4), and the solvent was carefully removed in vacuo (150 mbar,
25 °C) due to the high volatility of product. Pentane was added, and
filtration through a short pad of silica gel (0.5 ꢁ 2 cm, eluting with
pentane) afforded alkenyl azide 12 (253 mg, 95%).
(S)-6-Methyl-2-propyl-2,3,4,5-tetrahydropyridine (13). Tri-
phenylphosphine (polymer bound, 1290 mg, 3 mmol/g, 3.87 mmol)
was added to a stirred solution of azidoketone 4 (360 mg, 2.15 mmol) in
Et2O (6 mL), and the mixture was stirred at 40 °C in a sealed tube for 16
h. Solids were removed by filtration, and the yellow solution was
carefully concentrated in vacuo (100 mbar, 25 °C) to give cyclic imine
13 (269 mg, 90%).
Compound 13: yellow oil; [R]25 þ4.00 (c 0.15, CH2Cl2); IR
D
(ATR) νmax 2954, 2928, 2869, 1656, 1456, 1439, 1417, 1376, 1119,
722, 542 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 3.25 (1H, m, H-6), 2.06
(2H, m, H-3), 1.92 (3H, m, H-1), 1.06ꢀ1.78 (8H, m, H-4, H-5, H-7,
H-8), 0.94 (3H, t, H-9); 13C NMR (75 MHz, CDCl3) δ 167.2 (C, C-2),
57.4 (CH3, C-1), 39.9 (CH, C-6), 30.3, 27.6, 26.8, 19.4, 18.8 (5 ꢁ CH2,
C-3, C-4, C-5, C-7, C-8), 14.3 (CH3, C-9); HRMS m/z 139.1249 (calcd
for C9H17N, 139.1361).
(2S,6S)-2-Methyl-6-propylpiperidine Hydrochloride (2 HCl).
A solution of imine 13 (155 mg, 1.11 mmol) in anhydrous THF (10 mL)
3
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Journal of Natural Products
ARTICLE
was cooled to ꢀ78 °C, and a solution of Me3Al in hexane (2.3 M,
3.36 mL, 7.8 mmol) was added dropwise followed by addition of LiAlH4
powder (313 mg, 7.8 mmol). The mixture was stirred for 3 h while the
temperature of the cooling bath gradually rose to ꢀ20 °C. Then solid
C-8), 119.1 (CH2, C-1), 115.3 (CH2, C-9), 82.7 (CH, C-4), 39.21
(CH3, SO2CH3), 38.9 (CH2, C-3), 33.6 (CH2, C-5), 33.4 (CH2, C-7),
24.3 (CH2, C-6); HRMS m/z 218.0914 (calcd for C10H18O3S,
218.0977).
Na2SO4 10H2O (2 g) was added at ꢀ20 °C at once, and the mixture
(R)-4-Azidonona-1,8-diene (16). From Dienol 14. A solution
of dienol 14 (100 mg, 0.71 mmol) in anhydrous THF (8 mL) was cooled
to 0 °C, and triphenylphosphine (372 mg, 1.42 mmol) was added at
once. After 5 min stirring DIAD (287 mg, 280 μL, 1.42 mmol) and
subsequently DPPA (390 mg, 310 μL, 1.42 mmol) were added, the ice
bath was removed, and the resulting mixture was stirred from 0 °C to rt
for 16 h. Volatiles were evaporated in vacuo, and the residue was subjected
to FLC (SiO2, hexane) to yield azidodiene 16 (83 mg, 71%).
From Mesylate 15. Anhydrous NaN3 (276 mg, 4.26 mmol) was
added at rt to a solution of mesylate 15 (310 mg, 1.42 mmol) in
anhydrous dimethylacetamide (10 mL). The resulting suspension was
sonicated in an ultrasonic bath for 3 h while the bath temperature
reached 60 °C. After cooling the mixture to rt, pentane (15 mL) and
water (15 mL) were added, the solution was stirred for 10 min, the
phases were separated, and the aqueous layer was extracted with pentane
(2 ꢁ 15 mL). The combined organic layers were dried (Na2SO4), and
the solvent was carefully removed in vacuo (150 mbar, 25 °C) due to the
high volatility of the product. Pentane was added, and filtration through
a short pad of silica gel (0.5 ꢁ 2 cm, eluting with pentane) afforded
azidodiene 16 (222 mg, 95%).
3
was stirred for an additional 10 h. Dilution with Et2O (5 mL), subsequent
filtration, and evaporation in vacuo gave the crude product, which was
purified by FLC (silica gel, CH2CL2/MeOH/23% aq ammonia, 10/1/
1% w/w) to yield pure (ꢀ)-epidihydropinidine. Final addition of a HCl-
saturated Et2O solution (1.2 mL) afforded the corresponding hydro-
chloride 2 (125 mg, 64%). The subsequent crystallization from EtOH
afforded the single crystals suitable for X-ray analysis.
Compound 2: white solid; mp 156ꢀ158 °C; [R]25D ꢀ3.61 (c 0.166,
96% EtOH), [(ꢀ)-epidihydropinidine: [R]20D ꢀ5.1 (c 1.14, EtOH)4i];
IR (ATR) νmax 3392, 2954, 2942, 2845, 2820, 2710, 2545, 1591, 1464,
1435, 917, 730, 468 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 9.19ꢀ9.27
(2H, 2m, NþH2), 3.21ꢀ3.37, 3.46ꢀ3.62 (2H, 2m, H-2, H-6),
1.31ꢀ2.08 (10H, m, H-3, H-4, H-5, H-7, H-8), 1.49 (3H, d, J = 6.8
Hz, H-1), 0.95 (3H, t, J = 7.3 Hz, H-9); 13C NMR (75 MHz, CDCl3) δ
48.0, 51.6 (2 ꢁ CH, C-2, C-6), 32.9, 29.0, 26.4, 19.2, 17.5 (5 ꢁ CH2,
C-3, C-4, C-5, C-7, C-8), 16.9 (CH3, C-1), 13.9 (CH3, C-9); HRMS m/z
141.1491 (calcd for C9H20ClN, 141.1517).
(S)-Nona-1,8-dien-4-ol (14). Finely powdered NaOH (1.212 g,
30.30 mmol) was added to a solution of (S)-1-chlorohept-6-en-2-ol6
(1.501 g, 10.10 mmol) in anhydrous Et2O (10 mL). The mixture was
vigorously stirred at rt for 4 h, filtered, and dried over activated 4 Å
molecular sieves. After the filtration of solids, anhydrous CuI (384 mg,
2.02 mmol) was added under Ar, and the mixture was cooled to ꢀ78 °C.
After 5 min stirring a solution of vinylmagnesium bromide (1 M in THF,
20.2 mL, 20.20 mmol) was added dropwise over 20 min. After 4 h
stirring, a saturated aqueous solution of NH4Cl (40 mL) and water
(40 mL) was added at ꢀ20 °C. The cooling bath was removed, and the
mixture was left to stir for 30 min and then extracted with Et2O (2 ꢁ
50 mL). Combined organic extracts were dried over anhydrous MgSO4,
filtered, and concentrated in vacuo (120 mbar, 25 °C). The resulting
yellowish oil was subjected to short-path distillation (8 mbar, 100ꢀ120 °C),
yielding pure dienol 14 (1.189 g, 84%).
Compound 16: colorless oil; [R]25 þ14.97 (c 1.61, Et2O); IR
D
(ATR) νmax 3078, 2978, 2935, 2859, 2097, 1641, 1252, 991, 912 cmꢀ1
;
1H NMR (300 MHz, CDCl3) δ 5.70ꢀ5.88 (2H, m, H-2, H-8),
4.93ꢀ5.23 (4H, m, H-1, H-9), 3.28ꢀ3.40 (1H, m, H-4), 2.27ꢀ2.35
(2H, m, H-3), 2.03ꢀ2.13 (2H, m, H-7), 1.41ꢀ1.62 (2H, m, H-5, H-6);
13C NMR (75 MHz, CDCl3) δ 138.3 (CH, C-2), 134.0 (CH, C-8),
118.24 (CH2, C-1), 115.1 (CH2, C-9), 62.3 (CH, C-4), 38.9 (CH2,
C-3), 33.5 (CH2, C-5), 33.4 (CH2, C-7), 25.4 (CH2, C-6); HRMS m/z
165.1385 (calcd for C9H15N3, 165.1266).
(R)-4-Azidononane-2,8-dione (5). PdCl2 (64 mg, 0.36 mmol,
0.4 equiv) was added to the N-methylpyrrolidone/water (5 mL/0.5 mL)
solvent mixture, and the suspension was stirred under O2 atmosphere
(balloon) until PdCl2 had dissolved completely (approximately 1 h).
Azide 16 (150 mg, 0.91 mmol) was added, and the reaction mixture was
stirred for 24 h at rt under O2 atmosphere while maintaining a slight gas
pressure (approximately 1.25 bar). Water (10 mL) and Et2O (10 mL)
were added, and the mixture was stirred for 10 min. The aqueous layer
was extracted with Et2O (2 ꢁ 10 mL), the combined organic phases
were dried (Na2SO4), and the solvent was evaporated in vacuo. The
residue was purified by FLC (silica gel, Et2O) to give azidodiketone 5
(125 mg, 70%).
Compound 14: colorless oil; [R]25 ꢀ8.72 (c 0.321, CH2Cl2); IR
D
(ATR) νmax 3356, 3076, 2978, 2930, 2860, 1640, 1436, 1417, 992, 909,
1
633 cmꢀ1; H NMR (300 MHz, CDCl3) δ 5.76ꢀ5.93 (2H, m, H-2,
H-8), 4.94ꢀ5.21 (4H, m, H-1, H-9), 3.62ꢀ3.74 (1H, m, H-4),
2.28ꢀ2.42 (2H, m, H-3), 2.14 (2H, ddd, J = 21.5, 14.5, 7.1 Hz, H-7),
1.70 (1H, d, J = 3.2 Hz, exchangeable with D2O, OH), 1.42ꢀ1.63 (4H,
m, H-5, H-6); 13C NMR (75 MHz, CDCl3) δ 138.6 (CH, C-2), 134.7
(CH, C-8), 118.1 (CH2, C-1), 114.5 (CH2, C-9), 70.4 (CH, C-4), 41.9
(CH2, C-3), 36.1 (CH2, C-5), 33.6 (CH2, C-7), 24.9 (CH2, C-6);
HRMS m/z 140.1457 (calcd for C9H16O, 140.1201).
Compound 5: pale yellow oil; [R]25D ꢀ10.02 (c 0.161, CH2Cl2); IR
(ATR) νmax 2929, 2100, 1712, 1417, 1360, 1256, 1165, 966 cmꢀ1; 1H
NMR (300 MHz, CDCl3) δ 3.86 (1H, ddd, J = 12.9, 7.8, 5.2 Hz, H-4),
2.76ꢀ2.52 (1H, m, H-3), 2.46 (1H, dd, J = 17.8, 10.6 Hz, H-7), 2.19
(3H, s, H-9), 2.15 (3H, s, H-1), 1.60ꢀ1.79 (2H, m, H-6), 1.45ꢀ1.58 (m,
2H, H-5); 13C NMR (75 MHz, CDCl3) δ 205.8, 208.3 (2 ꢁ CH, C-2,
C-8), 57.9 (CH, C-4), 47.9 (CH2, C-3), 43.0 (CH2, C-7), 33.8 (CH2,
C-5), 30.7 (CH3, C-9), 30.1 (CH3, C-1), 20.0 (CH2, C-6); HRMS m/z
197.1153 (calcd for C9H15N3O2, 197.1164).
(S)-Nona-1,8-dien-4-yl Methanesulfonate (15). A solution of
dienol 14 (300 mg, 2.14 mmol) and triethylamine (238 mg, 327 μL, 2.35
mmol) in anhydrous CH2Cl2 (5 mL) was cooled to 0 °C, and meth-
anesulfonyl chloride (267 mg, 180 μL, 2.35 mmol) was added dropwise
over 5 min. The ice bath was removed, and the mixture was stirred for
3 h. After diluting with CH2Cl2 (25 mL) the solution was washed with
water (2 ꢁ 15 mL) and brine (15 mL) and dried over Na2SO4. Filtration,
evaporation of volatiles in vacuo, addition of Et2O (1 mL), and quick
filtration through a short pad of silica gel (0.5 ꢁ 2 cm, eluting with Et2O)
afforded 15 (420 mg, 90%).
1-((2R,6R)-6-Methylpiperidin-2-yl)propan-2-one (3). To a
solution of azidodiketone 5 (30 mg, 0.15 mmol) in anhydrous MeOH
(1.5 mL) was added 20% Pd(OH)2 on carbon (25 mg), and the mixture
was stirred at 25 °C under H2 atmosphere (balloon) for 4 h. The
reaction mixture was filtered and concentrated in vacuo. The residue was
purified by FLC (silica gel, CH2Cl2/MeOH, 10/1) to obtain pure (ꢀ)-
pinidinone (3) (16 mg, 70%).
Compound 15: pale yellow oil; [R]25D ꢀ18.5 (c 0.26, CH2Cl2); IR
1
(ATR) νmax 3078, 2941, 1641, 1332, 1171, 900, 527 cmꢀ1; H NMR
(300 MHz, CDCl3) δ 5.70ꢀ5.88 (2H, m, H-2, H-8), 5.18 (2H, dd, J =
10.5, 6.6 Hz, H-1), 5.02 (2H, ddd, J = 11.5, 6.7, 1.7 Hz, H-9), 4.75 (1H, p,
J = 6.0 Hz, H-4), 3.00 (1H, s, SO2CH3), 2.48 (2H, dd, J = 9.8, 3.7 Hz,
H-3), 2.04ꢀ2.15 (2H, m, H-7), 1.41ꢀ1.60, 1.64ꢀ1.78 (2 ꢁ 2H, 2m,
H-5, H-6); 13C NMR (75 MHz, CDCl3) δ 138.1 (CH, C-2), 132.6 (CH,
Compound 3: pale yellow oil; [R]25 ꢀ25.0 (c 0.158, CH2Cl2),
D
[(ꢀ)-pinidinone: [R]25D ꢀ4.0 (c 3.5, MeOH),1b [R]25D ꢀ41.0 (c 0.9,
EtOH),4g cf. (þ)-pinidinone: [R]23 þ25.3 (c 0.4, MeOH)17]; IR
D
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dx.doi.org/10.1021/np100852p |J. Nat. Prod. 2011, 74, 803–808

Journal of Natural Products
ARTICLE
(ATR) νmax 3396, 3307, 2926, 2856, 1705, 1437, 1373, 1360, 1158,
1111 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 3.01 (1H, dtd, J = 8.9, 6.3,
2.6 Hz, H-4), 2.74ꢀ2.63 (1H, m, H-8), 2.53 (2H, d, J = 6.3, H-3), 2.14
(3H, s, H-1), 1.90ꢀ1.73 (1H, brs, NH), 1.83ꢀ1.27 (6H, m, H-5, H-6,
H-7), 1.04 (3H, d, J = 6.3 Hz, H-9); 13C NMR (75 MHz, CDCl3) δ
208.1 (C, C-2), 52.5, 52.4 (2 ꢁ CH, C-4, C-8), 52.7 (CH2, C-3), 33.2,
31.0 (2 ꢁ CH2, C-5, C-7), 30.6 (CH3, C-1), 24.3 (CH2, C-6), 22.3
(CH3, C-9); HRMS m/z 155.1172 (calcd for C9H17NO, 155.1310).
Tetrahedron: Asymmetry 2006, 17, 1074–1080. (m) Gonzꢁalez-Gꢁomez,
J. C.; Foubelo, F.; Yus, M. Synlett 2008, 2777–2780.
(5) Passarella, D.; Riva, S.; Grieco, G.; Cavallo, F.; Checa, B.; Arioli,
F.; Riva, E.; Comi, D.; Danieli, B. Tetrahedron: Asymmetry 2009,
20, 192–197.
(6) Kubizna, P.; Spꢁanik, I.; Koꢀzíꢀsek, J.; Szolcsꢁanyi, P. Tetrahedron
2010, 66, 2351–2355.
(7) (a) Taber, D. F.; Deker, P. B. J. Org. Chem. 1988, 53, 2968–2971.
(b) Dinh, T. Q.; Du, X.; Smith, Ch. D.; Armstrong, R. W. J. Org. Chem.
1997, 62, 6773–6783.
ꢀ
(8) Selected reviews on WackerꢀTsuji oxidation: (a) Smidt, J.; Sieber,
R. Angew. Chem., Int. Ed. Engl. 1962, 1, 80–88. (b) Tsuji, J. Synthesis
1984, 369–383. (c) Hegedus, L. S. Transition Metals in the Synthesis of
Complex Organic Molecule; University Science Books, 1994; pp
199ꢀ208. (d) Feringa, B. L. Wacker Oxidation. In Transition Metals in
Organic Synthesis; Beller, M.; Bolm, C., Eds.; Wiley-VCH, 1998; Vol. 2,
pp 307ꢀ315. (e) Hintermann, L. Wacker-Type Oxidations. In Transi-
tion Metals in Organic Synthesis, 2nd ed.; Beller, M.; Bolm, C., Eds.;
Wiley-VCH, 2004; Vol. 2, pp 379ꢀ388. (f) Cornell, C. N.; Sigman,
M. S. Inorg. Chem. 2007, 46, 1903–1909. (g) Li, J. J. Wacker-Tsuji
Oxidation. In Name Reactions for Functional Group Transformations; Li,
J.; Corey, E. J., Eds.; John Wiley & Sons, 2007; pp 309ꢀ326.
(9) While the WackerꢀTsuji oxidation of azidoalkenes is previously
unknown, analogous transformation of corresponding alkenyl amines
was described. However, the terminal double bond of such substrates
tends to isomerize under the applied catalytic conditions, resulting in a
complex mixture of amino ketones and/or cyclic imines as final products.
Pugin, B.; Venanzi, M. L. J. Am. Chem. Soc. 1983, 105, 6877–6881.
(10) (a) Tsuji, J.; Nagashima, H.; Nemoto, H. Org. Synth., Coll. Vol. 7
1990, 137ꢀ139. (b) Cornell, C. N.; Sigman, M. S. Org. Lett. 2006,
8, 4117–4120. (c) Kulkarni, M. G.; Bagale, S. M.; Shinde, M. P.;
Gaikwad, D. D.; Borhade, A. S.; Dhondge, A. P.; Chavhan, S. W.; Shaikh,
Y. B.; Ningdale, V. B.; Desai, M. P.; Birhade, D. R. Tetrahedron Lett.
2009, 50, 2893–2894. (d) Wang, G.-W.; Yuan, T.-T. J. Org. Chem. 2010,
75, 476–479.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra of
S
b
compounds 4, 5, 8, 11, 12, and 14ꢀ16; X-ray structure refine-
ment details of (ꢀ)-epidihydropinidine hydrochloride (2 HCl);
3
screening results of the epoxide 6 ring-opening (Table 1),
screening results of the WackerꢀTsuji oxidation of alkenylazide
12 (Table 2), and screening results of the diastereoselective
reduction of cyclic imine 13 (Table 3). This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Tel: þ421 2 59325162. Fax: þ421 2 52495381. E-mail: peter.
szolcsanyi@stuba.sk.
’ ACKNOWLEDGMENT
We thank Prof. Dr. T. Gracza and Dr. F. Povaꢀzanec for helpful
discussions. We are grateful to Dr. N. Prꢁonayovꢁa for NMR
spectra and to Dr. P. Zꢁalupskꢁy for proofreading the manuscript.
We appreciate the chemicals kindly provided by the company
(11) (a) Mitsudome, T.; Umetani, T.; Nosaka, N.; Mori, K.; Mizugaki,
T.; Ebitani, K.; Kaneda, K. Angew. Chem., Int. Ed. 2006, 45, 481–485. (b)
Mitsudome, T.; Mizumoto, K.; Mizugaki, T.; Jitsukawa, K.; Kaneda, K.
Angew. Chem., Int. Ed. 2010, 49, 1238–1240.
ꢁ
VUP a.s., Prievidza, Slovakia. This work was supported by the
Science and Technology Assistance Agency under contract nos.
APVV-0164-07 and VMSP-P-0130-09 and the Scientific Grant
Agency under contract nos. VEGA 1/0340/10 and 1/0817/08.
We also thank Structural Funds, Interreg IIIA, for financial
support in purchasing the diffractometer.
(12) Langer,P.;Freifeld,I.;Shojaei,H.Chem. Commun. 2003, 3044–3045.
(13) (a) Matsumura, Y.; Maruoka, K.; Yamamoto, H. Tetrahedron
Lett. 1982, 23, 1929–1932. (b) Maruoka, K.; Miyazaki, T.; Ando, M.;
Matsumura, Y.; Sakane, S.; Hattori, K.; Yamamoto, H. J. Am. Chem. Soc.
1983, 105, 2831–2843. (c) Yamaguchi, R.; Nakazono, Y.; Matsuki, T.;
Hata, E.; Kawanisi, M. Bull. Chem. Soc. Jpn. 1987, 60, 215–222.
(14) For X-ray measurement details and structure determination of
2 see Supporting Information. Crystallographic data (excluding struc-
ture factors) for the structure reported in this paper have been deposited
with the Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-800711. Copies of the data can be obtained free
of charge on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK [fax: (internat.) þ 44 1223/336-033; e-mail: deposit@ccdc.
cam.ac.uk].
’ REFERENCES
(1) (a) Schneider, M. J.; Montali, J. A.; Hazen, D.; Stanton, C. E. J.
Nat. Prod. 1991, 54, 905–909. (b) Tawara, J. N.; Blokhin, A.; Foderaro,
T. A.; Stermitz, F. R.; Hope, H. J. Org. Chem. 1993, 58, 4813–4818.
(2) (a) Brown, W. V.; Moore, B. P. Aust. J. Chem. 1982, 35, 1255–1261.
(b)Attygalle, A. B.;Xu, S.-Ch.;McCormick, K. D.;Meinwald, J.Tetrahedron
1993, 49, 9333–9342.
(3) Shtykova, L.; Masuda, M.; Eriksson, C.; Sj€odin, K.; Marling, E.;
Schlyter, F.; Nydꢁen, M. Prog. Org. Coat. 2008, 63, 160–166.
(15) Enders, D.; Jegelka, U. Synlett 1992, 999–1002.
(16) Kumar, P.; Gupta, P. Synlett 2009, 1367–1382.
(17) Munchof, M. J.; Meyers, A. I. J. Am. Chem. Soc. 1995,
117, 5399–5400.
(4) (a) Husson, H.-P. J. Nat. Prod. 1985, 48, 894–906. (b) Lu, Z.-H.;
Zhou, W.-S. J. Chem. Soc., Perkin Trans. 1 1993, 593–596. (c) Ch^enevert,
R.; Dickman, M. J. Org. Chem. 1996, 61, 3332–3341. (d) Davis, F. A.;
Szewczyk, J. M. Tetrahedron Lett. 1998, 39, 5951–5954. (e) Yamauchi,
T.; Fujikura, H.; Higashiyama, K.; Takahashi, H.; Ohmiya, S. J. Chem.
Soc., Perkin Trans. 1 1999, 2791–2794. (f) Ciblat, S.; Besse, P.;
Papastergiou, V.; Veschambre, H.; Canet, J.-L.; Troin, Y. Tetrahedron:
Asymmetry 2000, 11, 2221–2229. (g) Frꢁeville, S.; Delbecq, P.; Thuy,
V. M.; Petit, H.; Cꢁelꢁerier, J. P.; Lhommet, G. Tetrahedron Lett. 2001,
42, 4609–4611. (h) Amat, M.; Llor, N.; Hidalgo, J.; Escolano, C.; Bosch,
J. J. Org. Chem. 2003, 68, 1919–1928. (i) Yamauchi, S.; Mori, S.; Hirai,
Y.; Kinoshita, Y. Biosci. Biotechnol. Biochem. 2004, 68, 676–684. (j)
Kranke, B.; Hebrault, D.; Schultz-Kukula, M.; Kunz, H. Synlett
2004, 671–674. (k) Kranke, B.; Kunz, H. Can. J. Chem. 2006,
84, 625–641. (l) Eriksson, C.; Sj€odin, K.; Schlyter, F.; H€ogberg, H.-E.
808
dx.doi.org/10.1021/np100852p |J. Nat. Prod. 2011, 74, 803–808