Synthesis of 2,6-disubstituted piperidine alkaloids from ladybird beetles Calvia 10-guttata and Calvia 14-guttata

Article abstract of DOI:10.1016/j.tet.2010.01.106

Optically pure (+)-calvine, (+)-2-epicalvine, (2S,6S)-(6-pentylpiperidin-2-yl)acetic acid methyl ester and (2R,6S)-(6-pentylpiperidin-2-yl)acetic acid methyl ester, four piperidine alkaloids isolated from ladybird beetles of the genus Calvia (Coccinellidae), were synthesised from a common precursor using cyclisative Pd(II)/Cu(II)-catalysed carboamination-(methoxy)carbonylation tandem reaction of alkenylamines as a key step. The first single-crystal X-ray analysis of (+)-calvine confirmed its proposed absolute configuration to be (2S,6S) corresponding to that of natural product.

Full text of DOI:10.1016/j.tet.2010.01.106

Tetrahedron 66 (2010) 2351–2355
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Tetrahedron
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Synthesis of 2,6-disubstituted piperidine alkaloids from ladybird beetles Calvia
10-guttata and Calvia 14-guttata
a
b
c
a,
*
ˇ
ꢀ
´
´ˇ
´
Peter Kubizna , Ivan Spanik , Jozef Kozısek , Peter Szolcsanyi
a Department of Organic Chemistry, Slovak University of Technology, Radlinske´ho 9, SK-812 37 Bratislava, Slovakia
c Department of Analytical Chemistry, Slovak University of Technology, Radlinske´ho 9, SK-812 37 Bratislava, Slovakia
b
´
Department of Physical Chemistry, Slovak University of Technology, Radlinskeho 9, SK-812 37 Bratislava, Slovakia
a r t i c l e i n f o
a b s t r a c t
Article history:
Optically pure (þ)-calvine, (þ)-2-epicalvine, (2S,6S)-(6-pentylpiperidin-2-yl)acetic acid methyl ester and
(2R,6S)-(6-pentylpiperidin-2-yl)acetic acid methyl ester, four piperidine alkaloids isolated from ladybird
beetles of the genus Calvia (Coccinellidae), were synthesised from a common precursor using cyclisative
Pd(II)/Cu(II)-catalysed carboamination-(methoxy)carbonylation tandem reaction of alkenylamines as
a key step. The first single-crystal X-ray analysis of (þ)-calvine confirmed its proposed absolute con-
figuration to be (2S,6S) corresponding to that of natural product.
Received 27 October 2009
Received in revised form 18 December 2009
Accepted 27 January 2010
Available online 2 February 2010
Keywords:
Palladium
Ó 2010 Elsevier Ltd. All rights reserved.
Carbonylation
Amino alcohols
Heterogeneous catalysis
Natural products
1. Introduction
1 Calvine (cis)
Insects use various toxic molecules as chemical weapons to
discourage potential predators.1 It is known that coccinellid beetles
often release small droplets of yellow hemolymph at their knee
joints, when molested or disturbed (so called ‘reflex bleeding’).2 As
a consequence, these insects are only rarely exploited as a food
source by other organisms, which is attributed to the presence of
deterrent compounds in their blood.3 Among them, piperidine al-
kaloids represent a prominent class of such natural products dis-
playing defensive properties.4
Recently, four 2,6-disubstituted piperidine alkaloids (þ)-calvine
1, (þ)-2-epicalvine 2, (2S,6S)-(6-pentylpiperidin-2-yl)acetic acid
methyl ester 3 and (2R,6S)-(6-pentylpiperidin-2-yl)acetic acid
methyl ester 4, were isolated from two species of ladybird beetles
Calvia 10-guttata and Calvia 14-guttata (Coccinellidae)5 (Fig. 1). To
the best of our knowledge, no biological activity of these alkaloids
has been determined so far.
N
2 Epicalvine (trans)
O
O
3 (cis)
4 (trans)
CO2Me
N
H
Figure 1. Piperidine alkaloids isolated from Calvia ladybird beetles.
synthesis.6 Since then, only one other preparation of 1 has
appeared7 along with two formal syntheses.8 All but one approach
known so far used alkaloids 3 and/or 4 as key intermediates for
the (formal) syntheses of 1 and/or 2.5,6,8 Recently, we have com-
municated racemic syntheses of calvine and epicalvine.9 In this
full account, we wish to report short and efficient stereoselective
total syntheses of all four naturally occurring piperidine alkaloids
1–4. Our approach relies on diastereoselective intramolecular
Pd(II)/Cu(II)-catalysed tandem aminocyclisation–carbonylation
reaction of alkenylamines 5 and/or 6 as a key step, while both
these substrates were prepared from the common precursor 7
(Scheme 1).
The structure and relative configuration of 1–4 was established
on the basis of NMR spectroscopy and HRMS studies and sub-
sequently confirmed via racemic total synthesis.5 The absolute
configuration was determined by enantioselective total
* Corresponding author.
´
E-mail address: peter.szolcsanyi@stuba.sk (P. Szolcsanyi).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.106

2352
P. Kubizna et al. / Tetrahedron 66 (2010) 2351–2355
Thus, we had to reverse the order of double-ring opening
transformation and conducted the ‘alkenylation first–alkylation
second’ sequence on the (S)-epichlorohydrin 11. This substrate was
initially opened with butenylmagnesium bromide and the resulting
chlorohydrin 12 subsequently closed under basic conditions to the
unsaturated epoxide 13.13 Gratifyingly, the following addition of
excess butyllithium catalysed by copper(I) iodide afforded the de-
sired alcohol 714 in 70% combined yield over three steps. Activation
of the hydroxyl group of 7 using TsCl gave tosylate 14, which was
treated either with excess ethanolamine to yield the unsaturated
amino alcohol 515 or with excess benzylamine to provide the cor-
responding alkenylamine 6 (Scheme 4).
1-4
H11C5
NH
R
H11C5
OH
5 R=(CH2)2OH
6 R=Bn
7
Scheme 1. Retrosynthetic analysis of alkaloids 1–4.
2. Results and discussion
Initial preparation of both substrates 5 and 6 needed for the key
Pd(II)-catalysed cyclisation started from the commercially available
(R)-epichlorohydrin 8 (Scheme 2). Our intention was to transform it
to (R)-undec-1-en-6-ol 7 via double-ring opening of the epoxide
using an ‘alkylation first–alkenylation second’ sequence. However,
such strategy surprisingly failed to provide the desired alcohol 7 in
a reasonable yield even after extensive experimentation. While the
CuCN-catalysed ring opening of 8 with butylmagnesium bromide
and subsequent base–promoted ring closure10 of crude chlorohy-
drin afforded the desired (R)-pentyloxirane 97 in 76% yield over two
steps, the following and analogous opening of the epoxide 9 with
butenylmagnesium bromide11 was unsatisfactory. It gave at best
a mixture of the undesired bromohydrin 10 and the desired alcohol
7 (in ratios ranging from 3:1 (Et2O) to 1:1 (THF)) or complex re-
action mixtures only (Scheme 2).
OH
O
(i)
Cl
Cl
86%
11
12
O
(ii)
(iii)
96%
84%
13
Cl
C4H7MgBr
Ref. 7
76%
O
O
H11C5
cat. CuCN
(v) or
(vi)
THF, -78°C
8
9
H11C5
OR
H11C5
NH
R
5 (R=(CH2)2OH)
6 (R=Bn)
Scheme 4. Optimised preparation of substrates 5 and 6. Reagents and conditions: (i)
1.5 equiv butenylmagnesium bromide, 0.15 equiv CuI, THF, ꢀ50 ꢁC to rt, 16 h, 86%; (ii)
11 equiv NaOH, THF/H2O (1/1), rt, six days, 96%; (iii) 2.2 equiv butyllithium, 0.2 equiv
CuI, Et2O, ꢀ78 ꢁC to rt, 2.5 h, 84%; (iv) 1.2 equiv TsCl, 19 equiv pyridine, CH2Cl2, 0 ꢁC to
rt, 40 h, 73%; (v) 15 equiv ethanolamine, THF, reflux, 40 h, 91%; (vi) 3 equiv benzyl-
amine, THF, reflux, eight days, 81%.
7 (R=H)
(iv)
73%
OH
14 (R=Ts)
+
(1:1)
Br
H11C5
H11C5
OH
10
7
Scheme 2. Initially attempted preparation of alcohol 7.
We speculated, that the formation of the undesired bromohy-
drin 10 from the epoxide 9 is due to the competitive attack of the
Brꢀ nucleophile from in situ formed HBr (and/or MgBr2). This may
With both substrates in hand, we subjected them to the final
key transformation. Under optimal reaction conditions,16 the
Pd(II)/Cu(II)-catalysed aminocyclisation–lactonisation17 of 5 di-
rectly provided the desired target alkaloids (þ)-calvine 1 and
(þ)-2-epicalvine 2 in a diastereoselective fashion depending
upon the applied catalytic conditions. Thus, using PdCl2 as
a catalyst and excess CuCl2 as reoxidant we obtained 1 as a major
product in a diastereomeric ratio of 2.2:1 and 18% yield over six
steps.9 On the other hand, the combination of molecular oxygen
(1 atm) with catalytic copper(II) chloride as reoxidant system
afforded the diastereomeric (þ)-2-epicalvine 2 as a major prod-
uct in a ratio of 7:3 resulting in the overall yield of 17% in six
steps (Scheme 5).
come from the b-hydride elimination of butenylmagnesium bro-
mide generating 1,3-butadiene followed by reductive elimination
of the magnesium hydride complex. This hypothesis is supported
by the experimental observation that grey precipitate (possibly
metallic Mg) is gradually deposited on the glassware during the
course of reaction (Scheme 3).12
β-hydride
elimination
+
Br Mg
reductive
elimination
Mg0
H
H
Br Mg
H
+ HBr
Cu+
O
H11C5
(i) or
(ii)
C4H7MgBr
cat. CuCN
+
7
H11C5
N
H11C5
NH
H11C5
N
BrMg
OH
O
O
O
vs.
Mg2+
O
H11C5
vs.
O
O
(+)-Calvine 1
5
(+)-2-Epicalvine 2
HBr
9
H11C5
10
(MgBr2)
Scheme 5. Finalisation and the key step of the total synthesis of (þ)-calvine 1 and (þ)-2-
epicalvine 2. Reagents and conditions: (i) CO (balloon), 0.1 equiv PdCl2, 2 equiv CuCl2,
2 equiv AcONa, dioxane, 40 ꢁC, 7 h, 55% (1/2¼2.2/1); (ii) CO/O2 (ca.1:1, balloon), 0.1 equiv
PdCl2, 0.2 equiv CuCl2, 3 Å molecular sieves, dioxane, 50 ꢁC, 45 h, 53% (1/2¼3/7).
Br-
Scheme 3. Proposal for the formation of undesired bromohydrin 10.

P. Kubizna et al. / Tetrahedron 66 (2010) 2351–2355
2353
So far, the exact structure of the true catalytic species involved in
3. Conclusion
our Pd(II)/Cu(II)-catalysed aminocyclisation–lactonisation of 5 re-
mains unclear. However, due to the metal composition of optimal
reaction conditions it inevitably should be of a heterobimetallic
nature. Such Pd/Cu-complexes in analogous transformations in-
volving both palladium and copper salts have been proposed and/
or isolated and characterised.18
After the convenient FLC separation of both diastereomers 1 and
2, the enantiomerically pure (þ)-calvine 1 turned out to be a crys-
talline compound.19 The first single-crystal X-ray analysis of 120
confirmed its proposed absolute configuration to be (2S,6S) corre-
sponding to that of the natural product. Moreover, it can be seen
that both piperidine and lactone rings adopt chair-like conforma-
tion in the solid state (Fig. 2).
We synthesised four optically pure alkaloids (þ)-calvine 1,
(þ)-2-epicalvine 2, (2S,6S)-(6-pentylpiperidin-2-yl)acetic acid
methyl ester 3 and (2R,6S)-(6-pentylpiperidin-2-yl)acetic acid
methyl ester 4 using intramolecular Pd(II)/Cu(II)-catalysed ami-
nocyclisation–carbonylation tandem reaction as a key step. Both
necessary alkenylamines 5 and 6 required for these crucial
transformations were efficiently prepared in five steps starting
from the common substrate (S)-epichlorohydrin in 46% and 41%
overall yields, respectively. By tuning the reaction parameters we
were able to direct the stereoselectivity of the respective Pd(II)/
Cu(II)-catalysed cyclisations in order to obtain either di-
astereomer of target natural compounds 1–4. Thus, using cata-
lytic PdCl2 and excess CuCl2 we obtained 2,6-cis-configured
alkaloid 1 as a major product in 18% overall yield in six steps. On
the other hand, the combination of molecular oxygen with cat-
alytic PdCl2 and CuCl2 afforded both 2,6-trans-configured alka-
loids 2 and 4 as main adducts in 17% and 13% overall yields.
Finally, we have performed the first single-crystal X-ray analysis
of (þ)-calvine 1 and confirmed its proposed absolute configura-
tion to be (2S,6S) corresponding to that of the isolated natural
product.
4. Experimental section
4.1. General
All solvents were distilled before use: diethylether, THF and
dioxane from Na/benzophenone, MeOH from MeONa and CH2Cl2
from P2O5. Thin layer chromatography (TLC) was performed on
aluminium plates pre-coated with 0.2 mm silica gel 60 F254
(Merck). Flash column liquid chromatography (FLC) was performed
on Kieselgel 60 (40–63
mm). GC was performed on HP-5 column
(30 m, ID 0.25 mm, film thickness 0.12
m
m) equipped with split/
splitless injector and FID detector. Optical rotations were measured
with a Perkin–Elmer 241 polarimeter with a 1.000 cm cell at
l
¼589 nm. Elemental analyses were performed by the Microana-
Figure 2. An ORTEP view of the crystal structure of natural (þ)-calvine 1.
lytical Service of Slovak Academy of Sciences. Infrared (IR) spectra
were recorded on a Nicolet 5700 FTIR spectrometer. X-ray analysis
was performed on Oxford Diffraction GEMINI R diffractometer.
In order to finalise the total synthesis of the other two target
alkaloids 3 and 4, we subjected alkenylamine 6 to the Pd(II)/Cu(II)-
catalysed aminocyclisation–methoxycarbonylation sequence.17e,21
As the cyclisative preparation of trans-2,6-disubstituted piperi-
¨
Melting point was determined on BUchi B-540 apparatus. NMR
spectra were recorded on Varian VXR-300 (300 MHz) and Inova
600 (600 MHz) spectrometers, respectively. Chemical shifts (d) are
dines bearing an ester group in the b
-position is more challenging22
quoted in parts per million and the residual protic solvent was used
as internal reference. The COSYand NOESY techniques were used in
assignment of 1H–1H relationships and the determination of rela-
tive configuration. The multiplicities of carbons were assigned from
a broadband decoupled analysis used in conjunction with APT. The
HMBC technique was used throughout for the assignment of the
1H–13C relationships.
in comparison to their cis-counterparts, we have focused particu-
larly on the conditions favouring the formation of the former one.23
Thus, exposure of 6 to catalytic PdCl2 and CuCl2 in MeOH under the
CO/O2 atmosphere afforded an inseparable mixture of the desired
piperidines 15/16 in the 68% combined yield. The final catalytic
debenzylation of methylesters 15/16 on Pearlman’s catalyst pro-
vided easily separable target alkaloids 3 and 4 in 81% combined
yield and in a ratio of 1:3 in favour of the 2,6-trans-configured pi-
peridine 424 (Scheme 6).
4.1.1. (S)-1-Chlorohept-6-en-2-ol (12). To a cooled freshly prepared
THF solution (0.96 M) of butenylmagnesium bromide (1.5 equiv)
[made of Mg turnings (2.339 g, 96.23 mmol) and butenyl bromide
(13.392 g, 10.07 mL, 96.23 mmol) in dry THF (100 mL)] was added
anhydrous CuI (1.833 g, 0.15 equiv) at ꢀ50 ꢁC in one portion under
Ar. After 5 min stirring, while the colour of the mixture changed
from grey to deep turqoise, the solution of (S)-epichlorohydrin 11
(5.936 g, 5.03 mL, 64.15 mmol) in dry THF (50 mL) was added
dropwise via syringe at ꢀ50 ꢁC over 20 min under Ar. The resulting
deep-blue mixture was left to stir for 16 h while the temperature
gradually rose to 25 ꢁC over the indicated time. The reaction was
then quenched by addition of satd aq NH4Cl solution (350 mL) and
water (200 mL). After 30 min stirring, the mixture was extracted
with Et2O (2ꢂ150 mL), combined organic extracts were dried over
(i)
+
CO2Me
CO2Me
H11C5
N
H11C5
N
H11C5
NH
Bn
Bn
16
Bn
15
6
(ii)
15
16
+
+
CO2Me
CO2Me
H11C5
N
H
H11C5
N
H
4
3
(1 : 3)
Scheme 6. Key step and finalisation of the total synthesis of 3 and 4. Reagents and con-
ditions: (i) CO/O2 (ca. 1:1, balloon), 0.1 equiv PdCl2, 0.2 equiv CuCl2, 3 Å molecular sieves,
MeOH, rt, 18 h, 68%; (ii) H2 (balloon), 0.2 equiv Pd(OH)2, MeOH, rt, 24 h, 81% (3/4¼1/3).

2354
P. Kubizna et al. / Tetrahedron 66 (2010) 2351–2355
anhydrous Na2SO4, filtered and concentrated in vacuo. The result-
ing brownish oil (9.54 g) was subjected to FLC (390 g SiO2,
6ꢂ28 cm, ethyl acetate/hexanes¼1/5) yielding pure chlorohydrin
(410 g SiO2, 6ꢂ30 cm, ethyl acetate/hexanes¼1/4) yielding pure
tosylate 14 (8.508 g, 73%) as a pale-yellow oil.
15
Compound 14: Rf¼0.59 (ethyl acetate/hexanes¼1/4); [
a
]
D
þ4.3
12 (8.196 g, 86%) as a pale-yellow oil.
(c 1, CH2Cl2). C18H28O3S (324.48): calcd C 66.63, H 8.70, O 14.79, S
9.88; found: C 66.70, H 8.44, O 14.92, S 10.06%. All other physico-
chemical data are identical with those obtained for its racemate,
see Ref. 9.
15
Compound 12: Rf¼0.35 (ethyl acetate/hexanes¼1/6); [
a]
þ2.4
D
(c 0.502, CH2Cl2); IR (film):
n
/cmꢀ1¼737, 911, 994, 1038, 1064, 1433,
1640, 2861, 2932, 3361 (br); 1H NMR (300 MHz, CDCl3): 1.40–1.64
(m, 4H, 3-H, 4-H), 2.04–2.13 (m, 2H, 5-H), 2.23 (d, 1H, J¼4.1 Hz,
exchange with D2O, OH), 3.47 (dd, 1H, J1a,2¼7.1, Jgem¼14.1, 1-Ha),
3.63 (dd, 1H, J1b,2¼3.2, Jgem¼14.1, 1-Hb), 3.73–3.87 (br s, 1H, 2-H),
4.94–5.05 (m, 2H, 7-H), 5.79 (tdd, 1H, J¼6.6, 10.2, 16.8 Hz, 6-H); 13C
NMR (75 MHz, CDCl3): 24.8 (CH2, 4-C), 33.6 (2ꢂCH2, 3-C, 5-C), 50.6
(CH2, 1-C), 71.3 (CH, 2-C), 115.0 (CH2, 7-C), 138.3 (CH, 6-C). C7H13ClO
(148.63): calcd C 56.57, H 8.82, Cl 23.85, O 10.7; found: C 56.38, H
8.97, Cl 23.81, O 10.84%.
4.1.4. (S)-2-(1-Pent-hex-5-enylamino)-ethanol (5). The solution of
tosylate 14 (1.537 g, 4.74 mmol) and ethanolamine (4.343 g, 4.3 mL,
71.1 mmol, 15 equiv) in dry THF (20 mL) was refluxed at 80 ꢁC un-
der condenser over 40 h. The reaction mixture was cooled, diluted
with Et2O (100 mL) and washed with satd aq NaHCO3 solution
(50 mL). Separated water layer was extracted with Et2O (2ꢂ50 mL),
combined organic extracts were dried over anhydrous Na2SO4, fil-
tered and concentrated in vacuo. The resulting oil (1.437 g) was
subjected to FLC (58 g SiO2, 4ꢂ11 cm, ethyl acetate containing 2% aq
NH4OH) yielding pure amino alcohol 5 (917 mg, 91%) as a pale-
yellow oil.
4.1.2. (R)-Undec-1-en-6-ol (7). Chlorohydrin 12 (1 g, 6.73 mmol)
was dissolved in THF (10 mL) and 0.3 M solution of NaOH (3 g,
75 mmol, 11 equiv) in H2O (10 mL) was added. The mixture was
stirred at 25 ꢁC for six days to ensure the complete conversion.
Then, mixture was diluted with Et2O (5 mL) and phases were
separated. The water layer was extracted with Et2O (10 mL),
combined organic extracts dried over anhydrous Na2SO4, filtered
and carefully concentrated in vacuo (300 mbar, 35 ꢁC) to ca. 1/10-
th of volume. The obtained THF solution (1.187 g) contained
highly volatile (S)-2-pent-40-enyl-oxirane 13 (727 mg, 96%) that
was shown to be essentially pure by NMR analysis of an aliquot
sample. Such THF solution containing crude epoxide 13 (710 mg,
6.333 mmol) was diluted with anhydrous Et2O (10 mL) and dry
CuI (241 mg, 1.267 mmol, 0.2 equiv) was added. The mixture was
cooled to ꢀ78 ꢁC and 2.1 M solution of n-BuLi in hexanes (6 mL,
12.67 mmol, 2 equiv) was added slowly dropwise. The colour has
changed from pale yellow to dark blue over 10 min. The mixture
was left to stir for 2.5 h while the temperature gradually rose to
20 ꢁC over the indicated time. The reaction was quenched by
addition of satd aq NH4Cl solution (40 mL). After 10 min. stirring,
the layers were separated and water phase was extracted with
Et2O (50 mL). Organic extract was dried over anhydrous Na2SO4,
filtered and concentrated in vacuo yielding crude alcohol 7 as
yellowish oil (900 mg, 84%) that was essentially pure by NMR. An
aliquot sample was subjected to FLC (SiO2, ethyl acetate/
hexanes¼1/4) to obtain analytically pure alcohol 7 as a pale-
yellow oil.
Compound 5: Rf¼0.29 (ethyl acetate containing 2% aq NH4OH);
15
[a
]
þ1.5 (c 0.74, CH2Cl2). C13H27NO (213.36): calcd C 73.18, H 12.76,
D
N 6.56, O 7.50; found: C 73.23, H 12.70, N 6.52, O 7.55%. All other
physico-chemical data are identical with those obtained for its ra-
cemate, see Ref. 9.
4.1.5. (S)-Benzyl-(1-pentyl-hex-5-enyl)-amine (6). The solution of
tosylate 14 (2 g, 6.17 mmol) and benzylamine (2 g, 2 mL, 18.5 mmol,
3 equiv) in dry THF (25 mL) was refluxed at 85 ꢁC under condenser
over eight days. The reaction mixture was cooled, diluted with H2O
(50 mL) and extracted with Et2O (2ꢂ20 mL). Combined organic ex-
tracts were dried over anhydrous Na2SO4, filtered and concentrated
in vacuo. The resulting oil (2.136 g) was subjected to FLC (85 g SiO2,
6ꢂ12 cm, gradient elution: ethyl acetate/hexanes¼1/10 containing
1% aq NH4OH–ethyl acetate/hexanes¼1/1 containing 1% aq NH4OH)
yielding pure aminoalkene 6 (1.3 g, 81%) as a pale-yellow oil.
15
Compound 6: Rf¼0.45 (ethyl acetate/hexanes¼1/4); [
a
]
þ1.5
D
(c 0.74, CH2Cl2); IR (film):
n
/cmꢀ1¼698, 733, 910, 993, 1028, 1073,
1099, 1147, 1377, 1455, 1495, 1641, 2857, 2928, 3390 (br); 1H NMR
(300 MHz, CDCl3): 0.89 (t, 3H, 50-H0),1.24–1.48 (m, 12H, 10-H, 2-H, 20-
H0, 3-H, 30-H, 40-H), 1.65 (br s, 1H, exchange with D2O, NH), 2.00–2.13
(m, 2H, 4-H), 2.52–2.60 (m, 1H, 1-H), 3.76 (s, 2H, CH2Ph), 4.92–5.05
(m, 2H, 6-H), 5.82 (tdd, 1H, J¼6.6, 10.1, 16.8 Hz, 5-H), 7.30–7.55 (m,
5H, Ph); 13C NMR (75 MHz, CDCl3): 14.1 (CH3, 50-C), 22.7, 24.9, 25.3,
32.1, 33.3, 33.8, 34.0 (all CH2, 10-C, 2-C, 20-C, 3-C, 30-C, 4-C, 40-C), 51.1
(CH2, CH2Ph), 56.6 (CH, 1-C), 114.4 (CH2, 6-C), 126.8, 128.2, 128.3 (all
CH, all CH-Ph), 138.9 (CH, 5-C), 140.7 (C, Cq-Ph). C18H29N (259.43):
calcd C 83.33, H 11.27, N 5.40; found: C 83.18, H 11.26, N 5.56%.
Compound 13: Rf¼0.8 (ethylacetate/hexanes¼1/4); IR (film):
n
/cmꢀ1¼639, 829, 856, 909, 993, 1132, 1259, 1410, 1441, 1457, 1483,
1641, 2560, 2927, 2978; 1H NMR (300 MHz, CDCl3): 1.50–1.60 (m,
4H, 10-H, 20-H), 2.07–2.15 (m, 2H, 30-H), 2.47 (dd, 1H, J2,3a¼2.8,
Jgem¼5.1 Hz, 3-Ha), 2.75 (dd, 1H, J2,3b¼4.0, Jgem¼5.1 Hz, 3-Hb), 2.88–
2.94 (m, 1H, 2-H), 4.94–5.06 (tdd, 2H, 50-H), 5.80 (tdd, 1H, J¼6.6,
10.1, 16.8 Hz, 40-H); 13C NMR (75 MHz, CDCl3): 25.2 (CH2, 20-C), 31.9,
33.4 (2ꢂCH2, 10-C, 30-C), 47.1 (CH2, 3-C), 52.2 (CH, 2-C), 114.8 (CH2,
4.1.6. (þ)-Calvine (1) and (þ)-2-epicalvine (2). PdCl2 (83 mg,
0.469 mmol, 0,1 equiv), CuCl2 (130 mg, 0.938 mmol, 0.2 equiv) and
activated 3 Å molecular sieves (1 g) were placed in a dry, argon
filled flask containing stirring bar and equipped with side-arm
stopcock. Balloon with CO/O2 mixture (ca. 1:1) was attached and
the gases were exchanged by repeated evacuation (20 Torr)
and filling (three times). Solids were left to stand as such for 20 min
and then anhydrous dioxane (80 mL) was added. The brown sus-
pension was stirred under CO/O2 atmosphere for 1 h at 25 ꢁC. The
solution of aminoalkenitol 5 (1 g, 4.69 mmol) in anhydrous dioxane
(14 mL) was then added and the resulting deep-green reaction
mixture was stirred under CO/O2 balloon for 45 h at 50 ꢁC. After
evaporation of volatiles in vacuo, ethyl acetate (150 mL) was added
and the mixture was washed with 3% aq NH4OH solution (150 mL).
The water layer was extracted with ethyl acetate (3ꢂ100 mL),
combined organic extracts were dried over anhydrous Na2SO4, fil-
tered and concentrated in vacuo. The resulting oil (1.299 g) was
subjected to FLC (52 g SiO2, 4ꢂ10 cm, ethyl acetate/hexanes/
50-C), 138.3 (CH, 40-C).
15
Compound 7: Rf¼0.65 (ethylacetate/hexanes¼1/4); [
a]
ꢀ1.5
D
(c 3.087, CH2Cl2). All other physico-chemical data are identical with
those reported for its (S)-enantiomer, see Ref. 14.
4.1.3. (R)-Toluene-4-sulfonic acid 1-pentyl-hex-5-enyl ester (14). To
the solution of crude alcohol 7 (6.2 g, 36.432 mmol) in dry CH2Cl2
(100 mL) was added anhydrous pyridine (67.6 mL, 0.831 mol,
19 equiv). The mixture was cooled to 0 ꢁC and TsCl (8.333 g,
43.719 mmol, 1.2 equiv) was added portionwise. The solution was
stirred at 25 ꢁC over 40 h, diluted with Et2O (100 mL) and washed
with satd aq CuSO4 solution (2ꢂ500 mL). The combined water
layers were extracted with Et2O (2ꢂ200 mL). Combined organic
extracts were dried over anhydrous Na2SO4, filtered and concen-
trated in vacuo. The resulting oil (10.22 g) was subjected to FLC

P. Kubizna et al. / Tetrahedron 66 (2010) 2351–2355
2355
triethylamine¼14/86/1) yielding (þ)-calvine 1 (177 mg, 16%) as
References and notes
colourless foam and (þ)-2-epicalvine 2 (412 mg, 37%) as a pale-
yellow oil. (þ)-Calvine 1 was subsequently crystallised from hep-
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tane to obtain single-crystal suitable for X-ray analysis.
15
Compound 1: mp¼59 ꢁC; [
a]
þ16.6 (c 0.451, CH2Cl2) {Ref. 6
20
D
20
[
a]
þ18 (c 0.66, CH2Cl2), Ref. 7 [
a]
þ18.3 (c 0.35, CH2Cl2)}. All
D
D
physico-chemical data were in perfect accordance with those pre-
viously published, see Ref. 6,7.
15
20
Compound 2: [
a]
þ8.7 (c 0.584, CH2Cl2) {Ref. 6 [
a
]
þ8 (c 0.58,
D
D
CH2Cl2)}. All physico-chemical data were in perfect accordance
with those previously published, see Ref. 6.
5. Braekman, J.-C.; Charlier, A.; Daloze, D.; Heilporn, S.; Pasteels, J.; Plasman, V.;
Wang, S. Eur. J. Org. Chem. 1999, 1749–1755.
4.1.7. (2S,6S)-(6-Pentylpiperidin-2-yl)acetic acid methyl ester (3) and
(2R,6S)-(6-pentylpiperidin-2-yl)acetic acid methyl ester (4). PdCl2
(68 mg, 0.385 mmol, 0,1 equiv), CuCl2 (104 mg, 0.77 mmol,
0.2 equiv) and activated 3 Å molecular sieves (1.04 g) were placed in
a dry, argon filled flask containing stirring bar and equipped with
side-arm stopcock. Balloon with CO/O2 mixture (ca. 1:1) was at-
tached and the gases were exchanged by repeated evacuation
(20 Torr) and filling (three times). Solids were stirred for 10 min and
then anhydrous MeOH (30 mL) was added. The deep-brown sus-
pension was stirred under CO/O2 atmosphere for 15 min at 25 ꢁC.
The solution of aminoalkene 6 (1 g, 3.85 mmol) in anhydrous MeOH
(10 mL) was then added and the resulting brown-black reaction
mixture was stirred under CO/O2 balloon for 20 h at 28 ꢁC. The
mixture was diluted with CH2Cl2 (5 mL), filtered through Celite pad
and rinsed with CH2Cl2 (2ꢂ15 mL). The residue after evaporation
(1.362 g) was redissolved in ethyl acetate (100 mL), washed with 2%
aq NH4OH solution (2ꢂ70 mL) and brine (50 mL). The water phase
was extracted with ethyl acetate (100 mL). Combined organic ex-
tracts were dried over anhydrous Na2SO4, filtered and concentrated
in vacuo. The resulting oil (1.225 g) was subjected to FLC (30 g SiO2,
4ꢂ7 cm, diethylether/hexanes¼4/1) yielding the mixture of mety-
lesters 15/16 (827 mg, 68%) as a pale-yellowoil. This was dissolved in
MeOH (45 mL) and Pd(OH)2 (73 mg, 0.521 mmol, 0.2 equiv) was
added. The resulting suspension was stirred under H2 atmosphere
(balloon) for 24 h at 25 ꢁC. The reaction mixture was filtered through
Celite pad and rinsed with CH2Cl2 (3ꢂ10 mL). The residue after
evaporation (632 mg) was subjected to FLC (38 g SiO2, 4ꢂ8 cm, 2-
propanol/chloroform¼1/25 containing 1% aq NH4OH) yielding 3
(127 mg, 21%) and 4 (350 mg, 60%) as pale-yellow oils.
6. Laurent, P.; Braekman, J.-C.; Daloze, D. Eur. J. Org. Chem. 2000, 2057–2062.
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C.; Fargeau-Bellassoued, M.-C.; Lhommet, G. Tetrahedron 2005, 61, 7774–7782.
ˇ
9. Szolcsa´nyi, P.; Gracza, T.; Spa´nik, I. Tetrahedron Lett. 2008, 49, 1357–1360.
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13
, 779–794; (d) Tremblay, A. E.; Whittle, E.; Buist, P. H.; Shanklin, J. Org.
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12. For the alternative formation of the undesired bromohydrine 10 via opening
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13505–13516; (b) Shimizu, M.; Nemoto, H.; Kakuda, H.; Takahata, H. Hetero-
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14. (S)-enantiomer of 7 is known: (a) Fu¨ rstner, A.; Mu¨ ller, T. J. Org. Chem. 1998,
63, 424–425; (b) Fu¨ rstner, A.; Mu¨ ller, T. J. Am. Chem. Soc. 1999, 121,
7814–7821.
15. It is noteworthy that while the analytically pure racemic amino alcohol is an oil
(see Ref. 9), (R)-enantiomer of 5 is a crystalline compound.
16. The extensive reaction screening was done earlier on a racemic substrate, see
Ref. 9.
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P.; Gracza, T.; Koman, M.; Pro´nayova´, N.; Liptaj, T. Chem. Commun. 2000, 471–
´
´
´
472; (g) Szolcsanyi, P.; Gracza, T.; Koman, M.; Pronayova, N.; Liptaj, T. Tetrahe-
dron: Asymmetry 2000, 11, 2579–2597.
18. (a) Fenton, D. M.; Steinwand, P. J. J. Org. Chem. 1974, 39, 701–704; (b) Hosokawa,
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Compound 3: Rf¼0.8 (2-propanol/chloroform¼1/25 containing 1%
15
20
aqNH4OH);[
a
]
þ22(c0.45, CH2Cl2){Ref. 6[
a
]
þ23(c0.52, CHCl3)}.
D
D
Compound 4: Rf¼0.63 (2-propanol/chloroform¼1/25 containing
15
20
1% aq NH4OH); [
a]
þ5.5 (c 0.58, CHCl3) {Ref. 6 [
a]
þ5 (c 0.53,
D
D
19. All previous reports on the total synthesis of (þ)-calvine 1 (see Ref. 6,7) de-
CHCl3)}. All physico-chemical data were in perfect accordance with
those previously published, see Ref. 6.
scribe the compound as an oil.
20. For X-ray measurement details and structure determination of
1 see
Supplementary data. Crystallographic data (excluding structure factors) for the
structure(s) reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no. CCDC-730656.
Copies of the data can be obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK fax: (internet.)þ441 223/336-033; e-mail:
deposit@ccdc.cam.ac.uk.
Acknowledgements
ˇ
We are very grateful to Prof. Tibor Gracza and Prof. Frantisek
ꢀ
Povazanec for their support and helpful discussions. We thank Dr.
21. Gallagher, A.; Davies, I. W.; Jones, S. W.; Lathbury, D.; Mathon, H. F.; Molloy, K.
C.; Shaw, R. W.; Vernon, P. J. Chem. Soc., Perkin Trans. 1 1992, 433–440.
22. (a) Adams, D. R.; Carruthers, W.; Crowley, P. J. J. Chem. Soc., Chem. Commun.
1991, 1261–1263; (b) Banwell, M. G.; Bui, C. T.; Pham, H. T. T.; Simpson, G. W. J.
Chem. Soc., Perkin Trans. 1 1996, 967–969; (c) Banwell, M. G.; Bissett, B. D.; Bui,
C. T.; Pham, H. T. T.; Simpson, G. W. Aust. J. Chem. 1998, 51, 9–18; (d) Lee, E.;
Jeong, E. J.; Min, S. J.; Hong, S.; Lim, J.; Kim, S. K.; Kim, H. J.; Choi, B. G.; Koo, K. C.
Org. Lett. 2000, 2, 2169–2172; (e) Bargiggia, F. C.; Murray, W. V. Tetrahedron Lett.
2006, 47, 3191–3193.
ˇ
Nada Pro´nayova´ for NMR service and Dr. Peter Za´lupsky´ for man-
uscript proof-reading. This work was supported by the Slovak Re-
search and Development Agency under the contract No. APVV-
0164–07. We also appreciate the financial support from EU Struc-
tural Funds, Interreg IIIA in purchasing the diffractometer.
Supplementary data
23. K. Csatayova´, PhD. Thesis, Slovak University of Technology, Bratislava, 2009.
24. The diastereomeric ratio of 3/4 was determined by the integration of MeO-
signals (3:
d
¼3.66 ppm, 4:
d
¼3.67 ppm) in the 1H NMR spectrum of crude
1H and 13C NMR spectra of 5-7, 12–14; X-ray structure re-
finement details of 1. Supplementary data associated with this ar-
ticle can be found in online version at doi:10.1016/j.tet.2010.01.106.
reaction mixture. The 2,6-cis-relative configuration of 3 was established by
NOESY experiment. There is a through space interaction between 2-H (
d
¼2.
94 ppm) and 6-H (
d
¼2.50 ppm).