Concise enantiospecific synthesis of (+)-calvine

Article abstract of DOI:10.1055/s-2006-926267

We report herein an efficient enantiospecific synthesis of (+)-calvine in nine steps from (R)-epichlorohydrine. The convergent synthesis is based on an olefin cross-metathesis (CM) reaction of a chiral homoallylamine and an enone. Subsequent reductive cyc

Full text of DOI:10.1055/s-2006-926267

LETTER
487
Concise Enantiospecific Synthesis of (+)-Calvine
E
nantiospecifi
u
c
Synthesis
o
r
f
(+)-Ca
n
lvine ama Dewi-Wülfing, Julian Gebauer, Siegfried Blechert*
Technische Universität Berlin, Institut für Chemie, Strasse des 17. Juni 135, 10623 Berlin, Germany
Fax +49(30)31423619; E-mail: blechert@chem.tu-berlin.de
Received 12 December 2005
Previous works within our group established the method-
ology for the synthesis of cis-2,6-disubstituted pipe-
ridines.4 We were therefore eager to apply the sequential
olefin cross-metathesis–reductive cyclization method to
Abstract: We report herein an efficient enantiospecific synthesis of
(+)-calvine in nine steps from (R)-epichlorohydrine. The conver-
gent synthesis is based on an olefin cross-metathesis (CM) reaction
of a chiral homoallylamine and an enone. Subsequent reductive
cyclization and lactonization of the cis-2,6-disubstituted piperidine synthesize calvine. In contrast to the synthesis of Braek-
intermediate furnished the product in good yield.
man, we found it advantageous to introduce the hydroxy-
ethyl group early in the synthesis to avoid the unselective
hydroxyethylation. We envisaged the ester 1 as a syn-
thetic precursor, which should result from the reductive
cyclization of enone 2, the CM product of enone 3 and
enantiopure homoallylamine 4. The homoallylamine
should be prepared via substitution of homoallylalcohol 5,
in turn available from oxirane 6 (Scheme 1). To avoid the
interconversion of calvine to 2-epicalvine, careful selec-
tion of the reaction solvents was crucial.
Key words: olefin cross-metathesis, hydrogenation, lactones, ru-
thenium catalyst, alkaloids
Ladybird beetles (Coccinellidae) are rarely exploited as
food sources by predators, owing to toxic alkaloids pro-
duced in their hemolymph, which are released as small
yellow droplets from their knee joints once they are dis-
turbed or molested.1 Calvine, a cis-2,6-disubstituted pipe-
ridine annulated with a seven-membered lactone, is the
major alkaloid found in two ladybird beetles Calvia 10-
guttata and Calvia 14-guttata. 2-Epicalvine, its corre-
sponding trans-lactone, was also found as the minor con-
stituent (about 10%, Figure 1).
CO2Me
N
O
N
H11C5
H11C5
O
O
OH
1
reductive
cyclization
O
N
N
H11C5
H11C5
OH
O
OMe
OH
O
O
CbzN
H11C5
O
CM
3
+
O
O
(+)-calvine
(+)-2-epicalvine
OMe
CbzN
H11C5
2
Figure 1 Alkaloids found in Calvia10- and 14-guttata
4
Braekman and coworkers isolated the alkaloids in 1999
and determined their absolute configuration by so far the
first and only total synthesis in 2000.2 They utilized the
CN(R,S) method3 as the key step to prepare a cis-2,6-di-
substituted piperidine methyl ester intermediate. The hy-
droxyethyl group was introduced later in the synthesis by
treating the piperidine intermediate with an excess of ox-
irane in methanol. This step, which was the major draw-
back of the synthesis, resulted in a complex mixture
containing calvine, 2-epicalvine, N-alkylated methyl ester
(cis/trans 1:1) and N,N-dialkylated retro-Michael prod-
uct. The low selectivity was caused by the interconversion
of calvine to 2-epicalvine in protic solvents via transester-
ification, ring-opening, and retro-Michael reaction. Inter-
estingly, both lactones are stable in aprotic solvents such
as THF or acetonitrile.2
SN2
OH
O
H11C5
H11C5
5
6
Scheme 1 Retrosynthetic analysis of calvine
The synthesis of calvine is presented in Scheme 2. The
CM partner 3 was prepared in two steps according to the
procedure of Zibuck and Streiber.5 The aldol reaction of
methyl acetate and acrolein occurred smoothly to furnish
the allyl alcohol 7. The Jones oxidation yielded after
Kugelrohr distillation the desired enone 3 in 55% yield.
The CM partner 4 should be prepared from an enantiopure
homoallylalcohol. Brown and coworkers reported the re-
action between allyldiisopinocampheylborane and n-bu-
tyraldehyde to furnish (R)-hept-1-en-4-ol in 72% yield
with moderate 87% ee.6 Another approach was the
SYNLETT 2006, No. 3, pp 0487–0489
1
5.
0
2.
2
0
0
6
Advanced online publication: 06.02.2006
DOI: 10.1055/s-2006-926267; Art ID: G38005ST
© Georg Thieme Verlag Stuttgart · New York

488
P. Dewi-Wülfing et al.
LETTER
Barbier reaction between allyltributyltin and hexanal in with vinyl magnesium bromide gave the homoallylalco-
the presence of a catalytic amount (20 mol%) of a chiral hol 5 in 84% yield.10,11 Copper cyanide works as well as
BINOL–TiCl2 complex to give (R)-non-1-en-4-ol in 75% CuCl(COD) in catalyzing the reaction. The transforma-
yield and 98.4% ee. However, the reaction was reported tion of homoallylalcohol 5 to homoallylamine 4 was ac-
on small scale (1.5 mmol of aldehyde) and elaborate tech- complished by tosylation, nucleophilic substitution, and
nique was required to prepare the chiral complex.7 An al- introduction of the Cbz protecting group, yielding the ho-
ternative method was reported by Fürstner and coworkers, moallylamine 4. The tosylation proceeded slowly and was
which involved an oxirane opening by vinylmagnesium complete after seven days. The substitution reaction was
bromide in the presence of catalytic amounts of complete after six days yielding the volatile homoallyl-
CuCl(COD) (COD = cyclooctadiene). This method is amine 8. The benzyloxycarbonylation was done in a two-
suitable for large scale and does not result in any erosion phase reaction system, which gave solely the N-protected
of ee.8
homoallylamine. We expected that the substitution reac-
tion occurred with complete inversion of configuration
(SN2 mechanism). As we could not determine the con-
figuration of 8 or 4 either via chiral HPLC or Mosher
derivatives, we decided to continue our synthesis since the
configuration of the final product would provide more
information about the substitution reaction.
O
OH
O
O
O
b
e
a
OMe
OMe
O
OMe
3
7
OH
c, d
O
CM between enone 3 and homoallylamine 4 was conduct-
ed in the presence of 7.5 mol% Hoveyda–Blechert ruthe-
nium catalyst [Ru]12 to afford exclusively the E-enone 2 in
70% yield.13 The catalyst was chosen as it shows higher
reactivity and stability than the second generation
Grubbs’ catalyst.14
Cl
H11C5
HN
H11C5
5
6
OH
OH
CbzN
H11C5
h
f, g
H11C5
4
8
We then investigated the reductive cyclization reaction of
enone 2. Suitable aprotic solvent was required for the
reaction as the hydrogenation with methanol as solvent
resulted in the epimerization due to the retro-Michael re-
action. Reaction in THF led only to the hydrogenation of
the double bond with retention of the N-Cbz protecting
group.15 Maki and coworkers reported a hydrogenation re-
action with various solvents, in which isopropyl ether
proved to be as effective as methanol in hydrogenating
benzyl ester moiety.16 Conducting the reductive hydroge-
nation in isopropyl ether at 3 bar of hydrogen and 40 °C
for three days afforded a mixture of the cis-2,6-disubsti-
tuted piperidine 1 and calvine in 61% and 13% yields, re-
spectively.17,18 Both products were chromatographically
separated and the piperidine 1 was subjected to lactoniza-
tion conditions.
13
OH
CbzN
O
O
1
14
7.5% [Ru]
3 + 4
i
OMe
H11C5
2
4
8
2
6
1
CO2Me
j
N
N
+
H11C5
H11C5
7
O
14
OH
O
15
1
(+)-calvine
k
[Ru] =
N
N
Cl
Ru
O
Cl
Braekman and coworkers reported a lactonization proce-
dure, in which the crude mixture resulted from hydroxy-
ethylation was heated in acetonitrile at 50 °C in the
presence of Amberlyst A15 and molecular sieve.2 Using
this procedure calvine was obtained in 60% yield together
with 25% recovered piperidine 1. We found out that the
TLC controls detected only the substances in the solution.
The adduct attached on the Amberlyst surface remained
undetected and it was released only during workup, giving
low yield and conversion. A complete conversion was
achieved by treating the piperidine 1 with a slight excess
of p-toluenesulfonic acid in refluxing benzene, affording
neat calvine in 66% yield.19,20 The spectral data and opti-
cal rotation of the final product were in agreement to the
reported values. The enantiopurity of calvine also con-
firmed the complete inversion of configuration of the
crucial nucleophilic substitution reaction.
Scheme 2 Reagents and conditions: (a) LDA, THF, –78 °C; acrole-
in, 5 min, quant.; (b) CrO3, H2SO4, acetone, 18 h, 55%; (c) n-BuMgCl,
CuCN (10 mol%), –78 °C to 0 °C, 2.5 h, quant.; (d) NaOH, THF–
H2O, 20 h, 87%; (e) vinylMgBr, CuCN (10 mol%), –78 °C to r.t., 24
h, 84%; (f) TsCl, DMAP (10 mol%), CH2Cl2, 7 d, 72%; (g) ethanol-
amine, THF, reflux, 6 d, 77%; (h) CbzCl, K2CO3, H2O–CH2Cl2, 4 h,
73%; (i) 3 (2 equiv), 4 (1 equiv), [Ru] (7.5 mol%), CH2Cl2, reflux, 18
h, 70%; (j) 10% Pd/C, i-Pr2O, 3 bar H2, 40 °C, 3 d, 61% 1 and 13%
calvine; (k) PTSA (1.1 equiv), benzene, reflux, 18 h, 66%.
The homoallyalamine 4 was prepared in six steps, starting
from (R)-epichlorohydrine. Its conversion to pentyl ox-
irane 6 was done by copper-catalyzed oxirane opening
with n-butyl magnesium chloride followed by oxirane for-
mation in basic conditions.9 Successive oxirane opening
Synlett 2006, No. 3, 487–489 © Thieme Stuttgart · New York

LETTER
Enantiospecific Synthesis of (+)-Calvine
489
column chromatography (SiO2, cyclohexane–EtOAc 3:2) to
give 2 (70 mg, 70%, as keto–enol mixture) as a brown oil.
[a]D20 –8.0 (c 1, CHCl3). 1H NMR (500 MHz, CDCl3): d =
0.81 (br s, 3 H, H-12), 1.20 (br s, 8 H, H-9–11), 1.45–1.59
(m, 2 H, H-8), 2.20–2.68 (m, 2 H, H-6), 3.29 (br s, 2 H, H-
13), 3.45 (s, H-2 keto), 3.50 (br s, 2 H, H-14), 3.68, 3.70 (s,
3 H, OCH3), 4.05 (br s, 1 H, H-7), 4.96 (s, H-2 enol), 5.12 (s,
2 H, H-16), 5.69–5.85 and 6.05–6.20 (m, 1 H, H-4), 6.45–
6.62 and 6.69–6.86 (m, 1 H, H-5), 7.21–7.41 (br s, 5 H, Ar),
11.75 (s, OH enol) ppm. 13C NMR (125 MHz, CDCl3): d =
14.0 (C-12), 22.6 (C-11), 26.1 (C-10), 31.6 (C-9), 33.1, 33.4
(C-8), 36.5, 37.0 (C-6), 46.4, 46.7 (C-13), 51.3 (C-7), 52.4
(OMe), 61.6, 62.6 (C-14), 67.2, 67.8 (C-15), 90.5 (C-2),
126.6 (C-4), 1276.9, 128.1, 128.3, 128.7, 131.3, 136.8 (Ar),
145.9, 147.0 (C-5), 155.6 (C-16), 173.3 (C-1), 191.7 (C-3)
ppm.
In summary, we have performed an enantioselective syn-
thesis of (+)-calvine in nine steps starting from (R)-epi-
chlorohydrine with an overall yield of 10%. The key
strategies included the copper-catalyzed oxirane opening,
SN2 reaction, and sequential CM–reductive cyclization
method. Further investigations and syntheses based on
this concept are currently under study in our laboratories
and the results will be reported in due course.
Acknowledgment
We are grateful to Daisho Ltd. Japan for their generous donation of
(R)-epichlorohydrine. P.D. thanks Prof. D. Daloze (Belgium) and
Dr. S. Maechling for valuable discussions.
(14) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953.
(15) Hattori, K.; Sajiki, H.; Hirota, K. Tetrahedron 2000, 56,
8433.
(16) Maki, S.; Okawa, M.; Makii, T.; Hirano, T.; Niwa, H.
Tetrahedron Lett. 2003, 44, 3717.
References and Notes
(1) Review on coccinellids: King, A. G.; Meinwald, J. Chem.
Rev. 1996, 96, 1105.
(2) (a) Laurent, P.; Braekman, J.-C.; Daloze, D. Eur. J. Org.
Chem. 2000, 2057. (b) Braekman, J.-C.; Chaelier, A.;
Daloze, D.; Heilporn, S.; Pasteels, J.; Plasman, V.; Wang, S.
Eur. J. Org. Chem. 1999, 1749.
(3) Review on CN(R,S) method: Husson, H.-P.; Royer, J. Chem.
Soc. Rev. 1999, 28, 393.
(4) (a) Gebauer, J.; Blechert, S. Synlett 2005, 2826.
(b) Gebauer, J.; Dewi, P.; Blechert, S. Tetrahedron Lett.
2005, 46, 43. (c) Randl, S.; Blechert, S. Tetrahedron Lett.
2004, 45, 1167.
(5) (a) Zibuck, R.; Streiber, J. Org. Synth. 1993, 71, 236.
(b) Zibuck, R.; Streiber, J. M. J. Org. Chem. 1989, 54, 4717.
(6) Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J.
Org. Chem. 1986, 51, 432.
(7) (a) Costa, A. L.; Piazza, M. G.; Tagliavini, E.; Trombini, C.;
Umani-Ronchi, A. J. Am. Chem. Soc. 1993, 115, 7001. (b)
A similar method with a different titanium complex:
Hanawa, H.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc.
2003, 125, 1708.
(17) Gómez-Monterrey, I.; González-Muñiz, R.; Herranz, R.;
Garcia-Gomez, T. Tetrahedron Lett. 1993, 34, 3593.
(18) Preparation and Selected Data of Piperidine 1.
Cross-metathesis product 2 (270 mg, 0.64 mmol) in
isopropyl ether (20 mL) was hydrogenated over 10% Pd/C
(68 mg, 60 mmol) at 3 bar and 40 °C for 3 d. After filtration
over Celite® and evaporation, the residue was purified by
column chromatography (SiO2, CH2Cl2–MeOH–NH3
97:3:0.1) to afford piperidine 1 (105 mg, 61%) and calvine
(20 mg, 13%) as a light-yellow oil. [a]D20 +8.5 (c 1.3,
CH2Cl2). 1H NMR (200 MHz, CDCl3): d = 0.88 (t, J = 7 Hz,
3 H, H-13), 1.10–1.80 (m, 14 H, H-3–5,9–12), 2.39 (dd,
J = 15, 9 Hz, 1 H, H-7), 2.51–2.77 (m, 4 H, H-6,7,14), 3.09–
3.25 (m, 1 H, H-2), 3.46 (t, J = 6 Hz, 2 H, H-15), 3.68 (s, 3
H, OCH3) ppm. 13C NMR (125 MHz, CDCl3): d = 14.1 (C-
13), 21.7 (C-4), 22.7 (C-12), 26.2 (C-3), 27.0 (C-10), 27.3
(C-5), 32.1 (C-11), 34.1 (C-9), 39.3 (C-7), 48.4 (C-14), 51.7
(OMe), 58.3 (C-2), 60.5 (C-15), 61.9 (C-6), 173.0 (C-8)
ppm.
(8) (a) Fürstner, A.; Thiel, O. R.; Kindler, N.; Bartkowska, B. J.
Org. Chem. 2000, 65, 7990. (b) Fürstner, A.; Konetzki, I. J.
Org. Chem. 1998, 63, 3072.
(19) Nilov, D.; Räcker, R.; Reiser, O. Synthesis 2002, 2232.
(20) Preparation and Selected Data of (+)-Calvine.
To a solution of 1 (12 mg, 44 mmol) in benzene (3 mL), p-
TSA monohydrate (9.2 mg, 48 mmol) was added and the
mixture was heated at reflux under a nitrogen atmosphere for
18 h. Then, CH2Cl2 (10 mL) and sat. aq NaHCO3 solution
(10 mL) were added and the layers were separated. The
aqueous layer was extracted with CH2Cl2 (3 × 10 mL), and
the collected organic layers were evaporated to give neat
calvine (7 mg, 66%) as a light-yellow oil. [a]D20 +18.3 (c
0.35, CH2Cl2) {lit.2 [a]D20 +18 (c 0.66, CH2Cl2)}. 1H NMR
(200 MHz, CDCl3): d = 0.88 (t, J = 7 Hz, 3 H, H-13), 1.15–
1.81 (m, 14 H, H-3–5,9–12), 2.19–2.89 (m, 5 H, H-6,7,14),
(9) Nakayama, Y.; Kumar, G. B.; Kobayashi, Y. J. Org. Chem.
2000, 65, 707.
(10) The optical rotation of the product [a]D20 +8.7 (c 1.4, CHCl3)
was in agreement with the reported value {lit.11 [a]D25 +8.3
(c 1.4, CHCl3)}.
(11) Ito, T.; Yamakawa, I.; Okamoto, S.; Kobayashi, Y.; Sato, F.
Tetrahedron Lett. 1991, 32, 371.
(12) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A.
H. J. Am. Chem. Soc. 2000, 122, 8168. (b) Gessler, S.;
Randl, S.; Blechert, S. Tetrahedron Lett. 2000, 41, 9973.
(13) Preparation and Selected Data of Enone 2.
[Ru] (11 mg, 18 mmol) was added to a solution of
homoallylamine 4 (76 mg, 0.2 mmol) and enone ester 3 (60
mg, 0.4 mmol) in anhyd CH2Cl2 (4.7 mL) under a nitrogen
atmosphere. The mixture was heated at reflux for 20 h. The
solvent was evaporated and the residue was purified by
3.23–3.37 (m, 1 H, H-2), 4.21–4.36 (m, 2 H, H-15) ppm. 13
C
NMR (125 MHz, CDCl3): d = 14.1 (C-13), 21.5 (C-4), 22.7
(C-12), 24.6 (C-3), 25.2 (C-5), 32.3 (C-10, 11), 34.2 (C-9),
43.2 (C-7), 53.5 (C-14), 59.0 (C-2), 62.8 (C-6), 69.0 (C-15),
174.7 (C-8) ppm.
Synlett 2006, No. 3, 487–489 © Thieme Stuttgart · New York