A novel C(2)-symmetric 2,6-diallylpiperidine carboxylic acid methyl ester as a promising chiral building block for piperidine-related alkaloids.

Article abstract of DOI:10.1021/ol0265620

C(2)-symmetric 2,6-diallylpiperidine 1-carboxylic acid methyl ester (5) was examined via the double asymmetric allylboration of glutaraldehyde followed by aminocyclization and carbamation as a promising chiral building block for piperidine-related alkaloids, which were synthesized by the desymmetrization of 5 using intramolecular iodocarbamation as a key step. [reaction: see text]

Full text of DOI:10.1021/ol0265620

ORGANIC
LETTERS
2002
Vol. 4, No. 20
3459-3462
A Novel C -Symmetric
2
2,6-Diallylpiperidine Carboxylic Acid
Methyl Ester as a Promising Chiral
Building Block for Piperidine-Related
Alkaloids†
,‡
Hiroki Takahata,* Hidekazu Ouchi,‡ Motohiro Ichinose,§ and Hideo Nemoto§
Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical UniVersity, Sendai,
981-8558, Japan, and Faculty of Pharmaceutical Sciences, Toyama Medical and
Pharmaceutical UniVersity, Toyama 930-0194, Japan
takahata@tohoku-pharm.ac.jp
Received July 18, 2002
ABSTRACT
C -Symmetric 2,6-diallylpiperidine 1-carboxylic acid methyl ester (5) was examined via the double asymmetric allylboration of glutaraldehyde
2
followed by aminocyclization and carbamation as a promising chiral building block for piperidine-related alkaloids, which were synthesized by
the desymmetrization of 5 using intramolecular iodocarbamation as a key step.
Substituted piperidines are among the most ubiquitous
heterocyclic building blocks in both natural products and
synthetic compounds with important biological activities.
Therefore, considerable effort has been directed toward
synthesizing these systems.1 With respect to biologically
active target molecules, there is an increasing interest in the
diastereo- and enantioselective synthesis of piperidines.2 Our
interest in this field has been focused on the synthesis of
C2-symmetric 2,6-disubstituted piperidines using a double
asymmetric reaction of achiral symmetrically bifunctionalized
substrates.3 Recently, Brown reported a double asymmetric
allylboration of glutaraldehyde (1) to provide C2-symmetric
1,5-diol 2 in 90% de and >98% ee.4 However, its utility to
date has been hampered by the difficulty of separating C2
and meso diastereomers. To circumvent this drawback, we
developed the following protocol for the transformation of
acyclic compounds such as 1,5-diols to cyclic derivatives
such as 2,6-disubstituted piperidines, which involves both
rigid conformation and close proximity (1,3-relationship)
between two chiral centers to give a better separation of
diastereomers (Scheme 1).5 In this Letter, we describe an
asymmetric synthesis of C2-symmetric 2,6-diallylpiperidine
5 as an attractive chiral building block and the subsequent
synthesis of piperidine-related alkaloids via desymmetrization
of 5 using iodocarbamation as a key step.
† Dedicated to the memory of the late Professor Henry Rapoport,
University of California, Berkeley.
‡ Tohoku Pharmaceutical University.
§ Toyama Medical and Pharmaceutical University.
(1) Rubiralta, M.; Giralt, E.; Diez, A. Piperidine. Structure, Preparation,
ReactiVity and Synthetic Applications of Piperidine and Its DeriVatiVes;
Elsevier: Amsterdam, 1991.
According to Brown’s procedure,4 treatment of 1 with
B-allyldiisopinocamphenylborane, prepared using B-chloro-
(2) For a recent review, see: Laschat, S.; Dickner, T. Synthesis 2000,
1781.
(3) Takahata, H.; Takahashi, S.; Kouno, S.; Momose, T. J. Org. Chem.
1998, 63, 2224.
(4) Ramachandran, P. V.; Chen, G.-M.; Brown, H. C. Tetrahedron Lett.
1997, 38, 2417.
(5) (a) Takahata, H.; Yotsui, Y.; Momose, T. Tetrahedron 1998, 54,
13505. (b) Takahata, H.; Shimizu, M. Amino Acids, in press.
10.1021/ol0265620 CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/05/2002

Scheme 1
diisocamphenylborane (DIP-chloride) and allylmagnesium
bromide, followed by alkaline H2O2 oxidation gave a
diastereomeric mixture of diols 2 in 74% yield. The diols 2
were successively subjected to ditosylation of secondary
hydroxyls and cyclic amination with benzylamine to give
diastereomeric isomers of piperidines 3, which were sepa-
rated as expected by chromatography to yield C2-symmetric
2,6-diallylpiperidine 4 and σ-4 in respective yields of 61 and
14%. Changing the N-protecting group from benzyl to a
carbamate group using methyl chloroformate gave the title
carbamate 5 in 93% yield.6 With the C2 chiral building block
5 in hand, we turned our attention to its transformation into
biologically active 2,6-trans-disubstituted piperidine-related
alkaloids (Figure 1).
Figure 1. 2,6-trans-Disubstituted piperidine-related alkaloids.
iodine was carried out to provide a diastereomeric and
inseparable mixture of oxazolidinones 11 in 98% yield. This
desymmetrization means that one of two allyl groups is
protected. With the promising piperidine 11, we then focused
on the synthesis of 2,6-trans-dialkylpiperidines such as (-)-
epi-dihydropinidine (6),7 a constituent of pine and spruce
species, and (2R,6R)-trans-solenopsin A (7),8 a constituent
of fire ant venom. Cat. OsO4-mediated dihydroxylation of
11 followed by an oxidative cleavage of the resulting diol
with NaIO4 provided the aldehyde, which was decarbonylated
with (Ph3P)3RhCl to afford the methyl-substituted piperidine
Scheme 2a
Scheme 3a
a Reaction conditions: (a) (i) TsCl, NEt3; (ii) BnNH2. (b)
ClCOOMe.
Our synthesis began with the selective monofunctional-
ization of diallyl appendages in 5. All attempts such as
hydroboration, dihydroxylation, and the Wacker oxidation
nonselectively resulted in a mixture of mono- and difunc-
tionalized products together with the recovery of starting 5.
We considered that this trouble could be overcome by
intramolecular iodocarbamation with one of two allyls, since
a second iodocarbamation could not occur with the other
allyl. Thus, the intramolecular iodocarbamation of 5 with
a Reaction conditions: (a) I2. (b) (i) cat. OsO4; (ii) NaIO4; (iii)
(Ph3P)3RhCl. (c) (i) Zn, CH3CO2H; (ii) Boc2O, NaOH. (d) (i) cat.
OsO4, NaIO4; (ii) Ph3P+CH2(CH2)8Br-, n-BuLi. (e) H2, cat.
Pd(OH)2. (f) TFA.
(6) Attempts with other alkyl chloroformates such as ethyl, benzyl, and
trichloromethyl chlorofornates were unsuccessful.
3460
Org. Lett., Vol. 4, No. 20, 2002

Scheme 4a
Scheme 5a
a Reaction conditions: (a) cat. PdCl2, O2, DMF, H2O. (b) (i) Zn,
CH3CO2H; (ii) Boc2O, K2CO3. (c) (i) cat. OsO4, NaIO4; (ii)
Ph3PdCHCHO. (d) H2, cat. Pd(OH)2. (e) (i) TFA; (ii) CSA.
12 in 48% yield. Deprotection of oxazolidine occurred upon
exposure of 12 to zinc in acetic acid to give the allylpiperi-
dine, N-protection of which with Boc2O gave N-Boc-2-allyl-
6-methylpiperidine 13. Transformation of 13 into 6 has been
reported previously.9 The oxidative cleavage of 13 with
catalytic OsO4 in combination with NaIO4 provided the
aldehyde, which was coupled by the Wittig olefination with
n-nonyltriphenylphosphonium bromide in the presence of
n-BuLi to give the 2,6-disubstituted piperidine 14 in 66%
yield. Hydrogenation of 14 with catalytic Pd(OH)2 gave 15
in 97% yield. N-Deprotection of 15 by treatment with
trifluoroacetic acid (TFA) in CH2Cl2 provided 7 in 84% yield.
Next, the transformation of 11 into precoccinelline (8),10
a ladybug defense alkaloid, was pursued. Wacker oxidation
of 11 provided the ketone 16 in 86% yield. By a procedure
similar to that described for 13, a two-step treatnent
(deprotection of the oxazolidine and N-protection) of 16 gave
the allylpiperidine 17 in 81% yield. Treatment of 17 with
catalytic OsO4 in combination with NaIO4 followed by the
Wittig reaction of the resulting aldehyde with (triphenylphos-
phoranylidene)acetaldehyde afforded the R,â-unsaturated
aldehyde 18 in 60% yield. Exposure of 18 to hydrogen in
the presence of catalytic Pd(OH)2 in ethyl acetate gave the
keto aldehyde 19 in 99% yield. N-Deprotection of 19 with
TFA followed by an intramolecular Mannich-type cyclization
a Reaction conditions: (a) AD-mix-R. (b) (i) Zn/CH3CO2H; (ii)
ClCOOCH3, K2CO3. (c) (i) n-Bu2SnO; (ii) TsCl, Et3N; (iii) K2CO3.
(d) EtMgBr, CuBr-Me2S. (e) (i) cat. OsO4, NaIO4; (ii) Ph3PCHd
COCH3; (iii) H2, cat. Pd(OH)2. (f) n-PrSLi; (g) ethylene glycol,
TsOH.
with 10-camphorsulfonic acid (CSA) gave the known
synthetic intermediate 2010a for 8 in 52% yield, which
constitutes a formal synthesis of precoccinelline.
In addition, we sought an efficient synthesis of (-)-
porantheridine (9),11,12 a novel tricyclic alkaloid of Poran-
thera corymbosa, from 11. The Sharpless asymmetric
dihydroxylation (AD-mix-R) of 11 provided diastereomeric
mixtures of diols 21 in 90% yield. A two-step treatment
(deprotection and N-carbamation) of 21 gave 22 and 23 in
respective yields of 43 and 12%. Treatment of the diol 22
with a three-step process (cyclic stannoxanation, primary
(7) (a) Tawara, J. N.; Blokhin, A.; Foderaro, T. A.; Stermitz, F. R.; Hope,
H. J. Org. Chem. 1993, 58, 4813. (b) Adamo, M. F. A.; Aggarwal, V. K.;
Sage, M. A. Synth. Commun. 1999, 29, 1747.
(8) Recent synthesis: (a) Reding, M. T.; Buchwald, S. L. J. Org. Chem.
1998, 63, 6344. (b) Wilkinson, T. J.; Stehle, N. W.; Beak, P. Org. Lett.
2000, 2, 155. (c) Jefford, C. W.; Wang, J. B. Tetrahedron Lett. 1993, 34,
2911.
(9) Takahata, H.; Kubota, M.; Takahashi, S.; Momose, T. Tetrahedron:
Asymmetry 1996, 7, 3047.
(10) (a) Yue, C.; Nicolay, F.; Royer, J.; Husson, H. P. Tetrahedron 1994,
50, 3139. (b) Stevens, R. V.; Lee, A. W. M. J. Am. Chem. Soc. 1979, 101,
7032.
(11) Isolation and identification; Denne, W. A.; Johns, S. R.; Lamberton,
J. A.; Mathieson, A. McL.; Suares, H. Tetrahedron Lett. 1972, 18, 1767.
(12) (a) David, M.; Dhimane, H.; Vanucci-Bacque, C.; Lhommet, G. J.
Org. Chem. 1999, 64, 8402. (b) Comins, D. L.; Hong, H. J. Am. Chem.
Soc. 1993, 115, 8851.
Org. Lett., Vol. 4, No. 20, 2002
3461

tosylation, and epoxidation) gave the epoxide 24 in 92%
yield, which was cleaved with ethylmagnesium bromide in
the presence of CuBr-Me2S to give the hydroxyl 25 in 76%
yield. Oxidative cleavage of 25 with catalytic OsO4 in
combination with NaIO4 followed by Wittig reaction of the
resulting aldehyde with 1-triphenylphosphoranylidene-2-
propanone afforded the R,â-unsaturated ketone, which was
hydrogenated with catalytic Pd(OH)2 to give the keto alcohol
26 in 79% yield. Decarbamation of 26 with n-PrSLi13
unpredictably provided the oxazolidinone 27 in 90% yield.
It is possible that an intramolecular attack by a secondary
alkoxide anion, generated by n-PrSLi, of the carbamate
carbonyl would occur. Fortunately, 27 was converted by
acetalization to Comin’s synthetic intermediate 2812b for 9
in quantitative yield.
asymmetric allylboration of 1 followed by aminocyclization
and carbamation. Its synthetic utility has been demonstrated
in the expedient synthesis of piperidine-related alkaloids such
as 6-9 based on distinctive desymmetrization using iodocar-
bamation as a key step, along with the protection of one
allyl group. Further application of this procedure to other
alkaloids such as 10 is currently under investigation.
Acknowledgment. This work was supported in part by
a Grant-in-Aid for Scientific Research from the Ministry of
Education, Science, Sports and Culture of Japan.
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of 1H NMR spectra
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
In summary, we explored a novel C2-symmetric 2,6-
diallylpiperidine 5 as a chiral building block via the double
(13) Corey, E. J.; Weigel, L. O.; Floyd, D.; Bock, M. G. J. Am. Chem.
Soc. 1978, 100, 2916.
OL0265620
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