Stereospecific route to enantiopure all cis-2,3,6-trisubstituted piperidines. Facile synthesis of (-)-deoxocassine and (+)-azimic acid

Article abstract of DOI:10.1016/S0040-4039(03)00820-7

Reduction of the enantiopure β-amino esters 10 provides the γ-amnio alcohol 11, which is condensed with 2,4-pentadione to afford 12. Stepwise cyclization of 12 produced the cyclic enamine 13, which is hydrogenated to deliver all cis-2,3,6-trisubstituted piperidine 14. Using this reaction sequence and subsequent Baeyer-Villiger oxidation as the key step (-)-deoxocassine and (+)-azimic acid are synthesized.

Full text of DOI:10.1016/S0040-4039(03)00820-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3963–3965
Stereospecific route to enantiopure all cis-2,3,6-trisubstituted
piperidines. Facile synthesis of (−)-deoxocassine and
(+)-azimic acid
Dawei Maa,* and Nan Mab
aState Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
bDepartment of Chemistry, Fudan University, Shanghai 200433, China
Received 6 December 2002; revised 14 March 2003; accepted 21 March 2003
Abstract—Reduction of the enantiopure b-amino esters 10 provides the g-amnio alcohol 11, which is condensed with 2,4-penta-
dione to afford 12. Stepwise cyclization of 12 produced the cyclic enamine 13, which is hydrogenated to deliver all cis-2,3,6-trisub-
stituted piperidine 14. Using this reaction sequence and subsequent Baeyer–Villiger oxidation as the key step (−)-deoxocassine and
(+)-azimic acid are synthesized. © 2003 Published by Elsevier Science Ltd.
3-Hydroxy-2,6-disubstituted piperidines are a large
group of natural alkaloids which possess important
biological activities.1,2 Typical representatives of this
family include spectaline (1), azimic acid (2), carpamic
acid (3), prosafrinine (4), cassine (5), prosophylline (7),
and prosopinine (9)1,2 (Fig. 1). Since their discovery in
the 1960s, much effort has been directed to the synthe-
sis of these alkaloids and their derivatives such as
deoxocassine (6) and deoxoprosophylline (8).2 Very
recently, these compounds were still the target
molecules for new synthetic methodologies in many
research groups.3
As part of our effort on the synthesis of natural alka-
loids from enantiopure b-amino esters, we have
reported the facile constructions of 2,4,5- and 2,4,6-
trisubstituted piperdines.4 In this communication, we
wish to describe a new method to prepare enantiopure
2,3,6-trisubstituted piperidines.
As outlined in Scheme 1, our synthesis started from
b-amino ester 10, which was prepared from 2-tetra-
decenoic acid methyl ester according to the known
procedure.5 After the ester moiety of 10 was reduced
with LAH, Pd(OH)2-catalyzed hydrogenolysis was car-
ried out to provide g-amino alcohol 11. Condensation
of 11 with 2,4-pentadione in refluxing toluene with
azeotropic removal of water afforded the enamine 12 in
74% yield. Next, we planned to transform 12 to cyclic
enamine 13 by an intramolecular SN2 reaction, which
was found to be a difficult task and several methods
were thus investigated.
Initially, an one-pot conversion from 12 to 13 was
attempted because in a similar case excellent result was
obtained using I2/Ph3P/imidazole as the mediating
reagents.6 However, in our case it was found that the
reaction in refluxing toluene worked and gave the
desired cyclization product 13, but the yield was only
25% (Table 1, entry 1). Changing the reagent system to
Figure 1. Structures of some naturally occuring 2,3,6-trisub-
stituted piperidines.
* Corresponding author. Tel.: +86-21-6416-3300; fax: +86-21-6416-
6128; e-mail: madw@pub.sioc.ac.cn
0040-4039/03/$ - see front matter © 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0040-4039(03)00820-7

3964
D. Ma, N. Ma / Tetrahedron Letters 44 (2003) 3963–3965
Scheme 2.
tion of 13 under the catalysis of PtO2 in acetic acid
produced the saturated piperidine, which was protected
with trifluoroacetyl anhydride to provide the ketone 14.
Baeyer–Villiger oxidation7 of 14 was carried out with
95% H2O2/trifluoroacetyl anhydride to afford the corre-
sponding ester, which was hydrolyzed under acidic
condition to deliver 6 in 45% yield. Its analytic data
([h]D20=−12.4 (c 0.8, CHCl3), lit.8 [h]2D0=−12.3 (c 0.19,
CHCl3)) were all identical with those reported.8
Scheme 1.
Table 1. Conversion of 12 to 13
Entry
Reaction conditions
Isolated
yield (%)
Having successfully obtained (−)-deoxocassine (6), we
extended the above strategy to the synthesis of (+)-
azimic acid (2). This acid is a monomeric component of
azimine, a macrocyclic dilactone that was isolated from
Azima tetracantha.9 Several groups have disclosed their
investigations on the synthesis of this piperidine deriva-
tive in which natural carbohydrates or amino acid were
use as ‘chiral templates’ in most cases.10 Our protocol is
described in Scheme 3. Following diastereoselective
Michael addition of lithium (S)-N-benzyl-a-methylben-
zylamide to a,b-unsaturated ester 15 to give the b-
amino ester 16, LAH reduction and Pd(OH)2-catalyzed
hydrogenolysis were employed to obtain the g-amino
alcohol 17. Condensation of 16 with 2,4-pentadione
afforded the enamine 18, which was subjected to step-
wise cyclization as mentioned above to provide 19.
After hydrogenation of 19 to afford the piperidine 20,
the THP protecting group was removed under acidic
condition and the free primary alcohol generated was
oxidized with PDC to produce the acid 21. Subjecting
21 to Baeyer–Villiger oxidation followed by deprotec-
tion yielded azimic acid (2). Its specific rotation ([h]2D0=
+7.6 (c 1.1, MeOH), lit.10a [h]D20=+7.9 (c 1.0, MeOH))
and spectral data were in good agreement with those
reported.10
1
2
3
I2/Ph3P/imidazole, toluene, rt to reflux
CBr4/Ph3P/Et3N/MeCN, 0°C to reflux
25
14
CBr4/Ph3P/Et3N/CH2Cl2, 0°C to rt, then 29
2 equiv. Et3N/MeCN, reflux
CBr4/Ph3P/Et3N/CH2Cl2, 0°C to rt, then 12
4
5
6
7
2 equiv. imidazole/MeCN, reflux
CBr4/Ph3P/Et3N/CH2Cl2, 0°C to rt, then
2 equiv. K2CO3/MeCN, reflux
a
–
CBr4/Ph3P/Et3N/CH2Cl2, 0°C to rt, then 41
1 equiv. Et3N/MeCN, 80–85°C
CBr4/Ph3P/Et3N/CH2Cl2, 0°C to rt, then 52
1.1 equiv. Et3N/MeCN, 80–85°C
a Complicated products were determined by TLC.
CBr4/Ph3P/Et3N gave even worse result (entry 2). In
these cases we found that many unidentified side prod-
ucts were formed, which prompted us to try the step-
wise cyclization in order to depress the side reactions.
Accordingly, bromination of 12 with CBr4/Ph3P in
methylene chloride provided the corresponding bro-
mide in about 73% yield, which was subjected to
cyclization in acetonitrile under the assistance of tri-
ethylamine at 80–85°C to provide 13 in 71% yield.
Thus, the overall yield for the stepwise cyclization was
about 52% (entry 7). It is notable that in the second
step the reaction temperature, choice of base and its
amount were all key factors for reaction yield (compare
entries 3–7).
In conclusion, we have developed a new protocol to
prepare enantiopure 2,3,6-trisubstituted piperidines
using conveniently available enantiopure b-amino esters
as the chiral templates. Its usage was illustrated by the
facile synthesis of (−)-deoxocassine and (+)-azimic acid.
Further applications in preparing other natural pipe-
ridine alkaloids are in progress.
With the cyclic enamine 13 in hand, we obtained (−)-
deoxocassine (6) in four steps (Scheme 2). Hydrogena-

D. Ma, N. Ma / Tetrahedron Letters 44 (2003) 3963–3965
3965
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Scheme 3.
Acknowledgements
The authors are grateful to the Chinese Academy of
Sciences, National Natural Science Foundation of
China (Grants 29725205 and 29972049), and Qiu Shi
Science & Technologies Foundation for their financial
support.