Concise total synthesis of (+)-carpamic acid

Article abstract of DOI:10.1016/j.tetlet.2003.12.010

We report herein an efficient enantioselective synthesis of (+)-carpamic acid, with nine steps as the longest linear sequence, the key strategy being based on a novel sequence of a cross-metathesis (CM) reaction and a subsequent cyclizing reductive amination to form the piperidine ring.

Full text of DOI:10.1016/j.tetlet.2003.12.010

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1167–1169
Concise total synthesis of (+)-carpamic acid
Stefan Randl and Siegfried Blechert*
Technische Universit€at Berlin, Institut f€ur Chemie, Strasse des 17. Juni 135, D-10623 Berlin, Germany
Received 30 October 2003; revised 26 November 2003; accepted 2 December 2003
Abstract—We report herein an efficient enantioselective synthesis of (+)-carpamic acid, with nine steps as the longest linear
sequence, the key strategy being based on a novel sequence of a cross-metathesis (CM) reaction and a subsequent cyclizing reductive
amination to form the piperidine ring.
ꢀ 2003 Elsevier Ltd. All rights reserved.
Piperidine alkaloids are widespread in nature and many
compounds of this family exhibit important biological
activities.1 2,6-Disubstituted 3-piperidinols represent a
small subgroup and as a common structure these alka-
loids possess a b-hydroxypiperidine ring with a methyl
or hydroxymethylene group in position 2 and an alkyl
side chain in position 6 of the heterocycle.2 Due to their
interesting structures and their pharmacological prop-
erties much effort has been directed towards the stereo-
selective synthesis of this class of compounds.3 Carpaine
and azimine are two of the macrocyclic dilactones
consisiting of two molecules of the characteristic 3-
piperidinol structure designated as azimic acid 1 and
carpamic acid 2 with a carboxy group in the C-6 alkyl
chain and an all-cis-configuration of the substituents.
We herein describe an enantioselective total synthesis of
(+)-carpamic acid 2.4 With the conversion of 2 into
carpaine being described in the literature, our synthesis
represents a formal total synthesis of carpaine.5
are converted into piperidines with the desired 2,6-cis-
stereochemistry in a sequence of hydrogenation of the
double bond, N-deprotection and cyclizing reductive
amination.6 Compound 3 was envisaged to be synthe-
sized via cross-metathesis (CM) between olefins 4 and 5.
We considered the Cbz group as an appropriate
N-protecting group due to both its compatibility with
the metathesis step and its lability to hydrogenolysis.
Aminoalcohol 4 was envisaged to be synthesized from
(L)-alanine.
The addition of vinyl anions to variously N-protected
a-alaninals to afford a-vinyl-b-aminoalcohols has been
intensively investigated in the literature, but diastereo-
selectivities obtained were low.7 Good diastereoselec-
tivities in favour of the desired syn-isomer8 (syn/anti
15:1) were reported by Yamamoto9 starting from
N-Boc-alanine methyl ester 6 by DIBAL-H reduction of
the ester moiety and in situ conversion of the reaction
intermediate––presumably the aluminoxy acetal––by
H
(H2C)n
N
O
HO
O
O
N
H
(CH2)nCO2H
O
N
H
(CH2)n
O
RO
Azimine (n = 5)
1 (+)-Azimic acid (n = 5)
2 (+)-Carpamic acid (n = 7)
(CH2)7CO2R'
Carpaine (n = 7)
2
NHCbz
We envisaged an aminoketone of type 3 as the retro-
synthetic precursor (Scheme 1). Upon treatment with
hydrogen and a Pd-catalyst, d-aminoketones of type 3
bearing an N-protecting group labile to hydrogenation
3
CM
RO
O
+
(CH2)7CO2R'
NHCbz
4
5
* Corresponding author. Tel.: +49-30-31422255; fax: +49-30-314236-
19; e-mail: blechert@chem.tu-berlin.de
Scheme 1. Retrosynthetic analysis of 2.
0040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.010

1168
S. Randl, S. Blechert / Tetrahedron Letters 45 (2004) 1167–1169
subsequent addition of vinylmagnesium chloride.
According to this protocol, 7 was synthesized in 52%
yield with a diastereoselectivity of 8:1 (Scheme 3).10 In
order to separate the isomers, they were converted into
their corresponding TBS-ethers 8, which were separable
by column chromatography.9 The difference in Rf values
was very small, and the separation turned out to be
troublesome. Furthermore, the use of the Boc protecting
group would require additional deprotection/protection
steps due to the necessary change of the protecting
group for the reductive amination. Instead, it would be
conceiveable to start directly from Cbz-protected
a-alanine methyl ester, but problems might arise due to
the limited stability of the Cbz group towards Grignard
reagents.
a,b
(CH2)7CO2Me
(CH2)8OH
14
X
c
15 X = CH2
16 X = O
d
O
11,
cat. [Ru]
RO
Y
(CH2)7CO2Me
(CH2)7CO2Me
f
NHCbz
19 R = TMS
20 R = H
17 Y = OH, H
18 Y = O
g
e
h
IHMes
Ru
HO
Cl
Cl
Therefore, we focused our attention on an alternative
preparation by Taddei and co-workers11 who described
the syntheses of various a-vinyl-b-aminoalcohols in
good syn-diastereoselectivities of generally higher than
20:1 by reaction of various N-Boc-protected a-amino-
N
H
(CH2)7CO2R
O
21 R = CH3
2 R = H
i
[Ru]
aldehydes
with
the
Seyferth–Fleming
ylide12
Scheme 3. (a) CrO3, H2SO4, acetone (75%); (b) MeOH, cat. H2SO4
(98%); (c) (i) O3, CH2Cl2, )78 ꢁC, (ii) Zn, HOAc (72%); (d) C2H3Br,
CrCl2, NiBr2 (cat.), DMF (78%); (e) DMP, CH2Cl2 (93%); (f)
18:11 ¼ 1:1.2, 5 mol % [Ru], toluene, 80 ꢁC; (g) TBAF, THF (78%, two
steps); (h) H2, Pd/C, MeOH; (i) KOH, MeOH (quantitative, two
steps).
Ph3P@CHCH2TMS 13 and subsequent desilylation of
the initially formed TMS-ether. The formation of the
products was rationalized by
a 1,4-shift of the
TMS-group and concomitant extrusion of PPh3 (see
intermediate 10, Scheme 2).13 Applying the literature
protocol to N-Cbz protected alaninal 9, which was
synthesized from L-alanine using standard procedures,
11 was obtained in yields of less than 15%, presumably
due to the enhanced lability of the Cbz group compared
to the Boc-group under the basic reaction conditions.
Taking this lability into account, the literature protocol
was slightly modified. Instead of allowing the reaction
mixture to warm to room temperature after addition of
the aldehyde 9 to the ylide 13 at )78 ꢁC, the reaction
mixture was only allowed to warm to 0 ꢁC and stirred at
that temperature for 1 h before quenching. This modi-
fication involved an increased yield of 11 of 64%. The
diastereoselectivity was found to be syn/anti 12:1. Desi-
lylation using TBAF in THF afforded 12 in 90% yield in
diastereomerically pure form.14
9-Decen-1-ol 14 served as the starting material for the
second CM partner (Scheme 3). Jones oxidation and
subsequent esterification furnished ester 15. We would
like to point out that we chose to protect the carboxylic
acid functionality as an ester for practical reasons in
order to avoid difficulties concerning work-up and solu-
bility problems of the free acid; the following reactions
including the metathesis step would not necessarily
require this protection. Ozonolysis of 15 followed by
reductive work-up afforded aldehyde 16, which was
vinylated using the Nozaki–Hiyama–Kishi reaction15 to
provide the allylic alcohol 17. Competing vinylation of
the ester moiety was not observed. Subsequent Dess–
Martin oxidation16 provided the enone 18.
RO
CO2CH3
NHBoc
6
a
NHBoc
7 (R = H)
8 (R = TBS)
b
CO2H
NH2
CHO
c,d
NHCbz
L-alanine
9
e
Next, the CM step was investigated. Ruthenium com-
plexes bearing N-heterocyclic carbene ligands such as
the second generation Grubbs catalyst (IH-
Mes)(PCy3)Cl2Ru(@CHPh)17 and its phosphine-free
variant [Ru]18 have proved to be efficient catalysts for
CM reactions between terminal olefins and acceptor-
substituted alkenes.19 Using either catalyst, CM between
18 and 12 afforded the desired product 20 in yields of
less than 60% due to competing homodimerization of 12
as the major side reaction. When using the synthetic
precursor 11 (syn/anti 12:1) as the CM partner instead of
12, gratifyingly, homodimerization could almost com-
pletely be suppressed. We assume that the decreased
RO
SiMe3
O
NHCbz
PPh3
NHCbz
10
11 (R = TMS)
12 (R = H)
f
Scheme 2. (a) (i) DIBAL-H, CH2Cl2, )78 ꢁC, (ii) C2H3MgCl, THF,
)78 ꢁC fi rt (52%, syn/anti 8:1); (b) TBS-Cl, imidazole, DMF; (c) (i)
MeOH, SOCl2; (ii) CbzCl, NaHCO3 (71%, two steps); (d) DIBAL-H,
toluene, )78 ꢁC (68%); (e) 13 (2.5 equiv), THF, )78 ꢁC fi 0 ꢁC, then
NH4Cl (aq) (64%, syn/anti 12:1); (f) TBAF, THF (90%, syn/anti-
> 20:1).

S. Randl, S. Blechert / Tetrahedron Letters 45 (2004) 1167–1169
1169
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high steric demand of the bulky TMS-group. Using
5 mol % of [Ru], the mixed CM product 19 could be
obtained in good yield. TMS-ether 11 was employed in a
slight excess of 1.2 equiv in order to suppress homo-
dimerization of 18, which occurred to a small extent as
the major side reaction in this CM. Subsequent treat-
ment of the crude product with TBAF furnished alcohol
20 in diastereomerically pure form.20 Treatment of 20
with Pd/C under a hydrogen atmosphere afforded (+)-
carpamic acid methyl ester 21 quantitatively and with
complete stereoselectivity. Subsequent saponification
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In summary, we have described a concise and highly
efficient total synthesis of (+)-carpamic acid. The key
steps of our convergent synthesis were the highly dia-
stereoselective vinylation of aldehyde 9, a selective CM
reaction and the reductive cyclization of aminoketone
20. Given the high functional group tolerance of the Ru
metathesis catalysts, our concept of CM in combination
with a subsequent cyclizing reductive amination in
general opens up a facile entry into the class of cis-2,6-
disubstituted piperidines. Further syntheses based on
this strategy are currently underway in our laboratories
and will be reported in due course.
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Acknowledgements
Financial support from the ÔFonds der chemischen
IndustrieÕ is gratefully acknowledged. S.R. thanks the
Graduiertenkolleg ÔSynthetische, mechanistische und
reaktionstechnische Aspekte von MetallkatalysatorenÕ
for a stipend.
13. Reactions of this type had previously been reported by
Tokoroyama et al.: (a) Tsukamoto, M.; Iio, H.; Tokoro-
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was obtained via column chromatography, afforded 12 as
a mixture of syn/anti 18:1. Since after the reaction, the
anti-isomer 11 was no longer detected in the reaction
mixture, the change in ratio of the diastereomers is not
based on kinetic reasons. The product(s) formed from
anti-11 could not be determined.
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