Organocatalytic entry into 2,6-disubstituted aza-Achmatowicz piperidinones: Application to (-)-sedacryptine and its epimer

Article abstract of DOI:10.1021/ol500633u

Enantiomerically pure 2,6-disubstituted piperidinones were synthesized from furfural involving an organocatalyzed Mannich reaction, aza-Achmatowicz reaction, and an N-acyliminium ion-mediated coupling step. This approach was also successfully applied to a total synthesis of (-)-sedacryptine and one of its epimers.

Full text of DOI:10.1021/ol500633u

Letter
pubs.acs.org/OrgLett
Organocatalytic Entry into 2,6-Disubstituted Aza-Achmatowicz
Piperidinones: Application to (−)-Sedacryptine and Its Epimer
Ferdi van der Pijl, Robert K. Harmel, Gaston J. J. Richelle, Peter Janssen, Floris L. van Delft,
and Floris P. J. T. Rutjes*
Institute for Molecules and Materials, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
S
* Supporting Information
ABSTRACT: Enantiomerically pure 2,6-disubstituted piperidi-
nones were synthesized from furfural involving an organo-
catalyzed Mannich reaction, aza-Achmatowicz reaction, and an
N-acyliminium ion-mediated coupling step. This approach was
also successfully applied to a total synthesis of (−)-sedacryptine
and one of its epimers.
he 3-hydroxypiperidine scaffold is considered a privileged
structural moiety in Nature. Various natural products
share this skeletal basis, and many of them exhibit relevant
biological activities.1 Prominent examples of natural products
containing this scaffold include (−)-sedacryptine (1) and
(+)-febrifugine (2) (Figure 1). A number of synthetic
bonyl)-protected amines as substrates for the aza-Achmatowicz
reaction.6 These N-Boc-protected amines were prepared via the
proline-catalyzed asymmetric Mannich reaction by applying the
conditions reported by List et al.6c,d Thus, under basic
conditions, sulfone 5 was eliminated to give the corresponding
crude imine,7 which was directly treated with L-proline (20 mol
%) and an aldehyde to give the corresponding β-amino
aldehydes (Table 1). The resulting crude Mannich products
were directly in situ reduced, resulting in γ-amino alcohols 7a−f
which were readily isolated by precipitation from n-heptane.
Aliphatic (Table 1, entries 1−3), allylic (Table 1, entry 4), and
aromatic substituents (Table 1, entries 5 and 6) were smoothly
introduced in reasonable yields and with excellent selectivities.
T
Table 1. Asymmetric Organocatalytic Mannich Reaction
Figure 1. 3-Hydroxypiperidine-containing alkaloids.
approaches to this scaffold have been reported,2 including
strategies that have been published by our group to synthesize
(+)-febrifugine (2).3 Despite the existing methods, there is a
need for preferably catalytic methodologies to asymmetrically
synthesize these scaffolds and have access to new substitution
patterns. We considered the substituted piperidinones 4
versatile precursors for the target 3-hydroxypiperidines, which
in turn should be accessible via the aza-Achmatowicz reaction
from the corresponding enantiopure aminomethyl furans 3.4
Based on our experience with the proline-catalyzed Mannich
reaction,5 we envisioned that these enantiopure furans should
be readily accessible from furfural.
a
b
b
entry
product
R
yield (%)
dr
ee (%)
1
2
3
4
5
6
7a
7b
7c
7d
7e
7f
Me
Pr
54
57
58
71
50
43
>1:20
>1:20
>1:20
>1:20
>1:20
>1:20
>99
>99
97
i-Pr
allyl
Ph
99
>99
c
4-BrC6H4
95
a
b
Isolated yield. Determined after precipitation from n-heptane.
Absolute stereochemistry determined by X-ray structure analysis.9
c
Considering the facile deprotection and their ability to
induce high stereoselectivity in organocatalyzed Mannich
reactions, we chose to work with N-Boc (N-tert-butyloxycar-
Received: February 28, 2014
Published: March 26, 2014
© 2014 American Chemical Society
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Letter
The next step was the aza-Achmatowicz reaction, which
according to the literature in the case of carbamoylated amines
with NBS/MeOH is likely to result in formation of significant
amounts of side products, in particular the overoxidized 3-
hydroxypyridine.4 By using m-CPBA as the oxidant, the
pyridine formation could to a large extent be suppressed.8
Indeed, aza-Achmatowicz reactions with m-CPBA of γ-amino
alcohols 7a−e afforded the intended hemiaminals, which due to
the anticipated lability, were directly converted with CH(OEt)3
and BF3·Et2O into the N,O-acetals 10a−e in moderate to good
yields (Table 2, entries 1−4 and 6). Nevertheless, we observed
Table 3. N-Acyliminium Ion Addition Reactions
a
Table 2. Aza-Achmatowicz Reactions
b
c
entry substrate product
R
R1
R2
yield (%)
dr
1
2
3
4
5
6
7
7a
7b
7c
7d
7e
9
10a
10b
10c
10d
9e
Me
Pr
H
H
H
H
H
H
Ac
Et
Et
Et
Et
H
88
89
45
79
84
78
70
1:1.1
1:1.2
1:1.1
1:1.0
1:4
a
b
Isolated yield of major diastereoisomer after chromatography. Based
c
on 1H NMR of crude product. Isolated as a mixture of
diastereoisomers. Reaction in CH2Cl2 at −50 °C. With BF3·Et2O
(3 equiv) in CH2Cl2 at −78 °C.
i-Pr
allyl
Ph
d
e
10e
11
Ph
Et
H
1:1.2
1:6
(trimethylsiloxy)styrene surprisingly gave inversion of the
selectivity so that the trans-isomer was formed as the major
product (Table 3, entry 6).
8
Ph
a
Conditions: (a) Ac2O, Et3N, DMAP; (b) BF3·Et2O, CH(OEt)3.
Isolated yield. Based on H NMR of crude product.
b
c
1
Having established a robust sequence of steps to prepare
enantiopure piperidinones, we aimed to apply this pathway in a
total synthesis of (−)-sedacryptine (1).11
that 9e was more stable than expected and could be purified by
flash chromatography (Table 2, entry 5). NMR analysis
revealed that N,O-acetals 10a−e and 9e were isolated as
bicyclic hemiacetals rather than the corresponding hydrox-
yketones. The monocyclic piperidinone 11 was prepared by
acetylation of the primary alcohol prior to the aza-Achmatowicz
reaction (Table 2, entry 7).
A retrosynthetic analysis of (−)-1 is shown in Scheme 1. We
envisioned that the 2-hydroxy-2-phenylethyl substituent of
Scheme 1. Retrosynthetic Analysis
With these enantiopure N,O-acetal scaffolds in hand, we
studied further functionalization via N-acyliminium ion
chemistry.3,10 Initial attempts showed that allyltrimethylsilane
addition to the N-acyliminium ion derived from 10e did not
give the desired results. On the other hand, N-acyliminium ion
reactions starting from 9e afforded the anticipated 2,6-
disubstituted products, although with poor diastereoselectiv-
ities.
Preferred axial attack of the nucleophile is hampered by steric
interactions with the concave side of the molecule. Con-
sequently, we expected better selectivities when monocyclic
piperidinone 11 was subjected to N-acyliminium ion chemistry.
Gratifyingly, reacting 11 with allyltrimethylsilane in the
presence of a catalytic amount of tin(II)triflate, followed by
deprotection of the crude product with TFA, resulted in
formation of 2,6-disubstituted piperidinone 12a as a single cis-
diastereoisomer (Table 3, entry 1).
We also observed that increasing the steric bulk of the
nucleophile had a large effect on the selectivity of the reaction
due to hindrance of the axially positioned 2-substituent (Table
3, entries 2 and 3), while addition of the smaller 3-
trimethylsilyl-1,2-butadiene afforded 12d again as a single
diastereoisomer (Table 3, entry 4). Addition of 2-
(trimethylsiloxy)propene yielded a 1:1 mixture of diaster-
eoisomers (Table 3, entry 5), while addition of α-
(−)-1 could be introduced either from 22 by ozonolysis and
subsequent Grignard addition or via reduction of benzylic
ketone 17. Both 17 and 22 can be traced back to N-
acyliminium ion precursor 15, which in turn will be derived
from β-amino ketone 13.
The synthesis of 13 commenced with the conversion of α-
amido sulfone 5 into the corresponding imine (Scheme 2),
which was subsequently reacted with acetone in a proline-
catalyzed asymmetric Mannich reaction affording 13 in 71%
yield and excellent ee (99%). It appeared necessary to conduct
this reaction under dilute conditions (0.02 M) to prevent the
product from reacting with a second imine leading to the
bisadduct. After protection of the ketone as a dioxolane with
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Organic Letters
Letter
Scheme 2. Preparation of the N-Acyliminium Ion Precursor
Scheme 3. Synthesis of 6-epi-sedacryptine
ethylene glycol and TsOH, the stage was set for the aza-
Achmatowicz reaction. Unfortunately, the reaction with m-
CPBA in CH2Cl2 resulted in oxidation of the desired
hemiaminal into 3-hydroxypyridine derivative 16. We reason
that 16 was formed via a 3-chlorobenzoic acid-facilitated
dehydration of 15, followed by a Baeyer−Villiger type oxidation
of the intermediate iminium ion, driven by the resulting
aromatic character of the ring. Switching to nonacidic oxidants
might suppress iminium ion formation and hence oxidation of
the product. Investigating the aza-Achmatowicz reaction of 14
with alternative oxidants (e.g., singlet oxygen,12 NBS, Br2, or
dioxiranes)13 showed that only dimethyldioxirane (DMDO)
resulted in clean product formation (82% yield).
Scheme 4. Total Synthesis of (−)-Sedacryptine
However, since the preparation of large quantities of DMDO
is rather laborious, we adjusted the initial procedure by
introducing a biphasic system to remove the acidic remainder
of the reaction. Indeed, conducting the aza-Achmatowicz
reaction with m-CPBA in a CH2Cl2/phosphate buffer at pH
7.4 furnished 15 in 60% yield. At this point, introduction of the
C-6 substituent had to be realized via N-acyliminium ion
addition. Applying the conditions to prepare compounds 12
(vide supra) smoothly afforded ketone 17 as a single
diastereoisomer in 88% yield. Since NMR did not give
conclusive information of the stereochemistry at this stage,
we chose to continue the synthesis with reduction of both
ketones with (R)-CBS/BH3·Me2S and subsequent olefin
hydrogenation to give diol 19. The stereochemistry of 19 was
confirmed by 2D NOESY analysis of cyclic carbamate 21.11e,g
Subsequent LiAlH4 reduction, deprotection, and acetal
hydrolysis then provided 6-epi-sedacryptine 20 in 9% overall
yield (Scheme 3).
In order to synthesize the naturally occurring diaster-
eoisomer of sedacryptine, we decided to continue with the
cis-substituted piperidinone 22, readily obtained as a single
diastereoisomer in 46% yield by addition of allyltrimethylsilane
to the N-acyliminium ion derived from 15 (Scheme 4).
Subsequent conjugate reduction with a copper hydride
species followed by fluoride-mediated desilylation afforded
ketone 23 in 85% yield.14 Stereoselective ketone reduction and
ozonolysis of the double bond resulted in an inseparable
mixture of the aldehyde and triphenylphosphine oxide, but
subsequent silylation with TBSCl allowed us to obtain aldehyde
25 in pure form. Construction of the 2-hydroxy-2-phenylethyl
substituent was finished by Grignard addition of PhMgBr to
aldehyde 25 resulting in the benzylic alcohol obtained as a
separable mixture of diastereoisomers. The action of LiAlH4 in
refluxing THF then resulted in removal of the TBS group and
reduction of the carbamate. Finally, ketone deprotection and
isomerization of the resulting hemiacetal in hot aqueous HCl
furnished (−)-sedacryptine (1) of which the optical rotation
and NMR spectra were in accordance with literature values.11b,g
In conclusion, we have developed an organocatalyzed
Mannich/aza-Achmatowicz/N-acyliminium ion reaction se-
quence for straightforward preparation of enantiopure 2,6-
disubstituted piperidines. This sequence was successfully
applied to a total synthesis of natural (−)-sedacryptine (1)
and its C-6-trans epimer 20.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization of new products, and
1
copies of H and 13C NMR spectra, including NOESY analysis
for the structural assignments of 12a, 12f, and 21. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: f.rutjes@science.ru.nl.
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Organic Letters
Letter
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was part of the CatchBio program, which was
supported by the Smart Mix Program of The Netherlands
Ministry of Economic Affairs and The Netherlands Ministry of
Education, Culture and Science.
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