Enantioselective Construction of 3-Hydroxypiperidine Scaffolds by Sequential Action of Light and Rhodium upon N-Allylglyoxylamides

Article abstract of DOI:10.1002/anie.201502584

3-Hydroxypiperidine scaffolds were enantioselectively constructed in an atom-economical way by sequential action of light and rhodium upon N-allylglyoxylamides. In a formal sense, the allylic C-H bond was selectively cleaved and enantioselectively added a

Full text of DOI:10.1002/anie.201502584

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201502584
German Edition: DOI: 10.1002/ange.201502584
Asymmetric Synthesis
Enantioselective Construction of 3-Hydroxypiperidine Scaffolds by
Sequential Action of Light and Rhodium upon N-Allylglyoxylamides**
Naoki Ishida, David Ne cˇ as, Yusuke Masuda, and Masahiro Murakami*
Abstract: 3-Hydroxypiperidine scaffolds were enantioselec-
tively constructed in an atom-economical way by sequential
action of light and rhodium upon N-allylglyoxylamides. In
a formal sense, the allylic CÀH bond was selectively cleaved
unsaturated ketones provides a mixture of a four-membered
cyclic product and six-membered one together with other
byproducts derived from Norrish-type fragmentation reac-
tions. We initially examined a photocyclization reaction of
N-allylglyoxylamides, in which a C=C bond is located at the
[
4]
and enantioselectively added across the ketonic carbonyl group
with migration of the double bond (carbonyl-ene-type reac-
tion).
d,e-position of the ketonic carbonyl group. The substrate
amide 1a (for structure see Scheme 1) was synthesized
through a conventional amide-forming reaction of commer-
cially available phenylglyoxylic acid with aniline followed by
a simple N-allylation reaction. When a benzene solution of 1a
in an ordinary Pyrex tube was irradiated using an LED lamp
(l = 365 nm), the four-membered lactam (Æ)-2a was pro-
duced in 43% yield [diastereomeric ratio (d.r.) = 67:33]
together with various byproducts including the six-membered
lactam 3a and olefin isomerized acyclic amides. In contrast,
photoirradiation of an acetonitrile solution of 1a with the
same lamp selectively furnished 2a in 80% yield with
d.r. value of 77:23 (Scheme 1). The vinyl and the hydroxy
A
piperidine scaffold is one of the structural motifs most
prevalent among biologically active compounds, including
[
1]
natural products (Figure 1). Although a wide variety of
methods have been developed for the construction of
Figure 1. Biologically active piperidine derivatives.
[
2]
piperidine scaffolds, there is still a strong demand for
catalytic asymmetric procedures offering straightforward
access starting from simple molecules. We herein report
enantioselective construction of 3-hydroxypiperidine scaf-
folds by the sequential action of light and rhodium upon N-
allylglyoxylamides. In a formal sense, the allylic CÀH bond is
Scheme 1. Photocyclization of the N-allylglyoxylamide 1a.
groups of the major diastereomer were cis to each other.
Mechanistically, the formation of (Æ)-2a from 1a can be
explained by a conventional pathway of a Norrish–Yang-type
selectively cleaved and added across the ketonic carbonyl
group with migration of the double bond (carbonyl-ene type
reaction), thus forming the six-membered ring with a chiral
quaternary carbon center in an atom-economical way.
It has been reported that N-alkylglyoxylamide derivatives
undergo photocyclization upon UV irradiation to furnish b-
[5]
cyclization reaction, wherein 1a initially absorbs a photon to
be promoted into an excited state. The excited carbonyl
oxygen atom of the benzoyl group abstracts the g-hydrogen
via a six-membered cyclic transition state to produce the 1,4-
biradical species A. The two radical centers intramolecularly
[3]
[6]
lactams and/or oxazolidinones. Photoirradiation of d,e-
couple to furnish the strained b-lactam scaffold.
Next, a restructuring reaction of the vinyl-substituted b-
lactam (Æ)-2a was examined (Scheme 2). It has been known
[
*] Dr. N. Ishida, Dr. D. Ne cˇ as, Y. Masuda, Prof. Dr. M. Murakami
Department of Synthetic Chemistry and Biological Chemistry
Kyoto University, Katsura, Kyoto 615-8510 (Japan)
E-mail: murakami@sbchem.kyoto-u.ac.jp
[
**] This work was supported in part by a Grant-in-Aid for Scientific
Research on Innovative Areas “Molecular Activation Directed
toward Straightforward Synthesis”, a Grant-in-Aid for Scientific
Research (B), and a Grant-in-Aid for Challenging Exploratory
Research from MEXT, and the ACT-C program of the JST. D.N. and
Y.M. acknowledged JSPS fellowship for young scientists.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201502584.
Scheme 2. Rhodium-catalyzed rearrangement of (Æ)-2a into (Æ)-3a.
cod=1,5-cyclooctadiene.
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[
7]
that four-membered cyclic alcohols undergo a ring-opening
[
8]
[9]
reaction by cleavage of a CÀC bond upon treatment with
a transition-metal complex. Various unique restructuring
reactions involving both cleavage and formation of a CÀC
bond have been reported based on the ring-opening proc-
[
8b–e]
ess.
We found that the restructuring of the diastereomeric
mixture of (Æ)-2a took place when treated with a rhodium
catalyst prepared in situ from [{Rh(OH)(cod)} ] (5 mol%)
2
and DPPF (1,1’-bis(diphenylphosphino)ferrocene, 12 mol%)
in 1,4-dioxane at 1108C. The 3,4-dihydropyridone (Æ)-3a was
Figure 2. Energies of 1a, 2a, and 3a estimated by DFT calculations.
[
10]
obtained in 67% yield upon isolation.
A plausible mechanistic pathway of the rearrangement
reaction of (Æ)-2a to (Æ)-3a is depicted in Scheme 3. Initially,
the hydroxide ligand on rhodium is exchanged with the
hydroxy group of (Æ)-2a to generate the rhodium alkoxide B
Scheme 4. Enantioselective restructuring of (Æ)-2a into (R)-3a.
Scheme 3. Plausible mechanism of rearrangement of (Æ)-2a into (Æ)-
3
a.
failed to afford 3a selectively. Diphosphine ligands with biaryl
backbones, such as (R)-BINAP (2,2’-bis(diphenylphosphino)-
1,1’-binaphthyl), produced 3a with moderate enantioselectiv-
ities. (R)-(S)-JOSIPHOS (1-[(2-diphenylphosphino)ferroce-
nyl])ethyldi(tert-butyl)phosphine) gave the highly enantioen-
riched (R)-3a (98% ee) in 69% yield. Thus, the chiral
quaternary carbon center of (Æ)-2a was formally derace-
mized to create the chiral quaternary carbon center of (R)-3a.
The restructuring mechanism shown in Scheme 3 is compat-
ible with this stereochemical outcome; the chiral centers of
(Æ)-2a once disappear upon ring opening from B to C, and
a new chiral quaternary carbon center is created in an
enantioselective manner at the subsequent CÀC bond-form-
and water. There are two modes available to open the
strained four-membered ring of B through b-carbon elimi-
3
nation: 1) cleavage of the bond bound to the allylic sp -carbon
[
9h,l]
atom
and 2) cleavage of the bond bound to the carbonyl
2
3
sp -carbon atom. The bond bound to the allylic sp -carbon
[11]
atom is preferentially cleaved to furnish the ring-opened
allylrhodium species C. It recyclizes by intramolecular
nucleophilic addition to the carbonyl group at the terminal
methylene carbon atom to construct the six-membered lactam
scaffold, which would be far less strained than the four-
membered lactam B. The rhodium alkoxide D is protonated
by water (or (Æ)-2a) to release (Æ)-3a along with the
rhodium hydroxide (or alkoxide B).
ing step from C to D.
The substrate scope of the sequential procedure from 1 to
3 was examined and the results are summarized in Table 1.
First, variously substituted N-allyl-N-arylglyoxylamides (1b–
m) were subjected to the photocyclization reaction under the
reaction conditions almost identical to those for 1a. The b-
lactams 2b–m were produced in yields ranging from 54 to
92% as the diastereomeric and racemic mixture. In case of N-
alkyl-N-allylglyoxylamides, photoirradiation induced g-
hydrogen abstraction at both N-alkyl and N-allyl sites, thus
giving a mixture of constitutional isomers of b-lactams. An N-
p-toluenesulfonyl derivative afforded the desired vinyl-b-
lactam together with various unidentified byproducts. We
then examined the rhodium-catalyzed rearrangement reac-
tion of 2b–m, which produced the corresponding 3,4-dihy-
dropyridones 3b–m. Of note were the high enantioselectiv-
ities, ranging from 96 to 98%, which were generally attained.
Thus, N-allylglyoxylamide 1a was atom-economically
cyclized to (Æ)-3a by the sequential action of light and
a rhodium catalyst. The energetics of the whole transforma-
tion was roughly estimated by DFT calculations (Figure 2).
The first photocyclization step is energetically uphill by about
À1
1
3 kcalmol . The light energy is absorbed by 1a and is stored
in the four-membered structure of (Æ)-2a as the ring strain.
The second rearrangement reaction of (Æ)-2a is energetically
À1
downhill by about 14 kcalmol , which would be mainly
ascribed to the release of the ring strain of the four-membered
structure.
We then examined induction of enantioselectivity by
using chiral ligands in the rhodium(I)-catalyzed restructuring
reaction of a diastereomeric mixture of (Æ)-2a to 3a
(
Scheme 4). Monodentate phosphoramidite ligands like 4
2
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Chemie
[
a]
Table 1: Enantioselective synthesis of 3.
diastereomeric mixtures. Treatment of the resulting mixture
with a chiral rhodium complex induces an enantioselective
restructuring reaction of the four-membered lactam into the
six-membered one through cleavage and formation of CÀC
bonds. In a formal sense, the allylic CÀH bond is cleaved and
atom-economically added across the ketonic carbonyl group
with migration of the double bond (carbonyl-ene-type
reaction).
Keywords: asymmetric synthesis · CÀC activation ·
Entry 1 (R, Ar)
2
3
[
b]
[c]
[b]
[d]
homogeneous catalysis · nitrogen heterocycles · rhodium
Yield [%]
d.r.
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
9
1
1
1
1b (4-MeOC H , Ph)
83
92
89
54
73
82
80
86
79
90
64
88
78:22
82:18
73:27
68:32
39:61
79:21
76:24
78:22
78:22
72:28
69:31
79:21
67
66
72
67
60
60
75
97
96
98
96
96
98
98
98
98
97
97
96
6
4
1c (4-ClC H , Ph)
6
4
1d (4-FC H , Ph)
6
4
1e (4-CF C H , Ph)
3
6
4
1 f (1-naphthyl, Ph)
1g (2-furyl, Ph)
1h (2-thienyl, Ph)
1i (Me, Ph)
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1j (Ph, 4-MeOC H )
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75
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6
4
0
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1k (Ph, 4-CF C H )
3 6 4
1l (Ph, 4-MeO CC H )
2
6
4
1m (Ph, 4-ClC H )
6
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(
[
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1
c] Determined by H NMR analysis. [d] Determined by HPLC analysis
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[
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Angew. Chem. Int. Ed. 2015, 54, 1 – 5
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Received: March 19, 2015
Published online: && &&, &&&&
4
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These are not the final page numbers!

Angewandte
Chemie
Communications
Asymmetric Synthesis
N. Ishida, D. Ne cˇ as, Y. Masuda,
M. Murakami*
&&&& — &&&&
Enantioselective Construction of 3-
Hydroxypiperidine Scaffolds by
Sequential Action of Light and Rhodium
upon N-Allylglyoxylamides
Action packed: 3-Hydroxypiperidine scaf-
folds were enantioselectively constructed
in an atom-economical way by the title
reaction. In a formal sense, the allylic CÀ
H bond was selectively cleaved and
added across the ketonic carbonyl group
with migration of the double bond.
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!