Reductive and oxidative transformations of the N-(cyanomethyl)oxazolidine system to expand the chiral pool of piperidines

Article abstract of DOI:10.1002/ejoc.200400404

Two new reactions have been exploited to modify piperidine scaffolds containing the chiral, non-racemic N-(cyanomethyl)oxazolidine system. A Raney nickel mediated decyanation was studied first, followed by an oxidative process using potassium permanganate

Full text of DOI:10.1002/ejoc.200400404

FULL PAPER
Reductive and Oxidative Transformations of the N-(Cyanomethyl)oxazolidine
System to Expand the Chiral Pool of Piperidines
David Francois,[a] Erwan Poupon,[b] Nicole Kunesch,[a] and Henri-Philippe Husson*[a]
¸
Keywords: Chirality / Lactams / Piperidines / Potassium permanganate / Raney nickel
Two new reactions have been exploited to modify piperidine
using potassium permanganate to furnish enantiopure lac-
scaffolds containing the chiral, non-racemic N-(cyano- tams including oxopipecolic acid derivatives.
methyl)oxazolidine system. A Raney nickel mediated de-
cyanation was studied first, followed by an oxidative process
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
dine ring system: an α-amino nitrile at the C-2 position and
an α-amino ether at the C-6 position. We focus in this paper
on two original reactions that we have observed with regard
to the N-(cyanomethyl)oxazolidine system: namely the re-
duction of the α-amino nitrile and the oxidation of the α-
amino ether.
Piperidin-6-ones have generally been regarded as precur-
sors to the corresponding piperidines,[3] but these two meth-
odologies can be used, from a synthetic viewpoint, as new
routes to functionalized piperidin-6-one structures from
their piperidine counterparts.
Contemporary organic chemists face the challenge of in-
venting and developing simple methodologies for easing ac-
cess to a wide range of biologically relevant compounds,
notably six-membered nitrogen-containing heterocycles.
Among these, the piperidine ring system is one of the most
common structural subunits found in alkaloids, pharma-
ceuticals, and synthetic intermediates. Because of the rich
chemistry and biology of this class of compounds, the syn-
thesis of diversely substituted enantiopure piperidine de-
rivatives has been a central and important theme in organic
chemistry in recent years. The variety of functionalities and
substitution patterns found in piperidine targets continues
to drive the search for new methodologies.[1]
Results and Discussion
Reductive Decyanation
In continuance of our efforts to expand the chiral pool
in the piperidine series, we report in this article an efficient
and straightforward route to substituted piperidines and pi-
peridones by taking advantage of the functionalizations of
the known and commercially available 3-phenylhexahydro-
5H-[1,3]oxazolo[3,2-a]pyridine-5-carbonitrile (1). The syn-
thetic potential of this chiral, non-racemic starting material
has already been demonstrated in numerous applications.[2]
Among its structural features, this building block contains
an N-(cyanomethyl)oxazolidine system and, accordingly,
possesses two non-equivalent reactive sites on the piperi-
The reductive decyanation of α-amino nitriles involves
selective replacement of a cyano group by a hydrogen atom.
The nature of this reaction, either ionic or radical, is dic-
tated by the choice of the reducing agent. The standard pro-
cedure involves reduction of the α-amino nitrile with an alk-
ali metal, usually lithium[4] or sodium,[5] in a mixture of
liquid ammonia and THF at low temperatures. It has also
been reported that α-amino nitriles can be decyanated with
[6]
systems such as AgBF4/Zn(BH4)2
or with classical hy-
dride donors (NaBH4,[7] LiAlH4,[8] BH3,[9] NaBH3CN[10]).
However, these methods have one or more limitations: (i)
metal/liquid ammonia requires a strongly basic medium,
[a]
´
Laboratoire de Chimie Therapeutique et Laboratoire de
´
Pharmacognosie, Faculte des Sciences Pharmaceutiques et and (ii) hydrides lack selectivity if the molecule has reduc-
´
`
´
Biologiques, UMR 8638 associee au CNRS et a l’Universite
ible moieties. Furthermore, in some cases, the use of hy-
drides has produced unsuccessful results[11] or has resulted
in the reduction of the cyano group into an amine.[12] The
outcome is highly dependent on the substitution pattern.
Overall, each of these methods represents a different bal-
ance of yield, toxicity, expense, and technical convenience.
Further, these methods frequently result in competitive side
reactions, notably in the presence of benzylamines and α-
´
Rene-Descartes (Paris 5),
4, avenue de l’Observatoire, 75256 Paris Cedex 06
Fax: (internat.) ϩ 33-1-43291403
E-mail: henri-philippe.husson@univ-paris5.fr
[b]
´
Laboratoire de Pharmacognosie associe au CNRS, UMR 8076
´
´
(BioCIS), Centre d’Etudes Pharmaceutiques, Universite Paris-
Sud 11,
´
ˆ
5, rue Jean-Baptiste Clement, 92296 Chatenay-Malabry, France
Fax: (internat.) ϩ 33-1-46835399
E-mail: erwan.poupon@cep.u-psud.fr
Eur. J. Org. Chem. 2004, 4823Ϫ4829
DOI: 10.1002/ejoc.200400404
© 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4823

D. Franc¸ois, E. Poupon, N. Kunesch, H.-P. Husson
FULL PAPER
amino ethers, groups that are readily hydrogenolysable and
reducible, respectively. Previous studies have shown, for ex-
ample, that α-amino ether moieties are not tolerated by DI-
BALH, LiAlH4,[13] or NaBH4.[14] Given the structural fea-
tures of our compounds, it is necessary to find reaction con-
ditions that are selective for the removal of the cyano group
without opening of the oxazolidine ring and/or without
cleavage of the chiral auxiliary.
Although a decyanation with metal/liquid ammonia or
with AgBF4/Zn(BH4)2 could theoretically be considered in
our case, we sought to develop a new practical method that
would complement existing methodologies. Earlier, we re-
ported the first example of reductive decyanation on the 3-
phenylhexahydro-5H-[1,3]oxazolo[3,2-a]pyridine-5-
Scheme 2. Decyanation of building block 1 derivatives; reagents
and conditions: (a) (i) LDA (3 equiv.), THF, Ϫ78 °C, 20 min, (ii)
MeI (2 equiv.), Ϫ78 °C Ǟ room temp. (95%); (b) Raney nickel
carbonitrile building block 1 [the key element of the
CN(R,S) strategy[2]] with Raney nickel (Scheme 1).[15] We
were pleased to observe that the process took place under (excess), THF, room temp., 1.5 h (quant., 4a/4b ϭ 1.8); (c) NaBH4
(5 equiv.), MeOH, room temp., 20 min (92%); (d) (i) LDA (3
extremely mild conditions, without causing the reduction of
equiv.), THF, Ϫ78 °C, 20 min, (ii) TsCN (2 equiv.), Ϫ78 °C, 4 h
any reducible or hydrogenolysable substituents. Despite the
widespread use of Raney nickel in reductive applications,
its use in decyanation has not received any attention and
therefore its potential is unknown. This prompted us to in-
vestigate the generality and scope of this method further
with various cyclic α-amino nitriles.
(67%); (e) Raney nickel (excess), THF, reflux, 3 h (20%, not optim-
ized, 7b/7a ϭ 3)
equatorial oxazolidine ring (Scheme 2). Some of these
NMR spectroscopic data are noteworthy as they indicate
the stereochemistry at C-2 and C-6 (Figure 1). The two
1
most significant H NMR signals of the 7a/7b mixture are
a doublet of doublets (J ϭ 10 Hz and 3.5 Hz) at δ ϭ
3.66 ppm attributable to the C-2 proton of the major dia-
stereomer 7b and a doublet of doublets (J ϭ 11 Hz and
3 Hz) at δ ϭ 3.23 ppm attributable to the C-2 proton of the
minor isomer 7a. The coupling constant and signal patterns
are characteristic of axial orientations for 2-H in 7a and 7b
and consequently reveal that the cyano groups are located
equatorially in these compounds. Moreover, close similarit-
ies in the NMR spectra of 4a and 7a as well as those of 4b
and 7b allowed us to assign the stereochemistry at C-6 in
7a and 7b. For example, the 13C chemical shifts of C-6 for
7b (δ ϭ 87.4 ppm) and C-2 for 4b (δ ϭ 89.1 ppm) are both
nearly identical and upfield with respect to those of the cor-
responding carbon atoms in 7a (δ ϭ 94.3 ppm) and 4a (δ ϭ
95.7 ppm). These comparisons and correspondences can be
accounted for by an axial position for 6-H in 7a and an
equatorial one in 7b. Also, the orientation of 6-H in 7a was
secured from the observation of a doublet of doublets (J ϭ
10 Hz and 2.5 Hz) at δ ϭ 3.73 ppm. This is in agreement
with an axial orientation, whereas the analogous hydrogen
atom in 7b appears as an undefined multiplet (δ ϭ
4.51Ϫ4.53 ppm). Moreover, the correlations between 2-Hb
and 7-Hb and between 2-Ha and the axial protons 6-Ha
Scheme 1. Decyanation of building block 1; reagent and con-
ditions: Raney nickel (excess), THF, reflux, 24Ϫ48 h (90%)
This study aims to address the following inquiries: (i)
what is the facial selectivity for quaternary α-amino nitriles,
(ii) what is the behavior of an α,α-dicyanopiperidine, and
(iii) with the support of these answers, can we put forward
a mechanism?
The stereoselectivity outcome of the reaction was first
addressed with quaternary α-amino nitriles. On the C-2
methyl derivative 3, prepared from 1,[6a] Raney nickel me-
diated decyanation was quantitative and afforded com-
pounds 4 as a mixture of two isomers, which were deter-
mined to be epimers at the 6-position without any racemiz-
ation of the C-2 methyl group. This was confirmed by re-
duction of the mixture of 4a and 4b with sodium
borohydride to a single diastereomer 5 (Scheme 2).[16]
Preference for an axial decyanation was demonstrated
when dicyano compound 6, obtained from 1,[15] was treated
under our conditions and afforded a 75:25 mixture of two
compounds in a moderate non-optimized yield. Mass
analysis of the mixture showed a single peak, m/z ϭ 229 [M
ϩ Hϩ], signifying the elimination of a single cyano group.
Careful NMR studies resulted in a complete understanding
of the composition of the mixture. The major compound
was assigned with certainty as 7b, possessing an axial ox-
Figure 1. Selected NMR spectroscopic data for compounds 7a
azolidine system, the minor compound being 7a with an and 7b
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© 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 4823Ϫ4829

Transformations of the N-(Cyanomethyl)oxazolidine System
FULL PAPER
and 7-Ha in the NOESY experiments confirmed the Regioselective Oxidation of the Oxazolidine System with
relative configurations of C-2 and C-6 with respect to 7-H Potassium Permanganate ؊ Easy Access to Enantiopure
(Figure 1). Thus, compound 7a has a cis relationship of the Lactams
hydrogen atoms at C-6 and C-7 (cis-oxazolidine), whereas
7b has a trans relationship for the same protons (trans-
oxazolidine).
To summarize, compounds 7a and 7b are stereomers of
the parent cyanopiperidine 1 and, more interestingly, they
display an antianomeric equatorial cyanopiperidine feature.
The 2-substituted piperidin-6-one pattern is noteworthy,
as it is found as a part of some natural products (e.g., cadi-
amine[19] and other natural products from Leguminosae),
as well as in some biologically interesting peptidomimetic
molecules (e.g., conformationally restrained peptides as po-
tent integrin antagonists[20]). Concerning oxopipecolic acid
The reaction was also carried out on the highly hindered
derivatives more particularly, they constitute, for example,
polyhydroxylated piperidine 8.[17] Despite a low yield due
a part of posatireline,[21] a TRH-like drug prescribed for the
treatment of senile dementia. They have also been used as
to purification problems relating to the high polarity of the
compounds, a single stereomer 9 was obtained in a very
synthetic intermediates for access to C-glycosylated amino
clean reaction, giving access to a new building block for the
acids[22] or γ- or δ-substituted α-amino acids.[23] Various es-
ters of N-protected 6-oxopipecolic acids have also been used
design of glycosidase inhibitors (Scheme 3).
as key compounds in the synthesis of dual metalloprotease
inhibitors,[24] and recently for the preparation of prototypi-
cal piperidone libraries and constrained analogues of ad-
ipic acid.[25]
Interest in such compounds has prompted us to develop
a general approach to a large variety of N-protected 2-sub-
stituted piperidin-6-ones (Figure 3). To this end, it appears
that building block 1 possesses two essential features. On
the one hand, the N,O-acetal system can be regarded as the
precursor of a lactam function after oxidation. On the other
hand, the presence of the cyano group might allow us to
accomplish some transformations in order to provide a gen-
eral and versatile route into the pipecolic series.
Scheme 3. Decyanation of polyhydroxylated building block 8; re-
agents and conditions: Raney nickel (excess), THF, reflux, 30 min
(30%)
This new decyanation method was shown to be highly
stereoselective and easy to use in the laboratory, despite epi-
merization at the C-6 position (oxazolidine moiety) in some
cases. This drawback was not so problematic, since these
compounds constitute synthetic intermediates and nucleo-
philic substitutions could eventually take place at this posi-
tion via the iminium salt form (potential iminium reactiv-
ity).
A reasonable mechanism, based on principles of stereoe-
lectronic control, is outlined below (Figure 2).[18] The initial
step could proceed by the expected generation of a prochi-
ral iminium ion, which could be explained in terms of a
‘‘push-pull’’ mechanism. The most favored conformation of
the iminium ion is shown in Figure 2. The reduction by the
hydrogen present in Raney nickel permits the subsequent
reduction of the iminium carbon atom from the upper face.
It should be noted that the delivery of the hydrogen is the
result of a stereoelectronically controlled process. The deliv-
ery occurs so that maximum orbital overlap is maintained
between the incoming hydrogen atom and the developing
lone-electron pair on the nitrogen atom, thereby resulting
in molecules in which the generated sp3-hybridized orbitals
are anticoplanar. Oxazolidine epimerization, as observed in
compounds 4 and 7, for example, probably occurs during
workup of the reaction mixtures.
Figure 3. Looking for an oxidation process
However, the synthetic methods that permit the oxidation
of the N,O-acetal without alteration of the CN group are
still limited. Our group has already shown that the α-amino
ether functions of (phenyloxazolo)piperidines could be oxi-
dized to the corresponding δ-lactams.[26] Despite favorable
yields, this method, by use of bromine followed by basic
treatment, was not very versatile with regard to the sub-
stituents at the 2-position on the piperidine ring. In fact, it
was impossible to oxidize 1 to the corresponding lactam.
Indeed, only 2,2-disubstituted (i.e., a cyano and an alkyl
group) or 2-alkyl-substituted molecules could be oxidized,
not allowing access to oxopipecolate derivatives.
We therefore looked for a new, convenient, and reliable
oxidation method with an appropriate oxidant that would
respect the integrity of the cyano group and could also be
a cornerstone reaction for the preparation of lactams.
Screening for an inexpensive and less toxic oxidizing agent,
we chose potassium permanganate. Many oxidations of ter-
tiary amines by use of potassium permanganate in aqueous
media have been reported: notably, the observed oxidation
Figure 2. Mechanistic considerations for Raney nickel decyanation occurred with monocyclic[27] or bicyclic systems.[28] Conse-
Eur. J. Org. Chem. 2004, 4823Ϫ4829
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D. Franc¸ois, E. Poupon, N. Kunesch, H.-P. Husson
FULL PAPER
quently, we set out to study the behavior of 1 and its deriva-
tives with this oxidant.
The key step of our scheme was the preparation of com-
pound 10 in 80% yield and on multigram scales from 1
(Scheme 4).[29] Most importantly, neither degradation nor
racemization at the CN group was observed. The presumed
mechanism for the reaction path is depicted in Scheme 4.
Firstly, permanganate ion oxidized the α-amino ether func-
tion to produce an iminium intermediate. The reduction of
permanganate ion to manganese dioxide in an aqueous me-
dium liberated hydroxy ions, which could trap the iminium
species. Finally, the opening of the oxazolidine and the sub-
sequent creation of the lactam function could explain the
formation of 10. Regioselective discrimination between the
two masked potential iminium functions was observed in
this reaction, with oxidation only on the oxazolidine side of
the nitrogen atom.
Scheme 5. Lactams derived from building block 1; reagents and
conditions: (a) KMnO4 (4 equiv.), acetone/H2O (7:3), room temp.,
20 h (90%); (b) KMnO4 (3 equiv.), acetone/H2O (1:1), room temp.,
24 h (75%); (c) KMnO4 (3 equiv.), acetone/H2O (1:1), room temp.,
12 h (60%); (d) H2O2 (1.2 equiv.), K2CO3, DMSO, 60 °C, 1 h
(70%); (e) KMnO4 (4 equiv.), acetone/H2O (1:1), room temp.,
24 h (50%)
Scheme 6. Lactam formation in the pyrrolidine series; reagents and
conditions: KMnO4 (4 equiv.), acetone/H2O (1:1), room temp.,
12 h (94%)
Scheme 4. Oxidation of building block 1 with potassium per-
manganate and plausible mechanism; reagents and conditions:
KMnO4 (7 equiv.), acetone/H2O (8:2), room temp., 2 d (80%)
Having performed this reaction successfully, we decided
to continue the study of KMnO4’s oxidative capacity with
a range of 2-substituted piperidin-6-ones and to try to es-
tablish its scope and limitations (Scheme 5). The decyan-
ated compound 2 was oxidized into lactam 12 in 75%
yield.[30] A better yield (90%) was observed when lactam
11[26] was targeted from decyanated derivative 4. Treatment
of the equatorial cyano derivatives 7a and 7b gave lactam
13.[31] It seems that an equatorial or pseudo-equatorial cy-
ano group does not behave like its axial counterpart in the
oxidative process; this was confirmed when the known
pyrrolidine building block 16[32] was oxidized by potassium
permanganate to afford compound 17 in high yield
(Scheme 6). The cyano group of 1 can be converted into an
Scheme 7. Lactams derived from building block 10; reagents and
conditions: (a) H2 (11 bar), PtO2 (1 equiv., w/w), EtOH, room
temp., 5 d (70%); (b) HCl/EtOH, room temp., 20 d (19: 65%; 20: Ͻ
5%, conversion 80%); (c) NaBH4 (1.2 equiv.), MeOH, room temp.,
30 min (93%)
amide function as described previously,[33] and oxidation of companied by small amounts (Ͻ 5%) of ethyl ester 20 and
14 gave, albeit in moderate yield, the interesting lactam 15. 20% of recovered 10. We then decided to investigate the
It then appeared that compound 10 was rich in synthetic possibility of obtaining an aldehyde (or equivalent) func-
potential. We now describe our first studies concerning the tion. The reduction of the lactone function with sodium
nitrile transformation possibilities of 10 (Scheme 7).
borohydride at room temperature in methanol afforded lac-
Firstly, reactivity studies suggested the synthesis of amine tol 21 (93% yield);[34] again, no racemization at C-2 oc-
18 by high-pressure PtO2 catalytic hydrogenation of 10 curred. This lactol, as a protected aldehyde, is of great inter-
(yield: 70%). Treatment of 10 with HCl/ethanol at room est for future exploration.
temperature afforded a slow but non-racemizing hydrolysis
We have shown that a small, discrete library of mono- or
of the CN group, providing lactone 19 in 65% yield, ac- bicyclic chiral, non-racemic lactams could easily be ob-
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© 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Transformations of the N-(Cyanomethyl)oxazolidine System
FULL PAPER
ν˜ ϭ 2244 cmϪ1
.
1H NMR (300 MHz, CDCl3): δ ϭ 1.6Ϫ2.1 (m),
tained from oxazolidine oxidation through the use of an
inexpensive, commercially available starting material and
potassium permanganate, and in a maximum of three steps
from 1. All compounds are enantiomerically pure (de Ͼ
96%, NMR) at crucial stereocenters (this point contrasts
with some of the other known methods for lactam syn-
thesis[35]). Compound 10, which is obtained in one step and
high yield from 1, possesses several structural elements re-
quired for an efficient and versatile building block (Figure 4
3.23 (dd, 3J ϭ 11, 3J ϭ 3 Hz), 3.66 (dd, 3J ϭ 10, 3J ϭ 3.5 Hz), 3.73
3
3
2
3
(dd, J ϭ 10, J ϭ 2.5 Hz), 3.75Ϫ3.8 (m), 3.93 (dd, J ϭ 8.3, J ϭ
4.3 Hz), 4.24 (t, 2J ϭ 3J ϭ 6.5 Hz), 4.39 (t, 2J ϭ 3J ϭ 8 Hz),
4.48Ϫ4.54 (m), 7.25Ϫ7.5 (m) ppm. 7a: 13C NMR (75 MHz,
CDCl3): δ ϭ 21.4, 29.0, 30.7, 49.7, 66.9, 73.8, 94.3, 117.4,
126.8Ϫ128.6, 139.8 ppm. 7b: 13C NMR (75 MHz, CDCl3): δ ϭ
17.4, 26.0, 28.4, 49.4, 66.2, 69.0, 87.4, 119.8, 126Ϫ128.6,
138.7 ppm. MS (CI, isobutane): m/z ϭ 229 [M ϩ 1]ϩ. HRMS (CI,
CH4): m/z calcd. for C14H17N2O 229.1341 [M ϩ 1]ϩ, found
examines its potential as a synthetic equivalent: i.e., cationic 229.1340.
or anionic synthons). It is particularly and notably an ex-
(3R,6S,7R,8S,8aS)-3-Phenylhexahydro-5H-[1,3]oxazolo[3,2-a]-
ample of a potential endocyclic N-acyliminium ion.[36] The
high flexibility of our approach is currently being studied,
with functionalization of, for example, the other positions
on the piperidine ring system of building blocks 10.[37] Fi-
nally, by starting from (S)-phenylglycinol, all compounds
are available in the enantiomeric series.
pyridine-6,7,8-triol (9): Hygroscopic, colorless crystals. Rf ϭ 0.25
(CH2Cl2/MeOH, 9:1). [α]2D0 ϭ Ϫ165 (c ϭ 1, MeOH). 1H NMR
(300 MHz, CD3OD): δ ϭ 2.14 (t, 2J ϭ 3J ϭ 10.5 Hz, 1 H), 2.94
3
2
3
(dd, J ϭ 5.5, J ϭ 10.5 Hz, 1 H), 3.33 (t, J ϭ 8.5 Hz, 1 H), 3.56
(dd, 3J ϭ 8.5, 3J ϭ 8 Hz, 1 H), 3.67 (ddd, 3J ϭ 10.5, 3J ϭ 5.5, 3J ϭ
3
1 Hz, 1 H), 3.71Ϫ3.83 (m, 2 H), 3.84 (d, J ϭ 8 Hz, 1 H), 4.35 (t,
2J J ϭ 6 Hz, 1 H), 7.2Ϫ7.4 (m, 5 H) ppm. 13C NMR (75 MHz,
3
CD3OD): δ ϭ 50.7, 67.3, 72.3, 75.6, 75.7, 79.4, 97.5, 128.7, 129.1,
129.7, 139.5 ppm. MS (CI, NH3): m/z ϭ 252 [M ϩ 1]ϩ. HRMS
(CI, CH4): m/z calcd. for C13H18NO4 252.1236 [M ϩ 1]ϩ, found
252.1240.
Oxidation with Potassium Permanganate: The preparation of lac-
tam 10 is representative. For individual conditions (KMnO4 equiv-
alents, solvents, time) and yields, see Schemes 5 and 6.
(2S)-1-[(1R)-2-Hydroxy-1-phenylethyl]-6-oxopiperidine-2-carbo-
nitrile (10): Building block 1 (1 g, 4.38 mmol) was dissolved in a
mixture of acetone and water (8:2, 250 mL), and KMnO4 (4.84 g,
30.6 mmol, 7 equiv.) was added in small portions over 4 h. The
mixture was stirred at room temp. for 2 d. The resulting suspension
was filtered and the filtrate was concentrated under reduced press-
ure. The resulting aqueous phase was diluted with a saturated solu-
tion of NaHCO3 and extracted with CH2Cl2 (3 times). The com-
bined organic layers were dried (Na2SO4) and concentrated under
reduced pressure to yield lactam 10 as a colorless oil (850 mg, 80%)
that crystallized slowly; recrystallization from diethyl ether is pos-
Figure 4. Lactams obtained from 1
sible. Colorless crystals. Rf ϭ 0.3 (CH2Cl2/MeOH, 98:2). [α]D25
Ϫ41 (c ϭ 1, CHCl3). M.p. 116Ϫ119 °C (diethyl ether). IR (CHCl3,
film): ν˜ ϭ 1631, 2337, 3370 cmϪ1 1H NMR (300 MHz, CDCl3):
δ ϭ 1.8Ϫ2.2 (m, 4 H), 2.45Ϫ2.6 (m, 1 H), 2.6Ϫ2.75 (m, 1 H), 3.4
ϭ
.
Conclusion
3
3
(br. s, 1 H), 4.1 (br. s, 2 H), 4.48 (dd, J ϭ 2, J ϭ 4.5 Hz, 1 H),
We have shown two simple methods for the rapid con-
struction of enantiopure scaffolds from easily obtainable
compounds. This work provides reliable, convenient, and
high-yielding reductive and oxidative methods with econ-
omical reagents to modify the N-(cyanomethyl)oxazolidine
system selectively.
3
5.57 (dd, J ϭ 6.5, 3J ϭ 5.5 Hz, 1 H), 7.2Ϫ7.5 ppm (m, 5 H) ppm.
13C NMR (75 MHz, CDCl3): δ ϭ 17.6, 27.4, 31.5, 46.4, 60.8, 61.8,
117.6, 128.5, 128.7, 128.9, 135.1, 170.7 ppm. MS (CI, NH3): m/z ϭ
245 [M ϩ 1]ϩ.
(2S)-1-[(1R)-2-Hydroxy-1-phenylethyl]-6-oxopiperidine-2-carb-
oxamide (15): Colorless oil (141 mg from 267 mg of 14). Rf ϭ 0.3
(CH2Cl2/MeOH, 91:9). [α]2D0 ϭ ϩ81 (c ϭ 1, CHCl3). IR (CHCl3,
film): ν˜ ϭ 1622, 1681, 3404 cmϪ1 1H NMR (300 MHz, CDCl3):
.
Experimental Section
δ ϭ 1.65Ϫ1.85 (m, 3 H), 2.3Ϫ2.6 (m, 3 H), 3.8Ϫ3.95 (m, 2 H), 4.34
(dd, 3J ϭ 11, 3J ϭ 6 Hz, 2 H), 4.81 (t, 2J 3J ϭ 11 Hz, 1 H), 7.2Ϫ7.4
(m, 5 H), 8.0 ppm (s, 2 H). 13C NMR (75 MHz, CDCl3): δ ϭ 17.3,
26.9, 32.9, 62.5, 63.7, 68.7, 127.7, 128.2, 128.7, 136.3, 172.6,
174.3 ppm. MS (CI, NH3): m/z ϭ 263 [M ϩ 1]ϩ. HRMS (CI, CH4):
m/z calcd. for C14H19N2O3 263.1396 [M ϩ 1]ϩ, found 263.1397.
General: For general techniques, see ref.[15]
Raney Nickel Decyanations: The preparation of piperidine 2 is
representative (see ref.[15]) of individual conditions and yields; see
Schemes 1Ϫ3.
(3R,5R,8aR)-3-Phenylhexahydro-5H-[1,3]oxazolo[3,2-a]pyridine-5-
carbonitrile (7a, minor) and (3R,5R,8aS)-3-Phenylhexahydro-5H-
[1,3]oxazolo[3,2-a]pyridine-5-carbonitrile (7b, major): Inseparable
mixture of diastereomers: Colorless oil. Rf ϭ 0.2 (cyclohexane/di-
(6S)-6-(Aminomethyl)-1-[(1R)-2-hydroxy-1-phenylethyl]piperidin-2-
one (18): Cyanolactam 10 (150 mg, 0.614 mmol) was dissolved in
EtOH (10 mL) and hydrogenated in the presence of PtO2 (100 mg)
under a pressure of 11 bar over 5 d. The catalyst was removed by
ethyl ether, 7:3). [α]2D0 ϭ Ϫ21 (c ϭ 1, CHCl3). IR (CHCl3, film): filtration, and the solution was concentrated under reduced press-
Eur. J. Org. Chem. 2004, 4823Ϫ4829
www.eurjoc.org
© 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4827

D. Franc¸ois, E. Poupon, N. Kunesch, H.-P. Husson
FULL PAPER
ure. The residue was purified by flash chromatography on silica gel
(CH2Cl2/MeOH, 85:15) to furnish the lactam 18 (106 mg, 70%).
Colorless oil. Rf ϭ 0.3 (CH2Cl2/MeOH, 85:15). [α]2D8 ϭ ϩ38 (c ϭ
1, CHCl3). IR (CHCl3, film): ν˜ ϭ 1616 cmϪ1. 1H NMR (300 MHz,
CDCl3): δ ϭ 1.65Ϫ2.00 (m, 4 H), 2.43 (m, 2 H), 2.6Ϫ2.9 (m, 3 H),
3.3Ϫ3.4 (m, 1 H), 4.0 (dd, 2J ϭ 12, 3J ϭ 6 Hz, 1 H), 4.41 (dd, 2J ϭ
12, 3J ϭ 8 Hz, 1 H), 4.71 (dd, 3J ϭ 6, 3J ϭ 8 Hz, 1 H), 7.2Ϫ7.4 ppm
(m, 5 H). 13C NMR (75 MHz, CDCl3): δ ϭ 16.3, 24.8, 32.0, 43.6,
59.4, 63.3, 65.6, 127.4, 128.4, 137.5, 172.1 ppm. MS (CI, NH3):
m/z ϭ 249 [M ϩ 1]ϩ. HRMS (CI, CH4): m/z calcd. for C14H20N2O2
248.1525 [M ϩ 1]ϩ, found 248.1523.
Acknowledgments
´
Joe¨lle Viret-Perard is gratefully acknowledged for providing us with
pyrrolidine 16. We also thank Sara M. Hasson for her helpful com-
ments.
[1]
[2]
[3]
[1a]
Recent reviews:
P. M. Weintraub, J. S. Sabol, J. M. Kane,
[1b]
D. R. Borcherding, Tetrahedron 2003, 59, 2953Ϫ2989.
G. P. Buffat, Tetrahedron 2004, 60, 1701Ϫ1729.
H.-P. Husson, J. Royer, Chem. Soc., Rev. 1999, 28, 383Ϫ394.
Preparation of 1: M. Bonin, D. S. Grierson, J. Royer, H.-P.
Husson, Org. Synth. 1991, 70, 54Ϫ59.
For representative examples, see:
M.
(4R,9aS)-4-Phenylhexahydropyrido[2,1-c][1,4]oxazine-1,6-dione (19)
and Ethyl (2S)-1-[(1R)-2-Hydroxy-1-phenylethyl)-6-oxopiperidine-2-
carboxylate (20): A solution of cyanolactam 10 (200 mg Ϫ0.985
mmol) in saturated HCl/ethanol (4 mL) was stirred at room temp.
for 20 d. The reaction mixture was diluted with a saturated solution
of NaHCO3 and extracted with CH2Cl2 (3 times). The combined
organic layers were dried (Na2SO4) and concentrated under re-
duced pressure. Purification by flash chromatography on silica gel
(CH2Cl2/MeOH, 98:2) first gave ester 20 (0Ϫ12 mg, 0Ϫ5%, un-
stable, spontaneous cyclization into 19), followed by lactone 19
(120Ϫ130 mg, 60Ϫ65%) and recovered 10 (30Ϫ40 mg, 15Ϫ20%).
Lactone 19: Colorless crystals. [α]2D5 ϭ Ϫ20 (c ϭ 1, CHCl3); m.p.
156Ϫ158 °C (diethyl ether). Rf ϭ 0.3 (CH2Cl2/MeOH, 97:3). IR
(CHCl3, film): ν˜ ϭ 1763, 1629 cmϪ1. 1H NMR (300 MHz, CDCl3):
δ ϭ 1.7Ϫ1.85 (m, 1 H), 1.85Ϫ2.0 (m, 1 H), 2.15Ϫ2.35 (m, 2 H),
2.35Ϫ2.55 (m, 2 H), 4.33 (dd, 3J ϭ 7.5, 3J ϭ 6 Hz, 1 H), 4.45Ϫ4.65
(m, 2 H), 5.71 (t, 3J ϭ 7.5 Hz, 1 H), 7.2Ϫ7.5 ppm (m, 5 H). 13C
NMR (75 MHz, CDCl3): δ ϭ 18.4, 24.5, 32.1, 52.0, 54.3, 68.4,
126.2, 128.6, 129.0, 136.0, 168.4, 169.2 (2 C) ppm. MS (CI, NH3):
m/z ϭ 246 [M ϩ 1]ϩ. HRMS (CI, CH4): m/z calcd. for C14H15NO3
245.1052 [M ϩ 1]ϩ, found 245.1051. Ester 20: Colorless oil. Rf ϭ
0.5 (CH2Cl2/MeOH, 97:3). IR (CHCl3, film): ν˜ ϭ 3417, 1734, 1636
[3a]
F. A. Davis, B. Chao, T.
[3b]
Fang, J. M. Szewczyk, Org. Lett. 2000, 2, 1041Ϫ1043.
C.
´
Agami, L. Dechoux, C. Menard, S. Hebbe, J. Org. Chem. 2002,
[3c]
67, 7573Ϫ7576.
M. K. S. Vink, C. A. Schortinghuis, J.
Luten, J. H. van Maarseveen, H. E. Schoemaker, H. Hiemstra,
F. P. J. T. Rutjes, J. Org. Chem. 2002, 67, 7869Ϫ7871.
[3d]
M.
Amat, N. Llor, J. Hidalgo, C. Escolano, J. Bosch, J. Org. Chem.
2003, 68, 1919Ϫ1928.
[4]
[5]
Representative example, see: S. Arseniyadis, P. Q. Huang, D.
Piveteau, H.-P. Husson, Tetrahedron 1988, 44, 2457Ϫ2470.
See for example: W. H. Bunnelle, C. G. Shevlin, Tetrahedron
Lett. 1989, 30, 4203Ϫ4206.
[6] [6a]
L. Guerrier, J. Royer, D. S. Grierson, H.-P. Husson, J. Am.
[6b]
Chem. Soc. 1983, 105, 7754Ϫ7755.
J. Royer, H.-P. Husson,
Tetrahedron Lett. 1985, 26, 1515Ϫ1518. [6c] J. Royer, H.-P. Hus-
son, J. Org. Chem. 1985, 50, 670Ϫ673.
Representative example: S.-I. Yamada, H. Akimoto, Tetra-
hedron Lett. 1969, 36, 3105Ϫ3108.
Representative example: M. G. Reinecke, R. G. Daubert, J.
Org. Chem. 1973, 38, 3281Ϫ3287.
[7]
[8]
[9]
K. Ogura, Y. Shimamura, M. Fujita, J. Org. Chem. 1991, 56,
2920Ϫ2922.
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
J. E. Baldwin, D. R. Spring, R. C. Whitehead, Tetrahedron
Lett. 1998, 39, 5417Ϫ5420.
1
3
cmϪ1. H NMR (300 MHz, CDCl3): δ ϭ 1.03 (t, J ϭ 7 Hz, 3 H),
S.-I. Yamada, K. Tomioka, K. Koga, Tetrahedron Lett. 1976,
2
3
1.6Ϫ1.8 (m, 3 H), 1.9Ϫ2.1 (m, 2 H), 2.5 (dd, J ϭ 10, J ϭ 7 Hz,
1, 61Ϫ64.
1 H), 2.56 (dd, J ϭ 7, 3J ϭ 4 Hz, 1 H), 3.6Ϫ3.8 (m, 2 H), 4.0Ϫ4.2
2
N. J. Leonard, F. P. Hauck, Jr., J. Am. Chem. Soc. 1957, 79,
5279Ϫ5292.
O. Froelich, P. Desos, M. Bonin, J.-C. Quirion, H.-P. Husson,
J. Zhu, J. Org. Chem. 1996, 61, 6700Ϫ6705.
C. Yue, I. Gauthier, J. Royer, H.-P. Husson, J. Org. Chem. 1996,
61, 4949Ϫ4954.
D. Franc¸ois, E. Poupon, M.-C. Lallemand, N. Kunesch, H.-P.
Husson, J. Org. Chem. 2000, 65, 3209Ϫ3212.
H. Poerwono, K. Higashiyama, T. Yamauchi, H. Takahashi,
Heterocycles 1997, 46, 385Ϫ400.
E. Poupon, B.-X. Luong, A. Chiaroni, N. Kunesch, H.-P. Hus-
son, J. Org. Chem. 2000, 65, 7208Ϫ7210.
R. V. Stevens, Acc. Chem. Res. 1984, 17, 289Ϫ296.
J. L. Van Eijk, M. H. Radema, Tetrahedron Lett. 1976, 24,
2053Ϫ2054.
L. Belvisi, A. Bernardi, A. Checchia, L. Manzoni, D. Potenza,
C. Scolastico, M. Castorina, A. Cupelli, G. Giannini, P. Carmi-
nati, C. Pisano, Org. Lett. 2001, 3, 1001Ϫ1004.
Drugs Fut. 1999, 24, 577.
(m, 3 H), 5.83 (t, 3J ϭ 7 Hz, 1 H), 7.2Ϫ7.4 ppm (m, 5 H). 13C
NMR (75 MHz, CDCl3): δ ϭ 13.8, 17.3, 26.5, 31.2, 43.0, 56.4, 58.3,
61.1, 128.3, 129.1, 135.2, 170.6, 171.2 (2 C) ppm. MS (CI, NH3):
m/z ϭ 292 [M ϩ 1]ϩ.
(1RS,4R,9aS)-1-Hydroxy-4-phenylhexahydropyrido[2,1-c][1,4]-
oxazin-6-one (21): Lactone 19 (90 mg, 0.37 mmol) was dissolved in
methanol (5 mL) and reduced with sodium borohydride (18 mg,
0.44 mmol, 1.2 equiv.) at room temp. After 0.5 h, the mixture was
concentrated under reduced pressure and the residue was dissolved
in CH2Cl2. The solution was washed with a saturated solution of
NaHCO3, dried (Na2SO4), and concentrated to furnish, after tritu-
ration in diethyl ether, lactol 21 (6:4 mixture of epimers, 85 mg,
93%). Amorphous white powder. Rf ϭ 0.2 (CH2Cl2/MeOH, 97:3).
[18]
[19]
[20]
IR (CHCl3, film): ν˜ ϭ 3320, 1616 cmϪ1
.
1H NMR (300 MHz,
CDCl3): major isomer: δ ϭ 1.35Ϫ2.15 (m, 4 H), 2.2Ϫ2.5 (m, 2 H),
3
2
3
[21]
[22]
3.31 (q, J ϭ 8 Hz, 1 H), 3.9 (dd, J ϭ 12, J ϭ 4 Hz, 1 H), 4.35
(br. d, 2J ϭ 12 Hz, 1 H), 4.54 (d, J ϭ 8 Hz, 1 H), 5.64 (br. t, 3J ϭ
3
B. Westermann, A. Walter, N. Diedrichs, Angew. Chem. Int.
Ed. 1999, 38, 3384Ϫ3386.
2
4 Hz, 1 H), 7.2Ϫ7.5 ppm (m, 5 H); minor isomer: δ ϭ 1.21 (td, J
[23] [23a]
3J ϭ 7, 3J ϭ 1 Hz, 1 H), 1.35Ϫ2.15 (m, 3 H), 2.2Ϫ2.5 (m, 2 H),
K. M. Muller, A. Schoenfelder, B. Didier, A. Mann, C.-G.
[23b]
2
2
Wermuth, Chem. Commun. 1999, 683Ϫ684.
J. Marin, A.
3.4Ϫ3.55 (m, 1 H), 4.07 (d, J ϭ 12 Hz, 1 H), 4.43 (dd, J ϭ 12,
3J ϭ 3.5 Hz, 1 H), 4.85 (s, 1 H), 5.78 (d, 3J ϭ 3.5 Hz, 1 H),
7.2Ϫ7.5 ppm (m, 5 H). 13C NMR (75 MHz, CDCl3): major isomer:
δ ϭ 17.9, 24.3, 32.3, 50.4, 55.9, 65.2, 97.3, 127.2, 127.5, 128.4,
138.2, 170.3 ppm; minor isomer: δ ϭ 18.0, 23.9, 32.5, 49.6, 53.2,
59.1; 91.2, 127.2, 127.6, 128.4, 138.4, 171.0 ppm. MS (CI, NH3):
m/z ϭ 248 [M ϩ 1]ϩ. HRMS (CI, CH4): m/z calcd. for C14H17NO3
247.1208 [M ϩ 1]ϩ, found 247.1208.
Violette, J.-P. Briand, G. Guichard, Eur. J. Org. Chem. 2004,
3027Ϫ3039.
[24] [24a]
K. Akasaka, H. Akamatsu, Y. Kimoto, Y. Komatsu, T.
Shimizu, N. Shimomura, K. Tagami, S. Negi, Chem. Pharm.
Bull. 1999, 47, 1525Ϫ1531.
Tagami, T. Shimizu, N. Shimomura, H. Naka, K. Hayashi, S.
[24b]
K. Akasaka, Y. Komatsu, K.
Negi, Chem. Pharm. Bull. 1999, 47, 1532Ϫ1537.
[25] [25a]
S. Hanessian, M. Seid, I. Nilsson, Tetrahedron Lett. 2002,
4828
© 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4823Ϫ4829

Transformations of the N-(Cyanomethyl)oxazolidine System
43, 1991Ϫ1992. [25b] S. Hanessian, W. A. L. van Otterlo, I. Nils-
FULL PAPER
P. Q. Huang, S. Arseniyadis, H.-P Husson, Tetrahedron
[32] [32a]
[32b]
son, U. Bauer, Tetrahedron Lett. 2002, 43, 1995Ϫ1998.
Lett. 1987, 28, 547Ϫ550.
J. Royer, H.-P. Husson, Tetra-
[26]
´
P. L i e nard, T. Varea, J.-C. Quirion, H.-P. Husson, Synlett
hedron Lett. 1987, 28, 6175Ϫ6178.
[33]
[34]
1994, 143Ϫ144.
Obtained as a 55:45 mixture of diastereomers in favor of α-
oxazolidine (1H NMR evaluation), see: J.-F. Berrien, J. Royer,
H.-P. Husson, J. Org. Chem. 1994, 59, 3769Ϫ3774.
7:3 ratio of epimers.
[27]
[28]
R. C. Cookson, M. E. Trevett, J. Chem. Soc. 1956, 2689Ϫ2695.
A. Cave, C. Kan-Fan, P. Potier, J. Le Men, M. M. Janot, Tetra-
hedron 1967, 23, 4691Ϫ4696.
[29] [29a] It should be noted that this compound has previously been
prepared in our group by electrochemistry (85% yield on a 110-
Methyl oxopipecolate (de 90%): S. A. Hermitage, M. G.
Moloney, Tetrahedron: Asymmetry 1994, 5, 1463Ϫ1464. 6-
[35] [35a]
[35b]
mg scale), see: F. Billon-Souquet, T. Martens, J. Royer, Tetra-
Alkylpiperidin-2-one (de 75%):
F. Bois, D. Gardette, J.-C.
[29b]
[35c]
hedron 1996, 52, 15127Ϫ15136.
For a recent two-step syn-
Gramain, Tetrahedron Lett. 2000, 41, 8769Ϫ8772.
For
thesis (470-mg scale), see: M. Amat, C. Escolano, N. Llor, M.
Huguet, M. Perez, J. Bosch, Tetrahedron: Asymmetry 2003,
other examples of synthesis of N-protected oxopipecolates
´
without reference to optical purity, see: I. G. C. Coutts, R. E.
14, 1679Ϫ1683.
Saint, S. L. Saint, D. M. Chambers-Asman, Synthesis 2001,
[30]
[35d]
Previous synthesis, see: L. Micouin, T. Varea, C. Riche, A. Chi-
aroni, J.-C. Quirion, H.-P. Husson, Tetrahedron Lett. 1994,
35, 2529Ϫ2532.
247Ϫ250.
N-Protected 6-alkylpiperidin-2-ones: J. R.
Casimir, C. Didierjean, A. Aubry, M. Rodriguez, J.-P. Briand,
G. Guichard, Org. Lett. 2000, 2, 895Ϫ897.
[31] [31a]
[36] [36a]
Obtained as a 75:25 mixture of epimers in favor of the
β-oxazolidine. First description of this lactam: J. Royer, H.-
Recent examples: A. A. Bahajaj, M. H. Moore, J. M. Ver-
[36b]
non, Tetrahedron 2004, 60, 1235Ϫ1246.
A. A. Bahajaj, J.
[31b]
P. Husson, Heterocycles 1993, 36, 1493Ϫ1496.
For recent
M. Vernon, G. D. Wilson, Tetrahedron 2004, 60, 1247Ϫ1253.
For recent and efficient alkylations of enantiopure bicyclic pip-
eridones derived from 6-oxopipecolic acid, see: A. G. Brewster,
S. Broady, C. E. Davies, T. D. Heightman, S. A. Hermitage, M.
Hughes, M. G. Moloney, G. Woods, Org. Biomol. Chem. 2004,
2, 1031Ϫ1043.
[37]
synthetic applications, see: N. Casamitjana, M. Amat, N. Llor,
´
´
M. Carreras, X. Pujol, M. M. Fernandez, V. Lopez, E. Molins,
C. Miravitlles, J. Bosch, Tetrahedron: Asymmetry 2003, 14,
2033Ϫ2039 and references cited therein. [31c] M. Amat, N. Llor,
´
C. Escolano, M. Huguet, M. Perez, E. Molins, J. Bosch, Tetra-
hedron: Asymmetry 2003, 14, 293Ϫ295.
Received June 7, 2004
Eur. J. Org. Chem. 2004, 4823Ϫ4829
www.eurjoc.org
© 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4829