Novel Routes to Chiral 2-Alkoxy-5-/6-methoxycarbonylmethylidenepyrrolidines/-piperidines

Article abstract of DOI:10.1021/jo049961c

We report the results of a study aimed at the diastereoselective synthesis of chiral 2-alkoxy-5-/6-methoxy carbonylmethylidenepyrrolidines/-piperidines by condensation of chiral amines onto ω-oxo alkynoates and ω-oxo β-keto esters.

Full text of DOI:10.1021/jo049961c

SCHEME 1
Novel Rou tes to Ch ir a l 2-Alk oxy-5-/6-
m eth oxyca r bon ylm eth ylid en ep yr r olid in es/
-p ip er id in es
Olivier David, Sandrine Calvet, Franc¸ois Chau,†
Corinne Vanucci-Bacque´,
Marie-Claude Fargeau-Bellassoued, and
Ge´rard Lhommet*
Universite´ P. et M. Curie, Chimie des He´te´rocycles, UMR
7611, 4 Place J ussieu, 75252 Paris Cedex 05, France
SCHEME 2
lhommet@ccr.jussieu.fr
Received J anuary 6, 2004
Abstr a ct: We report the results of a study aimed at the
diastereoselective synthesis of chiral 2-alkoxy-5-/6-methoxy-
carbonylmethylidenepyrrolidines/-piperidines by condensa-
tion of chiral amines onto ω-oxo alkynoates and ω-oxo â-keto
esters.
droxy alkynes according to literature procedures.5 The
related methyl ketones 2a and 2b6 were prepared in two
steps from aldehydes 1a and 1b in, respectively, 50% and
54% overall yield, by chemoselective addition of methyl-
magnesium chloride on the aldehyde moieties followed
by IBX oxidation7 of the resulting crude alcohols (Scheme
2).
When reacted in methanol in the presence of 1 equiv
of (S)-1-phenylethylamine and 4 Å molecular sieves,
aldehyde 1a afforded the expected chiral â-enamino ester
3 in 76% yield (Scheme 3) as the E configuration for the
double bond1a and a 7:3 diastereomeric mixture at C-2
(determined by NMR analysis). Upon chromatography on
silica gel, compound 3 tended to lose methanol leading,
after aromatization, to the unprecedented chiral pyrrole
4. Based on this observation, we anticipated that the
condensation of (S)-1-phenylethylamine on 1a would lead
to 4 in the absence of methanol. Indeed, when conducted
in refluxing toluene, the reaction afforded 4 in moderate
60% yield (Scheme 3). One can note indeed the formation
of unidentified secondary products which lowered the
isolated yield of 4.
We assumed that this reaction had proceeded through
the initial formation of an acyclic hemiaminal resulting
from addition of the chiral amine on the carbonyl of the
aldehyde, the most electrophilic center of the molecule,
followed by dehydration to give an imine intermediate.
In aprotic solvent, subsequent imine/enamine isomeriza-
tion followed by addition of the nitrogen atom on the
triple bond would afford the corresponding 2,3-dihydro-
pyrrole that would rearrange to pyrrole 4 (Scheme 3).
On the other hand, in the presence of methanol, addition
of the solvent on the imine would afford two diastereo-
meric hemiaminals with little diastereofacial selectivity.
Subsequent intramolecular attack of the nitrogen atom
on the triple bond would then lead to the target molecule
3 with the observed poor stereoselectivity (Scheme 3). To
Saturated nitrogen-containing heterocycles bearing a
â-enamino ester are versatile and useful synthetic inter-
mediates for the preparation of natural products.1 We
have recently introduced a new strategy to synthesize
such chiral pyrrolidines and piperidines by condensation
of chiral amines on ω-halogeno alkynoates2 or â-keto
esters.3 This approach constitutes a valuable alternative
to the Eschenmoser procedure4 in terms of workup, ease
of purification, and sparing of the sacrificial chiral
auxiliaries owing to their introduction in the late stage
of the synthesis. However, this methodology only yields
2-monosubstituted pyrrolidines and piperidines. To ac-
cess polysubstituted heterocycles, we were interested in
increasing the synthetic potential of our target â-enamino
esters by introducing an additional hemiaminal moiety
which would act as a masked iminium ion allowing easy
nucleophilic subtitutions at the R position of the nitrogen
atom. We thus envisioned that reaction of ω-oxo alkyn-
oates (route a) or ω-oxo â-keto esters (route b) with chiral
amines would lead to such structures (Scheme 1). We now
report the results of this study which features the
reaction of (S)-1-phenylethylamine and (S)-phenylglycinol
with alkynoates and â-keto esters possessing a terminal
aldehyde or methyl ketone moiety.
We first considered synthesizing the target compounds
starting from various ω-oxo alkynoates (Scheme 1, route
a). The required aldehydes 1a and 1b were readily
obtained starting from the corresponding terminal ω-hy-
† Current address: Universtite´ Denis Diderot, Laboratoire de Phar-
macochimie Mole´culaire, 2 Place J ussieu,75251 Paris Cedex 05, France.
(1) (a) Michael, J . P.; Gravestock, D. Eur. J . Org. Chem. 1998, 865.
(b) Hart, D. J .; Hong, W.-P.; Hsu L.-Y. J . Org. Chem. 1987, 52, 4665.
(c) Petersen, J . S.; Fels, G.; Rapoport, H. J . Am. Chem. Soc. 1984, 106,
4539. (d) Cook, G. R.; Beholz, L. G.; Stille, J . R. Tetrahedron Lett. 1994,
35, 1669.
(2) David, O.; Fargeau-Bellassoued, M.-C.; Lhommet, G. Tetrahedron
Lett. 2002, 43, 3471.
(3) Calvet, S.; David, O.; Vanucci-Bacque´, C.; Fargeau-Bellassoued,
M.-C.; Lhommet G. Tetrahedron 2003, 59, 6333.
(4) Roth, M.; Dubs, P.; Go¨tschi, E.; Eschenmoser, A. Helv. Chim.
Acta 1971, 54, 710.
(5) Trost, B. M.; Shi, Y. J . Am. Chem. Soc. 1993, 115, 12491.
(6) Lee, G. H.; Choi, E. B.; Lee, E.; Pak, C. S. J . Org. Chem. 1994,
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(7) More, J . D.; Finney, N. S. Org. Lett. 2002, 4, 3001.
10.1021/jo049961c CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/13/2004
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J . Org. Chem. 2004, 69, 2888-2891

SCHEME 3
SCHEME 4
support these hypotheses, we conducted an experiment
in which the progress of the reaction was followed in a
from 6 in, respectively, 16% and 62% isolated yields (from
the initial mixture). Progress of this hydrogenation by
NMR showed that known cyclohexene 99 was an inter-
mediate toward 8 resulting from partial reduction. The
stereochemistry of 8 was assigned as (1R,2S,RS) by
comparison of its NMR data with those of the known
analogue ethyl esters10 for which all possible diastereo-
mers have been described (Scheme 4).
As in the case of aldehyde 1a , the obtention of
compounds 5 and 6 can be rationalized by the initial
formation of an intermediate imine 10 (Scheme 5) whose
formation was clearly established during an NMR ex-
periment. When equimolar amounts of 1b and (S)-1-
phenylethylamine were added in an NMR tube, we
indeed observed the immediate disappearance of the
aldehyde proton and carbon signals (δ 9.76 and 200.8)
while the signals of the imine (δ 7.76 (t, J ) 4 Hz) and
161.7) clearly appeared. At this stage, we assumed that
imine 10 could afford enamino piperidine 5 according to
a process similar to the one leading to 4 (see Scheme 3).
In parallel, a second molecule of (S)-1-phenylethylamine
would add to the activated triple bond of 10 to give rise
to a transient enamine that would then react intramo-
lecularly on the imine moiety to give a cyclic intermedi-
ate. Subsequent isomerization of the imine/enamine
followed by elimination of (S)-1-phenylethylamine and
1
tube by H and 13C NMR: 1a was dissolved in deuterio-
chloroform and an equimolar amount of (S)-1-phenyl-
ethylamine was added. We immediately observed the
disappearance of the aldehyde proton at δ 9.79 and the
simultaneous appearance of a triplet at δ 7.80 (J ) 4 Hz)
assigned to the presence of the transient imine and of
the signals characteristic of pyrrole 4.
Concerning alkynoate 1b, reaction in methanol in the
presence of 4 Å molecular sieves did not give rise to the
expected heterocycle at all but to an intractable complex
mixture. At this stage, we envisaged running the reaction
in nonalcoholic solvents in order to prepare, via a process
similar to that leading to pyrrole 4, the enaminopiperi-
dine 5 that we expected to act as an iminium precursor
(Scheme 4). However, when 1b and the amine were
reacted in CH2Cl2 at room temperature in the presence
of MgSO4 as a dehydrating agent, we identified not only
the expected compound 5 but also more surprisingly
cyclohexadiene 6 as the major product (Scheme 4). This
mixture, obtained in 93% yield (ratio 5/6 17:83 according
to NMR and GC analysis), underwent degradation upon
silica gel chromatography, which prevented clean isola-
tion of 5 and 6. A bulb-to-bulb distillation did not allow
their isolation either. Therefore, we performed a catalytic
hydrogenation on the crude mixture in order to secure
the proposed structures. This reaction afforded the known
compound 78 arising from 5 and cyclohexane 8 arising
(9) Cave´, C.; Daley, V.; d’Angelo, J .; Guingant, A. Tetrahedron:
Asymmetry 1995, 6, 79.
(10) (a) Xu, D.; Prasad, K.; Repic, O.; Blacklock, T. J . Tetrahedron:
Asymmetry 1997, 8, 1445. (b) Schinnerl, M.; Murray, J . K.; Langenhan,
J . M.; Gellman, S. H. Eur. J . Org. Chem. 2003, 721.
(8) Ledoux, S. Ph.D. Thesis, Universite´ P. et M. Curie, Paris, 2000.
J . Org. Chem, Vol. 69, No. 8, 2004 2889

SCHEME 5
SCHEME 6
SCHEME 7
final prototropy would lead to compound 6. This process,
catalytic in amine, is summarized in Scheme 5.
As far as methyl ketones 2a and 2b were concerned,
we obtained disappointing results: reactions with (S)-1-
phenylethylamine in methanol only yielded intractable
complex mixtures.
signals (δ 7.78 (t, J ) 4 Hz) and 165.1) along with those
characteristic of two oxazolidines in a 3:7 ratio (in
particular, CH signals at δ 91.7 and 92.1). Based on these
observations and in order to rationalize the stereochem-
ical outcome of these reactions, we postulated that they
proceeded through the initial formation of an intermedi-
ate imine that subsequently underwent an intramolecu-
lar addition of the hydroxyl of the N-(2-phenyl-1-hydroxy
ethyl) moiety to afford a diastereomeric mixture of
oxazolidines A and B (Scheme 7). The resulting hemi-
aminal nitrogen atom would then attack the activated
triple bond. The observed diastereoselectity during this
step (de > 90%) suggested that a dynamic kinetic
resolution occurred during the final cyclization step, as
previously proposed in the case of a diastereoselective
preparation of oxazolopiperidones.13 The preferential
formation of the major isomer would be a consequence
of a cyclization occurring faster from trans oxazolidine
A and of the progressive isomerization of B into A driven
by the cyclization of A. We supposed that oxazolidine A
would allow an access of the nitrogen atom toward the
triple bond more appropriate than the one possible for
oxazolidine B.14 In contrast with the previous reports on
the lactam preparation,13 the stereoselectivity observed
in our case was independent of the nature of the R
substituent (Scheme 7).
We next examined the reaction of ω-oxo alkynoates
with (S)-phenylglycinol. This chiral amine that presented
the advantage of bearing both an amine and an alcohol
function was expected to lead to bicyclic structures upon
intramolecular addition of the hydroxyl onto the inter-
mediary imine. Indeed, when reacted in the presence of
this amine and molecular sieves at room temperature,
alkynoates 1a ,b and 2a ,b readily afforded the expected
bicyclic heterocycles 11a ,b and 12a ,b in moderate yields
for the pyrrolidines 11a (64%) and 12a (40%)11 and in
good yields for the piperidines 11b (88%) and 12b (85%)
(Scheme 6). In all cases, excellent diastereoselectivity (de
> 90% determined by GC and NMR analyses) at C-2 (now
positions C-7a (n ) 1) or C-8a (n ) 2) of the bicycles)
was observed. X-ray analyses performed on crystallized
samples of the major isomers of 11a , 11b, and 12a
allowed us to assign a E-configuration for the double
bonds and a 7a(R) or 8a(R) absolute configuration. As
far as the methyl-substituted piperidine 12b was con-
cerned, the same 8a(R) configuration was ascribed for the
major isomer after comparison of its spectroscopic data
with that described by Munchhof and Meyers12 for the
same molecule, obtained via an Eschenmoser reaction
from the appropriate thiolactam and subsequently used
for the total synthesis of two piperidine alkaloids, (+)-
pinidinone and (+)-monomorine.
We then investigated the alternative route featuring
ω-oxo â-keto esters as the substrates in place of ω-oxo
alkynoates (Scheme 1, route b). The required aldehydes
15a ,b and methyl ketones 16a 15 and 16b (Scheme 8) were
synthesized by ozonolysis of the corresponding known
terminal alkenes 13a ,b16 and 14a ,b17 which in turn were
readily obtained by condensation of the dianion of me-
Noteworthy were the excellent diastereomeric excesses
observed in these cases by opposition to that obtained
for 3. We also followed by NMR the reaction of an
equimolar amount of 1b and (S)-phenylgycinol in deu-
teriochloroform. We rapidly observed the disappearance
of the aldehyde signals and the appearance of the imine
(13) Amat, M.; Canto, M.; Llor, N.; Escolano, C.; Molins, E.;
Espinosa, E.; Bosch, J . J . Org. Chem. 2002, 67, 5343.
(14) Meyers, A. I.; Downing, S. V.; Weiser, M. J . J . Org. Chem. 2001,
66, 1413.
(15) For 16a , see: Finch, N.; Fitt, J . J .; Hsu, I. H. C. J . Org. Chem.
1971, 36, 3191.
(11) Pyrrolidine derivatives 11a and 12a are particularly sensitive
to column chromatography which lowered their isolated yields.
(12) Munchhof, M. J .; Meyers, A. I. J . Am. Chem. Soc. 1995, 117,
5399.
2890 J . Org. Chem., Vol. 69, No. 8, 2004

SCHEME 8
such in the next step. Upon reaction with (S)-1-phenyl-
ethylamine in methanol, we only obtained inextricable
mixtures. On the other hand, reaction of 15a and 16a (n
) 1) in the presence of (S)-phenylglycinol in appropriate
solvents smoothly led to bicyclic â-enamino esters 11a
and 12a in, respectively, 52% and 65% overall yields from
the corresponding alkenes (Scheme 8). However, in the
case of the sensitive aldehyde 15b (n ) 2), the sole
identifiable product was again cyclohexenone 17, what-
ever the reaction conditions. Concerning ketone 16b, the
expected bicyclic compound 12b was isolated in only 21%
yield along with undesired 18 in 24% yield. In all cases,
the diastereoselectivity of these reactions was similar to
that obtained from alkynoates (de > 90%) which was
suggestive of a similar mechanistic process (Scheme 8).
In conclusion, we have developed valuable alternative
routes to the Eschenmoser procedure for the synthesis
of chiral 2-alkoxy-5-/6-methoxycarbonylidenepyrrolidines/-
piperidines by condensation of chiral amines on ω-oxo
alkynoates and â-keto esters. Our approach is particu-
larly attractive for the diastereoselective preparation of
bicyclic structures 11a ,b and 12a ,b from (S)-phenylgly-
cinol. In particular, pyrrolidines 11a and 12a were
obtained from ω-oxo â-keto esters very efficiently in terms
of ease of access and cost of the starting materials
whereas synthesis of piperidines 11b and 12b required
the use of ω-oxo alkynoates as precursors. Further work
to develop the synthetic applications of these polyfunc-
tional heterocycles is underway in our laboratory.
thylacetoacetate on the appropriate allylic or homoallylic
halogenides. It was noteworthy that the intermediate
ozonides were quite stable and even isolable, requiring
long reaction time (48 h) and a large excess of dimethyl
sulfide to be reduced. However, all attempts to isolate
the resulting pure ω-oxo â-keto esters invariably failed,
due to a spontaneous intramolecular aldolization-
dehydration process that afforded undesirable cyclic
enones during aqueous workup. This process was par-
ticularly easy and rapid in the case of 15b and 16b to
give cyclohexenones 1718 and 18.19
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for all the new compounds.
Tables of X-ray crystallographic data for compounds 11a ,b and
12a as well as CIF files. This material is available free of
charge via the Internet at http://pubs.acs.org.
To overcome this stability issue, crude oxo derivatives
containing residual dimethyl sulfoxyde were engaged as
J O049961C
(18) Hamed, O.; El-Qisairi, A.; Henry, P. M. J . Org. Chem. 2001,
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(19) Belmont, D. T.; Paquette, L. A. J . Org. Chem. 1985, 50, 4102.
(16) Snider, B. B.; Patricia, J . J . J . Org. Chem. 1989, 54, 38.
(17) Poirier, J .-M.; Hennequin, L. Tetrahedron 1989, 45, 4191.
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