A practical synthetic route to enantiopure 6-substituted cis-decahydroquinolines

Article abstract of DOI:10.1021/ol2030058

Starting from 4-substituted cyclohexanones, a practical synthetic route to enantiopure 6-substituted cis-decahydroquinolines has been developed, the key steps being a stereoselective cyclocondensation of an unsaturated δ-keto ester derivative with (R)-phenylglycinol and the stereoselective hydrogenation of the resulting tricyclic oxazoloquinolone lactams.

Full text of DOI:10.1021/ol2030058

ORGANIC
LETTERS
2012
Vol. 14, No. 1
210–213
A Practical Synthetic Route to
Enantiopure 6-Substituted
cis-Decahydroquinolines
,†
Mercedes Amat,* Laura Navıo, Nuria Llor, Elies Molins, and Joan Bosch
†
†
‡
†
ꢀ
´
Laboratory of Organic Chemistry, Faculty of Pharmacy, and Institute of Biomedicine
ꢁ
(IBUB), University of Barcelona, 08028-Barcelona, Spain, and Institut de Ciencia de
Materials de Barcelona (CSIC), Campus UAB, 08193-Cerdanyola, Spain
amat@ub.edu
Received November 7, 2011
ABSTRACT
Starting from 4-substituted cyclohexanones, a practical synthetic route to enantiopure 6-substituted cis-decahydroquinolines has been
developed, the key steps being a stereoselective cyclocondensation of an unsaturated δ-keto ester derivative with (R)-phenylglycinol and the
stereoselective hydrogenation of the resulting tricyclic oxazoloquinolone lactams.
Bicyclic phenylglycinol-derived oxazolopiperidone lac-
tams provide a general solution for the synthesis of en-
antiopurepolysubstitutedpiperidinesbearingvirtuallyany
type of substitution pattern, including indolizidines, quino-
lizidines, hydroisoquinolines, other fused and bridged piper-
idine derivatives, and more complex piperidine-containing
natural products and bioactive compounds.1
Using related tricyclic oxazoloquinolone lactams as en-
antiomeric scaffolds, we have recently developed a proce-
dure that allows easy access to enantiopure 5-substituted
decahydroquinolines.2 Apart from their interest as bioac-
tive compounds,3 decahydroquinolines bearing substitu-
ents at the carbocyclic ring are very attractive synthetic
targets as there are few methodologies for their enantiose-
lective synthesis,4 withno precedents for the preparation of
6-substituted derivatives.
In this letter, we disclose a practical synthetic route
to enantiopure 6-substituted cis-decahydroquinolines
using 4-substituted cyclohexanones 1 as the start-
ing materials. The key steps of the synthesis are a
stereoselective cyclocondensation of (R)-phenylglyci-
nol with an unsaturated δ-keto ester derivative 3 and
the stereoselective carbonÀcarbon double bond hy-
drogenation of the resulting tricyclic lactam 4, taking
advantage of the conformational rigidity of the tricyc-
lic system.
† University of Barcelona.
‡
ꢁ
Institut de Ciencia de Materials de Barcelona.
ꢀ
(1) For recent reviews, see: (a) Amat, M.; Perez, M.; Bosch, J. Synlett
ꢀ
2011, 143–160. (b) Amat, M.; Llor, N.; Griera, R.; Perez, M.; Bosch, J.
ꢀ
Nat. Prod. Commun. 2011, 6, 515–526. (c) Amat, M.; Perez, M.; Bosch, J.
Chem.;Eur. J. 2011, 17, 7724–7732. For pionering work in the field,
see:(d) Brengel, G. P.; Meyers, A. I. Chem. Commun. 1997, 1–8.
(e) Groaning, M. D.; Meyers, A. I. Tetrahedron 2000, 56, 9843–9873.
(2) Amat, M.; Fabregat, R.; Griera, R.; Florindo, P.; Molins, E.;
Bosch, J. J. Org. Chem. 2010, 75, 3797–3805.
(3) (a) Daly, J. W. In The Alkaloids; Cordell, G. A., Ed.; Academic
Press: New York, 1998; Vol. 50, pp 141À169. (b) Daly, J. W.; Garraffo,
H. M.; Spande, T. F. In Alkaloids: Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; Pergamon: New York, 1999; Vol. 13, pp 1À161.
(c) Spande, T. F.; Jain, P.; Garraffo, H. M.; Pannell, L. K.; Yeh, H. J. C.;
Daly, J. W.; Fukumoto, S.; Inamura, K.; Tokuyama, T.; Torres, J. A.;
Snelling, R. R.; Jones, T. H. J. Nat. Prod. 1999, 62, 5–21. (d) Daly, J. W.;
Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68, 1556–1575.
(e) For a review on the synthesis of decahydroquinolines, see: Kibayashi,
C.; Aoyagi, S. In Studies in Natural Products Chemistry; Atta-ur-Rahman,
Ed.; Elsevier: Amsterdam, 1997; Vol. 19, pp 3À88.
The required cyclohexenone esters 3 were prepared
from cyclohexanones 1 as outlined in Scheme 1, either
via brominationÀelimination of δ-keto esters 2 (series a,b;
55À60% overall yield) or by alkylation of a keto sulfoxide5
intermediate with methyl acrylate, followed by thermal
elimination (series cÀe; ∼75% overall yield).
€
(4) (a) Heitbaum, M.; Frohlich, R.; Glorius, F. Adv. Synth. Catal.
ꢀ
2010, 352, 357–362. (b) Pham, V. C.; Jossang, A.; Grellier, P.; Sevenet,
T.; Nguyen, V. H.; Bodo, B. J. Org. Chem. 2008, 73, 7565–7573.
(5) Monteiro, H. J.; De Souza, J. P. Tetrahedron Lett. 1975, 921–924.
r
10.1021/ol2030058
Published on Web 12/01/2011
2011 American Chemical Society

Scheme 1. Preparation of the Starting Unsaturated Keto Esters
Scheme 3. Mechanistic Pathway for the Cyclocondensation
Reaction
Treatment of unsaturated keto esters 3bÀe with (R)-
phenylglycinol in a DeanÀStark apparatus, in refluxing
toluene containing isobutyric acid, stereoselectively led to
tricyclic cis-hydroquinoline lactams 4, in which the migra-
tion of the carbonÀcarbon double bond has occurred
(Scheme 2). Minor amounts of the cis-diastereoisomers 5
(7aR,11aR) were also formed (approximate 4:1 ratio;
75À80% overall yield).
Scheme 4. The Lactamization Step
Scheme 2. Cyclocondensation Reactions with (R)-Phenylglyci-
nol
The formation of these lactams can be accounted for by
considering that the initially formed conjugated imines
A are in equilibrium, via dienamines B, with two epimeric
β,γ-unsaturated imines C and four diastereoisomeric ox-
azolidines D, as outlined in Scheme 3.
Due to steric constraints, the subsequent irreversible
lactamization occurs only from the diastereoisomers
ox-1 and ox-2 that lead to the cis fused hydroquino-
lones 4 (major) and 5 (minor), via a chairlike transition
state in which the unsaturated carbon moiety of the
cyclohexene ring adopts an equatorial disposition with
respect to the incipient six-membered lactam ring
(Scheme 4). The cyclization occurs faster from ox-1,
and consequently tricyclic lactam 4 is the major pro-
duct of the cyclocondensation reaction, as this oxazo-
lidine allows a less hindered approach of the ester
group to the nitrogen atom, avoiding the repulsive
interaction with the phenyl substituent.6 No lactams
with a trans hydroquinoline ring fusion were observed.
(6) For the stereochemical outcome of related cyclocondensation
ꢀ
reactions from δ-keto esters, see: (a) Amat, M.; Canto, M.; Llor, N.;
Escolano, C.; Molins, E.; Espinosa, E.; Bosch, J. J. Org. Chem. 2002, 67,
ꢀ
ꢀ
5343–5351. (b) Amat, M.; Bassas, O.; Llor, N.; Canto, M.; Perez, M.;
Molins, E.; Bosch, J. Chem.;Eur. J. 2006, 12, 7872–7881.
Org. Lett., Vol. 14, No. 1, 2012
211

Catalytic hydrogenation of lactams 4b,d,e in MeOH
using PtO2 as the catalyst took place in excellent yield with
high facial selectivity, with an uptake of hydrogen by the
most accessible R-face to give the respective decahydro-
quinolines 6 (Scheme 5). Minor amounts of the corre-
sponding C-9 epimers were also formed.
An X-ray crystallographic analysis of lactam 6b unam-
biguously confirmed the absolute configuration of the new
stereogenic center generated in the hydrogenation step and
of the hydroquinoline ring junction carbons formed in the
cyclocondensation reaction.
which was the role of (R)-phenylglycinol, but also can be
used to assemble more complex hydroquinoline-fused
derivatives. Thus, BischlerÀNapieralski cyclization of tri-
cyclic lactams 9a,c,f10 followed by LiAlH4 reduction of the
resulting all-cis hexacyclic derivatives 10 stereoselectively
ledinexcellent yields(85À90% overallyield) to pentacyclic
amino alcohols 11, which embody the pentacyclic skeleton
of tangutorine.11
Scheme 6. Cyclocondensation Reactions with (S)-Tryptopha-
nol
Scheme 5. Synthesis of Enantiopure 6-Substituted cis-Decahy-
droquinolines
Alane reduction of crude tricyclic lactams 6 brought
about the stereoselective7 reductive opening of the oxazo-
lidine ring and the reduction of the lactam and ester (in
series b) carbonyl groups to give cis-decahydroquinolines 7.8
A subsequent catalytic debenzylation in the presence of
Boc2O led to 6-substituted decahydroquinolines 8. Taking
into account the availability of the starting 4-substituted
cyclohexanones, the sequence reported here provides a general
route to enantiopure 6-substituted cis-decahydroquinolines.
Similar cyclocondensation reactions of unsaturated keto
esters 3aÀc and the saturated keto ester 3f with (S)-
tryptophanol9 (Scheme 6) were also highly stereoselective,
leading to the corresponding cis lactams 9 (3S,7aR,11aR)
as the major products [the ratio 9:(3S,7aS,11aS)-isomers
was 4:1; 65%À75% overall yield]. This significantly ex-
pands the potential of tricyclic oxazoloquinolone lactams
as chiral building blocks since (S)-tryptophanol not only
acts as a chiral inductor in the cyclocondensation reaction,
The configuration of the two stereogenic centers
generated in the cyclocondensation reaction was un-
ambiguously established by X-ray diffraction analysis
of the thiolactam derived from 9a, which was prepared
in 77% yield by treatment of 9a with Lawesson’s
reagent. On the other hand, the configuration of the
C-6a and C-14b stereocenters of 11 was deduced from
the NMR data (COSY, HETCOR, and NOESY experiments),
by considering a preferred cis-cisoid-cis conformation,12
and by comparison of the 13C NMR chemical shifts
with the values reported for tangutorine11 (see Supporting
Information).
The stereoselectivity of the BischerÀNapieralski cy-
clization can be rationalized by considering that the
attack of the hydride on the electrophilic carbon center
ꢀ
ꢀ ꢀ
(7) Freville, S.; Celerier, J. O.; Thuy, V. M.; Lhommet, G. Tetrahe-
dron Asymmetry 1995, 6, 2651–2654. See also ref 6a.
(10) Under classical conditions (POCl3, then NaBH4) an attempted
BischlerÀNapieralski cyclization from (S)-tryptophanol-derived lac-
tams lacking the substituent at the aminal carbon resulted in failure
due to the tendency of these lactams to undergo R-amidoalkylation
under acidic condicitions: see ref 9c.
(11) Duan, J.-A.; Williams, I. D.; Che, C.-T.; Zhou, R.-H.; Zhao, S.-X.
Tetrahedron Lett. 1999, 40, 2593–2596.
(12) For the conformational behavior of complex quinolizidine-
(8) At this stage, minor amounts of 6-epi-7d and 6-epi-7e, formed
from the minor epimers generated in the hydrogenation step, were
isolated.
(9) For cyclocondensation reactions of δ-oxo acid derivatives with
(S)-tryptophanol, see: (a) Allin, S. M.; Thomas, C. I.; Doyle, K.;
Elsegood, M. R. J. J. Org. Chem. 2005, 70, 357–359. (b) Amat, M.;
ꢀ
ꢀ
Santos, M. M. M.; Bassas, O.; Llor, N.; Escolano, C.; Gomez-Esque, A.;
ꢀ
containing derivatives, see: (a) Tourwe, D.; Laus, G.; Van Binst, G.
Molins, E.; Allin, S. M.; McKee, V.; Bosch, J. J. Org. Chem. 2007, 72,
ꢀ
ꢀ
ꢀ
5193–5201. (c) Amat, M.; Gomez-Esque, A.; Escolano, C.; Santos,
M. M. M.; Molins, E.; Bosch, J. J. Org. Chem. 2009, 74, 1205–1211.
(d) Allin, S. M.; Duffy, L. J.; Towler, J. M. R.; Page, P. C. B.; Elsegood,
M. R. J.; Saha, B. Tetrahedron 2009, 65, 10230–10234.
J. Org. Chem. 1978, 43, 322–324. (b) Tourwe, D.; Van Binst, G. Hetero-
cycles 1978, 9, 507–533. (c) Lounasmaa, M.; Jokela, R.; Tamminen, T.
Heterocycles 1985, 23, 1367–1371. (d) Lounasmaa, M.; Hanhinen, P.
Heterocycles 1999, 51, 2227–2254.
212
Org. Lett., Vol. 14, No. 1, 2012

of the conformationally rigid iminium intermediate
A occurs from the less hindered R-face, as depicted in
Scheme 6. In contrast with related hydride reductions,9c
the alternative attack from the β-face, under stereoelec-
tronic control,13 is hindered due to the presence of the
cyclohexene ring.
In summary, starting from 4-substituted cyclohexa-
nones, we have developed a practical route to enantiopure
6-substituted cis-decahydroquinolines, the key steps being
a cyclocondensation reaction of (R)-phenylglycinol with a
3-substituted 6-oxocyclohexenepropionate and the subse-
quent stereoselective carbonÀcarbon double bond hy-
drogenation of the resulting tricyclic lactam. Similar
cyclocondensation reactions using (S)-tryptophanol
provide access to more complex pentacyclic derivatives
related to natural products.
Acknowledgment. Financial support from the Ministerio
ꢀ
de Ciencia e Innovacion (MICINN), Spain (Project
ꢁ
ꢀ
CTQ2009-07021/BQU), and the Agencia de Gestio d’Ajuts
Universitaris i de Recerca (AGAUR), Generalitat de Cata-
lunya (Grant 2009-SGR-1111) is gratefully acknowledged.
Thanks are also due to the MICINN (Spain) for a fellowship
to L.N. Dedicated to Prof. Francisco Palacios on the occa-
sion of his 60th birthday.
Supporting Information Available. General experimental
procedures and copies of the 1Hand13C spectra of compounds
3À9 and 11, and X-ray crystallographic data for compounds
6b and the thiolactam derived from 9a. This material is
available free of charge via the Internet at http://pubs.acs.org.
(13) Deslongchamps, P. In Stereoelectronic Effects in Organic Chem-
istry; Baldwin, J. E., Ed.; Pergamon: Oxford, UK, 1983.
Org. Lett., Vol. 14, No. 1, 2012
213