Biomimetic construction of the hydroquinoline ring system. Diastereodivergent enantioselective synthesis of 2,5-disubstituted cis -decahydroquinolines

Article abstract of DOI:10.1021/jo1005894

Figure presented The straightforward enantioselective construction of the hydroquinoline ring system from 1,5-polycarbonyl derivatives, using (R)-phenyglycinol as a chiral latent form of ammonia, is reported. The process mimics the key steps believed to o

Full text of DOI:10.1021/jo1005894

pubs.acs.org/joc
Biomimetic Construction of the Hydroquinoline Ring System.
Diastereodivergent Enantioselective Synthesis of 2,5-Disubstituted
cis-Decahydroquinolines†
Mercedes Amat,*,‡ Robert Fabregat,‡ Rosa Griera,‡ Pedro Florindo,‡ 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 Universitari de Bellaterra, 08193 Cerdanyola, Spain
amat@ub.edu; joanbosch@ub.edu
Received March 31, 2010
The straightforward enantioselective construction of the hydroquinoline ring system from 1,5-poly-
carbonyl derivatives, using (R)-phenyglycinol as a chiral latent form of ammonia, is reported. The
process mimics the key steps believed to occur in nature in the biosynthesis of amphibian deca-
hydroquinoline alkaloids. Diastereodivergent routes to enantiopure cis-2,5-disubstituted decahydro-
quinolines, including the alkaloid pumiliotoxin C (cis-195A), are developed.
Introduction
unprecedented in the plant kingdom, also occur in bufonid
toads,3 tunicates,4 marine flatworms,4b and myrmicine
ants.5 The biosynthetic origin of decahydroquinoline
amphibian alkaloids remains an intriguing question and
a major research challenge for chemical ecologists,1 par-
ticularly since the isolation of some of these alkaloids
from ants has opened a dietary hypothesis for their
presence in frogs.5
2,5-Disubstituted decahydroquinolines (Figure 1) re-
present one of the major classes of amphibian alkaloids,1
which were first isolated from the skin extracts of den-
drobatid frogs.2 These biologically active natural products,
†
ꢁ
Dedicated to Prof. Jose Barluenga on the occasion of his 70th birthday.
€
(1) (a) Witkop, B.; Gossinger, E. In The Alkaloids; Brossi, A., Ed.; Academic
Press: New York, 1983; Vol. 21, pp 139-253. (b) Daly, J. W.; Spande, T. F. In
Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Wiley:
New York, 1986; Vol. 4, pp 1-274. (c) Daly, J. W.; Garraffo, H. M.; Spande, T. F.
In The Alkaloids; Cordell, G. A., Ed.; Academic Press: San Diego, CA, 1993; Vol.
43, pp 185-288. (d) Daly, J. W. In The Alkaloids; Cordell, G. A, Ed.; Academic
Press: New York, 1998; Vol. 50, pp 141-169. (e) 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 1-161. (f) Daly, J. W.; Spande,
T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68, 1556–1575.
(2) (a) Tokuyama, T.; Nishimori, N.; Karle, I. L.; Edwards, M. W.; Daly,
J. W. Tetrahedron 1986, 42, 3453–3460. (b) Tokuyama, T.; Tsujita, T.;
Shimada, A.; Garraffo, H. M.; Spande, T. F.; Daly, J. W. Tetrahedron
1991, 47, 5401–5414. (c) Garraffo, H. M.; Caceres, J.; Daly, J. W.; Spande,
T. F.; Andriamaharavo, N. R.; Andriantsiferana, M. J. Nat. Prod. 1993, 56,
1016–1038.
(3) Garraffo, H. M.; Spande, T. F.; Daly, J. W.; Baldessari, A.; Gros,
E. G. J. Nat Prod. 1993, 56, 357–373.
(4) (a) Steffan, B. Tetrahedron 1991, 47, 8729–8732. (b) Kubanek, J.;
Williams, D. E.; Dilip de Silva, E.; Allen, T.; Andersen, R. J. Tetrahedron
Lett. 1995, 36, 6189–6192. (c) Davis, R. A.; Carroll, A. R.; Quinn, R. J.
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Kaminsky, R. J. Med. Chem. 2002, 45, 3067–3072.
(5) (a) Spande, T. F.; Jain, P.; Garraffo, H. M.; Pannell, L. K.; Yeh,
H. J. C.; Daly, J. W.; Fukumoto, S.; Imamura, K.; Tokuyama, T.; Torres,
J. A.; Snelling, R. R.; Jones, T. H. J. Nat. Prod. 1999, 62, 5–21. (b) Jones,
T. H.; Gorman, J. S. T.; Snelling, R. R.; Delabie, J. H. C.; Blum, M. S.;
Garraffo, H. M.; Jain, P.; Daly, J. W.; Spande, T. F. J. Chem. Ecol. 1999, 25,
1179–1193. (c) Daly, J. W.; Garraffo, H. M.; Jain, P.; Spande, T. F.; Snelling,
R. R.; Jaramillo, C.; Rand, A. S. J. Chem. Ecol. 2000, 26, 73–85.
DOI: 10.1021/jo1005894
r
Published on Web 04/30/2010
J. Org. Chem. 2010, 75, 3797–3805 3797
2010 American Chemical Society

Amat et al.
SCHEME 2. Discovery of the Biomimetic Aminocyclization
JOCArticle
FIGURE 1. Representative amphibian cis-decahydroquinoline alka-
loids.
SCHEME 1. Biogenetic Hypothesis
SCHEME 3. Synthesis of 1,5-Polycarbonyl Derivatives 2
The structural diversity and pharmacological activities of
these alkaloids, as well as the limited amounts available from
natural sources, have stimulated considerable synthetic
effort in this area,6 including some biomimetic approaches.7
Although there are no conclusive studies concerning their
biosynthesis, it is thought that decahydroquinoline alkaloids
might derive from the polyketide pathway, by aminocycliza-
tion of straight-chain 1,5-polycarbonyl derivatives A, via
cyclohexenone intermediates, as outlined in Scheme 1.8
Mimicking these key steps believed to occur in nature, we
present here a straightforward enantioselective construction
of the hydroquinoline ring system from 1,5-polycarbonyl
derivatives, using (R)-phenylglycinol as a chiral latent form
of ammonia. Appropriate elaboration of the resulting tri-
cyclic lactams results in diastereodivergent routes to enantio-
pure cis-2,5-disubstituted decahydroquinolines, including
the most representative alkaloid of this group, pumiliotoxin
C (cis-195A).9
SCHEME 4. Biomimetic Construction of the Hydroquinoline
Ring System
Results and Discussion
Our biomimetic approach was inspired by a serendipitous
observation when attempting a double phenyglycinol-in-
duced cyclocondensation from the polycarbonyl derivative
(6) For a review, see: Kibayashi, C.; Aoyagi, S. In Studies in Natural
ProductsChemistry; Atta-ur-Rahman, Ed.; Elsevier Science B. V.: Amsterdam,
The Netherland, 1997; Vol. 19, pp 3-88.
€
(7) (a) Glanzmann, M.; Karalai, C.; Ostersehlt, B.; Schon, U.; Frese, C.;
2a in the context of model studies on the synthesis of
(þ)-anaferine (Scheme 2).
Winterfeldt, E. Tetrahedron 1982, 38, 2805–2810. (b) Bonin, M.; Royer, J.;
Grierson, D. S.; Husson, H.-P. Tetrahedron Lett. 1986, 27, 1569–1572. For
reviews, see: (c) Scholz, U.; Winterfeldt, E. Nat. Prod. Rep. 2000, 17, 349–366.
(d) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun. 2003,
551–564. (e) De la Torre, M. C.; Sierra, M. A. Angew. Chem., Int. Ed. 2004,
43, 160–181.
(8) Winterfeldt, E. Heterocycles 1979, 12, 1631–1650. See also refs 1a, 1b,
and 7c.
(9) For a preliminary account on the synthesis of pumiliotoxin C, see:
Amat, M.; Griera, R.; Fabregat, R.; Molins, E.; Bosch, J. Angew. Chem., Int.
Ed. 2008, 47, 3348–3351.
Thus, treatment of diketo diester 2a, which was prepared
in excellent yield (82%) by Pd-catalyzed coupling of glutaryl
dichloride with the functionalized organozinc derivative
1 (Scheme 3), with (R)-phenylglycinol in refluxing ben-
zene containing AcOH unexpectedly led to the tricyclic
hydroquinoline lactam 5a (37% yield) instead of the desired
bis(oxazolopiperidone) lactam 3 (X=H,H). Cyclohexenone
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Amat et al.
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4a (22% yield, see Scheme 4) and enaminone 6 (25% yield;
∼1:1 mixture of stereoisomers) were also isolated.
SCHEME 5. Enantioselective Synthesis of Pumiliotoxin C
The formation of 5a can be rationalized by considering
that the starting symmetrical diketone 2a undergoes an aldol
cyclocondensation leading to cyclohexenone 4a, which then
undergoes an in situ phenylglycinol-promoted cycloconden-
sation reaction in an overall process that parallels the
biogenetic postulate outlined in Scheme 1.
In accordance with this interpretation, diketo diester 2a
was first converted to the intermediate cyclohexenone 4a
(Scheme 4) in excellent yield (90%) by sequential treatment
with aqueous LiOH and TMSCl-EtOH, and then this ketone
was satisfactorily cyclized (60% yield) to lactam 5a by
treatment with (R)-phenylglycinol.10
The application of this biomimetic double cyclocondensa-
tion methodology to the enantioselective synthesis of the
decahydroquinoline alkaloid cis-195A, which incorporates a
C-5 methyl substituent, required starting from a diketoester
2b, bearing a methyl ketone moiety. This 1,5-polycarbonyl
derivative was prepared in 65% yield by Pd-catalyzed coup-
ling of the organozinc derivative 1 with 5-oxohexanoyl
chloride. In this series, the initial aldol cyclocondensation
to 4b took place in 82% yield, whereas the phenylglycinol-
promoted cyclocondensation stereoselectively provided tri-
cyclic lactam 5b in 70% yield. The configuration of the
stereogenic ring fusion carbon atoms generated in this step
was unambiguously established by X-ray crystallographic
analysis.
The conversion of lactam 5b to the target alkaloid required
the stereoselective hydrogenation of the carbon-carbon
double bond, the introduction of the propyl substituent at
C-2, and the reductive removal of the chiral inductor. The
catalytic hydrogenation of 5b with PtO2 as the catalyst took
place in nearly quantitative yield and complete selectivity
from the most accessible face to give lactam 6, whose
absolute configuration was unambiguously established by
X-ray crystallographic analysis (Scheme 5).
The lactam carbonyl present in tricyclic lactam 6 allows
the introduction of substituents at the 2-position of the
hydroquinoline ring, ultimately leading to enantiopure 2,5-
disubstituted cis-decahydroquinolines. Thus, lactam 6 was
converted into the corresponding thioamide, which was then
subjected to Eschenmoser sulfide contraction11 conditions
(BrCH2CO2Me; then (MeO)3P, Et3N) to give β enamino
ester 8 in 50% overall yield.
At this point, the complete relative stereochemistry of
the target alkaloid cis-195A was installed by hydrogena-
tion of 8 in the presence of PtO2 under acidic conditions
(AcOH, MeOH, 24 h), which brought about both the
stereoselective reduction of the vinylogous urethane dou-
ble bond12 and the cleavage of the oxazolidine C-O bond.
A subsequent debenzylation with hydrogen and Pd(OH)2
in the presence of Boc2O led to the protected cis-deca-
hydroquinoline 10.
Finally, the conversion of ester 10 into pumiliotoxin C
was accomplished in satisfactory overall yield by LiAlH4
reduction to alcohol 11, followed by methylenation of the
corresponding aldehyde, subsequent catalytic hydrogena-
tion of the resulting N-Boc-2-allyldecahydroquinoline,
and finally deprotection of the piperidine nitrogen. The
NMR spectroscopic data and [R]22D value (-15.3, c 0.5 in
MeOH) of cis-195A (pumiliotoxin C) hydrochloride were
consistent with those reported in the literature.13
Unexpectedly, reversing the order of the catalytic hydro-
genation of the endocyclic double bond and the Eschenmoser
sulfide contraction reactions resulted in a dramatic change in
the overall stereochemical outcome of the process. Thus, cata-
lytic hydrogenation of enamino ester 13 (PtO2, AcOH, MeOH,
16 h), which was prepared in 76% overall yield from lactam 5b
as outlined in Scheme 6, followed by reaction of the result-
ing secondary amine with Boc2O did not lead to the expected
decahydroquinoline-2-acetate derivative 10, but to a stereo-
isomer, ent-2-epi-10, instead (45% overall yield).14 The
configuration of this ester was initially misassigned as that of
2-epi-10 on the basis of the 2,8a-trans, 4a,5-trans, 4a,8a-cis
relationship (evident by X-ray crystallography) of the alcohol
resulting from its LiAlH4 reduction and bearing in mind the
known C-4a absolute configuration of the starting material 13.
(13) For previous enantioselective syntheses of cis-195A ((-)-pumiliotox-
in C), see: (a) Oppolzer, W.; Flaskamp, E. Helv. Chim. Acta 1977, 60, 204–
207. (b) Murahashi, S.-I.; Sasao, S.; Saito, E.; Naota, T. Tetrahedron 1993,
49, 8805–8826. (c) Comins, D. L.; Dehghani, A. J. Chem. Soc., Chem.
Commun. 1993, 1838–1839. (d) Naruse, M.; Aoyagi, S.; Kibayashi, C.
J. Chem. Soc., Perkin Trans. 1 1996, 1113–1124. (e) Riechers, T.; Krebs,
H. C.; Wartchow, R.; Habermehl, G. Eur. J. Org. Chem. 1998, 2641–2646.
(f) Oppolzer, W.; Flaskamp, E.; Bieber, L. W. Helv. Chim. Acta 2001, 84,
141–145. (g) Dijk, E. W.; Panella, L.; Pinho, P.; Naasz, R.; Meetsma, A.;
Minaard, A. J.; Feringa, B. L. Tetrahedron 2004, 60, 9687–9693. For the
synthesis of (þ)-pumiliotoxin C, see: (h) Dieter, R. K.; Fishpaugh, J. R.
J. Org. Chem. 1983, 48, 4441–4444. (i) Schultz, A. G.; McCloskey, P. J.;
Court, J. J. J. Am. Chem. Soc. 1987, 109, 6493–6502. (j) Toyota, M.; Asoh, T.;
Matsuura, M.; Fukumoto, K. J. Org. Chem. 1996, 61, 8687–8691. (k) Lauzon,
S.; Tremblay, F.; Gagnon, D.; Godbout, C.; Chabot, C.; Mercier-Shanks, C.;
(10) For related cyclocondensation reactions, see: (a) Amat, M.; Bassas,
ꢁ
ꢁ
O.; Llor, N.; Canto, M.; Perez, M.; Molins, E.; Bosch, J. Chem.;Eur. J.
2006, 12, 7872–7881. (b) Amat, M.; Fabregat, R.; Griera, R.; Bosch, J. J. Org.
Chem. 2009, 74, 1794–1797. For reviews on the use of phenylglycinol-derived
lactams, see: (c) Groaning, M. D.; Meyers, A. I. Tetrahedron 2000, 56, 9843–
9873. (d) Escolano, C.; Amat, M.; Bosch, J. Chem.;Eur. J. 2006, 12, 8198–
8207.
ꢀ
(11) Shiozaki, K. In Comprehensive Organic Synthesis; Trost, B. M., Ed.;
Pergamon Press: Oxford, UK, 1991, pp 865-892.
Perrault, S.; DeSeve, H.; Spino, C. J. Org. Chem. 2008, 73, 6239–6250.
(14) In some runs, the seven-membered lactone 14 was isolated as a
byproduct, which was subsequently converted to ent-2-epi-10 by catalytic
hydrogenation (Pd-C, MeOH) in the presence of Boc2O.
ꢁ
(12) Calvet-Vitale, S.; Vanucci-Bacque, C.; Fargeau-Bellassoued, M.-C.;
Lhommet, G. Tetrahedron 2005, 61, 7774–7782.
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SCHEME 6. Enantioselective Synthesis of ent-2-Epi-cis-195A
SCHEME 7
SCHEME 8. Stereochemical Outcome of the C-C Double
Bond Hydrogenation
The hydrogenation of the exocyclic C-C double bond of
13 is the first event of this multistep sequence, as evidenced by
the rapid disappearance (3 h) of the NMR singlet at δ 4.38
attributable to the vinyl proton R to the carbonyl group when
operating under neutral conditions (PtO2, MeOH). The
resulting intermediate B is then converted to the perhydro
derivative C, as indicated by the successive disappearance of
the NMR signals due to the exocyclic and endocyclic (broad
singlet at δ 5.42) double bonds, when the hydrogenation
was effected by using Pd/C as the catalyst in methanol.
Under acidic conditions (PtO2, MeOH, excess AcOH), this
intermediate was formed in 30 min, and after prolonged
reaction times it evolved into the secondary amine precursor
of ent-2-epi-10.
A similar stereochemical result was obtained starting from
diester 16. Catalytic hydrogenation of 16 in the presence of
PtO2 under acidic conditions (AcOH, EtOH), followed by
protection of the resulting secondary amine with Boc2O, led
to the cis-decahydroquinoline 17 (Scheme 7). Diester 16 was
prepared in 71% overall yield from lactam 5a by Eschenmo-
ser sulfide contraction of the corresponding thiolactam 15.
The stereochemical outcome of the hydrogenation of 13
was quite surprising because two configurationally related
substrates (5b and 13) lead to two diastereoisomers (10 and
ent-2-epi-10, respectively) differing in the absolute configura-
tion of three stereocenters. This result can be rationalized by
The correct absolute configurations of the above ester and
alcohol were only unambiguously established as those depi-
cted in Scheme 6 for ent-2-epi-10 and ent-2-epi-11, respec-
tively, once this alcohol was converted to ent-2-epi-cis-195A15
following a synthetic sequence similar to that previously
developed in the above pumiliotoxin C series. This compound
showed NMR spectroscopic data16 and an [R]22 value13f
D
consistent withthose reported inthe literature for (-)-4a,5,8a-
epipumiliotoxin C.17
The formation of ent-2-epi-10 from 13 involves six chemi-
cal transformations: stereoselective hydrogenation of two
carbon-carbon double bonds, reductive cleavage of the
oxazolidine ring, epimerization at the perhydroquinoline
C-4a position, debenzylation, and, finally, introduction of
the protective group.
(15) For a previous enantioselective synthesis, see ref 13f.
(16) (a) Polniaszek, R. P.; Dillard, L. W. J. Org. Chem. 1992, 57, 4103–
4110. (b) Meyers, A. I.; Milot, G. J. Am. Chem. Soc. 1993, 115, 6652–6660.
(c) Back, T. G.; Nakajima, K. Tetrahedron Lett. 1997, 38, 989–992.
(d) Lebrun, M.-E.; Pfeiffer, J. Y.; Beauchemin, A. M. Synlett 2009, 7,
1087–1090. See also ref 13f.
(17) For a previous enantioselective synthesis of 2-epi-cis-195A, see:
Back, T. G.; Nakajima, K. J. Org. Chem. 1998, 63, 6566–6571.
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SCHEME 9. The Configuration of the Ring Junction
SCHEME 11. A Synthetic Approach to cis-Decahydroquinoline
Alkaloids Epimeric at C-2
on the concave face of the hydroquinoline moiety in B reverses
this situation and the hydrogenation occurs on the less hindered
β-face to provide the intermediate C.
On the other hand, the C-4a configuration in ent-2-epi-10,
opposite to that in 13, can be accounted for by considering that
the acid-promoted opening of the oxazolidine ring in C leads
to an intermediate iminium salt Xa (Scheme 9), which is in
equilibrium via the corresponding enamine with the most stable
epimer Ya (equatorial methyl group) in a process involving the
inversion of the configuration at the C-4a stereocenter. A
subsequent stereoselective hydrogenation of the iminium func-
tion and debenzylation, followed by protection with Boc2O,
leads to cis-decahydroquinoline ent-2-epi-10.18
SCHEME 10. Diastereodivergent Enantioselective Synthesis of
2,5-Disubstituted cis-Decahydroquinolines
In contrast, the C-4a epimerization does not occur in the
pumiliotoxin C series, in which the iminium intermediate Xb
(equatorial methyl group), generated after an initial stereo-
selective reduction of the exocyclic double bond of 8, is
directly converted to the cis-decahydroquinoline 10.
Conclusion
In summary, starting from an easily accessible (R)-phenyl-
glycinol-derived tricyclic lactam 5b, depending on the order
of the synthetic transformations (paths A or B), it is possible
to enantioselectively access 5-substituted cis-decahydro-
quinoline-2-acetate derivatives that differ in the configura-
tion of the 4a, 5, and 8a stereocenters (Scheme 10).
The results reported in this paper not only provide experi-
mental support for the presumed biosynthetic pathway to
amphibian decahydroquinoline alkaloids but also open gen-
eral enantioselective routes to both the cis and the 2-epi-cis
series of these alkaloids, which differ in the nature of the
substituents at the 2 and 5 positions and in the relative C-2
configuration (see Figure 1). Starting from an appropriate
(R)-phenyglycinol-derived tricyclic lactam, the above path A
provides access to the normal cis series, whereas when using
an (S)-phenylglycinol-derived lactam, the above path B
would lead to decahydroquinoline alkaloids of the 2-epi-cis
series (Scheme 11).
considering that the hydrogenation of the endocyclic C-C
double bond of the conformationally rigid tricyclic derivatives
5b and B occurs with differing facial selectivity and that the
absolute configuration of the stereocenter generated in this
step (C-5) determines the stereochemistry of the configura-
tionally labile C-4a stereocenter under the acidic conditions
required for the reductive cleavage of the oxazolidine ring.
A reasonable explanation for the contrasting stereoselectiv-
ity in the above hydrogenation step can be obtained by
analyzing the most stable conformations of 5b and B obtained
by molecular orbital calculations (Scheme 8). Thus, although
the presence of an axial C-O bond in 5b directs the uptake of
hydrogen to the opposite R face to give 6, the axial acetate chain
(18) For related examples on the reduction of 5-substituted-1,2,3,4,
5,6,7,8-octahydroquinoline derivatives to give 4a,5-trans,cis-decahydroqui-
nolines, see: (a) Murahashi, S.-I.; Sasao, S.; Saito, E.; Naota, T. Tetrahedron
1993, 49, 8805–8826. (b) Padwa, A.; Heidelbaugh, T. M.; Kuethe, J. T.
J. Org. Chem. 2000, 65, 2368–2378. (c) Akashi, M.; Sato, Y.; Mori, M. J. Org.
Chem. 2002, 66, 7873–7874.
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Experimental Section
ketoester 4b (5.5 g, 85%) was obtained as an oil: 1H NMR (300
MHz, CDCl3) δ 1.88-1.96 (m, 2H), 1.97 (s, 3H, CH3),
2.33-2.40 (m, 6H), 2.59-2.64 (m, 2H), 3.65 (s, 3H, CH3O);
13C NMR (75.4 MHz, CDCl3) δ 21.0 (CH2), 21.1 (CH3),
22.1 (CH2), 32.8 (CH2), 33.0 (CH2), 37.7 (CH2), 51.4 (CH3O),
133.6 (C), 156.5 (C), 173.5 (COO), 198.2 (CO); IR (NaCl) 1738,
1663 cm-1; HRMS calcd for [C11H16O3 þ Na] 219.100, found
219.099.
Diethyl 5,9-Dioxotridecanedioate (2a). Pd[P(C6H5)3]4 (2.9 g,
2.5 mmol) was added to a solution of 4-ethoxy-4-oxobutylzinc
bromide (1; 100 mL of a 0.5 M solution in THF, 50 mmol) in
THF (150 mL), and the mixture was stirred at rt for 30 min.
Glutaryl dichloride (3.2 mL, 25 mmol) was added, and the
mixture was stirred at rt for an additional 90 min. The mixture
was poured into saturated aqueous NH4Cl and extracted with
Et2O. The combined organic extracts were washed with satu-
rated aqueous NaCl, dried, and concentrated to give a solid.
Flash chromatography (from 9:1 to 8:2 hexane-EtOAc) af-
Ethyl (3R,7aS,11aS)-5-Oxo-3-phenyl-2,3,5,6,7,7a,10,11-octa-
hydrooxazolo[2,3-j]quinoline-8-butyrate (5a). (R)-Phenylglycinol
(466 mg, 3.4 mmol) was added to a solution of ketodiester 4a
(350 mg, 1.1 mmol) and AcOH (0.2 mL, 3.4 mmol) in benzene
(15 mL). The mixture was heated at reflux for 48 h with
azeotropic elimination of water produced by a Dean-Stark
apparatus. The resulting mixture was cooled and concentrated.
Flash chromatography (from 3:2 to 1:1 hexane-EtOAc) af-
forded lactam 5a (253 mg, 60%) as a solid and its 3R,7aR,11aR
1
forded 2a (6.7 g, 82%): mp 73-74 °C; H NMR (200 MHz,
CDCl3) δ 1.26 (m, 6H, 2CH3), 1.88 (m, 6H), 2.32 (m, 4H), 2.45
(m, 8H), 4.12 (m, 4H, 2CH2-ethyl); 13C NMR (50.3 MHz,
CDCl3) δ 14.2 (2CH3), 17.6 (CH2), 18.8 (2CH2), 33.3 (2CH2),
41.4 (2CH2), 41.5 (2CH2), 60.3 (2CH2), 173.0 (2COO), 209.4
(2CO); IR (NaCl) 1735, 1721 cm-1. Anal. Calcd for C17H28O6:
C 71.52, H 7.37, N 3.79. Found: C 71.50, H 7.42, N 3.84.
Ethyl 5,9-Dioxodecanoate (2b). A mixture of oxalyl chloride
(38 mL, 0.44 mol) and 5-oxohexanoic acid (12 mL, 0.1 mol) in
anhydrous Et2O (100 mL) was stirred at rt for 6 h. The solution
was concentrated, and the resulting residue was dried to give the
acid chloride, which was used in the next step without further
purification. A solution of 4-ethoxy-4-oxobutylzinc bromide
(1; 200 mL of a 0.5 M solution in THF, 0.1 mol) and Pd-
[P(C6H5)3]4 (5.8 g, 5 mmol) in THF (400 mL) was stirred at rt for
30 min. Then, the above acid chloride was added, and the
resulting mixture was stirred at rt for 16 h. The mixture was
poured into saturated aqueous NH4Cl and extracted with Et2O.
The combined organic extracts were washed with saturated
aqueous NaCl, dried, and concentrated to give an oil. Flash
chromatography (from 9:1 to 8:2 hexane-EtOAc) afforded
1
diastereomer (76 mg, 18%). 5a (higher Rf): mp 89-91 °C; H
NMR (300 MHz, CDCl3, COSY, HSQC) δ 1.26 (t, J=7.2 Hz,
3H, CH3), 1.65-1.92 (m, 4H, H-7, H-20), 2.07-2.11 (m, 7H,
H-7a, H-10, H-11, H-10), 2.18-2.76 (m, 4H, H-6, H-30), 3.89 (t,
J=8.8 Hz, 1H, H-2), 4.13 (q, J=7.2 Hz, 2H, CH2-ethyl), 4.56 (t,
J=8.8 Hz, 1H, H-2), 5.30-5.45 (m, 2H, H-3, H-9), 7.17-7.37 (m,
5H, H-Ar); 13C NMR (100.6 MHz, CDCl3) δ 14.2 (CH3), 22.9
(CH2), 23.1 (CH2), 25.1 (CH2), 26.0 (CH2), 31.4 (CH2), 33.7
(2CH2), 43.3 (C-7a), 58.5 (C-3), 60.2 (CH2-ethyl), 69.5 (C-2),
94.3 (C-11a), 121.0 (C-9), 125.3 (CH-o), 127.1 (CH-p), 128.6
(CH-m), 136.4 (C-8), 140.3 (C-i), 169.6 (COO), 173.5 (COO); IR
(NaCl) 1731, 1655 cm-1; [R]22 -97.3 (c 1.0, MeOH). Anal.
D
Calcd for C23H29NO4: C 72.04, H 7.62, N 3.65. Found: C 71.63,
H 7.62, N 3.53. 7aR,11aR-epi-5a (lower Rf): 1H NMR(200 MHz,
CDCl3) δ 1.27 (t, J =7.2 Hz, 3H, CH3), 1.61-1.97 (m, 4H),
2.00-2.48 (m, 11H), 3.93 (dd, J=9.2 Hz, 1H, 1.8 Hz, H-2), 4.15
(q, J=7.2 Hz, 2H, CH2-ethyl), 4.41 (dd, J=9.2 Hz, 1H, 7.2 Hz,
H-2), 4.98 (dd, J=7.2 Hz, 1H, 1.8 Hz, H-3), 5.45 (s, 1H, H-9),
7.26-7.31 (m, 5H, H-Ar); 13C NMR (75.4 MHz, CDCl3) δ 14.1
(CH3), 23.0 (CH2), 23.3 (CH2), 25.7 (CH2), 26.0 (CH2), 30.5
(CH2), 33.6 (CH2), 33.9 (CH2), 42.3 (C-7a), 59.3 (C-3), 60.1
(CH2-ethyl), 70.9 (C-2), 93.6 (C-11a), 120.0 (C-9), 126.1
(CH-o), 127.2 (CH-p), 128.4 (CH-m), 137.5 (C-8), 141.6 (C-i),
1
diketoester 2b (14.8 g, 65%): H NMR (200 MHz, CDCl3) δ
1.26 (t, J=7.1 Hz, 3H, CH3-ethyl), 1.76-1.96 (m, 4H), 2.13 (s,
3H, CH3), 2.84-2.36 (m, 2H), 2.41-2.51 (m, 6H), 4.12 (q, J=7.1
Hz, 2H, CH2-ethyl); 13C NMR (50.3 MHz, CDCl3) δ 14.2
(CH3-ethyl), 17.6 (CH2), 18.8 (CH2), 29.8 (CH3), 33.2 (CH2),
41.4 (2CH2), 42.4 (CH2), 60.3 (CH2-ethyl), 172.9 (COO), 208.1
(CO), 209.4 (CO); IR (NaCl) 1715 cm-1. Anal. Calcd for
C12H20O4: C 63.14, H 8.83. Found: C 63.05, H 8.91.
167.1 (COO), 173.4 (COO); IR (NaCl) 1731, 1657 cm-1
;
[R]22 þ53.1 (c 0.9, MeOH); HRMS calcd for [C23H29NO4]
Ethyl 2-(2-Ethoxycarbonylethyl)-3-oxocyclohexenebutyrate
(4a). A solution of LiOH H2O (8 g, 0.2 mol) in water (125
D
383.2097, found 383.2099.
3
mL) was added to a solution of 2a (6 g, 18.3 mmol) in THF (300
mL) and EtOH (350 mL), then the mixture was stirred at rt for
3 h. The mixture was concentrated, and the residue was taken up
in 2 N aqueous HCl and extracted with EtOAc. The combined
organic extracts were dried and concentrated to give 2-(2-
carboxyethyl)-3-oxocyclohexenebutyric acid, which was used
in the next step without further purification. Me3SiCl (10 mL, 80
mmol) was added to a solution of the acid in EtOH (105 mL),
and the mixture was stirred at rt for 16 h. The mixture was
concentrated, and the residue was taken up in EtOAc and
washed with saturated aqueous NaHCO3. The combined or-
ganic extracts were dried and concentrated to give ketodiester 4a
(3R,7aS,11aS)-8-Methyl-5-oxo-3-phenyl-2,3,5,6,7,7a,10,11-
octahydrooxazolo[2,3-j]quinoline (5b). Operating as in the above
preparation of 5a, from ketoester 4b (9.5 g, 48 mol), (R)-
phenylglycinol (20 g, 145 mol), and AcOH (8.3 mL, 145 mol)
in benzene (750 mL), lactam 5b (9.5 g, 70%) and its 3R,7aR,11aR
diastereomer (2.4 g, 19%) were obtained after flash chromato-
graphy (from 3:2 to 1:1 hexane-EtOAc). 5b (higher Rf): mp
1
115-120 °C; H NMR (300 MHz, CDCl3, COSY, HSQC) δ
1.59-1.79 (m, 2H, H-7, H-11), 1.78 (s, 3H, CH3), 1.86 (dd,
J=13.2 Hz, 1H, 6.6 Hz, H-11), 1.96-2.13 (m, 3H, H-7a, H-10),
2.20-2.29 (m, 1H, H-7), 2.44-2.56 (m, 1H, H-6), 2.70 (dd,
J=18.6 Hz, 1H, 6.0 Hz, H-6), 3.91 (t, J=8.5 Hz, 1H, H-2), 4.57
(t, J=8.5 Hz, 1H, H-2), 5.44-5.50 (m, 2H, H-3, H-9), 7.18-7.36
(m, 5H, H-Ar); 13C NMR (75.4 MHz, CDCl3) δ 21.5 (CH3),
22.9 (C-10), 24.7 (C-7), 25.7 (C-11), 31.3 (C-6), 44.8 (C-7a), 58.3
(C-3), 69.4 (C-2), 94.3 (C-11a), 120.9 (C-9), 125.1 (CH-o), 127.0
(CH-p), 128.4 (CH-m), 133.0 (C-8), 140.2 (C-i), 169.6 (NCO); IR
(NaCl) 1657 cm-1; [R]22D -102.6 (c 1.1, MeOH). Anal. Calcd for
C18H21NO2: C 76.29, H 7.47, N 4.94. Found: C 76.60, H 7.52, N,
4.92. 7aR,11aR-epi-5b (lower Rf): 1H NMR (300 MHz, CDCl3) δ
1.56-1.72 (m, 2H), 1.82 (s, 3H, CH3), 1.96-2.45 (m, 7H), 3.94
(dd, J=9.0, 2.0 Hz, 1H, H-2), 4.42 (dd, J=9.0, 7.5 Hz, 1H, H-2),
4.98 (dd, J=7.5, 2.0 Hz, 1H, H-3), 5.45 (s, 1H, H-9), 7.20-7.35
(m, 5H, H-Ar); 13C NMR (75.4 MHz, CDCl3) δ 21.7 (CH3),
23.4 (CH2), 25.6 (CH2), 25.8 (CH2), 30.7 (C-6), 43.9 (C-7a),
1
(5.1 g, 90%) as an oil: H NMR (200 MHz, CDCl3) δ 1.24 (t,
J =7.2 Hz, 3H), 1.27 (t, J =7.2 Hz, 3H), 1.72-2.05 (m, 4H),
2.28-2.41 (m, 10H), 2.55-2.63 (m, 2H), 4.10 (q, J=7.2 Hz, 2H),
4.14 (q, J=7.2 Hz, 2H); 13C NMR (50.3 MHz, CDCl3) δ 14.1
(2CH3), 20.7 (CH2), 22.2 (CH2), 22.9 (CH2), 30.4 (CH2), 33.5
(CH2), 33.7 (CH2), 34.0 (CH2), 37.8 (CH2), 60.0 (CH2), 60.3
(CH2), 133.9 (C), 158.7 (C), 172.6 (COO), 172.8 (COO), 198.4
(CO); IR (NaCl) 1778, 1664 cm-1; HRMS calcd for [C17H26O5]
310.1780, found 310.1778.
Methyl 2-Methyl-6-oxocyclohexenepropionate (4b). Operat-
ing as in the above preparation of 4a, from diketoester 2b (7.5 g,
33 mmol), LiOH H2O (15 g, 0.35 mol), and EtOH (375 mL) for
3
5 h, and then Me3SiCl (13 mL, 0.1 mol) and MeOH (80 mL),
3802 J. Org. Chem. Vol. 75, No. 11, 2010

Amat et al.
JOCArticle
59.4 (C-3), 71.1 (C-2), 93.8 (C-11a), 120.2 (C-9), 126.2 (CH-o),
127.4 (CH-p), 128.5 (CH-m), 134.4 (C-8), 141.8 (C-i), 167.3
mL) containing 40% PtO2 (14 mg) was stirred under hydrogen
at rt for 24 h. The catalyst was removed by filtration through a
Celite pad, the filtrate was concentrated, and the residue was
taken up with EtOAc. The organic solution was washed with
10% aqueous KOH, dried, and concentrated. The resulting oil
was chromatographed (from 9:1 to 8:2 hexane-EtOAc) to
(NCO); IR (NaCl) 1657 cm-1; [R]22 þ13.7 (c 1.2, MeOH).
D
Anal. Calcd for C18H21NO2: C 76.29, H 7.47, N 4.94. Found: C
76.25, H 7.54, N 4.83.
(3R,7aS,8R,11aS)-8-Methyl-5-oxo-3-phenyldecahydrooxazolo-
[2,3-j]quinoline (6). A solution of lactam 5b (2 g, 7.1 mmol) in
MeOH (150 mL) containing 40% PtO2 (0.8 g) was stirred under
hydrogen at rt for 24 h. The catalyst was removed by filtration
and washed with MeOH. The combined organic solutions were
concentrated, and the resulting oil was chromatographed (98:2
hexane-Et2O) affording pure compound 6 (1.98 g, 98%) as a
colorless solid: mp 81-84 °C; 1H NMR (400 MHz, CDCl3,
COSY, HSQC) δ 1.21 (d, J=7.6 Hz, 3H, 3H, CH3), 1.35-1.44
(m, 2H, H-10, H-11), 1.57-1.83 (m, 6H, H-7, H-7a, H-9, H-10,
H-11), 1.90-1.98 (m, 1H, H-8), 2.08-2.19 (m, 1H, H-7), 2.46
(ddd, J=18.4, 11.2, 7.6 Hz, 1H, H-6), 2.63 (dd, J=18.4, 7.6 Hz,
1H, H-6), 3.84 (t, J=8.4 Hz, 1H, H-2), 4.52 (t, J=8.4 Hz, 1H,
1
afford 9 (170 mg, 50%): H NMR (400 MHz, CDCl3, COSY,
HSQC) δ 0.91 (d, J=7.2 Hz, 3H, CH3), 1.12-1.20 (m, 3H, H-4,
H-6, H-7), 1.24-1.33 (m, 1H, H-8), 1.35-1.51 (m, 5H, H-3,
H-4a, H-6, H-7, H-8), 1.52-1.67 (m, 2H, H-3, H-5), 1.74 (qd,
J=13.2, 3.6 Hz, 1H, H-4), 2.49 (dd, J=14.4, 9.2 Hz, 2H, H-100),
2.68 (dd, J=14.4, 4.8 Hz, 1H, H-100), 2.86-2.96 (m, 1H, H-8a),
3.54-3.63 (m, 1H, H-2), 3.64-3.71 (m, 1H, H-10), 3.70 (s, 3H,
CH3), 3.84-3.94 (m, 1H, H-10), 7.21-7.38 (m, 5H, H-Ar); 13C
NMR (100.6 MHz, CDCl3) δ 19.2 (CH3), 20.9 (C-7), 21.4 (C-4),
27.1 (C-6), 28.5 (C-3), 29.3 (C-8), 34.5 (C-5), 39.2 (C-100), 42.0
(C-4a), 49.3 (C-2), 51.6 (CH3O), 55.5 (C-8a), 62.5 (C-20), 68.9 (C-
10), 127.6 (CH-o), 128.3 (CH-p), 128.4 (CH-m), 140.6 (NCO),
173.4 (COO); IR (NaCl) 2925, 1736 cm-1; [R]22D -10.9 (c 1.4,
MeOH); HRMS calcd for [C21H31NO3 þ H] 346.2376, found
346.2387.
H-2), 5.30 (t, J=8.4 Hz, 1H, H-3), 7.15-7.33 (m, 5H, H-Ar); 13
C
NMR (100.6 MHz, CDCl3) δ 17.7 (C-10), 20.2 (CH3), 24.8 (C-7),
26.4 (C-11), 30.3 (C-9), 31.2 (C-6), 34.2 (C-8), 45.2 (C-7a), 57.9
(C-3), 69.7(C-2), 95.5 (C-11a), 125.3(CH-o), 127.0(CH-p), 128.5
(2R,4aS,5R,8aR)-1-(tert-Butoxycarbonyl)-2-(methoxycarbo-
nylmethyl)-5-methyldecahydroquinoline (10). A solution of 8
(560 mg, 1.6 mmol) and AcOH (4.1 mL, 69 mmol) in MeOH
(40 mL) containing 40% PtO2 (230 mg) was stirred under
hydrogen at rt for 24 h. The catalyst was removed by filtration
through a Celite pad, the filtrate was concentrated, and the
residue was taken up with EtOAc. The organic solution was
washed with 10% aqueous KOH, dried, and concentrated,
affording an oil, which was used without further purification
in the next step. A solution of the oil and di-tert-butyl dicarbo-
nate (700 mg, 3.2 mmol) in MeOH (30 mL) containing 40%
Pd(OH)2/C (200 mg) was stirred under hydrogen at rt for 16 h.
The catalyst was removed by filtration through a Celite pad, and
the filtrate was concentrated. The residue was chromatographed
(9:1 hexane-Et2O) to afford unsaturated ester 10 (280 mg, 54%)
as an oil: 1H NMR (400 MHz, CDCl3, COSY, HSQC) δ 1.06 (d,
J=7.2 Hz, 3H, CH3), 1.25-1.30 (m, 2H, H-3, H-4), 1.44-1.53
(m, 6H, H-3, H-4a, H-6, H-7), 1.46 (s, 9H, tBu), 1.67-1.71 (m,
2H, H-8), 1.78-1.84 (m, 2H, H-4, H-5), 2.45 (dd, J=14.7, 3.3
Hz, 1H, H-10), 2.63 (dd, J=14.7, 10.5 Hz, 1H, H-10), 3.67 (s, 3H,
(CH-m), 140.3 (C-i), 169.4 (NCO); IR (NaCl) 1654 cm-1; [R]22
D
-113.5 (c 1.0, MeOH). Anal. Calcd for C18H23NO2: C 75.76, H
8.12, N 4.91. Found: C 75.86, H 8.06, N 4.88.
(3R,7aS,8R,11aS)-8-Methyl-3-phenyl-5-thiodecahydrooxazolo-
[2,3-j]quinoline (7). Lawesson’s reagent (640 mg, 1.6 mmol) was
added to a solution of saturated lactam 6 (718 mg, 2.5 mmol) in
benzene (50 mL). The resulting mixture was heated at reflux for
3 h, cooled, and concentrated to give an oil. Flash chromato-
graphy (9:1 hexane-EtOAc) afforded 7 (500 mg, 66%): 1H
NMR (400 MHz, CDCl3, COSY, HSQC) δ 1.20 (d, J=7.2 Hz,
3H, CH3), 1.37-1.47 (m, 2H, H-10, H-11), 1.58-1.79 (m, 5H,
H-7, H-7a, H-9, H-10, H-11), 1.84-1.90 (m, 1H, H-9), 1.92-1.98
(m, 1H, H-8), 1.99-2.11 (m, 1H, H-7), 3.08-3.26 (m, 2H, H-6),
3.94 (t, J=8.6 Hz, 1H, H-2), 4.59 (t, J=8.6 Hz, 1H, H-2), 5.79 (t,
J=8.6 Hz, 1H, H-3), 7.10-7.12 (m, 2H, H-Ar), 7.22-7.34 (m,
3H, H-Ar); 13C NMR (100.6 MHz, CDCl3) δ 17.6 (C-10), 20.0
(CH3), 24.7 (C-7), 26.0 (C-11), 29.2 (C-9), 34.2 (C-8), 40.7 (C-6),
44.2 (C-7a), 63.5 (C-3), 69.2 (C-2), 97.6 (C-11a), 125.4 (CH-o),
127.1 (CH-p), 128.5 (CH-m), 138.7 (C-i), 198.3 (NCS); IR (NaCl)
1452 cm-1; [R]22 -138.1 (c 1.5, MeOH); HRMS calcd for
CH3O), 4.17-4.21 (m, 1H, H-8a), 4.48-4.55 (m, 1H, H-2); 13
C
D
[C18H23NSO þ H] 302.1579, found 302.1573.
NMR (100.6 MHz, CDCl3) δ 19.3 (CH3), 20.3 (C-7), 20.9 (C-4),
26.7 (C-3), 28.4 (C-6), 28.5 (CH3-tBu), 28.5 (C-8), 34.4 (C-5),
39.6 (C-10), 41.6 (C-4a), 47.1 (C-2), 49.3 (C-8a), 51.6 (CH3O),
79.5 (C-tBu), 155.0 (NCO), 172.1 (COO); IR (NaCl) 1740, 1687
(3R,7aS,8R,11aS)-5-(Methoxycarbonylmethylene)-8-methyl-
3-phenyldecahydrooxazolo[2,3-j]quinoline (8). A solution of 7
(1.4 g, 4.7 mmol) and methyl bromoacetate (4.3 mL, 46.5 mmol)
inCHCl3 (18 mL) wasstirredatrtfor17hinthe dark. The mixture
was concentrated, and the residue was taken up with CHCl3
(18 mL). Trimethyl phosphite (2.2 mL, 18.6 mmol) and Et3N
(6 mL) were added, and the resulting solution was heated at reflux
for 24 h. The mixture was allowed to cool to rt and concen-
trated. The residue was chromatographed(9:1 hexane-EtOAc) to
cm-1; [R]22 -25.9 (c 0.9, MeOH); HRMS calcd for [C18H31-
D
NO4 þ H] 326.2331, found 326.2335.
(2R,4aS,5R,8aR)-1-(tert-Butoxycarbonyl)-2-(2-hydroxyethyl)-
5-methyldecahydroquinoline (11). LiAlH4 (200 mg, 5.3 mmol)
was slowly added to a cooled solution (0 °C) of 10 (173 mg, 0.53
mmol) in anhydrous THF (5 mL), and the mixture was stirred at
rt for 1 h. The reaction was quenched with water, and the
resulting mixture was extracted with EtOAc. The organic extra-
cts were dried and concentrated, and the resulting residue was
chromatographed (8:2 hexane-EtOAc) to give alcohol 11 (150
mg, 94%) as an oil: 1H NMR (400 MHz, CDCl3, COSY, HSQC)
δ 1.06 (d, J=7.2 Hz, 3H, CH3), 1.25-1.31 (m, 3H, H-3, H-4),
1
afford 8 (1.2 g, 75%) as an oil: H NMR (400 MHz, CDCl3,
COSY, HSQC) δ 1.18 (d, J=7.2 Hz, 3H, CH3), 1.33-1.43 (m, 2H,
H-10, H-11), 1.56-1.99 (m, 8H, H-7, H-7a, H-8, H-9, H-10,
H-11), 3.11-3.21 (m, 1H, H-6), 3.25-3.37 (m, 1H, H-6), 3.49 (s,
3H, CH3O), 3.70 (t, J=8.4 Hz, 1H, H-2), 4.29 (s, 1H, H-10), 4.51 (t,
J=8.4 Hz, 1H, H-2), 4.73 (t, J=8.4 Hz, 1H, H-3), 7.11-7.17 (m,
2H, H-Ar), 7.23-7.36 (m, 3H, H-Ar); 13C NMR (100.6 MHz,
CDCl3) δ 17.9 (C-10), 20.2 (CH3), 23.9 (C-7), 26.1 (C-6), 26.2
(C-11), 30.2 (C-9), 34.5 (C-8), 44.7 (C-7a), 49.8 (CH3O), 61.7
(C-3), 70.2 (C-2), 84.7 (C-10), 96.0 (C-11a), 125.3 (CH-o), 127.4
(CH-p), 128.8 (CH-m), 139.2 (C-i), 159.0 (C-5), 169.0 (COO); IR
t
1.42-1.53 (m, 5H, H-3, H-4a, H-6, H-7), 1.48 (s, 9H, Bu),
1.59-1.65 (m, 3H, H-10, H-6, H-8), 1.75-1.86 (m, 4H, H-10,
H-5, H-8), 3.40 (br s, 1H, H-20), 3.58 (br s, 1H, H-20), 4.20 (br s,
1H, H-8a), 4.33 (br s, 1H, H-2); 13C NMR (100.6 MHz, CDCl3)
δ 19.1 (CH3), 20.3 (C-7), 21.4 (C-4), 26.7 (C-3), 28.3 (CH3-tBu),
28.7 (C-6), 30.1 (C-8), 34.3 (C-5), 38.4 (C-10), 42.0 (C-4a), 45.8
(C-2), 49.8 (C-8a), 58.9 (C-20), 80.0 (C-tBu), 156.8 (NCO); IR
(NaCl) 1788 cm-1; [R]22 -132.2 (c 0.5, MeOH); HRMS calcd
D
for [C21H27NO3 þ H] 342.2069, found 342.2063.
(2R,4aS,5R,8aR)-1-[(R)-2-Hydroxy-1-phenylethyl]-2-(methoxy-
carbonylmethyl)-5-methyldecahydroquinoline (9). A solution of 8
(340 mg, 1.0 mmol) and AcOH (2.5 mL, 44 mmol) in MeOH (25
(NaCl) 3449, 1659 cm-1; [R]22 þ15.5 (c 1.0, MeOH); HRMS
D
calcd for [C17H31NO3 þ H] 298.2382, found 298.2376.
J. Org. Chem. Vol. 75, No. 11, 2010 3803

Amat et al.
JOCArticle
(-)-Pumiliotoxin C. Dess-Martin reagent (360 mg, 0.86
mmol) was added to a solution of alcohol 11 (180 mg, 0.61
mmol) in anhydrous CH2Cl2 (5 mL), and the mixture was stirred
at rt for 2.5 h. Then, Et2O (9 mL), 1 M aqueous Na2S2O4 (2 mL),
and saturated aqueous NaHCO3 (2 mL) were added, and the
resulting mixture was stirred for 45 min. The aqueous layer was
extracted with Et2O, and the combined organic extracts were
washed with brine, dried, and concentrated to give the corre-
sponding aldehyde as an oil, which was used without further
purification in the next step. BuLi (0.9 mL of a 1.6 M solution in
hexane, 1.4 mmol) was added to a solution of methyltriphenyl-
phosphonium bromide (535 mg, 1.5 mmol) in THF (5 mL) at
0 °C, and the mixture was stirred for 1.5 h. Then, a solution of
the above aldehyde in THF (2 mL) was added, and the resulting
mixture was stirred at rt for 16 h. Saturated aqueous NH4Cl was
added, and the resulting mixture was extracted with CH2Cl2.
The combined organic extracts were washed with saturated
aqueous NaCl, dried, and concentrated. The residue was chro-
matographed (95:5 hexane-EtOAc) to give (2R,4aS,5R,8aR)-
2-allyl-1-(tert-butoxycarbonyl)-5-methyldecahydroquinoline
(114 mg, 64%) as an oil: 1H NMR (400 MHz, CDCl3, COSY,
HSQC) δ 1.07 (d, J=7.2 Hz, 3H, CH3), 1.20-1.37 (m, 3H, H-3,
H-7), 1.42-1.50 (m, 5H, H-3, H-4, H-4a, H-6), 1.46 (s, 9H, tBu),
1.50-1.84 (m, 4H, H-5, H-6, H-8), 2.23-2.32 (m, 2H, H-10),
4.02-4.10 (m, 1H, H-2), 4.18-4.25 (m, 1H, H-8a), 4.99-5.05
(m, 2H, H-30), 5.70-5.81 (m, 1H, H-20); 13C NMR (100.6 MHz,
CDCl3) δ 19.4 (CH3), 20.4 (C-4), 21.1 (C-7), 26.8 (C-3), 27.2
(C-6), 28.5 (CH3-tBu), 28.6 (C-8), 34.5 (C-5), 40.0 (C-10), 41.9
(C-4a), 49.3 (C-2), 50.2 (C-8a), 79.1 (C-tBu), 116.5 (C-30),
(3R,7aS,11aS)-8-Methyl-3-phenyl-5-thio-2,3,5,6,7,7a,10,11-
octahydrooxazolo[2,3-j]quinoline (12). Operating as in the pre-
paration of 7, from lactam 5b (2.4 g, 8.5 mmol) and Lawesson’s
reagent (2.1 g, 5.3 mmol), thiolactam 12 (2.35 g, 93%) was obtai-
ned as a solid after flash chromatography (9:1 hexane-EtOAc):
1
mp 117-122 °C; H NMR (200 MHz, CDCl3, COSY, HET-
COR) δ 1.57-1.75 (m, 1H, H-7), 1.76-1.81 (m, 1H, H-11), 1.78
(s, 3H, CH3), 1.85-1.98 (m, 1H, H-11), 1.98-2.18 (m, 2H,
H-10), 2.20-2.28 (m, 2H, H-7, H-7a), 3.03-3.19 (m, 1H, H-6),
3.21-3.38 (m, 1H, H-6), 4.00 (dd, J=8.8, 7.8 Hz, 1H, H-2), 4.63
(t, J=8.8 Hz, 1H, H-2), 5.45 (s, 1H, H-9), 5.96 (t, J=7.8 Hz, 1H,
H-3), 7.11-7.16 (m, 2H, H-Ar), 7.26-7.39 (m, 3H, H-Ar); 13
C
NMR (75.4 MHz, CDCl3) δ 21.5 (CH3), 22.8 (C-10), 25.0 (C-
11), 25.3 (C-7), 40.7 (C-6), 44.1 (C-7a), 64.1 (C-3), 69.0 (C-2),
96.0 (C-11a), 120.4 (C-9), 125.2 (CH-o), 127.1 (CH-p), 128.5
(CH-m), 133.5 (C-8), 138.6 (C-i), 199.0 (NCS); IR (NaCl)
1450 cm-1; [R]22 -209.1 (c 0.6, MeOH); HRMS calcd for
D
[C18H21NOS] 299.1344, found 299.1347.
(3R,7aS,11aS)-5-(Methoxycarbonylmethylene)-8-methyl-3-
phenyl-2,3,5,6,7,7a,10,11-octahydrooxazolo[2,3-j]quinoline (13).
Operating as in the preparation of 8, from thiolactam 12 (700
mg, 2.34 mmol), methyl bromoacetate (2 mL, 23.4 mmol) in
CHCl3 (10 mL), and then trimethyl phosphite (1.1 mL, 9.4
mmol) and Et3N (3 mL), compound 13 (650 mg, 82%) was
obtained as an oil after flash chromatography (7:3 hexane-
EtOAc): 1H NMR (300 MHz, CDCl3, COSY, HETCOR) δ
1.45-1.59 (m, 1H, H-7), 1.72-1.83 (m, 1H, H-11), 1.77 (s, 3H,
CH3), 1.80-2.10 (m, 4H, H-7a, H-10, H-11), 2.20-2.30 (m, 1H,
H-7), 3.15-3.39 (m, 2H), 3.50 (s, 3H, CH3O), 3.77 (t, J=8.5 Hz,
1H, H-2), 4.38 (s, 1H, CHd), 4.55 (t, J=8.5 Hz, 1H, H-2), 4.86 (t,
J =8.5 Hz, 1H, H-3), 5.42 (s, 1H, H-9), 7.15-7.18 (m, 2H,
H-Ar), 7.27-7.38 (m, 3H, H-Ar); 13C NMR (75.4 MHz,
CDCl3) δ 21.6 (CH3), 23.0 (C-10), 24.4 (C-7), 25.9 (C-11), 26.4
(C-6), 44.7 (C-7a), 49.9 (CH3O), 62.6 (C-3), 70.0 (C-2), 85.3
(CHd), 94.5 (C-11a), 120.2 (C-9), 125.2 (CH-o), 127.5 (CH-p),
128.9 (CH-m), 134.2 (C-8), 139.2 (C-i), 159.3 (C-5), 168.8
136.7 (C-20), 155.7 (NCO); IR (NaCl) 1686 cm-1; [R]22 þ4.7
D
(c 0.8, MeOH); HRMS calcd for [C18H31NO2 þNa] 316.2252,
found 316.2247. A solution of the above alkene (60 mg, 0.2
mmol) in MeOH (7 mL) containing 40% PtO2 (25 mg) was
stirred under hydrogen at rt for 1 h. The catalyst was removed by
filtration and washed with MeOH. The combined organic
solutions were concentrated, and the resulting oil was chroma-
tographed (98:2 hexane-Et2O) affording pure (2S,4aS,5R,
8aR)-1-(tert-butoxycarbonyl)-5-methyl-2-propyldecahydroqui-
(COO); IR (NaCl) 1739 cm-1; [R]22 -155.2 (c 0.8, MeOH);
D
HRMS calcd for [C21H25NO3] 339.1834, found 339.1832.
(2R,4aR,5S,8aS)-1-(tert-Butoxycarbonyl)-2-(methoxycarbo-
nylmethyl)-5-methyldecahydroquinoline (ent-2-epi-10). A solu-
tion of 13 (100 mg, 0.3 mmol) and AcOH (0.9 mL, 15 mmol)
in MeOH (10 mL) containing 40% PtO2 (40 mg) was stirred
under hydrogen at rt for 16 h. The catalyst was removed by
filtration, the filtrate was concentrated, and the residue was
taken up with EtOAc and extracted with 2 N aqueous HCl. The
aqueous solution was basified with saturated aqueous NaHCO3
and extracted with EtOAc. These organic extracts were dried
and concentrated to give an oil, which was used without further
purification in the next step. A solution of the oil and di-tert-
butyl dicarbonate (65 mg, 0.3 mmol) and Et3N (50 μL, 0.3
mmol) in CH2Cl2 (5 mL) was stirred under hydrogen at rt for
16 h. The solution was washed with 2 N aqueous HCl, dried, and
concentrated. The resulting residue was chromatographed (9:1
hexane-EtOAc) to afford ent-2-epi-10 (43 mg, 45%) as an oil:
1H NMR (300 MHz, CDCl3, COSY, HETCOR) δ 0.78-0.86
(m, 2H, H-4), 0.99 (d, J=7.3 Hz, 3H, CH3), 1.14-1.23 (m, 2H,
H-6), 1.39 (s, 9H, tBu), 1.48-1.91 (m, 8H, H-3, H-4a, H-5, H-7,
H-8), 2.40 (dd, J=15.0, 10.0 Hz, 1H, H-10), 2.65 (dd, J=15.0, 4.0
Hz, 1H, H-10), 3.60 (s, 3H, CH3O), 3.84 (dt, J=12.0, 4.5 Hz, 1H,
H-8a), 4.12-4.19 (m, 1H, H-2); 13C NMR (75.4 MHz, CDCl3) δ
19.0 (CH3), 19.7 (C-4), 19.9 (C-7), 24.0 (C-3), 25.9 (C-6), 28.5
(3CH3-tBu), 29.7 (C-8), 33.2 (C-5), 36.8 (C-4a), 39.9 (C-10), 48.0
(C-2), 50.1 (C-8a), 51.5 (CH3O), 79.4 (C-tBu), 154.8 (COO),
1
noline (56 mg, 95%) as an oil: H NMR (400 MHz, CDCl3,
COSY, HSQC) δ 0.92 (t, J=7.0 Hz, 3H, H-30), 1.06 (d, J=7.2 Hz,
3H, CH3), 1.20-1.26 (m, 3H, H-3, H-4), 1.40-1.56 (m, 9H,
t
H-10, H-20, H-3, H-4a, H-7, H-8), 1.46 (s, 9H, Bu), 1.62-1.67
(m, 2H, H-6), 1.77-1.84 (m, 2H, H-4, H-5), 4.00 (br s, 1H,
H-8a), 4.20 (br s, 1H, H-2); 13C NMR (100.6 MHz, CDCl3) δ
14.2 (C-30), 19.3 (CH3), 20.4 (C-20), 20.8 (C-7), 21.4 (C-4), 26.8
(C-3), 28.0 (C-6), 28.5 (C-8), 28.5 (CH3-tBu), 34.6 (C-5), 37.9
(C-10), 42.1 (C-4a), 49.2 (C-2), 50.3 (C-8a), 78.9 (C-tBu), 155.4
(NCO); IR (NaCl) 1686 cm-1; [R]22 þ18.8 (c 1.5, MeOH);
D
HRMS calcd for [C18H33NO2 þ H] 296.2590, found 296.2584.
To a solution of the above saturated compound (50 mg, 0.17
mmol) in anhydrous CH2Cl2 (0.5 mL) was added TFA (0.5 mL,
6.5 mmol), and the mixture was stirred at rt for 15 min. Then,
CH2Cl2 (3 mL) was added, and the solution was washed with
10% aqueous KOH, dried, and filtered. A 1 M HCl in MeOH
sample was added to the filtrate, and the solution was concen-
trated to give (-)-pumiliotoxin C hydrochloride (39 mg, 99%)
as a colorless solid: mp 248-250 °C; 1H NMR (400 MHz,
CDCl3, COSY, HSQC) δ 0.90 (d, J=6.4 Hz, 3H, CH3), 0.92
(t, J=7.4 Hz, 3H, H-30), 0.97-1.03 (m, 1H, H-6), 1.22-1.27 (m,
1H, H-20), 1.40-1.45 (m, 4H, H-20, H-3, H-4a, H-7), 1.46-1.62
(m, 2H, H-4, H-8), 1.76-1.88 (m, 2H, H-4, H-6), 2.07-2.17 (m,
4H, H-10, H-3, H-5), 2.33-2.50 (m, 2H, H-7, H-8), 2.98 (br s,
1H, H-2), 3.32 (br s, 1H, H-8a), 8.40 (br s, 1H, NH), 9.45 (br s,
172.1 (COO); IR (NaCl) 1740, 1690 cm-1; [R]22 -5.1 (c 0.9,
D
13
1H, NH); C NMR (100.6 MHz, CDCl3) δ 13.7 (C-30), 19.1
MeOH). Anal. Calcd for C18H31NO4: C 66.43, H 9.60, N 4.30.
Found: C 66.79, H 9.90, N 4.26.
(C-20), 19.7 (CH3), 20.4 (C-7), 23.1 (C-4), 25.1 (C-3), 27.1 (C-5),
29.1 (C-8), 34.3 (C-10), 34.8 (C-6), 40.8 (C-4a), 58.0 (C-8a), 60.1
(C-2); IR (NaCl) 2930, 2872 cm-1; [R]22D -15.3 (c 0.5, MeOH).
(2R,4aR,5S,8aS)-1-(tert-Butoxycarbonyl)-2-(2-hydroxyethyl)-
5-methyldecahydroquinoline (ent-2-epi-11). Operating as in the
3804 J. Org. Chem. Vol. 75, No. 11, 2010

Amat et al.
JOCArticle
preparation of 11, from ent-2-epi-10 (1.4 g, 4.3 mmol) and
LiAlH4 (1.7 g, 43.8 mmol), alcohol ent-2-epi-11 (1.2 g, 94%)
was obtained as a solid after flash chromatography (from 9:1
to 8:2 hexane-EtOAc): mp 85-89 °C; H NMR (300 MHz,
(C-8), 33.2 (C-5), 36.6 (C-4a), 39.9 (C-10), 49.9 (C-8a), 50.8 (C-2),
78.9 (C-tBu), 116.4 (C-30), 136.2 (C-20), 155.0 (NCO); IR (NaCl)
1688 cm-1; [R]22 -2.1 (c 1.0, MeOH); HRMS calcd for
D
1
[C18H31NO2 þ Na] 316.2247, found 316.2236. A solution of
the above alkene (60 mg, 0.2 mmol) in MeOH (7 mL) containing
40% Pd-C (25 mg) was stirred under hydrogen at rt for 1 h.
After the usual workup, flash chromatography (98:2 hexane-
Et2O) afforded pure (2S,4aR,5S,8aS)-1-(tert-butoxycarbonyl)-
5-methyl-2-propyldecahydroquinoline (57 mg, 97%) as an oil:
1H NMR (400 MHz, CDCl3, COSY, HETCOR) δ 0.92 (t, J=7 . 2
Hz, 4H, CH3, H-4), 1.05 (d, J=7 . 2 H z , 3 H , C H 3), 1.17-1.38 (m,
5H, H-6, H-8, H-20), 1.42-1.52 (m, 3H, H-4, H-7, H-10), 1.46 (s,
CDCl3, COSY, HETCOR) δ 1.05 (d, J =7.5 Hz, 3H, CH3),
1.13-1.27 (m, 3H, H-6, H-8), 1.41-1.45 (m, 3H, H-4, H-7), 1.48
(s, 9H, tBu), 1.58-1.78 (m, 5H, H-3, H-4, H-5, H-10), 1.84-1.94
(m, 2H, H-4a, H-8), 1.96-2.06 (m, 1H, H-3), 3.47-3.65 (m, 2H,
H-20), 3.80 (dt, J=12, 4.2 Hz, 1H, H-8a), 4.06-4.16 (m, 1H, H-2);
13C NMR (75.4 MHz, CDCl3) δ 19.1 (CH3), 19.5 (C-4), 19.7
(C-7), 25.0 (C-3), 25.9 (C-6), 28.4 (3CH3-tBu), 29.9 (C-8), 32.8
(C-5), 35.9 (C-4a), 39.6 (C-10), 46.8(C-2), 50.8 (C-8a), 59.1 (C-20),
79.7 (C-tBu), 156.7 (NCO); IR (NaCl) 3450, 1662 cm-1
;
9H, Bu), 1.53-1.94 (m, 7H, H-3, H-4a, H-5, H-7, H-8, H-10),
t
[R]22 -0.8 (c 1.0, MeOH). Anal. Calcd for C17H31NO3: C
68.65, H 10.51, N 4.71. Found: C 68.62, H 10.85, N 4.62.
3.70-3.76 (m, 1H, H-2), 3.88 (dt, J=12.0, 4.4 Hz, 1H, H-8a); 13
C
D
NMR (75.4 MHz, CDCl3) δ 14.1 (CH3), 19.1 (CH3), 19.8 (C-4),
19.9 (C-7), 20.4 (C-20), 22.6 (C-3), 26.0 (C-6), 28.6 (3CH3-tBu),
29.9 (C-8), 33.1 (C-5), 36.5 (C-4a), 37.6 (C-10), 49.9 (C-2),
ent-2-epi-Pumiliotoxin C. Operating as in the pumiliotoxin C
series, from alcohol ent-2-epi-11 (180 mg, 0.61 mmol) and
Dess-Martin reagent (365 mg, 0.86 mmol), (2R,4aR,5S,8aS)-
1-(tert-butoxycarbonyl)-5-methyl-2-(2-oxoethyl)decahydroquino-
line (140 mg, 78%) was obtained as a solid after flash chroma-
tography (95:5 hexane-EtOAc): mp 81-85 °C; 1H NMR (300
MHz, CDCl3, COSY, HETCOR) δ 0.85-0.93 (m, 1H, H-4),
1.07 (d, J=7.2 Hz, 3H, CH3), 1.19-1.34 (m, 3H, H-6, H-8), 1.45
(s, 9H, tBu), 1.58-2.06 (m, 8H, H-3, H-4, H-4a, H-5, H-7, H-8),
2.56 (ddd, J=16.0, 7.5, 2.1 Hz, 1H, H-10), 2.78 (ddd, J=16.0, 5.7,
2.1 Hz, 1H, H-10), 3.94 (dt, J=12.0, 4.5 Hz, 1H, H-8a), 4.28-4.35
(m, 1H, H-2), 9.75 (t, J =2.1 Hz, 1H, H-20); 13C NMR (75.4
MHz, CDCl3) δ 19.0 (CH3), 19.7 (C-4), 20.3 (C-7), 25.7 (C-3),
25.9 (C-6), 28.4 (3CH3-tBu), 29.4 (C-8), 33.2 (C-5), 37.1 (C-4a),
46.0 (C-2), 50.1 (C-10), 50.4 (C-8a), 79.6 (C-tBu), 154.9 (NCO),
50.9 (C-8a), 78.6 (C-tBu), 155.1 (NCO); IR (NaCl) 1688 cm-1
;
[R]22 þ14.7 (c 0.9, MeOH). Anal. Calcd for C18H33NO2: C
D
73.17, H 11.26, N 4.74. Found: C 72.84, H 11.65, N 4.74. To a
solution of the above saturated compound (100 mg, 0.34 mmol) in
anhydrous CH2Cl2 (2 mL) was added TFA (0.5 mL, 26 mmol), and
the mixture was stirred at rt for 15 min. Then, CH2Cl2 (3 mL) was
added, and the solution was washed with 10% aqueous KOH,
dried, and concentrated to give ent-2-epi-pumiliotoxin C (65 mg,
1
100%) as a colorless oil: H NMR (400 MHz, CDCl3, COSY,
HSQC) δ 0.88-0.92 (t, J=6.8 Hz, 3H, H-30), 0.98-1.00 (d, J=
7.2 Hz, 3H, CH3), 1.06-2.05 (m, 16H), 2.79-2.82 (m, 1H, H-2),
3.10-3.15 (dt, J=10.8, 4.1 Hz, 1H, H-8a); 13C NMR (75.4 MHz,
CDCl3) δ 14.2 (C-30), 19.2 (C-4), 19.3 (CH3), 20.5 (C-7), 25.2 (C-3),
28.3 (C-8), 29.7 (CH2), 31.4 (CH2), 32.5 (C-5), 38.3 (C-10), 41.8
(C-4a), 49.6 (C-2), 50.0 (C-8a); IR (NaCl) 2859 cm-1; [R]22D -22.2
200.7 (CO); IR (NaCl) 1725, 1686 cm-1; [R]22 -5.2 (c 0.9,
D
MeOH); HRMS calcd for [C17H29NO3 þ Na] 318.2045, found
318.2040. Operating as in the previous series, from the above
aldehyde (100 mg, 0.34 mmol), BuLi (0.4 mL of a 1.6 M solution
in hexane, 0.63 mmol), and methyltriphenylphosphonium bro-
mide (243 mg, 0.68 mmol) in THF (2.7 mL), (2R,4aR,5S,8aS)-2-
allyl-1-(tert-butoxycarbonyl)-5-methyldecahydroquinoline (70 mg,
70%) was obtained as an oil after flash chromatography
(95:5 hexane-EtOAc): 1H NMR (300 MHz, CDCl3, COSY,
HETCOR) δ 0.81-0.84 (m, 1H, H-4), 0.99 (d, J=7.2 Hz, 3H,
CH3), 1.03-1.19 (m, 3H, H-6, H-8), 1.40 (s, 9H, tBu), 1.42-1.88
(m, 8H, H-3, H-4, H-4a, H-5, H-7, H-8), 2.03-2.22 (m, 1H,
H-10), 2.32-2.40 (m, 1H, H-10), 3.66 (m, 1H, H-2), 3.82 (dt,
J=12.3, 4.5 Hz, 1H, H-8a), 4.92-5.01 (m, 2H, H-30), 5.62-5.76
(m, 1H, H-20); 13C NMR (75.4 MHz, CDCl3) δ 19.1 (CH3), 19.6
(C-4), 19.7 (C-7), 22.1 (C-3), 25.9 (C-6), 28.5 (3CH3-tBu), 29.9
(c 0.6, MeOH). For the hydrochloride: mp 230-235 °C; [R]22
D
-13.3 (c 1.1, MeOH).
Acknowledgment. Financial support from the Ministry of
Science and Innovation, Spain (Project CTQ2009-07021
BQU) and the AGAUR, Generalitat de Catalunya (Grant
2009-SGR-1111) is gratefully acknowledged.
Supporting Information Available: Experimental proce-
dures for compounds 14-17, copies of the H and 13C NMR
1
spectra of all compounds, and X-ray crystallographic data for
compounds 5b, 6, and ent-2-epi-11. This material is available
free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 11, 2010 3805