Straightforward assembly of the octahydroisoquinoline core of morphinan alkaloids

Article abstract of DOI:10.1021/ol1004627

The octahydroisoquinoline core of morphinan was assembled starting from readily available arylcyclohexadienes. Three different approaches were developed, including a metal- and an acid-mediated Mannich type process and an anionic-mediated cyclization. All

Full text of DOI:10.1021/ol1004627

ORGANIC
LETTERS
2010
Vol. 12, No. 10
2178-2181
Straightforward Assembly of the
Octahydroisoquinoline Core of
Morphinan Alkaloids
Julie Dunet, Raphae¨l Lebeuf, Gopal Bose, Fre´de´ric Robert, and Yannick Landais*
UniVersite´ de Bordeaux, Institut des Sciences Mole´culaires, UMR-CNRS 5255, 351,
cours de la libe´ration, 33405 Talence cedex 05, France
y.landais@ism.u-bordeaux1.fr
Received February 24, 2010
ABSTRACT
The octahydroisoquinoline core of morphinan was assembled starting from readily available arylcyclohexadienes. Three different approaches
were developed, including a metal- and an acid-mediated Mannich type process and an anionic-mediated cyclization. All provided the desired
motif as a single diastereomer having a C9-C13-C14 trans-cis relative configuration.
The octahydroisoquinoline moiety I (in red, Figure 1) is a
key component of the skeleton of naturally occurring
alkaloids of PapaVer somniferum including morphine 11 and
its closely related analogue pallidinine 2, isolated from
Ocotea acutangula. The highly functionalized aza-decaline
core is substituted at C13 by an aromatic ring, leading to a
trans (for 1) or a cis-C-D-ring junction (for 2 and 3), and
possesses a quaternary center, for which installation is
generally considered as the critical point in the synthesis of
morphinan alkaloids.1b These biologically relevant com-
pounds2 have been assembled in a number of ways,1,3 but
their structural complexity still serves as the impetus for
novel synthetic investigations. In the course of our ongoing
research on the use of arylcyclohexadienes as a unified
building block for the synthesis of amaryllidaceae, aspi-
dosperma, and papaver alkaloids,4 we recently focused our
attention on the elaboration of the isoquinoline C-D rings
of the morphinans.
Figure 1. Isoquinoline moiety of morphinan alkaloids.
(1) (a) Kutchan, T. M. The Alkaloids: Chemistry and Biology; Cordell,
G. A., Ed.; Academic Press: London, 1998; Vol. 50, pp 257-316. (b)
Blakemore, P. R.; White, J. D. Chem. Commun. 2002, 1159–1168.
(2) Sza´ntay, C.; Do¨rnyel, G.; Blasko´, G. The Alkaloids: Chemistry and
Pharmacology; Cordell, G. A., Brossi, A., Eds.; Academic Press: London,
1994; Vol. 45, pp 128-222.
(3) (a) Zezula, J.; Hudlicky, T. Synlett 2005, 388–405. (b) Taber, D. F.;
Neubert, T. D.; Schlecht, M. F. Strategies and Tactics in Organic Synthesis;
Harmata, M., Ed.; Academic Press: Oxford, 2004; Vol. 5, pp 353-389.
Cyclohexa-1,4-dienes have recently garnered a lot of
attention, their desymmetrization offering an entry into a
(4) (a) Beniazza, R.; Dunet, J.; Robert, F.; Schenk, K.; Landais, Y. Org.
Lett. 2007, 9, 3913–3916. (b) Lebeuf, R.; Robert, F.; Schenk, K.; Landais,
Y. Org. Lett. 2006, 8, 4755–4558, and references cited therein.
10.1021/ol1004627  2010 American Chemical Society
Published on Web 04/21/2010

large variety of natural products and valuable intermediates.5
We report herein our preliminary studies on the elaboration
of the octahydroisoquinoline framework of isoquinoline
alkaloids, using as key precursors, cyclohexadienes V
(Scheme 1). These building blocks constitute valuable motifs
for the construction of aza-decaline IV as the quaternary
center bearing the aryl ring, and the ethylamino chain of
targets 1-3 is already installed. Further stereocontrolled
reactions on the cyclohexadiene moiety should concomitantly
allow a control of its stereochemistry. It was anticipated that
the fused C-D rings of IV could be elaborated through an
intramolecular reaction between the dienyl system of V and
an imine or an iminium electrophile, generated in situ from
the ethylamino chain. Activation of the imine could be
carried out in several ways as a function of the nature of the
R′ substituent. Further elaboration of the 1,3-diene moiety
of IV, followed by formation of ring-B through a Friedel-
Crafts reaction from III, should complete the synthesis. Three
different approaches have thus been devised to construct
skeleton IV, varying the nature of the aldehyde and that of
the starting amine.
submitted to the copper-catalyzed reaction (Scheme 2). 4b
reacted efficiently and exclusively on the enol ether side to
give 5b as a single diastereomer possessing three new
stereogenic centers, including the quaternary center present
in the targeted alkaloids. In contrast, its isomer 4a was
recovered unchanged, suggesting that these dienes react as
enol ethers through a Mannich-type process.7
Scheme 2. Copper-Mediated Cyclization of Dienes 4a,b
Similarly, analogues 4c-f provided, under Lewis acid
catalysis, using either CuClO4(CH3CN)48 or Yb(OTf)3,9 the
desired aza-decaline 5c-f in excellent yields (Table 1), as
single diastereomers.
Scheme 1. Disconnection Approach to Isoquinoline Alkaloids
Table 1. Lewis-Acid Mediated Cyclizations of Dienes 4c-f
entry
Ar
cat.a
diene
product
yieldb
1
2
3
4
Ph
Cu
Cu
Cu
Yb
4c
4d
4e
4f
5c
5d
5e
5f
96(73)
79
89
3-MeO-4-BnOPh
3-MeOPh
3,5-(MeO)2Ph
quant.
a Cu: CuClO4(CH3CN)4; Yb: Yb(OTf)3. b Yield estimated from the 1H
NMR of the crude reaction mixture (isolated yields after chromatography).
Arylcyclohexadiene precursors are easily available through
Birch reductive alkylation of suitably substituted biaryls VI,6
followed by the reduction of the nitrile group into the desired
ethylamino chain. A series of arylcyclohexadienes 4a-f were
thus prepared, which were then condensed with ethyl
glyoxylate to produce in situ the corresponding imine. In a
preliminary experiment, an unseparable 74:26 mixture of 4b
and its regioisomer 4a (issued from the Birch reduction) was
The imine intermediate may be isolated first, before being
submitted to the Lewis acidic conditions. Alternatively, the
two steps may be carried out in one pot by successive
formation of the imine and addition of the Lewis acid to the
crude reaction mixture (Supporting Information). While crude
yields were generally high, we noticed that chromatography
resulted in a loss of material over silica (entry 1, Table 1).
The relative configuration of bicyclic amine 5c was obtained
from X-ray diffraction studies carried out on intermediate 6
(Scheme 3). The latter was obtained, as a crystalline
compound, through a regioselective hydrolysis of the bisenol
(5) (a) Abd Rahman, N.; Landais, Y. Curr. Org. Chem. 2002, 6, 1369–
1395. (b) Studer, A.; Schleth, F. Synlett 2005, 3033–3041. (c) Elliott, M. C.;
Paine, J. S. Org. Biomol. Chem. 2009, 7, 3455–3462. (d) Maji, M. S.;
Frohlich, R.; Studer, A. Org. Lett. 2008, 10, 1847–1850. (e) Umeda, R.;
Studer, A. Org. Lett. 2007, 9, 2175–2178. (f) Butters, M.; Elliott, M. C.;
Hill-Cousins, J.; Paine, J. S.; Walker, J. K. E. Org. Lett. 2007, 9, 792–803.
(g) Errasti, G.; Kounde´, C.; Mirguet, O.; Lecourt, T.; Micouin, L. Org.
Lett. 2009, 11, 2912–2915. (h) Umeda, R.; Studer, A. Org. Lett. 2008, 10,
993–996. (i) Roberson, C. W.; Woerpel, K. A. J. Am. Chem. Soc. 2002,
124, 11342–11348. (j) Chappell, D.; Drew, M. G. B.; Gibson, S.; Harwood,
L. M.; Russell, A. T. Synlett 2010, 517–520.
(7) An imino-ene-type process may also be envisioned.
(8) Yao, S.; Fang, X.; Jorgensen, K. A. Chem. Commun. 1998, 2547–
2548.
(6) (a) Lebeuf, R.; Dunet, J.; Beniazza, R.; Ibrahim, D.; Bose, G.; Robert,
F.; Landais, Y. J. Org. Chem. 2009, 74, 6469–6478. (b) Lebeuf, R.; Robert,
F.; Landais, Y. Org. Lett. 2005, 7, 4557–4560.
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Cheng, J. P.; Ksebati, M. B.; Wang, P. G. Tetrahedron Lett. 2002, 43, 2339–
2342. (b) Tietze, L. F.; Utecht, J. Chem. Ber. 1992, 125, 2259–2263.
Org. Lett., Vol. 12, No. 10, 2010
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ether moiety of 5c with H2SO4, followed by methylation,
using NaBH4-HCO2H.10 X-ray crystallography of 6 led us
to assume that 5b-f all possess the same C9-C13-C14
trans-cis relative configuration.11
benzoic acid (1 equiv) to a moderate yield of bicyclic
benzylamine 8b (entry 2). It is noteworthy that the cyclization
was accompanied by the regioselective hydrolysis of one of
the enol ethers. Among other acids tested, Lewis acidic
12
BF3-OEt2 and B(OH)3 gave only recovered starting
material, whereas pyridinium p-toluene sulfonate (PPTS,
entry 3) led to moderate yield of 8b. Using trifluoroacetic
acid (entry 4) or decreasing the temperature from 115 to 70
°C (entry 5) led to similar results. In constrast, furfural was
found to be more reactive under the given conditions,
offering access to the desired amines 8c,d in excellent yields
as a single diastereomer in each case (entries 7 and 8).14
Scheme 3. Synthesis and X-ray Structure of 6
Table 2. Acid-Mediated Cyclizations of Dienes 7a-c
The high stereoselectivity observed above could be
rationalized invoking an exo-transition state with a metal-
complexed (E)-imino ester (Figure 2). The chairlike confor-
mation in the exo approach appears more favorable than the
boatlike conformation of the endo mode.
entry
diene
Ar’
Ph
Ph
Ph
Ph
Ph
Ph
furyl
acida
t (h)
producte
yieldf
1
2
3
4
5
6
7
8
7a
7b
7b
7b
7b
7b
7b
7c
PhCO2H
PhCO2H
PPTS
TFA
20c
21c
21c
21c
21d
21d
21d
21d
8a
8b
8b
8b
8b
8b
8c
8d
-
50
37
50
52
47
96g
83g
TFA
TFAb
TFA
furyl
TFA
a 1 equiv of acid was used. b 0.5 equiv of TFA was used. c 115 °C. d 70
e
1
°C. dr > 98:2 as measured from H NMR of the crude reaction mixture.
f Isolated yield of 8a-d after chromatography. g Crude yields. Used without
purification.
Figure 2. Transition state model for the metal-catalyzed cyclization
of imines issued from dienes 4.
The relative configuration of tertiary amines 8b-d was
assigned based on the X-ray structure determination of
ketoacetamide 9 (Figure 3), obtained from 8d,15 and was
found identical to that obtained using the first approach.
Importantly, examination of the crystal structure of 9 revealed
that aromatic substituents at C9 and C14 are in close
proximity, as a result of A1,3-strain,16 induced by the
acetamide group. This point is critical for the future
functionalization of these substrates, which includes in the
late stage a Friedel-Crafts reaction between the phenyl ring
(C14) and a carbonyl group at C9,17 which will be generated
through the oxidation of the furyl ring.18 The short distance
between both aromatic groups, estimated to be in the range
of 3.4 to 3.6 Å, indicates that such a close proximity should
allow the coupling between these entities and construction
of ring B.
Encouraged by these results, we devised a second route
with the aim of directly generating protected secondary
amines, starting from more reactive iminium salts.12 For this
purpose, benzyl amines 7a-c13 were reacted with aromatic
aldehydes in the presence of an equimolar amount of
Bro¨nsted (Table 2) or Lewis acids. Benzaldehyde and furfural
were found to be the most suitable candidates, while ethyl
glyoxylate was discarded, giving rise to a complex mixture
of products under the reaction conditions. As before, “naked”
1,4-arylcyclohexadiene 7a led to no reaction (entry 1, Table
2), whatever the conditions tested, indicating that these
olefins were not nucleophilic enough to react with iminium
species. After extensive studies, precursor 7b led upon
reaction with 1.2 equiv of benzaldehyde in the presence of
1
(10) Gribble, G. W.; Lord, P. D.; Skotnicki, J.; Dietz, S. E.; Eaton, J. T.;
Johnson, J. L. J. Am. Chem. Soc. 1974, 96, 7812–7814.
(11) Numbering follows that of the natural products 1-3 (Figure 1).
(12) (a) Parsons, R. L.; Berk, J. D.; Kuehne, M. E. J. Org. Chem. 1993,
58, 7482–7489. (b) Kuehne, M. E.; Xu, F. J. Org. Chem. 1997, 62, 7950–
7960.
(14) No trace of the other diastereomer could be detected from the H
NMR of the crude reaction mixture.
(15) 8d was converted in 5 steps into ketone 9 (Supporting Informa-
tion). It is assumed that no epimerization took place under the reaction
conditions.
(16) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841–1860.
(17) Kano, S.; Yokomatsu, T.; Nemoto, H.; Shibuya, S. J. Am. Chem.
Soc. 1986, 108, 6746–6748.
(13) Benzylamines were easily formed through reductive amination of
amine 4c,d with benzaldehyde (Supporting Information).
2180
Org. Lett., Vol. 12, No. 10, 2010

Scheme 4. LDA-Mediated Cyclizations of Dienes 10a,b
Figure 3
9.
.
X-ray structure determination of octahydroisoquinolines
The results above have shown that electron-rich dienyl
systems are more reactive, which strongly supports a
Mannich-type mechanism for the copper- and acid-mediated
cyclization of enol ethers 4b-f and 7b-c. In contrast, 1,4-
dienes lacking OMe substituents (i.e., 7a) do not react under
these conditions. We therefore envisaged a complementary
approach that would offer access to a C ring at a lower
oxidation state that could be easily functionalized later, to
access isoquinoline alkaloids. This third approach is based
on an anionic-mediated cyclization using lithium amides. It
was foreseen that the acidic bis-allylic proton at C7 (pKa∼35
in DMSO)4b of dienes 4 and 7 would be abstracted under
such basic conditions4b,5i,19 to provide a pentadienyl anion
that could then cyclize by reaction with the imine functional
group. Imine 10a was thus prepared by condensing the
corresponding amine with furfural, then treated with LDA
(1.1 equiv), furnishing, after acidic workup, the desired
bicyclic amine 11a as a unique diastereomer, albeit in
moderate yield (Scheme 4). Similarly, workup using acetic
anhydride led to acetamide 11b, again as a single diastere-
omer. Interestingly, the methodology could also be applied
to diene 10b having enol ether groups.
quinoline having a “naked” cyclohexa-1,3-diene moiety,
ready for further functionalization, and an N-acetyl-protected
amine that should, as in 9, force substituents at C9 and C14
to be in close proximity through the A1,3-strain.
In summary, we have described along these lines a new
and straightforward access to an A-C-D tricyclic skeleton
of morphinans from symmetrical arylcyclohexadienes. Three
complementary approaches have been devised, which provide
the octahydroisoquinoline moiety with the relative config-
uration of pallidinine and congeners in no more than three
or four steps from simple biaryls. This strategy also provides
a simple solution to the critical problem of the control of
the stereochemistry of the quaternary center in the synthesis
of isoquinoline alkaloids.1b Studies are now underway in our
laboratory to functionalize intermediates such as 5, 8, and
11 en route to pallidinine synthesis.
Acknowledgment. We thank the MNERT and CNRS for
financial support and grants for JD, RL, and GB. We are
grateful to B. Kauffmann (IECB, Bordeaux) for X-ray
diffraction studies and J. C. Lartigues and N. Pinaud (ISM,
University Bordeaux-1) for NMR experiments.
Cyclization of 10b thus provided octahydroisoquinoline
11c in moderate yield. The relative configuration of 11a-c
was determined through X-ray diffraction studies on a 2,4-
dinitrobenzoic acid salt of 11a and proved to be the same as
that observed before for the first two approaches. This
strategy thus offers a one-pot approach to octahydroiso-
Supporting Information Available: Experimental details
and spectral data for new compounds and cif files for 6, 9,
and 11a. This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) Danishefsky, S. J.; DeNinno, M. P.; Chen, S.-H. J. Am. Chem. Soc.
1988, 110, 3929–3940.
(19) Studer, A.; Amrein, S. Angew. Chem., Int. Ed. 2000, 39, 3080–
3082
.
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