The stereocontrolled total synthesis of (-)-O-methylpallidinine.

Article abstract of DOI:10.1021/ol027040n

[reaction: see text] The stereocontrolled total synthesis of (-)-O-methylpallidinine, a naturally occurring Morphinan alkaloid with a B/C-trans-hydrophenanthrene framework, has been achieved starting from the chiral bicyclo[3.2.1]octenone building block b

Full text of DOI:10.1021/ol027040n

ORGANIC
LETTERS
2002
Vol. 4, No. 25
4515-4517
The Stereocontrolled Total Synthesis of
(−)-O-Methylpallidinine
Keisuke Hanada, Norio Miyazawa, and Kunio Ogasawara*
Pharmaceutical Institute, Tohoku UniVersity, Aobayama, Sendai 980-8578, Japan
konol@mail.cc.tohoku.ac.jp
Received October 7, 2002
ABSTRACT
The stereocontrolled total synthesis of (−)-O-methylpallidinine, a naturally occurring Morphinan alkaloid with a B/C-trans-hydrophenanthrene
framework, has been achieved starting from the chiral bicyclo[3.2.1]octenone building block by employing a single-step dihydrophenanthrene
formation reaction as the key step.
(-)-O-Methylpallidinine 1,1 isolated from the leaves of the
South American plant Ochotea acutangula, is a Morphinan
alkaloid the B/C-trans-hydrophenanthrene stereochemistry
of which is diastereoisomeric with that of (-)-morphine 22
having a B/C-cis-hydrophenanthrene stereochemistry (Figure
1). We recently developed a concise enantio- and diastereo-
methodology to extend the versatility of the enantiopure
enone 3 as a chiral building block and to widen the
applicability of our tandem hydrophenanthrene formation
reaction to the construction of Morphinan alkaloids having
a B/C-trans stereochemistry. Because of its inherent stereo-
chemical and chemical nature with a sterically biased
structure, the enone (-)-3 exhibits convex-face selectivity
to allow diastereoselective construction of the benzylic
quaternary stereogenic center and facile retro-aldolization
leading to the tandem single-step formation of the B/C-cis-
hydrophenanthrene required for (-)-morphine 2 in the
previous synthesis.3 In the present investigation, we employed
the same methodology to synthesize (-)-O-methylpallidinine
1 having the trans-morphinan stereochemistry from the same
(1) Vecchietti, V.; Casagrande, C.; Ferrari, G.; Danieli, B.; Palmisano,
G. J. Chem. Soc. 1981, 578.
(2) For a pertinent review, see: Szantay, C.; Dørnyei, G. The Alkaloids;
Brossi, A., Ed.; Academic Press: New York, 1994; Vol. 45, pp 127-232.
(3) Nagata, H.; Miyazawa, N.; Ogasawara, K. Chem. Commun. 2001,
1094.
Figure 1.
(4) Nagata, H.; Miyazawa, N.; Ogasawara, K. Org. Lett. 2001, 3, 1737.
(5) Hanada, K.; Miyazawa, N.; Nagata, H.; Nagata, H.; Ogasawara, K.
Synlett 2002, 125.
(6) Racemic synthesis of O-methylpallidinine, see: (a) MacMurry, J.
E.; Farina, V. Tetrahedron Lett. 1983, 24, 4653. (b) McMurry, J. E.; Farina,
V.; Scott, W. J.; Davidson, A. H.; Summers, D. R.; Shenvi, D. R. J. Org.
Chem. 1984, 49, 3803. (c) Kano, S.; Yokomatsu, T.; Nemoto, H.; Shibuya,
S. J. Am. Chem. Soc. 1986, 108, 6746.
controlled route3 to (-)-morphine 2 starting from the
enantiopure bicyclo[3.2.1]octenone (-)-3 accessible either
by an enzymatic4 or a chemical5 resolution method. We have
now investigated the enantio- and diastereocontrolled syn-
thesis6 of (-)-O-methylpallidinine 1 applying the same
10.1021/ol027040n CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/14/2002

chiral building block (-)-3 by control of the stereochemistry
at the benzylic quaternary stereogenic center. This was
accomplished by simply inverting the order of introduction
of the aliphatic and aromatic nucleophiles on the chiral
building block to lead to the key intermediate with the
requisite benzylic quaternary center that is opposite in
configuration to that of (-)-morphine 2. We report here the
first diastereo- and enantiocontrolled synthesis of (-)-O-
methylpallidinine 1, which required a 12-step sequence of
reactions starting from the enantiopure bicyclo[3.2.1]-
octenone (-)-3.
hydrophenanthrene moiety. The reaction may be triggered
by the â′-alkoxy functionality which induced a hydrophenan-
threne formation involving the following tandem sequence
of reactions: (i) deprotection of the MOM ether and
ketoxonium formation (8-9), (ii) retro-aldolization forming
the aldehyde (9-10), (iii) aldoxonium ion formation (11-
12), (iv) cyclization to form the quinone methide intermedi-
ate, and (v) C-N cyclization (12-13). In the synthesis of
(-)-morphine 2 previously reported,3 the tricyclic 9,10-
dehydro derivative having a B/C-cis stereochemistry was
directly generated since the secondary carbamate nitrogen
was absent. In the present reaction, the cyclization by the
secondary nitrogen occurred to give the tetracyclic product
13 instead of forming the 9,10-double bond. The tetracyclic
carbamate 13 generated was reduced with lithium aluminum
hydride to afford the tertiary amine 14, [R]D22 +98.0 (c 1.4,
CHCl3), without affecting the tetracyclic ring system (Scheme
2).
Thus, the reaction of the enone (-)-3 with lithioacetonitrile
generated in situ from acetonitrile and butyllithium gave the
single 1,2-addition product 4, [R]D21 -191.1 (c 1.5, CHCl3),
which was sequentially reduced with lithium aluminum
hydride and acylated with methyl chlorocarbonate to give
22
the carbamate 6, [R]D -139.4 (c 1.2, CHCl3), via the
primary amine 5. Oxidation of 6 with pyridinium chloro-
24
chromate (PCC) afforded the enone 7, [R]D +87.5 (c 1.1,
CHCl3), with rearrangement of the double bond. Upon
reaction with the cuprate, prepared in situ from veratryl-
magnesium bromide and copper(I) bromide, in the presence
Scheme 2a
25
of trimethylsilyl chloride,7 the ketone 8, [R]D +108.4 (c
1.2, CHCl3), was obtained with a â-benzylic quaternary
center and a â′-alkoxyl functionality as the single product
after treatment of the intermediate crude silyl enol ether with
tetrabutylammonium fluoride (TBAF). During the conversion
both the 1,2- and 1,4-additions occurred diastereoselectively
from the convex-face, respectively, owing to the sterically
biased molecular structure of the chiral building block
(Scheme 1).
Scheme 1a
a Reagents and conditions: (A) (CH2OH)2, p-TsOH (cat.),
toluene, reflux (77%). (B) LiAlH4, THF, reflux (95%).
a Reagents and conditions: (A) MeCN, BuLi, THF, -78 °C
(92%). (B) LiAlH4, THF. (C) ClCO2Me, Et3N, CH2Cl2 (75%, 2
steps). (D) PCC, CH2Cl2 (89%). (E) 3,4-(MeO)2C6H3MgBr, CuBr-
Me2S, TMS-Cl, HMPA, THF, -78 °C then TBAF (82%).
To introduce the 9,10-olefin functionality required for the
construction of the morphinan framework,3,8 the amine 14
was treated with phenylsulfonyl chloride in the presence of
triethylamine. As expected, a facile sulfonylative elimination
took place to furnish the tricyclic compound 17, [R]D20 +81.1
(c 1.2, CHCl3), having a 9,10-double bond in 82% yield,
presumably through transient intermediates such as 15 and
16 (Scheme 3).
When the ketone 8 was refluxed with ethylene glycol in
toluene in the presence of a catalytic amount of p-toluene-
sulfonic acid, a facile reaction occurred to give a single
product that was found to be not the expected tricyclic
secondary carbamate but the tetracyclic tertiary carbamate
As in the morphine synthesis,3,8 exposure of the sulfon-
amide 17 to lithium in liquid ammonia resulted in reductive
26
13, [R]D +155.8 (c 1.1, CHCl3), having a B/C-trans-
4516
Org. Lett., Vol. 4, No. 25, 2002

controlled total synthesis. The spectroscopic data of the
synthetic material were identical with those reported for the
natural and synthetic products.1,6a,b The overall yield of (-)-
O-methylpallidinine 1 from the bicyclo[3.2.1]octenone chiral
building block (-)-3 was 5% in 12 steps after correction
for recovered starting material in the final step (Scheme 4).
Scheme 3
Scheme 4a
cyclization to furnish the morphinan 18, [R]D29 +47.1 (c 0.8,
CHCl3), in good yield. Cyclization of 17 also occurred with
sodium naphthalenide in THF9 to give the same cyclization
product 18 in moderate yield. Acid hydrolysis of the ketal
27
functionality of 18 afforded the ketone 19, [R]D +61.3 (c
1.0, CHCl3), whose spectroscopic data were identical with
those reported for the racemate (()-18 synthesized using
completely different procedures.6b,c Since the racemic ketone
19 has been transformed into racemic O-methylpallidinine
(()-1,6 the present synthesis of the optically active ketone
(+)-19 constitutes a formal enantiocontrolled synthesis of
(-)-O-methylpallidinine 1. To complete the total synthesis,
the optically active ketone (+)-19 thus obtained was first
a Reagents and conditions: (A) Li, NH3. t-BuOH, THF, -78
°C (76%) or sodium naphthalenide, THF, -30 °C (35%). (B)
p-TsOH (cat.), aq. acetone, reflux (90%). (C) pyrrolidine,
CH2(CH2STs)2 (76%). (D) m-CPBA (1.2 equiv), -30 °C, then dil.
HCl, reflux (69%). (E) p-TsOH, MeOH, reflux (20%, 44% based
on recovered 21).
In conclusion, we have achieved the enantio- and dia-
stereocontrolled synthesis of (-)-O-methylpallidinine 1, a
morphinan alkaloid with B/C-trans stereochemistry, from our
bicyclo[3.2.1]octenone chiral building block (-)-3 on the
basis of its inherent stereochemical and chemical nature.12
The same methodology developed in the synthesis of (-)-
morphine 2 with B/C-cis stereochemistry utilizing the same
chiral building block was applied to this synthesis.
25
transformed into the R-diketone monothioketal6a,b 20, [R]D
-81.0 (c 1.0, CHCl3), on treatment with trimethylene
dithiotosylate10,11 via the pyrrolidine enamine intermediate.
The dithiane functionality was then removed by following
28
the McMurry procedure6a,b to give the R-diketone 21, [R]D
+21.9 (c 0.4, CHCl3). Finally, the diketone 21 was then
refluxed in methanol6a,b containing a catalytic amount of
p-toluenesulfonic acid to give (-)-O-methylpallidinine 1,
28
Acknowledgment. We are grateful to the Ministry of
Education, Culture, Sports, Science and Technology, Japan
for support of this research. We also thank Professor
Yoshiharu Iwabuchi, Pharmaceutical Institute, Tohoku Uni-
versity, for helpful discussions.
[R]D -33.8 (c 0.4, CHCl3), hydrochloride (mp 195-197
27
°C, [R]D -21.3 (c 0.4, MeOH) {natural1 hydrochloride;
mp 195-200 °C, [R]D20 -50 (MeOH)}), in 20% yield with
55% recovery of starting 21, to complete the first enantio-
(7) Horiguchi, Y.; Matsuzawa, S.; Nakamura, E.; Kuwajima, I. Tetra-
hedron Lett. 1986, 27, 4025.
(8) Parker, K. A.; Fokas, D. J. Am. Chem. Soc. 1992, 114, 9688.
(9) Yamada, O.; Ogasawara, K. Org. Lett. 2000, 2, 2785.
(10) Woodward, R. B.; Pachter, I. J.; Scheinbaum, M. L. Organic
Syntheses; Wiley: New York, 1988; Collect. Vol. VI, p 1014.
(11) Takano, S.; Hiroya, K.; Ogasawara, K. Chem. Lett. 1983, 255.
OL027040N
(12) Utilization of the bicyclo[3.2.1]octenone chiral building block for
natural product synthesis other than (-)-morphine, see: (a) (+)-ferrugi-
nol: ref 4. (b) Calcitriol CD-ring: ref 5. (c) (+)-Vernolepin: Miyazawa,
N.; Ogasawara, K. Synlett 2002, 125. (d) 18-Ketoyohimbone: Miyazawa,
N.; Ogasawara, K. Tetrahedron Lett. 1983, 43, 4773.
Org. Lett., Vol. 4, No. 25, 2002
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