A concise route to (-)-morphine

Article abstract of DOI:10.1039/b101668g

A concise enantio- and diastereocontrolled route to (-)-morphine has been developed starting from a bicyclo[3.2.1]octenone chiral building block through an acid-catalyzed tandem retro-aldol-oxonium ion-mediated hydrophenanthrene formation reaction as the

Full text of DOI:10.1039/b101668g

A concise route to (2)-morphine
Hiroshi Nagata, Norio Miyazawa and Kunio Ogasawara*
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan.
E-mail: konol@mail.cc.tohoku.ac.jp; Fax: +81 22-217-6845; Tel: +81 22-217-6846
Received (in Cambridge, UK) 20th February 2001, Accepted 3rd May 2001
First published as an Advance Article on the web 25th May 2001
A concise enantio- and diastereocontrolled route to (2)-mor-
phine has been developed starting from a bicyclo[3.2.1]octe-
none chiral building block through an acid-catalyzed
tandem retro-aldol-oxonium ion-mediated hydrophenan-
threne formation reaction as the key step.
using 1,2-bis(trimethylsiloxy)ethane in the presence of trime-
thylsilyl triflate. Under these conditions, 8 furnished hydroxy-
ketal 9 in 71% yield with concurrent removal of the MOM-
protecting group. Primary hydroxylation carried out at this stage
under standard hydroboration–oxidation conditions8 afforded
diol 10 whose primary hydroxy functionality was selectively
acylated with pivaloyl chloride to give hydroxypivalate 11, the
substrate of the key acid-catalyzed hydrophenanthrene forma-
tion reaction, in 72% yield. Overall yield of 11 from (2)-3 was
22% in eight steps (Scheme 2).
Conversion of 11 into the key hydrophenanthrene inter-
mediate 16 could be accomplished in one step just by refluxing
with ethylene glycol in benzene with removal of generating
water. Thus, 11, on reflux with ethylene glycol in benzene using
a Dean–Stark apparatus in the presence of a catalytic amount of
toluene-p-sulfonic acid,2c furnished the hydrophenanthrene 16,
The total synthesis of (2)-morphine 1, the main alkaloid of the
opium poppy, has been a challenging target for organic chemists
for many decades.1,2 Although a number of successful synthe-
ses have been developed to date since the first accomplishment
by Gates3 in 1952, only a few could produce the alkaloid in an
enantio- and diastereocontrolled manner. We report here a
concise diastereocontrolled synthesis of the key intermediate4
dihydrocodeinone ethylene ketal (2)-2 of (2)-morphine 1 and
the related opium alkaloids starting from the bicyclo[3.2.1]octe-
none chiral building block5 (2)-3 by employing a tandem retro-
aldol cleavage and oxonium ion-mediated cyclization6 as the
key step (Scheme 1).
26
Enantiopure enone 3, [a]D 2438.6 (c 1.6, CHCl3)], was
reacted with 3-lithioveratrole generated in situ by reaction of
veratrole with butyllithium,7 to give diastereoselectively terti-
26
ary alcohol† 4, mp 82–84 °C, [a]D 2151.6 (c 1.5, CHCl3)],
which on oxidation with pyridinium chlorochromate (PCC)
afforded b-aryl-enone 5, [a]D26 +173.5 (c 3.0, CHCl3)], in 81%
yield. Construction of the dihydrobenzofuran moiety of the
target molecule was carried out at this point by employing the
procedure developed by Mulzer and coworkers4 in their
synthesis of 1. Thus, reaction of 5 with vinylmagnesium
chloride in THF containing HMPA in the presence of copper( )
I
bromide and trimethylsilyl chloride furnished silyl enol ether 6
in 75% yield by concurrent diastereoselective 1,4-addition and
O-silylation. Exposure of 6 to N-bromosuccinimide (NBS) gave
a-bromoketone 7 in excellent yield as an inseparable mixture of
two epimers (5:1). When the mixture was refluxed in DMF,4e
intramolecular etherification took place to give rise to dihy-
23
drobenzofuran 8, mp 80–82 °C, [a]D 2109.7 (c 0.5, CHCl3)],
in 81% yield as a single diastereomer. Since terminal hydrox-
ylation of the vinyl functionality of 8 under hydroboration–
oxidation conditions8 brought about formation of a mixture by
concomitant reduction of the carbonyl functionality in the
molecule, the ketone was first protected under mild conditions9
Scheme 2 Reagents and conditions: i) 3-Li-veratrole, THF, 278 °C. ii)
PCC, CH2Cl2 (81% in 2 steps). iii) vinyl-MgCl, CuBr-Me2S, TMS-Cl,
HMPA, THF (75%). iv) NBS, CH2Cl2, rt (99%). v) DMF, reflux, 30 min
(82%). vi) (CH2OTMS)2, TfOTMS(cat.), CH2Cl2 (71%). vii) BH3-Me2S
then 30% H2O2, NaOH (72%). viii) Piv-Cl, pyridine (87%).
Scheme 1
1094
Chem. Commun., 2001, 1094–1095
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b101668g

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Scheme 4 Reagents and conditions: i) LiAlH4, THF, rt (100%). ii)
PhSO2NHMe, 1,1A-(azodicarbonyl)dipiperidine, Bu3P, THF (78%). iii) Li,
NH3, t-BuOH, THF (70%).
The present methodology for the synthesis of the key
intermediate of (2)-morphine may be utilized widely not only
for the construction of the alkaloids having a cis-fused
tetrahydrophenanthrene framework but also for the synthesis of
the trans-fused congeners as the bicyclo[3.2.1]octenone chiral
building block allows diastereocontrolled construction of the
pivotal stereogenic center owing to its inherent convex-face
selectivity.
Scheme 3
25
[a]D +20.6 (c 0.7, CHCl3), in 50% yield as a single product
after 15 h. The reaction may be explained by initial formation of
oxonium ion 12 which underwent retro-aldol cleavage leading
to another oxonium ion 14 via protonated aldehyde 13 after
reaction with an ethylene glycol in the reaction medium.2c The
reaction proceeded further under the conditions to bring about
cyclization to give hydrophenanthrene 16 through a transient
15. Although we did not examine this point extensively, the
addition of ethylene glycol seemed to be essential to accelerate
this cyclization reaction2c (Scheme 3).
Notes and references
† Satisfactory analytical (combustion and/or high resolution mass) and
spectral (IR, 1H NMR, and MS) data were obtained for new compounds.
1 For pertinent reviews, see: T. Hudlicky, G. Butora, S. P. Fearnley, A. G.
Gum and M. R. Stabile, Studies in Natural Products Chemistry, Atta-
ur-Rahman ed., Elsevier, Amsterdam, 1996, Vol. 18, pp. 43–154; B. H.
Novak, T. Hudlicky, J. W. Reed, J. Mulzer and D. Trauner, Curr. Org.
Chem., 2000, 4, 343; K. W. Bentley, Nat. Prod. Rep., 2000, 17, 247 and
previous reports.
2 For the synthesis of morphine alkaloids after ref. 1, see: (a) J. D. White
and P. Hrncier, J. Org. Chem., 1999, 64, 7271; (b) J. D. White, P.
Hrncier and F. Stappenbeck, J. Org. Chem., 1999, 64, 7871; (c) O.
Yamada and K. Ogasawara, Org. Lett., 2000, 2, 2785.
3 M. Gates and G. Tschudi, J. Am Chem. Soc., 1952, 72, 1109.
4 (a) J. Mulzer, G. Durner and D. Trauner, Angew. Chem., Int. Ed.
Engl.,1996, 35, 2836; (b) J. Mulzer, J. W. Bats, B. List, T. Opatz and D.
Trauner, Synlett, 1997, 441; (c) D. Trauner, S. Porth, T. Opatz, J. W.
Bats, G. Giester and J. Mulzer, Synthesis, 1998, 653; (d) D. Trauner,
J. W. Bats, A. Werner and J. Mulzer, J. Org. Chem., 1998, 63, 5908; (e)
J. Mulzer and D. Trauner, Chirality, 1999, 11, 475.
5 H. Nagata, M. Kawamura and K. Ogasawara, Synthesis, 2000, 1825; H.
Nagata, N. Miyazawa and K. Ogasawara, Synthesis, 2000, 2013.
6 H. Nagata, N. Miyazawa and K. Ogasawara, Org. Lett., 2001, in
press.
7 E. D. Bergmann, P. Pappo and D. Ginsburg, J. Chem. Soc., 1950,
1369.
8 C. F. Lane, J. Org. Chem., 1974, 39, 1437.
9 T. Tsunoda, M. Suzuki and R. Noyori, Tetrahedron Lett.,198, 21,
1357.
Transformation of 16 into the penultimate intermediate 18 of
the target molecule (2)-2 could be carried out in a straightfor-
ward manner. The pivaloyl group from 16 was first removed by
reduction and the resulting primary alcohol 17, mp 92–94 °C,
28
[a]D +31.4 (c 0.7, CHCl3), was then transformed into the
tertiary sulfonamide 18 by employing the modified Mitsunobu
reaction.4,10 Thus, the reaction of 17 with N-methylbenzene-
sulfonamide in the presence of 1,1A-(azodicarbonyl)-
dipiperidine10 and tributylphosphine gave 18, mp 113–115 °C,
[a]D 228.5 (c 0.1, CHCl3)]{ref. 4d: mp 115–117 °C, [a]D
26
20
224.1 (c 1.0, CHCl3)}, in 78% yield, whose spectroscopic data
were identical with those reported.4d Since this compound has
been transformed into (2)-morphine 1 and the related opium
alkaloids via the key intermediate (2)-2,4 the present synthesis
constitutes a formal synthesis at this point. Actually, our
product (2)-18 furnished the key morphinan (2)-2, mp
170–172 °C, [a]D 2167.1 (c 0.1, CHCl3)]{ref.4d: mp 173–175
27
20
°C, [a]D 2173.3 (c 1.0, CHCl3)}, in 70% yield on treatment
with lithium in liquid ammonia containing tert-butanol.4d,11
Overall yield of (2)-2 from 11 was 27% in four steps, thus, 6%
in twelve steps from the chiral building block (2)-3 (Scheme
4).
10 T. Tsunoda, Y. Yamamiya and S. Ito, Tetrahedron Lett., 1993, 34,
1639.
11 K. A. Parker and D. Fokas, J. Am. Chem. Soc., 1992, 114, 9688.
Chem. Commun., 2001, 1094–1095
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