Enantioselective synthesis of (-)-dihydrocodeine and formal synthesis of (-)-thebaine, (-)-codeine, and (-)-morphine from a deprotonated α-aminonitrile

Article abstract of DOI:10.1021/ol5023849

The α-benzylation of a deprotonated bicyclic α-aminonitrile, followed by Noyori's asymmetric transfer hydrogenation combined with the Grewe cyclization onto a symmetrical A-ring precursor, are the key steps of a short and high-yielding enantioselective synthesis of the morphinan (-)-dihydrocodeine. This compound can be converted to (-)-thebaine in high yield by known transformations, while (-)-codeine and (-)-morphine are available from an advanced intermediate. (Chemical Equation Presented).

Full text of DOI:10.1021/ol5023849

Letter
pubs.acs.org/OrgLett
Enantioselective Synthesis of (−)-Dihydrocodeine and Formal
Synthesis of (−)-Thebaine, (−)-Codeine, and (−)-Morphine from a
Deprotonated α‑Aminonitrile
Mario Geffe and Till Opatz*
Institute of Organic Chemistry, Johannes Gutenberg University, Duesbergweg 10-14, 55128 Mainz, Germany
S
* Supporting Information
ABSTRACT: The α-benzylation of a deprotonated bicyclic α-
aminonitrile, followed by Noyori’s asymmetric transfer hydro-
genation combined with the Grewe cyclization onto a
symmetrical A-ring precursor, are the key steps of a short
and high-yielding enantioselective synthesis of the morphinan
(−)-dihydrocodeine. This compound can be converted to
(−)-thebaine in high yield by known transformations, while
(−)-codeine and (−)-morphine are available from an advanced
intermediate.
orphine (1, Figure 1), the major constituent of the
opium poppy latex, has been used for medical purposes
however, still attractive. Herein, we report an efficient
enantioselective total synthesis of (−)-dihydrocodeine (3)
from a deprotonated α-aminonitrile, which also represents a
formal total synthesis of (−)-morphine (1), (−)-codeine (2),
and (−)-thebaine (4).
M
Our synthesis began with the preparation of bicyclic α-
aminonitrile 7 by addition of HCN to commercial dihydroi-
soquinoline 6, which can alternatively be prepared from 3-
methoxyphenethylamine (5) in two steps.3 In a screening of
different cyanide sources, acetone cyanohydrin was found to be
superior in terms of yield, purity of the product, and ease of
workup and allowed the preparation of 7 in 92% yield (Scheme
1).4
Figure 1. Structures of bioactive opioids.
since as early as 3000 B.C. by the Sumerians in Mesopotamia.1
Today it is still one of the most common and effective analgesic
drugs with a strong influence on mankind, both in a positive
and negative sense. For decades, this fascinating molecule has
attracted attention not only for its extraordinary pharmaco-
logical effects but also because it is a challenging target for total
synthesis due to its unique and complex molecular architecture.
More than 60 years after the first total synthesis by Gates in
1952, around 30 papers have been published concerning
synthetic approaches to morphine (1) or its relatives codeine
(2), dihydrocodeine (3), and thebaine (4),2 but until now only
10 of them reported enantioselective syntheses.2n,r,y−ab,af,ai,ak,am
Among these, the highest yield (6.8%) was achieved by Trost in
his synthesis of (−)-codeine in 15 steps.2aa
Scheme 1. Synthesis of α-Aminonitrile 7, Benzylic Bromide
11, and Asymmetric Transfer Hydrogenation of 12
Although highly creative approaches toward the morphinan
skeleton have been developed, most routes suffer from a low
yield. From a practical viewpoint, the Rice synthesis of
dihydrocodeinone in 29% overall yield is the most efficient
route known to date but furnishes only the racemate.2h The
isolation of morphinan alkaloids from the dried plant material
of Papaver somniferum (poppy straw) is currently the
predominant source, but due to uncertain social, political, and
climatic conditions in some producing regions, high-yielding
methods for the chemical synthesis of opium alkaloids are,
Received: August 11, 2014
Published: October 1, 2014
© 2014 American Chemical Society
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Letter
The synthesis of the second building block started from
commercial ester 9 which itself can be obtained in a single step
from methyl gallate (8).5 Benzylation and reduction of 9
followed by treatment with N-bromosuccinimide and triphe-
nylphosphine furnished benzylic bromide 11 in 97% yield.6
While Rice used a bromine atom to block the more reactive
position in the A ring fragment, the symmetrical oxygenation
pattern used here was first employed by Beyerman to solve the
regioselectivity problem in the Grewe cyclization.2f
Scheme 2. Synthesis of (−)-Dihydrocodeine (3)
The deprotonation of 7 with KHMDS under controlled
conditions furnished a stabilized α-aminocarbanion which was
C-alkylated with 11 to yield 1-benzyl-3,4-dihydroisoquinoline
12 upon spontaneous dehydrocyanation. This compound was
sensitive to aerial oxidation and was therefore directly carried
on to the next step without purification.7 The alternative
synthesis of 12 by Bischler−Napieralski cyclization requires the
same number of steps and is less convergent than the present
route.8 Moreover, similar ring closures were found to be less
reliable for related substrates.
The enantioselective reduction of 12 introduced the first
stereocenter at C-1 of the isoquinoline moiety. The use of
RuCl[(S,S)-TsDPEN](p-cymene) as the catalyst and the formic
acid/triethylamine azeotrope as the hydride source for the
reduction of 3,4-dihydroisoquinolines was developed by
Noyori9 and also proved highly useful for the asymmetric
synthesis of various alkaloids from deprotonated α-amino-
nitriles.7a,10 Meuzelaar et al. achieved the highly enantiose-
lective reduction of the dihydroisoquinoline intermediate of the
Rice synthesis but reported poor results (23% yield, 86% ee)
for the Beyerman intermediate 12.8 No further steps in the
direction of morphine were undertaken by these authors.
On the basis of our previous experience with this reaction,
attempts for optimization were made, and three variables with
influence on the enantiomeric excess were identified: temper-
ature, addition time of reductant, and removal of carbon
dioxide from the reaction mixture by argon.11 These intricacies
were not observed for other 1-benzyl-3,4-dihydroisoquinolines,
and the electronic properties of the trialkoxybenzyl substituent
in 12 are likely to be responsible for the deviant behavior.7a,8,10
Under the optimized conditions, (R)-13 was obtained in 68%
yield over two steps with an ee of 95% (chiral HPLC). After
alkoxycarbonylation of 13 with methyl chloroformate, the
resulting carbamate 14 was subjected to Birch reduction
immediately followed by Grewe cyclization to establish the
morphinan skeleton of 16 carrying two new stereogenic centers
with defined geometry in 88% yield over two steps (Scheme
2).2d,f,12 N-Methoxycarbonyl was found to be the substituent of
choice, while an N-methyl group caused problems in the
isolation of the product of the Grewe cyclization due to the
amphoteric nature of the resulting basic phenol. Noyori
reported the catalytic asymmetric pressure hydrogenation of
the (Z)-N-formylenamide derived from 12 and obtained the N-
formyl derivative of 13 in 70% and 97% ee over three steps
including a photochemical E/Z-isomerization.13 We found
formyl protection to be cumbersome since the formamides
displayed an unusually high rotational barrier and the
corresponding separable rotamers14 hampered the purification
by chromatographic methods. Moreover, the formyl group is
partially cleaved and reduced under Birch conditions.
attempts were undertaken for the introduction of a suitable
leaving group into the α-position of the ketone at C-5
(morphine numbering) to enable the closure of ring E. Neither
phenyltrimethylammonium tribromide,15 tetra-n-butylammo-
nium iodide/H2O2,16 Kosers reagent,17 or copper oxide/
iodine18 gave satisfying results, while the method of Razdan19
employing copper(II)bromide as a brominating agent success-
fully closed the ether bridge. A 1:1 mixture of chloroform and
ethyl acetate was found to be the solvent of choice and gave
fewer side products than chloroform alone. Although copper-
(II)bromide is known to selectively brominate enolizable
ketones in the presence of arenes,20 the electron density of
ring A in 16 is very high so that partial bromination (ca. 50%)
at C-1 could not be avoided. Since 17 and 18 were difficult to
separate and the additional bromine could be removed
simultaneously with the triflate on a later stage, the sequence
was continued with the obtained compound mixture.
After triflylation of the remaining phenolic OH group (97%
yield), the mixture of 19 and 20 was subjected to a Pd-catalyzed
detriflylation/dehalogenation furnishing 21 as single product in
80% yield.5 Formic acid served as a nontoxic and inexpensive
hydride source in this step, which might also be performed with
a heterogeneous catalyst to meet the requirements of industrial
application. Reduction of the carbonyl group in 21 with DIBAL
afforded (−)-dihydrocodeine (3) in 81% yield, [α]28 = −124
D
(c = 1, 96% EtOH) [lit.21 [α]20D = −130 (c = 1, 96% EtOH)].
The use of this reducing agent turned out to be crucial for a
high diastereoselectivity and reduction with LiAlH4 led to the
formation of about 20% of the undesired C-6 epimer.
(−)-Dihydrocodeine (3) can be converted to (−)-thebaine
(4) in five steps (67% overall yield) by known procedures.22 As
ketone 21 is a suitable precursor for the introduction of the
In the course of the Birch reduction, the benzyl groups were
removed as well so that no additional deprotection was
required and the future A ring was protected from reductive
dearomatization by its increased electron density. Various
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Organic Letters
Letter
Δ7,8-double bond, the route also represents a formal total
synthesis of (−)-morphine (1) and (−)-codeine (2).2z,23
In summary, an enantioselective total synthesis of (−)-dihy-
drocodeine (3) in 31% overall yield over 12 linear steps from
commercial starting materials was developed. It is based on the
α-alkylation of a deprotonated α-aminonitrile and follows the
Beyerman strategy to alleviate the regioselectivity problem in
the Grewe cyclization generating the morphinan skeleton.
Ketone 21, which can serve as a starting point for the formal
total syntheses of (−)-morphine (1) and (−)-codeine (2), was
obtained in 11 linear steps with an overall yield of 38%. To the
best of our knowledge, the present route is by far the most
efficient asymmetric approach to morphinan alkaloids reported
to date (a comparison of enantioselective approaches to
morphinans can be found in the Supporting Information). A
first attempt of a linear scale-up to a multigram scale produced
ketone 21 in 15% overall yield and 95% ee (unoptimized), still
clearly superior to all published small-scale procedures (see the
Supporting Information).
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterization data, and H, 13C,
■
S
1
and 2D NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: opatz@uni-mainz.de.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank Dr. Johannes C. Liermann (Mainz) for NMR
spectroscopy, Dr. Norbert Hanold (Mainz) for mass
spectrometry, and graduate students Tamara Beisel, Danijel
Vidakovic, Carina Weber, and Laura Besch for preparative
assistance.
DEDICATION
■
(8) Meuzelaar, G. J.; van Vliet, M. C. A.; Maat, L.; Sheldon, R. A. Eur.
J. Org. Chem. 1999, 1999, 2315.
Dedicated to Professor Johann Mulzer on the occasion of his
70th birthday.
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