A Cascade Strategy Enables a Total Synthesis of (±)-Morphine

Article abstract of DOI:10.1002/anie.201608526

Morphine has been a target for synthetic chemists since Robinson proposed its correct structure in 1925, resulting in a large number of total syntheses of morphine alkaloids. Here we report a total synthesis of (±)-morphine that employs two key strategic cyclizations: 1) a diastereoselective light-mediated cyclization of an O-arylated butyrolactone to form a tricyclic cis-fused benzofuran and 2) a cascade ene–yne–ene ring closing metathesis to forge the tetracyclic morphine core. This approach enables a short and stereoselective synthesis of morphine in an overall yield of 6.6 %.

Full text of DOI:10.1002/anie.201608526

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201608526
German Edition: DOI: 10.1002/ange.201608526
Total Synthesis
A Cascade Strategy Enables a Total Synthesis of (Æ)-Morphine
Shuyu Chu, Niels Mꢀnster, Tudor Balan, and Martin D. Smith*
Abstract: Morphine has been a target for synthetic chemists
since Robinson proposed its correct structure in 1925, resulting
in a large number of total syntheses of morphine alkaloids.
Here we report a total synthesis of (Æ)-morphine that employs
two key strategic cyclizations: 1) a diastereoselective light-
mediated cyclization of an O-arylated butyrolactone to form
a tricyclic cis-fused benzofuran and 2) a cascade ene–yne–ene
ring closing metathesis to forge the tetracyclic morphine core.
This approach enables a short and stereoselective synthesis of
morphine in an overall yield of 6.6%.
M
orphine (1), named by Sertꢀrner for its tendency to
induce sleep, is the most abundant alkaloid isolated from the
opium poppy Papaver somniferum.[1] As the main constituent
of opium, morphineꢁs pain relieving properties have been
exploited for thousands of years, and in modern times have
resulted in its place on the World Health Organizationꢁs list of
essential medicines.[2] Its correct structure was proposed by
Robinson in 1925,[3] and was confirmed by Gates (through
total synthesis, 1952)[4] and Hodgkin (using X-ray crystallog-
raphy, 1955).[5] Currently, all medicinal (and illicit) morphine
is derived from natural sources; there is no synthetic route
that competes on scale and cost with isolation from natural
sources. This problem has been elegantly outlined in a recent
perspective from Hudlicky, which focuses on his groupꢁs
chemoenzymatic approaches to the morphine skeleton,[6] and
in other reviews which focus on the range of strategies
employed in total syntheses of morphine alkaloids.[7] None-
theless, the combination of potent biological effects and
a complex pentacyclic structure bearing five contiguous
stereocentres has made morphine and its associated alkaloids
an enduring challenge for synthetic chemistry, resulting in
more than 30 total or formal syntheses of morphine alka-
loids.[8,9] Our proposed strategy for the total synthesis of
morphine is outlined below (Scheme 1). It has been demon-
strated by Fuchs that the piperidine ring in morphine (1) can
be made by an intramolecular 1,6-addition of an amine
analogous to that in 2.[10] This requires an a,b,g,d-unsaturated
ketone, which we envisaged could be constructed via a cascade
ene–yne–ene ring closing metathesis from the heavily func-
tionalized benzofuran 3.[11,12] A metathesis cascade cyclization
offers the potential for a new end-game to the total synthesis
of morphine in which the requisite functional groups are
Scheme 1. Strategy for the synthesis of (Æ)-morphine.
installed prior to the formation of the B and C rings. This has
the advantage of minimizing late-stage functional group
interconversions once the ABCD tetracycle is complete.
The benzofuran 3 could be synthesized from the tricyclic
butyrolactone 4 by a series of functional group interconver-
sions to install the vinyl ketone and alkyne functional groups.
We recognized that the cis-fused butyrolactone 4, bearing an
all-carbon quaternary stereocentre, could be generated via
a photocyclization from substituted butenolide 5, with the
relative stereochemistry a consequence of the 5,5-cis-fused
nature of the tricycle. The butenolide 5 should be accessible
through the connection of three components: phenol 6,
mucobromic acid (7) and protected amino-borane 8.
Our route begins with the union of phenol 6[13] with
mucobromic acid (7) (Scheme 2). Treatment of phenol 6 with
an excess of mucobromic acid (7) in the presence of aqueous
sodium hydroxide led to smooth 1,4-addition-elimination
with exclusive displacement of the bromide b to the masked
aldehyde. In situ reduction of the resultant aldehyde and citric
acid mediated lactonization afforded butyrolactone 9 in 86%
overall yield.[14] The vinyl bromide in 9 can be cross-coupled
with protected b-amino borane derivative 8 (synthesized by
addition of 9-borabicyclo[3.3.1]nonane across tert-butyl
methyl(vinyl) carbamate)[15] by employing a Suzuki–Miyaura
coupling. This sp3–sp2 coupling[16] was particularly challenging
and required extensive experimentation to discover the
optimum conditions of catalytic Pd(dppf)Cl2·CH2Cl2 in the
presence of cesium carbonate in an aqueous DMF/THF
[*] S. Chu, Dr. N. Mꢀnster, T. Balan, Prof. Dr. M. D. Smith
Chemistry Research Laboratory, University of Oxford
12 Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: martin.smith@chem.ox.ac.uk
Homepage: http://msmith.chem.ox.ac.uk
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201608526.
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Scheme 2. Total synthesis of morphine: i) Mucobromic acid 7 (5.0 equiv), aq. NaOH (9.5 equiv), 208C; then NaBH4 (4.5 equiv), 08C; then aq.
citric acid (14 equiv), CHCl3/H2O, 208C. ii) B-alkyl-9-BBN reagent 8 (1.2 equiv), Pd(dppf)Cl2·CH2Cl2 (0.1 equiv), Cs2CO3 (2.0 equiv), DMF/THF/
H2O, 408C. iii) High-pressure mercury vapor lamp irradiation with Pyrex filter, DCE/HFIP, 208C. iv) Aq. KOH (20 equiv), t-BuOH/H2O, 208C; then
aq. Na2RuO4 (1.1 equiv), 508C. v) Dimethyl(diazomethyl)phosphonate (2.0 equiv), K2CO3 (5.0 equiv), MeOH, 208C; then Me(MeO)NH·HCl
(6.0 equiv), NMM (6.0 equiv), DMTMM (4.0 equiv), 208C. vi) Vinylmagnesium bromide (4.0 equiv), THF, 08C. vii) Hoveyda–Grubbs 2nd generation
catalyst (0.05 equiv), CH2Cl2, 208C; then TFA (40 equiv), 208C; then aq. Na2CO3 (60 equiv), 208C. viii) HCl (4.0 equiv), Et2O/CH2Cl2, 208C; then
aq. NaOH (8.0 equiv), 208C; then NaBH4 (10 equiv), 208C. ix) BBr3 (6.0 equiv), CH2Cl2/CHCl3, 208C. BBN=9-borabicyclo[3.3.1]nonane,
dppf=1,1’-ferrocenediyl-bis(diphenylphosphine), DMF=dimethylformamide, THF=tetrahydrofuran, DCE=1,2-dichloroethane, HFIP=hexa-
fluoroisopropanol, NMM=4-methylmorpholine, DMTMM=4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, TFA=trifluoro-
acetic acid.
mixture at 408C. This yielded the required functionalized
butenolide 5 in 58% yield (on a greater than 5 g scale). We
investigated the photocyclization of this material through
irradiation with a high-pressure mercury vapor lamp. In
seminal work in this field, Schultz demonstrated that related
substrates can cyclize efficiently via a process best described
as a 6p photoelectrocyclization followed by a concerted 1,4-
hydrogen shift.[17] After extensive investigation we were able
to demonstrate that a mixed dichloroethane/hexafluoroiso-
propanol solvent system was optimal, leading to the forma-
tion of 4 in an isolated yield of 37% after 120 h of irradiation
(plus 22% recovered starting material; yield 47% based on
recovered starting material, on a > 2 g scale). As expected,
only the cis-fused 5,5-system was isolated, presumably due to
strain associated with the alternative trans-fused stereochem-
istry. With this material in hand, we investigated the
installation of a C-14 alkyne, which requires a change in
oxidation state at C-14. This was achieved through ring
opening of the lactone in 4 under basic conditions using
aqueous KOH in tert-butanol to afford a hydroxy acid, which
was selectively oxidized using aqueous sodium ruthenate[18] to
afford hemiacetal 10. This was difficult to isolate cleanly, and
in practice was trapped without delay using dimethyl(diazo-
methyl)phosphonate in methanol in the presence of potas-
sium carbonate to install the requisite C-14 alkyne. This
carboxylic acid intermediate was also challenging to isolate
effectively and hence we employed 4-(4,6-dimethoxy-1,3,5-
triazin-2-yl)-4-methylmorpholinium chloride to generate an
activated ester in situ that was intercepted by N,O-dimethyl-
hydroxylamine in the presence of N-methylmorpholine to
afford Weinreb amide 11 in 73% yield over two steps from
4.[19] Addition of vinylmagnesium bromide in THF at 08C
proceeded smoothly to afford ketone 3 in 87% yield. This
heavily functionalized benzofuran is the key intermediate for
our cascade approach to the morphine skeleton. Treatment of
this intermediate with 5 mol% of the Hoveyda–Grubbs
second generation catalyst[20] in dichloromethane at room
temperature afforded tetracycle 2 which could be isolated in
94% yield. It is likely that this transformation proceeds via
reaction of the ruthenium alkylidene precatalyst with the allyl
component of 3, followed by intramolecular reaction with the
alkyne to ultimately give alkylidene intermediate 12.[21] Ring
closing metathesis with the a,b-unsaturated ketone affords
the tetracycle 2 as effectively the sole product in this
transformation.[22] In practice this step could be combined
with a subsequent 1,6-addition through removal of the tert-
butoxycarbonyl group with trifluoroacetic acid to afford an N-
methyl ammonium salt followed by free-basing with sodium
2
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This affords a 10:1 mixture of neopinone 13[23] and codeinone
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method employed by Rapoport.[24] This reaction likely
proceeds via transient formation of a b-halo ketone followed
by elimination on treatment with aqueous sodium hydroxide
to afford the thermodynamically favoured product 14. This
material can be isolated, but diastereoselective reduction of
the C-6 ketone can be achieved by the addition of sodium
borohydride to afford codeine (15) as a single diastereoisomer
in 65% overall yield from 3.[25] Demethylation of the C-3
methyl ether with boron tribromide afforded morphine 1 in
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1
86% yield.[26] The H and 13C NMR spectra of our synthetic
material were identical to those reported for both natural and
other synthetic materials.
In conclusion, we have described a short[27] and stereose-
lective synthesis of morphine in which a cascade ene–yne–ene
metathesis provides a new disconnection of this most endur-
ing of targets. The value of this approach is most clearly
reflected in the installation of key functional groups at an
appropriate oxidation level, which minimizes late stage
transformations and protecting group manipulations. Our
future work will focus on an enantioselective synthesis and
further investigation of the photocyclization, which we hope
may result in a more efficient and scalable synthetic route.
Acknowledgements
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The ERC has provided financial support (FP7/2007-2013,
ERC grant agreement 259056). We are grateful to the
Deutsche Forschungsgemeinschaft (MU 3987/1-1) for a fel-
lowship (to N.M.) and the EPSRC Centre for Doctoral
Training in Synthesis for Biology and Medicine (EP/ L015838/
1) for a studentship (to T.B.).
Keywords: cascade reactions · metathesis · morphine ·
photochemistry · total synthesis
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Received: August 31, 2016
Published online: && &&, &&&&
4
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Communications
Total Synthesis
S. Chu, N. Mꢁnster, T. Balan,
M. D. Smith*
&&&& — &&&&
A Cascade Strategy Enables a Total
Synthesis of (Æ)-Morphine
A classical target: A novel total synthesis
of (Æ)-morphine employs two key strate-
gic cyclizations: 1) a diastereoselective
light-mediated cyclization of an O-ary-
lated butyrolactone to form a tricyclic cis-
fused benzofuran and 2) a cascade ene–
yne–ene ring closing metathesis to forge
the tetracyclic morphine core. This ste-
reoselective approach affords morphine
in an overall yield of 6.6%.
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These are not the final page numbers!