Evolution of the Morphinan Synthesis
Daniel Lednicwl
University of Missouri-Columbia, Columbia, MO 65211
One of the earliest and longest lasting targets for medici-
nal chemists has been the relief of pain. Most of the central
analgetics, though quite effective, present a serious draw-
back in that thev often lead to addiction. A considerable
amount of effort has thus been devoted toward attempts to
oroduce structural analoeues. Moruhinans such as levallor-
&an. I, and benzomorpians surhas pentazocine, 2, which
are essentiallv ahbreviawd versions of morphine and are but
single ~e~reskntatives of very large seriesof analogues, do
show reduced addiction potential. The key reaction to the
preparation of these structures is the Grewe carbocation
cyclization.
J
.
The original central analgetic agent, morphine, 3, was first
isolated from opium, the dried sap from the seed pod of
Papauer somniferum, in pure crystalline form by Serturner
as early as 1803. Structural proposals by Robinson (I) and by
Schopf (2) followed 120 years later, after organic chemistry
had developed sufficiently to tackle complex molecules.
Grewe's research led to the first synthesis for the morphine
skeleton and also provided the first generalized entry to
simplified analogues of morphine.
It is fitting that Rudolf Grewe received his training in the
natural products laboratory of Windaus at Gottingen. His
initial work actually involved heterocyclic rather than alicy-
clic chemistry and led to a paper, with Windaus, (3) on the
structural determination of the newly purified "antineuri-
tic" vitamin (4), a substance known today as thiamine or
vitamin B.
The structural analysis that identifies the isoquinoline
and phenanthrene moieties present in morphine appeared in
the first of a small series of papers on the synthesis of this
alkaloid. The synthetic plan was made explicit by the run-
ning title for the series: "Syntheses in the Phenanthrene
Series". The initial approach involved preparation of some
intermediate such as 4 containing groups at the 4a and 9
positions that could he used later to construct the additional
isoquinoline ring required for morphine (5). Earlier work
'
Prewnt address: DS(LC8, National Cancer Institute, EPN. Suite
831, Bslhesda. MD 20892.
718 Journal of Chemical Education
from other laboratories had shown that angularly substitut-
ed hvdroohenanthrenes could be obtained by proper choice
of s&ting materials; treatment of phenethil cyclohexanol,
5, with strong acid, for example, gives the phenanthrene 6
(6),while 7 leads to the alternate methylated product 8 (7).
(That earlier work was also directed at the total synthesis of
natural products containing angular substitution-the ste-
roids.) Grewe shortly published two additional communica-
tions in which he reported on the preparation of compounds
such as 8 that had the required substitution pattern (8,9).
The only available instrumental method for organic struc-
tural determination a t that time was ultraviolet spectrosco-
py. Infrared spectroscopy had not yet adapted to instrumen-
tation. The routine method for structural assignment of
these cyclization products involved treatment ivith a dehy-
drogenation catalyst such as platinum or palladium. It had
been established empirically that angularly substituted
products would lose the alkyl groups to give phenanthrene
proper; nuclearly alkylated products would give the corre-
sponding alkylphenanthrenes.
All these publications appeared under Grewe's name as
sole author; as a junior member of a well-established depart-
ment he no doubt had to carry out all the laboratory work
that appeared in print under his name. This, and the fact
that Germany had by then entered a major war, prohably
accounts for the fact that the solution to the morphinan
problem did not appear until 1943. In a stepwise exploration
of his original strategy, he applied the cyclizationreaction to
the cyclohexanol9. The major product, as determined by its
dehydrogenation to 12, disappointingly consisted of 10 rath-
er than the hoped-for angularly alkylated product 11,which
would have provided a nitrogen atom in the position re-
quired for a morphine-like structure (10). This is in marked
contrast to findings with the methyl analogue 7 or the ally1
comnound 13 (10). This can be rationalized in resent-day
k&hy assuming that the initially formed ca;bocation in
anv of these cvclizations needs to underao a 1.2 hydride shift
prior to ring &sure. That leading to logives greater separa-
tion between the charge on carbon and that on the protonat-
ed side chain amino Goup in the intermediate to 11.

Repetition of the experiment that led to the dialkylated
product 8 starting with the ally1 derivative 15 surprisingly
led to a product, 20, that contained the carhocyclic equiva-
lent of the morphine ring system (11). Grewe reasoned that
the initial reaction in this case involved formation of a hy-
dronaphthalene system such as 18, which includes a new
.carhocyclic ring. This was then postulated to undergo fur-
ther cyclization to the bridged system. In today's terms,
carbocation 16, from loss of a hydroxyl from 15, would un-
dergo a 1,2 hydride shift to form 17; electrophilic attack on
the ally1 double bond will lead to 18. The intermediate 18
then rearranges to the favored tertiary carbocation 19; elec-
trophilic attack on the aromatic ring leads to the observed
hicyclic product 20.
CWH ,COO11
The seemingly serendipitous discovery that the bridging
ring can be incorporated in prefabricated form in the cycliza-
tion reaction may have provided inspiration for the s h t h e -
sis in its fmal form. The three-year delay in the publication
of this work was, in all probability, due to the massive dis-
ruption of life in Germany at the end of World War 2.
Working now with a collaborator, Alhert Mondon. Grewe
first developed a route to an octah;droquinoline designed as
a heterocyclic analogue of the postulated reaction interme-
diate 18. The synthesis star& with the relatively routine
construction of the fused pyridinium salt 27. Though Gri-
~.
m a d reaeents will not add to imines., thev do so readilv
~~~
" to
~~-~~~~~
~
--
the far m&e electrophilic ternary iminium salts such as 27;
addition of henzylmagnesium chloride to 27 leads to 2% the
enaminelike double bond a t the 2 position (pyridine num-
bering) can be reduced selectively to leave the tetrasuhsti-
tuted olefin 29. Treatment with strong acid leads to the
morphinan 31, via the intermediacy of carbocation 30. Only
a single product is possible in this case, neglecting a theoreti-
cally possible spiroannulated compound (12).
Grewe highlighted the significance of the work by conclud-
ing the written account of a talk announcing the synthesis
".
with the note, ..this preparation will allow access to nu-
merous morphine type structures which may show special
pharmacological properties." This optimism was no doubt
prompted by the observation that "This synthetic base pos-
sesses good analgetic properties; its pain killing properties
are of the same magnitude as those of natural morphine"
(13).
. .
The first total synthesis of a derivative of a naturally
occurring morohinan started bv oreoaration of odahvdroi-
soquinolhe 32 by suitable &dikcation of the dar~ier
scheme. Treatment of this intermediate with strong acid
gave the cyclization product 34 in which the ether ortho to
the phenanthrene ring fortuitously demethylated under the
reaction conditions. The levorotatory isomer ohtained by
resolution proved identical to a sample of the same product
ohtained in several steps from dihydrothehainone, a minor
constituent of opium (14).
Practical consequences from this work appeared in very
short order with the synthesis of the analgetic agent race-
morphan, 37, by chemists at Hoffman LaRoche (15). In
practice, the compound is marketed as an analgetic drug as
its levorotatow isomer. levorohanol. The dextrorotarv iso-
mer, which is used separately,is inactive as an andgetic; it is
familiar to all as a part of cold remedies as the antitussive
agent dextromorphan. The subsequent finding that com-
pounds that lacked yet one more ring as in 2 retained eood
activity led to a second wave of research. The Grewe cycriza-
tion again provided the key reaction. This culminated in the
preparation of the benzomorphan, pentazocine, 2 (16), an
analgetic that shows reduced addiction potential (17).
Literature Clted
1. G d h d , J. M.;Robinson, R. Mem. R a c . Monch. tif.Phi1.Sac. 1)25,69,79-86
2. Sehopf, C.Ann. 1327,452,211-267.
3. Windaus,A.: Twhesche, R.: Gmare,R.Z.phwiol. C k m . 19U.118.27-32.
4. Glewe,R.Nofurmken. 1936.2.1.657462.
5. Gcewe. R . C k m . B w . 19J9.72,426432. :
Volume 66 Number 9 September 1989 719
 14. Greae, R.;Mondon.A.; Nolte. E. Ann. 1949.5M, 161-198.
15. Schnidu. 0.: G-ner, k Helo. Chirn.Acto 1949,32,821-929.
16. Archer, S.; Albertaon. N. F.; Harris, L. S.; Piersen, k K.: Bird, J. G. J Mad. Chem.
19U,7,12Fl21.
17. For detailed aemunrs ofthi m r k w Burger,A,: Anolgofies: Academic New Ywk,
1965. Johoson,M. R.;Milne, G. M. InBurger8MediciwIChernO*t~.4~th.; Waf,
M. E.: Ed.: Wiiey: New York, 1981; Part nI, Chapter 52. Lednieer, D. la Centrol
Awlgefic8; Ledni~er.D.; Ed.; Wiiey: New York, 1982: Chapter(.

720 Journal of Chemical Education