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Morphine Synthesis and Biosynthesis-An Update

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 Current Organic Chemistry, 2000, 4, 343-362 343

Morphine Synthesis and Biosynthesis—An Update

Bennett H. Novak1 , Tomas Hudlicky* 1 , Josephine W. Reed1 ,

Johann Mulzer* 2 and Dirk Trauner2

1Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA

2Institut für Organische Chemie der Universität Wien, Währingerstraß e 38 A-1090

Vienna, Austria

Abstract: This review covers recent developments in the area of morphine

synthesis and biosynthesis. Literature is reviewed since the publication of
the last major review. The first part of the chapter discusses recent advancements in
biosynthesis of morphine alkaloids. Total syntheses published since 1996 are reviewed next
and the third section discusses all published approaches to morphine skeleton. At the end of
the of the chapter, an additional reference list is provided for synthesis of medicinally important
derivatives, improvements in alkoloid interconversion, as well as a list of all dissertations dealing
with morphine synthesis.

Introduction in medicine both as an analgesic and as an anesthetic

Morphine (1 ) and its derivatives continue to attract
the undiminished attention of organic chemists. The
last major review in 1996 covered the sixteen total
syntheses reported in the literature up to that date
[1,2], and the history of its structure elucidation was
published in 1998 [3]. Morphine continues to be useful
[4]. Two commercially produced derivatives, naltrexone
(2 ) and naloxone (3 ), Fig. (1 ), are used for treatment of
opiate overdoses [5] and alcohol addiction [6]. These
are related to noroxymorphone (4 ), which is
manufactured from morphine or thebaine (5 ). All of
these compounds are still derived from natural opium
by isolation or semisynthesis from an isolated

HO HO HO HO

11
10
O O O O

9 NMe N N NH
5 14
OH OH OH
HO 6 O O O

morphine (1) naltrexone (2) naloxone (3) noroxymorphone (4)

MeO MeO MeO MeO

O O O O

NMe NMe NMe NMe

OH
MeO HO O O

thebaine (5) codeine (6) codeinone (7) hydroxycodeinone (8)

Fig. (1). Morphine and related compounds.

*Address correspondence to Tomas Hudlicky at the Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA; Fax No.: +1-
352-846-1203; e-mail:hudlicky@chem.ufl.edu

*Address correspondence to Tomas Hudlicky at the Institut für Organische Chemie der Universität Wien, Währingerstraße 38 A-1090 Vienna, Austria

1385-2728/00 $19.00+.00 © 2000 Bentham Science Publishers B.V.

344 Current Organic Chemistry, 2000, Vol. 4, No. 3 Novak et al.

compound, and there is no commercially viable synthesis and biosynthesis, with the literature
preparation of morphine in sight. coverage complete through December 1999.

To date the most efficient synthesis of morphine is

that of Rice, which proceeds on medium scale with an
overall yield of 29% [7]. In order for its de novo total
synthesis of morphine to be competitive with its
isolation, morphine should be produced in 6–8 steps
from inexpensive materials. Although such a goal
appears almost unattainable given the current state of
the art, a 6–8 step preparation of any of the morphine
derivatives that are now produced by semisynthesis
would approach competitive requirements at least for
these compounds, whose preparations require a similar
number of steps from morphine itself. For purely
scientific reasons, morphine therefore remains a
challenging structure. To insure against a drop in
supply brought about by either natural or social causes
in opium-producing regions of the world, the goal of
synthesizing morphine or producing it by biocatalytic
means remains a high priority. This update summarizes
the most recent developments in the area of chemical
Recent Advances in Biosynthesis
The biosynthesis of morphine is almost completely
elucidated [8]. Recent investigations have shown that
morphine and its congeners are produced not only in
plants (Papaver somniferum) but also in mammalian
organisms along essentially analogous pathways.
The first crucial key intermediate is (S)-reticuline (9 ,
Scheme 1), whose biosynthesis proceeds from L-
tyrosine via intermediates (S)-norcoclaurine, (S)-
coclaurine, (S)-N-methylcoclaurine, and (S)-3'-hydroxy-
N-methylcoclaurine, as discussed in the previous
review [1]. It is converted into its (R)-enantiomer via an
(S)-reticuline-oxydase-mediated oxidation to the 1,2-
dehydroreticulinium ion (1 0 ), which is
stereospecifically reduced to (R)-reticuline (1 1 ) by 1,2-
dehydroreticuline reductase [EC 1.5.1.27] [9]. Unlike

MeO MeO

dehydroreticulinium ion
NMe NMe reductase
HO (S)-reticuline HO
H
HO oxygenase HO

MeO MeO
NADPH NADP+
(S)-reticuline (9) 1,2-dehydroreticulinium ion (10)

MeO MeO MeO

NMe
HO HO salutaridine synthase HO
H
HO NADPH, O 2
NMe NMe
H H

MeO MeO MeO

OH O
(R)-reticuline (11) salutaridine (12)

MeO MeO
salutaridinol
acetyltransferase
salutaridine reductase
HO HO

NMe NMe
H H
MeO
NADPH NADP+ AcCoA CoA MeO
OH OAc
salutaridinol (13) salutaridinol-7-O-acetate (14)
Scheme 1.
Morphine
many other oxidoreductases, this NADPH-dependent
enzyme does not catalyze the physiologically reverse
reaction in vitro. (R)-Reticuline is then converted into
salutaridine (1 2 ) by an oxidative phenol coupling that
establishes the characteristic stereochemistry of the
morphinan skeleton.
This coupling is catalyzed by salutaridine synthase,
a microsomal NADPH-dependent cytochrome P-450
enzyme [EC 1.1.3.35] [10], which defines a new role
for cytochrome P-450 in alkaloid biosynthesis. Unlike
most of the described enzymes of this class,
salutaridine synthase functions as an oxidase rather
than as a mono-oxygenase — there is no concomitant
incorporation of oxygen into the substrate during the
course of reaction. The characterization of salutaridine
synthase as a cytochrome P-450 supports the
hypothesis of Barton and Cohen that the mechanism of
oxidation of plant phenols involves single-electron
transfer to afford phenolic radicals that form new C–C
and C–O bonds by radical coupling [11]. The substrate-
and stereospecificity of the reaction refutes the
possibility that this reaction could be catalyzed in vivo
by nonspecific phenol oxidases, lactases and
peroxidases [12].
Salutaridine (1 2 ) is then reduced by the NADPH-
dependent salutaridine reductase [EC 1.1.1.248] to
form salutaridinol (1 3 ) [13], followed by the closure of
the oxygen bridge between C4 and C5 to form the
characteristic pentacyclic morphinan skelton. In effect
this operation proceeds via an SN2'-type reaction
MeO
– HOAc
14 O
(spontaneous)
MeO
thebaine (5)
HO
O O
demethylation
NMe
(unknown enzyme)
HO
morphine (1)
Scheme 2.
Current Organic Chemistry, 2000, Vol. 4, No. 3 345
involving the allylic alcohol moiety in the C ring. First the
hydroxyl group is activated by an acetylation catalyzed
by salutaridinol 7-O-acetyltransferase [EC 2.3.1.150].
(This enzyme has been purified and characterized as a
single polypeptide, Mr = 50 000; it catalyzes the
stoichiometric transfer of the acetyl group from acetyl
coenzyme A to the 7-OH group of salutaridinol.)
Salutaridinol-7-O-acetate (1 4 ) undergoes a
spontaneous SN2'-type cyclization to produce
thebaine (5 , Scheme 2) [14]. Thebaine is
demethylated by an as-yet uncharacterized enzyme to
neopinone (1 5 ), which exists in an equilibrium with its
carbonyl-conjugated regioisomer, codeinone (7 ).
Codeinone is reduced to codeine (6 ) by codeinone
reductase [EC 1.1.1.247], an enzyme which has been
purified and characterized as monomeric protein of 35
kDa that is highly substrate specific, reducing only the
C6 oxo group of codeinone and morphinone as well as
that of a few analogues [15]. Additionally, four cDNAs
encoding codeinone reductase isoforms have been
isolated from Papaver somniferum and have been
expressed in Escherichia coli. These four isoforms
demonstrate very similar properties and substrate
specificity. At least six alleles appear to be present in
the poppy genome [16]. In vitro, the equilibrium is
continually driven from neopinone to codeinone until
the substrates are depleted. The demethylation of
codeine to morphine has been characterized in
mammalian liver, but the reaction has not yet been
detected in the poppy plant [17]. Additionally, the
hope has been expressed [8] that, by appropriate
MeO
demethylation O
(unknown enzyme) NMe
NMe
O
neopinone (15)
nonenzymatic
equilibration
MeO MeO
O
codeinone
NMe NMe
reductase
HO O
codeine (6) codeinone (7)
346 Current Organic Chemistry, 2000, Vol. 4, No. 3 Novak et al.

genetic manipulation of the poppy plant, enzymatic
pathways that lead to side alkaloids might be switched
off and the overall production of morphine be
increased.
The detection and isolation of highly morphine-
selective µ-receptors in mammalians indicates that
morphine naturally occurs not only in plants but also in
the mammalian organism. In fact, morphine has been
isolated from the skin of rats and rabbits [18]. Codeine
and morphine have been isolated from human
cerebrospinal liquid [19] and from human and bovine
milk [20]. It remains, however, to be clarified whether
these opioids stem from nutritional sources or whether
they are real mammalian products. In fact, it has been
shown that reticuline (9 ) is converted into salutaridine
(1 2 ) in rat liver, and salutaridine synthase has been
isolated and characterized from pig liver [21].
Furthermore, the conversion of thebaine into codeine
and morphine in rat liver has been demonstrated [22].
With respect to the physiological role of endogenous
opioids, there is speculation that they act as pain
regulators when the organism suffers from certain
diseases that are associated with chronic pain, such as
arthritis [23].
Total Syntheses of Morphine
Since the publication of the last review, three total
syntheses of morphine have been reported. Two,
those of White and Mulzer, focus on the phenanthrene
core of the molecule from two different angles. The
third, formally disclosed in a Chemical Review article by

Br
CHO CO2 Me 9 CO2 Me
9 CO2 Me
a b,c d–f

MeO MeO CO2 H MeO

MeO CO2 H
OH OH OH O
OH
isovanillin (16) 17 19 20

MeO MeO Br MeO

g–i HO j–l m,n

O 9 O
9
14 14 13 9
CO2 Me CO2 Me 14
CO2 Me
H H H H
O O HO

21 22 23

Reagents and conditions: (a) Stobbe condensation; (b) H2 , 18; (c) Br2 , HOAc; (d) MsOH, P2O 5; (e) H 2, Pd/C, NaHCO 3 ; (f) LiOH,
THF–H2O; (g) KH, HCO 2Me, DME, 0 °C; (h) methyl vinyl ketone, Et3 N, CH2Cl 2; (i) NaOH, H 2O, THF; (j) CH2 N2 , Et2O–CH 2Cl 2; (k)
Br2 , NaHCO3 , CH2Cl 2; (l) DBU, PhH, 50 °C; (m) NaBH 4, iPrOH, CH2 Cl2 ; (n) H2 , Pd/C, MeOH.

MeO OMe

P
H
O
[Rh(COD)Cl2 ]
O
H
P

MeO OMe

18
Scheme 3.
Morphine Current Organic Chemistry, 2000, Vol. 4, No. 3 347

Parsons, employs a nitrone–olefin cycloaddition.
Synopses of these achievements are summarized
below.
White (1997)
White’s synthesis of (+)-morphine [24] begins with
isovanillin (1 6 ), which was converted via Stobbe
condensation to cinnamate 1 7 , Scheme 3. Asymmetric
hydrogenation of this material with a chiral rhodium
catalyst (1 8 ) set the incipient C9 center (morphine
numbering) in the ent configuration (94% ee). In
principle, the route is enantiodivergent as both
enantiomers of 1 9 are accessible by asymmetric
hydrogenation. Bromination of the protected catechol
preceded the closure to tetralone 2 0 , which was
followed by formylation, Robinson annulation, and
base-catalyzed deformylation to set the C14 center
correctly in enone 2 1 . As C9 and C14 are traditionally
proper stereochemistry at C13 for the rhodium-
catalyzed carbenoid insertion into the CH bond,
accomplished in 50% yield, Scheme 4. Beckmann
rearrangement of the brosylate derivative of oxime 2 4
provided the fully functionalized skeleton of morphine
in 2 5 . The synthesis of ent-morphine was completed
as shown. Overall, its preparation was accomplished in
28 steps from isovanillin in an overall yield of 2–3%.
Mulzer (1996, 1998)
During early work in structural elucidation [3], double
Hoffmann degradation of morphine produced the
phenanthrene 2 7 , as shown in Scheme 5. Mulzer’s
synthesis [25-29] is formally the reverse of this
degradation process. His synthesis begins with the
known tetralone 2 9 , which was prepared from
commercially available carboxylic acid 2 8 as described
in Scheme 6. Activation of 2 9 as its formyl derivative

MeO MeO HO

O
a–f O g–h O i–o O
23 NOH
NR NR
H H H

MOMO MOMO HO

24 25 ent-1

Reagents and conditions: (a) CH2(OMe) 2, P2O5, CHCl 3; (b) LiOH, THF–H2O; (c) (COCl) 2, PhH; (d) CH 2N2; (e) Rh2(OAc)4, CH 2Cl 2; (f) H2NOH-
HCl, NaOAc, MeOH; (g) p-BrC 6H4SO2Cl, Et 3N; (h) AcOH, rt;( i) NaH, MeI, PhH; (j) HBr, MeCN; (k) Dess–Martin; (l) PhSeCl, MsOH, CH2Cl 2;
(m) NaIO4; (n) LiAlH4, THF, ∆; (o) Rice’s demethylation.

Scheme 4.

the problematic centers, setting these early is highly
advantageous. The C14 center maintained its
stereochemical integrity throughout bromination,
displacement of C5 halide, and reconjugation to
tetracyclic enone 2 2 , which was reduced and
hydrogenated to 2 3 . This compound possesses the
(3 0 ), followed by Robinson annulation and retro-
Claisen cleavage, provided the crystalline key
phenanthrenone 31 in good overall yield.
Phenanthrenone 3 1 was resolved (ee > 99.5%) by
chromatography on cellulose triacetate (CTA) either by
flash chromatography (1-gram scale) or by MPLC (10-

MeO
HO MeO

A
Hofmann Hofmann
B degradation degradation
O E O O
13 9
14 – CH2 =CH2
NMe
5 D – HNMe2
C
HO 6 HO NMe2

1 26 27

Scheme 5.
348 Current Organic Chemistry, 2000, Vol. 4, No. 3
MeO MeO
a–c
MeO MeO
O O
CO2 H
28 29
Reagentsandconditions: (a) Cl2, AcOH (99 %); (b) (COCl)2, PhH, ∆; (c) SnCl4, PhH, 0 °C (71 %); (d) HCOOMe, NaOMe, PhH (95 %); (e)
CH 2=CH-COCH3, Et3N, MeOH; (f) KOH, dioxane, H2O (81 %).
Scheme 6.
gram scale). The absolute configuration of (–)- 3 1
became clear once the final product (3 7 ) was reached.
The undesired enantiomer (+)-3 1 undergoes rapid
racemization upon treatment with base.
Conjugate addition of (H2C=CH)2CuMgCl to 3 1 ,
followed by addition of TMSCl afforded silyl enol ether
3 2 , which was treated with N-bromosuccinimide (NBS)
in THF at low temperature to furnish a 3:1 mixture of
bromo ketone 3 3 and its α-epimer (Scheme 7). This
vicinal difunctionalization not only established the
benzylic quaternary carbon and introduced a C2-
residue corresponding to the ethanamine bridge but
also provided the electrophilic functionalization of the
neopentylic position required for the subsequent
formation of the E-ring ether bridge. Because of the α-
haloketone effect, 3 3 is forced into a morphine-like, L-
shaped conformation that facilitates intramolecular
nucleophilic attack of the proximate methoxy group. In
fact, when heated in DMF at 140 °C, bromo ketone 3 3
cleanly afforded the dihydrobenzofuran derivative 3 4
(Scheme 8). Ketone 3 4 was protected as its ethylene
ketal under Chan’s conditions [30], and the vinyl group
was hydroborated with BH3•SMe 2. Oxidation gave the
primary alcohol 3 5 , which was dechlorinated by
catalytic hydrogenation. A novel variant of the
Mitsunobu reaction [31] converted the alcohol directly
MeO OMe
SMTO
a O
31
Cl
32
Reagents and conditions: (a) (H2C=CH) 2CuMgCl, THF, –78 to 0 °C; then TMSCl, Et3N, 0 to 25 °C; (b) NBS, THF (60 %; two steps).
Scheme 7.
Novak et al.
Cl MeO Cl MeO Cl
d e,f
MeO MeO
HO O
30 31
to the benzenesulfonamide, whose exposure to one
equivalent of NBS and a catalytic amount of dibenzoyl
peroxide in refluxing carbon tetrachloride afforded
styrene 3 6 . This benzylic dehydrogenation sets the
stage for the final heterocyclization and the completion
of the synthesis. Treatment of 3 6 to the conditions of
Parker and Focas [32] (Li, THF/NH3) cleanly effected
the desired piperidine ring closure in good yield.
Hydrolysis of the ethylene ketal with aqueous
hydrogen chloride at 90 °C afforded an excellent yield
of (–)-dihydrocodeinone (3 7 ). The attainment of 3 7
represents an asymmetric formal synthesis of (–)-
morphine.
In summary, the synthesis requires only 13 isolated
intermediates (all of which are crystalline) from
commercially available 4-(3,4-dimethoxyphenyl)butyric
acid (2 8 ) to (–)-dihydrocodeinone (3 7 ) (total yield:
11.5 %). The stereochemical course of all additions is
efficiently controlled by the growing ring system in the
sequence of ring closures A → AB → ABC → ABCE →
ABCED. The reagents are inexpensive and readily
available. All the carbons and heteroatoms of morphine
are derived from veratrol, succinic anhydride, vinyl
magnesium chloride, methyl vinyl ketone, and
methylamine. The use of protecting groups is confined
to the ethylene ketal, and undesired isomers are
recycled.
MeO Cl Cl OMe
b OMe
MeO
Br
Br
O
33
Morphine Current Organic Chemistry, 2000, Vol. 4, No. 3 349

Cl OMe Cl OMe
OMe

OMe
a b–d e,f
O
O O O O

HO O
Br

33 34 35

OMe OMe
OMe

g O steps O
O
O O

N N
N O

SO 2Ph OH

(–)-dihydrocodeinone (37) (–)-morphine (1)

36

Reagents and conditions: (a) DMF, 140 °C (99%); (b) TMSCl, (CH2OH) 2, CH2Cl 2 (92%); (c) BH3•SMe2, THF, then H2O2, OH- (70%); (d) Raney-Ni,
MeOH, KOH (98%); (e) PhSO2NHMe, ADDP, Bu3P (81%); (f) NBS, (PhCOO)2, CCl4, ∆, Et3N (67%); (g) Li, NH3, THF, t-BuOH, –78 °C (79 %); (h)
3N HCl, 90 °C (95%).

Scheme 8.

In addition to the cuprate chemistry, the Mulzer Eschenmoser–Claisen rearrangement, which afforded
group also has investigated sigmatropic an acceptable overall yield of dimethyl amide 3 8 .
rearrangements for establishing the benzylic Reduction to the corresponding primary alcohol
quaternary stereocenter (Scheme 9). followed by Mitsunobu reaction gave N-
Diastereoselective 1,2-reduction of 3 1 to the methylbenzene-sulfonamide 3 9 . Stereoselective
corresponding allylic alcohol set the stage for an epoxidation of 3 9 with dimethyldioxirane followed by

MeO Cl MeO Cl MeO Cl

MeO MeO MeO

a,b c,d e
31

NMe2 O
N N
O
38 39 SO 2Ph 40 SO 2Ph

Cl OMe Cl OMe OMe

O
Me
O O O O
f g–i

N O O
N N
OH
SO 2Ph SO 2Ph
41 42 43

Reagents and conditions: (a) DIBAH, THF,–78 °C (80%); (b) N,N-dimethyl-acetamide dimethyl acetal, PhMe, ∆ (64%); (c) LiBHEt3, THF, rt (96%); (d)
PhSO2NHMe, ADDP, Bu3P, rt (90%); (e) dimethyl dioxirane, CH2Cl 2, 0 °C to rt (80%); (f) TFA, THF, rt (83%); (g) H2, Pd/C, Et3N, MeOH, rt (88%);
(h) Swern oxidation (90%); (i) TMSCl, (CH2OH) 2, CH2Cl 2, rt (92%).

Scheme 9.
350 Current Organic Chemistry, 2000, Vol. 4, No. 3 Novak et al.

treatment of the resultant β-epoxide 4 0 with
trifluoroacetic acid (TFA) in dry THF again resulted in
dihydrobenzofurane ring closure with concomitant
demethylation (via 4 1 ) to provide a good yield of
secomorphinane 4 2 . Finally, dechlorination followed
by Swern oxidation [33] and ketalization afforded
ethylene ketal 4 3 , thus intercepting the previous
synthetic route.
Parsons (1996)
In 1996, Parsons disclosed his synthesis of
morphine in an article written for Chemical Reviews
[34]. To date, the full details of this approach remain
published only in dissertation form [35-37]. The key
step in this sequence is a [2+3] cycloaddition of a
nitrone to construct simultaneously both C9 and C14
centers, Scheme 10 [38]. Starting from enone 4 4 , the
C13 center was set by the application of the
Eschenmoser–Claisen rearrangement. Amide 4 5 was
transformed to the nitrone substrate 4 6 , which upon
cycloaddition provided the intermediate 4 7 with C9
and C14 set correctly. Following transamidation to 4 9 ,
morphine synthesis was completed as shown.
Approaches to the Morphine Skeleton
Several studies have been published since the
1996 review of morphine syntheses [1]. The Hudlicky
group continues to pursue morphine as a target by
three different strategies— by a Diels–Alder approach,
by Claisen rearrangement, and by radical or Heck-type
cyclizations.
Diels–Alder Approach
Model studies published in 1992 [39] indicate that
the tricyclic nucleus 5 5 can be constructed in two
ways—by the Diels–Alder reaction of 5 4 , available from
partial saturation of diene diol 50, and by Diels–Alder
cycloaddition of 5 1 , in which the cyclic diene
participates in the cycloaddition to a
bicyclo[2.2.2]octane intermediate 5 2 , subsequently
transformed to 5 3 via a Cope rearrangement (Scheme
11). The stereochemistry of 5 5 was assigned with the
aid of nOe arguments under the assumption that an
endo-transition state operates during the
cycloaddition.
Unfortunately, 5 3 and 5 5 have never been
compared by conversion to a common intermediate.
Although the stereochemistry shown in 5 3 is
undoubtedly correct, that of 5 5 was proven wrong
during a second-generation investigation [40]. In this
approach (Scheme 12), diols 5 6 and 5 7 , available by
biooxidation of (2-bromoethyl)- and (2-
azidoethyl)benzene respectively, were converted to
triene 5 8 , which was subjected to thermal cyclization to
produce tricyclic alcohol 5 9 , whose structure was

O O O

O NMe2
O O O

NMe2 O
a,b c–e
Me
N

O¯
O

OBn OBn OBn

44 45 46

O O

O
O O O

NMe2 NMe j,k

f–i
NMe 1
O O

OBn
47 49

Reagentsandconditions: (a) NaBH4, CeCl 3; (b) MeC(OMe)2; (c) OsO4; (d) NaIO 4; (e) MeNHOH; (f) H2, PdCl2; (g) HCl, ∆, vacuum; (h) p-
NO2C6H4SeCN, Bu3P, then H2O2; (i) O3, Ph3P; (j) CuBr2, MeCN, then tBuOK; (k) LiAlH4.

Scheme 10.
Morphine Current Organic Chemistry, 2000, Vol. 4, No. 3 351

O O
O

OR
RO O

HO 51 52 53

HO

50

O O

RO RO

54 55

Scheme 11.

confirmed by x-ray analysis. The suspicion that
structure 5 5 had been erroneously assigned was
confirmed by repetition of the experiment and
verification of structure 6 0 by x-ray analysis [40]. The
stereochemistry of the Diels–Alder adduct indicates
that the cycloaddition proceeds via an exo rather than
an endo transition state.
Based on these results and isolation of both 6 0 and
the advanced model compound 5 9 , the strategy for an
intramolecular Diels–Alder approach in setting the C13,
C14, and C9 centers focused on the ideas depicted in
Fig. (2 ). As the cycloaddition seems to proceed
through an exo transition state, the trans diene 6 1 ,
where Nu is a nucleophilic functionality (e.g., NR2),
should lead to 6 2 . The ethylamino bridge would be
formed by SN2 displacement of a leaving group (X = Br)
from the ethyl side chain. Conversely, the nucleophilic
tether in 6 3 would displace an allylic halide in 6 4 ,
whose stereochemistry would be dictated by Z
geometry in the starting diene. Combining this model
with one that includes ring A of morphine, the design

X
O O
HO d–g h

HO RO NHAc RO NHAc

56 X = Br 58 59
a–c
57 X = N 3

O O

RO RO

54 60

Reagents and conditions: (a) DMP, p-TsOH, acetone; (b) NaN3, DMF; (c) HCl, MeOH; (d) THSCl, imidazole, DMF, 0 °C; (e) NaH, sorbyl bromide,
THF; (f) PPh3, THF/H2O; (g) CH3COCl, Et3N, CH2Cl 2; (h) sealed tube, 230 °C, PhH.

Scheme 12.
352 Current Organic Chemistry, 2000, Vol. 4, No. 3 Novak et al.

corresponding arenes (6 5 and 6 8 ) [41] and can be

connected to provide triene 70, the precursor to
Diels–Alder cyclization, Scheme 13. Unfortunately, 7 0
Nu
O O fragmented before undergoing thermal cyclization to
exo 7 1 , probably because of the unfavorable Z geometry
Nu
and the large terminal substituent.
X X
RO RO Current model studies involve the synthesis of
61 trienes 7 4 , first with a trans-situated methyl group to
62
ascertain the stereochemistry at the C9 center, and
later, if successful, with a nucleophilic functionality to
pursue the alternative strategy illustrated in Fig. (2 )
[42].
O O
exo
X X The Claisen Rearrangement
Nu Nu The Claisen rearrangement approach to morphine
RO RO
was inspired by the recent efforts of Kazmaier and his
63 64
α-amino acid synthesis via a zinc-chelated Claisen
Nu = nucleophile; X = leaving group
rearrangement [43]. In this approach, glycinate 7 6 ,
Fig. ( 2 ) . Strategy for an intramolecular Diels–Alder obtained from the diene diol 7 5 , is rearranged to amino
approach to morphine. acid 7 7 , in which C14 is set with complete
stereocontrol at the same time C9 is generated as a
focuses on the exploitation of two synthons, 6 6 and mixture of diastereomers. The stereochemistry can be
6 9 . These are available by the biooxidation of controlled further by lactonization and epimerization of

Br Br
Br
OH O

O O
O
OH O
O RO O RO
65 66 67

O O
N3 N3 NHR
Br Br
OH

RO NHR RO
OH
70 71
68 69

O O

RO O RO O
Br

O
Br
O O
O
Y
O

72 RO X RO X

73 74
X = Br, NHAc; Y = Me, NHAc
Scheme 13.
Morphine Current Organic Chemistry, 2000, Vol. 4, No. 3 353

MeO MeO

MeO MeO

OH O O

OH OR NHBOC

75 76

MeO MeO

MeO CO2 H MeO

O
NHBOC O

RO
NHBOC
77 78
Scheme 14.

the BOC-protected amine to the less hindered exo cascade closure [32]. Inspired by this strategy, the
face of 78 (Scheme 14) [44]. This approach is Hudlicky group pursued a tandem radical cyclization
appealing in that it provides in a few operations an approach, as shown in Scheme 15.
intermediate in which C14 and C9 can be easily
controlled. In this approach, arenes 7 9 and 8 2 [45] were
oxidized with two organisms developed by the Gibson
group [46]. The recombinant clone E. coli
Radical or Heck-type Cyclizations JM109(DTG601A), which expresses toluene
dioxygenase, furnished diol 83 from (2-
In 1992, Parker published a stereocontrolled bromoethyl)benzene (8 2 ). This diol, which exhibits the
synthesis of morphine that makes use of a radical chirality appropriate for ring C of morphine, was

Br Br Br MeO

P. putida (TG02C) OH OH
O
O O
OH OMe 9
or
N
14
79 E. coli (pDTG602) 80 81 H

RO

86 (~15%) + isomers

O
h

Br N
Br O

MeO Br
O
OH OH O
a b–f g N

O
OH OTBS RO

82 83 84 85
Reagentsandconditions. (a) E. coli JM109(pDTG601A); (b) potassium azodicarboxylate, AcOH; (c) TBSCl, CH2Cl 2, iPr2NEt; (d) benzoic acid,
nBu3P, DEAD, THF; (e) 2-oxazolidone, NaH, DMSO; (f) aq. NaOH; (g) 81, nBu3P, DEAD, THF; (h) (TMS)3SiH, AIBN, PhH, 140 °C, sealed tube.

Scheme 15.
354 Current Organic Chemistry, 2000, Vol. 4, No. 3 Novak et al.

converted to TBS derivative 8 4 (Scheme 15).
Treatment of bromobenzene with another organism
[Pseudomonas putida (TG02C) or E. coli (pDTG602)],
provided bromocatechol 8 0 , which was mesylated to
give 8 1 . Connection of synthons 8 1 and 8 4 via a
double Mitsunobo inversion provided key intermediate
8 5 , whose treatment with (TMS)3SiH and AIBN
furnished pentacyclic 8 6 , along with other
stereoisomers, in only 15% yield. Its structure was not
unambiguously assigned; however, it was clear that
C14 and C9 were situated trans to each other.
The second generation approach [45], depicted in
Scheme 16, addressed a stepwise radical cyclization by
taking advantage of a metabolite (8 8 ) obtained from
the biooxidation of 1-bromo-2-(2-bromoethyl)-benzene
(8 5 ) [47]. This diol (8 8 ) was converted to the
oxazolone 8 9 , which was treated with Bu3SuH to
provide a 2:1 mixture of 9 0 and its stereoisomer in an
improved yield but without the control of C9 (morphine
numbering) stereochemistry. Nevertheless, the major
isomer 9 0 , possessing the C9 center in the ent-
configuration, was successfully converted to the ent-
morphinan skeleton 9 4 , which was also produced in
the epi C14 configuration [45,48].
A thorough study of the stereochemical as well as
experimental details of the synthesis of
octahydroquinolines 9 0 and its C9 (morphine
numbering) stereoisomer followed [45], and major
experimental improvements were also reported
[49,50]. For example, electrochemical methods were
incorporated into the preparation of precursors for the
iminium cyclization, namely the oxidation of 9 5 to 9 6 ,
in yields comparable to those of the aminal obtained by
chemical reduction of 9 7 (Scheme 17) [49].

O
OH O
Br O
O
HO
Br a b–d O e
N N
Br O
Br Br O 9
H
O

90 + isomer
87 88 89 2:1

MeO MeO

MeO Br
O
O CHO
O O j–k O
f,g h
RO N N

N
O RO O
H
O
92 93
91

MeO

OH

O
l
N
9
14

94

Reagents and conditions: (a) E. coli JM109(pDTG601A); (b) potassium azodicarboxylate, AcOH; (c) 2,2-dimethoxypropane, p-TsOH; (d) 2-oxazolone,
NaH, DMSO; (e) nBu 3SnH, AIBN, PhH, reflux; (f) TBSTf, iPr2NEt, CH2Cl2, –78 °C; (g) 81, nBu 3P, DEAD, THF; (h) nBu3SnH, AIBN, PhH, ∆;
(i) TBAF, THF; (j) DIBAL-H, CH2Cl 2; (k) oxalyl chloride, DMSO, Et3N; (l) trifluoromethanesulfonic acid.

Scheme 16.
Morphine Current Organic Chemistry, 2000, Vol. 4, No. 3 355

OR OR OR

RO RO RO

O a O b O
N N N

O
O X O O

95 96 97

R = Bz X = OMe, OH

Reagents and conditions: (a) Et4N+TsO-, MeOH, 1.85 V vs Ag/Ag+; (b) BH4-

Scheme 17.

An especially significant improvement was realized
by carrying out the cyclization of 9 6 under acidic
conditions and with benzoates as protecting groups,
capable of anchimeric assistance (Scheme 18). These
conditions resulted in 60% yields of decahydroquino-
lines 9 8 [49], which was dehydrated (or
dehydrohalogenated) to 9 9 , the sole product in the
acid-catalyzed cyclizations. A more detailed study was
conducted with the cis and trans benzoates, 100 and
Finally, a recent publication describes a new
approach with potential not only for an
enantiodivergent synthesis of morphine but also for a
general synthesis of noroxymorphone [51]. In a model
study (Scheme 20) designed to test the
regioselectivity of the Heck cyclization, benzoate 9 9
was converted via a single Mitsunobo inversion to aryl
bromide 1 0 2 , which underwent smooth cyclization to
1 0 3 in 57% yield. There was no detectable production

BzO
OBz
X
BzO
BzO
96 a
R = Bz N
O N
O
H
O
98 99 O
X = OH, Cl, Br
Reagents and conditions: (a) BF3•Et2O or AlX3 (X = Cl, Br).

Scheme 18.

1 0 1 , with full control in the production of 9 9 and 1 0 2 , of any regioisomer resulting from β-hydride elimination
representing entry points to both the natural and the at C9, which is syn in this case but would always be
ent series of morphinans (Scheme 19) [50]. trans to the organopalladium intermediate in the aryl

OBz OBz

BzO BzO

O
N N natural morphine
O
HO O
O
100 99
cis benzoates

OBz OBz

BzO BzO

O ent-morphine
N N
O
HO O H
O
101 102
trans benzoates
Scheme 19.
356 Current Organic Chemistry, 2000, Vol. 4, No. 3 Novak et al.

MeO

MeO Br

O H
O
BzO N
99
N 57% O
O
O SBTO

O
102 103

Scheme 20.

ether derived from 9 9 or 1 0 2 via simple or double
Mitsunobo reaction. Of special significance is the fact
that the Heck cyclization returns the oxidation state to
ring C of morphine and the neopine-type double bond
can be utilized for the synthesis of either morphine or
noroxymorphone (i.e., C14 oxidation).
The Cheng Study
In 1995, Cheng disclosed a rare case of successful
Heck-type cyclization onto a tetrasubstituted olefin
[52]. In this study, which served as a precedent for
Hudlicky's model approach, aryl halides 1 0 4 were
found to cyclize preferentially to 1 0 5 . The
regiochemistry problem related to morphine was solved
by the cyclization of the corresponding enamides 1 0 6
to 1 0 7 (Scheme 21).
Cheng's Heck cyclization study closely followed one
on a radical cyclization (Scheme 21) [53]. The
abstraction of a hydrogen atom by the C14 radical
(morphine numbering) was not stereospecific as
indicated by the mixture of 1 0 8 and 1 0 9 , in addition to
enol ether 1 1 0 , formed by intramolecular hydrogen
abstraction from C13 (morphine numbering). These
results are in accord with the observations made by
Hudlicky with similar intermediate. (See compounds 5 8
in reference 45.)

MeO
MeO
MeO X
MeO X
O
Heck rxn Heck rxn O
O NMe
O
NMe
O

NMe
NMe
O 107
104 105 106
X = Br, I X = Br, I

MeO MeO

MeO Br
Bu3 SnH O + O
104 +
NMe NMe O
X = Br AIBN
H

NMe

108 109 110

25% 16% 17%

Scheme 21.
Morphine Current Organic Chemistry, 2000, Vol. 4, No. 3 357

MeO
R
O CO2 Me
HO HO

+ R

MeO CO2 Me

111 112 113

Scheme 22.

The Rodrigo Approach Synthesis of Morphine Derivatives

Phenanthrofurans related to morphine nucleus
have been synthesized by the Rodrigo group. In 1998,
a tandem Diels–Alder and Cope sequence was
reported by this group [54]. This approach is
conceptually identical to one published by Hudlicky in
1992, except for the inclusion of ring A in this particular
design. A Dess–Martin type oxidation of 1 1 1 in the
presence of dienyl alcohol 1 1 2 provided ketal 1 1 3
(Scheme 22), which underwent a thermal cyclization to
produce a mixture of adducts 1 1 4 , 1 1 5 , and 1 1 6
(Scheme 23). The endo adduct was aromatized to 1 2 1
directly, while the bridged system 1 1 6 underwent a
Cope-type rearrangement to 1 2 2 , which was
converted to the tetracyclic compound 1 2 1 . This is a
very efficient route to a morphinan precursor in just four
steps.
The chemistry of morphine derivatives is too
voluminous to be discussed in this update.
Nevertheless a few important accomplishments are
included. Rice has published a conversion of codeine
to thebaine [55] and provided a procedure for oxidation
of codeinone to 14-hydroxycodeinone [56] as well as
for the conversion of codeine to thebainone-A [57]. His
group has also published the O-demethylation of
thebaine to oripavine [58]. Bruce continues to study
the biocatalytic approach to morphine derivatives and
their oxidized version [59].
References to other chemistry of morphine-like
compounds are listed in the citation section at the end
of the review. Excluded are papers dealing exclusively
with biological and medicinal properties of derivatives.

O O

MeO CO2 Me MeO CO2 Me

R O
O O O
+ +
113

R R
OMe

R=H 114 (exo) 115 (endo) 116

R = CH2 CHCH2 31% 21% 7%
13% 11% 17%

(3,3)
∆

HO O

CO2 Me

HO¯
O O
MeOH
R R

121 122
R = H, 90%
R = CH 2CHCH 2, 94%
Scheme 23.
358 Current Organic Chemistry, 2000, Vol. 4, No. 3 Novak et al.

Conclusions [12] Kametani, T.; Mizushima, M.; Takano, S.; Fukumoto, F.

It is evident from the number of active groups [13]
pursuing morphine synthesis that interest in this
fascinating molecule has not waned. Although a truly
practical approach has not materialized, a number of
[14]
useful derivatives have been prepared, and several
important technological advancements in the
interconversion of the morphine-type alkaloids have [15]
been attained. The biosynthesis of morphine also [16]
continues to be an area of vigorous activity. Finally,
biocatalytic approaches to derivatives of morphine have
[17]
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investigation in the area of morphine alkaloids. There is
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[21]
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Morphinan Chemistry
[1] Yu, H.; Wang, L. J.; Flippen-Anderson, J. L.; Tian, X. R.; Coop,
A.; Rice, K. C. Synthesis of a novel 7,14-β-ethano-bridged opiate.
Heterocycles 1999, 51, 2343.
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[2] Ananthan, S.; Kezar, H. S.; Carter, R. L.; Saini, S. K.; Rice, K. C.;
Wells, J. L.; Davis, P.; Xu, H.; Dersch, C. M.; Bilsky, E. J.;
Porreca, F.; Rothman, R. B. Synthesis, opioid receptor binding,
and biological activities of naltrexone-derived pyrido- and
pyrimidomorphinans. J. Med. Chem. 1999, 42, 3527
[3] Linders, J.T.M.; Flippen-Anderson, J.L.; George, C.F.; Rice,
K.C. An expedient synthesis of 9-keto-2-methyl-5-
(dimethoxyphenyl)morphans. Tetrahedron Lett. 1999, 40, 3905.
[4] Ananthan, S.; Johnson, C.A.; Carter, R.L.; Clayton, S.D.; Rice,
K.C.; Xu, H.; Davis, P.; Porreca, F.; Rothman, R.B. Synthesis,
opioid receptor binding, and bioassy of naltrindole analogues
substituted in the indolic benzene moiety. J. Med. Chem. 1998,
41, 2872.
[5] Coop, A.; Janetka, J. W.; Lewis, J. W.; Rice, K. C. L-Selectride
as a general reagent for the O-demethylation and N-
decarbomethoxylation of opium alkaloids and derivatives. J. Org.
Chem. 1998, 63, 4392.
[6] Kubota, H.; Rothman, R. B.; Dersch, C.; McCullough, K.; Pinto,
J.; Rice, K. C. Synthesis and biological activity of 3-substituted
3-desoxynaltrindole derivatives. Bioorg. Med. Chem. Letter
1998, 8, 799.
[7] Katsura, Y.; Zhang, X. Y.; Homma, K.; Rice, K. C.; Calderon, S.
N.; Rothman, R. B.; Yamamura, H. I.; Davis, P.; Flippen–
Anderson, J. L.; Xu, H.; Becketts, K.; Foltz, E. J.; Porreca, F.
Probes for narcotic receptor-mediated phenomena. 25.
Synthesis and evaluation of N-alkyl-substituted (alpha-
piperazinylbenzyl)-benzyamides as novel, highly selective delta
opioid receptor agonists. J. Med. Chem. 1997, 40, 2936.
[8] Calderon, S. N.; Rice, K. C.; Rothman, R. B.; Porreca, F.;
Flippen–Anderson,J. L.; Kayakiri, H.; Xu, H.; Becketts, K.;
Smith, L. E.; Bilsky, E. J.; Davis, P.; Horvath, R. Probes for
narcotic receptor mediated phenomena. 23. Synthesis, opioid
receptor binding, and bioassay of the highly selective delta
agonist (+)-4-[(alpha R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-
piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC 80)
and related novel nonpeptide delta opioid ligands. J. Med. Chem.
1997, 40, 695.
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H.; Flippen–Anderson, J. L.; George, C.; Aceto, M. D.; Bowman,
E. R.; Harris, L. S.; May, E. L.; Partilla, J. S.; Becketts, K. Probes
for narcotic receptor mediated phenomena .24. Synthesis, single
crystal x-ray analyses, in vitro and in vivo properties of 6 alpha-
and 6 beta-iodo-3,14-dihydroxy-17-methyl-4,5 alpha-
epoxymorphinans. Med. Chem. Res. 1996, 6, 427.
[10] Calderon, S. N.; Bertha, C. M.; Gutkind, J. S.; Xu, H.; Partilla, J.
S.; Rothman, R. B.; Rice, K. C. Probes for narcotic receptor
mediated phenomena. 22. Synthesis and characterization of
optically pure [H-3] (+)-4-[(alpha R)-alpha-((2S,5R)-4-propyl-
2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-
diethylbenzamide [H-3] SNC 121, a novel high affinity and
selective ligand for delta opioid receptors. J. Labelled Compd.
Rad. 1996, 38, 847.
[11] Lister, D. L.; Kanungo, G.; Rathbone, D. A.; Bruce, N. C.
Transformations of codeine to important semisynthetic opiate
derivatives by Pseudomonas putida m10. FEMS Microbiol. Lett.
1999, 181, 137.
[12] Stabler, P. J.; Bruce, N. C. Oxidation of morphine to 2,2’-
bimorphine by Cylindrocarpon didymum. Appl. Environ. Microb.
1998, 64, 4106.
360 Current Organic Chemistry, 2000, Vol. 4, No. 3
[13] Craig, D. H.; Moody, P. C. E.; Bruce, N. C.; Scrutton, N. S.
Reductive and oxidative half-reactions of morphinone reductase
from Pseudomonas putida M10: A kinetic and thermodymanic
analysis. Biochemistry 1998, 37, 7598.
[14] Walker, E. H.; Bruce, N. C. Towards engineering an improved
morphine dehydrogenase. Ann. N.Y. Acad. Sci. 1996, 799, 6.
[15] French, C. E.; Hailes, A. M.; Rathbone, D. A.; Bruce, N. C.
Morphinone reductase— characterization, cloning, and
application to biocatalytic hydromorphone production. Ann. N.Y.
Acad. Sci. 1996, 799, 97.
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