Article

pubs.acs.org/accounts

The Quest for a Practical Synthesis of Morphine Alkaloids and Their

Derivatives by Chemoenzymatic Methods
Published as part of the Accounts of Chemical Research special issue “Synthesis, Design, and Molecular Function”.
Josephine W. Reed and Tomas Hudlicky*
Department of Chemistry, Brock University, 500 Glenridge Avenue, St. Catharines, Ontario L2S 3A1, Canada
*
S Supporting Information

CONSPECTUS: We became interested in approaches to

morphine in the early 1990s following our immersion into the
new program on the enzymatic dihydroxylation of aromatics.
Larry Kwart, a former classmate of one of us at Rice University,
who worked with our group at Virginia Tech in the mid-1980s,
introduced to us the use of blocked mutants of Pseudomonas
putida (Pp39D) for the production of arene-cis-dihydrodiols.
Larry had gained expertise in microbiology from a postdoctoral
stay with David Gibson, who discovered this unique enzymatic
transformation, and he helped us to establish a strong program
in chemoenzymatic synthesis that continues to this day. Without his pioneering effort, none of our accomplishments in
chemoenzymatic synthesis, including the various approaches to morphine, would have materialized.
Here we trace the evolution of our approaches to morphine alkaloids and some commercial opiate-derived medicinal agents. The
design features and chronology of our approaches are discussed in a way that allows the reader to appreciate a number of errors
that were made in conception as well as in execution. Experience acquired from many failed or less-than-effective attempts has
finally led to an “almost reasonable” total synthesis, the key concept being based on our very first but unsuccessful attempt more
than two decades ago. The irony of this accomplishment has not been lost on us. Each section of this Account presents
a summary of distinctly different approaches to morphine alkaloids. Each ends with a short and philosophical lesson that was
(or should have been) learned in the process.
We intend for this Account to offer more than the history of a search for the perfect design solution to a synthetic problem. In
today’s era of rapid and often careless publication of results, it should serve also as a reminder that the success and the integrity of
synthetic ventures depends on perseverance, adjustment of strategy, improvements of previous attempts, and serious attention to
the quality of experimental data.
Although somewhat satisfied with our latest accomplishment in morphinan synthesis, we plan to improve our design in the hope
that a six-step synthesis is no longer in the realm of fantasy. With more than 20 years of effort in this area, our continuing
involvement may qualify as obsession.

1. INTRODUCTION during the golden era of total synthesis of natural products, many
Tom writ, his readers still slept o’er his book. For Tom took other syntheses of morphine alkaloids followed. The effort con-
opium, and they opiates took. tinues to the present day. And yet, with almost 30 total syntheses
Sir Thomas Browne, mock epitaph for Thomas Shadwell, English
on record, no truly practical preparation of this alkaloid, or the
dramatist and poet, who died of opium overdose, 1692. medicinal agents derived from it, has materialized.6 A synthesis
of morphine competitive in cost with its isolation should be no
Morphine: much has been written about the oldest drug known longer than five or six steps and originate from commodity
to man.1,2 Sir William Osler, a Canadian physician, called chemicals. The latest figures on the annual legal consumption of
morphine “God’s own medicine”, advocating the use of natural morphine and codeine, Figure 1, demonstrate that the scale of
substances in medical applications.3 Before and after Serturner’s any industrial de novo synthesis must be achieved at metric ton
isolation of the active ingredient of opium in 1806, writers levels. Such an accomplishment is unrealistic given the state of
commemorated its effects.4 It took 125 years from its isolation by the art of synthesis. Even if the most efficient synthesis to date,
Serturner for the structure of morphine to be solved and two reported by Rice, were implemented at large-scale, the cost of
more decades before Gates reported the first total synthesis.5 morphine would be prohibitive.
During the period of structure elucidation of morphine (and
other natural products), scores of organic reactions that we now Received: November 28, 2014
take for granted were discovered. After Gates’s synthesis and Published: March 2, 2015

© 2015 American Chemical Society 674 DOI: 10.1021/ar500427k

Acc. Chem. Res. 2015, 48, 674−687
Accounts of Chemical Research Article

Figure 1. Morphine and congeners: their annual production and (legal) consumption.7

2. HISTORICAL OVERVIEW Table 1. Summary of Historical Milestones in Morphine

Morphine (1) and some of its congeners isolated from the Chemistry
latex of the opium poppy are shown in Figure 1. The fascinating 3400 BCE cultivation of poppies by Sumerians in Mesopotamia
history of this molecule began with its isolation in 1806 by (Tigris−Euphrates)
Serturner,8 a German pharmacist, who was also the first to 2000 use in the Mediterranean region, Europe, North Africa
perform some limited animal and human dose studies.8d,9 When 1550 use in Egypt; first written record (Ebers Papyrus)
Serturner’s follow-up paper, published in 1817,8b was translated 700 use by the Assyrians (Babylon)
into English in 1818,8c,d the translator(s) made the following 700 Homer’s Odyssey (“nepenthe”, the drug of forgetfulness, was
an opium preparation)
interesting comment:
77 CE Dioscorides (Greece) described method for obtaining opium
from poppies
We are surprised that the former memoir of Mr. Serturner 150 Galen (Rome) recommended “mithridate”, an opium
has not more attracted the attention of chemists; not in concoction to patients
France, where it appears to have been unknown, but on the 183 Hannibal’s suicide with opium
rest of the continent... We are not afraid to declare, that the 900 Arab texts on “af-yum” (ufian, asium)
discovery of morphium will open a new field, and that we 1525 Paracelsus invents laudanum
shall soon acquire precise notions with respect to poisons 1700 Mysteries of Opium Reveal’d  Dr. John Jones
drawn from vegetables or animals... 1790−1840 use by Coleridge, Shelley, De Quincey, Crabbe
1806 isolation of morphine (Serturner)
The arduous elucidation of its structure was completed in 1925 1828 beginning of “organic chemistry”: synthesis of urea (Wöhler)
(performed on codeine once its relationship to morphine was 1831 empirical formula for morphine established (Liebig)
established) and reviewed in 1998.10 The biosynthetic pathway 1833 isolation of codeine (Robiquet)
of morphine in the opium poppy has been largely elucidated, 1839−1842 First Opium War (China and Great Britain)
with the alkaloid arising from L-tyrosine.11 1842 correct empirical formula for codeine established (Gerhardt)
The existence of endogenous morphine-like compounds in 1847 correct empirical formula for morphine established (Laurent)
mammalian cells was first hypothesized as early as 1903,12 and a 1874 synthesis of heroin (Wright)
biosynthetic pathway similar to that in plants was postulated in 1881 isolation of phenanthrene after pyrolysis of morphine
1970.13 Morphine was first identified in bovine brain and adrenal (von Gerichten)
tissue in 1985.14 The occurrence and biosynthesis of endogenous 1906 attachment of N-ethylamino bridge (Knorr)
morphine in mammals have been recently reviewed.15 The mile- 1925 attachment of C-terminus (Robinson)
stones in the history of morphine and its structure elucidation are 1927 structure proof of morphine (Robinson, Gulland, Schopf)
listed in Table 1. 1952 total synthesis of morphine (Gates)
Given that production of morphine and opiate-derived phar- 1954 X-ray structure and absolute stereochemistry of morphine
(Mackay, Hodgkin)
maceuticals is fully dependent on natural sources, pursuit of 1980 first practical synthesis of morphine (Rice)
alternate methods is a good idea. So far, strategies involving tissue 1985 morphine identified in mammalian cells
culture or fermentation cannot compete in titer or in cost with 2004 development of mutant poppies (top1) producing thebaine
morphine obtained by isolation. Although the cost of producing and oripavine
morphine fluctuates around $600−1200/kg (accurate figures are 2005 morphine biosynthesis in mammalian cells confirmed
not available because such information constitutes a closely 2011 patent issued for production of thebaine and oripavine in
guarded trade secret), it is still far below the cost of fermentation poppies
or synthesis. Of course, efforts toward biological and organic 2012 global production: morphine, 440 tons; codeine, 381 tons;
thebaine, 145 tons; oripavine, 23 tons
syntheses should continue as insurance against possible interrup- 2014 low titer production of morphine alkaloids in yeast reported
tion in supply because of either climate or political instability.
Adapted from ref 20b, Page 729. Copyright 2007 Wiley-VCH Verlag
Advances in molecular biology have allowed for the develop-
GmbH & Co. KGaA. Reproduced with permission.
ment (by chemical mutagenesis) of top1, a strain of opium poppy
that produces thebaine and oripavine at the expense of morphine
and codeine.16 The dry weight yields of alkaloids from top1 Recently, Smolke showed that recombinant yeast can convert
poppies (compared with traditional Papaver somniferum L.) are as thebaine into certain opiates, albeit in low titers.19 A biocatalytic
follows: thebaine 2% (0.1%), oripavine 0.8% (0.03%), codeine synthesis of morphine or other opiates would be a major
0.01% (0.1%), and morphine 0.05% (2.4%). There are now other breakthrough provided the yields were at practical levels.
mutant strains of poppies that produce a mixture of thebaine and The effort toward the total synthesis of morphine and related
oripavine17 as well as those that produce only thebaine.18 alkaloids continues unabated. A review published in 20126a lists
675 DOI: 10.1021/ar500427k
Acc. Chem. Res. 2015, 48, 674−687
Accounts of Chemical Research Article

26 total or partial syntheses. Connectivity analysis for morphine Table 2. Chronological Summary of Total Syntheses
leads to recognition of complete “synthetic dissonance”.20 The of Morphine and Derivatives
difficulty in designing a convergent approach in which the
year author target steps ref
connectivity of any two segments is experimentally feasible has
been discussed on several occasions.6b,20b The dissonant assign- 1952 Gates morphine 31 5
ments for morphine with both nitrogen and oxygen priorities 1954 Ginsburg dihydrothebainone 21 22
(Figure 2) demonstrate the impossibility of an electrostatically 1967 Grewe dihydrothebainone 9 23
neutral design. 1980 Rice dihydrocodeinone 14 24
1982 Evans thebainone 12 25
1983 White codeine 8a 26
1983 Rapoport codeine 26 27
1987 Fuchs codeine 23 28
1992 Tius thebainone 24 29
1992 Parker dihydrocodeinone 11 30
1993 Overman dihydrocodeinone 14 31
1996 Mulzer dihydrocodeinone 15 32
1996 Parsons morphine 5b 33
Figure 2. Dissonant connectivity of morphine and morphine numbering 1997 White ent-morphine 28 34
system. Parts of the figure reproduced with permission from ref 6b 1997 Mulzer dihydrocodeinone 18 35
(Copyright 2005 Georg Thieme Verlag) and from ref 20b, page 732 2001 Ogasawara dihydrocodeinone 21 36
(Copyright 2007 Wiley-VCH Verlag GmbH & Co. KGaA). 2002 Taber morphine 27 37
2002 Trost codeine 15 38
2006 Fukuyama morphine 25 39
3. TOTAL SYNTHESIS EFFORT TO DATE 2007 Hudlicky ent-codeine 15 40
All styles are good except the boring kind. 2008 Iorga/Guillou codeine 17 41
2008 Chida dihydroisocodeine 24 42
Voltaire 2009 Hudlicky codeine 18 9
2009 Magnus codeine 13 43
The chronology of total syntheses of morphine, codeine, and 2009 Stork codeine 22 44
closely related derivatives is shown in Table 2. Not listed are 2010 Fukuyama morphine 18 45
several partial syntheses from advanced intermediates. A sum- 2011 Hudlicky ent-neopinone 15 46
mary of these and advanced model studies and strategies can be 2011 Metz codeine 23 47
found in our 1996 review6e and in more recent reviews.6a,b 2013 Hudlicky hydrocodone 21 48
Strategies used in the design of the morphine skeleton range 2014 Hudlicky ent-codeine 15 49
from cycloadditions to radical or metal-promoted cascades, as 2014 Hudlicky ent-hydromorphone 12 50
well as C−H insertion. Most bond disconnections anticipate the 2014 Opatz dihydrocodeine 14 51
construction of rings B, C, and D. To our knowledge there is no 2014 Gaunt morphine 25c 52
report of a synthesis of morphine involving a de novo assembly of a
Advanced starting material was used. bOnly the last five steps were
the aromatic ring A by the cyclotrimerization strategy that has
described. cFormal synthesis, 18 steps to known intermediate.
been used to synthesize aromatic steroids and certain alkaloids.21
Essentially all bonds in rings B, C, and D have been subjected to however, the expected adduct 7 was not detected. Instead the
strategic disconnections in the published syntheses. These tricyclic adduct 8 was obtained and converted into enone 955 in
strategies were discussed in detail in recent reviews,6 and some three steps, including a Cope rearrangement. Beginning again,
that are similar to our approaches are mentioned here. we reduced the less substituted olefin in 5 and then proceeded
with the [4 + 2] cycloaddition of 10 to obtain a tricyclic adduct,
4. DEVELOPMENT OF OUR DESIGN FOR MORPHINANS assigned at that time as 11a (α-C-9).
The hardest thing of all is to find a black cat in a dark room, Six years later we completed an advanced model study based
especially if there is no cat. on cis-diol 12 (from β-azidoethylbenzene) or diol 13, (from
β-bromoethylbenzene), with two carbons in place for the incipient
Confucius ethylamino bridge in 1. Conversion of 12 into 14 and subsequent
cycloaddition yielded tricycle 15, assigned as shown with the β-
We first attempted to design a synthesis of morphine in the early
stereochemistry of the C-9 methyl group (morphine numbering).
1990s. At that time, our early ventures into chemoenzymatic
At this time, we corrected the structure of 11a to 11b (β-C-9).56
methodology with the blocked mutant P. putida 39/D had yielded
Attaining tricycles 9 and 15 was exciting. All five stereogenic
syntheses of zeylena and simple sugars.53 We had also converted
centers of morphine are correctly set in 15, and having two different
diol 5, derived from toluene by enzymatic dihydroxylation, into a
stereochemical outcomes at C-9 (9 vs 11b and 15) allowed us to
prostaglandin intermediate.54 We envisioned applying the strategy
design a dual strategy in the next model study, Figure 3.
to a model study toward part of morphine because diol 5 has the
It was easy for us to see the subsequent transformations of diol
same absolute stereochemistry as ring C.
13 to either 16 or 18 and thence into tricyclic systems 17 or 19,
4.1. Cycloaddition Approaches each with orthogonally disposed functionalities for closure of the
We initiated a model study based on [4 + 2] cycloaddition ethylamino bridge in 20. Manipulating the placement of a leaving
(Scheme 1). After protection of the distal alcohol in 5, we group (LG) and a nucleophile (Nu) in the starting material and
attached sorbyl bromide to the proximal hydroxyl and subjected then choosing one or both methods of cycloaddition should
the dienyl ether to an intramolecular Diels−Alder reaction; ultimately lead to a complete morphine skeleton such as 21.
676 DOI: 10.1021/ar500427k
Acc. Chem. Res. 2015, 48, 674−687
Accounts of Chemical Research Article

Scheme 1. Early Cycloaddition-Based Model Studiesa

a
Reagents and conditions: (a) THSCl, imidazole, DMF, 0 °C, 18 h; (b) NaH, sorbyl bromide, THF, 0 °C, then rt, 30 h; (c) CCl4, 77 °C, 7 h;
(d) Bu4NF, H2O, THF, rt, 24 h; (e) PCC, CH2Cl2, rt, 21 h; (f) xylenes, 250 °C (sealed tube), 22 h; (g) potassium azodicarboxylate (PAD), HOAc,
MeOH, 0 °C to rt; (h) toluene, 210 °C (sealed tube), 24 h; (i) NaN3, DMF; (j) PAD, HOAc, MeOH, 0 °C to rt, 14 h; (k) PPh3, 0.4% H2O, THF,
45 °C, 18 h; (l) Ac2O, pyridine, rt, 2 h; (m) toluene, 239 °C (sealed tube), 20 h.

Figure 3. Advanced model proposed for the construction of morphine by dual strategy.

677 DOI: 10.1021/ar500427k

Acc. Chem. Res. 2015, 48, 674−687
Accounts of Chemical Research Article

Figure 4. Bergman cyclization cascade design for morphine.

Our progress stopped here for a variety of “philosophical” cyclization to diradical 28, whose further closure and proto-
reasons. We could not arrive at a reasonable way to incorporate desilylation would provide 29, easily convertible to morphine.
the three additional carbons required for 21. Of course, oxidative Had it been successful, the synthesis would have been one of
dearomatization of phenols (the process providing the eventual the shortest at that time, provided, of course, that we could
solution to the design of precursors such as 21) had been known prepare enediyne 23 in fewer than the 10 steps that were actually
since the 1950s57 and other oxidants besides lead(IV), such required. Unfortunately, the model substrate 23 was inert to
as Dess−Martin periodinane,58 were also known to accomplish Bergman cyclization even at temperatures above 225 °C, an
such a task. The required components for completing the design observation rationalized by the detrimental effect of adjacent
were known, even to us; but these were not in the forefront of our silicon atoms on the reaction intermediates.60
chemical imagination at the time, and we did not integrate this Undeterred, we adjusted the radical cascade strategy and
existing information with pattern recognition.59 It took another utilized the aryl ether 31 in a second-generation approach, this
20 years before the design of an intermediate such as 21 finally time toward codeine, Scheme 2.
materialized, resulting in a very short synthesis of hydromor- Aryl ether 31 was accessible in six steps from diol 13. The
phone.50 We learned an important lesson on information pro- major difficulty was the disappointing 28% yield for the second
cessing, retention of information, and pattern recognition. Mitsunobu inversion of the C-5 hydroxyl (morphine numbering)
because of hindrance from the adjacent TBS group. Even more
Lesson 1: In a productive and ef ficient design, all of the disappointing were the results of the cyclization: complex
components required for reduction to practice must be recognized and mixtures were produced, from which we were able to isolate 32
mutually connected by pattern recognition. A single missing item (incorrect C-14 stereochemistry) in ∼15% yield and 33, with the
becomes a zero multiplier for the entire process. correct configuration at C-9/C-14, as a minor component.
Detailed analysis of the stereochemical outcome60 led to the
4.2. Radical Cascade Approaches conclusion that the stereochemical integrity of C-9/C-14 centers
cannot be controlled during a cascade cyclization of conforma-
The definition of insanity is doing the same thing over and tionally free ether 31. On the plus side, identification of iso-
over and expecting different results. quinoline 34, isolated as a minor component and originating as
Rita Mae Brown in Sudden Death (1983) (attributed to Albert depicted in Scheme 2, inspired a new design via the enzymatic
Einstein and others) dihydroxylation of dibromide 38.
Diol 39 was transformed into oxazol-2(3H)-one 40, which
In 1992, Parker published a creative synthesis of dihydrocodei- underwent radical cyclization to the octahydroisoquinoline 41.
none based on a radical cascade30 that produced a racemate; the The second radical cyclization of aryl ether 42, obtained by
second-generation approach was enantioselective.30b We were Mitsunobu inversion at C-5, led to 43, with the epi-configuration
inspired by the idea that a diol such as 22 might be accessible at C-14. The oxazolidinone moiety was reduced to furnish the
in optically pure form from β-bromoethylbenzene and diol 13. N-methyl functionality, and alcohol 44 was cyclized to either
Our initial ambitious design involved a Bergman cyclization ent-10-hydroxy-morphinan 45 or the C-6/C-14 epimer of
cascade as shown in Figure 4. Our plan was to convert the cyclic ent-dihydrocodeine 46, Scheme 3.
enediyne 23 to its epoxide, which was to be opened with the C-2 None of our radical cyclization approaches was highly stereo-
hydroxyl of 25 (previously alkylated with oxazol-2(3H)-one 26). selective, with major products produced in the epi-configuration
After oxidation, the enolized 27 would undergo the Bergman at C-14. Although the syntheses of complete morphinan skeletons
678 DOI: 10.1021/ar500427k
Acc. Chem. Res. 2015, 48, 674−687
Accounts of Chemical Research Article

Scheme 2. Second-Generation Radical Cyclization Approacha

a
Reagents and conditions: (a) potassium azodicarboxylate (PAD), HOAc; (b) TBSOTf, CH2Cl2, i-Pr2Et; (c) n-Bu3P, DEAD, PhCO2H, THF; (d) oxazol-
2(3H)-one, NaH, DMSO; (e) NaOH, H2O; (f) n-Bu3P, DEAD, 2-methoxy-6-bromophenol, THF; (g) (TMS)3SiH, AIBN, PhH, 140 °C (sealed tube).

Scheme 3. Third-Generation Radical Cyclization Approacha

a
Reagents and conditions: (a) potassium azodicarboxylate (PAD), HOAc; (b) 2,2-dimethoxypropane (DMP), acetone, TsOH, rt, 3 h; (c) oxazol-
2(3H)-one, NaH, DMSO, 0 °C to rt, 12 h; (d) n-Bu3SnH, AIBN, PhH, reflux, 1 h; (e) DOWEX50×8−100, MeOH, rt, 12 h; (f) TBSOTf, i-Pr2NEt,
CH2Cl2, −78 °C, 4 h; (g) n-Bu3P, DEAD, THF, 2-methoxy-6-bromophenol, 0 °C, 1.5 h; (h) DIBAL-H, CH2Cl2, 0 °C, 0.5 h; (i) TBAF, THF, rt, 4 h;
(j) (COCl)2, DMSO, Et3N, CH2Cl2, −78 to 0 °C, 4 h; (k) CF3SO3H (neat) rt, 10 min; (l) MsCl, Et3N, LiCl, THF, 0 °C, 6 h; (m) AlCl3, PhH, reflux.

were relatively short, the lack of stereoselectivity rendered them literature before the experiments, not after! Parker’s radical cascade
ineffective. It became clear that a radical cascade cannot proceed seems to be a unique exception.
with stereoselectivity in conformationally flexible compounds,
such as the bromoarene 31. Nevertheless, these failures provided 4.3. Heck Cyclization Approaches
important information toward future design of Heck reaction The disappointing results from our radical cascade approaches
cascades and, ultimately, to a successful cycloaddition approach. led us to recognize that the configuration at C-5 controls
subsequent bond-forming events. Thus, the stereochemistry at
Lesson 2: Stereoselectivity cannot be expected in those processes C-6 can be adjusted by an oxidation−reduction sequence with
leading to morphine skeleton that proceed through conformationally the C-13 center set cis to C-6, and the C-14/C-9 relationship can
f lexible transition states. It would have been wise to read more of the be controlled before or during cyclization. The radical cyclization
679 DOI: 10.1021/ar500427k
Acc. Chem. Res. 2015, 48, 674−687
Accounts of Chemical Research Article

Scheme 4. First61a and Second62 Generations of Heck Cyclization Approachesa

a
Reagents and conditions: (a) potassium azodicarboxylate (PAD), HOAc, MeOH; (b) PhCO2H, DCC, DMAP, CH2Cl2, 0 °C to rt, 12 h;
(c) oxazolidinedione, 1,1,3,3-tetramethylguanidine,THF, reflux, 48 h; (d) NaBH4, MeOH, 0 °C, 0.5 h; (e) BF3, CH2Cl2, 0 °C to rt, 12 h, or AlCl3,
CH2Cl2, 0 °C to rt, 12 h; (f) DBU, DMSO, reflux; (g) LiOH, MeOH; (h) TBSOTf, imidazole, DMF; (i) n-Bu3P, DEAD, 2-methoxy-6-
bromophenol, THF, reflux, 5 days; (j) Pd(PPh3)4, proton sponge, PhMe, reflux; (k) TsCl, pyridine, DMAP; (l) PhCO2H, PPh3, DEAD, THF;
(m) MeONa, MeOH, THF; (n) potassium 2-bromo-6-methoxyphenoxide, DME, 18-C-6, reflux; (o) TBSOTf, i-Pr2NEt, CH2Cl2; (p) Pd(PPh3)4,
proton sponge, PhMe, reflux, 21 h; (q) DIBAL-H, CH2Cl2; (r) H2, PtO2, HOAc; (s) TBAF, THF, H2O; (t) (COCl)2, DMSO, Et3N, CH2Cl2;
(u) CF3SO3H, rt, 0.5 h.

Scheme 5. Attempted Heck Cascade61ca

a
Reagents and conditions: (a) Pd(PPh3)4, PPh3, Et3N, PhMe, 120 °C (sealed tube), 19 d.

of 40 produced isoquinoline 41 as the major product (2:1) with The short synthesis also led to (−)-codeine via double
the ent-configuration of C-9. In contrast, isoquinoline 49, with Mitsunobu inversion at C-5, accomplished by opening the allylic
C-9 in the natural configuration, was the major product of an β-epoxide generated from the cis-diol in 13, Scheme 6.9 In our
acyl-imminium closure of 48, Scheme 4.61 The Heck closure of hands, Trost’s hydroamination was not successful and had to be
50 yielded neopinone-type intermediate 51 in 57% yield. A modified. We eventually learned that the best and most reliable
double Mitsunobu of the C-5 center (morphine numbering) in conditions for C-9 amination were those reported by Parker in
49 provided the opportunity to synthesize the natural enantiomer 1992.30
of 10-hydroxymorphinan 45 via the Heck cyclization of 52 and Our fourth-generation approach validated our hypothesis that
C-10/C-11 closure of 53.62 the C-5 center controlled all subsequent bond-forming events in
Both syntheses of ent-45 and 45 yielded the epi-configuration any cyclizations to the morphine skeleton. It was clear that
at C-14, but in different ways, the former from radical cyclization Parker’s unique stereoselective cascade could not be applied to
and the latter from hydrogenation of the C-8/C-14 olefin. nonrigid systems and that all future generation approaches must
Attempts at a Heck cascade of 54 failed; only the first cyclization proceed in stepwise manner.
occurred with a low yield of 55 in the ent series, Scheme 5. It would
be a few years before we pursued the next-generation strategy. Lesson 3: After 15 years, we recognized that stepwise bond
In 2007, we synthesized (+)-codeine by a double Heck construction is more effective than a cascade approach and f inally
cyclization strategy,40 inspired in part by Trost’s report.38 achieved an enantiodivergent synthesis.
680 DOI: 10.1021/ar500427k
Acc. Chem. Res. 2015, 48, 674−687
Accounts of Chemical Research Article

Scheme 6. Enantiodivergent Synthesis of Codeine by Double Heck Cyclizationa

a
Reagents and conditions: (a) potassium azodicarboxylate (PAD), HOAc, MeOH, 0 °C; (b) Ac2O, Et3N, DMAP, CH2Cl2, 0 °C to rt; (c) MeNH2,
K2CO3, THF, −40 °C to rt; then (Boc)2O, Et3N, MeOH; (d) TBSCl, imidazole, CH2Cl2, −78 °C to rt; (e) n-Bu3P, DIAD, 5-bromovanilin, THF,
0 °C to rt; (f) Pd(OAc)2, Ag2CO3, dppf, toluene, 110 °C, 3 h; (g) BrCH2PPh3Br, t-BuOK, THF, −60 °C; (h) TBAF, THF, rt; (i) IBX, DMF, rt;
(j) NaBH4, CeCl3, H2O, MeOH, 0 °C; (k) TFA, CH2Cl2, 0 °C to rt; (l) Hg(OAc)2, Et3N, THF, 48 h; then LiAlH4, rt, 2 h; (m) TsCl, Et3N, DMAP,
0 °C to rt; (n) DIAD, PPh3, THF, p-NO2PhCO2H, 0 °C; (o) NaOMe, MeOH, THF, 0 °C; (p) potassium salt of 5-bromovanilin, DME-DMF,
18-crown-6, 80 °C, 48 h.

Scheme 7. Miscellaneous Approaches to Morphinansa

a
Reagents and conditions: (a) Br2, MeOH, then camphor sulfonic acid, PhH, reflux; (b) NaH, mesylate of 2-phenyl-4-hydroxybutene, DMSO, rt;
(c) toluene, >250 °C (sealed tube); (d) 2,2-dimethoxypropane (DMP), TsOH, CH2Cl2, rt, 45 min; (e) PPh3, THF, H2O, rt, 22 h; (f) DCC, ethyl
fumaric acid, 0 °C to rt, 18 h; (g) PhH, reflux, 21 h.

4.4. Miscellaneous Approaches from the known furan derivative 6265) but low-yielding synthesis
We pursued other strategies such as one based on intramolecular of the tricyclic hydroxyenone 64.63 We envisioned two successive
furan Diels−Alder reactions63 and a rather ambitious fragmenta- Diels−Alder cyclizations in amide 65, the first providing bridged
tion approach that was not successful.64 A model study for an isoquinolone 66 and the second depending on an endo-situated
approach to oxycodone (Scheme 7) yielded a short (three steps furanylmethyl side chain in 67, which eluded us. In principle, the
681 DOI: 10.1021/ar500427k
Acc. Chem. Res. 2015, 48, 674−687
Accounts of Chemical Research Article

Scheme 8. Synthesis of ent-Neopinone46a

a
Reagents and conditions: (a) DIAD, Bu3P, THF, 0 °C to rt, 12 h; (b) Pd2(dba)3, t-Bu3P, K2CO3, toluene, 110 °C, 16 h; (c) TBAF, THF, −78 °C to
rt, 16 h; (d) TFA, CH2Cl2, 0 °C, 15 min; (e) DNS-Cl, i-Pr2NEt, CH2Cl2, rt, 20 min; (f) IBX, EtOAc, 80 °C, 4 h; (g) 50% aqueous TFA, PhMe,
50 °C, 2 h, then MsCl, i-Pr2NEt, CH2Cl2, 0 °C, 30 min; (h) thioglycolic acid, i-Pr2NEt, CH2Cl2, 0 °C, 30 min.

Scheme 9. Synthesis of Hydrocodone by Claisen Rearrangement Strategy48a

a
Reagents and conditions: (a) potassium azodicarboxylate (PAD), HOAc, MeOH; (b) thexyldimethylsilyl chloride, imidazole, CH2Cl2, −78 °C to
rt; (c) N-Boc glycine, DCC, DMAP, CH2Cl2; (d) LDA, ZnCl2,THF, −78 °C to rt, 18 h; (e) CH2N2, Et2O then DBU, THF, reflux to eqilibrate C-9
isomers; (f) 2,3-dimethoxyphenylboronic acid, Pd(dppf)2Cl2, Cs2CO3, THF, reflux; (g) TBAF, THF; n-Bu3P, DEAD, PhCO2H, THF, 0 °C to rt;
LiAlH4, THF, 0 °C to rt; (h) NaH, DMF, 0 °C to rt; (i) NaH, MeI, THF, 0 °C; (j) MeC(OMe)3, o-NO2Phenol, 130 °C, 6 d; (k) 59% aqueous
NaOH, MeOH, 80 °C; (l) HBTU, i-Pr2NEt, CH2Cl2, rt; (m) Dess−Martin periodinane, CH2Cl2; (n) BF3·OEt2, CH2Cl2, −10 °C to rt, 3 h;
(o) Ph2SiHCl, InCl3, DCE, reflux, 20 h; (p) m-CPBA, CH2Cl2, 0 °C to rt, then camphorsulfonic acid, THF, reflux; (q) LiAlH4, dioxane, reflux;
(r) Dess−Martin periodinane, CH2Cl2, 0 °C to rt, 2.5 h.

fragmentation of 68 could lead to morphinan skeleton 69, More recently, we were successful with strategies based on Claisen
Scheme 7.63 rearrangements48 and [2 + 3] nitrone cycloadditions.49 Although we
The Heck−aldol approach (Scheme 8) was originally designed had accomplished a Kazmaier−Claisen rearrangement of the
to study intramolecular aza-Prins and Mannich cyclizations of the glycinate enolate derived from diol 77 to amino acid 78 as early as
olefinic aldehyde derived from 73. Because these proved unsuccessful, 1997, the project did not progress for a variety of reasons. Returning
we resorted to an intramolecular aldol cyclization and subsequent to it after more than 15 years, we successfully implemented this
1,6-conjugate addition to dienone 74, completing the synthesis of strategy by manipulating the amino acid moiety, adding a second
ent-neopinone,46 according to a similar approach by Fukuyama.45 Claisen rearrangement to set the C-13 center followed by C-10/C-11
closure of 79, Scheme 9.48 Amide 83 was converted to hydrocodone
Lesson 4: Sometimes increasing the ef fort on an arduous project and dihydrocodeine according to Chida’s synthesis.42
does not produce improvements. It is more effective to change A nitrone cycloaddition of 87 led to the epi-configuration of
direction and focus on other ideas to provide new inspiration. C-9. This outcome, different from that reported by Metz,47 was
corrected by Hofmann elimination and subsequent hydro-
4.5. Recent Solutions amination of 90 to ent-codeinone, Scheme 10.49
Things are often exactly as they seem. Confusing isn’t it. We also discovered that aldehyde 91, the precursor to nitrone
87, on exposure to SmI2 cyclized readily to tetracyclic morphinans
Richard Butchins 92 (formed via Prins reaction catalyzed by Sm(III)) and 93
682 DOI: 10.1021/ar500427k
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Scheme 10. Cycloaddition and Radical Cyclization Approaches49a

a
Reagents and conditions: (a) potassium azodicarboxylate (PAD), HOAc, MeOH; (b) TBSCl, imidazole, DMF; (c) DIAD, n-Bu3P, methoxy acetal
derivativel of phenol 71; (d) Pd2(dba)3, K2CO3, t-Bu3P, toluene, reflux, 16 h; (e) 50% aqueous TFA, PhMe, 50 °C, 30 min; (f) NHMeOH (HCl),
i-Pr2NEt, toluene, reflux, 5 h; (g) Meerwein’s salt, CH2Cl2, rt, 2 h; then LiAlH4, THF, rt, 30 min; (h) Dess−Martin periodinane, CH2Cl2;
(i) NH2Me(HCl), Et3N, Ti(i-PrO)4, MeOH; then NaBH4, MeOH; (j) (Boc)2O, EtOH; (k) TBAF, THF; (l) Dess−Martin periodinane, CH2Cl2;
(m) SmI2, HMPA, THF, rt, 20 h; (n) H2, Pd/C, MeOH; (o) MsCl, Et3N, CH2Cl2; (p) NaOH, H2O, MeOH.

(formed by radical cyclization). Both were converted to Chida’s more than 20 years ago. Coupling of the C-ring unit with phenol
intermediate and to ent-hydrocodone, as shown in Scheme 10.49 95 and elaboration to styrene 97 provided the precursor to the
oxidative dearomatization accomplished with Pb(OAc)4 or IBX.67
Lesson 5: That some projects seemed to have taken an inordinate We were further inspired by the recent work of Rodrigo, who also
amount of time may be explained by the nature and attitude of persons approached morphinan synthesis through dearomatization/
engaged in the project. Ernest Wenkert once said “When the proposed cycloaddition strategy.68 Dienone 98 underwent intramolecular
chemistry on paper makes sense the success or failure at the bench is strictly cycloaddition to the tetracyclic phenanthrene core 99, which,
the function of the operator.” Wiser words have never been spoken. after rearomatization, was rapidly converted to the full morphinan
skeleton 102 by Parker’s hydroamination. ent-Hydromorphone
4.6. Return to the Original Idea was attained in just five operations from aryl ether 96 (11 steps
from diol 13). The current strategy could be further improved by
Good judgment comes from experience. Experience comes replacing chemical oxidants with electrochemical oxidation in the
from bad judgment. dearomatization step. Such improvements will be pursued during
attributed to Mullah Nasrudin, 13th century the subsequent generations. For the moment, however fleeting,
we are content with this accomplishment.
Sometimes ideas based on pattern recognition require substantial
incubation before they can be successfully implemented. It seems Lesson 6: Never give up on the original idea!
that the initial intuitive idea based on imagery and super-
imposition of patterns almost always ends up being the correct 5. OUTLOOK
one. This is precisely how the initial idea of using cis-dienediols We have summarized our efforts toward (and obsession with) a
for morphine design originated, by seeing the required patterns practical synthesis of morphine and opiate-derived agents. Our
in a snow-covered tree!66 That we were not successful the first quest for practicality is in no small part aided by experience
time was a tactical problem, not a strategic one; we simply did not acquired from our long collaboration on industrial projects. For
connect the oxidative aromatization of phenols to the design of a the last 10 years, we have been working with Noramco, Inc., on
suitable compound such as 21, Figure 3. process development for commercial analgesics and antagonists
Returning to our cycloaddition strategy, we were rewarded such as buprenorphine, oxymorphone, oxycodone, and naltrex-
with one of the shortest syntheses of a morphinan.50 Scheme 11 one, naloxone, and nalbuphine. The results of our work in this
shows the solution to the cycloaddition design we had pursued area have been reported in many publications and summarized
683 DOI: 10.1021/ar500427k
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Scheme 11. Short Synthesis of ent-Hydromorphonea

a
Reagents and conditions: (a) tetramethylazodicarboxamide, n-Bu3P, THF, −10 °C to rt, 22 h; (b) CH3PPh3Br, BuLi, THF, −78 to 0 °C; then
reflux 4 h; (c) ZnBr2, 1-dodecanethiol, CH2Cl2, 0 °C to rt, 10 min; (d) Pb(OAc)4, DCE, reflux 4 h; (e) TFA, CH2Cl2, 0 °C, 15 min; (f) TsCl, Et3N,
CH2Cl2, 0 °C to rt, 10 h; (g) Li, t-BuOH, NH3(l),THF, −78 °C, 10 min; (h) TBAF, THF, rt, 6 h; (i) t-BuOK, PhCOPh, PhMe, DME, 85 °C, 8 h.

recently.69 Industrial process development demands the credi-

bility of reported yields and precise communication of results.70
■ AUTHOR INFORMATION
Corresponding Author
Our participation in real-world projects, coupled with more
fundamental endeavors, positions us to be able to further refine *E-mail: [email protected].
another generation of morphinan synthesis. Perhaps in time an Notes
almost-ideal five- or six-step synthesis will materialize if the craft
of synthesis continues to progress. Organic synthesis is a tenuous The authors declare no competing financial interest.
and under-appreciated field. We end with a comment made Biographies
recently by Marc Tius with the hope that future endeavors within
our guild deliver the required paradigm shift(s). A North Carolina native, Josephine Reed was educated at the
University of North Carolina at Greensboro (B.A., English),
Consider that if you could resurrect an organic chemist from Appalachian State University (B.A., biology and chemistry), and
100 years ago, he would recognize most of the glassware in Virginia Tech (Ph.D., chemistry, with Professor David Kingston). She
the lab, and once he spent a month reading about transition has worked with Tomas Hudlicky and his group for more than 25 years.
metal reagents and a few other novelties from the past 50 She has expanded her efforts in supporting faculty in the natural and
years he could understand pretty much everything we are health sciences through her position as Research Officer in Brock
doing, because the goals of organic synthesis have scarcely University’s Office of Research Services.
changed in a century. Now think about performing the same Tomas Hudlicky was born in 1949 in Prague, Czechoslovakia. In 1968,
thought experiment with a biologist. The biologist of 100 he immigrated to the U.S. He received his B.S. in chemistry in 1973
years ago would be completely mystified by today’s biology. (Virginia Tech) and went on to pursue graduate studies in the field of
Organic synthesis either finds its mojo again or this branch of indole alkaloid total synthesis, earning his Ph.D. in 1977 (Rice
chemistry as we know it and practice it will be extinct. University, Professor Ernest Wenkert). After a postdoctoral fellowship
Marc Tius, October 2014 (Univeristy of Geneva, Professor Wolfgang Oppolzer), he began his

■
research career at Illinois Institute of Technology in 1978, returned to
ASSOCIATED CONTENT Virginia Tech in 1982, then moved to the University of Florida in
Gainesville in 1995. In 2003, Hudlicky accepted an offer from Brock
*
S Supporting Information
University, where he is currently Canada Research Chair in Organic
Additional relevant references are included in this section. Synthesis and Biocatalysis. Current research interests include the
This material is available free of charge via the Internet at development of enantioselective synthetic methods, bacterial dioxyge-
http://pubs.acs.org. nase-mediated degradation of aromatics, design and synthesis of

684 DOI: 10.1021/ar500427k

Acc. Chem. Res. 2015, 48, 674−687
Accounts of Chemical Research Article

fluorinated inhalation anesthetic agents, synthesis of morphine and English and published in the American Medical Recorder, Vol. 1, No.1, pp
Amaryllidaceae alkaloids, and design of unnatural oligosaccharide 37−52. (d) For the URL source to the English translation and
conjugates with new molecular properties. additional references, see Supporting Information, ref 2.

■
(9) For a brief description, see: Leisch, H.; Omori, A. T.; Finn, K. J.;
Gilmet, J.; Bissett, T.; Ilceski, D.; Hudlicky, T. Chemoenzymatic
ACKNOWLEDGMENTS enantiodivergent total syntheses of (+)- and (−)-codeine. Tetrahedron
The authors are grateful to the following agencies for financial 2009, 65, 9862−9875. For details see ref 8d.
support of work related to opiate synthesis: Mallinckrodt (1992− (10) Butora, G.; Hudlicky, T. The story of morphine structure
1994); National Science Foundation (1994−2002); ACS elucidation: one hundred years of deductive reasoning. In Organic
Petroleum Research Fund (2002−2005); Natural Sciences and Synthesis: Theory and Applications; Hudlicky, T., Ed.; JAI Press:
Engineering Research Council of Canada (since 2003); Canada Stamford, CT, 1998; Vol. 4, pp 1−51.
Research Chairs Program (since 2003); Canada Foundation for (11) For recent reviews on morphine biosynthesis, see: (a) Ziegler, J.;
Innovation; TDC Research, Inc.; TDC Research Foundation; Facchini, F. J.; Geissler, R.; Schmidt, J.; Ammer, C.; Kramell, R.;
Ontario Partnership for Innovation and Commercialization; Viogtländer; Gesell, A.; Pienkny, S.; Brandt, W. Evolution of morphine
biosynthesis in opium poppy. Phytochemistry 2009, 70, 1696−1707.
Advanced Biomanufacturing Centre (Brock University, since
(b) Dimise, E. J.; Bruner, S. D. Unmasking morphine. Nat. Chem. Biol.
2013); Noramco, Inc. (since 2006). The authors thank all those 2010, 6, 251−252. For additional references, see Supporting
who worked on these projects since 1992; their names are listed Information, ref 3.
in the relevant citations. We acknowledge the following agencies (12) Mavrojannis, M. Action cataleptique de la morphine chez les rats.
for providing postdoctoral fellowships: CAPES, Brazil (T. Contribution de la theorie toxique de la catalepsie. C. R. Soc. Biol. 1903,
Omori, 2006−2007); NSERC (S. Banfield, 2005−2007); Swiss 55, 1092−1094.
National Foundation (J. Duchek, 2009−2010); Charles (13) Davis, V. E.; Walsh, M. J. Alcohol, amines, and alkaloids: A
University (M. Ghavre, 2014). possible biochemical basis for alcohol addiction. Science 1970, 167,

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Dedicated to the memory of Christie Hopkins Boros (1964−
1005−1007.
(14) Goldstein, A.; Barrett, R. W.; James, I. F.; Lowney, L. I.; Weitz, C.
J.; Knipmeyer, L. L.; Rapoport, H. Morphine and other opiates from beef
brain and adrenal. Proc. Natl. Acad. Sci. U.S.A. 1985, 82, 5203−5307.
2012).

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687 DOI: 10.1021/ar500427k

Acc. Chem. Res. 2015, 48, 674−687