Chemoenzymatic Total Synthesis of ent-Oxycodone: Second-, Third-, and Fourth-Generation Strategies

Article abstract of DOI:10.1021/jacs.9b05033

Four distinct approaches to ent-oxycodone were designed and accomplished. All rely on the same starting material, the diene diol derived from phenethyl acetate by the whole-cell fermentation with E. coli JM109 (pDTG601A), a strain that overexpresses toluene dioxygenase. The key step in the first-generation approach involves the construction of the C-9/C-14 bond by a SmI₂-mediated cyclization of a keto aldehyde. The second-generation design relies on the use of the Henry reaction to accomplish this task. In both of these syntheses, Parker's cyclization was employed to construct the D-ring. The third-generation synthesis provides an improvement over the second in that the nitrogen atom at C-9 is introduced by azidation of the C-9/C-10 olefin, followed by reduction and lactam formation between the C-9 amine and the Fukuyama-type lactone. Finally, the fourth generation takes advantage of the keto-nitrone reductive coupling to generate the C-9/C-14 linkage. The four generations of the total syntheses of ent-oxycodone were accomplished in 13, 18, 16, and 11 operations (19, 23, 24, and 18 steps), respectively. Experimental and spectral data are provided for all new compounds.

Full text of DOI:10.1021/jacs.9b05033

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Article
Chemoenzymatic total synthesis of ent-oxycodone:
Second, third and fourth generation strategies
Mariia Makarova, Mary Ann Endoma-Arias, Helen Dela Paz, Razvan Simionescu, and Tomas Hudlicky
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b05033 • Publication Date (Web): 11 Jun 2019
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Chemoenzymatic total synthesis of ent-oxycodone: Second, third and fourth generation
strategies
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Mariia Makarova, Mary Ann A. Endoma-Arias, Helen E. Dela Paz, Razvan Simionescu and
Tomas Hudlicky
Department of Chemistry and Centre for Biotechnology, Brock University, 1812 Sir Isaac
Brock Way St. Catharines, Ontario L2S 3A1, Canada
thudlicky@brocku.ca
Abstract
Four distinct approaches to ent-oxycodone were designed and accomplished. All rely on
the same starting material, the diene diol derived from phenethyl acetate by the whole-cell
fermentation with E.coli JM109(pDTG601A), a strain that over-expresses toluene
dioxygenase. The key step in the first-generation approach involved the construction of the
C-9/C-14 bond by a SmI -mediated cyclization of a keto aldehyde. The second-generation
2
design relied on the use of the Henry reaction to accomplish this task. In both of these
syntheses Parker’s cyclization was employed to construct the D-ring. The third-generation
synthesis provided an improvement over the second in that the nitrogen atom at C-9 was
introduced by azidation of the C-9/C-10 olefin, followed by reduction and lactam formation
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between the C-9 amine and the Fukuyama-type lactone. Finally, the fourth generation took
advantage of the keto-nitrone reductive coupling to generate the C-9/C-14 linkage. The
four generations of the total syntheses of ent-oxycodone were accomplished in 13, 18, 16,
and 11 operations (19, 23, 24, 18 steps), respectively. Experimental and spectral data are
provided for all new compounds.
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Introduction
Morphine (1) and its congeners (Figure 1) have proven to be challenging targets for
synthetic organic chemists. Since the first total synthesis of morphine by Gates in 1952,1
2
more than 30 total or formal syntheses have been reported; the most recent is Metz’s
3
synthesis of (−)-codeine in 2018. Most synthetic strategies have targeted codeine (2),
which is easier to handle than the more sensitive morphine and whose O-demethylation to
4a
morphine has been well established by Rice. In 2009 Stork reported a successful
synthesis of the racemic 6-methoxycodeine with a subsequent one-step transformation to
5
thebaine. Five years later, Opatz accomplished an enantioselective synthesis of (−)-
dihydrocodeine in 12 linear steps in a 31% yield, which also constituted a formal synthesis
6
7a
of (−)-thebaine. In 2018, he achieved the de novo total synthesis of thebaine (4).
Attainment of dihydrocodeinone,7b-7d dihydrothebainone,7e-7g codeinone7h-7k or other
advanced intermediates7l-7m may be considered as formal synthesess of thebaine as well.
Our own group published a model study toward the synthesis of thebaine by cycloaddition
strategy based on 1,2-pyridazines and considerations of latent symmetry issues in design.8
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The pentacyclic skeleton of morphine alkaloids possesses fully dissonant connectivity,9
presenting a serious challenge in design to any practitioner. The likelihood of a truly
practical chemical synthesis of any morphine alkaloid that is competitive in cost with the
compounds available from natural sources is extremely low; even the most efficient
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synthesis accomplished on a kilo scale by Rice would not meet such a requirement.
There are, however, at least two reasons to continue the quest for an efficient synthesis.
The first is purely educational and aesthetic, as any total synthesis effort offers the ultimate
in training of students. The second reason may present itself in the effective combination of
molecular biology and chemistry by approaching the preparation by means of well-
understood biosynthetic pathways over-expressed in robust bacterial strains. Such an
approach would yield key intermediates by fermentation and allow access not only to the
natural alkaloids but also to those medicinal agents derived by semisynthesis.
A commercial preparation of both analgesics and antagonists is now best accomplished
from either oripavine (3) or thebaine (4) as these compounds are now available in large
10
amounts from selectively cloned plants developed by Tasmanian Alkaloids. It was
established that the main factors controlling the yield of morphine alkaloids are the
genotype and the nitrogen nutrition of the crop along with phosphorus nutrition, soil water
status, weeds, pests, and disease. Researchers from Tasmanian Alkaloids successfully
attempted to arrest the biosynthetic pathway of morphine at thebaine by means of
mutagenesis. The most valuable selection was named Norman. The latex of this plant
contained only two major alkaloids, thebaine and oripavine, with no morphine or codeine.
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The development of the Norman poppy paralleled the production of a slow-release
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formulation of oxycodone in USA. Thus a two-step sequence involving oxidation of
thebaine with peroxy acid to 14-hydroxycodeinone followed by hydrogenation of the enone
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moiety produces oxycodone (5), first developed by Freund and Speyer in 1916 in Germany
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in attempts to improve the analgesic properties of morphine. This is now the method of
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choice for large-scale manufacturing of this important analgesic. Similarly, oripavine is
converted to oxymorphone (6), essential for the preparation of the important antagonists
such as naloxone (7), naltrexone (8) and the mixed agonist – antagonist nalbuphine (9),
Figure 1. Their preparation is more arduous as it requires several steps for the N-
demethylation/alkylation sequence.15
Natural morphine alkaloids
HO
HO
HO
MeO
A
C
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O E
O
O
O
B
D
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NMe
NMe
NMe
NMe
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H
H
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HO
HO
MeO
oripavine (3)
MeO
thebaine (4)
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morphine (1)
codeine (2)
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steps
2 steps
Semisyntehtic derivatives
HO
HO
MeO
semisynthesis
O
O
O
NR
OH
NMe
OH
NMe
OH
X
O
O
Antagonists:
R = allyl, X = O, naloxone (7)
R = cyclopropylmethyl, X = O, naltrexone (8)
oxymorphone (6)
oxycodone (5)
Fukuyama (2014), 24 steps from 2-bromo isovanillin
synthesis
R = cyclobutylmethyl, X = -H, -OH, nalbuphine (9) Hudlicky (2019), 13 steps from phenyl acetate
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Figure 1. Natural morphine alkaloids and some opiate-derived agents.
For more than 25 years, our own group has pursued a chemoenzymatic strategy toward
the synthesis of morphine alkaloids by utilizing cis-dihydrodiols derived by toluene
dioxygenase-mediated dihydroxylation of aromatic substrates. A summary of our efforts
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was recently published. Access to cis-dihydrodiols is accomplished by fermentation of
aromatic substrates with a recombinant strain of E. coli JM109(pDTG 601A), developed by
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Gibson and over-expressing toluene dioxygenase. The applications of these metabolites
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in enantioselective synthesis of natural products have been extensively reviewed. It
seemed prudent to us to pursue a direct synthesis of oxycodone from commercially
available materials rather than a synthesis of any of the natural morphinans, given that only
19
two such accomplishments were already reported by Fukuyama in 2014 and by Chen at
the end of 2018.20 Our own first-generation effort was published in early 2019. Also in
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early 2019, Opatz accomplished a total synthesis of (−)-oxycodone by means of
22
electrochemical methods. In the present paper we report the details of several
generations of chemoenzymatic total synthesis of ent-oxycodone from phenethyl acetate.
Results and discussion
The first de novo total synthesis of oxycodone, reported by Fukuyama and coworkers,19
was accomplished in 24 steps from 2-bromoisovanillin (10) with an overall yield of 0.016%
(Scheme 1). The key steps included direct intramolecular arylation to form the tricyclic
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core, an oxidative dearomatization to install the C-14 hydroxyl group, an intramolecular
Michael addition, and a Hofmann rearrangement/lactamization cascade to introduce the
amino group and to construct the D-ring. Evans’ oxazolidinone chiral auxiliary established
the chirality and absolute stereochemistry, as shown in Scheme 1. Four years later, Chen
achieved the second synthesis of oxycodone in 16 steps starting from MOM-protected 2-
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bromoisovanillin (15). This synthesis shares some of the key features with the one
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reported by Fukuyama. The C-14 hydroxyl group was installed early in the synthesis by
means of oxidative dearomatization followed by Rovis desymmetrization of peroxyquinol 16
to introduce the chirality (Scheme 1). Heck cyclization allowed the construction of B-ring
followed by the Stork−Ueno reaction to form the C-13 quaternary center. Amidation and the
introduction of the olefin provided the allylic alcohol 19, which successfully underwent
Paker-type cyclization to complete the synthesis of (−)-oxycodone.
21
We published our first-generation synthesis of oxycodone in early 2019 (Scheme 2). The
synthesis, starting with the enzymatic dihydroxylation of phenethyl acetate to diene-diol 20,
was completed in 13 operations (19 steps) and an overall yield of 1.5%. The crucial steps
involved a Mitsunobu reaction to couple the A- and C-rings, a Heck cyclization to construct
the tricyclic core, introduction of the keto group with the subsequent SmI -mediated closure
2
of the B-ring, the simultaneous formation of the C-14 hydroxyl group, and Parker’s
hydroamination to furnish the D-ring.
Most recently, Opatz prepared oxycodone in 11 steps from methyl gallate (25) (Scheme 2).
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The key transformations employed a Bischler–Napieralski reaction followed by a Noyori
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asymmetric transfer hydrogenation to obtain the core of (R)-reticuline (Scheme 2). Anodic
coupling allowed the cyclization of the B-ring and furnished tetracyclic intermediate 27. The
dihydrofuran ring was constructed by means of conjugate nucleophilic substitution by the
phenol liberated from acetate 27. The C-14 hydroxyl group was introduced by [4 + 2]
cycloaddition of singlet oxygen to the diene in 28.
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Scheme 1. Synopses of Fukuyama’s and Chen’s syntheses of oxycodone.
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Scheme 2. Synopses of Hudlicky’s and Opatz’s syntheses of oxycodone.
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Second-generation approach
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Following the completion of our first approach, we embarked on subsequent generations of
design in order to shorten and improve the synthesis. We envisioned a second-generation
approach where the C-9 and C-14 stereogenic centers are created by means of nitroalkyl
anionic addition to a C-14 ketone (morphine numbering). We assumed that ent-oxycodone
(5) could be simplified to aminoalcohol 30, which could be obtained from ketoaldehyde 32
by means of a double Henry reaction, Scheme 3. The formation of the ketone at C-14
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morphine numbering) could be achieved via the dihydroxylation/elimination sequence of
intermediate 33. Heck cyclization would allow the construction of dihydrofuran ring and C-
3 quaternary center. The coupling of 2-bromoisovanillin (10) (to become the A-ring) and
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cis-dihydrodiol (20) (to become the C-ring) could be performed using Mitsunobu reaction.
cis-Dihydrodiol (20) is produced from phenethyl acetate (35) by enzymatic dihydroxylation
as reported previously.21
Scheme 3. Retrosynthetic analysis for the second-generation synthesis.
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The first Henry reaction would allow the introduction of nitrogen functionality while the
second would produce the B-ring with two stereocenters at C-14 and C-9, Scheme 3. We
were hopeful for a cis-stereochemical relationship between the resulting hydroxyl group at
C-14 and the nitro group at C-9 in order to facilitate the closure of the D-ring. Thus, we
envisioned two different pathways for the transformation of amino alcohol 30 to ent-
23
19
oxycodone (5) via Parker-type and Fukuyama-type chemistry, as shown in Scheme 4.
The details of the second-generation synthesis of ent-oxycodone follow.
Scheme 4. Different pathways to the C-9/N-17 closure in ent-oxycodone.
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Synthesis of amino alcohol 30. Our synthesis began with the enzymatic dihydroxylation of
phenethyl acetate (35) by whole-cell fermentation with E. coli JM109 (pDTG601A) to
24
produce cis-dihydrodiol 20, which was immediately subjected to selective reduction of the
25
less substituted double bond with diimide (Scheme 3). The protection of the distal, more
accessible, hydroxyl group as its silyl ether was followed by the Mitsunobu coupling of the
26
allylic alcohol 37 with 2-bromoisovanillin (10) to afford intermediate 34, (Sceme 5).A
27
reagent system consisting of N,N,N’,N’- tetramethylazodicarboxamide (TMAD) and n-
Bu P was found to give the highest conversion. The dihydrofuran ring as well as the C-13
3
quaternary carbon were constructed by means of an intramolecular Heck reaction and
furnished tricycle 33. Three routes were investigated to install the keto group at the C-14
carbon: an oxidation/dihydroxylation/lactonization/elimination sequence, a
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dihydroxylation/elimination sequence, and a dihydroxylation/mesylation/elimination
sequence. (These are described in detail in the Supporting Information, Part 2.)
In the final and most successful route, olefin 33 was dihydroxylated and converted to
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mono-mesylate 38, whose subsequent DBU-mediated elimination, via the formation of an
intermediate lactol 39, furnished ketone 32 in high yield (80%). Ketoaldehyde 32 was
28
subjected to the first Henry reaction, according to a procedure reported by Magnus, to
provide the conjugated nitroalkene, which was selectively reduced to nitroalkane 31 in 88%
29
yield with Hantzsch ester (Scheme 5). The use of NaCNBH in AcOH gave only 25% of
3
the desired product, and magnesium in MeOH reduced the keto group along with the
olefin. The key nitroalkane 31 was subjected to the DBU-mediated
cyclization (the use of Et N and/or N-ethyl-N,N-diisopropylamine (DIPEA) showed < 5%
3
conversion) to produce the desired nitroalcohol 40 with a successfully constructed B-ring
and the C-14 hydroxyl. Nitro alcohol 40, however, suffered from a tendency to partially
undergo a retro-Henry reaction upon any manipulation. Any attempt to capture the cyclized
nitro alcohol by in situ acetylation or mesylation failed, and led only to recovery of the
starting nitroalkane 31. The nitro group in 40 was therefore reduced to the amine with
nickel boride (formed in situ) or hydrogenation over PtO to give the stable amino alcohol
2
30 in 45% and 43% yield, respectively. (over two steps).
Scheme 5. Synthesis of aminoalcohol 30.a
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Reagents and conditions: (a) 2-bromoisovanillin (10), TMAD, n-Bu P, THF, 0 °C to rt,
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85%; (b) Pd(OAc) , dppf, Ag CO , PhCH , reflux, 89%; (c) (i) K OsO ∙2H O, NMO,
2
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acetone/H O, 63%; (ii) MsCl, NEt , DCM, 0 °C to rt, 91%; (d) DBU, PhCH , reflux, 80%; (e)
2
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(
i) CH NO , NH OAc, AcOH, reflux, 77%; (ii) Hantzsch ester, silica gel, PhH, reflux, 88%;
3
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(f) DBU, DCM; (g) NiCl ∙H O, NaBH , MeOH, 0 °C to rt, 45% (over two steps).
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Stereochemistry of amino group at C-9. The amine 30 already possesses the ABCE-ring
system of the target ent-oxycodone. The stereochemical relationship between the two
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newly formed stereocenters at C-9 (amino group) and C-14 (hydroxyl group) arising from
the second Henry reaction (Scheme 5) was determined using NMR techniques. A selective
1D NOESY experiment performed on amine 30 indicated a trans relationship. When one of
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the hydrogens at C-15 was irradiated, NOE correlations with those at C-5 and C-9
indicated a syn configuration of all three hydrogens (Figure 2). The 2D NOESY NMR
experiment allowed the establishment of relative distances between hydrogens at C-10 and
the one of interest at C-9; it confirmed, unfortunately, the less desirable trans relationship.
In order to avoid any possible confusion, the 2D NOESY NMR experiment was carried out
on cyclic oxazolidinone 41 (Figure 2). Strong correlations between both hydrogens at C-15
and the one at C-9 were detected, proving that the previous assignment of stereochemistry
of the amino group was correct. The coupling constants in the 1D proton spectrum for
oxazolidinone 41 were in accordance with previous stereochemical assignments of its
precursors. (For a more detailed explanation of the assignment, please see the Supporting
Information Section, Part 3.)
Figure 2. Correlations between hydrogens based on NOESY experiments.
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Synthesis of Parker-type intermediate. The possibility of closing ring D between the C-9
amine and the side chain directly was precluded by the unfavorable stereochemistry at the
C-9 amino group. We made an attempt to correct the stereochemistry at C-9 by applying
the Baylis–Hillman reaction in the construction of the B-ring with the subsequent reduction
of the resulting conjugated alkene 43 (Scheme 6). However, the resulting nitro alkane 40
also possessed trans stereochemistry and was shown to be identical to the nitro alcohol
previously obtained by the Henry reaction from 31.
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Scheme 6. Attempt to correct stereochemistry at C-9.a
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a
Reagents and conditions: (a) CH NO , NH OAc, AcOH, reflux, 77%; (b) PhSNa, THF,
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reflux, 71%; (c) Hantzsch ester, silica gel, PhH, reflux, 88% of 31; (d) DBU, DCM.
The introduction of the C-9/C-10 olefin (required for the planned Parker-type closure)
necessitated the elimination of the amino group, which could be achieved via the formation
of a quaternary salt or N-oxide. Initially, establishing conditions for the alkylation of the
amino group proved challenging, presumably because of the hydrogen bond between the
amino and hydroxyl groups. Thus, our attempt at the elimination comprised four
approaches: alkylation–elimination, reduction–elimination, oxidation–elimination, and
protection of C-14 hydroxyl group. (Details are summarized in the Supporting Information
Section, Part 4.) The difficulties related to the elimination of the amino group were solved
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by means of alkylation–elimination and reduction–elimination (Scheme 7). The amine in 30
was methylated (NaH, MeI, MeCN) to provide compound 46 (54% yield), which could also
also obtained from amine 30 via its conversion to oxazolidinone (63% yield), and
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subsequent methylation to 44 (74% yield) followed by reduction with Red-Al (97% yield)
and reprotection. Dimethylamine 46 was oxidized to its N-oxide 47 (63% yield), which was
30
subjected to a Cope elimination, which provided the allylic alcohol 48 in 51% yield
Scheme 7).
(
Scheme 7: Elimination of amino group.a
aReagents and conditions: (a) MeI, NaH, MeCN, 0 °C to rt, 54%; (b) (i) N,N’-
Carbonyldiimidazole (CDI), DMAP, THF, 63%; (ii) MeI, NaH, DMF, 74%; (c) Red-Al®,
PhCH , 0 °C to rt, 97%; (d) Ac O, Et N, DMAP, DCM, 90%; (e) 30% H O , CH CN/H O,
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63%; (f) Δ, 185 °C, 0.8 mmHg, 51%.
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With these successful results attained we were able to proceed with the construction of the
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D-ring. Two pathways were designed: one employs Parker-type chemistry, the other
19
Fukuyama-type chemistry. The synthesis of Parker-type intermediate 24 was first
attempted with compound 45 by a Mitsunobu reaction with TsNHMe; however, only ether
49 was isolated (Scheme 8), consistent with the observations made by Chen and co-
workers.20
Scheme 8: Mitsunobu reaction on dimethyl amine 45. a
a
Reagents and conditions: (a) TsNHMe, TMAD, n-Bu P, THF, 72%.
3
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Clearly the functional incompatibility of the side chain with the C-14 hydroxyl called for a
different strategy. We returned to the oxazolidinone intermediate 44 in which the hydroxyl
group at C-14 is internally protected (Scheme 7). The sequence used to form intermediate
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24, required for the well-established radical cyclization as reported by Parker during the
synthesis of the racemic dihydroisocodeine,23a is depicted in Scheme 9. The amine 30 was
converted to methyl oxazolidinone 44. Deprotection of the side chain acetate was followed
by a Mitsunobu reaction to obtain sulfonamide 50 in 57% yield. The reduction of
®
oxazolidinone moiety in 50 with Red-Al was accompanied by the detosylation and
provided unstable methylamine 51, which was immediately reprotected as the more stable
sulfonamide 52 (40% yield over two steps). Finally, oxidation of 52 (96% yield) and a
30
subsequent Cope elimination furnished the key intermediate 24 in 74% yield. Inspired by
31
reports suggesting that tosyl groups can be cleaved electrochemically, the cyclization of
the D-ring was attempted by applying electrochemical methods to the tosyl amide 24;
however, the result was a complex mixture of products containing no detectable amount of
the desired ent-oxycodol. (See Supporting Information Section, Part 5.) Application of
23
standard Parker’s cyclization conditions by means of Li/NH (liq.) followed by deprotection
3
and oxidation furnished ent-oxycodone (5) as reported earlier by our group.21
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Scheme 9. The completion of the synthesis of ent-oxycodone via a Parker-type
intermediate. a
aReagents and conditions: (a) (i) CDI, DMAP, THF, 63%; (ii) MeI, NaH, DMF, 74%; (b) (i)
®
0
.1 M NaOMe, MeOH, 93%; (ii) TsNHMe, TMAD, n-Bu P, THF, 57%; (c) Red-Al , PhCH ;
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(d) TsCl, DIPEA, DMAP, DCM, 0 °C, (40% over two steps); (e) m-CPBA, DCM, 0 °C to rt,
96%; (f) Ag CO on Celite, PhH, reflux, 24 h, 74%; (g) Li, t-BuOH, THF, liq. NH , −78 °C,
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76%; (h) (i) TBAF, THF; (ii) DMP, DCM, 59% (over two steps).
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The chemoenzymatic synthesis of ent-oxycodone via Parker-type intermediate 24 was
accomplished in 18 operations from phenethyl acetate. Because of the rather lengthy
protocol (~five steps) required to generate the Parker-type styrene 24, the second
generation approach was not an improvement of our earlier attempt. Despite the interesting
chemistry employed in the formation of the C-9/C-14 centers, a relatively long sequence
was required to correct the consequences of the unfavorable stereochemistry at C-9.
Third-generation approach
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Synthesis of a Fukuyama-type intermediate. The design of another approach was inspired
19
in part by Fukuyama’s synthesis of (−)-oxycodone. Formation of lactone 36 with the
subsequent installation of a nitrogen functionality at C-9 would lead, through
transamidation, to the thermodynamically more stable amide, which would be further
converted to ent-oxycodone by reduction, e.g., the transformation of 57 to 58, as shown in
Scheme 10. The key lactone 36 was synthesized as depicted in Scheme 10. In the second
generation, elimination of the amino group required five steps because the introduction of
the tosyl amide by Mitsunobu reaction was impeded by the free C-14 hydroxyl group, which
readily reacted with the side chain under the reaction conditions. We were able to avoid
this problem in the third-generation approach, and the elimination of the amino group
proceeded in three steps. Methylation of amine 30 with MeI, NaH provided the
corresponding dimethylamine in 54% yield, and subsequent hydrolysis of the acetate
provided diol 45. (This sequence was eventually reduced to a one-pot operation.) Initially,
diol 45 was subjected to oxidation to install the lactone; however, the yields were low
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(
<15%) under several conditions tested. (See Supporting Information Section, Part 6.) We
had assumed that the oxidation to the acid (and the eventual lactone formation) was
prevented by hydrogen-bond interactions between the dimethylamine at C-9 and the
hydroxyl group at C-14. Therefore, dimethylamine 45 was first oxidized to N-oxide 55. At
this stage, we attempted to generate the lactone moiety again using Ag CO on Celite as
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an oxidant; however, under these conditions, in refluxing benzene, N-oxide 55 underwent
Cope elimination to the unstable diol 56. Presumably, Ag CO serves as a base and
2
3
provides for a competing E elimination, as no reaction was observed in refluxing benzene.
2
Compared to standard Cope elimination conditions (heating neat or in high-boiling
solvents), the use of Ag CO on Celite in benzene improved the yield from 50% to 75% (as
2
3
1
judged by H NMR spectrosopy). The crude diol 56 was oxidized with
tetrapropylammonium perruthenate (TPAP) to furnish lactone 36 in 40% yield over two
steps.
We considered several options for installing the desired amino functionality at C-9 in
lactone 36: (a) Epoxidation of the styrene moeity followed by nucleophilic attack of azide
32
anion that would likely result in a benzylic amine with the incorrect regiochemistry. (b)
33
34
Direct aziridination according to Evans' protocol (the use of Yamada reagent ) would
afford an aziridine that could be subjected to reduction (hydride or catalytic hydrogenation).
(c) Haloamination followed by base treatment would form an aziridine (with opposite
35
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stereochemistry); (d) a more direct route involving Sharpless aminohydroxylation, which
is known to yield preferentially the Markovnikov addition of the amino group. Depending on
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the catalyst, a mixture of both Markovnikov and anti-Markovnikov products could result and
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lead to lack of regioselectivity; (e) Hydroxyamination of the styrene moiety in an anti-
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Markovnikov fashion (proposed to procede via an intermediate azide radical ) followed by
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benzylic deoxygenation was the last approach we considered.
We briefly investigated the outcome of stereochemistry in electrophilic additions to the
styrene unit in 36 and found that the preferential attack to form either an epoxide or a
bromonium ion would occur from the -face and therefore eliminate most of the options
mentioned above, except for the direct introduction of nitrogen at C-9 through the use of a
suitable electrophilic reagent. We have shown that the epoxidation of lactone 36 led to the
corresponding -epoxide, whose complete reduction furnished a triol with -C-9 hydroxyl,
identical to the triol derived from the hydrolysis of the acetate-diol 23 (Scheme 2). (For a
discussion of experiments designed to study the face selectivity of additions to the styrene
unit of 36 and detailed results see the Supporting Information Section, Part 7.)
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Scheme 10. The completion of the synthesis of ent-oxycodone via Fukuyama-type
intermediate. a
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a
Reagents and conditions: (a) (i) MeI, NaH, MeCN, 0 °C to rt, 54%; (ii) K CO , MeOH,
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2%; (b) m-CPBA, 4 Å mol. sieves, DCM, 0 °C to rt, 62%; (c) Ag CO on Celite, PhH,
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reflux, 1d; (d) TPAP, NMO, 4 Å mol. sieves, DCM, 40% (over two steps); (e) NaN , CAN,
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MeCN; (f) H , Pd/C, NEt , MeOH, 81% (over two steps); (g) (i) BH , THF, 65 °C; (ii) aq.
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CH O, NaBH(OAc) , (iii) Li, t-BuOH, THF, liq. NH , −78 °C, 48% (over 3 steps); (h) (i)
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TBAF, THF; (ii) DMP, DCM, 59% (over two steps).
Thus treatment of lactone 36 with sodium azide in the presence of ceric ammonium nitrate
(CAN) afforded azido nitrate 57, which was subjected to hydrogenation to furnish the
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lactam 58 in 81% yield over two steps (Scheme 10). The formation of intermediate 57 was
easily monitored by TLC or by NMR. (The azide stained yellow with cerric ammonium
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molybdate (CAM) whereas the lactone stained blue.) The H NMR spectrum of 57 showed
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signals at  4.72 ppm (hydrogen at C-10 nitrate ester) and  3.84 ppm (hydrogen at C-9
azide). The disappearance of the olefinic signals at  6.43 and 5.47 ppm can be monitored
as well. Presumably, upon hydrogenation in MeOH the nitrate at C-10 was displaced by
methanol, and the C-9 amine cyclized to the lactam 58. Reduction of the lactam moiety
with borane was followed by reductive amination to install the N-methyl group. Removal of
the benzylic methoxy group was accomplished via Birch reduction with Li in liquid ammonia
to afford the known compound 54 (48% yield over three steps), which was taken to ent-
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oxycodone as reported earlier. In conclusion, the chemoenzymatic synthesis of ent-
oxycodone via Fukuyama-type intermediate 36 was accomplished in 16 operations from
phenethyl acetate, providing a mild improvement over the second-generation approach.
Fourth generation approach
Keto-nitrone coupling approach. A more direct approach for the introduction of the C-9
39
amino functionality was based on a SmI -mediated keto-nitrone coupling, as shown in
2
Scheme 11. The key intermediate 22 was prepared from phenethyl acetate (35) in the
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same manner as reported previously. The side chain in ketone 22 was transformed to an
ester by deprotection/oxidation/esterification sequence (70% over three steps). The
deprotection of the acetal in compound 60 afforded an intermediate keto aldehyde, which
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was treated with N-methyl hydroxylamine to provide nitrone 61. The formation of the
nitrone was evidenced by a drastic drop in the R value of the product on TLC. While the
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intermediate aldehyde resulting from the deprotection of the acetal had a high R value
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(
silica gel, R 0.60, [hexanes/EtOAc (2:1)]), the nitrone was immobile in this eluent.
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Treatment of nitrone 61 with SmI led to lactone 62, whose reduction with Raney nickel
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furnished lactam 63 in 29% yield over four steps. The formation of lactone 62 was deduced
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based on the analysis of the crude product; The H NMR spectrum lacked the
characteristic methyl ester signal at ~ 3.50, the upfield shift of the signal of the hydrogen
at C-5 from  5.1 (in the starting ester 60) to 4.6 ppm, indicating a loss of deshielding by
the carbonyl group, and the R on TLC has increased from zero to around 0.30 (silica gel,
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hexanes/EtOAc (1:1)]), indicating a less polar hydroxylamine product in comparison with
the very polar starting nitrone. Reduction of the hydroxyl amine in 62 with Raney nickel
provided lactam 63, whose further reduction followed by TBS removal and subsequent
oxidation of the C-6 alcohol, furnished ent-oxycodone (5). In conclusion, the fourth
generation chemoenzymatic synthesis of ent-oxycodone via the key nitrone intermediate
61 was accomplished in eleven operations from phenethyl acetate, affording a reasonable
improvement over all of the previous attempts. Further improvement and a reduction in
step count can be expected from combining a few of the sequences into one-pot.
Scheme 11. Synthesis of ent-oxycodone (5) by keto-nitrone coupling as the key
transformation.
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