Chemoenzymatic total synthesis of ent-oxycodone - ACS Publications

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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 Downloaded from http://pubs.acs.org on June 11, 2019

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Journal of the American Chemical Society

Chemoenzymatic total synthesis of ent-oxycodone: Second, third and fourth generation strategies

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

[email protected]

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 SmI2-mediated cyclization of a keto aldehyde. The second-generation 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. 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 more than 30 total or formal syntheses have been reported;2 the most recent is Metz’s synthesis of (−)-codeine in 2018.3 Most synthetic strategies have targeted codeine (2), which is easier to handle than the more sensitive morphine and whose O-demethylation to morphine has been well established by Rice.4a In 2009 Stork reported a successful synthesis of the racemic 6-methoxycodeine with a subsequent one-step transformation to thebaine.5 Five years later, Opatz accomplished an enantioselective synthesis of (−)dihydrocodeine in 12 linear steps in a 31% yield, which also constituted a formal synthesis of (−)-thebaine.6 In 2018, he achieved the de novo total synthesis of thebaine (4).7a 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 synthesis accomplished on a kilo scale by Rice4b 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 wellunderstood 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 amounts from selectively cloned plants developed by Tasmanian Alkaloids.10 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 formulation of oxycodone in USA.11 Thus a two-step sequence involving oxidation of thebaine with peroxy acid to 14-hydroxycodeinone followed by hydrogenation of the enone moiety produces oxycodone (5), first developed by Freund and Speyer in 1916 in Germany in attempts to improve the analgesic properties of morphine.12 This is now the method of choice for large-scale manufacturing13 of this important analgesic.14 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 Ndemethylation/alkylation sequence.15

Natural morphine alkaloids HO

HO

HO

MeO

A O E

10

O

B D NMe C H

6

HO

HO morphine (1)

O

9 14 7

H

O

NMe

8

codeine (2)

NMe MeO oripavine (3)

NMe MeO thebaine (4)

2 steps

2 steps Semisyntehtic derivatives HO

HO

MeO

semisynthesis O

O NR OH

O NMe OH

NMe OH

X O O Antagonists: oxymorphone (6) oxycodone (5) R = allyl, X = O, naloxone (7) R = cyclopropylmethyl, X = O, naltrexone (8) 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 was recently published.16 Access to cis-dihydrodiols is accomplished by fermentation of aromatic substrates with a recombinant strain of E. coli JM109(pDTG 601A), developed by Gibson and over-expressing toluene dioxygenase.17 The applications of these metabolites in enantioselective synthesis of natural products have been extensively reviewed.18 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 two such accomplishments were already reported by Fukuyama in 201419 and by Chen at the end of 2018.20 Our own first-generation effort was published in early 2019.21 Also in early 2019, Opatz accomplished a total synthesis of (−)-oxycodone by means of electrochemical methods.22 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 2bromoisovanillin (15).20 This synthesis shares some of the key features with the one reported by Fukuyama.19 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. We published our first-generation synthesis of oxycodone in early 2019 (Scheme 2).21 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 SmI2-mediated closure 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). 22 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. 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 (morphine numbering) could be achieved via the dihydroxylation/elimination sequence of intermediate 33. Heck cyclization would allow the construction of dihydrofuran ring and C13 quaternary center. The coupling of 2-bromoisovanillin (10) (to become the A-ring) and

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 entoxycodone (5) via Parker-type23 and Fukuyama-type chemistry,19 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 produce cis-dihydrodiol 20,24 which was immediately subjected to selective reduction of the less substituted double bond with diimide (Scheme 3).25 The protection of the distal, more accessible, hydroxyl group as its silyl ether was followed by the Mitsunobu coupling of the allylic alcohol 37 with 2-bromoisovanillin (10)26 to afford intermediate 34, (Sceme 5).A reagent system27 consisting of N,N,N’,N’- tetramethylazodicarboxamide (TMAD) and nBu3P was found to give the highest conversion. The dihydrofuran ring as well as the C-13 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 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 subjected to the first Henry reaction, according to a procedure reported by Magnus,28 to provide the conjugated nitroalkene, which was selectively reduced to nitroalkane 31 in 88% yield with Hantzsch ester29 (Scheme 5). The use of NaCNBH3 in AcOH gave only 25% of 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 Et3N and/or N-ethyl-N,N-diisopropylamine (DIPEA) showed < 5% 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 PtO2 to give the stable amino alcohol 30 in 45% and 43% yield, respectively. (over two steps).

Scheme 5. Synthesis of aminoalcohol 30.a


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aReagents

and conditions: (a) 2-bromoisovanillin (10), TMAD, n-Bu3P, THF, 0 °C to rt,

85%; (b) Pd(OAc)2, dppf, Ag2CO3, PhCH3, reflux, 89%; (c) (i) K2OsO4∙2H2O, NMO, acetone/H2O, 63%; (ii) MsCl, NEt3, DCM, 0 °C to rt, 91%; (d) DBU, PhCH3, reflux, 80%; (e) (i) CH3NO2, NH4OAc, AcOH, reflux, 77%; (ii) Hantzsch ester, silica gel, PhH, reflux, 88%; (f) DBU, DCM; (g) NiCl2∙H2O, NaBH4, MeOH, 0 °C to rt, 45% (over two steps).

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 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.

Scheme 6. Attempt to correct stereochemistry at C-9.a


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aReagents

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and conditions: (a) CH3NO2, NH4OAc, AcOH, reflux, 77%; (b) PhSNa, THF,

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 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 subjected to a Cope elimination,30 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®, PhCH3, 0 °C to rt, 97%; (d) Ac2O, Et3N, DMAP, DCM, 90%; (e) 30% H2O2, CH3CN/H2O, 63%; (f) Δ, 185 °C, 0.8 mmHg, 51%. ACS Paragon Plus Environment

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With these successful results attained we were able to proceed with the construction of the D-ring. Two pathways were designed: one employs Parker-type23 chemistry, the other Fukuyama-type19 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 coworkers.20

Scheme 8: Mitsunobu reaction on dimethyl amine 45. a

aReagents

and conditions: (a) TsNHMe, TMAD, n-Bu3P, THF, 72%.


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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 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 subsequent Cope elimination30 furnished the key intermediate 24 in 74% yield. Inspired by reports suggesting that tosyl groups can be cleaved electrochemically,31 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 standard Parker’s cyclization conditions23 by means of Li/NH3 (liq.) followed by deprotection 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-Bu3P, THF, 57%; (c) Red-Al®, PhCH3; (d) TsCl, DIPEA, DMAP, DCM, 0 °C, (40% over two steps); (e) m-CPBA, DCM, 0 °C to rt, 96%; (f) Ag2CO3 on Celite, PhH, reflux, 24 h, 74%; (g) Li, t-BuOH, THF, liq. NH3, −78 °C, 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

Synthesis of a Fukuyama-type intermediate. The design of another approach was inspired in part by Fukuyama’s synthesis of (−)-oxycodone.19 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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Chemoenzymatic total synthesis of ent-oxycodone - ACS Publications

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