DOI: 10.1002/slct.

201701817 Communications

1
2 z Organic & Supramolecular Chemistry
3
4
5
Model Studies toward the Total Synthesis of Thebaine by
6 an Intramolecular Cycloaddition Strategy
7
8 Petr Koukal,*[a, b] Josef Hájı́ček,[a, b] Setu Gupta,[b, c] and Tomáš Hudlický[b]
9
10
Three model compounds required for an approach to thebaine diene),[7] Bodwell (indole / pyridazine),[8] Snyder (indole /
11
by intramolecular [4 + 2] cycloaddition were prepared. In the tetrazine),[9] Stork (benzofuran / methoxybutadienyl),[10] Ciganek
12
first two cases the anticipated cycloaddition products were (benzofurane / pyranone)[11] and Hudlický.[5,12] Based on these
13
obtained under thermal conditions. Thermolysis of the third, reports, the implementation of pyridazines[13] in an approach to
14
more advanced model compound, afforded products resulting thebaine via the model compounds 1 using intramolecular
15
from rearrangements and/or elimination. A study of analogous Diels-Alder reaction of amide or amine[14] 2 was envisaged.
16
intra- and intermolecular reactions using benzofuran as dien- Although compound 1 contains all of the thebaine carbon
17
ophile and various electron-poor and electron-rich dienes atoms and functionalities, it lacks the C10-C11 bond. Even
18
(pyridazines, pyranones, Danishefsky diene) was undertaken. though the construction of this bond requires further function-
19
alization of C10, the synthesis of 1 was intended as an
20
advanced proof of concept (Scheme 1).
21
22
23 Introduction
24
Thebaine is a natural product occurring in plant genus Papaver
25
together with morphine, papaverine, noscapine, codeine, and
26
other minor alkaloids. Thebaine itself has no medical use as it
27
possesses stimulatory rather than analgesic properties.[1] How-
28
ever, together with oripavine it serves as a starting material for
29
production of semi-synthetic analgesics (oxycodone, oxymor- Scheme 1. Retrosynthetic analysis for thebaine model compound 1.
30
phone, nalbuphine or etorphine) and opioid overdose medi-
31
cations (naloxone, naltrexone or buprenorphine).[2] No current
32
synthesis of thebaine or other opioid can compete with
33
extraction of the plant material because of cost, difficult
34
scalability, or low overall yields[3] – notwithstanding some
35 Results and Discussion
excellent progress in this area: currently the best enantioselec-
36
tive synthesis of a) dihydrocodeine accomplished in 31 % yield First, and as a basic proof of concept, we decided to study [4 +
37
over 12 steps (shortest linear path) by Opatz[4] and b) ent- 2] cycloaddition of a simplified substrate 6 (Scheme 2).[12] Thus,
38
hydromorphone in 3 % over 12 steps by Hudlický.[5]
39
Normal or inverse electron demand intramolecular [4 + 2]
40
cycloadditions[6] enable the construction of polycyclic scaffolds
41
and have therefore been often used in alkaloid synthesis,
42
namely by Padwa (benzofurane as the dienophile / furan as the
43
44
45 [a] P. Koukal, Dr. J. Hjček
46 Department of Organic Chemistry
47 Faculty of Science
Charles University
48 Hlavova 8, Praha 2, 123 43 (Czech Republic)
49 E-mail: petr.koukal@natur.cuni.cz
50 [b] P. Koukal, Dr. J. Hjček, S. Gupta, Prof. Dr. T. Hudlický Scheme 2. Syntheses of thebaine model compounds 7 and 11. Reagents and
51 Chemistry Department and Centre for Biotechnology conditions: a) 1) LiTMP / THF, 85 8C; 2) MeCHO, 85 8C, 1.5 h, 79 %; b) MsCl,
Brock University Et3N / DCM, 0 8C to r.t., 1.5 h, 52 %; c) MeNH2 / DCM/THF, 78 8C to r.t., 2 days,
52 1812 Sir Isaac Brock Way, St. Catharines, Ontario, L2S 3 A1 (Canada) 93 %; d) (CH2 = CH-CH2-CO)2O, DMAP, Et3N / DCM, rt, 20 h; e) o-xylene, reflux
53 [c] S. Gupta (156 8C), 26 h; f) KOH / EtOH, 50 8C, 16 h.; g) HBTU, iPr2NEt / DMF, r.t., 48 h.; h)
54 ALS Environmental – North America 1,2,4-trichlorobenzene, 200 8C, 14 h.
55 95 West Beaver Creek Road, Richmond Hill, Ontario, L4B 1 K5 (Canada)

56 Supporting information for this article is available on the WWW under

https://doi.org/10.1002/slct.201701817
57

ChemistrySelect 2017, 2, 7783 – 7786 7783  2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Wiley VCH
1726 / 98680
Montag, 11.09.2017
[S. 7783/7786] 1
 Communications
a-lithio pyridazine was converted to pyridazinylethanamine 5 isolated in both cases. The thermolysis of amide 2 b provided
1
by condensation with acetaldehyde followed by mesylation products analogous to 15 a and 15 b (based on 1H NMR spectra
2
and displacement of the mesylate with N-methylamine. of the crude reaction mixture) while microwave-assisted
3
Acylation of the resulting amine 5 with but-3-enoic acid reactions of 2 b did not yield any product (reaction temperature
4
anhydride provided the amide 6 in 71 % yield. This amide was up to 200 8C, 30 minutes). Thermal migration of O-alkyl groups
5
then subjected to [4 + 2] cycloaddition in refluxing o-xylene onto nitrogen atom has been reported for a variety of
6
and the desired product of cycloaddition amide 7, which alkoxyheteroarenes heated to 200–300 8C,[17] excluding alkox-
7
contains the thebaine rings C and D, was obtained in 50 % ypyridazines.
8
yield. To test the assumption that this reaction pathway might be
9
With this result in hand a Diels-Alder reaction of a more caused by an unfavorable electron density of the pyridazine
10
complex substrate 10, containing the thebaine ring E, was moiety, intermolecular inverse-electron-demand Diels-Alder
11
envisioned. Compound 9, prepared by alkaline hydrolysis of reactions of dienophile 3 with several dienes of decreased
12
ester 8, was coupled with amine 5 in a HBTU-promoted electron density were attempted. However, no cycloadducts
13
reaction yielding the desired amide 10 in 69 % yield. This amide were detected in any of these trials (it should be noted that
14
was then subjected to [4 + 2] cycloaddition in 1,2,4 trichlor- intermolecular reactions are entropically disfavoured over the
15
obenzene at 200 8C for 14 hours. The tricyclic diene 11 was corresponding intramolecular reactions). Reactions of ester 3
16
obtained in 58 % isolated yield. This compound contains the with acetylpyridazine 13 and cyanopyridazine 16 provided the
17
thebaine rings E, C and D and its successful synthesis corresponding products of methyl shift 21 and 22 in high
18
encouraged us to focus on the preparation and thermolysis of yields (Table 1, entry 1 and 2). Similarly, the reaction of 3 with
19
the advanced model compound 2 (containing also the
20
thebaine ring A).
21 Table 1. Attempted intramolecular [4 + 2] cycloaddition reactions.
For this purpose, amines 4 a and 4 b were prepared by
22
reductive amination of acetylpyridazine 12[15] (Scheme 3). Both
23
24
25
26
27
Entry Diene Solvent Product[a] Yield [%][b]
28
29
30 1 13 PhNMe2 21 73
31
32
33 2 16 PhNMe2 22 89
34
35
36 3 17 PhNMe2 23 23
Scheme 3. Preparation of amides 2 and the attempted reduction and [4 + 2]
37 cycloaddition. Reagents and conditions: a) KOH / MeOH, 23 8C, 1 h.; b)
38 AcONH4 (for R = H) or MeNH2.HCl (for R = Me), NaBH3CN / THF, 40 8C, 15 h.; c)
39 EDC, DMAP / DCM, 23 8C, 15 h.; d) Reaction of 2 b: LiAlH4 / THF, 23 8C, 15 h.; e)
4 18 TCB 24 6
Reaction of 2 a: 1,2,4-Cl3C6H3, > 250 8C, 3 days, yield of 15 a 5 %, 15 b 10 %.; f)
40
Reaction of 2 a: Me2NPh, > 250 8C, 3 days, yield of 15 a 15 %, 15 b 3 %.
41
42 5 19 TCB 24 -[c]
43
44
amines were then coupled with benzofurylacetic acid 13
45 6 20 TCB 24 22
(prepared by hydrolysis of the corresponding methyl ester 3[16])
46
in EDC/DMAP promoted reactions. The resulting amides 2 a
47
and 2 b were obtained in good overall yields. Reduction of the [a] No other products detected, except for tars. [b] Isolated yield. [c] Not
48 determined. TCB = 1,2,4-trichlorobenzene.
amide 2 b by LiAlH4 failed to provide the amine-tethered [4 + 2]
49
substrate 2 c. Instead, acylhydrazone 14, resulting from partial
50
reduction of the pyridazine ring, was isolated in 56 % yield.
51
Amide 2 a was subjected to a thermal [4 + 2] cycloaddition. more electron deficient 3,6-dichloropyridazine 17 was under-
52
The thermolysis required > 250 8C for the starting material to taken. The reaction in dimethylaniline afforded 23, an un-
53
be consumed, but the desired tetracyclic compound 1 was not expected product of double aromatic substitution of dichlor-
54
formed either in 1,2,4 trichlorobenzene or in N,N-dimethylani- opyridazine, in 23 % yield (entry 3),[18] while the reaction in
55
line as the solvent. Instead, products resulting from the loss of trichlorobenzene led to decomposition of 17 and to decarbox-
56
the N-methyl group (15 a) or methyl-migration (15 b) were ylation of ester 3 yielding methylbenzofuran 24 (entry 4). A
57

ChemistrySelect 2017, 2, 7783 – 7786 7784  2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Wiley VCH
1726 / 98680
Montag, 11.09.2017
[S. 7784/7786] 1
 Communications
similar outcome was observed in the reaction of 3 with bare However, in all cases substitution, rearrangement and/or
1
pyridazine 19 (entry 5). 3,5-Dibromopyranone 20, known to elimination products were isolated.
2
react with both electron rich[19] and electron deficient[20] These reactions as well as the use of benzofuran as a
3
dienophiles, also yielded compound 24 in the thermal reaction dienophile in thermal intramolecular Diels-Alder reactions
4
(entry 6). No products were detected in reactions of ester 3 reported elsewhere[7,10,11,21] indicate, that for further attempts on
5
with 3,5-dibromopyranone 19, 2-pyranone or Danishefsky’s synthesis of thebaine using this methodology preparation of
6
diene in 5 M solution of LiClO4 (r.t., 7 days) as well as under substrates either with electron-rich diene or conversely with
7
ultra-high pressure (15 kbar, 2 days) in dichloromethane. pyridazine substituted with electron-withdrawing group (allow-
8
Absence of cycloaddition products in all trials with 7- ing later transformation into methoxyl) should be considered.
9
methoxybenzofuran 3 led to a hypothesis that modification of Last but not least, changing the amide N-methyl for some
10
the electronic properties of 7-methoxybenzofuran could pro- sterically demanding group might promote the cycloaddition
11
mote the reaction. This approach was based on the work of by increasing the reactive s-cis conformer abundance.[7]
12
Piettre, who reported normal electron demand Diels-Alder
13
reactions of 3-carbonylbenzofuranes with dienes.[21] For this
14 Supporting Information Summary
reason, the synthesis of ketoamides 27 was undertaken. Ester 3
15
was oxidized at the a-carbon with selenium dioxide. The The Supporting Information includes the experimental section
16
resulting ketoester 25 was then hydrolyzed and the ketoacid and 1H and 13C NMR spectra.
17
26 was treated with amines 4 a and 4 b using the EDC/DMAP
18
method to yield ketoamides 26 a and 26 b. Disappointingly, the
19 Acknowledgements
subsequent thermal reactions (in 1,2,4-trichlorobenzene,
20
> 250 8C, 5 days) did not offer the corresponding cycloaddition The authors are grateful to the following agencies for financial
21
products either, judging from 1H NMR of crude reaction support of this work: Natural Sciences and Engineering Research
22
mixtures and yielded only tars. A comparative intermolecular Council of Canada (NSERC) (Idea to Innovation and Discovery
23
reaction of ketoester 25 with pyridazine 13 provided the Grants), Canada Research Chair Program, Canada Foundation for
24
already known product of methyl-migration 21 accompanied Innovation (CFI), TDC Research, Inc., TDC Research Foundation,
25
by 29 and also ketoester decarbonylation products 28 a and the Ontario Partnership for Innovation and Commercialization
26
28 b (Scheme 4). (OPIC), and The Advanced Biomanufacturing Centre (Brock
27
University). Skillful assistance of Mike Kerr’s group (Western
28
Unicversity) with the high pressure reactions and Travis Dudding’s
29
group with microwave reactions are appreciated. P.K. gratefully
30
acknowledges the Charles University Mobility Fund.
31
32
33 Conflict of Interest
34
The authors declare no conflict of interest.
35
36
37 Keywords: cycloaddition · pyridazine · thebaine · thermolysis ·
38 total synthesis
39
40 [1] S. Hosztafi, Adv. Biosci. Biotechnol. 2014, 5, 704–717.
[2] For overview of drugs syntheses, see: a) T. Hudlický, Can. J. Chem. 2015,
41 Scheme 4. Syntheses and thermolyses of a-keto compounds 27 and 28.
93, 492–501. b) A. Machara, M. A. A. Endoma-Arias, I. Csařov. D. P. Cox,
Reagents and conditions: a) SeO2 / dioxane, reflux, 15 h; b) NaOH (aq.) /
42 T. Hudlický, Eur. J. Org. Chem. 2016, 1500–1503; c) J. R. Giguere, K. E.
MeOH, 0 8C, 1 h; c) EDC, DMAP / DCM, 23 8C, 15 h. d) 1,2,4-Cl3C6H3, > 250 8C,
43 McCarthy, M. Schleusner, WO 2015107471 A1, 2015.
15 h. [a] Low yield was caused by an experimental error.
44 [3] For a review, see: J. W. Reed, T. Hudlický, Acc. Chem. Res. 2015, 48, 674–
687.
45 [4] M. Geffe, T. Oppatz, Org. Lett. 2014, 16, 5282–5285.
46 [5] a) L. Rycek, J. J. Hayward, M. A. Latif, J. Tanko, T. Hudlický, J. Org. Chem.
47 2016, 81, 10930–10941; b) V. Varghese, T. Hudlický, Angew. Chem. Int. Ed.
48 Conclusions 2014, 53, 4355–4358.
[6] For recent literature on intramolecular Diels-Alder reaction in natural
49 product synthesis, see: a) M. M. Heravi, V. F. Vavsari, RSC Adv. 2015, 5,
Three model studies related to synthesis of thebaine by
50 50890–50912; b) D. Tanner, E. Ascic in Comprehensive Organic Synthesis II
intramolecular Diels-Alder reaction were carried out. While the
51 2nd ed., Vol. 5 (Ed.; P. Knochel), Elsevier, Amsterdam, 2014, pp. 466–517;
compounds 6 and 10 provided the anticipated [4 + 2] cyclo- c) P. T. Parvatkar, H. K. Kadam, S. G. Tilve Tetrahedron 20143 70, 2857–
52
addition products 7 and 11 under thermal conditions, the 2888; d) A. Padwa, A. C. Flick in Advances in Heterocyclic Chemistry, Vol.
53 110 (Ed.: A. R. Katritzky), Elsevier, Amsterdam, 2013, pp. 1–41; e) K. Takao,
thermolysis of 2 a resulted in demethylation and methyl trans-
54 R. Munakata, K. Tadano, Chem. Rev. 2005, 105, 4779–4807.
position in lieu of cycloaddition. To further study the reaction
55 [7] S. France, J. Boonsombat, C. A. Leverett, A. Padwa, J. Org. Chem. 2008,
several substrates for intra- and intermolecular Diels-Alder 73, 8120–8123.
56
reaction of benzofuran as the dienophile were prepared. [8] G. J. Bodwell, J. Li, Org. Lett. 2002, 4, 127–130.
57

ChemistrySelect 2017, 2, 7783 – 7786 7785  2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Wiley VCH
1726 / 98680
Montag, 11.09.2017
[S. 7785/7786] 1
 Communications
[9] S. C. Benson, L. Lee, L. Yang, J. K. Snyder, Tetrahedron, 2000, 56, 1165– [17] See the references in: T. Lister, R. H. Prager, M. Tsaconas, K. L. Wilkinson,
1 1180. Aust. J. Chem. 2003, 56, 913–916; The reaction can be mediated by
2 [10] G. Stork, A. Yamashita, J. Adam, G. R. Schulte, R. Chestworth, Y. Miyazaki, alkylating agents to proceed at lower temperatures, see: L. Knorr, Ber.
3 J. J. Farmer, J. Am. Chem. Soc. 2009, 131, 11402–11406. Dtsch. Chem. Ges. 1897, 30, 929–933.
[11] E. Ciganek, J. Am. Chem. Soc. 1981, 103, 6261–6262. [18] It is worth noting that the oxygen atom in 23 comes from the ester
4
[12] S. Gupta, MSc. thesis, Brock University (Canada), 2014. function group of 3.
5 [13] For the use of pyridazine in Diels-Alder reactions, see: a) D. Giomi, M. [19] C.-G. Cho, Y.-W. Kim, W.-K. Kim, Tetrahedron Lett. 2001, 42, 8193–8195.
6 Cecchi, Tetrahedron 2002, 58, 8067–8071; b) D. L. Boger, R. S. Coleman, J. [20] C.-G. Cho, Y.-W. Kim, Y.-K. Lim, J.-S. Park, H. Lee, S. Koo, J. Org. Chem.
7 Org. Chem. 1984, 49, 2240–2245; c) Ref. 8. 2002, 67, 290–293.
[14] Significant acceleration of the Diels-Alder reaction of amide-tethered [21] N. Chopin, H. Grard, I. Chataigner, S. R. Piettre, J. Org. Chem. 2009, 74,
8
dienes and dienophiles (in comparison with amine-tethered com- 1237–1246.
9 pounds) has been reported, see: S. K. Bur, S. M. Lynch, A. Padwa, Org.
10 Lett. 2002, 4, 473–476.
11 [15] N. Kanaya, T. Ishiyama, R. Muto, T. Watanabe, Y. Ochiai, (Daiichi
Pharmaceutical Co., Ltd.) EP Appl. No. 1762568 A1, 2005. Submitted: August 8, 2017
12 Revised: August 22, 2017
[16] a) W. M. Bryant III, G. F. Huhn, Synth. Commun. 1995, 25, 915–920;
13 b) M. E. Jung, S. Abrecht, J. Org. Chem. 1988, 53, 423–425. Accepted: August 29, 2017
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57

ChemistrySelect 2017, 2, 7783 – 7786 7786  2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Wiley VCH
1726 / 98680
Montag, 11.09.2017
[S. 7786/7786] 1