The Synthesis of (±)-1,2,3,4,6,7,12,12b-Octahydroindolo[2,3-a]quinolizine from Tryptophan and Dihydropyran

Full text of DOI:10.1080/00304948.2018.1468988

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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The Synthesis of (±)-1,2,3,4,6,7,12,12b-
Octahydroindolo[2,3-a]quinolizine from
Tryptophan and Dihydropyran
Jeanese C. Badenock & Gordon W. Gribble
To cite this article: Jeanese C. Badenock & Gordon W. Gribble (2018) The Synthesis
of (±)-1,2,3,4,6,7,12,12b-Octahydroindolo[2,3-a]quinolizine from Tryptophan and
Dihydropyran, Organic Preparations and Procedures International, 50:4, 449-453, DOI:
10.1080/00304948.2018.1468988
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Organic Preparations and Procedures International, 50:449–453, 2018
# 2018 Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2018.1468988
OPPI BRIEF
The Synthesis of ( )-1,2,3,4,6,7,12,12b-
Octahydroindolo[2,3-a]quinolizine from
Tryptophan and Dihydropyran
Jeanese C. Badenock1 and Gordon W. Gribble1,2
1Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA
2Department of Chemistry, University of Oregon, Eugene, OR 97403, USA
Indolo[2,3-a]quinolizidine 1 (Scheme 1) has an interesting history. First synthesized by
Keufer1 in 1950, this tetracyclic amine was subsequently prepared by several others,2–7
only later to be discovered as a naturally occurring plant alkaloid from the New Guinea
tree Dracontomelum mangiferum.8,9 This represents a rare case of a natural product
being discovered after its synthesis. Several enantioselective syntheses established the
S-configuration for 1,7,10–19 although the isolated alkaloid was found to be partially
racemic. Other syntheses have been reported.20–28 The 10-bromo derivative (arboresci-
dine A) was isolated in 1993 from the marine tunicate Pseudodistoma arborescens,29
and, accordingly, 1 has been named desbromoarborescidine A.24
Despite myriad syntheses of 1, we felt that none are suitable for a large-scale prepar-
ation that we required for a project in our laboratory. We now describe a simple and
atom-economical synthesis of ( )-1 from tryptophan (2) and dihydropyran (3) (Scheme 1).
A classic Pictet-Spengler acid-catalyzed condensation of tryptophan (2) with 3,4-dihy-
dro-2H-pyran (3) afforded 1-(4-hydroxybutyl)-1,2,3,4-tetrahydro-b-carboline-3-carboxylic
acid (4) in yields up to 60%, presumably as a mixture of diastereomers (Scheme 2).
Treatment of 4 with hot acidic potassium dichromate resulted in oxidative decarboxylation
to afford 1-(4-hydroxybutyl)-b-carboline (5) in yields up to 89%. Treatment of carboline
alcohol 5 with hydrogen bromide followed by sodium hydroxide yielded the ring-closed
zwitterionic 7, via the bromide 6. Without isolation, the crude 7 was treated with sodium
borohydride to give tetracyclic amine 1 in yields of up to 40–45% overall from tryptophan.
In summary, we believe that this procedure is atom-economical and practical for
preparing racemic 1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine (1) both effi-
ciently and on a reasonably large scale.
Received December 4, 2017; in final form February 2, 2018.
Address correspondence to Gordon W. Gribble, Department of Chemistry, Dartmouth College,
Hanover, NH 03755. E-mail: gordon.w.gribble@dartmouth.edu
449

450
Badenock and Gribble
Experimental Section
General Methods
Caution: dichromate reactions were performed in a well-ventilated hood using gloves
and eye protection. Handling of all chromium compounds followed institutional proto-
cols. Melting points were determined on a Laboratory Devices Mel Temp capillary
melting point apparatus, in open capillaries and are uncorrected. Thin layer chromatog-
raphy (TLC) was performed on Whatman brand 20 ꢀ 20 cm polyester backed silica
plates with fluorescent indicator. Plates were visualized by 254 nm UV light.
Alternative visualization was accomplished by dipping of the plate into a solution of
ceric ammonium sulfate in 10% H2SO4 then drying. Column chromatography was car-
1
ried out using Silicycle ultra pure silica gel 60Å (230-400 mesh). H (300 MHz) and
13C (75 MHz) NMR spectra were recorded on a Varian XL-300 Fourier transform spec-
trometer unless otherwise indicated (by frequency) in which they were recorded on a
1
Varian Unity plus spectrometer: H (500 MHz) and 13C (125 MHz). The chemical shifts
are reported in d (ppm) using the d 7.27 signal of CHCl3 (1H-NMR) and the d 77.23
signal of CDCl3 (13C-NMR), the d 4.87 signal of CD3OH (1H-NMR) and the d 49.15
signal of CD3OD (13C-NMR), the d 2.51 signal of (CH3)2SO (1H-NMR) and the d
39.50 signal of (CD3)2SO (13C-NMR), or the d 2.05 signal of CO(CD3)CD2H (1H-
NMR) and d 29.92 signal of CO(CD3)2 (13C-NMR) as internal standards. The apparent
multiplicity (s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, p ¼ pentet, h ¼ hextet,
m ¼ multiplet, b ¼ broad), the number of protons, and the coupling constants (in Hz)
are reported where appropriate. “In vacuo” refers to solvent removal first by rotary
evaporation followed by a lower pressure environment (ꢁ0.2 Torr).
1-(4-Hydroxybutyl)-1,2,3,4-tetrahydro-b-carboline-3-carboxylic acid (4)
To a stirred suspension of tryptophan (2) (2.5 g, 12.2 mmol, 1 eq.) and 3,4-dihydro-2H-
pyran (3) (2 mL, 21.9 mmol, 1.8 eq.) in water (35 mL) was added 1M H2SO4 (3 mL).
This was heated until the solid dissolved (ca. 20 min). The solution was cooled to room
temperature and formed a white solid that was filtered and washed repeatedly with acet-
one and diethyl ether. This was collected and dried in vacuo to give the amino carbox-
ylic acid 4 (2.02 g) as a white solid in 57% yield: mp 230–231 ꢂC; 1H-NMR
((CD3)2SO) d 11.0 (s, 1H), 10.98 (s, 1H), 7.41–7.43 (d, 1H, J ¼ 7.7 Hz), 7.32–7.35 (d,
1H, J ¼ 8.1 Hz), 7.05–7.10 (td, 1H, J0 ¼ 1.5 Hz, J00 ¼ 7.0 Hz), 6.96–7.00 (td, 1H,
J0 ¼ 1.5 Hz, J00 ¼ 7.0 Hz), 4.52 (bs, 2H), 3.59–3.65 (dd, 1H, J0 ¼ 4.6 Hz, J00 ¼ 11.9 Hz),
3.43–3.47 (t, 2H, J ¼ 5.9 Hz), 3.10–3.16 (dd, 1H, J0 ¼ 4.2 Hz, J00 ¼ 15.9 Hz), 2.73–2.82
(t, 1H, J ¼ 12.8 Hz), 2.13–2.16 (m, 1H), 1.86–1.92 (m, 1H), 1.45–1.58 (m, 5H);
13C-NMR ((CD3)2SO) d 170.7, 136.4, 132.2, 126.2, 121.2, 118.8, 117.9, 111.2, 106.9,
60.5, 57.4, 52.9, 32.5, 31.7, 23.4, 21.1. A 300 g scale gave 4 in 58% yield. This product
was carried on directly in the next step.
1-(4-Hydroxybutyl)-b-carboline (5)
To a stirred solution of amino carboxylic acid 4 (5.02 g, 17.4 mmol, 1 eq.) and glacial
acetic acid (18 mL) in hot water (570 mL) was added dropwise a solution of potassium
dichromate (3.57 g, 12.1 mmol, 0.7 eq.) in water (15 mL). The solution became green

( )-1,2,3,4,6,7,12,12b-Octahydroindolo[2,3-a]quinolizine
451
Scheme 1
immediately and was stirred for 20 min. After cooling, the solution was basified with
2M Na2CO3 and the green solid that formed was collected. Methanol was added, which
partially dissolved the solid. The methanol mixture was filtered and the filtrate was con-
centrated in vacuo to give carboline 5 as a light yellow solid (3.5 g) in 84% yield: mp
1
177–178 ꢂC (lit.3 mp 165–169 ꢂC); H-NMR (CD3OD) d 8.15–8.17 (d, 1H, J ¼ 5.1 Hz),
8.10–8.13 (d, 1H, J ¼ 8.1 Hz), 7.88–7.90 (d, 1H, J ¼ 5.5 Hz), 7.49–7.58 (m, 2H),
7.19–7.24 (app. t, 1H), 3.55–3.67 (t, 2H, J ¼ 6.6 Hz), 3.59–3.65 (dd, 1H, J0 ¼ 4.6 Hz,
J00 ¼ 11.9 Hz), 3.43–3.47 (t, 2H, J ¼ 5.9 Hz), 3.28–3.29 (t, 1H, J ¼ 1.5 Hz), 3.12–3.17 (t,
2H, J ¼ 7.7 Hz), 1.84–1.94 (m, 2H), 1.61–1.70 (m, 2H). Leaching the solids with metha-
nol effectively removed the inorganic salts. A 245 g scale gave 5 in 81% yield. This
product was carried on directly in the next step.
1,2,3,4-Tetrahydro-12H-indolo[2,3-a]quinolizine (7)
To the carboline 5 (2.32 g, 9.65 mmol, 1 eq.) was added 48% aqueous hydrogen brom-
ide (48 mL) and refluxed for 10 min with efficient stirring. The dark brown solution
was cooled to room temperature while maintaining efficient stirring and to this was
slowly added excess 50% sodium hydroxide solution until strongly basic. Efficient stir-
ring is necessary during the cooling and basification steps to avoid formation of dark
polymeric material that will affect the yield of 1. The solution became yellow-green
and the yellow and brown solids (7) were collected and directly reduced in the next
step without further purification. The intermediate bromide salt from 7 after acidifica-
tion with 48% HBr could be crystallized from methanol-ether, mp 280–285 ꢂC (lit.3 mp
280 ꢂC dec.).
1,2,3,4,6,7,12,12b-Octahydroindolo[2,3-a]quinolizine (1)
The yellow and brown crude 7 was dissolved in 50% aqueous ethanol (20 mL) and to
this was added sodium borohydride (NaBH4) (1.3 g, 34.4 mmol, 3.6 eq.). The reaction
mixture was warmed on the steam bath for 5 min and then stirred at room temperature
overnight. The solvent was removed in vacuo and to the straw colored residue was
added water (50 mL) and stirred for 5 min. The aqueous solution was extracted with
CH2Cl2 (3 ꢀ 50 mL) and the organic extracts were collected and washed with brine,
dried and concentrated in vacuo. Column chromatography (90:10 ethyl acetate; triethyl-
amine) gave 1 (1.3 g) as a yellow solid in 60% yield: mp 151–152 ꢂC (lit.4 mp
152–153 ꢂC); crystallization from benzene-petroleum ether (30–60ꢂ) gave tiny colorless
crystals, mp 153–154 ꢂC, identical to 1 prepared by us earlier;20 1H NMR (CDCl3)
d 7.73 (s, 1H), 7.47–7.50 (dd, 1H, J0 ¼ 1.8 Hz, J00 ¼ 7.0 Hz), 7.30–7.33 (dd, 1H,
J0 ¼ 1.5 Hz, J00 ¼ 7.0 Hz), 7.07–7.17 (m, 2H), 3.23–3.27 (d, 1H, J ¼ 11 Hz), 2.97–3.12

452
Badenock and Gribble
Scheme 2
(m, 3H), 2.60–2.77 (m, 2H), 2.36–2.45 (td, 1H, J0 ¼ 4.0 Hz, J00 ¼ 11 Hz), 2.05–2.10 (m,
1H), 1.89–1.94 (m, 1H), 1.43–1.82 (m, 4H); C NMR (CDCl3) d 136.6, 135.8, 128.1,
121.9, 120.0, 118.7, 111.3, 108.8, 60.9, 56.4, 54.2, 30.6, 26.4, 25.0, 22.2. A 70 g scale
of 5 gave 1 in 65% yield, and a 7.5 g scale of 5 gave 1 in 88% yield.
References
1. J. Keufer, Ann. Pharm. Fran., 8, 816 (1950).
2. W. A. Reckhow and D. S. Tarbell, J. Am. Chem. Soc., 74, 4960 (1952).
3. L. H. Groves and G. A. Swan, J. Chem. Soc., 650 (1952).
4. E. Wenkert and B. Wickberg, J. Am. Chem. Soc., 84, 4914 (1962).
5. J. Gootjes and W. Th. Nauta, Rec. Trav. Chim. Pays-Bas, 84, 1427 (1965).
6. E. Ochiai and M. Takahashi, Chem. Pharm. Bull., 13, 618 (1965).
7. S. Yamada and T. Kunieda, Chem. Pharm. Bull., 15, 499 (1967).
8. S. R. Johns, J. A. Lamberton, and J. L. Occolowitz, Chem. Commun., 421 (1966).
9. S. R. Johns, J. A. Lamberton, and J. L. Occolowitz, Aust. J. Chem., 19, 1951 (1966).
10. H. Akimoto, K. Okamura, M. Yui, T. Shioiri, M. Kuramoto, Y. Kikugawa, and S. Yamada,
Chem. Pharm. Bull., 22, 2614 (1974).
11. M. F. Loewe and A. I. Meyers, Tetrahedron Lett., 26, 3291 (1985).
12. D. H. Hua, S. N. Bharathi, J. A. K. Panangadan, and A. Tsujimoto, J. Org. Chem., 56, 6998
(1991).

( )-1,2,3,4,6,7,12,12b-Octahydroindolo[2,3-a]quinolizine
453
13. T. Itoh, M. Miyazaki, K. Nagata, S. Nakamura, and A. Ohsawa, Heterocycles, 63, 655
(2004).
14. S. M. Allin, C. I. Thomas, J. E. Allard, K. Doyle, and M. R. J. Elsegood, Tetrahedron Lett.,
45, 7103 (2004).
15. S. M. Allin, C. I. Thomas, J. E. Allard, K. Doyle, and M. R. J. Elsegood, Eur. J. Org.
Chem., 4179 (2005).
16. J. Szawkało, S. J. Czarnocki, A. Zawadzka, K. Wojtasiewicz, A. Leniewski, J. K. Maurin, Z.
Czarnocki, and J. Drabowicz, Tetrahedron: Asymmetry, 18, 406 (2007).
17. L. S. Santos, C. Theoduloz, R. A. Pilli, and J. Rodriguez, Eur. J. Med. Chem., 44, 3810
(2009).
18. L. Evanno, J. Ormala, and P. M. Pihko, Chem. Eur. J., 15, 12963 (2009).
19. P. Mondal and N. P. Argade, J. Org. Chem., 78, 6802 (2013).
20. G. W. Gribble, J. Org. Chem., 37, 1833 (1972).
21. T. Fujii, S. Yoshifuji, and H. Ito, Heterocyles, 7, 149 (1977).
22. S. B. Mandal, V. S. Giri, M. S. Sabeena, and S. C. Pakrashi, J. Org. Chem., 53, 4236
(1988).
23. E. Cheng, J. Bozem, M. J. Wanner, B. E. A. Burm, and G.-J. Koomen, Tetrahedron, 52,
6725 (1996).
ꢀ
24. K. Diker, K. El Biach, M. D. de Maindreville, and J. Levy, J. Nat. Prod., 60, 791 (1997).
25. M.-Y. Chang, S.-T. Chen, and N.-C. Chang, Heterocycles, 60, 99 (2003).
26. Y. Zhang, R. P. Hsung, X. Zhang, J. Huang, B. W. Slafer, and A. Davis, Org. Lett., 7, 1047
(2005).
27. F. D. King, J. Heterocyclic Chem., 44, 1459 (2007).
28. I. Dion, J.-F. Vincent-Rocan, L. Zhang, P. H. Cebrowski, M.-E. Lebrun, J. Y. Pfeiffer, A.-C.
ꢀ
Bedard, and A. M. Beauchemin, J. Org. Chem., 78, 12735 (2013).
29. M. Chbani, M. Païs, J.-M. Delauneux, and C. Debitus, J. Nat. Prod., 56, 99 (1993).