An efficient stereoselective total synthesis of (±)-trans-dihydronarciclasine

Article abstract of DOI:10.1016/j.tetlet.2016.02.089

A short and efficient stereoselective total synthesis of (±)-trans-dihydronarciclasine (1), a highly potent naturally occurring antineoplastic agent, was developed from readily available vanillin (7). The key intermediate of this new synthesis was a butenone derivative (11), from which the target molecule could be obtained in 14, mostly stereoselective, reaction steps. Our total synthesis has provided an easy and, up to now, the least expensive access to the title alkaloid.

Full text of DOI:10.1016/j.tetlet.2016.02.089

Reference:
TETL 47364
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 December 2015
16 February 2016
23 February 2016
Please cite this article as: Varró, G., Hegedűs, L., Simon, A., Kádas, I., An efficient stereoselective total synthesis
of ( )-trans-dihydronarciclasine, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.02.089
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

An efficient stereoselective total synthesis of (±)-trans-dihydronarciclasine
Gábor Varróa, László Hegedűsb, András Simonc, István Kádasa, *
a Department of Organic Chemistry and Technology, Budapest University of Technology and Economics,
Budafoki út 8, H-1111 Budapest, Hungary
b MTA-BME Organic Chemical Technology Research Group, Hungarian Academy of Sciences, Department of
Organic Chemistry and Technology, Budapest University of Technology and Economics, Budafoki út 8, H-1111
Budapest, Hungary
c Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, Szt.
Gellért tér 4, H-1111 Budapest, Hungary
Abstract
A short and efficient stereoselective total synthesis of (±)-trans-dihydronarciclasine
(1), a highly potent naturally occuring antineoplastic agent, was developed from readily
available vanillin (7). The key intermediate of this new synthesis was a butenone derivative
(11), from which the target molecule could be obtained in 14, mostly stereoselective, reaction
steps. Our total synthesis has provided an easy and, up to now, the least expensive access to
the title alkaloid.
Keywords: Alkaloids; (±)-trans-Dihydronarciclasine; Stereoselective synthesis
Graphical Abstract
*Corresponding author. Tel.: +36 1 463 3695, fax: +36 1 463 3648; e-mail: ikadas@mail.bme.hu.
1

trans-Dihydronarciclasine (1) was first isolated from the bulbs of the white rain lily
(Zephyranthes candida),1 a tropical medicinal plant, and is the most potent antitumor
phenanthridone alkaloid according to data obtained from the National Cancer Institute
(USA).2 Dihydronarciclasine can be obtained by the catalytic hydrogenation of narciclasine
(4),3 but the inactive and unfavourable cis-isomer (2) could also be formed in considerable
amounts (Figure 1). Although extraction of the starting material from Narcissus species has
been realized,4 it is very expensive and, moreover, the separation of these diastereomers is
relatively difficult resulting in significant loss of compound 1.
For the total syntheses of the less active members of this alkaloid group, which is a
subgroup of the Amaryllidaceae alkaloid family [e.g. pancratistatin (3), narciclasine (4), 7-
deoxypancratistatin (5), and lycoricidine (6) (Figure 1)], a great number of methods were
reported in the last two decades.5 So far only a few methods for the total synthesis of trans-
dihydronarciclasine have been published6 from expensive starting materials and the final
product was obtained after numerous synthetic steps. Thus, the development of an efficient
synthesis for this alkaloid is still required to enable a thorough biological evaluation.
Figure 1. Structures of trans- (1) and cis-dihydronarciclasine (2), as well as less active members of the
phenanthridone alkaloids (3–6).
Furthermore, compound 1 is not only the strongest antitumor agent amongst the other
highly potent phenanthridone alkaloids, as demonstrated by its nanomolar activity, it is devoid
of inhibition of the human cytochrome P450s. This is a very important biological function,
because this activity potentially causes the toxicity of narciclasine 4 and can probably be
attributed to its double bond.7
2

Previously we described the stereoselective total syntheses of racemic8 and ent-(–)-7-
deoxy-trans-dihydronarciclasine.9 In this work, based on our previous experience, we report a
new synthetic route to compound 1 (Scheme 1) which is significantly easier and less
expensive than previous syntheses.6
The first step, iodination of vanillin to give compound 8 in 99% yield, was carried out
according to literature procedures.10 Iodovanillin 8 was then hydrolysed with sodium
hydroxide in water in the presence of cupric sulfate;11 some dehalogenation was observed in
this step. After recrystallizing the crude product from toluene, pure dihydroxy aldehyde
derivative 9 was obtained. To convert 9 into myristicine aldehyde 10, dioxolane ring closure
was achieved using methylene bromide in dimethyl formamide, in the presence of potassium
carbonate and cupric oxide.12 Due to an improved work-up procedure, aqueous precipitation
of the product instead of its extraction from DMF,12 compound 10 was prepared in 94% yield.
Condensing 10 with acetone to form enone derivative 11, using sodium hydroxide in water,
took place smoothly. Conjugate addition of nitromethane to enone 11 in the presence of
sodium methoxide in methanol gave nitropentanone 12, which was converted into hydroxy
cyclohexanone 13 via a Claisen aldol reaction. This cyclization resulted in formation of one
stereoisomer and was likely promoted by a hydrogen bond which formed during the
cyclization (Figure 2). Similar observations were made by Walker and co-workers13 in the
synthesis of 3-hydroxy-4-nitro-5-arylcyclohexanones. This strong interaction between the
hydroxyl and nitro groups can be demonstrated by the significantly shifted peak of the -OH
1
group in the H NMR spectrum of compound 13. This value was 6.02 ppm, while in case of
the other intermediates (14 and 15) it was 4.09 ppm.
Figure 2. Presumed structure of hydroxy cyclohexanone derivative (13) and its stabilization by hydrogen bonds.
Protection of hydroxy ketone 13 was achieved using ethylene glycol affording
nitroketal 14. The nitro group of 14 was hydrogenated to give amine 15 in quantitative yield
using 10% Pd/C (Selcat Q14) in methanol. Contrary to our previous results,8,9 where 60 C
was sufficient to complete the reduction, this hydrogenation required a higher temperature
3

Scheme 1. Reagents and conditions: a) I2, KI, K2CO3, H2O, rt, 3 h, 99%; b) 20% NaOH/H2O, CuSO4, reflux, 16 h, 64%; c) CH2Br2, K2CO3,
CuO, DMF, 110 °C, 4 h, 94%; d) acetone, NaOH, H2O, rt, 20 h, 67% (after distillation); e) CH3NO2, NaOCH3/CH3OH, reflux, 5.5 h, 54%; f)
HCOOEt, NaOCH3, Et2O, rt, 20 h, 54%; g) (CH2OH)2, (COOH)2, CH3CN, rt, 3 d, 90%; h) H2, 10% Pd/C, MeOH, 80 °C, 7 h, quant.; i)
ClCOOCH3, NaOH/H2O, THF, rt, 2 h, 99%; j) p-TsOH, acetone, reflux, 1 h, 99%; k) NaBH4, CaCl2, CH3OH, 0 °C, 2 h, 96%; l) PhCOOH,
DEAD, PPh3, THF, rt, 4 h, 63%; m) OsO4, H2O, THF, Ar atm., rt, 24 h, quant.; n) AcCl, rt, 24 h, quant.; o) Tf2O, DMAP, CH2Cl2, 0 °C → rt,
22 h, 99%; p) (i) 2M HCl/H2O, THF, rt, 21 h, (ii) AcCl, rt, 21 h, 92%; q) TMS-Cl, KI, CH3CN, 60 °C, 1.5 h, 50%; r) NaOCH3/CH3OH, THF,
rt, 1 h, 99%.
4

(80 C) which was presumably due to the stronger adsorption of compound 15 on palladium
caused by the additional substituent (methoxy group) attached to the aromatic ring.
Aminoketal 15 was selectively converted to urethane 16 in a biphasic (THF/H2O) reaction
with methyl chloroformate, while the hydroxyl group remained untouched. Next, compound
16 was deketalized using stoichiometric p-toluenesulfonic acid in acetone. During this
reaction, however, elimination of water also took place giving enone 17. To convert this into
allylic alcohol 18, Utimoto’s reduction method (NaBH4, CaCl2)15 was used. Compound 18
was obtained stereoselectively in very good yield (96%), due to calcium chloride forming a
chelate complex providing a quasi cis-equatorial position of the formed hydroxyl group. Since
its orientation in the final product is quasi trans-axial, it was deemed necessary to invert the
stereochemistry of this substituent. To fulfil this aim, the Mitsunobu reaction seemed to be the
best procedure.16 Thus, the conversion of 18 under Mitsunobu conditions (DEAD, PPh3, THF)
using benzoic acid afforded benzoate 19 in 63% yield after column chromatography. cis-
Dihydroxylation of compound 19 with OsO4/NMO in THF/water gave the required diol 20 as
the major product. Protection of the hydroxyl groups was achieved using acetyl chloride
giving 21 in quantitative yield.
Formation of the lactam ring was realized by applying the Banwell modification17 of
the Bischler-Napieralski reaction. During this cyclization, an unsaturated lactam intermediate
22 was prepared in 99% yield, which was subsequently converted to the corresponding lactam
23 under acidic conditions in 92% yield. Cleavage of the methoxy group attached to the
aromatic ring in compound 23 was accomplished using trimethylsilyl chloride in the presence
of potassium iodide in acetonitrile to give phenanthridone 24 in moderate yield (50%).
Finally, the acyl protective groups were hydrolysed using a methanolic solution of sodium
methoxide in THF to form the title compound 1 (99%).
In conclusion, (±)-trans-dihydronarciclasine (1), the most potent antitumor
phenanthridone alkaloid, was efficiently prepared from vanillin (7), an inexpensive and
readily available starting material, in 18 steps with 2.8% overall yield using a newly
developed synthetic route.
Supplementary data
All characterisation data for compounds 1 and 11–24 are available in ESI. Supplementary
data associated with this article can be found in the online version at doi:
5

References and notes
1. Pettit, G. R.; Cragg, G. M.; Singh, S. B.; Duke, J. A.; Doubek, D. L. J. Nat. Prod. 1990,
53, 176.
2. (a) Pettit, G. R.; Melody, N. J. Nat. Prod. 2005, 68, 207. b) Pettit, G. R.; Pettit III, G.R.;
Backhaus, R. A.; Boyd, M. R.; Meerow, A. W. J. Nat. Prod. 1993, 56, 1682. c) Paull, K.
D.; Shoemaker, R. H.; Hodes, L.; Monks, A.; Scudiero, D. A.; Rubinstein, L.; Plowman, J.;
Boyd, M. R. J. Nat. Cancer Inst. 1989, 81, 1088.
3. (a) Mondon, A.; Krohn, K. Chem. Ber. 1975, 108, 445. (b) Gabrielsen, B.; Monath, T. P.;
Huggins, J. W.; Kefauver, D. F.; Pettit, G. R.; Groszek, G.; Hollingshead, M.; Kirsi, J. J.;
Shannon, W. M.; Schubert, E. M.; DaRe, J.; Ugarkar, B.; Ussery, M. A.; Phelan, M. J. J.
Nat. Prod. 1992, 55, 1569. (c) Pettit, G. R.; Ducki, S.; Eastham, S. A.; Melody, N. J. Nat.
Prod. 2009, 72, 1279.
4. Dumont, P.; Ingrassia, L.; Rouzeau, S.; Ribaucour, F.; Thomas, S.; Roland, I.; Darro, F.;
Lefranc, F.; Kiss, R. Neoplasia 2007, 9, 766.
5. (a) Rigby, J. H.; Mateo, M. E. J. Am. Chem. Soc. 1997, 119, 12655. (b) Hudlicky, T.;
Rinner, U.; Gonzales, D.; Akgun, H.; Schilling, S.; Siengalewicz, P.; Martinot, T. A.;
Pettit, G. R. J. Org. Chem. 2002, 67, 8726. (c) Keck, G. E.; Wager, T. T.; Rodriquez, J. F.
D. J. Am. Chem. Soc. 1999, 121, 5176. (d) Elango, S.; Yan, T.-H. J. Org. Chem. 2002, 67,
6954. (e) Danishefsky, S.; Lee, J. Y. J. Am. Chem. Soc. 1989, 111, 4829. (f) Tian, X.;
Hudlicky, T.; Königsberger, K. J. Am. Chem. Soc. 1995, 117, 3643 (g) Trost, B. M.;
Pulley, S. R. J. Am. Chem. Soc. 1995, 117, 10143. (h) Doyle, T. J.; Hendrix, M.;
VanDerveer, D.; Javanmard, S.; Haseltine, J. Tetrahedron 1997, 53, 11153. (i) Magnus, P.;
Sebhat, I. K. J. Am. Chem. Soc. 1998, 120, 5341. (j) Li, M .; Wu, A.; Zhou, P. Tetrahedron
Lett. 2006, 47, 3707. (k) Ohta, S.; Kimoto, S. Tetrahedron Lett. 1975, 2279. (l) Paulsen,
H.; Stubbe, M. Tetrahedron Lett. 1982, 23, 3171. (m) Chida, N.; Ohtsuka, M.; Ogawa, S.
Tetrahedron Lett. 1991, 32, 4525. (n) Hudlicky, T.; Olivo, H. F. J. Am. Chem. Soc. 1992,
114, 9694. (o) Martin, S. F.; Tso, H.-H. Heterocycles 1993, 35, 85. (p) Keck, G. E.; Wager,
T. T. J. Org. Chem. 1996, 61, 8366. (q) Keck, G. E.; Wager, T. T.; Rodriquez, J. F. D. J.
Am. Chem. Soc 1999, 121, 5176. (r) Elango, S.; Yan, T.-H. Tetrahedron 2002, 58, 7335.
6. (a) Shin, I.-J.; Choi, E.-S.; Cho, C.-G. Angew. Chem., Int. Ed. 2007, 46, 2303. b) Jana, C.
K.; Studer, A. Chem.;Eur. J. 2008, 14, 6326. c) Hwang, S.; Kim, D.; Kim, S. Chem. Eur. J.
2012, 18, 9977. (d) Yamada, K.; Mogi, Y.; Mohamed, M. A.; Takasu, K.; Tomioka, K.
Org. Lett. 2012, 14, 5868.
7. (a) McNulty, J.; Zepeda-Velazquez, C. Angew. Chem. Inter. Ed. 2014, 53, 8450. (b)
McNulty, J.; Thorat, A.; Vurgun, N.; Nair, J. J.; Makaji, E.; Crankshaw, D. J.;Holloway, A.
C.; Pandey, S. J. Nat. Prod. 2011, 74, 106. (c) McNulty, J.; Nair, J. J.; Singh, M.;
Crankshaw, D. J.; Holloway, A. C.; Bastida, J. Bioorg. Med. Chem. Lett. 2009, 19, 3233.
8. Szántó, G.; Hegedűs, L., Mattyasovszky, L.; Simon, A.; Simon, Á.; Kádas I. Tetrahedron
Lett. 2009, 50, 2857.
9. Szántó, G.; Hegedűs, L., Mattyasovszky, L.; Simon, A.; Simon, Á.; Bitter. I.; Tóth G.;
Tőke, L.; Kádas I. Tetrahedron 2009, 65, 8412.
10. Smith, P. J. Chem. Soc. 1958, 3740.
11. Altemöller, M.; Gehring, T.; Cudaj, J.; Podlech, J.; Goessmann, H.; Feldmann, C.;
Rothenberger, A. Eur. J. Org. Chem. 2009, 2130.
12. Pettit, G. R.; Thornhill, A.; Melody, N.; Knight, J. C. J. Nat. Prod. 2009, 72, 380.
13. Walker, G. N. J. Org. Chem. 1965, 30, 1416.
14. Máthé, T.; Tungler, A.; Petró, J. U.S. Patent 4,361,500, 1982.
15. Fuji, H.; Oshima, K.; Utimoto, K. Chem. Lett. 1991, 303.
16. Shull, B. K.; Sakai, T.; Nichols, J. B.; Koreeda, M. J. Org. Chem. 1997, 62, 8294.
6

17. Banwell, M. G.; Bissett, B. D.; Busato, S.; Cowden, C. J.; Hockless, D. C. R.; Holman, J.
W.; Read, R. W.; Wu, A. W. J. Chem. Soc., Chem. Commun. 1995, 255.
7

Graphical Abstract
8

Research Highlights
►A new stereoselective total synthesis of (±)-trans-dihydronarciclasine was developed.
►This synthesis has provided an easy and the least expensive access to the title alkaloid.
►The key intermediate of this new synthesis is an aromatic substituted butenone derivative.
9