Tetrahedron Letters 52 (2011) 4014–4016

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Tetrahedron Letters

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Facile two-step synthesis of crispine A and harmicine by cyclopropyliminerearrangement

Sanjay Saha a,b, Ch. Venkata Ramana Reddy b, Balaram Patro a,⇑a GVK Biosciences Private Limited, Medicinal Chemistry Division, 28A, IDA Nacharam, Hyderabad 500076, Indiab Department of Chemistry, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500085, India

a r t i c l e i n f o a b s t r a c t

Article history:Received 30 March 2011Revised 23 May 2011Accepted 25 May 2011Available online 2 June 2011

This Letter is dedicated to ProfessorH. Junjappa on the occasion of his 75thbirthday

0040-4039/$ - see front matter � 2011 Elsevier Ltd. Adoi:10.1016/j.tetlet.2011.05.117

⇑ Corresponding author. Tel.: +91 40 66281666; faxE-mail address: balaram.patro@gvkbio.com (B. Pat

The synthesis of 4 and 8 is reported. These intermediates are obtained by a one-pot tandem cyclization of1 and 6, respectively, via Bischler Napieralski reaction followed by cyclopropylimine rearrangement.Compounds 4 and 8 were reduced by sodium borohydride in methanol to afford cytotoxic alkaloid (±)-crispine A and antileishmania compound (±)-harmicine.

� 2011 Elsevier Ltd. All rights reserved.

N O

MeOOMe

N

N

N N

OMeMeO

The thermal rearrangement of cyclopropyl ketimine hydrochlo-rides to 2-pyrrolines was observed about 80 years ago by J. B.Cloke.1 Four decades later this phenomenon caught the attentionof Stevens who further developed it as a general methodologyand applied it toward the synthesis of a variety of alkaloids.2 He fur-ther proved that this rearrangement was not purely thermal andwas facile only in presence of an acid catalyst. Many researchgroups have since then published their findings on the applicationof this rearrangement toward synthesis of pyrrolidine-containingalkaloids or simple heterocycles.3–5 Recently, Tomilov et al. have re-ported the rearrangement of hydrohalogenides of cyclopropylsubstituted thiazoles, benzimidazoles, and benzoxazoles and thusexpanded the scope of this reaction beyond acyclic derivativesof cyclopropylimines.5 Figure 1 shows examples of somecompounds synthesized by application of the cyclopropyliminerearrangement.2

Our investigations on the rearrangement of cyclopropyl carbi-nols and bis(methylthio)methylene arylcyclopropyl ketones havealso revealed that the cyclopropane ring when suitably substitutedundergoes acid-catalyzed ring-opening and rearrangement leadingto tandem cyclization.6 This prompted us to further investigate thepotential of compounds containing cyclopropane rings and devel-op a methodology which would facilitate the synthesis of bioactivenatural products. Hence, we envisaged the synthesis of crispine Aand harmicine by using a cyclopropylimine rearrangement.Crispine A (Fig. 2) was isolated along with four other isoquinolinealkaloids crispine B–E from Cardus crispus by Zhao and co-work-ers.7 Crispine A is an isoquinoline alkaloid having cytotoxic activityagainst SKOV3, KB and HeLa human cancer cell lines.7 Similarly,

ll rights reserved.

: +91 40 66281505.ro).

harmicine, isolated from the leaf of the Malaysian plant Kopsiagriffithii exhibits strong antileishmania activity.10a

Since their isolation, a number of research groups have publishedthe synthesis of crispine A and harmicine in racemic or enantiome-rically pure form.8–10 Some recent examples include: the synthesisof crispine A by Gallos and co-workers,8g via a nitrosoalkene heteroDiels–Alder addition to ethyl vinyl ether, the synthesis by Chiouet al.,8f using a Rh-catalyzed cyclohydrocarbonylation as the keystep and the synthesis by Knölker and Agarwal,8b by silver(I)-pro-moted oxidative cyclization as the key step. Apart from these, otherresearch groups have employed N-chloramine rearrangement,8a

1,4-addition of alpha-amino nitrile to a,b-unsaturated carbonylcompounds,8c N-acyliminium ion cyclization,8d and intramolecularSchmidt reaction8e as the key steps. Many approaches to the synthe-sis of racemic, (R), and (S)-harmicine have also been developed.10

These include: the synthesis by Jacobsen and co-workers, usingsubstituted thiourea catalyzed enatioselective Pictet–Spenglarcyclizations of tryptamine derived hydroxylactams,10f the synthesisby Ohsawa and co-workers, using chiral 1-allyl-1,2,3,4-tetrahydro-b-carboline as key intermediates,10b,e and the synthesis by Allinet al.,10g using diastereoselective N-acyliminium cyclizationreaction as the key synthetic step.

H+) mesembrine_( nicotine OHipalbidine OMe

OMesepticine

Figure 1. Examples of pyrrolidine-containing natural products.

MeO

MeON

crispine A (5)

Cl

crispine B (5A)

MeO

MeON

NH

N

harmicine (9)

Figure 2. Alkaloids from C. crispus and Kopsia griffithii.

Table 1Conditions for conversion of 2 to 4

Entry Conditions Result/yield of 4 (%)

1 NH4Cl (cat.), toluene/xylene, reflux,48 h

Negligible

2 NH4Cl (cat.), ethanol, reflux, 24 h Proportional toequivalentsof NH4Cl used in reaction

3 NH4Cl (2.8 equiv), ethanol, reflux, 24 h 82%4 HCl (aq) or HBr (aq) (2 equiv), 24 h Quantitative

10

N

MeO

MeO

11

N

MeO

MeO

N

MeO

MeO

Cl

MeO

MeO

NHO

MeO

MeO

NHO

12

13

14

X

X

POCl3

Solvent,reflux

POCl3Solvent,reflux

Scheme 2. Synthesis of hexahydropyrido[2,1-a] isoquinolinium ring system.

NHO

NH

NH

N

NH

N

NH

N

6

7

8 9POCl3/toluenereflux, 12 h NH4Cl, ethanol

reflux, 20 h

NaBH4,MeOHPOCl3/CH3CN

120 °C, 24 h

Cl

45%

70% 90%

85%

Scheme 3. Synthesis of harmicine.

S. Saha et al. / Tetrahedron Letters 52 (2011) 4014–4016 4015

We report herein a very short and efficient synthesis of crispineA and harmicine using tandem cyclization via a Bischler Napieral-ski reaction followed by a cyclopropylimine rearrangement as thekey step. We started our synthesis of crispine A (Scheme 1) byreacting 112 with phosphoryl chloride in refluxing toluene for 4 hwhich afforded 2 in 74% yield. In order to find the optimum condi-tions for rearrangement, compound 2 was subjected to variousreaction conditions shown in Table 1.

It was, however, surprising to find that under these conditions,3 was not formed as expected. The formation of 2-pyrrolines fromcyclopropyl imines is well documented when the latter are treatedwith ammonium halides in a suitable solvent.2 Under similar con-ditions we have observed formation of 4, which is supported by 1H,13C NMR, DEPT and mass spectrum.14

When 1 was treated with excess POCl3 in toluene under refluxfor 48 h, compound 4 was isolated in 30% yield along with 2(40%). For further optimization of this reaction, we heated a solu-tion of 1 in acetonitrile with 5.4 equiv of phosphoryl chloride at120 �C for 24 h. It was indeed gratifying to find that intermediate2 had completely rearranged to 4 which was the only isolableproduct from the aqueous portion after basic work-up. Purificationby column chromatography over silica gel yielded 4 in 75% yield.Xylene as a solvent for the above reaction further improved theyield of compound 4 to 85% in just 5 h. Reduction of 4 with sodiumborohydride in methanol followed by basic work-up afforded race-mic crispine A (5) in almost quantitative yield.15 1H, 13C NMR, DEPTand mass spectral data of 5 are in agreement with the data re-ported in the literature.8b

To further explore the generality of our methodology, reactionof 10 and 11 with phosphoryl chloride was explored in toluene, xy-lene, and acetonitrile under reflux conditions whereby 12 and 13were formed, respectively (Scheme 2). Acid-catalyzed rearrange-ments of cyclobutylimine 12 and cyclopropylmethylimine 13 werealso examined.11 However, both substrates remained unreactedunder conditions (entries 1–4) mentioned in Table 1.

We have extended the same strategy for the synthesis of harm-icine,10 which was synthesized from tryptamine derivative 6 usinga cyclopropylimine rearrangement reaction as the key step(Scheme 3).

We initiated the synthesis by reacting 613 with 5.4 equiv ofphosphoryl chloride in toluene under reflux for 4 h whereby 7was isolated in 45% yield. When the reaction of 6 with POCl3

in toluene was prolonged for 24 h, 8 was formed in modest30% yield.16 Similar to the synthesis of crispine A, the abovereaction was also carried out at 120 �C in acetonitrile for 24 h

NH

MeO

MeO O1

2

MeO

MeO

N

3

POCl3/toluenereflux, 8 h

N

MeO

MeO

MeO

MeO

X

POCl3, CH3CN,120 °C

NH4Cl, ethanreflux, 24 h

74%

75%

82%

Scheme 1. Synthesi

which improved the yield of 8 to 70%. Compound 7 was alsofound to undergo facile cyclopropylimine rearrangement ontreatment with 2.8 equiv of ammonium chloride in refluxing eth-anol for 24 h, resulting in clean conversion to 8. Reduction of 8with sodium borohydride in methanol at 0 �C afforded racemicharmicine (9) in almost quantitative yield.17 1H, 13C NMR, DEPTand mass spectral data of 9 are in agreement with the data re-ported in literature.10d

In conclusion, we have prepared crispine A and harmicine bytwo-step synthesis from readily obtainable starting materials 1and 6 by tandem cyclization, followed by reduction with sodiumborohydride. Enantiopure forms of crispine A and harmicine couldbe synthesized from 4 and 8, respectively, by Ru(II)9a or Ir(III)9c cat-alyzed asymmetric hydrogenation.

ClN

4

N

MeO

MeO5

NaBH4,MeOH

ol

90%

s of crispine A.

4016 S. Saha et al. / Tetrahedron Letters 52 (2011) 4014–4016

Further investigations are going on in our laboratory on applica-tion of this methodology for preparation of pyrrolidine-containingnatural products and on expansion of the scope of the key step ofour synthesis.

Acknowledgments

We sincerely thank the GVK Biosciences Private Limited forfinancial support and encouragement. Support from the analyticaldepartment is also acknowledged.

Supplementary data

Supplementary data (1H and 13C NMR scans of compounds 4, 5and 9) associated with this article can be found, in the online ver-sion, at doi:10.1016/j.tetlet.2011.05.117.

References and notes

1. Cloke, J. B. J. Am. Chem. Soc. 1929, 51, 1174–1187.2. Stevens, R. V. Acc. Chem. Res. 1977, 106, 193–198. and references cited therein.3. (a) Wasserman, H. H.; Dion, R. P. Tetrahedron Lett. 1983, 24, 3409–3412; (b)

Heidt, P. J.; Bergmeier, S. C.; Pearson, W. H. Tetrahedron Lett. 1990, 31, 5441–5444. and references cited therein.

4. For review on cyclopropylimine rearrangement, see: Boeckman, R. K., Jr.;Walters, M. A. In Advances in Heterocyclic Natural Product Synthesis; Pearson, W.H., Ed.; JAI Press: Greeenwich, 1990; Vol. 1, pp 1–40.

5. Tomilov, Y. V.; Platonov, D. N.; Frumkin, A. E.; Dmitry, L.; Lipilin, D. L.; Salikov,L. F. Tetrahedron Lett. 2010, 51, 5120–5123. and references cited therein.

6. (a) Patro, B.; Ila, H.; Junjappa, H. Tetrahedron Lett. 1992, 33, 809–812; (b) Patra,P. K.; Patro, B.; Ila, H.; Junjappa, H. Tetrahedron Lett. 1993, 34, 3951–3954. andreferences cited therein.

7. Zhang, Q.; Tu, G.; Zhao, Y.; Cheng, T. Tetrahedron 2002, 58, 6795–6798.8. For synthesis of (±)-Crispine A, see: (a) Schell, F. M.; Smith, A. M. Tetrahedron

Lett. 1983, 24, 1883–1884; (b) Knölker, H.-J.; Agarwal, S. Tetrahedron Lett. 2005,46, 1173–1175; (c) Meyer, N.; Opatz, T. Eur. J. Org. Chem. 2006, 17, 3997–4002;(d) King, F. D. Tetrahedron 2007, 63, 2053–2056; (e) Kapat, A.; Senthil Kumar, P.Beilstein J. Org. Chem. 2007, 3, 49. doi:10.1186/1860-5397-3-49; (f) Chiou, W.H.; Lin, G. H.; Hsu, C. C.; Chaterpaul, S. J. Org. Lett. 2009, 11, 2659–2662; (g)Yioti, E. G.; Mati, I. K.; Arvanitidis, A. G.; Massen, Z. S.; Alexandraki, E. S.; Gallos,J. K. Synthesis 2011, 1, 142–146.

9. For enantioselective synthesis of Crispine A, see: (a) Szawkalo, J.; Zawadzka, A.;Wojtasiewicz, K.; Leniewski, A.; Drabowicz, J.; Czarnocki, Z. Tetrahedron:Asymmetry 2007, 18, 406–413; (b) Allin, S. M.; Gaskell, S. N.; Towler, J. M. R.;Page, P. C. B.; Saha, B.; McKenzie, M. J.; Martin, W. P. J. Org. Chem. 2007, 72,8972–8975; (c) Hou, G.; Xie, J.; Yan, P.; Zhou, Q. J. Am. Chem. Soc. 2009, 131,1366–1367; (d) Miyazaki, M.; Ando, N.; Sugai, K.; Seito, Y.; Fukuoka, H.;Kanemitsu, T.; Nagata, K.; Odanaka, Y.; Nakamura, K. T.; Itoh, T. J. Org. Chem.2011, 76, 534–542; (e) Gurram, M.; Gyimóthy, B.; Wang, R.; Lam, S. Q.; Ahmed,F.; Herr, R. J. Org. Chem. 2011, 76, 1605–1613; (f) Amat, M.; Elias, V.; Llor, N.;Subrizi, F.; Molins, E.; Bosch, J. Eur. J. Org. Chem. 2010, 4017–4026.

10. For isolation and anti-leishmania activity of harmicine, see: (a) Kam, T.-S.; Sim,K.-M. Phytochemistry 1998, 47, 145–147; For synthesis, see: (b) Itoh, T.;Miyazaki, M.; Nagata, K.; Yokoya, M.; Nakamura, S.; Ohsawa, A. Heterocycles

2002, 58, 115–118; (c) Allin, S. M.; Thomas, C. I.; Allard, J. E.; Duncton, M.;Elsegood, M. R. J.; Edgar, M. Tetrahedron Lett. 2003, 44, 2335–2337; (d) Knölker,H.-J.; Agarwal, S. Synlett 2004, 1767–1768; (e) Itoh, T.; Miyazaki, M.; Nagata, K.;Nakamura, S.; Ohsawa Heterocycles 2004, 63, 655–661; (f) Raheem, I. T.; Thiara,P. S.; Peterson, E. A.; Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404–13405;(g) Allin, S. M.; Gaskell, S. N.; Elsegood, M. R. J.; Martin, W. P. Tetrahedron Lett.2007, 48, 5669–5671.

11. Stevens, R. V.; Sheu, J. T. J. Chem. Soc., Chem. Commun. 1975, 682.12. Seo, J. W.; Srisook, E.; Son, H. J.; Hwang, O. Eur. J. Med. Chem. 2008, 43, 1160–

1170.13. Yamada, K.; Tanaka, Y.; Somei, M. Heterocycles 2009, 79, 635–645.14. Experimental and spectral data of compound 4: To a solution of compound 1

(100 mg, 0.401 mmol) in acetonitrile (4 mL), phosphorous oxychloride (0.2 mL,2.14 mmol) was added and the reaction mixture was heated in a screw cap vialat 120 �C for 24 h. Reaction mixture was cooled to room temperature andconcentrated under reduced pressure. It was basified with 5% sodiumbicarbonate solution (5 mL) and washed with ethyl acetate. The aqueoussolution was diluted with methanol (20 mL) and the precipitated inorganicsalts were filtered. The filtrate was concentrated and the obtained residue waspurified by column chromatography over silica-gel (230–400 mesh) elutingwith 5–20% MeOH–DCM to afford 4 (80 mg, 75%) as a greenish white solid; mp121–124 �C; 1H NMR (400 MHz, DMSO-d6): d 2.24 (qn, 2H), 3.14 (t, 2H,J = 8.4 Hz), 3.25 (t, 2H, J = 8 Hz), 3.85 (s, 3H), 3.92 (s, 3H), 3.90–3.94 (m, 2H),4.18 (t, 2H, J = 8 Hz), 7.20 (s, 1H), 7.40 (s, 1H). 13C NMR (100 MHz, CDCl3): d18.66, 24.95, 33.31, 44.55, 56.29, 56.36, 58.83, 111.38, 113.01, 115.36, 132.28,132.28, 147.87, 155.70, 176.16. ESI-MS (m/z): 232.3 which corresponds toM+[C14H18NO2

+].15. (±)-Crispine A (5): A solution of compound 4 (100 mg, 0.37 mmol) in methanol

(5 mL) was cooled to 0 �C and sodium borohydride (14 mg, 0.37 mmol) wasadded portion wise to it. The reaction mixture was stirred for 1 h after which itwas concentrated to dryness. The residue was dissolved in ethyl acetate(15 mL) and treated with 5% potassium hydroxide solution (5 mL). Organiclayer was separated, dried over anhydrous sodium sulfate and concentrated todryness to yield 80 mg (90%) colorless crystalline solid; mp 89–91 �C (lit.8f 88–89 �C); IR(KBr): 2929, 2790, 1608, 1517, 1510, 1472, 1456, 1373, 1259, 1015,815 cm�1. 1H NMR (400 MHz, CDCl3): d 1.58–1.77 (m, 1H), 1.82–1.97 (m, 2H),2.28–2.36 (m, 1H), 2.52 (q, J = 8.4 Hz, 1H), 2.60 (dt, J = 4.4, 10.4 Hz, 1H), 2.67–2.74 (br dt, J = 16.4, 3.5 Hz, 1H), 2.98–3.10 (m, 2H), 3.17–3.20 (m, 1H), 3.38–3.42 (br t, J = 8.0 Hz, 1H), 3.85 (s, 6H), 6.57 (s, 1H), 6.61 (s, 1H). 13C NMR(100 MHz, CDCl3): d 22.20, 28.05, 30.45, 48.38, 53.12, 55.87, 55.98, 62.94,108.87, 111.35, 126.24, 131.02, 147.19, 147.31. ESI-MS (m/z): 234.3 (100)[M+1]+, 235.3 (30) [M+2]+, HRMS (m/z): calcd for C14H19NO2 [M]+: 233.1416;found: 234.1496 which corresponds to C14H20NO2 [M+H]+.

16. Compound 8: pale yellow solid; 1H NMR (400 MHz, DMSO-d6): d 2.28–2.32 (m,2H), 3.32–3.36 (m, 2H), 3.42–3.45 (m, 2H), 4.00–4.14 (m, 4H), 7.20 (t, 1H,J = 8 Hz), 7.45 (m, 1H, J = 7.6 Hz), 7.55 (d, 1H, J = 8.8 Hz), 7.77 (d, 1H, J = 8.4 Hz),12.44 (br s, 1H). 13C NMR (100 MHz, CD3OD): d 20.62, 30.08, 30.73, 47.35,58.90, 114.22, 122.61, 122.90, 124.33, 125.74, 129.86, 140.13, 142.98, 170.60.ESI-MS (m/z): 211.3 which corresponds to M+[C14H15N2

+].17. (±)-Harmicine (9): pale yellow crystalline solid; mp 171–174 �C (lit.8f 174–

175 �C); IR (KBr): 2924, 2853, 1634, 1452, 1064, 1033, 802, 736 cm�1. 1H NMR(400 MHz, CDCl3): d 1.81–1.87 (m, 1H), 1.88–1.96 (m, 2H), 2.35–2.39 (m, 1H),2.71–2.79 (m, 1H), 2.94–2.98 (m, 3H), 3.12–3.20 (m, 1H), 3.35–3.40 (m, 1H),4.43 (br s, 1H), 7.08–7.18 (m, 2H), 7.36 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 7.8 Hz,1H), 8.22 (br s, 1H). 13C NMR (100 MHz, CDCl3): d 17.47, 23.25, 29.68, 45.67,49.05, 56.88, 107.48, 110.82, 118.10, 119.47, 121.61, 127.10, 134.30, 136.10;HRMS (m/z): calcd for C14H16N2[M]+: 212.1313; found: 213.1387 whichcorresponds to C14H17N2[M+H]+.