Catalytic Asymmetric Synthesis of

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substituted tetrahydroisoquinoline nuclei, there are no general synthetic methods to ... the introduction of an electrophilic carbon unit at C-1 po- sition would be of ...
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Catalytic Asymmetric Synthesis of (R)-(–)-Calycotomine, (S)-(–)-Salsolidine and (S)-(–)-Carnegine Synthesi of(R)-(–)-Calycot mine,(S)-(–)-Salsolidneand(S)-(–)-Carnegine Kanemitsu, Yuki Yamashita, Kazuhiro Nagata, Takashi Itoh* Takuya School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan Fax +81(3)37845982; E-mail: [email protected] Received 15 March 2006

Abstract: A simple and efficient procedure for a synthesis of isoquinoline alkaloids is described. The key step of the synthesis was a hydrocyanation of 6,7-dimethoxy-3,4-dihydroisoqunoline giving the corresponding 1-cyano-1,2,3,4-tetrahydroisoquinoline. The asymmetric Strecker reaction was accomplished in high yield and high enantiomeric excess using Jacobsen’s thiourea-containing catalyst. The 1-cyanoisoquinoline thus obtained was transformed to natural products, (R)-(–)-calycotomine, (S)-(–)-salsolidine and (S)-(–)-carnegine. Key words: isoquinoline alkaloid, asymmetric synthesis, Strecker reaction, Jacobsen’s catalyst, calycotomine

Tetrahydroisoquinoline alkaloids are often selected as synthetic targets due to their various physiological activities and structural properties,1 and some of them are relevant to Parkinson’s and other neurotic diseases.2 Although many of the most interesting isoquinolines have chiral 1substituted tetrahydroisoquinoline nuclei, there are no general synthetic methods to obtain optically active derivatives. The Pictet–Spengler3 and Bischler–Napieralski4 condensation are useful methods for the formation of isoquinoline ring systems, but there are only a few papers that present a synthesis of 1-substituted tetrahydroisoquinoline in a highly enantioselective manner, and these studies adopted chiral auxiliaries for constructing the chiral structures. Only recently, Ukaji and Inomata have succeeded in an enantioselective addition of carbon unit into the C-1 position of 6,7-dimethoxy-3,4-dihydroisoquinoline N-oxide using external chiral auxiliary.5 In addition, there are a few papers that mentioned catalytic asymmetric addition of a carbon unit into the C-1 position. Firstly, Jørgensen et al. reported aluminum–BINOL-complex-catalyzed enantioselective 1,3-dipolar cycloaddition reaction of cyclic nitrones with alkyl vinyl ethers, giving 1,2,3,4-tetrahydroisoquinolines.6 Then, Murahashi et al. revealed the synthetic method of 1,2,3,4-tetrahydro-1-isoquinolineacetic acid derivatives by enantioselective addition reaction of ketene silyl acetals to cyclic nitrones catalyzed by titanium–BINOL complex.7 Recently, Chrzanowska et al. showed a method of catalytic enantioselective addition of organometallic compounds to the C-1 position of 6,7dimethoxy-3,4-dihydroisoquinoline.8 SYNLETT 2006, No. 10, pp 1595–159721.06206 Advanced online publication: 12.06.2006 DOI: 10.1055/s-2006-941586; Art ID: U02806ST © Georg Thieme Verlag Stuttgart · New York

In the synthetic study of isoquinoline alkaloids, we have been interested in synthesis of optically active structure using catalytic process, and found that the enantioselective allylation of 6,7-dimethoxy-3,4-dihydroisoquinoline (1) at C-1 position proceeded smoothly by the Cu(I)-tolBNAP catalyst, and applied the reaction to the total synthesis of (–)-emetine.9 In the process, it was thought that the introduction of an electrophilic carbon unit at C-1 position would be of immense use due to its applicability as a reaction site of nucleophiles. Thus, we studied catalytic addition of a carbon unit at C-1, and Jacobsen’s thioureacontaining catalyst10 was found to be efficient for asymmetric Strecker reaction to the substrate 1. The adduct thus obtained was readily converted to three simple isoquinoline alkaloids. This paper describes these results. MeO

MeO

a N

MeO

N

MeO

CN 1

CF3

b

O

3 MeO

MeO c

NH

MeO HO 4

NH

MeO MeO

O

O

5 Me Me

N O

S N H

N H

N

HO

O O

Jacobsen's catalyst 2

Scheme 1 Reagents and conditions: (a) HCN (1.5 equiv), Jacobsen’s catalyst 2 (0.05 equiv), toluene, –70 °C, 40 h, then TFAA (4.0 equiv), –60 °C, 2 h, 86%, 95% ee; (b) H2SO4–H2O (1:1), r.t., 40 h; (c) H2SO4–MeOH (1:5), reflux, 4 h, 72% (2 steps).

Recently, Jacobsen and co-workers described an asymmetric Strecker reaction catalyzed by thiourea-containing catalyst.10 Since the reaction was supposed to proceed via syn-imines isomerized from corresponding anti-isomers in the reaction mixture, cyclic imine 1 is thought to be a good substrate for the reaction. The substrate 1 was obtained from 2-(3,4-dimethoxyphenyl)ethylamine and hexamethylenetetramine according to a literature procedure.11 The catalyst 2 was synthesized according to Jacobsen’s procedure.10d Hydro-

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cyanation of 6,7-dimethoxy-3,4-dihydroisoquinoline (1) by adding of HCN solution slowly in the presence of 5 mol% of the thiourea-containing catalyst 2 followed by protection by trifluoroacetyl group gave 1-cyano-6,7dimethoxy-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline (3) in high yield (86%) and enantiomeric excess (95% ee).12 Hydrolysis of the cyano group under acidic conditions and subsequent esterification afforded methyl ester 5 (Scheme 1). The compound 5 was protected with Boc group, and the ester group was reduced by lithium aluminum hydride to give an alcohol 7 in high yield. The 1-hydoxymethyl isoquinoline 7 was treated with acidic conditions for deprotection of Boc group to obtain (R)-(–)-calycotomine (8, Scheme 2). The absolute configuration of the product was confirmed as R by comparison of the specific rotation ([a]D21 –37.9) with a reported value.13 MeO

MeO a

NH

MeO MeO 5

N

MeO MeO

O

O

b

O

MeO

MeO N

MeO

a

O O

HO

N

MeO

O O

TsO 9

7

MeO

MeO b

N

MeO

Me

O O

c MeO

NH Me

(S)-(–)-salsolidine (11)

10 MeO d MeO

NMe Me

(S)-(–)-carnegine (12)

Scheme 3 Reagents and conditions: (a) TsCl (1.5 equiv), pyridine, r.t., 10 h, 81%; (b) LiAlH4 (4 equiv), THF, 60 °C, 5 h, 56%; (c) TMSOTf (2 equiv), CH2Cl2, r.t., 30 min, 86%; (d) HCHO aq (5 equiv), NaBH3CN (1.6 equiv), MeCN, r.t., 2 h, 87%.

O

6

MeO

References and Notes

MeO N

MeO

O O

HO 7

c

NH

MeO HO

(R)-(–)-calycotomine (8)

Scheme 2 Reagents and conditions: (a) (Boc)2O (2 equiv), CH2Cl2, r.t., 30 min, 99%; (b) LiAlH4 (1 equiv), THF, r.t., 3 h, 99%; (c) TMSOTf (2 equiv), CH2Cl2, r.t., 30 min, 81%.

In order to synthesize (S)-(–)-salsolidine and (S)-(–)-carnegine, compound 7 was tosylated to give compound 9, which was treated with lithium aluminum hydride to give the precursor of salsolidine. The compound 10 was deprotected in acidic conditions to obtain (S)-(–)-salsolidine (11).14 (S)-(–)-Salsolidine (11) was transformed to (S)(–)-carnegine (12) by N-methylation using formaldehyde and NaBH3CN (Scheme 3).15 In this paper, we have presented an efficient enantioselective synthesis of three isoquinoline alkaloids. The key step of the synthesis of (R)-(–)-calycotomine, (S)-(–)-salsolidine and (S)-(–)-carnegine is construction of an optically active 1-cyano-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline using Jacobsen’s thiourea-containing catalyst. The product was readily transformed to these alkaloids, which were identical with natural compounds in terms of 1H NMR and 13C NMR spectral data.16 In addition, it is thought that the 1-cyano group is an electrophilic site at which various nucleophiles are able to attack, and the products thus obtained are good starting material for other alkaloid syntheses. The application of the addition product 3 to the synthesis of other isoquinoline alkaloids is now in progress in our laboratory.

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© Thieme Stuttgart · New York

(1) (a) Rozwadowska, M. D. Heterocycles 1994, 39, 903. (b) Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev. 2004, 104, 3341. (c) Kaufman, T. S. Tetrahedron: Asymmetry 2004, 15, 1203. (d) Bracca, A. B. J.; Kaufman, T. S. Tetrahedron 2004, 60, 10575. (e) Kaufman, T. S. Synthesis 2005, 339. (2) (a) Thull, U.; Kneubuler, S.; Gaillard, P.; Carrupt, P. A.; Testa, B.; Altomare, C.; Carotti, A.; Jenner, P.; McNaught, K. S. P. Biochem. Pharmacol. 1995, 50, 869. (b) Nagatsu, T. Neurosci. Res. 1997, 29, 99. (c) Yamakawa, T.; Ohta, S. Biochem. Biophys. Res. Commun. 1997, 236, 676. (d) McNaught, K. S.; Carrupt, P. A.; Altomare, C.; Cellamare, S.; Carotti, A.; Testa, B.; Jenner, P.; Marsden, C. D. Biochem. Pharmacol. 1998, 56, 921. (e) Sano, T. J. Synth. Org. Chem. Jpn. 1999, 57, 136. (3) (a) Chan, W. H.; Lee, A. W. M.; Jiang, L. Tetrahedron Lett. 1995, 36, 715. (b) Bravo, P.; Crucianelli, M.; Farina, A.; Meille, S. V.; Volonterio, A.; Zanda, M. Eur. J. Org. Chem. 1998, 435. (c) Gremmen, C.; Wanner, M. J.; Koomen, G.-J. Tetrahedron Lett. 2001, 42, 8885. (4) (a) Polniaszek, R. P.; Kaufman, C. R. J. Am. Chem. Soc. 1989, 111, 4859. (b) Suzuki, H.; Aoyagi, S.; Kibayashi, C. Tetrahedron Lett. 1995, 36, 6709. (c) Ziółkowski, M.; Czarnocki, Z. Tetrahedron Lett. 2000, 41, 1963. (5) (a) Ukaji, Y.; Shimizu, Y.; Kenmoku, Y.; Ahmed, A.; Inomata, K. Chem. Lett. 1997, 59. (b) Ukaji, Y.; Shimizu, Y.; Kenmoku, Y.; Ahmed, A.; Inomata, K. Bull. Chem. Soc. Jpn. 2000, 73, 447. (c) Ukaji, Y.; Inomata, K. Synlett 2003, 1075. (6) Jensen, K. B.; Roberson, M.; Jørgensen, K. N. J. Org. Chem. 2000, 65, 9080. (7) Murahashi, S.-I.; Imada, Y.; Kawakami, T.; Harada, K.; Yonemushi, Y.; Tomita, N. J. Am. Chem. Soc. 2002, 124, 2888. (8) Chrzanowska, M. Tetrahedron: Asymmetry 2002, 13, 2497. (9) Itoh, T.; Miyazaki, M.; Fukuoka, H.; Nagata, K.; Ohsawa, A. Org. Lett. 2006, 8, 1295.

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Synthesis of (R)-(–)-Calycotomine, (S)-(–)-Salsolidine and (S)-(–)-Carnegine

(10) (a) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901. (b) Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2000, 39, 1279. (c) Vachal, P.; Jacobsen, E. N. Org. Lett. 2000, 2, 867. (d) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012. (e) Wenzel, A. G.; Lalonde, M. P.; Jacobsen, E. N. Synlett 2003, 1919. (f) Gröger, H. Chem. Rev. 2003, 103, 2795. (g) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299. (h) Taylor, M. S.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2006, 45, 1520. (11) Ivanov, I.; Venkov, A. Heterocycles 2001, 55, 1569. (12) Synthesis of (R)-(+)-1-Cyano-6,7-dimethoxy-1,2,3,4tetrahydroisoquinoline (3). A 50 mL round-bottom flask equipped with a stir bar was charged with 6,7-dimethoxy-3,4-dihydroisoquinoline (1, 190 mg, 0.994 mmol), the catalyst 2 (28 mg, 0.049 mmol, 0.05 equiv), and toluene (15 mL). The reaction was cooled to –70 °C by means of a constant-temperature bath. In another 30 mL flask equipped with a stir bar, 10 mL of toluene and 200 mL of TMSCN (1.5 mmol, 1.5 equiv) were combined. This solution was cooled to 0 °C and 60 mL of MeOH (1.5 mmol, 1.5 equiv) were added. The solution was allowed to stir for 2 h at 0 °C and then added to the reaction flask by syringe addition over 20 h at –70 °C. The reaction was allowed to stir for 40 h at –70 °C. To the reaction mixture, an excess of TFAA (560 mL, 4.0 mmol, 4 equiv) was added and the mixture was stirred for 2 h at –60 °C. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography with 40% EtOAc in hexanes to afford 3 (269 mg, 86%) as colorless needles, mp 96 °C; [a]D18 +127.1 (c 1.05, CHCl3). HPLC: tR (S) = 16.7 min; tR (R) = 19.5 min [Chiralpak OD (0.46 cm × 25 cm, Daicel Chemical Ind., Ltd.), hexane–i-PrOH, 90:10, 1.0 mL/ min] 95% ee. 1H NMR (CDCl3): d = 6.82 (s, 1 H), 6.67 (s, 1 H), 6.28 (s, 1 H), 4.24–4.20 (m, 1 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.81–3.73 (m, 1 H), 3.07–2.99 (m, 1 H), 2.91–2.87 (m, 1 H). 13C NMR (CDCl3): d = 156.96 (q, J = 37.2 Hz), 149.85, 148.79, 125.18, 118.17, 116.47, 111.33, 109.17, 56.05, 55.92, 44.60, 41.72, 41.69, 27.79. Anal. Calcd for C14H13F3N2O3: C, 53.51; H, 4.17; N, 8.91. Found: C, 53.62; H, 3.96; N, 8.63.

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(13) Analytical Data for (R)-(–)-Calycotomine (8). Colorless solid; mp 138 °C; [a]D21 –37.9 (c 0.13, H2O); lit.17 [a]D29 +33.7 (c 1.05, H2O); lit.18 [a]D25 +37.9 (c 0.2, H2O), both of these values referred to the S enantiomer. 1H NMR (CDCl3): d = 6.59 (s, 1 H), 6.58 (s, 1 H), 4.00 (dd, 1 H, J = 4.1, 9.3 Hz), 3.850 (s, 3 H), 3.846 (s, 3 H), 3.77 (dd, 1 H, J = 4.1, 10.7 Hz), 3.63 (dd, 1 H, J = 9.5, 10.7 Hz), 3.13–3.02 (m, 2 H), 2.76–2.63 (m, 2 H). 13C NMR (CDCl3): d = 147.82, 147.49, 127.49, 126.77, 111.96, 109.13, 63.98, 56.00, 55.97, 55.86, 38.70, 28.95. HRMS–FAB: m/z calcd for C12H18NO3: 224.1287 [M + H]+; found: 224.1294. (14) Analytical Data for (S)-(–)-Salsolidine (11). Colorless oil; [a]D20 –57.9 (c 0.11, EtOH); lit.18 [a]D25 +59.5 (c 0.9, EtOH); lit.19 [a]D25 +54.0 (c 0.63, EtOH), both of these values referred to the R enantiomer. 1H NMR (CDCl3): d = 6.62 (s, 1 H), 6.58 (s, 1 H), 4.13 (q, 1 H, J = 6.8 Hz), 3.86 (s, 3 H), 3.85 (s, 3 H), 3.33–3.27 (m, 1 H), 3.06 (ddd, 1 H, J = 4.9, 8.3, 13.2 Hz), 2.89–2.82 (m, 1 H), 2.75–2.68 (m, 1 H), 1.51 (d, 3 H, J = 6.8 Hz). 13C NMR (CDCl3): d = 148.16, 147.88, 127.53, 124.40, 111.38, 108.74, 55.94, 55.79, 50.32, 39.40, 26.34, 20.52. HRMS–FAB: m/z calcd for C12H18NO2: 208.1338 [M + H]+; found: 208.1359. (15) (S)-(–)-Carnegine (12). Colorless oil. [a]D20 –47.8 (c 0.10, EtOH); lit.20 [a]D25 –51.5 (c 1.70, EtOH). 1H NMR (CDCl3): d = 6.59 (s, 1 H), 6.57 (s, 1 H), 3.848 (s, 3 H), 3.845 (s, 3 H), 3.57 (q, 1 H, J = 6.6 Hz), 3.04 (ddd, 1 H, J = 4.9, 6.6, 11.7 Hz), 2.85–2.72 (m, 2 H), 2.65 (ddd, 1 H, J = 4.9, 7.1, 12.0 Hz). 2.49 (s, 3 H), 1.39 (d, 3 H, J = 6.6 Hz). 13C NMR (CDCl3): d = 147.28, 147.23, 131.38, 125.77, 111.17, 109.86, 58.66, 55.94, 55.78, 48.80, 42.80, 27.37, 19.73. HRMS–FAB: m/z calcd for C13H20NO2: 222.1494 [M + H]+; found: 222.1502. (16) Menachery, M. D.; Lavanier, G. L.; Wetherly, M. L.; Guinaudeau, H.; Shamma, M. J. Nat. Prod. 1986, 49, 745. (17) Morimoto, T.; Suzuki, N.; Achiwa, K. Tetrahedron: Asymmetry 1998, 9, 183. (18) Pedrosa, R.; Andrés, C.; Iglesias, J. M. J. Org. Chem. 2001, 66, 243. (19) Taniyama, D.; Hasegawa, M.; Tomioka, K. Tetrahedron Lett. 2000, 41, 5533. (20) Brown, S. D.; Hodgkins, J. E.; Massingill, J. L.; Reinecke, M. G. J. Org. Chem. 1972, 37, 1825.

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