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Total synthesis of the indole alkaloid (±)-tacamonine
Tetrahedron Letters, Vol. 36, No. 39, pp. 7141-7144, 1995 ElsevierScienceLtd Printed in Great Britain 0040-4039/95 $9.50+0.00
Pergamon 0040-4039(95)01419-5
Total Synthesis of the Indole Alkaloid (:t:)-Tacamonine Mauri Lounasmaa*, David Din Belle, and Arto Tolvanen
Laboratory for Organic and Biaorganic Chemistry, Technical University of H¢lsinlu, FIN-02150 Espoo, Finland
Abstract: A simple and efficient method is described for the preparation of tacamonine (1) from the
easily accessible ester 3. The method is based on the ster~selective synthesis of 20-epitacamonine (7), which is transformed to 1 using the Polonovski-Potier reaction.
Tacamonine (1), an indole alkaloid found in Tabernaemontana eglandulosa I , has recently received synthetic attention, presumably due to its close structural similarity to the well-known cerebral vasodilator (-)-eburnamonine (2). 2 In the pioneering work of L6vy and co-workers 3, all four possible tacamonine isomers (pseudovincamones) were prepared - well before the isolation of the naturally occurring isomer 1. Just recently, the first asymmetric synthesis of 1 was introduced by Fukumoto and his group. 4 However, no stereoselective route to 1 has been published.
9
6
11~N 10
8
7
12
3
g
6
I~~N
5
10
21
8
7
12
1
5
21
2
3
ts
The major challenge in the preparation of tacamonine is to control the relative configurational relationship at centres C-3, C-14 and C-20 (all cis). We have developed a strategy 5 to avoid this difficulty: the stereoselective synthesis of the 20-epimers of these compounds followed by epimerization o f the 20position using the Polonovski-Potier reaction. 6 In the present communication we outline the first stereoselective total synthesis of taeamonine via this method. 7141
7142
3
4
We fotmd that ester 3 7, obtained in an efficient way from tryptophyl bromide and methyl 5-ethylnicotinate8 in 77% overall yield, can be epimerized with trifluoroacetic acid (TFA) 9 to give the thermodynamically more stable ester 4. This was obtained pure from the reaction mixture in 79% yield by taking advantage of its insolubility in hexane. Homologation of ester 4 was achieved by the following route. Reduction of ester 4 with LiA1H4 at 60°C for 45 min produced alcohol 5 (92%), which was converted into a tosylate in 80% yield by treatment with TsCI in pyridine at -20°C (Scheme 1). The corresponding nitrile 6 ~° was obtained in 95% yield by heating the tosylate with NaCN in DMF at 60°C. Direct base-catalysed cyclization of nitrile 6 was not successful. H However, nitrile 6 could easily be converted into the C/D cis-fused pentacycle, 20-epitacamonine (7) 3'12, via the corresponding acid in 90% yield.
.
N
pyri ioo
.
82O
2) NaCN DMF 5
2) POCI3 6
7
Scheme 1
Epimerization at the 20-position of 7 was then achieved by means of the Polonovski-Potier reaction. Oxidation of 7 with m-chloroperbenzoic acid (m-CPBA) afforded only one N-oxide, which, when treated with trifluoroacetic anhydride (TFAA) in CH2CI2 at room temperature, yielded a mixture of two enamines 8 and 9 (3:1 as determined by ~H NMR). From this mixture the desired enamine 8J3, the assumed precursor of tacamonine (1), was isolated by column chromatography in 52% yield (Scheme 2). Enamine 9 appeared to be somewhat less stable ~4 (e.g. during chromatography) than enamine 8. Alternatively, a regioselective route to 9 is available via an analogous series of reactions from ester 3 (Scheme 3). Reduction of ester 3 gave alcohol 10, which was transformed to nitrile 11. ~s The base-catalysed cyclization of 11, followed by acid treatment, led in high yield to 14-epitacamonine (12) 3'16, the N-oxide of which was subjected to the Polonovski-Potier conditions as above to furnish enamine 9 as the only isolable product in ca. 70% yield. ~7
7143
7 NaOH 1
NaOH 1
8
9
NaBH4 0
N
AcOH MeOH
1
Scheme 2
TSc, l l NaoMe pyridine
MeOH
2) 14D H20
2) NaCN
DMF 10
N
11
12
Scheme 3
Finally, enamine 8 was reduced with NaBH 4 under acidic conditions to give (+)-tacamonine (1) in 50% yield along with its 20-epimer 7 (25%). The NMR spectral data of I were in complete agreement with those published earlier. 1'3 In fact, the overall yield of 1 is higher because the 20-epimer can be recycled to provide more of the desired product. Thus, an efficient, stereoselective route to (_+)-tacamonine (1) has been achieved.
REFERENCES AND NOTES
1.
van Beck, T. A.; Verpoorte, R.; Baerheim Svendsen, A. Tetrahedron, 1984, 40, 737-748.
2.
Lounasmaa, M.; Tolvanen, A. The Eburnamine-Vincamine Alkaloids. In The Alkaloids; Cordell, G. A. Ed., Academic Press, New York, 1992, vol. 42, pp. 1-116.
3.
Massiot, G.; Sousa Oliveira, F.; L6vy, J. Bull Soc. Chim. Fr. II, 1982, 185-190.
7144
4.
(a) Ihara, M.; Setsu, F.; Shohda, M.; Taniguchi, N.; Fukumoto, K. Heterocycles, 1994, 37, 289-292; (b) Ihara, M.; Setsu, F.; Shohda, M.; Taniguchi, N.; Toktmaigeg Y.; Fukumoto, K. d. Org. Chem., 1994, 59, 5317-5323.
5.
Lounasmaa, M.; Din Belle, D.; Tolvanen, A. Liebigs Ann., 1995, 1385-1387.
6.
Grierson, D. Org. React., 1990, 39, 85-295.
7.
Tolvanen, A.; Din Belle, D.; Lounasmaa, M. Helv. Chim. Acta, 1994, 77, 709-715.
8.
The earlier synthetic routes to this pyridine have been somewhat lengthy and/or laborious. A threestep synthesis from simple starting materials is now available and will be reported later.
9.
Rosentreter, U.; Born, L.; Kurz, J. £ Org. Chem., 1986, 51, 1165-1171.
10.
Selected spectral data of nitrile 6: MS (El, m/z): 293 (82), 292 (100), 225 (20), 170 (62), 169 (30); ~H NMR (400 MHz, CDCI3): 7.96 (IH, br s, N-H), 3.40 (1H, d, d = 1.6 Hz, H-12b), 0.96 (3H, t, Me); 13C NMR (100 MHz, CDC13): 120.3 (C-=N), 21.6 (C-6), 11.3 (C-18).
11.
Szab6, L.; S~pi, J.; Kalaus, Gy.; Argay, Gy.; Kfilmfin, A.; Baitz-G~s, E.; Tam,is, J.; SzAntay, Cs.
Tetrahedron, 1983, 39, 3737-3747. 12.
Selected spectral data of 20-epitacamonine (7): MS (El, m/z): 294 (100), 293 (93), 250 (27), 209 (38); ~H NMR (400 MHz, CDC13): 8.38 (1H, m, H-12), 4.35 (1H, m, H-3), 0.93 (3H, t, Me); t3C NMR (100 MHz, CDC13): 167.5 (C=O), 16.3 (C-6), 12.5 (C-18).
13.
Selected spectral data of enamine 8: MS (EI, m/z): 292 (100), 277 (78), 209 (60); ~H NMR (400 MHz, CDC13): 8.37 (1H, m, H-12), 5.65 (1H, br s, H-21), 4.48 (1H, m, H-3), 0.95 (3H, t, Me); 13C NMR (100 MHz, CDCI3): 167.3 (C=O), 126.6 (C-21), 19.3 (C-6), 12.6 (C-18).
14.
For the unusual reactivity of the desethyl derivative of enamine 9, see Jokela, R.; Lounasmaa, M.
Tetrahedron, 1989, 45, 303-308. 15.
Selected spectral data of nitrile 11: MS (El, m/z): 293 (72), 292 (100), 225 (19), 170 (58), 169 (30); ~H NMR (400 MHz, CDC13): 7.90 (1H, br s, N-H), 4.21 (IH, br s, H-12b), 0.84 (3H, t, Me); ~3C NMR (100 MHz, CDCI3): 119.5 (C-=N), 16.9 (C-6), 11.2 (C-18).
16.
Selected spectral data of 14-epitacamonine (12): MS (El, m/z): 294 (80), 293 (100); IH NMR (400 MHz, CDC13): 8.33 (1H, m, H-12), 0.92 (3H, t, Me); ~3C NMR (100 MHz, CDC13): 168.0 (C=O), 21.4 (C-6), 12.5 (C-18).
17.
Selected spectral data of enamine 9: MS (El, m/z): 292 (100), 291 (38), 263 (33); IH NMR (400 MHz, CDCI3): 8.38 (1H, m, H-12), 1.01 (3H, t, Me); 13C NMR (100 MHz, CDCI3): 167.0 (C=O), 21.2 (C-6), 11.4 (C-18).
(Received in UK 30 June 1995; accepted 28 July 1995)
Pergamon 0040-4039(95)01419-5
Total Synthesis of the Indole Alkaloid (:t:)-Tacamonine Mauri Lounasmaa*, David Din Belle, and Arto Tolvanen
Laboratory for Organic and Biaorganic Chemistry, Technical University of H¢lsinlu, FIN-02150 Espoo, Finland
Abstract: A simple and efficient method is described for the preparation of tacamonine (1) from the
easily accessible ester 3. The method is based on the ster~selective synthesis of 20-epitacamonine (7), which is transformed to 1 using the Polonovski-Potier reaction.
Tacamonine (1), an indole alkaloid found in Tabernaemontana eglandulosa I , has recently received synthetic attention, presumably due to its close structural similarity to the well-known cerebral vasodilator (-)-eburnamonine (2). 2 In the pioneering work of L6vy and co-workers 3, all four possible tacamonine isomers (pseudovincamones) were prepared - well before the isolation of the naturally occurring isomer 1. Just recently, the first asymmetric synthesis of 1 was introduced by Fukumoto and his group. 4 However, no stereoselective route to 1 has been published.
9
6
11~N 10
8
7
12
3
g
6
I~~N
5
10
21
8
7
12
1
5
21
2
3
ts
The major challenge in the preparation of tacamonine is to control the relative configurational relationship at centres C-3, C-14 and C-20 (all cis). We have developed a strategy 5 to avoid this difficulty: the stereoselective synthesis of the 20-epimers of these compounds followed by epimerization o f the 20position using the Polonovski-Potier reaction. 6 In the present communication we outline the first stereoselective total synthesis of taeamonine via this method. 7141
7142
3
4
We fotmd that ester 3 7, obtained in an efficient way from tryptophyl bromide and methyl 5-ethylnicotinate8 in 77% overall yield, can be epimerized with trifluoroacetic acid (TFA) 9 to give the thermodynamically more stable ester 4. This was obtained pure from the reaction mixture in 79% yield by taking advantage of its insolubility in hexane. Homologation of ester 4 was achieved by the following route. Reduction of ester 4 with LiA1H4 at 60°C for 45 min produced alcohol 5 (92%), which was converted into a tosylate in 80% yield by treatment with TsCI in pyridine at -20°C (Scheme 1). The corresponding nitrile 6 ~° was obtained in 95% yield by heating the tosylate with NaCN in DMF at 60°C. Direct base-catalysed cyclization of nitrile 6 was not successful. H However, nitrile 6 could easily be converted into the C/D cis-fused pentacycle, 20-epitacamonine (7) 3'12, via the corresponding acid in 90% yield.
.
N
pyri ioo
.
82O
2) NaCN DMF 5
2) POCI3 6
7
Scheme 1
Epimerization at the 20-position of 7 was then achieved by means of the Polonovski-Potier reaction. Oxidation of 7 with m-chloroperbenzoic acid (m-CPBA) afforded only one N-oxide, which, when treated with trifluoroacetic anhydride (TFAA) in CH2CI2 at room temperature, yielded a mixture of two enamines 8 and 9 (3:1 as determined by ~H NMR). From this mixture the desired enamine 8J3, the assumed precursor of tacamonine (1), was isolated by column chromatography in 52% yield (Scheme 2). Enamine 9 appeared to be somewhat less stable ~4 (e.g. during chromatography) than enamine 8. Alternatively, a regioselective route to 9 is available via an analogous series of reactions from ester 3 (Scheme 3). Reduction of ester 3 gave alcohol 10, which was transformed to nitrile 11. ~s The base-catalysed cyclization of 11, followed by acid treatment, led in high yield to 14-epitacamonine (12) 3'16, the N-oxide of which was subjected to the Polonovski-Potier conditions as above to furnish enamine 9 as the only isolable product in ca. 70% yield. ~7
7143
7 NaOH 1
NaOH 1
8
9
NaBH4 0
N
AcOH MeOH
1
Scheme 2
TSc, l l NaoMe pyridine
MeOH
2) 14D H20
2) NaCN
DMF 10
N
11
12
Scheme 3
Finally, enamine 8 was reduced with NaBH 4 under acidic conditions to give (+)-tacamonine (1) in 50% yield along with its 20-epimer 7 (25%). The NMR spectral data of I were in complete agreement with those published earlier. 1'3 In fact, the overall yield of 1 is higher because the 20-epimer can be recycled to provide more of the desired product. Thus, an efficient, stereoselective route to (_+)-tacamonine (1) has been achieved.
REFERENCES AND NOTES
1.
van Beck, T. A.; Verpoorte, R.; Baerheim Svendsen, A. Tetrahedron, 1984, 40, 737-748.
2.
Lounasmaa, M.; Tolvanen, A. The Eburnamine-Vincamine Alkaloids. In The Alkaloids; Cordell, G. A. Ed., Academic Press, New York, 1992, vol. 42, pp. 1-116.
3.
Massiot, G.; Sousa Oliveira, F.; L6vy, J. Bull Soc. Chim. Fr. II, 1982, 185-190.
7144
4.
(a) Ihara, M.; Setsu, F.; Shohda, M.; Taniguchi, N.; Fukumoto, K. Heterocycles, 1994, 37, 289-292; (b) Ihara, M.; Setsu, F.; Shohda, M.; Taniguchi, N.; Toktmaigeg Y.; Fukumoto, K. d. Org. Chem., 1994, 59, 5317-5323.
5.
Lounasmaa, M.; Din Belle, D.; Tolvanen, A. Liebigs Ann., 1995, 1385-1387.
6.
Grierson, D. Org. React., 1990, 39, 85-295.
7.
Tolvanen, A.; Din Belle, D.; Lounasmaa, M. Helv. Chim. Acta, 1994, 77, 709-715.
8.
The earlier synthetic routes to this pyridine have been somewhat lengthy and/or laborious. A threestep synthesis from simple starting materials is now available and will be reported later.
9.
Rosentreter, U.; Born, L.; Kurz, J. £ Org. Chem., 1986, 51, 1165-1171.
10.
Selected spectral data of nitrile 6: MS (El, m/z): 293 (82), 292 (100), 225 (20), 170 (62), 169 (30); ~H NMR (400 MHz, CDCI3): 7.96 (IH, br s, N-H), 3.40 (1H, d, d = 1.6 Hz, H-12b), 0.96 (3H, t, Me); 13C NMR (100 MHz, CDC13): 120.3 (C-=N), 21.6 (C-6), 11.3 (C-18).
11.
Szab6, L.; S~pi, J.; Kalaus, Gy.; Argay, Gy.; Kfilmfin, A.; Baitz-G~s, E.; Tam,is, J.; SzAntay, Cs.
Tetrahedron, 1983, 39, 3737-3747. 12.
Selected spectral data of 20-epitacamonine (7): MS (El, m/z): 294 (100), 293 (93), 250 (27), 209 (38); ~H NMR (400 MHz, CDC13): 8.38 (1H, m, H-12), 4.35 (1H, m, H-3), 0.93 (3H, t, Me); t3C NMR (100 MHz, CDC13): 167.5 (C=O), 16.3 (C-6), 12.5 (C-18).
13.
Selected spectral data of enamine 8: MS (EI, m/z): 292 (100), 277 (78), 209 (60); ~H NMR (400 MHz, CDC13): 8.37 (1H, m, H-12), 5.65 (1H, br s, H-21), 4.48 (1H, m, H-3), 0.95 (3H, t, Me); 13C NMR (100 MHz, CDCI3): 167.3 (C=O), 126.6 (C-21), 19.3 (C-6), 12.6 (C-18).
14.
For the unusual reactivity of the desethyl derivative of enamine 9, see Jokela, R.; Lounasmaa, M.
Tetrahedron, 1989, 45, 303-308. 15.
Selected spectral data of nitrile 11: MS (El, m/z): 293 (72), 292 (100), 225 (19), 170 (58), 169 (30); ~H NMR (400 MHz, CDC13): 7.90 (1H, br s, N-H), 4.21 (IH, br s, H-12b), 0.84 (3H, t, Me); ~3C NMR (100 MHz, CDCI3): 119.5 (C-=N), 16.9 (C-6), 11.2 (C-18).
16.
Selected spectral data of 14-epitacamonine (12): MS (El, m/z): 294 (80), 293 (100); IH NMR (400 MHz, CDC13): 8.33 (1H, m, H-12), 0.92 (3H, t, Me); ~3C NMR (100 MHz, CDC13): 168.0 (C=O), 21.4 (C-6), 12.5 (C-18).
17.
Selected spectral data of enamine 9: MS (El, m/z): 292 (100), 291 (38), 263 (33); IH NMR (400 MHz, CDCI3): 8.38 (1H, m, H-12), 1.01 (3H, t, Me); 13C NMR (100 MHz, CDCI3): 167.0 (C=O), 21.2 (C-6), 11.4 (C-18).
(Received in UK 30 June 1995; accepted 28 July 1995)