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A highly efficient synthesis of taxanes via the tandem Diels-Alder reaction
Tetrahedron Letters, Vol. 36, No. 5, pp. 687-690, 1995
Pergamon
Elsevier Science Lid Printed in Great Britain 0040-4039/95 $9.50+0.00
0040-4039(94)02353-0
A HIGHLY EFFICIENT SYNTHESIS OF TAXANES VIA THE TANDEM DIELS-ALDER REACTION +
Jeffrey D. Winkler .1, Hak Sung Kim and Sanghee Kim Chemistry Department, The University of Pennsylvania, Philadelphia, PA 19104
Summary: The tandem Diels-Alder reaction leads to a highly stereoselective two-step synthesis of a taxane nucleus from two readily available acyclic precursors in 50% overall yield. The synthesis of taxol, 1, has been the subject of intense effort in laboratories around the world.2, 3 A notable feature of many of these approaches is the application of either the intra- or intermolecular Diels-Alder reaction to prepare the A and C rings of taxol, respectively.4 We have recently reported that the tandem Diels-Alder reaction leads to the preparation of polycyclic structures with excellent stereochemical control.5,6 We describe herein the application of this methodology to the synthesis of the tricyclic taxane nucleus, in which both the A and C rings are prepared via Diels-Alder cycloaddition reactions. The power of this tandem process is exemplified by the highly efficient construction of the taxane ring system from the two simple acyclic precursors, 4 and 5, as outlined in Scheme I. Scheme I
AcO O
Ph H
O
O OH
OH PhCOO AcO
-I-
O H
o H
2
3
o 5
+ Dedicated to our friend and teacher Professor Deukjoon Kim 687
688
The preparation of the requisite tetraene 4 is outlined in Scheme I1. The known diene alcohol 67 was converted to the corresponding mesylate 7, which on reaction with sodium iodide, provided iodide 8. 8 Reaction of the monoanion of butadiene sulfone with 8 gave 9 in 57% yield (based on recovered starting material).9 Extrusion of SO2 from 9 resulted in the formation of 4. S c h e m e II
----~.~fX
O
toluene reflux 50 rain, 80%
O
LHMDS, THF -78°C, 57%
MsCI, Et3N r CH2Cl2, 100% Nal, Me2CO 87%
6 X--OH 7 X=OMs
9
0
4
8 X=I
I I 2 equiv ZnCl 2
o
6 equiv BF3-Et20 reflux, 92% (1/1: 2/10)
10
82%
2
3
The intermolecular Diels-Alder reaction of 4 with 5 proceeded via ZnCI2 catalysis to give cyclohexene 3 in 63% yield. In contrast to our preliminary study of the tandem Diels-Alder reaction, 5 we find here that the difference in reactivity of the mono- and tetra-substituted diene units in 4 is sufficiently great that protection of the second diene moiety is not necessary for this highly regioselective cycloaddition to occur. The second, intramolecular, Diels-AIder cycloaddition occurs via BF3-Et20 catalysis to give the tricyclic ketone 2 as a single diastereomer in 82% yield. It is interesting to note that neither Lewis acid is capable of catalyzing both Diels-Alder reactions. The stereochemistry of 2 could be unambiguously established by 1H nOe experiments on 2 and on 10 (the C-3 epimer obtained on equilibration of 2 under basic reaction conditions). 10 As shown in Scheme III, the cis relationship of the C-3 and C-8 protons in 2, as well as the proximity of the C-12 allylic methyl group to the C-3 hydrogen, could be established by 4 and 3% nOes, respectively. In contrast, the equilibrated B/C trans-fused isomer 10 gave a 10% nOe from the C-3 hydrogen to one of the two C-15 quarternary methyl groups and a 1% nOe from the C-3 to the C-1 hydrogen. These experiments are consistent with MM2 minimizations conducted on 2 (cis) and 10 (trans), in which the conformation of 2 shown in Scheme III is ca. 7 kcal/mol more stable than the conformation in which the orientation of the carbonyl is as shown in 2' (Scheme III). Similarly, the conformation of 10 shown in Scheme III is ca. 4.5 kcal/mol more stable than that shown in 10'. These results highlight the
689
significance of the B,C ring fusion stereochemistry in controlling both the conformation and stereoselectivities in this remarkable ring system. 11 Scheme III 10%
3%
2
10
2'
10'
This exceedingly direct, two-step synthesis of the taxane nucleus in 50% overall yield from the readily available acyclic precursors 4 and 5 proceeds with excellent stereochemical control. Further studies on the preparation of more highly substituted acyclic precursors that will lead to more highly functionalized taxanes (and to the establishment of the naturally occurring C-8~, C-3o~ trans-B/C ring fusion stereochemistry) using this approach are currently underway in our laboratory. Acknowledgments. acknowledged.
Financial support from the National Institutes of Health (CA40250) is gratefully
References
Recipient of the American Cyanamid Young Faculty Award (1989-1992) and a National Institutes of Health Research Career Development Award (1988-1993). The first two total syntheses of taxol have recently appeared: a) Holton, R. A.; Somoza, C.; Kim, H.; Liang, F.; Biediger, R.; Boatman, P.; Shindo, M.; Smith, C.; Kim, S.; Nadizadeh, H.; Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.; Zhang, P.; Murthi, K.; Gentile, L.; Liu, J. J. Am. Chem. Soc. 1994, 116, 1597, 1599; b) Nicolaou, K. C.; Yang, Z.; Liu, J.; Ueno, H.; Nantermet, P.; Guy, R.; Claiborne, C.; Renaud, J.; Couladouros, E.; Paulvannan, K.; Sorensen, E. Nature, 1994, 367, 630. For excellent recent reviews on the synthesis of taxanes, see a) Swindell, C. S. Org. Prep. Procedures Intl. 1992, 23, 465; b) Nicolaou, K. C.; Dai, W.; Guy, R. Angew. Chem. Intl. Ed. 1994, 33, 15; c) Boa, A. N.; Jenkins, P. R.; Lawrence, N. J. Contemporary Organic Synthesis 1994, 47.
690
4 For the application of the Diels-Alder cycloaddition to the synthesis of taxanes, see--Intermolecular A- ring: a) Nicolaou, K. C.; Hwang, C.; Dai, W.; Guy, R. J. Chem. Soc., Chem. Comm. 1992, 1117; intramolecular A- ring: b) Jackson, R. W.; Shea, K. J. Tetrahedron Lett. 1994, 1317; c) Shea, K.; Wise, S. J. Am. Chem. Soc. 1978, 100, 6519; d) Bonnert, R.; Jenkins, P. J. Chem. Soc., Perkin Trans. 11989, 413; intermolecular C-ring: e) Nicolaou, K. C.; Liu, J.; Hwang, C.; Dai, W.; Guy, R. J. Chem. Soc., Chem. Comm. 1992, 1118; intramolecular C-ring: f) Sakan, K.; Smith, D.; Babirad, S.; Fronczek, F.; Houk, K. J. Org. Chem. 1991, 56, 2311 and references cited therein; g) Lu, F.; Fallis, A. Tetrahedron Lett. 1993, 3367. 5 Winkler, J.; Kim, S.; Amparao, A.; Condroski, K.; Houk, K. N. J. Org. Chem., in press. 6 An example of the use of the tandem Diels-Alder reaction for the synthesis of perhydrophenanthrenes has recently appeared: Spino, C.; Crawford, J. Tetrahedron Lett. 1994, 5559. 7 We thank Professor Kenneth J. Shea (UC Irvine) for kindly supplying the experimental procedure for the preparation of 6. 8 All new compounds were characterized by full spectroscopic (NMR, IR, high resolution MS) data. Yields refer to spectroscopically and chromatographically homogeneous (>95%) materials. Selected spectral data---Diels-Alder diene 4:1H NMR (CDCI3, 500 MHz): 5 6.27 (dt, J = 17.0, 10.2 Hz, 1H), 6.04 (bdd, J = 15.2, 10.4 Hz, 1H), 5.69 (dt, J = 15.2, 6.8 Hz, 1H), 5.07 (bd, J = 17.0 Hz, 1H), 4.82-4.96 (m, 2H), 4.54 (m, 1H), 2.00-2.21 (m, 4H), 1.74 (bs, 3H), 1.53-1.64 (two singlets, 6H); 13C NMR (CDCI3, 125 MHz): 5 146.36, 137.27, 135.88, 135.29, 130.82, 125.47, 114.64, 113.25, 31.41, 30.67, 22.69, 21.72, 19.64; FT-IR (film, cm'l): 3073, 2933, 1632, 1444, 1372, 1112; exact mass calculated for 013H21 (M + + H): 177.1643; found, 177.1643; cis-tricyclic ketone 2: 1H NMR (CDCI3, 500 MHz): 8 5.73 (ddd, J = 10.2, 5.3, 2.7 Hz, 1H), 5.22 (dd, J = 10.2, 2.0 Hz, 1H), 3.08 (m, 1H), 2.67 (dt, J = 13.3, 6.2 Hz, 1H), 2.53 (m, 1H), 2.32 -2.46 (m, 2H), 2.32 (d, J = 7.7 Hz, 1H), 2.11 (m, 1H), 2.07 (ddd, J = 18.4, 10.1, 2.4 Hz, 1H), 1.99 (dddd, J = 14.8, 11.0, 7.8, 2.5 Hz, 1H), 1.83 (m, 1H), 1.81 (dt, J = 10.2, 5.0 Hz, 1H), 1.55 (s, 3H), 1.42-1.61 (m, 4H), 1.19 (s, 3H), 1.08 (s, 3H); 13C NMR (CDCI3, 125 MHz): 8 218.99, 136.96, 130.97, 130.60, 126.68, 61.86, 41.30, 38.25, 36.48, 34.05, 28.95, 28.44, 27.05, 24.89, 24.61, 21.47, 21.45, 19.04; FT-IR (film, cm-1): 3015, 2916, 1693, 1682, 1455, 1389, 1301, 1170, 1128, 1112, 1027; exact mass calculated for C18H270 (M + + H): 259.2061, found 259.2050; trans-ketone 1 0 : 1 H NMR (C6D6, 500 MHz): 8 5.70 (m, 1H), 5.39 (bd, J = 10.0 Hz, 1H), 2.82 (ddd, J = 12.1, 8.5, 3.4 Hz, 1H), 2.60 (m, 1H), 2.39 (dt, J = 14.0, 9.9 Hz, 1H), 2.10-2.25 (m, 2H), 2.06 (d, J = 3.8 Hz, 1H), 1.92-2.05 (m, 3H), 1.61-1.79 (m, 5H), 1.51 (m, 1H), 1.46 (s, 3H), 1.39 (s, 3H), 0.96 (s, 3H); 13C NMR (C6D6, 125 MHz): 5212.17, 137.68, 133.90, 132.21, 126.35, 60.05, 51.13, 39.53, 36.92, 36.69, 30.50, 29.60, 28.03, 27.76, 25.31, 24.25, 21.56, 20.27; FT-IR (film, cm-1): 2914, 1682, 1446, 1391, 1367, 1345, 1303, 1280. 1204, 1177, 1114, 1089, 1066, 1048, 1014; exact mass calculated for C18H270 (M + + H): 259.2061, found 259.2067. 9 a) Chou, S.; Lee, C.; Cheng, M.; Tai, H. J. Org. Chem. 1994, 59, 2010; b) Chou, T.; Tso, H.; Hung, S. J. Org. Chem. 1987, 52, 3394. 10 Exposure of 2 to 10% methanolic sodium methoxide at reflux for 72 h led to a 1:1 mixture of 2 and its C-3 epimer, 10. 11 For an insightful analysis of related conformational effects in the taxane ring system, see Swindell, C. ; Patel, B. Tetrahedron Lett. 1987, 5275.
(Received in USA 12 October 1994; revised 23 November 1994; accepted 1 December 1994)
Pergamon
Elsevier Science Lid Printed in Great Britain 0040-4039/95 $9.50+0.00
0040-4039(94)02353-0
A HIGHLY EFFICIENT SYNTHESIS OF TAXANES VIA THE TANDEM DIELS-ALDER REACTION +
Jeffrey D. Winkler .1, Hak Sung Kim and Sanghee Kim Chemistry Department, The University of Pennsylvania, Philadelphia, PA 19104
Summary: The tandem Diels-Alder reaction leads to a highly stereoselective two-step synthesis of a taxane nucleus from two readily available acyclic precursors in 50% overall yield. The synthesis of taxol, 1, has been the subject of intense effort in laboratories around the world.2, 3 A notable feature of many of these approaches is the application of either the intra- or intermolecular Diels-Alder reaction to prepare the A and C rings of taxol, respectively.4 We have recently reported that the tandem Diels-Alder reaction leads to the preparation of polycyclic structures with excellent stereochemical control.5,6 We describe herein the application of this methodology to the synthesis of the tricyclic taxane nucleus, in which both the A and C rings are prepared via Diels-Alder cycloaddition reactions. The power of this tandem process is exemplified by the highly efficient construction of the taxane ring system from the two simple acyclic precursors, 4 and 5, as outlined in Scheme I. Scheme I
AcO O
Ph H
O
O OH
OH PhCOO AcO
-I-
O H
o H
2
3
o 5
+ Dedicated to our friend and teacher Professor Deukjoon Kim 687
688
The preparation of the requisite tetraene 4 is outlined in Scheme I1. The known diene alcohol 67 was converted to the corresponding mesylate 7, which on reaction with sodium iodide, provided iodide 8. 8 Reaction of the monoanion of butadiene sulfone with 8 gave 9 in 57% yield (based on recovered starting material).9 Extrusion of SO2 from 9 resulted in the formation of 4. S c h e m e II
----~.~fX
O
toluene reflux 50 rain, 80%
O
LHMDS, THF -78°C, 57%
MsCI, Et3N r CH2Cl2, 100% Nal, Me2CO 87%
6 X--OH 7 X=OMs
9
0
4
8 X=I
I I 2 equiv ZnCl 2
o
6 equiv BF3-Et20 reflux, 92% (1/1: 2/10)
10
82%
2
3
The intermolecular Diels-Alder reaction of 4 with 5 proceeded via ZnCI2 catalysis to give cyclohexene 3 in 63% yield. In contrast to our preliminary study of the tandem Diels-Alder reaction, 5 we find here that the difference in reactivity of the mono- and tetra-substituted diene units in 4 is sufficiently great that protection of the second diene moiety is not necessary for this highly regioselective cycloaddition to occur. The second, intramolecular, Diels-AIder cycloaddition occurs via BF3-Et20 catalysis to give the tricyclic ketone 2 as a single diastereomer in 82% yield. It is interesting to note that neither Lewis acid is capable of catalyzing both Diels-Alder reactions. The stereochemistry of 2 could be unambiguously established by 1H nOe experiments on 2 and on 10 (the C-3 epimer obtained on equilibration of 2 under basic reaction conditions). 10 As shown in Scheme III, the cis relationship of the C-3 and C-8 protons in 2, as well as the proximity of the C-12 allylic methyl group to the C-3 hydrogen, could be established by 4 and 3% nOes, respectively. In contrast, the equilibrated B/C trans-fused isomer 10 gave a 10% nOe from the C-3 hydrogen to one of the two C-15 quarternary methyl groups and a 1% nOe from the C-3 to the C-1 hydrogen. These experiments are consistent with MM2 minimizations conducted on 2 (cis) and 10 (trans), in which the conformation of 2 shown in Scheme III is ca. 7 kcal/mol more stable than the conformation in which the orientation of the carbonyl is as shown in 2' (Scheme III). Similarly, the conformation of 10 shown in Scheme III is ca. 4.5 kcal/mol more stable than that shown in 10'. These results highlight the
689
significance of the B,C ring fusion stereochemistry in controlling both the conformation and stereoselectivities in this remarkable ring system. 11 Scheme III 10%
3%
2
10
2'
10'
This exceedingly direct, two-step synthesis of the taxane nucleus in 50% overall yield from the readily available acyclic precursors 4 and 5 proceeds with excellent stereochemical control. Further studies on the preparation of more highly substituted acyclic precursors that will lead to more highly functionalized taxanes (and to the establishment of the naturally occurring C-8~, C-3o~ trans-B/C ring fusion stereochemistry) using this approach are currently underway in our laboratory. Acknowledgments. acknowledged.
Financial support from the National Institutes of Health (CA40250) is gratefully
References
Recipient of the American Cyanamid Young Faculty Award (1989-1992) and a National Institutes of Health Research Career Development Award (1988-1993). The first two total syntheses of taxol have recently appeared: a) Holton, R. A.; Somoza, C.; Kim, H.; Liang, F.; Biediger, R.; Boatman, P.; Shindo, M.; Smith, C.; Kim, S.; Nadizadeh, H.; Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.; Zhang, P.; Murthi, K.; Gentile, L.; Liu, J. J. Am. Chem. Soc. 1994, 116, 1597, 1599; b) Nicolaou, K. C.; Yang, Z.; Liu, J.; Ueno, H.; Nantermet, P.; Guy, R.; Claiborne, C.; Renaud, J.; Couladouros, E.; Paulvannan, K.; Sorensen, E. Nature, 1994, 367, 630. For excellent recent reviews on the synthesis of taxanes, see a) Swindell, C. S. Org. Prep. Procedures Intl. 1992, 23, 465; b) Nicolaou, K. C.; Dai, W.; Guy, R. Angew. Chem. Intl. Ed. 1994, 33, 15; c) Boa, A. N.; Jenkins, P. R.; Lawrence, N. J. Contemporary Organic Synthesis 1994, 47.
690
4 For the application of the Diels-Alder cycloaddition to the synthesis of taxanes, see--Intermolecular A- ring: a) Nicolaou, K. C.; Hwang, C.; Dai, W.; Guy, R. J. Chem. Soc., Chem. Comm. 1992, 1117; intramolecular A- ring: b) Jackson, R. W.; Shea, K. J. Tetrahedron Lett. 1994, 1317; c) Shea, K.; Wise, S. J. Am. Chem. Soc. 1978, 100, 6519; d) Bonnert, R.; Jenkins, P. J. Chem. Soc., Perkin Trans. 11989, 413; intermolecular C-ring: e) Nicolaou, K. C.; Liu, J.; Hwang, C.; Dai, W.; Guy, R. J. Chem. Soc., Chem. Comm. 1992, 1118; intramolecular C-ring: f) Sakan, K.; Smith, D.; Babirad, S.; Fronczek, F.; Houk, K. J. Org. Chem. 1991, 56, 2311 and references cited therein; g) Lu, F.; Fallis, A. Tetrahedron Lett. 1993, 3367. 5 Winkler, J.; Kim, S.; Amparao, A.; Condroski, K.; Houk, K. N. J. Org. Chem., in press. 6 An example of the use of the tandem Diels-Alder reaction for the synthesis of perhydrophenanthrenes has recently appeared: Spino, C.; Crawford, J. Tetrahedron Lett. 1994, 5559. 7 We thank Professor Kenneth J. Shea (UC Irvine) for kindly supplying the experimental procedure for the preparation of 6. 8 All new compounds were characterized by full spectroscopic (NMR, IR, high resolution MS) data. Yields refer to spectroscopically and chromatographically homogeneous (>95%) materials. Selected spectral data---Diels-Alder diene 4:1H NMR (CDCI3, 500 MHz): 5 6.27 (dt, J = 17.0, 10.2 Hz, 1H), 6.04 (bdd, J = 15.2, 10.4 Hz, 1H), 5.69 (dt, J = 15.2, 6.8 Hz, 1H), 5.07 (bd, J = 17.0 Hz, 1H), 4.82-4.96 (m, 2H), 4.54 (m, 1H), 2.00-2.21 (m, 4H), 1.74 (bs, 3H), 1.53-1.64 (two singlets, 6H); 13C NMR (CDCI3, 125 MHz): 5 146.36, 137.27, 135.88, 135.29, 130.82, 125.47, 114.64, 113.25, 31.41, 30.67, 22.69, 21.72, 19.64; FT-IR (film, cm'l): 3073, 2933, 1632, 1444, 1372, 1112; exact mass calculated for 013H21 (M + + H): 177.1643; found, 177.1643; cis-tricyclic ketone 2: 1H NMR (CDCI3, 500 MHz): 8 5.73 (ddd, J = 10.2, 5.3, 2.7 Hz, 1H), 5.22 (dd, J = 10.2, 2.0 Hz, 1H), 3.08 (m, 1H), 2.67 (dt, J = 13.3, 6.2 Hz, 1H), 2.53 (m, 1H), 2.32 -2.46 (m, 2H), 2.32 (d, J = 7.7 Hz, 1H), 2.11 (m, 1H), 2.07 (ddd, J = 18.4, 10.1, 2.4 Hz, 1H), 1.99 (dddd, J = 14.8, 11.0, 7.8, 2.5 Hz, 1H), 1.83 (m, 1H), 1.81 (dt, J = 10.2, 5.0 Hz, 1H), 1.55 (s, 3H), 1.42-1.61 (m, 4H), 1.19 (s, 3H), 1.08 (s, 3H); 13C NMR (CDCI3, 125 MHz): 8 218.99, 136.96, 130.97, 130.60, 126.68, 61.86, 41.30, 38.25, 36.48, 34.05, 28.95, 28.44, 27.05, 24.89, 24.61, 21.47, 21.45, 19.04; FT-IR (film, cm-1): 3015, 2916, 1693, 1682, 1455, 1389, 1301, 1170, 1128, 1112, 1027; exact mass calculated for C18H270 (M + + H): 259.2061, found 259.2050; trans-ketone 1 0 : 1 H NMR (C6D6, 500 MHz): 8 5.70 (m, 1H), 5.39 (bd, J = 10.0 Hz, 1H), 2.82 (ddd, J = 12.1, 8.5, 3.4 Hz, 1H), 2.60 (m, 1H), 2.39 (dt, J = 14.0, 9.9 Hz, 1H), 2.10-2.25 (m, 2H), 2.06 (d, J = 3.8 Hz, 1H), 1.92-2.05 (m, 3H), 1.61-1.79 (m, 5H), 1.51 (m, 1H), 1.46 (s, 3H), 1.39 (s, 3H), 0.96 (s, 3H); 13C NMR (C6D6, 125 MHz): 5212.17, 137.68, 133.90, 132.21, 126.35, 60.05, 51.13, 39.53, 36.92, 36.69, 30.50, 29.60, 28.03, 27.76, 25.31, 24.25, 21.56, 20.27; FT-IR (film, cm-1): 2914, 1682, 1446, 1391, 1367, 1345, 1303, 1280. 1204, 1177, 1114, 1089, 1066, 1048, 1014; exact mass calculated for C18H270 (M + + H): 259.2061, found 259.2067. 9 a) Chou, S.; Lee, C.; Cheng, M.; Tai, H. J. Org. Chem. 1994, 59, 2010; b) Chou, T.; Tso, H.; Hung, S. J. Org. Chem. 1987, 52, 3394. 10 Exposure of 2 to 10% methanolic sodium methoxide at reflux for 72 h led to a 1:1 mixture of 2 and its C-3 epimer, 10. 11 For an insightful analysis of related conformational effects in the taxane ring system, see Swindell, C. ; Patel, B. Tetrahedron Lett. 1987, 5275.
(Received in USA 12 October 1994; revised 23 November 1994; accepted 1 December 1994)