Chapter 23
Toward the Design of a Convergent Practical Route to All Classes of Taxanes Leo A. Paquette
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Evans Chemical Laboratories, Ohio State University, Columbus, OH 43210 The taxane diterpenes constitute a structurally intricate class of compounds which has been accorded considerable attention in recent years because one of its members, taxol, is remarkably effective against advanced ovarian cancer. The varied complexity and functional group arrays present in the various taxanes represent a major challenge to synthetic chemists. The present goal is to utilize (+)-camphor, an abundant enantiopure product of the camphor tree, as the key building block in a convergent approach to the several types of taxanes, as well as to suitable analogs not available by semi-synthesis or direct structural modification. The pathway under development is capable of rapid construction of the complete carbocyclicframeworkof the taxanes, with exceptional control of the bridgehead oxidation level. Since the discovery by Wani and Wall of the antineoplastic agent taxol (1) in 1971 (7) and the subsequent demonstration by Horwitz that 1 functions as a mitotic spindle poison capable of inhibiting microtubule depolymerization (2), intense interest has arisen within the international synthetic organic chemistry community in the de novo construction of 1 and its congeners (J-7). Spurred on by the exciting inhibitory properties of taxol against ovarian, lung, and breast cancer and by the original scarce supply of this drug, researchers have responded admirably to the challenge of realizing the step-by-step assembly of the complex structural features inherent in taxane systems. Two syntheses of taxol have recently been reported (8, 9). Several years ago, a means for preparing the unnatural (-)-enantiomer of taxusin (2) was detailed (10).
1 N O T E : Paclitaxel is the generic name for Taxol, which is now a registered trademark.
0097-6156/95/0583-0313$08.00/0 © 1995 American Chemical Society
In Taxane Anticancer Agents; Georg, Gunda I., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
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Formulation of the Synthetic Plan Specific attention is called to the fact that 1 and 2 carry different levels of oxidation at C - l , a feature which broadly segregates the two sub-classes of taxanes. Although structural modifications of taxol have been investigated to some extent (11-13), 1deoxytaxol is as yet unknown and seemingly unattainable by degradation because of the onset of framework rearrangement (77,14). At the time that we began our work, the most attractive opportunity appeared to reside in the development of a practical (viz., 25 steps or less), convergent protocol that would allow enantioselective synthetic entry into either sub-class of the taxane family on demand. The tactical plans were formulated with (+)-(/?)-camphor in mind as a suitable starting material having the proper absolute configuration. An efficient means for transforming camphor into the optically pure bicyclic ketone 3 had already been documented (75). Our first objective was to determine specifically those features of the [3.3] sigmatropic rearrangement transition state which would be manifested by 4, produced by coupling with a cyclohexenyl anionfromthe more accessible endo surface of the carbonyl (Scheme 1). Scheme 1
β
KN(SiMe3) . 18-crown-6, T H F , rt; CH3I; T H F , 40 °C. * Dibal-H, Q H Ô , 0 ° C . AcCl, py. c
2
NaHS0 . * MsCl, py. ' E t ^ l C l , C H j C ^ , -78 °C - » 2 5 °C. * O s 0 , py; UKV^. 3
1
Swern.
4
J
d
O s 0 , py; 4
+
* A c 0 , py; B u N F~. 2
(2Cl Et N, C ^ a . 3
6
6
3
3
2
The Issue of C-7 Oxygenation When 46 and its diastereomer were subjected to anionic oxy-Cope rearrangement in the presence of potassium hexamethyldisilazide and then to air, the intermediate enolates experienced spontaneous α-oxygenation (29) to give 47 and 48. These α-hydroxy ketones were examined for their ability to experience dehydration. This transformation was possible only for 48, which underwent regioselective conversion to 49 spontaneously during mesylation. Surprisingly, 47 was totally resistant to the loss of water. Subsequent determination that 49 could not be epoxidized under a variety of conditions caused us to turn to a more viable tactic for introduction of the C-7 hydroxyl substituent. From among the several attractive alternatives, the possibility of deploying ketals constituted of a 2-halo-2-cyclohexenone core has been evaluated. Pilot studies performed with the well-known building block 51 was a forerunner to the utilization of enantiomerically pure 52, which is available from Z)-(-)-quinic acid (30). Relevandy, 52 is so constituted that it possesses a complementary sidechain that is to serve ultimately as the carbon atom of the oxetane ring. In a model study involving 51, addition to ketone 53 gave alcohol 54 (88%), which was converted into its potassium salt in the usual manner (Scheme 10). To our amazement, the efficacious rearrangement to 55 was complete within 30 min at -40 °C. This discovery, which represented by far the most rapid [3.3] sigmatropic isomerization seen to that time in this series, foreshadowed comparable rate increases for related two-step processes
In Taxane Anticancer Agents; Georg, Gunda I., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
23.
PAQUETTE
Br
A Convergent Practical Route to Taxanes
HO
COOH
OTBS
I
51
323
52
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involving other norbornanones. The two-step sequence leadingfrom54 to 56 has also been implemented. Quite heartening has been our ability to produce 58from57 under extremely mild conditions. Since the precursor to 57 is optically pure, the carbinol having the proper absolute configuration at several key centers is formed exclusively. The highly selective nature of this chemistry and the overall brevity of the sequence are obvious and will continue to be exploited. Scheme 10
57
58
56
β
/-BuLi on 51, THF, -78 °C; add 5 3. * KN(SiMe3> ,18-crown-6, T H F , -50 °C.
c
PPTS, acetone. 'KOf-Bu, DMSO; Mel
2
The richness of the substitution level in 56 and 58 requires modest enhancement. A C-2 hydroxyl needs to be incorporated and epimerization of C-3 is mandatory. This stereochemical modification can presumably be realized by unmasking and oxidizing the C-2 hydroxyl. Should this course of action be followed, then the initial stereochemical disposition of the C-O bond is of no real consequence. As a result, the E- and Z-isomers of the vinyl ether precursor can be used in combination in order to maximize efficiency. The implementation of bridge migration in advance of setting trans B/C ring junction stereochemistry warrants exploration because a greater thermodynamic driving force may underlie the conversion to the natural taxane skeleton. Note that the epimerization will not be beset with potential
In Taxane Anticancer Agents; Georg, Gunda I., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
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complications stemming from β-elimination were 52 to be utilized. Reaction economy would be best served if the oxetane ring was subsequently introduced by one of several established options (8,9,28,31). The Α-ring substitution plan to be adopted will be closely allied to that developed in the taxusin series. Concurrent with implementation of the above tactics, other stratagems having as their objective a significant reduction in the number of steps associated with this convergent route to taxol will be studied. We are optimistic that the discoveries awaiting us in the course of this streamlining shall serve us proficiently in our quest of the fascinating taxane diterpenes.
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Acknowledgments This overview of our taxane synthesis program has been made possible by the efforts of a small, select group of students whose skill and devotion to chemistry have enabled us to come far. Their names are cited in the references. Collectively, we express our heartfelt thanks to the Bristol-Myers Squibb Company for the requisite financial support. The advances that we have made were facilitated at various times by Professor Robin Rogers (X-ray crystallography), Dr. Dirk Friedrich (NOE and COSY NMR studies), and Dr. Eugene Hickey and Mr. Scott Edmondson (molecular mechanics calculations). We thank them for their valuable input. Literature Cited (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18)
Wani, M. C.; Taylor, H. L.; Wall, M . E.; Coggon, P.; McPhail, A. T. J. Am. Chem. Soc. 1971, 93, 2325-2327. Schiff, P. B.; Fant, J.; Horwitz, S. B. Nature 1979, 277, 665-667. Suffness, M.; Cordell, G. A. In The Alkaloids. Chemistry and Pharmacology; Brossi, Α., Ed.; Academic Press: New York, 1985; Vol. 25; pp 3-355. Kingston, D. G. I. Pharmacol. Ther. 1991, 52, 1-34. Swindell, C. S. Org. Prep. Proced. Int. 1991, 23, 465-543. Paquette, L. A. In Studies in Natural ProductsChemistry;Rahman, A. U.; Basha, F. Z., Eds.; Elsevier: Amsterdam, 1992; Vol. 11, pp 3-69. Kingston, D. G. I.; Molinero, Α. Α.; Rimoldi, J. M . Prog. Chem. Org. Nat. Prod. 1993, 61, 1-206. Nicolaou, K. C., et al Nature 1994, 367, 630-634. Holton, R. Α.; et al. J. Am. Chem. Soc. 1994, 116, 1597-1600. Holton, R. Α.; Juo, R. R.; Kim, Η. B.; Williams, A. D.; Harusawa, S.; Lowenthal, R. E.; Yogai, S. J. Am. Chem. Soc. 1988, 110, 6558-6560. Samaranayake, G.; Magri, N. F.; Jitraugsri, C.; Kingston, D. G. I. J. Org. Chem. 1991, 56, 5114-5119. Chen, S.-H.; Wei, J.-M.; Vyas, D. M.; Doyle, T. W.; Farina, V. Tetrahedron Lett. 1993, 34, 6845-6848 and earlier references cited therein. Klein, L. L. Tetrahedron Lett. 1993, 34, 2047-2050. Chen, S.-H; Huang, S.; Wei, J.; Farina, V. Tetrahedron 1993, 49, 28052828. Fischer, N.; Opitz, G. Org. Synth., Collect. Vol. V 1973, 877-879. Paquette, L. Α.; Pegg, Ν. Α.; Toops, D.; Maynard, G. D.; Rogers, R. D. J. Am. Chem. Soc. 1990, 112, 277-283. Paquette, L. Α.; Combrink, K. D.; Elmore, S. W.; Rogers, R. D. J. Am. Chem. Soc. 1991, 113, 1335-1344. Elmore, S. W.; Paquette, L. A. Tetrahedron Lett. 1991, 32, 319-322.
In Taxane Anticancer Agents; Georg, Gunda I., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
23. (19) (20) (21) (22) (23)
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(24) (25) (26) (27) (28) (29) (30) (31)
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Pegg, Ν. Α.; Paquette, L. A. J. Org. Chem. 1991, 56, 2461-2468. Paquette, L. Α.; Zhao, M.; Friedrich, D. Tetrahedron Lett. 1992, 33, 73117314. Elmore, S. W.; Combrink, K. D.; Paquette, L. A. Tetrahedron Lett. 1991, 32, 6679-6682. Paquette, L. Α.; Elmore, S. W.; Combrink, K. D.; Hickey, E. R.; Rogers, R. D. Helv. Chim. Acta 1992, 75, 1755-1771. Paquette, L. Α.; Combrink, K. D.; Elmore, S. W.; Zhao, M . Helv. Chim. Acta 1992, 75, 1772-1791. Paquette, L. Α.; Zhao, M . J. Am. Chem. Soc. 1993, 115, 354-356. Paquette, L. Α.; Huber, S. K.; Thompson, R. C. J. Org. Chem. 1993, 58, 6874-6882. Elmore, S. W. Ph.D. Dissertation, The Ohio State University, 1993. Elmore, S. W.; Paquette, L. A. J. Org. Chem. 1993, 58, 4963-4970. Paquette, L. Α.; Thompson, R. C. J. Org. Chem. 1993, 58, 4952-4962. Paquette, L. Α.; DeRussy, D. T.; Pegg, Ν. Α.; Taylor, R. T.; Zydowsky, T. M . J. Org. Chem. 1989, 54, 4576-4581. Paquette, L. Α.; Su, Z.; Bailey, S. submitted for publication. Magee, T. V.; Bornmann, W. G.; Issacs, R. C. Α.; Danishefsky, S. J. J. Org. Chem. 1992, 57, 3274-3276.
R E C E I V E D August 23, 1994
In Taxane Anticancer Agents; Georg, Gunda I., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
