Interphylal product splicing: The first total syntheses of cephalostatin 1, the North hemisphere of ritterazine G, and the highly active hybrid analogue, ritterostatin G(N)1(N)1

Journal of the American Chemical Society

Volumn 120, Issue 4, 1998, Pages 692-707

  LaCour, Thomas G ^a   Guo, Chuangxing ^a   Bhandaru, Sudhakar ^a   Boyd, Michael R ^b   Fuchs, P L ^a  

^a PURDUE UNIVERSITY   (United States)

^b NATIONAL CANCER INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; CEPHALOSTATIN 1; RITTERAZINE G; RITTEROSTATIN; UNCLASSIFIED DRUG;

ANTINEOPLASTIC ACTIVITY; ARTICLE; CELL GROWTH; CONTROLLED STUDY; DRUG ACTIVITY; DRUG SYNTHESIS; NONHUMAN; PHOTOLYSIS;

EID: 0032481403     PISSN: 00027863     EISSN: None     Source Type: Journal    
DOI: 10.1021/ja972160p     Document Type: Article

References (91)

1. Cephalostatin synthesis. 11. Portions of this work have been communicated in ref 12a and in paper 10 of this series: Guo, C.; Bhandaru, S.; Fuchs, P. L.; Boyd, M. R. J. Am. Chem. Soc. 1996, 118, 10672; see also references therein for syntheses of the cephalostatin subunit precursors 29 and 37 from hecogenin acetate.
2. 50 1.2 nM (ref b), 2.3 nM (ref 1), 3.5 nM (8/4/97 test, this work).
3. -9 molar = 7.9 nM) renal RXF-393, -8.0 (10 nM) leukemia RPMI-8226, but -6.6 (229 nM) for the breast MCF-7 line, also see ref 2. Finally, Professor Pettit has indicated that these latter results are in accord with his own and may be considered definitive. (Personal communication, G. R. Pettit, December 1997.)
4. (b) Pettit, G. R.; Xu, J.; Schmidt, J. M.; Boyd, M. R. Bioorg. Med. Chem. Lett. 1995, 5, 2027 and references therein.
5. 50 0.15 and 0.73 ng/mL (P388 leukemia).
6. (b) Fukuzawa, S.; Matsunaga, S.; Fusetani, N. J. Org. Chem. 1997, 62, 4484. The southern hemisphere is acid sensitive and isomerizes even at 25°C to several compounds, including some apparently related to North 5, the sixth and least active "basic"steroidal subunit: see refs 5, 7, and 11.
7. 14 function permits access to all the D ring functions seen in the ritterazines; see ref 4.
8. Pettit reports that ∼0.5 ton of the organisms yielded approximately 100 mg of cephalostatin 1 (1); ∼1 g of material is required for the initial phases of the trials. Personal communication, Professor G. R. Pettit, 12/94.
9. (a) Jeong, J. U.; Sutton, S. C.; Kim, S.; Fuchs, P. L. J. Am. Chem. Soc. 1995, 117, 10157.
10. (b) Kim, S.; Fuchs, P. L. Tetrahedron Lett. 1994, 35, 7163.
11. N. While this latter designation is extremely attractive in recognition of Pettit's seminal contributions to the discovery and structural elucidation of the cephalostatins, we ultimately opted for the ritterostatin appellation in deference to the "statin" suffix which provides more immediate information vis-à-vis the compound's biological activity.
12. (a) Smith, S. C.; Heathcock, C. H. J. Org. Chem. 1992, 57, 6379.
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14. Drogemuller, M.; Jautelat, R.; Winterfeldt, E. Angew. Chem., Int. Ed. Engl. 1996, 35, 1572.
15. (a) The Southern hemisphere of cephalostatin 7, "South 7", contains an acid-labile [5,6] spiroketal which undergoes extensive isomerization (<50% remaining South 7 after brief reflux at 80°C with catalytic PPTs) when heated with acid and has exhibited a tendency to isomerize under even mild provocation to a mixture of spiroketals (Jeong, J. U.; Guo, C.; Fuchs, P. L. Synthesis of the South Hexacyclic Portion of Cephalostatin 7, manuscript in preparation, and see ref 23). The 20α,22α [5,5] spiroketal isomer, precisely "South C" (the southern hemisphere of ritterazine C, is calculated to lie only 0.04 kcal above that of the natural 20α,22α [5,6] spiroketal of South 7.
16. (b) Calculations performed using CAChe 3.1; see the Supporting Information for the energies of all isomers.
17. (a) Bhandaru, S.; Fuchs, P. L. Tetrahedron Lett. 1995, 36, 8351.
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20. (b) In response to a reviewer's question, Welzel reports reactions on what he terms "Gemisches von 4 und 5" [here 13 and 14] obtained directly from photolysis of 11; Winterfeldt (ref 14a) makes no mention of the composition of his photolysate, but simply references Bladon and Welzel. However, the crude product from photolysis demonstrably contains multiple products and is not merely a mixture of 13 and 14. The amorphous mass in the mother liquor after crystallization of 13 contained little or no 14 by NMR, and its quantitative conversion to diols 15, as well as the quantitative conversion of the crude photolysate, is in our opinion a repetition of neither Winterfeldt's nor Welzel's efforts but a useful improvement;
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49. Interestingly, the Prins reaction produces a higher proportion of 15β if allowed to stir for extended periods of time. The implied equilibrium between the diols was explored by resubjecting pure 15α (the apparent kinetic product) to the reaction conditions (25°C) for 15 h, whereupon a 6:1 ratio of 15α/15β was obtained, presumably via a retro-Prins/Prins sequence. A 4:1 mixture of 15α/15β was heated at 75°C in 75% acetic acid for 15 h, at which time a 1:6 ratio of 15α/15β was produced, the thermodynamic product 15β greatly predominating; neither decomposition nor dehydration was observed. For similar evidence of such equilibrium in a related 1,3-diol, see ref 30a.
50. Corey, E. J.; Gin, D. Y.; Kania, R. S. J. Am. Chem. Soc. 1996, 118, 9202.
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52. Jeong, J. U.; Fuchs, P. L. J. Am. Chem. Soc. 1994, 116, 773-774. See also: Cameron, A. F. B.; Evans, R. M.; Hamlet, J. C.; Hunt, J. S.; Jones, P. G.; Long, A. G. J. Chem. Soc. 1955, 2807 for high-yield openings using fatty acid solvents (T > 150°C) but which also fail on unsaturated steroids.
53. Jeong, J. U.; Fuchs, P. L. J. Am. Chem. Soc. 1994, 116, 773-774. See also: Cameron, A. F. B.; Evans, R. M.; Hamlet, J. C.; Hunt, J. S.; Jones, P. G.; Long, A. G. J. Chem. Soc. 1955, 2807 for high-yield openings using fatty acid solvents (T > 150°C) but which also fail on unsaturated steroids.
54. (a) Digipurpurogenins I and II (∼30% in the photostep): Welzel, P.; Moschner, R.; Ponty, A.; Pommerenk, U.; Sengewein, H. Liebigs. Ann. Chem. 1982, 564.
55. (b) Digitoxigenin (from hecogenin acetate): Milkova, T.; Stein, H.; Ponty, A.; Böttger, D.; Welzel, P. Tetrahedron Lett. 1982, 23, 413.
56. (c) Milkova, T.; Stein, H.; Welzel, P. Liebigs. Ann. Chem. 1982, 2119.
57. (d) Bufalin (36% in the photostep): Hoppe, H.-W.; Welzel, P. Tetrahedron Lett. 1986, 27, 2459.
58. (e) Digoxigenin (72% in the photostep): Stein, H.; Welzel, P. Tetrahedron Lett. 1981, 22, 3385 and ref 30c.
59. For leading examples, see: (a) Fieser, L. F.; Fieser, M. Steroids; Rheinhold: New York, 1959, and references therein. (b) Djerassi, C. Reactions of Steroids; Holden-Day: San Francisco, 1963, and references therein.
60. For leading examples, see: (a) Fieser, L. F.; Fieser, M. Steroids; Rheinhold: New York, 1959, and references therein. (b) Djerassi, C. Reactions of Steroids; Holden-Day: San Francisco, 1963, and references therein.
61. The stereochemistry of 19 (20S,22S) was determined by Luche reduction at C-12 (13:1 β/α) followed by acetylation, and comparison of the resulting furostandiol diacetate to material previously synthesized by an independent route (S. Ma, unpublished results) for which single-crystal X-ray confirmation had been obtained.
62. For production of a related homoallylic alcohol as a minor product during the Prins, see ref 30a. Attempted equilibration of 23α by resubjection to the reaction conditions for 18 h gave unchanged 23α (89%), 23β (6%), and further 12α-hydroxy-14-alkene (5%). This confirmed both the acid-catalyzed equilibration of the diols (noted for the spirostanols 15α/15β, vide supra) and the willingness of this 12α-furostanol to produce the formal ene adduct (also probably via a retro-Prins, but conceivably via direct dehydration). An equilibration attempt on 23α at 95°C resulted in extensive decomposition.
63. Gong, J.; Fuchs, P. L. Tetrahedron Lett. 1997, 38, 787 and references therein.
64. Agyin, J. K.; Timberlake, L. D.; Morrison, H. J. Am. Chem. Soc. 1997, 119, 7945. Since the excited endocyclic C20,22 π bond resulting from intraTTET cannot relax via rotation and has no H atom within abstractable range, we consider it possible that subsequent transfer, probably through space, to the terminal 26-ene (a "free rotor", see:
65. Zimmerman, H. E.; Epling, G. A. J. Am. Chem. Soc. 1972, 94, 8749) completes the dissipation of the excitation energy. We cannot, at this point, exclude attack of the excited E ring olefin/biradical onto the 26-ene moiety, but we have no evidence for cyclic products or polymers expected from such addition, nor those from 17H abstraction. See Scheme 8a in the Supporting Information.
66. (a) Only after we obtained the X-ray of 25b, which we expected to be the 20β epimer of 25a, did we suspect this possible identity. The NMR changes seen in going from 25a to 25b are similar to those visible for the side product in 24. However, while 25a is calculated to lie only 0.83 kcal/ mol lower than 25b, 24 is calculated to lie 3.81 kcal/mol lower than (22R)-epi-24, the Prins products 23α 3.96 kcal/mol and 23β 3.90 kcal/mol lower than their respective 22R isomers, and 19 4.40 kcal/mol lower than (22R)-epi-19. In the face of such large energy differences, it seems rather more likely that any 22R epimer 25b is produced from 25a directly via Lewis acid catalysis after elimination. It remains difficult at this point to assign the identity of the side product in 24 with any certainty, and the possibility that it is the source of the unidentified side product 25e remains viable.
67. (b) For compounds 26, 27, 28, 3,12-diol 8 and deacetylated 8, each 22S isomer is calculated to lie 1.99-2.17 kcal/mol lower than its respective 22R isomer.
68. (c) All calculations performed using CAChe version 3.5.
69. (d) Brown-Jones oxidation produced even more of the impurity in 24, see ref 25. Swern conditions gave less impure product but in lower yield.
70. One referee questioned why we explored the Prins and elimination reactions to give 18 rather than access it more directly via 16: to reiterate, we had already explored the chemistry proceeding from 11 and had moved on to an alternate approach via 19 (because substrates 17 and 18 proved unstable to spiroketal opening) several months prior to the appearance of ref 14b. The ene reaction of 22 was, however, attempted. These reactions were performed on crude photolysate 22 by Mr. Zhiwei Tong. Some adjustment of conditions was attempted in order to obtain yields more like those available from crude 13 without success, but more fine-tuning of the conditions may yet provide a synthetically useful reaction for this compound.
71. X-ray data for compounds 24, 25b, and 25c have been submitted to the Cambridge Crystallographic database.
72. Kim, S. Ph.D. Thesis, Purdue University, 1994.
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74. (a) Wagner, P. J.; Kemppainen, A. E. J. Am. Chem. Soc. 1972, 94, 7495.
75. (b) Reference 21c.
76. See the expanded Scheme 10a and CAChe 3D drawings in the Supporting Information.
77. For recent advances in the addition of nitroalkanes to carbonyl compounds, see: Simoni, D.; Invidiata, F. P.; Manfredini, S.; Ferroni, R.; Lampronti, I.; Roberti, M.; Pollini, G. P. Tetrahedron Lett. 1997, 38, 2749 and references therein.
78. Procedure taken from the following: Nagarajan, S.; Ganem, B. J. Org. Chem. 1987, 52, 5044. For a review, see: Gololobov, Y. G.; Kasukhin, L. F. Tetrahedron 1992, 48, 1353.
79. Procedure taken from the following: Nagarajan, S.; Ganem, B. J. Org. Chem. 1987, 52, 5044. For a review, see: Gololobov, Y. G.; Kasukhin, L. F. Tetrahedron 1992, 48, 1353.
80. The mixing order is critical: less than 3% of α-amino enone (not shown) and 5-10% of the axial azide were produced when a cold solution of bromide 39 was added to a cold solution of TMGA prior to warming, but the reverse order produced ∼15% α-amino enone and > 10% axial azide.
81. Stein, C.; de Jeso, B.; Pommier, J. C. Synth. Commun. 1982, 12, 495.
82. We thank Professor G. R. Pettit of Arizona State University for kindly providing us with a sample of natural cephalostatin 1 (1) and Dr. Douglas Lantrip for performing the HPLC comparisons of synthetic and natural cephalostatin 1 (1).
83. See the Supporting Information for a comparison of the NMR data of each ritterostatin with its constituent subunits as observed in the relevant ritterazine or cephalostatin.
84. 50 of -8.45 (3.5 ± 0.7 nM) was observed.
85. Detailed testing information for all standard therapeutic agents (∼150) is available on the World Wide Web: http://epnws1.ncicrf.gov: 2345/dis3d/itb/stdagnt/tab.html. Useful NSC numbers: cyclophosphamide (NSC 26271), 5-fluorouracil (NSC 19893), cisplatin (NSC 119875), adriamycin (NSC 123127), tamoxifen (NSC 180973), and paclitaxel (NSC 125973). Our compliments to Professor Winterfeldt for disseminating this site in his report (ref 10) as well.
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