Taxane Anticancer Agents - ACS Publications - American Chemical

Chapter 15

Recent Advances in the Chemistry and Structure—Activity Relationships of Paclitaxel David G. I. Kingston

Downloaded by CORNELL UNIV on May 18, 2017 | http://pubs.acs.org Publication Date: December 7, 1994 | doi: 10.1021/bk-1995-0583.ch015

Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061-0212

Recent studies on the chemistry of taxol are described. Side chain chemistry includes the conversion of cephalomannine to taxol, and the attachment of the taxol side chain to baccatin III. Chemistry of the northern hemisphere includes deoxygenation at C-10 and C-7, and chemistry of the southern hemisphere includes deacetylation at C-4 and debenzoylation and reacylation at C-2; this last transformation has yielded several derivatives with significantly improved tubulin-assembly activity as compared with taxol. A summary of structure-activity relationships of taxol is given. The effectiveness of taxol (1) as a chemotherapeutic agent against ovarian and breast cancer has sparked a worldwide study of its synthesis, biosynthesis, mechanism of action, nad chemistry, and recent work in the chemical areas has been reviewed on several occasions, both by ourselves (1-4) and others (5-9). In our group we have elected to focus on the chemistry and structure-activity relationships of taxol, and this review will describe results since the publication of our recent reviews (1-4). The work will be presented in the form of a tour of the taxol structure, beginning with the side chain, and proceeding on to the northern hemisphere, and then on to the southern hemisphere. The tour will conclude with a summary of the known structure-activity relationships of taxol.

OCOPh

OH = OAc OCOPh

2 R = Ac 3 R= H

N O T E : Paclitaxel is the generic name for Taxol, which is now a registered trademark.

0097-6156/95/0583-0203$08.00/0 © 1995 American Chemical Society

Georg et al.; Taxane Anticancer Agents ACS Symposium Series; American Chemical Society: Washington, DC, 1994.

204

TAXANE ANTICANCER AGENTS


The Side Chain The partial synthesis of taxol by attachment of the β-phenylisoserine side chain to a suitably protected baccatin III (2) has been the subject of intense study, since this conversion offers the capability of preparing taxol from the much more readily available 10-deacetylbaccatin ΙΠ (3), and thus avoiding the supply problems inherent in the production of taxol from the bark of the relatively scarce and slow-growing western yew (70). Notable achievements in this area have been made by Greene (7773), Holton (14), Ojima (75), Georg (76), and Commercon (77), and Holton's βlactam process has been selected by Bristol-Myers Squibb for the synthesis of taxol from 10-deacetylbaccatin ΙΠ. One aspect of the partial synthesis of taxol that has been overlooked, however, is that of its synthesis from cephalomannine (4). Cephalomannine occurs with taxol in T. brevifolia and other Taxus species, and it can be a major component of the mixture in some situations. A method to convert cephalomannine to taxol would thus be of interest as a means of extending the usefulness of the direct isolation process. The conversion of cephalomannine to taxol could in principle be achieved by reductive removal of the side chain (18), followed by reacylation by one of the methods described above (77-77). The possibility of a direct conversion intrigued us, however, because it presented the challenge of hydrolysing an amide selectively in the presence of various ester linkages. In the event, the problem was solved by the reaction scheme shown below. Osmylation of cephalomannine as previously described (79), followed by periodate cleavage, yielded the ketoamide 5 in excellent yield. Benzoylation of 5 gave the 2-benzoyl derivative 6 in quantitative yield, and treatment of 6 with o-phenylenediamine and acid selectively cleaved the ketoamide group and allowed intramolecular 0-»N acyl transfer to occur, yielding taxol (1) in good yield. This process thus provides an efficient and high-yield pathway for the conversion of cephalomannine to taxol. The Oxazoline Route. Although the conversion described above is effective for the preparation of taxol from cephalomannine, the preparation of taxol from baccatin III remains the most important method for the semisynthesis of this compound. We thus elected to investigate this conversion. Our interest was sparked by the observation that treatment of taxol with triphenylphosphine and carbon tetrachloride converts it to a mixture of the cis~ and fra/w-oxazolines 7 and 8, with the isomer with inverted stereochemistry at C-2' (7), being the major product (Scheme 2). Hydrolysis of the minor product 8 with refluxing O.IN HC1 yielded taxol in good yield. The minor product 8 could be prepared (as its 7-triethylsilyl derivative) in excellent yield by reacting the known oxazoline 10 (20) with 7-(triethylsilyl)baccatin ΠΙ (9) in the presence of DCC and PP. The coupled product 11 was formed in 90% yield, and hydrolysis as before gave taxol in 75% yield (Scheme 2). This process thus provides an efficient method for the synthesis of taxol from 10-deacetylbaccatin ΠΙ, and it will probably be comparable with other methods in terms of overall efficiency and yield once it has been optimized (27). The Northern Hemisphere The northern hemisphere of taxol consists of the region from C-l2 to C-6, and comprises the C - l l (72) double bond, the C-10 acetoxyl group, the C-9 carbonyl group, and the C-7 hydroxyl group. We have earlier shown that the C - l l (72) double bond is resistnat both to hydrogénation (22) and to oxidation (79), and in our present studies we elected to investigate the significance of the oxygen functions at C-10 and C-7. The C-10 Acetoxyl group. The C-10 acetoxyl group was removed in a six-step sequence starting from 10-deacetylbaccatin ΠΙ (3) (Scheme 3). Treatment of 3 with triethylsilyl chloride yielded 10-deacetyl-7-(triethylsilyl) baccatin ΠΙ (12), which was Georg et al.; Taxane Anticancer Agents ACS Symposium Series; American Chemical Society: Washington, DC, 1994.

KINGSTON

Chemistry & Structure-Activity Relationships of Paclitaxel


15.

converted to its lO-(S-methylthiocarbonyl) derivative 13 with sodium hydride, carbon disulfide, and methyl iodide. Attachment of a protected C-13 side chain by Commercon's method (77) yielded the xanthate 14, which was deoxygenated by Barton-McCombie reduction (23) to yield the 10-deacetoxy derivative 15. Hydrolysis followed by benzoylation then gave 10-deacetoxy taxol (16) in 11% overall yield from 3 (24). Georg et al.; Taxane Anticancer Agents ACS Symposium Series; American Chemical Society: Washington, DC, 1994.

205

206


NaH, C S * Mel


THF, 25°

Reprinted with permission from réf. 24. Copyright 1993. With kind permissionfromElsevier Science Ltd, The Boulevard, Langford Lane, Kidlington 0X5 1GB, UK The cytotoxicity of 16 was determined in the P-388 lymphocytic leukemia cell line, and it was found to be identical to that of taxol. It is worth noting that other investigators have also prepared 10-deacetoxy taxol by different routes; thus Chen and his co-workers deoxygenated taxol through an unexpected elimination reaction (25), while recently Holton has shown that taxol can readily be deoxygenated at C10 in one step with samarium diiodide (26). The C-7 Hydroxyl Group. Deoxygenation studies at C-7 yielded some interesting chemistry, leading to a method for epimerization of the C-7 hydroxyl group in both directions (27). Thus treatment of taxol (1, Scheme 4) with sodium hydride in dry THF cleanly converted it to 7-epitaxol (17) in about 85% yield. The reverse process could be achieved by conversion of 7-epitaxol to its 2'-triethylsilyl derivative 18 and thence to its 7-(5-methylthiocarbonyl) derivative 19. During this conversion the C-7 position is epimerized back to the normal configuration, since the 7-e/?/-hydroxyl group is in a very crowded environment and cannot form a xanthate derivative. Hydrolysis of the xanthate 19 by treatment with tributtin hydride and AIBN in wet Georg et al.; Taxane Anticancer Agents ACS Symposium Series; American Chemical Society: Washington, DC, 1994.

15. KINGSTON


tributyltin toluene gave 2-(triethylsilyl)taxol 20, which could readily be hydrolyzed back to taxol. The conversion of 7-é?/?/taxol 17 to taxol 1 was achieved in 62% overall yield.


Scheme 4

1. Bu SnH, AIBN 3

2. H 0

+

3

22

21

Reprinted with permission from ref. 27. Copyright 1993

7-Desoxytaxol was prepared in good yield by deoxygenation of the xanthate 19 under standard conditions, to give the 7-desoxyderivative 21. Hydrolysis of 21 then gave 7-desoxytaxol, 22. This compound was somewhat more active than taxol in the P-388 cytotoxicity assay (27), but it was only as active as taxol in the HCT116 cytotoxicity assay (28). The Southern Hemisphere Changes to the northern hemisphere appear to make little difference to the bioactivity of taxol, but the same is not true of the southern hemisphere. Here, relatively minor changes in the structure of the molecule can have profound consequences on its activity, as described below. The Oxetane Ring. The first indication that the southern hemisphere was important to the activity of taxol came from studies that we carried out on the oxetane ring Georg et al.; Taxane Anticancer Agents ACS Symposium Series; American Chemical Society: Washington, DC, 1994.

207

208

T A X A N E ANTICANCER AGENTS

(29). Taxol analogues in which the oxetane ring was opened, such as the Dsecotaxol 23, were uniformly inactive in both tubulin-assembly and cytotoxicity assays. As a follow-up to this work, we chose to examine the effect of the formation of a tetrahydrofuran ring in place of the oxetane ring. Both we (27) and others (30,31) had discovered that baccatin ΙΠ rearranges to an isomeric tetrahydrofuran derivative such as 24 on treatment with certain acidic or basic reagents. The effect of such a modification on the activity of taxol was unknown, however. HQ PhCONH

Ο

OTES

Ο


OH OH

"HO

I HO^OAc OCOPh

23

Treatment of taxol with di-r-butyl dicarbonate and DMAP under forcing conditions gave a mixture of products from which the tri-i-BOC derivative 25 could be isolated in reasonable yield. Treatment of this product with LiOH gave the rearranged product 26, in which the 2-benzoate group had been hydrolyzed and the resulting alkoxide ion had attacked the oxetane ring. Benzoylation with benzoic acid and DCC, followed by removal of the BOC groups with formic acid, then yielded the isotaxol derivative 27, in which the oxetane ring has been replaced by a tetrahydrofuran ring (Scheme 5). This compound was less active than taxol in the P388 cytotoxicity assay. This result thus confirms and extends our earlier observations (29) on the necessity of the oxetane ring for the activity of taxol. Scheme 5

The C-4 Acetate. Given that the oxetane ring is required, the question then arose as to the importance of the C-4 acetate group. This question was resolved by the development of various selective methods for the hydrolysis of this group. In one method, 7-(triethylsilyl)baccatin III (9) was converted to its 4, 10-dideacetyl derivative 28 in 72% by treatment with potassium-ί-butoxide. Coupling with Commercon's side chain (77) gave the product 29, which was acetylated to give the Georg et al.; Taxane Anticancer Agents ACS Symposium Series; American Chemical Society: Washington, DC, 1994.

15.

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corresponding 10-acetate 30. Deprotection with formic acid and benzoylation then gave 4-deacetyl taxol (31) in 46% yield from 30 and 16% overall yield from 9 (Scheme 6) (Neidigh et al., Tetrahedron Lett., in press).


A second process for the preparation of 31 proved to be even more efficient. Treatment of taxol with t-butyldimethylsilyl chloride followed by triethylsilyl chloride yielded the diprotected derivative 32, which was converted to its 2debenzoyl-4-deacetyl derivative 33 in 69% yield on treatment with benzyltrimethylammonium methoxide in methanol. Rebenzoylation (PhCC^H, DCC, DMAP), followed by deprotection gave 4-deacetyltaxol 31 in 42% overall yield from taxol (Scheme 7) (Neidigh et al., Tetrahedron Lett., in press). The bioactivity of 31 proved to be slightly less than that of taxol in the P-388 cytotoxicity assay, suggesting that the C-4 acetate group only makes a small contribution to the activity of taxol. Deoxygenation at C-2. Removal of the benzoyloxy group at the C-2 position has been accomplished in at least two ways. In one approach, 2-debenzoyltaxol was prepared in a nine-step sequence from baccatin ΠΙ by Chen et al. (33). In the second approach, we prepared l-benzoyl-2-debenzoyloxytaxol from taxol in three steps by the route shown in Scheme 8. Scheme 6


209

210


Scheme 7 AcO Ph^MH

Ο OH

AcO

1. TBDMSCI, Imid., DMF, 60 - 65oC,

p

QSiEta

n

V

Ο

PrT OH

M

DMF, r.t., 1hr (80 - 90%)

HO OAcO

t

OSiBirMe

2

HO QAcO 7=0 32 Ph

1 Ph

CH2CI2,


Phi

AcO

N^MeO-

OH

p

-78°C to r.t., 12 min

AcO

Ο

OSiEto

1. PhCOOH, DCC, DMAP 2. HCI OSiBu'M^

OH 33

Scheme 8 AcQ

p

QSiEta

PhCONH Ο

PhCONH Ο Ph' OSiEt

3

3

5

Ph SMe

Bu SnH, AIBN, Toluene, 900 3

AcO

Ο 5% HCI MeOH PhCONH Ο

Ph^VV OSiEt

3

l

2 ,7-Di(triethylsilyl)taxol (34) was treated with carbon disulfide, sodium hydride, and methyl iodide in an attempt to prepare the l-(S-methylthiocarboxyl) derivative. To our surprise, the product obtained was l-benzoyl-2-debenzoyl-2-(Smethylthiocarboxyl)taxol 35, in which the C-2 benzoate group had undergone an Georg et al.; Taxane Anticancer Agents ACS Symposium Series; American Chemical Society: Washington, DC, 1994.

15.

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acyl migration to the C-l position. The structure of 35 was confirmed by HMBC experiments, which showed three-bond correlations from the SMe protons to the thiocarbonyl carbon, and from the C-2 proton to the thiocarbonyl carbon. Deoxygenation of 35 in the usual way then gave the 2-desoxy derivative 36, which was deprotected to yield l-benzoyl-2-debenzoyloxytaxol (37). This product, like 2debenzolyoxy taxol itself (32), was much less cytotoxic than taxol, suggesting the need for a benzoyl or other aroyl group at the 2-position of taxol for bioactivity. It should also be noted that the baccatin III analog of compound 37 has recently been prepared by Chen and his co-workers, although the mechanism proposed for the conversion differed slightly from that described above (33). Preparation of 2-Aroyl-2-debenzoyltaxol Analogs. Given the significance of the 2-benzoate group of taxol described above, it became of interest to prepare various 2aroyl-2-debenzoyl analogs. One method for accomplishing this was by a modification of the pathway of Scheme 5. If the hydrolysis of 25 with LiOH was carried out under carefully controlled conditions, oxetanering-openingcould be avoided and the resulting 2-debenzoyltaxol could be rebenzoylated and deprotected to yield 2-aroyl-2-debenzoyltaxol analogs. A better approach, however, became available through studies on phasetransfer catalysis of taxol hydrolysis (34). Treatment of 2',7-di(triethylsilyl)taxol (34 ) with sodium hydroxide in benzeneidichloromethane with aqueous NaOH and a PTC catalyst yielded the 2-debenzoyl derivative 38 in 65-75% yield (Scheme 9). Reacylation of 38 under controlled conditions, followed by deprotection, then gave 2-aroyl-2-debenzoyltaxol analogs of general structure 40, where ArCO is any desired aroyl group. Scheme 9

ArCOOH DCC/PP 83%

Interestingly, the bioactivities of analogs of general structure 40 are highly variable, depending on the nature of the aroyl group (Table I). Analogs with a parasubstituted ring were uniformly much less active than taxol, except for the small pfluoro substituent. Analogs with meto-substituted rings were, however, often more cytotoxic than taxol. This increased activity was particularly marked with the mchloro, m-azido, and m-methoxy substituted analogs. Georg et al.; Taxane Anticancer Agents ACS Symposium Series; American Chemical Society: Washington, DC, 1994.

111

212


Table I. Cytotoxicity of 2-Aroyl-2-debenzoyltaxol Analogs 40.


Substituent onAr

Cytotoxicity in the P-388 assay, ortho meta

ED50ÎED50

para

CI

0.01

0.0014

150

CN

N.D.

0.33

28

N

N.D.

0.002

175,000

OCII3

N.D.

0.001

N.D.

N0

2

N.D.

0.3

8.3

NH

2

N.D.

1500

N.D.

N.D.

15

28

0.07

0.35

0.5

3

CF F

3


(taxol)

15.

KINGSTON


213


Additional studies of these exciting new analogs were carried out by our colleague Dr. B. Hamel at the National Cancer Institute. In these studies (35), the three anlaogs referred to above were all found to promote the assembly of tubulin to microtubules more efficiently than taxol (Table Π). In addition, the m-azido and, to a small extent, the m-methoxy analogs assembled tubulin under conditions where taxol was unable to do so (Figure 1). These data thus confirm and extend the results of Table I, and offer an exciting glimpse of possible enhancements of taxol's activity by carefully chosen structural modifications.

Table Π. Comparison of Taxol and C-2-Derivatives on Assembly Rates at 15°C and Extent of Assembly at 37°C Compound

10 μΜ drug Maximum Rate Extent atl5°C (Relative to Taxol) munits ΔΑ 350/ min ΔΑ350

2

l

40 μΜ drug Maximum Rate Extent at 150C (Relative to Taxol) munits ΔΑ 350/ min ΔΑ350

2

1

Taxol (1)

1.2(1)

0.38 (1)

23(1)

0.60 (1)

6a (m-N )

119(99)

0.34 (0.9)

NM3

0.60 (1)

6e (m-OCH )

51 (43)

0.37 (1)

271 (12)

0.54 (0.9)

6g(m-Cl)

28 (23)

0.38 (1)

128 (6)

0.44 (0.7)

6c (m-CN)

1.3(1.1)

0.40(1.1)

33 (1.4)

0.51 (0.9)

61 (o-Cl)

0.7 (0.6)

0.25 (0.7)

9.3 (0.4)

0.43 (0.7)

6h (p-Cl)

0(0)

0.15 (0.4)

0(0)

0.32 (0.5)

6f(p-OCH ) 3

0(0)

0(0)

0(0)

0(0)

6d(p-CN)

0(0)

0(0)

0(0)

0(0)

6b (p-N )

0(0)

0(0)

0(0)

0(0)

3

3

3

^The maximum assembly rate at 1 5 ° C was determined from the experiments shown in Fig. 1, together with additional experiments performed with analogs at 10 μ Μ that are not presented here. Individual experiments were performed with 4 samples in the spectrophotometers, with a dwell time at each position of 5 sec. About 0.42 min. elapsed between successive readings at each position. The maximum interval increase in reading was used to calculate the maximum rate. ^Maximum extent of assembly was determined from the same experiments, subtracting the initial turbidity reading at 0 ° C from the final reading at 3 7 ° C . ^NM, not meaningful, since the reaction at 0 ° C was so extensive (see Fig. 1).

SOURCE: Reprinted with permission from ref. 34. Copyright 1994.


214


Summary and Conclusions


The work that we and others have done on structure-activity correlations for taxol can be summarized by the chart of Figure 2 (36). Although much has been accomplished in this area, much yet remains to be done, and it is expected that continuing studies will yield further insights into the chemistry and bioactivity of this fascinating molecule. Ultimately, it seems highly likely that taxol analogs with significantly improved clinical bioactivities will be developed through research such as we and others have carried out. acetyl or acetoxy] group may be removed without significant loss of activity

reduction improves activity slightly

may be esterified| epimerized or removed without significant loss of activity

oxetane ring) required for activity

phenyl group or a close analog required

removal of acetate reduces activity slightlJ free 2-hydroxyl group, or a hydroly sable ester thereof required

benzoyloxy group essential; certain substituted groups have improved activity

Figure 2. Structure-activity relationships of taxol Reproduced with permission from ref. 35. Copyright 1994. Acknowledgments The work from my laboratory has been carried out with the help of an able and dedicated group of co-workers. The recent work described in this report was carried out by Dr. A. G. Chaudhary, Dr. M . D. Chordia, Dr. M . M . Gharpure, Dr. A. A. L. Gunatilaka, Mr. K. A. Neidigh, and Mr. (now Dr.) J. M . Rimoldi. Biological work was carried out by Dr. E. Hamel and his co-workers at the National Cancer Institute. To all of these associates I owe a great debt of gratitude, since the work described is really theirs and not mine. Financial support from the National Cancer Institute (Grants CA 55131 and CA 48974) and Bristol-Myers Squibb is gratefully acknowledged, and Dr. K. Snader (National Cancer Institute) is thanked for a gift of crude taxol-containing fractions from T. brevifolia.


15.

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215

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(4)


(5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) (27)

Kingston, D. G. I.; Samaranayake, G. ; Ivey, C. A. J. Nat. Prod., 1990 , 53:, 1-12. . Kingston, D. G. I. Pharmac. Ther. 1991, 52, 1-34. Kingston, D. G. I.; Molinero, Α. Α.; Rimoldi, J. M. In Progress in the Chemistry of Organic NaturalProducts;W. Herz; G. W. Kirby; R. E. Moore; W. Steglich and C. Tamm, Ed.; Springer-Verlag: New York, 1993; Vol. 61; pp 1-206. Kingston, D. G. I. In Human Medicinal Agents fromPlants;A. D. Kinghorn and M. F. Balandrin, Ed.; American Chemical Society: Washington, D. C., 1993; Vol. 534; pp 138-148. Suffness, M.; Cordell, G. A. In The Alkaloids; A. Brossi, Ed.; Academic Press: Orlando, 1985; Vol. 25; pp 1-369. Blechert, S.; Guenard, D. In The Alkaloids, Chemistry andPharmacology;A. Brossi, Ed.; Academic Press, Inc.: San Diego, 1990; Vol. 39; pp 195-238. Guénard, D.; Guéritte-Voegelein, F.; Potier, P. Acc. Chem. Res. 1993, 26, 160-167. Nicolaou, K. C.; Dai, W.-M.; Guy, R. K. Angew. Chem. Int. Ed. Engl. 1994, 33, 15-44. Swindell, C. S. In Studies in Natural Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier Science Publishing: New York, 1993; Vol. 12; pp 179-231. Cragg, G. M.; Schepartz, S. Α.; Suffness, M.; Grever, M. R. J. Nat. Prod. 1993, 56, 1657-1668. Denis, J.-N.; Greene, A. E.; Guénard, D.; Guéritte-Voegelein, F.; Mangatal, L.; Potier, P. J. Am. Chem. Soc. 1988, 110, 5917-5919. Denis, J.-N.; Kanazawa, A. M.; Greene, A. E. Tetrahedron Lett. 1994, 35, 105-108. Kanazawa, A. M.; Denis, J.-N.; Greene, A. E. J. Org. Chem. 1994, 59, 12381240. Holton, R. A. Eur. Pat. Appl. EP 400,971 1990: 05 December (Chem. Abstr. 1991 164568q). Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.; Park, Y. H.; Sun, C. M.; Brigaud, T. Tetrahedron 1992, 48, 6985-7012. Georg, G. I.; Cheruvallath, Z. S.; Harriman, G. C. B.; Hepperle, M.; Park, H. Bioorg. Med. Chem. Lett. 1993, 3, 2467-2470. Commerçon, Α.; Bezard, D.; Bernard, F.; Bourzat, J. D. Tetrahedron Lett. 1992, 33, 5185-5188. Magri, N. F.; Kingston, D. G. I.; Jitrangsri, C.; Piccariello, T. J. Org. Chem., 1986, 51, 3239-3242. Kingston, D. G. I.; Gunatilaka, A. A. L.; Ivey, C. A. J. Nat. Prod. 1992, 55, 259-261. Gou, D.; Liu, Y.; Chen, C. J. Org. Chem. 1993, 58, 1287-1289. Kingston, D. G. I.; Chaudhary, A. G.; Gunatilaka, A. A. L.; Middleton, M. L. Tetrahedron Lett. 1994, 35, 4483-4484. Samaranayake, G.; Neidigh, Κ. Α.; Kingston, D. G. I. J. Nat. Prod. 1993, 56, 884-898. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. I 1975, 1574-1585. Chaudhary, A. G.; Kingston, D. G. I. Tetrahedron Lett. 1993, 34, 4921-4924. Chen, S.-H.; Fairchild, C.; Mamber, S. W.; Farina, V. J. Org. Chem. 1993, 58, 2927-2928. Holton, R. Α.; Somoza, C.; Chai, K.-B. Tetrahedron Lett. 1994, 35, 16651668. Chaudhary, A. G.; Rimoldi, J. M.; Kingston, D. G. I. J. Org. Chem. 1993, 58, 3798-3799. Georg et al.; Taxane Anticancer Agents ACS Symposium Series; American Chemical Society: Washington, DC, 1994.

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Chen, S.-H.; Huang, S.; Kant, J.; Fairchild, C.; Wei, J.; Farina, V. J. Org. Chem. 1993, 58, 5028-5029. Samaranayake, G.; Magri, N. F.; Jitrangsri, C.; Kingston, D. G. I. J. Org. Chem. 1991, 56, 5114-5119. Farina, V.; Huang, S. Tetrahedron Letters 1992, 33, 3979-3982. Wahl, Α.; Guéritte-Voegelein, F.; Guénard, D.; Le Goff, M.; Potier, P. Tetrahedron 1992, 48, 6965-6974. Chen, S.-H.; Wei, J.-M.; Farina, V. Tetrahedron Lett. 1993, 34, 3205-3206. Chen, S.-H.; Huang, S.; Gao, Q.; Golik, J.; Farina, V. J. Org. Chem. 1994, 59, 1475-1484. Chaudhary, A. G.; Gharpure, M. M.; Rimoldi, J. M.; Chordia, M. D.; Gunatilaka, A. A. L.; Kingston, D. G. I.; Grover, S.; Lin, C. M.; Hamel, E. J. Am. Chem. Soc. 1994, 116, 4097-4098. Kingston, D. G. I. Trends Biotechnol. 1994, 12, 222-227.

R E C E I V E D August 8, 1994


Taxane Anticancer Agents - ACS Publications - American Chemical

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