ORGANIC LETTERS
Tandem RCM of Dienynes for the Construction of Taxol-Type Carbocyclic Systems
2004 Vol. 6, No. 2 193-196
Rebeca Garcia-Fandin˜o, Eva M. Codesido, Eduardo Sobarzo-Sa´nchez, Luis Castedo, and Juan R. Granja* Departamento de Quı´mica Orga´ nica e Unidade Asociada o´ CSIC, Facultade de Quı´mica, UniVersidade de Santiago, 15706 Santiago de Compostela, Spain
[email protected] Received October 22, 2003
ABSTRACT
Tandem ring-closing metathesis of hydrindanone dienynes allows access to taxosteroids, a new class of compounds that combine the [5.3.1] carbocyclic system of taxanes with rings C and D of the steroid skeleton.
Interest in polycyclic systems containing eight-membered carbocycles stems both from the synthetic challenge of their construction and from their wide range of biological activities.1 We have recently embarked on the preparation of linearly fused 6-8-6 carbocyclic systems with a view to obtaining steroid-like compounds that simulate the transitionstate structure of the previtamin-vitamin D3 isomerization process.2 For these syntheses, we have developed a very efficient ring-closing metathesis reaction (RCM)3 that allows efficient construction of the desired systems from dienyne 2a.2a Here, we report that RCM of dienyne 2b achieves one(1) For reviews, see: (a) Oishi, T.; Ohtsuka, Y. In Studies in Natural Products Synthesis; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1989; Vol. 3, pp 73-115. (b) Petasis, N. A.; Patane, M. A. Tetrahedron 1992, 48, 5757-5821. (c) Rousseau, G. Tetrahedron 1995, 51, 2777-2849. (d) Molander, G. A. Acc. Chem. Res. 1998, 31, 603-609. (e) Mehta, G.; Singh, V. Chem. ReV. 1999, 99, 881-990. (2) (a) Codesido, E. M.; Castedo, L.; Granja, J. R. Org. Lett. 2001, 3, 1483-1486. (b) Codesido, E. M.; Castedo, L.; Granja, J. R. Org. Lett. 2002, 4, 1651-1654. (3) For reviews of metathesis, see: (a) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012-3043. (b) Chang, S.; Grubbs, R. H. Tetrahedron 1998, 54, 4413-4450. For a recent view of the synthesis of medium-sized rings by RCM, see: (c) Maier, M. E. Angew. Chem., Int. Ed. 2000, 39, 20732077. For a more general review of the synthesis of medium-sized rings, see: (d) Yet, L. Chem. ReV. 2000, 100, 2963-3007. 10.1021/ol036062m CCC: $27.50 Published on Web 12/19/2003
© 2004 American Chemical Society
step construction of the [5.3.1] system of Taxol (1), within a “taxosteroid” structure in which the [5.3.1] system is fused to the [4.3.0] bicycle constructing rings C and D of the steroid system. Interest in this type of structure derives from the recently shown ability of synthetic 2-ethoxyestradiol and steroid analogues to mimic paclitaxel in increasing tubulin assembly and stabilizing microtubules.4 Following our success with dienyne 2a,2a we wished to evaluate the scope of dienyne RCM5 for the construction of polycarbocyclic systems containing an eight-membered ring. We envisaged that elongation of the alkynyl chain (n ) 1) would allow construction of the bicyclo[5.3.1]undecadiene system characteristic of taxanes (Figure 1).6 The use of hydrindanone 3 as a platform would both aid formation of (4) Wang, Z. Q.; Yang, D. L.; Mohanakrishnan, A. K.; Fanwick, P. E.; Nampoothiri, P.; Hamel, E., Cushman, M. J. Med. Chem, 2000, 43, 24192429. Wu, J. H.; Batist, G.; Zamir, L. O. Anti-Cancer Drug Design 2001, 16, 129-133. (5) (a) Kim, S.-H.; Bowden, N.; Grubbs, R. H. J. Am. Chem. Soc. 1994, 116, 10801-10802. (b) Kim, S.-H.; Zuercher, W. J.; Bowden, N. B.; Grubbs, R. H. J. Org. Chem. 1996, 61, 1073-1081. (c) Zuercher, W. J.; Scholl, M.; Grubbs, R. H. J. Org. Chem. 1998, 63, 4291-4298. (d) Fu¨rstner, A.; Liebl, M.; Hill, A. F.; Wilton-Ely, J. D. E. T. Chem. Commun. 1999, 601-602. (d) Boyer, F.-D.; Hanna, I.; Ricard, L. Org. Lett. 2001, 3, 30593098.
Scheme 1 a
Figure 1. Retrosynthetic analysis of the construction of the taxosteroid skeleton by RCM of dienyne 2b.
the eight-membered ring2 and provide a CD system on which the side-chain characteristic of steroids could be introduced. Like 2a, dienyne 2b would be prepared from ketone 3 by alkylation of its kinetic enolate followed by ketone allylation. The alkylating agent, iodide 5a, was prepared in four steps from 4-hexenoic acid by esterification with methyl iodide in basic DMF, alkylation of the LDA-generated enolate of the resulting ester, reduction with lithium aluminum hydride, and treatment of the resulting alcohol with triphenylphosphine, imidazole, and iodine (Scheme 1). Iodide 5a was reacted with the kinetic enolate of 3 (formed by reaction with potassium hexamethyldisilazide in 1:1 DMF/toluene at -80 °C),7 and the resulting ketone 6a was allylated, giving dienyne 7a in 59% yield (from 3) as an inseparable 1:1 mixture of C10-epimers. Treatment of 7a with 15% of Grubbs catalyst 11a provided a 2:2:1 mixture of RCM products 8a, 9a, and 10 with a global yield of 44%. Compound 8a is formed by simple diene RCM. Compound 10 is a single isomer, suggesting that only one of the diastereomers of 7a can undergo the double cyclization, the other giving compound 9a (an hypothesis that was confirmed by the nonformation of 10 upon treatment of triene 9a with catalysts 11a or 11b). Although the above results showed the feasibility of the proposed strategy, the Taxol-like skeleton was only a minor product. (6) Taxol: Science and Applications; Suffness, M., Ed.; CRC: Boca Raton, FL, 1995. Taxane Anticancer Agents: Basic Science and Current Status; Georg, G. I., Chen, T. T., Ojima, I., Vyaqs, D. M., Eds.; ACS Symposium Series 583; American Chemical Society: Washington, DC, 1995. Kingston, D. G. I.; Jagtap, P. G.; Yuan, H.; Samala, L. Prog. Chem. Org. Prod. 2002, 84, 53-225. Mekhail, T. M.; Markman, M. Expert Opin. Pharmacother. 2002, 3, 755-766. Miller, M. L. Ojima, I. Chem. Rec. 2001, 1, 195-211. Kingston, D. G. I. Chem. Commun. 2001, 867-880. Nicolaou, K. C.; Guy, R. K. Angew. Chem., Int. Ed. Engl. 1995, 34, 2079-2090. Rowinsky, E. K.; Cazenave, L. A.; Donebower, R. C. J. Natl. Cancer Inst. 1990, 82, 1247-1259. (7) Palomo, C.; Oiarbide, M.; Mielgo, A.; Gonza´lez, A.; Garcı´a, J.; Landa, C.; Lecumberri, A.; Linden, A. Org. Lett. 2001, 3, 3249-3252. 194
a
Key: (a) MeI, CO3Na, DMF, 77%; (b) LDA, propargyl bromide, THF, 43%; (c) LiAlH4, THF, 94%; (d) I2, PPh3, imidazole, 85%; (e) (i) KHMDS, toluene/DMF, -78 °C, (ii) 5a, 79%; (f) allylMgBr, THF, 95%; (g) 11a, CH2Cl2, ∆, 44%.
We therefore decided to try the more reactive Grubbs catalyst 11b,8 which has also been shown to be very useful for dienyne RCM.5d To our surprise, none of the previous compounds containing eight-membered rings were formed when dienyne 7a was treated with this catalyst; only the triene 12a was isolated (Scheme 2).
Scheme 2
These results suggest a different reaction mechanism for catalysts 11a and 11b due to their binding to the substrate at different sites. In the case of 11a, it would appear that (8) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953-956. Org. Lett., Vol. 6, No. 2, 2004
initial reaction of the catalyst with the less-substituted double bond allows reaction of the resulting intermediate 13a with either the other olefin (generating enyne 8a) or with the alkynyl group (affording the new vinylideneruthenium(II) intermediate 14a); RCM of the R isomer of 14a would then afford 10, while the S isomer, cyclization of which would be prevented by its geometry,9 would react with another molecule of 7a (CM), generating a new molecule of 13a and leaving compound 9a as product. In the case of 11b, on the other hand, it would seem that initial reaction of the catalyst with the acetylene group must provide the conjugated metallovinylidene 15a, in which the Ru would react preferentially to form the cyclopentene 12a (thermodynamically more stable than the cyclooctene alternative) despite the formation of the five-membered ring requiring reaction with the more substituted olefin.
Table 1. Results of Subjecting Substrates 6 to RCM Conditions
relative ratiosb entry
7a
R1
R2
R3
catalyst
1 2 3 4 5 6 7 8 9
7a 7a 7b1 7b2 7c1 7c2 7d 7d 7e
Me Me Et Et H H Me Me Me
H H H H iPr iPr Me Me Me
H H H H H H H H Me
11a 11b 11a 11a 11a 11a 11a 11b 11a
8
9
10
12
40 40 20 0 0 0 0 100 50 0 50d 0 90 0 0 10 0 11 89d 0 0 100 0 0 0 80 0 20 0 0 0 100 0 100 0 0
global yieldc 44 20 80 97 90 55 60 20 38
a C10 epimers separated by flash chromatography are differentiated by an arbitrary suffix, where 1 denotes the 10R-isomer and 2 the 10S-isomer. b Relative ratios were calculated by NMR of crude mixture. c Global isolated yields. d Higher isolated yields of 10 were obtained when neutral alumina was used to purify the crude RCM product.
Since the use of catalyst 11b had failed to improve the yield afforded by substrate 7a, we prepared the alternative substrates 7b-e (Table 1), which were designed to prevent the undesired formation of the diene RCM products (8) and/ or the tetraene intermediates 15. The method used to obtain the alkylating agents needed it to prepare these substrates is shown in Scheme 3: propargylation of the triethyl methanetricarboxylate, followed by decarboxylation and in situ Org. Lett., Vol. 6, No. 2, 2004
Scheme 3 a
a Key: (a) NaOEt, BrCH CCH, THF, ∆, 86%; (b) NaOEt, 2 BrCH2CHCH-R, 77-85%; (c) NaOEt, EtOH, 32-55%; (d) LiAlH4, THF, 89-94%; (e) I2, PPh3, imidazole, 86-98%.
alkylation of the resulting anion of the diethyl ester of 2-propargylmalonate, and then decarboxylation, reduction, and iodine substitution provided the iodides 5a-c. The results of using the various substrates with 11a or 11b are listed in Table 1. Substrates 7a, 7b, and 7c all afforded the desired taxosteroid 10, but as expected, the yield increased upon increasing the steric impediment to the diene RCM (R1 or R2 ) Me, Et, i-Pr; entries 1, 3, and 5). In the case of 7b and 7c,10 it was possible to separate the two C10 diastereomers, and as expected, only one gave the desired product 10 (entries 3 and 5).11 Neither of the substrates with a disubstituted olefin afforded compound 10. With 7d, the use of catalyst 11a led to triene 9d as major product (48%), while the use of 11b produced 12d.12 With 7e, in which the alkynyl group is also methylated, catalyst 11a afforded triene 9e in 48 % yield as the sole isolable product. These results show that formation of the [5.3.1] bicyclic-ring system by RCM is possible, but it also suggests that only one of the isomers can adopt the conformation necessary for the annulation. Selection of appropriate substituents on the olefin allows the tuning of the RCM process. In view of the molecular mechanical evidence that only the R C10 isomers of 14 can cyclize, and in order to establish the configuration of the taxosteroids, we prepared enantiopure alkylating agent 5c. Stereoselective alkylation of (4E)-6methyl-4-heptenoic13 acid (16) with 1-bromo-3-trimethylsilylpropyne using (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone as chiral auxiliary, followed by reduction with lithium aluminum hydride, desilylation with TBAF, and treatment with iodine/triphenylphosphine, provided 5c-(S) (Scheme 4).14 Alkylation of the kinetic enolate of 3 with iodide 5c-(S), followed by allylation of the resulting ketone, then gave a 74% yield of compound 7c-(R), the spectroscopic characteristics of which agreed with those of the reactive 7c epimer. The stereochemistry of 10 at C10 was confirmed (9) As is supported by molecular mechanical calculations. (10) Alkylation of the kinetic enolate of 3 with iodide 5c gave the two C10-diastereomers in 4:1 ratio, the one affording compound 10 being the minor isomer. (11) The other isomer failed to afford 10 even when other conditions were tried (different solvent, catalyst, etc.). (12) Treatment of compound 9d with 11b for 12 h gave compound 10 in 18% yield. (13) Kaga, H.; Goto, K.; Takahashi, T.; Hino, M.; Tokuhashi, T.; Orito, K. Tetrahedron 1996, 52, 8451-8470. (14) The enantiomeric excess was determined by using the Mosher modified method; see: Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543-2549. 195
Scheme
4a
a Key: (a) (i) pivaloyl chloride, Et N, THF, -78 °C, (ii) (4R,4S)3 (+)-4-methyl-5-phenyl-2-oxazolidinone, DMPA, rt, 80%; (b) LiHMDS, BrCH2CCTMS, THF, -78 °C, 67%; (c) LiAlH4, THF, 0 °C; (d) TBAF, THF, 90% (two steps); (e) I2, PPh3, imidazole, 75%; (f) (i) KHMDS, DMF, -78 °C, (ii) 5c-(S), 70%; (g) allylMgBr, THF, 90%; (h) 11a, CH2Cl2, ∆, 90%.
when subjecting 7c-(R) to the RCM condition that with 11a as catalyst afforded 10 in 80% yield. In conclusion, we have shown for the first time that [5.3.1] systems can be constructed by tandem ring-closing metathesis
196
of dienynes and have used this approach to construct the first member of a novel class of compounds that we have called taxosteroids because they contain both the characteristic [5.3.1] system of taxanes and the side chain and CD system of steroids. Studies aimed at introducing additional functional groups on the taxosteroid skeleton and at establishing the pharmacological and biological properties of the new compounds are underway. It is envisaged that this approach should allow access to other complex polycyclic systems starting from conformationally locked cycloalkanones. Acknowledgment. Financial support from the Ministerio de Ciencia y Tecnologı´a and the Xunta de Galicia, under projects SAF2001-3120 and PGIDIT02PXIC20902PN, respectively, is gratefully acknowledged. We also thank the Xunta de Galicia and Ministerio de Ciencia y Tecnologı´a (FPI) for fellowships awarded to R.G.-F. Supporting Information Available: Experimental procedure as well as 1H and 13C NMR spectra of compounds 4, 5a-d, 5c-(S), 6a-e, 6c-(R), 7a, 7b-(R), 7b-(S), 7c-(R), 7c-(S), 7e, 17, 19c, and 10. This material is available free of charge via the Internet at http://pubs.acs.org. OL036062M
Org. Lett., Vol. 6, No. 2, 2004
