Such substrate-controlled selectivity in RCM, though sometimes favors the formation of
2.4 Z-‐Selective Macrocyclic RCM en route to Epothilone C
The next objective of our studies is to examine the catalytic RCM reaction that has served as precursors to biologically important macrolactone epothilone C (2.4, Table 2.4) and A. As discussed in earlier sections, lack of stereoselectivity in the late-stage RCM reactions significantly reduce the efficiency of the synthesis; further complicating the matter, as reported previously and in our experience, the desired isomer of macrocyclic alkene is virtually inseparable from the E isomer. Moreover, it has been demonstrated that olefin geometry of the macrolactone impacts the level of biological activity.32 Additionally, obtaining the desired macrocyclic alkene precursor is prerequisite because the subsequent functionalization has to
(31) Lehmann, J.; Tochtermann, W. Tetrahedron 1999, 55, 2639–2644.
(32) Altmann, K. H.; Bold, G.; Caravatti, G.; Denni, D.; Florsheimer, A.; Schmidt, A.; Rihs, G.; Wartmann, M. Helv.
Chim. Acta 2002, 85, 4086–4110.
proceed with the desired sense of stereochemical control, for examples, epoxidation to epothilone A or cyclopropanation33 to an analog.
Our major goal is to showcase the practical utility of the catalytic RCM approach by an efficient and highly Z-selective RCM leading to epothilones, particularly if performed on a large scale and in a practical manner. Such an approach would represent notable implications regarding the efficiency with which macrocyclic natural products and their corresponding analogues, including those not accessible through fermentation procedures, can be accessed.
Furthermore, the epothilone precursor is significantly more functionalized than the simpler substrates, thus its conformational availability is more limited than those studied earlier.
Accordingly, we set out to establish whether the requirements for stereoselective epothilone RCM are distinct from those that influence cyclizations furnishing the less substituted macrocycles.
(33) Johnson, J.; Kim, S.; Bifano, M.; Dimarco, J.; Fairchild, C.; Gougoutas, J.; Lee, F.; Long, B.; Tokarski, J.; Vite, G. Org. Lett. 2000, 2, 1537–1540.
O Table 2.4: Catalytic RCM for Stereoseletive Total Synthesis of Epothione C a
a Reactions were carried out in benzene or toluene under an atmosphere of nitrogen gas or a vacuum, as noted. b Complexes 2.26 and 2.28 were prepared before use; Alkylidene 2.24 and 2.25 were synthesized in situ from the corresponding bis-pyrrolide and aryl alcohol. c Conversion and Z:E ratios were determined by analysis of 400 MHz 1H NMR spectra of unpurified mixtures; d Yields of purified products.
N
As investigated by several research groups, however, the desired Z olefin was formed as the minor isomer in most cases of their RCM-based approach.34 The example in entry 1 of Table 2.4 is illustrative: with 5 mol % Hoveyda-Grubbs 2nd generation catalyst, only 34% Z isomer is obtained along with 66% E olefin. Treatment of diene 2.39 with Mo-based 2.24 leads to 57%
conversion and a reversal of selectivity in favor of the desired Z isomer (64% Z, entry 2, Table 2.4). Under the same conditions, adamantylimido complex 2.25 gives rise to 85% Z selectivity and an improved conversion, presumably as a result of a more accessible metal center and larger
(34) (a) Ref 11. For reviews on RCM approaches to epothilones, see: (b) Harris, C. R.; Danishefsky, S. J. J. Org.
Chem. 1999, 64, 8434–8456. (c) Mulzer, J. J. Monat. Chem. 2000, 131, 205–238. (d) Nicolaou, K. C.; Ritzen, A.;
Namoto, K. Chem. Commun. 2001, 1523–1535. (e) Rivkin, A.; Cho, Y.; Gabarda, A.; Yoshimura, F.; Danishefsky, S. J. J. Nat. Prod. 2004, 67, 139–143. (f) Rivkin, A.; Chou, T.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2005, 44, 2838–2850. (g) Altmann, K.; Pfeiffer, D.; Arseniyadis, S.; Pratt, B. A.; Nicolaou, K. C. ChemMedChem. 2007, 2, 396–423. (h) Mulzer, J.; Altmann, K.; Hofle, G.; Müller, R.; Prantz, K. Chimie 2008, 11, 1336–1368.
size differential between the aryloxide and the alkylimido unit (entry 3, Table 2.4). Only a limited enhancement of conversion and stereoselectivity is observed under reduced pressure (91% conv, 90% Z, entry 4, Table 2.4). When RCM is carried out with tungsten alkylidene 2.28, the other optimal catalyst identified in model systems, there is only 79% selectivity of the resulting Z macrolactone (entry 5, Table 2.4). Finally, we discover that in the presence of tungsten catalyst 2.26, the Z selectivity is further improved to 96% (entry 6, Table 2.4), and when RCM is performed under vacuum, reaction proceeds to 86% yield and with only 4%
contamination of undesired E isomer (entry 7, Table 2.4). As the data in entries 8 and 9 illustrate, with the reaction under more concentrated condition, 5 mol % 2.26 is sufficient to deliver epothilone C precursor 2.40 in 86% yield and 96% Z; even 3 mol % catalyst can be used to deliver the desired product in 63% yield. Lactone 2.40 is subsequently converted to epothilone C on silyl ether removal (81% yield); diastereoselective epoxidation of epothilone C affords epothilone A.
The exceptional Z selectivity offered by tungsten alkylidene 2.26, as stated earlier, reaffirms the notion that a large size differential between the two ligands generates high kinetic Z selectivity as well as possesses desired balance of sufficient reactivity level. Thus, tungsten complex bearing a sterically hindered 2,6-di-[2,4,6-(iPr)3]-phenoxy ligand is the most attractive choice for macrocyclic RCM of the heavily functionalized dienes such as 2.39. Such unique identity of the catalyst can find additional support in low conversion together with high Z selectivity obtained for RCM of sparsely functionalized diene substrates, such as 2.21 (Table 2.2):
the catalyst affords generally low conversion because of its subordinate activity, but the less effective complex does not promote post-RCM isomerization or at least to a minimal degree.
Schrock:
Scheme 2.7: Z Selectivity as a Function of Time in RCM Promoted by Schrock's Catalyst
Considering the fact that Z to E olefin interconversion plays an important role in determining the stereochemical purity of a macrocyclic product, we next examined the extent of the influence of such process. We first probed the RCM performed in the presence of Schrock catalyst (Scheme 2.7), which was originally disclosed in 1997, delivering 2.40 in 86% yield and 33% Z selectivity within one hour.11b Based on our aforementioned investigations, we suspect that such preference of E olefin partly originates from post-RCM isomerization. To test this possibility, we investigated the degree of stereochemical control in the RCM of 2.39 as a function of time. These studies allowed us to discover that, as shown in Scheme 2.7, RCM proceeds to 92% conversion and an isomeric mixture of 2.40 is isolated in 89% yield and 72:28 Z:E ratio within only ten minutes. Our observation is much superior to the 33% Z reported
previously for the same reaction being performed for the duration of one hour. These findings indicate the importance of the need for careful determination of the optimal catalyst loading and reaction time when performing RCM reactions that generate disubstituted macrocyclic alkenes.
It is noteworthy that the reduced size differential between the arylimido and hexa-fluoro-tert-butoxide ligands within Schrock catalyst is capable of delivering relatively moderate Z selectivity. The higher reactivity of the Mo bis-alkoxide, compared to a MAP complex, such as
2.26, however, represents a more efficient post-RCM isomerization, providing a more facile erosion of kinetic Z selectivity. Though no detectable difference in Z selectivity is observed during the first ten minutes, substantial Z to E isomerization occurs within 30 minutes (72% Z to 33% Z, Scheme 2.7). In sharp contrast, in the Ru-catalyzed transformation with HG-II, the E isomer of 2.40 is favored at the beginning, suggesting there is no such catalyst control favoring the formation of the Z olefin.
We then turned to a more detailed analysis of post-RCM isomerization in transformations in the presence of Mo-based complex 2.25 and W-based complex 2.26. Because of the relatively high Z selectivity obtained with the two complexes (>85% Z), we decided to investigate the extent of loss of Z selectivity that could occur upon re-subjection of Z-2.40 (92% stereoisomeric purity) to a reaction containing the activated forms of catalyst 2.25 and 2.26. As illustrated in Scheme 2.8, Mo alkylidene 2.25 is first treated with diallyl ether to generate methylidene complex 2.41. Subsequent in vacuo removal of the volatiles, including the residual diallyl ether and ethylene generated during the aforementioned process, is followed by the addition of excess 2.40 (ten equivalents, corresponding to 10 mol % catalyst loading). Macrocyclic alkene 2.40 is recovered as an 81:19 mixture of Z and E isomer after 90 minutes (vs the initial 92:8 ratio). On the other side, when tungsten complex 2.26 is employed under the identical procedure, no detectable loss of olefin stereoisomeric purity is observed. Such experiments clearly suggest, though some loss of Z selectivity can take place in the course of RCM when Mo complex 2.25 is used, the methylidene derived from W-based catalyst shows exceptional chemoselectivity in favor of the terminal alkenes of 2.39 versus the disubstituted alkenes of 2.40. The trace amount of E olefin of macrolactone 2.40, generated in the RCM with W-based catalyst 2.26, is probably the result of a lack of perfection in kinetic selectivity.
!"##$"%$&$#'!'()*+*),$-."/$0'1#-23'()*"/ Scheme 2.8: Catalyst-Induced Post-RCM Isomerization of Epothilone C Precursor 2.40 with a Mo- or W-based Complex
N sufficiently stable that it can be weighed and handled in open air, which allows us to perform RCM reaction with requisite apparatus in a typical fume hood without the need for strict exclusion of air and moisture. To challenge the practical aspects of the W-catalyzed protocol, we decided to establish a robust procedure for an efficient and stereoselective RCM of diene 2.39 on a gram-scale with tungsten complex 2.26. The reliability of the catalytic protocol would be convincingly illustrated if the RCM reaction could be conducted with such complicated starting material prepared by a relatively long sequence (16 steps to 2.39). To accomplish this task, however, a revision of the originally reported procedure to epothilone C precursor (diene 2.39) is necessary; otherwise, access to such sufficient quantities of 2.39 would be too costly and labor intensive.
2.43 Scheme 2.9: Modification of the Synthetic Route En Route to Epothilone C Precursor 2.39
2.50 nearly 12 grams of diene substrate (Scheme 2.9). In our previous route, aldol addition involving carboxylic acid-containing ketone 2.45 only provides 2.47 in 60:40 diastereoselectivity, as well as requiring the use of 1.8 equivalents of valuable chiral aldehyde 2.46,35 prepared in four chemical transformations.11a To address this problem, the carboxylic acid unit is substituted with a TES ether in ketone 2.49;36 only 0.9 equivalents of aldehyde 2.46 is sufficient to secure the subsequent aldol reaction, leading to the formation of 2.50 in 96:4 diastereoselectivity. Another
(35) Schinzer, D.; Bauer, A.; Bohm, O. M.; Limberg, A.; Cordes, M. Chem. Eur. J. 1999, 5, 2483–2491.
(36) Storer, R. I.; Takemoto, T.; Jackson, P. S.; Brown, D. S.; Baxendale, I. R.; Ley, S. V. Chem. Eur. J. 2004, 10, 2529–2547.
notable attribute of the revised route is that smaller numbers of purifications through silica gel chromatography are required: four chromatography separations are necessary in our previous approach to ketone 2.45; only one chromatography is required for the access of 2.49.
Additionally, 1.1 equivalents of chiral thiazole-containing alcohol 2.4837 are needed for our current route, more economical than the 3 equivalents of requisite alcohol in previous approach.
With huge quantities of 2.39 in hand, we subsequently determine that in the presence of 6.5 mol % W catalyst 2.26, gram-scale RCM proceeded to 95% conversion, affording macrocyclic alkene 2.40 in 83% yield and 95% Z selectivity.