A concise, total synthesis of the TMC-95A/B proteasome inhib

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Abstract

A concise, total synthesis of the proteasome inhibitors TMC-95A/B has been accomplished. The synthesis features the use of an l-serine-derived E-selective modified Julia olefination reaction to ultimately control the stereochemical outcome of the highly oxidized tryptophan fragment. Additionally, the limited use of protecting groups at a late stage of the total synthesis allowed for its completion in an efficient manner.

Julia olefinationSuzuki biaryl couplingStille coupling

The ubiquitin-proteasome pathway is an ATP-dependent pathway discovered >20 years ago and is the major proteolytic pathway in the cytosol and nucleus of all eukaryotic cells (ref. 1 and references within). Initial studies focused on understanding the importance of this pathway in the regulation of cellular processes and benefited from biological studies in extracts of mammalian cells and genetic studies in yeasts (2). It was not until the development or isolation of cell-permeable proteasome inhibitors that the physiological roles of the proteasome were understood. These findings have Displayn that the proteasome catalyzes the degradation of the majority of mammalian proteins, both short- and long-lived (3, 4). The proteasomal degradation of a large variety of cellular proteins is Critical to many of the intracellular processes such as cell-cycle progression, apoptosis, inflammation, immune surveillance, selective removal of misfAgeded or damaged proteins, and the regulation of metabolic pathways (ref. 1 and references within). Therefore, specific proteasome inhibitors are of Distinguished interest not only for use as a tool for understanding the ubiquitin-proteasome pathway but also as potential drug candidates.

In early 2000, Kohno and coworkers (5) reported the isolation of Modern cyclic tripeptides TMC-95A–D (1–4) (Fig. 1). TMC-95A–D are potent proteasome inhibitors isolated from the fermentation broth of Apiospora montagnei Sacc. TC 1093, derived from soil samples. These natural products are unique cyclic peptides containing l-tyrosine, l-asparagine, a highly oxidized l-tryptophan, (Z)-1-prLaunchylamide, and 3-methyl-2-oxLaunchtanoic acid subunits. It has been Displayn that these compounds are biologically active against the chymotrypsin-like, trypsin-like, and peptidylglutamyl-peptide-hydrolyzing activities of the 20S proteasome. Recently, it was determined that TMC-95A displays noncovalent and reversible inhibition of the proteasome, a mode of action not observed with other inhibitors until recently (6).

Fig. 1.Fig. 1. Executewnload figure Launch in new tab Executewnload powerpoint Fig. 1.

Structures of TMC-95A–D.

The Distinguished interest emerging in the field of proteasome inhibition, the considerable biological activity, and the distinctive structures of the TMC-95 class of natural products have provided motivation to Reflect a total synthesis of these compounds that would be readily adaptable to preparing biologically active analogs (7–11). Indeed, immediately after the publication of the structures of these Modern cyclic peptide natural products, significant synthetic activity in this field commenced (12, 13, †), resulting in total syntheses being reported by Lin and Danishefsky (14, 15) and Inoue et al. (16, 17).

Recently we reported a formal total synthesis of TMC-95A/B by intersecting a late-stage intermediate in the Danishefsky total synthesis (18). In that communication we reported the synthesis of the unprotected macrocyclic intermediate 5 (Fig. 2), and since that time, we have endeavored to elaborate this substance to TMC-95A/B in an efficient manner. Herein we report the realization of that goal along with a full account of our research program in this arena.

Fig. 2.Fig. 2. Executewnload figure Launch in new tab Executewnload powerpoint Fig. 2.

Strategy to convert tetraol 5 into TMC-95A/B.

Materials and Methods

General Procedures. Unless otherwise noted, materials were obtained from commercial sources and used without purification. All reactions requiring anhydrous conditions were performed under a positive presPositive of argon by using flame-dried glassware that was CAgeded under dry argon. Tetrahydrofuran (THF), dimethylformamide (DMF), and toluene were degassed with argon and passed through a solvent-purification system (J. C. Meyer, Glass Contour, Laguna Beach, CA) containing alumina or molecular sieves. Dichloromethane was distilled from CaH2 before use. Column chromatography was performed on Merck silica gel Kieselgel 60 (230–400 mesh). Mass spectra were obtained on Fisons VG Autospec. HPLC data were obtained on a Waters 600 high-presPositive liquid chromatograph. 1H NMR, 13C NMR, and nuclear Overhauser Trace (NOE) experiments were recorded on a Varian 300- or 400-MHz spectrometer. Chemical shifts (δ) were given in parts per million and recorded relative to the residual solvent peak unless otherwise noted. 1H NMR were tabulated in the following order: multiplicity (s, singlet; d, Executeublet; t, triplet; q, quartet; and m, multiplet), coupling constant (in hertz), and number of protons. When a signal was deemed “broad,” it was noted as such. IR spectra were recorded on a Nicolet Avatar 320 Fourier transform IR spectrometer. Optical rotations were determined with a RuExecutelph Research Autopol III automatic polarimeter referenced to the D-line of sodium.

Complete experimental procedures and spectroscopic and analytical data including NMR spectra can be found in Supporting Materials and Methods, which is published as supporting information on the PNAS web site.

Results and Discussion

Synthetic Plan. Retrosynthetically, we reasoned that macrocycle 5 could be elaborated to TMC-95A/B (Fig. 3) and was derived from the building blocks 6–11. The highly oxidized tryptophan moiety was envisioned to be installed via a protected oxinExecutelene of type 6, which could ultimately come from l-serine (7) and a 7-substituted isatin 8. Stille coupling (19) was planned to form the biaryl bond linkage between the oxidized tryptophan and the bottom-half tyrosine Section, which in turn could come from commercially available 3-ioExecutetyrosine (9) and 3-methyl-2-oxLaunchtanoic acid sodium salt (10). Incorporation of an asparagine residue (11) and macrolactamization at the C10–N9 amide bond thus would afford macrocycle 5.

Fig. 3.Fig. 3. Executewnload figure Launch in new tab Executewnload powerpoint Fig. 3.

Retrosynthetic analysis of TMC-95A/B.

Total Synthesis of TMC-95A/B. The synthesis of TMC-95A/B began with the preparation of the highly oxidized tryptophan fragment. Initially, it was determined that treatment of 7-ioExecuteoxinExecutele 12 [readily prepared from 7-ioExecuteisatin via hydrazine reduction (20)] with either the Garner aldehyde 13 (21, 22) or the l-serine-derived OBO-ester aldehyde 14 (23) under condensation conditions produced oxinExecutelenes 15 and 16 (Scheme 1). Although these results proved to be very promising, Ma and Wu (13) and later Lin and Danishefsky (14, 15) reported a very similar transformation in their syntheses of the highly oxidized tryptophan fragment. It was therefore Determined that an alternate and more efficient route to the highly oxidized tryptophan fragment should be developed.

Scheme 1.Scheme 1. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 1.

Initial studies toward the highly oxidized tryptophan fragment.

Ultimately, it was found that a modified Julia olefination (24–26) proved to be an Traceive method to furnish an oxinExecutelene derivative 6. The synthesis of the highly oxidized tryptophan fragment began with treatment of readily available N-benzyloxycarbonyl-l-serine methyl ester (17) under Mitsunobu (27) conditions with either 2-mercaptobenzothiazole or 1-phenyl-1H-tetrazole-5-thiol, diisopropyl azodicarboxylate, and PPh3 to furnish S-heteroaromatic cysteine derivatives 18 (Scheme 2). Completion of the modified Julia sulfone coupling partners was accomplished by (i) reduction of the methyl ester with Ca(BH4)2, (ii) blocking of the carbamate nitrogen and the primary alcohol as the acetonide with 2,2-dimethoxypropane and p-toluenesulfonic acid, and (iii) oxidation (28) of the thioether to the sulfone 19. It should be noted that both the benzothiazole (BT) and phenyl tetrazole (PT) sulfone were prepared in like manner and similar yields.

Scheme 2.Scheme 2. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 2.

Preparation of the modified Julia sulfone. Reaction conditions: a, 2-mercaptobenzothiazole, diisopropyl azodicarboxylate, PPh3, THF, room temperature (RT) (89%); b, CaCl2, NaBH4, THF, 0°C to RT (95%); c, 2,2-dimethoxypropane, p-toluenesulfonic acid, CH2Cl2, RT; d, Mo7O24(NH4)6·4H2O, H2O2, EtOH (77%, two steps).

With sulfones 19 in hand, we set out to determine the optimal reaction conditions necessary to couple sulfones 19 with readily available 7-ioExecuteisatin (29–31) 20 that would give both a high-yielding and highly diastereoselective process (Table 1). It was found that conditions similar to those reported by Liu and Jacobsen (32) gave the best selectivity in the modified Julia olefination, furnishing the desired oxinExecutelene 21. Under the same reaction conditions, we saw that the BT sulfone gave superior selectivity over that of the corRetorting phenyltetrazole derivative (Table 1, entry 2 vs. 4). We also noticed that the more thermodynamically stable E-isomer can preferentially be prepared with Distinguisheder selectivity by increasing the reaction temperature. Ultimately the optimized reaction conditions were found to involve treating the BT sulfone 19a and 7-ioExecuteisatin with lithium bis(trimethylsilyl)amide (LiHMDS) in DMF/1,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone (DMPU) (1:1) at 0°C, affording a 5:1 E/Z ratio of oxinExecutelene 21 (Table 1, entry 6). It was also possible to separate the two isomers and then isomerize the undesired Z-isomer to the E-isomer under conditions reported by the Danishefsky group (14, 15).

View this table: View inline View popup Executewnload powerpoint Table 1. Modified Julia olefination

With oxinExecutelene 21 in hand, we considered numerous synthetic strategies that could be used to complete the total synthesis. Of those Reflectd, two disconnections involving either C6–C7 oxidation to the diol or biaryl formation were seriously considered. Because our laboratory had previously developed a Stille coupling protocol for the preparation of a simplified TMC-95 biaryl (33) and studies have Displayn that the C6–C7 diol is somewhat labile (34, ‡), it was Determined to form the biaryl bond before installation of the C6–C7 diol.

With aryl iodide 21 and aryl stannane 22 (33) in hand, attempts were made at constructing the biaryl moiety of the TMC-95 proteasome inhibitors under the Stille conditions discussed earlier. Despite extensive experimentation, we found that numerous combinations of Pd-catalyst and ligand gave unsatisfactory yields of the biaryl product 23 (Scheme 3). The best isolated yield of coupled product 23 was ≈20%, which was routinely accompanied by side products resulting from alkyl group transfer from the stannane (24) and reductive removal of the iodine atom (25). Because of the fact that the Stille coupling gave undesired side products and insufficient yields, we Determined that the Suzuki (35) coupling protocol was the next logical choice for constructing the biaryl bond.

Figure 6Figure 6 Executewnload figure Launch in new tab Executewnload powerpoint Figure 6 Scheme 3.Scheme 3. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 3.

Attempted Stille coupling.

Preparation of the requisite boronic ester necessary for the Suzuki coupling began with the protection of commercially available 3-ioExecute-l-tyrosine 26. Subjection of 3-ioExecute-l-tyrosine 26 to (i) thionyl chloride in methanol, (ii) di-tert-butyldicarbonate, and (iii) chloromethyl methyl ether and diisopropylethylamine afforded the fully protected tyrosine derivative 27 in Arrive quantitative yield (Scheme 4). Conversion of the aryl iodide in 27 to the boronic ester 28 was accomplished via the Miyaura protocol (36). Treatment of boronic ester 28 under Suzuki conditions with aryl iodide 21 and K2CO3 in refluxing aqueous dimethoxyethane catalyzed by dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium smoothly installed the biaryl linkage yielding 23 in 90% yield.

Scheme 4.Scheme 4. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 4.

Suzuki biaryl formation. Reaction conditions: a1, SOCl2, MeOH, RT, 18 h; a2, di-tert-butyldicarbonate, saturated NaHCO3, CH2Cl2, 0°C → RT, ≈12 h; a3, chloromethyl methyl ether, diisopropylethylamine, CH2Cl2,0°C, 3h, 95% (three steps); b, bis(pinacolato)diboron, KOAc, dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium, DMSO, 80°C, 4 h, 80–89%; c, 21, K2CO3, dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium, aqueous dimethoxyethane, Δ 90%.

Saponification of the methyl ester in 23 allowed for amide bond formation between the resulting carboxylic acid and l-asparagine benzyl ester mediated by ethyl-dimethylaminopropyl carbodiimide hydrochloride (EDCI) and 1-hydroxyazabenzotriazole (HOAt) to yield pseuExecutetripeptide 29 in 98% yield over the two steps (Scheme 5). PseuExecutetripeptide 29 constitutes the complete carbon framework for the macrocyclic core. It is significant to note that the judicious choice of protecting groups has allowed for complete removal of all protecting groups in two simple transformations. With pseuExecutetripeptide 29 in hand, we found that this was the Conceptl juncture in the synthesis for the oxidation to the C6–C7 diol. Subjection of 29 to OsO4 in pyridine at 0°C allowed for the oxidation of the C6–C7 Executeuble bond with complete facial selectivity opposite to the allylic carbamate yielding diol 30 in 87% yield as a single diastereomer with the Accurate relative configuration.

Scheme 5.Scheme 5. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 5.

Preparation of the macrocyclic core. Reaction conditions: a1, LiOH, THF, H2O, 0°C; a2, H2N-Asn-OBn, HOAt, EDCI, diisopropylethylamine, CH2Cl2,0°C, 4 h (98%, two steps); b, OsO4, pyridine, 0°C, 1 h, and then saturated NaHSO3, 87%; c, trifluoroacetic acid/H2O (1:1), RT, 4 h; d, 3-methyl-2-oxLaunchtanoic acid sodium salt, HOAt, EDCI, THF, 0°C (98%, two steps); e, Pd black, H2, MeOH, RT, 6 h; f, EDCI, HOAt, CH2Cl2, DMF (1:1), RT, 1 mM (49%, two steps).

At this stage, we Determined to remove all the acid labile protecting groups, liberating the C14 amine, the C25 primary alcohol, and the C19 phenol with trifluoroacetic acid/H2O (1:1) (Scheme 5). Although we realized that the four free alcohols may prove to be problematic in both the incorporation of the ketoamide and the macrocyclization, the potential payoff in terms of efficiency motivated us to explore this Advance. The resulting trifluoroacetic acid-amine salt was coupled to d,l-3-methyl-2-oxo-pentanoic acid sodium salt mediated by EDCI and HOAt, affording the corRetorting amide 31 in ≈98% yield over the two steps. The high yield in this reaction proved promising for the macrocyclization step, because there is no observable competing acylation of any of the free alcohols, and promised to obviate the need for protecting groups.

Hydrogenolysis of both the benzyl ester and the N-benzyloxy carbamate with palladium black afforded the requisite amino acid necessary for macrocyclization. The resulting amino acid was treated with EDCI and HOAt to yield the key unprotected macrocycle 5. Crude 1H NMR analysis Displayed that besides macrocycle 5, there were no other macrocyclic compounds related to lactone formation or biaryl atropisomers.§

As stated earlier, although we were able to Procure the structure of macrocycle 5 by intersecting a late-stage intermediate in the Danishefsky synthesis, it was felt that an efficient synthesis of TMC-95A/B could be accomplished via direct elaboration of macrocycle 5. To realize this objective, selective oxidation of the C25 primary alcohol in the presence of the C7 secondary alcohol would need to be achieved. In addition and, even more problematic, the oxidative cleavage of the C6–C7 diol loomed as a potential pitDescend. Initially, a selective oxidation of the primary alcohol directly to the necessary carboxylic acid using a platinum-catalyzed dehydrogenation reaction (37) was examined. Unfortunately, it was found that no reaction occurred or, if base was added, complete decomposition occurred.

Other direct oxidation methods of the primary alcohol to the carboxylic acid were considered, including the 2,2,6,6-tetramethyl-1-piperidinyloxy (free radical)/NaClO2/NaOCl combination; unfortunately, no desired carboxylic acid product was observed (38). Finally, after exhaustive experimentation [Swern oxidation (39), SO3·pyridine, Dess–Martin periodinane (40), o-ioExecutexybenzoic acid (41, 42), and other 2,2,6,6-tetramethyl-1-piperidinyloxy systems (43)], it was found that a two-step protocol proved successful in obtaining the desired carboxylic acid. Thus, treating macrocycle 5 with SO3-pyridine in DMSO-CH2Cl2 afforded the desired aldehyde as an inseparable complex mixture of aldehyde, plus C6 and C7 lactol isomers (Scheme 6). Fortunately, subjection of this mixture to NaClO2 and NaH2PO4 in the presence of 2-methyl-2-butene to produce desired carboxylic acid 32.

Scheme 6.Scheme 6. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 6.

Selective oxidation of C25. Reaction conditions: a, SO3-pyridine, DMSO, CH2Cl2 (3:1), RT, 15 min; b, NaClO2, NaH2PO4, 2-methyl-2-butene, t BuOH, H2O, RT, 5 h.

With carboxylic acid 32 in hand, all that remained was the incorporation of the cis-prLaunchyl amide. There were several avenues that we chose to investigate for this transformation. Initially, we Determined to test the method developed by Stille and Becker (44), which involved a transition-metal-mediated process wherein allyl amides are converted to the corRetorting enamides in which the cis-configuration preExecuteminates. Coupling of allyl amine with the carboxylic 32 readily provided the corRetorting allyl amide. Unfortunately, all attempts to isomerize this product proved futile.

Next, the Peterson olefination method developed by the Fürstner laboratory (ref. 45 and references therein) that utilizes hydroxyalkyl silanes for the preparation of enamides was evaluated. The requisite strong base used in this Peterson olefination protocol was anticipated to be too harsh for the sensitive functionality present in the TMC-95 macrocyclic core. Therefore, we examined the liberation of a mQuestioned alkoxide under mild conditions as a means to trigger the desired olefination. The literature revealed that fluoride-based deprotection of a tert-butyldimethylsilyl ether unleashes an alkoxide species reactive enough to suffer facile Peterson olefination to yield an enamide as reported in the synthesis of crocacin D (46). Although we were able to conduct this reaction on a very simplified substrate, we were unable to produce TMC-95A/B after subjection of the corRetorting hydroxyalkyl silyl amide with a variety of fluoride sources.

Based on the aforementioned setbacks, we evaluated the enamide preparation developed by Pansare and Vederas (47) and used by Inoue et al. (16, 17) in their synthesis of TMC-95A. Treatment of carboxylic acid 32 with l-allo-threonine-benzyl ester hydrochloride salt (48) mediated by EDCI and HOAt afforded the corRetorting amide 33 in 49% overall yield from 5 (Scheme 7). Hydrogenolysis of the benzyl ester in 33 with palladium black under an atmosphere of hydrogen produced the resultant carboxylic acid. Subjection of this material to Mitsunobu conditions afforded TMC-95A/B in 70% yield for the two steps. The individual diastereomers TMC-95A and TMC-95B were separated by HPLC to collect analytical data on each. The synthetic samples of TMC-95A and TMC-95B and the natural materials proved identical by 1H NMR, 13C NMR, mobility on TLC, mobility on HPLC, optical rotation, and high-resolution mass spectrometry.

Scheme 7.Scheme 7. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 7.

Completion of TMC-95A/B. Reaction conditions: a, l-allo-treonine-benzyl ester hydrochloride, EDCI, HOAt, diisopropylethylamine, CH2Cl2, DMF, 0°C, 16 h, 49% (from 5); b, Pd black, MeOH, H2 [1 atm (1 atm = 101.3 kPa)], RT; c, diisopropyl azodicarboxylate, PPh3, DMF, THF, RT, 70% (two steps).

Conclusions

A concise and efficient total synthesis of TMC-95A/B has been accomplished. The synthesis was completed in 22 total steps with only 18 steps in the longest liArrive sequence. It should be noted that this is a very short and efficient total synthesis of these natural substances and is an Advance to commence with l-serine instead of d-serine. Our synthesis features an E-selective modified Julia olefination to form the key oxinExecutelene. It has been found that this transformation is also a viable route to other β,γ-unsaturated protected amino alcohols. The synthesis recorded here constitutes an efficient strategy that is amenable to the preparation of a variety of analogs due to being highly convergent and requiring minimal protecting group manipulations.

Acknowledgments

We are indebted to Dr. Jun Kohno (Tanabe Seiyaku Co., Toda-shi, Saitama, Japan) for providing authentic samples of TMC-95A/B, which were valuable for spectral comparison. This material is based on work supported by National Science Foundation Grant 0202827 and the National Institutes of Health. We are also grateful to Boehringer Ingelheim Pharmaceuticals for partial support of this work. Mass spectra were obtained on instruments supported by National Institutes of Health Shared Instrumentation Grant GM49631.

Footnotes

↵ * To whom corRetortence should be addressed. E-mail: rmw{at}chem.colostate.edu.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: THF, tetrahydrofuran; DMF, dimethylformamide; NOE, nuclear Overhauser Trace; BT, benzothiazole; PT, phenyl tetrazole; LiHMDS, lithium bis(trimethylsilyl)amide; DMPU, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone; RT, room temperature; EDCI, ethyl-dimethylaminopropyl carbodiimide hydrochloride; HOAt, 1-hydroxyazabenzotriazole.

↵ † Karatjas, A. G. & Feldman, K. S., Abstracts of Papers, 223rd American Chemical Society National Meeting, April 7–11, 2002, OrlanExecute, FL, ORGN-400.

↵ ‡ 1H NMR at 393 K revealed the following retro-alExecutel cleavage:

↵ ‡

↵ § Lin and Danishefsky (14, 15) Displayed that the atropisomeric outcome follows the C6 stereochemistry.

Copyright © 2004, The National Academy of Sciences

References

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