Total Synthesis of Tryprostatin B: Synthesis and Asymmetric Phase

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Cite This: Org. Lett. 2019, 21, 134−137

Total Synthesis of Tryprostatin B: Synthesis and Asymmetric PhaseTransfer-Catalyzed Reaction of Prenylated Gramine Salt Matthew Huisman,†,§ Mizzanoor Rahaman,†,§ Sharif Asad,† Sarah Oehm,† Sherwin Novin,† Arnold L. Rheingold,‡ and M. Mahmun Hossain*,† †

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Department of Chemistry and Biochemistry, University of WisconsinMilwaukee, 3210 North Cramer Street, Milwaukee, Wisconsin 53211-3029, United States ‡ Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States S Supporting Information *

ABSTRACT: A concise and efficient total synthesis of microtubule inhibitor tryprostatin B (1) is described. The key step is the preparation of a diprenylated gramine salt 9a. In this step, the prenyl group is incorporated at the 2-position of the indole moiety by direct lithiation of the Boc-protected gramine. We also developed and optimized the asymmetric phase-transfer-catalyzed reaction with salt 9a to provide the C2-prenyl tryptophan intermediate 2 resulting in 93% enantiomeric excess (ee) and 65% yield. The total synthesis of 1 is done in six steps with 35% overall yield.

T

Scheme 1. Previous Syntheses of C2 Prenyl Indole Moiety

ryprostatin (TPS) A and B are members of a family of prenylated Trp-Pro diketopiperzine alkaloids. These two natural products were isolated in 1995 from the fermentation broth of Aspergillus f umigatus BM939 by Osada and coworkers.1 TPS and related diketopiperazine ring containing compounds such as phenylahistins, spirotryprostatins, and cyclotryprostatins are inhibitors of the mammalian cell cycle.2 They prevent cell cycle progression at the G2/M phase through a unique mechanism consisting of inhibiting the interaction between microtubule-assisted proteins (MAP-2) and the C-terminal end of tubulin.3,4 TPS A and B have great potential because they were found to have inhibitory activity on the cell cycle progression of mouse tsFT210 cells with minimum inhibitory concentration (MIC) values: 16.4 μM for TPS A and 4.4 μM for TPS B, respectively.4 The scarcity of TPS A and B in nature and long, low-yielding synthetic procedures have limited their development as viable anticancer therapeutics. On the other hand, their interesting biological activity and simple structure have drawn attention from the synthetic community, and several total syntheses have been reported.5−14 TPS A and B contain a 2-prenylindole moiety and diketopiperazine unit. The prenylation at the C2 position of the indole ring is a big challenge for synthetic chemists; several procedures have been described to introduce the prenyl group. In 1996, Danishefsky and co-workers reported the synthesis of 1 by adding the prenyl group at the C2 position by reacting 3chloroindolenine with nucleophile, which was generated from the reaction of tributylprenylstannane and boron trichloride (Scheme 1a).5 Later, Cook et al. developed a method for the synthesis of 1 in which the prenyl group was inserted by direct lithiation of the Schöllkopf chiral auxiliary containing N-Boc© 2018 American Chemical Society

indolylmethyl derivative (Scheme 1b).6,15 In 2010, Fukuyama and co-workers prepared C2-prenylated protected tryptophan from ortho-alkenyl isocyanide by a palladium catalyzed coupling reaction involving tributyltin chloride and prenyl acetate.14 The corresponding o-alkenyl isocyanide was prepared from the N-arylformamide substrate by the dehydration reaction in the presence of triphosgene (Scheme 1c). Herein, we report a concise asymmetric synthesis of 1 in six steps by using commercially available, cheap, and environReceived: November 9, 2018 Published: December 18, 2018 134

DOI: 10.1021/acs.orglett.8b03593 Org. Lett. 2019, 21, 134−137

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Organic Letters mentally friendly reagents. In this synthesis, we also describe an unusual procedure to incorporate the prenyl group at the C2 positon of the indole ring. Our main objective was to obtain compound 1 and other desired analogues from a short synthetic pathway, which is viable for commercial application. In our previous work, we synthesized the chiral tryptophan 3 from commercially available gramine 4 by using a chiral phasetransfer catalyst (PTC).16 On the basis of our previous synthesis, we designed a new method to prepare 1 as presented in Scheme 2. In order to prepare the intermediate 2, our

Scheme 4. Synthesis of Dialkylated Gramine Salt 9a,b and PTC Reaction of 9a

Scheme 2. Retrosynthetic Scheme for Tryprostatin B

synthesize C2-prenylated indole moiety in only two steps from 4. To the best of our knowledge, this is the easiest way to incorporate the prenyl group at the C2 position of the indole moiety. The structure of 9a was confirmed by X-ray diffractrometry (Figure 1).17 In order to observe if the C2-

strategy envisaged the installation of the prenyl group at the C2 position of the indole ring of compound 3. Consequently, compound 3 was Boc-protected and treated with prenyl bromide 5a in the presence of n-butyllithium or lithium diisopropylamide (LDA).6 However, the attempts of prenylation were unsuccessful. Receiving important data from the reactions, we decided that the prenyl group containing the indole moiety of the target compound could be constructed before the PTC reaction. To incorporate the prenyl group at the C2 position, we first reacted the Boc-protected gramine 6 with 1 equiv of 5a in the presence of n-butyllithium. The reaction provided exclusively N-prenylated gramine salt 7 with 88% yield (Scheme 3a); no C2-prenylation was observed. Scheme 3. Prenylation of Boc-Protected Gramine 6 and PTC Reaction of Monoprenylated Gramine Salt 7

Figure 1. Crystal structure of diprenylated gramine salt 9a.

Compound 7 was found to undergo a PTC reaction with Schiff base 8 in the presence of 50% KOH to provide the tryptophan 3 (Scheme 3b). The formation of compound 3 revealed that the N-prenylated gramine salt is also viable for a PTC reaction, and later, it gave a comparable yield (75%) to the previously reported reaction involving N-(4trifluoromethoxy)benzyl gramine salt.16 To our surprise, we observed during our investigation that using 2 equiv of n-butyllithium and excess of 5a (4.5 equiv) led to the formation of the C2,N-diprenylated gramine salt 9a with 92% yield (Scheme 4). These findings open a new window to

alkylation of indole ring is feasible with other electrophiles, we reacted 6 with benzyl bromide 5b, and the reaction was successful with 73% yield of dibenzylated gramine salt 9b (Scheme 4). With the C2-prenyl group containing diprenylated gramine salt 9a, we plan to investigate the PTC reaction. By performing a racemic PTC reaction of 9a, the desired C2-prenyl tryptophan 2 was isolated with 82% yield (Scheme 4). Encouraged by the results from a racemic PTC reaction, we then turned our attention to the asymmetric PTC reaction of the diprenylated gramine salt 9a to prepare chiral C2-prenyl tryptophan 2. For the reaction, we chose O-allyl-N-(9anthracenylmethyl)cinchonidinium bromide 10 as the PTC, which was an effective catalyst for enantioselectivity, as observed by our previous studies.16 To optimize the reaction conditions for higher asymmetric induction, we investigated the effects of systematic variations in the solvents, mixed solvent systems, temperature, and time on enantiodiscrimination (Table 1). In order to find the best solvent for high enantioselectivity, several solvents were examined as presented in Table 1. 135

DOI: 10.1021/acs.orglett.8b03593 Org. Lett. 2019, 21, 134−137

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Organic Letters Scheme 5. Total Synthesis of Tryprostatin Ba

Table 1. Selected Optimization Studies of Asymmetric Phase-Transfer-Catalyzed Reaction

entrya 1 2 3 4 5 6 7 8 9 10

solvents DCM dioxane DME toluene diox/DME (1:1) DCM/DME (10:1) diox/chloroform (10:1) DCM DCM DME

tempb (°C)

time (h)

convc (%)

eed (%)

rt rt rt rt rt 0 0

12 12 12 12 12 24 24

100 100 100 100 100 95 91

56 61 60 38 69 81 88

−10 −20 −20

36 72 72

85 82 83

80 93 85

Conditions: (A) Boc2O, DMAP, TEA, THF, 0 °C, 99%; (B) prenyl bromide 5a, nBuLi, THF, −78 °C, 92%; (C) Schiff base 8, catalyst 10, KOH, Dicholoromethane, −20 ̊C, 65%; (D) 1 N HCl (aq), THF, 0 °C, 95%; (E) (i) N-Fmoc-L-prolyl chloride 12, TEA, CHCl3, rt; (ii) DEA, CH3CN, rt, 76%; (F) H2O, MW (250 °C, 250 W, 150 psi), 81%. DMAP = 4-(dimethylamino)pyridine, TEA = triethylamine, THF = tetrahydrofuran, DEA = diethylamine, MW = microwave. a

a

The reaction was performed with 9a (0.10 mmol) and Schiff base 8 (0.12 mmol) in solvent (2.0 mL). bOptimum temperature for the best ee value. cDetermined by analysis of the reaction mixture by 1H NMR spectroscopy. dDetermined by HPLC analysis by using a chiral stationary phase. DCM = dichloromethane, diox = 1, 4-dioxane, DME = dimethoxyethane.

dipeptide 13. At the outset of the program, we undertook a study to identify an efficient method for cyclization. Initially, to prepare 1, we refluxed compound 13 in xylene, following a procedure described by Cook et al.13 Their ethyl ester substrate was easily cyclized in reflux condition, whereas our tert-butyl ester substrate 13 was difficult to cyclize. We applied an alternative procedure reported by Carvalho and co-workers by reacting 13 with 20% piperidine in DMF followed by the addition of DIPEA in CH3CN at room temperature.19 However, no desired product resulted from this reaction. Later, cyclization as described by Williams using 2-hydroxypyridine in toluene under reflux was also unsuccessful with compound 13.20 In seeking a workable solution to the goal of cyclization involving a tert-butyl ester group, we were influenced by the microwave method developed by Rios and co-workers.21 Based on their work, we developed a model microwave experiment with a tert-butyl ester group containing compound 16. Compound 16 was synthesized from Fmoc proline 14 and glycine tert-butyl ester 15 through a coupling reaction.19 The model compound 16 was heated in water for 10 min at 250 °C and 150 psi using a CEM Discover microwave at 250 W (Scheme 6). The desired bicyclo[4.3.0]2,5-diketopiperazine 17 product was obtained with high yield and NMR was matched with the values reported in the literature.22

Conventional purification of the asymmetric reaction by silica gel column chromatography and analysis using chiral stationary HPLC showed that polar solvents such as dichloromethane (56% ee), dioxane (61% ee), and dimethoxyethane (60% ee) worked well at room temperature (Table 1, entries 1−3). Less polar solvents like toluene did not give a satisfactory result due to the poor solubility of the Boc-protected diprenylated gramine salt (Table 1, compare entry 4 with entries 1−3). To improve the asymmetric induction, we investigated mixed solvent systems in different ratios, but no significant improvement was observed at room temperature (Table 1, entries 5). However, lowering the temperature from 25 to 0 °C resulted in an increase of enantioselectivity (Table 1, entries 6 and 7). Better enantiomeric excess (88% ee) was obtained in a dioxane−chloroform mixture (10:1 ratio) at 0 °C (Table 1, entry 7). We were not able to carry out lower temperature reactions with this mixture because of the relatively high freezing point of dioxane. Other mixed solvent systems at lower temperature did not provide promising results compared to the single solvent system (Table 1, entries 8−10) at the same temperature. By further cooling to −20 °C, DCM improved the enantioselection up to 93% (Table 1, entry 9). During our study, it was revealed that a longer reaction length resulted in a higher conversion to product. With the optimized reaction conditions (DCM, −20 °C, 72 h, 93% ee, and 65% isolated yield) in hand, we then focused on the total synthesis of 1 from 2 (Scheme 5). The diphenylmethylene group was removed from 2 under acidic conditions (aqueous HCl, THF) in 95% yield to provide the 2-prenyl tryptophan 11.18 The reaction of compound 11 with the NFmoc-L-prolyl chloride 12 in the presence of trimethylamine and followed by removal of the Fmoc protecting group with diethylamine provided dipeptide 13 with 76% yield.13 Lastly, to synthesize TPS B, we performed the cyclization reaction for the formation of bicyclic diketopiperazine unit in

Scheme 6. Synthesis of Bicyclo[4.3.0]-2,5-diketopiperazine

136

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(5) Depew, K. M.; Danishefsky, S. J.; Rosen, N.; Sepp-Lorenzino, L. J. Am. Chem. Soc. 1996, 118, 12463−12464. (6) Zhao, S.; Gan, T.; Yu, P.; Cook, J. M. Tetrahedron Lett. 1998, 39, 7009−7012. (7) Schkeryantz, J. M.; Woo, J. C. G.; Siliphaivanh, P.; Depew, K. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 11964−11975. (8) Cardoso, A. S.; Lobo, A. M.; Prabhakar, S. Tetrahedron Lett. 2000, 41, 3611−3613. (9) Wang, B.; Chen, L.; Kim, K. Tetrahedron Lett. 2001, 42, 1463− 1466. (10) Zhao, S.; Smith, K.; Deveau, A.; Dieckhaus, C.; Johnson, M.; Macdonald, T.; Cook, J. M. J. Med. Chem. 2002, 45, 1559−1562. (11) Caballero, E.; Avendaño, C.; Menéndez, J. C. J. Org. Chem. 2003, 68, 6944−6951. (12) Cardoso, A. S. P.; Marques, M. M. B.; Srinivasan, N.; Prabhakar, S.; Lobo, A. M.; Rzepa, H. S. Org. Biomol. Chem. 2006, 4, 3966−3972. (13) Jain, H.; Zhang, C.; Zhou, S.; Zhou, H.; Ma, J.; Liu, X.; Liao, X.; Deveau, A.; Dieckhaus, C.; Johnson, M.; Smith, K.; Macdonald, T.; Kakeya, H.; Osada, H.; Cook, J. M. Bioorg. Med. Chem. 2008, 16, 4626−4651. (14) Yamakawa, T.; Ideue, E.; Shimokawa, J.; Fukuyama, T. Angew. Chem., Int. Ed. 2010, 49, 9262−9265. (15) Ma, C.; Liu, X.; Li, X.; Flippen-Anderson, J.; Yu, S.; Cook, J. M. J. Org. Chem. 2001, 66, 4525−4542. (16) Todd, R.; Huisman, M.; Uddin, N.; Oehm, S.; Hossain, M. M. Synlett 2012, 23, 2687−2691. (17) Huisman, M.; Oehm, S.; Rheingold, A.; Hossain, M. CSD Commun., 2016. (18) Zheng, B.-H.; Ding, C.-H.; Hou, X.-L.; Dai, L.-X. Org. Lett. 2010, 12, 1688−1691. (19) Campo, V. L.; Martins, M. B.; da Silva, C. H. T. P.; Carvalho, I. Tetrahedron 2009, 65, 5343−5349. (20) Stocking, E.; Sanz-Cervera, J.; Williams, R. J. Am. Chem. Soc. 2000, 122, 1675−1683. (21) Pérez-Picaso, L.; Escalante, J.; Olivo, H. F.; Rios, M. Y. Molecules 2009, 14, 2836−2849. (22) Furtado, N. A. J. C.; Pupo, M. T.; Carvalho, I.; Campo, V. L. C.; Duarte, M. C. T.; Bastos, J. K. J. Braz. Chem. Soc. 2005, 16, 1448− 1453.

Encouraged by this successful reaction involving the tertbutyl ester group, we turned our interest to the dipeptide 13. Under the above-mentioned microwave conditions, spontaneous cyclization occurred to create 1 with 81% yield. The proton and carbon NMR spectra of the final compound matched that of the published data.14 In summary, we described a concise and efficient asymmetric synthesis of tryprostatin B (1). The key steps involved (i) the preparation of C2-prenyl gramine salt by direct lithiation from Boc-protected gramine and (ii) the asymmetric PTC reaction of the prenylated gramine salt. The PTC reaction was optimized by changing the solvent, temperature, and time. From our developed method, TPS B was synthesized from gramine in six steps with 35% overall yield. Further investigations into the synthesis of TPS A and their analogues are underway.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03593. Experimental procedures, analytical data, and copies of the 1H NMR, 13C NMR, HRMS, and HPLC charts for all new products (PDF) Accession Codes

CCDC 922382 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*Fax: +1(414) 229-5530. E-mail: [email protected]. ORCID

M. Mahmun Hossain: 0000-0002-0874-4480 Author Contributions §

M.H. and M.R. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are thankful to the Graduate School of UWM for their support of this research through grant RGI-101X170. We thank the UWM office of undergraduate research for summer support of S.O. through SURF. We also thank the Aldrich Chemical Co. for supplying some of the chemicals.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b03593 Org. Lett. 2019, 21, 134−137