Letter Cite This: Org. Lett. 2018, 20, 6398−6402
pubs.acs.org/OrgLett
Stereoselective Protection-Free Asymmetric Total Synthesis of (+)-Chamuvarinin, a Potent Anticancer and Antitrypanosomal Agent: Substrate-Controlled Construction of the Adjacently Linked Oxatricyclic Core by Internal Alkylation Mallesham Samala,† Thien Nhan Lu,† Suresh Mandava,† Jungjoong Hwang,† Ganganna Bogonda,† Donghoon Kim,† Haeil Park,† Deukjoon Kim,‡ and Jongkook Lee*,† Org. Lett. 2018.20:6398-6402. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 10/19/18. For personal use only.
†
College of Pharmacy, Kangwon National University, 1 Kangwondaehak-gil, Chuncheon, Gangwon-do 24341, Republic of Korea College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
‡
S Supporting Information *
ABSTRACT: A stereoselective protection-free asymmetric total synthesis of (+)-chamuvarinin (1), a potent anticancer and antitrypanosomal agent, has been accomplished. The adjacently linked [bis(tetrahydrofuran)]tetrahydropyran (THF−THF− THP) core of this natural product with seven stereogenic centers was constructed in a completely substrate-controlled fashion. The inter-ring stereochemistry (threo,threo,threo) of the oxatricyclic core was established in a stereoselective fashion by a chelation-controlled Keck allylation, whereas the intraring cis or trans relative stereochemistry was controlled by a stereoselective internal alkylation. hamuvarinin (1), the first reported annonaceous acetogenin bearing a tetrahydropyran (THP) ring adjacent to a bis-tetrahydrofuran (THF−THF) ring system, was isolated from the root of Uvaria chamae by Laurens and co-workers in 2004.1 The structure of this unusual acetogenin was determined by extensive NMR studies and high-resolution mass spectrometric measurements, which established the relative stereochemistry of the 2,5-trans-THF-containing C15−C19 region of the adjacently linked THF−THF−THP core spanning the C15−C28 region of the carbon backbone. In 2007, Poupon and co-workers secured the relative stereochemistry of the entire C15−C28 region of (+)-chamuvarinin based on a detailed reanalysis of the spectroscopic data for 1 as well as a semisynthetic study on the biosynthetic origin of chamuvarinin and the co-occurring squamocin.2 This study concluded that squamocin (a C37 oxabicyclic annonaceous acetogenin with a THF−THF core) is not a precursor of chamuvarinin. Finally, the structure and absolute stereochemistry of (+)-chamuvarinin (1) was firmly established by a total synthesis by Florence and co-workers in 2011.3 This unique C37 acetogenin showed strong antiproliferative activity against KB-3-1, a multidrug resistant cervical cancer cell line (GI50 = 0.8 nM).1 More interestingly, (+)-chamuvarinin (1)
C
© 2018 American Chemical Society
displayed antitrypanosomal activity, which implies that this acetogenin may lead to therapeutic agents for the treatment of neglected parasitic diseases such as sleeping sickness and Chagas disease.3b,4 Chamuvarinin (1) possesses an adjacently linked oxatricyclic core with seven stereogenic centers along with a butenolide moiety with an eighth stereocenter, and these challenging structural features and its unique biological activity have prompted us to seek an efficient synthetic pathway to this target. We herein report a stereoselective and protection group free synthetic approach to (+)-chamuvarinin (1) from readily available chiral alcohol 7,3 wherein its threo,trans,threo,cis,threo,cis backbone was constructed from alcohol 7 in a substrate-controlled fashion by utilizing iterative chelationcontrolled nucleophilic addition and intramolecular alkylation. It is worth noting that, in contrast to our substrate-controlled synthesis of the adjacently linked oxatricyclic core 2, the aforementioned total synthesis employed a strategy of coupling two chiral subunits to yield the oxatricyclic core. Another difference is that the present route fashions the oxatricyclic Received: August 23, 2018 Published: October 8, 2018 6398
DOI: 10.1021/acs.orglett.8b02706 Org. Lett. 2018, 20, 6398−6402
Letter
Organic Letters
be generated by IAEA in a stereoselective manner as indicated in the retrosynthetic plan. Our synthesis commenced with the application of our IAEA strategy to construct the 2,6-disubstituted-THP ring present in the oxatricyclic core of (+)-chamuvarinin (1), as depicted in Scheme 2. The requisite IAEA substrate 10 was prepared from
core by C−C bond formation, while the aforementioned route constructs this feature using the Williamson ether synthesis. As shown in our retrosynthetic plan for (+)-chamuvarinin (1) (Scheme 1), we envisioned that the target could be Scheme 1. Retrosynthetic Plan for (+)-Chamuvarinin (1)a
Scheme 2. Construction of Mono-THP System 6 via Intramolecular Amide Enolate Alkylation
readily available chiral homoallylic alcohol 73 in a straightforward manner. Williamson ether synthesis between homoallylic alcohol 7 and N,N-dimethyl α-chloroacetamide afforded αalkoxyacetamide 8 in 92% yield. Ozonolysis of olefin 8 followed by NaBH4 reduction of the resulting ozonide produced primary alcohol 9,6 which was converted to the corresponding tosylate 10 in 85% yield for the two steps. Upon exposure to KHMDS, 10 furnished a 96:1 mixture (by 1H NMR analysis) of the desired 2,6-cis-THP 6 (92% isolated yield) and its trans isomer.7,8 The observed high stereoselectivity of the IAEA reaction can be best rationalized by considering that the reaction proceeds via the folding and allylic strain-controlled chairlike transition state geometry A, where the nucleophilic amide enolate moiety assumes an “Heclipsed” conformation with the bulky R group in an equatorial position, to give rise to the desired tetrahydropyran amide 6. The relative configuration of the newly generated stereocenter of 6 was assigned by NOESY studies as illustrated in the scheme (see the Supporting Information). We next proceeded to address the construction of the 2,5cis-THF ring in (+)-chamuvarinin (1), as described in Scheme 3. Hydrozirconation of amide 6 with Schwartz’s reagent produced aldehyde 11,7,9 and the chelation-controlled nucleophilic addition of allyltributylstannane proceeded stereoselectively to afford a 27:1 mixture (by 1H NMR analysis) of homoallylic alcohol 12 and its anti-isomer via attack from the less hindered face of chelated intermediate B in a total 82% yield for the two steps.10 Homoallylic alcohol 12 was then uneventfully transformed into the desired IAEA substrate 15 in 76% overall yield by a three-step sequence analogous to that employed for synthesis of tosylate 10, (1) Williamson ether coupling with N,N-dimethyl α-chloroacetamide, (2) ozonolysis and subsequent reductive workup with NaBH4,6 and (3)
a
IAEA = intramolecular amide enolate alkylation, INAA = intramolecular nitrile anion alkylation, CM = cross-metathesis.
synthesized via cross-metathesis (CM) of oxatricyclic core 2 with readily available chiral butenolide 3.5 We further envisaged that the inter-ring stereochemistry (threo,threo) and the intraring stereochemistry (cis or trans) of the pivotal intermediate 2 could be established by employing chelationcontrolled Keck allylation and internal alkylation as key steps, respectively. Thus, 2 would be derived from oxatricylic nitrile 4 via reduction followed by the chelation-controlled Keck allylation protocol. The challenging 2,5-trans-disubstituted THF ring in oxatricyclic intermediate 4 would be incorporated into oxabicylic amide 5 through Keck allylation and our intramolecular nitrile anion alkylation (INAA) as key steps, which in turn could be constructed by appending the 2,5-cisdisubstituted THF ring to monocyclic THP amide 6 via Keck allylation and intramolecular amide enolate alkylation (IAEA) in an iterative fashion. Finally, tetrahydropyran amide 6 could 6399
DOI: 10.1021/acs.orglett.8b02706 Org. Lett. 2018, 20, 6398−6402
Letter
Organic Letters Scheme 3. Construction of THF−THP System 5 via Intramolecular Amide Enolate Alkylation
Scheme 4. Construction of THF−THF−THP System 4 via Intramolecular Nitrile Anion Alkylation
tosylation, thus setting the stage for the pivotal IAEA reaction. When tosylate 15 was subjected to IAEA with KHMDS as the base, the 2,5-cis-disubstituted THF 5 was generated in an excellent yield with >99:1 stereoselectivity, probably via an “Heclipsed” conformation C with the bulky R group in a pseudoequatorial position.11,12 The observed NOE interactions between the protons on C20 and C23 are supportive of the structural assignment of 5. Following the installation of THF−THP core 5, we set out to tackle the challenging task of using INAA to construct the pivotal 2,5-trans-disubstituted THF ring and complete the adjacently linked THF−THF−THP core 4 (Scheme 4). For this purpose, reduction of the amide functionality in 5 with Schwartz’s reagent under conditions analogous to those employed for amide 6,7,9 followed by Keck allylation of the resulting aldehyde 16,10 stereoselectively furnished syn-alcohol 17 as a single diastereomer in 80% overall yield for the two steps. Williamson ether coupling of homoallylic alcohol 17 with α-bromoacetonitrile produced α-alkoxyacetonitrile 18 in moderate yield (58%; 83% BRSM).12b Reductive ozonolysis of the terminal olefin functionality of 18,6 followed by tosylation of the resulting primary alcohol 19, paved the way for the projected INAA closure to install the crucial 2,5-trans stereochemistry in 4. After a series of experiments, we were delighted to find that the 2,5-trans-disubstituted THF motif in
4 could be achieved in a stereoselective fashion upon treatment of tosylate 20 with KHMDS in ether −30 °C for 30 min in 80% total yield (4/4-cis = 3.1:1 by 1H NMR analysis).12 However, further experimentation demonstrated that the observed 3.1:1 stereoselectivity is not a result of kinetic control, in contrast to the two previous IAEA cyclizations [10 → 6] and [15 → 5] (see Schemes 2 and 3, respectively), but rather the stereoselection proceeded under thermodynamic control since subjection of either 4 or 4-cis to the above cyclization conditions furnished the same 3.1:1 mixture of 4 and 4-cis. In fact, this epimerization process with KHMDS is so facile that it occurred even at −78 °C {KHMDS (1.6 equiv), ether, −78 °C, 5 min, 88%}. This epimerization incidentally provided a pathway to recycle the undesired isomer 4-cis. Although we were able to secure an efficient and practical route to prepare the 2,5-trans-disubstituted THF motif in 4, we decided to investigate whether we could elicit kinetic control of the INAA cyclization of tosylate 20. To this end, treatment of tosylate 20 with LiHMDS (3.0 equiv) in ether at −30 °C for 4 h produced a disappointing 1.7 to 1 mixture (by 1H NMR analysis) of 4 and 4-cis in 63% total yield. The fact that treatment of the minor isomer 4-cis with LiHMDS under 6400
DOI: 10.1021/acs.orglett.8b02706 Org. Lett. 2018, 20, 6398−6402
Letter
Organic Letters
0.1, CHCl3) {lit.1 [α]20D = +25 (c 0.026, CHCl3), lit.3 [α]20D = +9.9 (c 0.1, CHCl3)}. In summary, we have accomplished a stereoselective protection group-free asymmetric total synthesis of (+)-chamuvarinin (1), an annonaceous acetogenin with potent anticancer and antitrypanosomal activities, in 20 steps in >3% overall yield from the readily available starting material 7. The seven stereogenic centers in this synthetically challenging adjacently linked threo,trans,threo,cis,threo,cis backbone were stereoselectively constructed through carbon−carbon bond formation in a completely substrate-controlled fashion by iteratively employing chelation-controlled nucleophilic addition and internal alkylation. These results showcase the utility of our approach to the construction of the adjacently linked oxacycles in annonaceous acetogenins and other similar structures.
identical conditions did not produce any of trans isomer 4 strongly suggests that this observed 1.7:1 stereoselectivity is of kinetic origin. We reasoned that stereoelectronic stabilization in transition state geometry D, due to the nitrile anion moiety being antiperiplanar to the oxygen lone pair on the ether oxygen,13 may contribute to the moderate stereoselectivity observed for this nitrile anion cyclization as described in our previous publications12 based on the pioneering work by Stork et al.14 and ensuing elegant investigations by Fleming et al.8b,15,16 It is worth mentioning that we were unable to observe NOE interactions between the protons on C16 and C19 in 4, although NOE effects were observed in 4-cis. After construction of the requisite oxatricyclic core, we directed our attention to the assembly of the butenolide chain to complete the synthesis (Scheme 5). Toward this end,
■
Scheme 5. Completion of the Synthesis of (+)-Chamuvarinin (1)
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02706.
■
Detailed experimental procedures, characterization data and copies of NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Deukjoon Kim: 0000-0003-4079-8734 Jongkook Lee: 0000-0003-0739-7963 Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (NRF-2015R1A2A2A01004708 and NRF-2018R1A2B6001314). We thank the Central Laboratory of Kangwon National University for providing us with technical assistance on the spectroscopic experiments.
■
REFERENCES
(1) Fall, D.; Duval, R. A.; Gleye, C.; Laurens, A.; Hocquemiller, R. J. Nat. Prod. 2004, 67, 1041−1043. (2) Derbré, S.; Poupon, E.; Gleye, C.; Hocquemiller, R. J. Nat. Prod. 2007, 70, 300−303. (3) (a) Florence, G. J.; Morris, J. C.; Murray, R. G.; Osler, J. D.; Reddy, V. R.; Smith, T. K. Org. Lett. 2011, 13, 514−517. (b) Florence, G. J.; Morris, J. C.; Murray, R. G.; Vanga, R. R.; Osler, J. D.; Smith, T. K. Chem. - Eur. J. 2013, 19, 8309−8320. (4) Gould, E. R.; King, E. F.B.; Menzies, S. K.; Fraser, A. L.; Tulloch, L. B.; Zacharova, M. K.; Smith, T. K.; Florence, G. J. Bioorg. Med. Chem. 2017, 25, 6126−6136. (5) Marshall, J. A.; Sabatini, J. J.; Valeriote, F. Bioorg. Med. Chem. Lett. 2007, 17, 2434−2437. (6) (a) Boyle, G. A.; Govender, T.; Kruger, H. G.; Maguire, G. E. M. Tetrahedron: Asymmetry 2004, 15, 2661−2666. (b) Lautens, M.; Colucci, J. T.; Hiebert, S.; Smith, N. D.; Bouchain, G. Org. Lett. 2002, 4, 1879−1882. (c) Eguchi, T.; Arakawa, K.; Terachi, T.; Kakinuma, K. J. Org. Chem. 1997, 62, 1924−1933.
DIBAL-H reduction of the nitrile functionality in 4, followed by Keck allylation of the resulting aldehyde group in 21,10 delivered syn-alcohol 2 along with its anti-alcohol isomer (syn/ anti = 10:1 by 1H NMR analysis) in a total 62% yield for the two steps. Cross-metathesis of terminal alkene 2 with readily available butenolide 35 using the Stewart−Grubbs catalyst17 and subsequent chemoselective diimide reduction of the resulting olefin 22 (3:1 E/Z mixture by HPLC analysis) afforded (+)-chamuvarinin (1) in 57% overall yield,5,18 the spectral data and optical rotation for which were consistent with those reported for the natural product and synthetic material: [α]20D = +11.9 (c 0.026, CHCl3), [α]20D = +11.4 (c 6401
DOI: 10.1021/acs.orglett.8b02706 Org. Lett. 2018, 20, 6398−6402
Letter
Organic Letters (7) Latif, M.; Yun, J. I.; Seshadri, K.; Kim, H. R.; Park, C. H.; Park, H.; Kim, H.; Lee, J. J. Org. Chem. 2015, 80, 3315−3320. (8) For reviews of intramolecular enolate alkylations, see: (a) Kim, D. Synlett 2014, 25, 33−57. (b) Vyas Devambatla, R. K.; Velagaleti, R.; Yarravarapu, N.; Fleming, F. F. Tetrahedron 2012, 68, 2925−2942. (9) Spletstoser, J. T.; White, J. M.; Tunoori, A. R.; Georg, G. I. J. Am. Chem. Soc. 2007, 129, 3408−3419. (10) Keck, G. E.; Boden, E. P. Tetrahedron Lett. 1984, 25, 265−268. (11) Jang, H.; Shin, I.; Lee, D.; Kim, H.; Kim, D. Angew. Chem., Int. Ed. 2016, 55, 6497−65011. (12) (a) Kim, M. J.; Sohn, T.; Kim, D.; Paton, R. S. J. Am. Chem. Soc. 2012, 134, 20178−20188. (b) Jeong, W.; Kim, M. J.; Kim, H.; Kim, S.; Kim, D.; Shin, K. J. Angew. Chem., Int. Ed. 2010, 49, 752−756. (13) (a) Rychnovsky, S. D.; Takaoka, L. R. Angew. Chem., Int. Ed. 2003, 42, 818−820. (b) Taylor, R. E.; Kartika, R. Heterocycles 2007, 74, 447−459. (14) (a) Stork, G.; Boeckman, R. K., Jr. J. Am. Chem. Soc. 1973, 95, 2016−2017. (b) Stork, G.; Gardner, J. O.; Beckman, R. K., Jr.; Parker, K. A. J. Am. Chem. Soc. 1973, 95, 2014−2016. (15) (a) Fleming, F. F.; Wei, Y.; Liu, W.; Zhang, Z. Tetrahedron 2008, 64, 7477−7488. (b) Fleming, F. F.; Wei, Y.; Liu, W.; Zhang, Z. Org. Lett. 2007, 9, 2733−2736. (c) Fleming, F. F.; Zhang, Z.; Wang, Q.; Steward, O. W. J. Org. Chem. 2003, 68, 7646−7650. (d) Fleming, F. F.; Shook, B. C. J. Org. Chem. 2002, 67, 2885−2888. (e) Fleming, F. F.; Shook, B. C.; Jiang, T.; Steward, O. W. Org. Lett. 1999, 1, 1547−1550. (16) For reviews on nitrile anion cyclizations, see ref 8b in addition to the following: (a) Yang, X.; Fleming, F. F. Acc. Chem. Res. 2017, 50, 2556−2568. (b) Fleming, F. F.; Gudipati, S. Eur. J. Org. Chem. 2008, 2008, 5365−5374. (c) Fleming, F. F.; Shook, B. C. Tetrahedron 2002, 58, 1−23. (17) (a) Stewart, I. C.; Douglas, C. J.; Grubbs, R. H. Org. Lett. 2008, 10, 441−444. (b) Hernandez-Torres, G.; Urbano, A.; Carreño, M. C.; Colobert, F. Org. Lett. 2009, 11, 4930−4933. (c) Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips, A. Angew. Chem., Int. Ed. 2009, 48, 2346−2350. (18) (a) Suzuki, A.; Sasaki, M.; Nakagishi, T.; Ueda, T.; Hoshiya, N.; Uenishi, J. Org. Lett. 2016, 18, 2248−2251. (b) Sohn, T.; Kim, M. J.; Kim, D. J. Am. Chem. Soc. 2010, 132, 12226−12227. (c) Konno, H.; Makabe, H.; Hattori, Y.; Nosaka, K.; Akaji, K. Tetrahedron 2010, 66, 7946−7953. (d) Donohoe, T. J.; Harris, R. M.; Williams, O.; Hargaden, G. C.; Burrows, J.; Parker, J. J. Am. Chem. Soc. 2009, 131, 12854−12861. (e) Sinha, S. C.; Chen, Z.; Huang, Z.-Z.; NakamaruOgiso, E.; Pietraszkiewicz, H.; Edelstein, M.; Valeriote, F. J. Med. Chem. 2008, 51, 7045−7048. (f) Keum, G.; Hwang, C. H.; Kang, S. B.; Kim, Y.; Lee, E. J. Am. Chem. Soc. 2005, 127, 10396−10399.
6402
DOI: 10.1021/acs.orglett.8b02706 Org. Lett. 2018, 20, 6398−6402
