Letter Cite This: Org. Lett. 2017, 19, 5581-5584
pubs.acs.org/OrgLett
Total Synthesis of Brasilicardins A and C Masahiro Anada,* Taiki Hanari, Kosuke Kakita, Yasunobu Kurosaki, Kazuki Katsuse, Yuta Sunadoi, Yu Jinushi, Koji Takeda, Shigeki Matsunaga, and Shunichi Hashimoto Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan S Supporting Information *
ABSTRACT: The first total synthesis of brasilicardins A and C, novel diterpenoid− saccharide−amino acid hybrid metabolites with unique immunosuppressive activity, is described. The key step is a Diels−Alder/reductive angular methylation sequence capitalizing on a trans-fused bicyclic α-cyano-α,β-enone as its precursor to construct the 8,10-dimethyltrans/syn/trans-perhydrophenanthrene skeleton. Other notable features include an antiselective aldol reaction, a stereocontrolled glycosylation of a C2 alcohol, and a one-pot, twostep global deprotection sequence that did not damage these sensitive molecules.
B
C-methylated ketone 9 was obtained in reasonable yield (66% based on ketosulfone 7) along with the O-methylated enol ether 10 (9/10 = 2.3:1) (Scheme 1a).5 Jung et al. reported an efficient
rasilicardins A−D (1−4), isolated from the cultured broth of the pathogenic actinomycete Nocardia brasiliensis and characterized by Kobayashi et al., are tricyclic metabolites containing a highly strained trans/syn/trans-perhydrophenanthrene skeleton with a mono- or disaccharide moiety and an amino acid side chain attached.1,2 Of these congeners, brasilicardin A (1, Figure 1) has been shown to exhibit the most potent immunosuppressive activity in a mouse mixed lymphocyte reaction assay (IC50 = 0.057 μg/mL);3 it also exhibits cytotoxic activity against adriamycin-resistant murine lymphoma cells (IC50 = 0.078 μg/mL). Although the mechanism of action of 1 remains to be elucidated, it has recently been suggested that the immunosuppressive activity of brasilicardin A is induced by amino acid deprivation via the inhibition of amino acid transport system L, thereby leading to arrest of the cell-cycle progression of T cell lymphocytes at the G1 phase.4 It is notable that the characteristics of this inhibition process are very different from those of known immunosuppressive agents such as cyclosporin A and FK-506, which inhibit interleukin-2 production via the inhibition of calcineurin from helper T cells.
Scheme 1. Synthetic Studies of Brasilicardin A
synthesis of the acetyl-protected carbohydrate moiety 13 of brasilicardin A from D-glucosamine and L-rhamnose (Scheme 1b).6 Coupling of imidate 13 with model aglycones such as a rationally designed mimic core 14 using TMSOTf as a promoter was achieved in good yield with the desired α-glycosides 15 as the major product (α:β = 3:1).3,6 It is also noteworthy that all of the five acetate groups of 15 were selectively cleaved without affecting the hindered benzoate functionality of the disaccharide unit. Despite these remarkable achievements, however, there exists no reported total synthesis of 1 to date. Herein, we report the first total synthesis of brasilicardins A (1) and C (3).
Figure 1. Structures of brasilicardins A−D (1−4).
Owing to its great potential as a new drug lead for immunosuppressants and its unprecedented hybrid molecular architecture, brasilicardin A (1) has emerged as a highly attractive target for synthetic investigations. Coltart and Danishefsky reported the first synthetic approach to the 8,10-dimethyl trans/ syn/trans-perhydrophenanthrene skeleton of 1 by exploiting a stereocontrolled Diels−Alder reaction between trans-fused bicyclic α-phenylsulfonyl-α,β-enone 5 and silyloxydiene 6 followed by reductive angular methylation, in which the desired © 2017 American Chemical Society
Received: September 1, 2017 Published: October 4, 2017 5581
DOI: 10.1021/acs.orglett.7b02728 Org. Lett. 2017, 19, 5581−5584
Letter
Organic Letters Scheme 3. Synthesis of Tricyclic α-Cyanoketone 26
An obvious strategic point in the synthesis of brasilicardins lies in the construction of the 8,10-dimethyl trans/syn/transperhydrophenanthrene core structure with a chair/boat/chair conformation.7 Apart from the foregoing Diels−Alder cycloaddition/reductive alkylation sequence, a variety of elegant approaches to tricyclic trans/syn/trans systems have been developed,8 including a Lewis acid promoted rearrangement of a β-epoxide of the syn/trans-tricyclic framework,9 a [3,3]sigmatropic rearrangement of a Δ4-olefinic 3α-hydrodiazene,10 a hydroxy-directed cyclopropanation followed by oxidation and subsequent reductive opening of the cyclopropane ring,11 a transannular Diels−Alder reaction of a 14-membered ring (E,E,Z)-triene,12 and an intermolecular/transannular Michael reaction cascade of a trans-fused 6,10-membered ring system.13 In the context of this synthesis, the sequential Diels−Alder/ reductive angular methylation approach developed by Coltart and Danishefsky5 was deemed highly attractive from the standpoint of conciseness and amenability to appropriate functional group transformations on the C-ring, though selective C-alkylation of an intermediate enolate over O-alkylation has remained a major challenge.14 Given that the nature of activating groups had some effect on the stereoselectivity in the reductive angular alkylation,15 we envisioned that selective C-alkylation over O-alkylation could also be achieved by the judicious choice of an appropriate activating group. In this regard, we decided to explore the use of α-cyano-α,β-enone16 as a precursor for the sequential Diels−Alder/reductive alkylation process. With this background in mind, our synthetic strategy is outlined retrosynthetically in Scheme 2. Of particular note is that the C2 and C3 hydroxy groups are protected as MOM and TBS ethers, respectively, as both C2-selective glycosylation of diol 17c and monodesilylation of disilyl ether 17d would be difficult.17
Diels−Alder reaction of α-cyano-α,β-enone 20 with silyloxydiene 6 in a sealed tube at 140 °C proceeded uneventfully to give the target cycloadduct 26 as a single product in 98% yield.5 With a viable route to tricyclic α-cyanoketone 26 secured, we set out to investigate the crucial reductive methylation at C8. Following the procedure of Liu16 and Danishefsky,5,15 the reaction of 26 was initially carried out by sequential treatment with lithium naphthalenide in THF at −78 °C and CH3I (50 equiv), which provided the desired C-methylated ketone 19 as a single diastereomer in 41% yield along with 23% of O-methylated enol ether 27 (Table 1, entry 1). The trans/syn/trans Table 1. Reductive Methylation of α-Cyanoketone 26
yieldb (%)
Scheme 2. Retrosynthetic Analysis
a
entry
solvent
temp (°C)
time (h)
19/27
1 2c 3 4 5 6 7 8
THF THF Et2O DME Et2O/DME (2:1) Et2O/THF (2:1) Et2O/DME (6:1) Et2O/DME (6:1)
23 23 23 23 23 23 23 0
2 2 2 2 2 2 2 16
58:42 11:89 d 74:26 83:17 78:22 88:12 91:9
19
27
41 6 d 51 67 55 67 74
23 53 d 17 13 16 9 7
a Determined by 1H NMR of the crude product. bIsolated yield. cThis reaction was performed in the presence of 20 equiv of HMPA. d Complex mixture of products.
stereochemistry of 19 was established by 1H NOE experiments.27 We next turned our attention to a higher level of C-alkylation selectivity. As might be expected,28 the reaction in the presence of HMPA gave 27 as a major product (entry 2). Whereas the reaction in ether resulted in the formation of a complex mixture of products (entry 3), the use of DME provided a good C-/Oalkylation ratio (74:26, entry 4). A much better C-alkylation selectivity was obtained when the reaction was conducted in a 2:1 mixture of ether/DME (83:17, entry 5), whereas the use of THF as a cosolvent was less effective (entry 6). The C-/O-alkylation ratio was further improved to 88:12 when the ratio of ether to DME was increased to 6:1 (entries 5 vs 7). Eventually, lowering the alkylation temperature to 0 °C afforded the target ketone 19 in 74% yield with a very high C-alkylation selectivity (91:9), though a significantly longer reaction time was required to reach completion (entry 8).
The synthesis of the requisite tricyclic α-cyanoketone 26 was implemented as shown in Scheme 3. Formation of the silyl enol ether from known bicyclic ketone 2118 followed by Rubottom oxidation19 gave the α-hydroxyketone, which was protected with MOMCl to produce ketone 22. Stereoselective reduction of 22 with nBu3SnH/TBAF20 followed by protection of the resultant alcohol provided TBS ether 23. Removal of the ketal protection in 23 using FeCl3−silica gel21 without affecting the MOM ether was followed by a Banford−Stevens reaction22 to produce octalin 24. Allylic oxidation of 24 using Mn(OAc)3/tBuOOH afforded α,β-enone 25 in 68% yield,23,24 and it was converted into αcyano-α,β-enone 20 by a Johnson-type iodination25 and subsequent treatment with CuCN in DMSO at 120 °C.26 5582
DOI: 10.1021/acs.orglett.7b02728 Org. Lett. 2017, 19, 5581−5584
Letter
Organic Letters The remaining task in the synthesis of the appropriately protected aglycone moiety 17a required deoxygenation at C7 and installation of the C14 amino acid side chain (Scheme 4).
Scheme 6. Total Synthesis of Brasilicardins A and C
Scheme 4. Synthesis of Anti-Aldol Product 32
Reduction of the C7 ketone of 19 with LiAlH4 and subsequent Barton−McCombie deoxygenation furnished silyl enol ether 28.29 Selenation of 28 with PhSeCl followed by a selenoxide elimination afforded α,β-enone, which underwent reduction under Luche conditions30 to provide exclusively 12β-allylic alcohol 29 instead of the desired 12α-allylic alcohol 18. Since no reduction conditions were found that favored the formation of 18, our efforts were focused on stereoinversion at C12. The Mitsunobu reaction31 of 29 followed by treatment of the resultant acetate with LiAlH4 provided the desired alcohol 18 as a sole product. The Johnson−Claisen rearrangement32 of 18 with triethyl orthoacetate in the presence of a catalytic amount of onitrophenol33 was followed by reduction of the resultant ester with DIBAL-H to produce aldehyde 30. Aldol coupling5b of 30 with a titanium enolate (3 equiv) generated from 31 under Solladié−Cavallo conditions34 led to the formation of anti-aldol product 32 as a single product in 86% yield. Removal of the chiral auxiliary was easily carried out under acidic conditions to give β-hydroxy-α-aminoester, which was converted to tetrachlorophthalimide 3335 using methyl 2(succinimidooxycarbonyl)-3,4,5,6-tetrachlorobenzoate (34) as a new reagent (Scheme 5).27,36,37 O-Methylation of the C16hydroxy group in 33 using Me3O·BF4 in the presence of a proton sponge was followed by selective removal of the MOM group using TMSBr38 to provide the C2 alcohol 17a in 74% yield.
37 formed via isomerization of a 1,2-orthoacetate intermediate 38a was also isolated in 45% yield.40 After considerable experimentation, we were pleased to find that glycosylation using P,P-diphenyl-N-(p-toluenesulfonyl)-phosphinimidate 35b as a glycosyl donor41 under the same conditions as those for 35a furnished 36 in 45% yield (82% brsm) along with 8% of 37. The difference in reaction mode between the two glycosyl donors 35a and 35b remains to be elucidated. We next focused on the introduction of a disaccharide unit. Since attempts to prepare diphenylphosphinimidate 39 met with failure, we tried Schmidt’s trichloroacetimidate method again. Gratifyingly, coupling of 17a with the readily prepared donor 13 under the same conditions as those for 35a, except for the reaction being performed at −40 °C for 0.5 h, provided 40 as a sole product in 61% yield (94% brsm). Notably, formation of acetate 37 was not observed in the glycosylation with 13, suggesting that the sterically demanding N-acetylglucosamine moiety strongly disfavored the formation of an orthoacetate intermediate 38b. Simultaneous removal of the tert-butyl and TBS groups in 40 using trifluoroacetic acid in the presence of Et3SiH and subsequent treatment with 1,2ethylenediamine to remove concurrently the TCP group and the five acetyl groups followed by gel filtration chromatography on Sephadex completed the synthesis of brasilicardin A (1), in 89% yield for the two steps. Synthetic 1 was spectroscopically identical to natural 1. Brasilicardin C (3) was also obtained from 36 under the same conditions as those for 40 in 66% yield .1c In summary, we have accomplished the first total synthesis of brasilicardins A and C from known bicyclic ketone 21 in 29 steps and overall yields of 2.1% and 1.4%, respectively. Key features of the synthesis include a Diels−Alder/reductive angular methylation sequence capitalizing on a trans-fused bicyclic α-cyano-α,βenone as its precursor to construct the 8,10-dimethyl trans/syn/ trans-perhydrophenanthrene ring system, an anti-selective aldol reaction using a titanium enolate generated from a chiral iminoglycinate, a stereocontrolled glycosylation of a C2 alcohol, and a one-pot, two-step global deprotection sequence that did not destroy these sensitive molecules. Clearly, this approach showcases the power of a trans-Diels−Alder paradigm developed by Danishefsky.15 Importantly, the strategy potentially allows for the introduction of a variety of saccharides and amino acid side chains into the core structure. The synthesis of such analogues for biological investigations is currently underway.
Scheme 5. Synthesis of Protected Aglycon 17a
The stage was now set for the completion of the total synthesis of brasilicardins A and C as shown in Scheme 6. Patterned after the work of Jung,3,6 we initially explored the glycosylation of 17a with trichloroacetimidate 35a (2 equiv) under Schmidt’s conditions39 using BF3·OEt2 (2 equiv) as a promoter in the presence of 4 Å MS in CH2Cl2 at 0 °C. In this reaction, the desired α-glycoside 36 was obtained in 23% yield (29% brsm) with no signs of the formation of its β-anomer, and the C2 acetate 5583
DOI: 10.1021/acs.orglett.7b02728 Org. Lett. 2017, 19, 5581−5584
Letter
Organic Letters
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methylated enol ether C (25%) and the desired C-methylated product B was obtained in only 15% yield. See ref 5b.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02728. Experimental procedures and spectral data (PDF)
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(15) (a) Lee, J. H.; Zhang, Y.; Danishefsky, S. J. J. Am. Chem. Soc. 2010, 132, 14330. (b) Peng, F.; Grote, R. E.; Danishefsky, S. J. Tetrahedron Lett. 2011, 52, 3957. (16) For the Diels−Alder reaction/reductive alkylation sequence using α-cyano-α,β-enones, see: (a) Zhu, J.-L.; Shia, K.-S.; Liu, H.-J. Tetrahedron Lett. 1999, 40, 7055. (b) Zhu, J.-L.; Shia, K.-S.; Liu, H.-J. Chem. Commun. 2000, 1599. (17) No regioselectivity was observed in the glycosylation of a model of 17c using L-rhamnosyl donors. See the Supporting Information. (18) Hagiwara, H.; Uda, H. J. Org. Chem. 1988, 53, 2308. (19) (a) Rubottom, G. M.; Vazquez, M. A.; Pelegrina, D. R. Tetrahedron Lett. 1974, 15, 4319. (b) Yajima, A.; Mori, K. Eur. J. Org. Chem. 2000, 2000, 4079. (20) Shibata, I.; Yoshida, T.; Baba, A.; Matsuda, H. Chem. Lett. 1991, 20, 307. (21) Kim, K. S.; Song, Y. H.; Lee, B. H.; Hahn, C. S. J. Org. Chem. 1986, 51, 404. (22) Bamford, W. R.; Stevens, T. S. J. Chem. Soc. 1952, 4735. (23) (a) Shing, T. K. M.; Yeung, Y.-Y.; Su, P. L. Org. Lett. 2006, 8, 3149. For recent reviews on allylic oxidations, see: (b) Nakamura, A.; Nakada, M. Synthesis 2013, 45, 1421. (c) Weidmann, V.; Maison, W. Synthesis 2013, 45, 2201. (24) Results of allylic oxidation of 24 with other reagents are described in the Supporting Information. (25) Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake, C. B. W.; Wovkulich, P. M.; Uskoković, M. R. Tetrahedron Lett. 1992, 33, 917. (26) You, R.; Long, W.; Lai, Z.; Sha, L.; Wu, K.; Yu, X.; Lai, Y.; Ji, H.; Huang, Z.; Zhang, Y. J. Med. Chem. 2013, 56, 1984. (27) See the Supporting Information for details. (28) House, H. O. In Modern Synthetic Reactions, 2nd ed.; Benjamin: Menlo Park, 1972; Chapter 9. (29) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574. (30) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226. (31) For a review, see: Mitsunobu, O. Synthesis 1981, 1981, 1. (32) Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.; Li, T.-T.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem. Soc. 1970, 92, 741. (33) Fukazawa, T.; Shimoji, Y.; Hashimoto, T. Tetrahedron: Asymmetry 1996, 7, 1649. (34) (a) Solladié-Cavallo, A.; Koessler, J. L. J. Org. Chem. 1994, 59, 3240. (b) Shioiri, T.; Irako, N. Tetrahedron 2000, 56, 9129. (35) Debenham, J. S.; Madsen, R.; Roberts, C.; Fraser-Reid, B. J. Am. Chem. Soc. 1995, 117, 3302. (36) Casimir, J. R.; Guichard, G.; Briand, J.-P. J. Org. Chem. 2002, 67, 3764. (37) Protection with tetrachlorophthalic anhydride under standard phthaloylation conditions did not give satisfactory results. See: Wuts, P. G. M. Greene’s Protective Groups in Organic Synthesis, 5th ed.; John Wiley & Sons: Hoboken, 2014. (38) Hanessian, S.; Delorme, D.; Dufresne, Y. Tetrahedron Lett. 1984, 25, 2515. (39) (a) Schmidt, R. R.; Michel, J. Angew. Chem., Int. Ed. Engl. 1980, 19, 731. (b) Zhu, X.; Schmidt, R. R. Angew. Chem., Int. Ed. 2009, 48, 1900. (40) (a) Banoub, J.; Bundle, D. R. Can. J. Chem. 1979, 57, 2091. (b) Ziegler, T.; Kovác,̌ P.; Glaudemans, C. P. J. Liebigs Ann. Chem. 1990, 1990, 613. (41) (a) Hashimoto, S.; Honda, T.; Ikegami, S. Heterocycles 1990, 30, 775. (b) Hashimoto, S.; Honda, T.; Ikegami, S. Tetrahedron Lett. 1991, 32, 1653.
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Masahiro Anada: 0000-0002-7691-5114 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This research was supported in part by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS). T.H. and K.K. are grateful to JSPS for a graduate fellowship. We thank Prof. J. Kobayashi (Hokkaido University) for helpful discussions and Ms. S. Oka, Ms. M. Kiuchi, and Mr. T. Hirose (Center for Instrumental Analysis, Hokkaido University) for mass measurement and elemental analysis.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b02728 Org. Lett. 2017, 19, 5581−5584
