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Cite this: DOI: 10.1039/c4cc10041g Received 16th December 2014, Accepted 19th January 2015 DOI: 10.1039/c4cc10041g
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First enantioselective total synthesis and configurational assignments of suberosenone and suberosanone as potential antitumor agents† a a a Mohammad Kousara,a Ange ´lique Ferry, Franck Le Bideau, Kathalyn L. Serre ´, b c d ef Isabelle Chataigner, Estelle Morvan, Joe ´ron and ¨lle Dubois, Monique Che Françoise Dumas*a
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The first enantioselective total syntheses of two marine sesquiterpenes (1R)-suberosenone and (1R)-suberosanone are achieved leading to revision of the AC of natural (1S)-suberosanone. Key elements of the synthesis include hyperbaric asymmetric Michael addition and highly efficient silver trifluoroacetate mediated a-alkylation for the formation of ring A.
Suberosenone (1) is a sesquiterpene isolated from the marine gorgonian Subergorgia suberosa in 1996 (Fig. 1) which displays potent differential cytotoxicity in the NCI human tumor-based primary screen, particularly against ovarian, breast, renal and melanoma cell lines (IC50 0.1 to 0.01 mg mL 1).1 Since its characterization, several new related members were isolated and their cytotoxicity studied.2 Among them, suberosanone (2), isolated in 2000 from the Taiwanese gorgonian Isis hippuris, was found to exhibit impressive cytotoxicity toward P388, A549 and HT29 cell lines (up to o5 10 6 mg mL 1).2b Owing to these particularly interesting biological properties, straightforward access to these compounds and their analogues is highly desirable. Their structures were determined through extensive NMR studies albeit without experimental assignment of their absolute configurations (ACs), while DFT calculations have concluded that ACs of their tricyclic cores were identical to that found in natural quadrone (4), i.e. (1R).3 The stimulating common features of these marine sesquiterpenes lie in a tricyclo[4.3.2.01,5]undecane core 3 possessing up to five contiguous adjacent stereocenters, surrounding a
CNRS-BioCIS UMR 8076, Chimie des Substances Naturelles, IPSIT and LabEx LERMIT, Faculte´ de Pharmacie, Universite´ de Paris Sud, 5, rue J.-B. Cle´ment, ˆtenay-Malabry, France. E-mail: [email protected] 92296 Cha b Normandie University, COBRA, UMR CNRS 6014 and FR 3038, Universite´ de Rouen, 1 rue Tesnie`re, 76821 Mont Saint Aignan, France c ˆtenay-Malabry, France De´partement RMN, BioCIS, 5, rue J.-B. Cle´ment, 92296 Cha d Institut de Chimie des Substances Naturelles, UPR CNRS 2301, avenue de la terrasse, Gif sur Yvette F-91198, France e ˆtenay-Malabry, Institut Galien, UMR CNRS 8612, Biophysics, Faculte´ de Pharmacie, Cha France f ANBiophy, FRE 3207 CNRS, Universite´ Pierre et Marie Curie, 75252 Paris, France † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c4cc10041g
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Fig. 1 Marine cytotoxic suberosenone (1), suberosanone (2), the common ABC core 3, (1R)-( )-quadrone (4), (1S)-(+)-terrecyclic acid (5) (1R)-( )-isishippuric acids A (6a). and B (6b).
a stereogenic quaternary carbon center (QCC), and the various substitutions of ring C (Fig. 1). Such a bridged tricyclic skeleton 3 was initially discovered in the antitumor terrestrial fungal congener ( )-quadrone (4)4 and its biosynthetic progenitor (+)-terrecyclic acid (5),5 both exhibiting cytotoxic properties, however to a much lesser extent.6 While nineteen total syntheses of 4, including three asymmetric routes have been described,7 only one synthesis of ()-suberosenone (1) based on an elegant radical cascade sequence (29 steps, 0.43% overall yield (OY)), and one synthesis of ()-suberosanone (2) (terrecyclan-3-one) prior its isolation from a natural source (9 steps, 5.5% OY), have been reported to date.8 We report herein the first enantioselective and concise syntheses of (1R)-suberosenone (1) and (1R)-suberosanone (2) allowing the experimental configurational assignments of the corresponding natural products. Retrosynthetically, these tricyclic sesquiterpenes could be generated from the intermediary enone 7 by alkylation at the C5 position (Scheme 1).9 Synthesis of 7 from enantiopure bicyclic AB subunit 8 would rely on a Wacker oxidation of the pendant vinyl group and intramolecular aldol condensation of the resulting dione.10 Precursor of 8 could be the key keto-ester 9,
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Scheme 1 Retrosynthetic analysis plan for suberosenone (1) and suberosanone (2).
resulting from the assembly of allyl-cyclopentanone 10 with methyl crotonate, through a highly regio- and stereoselective Michael addition.11 This crucial step would allow the diastereoand enantioselective formation of two contiguous stereogenic centers, the C1 QCC and C8 tertiary one, which are expected to retain their integrity under the reaction conditions used until the end of the synthesis, and thus dictate the stereochemistry of the final suberosane products. We first planned to synthesize (1R,2R,8R,11R)-1, assuming that the AC exhibited by marine natural suberosanes matched those found in natural quadrone, i.e. ( )-(1R,2R,5R,8R,11R)-4, and natural (1R,2R,8R,11R)-4,5-secosuberosanoids isishippuric acid A ( )-6a and B ( )-6b (Fig. 1).12 Thus, (R)-1-phenylethylamine was chosen as the chiral inductor on the basis of the stereochemical result known for this asymmetric Michael process.11 We initiated our synthetic studies with the b-keto-ester 11.13 Cyclopentanone 10 was next obtained in 69% yield14 and engaged in the key asymmetric Michael reaction (Scheme 2). Although unsubstituted electrophilic alkenes smoothly underwent Michael addition with chiral imine/secondary enamines under neutral conditions, the reactivity of b-substituted Michael acceptors such as alkyl crotonates is sluggish and their condensation requires activation.11b An equimolar mixture of the imine derived from 10 and methyl crotonate was subjected to 1.4 GPa pressure leading to the corresponding Michael adduct in gram quantities as a single diastereomer, as the result of a complete regio- (re 4 95%) and stereocontrol (de 4 95%) of the Michael process.15 Subsequent acidic hydrolysis yielded cyclopentanone 9 in 60% yield (ee 4 95%) from 10. ACs in Michael adduct 9 were proposed to be (1S,8R) on the basis of the empirical rule cited below,11a by analogy with related Michael adducts11d,15b and will be confirmed during completion of the synthesis. With this key highly functionalized chiral Michael adduct 9 in hand, we turned our attention toward the construction of tricyclic enone 7 (Scheme 2). We began with formation of the six-membered ring A through an aldol ring closure.10 Toward this end, chemoselective protection of the ketone carbonyl group in 9 as a silyl enol ether, subsequent reduction of the ester group and hydrolytic removal of the silyl enol ether deliver
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Scheme 2 Synthesis of the common tricyclic intermediate 7. Reagents and conditions: (a) NaH (2.3 equiv.), THF, 0 1C to 20 1C then BrCH2CH = CH2, THF, 16 h then LiI.7H2O (3 equiv.), collidine D, 16 h, 69%; (b) 1(R)-phenylethylamine, cyclohexane, Dean–Stark, 16 h, 82%; (c) methyl crotonate (1 equiv.), THF, 1.4 GPa, 62 1C, 72 h, then AcOH (20% aq), THF reflux, 50 h, 73%; (d) TMSCl (3 equiv.), Et3N (5 equiv.), DMF D, overnight; (e) LiAlH4, Et2O, 0 1C, 2 h; (f) TBAF (1 M in THF), 25 1C, 10 min, 94% (3 steps); (g) (COCl)2, DMSO, Et3N, CH2Cl2, 60 1C to 20 1C, 1.5 h, 87%; (h) HCl (3.5 N), DME/THF, 48 1C, 17 h, 93%; (i) C6H5OC(S)Cl, py, 89 h, 20 1C; (j) (TMS)3SiH, AIBN, toluene, 110 1C, 24 h, 53% (2 steps); (k) MsCl, Et3N, DMAP, CH2Cl2, 0 1C, 2 h; (l) NaI, NaHCO3, acetone, rt, 42 h, 92% (2 steps); (m) TMSOTf, Et3N, CH2Cl2, rt, 2.5 h, 100%; (n) CF3CO2Ag, CH2Cl2, THF, rt, 5 min, 87%; (o) Pd(OAc)2 (10 mol%) H2O, benzoquinone, HClO4, CH3CN, 25 1C, 24 h, 83%; (p) tBuOK (5 equiv.)/tBuOH D, 48 h, 83%.
the ketoalcohol 12a in 94% yield which upon Swern oxidation gave the labile ketoaldehyde 12b. Cyclization of 12b in acidic conditions10 led to a 2 : 1 mixture of epimeric bicyclic aldols 13a and 13b in 91% yield (2 steps, 1.6 : 1). For stereochemical purpose, the major epimer was separated by flash chromatography and subjected to spectroscopic studies. The spatial proximities of the equatorial hydrogen atom at C10 and C14 methyl group in aldol 13a as well as the equatorial hydrogen atom at C8 and H12 endo were established by NOESY correlations. This confirmed the (R) stereochemistry at C8, with the desired axial methyl group required for the synthesis of natural suberosanes, and then confirmed the proposed stereochemistry. Removal of the excess hydroxyl functions in aldols 13 using Barton Mc Combie protocol afforded the bicyclic ketone 8 in 48% yield from keto-alcohol 12a. Looking for a more efficient elaboration of the AB subunit 8, we envisaged the a-alkylation of cyclopentanone 12a. To this end, this product was converted into the corresponding iodide 12c whose direct a-alkylation under basic conditions (tert-BuOK)16 led to no more than 27% yield of the desired C-alkylated product 8, in mixture with the corresponding O-alkylated enol ether. Various reaction conditions (base, solvents, counter anion. . .) did not improve the proportion of the desired C-alkylated product 8 (Table S3, ESI†). These disappointing results can be explained by the peculiar situation of the ketone a-position which is also a to the
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quaternary carbon centre C13 driving the alkylation to the less hindered O-site of the ambident enolate. We therefore turned our attention toward reaction conditions involving enolate surrogates such as silyl enol ethers which are more prone to C-alkylation in the presence of silver trifluoroacetate.17 To our delight, silyl enol ether 14, easily synthesized from 12a, was successfully transformed in slightly modified conditions into the desired target 8 in high yield (80% yield, 3 steps from 12a). The diketone 15 required for the cyclopentannulation of ring C was then prepared in 83% yield from 8 by Wacker oxidation of the vinyl function.18 Intramolecular aldol condensation of the diketone 15 using excess potassium tert-butylate in tert-butanol at reflux10 furnished the pivotal tricylic cyclopentenone 7 in 83% yield. Completion of suberosenone synthesis was achieved through a three steps sequence (Scheme 3).9 Regioselective functionalization of ring C takes advantage of the enone function, preventing alkylation at the more reactive C3 position of the corresponding cyclopentanone.9 Introduction of the fifteenth carbon atom was thus done through trapping of the lithium dienolate of 7 by gaseous formaldehyde affording 16 in 72% yield. The relative stereochemistry in 16 was unambiguously established from 2D NOE experiments: H-5 shows strong correlation with axial H3-7 and H3-6 does not exhibit correlation with H3-7 indicating a b-orientation of the hydroxymethyl substituent at C5. Stereoselective catalytic hydrogenation of the enone moiety using 10% Pd/C gave the penultimate intermediate 17 in quantitative yield. Dehydration occurred smoothly in the presence of PTSA at 50 1C affording (1R)-suberosenone (1) in 48% yield. The spectroscopic data of that synthetic compound were found identical to literature data1 and the sign of the optical rotation, [a]20 D + 66.7 (c 0.3 CHCl3), identical to the one of natural suberosenone (+)-(1), [a]20 D + 55.7 (c 0.8, CHCl3), which is therefore (1R,2R,8R,11R), in accordance with theoretical calculations of its optical rotation.3 The synthesis of (1R)-suberosanone 2 was then completed (Scheme 3) in two steps from the common tricyclic intermediate
Scheme 3 Achievement of the synthesis of suberosenone and suberosanone (selected nOe correlations indicated by double-headed curved arrows). Reagents and conditions: (a) LDA, THF, 23 1C, 1.5 h then CH2O, 23 1C to 25 1C, 72%; (b) H2 (1 atm) Pd/C (10 mol%), AcOEt, 1 h, 100%; (c) PTSA, benzene, 50 1C, 48%; (d) LDA, THF, 23 1C, 1.5 h then CH3I, 23 1C to 25 1C, 88%.
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enone (1R)-7: the lithium dienolate of 7 was alkylated with methyl iodide affording stereoselectively enone 18 (88% yield, de 4 95%) which was hydrogenated in the presence of 10% Pd/C affording synthetic (1R)-suberosanone 2 in quantitative yield. The relative stereochemistry in 18 and 2 was established from 2D NOE experiments: H-5 shows strong correlation with axial H3-7 and no correlation was found between H3-6 and H3-7. Moreover, the b-orientation of the Me at C5 in 2 was supported by NOE correlation between H-5 and H-11, and between H3-6 and H-12, the latter exhibiting correlation with H-9b. Intriguingly, the sign of its optical rotation, [a]19 D + 53.4 (c 0.1 CHCl3), was found opposite to the corresponding natural product’s one, [a]20 60.0 D (c 0.1 CHCl3). To the best of our knowledge it would represent the first example of quadrane-type natural product that is not related to the 1R-configurational quadrone series. Although their absolute configuration has not always yet been established, the vast majority of known quadranes belongs to the 1R-series.6 The experimentally determined AC of natural suberosanone is thus (1S,2S,5R,8S,11S), an exception to the unified (1R) AC of the tricyclic core of natural suberosanes as established on the basis of DFT calculations of their chiroptical properties.3 Furthermore, the single positive Cotton effect of the ketone group centered at 291 nm, with a dichroic absorption De + 3.19 obtained from the ECD spectrum of synthetic (+)-2 correlates well the one of natural ( )-(1R)-quadrone 47d (298 nm, De + 2.68) which supports the (1R,2R,5S,8R,11R) AC of synthetic (+)-2. The isolation of both enantiomers of a natural product from either single or different genera and/or species is well known, and has been reported for different classes of products, including sesquiterpenes.19 Therefore, biogenesis of these suberosane sesquiterpenes is divergent, a situation not described in the terrestrial quadrane congeners, probably because they originate from different gorgonians20 and will deserve further studies to elucidate these divergent biosynthetic pathways. Synthetic (1R)-suberosanone (+)-2 was found to have no significant cytotoxic activity against MDA231, HT29, A549, MCF7, SF268 and MRC5 cell lines. In summary, we have achieved the total synthesis of (+)-suberosenone (1) in 15 steps and 7.4% overall yield, and of (+)-suberosanone (2) in 14 steps and 18.8% overall yield from commercially available keto-ester 11 and determined the absolute configurations of these products under their natural forms. The synthesis features (i) hyperbaric asymmetric Michael addition for the efficient generation of two contiguous quaternary and tertiary stereocenters in excellent regio-, diastereo- and enantiomeric selectivities (ii) chemoselective silver trifluoroacetate-promoted a-alkylation of a congested silyl enol ether to build the bridged AB subunit and set up the stereochemistry at C11 (iii) aldol ring closure to elaborate a common tricyclic suberosane intermediate followed by stereoselective functionalization of ring C. The synthesis led to assignment of the ACs of the natural products and revision of the proposed AC of natural ( )-suberosanone (2) as the first identified (1S) marine sesquiterpene suberosane. The flexibility and conciseness of the synthetic route developed here now paves the way for further structural and biological studies of natural suberosanes and analogues. Further studies toward the
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total synthesis of related natural suberosanes using this strategy are currently ongoing in our laboratory. The authors thank the Centre National de la Recherche `re de l’Education Nationale, Scientifique (CNRS), the Ministe ´rieur et de la Recherche (Paris, France), de l’Enseignement Supe the Fondation ARC pour la Recherche sur le Cancer (Villejuif, France) for financial support, and Ministry of Higher Education (Damascus, Syria) for a PhD fellowship to M.K. We thank Dr C. Miet, Dr C. Camara and P.-E. Venot for performing preliminary experiments, Dr J. Mahuteau for NMR studies, Mrs S. Mairesse-Lebrun and K. Leblanc for performing the combustion and high-resolution MS analyses (BioCIS).
Notes and references 1 H. R. Bokesch, T. C. McKee, J. H. Cardellina II and M. R. Boyd, Tetrahedron Lett., 1996, 37, 3259. 2 (a) H. R. Bokesch, J. W. Blunt, C. K. Westergaard, J. H. Cardellina II, T. R. Johnson, J. A. Michael, T. C. McKee, M. G. Hollingshead and M. R. Boyd, J. Nat. Prod., 1999, 62, 633; (b) J.-H. Sheu, K.-C. Hung, G.-H. Wang and C.-Y. Duh, J. Nat. Prod., 2000, 63, 1603; (c) S.-H. Qi, S. Zhang, X. Li and Q.-X. Li, J. Nat. Prod., 2005, 68, 1288. 3 P. J. Stephens, D. M. McCann, F. J. Devlin and A. B. Smith, III, J. Nat. Prod., 2006, 69, 1055. 4 R. L. Ranieri and G. J. Calton, Tetrahedron Lett., 1978, 499. 5 (a) M. Nakagawa, A. Hirota, H. Sakai and A. Isogai, J. Antibiot., 1982, 35, 778; (b) T. J. Turbyville, E. M. K. Wijeratne, L. Whitesell and A. A. L. Gunatilaka, Mol. Cancer Ther., 2005, 4, 1569. 6 Review: M. Presset, Y. Coquerel and J. Rodriguez, Eur. J. Org. Chem., 2010, 2247. 7 (a) K. Kon, K. Ito and S. Isoe, Tetrahedron Lett., 1984, 25, 3739; (b) A. B. Smith III and J. P. Konopelski, J. Org. Chem., 1984, 49, 4094; (c) H.-J. Liu and M. Llinas-Brunet, Can. J. Chem., 1988, 66, 528; (d) A. B. Smith III, J. P. Konopelski, B. A. Wexler and P. A. Sprengeler, J. Am. Chem. Soc., 1991, 113, 3533. 8 (a) H.-Y. Lee and B. G. Kim, Org. Lett., 2000, 2, 1951; (b) R. M. Coates, J. Z. Ho, M. Klobus and L. Zhu, J. Org. Chem., 1998, 63, 9166. 9 (a) S. Danishefsky, K. Vaughan, R. C. Gadwood and K. Tsuzuki, J. Am. Chem. Soc., 1980, 102, 4262; (b) S. Danishefsky, K. Vaughan, R. C. Gadwood and K. Tsuzuki, J. Am. Chem. Soc., 1981, 103, 4136. 10 A. B. Smith III, B. A. Wexler and J. Slade, Tetrahedron Lett., 1982, 23, 1631.
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ChemComm ¨le, F. Dumas and A. Guingant, 11 (a) Review: J. d’Angelo, D. Desmae Tetrahedron: Asymmetry, 1992, 3, 459; Relevant examples: (b) I. Jabin, G. Revial, A. Tomas, P. Lemoine and M. Pfau, Tetrahedron: Asymmetry, 1995, 6, 1795; (c) M. J. Lucero and K. N. Houk, J. Am. Chem. Soc., 1997, 119, 826; (d) A. Chiaroni, C. Riche, F. Dumas, M. Mauduit and C. Miet, Acta Crystallogr., Sect. C: Cryst. Struct. Commun., 1998, C54, 401; (e) M. E. Tran Huu Dau, C. Riche, F. Dumas and J. d’Angelo, Tetrahedron: Asymmetry, 1998, 9, 1059; ( f ) L. Keller, F. Dumas and J. d’Angelo, Eur. J. Org. Chem., 2003, 2488; ( g) H. ´ski, J. Kedzia, J. Wojciechowski and W. M. Wolf, Krawczyk, M. ´ Sliwin Tetrahedron: Asymmetry, 2007, 18, 2712. 12 (a) M. Torihata and S. Kuwahara, Biosci., Biotechnol., Biochem., 2008, 72, 1628; (b) M. Torihata, T. Nakahata and S. Kuwahara, Org. Lett., 2007, 9, 2557. 13 (a) J. Froborg and G. Magnuson, J. Am. Chem. Soc., 1978, 100, 6728; (b) For a microwave alternative to the photolysis of diazodimedone, see: M. Presset, Y. Coquerel and J. Rodriguez, J. Org. Chem., 2009, 74, 415. 14 A. L. Veretenov, D. O. Koltun, W. A. Smit and Y. A. Strelenko, Tetrahedron Lett., 1995, 36, 4651. 15 (a) High Pressure Chemistry, ed. R. van Eldik and F.-G. Klarner, Wiley-VCH, 2008; L. Minuti, in Eco-friendly synthesis of materials, ed. R. Ballini, RSC, Cambridge, UK, 2009, pp. 237–270; (b) C. Camara, D. Joseph, F. Dumas, J. d’Angelo and A. Chiaroni, Tetrahedron Lett., 2002, 43, 1445. 16 R. Rodriguez, A.-S. Chapelon, C. Ollivier and M. Santelli, Tetrahedron, 2009, 65, 7001. 17 (a) C. W. Jefford, A. W. Sledeski, P. Lelandais and J. Boukouvalas, Tetrahedron Lett., 1992, 33, 1855; (b) P. Angers and P. Canonne, Tetrahedron Lett., 1994, 35, 367; (c) H. Takagaki, N. Yasuda, M. Asaoka and H. Takei, Bull. Chem. Soc. Jpn., 1979, 52, 1241. 18 D. J. Miller and D. D. M. Wayner, J. Org. Chem., 1990, 55, 2924. 19 (a) Review: J. M. Finefield, D. H. Sherman, M. Kreitman and R. M. Williams, Angew. Chem., Int. Ed., 2012, 51, 4802(b) See for ¨nig, example: I. Prosser, I. G. Altug, A. L. Phillips, W. A. Ko H. J. Bouwmeester and M. H. Beale, Arch. Biochem. Biophys., 2004, 432, 136. 20 Within the order Alcyonacea, Subergorgia suberosa is a species of the soft coral genus belonging to the family Subergorgiidae of the suborder Scleraxonia, while Isis hippuris is a species of the genus Isis, one of the 38 genera of the family Isididae of the suborder Calcaxonia: M. Daly, M. R. Brugler, P. Cartwright, A. G. Collins, M. N. Dawson, D. G. Fautin, S. C. France, C. S. McFadden, D. M. Opresko, E. Rodriguez, S. L. Romano and J. L. Stake, Zootaxa, 2007, 1668, 127.
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Cite this: DOI: 10.1039/c4cc10041g Received 16th December 2014, Accepted 19th January 2015 DOI: 10.1039/c4cc10041g
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First enantioselective total synthesis and configurational assignments of suberosenone and suberosanone as potential antitumor agents† a a a Mohammad Kousara,a Ange ´lique Ferry, Franck Le Bideau, Kathalyn L. Serre ´, b c d ef Isabelle Chataigner, Estelle Morvan, Joe ´ron and ¨lle Dubois, Monique Che Françoise Dumas*a
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The first enantioselective total syntheses of two marine sesquiterpenes (1R)-suberosenone and (1R)-suberosanone are achieved leading to revision of the AC of natural (1S)-suberosanone. Key elements of the synthesis include hyperbaric asymmetric Michael addition and highly efficient silver trifluoroacetate mediated a-alkylation for the formation of ring A.
Suberosenone (1) is a sesquiterpene isolated from the marine gorgonian Subergorgia suberosa in 1996 (Fig. 1) which displays potent differential cytotoxicity in the NCI human tumor-based primary screen, particularly against ovarian, breast, renal and melanoma cell lines (IC50 0.1 to 0.01 mg mL 1).1 Since its characterization, several new related members were isolated and their cytotoxicity studied.2 Among them, suberosanone (2), isolated in 2000 from the Taiwanese gorgonian Isis hippuris, was found to exhibit impressive cytotoxicity toward P388, A549 and HT29 cell lines (up to o5 10 6 mg mL 1).2b Owing to these particularly interesting biological properties, straightforward access to these compounds and their analogues is highly desirable. Their structures were determined through extensive NMR studies albeit without experimental assignment of their absolute configurations (ACs), while DFT calculations have concluded that ACs of their tricyclic cores were identical to that found in natural quadrone (4), i.e. (1R).3 The stimulating common features of these marine sesquiterpenes lie in a tricyclo[4.3.2.01,5]undecane core 3 possessing up to five contiguous adjacent stereocenters, surrounding a
CNRS-BioCIS UMR 8076, Chimie des Substances Naturelles, IPSIT and LabEx LERMIT, Faculte´ de Pharmacie, Universite´ de Paris Sud, 5, rue J.-B. Cle´ment, ˆtenay-Malabry, France. E-mail: [email protected] 92296 Cha b Normandie University, COBRA, UMR CNRS 6014 and FR 3038, Universite´ de Rouen, 1 rue Tesnie`re, 76821 Mont Saint Aignan, France c ˆtenay-Malabry, France De´partement RMN, BioCIS, 5, rue J.-B. Cle´ment, 92296 Cha d Institut de Chimie des Substances Naturelles, UPR CNRS 2301, avenue de la terrasse, Gif sur Yvette F-91198, France e ˆtenay-Malabry, Institut Galien, UMR CNRS 8612, Biophysics, Faculte´ de Pharmacie, Cha France f ANBiophy, FRE 3207 CNRS, Universite´ Pierre et Marie Curie, 75252 Paris, France † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c4cc10041g
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Fig. 1 Marine cytotoxic suberosenone (1), suberosanone (2), the common ABC core 3, (1R)-( )-quadrone (4), (1S)-(+)-terrecyclic acid (5) (1R)-( )-isishippuric acids A (6a). and B (6b).
a stereogenic quaternary carbon center (QCC), and the various substitutions of ring C (Fig. 1). Such a bridged tricyclic skeleton 3 was initially discovered in the antitumor terrestrial fungal congener ( )-quadrone (4)4 and its biosynthetic progenitor (+)-terrecyclic acid (5),5 both exhibiting cytotoxic properties, however to a much lesser extent.6 While nineteen total syntheses of 4, including three asymmetric routes have been described,7 only one synthesis of ()-suberosenone (1) based on an elegant radical cascade sequence (29 steps, 0.43% overall yield (OY)), and one synthesis of ()-suberosanone (2) (terrecyclan-3-one) prior its isolation from a natural source (9 steps, 5.5% OY), have been reported to date.8 We report herein the first enantioselective and concise syntheses of (1R)-suberosenone (1) and (1R)-suberosanone (2) allowing the experimental configurational assignments of the corresponding natural products. Retrosynthetically, these tricyclic sesquiterpenes could be generated from the intermediary enone 7 by alkylation at the C5 position (Scheme 1).9 Synthesis of 7 from enantiopure bicyclic AB subunit 8 would rely on a Wacker oxidation of the pendant vinyl group and intramolecular aldol condensation of the resulting dione.10 Precursor of 8 could be the key keto-ester 9,
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Scheme 1 Retrosynthetic analysis plan for suberosenone (1) and suberosanone (2).
resulting from the assembly of allyl-cyclopentanone 10 with methyl crotonate, through a highly regio- and stereoselective Michael addition.11 This crucial step would allow the diastereoand enantioselective formation of two contiguous stereogenic centers, the C1 QCC and C8 tertiary one, which are expected to retain their integrity under the reaction conditions used until the end of the synthesis, and thus dictate the stereochemistry of the final suberosane products. We first planned to synthesize (1R,2R,8R,11R)-1, assuming that the AC exhibited by marine natural suberosanes matched those found in natural quadrone, i.e. ( )-(1R,2R,5R,8R,11R)-4, and natural (1R,2R,8R,11R)-4,5-secosuberosanoids isishippuric acid A ( )-6a and B ( )-6b (Fig. 1).12 Thus, (R)-1-phenylethylamine was chosen as the chiral inductor on the basis of the stereochemical result known for this asymmetric Michael process.11 We initiated our synthetic studies with the b-keto-ester 11.13 Cyclopentanone 10 was next obtained in 69% yield14 and engaged in the key asymmetric Michael reaction (Scheme 2). Although unsubstituted electrophilic alkenes smoothly underwent Michael addition with chiral imine/secondary enamines under neutral conditions, the reactivity of b-substituted Michael acceptors such as alkyl crotonates is sluggish and their condensation requires activation.11b An equimolar mixture of the imine derived from 10 and methyl crotonate was subjected to 1.4 GPa pressure leading to the corresponding Michael adduct in gram quantities as a single diastereomer, as the result of a complete regio- (re 4 95%) and stereocontrol (de 4 95%) of the Michael process.15 Subsequent acidic hydrolysis yielded cyclopentanone 9 in 60% yield (ee 4 95%) from 10. ACs in Michael adduct 9 were proposed to be (1S,8R) on the basis of the empirical rule cited below,11a by analogy with related Michael adducts11d,15b and will be confirmed during completion of the synthesis. With this key highly functionalized chiral Michael adduct 9 in hand, we turned our attention toward the construction of tricyclic enone 7 (Scheme 2). We began with formation of the six-membered ring A through an aldol ring closure.10 Toward this end, chemoselective protection of the ketone carbonyl group in 9 as a silyl enol ether, subsequent reduction of the ester group and hydrolytic removal of the silyl enol ether deliver
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Scheme 2 Synthesis of the common tricyclic intermediate 7. Reagents and conditions: (a) NaH (2.3 equiv.), THF, 0 1C to 20 1C then BrCH2CH = CH2, THF, 16 h then LiI.7H2O (3 equiv.), collidine D, 16 h, 69%; (b) 1(R)-phenylethylamine, cyclohexane, Dean–Stark, 16 h, 82%; (c) methyl crotonate (1 equiv.), THF, 1.4 GPa, 62 1C, 72 h, then AcOH (20% aq), THF reflux, 50 h, 73%; (d) TMSCl (3 equiv.), Et3N (5 equiv.), DMF D, overnight; (e) LiAlH4, Et2O, 0 1C, 2 h; (f) TBAF (1 M in THF), 25 1C, 10 min, 94% (3 steps); (g) (COCl)2, DMSO, Et3N, CH2Cl2, 60 1C to 20 1C, 1.5 h, 87%; (h) HCl (3.5 N), DME/THF, 48 1C, 17 h, 93%; (i) C6H5OC(S)Cl, py, 89 h, 20 1C; (j) (TMS)3SiH, AIBN, toluene, 110 1C, 24 h, 53% (2 steps); (k) MsCl, Et3N, DMAP, CH2Cl2, 0 1C, 2 h; (l) NaI, NaHCO3, acetone, rt, 42 h, 92% (2 steps); (m) TMSOTf, Et3N, CH2Cl2, rt, 2.5 h, 100%; (n) CF3CO2Ag, CH2Cl2, THF, rt, 5 min, 87%; (o) Pd(OAc)2 (10 mol%) H2O, benzoquinone, HClO4, CH3CN, 25 1C, 24 h, 83%; (p) tBuOK (5 equiv.)/tBuOH D, 48 h, 83%.
the ketoalcohol 12a in 94% yield which upon Swern oxidation gave the labile ketoaldehyde 12b. Cyclization of 12b in acidic conditions10 led to a 2 : 1 mixture of epimeric bicyclic aldols 13a and 13b in 91% yield (2 steps, 1.6 : 1). For stereochemical purpose, the major epimer was separated by flash chromatography and subjected to spectroscopic studies. The spatial proximities of the equatorial hydrogen atom at C10 and C14 methyl group in aldol 13a as well as the equatorial hydrogen atom at C8 and H12 endo were established by NOESY correlations. This confirmed the (R) stereochemistry at C8, with the desired axial methyl group required for the synthesis of natural suberosanes, and then confirmed the proposed stereochemistry. Removal of the excess hydroxyl functions in aldols 13 using Barton Mc Combie protocol afforded the bicyclic ketone 8 in 48% yield from keto-alcohol 12a. Looking for a more efficient elaboration of the AB subunit 8, we envisaged the a-alkylation of cyclopentanone 12a. To this end, this product was converted into the corresponding iodide 12c whose direct a-alkylation under basic conditions (tert-BuOK)16 led to no more than 27% yield of the desired C-alkylated product 8, in mixture with the corresponding O-alkylated enol ether. Various reaction conditions (base, solvents, counter anion. . .) did not improve the proportion of the desired C-alkylated product 8 (Table S3, ESI†). These disappointing results can be explained by the peculiar situation of the ketone a-position which is also a to the
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quaternary carbon centre C13 driving the alkylation to the less hindered O-site of the ambident enolate. We therefore turned our attention toward reaction conditions involving enolate surrogates such as silyl enol ethers which are more prone to C-alkylation in the presence of silver trifluoroacetate.17 To our delight, silyl enol ether 14, easily synthesized from 12a, was successfully transformed in slightly modified conditions into the desired target 8 in high yield (80% yield, 3 steps from 12a). The diketone 15 required for the cyclopentannulation of ring C was then prepared in 83% yield from 8 by Wacker oxidation of the vinyl function.18 Intramolecular aldol condensation of the diketone 15 using excess potassium tert-butylate in tert-butanol at reflux10 furnished the pivotal tricylic cyclopentenone 7 in 83% yield. Completion of suberosenone synthesis was achieved through a three steps sequence (Scheme 3).9 Regioselective functionalization of ring C takes advantage of the enone function, preventing alkylation at the more reactive C3 position of the corresponding cyclopentanone.9 Introduction of the fifteenth carbon atom was thus done through trapping of the lithium dienolate of 7 by gaseous formaldehyde affording 16 in 72% yield. The relative stereochemistry in 16 was unambiguously established from 2D NOE experiments: H-5 shows strong correlation with axial H3-7 and H3-6 does not exhibit correlation with H3-7 indicating a b-orientation of the hydroxymethyl substituent at C5. Stereoselective catalytic hydrogenation of the enone moiety using 10% Pd/C gave the penultimate intermediate 17 in quantitative yield. Dehydration occurred smoothly in the presence of PTSA at 50 1C affording (1R)-suberosenone (1) in 48% yield. The spectroscopic data of that synthetic compound were found identical to literature data1 and the sign of the optical rotation, [a]20 D + 66.7 (c 0.3 CHCl3), identical to the one of natural suberosenone (+)-(1), [a]20 D + 55.7 (c 0.8, CHCl3), which is therefore (1R,2R,8R,11R), in accordance with theoretical calculations of its optical rotation.3 The synthesis of (1R)-suberosanone 2 was then completed (Scheme 3) in two steps from the common tricyclic intermediate
Scheme 3 Achievement of the synthesis of suberosenone and suberosanone (selected nOe correlations indicated by double-headed curved arrows). Reagents and conditions: (a) LDA, THF, 23 1C, 1.5 h then CH2O, 23 1C to 25 1C, 72%; (b) H2 (1 atm) Pd/C (10 mol%), AcOEt, 1 h, 100%; (c) PTSA, benzene, 50 1C, 48%; (d) LDA, THF, 23 1C, 1.5 h then CH3I, 23 1C to 25 1C, 88%.
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enone (1R)-7: the lithium dienolate of 7 was alkylated with methyl iodide affording stereoselectively enone 18 (88% yield, de 4 95%) which was hydrogenated in the presence of 10% Pd/C affording synthetic (1R)-suberosanone 2 in quantitative yield. The relative stereochemistry in 18 and 2 was established from 2D NOE experiments: H-5 shows strong correlation with axial H3-7 and no correlation was found between H3-6 and H3-7. Moreover, the b-orientation of the Me at C5 in 2 was supported by NOE correlation between H-5 and H-11, and between H3-6 and H-12, the latter exhibiting correlation with H-9b. Intriguingly, the sign of its optical rotation, [a]19 D + 53.4 (c 0.1 CHCl3), was found opposite to the corresponding natural product’s one, [a]20 60.0 D (c 0.1 CHCl3). To the best of our knowledge it would represent the first example of quadrane-type natural product that is not related to the 1R-configurational quadrone series. Although their absolute configuration has not always yet been established, the vast majority of known quadranes belongs to the 1R-series.6 The experimentally determined AC of natural suberosanone is thus (1S,2S,5R,8S,11S), an exception to the unified (1R) AC of the tricyclic core of natural suberosanes as established on the basis of DFT calculations of their chiroptical properties.3 Furthermore, the single positive Cotton effect of the ketone group centered at 291 nm, with a dichroic absorption De + 3.19 obtained from the ECD spectrum of synthetic (+)-2 correlates well the one of natural ( )-(1R)-quadrone 47d (298 nm, De + 2.68) which supports the (1R,2R,5S,8R,11R) AC of synthetic (+)-2. The isolation of both enantiomers of a natural product from either single or different genera and/or species is well known, and has been reported for different classes of products, including sesquiterpenes.19 Therefore, biogenesis of these suberosane sesquiterpenes is divergent, a situation not described in the terrestrial quadrane congeners, probably because they originate from different gorgonians20 and will deserve further studies to elucidate these divergent biosynthetic pathways. Synthetic (1R)-suberosanone (+)-2 was found to have no significant cytotoxic activity against MDA231, HT29, A549, MCF7, SF268 and MRC5 cell lines. In summary, we have achieved the total synthesis of (+)-suberosenone (1) in 15 steps and 7.4% overall yield, and of (+)-suberosanone (2) in 14 steps and 18.8% overall yield from commercially available keto-ester 11 and determined the absolute configurations of these products under their natural forms. The synthesis features (i) hyperbaric asymmetric Michael addition for the efficient generation of two contiguous quaternary and tertiary stereocenters in excellent regio-, diastereo- and enantiomeric selectivities (ii) chemoselective silver trifluoroacetate-promoted a-alkylation of a congested silyl enol ether to build the bridged AB subunit and set up the stereochemistry at C11 (iii) aldol ring closure to elaborate a common tricyclic suberosane intermediate followed by stereoselective functionalization of ring C. The synthesis led to assignment of the ACs of the natural products and revision of the proposed AC of natural ( )-suberosanone (2) as the first identified (1S) marine sesquiterpene suberosane. The flexibility and conciseness of the synthetic route developed here now paves the way for further structural and biological studies of natural suberosanes and analogues. Further studies toward the
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total synthesis of related natural suberosanes using this strategy are currently ongoing in our laboratory. The authors thank the Centre National de la Recherche `re de l’Education Nationale, Scientifique (CNRS), the Ministe ´rieur et de la Recherche (Paris, France), de l’Enseignement Supe the Fondation ARC pour la Recherche sur le Cancer (Villejuif, France) for financial support, and Ministry of Higher Education (Damascus, Syria) for a PhD fellowship to M.K. We thank Dr C. Miet, Dr C. Camara and P.-E. Venot for performing preliminary experiments, Dr J. Mahuteau for NMR studies, Mrs S. Mairesse-Lebrun and K. Leblanc for performing the combustion and high-resolution MS analyses (BioCIS).
Notes and references 1 H. R. Bokesch, T. C. McKee, J. H. Cardellina II and M. R. Boyd, Tetrahedron Lett., 1996, 37, 3259. 2 (a) H. R. Bokesch, J. W. Blunt, C. K. Westergaard, J. H. Cardellina II, T. R. Johnson, J. A. Michael, T. C. McKee, M. G. Hollingshead and M. R. Boyd, J. Nat. Prod., 1999, 62, 633; (b) J.-H. Sheu, K.-C. Hung, G.-H. Wang and C.-Y. Duh, J. Nat. Prod., 2000, 63, 1603; (c) S.-H. Qi, S. Zhang, X. Li and Q.-X. Li, J. Nat. Prod., 2005, 68, 1288. 3 P. J. Stephens, D. M. McCann, F. J. Devlin and A. B. Smith, III, J. Nat. Prod., 2006, 69, 1055. 4 R. L. Ranieri and G. J. Calton, Tetrahedron Lett., 1978, 499. 5 (a) M. Nakagawa, A. Hirota, H. Sakai and A. Isogai, J. Antibiot., 1982, 35, 778; (b) T. J. Turbyville, E. M. K. Wijeratne, L. Whitesell and A. A. L. Gunatilaka, Mol. Cancer Ther., 2005, 4, 1569. 6 Review: M. Presset, Y. Coquerel and J. Rodriguez, Eur. J. Org. Chem., 2010, 2247. 7 (a) K. Kon, K. Ito and S. Isoe, Tetrahedron Lett., 1984, 25, 3739; (b) A. B. Smith III and J. P. Konopelski, J. Org. Chem., 1984, 49, 4094; (c) H.-J. Liu and M. Llinas-Brunet, Can. J. Chem., 1988, 66, 528; (d) A. B. Smith III, J. P. Konopelski, B. A. Wexler and P. A. Sprengeler, J. Am. Chem. Soc., 1991, 113, 3533. 8 (a) H.-Y. Lee and B. G. Kim, Org. Lett., 2000, 2, 1951; (b) R. M. Coates, J. Z. Ho, M. Klobus and L. Zhu, J. Org. Chem., 1998, 63, 9166. 9 (a) S. Danishefsky, K. Vaughan, R. C. Gadwood and K. Tsuzuki, J. Am. Chem. Soc., 1980, 102, 4262; (b) S. Danishefsky, K. Vaughan, R. C. Gadwood and K. Tsuzuki, J. Am. Chem. Soc., 1981, 103, 4136. 10 A. B. Smith III, B. A. Wexler and J. Slade, Tetrahedron Lett., 1982, 23, 1631.
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ChemComm ¨le, F. Dumas and A. Guingant, 11 (a) Review: J. d’Angelo, D. Desmae Tetrahedron: Asymmetry, 1992, 3, 459; Relevant examples: (b) I. Jabin, G. Revial, A. Tomas, P. Lemoine and M. Pfau, Tetrahedron: Asymmetry, 1995, 6, 1795; (c) M. J. Lucero and K. N. Houk, J. Am. Chem. Soc., 1997, 119, 826; (d) A. Chiaroni, C. Riche, F. Dumas, M. Mauduit and C. Miet, Acta Crystallogr., Sect. C: Cryst. Struct. Commun., 1998, C54, 401; (e) M. E. Tran Huu Dau, C. Riche, F. Dumas and J. d’Angelo, Tetrahedron: Asymmetry, 1998, 9, 1059; ( f ) L. Keller, F. Dumas and J. d’Angelo, Eur. J. Org. Chem., 2003, 2488; ( g) H. ´ski, J. Kedzia, J. Wojciechowski and W. M. Wolf, Krawczyk, M. ´ Sliwin Tetrahedron: Asymmetry, 2007, 18, 2712. 12 (a) M. Torihata and S. Kuwahara, Biosci., Biotechnol., Biochem., 2008, 72, 1628; (b) M. Torihata, T. Nakahata and S. Kuwahara, Org. Lett., 2007, 9, 2557. 13 (a) J. Froborg and G. Magnuson, J. Am. Chem. Soc., 1978, 100, 6728; (b) For a microwave alternative to the photolysis of diazodimedone, see: M. Presset, Y. Coquerel and J. Rodriguez, J. Org. Chem., 2009, 74, 415. 14 A. L. Veretenov, D. O. Koltun, W. A. Smit and Y. A. Strelenko, Tetrahedron Lett., 1995, 36, 4651. 15 (a) High Pressure Chemistry, ed. R. van Eldik and F.-G. Klarner, Wiley-VCH, 2008; L. Minuti, in Eco-friendly synthesis of materials, ed. R. Ballini, RSC, Cambridge, UK, 2009, pp. 237–270; (b) C. Camara, D. Joseph, F. Dumas, J. d’Angelo and A. Chiaroni, Tetrahedron Lett., 2002, 43, 1445. 16 R. Rodriguez, A.-S. Chapelon, C. Ollivier and M. Santelli, Tetrahedron, 2009, 65, 7001. 17 (a) C. W. Jefford, A. W. Sledeski, P. Lelandais and J. Boukouvalas, Tetrahedron Lett., 1992, 33, 1855; (b) P. Angers and P. Canonne, Tetrahedron Lett., 1994, 35, 367; (c) H. Takagaki, N. Yasuda, M. Asaoka and H. Takei, Bull. Chem. Soc. Jpn., 1979, 52, 1241. 18 D. J. Miller and D. D. M. Wayner, J. Org. Chem., 1990, 55, 2924. 19 (a) Review: J. M. Finefield, D. H. Sherman, M. Kreitman and R. M. Williams, Angew. Chem., Int. Ed., 2012, 51, 4802(b) See for ¨nig, example: I. Prosser, I. G. Altug, A. L. Phillips, W. A. Ko H. J. Bouwmeester and M. H. Beale, Arch. Biochem. Biophys., 2004, 432, 136. 20 Within the order Alcyonacea, Subergorgia suberosa is a species of the soft coral genus belonging to the family Subergorgiidae of the suborder Scleraxonia, while Isis hippuris is a species of the genus Isis, one of the 38 genera of the family Isididae of the suborder Calcaxonia: M. Daly, M. R. Brugler, P. Cartwright, A. G. Collins, M. N. Dawson, D. G. Fautin, S. C. France, C. S. McFadden, D. M. Opresko, E. Rodriguez, S. L. Romano and J. L. Stake, Zootaxa, 2007, 1668, 127.
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