FULL PAPER DOI: 10.1002/chem.201303570
Bio-Inspired Formal Synthesis of Hirsutellones A–C Featuring an Electrophilic Cyclization Triggered by Remote Lewis Acid-Activation Xu-Wen Li,[a, b] Alexandre Ear,[a, b] Lukas Roger,[a, b] Nassima Riache,[a, b] Alexandre Deville,[a, b] and Bastien Nay*[a, b] Abstract: A bio-inspired strategy was used to complete the formal synthesis of the antitubercular hirsutellone B and congeners A and C, through construction of its decahydrofluorene core from a linear polyene strand activated at both ends by a silyl enol ether and an allyl acetate. Our synthesis features a key electrophilic cyclization, starting
with the remote activation (by [YbACHTUNGRE(OTf)3] or BF3·OEt2) of the allyl acetate and stereoselectively affording the Keywords: biomimetic synthesis · electrophilic cyclization · Lewis acids · natural products · synthetic methods
C ring. This was followed by an intramolecular Diels–Alder reaction to get the tricyclic core of the natural product. The stereoselective reduction of the resulting ketone towards the formal intermediate was critical to the success of this strategy.
Introduction Tuberculosis is a serious disease that engenders over nine million new cases each year, killing 1.7 million people, mostly in developing countries, and threatening the weakest of us.[1, 2] A dramatic resurgence was observed in the 1990s, associated with overcrowding, poverty, undernutrition, or immunodeficiency, and also the rapid development of multidrug resistance of the microbial agent Mycobacterium tuberculosis to marketed drugs (e.g., isoniazid, ethambutol, rifampicine). The disease was declared by the WHO as a global emergency in 1993 and since then, the search for new antitubercular drugs is a priority worldwide. In 2005, the discovery of hirsutellones (1–3) by Isaka and co-workers from the entomopathogenous fungus Hirsutella nivea[3] was therefore providential, displaying strong and specific antitubercular activity at a minimum inhibitory concentration (0.78 mg mL1) only tenfold higher than standard isoniazid on a resistant strain of M. tuberculosis (Figure 1). Their complexity rapidly intrigued organic chemists who ventured in their total synthesis. We now wish to describe a concise and bio-inspired formal synthesis of hirsutellone B (2) and its congeners A and C. To date, two total syntheses of hirsutellone B (2) have been reported by Nicolaou in 2009[4] and by Uchiro in 2011.[5] Among other works, Sorensens partial synthesis was [a] X.-W. Li, A. Ear, L. Roger, Dr. N. Riache, A. Deville, Dr. B. Nay Musum National dHistoire Naturelle 57 rue Cuvier (CP 54), 75005 Paris (France) E-mail: [email protected] [b] X.-W. Li, A. Ear, L. Roger, Dr. N. Riache, A. Deville, Dr. B. Nay CNRS, UMR 7245, Unit Molcules de Communication et Adaptation des Micro-organismes, Paris (France) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201303570.
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Figure 1. Structure of hirsutellones A–C (1–3).
of particular interest since a tricyclic decahydrofluorene intermediate was found active against M. tuberculosis at a concentration (1.21 mg mL1) in the same range as the natural product.[6] The decahydrofluorene core may thus stand as the pharmacophoric moiety of hirsutellones, an important finding for future medicinal works. Hirsutellones are members of an increasing family of natural products, the first of which, known as the GKK1032 components, were described in 2001 from a Penicillium strain.[7] Biosynthetic studies on GKK1032s by Oikawa revealed their polyketide synthetases (PKS)/nonribosomal peptide-synthetase (NRPS) nature, originated from tyrosine and nine acetate units.[8] Oikawas study allowed us to predict the biosynthetic origin of hirsutellones (Scheme 1). The most intriguing biosynthetic event is the conversion of a linear tyrosine-nonaketide precursor (4) into the skeleton 7, which is supposed to take place in an auxiliary enzyme active site after an oxidative activation, following two mechanistic hypotheses (Scheme 1, pathways a and b).[9] Considering these biosynthetic hypotheses, we imagined a biomimetic strategy towards the total synthesis of hirsutellones. Not only would such a strategy bring clues to the biosynthetic pathways, but also would give a straightforward access to the natural product and potential antitubercular analogues.[10] Among the two biosynthetic propositions
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the linear precursor 9 (Scheme 1, bottom frame), being doubly activated thanks to an electron-accepting 2,4,6-trien1-yl carboxylate tail and a nucleophilic silyl enol ether head. This linear precursor was foreseen from (R)-(+)-citronellal 10, with no use of protecting group if we consider that the silyl and R groups in 9 are important to the expected cyclization process. Starting from (R)-(+)-citronellal (10), the trienoate 11 was readily constructed in 74 % yield by a Horner–Wadsworth–Emmons (HWE) reaction with the deprotonated 6phosphonohexa-2,4-dienoate 12 (Scheme 2).[11] Taking ad-
Scheme 1. Two divergent polycyclization hypotheses for the biosynthesis of hirsutellone skeleton 7. Both pathways (a) and (b) are supported by Nicolaous total synthesis of hirsutellone B (1) and by this work (bottom frame), respectively.
(Scheme 1), we identified pathway b involving a terminal allylic alcohol (electrophilic tail in 6) as a straightforward alternative strategy to perform a biomimetic cyclization. Basically, the other biosynthetic pathway had previously been experienced by Nicolaou and co-workers who used an epoxide resembling intermediate 5 (electrophilic head for pathway a) as the activated precursor leading to the decahydrofluorene core of hirsutellones.[4] In the two pathways, an electrophilic cyclization of ring C is followed by an intramolecular Diels–Alder (IMDA) reaction leading to the full tricyclic core. Both synthetic strategies are in agreement with the hypothetical biosyntheses, yet with a complete inversion of the electronic activation, that is, head-to-tail (the following work) versus tail-to-head (Nicolaous work).
Results and Discussion Short synthesis of the linear polyunsaturated precursor 9: Our initial attempts to construct a biomimetic linear precursor like 6 or a tetramate analogue proved unsuccessful despite the many disconnections we envisaged. The formal intermediate 8[4] was thus envisioned to be constructed from
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Scheme 2. Synthesis of the bio-inspired substrate 9. LDA = lithium diisopropylamide; DIBAL-H = diisobutylaluminium hydride; DMAP = 4-dimethylaminopyridine.
vantage of the electron-deficiency of 11, the trisubstituted double bond was selectively dihydroxylated in the presence of OsO4 and N-methylmorpholine-N-oxide (NMO), giving the diol 13 in 83 % yield (based on recovered starting material, b.r.s.m.) as a 1:1 mixture of diastereoisomers. Then reduction of the ester and selective acetylation of the resulting alcohol afforded the 2,4,6-trien-1-yl acetate 14 in 67 % yield over two steps and definitely installed the necessary electrophilic tail for the biomimetic cyclization. After cleavage of the diol into the aldehyde 16,[12] a second HWE reaction with the lithium salt of a-silyloxyphosphonate 15[13] furnished the bio-inspired substrate 9 in 45 % yield with complete Z geometry. Six steps were thus necessary to obtain this polyene, which was then submitted to screening for the best cyclization conditions (Table 1). Lewis acid-promoted electrophilic cyclizations; a bio-inspired route towards hirsutellones: Considering the allyl acetate of substrate 9, Tsuji–Trost conditions were first applied,[14, 15] using [PdACHTUNGRE(PPh3)4] or [Pd2ACHTUNGRE(dba)3] (dba = dibenzyli-
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Table 1. Attempts of cyclization of the linear intermediate 9.
Entry
Conditions[a]
Product ACHTUNGRE(yield [%])
1 2 3 4 5 6 7 8 9
[PdACHTUNGRE(PPh3)4] (0.1), THF, reflux ACHTUNGRE[TiCl4] (1.5), CH2Cl2, 78!20 8C ACHTUNGRE[AlClEt2] (10),[b] CH2Cl2, 78 8C!RT ACHTUNGRE[AlClEt2] (10),[c] CH2Cl2, 78!30 8C [YbACHTUNGRE(OTf)3] (1.5), CH2Cl2, 0 8C [YbACHTUNGRE(OTf)3] (1.5), MeOH, 0 8C!RT [ScACHTUNGRE(OTf)3] (1.5), CH2Cl2, 0 8C BF3·OEt2 (10), CH2Cl2, 78 8C CSA (10), CH2Cl2, 0 8C!RT
17 (30) 18 (69) 19 (38) 20 (50) 20 (67) no reaction 20 (51) 20 (52)[d] 20 (< 5 %)
[a] Number of catalyst equivalents in parentheses; [b] 1 m solution in toluene; [c] 1 m solution in hexane; [d] 87 % b.r.s.m.
deneacetone) in THF heated at reflux (Table 1, entry 1). Only the IMDA cycloadduct 17 was obtained in 30 % yield, being attributed to a thermal effect. This compound is reminiscent of equisetin, a fungal polyketide, whose biosynthesis indeed involves a Diels–Alder reaction to form the decalin core.[16] Lewis acids were then considered not only to promote the first electrophilic cyclization of ring C, but eventually the final IMDA reaction. Only a partial cyclization was observed with TiCl4 (Table 1, entry 2), stereoselectively forming rings B and C (18) of hirsutellones whereas the terminal allyl acetate was chlorinated. When a toluene solution of [AlClEt2] was used instead, the same bicyclization occurred, but surprisingly, a Friedel–Crafts alkylation of toluene was also observed, furnishing compound 19 (Table 1, entry 3) and showing the high reactivity of the terminal position of 9. This problem was overcome by the use of a hexane solution of the same catalyst, which finally provided stereoselectively the expected monocyclization product 20, albeit in a moderate yield of 50 % (Table 1, entry 4). The use of [YbACHTUNGRE(OTf)3] in CH2Cl2 at 0 8C significantly improved the yield of 20 to 67 % (Table 1, entry 5), whereas the same reaction was inhibited in a protic solvent like methanol (Table 1, entry 6). Replacing [YbACHTUNGRE(OTf)3] by [ScACHTUNGRE(OTf)3] in CH2Cl2 only provided 20 in a moderate yield of 51 % (entry 7). Better efficacy was finally observed with BF3·OEt2 in CH2Cl2 at 78 8C, isolating 20 in 52 % yield, which was corrected to 87 % yield based on the recovered starting material (Table 1, entry 8). Finally, we found no significant conversion when a Brønsted acid (camphorsulfonic acid, CSA) was used (Table 1, entry 9). Even though the one-step formation of the tricyclic core of hirsutellones through domino IMDA reaction was not achieved at this stage, BF3·OEt2 was retained as the best
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catalyst for the electrophilic cyclization, furnishing the key intermediate 20 after the remote departure of the acetate leaving group. Such a cyclization of a silyl enol ether on an electrophilic polyene is unique owing to the remote mode of activation as is shown in intermediate 21 (Scheme 3). The stereoselectivity of the electrophilic cyclization was in all cases controlled by the sole methyl substituent of 9 adopting an equatorial position in the activated conformer 21 (Scheme 3). The cyclization unveiled the fumaroyl dienophile and diene partners for an IMDA reaction that was expected to follow an exo selectivity relatively to the internal carbonyl.[17] Interestingly, Uchiro and co-workers previously reported a total synthesis of hirsutellone B through an intermediate bearing a fumaroyl dienophile similar to our compound 20.[4] However, during their synthesis, this highly reactive intermediate had to be protected as a transient cycloadduct with 1,2,3,4,5-pentamethylcyclopentadiene during five steps before the IMDA reaction occurred.
Scheme 3. First attempts and difficulties in synthesizing the tricyclic core 8 of hirsutellone B.
End game: overcoming the ketone reduction trick: The decahydrofluorene core of hirsutellones was obtained by submitting intermediate 20 to o-xylene heated at reflux. The reaction furnished the cycloadduct 22 in 92 % yield with a 5:1 selectivity in favor of the exo product as expected. With this pleasing result in hand, we wished to complete a formal synthesis of hirsutellones after the selective reduction of the carbonyl group of 22. In fact, this was more chal-
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lenging than expected since, as agreeing with Uchiros result on related tricyclic intermediates,[5] NaBH4 reduction furnished a mixture of the desired (S)- and the undesired (R)alcohols 8 and 23 in a 1:3 ratio, respectively, and 68 % global yield. Unfortunately, the use of more hindered reducing reagents such as L-selectride, LiAlHACHTUNGRE(OtBu)3, or the Luche conditions[18] mainly resulted in the formation of the undesired alcohol 23 (Scheme 3). To circumvent this difficulty and improve our strategy, the stereoselective reduction of the cyclohexylketone 20 was envisaged. According to the classical Felkin–Anh model, the reduction occurred in favor of the undesired alcohol 25 when performed with NaBH4 or LiHAlACHTUNGRE(OtBu)3 (ca. 50 % diastereomeric excess (de) in both cases). Nevertheless, the Luche conditions[18] gratifyingly afforded the allylic alcohol 24 in 67 % yield with an anti-Felkin–Anh selectivity supposedly resulting from coordination and cyclohexyl conformational effects (Scheme 4). Finally, the decahydrofluorene
biosynthesis of GKK1032s[8] and adapted to hirsutellones in Scheme 1 (pathway b).[9] It shows that from a linear biosynthetic precursor like 4, an oxidation at the terminal position of the acyl chain is conceivable to trigger the cyclization. Moreover, during the stereoselective sequence from the chiral intermediate 9 to the tricyclic compound 8, we were able to control the formation of seven new stereocenters, which originate from the stereochemistry of the methyl substituent in 9. This work thus provides an expedient biomimetic access to the antitubercular pharmacophore of the natural product and may be useful to design diversity oriented strategies and biological tools in the future. At last, to decide between both biosynthetic pathways (head-to-tail vs. tail-to-head), further biological experiments may be needed in vivo. In fact, this question may be answered the day when the biological macrocyclization of the paracyclophane ring will be understood.
Acknowledgements We acknowledge receipt of scholarships by the China Scholarship Council for X.W.L. and by the French Ministry of Research for A.E. and N.R. We thank the ANR (project ANR-12-BS07-0028-01 SYNBIORG) and the CNRS (interdisciplinary call Physics–Chemistry–Biology) for funding.
Scheme 4. Formal synthesis of hirsutellone B through the stereoselective reduction of enone 20.
core 8 was stereoselectively obtained by the [AlClEt2]-catalyzed IMDA reaction as previously described by Nicolaou (Scheme 4), allowing us to complete the formal synthesis of hirsutellone B (2),[4, 5] and the natural analogues A (1) and C (3).[19]
Conclusion This work, in addition to providing a bio-inspired formal synthesis of hirsutellone B (2), also gives clues to the alternative biosynthetic pathway suggested by Oikawa for the
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[1] S. D. Lawn, A. I. Zumla, Lancet 2011, 378, 57 – 72. [2] a) M. C. Raviglione, M. W. Uplekar, Lancet 2006, 367, 952 – 955; b) Stop TB Partnership, The Global Plan to Stop TB, 2006 – 2015: Actions for Life: Towards a World Free of Tuberculosis, WHO; Geneva, 2006; available at: http://www.stoptb.org/global/plan/main/. [3] M. Isaka, N. Rugseree, P. Maithip, P. Kongsaeree, S. Prabpai, Y. Thebtaranonth, Tetrahedron 2005, 61, 5577 – 5583. [4] K. C. Nicolaou, D. Sarlah, T. R. Wu, W. Zhan, Angew. Chem. 2009, 121, 7002 – 7006; Angew. Chem. Int. Ed. 2009, 48, 6870 – 6874. [5] H. Uchiro, R. Kato, Y. Arai, M. Hasegawa, Y. Kobayakawa, Org. Lett. 2011, 13, 6268 – 6271. [6] S. D. Tilley, K. P. Reber, E. J. Sorensen, Org. Lett. 2009, 11, 701 – 703. [7] K. Fumito, H. Atsuhiro, A. Katsuhiko, O. Tatsuhiro, H. Mitsunobu, Patent JP 2001247574 (2001). [8] H. Oikawa, J. Org. Chem. 2003, 68, 3552 – 3557. [9] For a tutorial review on the generation of complexity in PKS/NRPS compounds exemplified by hirsutellones, see: X.-W. Li, A. Ear, B. Nay, Nat. Prod. Rep. 2013, 30, 765 – 782. [10] Concerning biomimetic synthesis, see: Biomimetic Organic Synthesis (Eds.: E. Poupon, B. Nay), Wiley-VCH, Weinheim, 2011. [11] This phosphonate was first synthesized through cross metathesis, according to D. Amans, V. Bellosta, J. Cossy, Angew. Chem. 2006, 118, 6002 – 6006; Angew. Chem. Int. Ed. 2006, 45, 5870 – 5874. However, owing to the cost of the metathesis catalysts, a synthesis of 12 was designed from the abundant (Z)-2-buten-1,4-diol, as described in the Supporting Information. [12] This five-step sequence to the aldehyde 16 can be compared with the antipodal nine-step one from (S)-()-citronellal recently reported by Li and co-workers for the synthesis of fusarisetin A: J. Deng, B. Zhu, Z. Lu, H. Yu, A. Li, J. Am. Chem. Soc. 2012, 134, 920 – 923. [13] a) W. Dumont, C. Vermeyen, A. Krief, Tetrahedron Lett. 1984, 25, 2883 – 2886; b) H. Uchiro, R. Kato, Y. Sakuma, Y. Takagi, Y. Arai, D. Hasegawa, Tetrahedron Lett. 2011, 52, 6242 – 6245. [14] Such conditions were previously applied to (2E,4E,6E)-octatrienyl acetate leading to (3E,5E)-1,3,5,7-octatetraene through elimination and showing that such substrates can be reactive in the presence of
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a Pd catalyst: K. Yamamoto, S. Suzuki, J. Tsuji, Bull. Chem. Soc. Jpn. 1981, 54, 2541 – 2542. [15] For the intramolecular reaction of silyl enol ethers and allyl carboxylates, see: a) F. T. Luo, E. Negishi, J. Org. Chem. 1985, 50, 4762 – 4766; b) D. M. Johns, M. Mori, R. M. Williams, Org. Lett. 2006, 8, 4051 – 4054; c) T.-h. Fu, W. T. McElroy, M. Shamsza, S. F. Martin, Org. Lett. 2012, 14, 3834 – 3837. [16] a) H. R. Burmeister, G. A. Bennett, R. F. Vesonder, C. W. Hesseltine, Antimicrob. Agents Chemother. 1974, 5, 634 – 639; b) N. J. Phil-
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FULL PAPER lips, J. T. Goodwin, A. Fraiman, R. J. Cole, D. G. Lynn, J. Am. Chem. Soc. 1989, 111, 8223 – 8231. [17] C. I. Turner, R. M. Williamson, M. N. Paddon-Row, M. S. Sherburn, J. Chem. Soc. 2001, 66, 3963 – 3969. [18] A. L. Gemal, J. L. Luche, J. Am. Chem. Soc. 1981, 103, 5454 – 5459. [19] K. C. Nicolaou, Y.-P. Sun, D. Sarlah, W. Zhan, T. R. Wu, Org. Lett. 2011, 13, 5708 – 5710. Received: September 9, 2013 Published online: October 18, 2013
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Bio-Inspired Formal Synthesis of Hirsutellones A–C Featuring an Electrophilic Cyclization Triggered by Remote Lewis Acid-Activation Xu-Wen Li,[a, b] Alexandre Ear,[a, b] Lukas Roger,[a, b] Nassima Riache,[a, b] Alexandre Deville,[a, b] and Bastien Nay*[a, b] Abstract: A bio-inspired strategy was used to complete the formal synthesis of the antitubercular hirsutellone B and congeners A and C, through construction of its decahydrofluorene core from a linear polyene strand activated at both ends by a silyl enol ether and an allyl acetate. Our synthesis features a key electrophilic cyclization, starting
with the remote activation (by [YbACHTUNGRE(OTf)3] or BF3·OEt2) of the allyl acetate and stereoselectively affording the Keywords: biomimetic synthesis · electrophilic cyclization · Lewis acids · natural products · synthetic methods
C ring. This was followed by an intramolecular Diels–Alder reaction to get the tricyclic core of the natural product. The stereoselective reduction of the resulting ketone towards the formal intermediate was critical to the success of this strategy.
Introduction Tuberculosis is a serious disease that engenders over nine million new cases each year, killing 1.7 million people, mostly in developing countries, and threatening the weakest of us.[1, 2] A dramatic resurgence was observed in the 1990s, associated with overcrowding, poverty, undernutrition, or immunodeficiency, and also the rapid development of multidrug resistance of the microbial agent Mycobacterium tuberculosis to marketed drugs (e.g., isoniazid, ethambutol, rifampicine). The disease was declared by the WHO as a global emergency in 1993 and since then, the search for new antitubercular drugs is a priority worldwide. In 2005, the discovery of hirsutellones (1–3) by Isaka and co-workers from the entomopathogenous fungus Hirsutella nivea[3] was therefore providential, displaying strong and specific antitubercular activity at a minimum inhibitory concentration (0.78 mg mL1) only tenfold higher than standard isoniazid on a resistant strain of M. tuberculosis (Figure 1). Their complexity rapidly intrigued organic chemists who ventured in their total synthesis. We now wish to describe a concise and bio-inspired formal synthesis of hirsutellone B (2) and its congeners A and C. To date, two total syntheses of hirsutellone B (2) have been reported by Nicolaou in 2009[4] and by Uchiro in 2011.[5] Among other works, Sorensens partial synthesis was [a] X.-W. Li, A. Ear, L. Roger, Dr. N. Riache, A. Deville, Dr. B. Nay Musum National dHistoire Naturelle 57 rue Cuvier (CP 54), 75005 Paris (France) E-mail: [email protected] [b] X.-W. Li, A. Ear, L. Roger, Dr. N. Riache, A. Deville, Dr. B. Nay CNRS, UMR 7245, Unit Molcules de Communication et Adaptation des Micro-organismes, Paris (France) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201303570.
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Figure 1. Structure of hirsutellones A–C (1–3).
of particular interest since a tricyclic decahydrofluorene intermediate was found active against M. tuberculosis at a concentration (1.21 mg mL1) in the same range as the natural product.[6] The decahydrofluorene core may thus stand as the pharmacophoric moiety of hirsutellones, an important finding for future medicinal works. Hirsutellones are members of an increasing family of natural products, the first of which, known as the GKK1032 components, were described in 2001 from a Penicillium strain.[7] Biosynthetic studies on GKK1032s by Oikawa revealed their polyketide synthetases (PKS)/nonribosomal peptide-synthetase (NRPS) nature, originated from tyrosine and nine acetate units.[8] Oikawas study allowed us to predict the biosynthetic origin of hirsutellones (Scheme 1). The most intriguing biosynthetic event is the conversion of a linear tyrosine-nonaketide precursor (4) into the skeleton 7, which is supposed to take place in an auxiliary enzyme active site after an oxidative activation, following two mechanistic hypotheses (Scheme 1, pathways a and b).[9] Considering these biosynthetic hypotheses, we imagined a biomimetic strategy towards the total synthesis of hirsutellones. Not only would such a strategy bring clues to the biosynthetic pathways, but also would give a straightforward access to the natural product and potential antitubercular analogues.[10] Among the two biosynthetic propositions
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the linear precursor 9 (Scheme 1, bottom frame), being doubly activated thanks to an electron-accepting 2,4,6-trien1-yl carboxylate tail and a nucleophilic silyl enol ether head. This linear precursor was foreseen from (R)-(+)-citronellal 10, with no use of protecting group if we consider that the silyl and R groups in 9 are important to the expected cyclization process. Starting from (R)-(+)-citronellal (10), the trienoate 11 was readily constructed in 74 % yield by a Horner–Wadsworth–Emmons (HWE) reaction with the deprotonated 6phosphonohexa-2,4-dienoate 12 (Scheme 2).[11] Taking ad-
Scheme 1. Two divergent polycyclization hypotheses for the biosynthesis of hirsutellone skeleton 7. Both pathways (a) and (b) are supported by Nicolaous total synthesis of hirsutellone B (1) and by this work (bottom frame), respectively.
(Scheme 1), we identified pathway b involving a terminal allylic alcohol (electrophilic tail in 6) as a straightforward alternative strategy to perform a biomimetic cyclization. Basically, the other biosynthetic pathway had previously been experienced by Nicolaou and co-workers who used an epoxide resembling intermediate 5 (electrophilic head for pathway a) as the activated precursor leading to the decahydrofluorene core of hirsutellones.[4] In the two pathways, an electrophilic cyclization of ring C is followed by an intramolecular Diels–Alder (IMDA) reaction leading to the full tricyclic core. Both synthetic strategies are in agreement with the hypothetical biosyntheses, yet with a complete inversion of the electronic activation, that is, head-to-tail (the following work) versus tail-to-head (Nicolaous work).
Results and Discussion Short synthesis of the linear polyunsaturated precursor 9: Our initial attempts to construct a biomimetic linear precursor like 6 or a tetramate analogue proved unsuccessful despite the many disconnections we envisaged. The formal intermediate 8[4] was thus envisioned to be constructed from
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Scheme 2. Synthesis of the bio-inspired substrate 9. LDA = lithium diisopropylamide; DIBAL-H = diisobutylaluminium hydride; DMAP = 4-dimethylaminopyridine.
vantage of the electron-deficiency of 11, the trisubstituted double bond was selectively dihydroxylated in the presence of OsO4 and N-methylmorpholine-N-oxide (NMO), giving the diol 13 in 83 % yield (based on recovered starting material, b.r.s.m.) as a 1:1 mixture of diastereoisomers. Then reduction of the ester and selective acetylation of the resulting alcohol afforded the 2,4,6-trien-1-yl acetate 14 in 67 % yield over two steps and definitely installed the necessary electrophilic tail for the biomimetic cyclization. After cleavage of the diol into the aldehyde 16,[12] a second HWE reaction with the lithium salt of a-silyloxyphosphonate 15[13] furnished the bio-inspired substrate 9 in 45 % yield with complete Z geometry. Six steps were thus necessary to obtain this polyene, which was then submitted to screening for the best cyclization conditions (Table 1). Lewis acid-promoted electrophilic cyclizations; a bio-inspired route towards hirsutellones: Considering the allyl acetate of substrate 9, Tsuji–Trost conditions were first applied,[14, 15] using [PdACHTUNGRE(PPh3)4] or [Pd2ACHTUNGRE(dba)3] (dba = dibenzyli-
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Table 1. Attempts of cyclization of the linear intermediate 9.
Entry
Conditions[a]
Product ACHTUNGRE(yield [%])
1 2 3 4 5 6 7 8 9
[PdACHTUNGRE(PPh3)4] (0.1), THF, reflux ACHTUNGRE[TiCl4] (1.5), CH2Cl2, 78!20 8C ACHTUNGRE[AlClEt2] (10),[b] CH2Cl2, 78 8C!RT ACHTUNGRE[AlClEt2] (10),[c] CH2Cl2, 78!30 8C [YbACHTUNGRE(OTf)3] (1.5), CH2Cl2, 0 8C [YbACHTUNGRE(OTf)3] (1.5), MeOH, 0 8C!RT [ScACHTUNGRE(OTf)3] (1.5), CH2Cl2, 0 8C BF3·OEt2 (10), CH2Cl2, 78 8C CSA (10), CH2Cl2, 0 8C!RT
17 (30) 18 (69) 19 (38) 20 (50) 20 (67) no reaction 20 (51) 20 (52)[d] 20 (< 5 %)
[a] Number of catalyst equivalents in parentheses; [b] 1 m solution in toluene; [c] 1 m solution in hexane; [d] 87 % b.r.s.m.
deneacetone) in THF heated at reflux (Table 1, entry 1). Only the IMDA cycloadduct 17 was obtained in 30 % yield, being attributed to a thermal effect. This compound is reminiscent of equisetin, a fungal polyketide, whose biosynthesis indeed involves a Diels–Alder reaction to form the decalin core.[16] Lewis acids were then considered not only to promote the first electrophilic cyclization of ring C, but eventually the final IMDA reaction. Only a partial cyclization was observed with TiCl4 (Table 1, entry 2), stereoselectively forming rings B and C (18) of hirsutellones whereas the terminal allyl acetate was chlorinated. When a toluene solution of [AlClEt2] was used instead, the same bicyclization occurred, but surprisingly, a Friedel–Crafts alkylation of toluene was also observed, furnishing compound 19 (Table 1, entry 3) and showing the high reactivity of the terminal position of 9. This problem was overcome by the use of a hexane solution of the same catalyst, which finally provided stereoselectively the expected monocyclization product 20, albeit in a moderate yield of 50 % (Table 1, entry 4). The use of [YbACHTUNGRE(OTf)3] in CH2Cl2 at 0 8C significantly improved the yield of 20 to 67 % (Table 1, entry 5), whereas the same reaction was inhibited in a protic solvent like methanol (Table 1, entry 6). Replacing [YbACHTUNGRE(OTf)3] by [ScACHTUNGRE(OTf)3] in CH2Cl2 only provided 20 in a moderate yield of 51 % (entry 7). Better efficacy was finally observed with BF3·OEt2 in CH2Cl2 at 78 8C, isolating 20 in 52 % yield, which was corrected to 87 % yield based on the recovered starting material (Table 1, entry 8). Finally, we found no significant conversion when a Brønsted acid (camphorsulfonic acid, CSA) was used (Table 1, entry 9). Even though the one-step formation of the tricyclic core of hirsutellones through domino IMDA reaction was not achieved at this stage, BF3·OEt2 was retained as the best
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catalyst for the electrophilic cyclization, furnishing the key intermediate 20 after the remote departure of the acetate leaving group. Such a cyclization of a silyl enol ether on an electrophilic polyene is unique owing to the remote mode of activation as is shown in intermediate 21 (Scheme 3). The stereoselectivity of the electrophilic cyclization was in all cases controlled by the sole methyl substituent of 9 adopting an equatorial position in the activated conformer 21 (Scheme 3). The cyclization unveiled the fumaroyl dienophile and diene partners for an IMDA reaction that was expected to follow an exo selectivity relatively to the internal carbonyl.[17] Interestingly, Uchiro and co-workers previously reported a total synthesis of hirsutellone B through an intermediate bearing a fumaroyl dienophile similar to our compound 20.[4] However, during their synthesis, this highly reactive intermediate had to be protected as a transient cycloadduct with 1,2,3,4,5-pentamethylcyclopentadiene during five steps before the IMDA reaction occurred.
Scheme 3. First attempts and difficulties in synthesizing the tricyclic core 8 of hirsutellone B.
End game: overcoming the ketone reduction trick: The decahydrofluorene core of hirsutellones was obtained by submitting intermediate 20 to o-xylene heated at reflux. The reaction furnished the cycloadduct 22 in 92 % yield with a 5:1 selectivity in favor of the exo product as expected. With this pleasing result in hand, we wished to complete a formal synthesis of hirsutellones after the selective reduction of the carbonyl group of 22. In fact, this was more chal-
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lenging than expected since, as agreeing with Uchiros result on related tricyclic intermediates,[5] NaBH4 reduction furnished a mixture of the desired (S)- and the undesired (R)alcohols 8 and 23 in a 1:3 ratio, respectively, and 68 % global yield. Unfortunately, the use of more hindered reducing reagents such as L-selectride, LiAlHACHTUNGRE(OtBu)3, or the Luche conditions[18] mainly resulted in the formation of the undesired alcohol 23 (Scheme 3). To circumvent this difficulty and improve our strategy, the stereoselective reduction of the cyclohexylketone 20 was envisaged. According to the classical Felkin–Anh model, the reduction occurred in favor of the undesired alcohol 25 when performed with NaBH4 or LiHAlACHTUNGRE(OtBu)3 (ca. 50 % diastereomeric excess (de) in both cases). Nevertheless, the Luche conditions[18] gratifyingly afforded the allylic alcohol 24 in 67 % yield with an anti-Felkin–Anh selectivity supposedly resulting from coordination and cyclohexyl conformational effects (Scheme 4). Finally, the decahydrofluorene
biosynthesis of GKK1032s[8] and adapted to hirsutellones in Scheme 1 (pathway b).[9] It shows that from a linear biosynthetic precursor like 4, an oxidation at the terminal position of the acyl chain is conceivable to trigger the cyclization. Moreover, during the stereoselective sequence from the chiral intermediate 9 to the tricyclic compound 8, we were able to control the formation of seven new stereocenters, which originate from the stereochemistry of the methyl substituent in 9. This work thus provides an expedient biomimetic access to the antitubercular pharmacophore of the natural product and may be useful to design diversity oriented strategies and biological tools in the future. At last, to decide between both biosynthetic pathways (head-to-tail vs. tail-to-head), further biological experiments may be needed in vivo. In fact, this question may be answered the day when the biological macrocyclization of the paracyclophane ring will be understood.
Acknowledgements We acknowledge receipt of scholarships by the China Scholarship Council for X.W.L. and by the French Ministry of Research for A.E. and N.R. We thank the ANR (project ANR-12-BS07-0028-01 SYNBIORG) and the CNRS (interdisciplinary call Physics–Chemistry–Biology) for funding.
Scheme 4. Formal synthesis of hirsutellone B through the stereoselective reduction of enone 20.
core 8 was stereoselectively obtained by the [AlClEt2]-catalyzed IMDA reaction as previously described by Nicolaou (Scheme 4), allowing us to complete the formal synthesis of hirsutellone B (2),[4, 5] and the natural analogues A (1) and C (3).[19]
Conclusion This work, in addition to providing a bio-inspired formal synthesis of hirsutellone B (2), also gives clues to the alternative biosynthetic pathway suggested by Oikawa for the
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[1] S. D. Lawn, A. I. Zumla, Lancet 2011, 378, 57 – 72. [2] a) M. C. Raviglione, M. W. Uplekar, Lancet 2006, 367, 952 – 955; b) Stop TB Partnership, The Global Plan to Stop TB, 2006 – 2015: Actions for Life: Towards a World Free of Tuberculosis, WHO; Geneva, 2006; available at: http://www.stoptb.org/global/plan/main/. [3] M. Isaka, N. Rugseree, P. Maithip, P. Kongsaeree, S. Prabpai, Y. Thebtaranonth, Tetrahedron 2005, 61, 5577 – 5583. [4] K. C. Nicolaou, D. Sarlah, T. R. Wu, W. Zhan, Angew. Chem. 2009, 121, 7002 – 7006; Angew. Chem. Int. Ed. 2009, 48, 6870 – 6874. [5] H. Uchiro, R. Kato, Y. Arai, M. Hasegawa, Y. Kobayakawa, Org. Lett. 2011, 13, 6268 – 6271. [6] S. D. Tilley, K. P. Reber, E. J. Sorensen, Org. Lett. 2009, 11, 701 – 703. [7] K. Fumito, H. Atsuhiro, A. Katsuhiko, O. Tatsuhiro, H. Mitsunobu, Patent JP 2001247574 (2001). [8] H. Oikawa, J. Org. Chem. 2003, 68, 3552 – 3557. [9] For a tutorial review on the generation of complexity in PKS/NRPS compounds exemplified by hirsutellones, see: X.-W. Li, A. Ear, B. Nay, Nat. Prod. Rep. 2013, 30, 765 – 782. [10] Concerning biomimetic synthesis, see: Biomimetic Organic Synthesis (Eds.: E. Poupon, B. Nay), Wiley-VCH, Weinheim, 2011. [11] This phosphonate was first synthesized through cross metathesis, according to D. Amans, V. Bellosta, J. Cossy, Angew. Chem. 2006, 118, 6002 – 6006; Angew. Chem. Int. Ed. 2006, 45, 5870 – 5874. However, owing to the cost of the metathesis catalysts, a synthesis of 12 was designed from the abundant (Z)-2-buten-1,4-diol, as described in the Supporting Information. [12] This five-step sequence to the aldehyde 16 can be compared with the antipodal nine-step one from (S)-()-citronellal recently reported by Li and co-workers for the synthesis of fusarisetin A: J. Deng, B. Zhu, Z. Lu, H. Yu, A. Li, J. Am. Chem. Soc. 2012, 134, 920 – 923. [13] a) W. Dumont, C. Vermeyen, A. Krief, Tetrahedron Lett. 1984, 25, 2883 – 2886; b) H. Uchiro, R. Kato, Y. Sakuma, Y. Takagi, Y. Arai, D. Hasegawa, Tetrahedron Lett. 2011, 52, 6242 – 6245. [14] Such conditions were previously applied to (2E,4E,6E)-octatrienyl acetate leading to (3E,5E)-1,3,5,7-octatetraene through elimination and showing that such substrates can be reactive in the presence of
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Bio-Inspired Synthesis of Hirsutellones A–C
a Pd catalyst: K. Yamamoto, S. Suzuki, J. Tsuji, Bull. Chem. Soc. Jpn. 1981, 54, 2541 – 2542. [15] For the intramolecular reaction of silyl enol ethers and allyl carboxylates, see: a) F. T. Luo, E. Negishi, J. Org. Chem. 1985, 50, 4762 – 4766; b) D. M. Johns, M. Mori, R. M. Williams, Org. Lett. 2006, 8, 4051 – 4054; c) T.-h. Fu, W. T. McElroy, M. Shamsza, S. F. Martin, Org. Lett. 2012, 14, 3834 – 3837. [16] a) H. R. Burmeister, G. A. Bennett, R. F. Vesonder, C. W. Hesseltine, Antimicrob. Agents Chemother. 1974, 5, 634 – 639; b) N. J. Phil-
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FULL PAPER lips, J. T. Goodwin, A. Fraiman, R. J. Cole, D. G. Lynn, J. Am. Chem. Soc. 1989, 111, 8223 – 8231. [17] C. I. Turner, R. M. Williamson, M. N. Paddon-Row, M. S. Sherburn, J. Chem. Soc. 2001, 66, 3963 – 3969. [18] A. L. Gemal, J. L. Luche, J. Am. Chem. Soc. 1981, 103, 5454 – 5459. [19] K. C. Nicolaou, Y.-P. Sun, D. Sarlah, W. Zhan, T. R. Wu, Org. Lett. 2011, 13, 5708 – 5710. Received: September 9, 2013 Published online: October 18, 2013
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