Letter Cite This: Org. Lett. 2018, 20, 1388−1391
pubs.acs.org/OrgLett
Stereoselective Synthesis of the Benzodihydropentalene Core of the Fijiolides Timon Kurzawa, Klaus Harms, and Ulrich Koert* Fachbereich Chemie, Philipps-University Marburg, Hans-Meerwein-Strasse 4, D-35043 Marburg, Germany S Supporting Information *
ABSTRACT: An efficient stereoselective synthesis of the enantiomer of the benzodihydropentalene core of fijiolides A and B has been achieved. The asymmetric conjugate addition of styrylboronic acid to an indenone produced the first stereocenter. Ring C was installed by ring-closing metathesis of a cis disubstituted indanone. Regioselective epoxide opening by NaSePh and subsequent oxidative elimination produced an allylic alcohol. The final introduction of the cyclopentadiene was possible by elimination of an in situ formed triflate.
F
ijiolides A and B are potent inhibitors of TNF-α-induced NFKB activation, which were isolated in 2010 by Fenical from a marine derived sediment bacterium of the genus Norcardiopsis (Figure 1).1 The fijiolides consist of a tricyclic
Scheme 1. Retrosynthetic Analysis of Benzodihydropentalene 2
Figure 1. Natural products related to the benzodihydropentalene core.
assembled from 5. A similar approach to the cyclopentadiene part of C-1027 was reported by Inoue.5b,c An alternative route to 2 could use the cyclopentene 6 as a key intermediate. The cyclopentene ring could result from a ring-closing metathesis of the diene 7, which leads to the indenone 8 as starting material. Indenones are readily accessible starting materials. General methods for the conversion of a substituted cyclopentene into a cyclopentadiene are rare. Here following the latter strategy, a stereoselective route to the enantiomer of the natural benzodihydropentalene core is reported. The starting point for the synthesis of the indenone 14 was aldehyde 9,6 which was converted into (Z)-cinnamic acid ester 11 using a Still−Gennari olefination7 (Scheme 2). An alternative toward (Z)-11 was achieved by a Wittig reaction
benzodihydropentalene substructure, a 3′-chloro-5′-hydroxy-βtyrosine and an aminosugar. The benzodihydropentalene probably results biosynthetically from an enedyne precursor via a Masamune−Bergman cyclization.2 The structurally closely related enediyne C-1027 chromophore is a known natural product.3 The cyanosporasides contain a benzodihydropentalene too, however with a different diene unit.4 The benzodihydropentalene core structure 1 with its two trans configurated oxygen functions at C8 and C9 in ring B and the cyclopentadiene ring C is a unique substructure and a synthetic challenge. A total synthesis of fijiolide A has been reported by Cramer.5a They installed the cyclopentadiene in 2 at the end of the synthesis by a Grieco elimination from 3 (Scheme 1). The latter was accessible from the cyclopentenone 4 which was © 2018 American Chemical Society
Received: January 16, 2018 Published: February 16, 2018 1388
DOI: 10.1021/acs.orglett.8b00163 Org. Lett. 2018, 20, 1388−1391
Letter
Organic Letters Scheme 2. Synthesis of Indenone 14
Table 1. Screening Conditions for the Asymmetric Addition of Styrylboronic Acid 15 to Indenone 14 entry
precursor cat.
ligand
solvent
yield (%)a
eed (%)
1 2 3 4 5 6 7 8
A A A B B B B B
L1 L1 L2 L3 L4 L4 L5 L6
1,4-dioxane toluene toluene toluene toluene toluene toluene toluene
65 66 56 62 99 99 45 85
41 41 38b 44 59 74c 22 95
a
Isolated yields; catalyst precursor A, [Rh(cod)OH]2 (5 mol %); catalyst precursor B, [Rh(C2H4)2Cl]2 (2 mol %). bThe (S)-enantiomer was obtained; reactions were performed at 20 °C. cReaction was performed at 0 °C. dee was determined by HPLC, the absolute configuration by X-ray.
With L4 the product 16 was obtained in good yield with 74% ee (entry 6). With L6 the highest ee of 95% was achieved (entry 8). After recrystallization the enantiomeric excess was increased to >99%. The structure of 16 could be secured by Xray crystallography (see Supporting Information). Due to the better commercial availability of (R,R,R)-L4, the (R)-enantiomer 16 was synthesized and used for subsequent chemistry. The synthetic route led therefore to the enantiomer of the natural benzodihydropentalene core. For the natural occurring fijiolides the respective (S)-enantiomer of 16 is accessible using ent-L4.12 To the best of our knowledge, the reaction (14 + 15 → 16) is the first example of a rhodium-catalyzed asymmetric conjugate addition of an alkenyl moiety to an indenone. After the stereocontrolled introduction of a styryl residue in the β-position of the indanone, a cis configurated allyl substituent was required in order to perform a ring-closing metathesis to install ring C (Scheme 4). The α-allylation of 16 with allyl bromide gave the trans indanone 17 in 62% yield
using ylide 12, which afforded 13 in 97% yield (E/Z = 4:1). A subsequent olefin isomerization using (−)-riboflavin8 as a photosensitizer gave 11 with a Z/E ratio of 8:1 upon irradiation with LEDs (365 nm) even on 2.5 g scale. After saponification of 11 and subsequent conversion of the carboxylic acid into the corresponding acid chloride, a Friedel−Crafts acylation gave indenone 14 in very good yield. With indenone 14 in hand, a route for the construction of ring C was investigated. A rhodium-catalyzed asymmetric addition of an alkenyl boronic acid should be suitable for the stereocontrolled introduction of the β alkenyl side chain in 7.9 A number of ligands L1−L6 and experimental conditions were screened for the asymmetric conjugate addition of the boronic acid 15 to the indenone 14 to obtain the indanone 16 (Scheme 3, Table 1). Ligands L3−L5 are derived from (R)(−)-phellandrene.10 Ligand L6 can be prepared in 7 steps from carvone.11 L4 and L6 could be identified as the best ligands for the addition of an alkenyl moiety to indenone 14.
Scheme 4. Construction of Ring C in 21
Scheme 3. Asymmetric Conjugate Addition to Indenone 14
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DOI: 10.1021/acs.orglett.8b00163 Org. Lett. 2018, 20, 1388−1391
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Organic Letters brsm. The formation of the doubly allylated compound 18 as a side product could not be prevented even by variation of base (KHMDS, LDA), leaving group (Br, I), or reaction temperature (−80 to −20 °C). Due to the high instability of the styrylic double bond in 16 (complete isomerization into conjugation for the enolate of 16 within 20 min at −20 °C) other methods (silyl enol ether addition, Tsuji−Trost allylation, enamine) presented no alternatives for the introduction of the allyl moiety. A substrate controlled trans/cis isomerization at the αposition of 17 using ethyl salicylate13 to reprotonate the enolate of 17 gave a cis/trans mixture of 2:1. After ring-closing metathesis (RCM) with Grubbs II an inseparable mixture of tricyclic compound 19 and trans 17 was obtained. Therefore, it was decided to combine the cis/trans isomerization of 17 with the introduction of the hydroxyl group at C9 by treatment of the potassium enolate with dimethyldioxirane (DMDO, acetone solution).14 This approach provided alcohol 20 in 95% yield as a single diastereomer. A subsequent RCM gave hydroxylated tricycle 21 in 70% yield, structurally secured by Xray crystallography (see Supporting Information). In order to minimize the risk of double-bond isomerization in 17, the construction of ring C was streamlined to give 21 in 25% yield starting from 16 with only one final chromatographic purification step. After successful assembly of the carbon core structure in 21 the oxidation states had to be adjusted to give 2, starting with a substrate directed reduction at C8 (Scheme 5). An Evans−
Scheme 6. Unsuccessful Attempts To Convert 25 into Diene 28
A SeO2-mediated oxidation of 25 was tested, where after the ene reaction to allyl selenide 27 the β-hydride elimination at sterically hindered cyclopentenes could yield a diene instead of the allylic alcohol.17 For the present case, only traces of the diene 28 could be detected via GCMS. Epoxidation of 25 with DMDO gave epoxide 29 stereoselectively (Scheme 7). An epoxide opening under basic Scheme 7. Conversion of Olefin 25 into Allylic Alcohol 32
Scheme 5. Diastereoselective Reduction of Ketone 21
conditions toward allylic alcohol 30 was not successful. The epoxide could be opened by NaSePh at C11 selectively leading to selenide 31. Oxidation of the latter and subsequent thermal syn elimination gave the allylic alcohol 32. With respect to the extremly acid labile tertiary ether at C9 the amount of purifications had to be minimized. Therefore, the transformations were streamlined to give allylic alcohol 32 starting from ketone 21 in 32% yield over 5 steps with only one final column chromatography necessary. For the final elimination of 32 to 28 a screening of conditions (Table 2) revealed a syn elimination of an in situ formed triflate18 to produce smoothly the desired cyclopentadiene in 82% yield. In summary, we have developed a 12 step synthesis of the enantiomer of the tricyclic core structure of the fijiolides A and B. The synthesis is adaptable for the synthesis of the natural enantiomer. An indenone as readily available starting material allows the introduction of the first stereocenter via an asymmetric conjugate addition. All following stereocenters can be installed via substrate controlled reactions. The highly diastereoselective installation of the diol offers some advantages over the bishydroxylation strategy of the indene moiety used by Cramer et al. The present strategy is modular and flexible. It can find applications in the synthesis of natural products and
Saksena reduction with Me4NHB(OAc)3 failed to give any diol even at elevated temperatures and prolonged reaction times.15 We were satisfied to find a Red-Al reduction16 in the temperature range between −78 and −60 °C to produce almost exclusively trans-diol 22 (trans/cis > 15:1) in 99% yield. Reaction temperatures above −60 °C gave lower trans/cis mixtures of up to 2:1. The isolation of cis-diol 23 helped to assign the trans configuration of the epimer 22 by showing an NOE correlation of the benzylic proton with the allylic protons of 23 (see Supporting Information for details). Benzoylation of the trans diol occurred preferentially at the secondary alcohol (22 → 24). This discrimination of both alcohols could be useful for the attachment of the ansa bridge in the synthesis of the fijiolides. Treatment of 22 with KHMDS and excess MeI led to the dimethyl ether 25. The introduction of the cyclopentadiene in ring C was a challenging task (Scheme 6). Bromination/elimination of 25 using an excess of base gave the allyl bromide 26 only. Attempts for a further HBr elimination to 28 were unsuccessful. 1390
DOI: 10.1021/acs.orglett.8b00163 Org. Lett. 2018, 20, 1388−1391
Letter
Organic Letters
(6) Giles, R. G. F.; Green, I. R.; Li, S.-H. Aust. J. Chem. 2005, 58, 565−571. (7) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405−4408. (8) Metternich, J. B.; Gilmour, R. J. Am. Chem. Soc. 2015, 137, 11254−11257. (9) (a) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829−2844. (b) Hickmann, V.; Alcarazo, M.; Fürstner, A. J. Am. Chem. Soc. 2010, 132, 11042−11044. (10) Okamoto, K.; Hayashi, T.; Rawal, V. H. Org. Lett. 2008, 10, 4387−4389. L5 was prepared by addition of n-BuLi to L3. (11) Defieber, C.; Paquin, J.-F.; Serna, S.; Carreira, E. M. Org. Lett. 2004, 6, 3873−3876. (12) (S)-α-Phellandrene can be prepared in three steps from (R)(−)-carvone: (a) Sen, A.; Grosch, W. Flavour Fragrance J. 1990, 5, 233−234. (b) Dauben, W. G.; Lorber, M. E.; Vietmeyer, N. D.; Shapiro, R. H.; Duncan, J. H.; Tomer, K. J. Am. Chem. Soc. 1968, 90, 4762−4763. (13) Krause, N. Angew. Chem., Int. Ed. Engl. 1994, 33, 1764−1765. (14) Adam, W.; Mueller, M.; Prechtl, F. J. Org. Chem. 1994, 59, 2358−2364. (15) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988, 110, 3560−3578. (16) Bajwa, N.; Jennings, M. P. J. Org. Chem. 2008, 73, 3638−3641. (17) Shao, L.-D.; Xu, J.; Li, X.-N.; Zhang, Z.-J.; Shi, X.; Ren, J.; He, J.; Zhao, Y.; Leng, Y.; Xia, C.; Zhao, Q.-S. RSC Adv. 2016, 6, 35792− 35803. (18) Münster, N.; Nikodemiak, P.; Koert, U. Org. Lett. 2016, 18, 4296−4299.
Table 2. Screening Conditions for Elimination of Allylic Alcohol 32 to Cyclopentadiene 28
entry
conditions
yield (%)
1 2 3 4
Burgess reagent, C6H6, 80 °C, 2 h Martin sulfurane, CH2Cl2, 0 °C to rt, 1 d PPh3, NBS, CH2Cl2, rt, 2 d KHMDS, PhN(Tf)2, THF, −78 °C, 20 min
