Asymmetric Synthesis of 1,2-Dioxolane-3-acetic Acids: Synthesis and Configurational Assignment of Plakinic Acid A Peng Dai, Tony K. Trullinger, Xuejun Liu, and Patrick H. Dussault* Department of Chemistry, UniVersity of Nebraska-Lincoln, Lincoln, Nebraska 68588-0304
[email protected] ReceiVed October 26, 2005
The first asymmetric synthesis of 1,2-dioxolane-3-acetic acids is reported. Key features include the stereoselective opening of enantiomerically enriched oxetanes by hydrogen peroxide, conversion of the resulting 4-hydroperoxy-2-alkanols to 3-alkoxy-1,2-dioxolanes, and Lewis acid mediated homologation of the latter with a thioester silyl ketene acetal. The approach is modeled on 3,5-dimethyl-5-hexadecyl1,2-dioxolane-3-acetic acid (1a), an unnamed natural product, and an optimized strategy is applied to the synthesis of four stereoisomers of plakinic acid A (2), allowing a configurational assignment of this incompletely characterized natural product.
Introduction
CHART 1.
Plakinic Acids and Related Compounds
The plakinic acids are a large family of marine natural products that have been reported to display cytotoxicity against fungal and cancer cell lines (Chart 1).1-9 The absolute stereochemistry has not been established for any member of the family and no asymmetric synthesis of a plakinic acid has yet been reported. A racemic synthesis of 1b has been reported based upon sequential inter- and intramolecular peroxymercurations of a dienoate.10 This approach, while unquestionably efficient, is neither stereoselective nor compatible with the side chain (1) Patil, A. D. PCT Int. Appl. WO 8704708, 2987; Chem. Abstr. 1988, 109, 17027f. (2) Phillipson, D. W.; Rinehart, K. L., Jr. J. Am. Chem. Soc. 1983, 105, 7735-7736. (3) Davidson, B. S. J. Org. Chem. 1991, 56, 6722-6724. (4) Horton, P. A.; Longley, R. E.; Kelly-Borges, M.; McConnell, O. J.; Ballas, L. M. J. Nat. Prod. 1994, 57, 1374-1381. (5) Chen, Y.; Killday, K. B.; McCarthy, P. J.; Schimoler, R.; Chilson, K.; Selitrennikoff, C.; Pomponi, S. A.; Wright, A. E. J. Nat. Prod. 2001, 64, 262-264. (6) Sandler, J. S.; Colin, P. L.; Hooper, J. N. A.; Faulkner, D. J. J. Nat. Prod. 2002, 65, 1258-1261. This paper describes “epiplakinic acid H”, which might be better described as plakinic acid G. (7) Chen, Y.; McCarthy, P. J.; Harmody, D. K.; Schimoler-O’Rourke, R.; Chilson, K.; Selitrennikoff, C.; Pomponi, S.; Wright, A. E. J. Nat. Prod. 2002, 65, 1509-1512. (8) Rudi, A.; Afanil, R.; Gravalos, L, G.; Aknin, M.; Gaydou, E.; Vacelet, J.; Kashman, Y. J. Nat. Prod. 2003, 66, 682-685. (9) For reviews of peroxide natural products, see: Casteel, D. A. Nat. Prod. Rep. 1999, 16, 55-73; 1992, 9, 289-311. (10) Bloodworth, A. J.; Bothwell, B. D.; Collins, A. N.; Maidwell, N. L. Tetrahedron Lett. 1996, 37, 1885-1888.
unsaturation present in many members of the family. We recently reported a racemic approach to substituted dioxolanes, including 1a, via Lewis acid mediated reactions of alkoxydiox-
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J. Org. Chem. 2006, 71, 2283-2292
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Dai et al. SCHEME 1.
Retrosynthetic Approach to 1a
olanes with electron-rich alkenes.11 However, the utility of this methodology was limited by the absence of methods for asymmetric synthesis of alkoxydioxanes. We recently reported a new method for synthesis of 1,3-peroxyalkanols that appeared to offer a route to enantiomerically enriched alkoxydioxanes and therefore dioxolane acetic acids.12 We now describe the asymmetric synthesis of dioxolane 1a as well as four candidate structures for plakinic acid A (2).13 Results and Discussion As an initial target on which to model our approach, we chose 1a, in which stereochemical issues are limited to the substitution on the dioxolane ring (Scheme 1). As in the racemic studies, introduction of the 1,2-dioxolane-3-acetic acid would be achieved through reaction of a thioester silyl ketene acetal with an alkoxydioxolane,11 a reaction that proceeds via an intermediate peroxycarbenium ion. However, in contrast to the earlier work, the 1,2-dioxolane would be derived from an enantiomerically enriched 2,4-hydroperoxyalkanol prepared through opening of a tertiary oxetane by hydrogen peroxide.12 Enantiomerically enriched oxetanes are available from 2,3-epoxy alcohols, making it possible to select the absolute stereochemistry of the dioxolane acetic acid through the choice of asymmetric epoxidation catalyst. The synthesis began with allyl alcohol 3, derived from carbalumination of octadecyne, (Scheme 2). Asymmetric epoxidation under stoichiometric conditions and in the presence of pentane as a nonpolar additive14 provided the 2,3-epoxyalcohol 4 in 84% enantiomeric excess.15 The derived aldehyde underwent addition of MeMgBr to furnish a 3:1 mixture of epimeric epoxy alcohols (5). As the hydroxyl-bearing stereocenter would be eventually destroyed, we elected to carry on the mixture of epimers. Red-Al reduction of the epoxy alcohols provided an excellent yield of 2,4-diols (6),16 which were subjected to one-pot tosylation/cyclization to form a mixture of epimeric oxetanes.12,17,18 The oxetanes were accompanied by a small amount of an elimination byproduct (8), which could (11) Dussault, P. H.; Liu, X. Org. Lett. 1999, 1, 1391-1393. A related approach to substituted 1,2-dioxolanes based upon Lewis acid mediated reactions of 1,1-bisperoxyacetals has recently been reported: Ramirez, A.; Woerpel, K. A. Org. Lett. 2005, 7, 4617-4620. (12) Dussault, P. H.; Trullinger, T. K.; Noor-e-Ain, F. Org. Lett. 2002, 4, 4591-4593. (13) Portions of this work were reported in doctoral dissertations: Trullinger, T. K. University of Nebraska, Lincoln, NE, 2002. Dai, P. University of Nebraska, Lincoln, NE, 2004. (14) Bernet, B.; Vasella, A. Tetrahedron Lett. 1983, 24, 5491-5494. (15) Based upon 19F NMR of the derived methoxytrifluoromethylphenylacetates: Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512-519. (16) Ma, P.; Martin, V. S.; Masamune, S.; Sharpless, K. B.; Viti, S. M. J. Org. Chem. 1982, 47, 1378-1380; Minami, N.; Ko, S. S.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 1109-1111. (17) Balsamu, A.; Ceccarelli, G.; Crotti, P.; Macchia, F. J. Org. Chem. 1975, 40, 473-476. (18) Picard, P.; LeClerq, D.; Bats, J.-P.; Moulines, J. Synthesis 1981, 550-551.
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Synthesis of 4-Hydroperoxy-2-alkanola
SCHEME 2.
a Reagents and conditions: (a) LiCCH, ethylenediamine; (b) Cp ZrCl , 2 2 AlMe3, n-BuLi, (CH2O)n; (c) Ti(OiPr)4, (-)-DET, 3, t-BuOOH, CH2Cl2/ pentane; (d) Dess-Martin periodinane; (e) MeMgBr; (f) Red-Al; (g) t-BuOK, TsCl, t-BuOK, THF; (h) ethereal H2O2, Yb(OTf)3; (i) LiHMDS, TBSCl; (j) NIS; (k) n-Bu3SnH, AIBN.
SCHEME 3
a
a Reagents and conditions: (a) LiHMDS, TBSCl; (b) Dess-Martin periodinane; (c) Me3Al.
be recycled to oxetane via iodoetherification and reductive dehalogenation.19 Yb(OTf)3-catalyzed opening of oxetane 7 with ethereal H2O2 proceeded smoothly to provide 4-hydroperoxy2-alkanol 9.12 Selective protection of the hydroperoxide group with a lithium amide and TBSCl cleanly furnished peroxyalkanol 10. We briefly explored an alternate approach to peroxyalkanol 10 based upon homologation of a 3-peroxyalkanal (Scheme 3). Hydroperoxyalkanol 12 was prepared via acid-catalyzed opening of 2,2-disubstituted oxetane (11) with H2O2.12 Selective protection of the hydroperoxide proceeded in low yield; oxidation of the resulting alcohol afforded the 3-methyl-3-peroxyalkanal (13). Attempted homologation of 13 with MeMgBr, MeLi, or MeTi(OiPr)3 resulted only in fragmentation. Although conversion to 10 could be achieved in low yield with Me3Al,20 this approach was ultimately abandoned in favor of the route described in Scheme 2. Peroxyketone 14, prepared in high yield via perruthenate oxidation of alcohol 10, was deprotected to furnish a mixture of 1,2-dioxolan-3-ols. These tended to decompose upon chromatography, and the crude product was directly subjected to acid-catalyzed etherification to provide a nearly inseparable 1:1 mixture of cis- and trans-alkoxydioxolanes 15 (Scheme 4). Treatment of the alkoxydioxolanes with TiCl4 and the trimethylsilyl ketene acetal of ethyl thioacetate furnished a 1:1 mixture of thioesters cis-16 and trans-16. The derived aldehydes cisand trans-17 were separated and individually oxidized to furnish diastereomerically pure samples of (+)-cis- 1a and (-)-trans-1a. (19) Evans, R. D.; Magee, J. W.; Schauble, J. H. Synthesis 1988, 862868. (20) Allen, J. L.; Paquette, K. P.; Porter, N. A. J. Am. Chem. Soc. 1998, 120, 9362-9363.
Asymmetric Synthesis of 1,2-Dioxolane-3-acetic Acids SCHEME 4.
Synthesis of (+)-cis-1a and (-)-trans-1aa
SCHEME 6.
a
a
Reagents and conditions: (a) TPAP, NMO; (b) aq HF, CH3CN/THF; (c) 2-methoxyethanol, HCl (cat.); (d) TiCl4 (1.1 equiv) H2CdCH2(OTMS)SEt (2.5-4 equiv), -50 to 0 °C; (e) DIBAL, CH2Cl2, -78 °C; (f) NaClO2, NaH2PO4‚H2O, t-BuOH, 2-methyl-2-propene.
SCHEME 5.
Plakinic Acid A Retrosynthesisa
Illustrated for one stereoisomer.
SCHEME 7.
Synthesis of Plakinic A Sidechaina
Preparation of (-)-cis-1a and (+)-trans-1a
The enantiomers, (-)-cis-1a and (+)-trans-1a, were prepared from ent-4 by an identical route. (Scheme 5). The disparity in the specific rotations for the two series led us to assess enantiomeric purity of formation of diastereomeric derivatives (eq 1). Our previous research had demonstrated
resolution of racemic 3,5,5-trimethyl-1,2-dioxolane acetic acids as diastereomeric thioesters.21 Application of this method to (+)and (-)-trans-1a revealed low and variable stereochemical purity, suggesting that the oxetane openings proceeded with highly inconsistent stereoselectivity. Lessons from the Model Synthesis: Synthesis of Candidate Structures for Plakinic Acid A. Any synthetic approach to plakinic acid A faced the challenge of controlling both dioxolane and side chain stereocenters. As before, our approach was based upon installation of the 1,2-dioxolane acetic acid via reaction of a thioester silyl ketene acetal with an enantiomerically enriched alkoxydioxolane (Scheme 6). However, drawing upon our experience with the synthesis of 1a, the crucial oxetane opening would be conducted on a single stereoisomer, using the displaced secondary alcohol as an internal stereochemical marker and resolving agent. The oxetane would arise from an enantiomerically enriched 2,3-epoxy alcohol now containing four stereocenters. (21) Dussault, P. H.; Trullinger, T. K.; Cho-Shultz, S. Tetrahedron 2000, 56, 9213-9220.
a Reagents and conditions: (a) Mg, crotonaldehyde; (b) (EtO) CCH , 3 3 propionic acid, 140 °C; (c) LAH; (d) Swern; (e) (E)-propenyl bromide, t-BuLi, THF; (f) Zn, CBr4, PPh3; (g) n-BuLi; (h) Me3Al, Cp2ZrCl2 then n-BuLi, (CH2O)n; (i) Ti(OiPr)4, (-)-DET, t-BuOOH.
The synthesis of the plakinic acid A side chain began with Claisen homologation of allylic alcohol 20 to ester 21 (Scheme 7). Conversion to the corresponding aldehyde, followed by addition of (E)-propenyllithium, furnished a 1:1 mixture of diasteromeric allylic alcohols 22a and 22b, for which the relative stereochemistry was determined by conversion to 2,4-disubstituted butyrolactones.22 Alternatively, use of propenylmagnesium bromide as a nucleophile resulted in predominant formation of 22a and 22b, along with smaller amounts of the corresponding (Z)-allylic alcohols 22c and 22d.23 An iteration of the Claisen/ DIBAL sequence on 22a (or 22d) produced ester 23. Homologation of the derived aldehyde furnished alkyne 24, which underwent carbalumination and trapping with formaldehyde to (22) Kiyooka, S.-i.; Li, Y.-N.; Shahid, K. A.; Okazaki, M.; Shuto, Y. Tetrahedron Lett. 2001, 42, 7299-7301. See Supporting Information for details. (23) Alcohols 22a and 22d both underwent the Johnson Claisen reaction to furnish ester 23, whereas 22b/22c furnished an epimeric ester under the same conditions.
J. Org. Chem, Vol. 71, No. 6, 2006 2285
Dai et al. SCHEME 8.
Synthesis of Oxetane 29a
SCHEME 9.
Synthesis of cis-2a and trans-2aa
a Reagents and conditions: (a) Dess-Martin periodinane; (b) MeMgBr; (c) (1) DEAD, PPh3, 4-NO2PhCO2H, (2) NaOMe, MeOH; (d) Red-Al; (e) TsCl, t-BuOK, THF; (f) TsCl, t-BuOK; NaH.
furnish racemic alkenol 25. Asymmetric epoxidation furnished separable diastereomers 26a and 26b, each found to be >80% enantiomeric excess.17 Assignment of stereochemistry for 26a and 26b is based upon a subsequent correlation of the C3 and C5 centers (vide infra). At this point, we chose to carry forward stereoisomer 26a (Scheme 8). Addition of methylmagnesium bromide to the corresponding epoxyaldehyde furnished a mixture of diastereomeric epoxy alcohols 27a and 27b, which after separation were individually reduced to the corresponding 1,3-diols, 28a and 28b. For preparative routes, the minor epoxy alcohol 27b was epimerized to 27a via a Mitsonobu inversion.24 The syn stereochemistry of the major diol (28a) was confirmed by conversion to the 2,2-dimethyl-1,3-dioxane.25 Treatment of 28a with a stoichometric quantity of toluenesulfonyl chloride and excess t-BuOK produced a 5:1 mixture of oxetane 29 and alkenol 30; similar results were obtained upon treatment of the preformed monosulfonate with NaH. anti-1,3-Diol 28b underwent cyclization in much poorer yield, but this problem was rendered moot by the successful epimerization of 27b. The presence of multiple alkenes meant that that the byproduct of elimination (30) could not be “recycled” to oxetane 29 via iodoetherification as in the model system. However, this byproduct did provide a means to determine the absolute stereochemistry of the side chain stereocenters (eq 2). Ringclosing metathesis of 30 furnished a cyclohexene, which was hydrogenated to furnish the known cis-1,3-dimethyl cyclohexanol (32).26,27
Opening of oxetane 29 with ethereal hydrogen peroxide in the presence of Yb(OTf)3 proceeded at temperatures g0 °C to provide a 4:1 ratio of hydroperoxyalkanols 33 and epi-33 (24) Dodge, J.; Trujillo, J. I.; Presnell, M. J. Org. Chem. 1994, 59, 234236. Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017-3020. Roush, W. R.; Brown, R. J.; DiMare, M J. Org. Chem. 1983, 48, 3-93.
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a Reagents and conditions: (a) TMSOTf, H O , ether, -78 °C; (b) 2 2 LiHMDS, TBSCl; (c) Dess-Martin periodinane; (d) HF, 2-methoxyethanol, 2 days; (e) TiCl4 (1.1 equiv) H2CdCH2(OTMS)SEt (16 equiv), -50 to 0 °C; (f) NaOMe, MeOH; (g) LiOH, 30% H2O2, THF.
(Scheme 9).12 The use of TMSOTf allowed performance of the same reaction between -78 and 0 °C and reproducibly afforded an 8:1 mixture of 33 and epi-33, which were easily separated by semipreparative HPLC. The stereochemistry of the major diastereomer was confirmed by reduction (Me2S) to the diol and correlation with the syn-1,3-diol derived from reduction of epoxy alcohol 26b. Selective silylation and oxidation furnished peroxyketone 34, which underwent deprotection to provide the 1,2-dioxolane-3-ol. Acidic transetherification, an uneventful reaction in the saturated model, proved problematic, with strongly acidic conditions resulting in fragmentation to nonperoxidic products whose identity would become clear later (vide infra). However, treatment of 34 with HF and 2-methoxyethanol achieved a one-pot conversion to a mixture of cisand trans-alkoxydioxolanes (35); TLC monitoring suggested this transformation proceeds via a rapid deprotection (
