pubs.acs.org/joc Heteroatom-Directed Reverse Wacker Oxidations. Synthesis of the Reported Structure of (-)-Herbaric Acid Peter J. Choi, Jonathan Sperry, and Margaret A. Brimble* Department of Chemistry, University of Auckland, 23 Symonds St., Auckland, New Zealand [email protected] Received August 22, 2010 A microwave-assisted chemoenzymatic resolution has been used to install the C3 stereocenter of the reported structure of the fungal metabolite herbaric acid in high enantiomeric excess. The synthesis and stereochemical assignment was accomplished using a completely regioselective anti-Markovnikov addition of water to vinylphthalide 3, achieved using a heteroatom-directed Wacker oxidation that proceeds with retention of stereochemistry. These results establish that so-called “reverse” Wacker oxidations are a viable alternative to hydroboration/oxidation procedures. Introduction Significant effort has been directed toward the synthesis of phthalides bearing 3-alkyl substituents. Existing asymmetric The phthalide [1(3H)-isobenzofuranone] moiety is present in methods primarily involve the use of chiral auxiliaries3 and a rich and diverse group of natural products.1 A smaller subset chiral organometallics,4 but recently reported organocatalytic5 of this class are phthalides that contain a chiral C3-substituent, and hydroacylation6 methodologies have provided elegant addi- many of which possess a vast array of biological activities. tions to the synthetic repertoire. Nonetheless, efficient new Representative examples include spirolaxine methyl ether,2a methods for the asymmetric synthesis of this medicinally hydrastine,2b vermastatin,2c alcyopterosin,2d typhaphthalide,2e important motif are highly sought after. Herein, we report a 3-butylphthalide,2f and herbaric acid2g (Figure 1). procedure for the efficient installation of the phthalide C-3 stereocenter using an operationally simple microwave-assisted (1) (a) Ge, L.; Chan, S-K. S.; Chung, H-S; Li, S.-L. Studies in Natural Products Chemistry; Rahman, A., Ed.; Elsevier: Amsterdam, 2005; Vol. 32, enzymatic resolution. Furthermore, an entirely regioselective pp 611-671. (b) Beck, J. J.; Chou, S.-C. J. Nat. Prod. 2007, 70, 891–900. anti-Markovnikov hydroxypalladation of the chiral 3-vinylpht- (2) (a) Arnone, A.; Assante, G.; Nasini, G.; De Pava, O. V. Phytochem- istry 1990, 29, 613–616. (b) Blasko, G.; Gula, D. J.; Shamma, M. J. Nat. Prod. halide intermediate used herein demonstrates that heteroatom- 1982, 45, 105–122. (c) Fuska, J.; Uhrin, D.; Proksa, B.; Voticky, Z.; Ruppeldt, directed Wacker oxidations are a useful alternative for the syn- J. J. Antibiot. 1986, 39, 1605–1608. (d) Palermo, J. A.; Brasco, M. V. R.; thesis of aldehydes from terminal alkenes.7 The synthetic utility Spagnuolo, C.; Seldes, A. M. J. Org. Chem. 2000, 65, 4482–4486. (e) Shode, F. O.; Mahomed, A. S.; Rogers, C. B. 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(b) Kitamura, M.; Okhuma, T.; Inoue, S.; Sayo, shown in Scheme 1, involving oxidation and deprotection of N.; Kumobayshi, H.; Akutagawa, S.; Takaya, H.; Noyori, R. J. Am. Chem. aldehyde 2. It was envisaged that upon subjecting vinylphth- Soc. 1998, 110, 629–631. (c) Lei, J.-G.; Hong, R.; Yuan, S.-G.; Lin, G.-Q. alide 3 to Wacker oxidation conditions, the bridging oxygen Synlett 2002, 927–930. (d) Witulski, B.; Zimmermann, A. Synlett 2002, 1855– 1859. (e) Trost, B. M.; Weiss, A. H. Angew. Chem., Int. Ed. 2007, 46, 7664– 7666. (f) Knepper, K.; Ziegert, R. E.; Brase, S. Tetrahedron 2004, 60, 8591– (5) Zhang, H.; Zhang, S.; Liu, L.; Luo, G.; Duan, W.; Wang, W. J. Org. 8603. (g) Tanaka, K.; Osaka, T.; Noguchi, K.; Hirano, M. Org. Lett. 2007, 9, Chem. 2010, 75, 368–374. 1307–1310. (h) Chang, H.-T.; Jeganmohan, M.; Cheng, C.-H. Chem.—Eur. (6) (a) Phan, D. H. T.; Kim, B.; Dong, V. M. J. Am. Chem. Soc. 2009, 131, J. 2007, 13, 4356–4363. (i) Everaere, K.; Mortreux, A.; Carpentier, J.-F. Adv. 15608–15609. (b) Willis, M. C. Angew. Chem., Int. Ed. 2010, 49, 6026–6027. Synth. Catal. 2003, 345, 67–77. (7) Muzart, J. Tetrahedron 2007, 63, 7505–7521. 7388 J. Org. Chem. 2010, 75, 7388–7392 Published on Web 09/27/2010 DOI: 10.1021/jo1016585 r 2010 American Chemical Society Choi et al. JOCArticle SCHEME 2. Synthesis of Vinylphthalide 3 ( a FIGURE 1. Phthalide natural products. TABLE 1. Chemoenzymatic Resolution of ( )-5 entry heatingb time (h) ee (S)-5 (%)c yield (%) . SCHEME 1 Retrosynthetic Analysis of Herbaric Acid 1 1 conventional 24 50 62 2 microwave; open vessel 24 59 54 3 microwave; closed vessel 24 74 46 4 microwave; closed vessel 48 84 50 5 microwave; closed vessel 60 66 50 aConditions: Novozyme 435, p-chlorophenyl acetate 7,toluene,55°C. bAll microwave reactions were conducted at 300 W. cEnantiomeric excess calculated by HPLC [Chiralcel OD-H, hexanes/i-PrOH (93:7)] (see Experimental Section section and Supporting Information for full details). donor, respectively.9 Preliminary screening of the conversion of (()-5 to (S)-5 and (R)-8 using several solvents and acyl donors confirmed these conditions as the most promising, and further optimization of these baseline conditions is shown in Table 1. Conventional heating (entry 1) led to present in the lactone would provide an anchor enabling disappointing enantioselectivities, as did the use of micro- chelation to palladium, thereby facilitating delivery of water wave heating in an open vessel (entry 2). After much experi- mentation, it was eventually found that microwave irradiation to the methylene carbon and affording the desired aldehyde 2. - The successful realization of this heteroatom-directed Wacker using a closed vessel (entries 3 5) was vital for the success of oxidation would provide a basis for a convenient and mild this reaction, as was the careful monitoring of the total re- alternative to hydroboration/oxidation, a harsh procedure action time. Gratifyingly, conducting the resolution for 48 h traditionally used for the synthesis of aldehydes from terminal led to a 50% yield of (S)-5 with good enantioselectivity. The alkenes.8 The chiral vinylphthalide 3 would be constructed resolution showed no appreciable drop in yield or enantio- by lactonization of carbamate 4, which in turn is accessed using selectivity upon scale-up and was routinely conducted on a 9 2 g scale. The stereochemistry of the products was evaluated our recently described microwave-assisted kinetic resolution 11 of benzylic alcohol (()-5. according to Kazlauskas’ rule, and the resolved products were unequivocally assigned as (S)-5 and (R)-8. With these ideas in mind, the synthesis of the enantioen- 0 riched alkene 3 was initiated (Scheme 2). Smooth Grignard Compound (S)-5 was treated with 1,1 -carbonyldiimida- addition of vinylmagnesium bromide to the readily available zole and diethylamine to furnish the carbamate 4, which benzaldehyde10 6 provided (()-benzylic alcohol 5, the substrate upon treatment with n-BuLi led to smooth intramolecular for the key kinetic resolution (Table 1). Previous experience acylation and subsequent acid-mediated lactonization to deliver the key vinylphthalide 3. A similar intramolecular in our laboratory has established that the optimum conditions 12 13 for this microwave-assisted chemoenzymatic resolution used Parham-type cyclization served us and others well during toluene and p-chlorophenyl acetate 7 as the solvent and acyl the total syntheses of the spirolaxine antibiotics and was (11) Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia, (8) Brown, H. C.; Zweifel, G. J. Am. Chem. Soc. 1959, 81, 247. L. A. J. Org. Chem. 1991, 56, 2656–2665. (9) Bachu, P.; Gibson, J. S. S.; Sperry, J.; Brimble, M. A. Tetrahedron: (12) (a) Robinson, J. E.; Brimble, M. A. Chem. Commun. 2005, 1560– Asymmetry 2007, 18, 1618–1624. 1562. (b) Robinson, J. E.; Brimble, M. A. Org. Biomol. Chem. 2007, 5, 2572– (10) (a) Lock, G.; Nottes, G. Monatsch. Chem. 1936, 68,51–57.(b)Merlic, 2582. (c) Brimble, M. A.; Bryant, C. J. Chem. Commun. 2006, 4506–4508. C.A.;Aldrich,C.C.;Albaneze-Walker,J.;Saghatelian,A.;Mammen,J.J. Org. (d) Brimble, M. A.; Bryant, C. J. Org. Biomol. Chem. 2007, 5, 2858–2866. Chem. 2001, 66, 1297–1309. (13) Keaton, K. A.; Phillips, A. J. Org. Lett. 2007, 14, 2717–2719. J. Org. Chem. Vol. 75, No. 21, 2010 7389 JOCArticle Choi et al. employed in this instance, especially since the aryllithium SCHEME 3. Regioselective Reverse Wacker Oxidation derived from 4 readily underwent protonation when quenched with external electrophiles (e.g., DMF), even under strictly anhydrous conditions. With multigram quantities of vinylphthalide 3 secured, attention turned toward the pivotal Wacker oxidation step. Upon Wacker oxidation, terminal alkenes predominantly form methylketones, inferring that hydroxypalladation takes place following Markovnikov’s rules.14 A reliable procedure for the anti-Markovnikov addition of nucleophiles during the Wacker oxidation of terminal alkenes would greatly enhance the synthetic utility of this widely employed reaction. Currently, the few successful examples of so-called “reverse” Wacker transformations are controlled by heteroatoms15 and π-complexation,16 and studies involving the anti-Markovnikov addition of nucleophiles to styrenes using Wacker conditions exist.17 To the best of our knowledge this reaction has not found any use in natural product synthesis, primarily due to the rarely observed7,18 total reversal of regioselectivity, with SCHEME 4.